π-allylic C1-substitution in water with nitromethane using amphiphilic resin-supported palladium complexes

Article abstract of DOI:10.1021/jo061250m

Nitromethane was safely applied as a C1 nucleophile for palladium-catalyzed π-allylic substitution in water with amphiphilic PS-PEG resin-supported phosphine-palladium complexes. Catalytic asymmetric nitromethylation of cycloalkenyl esters was achieved in water as a single reaction medium under heterogeneous conditions using 5 mol % palladium of a PS-PEG resin-supported palladium-imidazoindolephosphine complex to give optically active (cycloalkenyl)nitromethanes with up to 98% ee.

Full text of DOI:10.1021/jo061250m

even under basic conditions. Here, we report a heterogeneous
aquacatalytic π-allylic substitution with nitromethane as a safe
C1 nucleophile3,4 where asymmetric catalysis (up to 98% ee)
is also described.
π-Allylic C1-Substitution in Water with
Nitromethane Using Amphiphilic
Resin-Supported Palladium Complexes
Preliminary studies on the aquacatalytic π-allylic nitrom-
ethylation were carried out with the PS-PEG resin-supported
triarylphosphine-palladium complex 3. Thus, methyl cinnamyl
carbonate (1) reacted with 3 equiv of nitromethane in aqueous
Li2CO3 solution in the presence of 5 mol % palladium of the
polymeric complex 3 at 60 °C for 12 h to give 92% isolated
yield of the nitromethylated products 2 and 2′ (2/2′ ) 89/11)
(Scheme 1). Nitromethylation of 1 with [PdCl(η3-C3H5)]2/PPh3
in THF or CH2Cl2 showed little or low reactivity at 25 °C to
result in a poor chemical yield and exploded at 40 °C.
Acyclic and cyclic secondary allylic esters also underwent
the aquacatalytic nitromethylation under similar conditions
(Schemes 2 and 3). Thus, nitromethylation of benzylic esters
1′ proceeded smoothly under similar conditions to give a mixture
of linear and branch products 2 and 2′ in 84% yield in a ratio
of 86:14 where the plausible π-allylpalladium intermediate
should be the same as the intermediate for the reaction of
cinnamyl ester 1. Benzylic esters 4 and 6 bearing 4-methyl and
4-methoxy aromatic substituents also gave the corresponding
nitromethylation products 5/5′(93:7) and 7/7′(77:23) in 80% and
86% yield, respectively. 1,3-Diphenylpropenyl carbonate 8 gave
95% yield of 9 under similar conditions. The cyclic substrates
10, 12, and 14 also underwent π-allylic nitromethylation to
afford the corresponding products 7, 9, and 11 in 78%, 90%,
and 89% isolated yield, respectively (Scheme 3). 5-cis-Car-
bomethoxycyclohexenyl carbonate 16 reacted with nitromethane
under similar conditions to give the cis-1-nitromethyl-5-car-
bomethoxy product 17 as a single diastereoisomer in 93% yield.
The exclusive stereochemical outcome indicates that this
nitromethylation proceeded via a double inversion pathway:
π-allylpalladium complexation and nucleophilic attack of the
nitromethyl group.
Yasuhiro Uozumi* and Toshimasa Suzuka
Institute for Molecular Science (IMS) and CREST, Higashiyama
5-1, Myodaiji, Okazaki 444-8787, Japan
uo@ims.ac.jp
ReceiVed June 19, 2006
Nitromethane was safely applied as a C1 nucleophile for
palladium-catalyzed π-allylic substitution in water with
amphiphilic PS-PEG resin-supported phosphine-palladium
complexes. Catalytic asymmetric nitromethylation of cy-
cloalkenyl esters was achieved in water as a single reaction
medium under heterogeneous conditions using 5 mol %
palladium of a PS-PEG resin-supported palladium-imida-
zoindolephosphine complex to give optically active (cy-
cloalkenyl)nitromethanes with up to 98% ee.
The palladium-catalyzed allylic substitution reaction, the so-
called Tsuji-Trost reaction, has been recognized as one of the
most powerful carbon-carbon bond-forming catalytic transfor-
mations. However, in contrast to the vast amount of research
on palladium-catalyzed π-allylic substitution with active me-
thylene and methine compounds (e.g., malonates), only scattered
attention has been paid to reactions with C1 nucleophiles. If
the palladium-catalyzed π-allylic substitution of allylic esters
took place with nitromethane as the C1 nucleophile, it would
allow introduction of various C1 functionalities at the allylic
position due to the versatile reactivity of the nitromethyl group.
