A Ring-Closing Strategy for the Synthesis of Î²,Î³ ...OH 11 12 ~ { R=CH(SEt)2 } I) PhCH2Br, NaH,...

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Masters Theses Student Theses & Publications

2001

A Ring-Closing Strategy for the Synthesis of β,γ-Unsaturated δ-LactonesErbing HuaEastern Illinois UniversityThis research is a product of the graduate program in Chemistry at Eastern Illinois University. Find out moreabout the program.

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Recommended CitationHua, Erbing, "A Ring-Closing Strategy for the Synthesis of β,γ-Unsaturated δ-Lactones" (2001). Masters Theses. 1454.https://thekeep.eiu.edu/theses/1454

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DATE

A Ring-Closing Strategy For the Synthesis of

~.y-Unsaturated 8-Lactones (TITLE)

BY

Erbing Hua

I '16..Y-

THESIS

SUBMITIED IN PARTIAL FULLMENT OF THE REQUIREMENTS

FOR THE DEGREE OF

Master of Science in Chemistry

IN THE GRADUATE SCHOOL, EASTERN ILLINOIS UNIVERSITY

CHARLESTON, ILLINOIS

2001 YEAR

I HEREBY RECOMMEND THAT THIS THESIS BE ACCEPTED AS FULFILLING

THIS PART OF THE GRADUATE DEGREE CITED ABOVE

to(t.ffo1 DATE I -;. 4

Abstract

Acknowledgment

List of Figures

Introduction

Results and Discussion

Summary

Experimental Section

References

Figures

Table of Contents

I

II

III

1

11

25

26

42

44

A ring-closing strategy for the synthesis of ~,y-unsaturated o-

lactones

Abstract

Spiro p,y-unsaturated 8-lactones and fused p,y-unsaturated 8-lactones

are integral to a large number of naturally occurring compounds exhibiting a

diverse range of biological activity. A new synthetic route to p,y-

unsaturated 8-lactones, consisting of a three-step sequence, has been

investigated for the synthesis of these kinds of pharmacological

intermediates. Ring closure of a P-hydroxy acid by dehydration, providing a

4-vinyl substituted P-lactone, and its ring expansion/rearrangement are the

two key steps in this protocol. The results have proved that this new method

is efficient and quite expeditious. One spiro and four fused p,y-unsaturated

8-lactones were synthesized through this protocol albeit in somewhat modest

yield for the two-carbon ring expansion.

HO 0

R':@O R2 __ ,..R" R"'

R"~R"'O O BF3 - R2

R' ~ R,

R(H)

I

Acknowledgement

I would like to thank my advisor, Dr. T. Howard Black, for his

professional academic guidance for my graduate research project and his

time for the careful revision of my thesis.

Also I thank my fellow group members for their generous assistance,

and I also would like to thank the faculty of chemistry department for their

help, especially Dr. Ellen A. Keiter and Dr. Barbara A. Lawrence for their

training on the 300 MHz and 60 MHz NMR spectrometers.

II

List of Figures

Figure 1: 1H NMR spectrum of cyclohexylideneacetaldehyde (69)

Figure 2: 1 H NMR spectrum of 1-acetylcyclopentene (78)

Figure 3: 1H NMR spectrum of 1-acetylcyclohexene (79)

Figure 4: 1H NMR spectrum of 1-acetylcycloheptene (80)

Figure 5: 1H NMR spectrum of 4-cyclohexylidene-3-hydroxy-2,

2-dimethylbutanoic acid (81)

Figure 6: IR spectrum of 4-cyclohexylidene-3-hydroxy-2, 2-dimethyl

butanoic acid (81)

Figure 7: 1H NMR spectrum of 4-cyclohexylidene-3-hydroxy-2-phenyl

butanoic acid (82)

Figure 8: IR spectrum of 4-cyclohexylidene-3-hydroxy-2-phenyl

butanoic acid (82)

Figure 9: 1H NMR spectrum of 4-cyclohexylidene-3-hydroxy-2-(1-

naphthyl)butanoic acid (83)

Figure 10: IR spectrum of 4-cyclohexylidene-3-hydroxy-2-(1-naphthyl)

butanoic acid (83)

Figure 11: 1 H NMR spectrum of 3-( 1-cyclopentenyl)-3-hydroxy-2, 2, 3-

trimethylpropanoic acid (84)

III

Figure 12: IR spectrum spectrum of 3-(1-cyclopentenyl)-3-hydroxy-2, 2,

3-trimethylpropanoic acid (84)

Figure 13: 1H NMR spectrum of 3-(1-cycloheptenyl)-3-hydroxy-2, 2, 3-


Figure 14: IR spectrum of 3-(1-cycloheptenyl)-3-hydroxy-2, 2, 3-


Figure 15: 1H NMR spectrum of 3-hydroxy-3-(1-hydroxycyclohexyl)-

3-methyl-2-phenylpropanoic acid (86)

Figure 16: IR spectrum of 3-hydroxy-3-(1-hydroxycyclohexyl)-


Figure 17: 1H NMR spectrum of 3-hydroxy-3-(1-hydroxycyclohexyl)-

3-methyl-2-(1-naphthyl)propanoic acid (87)

Figure 18: IR spectrum of 3-hydroxy-3-(1-hydroxycyclohexyl)-


Figure 19: 1H NMR spectrum of 3-hydroxy-3-(1-hydroxycycloheptyl)-


Figure 20: IR spectrum of 3-hydroxy-3-( 1-hydroxycycloheptyl)-


IV

Figure 21: 1H NMR spectrum of 4-(1-cyclopentenyl)-3, 3, 4-

trimethyloxetan-2-one (92)

Figure 22: IR spectrum of 4-(1-cyclopentenyl)-3, 3, 4-trimethyloxetan-

2-one (92)

Figure 23: 1H NMR spectrum of trans-4-cyclohexylidenemethyl-3-

phenyloxetan-2-one (90) after silica gel

Figure 24: 1H NMR spectrum of 3-(l-naphthyl)-l-oxaspiro[5, 5]-5-

undecene-2-one (97)

Figure 25: IR spectrum of 3-(l-naphthyl)-1-oxaspiro[5, 5]-5-

undecene-2-one (97)

Figure 26: 1H NMR spectrum of 3, 5, 6, 7, 8-pentahydro-3, 3, 4-

trimethyl-2H-pentenopyranone (98)

Figure 27: 13e NMR spectrum of 3, 5, 6, 7, 8-pentahydro-3, 3, 4-

trimethyl-2H-pentenopyranone (98)

Figure 28: IR spectrum of 3, 5, 6, 7, 8-pentahydro-3, 3, 4-trimethyl-2H-

pentenopyranone (98)

Figure 29: 1H NMR spectrum of 3, 5, 6, 7, 8, 9-hexahydro-3-phenyl-4-

methyl-2(3H)-benzopyranone (99)

Figure 30: 13e NMR spectrum of 3, 5, 6, 7, 8, 9-hexahydro-3-phenyl-4-


v

Figure 31: IR spectrum of 3, 5, 6, 7, 8, 9-hexahydro-3-phenyl-4-


Figure 32: 1H NMR spectrum of 3, 5, 6, 7, 8, 9-hexahydro-3-(1-

naphthyl)- 4-methyl-2(3H)-benzopyranone (100)

Figure 33: IR spectrum of 3, 5, 6, 7, 8, 9-hexahydro-3-(1-naphthyl)-4-


Figure 34: 1H spectrum of 3, 5, 6, 7, 8, 9, 10-heptahydro-3-phenyl-4-

methyl-2(3H)-heptenopyranone (101)

Figure 35: 13C NMR spectrum of 3, 5, 6, 7, 8, 9, 10-heptahydro-3-

phenyl-4-methyl-2(3H)-heptenopyranone (101)

Figure 36: IR spectrum of 3, 5, 6, 7, 8, 9, 10-heptahydro-3-phenyl-4-

methyl-2(3H)-heptenopyranone (101)

VI

" Introduction

Lactones (intramolecular esters) and their derivatives, which include~-,

y-, 8-, medium-ring, macrolides and spirolactones, play important biological

functional roles in many natural products such as flavors, fragrances and

antibiotics. For example, erythromycin A (1, Scheme 1) and vitamin C (2,

Scheme 1) are both naturally occurring lactones.

Scheme 1

0

H HO

..

