Palladium-catalyzed allylation of imines with allyl alcohols

Article abstract of DOI:10.1021/ol047609f

(Chemical Equation Presented) A catalytic system, Pd(OAc)₂ (10 mol %)-P(n-Bu)₃ (20 mol %)-Et₃B (360 mol %), promotes allylic alcohols to undergo the allylation of anisidineimines of aromatic and aliphatic aldehydes and furnishes homoallylamines in good to moderate yields. The reaction shows unique stereoselectivity, giving anti-isomers selectively.

Full text of DOI:10.1021/ol047609f

ORGANIC
LETTERS
2005
Vol. 7, No. 4
637-640
Palladium-Catalyzed Allylation of Imines
with Allyl Alcohols
Masamichi Shimizu, Masanari Kimura,† Toshiya Watanabe, and
Yoshinao Tamaru*
Department of Applied Chemistry, Faculty of Engineering, Nagasaki UniVersity,
1-14 Bunkyo-machi, Nagasaki 852-8521, Japan, and Graduate School of Science and
Technology, Nagasaki UniVersity, 1-14 Bunkyo-machi, Nagasaki 852-8521, Japan
tamaru@net.nagasaki-u.ac.jp
Received November 19, 2004
ABSTRACT
A catalytic system, Pd(OAc)2 (10 mol %)−P(n-Bu)3 (20 mol %)−Et3B (360 mol %), promotes allylic alcohols to undergo the allylation of anisidine−
imines of aromatic and aliphatic aldehydes and furnishes homoallylamines in good to moderate yields. The reaction shows unique
stereoselectivity, giving anti-isomers selectively.
Allylations both at the carbonyl carbon and at the R-carbon
to the carbonyl of aldehydes are among the most useful
methods to elaborate molecules. As compared with alde-
hydes, aldimines are less reactive, and their nucleophilic
allylation has been less explored, though this is very useful
for the preparation of homoallylamines of an ubiquitous
structural motif of natural products.1
Here, we would like to disclose that the same Pd-Et3B
catalytic system is successfully extended to the nucleophilic
allylation of aldimines of aromatic aldehydes and even
aldimines of aliphatic aldehydes bearing enolizable protons.
In Scheme 1 are shown typical reaction conditions; the
reaction was conducted as follows: in situ formation of a
Recently, we have demonstrated that a Pd-Et3B catalytic
system nicely activates allylic alcohols to promote both
nucleophilic allylation at the carbonyl carbon2 and electro-
philic allylation at the R-carbon of aldehydes.3 Unfortunately,
however, the catalytic system failed in selective nucleophilic
allylation of primary and secondary aliphatic aldehydes,
providing mixtures of C1 (nucleophilic) and C2 (electro-
philic) allylation products in comparable amounts.2b
Scheme 1. Pd-Catalyzed Allylation of a Variety of
Benzaldehyde-Imines with Allyl Alcohol
† Graduate School of Science and Technology, Nagasaki University.
(1) For recent reviews on allylation of aldehydes and imines, see: (a)
Puentes, C. O.; Kouznetsov, V. J. Heterocycl. Chem. 2002, 39, 595. (b)
Denmark, S. E.; Almstead, N. G. In Modern Carbonyl Chemistry; Otera,
J., Ed.; Wiley-VHC: Weinheim, 2000; Chapter 10. (c) Chemler, S. R.;
Roush, R. W. In Modern Carbonyl Chemistry; Otera, J., Ed.; Wiley-VHC:
Weinheim, 2000; Chapter 11. (d) Kobayashi, S.; Ishitani, H. Chem. ReV.
1999, 99, 1069.
(2) (a) Kimura, M.; Kiyama, I.; Tomizawa, T.; Horino, Y.; Tanaka, S.;
Tamaru, Y. Tetrahedron Lett. 1999, 40, 6795. (b) Kimura, M.; Tomizawa,
T.; Horino, Y.; Tanaka, S.; Tamaru, Y. Tetrahedron Lett. 2000, 41, 3627.
(3) (a) Kimura, M.; Horino, Y.; Mukai, R.; Tanaka, S.; Tamaru, Y. J.
