Multicomponent [5 + 2] cycloaddition reaction for the synthesis of 1,4-diazepines: Isolation and reactivity of azomethine ylides

Article abstract of DOI:10.1021/ja5061609

Air-stable azomethine ylides with an unusual pattern of charge distribution were efficiently prepared via the rhodium-catalyzed reaction between pyridines and 1-sulfonyl-1,2,3-triazoles. This reaction allowed for the first example of the catalytic multicomponent [5 + 2] cycloaddition reactions, thus resulting in the formation of biologically active 1,4-diazepine compounds.

Full text of DOI:10.1021/ja5061609

Communication
pubs.acs.org/JACS
Multicomponent [5 + 2] Cycloaddition Reaction for the Synthesis of
1,4-Diazepines: Isolation and Reactivity of Azomethine Ylides
Dong Jin Lee, Hong Sik Han, Jinhwan Shin, and Eun Jeong Yoo*
Department of Chemistry, Kangwon National University, 1 Kangwondaehak-gil, Chuncheon 200-701, Korea
S
* Supporting Information
Despite the difficulties of the [5 + 2] cycloaddition,
considerable progress has recently been made (Scheme 1).
ABSTRACT: Air-stable azomethine ylides with an
unusual pattern of charge distribution were efficiently
prepared via the rhodium-catalyzed reaction between
pyridines and 1-sulfonyl-1,2,3-triazoles. This reaction
allowed for the first example of the catalytic multi-
component [5 + 2] cycloaddition reactions, thus resulting
in the formation of biologically active 1,4-diazepine
compounds.
Scheme 1. Hetero-[5 + 2] Cycloadditions with Alkyne
iazepines represent one of the most prominent
D
compound classes which are widely distributed in natural
products and pharmaceuticals.1 Especially, over 40 medications
highlight 1,4-benzodiazepine as a privileged structure with a
broad range of therapeutic treatment for the central nervous
system (Figure 1).2 More importantly, the bioactivity of these
Figure 1. Psychoactive drugs containing the 1,4-diazepine core
structure.
Wender and co-workers first reported the transition-metal-
catalyzed hetero-[5 + 2] cycloaddition to synthesize azepine
derivatives in 2002 (Scheme 1a).5a Li et al. reported the [5 + 2]
cycloaddition between γ-amino ketones and alkynes in the
presence of silver catalyst to give azepines (Scheme 1b).5b Most
derivatives has been known to be significantly improved
through the fusion of the 1,4-diazepine scaffold to various
heterocycles. For example, marketed drugs such as triazole-
fused Xanax and imidazole-fused Dormicum possess anxiolytic
sedative and muscle relaxant properties. Therefore, an exciting
new approach which has recently come into focus is to fuse the
1,4-diazepine moiety with heterocycles for further structure−
activity relationship (SAR) studies. However, straightforward
methods of core structure modification are still rare and
restricted.
The [m + n] cycloaddition reaction has been established as a
reliable and powerful tool for the synthesis of heterocycles from
simple starting materials.3 However, in contrast with catalytic [3
+ 2] and [4 + 2] cycloadditions for preparing five- and six-
membered heterocyclic rings, synthetic strategies using a [5 +
2] cycloaddition for the construction of seven-membered
heterocycles have been less explored mainly owing to entropic
factors and the presence of nonbonding interactions in the
transition state.4
́
recently, Gulıas and co-workers reported the Rh(III)-catalyzed
[5 + 2] cycloaddition of 2-alkenylphenols with alkynes, leading
to the corresponding benzoxepines (Scheme 1c).5c Although
reported cycloaddition reactions toward seven-membered
heterocycles are efficient, the development of multicomponent
[5 + 2] cycloaddition reactions which have a great influence in
discovery chemistry has been rather limited. Herein, we report
new multicomponent cycloaddition reactions using simple
pyridines, 1-sulfonyl-1,2,3-triazoles, and alkynes via an isolable
azomethine ylide, which results in 1,4-diazepines (Scheme 1d).
To the best of our knowledge, this is the first example of metal-
catalyzed multicomponent [5 + 2] cycloaddition reactions.
