α-Bromodiazoacetamides a new class of diazo compounds for ... · α-Bromodiazoacetamides – a new...

1

Supporting Information

for

α-Bromodiazoacetamides – a new class of diazo

compounds for catalyst-free, ambient temperature

intramolecular C–H insertion reactions

Åsmund Kaupang and Tore Bonge-Hansen*

Address: Department of Chemistry, University of Oslo, P.O. Box 1033 Blindern, NO-

0315 Oslo, Norway

Email: Åsmund Kaupang – [email protected]; Tore Bonge-Hansen* -

[email protected]

*Corresponding author

Detailed experimental procedures and physical data for the

obtained products

mailto:[email protected]

mailto:[email protected]

Contents

Contents 2

General introduction 4

Experimental procedures 5

1 N-bromoimides 5

1.1 N-bromophthalimide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5

1.2 N-bromosuccinimide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6

2 N,N’-ditosylhydrazine 6

3 α-bromoacetamides 8

3.1 2-bromo-1-(pyrrolidin-1-yl)ethanone (2a) . . . . . . . . . . . . . . . . . . . . . . . . . . 8

3.2 2-bromo-1-(piperidin-1-yl)ethanone (2b) . . . . . . . . . . . . . . . . . . . . . . . . . . 9

3.3 1-(azepan-1-yl)-2-bromoethanone (2c) . . . . . . . . . . . . . . . . . . . . . . . . . . . 9

3.4 tert-butyl 4-(2-bromoacetyl)piperazine-1-carboxylate (2d) . . . . . . . . . . . . . . . . . 10

3.5 2-bromo-1-morpholinoethanone (2e) . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10

3.6 2-bromo-1-(1,1-dioxidothiomorpholino)ethanone (2f) . . . . . . . . . . . . . . . . . . . 11

4 α-diazoacetamides 11

4.1 2-diazo-1-(pyrrolidin-1-yl)ethanone (3a) . . . . . . . . . . . . . . . . . . . . . . . . . . 12

4.2 2-diazo-1-(piperidin-1-yl)ethanone (3b) . . . . . . . . . . . . . . . . . . . . . . . . . . . 13

4.3 1-(azepan-1-yl)-2-diazoethanone (3c) . . . . . . . . . . . . . . . . . . . . . . . . . . . 13

4.4 tert-butyl 4-(2-diazoacetyl)piperazine-1-carboxylate (3d) . . . . . . . . . . . . . . . . . 14

4.5 2-diazo-1-morpholinoethanone (3e) . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15

4.6 2-diazo-1-(1,1-dioxido-4-thiomorpholinyl)ethanone (3f) . . . . . . . . . . . . . . . . . . 15

5 β-lactams 16

5.1 6-bromo-1-azabicyclo[3.2.0]heptan-7-one (5a) . . . . . . . . . . . . . . . . . . . . . . . 18

5.2 7-bromo-1-azabicyclo[4.2.0]octan-8-one (5b) . . . . . . . . . . . . . . . . . . . . . . . 18

5.3 8-bromo-1-azabicyclo[5.2.0]nonan-9-one (5c) . . . . . . . . . . . . . . . . . . . . . . . 19

5.4 tert-butyl 7-bromo-8-oxo-1,4-diazabicyclo[4.2.0]octane-4-carboxylate (5d) . . . . . . . . 20

5.5 7-bromo-4-oxa-1-azabicyclo[4.2.0]octan-8-one (5e) . . . . . . . . . . . . . . . . . . . . 20

5.6 7-bromo-4-thia-1-azabicyclo[4.2.0]octan-8-one 4,4-dioxide (5f) . . . . . . . . . . . . . . 20

5.7 Synthesis and thermolysis of α-chloro- and α-iodo-4d . . . . . . . . . . . . . . . . . . . 21

5.8 Dirhodium(II) catalysis results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21

6 Additional procedures 22

6.1 1,1,3,3-tetramethylguanidine p-toluenesulfinate . . . . . . . . . . . . . . . . . . . . . . 22

References 23

2

NMR Spectra 25

6.2 N-bromophthalimide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25

6.3 N,N’-ditosylhydrazine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26

6.4 2-bromo-1-(pyrrolidin-1-yl)ethanone (2a) . . . . . . . . . . . . . . . . . . . . . . . . . . 28

6.5 2-bromo-1-(piperidin-1-yl)ethanone (2b) . . . . . . . . . . . . . . . . . . . . . . . . . . 30

6.6 1-(azepan-1-yl)-2-bromoethanone (2c) . . . . . . . . . . . . . . . . . . . . . . . . . . . 32

6.7 tert-butyl 4-(2-bromoacetyl)piperazine-1-carboxylate (2d) . . . . . . . . . . . . . . . . . 35

6.8 2-bromo-1-morpholinoethanone (2e) . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37

6.9 2-bromo-1-(1,1-dioxidothiomorpholino)ethanone (2f) . . . . . . . . . . . . . . . . . . . 39

6.10 2-diazo-1-(pyrrolidin-1-yl)ethanone (3a) . . . . . . . . . . . . . . . . . . . . . . . . . . 41

6.11 2-diazo-1-(piperidin-1-yl)ethanone (3b) . . . . . . . . . . . . . . . . . . . . . . . . . . . 43

6.12 1-(piperidin-1-yl)-2-tosylethanone . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46

6.13 1-(azepan-1-yl)-2-diazoethanone (3c) . . . . . . . . . . . . . . . . . . . . . . . . . . . 48

6.14 tert-butyl 4-(2-diazoacetyl)piperazine-1-carboxylate (3d) . . . . . . . . . . . . . . . . . 51

6.15 2-diazo-1-morpholinoethanone (3e) . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53

6.16 2-diazo-1-(1,1-dioxido-4-thiomorpholinyl)ethanone (3f) . . . . . . . . . . . . . . . . . . 56

6.17 Crude 6-bromo-1-azabicyclo[3.2.0]heptan-7-one (5a) . . . . . . . . . . . . . . . . . . . 58

6.18 Crude 7-bromo-1-azabicyclo[4.2.0]octan-8-one (5b) . . . . . . . . . . . . . . . . . . . . 59

6.19 Crude 7-bromo-1-azabicyclo[4.2.0]octan-8-one (5b) without int. standard . . . . . . . . 60

6.20 Crude 8-bromo-1-azabicyclo[5.2.0]nonan-9-one (5c) . . . . . . . . . . . . . . . . . . . 61

6.21 exo-8-bromo-1-azabicyclo[5.2.0]nonan-9-one (exo-5c) . . . . . . . . . . . . . . . . . . 62

6.22 endo-8-bromo-1-azabicyclo[5.2.0]nonan-9-one (endo-5c) . . . . . . . . . . . . . . . . . 64

6.23 Crude tert-butyl 7-bromo-8-oxo-1,4-diazabicyclo[4.2.0]octane-4-carboxylate (5d) . . . . 66

6.24 Crude 7-bromo-4-oxa-1-azabicyclo[4.2.0]octan-8-one (5e) . . . . . . . . . . . . . . . . 67

6.25 Crude 7-bromo-4-thia-1-azabicyclo[4.2.0]octan-8-one 4,4-dioxide (5f) . . . . . . . . . . 68

6.26 1,1,3,3-tetramethylguanidine sulfinate (and sulfonate) . . . . . . . . . . . . . . . . . . . 69

6.27 2,2-dibromo-1-(piperidin-1-yl)ethanone . . . . . . . . . . . . . . . . . . . . . . . . . . . 70

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General introduction

All commercially available reagents and solvents were used as received except in the caseof N-bromosuccinimide (NBS), which was recrystallized from water (see details below). TheCH2Cl2 used in the acylation of the amines and in the thermolysis reactions was obtainedfrom an MBraun MB SPS-800 solvent purification system and is dry, but more importantly freeof alcoholic stabilizers. Alcohol-stabilized CH2Cl2 does not completely inhibit the reactionsin question, but traces of ethyl esters (O-acylation) and ethyl ethers (carbene O-H insertionproduct) have been been observed spectroscopically when running the reactions in alcohol-stabilized CH2Cl2. The prepared/recrystallized N-bromoimides and diazoamides were storedin a freezer at −20 °C to ensure their integrity and were left in ambient temperature for about 5minutes before exposing them to air in order to minimize weighing errors caused by condensedwater.

Except for the above stated routine, no special precautions were taken to exclude air orairborne moisture at any point during the syntheses described in this work, except in theacylation reactions where it was clearly detrimental. Inert atmosphere (Ar or N2) is used onlywhere stated specifically (acylations and catalyzed reactions). Stirring refers to magnetic stirringin all the procedures. Heating was performed with fluoropolymer-coated all-metal heatingmantles.

Chromatography was performed on silica gel (Merck 60, 40-63 µm) and thin layer chromatog-raphy (TLC) on aluminium sheets coated with silica gel (Fluka 6607780, 20 mm, fluorescentcoating for 254 nm) or neutral alumina (Macherey Nagel Alugram Alox N, 0.20 mm, unacti-vated, no fluorescent coating). The plates were visualized with KMnO4, K2CO3 and NaOHin water for the α-bromo amides (alumina) and UV-light and/or a solution of p-anisaldehyde,concentrated H2SO4 and glacial CH3CO2H in 96% EtOH for the α-diazoacetamides (silica gel),followed by heating with a heat gun for both. The β-lactams (alumina) were visualized witha solution of ninhydrin and pyridine in absolute EtOH followed by heating or with a solutioncontaining AgNO3, H2O, 2-phenoxyethanol, acetone and H2O2 (30 %, aq) followed by exposingthe plate to UV-light for about 10 minutes (white spots on beige background).

Nuclear magnetic resonance (NMR) spectroscopy was performed on Bruker DXP300/DXP200spectrometers operating at 300/200 MHz for 1H and 75/50 MHz for 13C. The chemical shifts arereported in parts per million (δ) relative to the residual solvent signal in general accordancewith the literature1: δ-1H/δ-13C (Solvent); 7.26/77.00 (CDCl3), 5.32/53.80 (CD2Cl2), 2.50/39.52(DMSO−d6) and 1.94/118.26 (CD3CN). Chemical shifts are given in the section for physicaldata for each compound. Additionally, the spectra for the reported compounds are included inthe appendix where their signals are tentatively assigned to numbered structures appearing oneach spectrum, based on the information gained from the performed NMR experiments. TheDEPT-135 spectra were referenced using the 13C-NMR, as noted in the spectra. The NMR datawere processed with ACD/Labs NMR Processor Academic Edition.

Mass spectrometry experiments were carried out with a Fisons VG ProSpec for electronimpact ionisation (EI) and a Micromass Q-TOF 2 or a Bruker Apex FTMS (FT-ICR, 4.7 T) forelectrospray ionisation (ESI). The data from the three instruments are marked (EI), (ESI, Q-TOF) and (ESI, FT-ICR), respectively. The solvent used and other essential details are notedin each case. NOTE: Diazo compounds are prone to dinitrogen extrusion, a process that canbe effected by means of both heat and acidic media. While the obtention of molecular ionsusing electron impact ionisation (EI) was straightforward, like others,2a we did not observe

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molecular ions using electrospray ionisation (ESI) with added HCOOH. The ESI-data for thediazoacetamides could indicate, however, that the observed radical cations are produced uponextrusion of dinitrogen and the inclusion of a molecule of solvent (tentatively assigned). Onecan speculate if this owes to an interaction of the carbene produced upon nitrogen extrusionwith a molecule of solvent.3 Such a reproducible m/z, not corresponding to the molecular ion,has also been noted by others in ESI experiments with EDA.2a Interestingly, when running theESI without added HCOOH, simple sodium adducts of the molecular ions was observed, exceptin the case of 3f.

Melting points were measured using a Stuart SMP10 melting point apparatus (BarloworldScientific Ltd., UK) and are uncorrected.

Yield measurement using an internal standard: The reactions were left to expire overnight,before evaporating the solvent under reduced pressure at or below 23 ◦C. 0.5 molar equivalentsof 2-naphthaldehyde was then added and the exact weight noted, before dissolving the entirecrude material in CDCl3. The solution was transferred to an NMR-tube and a 1H-NMR spectrumrecorded. The integral of the aldehyde proton of the internal standard was calculated based onits molar fraction in relation to the starting material. Thus, the yields can be read out from theintegral of the signal from the β--lactam α--proton in the NMR spectra in the appendix.

1 N-bromoimides

1.1 N-bromophthalimide

N-bromophthalimide was prepared from phthalimide by extendinga procedure published by Souza et. al4 for the preparation ofN-chloro- and N-bromosaccharin, in which bromine is generatedin situ by oxidation of KBr in water. The original procedure ismodified by an additional 0.25 eq of Na2CO3.

N

O

O

Br

The reaction proceeds noticeably slower than in the case of sodium saccharin (as in the originalpublication - preparation not shown), possibly due to the fairly low solubility of phthalimideeven in basic water. Another consequence of this, was a prolonged and more visible releaseof bromine. As the consumption of the released bromine is slower than with saccharin, it wasnecessary to close the reaction vessel with a glass stopper to contain the evolution of brominegas. The yield was 65 %. The obtained spectroscopic data were in accordance with the publisheddata.5 The measured melting point was lower, however, possibly owing to the fact that therecrystallization from toluene left a slightly amorphous crystal mass.

1.1.1 Experimental procedure

Phthalimide (7.36 g, 50.0 mmol, 1.0 eq), Na2CO3 (3.98 g, 37.6 mmol, 0.75 eq) and KBr (5.95 g,50.0 mmol, 1.0 eq) were added through a solid addition funnel to a 500 mL round bottom flaskfollowed by H2O (Type II, 200 mL). The flask was cooled on an ice/water bath for 10 minutes,after which potassium peroxymonosulfate (as its triple salt 2 KHSO5 · KHSO4 · K2SO4, oxone®)(30.8 g, 50.1 mmol, 1.0 eq) suspended in H2O (Type II, 75 mL) was added in small aliquots, withvigorous stirring (700 rpm), over a period of 10 minutes. The addition of the oxidant resultedin vigorous release of bromine gas, and thus the flask was capped with a glass stopper betweenadditions. The mixture quickly turned into an orange frothing suspension with visible brominegas above it. The suspension was left to stir for 24 hours, at which point it had become a yellowsolution with a white precipitate. Stirring was continued another 24 hours, until the solution

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above the precipitate was almost clear. The suspension was filtered on a Büchner-funnel and thefilter cake sucked dry for a period of 30 minutes. The white precipitate was dissolved in boilingtoluene (150 mL), hot filtered into a beaker and left to cool slowly to ambient temperature,covered with an aluminium foil. Upon reaching ambient temperature, precipitation had begunand the beaker was placed in a refrigerator at 4 °C for a period of 17 hours, before filtering theprecipitate on a Büchner-funnel. The filter cake was washed with n-pentane (30 mL) to give 6.52g (57 %) of small white crystals. The mother liquor was concentrated, filtered and the filter cakewashed with toluene (5 mL) and n-pentane (10 mL) to give 0.91 g (8 %). Both crops were ofequal purity by 1H-NMR. The total yield was 65%.

Physical data

• 1H-NMR (200 MHz, CDCl3) δ 7.95 – 7.81 (m, 2H), 7.81 – 7.68 (m, 2H)

• Melting point: 176 – 184 °C (C6H5CH3, decomposition)(lit. 199 – 200 °C,5 CH2Cl2)

1.2 N-bromosuccinimide

N-bromosuccinimide was purchased from Sigma-Aldrich and re-crystallized from boiling water (10 mL g−1) to give thin transparentplates in accordance with the literature (purification method “Aa”).6

N

O

O

Br

2 N,N’-ditosylhydrazine

Synthesis route and comments

N,N’-ditosylhydrazine was synthesized in 92 % yieldin one step by the reaction of tosylhydrazine with tosylchloride in the presence of pyridine, as described byToma et al.,7 albeit with a slight modification of thework-up procedure. The modified procedure requiresless methanol than the original procedure, making thework-up easier and safer to perform on a preparative scale(∼ 100 g), without compromising the purity of the isolatedproduct.

S

HN

NH

S

O O

OO

The reaction was performed once following the original procedure, affording a yield compa-rable to that reported (∼ 15 g, 85 %). The procedure was originally performed on a 50 mmolscale and employed a recrystallization from 400 mL of boiling MeOH as the final purificationstep.In the modified work-up procedure, the crude precipitate (see experimental details below) issimply slurried in methanol at reflux, lowering the expenditure of MeOH considerably.

The reaction could thus be performed at various scales with a low methanol expenditure:

Scale (mmol) MeOH volume (mL) Yield (g) Yield (%)100 400 31 92192 500 61 93300 800 95 93350 900 109 92

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The 1H-NMR and 13C-NMR spectra of the obtained products were identical to those of theproduct obtained using the original procedure, and are in accordance with the publishedspectroscopic data.7 An X-ray structure can also be found in the literature.8

Representative experimental procedure

Tosyl chloride (100.0 g, 524.5 mmol, 1.5 eq) and tosylhy-drazide (65.12 g, 349.7 mmol, 1.0 eq) were added to a 1000mL round-bottom flask through a solid addition funnel, anddissolved/suspended in anhydrous CH2Cl2 (250 mL), givinga concentration of approximately 1 M based on the limitingreactant. An oval stir bar (3.5 × 1.5 cm) was added and thesuspension stirred (700 rpm) while cooling on an ice/waterbath, until an internal temperature of 3 °C was reached.Addition of a solution of pyridine (41.49 g, 524.5 mmol, 1.5eq) in anhydrous CH2Cl2 (80 mL) over a period of 10 minutes,in such a way that the internal temperature did not riseabove 20 °C. This gave a transparent yellow solution whichsoon deposited a white precipitate, upon which stirring wasincreased to 1000 rpm, and continued for a period of 3 hours.Et2O (200 mL) was added and the suspension solidified. Theheavy precipitation was broken up with a spatula and thesuspension was transferred to a 1500 mL beaker, where itwas stirred with a triangular stir bar (5 × 1 × 1 cm). H2O(Type II, 200 mL) and Et2O (200 mL) was added in the givenorder. Stirring was continued for 10 minutes, before filteringthe precipitate on a 13 cm Büchner-funnel, where it was leftto air dry with suction for a period of 5 minutes.The solid was transferred directly to a 2000 mL round bottomflask and suspended in MeOH (900 mL). The flask wasequipped with a reflux-condenser and an oval stir bar (5× 2 cm) before heating the suspension to reflux (mantletemperature 67 °C) and stirring for a period of 3 hours.

