to the syn-adduct (Scheme 2). Note that the hydrogenation
of 1a in the presence of MgBr2 is 2-3 times slower than in
its absence (entries 5 and 11). This could be explained by
the steric hindrance caused by the Lewis acid in the six-
membered chelate, which can render difficult its approach
to the catalyst surface.
Table 2. Diastereoselective Heterogeneous Hydrogenation of
Baylis-Hillman Adducts
Complete loss of diastereoselectivity was noticed when
other Lewis acids, such as MgCl2, ZnCl2, and ZnBr2, were
used instead of MgBr2 (entries 12-14), and total inhibition
was obtained in the case MgI2 (entry 15).
yielda 2:3
(%) ratiob ratioc
2:3
3J 2,3
olefin R1 R2
R3
(Hz)
ref
1a
1c
1d
1e
1f
Ph
Et
H
H
H
H
H
OMe
OMe
OMe
Me
93
71
95
87
92
98
1:1
1:1
1:2
62:1 2a , 3.2; 3a , 8.8 11, 5a
28:1 2c, d; 3c, d 18
88:1 2d , 3.3; 3d , 6.0 19
As we checked the behavior of each Lewis acid with
Baylis-Hillman olefins before every catalytic hydrogenation,
we found that treatment of 1a with SnCl4, TiCl4, and FeCl3
in CH2Cl2 led exclusively to Z-allyl chloride 4 in good
yields.14 Such a compound was already obtained by different
methods,15 but to our knowledge, no synthesis of 4 from 1a
has been performed employing the cited Lewis acids.
iPr
iPr
Ph
1:1.5 83:1 2e, 3.2; 3e, 6.2
1:1
3:1
20
21
OEt
66:1 2f, 4.0; 3f, 9.0
63:1 2g, 7.0; 3g, 10.0 22
1g
Ph Me OMe
a Isolated yields referring to reduced products obtained in the presence
of Pd/C/MgBr2. b In the absence of MgBr2. c In the presence of MgBr2.
d Value for J2,3 was difficult to calculate because of the coupling of H-3
3
with methylenic protons.
Scheme 3
the reduced adducts 2g:3g in good yield and with syn-
selectivity comparable to that observed with the parent
alcohol 1a. Hydrogenation of 1g in the absence of MgBr2
showed a slight preference for the syn-isomer.
The relative stereochemistry (C-2/C-3) of the reduced
1
products was determined on the basis of H NMR (500
MHz); in all cases, the vicinal coupling constant (3J2,3) for
the syn-isomer is inferior to that of the anti-one (Table 2).
Moreover, H-3 resonated in all cases downfield for the syn-
adducts relative to the corresponding resonance of the anti-
isomers.17
In conclusion, we have shown for the first time that Pd/C
combined with MgBr2 can catalyze hydrogenation of alkenes
in a highly diastereoselective fashion. The ease by which
Baylis-Hillman olefins can be prepared23 followed by the
present catalytic hydrogenation in the presence of MgBr2
will constitute an alternative route for the preparation of syn-
aldol derivatives. Although the present work was restricted
to Baylis-Hillman olefins, the chelation-controlled hydro-
genation in the presence of MgBr2 could be expanded to
other olefin and imine substrates.24
To explore the generality of this highly diastereoselective
hydrogenation, other substrates containing an olefin flanked
by a carbonyl and a stereogenic hydroxyl group were
subjected to our reduction conditions (Table 2). For instance,
Pd-catalyzed hydrogenation of hydroxy-acrylate 1c in the
presence of 1.5 equiv of MgBr2 yielded the aldols 2c:3c with
a 28:1 ratio in favor of syn-isomer. As predicted, the ratio
raised to 88:1 in the case of 1d where the R1 group is an
isopropyl. Similarly, hydrogenation of vinyl ketone 1e gave
the aldols 2e:3e with a 83:1 ratio.16 Low anti-selectivity was
obtained when 1d and 1e were reduced in the absence of
Lewis acid. The reaction was extended to alkoxy-acrylate
1g, and its hydrogenation in the presence of MgBr2 afforded
(17) Heathcock, C. H. Asymmetric Synthesis; Morrison, J. D., Ed.;
Academic: London, 1984; Vol. 3 (Part B).
(18) Brown, J. M.; Evans, P. L.; James, A. P. Org. Synth. 1989, 68,
64-75.
(14) To a solution of 1a (96 mg, 0.5 mmol) in CH2Cl2 (4 mL) was added
Lewis acid (0.75 mmol). The reaction was stirred until complete consump-
tion of the starting material (15-24 h). It was then diluted with H2O and
CH2Cl2. The organic layer was dried over MgSO4 and concentrated under
reduced pressure. The crude was purified by column to afford Z-allyl
chloride 4 (82-96%): 1H NMR (500 MHz, CDCl3) δ 3.89 (s, 3H), 4.49
(s, 3H), 7.40-7.50 (m, 3H), 7.56 (d, J ) 7.5 Hz, 2H), 7.89 (s, 1H).
(15) The previous methods used to obtain 4 from 1a are as follows.
NCS-SMe2, see: Hoffman, H. M. R.; Rabe, J. Org. Chem. 1985, 50, 3849-
3850. NEt3-MsCl, see: Chavan, S P.; Ethiraj, K. S.; Kamat, S. K.
Tetrahedron Lett. 1997, 38, 7415-7416. Oxalyl chloride-CHCl3, see:
McFadden, H. G.; Harris, R. L. N.; Jenkins, C. L. D. Aust. J. Chem. 1989,
42, 301-314. Treatment of the acetate derived from the corresponding
alcohol with AlCl3/CH2Cl2, see: Basaviah, D.; Pandiaraju, S.; Padmaja,
K. Synlett 1996, 4, 393-395.
(19) Walba, D. M.; Thurmes, W. N.; Haltiwanger, R. C. J. Org. Chem.
1988, 53, 1046-1056.
(20) Hoffman, R. W.; Ditrich, K.; Froech, S. Liebigs Ann. Chem. 1987,
977-986.
(21) Smith, A. B.; Levenberg, P. A. Synthesis 1981, 567-570.
(22) (a) Drewes, S. E.; Hode, R. F. A. Synth. Commun. 1985, 15, 1067-
1072. Murata, S.; Suzuki, M.; Noyori, R. Tetrahedron 1988, 44, 4259-
4270.
(23) For the synthesis of enantiomerically enriched Baylis-Hillman
adducts, see: (a) Iwabuchi, Y.; Nakatani, M.; Yokoyama, N.; Hatakeyama,
S. J. Am. Chem. Soc. 1999, 121, 10219-10220. (b) Iwabuchi, Y.; Sugihara,
T.; Esumi, T.; Hatakeyama, S. Tetrahedron Lett. 2001, 42, 7867-7871.
(c) Brzezinski, L. J.; Rafel, S.; Leahy, J. W. J. Am. Chem. Soc. 1997, 119,
4317-4318. (d) Burgess, K.; Jennings, L. D. J. Org. Chem. 1990, 55, 1138-
1139.
(24) For a recent diastereoselective heterogeneous hydrogenation of
imines, see: Huffman, M. A.; Reider, P. J. Tetrahedron Lett. 1999, 40,
831-834.
(16) In contrast to the hydrogenation mediated with rhodium or iridium
catalysts, no olefin isomerization was observed under our conditions. Brown,
J. M.; Naik, R. G. J. Chem. Soc., Chem. Commun. 1982, 348-350.
Org. Lett., Vol. 4, No. 8, 2002
1349