Ruthenium-Catalyzed C-C Bond Cleavage of 2H-Azirines: A Formal [3+2+2] Cycloaddition to Fused Azepine Skeletons

Article abstract of DOI:10.1002/anie.201510820

2H-azirines can serve as three-atom synthons by C-C bond cleavage, however, it involves a high energy barrier under thermal conditions (>50.0 kcal mol^-1). Reported is a ruthenium-catalyzed [3+2+2] cycloaddition reaction of 2H-azirines with diyn

Full text of DOI:10.1002/anie.201510820

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International Edition: DOI: 10.1002/anie.201510820
German Edition: DOI: 10.1002/ange.201510820
Heterocycle Synthesis
À
Ruthenium-Catalyzed C C Bond Cleavage of 2H-Azirines: A Formal
[3+2+2] Cycloaddition to Fused Azepine Skeletons
Tengfei Li, Fen Xu, Xincheng Li, Chunxiang Wang,* and Boshun Wan*
Abstract: 2H-azirines can serve as three-atom synthons by
À
C C bond cleavage, however, it involves a high energy barrier
under thermal conditions (> 50.0 kcalmolÀ1). Reported is
a ruthenium-catalyzed [3+2+2] cycloaddition reaction of
2H-azirines with diynes, thus leading to the formation of
fused azepine skeletons. This approach features an unprece-
À
dented metal-catalyzed C C bond cleavage of 2H-azirines at
room temperature, and the challenging construction of aza-
seven-membered rings from diynes. The results of this study
provide a new reaction pattern for constructing nitrogen-
containing seven-membered rings and may find applications in
the synthesis of other complex heterocycles.
À
T
ransition-metal-catalyzed C C bond activation represents
a straightforward but challenging strategy to discover new
transformations and construct complex molecules in modern
organic synthesis.[1] In comparison with achievements in C H
bond activation, the development of C C bond activation still
lags behind because of its inert character and poor interaction
of the C C s bond with transition metals. In contrast, C C
bond activation of small rings has gained considerable
attention in the past decade. As a paradigm, 2H-azirines can
undergo diverse ring-opening reactions by different bond-
cleavage modes.[3] To date, the chemistry of 2H-azirines
À
À
Scheme 1. Ring-opening reactions of 2H-azirines. EWG=electron-with-
drawing group, Ts =4-toluenesulfonyl.
[2]
À
À
À
transition-metal-catalyzed C C bond cleavage of 2H-azirines
remains largely unexploited, possibly because of the higher
energy barrier.[11]
À
mainly focuses on the cleavage of a C N single bond. For
example, 2H-azirines can serve as synthetic equivalents of
Azepine derivatives are important skeletal motifs which
are widely distributed in numerous natural products and
pharmaceuticals (Figure 1).[12] Owing to the significant medic-
inal and bioactive properties of the azepine moiety, many
methods for the preparation of azepine-containing hetero-
cycles have been developed in recent decades.[13,14] Particu-
larly, azepine frameworks have been constructed by [4+3],
[5+2], and [3+2+2] cycloadditions of unsaturated hydro-
carbons with triazoles, aziridines, azomethine imines, cyclo-
propyl imines, imine esters, and amino ketones.[14] Despite the
significant advances made in this subject, there are only
limited reports on the preparation of ring-fused azepine
derivatives.[13k,14l,m]
À
vinyl nitrenes by C N bond cleavage to construct various N-
heterocycles, such as indoles,[4] pyrroles,[5] pyridines[6] and
pyrazines[7] (Scheme 1a). In contrast, reactions of 2H-azirines
À
with unsaturated compounds by C C bond cleavage have
been rarely explored.[8–10] Recently, Xiao and Lu disclosed the
À
visible-light-induced C C bond cleavage of 2H-azirines under
metal-free conditions, which allowed the divergent synthesis
of polysubstituted pyrroles and oxazoles by formal [3+2]
