N-Heterocyclic carbene-catalyzed formal cross-coupling reaction of α-haloenals with thiols: Organocatalytic construction of sp2 carbon-sulfur bonds

Article abstract of DOI:10.1039/c4cc00154k

A novel N-heterocyclic carbene (NHC)-catalyzed formal cross-coupling reaction between α-haloenals and thiols was developed. In the presence of 5 mol% NHC precursors and 1.6 equiv. potassium carbonate, various thiols coupled with α-haloenals to produce α-thioenals in 53% to 91% yield and excellent Z-selectivity. This journal is the Partner Organisations 2014.

Full text of DOI:10.1039/c4cc00154k

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N-Heterocyclic carbene-catalyzed formal
cross-coupling reaction of a-haloenals with
thiols: organocatalytic construction of sp2
carbon–sulfur bonds†
Cite this: Chem. Commun., 2014,
50, 3719
Received 8th January 2014,
Accepted 11th February 2014
Lin He,* Hao Guo, Yuan-Zhen Li, Guang-Fen Du and Bin Dai*
DOI: 10.1039/c4cc00154k
www.rsc.org/chemcomm
A novel N-heterocyclic carbene (NHC)-catalyzed formal cross-
coupling reaction between a-haloenals and thiols was developed.
In the presence of 5 mol% NHC precursors and 1.6 equiv. potassium
carbonate, various thiols coupled with a-haloenals to produce
a-thioenals in 53% to 91% yield and excellent Z-selectivity.
The carbon–sulfur (C–S) bond is a key structure that occurs ubiqui-
tously in biologically active compounds and pharmaceuticals.1
Several strategies, including transition metal-catalyzed substitution,
thiocarbonylation, insertion reaction, and transition metal-catalyzed
or organocatalyzed Michael additions, have been well established
over the past decades to construct C–S bonds.2 Despite the remark-
able progress made in this research field, the development of an
Scheme 1 NHC-mediated reactions of a-haloaldehydes.
efficient and environmentally friendly catalytic method for the presence of 5 mol% imidazolium A or imidazolinium B and
construction of C–S bonds is still lacking. To the best of our 1.2 equiv. triethylamine, the cross-coupling reaction proceeded
knowledge, no organocatalyzed cross-coupling reaction of alkenyl smoothly to produce a-thioenal 3a in high yield and good
halides with thiols has been reported.3
Z-selectivity (Table 1, entries 1 and 2).13 Notably, thiazolium C and
The N-heterocyclic carbene (NHC)4-catalyzed redox reaction of triazolium D, which were used as highly efficient catalysts in the
functional aldehydes provides a powerful yet unconventional strategy redox reaction,6,7 can also catalyze the coupling reaction to provide
for the construction of carbon–carbon,5 carbon–oxygen (C–O),6 and 3a in high yield (entries 3 and 4). Interestingly, an increase in the
carbon–nitrogen (C–N)7 bonds. However, only two examples of C–S base amount to 1.6 equiv. led to a higher yield (entry 5). A similar
bond formation reactions via the NHC-catalyzed redox protocol were yield was obtained when inorganic base K2CO3 was used instead of
reported.8 We and Jiao9 also independently found that a-haloenals triethylamine (entry 6). The following screening of the reaction
can undergo a similar redox reaction to form C–O and C–N bonds media indicated that dichloromethane was the best choice with
efficiently, which inspired us to further explore the NHC-catalyzed respect to the yield (entries 7 to 9). Finally, a control experiment
redox–thioesterification of a-haloenals for the formation of C–S showed that only a trace amount of the desired product was
bonds.10 However, no redox product was obtained, and a formal produced in the absence of NHCs (entry 11).
cross-coupling reaction between a-haloenals and thiols occurred
to produce a-thioenals11 as the major products (Scheme 1). We conditions (Table 1, entry 8). As shown in Table 2, primary and
herein report these interesting results. sterically hindered secondary thiols coupled with a-bromo-
The scope of the reaction was next studied under the optimized
Our initial experiment began with the investigation of the readily cinnamaldehyde to produce the corresponding a-thiocinnam-
available a-bromocinnamaldehyde 1a 12 and ethanethiol 2a. In the aldehyde with moderate to high yields. Furthermore, the alkene,
ester, and heterocyclic groups can all be well tolerated in these
Key Laboratory for Green Processing of Chemical Engineering of Xinjiang Bingtuan,
reactions (Table 2, entries 3 to 5). When the bulky tert-butyl thiol 2k
was used for the reaction, the desired product can also be isolated
with 53% yield (entry 8). Thiophenol was proven to be a competent
School of Chemistry and Chemical Engineering, Shihezi University,
Xinjiang Uygur Autonomous Region, 832000, China. E-mail: helin@shzu.edu.cn,
db_tea@shzu.edu.cn; Fax: +86-993-2057270
substrate in this cross-coupling reaction, producing a-thiophenol-
substituted cinnamaldehyde 3l in 89% yield (entry 9).
