Asymmetric Alkylation of N-Toluenesulfonylimines with Dialkylzinc Reagents Catalyzed by Copper-Chiral Amidophosphine

Article abstract of DOI:10.1021/jo035234q

The synthetic procedure of a chiral amidophosphine ligand 5 bearing two bulky substituents, 2,4,6-trimethylphenylmethyl or 2,4,6-triisopropylphenylmethyl groups, on the pyrrolidine ring was improved by employing the borane-THF reduction of the lactam-alco

Full text of DOI:10.1021/jo035234q

Asym m etr ic Alk yla tion of N-Tolu en esu lfon ylim in es w ith
Dia lk ylzin c Rea gen ts Ca ta lyzed by Cop p er -Ch ir a l
Am id op h osp h in e
Takahiro Soeta, Kazushige Nagai, Hidetaka Fujihara, Masami Kuriyama, and
Kiyoshi Tomioka*
Graduate School of Pharmaceutical Sciences, Kyoto University, Yoshida, Sakyo-ku,
Kyoto 606-8501, J apan
tomioka@pharm.kyoto-u.ac.jp
Received August 23, 2003
The synthetic procedure of a chiral amidophosphine ligand 5 bearing two bulky substituents, 2,4,6-
trimethylphenylmethyl or 2,4,6-triisopropylphenylmethyl groups, on the pyrrolidine ring was
improved by employing the borane-THF reduction of the lactam-alcohol intermediate 8. The
resulting amino alcohol was selectively acylated to give an amide-alcohol 11, which was then
converted to the chloride 12 in 55-73% yields by the treatment with methanesulfonyl chloride in
collidine. The reaction of the chloride 12 with NaPPh2 in dioxane-THF gave an amidophosphine
5 in an acceptably high 82-83% yields. Addition of a hexane solution of dialkylzinc reagent to a
mixture of catalytic amount of an amidophosphine 5, copper species, and N-toluenesulfonylimine
1a of benzaldehyde in toluene provided a solution which gave the alkylated amide 3 in high yield
and enantioselectivity up to 96%. A survey of copper sources and solvents concluded that copper-
(II) ditriflate and copper(I) triflate-benzene complex as good copper sources and toluene as a choice
of solvent. N-Toluenesulfonylimines 1a -e of arylaldehydes, furfural, and alkanals were successfully
ethylated with diethylzinc to give the corresponding N-toluenesulfonylamides 3a E-eE in satis-
factorily good 69-97% yields and high 86-96% enantioselectivities.
In tr od u ction
stannane or allylsilane,9 and rhodium-MOP-based-phos-
phine-catalyzed arylation with arylstannanes10 showed
The catalytic asymmetric reactions that lead to C-C
bond formation by the addition of organometallic re-
agents to CdN of imines are of fundamental importance
in the continuing development of efficient chemical
synthetic processes.1 Even the reactive organolithium
reagents have been applied into a catalytic asymmetric
addition to CdN of imines by activation with a chiral
amino ether ligand.2-4 Among considerably energetic
approaches toward the catalytic asymmetric addition of
organometallic reagents to CdN of imines,5,6 zinc tri-
flate-chiral amino alcohol-catalyzed acetylide addition,7
chiral amino alcohol-controlled addition of organozinc,8
chiral π-allylpalladium-catalyzed allylation with allyl-
(4) For a catalytic asymmetric reaction of enolate equivalents with
imines, see: (a) Ishihara, K.; Miyata, M.; Hattori, K.; Tada, T.;
Yamamoto, H. J . Am. Chem. Soc. 1994, 116, 10520-10524. (b) Ishitani,
H.; Ueno, M.; Kobayashi, S. J . Am. Chem. Soc. 1997, 119, 7153-7154.
(c) Hagiwara, E.; Fujii, A.; Sodeoka, M. J . Am. Chem. Soc. 1998, 120,
2474-2475. (d) Ferraris, D.; Young, B.; Dudding, T.; Lectka, T. J . Am.
