Selective diethylzinc reduction of imines in the presence of ketones catalyzed by Ni(acac)2

Article abstract of DOI:10.1021/ol052628q

(Chemical Equation Presented) A selective reduction method of an electronically deficient imine in the presence of ketone was developed by employing Et₂Zn and 5 mol % of Ni(acac)₂. The method was applied in the reduction of S_S-tert-butanesulfinyl ketimines 1 to afford amines 2 in 23-92% yields and 73:27 to 98:2 diastereoselectivities. A plausible mechanism was proposed on the basis of an NMR study.

Full text of DOI:10.1021/ol052628q

ORGANIC
LETTERS
2006
Vol. 8, No. 1
139-142
Selective Diethylzinc Reduction of
Imines in the Presence of Ketones
Catalyzed by Ni(acac)2
Xue Xiao, Haowei Wang, Zhiyan Huang, Jun Yang, Xiaoxia Bian, and Yong Qin*
Department of Chemistry of Medicinal Natural Products, West China School of
Pharmacy, Sichuan UniVersity, Chendu 610041, P. R. China
yanshuqin@yahoo.com
Received October 28, 2005
ABSTRACT
A selective reduction method of an electronically deficient imine in the presence of ketone was developed by employing Et2Zn and 5 mol %
of Ni(acac)2. The method was applied in the reduction of SS-tert-butanesulfinyl ketimines 1 to afford amines 2 in 23
98:2 diastereoselectivities. A plausible mechanism was proposed on the basis of an NMR study.
−92% yields and 73:27 to
The amine functional group is widely present in bioactive
natural products and many pharmaceutically important
substances. A large number of methods have been developed
to prepare amine. The most used method is the reduction of
imine by commonly used reductants such as DIBAL, LiAiH4,
NaBH4, BH3, and 9-BBN.1 Although high yields were
achieved in the reduction of imines, those reductants were
not compatible with a variety of functional groups such as
ketones, esters, and nitriles. In this letter, we report an
effective reduction of imines by employing diethylzinc as a
reductant in the presence of a catalytic amount of Ni(acac)2
(Scheme 1) as an important complement to imine reduction
protocols.
diethylzinc to imine has proved to be difficult without the
aid of a ligand;3 sometimes, additional metal salts were also
necessary for a successful addition.4 In Hoveyda’s study of
diethylzinc addition to o-anisidyl imines catalyzed by dipep-
tide and Zr(OiPr)4, variable amounts of the reduction product
were observed along with the addition product.4d During the
course of our study to screen metal salts for catalyzing
diethylzinc addition to phenyl methyl tert-butanesulfinyl
ketimine 1a,5 we found that the ketimine 1a was predomi-
nantly reduced to provide sulfonamide 2a as a mixture of
two diastereoisomers with 5 equiv of Et2Zn in the presence
of 5 mol % of Ni(acac)2 in CH2Cl2 at room temperature.6
(2) For reviews on asymmetric addition to imines, see: (a) Ding, H.;
Friestad, G. K. Synthesis 2005, 2815. (b) Kobayashi, S.; Ishitani, H. Chem.
ReV. 1999, 99, 1069.
(3) For ligand-aided dialkylzinc addition to imines, see: (a) Jiang, B.;
Si, Y. Angew Chem., Int. Ed. 2004, 43, 216. (b) Keith, J.; Jacobsen, E. N.
Org. Lett. 2004, 6, 153. (c) Wang, Ch.-J.; Shi, M. J. Org. Chem. 2003, 68,
6229. (d) Soeta, T.; Nagai, K.; Fujihara, H.; Kuriyama, M.; Tomioka, K. J.
Org. Chem. 2003, 68, 9723. (e) Zhang, X.-M.; Zhang, H.-L.; Lin, W.-Q.;
Gong, L.-Zh.; Mi, A.-Q.; Cui, X.; Jiang, Y.-Zh.; Yu, K.-B. J. Org. Chem.
