Rhodium(ii)-catalyzed intramolecular formal [4 + 3] cycloadditions of dienyltriazoles: Rapid access to fused 2,5-dihydroazepines

Article abstract of DOI:10.1039/c4ob01910e

Rhodium(ii)-catalyzed intramolecular [4 + 3] cycloadditions of dienyltriazoles have been developed, which enable the efficient synthesis of various fused 2,5-dihydroazepines. Mechanistically, the titled reaction proceeds via an interesting tandem cyclopropanation/aza-cope rearrangement.

Full text of DOI:10.1039/c4ob01910e

Organic &
Biomolecular Chemistry
View Article Online
View Journal | View Issue
PAPER
Rhodium(II)-catalyzed intramolecular formal
[4 + 3] cycloadditions of dienyltriazoles: rapid
access to fused 2,5-dihydroazepines†
Cite this: Org. Biomol. Chem., 2015,
13, 612
Yu Tian,a Yuanhao Wang,b Hai Shang,b Xudong Xua and Yefeng Tang*b,c,d
Received 9th September 2014,
Accepted 29th October 2014
Rhodium(II)-catalyzed intramolecular [4 + 3] cycloadditions of dienyltriazoles have been developed,
which enable the efficient synthesis of various fused 2,5-dihydroazepines. Mechanistically, the titled reac-
tion proceeds via an interesting tandem cyclopropanation/aza-cope rearrangement.
DOI: 10.1039/c4ob01910e
www.rsc.org/obc
Introduction
Development of new cycloaddition reactions for the rapid
generation of azaheterocycles has been a subject of continued
interest in organic synthesis. Various methods have been docu-
mented for the synthesis of five- and six-membered azahetero-
cycles.1 Comparably, the approaches to construct seven-
membered azaheterocycles are limited,2 mainly due to the
inherent challenges associated with their synthesis, such as
the unfavorable entropic and enthalpic factors. Azepine re-
presents a privileged structural element widely distributed in
natural products and medicinally valuable molecules, such as
stemoamide, galantamine and cephalotaxine (Scheme 1a).3
Among the many strategic bond disconnections of azepines,4
the cycloaddition reactions are particularly attractive because
of their highly convergent and straightforward nature.5
Recently, Rh(ιι)-iminocarbenes, which are readily generated
from 1-sulfonyl 1,2,3-triazoles upon treatment with Rh(II)-cata-
lysts, have emerged as versatile intermediates in various
cycloadditions that lead to diverse azaheterocycles.6 As an
example, we recently reported the novel Rh(II)-catalyzed
cycloadditions of 1-sulfonyl 1,2,3-triazoles with 1,3-dienes,
Scheme 1 Representative azepine-containing natural products and
Rh(II)-catalyzed formal [4 + 3] cycloadditions leading to azepines.
which enabled the efficient and divergent synthesis of two
different types of azaheterocycles, 2,5-dihydroazepines and
2,3-dihydropyrroles, respectively, via the formal [4 + 3] and
[3 + 2] cycloadditions (Scheme 1b).7 As a continuation of our
ongoing project directed toward the construction of hetero-
cycle-based fragments which could be applied to the fragment-
based drug discovery (FBDD),8 we initiated a program with
the objective to synthesize the structurally more diverse,
fused 2,5-dihydroazepines via intramolecular [4 + 3] cyclo-
addition of dienyltriazoles. Of note, a similar transformation
was independently achieved by Sarpong and co-workers very
recently,9 which stimulated us to disclose our progress on this
topic.
aInstitute of Medicinal Plant Development, Chinese Academy of Medical Sciences,
Peking Union Medical College, Beijing 100193, P. R. China
bThe Comprehensive AIDS Research Center, and The Department of Pharmacology &
Pharmaceutical Sciences, School of Medicine, Tsinghua University, Beijing 100084,
P.R. China. E-mail: yefengtang@tsinghua.edu.cn; Tel: +86 10 62798236
cCollaborative Innovation Center for Biotherapy, Tsinghua University,
Beijing 100084, China
dCollaborative Innovation Center for Biotherapy, West China Hospital,
Sichuan University, Chengdu 610041, P.R. China
†Electronic supplementary information (ESI) available: General procedure for
the preparation of 1a–t and 2a–t, copies of NMR spectra of 1a–t and 2a–t, and
the CIF file of compound 2p. CCDC 1016527. For ESI and crystallographic data
in CIF or other electronic format see DOI: 10.1039/c4ob01910e
612 | Org. Biomol. Chem., 2015, 13, 612–619
This journal is © The Royal Society of Chemistry 2015

View Article Online
Organic & Biomolecular Chemistry
Paper
triazoles were examined (Table 2). All of them (1b–g), either
bearing electron-donating (4-Me and 2-OMe) or -withdrawing
Results and discussion
In accordance with the previous work,7 we commenced our (4-Cl, 4-F, 4-Br and 4-CF3) substitutes underwent the trans-
investigations with the treatment of the dienyltriazole 1a10 in formations smoothly to afford the corresponding azepines
the presence of 1 mol% Rh2(oct)4 in 1,2-DCE at 140 °C. Gratify- (2b–g) in excellent yields (entries 2–7). The naphthyl-derived
ingly, the starting material was consumed quickly after 0.5 h, substrate 1h was also tolerated in the reaction (entry 8). More-
leading to the 5–7 bicyclic fused 2,5-dihydroazepine 2a as a
single isomer in 67% yield. Moreover, different from the inter-
molecular reactions,7 no trace amount of the corresponding
Table 2 Scope of intramolecular cycloadditions of C-tethered
dienyltriazoles
[3 + 2] cycloadduct was detected in the reaction. Encouraged
by this result, we launched a systematic study to improve the
efficiency of the reaction. First of all, the effect of Rh(II)-cata-
lysts was evaluated (Table 1, entries 1–5). It was shown that
while Rh2(OAc)4 and Rh2(esp)2 showed comparable efficiency
with Rh2(oct)4, the sterically more hindered Rh2(S-ptad)4 and
Yield of
Entrya Substrate
Products
2b
Rh2(S-dosp)4 displayed
a superior reactivity by affording
improved yields (up to 85%, entry 4). Furthermore, it was
found that the reaction temperature had a notable influence
on the reaction. Indeed, the lower temperature (80, 100 or
120 °C) turned out to be detrimental to the reaction by giving
decreased yields (entries 6–8). Finally, besides 1,2-DCE, several
other solvents (e.g. CHCl3, toluene, PhCl and p-xylene) were
also examined in the reaction; however, none of them provided
satisfying results (entries 9–12). It is worth noting that, while
both Rh2(S-ptad)4 and Rh2(S-dosp)4 are chiral catalysts and
have been applied to various asymmetric transformations,11
they failed to provide good enantioselectivity in our case.
Indeed, only a poor ee value (5–10%) was obtained under the
currently optimized conditions.
1
2
3
4
5
6
7
1a: R = H
2a: R = H
85%
78%
81%
81%
74%
87%
80%
1b: R = 4-Me
1c: R = 2-OMe
1d: R = 4-Cl
1e: R = 4-F
1f: R = 4-Br
1g: R = 4-CF3
2b: R = 4-Me
2c: R = 2-OMe
2d: R = 4-Cl
2e: R = 4-F
2f: R = 4-Br
2g: R = 4-CF3
8
85%
Under optimal conditions, we turned to evaluate the gener-
ality of the reaction. First of all, various aryl-substituted dienyl-
9
75%
10
75%
86%
91%
77%
Table 1 Condition optimization of the intramolecular cycloadditions of
dienyltriazole
11
Entrya
Cat.
