A Rh-catalyzed regio- and stereoselective route to enamides: Benzamides as assembling reagents

Article abstract of DOI:10.1039/c4cc02155j

A new protocol for the synthesis of fully substituted enaminones has been achieved using a diverse range of benzamides and 1-sulfonyl-1,2,3-triazoles. Selective removal of the β-amino moiety of the obtained α-amido-enaminones to form Z-enamides was also demonstrated thus improving the synthetic value of benzamides for structural diversities in a minimum number of synthetic steps. This journal is the Partner Organisations 2014.

Full text of DOI:10.1039/c4cc02155j

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A Rh-catalyzed regio- and stereoselective route to
enamides: benzamides as assembling reagents†
Cite this: Chem. Commun., 2014,
50, 6620
Dong Jin Lee, Jinhwan Shin and Eun Jeong Yoo*
Received 24th March 2014,
Accepted 4th May 2014
DOI: 10.1039/c4cc02155j
www.rsc.org/chemcomm
A new protocol for the synthesis of fully substituted enaminones has
been achieved using a diverse range of benzamides and 1-sulfonyl-
1,2,3-triazoles. Selective removal of the b-amino moiety of the obtained
a-amido-enaminones to form Z-enamides was also demonstrated thus
improving the synthetic value of benzamides for structural diversities in
a minimum number of synthetic steps.
The strategy of pot, atom and step economy (PASE) provides a line of
green trend and approach towards efficient tools to synthesize target
molecules.1 The beauty of the PASE concept is that it provides
maximum structural complexity and diversity with the least number
of synthetic steps and few or no by-products to assemble the
compounds. In this regard, the 1,3-dipolar cyclization has become
Scheme 1 Transformation reactions of amides.
a powerful and widely used strategy as it ensures 100% atom diamines or benzils have also been researched by a few groups.6
economy with a single operation.2 The proximity and conforma- Although established transformation methods are quite general, there
tional constraints between 1,3-dipoles and dipolarophiles often lead are still remaining synthetic challenges from the perspective of atom
to regio- or stereoselectivity, and therefore the development of a and redox economy (Scheme 1).
straightforward method for dipolarophiles, selectively matched to
1,3-dipoles, is still in demand and need to be investigated.
Herein, we demonstrate the atom-economic reaction of
benzamides with 1-sulfonyl-1,2,3-triazoles to synthesize fully
Amides are one of the most common and reliable functional substituted enaminones (eqn (3)). Particularly, benzamides
groups in all branches of chemistry because of their distinct features, stereoselectively matched triazoles, which results in the formation
such as high polarity, stability and conformational diversity.3 These of (Z)-a-amido-enaminones. Selective cleavage of the b-amino
widespread amide bonds are present in all natural peptides and many moiety of the obtained product is also reported.
pharmaceuticals. Also some of the amides serve as directing groups in
Rh-Azavinyl carbene (Scheme 2, A), readily prepared from 1-sulfonyl-
the C–H activation reactions.4 Thus, it is not surprising that the 1,2,3-triazoles and a rhodium catalyst,7 has electrophilic character in
development of an organic method for the transformation of amides addition to its nucleophilic site because of the a-imino moiety. Thus,
into other functional groups is of vital importance. Among many the Rh-azavinyl carbene (A) behaved as a 1,3-dipole to participate in
transformation reactions, synthesis of aldehydes, ketones, alcohols, cyclization reactions with dipolarophiles, including nitriles, alkynes,
(eqn (1)) and amines via selective reduction by alkali-metal hydrides, isocyanates, and allenes to form heterocycles.8 It is noted that other
borohydrides, and transition metal catalyst has mainly been devel- 2p-moieties such as carbonyl could also undergo cyclization with such a
oped (eqn (2)).5 Conversions from amides to enediamines, vicinal dipole.9 For example, cyclization reaction of Rh-azavinyl carbenes A
with simple benzaldehyde to give 4-oxazolines was reported by Fokin
Department of Chemistry, Kangwon National University, 1 Kangwondaehak-gil,
Chuncheo-si, Gangwon-do, 200-791, Republic of Korea.
and co-workers,9a and Murakami et al. reported that A reacted
with a,b-unsaturated aldehydes leading to the production of trans-
2,3-dihydropyrroles.9b We envisioned that benzamides could
provide molecular complexities and structural diversities in the
reaction with dipole A because of their variable substituents.