Chem. Soc. 1998, 120, 4548-4549. (e) Yamada, K.; Harwood, S. J .;
Groger, H.; Shibasaki, M. Angew. Chem., Int. Ed. 1999, 38, 3504-
3506. (f) Li, X.; Schenkel, L. B.; Kozlowski, M. C. Org. Lett. 2000, 2,
875-878. (g) Derdau, V.; Snieckus, V. J . Org. Chem. 2001, 66, 1992-
1998. (h) Cordova, A.; Watanabe, S.; Tanaka, F.; Notz, W.; Barbas, C.
F., III. J . Am. Chem. Soc. 2002, 124, 1866-1867. (i) J uhl, K.;
J o¨rgensen, K. A. J . Am. Chem. Soc. 2002, 124, 2420-2421. (j) Bernardi,
L.; Gothelf, A. S.; Hazell, R. G.; J o¨rgensen, K. A. J . Org. Chem. 2003,
68, 2583-2591. (k) Kobayashi, S.; Matsubara, R.; Nakamura, Y.;
Kitagawa, H.; Sugiura, M. J . Am. Chem. Soc. 2003, 125, 2507-2515.
(5) For excellent reviews, see: (a) Denmark, S. E.; Nicaise, O. J .-C.
J . Chem. Soc., Chem. Commun. 1996, 999-1004. (b) Enders, D.;
Reinhold, U. Tetrahedron: Asymmetry 1997, 8, 1895-1946. (c) Bloch,
R. Chem. Rev. 1998, 98, 1407-1438. (d) Arend, M.; Westermann, B.;
Risch, N. Angew. Chem., Int. Ed. 1998, 37, 1044-1070. (e) Kobayashi,
S.; Ishitani, H. Chem. Rev. 1999, 99, 1069-1094.
(1) (a) Tomioka, K. Synthesis 1990, 541-549. (b) Noyori, R. Asym-
metric Catalysis in Organic Synthesis; J ohn Wiley & Sons: New York,
1994. (c) Comprehensive Asymmetric Catalysis; J acobsen, E. N., Pfaltz,
A., Yamamoto, H., Eds.; Springer: Berlin, 1999. (d) Lagasse, F.; Kagan,
H. B. Chem. Pharm. Bull. 2000, 48, 315-324. (e) Iguchi, M.; Yamada,
K.; Tomioka, K. In Organolithiums in Enantioselective Synthesis;
Hodgson, D. M., Ed.; Springer, Berlin, 2003; pp 22-36.
(2) (a) Tomioka, K.; Inoue, I.; Shindo, M.; Koga, K.Tetrahedron Lett.
1990, 31, 6681-6684. (b) Taniyama, D.; Hasegawa, M.: Tomioka, K.
Tetrahedron Lett. 2000, 41, 5533-5536. (c) Hasegawa, M.; Taniyama,
D.; Tomioka, K. Tetrahedron 2000, 56, 10153-10158. (d) Denmark,
S. E.; Stiff, C. M. J . Org. Chem. 2000, 65, 5875-5878.
(3) For a chiral ligand-catalyzed asymmetric addition of lithium
enolates to imines, see: (a) Fujieda, H.; Kanai, M.; Kambara, T.; Iida,
A.; Tomioka, K. J . Am. Chem. Soc. 1997, 119, 2060-2061. (b) Tomioka,
K.; Fujieda, H.; Hayashi, S.; Hussein, M.-A.; Kambara, T.; Nomura,
Y.; Kanai, M.; Koga, K. Chem. Commun. 1999, 715-716. (c) Kambara,
T.; Tomioka, K. J . Org. Chem. 1999, 64, 9282-9285.
