Zinc-mediated highly α-regioselective prenylation of imines with prenyl bromide

Article abstract of DOI:10.1021/ol203410m

A highly α-regioselective prenylation of imines has been successfully developed. The efficiency of this approach is confirmed by a wide range of imines including N- and C-aryl aldimines, N-alkyl aldimines, C-alkyl aldimines, and N- and C-aryl ketimines. T

Full text of DOI:10.1021/ol203410m

ORGANIC
LETTERS
2012
Vol. 14, No. 3
886–889
Zinc-Mediated Highly r-Regioselective
Prenylation of Imines with Prenyl Bromide
Li-Ming Zhao,* Shu-Qing Zhang, Hai-Shan Jin, Li-Jing Wan, and Fei Dou
School of Chemistry and Chemical Engineering, and Jiangsu Key Laboratory of Green
Synthetic Chemistry for Functional Materials, Xuzhou Normal University,
Xuzhou 221116, Jiangsu, China
lmzhao@xznu.edu.cn
Received December 21, 2011
ABSTRACT
A highly R-regioselective prenylation of imines has been successfully developed. The efficiency of this approach is confirmed by a wide range of
imines including N- and C-aryl aldimines, N-alkyl aldimines, C-alkyl aldimines, and N- and C-aryl ketimines. The approach uses prenyl bromide as
the prenyl source and inexpensive and convenient zinc as the mediator as well as environmentally benign 1,3-dimethyl-2-imidazolidinone (DMI) as
the solvent.
Allylation is one of the most valuable and important
reactions for the construction of CÀC bonds.1 Regioselec-
tivity is a very important issue in allylation. Generally,
highly R-regioselective allylation is difficult to achieve
whenR-substituted allylmetalreagents suchasprenylmetal
are employed.2 However, despite the difficulty in obtaining
an R-adduct, many successful examples of R-regioselective
allylation of aldehydes and ketones have been reported.3
While great progress has been made on the regioselective
allylation of carbonyl compounds, very few examples have
been described for their aza analogues. The difficulty is
mainly ascribed to the poor electrophilicity of imines and
deprotonation of imines derived from enolization.4 In the
past 15 years, only two efficient methods for the synthesis
of linear homoallylic amines via allylation of imines with
prenylmetals have been reported. The first R-regioselective
prenylation of an imine with a prenyl halide was reported
by Yamamoto in 1996.5 Another successful R-selective
addition to imines was described by Shibata in 2009.6
However, despite the success, both methods are limited
