A facile highly regio- and stereoselective preparation of N-tosyl allylic amines from allylic alcohols and tosyl isocyanate via palladium(II)-catalyzed aminopalladation-β-heteroatom elimination

Article abstract of DOI:10.1021/ol006130u

(equation presented) The high regio- and stereoselectivity have been obtained from the allylic substitution reaction catalyzed by palladium(II) species. From allylic alcohols, one-pot reaction with tosyl isocyanate followed by palladium(II)-catalyzed ally

Full text of DOI:10.1021/ol006130u

ORGANIC
LETTERS
2000
Vol. 2, No. 15
2357-2360
A Facile Highly Regio- and
Stereoselective Preparation of N-Tosyl
Allylic Amines from Allylic Alcohols and
Tosyl Isocyanate via
Palladium(II)-Catalyzed
Aminopalladation−â-Heteroatom
Elimination
Aiwen Lei and Xiyan Lu*
Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry,
Chinese Academy of Sciences, 354 Fenglin Lu, Shanghai, 200032, China
xylu@pub.sioc.ac.cn
Received May 30, 2000
ABSTRACT
The high regio- and stereoselectivity have been obtained from the allylic substitution reaction catalyzed by palladium(II) species. From allylic
alcohols, one-pot reaction with tosyl isocyanate followed by palladium(II)-catalyzed allylic substitution gives N-tosyl (E)-allylic amines in high
yield. The substitution occurs only at the γ-position of the 1- or 3-substituted allylic alcohols.
Allylic amines are important synthetic intermediates for the
preparation of a number of biologically active molecules.1
In recent years, the Pd(0)-catalyzed amination of allyllic
substrates has been extensively studied for its relevance to
organic synthesis.2 However, the two terminal carbons of
the π-allyl palladium complex are nearly equivalent, and the
nucleophilic substitution usually gave a mixture of regio-
isomers (Scheme 1).3 Thus, controlling of regioselectivity
in the unsymmetric π-allylic system has been a major
challenge.4 In general, a sterically demanding group at one
terminus of the allylic system usually blocks the incoming
nucleophile, or an electron-withdrawing group at an allylic
carbon atom has been used to change the electronic density
of the two carbon atoms of the π-allyl intermediate.5 Herein,
(1) (a) Johannsen, M.; Jørgensen, K. A. Chem. ReV. 1998, 98, 1689. (b)
Cheikh, R. B.; Chaabouni, R.; Laurent, A.; Mison, P.; Nafti, A. Synthesis
1983, 685. (c) Wei, Z.-Y.; Knaus, E. E. Synthesis 1994, 1463. (d)
Spaltenstein, A.; Carpino, P. A.; Miyake, F.; Hopkins, P. B. J. Org. Chem.
1987, 52, 3759.
(2) (a) Trost, B. M. Angew. Chem., Int. Ed. Engl. 1989, 28, 1173. (b)
Godleski, S. A. In ComprehensiVe Organic Synthesis; Trost, B. M., Fleming,
I., Semmelbach, M. F., Eds.; Pergamon: Oxford, 1991; Vol. 4, p 585. (c)
Tsuji, J. Palladium Reagents and Catalysis: InnoVations in Organic
Synthesis; John Wiley: Chichester, 1995.
Scheme 1
(3) Trost, B. M.; Toste, F. D. J. Am. Chem. Soc. 1999, 121, 4545.
(4) (a) Trost, B. M.; Verhoeven, T. R. J. Am. Chem. Soc. 1980, 102,
4730. (b) Pretot, R.; Pfaltz, A. Angew. Chem., Int. Ed. 1998, 37, 323. (c)
Hayashi, T.; Kawatsura, M.; Uozumi, Y. J. Chem. Soc., Chem. Commun.
1997, 561. (d) Hayashi, T.; Kishi, K.; Yamamoto, A.; Ito, Y. Tetrahedron
Lett. 1990, 31, 1743. (e) Hayashi, T.; Kawatsura, M.; Uozumi, Y. J. Am.
Chem. Soc. 1998, 120, 1681. (f) Trost, B. M.; Krische, M. J.; Radinov, R.;
Zanoni, G. J. Am. Chem. Soc. 1996, 118, 6297.
10.1021/ol006130u CCC: $19.00 © 2000 American Chemical Society
Published on Web 07/06/2000

