S. Lee, S. Kim / Tetrahedron Letters 50 (2009) 3345–3348
3347
Table 4
Modification on imines
Ph
Ph
X
N
X
i-PrI, t-BuSH, 4a, TTMSSH, Et3B/O2
HN
HN
Ph
Et-I, TTMSSH, 4a, Et3B/O2
HN
Ph
6k
+
THF
Ph
i-Pr
Et
THF, -40 oC
Ph
Et
10a
7k
6a-n
7a-n
-40 oC 45%, 69% ee 9%, 78% ee
-78 oC 52%, 72% ee 21%, 82% ee
Entry
X
Time (h)
Yield (%)
42
ee (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
6a
6b
6c
6d
6e
6f
6g
6h
6i
Ph
24
24
24
24
24
24
6
12
24
24
24
6
77
19
68
76
53
23
64
65
19
60
83
1
Scheme 3. Effect of polarity-reversal catalyst.
a
2-MePh
3-MePh
4-MePh
4-MeOPh
2-ClPh
4-ClPh
4-BrPh
1-Naph
2-Naph
4-Ph–Ph
Tosyl
36 (27)
29 (15)
a
23
12
24 (16)
with the present reaction is the formation of the ethyl radical addi-
tion byproduct (20–35%), which is due to competition between the
iodine atom transfer and the direct addition of the ethyl radical to
the imine.
a
62
61
10
34
56
In order to reduce the formation of the byproduct, tert-butyl
mercaptan was employed as a polarity-reversal catalyst.16 Since
the hydrogen atom transfer from an alkyl mercaptan to a nucleo-
6j
6k
6l
6m
6n
b
30 (39)
philic alkyl radical (k = 7.2 ꢁ 106 Mꢀ1sꢀ1 17
)
is much faster than that
OBn
NHNTs
24
24
NR
NR
from TTMSSH (k = 7.0 ꢁ 103 Mꢀ1sꢀ1),18 the ethyl radical would be
captured by the alkyl mercaptan prior to its addition onto the
imine. As we expected, in the presence of 2.0 equiv of tert-butyl
mercaptan, the ratio of the ethyl addition product 7k to the desired
product 10a was increased to 5 to 1 from 1.75 to 1, but at the same
time the enantioselectivity was reduced to 69% ee at ꢀ40 °C
(Scheme 3). At ꢀ78 °C the enantioselectivity was slightly increased
to 72% ee but 21% of 7k was isolated.
Reaction condition is the same as that in Table 2.
Benzaldehyde from decomposition by 1H NMR with mesitylene as internal
a
standard.
b
Reduction product (PhCH2NHX).
6). The low chemical yields with 2-substituted imines seemed to
result from their instability (entries 2 and 6). Furthermore, 1-
and 2-naphthyl imines 6i and 6j were not attractive in chemical
yield and the ee. The best ee was achieved with 4-biphenyl imine
6k (83% ee) (entry 11). In addition, more electrophilic tosyl imine
6l afforded a mixture of the desired addition product along with
the direct reduction product (30%) (entry 12). In the cases of O-
benzyl imine 6m and N-tosyl hydrazone 6n, the reaction did not
proceed.
To determine the scope and limitation of the present method,
the reaction was carried out with several phenyl imine derivatives
using several alkyl radicals and the experimental results are sum-
marized in Table 5. When isopropyl iodide and tert-butyl iodide
were used, the same level of enantioselectivities was obtained (en-
tries 2 and 3). The enantioselectivities were not altered by modify-
ing the electronic properties of the benzene ring (entries 4–9) and
ranged from 73% ee to 84% ee. Another important issue associated
In summary, we have developed the enantioselective radical
addition reactions to imines using chiral N-triflyl phosphoramide
catalyst 4a with various substrates. The enantioselectivities were
ranged from 73% to 84% and were not affected by electronic prop-
erties of imines. To obviate the problem of the ethyl radical addi-
tion byproduct along with higher ee, further studies are underway.
Acknowledgments
We thank Korea Science and Engineering Foundation (R01-
2007-000-21315-0) and the KEPCO for financial support.
References and notes
1. For reviews: (a) Sibi, M. P.; Manyem, S.; Zimmerman, J. Chem. Rev. 2003, 103,
3263; (b) Bar, G.; Parsons, A. F. Chem. Soc. Rev. 2003, 32, 251; (c)Radicals in
Organic Synthesis; Renaud, P., Sibi, M. P., Eds.; Wiley-VCH: Weinheim, 2001;
Vols. 1 and 2, (d) Curran, D. P.; Porter, N. A.; Giese, B. Stereochemistry of Radical
Reactions. Concepts, Guidelines and Synthetic Applications; VCH: Weinheim,
1996; (e) Sibi, M. P.; Porter, N. A. Acc. Chem. Res. 1999, 32, 163; (f) Sibi, M. P.;
Manyem, S. Tetrahedron 2000, 56, 8033.