cycloadditions (Scheme 1b).[8] These reactions are initiated
by single-electron oxidation of the 2H-azirines in the presence
of an excited photocatalyst with subsequent homolytic
À
cleavage of the C C bond. To the best of our knowledge,
Cycloadditions involving diynes enable the straightfor-
ward construction of medium-sized carbo- or heterocycles
with high atom efficiency.[15] Along with our ongoing research
interest in the metal-catalyzed cycloaddition reactions by
[*] T. F. Li, Dr. F. Xu, Dr. X. C. Li, Dr. C. X. Wang, Prof. Dr. B. S. Wan
Dalian Institute of Chemical Physics, Chinese Academy of Sciences
457 Zhongshan Road, Dalian 116023 (China)
E-mail: cxwang@dicp.ac.cn
bswan@dicp.ac.cn
Dr. F. Xu
Department of Material and Chemical Engineering
Zhengzhou University of Light Industry
5 Dongfeng Road, Zhengzhou 450002 (China)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201510820.
Figure 1. Natural products containing fused azepine skeletons.
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using diynes as C4 units,[16] we surmized that the azepine
framework could be assembled by [3+2+2] cycloaddition of
diynes with 2H-azirines, in which the 2H-azirines would serve
as three-atom components. Indeed, examples of the forma-
tion of aza-seven-memberd rings from diynes are extremely
rare.[17] Our previous studies demonstrated that [3+2] rather
than [3+2+2] cycloadducts were preferentially constructed in
the reaction of diynes with methyleneaziridines, thus leaving
an alkyne unit intact.[16c] To our delight, the reaction of diynes
with 2H-azirines follows the [3+2+2] pathway by using an
appropriate ruthenium catalyst,[18] thus providing the desired
azepine architectures (Scheme 1c). This approach features an
À
unprecedented metal-catalyzed C C bond cleavage of 2H-
azirines, and the challenging construction of aza-seven-
membered rings from diynes. Herein, we report our prelimi-
nary results.
At the outset, the diyne 1a and 2H-azirine 2a were chosen
as model substrates for the optimization of the reaction
conditions [Eq. (1)]. The results are summarized in Table S1
in the Supporting Information. Some typical transition-metal
catalysts for cycloadditions were first investigated. Unfortu-
nately, no desired product was observed with our previously
developed iron catalyst[16a] (Table S1, entry 1). In addition,
cobalt,[19a] nickel,[19b] rhodium,[19c] and iridium[19d] catalysts
also failed to provide any new products (entries 2–5). How-
ever, the possibility that the above systems might be workable
could not be completely excluded if an in-depth investigation
is done. Gratifyingly, the product 3H-azepine 3a was obtained
in 71% yield using 10 mol% [Cp*Ru(COD)Cl] (entry 6;
COD = 1,5-cyclooctadiene, Cp* = C5Me5). The structure of
3a was unambiguously confirmed by X-ray crystal diffrac-
tion.[20] Various ruthenium (II) catalysts were then evaluated
in the reaction, however, none of them led to better results
(entries 7–11). Intriguingly, ruthenium(II) complexes lacking
either the Cp or Cp* ligand exhibited no appreciable catalytic
activity (entries 9–11). Subsequently, a screening of solvents
revealed that both DCE and DCM (DCE = 1,2-dichloro-
ethane, DCM = dichloromethane) showed the best perfor-
mance (entries 12–15). Furthermore, a simple inspection on
the reaction temperatures indicated that lowering the temper-
ature to 258C can afford a better yield (entry 17). A slight
improvement in product yield can be achieved by prolonging
the reaction time to 20 hours (80%, entry 19). It is note-
worthy that the dimerization of diynes was commonly
detected under ruthenium catalysis,[18d,e] thus slightly lowering
the yield of 3a. Remarkably, decreasing the catalyst loading
to 5 mol% displayed lower activity (entry 20).
Scheme 2. Substrate scope. Yields of isolated products are given.
electron-donating and electron-withdrawing groups on the
phenyl ring could be successfully introduced, thus providing
the corresponding polysubstituted azepines (3b–e, 3g–i) in
moderate to excellent yields. The R1 group is placed near to
the methylene unit (CH2) in the product, as identified by the
X-ray crystal diffraction of 3g.[20] However, the 2H-azirine 2 f,
bearing a strong electron-withdrawing aryl group, provided
3 f in low yield. 2H-azirines bearing an ortho-substituted
phenyl ring (2h, 2i) or 1-naphthyl group (2j) reacted
smoothly to afford the corresponding azepines in high
yields, thus suggesting that steric hindrance is well tolerated
(3h–j). Moreover, the 2-thienyl group was tolerated and
provided the desired product 3k albeit with moderate yield.