Solvent
Other conditions
Yield of 2ab
12d
13
1
2
3
4
5
6
7
8
Rh2(oct)4
Rh2(OAc)4
Rh2(esp)2
1,2-DCE
1,2-DCE
1,2-DCE
1,2-DCE
1,2-DCE
1,2-DCE
1,2-DCE
1,2-DCE
CHCl3
140 °C, 0.5 h
140 °C, 0.5 h
140 °C, 0.5 h
140 °C, 0.5 h
140 °C, 0.5 h
120 °C, 0.5 h
100 °C, 0.5 h
80 °C, 0.5 h
140 °C, 0.5 h
140 °C, 0.5 h
140 °C, 0.5 h
140 °C, 0.5 h
67%
63%
60%
85%
79%
71%
58%
50%
52%
40%
35%
40%
Rh2(S-ptad)4
Rh2(S-dosp)4
Rh2(S-ptad)4
Rh2(S-ptad)4
Rh2(S-ptad)4
Rh2(S-ptad)4
Rh2(S-ptad)4
Rh2(S-ptad)4
Rh2(S-ptad)4
9
14d
60% (4n)
(dr =
10
11
12
Toluene
PhCl
p-Xylene
2 : 1)c
a The reaction was run with 0.1 mmol of 1a in 0.5 mL 1,2-DCE in a
sealed tube. b Refers to isolated yield. DCE = dichloroethane, esp =
a The reaction was run with 0.1 mmol of 1a in 0.5 mL 1,2-DCE in a
sealed tube. b Refers to isolated yield. c Determined by 1H NMR.
d Extended reaction time (>12 h) was required for complete conversion.
α,α,α′,α′-tetramethyl-1,3-benzenedipropionic acid, oct
= octanoate,
(S)-ptad = N-phthaloyl-(S)-adamantylglycine, (S)-dosp = 4-(dodecyl-phenyl)-
sulfonyl-(2S)-prolinate.
This journal is © The Royal Society of Chemistry 2015
Org. Biomol. Chem., 2015, 13, 612–619 | 613

View Article Online
Paper
Organic & Biomolecular Chemistry
over, the cycloadditions could be extended to the alkyl-substi-
tuted dienyltriazoles, as witnessed in the cases leading to 2i–l
(entries 9–12). Notably, for 2l which bear a bulky t-butyl
group on the C-1 position of the diene unit, the elongation of
reaction time (16 h) was required in order to obtain good
yield of 2l (entry 12). Finally, besides the substrates bearing a
1,4-disubstituted diene unit, some more sterically encumbered
dienyltriazoles were checked. It was found that while the
1,2,4-trisubstituted 1m was amenable to the reaction (entry
13), the 1,1,4-trisubstituted 1n (prepared as a mixture of
isomers, E/Z = 3 : 1) failed to yield the expected [4 + 3] product.
Instead, the fused dihydropyrrole 4n was obtained as a
mixture of diastereoisomers (cis–trans = 2 : 1) in 60% yield.
Interestingly, shortening the reaction time (0.5 h) mainly
resulted in the formation of another new product, which was
proved to be the cyclopropylaldimine derivative 3n. The inter-
mediacy of 3n was proved by its conversion into 4n at high
temperature (140 °C) in 1,2-DCE, apparently via the cyclopro-
pylimine rearrangement.12 Of note, an intermediate similar to
3n was also identified in Sarpong’s work,9 however, it failed to
undergo the ring-expansion as observed in our case. This
might be attributed to the relatively low reaction temperature
(60 °C) adopted in that case.
To further extend the substrate scope of the cycloaddition,
we attempted several other dienyltriazoles which bear different
tethers (Table 3). Among them, 1o, wherein the triazole and
diene units were attached to the ortho positions of a phenyl
ring, underwent the reaction smoothly to afford the tricyclic
fused azepine 2o in 90% yield (entry 1, Table 3). Comparably,
although the dienyltriazoles bearing the N-tosylamine, ether,
diester or diketone groups were also tolerated in the reactions,
only moderate yields of the corresponding products were
obtained (entries 2–6). It is likely that the presence of some
coordinative functionalities (e.g. ether, ester or ketone) might
interfere with the reactivity of the rhodium carbene intermedi-
ate, thus decreasing the overall efficiency of the reaction.
Notably, the structure of 2p was confirmed by the X-ray crystal-
lographic study (Fig. 1).13
Table 3 Scope of intramolecular cycloadditions of dienyltriazoles with
other tethers
Entrya
1
Substrate
Products
Yield of 2b
90%
2
3
56%
35%
4
5
42%
42%
6
59%
a The reaction was run with 0.1 mmol of 1a in 0.5 mL 1,2-DCE in a
sealed tube. b Refers to isolated yield. c Determined by 1H NMR.
In addition to the aforementioned outcomes, some other
interesting observations deserved further discussion. For
instance, when the cycloaddition of 1l was performed with a
shorter reaction time (0.5 h), the cyclopropylaldimine deriva-
tive 3l instead of the azepine 2l was isolated as the major
product (69%). The cis-relationship of the imine and vinyl moi-
eties of 3l was established by the NOE studies (for details, see
Fig. 1 X-ray crystal structure of 2p.
This observation was in sharp contrast with that in cyclo-
ESI†).14 As expected, 3l could readily convert into 2l in nearly addition of 1a, wherein the corresponding 1,2-cis cyclopropyl-
quantitative yield (>95%) under the thermal conditions aldimine intermediate (cis-3a, structure not shown) could not
(1,2-DCE, 140 °C), apparently via the aza-cope rearrangement be detected. We assumed that, cis-3a, once formed, would
([eqn(1)], Scheme 2).15 Moreover, we found that the geometry in situ advance into 2a via the concerted aza-cope rearrangement.
of the diene unit had a profound effect on the reaction. Comparably, such a process was precluded for trans-3a for the
Indeed, when the dienyltriazole (1E,3Z)-1a was treated under unattainable stereochemical requirement. Instead, in this
the standard conditions (entry 4, Table 1), a mixture of 1,2- scenario the aza-cope rearrangement should proceed via the
trans-cyclopropylaldimine 3a (49%) and 2,5-dihydroazepine 2a diradical or zwitterionic intermediates, which generally
(37%) was obtained. Interestingly, trans-3a could also advance require harsher conditions (e.g. high temperature and long
into 2a in high yield under the thermal conditions ([eqn (2)], reaction time). This assumption was further supported by the
Scheme 2).
experiments listed in [eqn (3)] (Scheme 2). As shown, when the
614 | Org. Biomol. Chem., 2015, 13, 612–619
This journal is © The Royal Society of Chemistry 2015

View Article Online
Organic & Biomolecular Chemistry
Paper
the dihydropyrrole E via the cyclopropylimine rearrangement.
This pathway may play a dominant role for some kinds of sub-
strates, such as the 1,1,4-trisubstituted dienyltriazole 1n. In
this scenario, the huge steric hindrance of the C-1 position of
the diene unit largely inhibits the pathway leading to azepine
D, thus favoring the formation of E as the major product.