(

1 2

Saturated and unsaturated 8-lactones are found as structural subunits in

a wide variety of natural products with diverse biological activities 1 such as

antitumor and antifungal properties, as well as antibiotic potential, 2 which

have resulted in a high level of interest in the development of novel synthetic

routes for their preparation. George A. O' Doherty and co-workers have

reported a flexible enantioselective synthesis of highly functionalized 5-

1

substituted a, P-unsaturated 8-lactones by applying Sharpless catalytic

asymmetric dihydroxylation to vinylfuran as the key step.3 The resulting

diols can be stereoselectively transformed into differentially protected 8-

lactones (Scheme 2). 2

Scheme 2

QH 0 ::

UbH TBSCI or PivCI Et3N, DMAP 3

QBz

BzCI, EtsN ~~o I DMAP (Y

P10

6

OH

1) NaBH.i, CeCI~

2) TBSCI or PivCI Et3N, DMAP

0

R Mn02 R P10 P10 8 9

9sz

R P10

7

P1 =TBS or Piv

Another stereoselective total synthesis of 5,6-disubstituted-5, 6-

5

dihydro-2H-pyran-2-one, the natural pyranoid C6-unit from D-glucose, has

also been reported (Scheme 3).1

2

a) Ac20, perchloric acid(70%) D-Glucose

b) Br2, red P, Zn dust

10

Scheme 3

8Ac 0 §

c) 0.005M H2S04, HgS04, Dioxane

AcO

OAc

AcO~HO. OH

11 12

~ { R=CH(SEt)2 } I) PhCH2Br, NaH, Bu4NI, DMF AcO ~ (s)

- R= g) NaOMe, MeOH OH S

e) 1,3-propanedithiol, BF3.0Et2, CHCl3

13 ox

~ I ,,,~ ,S) h) 4-methoxytritylchloride, Py xo/Y~

~ S i) Ac20, Py OBn

(X=COCH3

g)

X=H

14

z~) OBn

16

CZ= CH20H k) Z=CHO

OY

- ' _,,_ ,S) j) 0.01 N HCI XO~ O~ S k) (COCl)2. DMSO, Et3N, CH2Cl2 Bn

ex= MMTr; y = H i) X = MMTr; Y = COCH3

15

OBn

~) 17

m) 0.5N LiOH, THF/MeOH(2:1)

OBn

18

4-Hydroxycoumarins, medicinally important unsaturated bicyclic 8

lactones, were also made by Snieckus and co-workers through an anionic

carbamoyl Baker-Venkataraman rearrangement (Scheme 4).4' 5

3

Scheme 4

o-O~Et2 1. BuLi, ZnCl2 q;c,, 1. NaH, Heat QY( 0 ~ 0 2. R2CH2COCI 2 1 2. CF3C02H 2 #

PdCl2(PPh3)2 0 R2 = H, Me, Ph

DIBAL-H OH

19 20 21

p,y-Unsaturated B-lactones have been found in naturally occurring

compounds as an important functional group. 6' 7' 8 They may act as a

precursor for many compounds with biological activity such as polyhydroxy

amino acids (22, Scheme 5)9 and as building blocks to large molecules such

as compactin, for which the B-lactone functions as the pharmacophore unit

(23, Scheme 5). 10 Some p,y-unsaturated B-lactones such as FD-211 (24,

Scheme 5) have antitumor biological activity. 11

9H ~H2 ~ w

~C02H OH OH

22

Scheme 5

23

MeCH= H

24

There are some traditional synthetic routes for preparation of p, y-

unsaturated B-lactones. 3-(4'-Methoxyphenyl)-5-methyl-5-substituted-p,y-

unsaturated B-lactones were synthesized in low yields by condensing

4

Grignard reagents with P-(4-methoxyphenyl)-y-acetovinylacetic acid. 12 G.

Rousseau and co-workers obtained other p,y-unsaturated 8-lactones by the

reaction of ketene alkylsilyl acetals with ethyl propiolate in the presence of

TiC14 (Scheme 6). 13' 14

OMe

!=(,.~ 25

27

Scheme 6

Hc==ccooEt ~Tl~

COO Et

y/ 26 COOEt / PhCHOj

v-0\_ /~--Ph

COO Et

28

Although most fused p,y-unsaturated 8-lactones synthesized possess

aromatic rings, 15• 16 some fused p,y-unsaturated 8 lactones with non-aromatic

rings have also been obtained successfully. 17' 18' 19' 20 Lythgo's group has

prepared this kind of lactone, 17 and the same product was also achieved by

completely different starting materials and routes (Scheme 7). 18

5

Scheme 7

i) COOR

35%HCHO (Et0)2P(O)CH2COCI ROOC:o m Et3N HO 0 R=Me,Et (O)P(OEI),

29 30 31

NaHorKH ro CaCl2-DMSO )J) DME lert·C7H15SH 32 33

Furthermore, variously 8-substituted fused ~,y-unsaturated 8 lactones

have also been synthesized (Scheme 8). 19

Scheme 8

0 0 OH

~ -0 w ~ p-toluenesufonic acid CH3 ~ R R-CHO_.CH3 R benzene CH3 + LOA CH3 z 34 35 36 37

c:Hb"o ,:? R 1. LICH.--COOLI ~H3 c::H Tos-OH/benzene ~o 0 3 •cH ,:? R _____ H3C 2. Hydrolysis 3 heat ~ R

R=CH3 R=n·C4Ho R=l·C3H7 R=C•Hs

H3C E

38 39 40

The range of chemistry used for the preparation of unsaturated 8

lactones is broad, but ring-closing strategy has been firmly established as a

new route.21 Although the Black research group successfully developed

6

protocols for the synthesis of a variety of unsaturated y-lactones a few years

ago, the invention of effective syntheses of p,y-unsaturated 8-lactones is a

new challenge. Therefore, new synthetic routes to p,y-unsaturated 8-

lactones based on a substantial extension of the y-lactone protocol are being

investigated in his lab. Recent experimental results have indicated that this

protocol is quite expeditious, 11 and is generally more capable of placing

substituents on the lactone ring regioselectively than other methods, such as

the Reformatsky reaction of bromomethyl acrylate esters, in the synthetic

strategy.22 Formulation of this protocol is based mainly on the idea that a P-

lactone moiety appended to a vinyl group would undergo two-carbon ring

expansion to form p, y-unsaturated 8-lactones under the influence of a Lewis

acid such as magnesium bromide, boron trifluoride or titanium

tetrachloride.23 As illustrated in Scheme 9, when a P-lactone is treated with

a Lewis acid, the ionization should afford an allylic cation and lead to a two-

carbon expansion.

Scheme 9

A-l. 41 42 43 44

7

These kinds of ~-lactone precursors result from the condensation of a,

~-unsaturated aldehydes or ketones with the corresponding acetic acid

derivative dianions23 and then dehydration via benzensulfonyl chloride to

form ~-lactones (Scheme 10).

Scheme 10

R~H LOA + THF,·78°C 45 46 47

48

0

- ~ ·PhSOa H R2 ' H 1

55

8

One possible application of ~,y-unsaturated 8-lactones is an

asymmetric dihydroxylation reaction on the double bond of ~,y-unsaturated

8-lactones, which would, upon hydrolysis, afford a series of monosaccharide

acids by controlling the stereochemistry of substituents on the 8-lactone

ring.24

My graduate project was to synthesize regioselectively both spiro ~,y-

unsaturated 8-lactones (59, Scheme 11) and fused ~,y-unsaturated 8-lactones

(63, Scheme 12) through this protocol, employing a three-step sequence, by

selection of a, ~-unsaturated aldehyde and ketone starting materials.

OH O

O CHCHO ~ r\_ ~OH \_T l'R2. 56 57

Scheme 11

b

58

As for step a in Scheme 11, cyclohexylideneacetaldehyde

59

(56, Scheme 11) undergoes an aldol reaction with a carboxylic acid to give

the unsaturated ~-hydroxy acid (57). Step b of this reaction shows that the

unsaturated ~-hydroxy acid undergoes dehydration reaction to give vinyl~-

lactones (58) through ring closure. Step c indicates vinyl ~-lactone

9

ionization instigated by the Lewis acid catalyst boron trifluoride to give an

allylic cation stabilized by resonance, ready for two-carbon expansion to

form six-membered ring target compounds (59).

Scheme 12

0 0

.€f~ # b .fi ' CSX. - (CH,)., ~ R2 (C R1 60 61 62 63

Scheme 12 illustrates the same route to fused ~.y-unsaturated 8-

lactones; only different starting materials from those employed in Scheme

11 are utilized. As for Scheme 12, the starting materials, 1-acetylcyclo-

alkenes (five-, six-, seven-membered rings), are procured via the

condensation of cycloalkanones (five-, six-, seven-membered rings) with

sodium acetylide followed by an acid-catalyzed Rupe rearrangement. 25 The

experimental results will be discussed in detail in the main section.

10

Result and Discussion

1. Steroeselective Preparation of a, P-Unsaturated Aldehydes

The Wadsworth-Emmons reaction, for the conversion of ketones

and aldehydes into a, P-unsaturated aldehydes containing two additional

carbon atoms, illustrates an excellent, general method by using diethyl 2-

( cyclohexylamino )vinylphosphonate ( 67) as the two-carbon synthon. 26 In

general, this reaction proceeds stereoselectively, affording only the trans

isomer, with yields typically over 50%. The reaction sequence is

illustrated in Scheme 13.

Scheme 13

(Et0)3P

64 160 °c (66%)

(42%)

66

(Et0)2P(O)CH=CH-NH -0 67

(EtOl2P(O)CH2CH(OEt)2

65

MeOH (69%)

Oo NaH THF

H30+ 0 O CH-CH=N-o------- CHCHO Benzene (57%) 68 69

11

Bromoacetaldehyde diethyl acetal (64) underwent Michaelis-Arbuzov

reaction with triethylphosphite to produce diethyl 2,2-diethoxyethyl-

phosphonate (65), which was hydrolyzed to diethyl formylmethyl-

phosphonate (66). Diethyl formylmethylphosphonate (66) underwent

nucleophilic addition with cyclohexylamine to form diethyl 2-

( cyclohexylamino )vinylphosphonate (67), which is an excellent reagent for

the Wadsworth-Emmons reaction. Diethyl 2-(cyclohexylamino)-

vinylphosphonate (67), upon deprotonation with sodium hydride, underwent

Wadsworth-Emmons reaction with cyclohexanone to give the cyclohexyl

imine derivative of the product (68), which was hydrolyzed to the a, ~

unsaturated aldehyde cyclohexylideneacetaldehyde (69). This procedure has

several advantages over the Wittig reaction. The phosphonate anions are

more reactive than the neutral ylids and very easily react under standard

Wittig reaction conditions in situations under which normal Wittig ylids are

unreactive. Another is that a water-soluble phosphate by-product is easily

separated from the organic solvent to simplify the work-up procedure.