Replacement of the aryl group with an alkyl substituent also
led to the effective formation of the corresponding apezine
(3l), although a much lower yield was observed. Notably, the
reaction was sensitive to the electronic and steric effect of the
R2 substituent. 2H-azirine, having an electron-donating group
(Me) on the para position of the phenyl ring (2m), showed
higher reactivity than that bearing an electron-withdrawing
group (NO2, 2n). When a sterically more demanding 2-
methoxyphenyl-substitued 2H-azirine (2o) was employed,
a satisfactory yield can still be achieved.
Next, the reactions of various terminal diynes with 2H-
azirines were investigated. The sulfonamide-based diynes (1a,
1p) could undergo this cyclization and be transformed into
the corresponding cycloadducts in moderate yields. However,
malonate-tethered terminal diynes were found to be less
effective, thus affording the azepines in 30 and 24% yield,
With the optimal reaction conditions secured, we turned
our attention to the scope of this reaction. The variations of
1
=
the R group on the C N double bond moiety of 2H-azirines
were first examined. As highlighted in Scheme 2, both
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respectively (3q and 3r). Interestingly, ketones, which are
unsaturated groups that also undergo cycloadditions with
diynes,[18f] did not interfere with the reaction involving the
azirines (3s and 3t). In addition, the O-tethered diyne 1u
reacted with 2H-azirine 2h to deliver 3u in moderate yield.
Unfortunately, unlike our previous observation in the ruthe-
nium-catalyzed [2+2+2] cycloaddition,[16b] the methylene-
linked diyne was completely unreactive, thus indicating that
the Thorpe–Ingold effect[21] was crucial for this transforma-
tion (3v). Furthermore, when the unsymmetrical diyne 1w,
bearing a methyl group at one alkyne terminus, was subjected
to the reaction, the azepine compound 3w was obtained albeit
with low yield. However, the diyne 1x, with a phenyl group at
one alkyne terminus, showed no reactivity under the opti-
mized reaction conditions, probably because of steric hin-
drance.[22]
Scheme 3. Proposed mechanism.
To explore the reaction mechanism, the reaction of 1a
with deuterated 2H-azirine, [D]-2a, was first investigated
[Eq. (2)]. As expected, the desired product [D]-3a was
mediate A.[18] Then, the insertion of the imine moiety on 2H-
azirine 2 into the intermediate A affords either the inter-
mediate B or B’. The intermediate B’ is less favored as a result
of the steric repulsion between R1 and R. Subsequently, b-
carbon elimination[23] results in C C bond cleavage. The
À
bicyclic [5.1.0] skeleton of B is expanded with the release of
the strain of three-membered aziridine ring to give the eight-
membered ruthenacycle intermediate C. The reductive elim-
ination of C provides the 2H-azepine D and regenerates the
catalyst. Finally, 1,5-H shift of D provides the thermodynami-
cally stable product 3H-azepine 3.[24] In the case of unsym-
metrical diynes 1w and 1x, the steric repulsion between R and
R2 may cause the diminished yields in products.[25]
In summary, we have successfully developed a formal
[3+2+2] approach to construct seven-membered heterocycles
through the ruthenium-catalyzed cycloaddition of diynes with
2H-azirines under mild reaction conditions, in which 2H-
obtained with more than 99% deuterium incorporation.
This observation reveals that a 1,5-sigmatropic hydrogen shift
occurs in the reaction. Additionally, the reaction of 1a and 2a
in the presence of CH3COOD did not provide any deuterated
product [Eq. (3)], thus indicating an intramolecular proton-
À
azirines undergo the cleavage of C C single bond. This
transformation provides a facile and straightforward method
for the synthesis of fused azepine derivatives with broad
substrate scope and a wide range of functional groups. We
expect that these results may provide new insight into the
chemistry of 2H-azirines and find applications in the synthesis
of complex heterocycles.
