Methods for DearomatizationMethods for Dearomatization Florina Voica Baran lab GM 11/6/2010 CO 2H A....
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Methods for Dearomatization Florina Voica Baran lab GM 11/6/2010 Any hydrocarbon or heterocycle with 4n+2 electrons in a fully conjugated cyclic π system is considered aromatic. General characteristics of aromatic compounds: - chemical behavior (electrophilic substitution vs addition, resistance to oxidation) - structural characteristics (bond length equalization) - energetic profile (resonance energy) - magnetic properties (ring current effects-downfield shifts of peripheral protons) Pure&Appl. Chem. 1996, 68, 209 Why are aromatic compounds desirable building blocks? - ubiquitous - very stable (many are crystalline) - easy to functionalize - aromaticity can be view as masked functionality Available methods for "controlled" dearomatization: - Enzymatic - Photochemical / Thermal (concerted) - Radical - Transition-metal mediated - Nucleophilic ------------------------------------------------------------------------------------------- - Oxydative (polyvalent iodine mediated) - Reductive (Birch reduction/reductive alkylation; cat hydrogenation) Dearomatization under enzymatic conditions R P 450 O R O - O H H H R R NIH shift OH R epoxide hydrase R OH OH GSH S-transferase OH SR' R glutathione conjugate The carcenogenicity of polyaromatic compounds might be due to reactive intermediates generated upon dearomatization. For polyaromatic hydrocarbons, oxidation occurs primarily in the K-region. Among the oxidized products, epoxide-diols are particularly prone to nucleophilic ring-opening by DNA. O HO OH O Acc. Chem. Res., 1981, 14, 218 on heme oxygenases Chem. Rev., 1996, 96, 2841 on arene oxides Science, 1974, 185, 573 TFDO -20 °C, 8 min 96% O TFDO -20 °C, 30 min 90% O O TFDO, freon 0 °C, 6 h 35% CHO CHO Tet. Lett., 1990, 31, 6097 muconic aldehyde Other reagents for direct epoxidation of polycyclic aromatics: DMDO J. Am. Chem. Soc., 1984, 106, 2462 mCPBA Angew. Chem. Int. Ed., 1977, 16, 171 Mn(TDCPP)Cl, H 2 O 2 Chem. Commun., 2004, 608 NaOCl, Na 2 HPO 4 J. Am. Chem. Soc. 1984, 106, 2463 OH OH O
Transcript of Methods for DearomatizationMethods for Dearomatization Florina Voica Baran lab GM 11/6/2010 CO 2H A....
Methods for Dearomatization Florina Voica Baran lab GM 11/6/2010
Any hydrocarbon or heterocycle with 4n+2 electrons in a fully conjugated cyclic πsystem is considered aromatic. General characteristics of aromatic compounds: - chemical behavior (electrophilic substitution vs addition, resistance to oxidation) - structural characteristics (bond length equalization) - energetic profile (resonance energy) - magnetic properties (ring current effects-downfield shifts of peripheral protons) Pure&Appl. Chem. 1996, 68, 209
Why are aromatic compounds desirable building blocks? - ubiquitous - very stable (many are crystalline) - easy to functionalize - aromaticity can be view as masked functionality
Available methods for "controlled" dearomatization: - Enzymatic - Photochemical / Thermal (concerted) - Radical - Transition-metal mediated - Nucleophilic------------------------------------------------------------------------------------------- - Oxydative (polyvalent iodine mediated) - Reductive (Birch reduction/reductive alkylation; cat hydrogenation)
Dearomatization under enzymatic conditions
RP450 OR
O- O
H
H
H
R R
NIH shift
OHR
epoxidehydrase
R
OH
OH
G
SH
S-transfe
rase
OH
SR'R
glutathioneconjugate
The carcenogenicity of polyaromatic compounds might be due to reactive intermediates generated upon dearomatization. For polyaromatic hydrocarbons, oxidation occurs primarily in the K-region. Among the oxidized products, epoxide-diols are particularly prone to nucleophilic ring-opening by DNA.
