Reactions of azepinones with electrophiles

Article abstract of DOI:10.1016/j.tetlet.2010.12.091

Azepinones are available via a one-pot cycloaddition-ring expansion reaction sequence in good yield. The reactions of azepinones with alkyl halides and epoxides were studied. We report herein protocols for the alkylation of azepinones at nitrogen with alk

Full text of DOI:10.1016/j.tetlet.2010.12.091

Tetrahedron Letters 52 (2011) 939–942
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Reactions of azepinones with electrophiles
Galyna G. Dubinina a, , William J. Chain a,b,
⇑
a Department of Chemistry, University of Hawaii, 2545 McCarthy Mall, Honolulu, HI 96822, United States
b University of Hawaii Cancer Center, 651 Ilalo Street, Honolulu, HI 96813, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
Azepinones are available via a one-pot cycloaddition-ring expansion reaction sequence in good yield. The
reactions of azepinones with alkyl halides and epoxides were studied. We report herein protocols for the
alkylation of azepinones at nitrogen with alkyl halides and epoxides and the isomerizations that occur in
the presence of a base. We also report an unexpected ring contraction under oxidative conditions.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 14 November 2010
Revised 8 December 2010
Accepted 19 December 2010
Available online 24 December 2010
Keywords:
Azepinone
Isomerization
Ring-expansion
Ring-contraction
Alkylation
Alkyl halide
Epoxide
Synthesis
Alkaloid
Azepinones are important heterocycles embedded in the struc-
tures of many biologically-relevant alkaloids, and can serve as
intermediates in the synthesis of a variety of complex nitrogen-
containing molecules. Thus, methods for the generation and manip-
ulation of azepinones are of interest to the synthetic community.
We recently reported a one-pot synthesis of 1H-azepin-5(2H)-
ones and noted their sensitivity to base;1 1H-azepin-5(2H)-ones
undergo an unexpectedly facile isomerization to the corres-
ponding 1H-azepin-5(4H)-ones under conditions that were previ-
ously described for their synthesis.2 The 1H-azepin-5(2H)-ones
are robust toward acid, an observation we used to our advantage
in developing an efficient synthetic protocol. The 1H-azepin-
5(2H)-one 1 is obtained in high yield in a one-pot procedure via
the cycloaddition of Danishefsky’s diene3 to 2H-azirine-3-carbox-
ylate ethyl ester,2 followed by a ring expansion in the presence
of silica gel (Scheme 1). The previously described synthetic proto-
col3 for azepinones of this type is problematic due to base-induced
isomerizations of the desired products, however, this issue is com-
pletely avoided by employing the one-pot reaction sequence. Dur-
ing the course of our studies, we demonstrated that bases as mild
as fluoride anion (conjugate acid HF pKa ꢀ3 in water) are sufficient
to induce the undesired (and effectively irreversible) isomeriza-
tion, so we anticipated that transformations as trivial as alkylation
of azepinones at nitrogen would be problematic. We report herein
conditions for the further elaboration of 1H-azepin-5(2H)-ones and
1H-azepin-5(4H)-ones, and the unexpected reactivity of the
alkylated azepinones toward oxidants.
In the absence of exogenous base, alkylation of 1H-azepin-
5(2H)-one 1 at nitrogen with reactive electrophiles such as benzyl
bromide does not proceed at any appreciable rate (Table 1, entry
1), even in the presence of mild amine bases (Table 1, entry 2).
However, addition of sodium hydride is sufficient to induce alkyl-
ation (51% yield, Table 1, entry 3) at the cost of a significant
amount of isomerization to give the corresponding N-benzyl-aze-
OTMS
O
TMSO
Δ
EtO
CO2Et
CH2Cl2
H3CO
N
N
OCH3
silica gel
O
CO2Et
1, 86%
⇑
Corresponding author. Tel.: +1 808 956 5795; fax: +1 808 956 5908.
N
E-mail address: chain@hawaii.edu (W.J. Chain).
Present address: SensoPath Technologies, Inc., 920 Technology Boulevard, Suite B,
Bozeman, MT 59718, USA.
H
Scheme 1. One-pot preparation of 1H-azepin-5(2H)-ones.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.12.091

