Efficient three-component one-pot benzylation and allylation of aldehydes and amines for synthesis of homobenzylamines and homoallylamines

Article abstract of DOI:10.1021/jo062616y

(Chemical Equation Presented) A highly efficient, three-component one-pot benzylation and allylation of aromatic and aliphatic aldehydes and amines affords the corresponding homobenzylamines and homoallylamines in good to excellent yield. The procedure is

Full text of DOI:10.1021/jo062616y

reactivity of other imines. The inclination of the R-deprotonation
of aliphatic imines significantly reduces the versatility of the
reactions involving basic organometallic reagents. The ap-
plicability is therefore limited within the scope of the imines
derived from nonenolizable or R-alkyl-substituted aliphatic
aldehydes.4
Efficient Three-Component One-Pot Benzylation
and Allylation of Aldehydes and Amines for
Synthesis of Homobenzylamines and
Homoallylamines
Renhua Fan,* Dongming Pu, Luoheng Qin, Fengqi Wen,
Guoping Yao, and Jie Wu*
Significant advances have been made in the Barbier-type
imine alkylation in recent years.5 Most of them, however, have
been focused on the imine allylation because of the favorable
reactivity of allylic organometallic reagents as the result of the
resonance stabilization of the allyl anion.6 The difficulty in both
synthesis and stability of the imines derived from aliphatic
aldehydes and amines makes a multicomponent one-pot pro-
cedure for allylation of imines preferred in practice. On the other
hand, compared to the extensive studies on the allylation of
imines,7 the benzylation of imines has received much less
scrutiny until recently.8 We report herein the results regarding
a three-component one-pot benzylation and allylation of aro-
matic and aliphatic aldehydes and amines under the Barbier-
type conditions. The simplicity of the procedure lies in the fact
that no further activation of the zinc powder and no isolation
of the unstable imine intermediates are necessary.
Department of Chemistry, Fudan UniVersity, 220 Handan Road,
Shanghai 200433, China
frenhua@yahoo.com
ReceiVed December 20, 2006
In 1996, Hou’s group has reported an efficient allylation of
inactivated aldimines under the Barbier-type conditions using
allyl bromide and zinc dust in anhydrous tetrahydrofuran
(THF).7e However, the benzylation of imine 1 did not give rise
to the expected benzylation product 2 under the same conditions
but a reduction N-benzylation byproduct 3 in 82% yield (eq 1).
A highly efficient, three-component one-pot benzylation and
allylation of aromatic and aliphatic aldehydes and amines
affords the corresponding homobenzylamines and homoal-
lylamines in good to excellent yield. The procedure is lauded
by its simplicity and manipulability.
In carbon-carbon bond formation reactions, the addition of
organometallic reagents to imines provides a versatile method
for the synthesis of amines.1 The versatility, however, was
compromised by the poor electrophilicity of the azomethine
carbon of imines, which gives rise to the competitive byproducts
through reduction, enolization, or coupling reaction as well as
to the desirable adducts.1d In order to expand the scope of the
organometallic addition to imines, several approaches have been
exploited. The CdN bond could be activated by an electron-
withdrawing group on nitrogen. The use of N-activated imines,
however, is generally restricted in nonenolizable aldimines. This
approach is further complicated by the harsh deprotection
condition if the removal of the N-protecting group is necessary.2
An alternative method is to activate the N-inactivated imine by
coordinating a Lewis acid to the nitrogen of the CdN moiety.
The applicability of this approach is possibly hampered by other
Lewis basic centers in the imine structure.3 In most of the cases,
imines are mainly restricted to aryl aldimines due to the low
In the following condition screening experiments, the benzy-
lation product 2 could be detected with moist THF as solvent
while the yield of 3 decreased to 26%. When 1 equiv of H2O
(3) (a) Katritzky, A. R.; Hong, Q.; Yang, Z. J. Org. Chem. 1994, 59,
7947. (b) Katritzky, A. R.; Hong, Q.; Yang, Z. J. Org. Chem. 1995, 60,
3405.
(4) (a) Stork, G.; Dowd, S. R. J. Am. Chem. Soc. 1963, 85, 2178. (b)
Huet, J. Bull. Soc. Chim. Fr. 1964, 952.
(5) For selected recent examples, see: (a) Sain, B.; Prajapati, D.; Sandhu,
J. S. Tetrahedron Lett. 1992, 33, 4795. (b) Bhuyan, P. J.; Prajapati, D.;
Sandhu, J. S. Tetrahedron Lett. 1992, 33, 7975. (c) Lu, W.; Chan, T. H.