2. Rupe Rearrangement for a, ~-Unsaturated Ketones

a, ~-Unsaturated ketones are versatile intermediates in organic

synthesis. 27' 28 One of the most feasible routes to a, ~-unsaturated ketones is

12

the acid catalyzed rearrangement of alkynyl tertiary alcohols, which

proceeds through a dehydration-hydration sequence with enynes as

intermediates. By Rupe rearrangement, unsaturated ketones of varying ring

size were synthesized as follows (Scheme 14):

CH==CH

70

Scheme 14

CH..,.CNa

71

~OH (C~C=CH

75-77

n: 1 2 3

33% 46% 54%

Benzene

.~Na (C~ '-'=CH

72-74 (n=1-3)

78-80

n: 1 2 3

35% 50% 46%

Acetylene (70) was bubbled through liquid ammonia and reacted with

sodium to produce sodium acetylide (71), which underwent simple

nucleophilic addition to different size cyclic ketones to give products (72-

74). The products (72-74) were hydrolyzed to a-acetylenic alcohols (75-

77), which underwent Rupe rearrangement under the influence of

phosphorous pentoxide to form different ring-membered a, ~-unsaturated

ketones (78-80).

13

3. Regioselective Preparation of Vinyl ~-Lactones

There are many methods, working with variable degrees of success, for

the preparation of ~-lactones as objects of synthetic investigations. The

direct cyclization of a ~-hydroxy acid, using different cyclants such as acetic

anhydride, ethyl chlorformate, benzoyl chloride, and thionyl chloride all in

pyridine as solvent, gave ~-lactones in modest yields.29 In our study we

converted ~-hydroxy acids to ~-lactones by treatment with benzensulfonyl

chloride in pyridine at subambient temperature; its reaction mechanism is

shown in Scheme 10. Other cyclants, such as dicyclohexycarbodiimide

(DCC) and trifluoroacetic anhydride, were also considered but convenience

of work-up and availability of reagents made our choice the use of

benzensulfonyl chloride.

In order to attach various substituents to the a position of the target 8-

lactones, the preparation of suitably functionalized precursor ~-lactones is

necessary, which in turn come from regiochemically defined ~-hydroxy

acids. Much success has been realized in the regioselective synthesis of~

hydroxy acids as precursors of ~-lactones. We used three carboxylic acids

(isobutyric acid, phenylacetic acid and 1-naphthylacetic acid) to condense

with cyclohexylideneacetaldehyde (Scheme 15), 1-acetylcyclopentene and

14

1-acetylcycloheptene (Scheme 16) to regioselectively form ~-hydroxy acids.

As for the synthesis of ~-hydroxy acids, the reactions are known to favor the

formation of the threo diastereomers because of thermodynamic control in

this reaction. 30 Most products were solid and easily purified via

recrystallization. In addition, some ~,y-dihydroxy acids from 1-

acetylcyclohexene and 1-acetylcycloheptene were also produced, which

probably was due to acid-catalyzed double bond hydration during

acidification with concentration hydrochloric acid in the work-up. This is

inferred from the disappearance of peaks of protons of the double bond

within the rings of the products 86, 87, 88 (Scheme 17) in the 1 H-NMR

spectra (Figures 15, 17, 19).

/ OCHCHO

69

~

Scheme 15

0

>--ZoH

LOA, THF (70%) 81

0 OH O

Ph~OH., 0=·'''~,/\_0H LOA, THF( 23%) .,. f\'~h.

0

C10H1~0H LOA, THF (71 %)

15

83

IR(cm-1): 1697

IR(cm·\ 1704

Scheme 16

0 0

>-ZOH

OH O

oA O''~OH IR(cm·\ 1701 LOA, THF (77%) 78 84

0 0

oA >-ZoH OH O O·''~OH LOA, THF ( 94%) IR(cm·\ 1701 80 85

Scheme 17

0

OH~ Ph__)lDl:t., I 0''''" if h OH IR(cm·\ 1705 LOA, THF ( 85%)

0 86 QA 0 79 \ ~ OHO

C10H7 OH~ OH ·'' < OH IR(cm·\ 1704

LOA, THF (42%) H C10H7 87

0 0

d~~ QA Ph__)l Dl:t., '° OH IR(cm-1):1722 LOA, THF ( 85%) ff h 80 88

The ~-hydroxy acids and ~;y-dihydroxy acids thus obtained were

converted to ~-lactones via treatment with two equivalents of

benzenesulfonyl chloride in pyridine at 0 °C (Schemes 18, 19, 20).

16

82

83

OH O

O·''~OH 84

OH O O·''~OH

85

OH.r ),_ O·'''f .f'ih 'OH 86

OH.ct j a,,~_'oH Ff C10H1

87

OHOH o

O·''~OH 88

Scheme 18

PhS02CI

Pyridine{63%)

?----fo 0

O·''P"''I - 0:5< 89

IR(cm-1): 1817, 1735

IR(cm-1): 1767, 1745, 1709

IR(cm-1): 1737, 1708

Scheme 19

o-h( PhS02CI IR(cm-\ 1814 Pyridine(15%)

92

oM cx;xo PhS02CI -Pyridine(39%) 93 IR(cm·\ 1823, 1759

Scheme 20

PhS02CI

Pyridine (24%)

WO O .•''' 'II. --~O OH Ph H ~

Ph

94 IR(cm-1): 1811, 1756, 1704 w.o 0 0 PhS02CI O··''' 'II. -- (l~~H

Pyridine{42%) c,.H;H '-../l'-....c,.H7

PhS02CI

Pyridine (5%)

17

95 IR{cm-1): 1754

96 IR(cm-1): 1804, 1758, 1709

As for the synthesis of vinyl P-lactones from P-hydroxy acids or p,y-

dihydroxy acids, most products obtained were mixtures of vinyl P-lactones

and unsaturated 8-lactones due to the further rearrangement of vinyl P-

lactones induced by the ambient heat. No further isolation of the mixture

was made because the P-lactones are somewhat thermally labile and best

converted to the final target without delay. 30 At one point, we tried to isolate

one of the P-lactones (90, Scheme 18) through silica gel column

chromatography but failed; analysis of the isolated compound indicated that

the carbonyl stretching absorption was almost gone in the IR spectrum and

the 1H-NMR spectrum was consistent with the chemical shift of dienes, not

lactones (Figure 23).

The low yield of some P-lactones may be due to extraction with dilute

hydrochloric acid, which hydrolyzed them to acids, or due to warming up

above 5-10 °C, which may have decarboxylated the P-lactones to dienes

during the aqueous work-up of products. For example, the carbonyl

stretching absorption of acids was observed in the IR spectra of P-lactones

(90, 91, Scheme 18; 94, 96, Scheme 20), which could mostly be explained

by hydrolysis of the P-lactones. To solve this problem of low yield, a

possible optimization would be that the residual pyridine could be washed

away with 10% copper sulfate solution or removed at reduced pressure to

18

avoid extraction with dilute hydrochloric acid.29 In general, relatively stable

P-lactones have large substituents adjacent to the carbonyl group,30 which

may account for our results of order for yield: C10H7>Ph>CH3 (Scheme 18,

19, 20).

In the case of mixtures, the yield represented the sum of P-lactones and

8-lactones. The best identification of the components of mixtures came

mainly from IR spectra. The spectral characteristic of P-lactones is a

carbonyl stretching absorption at 1810-1840 cm-1 depending on substituents

at the a position of P-lactones.30 The carbonyl stretching of the unsaturated

8-lactones is at 1720-1760 cm-1 depending on the position of the double

bond in the 8-lactone ring. An a, p double bond reduces the carbonyl

absorption frequency, while unsaturation adjacent to ring oxygen atom (enol

lactone) increases it.31 Also, infrared spectroscopy is certainly a very useful

method to distinguish vinyl P-lactones from unsaturated 8-lactones.

Although most products of P-lactone-forming reactions were mixtures of P-

and 8-lactones, in one case, almost pure P-lactone (92, Scheme 19) was

obtained. It was a slightly yellow, sticky solid at room temperature, and its

proprieties are summarized in Table 1.

19

Table 1 Summary of Characterization Data of 92

Entry Rt (CH2Cli) IR (cm-1) (KBr) 1H-NMR (CD3Cl)

92 0.60 2964, 1814, 5.74 (broad, lH, vinyl proton), 2.49-

1470, 1375, 1.87 (m, 6H, cyclopentene protons),

1177 1.56 (s, 3H, CH3CO), 1.34, 1.24 (d,

6H, 2CH3 gem dimethyl)

4. Synthesis of Spiro and Fused Unsaturated 8-Lactones

Based on the previous investigation of the optimized conditions and

catalysts required for the rearrangement of ~-lactones to the target

unsaturated 8-lactones, 11 we chose the Lewis acid boron trifluoride rather

than magnesium bromide, zinc chloride, titanium tetrachloride and diethyl

aluminium chloride as an effective catalyst for the rearrangement. At this

point, one spiro and four fused unsaturated 8-lactones were synthesized

(Scheme 21, Scheme 22).