The suspension, which at this point would separate to slightly yellow solution above a brightwhite precipitate, was allowed to cool before filtering on a 13 cm Büchner-funnel. The filtercake was washed with MeOH (300 mL) and Et2O (300 mL). The filtrate was then concentratedon a rotary evaporator (bath temperature ∼ 45 °C) to a volume of approximately 150 mL,before cooling the flask under running tap water. The precipitate was filtered on a Büchner-funnel, washed with MeOH (200 mL) and Et2O (200 mL) giving a second crop. The first cropwas a voluminous white powder, while the second more crystalline crop consisted of shortwhite needles. Both crops were dried in air in a fume hood over a period of 48 hours beforedetermining the yield. Crop I: 97.60 g (81 %), crop II: 12.34 g (10 %). The total yield was 109.94g (92 %). Both crops were of equal purity by NMR analysis and were subsequently mixed andstored in a screw-capped PTFE jar at ambient temperature.

Physical data

• 1H-NMR (300 MHz, DMSO−d6) δ 2.40 (s, 6H), 7.37 – 7.40 (m, 4H), 7.64 – 7.67 (m, 4H), 9.59(s, 2H)

• 13C-NMR (75 MHz, DMSO−d6) δ 21.0, 127.8, 129.4, 135.5, 143.4

• Melting point: 212 – 215 °C (decomposition)

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3 α-bromoacetamides

Synthesis route and comments

The α-bromoacetamides were synthesized by the dropwise addition of the amine in CH2Cl2to bromoacetyl bromide and tribasic potassium phosphate in dry, alcohol-free CH2Cl2. Theprocedure was based on a recent publication where the authors investigated the effect ofdifferent bases on the formation of amides from amines and acid chlorides.9 The obtainedα-bromoacetamides were sufficiently pure after work-up to be used in the next step withoutfurther purification.


A 250 mL round bottom flask was charged, in the given order, with bromoacetyl bromide (30mmol, 1.5 eq), anhydrous CH2Cl2 (20 mL) and K3PO4 (50 mmol, 2.5 eq). An oval stir bar (3.5 ×1.5 cm) was added and the flask was fitted with a 100 mL addition funnel, containing the amine(20 mmol, 1 eq) in CH2Cl2 (30 mL). The flask was cooled on an ice/water bath, while purgingthe system with argon for a period of 5 minutes. Stirring (500 rpm) was commenced and theamine solution added dropwise over a period of 30 minutes, after which the addition funnelwas washed with CH2Cl2 (5 mL). Stirring was then continued for a period of 3 hours, beforequenching the excess acid bromide with aqueous HCl (0.5 M, 30 mL). After stirring another5 minutes, H2O (10 mL) and brine (10 mL) were added and the now transparent two phasestransferred to a separatory funnel and the organic phase drained off. The aqueous phase wasextracted with CH2Cl2 (1 × 20 mL), before washing the joint organic phases with a mixtureof aqueous KHCO3 (10 %wt, 20 mL) and brine (10 mL), and then with brine (20 mL). Dryingover MgSO4 and evaporating under reduced pressure at 30 °C bath temperature, afforded theα-bromoacetamides. The crude material was stored at −20 °C before submission to the nextstep.

3.1 2-bromo-1-(pyrrolidin-1-yl)ethanone (2a)

Yield: 3.466 g (90 %) from 20.01 mmol of pyrrolidine.NMR spectra can be found on page 28. N

O

Br

Physical data

• 1H-NMR (300 MHz, CDCl3) δ 3.77 (s, 2H), 3.51 – 3.42 (m, 4H), 2.03 – 1.80 (m, 4H)

• 13C-NMR (75 MHz, CDCl3) δ 164.9, 46.9, 46.3, 27.3, 26.0, 24.2

• MS (EI) m/z (% rel. int.) 193/191 (M+, 16/16), 121/123 (4/4), 112 (100), 98 (81), 93/95 (6/6),70 (48)

• HRMS (EI) Calcd. for C6H1079BrNO [M+]: 190.9946; found 190.9950 (−2.2 ppm)

• TLC (Neutral Al2O3, CH2Cl2) R f : 0.35

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3.2 2-bromo-1-(piperidin-1-yl)ethanone (2b)

Yield: 7.750 g (94 %) from 40.01 mmol of piperidine.NMR spectra can be found on page 30. N

O

Br

Physical data

• 1H-NMR (300 MHz, CDCl3) δ 3.84 (s, 2H), 3.57 – 3.49 (m, 2H), 3.46 – 3.36 (m, 2H), 1.69 –1.59 (m, 4H), 1.59 – 1.48 (m, 2H)

• 13C-NMR (75 MHz, CDCl3) δ 165.0, 47.8, 43.2, 26.1, 26.1, 25.3, 24.2

• MS (EI) m/z (% rel. int.) 207/205 (M+, 4/4), 126 (100), 123/121 (3/4), 112 (20), 95/93 (2/2),84 (18)

• MS (ESI, Q-TOF) (MeOH) m/z 230.0/228.0 [M + Na]+, 208.0/206.0 [M + H]+

• HRMS (EI) Calcd. for C7H1279BrNO) [M+]: 205.0102; found 205.0104 (−1.0 ppm)


3.3 1-(azepan-1-yl)-2-bromoethanone (2c)

Yield: 4.151 g (94 %) from 20.01 mmol of azepane.NMR spectra can be found on page 32. N

O

Br

Physical data

• 1H-NMR (300 MHz, CDCl3) δ 3.84 (s, 2H), 3.54 – 3.42 (m, 4H), 1.82 – 1.62 (m, 4H), 1.62 –1.47 (m, 4H)

• 13C-NMR (75 MHz, CDCl3) δ 166.3, 48.5, 46.3, 28.9, 27.2, 27.1, 26.4, 26.4

• MS (EI) m/z (% rel. int.) 221/219 (M+, 1/1), 140 (100), 126 (7), 123/121 (2/3), 98(8), 95/93(2/2)

• HRMS (EI) Calcd. for C8H1479BrNO) [M+]: 219.0259; found 219.0257 (0.6 ppm)


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3.4 tert-butyl 4-(2-bromoacetyl)piperazine-1-carboxylate (2d)

Yield: 5.885 g (95 %) from 20.00 mmol of tert-butylpiperazine-1-carboxylate.NMR spectra can be found on page 35.

N

O

Br

N

O

O

Physical data

• 1H-NMR (300 MHz, CDCl3) δ 3.85 (s, 2H), 3.62 – 3.38 (m, 8H), 1.45 (s, 9H)

• 13C-NMR (75 MHz, CDCl3) δ 165.4, 154.4, 80.4, 46.5 (2C), 41.9 (2C), 28.3 (3C), 25.6

• MS (EI) m/z (% rel. int.) 308/306 (M+, 4/4), 252/250 (9/9), 235/233 (9/9), 207/205 (2/1),171 (22), 170 (37), 127 (16), 123/121 (3/3), 113 (14), 95/93 (1/2), ( 85 (35), 57 (100)

• HRMS (EI) Calcd. for C11H1979BrN2O3) [M+]: 306.0579; found 306.0587 (−2.7 ppm)


3.5 2-bromo-1-morpholinoethanone (2e)

Yield: 3.737 g (89 %) from 20.00 mmol of morpholine.NMR spectra can be found on page 37. N

O

Br

O

Physical data

• 1H-NMR (300 MHz, CDCl3) δ 3.83 (s, 2H), 3.75 – 3.64 (m, 4H), 3.64 – 3.56 (m, 2H), 3.54 –3.47 (m, 2H)

• 13C-NMR (75 MHz, CDCl3) δ 165.3, 66.5, 66.3, 47.1, 42.3, 25.4

• MS (EI) m/z (% rel. int.) 209/207 (M+, 21/21), 194/192 (14/15), 128 (100), 123/121 (14/14),114 (16), 95/93 (5/5), 86 (79)

• HRMS (EI) Calcd. for C6H1079BrNO2) [M+]: 206.9895; found 206.9888 (3.5 ppm)


10

3.6 2-bromo-1-(1,1-dioxidothiomorpholino)ethanone (2f)

The solubilities of both the amine thiomorpholine-1,1-dioxide andthe obtained amide are relatively low in CH2Cl2. As such, thevolume of CH2Cl2 in which the amine was initially dissolved wasincreased to 7.40 mmol/30 mL. Additionally, on the same scale, thereaction mixture was diluted with CH2Cl2 (100 mL) after quenchingwith HCl (aq), before separating the phases. A longer reaction timeof 24 hours was also needed to achieve full conversion of the amine.

Yield: 1.733 g (91 %) from 7.40 mmol of thiomorpholine-1,1-dioxide.NMR spectra can be found on page 39.

N

O

Br

S

O

O

Physical data

• 1H-NMR (300 MHz, CD3CN) δ 4.06 (s, 2H), 4.01 – 3.86 (m, 4H), 3.20 – 2.96 (m, 4H)

• 13C-NMR (75 MHz, CD3CN) δ 163.2, 52.3, 52.1, 45.7, 41.6, 27.8

• MS (EI) m/z (% rel. int.) 257/255 (M+, 1/1), 193/191 (1/1), 192/190 (2/2), 176 (41), 162 (9),134 (45), 123/121 (14/14), 112 (100), 95/93 (8/9), 70 (44)

• HRMS (EI) Calcd. for C6H1079BrNO3S) [M+]: 254.9565; found 254.9565 (−0.2 ppm)


4 α-diazoacetamides

4.0.1 Synthesis route and comments

In the procedure reported by Toma et al. the amidine base 1,8-Diazabicyclo-[5.4.0]-undec-7-ene (DBU) was used to effect the nucleophilic attack of the N,N’-ditosylhydrazine anion onthe α-carbon of α-bromoacetic esters, as well as the subsequent decomposition of the resultinghydrazide/hydrazone intermediate to yield an α-diazo group.7 The lower cost and similar basestrength10 of 1,1,3,3-Tetramethylguanidine (TMG), as well as its properties as a nucleophiliccatalyst,11 made it an interesting alternative to DBU in this transformation. Furthermore, inthe original procedure, the crude reaction mixture was quenched with NaHCO3(aq) and thenextracted with Et2O. In our experience it was problematic to perform a clean aqueous extractionin the presence of the at least 2 molar equivalents of DBU−HO2S-C6H4CH3 produced during thereaction. This situation manifested itself more gravely on a > 5 mmol scale. The problem couldlie in the intermediate solubility of the DBU−HO2S-C6H4CH3 complex between the aqueousphase and the Et2O phase. What further complicated the matter of an aqueous extractionprocedure, was the aqueous solubility of some of the obtained α-diazoacetamides.

The use of TMG instead of DBU resulted in the partial precipitation of the TMG · HO2S-C6H4CH3salt from THF during the reaction. Thus, in the cases where the diazoamide was soluble inEt2O (products 3a - e), the reaction solvent (THF) could be destilled off under reduced pressureand the diazoamide extracted from the resulting solid with Et2O (the TMG · HO2S-C6H4CH3salt is poorly soluble in Et2O). A final clearing of the Et2O-phase by slurrying with silica geland filtering, yielded the diazoamides with decent purities, without the need for an aqueouswork-up. As noted by Toma et al., we also observed the formation of the correspondingα-tosylacetamides, resulting from the nucleophilic attack of the produced p-toluenesulfinicacid on the substrate α-bromoacetamides. This side-reaction can however be minimized bymaintaining the reaction temperature below 0 ◦C (see procedure below).

11

In the case where the diazoamide was not soluble in Et2O (product 3f), a THF/Et2O (2:1)mixture could be used to extract the diazoamide with adequate results (see the experimentalprocedure for product 3f below).

All the obtained diazoamides were subsequently chromatographed on silica gel to ensurethat they were free of contaminations (e.g. their corresponding α-tosylacetamides) that couldinterfere in the investigation of their halogenation and subsequent reactions. The detailspertaining to the chromatography for each compound are given below.

4.0.2 Representative experimental procedure (products 3a - e)

To a 250 mL round bottom flask containing the α-bromoacetamide (20 mmol, 1 eq), were addedthrough a solid addition funnel; N,N’-ditosylhydrazine (40 mmol, 2 eq), THF (35 mL) and anoval stir bar (3.5 × 1.5 cm). The suspension was cooled on an acetone/CO2 (s) bath with stirring(400 rpm) until reaching an internal temperature of −10 ◦C, upon which a solution of 1,1,3,3-tetramethylguanidine (100 mmol, 5 eq) in THF (10 mL) was added in aliquots using a pasteurpipette, while maintaining the internal temperature below 0 ◦C by the addition of CO2 (s). Theresulting yellow solution was removed from the cooling bath and allowed to warm to ambienttemperature over a period of 30 minutes, during which time a white precipitate is deposited.This suspension was stirred for a period of 90 minutes, before removing the THF under reducedpressure at or below 23 ◦C. The resulting solid was treated with anhydrous Et2O (150 mL) andvigorously stirred for 10 minutes, before being filtered on a Büchner-funnel. The filter cakewas washed with anhydrous Et2O (2 - 5 × 50 mL), until leaving an almost white filter cake.Approximately 25 g (1 large tablespoon) of silica gel was added to the filtrate and the suspensionstirred for 5 minutes, followed by vacuum filtration through a pad of silica gel (∼ 25 g, column �

3.5 cm). The column was washed with Et2O (50 mL) and the Et2O evaporated under reducedpressure at or below 23 ◦C. The thus obtained crude diazoacetamides were then subjected toflash chromatography on silica gel eluting increasing amounts of Et2O in Pet.Ether. The productswere stored at −20 ◦C before submission to the next step.

4.1 2-diazo-1-(pyrrolidin-1-yl)ethanone (3a)

Yield: 1.706 g (67 %) as a yellow oilstarting from 18.05 mmol 2a. Thecompound is a solid at −20 ◦C (pic-ture), and is previously reported in theliterature.12, 13

NMR spectra can be found on page 41.

N

O

N2

H

Physical data

• 1H-NMR (300 MHz, CD2Cl2) δ 4.92 (s, 1H), 3.54 – 2.98 (m, 4H), 2.06 – 1.64 (m, 4H)

• 13C-NMR (75 MHz, CD2Cl2) δ 163.8, 46.4, 46.2 (2C), 26.1, 24.8

• MS (ESI, FT-ICR) (MeCN, no HCOOH) m/z 162.0 [M + Na]+

• TLC (SiO2, Et2O) R f : 0.13

12

4.2 2-diazo-1-(piperidin-1-yl)ethanone (3b)

Yield: 3.008 g (52 %) as a yellow oilstarting from 37.61 mmol 2b. The com-pound is a solid at −20 ◦C (picture),and is previously reported in severalpublications.14–21


N

O

N2

H

Physical data

• 1H-NMR (300 MHz, CD2Cl2) δ 5.16 (s, 1H), 3.30 (bs, 4H), 1.66 – 1.55 (m, 2H), 1.55 – 1.42 (m,4H)

• 13C-NMR (75 MHz, CD2Cl2) δ 164.3, 46.1, 45.2 (2C), 26.2, 24.8 (2C)

• MS (EI) m/z (% rel. int.) 154 (5), 153 (M+, 25), 125 (19), 112 (11), 96 (45), 84 (38), 69 (53), 55(71), 42 (100), 41 (79)

• MS (ESI, Q-TOF) (MeCN) m/z 167.1 [M + H−N2 + MeCN]+

• MS (ESI, Q-TOF) (MeOH) m/z 180.1 [M+Na−N2 +MeOH]+, 158.1 [M+H−N2 +MeOH]+


• HRMS (EI) Calcd. for C7H11N3O) [M+]: 153.0902; found 153.0891 (7.2 ppm)

• TLC (SiO2, Et2O) R f : 0.28

1-(piperidin-1-yl)-2-tosylethanone –– a commonly observed by-product.7 See NMR-spectra on page 46:

• MS (EI) m/z (% rel. int.) 282 (M++1, 1), 217 (26), 155 (6), 127 (14), 126 (100), 112 (42), 110(30), 97 (29), 91 (43), 84 (34)

• MS (ESI, Q-TOF) (MeCN) m/z 282.2 [M + H]+, 585.3 [2M + Na]+

4.3 1-(azepan-1-yl)-2-diazoethanone (3c)

Yield: 2.217 g (66 %) as a soft yellowsolid starting from 18.85 mmol 2c.The compound is previously reportedas a reagent,21 however no details onits synthesis were disclosed.NMR spectra can be found on page 48.

