Trisoxazoline/Cu(II)-promoted Kinugasa reaction. Enantioselective synthesis of β-lactams

Article abstract of DOI:10.1021/jo0602874

The reactions of nitrones with terminal alkynes, catalyzed by chiral _iPr-trisoxazoline 23/Cu(ClO₄)₂·6H ₂O under air atmosphere, afforded β-lactams in moderate to good yields with up to 85% ee. The diastereoselec

Full text of DOI:10.1021/jo0602874

Trisoxazoline/Cu(II)-Promoted Kinugasa Reaction.
Enantioselective Synthesis of â-Lactams
Meng-Chun Ye, Jian Zhou, and Yong Tang*
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry,
354 Fenglin Road, Shanghai 200032, China
tangy@mail.sioc.ac.cn
ReceiVed February 11, 2006
The reactions of nitrones with terminal alkynes, catalyzed by chiral iPr-trisoxazoline 2a/Cu(ClO4)2‚6H2O
under air atmosphere, afforded â-lactams in moderate to good yields with up to 85% ee. The
diastereoselectivity depends on the alkyne. Propiolate gives the trans-isomer as a major product, while
the other alkynes afford cis-disubstituted lactams predominantly. Copper(II) salt proved to be an efficient
catalyst precursor for the first time in the Kinugasa reaction, and this allowed the reaction to be performed
under a practical and convenient condition. An appropriate base used in this reaction was essential to
control both diastereoselectivity and enantioselectivity. Compared with primary and tertiary amines,
secondary amines gave higher enantioselectivities. The reaction scope and limitation as well as the
mechanism were also studied.
Introduction
to its appealing virtues, such as readily available starting
materials, high functional-group tolerance, and atom-economical
character.
â-Lactam is a core structure of many natural and synthetic
â-lactam antibiotics,1 such as penicillin, cephalosporin, thiena-
mycin, and monocyclic â-lactams, as well as a useful synthetic
intermediate2 in organic synthesis. Although many synthetic
methods have been developed, most of them are based on the
use of chiral precursors.1,3 Of the direct catalytic enantioselective
approaches,4 the most successful is the asymmetric Staudinger
condensation of ketenes with imines, developed by Lectka et
al.4h Asymmetric Kinugasa reaction5 also provides an easy
access to optically pure â-lactams with different structures due
Kinugasa and Hashimoto first reported the reaction of
copper(I) phenylacetylide with nitrone in dry pyridine, providing
an atom-economical and a facile way to synthesize â-lactams
in 1972.5b Later on, Miura and co-workers developed the first
catalytic version of this reaction and found that the coupling
reactions between phenylacetylene 4a and a series of C,N-
diarylnitrones could be accomplished well directly in the
presence of substoichiometric CuI.5c They also pioneered the
asymmetric reaction of phenylacetylene 4a with diphenylnitrone
5a using chiral ligands 1a-1c (Figure 1).
With 10 mol % of CuI and 20 mol % of bisoxazoline 1a in
the presence of K2CO3, the reaction provided â-lactams in 57%
ee and in 30% de. Recently, great progress was made by Fu
and and Lo.5d They found that 1 mol % of bis(azaferrocenes)
3/CuCl (Figure 1) could catalyze intermolecular Kinugasa
reaction very well to afford the desired products with good to
high enantioselectivities (up to 93% ee) and with high cis
diastereoselections. By a similar strategy, they demonstrated that
an intramolecular Kinugasa reaction could be used to construct
fused tricyclic ring systems efficiently with good enantioselecti-
vities.5eAs described above, Cu(I) is always used as the catalyst
for the Kinugasa reaction. Thus, this reaction gets to be
(1) (a) Morin, R. B., Gorman, M., Eds.; Chemistry and Biology of
â-Lactams Antibiotics; Academic Press: New York, 1982. (b) Katritzky,
A. R., Rees, C. W., Scriven, E. F. V., Eds.; ComprehensiVe Heterocyclic
Chemistry II; Pergamon: New York, 1996; Vol. 1B, Chapters 1.18-1.20.
(2) (a) Ojima, I. Acc. Chem. Res. 1995, 28, 383. (b) Ojima, I.; Delaloge,
F. Chem. Soc. ReV. 1997, 26, 377. (c) Palomo, C.; Aizpurua, J. M.; Ganboa,
I.; Oiarbide, M. Pure Appl. Chem. 2000, 72, 1763. (d) Bruggink, A., Ed.;
Synthesis of â-Lactam Antibiotics; Kluwer: Dordrecht, The Netherlands,
2001.
(3) For some reviews on employing chiral precursors, see: (a) Georg,
G. I.; Ravikumar, V. T. In The Organic Chemistry of â-Lactams; Georg,
G. I., Ed.; VCH: New York, 1993; p 295. (b) Ghosez, L.; Marchand-
Brynaert, S. In ComprehensiVe Organic Synthesis; Trost, B., Fleming, I.,
Eds.; Pergamon: Oxford, 1991; Vol. 5, p 85. (c) Hart, D. J.; Ha, D.-C.
Chem. ReV. 1989, 89, 1447.
