Initiator-dependent chemoselective addition of THF radical to aldehyde and aldimine and its application to a three-component reaction

Article abstract of DOI:10.1021/ol034473x

(Matrix presented) The product distribution of the three-component reaction of aldehydes, arylamines, and THF was dependent on a radical initiator, preferentially giving the corresponding THF adducts of imines with dimethylzinc and adducts of aldehyde wit

Full text of DOI:10.1021/ol034473x

ORGANIC
LETTERS
2003
Vol. 5, No. 10
1797-1799
Initiator-Dependent Chemoselective
Addition of THF Radical to Aldehyde
and Aldimine and Its Application to a
Three-Component Reaction
Ken-ichi Yamada, Yasutomo Yamamoto, and Kiyoshi Tomioka*
Graduate School of Pharmaceutical Sciences, Kyoto UniVersity, Yoshida, Sakyo-ku,
Kyoto 606-8501, Japan
tomioka@pharm.kyoto-u.ac.jp
Received March 19, 2003
ABSTRACT
The product distribution of the three-component reaction of aldehydes, arylamines, and THF was dependent on a radical initiator, preferentially
giving the corresponding THF adducts of imines with dimethylzinc and adducts of aldehyde with triethylborane.
Chemoselectivity has been one of the goals of organic
chemistry. Especially differentiation of CdO and CdN
double bonds as nucleophilic targets has been the topic of
recent allylation1 and Mannich-type reactions.2 However, to
the best of our knowledge, there has been no report on such
differentiation for radical reactions.3 We describe herein that
a THF radical4 undergoes chemoselective addition to alde-
hydes and aldimines depending on the choice of radical-
generating agents, dimethylzinc and triethylborane. The
chemoselectivity was well demonstrated in the three-
component reaction of aldehydes, amines, and THF.
We have recently reported radical addition reaction of
ethers with aldimines, in which methyl radicals, generated
from dimethylzinc as an initiator and molecular oxygen,
abstract an R-hydrogen of ethers to generate ether radicals,
(4) For the reaction of an ether radical, see: (a) Yoshimitsu, T.; Arano,
Y.; Nagaoka, H. J. Org. Chem. 2003, 68, 625-627. (b) Hirano, K.;
Sakaguchi, S.; Ishii, Y. Tetrahedron Lett. 2002, 43, 3617-3620. (c) Mosca,
R.; Fagnoni, M.; Mella, M.; Albini, A. Tetrahedron 2001, 57, 10319-
10328. (d) Kim, S.; Kim, N.; Chung, W.-J.; Cho, C. H. Synlett 2001, 937-
940. (e) Hirano, K.; Iwahama, T.; Sakaguchi, S.; Ishii, Y. Chem. Commun.
2000, 2457-2458. (f) Iwahama, T.; Sakaguchi, S.; Ishii, Y. Chem. Commun.
2000, 613-615. (g) Yoshimitsu, T.; Tsunoda, M.; Nagaoka, H. Chem.
Commun. 1999, 1745-1746. (h) Inoue, A.; Shinokubo, H.; Oshima, K.
Synlett 1999, 1582-1584. (i) Alves, M. J.; Gilchrist, T. L.; Sousa, J. H. J.
Chem. Soc., Perkin Trans. 1 1999, 1305-1310. (j) Xiang, J.; Evarts, J.;
Rivkin, A.; Curran, D. P.; Fuchs, P. L. Tetrahedron Lett. 1998, 39, 4163-
4166. (k) Xiang, J.; Jiang, W.; Fuchs, P. L. Tetrahedron Lett. 1997, 38,
6635-6638. (l) Xiang, J.; Jiang, W.; Gong, J.; Fuchs, P. L. J. Am. Chem.
Soc. 1997, 119, 4123-4129. (m) Xiang, J.; Fuchs, P. L. J. Am. Chem. Soc.
1996, 118, 11986-11987. (n) Gong, J.; Fuchs, P. L. J. Am. Chem. Soc.
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P. C. Tetrahedron Lett. 1996, 37, 909-912. (p) Ishida, A.; Sugita, D.; Itoh,
Y.; Takamuku, S. J. Am. Chem. Soc. 1995, 117, 11687-11694. (q) Jung,
J. C.; Choi, H. C.; Kim, Y. H. Tetrahedron Lett. 1993, 34, 3581-3584. (r)
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2973-2975. (t) Gevorgyan, V.; Priede, E.; Liepins, E.; Gavars, M.;
Lukevics, E. J. Organomet. Chem. 1990, 393, 333-338. (u) Russell, G.
(1) (a) Akiyama, T.; Iwai, J.; Onuma, Y.; Kagoshima, H. Chem. Commun.
1999, 2191-2192. (b) Akiyama, T.; Iwai, J. Synlett 1998, 273-274. (c)
Nakamura, H.; Iwama, H.; Yamamoto, Y. J. Am. Chem. Soc. 1996, 118,
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6, 3491-3494. (b) Shimizu, M.; Itohara, S. Synlett 2000, 1828-1830. (c)
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(3) For initiator-dependent chemoselective radical addition to CdO and
CdC double bonds, see: Devin, P.; Fensterbank, L.; Malacria, M.
Tetrahedron Lett. 1999, 40, 5511-5514.
10.1021/ol034473x CCC: $25.00 © 2003 American Chemical Society
Published on Web 04/10/2003

