Acid-mediated ring-expansion reaction of N-aryl-2-vinylazetidines: Synthesis and unanticipated reactivity of tetrahydrobenzazocines

Article abstract of DOI:10.1021/jo500249c

The aza-Clasen rearrangement of N-aryl-2-vinylazetidines has been explored. N-Aryl-2-vinylazetidines were transformed to corresponding tetrahydrobenzazocines in good yields. Unexpectedly, the tetrahydrobenzazocine was unstable and readily isomerized to vi

Full text of DOI:10.1021/jo500249c

Article
pubs.acs.org/joc
Acid-Mediated Ring-Expansion Reaction of N‑Aryl-2-vinylazetidines:
Synthesis and Unanticipated Reactivity of Tetrahydrobenzazocines
Tomoaki Shimizu,† Shunsuke Koya,† Ryu Yamasaki,†,§ Yuichiro Mutoh,† Isao Azumaya,‡,#
Kosuke Katagiri,‡,¶ and Shinichi Saito*,†
†Department of Chemistry, Faculty of Science, Tokyo University of Science, Kagurazaka, Shinjuku, Tokyo 162-8601, Japan
‡Faculty of Pharmaceutical Sciences at Kagawa Campus, Tokushima Bunri University, 1314-1 Shido, Sanuki, Kagawa 769-2193, Japan
S
* Supporting Information
ABSTRACT: The aza-Clasen rearrangement of N-aryl-2-
vinylazetidines has been explored. N-Aryl-2-vinylazetidines
were transformed to corresponding tetrahydrobenzazocines in
good yields. Unexpectedly, the tetrahydrobenzazocine was
unstable and readily isomerized to vinyltetrahydroquinoline in
the presence of acid. The mechanism of this ring contraction
was studied in detail.
the acceleration of the reaction, and the progress of the
rearrangement has been observed at lower temperature.
A practical application of this rearrangement in synthetic
organic chemistry has been developed by using a strained
substrate, which was more reactive, and some aza-Claisen
rearrangement reactions of vinylaziridines have been reported
to date.2−6 For example, Gallo and co-workers reported the aza-
Claisen rearrangement of N-aryl-2-vinylaziridines, which were
vulnerable to heat and acids.4 Gin and co-workers demon-
strated an example of strain release aza-Claisen rearrangement/
ring-expansion reaction of N-alkenyl-2-arylaziridine in the
context of the total synthesis of a natural product,
(−)-deoxyharringtonine.5,6
INTRODUCTION
■
The aza-Claisen rearrangement is a [3,3]-sigmatropic rear-
rangement that incorporates a nitrogen atom at the 3-position,
and the reactions of various allylenamines or allylanilines have
been reported to date (Figure 1a). The ability to construct an
On the basis of the chemistry of N-aryl-2-vinylaziridines, one
would expect that the corresponding azetidine analogue, an N-
aryl-2-vinylazetidine, would be a good substrate for the aza-
Claisen rearrangement. Surprisingly, to the best of our
knowledge, the aza-Claisen rearrangement of N-phenyl-2-
vinylazetidine has not been reported, and only the rearrange-
ment of N-quinonylazetidine has appeared in the literature
(Figure 1b).7
Recently, we studied a series of the ring-expansion reactions
of vinylaziridines as well as vinylazetidines and developed new
methods for the synthesis of medium-sized heterocyclic
compounds.8 Herein we report the acid-catalyzed aza-Claisen
rearrangement of N-aryl-2-vinylazetidine to yield tetrahydro-
benzazocine (Figure 1c). The unanticipated instability of the
benzazocine derivatives is also disclosed.
Figure 1. Aza-Claisen rearrangement reaction.
elaborate structure from a readily available material with
chemo-, regio-, and/or stereoselective manner by this
rearrangement has attracted considerable interest of organic
chemists. Aza-Claisen rearrangement under thermal conditions
classically requires high reaction temperature of 200 °C or
above and is plagued with undesired side reactions.1 Mean-
while, the protonation or quaternization of the amine results in
Received: February 1, 2014
Published: April 14, 2014
© 2014 American Chemical Society
4367
dx.doi.org/10.1021/jo500249c | J. Org. Chem. 2014, 79, 4367−4377

The Journal of Organic Chemistry
Article
carried out at low temperature (0 °C) and with a higher
concentration of 1a (0.5 M, entry 9). The best result was
achieved when the reaction was initially carried out at 0 °C and
then allowed to warm to room temperature: the reaction
completed in 3 h, and the selective formation of 2a was
observed (entry 10). The structure of a tetrahydrobenzazocine
was confirmed by carrying out the reaction of N-(3,4-
dimethoxyphenyl)-2-vinylazetidine (1b, Scheme 1). Thus, the
RESULTS AND DISCUSSION
■
Acid-Mediated Ring-Expansion Reaction of N-Aryl-2-
vinylazetidine. The ring-expansion reaction of N-(4-methox-
yphenyl)-2-vinylazetidine (1a) was investigated under various
reaction conditions to selectively obtain tetrahydrobenzazocine
2a. Due to the instability of 2a (vide infra), the ratio of products
was analyzed by NMR spectroscopy. The results are
summarized in Table 1.
Scheme 1. Isolation of Tetrahydrobenzazocine
a
Table 1. Screening of Reaction Conditions
time
b
c
entry acid (equiv)
1
solvent (M)
temp
(h)
1a/2a/3a
ClCH2CH2Cl
(0.05)
83 °C
24
100/0/0
(reflux)
120 °C
2
PhMe (0.05)
24
100/0/0
3
4
5
6
7
8
H2SO4 (0.2) ClCH2CH2Cl
(0.05)
rt
101
41/10/49
17/33/50
0/7/93
H2SO4 (0.2) ClCH2CH2Cl
(0.05)
50 °C
28
20
27
TfOH (0.3) ClCH2CH2Cl
(0.05)
rt
rt
rt
rt
CF3CO2H
(0.8)
ClCH2CH2Cl
(0.05)
0/9/91
ring-expansion reaction of 1b was carried out under optimized
reaction conditions, and 8,9-dimethoxy-1,2,3,6-tetrahydroben-
zazocine (2b) was isolated by recrystallization, which also
allowed for the elucidation of its structure by an X-ray
crystallographic analysis (Scheme 1). The structure of a
vinyltetrahydroquinoline was also confirmed by an X-ray
analysis (vide infra). It is noteworthy that the reaction
proceeded regioselectively, and a possible regioisomer 2b′
was not isolated.
H2SO4 (1.5) ClCH2CH2Cl
(0.05)
1.5
0/87/13
5/60/35
H2SO4 (2.0) ClCH2CH2Cl
(0.05)
2
9
H2SO4 (1.5) CH2Cl2 (0.5)
H2SO4 (1.5) CH2Cl2 (0.5)
0 °C
0 °C to rt
24
3
0/90/10
d
10
0/>95/<5
a
Reaction procedure: compound 1a (0.5 mmol) was dissolved in
solvent, and the mixture was stirred at the indicated temperature under
argon atmosphere for the indicated period. At the completion of the
reaction, the mixture was treated with aqueous sodium bicarbonate,
separated, and concentrated. The products were analyzed by 1H NMR
To our surprise, the isolation of benzazocine derivatives
proved challenging due to their instability. The attempted
purification of 2a (or 2b) by column chromatography under
typical conditions (e.g., silica gel or alumina, hexane/EtOAc,
with or without Et3N) induced the ring-contraction reaction of
2a and a vinyltetrahydroquinoline 3a was isolated. We were
thus focused on the derivatization of the initially formed
tetrahydrobenzazocine 2a to isolate the product in a stable
form. Catalytic hydrogenation of the crude product (2a·
H2SO4) afforded hexahydrobenzazocine 4a in 91% yield
(Scheme 2a). This compound was stable and the ring-
contraction reaction of the product was not observed.
Alternatively, the protection of the amino group by acylation
resulted in the increased stability of the tetrahydrobenzazocine
(Scheme 2b). Several different acyl groups were surveyed, and
all of the acylated benzazocine derivatives were isolated as
stable compounds (Table 2). Protection with a benzylox-
ycarbonyl (Cbz), benzoyl (Bz), tert-butoxycarbonyl (Boc), or
acetyl (Ac) group efficiently provided the products in high
yields. Among them, the N-acetyl derivative was easier to
handle, and the acetylation was harnessed for further studies.9
These results indicated that the presence of the CC double
bond and the free secondary amino group of the benzazocine
derivatives were responsible for the instability of 2a. The
instability of 2a could be a reason for the presence of few
reports concerning the aza-Claisen rearrangement reactions of
N-aryl-2-vinylazetidines.
b
spectroscopy. External temperature, unless otherwise noted.
c
d
Determined by 1H NMR integration of the crude product. The
reaction mixture was stirred at 0 °C for 2 h and then allowed to warm
to room temperature.
Compound 1a was stable at high temperature, and the
expected rearrangement did not take place at 83 °C in 1,2-
dichloroethane or 120 °C in toluene (entries 1 and 2). The
observed stability of 1a is in contrast to the reported high
reactivity7 of a vinylazetidine derivative. Interestingly, the
reaction of 1a proceeded sluggishly in the presence of H2SO4 to
give a mixture of the desired tetrahydrobenzazocine 2a and 3-
vinyl-1,2,3,4-tetrahydroquinoline 3a (entry 3). An attempt to
accelerate the reaction by heating the reaction mixture to 50 °C
failed, and the formation of a large amount of 3a was observed
(entry 4). Employing TfOH or CF3CO2H as the catalyst
resulted in the formation of a mixture predominantly
containing 3a (entries 5 and 6). Increasing the amount of
H2SO4 was beneficial, and the reaction proceeded at a
reasonable rate with 1.5 equiv of H2SO4 (entry 7). Using a
larger amount of H2SO4 was detrimental, and the proportion of
vinyltetrahydroquinoline byproduct increased with 2.0 equiv of
H2SO4 (entry 8). The ratio of tetrahydrobenzazocine to
vinyltetrahydroquinoline improved when the reaction was
4368
dx.doi.org/10.1021/jo500249c | J. Org. Chem. 2014, 79, 4367−4377

The Journal of Organic Chemistry
Article
a
a
Scheme 2. Isolation of Stable Benzazocine Derivatives
Table 3. Substrate Scope
a
Reagents and conditions: (a) H2SO4 (1.5 equiv), CH2Cl2 (0.5 M), 0
°C to rt, 3 h; H2, Pd/C, EtOH, rt, 2 h; aq NaHCO3. (b) H2SO4 (1.5
equiv), CH2Cl2 (0.5 M), 0 °C to rt, 3 h; aq NaHCO3; RCOX (1.2
equiv), i-Pr2NEt (1.3 equiv), CH2Cl2, rt, 4 h. R = Cbz, Bz, Boc, or Ac.
a
Table 2. Isolation of N-Acyl Derivatives
a
Reaction conditions: 1a (0.5 mmol), H2SO4 (1.5 equiv), CH2Cl2 (0.5
a
Reaction conditions: 1a (0.5 mmol), H2SO4 (1.5 equiv), CH2Cl2 (0.5
M), 0 °C to rt, 3 h; aq NaHCO3; AcCl (1.2 equiv), i-Pr2NEt (1.3
M), 0 °C to rt, 3 h; aq NaHCO3; RCOX (1.2 equiv), i-Pr2NEt (1.3
b
equiv), CH2Cl2, rt, 4 h. Isolated yield by column chromatography.
b
equiv), CH2Cl2, rt, 4 h. Isolated yield.
