Two unprecedented multicomponent reactions involving N-heterocyclic carbenes, activated acetylenes, and aldehydes

Article abstract of DOI:10.1021/ol0502782

(Chemical Equation Presented) Two unprecedented multicomponent reactions of N-heterocyclic carbenes involving activated acetylenes and aldehydes are described.

Full text of DOI:10.1021/ol0502782

ORGANIC
LETTERS
2005
Vol. 7, No. 12
2297-2300
Two Unprecedented Multicomponent
Reactions Involving N-Heterocyclic
Carbenes, Activated Acetylenes, and
Aldehydes†
Vijay Nair,*,‡ V. Sreekumar,‡ S. Bindu,‡ and Eringathodi Suresh§
Organic Chemistry DiVision, Regional Research Laboratory (CSIR),
TriVandrum, India, and Central Salt and Marine Chemicals Research Institute (CSIR),
BhaVnagar 364 002, India
Vijaynair_2001@yahoo.com
Received February 10, 2005 (Revised Manuscript Received April 9, 2005)
ABSTRACT
Two unprecedented multicomponent reactions of N-heterocyclic carbenes involving activated acetylenes and aldehydes are described.
Ever since Breslow’s original demonstration of the remark-
able catalytic properties of N-heterocyclic carbenes (NHCs),1
the bold but unsuccessful attempt to synthesize an NHC by
Wanzlick,2 and the more recent isolation of stable NHCs by
Arduengo,3 these species have attracted considerable attention
from organic chemists. Their role as excellent ligands for
transition metals4 and their ability to efficiently catalyze a
number of organic reactions, most notably benzoin conden-
sation,1 transesterification,5 aldol reaction, and Michael-
Stetter reaction,6,7 has contributed significantly to the enor-
mous interest in NHCs. There is also a growing awareness
of their potential application as reagents8 in organic reactions
as illustrated by their participation in 1,3-dipolar cycload-
ditions9 and [4 + 1] cycloaddition reactions.10
species, we envisioned the possibility of initiating MCRs by
NHCs, and our effort in this area led to the first application
of these species in MCRs (Scheme 1).12
Scheme 1
In the context of our interest in multicomponent reactions
(MCRs)11 triggered by nucleophilic carbenes and related
† This paper is dedicated with best wishes to Professor Dr. Henning Hopf
on the occasion of his 65th birthday.
‡ Regional Research Laboratory (CSIR).
§ Central Salt and Marine Chemicals Research Institute.
(1) Breslow, R. J. Am. Chem. Soc. 1958, 80, 3719.
(2) Wanzlick, H.-W. Angew. Chem. Int. Ed. 1962, 1, 75.
(3) Arduengo, A. J., III; Harlow, R. L.; Kline, M. K. J. Am. Chem. Soc.
1991, 113, 361.
While the implications of the results are not fully apparent,
they clearly warranted further research. Thus, we began to
investigate the influence of the N-substituents on the reactiv-
10.1021/ol0502782 CCC: $30.25
© 2005 American Chemical Society
Published on Web 05/12/2005