Scheme 21

91 97

20

Scheme 22

0 o .. ,H,,, 8F3 --Et20 6 (75%)

92 98

0··''11: 1

~ BF3 --Et20 7 1H 6 Ph H (15%) Ph 94 99

0-'ii; 1

BF3 --El20 ~o 7 H \\ (20%) 6 C10H7H 4 C10H1

95 100

o-M. BF3 --El20 (90%) Ph H 96 101

We now had successfully obtained the unsaturated o-lactones (97,

Scheme 21; 98, 99, 100, 101, Scheme 22); the mechanism of the key

rearrangement is based mainly on the three-step sequence mentioned in

Scheme 9, which entails the initial ionization of ~-lactones, subsequently

forming allylic cations ready for the two-carbon ring expansion. This

rearrangement process must be extremely rapid, otherwise isomeric

impurities would be obtained because the carbon at ring fusion may form the

Rand S configurations, resulting in the cis- and trans-isomers between the

hydrogen at ring fusion and the phenyl or naphthyl group a to the lactone

21

ring carbonyl. Theoretically, we could rule out the possibility of a concerted

dyotropic reaction for the ~-lactone rearrangements, like the dyotropic

rearrangement initially assumed by the Black group.30

By-products of ~-lactone rearrangement reactions may be partly due to

hydrolysis of the unsaturated C5-lactone products.32 We inferred that the

carbonyl group stretching absorption in the IR spectrum for crude

unsaturated C5-lactone products came mainly from the by-product diene acids

(104, 105, Scheme 23; 108, 109, Scheme 24). The suggested mechanism for

the by-products of spiro lactones and of fused lactones is shown in Scheme

23 and Scheme 24, respectively. Because of the initial ionization of the ~

lactones, carboxylate anion was the most likely base to remove adjacent

protons to form an alkene bond. 33 Whether this is an intra- or intermolecular

process would need to be further determined.

As for Schemes 23 and 24, route I for the production of dienoic acid

by-products seems the most likely, because the Black group has already

determinded that no a-protons of ~-lactones are involved in forming alkene

bonds. This is based on the study of the rearrangement of substituted spiro

~-lactones to provide ~,y-unsaturated carboxylic acids; in no case was any

conjugated alkene formed, which would have occurred via elimination of an

a-proton (Scheme 25). 33

22

Scheme 23

B:"'"" _ o tj~,:-1 ~C02H

Route/~R ___..~ /\ ,., 11° 103a 104 ~R (B: = carboxylate anion)

""~o - (\ __ ~-. C02H Route 2 _ + \__/ "'\, B..__)J R R

102

103b 105

Scheme 24

B:~~o C02H ~+ __..-A"

Ro

Probably the most potentially useful aspect of unsaturated 8-lactones is

the stereochemistry of their asymmetric centers, which is important for

pharmacological activities. Thus, the determination of the relative

stereochemistry between the protons at the 3- and 9-position (99, 100,

Scheme 22) or 3- and IO-positions (101, Scheme 22) for these fused

unsaturated 8-lactones will next be ascertained by employing nOe (nuclear

Overhauser effect) techniques. What will actually be measured is the mutual

enhancement between the proton at the ring fusion and a proton on the

phenyl or naphthyl ring a to the lactone ring carbonyl. These two entities

are in quite close proximity in the cis isomer, and very distant in the trans

case. This work will constitute a good project for future research.

24

Summary

A new protocol (three-step sequence) for the synthesis of p;y-

unsaturated o-lactones has been investigated, employing a, P-unsaturated

aldehydes or ketones and carboxylic acids as starting materials. The a, P-

unsaturated aldehydes or ketones themselves were also successfully

procured via multi-step synthesis. Using this new procedure, one spiro and

four fused p,y-unsaturated 0-lactones were obtained in modest yield.

Additionally, an almost pure vinyl P-lactone, the precursor to a o-lactone,

was also obtained, albeit in low yield.

Although this new protocol has already been proven to be quite

expeditious, additional work on the optimization of the reaction conditions,

including work-up conditions, will be expended; doing so should render our

new synthetic scheme an easier, more inexpensive, and faster preparation of

o-lactones for organic synthetic applications.

25

Experimental Section

Anhydrous solvents and isobutyric acid were purified via distillation

before use. Diethyl ether and tetrahydrofuran were freshly distilled from

sodium and benzophenone, diisopropylamine from barium oxide, and

pyridine and dichloromethane from calcium hydride under nitrogen.

Aldehydes and all ketones were prepared immediately before use.

All reactions were carried out under nitrogen unless otherwise

specified and glassware was dried in an oven at 120 °C for a minimum of 4

h. 1H-NMR spectra were recorded on 60 or 300 MHz FT-NMR

spectrometers using deuterated chloroform (CDCh) or acetone-d6 as solvents

and tetramethylsilane (TMS) as the internal standard. Chemical shifts are

reported downfield from TMS in parts per million (ppm) of the applied field.

Peak multiplicities are abbreviated as follows: singlet, s; broad, b; doublet,

d; triplet, t; quartet, q; multiplet, m. 13C-NMR spectra were recorded on a

GE QE-300 MHz FT-NMR spectrometer. Infrared spectra were recorded on

a Nicolet 360 FT-IR spectrophotometer. Melting points were obtained in

capillary tubes with a Thomas-Hoover capillary melting point apparatus and

are uncorrected. Thin-layer chromatographic (TLC) analyses were carried

out on Analtech silica gel GF chromatography plates using specified eluents;

visualization was effected by either ultraviolet light or by charring with

26

phosphomolybdic acid. Preparative column chromatography employed

Aldrich silica gel (70-230 mesh).

General Procedure for the Preparation of ~-Hydroxy Acids

An oven-dried, three-necked flask, equipped with a low-temperature

thermometer, nitrogen inlet, rubber septum, and magnetic stirring bar, was

charged with 35 mL of tetrahydrofuran (THF), followed by 3.31 g (4.6 mL,

32.8 mmol) of diisopropylamine. The solution was stirred and cooled to - 78

°C with an ethyl acetate-liquid nitrogen bath, and 20.5 mL of a 1.6 M

solution (32.8 mmol) of n-butyllithium in hexane was added over a 10-min

period. The resulting clear yellow solution of lithium diisopropylamide was

stirred at ca. -40 °C for 15 min, whereupon 16.4 mL of a 1.0 M solution

(16.4 mmol) of the acetic acid derivative in THF was added dropwise via

syringe over a 10-min period. The cooling bath was removed, and the

resulting mixture was stirred for 1 h, returning to room temperature. A 1.97

g (15.9 mmol) portion of cyclohexylideneacetaldehyde was added via

syringe, causing an exotherm to ca. 35 °C and a lessening of the yellow

color. Stirring at ambient temperature was continued for 16 h, at which

point the mixture was poured onto ca. 50 g of ice, the layers were separated,

and the aqueous phase was extracted twice with 20 mL of ether. The ether

27

extracts were discarded, the aqueous phase acidified with 6 N hydrochloric

acid, and the resulting mixture extracted with three 20-mL portions of ether.

The consolidated extracts were washed with brine, and dried over anhydrous

magnesium sulfate and filtered; the solvents were then removed under

reduced pressure to afford the crude product.

4-Cyclohexylidene-3-hydroxy-2, 2-dimethylbutanoic acid (81)

A slightly yellow oil was obtained in 70% yield via Kugelrohr

distillation (98-100 °C, 6 mm): IR (film) 2932(b), 1704, 1473, 1448, 1238,

1167, 1130, 1024, 1002 cm-1; 1H-NMR (CDCh) 8 5.173, 5.141 (d, lH, vinyl

proton), 4.531, 4.500 (d, lH, CHCOH), 2.222-2.121 (m, 4H, cyclohexane

2CHrC=C), 1.577 (broad, 6H, cyclohexane 3CH2 ~,yto C=C), 1.230-1.185

(q, 6H, 2CH3); TLC (MeOH/EtOAc 1: 3) Rr 0.73 (single spot).

4-Cyclohexylidene-3-hydroxy-2-phenylbutanoic acid (82)

A white solid was obtained in 23% yield via recrystallization from

EtOH/hexane: mp. 155-157 °C; IR (KBr) 3289, 2944, 2929, 2852, 1696,

1436, 1279, 1241, 987, 700 cm-1; 1H-NMR (acetone-d6) 8 7.769-7.155 (m,

SH, ArH), 4.983-4.845 (m, 2H, =CH, CHOH), 3.543, 3.511 (d, lH, PhCH),

1.928-1.740 (m, 4H, cyclohexane 2CHrC=C), 1.420-0.616 (m, 6H,

28

cyclohexane 3CH2 p,y to C=C); TLC (MeOH/EtOAc 1: 3) Rf 0.70 (single

spot).

4-Cyclohexylidene-3-hydroxy-2-(1-naphthyl) butanoic acid (83)

A white solid was obtained in 71 % yield via recrystallization from


1512, 1449, 1394, 1053, 775 cm-1; 1H-NMR (CDCh) o 8.030-7.244 (m, 7H,

Arlf), 4.566, 4.420 (d, lH, vinyl proton), 3.886-3.536 (q, lH, HCOH),

2.162-1.690 (b, 5H, 2CH2C=C, lHCAr), l.410-l.097(m, 6H, cyclohexane

3CH2 p,y to C=C); TLC (MeOH/EtOAc 1: 3) Rf 0.42 (single spot).

3-(1-Cyclopentenyl)-3-hydroxy-2, 2, 3-trimethylpropanoic acid (84)

A yellow oil was obtained in 77% yield via Kugelrohr distillation (88-

890C, 6mm): IR (film) 2952, 1701, 1472, 1392, 1283, 1157, 1101, 1052,

955, 910, 822 cm- 1; 1H-NMR (CDCh) o 5.715 (b, lH, vinyl proton), 2.394-

2.219 (m, 4H, cyclopentene 2CH2C=C), 1.423 (s, 3H, CH3COH), 1.286,

1.266 (d, 6H, 2CH3), 1.170 (s, 2H, cyclopentene CH2CH2C=C); TLC

(Et0Ac/CH3COOH 9.9: 0. 1) Rf 0.60 (single spot).

