N-heterocyclic carbene ligands in copper-catalyzed addition of diethylzinc to N-sulfonylimines

Article abstract of DOI:10.1248/cpb.56.57

N-Heterocyclic carbenes (NHCs) were generated in-situ from imidazolium and imidazolinium salts by deprotonation of C-2 hydrogen and were used as ligands in the copper-catalyzed addition of diethylzinc to N-sulfonylimines. The copper-NHC complexes were sho

Full text of DOI:10.1248/cpb.56.57

January 2008
Chem. Pharm. Bull. 56(1) 57—59 (2008)
57
N-Heterocyclic Carbene Ligands in Copper-Catalyzed Addition of
Diethylzinc to N-Sulfonylimines
Abu Bakar MD., Yumiko SUZUKI,* and Masayuki SATO*
School of Pharmaceutical Sciences, University of Shizuoka; 52–1 Yada, Suruga-ku, Shizuoka 422–8526, Japan.
Received August 22, 2007; accepted October 10, 2007; published online October 17, 2007
N-Heterocyclic carbenes (NHCs) were generated in-situ from imidazolium and imidazolinium salts by de-
protonation of C-2 hydrogen and were used as ligands in the copper-catalyzed addition of diethylzinc to N-sul-
fonylimines. The copper–NHC complexes were shown to possess an efficient ligand acceleration effect (LAE).
Key words N-heterocyclic carbene ligand; N-sulfonylimine; diethylzinc; copper-catalyzed addition
N-Heterocyclic carbenes (NHCs) are strong s-donating tion, the reaction was carried out at 0 °C. It was observed that
species, showing coordination properties similar to those of though the yield of 3a was increased to 65%, byproduct 4a
phosphines.1,2) Initially, the widespread use of catalysts con- (12%) was still obtained. Further lowering of the reaction
taining carbene ligands was limited due to their relatively dif- temperature to ꢁ5 °C led to the exclusive formation of 3a
ficult preparation. Since the discovery of stable carbenes by (entry 5).
Arduengo3) in 1991, interest in the use of N-heterocyclic car-
At ꢁ5 °C, the addition reactions of diethylzinc to 1a were
bene–metal complexes have increased, and it has been carried out by using imidazolium and imidazolinium salts
demonstrated that they are efficient catalysts in important 2b—d as ligand precursors, and the addition products 3a
chemical transformations such as Pd-catalyzed coupling re- were isolated in good yields (66—72%, Table 2, entries 1—
actions,4) Ru-catalyzed olefin metathesis,5) and Rh-catalyzed 3). The use of imidazolium and imidazolinium compounds
hydrosilylations.6—8) NHCs have also attracted great attention
as organocatalysts in several reactions (e.g., benzoin conden-
Table 1. Addition of Diethylzinc to N-Sulfonylimine 1a Catalyzed by
Copper–NHC Complex from 2a
sation,9—14) Stetter reaction,15—17) transesterification/acylation
reactions,18,19) and nucleophilic substitution reactions).20—22)
Recently, our research group as well as other groups have re-
ported the cyanosilylation of aldehydes catalyzed by
NHCs.23—26)
In the course of our studies on the use of NHCs in organic
synthesis, we have found that copper–NHC complexes ex-
hibit the ligand acceleration effect (LAE) in the addition of
Yield (%)
Entry
Condition
Recovery (%)a)
diethylzinc to N-sulfonylimines. The LAE of copper–NHC
complexes was first reported in the addition of diethylzinc to
cyclohexenone,27) and later the asymmetric version of these
conjugate addition reactions was accomplished by using chi-
ral NHC ligands.28,29) In this study, we report our results on
the addition of diethylzinc to N-sulfonylimines by using cat-
alytic amounts of copper–NHC complexes.
3aa)
4ab)
1
rt, 1.5 h
rt, 2 h
rt, 6 h
0 °C, 24 h
ꢁ5 °C, 24 h
50
15
31
65
63
28
46
22
12
0
10
30
46
12
28
2c)
3d)
4
5
a, b) Isolated yields. c) Without imidazolium salt 2a. d) Without copper iodide.