À
transfer process and an irreversible C H functionalization.
Under this premise, kinetic isotope effect (KIE) studies were
performed. The intermolecular competitive reactions
between 2a and [D]-2a with 1a gave a KIE value of
Acknowledgments
We thank NSFC (21372219, 21572225) for the financial
support.
approximately 1.0 at 5 minutes (or 10 min) on the basis of
H NMR analysis [Eq. (4)]. These data suggest that the C H
bond cleavage is not involved in the rate-determining step.
1
À
À
Keywords: alkynes · C C activation · cycloaddition ·
heterocycles · ruthenium
Consequently,
a
plausible mechanism was outlined
(Scheme 3) on the basis of the present results. The catalytic
cycle starts with the oxidative cyclization of the diyne 1 on the
ruthenium center to form the ruthenacyclopentatriene inter-
How to cite: Angew. Chem. Int. Ed. 2016, 55, 2861–2865
Angew. Chem. 2016, 128, 2911–2915
À
[1] For selected reviews of C C bond cleavage, see: a) C. Jun,
Chem. Soc. Rev. 2004, 33, 610; b) M. Murakami, T. Matsuda,
Chem. Commun. 2011, 47, 1100; c) T. Seiser, T. Saget, D. N. Tran,
N. Cramer, Angew. Chem. Int. Ed. 2011, 50, 7740; Angew. Chem.
2011, 123, 7884; d) F. Chen, T. Wang, N. Jiao, Chem. Rev. 2014,
114, 8613; e) A. Dermenci, J. W. Coe, G. Dong, Org. Chem.
Angew. Chem. Int. Ed. 2016, 55, 2861 –2865
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Front. 2014, 1, 567; f) H. Liu, M. Feng, X. Jiang, Chem. Asian J.
2014, 9, 3360; g) L. Souillart, N. Cramer, Chem. Rev. 2015, 115,
9410.
Kershaw, S. Lilienfeld, C. Ding, Neurology 2000, 54, 2269; g) J.
Kobayashi, M. Yoshinaga, N. Yoshida, M. Shiro, H. Morita, J.
Org. Chem. 2002, 67, 2283; h) D. Kakuta, Y. Hitotsuyanagi, N.
Matsuura, H. Fukaya, K. Takeya, Tetrahedron 2003, 59, 7779;
i) S. Berkov, C. Codina, F. Viladomat, J. Bastida, Bioorg. Med.
Chem. Lett. 2008, 18, 2263.
[2] a) M. Murakami, Y. Ito, Top. Organomet. Chem. 1999, 3, 97;
b) B. Rybtchinski, D. Milstein, Angew. Chem. Int. Ed. 1999, 38,
870; Angew. Chem. 1999, 111, 918; c) H. Li, Y. Li, X. S. Zhang, K.
Chen, X. Wang, Z. J. Shi, J. Am. Chem. Soc. 2011, 133, 15244;
d) L. Liu, N. Ishida, M. Murakami, Angew. Chem. Int. Ed. 2012,
51, 2485; Angew. Chem. 2012, 124, 2535; e) C. Qin, P. Feng, Y.
Ou, T. Shen, T. Wang, N. Jiao, Angew. Chem. Int. Ed. 2013, 52,
7850; Angew. Chem. 2013, 125, 8004.
[3] For reviews on reactions of 2H-azirines, see: a) F. Palacios,
A. M. O. de Retana, E. M. de Marigorta, J. M. de los Santos,
Eur. J. Org. Chem. 2001, 2401; b) A. F. Khlebnikov, M. S.
Novikov, Tetrahedron 2013, 69, 3363; c) C. Y. Huang, A. G.
Doyle, Chem. Rev. 2014, 114, 8153.
[4] a) D. F. Taber, W. W. Tian, J. Am. Chem. Soc. 2006, 128, 1058;
b) D. A. Candito, M. Lautens, Org. Lett. 2010, 12, 3312; c) S.
Jana, M. D. Clements, B. K. Sharp, N. Zheng, Org. Lett. 2010, 12,
3736.