(6) For the leading references of chiral ligand-catalyzed asymmetric
addition to imines, see: (d) Itsuno, S.; Yanaka, H.; Hachisuka, C.; Ito,
K. J . Chem. Soc., Perkin Trans. 1 1991, 1341-1342. (e) Katritzky, A.
R.; Harris, P. A. Tetrahedron: Asymmetry 1992, 3, 437-442. (f) Soai,
K.; Hatanaka, T.; Miyazawa, T. J . Chem. Soc., Chem. Commun. 1992,
1097-1098. (g) Nakamura, M.; Hirai, A.; Nakamura, E. J . Am. Chem.
Soc. 1996, 118, 8489-8490. (h) Denmark, S. E.; Stiff, C. M. J . Org.
Chem. 2000, 65, 5875-5878. (i) Ukaji, Y.; Shimizu, Y.; Kenmoku, Y.;
Ahmed, A.; Inomata, K. Bull. Chem. Soc. J pn. 2000, 73, 447-452.
(7) Frantz, D. E.; Fa¨ssler, R.; Carreira, E. M. J . Am. Chem. Soc.
1999, 121, 11245-11246.
(8) J imeno, C.; Reddy, K. S.; Sola`, L.; Moyano, A.; Perica`s, M. A.;
Riera, A. Org. Lett. 2000, 2, 3157-3159.
10.1021/jo035234q CCC: $25.00 © 2003 American Chemical Society
Published on Web 11/15/2003
J . Org. Chem. 2003, 68, 9723-9727
9723

Soeta et al.
SCHEME 1. Asym m etr ic Alk yla tion of N-Su lfon ylim in e 1 w ith Dia lk ylzin c 2 u n d er 5-Cop p er Ca ta lysis
SCHEME 2. Syn th etic Sch em e for 5 fr om 6
impressive success.11 However, undeveloped situation of
the catalytic and efficient asymmetric reaction of simple
alkylmetals12 was in contrast to the chiral amino alcohol-
catalyzed asymmetric alkylation of aldehydes with or-
ganozinc reagents.13 We have previously documented our
observations involving the addition of diethylzinc to CdN
of N-sulfonylimines 1 of arylaldehydes in the presence
of a catalytic amount of copper(II) triflate and a chiral
amidophosphine 5 in a toluene solvent under mild
conditions (0 °C) yielding an ethylation product 3 in high
enantioselectivity (Scheme 1).14 The enantioselectivity
reached to 94% by using the most suitable N-methane-
sulfonylimine 1 (R2 ) Me) and dibenzylamidophosphine
5c (R4 ) Bn). A series of impressive approaches has
followed using catalysts derived from zirconium-pep-
tide,15 copper-oxazoline,16 amino alcohol,17 and copper-
binaphthylthiophosphoramide18 to provide the addition
product with high enantioselectivity.19 In these ap-
proaches, attention has been paid to the removal of the
activating group of the imine functionality. In our ap-
proach, N-methanesulfonylimine 1 (R2 ) Me) was alky-
lated to the N-methanesulfonylamide 3 (R2 ) Me) in
higher enantioselectivity than N-toluenesulfonylimine 1
(R2 ) Tol); however, the removal of a methanesulfonyl
group of 3 by a DIBAL reduction proceeded with a
concomitant partial racemization.14 Since the removal of
a toluenesulfonyl group of 3 was conveniently carried out
without racemization by a samarium iodide treatment
to give the corresponding chiral amine, a chiral ligand 5
was modified to give satisfactorily high enantioselectivity
in the ethylation of N-toluenesulfonylimine 1 (R2 ) Tol).20
We describe herein that further studies including steric
modification of an amidophosphine structure provided a
better catalyst by which alkylation of N-toluenesulfony-
imine 1 (R2 ) Tol) with dimethyl- and diisopropylzinc
reagents gave 3 in high enantioselectivity. Furthermore,
enolizable N-toluenesulfonyimines 1d ,e bearing alkyl
substituents (R1) were successfully alkylated to the
corresponding N-toluenesulfonylamides 3 in high enan-
tioselectivity.