Am. Chem. Soc. 2001, 123, 10401. (b) Mukai, R.; Horino, Y.; Tanaka, S.;
Tamaru, Y.; Kimura, M. J. Am. Chem. Soc. 2004, 126, 11138.
a A complex mixture of products.
benzaldehyde-imine (30 min at reflux in 1 mL of THF),
distillation of an azeotropic mixture of THF-H2O two times,4
10.1021/ol047609f CCC: $30.25
© 2005 American Chemical Society
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and exposure of the imine residue to a mixture of Pd(OAc)2
(10 mol %), P(n-Bu)3 (20 mol %), Et3B (360 mol %), and
allyl alcohol (120 mol %) at 50 °C for 24 h under N2. The
table shown in Scheme 1 indicates that yields of homo-
allylamine 1 sharply depend on the kinds of amines, and
aromatic amines are the reagents of choice. The best yield
was recorded with p-toluidine; however, we utilized p-
anisidine because of its synthetic utility. p-Anisidine could
be readily removed to give rise to a primary homoallylamine.
Table 1 summarizes the allylation of p-anisidine-imines
of aromatic aldehydes. The reaction is compatible with
The yields of 1d decreased to 31%, 29%, and 0% when
PPh3 (20 mol %), P(c-Hex)3 (20 mol %), and DPPP (10 mol
%) were used, respectively, in place of P(n-Bu)3 (20 mol
%). Reduction of the amount of Et3B (360 mol %) to 240
mol % caused an apparent drop in the yield of 1d (56%);
however, loading half amounts of Pd(OAc)2-P(n-Bu)3, i.e.,
5-10 mol %, caused only a slight fall in the yield of 1d
(65%). Interestingly, yields are temperature dependent;
reactions take place and are completed at room temperature
within 24 h; however, at this temperature the yields drop
significantly (e.g., 1d in 28% yield).
It may be worth noting that even in the presence of an
acidic OH group (run 2) and a basic amino group (run 7) it
is not necessary to use any extra amount of Et3B; i.e., the
optimized amount of Et3B for ordinary aldehydes is sufficient
enough for the allylation of such substrates.
Table 1. Allylation of Aromatic Aldehydes-p-Anisidine Imine
with Allyl Alcohola
In Table 2 is summarized the allylation of p-anisidine-
imines of aliphatic aldehydes. Except for primary aldehydes
Table 2. Allylation of Aliphatic Aldehydes-p-Anisidine Imine
with Allyl Alcohola
a See footnote a in Table 1. b See footnote b in Table 1. c Complex
mixture of products.
a Reaction conditions: an aldehyde (1.0 mmol) and p-anisidine (1.05
mmol) in THF (1 mL) at reflux for 0.5 h; distillation of THF (azeotropic
removal of water) under N2; then Pd(OAc)2 (0.1 mmol), P(n-Bu)3 (0.2
mmol), allyl alcohol (1.2 mmol), and Et3B (3.6 mmol, 1 M n-hexane) and
THF (1 mL) at 50 °C. b Yields refer to the isolated, spectroscopically
homogeneous materials. c At room temperature.
(run 6), ordinary secondary aldehydes recorded acceptable
yields. Runs 2 and 4, as compared with runs 1 and 3,
respectively, clearly suggest that the yields go down as the
acidities of R-protons increase. This is supported by the
reaction of cinnamaldehyde (run 6, Table 1), which does not
possess enolizable protons. The good yield encountered with
myrtenal (run 5) may be attributed to steric protection of
electron-donating (runs 1-3) and electron-withdrawing sub-
stituents (run 5). Heteroaromatic aldehydes also behave
similarly and provide homoallylamines in reasonable yields
(runs 7 and 8).
(4) Without removing water, reactions become dirty (many tailing spots
on TLC) and no allylation products are detected.