Conclusions
In summary, we have successfully achieved the Rh(II)-catalyzed
intramolecular formal [4 + 3] cycloadditions of dienyltriazoles.
Mechanistically, the titled reaction may proceed via the
tandem cyclopropanation/aza-cope rearrangement. Compar-
able with our previously reported intermolecular cycloaddi-
tions of triazoles with 1,3-dienes, the intramolecular version
allows to access various fused azepine derivatives with increas-
ing structural diversity, which could not be readily achieved by
the other known methods. The application of this method for
the construction of the azepine-based fragment library is
underway in our lab.
Scheme 2 Identification of the key cyclopropylaldimine intermediates.
alkyl substituted dienyltriazole 1i (prepared as a mixture of
E/Z-isomers, 0.6 : 1 ratio) was submitted to the reaction,
trans-3i and azepine 2i were obtained in 49% and 37% yields,
respectively. The isolated trans-3i could also convert into 2i as
expected under the thermal conditions (140 °C, 1,2-DCE),
albeit only resulting in moderate yield (30%) with a long reac-
tion time. It should be pointed out that, an intermediate
similar to trans-3a was also identified in Sarpong’s work,9
however, it failed to undergo the aza-cope rearrangement to
give the corresponding azepine product, presumably due to
the milder reaction conditions (60 °C) employed in that case.
Taking into consideration all of the above-mentioned
results, we proposed that the intramolecular formal aza-[4 + 3]
cycloaddition may follow the mechanism depicted in
Scheme 3. Thus, the Rh(ιι)-iminocarbene B, generated from
the dienyltriazole A upon treatment with the Rh-catalyst, first
undergoes the [2 + 1] cycloaddition to give C-1 (from E-isomer)
and (or) C-2 (from Z-isomer). C-1 and (or) C-2 could further
convert into the azepine D, respectively, via the concerted
(path a-1) or stepwise (path a-2) aza-cope rearrangement. This
process may account for the majority of the cycloadditions dis-
cussed in this work. Besides, the reactions could also be
diverted into the path b, in which C-1 and (or) C-2 evolve into
Experimental section
General information
NMR spectra were recorded on a Bruker AV400 instrument.
1
TMS was used as the internal standard for H NMR (0 ppm),
and a solvent signal was used as a reference for 13C NMR
(CDCl3, 77.16 ppm). The following abbreviations were used to
explain the multiplicities: s = singlet, d = doublet, t = triplet, q
= quartet, dt = doublet of triplets, td = triple doublet, m = mul-
tiplet. Infrared (IR) spectra were recorded on a Thermo Nicolet
Avatar 330 FT-IR spectrometer. High-resolution mass spectra
(HRMS) were recorded on a Bruker ESI-Q/TOF MS. Low resolu-
tion mass spectra were recorded on a Waters’s UPLC-Mass
instrument.
Reactions were monitored by Thin Layer Chromatography
on plates (GF254) supplied by Yantai Chemicals (China) using
UV light as the visualizing agent and an ethanolic solution
of phosphomolybdic acid and cerium sulfate, and heat as
developing agents. If not specially mentioned, flash column
chromatography uses silica gel (200–300 mesh) supplied by
Tsingtao Haiyang Chemicals (China). Solvent purification was
conducted according to Purification of Laboratory Chemicals
(D. D. Peerrin, W. L. Armarego and D. R. Perrins, Pergamon
Press, Oxford, 1980).
General procedure for Rh(II)-catalyzed intramolecular [4 + 3]
cycloadditions
A 10 mL pressure tube, fitted with a rubber septum, was
charged with triazole (0.10 mmol, 1.0 equiv.) and Rh2(S-
PTAD)4 (1.6 mg, 1.0 mol%). To the reaction vessel was added
freshly distilled 1,2-dichloroethane (0.5 mL) and was then
sealed with a Teflon screwcap and placed in an oil bath pre-
Scheme 3 Proposed mechanisms of the cycloadditions of dienyltriazoles. heated to 140 °C. The resulting solution was heated at this
This journal is © The Royal Society of Chemistry 2015
Org. Biomol. Chem., 2015, 13, 612–619 | 615

View Article Online
Paper
Organic & Biomolecular Chemistry
temperature for 0.5 h before being cooled to room temperature
3-(4-Fluorophenyl)-2-tosyl-2,3,5a,6,7,8-hexahydrocyclopenta-
and concentrated in vacuo. The residue was purified by flash [c]azepine (2e). Yield: 74%; 1H NMR (400 MHz, CDCl3) δ
chromatography (SiO2, hexanes–EtOAc) to give the products 1.27–1.42 (m, 2H), 1.66–1.74 (m, 1H), 1.90–1.99 (m, 1H),
2a–2t.
2.13–2.25 (m, 1H), 2.35 (dd, J = 17.1 Hz, 5.9 Hz, 1H), 2.42 (s,
3-Phenyl-2-tosyl-2,3,5a,6,7,8-hexahydrocyclopenta[c]azepine 3H), 2.54–2.63 (m, 1H), 5.52 (ddd, J = 11.5 Hz, 4.6 Hz, 2.5 Hz,
(2a). Yield: 85%; 1H NMR (400 MHz, CDCl3) δ 1.29–1.42 (m, 1H), 5.58 (d, J = 11.5 Hz, 1H), 5.69 (s, 1H), 5.92 (t, J = 4.3 Hz,
2H), 1.66–1.73 (m, 1H), 1.90–1.97 (m, 1H), 2.14–2.23 (m, 1H), 1H), 6.97 (t, J = 8.6 Hz, 2H), 7.24 (d, J = 8.0 Hz, 2H), 7.33 (dd,
2.34 (dd, J = 17.2 Hz, 6.0 Hz, 1H), 2.41 (s, 3H), 2.55–2.64 (m, J = 8.4 Hz, 5.6 Hz, 2H), 7.73 (d, J = 8.1 Hz, 2H); 13C NMR
1H), 5.52–5.60 (m, 2H), 5.70 (s, 1H), 5.92–5.95 (m, 1H), (100 MHz, CDCl3) δ 21.7, 24.9, 31.8, 34.9, 42.1, 59.2, 115.1 (d,
7.21–7.30 (m, 5H), 7.36 (dd, J = 8.0 Hz, 1.2 Hz, 2H), 7.73 (d, J = J = 21.2 Hz), 117.0, 126.5, 127.1, 129.5, 130.3, 130.5 (d, J = 8.1
8.3 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 21.7, 24.9, 31.7, Hz), 135.5 (d, J = 3.0 Hz), 138.6, 143.2, 149.8, 162.4 (d, J = 244.7
35.0, 42.1, 59.9, 117.1, 126.6, 127.1, 127.8, 128.3, 128.8, 129.4, Hz); IR νmax (film): 2960.5, 1506.2, 1337.4, 1259.9, 1159.8,
130.1, 138.6, 139.7, 143.0, 149.7; IR νmax (film): 1700.1, 1652.8, 1092.3, 1016.2, 812.7, 810.5, 799.4, 684.78 cm−1; HRMS m/z
1559.7, 1161.2, 1094.7, 698.2, 687.0, 682.8, 676.3 cm−1; HRMS calcd for C22H23FNO2S [M + H]+: 384.1428; found: 384.1432.
m/z calcd for C22H23NNaO2S [M + Na]+: 388.1342; found:
388.1346.
