Pd·Et3B-catalyzed alkylation of amines with allylic alcohols

Article abstract of DOI:10.1039/b210920d

A combination of catalytic amounts of Pd (0.05 mmol) and Et₃B (0.3 mmol) promotes allylic alkylation of primary and secondary aromatic and aliphatic amines (1.0 mmol) by the direct use of allylic alcohols, providing tertiary amines in excellent yields under mild conditions (room temperature ～ 50°C).

Full text of DOI:10.1039/b210920d

Pd·Et3B-catalyzed alkylation of amines with allylic alcohols†
Masanari Kimura,* Makoto Futamata, Kazufumi Shibata and Yoshinao Tamaru*
Department of Applied Chemistry, Faculty of Engineering, Nagasaki University, 1-14 Bunkyo-machi,
Nagasaki 852-8521, Japan. E-mail: masanari@net.nagasaki-u.ac.jp, tamaru@net.nagasaki-u.ac.jp;
Fax: +81-95-847-9008; Tel: +81-95-847-9008
Received (in Cambridge, UK) 7th November 2002, Accepted 25th November 2002
First published as an Advance Article on the web 9th December 2002
A combination of catalytic amounts of Pd (0.05 mmol) and
Et3B (0.3 mmol) promotes allylic alkylation of primary and
secondary aromatic and aliphatic amines (1.0 mmol) by the
direct use of allylic alcohols, providing tertiary amines in
excellent yields under mild conditions (room temperature
~ 50 °C).
interesting observation that catalytic amounts of Et3B and Et3N
(0.3 equivalents each) are sufficient enough to promote the a-
alkylation of alkyl aldehydes.7 Taking into consideration that
Et3B and Et3N form a tight 1+1 Lewis acid–base complex;8 our
observation suggests that the presence of very tiny fractions of
free Et3B and Et3N, in the Lewis acid–base equilibrium, is
responsible for the reaction. This posed a question; what takes
place when alkylation is carried out in the presence of a large
excess of amine? Does Et3B still maintain its capability of
activating allylic alcohols under such conditions?
An ideal way to address this question may be to examine the
alkylation of an amine itself since, under such conditions, the
amine is necessarily present in a large excess as compared with
Et3B during the whole course of the reaction. Herein we
disclose that a catalytic amount of Et3B efficiently promotes the
Pd-catalyzed alkylation of primary and secondary aromatic and
aliphatic amines directly using allylic alcohols with a wide
range of structural variety.
The alkylation of N-methylaniline (1.0 mmol) with allyl
alcohol (1.2 mmol) was first examined in the presence of
Pd(PPh3)4 (5 mol%) and an excess amount of Et3B (2.4 mmol)
in THF at room temperature under N2 (eqn. (1) and run 1 in
Table 1). The reaction proceeded smoothly and was completed
after 30 h, giving rise to the expected alkylation product 1a in
84% isolated yield. Significantly, as is shown in run 2, a
catalytic amount of Et3B turned out to effectively promote the
reaction. Moreover, the reaction with a catalytic amount of Et3B
gave 1a in a better yield within the same reaction time. Both the
Pd catalyst and Et3B, of course, were indispensable. In the
absence of either of them, no alkylation took place and N-
methylaniline was recovered (e.g., run 3). Dibenzylamine was
remarkably reactive, and the reaction was completed within 5 h
at room temperature with 0.3 equivalents of Et3B, providing 1b
in quantitative yield (run 4). On the other hand, dicyclohex-
ylamine, although belonging to the same class of secondary
alkyl amines but being quite different in the steric bulk, was
marginally successful under the conditions applied to runs 1 and
2 (46% isolated yield, at 50 °C for 24 h). After screening of
Palladium-catalyzed C–N bond formation is an efficient,
indispensable method for the synthesis of nitrogen-containing
natural and unnatural compounds of physiological interest.1
Allylic alkylation of nitrogen-nucleophiles catalyzed by palla-
dium has been widely explored so far;2 however, although being
the most straightforward and desirable from a practical,
economical, and environmental point of view, the direct use of
allylic alcohols as the allylating agents has been limited3
primarily owing to the poor capability of the hydroxy group as
a leaving group.
Recently, we have disclosed that allylic alcohols are
converted directly to the corresponding p-allylpalladium inter-
mediates in the presence of Et3B and a catalytic amount of a Pd
species. The thus-formed p-allylpalladium species are reactive
enough to undergo a-alkylation of soft carbon-nucleophiles,
such as malonates, Meldrum’s acid,4 o-hydroxyphenyl alkyl
ketones,5 and primary and secondary alkyl aldehydes [eqn.
(1)].6
(1)
The palladium-catalyzed a-alkylation of alkyl aldehydes
with allylic alcohols requires Et3B (2.4 equivalents) and Et3N
(1.2 equivalents). Originally, we expected the primary role of
Et3B as a Lewis acid to activate allylic alcohols and that of Et3N
as a Lewis base to generate the enols of aldehydes activated by
coordination with Et3B. Recently, however, we have made an
† Electronic supplementary information (ESI) available: experimental
section. See http://www.rsc.org/suppdata/cc/b2/b210920d/
Table 1 Pd·Et3B promoted direct allylation of amines with allyl alcohola
a Reaction conditions: amine (1 mmol), allyl alcohol (1.2 mmol in runs 1–5; 3.0 mmol in runs 6–9), Pd catalyst (0.05 mmol), n-Bu3P (0.2 mmol) and Et3B
(indicated amount) in dry THF (5 mL) under nitrogen.
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CHEM. COMMUN., 2003, 234–235
This journal is © The Royal Society of Chemistry 2003

