Simple conversion of enamines to 2h-azirines and their rearrangements under thermal conditions

Article abstract of DOI:10.1021/ol9006663

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-2W-azirines could be applied in the synthesis of indole-3-carbon

Full text of DOI:10.1021/ol9006663

ORGANIC
LETTERS
2009
Vol. 11, No. 12
2643-2646
Simple Conversion of Enamines to
2H-Azirines and Their Rearrangements
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) Salomo´n, C. E.;
Williams, D. H.; Faulkner, D. J. J. Nat. Prod. 1995, 58, 1463–1466. (e)
Skepper, C. K.; Molinski, T. F. J. Org. Chem. 2008, 73, 2592–2597.
(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,
219–269. (b) Palacios, F.; Ochoa de Retana, A. M.; Martinez de Marigorta,
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.
2004, 1, 275–292.
Figure 1). (3) Elimination reaction or Swern oxidation of
aziridine derivatives (route c in Figure 1). (4) Ring contrac-
tion of isoxazoles, oxazaphospholes or azete derivatives
(route d and e in Figure 1). (5) Intermolecular reactions
between nitriles and carbenes or nitrenes and acetylenes
(route f and g in Figure 1). To the best of our knowledge,
there has been no report on the synthesis of 2H-azirines
10.1021/ol9006663 CCC: $40.75
Published on Web 05/13/2009
 2009 American Chemical Society

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
in Figure 1). In this communication, we report that various
substituted enamine compounds could be oxidized by phe-
nyliodine(III) diacetate (PIDA), a readily available hyper-
valent iodine reagent, into an assortment of 2-functionalized
2H-azirine derivatives. Literature survey indicated that this
could represent the first example of the formation of such
smallest unsaturated nitrogen heterocycles via intramolecuar
azirination of enamine derivatives.
enamines with PIFA under the same conditions would afford
an inseparable, complex mixture of unidentifiable com-
pounds. Further study on the reaction conditions led us to
discover that mediated by phenyliodine (III) diacetate
(PIDA), a less potent oxidant than PIFA, a variety of
2-arylethenamines could be conveniently converted to the
corresponding 2H-azirine derivatives.
The required enamine substrates could be easily obtained
via condensation by the known procedures6 (see Supporting
Information for details). Thus intramolecular azirination of
various substituted enamine compounds7 was carried out
under optimized conditions8 to study the scope and generality
of the process, and the results are summarized in Table 1. A
variety of ꢀ-enaminonitriles with different substitution pat-
terns could be used to the methodology (entries 1-7, Table
1), and the corresponding 2-aryl-2H-azirine-2-carbonitriles
In our previous work,5 the formation of a variety of
N-arylated or N-alkylated indole derivatives were realized
via intramolecular cyclization of 2-aryl-3-arylamino (or alkyl-
amino)-2-alkenenitriles mediated by phenyliodine bis(trif-
luoroacetate) (PIFA). However, this approch was not desir-
able for the synthesis of the N-unsubstituted indoles since
the reaction of the corresponding N-unsubstituted 2-aryleth-
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
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.
Scheme 1
.
Proposed Pathway for the Azirination of Enamine
Derivatives 1
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
correponding 2H-azirines (2j-l) in desirable yields (68-88%)
under the same reaction conditions, and both electron-
withdrawing and electron-donating aromatic substituents
were well tolerated. However, when the electron-withdrawing
group was an ethoxycarbonyl group, we got only the two
desired azirine products 2m and 2n prepared from the
enamine substrates 1m and 1n, repectively. Similar substrates
1o and 1p (Figure 2), differing from 1m by replacing the
react with PIDA to form intermediate A by losing one
equivalent of AcOH. Then tautomerization of A would
generate an imine ylide B, in which the carbanion could be
greatly stabilized by the electron-withdrawing substituents
(E groups). Next, the carbanion would nucleophilicly attact
the nitrogen center, with the concomitant release of phenyl
iodide and acetate anion, to produce intermediate C. Finally,
the positively charged nitrogen atom in C was deprotonated
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-
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
and always afforded the intramolecularly cyclized 5-ami-
noisoxazole derivatives in the reaction system.3b,10
Figure 2. Other models that failed to afford 2H-azirine products.
nitro group with H or methoxy substituents, yielded no
desired corresponding azirine product in each case. Another
closely related substrate 1q9 (Figure 2) also failed the
azirination under the same reaction conditions.
In addition to the spectroscopic data, X-ray crystallography
of the colorless crystals of both 2c (shown in Figure 3) and
2l (see Supporting Information for details) were achieved,
which unambiguously confirmed the structures of the ob-
tained 2H-azirine compounds.
One important application of the obtained 2-aryl-2H-azirine
derivatives 2 we can envisage is to transform them into various
indole compounds via a thermal rearrangement3a-h or metal-
catalyzed isomerization process.3i-k Thus pyrolysis of vari-
ous prepared 2-aryl-substitued 2H-azirine derivatives was
tested in xylene under N2 protection. The results listed in
Table 2 demonstrated that by heating in xylene at 140 °C,
all 2-aryl-2H-azirine-2-carbonitriles (2a-g, Table 2) could be
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.
A plausible mechanism for the above azirination process
is shown in Scheme 1. Initially, enamine compound 1 would
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
ring by the nitro group might be the reason for the failure
of the expected rearrangement process under thermolysis
Figure 3. X-ray crystallography of 2H-azirine 2c.
Org. Lett., Vol. 11, No. 12, 2009
2645