Using the established protocol for the formation and
isolation of the tetrahydrobenzazocine, the substrate scope of
the reaction was explored (Table 3). The ring-expansion
reaction and subsequent acetylation of N-(3,4-dimethoxyphen-
yl)-2-vinylazetidine (1b) proceeded efficiently, and the
corresponding product was isolated in excellent yield (entry
2). The reaction proceeded smoothly even when two methoxy
groups were introduced to the ortho and para positions of the
aromatic ring (entry 3). The parent N-phenyl derivative 1d was
a good substrate for the reaction, and the product was obtained
in 84% yield (entry 4). The use of N-tolyl derivative 1e resulted
in efficient transformation (entry 5). Vinylazetidine bearing a 4-
(trifluoromethyl)phenyl group (1f) was a viable substrate,
although the corresponding product was isolated in a decreased
yield (entry 6). It is noteworthy that the electronic nature of
the aryl group bound to the nitrogen atom of vinylazetidine did
not have strong effect on the rearrangement reaction, though
4369
dx.doi.org/10.1021/jo500249c | J. Org. Chem. 2014, 79, 4367−4377

The Journal of Organic Chemistry
Article
the products bearing electron-rich aromatic groups were
obtained in slightly better yields. The ring-expansion reaction
of a vinylazetidine bearing 2-methyl group (1g) gave two
products: 4-methylbenzazocine derivative 8g was isolated in
59%, and 3-(1-methylvinyl)tetrahydroquinoline 9 was isolated
in 26% yield (entry 7).
Scheme 3. Ring-Contraction Reaction of
Tetrahydrobenzazocines in the Presence of Aldehydes
Ring-Contraction Reaction of Tetrahydrobenzazocine
to Vinyltetrahydroquinoline. We were interested in the
instability of 2a,2b, since the cleavage of the C−C bond
proceeded under mild conditions and the selective formation of
3a,3b was observed. To understand the mechanism of this
transformation, we studied the acid-catalyzed ring-contraction
reaction of 2b under various reaction conditions. The results
are summarized in Table 4. As expected, the treatment of 2b
Table 4. Acid-Catalyzed Ring-Contraction Reaction of
a
Tetrahydrobenzazocine
b
c
entry
acid
time (h)
convn (%)
yield (%)
d
1
2
3
4
5
6
silica gel
TfOH
9
16
24
24
28
24
100
100
20
81
91
e
CF3CO2H
H2SO4
12
e
of the exogenous carbon atom to the final product is a
characteristic feature of these reactions.
12 M HCl
AcOH
18
e
13
e
Mechanistic Considerations of the Ring-Expansion
Reaction of N-Aryl-2-vinylazetidine. The ring-expansion
reaction of N-aryl-2-vinylazetidine to tetrahydrobenzazocine
failed to proceed under thermal conditions, whereas the
addition of an acid successfully promoted the reaction. We
postulate that this transformation proceeds through the charge-
accelerated [3,3]-sigmatropic rearrangement (Scheme 4).1
a
Reaction conditions: 2b (0.2 mmol), acid (0.5 equiv), CH2Cl2, rt.
b
c
1
Determined by H NMR integration of the crude product. Isolated
d
yield. Silica gel (300 mg, Kanto Chemical silica gel 60N, spherical,
neutral, 63-210 μm) was added. No attempt was made to determine
the yield.
e
with silica gel gave 6,7-dimethoxy-3-vinyl-1,2,3,4-tetrahydroqui-
noline (3b) in 81% yield, reproducing the phenomenon
observed upon the attempted chromatographic isolation of 2a
(entry 1). We confirmed the structure of 3b by an X-ray
crystallographic analysis (see Supporting Information). Assum-
ing that the reaction would be accelerated in the presence of
acid, we treated 2b with a series of acids. The treatment of 2b
with 0.5 equiv10 of TfOH in CH2Cl2 induced the slow ring-
contraction reaction, and 3b was obtained in 91% yield (entry
2). The ring-contraction reaction of 2b proceeded less
effectively in the presence of weaker acids such as CF3CO2H,
H2SO4, HCl, and AcOH (entries 3−6). It is noteworthy that
this ring-contraction reaction was dramatically accelerated in
the presence of formaldehyde (Scheme 3a). Thus, the reaction
of 2b and formaldehyde proceeded rapidly (rt, 2 min) to
provide 3b in 76% yield. This result is in marked contrast to the
result of the reaction in the absence of formaldehyde, which did
not complete after 24 h (Table 4, entry 3). Exposure of 2b to
formaldehyde-d2 gave rise to a mixture of the vinylquinoline
derivatives in 74% yield, in which 3b and vinylquinoline-d2 (3b-
d2) were present in a ratio of 83:17 (Scheme 3b). When the
same experiment was performed using acetaldehyde instead of
formaldehyde-d2, a diastereomeric mixture of 2-methyl vinyl-
quinoline derivative (3b-Me) was obtained in 35% yield
together with 3b in 7% yield (Scheme 3c).11 The incorporation
Scheme 4. Proposed Mechanism for the Ring-Expansion
Reaction of N-Aryl-2-vinylazetidine to
Tetrahydrobenzazocine
Vinylazetidine I is first protonated to form an azetidinium
ion intermediate II, followed by the [3,3]-sigmatropic
rearrangement to give a protonated arene III. Deprotonation
of this intermediate and restoration of aromaticity leads to the
formation of tetrahydrobenzazocine IV.
It is interesting to note that the N-aryl-2-vinylezetidine
studied in this work was stable under thermal reaction
4370
dx.doi.org/10.1021/jo500249c | J. Org. Chem. 2014, 79, 4367−4377

The Journal of Organic Chemistry
Article
conditions, contrary to the N-arylaziridine or N-quinonylaze-
tidine analogues reported in the literature.3,4,7 The reduced ring
strain of the four-membered ring can be invoked to explain the
increased thermal stability of N-aryl-2-vinylazetidine over the
aziridine analogue. The ring strain in the starting molecule is
also considered to have profound effect on the reaction profile.
In contrast to the aza-Claisen rearrangement of N-aryl-2-
vinylazirdines,4 in which there are several byproducts arising
from other bond breaking pathways, no byproduct generated
from processes other than aza-Claisen rearrangement was
observed (the generation of the vinyltetrahydroquinoline
byproduct such as 1b will be discussed below in detail). This
dissimilar byproduct distribution could be explained by the
increased stability of azetidine over aziridine. The aza-Claisen
rearrangement of allylanilines is reported to proceed much
faster if the aromatic ring is substituted with an electron
withdrawing group.12 The increased reactivity of N-quinonyl-2-
vinylazetidine7 can be ascribed to the electron deficiency of the
quinone ring. In our experiments under the optimized
conditions, however, such dependence of the rate of the aza-
Claisen rearrangement on the electronic nature of the benzene
ring was not observed, and N-aryl-2-vinylazetidines bearing
both electron withdrawing and donating substituents provided
products in comparable reaction time.
Mechanistic Considerations of the Ring-Contraction
Reaction of Tetrahydrobenzazocine to Vinyltetrahydro-
quinoline. The observed ring-contraction reaction of 2b to 3b
in the presence of a small amount of acid (Table 4) provided
strong supporting evidence that the vinyltetrahydroquinoline
byproduct 3a was generated by the ring-contraction reaction of
the initially formed 2a in the reaction mixture (Table 1). As
shown in Table 1, this process proceeded when the amount of
acid was small: at higher acid loadings, the acceleration of the
rate of the ring-expansion reaction was observed and the
formation of 3a was suppressed. This result could be explained
by postulating that the ammonium salt of 2a was more stable
compared to 2a. The observed stability of N-acylated
benzazocine derivatives also supports the idea that the presence
of a nucleophilic nitrogen atom would destabilize the
benzazocine framework. As discussed earlier, formaldehyde
proved to be a viable reagent for the ring-contraction reaction
of tetrahydrobenzazocine to vinyltetrahydroquinoline (Scheme
3a). We hypothesized that the ring-contraction reaction could
involve the formation of iminium ion of tetrahydrobenzazocine
(Scheme 5). Tetrahydrobenzazocine IV would condense with
formaldehyde under acidic condition to afford iminium ion V.
This intermediate then undergoes aza-Cope rearrangement to
form iminium ion VII.13,14 The methylene group of VII is
expected to transfer to another molecule of tetrahydrobenza-
zocine through the formation and subsequent decomposition of
aminal VIII. The generation of vinyltetrahydroquinoline IX is
accompanied by the liberation of N-methylidenetetrahydro-
benzazocine V, which could recommence the new cycle.
Overall, the formation of six-membered ring compound is
presumed to be thermodynamically favorable. The protection
of the secondary amino group of tetrahydrobenzazocine turned
out to be an effective strategy to circumvent the ring-
contraction reaction to vinyltetrahydroquinoline during chro-
matographic purification (Scheme 2b). The observed stability
of N-acylated benzazocine derivatives could be explained, again,
by the reduced nucleophilicity of the nitrogen atom. If the
proposed mechanism is indeed operable, a desired alkyl group
could be incorporated to the vinylquinoline scaffold by adding
Scheme 5. Proposed Mechanism for the Ring-Contraction
Reaction of Tetrahydrobenzazocine to
Vinyltetrahydroquinoline
an aldehyde to tetrahydrobenzazocine. The results given in
Scheme 3 provided supporting evidence that the iminium ion
was formed by the reaction of tetrahydrobenzazocine with an
exogenous methylene source. As illustrated in Scheme 6, these
Scheme 6. Proposed Mechanism for the Incorporation of the
Exogenous Methylene Group into the Vinylquinoline
Scaffold
products, 3b-d2 and 3b-Me, presumably arise from aza-Cope
rearrangement of incipient iminium ion intermediate X, which
was formed by the condensation of tetrahydrobenzazocine with
the corresponding aldehyde. In the above-mentioned process,
methylene group of the iminium ion XII is transferred to
another molecule of IV, which then undergoes aza-Cope
rearrangement to form vinyltetrahydroquinoline, devoid of
4371
dx.doi.org/10.1021/jo500249c | J. Org. Chem. 2014, 79, 4367−4377

The Journal of Organic Chemistry
Article
deuterium atoms or methyl group at its 2-position. While a
decent amount of acetaldehyde was incorporated to the
vinylquinoline structure, a smaller amount of formaldehyde-d2
was incorporated (Scheme 3b and c). The difference of the
degree of the incorporation might be explained by considering
the structure of the aldehyde in water. Formaldehyde exists
predominantly as methanediol (hydrated form of form-
aldehyde),15 which would be less reactive compared to the
iminium ion (i.e., XII in Scheme 6) or nonhydrated
formaldehyde. On the other hand, the concentration of the
reactive nonhydrated acetaldehyde would be much higher, and
the rate of the reaction of tetrahydrobenzazocine with
acetaldehyde would be faster. These findings support the
iminium ion-initiated aza-Cope rearrangement and “methylene-
catalyzed” ring-contraction mechanism.