[5] a) X. Qi, X. Xu, C. M. Park, Chem. Commun. 2012, 48, 3996;
b) A. F. Khlebnikov, M. V. Golovkina, M. S. Novikov, D. S.
Yufit, Org. Lett. 2012, 14, 3768; c) C. M. Park, Y. Jiang, Chem.
Sci. 2014, 5, 2347; d) T. Li, X. Xin, C. Wang, D. Wang, F. Wu, X.
Li, B. Wan, Org. Lett. 2014, 16, 4806; e) L. Zhu, Y. Yu, Z. Mao, X.
Huang, Org. Lett. 2015, 17, 30; f) S. K. Pawar, R. L. Sahani, R. S.
Liu, Chem. Eur. J. 2015, 21, 10843.
[6] a) Y. F. Wang, K. K. Toh, J. Y. Lee, S. Chiba, Angew. Chem. Int.
Ed. 2011, 50, 5927; Angew. Chem. 2011, 123, 6049; b) N. S. Loy,
A. Singh, X. Xu, C. M. Park, Angew. Chem. Int. Ed. 2013, 52,
2212; Angew. Chem. 2013, 125, 2268; c) A. Prechter, G. Henrion,
P. Faudot dit Bel, F. Gagosz, Angew. Chem. Int. Ed. 2014, 53,
4959; Angew. Chem. 2014, 126, 5059; d) Y. Jiang, C. M. Park,
T. P. Loh, Org. Lett. 2014, 16, 3432.
[7] a) F. Palacios, A. M. Ochoa de Retana, J. I. Gil, R. Lopez de
Munain, Org. Lett. 2002, 4, 2405; b) N. S. Y. Loy, S. Kim, C. M.
Park, Org. Lett. 2015, 17, 395; c) T. Ryu, Y. Baek, P. H. Lee, J.
Org. Chem. 2015, 80, 2376.
[8] a) J. Xuan, X. Xia, T. Zeng, Z. Feng, J. Chen, L. Lu, W. Xiao,
Angew. Chem. Int. Ed. 2014, 53, 5653; Angew. Chem. 2014, 126,
5759; b) T. Zeng, J. Xuan, W. Ding, K. Wang, L. Lu, W. Xiao,
Org. Lett. 2015, 17, 4070.
[9] a) B. Singh, E. F. Ullman, J. Am. Chem. Soc. 1967, 89, 6911; b) A.
Padwa, J. Smolanoff, J. Am. Chem. Soc. 1971, 93, 548; c) B.
Singh, A. Zweig, J. B. Gallivan, J. Am. Chem. Soc. 1972, 94, 1199;
d) E. Albrecht, J. Mattay, S. Steenken, J. Am. Chem. Soc. 1997,
119, 11605; e) C. M. Nunes, I. Reva, R. Fausto, J. Org. Chem.
2013, 78, 10657.
[13] For reports on the classical methods for azepine synthesis: Heck
coupling, see: a) M. Qadir, J. Cobb, P. W. Sheldrake, N. Whittall,
A. J. White, K. K. Hii, P. N. Horton, M. B. Hursthouse, J. Org.
Chem. 2005, 70, 1545; radicals: b) L. Yet, Tetrahedron 1999, 55,
9349; c) C. E. Masse, A. J. Morgan, J. S. Panek, Org. Lett. 2000, 2,
2571; ring expansion: d) R. M. Kellogg, T. Van Bergen, J. Org.
Chem. 1971, 36, 978; e) E. J. Kantorowski, M. J. Kurth, Tetrahe-
dron 2000, 56, 4317; f) J. Yadav, B. S. Reddy, M. K. Gupta, A.
Prabhakar, B. Jagadeesh, Chem. Commun. 2004, 2124; g) E. A.
Ilardi, J. T. Njardarson, J. Org. Chem. 2013, 78, 9533; ring-closing
metathesis: h) M. E. Maier, Angew. Chem. Int. Ed. 2000, 39,
2073; Angew. Chem. 2000, 112, 2153; i) P. Jakubec, A. Hawkins,
W. Felzmann, D. J. Dixon, J. Am. Chem. Soc. 2012, 134, 17482;
Cope rearrangement: j) T. Sasaki, S. Eguchi, M. Ohno, J. Am.