3-(4-Bromophenyl)-2-tosyl-2,3,5a,6,7,8-hexahydrocyclopenta-
[c]azepine (2f). Yield: 87%; 1H NMR (400 MHz, CDCl3) δ
3-(p-Tolyl)-2-tosyl-2,3,5a,6,7,8-hexahydrocyclopenta[c]azepine 1.29–1.41 (m, 2H), 1.64–1.73 (m, 1H), 1.89–1.99 (m, 1H),
(2b). Yield: 78%; 1H NMR (400 MHz, CDCl3) δ 1.30–1.41 (m, 2.12–2.22 (m, 1H), 2.34 (dd, J = 16.9 Hz, 6.0 Hz, 1H), 2.42 (s,
2H), 1.65–1.74 (m, 1H), 1.89–1.99 (m, 1H), 2.13–2.25 (m, 1H), 3H), 2.53–2.62 (m, 1H), 5.51 (ddd, J = 11.5 Hz, 5.0 Hz, 2.7 Hz,
2.30–2.37 (m, 4H), 2.42 (s, 3H), 2.55–2.64 (m, 1H), 5.50–5.58 1H), 5.59 (dt, J = 11.5 Hz, 1.6 Hz, 1H), 5.69 (s, 1H), 5.89 (t, J =
(m, 2H), 5.70 (s, 1H), 5.89–5.91 (m, 1H), 7.10 (d, J = 7.9 Hz, 4.4 Hz, 1H), 7.21–7.25 (m, 4H), 7.41 (dt, J = 8.4 Hz, 2.5 Hz, 2H),
2H), 7.21–7.25 (m, 4H), 7.74 (d, J = 8.2 Hz, 2H); 13C NMR 7.73 (d, J = 8.3 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 21.7,
(100 MHz, CDCl3) δ 21.3, 21.7, 24.9, 31.8, 35.0, 42.2, 59.7, 24.9, 31.8, 34.9, 42.2, 59.2, 117.0, 122.0, 126.1, 127.1, 129.5,
117.2, 126.9, 127.2, 128.8, 129.0, 129.4, 129.9, 136.7, 137.5, 130.5, 130.6, 131.4, 138.5, 138.8, 143.2, 149.9; IR νmax (film):
138.7, 143.0, 149.7; IR νmax (film): 2923.2, 2358.4, 2340.7, 1700.2, 1695.7, 1684.6, 711.7, 680.7 cm−1; HRMS m/z calcd for
1337.4, 1159.9, 1093.4, 1027.4, 822.3, 813.2, 683.9, 676.2 cm−1
;
C22H23BrNO2S [M + H]+: 444.0627; found: 444.0631.
2-Tosyl-3-(4-(trifluoromethyl)phenyl)-2,3,5a,6,7,8-hexahydro-
cyclo-penta[c]azepine (2g). Yield: 80%; 1H NMR (400 MHz,
HRMS m/z calcd for C23H25NNaO2S [M + Na]+: 402.1498;
found: 402.1498.
3-(2-Methoxyphenyl)-2-tosyl-2,3,5a,6,7,8-hexahydrocyclo- CDCl3) δ 1.30–1.42 (m, 2H), 1.65–1.74 (m, 1H), 1.92–1.99 (m,
1
penta[c]azepine (2c). Yield: 81%; H NMR (400 MHz, CDCl3) δ 1H), 2.13–2.23 (m, 1H), 2.35 (dd, J = 17.2 Hz, 5.8 Hz, 1H), 2.42
1.32–1.43 (m, 2H), 1.67–1.75 (m, 1H), 1.92–1.99 (m, 1H), (s, 3H), 2.53–2.61 (m, 1H), 5.54 (ddd, J = 11.5 Hz, 5.4 Hz,
2.17–2.28 (m, 1H), 2.33–2.41 (m, 4H), 2.60–2.70 (m, 1H), 3.85 2.7 Hz, 1H), 5.63 (dt, J = 11.5 Hz, 1.6 Hz, 1H), 5.71 (s, 1H), 5.98
(s, 3H), 5.47 (ddd, J = 11.5 Hz, 5.0 Hz, 2.7 Hz, 1H), 5.56 (dt, J = (t, J = 4.3 Hz, 1H), 7.25 (d, J = 8.1 Hz, 2H), 7.48 (d, J = 8.2 Hz, 2H),
11.5 Hz, 1.6 Hz, 1H), 5.65 (s, 1H), 6.37 (t, J = 4.2 Hz, 1H), 6.81 7.55 (d, J = 8.2 Hz, 2H), 7.73 (d, J = 8.3 Hz, 2H); 13C NMR
(t, J = 7.5 Hz, 1H), 6.85 (d, J = 8.1 Hz, 1H), 7.14 (dd, J = 7.6 Hz, (100 MHz, CDCl3) δ 21.7, 24.9, 31.8, 34.9, 42.1, 59.4, 116.9,
1.6 Hz, 1H), 7.18 (d, J = 8.0 Hz, 2H), 7.23 (td, J = 8.2 Hz, 1.6 Hz, 124.2 (q, J = 270.4 Hz), 125.3 (q, J = 3.6 Hz), 125.8, 127.1, 129.1,
1H), 7.71 (d, J = 8.2 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 129.5, 130.0 (q, J = 32.1 Hz), 130.9, 138.4, 143.3, 143.8, 150.0;
21.7, 24.9, 31.8, 35.1, 42.5, 53.8, 55.6, 110.8, 117.7, 119.7, IR νmax (film): 1700.4, 1684.6, 1652.9, 1559.8, 684.2, 679.4,
127.5, 127.6, 129.1, 129.2, 129.6, 130.2, 138.5, 142.7, 150.3, 677.9 cm−1; HRMS m/z calcd for C23H22F3NNaO2S [M + Na]+:
157.2; IR νmax (film): 2957.1, 2923.7, 2332.0, 1464.2, 1341.7, 456.1216; found: 456.1213.
1259.2, 1246.7, 1160.5, 1094.6, 1065.9, 1027.6, 685.5,
677.8 cm−1; HRMS m/z calcd for C23H25NNaO3S [M + Na]+: [c]azepine (2h). Yield: 85%; 1H NMR (400 MHz, CDCl3) δ
418.1447; found: 418.1448. 1.32–1.47 (m, 2H), 1.66–1.74 (m, 1H), 1.94–2.02 (m, 1H),
3-(Naphthalen-2-yl)-2-tosyl-2,3,5a,6,7,8-hexahydrocyclopenta-
3-(4-Chlorophenyl)-2-tosyl-2,3,5a,6,7,8-hexahydrocyclopenta- 2.11–2.22 (m, 1H), 2.33 (dd, J = 16.0 Hz, 5.9 Hz, 1H), 2.42 (s,
[c]azepine (2d). Yield: 81%; 1H NMR (400 MHz, CDCl3) δ 3H), 2.60–2.67 (m, 1H), 5.64–5.71 (m, 3H), 6.07–6.11 (m, 1H),
1.28–1.40 (m, 2H), 1.65–1.75 (m, 1H), 1.89–1.98 (m, 1H), 7.24 (d, J = 8.0 Hz, 2H), 7.44–7.48 (m, 2H), 7.58 (d, J = 8.4 Hz,
2.12–2.23 (m, 1H), 2.34 (dd, J = 16.8 Hz, 5.7 Hz, 1H), 2.42 (s, 1H), 7.67 (s, 1H), 7.74–7.83 (m, 5H); 13C NMR (100 MHz,
3H), 2.53–2.62 (m, 1H), 5.52 (ddd, J = 11.5 Hz, 5.0 Hz, 2.7 Hz, CDCl3) δ 21.7, 24.9, 31.8, 35.0, 42.4, 60.1, 117.2, 126.1, 126.2,
1H), 5.59 (dt, J = 11.5 Hz, 1.9 Hz, 1H), 5.69 (s, 1H), 5.91 (t, J = 126.6, 126.9, 127.3, 127.7, 127.8, 128.2, 128.3, 129.4, 130.5,
4.3 Hz, 1H), 7.23–7.30 (m, 6H), 7.73 (d, J = 8.3 Hz, 2H); 13C 133.0, 133.1, 137.1, 138.7, 143.1, 149.7; IR νmax (film): 1700.3,
NMR (100 MHz, CDCl3) δ 21.7, 24.9, 31.8, 34.9, 42.2, 59.2, 1652.9, 1559.8, 739.4, 680.4, 676.1 cm−1; HRMS m/z calcd for
117.0, 126.2, 127.1, 128.5, 129.5, 130.2, 130.5, 133.7, 138.3, C26H26NO2S [M + H]+: 416.1679; found: 416.1677.
