A novel copper-catalyzed synthesis of functionalized alkynyl imidates and alkynyl thioimidates

Article abstract of DOI:10.1016/j.tetlet.2013.07.029

A copper-catalyzed one-pot synthesis of alkynyl imidates and alkynyl thioimidates via coupling reactions of terminal alkynes with trichloroimidates, generated in situ from trichloroacetonitrile and benzyl alcohols or thiols, is reported.

Full text of DOI:10.1016/j.tetlet.2013.07.029

Tetrahedron Letters 54 (2013) 4973–4974
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A novel copper-catalyzed synthesis of functionalized alkynyl
imidates and alkynyl thioimidates
⇑
Issa Yavari , Manijeh Nematpour
Department of Chemistry, Tarbiat Modares University, PO Box 14115-175, Tehran, Iran
a r t i c l e i n f o
a b s t r a c t
Article history:
A copper-catalyzed one-pot synthesis of alkynyl imidates and alkynyl thioimidates via coupling reactions
of terminal alkynes with trichloroimidates, generated in situ from trichloroacetonitrile and benzyl alco-
hols or thiols, is reported.
Received 23 May 2013
Revised 25 June 2013
Accepted 5 July 2013
Available online 13 July 2013
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Cross-coupling
Alkynyl imidates
Alkynyl thioimidates
Copper iodide
Trichloroimidates
Terminal alkynes
Alkynyliminesandalkynylimidatesrepresentanimportantclass
of functionalizedalkynes because of their applications in the synthe-
sis of a broad range of biologically important compounds. Alkynyl
imidates are versatile intermediates, which are used to synthesize
different types of N-heterocyclic systems.1–8 Furthermore, they
can react with conjugated dienes to give bicyclic compounds.9,10
Despite their synthetic importance, relatively few methods
have been described for the preparation of alkynyl imidates and
alkynyl thioimidates. One such important methodology involves
metal-catalyzed coupling reactions of imidoyl halides,11,12 diaryl-
nitrones,13 or the palladium-catalyzed reaction product of bromo-
benzene and tert-butyl isocyanide14 with organometallic reagents
derived from 1-alkynes. Alternatively, alkynyl imines have been
prepared via imination of the corresponding alkynyl ketones.2,15
Herein, we report an efficient procedure for the synthesis of
alkynyl imidates and alkynyl thioimidates via the Cu-catalyzed,
three-component coupling reaction of trichloroacetonitrile, benzyl
alcohol (thiol), and terminal alkynes (Scheme 1).16
yield (Scheme 1). Thus, the optimized reaction conditions are as
follows: 10 mol % of CuI, 1 mmol of alkyne, 1 mmol of Et3N,
1 mmol of benzyl alcohol (thiol), and 1 mmol of trichloroacetoni-
trile in MeCN at room temperature.
Phenylacetylene readily participates in the coupling to furnish
the corresponding 3-phenylpropiolimidates in good yields
Cl3C CN
R' XH
3
2
MeCN, r.t
NH
CuI 10 mol%
Et3N, MeCN
r.t., 8 h
NH
R'
R'
X
R
X
CCl3
R
1
5
4
In our initial investigations, phenylacetylene (1a), trichloroace-
tonitrile (2), and benzyl alcohol (3a) were selected as model sub-
strates. Several catalysts including CuI, CuBr, CuCl, and copper
powder were tested with CuI giving the best results. Among
several solvents screened, acetonitrile proved to be the best. When
this reaction was performed in MeCN in the presence of one
equivalent of Et3N at room temperature for eight hours, the desired
product, benzyl 3-phenylpropiolimidate (5a), was obtained in 84%
Yield (%) of 5
1,3,5
X
R
R'
Bn
a
b
c
d
e
f
O
O
O
O
O
O
S
84
80
74
Ph
Ph
Ph
4-Cl-C6H4CH2
4-Me-C6H4CH2
4-Cl-C6H4CH2 67
n-Pr
63
62
81
68
61
n-Bu 4-Cl-C6H4CH2
n-Bu
Ph
4-Me-C6H4CH2
g
h
i
Bn
Bn
Bn
S
n-Pr
n-Bu
S
⇑
Corresponding author. Tel.: +98 21 82883465; fax: +98 21 82883455.
E-mail address: yavarisa@modares.ac.ir (I. Yavari).
Scheme 1. Synthesis of compounds 5.
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.07.029