Results and Discussion
In order to examine the catalytic abilities of the Table 2. Diethylzinc Addition to 1a Catalyzed by Copper–NHCs 2a—d
copper–NHC complexes, an addition reaction of diethylzinc
to N-(benzylidene)-p-methylbenzenesulfonamide (N-sul-
fonylimine) 1a30) was carried out in the presence of 5 mol%
of imidazolium salt 2a as a ligand source, 5 mol% of CuI,
and 5 mol% of t-BuOK in toluene (Table 1). After reacting at
room temperature for 1.5 h, the addition product 3a (50%)
and the reduction product 4a (28%) were obtained (Table 1,
Entry
CuX
CuI
CuI
CuI
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Azolium salt Yield (%)a) Recovery (%)a)
entry 1). The formation of 4a could be due to the transfer of
the b-hydrogen of the ethyl functionality to the CꢀN bond of
the N-sulfonylimine 1a. In the absence of 2a, the reaction af-
forded the desired product 3a in only 15% yield and afforded
4a as the major product (entry 2). The reaction without CuI
at room temperature for 6 h afforded 3a and 4a in 31% and
22% yields, respectively (entry 3). These results indicate that
the LAE of NHC is involved in the addition reaction. To in-
crease the yield of 3a and to suppress the byproduct forma-
1
2
3
4
5
6
7
2b
2c
2d
2a
2b
2c
2d
69
72
66
71
66
69
64
23
13
30
12
22
15
23
a) Isolated yield.
∗ To whom correspondence should be addressed. e-mail: msato@u-shizuoka-ken.ac.jp;
© 2008 Pharmaceutical Society of Japan
suzuyumi@u-shizuoka-ken.ac.jp

58
Vol. 56, No. 1
Table 3. Diethylzinc Addition to 1a in Various Solvents
Table 5. Asymmetric Diethylzinc Addition to 1a Catalyzed by
Copper–Chiral NHCs
Azolium Temperature Yield 3a
salt
Recovery
(%)a)
ee
Entry
(%)a)
(%)b)
Entry
Solvent
Yield (%)a)
Recovery (%)a)
1
2
3
5
5
6
ꢁ5 °C
ꢁ78 °C
ꢁ78 °C
83
50
50
12
40
46
1
1
7
1
2
3
4
Toluene
THF
Ether
71
22
18
21
12
68
73
75
CH2Cl2
a) Isolated yield. b) ee was determined by chiralcel OD.
a) Isolated yield.
Table 4. Diethylzinc Addition to N-Sulfonylimines 1b—e Catalyzed by
Copper–NHCs
(Table 5, entries 1, 2). We envisioned that the enantioselec-
tivity could increase by using bidentate-type N-heterocyclic
carbenes. As a bidentate ligand precursor, we synthesized the
chiral pyrrolidinylmethyl imidazolium compound 6. The ad-
dition reaction was carried out by using copper–chiral NHC
generated from imidazolium salt 6 at ꢁ78 °C for 24 h. Com-
pound 3a was isolated in 50% yield with a slightly increased
enantioselectivity of 7% ee (Table 5, entry 3).
1b—e
3b—e
Entry
Ar
Yield (%)a)
87
Recovery (%)a)
1
7
Conclusion
2
3
81
69
9
In conclusion, we have demonstrated the LAE of NHCs in
the addition of diethylzinc to N-sulfonylimines. The cop-
per–NHC complexes accelerate the formation of the adducts.
To the best of our knowledge, this is the first example of the
addition of diethylzinc to N-sulfonylimines using copper–
NHC complexes. Further investigations are in progress in our
laboratory to elucidate the mechanistic details of the catalytic
system and to develop an asymmetric version of the addition
reaction.
15
4
45
44
a) Isolated yield.
resulted in comparable yields of the addition product.
It has been reported that copper sources and solvents influ-
ences the efficiency of the diethylzinc addition reaction.31)
Therefore, the reactions were carried out by using Cu(OTf)2
instead of CuI. However, no significant change in the yields
of 3a was observed (Table 2, entries 4—7). The addition re-
actions were carried out in various solvents such as toluene,
THF, ether, and dichloromethane; toluene was found to be
the solvent of choice (Table 3).