3-(1-Cycloheptenyl)-3-hydroxy-2, 2, 3-trimethylpropanoic acid (85)

A slightly yellow oil was obtained in 94% yield: IR (film) 2980, 2923,

2851, 1701, 1460, 1380, 1275, 1158, 1101, 1051, 847 cm- 1; 1H-NMR

(CDC13) o 6.127-5.901 (t, lH, cycloheptene vinyl proton), 2.187 (b, 4H,

29

2CH2C=C), 1.432 (s, 6H, 2CH3), 1.248-1.139 (m, 9H, cycloheptene 3CH2

~,y to C=C; CH3COH); TLC (MeOH/EtOAc 1: 3) Rf 0.62.

3-Hydroxy-3-(1-hydroxycyclohexyl)-3-methyl-2-phenylpropanoic acid

(86)

A slightly yellow oil was obtained in 85%: IR (film) 2933, 2858, 1705,

1601, 1496, 1453, 1414, 1353, 1283, 1236, 1161, 942, 702 cm-1; 1H-NMR

(CDCb) () 7.262 (m, 5H, ArH), 3.397, 3.362 (d, lH, PhCH), 1.602-1.369 (m,

13H, 5CH2, cyclohexane; CH3); TLC (EtOAc) Rf0.70.

3-Hydroxy-3-(1-hydroxycyclohexyl)-3-methyl-2-(1-naphthyl)propanoic

acid (87)

A white solid was obtained in 42% yield via recrystallization from

EtOH/hexane: mp. 49-52 °C; IR (KBr) 3048, 2932, 2855, 1704, 1596, 1511,

1448, 1396, 1353, 1160, 778 cm-1; 1H-NMR (CDCh) () 8.219-7.234 (m, 7H,

ArH), 4.064 (b, lH, ArCH), 2.547-2.912 (m, 3H, CH3COH), 1.618-0.883

(m, lOH, cyclohexane 5 CH2). TLC (MeOH/EtOAc 1: 3) Rf0.70 (single

spot).

3-Hydroxy-3-(1-hydroxycycloheptyl)-3-methyl-2-phenylpropanoic acid

(88)

A white solid was obtained in 85 % yield via recrystallization from


30

1435, 1380, 1290, 1161, 698 cm-1; 1H-NMR (CDCh) o 7.278 (s, 5H, ArH),

3.345 (s, lH, HCPh), 1.580-1.430 (m, 15H, cycloheptane 6CH2; CH3COH);

TLC (EtOAc) Rt 0.72 (single spot).

General Procedure for the Preparation of ~-Lactones

An oven-dried 25-mL Erlenmeyer flask was fitted with a rubber

septum and magnetic stirring bar and was charged with 10 mL of pyridine.

A 500-mg portion of ~-hydroxy acid was added, and the stirred solution was

cooled in an ice bath to 0 °C. Benzenesulfonyl chloride (two equivalents)

was added dropwise via syringe with stirring, and the resulting solution was

stored at 0 °C for 16 h. The resulting orange/red solution was poured onto

ca. 50 g of ice, and the mixture was extracted with three 15-mL portions of

ether. The consolidated extracts were sequentially washed with 10%

hydrochloric acid, ice-cooled 5% sodium hydroxide solution, water, and

finally brine. After being dried over anhydrous magnesium sulfate and

filtered, the solvents were removed under reduced pressure to afford the

crude product. At this step no further purification was attempted since the

intermediates are sensitive to silica gel and are thermally unstable.

31

4-Cyclohexylidenemethyl-3, 3-dimethyloxetan-2-one (89) (mixture with

C>-lactone)

A yellow oil was obtained in 63 % yield: IR (film) 2928, 2854, 1817,

1735, 1622, 1469, 1447, 1148, 1029, 981 cm-1; TLC (CH2Clz) Rf0.92, 0.65.

Trans-4-cyclohexylidenemethyl-3-phenyloxetan-2-one (90) (transformed

to C>-lactone)

A colorless oil was obtained in 76 % yield: IR (film) 3029, 2929, 2853,

1767, 1745, 1709, 1621, 1446, 1090 cm- 1; TLC (CH2Clz) Rf0.87, 0.64, 0.40.

Trans-4-cyclohexylidenemethyl-3-(1-naphthyl)oxetan-2-one (91)

(tr an sf armed to C>-lactone)


1737, 1708, 1621, 1447, 1187, 1039 cm-1; TLC (CH2Clz) Rf 0.92, 0.71, 0.42.

4-(1-Cyclopentenyl)-3, 3, 4-trimethyloxetan-2-one (92)

A slightly yellow sticky solid was obtained in 15 % yield via

recrystallization from EtOH/hexane: IR (KBr) 2964, 1814, 1177 cm- 1; 1H-

NMR (CDCh) () 5.747 (b, lH, vinyl proton), 2.493-1.873 (m, 6H,

cyclopentene protons), 1.569 (s, 3H, CH3CO), 1.342, 1.240 (d, 6H, 2CH3

gem methyl); TLC (CH2Clz) Rr 0.60.

4-(1-Cycloheptenyl)-3, 3, 4-trimethyloxetan-2-one (93) (mixture with C>-

lactone)

32


1823, 1723, 1759, 1446, 1173, 1126, 1030 cm- 1; TLC (CH2Ch) Rr 0.89,

0.60.

Trans-4-(1-cyclohexenyl)-4-methyl-3-phenyloxetan-2-one (94) (mixture

with 8-lactone)


2857, 1811, 1756, 1704, 1667, 1581, 1438, 1146, 1099, 1030 cm-1; TLC

(CH2Ch) Rr 0.92, 0.59.

Trans-4-(1-cyclohexenyl)-4-methyl-3-(1-naphthyl)oxetan-2-one (95)

(transformed to 8-lactone)


1754, 1597, 1511, 1447, 1385, 1357, 1174, 777 cm-1; TLC (CH2Ch) Rr

0.67, 0.61.

Trans-4-(1-cycloheptenyl)- 4-methyl-3-phenyloxetan-2-one (96) (mixture

with 8-lactone)


1758, 1709, 1452, 1136 cm-1; TLC (CH2Ch) Rt 0.46.

General Procedure for the Preparation of 8-Lactones

33

An oven-dried 50 ml three-necked flask equipped with a condenser, a

nitrogen inlet, and a stirring bar was cooled to room temperature under a

stream of nitrogen. Upon cooling, the flask was charged with 10 mL of

freshly distilled anhydrous ether and the ~-lactone in ether solution. The

resulting mixture was then cooled to 0 °C with an ice bath, whereupon boron

trifluoride etherate in diethyl ether (four equivalents) was added dropwise

and the mixture was stirred and warmed to room temperature under nitrogen

for 48 h. The reaction was terminated by recooling the reaction mixture to 0

°C with ice bath and slowly adding 10 mL of saturated aqueous sodium

chloride. The layers were separated and the aqueous layer was extracted

twice with 10 mL ether; the combined organic layers were dried over

magnesium sulfate, filtered, and the solvent was removed under reduced

pressure to afford the product.

3-(1-N aphthyl)-1-oxaspiro[ 5, 5]-5-undecene-2-one (97)

A pink oil was obtained in 23 % yield via silica gel column

chromatography: IR (film) 3066, 2986, 2933, 1734, 1448, 1357, 1188, 1094,

1004, 918 cm-1; 1H-NMR (CDCb) () 7.980-7.512 (m, 7H, ArH), 4.545-3.714

(m, 3H, HC=CH, HCAr), 2.469-0.530 (m, lOH, 5CH2, cyclohexane); TLC

(CH2Ch) Rt 0.67 (single spot).

3, 5, 6, 7, 8-Pentahydro-3, 3, 4-trimethyl-2H-pentenopyranone (98)

34

A colorless oil was obtained in 75 % yield: IR (film) 2970, 2872, 1732,

1468, 1378, 1288, 1244, 1138, 1109 cm-1; 1H-NMR (CDCb) 8 4.954 (b, lH,

HCO), 2.73(b, 3H, CH3), 1.887-1.562 (m, 6H, cyclopentane proton), 1.324,

1.187 (d, 6H, gem dimethyl); 13C-NMR (CDCb) 8 177.586 (lC, carbonyl

carbon), 134.120 (ring fusion vinyl carbon, C-9), 130.232 (ring fusion vinyl

carbon, C-4), 79.864 (ring fusion tertiary carbon, C-8), 41.562 (quaternary

carbon, C-3), 33.620 (C-5), 27.083 (C-7), 23.923 (gem dimethyl), 21.112 (C-

6), 14.797 (CH3); TLC (CH2Clz) Rf 0.38 (single spot).

3, 5, 6, 7, 8, 9-Hexahydro-3-phenyl-4-methyl-2(3H)-benzopyranone (99)


1496, 1453, 1385, 1179, 700 cm-1; 1H-NMR (CDCb) 8 7 .238 (m, 5H, ArH),

4.008, 3.982 (d, lH, HCO), 2.500 (b, lH, HCPh), 1.924 (s, 3H, CH3), 1.729

(m, 2H, H2CC=C, cyclohexane), 1.244-0.861 (m, 6H, cyclohexane); 13C-

NMR (CDC13) 8 169.766 (lC, carbonyl carbon), 135.635 (ring fusion vinyl

carbon, C-10), 133.729 (ring fusion vinyl carbon, C-4), 130.149 (2C, Ar-

meta), 129.829 (lC, Arc-1), 128.971 (2C, Ar-ortho), 128.033 (lC, Ar-para),

114.553 (ring fusion tertiary carbon, C-9), 50.513 (quaternary carbon, C-3),

41.651(C-5),29.714 (C-8), 27.612 (C-6), 26.250 (C-7), 15.744 (CH3); TLC

(CH2Clz) Rf 0.42 (single spot).