To summarize, we demonstrated herein the first example
of intramolecular azirination of enamine derivatives by using
PIDA as the oxidant. The obtained 2-aryl-2H-azirine-2-
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.
Table 2. Preparation of 3-Functionalized Indoles 3 via
Thermolysis of 2-Aryl-2H-azirines (E ) CN or COOEt)a
Acknowledgment. Y. Du acknowledges the National
Natural Science Foudation of China (#20802048) and
Cultivation Foundation (B) for New Faculty of Tianjin
University (#5110109). Z. Liang thanks the National Un-
dergraduate Innovative Test Program. We also thank Miss
Xiling Zhao, University of California, San Diego, for revising
our English text.
indole 3
entry
2
R
R2
E
time (h) yield (%)b
1
2
3
4
5
6
7
8
2a H
2b 6-F
2c 6-Cl
Me
CN
3a
3b
3c
3d/3d′
3e
10
4
85
90
Me
Me
CN
CN
5
94
2d 5-Cl/7-Cl Me
CN
5
6
72/20
88
2e 6-Br
2f 6-Cl
2g 4-Me
2n H
n-Pr
CN
4-Cl-Ph CN
3f
3g
12
6
85
92
Supporting Information Available: Detailed experimen-
tal procedures and spectral data for all new compounds and
X-ray structural data of 2c and 2l. This material is available
free of charge via the Internet at http://pubs.acs.org.
Me
Bn
CN
COOEt 3n
6
42
a Conditions: all reactions were carried out in xylene at 140 °C under
N2. b Isolated yields after silica gel chromatography.
OL9006663
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conditions, and future studies should be directed to the use
of metal catalysis3i-k for this conversion.
To our surprise, an exceptional result was obtained for
the thermolysis of the 2H-azirine compounds, where E was
an acetyl group. Under identical conditions, substrate 2j-l
underwent an intramolecular O-N bond formation, which
resulted in the formation of isoxazole derivatives11 (3j-l,
Table 3) in pleasant yields (80-92%),without any detection
of the desired indole compounds. Literature survey implied
that these results were consistent with previous reports on
the thermolysis of such similar azirine compounds.12
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(8) (a) CaH2-dried CH2Cl2, ClCH2CH2Cl, MeCN, THF, and EtOAc were
screened as solvents for azirination of 1a into 2a, the result indicated by
TLC showed that ClCH2CH2Cl was the best one. (b) Parallel experiments
using 1.1, 1.2, and 1.4 equiv of PIDA indicated that 1.2 equiv of PIDA
was optimal for the total consumption of 1a. (c) All reactions were first
studied at 0 °C to inhibit the possible formation of byproducts, for detailed
reaction temperature, see Table 1.
Table 3. Formation of Isoxazoles via Thermolysis of
2-aryl-2H-azirines (E ) acetyl group)
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entry
2
isoxazole 3
time (h)
yield(%)b
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(11) Kidwai, M.; Sapra, P. Org. Prep. Proced. Int. 2001, 33, 381–386.
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C. S.; J, Rocha; Gonsalves, A. M. d’A.; Storr, R. C. Synthesis 2002, 605–
608.
1
2
3
2j
2k
2l
3j (R ) H)
3k (R ) OMe)
3l (R ) NO2)
6
6
4
86
80
92
a Conditions: all reactions were carried out in xylene at 140 °C under
N2. b Isolated yields after silica gel chromatography.
2646
Org. Lett., Vol. 11, No. 12, 2009