Thus, the new reaction with benzamide as a partner of A meets
E-mail: ejyoo@kangwon.ac.kr
† Electronic supplementary information (ESI) available: Experimental proce-
dures, characterization data, and 1H and 13C NMR spectra for new compounds,
CIF file of 3b. CCDC 992959. For ESI and crystallographic data in CIF or other
electronic format see DOI: 10.1039/c4cc02155j
6620 | Chem. Commun., 2014, 50, 6620--6622
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Table 1 Investigation of N,N-disubstituted benzamide scopea,b,c
Scheme 2 Proposed mechanism.
the high demand of diversity-oriented synthesis (DOS). However,
amides displayed very low reactivity in reactions with a dipole due
to both electronic and steric factors as opposed to aldehydes. In
our further studies, we observed that N,N-dimethylbenzamide (1a)
reacted with 1-sulfonyl-1,2,3-triazole (2a) unexpectedly leading to the
formation of the fully substituted a-amido-enaminone 3a, a valuable
building block of various medicinal compounds,10 in 83% yield using
Rh2(esp)2 as the catalyst in toluene at 80 1C (eqn (4)). Other Rh(II)
catalysts including Rh2(OAc)4 and Rh2(Oct)4 were incompatible
with the reaction of amides and no conversion was observed at
room temperature even in the presence of Rh2(esp)2.
a
Reaction conditions: 1 (3.0 equiv.), 2b (0.5 mmol), Rh2(esp)2 (1.0 mol%) and
toluene (5.0 mL) at 80 1C for 4 h. b Isolated yields. c The number in
parentheses is the Z:E isomeric ratio of the product determined by 1H NMR.
We were also pleased to find that 1-sulfonyl-1,2,3-triazoles reacted
with other N,N-disubstituted benzamides in good to excellent yields,
allowing for the introduction of a variety of amine groups (3n–3q).
Notably, the benzyl group in 3n can be cleaved to afford a secondary
amine. Also, the synthesis of product 3 was performed on the gram
scale without encountering any problems.12 However, when N,N-
(4)
As shown in Scheme 2, a possible reaction pathway can be dimethylacetamide was used instead of N,N-disubstituted benza-
postulated that benzamide reacted with Rh-azavinyl carbene A to mides, the corresponding adduct was not produced.
form unstable 4-oxazoline (C) via carbonyl ylide (B) at first. Then, the
The reaction conditions were subsequently applied to a range of
unstable 4-oxazoline (C) transformed the short-lived azomethine 1-sulfonyl-1,2,3-triazoles (Table 2). All types of 1-sulfonyl-1,2,3-triazole
ylide (D) through ring-opening of C, a well-known thermal prepara- examined worked with high efficiency, affording the desired pro-
tion method of azomethine ylide,11 followed by the intramolecular ducts in satisfactory yields. Electronic or steric variation of the
1,3-cyclization and subsequently the formation of aziridine (E) at an C4-substituent on the triazoles exhibited small effects on the reac-
elevated temperature. Following ring-opening of E, zwitterionic tion efficiency, and the corresponding products were obtained in
intermediate F allowed the synthesis of the Z-selective enaminone good yields. Not only aryl but also alkyl substituents on the sulfonyl
3 through proton rearrangement. The geometry of the double bond, group were readily employed resulting in comparable product yields.
presumably controlled by the shape of D, was assigned using single-
To demonstrate the synthetic utility of this reaction, we also
performed the reduction of product a-amido-enaminones using
crystal X-ray analysis.12
Reactions of various N,N-disubstituted benzamide derivatives (1) NaBH4. Surprisingly, compound 3 directly transformed to furnish
with 2b were carried out under the reaction conditions to determine the sterically less favourable Z-enamide (4),13,14 which constitutes
the scope of the present method (Table 1). It turns out that the the core structure of many functional materials and natural
variation of the para- or meta-substituent in benzamide does not products of biological significance (Scheme 3).15 The reaction is
alter the efficiency of the reactions. Nitro and halide functional thought to be initiated by NaBH4 to form the a,b-diaminoketone
groups were also tolerated under the reaction conditions. The intermediate followed by the stereoselective elimination to give the
reaction with N,N-dimethyl-2-naphthamide afforded the desired Z-enamide under the acidic reaction conditions,16 however, we
product (3i) in 81% isolated yield. However, the 3-bromo-N,N- have no evidence supporting the intermediacy of this species. With
dimethybenzamide substrate was slightly less reactive due to the this newly developed elimination conditions in hand, we examined
steric effect and the desired product 3h was isolated in 54% yield. the reactivity of representative substrates. Substrates possessing
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Table 2 Examination of various 1-sulfonyl-1,2,3-triazolesa,b
with the CRI (2012-0001245) program funded by the National
Research Foundation of Korea. E. J. Yoo thanks Prof. Sukbok
Chang (KAIST) for helping with manuscript preparation.