to aldimines only and are not applicable to ketimines, so
the regioselectivity issue of imines is not addressed com-
pletely. On the other hand, the very few examples of R-
regioselective prenylation have limited the availability of
linear homoallylic amines, which have proved to be im-
portant building blocks of natural products and biologi-
cally active molecules.7 Thus, the development of more
efficient R-regioselective prenylation of imines for the
facile preparation of linear homoallylic amines in high
yields, which has a broader substrate scope and uses
(1) (a) Yamamoto, Y.; Asao, N. Chem. Rev. 1993, 93, 2207. (b)
Denmark, S. E.; Fu, J. Chem. Rev. 2003, 103, 2763.
(2) (a) Sinha, P.; Roy, S. Organometallics 2004, 23, 67. (b) Kaellstroem,
S.; Erkkilae, A.; Pihko, P. M.; Sjoeholm, R.; Sillanpaeae, R.; Leino, R.
Synlett 2005, 751. (c) Moslin, R. M.; Jamison, T. F. J. Org. Chem. 2007,
72, 9736. (d) Zhang, Z.; Huang, J.; Ma, B.; Kishi, Y. Org. Lett. 2008, 10,
3073. (e) Alcaide, B.; Almendros, P.; del Campo, T. M. Eur. J. Org.
Chem. 2008, 2628. (f) Millan, A.; Campana, A. G.; Bazdi, B.; Miguel, D.;
Alvarez de Cienfuegos, L.; Echavarren, A. M.; Cuerva, J. M. Chem.;Eur.
J. 2011, 17, 3985.
(3) (a) Guo, B. S.; Doubleday, W.; Cohen, T. J. Am. Chem. Soc. 1987,
109, 4710. (b) Yanagisawa, A.; Habaue, S.; Yamamoto, H. J. Am. Chem.
Soc. 1991, 113, 8955. (c) Yanagisawa, A.; Habaue, S.; Yasue, K.;
Yamamoto, H. J. Am. Chem. Soc. 1994, 116, 6130. (d) Estevez, R. E.;
Justicia, J.; Bazdi, B.; Fuentes, N.; Paradas, M.; Choquesillo-Lazarte,
D.; Garcia-Ruiz, J. M.; Robles, R.; Gansauer, A.; Cuerva, J. M.; Oltra,
J. Chem.;Eur. J. 2009, 15, 2774. (e) Zhao, L. M.; Jin, H. S.; Wan, L. J.;
Zhang, L. M. J. Org. Chem. 2011, 76, 1831.
(5) Yanagisawa, A.; Ogasawara, K.; Yasue, K.; Yamamoto, H.
Chem. Commun. 1996, 367.
(6) Shibata, I.; Miyamoto, S.; Tsunoi, S.; Sakamoto, K.; Baba, A.
Eur. J. Org. Chem. 2009, 3508.
(7) (a) van Lierop, B. J.; Jackson, W. R.; Robinson, A. J. Tetrahedron
2010, 66, 5357. (b) Griffiths-Jones, C. M.; Knight, D. W. Tetrahedron
2010, 66, 4150. (c) Smith, A. B., III; Wang, W.; Charnley, A. K.; Carroll,
P. J.; Kenesky, C. S.; Hirschmann, R. Org. Lett. 2010, 12, 2990. (d)
Datta, S.; Kazmaier, U. Org. Biomol. Chem. 2011, 9, 872.
(4) (a) Bloch, R. Chem. Rev. 1998, 98, 1407. (b) Kobayashi, S.;
Ishitani, H. Chem. Rev. 1999, 99, 1069.
r
10.1021/ol203410m
Published on Web 01/20/2012
2012 American Chemical Society