10.1021/jo0602874 CCC: $33.50 © 2006 American Chemical Society
Published on Web 04/06/2006
3576
J. Org. Chem. 2006, 71, 3576-3582

Trisoxazoline/Cu(II)-Promoted Kinugasa Reaction
SCHEME 1. Plausible Mechanism
TABLE 1. Effect of Copper Salt on the Kinugasa Reactiona
performed strictly under nitrogen to mitigate the Glaser oxidative
coupling. In our efforts to develop superior catalysts that are
cheap, easy to access, air-stable, and water-tolerant, we designed
a pseudo C3-symmetric trisoxazoline (TOX) 2a6,7 (Scheme 1)
by sidearm approach and found that TOX 2a/Cu(II) was an
efficient catalyst for the asymmetric Friedel-Crafts reaction of
indole with alkylidene malonate,7 asymmetric 1,3-cycloaddition,8a
and Diels-Alder reaction.8b Recently, we extended the TOX
(4) For relative reviews, see: (a) Magriotis, P. A. Angew. Chem., Int.
Ed. 2001, 40, 4377. (b) France, S.; Weatherwax, A.; Taggi, A. E.; Lectka,
T. Acc. Chem. Res. 2004, 37, 592. For direct asymmetric catalytic Gilman-
Speeter reaction, see: (c) Gilman, H.; Speeter, M. J. Am. Chem. Soc. 1943,
65, 2255. (d) Fujieda, H.; Kanai, M.; Kambara, T.; Iida, A.; Tomioka, K.
J. Am. Chem. Soc. 1997, 119, 2060. (e) Tomioka, K.; Fujieda, H.; Hayashi,
S.; Hussein, M. A.; Kambara, T.; Nomura, Y.; Kanai, M.; Koga, K. Chem.
Commun. 1999, 715. (f) Kambara, T.; Hussein, M. A.; Fujieda, H.; Iida,
A.; Tomioka, K. Tetrahedron Lett. 1998, 39, 9055. For direct asymmetric
catalytic Staudinger reaction, see: (g) Staudinger, H. Justus Liebigs Ann.
Chem. 1907, 356, 51. (h) Taggi, A. E.; Hafez, A. M.; Wack, H.; Young,
B.; Drury, W. J., III; Lectka, T. J. Am. Chem. Soc. 2000, 122, 7831-7832.
(i) Wack, H.; Drury, W. J., III; Taggi, A. E.; Ferraris, D.; Lectka, T. Org.
Lett. 1999, 1, 1985. (j) Hodous, B. L.; Fu, G. C. J. Am. Chem. Soc. 2002,
124, 1578. For rhodium-catalyzed carbonylation of an aziridine, see: (k)
Calet, S.; Urso, F.; Alper, H. J. Am. Chem. Soc. 1989, 111, 931. For
rhodium-catalyzed intramolecular insertion of a R-diazo amide into a C-H
bond, see: (l) McCarthy, N.; McKervey, M. A.; Ye, T.; McCann, M.;
Murphy, E.; Doyle, M. P. Tetrahedron Lett. 1992, 33, 5983. (m) Doyle,
M. P.; Protopopova, M. N.; Winchester, W. R.; Daniel, K. L. Tetrahedron
Lett. 1992, 33, 7819. (n) Doyle, M. P.; Kalinin, A. V. Synlett 1995, 1075.
(o) Watanabe, N.; Anada, M.; Hashimoto, S.-i.; Ikegami, S. Synlett 1994,
1031. (p) Anada, M.; Watanabe, N.; Hashimoto, S.-i. Chem. Commun. 1998,
1517. (q) Anada, M.; Hashimoto, S.-i. Tetrahedron Lett. 1998, 39, 9063.
For direct asymmetric catalytic Kinugasa reaction, see ref 5.
Et3N
(equiv)
time yield
(h)
ee
entry
metal salt
CuCl
CuBr
CuI
CuOTf‚1/2C6H6
Cu(ClO4)2‚6H2O
Cu(OTf)2
Cu(BF4)2‚xH2O
Cu(ClO4)2‚6H2O
Cu(ClO4)2‚6H2O
Cu(ClO4)2‚6H2O
Cu(ClO4)2‚6H2O
(%)b cis/transc (%)d
1
2
3
4
5
6
7
8
2.0
2.0
2.0
2.0
2.0
2.0
2.0
1.5
1.0
1.0
0.5
7
96
16
40
12
6
42
19
19
18
19
42
30
46
36
42
60
53
50
56
45
43
13/1
11/1
12/1
11/1
10/1
11/1
13/1
11/1
11/1
12/1
11/1
33
49
51
5
56
3
56
61
61
63
63
9
10e
11
a Reactions were run at 15 °C using 12 mol % of TOX 2a and 10 mol
% of Cu(ClO4)2‚6H2O under N2 on 0.25 mmol scale. b Total isolated yield
of cis- and trans-isomers. c Determined by 1H NMR. d The enantiomeric
excess of the cis-isomer was determined by chiral HPLC. e Under air
atmosphere.
(5) For a recent review, see: (a) Marco-Contelles, J. Angew. Chem., Int.
Ed. 2004, 43, 2198. For the initial report, see: (b) Kinugasa, M.; Hashimoto,
S. J. Chem. Soc., Chem. Commun. 1972, 466. For direct asymmetric catalytic
versions, see: (c) Miura, M.; Enna, M.; Okuro, K.; Nomura, M. J. Org.
Chem. 1995, 60, 4999. (d) Lo, M. M.-C.; Fu, G. C. J. Am. Chem. Soc.
2002, 124, 4572. (e) Shintani, R.; Fu, G. C. Angew. Chem., Int. Ed. 2003,
42, 4082. For relative studies and applications, see: (f) Ding, L. K.; Irwin,
W. J. J. Chem. Soc., Perkin Trans. 1 1976, 2382. (g) Dutta, D. K.; Boruah,
R. C.; Sandhu, J. S. Heterocycles 1986, 24, 655. (h) Dutta, D. K.; Boruah,
R. C.; Sandhu, J. S. Indian J. Chem., Sect. B 1986, 25, 350. (i) Okuro, K.;
Enna, M.; Miura, M.; Nomura, M. J. Chem. Soc., Chem. Commun. 1993,
1107. (j) Basak, A.; Mahato, T.; Bhattacharya, G.; Mukherjee, B.
