Magnesium Bromide Mediated Highly Diastereoselective Heterogeneous Hydrogenation of Olefins

Article abstract of DOI:10.1021/ol020032m

(Matrix Presented) Palladium on carbon combined with magnesium bromide catalyzed hydrogenation of Baylis-Hillman olefins to afford the corresponding aldol derivatives in a highly syn-diastereoselective manner is described.

Full text of DOI:10.1021/ol020032m

ORGANIC
LETTERS
2002
Vol. 4, No. 8
1347-1350
Magnesium Bromide Mediated Highly
Diastereoselective Heterogeneous
Hydrogenation of Olefins
,†
Abderrahim Bouzide*
INRS-Institut Armand Frappier, 531, BouleVard des prairies,
LaVal, QC, Canada H7V 1B7
abouzide@inVenux.com
Received January 31, 2002
ABSTRACT
Palladium on carbon combined with magnesium bromide catalyzed hydrogenation of Baylis−Hillman olefins to afford the corresponding aldol
derivatives in a highly syn-diastereoselective manner is described.
Catalytic hydrogenation of a carbon-carbon double bond
is a reaction of great importance in organic synthesis, and it
can be accomplished in a homogeneous or heterogeneous
fashion. While homogeneous hydrogenation of olefins cata-
lyzed by ruthenium, rhodium, and iridium complexes af-
forded the reduced product with high diastereoselectivity,1
the heterogeneous counterpart catalyzed by palladium,
platinum, and nickel showed generally low selectivity.2 The
difference in reactivity between these two classes of catalysts
is attributed to the ability of the soluble catalysts to coordinate
with the unsaturation and a neighboring directing hetero-
atom.3 For example, the hydrogenation of Baylis-Hillman
adduct 1a in the presence of rhodium catalyst afforded the
reduced products 2a:3a with a high anti-selectivity4 (Scheme
1), whereas the hydrogenation of the same substrate 1a
catalyzed by palladium on carbon produced 2a:3a without
any selectivity.4 Almeida and Coelho have recently reported
a heterogeneous hydrogenation of the derived ButMe2Si ether
1b in the presence of Pd/C in EtOAc to produce 2b:3b with
a moderate syn-selectivity5 (Scheme 1).
Scheme 1
† Present address: Invenux Inc., 6840 N. Broadway, Suite F, Denver,
CO 80221.
(1) (a) Brown, J. M. Chem. Soc. ReV. 1993, 25-41. (b) Brown, J. M.
Angew. Chem., Int. Ed. Engl. 1987, 26, 190-203. (c) Halpern, J. Science
1982, 217, 401-407.
(2) Bartok, M.; Czombos, J.; Felfoldi, K.; Gera, L.; Gondos, G.; Molnar,
A.; Notheisz, F.; Palinko, I.; Wittman, G.; Zsgmond, A. G. In Stereochemisry
of Heterogeneous Metal Catalysis; Wiley: Chichester, 1985.
(3) Hoveyda, A. H.; Evans, D. A.; Fu, G. C. Chem. ReV. 1993, 93, 1307-
1370.
Although Lewis acids have played an important role in
the chelation-controlled ionic,6 pericyclic,7 and radical reac-
tions,8 no report has dealt with the utilization of a Lewis
(4) (a) Brown, J. M.; Cutting, I.; James, A. P.; Bull. Soc. Chim. Fr. 1988,
211-217. (b) Brown, J. M.; Cutting, I. J. Chem. Soc., Chem. Commun.
1985, 578-579.
(5) (a) Mateus, C. R.; Almeida, W. P.; Coelho, F. Tetrahedron Lett. 2000,
41, 2533-2536. (b) Mateus, C. R.; Feltrin, M. P.; Costa, A. N.; Coelho,
F.; Almeida, W. P. Tetrahedron 2001, 57, 6901-6908.
10.1021/ol020032m CCC: $22.00 © 2002 American Chemical Society
Published on Web 03/16/2002