we report a facile, highly regio- and stereoselective method
for the synthesis of N-tosyl allylic amines directly from allylic
alcohols via divalent palladium-catalyzed intramolecular
allylic substitution.
examples of facile reduction of Pd(II) to Pd(0).2c,7 However,
it is inconsistent with the fact that the control experiment
only in the presence of Pd(OAc)2 without LiBr in DMF gave
no reaction. In addition, in a parallel study, when compound
1a (1 mmol) was subject to a Pd catalytic system (Pd(OAc)2
(0.05 mmol)) in the presence of LiBr (4 mmol) and CuBr2
(8 mmol) in DMF (5 mL), 3a was the sole product in 98%
yield. Furthermore, the reaction of 1a (1 mmol) could
proceed with Pd(OAc)2 (0.05 mmol) and LiBr (4 mmol)
without the presence of CuBr2 in DMF (5 mL) at room
temperature to produce 3a in 95% yield. No reaction occurred
in the absence of Pd(II) catalyst even at 100 °C. These
observations led us to believe that the reaction is actually
catalyzed by Pd(II) instead of Pd(0).
In our laboratory, we have developed a series of regio-
and stereoselective reactions based on Pd(II)-mediated nu-
cleopalladation of alkynes and tandem carbon-carbon bond
coupling.6 With these previous developments, we explored
the intramolecular nucleopalladation of alkenes by nitrogen
nucleophiles and wished to achieve a tandem nucleopalla-
dation-conjugate addition reaction (Scheme 2, a). However,
Scheme 2
To further clarify the reaction mechanism, we studied the
substitution reaction with O-[but-(2Z)-enyl]tosylcarbamate
(1b) (Scheme 3). From 1b (1 mmol), a Pd(0) [Pd(OAc)2,
Scheme 3
when we attempted the reaction of 1a (0.1 mmol) with
acrolein (1.5 mmol) in the presence of Pd(OAc)2 (0.005
mmol) and LiBr (0.5 mmol) in THF, we only obtained the
compounds 3a (yield: 57%) and 4 (yield: 30%) instead of
2. The formation of 4 may be explained by the direct Michael
addition of 1a to acrolein; but the formation of 3a was
somewhat unexpected in Pd(II)-catalyzed reactions. Usually,
the transformation of 1a to 3a could be speculated by a
Pd(0)-catalyzed allylic cleavage followed by decarboxylation
and nucleophilic substitution by tosylamide anion. This
appeared a reasonable supposition in light of the numerous
(0.05 mmol), PPh3, (0.2 mmol)]7 catalyzed allylic substitution
leads to 3b and (E)-3e as the main products together with a
minor amount of unidentified product.8 While under
Pd(OAc)2-LiBr catalysis, only the γ-substituted product 3b
was isolated in 96% yield.
It is significant that the N-tosyl carbamates can be prepared
in situ from the corresponding allylic alcohols9 and undergo
allylic substitution without isolation. For example, allyl
alcohol 5a (1 mmol) reacted with TsNCO (1.1 mmol) in THF
for 20 min; after THF was removed, the catalytic reaction
was carried out in DMF in the presence of Pd(OAc)2 (0.05
mmol) and LiBr (4 mmol). This procedure afforded 3a in
96% yield. A wide range of 1-, 3-substituted or 1,3-
disubstituted (Z)-allylic alcohols were examined under the
same conditions (Scheme 4, Table 1), and they all gave
exclusively the γ-substitution products.10
(5) (a) Tetsuo, T.; Horii, Y.; Nakagawa, Y.; Ishida, T.; Saegusa, T. J.
Org. Chem. 1989, 54, 977. (b) Tanikaga, R.; Takeuchi, J.; Takyu, M.; Kaji,
A. J. Chem. Soc., Chem. Commun. 1987, 386. (c) Geneˆt, J. P.; Balabane,
M.; Ba¨ckvall, J. E.; Nystro¨m, J. E. Tetrahedron Lett. 1983, 27, 2745. (d)
Tsuji, J.; Ueno, H.; Kobayashi, Y.; Okumoto, H. Tetrahedron Lett. 1981,
22, 2573. (e) Inami, H.; Ito, T.; Urabe, H.; Sato, F. Tetrahedron Lett. 1993,
34, 5919. (f) Urade, H.; Inami, H.; Sato, F. J. Chem. Soc., Chem. Commun.
1993, 1595. (g) Tsuji, J.; Yuhara, M.; Minato, M.; Yamada, H.; Sato, F.;
Kobayashi, Y. Tetrahedron Lett. 1988, 29, 343. (h) Hirao, T.; Enda, J.;
Ohshiro, Y.; Agawa, T. Tetrahedron Lett. 1981, 22, 3079. (i) Trost, B. M.;
Self, C. R. J. Am. Chem. Soc. 1983, 105, 5942. (j) Kang, J.; Cho, W.; Lee,
W. K. J. Org. Chem. 1984, 49, 1838.
(6) (a) Lu, X.; Zhu, G.; Wang, Z. Synlett 1998, 115. (b) Lu, X.; Ma, S.
New Age of Divalent Palladium Catalysis. In Transition Metal Catalyzed
Reaction; Murahashi, S-I., Davies, S. G., Eds.; 1999; Chapter 6, p 133. (c)
Ma, S.; Lu, X. J. Chem. Soc., Chem. Commun. 1990, 733. (d) Ma, S.; Lu,
X. J. Org. Chem. 1991, 56, 5112. (e) Ma, S.; Zhu, G.; Lu, X. J. Org. Chem.
1993, 58, 3692. (f) Ma, S.; Lu, X. J. Organomet. Chem. 1993, 447, 305.
(g) Ma, S.; Lu, X. J. Org. Chem. 1993, 58, 1245. (h) Zhu, G.; Ma, S.; Lu,
X. J. Chem. Res. (S) 1993, 367. (i) Zhu, G.; Lu, X.; Organometallics 1995,
14, 4899. (j) Zhu, G.; Lu, X. J. Org. Chem. 1995, 60, 1087.
Scheme 4
(7) (a) Amatore, C.; Jutand, A.; M’Barki, M. A. Organometallics
1992, 11, 3009. (b) Ozawa, F.; Kabo, A.; Hayashi, T. Chem. Lett. 1992,
2177. (c) Hayashi, T.; Kubo, A.; Ozawa, F. Pure Appl. Chem. 1992, 64,
421.
2358
Org. Lett., Vol. 2, No. 15, 2000