† Electronic supplementary information (ESI) available. See DOI: 10.1039/
c4cc00154k
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Table 1 Screening reaction conditionsa
Table 3 Evaluation of a-haloenalsa
Entry
1d
R
Product
Yieldb (%)
Z/Ec
4-MeOC6H4
4-ClC6H4
3m 83
3n 83
420 : 1
420 : 1
2d
Entry
Catalyst
Conditions
Yieldb (%)
Z/Ec
1
2
3
4
5
6
7
8
A
B
C
D
A
A
A
A
A
A
—
THF, 1.2 eq. Et3N
THF, 1.2 eq. Et3N
THF, 1.2 eq. Et3N
THF, 1.2 eq. Et3N
67
66
52
65
75
74
79
90
76
420 : 1
420 : 1
420 : 1
420 : 1
420 : 1
420 : 1
420 : 1
420 : 1
420 : 1
420 : 1
—
3d
2-NO2C6H4
3o 76
420 : 1
4d
5d
6e
2-Furyl
n-Pr
3p 78
420 : 1
420 : 1
420 : 1
THF, 1.6 eq. Et3N
THF, 1.6 eq. K2CO3
PhCH3, 1.6 eq. K2CO3
CH2Cl2, 1.6 eq. K2CO3
CH3CN, 1.6 eq. K2CO3
CH2Cl2, 1.6 eq. K2CO3
CH2Cl2, 1.6 eq. K2CO3
3q 64
9
10d
11e
69
o10
Ph
3a 56 (74) f
a
b
1a (1.0 eq.), 2a (1.5 eq.). Isolated yield. c Determined by 1H NMR analysis
3r X = Br, 80;
7
8
—
—
d
e
of the crude product. Using 1.0 mol% catalyst. No NHC precursor.
X = Cl, 77(73) g
3s 83h
Table 2 Evaluation of thiolsa
a
b
c
1 (1.0 eq.), 2 (1.5 eq.), CH2Cl2 2.0 mL. Isolated yield. Determined by
1H NMR analysis of crude product. X = Br. X = Cl. Using 10 mol%
catalyst. Using 5 mol% DBU instead of NHC. Yield based on thiol.
d
e
f
g
h
of NHCs, the reaction could also proceed smoothly to produce the
desired product in good yield. This result suggests that NHCs might
act as a Brønsted base in this transformation.
The intermolecular and intramolecular selective reactions
between alcohol and thiol were also investigated (eqn (1) and (2)).
The results indicated that a-bromoenal preferentially reacted with
thiol to produce a-sulfenylated enals as the major product. No
redox-esterification was observed in this process.
Entry
1
R
Product
Yieldb (%)
Z/Ec
CH3(CH2)n
3a
3b
3c
3d
3e
3f
3g
3h
3i
(n = 1) 90
(n = 2) 88
(n = 3) 90
(n = 17) 70
86
60
79
92
65
90
53
89
420 : 1
2
3
4
5
6
7
8
9
Bn
Allyl
CH2CO2CH3
2-(Furyl)methyl
i-Pr
c-Hexyl
t-Bu
420 : 1
420 : 1
420 : 1
420 : 1
420 : 1
420 : 1
420 : 1
420 : 1
3j
3k
3l
Ph
(1)
a
b
c
1a (1.0 eq.), 2 (1.5 eq.). Isolated yield. Determined by 1H NMR
analysis of the crude product.