Experimental
General The melting points were determined using a Yazawa micro
melting point apparatus (without correction). The H-NMR (500 MHz) and
1
13C-NMR (126 MHz) spectra were recorded on a JEOL ECA-500 NMR
spectrometer. The IR spectra were recorded on a Shimadzu IRPrestige-21
spectrophotometer. The FAB-MS spectra were recorded on a JEOL MSta-
tion JMS-700 mass spectrometer using m-nitrobenzyl alcohol as a matrix.
(S)-2-(Chloromethyl)pyrrolidine hydrochloride was prepared from (S)-(ꢂ)-
2-(hydroxymethyl)pyrrolidine, according to the literature,35) and was used
without purification. Column chromatography was performed with silica gel
The reaction of diethylzinc under the catalysis of cop- 60N (spherical, neutral; Kanto Chemical Co., Inc).
General Procedure for the Copper–NHCs Catalyzed Addition of Di-
per–NHC in toluene was successfully applied to the ethyla-
tion of N-sulfonylimines 1b—e that were derived from 4-
chlorobenzaldehyde, 2-chlorobenzaldehyde, 4-methylben-
zaldehyde, and 2-methoxy benzaldehyde, affording the corre-
sponding addition products 3b—e in moderate to high yields
(Table 4).
ethylzinc to N-Sulfonylimine Under an argon atmosphere, to a suspension
of azolium or azolinium salt (0.0125 mmol), the copper salt (0.0125 mmol)
in the solvent (1 ml), 1 M t-BuOK/THF (0.0125 mmol) was added at room
temperature and the mixture was stirred for 30 min. Then, the suspension
was maintained at ꢁ5 °C for 30 min with stirring, and then Et2Zn (0.375 ml,
0.375 mmol, 1 M solution in hexane) was added dropwise. After stirring for
5 min, a solution of 1a—e (0.25 mmol) in toluene (1 ml) was added drop-
wise. The resulting mixture was stirred for 24 h at the same temperature.
The reaction was quenched with 3 N HCl (1 ml) and stirred at room tempera-
ture for another 0.5 h. The products were extracted with diethyl ether. The
organic layer was dried over MgSO4 and concentrated. The residue was puri-
fied by silica gel column chromatography (n-hexane : ethyl acetateꢀ3 : 1) to
afford the addition products 3a—e and reduction product 4a.
Recently, Tomioka K. and co-workers32) and Wang M. et
al.33) have reported the asymmetric alkylation of N-sul-
fonylimines catalyzed by copper–chiral amidophosphine
complexes. We have also examined the asymmetric alkyla-
tion of N-sulfonylimines by using copper–chiral NHC com-
plexes. The reaction using C2-symmetric imidazolium salt
534) was carried out at ꢁ5 °C and ꢁ78 °C for 24 h to afford
3a in 83% (1% ee) and 50% yields (1% ee), respectively
N-(1-Phenylpropyl)-4-methylbenzenesulfonamide32) (3a): Colorless nee-
dles (recrystallized from n-hexane/CH2Cl2), mp 104—106 °C; IR (ATR)
cmꢁ1: 3271, 1599, 1317. 1H-NMR (CDCl3) d: 0.78 (3H, t, Jꢀ7.5 Hz),

January 2008
59
354.2545). [a]D24 ꢁ14.2 (cꢀ1.0, CHCl3).
1.67—1.83 (2H, m), 2.35 (3H, s), 4.17 (1H, q, Jꢀ7.5 Hz), 4.82 (1H, d,
Jꢀ7.5 Hz), 6.98—7.01 (2H, m), 7.10 (2H, d, Jꢀ8.6 Hz), 7.13—7.17 (3H,
m), 7.52 (2H, d, Jꢀ8.6 Hz). 13C-NMR (CDCl3) d: 10.5, 21.6, 30.7, 59.9,
126.6, 127.1, 127.4, 128.5, 129.4, 137.5, 140.7, 143.1. MS (FAB) m/z 290
(Mꢂ1). The enantiomeric excesses of 3a obtained by chiral ligands 5 and 6
were determined before recrystallization. HPLC condition: Daicel Chiralcel
OD, hexane/iPrOHꢀ10/1, 0.7 ml/min, 254 nm, minor 14.1 min and major
15.9 min.
