- ACCOUNT
- 21
Application of Organic Azides for the Synthesis of Nitrogen-Containing Molecules
Shunsuke Chiba*
Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological University, Singapore 637371, Singapore Fax +6567911961; E-mail: [email protected]
Received 31 May 2012
Organic azides possess diverse chemical reactivities.4 Owing to their 1,3-dipole character, they undergo [3+2] cycloaddition with unsaturated bonds, such as those in alkynes and alkenes as well as carbonitriles (Scheme 1, part a).5 Organic azides can also be regarded as nitrene equivalents (Scheme 1, part b).6 Accordingly, their reactions with nucleophilic anions, electrophilic cations, and radicals can formally provide the corresponding nitrogen anions, cations, and radicals, respectively, forming a new bond with the internal azido nitrogen and releasing molecular nitrogen. Moreover, the generation of anions, cations, and radicals at the a-position to the azido moiety can result in rapid denitrogenation to deliver the corresponding iminyl species, which can be used in further synthetic transformations (i.e., carbon–nitrogen bond formation).
Abstract: In this account, recent advances made on the reactions of several types of organic azides, such as vinyl azides, cyclic 2-azido alcohols, a-azido carbonyl compounds, towards the synthesis of nitrogen-containing molecules are described.
- 1
- Introduction
- 2
- Chemistry of Vinyl Azides
- 2.1
- Thermal [3+2]-Annulation of Vinyl Azides with 1,3-Dicar-
bonyl Compounds
2.2
2.3 2.4
Manganese(III)-Catalyzed Formal [3+2]-Annulation with 1,3-Dicarbonyl Compounds Manganese(III)-Mediated/Catalyzed Formal [3+3]-Annulation with Cyclopropanols Synthesis of Isoquinolines from a-Aryl-Substituted Vinyl Azides and Internal Alkynes by Rhodium–Copper Bimetallic Cooperation
33.1
Chemistry of Cyclic 2-Azido Alcohols Manganese(III)-Catalyzed Ring Expansion of 2-Azidocyclobutanols
(a) 1,3-Dipoles
N
R
N
N
- 3.2
- Palladium(II)-Catalyzed Ring Expansion of Cyclic 2-Azido
Alcohols
- C
- C
- N
- alkenes
alkynes nitriles
RR
NN
- N
- N
CCCCCN
R
N
C
Ntriazolines
44.1
Chemistry of a-Azido Carbonyl Compounds Orthogonal Synthesis of Isoindole and Isoquinoline Derivatives
+
C
Ntriazoles
R
N
C
N
- N
- N
N
tetrazoles
- 4.2
- Generation of Iminylcopper Species and Their Catalytic
Carbon–Carbon Bond Cleavage under an Oxygen Atmosphere
(b) Nitrene equivalents
+
N2
R
N
- N
- N
- R
N
4.3 5
Copper(II)-Catalyzed Aerobic Synthesis of Azaspirocyclohexadienones Conclusion
nitrenes
with carbanions or other nucleophiles
R
N
- N
- N
X–
- +
- +
+
RR
N
XC
N2
Key words: azides, nitrogen-containing heterocycles, radical reactions, redox reactions, oxygenations
with carbocations
R
N
- N
- N
C+
+
N
N2 N2
with carbon radicals
+
R
N
- N
- N
C
- +
- R
N
C
- 1
- Introduction
chemistry of α-azido anions, cations, and radicals
CCC
NNN
NNNNNN
+++
CCC
NNN
N2 N2 N2
The chemistry of organic azides commenced with the synthesis of phenyl azide by Griess in 18641 and the discovery of the rearrangement of acyl compounds with hydrogen azide (HN3) by Curtius in 1890.2 Since 1950, various synthetic organic reactions have been developed using acyl, aryl, and alkyl azides, which have been extensively applied for the synthesis of nitrogen-containing azaheterocycles as well as peptides.3
Scheme 1
We have been interested in the intriguing chemical reactivity of organic azides, such as vinyl azides, cyclic 2-azido alcohols, and a-azido carbonyl compounds (Scheme 2). In this account, we describe recent advances made on the reactions of these organic azides towards the synthesis of nitrogen-containing molecules which have been developed in our research group.