Tetrahedron Lett. 1997, 38, 643. (k) Basak, A.; Bhattacharya, G.; Bdour,
H. M. M. Tetrahedron 1998, 54, 6529. (l) Basak, A.; Ghosh, S. C.;
Bhowmick, T.; Das, A. K.; Bertolasi, V. Tetrahedron Lett. 2002, 43, 5499.
(m) Basak, A.; Ghosh, S. C. Synlett 2004, 1637.
(6) For a recent review on trisoxazolines, see: Zhou, J.; Tang, Y. Chem.
Soc. ReV. 2005, 34, 664.
(7) (a) Zhou, J.; Tang, Y. J. Am. Chem. Soc. 2002, 124, 9030 (b) Zhou,
J.; Ye, M.-C.; Huang, Z.-Z. Tang, Y. J. Org. Chem. 2004, 69, 1309. (c)
Zhou, J.; Ye, M.-C.; Tang, Y. J. Comb. Chem. 2004, 6, 301. (d) Zhou, J.;
Tang, Y. Chem. Commn. 2004, 432. (e) Ye, M.-C.; Li, B.; Zhou, J.; Tang,
Y. J. Org. Chem. 2005, 70, 6108.
FIGURE 1. Chiral ligands for the asymmetric Kinugasa reaction.
2a/Cu(I or II) system to the Kinugasa reaction and found that,
in the presence of a catalytic amount of TOX 2a, Cu(ClO4)2‚
6H2O could be used directly instead of Cu(I) salt to catalyze
the Kinugasa reaction between alkynes 4 and nitrones 5 very
well to provide the desired â-lactams 6 in moderate to good
enantioselectivities.9 In this article, we wish to report the reaction
modification, the scope and limitation in detail, and the
mechanistic studies.
(8) (a) Huang, Z.-Z.; Kang, Y.-B.; Zhou, J.; Ye, M.-C.; Tang, Y. Org.
Lett. 2004, 6, 1677. (b) Zhou, J.; Tang, Y. Org. Biomol. Chem. 2004, 2,
429.
(9) Ye, M.-C.; Zhou, J.; Huang, Z.-Z. Tang, Y. Chem. Commun. 2003,
2554.
J. Org. Chem, Vol. 71, No. 9, 2006 3577

Ye et al.
TABLE 2. Effect of Basea
entry
base
yield (%)b
cis/transc
ee (%)d
entry
base
yield (%)b
cis/transc
ee (%)d
1
2
3
4
5
6
7
8
Et3N
i-Pr2NEt
CyNEt2
45
51
56
45
41
12
41
61
62
52
55
12/1
>99/1
11/1
23/1
>99/1
20/1
5/1
9/1
15/1
9/1
63
55
56
58
58
55
56
72
73
68
79
12
13
14
15
16
17
18
19
20
21
22
n-octyl2NH
Et2NH
Cy2NH
c-amyl2NH
n-octylNHCy
TMPf
morpholine
i-PrNH2
59
61
63
65
66
54
16
39
53
28
14
6/1
6/1
13/1
16/1
7/1
>99/1
5/1
5/1
9/1
80
82
79
76
77
55
52
59
51
52
62
Cy2NMe
PMPe
NMO
Proton Sponge
i-Pr2NH
s-Bu2NH
i-Bu2NH
i-amyl2NH
9
10
11
t-BuNH2
i-BuNH2
cinchonidine
4/1
12/1
6/1
a Reactions were run at 15 °C using 12 mol % of TOX 2a and 10 mol % of Cu(ClO4)2‚6H2O under air atmosphere on 0.25 mmol scale. b Total isolated
yield of cis- and trans-isomers. c Determined by 1H NMR. d The enantiomeric excess of the cis-isomer was determined by chiral HPLC. e 1,2,2,6,6-
Pentamethylpiperidine. f 2,2,6,6-Tetramethylpiperidine.
TABLE 3. Effect of Solvent and Temperaturea
Results and Discussion
Preliminary Results. Initially, we tried the reaction of
phenylacetylene 4a with nitrone 5a using TOX 2a/CuCl as a
catalyst under conditions similar to Fu’s conditions,5d but
triethylamine instead of dicyclohexylmethylamine at 15 °C and
only 33% ee was obtained (Table 1, entry 1). Other copper(I)
salts were also examined (entries 2-4). As shown in Table 1,
CuI gave the best enantioselectivity (51% ee) but CuOTf‚1/
2C6H6 afforded a very low enantioselectivity (5% ee) in the
entry solvent T (°C) time (h) yield (%)b cis/transc ee (%)d
same conditions (entries 3 and 4). CuBr was less active, and
the corresponding reaction could not be complete even when
the reaction time was prolonged to 96 h (entry 2). Gratifyingly,
copper(II) salts were found to be good catalysts for this reaction
and usually gave better enantioselectivities than copper(I) salts
under the same conditions (entries 1-3 versus entries 7-11)
except that Cu(OTf)2 only gave 3% ee (entry 6). The results
suggested that the counterion of the copper salts played an
important role in the enantiofacial differentiation of this reaction.
