A R T I C L E S
Escoubet et al.
Figure 1.
amines 2a,b that resulted from the cleavage of the prenyl group.
This experimental observation was all the more intriguing as
no trace of prenyl benzylamine (4) (Figure 1), that would have
resulted from the cleavage of the most highly branched allylic
C-N bond, was detected.
A series of blank experiments led to the conclusion that both
the thiol and the radical initiator were needed for the reaction
to proceed, which of course pointed to a radical mechanism.
This article describes all the studies that were carried out in
order to determine the scope and limitations of this reaction.
As disclosed in the following discussion, the reaction involves
the thiyl radical-catalyzed migration of the double bond, leading
to the corresponding enamine, which is then hydrolyzed.
Theoretical calculations of S-H and C-H bond dissociation
energies were performed using density functional theory (DFT)
in order to reach a better understanding of the factors controlling
the reactivity of thiols toward a series of allylic amines (cf. Table
Figure 2.
Table 1. Deprenylation of Tertiary and Secondary Amines
substrate
product
yield, %
a
b
5a
6a
97, 64
e
7
9
9
8
c
a
5b
6b
77
57d
a
5c
6c
5d
6e
57
a
5
5
d
e
25% recovery
a
98
2
for S-H BDEs, and Table 3 for the C-H BDEs obtained by
a
TolSH, 1.2 equiv. b hν, room temperature. c TolSH, 0.1 equiv. d TolSH,
using UB3LYP/6-311++G(3df,3pd) and UB3LYP/6-31+G(d,p)
single-point energies on UB3LYP/6-31+G(d,p)-optimized
0
.2 equiv. e TolSH, 1.2 equiv, CH3CN, reflux.
7a
geometries ). The incidence of stereoelectronic factors was
7
b
only one allylic chain was selected to investigate the reaction
mechanism (Figure 2).
analyzed by using the natural bond orbital method (NBO).
Results and Discussion
Reactions using a stoichiometric amount of thiol (1.2 equiv)
were carried out first. The results are summarized in Table 1
(conditions described in footnote a). Yields varied within the
range of 57-98%, except for 5d, which was partially recovered
(a) Reactivity of Prenylamines in the Presence of a
Stoichiometric Amount of Thiol. A series of amines bearing
(
2) (a) Gigg, R.; Conant, R. J. Carbohydr. Chem. 1983, 1, 331. (b) Mori, M.;
Ban, Y. Chem. Pharm. Bull. 1976, 24, 1992. (c) Moreau, B.; Marquet, A.
Tetrahedron Lett. 1977, 30, 2591. (d) Corey, E. J.; Suggs, J. W. J. Org.
Chem. 1973, 38, 3224. (e) Laguzza, B. C.; Ganem, B. Tetrahedron Lett.
1
unchanged (25% based on H NMR using pentamethylbenzene
as internal standard). Most of the starting material was degraded
into unidentified products; however, 1,2,3,4-tetrahydroisoquino-
line (6d) was not detected. In a blank experiment, 6d was reacted
with TolSH (1.2 equiv) in the presence of AIBN for 7 h. Based
1
981, 22, 1483. (f) Mitsudo, T.-A.; Zhang, S.-W.; Satake, N.; Kondo, T.;
Watanabe, Y. Tetrahedron Lett. 1992, 33, 5533. (g) Alcaide, B.; Almendros,
P.; Alonso, J. M.; Aly, M. F. Org. Lett. 2001, 3, 3781. (h) Picq, D.; Cottin,
M.; Anker, D.; Pacheco, H. Tetrahedron Lett. 1983, 24, 1399. (i) Carless,
H. A. J.; Haywood, D. J. J. Chem. Soc., Chem. Commun. 1980, 980. (j)
Tomori, H.; Shibutami, K.; Ogura, K. Heterocycles 1997, 44, 213. (k)
Hubert, A. J.; Moniotte, P.; Goebbels, G.; Warin, R.; Teyssie, P. J. Chem.
Soc., Perkin Trans. 2 1973, 1954. (l) Barolo, P.; Rossi, P. F. Ann. Chim.
1
on the H NMR spectrum of the crude mixture, 63% remained
unchanged. If ever it had been formed throughout the de-
prenylation of 5d, it should have been detected.
(Rome) 1969, 59, 268. (m) Hubert, A. J.; Georis, A.; Warin, R.; Teyssi e´ ,
P. J. Chem. Soc., Perkin Trans. 2 1972, 366. (n) Kumobayashi, H.;
Akutagawa, S. J. Am. Chem. Soc. 1978, 100, 3949. (o) Yamamoto, A.;
Kitazume, S.; Pu, L. S.; Ikeda, S. J. Am. Chem. Soc. 1971, 93, 371. (p)
Taniguchi, T.; Ogasawara, K. Tetrahedron Lett. 1998, 39, 4679. For the
catalytic isomerization of N-allylamines, see also: (q) Novak, B. M.;
Cafmeyer, J. T. J. Am. Chem. Soc. 2001, 123, 11083.
