ORGANIC

LETTERS

Simple Conversion of Enamines to 2009

Vol. 11, No. 12
2H-Azirines and Their Rearrangements 2643-2646
under Thermal Conditions
Xiaoxun Li, Yunfei Du,* Zhidan Liang, Xiangke Li, Yan Pan, and Kang Zhao*

Tianjin Key Laboratory for Modern Drug DeliVery & High-Efficiency, School of
Pharmaceutical Science and Technology, Tianjin UniVersity, Tianjin 300072, China
duyunfeier@tju.edu.cn; combinology@yahoo.com

Received March 31, 2009

ABSTRACT

A variety of substituted enamine derivatives were first found to be conveniently converted to the corresponding 2H-azirines mediated by
phenyliodine (III) diacetate (PIDA). The formed 2-aryl-2H-azirines could be applied in the synthesis of indole-3-carbonitriles or isoxazoles via
thermal rearrangements.

2H-Azirines, a class of highly strained and reactive molecules

with a CdN bond incorporated into a three-membered ring,
have been extensively studied for their presence in natural
products1 and high synthetic potential in the synthesis of
functionalized aminoderivatives and N-containing hetero-
cycles.2 In particular, 2H-azirines bearing an R-aryl group,
are impressive intermediates for the preparation of various
substituted indoles: this unique approach starts from an alkyl-
substituted arene and joins the N-moiety on the side-chain
to the benzene ring via aryl C-H amination at the last
synthetic stage.3
Existing strategies for the synthesis of 2H-azirines can be
generalized2,4 into the following types: (1) The classic Neber
process, which is most extensively used (route a in Figure
1). (2) Pyrolysis or photolysis of vinyl azide (route b in Figure 1. General strategies for the construction of 2H-azirine
skeleton.
(1) (a) Miller, T. W.; Tristram, E. W.; Wolf, F. J. J. Antibiot. 1971, 24,
48–50. (b) Stapley, E. O.; Hendlin, D.; Jackson, M.; Miller, A. K.;
Hernandez, S.; Mata, J. M. J. Antibiot. 1971, 24, 42–47. (c) Molinski, T. F.;
Ireland, C. M. J. Org. Chem. 1988, 53, 2103–2105. (d) Salomón, C. E.; Figure 1). (3) Elimination reaction or Swern oxidation of
Williams, D. H.; Faulkner, D. J. J. Nat. Prod. 1995, 58, 1463–1466. (e) aziridine derivatives (route c in Figure 1). (4) Ring contrac-
Skepper, C. K.; Molinski, T. F. J. Org. Chem. 2008, 73, 2592–2597. tion of isoxazoles, oxazaphospholes or azete derivatives
(2) For reviews, see: (a) Palacios, F.; Ochoa de Retana, A. M.; Martinez
de Marigorta, E.; Manuel de los Santos, J. Org. Prep. Proc. Int. 2002, 34, (route d and e in Figure 1). (5) Intermolecular reactions
219–269. (b) Palacios, F.; Ochoa de Retana, A. M.; Martinez de Marigorta, between nitriles and carbenes or nitrenes and acetylenes
E.; Manuel de los Santos, J. Eur. J. Org. Chem. 2001, 13, 2401–2414. (c)
Pinho e Melo, T. M. V. D.; Rocha Gonsalves, A. M. d’A. Curr. Org. Chem. (route f and g in Figure 1). To the best of our knowledge,
2004, 1, 275–292. there has been no report on the synthesis of 2H-azirines
10.1021/ol9006663 CCC: $40.75  2009 American Chemical Society
Published on Web 05/13/2009
Table 1. Intramolecular Azirination of Enamines Mediated by PIDAd

a
Isolated yields after silica gel chromatography. b Ar herein represents 4-chlorophenyl group. c Reactions occurred at rt. d Conditions: all reactions were
carried out with 1 equiv of 1, 1.2 equiv of PIDA in ClCH2CH2Cl at 0 °C unless otherwise stated.