2003, 68, 4322. (f) Dahmen, S.; Brase, S. J. Am. Chem. Soc. 2002, 124,
5940. (g) Fujihara, H.; Nagai, K.; Tomioka, K. J. Am. Chem. Soc. 2000,
122, 12055. (h) Jimeno, C.; Reddy, K. S.; Sola, L.; Moyano, A.; Pericas,
M. A.; Riera, A. Org. Lett. 2000, 2, 3157.
(4) (a) Boezio, A. A.; Charette, A. B. J. Am. Chem. Soc. 2003, 125 1692.
(b) Boezio, A. A.; Pytkowicz, J.; Cote, A.; Charette, A. J. Am. Chem. Soc.
2003, 125, 14260. (c) Porter, J. R.; Traverse, J. F.; Hoveyda, A. H.; Snapper,
M. L. J. Am. Chem. Soc. 2001, 123, 10409. (d) Porter, J. R.; Traverse, J.
F.; Hoveyda, A. H.; Snapper, M. L. J. Am. Chem. Soc. 2001, 123, 984.
Scheme 1
Although the CdN double bond of an imine is potentially
susceptible to attack of alkylmetals,2 direct addition of
(1) Larock, R. C. ComprehensiVe Organic Transformations; Wiley-
VCH: New York, 1999 and references therein.
10.1021/ol052628q CCC: $33.50
© 2006 American Chemical Society
Published on Web 12/01/2005

This unexpected observation encouraged us to investigate
the details of Ni(acac)2-catalyzed diethylzinc reduction of
ketimine 1 and general imines.
Initially, the effect of a variety of solvents on the reduction
of racemic 1a by Et2Zn was investigated in the presence of
5 mol % of Ni(acac)2 at room temperature. As shown in
Table 1, the reduction of 1a with 5 equiv of Et2Zn proceeded
solvent, while toluene gave a high yield (Table 1, entries 5
and 6). Ethereal solvents were the best choice of solvents;
the reduction of 1a afforded 2a in high yields (Table 1,
entries 7-11). Notably, among the tested ethereal solvents,
dioxane generated the strongest reducing system, and the
reduction of 1a was completed within 0.5 h to give 2a in
89% yield. Further screening the quantity of Et2Zn needed
in the reduction reaction in dioxane, we found that 3 equiv
of Et2Zn was enough to drive the reaction to completion
(Table 1, entries 11-15).
Table 1. Reduction of 1a by Diethylzinc and Catalytic
The effects of solvents and temperature on the diastereo-
slectivity of reduction reaction were studied using enan-
tiopure phenylmethyl ketimine SS-1a as a substrate. As shown
in Table 2, a similar diastereoselectivity of around 96:4 was
Ni(acac)2
Table 2. Reduction of Ketimine SS-1 by Diethylzinc in the
Presence of 5 mol % of Ni(acac)2
entry
solvent
CH2Cl2
Et2Zn (equiv) time (h) yielda (%)
a
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
5
5
5
5
5
5
5
5
5
5
5
4
3
2
1
24
24
42
63
dichloroethane
b
CHCl3
CCl4
b
CH3CN
toluene
DME
iPr2O
Et2O
8
10
6
6
10
10
52
89
79
85
91
89
89
87
88
82
71
entry
1
R1
R2 solvent yieldb (%) dr and configc
1
2
3
4f
1a Ph
1a Ph
1a Ph
1a Ph
Me toluene
Me Et2O
Me THF
Me THF
Me THF
Me THF
Me dioxane
87
90
89
84
81
9
88
92
90
82
23
88
71
81
95:5 (S)d
96:4 (S)d
96:4 (S)d
96:4 (S)d
96:4 (S)d
THF
dioxane
dioxane
dioxane
dioxane
dioxane
0.5
0.5
0.5
1
5g 1a Ph
6h 1a Ph
7
8
9
10
11
12
13
14
1a Ph
96:4 (S)d
98:2 (S)d
89:11 (S)d
85:15 (S)e
96:4 (R)d
73:27 (S)d
82:18 (S)e
95:5 (R)d
20
1b 4-MeO-Ph Me dioxane
a Isolated yields. b A dark precipitate was formed.