more convenient and cheaper reagents, would be of great
importance.
Table 1. Optimization of Reaction Conditionsa
Recently, our group reported a highly R-regioselective
zinc-mediated prenylation of aldehydes and ketones.3e The
reaction is applicable to a wide range of carbonyls and is
convenient using commercially available and cheap metal.
In light of this work, we wondered whether the method
could be expanded to the prenylation of imines. Herein, we
report a facile and general zinc-mediated method for the
prenylation of aldimines and ketimines with high R-
regioselectivity in DMI to afford linear homoallylic amines
in good to excellent yields. The results presented show that
this approach is quite reliable and very general. Remark-
ably, we have been able to expand the reaction to N-
aliphatic aldimines and ketimines, broadening the applic-
ability of the R-prenylation reaction.
temp
t
yield
(%)b
entry
solvent
(°C)
(h)
R/γc
1
2
3
4
5
6
HMPA
DMPU
DMI
130
130
130
120
110
130
12
14
14
14
14
14
89
97
95
96
68
89
>99:1
100:0
100:0
100:0
74:26
100:0
DMI
DMI
TMU
Initially N-(4-bromophenyl)benzaldimine 1a was se-
lected as a model substrate to optimize the reaction con-
ditions. The results are summarized in Table 1. We are
pleased to find that the prenylation of the imine also
exhibits highly R-regioselectivity to give the R-product 2a
in89% yield underthe samereaction conditionspreviously
applied in the prenylation of carbonyl compounds (entry 1).
Although notable efficacy was achieved for the reac-
tion, the carcinogenic HMPA was used as the solvent.
Hence, we decided to explore alternative solvents for the
prenylation reaction of imines. Several solvents including
tetramethylurea (TMU), 1,3-dimethyl-3,4,5,6-tetrahydro-
2(1H)pyrimidinone (DMPU), and DMI were tested.
Among the solvents tested, DMI was found to be the most
suitable solvent for the prenylation of imines to afford R-
adduct 2a exclusively in 95% yield (entry 3). A similar
result was observed when DMPU was used as the solvent
(97% yield, entry 2). Although both DMPU and DMI
were developed as safe substitutes for the carcinogenic
HMPA, DMI was a better choice than DMPU due to its
lower toxicity. There have been several reports indicating
that DMPU also may act as a possible chemical mutagen,
and the potential carcinogenic risk of DMPU cannot be
ignored.8 In contrast, DMI is nontoxic to humans and the
potential toxicological risk is extremely low. DMI was thus
chosen for further investigation. The prenylation also can
be carried out in other solvents such as TMU with com-
plete R-regioselectivity, although a slightly lower product
yield is obtained (entry 6). To enable the reaction to be
performedunder muchmilder conditions, we subsequently
examined the reaction temperature. A decrease in the
temperature to 120 °C did not affect the R-prenylation
reaction efficiency (entry 4). In further lowering the tem-
perature to 110 °C, the reaction still efficiently afforded R-
addition product 2a as the major product but with an
amount of undesired γ-addition product 3a (entry 5).
These results showed that a reaction temperature of
120 °C was necessary to keep the high R-regioselectivity
and also highlighted the key role of temperature in the
regiocontrol of the reaction.
a Reactions were carried out with imine (1.0 equiv), prenyl bromide
(2.0 equiv), and zinc (2.5 equiv). b Isolated yield of 2a. c Determined by
GC-MS.
With optimized reaction conditions in hand, we next
investigated the scope of the prenylation of imines, and the
results are summarized in Table 2. A wide range of differently
substituted imines derived from aromatic aldehydes and
amines were investigated first. As can be seen in Table 2
(entries 1À11), linear homoallylic amines were obtained in
excellent yields in all the cases. The results clearly display
that a substituent on the two aromatic rings (i.e., R1 and
R2), whether C-aryl- or N-aryl-substituted, has no signifi-
cant influence on the R-prenylation reaction. Both elec-
tron-withdrawing and -donating substituents on R1 or R2,
such as fluoride (entries 2À5), chloride (entries 6 and 7),
bromide (entry 8), methoxyl (entries 9 and 10), and methyl
groups (entry 11), were well tolerated in the reaction. It
should be noted that the reaction allowed the use of
substrates previously considered incompatible with R-
prenylation. For instance, 4-methoxyphenyl-substituted
imine 1j has been reported as unreactive toward the
addition of prenyltributyltin in the presence of HfCl4 due
to its low electrophilicity.6 With the exception of the
relatively stabilized C-aryl imines, the less stable C-heteroaryl
imine such as C-2-thienyl imine 1m also gave total R-
regioselectivity in high yield (entry 12). Moreover, the
same reactions proceeded efficiently for substrate 1n bear-
ing an alkyl group on R1, providing the corresponding R-
prenylation product 2n in 82% yield (entry 13). It is
sometimes difficult to handle alkyl aldimines generated
from aliphatic aldehydes due to their low stability. So such
substrates have scarely proved to be viable in high yields
before. Further, we can also expand this reaction to new
classes of imines, such as N-alkyl imines. When the aro-
matic amines were replaced by the N-aliphatic amines, the
reaction also proceeded smoothly under the same condi-
tions to give exclusively the corresponding R-product,
albeit in slightly lower yield. For example, the N-tert-butyl
imine 1o afforded corresponding R-prenylation product 2o
in 82% yield with total R-regioselectivity (entry 14). Simi-
larly, the use of other N-aliphatic imines such as N-benzyl
(8) (a) Zijlstra, J. A.; Vogel, E. W. Mutat. Res. 1988, 201, 27. (b) Lo,
C. C.; Chao, P. M. J. Chem. Ecol. 1990, 16, 3245.
Org. Lett., Vol. 14, No. 3, 2012
887