N

O

N2

H

Physical data

• 1H-NMR (300 MHz, CD2Cl2) δ 5.07 (s, 1H), 3.68 – 3.00 (m, 4H), 1.79 – 1.61 (m, 4H), 1.61 –1.43 (m, 4H)

• 13C-NMR (75 MHz, CD2Cl2) δ 165.2, 47.8, 46.2 (2C), 28.8 (2C), 27.5, 27.3

13

• MS (EI) m/z (% rel. int.) 168 (7), 167 (M+, 16), 139 (7), 138 (15), 126 (8), 111 (9), 110 (21), 96(61), 69 (64), 55 (65), 41 (100)


• HRMS (EI) Calcd. for C8H13N3O [M+]: 167.1059; found 167.1060 (−0.6 ppm)

• TLC (SiO2, Et2O) R f : 0.39

• Melting point: 48 – 50 °C

Dimerization was observed in the mass spectrometer (EI) as has been noted by others.2b

The dimer radical cation had the following characteristics:

• MS (EI) m/z (% rel. int.) 279 (5), 278 (M+, 4), 181 (12), 180 (12), 152 (8), 149 (17), 110 (13), 98(100)

• HRMS (EI) Calcd. for C16H26N2O2 [M+]: 278.1994; found 278.1984 (3.8 ppm)

4.4 tert-butyl 4-(2-diazoacetyl)piperazine-1-carboxylate (3d)

Yield: 2.938 g (60 %) as a bright yellowsolid starting from 19.16 mmol 2d.The compound is to the best of ourknowledge previously unreported as areagent. Our group recently reportedthe x-ray structure of 3e.22


N

O

N2

N

O

OH

Physical data

• 1H-NMR (300 MHz, CD2Cl2) δ 5.13 (s, 1H), 3.47 – 3.21 (m, 8H), 1.42 (s, 9H)

• 13C-NMR (75 MHz, CD2Cl2) δ 165.0, 154.6, 80.1, 46.5, 43.9 (br, 4C), 28.4

• MS (EI) m/z (% rel. int.) 255 (1), 254 (M+, 10), 198 (11), 181 (6), 170 (64), 128 (8), 125 (6), 97(10), 85 (31), 69 (20), 57 (100), 41 (32)

• MS (ESI, Q-TOF) (MeCN) m/z 308.2 [M−N2 + 2 MeCN]+, 268.2 [M + H−N2 + MeCN]+,212.1 [M + H−N2−56 (iso−butene) + MeCN]+

• MS (ESI, Q-TOF) (MeOH) m/z 539.3 [2M + Na−2 N2 + 2 MeOH]+, 281.1 [M + Na−N2 +MeOH]+, 203.1 [M + H−N2−56 (iso−butene) + MeOH]+

• MS (ESI, Q-TOF) (MeCN, no HCOOH) m/z 277.1 [M + Na]+

• HRMS (EI) Calcd. for C11H18N4O3) [M+]: 253.1379; found 254.1374 (2.1 ppm)

• TLC (SiO2, Et2O) R f : 0.20

• Melting point: 108 – 111 °C

14

4.5 2-diazo-1-morpholinoethanone (3e)

Yield: 1.677 g (54 %) as a yellow oilstarting from 17.97 mmol 2e.The compound is previouslyreported in several publications.17, 20, 23


N

O

N2

OH

Physical data


• 13C-NMR (75 MHz, CD2Cl2) δ 165.1, 66.9 (2C), 46.3, 44.4 (2C)

• MS (EI) m/z (% rel. int.) 156 (10), 155 (M+, 74), 140 (13), 127(8), 114 (6), 98 (22), 86 (25), 69(65), 56 (81), 41 (100)


• HRMS (EI) Calcd. for C6H9N3O2) [M+]: 155.0695; found 155.0693 (1.1 ppm)

• TLC (SiO2, Et2O) R f : 0.15

4.6 2-diazo-1-(1,1-dioxido-4-thiomorpholinyl)ethanone (3f)

Yield: 0.987 g (64 %) as a light yellowsolid starting from 7.53 mmol 2f.The compound is generally poorlysoluble in common solvents, and is tothe best of our knowledge previouslyunreported as a reagent. Our grouprecently published the x-ray structureof 3f.24


N

O

N2

S

O

OH

4.6.1 Experimental procedure

To a 250 mL round bottom flask containing 2-bromo-1-(1,1-dioxidothiomorpholino)ethanone(1.928 g, 7.53 mmol, 1 eq), were added through a solid addition funnel N,N’-ditosylhydrazine(5.129 g, 15.07 mmol, 2 eq), THF (50 mL) and an oval stir bar (3.5 × 1.5 cm). The suspension wascooled on an ice/water bath with stirring (400 rpm) for a period of 15 minutes, upon which asolution of 1,1,3,3-tetramethylguanidine (4.337 g, 37.65 mmol, 5 eq) in THF (10 mL) was addedin bulk. The white suspension quickly became yellow, and was then stirred for a period of 70minutes, before adding Et2O (100 mL) causing the disappearance of the yellow colour from theTHF/Et2O phase, as the product was no longer soluble. Removal of some of the Et2O underreduced pressure, brought the yellow colour back to the liquid phase in the suspension. Themixture was filtered on a Büchner-funnel and the filter cake washed with THF/Et2O (2:1, 75mL) and THF (30 mL), leaving an almost white filter cake.

A preliminary purification was performed by adding Celite (∼ 60 g, 3 tablespoons) to thefiltrate, and evaporating the solvents under reduced pressure at or below 23 ◦C. The resulting

15

slightly sticky powder, was suspended in CH2Cl2 (15 mL) and loaded on top of 1 cm of sea-sandcovering a column of silica gel (8.0 × 3.5 cm) packed in CH2Cl2. A yellow band was eluted withMeOH/CH2Cl2 (5:95). To this fraction was added silica gel (∼ 50 g, 2 large tablespoons) and thesolvents evaporated, leaving a pale yellow powder. The powder was loaded on top of a column(5.5 × 3.5 cm) of silica gel packed in CH2Cl2, and the product slowly eluted with CH2Cl2 andfrom the point of elution CHCl3. The solvents were evaporated under reduced pressure at orbelow 23 ◦C affording 0.987 g (64 %) of a pale yellow powder which was stored at −20 °C.

Physical data


• 13C-NMR (75 MHz, CD2Cl2) δ 165.1, 52.4 (2C), 47.2, 42.8 (2C)

• MS (EI) m/z (% rel. int.) 205 (1), 204 (2), 203 (M+, 19), 175 (2), 162 (5), 134 (21), 118 (6), 111(5), 83 (100), 70 (30), 69 (94)

• MS (ESI, FT-ICR) (MeCN, no HCOOH) m/z 227.1 [M + Na + H]+

• HRMS (EI) Calcd. for C6H9N3O3S) [M+]: 203.0365; found 203.0366 (−0.7 ppm)

• Melting point: 165 – 176 °C (decomposition)

5 β-lactams

The halogenated α-bromodiazoacetic ethyl esters were reported to be stable for days at0 °C.25 The α-halodiazoamides, however, appear less stable. In our experience the 2 – 5 °Ctemperatures, obtainable with a common ice/water bath, were not sufficiently low to workwith the α-halodiazoacetamides with adequate reproducibility. Therefore, all procedures werecarried out at −5 °C using an acetone bath in which the temperature was controlled by a cryostat.

In the summaries from the mass spectrometry experiments, the R-group in “α, α′-Br2−NR2”refers to the cyclic amide side chain of the respective compound.


The diazoacetamide (0.5 mmol, 1.0 eq) was weighed out in a 25 mL pear shaped flask, DBU (0.7mmol, 1.4 eq) in a 10 mL beaker and the N-halo compound (0.65 mmol, 1.3 eq) in a weighingfunnel. The flask was charged with a small magnetic stir bar (10 × 2 mm) and CH2Cl2 (2mL, ambient temperature), and was subsequently mounted alongside a 250 mL round bottomflask containing CH2Cl2 (250 mL) in an acetone bath cooled by a cryostat to −5 °C (measuredwith an alcohol thermometer at the surface). Stirring (300 RPM) was commenced and after2 minutes the base in CH2Cl2 (2 mL, ambient temperature) was added. After 2 minutes theN-halo compound was added in bulk through the funnel and the funnel rinsed with CH2Cl2(1 mL, ambient temperature). The addition effected a colour change from bright yellow tobright red. While the reaction was stirring, a short plug of silica gel (2 × 2 cm) was packedin CH2Cl2 (ambient temperature) in a fritted flash chromatography column (15 × 2 cm) andmounted inside a holder which allows for the filling of dry ice around the column (covering∼ 300°, leaving an observation window, see figure 5.1 on the facing page). After stirring for 5minutes, the thermometer was placed in the 250 mL flask and CO2(s) was added to the bath untilthe internal temperature of the CH2Cl2 had reached −15 °C. The space between the jacket andthe chromatography column was filled with dry ice, and the column equilibrated with CH2Cl2(−15 °C, 20 mL). The reaction mixture was then poured directly onto the column, and the flaskrinsed with two pipette volumes of CH2Cl2 (−15 °C). The reaction mixture was run into thecolumn using pressurized air (ambient temperature), and the column filled up with CH2Cl2

16

(−15 °C). The column was then run with CH2Cl2 (−15 °C, ∼ 200 mL) under air pressure tocompletely elute a bright red band into a new 250 mL flask in the cooling bath. The elutedsolution is bright red/pink in colour with a temperature of approximately −30 °C.

Thermolysis: The flask was placed on the bench without stirringwhile the temperature rose from −30 °C towards ambienttemperature. The solution became clear in approximately 60minutes. In the chromatographic step, for the more polaranalogues, it was necessary to add Et2O (5 mL) to the last 50mL of the eluent to completely collect the red band. It shouldbe noted that Et2O has a much higher elution strength thanCH2Cl2 under these conditions and fortunately does not seem tointerfere with the C-H insertion reaction at this concentration. Wehave however observed that higher concentrations of Et2O willmake intermolecular reactions (ylide formation, C-H insertion)sufficiently favoured so as to compete with the intramolecularC-H insertions.

Catalyzed reactions: The flask was charged with a stir bar, capped with a septum andmaintained in the cooling bath at −15 °C (cryostat) while degassing with argon (5 minutes). Theflask was then taken out of the cooling bath and a degassed solution of the catalyst in CH2Cl2 (2mL) was added via syringe under vigorous stirring. The solution was then left to heat towardsroom temperature.

For an illustration of the CO2(s)-cooled column used in this procedure, see figure 5.1 below.

Figure 5.1: An illustration of the column with a compartment for CO2(s)

17

5.1 6-bromo-1-azabicyclo[3.2.0]heptan-7-one (5a)

The compound was prepared following the general procedure forthermolysis given above. In CDCl3, the compound decomposes overtime as indicated by a 1H-NMR spectrum recorded 48 hours after the first(data not shown). This could owe to the oxidative accumulation of HClin the CDCl3 resulting in β--lactam hydrolysis, and would be consistentwith the reported rapid hydrolysis of β-lactams fused with 5-memberedrings.14

An NMR spectrum of the crude reaction mixture, added internalstandard, can be found on page 58.

N

O

Br

Physical data

Crude reaction mixture from thermolysis:

• Partial 1H-NMR (300 MHz, CDCl3) δ 4.395 (d, J = 1.7 Hz, 1H)

• MS (ESI, FT-ICR) (MeCN) m/z 274/272/270 [α, α′-Br2−NR2 + H]+, 210/208 [M + H2O +

H]+ (hydrolysis)

5.2 7-bromo-1-azabicyclo[4.2.0]octan-8-one (5b)

The compound was prepared both following the general procedure forthermolysis and that for catalysis, given above.NMR spectra of the crude reaction mixtures and crude reactions mixtureadded internal standard, can be found on page 59.

N

O

Br

Physical data

Crude reaction mixture from thermolysis, mixture of endo/exo-isomers:

• 1H-NMR (300 MHz, CDCl3) δ 4.945 (dd, J = 4.43, 1.60 Hz, 1H, endo), 4.395 (d, J = 1.13 Hz,1H, exo), 3.805 (dd, J = 13.19 , 4.52 Hz, 1H), 3.50 (ddd, J = 10.69, 4.47, 1.04 Hz, 1H), 2.735(ddd, J = 13.47, 11.77, 4.33 Hz, 1H), 2.10 (m, 1H), 1.95 – 1.10 (comp, 5H)

Crude reaction mixture from dirhodium(II) catalysis:

• MS (ESI, Q-TOF) (MeOH) m/z 433/431/429 [C17H20Br2N2O2 + Na]+ (formal carbenedimer), 288/286/284 [α, α′-Br2−NR2 + H]+, 206/204 [M + H]+

Isolated by preparative TLC:

• MS (EI) m/z (% rel. int.) 205/203 (M+, 6/6), 134/132 (22/22), 124 (100), 121/119 (7/7), 96(8), 84 (11), 81 (22), 69 (9)

• HRMS (EI) Calcd. for C7H1079BrNO [M+]: 202.9946; found 202.9938 (3.6 ppm)

• TLC (SiO2, Et2O) R f exo: 0.29, endo: 0.19

18

α, α′-Br2−piperidine acetamide –– a common by-product. See 1H-NMR spectrum on page 70:

• 1H-NMR (300 MHz, CDCl3) δ 6.21 (s, HCBr2−NR2), 6.14 (s, HCBr2−NR2), 3.75 – 3.50 (m,4H), 1.80 – 1.50 (m, 6H)

• MS (EI) m/z (% rel. int.) 287/285/283 (M+, 6/13/6), 206/204 (56/57), 175/173/171(4/9/4), 122/120 (6/6), 112 (100), 84 (21), 69 (69)

• TLC (SiO2, Et2O) R f 0.54

5.3 8-bromo-1-azabicyclo[5.2.0]nonan-9-one (5c)

The compound was prepared following the general procedure forthermolysis given above.NMR spectra of the crude reaction mixture added internal standard, aswell as the exo/endo isomers isolated by chromatography, can be foundon page 61.

N

O

Br

Chromatographic procedure

The diastereomers exo-3e and endo-3e were separated on a column of neutral alumina (10 × 2.5cm �), using Et2O as the eluent.

Physical data

Isolated by chromatography:

exo-8-bromo-1-azabicyclo[5.2.0]nonan-9-one

• 1H-NMR (300 MHz, CDCl3) δ 4.255 (dd, J = 1.13, 1.13 Hz, 1H), 3.765 (ddd, J = 9.61, 2.83,1.70 Hz, 1H), 3.45 – 3.23 (m, 2H), 2.15 – 2.05 (m, 1H), 1.95 – 1.70 (m, 3H), 1.60 – 1.25 (m,4H)

• 13C-NMR (75 MHz, CDCl3) δ 162.5, 64.6, 45.7, 43.4, 33.7, 29.2, 27.2, 26.6

endo-8-bromo-1-azabicyclo[5.2.0]nonan-9-one

• 1H-NMR (300 MHz, CDCl3) δ 4.905 (ddd, J = 4.62, 1.79, 0.75 Hz, 1H), 3.85 (ddd, J = 10.13,4.66, 2.17 Hz, 1H), 3.40 – 3.25 (m, 2H), 2.00 – 1.75 (m, 5H), 1.60 – 1.20 (m, 5H)

• 13C-NMR (75 MHz, CDCl3) δ 163.2, 57.1, 47.9, 43.5, 33.3, 28.9, 28.1, 26.7

Crude reaction mixture from thermolysis, mixture of endo/exo-isomers:

• MS (ESI, FT-ICR) (MeCN) m/z 220/218 [M + H]+

• TLC (SiO2, Et2O) R f exo: 0.49, endo: 0.36, α, α′-Br2−NR2: 0.65

19

5.4 tert-butyl 7-bromo-8-oxo-1,4-diazabicyclo[4.2.0]octane-4-carboxylate (5d)

The compound was prepared following the general procedure forthermolysis given above.An NMR spectrum of the crude reaction mixture, added internalstandard, can be found on page 66.

N

O

Br

N

O

O

Physical data


• Partial 1H-NMR (300 MHz, CDCl3) δ 4.935 (dd, J = 4.52, 1.13 Hz, 1H, endo), 4.495 (d,J = 1.32 Hz, 1H, exo)

• MS (ESI, FT-ICR) (MeCN) m/z 325/323 [M + H2O + H]+ (hydrolysis), 251/249[M−56 (iso−butene) + H]+ (Boc-degradation pathway to carboxylate)

5.5 7-bromo-4-oxa-1-azabicyclo[4.2.0]octan-8-one (5e)


N

O

Br

O

Physical data


• Partial 1H-NMR (300 MHz, CDCl3) δ 4.935 (dd, J = 4.52, 1.32 Hz, 1H, endo), 4.485 (d,J = 1.32 Hz, 1H, exo)

• MS (ESI, FT-ICR) (MeCN) m/z 415/413/411 [C12H16Br2N2O4 + H]+ (formal carbenedimer), 208/206 [M + H]+

5.6 7-bromo-4-thia-1-azabicyclo[4.2.0]octan-8-one 4,4-dioxide (5f)


N

O

Br

S

O

O

Physical data


• Partial 1H-NMR (300 MHz, CDCl3) δ 5.20 (dd, J = 4.71, 1.32 Hz, 1H, endo), 4.70 (d, J = 1.51Hz, 1H, exo)

• MS (ESI, FT-ICR) (MeCN) m/z 274/272 [M + H2O + H]+ (hydrolysis)

20

5.7 Synthesis and thermolysis of α-chloro- and α-iodo-4d

It was desirable to investigate whether the reaction of the α-bromodiazoacetamides could beextended to its chlorine and iodine analogues. The piperazine-derivative 3d was chosen as themodel compound, since the C-H insertion reaction of Br-4d gave a moderate to low yield,which provided an opportunity for its chlorine and iodine analogues to expose theirdifferential reactivity. The halogenation reactions were carried out using DBU/NXS (X = Cl, Br,I), due to the availability of the halosuccinimides.