We also examined other metal salts, such as Zn(ClO4)2‚6H2O,
Co(ClO4)2‚6H2O, Ni(ClO4)2‚6H2O, PtCl2, and Ag(ClO4)2‚xH2O,
but no desired product was obtained. The reduction of triethyl-
amine from 2.0 equiv to 0.5 equiv did not influence enantiose-
lectivity of the predominant cis product but lowered the yield
slightly (entries 8-11). When triethylamine was reduced to 0.1
equiv, only a trace amount of lactam was detected. Noticeably,
it was found that TOX 2a/Cu(ClO4)2‚6H2O was air-stable and
water-tolerant, which allowed the Kinugasa reaction to be
performed under air atmosphere for the first time without loss
of enantiomeric excess (entry 10). This modification simplified
greatly the reaction operation.
1
2
3
4
5
6
7
8
9
10
PhCH3
Et2O
THF
EtOAc
acetone
DMF
CH3CN
CH3CN
CH3CN
CH3CN
15
15
15
15
15
15
15
30
0
18
18
18
18
18
40
16
14
38
52
44
40
44
42
35
39
63
47
60
64
4/1
6/1
72
74
78
77
74
63
79
76
82
83
13/1
11/1
16/1
8/1
13/1
14/1
15/1
27/1
-10
a Reactions were run using 12 mol % of TOX 2a and 10 mol % of
Cu(ClO4)2‚6H2O in air on 0.25 mmol scale. b Total isolated yield of cis-
and trans-isomers. c Determined by 1H NMR. d Determined by chiral HPLC
for the cis-isomer.
almost a single cis-isomer, but iso-butylamine only gave the
product with moderate diastereoselectivity (entries 2, 5, and 21).
Compared with tertiary and primary amines, secondary ones
afforded the desired products with higher enantioselectivity but
lower diastereoselectivity (entries 8-16). To obtain better
diastereoselectivity as well as enantioselectivity, we investigated
a variety of secondary amines (entries 14-16) and found that
the dicyclohexylamine gave the most satisfactory result (entry
14). In this case, the reaction of phenylacetylene 4a with nitrone
5a gave 79% ee, comparable to the result reported by Fu with
the use of 3/CuCl as a chiral catalyst.5d These results suggested
that the amine might coordinate to the copper center and relay
the chirality to the product. Compared with alkylamines, the
aromatic amines, such as N,N-dimethylaniline and aniline, did
Effect of Base. Further studies showed that the amines
strongly influenced diastereoselectivity, enantioselectivity, and
reaction rate. Bulkier amines always gave better diastereose-
lection. As summarized in Table 2, generally tertiary amines
provided higher diastereoselectivity than secondary ones, and
the latter were better than primary ones. For example, both
1,2,2,6,6-pentamethylpiperidine and diisopropylethylamine gave
3578 J. Org. Chem., Vol. 71, No. 9, 2006

Trisoxazoline/Cu(II)-Promoted Kinugasa Reaction
FIGURE 2. Chiral oxazoline ligands.
TABLE 4. Effect of Chiral Liganda
not catalyze this reaction at all. However, Proton Sponge (entry
7) promoted the reaction well (56% ee and 5/1 diastereomer
ratio). Noticeably, cinchonine could not promote this reaction,
and cinchonidine gave moderate enantioselectivity (entry 22).
Effects of Solvent and Temperature. We also examined
the effects of solvents and temperature on this reaction using
dicyclohexylamine as the optimal base.
As shown in Table 3, the reaction of phenylacetylene 4a with
nitrone 5a proceeded well in a number of solvents, providing
cis-isomer as the major product. However, in methanol, no
reaction was observed. In our screened conditions, acetonitrile
was the optimal solvent. In addition, we found that lowering
the temperature increased both the yield and the cis-selectivity
slightly in CH3CN (entries 7-10).
Effect of Ligand. Usually, the cooperation effects between
metal and ligands influence strongly the enantioselectivity and
yield.10 To further improve the asymmetric induction, we
synthesized a variety of trisoxazolines based on the frameworks
of bisoxazolines (Figure 2) to study the effect of ligand on the
reaction.
As shown in Table 4, bisoxazolines gave lower reaction rates
and enantioselectivities than trisoxazolines (entries 1-3 versus
entries 5-16). The reason, we proposed, is that trisoxazolines
provided stronger chelation with copper center than bisoxaza-
olines to prevent effectively phenylethynylcopper from its
coordination polymerization.11 During the experiments, we did
observe a small amount of yellow precipitation formed in the
bisoxazolines/Cu(II) reaction system, but a clear solution
occurred in the case of trisoxazolines. Generally, the pendant
oxazoline rarely influences the enantoselectivity of the Kinugasa
reaction (entries 5 and 8-13). For example, trisoxazolines 2h
and 2i, with opposite chiral center in the pendant oxazoline,
gave similar enantioselectivities (entries 11 and 12). Increasing
the steric hindrance decreased the reaction rate greatly (entry
7), and thus trisoxazoline 2c did not give the desired â-lactam.
Bisoxazaoline backbone proved to be essential to the reaction.