several kinds of Pd complexes and ligands, the combination of
Pd(OAc)2 and n-Bu3P turned out to be satisfactory in terms of
the yield of 1c and the reaction rate (run 5).
For the alkylation of primary amines, 3 equivalents of allyl
alcohol were applied. The alkylation of aniline stopped halfway
and provided a mono-alkylation product 1d in a considerable
amount (37%) together with a dialkylation product 1e (51%, run
6). Alkyl amines were reactive enough and provided dialkyla-
tion products in excellent yields (runs 8 and 9). Surprisingly, in
sharp contrast to the reaction of dibenzylamine, Pd(PPh3)4 was
decisively ineffective for the alkylation of benzylamine (run 7);
neither mono- nor dialkylation product was obtained at all.
The results for the alkylation of N-methylaniline with other
allylic alcohols of a wide structural variety are summarized in
Table 2, which reveal that the reaction is successful with
primary, secondary, and tertiary allylic alcohols. Allylic
alcohols bearing a methyl or a phenyl substituent either at the a-
or the g-position were converted exclusively into the corre-
sponding g-substituted allylamines with excellent stereose-
lectivity; thus, N-methylaniline was delivered at the least
substituted allylic terminus. Crotyl alcohol and a-methallyl
alcohol underwent alkylation with similar ease and provided N-
2-butenyl-N-methylaniline (1h) in almost the same yields and
with almost the same stereoselectivity (runs 1 and 2, Table 2).
These results apparently indicate that each of the two pairs of
reactions (runs 1 and 2; 3 and 4) proceeds via a common p-
allylpalladium intermediate. It should be noted that b-methallyl
alcohol provided 1j in excellent yield (run 5); Pd-catalyzed
alkylation of amines with b-substituted allylating agents are
sometimes low yielding.3b,c
Scheme 1 Plausible reaction mechanism for allylic alkylation of N-
methylaniline promoted by Pd·Et3B.
Et3B·OH, for an amine and the thus-formed amino(p-allyl)pal-
ladium(II) intermediate II would undergo reductive elimination
to furnish trans-3 with overall inversion of configuration. The
stereochemical outcome of the present reaction is in accord with
that reported for the Pd-catalyzed allylic amination of an acetic
acid ester analog of 2 with diethylamine.11
In conclusion, we have demonstrated that a combination of
Pd(0) and Et3B, both in a catalytic amount, nicely promotes the
di-alkylation of primary and the mono-alkylation of secondary
aromatic and aliphatic amines by the direct use of allylic
alcohols with a wide structural variety under mild conditions.
The reaction proceeds with exclusive regioselectivity, giving
rise to amines with the least branched allyl groups at the a-
position and with high E-selectivity with respect to the allylic
double bonds. The reaction, however, is not diastereoselective,
and a cis-3-hydroxycyclohexenyl derivative furnishes a mixture
of cis- and trans-3-aminocyclohexenes.
The reaction of cis-5-methoxycarbonylcyclohexen-3-ol (2)
with N-methylaniline in the presence of Pd(PPh3)4 and Et3B led
to a stereoisomeric mixture of cis- and trans-3 in a 2.6+1 ratio