138.5, 143.2, 149.9; IR νmax (film): 2955.1, 1488.9, 1338.0,
1160.7, 1092.7, 1070.0, 1015.3, 821.5, 818.6, 815.6, 677.3 cm−1
3-Phenethyl-2-tosyl-2,3,5a,6,7,8-hexahydrocyclopenta-
;
[c]azepine (2i). Yield: 75%; 1H NMR (400 MHz, CDCl3) δ
HRMS m/z calcd for C22H22ClNNaO2S [M + Na]+: 422.0952; 1.18–1.39 (m, 2H), 1.65–1.72 (m, 1H), 1.77–1.91 (m, 3H),
found: 422.0957.
2.21–2.33 (m, 1H), 2.36–2.47 (m, 5H), 2.64–2.80 (m, 2H),
616 | Org. Biomol. Chem., 2015, 13, 612–619
This journal is © The Royal Society of Chemistry 2015

View Article Online
Organic & Biomolecular Chemistry
Paper
4.63–4.71 (m, 1H), 5.25 (dt, J = 11.6 Hz, 1.7 Hz, 1H), 5.42 (ddd, 0.68–0.81 (m, 1H), 0.82–0.91 (m, 0.5H), 1.40–1.59 (m, (0.5 × 2)
J = 11.6 Hz, 5.1 Hz, 2.9 Hz, 1H), 6.06 (s, 1H), 7.16–7.20 (m, 3H), H), 1.74–2.03 (m, 3H + (0.5 × 2)H), 2.07–2.22 (m, 2H + 0.5H),
7.22 (d, J = 8.0 Hz, 2H), 7.28 (t, J = 8.1 Hz, 2H), 7.71 (d, J = 2.33 (s, 3H), 2.35 (s, (0.5 × 3)H), 2.80–2.91 (m, 0.5H), 3.02–3.13
8.2 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 21.7, 24.8, 31.8, 32.9, (m, 1H), 3.88 (t, J = 9.2 Hz, 1H), 4.38 (t, J = 9.9 Hz, 0.5H),
35.0, 37.0, 42.7, 57.3, 116.2, 126.0, 127.2, 128.1, 128.5, 128.6, 5.95–6.00 (m, 1.5H), 6.09 (d, J = 9.9 Hz, 0.5H), 6.30 (d, J = 9.5
128.8, 129.4, 138.6, 141.9, 143.0, 149.8; IR νmax (film): 1652.8, Hz, 1H), 7.01 (d, J = 7.9 Hz, 2H), 7.11 (d, J = 7.9 Hz, 1H), 7.17
1560.2, 1507.2, 1160.9, 757.8, 696.1, 687.1, 675.4 cm−1; HRMS (d, J = 7.9 Hz, 2H), 7.18–7.30 (m, 10H), 7.34–7.45 (m, 6H); 13C
m/z calcd for C24H28NO2S [M + H]+: 394.1835; found: 394.1833. NMR (100 MHz, CDCl3) δ 21.6, 21.6, 21.7, 22.3, 26.6, 27.2, 28.6,
3-Pentyl-2-tosyl-2,3,5a,6,7,8-hexahydrocyclopenta[c]azepine 30.4, 53.8, 57.4, 61.3, 67.4, 118.7, 119.9, 125.3, 127.5, 127.5,
1
(2j). Yield: 75%; H NMR (400 MHz, CDCl3) δ 0.88 (t, J = 6.8 127.6, 127.7, 127.9, 127.9, 128.2, 128.2, 128.3, 128.4, 129.2,
Hz, 3H), 1.20–1.40 (m, 8H), 1.42–1.54 (m, 2H), 1.64–1.71 (m, 129.3, 129.4, 129.9, 130.5, 132.4, 133.0, 135.0, 136.9, 139.5,
1H), 1.80–1.88 (m, 1H), 2.20–2.31 (m, 1H), 2.37–2.46 (m, 5H), 139.5, 141.5, 142.0, 142.8, 143.2; IR νmax (film): 2955.6, 2362.9,
4.54–4.61 (m, 1H), 5.22 (dt, J = 11.5 Hz, 1.5 Hz, 1H), 5.41 (ddd, 1559.8, 1340.6, 1161.8, 1093.4, 993.2, 908.6, 732.3, 701.4,
J = 11.5 Hz, 5.1 Hz, 2.9 Hz, 1H), 5.99 (s, 1H), 7.21 (d, J = 8.1 Hz, 698.9 cm−1; HRMS m/z calcd for C28H28NO2S [M + H]+:
2H), 7.70 (d, J = 8.2 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 442.1835; found: 442.1839.
14.2, 21.7, 22.7, 24.8, 26.2, 31.7, 31.8, 35.0, 35.4, 42.6, 57.5,
3-Phenyl-2-tosyl-2,3,5a,6-tetrahydroindeno[1,2-c]azepine
116.3, 127.2, 127.8, 129.3, 129.4, 138.8, 142.8, 149.6; IR νmax (2o). Yield: 90%; 1H NMR (400 MHz, CDCl3) δ 2.37 (s, 3H),
(film): 1695.6, 705.5, 685.5, 678.3, 675.7 cm−1; HRMS m/z 2.56–2.67 (m, 1H), 2.73–2.85 (m, 2H), 5.66–5.72 (m, 1H),
calcd for C21H30NO2S [M + H]+: 360.1992; found: 360.1992.