Chem. Soc. 1970, 92, 3192; k) E. E. Schultz, V. N. G. Lindsay, R.
Sarpong, Angew. Chem. Int. Ed. 2014, 53, 9904; Angew. Chem.
2014, 126, 10062.
[14] For reports on cycloaddition routes to azepine derivatives: [4+3]
cycloaddition, see: a) B. M. Trost, C. M. Marrs, J. Am. Chem.
Soc. 1993, 115, 6636; b) N. D. Shapiro, F. D. Toste, J. Am. Chem.
Soc. 2008, 130, 9244; c) C. S. Jeffrey, K. L. Barnes, J. A. Eickhoff,
C. R. Carson, J. Am. Chem. Soc. 2011, 133, 7688; d) X. Hu, J.
Chen, S. Gao, B. Feng, L. Lu, W. Xiao, Chem. Commun. 2013, 49,
7905; e) K. Liu, H. Teng, C. Wang, Org. Lett. 2014, 16, 4508; f) H.
Shang, Y. Wang, Y. Tian, J. Feng, Y. Tang, Angew. Chem. Int. Ed.
2014, 53, 5662; Angew. Chem. 2014, 126, 5768; [5+2] cyclo-
additon: g) E. L. Stogryn, S. J. Brois, J. Am. Chem. Soc. 1967, 89,
605; h) P. A. Wender, T. M. Pedersen, M. J. Scanio, J. Am. Chem.
Soc. 2002, 124, 15154; i) C. Roscini, K. L. Cubbage, M. Berry,
A. J. Orr-Ewing, K. I. Booker-Milburn, Angew. Chem. Int. Ed.
2009, 48, 8716; Angew. Chem. 2009, 121, 8872; j) E. Kanno, K.
Yamanoi, S. Koya, I. Azumaya, H. Masu, R. Yamasaki, S. Saito,
J. Org. Chem. 2012, 77, 2142; k) M. Zhou, R. Song, C. Wang, J.
Li, Angew. Chem. Int. Ed. 2013, 52, 10805; Angew. Chem. 2013,
125, 11005; l) J. J. Feng, T. Y. Lin, H. H. Wu, J. Zhang, J. Am.
Chem. Soc. 2015, 137, 3787; m) J. J. Feng, T. Y. Lin, H. H. Wu, J.
Zhang, Angew. Chem. Int. Ed. 2015, 54, 15854; Angew. Chem.
2015, 127, 16080; [3+2+2] cycloaddition: n) M. Zhou, R. Song, J.
Li, Angew. Chem. Int. Ed. 2014, 53, 4196; Angew. Chem. 2014,
126, 4280.
[15] M. I. Alexandrovna, B. I. Ionin, J. C. Tebby in Alkynes in
Cycloadditions (Ed.: J. Tebby), Wiley, New Delhi, 2014.
[16] a) C. Wang, X. Li, F. Wu, B. Wan, Angew. Chem. Int. Ed. 2011,
50, 7162; Angew. Chem. 2011, 123, 7300; b) F. Xu, C. Wang, X.
Li, B. Wan, ChemSusChem 2012, 5, 854; c) B. Pan, C. Wang, D.
Wang, F. Wu, B. Wan, Chem. Commun. 2013, 49, 5073; d) C.
Wang, D. Wang, F. Xu, B. Pan, B. Wan, J. Org. Chem. 2013, 78,
3065; e) F. Xu, C. Wang, D. Wang, X. Li, B. Wan, Chem. Eur. J.
2013, 19, 2252; f) C. Wang, D. Wang, H. Yan, H. Wang, B. Pan, X.
Xin, X. Li, F. Wu, B. Wan, Angew. Chem. Int. Ed. 2014, 53, 11940;
Angew. Chem. 2014, 126, 12134; g) F. Xu, C. Wang, H. Wang, X.
Li, B. Wan, Green Chem. 2015, 17, 799.
