Convenient synthesis of pyrrolidines by amphiphilic allylation of imines with 2-methylenepropane-1,3-diols

Article abstract of DOI:10.1002/anie.200801252

(Chemical Equation Presented). A straightforward route: The combination of a palladium catalyst and triethylborane promotes the amphiphilic (nucleophilic-electrophilic) allylation of aldimines, prepared in situ from a wide variety of aromatic and aliphatic aldehydes and amines, with commercially available 2-methylenepropane-1,3-diols to provide pyrrolidines (see scheme).

Full text of DOI:10.1002/anie.200801252

Angewandte
Chemie
DOI: 10.1002/anie.200801252
Amphiphilic Allylation
Convenient Synthesis of Pyrrolidines by Amphiphilic Allylation of
Imines with 2-Methylenepropane-1,3-diols**
Masanari Kimura,* Takato Tamaki, Masanori Nakata, Katsumi Tohyama, and
Yoshinao Tamaru*
Cycloaddition reactions using trimethylenemethane (TMM)
species are among the most interesting strategies for the
construction of cyclic biologically active molecules and
natural products.[1] Trost et al. reported that TMM–Pd com-
plexes generated from 3-acetoxy-2-trimethylsilylmethyl-1-
propene and Pd0 metal served successfully as zwitterionic
intermediates for 1,3-cycloaddition reactions with electron-
deficient olefins, aldehydes, and imines to give cycloalkanes
and heterocyclic compounds.[2]
In previous publications, we reported a method for the
direct allylic activation of allyl alcohols, promoted by a
combination of a Pd catalyst and triethylborane (Et3B), to
form a p-allylpalladium intermediate that serves as an allyl
cation equivalent for a variety of soft nucleophiles and
facilitates electrophilic allylation (Tsuji–Trost reaction).[3] In
the absence of nucleophiles, p-allylpalladium undergoes an
allyl–ethyl exchange reaction, thus providing allyldiethylbor-
ane as an allyl anion equivalent. This species reacts with
aldehydes, acetals, and aldimines to provide homoallyl
alcohols and homoallylamines.[4]
Scheme 1. Amphiphilic allylation of aldehydes (a) and aldimines (b)
with a bis-allyl alcohol promoted by Pd0 and Et3B.
give pyrrolidines (Scheme 1b). This is the first example of the
synthesis of pyrrolidines from nonactivated 2-methylenepro-
pane-1,3-diol as zwitterionic carbon framework. Notably, the
order of sequential amphiphilic allylation of aldimines is
apparently opposite to that of aldehydes (Scheme 1a and b).
Table 1 summarizes the Pd-catalyzed amphiphilic allyla-
tion reactions of aldimines prepared from a variety of
aromatic and aliphatic aldehydes and amines. The reaction
was conducted as follows: in situ aldimine formation (30 min
at reflux in 1 mL dry THF), distillation of an azeotropic
mixture of THF/H2O (twice), and exposure of the imine
residue to a mixture of 2-methylenepropane-1,3-diol, Pd-
(OAc)2, nBu3P, and Et3B at 508C under a nitrogen atmos-
phere.[7] Aldimines generated from aromatic amines and
aldehydes are suitable electrophiles for amphiphilic allyla-
tion. The reaction was successful for aromatic aldehydes and
amines with either electron-donating or electron-withdrawing
groups. When using aldimines substituted with halogens or
acidic OH groups, there was no need for the addition of extra
Et3B to obtain the expected pyrrolidines (Table 1, entries 3, 5,
and 6). Heteroaromatic and aliphatic aldehydes behaved
similarly, providing the corresponding pyrrolidines in reason-
able yields (Table 1, entries 7 and 8). Aldimines of aliphatic
amines performed comparably to those of aromatic amines.
N-benzylimines of aromatic and a,b-unsaturated aldehydes
underwent amphiphilic allylation in high yields (Table 1,
entries 9–12).