One of the major problems associated with nucleophilic utility
of nitromethane lies in the explosive nature of nitromethane
under basic conditions.1 We have developed amphiphilic
polystyrene-poly(ethylene glycol) (PS-PEG) resin-supported
palladium complexes, which catalyze various synthetic organic
reactions, π-allylic substitution, Heck reaction, carbonylation,
cross-coupling, etc., in water under heterogeneous conditions.2
These results prompted us to examine the π-allylic C1 substitu-
tion with nitromethane in water using amphiphilic polymeric
palladium catalysts in which nitromethane should not explode
Using this safe π-allylic nitromethylation protocol, we
examined catalytic asymmetric nitromethylation in water with
an amphiphilic PS-PEG resin-supported chiral palladium
complex (Scheme 4). We previously reported the heterogeneous
aquacatalytic chiral process by catalytic asymmetric π-allylic
alkylation and amination of cycloalkenyl esters using a pal-
ladium catalyst coordinated with a novel optically active ligand,
(3R,9aS)-(2-aryl-3-(2-diphenylphosphino)phenyl)tetrahydro-1H-
imidazo[1,5-a]indol-1-one, anchored onto an amphiphilic poly-
styrene-poly(ethylene glycol) copolymer (PS-PEG) resin.5,6
(2) For studies on polymer-supported palladium catalysts from the
author’s group, see: (a) Uozumi, Y.; Danjo, H.; Hayashi, T. Tetrahedron
Lett. 1997, 38, 3557 (π-allylic substitution). (b) Danjo, H.; Tanaka, D.;
Hayashi, T.; Uozumi, Y. Tetrahedron 1999, 55, 14341 (π-allylic substitu-
tion). (c) Uozumi, Y.; Danjo, H.; Hayashi, T. J. Org. Chem. 1999, 64, 3384
(cross-coupling). (d) Uozumi, Y.; Watanabe, T. J. Org. Chem. 1999, 64,
6921 (carbonylation reaction). (e) Uozumi, Y.; Nakai, Y. Org. Lett. 2002,
4, 2997 (Suzuki-Miyaura coupling). (f) Uozumi, Y.; Kimura, T. Synlett
2002, 2045 (Heck reaction). (h) Uozumi, Y.; Kobayashi, Y. Heterocycles
2003, 59, 71 (Sonogashira reaction). (o) Uozumi, Y.; Kikuchi, M. Synlett
2005, 1775 (cross-coupling).
(3) Deardorff, D. R.; Savin, K. A.; Justman, C. J.; Karanjawala, Z. E.;
Sheppeck, J. E.; Hager, D. C.; Aydin, N. J. Org. Chem. 1996, 61, 3616.
(4) (a) Imada, Y.; Fujii, M.; Kubota, Y.; Murahashi, S.-I. Tetrahedron
Lett. 1997, 38, 8277. (b) Tsuji, Y.; Yamada, N.; Tanaka, S. J. Org. Chem.
1993, 58, 16.
(1) (a) Material Safety Data Sheet Number N5740. (b) Makovsky, A.;
Lenji, L. Chem. ReV. 1958, 58, 627. (c) Pearson, A. J.; Chandler, M. J.
Organomet. Chem. 1980, 202, 175.
10.1021/jo061250m CCC: $33.50 © 2006 American Chemical Society
Published on Web 09/23/2006
8644
J. Org. Chem. 2006, 71, 8644-8646

SCHEME 1. π-Allylic Nitromethylation of Cinnamyl
Carbonate
SCHEME 2. π-Allylic Nitromethylation of Acyclic Secondary
Esters
To the best of our knowledge, well-developed research on
catalytic asymmetric substitution of cyclic substrates7 with C1
nucleophiles has been limited to Trost’s report8 citing the
asymmetric π-allylic nitromethylation of cycloalkenyl esters in
dichloromethane. Though high enantioselectivity of up to 98%
ee was achieved with Trost’s chiral bisphosphine ligand, the
risk of explosion still remains a serious problem.9 Clearly, while
pioneering strides have been made, additional studies on water-
based safe protocols are warranted.