ity of imidazolin-2-ylidene and imidazol-2-ylidene toward acti-
vated acetylenes and aldehydes. The resulting novel multi-
component reactions are the subject of this communication.
Our studies commenced with exposure of tert-butyl-
substituted imidazolin-2-ylidene, generated by the deproto-
nation of corresponding imidazolinium salt13 9 using NaH
in dry toluene, with methyl phenylpropiolate and 4-triflu-
oromethyl benzaldehyde at 90 °C. The reaction afforded the
aminofuran derivative 10a in good yield (Scheme 2).14
a
13C resonance signal at δ 165.1 supporting the IR
absorption at 1723 cm-1.
A variety of aromatic aldehydes were found to be suitable
candidates for aminofuran synthesis, and methyl phenylpro-
piolate was found to be a suitable acetylenic component. The
results are summarized in Table 1.
Table 1.
Scheme 2
entry
aldehyde
product
yield (%)
1
2
3
4
5
6
7
R′ ) 3,4-dichlorophenyl, 7b
R′) 4-chlorophenyl, 7c
R′ ) 4-bromophenyl, 7d
R′ ) phenyl, 7e
R′ ) 4-methylphenyl, 7f
R′ ) 4-fluorophenyl, 7g
R′ ) 2-thienyl, 7h
10b
10c
10d
10e
10f
53
55
65
47
40
54
55
The structure of the product 10a was established by
spectroscopic and X-ray analysis (Figure 1).15 The car-
10g
10h
Encouraged by the results obtained with tert-butyl-
substituted imidazolin-2-ylidene, we turned our attention to
1,3-di-tert-butylimidazol-2-ylidene. To our surprise, the car-
bene formed in situ failed to react with methyl phenylpropio-
late and aldehydes. However, the reaction of the carbene with
dimethyl acetylenedicarboxylate (DMAD) and 4-fluoroben-
zaldehyde proceeded smoothly to deliver an acyclic four-
component adduct 13a in 52% yield (Scheme 3).16
Scheme 3
Figure 1. Single-crystal X-ray structure of compound 10a.
The structure of the product 13a was established by
spectroscopic analysis. Four methoxycarbonyl groups reso-
bomethoxy protons resonated as a singlet at δ 3.63 while
the methylene protons displayed two separate sets of triplets,
centered at δ 3.12 (J ) 6.5 Hz) and δ 2.37 (J ) 6.5 Hz), in
(6) (a) Teles, J. H.; Melder, J. P.; Ebel, K.; Schneider, R.; Gehrer, E.;
Harder, W.; Brode, S.; Enders, D.; Breuer, K.; Rabbe, G. HelV. Chim. Acta
1996, 79, 1271. (b) Davis, J. H., Jr.; Forrester, K. Tetrahedron Lett. 1999,
40, 1621. (c) Enders, D.; Breuer, K.; Runsink, J.; Teles, J. H. HelV. Chim.
Acta 1996, 79, 1899. (d) Enders, D.; Kallfass, U. Angew. Chem., Int. Ed.
2002, 41, 1743. (e) Kerr, M. S.; Read de Alaniz, J.; Rovis, T. J. Am. Chem.
Soc. 2002, 124, 10298.
(7) Enders, D.; Balensiefer, T. Acc. Chem. Res. 2004, 37, 534 and
references therein.
(8) Nair, V.; Bindu, S.; Sreekumar, V. Angew. Chem., Int. Ed. 2004, 43,
5130.
1
the H NMR spectrum. The ester carbonyl group displayed
(4) (a) Herrmann, W. A. Angew. Chem., Int. Ed. 2002, 41, 1290. (b)
Herrmann, W. A.; Ko¨cher, C. Angew. Chem., Int. Ed. Engl. 1997, 36, 2162.
(c) Weskamp, T.; Schattenmann, W. C.; Spiegler, M.; Herrmann, W. A.
Angew. Chem., Int. Ed. 1998, 37, 2490. (d) Nolan, S. P.; Kelly, R. A., III;
Navarro, O. J. Am. Chem. Soc. 2003, 125, 16194.
(5) (a) Grasa, G. A.; Kissling, R. M.; Nolan, S. P. Org. Lett. 2002, 4,
3583. (b) Grasa, G. A.; Gu¨veli, T.; Singh, R.; Nolan, S. P. J. Org. Chem.
2003, 7, 2812. (c) Nyce, G. W.; Lamboy, J. A.; Connor, E. F.; Waymouth,
J. L.; Hedrick, R. M. Org. Lett. 2002, 4, 3587. (d) Singh, R.; Kissling, R.
M.; Letellier, M.-A.; Nolan, S. P. J. Org. Chem. 2004, 69, 209.
(9) Enders, D.; Breuer, K.; Raabe, J.; Runsink, J.; Teles, J. H. Liebigs
Ann. 1996, 2019.
(10) (a) Rigby, J. H.; Wang, Z. Org. Lett. 2002, 4, 4289. (b) Rigby, J.
H.; Wang Z. Org. Lett. 2003, 5, 263.
2298
Org. Lett., Vol. 7, No. 12, 2005