For instance, two trisoxazolines (2k, 2l) derived from (S)-Ph-
bisoxazoline and (R)-Ph-bisoxazoline, respectively, provided
â-lactams with opposite absolute configurations (entries 14 and
entry
ligand
time (h)
yield (%)b
cis/transc
ee (%)d
1
2
3
4
5
6
7
8
1b
1c
1d
1e
2a
2b
2d
2e
2f
2g
2h
2i
2j
2k
2l
7 days
7 days
6 days
19
15
11
6 days
15
14
11
12
15
11
32
80
25
10
26
5 days
31
25
33
40
60
71
47
51
51
56
56
60
56
52
51
47
49
62
14
9/1
60
54
36
54
80
80
-70
66
75
58
61
56
61
58
-52
49
71
73
2
20/1
43/1
10/1
13/1
20/1
13/1
9/1
10/1
9/1
9/1
10/1
10/1
9/1
10/1
12/1
17/1
6/1
9
10
11
12
13
14
15
16
17
18
19
2m
2n
2o
2p
9/1
a Reactions were run at 15 °C using 12 mol % of chiral ligand and 10
mol % of Cu(ClO4)2‚6H2O under N2 on 0.25 mmol scale. b Total isolated
yield of cis- and trans-isomers. c Determined by H NMR. d The enantio-
1
meric excess of the cis-isomer was determined by chiral HPLC.
15). C3-symmetric trisoxazoline 2m reported by Gade and co-
workers,12 afforded moderate ee (entry 16). Considering that
pyridine is in favor of the formation of â-lactams in the
Kinugasa reaction,5c we designed and synthesized pyridinyl- and
i
2-methylpyridinyl-derived Pr-bisoxazoline 2n and 2o, which
proved to catalyze the Kinugasa reaction well but only gave 71
and 73% ee, respectively (entries 17 and 18). In addition, a
bipyridine ligand 2p was synthesized but gave a poor result
(entry 19). In our screening conditions, the best result was
achieved by using TOX 2a as the ligand.
(10) For some recent examples on “ligand tuning”, see: (a) Reeta, M.
T. ComprehensiVe Coordination Chemistry II; McCleverty, J. A., Meyer,
T. J., Eds.; Elsevier Pergamon: Amsterdam, Boston, 2004; Vol. 9, p 509.
(b) RajanBabu, T. V.; Casalnuovo, A. L.; Ayers, T. A.; Nomura, N.; Jin,
J.; Park, H.; Nandi, M. Curr. Org. Chem. 2003, 7, 301. (c) Dai, L.-X.; Tu,
T.; You, S.-L.; Deng, W.-P.; Hou, X.-L. Acc. Chem. Res. 2003, 659.
(11) Probably phenylethynylcopper polymer formed. See: Okamoto, Y.;
Kundu, S. K. J. Phys. Chem. 1973, 22, 2677.
(12) (a) Bellemin-Laponnaz, S.; Gade, L. H. Chem. Commun. 2002, 1286.
(b) Bellemin-Laponnaz, S.; Gade, L. H. Angew. Chem., Int. Ed. 2002, 41,
3473. (c) Dro, C.; Bellemin-Laponnaz, S.; Welter, R.; Gade, L. H. Angew.
Chem., Int. Ed. 2004, 43, 4479. (d) Seitz, M.; Capacchione, C.; Bellemin-
Laponnaz, S.; Wadepohl, H.; Ward, B. D.; Gade, L. H. J. Chem. Soc., Dalton
Trans. 2006, 193.
J. Org. Chem, Vol. 71, No. 9, 2006 3579

Ye et al.
TABLE 5. Aymmetric Synthesis of â-Lactamsa
entry
R1
R2
C6H5
C6H5
C6H5
C6H5
C6H5
p-MeC6H4
p-MeOC6H4
p-F3CC6H4
R-furyl
p-F3CC6H4
cyclohexyl
C6H5
C6H5
C6H5
C6H5
C6H5
R3
lactam
yield (%)b
cis/transc
ee (%)d
1
2
3
4
5
6
7
8
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
6a
6b
6c
6d
6e
6f
6g
6h
56
36
36
70
98
50
58
75
56
35
15/1
19/1
31/1
13/1
10/1
18/1
18/1
14/1
2/1
82
82
84
74
70
82
83
82
85
84
p-MeC6H4
p-MeOC6H4
p-BrC6H4
p-EtO2CC6H4
C6H5
C6H5
C6H5
C6H5
9
6i
6j
10
11
12
13
14
15
16
17f
18g
19g
20g
p-MeOC6H4
C6H5
C6H5CH2
C6H5
25/1
no reaction
no reaction
6k
6l
p-F3CC6H4
1-cyclohexenyl
Me3Si
EtO2C
EtO2C
EtO2C
EtO2C
EtO2C
65
33
3/1
13/1
73
72
C6H5
C6H5
C6H5
C6H5
no reaction
6m
6m
6m
6n
25
45
67
80
78
1/6
1/5
1/6
1/4
1/8
46e
48e
50e
51e
45e
C6H5
C6H5
C6H5
R-furyl
C6H5
p-EtO2CC6H4
C6H5
6o
a Reactions were run at 0 °C using 12 mol % of TOX 2a and 10 mol % of Cu(ClO4)2‚6H2O under air atmosphere on 0.25 mmol scale. b Total isolated
1
yield of cis- and trans-isomers. c Determined by H NMR. d ee of the cis-isomer determined by chiral HPLC. e ee of the trans-isomer determined by chiral
i
HPLC. f Using 6 mol % of TOX 2a, 5 mol % of Cu(ClO4)2‚6H2O, and 20 mol % of Pr2NEt. g Using 6 mol % of BOX 1b, 5 mol % of Cu(ClO4)2‚6H2O,
i
and 20 mol % of Pr2NEt.