35

3, 5, 6, 7, 8, 9-Hexahydro-3-(1-naphthyl)-4-methyl-2(3H)-

benzopyranone (100)

A slightly yellow oil was obtained in 20 % yield: IR (film) 2928, 2855,

I 737, I597, I447, I360, I I58, 777 cm-1; 1H-NMR (CDCh) 8 7 .565 (m, 7H,

ArH), 4.055 (m, IH, HCO), 2.684-2.299 (m, IH, HCAr), 1.996 (s, 3H, CH3),

1.2IO (m, 8H, cyclohexane); TLC (CH2Ch) Rf 0.56 (single spot).

3, 5, 6, 7, 8, 9, 10-Heptahydro-3-phenyl-4-methyl-2(3H)-

heptenopyranone (101)

A colorless oil was obtained in 90 % yield: IR (film) 2922, 2852, I 75 I,

I497, I453, I386, II40, 700 cm-1; 1H-NMR (CDCh) 8 7.336 (m, 5H, ArH),

4.037-3.753 (dd, IH, HCO), 2.327 (b, 3H, H2CC=C, cyclohexane; HCPh),

1.958 (s, 3H, CH3), 1.788 (b, 8H, 4CH2, cyclohexane); 13C-NMR (CDCh) 8

I 70.3 I6 (IC, carbonyl carbon), I43.479 (ring fusion vinyl carbon, C-I 1),

I35.86I (ring fusion vinyl carbon, C-4), 130.379 (2C, Ar-meta), I29.279

(IC, Arc-I), I28.797 (2C, Ar-ortho), 127.890 (IC, Ar-para), 118.543 (ring

fusion tertiary carbon, C-IO), 51.5I9 (quaternary carbon, C-3), 42.840 (C-5),

29.385 (C-9), 29.030 (C-6), 27.470 (C-8), 27.274 (C-7), 15.935 (CH3); TLC

(CH2Ch) Rf 0.48 (single spot).

General Procedure for Preparation of a, ~-Unsaturated Aldehydes

36

A. A 2-1. three-necked, round-bottomed flask fitted with a magnetic

stirrer, dropping funnel, and nitrogen inlet was charged with 245 g (1.24

mol) of bromoacetaldehyde diethyl acetal under a gentle stream of nitrogen.

A 189 g (l.14 mol) portion of triethyl phosphite was added dropwise over a

30-minute period at 110-120 °C. The mixture was stirred for 3 hat 160 °C.

The ethyl bromide by-product was collected with a condenser and a receiver

cooled in an ice bath. The low-boiling material first distilled at 25-30 °C

under water aspirator vacuum. The residual oil was fractionated under

reduced pressure, and fraction boiling at 112-116 °C ( 1.4 mm) was collected

as diethyl 2,2-diethoxyethylphosphonate, yielding 191 g (66 %).

B. A mixture of 150 g (0.59 mol) of diethyl 2,2-diethoxyethyl-

phosphonate and 523 mL of 2% hydrochloric acid was refluxed for 10

minutes. To the cooled mixture at room temperature was added 187 g of

sodium chloride, and the resulting mixture was extracted with three 390 ml

portions of dichloromethane. The combined organic extracts were washed

successively with 30 ml of 5% aqueous sodium hydrogen carbonate solution

and 250 ml of saturated sodium chloride solution, dried over anhydrous

sodium sulfate, and distilled at 60-70 °C under water aspirator vacuum. The

residue was fractionated under reduced pressure, and the fraction boiling at

37

108-110 °C (3.4 mm of Hg) was collected as diethylformylmethyl-

phosphonate, yielding 45.6 g (42 %).

C. A 1-1., two-necked, round-bottomed flask fitted with a magnetic

stirrer, dropping funnel and nitrogen inlet was charged with 59 g (0.32 mol)

of diethyl formylmethylphosphonate and 260 ml of dry methanol. A 32.5 g

(0.328 mol) portion of cyclohexylamine was added to the stirred solution

over a five-minute period at a temperature range of 0-5 °C, maintained with

an ice bath. The mixture was stirred for additional 10 minutes at room

temperature, and then the methanol was distilled from the mixture under

reduced pressure (10-35 mm of Hg) at a water bath temperature of 25-30 °C.

The residue was dissolved in 300 ml of dry ether, dried over anhydrous

potassium carbonate ( 45 g) overnight, and evaporated to dryness. The

residual oil was fractionated under reduced pressure in the presence of 250

mg of anhydrous potassium carbonate, and the fraction boiling at 138-144

°C (0.15 mm) was collected as diethyl 2-( cyclohexylamino )-

vinylphosphonate, yielding 58.5 g (69 % ).

D. A 500-ml, three-necked, round-bottomed flask fitted with a

magnetic stirrer, dropping funnel and nitrogen inlet was charged with 2.58 g

(0.067 mol) of sodium hydride (60% oil dispersion) and 30 ml of dry

38

tetrahydrofuran. The solution of 17.4 g (0.067 mol) of diethyl 2-

( cyclohexylamino )vinylphosphonate in 80 ml of dry tetrahydrofuran was

added dropwise to the stirred mixture over a period of 15 minutes at a

temperature range of 0-5 °C with an ice bath. The mixture was stirred for an

additional 15 minutes to ensure complete reaction. A solution of 6.04 ml

(0.065 mol) of cyclohexanone was added with syringe over a period of 20

minutes without temperature over 5 °C. The mixture was stirred for

additional 90 minutes at room temperature with water bath. The resulting

mixture was poured into 300 ml cold water and extracted with three 160 ml

portion of ether. The combined ether extracts were washed twice with 150

ml of saturated aqueous sodium chloride solution, dried over anhydrous

sodium sulfate, filtered, and distilled under water aspirator vacuum. The

residue was dissolved in 160 ml dry benzene and transferred to a 2-1., three-

necked, round-bottomed flask equipped with a stirrer and a reflux condenser.

A solution of 44 g of oxalic acid dihydrate in 550 ml of water was then

added. The stirred mixture was refluxed for 2 h under nitrogen, cooled, and

transferred to a separatory funnel. The aqueous layer was extracted with two

160 ml portions of ether. The combined organic extracts were washed with

120 ml of water, then with 120 ml of saturated aqueous sodium chloride

solution, dried over anhydrous sodium sulfate, and filtered; the solvent was

39

then removed under reduced pressure at 25-30 °C by water aspirator. The

residue was fractionated under reduced pressure, and the fraction boiling at

78-84 °C (12 mm of Hg) was collected to afford 4.6 g (57 % ) of

cyclohexylideneacetaldehyde. The 1H-NMR spectra of all isolated products

were in accord with those of authentic samples. 26• 27

General Procedure for Preparation of a, ~-Unsaturated Ketones

A. A 2-1. three-necked, round-bottomed flask with a mechanical stirrer

was charged with 1 1. of liquid ammonia, and a rapid stream of dry acetylene

was passed through a gas inlet tube while 9.3 g (0.404 mol) of sodium was

added over 30 minutes, whereupon 35.7 ml (0.403 mol) of cyclopentanone

was added dropwise over about 1 h. The reaction mixture was allowed to

stand for about 20 h to permit the evaporation of nearly all the ammonia.

The solid residue was dissolved in approximately 200 ml of ice water, and

the resulting mixture was acidified with 50% sulfuric acid. The mixture was

extracted with two portions of 30 ml of ether, and the combined extracts

were washed with 30 ml of brine, and finally dried over anhydrous

magnesium sulfate and filtered. The ether was removed at 25-30 °C under

reduced pressure by water aspirator. The residue was fractionated under

40

reduced pressure, and the fraction collected at 61-65 °C ( - 30 mm) provided

14.6 g (33%) of 1-ethynyl-1-cyclopentanol.

B. A 250 ml round-bottomed flask fitted with a reflux condenser was

charged with 13.8 g (0.125 mol) of 1-ethynylcyclopentanol, 100 ml of dry

benzene, 4.0 g (0.028 mol) of phosphorus pentoxide, and a boiling chip. The

mixture was refluxed for 2.5 h in an oil bath, and then cooled. The benzene

was decanted from the phosphorus pentoxide and washed once with 30 ml of

5% sodium bicarbonate solution, then dried over 5.0 g of anhydrous sodium

sulfate, and filtered. The benzene was removed by distillation at

atmospheric pressure. The residue was fractionated at reduced pressure, and

the fraction collected at about 30 °C (-2 mm of Hg) provided 4.8 g (35%) of

1-acetyl-1-cyclopentene. The 1H-NMR spectra of all isolated products were

in accord with those of authentic samples. 25 ' 28

41

References:

1. Hassan, H. H. A. M.; Rahman, M. M.A. Synth. Commun. 2000, 30(2), 201.

2. Harris, J.M.; O'Doherty, G. A. Tetrahedron Lett. 2000, 41, 183.

3. Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B. Chem. Rev. 1994, 94, 2483.

4. Kalinin, A. V.; da Sliva, A. J.M.; Lopes, C. C.; Lopes, R. S. C.; Snieckus, V.

Tetrahedron Lett. 1998, 39, 4995.