J. Org. Chem. 2001, 66, 3467. (d) Lu, W.; Chan, T. H. J. Org. Chem.,
2000, 65, 8589.
(6) For selected recent examples, see: (a) Shen, K. H.; Yao, C. F.
J. Org. Chem. 2006, 71, 3980. (b) Han, R.; Choi, S.; Son, K.; Jun, Y. Lee,
B.; Kim, B. Synth. Commun. 2005, 35, 1725. (c) Andrews, P. C.; Peatt,
A. C.; Raston, C. L. Green Chem. 2004, 6, 119. (d) Andrews, P. C.; Peatt,
A. C.; Raston, C. L. Tetrahedron Lett. 2004, 45, 243. (e) Hilt, G.; Smolko,
K. I.; Waloch, C. Tetrahedron Lett. 2002, 43, 1437. (f) Kim, B. H.; Han,
R.; Park, R. J.; Bai, K. H.; Jun, Y. M.; Baik, W. Synth. Commun. 2001, 31,
2297. (g) Su, W. K.; Li, J. H.; Zhang, Y. M. Synth. Commun. 2001, 31,
273.
(7) For selected recent examples, see: (a) Sun, X. W.; Xu, M. H.; Lin,
G. Q. Org. Lett. 2006, 8, 4979. (b) Zhang, W. X.; Ding, C. H.; Luo, Z. B.;
Hou, X. L.; Dai, L. X. Tetrahedron Lett. 2006, 47, 8391. (c) Zhang, W.
X.; Hou, X. L. Chin. Chem. Lett. 2006, 17, 1037. (d) Liu, X. Y; Zhu, S. Z;
Wang, S. W. Synthesis 2004, 683. (e) Wang, D. K.; Dai, L. X.; Hou, X. L.;
Zhang, Y. Tetrahedron Lett. 1996, 37, 4187.
(1) For reviews, see: (a) Kleinman, E. F.; Volkmann, R. A. In
ComprehensiVe Organic Synthesis; Trost, B. M., Fleming, I., Eds.;
Pergamon: Oxford, 1991; Vol. 2, p 975. (b) Yamamoto, Y.; Asao, N. Chem.
ReV. 1993, 93, 2207. (c) Li, A. H.; Dai, L. X.; Aggarwal, V. K. Chem.
ReV. 1997, 97, 2431. (d) Bloch, R. Chem. ReV. 1998, 98, 1407. (e)
Kobayashi, S.; Ishitani, H. Chem. ReV. 1999, 99, 1069. (f) Marshall, J. A.
Chem. ReV. 2000, 100, 3163. (g) Davies, A. G. Organotin Chemistry; Wiley-
VCH: Weinheim, Germany, 2004. (h) Hisashi, Y.; Koichiro, O. MainGroup
Metals in Organic Synthesis; Wiley-VCH: Weinheim, Germany, 2004; Vol.
2, p 621. (i) Hou, X. L.; Wu, J.; Fan, R. H.; Ding, C. H.; Luo, Z. B.; Dai,
L. X. Synlett 2006, 181.
(2) (a) Volkmann, R. A. In ComprehensiVe Organic Synthesis: Additions
to CsX π-Bonds, Part 1; Schreiber, S. L., Ed.; Pergamon: Oxford, 1991;
Vol. 1, p 355. (b) Sisko, J.; Weinreb, S. M. J. Org. Chem. 1990, 55, 393.
(8) Hatano, M.; Suzuki, S.; Ishihara, K. J. Am. Chem. Soc. 2006, 128,
9998.
10.1021/jo062616y CCC: $37.00 © 2007 American Chemical Society
Published on Web 03/17/2007
J. Org. Chem. 2007, 72, 3149-3151
3149

TABLE 1. Three-Component One-Pot Benzylation
was added into the reaction mixture in anhydrous THF, the
reaction gave product 2 in 10% yield. The yield of 2 increased
to 64% while imine 1 was treated with 1 equiv of H2O in
anhydrous THF for 30 min before zinc and benzyl bromide were
added. Drastic decrease in yield (only 30%) occurred, however,
when 2 equiv of H2O was used while the other kept constant.