Nevertheless, the ring-contraction reaction did occur without
exogenous aldehyde (Table 4). The formation of vinyl-
tetrahydroquinoline was also observed in the ring-expansion
reaction of vinylazetidine, suggesting that an iminium ion
should be generated in the reaction mixture (Table 1). Scheme
7 depicts a plausible mechanism for the generation of an
tetrahydrobenzazocine and the iminium ion was incorporated
as the key step. These results provided a basis for the
understanding of the synthesis and reactivity of medium-sized
nitrogen heterocycles.
EXPERIMENTAL SECTION
■
General Experimental. Reagents were obtained from commercial
supplies and used without further purification unless otherwise stated.
NMR spectra were recorded on 500 or 300 MHz instruments. H
1
chemical shifts were referenced to the nondeuterated solvent signals in
CDCl3 (δ 7.26). 13C chemical shifts were referenced to the solvent
signals in CDCl3 (δ 77.00). Multiplicity is indicated by the following
abbreviations (or combinations thereof): s (singlet), d (doublet), t
(triplet), q (quartet), m (multiplet), br (broad). Coupling constants, J,
are reported in hertz. IR spectra were recorded on an FTIR
spectrometer. Column chromatography was performed using silica
gel 60N (spherical, neutral, 63-210 μm) or aluminum oxide 90 (active
neutral, 70−230 mesh). Melting points were uncorrected. Ethyl 2,4-
dibromobutyrate was prepared according to literature procedure.18
Synthesis of N-Aryl-2-vinylazetdines. Representative Proce-
dure for the Preparation of N-Aryl-2-ethoxycarbonylazeti-
dines.19,20 A solution of ethyl 2,4-dibromobutyrate (13.7 g, 50 mmol,
1.0 equiv), p-anisidine (6.16 g, 50 mmol, 1.0 equiv), and NaHCO3
(16.8 g, 200 mmol, 4.0 equiv) in DMF/H2O/HMPA (16:5:1, 110 mL,
0.45 M) was heated to 100 °C for 4 h under air. The reaction mixture
was cooled to room temperature, partitioned between hexane and
brine, and separated. The aqueous layer was extracted with Et2O. The
combined organic layer was washed with brine, dried over Na2SO4,
filtered, and concentrated under reduced pressure. The residue was
chromatographed on alumina (hexane/EtOAc, 25:1) to afford N-(4-
methoxyphenyl)-2-ethoxycarbonylazetidine (S1, 6.0 g, 51%) as an
Scheme 7. Possible Pathway for the Generation of the
Methylene Source
1
orange oil: H NMR (300 MHz, CDCl3) δ 6.81 (d, J = 9.3 Hz, 2H),
6.52 (d, J = 9.0 Hz, 2H), 4.39 (dd, J = 8.4, 8.1 Hz, 1H), 4.35−4.19 (m,
2H), 3.97 (ddd, J = 8.7, 6.6, 3.6 Hz, 1H), 3.75 (s, 3H), 3.63 (td, J =
8.1, 6.9 Hz, 1H), 2.68−2.45 (m, 2H), 1.31 (t, J = 7.2 Hz, 3H); 13C
NMR (125 MHz, CDCl3) δ 172.6, 152.9, 145.4, 114.6, 113.4, 64.1,
61.1, 55.7, 50.3, 21.5, 14.2; IR (neat) 2978, 1743, 1512, 1466, 1335,
1288, 1242, 1188, 1049, 825.4 cm−1. Anal. Calcd for C13H17NO3: C,
66.36; H, 7.28; N, 5.95. Found: C, 66.11; H, 7.15; N, 6.16.
N-(3,4-Dimethoxyphenyl)-2-ethoxycarbonylazetidine (S2).
40% yield (5.3 g) from 3,4-dimethoxyaniline (alumina, hexane/
1
EtOAc, 8:1), yellow oil; H NMR (300 MHz, CDCl3) δ 6.77 (d, J =
8.7 Hz, 1H), 6.22 (d, J = 2.4 Hz, 1H), 6.07 (d, J = 8.7, 2.4 Hz, 1H),
4.41 (t, J = 8.1 Hz, 1H), 4.35−4.19 (m, 2H), 3.97 (ddd, J = 10.2, 6.6,
3.9 Hz, 1H), 3.83 (s, 3H), 3.81 (s, 3H), 3.66 (td, J = 8.1, 7.2 Hz, 1H),
2.68−2.45 (m, 2H), 1.31 (t, J = 7.2 Hz, 3H); 13C NMR (125 MHz,
CDCl3) δ 172.5, 149.8, 146.0, 142.4, 112.8, 103.4, 97.8, 64.1, 61.1,
56.6, 55.7, 50.2, 21.2, 14.2; IR (neat) 2939, 2862, 1736, 1512, 1458,
1242, 1188, 1026 cm−1. Anal. Calcd for C14H19NO4: C, 63.38; H, 7.22;
N, 5.28. Found: C, 63.28; H, 7.44; N, 5.40.
N-(2,4-Dimethoxyphenyl)-2-ethoxycarbonylazetidine (S3).
38% yield (5.0 g) from 2,4-dimethoxyaniline (alumina, hexane/
EtOAc, 15:1), yellow solid; mp 74−75 °C; 1H NMR (300 MHz,
CDCl3) δ 6.44−6.37 (m, 3H), 4.50 (t, J = 7.8 Hz, 1H), 4.23 (q, J = 7.2
Hz, 2H), 4.01 (td, J = 7.2, 4.5 Hz, 1H), 3.75 (s, 3H), 3.70 (s, 3H), 3.64
(td, J = 8.1, 7.2 Hz, 1H), 2.54−2.38 (m, 2H), 1.28 (t, J = 7.2 Hz, 3H);
13C NMR (125 MHz, CDCl3) δ 172.9, 154.0, 150.0, 134.1, 113.4,
103.7, 99.8, 64.9, 60.6, 55.6, 55.1, 51.1, 22.2, 14.3; IR (KBr) 2962,
2939, 2908, 1751, 1512, 1450, 1288, 1250, 1173, 1157, 1057 cm−1.
Anal. Calcd for C14H19NO4: C, 63.38; H, 7.22; N, 5.28. Found: C,
63.33; H, 7.33; N, 5.24.
N-Phenyl-2-ethoxycarbonylazetidine (S4). 44% yield (4.5 g)
from aniline (alumina, hexane/EtOAc, 30:1), pale yellow oil; 1H NMR
(300 MHz, CDCl3) δ 7.22 (dd, J = 8.4, 7.5 Hz, 2H), 6.80 (t, J = 7.5
Hz, 1H), 6.54 (d, J = 8.7 Hz, 2H), 4.47 (dd, J = 8.4, 7.5 Hz, 1H),
4.35−4.20 (m, 2H), 4.02 (ddd, J = 8.4, 6.9, 4.2 Hz, 1H), 3.75−3.67
(m, 1H), 2.68−2.49 (m, 2H), 1.31 (t, J = 7.2 Hz, 3H); 13C NMR (125
MHz, CDCl3) δ 172.5, 150.8, 128.9, 118.6, 112.1, 63.7, 61.2, 50.0,
21.6, 14.2; IR (neat) 2978, 2862, 1743, 1597, 1504, 1335, 1188, 756.0,
iminium ion from tetrahydrobenzazocine. Tetrahydrobenzazo-
cine is protonated to form a dicationic species XIV in the
presence of acid, which then undergoes Grob-type fragmenta-
tion13a,16 to give an iminium ion XV. A molecule of
tetrahydrobenzazocine attacks the iminium ion to form aminal
XVI. The aminal decomposes to release an aniline XVII17 and
iminium ion V, which can now commence the ring-contraction
reaction. It is possible to explain the formation of 9 in the ring-
expansion reaction of 1g (Table 3, entry 7). The 4-methyl
group of tetrahydrobenzazocine may stabilize the positive
charge accumulating in the Grob-type elimination process, and
the iminium ion XV could be readily formed. Thus, the
presence of the methyl group in tetrahydrobenzazocine
facilitated the formation of the vinyltetrahydroquinoline.
CONCLUSION
■
In conclusion, we developed the acid-mediated ring-expansion
reaction of N-aryl-2-vinylazetidines. The benzazocine deriva-
tives thus generated exhibited intriguing and unprecedented
reactivity. The ring-contraction reaction of tetrahydrobenzazo-
cines to vinyltetrahydroquinolines proceeded under weakly
acidic conditions, and very selective C−C bond formation/
cleavage was observed. Detailed analysis of the ring-contraction
reaction indicated that the methylene transfer between
4372
dx.doi.org/10.1021/jo500249c | J. Org. Chem. 2014, 79, 4367−4377

The Journal of Organic Chemistry
Article
694.2 cm−1. Anal. Calcd for C12H15NO2: C, 70.22; H, 7.37; N, 6.82.
Found: C, 70.18; H, 7.46; N, 6.77.