[eqn. (2)].9 A rationale for this reaction is outlined in
We thank the Ministry of Education, Science, Sports and
Culture, Japanese Government, for financial support.
(2)
Notes and references
Scheme 1.10 Triethylborane may coordinate to the hydroxy
group of 2 to help it undergo oxidative addition to Pd(0). A
trans-p-allylpalladium intermediate I, formed via inversion of
configuration, may be subject to two pathways; one (path A)
involves displacement of Pd(0) via an attack of an amine on the
distal face of the cyclohexenyl ring with respect to Pd, which
gives rise to cis-3 with overall retention of configuration. The
other (path B) involves an exchange of the ligand on Pd(II),
1 (a) Y. Tamaru and M. Kimura, SYNLETT, 1997, 749; (b) L. S. Hegedus,
in, Comprehensive Organic Synthesis, eds. B. M. Trost and I. Fleming,
Pergamon, Oxford, U.K., 1991, vol. 4, pp. 551; (c) F. M. Hauser and S.
R. Ellenberger, Chem. Rev., 1986, 85, 35.
2 J. Tsuji, Transition Metal Reagents and Catalysis, Wiley, Chichester,
2000.
3 (a) F. Ozawa, H. Okamoto, S. Kawagishi, S. Yamamoto, T. Minami and
M. Yoshifuji, J. Am. Chem. Soc., 2002, 124, 10968; (b) S.-C. Yang and
C.-W. Hung, J. Org. Chem., 1999, 64, 5000; (c) J. Qu, Y. Ishimura, T.
Oe and N. Nagato, Nippon Kagaku Kaishi, 1996, 250; (d) Y. Masuyama,
M. Kagawa and Y. Kurusu, Chem. Lett., 1995, 1121; (e) K. E. Atkins,
W. E. Walter and R. M. Manyik, Tetrahedron Lett., 1970, 43, 3821.
4 Y. Tamaru, Y. Horino, M. Araki, S. Tanaka and M. Kimura,
Tetrahedron Lett., 2000, 41, 5705.
Table 2 Pd·Et3B promoted allylation of N-methylaniline with allylic
alcoholsa
5 Y. Horino, M. Naito, M. Kimura, S. Tanaka and Y. Tamaru,
Tetrahedron Lett., 2001, 42, 3113.
6 M. Kimura, Y. Horino, R. Mukai, S. Tanaka and Y. Tamaru, J. Am.
Chem. Soc., 2001, 123, 10401.
7 Unpublished data: A mixture of Et3B (0.3 mmol) and Et3N (0.3 mmol)
promotes the alkylation of 2-phenylpropanal (1.2 mmol) with cinnamyl
alcohol (1.0 mmol) in the presence of Pd(OAc)2 (0.05 mmol), PPh3 (0.1
mmol), and LiCl (1.0 mmol) in THF at 50 °C for 22 h, yielding
2,5-diphenyl-2-methyl-4-pentenal in 83% isolated yield.
8 H. C. Brown, H. Bartholomay Jr. and M. D. Taylor, J. Am. Chem. Soc.,
1944, 66, 435.
9 2-Cyclohexen-1-ol was exceptionally unreactive; N-methylaniline, in
the presence of 0.3, 1.0, and 2.4 equivalents of Et3B, provided a
corresponding allylation product in 26, 45, and 96% yield, respectively,
at 50 °C for 30 ~ 50 h. Accordingly, for the reaction of 2, an excess
amount of Et3B was employed [eqn. (2)].
10 Isomerization of a trans-p-allylpalladium I into the corresponding cis-
isomer via an intermolecular Pd(II) exchange mechanism might be
responsible for the production of a mixture of cis- and trans-3.
11 B. M. Trost and E. Keinan, J. Am. Chem. Soc., 1978, 100, 7779.
a The reaction was undertaken in the presence of N-methylaniline (1 mmol),
allylic alcohol (1.2 mmol), Pd(PPh3)4 (0.05 mmol), and Et3B (indicated
amount) in dry THF (5 mL) under nitrogen atmosphere. b A mixture of
crotyl alcohol (E+Z = 9+1) was used.
CHEM. COMMUN., 2003, 234–235
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