Further experiments showed that the ratio of benzyl bromide
and zinc relative to imine (2:1) was crucial for the completion
of the reaction.
entry
R1
R2
2 (%)
1
2
3
4
5
6
7
8
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
2a (74)
2b (76)
2c (72)
2d (80)
2e (77)
2f (66)
2g (80)
2h (63)
2i (82)
2j (73)
2k (93)
2l (67)
2m (60)
2n (61)
2o (66)
p-CH3O-C6H4
p-CH3-C6H4
p-Cl-C6H4
p-F-C6H4
o-Cl-C6H4
2-furan
2-thiophen
PhCH2
n-C6H13
i-C4H9
Ph
Ph
Ph
The further improvement of the specific reaction cannot be
done without the elucidation of the reaction mechanism. In order
to understand the reaction pathway, imine 1 and 1 equiv of H2O
were mixed in THF-d4, and the mixture was stirred at room
1
temperature for 30 min. The H NMR showed that imine 1
9
decomposed to the benzaldehyde, aniline, and another com-
pound. The obtained spectrum was similar to that of the mixture
of benzaldehyde and aniline in THF-d4. Under the Barbier-type
conditions, benzaldehyde, aniline, benzyl bromide, and zinc dust
were mixed in a 1:1:2:2 ratio in anhydrous THF, and the mixture
was stirred at room temperature for 24 h (eq 2). The benzylation
10
11
12
13
14
15
p-CH3O-C6H4
p-F-C6H4
PhCH2
Ph
n-C6H13
TABLE 2. Three-Component One-Pot Allylation
occurred with product 2 in 54% yield while the benzaldehyde
did not disappear. Only a trace amount of byproduct 3 was
detected while another byproduct from the reaction of aniline
and benzyl bromide was isolated in 24% yield. The optimization
of the reaction conditions showed that the best ratio among
benzaldehyde, aniline, benzyl bromide, and zinc was 1:2:3:3,
in which the yield of 2 increased to 74%. The 1H NMR for the
crude reaction product showed that, except the known byprod-
ucts, toluene was formed in the reaction. As a control experi-
ment, 8% yield of 2 and 61% yield 3 were obtained when
anhydrous MgSO4 was used as an additive in the three-
component procedure.
entry
R1
R2
4 (%)
1
2
3
4
5
6
7
8
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
4a (70)
4b (77)
4c (87)
4d (85)
4e (71)
4f (77)
4g (85)
4h (93)
4i (65)
4j (89)
4k (73)
4l (69)
4m (67)
4n (60)
4o (77)
p-CH3O-C6H4
p-CH3-C6H4
p-Cl-C6H4
p-F-C6H4
o-Cl-C6H4
2-furan
2-pyridin
n-C3H7
i-C4H9
Ph
9
10
11
12
13
14
15
p-CH3O-C6H4
p-F-C6H4
p-CF3-C6H4
PhCH2
Ph
Ph
Ph
Ph
The above results suggested that the reaction might not
proceed via an imine intermediate. A plausible pathway was
shown in Figure 1. The intermediate A was first formed either
n-C6H13
mediate B would react with the second PhCH2ZnBr via a
transition-state C to give rise to the desirable adduct 2 in the
last step.
The scope of the one-pot benzylation reaction of aryl and
aliphatic aldehydes and amines was examined (Table 1). For
aryl and heteroaryl aldehydes, the reactions proceeded smoothly
giving rise to the desirable benzylation products in moderate to
good yield (Table 1, entries 1-8). It turned out that our proposed
reaction system could adapt to various combinations of alde-
hydes and amines. Aliphatic aldehydes were good candidates
(Table 1, entries 9-11) despite the inherent instability, low
reactivity, and often preferable enolization of their respective
imine derivatives. Benzylation to the aryl amine with an
electron-withdrawing group or electron-donating group, benzyl
amine, and aliphatic amine also gave the corresponding products
in moderate yield (Table 1, entries 12-15). In all the cases,
only a trace amount of reduction N-benzylation byproduct 3
was observed, and the major byproduct (<10%yield) was the
material resulting from the further benzylation on the nitrogen
site of the expected product.
FIGURE 1. Plausible pathway.
from the reaction of benzaldehyde with aniline or from reaction
of imine 1 with H2O. One PhCH2ZnBr then acted as a base to
deprotonate A to form an intermediate B and PhCH3. Inter-
3150 J. Org. Chem., Vol. 72, No. 8, 2007

Addition of allylic organometallic species to the imine
constitutes a potentially valuable method for the preparation of
homoallylamines. Certain drawbacks of the approach such as
unsatisfactory yields with aliphatic aldehydes and amines and
the requirement of an additional Lewis acid or other additives
limit its range of application.9 Motivated by the efficient
benzylation of aryl and aliphatic aldehydes and amines, a three-
component allylation reaction under the same conditions was
examined (Table 2). As expected, for aryl, heteroaryl, and
aliphatic aldehydes, the allylation proceeded smoothly to
produce the desirable adducts in good to excellent yield (Table
2, entries 1-10). Moreover, the scalability of this reaction was
also proved to be good by the 73% yield of 4a when the reaction
of benzaldehyde and aniline run in 10 mmol scale.