4974
I. Yavari, M. Nematpour / Tetrahedron Letters 54 (2013) 4973–4974
2
3
NH
Cu
4
CCl3
-CuCCl3
CuI
R'
Ph
Cu
5
Ph
X
Ph
7
1
6
Scheme 2. A mechanism for the formation of products 5.
2. Kel’in, A. V.; Sromek, A. W.; Gevorgyan, V. J. Am. Chem. Soc. 2001, 123, 2074.
3. Lihar, P. R.; Subhas, M. S.; Roy, S.; Kantam, M. L. Org. Biomol. Chem. 2009, 7, 85.
4. Sha, F.; Wu, L.; Huang, X. Angew. Chem., Int. Ed. 2009, 48, 3458.
5. Hachiya, I.; Minami, Y.; Aramaki, T.; Shimizu, M. Eur. J. Org. Chem. 2008, 8, 1411.
6. Ueda, M.; Ikeda, Y.; Sato, A.; Ito, Y.; Kakiuchi, M.; Shono, H.; Miyoshi, T.; Naito,
T.; Miyata, O. Tetrahedron 2011, 67, 4612.
7. Mangelinckx, S.; Rooryck, S.; Jacobs, J.; De Kimpe, N. Tetrahedron Lett. 2007, 48,
6535.
8. Zhang, F. G.; Ma, H.; Zheng, Y.; Ma, J. A. Tetrahedron 2012, 68, 7663.
9. Rahm, R.; Espenlaub, S.; Werz, U. R.; Maas, G. Heteroatom Chem. 2005, 16, 437.
10. Feng, L.; Kerwin, S. M. Tetrahedron Lett. 2003, 44, 3463.
(Scheme 1). Aliphatic acetylenes served as low yielding substrates
compared to phenylacetylene.
The structures of products 5a–i were assigned by IR, 1H NMR,
and 13C NMR spectroscopies and by mass spectrometry data. The
1H NMR spectrum of 5a exhibited two singlets for the methylene
(4.45 ppm) and NH (5.10 ppm) protons, along with characteristic
multiplets for the phenyl protons. The 13C NMR spectrum of 5a
exhibited 12 signals in agreement with the proposed structure.
The mass spectrum of 5a displayed a molecular ion peak at
m/z = 235. The NMR spectra of compounds 5b–i were similar to
those of 5a, except for the substituents, which showed characteris-
tic signals in the appropriate regions of the spectra.
11. Gerster, H.; Espenlaub, S.; Maas, G. Synthesis 2006, 2251.
12. Schlegel, J.; Maas, G. Synthesis 1999, 100.
13. Miura, M.; Enna, M.; Okuro, K.; Nomura, M. J. Org. Chem. 1995, 60, 4999.
14. Kosugi, M.; Ogata, T.; Tamura, H.; Sano, H.; Migita, T. Chem. Lett. 1986, 1197.
15. Bishop, B. C.; Brands, K. M. J.; Gibb, A. D.; Kennedy, D. J. Synthesis 2004, 43.
16. General procedure for the synthesis of compounds 5: A solution of 2 (1 mmol) and
3 (1 mmol) in MeCN (2 mL) was stirred for 30 min. Next, a mixture of alkyne 1
(1 mmol), CuI (0.1 mmol) and Et3N (1 mmol) in MeCN (3 mL) was added slowly
at room temperature under an N2 atmosphere. After completion of the reaction
[about 8 h; TLC (EtOAc/hexane, 1:5) monitoring], the mixture was diluted with
CH2Cl2 (2 mL) and aqueous NH4Cl solution (3 mL), stirred for 30 min, and the
layers separated. The aqueous layer was extracted with CH2Cl2 (3 Â 3 mL) and