consequently giving the ether adducts of aldimines in high
yields.5-7 For example, the reaction of benzaldehyde N-4-
methoxyphenylimine (N-PMP-imine) 1 with THF was con-
ducted in the presence of 6 equiv of dimethylzinc under
constant air bubbling (10 mL/h), producing THF adduct 3a
in 83% yield after 5 h at room temperature (Table 1, entry
The initiator-dependent chemoselectivity was more high-
lighted by the reaction of imino-aldehyde 5 having both
carbonyl and imino groups (Scheme 1). Under the dimeth-
Scheme 1. Reaction of THF with Imino-aldehyde 5
Table 1. Initiator-Dependent Chemoselective Addition of THF
Radical to Benzaldehyde PMP-imine 1 and Benzaldehyde 2a
entry
1/2a
initiator (equiv)
t (h)
product
yield (%)
1
2
3
4
1
1
2a
2a
Me2Zn (6)
Et3B (12)
Me2Zn (12)
Et3B (12)
5
18
120
6
3a
3a a
4
83
63
<8
81
4
ylzinc-air conditions, the THF radical preferentially reacted
with the imino group to provide mono-THF adduct 6 in 81%
yield, and no other products resulting from the reaction of
THF with the aldehyde moiety were observed. In contrast,
under the triethylborane conditions, the addition of THF
occurred mainly to the carbonyl group, giving 7 as a major
product in 26% yield and di-THF adduct 8 in less than 5%
yield. Mono-THF adduct 6 further underwent the addition
reaction with THF under the triethylborane-air conditions,
giving 8 in 86% yield.
a An ethyl adduct of 1 was obtained in 26% yield.
1).8 As a logical extension of our approach, we then
examined the reaction of benzaldehyde 2a as a radical
acceptor, instead of aldimine 1. However, the addition
reaction of a THF radical with 2a was sluggish under the
dimethylzinc-air conditions, producing THF adduct 4 in less
than 8% yield even after 5 days (entry 3). This poor
efficiency is in dramatic contrast to the reaction of 2a with
the use of triethylborane-air as a radical initiator (a modified
Nagaoka procedure),4a,g giving 4 in 81% yield after 6 h (entry
4).9,10 It is also important to note that the reaction of 1 under
the triethylborane (12 equiv)-air conditions gave 3a in 63%
yield after prolonged reaction time of 18 h (entry 2).11
The chemoselectivity was more clearly demonstrated by
the reaction of a THF solution of a mixture of 2a and
p-anisidine 9a, those establishing equilibrium with an imine
and water (Scheme 2). A solution of 1 mmol each of 2a and
Scheme 2. Chemoselective THF Radical Addition Reaction of
an Equilibrium Mixture of 2a and 9a
A.; Ngoviwatchai, P. J. Org. Chem. 1989, 54, 1836-1842. (v) Citterio,
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(6) For radical reactions with dialkylzinc, see: (a) Bazin, S.; Feray, L.;
Siri, D.; Naubron, J.-V.; Bertrand, M. P. Chem. Commun. 2002, 2506-
2507. (b) Bertrand, M. P.; Feray, L.; Gastaldi, S. C. R. Chim. 2002, 5,
623-638. (c) Bertrand, M. P.; Coantic, S.; Feray, L.; Nouguier, R.; Perfetti,
P. Tetrahedron 2000, 56, 3951-3961. (d) Miyabe, H.; Konishi, C.; Naito,
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9193. (g) Ryu, I.; Araki, F.; Minakata, S.; Komatsu, M. Tetrahedron Lett.
1998, 39, 6335-6336.
(7) For reviews of radical addition to CdN bonds, see: (a) Ishibashi,
H.; Sato, T.; Ikeda, M. Synthesis 2002, 695-713. (b) Friestad, G. K.
Tetrahedron 2001, 57, 5461-5496. (c) Naito, T. Heterocycles 1999, 50,
505-541. (d) Fallis, A. G.; Brinza, I. M. Tetrahedron 1997, 53, 17543-
17594.
(8) Diastereomer ratios of the products described in this paper were
generally between 3:2 and 1:1 except for 3g (34:66), 4 (84:16), and 7
(7:7:43:43).
9a in 22 mL of THF was treated with 12 mmol of an initiator
(1.0 M solution in hexane) under a continuous air stream
(0.5 mL/h) at room temperature. By the dimethylzinc
(9) For reviews of radical reaction with organoborane, see: (a) Yorimitsu,
H.; Shinokubo, H.; Oshima, K. Synlett 2002, 674-686. (b) Olliver, C.;
Renaud, P. Chem. ReV. 2001, 101, 3415-3434.
(10) For radical addition to an aldehyde with triethylborane-air, see:
(a) Chareyron, M.; Devin, P.; Fensterbank, L.; Malacria, M. Synlett 2000,
83-85. (b) Devin, P.; Fensterbank, L.; Malacria, M. Tetrahedron Lett. 1998,
39, 833-836. See also refs 3, 4a, and 4g.
(11) For radical addition to an imino group with triethylborane-air,
see: (a) Ueda, M.; Miyabe, H.; Teramachi, M.; Miyata, O.; Naito, T. Chem.
Commun. 2003, 426-427. (b) Halland, N.; Jørgensen, K. A. J. Chem. Soc.,
Perkin Trans. 1 2001, 1290-1295. (c) Friestad, G. K.; Qin, J. J. Am. Chem.
Soc. 2001, 123, 9922-9923. (d) Miyabe, H.; Ueda, M.; Naito, T. J. Org.
Chem. 2000, 65, 5043-5047. (e) Miyabe, H.; Ueda, M.; Naito, T. Chem.
Commun. 2000, 2059-2060. (f) Miyabe, H.; Tanaka, H.; Naito, T.
1798
Org. Lett., Vol. 5, No. 10, 2003