SYNLETT 2012, 23, 21–44
- x
- x
- .x
- x
- .2
- 0
- 1
- 1
Advanced online publication: 09.12.2011 DOI: 10.1055/s-0031-1290108; Art ID: A59911ST © Georg Thieme Verlag Stuttgart · New York
22
S. Chiba
ACCOUNT
NN
N
inyl species serve for the formation of carbon–nitrogen bonds. In this section, we present the synthesis of azaheterocycles from vinyl azides via several types of reaction mode based on the above chemical reactivities.
NN
N
R
N
NN
HO
R'
R
O
a-azido carbonyl compounds cyclic 2-azido alcohols vinyl azides
- 2.1
- Thermal [3+2]-Annulation of Vinyl Azides
with 1,3-Dicarbonyl Compounds
Scheme 2
During the course of our study on the chemistry of 2H- azirine derivatives,11 it was found that the reaction of azirine 1 with acetylacetone (2) in 1,2-dichloroethane at room temperature gave tetrasubstituted pyrrole 3 in quantitative yield after 33 hours (Scheme 4).
- 2
- Chemistry of Vinyl Azides
Intermolecular annulation reactions can allow for the straightforward and selective construction of complex cyclic molecular structures in a one-pot manner from relatively simple building blocks, one of the most ideal processes in organic synthesis from an atom-7 and stepeconomical8 point of view. Inspired by this perspective, we have recently been interested in the application of vinyl azides as a three-atom unit including one nitrogen for various types of annulation reactions to prepare azaheterocycles.
EtO2C Cl
COMe Me
Cl
- O
- O
- CO2Et
+
N
Cl
1
N
- Me
- Me
DCE r.t., 33 h
H
Cl
2 (1.2 equiv)
3 quant
Scheme 4
While the reaction of azirine 1 with acetylacetone (2) in tetrahydrofuran (THF) has been reported, the yield of pyrrole 3 was low.12 The generation of 3 in high yield in the above reaction (Scheme 4) led us to further investigate the pyrrole formation.
One of the attractive chemical properties of vinyl azides is their ability to undergo thermal decomposition to give highly strained three-membered cyclic imines, 2H-azirines, via vinylnitrene intermediates following denitrogenation (Scheme 3, part a).9 Moreover, the carbon–carbon double bond of vinyl azides can be used for the formation of new carbon–carbon bonds with appropriate organometallic compounds (R′–[M]) or radical species (R¢) which results in the generation of iminyl metals or iminyl radicals, respectively (Scheme 3, parts b and c).10 These im-
The reaction may proceed through the addition of acetylacetone (2) to the imino carbon of azirine 1,13 followed by nucleophilic attack of the nitrogen in the resulting aziridine to a carbonyl group with concurrent ring opening of the strained three-membered ring.14 However, the instability and poor accessibility of the 2H-azirines prevented us using this strategy as a synthetic method for pyrroles. Accordingly, we planned to use vinyl azides as precursors of 2H-azirines which can be easily synthesized15 and handled (Scheme 5).
R
R
R
Δ
N
NN
(a)
N
– N2
N
2H-azirines vinylnitrenes
R
R
R
As proposed in Scheme 5, simple heating of a mixture of ethyl 2-azido-3-(2,6-dichlorophenyl)acrylate (4) and acetylacetone (2) in toluene at 100 °C provided pyrrole 5 in 86% yield (Table 1, entry 1).16 Various 2-azido-substituted cinnamates possessing electron-donating and -withdrawing groups on the phenyl group (entries 2–8), as well as a derivative containing a pyridyl moiety (entry 9), reacted with acetylacetone (2) to give the corresponding 2-
R
R'
R'
R'–[M]
[M]
N
NN
N
NN
(b) (c)
N
[M]
– N2
R
R'
R'
R
N
NN
N
NN
R'
– N2
N
Scheme 3
Biographical Sketch
- Shunsuke Chiba was born University of Tokyo (work- Nanyang
- Technological
in Zushi, Kanagawa, Japan, ing under Professor Koichi University, Singapore, as an in 1978. He obtained his Narasaka). He was appoint- assistant professor. His reB.Eng. from Waseda Uni- ed as a research associate at search focus is methodology versity in 2001 and received the University of Tokyo in development in the area of his Ph.D. in 2006 from the 2005. In 2007, he moved to synthetic organic chemistry.
Synlett 2012, 23, 21–44
© Thieme Stuttgart · New York
ACCOUNT
Applications of Organic Azides for the Synthesis of Nitrogen-Containing Molecules
23
indoles via intramolecular C–H amination.17,18 It is noteworthy that the above intermolecular reactions of 2-azidosubstituted cinnamate derivatives with acetylacetone (2) gave pyrroles exclusively without any indole formation.