5. Kalinin, A. V.; Snieckus, V. Tetrahedron Lett. 1998, 39, 4999.

6. Miller, J.M.; Oehlschlager, A. C.; Wong, J.M. J. Org. Chem. 1983, 48, 1.

7. Oehlschlager, A. C.; Wong, J.M.; Vengin, V. G.; Pierce, H. D. J. Org. Chem. 1983,

48, 5009.

8. Toshikazu, H.; Yoshimi, F.; Ken, K.; Yoshiki, O.; Toshio, A. J. Org. Chem. 1986, 51,

2830.

9. Campbell, M. M.; Floyd, A. J.; Lewis, T.; Mahon, M. F.; Ogivie, R. G. Tetrahedron

Lett. 1989, 30, 1993.

10. Rosen, T.; Heathcock, C.H. Tetrahedron 1986, 42, 4909.

11. Xiong, L. M.S. Thesis, EIU, 1997.

12. Kulkarini, R. A.; Gawand, V. G.; Kolli, M. S.; Palekar, A. D. Indian J. Chem. 1968,

6,492.

13. Quendo, A.; Ali, S. M.; Rousseau, G. J. Org. Chem. 1992, 57, 6890.

14. Quendo, A.; Rousseau, G. Tetrahedron Lett. 1988, 29, 6443.

15. Bowden, K.; Byrne, J.M. J. Chem. Soc, Perkin Trans. 2, 1996, 9, 1921.

16. Shishido, K.; Shitara, E.; Fukumoto, K.; Kametani, T. J. Am. Chem. Soc. 1985,

107, 5810.

42

17. Forsch, J. V.; Harrison, I. T.; Lythgoe, B. J. Chem. Soc., Perkin Trans. 11974, 2005.

18. Yoshisuke, T.; Akiko, I.; Saho, T.; Shinzo, H.; Kimiaki, I.; Kunihiko, M. Chem.

Pharm. Bull. 1991, 39, 2797.

19. Reuvers, T. A.; DeGroot, A. E. Synthesis 1982, 12, 1105.

20. Falbe, J.; Weitkamp, H.; Korte, F. Tetrahedron 1963, 19, 1479.

21. Collins, I. J. Chem. Soc., Perkin Trans. 1, 1999, 1377.

22. Rucker, G.; Gajewski, W. Eur. J. Med. Chem.-Chim. Ther. 1985, 20, 87.

23. Black, T. H. Trends Heterocycl. Chem. 1993, 3, 275.

24. Black, T. H. http://www.uxLeiu.edu/-cfihh/research/research.htm.

25. Olah, G. A.; Fung, A. P. Synthesis 1981, 6, 473.

26. Nagata, W.; Wakabayashi, T.; Hayash, Y. Org. Synth. Coll. Vol. VI, 448.

27. Alderley, J.B.; Burkhardt, G. N. J. Chem. Soc. 1938, 545

28. Swaminathan, S.; Narayanan, K. V. Chem. Rev. 1971, 71, 429.

29. Adam, W.; Baeza, J.; Liu, J.-C. J. Am. Chem. Soc. 1972, 94, 2000.

30. Black, T. H.; DuBay III, W. J.; Tully, P. S. J. Org. Chem. 1988, 53, 5922.

31. Silverstein, RM.; Bassler, G.C.; Morrill, T.C. Spectrometric Identification of

Organic Compounds, Fourth Edition, John Wiley & Sons, Inc.: (New York), 1981.

32. Edward, J. T.; Cooke, E.; Paradellis, T. C. Can. J. Chem. 1982, 60, 2546.

33. Black, T. H.; Maluleka, S. L. Tetrahedron Lett. 1989, 30, 53 l.

43

Figure 1: 1H NMR spectrum of cyclohexylideneacetaldehyde (69)

117

O=CHCHO

0.83

10 8 6 4 2 PPM

fi!r. USER: ·; d< -- DATE: Fl: 60.010 SW!: 1000 OF!: 376.l PTSld: 4096 EX: PW:O. usec PD: 0.0 ec N : 1 LB:O. Wi Nuts - nmr·un!Lj

Figure 2: 1H NMR spectrum of 1-acetylcyclopentene (78)

0

o~

/~

7 6 5 4 3 2 1 PPM

ii!C U ER: o:d< -- DATE: Fl: 60.010 PTSld: 40 6

w·nNut - n rau 0 24

Figure 3: 1H NMR spectrum of 1-acetylcyclohexene (79)

0

o~

7.80

___./Too

f84

7 6 5 4 3 2 PPM

fill' USER: --

Figure 4: 1H NMR spectrum of 1-acetylcycloheptene (80)

.79

7 6 5 4 3 2 PPM

ni--· Fl: 60.010

A: I LB:O.

~

>-< rn w

" H

Figure 5:

1H N

MR

spectrum of 4-cyclohexylidene-3-hydroxy-2,

2-dimethylbutanoic acid (81)

O,,JH J r~

'oH

J

1~( I!( I~( l!I

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ppm

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4 -.--,-

2 0

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NAME

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arameters

Date

20000814 T

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2. 6542580 sec

574. 7 81. 000 usec

6.00 usec 300. 0 K

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sec 7 .SO

usec 6.00 usec

300 .1317708 MHz

lH

0. 00 dB

F2 -

Processing param

eters SI

16384 SF

300 .1300041 MHz

WDW SSS LB GB PC

EM 0

0. 30 Hz

0 1.00

lD NM

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t parameters

ex 20. oo

cm

CY 12.50 cm

F

lP

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Fl

3001. 30 Hz

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F2

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PPMCM

0. 55000 ppm

/cm

HZCM

165. 07150 H

z/cm

65 --1--"~~";;1~/J,\ F

igure 6: IR spectrum

of 4-cyclohexylidene-3-hydroxy-2, 2-dimethyl-

butanoic acid (81)

60-I \ I

~r-~

I I I,

_j

55

I 5

0-

I

I \v{

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lo

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-

rn 35-:

1~ 30

i I 25

ro 0 c..)

20

..-

~ i~ ~

ro ro

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N

"

Figure 7:

1H N

MR

spectrum o

f 4-cyclohexylidene-3-hydroxy-2-phenyl-

butanoic acid (82)

OH

o

O··'~oH

i It

tt 1

•' "f'

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60

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c ~ f-

45 '#-

40

35

30

25

20

15 I I

4000 3500

L_

_

Figure 8: IR

spectrum o

f 4-cyclohexylidene-3-hydroxy-2-phenyl-

butanoic acid (82)

v~~

OH

o

O··'~oH I co I"-cri C"') "

~

N

~

:n 'I N

Ll"l o

) N

O

l N

i 0

\ \Ill Figure 9: 1H NMR spectrum of 4-cyclohexylidene-3-hydroxy-2-(1-

naphthyl)butanoic acid (83)

·s.20

1.34

7 6 5 4 3 2 PPM

Figure 10: IR

spectrum of 4-cyclohexylidene-3-hydroxy-2-(1-naphthyl)-

84,~

butanoic acid (83) ;"~''--.

82

-I

\v1 \

.I II\ l I

80-=I \A

!

\ n I~ ~ I

Mil

I I~ 0

.r~OH 78-=I

~ '

I Figure 11: 1H NMR spectrum of 3-(1-cyclopentenyl)-3-hydroxy-2, 2, 3-

trimethyl-propanoic acid (84)

61

I~ 1 .63 /-99

6 5 4 3 2 PPM

USER: ""Ed

Figure 12: IR

spectrum spectrum

of 3-(1-cyclopentenyl)-3-hydroxy-2, 2,

-----·-~

54 ~iN>'Ji~·

I 52

~-'11

3-trimethyl-propanoic acid (84)

__ \

50·-= ~

A

I 'If\\

48 \

f \\ I \I

46 __: \

I ~

I

44

: \

1 I 4

2

I I

40-1~ OH

0

38

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1 g 3

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~~ I t ~ cf?.

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co 26--

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; I I ~

14

co

~ v

0

I ~

©~

N

C')~

12--= ~

~

I -

J '

N - 0 - o m w u::i ui

Figure 13: 1H NMR spectrumof3-(1-Cycloheptenyl)-3-hydroxy-2, 2, 3-


1 .32

~01

6 5 4 3 2 PPM

iih" USER: Dd

' i I Q)

\~ I~ .c 'Cl] I~ I

-"-I -

-------F

igure 14: IR spectrum

of 3-(1-C

ycloheptenyl)-3-hydroxy-2, 2, 3-60 -

55J-~\

50~ \

45 \

40

35

-

30

-

25

-

20

-

15

-

10 5-

4000 3500


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N

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i ?J I~ I~ I~ 'I-!~ ! I

Figure 16: IR

spectrum o

f 3-hydroxy-3-(1-hydroxycyclohexyl)-

60J ._.~"'i ,.

55

--5

0--1

45-;

40 -3

5-

30

25

-j -2

0-

15-1 ~I 10 ·-

5-_,

0-

4000

3-methyl-2-phenylpropanoic acid (86) (

/_,-

-'-

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\; \

3500 \ \ \ \ \

OH~OH

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0 Ii

hO

H

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I

3000 ON

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N

I 2500 2000

...... ...... Lei 0 ......

())

C! ...... 0 (() I Ii' q ~~w~

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('t)ID

Ol

LO cx:>CIC!

• ('t)

N(()

('t') T

""' T

""'Ct)

LO

N

'

F° I · igure 17: H NMR spectrum of 3-hydroxy-3-(1-hydroxycyclohexyl)-


OHr .1 Ol·,'l~- bH Ff C10H7

9.71 9.82

9 8 7 6 5 4 3 2 PPM

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w· Nuts - nmrmar2 2

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u c: ro

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Figure 18: IR

spectrum o

f 3-hydroxy-3-(1-hydroxycyclohexyl)------------·-

---

70~1 /--\

3-methyl-2-(1-naphthyl)propanoic a

cid

/87

) ,/~--\ _____ ,,..