940
G. G. Dubinina, W. J. Chain / Tetrahedron Letters 52 (2011) 939–942
Table 1
azepin-5(4H)-one products 2b–5b arise via isomerization of the
Reaction of 1H-azepin-5(2H)-one 1 with alkyl halides
starting material followed by alkylation; exposure of N-alkyl-aze-
pin-5(2H)-ones 2a–5a to the alkylation reaction conditions for ex-
tended periods of time does not appear to induce any detectable
isomerization.
We also found that 1H-azepin-5(2H)-ones are sufficiently nucle-
ophilic to open terminal epoxides (Table 2). Again, the addition of
exogenous base was necessary, with the DMSO/K2CO3 reaction
conditions proving most efficient (Table 2, entries 6, 7, and 9). Unfor-
tunately, we found that the epoxide opening reactions gave N-alkyl-
azepin-5(4H)-ones exclusively, presumably due to the presence of
alkoxide intermediates. We attempted several epoxide opening
reactions under typical acidic conditions in order to avoid this issue,
with little success (e.g., Table 2, entries 1–3).
We examined analogous alkylation and epoxide opening reac-
tions using the isomeric 1H-azepin-5(4H)-one 11 and found that
it is also a competent nitrogen nucleophile (Table 3). We have
also been able to acylate both azepinone isomers efficiently to
afford the corresponding N-Boc compounds in high yield (Eqs.
1 and 2).
O
O
O
R–X
CO2Et
CO2Et
CO2Et
base
solvent
N
N
N
H
R
R
1
2-5a
2-5b
Entry R–X
Base
Solvent Temp (°C) Product Yield a/b (%)
1
2
3
4
5
6
7
8
9
BnBr
BnBr
BnBr
BnBr
BnBr
—
THF
66
23
23
40
60
60
66
40
66
60
60
2
2
2
2
2
3
4
4
4
4
5
—
—
i-Pr2NEt THF
NaH
LDA
THF
THF
DMSO
DMSO
51/18
45/—
75/5
70/6
—
—
—
58/30
21/26
K2CO3
Allyl-Br K2CO3
n-BuBr
n-BuBr
n-BuBr
n-BuBr
i-PrI
i-Pr2NEt THF
i-Pr2NEt CH2Cl2
K2CO3
K2CO3
K2CO3
THF
DMSO
DMSO
10
11
Reactions were conducted at 0.07 M in the indicated solvent for 24 h, with 1.5 equiv
alkyl halide and bases as follows: i-Pr2NEt (1.3 equiv), NaH (1.3 equiv), LDA
(1.1 equiv), K2CO3 (3 equiv).
O
O
O
Boc2O
CO2Et
CO2Et
CO2Et
NEt3
CH2Cl2
N
N
N
pin-5(4H)-one 2b (18% yield). After some experimentation, we
found that employing a more polar, aprotic solvent (DMSO) and
employing solid potassium carbonate as the base cleanly afforded
the desired N-benzyl-azepin-5(2H)-one 2a (75% yield, Table 1, en-
try 5).4 The isomeric alkylation product was barely detectable by
1H NMR analysis of the crude product mixture. We found these
conditions to be general; the 1H-azepin-5(2H)-one 1 undergoes
alkylation with activated, unactivated, and even hindered unacti-
vated electrophiles such as 2-iodopropane (Table 1, entries 6, 10,
and 11), though less active electrophiles result in isomeric
product mixtures. We have evidence to suggest that the N-alkyl-
H
Boc
Boc
23 °C, 16h
79% (9:1 12:13)
12
13
1
ð1Þ
O
O
Boc2O
CO2Et
CO2Et
ð2Þ
NEt3
CH2Cl2
23 °C, 16h
94%
N
N
H
Boc
13
11
Table 2
Reaction of 1H-azepin-5(2H)-one 1 with epoxides
O
O
O
O
R
CO2Et
CO2Et
CO2Et
additive
solvent
N
N
N
H
OH
O
1
R
6-9
10
Entry
Epoxide
Additive
Solvent
Temp (°C)
Product
Yield (%)
O
1
2
3
4
5
6
7
TsOHꢁH2O
BF3ꢁOEt2
—
CH2Cl2
CH2Cl2
CH2Cl2
THF
23?40
23?40
23?40
66
6
6
6
6
6
6
7
—
Ph
O
—
Ph
O
—
Ph
O
NaH
—
Ph
O
K2CO3
K2CO3
K2CO3
THF
66
37
65
19
Ph
O
DMSO
DMSO
60
Ph
O
60
n-Hex
O
8
9
K2CO3
K2CO3
DMSO
DMSO
60
60
8
9
—
O
Cl
34 (17% 10)
Reactions were conducted at 0.07 M in the indicated solvent for 24 h, with 1.5 equiv epoxide and additives as follows: TsOHꢁH2O (0.1 equiv), BF3ꢁOEt2 (0.2 equiv), Yb(OTf)3
(0.1 equiv), NaH (1.1 equiv), K2CO3 (3 equiv).