1c Ph
1d Ph
1e Ph
1f Pr
1g iPr
1h iBu
Et dioxane
iPr dioxane
tBu dioxane
Me dioxane
Me dioxane
Me dioxane
slowly to give moderate yield when halogenated solvents
such as CH2Cl2 and CH2ClCH2Cl were used (Table 1, entries
1 and 2). Since a dark precipitate was formed immediately
after the injection of diethylzinc into the mixture of 1a and
Ni(acac)2 in CHCl3 or CCl4, CHCl3 and CCl4 were not
suitable for this reaction (Table 1, entries 3 and 4). Aceto-
nitrile did not improve the yield compared with halogenated
a Reactions were conducted at room temperature with 3 equiv of Et2Zn
and 5 mol % of Ni(acac)2. b Isolated yield. c Absolute configuration of amine
was determined by comparing rotation with that of known amine after
removing the tert-butanesulfinyl group of 2. d Diastereomeric ratio was
1
determined by HPLC. e Diastereomeric ratio was determined by H NMR
of the crude product. f At 0 °C. g At -20 °C. h At -45 °C.
(5) For reviews on chiral sulfinylimine chemistry, see: (a) Zhou, P.;
Chen, B.-C.; Davis, F. A. Tetrahedron 2004, 60, 8003. (b) Ellman, J. A.;
Owens, T. D. Pure Appl. Chem. 2003, 75, 39. (c) Ellman, J. A.; Owens, T.
D.; Tang, T. P. Acc. Chem. Res. 2002, 35, 984. (d) Davis, F. A.; Zhou, P.;
Chen, B.-C. Chem. Soc. ReV. 1998, 27, 13.
observed either using toluene or ethereal solvents (Table 2,
entries 1-3 and 7). We had tested the reduction of SS-1a at
different temperatures such as 25, 0, -20, and -45 °C,
respectively, in THF (Table 2, entries 3-6). The results
indicated that lowering the temperature did not improve the
diastereoselectivity but dramatically decreased the reductant
capability of Et2Zn to SS-1a.
(6) A mixture of dialkylzinc with a catalytic amount of nickel has been
known to be an effective reagent for the alkylative carboxylation of alkynes
for the intramolecular cyclization of allenyl aldehyde, homoallylation of
aldehyde and aldimines with 1,3-dienes and with alkeyne, selective addition
of cyclic anhydrides, Reformatsky-type imine addition, and conjugate aldol
addtion; see: (a) Bercot, E. A.; Rovis, T. J. Am. Chem. Soc. 2005, 127,
247. (b) Kimura, M.; Miyachi, A.; Kojima, K.; Tanaka, Sh.; Tamaru, Y. J.
Am. Chem. Soc. 2004, 126, 14360. (c) Adrian, J. C., Jr.; Snapper, M. L. J.
Org. Chem. 2003, 68, 2143. (d) Montgomery, J.; Subburaj, K. J. Am. Chem.
Soc. 2003, 125, 11210. (e) Montgomery, J.; Lozanov, M. J. Am. Chem.
Soc. 2002, 124, 2106. (f) Montgomery, J.; Song, M. Org. Lett. 2002, 4,
4009. (g) Loh, T.-P.; Song, H.-Y.; Zhou, Y. Org. Lett. 2002, 4, 2715. (h)
Bercot, E. A.; Rovis, T. J. Am. Chem. Soc. 2002, 124, 174. (i) Takimoto,
M.; Shimizu, K.; Mori, M. Org. Lett. 2001, 3, 3345. (j) Kimura, M.;
Fujimatsu, H.; Ezoe, A.; Shibata, K.; Shimizu, M.; Matsumoto, S.; Tamaru,
Y. Angew. Chem., Int. Ed. 1999, 38, 8, 397. (k) Oblinger, E.; Montgomery,
J. J. Am. Chem. Soc. 1997, 119, 9065.
Since dioxane could generate the most powerful reduction
system, studies of dialkylzinc reduction to a variety of
enantiopure ketimines SS-1 were conducted in dioxane at
room temperature using 3 equiv of Et2Zn and 5 mol % of
Ni(acac)2.7 As shown in Table 2, for both aryl alkyl ketimines
and dialkyl ketimines, the dialkylzinc reduction of SS-1 was
completed within 1 h to afford SS-2 in high yields and
140
Org. Lett., Vol. 8, No. 1, 2006

moderate to high diastereoselectivities (Table 2, entries
7-14). The exception was the reduction with sterically
hindered phenyl tert-butyl ketimine 1e, where the reduction
was very sluggish to yield 2e in a low yield (Table 2, entry
11). The reductions with aromatic ketimines usually provided
higher diastereoselectivity than the reduction with aliphatic
ketimines.