Table 2. R-Prenylation of Various Aldimines and Ketimines
entry
imine
R1
R2
R3
adduct
yield (%)a
R/γb
1
1b
1c
1d
1e
1f
Ph
Ph
Ph
Ph
Ph
H
2b
2c
2d
2e
2f
90
84
90
96
90
95
85
94
87
91
87
87
82
82
70
61
83
88
84
86
100:0
>99:1
>99:1
>99:1
100:0
>99:1
100:0
100:0
100:0
>99:1
>99:1
100:0
100:0
100:0
100:0
100:0
100:0
100:0
100:0
100:0
2
2-FC6H4
3-FC6H4
4-FC6H4
Ph
H
3
H
4
H
5
4-FC6H4
Ph
H
6
1g
1h
1i
4-ClC6H4
Ph
H
2g
2h
2i
7
4-ClC6H4
4-BrC6H4
Ph
H
8
Ph
H
9
1j
4-CH3OC6H4
Ph
H
2j
10
11
12
13
14
15
16
17
18
19
20
1k
1l
4-CH3OC6H4
Ph
H
2k
2l
4-CH3C6H4
2-thienyl
cyclopropyl
Ph
H
1m
1n
1o
1p
1q
1r
1s
1t
Ph
H
2m
2n
2o
2p
2q
2r
2s
2t
Ph
H
tert-butyl
PhCH2
cyclohexyl
Ph
H
Ph
H
Ph
H
Ph
CH3
CH3
CH3
CH3
4-ClC6H4
4-CH3C6H4
4-CH3OC6H4
Ph
Ph
1u
Ph
2u
a Isolated yield. b Determined by GC-MS.
imine 1p and N-cyclohexyl imine 1q also gave satisfactory
R-regioselective results (entries 15 and 16). It is noteworthy
that this is the first example of using N-aliphatic imines as
the substrates in the R-prenylation of imines.
from D by regenerating the parent imine. Finally, the
dissociation of DMI from E liberates the ligand to
deliver amido-zinc species F (path B).
To test the proposed mechanism, an experiment
involving resubjection of the γ-isomer 3r to the reaction
conditions was performed. Resubjection of the initial
addition product 3r at 120 °C in DMI in the presence of
BuLi and zinc bromide led to R-isomer 2r in 80% yield
after column chromatography (Scheme 2). Although
the detailed mechanism is not fully understood, our
experiments make it clear that this is an equilibrium
process in which the readily available kinetic γ-isomer
rearranges to their less readily accessible thermody-
namic R-isomer at a high temperature in DMI. At this
stage, we have not yet been able to determine which
pathway is correct. However, both pathways can ex-
plain why the basic solvent effects this R-prenylation
reaction. In pathway A, the basicity of DMI leads to a
decrease in the proportion of primary allylmetallic type
and an increase of tertiary allylmetallic type.9 In path-
way B, it is quite probable that the Lewis acidity of zinc
of initially formed γ-adduct A is enhanced by coordi-
nation with DMI. The resulting complex B further
coordinates the imine to form the transition state C,
followed by a [3,5]-sigmatropic shift at an elevated
temperature to form the transition state D.
To broaden the scope of the R-prenylation reaction, the
subsequent study was focused on the ketimines derived
from methyl ketones. To our delight, the experiments show
that this method also was very effective for the R-prenylation
of various ketimines bearing electron-withdrawing
(entry 18) and electron-donating groups (entries 19
and 20) at the phenyl ring in high yields. Notably, for all
the substrates, the reactions afforded an R-adduct with
total R-regioselectivity and no γ-adduct was observed.
Although it is impossible to establish an exact mecha-
nism at the present time, we propose two possible pathways
to explain the highly R-regioselective prenylation of imines
based on our previous mechanistic study on the prenyla-
tion of carbonyls,3e as shown in Scheme 1. The initial step
of both pathways is the formation of γ-prenylation pro-
duct A. On the one hand, R-adducts are proposed to derive
from the addition of tertiary prenylzinc generated in situ to
the imine to give F via a six-membered cyclic transition
state (path A). On the other hand, the initially formed A
would coordinate to DMI to form complex B. The
subsequent coordination of complex B to the imine
results in the formation of transition state C, which
undergoes a metallo[3,5]-sigmatropic rearrangement to
afford transition state D. Then, complex E is formed
(9) Courtois, G.; Miginiac, L. J. Organomet. Chem. 1974, 69, 1.
Org. Lett., Vol. 14, No. 3, 2012
888

Scheme 1. Proposed Mechanism for the R-Regioselective Prenylation of Imines
can be carried out in an environmentally benign solvent,
which is of relevance from the viewpoint of green chem-
istry. To the best of our knowledge, this represents the
most general and easy procedure for the synthesis of linear
homoallylic amines so far. With these advantages, we
believe that this new methodology may find wide applica-
tion in organic chemistry.
Scheme 2. A Resubjection Experiment of γ-Adduct
Acknowledgment. We are thankful for financial support
from the Natural Science Foundation of Xuzhou Normal
University (No. 08XLR06) and Priority Academic Program
Development of Jiangsu Higher Education Institutions.
In conclusion, a general route to linear homoallylic
amines in good to excellent yields has been developed.
The reaction is highly efficient, and the scope of it is wide.
Although somewhat higher temperatures are needed, this
reaction is very convenient due to the use of prenyl halide as
the prenyl source and inexpensive, easily obtained zinc as
the mediator. Particularly noteworthy is that the reaction
Supporting Information Available. Experimental pro-
cedures, characterization data, and copies of 1H and
13C NMR spectra. This material is available free of charge
via the Internet at http://pubs.acs.org.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 3, 2012
889