Crude N-(4-methoxyphenyl)-2-formylazetidine in THF (20 mL, 1
M) was added via a cannula to a solution of methylenetriphenylphos-
phorane, prepared by the treatment of methyltriphenylphosphonium
bromide (14.3 g, 40 mmol, 2.0 equiv) in THF (133 mL, 0.3 M) with
n-BuLi in hexane (1.65 M, 22 mL, 36.8 mmol, 1.84 equiv) at 0 °C for
1.5 h under argon atmosphere. The mixture was then stirred at room
temperature for 20 h. The mixture was poured into water and
extracted with Et2O. The organic layer was washed with brine, dried
over Na2SO4, and concentrated under reduced pressure. The residue
was chromatographed on silica gel (hexane/EtOAc, 10:1) to furnish
N-(4-Methylphenyl)-2-ethoxycarbonylazetidine (S5). 47%
yield (4.2 g) from p-toluidine (alumina, hexane/EtOAc, 30:1), yellow
oil; 1H NMR (300 MHz, CDCl3) δ 7.03 (d, J = 7.8 Hz, 2H), 6.48 (d, J
= 8.4 Hz, 2H), 4.42 (dd, J = 8.7, 7.5 Hz, 1H), 4.35−4.20 (m, 2H), 3.99
(ddd, J = 8.4, 6.6, 3.9 Hz, 1H), 3.66 (td, J = 8.1, 6.9 Hz, 1H), 2.68−
2.46 (m, 2H), 2.26 (s, 3H), 1.32 (t, J = 7.2 Hz, 3H); 13C NMR (125
MHz, CDCl3) δ 172.6, 148.8, 129.4, 127.9, 112.2, 63.9, 61.1, 50.1,
21.6, 20.4, 14.2; IR (neat) 2978, 2924, 2862, 1743, 1520, 1335, 1273,
1234, 1188, 1065, 810.0 cm−1. Anal. Calcd for C13H17NO2: C, 71.21;
H, 7.81; N, 6.39. Found: C, 71.08; H, 7.86; N, 6.35.
Preparation of N-(4-Trifluoromethylphenyl)-2-ethoxycarbo-
nylazetidine (S6). A solution of ethyl 2,4-dibromobutyrate (5.48 g,
20 mmol, 2.0 equiv), aminobenzotrifluoride (1.61 g, 10 mmol, 1.0
equiv), NaI (8.99 g, 60 mmol, 6.0 equiv), and NaHCO3 (3.36 g, 40
mmol, 4.0 equiv) in DMF/H2O/HMPA (16:3.2:1, 20.2 mL, 0.5 M)
was heated to 100 °C for 5 h under air. The reaction mixture was
cooled to room temperature, partitioned between hexane and brine,
and separated. The aqueous layer was extracted with Et2O. The
combined organic layer was washed with brine, dried over Na2SO4,
filtered, and concentrated under reduced pressure. The residue was
chromatographed on alumina (hexane/EtOAc, 30:1) to afford the title
compound (S6, 0.98 g, 36%) as a yellow oil that solidified upon
standing at 4 °C for several days: mp 32−33 °C; 1H NMR (300 MHz,
CDCl3) δ 7.44 (d, J = 8.4 Hz, 2H), 6.53 (d, J = 8.4 Hz, 2H), 4.56 (t, J
= 7.8 Hz, 1H), 4.32−4.22 (m, 2H), 4.08 (q, J = 6.6 Hz, 1H), 3.79 (q, J
= 7.5 Hz, 1H), 2.66−2.58 (m, 2H), 1.31 (t, J = 7.2 Hz, 3H); 13C NMR
(125 MHz, CDCl3) δ 171.8, 152.5, 126.1 (q, J = 4.0 Hz), 124.9 (q, J =
269.8 Hz), 119.9 (q, J = 33.0 Hz), 111.2, 63.3, 61.3, 49.7, 21.3, 14.1; IR
(KBr) 2978, 2877, 1736, 1620, 1527, 1327, 1119, 1065, 833.1 cm−1.
Anal. Calcd for C13H14F3NO2: C, 57.14; H, 5.16; N, 5.13. Found: C,
57.09; H, 5.24; N, 4.96.
1
compound 1a (1.63 g, 43%) as a yellow oil: H NMR (300 MHz,
CDCl3) δ 6.89−6.76 (d, J = 8.9 Hz, 2H), 6.51−6.48 (d, J = 9.0 Hz,
2H), 6.14−6.02 (ddd, J = 17.0, 10.4, 6.6 Hz, 1H), 5.36−5.29 (dt, J =
17.3, 1.3 Hz, 1H), 5.17−5.13 (d, J = 10.4 Hz, 1H), 4.31−4.24 (q, J =
7.4 Hz, 1H), 3.87−3.81 (td, J = 7.6, 3.2 Hz, 1H), 3.72 (s, 3H), 3.55−
3.47 (td, J = 8.4, 6.7 Hz, 1H), 2.40−2.17 (m, 2H); 13C NMR (125
MHz, CDCl3) δ 152.4, 147.1, 140.8, 115.2, 114.5, 113.2, 67.0, 55.8,
49.9, 25.0; IR (neat) 2956, 2833, 1510, 1466, 1323, 1242, 1179, 1116,
1038, 992.2, 923.7, 821.5, 798.4, 606.5, 529.4 cm−1; HR-MS (EI) calcd
for C12H15NO: 189.1154. Found: 189.1153.
N-(3,4-Dimethoxyphenyl)-2-vinylazetidine (1b). 55% yield
(2.41 g) from compound S2 (silica gel, hexane/EtOAc, 8:1), pale
1
yellow oil; H NMR (300 MHz, CDCl3) δ 6.76 (d, J = 8.7 Hz, 1H),
6.19 (d, J = 2.4 Hz, 1H), 6.11 (ddd, J = 17.1, 10.5, 6.9 Hz, 1H), 6.07
(dd, J = 8.7, 2.7 Hz, 1H), 5.36 (ddd, J = 17.1, 1.5, 1.2 Hz, 1H), 5.18
(ddd, J = 10.2, 1.5, 0.9 Hz, 1H), 4.32 (td, J = 7.8, 6.9 Hz, 1H), 3.86
(ddd, J = 8.7, 6.6, 3.3 Hz, 1H), 3.82 (s, 3H), 3.80 (s, 3H), 3.56 (td, J =
8.3, 6.9 Hz, 1H), 2.43−2.33 (m, 1H), 2.31−2.17 (m, 1H); 13C NMR
(125 MHz, CDCl3) δ 149.7, 147.7, 141.8, 140.9, 115.2, 112.9, 103.2,
97.6, 67.0, 56.7, 55.6, 49.8, 24.8; IR (neat) 2955, 2831, 1515, 1465,
1452, 1239, 1218, 1139, 1027 cm−1. Anal. Calcd for C13H17NO2: C,
71.21; H, 7.81; N, 6.39. Found: C, 71.13; H, 8.04; N, 6.25.
N-(2,4-Dimethoxyphenyl)-2-vinylazetidine (1c). 42% yield
(1.84 g) from compound S3 (silica gel, hexane/EtOAc, 10:1), pale
Preparation of N-(4-Methoxyphenyl)-2-ethoxycarbonyl-2-
methylazetidine (S7).21 A solution of N-(4-methoxyphenyl)-2-
ethoxycarbonylazetidine (4.35 g, 18.5 mmol, 1.0 equiv) in THF (10.3
mL, 1.8 M) was added via a cannula to a solution of lithium
diisopropylamide in THF, prepared by the treatment of i-Pr2NH (2.93
mL, 20.9 mmol, 1.13 equiv) with n-BuLi in hexane (1.65 M, 12.7 mL,
20.9 mmol, 1.13 equiv) at −78 °C under argon atmosphere. Stirring
was continued for 15 min, whereupon methyl iodide (2.45 mL, 39.4
mmol, 2.13 equiv) was added. The mixture was gradually allowed to
warm to room temperature and after further 30 min was poured onto
water. The mixture was extracted with Et2O. The combined organic
layer was washed with brine, dried over Na2SO4, filtered, and
concentrated under reduced pressure. The residue was chromato-
graphed on silica gel (hexane/EtOAc, 12:1) to yield the title
1
yellow oil; H NMR (300 MHz, CDCl3) δ 6.50 (d, J = 8.4 Hz, 1H),
6.44 (d, J = 2.4 Hz, 1H), 6.37 (dd, J = 8.4, 2.4 Hz, 1H), 6.04 (ddd, J =
17.1, 10.2, 6.6 Hz, 1H), 5.27 (ddd, J = 17.1, 1.5, 0.9 Hz, 1H), 5.11 (d, J
= 10.2 Hz, 1H), 4.37 (q, J = 7.5 Hz, 1H), 4.06 (td, J = 7.5, 3.0 Hz,
1H), 3.78 (s, 3H), 3.75 (s, 3H), 3.46 (td, J = 8.1, 7.8 Hz, 1H), 2.35−
2.16 (m, 2H); 13C NMR (125 MHz, CDCl3) δ 154.0 150.5, 139.9,
135.4, 115.1, 113.6, 103.3, 99.8, 65.8, 55.6, 55.2, 52.6, 25.6; IR (neat)
2954, 2831, 1512, 1458, 1288, 1250, 1203, 1157, 1034 cm−1. Anal.
Calcd for C13H17NO2: C, 71.21; H, 7.81; N, 6.39. Found: C, 71.13; H,
7.97; N, 6.45.
N-Phenyl-2-vinylazetidine (1d). 53% yield (1.69 g) from
compound S4 (silica gel, hexane/EtOAc, 100:1), colorless oil; 1H
NMR (300 MHz, CDCl3) δ 7.23−7.17 (m, 2H), 6.75 (t, J = 7.2 Hz,
1H), 6.56 (d, J = 7.5 Hz, 2H), 6.12 (ddd, J = 16.8, 10.2, 6.6 Hz, 1H),
5.36 (ddd, J = 17.1, 1.5, 0.9 Hz, 1H), 5.19 (ddd, J = 10.2, 1.5, 0.9 Hz,
1H), 4.41 (q, J = 7.2 Hz, 1H), 3.92 (ddd, J = 8.7, 6.9, 3.6 Hz, 1H), 3.63
(td, J = 8.4, 6.9 Hz, 1H), 2.47−2.37 (m, 1H), 2.32−2.21 (m, 1H); 13C
NMR (125 MHz, CDCl3) δ 152.4, 140.5, 128.7, 117.8, 115.2, 112.0,
66.5, 49.4, 25.0; IR (neat) 3001, 2962, 2854, 1597, 1496, 1335, 925.7,
756.0, 694.2 cm−1. Anal. Calcd for C11H13N: C, 82.97; H, 8.23; N,
8.80. Found: C, 82.80; H, 8.36; N, 9.02.
N-(4-Methylphenyl)-2-vinylazetidine (1e). 65% yield (2.25 g)
from compound S5 (silica gel, hexane/EtOAc, 50:1), pale yellow oil;
1H NMR (300 MHz, CDCl3) δ 7.04 (d, J = 8.1 Hz, 2H), 6.50 (d, J =
8.7 Hz, 2H), 6.13 (ddd, J = 17.1, 10.5, 6.3 Hz, 1H), 5.38 (ddd, J =
17.1, 1.5, 1.2 Hz, 1H), 5.20 (ddd, J = 10.2, 1.5, 0.9 Hz, 1H), 4.37 (q, J
= 7.5 Hz, 1H), 3.91 (ddd, J = 8.7, 6.9, 3.3 Hz, 1H), 3.58 (td, J = 8.4,
6.9 Hz, 1H), 2.48−2.21 (m, 2H), 2.27 (s, 3H); 13C NMR (125 MHz,
CDCl3) δ 150.4, 140.7, 129.3, 127.1, 115.1, 112.2, 66.7, 49.6, 25.0,
20.4; IR (neat) 3004, 2959, 2921, 2851, 1613, 1515, 1323, 920.8, 810.9
cm−1. Anal. Calcd for C12H15N: C, 83.19; H, 8.73; N, 8.08. Found: C,
83.08; H, 8.87; N, 8.12.