Table 5.1: Yieldsa in % of exo/endo-tert-butyl 7-halo-8-oxo-1,4-diazabicyclo[4.2.0]octane-4-carboxylate X-5d (X = Cl, Br, I) obtainedfrom the thermolysis of α-chloro-, α-bromo- and α-iodo-tert-butyl 4-(2-diazoacetyl)piperazine-1-carboxylate

Diazo compound exo endoexo/endo

ratio Total

Cl-4d 10 2 5:1 12

Br-4d 34 2 17:1 36

I-4d 2b - bc n/a 2a Determined by 1H-NMR (method described above)b The bright red solution turned purple when passed through the short silica gel

column used (see experimental procedure), possibly indicating a release of I2.c Not detected by 1H-NMR

5.8 Dirhodium(II) catalysis results

The results were obtained following the representative experimental procedure for catalyzedreactions given above. NBS was used instead of NBP, due to the higher retention ofsuccinimide vs phthalimide on the short column used to purify the β-diazoacetamide.

Table 5.2: Yieldsa in % of exo/endo-7-bromo-1-azabicyclo[4.2.0]octan-8-one (5b) obtained from thecatalytic dediazotization of 4b.

Catalyst

Nominalcatalyst loading

(% mol) exo endoexo/endo

ratio Totalα, α′ − Br2-

Amide

Cu(acac)2 3 2 - b n/a 2 2

Rh2(tfa)4 3 22 6 3.7:1 28 25

Rh2(OAc)2(pc)226 1 30 4 7.5:1 34 10

Rh2(cap)427 3 38 6 6.3:1 44 14

a Determined by 1H-NMR (method described above)b Not detected by 1H-NMR

21

6 Additional procedures

6.1 1,1,3,3-tetramethylguanidine p-toluenesulfinate

The precipitation of this salt occurred during the prepa-rations of the α-diazoacetamides as described in theirexperimental procedure. In one instance, the precipitatewas weighed dry and it accounted for 98 %wt of thetheoretical amount. For the characterization of thesalt, a small amount of the precipitation was driedand stored under an argon atmosphere to ensure a lowdegree of oxidation before submitting the sample tomass spectrometry (ESI). The spontanous oxidation ofp-toluenesulfinates to p-toluenesulfinatessulfonates havebeen noted by others.28 The 1H-NMR shows a mixtureof 1,1,3,3-tetramethylguanidine p-toluenesulfinate and1,1,3,3-tetramethylguanidine p-toluenesulfonate (a tenta-tive assignment of the peaks can be found in the spectrumon page 69).

Physical data

• 1H-NMR (200 MHz, CDCl3) δ 8.92 (bs), 7.72 (m), 7.53 (m), 7.11 (m), 7.08 (m), 3.87 (bs), 2.80(s), 2.28 (s)

• MS (ESI) (H2O) (ES+) m/z 510/508/506 [2 TMG + 2 HBr + H]+, 403.4[2 TMG + p−Ts−SO3H + H]+, 387.5 [2 TMG + p−Ts−SO2H + H]+, 313/311[2 TMG + HBr]+, 231.3 [2 TMG + H]+, 116.2 [TMG + H]+

• MS (ESI) (H2O) (ES-) m/z 171 [p−Ts−SO3]–, 155 [p−Ts−SO2]–

22

References

[1] H. E. Gottlieb, V. Kotlyar, A. Nudelman, J. Org. Chem. 1997, 62, 7512–7515

[2] a) B. P. Axe, J. Pharm. Biomed. Anal. 2006, 41, 804–810

b) A. T. Lebedev, Mass Spectrom. Rev. 1991, 10, 91–132

[3] E. M. Tippmann, M. S. Platz, I. B. Svir, O. V. Klymenko, J. Am. Chem. Soc. 2004, 126, 5750–5762

[4] S. P. L. de Souza, J. F. M. da Silva, M. C. S. de Mattos, Synth. Commun. 2003, 33, 935–939

[5] J.-J. Kim, D.-H. Kweon, S.-D. Cho, H.-K. Kim, S.-G. Lee, Y.-J. Yoon, Synlett 2006, 2, 194–200

[6] H. J. Dauben, Jr., L. L. McCoy, J. Am. Chem. Soc. 1959, 81, 4863–4873

[7] T. Toma, J. Shimokawa, T. Fukuyama, Org. Lett. 2007, 9, 3195–3197

[8] S. K. Vasisht, P. Venugopalan, J. Kataria, A. Sharma, Indian J. Chem. 2002, 41A, 2054–2059

[9] L. Zhang, X. jun Wang, J. Wang, N. Grinberg, D. Krishnamurthy, C. H. Senanayake, Tetrahedron Lett.2009, 50, 2964–2966

[10] I. Leito, Acidity-Basicity Data (pKa Values) in Nonaqueous Solvents,http://tera.chem.ut.ee/~ivo/HA_UT/

[11] a) S. M. Ahmad, D. C. Braddock, G. Cansell, S. A. Hermitage, Tetrahedron Lett. 2007, 48, 915–918

b) R. S. Grainger, N. E. Leadbeater, A. M. Pàmies, Catal. Commun. 2002, 3, 449–452

[12] J. V. Ruppel, T. J. Gauthier, N. L. Snyder, J. A. Perman, X. P. Zhang, Org. Lett. 2009, 11, 2273–2276

[13] V. K. Aggarwal, P. Blackburn, R. Fieldhouse, R. V. H. Jones, Tetrahedron Lett. 1998, 39, 8517–8520

[14] R. H. Earle, D. T. Hurst, M. Viney, Journal of the Chemical Society C: Organic 1969, 0, 2093–2098

[15] M. Regitz, J. Hocker, A. Liedhegener, Org. Prep. Proced. 1969, 1, 99–104

[16] G. Lowe, J. Parker, J. Chem. Soc. D 1971, 18, 1135–1136

[17] N. P. Peet, S. Sunder, J. Heterocycl. Chem. 1975, 12, 1191–1197

[18] J. S. Wiering, H. Wynberg, J. Org. Chem. 1976, 41, 1574–1578

[19] K. Bott, Chem. Ber. 1987, 120, 1867–1871

[20] A. Ouihia, L. Rene, J. Guilhem, C. Pascard, B. Badet, J. Org. Chem. 1993, 58, 1641–1642

[21] M. P. Doyle, A. V. Kalinin, Synlett 1995, 1995, 1075–1076

[22] Å. Kaupang, C. H. Görbitz, T. Hansen, Acta Crystallogr. Sect. E: Struct. Rep. Online 2010, 66, o1299

[23] A. Saghatelian, J. Buriak, V. S. Y. Lin, M. R. Ghadiri, Tetrahedron 2001, 57, 5131–5136

[24] Å. Kaupang, C. H. Görbitz, T. Hansen, Acta Crystallogr. Sect. E: Struct. Rep. Online 2011, 67,o1844–o1845

[25] U. Schöllkopf, M. Reetz, Tetrahedron Lett. 1969, 20, 1541–1544

[26] A. R. Chakravarty, F. A. Cotton, D. A. Tocher, J. H. Tocher, Organometallics 1985, 4, 8–13

[27] M. P. Doyle, L. J. Westrum, W. N. E. Wolthuis, M. M. See, W. P. Boone, V. Bagheri, M. M. Pearson, J.Am. Chem. Soc. 1993, 115, 958–964

[28] F. C. Whitmore, F. H. Hamilton, Org. Synth. 1922, 2, 89

23

NMR Spectra

24

N-bromophthalimide – 1H-NMR

13

12

11

10

98

76

54

32

10

Chem

ical S

hift

(ppm

)

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Normalized Intensity

H2O

CH

LO

RO

FO

RM

-d

6a,7

a,8

a,9

a

7.9

0

7.8

87.8

7

7.8

67.7

6

7.7

47.7

3

7.7

1

7.2

61.6

9

Acq

uis

itio

n T

ime (

sec)

2.9

999

Fre

qu

en

cy (

MH

z)

200.1

3N

ucle

us

1H

Nu

mb

er

of

Tra

nsie

nts

16

Ori

gin

DP

X200

Ori

gin

al

Po

ints

Co

un

t12417

Po

ints

Co

un

t16384

Pu

lse S

eq

uen

ce

zg30

Receiv

er

Gain

1625.5

0S

W(c

ycli

cal)

(H

z)

4139.0

7

So

lven

tC

HLO

RO

FO

RM

-dS

pectr

um

Off

set

(Hz)

1233.7

882

Sp

ectr

um

Typ

eS

TA

ND

AR

D

Sw

eep

Wid

th (

Hz)

4138.8

2T

em

pera

ture

(d

eg

ree C

)25.1

60

Br

10

3 4

6 9

7 8

2

N 1

5

O 11

O 12

H 6a

H 9a

H 7a

H 8a

Fo

rmu

laC

8H

4B

rNO

2F

W226.0

269

25

1H-NMR – N,N’-ditosylhydrazine

11

10

98

76

54

32

10

Chem

ical S

hift (p

pm

)

0 0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0


6.0

44.0

84.0

72.0

0

DM

SO

-d6

H2O

in D

MS

O

9.5

9(1

1a,1

2a)

7.6

7(2

a,6

a,1

7a,2

1a)

7.6

4(2

1a,1

7a,6

a,2

a)

7.4

0(3

a,5

a,1

8a,2

0a)

7.3

7(3

a,5

a,1

8a,2

0a)

2.5

0

2.4

0(9

a,9

b,9

c,2

2a,2

2b,2

2c)

Acq

uis

ition

Tim

e (s

ec)

5.3

084

Co

mm

en

tP

RO

TO

N D

MS

O D

: {UIO

\aasm

uk} 3

1F

req

uen

cy (M

Hz)

300.1

3N

ucle

us

1H

Nu

mb

er o

f Tra

nsie

nts

16

Orig

inD

PX

300

Orig

inal P

oin

ts C

ou

nt

32768

Po

ints

Co

un

t32768

Pu

lse S

eq

uen

ce

zg30

Receiv

er G

ain

161.3

0S

W(c

yclic

al) (H

z)

6172.8

4S

olv

en

tD

MS

O-d

6S

pectru

m O

ffset (H

z)

1852.0

708

Sp

ectru

m T

yp

eS

TA

ND

AR

D

Sw

eep

Wid

th (H

z)

6172.6

5T

em

pera

ture

(deg

ree C

)25.1

6021

36

45

S7N1

1

N12

S13

19

18

20

17

21

16

O14

O15

O8

O10

9

22

H2a

H3a

H6a

H5a

H11a

H12a

H18a

H20a

H17a

H21a

H9a

H9b

H9c

H22a

H22b

H22c

Fo

rmu

laC

14 H

16 N

2 O4 S

2

FW

340.4

178

26

N,N’-ditosylhydrazine – 13C-NMR

220

200

180

160

140

120

100

80

60

40

20

0-2

0C

hem

ical S

hift

(ppm

)

00.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0


DM

SO

-d6

X

143.4

3(1

6,1

)135.5

1(1

9,4

)

129.4

3(1

7,2

1,2

,6)

127.7

8(1

8,2

0,3

,5)

39.5

2

21.0

3(9

,22)

Acq

uis

itio

n T

ime (

sec)

1.8

219

Co

mm

en

tC

13C

PD

DM

SO

D:

{UIO

\aasm

uk}

31

Fre

qu

en

cy (

MH

z)

75.4

8N

ucle

us

13C

Nu

mb

er

of

Tra

nsie

nts

512

Ori

gin

DP

X300

Ori

gin

al

Po

ints

Co

un

t32768

Po

ints

Co

un

t32768

Pu

lse S

eq

uen

ce

zgpg30

Receiv

er

Gain

3649.1

0S

W(c

ycli

cal)

(H

z)

17985.6

1S

olv

en

tD

MS

O-d

6S

pectr

um

Off

set

(Hz)

7511.2

959

Sp

ectr

um

Typ

eS

TA

ND

AR

D

Sw

eep

Wid

th (

Hz)

17985.0

6T

em

pera

ture

(d

eg

ree C

)25.1

60

2 1

3 6

4 5

S 7N

H

11

NH

12

S 13

19

18

20

17

21

16

O 14

O 15

O 8

O 10

CH

39

CH

322

Fo

rmu

laC

14H

16N

2O

4S

2

FW

340.4

178

27

1H-NMR – 2-bromo-1-(pyrrolidin-1-yl)ethanone (2a)

7.5

7.0

6.5

6.0

5.5

5.0

4.5

4.0

3.5

3.0

2.5

2.0

1.5

1.0

0.5

0C

hem

ical S

hift (p

pm

)

0 0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Normalized In ten sity

4.0

54.0

52.0

0

CH

LO

RO

FO

RM

-d

1.9

1(3

a,4

a,4

b)

1.9

2(3

b)

3.4

7(2

a,2

b,5

a,5

b)

3.7

7(8

a,8

b)

7.2

6

Acq

uis

ition

Tim

e (s

ec)

5.3

084

Fre

qu

en

cy (M

Hz)

300.1

3N

ucle

us

1H

Orig

inB

ruker

Orig

inal P

oin

ts C

ou

nt

32768

Po

ints

Co

un

t65536

Pu

lse S

eq

uen

ce

ZG

30

Sp

ectru

m O

ffset (H

z)

1847.2

621

Sp

ectru

m T

yp

eS

TA

ND

AR

DS

weep

Wid

th (H

z)

6172.8

4

N1

2

3

4

5

6 O7

8

H8a

Br

9

H8b

H2b

H2a

H3b

H3a

H4b

H4a

H5b

H5a

Fo

rmu

laC

6 H10 B

rNO

FW

192.0

537

28

2-bromo-1-(pyrrolidin-1-yl)ethanone (2a) – 13C-NMR & DEPT-135

170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0Chemical Shift (ppm)

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Norm

aliz

ed I

nte

nsity

CHLOROFORM-d

24.20(4,3)

26.04(8)

27.32(3,4)46.30(5,2)

46.93(2,5)

77.00

164.87(6)

Acquisition Time (sec) 1.8219 Comment C13CPD CDCl3 D: {UIO\aasmuk} 50 Frequency (MHz) 75.48 Nucleus 13C

Number of Transients 1024 Origin DPX300 Original Points Count 32768 Points Count 32768 Pulse Sequence zgpg30

Receiver Gain 11585.20 SW(cyclical) (Hz) 17985.61 Solvent CHLOROFORM-d Spectrum Offset (Hz) 7538.0913

Spectrum Type STANDARD Sweep Width (Hz) 17985.06 Temperature (degree C) 25.160

N

1

2

3

45

6

O

7

8

Br

9

Formula C6H

10BrNO FW 192.0537

60 55 50 45 40 35 30 25 20 15 10 5Chemical Shift (ppm)

-1.0

-0.9

-0.8

-0.7

-0.6

-0.5

-0.4

-0.3

-0.2

-0.1

0

Norm

aliz

ed I

nte

nsity

From 13C ��

24.20(4,3)

26.04(8)

27.33(3,4)

46.30(5,2)46.93(2,5)

Acquisition Time (sec) 1.8219 Comment C13DEPT135 CDCl3 D: {UIO\aasmuk} 50 Frequency (MHz) 75.48 Nucleus 13C

Number of Transients 256 Origin DPX300 Original Points Count 32768 Points Count 32768 Pulse Sequence dept135


Spectrum Type DEPT135 Sweep Width (Hz) 17985.06 Temperature (degree C) 25.160

N

1

2

3

45

6

O

7

8

Br

9

Formula C6H

10BrNO FW 192.0537

29

1H-NMR – 2-bromo-1-(piperidin-1-yl)ethanone (2b)

7.5

7.0

6.5

6.0

5.5

5.0

4.5

4.0

3.5

3.0

2.5

2.0

1.5

1.0

0.5

0C

hem

ical S

hift (p

pm

)

0 0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0


1.9

63.9

01.9

51.9

32.0

0

X

DC

MC

HLO

RO

FO

RM

-d

1.5

4(4

a,4

b)

1.6

3(3

a,3

b,5

a,5

b)

3.4

2(2

a,2

b,6

a,6

b)

3.5

3(2

a,2

b,6

a,6

b)

3.8

4(9

a,9

b)

7.2

6

Acq

uis

ition

Tim

e (s

ec)

5.3

084

Co

mm

en

tP

RO

TO

N C

DC

l3 D

: {UIO

\aasm

uk} 5

1F

req

uen

cy (M

Hz)

300.1

3N

ucle

us

1H

Nu

mb

er o

f Tra

nsie

nts

128

Orig

inD

PX

300

Orig

inal P

oin

ts C

ou

nt

32768

Po

ints

Co

un

t32768

Pu

lse S

eq

uen

ce

zg30

Receiv

er G

ain

143.7

0S

W(c

yclic

al) (H

z)

6172.8

4S

olv

en

tC

HLO

RO

FO

RM

-dS

pectru

m O

ffset (H

z)

1847.1

259

Sp

ectru

m T

yp

eS

TA

ND

AR

DS

weep

Wid

th (H

z)

6172.6

5T

em

pera

ture

(deg

ree C

)25.1

60

2

34

5

6 N1

7 O8

9

Br

10

H9a

H9b

H2b

H2a

H3b

H3a

H4b

H4a

H5b

H5a

H6b

H6a

Fo

rmu

laC

7 H12 B

rNO

FW

206.0

803

30

2-bromo-1-(piperidin-1-yl)ethanone (2b) – 13C-NMR & DEPT-135


0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Norm

aliz

ed I

nte

nsity

CHLOROFORM-d

24.17(4)

25.27(5,3)26.06(9)

26.10(3,5)43.18(6,2)

47.83(2,6)

77.00

164.95(7)





2

3

4

5

6

N

1

7

O

8

9

Br

10

Formula C7H

12BrNO FW 206.0803

50 45 40 35 30 25 20 15 10Chemical Shift (ppm)