Syn th esis of Ch ir a l Am id op h osp h in e 5. The syn-
thesis of amidophosphines 5d ,e bearing bulky substitu-
ents on the pyrrolidine ring was followed the previously
reported scheme for 5b,c that started from dialkylation
of 6 (Scheme 2).14,21 However, the synthesis of 5d bearing
two mesitylenemethyl groups were needed to be improved
because of the poor 13% yield at the final lactam
reduction and subsequent acylation steps of the phos-
phine 10d .20 The poor efficiency in the final step was
ascribable to the slow reduction of the sterically hindered
lactam carbonyl group of 10d and concomitant oxidation
(9) (a) Nakamura, H.; Nakamura, K.; Yamamoto, Y. J . Am. Chem.
Soc. 1998, 120, 4242-4243. (b) Nakamura, K.; Nakamura, H.; Yama-
moto, Y. J . Org. Chem. 1999, 64, 2614-2615. (c) Bao, M.; Nakamura,
H.; Yamamoto, Y. Tetrahedron Lett. 2000, 41, 131-134.
(10) Hayashi, T.; Ishigedani, M. J . Am. Chem. Soc. 2000, 122, 976-
977.
(11) For asymmetric ene-type addition to imines, see: (a) Drury,
W. J ., III; Ferraris, D.; Cox, C.; Young, B.; Lectka, T. J . Am. Chem.
Soc. 1998, 120, 11006-11007. (b) Martin, S. F.; Lopez, O. D. Tetra-
hedron Lett. 1999, 40, 8949-8953. (c) J ohannsen, M. Chem. Commun.
1999, 2233-2234. (d) Yao, S.; Fang, X.; J orgensen, K. A. Chem.
Commun. 1999, 2547-2548.
(12) Brandt, P.; Hedberg, C.; Lawonn, K.; Pinho, P.; Andersson, P.
G. Chem. Eur. J . 1999, 5, 1692-1699.
(13) (a) Noyori, R.; Kitamura, M. Angew. Chem., Int. Ed Engl. 1991,
30, 49-69. (b) Soai, K.; Shibata, T.; Sato, I. Acc. Chem. Res. 2000, 33,
382-390.
(14) Fujihara, H.; Nagai, K.; Tomioka, K. J . Am. Chem. Soc. 2000,
122, 12055-12056.
(15) A combination of peptidic ligand and zirconium has been proved
as an efficient catalysis in diorganozinc addition to imines. (a) Porter,
J . R.; Traverse, J . F.; Hoveyda, A. H.; Snapper, M. L. J . Am. Chem.
Soc. 2001, 123, 984-985. (b) Porter, J . R.; Traverse, J . F.; Hoveyda,
A. H.; Snapper, M. L. J . Am. Chem. Soc. 2001, 123, 10409-10410.
(16) Copper catalysis: Wei, C.; Li, C.-J . J . Am. Chem. Soc. 2002,
124, 5638-5639.
(17) Amino alcohol catalysis: (a) ref 8. (b) Hermanns, H.; Dahmen,
S.; Bolm, C.; Brase, S. Angew. Chem., Int. Ed. 2002, 41, 3692-3694.
(c) Dahmen, S.; Brase, S. J . Am. Chem. Soc. 2002, 124, 5940-5941.
(d) Zhang, H.-L.; Zhang, X.-M.; Gong, L.-Z.; Mi, A.-Q.; Cui, X.; J iang,
Y.-Z.; Choi, M. C. K.; Chan, A. S. C. Org. Lett. 2002, 4, 1399-1402. (e)
Zhang, X.-M.; Zhang, H.-L.; Lin, W.-Q.; Gong, L.-Z.; Mi, A.-Q.; Cui, X.;
J iang, Y.-Z.; Yu, K.-B. J . Org. Chem. 2003, 68, 4322-4329.