of Et2Zn, 5 mol % of Ni(acac)2 in dioxane), reduction of a
1:1 mixture of SS-1a and acetophenone 5 (1 equiv) afforded
SS-2a in 88% yield, ketone 5 totally remained unchanged as
shown by HPLC analysis of the crude product (Figure 1, eq
The applicable scope of Ni(acac)2-catalyzed diethylzinc
reduction to both electronically deficient and electronically
rich imine8 was then tested. As shown in Table 3, reduction
Table 3. Reduction of Imine 3 by Diethylzinc in the Presence
a
of 5 mol % of Ni(acac)2
entry
3
R1
R2
R3
yield of 4b (%)
1
2
3
4
5
6
7
3a
3b
3c
3d
3e
3f
Ph
Ph
Ph
Ph
Pr
H
Ts
Ts
Ts
tBuSO2
tBuSO2
tBuSO2
Ph
4a (83)
4b (78)
4c (92)
4d (88)
4e (19)
4f (22)
4g (0)
Me
Ph
Et
Me
Me
Me
Figure 1.
iBu
Ph
1). Reduction of a 1:1 mixture of SS-1h and isobutyl methyl
ketone 7 gave SS-2h in 80% yield, and ketone 7 completely
survived the reaction as shown by GC analysis of the crude
product (Figure 1, eq 2). Similarly, N-Ts imine 3b was
reduced to afford 4b in 78% yield without affecting the
acetophenone 5 under the same conditions (Figure 1, eq 3).
3g
a Reactions were conducted at room temperature with 3 equiv of Et2Zn
and 5 mol % of Ni(acac)2. b Isolated yield.
of electronically deficient aromatic imines 3a-d with 3 equiv
of Et2Zn and 5 mol % of Ni(acac)2 in dioxane gave amines
4a-d in high yields (Table 3, entries 1-4), while the
reduction of aliphatic imines 3e-f under the same conditions
gave poor yields (Table 3, entries 5-6). In contrast to the
reduction of electronically deficient imines, the reduction of
electronically rich imine 3g was unsuccessful (Table 3, entry
7).
It was interesting to know whether the selective reduction
of imine in the presence of ketone could be achieved by
employing the current reduction method, since selective
reduction between imine and ketone was always problematic
using common reductants such as DIBAL, LiAiH4, NaBH4,
BH3, and 9-BBN. Three competitive reactions were designed
to test the possibility. Thus, under our best condition (3 equiv
(7) The diastereoselective reduction of tert-butanesulfinyl ketimines by
Ti(OiPr)4-mediated NaBH4 was reported by Ellman; see: Borg, G.; Cogan,
D. A.; Ellman, J. A. Tetrahedron Lett. 1999, 40, 6709.
(8) For the preparation of N-sulfonyl imines, see: (a) Ruano, J. L. J.;
Aleman, J.; Cid, M. B.; Parra, A. Org. Lett. 2005, 7, 179. (b) Jin, T.; Feng,
G.; Yang, M.; Li, T. Synth. Commun. 2004, 34, 1277. (c) Wolf, J.; Ney, J.
E. Org. Lett. 2003, 5, 4607. (d) Lee, K. Y.; Lee, C. C.; Kim, J. N.
Tetrahedron Lett. 2003, 44, 1231. (e) Ram, R. N.; Khan, A. A. Synth.
Commun. 2001, 31, 841. (f) Chemla, F.; Hebbe, V.; Notmant, J.-F. Synthesis
2000, 11, 75. (g) Sandrinelli, F.; Perrio, S.; Belsin, P. J. Org. Chem. 1997,
62, 8626. (h) Georg, G. I.; Harriman, G. B.; Peterson, S. A. J. Org. Chem.