utilizing enamine derivatives as starting materials (route h enamines with PIFA under the same conditions would afford
in Figure 1). In this communication, we report that various an inseparable, complex mixture of unidentifiable com-
substituted enamine compounds could be oxidized by phe- pounds. Further study on the reaction conditions led us to
nyliodine(III) diacetate (PIDA), a readily available hyper- discover that mediated by phenyliodine (III) diacetate
valent iodine reagent, into an assortment of 2-functionalized (PIDA), a less potent oxidant than PIFA, a variety of
2H-azirine derivatives. Literature survey indicated that this 2-arylethenamines could be conveniently converted to the
could represent the first example of the formation of such corresponding 2H-azirine derivatives.
smallest unsaturated nitrogen heterocycles via intramolecuar The required enamine substrates could be easily obtained
azirination of enamine derivatives. via condensation by the known procedures6 (see Supporting
In our previous work,5 the formation of a variety of Information for details). Thus intramolecular azirination of
N-arylated or N-alkylated indole derivatives were realized various substituted enamine compounds7 was carried out
via intramolecular cyclization of 2-aryl-3-arylamino (or alkyl- under optimized conditions8 to study the scope and generality
amino)-2-alkenenitriles mediated by phenyliodine bis(trif- of the process, and the results are summarized in Table 1. A
luoroacetate) (PIFA). However, this approch was not desir- variety of
-enaminonitriles with different substitution pat-
able for the synthesis of the N-unsubstituted indoles since terns could be used to the methodology (entries 1-7, Table
the reaction of the corresponding N-unsubstituted 2-aryleth- 1), and the corresponding 2-aryl-2H-azirine-2-carbonitriles
2644 Org. Lett., Vol. 11, No. 12, 2009
were achieved in appreciable yields (65-83%). We next
prepared substrate 1h, structurely differing from 1a by
exchanging the position of the phenyl and methyl group, and Scheme 1. Proposed Pathway for the Azirination of Enamine
Derivatives 1
found that it could also conveniently give 3-aryl-2H-azirine-
2-carbonitrile 2h (85%) by the described method. This result
indicated that the R-aryl group in ketonitriles 1a-g was not
indispensable for the azirination to occur. The conversion
of 1j to azirinated product 2j could further support the above
conclusion and clearly implied that both R1 and R2 substit-
uents in substrate 1 could be alkyl groups.
The cyano group in substrates 1a-i was crucial for
maintaining the enamine, rather than the imine tautomer. In
light of this, we were intrested in replacing the cyano group
with other electron-withdrawing groups, for example, a
substituent with a carbonyl moiety. To our delight, the
enamines (1j-l) of 3-arylacetylacetones also rendered the react with PIDA to form intermediate A by losing one
correponding 2H-azirines (2j-l) in desirable yields (68-88%) equivalent of AcOH. Then tautomerization of A would
under the same reaction conditions, and both electron- generate an imine ylide B, in which the carbanion could be
withdrawing and electron-donating aromatic substituents greatly stabilized by the electron-withdrawing substituents
were well tolerated. However, when the electron-withdrawing (E groups). Next, the carbanion would nucleophilicly attact
group was an ethoxycarbonyl group, we got only the two the nitrogen center, with the concomitant release of phenyl
desired azirine products 2m and 2n prepared from the iodide and acetate anion, to produce intermediate C. Finally,
enamine substrates 1m and 1n, repectively. Similar substrates the positively charged nitrogen atom in C was deprotonated
1o and 1p (Figure 2), differing from 1m by replacing the by the acetate anion and thereby gave the title 2H-azirine
compounds 2. Based on the fact that an ethoxycarbonyl group
is less electron-withdrawing than a cyano or an acetyl group,
we tentatively propose that the unsuccessful or low-yield