À
[10] Lewis acid promoted C C bond cleavage of related aziridines
has been reported. For selected examples see: a) P. D. Pohlhaus,
R. K. Bowman, J. S. Johnson, J. Am. Chem. Soc. 2004, 126, 2294;
b) P. A. Wender, D. Strand, J. Am. Chem. Soc. 2009, 131, 7528;
c) Z. Chen, L. Wei, J. Zhang, Org. Lett. 2011, 13, 1170; d) L. Li,
X. Wu, J. Zhang, Chem. Commun. 2011, 47, 5049; e) L. Li, J.
Zhang, Org. Lett. 2011, 13, 5940.
[11] a) T. Pinho e Melo, A. M. R. Gonsalves, Curr. Org. Synth. 2004,
1, 275; b) S. Calvo-Losada, J. J. Quirante, D. Suµrez, T. L. Sordo,
J. Comput. Chem. 1998, 19, 912; c) Y. Liu, P. Guan, Y. Wang, L.
Liu, J. Gao, J. Phys. Chem. A 2015, 119, 67.
[17] Construction of seven-membered carbocycles from diynes:
a) K. E. Schwiebert, J. M. Stryker, J. Am. Chem. Soc. 1995,
117, 8275; b) K. Maeda, S. Saito, Tetrahedron Lett. 2007, 48,
3173; c) R. A. Bauer, C. M. DiBlasi, D. S. Tan, Org. Lett. 2010,
12, 2084; d) L. Saya, I. Fernµndez, F. López, J. L. MascareÇas,
Org. Lett. 2014, 16, 5008; e) T. Yoshida, Y. Tajima, M. Kobayashi,
K. Masutomi, K. Noguchi, K. Tanaka, Angew. Chem. Int. Ed.
2015, 54, 8241; Angew. Chem. 2015, 127, 8359. Construction of
[12] a) B. Renfroe, C. Harrington, G. Proctor, Heterocyclic Com-
pounds: Azepines, Wiley & Interscience, New York, 1984;
b) C. R. Ganellin, D. J. Triggle, Dictionary of Pharmacological
Agents, Chapman & Hall/CRC, London, 1996; c) D. OꢀHagan,
Nat. Prod. Rep. 1997, 14, 637; d) J. A. Builla, J. Vaguero, J.
Barluenga, Modern Heterocyclic Chemistry, Wiley-VCH, Wein-
heim, 2011, pp. 1865 – 1988; e) C. Y. Chen, D. J. Hart, J. Org.
Chem. 1990, 55, 6236; f) P. N. Tariot, P. Solomon, J. Morris, P.
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Chemie
aza-seven-membered rings from two identical alkynes, see:
[21] a) R. M. Beesley, C. K. Ingold, J. F. Thorpe, J. Chem. Soc. 1915,
ref. [14n].
107, 1080; b) M. E. Jung, J. Gervay, J. Am. Chem. Soc. 1991, 113,
224; c) M. E. Jung, G. Piizzi, Chem. Rev. 2005, 105, 1735.
[22] In the case of internal diyne bearing a methyl group at each
alkyne terminus, the reaction only provided trace amounts of
dimer at room temperature. The diyne can be completely
transformed at higher temperaure (808C), thus leading to the
formation of inseparable complex mixtures along with a small
amount of dimer. However, no desired azepine product can be
obained.
[23] For b-carbon elimination, see: a) P. Kumar, K. Zhang, J. Louie,
Angew. Chem. Int. Ed. 2012, 51, 8602; Angew. Chem. 2012, 124,
8730; b) P. Kumar, J. Louie, Org. Lett. 2012, 14, 2026; c) D.
CrØpin, J. Dawick, C. Aïssa, Angew. Chem. Int. Ed. 2010, 49, 620;
Angew. Chem. 2010, 122, 630; d) M. Murakami, S. Ashida, T.
Matsuda, J. Am. Chem. Soc. 2006, 128, 2166. Also see ref. [1b].
[24] For 1,5-H shift observed in azepine rings, see: a) Y. Kubota, K.
Satake, H. Okamoto, M. Kimura, Org. Lett. 2005, 7, 5215; b) Y.