Scheme 2
acid in Pd-catalyzed diastereoselective hydrogenation of
linearly with decreasing quantities of MgBr2 (Table 1, entries
5-11). Accordingly, one can conclude that the reaction is
stoichiometric and each MgBr2 chelates with one hydroxy-
acrylate 1a as shown in Scheme 2, C. Although the solubility
of MgBr2 in CH2Cl2 is low,13 higher ratios were obtained
than we expected. For example, the hydrogenation of 1a in
the presence of 0.5 equiv of MgBr2 should afford 2a:3a with
a 3:1 ratio if each MgBr2 chelate with one hydroxy-acrylate
1a. However, the obtained 21:1 ratio (Table 1, entry 8)
indicates that probably each MgBr2 chelates with two
hydroxy-acrylates as illustrated in Scheme 2, D. This result
would explain the moderate selectivity obtained when THF
was employed as the solvent, because of its competition with
1a in coordinating to the Lewis acid. It is worth noting that
no hydrogenation took place in the absence of Pd/C or when
it was replaced with Pt/C.
olefins. Herein, we would like to report that Pd/C combined
with MgBr2 is an excellent system to reduce alkenes with
high diastereoselectivity. As a model of our study, we chose
Baylis-Hillman9 adduct 1a.10
Addition of MgBr2 (1.5 equiv) to a solution of 1a in
EtOAc, followed by the addition of Pd/C and subsequent
hydrogenation under an atmospheric pressure of H2, afforded
the reduced products in which the syn-isomer 2a predomi-
nated by up to 32:1 over the anti-isomer 3a (Scheme 1).
The relative stereochemistry of 2a and 3a was determined
by comparing their 1H NMR spectral data with those reported
in the literature.5a,11 Replacement of EtOAc with THF, a
complexing solvent, resulted in a moderate syn-selectivity
(Table 1, entry 2). Low selectivity and chemical yield were
The stereochemical outcome of this hydrogenation reaction
can be rationalized on the basis of a chelation of the carbonyl
and hydroxy moieties to MgBr2 forcing the molecule into a
conformation that exposes the less sterically hindered bottom
face (re face) to hydrogen delivery and thus providing access
Table 1. Diastereoselective Heterogeneous Hydrogenation of
1a in the Presence of Lewis Acid
Lewis acid
(equiv)
time
(h)
yieldb
(%)
entrya
solvent
ratio 2a :3a
(6) ComprehensiVe Asymmetric Catalyst; Jacobsen, E. N., Pfaltz, A.,
Yamamoto, H., Eds.; Springer: New York, 1999, Vols. 1-3.
(7) Oppolzer, W. ComprehensiVe Organic Synthesis; Pergamon: New
York, 1991; Vol. 5, pp 315-399. Kagan, H. B.; Riant, O. Chem. ReV. 1992,
92, 1007-1019.
(8) (a) Renaud, P.; Gester, M. Angew. Chem., Int. Ed. Engl. 1998, 37,
2562-2579. (b) Curran, D. P.; Porter, N. A.; Giese, B. Stereochemistry of
Radical Reactions-Concept; VCH: New York, 1996. (c) Radicals in
Organic Synthesis; Renaud, P., Sibi, M. M., Eds.; Wiley-VCH: Weinheim,
2001.
(9) (a) Baylis, A. B.; Hillman, M. E. D. German Patent 2155113, 1972;
Chem. Abstr. 1972, 77, 34174q. (b) Basaviah, D.; Rao, P. D.; Suguna Hyma,
T. Tetrahedron 1996, 52, 8001-8062.
(10) The starting materials 1a and 1c-f were prepared according to the
Baylis-Hillman procedure;9 1g was prepared by methylation of 1a in the
presence of MeI and Ag2O in CH2Cl2.
(11) Mulzer, J.; Bruntrup, G. Chem. Ber. 1982, 115, 2057-2060.
(12) Typical procedure for the diastereoselective hydrogenation of 1a
in the presence of MgBr2. To a solution of 1a (96 mg, 0.5 mmol) in CH2-
Cl2 (4 mL) was added MgBr2 (138 mg, 0.75 mmol). The suspension was
stirred for 15 min to allow the formation of the chelate. Pd/C (40 mg) was
added, and the reaction was flushed with hydrogen and kept under
atmospheric pressure for 90 min. The reaction was diluted with water (3
mL) and CH2Cl2 (6 mL). The organic layer was dried over MgSO4, filtered,
and concentrated to afford cleanly 2a:2b (90 mg, 93%). 2a: 1H NMR (500
MHz, CDCl3) δ 1.14 (d, J ) 7.3 Hz, 3H), 2.82 (m, 1H), 3.68 (s, 3H), 5.11
(d, J ) 3.3 Hz, 1H), 7.27-7.37 (m, 5H). 3a: 1H NMR (500 MHz, CDCl3)
δ 1.02 (d, 7.3 H, 3H), 2.96 (m, 1H), 3.74 (s, 3H), 4.75 (d, J ) 8.8 Hz, 1H),
7.27-7.37 (m, 5H).
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
EtOAc
THF
MgBr2 (1.5)
MgBr2 (1.5)
MgBr2 (1.5)
MgBr2 (1.5)
MgBr2 (1.5)
MgBr2 (1.2)
MgBr2 (1.0)
MgBr2 (0.5)
MgBr2 (0.2)
MgBr2 (0.1)
none
1
1
4
95
68
42
81
93
92
92
95
96
98
97c
92
95
71
c
32:1
7:1
2:1
toluene
MeOH
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
1
1:1
1.5
1.5
1.5
1
1
1
0.5
5
5
24
5
62:1
51:1
45:1
21:1
7:1
3:1
1:1
1:1
1:1
MgCl2 (1.5)
ZnCl2 (1.5)
ZnBr2 (1.5)
MgI2 (1.5)
1:1.5
a All reactions were run on 0.5 mmol of 1a under an atmospheric pressure
of H2. b Isolated yields. c Only starting material was recovered.
obtained in the case of toluene (entry 3), and complete loss
of selectivity was observed when a polar solvent such as
methanol was used (entry 4). On the other hand, the use of
a noncomplexing solvent such as CH2Cl2 enhanced the ratio
to 62:1 (entry 5).12
(13) MgBr2 is known to have a low solubility in CH2Cl2, and the use of
excess (3-5 equiv) is essential to achieve acceptable selectivity. See: Ward,
D. E.; Hrapchak, M. J.; Sales, M. Org. Lett. 2000, 2, 57-60. Toru, T.;
Watanabe, Y.; Tsusaka, M.; Ueno, Y. J. Am. Chem. Soc. 1993, 115, 10464-
10466.
The reaction was found to be highly dependent on the
amount of Lewis acid, and the syn-selectivity diminished
1348
Org. Lett., Vol. 4, No. 8, 2002

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

Acknowledgment. I thank Professor Gilles Sauve´ for his
3a, 3c-g. This material is available free of charge via the
support and encouragement.
Internet at http://pubs.acs.org.
Supporting Information Available: Preparative proce-
dures and spectroscopic data for 1a, 1c-g, 2a, 2c-g, and
OL020032M
1350
Org. Lett., Vol. 4, No. 8, 2002