Received: June 19, 2014
Published: August 5, 2014
© 2014 American Chemical Society
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1-Sulfonyl-1,2,3-triazoles (Scheme 2, 2a) have attracted a
great deal of attention as precursors of Rh azavinyl carbene
limited applications of in situ generated azomethine ylides, this
method presents a novel approach for the transformation of
azomethine ylides.
a
An important feature of ylide 3 is the geometry of the dipole
unit and planarity of the azomethine in contrast with typical
azomethine ylides. As shown in Figure 2, two charges of the
ylide 3a are sufficiently stabilized similar to a 1,5-dipole.
Azomethine ylide 3a is twisted around the N(2)−C(9) bond
with an angle of 74.2°, suggesting that the two components are
arranged in an almost orthogonal manner. In view of the
nonplanarity of the dipole, the unexpected stability of 3a must
be due to a particular electronic stabilization of the ionic
centers and possibly steric effects.10 Further tests of 2-
substituted pyridine substrates also supported that azomethine
ylide 3 was only isolable if particular electronic requirements
were met (Scheme 2).11 On the basis of the preliminary studies,
we subsequently examined the reaction conditions and were
pleased to find the optimum conditions (Table 1).
Scheme 2. Isolable Azomethine Ylide Formation
a
Reaction conditions: 2-substituted pyridine (1; 0.2 mmol), 1-
sulfonyl-1,2,3-triazole (2a; 0.4 mmol), Rh2(esp)2 (1.0 mol %), and
1,2-DCE (2.0 mL) at 100 °C for 12 h.
a
Table 1. Optimization of the Reaction Conditions
(2a′), which is a practical intermediate for the synthesis of N-
heterocyclic complexes.6 Most studies on the Rh catalysis of 1-
sulfonyl-1,2,3-triazoles have been especially focused on [3 + 2]
or [4 + 3] cycloaddition reactions.7 Recently, our group and
others reported a Rh(II)-catalyzed reaction of 1-sulfonyl-1,2,3-
triazoles and amides to give enaminones via unstable
azomethine ylide intermediates which are otherwise difficult
to react with dipolarophiles.8 Inspired by these studies, it was
envisioned that relatively long-lived and stable azomethine
ylides which have conjugated double bonds could participate in
the annulation with reactive dipolarophiles.
To study the intrinsic aspects of such conjugated azomethine
ylides, we conducted a reaction between the 2-substituted
pyridine 1 and 1-sulfonyl-1,2,3-triazole 2a with a catalytic
amount of rhodium (Scheme 2). To our surprise, a mixture of
2-phenylpyridine, 2a, and Rh2(esp)2 (1.0 mol %) in DCE at
100 °C afforded red crystalline 3a together with a red solution.
Even more surprisingly, 3a was isolable by flash column
chromatography (47%) and could be fully characterized,
including by X-ray crystallography (Figure 2). Although
azomethine ylides could be easily prepared in situ from a
stable precursor,9 the isolation of typical azomethine ylides is
difficult in most cases because of their lability. Considering the
b
entry
cat. [Rh] (amt, mol %)
solvent
yield, %
1
2
3
4
5
6
7
Rh2(OAc)4 (1.0)
Rh2(oct)4 (1.0)
Rh2(S-PTAD)4 (1.0)
Rh2(esp)2 (1.0)
Rh2(esp)2 (1.5)
Rh2(esp)2 (1.5)
Rh2(esp)2 (1.5)
1,2-DCE
1,2-DCE
1,2-DCE
1,2-DCE
1,2-DCE
toluene
12
66
38
c
78
82
75
95
benzene
a
Reaction conditions: 1a (0.5 mmol), 2a (0.2 mmol), [Rh] (x mol %),
and solvent (2.0 mL) at 100 °C. Isolated yield of 3a. Reaction was
b
c
carried out at 80 °C.
While a number of catalysts such as Rh2(OAc)4, Rh2(oct)4,
and Rh2(S-PTAD)4 were less effective, the use of Rh2(esp)2
(1.0 mol %) in the reaction of 2-phenylpyridine (1a) with 1-
sulfonyl-1,2,3-triazole (2a) in 1,2-DCE at 80 °C generated the
desired product 3a in 78% yield (entry 4).12 While changing
the solvent from 1,2-DCE to toluene led to diminished yield,
the use of benzene allowed for the quantitative formation of 3a
(entries 6 and 7). Interestingly, the intramolecular 1,5-
electrocyclized product 3a′, imidazopyridine, was not observed
at all during optimization examinations.