Kubota, K. Satake, H. Okamoto, M. Kimura, Org. Lett. 2006, 8,
5469; c) C. E. Cordonier, K. Satake, H. Okamoto, M. Kimura,
Eur. J. Org. Chem. 2006, 3803.
[18] Ruthenium-catalyzed cycloaddition reactions of diynes: a) M. O.
Albers, D. J. De Waal, D. C. Liles, D. J. Robinson, E. Singleton,
M. B. Wiege, J. Chem. Soc. Chem. Commun. 1986, 1680; b) C.
Gemel, A. LaPensØe, K. Mauthner, K. Mereiter, R. Schmid, K.
Kirchner, Monatsh. Chem. 1997, 128, 1189; c) E. Rüba, K.
Mereiter, R. Schmid, V. N. Sapunov, K. Kirchner, H. Schotten-
berger, M. J. Calhorda, L. F. Veiros, Chem. Eur. J. 2002, 8, 3948;
d) Y. Yamamoto, H. Kitahara, R. Ogawa, H. Kawaguchi, K.
Tatsumi, K. Itoh, J. Am. Chem. Soc. 2000, 122, 4310; e) Y.
Yamamoto, H. Takagishi, K. Itoh, J. Am. Chem. Soc. 2002, 124,
28; f) Y. Yamamoto, H. Takagishi, K. Itoh, J. Am. Chem. Soc.
2002, 124, 6844; g) J. A. Varela, L. Castedo, C. Saµ, Org. Lett.
2003, 5, 2841; h) J. A. Varela, L. Castedo, C. Saµ, J. Org. Chem.
2003, 68, 8595; i) Y. Yamamoto, K. Kinpara, T. Saigoku, H.
Takagishi, S. Okuda, H. Nishiyama, K. Itoh, J. Am. Chem. Soc.
2005, 127, 605; j) Y. Yamamoto, K. Kinpara, H. Nishiyama, K.
Itoh, Adv. Synth. Catal. 2005, 347, 1913; k) Y. Yamamoto, K.
Kinpara, R. Ogawa, H. Nishiyama, K. Itoh, Chem. Eur. J. 2006,
12, 5618; l) J. A. Varela, S. G. Rubín, C. Gonzµlez-Rodríguez, L.
Castedo, C. Saµ, J. Am. Chem. Soc. 2006, 128, 9262; m) S. García-
Rubín, J. A. Varela, L. Castedo, C. Saµ, Chem. Eur. J. 2008, 14,
9772; n) S. Medina, G. Dominguez, J. Perez-Castells, Org. Lett.
2012, 14, 4982; o) K. Yamashita, Y. Yamamoto, H. Nishiyama, J.
Am. Chem. Soc. 2012, 134, 7660; p) K. Matsui, M. Shibuya, Y.
Yamamoto, ACS Catal. 2015, 5, 6468.
[25] An alternative mechanism involving the terminal alkyne addi-
tion to 2H-azirine followed by cycloisomerization might be
possible. To examine this possiblity, we conducted the reation of
structurally similar 1a’ with 2a. However, no new product was
observed under ruthenium(II) catalyst even at higher temper-
ature, thus excluding this pathway.
[19] a) K. Kase, A. Goswami, K. Ohtaki, E. Tanabe, N. Saino, S.
Okamoto, Org. Lett. 2007, 9, 931; b) M. M. McCormick, H. A.
Duong, G. Zuo, J. Louie, J. Am. Chem. Soc. 2005, 127, 5030; c) K.
Tanaka, N. Suzuki, G. Nishida, Eur. J. Org. Chem. 2006, 3917;
d) G. Onodera, Y. Shimizu, J. Kimura, J. Kobayashi, Y. Evihara,
K. Kondo, K. Sakata, R. Takeuchi, J. Am. Chem. Soc. 2012, 134,
10515.
[20] CCDC 1057257 (3a) and 1057258 (3g) contain the supplemen-
tary crystallographic data for this paper. These data can be
obtained free of charge from The Cambridge Crystallographic
Data Centre.
Received: November 23, 2015
Published online: January 21, 2016
Angew. Chem. Int. Ed. 2016, 55, 2861 –2865
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
2865