2. (a) Friestad, G. K.; Shen, Y.; Ruggles, E. L. Angew. Chem., Int. Ed. 2003, 42, 5061;
(b) Jang, D. O.; Cho, D. H. Chem. Commun. 2004, 5045; (c) Jang, D. O.; Kim, S. Y. J.
Am. Chem. Soc. 2008, 130, 16152.
Table 5
Radical addition reactions of various substrates15
Ph
Ph
3. For reveiws: (a) Akiyama, T. Chem. Rev. 2007, 107, 5744; (b) Doyle, A. G.;
Jacobsen, E. N. Chem. Rev. 2007, 107, 5713; (c) Taylor, M. S.; Jacobsen, E. N.
Angew. Chem., Int. Ed. 2006, 45, 1520; (d) Akiyama, T.; Itoh, J.; Fuchibe, K. Adv.
Synth. Catal. 2006, 348, 999; (e) Terada, M. Chem. Commun. 2008, 4097.
4. (a) Akiyama, T.; Itoh, J.; Yokota, K.; Fuchibe, K. Angew. Chem., Int. Ed. 2004, 43,
1566; (b) Uraguchi, D.; Terada, M. J. Am. Chem. Soc. 2004, 126, 5356.
5. Nakashima, D.; Yamamoto, H. J. Am. Chem. Soc. 2006, 128, 9626.
6. Uraguchi, D.; Sorimachi, K.; Terada, M. J. Am. Chem. Soc. 2005, 127, 9360.
7. Terada, M.; Machioka, K.; Sorimachi, K. Angew. Chem., Int. Ed. 2006, 45, 2254.
8. (a) Uraguchi, D.; Sorimachi, K.; Terada, M. J. Am. Chem. Soc. 2004, 126, 11804;
(b) Rowland, G. B.; Rowland, E. B.; Liang, Y.; Perman, J. A.; Antilla, J. C. Org. Lett.
2007, 9, 2609; (c) Kang, Q.; Zhao, Z.-A.; You, S.-L. J. Am. Chem. Soc. 2007, 129,
1484.
R-I, TTMSSH, 5a, Et3B/O2
N
HN
THF, -40 oC, 24 h
Ar
Ar
R
6k, 8, 9
7k, 10a-b, 11a-c, 12a-c
Entry
Ar
R
Pdt
Yield (%)
ee (%)
1
2
3
4
5
6
7
8
9
6k
6k
6k
8
8
8
9
9
9
Ph
Et
7k
56
83
Ph
Ph
i-Pr
t-Bu
Et
i-Pr
t-Bu
Et
10a
10b
11a
11b
11c
12a
12b
12c
35 (20)a
36 (31)a
77
75 (75)a
80 (83)a
73
4-MeOPh
4-MeOPh
4-MeOPh
4-ClPh
4-ClPh
4-ClPh
9. Rueping, M.; Theissmann, T.; Kuenkel, A.; Koenigs, R. M. Angew. Chem., Int. Ed.
2008, 47, 6798.
46 (35)a
56 (33)a
71
81 (65)a
74 (4)a
84
10. (a) Rueping, M.; Sugiono, E.; Azap, C.; Theissmann, T.; Bolte, M. Org. Lett. 2005,
7, 3781; (b) Hoffmann, S.; Seayad, A. M.; List, B. Angew. Chem., Int. Ed. 2005, 44,
7424; (c) Storer, R. I.; Carrera, D. E.; Ni, Y.; MacMillan, D. W. C. J. Am. Chem. Soc.
2006, 128, 84; (d) Martin, N. J. A.; List, B. J. Am. Chem. Soc. 2006, 128, 13368.
11. For other applications, phosphorylation: (a) Akiyama, T.; Morita, H.; Itoh, J.;
Fuchibe, K. Org. Lett. 2005, 7, 2583; Amination: (b) Rowland, G. B.; Zhang,
H.; Rowland, E. B.; Chennamadhavuni, S.; Wang, Y.; Antilla, J. C. J. Am. Chem.
i-Pr
t-Bu
43 (29)a
31 (29)a
75 (81)a
78 (85)a
Reaction condition is the same as that in Table 2.
a
Ethyl addition product.