1
compound (S7, 3.37 g, 73%) as a pale yellow oil: H NMR (300
MHz, CDCl3) δ 6.78 (d, J = 9.0 Hz, 2H), 6.51 (d, J = 9.3 Hz, 2H),
4.26−4.10 (m, 2H), 3.79 (ddd, J = 8.7, 6.3, 5.1 Hz, 1H), 3.74 (s, 3H),
3.74−3.66 (m, 1H), 2.66 (ddd, J = 10.5, 8.7, 6.3 Hz, 1H), 2.15 (ddd, J
= 10.8, 8.1, 5.1 Hz, 1H), 1.57 (s, 3H), 1.20 (t, J = 7.2 Hz, 3H); 13C
NMR (125 MHz, CDCl3) δ 174.3, 152.6, 142.3, 114.5, 114.1, 69.5,
60.9, 55.7, 46.6, 28.9, 20.7, 14.2; IR (neat) 2977, 2962, 2931, 1728,
1511, 1300, 1283, 1242, 1175, 1154, 1130, 1038, 821.5 cm−1. Anal.
Calcd for C14H19NO3: C, 67.45; H, 7.68; N, 5.62. Found: C, 67.66; H,
7.74; N, 5.73.
Representative Procedure for the Preparation of N-Aryl-2-
vinylazetidines.22 A solution of N-(4-methoxyphenyl)-2-ethoxycar-
bonylazetidine (4.71 g, 20 mmol, 1.0 equiv) in THF (80 mL, 0.25 M)
was cooled to −78 °C under argon atmosphere, followed by dropwise
addition of DIBAL in PhMe (1.0 M, 24 mL, 24 mmol, 1.2 equiv) over
1 h. After the reaction mixture was stirred at −78 °C for 1 h, several
small portions of Na2SO4·10H2O were added carefully and gradually
allowed to warm to room temperature. The mixture was then diluted
with EtOAc and filtered through a pad of Celite, and the filtrate was
concentrated under reduced pressure to afford N-(4-methoxyphenyl)-
2-formylazetidine. This material was used in the following step without
further purification.
N-(4-Trifluoromethylphenyl)-2-vinylazetidine (1f). 24% yield
(196 mg) from compound S6 (silica gel, hexane/EtOAc, 200:1),
colorless oil; 1H NMR (300 MHz, CDCl3) δ 7.41 (d, J = 8.4 Hz, 2H),
6.51 (d, J = 8.4 Hz, 2H), 6.08 (ddd, J = 16.8, 10.2, 6.6 Hz, 1H), 5.35
4373
dx.doi.org/10.1021/jo500249c | J. Org. Chem. 2014, 79, 4367−4377

The Journal of Organic Chemistry
Article
(ddd, J = 16.8, 1.5, 1.2 Hz, 1H), 5.22 (ddd, J = 10.2, 1.5, 1.2 Hz, 1H),
4.50 (q, J = 7.2 Hz, 1H), 3.97 (ddd, J = 9.0, 7.2, 3.9 Hz, 1H), 3.70 (td,
J = 8.1, 7.5 Hz, 1H), 2.55−2.45 (m, 1H), 2.32−2.21 (m, 1H); 13C
NMR (125 MHz, CDCl3) δ 154.1, 139.5, 126.0 (q, J = 4.1 Hz), 125.1
(q, J = 269.8 Hz), 119.0 (q, J = 33.0 Hz), 115.7, 111.0, 66.3, 49.0, 24.8;
IR (neat) 2970, 2862, 1612, 1527, 1327, 1157, 1111, 933.4, 825.4
cm−1. Anal. Calcd for C12H12F3N: C, 63.43; H, 5.32; N, 6.16. Found:
C, 63.31; H, 5.32; N, 6.13.
addition of H2SO4 (40 μL, 0.75 mmol, 1.5 equiv). The reaction
mixture was stirred at 0 °C for 2 h under argon atmosphere and then
allowed to warm to room temperature. After stirring for another 1 h,
EtOH (4.2 mL) and 10% palladium on carbon (42 mg) were
introduced, and the mixture was stirred at room temperature under
hydrogen atmosphere for 2 h. The reaction mixture was filtered
through a pad of Celite, and the filtrate was concentrated under
reduced pressure. The residue was partitioned between EtOAc and
saturated aqueous NaHCO3. The organic layer was separated, and the
aqueous layer was extracted with EtOAc. The combined organic layer
was washed with brine, dried over Na2SO4, filtered, and concentrated
under reduced pressure. The residue was chromatographed on silica
gel (hexane/EtOAc, 4:1) to yield compound 4a (87.1 mg, 91%) as a
yellow oil: 1H NMR (300 MHz, CDCl3) δ 6.92−6.87 (m, 1H), 6.69−
6.65 (m, 2H), 3.75 (s, 3H), 3.05−3.02 (m, 2H), 2.76−2.72 (m, 2H),
2.46 (br s, 1H), 1.71−1.63 (m, 2H), 1.51−1.39 (m, 4H); 13C NMR
(125 MHz, CDCl3) δ 156.3, 140.4, 139.2, 125.4, 115.0, 112.1, 55.3,
53.3, 31.8, 31.5, 27.8, 26.0; IR (neat) 3340, 2924, 2846, 1496, 1450,
1265, 1211, 1119, 1041, 810.0 cm−1. Anal. Calcd for C12H17NO: C,
75.35; H, 8.96; N, 7.32. Found: C, 75.33; H, 9.03; N, 7.09.
Representative Procedure for the Acylation of Tetrahydro-
benzazocines (Scheme 2b, Tables 2 and 3).24,25 A solution of
compound 1a (94.6 mg, 0.5 mmol, 1.0 equiv) in CH2Cl2 (1 mL, 0.5
M) was cooled to 0 °C, followed by addition of H2SO4 (40 μL, 0.75
mmol, 1.5 equiv). The reaction mixture was stirred at 0 °C for 2 h
under argon atmosphere and then allowed to warm to room
temperature. After stirring for another 1 h, the reaction mixture was
partitioned between EtOAc and saturated aqueous NaHCO3. The
organic layer was separated, and the aqueous layer was extracted with
EtOAc. The combined organic layer was washed with brine, dried over
Na2SO4, filtered, and concentrated under reduced pressure to afford
compound 2a. This material was used without purification in the
following reaction.
N-(4-Methoxyphenyl)-2-methyl-2-vinylazetidine (1g). 12%
yield (329 mg) from compound S7 (silica gel, hexane/EtOAc, 50:1),
1
pale yellow oil; H NMR (300 MHz, CDCl3) δ 6.78 (d, J = 9.0 Hz,
2H), 6.44 (d, J = 9.0 Hz, 2H), 6.13 (dd, J = 17.1, 10.5 Hz, 1H), 5.27
(dd, J = 17.4, 1.2 Hz, 1H), 5.14 (dd, J = 10.5, 1.2 Hz, 1H), 3.74 (s,
3H), 3.74−3.61 (m, 2H), 2.34−2.25 (m, 1H), 2.07 (ddd, J = 10.2, 8.1,
4.5 Hz, 1H), 1.44 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 152.0,
144.1, 143.3, 114.4, 113.9, 113.2, 68.6, 55.7, 45.7, 31.7, 20.6; IR (neat)
2962, 2924, 2831, 1512, 1327, 1304, 1242, 1041, 825.4 cm−1. Anal.
Calcd for C13H17NO: C, 76.81; H, 8.43; N, 6.89. Found: C, 76.77; H,
8.50; N, 6.99.
Screening of the Reaction Conditions (Table 1). Compound
1a (94.6 mg, 0.5 mmol, 1.0 equiv) was dissolved in solvent (CH2Cl2,
ClCH2CH2Cl, or PhMe, 1 or 10 mL, 0.5 or 0.05 M), followed by
addition of acid (H2SO4, TfOH, or CF3CO2H, 0.1−1.0 mmol, 0.2−2.0
equiv) at 0 °C or room temperature. The reaction mixture was stirred
at the indicated temperature for the indicated time period under argon
atmosphere, before the reaction mixture was partitioned between
EtOAc and saturated aqueous NaHCO3. The organic layer was
separated, and the aqueous layer was extracted with EtOAc. The
combined organic layer was washed with brine, dried over Na2SO4,
filtered, and concentrated under reduced pressure. The residue was
analyzed by 1H NMR spectroscopy to evaluate the ratio of the starting
material to the products. The results are summarized in Table 1.
1
2a. H NMR (300 MHz, CDCl3) δ 6.83 (d, J = 8.1 Hz, 1H), 6.70
To a solution of crude compound 2a in CH2Cl2 (2 mL, 0.25 M)
was added i-Pr2NEt (113 μL, 0.65 mmol, 1.3 equiv). After the mixture
was stirred at room temperature for 10 min under argon atmosphere,
AcCl (43 μL, 0.6 mmol, 1.2 equiv) was added and stirred for another 4
h. The reaction mixture was partitioned between Et2O and brine. The
organic layer was separated, and the aqueous layer was extracted with
EtOAc. The combined organic layer was washed with saturated
aqueous NaHCO3 and brine, dried over Na2SO4, filtered, and
concentrated under reduced pressure. Chromatography on silica gel
(hexane/EtOAc, 3:1) provided compound 8a (105.2 mg, 91%) as a
(d, J = 3.0 Hz, 1H), 6.68 (dd, J = 8.1, 3.0 Hz, 1H), 5.86 (dt, J = 11.1,
6.3 Hz, 1H), 5.62 (dtt, J = 11.1, 7.5, 1.2 Hz, 1H), 3.76 (s, 3H), 3.45 (d,
J = 6.3 Hz, 2H), 3.32 (br s, 1H), 3.08−3.05 (m, 2H), 2.23−2.17 (m,
2H).
1
3a. Orange solid; mp 44−45 °C; H NMR (300 MHz, CDCl3) δ
6.64−6.58 (m, 2H), 6.48 (d, J = 8.4 Hz, 1H), 5.87 (ddd, J = 17.1, 10.5,
6.6 Hz, 1H), 5.14 (d, J = 17.4 Hz, 1H), 5.09 (d, J = 10.5 Hz, 1H), 3.74
(s, 3H), 3.64 (br s, 1H), 3.35- 3.29 (m, 1H), 3.06−2.99 (m, 1H),
2.86−2.78 (m, 1H), 2.73−2.60 (m, 2H); 13C NMR (125 MHz,
CDCl3) δ 151.8, 140.1, 138.1, 121.8, 115.3, 114.8, 114.5, 113.0, 55.7,
47.2, 36.4, 33.0; IR (KBr) 3240, 2939, 2831, 1504, 1466, 1427, 1250,
1227, 1149, 802.4, 702.0 cm−1. Anal. Calcd for C12H15NO: C, 76.16;
H, 7.99; N, 7.40. Found: C, 76.03; H, 8.19; N, 7.28.