With the optimization conditions in hand, we decided to
explore the scope of both substituted pyridines 1 and 1-
sulfonyl-1,2,3-triazole 2 to obtain azomethine ylides 3, which
could be further utilized in other transformations (Table 2). We
were pleased to see that a wide range of reactants smoothly
underwent the process to afford the desired azomethine ylides
in high yields. The efficiency of this reaction was not much
influenced by either electronic or steric variation on 2-
arylpyridines. Also, the reaction conditions tolerated a ketone
functional group (3o). A substrate containing a naphthyl group
was readily employed, resulting in almost quantitative yield
(3p). Electronic variation of the sulfonyl group of 1-sulfonyl-
1,2,3-triazoles 2 exhibited little effect on the product yields
(3t−v).
Figure 2. Molecular structure of azomethine compound 3a.
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Communication
a b
,
a b
,
Table 2. Free Azomethine Formation Reactions
Table 3. Multicomponent [5 + 2] Cycloaddition Reaction
a
Reaction conditions: 1a (2.5 equiv), 2a (0.5 mmol), Rh2(esp)2 (1.5
b
mol %), and benzene (5.0 mL) at 100 °C for 12 h. Isolated yield.
In general, azomethine ylides are known to undergo dipolar
cycloaddition with π bonds, thus representing a tool for the
construction of azacyclic complexes. [5 + 2] cycloaddition of
isolated ylides 3 with dimethyl acetylenedicarboxylate (DMAD)
was highly successful to afford the desired 1,4-diazepines with
excellent yields (Scheme 3). As expected, metal mediation was
unnecessary for annulation, and [3 + 2] cyclized adducts of
ylides 3 with DMAD were not obtained under the reaction
conditions.
Scheme 3. [5 + 2] Cycloaddition of Azomethines
a
Reaction conditions: 1 (2.5 equiv), 2a (0.2 mmol), DMAD (3.0
equiv), Rh2(esp)2 (1.5 mol %), and benzene (2.0 mL) at 100 °C for 12
b
h. Isolated yield.
scope of three-component reactions. This new three-
component reaction was highly facile with a wide range of 1-
sulfonyl-1,2,3-triazoles 2 to provide the desired products (4l−
n). In addition, diethyl acetylenedicarboxylate gave the
corresponding 1,4-diazepines in good yields (4o,p). However,
when 2-methylpyridine was used as a reactant instead of the 2-
arylpyridine derivative, the yield was significantly low. Also, 4-
alkyl-substituted 1-sulfonyl-1,2,3-triazole was not a proper
reactant for this [5 + 2] cycloaddition reaction.
For a further investigation, a multicatalytic system with four
reactants was attempted, in which the first step was carried out
by copper catalyst to afford 1-sulfonyl-1,2,3-triazoles 2 that are
expected to be subjected to the rhodium catalyst for the
formation of the ylides 3. As a final step, in situ generated ylides
were anticipated to undergo thermal annulation with alkynes
(Scheme 4). Gratifyingly, the process exhibited the desired
reactivity, which was relayed until the final [5 + 2]
Intrigued by the great value of purified azomethine ylides 3
as a 1,5-dipole, three-component [5 + 2] cycloaddition
reactions of pyridines (1), 1-sulfonyl-1,2,3-triazole (2), and
activated alkynes via in situ generated azomethine ylides (3)
were conducted with the rhodium(II) catalyst in one pot
(Table 3). As a result, this new protocol affords a practical,
user-friendly, and operationally simple strategy for the system-
atic modification of the core structure of 1,4-diazepines. As
shown for 4a−h, the reaction was not hampered by para
substituents on 2-arylpyridines. It was of interest that the
presence of halogen-containing substrates posed no problems,
delivering the corresponding 1,4-diazepines in good yields
(4f,g). It is worth noting that the reaction conditions were
compatible with an acetyl group (4h). The one-pot annulation
system was not affected by steric variations (4i−k). Other 1-
sulfonyl-1,2,3-triazoles could also be employed to expand the
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Dipolar Cycloaddition Chemistry; Padwa, A., Ed.; Wiley: New York,
1984; Vols. 1 and 2, p 1521. For examples of multicomponent
cycloaddition reactions, see: (d) Galliford, C. V.; Scheidt, K. A. J. Org.
Chem. 2007, 72, 1181. (e) DeAngelis, A.; Taylor, M. T.; Fox, J. M. J.
Am. Chem. Soc. 2009, 131, 1101.