the combined organic fractions were dried (Na2SO4) and concentrated under
reduced pressure. The residue was purified by flash column chromatography
[silica gel (230–400 mesh; Merck), hexane/EtOAc, 5:1] to give the product.
Benzyl 3-Phenylpropiolimidate (5a): Cream powder, mp: 121–124 °C; yield:
A mechanism for the formation of products 5 is given in Scheme
2. Yellow copper acetylide 6, formed from 1 and CuI, takes part in a
nucleophilic addition reaction with trichloroimidates 4, generated
in situ from trichloroacetonitrile and benzyl alcohols or thiols, to
afford tetrahedral intermediate 7. This intermediate is converted
into 5 by the elimination of CuCCl3.
In conclusion, we have demonstrated that under ligand-free
conditions, CuI catalyzes the coupling reaction of trichloroacetoni-
trile and benzyl alcohols with terminal alkynes to produce alkynyl
imidates. Replacement of the alcohols with benzyl thiols furnishes
alkynyl thioimidates. The potential diversity of this type of reaction
and readily available starting materials and catalyst are the main
advantages of this methodology.
0.20 g (84%). IR (K Br) (m
max, cmÀ1): 3438, 2123, 1611, 1396, 1270, 1139, 1081.
1H NMR (500 MHz, CDCl3): dH = 4.45 (2H, s, CH2), 5.10 (1H, s, NH), 7.25–7.34
(3H, m, Ph), 7.47–7.50 (4H, m, Ph), 7.60 (1H, t, 3J = 7.5 Hz, Ar), 7.97 (2H, d,
3J = 7.9 Hz, Ar). 13C NMR (125.7 MHz, CDCl3): dC = 47.0 (CH2), 77.6 (C), 85.4 (C),
122.5 (C), 128.7 (2 CH), 129.2 (CH), 129.3 (2 CH), 129.4 (2 CH), 132.5 (2 CH),
134.4 (CH), 135.3 (C), 161.7 (C). MS: m/z (%) = 235 (M+, 2), 158 (8), 144 (43),
134 (23), 101 (100), 91 (70), 77 (54). Anal. Calcd for C16H13NO (235.10): C,
81.68; H, 5.57; N, 5.95. Found: C, 81.39; H, 5.63; N, 6.04. Benzyl 3-Phenylprop-
2-ynimidothioate (5g): Pale yellow powder, mp: 151–153 °C; yield: 0.20 g
Supplementary data
(81%). IR (K Br) (m
max, cmÀ1): 3452, 2133, 1620, 1401, 1370, 1218. 1H NMR
(500 MHz, CDCl3): dH = 4.39 (2 H, s, CH2), 5.10 (1H, s, NH), 7.25–7.33 (4H, m,
Ph), 7.43 (2H, d, 3J = 7.5 Hz, Ar), 7.48 (2H, d, 3J = 7.5 Hz, Ar), 7.90 (2H, d,
3J = 7.9 Hz, Ar). 13C NMR (125.7 MHz, CDCl3): dC = 46.7 (CH2), 77.7 (C), 85.4 (C),
122.5 (C), 128.8 (2 CH), 129.2 (CH), 129.3 (2 CH), 130.8 (2 CH), 132.5 (2 CH),
132.7 (CH), 141.0 (C), 160.7 (C). MS: m/z (%) = 251 (M+, 6), 174 (8), 160 (43),
123 (53), 101 (100), 91 (72), 77 (34). Anal. Calcd for C16H13NS (251.35): C,
76.46; H, 5.21; N, 5.57. Found: C, 76.79; H, 5.26; N, 5.63.
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2013.07.
029.
References and notes
1. Sromek, A. W.; Rheingold, A. L.; Wink, D. J.; Gevorgyan, V. Synlett 2006, 2325.