azirination of 1o-p or 1n might be explained by the fact
that the cabanions in corresponding B (if formed) would act
more strongly as bases to seize a proton, rather than as
nucleophiles to attack the nitrogen center.
It is worth noting that the substituted 2H-azirine-2-
Figure 2. Other models that failed to afford 2H-azirine products. carbonitriles (2a-i) achieved by our approch should be
superior to the classic Neber reaction in that the requisite
R-cyano ketone oximes for the Neber process were unstable
nitro group with H or methoxy substituents, yielded no and always afforded the intramolecularly cyclized 5-ami-
desired corresponding azirine product in each case. Another noisoxazole derivatives in the reaction system.3b,10
closely related substrate 1q9 (Figure 2) also failed the
One important application of the obtained 2-aryl-2H-azirine
azirination under the same reaction conditions.
derivatives 2 we can envisage is to transform them into various
In addition to the spectroscopic data, X-ray crystallography indole compounds via a thermal rearrangement3a-h or metal-
of the colorless crystals of both 2c (shown in Figure 3) and catalyzed isomerization process.3i-k Thus pyrolysis of vari-
2l (see Supporting Information for details) were achieved, ous prepared 2-aryl-substitued 2H-azirine derivatives was
which unambiguously confirmed the structures of the ob- tested in xylene under N2 protection. The results listed in
tained 2H-azirine compounds. Table 2 demonstrated that by heating in xylene at 140 °C,
A plausible mechanism for the above azirination process all 2-aryl-2H-azirine-2-carbonitriles (2a-g, Table 2) could be
is shown in Scheme 1. Initially, enamine compound 1 would efficiently rearranged to the correponding indole-3-carboni-
triles in good yields. For the meta-substituted 2H-azirine 2d,
a mixture of 7-substituted and 5-substituted regioisomeric
indole products were both achieved, in a yield of 70 and
20%, respectively.
For substrate 2n, in which E represents an ethoxy-
carbonyl group, the indole product 3n was obtained in
relatively low yield (42%), with concominant formation of
other unidentified byproducts. Unfortunatly, no desired indole
product was detected when the thermolysis of 2m was
conducted in the same way. The deactivation of the aromatic
Figure 3. X-ray crystallography of 2H-azirine 2c. ring by the nitro group might be the reason for the failure
of the expected rearrangement process under thermolysis
Org. Lett., Vol. 11, No. 12, 2009 2645
 To summarize, we demonstrated herein the first example
of intramolecular azirination of enamine derivatives by using
Table 2. Preparation of 3-Functionalized Indoles 3 via PIDA as the oxidant. The obtained 2-aryl-2H-azirine-2-
Thermolysis of 2-Aryl-2H-azirines (E ) CN or COOEt)a
carbonitriles could readily undergo the known thermal
rearrangement process3a-h to afford a variety of indole-3-
carbonitriles, which might be useful building blocks in the
synthesis of complex indole compounds.

indole 3 Acknowledgment. Y. Du acknowledges the National

entry 2 R R 2
E time (h) yield (%) b Natural Science Foudation of China (#20802048) and
Cultivation Foundation (B) for New Faculty of Tianjin
1 2a H Me CN 3a 10 85 University (#5110109). Z. Liang thanks the National Un-
2 2b 6-F Me CN 3b 4 90
dergraduate Innovative Test Program. We also thank Miss
3 2c 6-Cl Me CN 3c 5 94
4 2d 5-Cl/7-Cl Me CN 3d/3d′ 5 72/20
Xiling Zhao, University of California, San Diego, for revising
5 2e 6-Br n-Pr CN 3e 6 88 our English text.
6 2f 6-Cl 4-Cl-Ph CN 3f 12 85 Supporting Information Available: Detailed experimen-
7 2g 4-Me Me CN 3g 6 92
tal procedures and spectral data for all new compounds and
8 2n H Bn COOEt 3n 6 42
X-ray structural data of 2c and 2l. This material is available
a
Conditions: all reactions were carried out in xylene at 140 °C under
N2. b Isolated yields after silica gel chromatography.
free of charge via the Internet at http://pubs.acs.org.
OL9006663

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2646 Org. Lett., Vol. 11, No. 12, 2009