- R2
- R2
R1
COMe Me
R1
- O
- O
Δ
– N2 – H2O
+
N
- Me
- Me
N
N2
H
2
– N2
– H2O
As b-substituents (R1) of azidoacrylates, ethoxycarbonyl and alkyl groups could be introduced, giving the corresponding pyrroles in good yields (entries 12 and 13). Simple azidoacrylate 30 also reacted smoothly (entry 14). Using a-aryl-substituted vinyl azides, not only phenyl groups, but also naphthyl, indolyl, pyrrolyl, and benzothiophenyl moieties could be installed at the 3-position of the resulting trisubstituted pyrroles (entries 15–26). aAlkyl-substituted vinyl azide 56 reacted smoothly to give the corresponding pyrrole 57 in 82% yield (entry 27). An E,Z-mixture of 2-phenylvinyl azide (58) could also be used to prepare trisubstituted pyrrole 59 in 85% yield (entry 28). Tetrasubstituted pyrroles 61 and 63 were success-
R2
Me
- R2
- R2
R1
COMe
- R1
- R1
HN
- O
- Me
N
O
Me
OH
HO
H O
N
Me
H
Me
B
A
Scheme 5
arylpyrroles in good yields. Vinyl azides 22 and 24 bearing acetyl and (dimethylamino)carbonyl moieties instead of an a-ethoxycarbonyl group could be employed to give the corresponding pyrroles 23 and 25 (entries 10 and 11, respectively). It is known that the thermolysis of 2-azidosubstituted cinnamates and their derivatives delivers 1H-
Table 1 Synthesis of Pyrroles from Vinyl Azides and Acetylacetone (2)a
- R2
- R2
R1
COMe Me
R1
Δ
- O
- O
+
N
– N2 – H2O
- Me
- Me
N
N2
H
2
- Entry
- Vinyl azides
- Pyrrolesb
Entry
24
Pyrrolesb
O
Vinyl azides
: R = 2,6-Cl
5 86% 7 93% 9 90% 11 89% 13 96% 15 90% 17 90% 19 81%
4
1234567
8c
2
6: R = H 8: R = 4-Me 10: R = 2-Me 12: R = 3-NO2 14: R = 4-Br 16: R = 4-CN 18: R = 4-MeO
- EtO2C
- COMe
Me
TsN
- 51 92%
- 50
Me Me
- CO2Et
- N
Ts
R
N3
N3
NH
N
- H
- R
O
O
EtO2C
COMe Me
TsN
Me
Me
52 54
53 92%
25 26
NTs
CO2Et
9
- 20
- 21 94%
NH
N3
NH
N3
N
N
S
R2
COMe Me
R2
- 22: R2 = COMe
- 23 74%
25 quant
10d 11
Me Me
N3
24: R2 = CONMe2
55 96%
S
NH
NH
N3
EtO2C
R1
COMe Me
26: R1 = CO2Et
28: R1 = CH2Ph 30: R1 = H
27 82% 29 96% 31 85%
- 12
- CO2Et
N3
R1
O
13e
14
Ph
Me
Me
Ph
N
56
27
57 82%
H
N3
32: R = H
33 75% 35 98% 37 95% 39 86% 41 92% 43 91% 45 86%
- N
- 15
16 17 18 19 20 21
R
H
34: R = 4-Me 36: R = 4-OMe 38: R = 2-OMe 40: R = 4-Br 42: R = 3-Br 44: R = 4-CO2Me
COMe Me
R
COMe
Me
N3
N
- 58
- 59 85%
61 66% 63 91%
28 29 30
N
H
N3
(E:Z = 1:1)
H
O
Me
Me
COMe Me
- 47 94%
- 46
48
22 23
60 62
N
N3
N3
H
NH
O
Me
COMe
Me
Me Me
49 65%
- N3
- N3
Me
N
N
- H
- H
a Unless otherwise noted, the reactions were carried out by heating a mixture of the vinyl azide (0.3–0.5 mmol) and acetylacetone (2) (1.2 equiv) in toluene at 100 °C for 2–24 h. b Isolated yields are shown. c The reaction was performed at 85 °C for 16 h. d The reaction was performed at 85 °C for 20 h in the presence of acetylacetone (2) (2 equiv). e The reaction was performed at reflux for 5 h.
© Thieme Stuttgart · New York
Synlett 2012, 23, 21–44
24
S. Chiba