Notes and references
Entry
R1
R2
Product 3
Yieldc (%)
1 (a) B. M. Trost, Science, 1991, 254, 1471; (b) B. M. Trost, Angew.
Chem., Int. Ed. Engl., 1995, 34, 259; (c) P. A. Clarke, S. Santos and
W. H. C. Martin, Green Chem., 2007, 9, 438; (d) P. A. Wender, F. G. Bi,
G. G. Gamber, F. Gosselin, R. D. Hubbard, M. J. C. Scanio, R. Sun,
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2 (a) 1,3-Dipolar Cycloaddition Chemistry, ed. A. Padwa, Wiley, New York,
N.Y., 1984, vol. 1 & 2, p. 1521; (b) K. V. Gothelf and K. A. Jorgensen,
Chem. Rev., 1998, 98, 863.
1
2
3
4
5
6
7
8
4-tBuC6H4
4-MeOC6H4
4-BrC6H4
4-FC6H4
4-CF3C6H4
3-MeC6H4
3-FC6H4
3-Thienyl
Ph
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
C6H5
3r
3s
3t
3u
3v
3w
3x
3y
3z
86 (9 : 1)
88 (10 : 1)
81 (11 : 1)
82 (8 : 1)
79 (11 : 1)
81 (9 : 1)
86 (11 : 1)
79 (7 : 1)
80 (8 : 1)
64 (5 : 1)
92 (8 : 1)
84 (7 : 1)
3 W.-J. Yoo and C.-J. Li, J. Am. Chem. Soc., 2006, 138, 13064, and
references cited therein.
9
10
11
12
Ph
Ph
Ph
4-CF3C6H4
4-MeOC6H4
nBu
3aa
3ab
3ac
4 (a) G. Arthur, The Amide Linkage: Selected Structural Aspects in
Chemistry, Biochemistry, and Materials Science, Wiley-Interscience,
2000For examples of C–H activation reactions, see: (b) M. Wasa,
K. M. Engle and J.-Q. Yu, J. Am. Chem. Soc., 2009, 131, 9886;
(c) J. Ryu, K. Shin, S. H. Park, J. Y. Kim and S. Chang, Angew. Chem.,
Int. Ed., 2012, 51, 9904, and references cited therein.
5 Selective reviews, see: (a) Modern Amination Method, ed. A. Ricci, Wiley,
New York, 2000; (b) Modern Reduction Methods, ed. P. G. Andersson and
I. J. Munslow, Wiley, New York, 2000; (c) P. N. Rylander, Catalytic
Hydrogenation in Organic Syntheses, Academic Press, London, 1979.
6 For recent examples, see: (a) L. Fleming, U. Ghosh, S. R. Mack and
B. P. Clark, Chem. Commun., 1998, 711; (b) K. Rangareddy, K. Selvakumar
and J. F. Harrod, J. Org. Chem., 2004, 69, 6843; (c) T. Kumagai, T. Anki,
T. Ebi, A. Konishi, K. Matsumoto, H. Kurata, T. Kubo, K. Katsumoto,
C. Kitamura and T. Kawase, Tetrahedron, 2010, 66, 8968.
a
Reaction conditions: 1a (5.0 equiv.),
2 (0.2 mmol), Rh2(esp)2
b
(1.0 mol%) and toluene (2.0 mL) at 80 1C for 4 h. Isolated yields.
c
The number in parentheses is the Z : E isomeric ratio of the product
determined by 1H NMR.
7 (a) E. J. Yoo, M. Ahlquist, S. H. Kim, I. Bae, V. V. Fokin,
K. B. Sharpless and S. Chang, Angew. Chem., Int. Ed., 2007,
46, 1730; (b) J. Raushel and V. V. Fokin, Org. Lett., 2010, 12, 4952.
8 (a) T. Horneff, S. Chuprakov, N. Chernyak, V. Gevorgyan and
V. V. Fokin, J. Am. Chem. Soc., 2008, 130, 14972; (b) T. Miura,
M. Yanauchi and M. Murakami, Chem. Commun., 2009, 1470;
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(d) Y. Shi and V. Gevorgyan, Org. Lett., 2013, 15, 5394; (e) E. E. Schultz
and R. Sarpong, J. Am. Chem. Soc., 2013, 135, 4696; ( f ) A. V. Gulevich
and V. Gevorgyan, Angew. Chem., Int. Ed., 2013, 52, 1371; (g) T. Miura,
K. Hiraga, T. Biyajima, T. Nakamura and M. Murakami, Org. Lett.,
2013, 15, 3298; (h) M. Zibinsky and V. V. Fokin, Angew. Chem., Int. Ed.,
2013, 52, 1507; (i) S. Chuprakov, S. W. Kwok and V. V. Fokin, J. Am.