π-Allylic nitromethylation of cycloalkenyl esters was found
to proceed safely with high enantioselectivity in water. Thus,
when a suspension of cycloheptenyl carbonate 14 and 3 equiv
of nitromethane in water was shaken at 60 °C for 12 h in the
presence of 5 molar equiv of lithium carbonate and the PS-
PEG resin-supported chiral palladium-imidazoindole phosphine
18 (5 mol % palladium), 1-nitromethylcyclohept-2-ene (15) was
obtained in 91% yield. The enantiomeric purity of 15 was
determined by HPLC analysis (Chiralcel double AD-H, n-
hexane) to be 98% ee, and the absolute configuration was
determined to be S by measurement of the specific rotation
([R]25D +3.4 (c 0.5, chloroform)). The cyclic carbonates 10 and
12 took place asymmetric π-allylic nitromethylation to gave the
corresponding adducts 11 and 13 in 87% and 81% isolated yield
with 80% and 70% ee, respectively (not optimized).
These results prompted us to examine the asymmetric
nitromethylation of the tetrahydropyridyl ester rac-19 to prepare
the promising synthetic intermediate of Isofagomine10 and
Siastatin B.11 The tetrahydropyridyl ester rac-19 underwent
nitromethylation in water with the polymeric chiral catalyst 18
under similar conditions to give 81% isolated yield of (R)-
nitromethyl(tetrahydro)pyridine 20 with 97% ee (Mosher’s
method for tert-butyl 5-aminomethyl-1,2,3,4,5,6-hexahydropy-
ridinecarboxylate derived from 5-nitromethyl-1,2,5,6-tetrahy-
dropyridinecarboxylate), which was readily converted to the
tetrahydropyridyl carboxylic acid 21 also in water by the
modified Carreira conditions12 in the presence of n-BuI and
TentaGel at 100 °C ([R]25D -110 (c 1.0, chloroform) [lit.13 for
(R)-21 of 99% ee: [R]25 -112 (c 3.0, chloroform)].
(5) (a) Uozumi, Y.; Shibatomi, K. J. Am. Chem. Soc. 2001, 123, 2919.
(b) Shibatomi, K.; Uozumi, Y. Tetrahedron: Asymmetry 2002, 13, 1769.
(c) Uozumi, Y,; Tanaka, H.; Shibatomi, K. Org. Lett. 2004, 6, 281. (d)
Nakai, Y.; Uozumi, Y. Org. Lett. 2005, 7, 291. (e) Uozumi, Y.; Kimura,
M. Tetrahedron Asymmetry 2006, 17, 161.
(6) For other examples of heterogeneous aquacatalytic chiral processes
with PS-PEG resin-supported transition-metal complexes, see: (a) Uozumi,
Y.; Danjo, H.; Hayashi, T. Tetrahedron Lett. 1998, 39, 8303. (b) Hocke,
H.; Uozumi, Y. Synlett 2002, 12, 2049. (c) Hocke, H.; Uozumi, Y.
Tetrahedron 2003, 59, 619. (d) Hocke, H.; Uozumi, Y. Tetrahedron 2004,
60, 9297. (e) Otomaru, Y.; Senda, T.; Hayashi, T. Org. Lett. 2004, 6, 3357.
(7) For a recent review on asymmetric π-allylic substitution, see: (a)
Acemoglu, L.; Williams, J. M. J. Handbook of Organopalladium Chemistry
1945; Ed. Negishi, E., ed.; Wiley: New York, 2002. (b) Trost, B. M.;
Crawley, M. L. Chem. ReV. 2003, 103, 2921.
D
In summary, the palladium-catalyzed π-allylic C1 introduction
was achieved with nitromethane, which was carried out in water
to provide a safe nitromethylation protocol. Asymmetric ni-
tromethylation of cycloalkenyl esters was achieved with up to
98% ee in water under heterogeneous conditions by use of the
recyclable amphiphilic PS-PEG resin-supported palladium-
imidazoindolephosphine complex.
(10) Jakobsen, P.; Lundbeck, J. M.; Kristiansen, M.; Breinholt, J.;
Demuth, H.; Pawlas, J.; Candela, M. P.T.; Andersen, B.; Westergaard, N.;
Lundgren, K.; Asano, N. Bioorg. Med. Chem. 2001, 9, 744.
(11) Knapp, S.; Zhao, D. Org. Lett. 2000, 2, 2037.
(12) Czekelius, C.; Carreira, E. M. Angew. Chem., Int. Ed. 2005,
44, 612.
(8) Trost, B. M.; Surivet, J. P. Angew. Chem., Int. Ed. 2000, 39, 3122.
(9) Trost’s asymmetric nitromethylation was reproduced in our labora-
tories with the cycloheptenyl ester 8 (25 °C, 96 h, 71% yield, 96% ee),
whereas the reaction mixture exploded at 40 °C.