\ ----

\ 65-1

\ \ \ I 60--

\ 5

5-

50

-

45

40

-

35

30

-

25

-

20

15~L 4000

3500

OH O

O?.~~

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3000 ...... 0

0

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iri LO

0

0

N

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~

2500

LO

LO'

00

"

.45

7

fih' Fl: 60.010 EX:

Figure 19: 1H NMR spectrum of 3-hydroxy-3-(1-hydroxycycloheptyl)-

6


5

SW!: 1000

OH~OH 0 0 ,,, , OH ff h

_f-83

4

OFl: 343.4 PW: 0.0 usec PD: 0.0 sec NA:

3

LB:O.O

.04

2 PPM

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0 40..:

35

30..:

25 ~ 20-='

15

10 =1 J

5-'

4000

Figure 20: IR

spectrum of 3-hydroxy-3-(1-hydroxycycloheptyl)-


o~t_ )'._ 0·''~ ~h-OH

co 0 u-i U

")

~

11 ~

cx:i (!) 0 (')

11 N

O"l

oi

N

O"l

N

3500 3000

2500 2000

I Ill II '

f ~ O"l U") cx:i O"l (!)

500

Figure 21: 1H NMR spectrum of 4-(1-Cyclopentenyl)-3, 3, 4-

trimethyloxetan-2-one (92)

.70

72

10

fBO

6 5 4

QJ (,) c (1J ~

.E I/) c

I~ I i I

11 .4

11.2

11.0

10.8

10.6

10.4

10.2

10.0

9.8

9.6

9.4

9.2

8.6

8.0 :I

7.4 _:1 -7.2:: --7.o-~1

4000

::::

Figure 22: IR

spectrum o

f 4-(1-Cyclopentenyl)-3, 3, 4-trim

ethyloxetan-

)

3500

2-one (92)

?-f o 0 .. ,H··.,,,

or_J

v (V)

coco I,()()')!"-~(') lD tO

L_

CD

r----·--·-1

65

-

1 -,

'·-»-""" ,

-~~frl'I'' ~.

~-v·\ I'

-'""'-.°""

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_/

~ 60 -

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r

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55

-

50

45_,

40

-

35

-

30

-

25

-

20--

15

-

. 4000

~

CD

g Ct) 0 0

NC'°i

..-Ct)

·m

~N

O>

N

Figure 25: IR

spectrum o

f 3-(1-naphthyl)-1-oxaspiro[5, 5]-5-

undecene-2-one (97)

0

0/0-< ..... 1~ ~C10H7

3500 3000

2500 2000

O>

O>

~ ,.._

1"1 ,l

IA

~ I\ I /1 ~,I C') '

Figure 26:

1H N

MR

spectrum o

f 3, 5, 6, 7, 8-pentahydro-3, 3, 4-.[

trimethyl-2H

-pentenopyranone (98)

s\_

) 1 s .... 11

J--8_,,~0 5

9 4

~.iii

Figure 27:

13C N

MR

spectrum o

f 3, 5, 6, 7, 8-pentahydro-3, 3, 4-

trimethyl-2H

-pentenopyranone (98)

J--8

0 2 0

s\ _ _rr;r"' 5 914'~

)pp

LIHE# HEIGHT

HEIGHT(L) FREG(HZ!

1 190.54

196.11 1118.80

2 237.17

239. 52 1596. 29

499.26 502. 45

1808.81 4

196. 48 198.39

2047.76 5

207 .10 208. 39

2541. 97 6

158. 65 189. 84

3142 .44 7

779.21 870.50

5834.27 8

BOJ.7.5 821. 31

5866' 26 9

125.00 125.79

5880.42 10

94. 61 95. 00

5888. 97 11

826' 9 2 828. 32

5898,30 12

70.28 73.02

5919 .78 13

228. 74 234.42

603.J.56 14

94.46 97 .oo

60.JB.39 15

114' 29 142.BJ

9846.60 16

117.04 118.84

. 10140.53

17 61. 37

90.06 13426.94

>EJECTING SAHPLEEJECT AIR OFF >LD

PPM

PPH 14.797 21.112 2.l.923 27. 083 .Jl.620 41.562 77.164 77 .588 77.775 77 .888 78' 011 78.295 79 .800 79' 864

130.232 134.120 177 .586

·--~·---------- ·------

..:

--···------------~--- ~----- -8:1:

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-~

I Figure 29: 1H NMR spectrum of 3, 5, 6, 7, 8, 9-hexahydro-3-phenyl-4-


.02

.58

J63 ("' .93

7 6 5 4 3 2 PPM

: 0.

l l J4.06

1J4.14 40. J2

.m

2 170.26

172.58 46. 01

.608 J

85.28 86. 55

52. 77 .698

4 104.lJ

106. 2J 1190. 44

15. 7 44 5

n.91 79. 84

1194. 50 15 .798

65. J6 67. 52

1196.98 15. 831

~Figure 30: 13C

NM

R spectrum

of 3, 5, 6, 7, 8, 9-hexahydro-3-phenyl-

52. 41 55. OJ

1201.?J 15. 894

68. 81 68. 82

1932.36 25.557

12. 98 81. 71

1947 .37 2

U5

6

~I 4-m

ethyl-2(3H)-benzopyranone (99)

10 U

. OJ 61.19

1977. 70 26.157

11 205. 29

205. J2 1984.78

26. 250 12

54. 74 54.86

1994.47 26. 379

I J 58. OJ

58.40 1996.88

26.411 14

228 .00 . 231. 92

2087. 70 27. 612

15 m

.53

l27. 95

2203. 90 29 .149

16 132.29

1JJ. 62 2205. 46

29 .169 17

198 .07 213.65

2246.61 29. 714

18 141.80

142.26 3149.16

41.651 19

195. J7 200. 11

J819.18 50.513

-20

67.78 69. 74

5820.73 7 6. 985

21 94. 80

98. 21 5824.50

77 .035 22

1198.29 3207.17

5833.58 77 .155

2.J 3330.46

J339. 74 5865. 54

77 .578 24

.J279.8J 3367. 10

5897. 47 78. 000

2 5 122.71

m.0

1

8661.17 rn.m

26

l05. 76 312.49

9680.J5 128.0JJ

27 167.11

169 .61 968J.J5

128.073

I 8

1 28

213.01 21J.75

9694. 67 128.223

7d_...o,~o 27

58. 45 60. 4J

9734.34 128.747

6 ~_i·•'''H

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121. 80 9741. 61

128.843 5 10

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187. 71 188.82

9747.49 128.921

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128.971 JJ

86.65 86.78

9766.96 129.179

.)4 180 .86

182 .13 9771.94

129 .245 JS

m.4

2

155.44 9776.SJ

129.JOS

36 71. 29

71. 78 9785. 98

129. 430 l7

170. J9 I 89. 26

9791.75 129 .507

38 228.29

269.31 9816.09

129' 829 J'l

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9840.35 1JO

. 149 40

114.50 117. 32

9859.28 130.400

41 75. 85

76. 12 9888. 97

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98. BI 98. 82

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0 112.55

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135.635 44

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169. 766

PP

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-----------

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t l

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11 I (\ (' 11 I I \/ I~ t ~N l{) ..q-co ·M M ..-lO ..q-

Figure 31: IR

spectrumof3, 5, 6, 7, 8, 9-hexahydro-3-phenyl-4-

20 m

ethyl-2(3H)-benzopyranone (99)

15

10 5

~\:' ' ~

' ii' J

r-,_,\-_

-

·--~~~1----- -·-· -..., ..,("j

----·----?ks~-·-~-··-·-----~ .. N N N ~

I /(

Figure 32: 1H NMR spectrum of 3, 5, 6, 7, 8, 9-hexahydro-3-(1-

naphthyl)- 4-methyl-2(3H)-benzopyranone (100)

0.06

8.9

1.00

9 8 2

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N :4 : 0. Wi Nuts - nrnrun30a

12

~

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,...: ,...:r--:

;pp

um

HEIGHT

HEIGHT(LJ FREQIHZJ

PPH 1

127. J7 127. 54

1198. 76 15.855

2 128. 60

128.60 1202.34

15. 902

~ F

igure 35: 13C

NM

R ~pectrum o

f3, 5, 6, 7, 8, 9, 10-heptahydro-3-

.J 152.06

152 .09 1204.8J

15. 935 J2J.6.J

341. 44 2062.16

27.274 l02.79

328. 80 2076.95

27. 470

II phenyl-4-m

ethyl-2(3H)-heptenopyranone (101)

343.24 J45' 51

2194.96 29.0JO

Jl!.7

6

JJJ.89 2221.79

29 '385 120. 49

127.12 2242.91

29. 665 189.13

190, 99 2245. 74

29. 702 10

217.i5 2

2U

4

3239.09 42.840

11 275. 52

27.5.56 3895. 25

51.519 12

2106.14 2111. 81

5835.01 77.174

jJ t/50.08

221U2

5866.95 77.597

14 2062.11

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A Ring-Closing Strategy for the Synthesis of Î²,Î³ ...OH 11 12 ~ { R=CH(SEt)2 } I) PhCH2Br, NaH,...

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Transcript of A Ring-Closing Strategy for the Synthesis of Î²,Î³ ...OH 11 12 ~ { R=CH(SEt)2 } I) PhCH2Br, NaH,...