Scheme 4. Multicatalyzed Four-Component Reaction
(4) (a) Stogryn, E. L.; Brois, S. J. J. Am. Chem. Soc. 1967, 89, 605.
(b) Hassner, A.; D’Costa, R.; McPhail, A. T.; Butler, W. Tetrahedron
Lett. 1981, 22, 3691. (c) Wender, P. A.; Fournogerakis, D. N.; Jefferys,
M. S.; Quiroz, R. V.; Inagaki, F.; Pfaffenbach, M. Nat. Chem. 2014, 6,
448. (d) Ylijoki, K. E.; Stryker, J. M. Chem. Rev. 2013, 113, 2244.
(5) (a) Wender, P. A.; Pedersen, T. M.; Scanio, M. J. C. J. Am. Chem.
Soc. 2002, 124, 15154. (b) Zhou, M.-B.; Song, R.-J.; Wang, C.-Y.; Li, J.-
H. Angew. Chem., Int. Ed. 2013, 52, 10805. (c) Seoane, A.; Casanova,
́
N.; Quinones, N.; Mascarenas, J. L.; Gulıas, M. J. Am. Chem. Soc. 2014,
̃
̃
cycloaddition step despite the challenges in the cooperative
multicatalyst system with more than four reactants.14
Preliminary test reactions smoothly proceeded with four
reactants in an intermolecular fashion, offering a straightforward
route to generate complexity and diversity of the core structure
of 1,4-diazepines in acceptable yields.
In summary, we have described a new catalytic reaction of
pyridines and 1-sulfonyl-1,2,3-triazoles for the generation of
anomalous azomethine ylides which are isolable 1,5-dipoles. On
the basis of this novel protocol, unprecedented catalytic
multicomponent [5 + 2] cycloaddition reactions of pyridines,
1-sulfonyl-1,2,3-triazoles, and activated alkynes have been
realized for the synthesis of 1,4-diazepines. Further related
studies utilizing such azomethine ylides for the development of
other methodologies are currently underway in our laboratory.
136, 834.
(6) For earlier reports on the ring-opening reactions of 1-sulfonyl-
1,2,3-triazoles, see: (a) Horneff, T.; Chuprakov, S.; Chernyak, N.;
Gevorgyan, V.; Fokin, V. V. J. Am. Chem. Soc. 2008, 130, 14972.
(b) Miura, T.; Yanauchi, M.; Murakami, M. Chem. Commun. 2009,
1470. For recent reviews, see: (c) Gulevich, A. V.; Genorgyan, V.
Angew. Chem., Int. Ed. 2013, 52, 1371. (d) Davies, H. M. L.; Alford, J.
S. Chem. Soc. Rev. 2014, 43, 5151.
(7) (a) Chattopadhyay, B.; Gevorgyan, V. Org. Lett. 2011, 13, 3746.
(b) Shi, Y.; Gevorgyan, V. Org. Lett. 2013, 15, 5394. (c) Schultz, E. E.;
Sarpong, R. J. Am. Chem. Soc. 2013, 135, 4696. (d) Miura, T.; Hiraga,
K.; Biyajima, T.; Nakamura, T.; Murakami, M. Org. Lett. 2013, 15,
3298. (e) Zibinsky, M.; Fokin, V. V. Angew. Chem., Int. Ed. 2013, 52,
1507. (f) Chuprakov, S.; Kwok, S. W.; Fokin, V. V. J. Am. Chem. Soc.
2013, 135, 4652. (g) Parr, B. T.; Green, S. A.; Davies, H. M. L. J. Am.
Chem. Soc. 2013, 135, 4716. (h) Spangler, J. E.; Davies, H. M. L. J. Am.
Chem. Soc. 2013, 135, 6802. (i) Yang, J.-M.; Zhu, C.-Z.; Tang, X.-Y.;
Shi, M. Angew. Chem., Int. Ed. 2014, 53, 5142. (j) Kim, C.-E.; Park, S.;
Eom, D.; Seo, B.; Lee, P. H. Org. Lett. 2014, 16, 1900.
ASSOCIATED CONTENT
* Supporting Information
■
S
Text, tables, figures, and a CIF file giving experimental
procedures and characterization data for new compounds and
crystallographic data for 3a. This material is available free of
charge via the Internet at http://pubs.acs.org.
(8) (a) Lee, D. J.; Shin, J.; Yoo, E. J. Chem. Commun. 2014, 50, 6620.