-1.0

-0.9

-0.8

-0.7

-0.6

-0.5

-0.4

-0.3

-0.2

-0.1

0

Norm

aliz

ed I

nte

nsity

From 13C ��

24.17(4)25.27(5,3)

26.06(9)

26.10(3,5)43.17(6,2)

47.83





2

3

4

5

6

N

1

7

O

8

9

Br

10

Formula C7H

12BrNO FW 206.0803

31

1H-NMR – 1-(azepan-1-yl)-2-bromoethanone (2c)

7.5

7.0

6.5

6.0

5.5

5.0

4.5

4.0

3.5

3.0

2.5

2.0

1.5

1.0

0.5

0C

hem

ical S

hift (p

pm

)

0 0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0


3.8

93.9

03.8

52.0

0

CH

LO

RO

FO

RM

-d

1.5

5(4

a,4

b,5

a,5

b)

1.7

2(3

a,3

b,6

a,6

b)

3.4

8(2

a,2

b,7

a,7

b)

3.8

4(1

0a,1

0b)

7.2

6

Acq

uis

ition

Tim

e (s

ec)

5.3

084

Co

mm

en

tP

RO

TO

N C

DC

l3 D

: {UIO

\aasm

uk} 4

Fre

qu

en

cy (M

Hz)

300.1

3N

ucle

us

1H

Nu

mb

er o

f Tra

nsie

nts

16

Orig

inD

PX

300

Orig

inal P

oin

ts C

ou

nt

32768

Po

ints

Co

un

t32768

Pu

lse S

eq

uen

ce

zg30

Receiv

er G

ain

101.6

0S

W(c

yclic

al) (H

z)

6172.8

4S

olv

en

tC

HLO

RO

FO

RM

-dS

pectru

m O

ffset (H

z)

1847.1

124

Sp

ectru

m T

yp

eS

TA

ND

AR

DS

weep

Wid

th (H

z)

6172.6

5T

em

pera

ture

(deg

ree C

)25.1

60

H10a

Br

11

N1

28

7

O9

10

3

6

H10b

5

4

H2a

H2b

H7aH7

b

H3a

H3b

H6a

H6b

H5a

H5b

H4a H4b

Fo

rmu

laC

8 H14 B

rNO

FW

220.1

069

32

1-(azepan-1-yl)-2-bromoethanone (2c) – 13C-NMR & DEPT-135


0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Norm

aliz

ed I

nte

nsity

CHLOROFORM-d

168.53, X

26.31(10)

26.42(5,4)27.05(4,5)

27.21(6,3)

28.93(3,6)46.26(7,2)

48.54(2,7)

77.00

166.34





Br

11

N

1

28

7

O

9

103

65

4

Formula C8H

14BrNO FW 220.1069

50 48 46 44 42 40 38 36 34 32 30 28 26 24Chemical Shift (ppm)

-1.0

-0.9

-0.8

-0.7

-0.6

-0.5

-0.4

-0.3

-0.2

-0.1

0

Norm

aliz

ed I

nte

nsity

From 13C ��

26.31(10)

26.41(5,4)27.04(4,5)

27.20(6,3)

28.92(3,6)

46.26(7,2)

48.54(2)





Br

11

N

1

28

7

O

9

103

6 5

4

Formula C8H

14BrNO FW 220.1069

33

HMQC (1J13C,1 H) – 1-(azepan-1-yl)-2-bromoethanone (2c)

Acq

uis

ition

Tim

e (s

ec)

(0.5

308, 0

.0092)

Co

mm

en

t5 m

m Q

NP

1H

/15N

/13C

/31P

Z08011/0

020

Fre

qu

en

cy (M

Hz)

(300.1

3, 7

5.4

7)

Nu

cle

us

(1H

, 13C

)O

rigin

DP

X300

Orig

inal P

oin

ts C

ou

nt

(512, 1

28)

Po

ints

Co

un

t(5

12, 1

024)

Pu

lse S

eq

uen

ce

hm

qcqf

So

lven

tC

DC

l3S

pectru

m T

yp

eH

MQ

CS

weep

Wid

th (H

z)

(962.6

2, 1

3952.8

4)

Fo

rmu

laC

8 H14 B

rNO

FW

220.1

069

3.5

3.0

2.5

2.0

1.5

F2 C

hem

ical S

hift (p

pm

)

22

24

26

28

30

32

34

36

38

40

42

44

46

48

50

F1 Chemical Shift (ppm)

3.8

4, 2

6.2

6, 1

(10a, 1

0)(1

0b, 1

0)

1.5

6, 2

6.9

9, 0

.33 (4

a, 4

)(4b, 4

)(5a, 5

)(5b, 5

)

1.5

6, 2

6.3

6, 0

.33 (4

a, 4

)(4b, 4

)(5a, 5

)(5b, 5

)

3.4

8, 4

8.4

6, 0

.27 (2

a, 2

)(2b, 2

)(7a, 7

)(7b, 7

)

3.4

8, 4

6.1

9, 0

.17 (2

a, 2

)(2b, 2

)(7a, 7

)(7b, 7

)

1.7

6, 2

8.8

6, 0

.17 (3

a, 3

)(3b, 3

)(6a, 6

)(6b, 6

)

H10a

Br

11

N1

28

7

O9

10

3

6

H10b

5

4

H2a

H2b

H7aH7

b

H3a

H3b

H6a

H6b

H5a

H5b H4

a

H4b

34

tert-butyl 4-(2-bromoacetyl)piperazine-1-carboxylate (2d) – 1H-NMR

7.5

7.0

6.5

6.0

5.5

5.0

4.5

4.0

3.5

3.0

2.5

2.0

1.5

1.0

0.5

0C

hem

ical S

hift

(ppm

)

00.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0


9.0

58.0

01.9

7

DC

MC

HLO

RO

FO

RM

-d

1.4

5(1

0,1

4,1

5)

3.4

8(2

a,2

b,3

a,3

b,5

a,5

b,6

a,6

b)

3.8

5(1

6a,1

6b)

7.2

6

Acq

uis

itio

n T

ime (

sec)

5.3

084

Co

mm

en

tP

RO

TO

N C

DC

l3 D

: {U

IO\a

asm

uk}

46

Fre

qu

en

cy (

MH

z)

300.1

3N

ucle

us

1H

Nu

mb

er

of

Tra

nsie

nts

128

Ori

gin

DP

X300

Ori

gin

al

Po

ints

Co

un

t32768

Po

ints

Co

un

t32768

Pu

lse S

eq

uen

ce

zg30

Receiv

er

Gain

161.3

0S

W(c

ycli

cal)

(H

z)

6172.8

4S

olv

en

tC

HLO

RO

FO

RM

-dS

pectr

um

Off

set

(Hz)

1847.1

257

Sp

ectr

um

Typ

eS

TA

ND

AR

DS

weep

Wid

th (

Hz)

6172.6

5T

em

pera

ture

(d

eg

ree C

)25.1

60

2 N 1

3 6

N 4 5

11

O 12

16

Br

17

7 O 8

O 13

9

CH

310

CH

314

CH

315

H 2b

H 2a

H 3b

H 3a

H 6b

H 6a

H 5b

H 5a

H 16a

H 16b

Fo

rmu

laC

11H

19B

rN2O

3

FW

307.1

842

35

13C-NMR & DEPT-135 – tert-butyl 4-(2-bromoacetyl)piperazine-1-carboxylate (2d)


0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Norm

aliz

ed I

nte

nsity

CHLOROFORM-d

25.57(16)

28.29(10,14,15)

41.87(3,5)46.49(2,6)

77.00

80.38(9)

154.37(7)165.35(11)





2

N

1

3

6

N

4

5

11

O

12

16

Br

17

7

O

8

O

13

9

CH310

CH314

CH315

Formula C11

H19

BrN2O

3

FW 307.1842

50 48 46 44 42 40 38 36 34 32 30 28 26 24 22Chemical Shift (ppm)

-0.3

-0.2

-0.1

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Norm

aliz

ed I

nte

nsity

From 13C ��

25.57(16)

28.29(10,14,15)

41.87(3,5)46.49(2,6)





2

N

1

3

6

N

4

5

11

O

12

16

Br

17

7

O

8

O

13

9

CH310

CH314

CH315

Formula C11

H19

BrN2O

3

FW 307.1842

36

2-bromo-1-morpholinoethanone (2e) – 1H-NMR

7.5

7.0

6.5

6.0

5.5

5.0

4.5

4.0

3.5

3.0

2.5

2.0

1.5

1.0

0.5

0C

hem

ical S

hift

(ppm

)

00.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0


2.0

02.0

54.0

02.0

0

CH

LO

RO

FO

RM

-d

7.2

6

3.8

3(1

6a,1

6b)

3.6

8(2

a,2

b,6

a,6

b)

3.6

0(3

a,3

b,5

a,5

b)

3.4

9(3

a,3

b,5

a,5

b)

Acq

uis

itio

n T

ime (

sec)

5.3

084

Co

mm

en

tP

RO

TO

N C

DC

l3 D

: {U

IO\a

asm

uk}

52

Fre

qu

en

cy (

MH

z)

300.1

3N

ucle

us

1H

Nu

mb

er

of

Tra

nsie

nts

128

Ori

gin

DP

X300

Ori

gin

al

Po

ints

Co

un

t32768

Po

ints

Co

un

t32768

Pu

lse S

eq

uen

ce

zg30

Receiv

er

Gain

161.3

0S

W(c

ycli

cal)

(H

z)

6172.8

4S

olv

en

tC

HLO

RO

FO

RM

-dS

pectr

um

Off

set

(Hz)

1847.1

257

Sp

ectr

um

Typ

eS

TA

ND

AR

DS

weep

Wid

th (

Hz)

6172.6

5T

em

pera

ture

(d

eg

ree C

)25.1

60

2

3 6

N 4 5

11

O 12

16

Br

17

O 1

H 2a

H 2b

H 3a

H 3b

H 6a

H 6b

H 5a

H 5b

H 16a

H 16b

Fo

rmu

laC

6H

10B

rNO

2F

W208.0

531

37

13C-NMR & DEPT-135 – 2-bromo-1-morpholinoethanone (2e)

170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0C�!"#$%& '�#() *++",

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Norm

aliz

ed I

nte

nsity

CHLOROFORM-d

25.36(16)

42.31(5,3)

47.05(3,5)

66.26(6,2)

66.49(2,6)

77.00

165.25(11)





2

3

6

N

4

5

11

O

12

16

Br

17

O

1

Formula C6H

10BrNO

2FW 208.0531

70 65 60 55 50 45 40 35 30 25-./01234 5.167 8990:

-1.0

-0.9

-0.8

-0.7

-0.6

-0.5

-0.4

-0.3

-0.2

-0.1

0

Norm

aliz

ed I

nte

nsity

From 13C ;<=>?@AB

25.36(16)

42.31(3,5)

47.05(3,5)

66.26(6,2)66.49(2,6)





2

3

6

N

4

5

11

O

12

16

Br

17

O

1

Formula C6H

10BrNO

2FW 208.0531

38

2-bromo-1-(1,1-dioxidothiomorpholino)ethanone (2f) – 1H-NMR

5.5

5.0

4.5

4.0

3.5

3.0

2.5

2.0

1.5

1.0

0.5

0

00.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0


3.9

64.0

22.0

0

AC

ET

ON

ITR

ILE

-d3

X

4.1

5,

X

DC

M

1.9

6

3.1

0(3

a,3

b,5

a,5

b)

3.9

6(2

a,2

b,6

a,6

b)

4.0

6(1

1a,1

1b)

5.4

7

Acq

uis

itio

n T

ime (

sec)

5.3

084

Co

mm

en

tP

RO

TO

N C

D3C

N D

: {U

IO\a

asm

uk}

57

Fre

qu

en

cy (

MH

z)

300.1

3N

ucle

us

1H

Nu

mb

er

of

Tra

nsie

nts

16

Ori

gin

DP

X300

Ori

gin

al

Po

ints

Co

un

t32768

Po

ints

Co

un

t32768

Pu

lse S

eq

uen

ce

zg30

Receiv

er

Gain

512.0

0S

W(c

ycli

cal)

(H

z)

6172.8

4S

olv

en

tA

CE

TO

NIT

RIL

E-d

3S

pectr

um

Off

set

(Hz)

1851.8

181

Sp

ectr

um

Typ

eS

TA

ND

AR

DS

weep

Wid

th (

Hz)

6172.6

5T

em

pera

ture

(d

eg

ree C

)25.1

60

N 4

39

5

O 10

11 H 1

1a

Br

12

H 11b

2

6

S 1

O 7

O 8

H 3a

H 3b

H 5a

H 5b

H 2a

H 2b

H 6a

H 6b

Fo

rmu

laC

6H

10B

rNO

3S

FW

256.1

175

39

13C-NMR & DEPT-135 – 2-bromo-1-(1,1-dioxidothiomorpholino)ethanone (2f)

170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0DEFGHIJK LEHMN OPPGQ

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Norm

aliz

ed I

nte

nsity

ACETONITRILE-d3

27.58, XX

ACETONITRILE-d3

166.47, X

1.29

27.81(11)

41.57(5,3)45.71(3,5)52.07(6,2)

52.26(2,6)

118.26

163.17(9)

Acquisition Time (sec) 1.8219 Comment C13CPD CD3CN D: {UIO\aasmuk} 57 Frequency (MHz) 75.48 Nucleus 13C


Receiver Gain 11585.20 SW(cyclical) (Hz) 17985.61 Solvent ACETONITRILE-d3 Spectrum Offset (Hz) 7617.4600


N

4

39

5

O

10

11

Br

12

2

6

S

1

O

7

O

8

Formula C6H

10BrNO

3S

FW 256.1175

54 52 50 48 46 44 42 40 38 36 34 32 30 28 26 24RSTUVWXY ZSV[\ ]^^U_

-1.0

-0.9

-0.8

-0.7

-0.6

-0.5

-0.4

-0.3

-0.2

-0.1

0

0.1

0.2

Norm

aliz

ed I

nte

nsity

27.58, X

From 13C `abcdefg

27.81(11)

41.57(5,3)45.71(3,5)52.06(6,2)

52.26(2,6)

Acquisition Time (sec) 1.8219 Comment C13DEPT135 CD3CN D: {UIO\aasmuk} 57 Frequency (MHz) 75.48 Nucleus 13C


Receiver Gain 13004.00 SW(cyclical) (Hz) 17985.61 Solvent ACETONITRILE-d3 Spectrum Offset (Hz) 7617.6548


N

4

39

5

O

10

11

Br

122

6

S

1

O

7

O

8

Formula C6H

10BrNO

3S

FW 256.1175

40

2-diazo-1-(pyrrolidin-1-yl)ethanone (3a) – 1H-NMR

7.5

7.0

6.5

6.0

5.5

5.0

4.5

4.0

3.5

3.0

2.5

2.0

1.5

1.0

0.5

0

00.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0


4.1

54.1

31.0

0

Et2

OX

X

DIC

HLO

RO

ME

TH

AN

E-d

2

DC

M

1.8

5(3

a,3

b,4

a,4

b)

3.2

8(2

a,2

b,5

a,5

b)

4.9

2(8

a)

5.3

2

Acq

uis

itio

n T

ime (

sec)

5.3

084

Co

mm

en

t5 m

m

hij

klmknimkopmokj

qrsrkkmrrtr

Fre

qu

en

cy (

MH

z)

300.1

3N

ucle

us

1H

Nu

mb

er

of

Tra

nsie

nts

16

Ori

gin

DP

X300

Ori

gin

al

Po

ints

Co

un

t32768

Po

ints

Co

un

t32768

Pu

lse S

eq

uen

ce

zg30

Receiv

er

Gain

71.8

0S

W(c

ycli

cal)

(H

z)

6172.8

4S

olv

en

tD

ICH

LO

RO

ME

TH

AN

E-d

2S

pectr

um

Off

set

(Hz)

1842.9

987

Sp

ectr

um

Typ

eS

TA

ND

AR

DS

weep

Wid

th (

Hz)

6172.6

5T

em

pera

ture

(d

eg

ree C

)26.1

60

N 1

2

3

6

54

O 7

8

N

+

9

H 8a

N

-

10

H 2b

H 2a

H 3b

H 3a

H 5b

H 5a

H 4b

H 4a

Fo

rmu

laC

6H

9N

3O

FW

139.1

552

41

13C-NMR & DEPT-135 – 2-diazo-1-(pyrrolidin-1-yl)ethanone (3a)

170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0uvwxyz{| }vy~� ��x�

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Norm

aliz

ed I

nte

nsity

DICHLOROMETHANE-d2

X

24.79(4,3)26.14(3,4)

46.20(2,5)46.37(8)

53.80

163.79(6)

Acquisition Time (sec) 1.8219 Comment C13CPD CD2Cl2 D: {UIO\aasmuk} 27 Frequency (MHz) 75.48 Nucleus 13C


Receiver Gain 11585.20 SW(cyclical) (Hz) 17985.61 Solvent DICHLOROMETHANE-d2 Spectrum Offset (Hz) 7568.7197


N

1

2

3

6

54

O

7

8

N

+

9

H

8a

N

-

10

Formula C6H

9N

3O FW 139.1552

54 52 50 48 46 44 42 40 38 36 34 32 30 28 26 24 22 20��

-1.0

-0.9

-0.8

-0.7

-0.6

-0.5

-0.4

-0.3

-0.2

-0.1

0

0.1

0.2

0.3

0.4

Norm

aliz

ed I

nte

nsity

From 13C ��

XX

24.7924.80(4,3)

26.19(3,4)

46.18(2,5)

46.40(8)

Acquisition Time (sec) 1.8219 Comment C13DEPT135 CD2Cl2 D: {UIO\aasmuk} 27 Frequency (MHz) 75.48 Nucleus 13C