Reaction Scope. Under the optimal reaction conditions, we
examined the generality of the current reaction by employing a
variety of structurally different nitrones and alkynes. As shown
in Table 5, the electronic character of aromatic groups on
carbons of nitrones affected both the yields and the stereose-
lections. Electron-rich aromatic groups increased enantioselec-
tivities but decreased the yields (entries 1-3). Electron-deficient
ones slightly decreased enantioselectivities but increased the
reaction rates (entries 4 and 5).13 The electronic properties of
the N-bound aromatic groups of nitrones had almost no obvious
impact on the enantioselections (entries 6-10). Both electron-
deficient and electron-rich aromatic groups afforded good
enantioselectivities and diastereoselectivities. Nitrone with N-
bound furyl group furnished the best ee but lowest diastereo-
selectivity in moderate yield (entry 9). Neither R-alkyl nor
N-alkyl nitrone gave the desired product (entries 11 and 12).
Noticeably, both aryl and alkyl alkynes worked well to provide
the desired â-lactams (entries 13 and 14). For example,
1-cyclohexenyl acetylene gave 72% ee with high diastereose-
lectivity (entry 14).
the promoter. To understand the mechanism, it is very important
to clarify that the catalytic species is Cu(I) or Cu(II). In literature,
Cu(II) could be reduced into Cu(I) through a radical process.14,15
We also isolated a small amount (8.2 mg) of the coupling
product diphenylbutadiyne in the reaction of phenyl acetylene
4a (0.375 mmol) with nitrone 5a (0.25 mmol) in the presence
of 10 mol % of TOX 2a/Cu(ClO4)2‚6H2O and 1.0 equiv of Cy2-
NH under nitrogen atmosphere. Therefore, we proposed that
the Cu(II) was reduced in situ into Cu(I) by phenylacetylene in
the aforementioned Kinugasa reactions and the catalytic species
is still Cu(I). This is also consistent with the following
experimental phenomenon: a small amount of yellow precipitate
(a probable coordination polymer of copper(I) phenylacetylide11)
was observed in the reaction using bisoxazolines as ligands.
In literature, the Kinugasa reaction was proposed to proceed
via a [3 + 2] cycloaddition reaction, followed by a rearrange-
ment to give the â-lactam (path I in Scheme 1). Considering
that imine was found as a byproduct in some reactions described
above16 and the nitrones with N-bound electron-withdrawing
substituents gave better yields than those with N-bound electron-
rich substituents (Table 5, entries 4 and 5 versus entries 1-3),
We also investigated the reactions of ethyl propiolate with
nitrones.5j As shown in Table 5, ethyl propiolate was a good
substrate for the synthesis of desired â-lactam even in the
presence of 5 mol % of Cu(II)/TOX 2a (entries 16 and 17).
Noticeably, compared with Cu(II)/TOX 2a, Cu(II)/BOX 1b gave
better yield with comparable enantiomeric excess (entry 17
versus entry 18).
(14) Recently, Carreira and Knopfel used Cu(OAc)2 instead of Cu(I) to
produce copper acetylide in the presence of sodium ascorbate. See: Knopfel,
T. F.; Carreira, E. M. J. Am. Chem. Soc. 2003, 125, 6054.
(15) For Glaser coupling, see: (a) Glaser, C. Ber. Dtsch. Chem. Ges.
1869, 2, 422. (b) Youngblood, W. J.; Gryko, D. T.; Lammi, R. K.; Bocian,
D. F.; Holten, D.; Lindsey, J. S. J. Org. Chem. 2002, 67, 2111. (c) Siemsen,
P.; Livingston, R. C.; Diederich, F. Angew. Chem., Int. Ed. 2000, 39, 2632.
For Eglinton coupling, see: (d) Eglinton, G.; Galbraith, A. R. Chem. Ind.
1956, 737. (e) Inouchi, K.; Kabashi, S.; Takimiya, K.; Aso, Y.; Otsubo, T.
Org. Lett. 2002, 4, 2533. (f) Fabian, K. H. H.; Lindner, H.-J.; Nimmerfroh,
N.; Hafner, K. Angew. Chem., Int. Ed. 2001, 40, 3402.
Mechanism Discussion. The classical Kinugasa reaction is
catalyzed by Cu(I); however, in our case, Cu(II) was used as
(13) Please see the Supporting Information.
3580 J. Org. Chem., Vol. 71, No. 9, 2006

Trisoxazoline/Cu(II)-Promoted Kinugasa Reaction
we proposed another rationale, path II as shown in Scheme 1.
In path II, cycloaddition adduct A decomposed into intermediate
ketene C,17 followed by an intramolecular nucleophilic cycliza-
tion to give enolate D, as in the Stauginger reaction. The enolate
was protonated to afford the desired â-lactam. This mechanism
is more reasonably than that in path I for the following
observation: N-(4-carboethoxyphenyl)-R-phenylnitrone gave
much higher yield than diphenylnitrone. The reason is probably
that the N-bound electron-withdrawing group stabilized im-
mediate C and prevented immediate C from its decomposition
into the corresponding imine. An attempt to trap intermediate
C failed. A clear mechanism awaits further study.
Stereochemical Model. Very recently, Gade and co-workers
found that the pendant oxazoline of bisoxazoline-based tridentate
ligand was dynamically coordinated to Cu(II), stabilized the
catalytic species, and improved the catalytic efficiency greatly.18
To further understand the role of the sidearm oxazoline in 2a
in the present reaction, the 13C NMR technique was used for
our study. Considering that Cu(II) is paramagnetic and Cu(I)
was the possible catalytic species in our reaction, we chose CuCl
instead of Cu(ClO4)‚6H2O for the 13C NMR study. As shown
in Figure 3, without CuCl, the 13C chemical shifts of the three
sp2 carbon of oxazolines in TOX 2a appeared at δ 163.71,
167.38, and 167.43 ppm (region 1, Figure 3). However, in the
presence of equimolar CuCl, the 13C signals merged at δ 164.32
ppm (region 1′, Figure 3). The 13C signals merging were also
observed for both the O- and N-bound sp3 carbons (regions 2
and 2′, Figure 3). These results suggested that all three nitrogen
atoms of TOX 2a might coordinate to copper, as shown in
Scheme 2.