References
1) Herrrmann W. A., Kocher C., Angew. Chem. Int. Ed. Engl., 36, 2162—
2187 (1997).
2) Bourrissou D., Guerret O., Gabbai F. P., Bertrand G., Chem. Rev., 100,
39—91 (2000).
3) Arduengo III, A. J., Harlow R. L., Kline M. A., J. Am. Chem. Soc.,
113, 361—363 (1991).
4) Hillier A. C., Grasa G. A., Viciu M. S., Lee H. M., Yang C., Nolan S.
P., J. Organomet. Chem., 653, 69—82 (2002).
N-[1-(4-Chlorophenyl)propyl]-4-methylbenzenesulfonamide32) (3b): Col-
orless needles (recrystallized from n-hexane/CH2Cl2), 136—139 °C; IR
(ATR) cmꢁ1 3244, 1317, 1165. 1H-NMR (CDCl3) d: 0.77 (3H, t,
:
5) Ender D., Gielen H., J. Organomet. Chem., 617—618, 70—80 (2001).
6) Lappert M. F., Maskell R. K., J. Organomet. Chem., 264, 217—228
(1984).
7) Herrrmann W. A., Goosen L. J., Kocher C., Artus G. R. J., Angew.
Chem. Int. Ed. Engl., 35, 2805—2807 (1996).
8) Gade L. H., Cesar V., Bellemin-Laponaz S., Angew. Chem. Int. Ed.
Engl., 43, 1014—1017 (2004).
9) Ukai T., Tanaka R., Dokawa S., J. Pharm. Soc. Jpn., 63, 296—300
(1943).
10) Ugai T., Dokawa T., Tsubokawa S., J. Pharm. Soc. Jpn., 64, 3—4
(1944).
11) Breslow R., J. Am. Chem. Soc., 80, 3719—3726 (1958).
12) Breslow R., McNeils E., J. Am. Chem. Soc., 81, 3080—3082 (1959).
13) Miyashita A., Suzuki Y., Iwamoto K., Higashino T., Chem. Pharm.
Bull., 42, 2633—2635 (1994).
Jꢀ7.5 Hz), 1.63—1.79 (2H, m), 2.37 (3H, s), 4.16 (1H, q, Jꢀ7.5 Hz), 4.84
(1H, bs), 6.93 (2H, d, Jꢀ8.6 Hz), 7.09—7.13 (4H, m), 7.49 (2H, d,
Jꢀ8.6 Hz). 13C-NMR (CDCl3) d: 10.5, 21.6, 30.6, 59.2, 127.1, 128.1, 128.6,
129.4, 133.3, 137.5, 139.2, 143.4. MS (FAB) m/z 324 (Mꢂ1).
N-[1-(2-Chlorophenyl)propyl]-4-methylbenzenesulfonamide (3c): Color-
less needles (recrystallized from n-hexane/CH2Cl2), mp 130—132 °C; IR
(ATR) cmꢁ1 3269, 1319, 1155. 1H-NMR (CDCl3) d: 0.82 (3H, t,
:
Jꢀ7.5 Hz), 1.72—1.78 (2H, m), 2.32 (3H, s), 4.64 (1H, q, Jꢀ7.5 Hz), 5.32
(1H, d, Jꢀ7.5 Hz ), 7.03—7.15 (6H, m), 7.55 (2H, d, Jꢀ8.6 Hz). 13C-NMR
(CDCl3) d: 10.5, 21.5, 29.6, 57.0, 126.9, 127.1, 128.3, 128.5, 129.3, 129.7,
132.4, 137.2, 138.3, 143.1. FAB-MS m/z: 324.0840 (Mꢂ1) (Calcd for
C16H19NO2S: 324.0825).
N-[1-(4-Methylphenyl)propyl]-4-methylbenzenesulfonamide32) (3d): Col-
orless needles (recrystallized from n-hexane/CH2Cl2), mp 114—116 °C; IR
(ATR) cmꢁ1 3261, 1315, 1157. 1H-NMR (CDCl3) d: 0.76 (3H, t,
:
14) Miyashita A., Suzuki Y., Kobayashi M., Kuriyama N., Higashino T.,
Heterocycles, 43, 509—512 (1996).