1
pale yellow solid: mp 113−114 °C; H NMR (300 MHz, CDCl3) δ
7.03 (d, J = 8.4 Hz, 1H), 6.82 (d, J = 3.0 Hz, 1H), 6.75 (dd, J = 8.4, 3.0
Hz, 1H), 5.90−5.81 (m, 1H), 5.72−5.63 (m, 1H), 4.66−4.59 (m, 1H),
3.82 (s, 3H), 3.41 (dd, J = 14.7, 8.1 Hz, 1H), 2.96 (dd, J = 13.5, 6.9
Hz, 1H), 2.65−2.47 (m, 2H), 2.25−2.14 (m, 1H), 1.80 (s, 3H); 13C
NMR (125 MHz, CDCl3) δ 170.8, 159.2, 142.8, 134.9, 131.3, 129.6,
129.1, 114.9, 112.5, 55.4, 48.0, 32.7, 26.8, 22.6; IR (KBr) 2947, 2924,
1643, 1504, 1442, 1404, 1304, 1234, 1211, 1026 cm−1. Anal. Calcd for
C14H17NO2: C, 72.70; H, 7.41; N, 6.06. Found: C, 72.49; H, 7.34; N,
6.03.
Ring Expansion of Vinylazetidine 1b to Tetrahydrobenza-
zocine 2b (Scheme 1). A solution of compound 1b (109.6 mg, 0.5
mmol, 1.0 equiv) in CH2Cl2 (1 mL, 0.5 M) was cooled to 0 °C,
followed by addition of H2SO4 (40 μL, 0.75 mmol, 1.5 equiv). The
reaction mixture was stirred at 0 °C for 2 h under argon atmosphere
and then allowed to warm to room temperature. After stirring for
another 1 h, the reaction mixture was partitioned between EtOAc and
saturated aqueous NaHCO3. The organic layer was separated, and the
aqueous layer was extracted with EtOAc. The combined organic layer
was washed with brine, dried over Na2SO4, filtered, and concentrated
under reduced pressure. The residue was purified by recrystallization
from hexane/EtOAc to afford compound 2b (58.1 mg, 53%) as a
yellow crystal: mp 73−74 °C; 1H NMR (300 MHz, CDCl3) δ 6.63 (s,
1H), 6.48 (s, 1H), 5.84 (dt, J = 11.4, 6.0 Hz), 5.64−5.56 (m, 1H), 3.83
(s, 3H), 3.82 (s, 3H), 3.49 (br s, 1H), 3.42 (d, J = 6.0 Hz, 2H), 3.10 (t,
J = 5.4 Hz, 2H), 2.16 (td, J = 6.6, 4.5 Hz, 2H); 13C NMR (125 MHz,
CDCl3) δ 148.1, 144.5, 140.1, 130.9, 127.2, 125.1, 113.4, 107.7, 56.2,
55.9, 48.8, 34.1, 27.5; IR (KBr) 3356, 2931, 2908, 2839, 1520, 1489,
1442, 1211, 1165, 1126, 1072, 1011, 856.2, 763.7 cm−1. Anal. Calcd for
C13H17NO2: C, 71.21; H, 7.81; N, 6.39. Found: C, 71.36; H, 7.96; N,
6.50.
5a. 83% yield (134.2 mg) from compound 1a (silica gel, hexane/
EtOAc, 6:1), viscous colorless oil; the presence of a rotamer was
1
1
detected on the H and 13C NMR at room temperature; H NMR
(300 MHz, CDCl3) δ 7.44−7.16 (m, 5H), 7.02 (d, J = 8.1, 1H), 6.78−
6.72 (m, 2H), 5.88−5.77 (m, 1H), 5.69−5.57 (m, 1H), 5.11 (s, 2H),
4.35 (ddd, J = 13.2, 7.5, 1.8 Hz, 1H), 3.81 (s, 3H), 3.40 (dd, J = 14.1,
7.8 Hz, 1H), 2.92 (dd, J = 14.1, 6.6 Hz, 1H), 2.67 (ddd, J = 13.5, 9.0,
1.5 Hz, 1H), 2.56−2.46 (m, 1H), 2.21−2.11 (m, 1H); 13C NMR (125
MHz, CDCl3) δ 158.7, 155.7, 142.4, 137.0, 133.0, 131.6, 129.7, 128.2,
128.0, 127.6, 127.2, 114.4, 112.0, 66.7, 55.3, 49.5, 33.0, 26.5; IR (neat)
1712, 1709, 1703, 1698, 1694, 1505, 1499, 1404, 1305, 1303 cm−1.
Anal. Calcd for C20H21NO3: C, 74.28; H, 6.55; N, 4.33. Found: C,
74.32; H, 6.74; N, 4.29.
6a. 88% yield (129.1 mg) from compound 1a (silica gel, hexane/
EtOAc, 5:1), viscous colorless oil; the presence of a rotamer was
Catalytic Hydrogenation of Tetrahydrobenzazocine
(Scheme 2a).23 A solution of compound 1a (94.6 mg, 0.5 mmol,
1.0 equiv) in CH2Cl2 (1 mL, 0.5 M) was cooled to 0 °C, followed by
1
detected on the 1H NMR at room temperature; H NMR (300 MHz,
CDCl3) δ 7.28−7.12 (m, 5H), 6.87 (d, J = 8.4 Hz, 1H), 6.70 (d, J = 3.0
4374
dx.doi.org/10.1021/jo500249c | J. Org. Chem. 2014, 79, 4367−4377

The Journal of Organic Chemistry
Article
Hz, 1H), 6.56 (dd, J = 8.4, 3.0 Hz, 1H), 5.94−5.85 (m, 1H), 5.80−
5.72 (m, 1H), 4.93−4.86 (m, 1H), 3.73 (s, 3H), 3.58 (dd, J = 14.4, 7.2
Hz, 1H), 3.04 (dd, J = 14.1, 6.6 Hz, 1H), 2.78−2.61 (m, 2H), 2.37−
2.27 (m, 1H); 13C NMR (125 MHz, CDCl3) δ 170.3, 158.6, 141.6,
136.7, 134.7, 130.7, 130.6, 129.0, 128.8, 127.6, 127.5, 114.6, 112.1,
55.2, 48.7, 33.4, 26.4; IR (neat) 2939, 1643, 1504, 1442, 1396, 1311,
1273, 1242, 725.1, 702.0 cm−1. Anal. Calcd for C19H19NO2: C, 77.79;
H, 6.53; N, 4.77. Found: C, 77.63; H, 6.78; N, 4.70.
Hz), 125.0, 124.5 (q, J = 4.1 Hz), 123.4 (q, J = 271.8 Hz), 47.3, 32.0,
26.4, 22.3; IR (neat) 3024, 2939, 2862, 1666, 1396, 1327, 1304, 1165,
1126 cm−1. Anal. Calcd for C14H14F3NO: C, 62.45; H, 5.24; N, 5.20.
Found: C, 62.55; H, 5.30; N, 5.18.
8g. 59% yield (72.4 mg) from compound 1g (silica gel, hexane/
EtOAc, 4:1), pale yellow oil; 1H NMR (300 MHz, CDCl3) δ 7.01 (d, J
= 8.4 Hz, 1H), 6.78 (d, J = 2.7 Hz, 1H), 6.71 (dd, J = 8.7, 3.0 Hz, 1H),
5.66 (dd, J = 8.4, 7.2 Hz, 1H), 4.64 (ddd, J = 13.5, 6.9, 1.5 Hz, 1H),
3.80 (s, 3H), 3.32 (dd, J = 13.2, 9.0 Hz, 1H), 2.87 (dd, J = 13.2, 7.2
Hz, 1H), 2.75 (dd, J = 15.0, 9.9 Hz, 1H), 2.44 (dd, J = 12.6, 9.3, Hz,
1H), 2.03 (dd, J = 15.0, 6.9 Hz, 1H), 1.77 (s, 3H), 1.67 (s, 3H); 13C
NMR (125 MHz, CDCl3) δ 170.8, 159.1, 143.4, 137.4, 134.9, 129.6,
124.5, 114.6, 112.1, 55.4, 47.1, 32.9, 32.8, 26.3, 22.7; IR (neat) 2931,
1643, 1504, 1435, 1396, 1311, 1273, 1234, 1041 cm−1. Anal. Calcd for
C15H19NO2: C, 73.44; H, 7.81; N, 5.71. Found: C, 73.42; H, 7.98; N,
5.63.
9. 26% yield (31.9 mg) from compound 1g (silica gel, hexane/
EtOAc, 4:1), viscous yellow oil; 1H NMR (300 MHz, CDCl3) δ 7.68−
6.96 (m, 1H), 6.71−6.67 (m, 2H), 4.79 (br s, 1H), 4.72 (br s, 1H),
3.99−3.89 (m, 1H), 3.75 (s, 3H), 3.58 (br s, 1H), 2.83−2.78 (m, 1H),
2.67−2.59 (m, 1H), 2.56−2.46 (m, 1H), 2.15 (s, 3H), 1.76 (s, 3H);
13C NMR (125 MHz, CDCl3) δ 169.8, 156.9, 145.6, 133.8, 132.2,
7a. 89% yield (128.8 mg) from compound 1a (silica gel, hexane/
EtOAc, 12:1), viscous colorless oil; the presence of a rotamer26 was
1
1
detected on the H and 13C NMR at room temperature; H NMR
(300 MHz, CDCl3) δ 6.96 (d, J = 8.4 Hz, 1H), 6.78−6.67 (m, 2H),
5.90−5.79 (m, 1H), 5.68−5.59 (m, 1H), 4.29 (ddd, J = 12.9, 7.5, 1.8
Hz, 1H), 3.79 (s, 3H), 3.46 (dd, J = 13.8, 7.5 Hz, 1H), 2.94 (dd, J =
14.1, 6.6 Hz, 1H), 2.63 (dd, J = 12.9, 8.7 Hz, 1H), 2.56−2.46 (m, 1H),
2.17−2.08 (m, 1H), 1.33 (s, 9H); 13C NMR (125 MHz, CDCl3) δ
158.3, 155.2, 142.3, 134.1, 131.5, 129.7, 128.2, 114.1, 111.8, 79.4, 55.3,
48.7, 33.1, 28.3, 26.6; IR (neat) 1709, 1703, 1698, 1692, 1686, 1683,
1508, 1500, 1390, 1365, 1313 cm−1. Anal. Calcd for C17H23NO3: C,
70.56; H, 8.01; N, 4.84. Found: C, 70.37; H, 8.08; N, 4.74.