N

1

2

3

6

54

O

7

8

N

+

9

H

8a

N

-

10

Formula C6H

9N

3O FW 139.1552

42

2-diazo-1-(piperidin-1-yl)ethanone (3b) – 1H-NMR

7.5

7.0

6.5

6.0

5.5

5.0

4.5

4.0

3.5

3.0

2.5

2.0

1.5

1.0

0.5

0

00.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0


4.0

52.0

74.0

31.0

0

X

DIC

HLO

RO

ME

TH

AN

E-d

2

DC

M

1.4

9(3

a,3

b,5

a,5

b)

1.5

9(4

a,4

b)

3.3

0(2

a,2

b,6

a,6

b)

5.1

6(9

a)

5.3

2

Acq

uis

itio

n T

ime (

sec)

5.3

084

Co

mm

en

t5 m

m

��

�� ¡� ��

¢£¤£��££¥£

Fre

qu

en

cy (

MH

z)

300.1

3N

ucle

us

1H

Nu

mb

er

of

Tra

nsie

nts

16

Ori

gin

DP

X300

Ori

gin

al

Po

ints

Co

un

t32768

Po

ints

Co

un

t32768

Pu

lse S

eq

uen

ce

zg30

Receiv

er

Gain

50.8

0S

W(c

ycli

cal)

(H

z)

6172.8

4S

olv

en

tD

ICH

LO

RO

ME

TH

AN

E-d

2S

pectr

um

Off

set

(Hz)

1842.9

987

Sp

ectr

um

Typ

eS

TA

ND

AR

DS

weep

Wid

th (

Hz)

6172.6

5T

em

pera

ture

(d

eg

ree C

)25.1

60

2

3 4

5

6N 1

7O 8

9

H 2b

H 2a

H 3b

H 3a

H 4b

H 4a

H 5b

H 5a

H 6b

H 6a

N

+

10

H 9a

N

-

11

Fo

rmu

laC

7H

11N

3O

FW

153.1

817

43

13C-NMR & DEPT-135 – 2-diazo-1-(piperidin-1-yl)ethanone (3b)

160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0¦§¨©ª«¬ ®§ª¯° ±²²©³

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Norm

aliz

ed I

nte

nsity

DICHLOROMETHANE-d2

24.77(4)

26.20(3,5)

45.15(2,6)

46.11(9)

53.80

164.31(7)





2

3

4

5

6

N

1

7

O

8

9

N

+

10

N

-

11

H

9a

Formula C7H

11N

3O FW 153.1817

50 48 46 44 42 40 38 36 34 32 30 28 26 24 22´µ¶·¸¹º» ¼µ¸½¾ ¿ÀÀ·Á

-0.06

-0.05

-0.04

-0.03

-0.02

-0.01

0

0.01

0.02

0.03

0.04

0.05

0.06

0.07

0.08

Norm

aliz

ed I

nte

nsity

From 13C ÂÃÄÅÆÇÈÉ24.7726.20

45.12

46.10





2

3

4

5

6

N

1

7

O

8

9

N

+

10

N

-

11

H

9a

Formula C7H

11N

3O FW 153.1817

44

2-diazo-1-(piperidin-1-yl)ethanone (3b) – HMQC (1J13C,1 H)

Acq

uis

itio

n T

ime (

sec)

(0.3

211,

0.0

092)

Co

mm

en

t5 m

m Q

NP

1H

/15N

/13C

/31P

Z08011/0

020

Fre

qu

en

cy (

MH

z)

(300.1

3,

75.4

7)

Nu

cle

us

(1H

, 13C

)O

rig

inD

PX

300

Ori

gin

al

Po

ints

Co

un

t(5

12,

128)

Po

ints

Co

un

t(5

12,

1024)

Pu

lse S

eq

uen

ce

hm

qcqf

So

lven

tC

D2C

l2S

pectr

um

Typ

eH

MQ

CS

weep

Wid

th (

Hz)

(1591.2

7,

13952.8

4)

Fo

rmu

laC

7H

11N

3O

FW

153.1

817

5.0

4.5

4.0

3.5

3.0

2.5

2.0

1.5

F2 C

hem

ical S

hift

(ppm

)

15

20

25

30

35

40

45

50

55

60


1.4

9,

26.2

1,

0.9

6 (

3a,

3)(

3b,

3)(

5a,

5)(

5b,

5)

5.1

6,

46.1

1,

0.6

9 (

9a,

9)

3.3

, 45.1

5,

0.4

8 (

2a,

2)(

2b,

2)(

6a,

6)(

6b,

6)

1.5

9,

24.7

8,

0.2

6 (

4a,

4)(

4b,

4)

2

3 4

5

6N 1

7O 8

9

H 2b

H 2a

H 3b

H 3a

H 4b

H 4a

H 5b

H 5a

H 6b

H 6a

N+

10

H 9a

N-

11

45

1H-NMR – 1-(piperidin-1-yl)-2-tosylethanone

9.0

8.5

8.0

7.5

7.0

6.5

6.0

5.5

5.0

4.5

4.0

3.5

3.0

2.5

2.0

1.5

1.0

0.5

0

0 0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0


6.3

33.1

24.2

22.0

72.0

32.0

0

CH

LO

RO

FO

RM

-d

2a,2

b,6

a,6

b

3a,3

b,4

a,4

b,5

a,5

b

14a,1

5a,1

8a,1

7a

1.5

4

1.6

5

2.4

2(1

9a,1

9b,1

9c)

3.5

0

4.2

2(9

a,9

b)

7.2

6

7.3

2

7.3

6

7.7

6

7.8

1

Acq

uis

ition

Tim

e (s

ec)

2.9

999

Fre

qu

en

cy (M

Hz)

200.1

3N

ucle

us

1H

Nu

mb

er o

f Tra

nsie

nts

16

Orig

inD

PX

200

Orig

inal P

oin

ts C

ou

nt

12417

Po

ints

Co

un

t16384

Pu

lse S

eq

uen

ce

zg30

Receiv

er G

ain

406.4

0S

W(c

yclic

al) (H

z)

4139.0

7

So

lven

tC

HLO

RO

FO

RM

-dS

pectru

m O

ffset (H

z)

1227.4

727

Sp

ectru

m T

yp

eS

TA

ND

AR

D

Sw

eep

Wid

th (H

z)

4138.8

2T

em

pera

ture

(deg

ree C

)25.1

60

14

13

15

18

16

17

19

S10

O11

9

O12

7

N1

2

6

3

5

4

O8

H14a

H15a

H18a

H17a

H19a

H19b

H19c

H9a

H9b

H2a

H2b

H6a

H6b

H3a

H3b

H5a

H5b

H4a

H4b

Fo

rmu

laC

14 H

19 N

O3 S

FW

281.3

706

46

1-(piperidin-1-yl)-2-tosylethanone – 13C-NMR

160

150

140

130

120

110

100

90

80

70

60

50

40

30

20

10

0

00.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0


CH

LO

RO

FO

RM

-d

X

21.6

4(1

9)

24.1

2(4

)25.3

7(5

,3)

26.1

3(5

)

43.3

0(6

,2)

48.2

9(2

,6)

59.8

1(9

)

77.0

0

128.3

5(1

4,1

8)

129.6

9(1

5,1

7)

135.9

1(1

3)

145.0

8(1

6)

159.4

6(7

)

Acq

uis

itio

n T

ime (

sec)

1.8

219

Co

mm

en

tC

13C

PD

CD

Cl3

D:

{UIO

\aasm

uk}

24

Fre

qu

en

cy (

MH

z)

75.4

8N

ucle

us

13C

Nu

mb

er

of

Tra

nsie

nts

1024

Ori

gin

DP

X300

Ori

gin

al

Po

ints

Co

un

t32768

Po

ints

Co

un

t32768

Pu

lse S

eq

uen

ce

zgpg30

Receiv

er

Gain

10321.3

0S

W(c

ycli

cal)

(H

z)

17985.6

1S

olv

en

tC

HLO

RO

FO

RM

-dS

pectr

um

Off

set

(Hz)

7539.7

378

Sp

ectr

um

Typ

eS

TA

ND

AR

DS

weep

Wid

th (

Hz)

17985.0

6T

em

pera

ture

(d

eg

ree C

)25.1

60

14

13

15

18

16

17

CH

319

S 10

O 11

9

O 12

7

N 1

2

6

3

5

4

O 8

Fo

rmu

laC

14H

19N

O3S

FW

281.3

706

47

1H-NMR – 1-(azepan-1-yl)-2-diazoethanone (3c)

7.0

6.5

6.0

5.5

5.0

4.5

4.0

3.5

3.0

2.5

2.0

1.5

1.0

0.5

0

0 0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0


4.2

24.2

04.2

51.0

1

1.5

7(4

a,4

b,5

a,5

b)

1.7

1(3

a,3

b,6

a,6

b)

3.3

8(2

a,2

b,7

a,7

b)

5.0

7(1

0a)

5.3

6

Acq

uis

ition

Tim

e (s

ec)

5.3

084

Co

mm

en

t5 m

m

ÊËÌ

ÍÎÏÍÐËÏÍÑÒÏÑÍÌ

ÓÔÕÔÍÍÏÔÔÖÔ

Fre

qu

en

cy (M

Hz)

300.1

3N

ucle

us

1H

Nu

mb

er o

f Tra

nsie

nts

16

Orig

inD

PX

300

Orig

inal P

oin

ts C

ou

nt

32768

Po

ints

Co

un

t32768

Pu

lse S

eq

uen

ce

zg30

Receiv

er G

ain

80.6

0S

W(c

yclic

al) (H

z)

6172.8

4S

olv

en

tD

ICH

LO

RO

ME

TH

AN

E-d

2S

pectru

m O

ffset (H

z)

1853.4

263

Sp

ectru

m T

yp

eS

TA

ND

AR

DS

weep

Wid

th (H

z)

6172.6

5T

em

pera

ture

(deg

ree C

)25.1

60

N1

28

7

O9

10

3

6

N

+

11

H10a

N

-

12

5

4

H2a

H2b

H7a

H7b

H3a

H3b

H6a

H6b

H5a

H5b

H4a H4b

Fo

rmu

laC

8 H13 N

3 OF

W167.2

083

48

1-(azepan-1-yl)-2-diazoethanone (3c) – 13C-NMR & DEPT-135

170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0×ØÙÚÛÜÝÞ ßØÛàá âããÚä

-0.2

-0.1

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Norm

aliz

ed I

nte

nsity

X

27.25(5,4)27.51(4,5)

28.78(3,6)

46.15(10,7,2)47.76(2,7)

53.80

165.18(8)





N

1

28

7

O

9

103

6

N

+

11

H

10a

N

-

12

5

4

Formula C8H

13N

3O FW 167.2083

54 52 50 48 46 44 42 40 38 36 34 32 30 28 26 24 22åæçèéêëì íæéîï ðññèò

-1.0

-0.9

-0.8

-0.7

-0.6

-0.5

-0.4

-0.3

-0.2

-0.1

0

0.1

0.2

Norm

aliz

ed I

nte

nsity

From 13C óôõö÷øùú

27.25(5,4)27.51(4,5)

28.78(3,6)

46.04(7,2)

46.15(10)

47.72(2,7)





N

1

28

7

O

9

103

6

N

+

11

H

10a

N

-

12

5

4

Formula C8H

13N

3O FW 167.2083

49

HMQC (1J13C,1 H) – 1-(azepan-1-yl)-2-diazoethanone (3c)

Acq

uis

ition

Tim

e (s

ec)

(0.3

244, 0

.0092)

Co

mm

en

t5 m

m Q

NP

1H

/15N

/13C

/31P

Z08011/0

020

Fre

qu

en

cy (M

Hz)

(300.1

3, 7

5.4

7)

Nu

cle

us

(1H

, 13C

)O

rigin

DP

X300

Orig

inal P

oin

ts C

ou

nt

(512, 1

28)

Po

ints

Co

un

t(5

12, 1

024)

Pu

lse S

eq

uen

ce

hm

qcqf

So

lven

tC

D2C

l2S

pectru

m T

yp

eH

MQ

CS

weep

Wid

th (H

z)

(1575.2

0, 1

3952.8

4)

Fo

rmu

laC

8 H13 N

3 OF

W167.2

083

5.0

4.5

4.0

3.5

3.0

2.5

2.0

1.5

1.0

0.5

F2 C

hem

ical S

hift (p

pm

)

20

25

30

35

40

45

50

55


1.5

8, 2

7.4

6, 0

.94 (4

a, 4

)(4b, 4

)(5a, 5

)(5b, 5

)1.5

8, 2

7.2

, 0.9

2 (4

, 4)(4

b, 4

)(5a, 5

)(5b, 5

)

1.7

1, 2

8.7

5, 0

.67 (3

a, 3

)(3b, 3

)(6a, 6

)(6b, 6

)

5.0

8, 4

6.1

3, 0

.41 (1

0a, 1

0)

3.2

3, 4

7.7

1, 0

.17 (2

a, 2

)(2b, 2

)(7a, 7

)(7b, 7

)

3.5

5, 4

6.0

6, 0

.17 (2

a, 2

)(2b, 2

)(7a, 7

)(7b, 7

)

N1

28

7

O9

10

3

6

N+

11

H10a

N-

12

5

4

H2a

H2b

H7aH7

b

H3a

H3b

H6a

H6b

H5a

H5b H4

a

H4b

50

tert-butyl 4-(2-diazoacetyl)piperazine-1-carboxylate (3d) – 1H-NMR

6.5

6.0

5.5

5.0

4.5

4.0

3.5

3.0

2.5

2.0

1.5

1.0

0.5

0

00.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0


9.2

08.1

81.0

0

DIC

HLO

RO

ME

TH

AN

E-d

2

1.4

2(1

0,1

4,1

5)

3.3

6(2

a,2

b,3

a,3

b,5

a,5

b,6

a,6

b)

5.1

3(1

6a)

5.3

2

Acq

uis

itio

n T

ime (

sec)

5.3

084

Fre

qu

en

cy (

MH

z)

300.1

3N

ucle

us

1H

Ori

gin

Bru

ker

Ori

gin

al

Po

ints

Co

un

t32768

Po

ints

Co

un

t262144

Pu

lse S

eq

uen

ce

ZG

30

Sp

ectr

um

Off

set

(Hz)

1843.0

216

Sp

ectr

um

Typ

eS

TA

ND

AR

DS

weep

Wid

th (

Hz)

6172.8

4

N 4

3

2 1

6

5

11

16

O 12

N

+

17

N

-

18

7

O 13

O 89

10

14

15

H 16a

H 5b

H 6b

H 5a

H 6a

H 3b

H 2b

H 2a

H 3a

Fo

rmu

laC

12H

19N

3O

3F

W253.2

976

51

13C-NMR & DEPT-135 – tert-butyl 4-(2-diazoacetyl)piperazine-1-carboxylate (3d)

170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0ûüýþÿC�� üÿ�� þ�

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Norm

aliz

ed I

nte

nsity

DICHLOROMETHANE-d2

28.37(10,15,14)

43.89(2,3,5,6)46.48(16)

53.80

80.11(9)

154.64(7)164.95(11)





N

4

3

2

N

16

5

11

16

O

12

N

+

17

N

-

18

7

O

13

O

89

10

14

15

H

16a

Formula C11

H18

N4O

3FW 254.2856

48 46 44 42 40 38 36 34 32 30 28��

0

0.05

0.10

Norm

aliz

ed I

nte

nsity

From 13C ��

28.37(10,14,15)

43.83(2,3,5,6)

46.49(16)





N

4

3

2

N

16

5

11

16

O

12

N

+

17

N

-

18

7

O

13

O

89

10

14

15

H

16a

Formula C11

H18

N4O

3FW 254.2856

52

2-diazo-1-morpholinoethanone (3e) – 1H-NMR

7.0

6.5

6.0

5.5

5.0

4.5

4.0

3.5

3.0

2.5

2.0

1.5

1.0

0.5

0

00.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0


4.0

04.1

21.0

0

X

X

DIC

HLO

RO

ME

TH

AN

E-d

2

DC

M

5.3

35.3

25.0

5(9

a)

3.6

2(2

a,2

b,6

a,6

b)

3.3

6(3

a,3

b,5

a,5

b)

Acq

uis

itio

n T

ime (

sec)

5.3

084

Co

mm

en

t5 m

m Q

NP

1H

/15N

/13C

/31P

Z08011/0

020

Fre

qu

en

cy (

MH

z)

300.1

3N

ucle

us

1H

Nu

mb

er

of

Tra

nsie

nts

16

Ori

gin

DP

X300

Ori

gin

al

Po

ints

Co

un

t32768

Po

ints

Co

un

t32768

Pu

lse S

eq

uen

ce

zg30

Receiv

er

Gain

143.7

0S

W(c

ycli

cal)

(H

z)

6172.8

4S

olv

en

tD

ICH

LO

RO

ME

TH

AN

E-d

2S

pectr

um

Off

set

(Hz)

1842.8

103

Sp

ectr

um

Typ

eS

TA

ND

AR

DS

weep

Wid

th (

Hz)

6172.6

5T

em

pera

ture

(d

eg

ree C

)26.1

60

2

3 6

N 4 5

7O 8

9

O 1

H 2b

H 2a

H 3b

H 3a

H 6b

H 6a

H 5b

H 5a

N

+

10

H 9a

N

-

11

Fo

rmu

laC

6H

9N

3O

2F

W155.1

546

53

13C-NMR & DEPT-135 – 2-diazo-1-morpholinoethanone (3e)

170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0��!"#$% &�"'( )**!+

-0.1

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Norm

aliz

ed I

nte

nsity

X

DICHLOROMETHANE-d2

X

X44.41(5,3)

46.32(9)