(13) Schleich, S.; Helmchen, G. Eur. J. Org. Chem. 1999, 2515, 5.
J. Org. Chem, Vol. 71, No. 22, 2006 8645

SCHEME 3. π-Allylic Nitromethylation of Cycloalkenyl
Esters
SCHEME 5. Synthetic Application
5). A typical procedure is given for the reaction of methyl
cycloheptenyl carbonate (14) with nitromethane. To a mixture of
18 (68.0 mg, 0.02 mmol of Pd), lithium carbonate (116 mg, 1.60
mmol), and methyl cycloheptenyl carbonate (14) (76.8 mg, 0.40
mmol) in H2O (0.40 mL) was added nitromethane (73.2 mg, 1.2
mmol), and the mixture was stirred at 60 °C for 12 h. The reaction
mixture was filtered, and the resin beads were rinsed three times
with THF and MeOH. To the combined filtrate and washings was
added aqueous NH4Cl, and the mixture was extracted with MTBE.
The combined extracts were washed with aqueous sodium chloride
and dried over anhydrous magnesium sulfate. The solvent was
evaporated, and the residue was chromatographed on silica gel
((hexane/ethyl acetate/Et3N ) 9/1/0.5) to give 56.4 mg (91% yield)
of a cycloheptenylnitromethane (15).
SCHEME 4. Asymmetric Allylic Nitromethylation
Reaction of the tert-Butyl (5R)-5-Nitromethyl-1,2,5,6-tetrahy-
dropyridinecarboxylate (20) (97% ee) with Iodobutane Giving
(3S)-N-tert-Butoxycarbonyl-1,2,3,6-tetrahydropyridin-3-carbox-
ylic Acid (21). To a solution of tert-butyl (5R)-5-nitromethyl-
1,2,5,6-tetrahydropyridinecarboxylate (20) (97% ee) (76 mg, 0.3
mmol), KOH (67 mg, 1.2 mmol), and Tenta Gel (48 mg, 0.015
mmol) in H2O (1.0 mL) was added iodobutane (110 mg, 0.8 mmol),
and the mixture was stirred at 100 °C for 3 h. The reaction mixture
was filtered, and the resin beads were rinsed three times with H2O.
To the washings (H2O) were added aqueous citric acid, and the
mixture was extracted with MTBE. The combined extracts were
washed with aqueous sodium chloride and dried over anhydrous
magnesium sulfate. The solvent was evaporated, and the residue
was chromatographed on silica gel (AcOEt) to give 34.1 mg (51%
yield) of a corresponding carboxylic acid (21).
Experimental Section
Palladium-Catalyzed Allylic Substitution of Cinnamyl Car-
bonate (1) with Nitromethane (Schemes 1-3). A typical proce-
dure is given for the reaction with nitromethane and methyl
cinnamyl carbonate (2) (Scheme 1). To a solution of 3 (64.0 mg,
0.02 mmol), lithium carbonate (116 mg, 1.60 mmol), and methyl
cinnamyl carbonate (2) (76.8 mg, 0.40 mmol) in H2O (0.40 mL)
was added nitromethane (73.2 mg, 1.2 mmol), and the mixture was
stirred at 60 °C for 12 h. The reaction mixture was filtered, and
the resin beads were rinsed three times with THF and MeOH. To
the combined filtrate and washings were added aqueous NH4Cl,
and the mixture was extracted with methyl tert-butyl ether (MTBE).
The combined extract was washed with aqueous sodium chloride
and dried over anhydrous magnesium sulfate. After removal of the
solvent, the residual oil was chromatographed on silica gel (hexane/
ethyl acetate/Et3N ) 9/1/0.5) to give 65.1 mg (92% yield) of a
mixture of 4-nitro-1-phenylbutene (2) and 4-nitro-3-phenylbutene
(2′) in a ratio of 89:11.
Acknowledgment. This work was supported by the CREST
program, sponsored by the JST. We also thank the JSPS
(GRANT-in-AID for Scientific Research, No. 15205015) and
the MEXT (Scientific Research on Priority Areas) for partial
financial support of this work.
Supporting Information Available: Experimental procedures
and spectroscopic data. This material is available free of charge
via the Internet at http://pubs.acs.org.
Palladium-Catalyzed Asymmetric Allylic Substitution of
Cyclic Allylic Carbonates with Nitromethane (Schemes 4 and
JO061250M
8646 J. Org. Chem., Vol. 71, No. 22, 2006