5.85–5.91 (m, 2H), 6.70 (s, 1H), 7.07–7.20 (m, 6H), 7.28 (d, J =
3-Cyclohexyl-2-tosyl-2,3,5a,6,7,8-hexahydrocyclopenta[c]- 7.2 Hz, 1H), 7.33 (t, J = 7.1 Hz, 2H), 7.49 (d, J = 7.5 Hz, 2H),
azepine (2k). Yield: 86%; 1H NMR (400 MHz, CDCl3) δ 7.66 (d, J = 8.1 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 21.7,
1.05–1.34 (m, 7H), 1.42–1.53 (m, 1H), 1.62–1.92 (m, 7H), 34.3, 36.0, 59.0, 126.2, 126.3, 127.0, 127.1, 127.1, 127.4, 127.5,
2.20–2.30 (m, 2H), 2.37–2.44 (m, 4H), 4.31–4.38 (m, 1H), 5.26 127.9, 128.0, 128.7, 129.6, 133.2, 134.1, 134.3, 137.8, 140.4,
(d, J = 11.7 Hz, 1H), 5.51 (ddd, J = 11.7 Hz, 5.2 Hz, 2.6 Hz, 1H), 143.6; IR νmax (film): 2919.7, 1717.3, 1699.9, 1557.8, 681.9,
6.02 (s, 1H), 7.19 (d, J = 8.1 Hz, 2H), 7.68 (d, J = 8.1 Hz, 2H); 676.9 cm−1; HRMS m/z calcd for C26H24NO2S [M + H]+:
13C NMR (100 MHz, CDCl3) δ 21.7, 24.7, 26.2, 26.3, 26.5, 30.5, 414.1522; found: 414.1517.
30.6, 31.7, 35.0, 43.0, 43.4, 62.6, 116.9, 127.1, 127.9, 128.2,
6-Phenyl-2,5-ditosyl-1,2,3,5,6,8a-hexahydropyrrolo[3,4-c]-
1
129.2, 139.0, 142.7, 149.2; IR νmax (film): 1700.5, 1684.6, azepine (2p). Yield: 56%; H NMR (400 MHz, CDCl3) δ 2.43 (s,
1653.2, 1559.7, 688.0, 682.9 cm−1; HRMS m/z calcd for 3H), 2.46 (s, 3H), 2.64 (t, J = 9.7 Hz, 1H), 2.98–3.08 (m, 1H),
C22H30NO2S [M + H]+: 372.1992; found: 372.1994.
3.47 (dt, J = 14.2 Hz, 2.2 Hz, 1H), 3.66 (t, J = 8.8 Hz, 1H), 3.98
3-(tert-Butyl)-2-tosyl-2,3,5a,6,7,8-hexahydrocyclopenta[c]- (d, J = 14.2 Hz, 1H), 5.41 (dt, J = 11.5 Hz, 1.7 Hz, 1H), 5.64
azepine (2l). The reaction was run for 16 h instead of 0.5 h. (ddd, J = 11.5 Hz, 5.4 Hz, 2.8 Hz, 1H), 5.80 (d, J = 2.0 Hz, 1H),
Yield: 91%; 1H NMR (400 MHz, CDCl3) δ 1.01 (s, 9H), 5.92 (t, J = 4.2 Hz, 1H), 7.20–7.26 (m, 7H), 7.35 (d, J = 8.0 Hz,
1.12–1.30 (m, 2H), 1.58–1.66 (m, 1H), 1.74–1.82 (m, 1H), 2H), 7.64–7.69 (m, 4H); 13C NMR (100 MHz, CDCl3) δ 21.7,
2.01–2.20 (m, 2H), 2.34–2.43 (m, 4H), 4.54 (t, J = 4.0 Hz, 1H), 41.3, 50.9, 54.1, 59.9, 119.5, 125.2, 127.0, 128.1, 128.2, 128.5,
5.35 (d, J = 11.9 Hz, 1H), 5.49 (ddd, J = 11.9 Hz, 4.9 Hz, 2.8 Hz, 128.5, 128.9, 129.8, 130.0, 132.0, 138.0, 138.8, 140.6, 143.7,
1H), 6.05 (s, 1H), 7.19 (d, J = 8.0 Hz, 2H), 7.67 (d, J = 8.2 Hz, 144.3; IR νmax (film): 1700.4, 1653.0, 1559.8, 1340.6, 1160.5,
2H); 13C NMR (100 MHz, CDCl3) δ 21.6, 24.6, 28.5, 32.0, 35.0, 1092.2, 813.2, 685.1, 678.8 cm−1
37.0, 42.2, 66.0, 118.3, 125.3, 127.2, 129.2, 129.9, 138.6, 142.7, C28H29N2O4S2 [M + H]+: 521.1563; found: 521.1565.
148.4; IR νmax (film): 2959.9, 1652.7, 1336.9, 1159.4, 1093.7, 6-Phenyl-5-tosyl-3,5,6,8a-tetrahydro-1H-furo[3,4-c]azepine
831.8, 812.4, 684.5 cm−1; HRMS m/z calcd for C20H28NO2S [M (2q). Yield: 35%; 1H NMR (400 MHz, CDCl3) δ 2.43 (s, 3H),
+ H]+: 346.1835; found: 346.1831.
2.84–2.90 (m, 1H), 3.39 (dd, J = 10.3 Hz, 8.5 Hz, 1H), 4.11–4.19
; HRMS m/z calcd for
4-Methyl-3-phenyl-2-tosyl-2,3,5a,6,7,8-hexahydrocyclopenta[c]- (m, 2H), 4.41 (d, J = 13.6 Hz, 1H), 5.49 (dt, J = 11.5 Hz, 1.8 Hz,
azepine (2m). Yield: 77%; 1H NMR (400 MHz, CDCl3) δ 1H), 5.71 (ddd, J = 11.5 Hz, 5.4 Hz, 2.8 Hz, 1H), 5.80 (d, J = 2.4
1.30–1.42 (m, 2H), 1.57 (s, 3H), 1.63–1.74 (m, 1H), 1.89–2.01 Hz, 1H), 6.01 (t, J = 4.2 Hz, 1H), 7.25–7.28 (m, 2H), 7.29–7.34
(m, 1H), 2.07–2.21 (m, 1H), 2.34 (dd, J = 17.7 Hz, 6.3 Hz, 1H), (m, 3H), 7.36–7.39 (m, 2H), 7.74 (d, J = 8.3 Hz, 2H); 13C NMR
2.41 (s, 3H), 2.51–2.59 (m, 1H), 5.36 (s, 1H), 5.58 (s, 1H), 5.66 (100 MHz, CDCl3) δ 21.7, 42.7, 60.2, 70.3, 74.3, 116.7, 124.5,
(d, J = 3.0 Hz, 1H), 7.21–7.29 (m,7H), 7.71 (d, J = 8.1 Hz, 2H); 127.1, 128.1, 128.5, 128.8, 129.7, 138.3, 139.2, 143.5, 144.8; IR
13C NMR (100 MHz, CDCl3) δ 21.7, 24.2, 24.8, 31.6, 35.4, 42.6, νmax (film): 1739.1, 1729.2, 1717.2, 1365.3, 1229.2, 1217.3,
63.6, 116.9, 125.9, 127.1, 127.8, 128.3, 129.1, 129.4, 132.4, 751.9, 691.6 cm−1; HRMS m/z calcd for C21H22O3NS [M + H]+:
138.7, 138.9, 143.0, 148.7; IR νmax (film): 1684.5, 1559.7, 708.3, 368.1315; found: 368.1311.
688.0, 681.2, 679.7 cm−1; HRMS m/z calcd for C23H25NNaO2S
Dimethyl 3-phenyl-2-tosyl-2,3,5a,6-tetrahydrocyclo-penta[c]-
azepine-7,7(8H)-dicarboxylate (2r). Yield: 42%; 1H NMR
[M + Na]+: 402.1498; found: 402.1498.