53.80

66.85(6,2)

165.06(7)





2

3

6

N

4

5

7

O

8

9

O

1

N

+

10

H

9a

N

-

11

Formula C6H

9N

3O

2FW 155.1546

70 68 66 64 62 60 58 56 54 52 50 48 46 44 42 40,-./0123 4-056 788/9

-0.15

-0.10

-0.05

0

0.05

Norm

aliz

ed I

nte

nsity

From 13C :;<=>?@A

44.42(5,3)

46.33(9)

66.85(6,2)





2

3

6

N

4

5

7

O

8

9

O

1

N

+

10

H

9a

N

-

11

Formula C6H

9N

3O

2FW 155.1546

54

2-diazo-1-morpholinoethanone (3e) – HMQC (1J13C,1 H)

Acq

uis

itio

n T

ime (

sec)

(0.4

588,

0.0

092)

Co

mm

en

t5 m

m Q

NP

1H

/15N

/13C

/31P

Z08011/0

020

Fre

qu

en

cy (

MH

z)

(300.1

3,

75.4

7)

Nu

cle

us

(1H

, 13C

)O

rig

inD

PX

300

Ori

gin

al

Po

ints

Co

un

t(5

12,

128)

Po

ints

Co

un

t(5

12,

1024)

Pu

lse S

eq

uen

ce

hm

qcqf

So

lven

tC

D2C

l2S

pectr

um

Typ

eH

MQ

CS

weep

Wid

th (

Hz)

(1113.8

9,

13952.8

4)

Fo

rmu

laC

6H

9N

3O

2F

W155.1

546

5.2

5.1

5.0

4.9

4.8

4.7

4.6

4.5

4.4

4.3

4.2

4.1

4.0

3.9

3.8

3.7

3.6

3.5

3.4

3.3

F2 C

hem

ical S

hift

(ppm

)

35

40

45

50

55

60

65

70

75


3.6

2,

66.8

2,

0.9

3 (

2a,

2)(

2b,

2)(

6a,

6)(

6b,

6)

3.3

5,

44.4

, 0.4

9 (

3a,

3)(

3b,

3)(

5a,

5)(

5b,

5)

5.0

5,

46.3

4,

0.3

8 (

9a,

9)

2

3 6

N 4 5

7O 8

9

O 1

H 2b

H 2a

H 3b

H 3a

H 6b

H 6a

H 5b

H 5a

N+

10

H 9a

N-

11

55

1H-NMR – 2-diazo-1-(1,1-dioxido-4-thiomorpholinyl)ethanone (3f)

7.0

6.5

6.0

5.5

5.0

4.5

4.0

3.5

3.0

2.5

2.0

1.5

1.0

0.5

0

0 0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0


4.1

84.0

81.0

0

X

H2O

DIC

HLO

RO

ME

TH

AN

E-d

2

3.0

2(3

a,3

b,5

a,5

b)

3.8

7(2

a,2

b,6

a,6

b)

5.1

3(1

1a)

5.3

2

Acq

uis

ition

Tim

e (s

ec)

5.3

084

Co

mm

en

tP

RO

TO

N C

D2C

l2 D

: {UIO

\aasm

uk} 1

Fre

qu

en

cy (M

Hz)

300.1

3N

ucle

us

1H

Nu

mb

er o

f Tra

nsie

nts

16

Orig

inD

PX

300

Orig

inal P

oin

ts C

ou

nt

32768

Po

ints

Co

un

t32768

Pu

lse S

eq

uen

ce

zg30

Receiv

er G

ain

1448.2

0S

W(c

yclic

al) (H

z)

6172.8

4S

olv

en

tD

ICH

LO

RO

ME

TH

AN

E-d

2S

pectru

m O

ffset (H

z)

1842.8

202

Sp

ectru

m T

yp

eS

TA

ND

AR

DS

weep

Wid

th (H

z)

6172.6

5T

em

pera

ture

(deg

ree C

)25.1

60

N4

39

5

O10

11

2

6

S1

O7

O8

N

+

12

H11a

N

-

13

H3b

H3a

H5b

H5a

H2b

H2a

H6b

H6a

Fo

rmu

laC

6 H9 N

3 O3 S

FW

203.2

190

56

2-diazo-1-(1,1-dioxido-4-thiomorpholinyl)ethanone (3f) – 13C-NMR

170

160

150

140

130

120

110

100

90

80

70

60

50

40

30

20

10

0

0

0.0

5

0.1

0

0.1

5

0.2

0

0.2

5

0.3

0

Normalized IntensityD

ICH

LO

RO

ME

TH

AN

E-d

2

X

42.8

1(3

,5)

47.2

0(1

1)

52.4

2(2

,6)

53.8

0

165.1

3(9

)

Acq

uis

itio

n T

ime (

sec)

1.8

219

Fre

qu

en

cy (

MH

z)

75.4

7N

ucle

us

13C

Nu

mb

er

of

Tra

nsie

nts

990

Ori

gin

DP

X300

Ori

gin

al

Po

ints

Co

un

t32768

Po

ints

Co

un

t32768

Pu

lse S

eq

uen

ce

zgpg30

Receiv

er

Gain

13004.0

0S

W(c

ycli

cal)

(H

z)

17985.6

1

So

lven

tD

ICH

LO

RO

ME

TH

AN

E-d

2S

pectr

um

Off

set

(Hz)

7574.8

994

Sp

ectr

um

Typ

eS

TA

ND

AR

D

Sw

eep

Wid

th (

Hz)

17985.0

6T

em

pera

ture

(d

eg

ree C

)25.1

60

N 4

39

5

O 10

11

2

6

S 1

O 7

O 8

N

+

12

H 11a

N

-

13

Fo

rmu

laC

6H

9N

3O

3S

FW

203.2

190

57

1H-NMR – Crude 6-bromo-1-azabicyclo[3.2.0]heptan-7-one (5a)

11

10

98

76

54

32

10

0 0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0


0.0

715

0.3

447

0.4

974

0.4

929

CH

LO

RO

FO

RM

-d

J=

1.7

0 H

z

M01(d

,16a)

10.1

2(3

0a)

8.3

0(2

9a)

7.2

6

6.1

3(8

a)

6.0

6(8

a)

4.4

04.3

9

Acq

uis

ition

Tim

e (s

ec)

5.3

084

Co

mm

en

t5 m

m Q

NP

1H

/15N

/13C

/31P

Z08011/0

020

Fre

qu

en

cy (M

Hz)

300.1

3N

ucle

us

1H

Nu

mb

er o

f Tra

nsie

nts

16

Orig

inD

PX

300

Orig

inal P

oin

ts C

ou

nt

32768

Po

ints

Co

un

t32768

Pu

lse S

eq

uen

ce

zg30

Receiv

er G

ain

128.0

0S

W(c

yclic

al) (H

z)

6172.8

4S

olv

en

tC

HLO

RO

FO

RM

-dS

pectru

m O

ffset (H

z)

1847.3

009

Sp

ectru

m T

yp

eS

TA

ND

AR

DS

weep

Wid

th (H

z)

6172.6

5T

em

pera

ture

(deg

ree C

)25.1

60

Fo

rmu

laC

23 H

25 B

r3 N

2 O3

FW

617.1

682 (2

70.9

498+

190.0

378+

156.1

806)

N1

2

5

3

4

6 O7

8

Br

9

Br

10

H8a

H2a

H2b

H5b

H5a

H3a

H3b

H4b

H4a

H15a

N11

12

15

13

14

17

O19

16

Br

18

H16a

H12a

H12b

H13a

H13b

H14b

H14a

28

23

29

22

20

21

26

25

27

24

30

O31

H30a

H29a

H22a

H21a

H26a

H25a

H27a

H24a

trans-6

-bro

mo-1

-azabic

yclo

[3.2

.0]h

epta

n-7

-one

(cis

isom

er n

ot d

ete

cte

d)

58

Crude 7-bromo-1-azabicyclo[4.2.0]octan-8-one (5b) – 1H-NMR

11

10

98

76

54

32

10

00.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0


0.7

363

0.1

176

0.0

213

0.5

453

0.5

442

CH

LO

RO

FO

RM

-d

4.3

9(2

0a)

4.9

34.9

4(3

1a)

4.9

5

6.1

6(1

0a)

6.2

3(1

0a)

7.2

6

8.2

9(4

4a)

10.1

1(4

5a)

Acq

uis

itio

n T

ime (

sec)

5.3

084

Co

mm

en

tP

RO

TO

N C

DC

l3 D

: {U

IO\a

asm

uk}

2F

req

uen

cy (

MH

z)

300.1

3N

ucle

us

1H

Nu

mb

er

of

Tra

nsie

nts

16

Ori

gin

DP

X300

Ori

gin

al

Po

ints

Co

un

t32768

Po

ints

Co

un

t32768

Pu

lse S

eq

uen

ce

zg30

Receiv

er

Gain

101.6

0S

W(c

ycli

cal)

(H

z)

6172.8

4S

olv

en

tC

HLO

RO

FO

RM

-dS

pectr

um

Off

set

(Hz)

1847.6

909

Sp

ectr

um

Typ

eS

TA

ND

AR

DS

weep

Wid

th (

Hz)

6172.6

5T

em

pera

ture

(d

eg

ree C

)25.1

60

Fo

rmu

laC

32H

39B

r 4N

3O

4

FW

849.2

858

BDEFGEHFFIJKHGJLEHIDEFGEHFFIDLFGMNHOP

H 19a

N 13

14

19

18

21

O 23

20

Br

22

H 20a

H 14b

H 14a

H 18a

H 18b

17

15

H 17a

H 17b

H 15b

H 15a

43

38

44

37

35

36

41

40

42

39

45

O 46

H 45a

H 44a

H 37a

H 36a

H 41a

H 40a

H 42a

H 39a

H 30a

N 24

25

30

29

32

O 34

31

Br

33

H 31a

H 25b

H 25a

H 29a

H 29b

28

26

H 28a

H 28bH 2

6b

H 26a

N 1

2

7

8O 9

10

Br

11

Br

12

H 10a

H 2a

H 2b

H 7b

H 7a

6

3 4

H 6b

H 6a

H 3a

H 3b

H 4b

H 4a

59

1H-NMR – Crude 7-bromo-1-azabicyclo[4.2.0]octan-8-one (5b) without int. standard

5.5

5.0

4.5

4.0

3.5

3.0

2.5

2.0

1.5

1.0

0.5

0

0 0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

No rmalized In ten s ity

3.5

13.4

51.6

11.0

71.1

31.3

01.2

61.0

00.1

7

J=

1.0

4 H

z

J=

1.1

3 H

z

J=

1.6

0 H

z

J=

4.3

3 H

zJ=

4.4

3 H

z

J=

4.5

2 H

z

J=

4.4

7 H

z

J=

10.6

9 H

z

J=

11.7

7 H

z

J=

13.1

9 H

z

J=

13.4

7 H

z

M01(d

d,3

1a)

M02(d

,20a)

M04(d

dd,1

9a,3

0a)

M03(d

d,1

4a<

'>,2

5a<

'>)

18b,2

9b

M05(d

dd,1

4b<

'>,2

5b<

'>)

29a,1

8a

15a,1

5b,1

7a,1

7b,2

6a,2

6b,2

8a,2

8b

1.2

1

1.3

6

1.6

4

1.8

5

2.1

2

2.6

92.7

12.7

22.7

32.7

32.7

42.7

52.7

52.7

82.7

9

3.4

73.4

83.4

93.4

93.5

13.5

13.5

23.5

33.7

83.7

93.8

23.8

4

4.3

94.4

0

4.9

34.9

44.9

54.9

5

Acq

uis

ition

Tim

e (s

ec)

5.3

084

Co

mm

en

t5 m

m Q

NP

1H

/15N

/13C

/31P

Z08011/0

020

Fre

qu

en

cy (M

Hz)

300.1

3N

ucle

us

1H

Nu

mb

er o

f Tra

nsie

nts

16

Orig

inD

PX

300

Orig

inal P

oin

ts C

ou

nt

32768

Po

ints

Co

un

t32768

Pu

lse S

eq

uen

ce

zg30

Receiv

er G

ain

101.6

0S

W(c

yclic

al) (H

z)

6172.8

4S

olv

en

tC

HLO

RO

FO

RM

-dS

pectru

m O

ffset (H

z)

1847.3

009

Sp

ectru

m T

yp

eS

TA

ND

AR

DS

weep

Wid

th (H

z)

6172.6

5T

em

pera

ture

(deg

ree C

)25.1

60

Fo

rmu

laC

32 H

39 B

r4 N

3 O4

FW

849.2

858

(204.0

644+

156.1

806+

204.0

644+

284.9

763)

H19a

N13

14

19

18

21

O23

20

Br

22

H20a

H14b

H14a

H18a

H18b

17

15

H17a

H17b H1

5b

H15a

H30a

N24

25

30

29

32

O34

31

Br

33

H31a

H25b

H25a

H29a

H29b

28

26

H28a

H28b H2

6b

H26a

60

Crude 8-bromo-1-azabicyclo[5.2.0]nonan-9-one (5c) – 1H-NMR

11

10

98

76

54

32

10

00.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0


0.7

747

0.1

670

0.0

007

0.5

011

0.4

967

CH

LO

RO

FO

RM

-d

J=

0.9

4 H

z

J=

1.1

3 H

z

J=

1.7

0 H

z

J=

2.2

6 H

z

J=

4.7

1 H

z

M01(d

dd,3

1a)

M02(d

d,2

0a)

4.2

7

4.2

7

4.8

94.8

94.8

94.9

04.9

1

6.2

1(1

0a)

6.2

6(1

0a)

7.2

6

8.3

0(4

4a)

10.1

2(4

5a)

Acq

uis

itio

n T

ime (

sec)

5.3

084

Co

mm

en

t5 m

m Q

NP

1H

/15N

/13C

/31P

Z08011/0

020

Fre

qu

en

cy (

MH

z)

300.1

3N

ucle

us

1H

Nu

mb

er

of

Tra

nsie

nts

16

Ori

gin

DP

X300

Ori

gin

al

Po

ints

Co

un

t32768

Po

ints

Co

un

t32768

Pu

lse S

eq

uen

ce

zg30

Receiv

er

Gain

114.0

0S

W(c

ycli

cal)

(H

z)

6172.8

4S

olv

en

tC

HLO

RO

FO

RM

-dS

pectr

um

Off

set

(Hz)

1847.3

009

Sp

ectr

um

Typ

eS

TA

ND

AR

DS

weep

Wid

th (

Hz)

6172.6

5T

em

pera

ture

(d

eg

ree C

)25.1

60

Fo

rmu

laC

35H

45B

r 4N

3O

4

FW

891.3

655

(299.0

029+

218.0

910+

156.1

806+

218.0

910)

N 1

2

7

8O 9

10

Br

11

Br

12

H 10a

H 2a

H 2b

H 7b

H 7a

6

3

4

5

H 6b

H 6a

H 3a

H 3b

H 4b

H 4a

H 5a

H 5b

H 19a

N 13

14

19 1

8

21

O 23

20

Br

22

H 20a

H 14b

H 14a

H 18a

H 18b

17

15

16

H 17a

H 17b

H 15b

H 15a

H 16b

H 16a

43

38

44

37

35

36

41

40

42

39

45

O 46

H 45a

H 44a

H 37a

H 36a

H 41a

H 40a

H 42a

H 39a

H 30a

N 24

25

30 2

9

32

O 34

31

Br

33

H 31a

H 25b

H 25a

H 29a

H 29b

28

26

27

H 28a

H 28b

H 26b

H 26a

H 27b

H 27a

cis

-8-b

rom

o-1

-azabic

yclo

[5.2

.0]n

onan-9

-one

trans-8

-bro

mo-1

-azabic

yclo

[5.2

.0]n

onan-9

-one

61

1H-NMR – exo-8-bromo-1-azabicyclo[5.2.0]nonan-9-one (exo-5c)

7.5

7.0

6.5

6.0

5.5

5.0

4.5

4.0

3.5

3.0

2.5

2.0

1.5

1.0

0.5

0

0 0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0


4.1

93.1

21.0

12.0

60.9

81.0

0

CH

LO

RO

FO

RM

-d

QRSTSU

Hz

QRSTVW

Hz

QRXTYU

Hz

QRZT[S

Hz

M01(d

dd,7

a)

M02(d

d,8

a)

6b

3b,3

a,6

a

2a,2

b

4a,4

b,5

a,5

b

1.3

5

1.3

8

1.4

7

1.8

11.8

6

1.9

6

2.0

9

2.1

43.2

5

3.3

0

3.3

6

3.4

0

3.7

4

3.7

53.7

53.7

63.7

73.7

8

3.7

8

3.7

9

4.2

54.2

6

7.2

6

Acq

uis

ition

Tim

e (s

ec)

5.3

084

Co

mm

en

t5 m

m

\

]^

S_`Sa]`SUb`US^

cWYWSS`WWXW

Fre

qu

en

cy (M

Hz)

300.1

3N

ucle

us

1H

Nu

mb

er o

f Tra

nsie

nts

16

Orig

inD

PX

300

Orig

inal P

oin

ts C

ou

nt

32768

Po

ints

Co

un

t32768

Pu

lse S

eq

uen

ce

zg30

Receiv

er G

ain

101.6

0S

W(c

yclic

al) (H

z)

6172.8

4S

olv

en

tC

HLO

RO

FO

RM

-dS

pectru

m O

ffset (H

z)

1847.3

009

Sp

ectru

m T

yp

eS

TA

ND

AR

DS

weep

Wid

th (H

z)