With the addition of equimolar phenylacetylene 4a and Cy2-
NH, the single peak of the three sp2 carbon of oxazolines split
again into three peaks at δ 169.78, 169.47, and 163.71 ppm
(region 1′′, Figure 3). Compared with ligand 2a, one peak at
163.71 ppm was identical and the other two shifted to downfield
(167.38 and 167.43 versus 169.78 and 169.47). Similar shifts
were observed in 13C signals of the O- and N-bound sp3 carbons
(region 2′′, Figure 3). These facts suggested that decoordination
of the pendant oxazoline might occur when copper(I) phenyl-
acetylide formed (Scheme 2), consistent with the coordination/
decoordination equilibrium18 proposed by Gade et al. in the
trisoxazoline/Cu(II) catalytic system.
On the basis of these studies as well as the experimental
results, we developed a stereochemical model in Scheme 2 to
account for the enantioselection. Owing to the steric hindrance
between the nitrone and isopropyl group, cuprous phenylacetyl-
ide approached the Si-face of nitrone to afford the (4S)-
enantiomer of â-lactam.
FIGURE 3. 13C NMR study.
access to â-lactams in moderate to good yield and in moderate
to good diastereo- and enantioselectivity. Noticeably, Cu(II) salt
proved to be an efficient catalyst precursor for the first time in
the Kinugasa reaction. It is significant that this modification
allowed the Kinugasa reaction to be performed under air
atmosphere, whereas all documented protocols were run under
inert atmosphere. In addition, organic bases were found to
influence both the selectivity and the reactivity strongly, and
this provides probably some information for the catalyst design
to further improve the selectivity and reactivity in this reaction.
Conclusions
In summary, the air-stable and water-tolerant TOX 2a/Cu-
(ClO4)2‚6H2O complex proved to be a good catalyst in the
asymmetric Kinugasa reaction. This method provided a facile
Experimental Section
The Synthesis of Chiral Ligand 2p. To a solution of dipyridin-
2-ylmethane (272 mg, 1.6 mmol) in dried THF (30 mL) was added
dropwise t-BuLi (0.95 mL, 1.7 M in hexanes, 1.6 mmol) within
15-20 min at -78 °C under nitrogen. The resulting yellow solution
was stirred for an additional hour at this temperature. Then a
solution of (4S)-2-bromo-4-isopropyl-4,5-dihydrooxazole (357 mg,
1.9 mmol) in THF (10 mL) was added dropwise at -78 °C over
10 min. The solution was slowly warmed to room temperature,
was stirred for an hour, and then refluxed for 6 h. The mixture
was diluted with CH2Cl2 (30 mL) and was washed with H2O (5
(16) From â-lactam 6a to 6e, the ratios of corresponding imines to
lactams were 1/2.8, 1/1.4, 1.4/1, 1/7, 1/21, respectively, determined by 1H
NMR sepectroscopic analysis of the corresponding crude products. Also,
15% yield of (E)-N-benzylidenebenzeneamine was isolated in the reaction
of 4a and 5a.
(17) For similar ketene intermediate, see: Ahn, C.; Kennington, J. W.,
Jr.; DeSheong, P. J. Org. Chem. 1994, 59, 6282. In addition, Fu also
indicated this processes; see ref 5e.
(18) Foltz, C.; Stecker, B.; Marconi, G.; Bellemin-Laponnaz, S.; Wade-
pohl, H.; Gade, L. H. Chem. Commun. 2005, 5115.
J. Org. Chem, Vol. 71, No. 9, 2006 3581

Ye et al.
SCHEME 2
mL). The aqueous layer was extracted with CH2Cl2 (10 mL), and
the combined organic phases were dried over anhydrous Na2SO4,
filtered, and concentrated. The residue was purified by flash
chromatography (EtOAc/Et3N ) 200/1) to give the desired product
257 mg (syrup, 57%). [R]20D -37.0 (c 0.75, CHCl3); IR (neat) 2961,
2891, 1671, 1586, 1567, 1467, 1432, 1356, 997, 989 cm-1; 1H NMR
(300 MHz, CDCl3): δ 8.57-8.54 (m, 2H), 7.64-7.60 (m, 2H),
7.48-7.42 (m, 2H), 7.18-7.15 (m, 2H), 5.46 (s, 1H), 4.30-4.22
(m, 1H), 4.05-3.97 (m, 2H), 1.84-1.76 (m, 1H), 0.93 (d, J ) 6.9
Hz, 3H), 0.85 (d, J ) 6.9 Hz, 3H); 13C NMR (75 MHz, CDCl3):
δ 165.4, 158.1, 158.0, 149.4, 149.4, 136.6, 123.7, 123.6, 122.2,
122.2, 72.0, 70.0, 56.2, 32.4, 18.9, 17.7; LRMS-EI(m/z): 281 (M+),
169 (100); HRMS-ESI (m/z): [M + H]+ calcd for C17H19N3O,
282.1601; found, 282.1617.
sepectroscopic analysis of the crude product. The determination of
enantioselective excess of the trans-isomer was performed by chiral
HPLC with a Daicel Chiralcel OD-H column (eluent: hexane/i-
PrOH 85/15, flow rate: 0.9 mL/min).