We recently established a straightforward and convenient
method for amphiphilic allylation of sec-alkyl aldehydes with
commercially available 2-methylenepropane-1,3-diol through
a TMM equivalent by using a Pd catalyst/Et3B system.[5] One
of the allyl alcohol moieties of the symmetrical bis-allyl
alcohol undergoes electrophilic allylation with the a position
of the alkyl aldehyde to give a hemiacetal, while the
remaining allyl alcohol moiety selectively reacts as an allyl
anion equivalent with the carbonyl group of the aldehyde to
furnish 4-methylenecyclopentanols (Scheme 1a). The result
of this reaction is in contrast to that of Trostꢀs reaction, a
[3+2] cycloaddition reaction with a TMM–Pd complex and
aldehydes which provides 3-methylenetetrahydrofurans.[6]
Herein, we report that a catalytic system consisting of a Pd
salt and Et3B promotes amphiphilic (nucleophilic–electro-
philic) allylation of aldimines, prepared from a wide variety of
amines and aldehydes, with 2-methylenepropane-1,3-diol to
[*] Dr. M. Kimura, T. Tamaki, M. Nakata, K. Tohyama, Prof. Dr. Y. Tamaru
Department of Applied Chemistry, Faculty of Engineering
Nagasaki University, 1-14 Bunkyo-machi, Nagasaki 852-8521
(Japan)
Fax: (+81)95-819-2684
E-mail: masanari@nagasaki-u.ac.jp
tamaru@nagasaki-u.ac.jp
[**] We thank the Ministry of Education, Science, Sports, and Culture
(Japan) for financial support.
However, the combination of benzylamine and alkyl
aldehyde did not react, and a complex mixture was produced
(Table 1, entry 13). Therefore, we developed an alternative
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200801252.
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Table 1: Synthesis of pyrrolidines by amphiphilic allylation of imines with
a bis-allyl alcohol.[a]
Table 2: Amphiphilic allylation of unsymmetrically substituted bis-allyl
alcohols.[a]
Entry
R1[b]
R2[b]
t [h]
Yield of 1 [%]
1
2
3
4
5
6
7
8
Ph
Ph
Ph
p-anis
p-ClC6H4
p-OHC6H4
2-furyl
n-C5H11
Ph
Ph
45
18
40
18
20
18
18
18
1a: 89
1b: 91
1c: 82
1d: 84
1e: 85
1 f: 77
1g: 74
1h: 81
1i: 71
p-anis
p-ClC6H4
p-anis
p-anis
p-anis
p-anis
p-anis
Bn
Entry
R
R1
R2[b]
EtnM
Et3B
t [h] Yield of 1 [%]
2
1
2
3
4
5
H
Ph
PMP
PMP
72
0
2a: 72
Bn Ph
Bn Ph
H
Et2Zn 12
1n: 100
1o: 83
1p: 73[c]
1p: 92
0
0
0
0
p-BrC6H4 Et2Zn 12
Et3B 72
Et2Zn 24
Me PMP
Bn Me PMP
9
18
[a] Reaction conditions: amine (1.05 mmol) and aldehyde (1 mmol) in
dry THF (1 mL) at reflux for 0.5 h; distillation of THF (azeotropic removal
of water) and then Pd(OAc)2 (0.1 mmol), nBu3P (0.2 mmol), 2-methyl-
enepropane-1,3-diol (1.2 mmol), Et3B (4.8 mmol) at 508C (entries 1 and
4), bis-allyl dibenzyl ether (1.2 mmol), Et2Zn (4.8 mmol) at room
temperature (entries 2, 3, and 5). [b] PMP=p-methoxyphenyl. [c] As a
diastereomeric mixture of trans-1p and cis-1p in a 10:1 ratio.
10
11
12
13[c]
p-ClC6H4
2-furyl
cinnamyl
n-C5H11
Bn
Bn
Bn
Bn
18
18
18
18 (6)
1j: 79
1k: 80
1l: 67
1m: – (70)
[a] Reaction conditions: amine (1.05 mmol; R2) and aldehyde (1 mmol;
R1) in dry THF (1 mL) at reflux for 0.5 h; distillation of THF (azeotropic
removal of water) and then Pd(OAc)2 (0.1 mmol), nBu3P (0.2 mmol), 2-
methylenepropane-1,3-diol (1.2 mmol), and Et3B (4.8 mmol) in dry THF
(1 mL) under nitrogen. [b] p-anis=p-anisidine, Bn=benzyl. [c] In paren-
theses: results when 2-methylenepropane-1,3-dibenzyl ether (1.2 mmol)
and Et2Zn (4.8 mmol) were used.