O
HO
OHO
Acc. Chem. Res., 1981, 14, 218
on heme oxygenases Chem. Rev., 1996, 96, 2841on arene oxides Science, 1974, 185, 573
TFDO-20 °C, 8 min
96%
O
TFDO-20 °C, 30 min
90%
O
O
TFDO, freon 0 °C, 6 h
35%
CHO
CHO
Tet. Lett., 1990, 31, 6097
muconicaldehyde
Other reagents for direct epoxidation of polycyclic aromatics: DMDO J. Am. Chem. Soc., 1984, 106, 2462 mCPBA Angew. Chem. Int. Ed., 1977, 16, 171 Mn(TDCPP)Cl, H2O2 Chem. Commun., 2004, 608 NaOCl, Na2HPO4 J. Am. Chem. Soc. 1984, 106, 2463
OH
OH
O
Methods for Dearomatization Florina Voica Baran lab GM 11/6/2010
O
CO2tBu
+HN
N
O
O
SS
R Me
R = C6H4OMe-p
Triton-BDMSO
CO2tBu
N N
O
O
SS
RMe
OH66%
N N
O
O
SS
RMe
OH
Cl
BnO Cl
PhLi, THF
N N
OHO
O
Me
OBn
SS
R
45%
N N
OHO
O
Me
OH
SS
gliotoxinJ. Am. Chem. Soc., 1976, 98, 6723
For a biosynthetic proposal involving a benzene oxide: J. Org. Chem., 1980, 45, 3149
OBz
O
(5 steps from benzoic acid)
O2, hematoporphyrin
60%OO
O
OBz
P(OEt)3benzene
88%
OBz
O
O
10% AcOH THF
OBz
OH
HO
O
21%
+
OBz
OH
OH
HOHO
21%
+
OBz
OH
OH
O
32%
Ac2O
OBz
OAc
OAc
O
senepoxide
J. Am. Chem. Soc., 1978, 100, 6483
Br
Pseudomonas putida
Br
OH
OH99% ee
(Aldrich, $53/g)
For an extensive review on cyclohexane epoxide natural products Chem. Rev., 2004, 104, 2857Also, see Baran Lab GM Shikimic Acid, Ambhaikar, 2005. For more on biocatalysis, see Baran Lab GM Biocatalysis, Gulder, 2009
For an extensive list of substrates and applications in total synthesis (conduritols, inositols, carbohydrates, prostaglandins, some alkaloids) see Aldrichimica Acta, 1999, 32, 35; Synlett, 2009, 685
+ 22% epimer
Methods for Dearomatization Florina Voica Baran lab GM 11/6/2010
CO2HA. eutrophus
OH
CO2H
OH > 95% eeOrg. Lett., 2001, 3, 2923
mCPBA79%
OH
CO2H
OH
O
1.TMSCHN22. TBSOTf, Et3N
70%
OTBS
TBSO CO2Me
O
NO
OBnLi
N
73%
OTBS
TBSO
O
O
NO
OBn
N1. LiOTf (5 mol%), PhCH3, 60 °C2. TFA, DCM
62%N
O
HO
TBSOOH
HN
O OBn
NO
BnO2CO
O
H
O
N
OBnOTBS
Et
CO2PhOBoc
LDA, TMEDA,OH
OH
Me H
O
H
OH
H
O
N
OH
OH
1.
2. HF, ACN3. H2, Pd/C
71% (3 steps)
THF
O
NH2
(-) deoxycyclineScience, 2005, 308, 395
1. P. putida2. p-MBDMA
MeMe
O
OAr
Ar = C6H4OMe-p
Cl
CN
PhH, reflux
Cl CN
OO Ar
Me MeO
OBn
MgBr
MeOBn
OH
NaH, THF reflux
H
Me
O-OBn
aq NH4ClH
Me
OOBn
cat SnCl2CHCl3
Me
HOBn
OHmCPBA
Me
HOBn
OH
Ti(OiPr)4DCM, reflux
O
H
Me
OOBn
HO
Synlett, 1998, 897
1. OsO4(1.3 mol%), hv Ba(ClO4)22. Ac2O, Et3N
36%
OAc
OAcAcO
AcO
OAc
OAc
+
OAc
OAc
OAc
OAc6.2 : 1Angew. Chem. Int. Ed., 1995, 34, 2031
OH
OHOH
+
[FeII(TPA)(NCMe)2](OTf)2H2O2
4 : 1Chem. Commun., 2009, 50
6 5ABCD
quant70%
90%97%82%
"These experiments certainly demonstrate that the chemical equivalent of dihydroxylation of aromatics is feasible, although at this time it does not compete with the biological process in terms ofselectivity and efficiency. We hope that present and future generations of organic chemists are stimulated by the magnitude of this challenge and eventually succeed in the development of catalytic process that would rival the enzymatic transformation and allow for this reaction to be removed from the list of unsolved problems in organic chemistry"