(3S,4S)- 1,3,4-Triphenyl-2-azetidinone 6a. Procedure A: 56%
yield (solid, 35 h); [R]20D -8.0 (c 1.62, CHCl3; 82% ee); 1H NMR
(300 MHz, CDCl3): δ 7.43-7.40 (m, 2H), 7.29-7.24 (m, 2H),
7.09-7.03 (m, 11H), 5.45 (d, J ) 6.3 Hz, 1H), 5.00 (d, J ) 6.6
Hz, 1H).
(3S,4S)-1-(4-Methylphenyl)-3,4-diphenyl-2-azetidinone 6b. Pro-
cedure A: 36% yield (solid, 56 h); [R]20 -10.5 (c 0.68, CHCl3;
D
1
82% ee); H NMR (300 MHz, CDCl3): δ 7.32-7.26 (m, 2H),
7.11-7.03 (m, 12H), 5.44 (d, J ) 6.0 Hz, 1H), 5.00 (d, J ) 5.7
Hz, 1H), 2.29 (s, 3H).
General Procedures for Catalytic Asymmetric Synthesis of
â-Lactams. Procedure A. A mixture of Cu(ClO4)2‚6H2O (9.3 mg,
0.025 mmol) and (S)-isopropyl trisoxazoline 2a (11.3 mg, 0.03
mmol) in CH3CN (4 mL) was stirred under air atmosphere at 15
°C for 2 h. The solution was cooled to 0 °C, and then Cy2NH (50
µL, 0.25 mmol) was added. After 10 min, alkyne (0.375 mmol)
was added. When the color of the resulting mixture turned light
yellow, we added nitrone (0.25 mmol) to the solution. After the
reaction was complete (monitored by TLC), the mixture was passed
through a short silica gel column (neat CH2Cl2 as the eluent). The
filtrate was concentrated, and the residue was purified by flash
chromatography (PE/CH2Cl2) to afford the product. The diastereo-
selectivity was determined by 1H NMR sepectroscopic analysis of
crude product. The determination of enantioselective excess of the
cis-isomer was performed by chiral HPLC with a Daicel Chiralcel
OD-H column (eluent: hexane/iPrOH 80/20, flow rate: 0.7 mL/
min).
(3R,4S)-Ethyl 2-Oxo-1,4-diphenylazetidine-3-carboxylate 6m.
Procedure B: 67% yield (syrup, 1 h); [R]20D 34.9 (c 0.84, CHCl3;
1
50% ee); H NMR (300 MHz, CDCl3): δ 7.41-7.23 (m, 9H),
7.09-7.07 (m, 1H), 5.35 (d, J ) 3.0 Hz, 1H), 4.30 (q, J ) 6.9 Hz,
2H), 3.99 (d, J ) 2.7 Hz, 1H), 1.33 (t, J ) 7.2 Hz, 8H).
(3R,4S)-Ethyl 1-(4-(Ethoxycarbonyl)phenyl)-2-oxo-4-phenyl-
azetidine-3-carboxylate 6n. Procedure B: 80% yield (syrup, 1
1
h); [R]20 17.4 (c 0.88, CHCl3; 49% ee); H NMR (300 MHz,
D
CDCl3): δ 7.96-7.93 (m, 2H), 7.40-7.27 (m, 7H), 5.38 (d, J )
2.4 Hz, 1H), 4.33 (q, J ) 7.2 Hz, 2H), 4.30 (q, J ) 7.2 Hz, 2H),
4.03 (d, J ) 2.7 Hz, 1H), 1.35 (t, J ) 7.2 Hz, 3H), 1.34 (t, J ) 7.2
Hz, 3H); 13C NMR (75 MHz, CDCl3): δ 165.9, 165.8, 159.5, 140.5,
135.7, 130.8, 129.4, 129.2, 126.1, 126.0, 116.6, 36.7, 62.2, 60.9,
57.7, 14.2, 14.1; IR (KBr): 2982, 2938, 1768, 1723, 1606, 1514,
1456, 1365, 1173, 1114, 1013, 854, 769 cm-1; EI (m/z): 367 (M+),
131 (100); Anal. calcd for C22H16F3NO: C, 68.31; H, 5.76; N, 3.81.
Found: C, 68.31; H, 5.85; N, 3.46.
Procedure B. A mixture of Cu(ClO4)2‚6H2O (4.6 mg, 0.0125
mmol) and (S)-tBu-BOX 1b (4.5 mg, 0.015 mmol) in CH3CN (2
mL) was stirred under air atmosphere at 15 °C for 1 h. The solution
was cooled to 0 °C, and then iPr2NEt (9 µL, 0.05 mmol) and nitrone
(0.25 mmol) were added. After 10 min, ethyl propiolate (50.6 µL,
0.5 mmol) was added. After the reaction was complete (monitored
by TLC), the mixture was passed through a short silica gel column
(neat CH2Cl2 as the eluent). The filtrate was concentrated, and the
residue was purified by flash chromatography (PE/CH2Cl2) to afford
Acknowledgment. We are grateful for the financial support
from the Natural Sciences Foundation of China and the Science
and Technology Commission of Shanghai Municipality.
Supporting Information Available: Characterization data for
all compounds and experimental procedure. This material is
available free of charge via the Internet at http://pubs.acs.org.
1
the product. The diastereoselectivity was determined by H NMR
JO0602874
3582 J. Org. Chem., Vol. 71, No. 9, 2006