These regio-and stereoselectivities are in contrast to the
results obtained by using the Trost protocol: cycloaddition
with substituted TMM precursors generated from unsym-
metrical 2-[(trimethylsilyl)methyl]allyl acetate by using a Pd
catalyst (Scheme 2).[10] In that work, a 1-phenyl-TMM–Pd
complex was found to react with the imine carbon atom at the
more substituted allylic position to provide 2,3-diphen
ylpyrrolidines as a mixture of diastereomers. Thus, all
conceivable isomers involving TMM precursors can be
formed selectively by using either the reaction conditions
described herein or those developed by Trost.
Unsymmetrical methyl-substituted bis-allyl alcohols show
different regio-and stereoselectivities compared to those
substituted with a phenyl group. In this case, intramolecular
electrophilic allylation proceeds at the more substituted side
of p-allylpalladium to give trans-1p predominantly along with
a small amount of cis-1p (Table 2, entry 4), in contrast to the
reaction using Ph-substituted bis-allyl alcohol. The use of
Et2Zn accelerated the amphiphilic allylation reaction
smoothly at room temperature to afford trans-1p as a single
isomer in excellent yield (Table 2, entry 5).
reaction route, by using a Pd catalyst and Et2Zn, for the
amphiphilic allylation of aldimines composed of an aliphatic
aldehyde and an aliphatic amine with 2-methylenepropane-
1,3-dibenzyl ether. In this case, the reaction proceeded
smoothly at room temperature, reaching completion after
6 h, and the desired pyrrolidine was obtained in 70% yield
(Table 1, entry 13, values in parentheses). The Pd/Et2Zn
system achieves amphiphilic allylation despite the fact that
imines generated from aliphatic aldehydes and amines are
generally far less reactive than their aromatic counterparts.[8]
Thus, by employing either Et3B or Et2Zn, this one-pot
synthesis of pyrrolidines may be carried out with a wide
variety of aromatic and aliphatic aldehydes and amines.
Unsymmetrically substituted bis-allyl alcohols and bis-
allyl dibenzyl ethers show intriguing regio-and stereoselec-
tivities depending on whether Et3B or Et2Zn is used as
promoter. In the presence of Pd catalyst and Et3B, a 1-phenyl-
substituted unsymmetrical bis-allylic alcohol underwent
nucleophilic allylation at the less substituted allylic position,
followed by intramolecular electrophilic allylation at the less
sterically hindered end of the allyl moiety, to provide
pyrrolidine E-2a as a single isomer (Table 2, entry 1). In
contrast, the Pd/Et2Zn catalytic system promoted nucleo-
philic allylation of the dibenzyl ether at the less substituted
position, and subsequent electrophilic allylation proceeded at
the Ph-substituted allylic position to afford trans-2,5-diphen-
ylpyrrolidine 1n quantitatively as a single stereoisomer
(Table 2, entry 2). p-Bromoanaline imine displayed similar
regio-and stereoselectivities, yielding pyrrolidine 1o as a sole
product (Table 2, entry 3). The structure of 1o was unequivo-
cally determined by means of X-ray single-crystal analysis.[9]
The single stereoisomer trans-1n obtained by using the
Pd/Et2Zn system was successfully converted into internal
olefin E-2a with a Pd/Et3B catalyst at 508C for 72 h
Scheme 2. Selective synthesis of conceivable substituted pyrrolidines.
TMS=trimethylsilyl.
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(Scheme 3a) Interestingly, under similar conditions, trans-1p
isomerized to a diastereomeric mixture of trans-and cis-1p in
an approximately 1:1 ratio (Scheme 3b). The results of these
Keywords: aldimines · allylation · amphiphiles · palladium ·
pyrrolidines
.