6172.6

5T

em

pera

ture

(deg

ree C

)25.1

60

Fo

rmu

laC

8 H12 B

rNO

FW

218.0

910

326

N17

9

O11

8H8

aB

r

10

H7a

5

4

H3a

H3b

H2a

H2b

H6a

H6b

H5a

H5b

H4a

H4b

62

exo-8-bromo-1-azabicyclo[5.2.0]nonan-9-one (exo-5c) – 13C-NMR & DEPT-135


0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Norm

aliz

ed Inte

nsity

CHLOROFORM-d26.59(5)

27.24(4)

29.17(3)

33.70(6)

43.36(2)

45.69(8)

64.60(7)

77.00

162.52(9)

Acquisition Time (sec) 1.8219 Frequency (MHz) 75.48 Nucleus 13C Origin Bruker Original Points Count 32768 Points Count 65536

Pulse Sequence ZGPG30 Spectrum Offset (Hz) 7536.3345 Spectrum Type STANDARD Sweep Width (Hz) 17985.61

32

6

N

1

7

9

O

11

8

H

Br H

5

4

Formula C8H

12BrNO FW 218.0910

70 65 60 55 50 45 40 35 30 25 20 15 10 5 0Chemical Shift (ppm)

-1.0

-0.9

-0.8

-0.7

-0.6

-0.5

-0.4

-0.3

-0.2

-0.1

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

Norm

aliz

ed Inte

nsity

From 13C Spectrum

26.59(5)

27.24(4)29.17(3)

33.70(6)

43.36(2)

45.69(8)

64.60(7)

Acquisition Time (sec) 1.8219 Frequency (MHz) 75.48 Nucleus 13C Origin Bruker Original Points Count 32768 Points Count 65536

Pulse Sequence DEPT135 Spectrum Offset (Hz) 7536.2251 Spectrum Type DEPT135

Sweep Width (Hz) 17985.61

32

6

N

1

7

9

O

11

8

H

Br H

5

4

Formula C8H

12BrNO FW 218.0910

63

1H-NMR – endo-8-bromo-1-azabicyclo[5.2.0]nonan-9-one (endo-5c)

8.5

8.0

7.5

7.0

6.5

6.0

5.5

5.0

4.5

4.0

3.5

3.0

2.5

2.0

1.5

1.0

0.5

0

0 0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

No rmalized In ten s ity

5.0

45.1

22.1

51.0

41.0

0

CH

LO

RO

FO

RM

-d

J=

0.7

5 H

z

J=

1.7

9 H

z

J=

2.1

7 H

z

J=

4.6

6 H

z

J=

4.6

2 H

z

J=

10.1

3 H

zM

01(d

dd)

M02(d

dd,7

a)

3a,3

b,6

a,6

b4a,4

b,5

a,5

b

1.3

6

1.5

1

1.8

9

1.9

5

1.9

9

3.3

3

3.3

43.3

5

3.3

6

3.3

83.8

23.8

33.8

43.8

43.8

63.8

63.8

73.8

8

4.8

9

4.8

94.9

04.9

14.9

1

7.2

6

Acq

uis

ition

Tim

e (s

ec)

5.3

084

Co

mm

en

t5 m

m Q

NP

1H

/15N

/13C

/31P

Z08011/0

020

Fre

qu

en

cy (M

Hz)

300.1

3N

ucle

us

1H

Nu

mb

er o

f Tra

nsie

nts

16

Orig

inD

PX

300

Orig

inal P

oin

ts C

ou

nt

32768

Po

ints

Co

un

t32768

Pu

lse S

eq

uen

ce

zg30

Receiv

er G

ain

143.7

0S

W(c

yclic

al) (H

z)

6172.8

4S

olv

en

tC

HLO

RO

FO

RM

-dS

pectru

m O

ffset (H

z)

1847.1

124

Sp

ectru

m T

yp

eS

TA

ND

AR

DS

weep

Wid

th (H

z)

6172.6

5T

em

pera

ture

(deg

ree C

)26.1

60

326

N17

9

O11

8H8

aB

r

10

H7a

5

4

H3a

H3b

H2a

H2b

H6a

H6b

H5a

H5b

H4a

H4b

Fo

rmu

laC

8 H12 B

rNO

FW

218.0

910

64

endo-8-bromo-1-azabicyclo[5.2.0]nonan-9-one (endo-5c) – 13C-NMR & DEPT-135

160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0Chemical Shift (ppm)

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Norm

aliz

ed Inte

nsity

CHLOROFORM-d

exo

163.2

3(9

)

77.0

0

57.1

0(7

)

47.9

0(8

)

43.4

9(2

)

33.3

2(6

)

28.8

9(3

)28.1

4(4

)26.6

7(5

)





32

6

N

1

7

9

O

11

8H

BrH

5

4

Formula C8H

12BrNO FW 218.0910

exo exo

exo

exo exoexo

exo

65 60 55 50 45 40 35 30 25Chemical Shift (ppm)

-1.0

-0.9

-0.8

-0.7

-0.6

-0.5

-0.4

-0.3

-0.2

-0.1

0

0.1

0.2

0.3

0.4

Norm

aliz

ed Inte

nsity

From 13C Spectrum

exo

57.10(7)

47.91(8)

43.49(2)

33.32(6)

28.89(3)

28.14(4)

26.67(5)





Formula C8H

12BrNO FW 218.0910

32

6

N

1

7

9

O

11

8H

BrH

5

4

exo

exo exo exo exo exo

65

1H-NMR – Crude tert-butyl 7-bromo-8-oxo-1,4-diazabicyclo[4.2.0]octane-4-carboxylate (5d)

11

10

98

76

54

32

10

0

0.0

1

0.0

2

0.0

3

0.0

4

0.0

5

0.0

6

0.0

7

0.0

8

0.0

9

0.1

0

0.1

1

0.1

2

0.1

3

0.1

4

0.1

5


0.3

408

0.0

292

0.2

146

0.5

041

0.5

011

CH

LO

RO

FO

RM

-d

J=

1.1

3 H

z J=

1.3

2 H

z

J=

4.5

2 H

z

M02(d

,26a)

M01(d

d,4

3a)

10.1

1(6

3a)

8.2

9(6

2a)

7.2

6

6.2

1(1

6a)

6.1

3(1

6a)

4.9

44.9

44.9

34.9

2

4.5

04.4

9

Acq

uis

ition

Tim

e (s

ec)

5.3

084

Co

mm

en

t5 m

m Q

NP

1H

/15N

/13C

/31P

Z08011/0

020

Fre

qu

en

cy (M

Hz)

300.1

3N

ucle

us

1H

Nu

mb

er o

f Tra

nsie

nts

16

Orig

inD

PX

300

Orig

inal P

oin

ts C

ou

nt

32768

Po

ints

Co

un

t32768

Pu

lse S

eq

uen

ce

zg30

Receiv

er G

ain

90.5

0S

W(c

yclic

al) (H

z)

6172.8

4S

olv

en

tC

HLO

RO

FO

RM

-dS

pectru

m O

ffset (H

z)

1847.4

891

Sp

ectru

m T

yp

eS

TA

ND

AR

DS

weep

Wid

th (H

z)

6172.6

5T

em

pera

ture

(deg

ree C

)25.1

60

Fo

rmu

laC

44 H

60 B

r4 N

6 O10

FW

1152.5

974

(156.1

806+

386.0

802+

305.1

683+

305.1

683)

61

56

62

55

53

54

59

58

60

57

63

O64

H63a

H62a

H55a

H54a

H59a

H58a

H60a

H57aN4

3

5

11

O12

16

Br

17

Br

18

H16a

H3a

H3b

H5bH5

a

6

2N1

H6b

H6a

H2a

H2b7O8

O13

9CH

310

CH

315

CH

314

N22

21

23

25

O312

6

Br

32

H26a

H21a

H21b

H23a

24

20

N19

H24b

H24a

H20a

H20b2

7

O28

O33

29

CH

330

CH

335

CH

334

N39

38

40

42

O484

3

Br

49

H43a

H38a

H38b

H40a

41

37

N36

H41b

H41a

H37a

H37b4

4

O45

O50

46

CH

347

CH

352

CH

351

tert

tert

d T

he

efgehijekl

este

rsig

nal

is

mje

noo

toin

cre

ase

th

e

pqrqiqlqek

no

the o

ther s

ignals

66

Crude 7-bromo-4-oxa-1-azabicyclo[4.2.0]octan-8-one (5e) – 1H-NMR

11

10

98

76

54

32

10

00.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0


0.1

260

0.0

158

0.2

037

0.5

625

0.5

605

CH

LO

RO

FO

RM

-d

J=

1.3

2 H

zJ=

1.3

2 H

z

J=

4.5

2 H

z

M02(d

,19a)

M01(d

d,2

9a)

10.1

2(4

2a)

8.3

0(4

1a)

7.2

6

6.2

0(9

a)

6.1

2(9

a)

4.9

44.9

44.9

34.9

2

4.4

94.4

8

Acq

uis

itio

n T

ime (

sec)

5.3

084

Co

mm

en

t5 m

m Q

NP

1H

/15N

/13C

/31P

Z08011/0

020

Fre

qu

en

cy (

MH

z)

300.1

3N

ucle

us

1H

Nu

mb

er

of

Tra

nsie

nts

16

Ori

gin

DP

X300

Ori

gin

al

Po

ints

Co

un

t32768

Po

ints

Co

un

t32768

Pu

lse S

eq

uen

ce

zg30

Receiv

er

Gain

128.0

0S

W(c

ycli

cal)

(H

z)

6172.8

4S

olv

en

tC

HLO

RO

FO

RM

-dS

pectr

um

Off

set

(Hz)

1847.3

009

Sp

ectr

um

Typ

eS

TA

ND

AR

DS

weep

Wid

th (

Hz)

6172.6

5T

em

pera

ture

(d

eg

ree C

)25.1

60

Fo

rmu

laC

29H

33B

r 4N

3O

7

FW

855.2

042

(206.0

372+

156.1

806+

206.0

372+

286.9

492)

H 16a

N 15

14

16

17

18

O 20

19

Br

21

H 19a

H 14b

H 14a

H 17a

H 17b

O 12

13

H 13b

H 13a

40

35

41

34

32

33

38

37

39

36

42

O 43

H 42a

H 41a

H 34a

H 33a

H 38a

H 37a

H 39a

H 36a

H 26a

N 25

24

26

27

28

O 30

29

Br

31

H 29a

H 24b

H 24a

H 27a

H 27b

O 22

23

H 23b

H 23a

N 4

3

5

7O 8

9

Br

10

Br

11

H 9a

H 3a

H 3b

H 5b

H 5a

6

2 O 1

H 6b

H 6a

H 2a

H 2b

[4.2

.0]o

cta

n-8

-one

[4.2

.0]o

cta

n-8

-one

67

1H-NMR – Crude 7-bromo-4-thia-1-azabicyclo[4.2.0]octan-8-one 4,4-dioxide (5f)

11

10

98

76

54

32

10

0 0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0


0.1

478

0.0

397

0.1

265

0.6

157

0.6

105

CH

LO

RO

FO

RM

-d

J=

1.3

2 H

z J=

1.5

1 H

z

J=

4.7

1 H

z

M01(d

d,2

1a)

M02(d

,33a)

10.1

3(4

8a)

8.3

1(4

7a)

7.2

6

6.2

6(1

1a)

6.1

6(1

1a)

5.2

15.1

9

5.1

94.7

04.7

0

Acq

uis

ition

Tim

e (s

ec)

5.3

084

Co

mm

en

t5 m

m Q

NP

1H

/15N

/13C

/31P

Z08011/0

020

Fre

qu

en

cy (M

Hz)

300.1

3N

ucle

us

1H

Nu

mb

er o

f Tra

nsie

nts

16

Orig

inD

PX

300

Orig

inal P

oin

ts C

ou

nt

32768

Po

ints

Co

un

t32768

Pu

lse S

eq

uen

ce

zg30

Receiv

er G

ain

143.7

0S

W(c

yclic

al) (H

z)

6172.8

4S

olv

en

tC

HLO

RO

FO

RM

-dS

pectru

m O

ffset (H

z)

1847.3

009

Sp

ectru

m T

yp

eS

TA

ND

AR

DS

weep

Wid

th (H

z)

6172.6

5T

em

pera

ture

(deg

ree C

)25.1

60

Fo

rmu

laC

29 H

33 B

r4 N

3 O10 S

3

FW

999.3

974

(156.1

806+

335.0

136+

254.1

016+

254.1

016)

46

41

47

40

38

39

44

43

45

42

48

O49

H48a

H47a

H40a

H39a

H44a

H43a

H45a

H42a

O7

O8

N4

3

5

9 O10

11

Br

12

Br

13

H11a

H3a

H3b

H5b

H5a

6

2S1

H6b

H6a

H2a

H2b

O22

O23

H18a

N17

16

18

19

20

O24

21

Br

25

H21a

H16b

H16a

H19a

H19b

S14

15

H15b

H15a

O34

O35

H30a

N29

28

30

31

32

O36

33

Br

37

H33a

H28b

H28a

H31a

H31b

S26

27

H27b

H27a

cis

-7-b

rom

o-4

-thia

-1-a

zabic

yclo

[4.2

.0]

octa

n-8

-one

trans-7

-bro

mo-4

-thia

-1-a

zabic

yclo

[4.2

.0]

octa

n-8

-one

68

1,1,3,3-tetramethylguanidine sulfinate (and sulfonate) – 1H-NMR

10.0

9.5

9.0

8.5

8.0

7.5

7.0

6.5

6.0

5.5

5.0

4.5

4.0

3.5

3.0

2.5

2.0

1.5

1.0

0.5

0

00.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0


3.4

314.1

00.4

52.2

82.0

00.2

62.1

3

CH

LO

RO

FO

RM

-d

2a,3

a,5

a,6

a

12a,1

3a,1

5a,1

6a

12a,1

3a,1

5a,1

6a

2a,3

a,5

a,6

a

stsuvwxywzyw{y|wxy|wzy|w{}

stu~vs�xys�zys�{ys�xys�zys�{ys�xys�zys�{yswxyswzysw{}

3.8

7(2

8a,2

8b)

7.0

7

7.0

97.1

2

7.2

67.5

27.5

4

7.7

07.7

3

8.9

2(2

8a,2

8b)

Acq

uis

itio

n T

ime (

sec)

5.3

084

Co

mm

en

tP

RO

TO

N C

DC

l3 D

: {U

IO\a

asm

uk}

12

Fre

qu

en

cy (

MH

z)

300.1

3N

ucle

us

1H

Nu

mb

er

of

Tra

nsie

nts

16

Ori

gin

DP

X300

Ori

gin

al

Po

ints

Co

un

t32768

Po

ints

Co

un

t32768

Pu

lse S

eq

uen

ce

zg30

Receiv

er

Gain

114.0

0S

W(c

ycli

cal)

(H

z)

6172.8

4S

olv

en

tC

HLO

RO

FO

RM

-dS

pectr

um

Off

set

(Hz)

1846.7

491

Sp

ectr

um

Typ

eS

TA

ND

AR

DS

weep

Wid

th (

Hz)

6172.6

5T

em

pera

ture

(d

eg

ree C

)25.1

60

Fo

rmu

laC

19H

28N

3O

5S

2

FW

442.5

733

v|��t|w�u�|�|t|w�s�||�t|u�s}

2

13

64

59

S 7O 8

O

-

10

H 2a

H 3a

H 6a

H 5a

H 9a

H 9b

H w{

12

11

13

16

14

15

19

S 17

O 18

O

-

21

O 20

H 12a

H 13a

H 16a

H 15a

H 19a

H 19b

H |w{

H 28a

23

24

N 22

27

29

25

N

�

28

N 26

H 23aH 23b

H s�{

H 24a

H s�{

H 24b

H 27a

H s�{ H 2

7b

H 29a

H 29b

H sw{

H 28b

69

1H-NMR – 2,2-dibromo-1-(piperidin-1-yl)ethanone

9.5

9.0

8.5

8.0

7.5

7.0

6.5

6.0

5.5

5.0

4.5

4.0

3.5

3.0

2.5

2.0

1.5

1.0

0.5

0

0 0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0


6.0

24.4

21.0

0

Sig

nal p

resent in

all th

e

��

isola

ted

��

��

TLC

on

�� T

LC

pla

tes.

Possib

ly

��

��

the p

late

bonder.

Sig

nal p

resent in

all th

e

��

isola

ted

��

��

TLC

on

�� T

LC

pla

tes.

Possib

ly

��

��

the p

late

bonder.

CH

LO

RO

FO

RM

-d

3a,3

b,4

a,4

b,5

a,5

b

2a,2

b,6

a,6

b

1.6

3

1.6

7

3.5

6

3.5

83.6

13.6

5

6.1

4(9

a)

6.2

1(9

a)

7.2

6

Acq

uis

ition

Tim

e (s

ec)

2.9

999

Fre

qu

en

cy (M

Hz)

200.1

3N

ucle

us

1H

Nu

mb

er o

f Tra

nsie

nts

16

Orig

inD

PX

200

Orig

inal P

oin

ts C

ou

nt

12417

Po

ints

Co

un

t16384

Pu

lse S

eq

uen

ce

zg30

Receiv

er G

ain

2580.3

0S

W(c

yclic

al) (H

z)

4139.0

7

So

lven

tC

HLO

RO

FO

RM

-dS

pectru

m O

ffset (H

z)

1227.2

200

Sp

ectru

m T

yp

eS

TA

ND

AR

D

Sw

eep

Wid

th (H

z)

4138.8

2T

em

pera

ture

(deg

ree C

)25.1

60

34

25

N16

7 O8

9

Br

10

Br

11

H9a

H3a

H3b

H4a

H4b

H2a

H2b

H5a

H5b

H6a

H6b

Fo

rmu

laC

7 H11 B

r2 N

OF

W284.9

763

70

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