Jꢀ7.5 Hz), 1.66—1.82 (2H, m), 2.26 (3H, s), 2.36 (3H, s), 4.12 (1H, q,
Jꢀ6.9 Hz), 4.80 (1H, d, Jꢀ6.9 Hz), 6.88 (2H, d, Jꢀ8.0 Hz), 6.95 (2H, d,
Jꢀ8.0 Hz), 7.11 (2H, d, Jꢀ8.0 Hz), 7.53 (2H, d, Jꢀ8.0 Hz). 13C-NMR
(CDCl3) d: 10.6, 21.1, 21.6, 30.6, 59.7, 126.6, 127.2, 129.1, 129.4, 131.6,
137.2, 137.7, 143.0. MS (FAB) m/z 304 (Mꢂ1).
15) Stetter H., Angew. Chem., 88, 695—704 (1976).
16) Stetter H., Kuhlmann H., Chem. Ber., 109, 2890—2896 (1976).
17) Stetter H., Kuhlmann H., Organic Reactions, 40, 407—496 (1991).
18) Grasa G. A., Kissling R. M., Nolan S. P., Org. Lett., 4, 3583—3586
(2002).
19) Nyce G. W., Lamboy J. A., Connor E. F., Waymouth R. M., Hedrick
L., Org. Lett., 4, 3587—3590 (2002).
20) Miyashita A., Obae K., Suzuki Y., Iwamoto K., Oishi E., Higashino T.,
Heterocycles, 45, 2159—2173 (1997).
21) Miyashita A., Suzuki Y., Iwamoto K., Oishi E., Higashino T., Hetero-
cycles, 49, 405—413 (1998).
22) Miyashita A., Suzuki Y., Iwamoto K., Higashino T., Chem. Pharm.
Bull., 46, 390—399 (1998).
N-[1-(2-Methoxyphenyl)propyl]-4-methylbenzenesulfonamide (3e): Col-
orless crystalline powder (recrystallized from n-hexane/CH2Cl2), mp 115—
118 °C; IR (ATR) cmꢁ1: 3273, 1317, 1155. 1H-NMR (CDCl3) d: 0.82 (3H, t,
Jꢀ7.5 Hz), 1.69—1.90 (2H, m), 2.27 (3H, s), 3.68 (3H, s), 4.18—4.24 (1H,
m), 5.57 (1H, d, Jꢀ10.3 Hz), 6.56 (1H, d, Jꢀ8.0 Hz), 6.68 (1H, t,
Jꢀ7.5 Hz), 6.80 (1H, dd, Jꢀ7.5, 1.7 Hz), 6.96 (2H, d, Jꢀ8.6 Hz), 7.05
(1H, ddd, Jꢀ8.0, 7.5, 1.7 Hz), 7.42 (2H, d, Jꢀ8.6 Hz). 13C-NMR (CDCl3)
d: 11.2, 21.5, 29.0, 55.1, 59.4, 110.6, 120.5, 126.9, 127.9, 128.4, 128.9,
129.4, 129.8, 137.7, 142.5. FAB-MS m/z: 320.1304 (Mꢂ1) (Calcd for
C17H22NO3S: 320.1320).
N-Benzyl-4-methylbenzenesulfonamide36) (4a): Colorless crystalline pow-
der (recrystallized from n-hexane/CH2Cl2), mp 108—110 °C; IR (ATR)
cmꢁ1: 3267, 1321, 1159. 1H-NMR (CDCl3) d: 2.44 (3H, s), 4.12 (2H, d,
Jꢀ6.3 Hz), 4.61 (1H, t, Jꢀ6.3 Hz), 7.19 (2H, d, Jꢀ8.6 Hz), 7.26—7.32 (5H,
m), 7.76 (2H, d, Jꢀ8.6 Hz). 13C-NMR (CDCl3) d: 21.6, 47.4, 127.3, 128.0,
128.1, 128.8, 129.9, 136.3, 136.9, 143.7. MS (FAB) m/z 262 (Mꢂ1).