(18) Wang, C.-J .; Shi, W. J . Org. Chem. 2003, 68, ASAP.
(19) Koradin, C.; Polborn, K.; Knochel, P. Angew. Chem., Int. Ed.
Engl. 2002, 41, 2535-2538.
(20) Nagai, K.; Fujihara, H.; Kuriyama, M.; Yamada, K.; Tomioka,
K. Chem. Lett. 2002, 8-9.
(21) For the consecutive dialkylation, see: Tomioka, K.; Cho, Y.-S.;
Sato, F.; Koga, K. J . Org. Chem. 1988, 53, 4094-4098.
9724 J . Org. Chem., Vol. 68, No. 25, 2003

Asymmetric Alkylation of N-Toluenesulfonylimines
TABLE 1. Alk yla tion of N-su lfon yla ld im in es 1A,A′ of Ben za ld eh yd e w ith Dia lk ylzin c Rea gen ts 2 Ca ta lyzed by
Cu -a m id op h osp h in esa
1a ,a ′
2
5
CuX
3
4
entry
R2
R3
Et
Et
Et
Et
Et
Et
Et
Me
Me
Me
Me
Me
Me
Me
i-Pr
i-Pr
equiv
a -e
mol %
mol %
T/°C
time/h
yield/%
ee/%
yield/%
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
Tol
Tol
Tol
Tol
Tol
Tol
Tol
Tol
Tol
Me
Me
Me
Tol
Tol
Tol
Tol
3
3
2
2
2
2
2
2
15
30
15
8
8
8
a
b
c
d
d
e
e
d
d
d
d
e
e
e
d
e
1.3
1.3
1.3
1.3
6.5
6.5
19.5
6.5
19.5
6.5
22.5
22.5
19.5
19.5
19.5
19.5
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
(CuOTf)2-PhH
Cu(OTf)2
(CuOTf)2-PhH
(CuOTf)2-PhH
(CuOTf)2-PhH
Cu(OTf)2
1
1
1
1
5
0
0
0
0
0
0
0
rt
rt
rt
rt
rt
rt
rt
0
4
5
5
3
5
3a E
3a E
3a E
3a E
3a E
3a E
3a E
3a M
3a M
3a ′M
3a ′M
3a ′M
3a M
3a M
3a P
79
79
94
93
97
96
99
5b
39
62
95
96
97
96
79
92
63
79
90
95
96
88
93
12
82
81
85
86
87
86
71
78
20
15
<1
<1
<1
<1
<1
nd
nd
nd
nd
nd
<1
<1
10
5
5
4
2
15
2.5
15
2.5
7.5
7.5
15
7.5
7.5
15
23
20
19
19
20
20
17
1
Cu(OTf)2
(CuOTf)2-PhH
Cu(OTf)2
2
2
0
2
3a P
a
b
The results of entries 1-3 were referenced from ref 14. nd: not determined. The imine 1a was recovered as a major product.
SCHEME 3. Im p r oved Syn th etic Sch em e for 5d ,e
fr om 8
mol % (1.3 equiv to copper) of 5d in a toluene solvent, a
small amount of a brown gum precipitated. Further
addition of a toluene solution of 1a (R1 ) Ph, R2 ) Tol)
and stirring at 0 °C for 2 h afforded (S)-3a E23,24 (R1 )
Ph, R2 ) Tol, R3 ) Et) in 93% ee and 96% yield.
Ultrasonication of the reaction did not affect the gummy
precipitate, giving the same level of yield and enantio-
selectivity. Finally, we found that addition of diethylzinc
solution to a mixture of copper(II) triflate, 5d , and 1a in
toluene formed an almost clear solution without gummy
precipitate, and stirring of the mixture at 0 °C for 3 h
gave 3a E in an improved 95% ee and 93% yield (Table
1, entry 4). The 5 mol % catalyst loading gave 3a E in
96% ee and 97% yield, comparable to the 1 mol % catalyst
(entry 5).