Tomas Hudlicky, Synlett 2009, 685
Methods for Dearomatization Florina Voica Baran lab GM 11/6/2010
Photochemical methods
" The aromatic nucleus, known for its rigidity in the ground state, becomes an extremely flexible and extrovert acrobat when being doped with a light quantum"Egbert Havinga, Helv. Chem. Acta, 1967, 50, 2550[2+2] cycloadditions
OMe
+
CNhν
OMe CN
Me74%
Tet. Lett., 1977, 18, 3629
CN
O
hν
CN
O
O
NC NC
O
90%
J. Chem. Soc. Perkin Trans 1 1992, 1145
OMe
MeO2C O
O
OE
hνO
EH+
MeOH/H+
OH
OMe
OMe
E
OH
O
+
64% 16%Synthesis, 2001, 1236
OMe
O nBu
hνH+
O
H
OMenBu
35%
+O
H
OMenBu
32%
Tetrahedron, 2002, 58, 7933For more examples of [2+2] with arenes:J. Org. Chem. 1981, 46, 2405Tetrahedron 1985, 41, 2405J. Chem. Soc. Perkin Trans. 1 1980, 2425
[4+2]
+O
OO
Cl
Cl
hν
PhCOMe
O
OClCl
O
H+
O
O
Tet. Lett. 1974, 787
[4+4]
+ O
O
O
hν
OO
OO
O
O
hν
1. NaOH2. Pb(OAc)4, O2, pyr
Chem. Commun. 1979, 1038
hν, O2, Rose Bengal acetone, -78 °C
38%
O
O
OO J. Org. Chem. 1976, 41, 899; 900
tBu
Co(TPP) (5 mol%) acetone, -10 °C
51% OO
tBuO
O
J. Am. Chem. Soc. 102, 3641
85% 80%
+ H
H
HH
50%15%
cat Rh(I)
85%
Methods for Dearomatization Florina Voica Baran lab GM 11/6/2010
"The problems originally posed by many synthetic targets have now been solved at a practical level. However, for the majority of synthetic problems, solutions either do not exist or are far from beingpractical. In general, few solutions approach the ideal, wherein a target is prepared from readily-available starting materials in one step that proceeds in 100% yield and is operationally safe, simple and ecologically acceptable. Obviously, this is a rather demanding but no unrealistic objective. While it is unlikely to be commonly achieved, efforts to reach this standard of sophistication are of great importance as they are likely to lead to the fundamentally new science that will clearly have a profound impact on the ways in which total synthesis will be done in the future."
Paul Wender, Pure&Appl. Chem. 1990, 62, 1597[2+3] meta-photocycloaddition
R
hν*
RR1R1
R1
R1
R
R
R1
R1
R1
R1R
R1
R1
R
R1
R1
R
R1
R1
R
R = EDG
R = EWGGeneralities:- the nature of the reactive intermediates is not yet decided (biradical vs zwiterrion)- depending on the electronic nature of the arene substituents, the reaction is regioselective- RDS - bonding between the arene and the alkene- reaction proceeds via a concerted mechanism (alkene stereochemistry preserved)- reaction can be performed neat or in an inert solvent- it is temperature independent- for intermolecular reaction, an excess of the arene is required Chem. Rev. 1993, 93, 615
Li
Me
O
Me
hν
H
+
H
Li, NH3
Hsilphinene
Tet. Lett. 1985, 2625
For a review of applications in total synthesis seePure&Appl. Chem. 1990, 62, 1597
O
MeTMSO
hν (254 nm)cyclohexane
89% O
MeTMSO
H
OH
H
MeTMSO
+
1 : 1.2
TMSO Me
O
OMe
Me
Me
HH
OMe
CO2H
Me
HO
HO
H
O