In summary, we have developed a highly efficient, three-
component benzylation and allylation of aromatic and aliphatic
aldehydes and amines with the aid of commercially available
zinc powder under the Barbier-type conditions. The potential
of this reaction system can be evaluated by its adaptability to a
wide variety of reagents. In addition, the one-pot procedure
offers extra manipulability by avoiding the isolation of the
unstable imine intermediates. The further development of
asymmetric reactions is ongoing and will be reported in due
course.
Experiment Section
Typical Procedure for the Three-Component One-Pot Reac-
tion. A solution of R1CHO (1 mmol) and R2NH2 (2 mmol) in
anhydrous THF (3 mL) was stirred at rt under N2 for 30 min, and
then R3Br (3 mmol) and Zn dust (3 mmol) were added in. The
resultant mixture was stirred at rt for 12-24 h (determined by TLC),
then quenched with 1% HCl, extracted by DCM, and dried by
anhydrous Na2SO4, and the crude product was purified by flash
column chromatography to provide the corresponding product.
1
N-(1,2-Diphenylethyl)benzenamine 2a. H NMR (300 MHz,
CDCl3) δ 2.99 (dd, J ) 13.2, 8.4 Hz, 1H), 3.12 (dd, J ) 13.2, 8.4
Hz, 1H), 4.10 (br, 1H), 4.56 (t, J ) 8.4 Hz, 1H), 6.42 (d, J ) 8.8
Hz, 2H), 6.62 (t, J ) 8.2 Hz, 1H), 6.98-7.38 (m, 12H). The spectral
data are consistent with those reported in the literature.8
N-(1-Phenylbut-3-enyl)benzenamine 4a. 1H NMR (400 MHz,
CDCl3) δ 2.49-2.55 (m, 1H), 2.59-2.63 (m, 1H), 4.17 (br, 1H),
4.39 (dd, J ) 7.8, 4.8 Hz, 1H), 5.15-5.22 (m, 2H), 5.74-5.81 (m,
1H), 6.50 (d, J ) 8.2 Hz, 2H), 6.65 (t, J ) 7.2 Hz, 1H), 7.09 (t,
J ) 8.2 Hz, 2H), 7.22-7.26 (m, 1H), 7.31-7.39 (m, 4H). The
spectral data are consistent with those reported in the literature.9g
Acknowledgment. We thank Professor Xue-Long Hou for
his invaluable advice during the course of this research. Financial
support from National Natural Science Foundation of China
(20642006, 20502004), the Science and Technology Commis-
sion of Shanghai Municipality (05ZR14013), and Fudan Uni-
versity is gratefully acknowledged.
(9) For selected recent examples, see: (a) Das, B.; Ravikanth, B.;
Thirupathi, P.; Vittal Rao, B. Tetrahedron Lett. 2006, 47, 5041. (b) Das,
B.; Ravikanth, B.; Laxminarayana, K.; Vittal Rao, B. J. Mol. Catal. A:
Chem. 2006, 253, 92. (c) Shimizu, M.; Kimura, M.; Watanabe, T.; Tamaru,
Y. Org. Lett. 2005, 7, 637. (d) Yadav, J. S.; Reddy, B. V. S.; Raju, A. K.
Synthesis 2003, 883. (e) Akiyama, T.; Iwai, J.; Onuma, Y.; Kagoshima, H.
J. Chem. Soc., Chem. Commun. 1999, 2191. (f) Kobayashi, S.; Busujima,
T.; Nagayama, S. J. Chem. Soc., Chem. Commun. 1998, 19. (g) Yin,
Y. Y.; Zhao, G.; Li, G. L Tetrahedron 2005, 61, 12042.
Supporting Information Available: General experimental
information, characterization data of the isolated compounds, and
1H and 13C NMR spectra for 2 and 4. This material is available
free of charge via the Internet at http://pubs.acs.org.
JO062616Y
J. Org. Chem, Vol. 72, No. 8, 2007 3151