638
Org. Lett., Vol. 7, No. 4, 2005

allylic protons by bridged carbons from an approach of a
base.
results observed in runs 1, 2, and 4 (Table 3) suggest that
(Z)-allylboranes are formed selectively via transmetalation
between Et3B and π-allylpalladium species (syn- or anti-
isomer, which might equilibrate to each other) and react with
trans-imine through a transition state II (ML2 ) BEt2).11 To
the best of our knowledge, however, this is the first example
demonstrating anti-selectivity for the allylation of imines
starting with trans-crotyl-type (and R-methylallyl-) sub-
strates; all precedents starting with trans-crotyl substrates
suppose a transition state like I to rationalize their syn-
selective allylations.5,12 These transition states I and II share
a common structural feature, placing both substituents of
trans-aldimine at quasi-diaxial position of cyclic six-
membered chairlike conformation (Scheme 3). The confor-
As is expected,1 all allylic alcohols examined showed the
same regioselectivity providing the most branched homo-
allylamines (runs 1-4, Table 3); however, the stereoselec-
Table 3. Allylation of Benzaldehyde-p-Anisidine Imine with
Substituted Allylic Alcoholsa
Scheme 3. The Most Probable Transition State Leading to
anti-1
a See footnote a in Table 1. b See footnote b in Table 1. c Ratios were
1
determined on the basis of H NMR (400 MHz).
mation is preferred over the corresponding quasi-diequatorial
conformation because the latter experiences severe gauche
repulsion between p-anisyl and the ligands on metal (in this
case, two Et groups on B).13 A transition state III that is
characterized by cis-imine is another candidate, which seems
to be most stable because of no 1,3-diaxial repulsions. At
the moment, it is premature to assign which of the transitions
states II or III is responsible; the former supposing (Z)-
tivity was quite unexpected and turned out to be subject to
the kind of substituents and the substitution patterns. Gener-
ally, R-substituted allylic alcohols showed higher stereose-
lectivity, giving anti-1 preferentially over syn-1 (runs 1 vs 2
and runs 3 vs 4). Furthermore, in contrast to many prece-
dents1,5,6 indicating that phenyl group generally displays
better stereoselectivity than methyl group does, in the present
case, methyl group showed higher selectivity than phenyl
group (runs 2 vs 4).7 The structure of anti-1n was verified
(6) For example, in the presence of Pd(PPh3)4 (5 mol %) and Et2Zn (240
mol %) in THF (3 mL)-n-hexane (1.2 mL) at room temperature, R- and
γ-methylallyl alcohols (1 mmol) react with benzaldehyde (1.2 mmol) to
provide mixtures of anti- and syn-2-methyl-1-phenyl-3-buten-1-ols in the
same ratio (2.4:1). The same reactions with R- and γ-phenylallyl alcohols
provide anti- and syn-1,2-diphenyl-3-buten-1-ols in the same, but in higher
ratios of 10:1: Tamaru, Y. J. Organomet. Chem. 1999, 576, 215.
(7) Under present conditions, 1,3-disubstituted allylic alcohols, such as
1,3-dimethylallyl alcohols and 2-cyclohexenol, failed to give expected
homoallylamines.
1
by the comparison of the H NMR spectral data with those
of an authentic sample after conversion to an amine 2
(Scheme 2).8 Furthermore, the structure of anti-1n was
(8) Hoffmann, R. W.; Endesfelder, A. Liebigs Ann. Chem. 1987, 215.
(9) Crystallographic data (excluding structure factors) for the structure
of 2 have been deposited with the Cambridge Crystallographic Data Centre
as supplementary publication no. CCDC-256123. Copies of the data can
be obtained free of charge on application to CCDC, 12 Union Road,
Cambridge CB21EZ, UK (fax: (+44)1223-336-033; e-mail: deposit@
ccdc.cam.ac.uk).
Scheme 2. Structure Determination of anti-1n
(10) Itsuno, S.; Watanabe, K.; Ito, K.; El-Shehawy, A. A.; Sarhan, A.
A. Angew. Chem., Int. Ed. 1997, 36, 109.
(11) (a) Hirabayashi, R.; Ogawa, C.; Sugiura, M. Kobayashi, S. J. Am.
Chem. Soc. 2001, 123, 9493. (b) Kobayashi, S.; Ogawa, C.; Konishi, H.;
Sugiura, M. J. Am. Chem. Soc. 2003, 125, 6610.
(12) (a) Shibata, I.; Nose, K.; Sakamoto, K.; Yasuda, M.; Baba, A. J.
Org. Chem. 2004, 69, 2158. (b) Yanada, R.; Kaieda, A.; Takemoto, Y. J.
Org. Chem. 2001, 66, 7516. (c). Cooper, I. R.; Grigg, R.; MacLachlan, W.