8b. 93% yield (121.5 mg) from compound 1b (silica gel, hexane/
1
EtOAc, 1:1), colorless solid; mp 106−107 °C; H NMR (300 MHz,
CDCl3) δ 6.77 (s, 1H), 6.63 (s, 1H), 5.91−5.82 (m, 1H), 5.70−5.62
(m, 1H), 4.67−4.58 (m, 1H), 3.91 (s, 3H), 3.84 (s, 3H), 3.39 (ddd, J =
14.1, 8.1, 1.2 Hz, 1H), 2.93 (dd, J = 14.1, 6.9 Hz, 1H), 2.62−2.50 (m,
2H), 2.25−2.13 (m, 1H), 1.83 (s, 3H); 13C NMR (125 MHz, CDCl3)
δ 170.6, 148.6, 148.1, 134.0, 133.7, 131.6, 128.6, 111.8, 111.7, 56.1,
56.0, 47.6, 32.1, 26.6, 22.5; IR (KBr) 2939, 1651, 1512, 1450, 1412,
1265, 1227, 1196, 1142 cm−1. Anal. Calcd for C15H19NO3: C, 68.94;
H, 7.33; N, 5.36. Found: C, 68.98; H, 7.19; N, 5.39.
125.1, 113.3, 111.4, 110.9, 55.2, 46.4, 42.5, 32.6, 22.6, 20.7; IR (neat)
2935, 1655, 1500, 1450, 1377, 1308, 1273, 1234, 1188, 1038 cm−1.
Anal. Calcd for C15H19NO2: C, 73.44; H, 7.81; N, 5.71. Found: C,
73.19; H, 7.87; N, 5.67.
Ring-Contraction Reaction of Tetrahydrobenzazocine to
Vinyltetrahydroquinoline (Table 4). To a solution of compound
2b (43.8 mg, 0.2 mmol, 1.0 equiv) in CH2Cl2 (0.4 mL, 0.5 M) was
added silica gel 60N (spherical, neutral, 63-210 μm, 0.1 g), and the
reaction mixture was stirred at room temperature for 5 h under argon
atmosphere. The resulting mixture was filtered, and concentrated
under reduced pressure. The residue was then dissolved in CH2Cl2
(2.0 mL, 0.1 M) and treated with silica gel 60N (spherical, neutral,
63−210 μm, 0.2 g). The resulting mixture was stirred at room
temperature for 4 h, filtered, and concentrated under reduced pressure.
The residue was chromatographed on silica gel (hexane/EtOAc, 2:1)
to afford compound 3b (35.5 mg, 81%) as a yellow solid: mp 73−74
8c. 80% yield (104.5 mg) from compound 1c (silica gel, hexane/
1
EtOAc, 7:3), viscous pale yellow oil; H NMR (300 MHz, CDCl3) δ
6.38 (d, J = 2.7 Hz, 1H), 6.34 (d, J = 2.7 Hz, 1H), 5.87−5.78 (m, 1H),
5.69−5.60 (m, 1H), 4.56 (ddd, J = 12.9, 7.2, 1.8 Hz, 1H), 3.80 (s, 3H),
3.75 (s, 3H), 3.46- 3.39 (m, 1H), 2.90 (dd, J = 13.5, 7.2 Hz, 1H),
2.58−2.47 (m, 1H), 2.40 (dd, J = 12.6, 10.5 Hz, 1H), 2.23−2.10 (m,
1H), 1.75 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 171.5, 159.8,
156.3, 143.4, 131.3, 129.1, 123.6, 104.7, 97.0, 55.5, 55.3, 46.9, 32.7,
26.8, 21.6; IR (neat) 2939, 1658, 1597, 1496, 1442, 1396, 1327, 1211,
1157, 1088 cm−1. Anal. Calcd for C15H19NO3: C, 68.94; H, 7.33; N,
5.36. Found: C, 68.77; H, 7.47; N, 5.27.
1
°C; H NMR (300 MHz, CDCl3) δ 6.53 (s, 1H), 6.12 (s, 1H), 5.85
(ddd, J = 17.1, 10.5, 3.3 Hz, 1H), 5.14 (ddd, J = 17.1, 1.5, 1.2 Hz, 1H),
5.07 (ddd, J = 10.8, 1.5, 1.2 Hz, 1H), 3.78 (s, 6H), 3.31−3.27 (m, 1H),
3.05−2.96 (m, 1H), 2.81−2.70 (m, 1H), 2.65−2.54 (m, 2H); 13C
NMR (125 MHz, CDCl3) δ 148.3, 141.5, 140.3, 138.0, 114.5, 113.8,
111.9, 99.5, 56.7, 55.8, 47.1, 36.6, 32.3; IR (KBr) 3371, 2924, 2839,
1520, 1496, 1466, 1227, 1211, 1134, 910.2, 825.4 cm−1. Anal. Calcd for
C13H17NO2: C, 71.21; H, 7.81; N, 6.39. Found: C, 71.24; H, 7.96; N,
6.31.
To a solution of compound 2b (43.8 mg, 0.2 mmol, 1.0 equiv) in
CH2Cl2 (0.4 mL, 0.5 M) was added TfOH (8.8 μL, 0.1 mmol, 0.5
equiv), and the reaction mixture was stirred at room temperature for
16 h under argon atmosphere. The resulting mixture was then
partitioned between EtOAc and saturated aqueous NaHCO3. The
organic layer was separated, and the aqueous layer was extracted with
EtOAc. The combined organic layer was washed with brine, dried over
Na2SO4, filtered, and concentrated under reduced pressure. The
residue was chromatographed on silica gel to afford compound 3b
(40.1 mg, 91%).
Formaldehyde-Accelerated Ring-Contraction Reaction of
Tetrahydrobenzazocine (Scheme 3a). To a solution of compound
2b (65.8 mg, 0.3 mmol, 1.0 equiv) in CH2Cl2/MeOH (1:1, 3 mL, 0.1
M) were added CF3CO2H (11.5 μL, 0.15 mmol, 0.5 equiv) and
formaldehyde (37% aqueous solution, 83 μL, 0.6 mmol, 2.0 equiv),
and the reaction was stirred at room temperature for 2 min under
argon atmosphere. The resulting mixture was then partitioned
between EtOAc and saturated aqueous NaHCO3. The organic layer
was separated, and the aqueous layer was extracted with EtOAc. The
combined organic layer was washed with brine, dried over Na2SO4,
filtered, and concentrated under reduced pressure. The residue was
purified by silica gel column chromatography to afford compound 3b
(49.8 mg, 76%).
8d. 84% yield (84.5 mg) from compound 1d (silica gel, hexane/
1
EtOAc, 3:1), colorless oil; H NMR (300 MHz, CDCl3) δ 7.32−7.22
(m, 3H), 7.15−7.09 (m, 1H), 5.90−5.81 (m, 1H), 5.71−5.62 (m, 1H),
4.68−4.62 (m, 1H), 3.45 (ddd, J = 13.5, 8.1, 1.5 Hz, 1H), 3.02 (dd, J =
13.5, 7.2 Hz, 1H), 2.66−2.50 (m, 2H), 2.26−2.14 (m, 1H), 1.79 (s,
3H); 13C NMR (125 MHz, CDCl3) δ 170.2, 141.9, 141.4, 131.4,
129.6, 128.8, 128.7, 128.5, 127.8, 47.7, 32.4, 26.6, 22.6; IR (neat) 2937,
1666, 1650, 1490, 1446, 1438, 1395, 1361, 1320, 1304, 769.5, 722.2
cm−1. Anal. Calcd for C13H15NO: C, 77.58; H, 7.51; N, 6.96. Found:
C, 77.42; H, 7.72; N, 6.84.
8e. 92% yield (99.0 mg) from compound 1e (silica gel, hexane/
1
EtOAc, 4:1), colorless oil; H NMR (300 MHz, CDCl3) δ 7.10 (s,
1H), 7.04 (dd, J = 8.1, 1.5 Hz, 1H), 6.99 (d, J = 8.1 Hz, 1H), 5.89−
5.80 (m, 1H), 5.70−5.61 (m, 1H), 4.66−4.59 (m, 1H), 3.40 (dd, J =
13.5, 8.1 Hz, 1H), 2.96 (dd, J = 13.8, 6.9 Hz, 1H), 2.64−2.47 (m, 2H),
2.34 (s, 3H), 2.25−2.13 (m, 1H), 1.79 (s, 3H); 13C NMR (125 MHz,
CDCl3) δ 170.5, 141.1, 139.4, 138.5, 131.6, 130.3, 128.8, 128.5, 128.4,
47.8, 32.4, 26.7, 22.6, 21.0; IR (neat) 3016, 2931, 1736, 1658, 1504,
1442, 1396, 1304, 1242, 1049 cm−1. Anal. Calcd for C14H17NO: C,
78.10; H, 7.96; N, 6.51. Found: C, 78.04; H, 8.20; N, 6.43.
8f. 80% yield (107.7 mg) from compound 1f (silica gel, hexane/
EtOAc, 3:1), pale yellow solid; the presence of a rotamer was detected
on the 13C NMR at room temperature; mp 69−70 °C; 1H NMR (300
MHz, CDCl3) δ 7.59 (s, 1H), 7.54 (d, J = 8.4 Hz, 1H), 7.27 (d, J = 7.5
Hz, 1H), 5.92−5.83 (m, 1H), 5.76−5.67 (m, 1H), 4.69 (dd, J = 13.2,
6.9 Hz, 1H), 3.50 (dd, J = 13.5, 8.1 Hz, 1H), 3.11 (dd, J = 13.5, 6.9 Hz,
1H), 2.69−2.59 (m, 1H), 2.53 (dd, J = 12.9, 9.6 Hz, 1H), 2.28−2.17
(m, 1H), 1.80 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 169.2, 144.9,
142.4, 130.5, 130.3 (q, J = 32.0 Hz), 129.3, 129.3, 126.3 (q, J = 4.1
4375
dx.doi.org/10.1021/jo500249c | J. Org. Chem. 2014, 79, 4367−4377

The Journal of Organic Chemistry
Article
Isotopic Labeling Experiment (Scheme 3b). To a solution of
compound 2b (65.8 mg, 0.3 mmol, 1.0 equiv) in CH2Cl2/MeOH (1:1,
3 mL, 0.1 M) were added CF3CO2H (11.5 μL, 0.15 mmol, 0.5 equiv)
and formaldehyde-d2 (20% D2O solution, 87 μL, 0.6 mmol, 2.0 equiv),
and the reaction was stirred at room temperature for 2 min under
argon atmosphere. The resulting mixture was then partitioned
between EtOAc and saturated aqueous NaHCO3. The organic layer
was separated, and the aqueous layer was extracted with EtOAc. The
combined organic layer was washed with brine, dried over Na2SO4,
filtered, and concentrated under reduced pressure. The residue was
purified by silica gel column chromatography to afford an inseparable
mixture of compound 3b and compound 3b-d2 (48.7 mg, 74%, 83:17
(2) Ohno, H. Vinylaziridines in Organic Synthesis. In Aziridines and
Epoxides in Organic Synthesis; Yudin, A. K., Ed.; Wiley-VCH:
Weinheim, 2006; pp 37−71.