A variety of aldehydes were found to be suitable partners
in the reaction, and the results are summarized in Table 2.
Table 2.
entry
aldehyde
product yield (%)
1
2
3
4
5
6
7
8
R′ ) 3,4-dichlorophenyl, 11b
R′) 3-chlorophenyl, 11c
R′ ) 4-bromophenyl, 11d
13b
13c
13d
56
52
51
65
45
51
20
30
R′ ) 4-trifluoro methylphenyl, 11e 13e
R′ ) 4-nitrophenyl, 11f
R′ ) 1-naphthyl, 11g
R′ ) 4-methylphenyl, 11h
R′ ) 2-thienyl, 11i
13f
13g
13h
13i
Figure 2. Single-crystal X-ray structure of compound 13a.
It is especially noteworthy that both olefinic bonds created
in the reaction are formed with complete stereoselectivity.
The two reactions described here may be rationalized by
considering the stereoelectronic features of the carbene and
the dipolar intermediates generated during the course of the
reactions (Scheme 4). The imidazolin-2-ylidene adds first
nated at δ 3.78, 3.77, 3.52, and 3.42 in the 1H NMR
spectrum. The ester carbonyl groups displayed 13C resonance
signals at δ 169.3, 165.5, 163.9, and 163.1 supporting the
IR absorption at 1742 cm-1. The olefinic proton was
discernible at δ 4.96. The final proof for the structure and
stereochemistry was obtained from single-crystal X-ray
analysis (Figure 2).
(11) (a) Nair, V.; Rajesh, C.; Vinod, A. U.; Bindu, S.; Sreekanth, A. R.;
Balagopal, L. Acc. Chem. Res. 2003, 36, 899. (b) Nair, V.; Bindu, S.;
Sreekumar, V.; Balagopal, L. Synthesis 2003, 1446.
Scheme 4
(12) Nair, V.; Bindu, S.; Sreekumar, V.; Rath, N. P. Org. Lett. 2003, 5,
665.
(13) Arduengo, A. J., III; Krafczyk, R.; Schmutzler, R. Tetrahedron 1999,
55, 14523.
(14) Representative experimental procedure and spectral data: NaH (20
mg, 0.84 mmol) was added to a suspension of the carbene precursor 9 (122
mg, 0.56 mmol) in dry toluene under argon atmosphere. This was followed
by the addition of methyl phenylpropiolate (68 mg, 0.42 mmol) and the
aldehyde 7a (50 mg, 0.28 mmol), and the resulting solution was stirred for
24 h at 90 °C. The reaction mixture was then passed through a short pad
of Celite. After removal of the solvent, the residue was subjected to
chromatography on a neutral alumina column using 80:20 hexanes-ethyl
acetate solvent mixture to afford 10a (84 mg, 58%) as a white crystalline
solid. Mp: 105-106 °C. IR (KBr) νmax: 2969, 1723, 1619, 1506, 1326,
1164, 1130, 1104, 1023, 864, 697 cm-1. 1H NMR δ: 7.89 (d, J ) 9.0 Hz,
2H), 7.66 (d, J ) 9.0 Hz, 2H) 7.39-7.25 (m, 6H), 3.63 (s, 3H), 3.12 (t, J
) 6.5 Hz, 2H), 2.37 (t, J ) 6.5 Hz, 2H), 1.21 (s, 9H), 0.89 (s, 9H). 13C
NMR δ: 165.1, 152.6, 148.6, 140.3, 133.3, 132.1, 130.0, 129.0, 127.8,
127.3, 127.0, 125.2, 120.2, 115.6, 109.3, 108.2, 56.9, 51.6, 50.3, 48.6, 41.4,
28.5, 28.3, 27.3. HRMS (EI): calcd for C29H35F3N2O3 516.2599, found
516.2600. CCDC file no. 266011.
(15) On the basis of spectroscopic data, we had originally suggested the
structure 10a′ for this compound. One of the reviewers cast doubt on our
structure assignment and suggested that we should get X-ray data on this
compound. On the basis of the single-crystal X-ray data, we have now
revised the structure to 10a, which is an isomeric relationship to 10a′. The
mechanistic postulation has also been modified. It may be mentioned that
the spectroscopic data cannot distinguish the two structures. The insightful
suggestion of the reviewer prompting us to obtain single-crystal X-ray data,
which led to the correct structure assignment, is gratefully acknowledged.
to activated acetylene to form a dipole 15. The latter then
undergoes a dipolar cycloaddition/cyclization with aldehyde
to form the intermediate 17, which in turn opens to form
aminofuran derivatives 10a-h. The dipolar intermediate 18
Org. Lett., Vol. 7, No. 12, 2005
2299

generated by the reaction of 14 and 3 adds to the aldehyde
to form an alkoxide intermediate 19. This alkoxide 19 under-
goes nucleophilic addition to DMAD to form the zwitterionic
intermediate 20. The latter then stabilizes through an internal
proton abstraction furnishing the products 13a-i.
In conclusion, we have uncovered two new multicompo-
nent reactions; the first one constitutes a facile synthesis of
substituted aminofuran derivatives and the second reaction
is a three-reagent, pseudo-four-component process leading
to novel diene derivatives. The tunable reactivity of the car-
bene observed here may be useful for the synthesis of de-
signer oligomers and heterocycles with interesting properties.
(16) Representative Experimental Procedure and Spectral Data. NaH
(28 mg, 1.2 mmol) was added to a suspension of the carbene precursor 12
(172 mg, 0.80 mmol) in dry THF under argon atmosphere. This was
followed by the addition of DMAD (114 mg, 0.80 mmol) and the aldehyde
11a (50 mg, 0.40 mmol), and the resulting solution was stirred for 12 h.
The reaction mixture was then passed through a short pad of Celite. After
removal of the solvent, the residue was subjected to chromatography on a
neutral alumina column using 30:70 hexanes-ethyl acetate solvent mixture
to afford 13a (93 mg, 52%) as a red crystalline solid. Mp: 234-235 °C.
IR (KBr) νmax: 2929, 1742, 1636, 1563, 1444, 1346, 1212, 1139, 1056,
906, 643 cm-1. 1H NMR δ: 7.29-7.17 (m, 4H), 6.95-6.90 (m, 2H), 4.96
(s, 1H), 3.73 (s, 3H), 3.69 (s, 3H), 3.54 (s, 3H), 3.46 (s, 3H), 1.70 (s, 18H).
13C NMR δ: 169.3, 165.5, 163.9, 163.1, 162.6, 159.4, 149.4, 131.0, 130.9,
128.3, 128.2, 128.1, 117.3, 117.2, 115.3, 115.0, 99.5, 96.0, 63.2, 62.0, 52.3,
52.3, 52.0, 51.3, 48.9, 30.2. CCDC file no. 267780.
Acknowledgment. We thank the Council of Scientific
and Industrial Research (CSIR), New Delhi, for financial
assistance.
Supporting Information Available: Detailed synthetic
procedures and spectroscopic characterization of compounds
and single-crystal X-ray data of compound 10a and 13a. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL0502782
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Org. Lett., Vol. 7, No. 12, 2005