1-(2,2-Diphenylvinyl)-2-tosyl-1,2,4,5,6,6a-hexahydrocyclo- (400 MHz, CDCl3) δ 1.92 (dd, J = 12.5 Hz, 11.4 Hz, 1H), 2.43 (s,
penta[c]pyrrole (4n). Yield: 60%; the NMR spectra are reported 3H), 2.53 (ddd, J = 12.5 Hz, 8.3 Hz, 1.2 Hz, 1H), 2.63–2.72 (m,
for a mixture of two isomers. 1H NMR (400 MHz, CDCl3) δ 1H), 2.83 (dt, J = 16.9 Hz, 2.5 Hz, 1H), 2.97 (d, J = 16.9 Hz, 1H),
This journal is © The Royal Society of Chemistry 2015
Org. Biomol. Chem., 2015, 13, 612–619 | 617

View Article Online
Paper
Organic & Biomolecular Chemistry
3.71 (s, 3H), 3.71 (s, 3H), 5.49 (dt, J = 11.5 Hz, 1.5 Hz, 1H), 5.58
(ddd, J = 11.5 Hz, 5.0 Hz, 2.8 Hz, 1H), 5.78 (d, J = 2.5 Hz, 1H),
5.95 (t, J = 4.3 Hz, 1H), 7.24 (d, J = 8.2 Hz, 2H), 7.26–7.34 (m,
3H), 7.35–7.38 (m, 2H), 7.71 (d, J = 8.2 Hz, 2H); 13C NMR
(100 MHz, CDCl3) δ 21.7, 38.8, 40.2, 41.0, 52.9, 53.1, 58.5, 59.8,
119.1, 127.0, 127.4, 128.0, 128.3, 128.4, 128.8, 129.6, 138.6,
139.4, 143.2, 145.5, 170.9, 171.2; IR νmax (film): 2363.9, 2358.3,
1751.0, 1733.8, 1652.7, 1506.9, 721.9, 691.9, 686.7, 681.3,
676.4 cm−1; HRMS m/z calcd for C26H27NNaO6S [M + Na]+:
504.1451; found: 504.1453.
W. Tam, Chem. Rev., 1996, 96, 49; (c) T. L. Gilchrist,
J. Chem. Soc., Perkin Trans. 1, 1999, 2849; (d) G. Balme,
Angew. Chem., Int. Ed., 2004, 43, 6238; (e) C. Schmuck and
D. Rupprecht, Synthesis, 2007, 3095; (f) N. T. Patil and
Y. Yamamoto, ARKIVOC, 2007, 10, 121; (g) B. Heller and
M. Hapke, Chem. Soc. Rev., 2007, 36, 1085; (h) G. Masson,
C. Lalli, M. Benohoud and G. Dagousset, Chem. Soc. Rev.,
2013, 42, 902.
2 For selected related reviews, see: (a) L. Yet, Tetrahedron,
1999, 55, 9349; (b) L. Yet, Chem. Rev., 2000, 100, 2963;
(c) M. E. Maier, Angew. Chem., Int. Ed., 2000, 39, 2073.
3 For selected reviews, see: (a) T. Kametani and K. Fukumoto,
Heterocycles, 1975, 3, 931; (b) B. Renfroe, C. Harrington and
G. R. Proctor, Heterocyclic Compounds: Azepines, Wiley &
Interscience, New York, 1984; (c) C. R. Ganellin and
D. J. Triggle, Dictionary of Pharmacological Agents, Chapman
& Hall/CRC, London, 1996.
4 For radical methods, see: (a) C. E. Masse, A. J. Morgan and
J. S. Panek, Org. Lett., 2000, 2, 2571; For ring-expansion
methods, see: (b) T. J. V. Bergen and R. M. Kellogg, J. Org.
Chem., 1971, 36, 978; (c) E. J. Kantorowski and M. J. Kurth,
Tetrahedron, 2000, 56, 4317; For ring-closing metathesis
methods, see: (d) M. E. Maier, Angew. Chem., Int. Ed., 2000,
39, 2073; (e) P. Jakubec, A. Hawkins, W. Felzmann and
D. J. Dixon, J. Am. Chem. Soc., 2012, 134, 17482; for metal-
catalyzed cyclizations: (f) H. Ohno, H. Hamaguchi,
M. Ohata, S. Kosaka and T. Tanaka, J. Am. Chem. Soc., 2004,
126, 8744; (g) I. Nakamura, M. Okamoto, Y. Sato and
M. Terada, Angew. Chem., Int. Ed., 2012, 51, 10816;
(h) Z. Shi, C. Grohmann and F. Glorius, Angew. Chem., Int.
Ed., 2013, 52, 5393; (i) J. Yang, C. Zhu, X. Tang and M. Shi,
Angew. Chem., Int. Ed., 2014, 53, 5142.
2′,2′-Dimethyl-3-phenyl-2-tosyl-3,5a,6,8-tetrahydro-2H-spiro-
[cyclopenta[c]azepine-7,5′-[1,3]dioxane]-4′,6′-dione (2s). Yield:
42%; 1H NMR (400 MHz, CDCl3) δ 1.74 (s, 3H), 1.76 (s, 3H),
2.29 (t, J = 12.7 Hz, 1H), 2.42 (s, 3H), 2.49 (dd, J = 12.7 Hz, 9.4
Hz, 1H), 2.97 (d, J = 16.8 Hz, 1H), 3.10 (dt, J = 16.8 Hz, 2.4 Hz,
1H), 3.25–3.34 (m, 1H), 5.48 (dt, J = 11.5 Hz, 1.7 Hz, 1H), 5.62
(ddd, J = 11.5 Hz, 5.2 Hz, 2.9 Hz, 1H), 5.90 (d, J = 2.4 Hz, 1H),
5.96 (t, J = 4.2 Hz, 1H), 7.26–7.32 (m, 3H), 7.34 (t, J = 7.5 Hz,
2H), 7.44 (d, J = 7.1 Hz, 2H), 7.81 (d, J = 8.2 Hz, 2H); 13C NMR
(100 MHz, CDCl3) δ 21.7, 28.9, 29.1, 41.5, 42.5, 45.0, 51.8, 59.9,
105.2, 119.4, 126.9, 127.2, 127.5, 128.1, 128.5, 128.8, 129.8,
138.9, 139.3, 143.3, 144.2, 168.7, 170.0; IR νmax (film): 1739.0,
1733.0, 1652.2, 1301.7, 1161.7, 704.5, 678.2 cm−1; HRMS m/z
calcd for C27H27NNaO6S [M + Na]+: 516.1451; found: 516.1454.