[1] a) “Cycloaddition Reactions of Allylpalladium and Related
Derivatives”: S. Ogoshi in Handbook of Organopalladium
Chemistry for Organic Synthesis, Vol. 2 (Ed.: E. Negishi),
Wiley Interscience, New York, 2002, pp. 1995 – 2009; b) S.
Yamago, E. Nakamura, Organic Reactions, Vol. 61 (Ed.: L. E.
Overman), Wiley, New York, 2002, pp. 1 – 217; c) B. M. Trost, N.
Cramer, H. Bernsmann, J. Am. Chem. Soc. 2007, 129, 3086 –
3087; d) S. Xu, H. Arimoto, D. Uemura, Angew. Chem. 2007,
119, 5848 – 5851; Angew. Chem. Int. Ed. 2007, 46, 5746 – 5749.
[2] a) B. M. Trost, D. M. T. Chan, J. Am. Chem. Soc. 1979, 101,
6429 – 6432; b) B. M. Trost, N. Cramer, S. M. Silverman, J. Am.
Chem. Soc. 2007, 129, 12396 – 12397; c) B. M. Trost, S. M.
Silverman, J. P. Stambuli, J. Am. Chem. Soc. 2007, 129, 12398 –
12399; d) for [3+3] cycloaddition of TMM–Pd with azomethine
imines, see: R. Shintani, T. Hayashi, J. Am. Chem. Soc. 2006, 128,
6330 – 6331; e) for asymmetric [3+3] cycloaddition of TMM–Pd
with nitrones, see: R. Shintani, S. Park, W.-L. Duan, T. Hayashi,
Angew. Chem. 2007, 119, 6005 – 6007; Angew. Chem. Int. Ed.
2007, 46, 5901 – 5903.
[3] a) Y. Tamaru, Y. Horino, M. Araki, S. Tanaka, M. Kimura,
Tetrahedron Lett. 2000, 41, 5705 – 5709; b) Y. Horino, M. Naito,
M. Kimura, S. Tanaka, Y. Tamaru, Tetrahedron Lett. 2001, 42,
3113 – 3116; c) M. Kimura, Y. Horino, R. Mukai, S. Tanaka, Y.
Tamaru, J. Am. Chem. Soc. 2001, 123, 10401 – 10402; d) M.
Kimura, R. Mukai, N. Tanigawa, S. Tanaka, Y. Tamaru,
Tetrahedron 2003, 59, 7767 – 7777; e) M. Kimura, M. Futamata,
R. Mukai, Y. Tamaru, J. Am. Chem. Soc. 2005, 127, 4592 – 4593;
f) M. Kimura, M. Fukasaka, Y. Tamaru, Synthesis 2006, 3611 –
3616.
Scheme 3. Different reactivity of alkyl-and aryls-ubstituted products
towards our Pd/Et3B catalyst.
1
isomerization experiments indicated that intramolecular
electrophilic allylation in the presence of Pd/Et3B is a
reversible process; hence, isomerization from the kinetically
favorable pyrrolidines to the thermodynamically more stable
species occurs readily under this system.[11]
In conclusion, we have developed a convenient and
straightforward synthesis of pyrrolidines from commercially
available 2-methylenepropane-1,3-diols and their benzyl
ethers with a variety of aldimines prepared from aromatic
and aliphatic amines and aldehydes. The application and
extension of this method for the asymmetric synthesis of
physiologically active molecules with pyrrolidine frameworks
are currently being investigated.
[4] a) M. Kimura, I. Kiyama, T. Tomizawa, Y. Horino, S. Tanaka, Y.
Tamaru, Tetrahedron Lett. 1999, 40, 6795 – 6798; b) M. Kimura,
T. Tomizawa, Y. Horino, S. Tanaka, Y. Tamaru, Tetrahedron Lett.
2000, 41, 3627 – 3629; c) M. Kimura, M. Shimizu, K. Shibata, M.
Tazoe, Y. Tamaru, Angew. Chem. 2003, 115, 3514 – 3517; Angew.
Chem. Int. Ed. 2003, 42, 3392 – 3395; d) M. Shimizu, M. Kimura,
T. Watanabe, Y. Tamaru, Org. Lett. 2005, 7, 637 – 640.
[5] R. Mukai, Y. Horino, S. Tanaka, Y. Tamaru, M. Kimura, J. Am.