[3,3]-Sigmatropic rearrangements of allylic acetate is
known to be catalyzed efficiently by PdCl2(PhCN)2.14 In
addition, conversion of S-allylthioimidates into N-allylthio-
amide, and allylimidates into allylamides, are also catalyzed
by Pd(II).15 The mechanism of the rearrangement reaction
of allylic acetate was explained by the oxypalladation of the
double bond to form a six-membered cyclic Pd(II) intermedi-
ate. Resembling Pd-catalyzed [3,3]-rearrangement, we pro-
pose another plausible mechanism of the reaction as route b
in Scheme 5.
It is noteworthy that the reaction is highly stereoselective.
From 1-substituted or 1,3-disustituted allylic carbamates
(Table 1, entries 3-6), the reaction gives only N-tosyl (2E)-
allylic amines: no (Z)-products can be detected by 1H NMR
and HPLC. This feature allows for convenient selective
synthesis of (E)-allylic amines from readily available 1-sub-
stituted or 1,3-disustituted allylic alcohols. The high (E)-
selectivity can be explained by the favorable conformation
of the six-membered cyclic intermediate and the highly
specific trans-heteroatom elimination6b,i (Scheme 6): The
Table 1. Pd(II)-Catalyzed Synthesis of N-Tosyl (E)-Allylic
Ainesa
substrate
R2
product
yield (%)b
entry
5
R1
R3
3
1
2
3
4
5
6
7
5a
5c
5d
5e
5f
H
H
Ph
Me
n-C5H11
Ph
Me
H
H
H
H
H
H
H
3a
3c
3d
3e
3f
95
80
98
96
85
98
58
n-C4H9
H
H
H
Ph
H
5g
5h
3g
3h
Me
a Reaction condition: 5 (1 mmol) reacted with TsNCO (1.1 mmol) in
THF for 20 min; then THF was removed, the residue was dissolved in
DMF, and then Pd(OAc)2 (0.05 mmol) and LiBr (4 mmol) were added and
stirred at room temperature (for entry 1) or 100 °C (for entries 2-7).
b Isolated yields.
On the basis of these results, we speculate that the reaction
proceeds via a Pd(II)-mediated SN2′ substitution-decarbox-
ylation mechanism (Scheme 5, a): Compound 1a first
Scheme 6
Scheme 5
nucleopalladation of 1d-g can lead to two possible inter-
mediates in chair conformation: 6A and 6B. With the bulky
groups, Pd group, Ts, and R in equatorial positions, 6A is
more stable than 6B. The cyclization preferentially gives 6A,
and then trans-elimination of Pd-OCO-R leads to (E)-
double bond.
dissociates to give anion 6. The nitrogen anion attacks the
double bond activated by Pd(II), leading to a cyclic inter-
mediate 7. â-Heteroatom elimination assisted by bromide
ions11 then gives 8, which spontaneously releases CO2 to
afford 9. The proton exchange between 9 and 1a gives the
neutral product 3a and anion 6, which enters a second
catalytic cycle. The preferential elimination of the â-oxygen-
containing group of 7 results in the high regioselectivity of
the reaction.
(11) The role of bromide ions might be ascribed to (a) the presence of
excess bromide ion makes the Pd coordinatively saturated and the â-H
elimination not so feasible;12 (b) The coordination of bromide ion with Pd
increase the electron density of Pd, resulting in the weakening of the
carbon-palladium bond.13
(12) Wang, Z.; Zhang, Z.; Lu, X. Organometallics 2000, 19, 775.
(13) (a) Markies, B. A.; Canty, A. J.; de Graaf, W.; Boersma, J.; Janssen,
M. D.; Hogerheide, M. P.; Smeets, W. J. J.; Spek, A. L.; van Koten, G. J.
Organomet. Chem. 1994, 482, 191. (b) Ryabov, A. D.; Sakodinskaya, I.-
K.; Titov, V. M.; Yatsimirsky, A. K. Inorg. Chim. Acta 1981, 54, L195.
(c) Ryabov, A. D.; Sakodinskaya, I.-K.; Yatsimirsky, A. K. Inorg. Chim.
Acta 1986, 116, L55.
(8) A typical experiment showed that the products contained 37% of
3b, 51% of (E)-3e, and other unidentified products as characterized by
HPLC.
(9) Tamaru, Y.; Kimura, M.; Tanaka, S.; Kure, S.; Yoshida, Z. Bull.
Chem. Soc. Jpn. 1994, 67, 2838.
(10) Using the (E)-allylic alcohol as the substrate, no expected product
formed.
(14) (a) Overman, L. E. Angew. Chem., Int. Ed. Engl. 1984, 23, 579. (b)
Henry, P. M. J. Am. Chem. Soc. 1972, 94, 5200.
Org. Lett., Vol. 2, No. 15, 2000
2359

