Chiral tris(oxazoline)/Cu(II) catalyzed coupling of terminal alkynes and nitrones.

Article abstract of DOI:10.1039/b306653c

Novel chiral iPr-tris(oxazoline)/Cu(ClO4)2 x 6H2O catalyzed coupling of terminal acetylenes and nitrones to afford cis-disubstituted beta-lactams is described; the choice of base proves essential to both the diastereoselectivity and the enantioselectivity

Full text of DOI:10.1039/b306653c

Chiral tris(oxazoline)/Cu(II) catalyzed coupling of terminal alkynes and
nitrones†
Meng-Chun Ye, Jian Zhou, Zheng-Zheng Huang and Yong Tang*
Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, 354 Fenglin Lu,
Shanghai 200032, China. E-mail: tangy@mail.sioc.ac.cn
Received (in Cambridge, UK) 11th June 2003, Accepted 9th September 2003
First published as an Advance Article on the web 16th September 2003
i
Novel chiral Pr-tris(oxazoline)/Cu(ClO4)2·6H2O catalyzed
coupling of terminal acetylenes and nitrones to afford cis-
disubstituted b-lactams is described; the choice of base
proves essential to both the diastereoselectivity and the
enantioselectivity.
and poor yield (entry 12). Tertiary amines provided high
diastereoselectivity and moderate enantioselectivity (entries
1–4). Compared with both primary amines and tertiary amines,
secondary amines afforded the desired products with better
diastereoselectivity and enantioselectiviy (entries 6–11). Ob-
viously, bulkier amines gave better diastereoselection. For
example, both 2,2,4,4-tetramethylpyrollidine and diisopropyle-
thylamine gave the cis-isomer as the sole product (entries 2, 5).
Dicyclohexylamine (entry 11) proved to be the best base in our
screened conditions. In this case, the reaction of phenyl-
acetylene 4a with nitrone 5a gave 80% ee, comparable to that
when 3/CuCl was used (77% ee).6 These results suggested that
amines might coordinate to the copper center and relay the
effect of the chiral ligand. Under the optimized reaction
conditions, we next examined the generality of the reaction by
employing a variety of structurally different nitrones and
alkynes. As shown in Table 2, the electronic character of the a-
aryl group on nitrones had almost no effect on the enantioselec-
tion (entries 6–10). Whatever electron-deficient or electron-rich
a-aryl nitrones were used, all reactions gave good enantiose-
lectivity and diastereoselectivity. Nitrones with an a-furyl
group furnished good ee but low diastereoselectivity (entry 9).
C2-symmetric chiral bis(oxazoline)–metal complexes have
developed into versatile catalysts for numerous asymmetric
processes during the last decade.1 In sharp contrast to the great
success of bis(oxazolines), the development and application of
tris(oxazolines) are rather limited.2 In our efforts to develop
superior catalysts which are cheap, easy to access, air-stable and
water-tolerant, we designed a pseudo C3-symmetric tris(oxazo-
line) 2 (Scheme 1) by sidearm approach and found that 2/Cu(II
)
was an efficient catalyst for the asymmetric Friedel–Crafts
reaction of indole with alkylidene malonate.3 In this commu-
nication, we wish to report the application of ligand 2 in the
asymmetric Kinugasa reaction.4
The Kinugasa reaction was developed in 1972.4 Initially, it
was performed in dry pyridine using stoichiometric copper
acetylide. Later on, Miura et al. found that this reaction could be
accomplished with the use of terminal alkynes and nitrones
directly in the presence of substoichiometric CuI.5 They also
pioneered the asymmetric version but only phenylacetylene was
examined. In their study, 57% ee and 35% de were achieved
when a mixture of 10 mol% CuI and 20 mol% bis(oxazoline) 1c
was employed. Very recently, Fu and coworkers6 found that
bis(azaferrocenes)/CuCl (Scheme 1) could catalyze the Kinu-
gasa reaction very well to afford the desired products with good
to high enantioselectivity for cis-isomers (up to 93% ee, cis/
trans up to 95/5).
Table 1 Effects of organobases on Kinugasa coupling reactiona
Entry
Base
Time/h cis/transb ee (cis, %)c Yield (%)d
As mentioned above, Cu( ) is always used as the catalyst for
I
Kinugasa reaction.4–7 And thus, this reaction is performed
strictly under nitrogen to mitigate the Glaser oxidative coupling.
Fortunately, we found that Cu(ClO4)2·6H2O, instead of sensi-
1
2
3
18
17
35
92/8
> 99/1
92/8
63
56
56
45
51
57
tive Cu( ) salts, could catalyze this reaction very well in the air.
I
In this case, tris(oxazoline) 2/Cu(ClO4)2·6H2O provided the
desired b-lactam in moderate yield with 63% ee when
triethylamine was used as the base under air (entry 1, Table 1)
in the absence of reductant.8
Further studies showed that the amines strongly influenced
both the selectivity and the yield. As shown in Table 1, although
primary amines, secondary amines and tertiary amines all could
promote this reaction, primary amines gave moderate ee, low de
4
5
24
17
96/4
58
55
45
54
> 99/1
6
7
8
5
6
86/14
86/14
90/10
79
82
72
55
61
61
16
9
15
26
90/10
94/6
68
73
52
62
10
11
12
16
7
93/7
80
59
63
39
83/17
i
a Reactions were run at 15 °C using 12 mol% Pr-tris(oxazoline) and 10
mol% copper salt under air atmosphere on 0.25 mmol scale. b Determined
by 1H NMR. c Determined by chiral HPLC. d Total isolated yield of cis- and
trans-isomers.
Scheme 1
† Electronic supplementary information (ESI) available: experimental. See
http://www.rsc.org/suppdata/cc/b3/b306653c/
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CHEM. COMMUN., 2003, 2554–2555
This journal is © The Royal Society of Chemistry 2003