We then explored the scope of a-haloenals (Table 3). Both electron-
donating and electron-withdrawing groups substituted a-bromoenals
proceeded through the coupling reaction efficiently in high yield and
good Z-selectivity (entries 1–3). b-Heteroaryl-substituted a-bromoenal
exhibited a good conversion process (entry 4). Alkyl-substituted
a-haloenal also performed well, providing the desired product in
64% yield (entry 5). Notably, the relatively inactive a-chlorocinnam-
aldehyde was efficiently transformed into a-thioenal with moderate
increase in catalyst loading (entry 6). The saturated a-haloaldehydes
and a,a-dichloroaldehydes were also tested for the reaction. The
(2)
Although the actual mechanism for this coupling reaction
aldehyde group can be well tolerated in this process to produce the remains unclear, a plausible mechanism is illustrated in Scheme 2
cross-coupling product a-thioaldehyde 3r and a,a-dithioaldehyde 3s in based on the pioneering studies of Movassaghi,14 Scheidt,15 Zhang,16
high yield (entries 7 and 8). Surprisingly, when DBU was used instead and Wang.17 In this process, NHCs act as a carbon-centered Brønsted
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2 For reviews see: (a) T. Kondo and T.-A. Mitsudo, Chem. Rev., 2000,
100, 3205; (b) M. Sibi and S. Manyem, Tetrahedron, 2000, 56, 8033;
(c) D. Enders, K. Lu¨ttgen and A. A. Narine, Synthesis, 2007, 959;
(d) W. Liu and X. Zhao, Synthesis, 2013, 2051; for recent examples
see: (e) J. W. Sun and G. C. Fu, J. Am. Chem. Soc., 2010, 132, 4568;
( f ) X. Tian, C. Cassani, Y. K. Liu, A. Moran, A. Urakawa,
P. Galzerano, E. Arceo and P. Melchiorre, J. Am. Chem. Soc., 2011,
133, 17934; (g) O. Takanori, K. Naoya and S. Masakatsu, Angew.
Chem., Int. Ed., 2012, 51, 8551; (h) M. Roggen and E. M. Carreira,
Angew. Chem., Int. Ed., 2012, 51, 8652; (i) X. Tian, Y. K. Liu and
P. Melchiorre, Angew. Chem., Int. Ed., 2012, 51, 6439.
3 For other selected method for the construction of SP2 C–S bonds
under transition-metal-free conditions, see: (a) A. Kondoh,
K. Takami, H. Yorimitsu and K. Oshima, J. Org. Chem., 2005, 70,
6468–6473; (b) X. Huang, R. Goddard and N. Maulide, Angew. Chem.,
Int. Ed., 2010, 49, 8979; (c) M. Smith, F. Schumacher, C. Ryan,
L. Tedaldi, D. Papaioannou, G. Waksman, S. Caddick and J. Baker,
J. Am. Chem. Soc., 2010, 132, 1960–1965; (d) V. X. Truong and
A. P. Dove, Angew. Chem., Int. Ed., 2013, 52, 4132–4136; (e) Y. Liao,
S. Chen, P. Jiang, H. Qi and G. Deng, Eur. J. Org. Chem., 2013,
6878–6885; ( f ) M. Majek and A. Wangelin, Chem. Commun., 2013,
49, 5507–5509.
Scheme 2 The proposed mechanism.
4 For recent reviews of NHCs-catalysis, see: (a) D. Enders, O. Niemeier
and A. Henseler, Chem. Rev., 2007, 107, 5606; (b) A. T. Biju, N. Kuhl
and F. Glorius, Acc. Chem. Res., 2011, 44, 1182; (c) J. Mahatthananchai
and J. W. Bode, Chem. Sci., 2012, 3, 192–197; (d) A. Grossmann and
D. Enders, Angew. Chem., Int. Ed., 2012, 51, 314; for a comprehensive
review on NHCs-catalyzed redox reaction, see: (e) H. U. Vora,
P. Wheeler and T. Rovis, Adv. Synth. Catal., 2012, 354, 1617.
5 (a) C. Burstein and F. Glorius, Angew. Chem., Int. Ed., 2004, 43, 6205;
(b) S. S. Sohn, E. L. Rosen and J. W. Bode, J. Am. Chem. Soc., 2004,
126, 14370; (c) V. Nair, S. Vellalath, M. Poonoth and E. Suresh, J. Am.
Chem. Soc., 2006, 128, 8736–8737; (d) D. T. Cohen, B. Cardinal-David
and K. A. Scheidt, Angew. Chem., Int. Ed., 2011, 50, 1678.
6 (a) N. T. Reynolds, J. R. D. Alaniz and T. Rovis, J. Am. Chem. Soc.,
2004, 126, 9518; (b) K. Y.-K. Chow and J. W. Bode, J. Am. Chem. Soc.,
2004, 126, 8126; (c) A. Chan and K. A. Scheidt, Org. Lett., 2005, 7, 905;
(d) H. U. Vora and T. Rovis, J. Am. Chem. Soc., 2010, 132, 2860;
(e) J. Mahatthananchai, P. Zheng and J. W. Bode, Angew. Chem., Int.
Ed., 2011, 50, 1673; ( f ) J. Mo, X. Chen and Y. Chi, J. Am. Chem. Soc.,
2012, 134, 8810; (g) J. Izquierdo and K. A. Scheidt, J. Am. Chem. Soc.,
2013, 135, 10634.