S.; Thornton-Pett, M. Sridharan, V. J. Chem. Soc., Chem. Commun. 2002,
1372.
determined unequivocally by X-ray crystallographic analysis
of the tosylamide derivative.9
Under the reaction conditions, allylboranes are expected
to react with an imine as soon as it is formed;10 hence, the
(13) Kimura, M.; Miyachi, A.; Kojima, K.; Tanaka, S.; Tamaru, Y. J.
Am. Chem. Soc. 2004, 126, 14360.
(5) Kumar, S.; Kaur, P. Tetrahedron Lett. 2004, 45, 3413.
Org. Lett., Vol. 7, No. 4, 2005
639

allylboranes and the latter a less stable cis-aldimine as
intermediates.
allylic alcohols15 rather than other allylating agents, e.g.,
allylic metals (Zn,16 In,5,12b,c Pd)17 and metalloids (B,10 Si,18
Sn,11,19 Ge),20 may be apparent from their ready availability
and stability as well as nontoxic side products (H2O and
organoboric acids).
Finally, it should be noted that the success of the present
allylation is not due to increased reactivity of allylboranes
toward imines.14 In fact, competition reaction of allyl alcohol
with imine and benzaldehyde (1 mmol each) revealed that
the latter was ca. 7 times more reactive than the former
(Scheme 4). Rather, the success may owe its origin to
Acknowledgment. We acknowledge partial support of
this work from the Ministry of Education, Science, Sports,
and Culture, Japanese Government.
Supporting Information Available: Experimental pro-
cedures and characterization data for 1a-p and Chem3D
presentation of X-ray structure of 2 (CIF). This material is
available free of charge via the Internet at http://pubs.acs.org.
Scheme 4. Competition Reaction of Benzaldehyde-Imine and
Benzaldehyde under Catalytic Conditions
OL047609F
(14) (a) Nakamura, H.; Iwama, H.; Yamamoto, Y. J. Am. Chem. Soc.
1996, 118, 6641. (b) Kobayashi, S.; Nagayama, S. J. Am. Chem. Soc. 1997,
119, 10049.
(15) Allylation with allyl alcohol was reported for benzaldehyde-imine
using an umpolung technique of π-allylpalladium with indium(I) iodide.
Allyl bromide, iodide, acetate, and carbonate showed good yields; however
chloride and alcohol moderate and poor yields, respectively. See ref 12b.
(16) Boyer, F.-D.; Hanna, I. Tetrahedron Lett. 2001, 42, 1275.
(17) (a) Nakamura, H.; Aoyagi, K.; Shim, J.-G. Yamamoto, Y. J. Am.
Chem. Soc. 2001, 123, 372. (b) Fernandes, R. A.; Stimac, A.; Yamamoto,
Y. J. Am. Chem. Soc. 2003, 125, 14133.
minimization of side reactions that aldehydes suffer from,
especially to reduced capability of imines undergoing eno-
lization.
In conclusion, we have demonstrated that a Pd-Et3B
catalytic system is capable of promoting allylation of
anisidine-aldimines of aromatic and aliphatic aldehydes using
allylic alcohols as allylating agents. The advantage of using
(18) Yamasaki, S.; Fujii, K.; Wada, R.; Kanai, M.; Shibasaki, M. J. Am.
Chem. Soc. 2002, 124, 6536.
(19) (a) Gastner, T.; Ishitani, H.; Akiyama, R.; Kobayashi, S. Angew.
Chem., Int. Ed. 2001, 40, 1896. (b) Choudary, B. M.; Chidara, S.; Sekhar,
C. V. R. Synlett 2002, 1694. (c) Yadav, J. S.; Reddy, B. V. S.; Reddy, P.
S. R.; Rao, M. S. Tetrahedron Lett. 2002, 43, 6245. (d) Aspinall, H. C.;
Bissett, J. S.; Greeves, N.; Levin, D. Tetrahedron Lett. 2002, 43, 323. (e)
Yadav, J. S.; Reddy, B. V. S.; Raju, A. K. Synthesis 2003, 883.
(20) Akiyama, T.; Iwai, J. Synlett 1998, 273.
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Org. Lett., Vol. 7, No. 4, 2005