The catalytic efficiency of 5a -d -copper(II) complex is
highly dependent on the bulkiness of the substituents on
the pyrrolidine ring of 5; that is, the more bulky is, the
more efficient (entries 1-4). The poorer catalytic perfor-
mance yielded a greater amount of the reduction product
4, arising from direct reduction with diethylzinc. The
efficiency of 5e bearing the bulkiest triisopropylphenyl-
methyl group unfortunately did not exceed 5d , giving
3a E in 88% ee at the 5 mol % catalyst loading (entry 6).
The selectivity was improved upon loading 15 mol %
catalyst, giving 3a E quantitatively in 93% ee (entry 7).
The bulkiness of 5e should interfere the formation of the
reactive complex of copper-ligand-diethylzinc reagent
with imine 1a . The reaction of the less reactive dimeth-
ylzinc provided a good chance to bring 5e’s ability into
full play.
of the phosphorus moiety to its oxide. Fortunately, the
borane reduction of the lactam-alcohol 8d followed by
acylation successfully provided 11d in 73% yield (Scheme
3).22 The amidophosphine 5d was obtained in 82% yield
via chloride 12d . This synthetic scheme was beneficial
in the preparation of 5e bearing a more bulky triisopro-
pylphenylmethyl group, giving 5e in 45% from 8e.
Rea ction P r oced u r e a n d Ap p lica bility of Dia lk yl-
zin c Rea gen ts. Addition of a toluene solution of a chiral
amidophosphine ligand 5 to a suspension of copper(II)
ditriflate in toluene afforded a solution, indicating forma-
tion of a 5-copper(II) complex that is soluble in toluene.
Upon further addition of a hexane solution of diethylzinc
into a solution of 1 mol % of copper(II) triflate and 1.3
The methylation of 1a with dimethylzinc 2M (R3 ) Me)
was slow at room temperature to give 3a M (R3 ) Me) in
(23) The first
a and second M of 3a M refer to 1a and 2M,
respectively. For example, 3a M comes from 1a and 2M.
(24) Raban, M.; Moulin, C. P.; Lauderback, S. K.; Swilley, B.
Tetrahedron Lett. 1984, 25, 3419-3422.
(22) The borane reduction of 10d was not successful.
J . Org. Chem, Vol. 68, No. 25, 2003 9725

Soeta et al.
TABLE 2. Eth yla tion of N-Tosylim in e 1a of
(entry 11). The use of 5e was beneficial in methylation
giving (S)-(-)-3a M27 with 87% ee in nearly quantitative
yield irrespective to methanesulfonyl or toluenesul-
fonylimine 1a (entries 12-14). An isopropylation of 1a
(R2 ) Tol) with 2 equiv of diisopropylzinc was catalyzed
by 5e giving (S)-3a P (R2 ) i-Pr)27 in 92% yield and 78%
ee (entries 15 and 16).
Ben za ld eh yd e w ith Cop p er Ca ta lysts
3a E
4
Since the copper source and solvent influence the
efficiency of the reaction,28 we examined the reaction for
formation of 3a E using different copper salts and sol-
vents. Although copper(II) ditriflate gave the best ef-
ficiency (Table 2, entry 1), copper(I) triflate-benzene
complex was the most active catalyst that brought the
reaction to completion within 0.5 h, giving 3a E with 90%
ee (entry 2). Other copper carboxylates, oxide, cyanide,
and halides were the not choice of copper source (entries
3-10), while dimethyl sulfide complexes of copper chlo-
ride and bromide were better copper sources, giving 3a E
in relatively high yields and moderate enantioselectivities
(entries 11-13). It is important to note that copper(II)
triflate was purified through dissolution in acetonitrile
and then precipitation upon addition of ether.29 Direct
use of commercial copper salt without purification af-
forded 3a E in 21% ee and 97% yield.