Lancidifolactone FOrg. Lett. 2008, 10, 1223
For a recent application in an asymmetric synthesissee J. Am. Chem. Soc. 2009, 131, 452
OMe
O
OHH
O
MeO
H
O
H O
OH
H
H
H
H
OMe
hν (254 nm)
8%
J. Am. Chem. Soc. 2009, 130, 404
TMSO Me
O
OMe
O Me
O
HOOMe
Me HO
OH+
1. mCPBA, DCM2. pTsOH, MeOH
69%(3 steps)
H H
Thermal cycloaddition
CNNCΔ
CN
CN
14%J. Am. Chem. Soc. 1968, 90, 215
Cl
Cl
Cl
Cl
Cl Cl
Cl
Cl Na, tBuOH THF
86%
Synthesis 1975, 707
60%
PhH, -10°C
N
O
•
SiMe2Ph
ΔN
Me
O
Me
SiMe2Ph
Chem. Ber. 1986, 119, 1953
Br tBuOK, 180 °C
Tet. Lett. 1976, 4559
Methods for Dearomatization Florina Voica Baran lab GM 11/6/2010
OH
OH
O
O
O
+
O
O
O
O
Oneat, 250 °C
J. Chem. Soc. Perkin Trans. 1 1987, 1147
Radical methods for dearomatization
Bu3SnH, AIBN(PhSe)2, PhH, reflux
30%1,4 : 1,3 = 10:1
O
O
OH
I
CO2H
O
O
OH
CO2H
I2, NaHCO3
O
O
O
OH O
H
H I
71%
pancratistatin
J. Am. Chem. Soc. 1989, 111, 4829
Tetrahedron 2006, 62, 6830
Me
N
tBu
CCl3
O
Ni, AcOH reflux
N NtBu O
Cl
Cl
tBu O
Cl
Cl
Me Cl
Cl
21% 46%
+
Tet. Lett. 1997, 38, 5985
CO2Me
OMe
O
SmI2 (3.5 eq) THF
CO2Me OHMe
50%
SmI2 (5 eq), HMPA (18 eq)iPrOH (2 eq), THF, 0 °C
CO2Me
OMe
HHOMe α : β = 1 : 8
75%
Chem. Commun. 2002, 316
N
O
Me
SmI2, HMPA,tBuOH, THF, rt
N
H
H
H
OH
Me
56%
Chem. Eur. J. 2007, 13, 6047
benzobarrelene
Methods for Dearomatization Florina Voica Baran lab GM 11/6/2010
Pd-catalyzed dearomatization reactions
Cl
Me
Pd2(dba)3•CHCl3 (5 mol%)PPh3 (40 mol%), acetone, rt
SnBu3
82% Me
J. Am. Chem. Soc. 2001, 123, 759
Br
Cl
Pd2(dba)3 (5 mol%)PPh3 (20 mol%), DCM, rt
SnBu3
89%
Br
Angew. Chem. Int. Ed. 2008, 47, 4366
Me
Cl
Cl
Pd2(dba)3 (5 mol%)PPh3 (20 mol%), DCM, rt
SnBu3
71%
MeCl
Tetrahedron 2010, 66, 6013
Br
NH
Ph Pd2(dba)3 (3 mol%), ligand (4.5 mol%) Li(OtBu) (1.2 eq), THF, reflux
93%, 93% ee N
Ph
Pcy2NMe2
ligand =
J. Am. Chem . Soc. 2009, 131, 6676
Transition-metal mediated dearomatization methods
Cr(CO)3
- yellow to red (often) crystalline compounds- air stable in solid state- somewhat light sensitive- reactive towards strong nucleophiles (Cr(CO)3 enhances reactivity similar to a nitro group...)
+
Cr(CO)6 Inorg. Synth. 1990, 28, 136
Cr(CO)3L3 (L = ACN, Py, NH3) J. Org. Chem. 1992, 57, 6487
(naphtalene)Cr(CO)3 J. Organomet. Chem. 1985, 286, 183
unreactive successful metalation
LiCH(CO2R)2LiCH2CORMeMgBrtBuMgBrMe2CuLi
LiCH2CO2RLiCH2CNKCH2COtBuLiCH(CN)(OR)LiCH2SPhLiCH=CH2LiPhLiC≡CRLiCH2CH=CH2tBuLi
nBuLiLiMesBuLi
Reactivity of nucleophiles toward (PhH)Cr(CO)3 in THF
J. Am. Chem. Soc. 1979, 101, 3535
R
Cr(CO)3R'Li
R
Cr(CO)3
R'
R ProductOMe metaNMe2 metaMe, Et meta/orthoCl ortho/metaHydrazone orthoImine orthoOxazoline orthoSiMe3 paratBu paraCF3 para Chem. Rev. 2000, 100, 2917
Regioselectivity of nucleophilic addition
Methods for Dearomatization Florina Voica Baran lab GM 11/6/2010
NCy
Cr(CO)3
MeLi thenMeI, CO, HMPA THF
NHCy
Me
O
Me
BrNaH
58% (2 steps)
O
Me
Me
O
J. Org. Chem. 1994, 59, 4773
N
N
Cr(CO)3
OMe PhLi, THF, -90 °Cthen
TMSBr
73%, >98% ee
PhTMS
N
NR*
Pure Appl. Chem. 1997, 69, 543
N
OMe Li OEt1.