(b) Jung, D. J.; Jeon, H. J.; Kim, J. H.; Kim, Y.; Lee, S.-g. Org. Lett.
2014, 16, 2208. (c) Miura, T.; Funakoshi, Y.; Tanaka, T.; Murakami,
M. Org. Lett. 2014, 16, 2760.
(9) For recent reviews, see: (a) Coldham, I.; Hufton, R. Chem. Rev.
2005, 105, 2765. (b) Pandey, G.; Banerjee, P.; Gadre, S. R. Chem. Rev.
2006, 106, 4484. (c) Najera, C.; Sansano, J. M. Top. Hetereocycl. Chem.
2008, 12, 117. (d) Yeom, H.-S.; Shin, S. Acc. Chem. Res. 2014, 47, 966.
For selective examples, see: (e) Vedejs, E.; Grissom, J. W. J. Am. Chem.
Soc. 1986, 108, 6433. (f) Padwa, A.; Dean, D. C.; Zhi, L. J. Am. Chem.
Soc. 1992, 114, 593. (g) Song, G.; Chen, D.; Su, Y.; Han, K.; Pan, C.-
L.; Jia, A.; Li, X. Angew. Chem., Int. Ed. 2011, 50, 7791. (h) Xu, X.;
Zavalij, P. Y.; Doyle, M. P. Angew. Chem., Int. Ed. 2013, 52, 12664.
(10) Lopez-Calle, E.; Keller, M.; Eberbach, W. Eur. J. Org. Chem.
2003, 1438.
AUTHOR INFORMATION
Corresponding Author
*E-mail for E.J.Y.: ejyoo@kangwon.ac.kr.
Notes
■
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This research was supported by the Basic Science Research
Program through the National Research Foundation of Korea
(NRF) funded by the Ministry of Education, Science and
Technology (2013R1A1A1009618). This study was also
supported by a 2012 Research Grant from Kangwon National
University (No. C1009162-01-001). E.J.Y. thanks Prof. Sukbok
Chang (KAIST) for helpful manuscript preparation.
(11) Other N-containing heterocycles including quinoline, indole,
and pyrrole did not form corresponding isolable azomethine ylides
under identical reaction conditions.
(12) See the Supporting Information for details.
(13) When asymmetrical alkynes, such as methyl propiolate or
methyl 3-phenylpropiolate, and electron-rich alkynes were applied
with 3, the thermal annulation did not occur.
(14) For a review, see: (a) Lee, J. M.; Na, Y.; Han, H.; Chang, S.
Chem. Soc. Rev. 2004, 33, 302. For examples of three-component
reactions with Cu/Rh, see: (b) Miura, T.; Tanaka, T.; Biyajima, T.;
Yada, A.; Murakami, M. Angew. Chem., Int. Ed. 2013, 52, 3883.
(c) Miura, T.; Tanaka, T.; Yada, A.; Murakami, M. Chem. Lett. 2013,
42, 1308.
REFERENCES
■
(1) For reviews, see: (a) Renfroe, B.; Harrington, C.; Proctor, G. R.
Heterocyclic Compounds: Azepines; Wiley-Interscience: New York,
1984. (b) Ganellin, C. R.; Triggle, D. J. Dictionary of Pharmacological
Agents; Chapman & Hall/CRC: London, 1996.
(2) (a) Jiang, X. L.; Lee, G. T.; Prasad, K.; Repic, O. Org. Process Res.
Dev. 2008, 12, 1137. (b) Ebisawa, M.; Umemiya, H.; Ohta, K.;
Fukasawa, H.; Kawachi, E.; Christoffel, G.; Gronemeyer, H.; Tsuji, M.;
Hashimoto, Y.; Shudo, K.; Kagechika, H. Chem. Pharm. Bull. 1999, 47,
1778. (c) Sakaki, J.; Konishi, K.; Kishida, M.; Gunji, H.; Kanazawa, T.;
Uchiyama, H.; Fukaya, H.; Mitani, H.; Kimura, M. Bioorg. Med. Chem.
Lett. 2007, 17, 4808.
(3) (a) Xu, X.; Doyle, M. P. Acc. Chem. Res. 2014, 47, 1396.
(b) Gothelf, K. V.; Jorgensen, K. A. Chem. Rev. 1998, 98, 863. (c) 1,3-
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