Chem. Soc., 2013, 135, 4652; ( j) B. T. Parr, S. A. Green and
H. M. L. Davies, J. Am. Chem. Soc., 2013, 135, 4716; (k) J. E. Spangler
and H. M. L. Davies, J. Am. Chem. Soc., 2013, 135, 6802.
9 (a) M. Zibinsky and V. V. Fokin, Angew. Chem., Int. Ed., 2013,
52, 1507; (b) T. Miura, T. Tanaka, K. Hiraga, S. G. Stewart and
M. Murakami, J. Am. Chem. Soc., 2013, 135, 13652. After the
submission of this manuscript, a similar rhodium catalysis using
1-sulfonyl-1,2,3-triazoles and DMF was reported. See: (c) D. J. Jung,
H. J. Jeon, J. H. Kim, Y. Kim and S.-g. Lee, Org. Lett., 2014, 16, 2208.
10 (a) J. Svete, M. Aljaz-Rozic and B. J. Stanovnik, J. Heterocycl. Chem.,
1997, 34, 177; (b) N. Berer, A. Rudi, I. Goldberg, Y. Benayahu and
Y. Kashman, Org. Lett., 2004, 6, 2543; (c) D. Pappo, M. Vartanian,
S. Lang and Y. Kashman, J. Am. Chem. Soc., 2005, 127, 7682;
(d) D. Pappo and Y. Kashman, Org. Lett., 2006, 8, 1177; (e) Y. Kogon,
L. Goren, D. Pappo, A. Rudi and Y. Kashman, Eur. J. Org. Chem.,
2009, 1852.
Scheme 3 Synthetic reactions of Z-enamides.
electron-donating or electron-withdrawing groups all smoothly
reacted to provide the desired Z-enamides with high efficiency
(4a–4c). When substrates having 4-fluoro and 3-chloro groups were
subjected to reduction with NaBH4, corresponding products 4d and
4e were obtained in 86% and 81% yields, respectively. Gratifyingly,
the process can be successfully applied to a one-pot method
starting from benzamides and 1-sulfonyl-1,2,3-triazole.12
In summary, the efficient synthetic reaction of 1-sulfonyl-1,2,3-
triazoles with benzamides as sources of atom economic coupling
partners is described herein. Various tertiary benzamides stereo-
selectively react with in-situ generated Rh-azavinyl carbenes to
synthesize fully substituted a-amido-enaminones. The b-amino
substituent of the obtained product could be selectively removed
by treating with NaBH4 to form Z-enamides. Considering its
convenient reaction conditions and excellent stereoselectivity,
this method presents a novel approach for the construction of
multi-functionalized enaminones or enamides.
11 (a) E. Vedejs and J. W. Grissom, J. Org. Chem., 1988, 53, 1876;
(b) E. Vedejs and J. W. Grissom, J. Org. Chem., 1988, 53, 1882.
12 See ESI† for details.
This research was supported by Basic Science Research 13 (a) M. R. Tracey, R. P. Hsung, J. Antoline, K. C. M. Kurtz, L. Shen,
B. W. Slafer and Y. Zhang, Sci. Synth., 2005, 5, 387; (b) D. Chen,
L. Guo, J. Liu, S. Kirtane, J. F. Cannon and G. Li, Org. Lett., 2005,
7, 921.
Program through the National Research Foundation of Korea
(NRF) funded by the Ministry of Education, Science and Tech-
nology (2013R1A1A1009618). This study was also supported 14 Relative configuration of product 4a was confirmed from ref. 13b.
15 (a) L. Yet, Chem. Rev., 2003, 103, 4283; (b) R. Matsubara and
S. Kobayashi, Acc. Chem. Res., 2008, 41, 292.
16 M. I. N. C. Harris and A. C. H. Braga, J. Braz. Chem. Soc., 2004,
by 2012 Research Grant from Kangwon National University
(No. C1009162-01-001). This work was carried out by 400 MHz
FT-NMR spectrometer (Bruker AVANCE III 400) purchased
15, 971.
6622 | Chem. Commun., 2014, 50, 6620--6622
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