7 (a) H. U. Vora and T. Rovis, J. Am. Chem. Soc., 2007, 129, 13796;
(b) J. W. Bode and S. S. Sohn, J. Am. Chem. Soc., 2007, 129, 13798;
(c) Y. Kawanaka, E. M. Phillips and K. A. Scheidt, J. Am. Chem. Soc.,
2009, 131, 18028; (d) G.-Q. Li, Y. Li, L.-X. Dai and S.-L. You, Org. Lett.,
2007, 9, 3519; (e) D. E. A. Raup, B. Cardinal-David, D. Holte and
K. A. Scheidt, Nat. Chem., 2010, 2, 5345; ( f ) P. Wheeler, H. U. Vora
and T. Rovis, Chem. Sci., 2013, 4, 1674.
8 (a) S. S. Sohn and J. W. Bode, Angew. Chem., Int. Ed., 2006, 45, 6021;
(b) T. Uno, T. Inokuma and Y. Takemoto, Chem. Commun., 2012, 48, 1901.
9 (a) X. B. Wang, X. L. Zou, G. F. Du, Zh. Y. Liu and B. Dai, Tetrahedron,
2012, 68, 6498; (b) B. Zhang, P. Feng, Y. X. Cui and N. Jiao, Chem.
Commun., 2012, 48, 7280.
Scheme 3 Elimination reaction of IV.
base. The deprotonation of the acidic thiol by NHCs leads to the
formation of thioxy anion/azolium ion complex I, which might trigger
the conjugate addition of thiol and lead to the generation of II.
According to Baldwin’s rule, the conjugate adduct II undergoes an
intramolecular sulfenylation via a favorable 3-exo-tert attack to form
sulfonium ion intermediate III, The attack of the second molecule of
thiol leads to the ring opening of III and produces bisulfenylated
aldehyde IV, followed by b-elimination to produce the desired product.
During the study of the reaction mechanism, we failed to isolate
the intermediate III. But fortunately, after a careful analysis of the
crude reaction mixture using 1H NMR, bisulfenylated aldehyde IV
was detected. Then we synthesized this compound and isolated it
successfully. Under the standard reaction conditions, IV trans-
formed into the final product in excellent yield (Scheme 3), which
provides another piece of evidence to support the mechanism as
illustrated in Scheme 2.18
In summary, the first organocatalyzed cross-coupling reaction of
alkenyl halide and thiols was developed, providing a new approach
for the construction of sp2 C–S bonds. The aldehyde group can be
retained well and no redox reaction was observed in this formal
cross-coupling reaction. These data provide abundant opportunities
for the facile derivation of the desired products. Further studies of
NHC-catalyzed C–S bond formation, including the detailed reaction
mechanism and the application of these reactions in synthetic
chemistry, are underway in our laboratory.
10 For another example of NHCs-catalyzed construction of C–S bonds
via formal cycloaddtion of ketenes, see: T. Y. Jian, L. He, C. Tang and
S. Ye, Angew. Chem., Int. Ed., 2011, 50, 9104.
11 For recent studies on the synthesis of saturated a-thioaldehydes,
see: (a) D. Enders, T. Schiifer and W. Mies, Tetrahedron, 1998,
54, 10239; (b) D. A. Evans, K. R. Campos, J. S. Tedrow,
´
F. E. Michael and M. R. Gagne, J. Am. Chem. Soc., 2000, 122, 7905;
(c) M. Marigo, T. C. Wabnitz, D. Fielenbach and K. A. Jøgensen,
Angew. Chem., Int. Ed., 2005, 44, 794.
This work was supported by the National Natural Science
Foundation of China (No. 21162022, 21262027) and the Team
Innovation Project of Shihezi University (No. 2011ZRKXTD-04,
2012ZRKXJQ06). We thank Prof. Wan-Fu Sun of Xinjiang
University for assistance with NMR spectroscopy.
12 C. F. H. Allen and C. O. Edens, Jr., Org. Syn., 1955, 3, 731.
13 The stereoselectivity was determined by ROESY experiments, see
ESI† for details.
14 M. Movassaghi and M. A. Schmidt, Org. Lett., 2005, 7, 2453.
15 E. M. Phillips, M. Risdrich and K. A. Scheidt, J. Am. Chem. Soc., 2010,
132, 13179.
16 Q. Kang and Y. Zhang, Org. Biomol. Chem., 2011, 9, 6715–6720.
17 X. Song, A. Song, F. Zhang, H. Li and W. Wang, Nat. Commun., 2011,
2, 524.
Notes and references
1 J. R. Frau´sto da Silva and R. J. P. Williams, The Biological Chemistry 18 For saturated a-haloaldehydes, the formal cross-coupling reaction
of the Elements, Oxford University Press, New York, 2001.
might proceed via a SN2 substitution process.
This journal is ©The Royal Society of Chemistry 2014
Chem. Commun., 2014, 50, 3719--3721 | 3721