Chem. Soc. 2004, 126, 11138 – 11139.
Experimental Section
General procedure (see Table 1, entry 2): A solution of benzaldehyde
(106 mg, 1.0 mmol) and p-anisidine (129 mg, 1.05 mmol) in dry THF
(1 mL) was refluxed for 30 min under nitrogen and then the solvent
was removed by distillation (azeotropic removal of water). THF
(1 mL) was added and then removed by distillation under atmos-
pheric pressure of nitrogen. Pd(OAc)2 (22.5 mg, 0.1 mmol), nBu3P
(50 mL, 0.2 mmol), 2-methylenepropane-1,3-diol (106 mg, 1.2 mmol),
THF (1 mL), and Et3B (3.6 mmol, 1m in hexane) were successively
added to the imine residue. The homogeneous mixture was stirred
and heated for 18 h at 508C under nitrogen. The mixture was diluted
with EtOAc and washed with saturated NaHCO3 and brine, and then
the organic phase was dried (MgSO4) and concentrated in vacuo to
give a brown oil, which was purified by column chromatography over
silica gel (eluent: hexane) to give 1b (242 mg, 91%). Rf = (0.70,
EtOAc/hexane = 1:4); IR (neat): n˜ = 2947 (m), 1620 (w), 1234 (s),
[6] B. M. Trost, S. A. King, T. Schmidt, J. Am. Chem. Soc. 1989, 111,
5902 – 5915.
[7] 4.8 equivalents of Et3B were required to complete the amphi-
philic allylation successfully. Although the reaction proceeded in
the presence of 2.0 equivalents of Et3B, the conversion
decreased to 50%.
[8] a) M. Kimura, A. Miyachi, K. Kojima, S. Tanaka, Y. Tamaru, J.
Am. Chem. Soc. 2004, 126, 14360 – 14361; b) M. Kimura, Y.
Tatsuyama, K. Kojima, Y. Tamaru, Org. Lett. 2007, 9, 1871 –
1873.
[9] See the Supporting Information for the X-ray single-crystal
structure of 1o. Crystal data for 1o: C23H20BrN, Mr = 390.32,
orthorhombic, space group Pbca (no. 61), a = 8.2414(4), b =
18.2298(8), c = 25.0459(13) Š, V= 3762.9(3) Š3, T= 296 K, Z =
8, 1calcd = 1.378 gcmÀ3, m(MoKa) = 0.7107 mmÀ1, 25546 reflec-
tions measured, 4287 unique (Rint = 0.027), R(Rw) = 0.1071-
(0.1254). CCDC 671566 contains the supplementary crystallo-
graphic data for this paper. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
[10] B. M. Trost, C. M. Marrs, J. Am. Chem. Soc. 1993, 115, 6636 –
6645.
[11] Contrary to the isomerization experiment with the Pd/Et3B
system, the single isomer 1n was not converted to E-2a by
treatment with a Pd catalyst and Et2Zn at 508C for 72 h.
1
1042 (m), 810 (s) cmÀ1; H NMR (400 MHz, CDCl3, TMS): d = 2.51
(dd, J = 3.4, 15.1 Hz, 1H), 3.20 (dd, J = 8.8, 15.1 Hz, 1H), 3.70 (s, 3H),
4.09 (d, J = 13.2 Hz, 1H), 4.29 (d, J = 13.2 Hz, 1H), 4.78 (dd, J = 3.4,
8.8 Hz, 1H), 4.95 (s, 1H), 5.08 (s, 1H), 6.45 (d, J = 9.0 Hz, 2H), 6.75
(d, J = 9.0 Hz, 2H), 7.17–7.29 ppm (m, 5H); 13C NMR (100 MHz,
CDCl3, TMS): d = 42.8, 54.7, 55.8, 63.1, 106.7, 113.3, 114.7, 125.7,
126.6, 128.4, 141.3, 144.5, 144.8, 151.1 ppm; HRMS: m/z (%): calcd
for C18H19ON: 265.1467 [M+]; found: 265.1444 (100).
Received: March 15, 2008
Revised: May 12, 2008
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