initiation, THF-imine adduct 3a was preferentially isolated
in 74% yield after 21 h, whereas THF-aldehyde adduct 4
was obtained in 75% yield along with 3a (10%) and 9a
(65%) after 16 h under the triethylborane initiation. It is also
interesting to note that the reaction of the equilibrium mixture
in the presence of both initiators was not clean and gave a
mixture of 3a (13%), 4 (12%), ethyl adduct of aldimine (7%),
and aldimine 1 (56% recovery) after 12 days.
The utility of the imine-selective reaction with the use of
dimethylzinc initiator was further demonstrated by the
following three-component reaction of various aldehydes,
arylamines, and THF (Table 2).12 A mixture of benzaldehyde
robenzaldehyde 2b and 9a and 3e in 57% yield from
p-anisaldehyde 2c and 9a (entries 4 and 5). Acyclic and
cyclic aliphatic aldehydes 2d and 2e were also applicable,
giving 3f and 3g in 50 and 44% yields, respectively (entries
6 and 7). Thus, the three-component reaction can be
generalized.
The initiator-dependent chemoselective addition reaction
can be generalized and is interesting. Initiation by dimeth-
ylzinc favors THF-imine addition, and triethylborane initia-
tion provides a THF-aldehyde addition product. Mechanistic
details for the origin of the chemoselectivity are the focus
of our ongoing study.
Acknowledgment. This research was supported by a
Grant-in-Aid for Scientific Research from the Ministry of
Education, Culture, Sports, Science and Technology, Japan.
Table 2. Chemoselective Three-Component Reaction with the
Use of Dimethylzinc as an Initiator
Supporting Information Available: Experimental pro-
cedures and characterization data of the products. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL034473X
R1
9
R2
t (h)
3
yield (%)
(12) For recent examples of nonradical three-component reactions, see:
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2003, 59, 1599-1604. (b) Spanedda, M. V.; Hoang, V. D.; Crousse, B.;
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entry
2
1
2
3
4
5
6
7
2a Ph
2a Ph
2a Ph
2b 4-ClC6H4
2c PMP
9a PMP
9b Ph
9c 4-CF3C6H4
9a PMP
9a PMP
22 3a
16 3b
22 3c
22 3d
45 3e
46 3f
138 3g
74
66
47
64
57
50
44
2d PhCH2CH2 9a PMP
2e c-C6H11 9a PMP
2a with aniline 9b and 4-trifluoromethylaniline 9c in THF
provided THF adduct 3b in 66% yield and THF adduct 3c
in 47% yield (entries 2 and 3). The reaction also proceeded
smoothly whether aldehydes had an electron-withdrawing
or -donating group, giving 3d in 64% yield from 4-chlo-
Tetrahedron Lett. 1999, 40, 8387-8390. (g) Miyabe, H.; Fujii, K.; Naito,
T. Org. Lett. 1999, 1, 569-572. (h) Miyabe, H.; Shibata, R.; Sangawa, M.;
Ushiro, C.; Naito, T. Tetrahedron 1998, 54, 11431-11444. (i) Bertrand,
M. P.; Feray, L.; Nouguier, R.; Stella, L. Synlett 1998, 780-782. (j) Miyabe,
H.; Ushiro, C.; Naito, T. Chem. Commun. 1997, 1789-1790. See also refs
6b-f.
Org. Lett., Vol. 5, No. 10, 2003
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