2. MeI, CO, HMPA3. NaOEt, MeI
53%, >95% eeCr(CO)3
CHO
Me
OEt
O
Me O
OAc
H
Me
Me
(-) acetoxytubifuranJ. Am. Chem. Soc. 2002, 125, 5642
Ph
OR*(OC)5Cr
1. sBuLi, THF2. MeOTf
68%
Me
Ph
Me
OR*Cr(CO)5
R* = (-) menthyl
1. C5H5N+O-
2. LAH3. H+
Me
Ph sBu
HO
Me
Ph sBu
HO
+
3 : 1
J. Am. Chem. Soc. 1996, 118, 13099
Mn+(CO)3
- stable, yellow compounds- often crystalline- increased electrophilicity compared to Cr-arene complexes - most common reactivity pattern: sequential nucleophilic attack
+
Mn(CO)3+
(in situ from Mn(CO)3Br and AgBF4)Synlett 1990, 565
Mn(CO)3ClO4Mn(CO)3(acetone)+
Mn(CO)3Br, AlBr3(for arenes with sensitive functionality)
J. Organomet. Chem. 1981, 204, C25
J. Am. Chem. Soc. 1957, 79, 5826
Mn+(CO)3
LAH
Mn(CO)3
H HCN
1.
2. O2
88%
CN
Organometallics 1993, 12, 224
NMe
O
Ru+Cp
Bu3P (1 eq), NaH (2 eq) DME, rt, 12h
47%
NMe
RuCp
O
CuBr2THF/H2O, CO
NMe
OHO
55%[CpRu(CO)2]Br +
Angew. Chem Int. Ed. 2007, 46, 2887Tetrahedron 2008, 64, 10123
For a review on organo-iron complexes see Tetrahedron 1983, 39, 4027
Methods for Dearomatization Florina Voica Baran lab GM 11/6/2010
Os2+(NH3)5
- η2-Os complexes are e-rich and prone to electrophilic substitution- thermally stable complexes- stable under inert atmosphere in solution- decomplexation with Mg or Zg/Hg in DME or MeOH
+ [Os(NH3)5(OTf)](OTf)2 (1.5 - 20 eq) !!!
[Os]2+ H2, Pd/C
89%[Os]2+
CH2(OMe)2TfOH
[Os]2+
OMe OMeTMSO
MeO2C
OMe
[Os]2+
AgOTf
82%(3 steps)
MeO2C
MeO
OMe
Me
Me
[Os]2+MVK, TfOHACN, -40 °C
96%
O+Me
[Os]2+
MeMe O
MeDMAc96%
O+Me
[Os]2+
MeHOMe dr 7:1
O
Me
Me
H
J. Am. Chem. Soc. 1998, 120, 6205
OR
[Os]2+
OR
E1
[Os]2+E1
+ Nu1-
OR
E1
[Os]2+
Nu1
E2+
OR
E1
[Os]2+
Nu1
E2
Nu2-
OR
E1
[Os]2+
Nu1
E2
Nu2
H+
-ROH
E1
[Os]2+
Nu1
E2
Nu2
Nu3-
Nu2
E1
[Os]2+
Nu1
E2
Nu3
and/or
E1
[Os]2+
Nu1
E2
Nu2
Nu3
E = H+ (TfOH), acetals, ketals, Michael acceptors, (RCO)2O, pyrroles, furans Tetrahedron, 2001, 57, 8203
OMe
[Os]2+
O
H2O, rt
OMe
[Os]2+HH
H
O
71%
J. Am. Chem. Soc. 1998, 120, 2218
Other viable dienophiles:
NMe
O
O
OR
R = H, Ph
HN
[Os]2++
CO2Me
CO2Me
DMA, rt95%
HN
CO2Me
CO2Me
[Os]2+
1. TBSOTf, ACN2. H2O/MeOH
98%
N+
H CO2MeMeO2C
H[Os]2+TfO-
dr 1:11. TBAB, ACN/MeOH2. TfOH, MeOH
N+
H CO2MeMeO2C
H[Os]2+TfO-H1. Cu(OTf)2
2. Me3N, aq Na2CO3
65%
N O
MeO2CH dr 1:1
N N
H H
HOHO
supindine labournineTetrahedron, 2001, 57, 8203
Methods for Dearomatization Florina Voica Baran lab GM 11/6/2010
Nucleophilic methods for dearomatizationR* R*
R'R'M
M = Li, Mg
RO
R O R
O
NR
O
OR
O
NH2
X
OC
N O
N
R
R* =
etc.