entry
CuX
Cu(OTf)2
(CuOTf)2-PhH
Cu(naphthenate)2
Cu(OAc)2-H2O
CuTCa
Cu(O2CCPh3)2
CuCN
Cu2O
CuCl
CuI
CuCl-SMe2
CuBr-SMe2
CuI-SMe2
time/h yield/% ee/% yield/%
1
2
3
4
5
6
7
8
9
10
11
12
13
5
97
95
82
86
80
19
40
30
81
16
85
47
65
96
90
19
17
18
0
<1
<1
10
8
0.5
22
12
24
24
24
21
20
16
20
24
20
9
25
12
11
4
15
5
1
0
35
2
48
45
20
6
8
a
CuTC ) copper(I) thiophene-2-carboxylate.
TABLE 3. Solven t In flu en ce on Efficien cy
Toluene was the first choice of solvent followed by
cyclopentyl methyl ether30 in which 3 was obtained in
83% yield and 84% ee (Table 3, entries 1 and 2). Other
solvents were not the choice, especially acetonitrile in
which 3a E was obtained as a racemate, probably due to
the activation of diethylzinc by the high polarity of
acetonitrile (entry 6). Poor efficiency in ether and THF
solvents is attributable to coordination of etheral oxygen
to zinc, which interferes with coordination of zinc to the
amide carbonyl oxygen of 5 (entries 3 and 4).31,32
entry
solvent
toluene
c-C5H9OMe
Et2O
THF
CH2Cl2
MeCN
time/h
yield/%
ee/%
1
2
3
4
5
6
5
2
18
18
20
17
97
83
53
39
68
48
96
84
40
17
19
0
The reaction of diethylzinc under the catalysis of
copper(II) ditriflate 5d in toluene was successfully ap-
plied to the ethylation of a variety type of N-toluene-
sulfonylimines 1b-e33 (R2 ) Tol) of 4-methoxybenzalde-
hyde, 2-furfural, cyclohexanecarbaldehyde, and also
3-phenylpropanal, giving the corresponding products in
high yield and enantioselectivity (Table 4). It is notewor-
thy that enolizable imines 1d ,e (R1 ) c-hex, Ph(CH2)2,
entries 4 and 5) were successfully ethylated without
enolization, giving the corresponding products 3d E-eE
in reasonably high enantioselectivities and yields.
5% yield and 12% ee (entry 8). The attempted reaction
of 1a in a THF solvent gave the corresponding THF
adduct of 1a in high yield, which arises from the addition
of a THF radical.25 The improvement was observed by
using 15 equiv of dimethylzinc under 15 mol % of the
catalyst, giving 3a M in 39% yield and 82% ee (entry 9).
The more reactive methanesulfonylimine 1a ′ (R2 ) Me)
was converted to 3a ′M26 in 62% and 81% ee (entry 10).
The conversion was improved by using 15 mol % loading
of the catalyst to afford 3a ′M in 95% yield and 85% ee
TABLE 4. Eth yla tion of N-Tolu en esu lfon yla ld im in es 1a -e w ith Dieth ylzin c 2E Ca ta lyzed by Cu (OTf)2-5d
1
5d
3
4
entry
R1
mol %
Cu(OTf)2/mol %
time/h
yield/%
ee/%
yield/%
1
2
3
4
5
a
b
c
d
e
Ph
6.5
1.3
1.3
6.5
6.5
5
1
1
5
5
5
12
1
1
3
3a E
3bE
3cE
3d E
3eE
97
78
96
84
69
96
86
91
96
93
4a
4b
4c
4d
4e
<1
18
2
nda
nda
4-MeOC6H4
2-furyl
c-C6H11
Ph(CH2)2
a
nd: not determined.