Table 2 Aymmetric synthesis of b-lactamsa
increased the enantioselectivity but decreased the reactivity
(entries 1–3). By contrast, electron-deficient substituents
slightly decreased the enantioselectivity and increased the
reactivity (entries 4 and 5). Besides arylacetylenes (entries
1–11), alkyl alkyne worked well in this reaction (entry 12). For
example, cyclohexenyl acetylene gave also good ee with high
diastereoselectivity (entry 12).
In summary, the air-stable and water-tolerant tris(oxazoline)
2/Cu(ClO4)2·6H2O complex proved a catalyst in the asym-
metric Kinugasa reaction. This method provided a facile access
to cis-b-lactams with good enantioselectivty. Noticeably, the
Cu(II) salt proved an efficient catalyst precursor for the first time
in the Kinugasa reaction. It is significant that this modification
allowed the reaction to run under air atmosphere whereas all
documented protocols4–7 were run under nitrogen. In addition,
organic bases were found to influence both the selectivity and
the reactivity strongly and this probably provides some
information for ligand design to further improve the selectivity
and reactivity in this reaction.
Entry Alkyne Nitrone
cis/transb ee (cis, %)c Yield (%)d
1
2
4a
4a
94/6
95/5
82
82
56
36
3
4
5
4a
4a
4a
97/3
93/7
91/9
84
74
70
36
70
98
We are grateful for the financial support from the National
Natural Sciences Foundation of China.
Notes and references
6
7
8
4a
4a
4a
95/5
95/5
93/7
82
83
82
50
58
75
1 (a) A. K. Ghosh, P. Mathivanan and J. Cappiello, Tetrahedron:
Asymmetry, 1998, 9, 1; (b) K. A. Jørgensen, M. Johannsen, S. Yao, H.
Audrain and J. Thorhauge, Acc. Chem. Res., 1999, 32, 605; (c) J. S.
Johnson and D. A. Evans, Acc. Chem. Res, 2000, 33, 325.
2 (a) K. Kawasaki, S. Tsumura and T. Katsuki, Synlett, 1995, 1245; (b) T.
H. Chan and G. Z. Zheng, Can. J. Chem., 1997, 75, 629; (c) T.-H.
Chuang, J.-M. Fang and C. Bolm, Synth. Commun., 2000, 30, 1627; (d)
Y. Kohmura and T. Katsuki, Tetrahedron Lett., 2000, 41, 3941; (e) S.-G.
Kim and K. H. Ahn, Chem. Eur. J., 2000, 6, 3399; (f) S.-G. Kim and K.
H. Ahn, Tetrahedron Lett., 2001, 42, 4175; (g) S. Bellemin-Laponnaz and
L. H. Gade, Angew. Chem., Int. Ed., 2002, 41, 3473; (h) S.-G. Kim, K.-H.
Kim, J. Jung, S. K. Shin and K. H. Ahn, J. Am. Chem. Soc., 2002, 124,
591.
9
4a
4a
67/33
96/4
85
84
56
35
10
11
12
4b
4c
75/25
93/7
73
72
65
33
3 J. Zhou and Y. Tang, J. Am. Chem. Soc., 2002, 124, 9030.
4 M. Kinugasa and S. Hashimoto, J. Chem. Soc., Chem. Commun., 1972,
466.
5 M. Miura, M. Enna, K. Okura and M. Nomura, J. Org. Chem., 1995, 60,
4999.
6 M. M.-C. Lo and G. C. Fu, J. Am. Chem. Soc., 2002, 124, 4572.
7 (a) L. K. Ding and W. J. Irwin, J. Chem. Soc., Perkin Trans. 1, 1976,
2382; (b) D. K. Dutta, R. C. Boruah and J. S. Sandhu, Heterocycles, 1986,
24, 655; (c) A. Basak, G. Bhattacharya and H. M. M. Bdour, Tetrahedron,
1998, 54, 6529.
a Reactions were run at 15 °C using 12 mol% of iPr-tris(oxazoline) 2 and 10
mol% of copper salt under air atmosphere on 0.25 mmol scale. b Determined
by 1H NMR. c Determined by chiral HPLC. d Total isolated yield of cis- and
trans-isomers.
8 Most recently, Carreira used Cu(OAc)2 instead of Cu(I) to produce
copper acetylide in the presence of sodium ascorbate. See: T. F. Knopfel
and E. M. Carreira, J. Am. Chem. Soc., 2003, 125, 6054.
Substituents on the N-bound aromatic group of nitrones
influenced both the yield and the selection. Electron-rich ones
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