G. G. Dubinina, W. J. Chain / Tetrahedron Letters 52 (2011) 939–942
941
Table 3
might suggest that the isomerization of the double bond occurs
after formation of 2-pyrrolidinone if the reaction proceeds by the
proposed mechanism.
Reaction of 1H-azepin-5(4H)-one 11 with alkyl halides and epoxides
O
O
O
electrophile
O
O
CO2Et
CO2Et
or
CO2Et
Br
K2CO3
DMSO
60 °C
24h
N
N
Br2
N
CO2Et
CO2Et
H
R
OH
CH2Cl2
23 °C
99%
N
ð3Þ
•HBr
N
2b-5b
11
Ph
Br
16
6
3a
Entry
Electrophile
Product
Yield (%)
Br
1
2
3
4
BnBr
2b
3b
4b
5b
98
87
87
57
We have also observed that treatment of the N-allyl 1H-azepin-
Allyl bromide
n-BuBr
i-PrI
5(2H)-one 3a with molecular bromine affords a tribrominated
product 16 in which the allyl sidechain and the vinylogous amide
have both undergone electrophilic attack (Eq. 3). This tribrominat-
ed product dominates regardless of the stoichiometry of bromine,
but is formed cleanly and in good yield when 2 equiv of bromine
is employed. This result may lend some support to our proposed
mechanism above wherein the vinylogous amide acts as a carbon
nucleophile but is by no means conclusive.
O
5
6
62
Ph
Reactions were conducted at 0.07 M for 24 h with 1.5 equiv electrophile and 3 equiv
K2CO3.
We have developed conditions for the alkylation of 1H-azepin-
5(2H)-ones with alkyl halides with minimal isomerization to the
corresponding 1H-azepin-5(4H)-ones. Analogous alkylations with
terminal epoxides afford 1H-azepin-5(4H)-one products exclu-
sively, presumably due to basic alkoxides in the reaction mixtures.
We have documented the unexpected nucleophilicity of the vinyl-
ogous amide moiety of the azepinones, and an unexpected ring
contraction of N-alkyl 1H-azepin-5(2H)-ones in the presence of
an oxidizing peracid. We are continuing to study the unusual
behavior and synthetic potential of these important heterocycles,
and we are working toward rigorously establishing the mechanism
of the mCPBA-induced oxidative ring contraction.
We attempted to further elaborate the N-alkyl azepinones as
part of our studies in total synthesis and made some surprising
observations. For example, we observed no oxidation of the N-allyl
azepinone 3a upon treatment with osmium tetroxide (up to
10 mol %) and N-methylmorpholine N-oxide (NMO) even after a
prolonged reaction time. We also treated 3a with m-chloroperben-
zoic acid (mCPBA) in the presence of sodium bicarbonate in aque-
ous dichloromethane in an attempt to obtain the epoxide, but we
were surprised to observe clean formation of the ring-contracted
product, the N-allyl 2-pyrrolidinone 14 in 75% yield, with no evi-
dence of epoxidation of the allyl sidechain (Scheme 2). No epoxide
formation was observed even in the presence of excess mCPBA. The
N-benzyl azepinone 2a undergoes an analogous transformation as
well upon treatment with mCPBA.5 We are in the process of eluci-
dating the mechanism of this reaction, however, to date we have
not isolated or rigorously characterized any intermediates. We pro-
pose the ring contraction proceeds via epoxidation of the vinylo-
gous amide, followed by a ring closure to give a hemiaminal (see
Scheme 2). Isomerization of the hemiaminal epoxide moiety and
ring-opening affords an epoxy aldehyde that can undergo attack
by water and retro-aldol to give a 2-pyrrolidinone. Isomerization
of the double bond leads to the observed product. We have not
been successful in observing or isolating any glyoxaldehyde that
might lend support to this proposed mechanism. We noted that
the N-alkyl 1H-azepin-5(4H)-ones (2b and 3b) do not undergo this
ring contraction in the presence of mCPBA, presumably due to the
decreased nucleophilicity of the isomeric vinylogous amide. This
Acknowledgments
Financial support from the University of Hawaii and the Univer-
sity of Hawaii Cancer Center is gratefully acknowledged. We thank
Professors Tius and Navarro and their respective groups (UH) for
generous donations of equipment and chemicals and for helpful
discussions. We thank Dr. W. Niemczura (UH) for mass spectrom-
etry analyses and W. Yoshida (UH) for NMR assistance.
Supplementary data
Supplementary data (detailed experimental procedures, spec-
tral data for all new compounds) associated with this article can
be found, in the online version, at doi:10.1016/j.tetlet.2010.12.091.
O
O
O
O
O
O
mCPBA
NaHCO3
CO2Et
O
CO2Et
N
CO2Et
CO2Et
3a
O
CO2Et
CO2Et
O
N
N
N
N
N
CH2Cl2 / H2O
23 °C, 16h
75%
14
3a
O
mCPBA
NaHCO3
O
O
O
OH
O
OH
CO2Et
H2O
CO2Et
Retro
CO2Et
CO2Et
OHC
N
Ph
N
N
OHC
CO2Et
CH2Cl2 / H2O
23 °C, 16h
49%
N
CO2Et
N
Aldol
N
2a
15
14
Ph
Scheme 2. An unexpected oxidative ring contraction.

942
G. G. Dubinina, W. J. Chain / Tetrahedron Letters 52 (2011) 939–942
electrophile (0.75 mmol, 1.50 equiv) were added sequentially to
a
stirred
References and notes
solution of azepinone 1 (91 mg, 0.50 mmol, 1 equiv) in 7 mL dimethylsulfoxide
(0.07 M) at 23 °C. The resultant suspension was placed in an oil bath preheated to
60 °C and stirred at that temperature for 24 h, then was cooled and partitioned
between saturated aqueous sodium chloride solution (20 mL) and ethyl acetate
(20 mL). The layers were separated and the aqueous layer was extracted with
ethyl acetate (3 ꢂ 10 mL). The combined organic layers were dried over
anhydrous sodium sulfate and the dried solution was concentrated. The
residue was purified by flash column chromatography (80% ethyl acetate–
hexanes) to afford the alkylated product.
1. Dubinina, G.; Yoshida, W. Y.; Chain, W. J. Tetrahedron Lett. 2010, 51, 5325–5327.
2. (a) Alves, M. J.; Gilchrist, T. L. J. Chem. Soc., Perkin Trans. 1 1998, 299–303; (b)
Alves, M. J.; Gilchrist, T. L. Tetrahedron Lett. 1998, 39, 7579–7582; (c) Alves, M. J.;
Fortes, A. G.; Costa, F. T. Tetrahedron 2006, 62, 3095–3102; (d) Alves, M. J.; Fortes,
A. G.; Costa, F. T.; Duarte, V. C. M. Tetrahedron 2007, 63, 11167–11173.
3. (a) Danishefsky, S.; Kitahara, T.; Yan, C. F.; Morris, J. J. Am. Chem. Soc. 1979, 101,
6996–7000; (b) Danishefsky, S.; Yan, C.-F.; Singh, R. K.; Gammill, R. B.; McCurry,
P. M., Jr.; Fritsch, N.; Clardy, J. J. Org. Chem. 1979, 101, 7001–7008.
5. The ring contraction occurs with or without the inclusion of sodium
bicarbonate.
4. General procedure for alkylation and epoxide opening reactions with azepinone
1: anhydrous potassium carbonate (207 mg, 1.50 mmol, 3.00 equiv) and an