9726 J . Org. Chem., Vol. 68, No. 25, 2003

Asymmetric Alkylation of N-Toluenesulfonylimines
Con clu sion
level. Since the toluenesulfonyl activating group of imines
is easily removable from the product amide 3 by a
samarium iodide treatment, the procedure is applicable
to the synthesis of chiral amines. Furthermore, the
reaction was shown to be applicable to the enolizable
imines of alkanals, which provide an advantage over the
previous alkylation methodology with organolithium
reagents.
Steric tuning of a chiral amidophosphine ligand 5 and
optimization of the reaction procedure led to the copper-
catalyzed asymmetric alkylation of N-toluenesul-
fonylimines 1 with dialkylzincs in a satisfactorily high
(25) (a) Yamada, K.; Fujihara, H.; Yamamoto, Y.; Miwa, Y.; Taga,
T.; Tomioka, K.Org. Lett. 2002, 4, 3509-3511. (b) Yamada, K.;
Yamamoto, Y.; Tomioka, K. Org. Lett. 2003, 5, 1797-1799.
(26) The absolute configurations of 3, except for 3a E, 3a M, and 3a P ,
were assigned as shown in the schemes based on the reaction analogy.
(27) Annunziata, R.; Cinquini, M.; Cozzi, F. J . Chem. Soc., Perkin
Trans. 1 1982, 339-343.
Ack n ow led gm en t. This research was partially sup-
ported by the 21st Century COE (Center of excellence)
Program “Knowledge Information Infrastructure for
Genome Science” and a Grant-in-Aid for Scientific
Research on Priority Areas (A) “Exploitation of Multi-
Element Cyclic Molecules” from the Ministry of Educa-
tion, Culture, Sports, Science and Technology, J apan.
M.K. was supported by a fellowship from the J SPS.
(28) Alexakis, A.; Benhaim, C.; Rosset, S.; Humam, M. J . Am. Chem.
Soc. 2002, 124, 5262-5263.
(29) Some of the copper salts were prepared or were purified
according to the reported procedure. (CuOTf)2-PhH: Salomon, R. G.;
Kochi, J . K. J . Am. Chem. Soc. 1973, 95, 1889-1897. CuTC (copper(I)
thiophene-2-carboxylate) and Cu(O2CCPh3)2: Allerd, G. D.; Liebeskind,
L. S. J . Am. Chem. Soc. 1996, 118, 2748-2749. CuCl-SMe2, CuBr-
SMe2 and CuI-SMe2: House, H. O.; Chu, C. Y.; Wilkins, J . M.; Umen,
M. J . J . Org. Chem. 1975, 40, 1460-1469. Cu(OAc)2-H2O, Cu(OTf)2,
CuCN, CuCl, and CuI: Armarego, W. L. F.; Chai, C. L. L. In
Purification of Laboratory Chemicals, 5th ed.; Butterworth Heine-
mann: Amsterdam, 2003; pp 414-416. Cu(naphthenate)2 and Cu2O
were used without purification as obtained commercially.
(30) We are grateful for the generous gift from Nihon Zeon Ltd.
(31) (a) Nakagawa, Y.; Kanai, M.; Nagaoka, Y.; Tomioka, K.
Tetrahedron 1998, 54, 10295-10307. (b) Kuriyama, M.; Nagai, K.;
Yamada, K.; Miwa, Y.; Taga, T.; Tomioka, K. J . Am. Chem. Soc. 2002,
124, 8932-8939.
Su p p or tin g In for m a tion Ava ila ble: General experimen-
tal procedure and spectroscopic data for the products. This
material is available free of charge via the Internet at
http://pubs.acs.org.
J O035234Q
(33) (a) Love, B. E.; Raje, P. S.; Williams, T. C., II. Synlett 1994,
493-494. (b) Chemla, F.; Hebbe, V.; Normant, J . F. Synthesis 2000,
75-77.
(32) The sterically hindered oxygen of cyclopentyl methyl ether may
disturb its coordination to zinc.
J . Org. Chem, Vol. 68, No. 25, 2003 9727