An important application of the current reaction is the
preparation of conjugated N-tosyl dienylamines. From 1,4-
pentadien-3-ol, which can be easily prepared from acrolein
and vinyl Grignard reagent, N-tosyl (2E)-2,4-pentadienyl-
amines can be synthesized in high yield and stereoselectivity
by a two-step reaction sequence (Scheme 7). Conjugated
alcohols, one-pot reaction with tosyl isocyanate followed by
divalent palladium-catalyzed allylic substitution gives N-tosyl
allylic amines in high yield, and high stereo- and regio-
selectivity as compared with the drawback of regioselectivity
of allylic substitution catalyzed by Pd(0).
Acknowledgment. We thank the National Natural Sci-
ences Foundation of China and Chinese Academy of Sci-
ences for financial support.
Scheme 7
Supporting Information Available: General procedures,
spectral data, and the experiment of 1b under Pd(OAc)2-
PPh3. This material is available free of charge via the Internet
at http://pubs.acs.org.
OL006130U
(15) (a) Overman, L. E.; Donde, Y. J. Am. Chem. Soc. 1999, 121, 2933.
(b) Calter, M.; Hollis, T. K.; Overman, L. E.; Ziller, J.; Zipp, G. G. J. Org.
Chem. 1997, 62, 1449. (c) Overman, L. E. Acc. Chem. Res. 1980, 13, 218.
(d) Genda, J.; Helland, A. C.; Ernst, B. E.; Bellus, D. Synthesis 1993, 729.
(e) Tamaru, Y.; Kagotani, M.; Yoshida, Z.-I. J. Org. Chem. 1980, 45, 5221.
(f) Tamaru, Y.; Kagotani, M.; Yoshida, Z. Tetrahedron Lett. 1981, 22, 4245.
(g) Tamaru, Y.; Kagotani, M.; Yoshida, Z. J. Org. Chem. 1985, 50, 764.
(h) Schenck, T. G.; Bosnich, B. J. Am. Chem. Soc. 1985, 107, 2058. (i)
Mehmandoust, M.; Petit, Y.; Larcheveˆque, M. Tetrahedron Lett. 1992, 33,
4313. (j) Mizutani, M.; Sanemitsu, Y.; Tamrau, Y.; Yoshida, Z.-I. J. Org.
Chem. 1985, 50, 764.
dienes are important intermediates in the synthesis of
complex natural products because of their versatile reactivi-
ties, and dienylamines in particular have been used in the
synthesis of dihydropyridines et al.16 Using readily available
divinyl carbinols, the present method can provide facile
access to a wide range of dienylamines and is expected to
have broad applications in natural product synthesis.
In summary, we have developed a highly efficient method
for the synthesis of N-tosyl allylic amines. From allylic
(16) (a) Wyle, M. J.; Fowler, F. W. J. Org. Chem. 1984, 49, 4025. (b)
Birtwistle, D. H.; Brown, J. M.; Foxton, M. W. Tetrahedron 1988, 44, 7309.
2360
Org. Lett., Vol. 2, No. 15, 2000