(3) Scheiner, P. J. Org. Chem. 1967, 32, 2628−2630.
(4) (a) Piangiolino, C.; Gallo, E.; Caselli, A.; Fantauzzi, S.; Ragaini,
F.; Cenini, S. Eur. J. Org. Chem. 2007, 743−750. (b) Fantauzzi, S.;
Gallo, E.; Caselli, A.; Piangiolino, C.; Ragaini, F.; Re, N.; Cenini, S.
Chem.Eur. J. 2009, 15, 1241−1251.
(5) Eckelbarger, J. D.; Wilmot, J. T.; Gin, D. Y. J. Am. Chem. Soc.
2006, 128, 10370−10371.
(6) For other examples, see: (a) Calcagno, M. A.; Schweizer, E. E. J.
Org. Chem. 1978, 43, 4207−4215. (b) Figeys, H. P.; Jammar, R.
Tetrahedron Lett. 1980, 21, 2995−2998. (c) Figeys, H. P.; Jammar, R.
Tetrahedron Lett. 1981, 22, 637−640. (d) Hassner, A.; Wiegand, N. J.
Org. Chem. 1986, 51, 3652−3656. (e) Lindstrom, U. M.; Somfai, P. J.
1
by H NMR integration in DMSO-d6).
Incorporation of a Methyl Group into the Vinyltetrahy-
droquinoline Scaffold (Scheme 3c). To a solution of compound
2b (65.8 mg, 0.3 mmol, 1.0 equiv) in CH2Cl2/MeOH (1:1, 3 mL, 0.1
M) were added CF3CO2H (11.5 μL, 0.15 mmol, 0.5 equiv) and
acetaldehyde (34 μL, 0.6 mmol, 2.0 equiv), and the reaction was
stirred at room temperature for 2 min under argon atmosphere. The
resulting mixture was then partitioned between EtOAc and saturated
aqueous NaHCO3. The organic layer was separated, and the aqueous
layer was extracted with EtOAc. The combined organic layer was
washed with brine, dried over Na2SO4, filtered, and concentrated
under reduced pressure. The residue was purified by silica gel column
chromatography (hexane/EtOAc, 4:1) to afford compound 3b (4.6
mg, 7%) and compound 3b-Me (25.1 mg, 35%, 6:1 diastereomeric
Am. Chem. Soc. 1997, 119, 8385−8386. (f) Lindstrom, U. M.; Somfai,
̈
P. Chem.Eur. J. 2001, 7, 94−98.
(7) Viallon, L.; Reinaud, O.; Capdevielle, P.; Maumy, M. Tetrahedron
Lett. 1995, 36, 4787−4790.
(8) (a) Koya, S.; Yamanoi, K.; Yamasaki, R.; Azumaya, I.; Masu, H.;
Saito, S. Org. Lett. 2009, 11, 5438−5441. (b) Kanno, E.; Yamanoi, K.;
Koya, S.; Azumaya, I.; Masu, H.; Yamasaki, R.; Saito, S. J. Org. Chem.
2012, 77, 2142−2148. (c) Aoki, T.; Koya, S.; Yamasaki, R.; Saito, S.
Org. Lett. 2012, 14, 4506−4509.
(9) Attempts to transform N-aryl-2-vinylazetidines to N-acylated
benzazocine derivatives in one step by treating vinylazetidines with
acylating agents instead of acid were unsuccessful. Vinylazetidine 1a
did not react with, for example, Ac2O/DMAP or Boc2O/DMAP.
(10) Although we have not studied the effect of acid concentration
on the ring-contraction reaction in detail, the results in Table 1 suggest
that the reaction rate would be decreased both at lower acid loadings
and with over 1.0 equiv of the acid.
(11) The declined yield of 3b relative to the reaction with
formaldehyde may be due to possible side reactions of iminium ion
and enol form of acetaldehyde. This presumed decomposition of
iminium ion may also account for the increased incorporation of 2-
methyl group through suppression of the methylene transfer pathway.
(12) Cooper, M. A.; Lucas, M. A.; Taylor, J. M.; Ward, A. D.;
Williamson, N. M. Synthesis 2001, 621−625.
(13) For related examples of the isomerization of a cyclic iminium
ion to 3-vinylpiperidine, see: (a) Grob, C. A.; Kunz, W.; Marbet, P. R.
Tetrahedron Lett. 1975, 16, 2613−2616. (b) Martin, C. L.; Overman,
L. E.; Rohde, J. M. J. Am. Chem. Soc. 2010, 132, 4894−4906.
(14) For the examples of reactions involving aldehydes as the catalyst
operating via iminium ion intermediate, see: MacDonald, M. J.;
Schipper, D. J.; Ng, P. J.; Moran, J.; Beauchemin, A. M. J. Am. Chem.
Soc. 2011, 133, 20100−20103.
1
1
ratio by H NMR integration) as a pale yellow oil: H NMR (300
MHz, CDCl3, major isomer) δ 6.53 (s, 1H), 6.13 (s, 1H), 5.70 (ddd, J
= 17.1, 10.2, 8.7 Hz, 1H), 5.17−5.07 (m, 2H), 3.80 (s, 3H), 3.79 (s,
3H), 3.47 (br s, 1H), 3.11 (dq, J = 9.0, 6.3 Hz, 1H), 2.66 (d, J = 8.1
Hz, 2H), 2.22−2.11 (m, 1H), 1.17 (d, J = 6.3 Hz, 3H); 13C NMR (125
MHz, CDCl3, major isomer) δ 148.3, 141.3, 140.2, 138.0, 115.6, 113.5,
111.9, 99.1, 56.7, 55.8, 51.2, 44.5, 32.9, 21.0; IR (neat) 3379, 2962,
2839, 1620, 1520, 1458, 1257, 1234, 1211, 1134 cm−1. Anal. Calcd for
C14H19NO2: C, 72.07; H, 8.21; N, 6.00. Found: C, 72.16; H, 8.33; N,
5.99.
ASSOCIATED CONTENT
* Supporting Information
■
S
Spectroscopic data for new compounds and crystallographic
data for 2b and 3b. This material is available free of charge via
the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: ssaito@rs.kagu.tus.ac.jp.
■
Present Addresses
(15) Guthrie, J. P. Can. J. Chem. 1975, 53, 898−906.
(16) Iorio, M. A.; Ciuffa, P.; Damia, G. Tetrahedron 1970, 26, 5519−
5527.
(17) The attempted isolation of the intermediate XVII was
unsuccessful. The yield of XVII is presumed to be very low.
(18) Wasserman, H. H.; Lipshutz, B. H.; Tremper, A. W.; Wu, J. S. J.
Org. Chem. 1981, 46, 2991−2999.
(19) Takashima, Y.; Kudo, J.; Hazama, M.; Inoue, A. Process for
producing optically active N-substituted azetidine-2-carboxylic acid
compound. Eur. Pat. Appl. EP0974670 (A2), 2000.
§Showa Pharmaceutical University, 3-3165 Higashi-Tamagawa-
gakuen, Machida, Tokyo 194-8543, Japan.
#Faculty of Pharmaceutical Sciences, Toho University, 2-2-1
Miyama, Funabashi, Chiba 274-8510, Japan.
¶Department of Chemistry, Faculty of Science and Engineering,
Konan Univeristy 8-9-1 Okamoto, Higashinada-ku, Kobe 658-
8501, Japan.
Notes
(20) Juaristi, E.; Madrigal, D. Tetrahedron 1989, 45, 629−634.
(21) (a) Walker, J. R.; Rothman, S. C.; Poulter, C. D. J. Org. Chem.
2008, 73, 726−729. (b) Anderson, A.; Belelli, D.; Bennett, D. J.;
Buchanan, K. I.; Casula, A.; Cooke, A.; Feilden, H.; Gemmell, D. K.;
Hamilton, N. M.; Hutchinson, E. J.; Lambert, J. J.; Maidment, M. S.;
McGuire, R.; McPhail, P.; Miller, S.; Huntoni, A.; Peters, J. A.;
Sansbury, F. H.; Stevenson, D.; Sundaram, H. J. Med. Chem. 2001, 44,
3582−3591.
(22) Burnett, D. A.; Caplen, M. A.; Czarniecki, M. F.; Domalski, M.
S.; Ho, G. D.; Tulshian, D.; Wu, W. L. Azetidinyl diamines useful as
ligands of the nociceptin receptor ORL-1. PCT Int. WO 03043980
(A1), 2003.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
This work was supported by Nagase Science and Technology
Foundation and Hoansha Foundation.
■
REFERENCES
■
(1) For reviews on aza-Claisen rearrangement, see: (a) Majumdar, K.
C.; Bhattacharyya, T.; Chattopadhyay, B.; Sinha, B. Synthesis 2009, 13,
2117−2142. (b) Nubbemeyer, U. Top. Curr. Chem. 2005, 244, 149−
213.
4376
dx.doi.org/10.1021/jo500249c | J. Org. Chem. 2014, 79, 4367−4377

The Journal of Organic Chemistry
Article
(23) Kamei, K.; Maeda, N.; Nomura, K.; Shibata, M.; Katsuragi-
Ogino, R.; Koyama, M.; Nakajima, M.; Inoue, T.; Ohno, T.; Tatsuoka,
T. Bioorg. Med. Chem. 2006, 14, 1978−1992.
(24) Rivas, F. M.; Riaz, U.; Giessert, A.; Smulik, J. A.; Diver, S. T.
Org. Lett. 2001, 3, 2673−2676.
(25) Cordeiro, A.; Shaw, J.; O’Brien, J.; Blanco, F.; Rozas, I. Eur. J.
Org. Chem. 2011, 1504−1513.
(26) Qadir, M.; Cobb, J.; Sheldrake, P. W.; Whittall, N.; White, A. J.
P.; Hii, K. K. M.; Horton, P. N.; Hursthouse, M. B. J. Org. Chem. 2005,
70, 1552−1557.
4377
dx.doi.org/10.1021/jo500249c | J. Org. Chem. 2014, 79, 4367−4377