3-Phenyl-2-tosyl-3,5a,6,8-tetrahydro-2H-spiro[cyclopenta[c]-
azepine-7,2′-indene]-1′,3′-dione (2t). Yield: 59%; 1H NMR
(400 MHz, CDCl3) δ 1.96 (t, J = 12.4 Hz, 1H), 2.11 (ddd, J = 12.4
Hz, 8.4 Hz, 1.2 Hz, 1H), 2.47 (s, 3H), 2.58 (d, J = 16.9 Hz, 1H),
2.78 (dt, J = 16.9 Hz, 2.5 Hz, 1H), 3.34–3.44 (m, 1H), 5.49 (dt, J
= 11.5 Hz, 1.7 Hz, 1H), 5.60 (ddd, J = 11.5 Hz, 5.3 Hz, 2.9 Hz,
1H), 5.89 (d, J = 2.5 Hz, 1H), 5.96 (t, J = 4.3 Hz, 1H), 7.27–7.33
(m, 1H), 7.34–7.39 (m, 4H), 7.45–7.49 (m, 2H), 7.83–7.91 (m,
4H), 7.95–8.00 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 21.8,
38.0, 41.1, 41.7, 57.5, 59.9, 119.0, 123.6, 123.7, 127.1, 127.1,
128.0, 128.1, 128.5, 128.9, 129.9, 136.0, 136.2, 139.1, 139.5,
141.0, 141.4, 143.2, 145.5, 202.0, 202.2; IR νmax (film): 1705.7,
5 (a) D. J. Anderson and A. Fiassner, J. Am. Chem. Soc., 1971,
93, 4339; (b) N. D. Shapiro and F. D. Toste, J. Am. Chem.
Soc., 2008, 130, 9244; (c) H. Liu, X. Li, Z. Chen and
W.-X. Hu, J. Org. Chem., 2012, 77, 5184; (d) L. Wang,
J. Huang, S. Peng, H. Liu, X. Jiang and J. Wang, Angew.
Chem., Int. Ed., 2013, 52, 1768.
1703.9, 1539.4, 1506.6, 1160.8, 835.4, 703.0, 689.7, 686.2 cm−1
;
HRMS m/z calcd for C30H25NNaO4S [M + Na]+: 518.1397;
found: 518.1391.
6 For leading reviews on this topic, see: (a) B. Chattopadhyay
and V. Gevorgyan, Angew. Chem., Int. Ed., 2012, 51, 862;
(b) A. V. Gulevich and V. Gevorgyan, Angew. Chem., Int. Ed.,
2013, 52, 1371; (c) H. M. L. Davie and J. S. Alford, Chem.
Soc. Rev., 2014, 43, 5151. For selected recent studies on this
topic, see: (d) Y. Shi and V. Gevorgyan, Org. Lett., 2013, 15,
5394; (e) J. S. Alford, J. E. Spangler and H. M. L. Davies,
J. Am. Chem. Soc., 2013, 135, 11712; (f) B. T. Parr,
S. A. Green and H. M. J. Davies, J. Am. Chem. Soc., 2013,
135, 4716; (g) M. Zibinsky and V. V. Fokin, Angew. Chem.,
Int. Ed., 2013, 52, 1507; (h) S. Chuprakov, S. W. Kwok and
V. V. Fokin, J. Am. Chem. Soc., 2013, 135, 4652; (i) T. Miura,
T. Tanaka, K. Hiraga, S. G. Stewart and M. Murakami,
J. Am. Chem. Soc., 2013, 135, 13652; ( j) T. Miura, T. Tanaka,
T. Biyajima, A. Yada and M. Murakami, Angew. Chem., Int.
Ed., 2013, 52, 3883; (k) R. H. Liu, M. Zhang, G. Winston-
McPherson and W. P. Tang, Chem. Commun., 2013, 49,
4376; (l) S. Chuprakov, B. T. Worrell, N. Selander, R. K. Sit
Acknowledgements
We gratefully acknowledge the financial support provided by
the NSFC (21102081, 21272133), New Teachers’ Fund for
Doctor Stations Ministry of Education (20110002120011), The
Scientific Research Foundation for the Returned Overseas
Chinese Scholars, Ministry of Education (20121027968),
The Beijing Natural Science Foundation (2132037) and The
Tsinghua-Giti project.
Notes and references
1 For selected reviews, see: (a) A. R. Katritzky and N. Dennis,
Chem. Rev., 1989, 89, 827; (b) M. Lautens, W. Klute and
618 | Org. Biomol. Chem., 2015, 13, 612–619
This journal is © The Royal Society of Chemistry 2015

View Article Online
Organic & Biomolecular Chemistry
Paper
and V. V. Fokin, J. Am. Chem. Soc., 2014, 136, 195; 12 For reviews related with this topic, see: (a) H. N. C. Wong,
(m) T. Miura, Y. Funakoshi and M. Murakami, J. Am. Chem.
Soc., 2014, 136, 2272; (n) J. Yang, C. Zhu, X. Tang and
M. Shi, Angew. Chem., Int. Ed., 2014, 53, 5142.
7 H. Shang, Y. Wang, Y. Tian, J. Feng and Y. Tang, Angew.
Chem., Int. Ed., 2014, 53, 5662.
8 For selected reviews on this topic, see: (a) D. A. Erlanson,
R. S. McDowell and T. O’Brien, J. Med. Chem., 2004, 47,
3463; (b) D. C. Rees, M. Congreve, C. W. Murray and
R. Carr, Nat. Rev. Drug Discovery, 2004, 3, 660; (c) D. E. Scott,
A. G. Coyne, S. A. Hudson and C. Abell, Biochemistry, 2012,
51, 4990; (d) D. Joseph-McCarthy, A. J. Campbell and
M.-Y. Hon, C.-W. Tse, Y.-C. Yip, J. Tanko and T. Hudlicky,
Chem. Rev., 1989, 89, 165; (b) R. C. Stevens, Acc. Chem. Res.,
1984, 17, 289; For selected examples, see: (c) D. C. Lathbury,
P. J. Parsons and I. Pinto, J. Chem. Soc., Chem. Commun.,
1988, 2, 81; (d) S. Kagabu and I. Kawai, J. Chem. Soc., Chem.
Commun., 1990, 4, 1393; (e) Y. V. Tomilov, D. N. Platonov,
A. E. Frumkin, D. L. Lipilin and R. F. Salikov, Tetrahedron
Lett., 2010, 51, 5120; (f) S. Saha, Ch. V. R. Reddy and
B. Patro, Tetrahedron Lett., 2011, 52, 4014; (g) S. W. Kwok,
L. Zhang, N. P. Grimster and V. V. Fokin, Angew. Chem., Int.
Ed., 2014, 53, 3452.
G. K. Demetri Moustakas, J. Chem. Inf. Model., 2014, 54, 13 CCDC 1016527 (2p) contains the supplementary crystallo-
693. graphic data for this paper.
9 E. E. Schultz, V. N. G. Lindsay and R. Sarpong, Angew. 14 For a reference related with the stereochemistry assignment
Chem., Int. Ed., 2014, 53, 9904.
of the cis-divinylcyclopropane derivative, see: W. R. Cantrell
and H. M. L. Davies, J. Org. Chem., 1991, 56, 723.
15 For sporadic examples of the aza-cope rearrangement
leading to azepines, see: (a) L. A. Paquette and G. D. Ewing,
J. Am. Chem. Soc., 1978, 136, 2908; (b) R. K. Boeckman Jr.,
M. D. Shair, J. R. Vargas and L. A. Stolz, J. Org. Chem., 1993,
58, 1295.
10 The full description of the preparation of various dienyl-
triazoles presented in this study is included in the ESI.†
11 For selected cases, see: (a) S. Chuprakov, S. W. Kwok,
L. Zhang, L. Lercher and V. V. Fokin, J. Am. Chem. Soc.,
2009, 131, 18034; (b) B. T. Parr and H. M. L. Davies, Angew.
Chem., Int. Ed., 2013, 52, 10044.
This journal is © The Royal Society of Chemistry 2015
Org. Biomol. Chem., 2015, 13, 612–619 | 619