Chem. Rev. 2007, 107, 1580
O
CPh3
PhMgBr
Ph
O
CPh3
Ber. Dtsch. Chem. Ges. 1910, 43, 1145
PhMgBr
Ph
OH
Ph
CPh3
J. Am. Chem. Soc. 1953, 75, 4604
1,4-addition to aromatic ketones is favored in the case of hindered ketonesor when a bulky LA is employed
Mes O
OMe
MgBr1.
2. NH4Cl50%
Mes O
J. Org. Chem. 1961, 26, 756
Me
O 1. ATPH, Tol/THF2. tBuLi3. MeOTf
68%tBu
O
MeMe
J. Am. Chem. Soc. 1995, 117, 9091
OPh
PhATPH =
NCy1. nBuLi, HMPA2. MeI3. H+
60%
nBuMe CHO
nBuMe OH
NaBH4
Tet. Lett. 1987, 28, 5279
OMe
N OH3
1. iPrMgCl2. ClCO2Me3. H+
65%
iPrCHO
CO2Me
OMeKCN, MeOH
quant
iPr
CO2Me
OMe
J. Org. Chem. 2000, 65, 3018
CO2tBu NLi1., HMPA
2. MeI
Me CO2tBu
N
ON
+
64% 32%J. Org. Chem. 1995, 60, 7445
MeO
O
N Ph
Me Me
Ph
1. tBuLi (2 eq), HMPA2. NH4Cl3. 1M HCl
N
H
HMeO
O
Ph
MeMe
Ph94%
NBoc
O
MeH
HCO2Me
O
1. mCPBA2. NaOH3. TMSCHN2
NBoc
HHO CO2Me
Me
OH
CO2Me
NH
CO2H
Me CO2H
kainic acidChem. Commun. 2000, 317
For the synthesis of isodomoic acid C by a similar strategy see J. Am. Chem. Soc. 2005, 127, 2412
Al3
Methods for Dearomatization Florina Voica Baran lab GM 11/6/2010
MeO
N
O
tBu
Ph
LDA, THF
MeO
NtBu
H Ph
OLi1. hν, 500 nm2. NH4Cl
73%MeO
Ph
H
H
NHtBu
O
J. Am. Chem. Soc. 2003, 125, 9278
N
O N
Bn
O1. Tf2O, 2,6-lutidine2. Ph3COH
67%NTf
BnN
OCPh3
O
NTf
BnN
OCPh3
O+ dr 30:1
Chem. Commun. 2009, 1964
O
O
N
O
tBu
1. THMPLi2. MeSO3H
O
O CO2Me
OMe
OMeMeO
1. DMDO2. LHMDS3. NH4Cl
O
O CO2Me
OMe
OMeMeO
OH
89%dr 10:1
64%, 96% ee
O
O CO2Me
OMe
OMeMeO
OH
O
O
OMe
OMeMeO
OH 1. ClSiMe2CH2Br2. HSnBu3, AIBN3. KF, KHCO3, H2O2
OH
68%, 97% eeO
O
4A MSZnCl2
98%97% ee
(-) EpipodophyllotoxinAngew. Chem. Int. Ed. 2003, 42, 2487
NN
N 1. BuLi2. Boc2O
69% N
Boc
NN
N
Me
Me
1. BuLi2. Boc2O
75%N
NBocN
Me
Me
Angew. Chem. Int. Ed. 2002, 41, 484Tetrahedron 2006, 62, 10854
Me
NSi
iPr
tBu tBu
Ph O
95%Me
N
SiO
H
Ph
iPr
tBu
tBu
J. Org. Chem. 2008, 73, 8113
For an example of nucleophilic dearomatization of aryl phosphinamidines seeJ. Org. Chem. 2007, 72, 9704
Miscellaneous dearomatization methods
NNH
O iPr
MeON
N
MeO
iPr
1. Tf2O, 2-ClPyr2. nPrMgBr nPr
N nPrH
O77% (4 steps)
Org. Lett. 2009, 11, 3398