It can be noted that the reaction also worked at reflux in
acetonitrile (conditions described in Table 1, footnote e), and
at room temperature under photochemical initiation, but gave
lower yields (conditions described in footnote b).
(
3) (a) De Riggi, I.; Gastaldi, S.; Surzur, J.-M.; Bertrand, M. P.; Virgili, A. J.
Org. Chem. 1992, 57, 6118. (b) De Riggi, I.; Nouguier, R.; Surzur, J.-M.;
Bertrand, M. P.; Jaime, C.; Virgili, A. Bull. Soc. Chim. Fr. 1993, 130,
As shown in Scheme 2, when 5c was allowed to react with
p-thiocresol (1.2 equiv) in the presence of AIBN in benzene at
2
29. (c) Bertrand, M. P.; De Riggi, I.; Lesueur, C.; Gastaldi, S.; Nouguier,
reflux, thioaminal 9c was identified as the precursor of amine
R.; Jaime, C.; Virgili, A. J. Org. Chem. 1995, 60, 6040. (d) Bertrand, M.
P.; Gastaldi, S.; Nouguier, R. Tetrahedron Lett. 1996, 37, 1229. (e) Lesueur,
C.; Nouguier, R.; Bertrand, M. P.; Hoffmann, P.; De Mesmaeker, A.
Tetrahedron 1994, 50, 5369. (f) Bertrand, M. P.; Lesueur, C.; Nouguier,
R. Carbohydrate Lett. 1995, 1, 393. (g) Bertrand, M. P.; Gastaldi; S.;
Nouguier, R. Tetrahedron 1998, 54, 12829. (h) Nouguier, R.; Gastaldi, S.;
Stien, D.; Bertrand, M.; Renaud, P. Tetrahedron Lett. 1999, 40, 3371.
4) For general reviews, see: (a) Bertrand, M. P.; Ferreri, C. In Radicals in
Organic Synthesis; Renaud, P., Sibi, M., Eds.; Wiley-VCH: Weinheim,
1
6
c from the analysis of the H NMR spectrum of the crude
8
reaction mixture. This confirmed the validity of the above-
(7) (a) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb,
M. A.; Cheeseman, J. R.; Zakrzewski, V. G.; Montgomery, J. A., Jr.;
Stratmann, R. E.; Burant, J. C.; Dapprich, S.; Millam, J. M.; Daniels, A.
D.; Kudin, K. N.; Strain, M. C.; Farkas, O.; Tomasi, J.; Barone, V.; Cossi,
M.; Cammi, R.; Mennucci, B.; Pomelli, C.; Adamo, C.; Clifford, S.;
Ochterski, J.; Petersson, G. A.; Ayala, P. Y.; Cui, Q.; Morokuma, K.;
Malick, D. K.; Rabuck, A. D.; Raghavachari, K.; Foresman, J. B.;
Cioslowski, J.; Ortiz, J. V.; Stefanov, B. B.; Liu, G.; Liashenko, A.; Piskorz,
P.; Komaromi, I.; Gomperts, R.; Martin, R. L.; Fox, D. J.; Keith, T.; Al-
Laham, M. A.; Peng, C. Y.; Nanayakkara, A.; Gonzalez, C.; Challacombe,
M.; Gill, P. M. W.; Johnson, B. G.; Chen, W.; Wong, M. W.; Andres, J.
L.; Head-Gordon, M.; Replogle, E. S.; Pople, J. A. Gaussian 98, revision
A.11.4; Gaussian, Inc.: Pittsburgh, PA, 1998. (b) Reed, A. E.; Curtiss, L.
A.; Weinhold, F. Chem. ReV. 1988, 88, 899.
(
2
001; Vol. 2, pp 485-503. (b) Chatgilialoglu, C.; Bertrand, M. P.; Ferreri,
C. In S-Centered Radicals; Alfassi, Z. B., Ed.; Wiley: Chichester, 1999;
pp 312-354. (c) Crich D. In Organosulfur Chemistry; Page, P., Ed.;
Academic Press: London, 1995; Vol. 1, pp 49-88. (d) Chatgilialoglu, C.;
Guerra, M. In Supplement S: The Chemistry of Sulphur-Containing
Functional Groups; Patai, S., Rappoport, Z., Eds.; Wiley: Chichester, 1993;
pp 363-394.
(
5) Bertrand, M. P.; Escoubet, S.; Gastaldi, S.; Timokhin, V. I. J. Chem. Soc.,
Chem. Commun. 2002, 216.
(6) Gastaldi, S. Thesis, Marseille, 1997.
12344 J. AM. CHEM. SOC.
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VOL. 126, NO. 39, 2004