1995, 60, 7366. (i) Boger, D. L.; Corbett, W. L. J. Org. Chem. 1992, 57,
4777. (j) Trost, B. M.; Christopher, M. J. Org. Chem. 1991, 56, 6468. (k)
Jennings, W. B.; Lovely, C. J. Tetrahedron 1991, 47, 5561. (l) Davis, F.
A.; Lamendola, J., Jr.; Nadir, U.; Kluger, E. W.; Sedergran, T. C.; Panunto,
T. W.; Billmers, R.; Jenkins, R., Jr.; Turchi, I. J.; Watson, W. H.; Chen, J.
S.; Kimura, M. J. Am. Chem. Soc. 1980, 102, 2000.
Figure 2.
Org. Lett., Vol. 8, No. 1, 2006
141

gradual consumption of SS-1c during the reaction. The
methylene proton peak of SS-1c disappeared when the
reaction was completed at 8 h after adding Ni(acac)2 (Figure
2, spectrum e).
Based on the NMR study of the reduction reaction, a
plausible mechanism is suggested for the Ni(acac)2-catalyzed
diethylzinc reduction of imines (Figure 3).
Ni(II) is first reduced by diethylzinc to give Ni(0) as a
catalytically active species. The resulting Ni(0) coordinates
to the CdN double bond of imine 1 with the aid of solvent
to form a complex 9. Transmetalation of 9 with Et2Zn affords
the ethyl nickel complex 10. â-Hydrogen elimination of ethyl
in 10 releases elthylene to form hydride nickel complex 11.
Reductive elimination of Ni(0) provides intermediate 12 and
releases Ni(0) to complete one catalytic cycle.
In summary, we have described a highly efficient reduction
method to reduce tert-butanesulfinyl ketimines in moderate
to high yields and diastereoselectivityies by employing Et2-
Zn and a catalytic amount of Ni(acac)2. This method can be
expanded to the reduction of electronically deficient imines.
The remarkable aspect of this method is that the imine
reduction can be achieved in the presence of ketone, which
is an important complement to known methods. Further study
will be focused on the application of current method in
asymmetric reduction of achiral imines catalyzed by a chiral
nickel complex.
Figure 3. Plausible mechanism of Et2Zn reduction of imine
catalyzed by Ni(acac)2.
To understand the reaction mechanism, we had conducted
the reduction of SS-1c in an NMR tube in toluene-d8 at room
temperature. The reaction procedure was tracked by measur-
1
ing H NMR signals corresponding to the constituents of
1
reaction mixture. The H NMR spectra truncated between
2.0 and 6.0 ppm are compiled in Figure 2. When ketimine
SS-1c was mixed with Et2Zn in the absence of Ni(acac)2 for
2 h, we did not observe any change of the 1H NMR spectrum
of reaction mixture (Figure 2, spectrum a). Once the Ni-
(acac)2 (5 mol %) was added into the reaction mixture, the
NMR tube was then sealed to record the 1H NMR spectra at
different times. As shown in spectrum b of Figure 2, only a
trace amount of ethylene was detected at 5.28 ppm at 5 min
after adding Ni(acac)2. With the reaction proceeding smoothly,
more ethylene was released into the reaction mixture. As a
result, the peak at 5.28 ppm ascribed to ethylene proton
became a major peak (Figure 2, spectra c and d). At the
same time, an apparent shrinking of the methylene proton
peak of SS-1c at 3.05 ppm occurred, which indicated the
Acknowledgment. We gratefully acknowledge financial
support from the National Natural Science Foundation of
China (Nos. 20372048 and 20572072), Ministry of Education
(NCET, RFDP, and EYTP), and Sichuan Province Govern-
ment (No. 04ZQ026-011).
Supporting Information Available: Experimental de-
tails, spectra data of of compounds 2 and 4, and GC and
HPLC analysis data. This material is available free of charge
via the Internet at http://pubs.acs.org.
OL052628Q
142
Org. Lett., Vol. 8, No. 1, 2006