(S)-3-(1-Pivaloylpyrrolidin-2-ylmethyl)-1-(2,4,6-trimethylphenyl)imi-
dazolium Chloride 6 Triethylamine (2.8 ml, 20 mmmol) was added to a
solution of (S)-2-(chloromethyl)pyrrolidine hydrochloride (10 mmol) in
dichloromethane (20 ml) at 0 °C, and subsequently, pivaloyl chloride
(1.23 ml, 10 mmol) was added dropwise. The mixture was stirred overnight
at room temperature, and then dichloromethane was removed under reduced
pressure. The residue was extracted with diethyl ether, washed with 2 N HCl,
and dried over MgSO4. The solvent was removed to afford crude (S)-2-
(chloromethyl)-1-pivaloylpyrrolidine (1.28 g, 63%) as a brown oil, to which
chlorobenzene (20 ml) and 1-mesitylimidazole (1.18 g, 6.33 mmol) were
added and the mixture was refluxed for 3 d. After the mixture was cooled,
the resultant precipitates were collected by filtration to afford imidazolium
23) Suzuki Y., MD. A. B., Muramatsu K., Sato M., Tetrahedron, 62,
4227—4231 (2006).
24) Song J. J., Gallou F., Reeves J. T., Tan Z., Yee N. K., Senanayake C. H.,
J. Org. Chem., 71, 1273—1276 (2006).
25) Fukuda Y., Maeda Y., Ishii S., Kondo K., Aoyama T., Synthesis, 4,
589—590 (2006).
26) Kano T., Sasaki K., Konishi T., Mii H., Maruoka K., Tetrahedron Lett.,
47, 4615—4618 (2006).
27) Fraser P. K., Woodward S., Tetrahedron Lett., 42, 2747—2749 (2001).
28) Guillen F., Winn C. L., Alexakis A., Tetrahedron: Asymmetry, 12,
2083—2086 (2001).
29) Pytkowicz J., Roland S., Mangeney P., Tetrahedron: Asymmetry, 12,
2087—2089 (2001).
30) Lee K. Y., Lee C. G., Kim J. N., Tetrahedron Lett., 44, 1231—1234
(2003).
31) Alexakis A., Benhaim C., Rosset S., Human M., J. Am. Chem. Soc.,
124, 5262—5263 (2002).
32) Soeta T., Nagai K., Fujihara H., Kuriyama M., Tomioka K., J. Org.
Chem., 68, 9723—9727 (2003).
33) Wang M.-C., Xu C.-L., Zou Y.-X., Liu H.-M., Wang D.-K., Tetrahe-
dron Lett., 46, 5413—5416 (2005).
34) Herrrmann W. A., Goossen L. J., Kocher C., Artus G. R. J., Angew.
Chem. Int. Ed. Engl., 35, 2805—2807 (1996).
35) Nijhuis W. H. N., Verboom W., El-Fadl A. A., Van Hummel G. J.,
Reinhoudt D. N., J. Org. Chem., 54, 209—216 (1989).
36) Gao F., Deng M., Qiam C., Tetrahedron, 61, 12238—12243 (2005).
salt 6 as pale brown scales (1.05 g, 46%). mp 277—278 °C; IR (ATR) cmꢁ1
:
1
1604. H-NMR (CDCl3) d: 1.24 (9H, s, t-Bu), 1.84—1.92 (1H, m), 1.94—
2.22 (1H, m), 2.08 (6H, s, o-CH3), 2.14—2.20 (1H, m), 2.34 (3H, p-CH3),
2.37—2.47 (1H, m), 3.68 (1H, dt, Jꢀ10.3, 7.4 Hz), 3.82 (1H, ddd, Jꢀ10.3,
8.0, 4.6 Hz), 4.46—4.50 (1H, m), 4.71 (1H, dd, Jꢀ13.2, 4.0 Hz), 5.10 (1H,
dd, Jꢀ13.2, 7.4 Hz), 7.00 (2H, s), 7.07 (1H, t, Jꢀ1.7 Hz), 7.80 (1, t,
Jꢀ1.7 Hz), 10.9 (1H, s). 13C-NMR (CDCl3) d: 17.7, 17.8, 21.2, 25.3, 26.9,
27.6, 39.3, 48.4, 51.5, 59.7, 122.8, 123.0, 130.0, 130.8, 134.2, 134.2, 139.3,
139.3, 141.4, 178.0. FAB-MS m/z: 354.2559 (Calcd for C22H22N3O: