Cycloaddition reaction of 2-vinylazetidines with benzyne: A facile access to 1-benzazocine derivatives

Article abstract of DOI:10.1021/ol3019924

The cycloaddition reaction of 2-vinylazetidines with benzyne proceeded smoothly without a catalyst, and various benzazocine derivatives were isolated in good to high yields. The scope of the reaction, as well as the reactions of other arynes, has been studied.

Full text of DOI:10.1021/ol3019924

ORGANIC
LETTERS
2012
Vol. 14, No. 17
4506–4509
Cycloaddition Reaction of 2‑Vinylazetidines
with Benzyne: A Facile Access to
1‑Benzazocine Derivatives
Takashi Aoki, Shunsuke Koya, Ryu Yamasaki,† and Shinichi Saito*
Department of Chemistry, Faculty of Science, Tokyo University of Science, Kagurazaka,
Shinjuku, Tokyo, 162-8601, Japan
ssaito@rs.kagu.tus.ac.jp
Received July 18, 2012
ABSTRACT
The cycloaddition reaction of 2-vinylazetidines with benzyne proceeded smoothly without a catalyst, and various benzazocine derivatives were
isolated in good to high yields. The scope of the reaction, as well as the reactions of other arynes, has been studied.
The 1-benzazocine structure is found in many biologi-
cally activecompounds,1 and various syntheticapproaches
have been reported. A multistep synthesis, involving olefin
metathesis,2 a MizorokiꢀHeck reaction,3 or other reactions,4
is frequently required to synthesize benzazocine derivatives,
and the development of a new and efficient synthesis of these
compounds is highly desirable.
2-vinylazetidine with electron-deficient alkynes5 or tosyl
isocyanate6 gives eight-membered nitrogen-containing
heterocyclic compounds, and the palladium-catalyzed
reaction of 2-vinylazetidine with phenyl isocyanate af-
forded a six-membered nitrogen-containing heterocyclic
compound.7 The ring-expansion reaction of 2-alkenyl-
azetidium salts yielded azepane derivatives.8
We have been interested in the ring-expansion reactions
of 2-vinylazetidines which afforded nitrogen-containing
heterocyclic compounds. For example, the reaction of
Recently, Greaney and co-workers reported that ben-
zyne could promote aza-Claisen reactions: the ring expan-
sion reactions of some five- and six-membered cyclic
vinylamines proceeded, and the formation of unsaturated
nine- and ten-membered cyclic amines was observed.9
These results prompted us to study the ring expansion
reaction of 2-vinylazetidines. In this paper we report the
synthesis of 1-benzazocine derivatives by the reaction of
2-vinylazetidines with benzyne.
We first explored the reaction of 1-benzyl-2-vinylazeti-
dine (1a)6 with benzyne (2a), employing 2-(trimethylsilyl)-
phenyl trifluoromethanesulfonate (2a0) as the precursor.10
Reaction conditions were screened, and the results are
summarized in Table 1.
† Present address: Molecular Engineering Institute, Kinki University, 11-6
Kayanomori, Iizuka, Fukuoka, 820-8555, Japan.
(1) (a) Trost, B. M.; O’Boyle, B. M.; Torres, W.; Ameriks, M. K.
Chem.;Eur. J. 2011, 17, 7890–7903. (b) Namiki, H.; Chamberland, S.;
Gubler, D. A.; Williams, R. M. Org. Lett. 2007, 9, 5341–5344. (c) Hino,
K.; Nagai, Y.; Uno, H. Chem. Pharm. Bull. 1988, 36, 2386–2400.
(d) Ogawa, H.; Yamashita, H.; Kondo, K.; Yamamura, Y.; Miyamoto,
H.; Kan, K.; Kitano, K.; Tanaka, M.; Nakaya, K.; Nakamura, S.; Mori,
T.; Tominaga, M.; Yabuuchi, Y. J. Med. Chem. 1996, 39, 3547–3555.
(e) Seto, M.; Aikawa, K.; Miyamoto, N.; Aramaki, Y.; Kanzaki, N.;
Takashima, K.; Kuze, Y.; Iizawa, Y.; Baba, M.; Shiraishi, M. J. Med.
Chem. 2006, 49, 2037–2048.
(2) (a) Majumdar, K. C.; Samanta, S.; Chattopadhyay, B.; Nandi,
R. K. Synthesis 2010, 863–869. (b) Fujiwara, T.; Kato, Y.; Takeda, T.
Heterocycles 2000, 52, 147–150.
(3) Ayala, S. L. G.; Stashenko, E.; Palma, A.; Bahsas, A.; Amaro-
Luis, J, M. Synlett 2006, 14, 2275–2277.
(7) Inman, G. A.; Bulter, D. C. D.; Alper, H. Synlett 2001, 914–919.
(8) Couty, F.; Durrat, F.; Evano, G.; Marrot, J. Eur. J. Org. Chem.
2006, 4214–4223.
(9) Cant, A. A.; Bertrand, G. H. V.; Henderson, J. L.; Roberts, L.;
Greaney, M. F. Angew. Chem., Int. Ed. 2009, 48, 5199–5202.
(10) Himeshima, Y.; Sonoda, T.; Kobayashi, H. Chem. Lett. 1983,
1211–1214.
(4) Boger, D. L.; Turnbull, P. J. Med. Chem. 1997, 62, 5849–5863.
(5) (a) Stogryn, E. L.; Brois, S. J. J. Am. Chem. Soc. 1967, 89, 605–
609. (b) Hassner, A.; Wiegand, N. J. Org. Chem. 1986, 51, 3652–3656.
ꢀ
(c) Drouillat, B.; Couty, F.; Razafimahaleo, V. Synlett 2009, 3182–3186.
(6) Koya, S.; Yamanoi, K.; Yamasaki, R.; Azumaya, I.; Masu, H.;
Saito, S. Org. Lett. 2009, 11, 5438–5441.
r
10.1021/ol3019924
Published on Web 08/10/2012
2012 American Chemical Society

Table 1. Optimization of the [6 þ 2] Cycloaddition Reaction
Table 2. Reactions of Various 2-Vinylazetidines with Benzyne
X
R1
R2
Bn
3xa
yielda
entry
solvent
(equiv)
temp
yielda
entry
1x
1
2
3
4
5
6
1a
1b
1c
1d
1e
1f
H
3aa
3ba
3ca
3da
3ea
3fa
81%
73%
43%
78%
41%
59%
1
2
3
4
5
6
PhMe/MeCN (1:1)
PhMe/MeCN (1:1)
PhMe/MeCN (1:1)
PhMe/MeCN (1:1)
MeCN
3
50 °C
50 °C
rt
76%
81%
51%
79%
63%
0%
Me
Ph
H
Bn
4.5
4.5
4.5
4.5
4.5
Bn
PMB
n-Octyl
Cyb
80 °C
50 °C
50 °C
H
H
PhMe
a Isolated yield. b Cyclohexyl.
a Isolated yield.
To a suspension of CsF (3 equiv) in a 1:1 mixture of
toluene and acetonitrile was slowly added (5 h) a solution
of 1-benzyl-2-vinylazetidine (1a) and benzyne precursor
(2a0), and the mixture was stirred at 50 °C for an additional
14 h. The ring expansion reaction proceeded smoothly,
and the corresponding 1-benzazocine derivative (3aa) was
isolated in 76% yield (entry 1). It is noteworthy that the
reaction proceeded selectively and the formation of a
quinoline derivative was not observed. When a larger
amount (4.5 equiv) of CsF was used, compound 3aa was
isolated in 81% yield (entry 2). The yield of 3aa decreased
when the reaction was carried out at room temperature or
at 80 °C (entries 3 and 4). We also studied the solvent effect
on the reaction. When acetonitrile was selected as the sol-
vent, compound 3aa was isolated in 63% yield (entry 5).
On the other hand, compound 3aa was not isolated when
the reaction was carried out in toluene (entry 6). The lower
yields of 3aa in solvents other than tolueneꢀacetonitrile
could be attributed to the solubility of CsF. Thus, the
presence of a large amount of fluoride ion in acetonitrile
induced side reactions, and the solubility of CsF was very
low in toluene, preventing the formation of benzyne.
The generality of the cycloaddition was examined by
carrying out the reaction of 2-vinylazetidine with various
substituents. The results are summarized in Table 2.
Cycloaddition of 1b (R1 = Me)6 with benzyne proceeded
smoothly, and 3ba was isolated in 73% yield (entry 2). The
yield of the product decreased when the phenyl group6 was
introduced as the substrate (entry 3). We also studied the
reactions of various N-substituted 2-vinylazetidines. Thus,
the reaction of 1d (R2 = p-methoxybenzyl (PMB)) with
benzyne gave 3da in 78% yield (entry 4). The correspond-
ing benzazocine derivatives were isolated in lower yields
when the octyl or cyclohexyl group11 was introduced as the
substituent (entries 5 and 6).
(2b) proceeded with moderate regioselectivity, and 3ab-1
was isolated as the major product (Scheme 1). It is note-
worthy that the nitrogen atom of the azetidine attacked the
meta position of the methoxy group exclusively.
Scheme 1. Reaction of 1a with 2b0
We also studied the reaction of 1a with naphthalyne.
Thus, the reaction of 1a with 2c0 in the presence of CsF
gave 3ac in 63% yield, and other isomers were not isolated
(Scheme 2). A similar result was obtained in the reaction of
1a with 2d0, supporting the formation of 1,2-naphthalyne
as the intermediate.
To gain insight into the mechanism of this reaction, we
carried out the reaction of 1a with 2a0 in deuterated
acetonitrile (Scheme 3).9 The NMR analysis as well as
the mass spectroscopic analysis revealed that a 1:1 mixture
of 3aa and 3aa-D was isolated in a 43% combined yield.
The result indicated that the uptake of the proton from
acetonitrile proceeded during the reaction.
Based on our results and closely related studies,9 a pos-
sible mechanism of this reaction is shown in Scheme 4.
The reaction is initiated by the nucleophilic attack of the
nitrogen atom of vinylazetidine to benzyne. The zwitter-
ionic species would be protonated to give an azetidinium
salt. The isolation of the ammonium salt by the reaction of
allylaminewithbenzyne hasbeenreported by Greaneyand
Next, we studied the reaction of vinylazetidine 1a with
various arynes. The reaction of 1a with 3-methoxybenzyne
(11) Inman, G. A.; Butler, D. C. D.; Alper, H. Synlett 2001, 914–919.
Org. Lett., Vol. 14, No. 17, 2012
4507

The regioselective reactions of arynes would be ex-
plained in terms of the electronic effect and the steric effect
of the substituents. Thus, the attack of the nucleophile
(azetidine) would occur at the meta position to the meth-
oxy group of 3-methoxybenzyne (2b) (Scheme 5).12 Sub-
sequent rearrangementwouldproceedvia the lesssterically
hindered transition state, providing 3ab-1 as the major
product.13
Scheme 2. Reaction of 1a with Naphthalynes
Scheme 5. Regioselective Reaction of 2b
Scheme 6. Regioselective Reactions of 2c and 2e
Scheme 3. Reaction of 1a with 2a0 with Acetonitrile-d3
co-workers.9 The azetidinium salt would rearrange under
the reaction conditions to provide the ring expansion
product. When the rearrangement of 4 proceeded, half of
the incorporated deuterium would be lost and an equimo-
lar mixture of 3aa and 3aa-D would be isolated.
The regioselective reactions of naphthalynes could be
explained by considering the stability of the intermediates
(Scheme 6). Thus, the attack of the nucleophile toward 1,2-
naphthalyne would occur at the C-2 position which is less
sterically hindered, and 5a would be formed.12 The re-
arrangement of 5a would preferentially give 5b as another
intermediate, since the aromaticity is preserved in the
structure:14 if 5c were formed as the intermediate, the
aromatic nature would be lost. The formation of 3ac as
the product would be explained by the deprotonation of
5b. The reaction of 1a with 2,3-naphthalyne would also
Scheme 4. Proposed Mechanism for the [6 þ 2] Cycloaddition
(12) Sanz, R. Org. Prep. Proc. Int. 2008, 40, 215–291.
(13) The regioselective Claisen rearrangement of a 3-methoxyaniline
derivative was reported. See: Beholz, L. G.; Stille, J. R. J. Org. Chem.
1993, 58, 5095–5100.
(14) The regioselective Claisen rearrangement of a naphthalene
derivative has been studied, and a similar result was reported. See:
Gozzo, F. C.; Fernandes, S. A.; Rodorigues, D. C.; Eberlin, M. N.;
Marsaioli, A. J. J. Org. Chem. 2003, 68, 5493–5499.
4508
Org. Lett., Vol. 14, No. 17, 2012

give 5a as the intermediate, and 3ac would be isolated as
the product.
This work was supported by the Nagase Science and
Technology Foundation and MEXT-Supported Program
for the Strategic Research Foundation at Private Univer-
sities, 2012-2016.
In summary, we have developed a new and simple method
for the synthesis of benzazocine derivatives by the [6 þ 2]
cycloaddition reaction of 2-vinylazetidines with benzyne. The
reaction proceeds by the dropwise addition of 2-vinylazetidine
and the benzyne precursor to a suspension of CsF at 50 °C,
and no catalyst is required. Further extension of this reaction
to the synthesis of other medium-sized heterocycles is ongoing.
Supporting Information Available. Experimental pro-
cedures including the synthesis of vinylazetidines,
characterization data, and copies of NMR spectra. This
material is available free of charge via the Internet at
http://pubs.acs.org.
Acknowledgment. We thank Prof. Shuji Akai from
the University of Shizuoka for his helpful suggestions.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 17, 2012
4509