Palladium-catalyzed reaction of 4-cyclopentene-1,3-diol monoacetate with Grignard reagents producing hitherto unreachable cis-1,2-isomers

Article abstract of DOI:10.1039/b316596e

Reaction of 4-cyclopentene-1,3-diol monoacetate with RMgCl (R = alkyl, aryl) in the presence of a palladium catalyst proceeded with retention of configuration to give cis-1,2-regio-isomers as the major products.

Full text of DOI:10.1039/b316596e

Palladium-catalyzed reaction of 4-cyclopentene-1,3-diol monoacetate with
Grignard reagents producing hitherto unreachable cis-1,2-isomers†
Hatsuhiko Hattori,a Ashraf A. Abbasab and Yuichi Kobayashi*a
a Department of Biomolecular Engineering, Tokyo Institute of Technology, 4259 Nagatsuta-cho, Midori-ku,
Yokohama 226-8501, Japan. E-mail: ykobayas@bio.titech.ac.jp; Fax: +81-45-924-5789;
Tel: +81-45-924-5789
b Department of Chemistry, Faculty of Science, Cairo University, Giza, Egypt
Received (in Cambridge, UK) 22nd December 2003, Accepted 18th February 2004
First published as an Advance Article on the web 5th March 2004
Reaction of 4-cyclopentene-1,3-diol monoacetate with RMgCl
(R = alkyl, aryl) in the presence of a palladium catalyst
proceeded with retention of configuration to give cis-1,2-regio-
isomers as the major products.
An unexpected result to produce cis-1,2-isomer 2a (R = n-Bu)
was observed when reaction of monoacetate 1 with n-BuMgCl (3
equiv.) was carried out in the presence of Pd(PPh3)4 (10 mol%) in
THF at 0 °C for 1 h (Table 1, entry 1). Reaction proceeded in a
1
stereospecific manner with good regioselectivity as judged by H
Controlling the regio- and stereo-chemistries in the transition
metal-catalyzed reaction of secondary allylic substrates with
nucleophiles is an important issue, especially for construction of a
chiral carbon–carbon bond in organic synthesis.1 Regioselectivity
is usually controlled by steric as well as electronic factors in the
allylic partners, while the stereochemical outcome being retention
or inversion with respect to stereochemistry of a leaving group is
substantially dictated by the nature of the nucleophiles. Nucleo-
philes classified as being ‘hard’ proceed with inversion,2 and vice
versa.3 This generalization is well understood by the reaction
courses for hard and soft nucleophiles. Hard nucleophiles react with
the metal in the p-allylmetal intermediates generated transiently
from the allylic substrates, while soft nucleophiles approach a p-
allyl carbon from the side opposite to the metal.
NMR spectroscopy. The expected trans-1,2- and trans-1,4-isomers
were not produced. The chloride anion was indispensable for the
selectivities since n-BuMgBr gave a complex mixture of products,
among which cis isomer 2a could be detected spectroscopically, as
well as by TLC analysis (entry 2).11 Regioselectivity and yield were
influenced by additional ligands (entries 3 and 4), while the use of
Pd(PPh3)2, generated in situ from Pd2(dba)3·CHCl3 and PPh3, did
not show an appreciable difference (entry 5). Reactions in diethyl
ether (entry 6) and in dioxane/THF (entry 7) did not improve the
selectivity and yield of entry 1.
Next, we examined other alkyl Grignard reagents (RMgCl) listed
in Table 2 (entries 1–4). Reactions with primary alkyl reagents
proceeded with regioselectivities and yields similar to those for the
Table 1 Palladium-catalyzed reaction of monoacetate 1 with n-BuMgXa
Allylation of cis 4-cyclopentene-1,3-diol monoacetate (1), a
readily available4 and functional group-rich compound for organic
synthesis, is not an exception. Reaction with soft anions such as
those derived from malonate5 and nitromethane6 with palladium
catalysts produces the cis-1,4-isomers (retention products) ster-
eoselectively. In this case, regioselectivity is controlled as well by
the hydroxy group, which prevents reaction at the proximal carbon
of the allylic moiety due to steric as well as electronic reasons. On
the other hand, an example of a reaction with hard nucleophiles was
reported by us using aryl- and alkenyl-borates and a nickel catalyst
to afford, as expected, trans products as a mixture of the
regioisomers in an almost 1:1 ratio, which was then improved to a
5–20:1 ratio with the additives (NaI and MeCN).7–9 Nickel-
catalyzed alkylation with RMgX (R = alkyl) also affords a mixture
of regioisomers with trans stereochemistry.10 However, we found
that palladium-catalyzed reaction of 1 and RMgCl affords cis-
1,2-isomers 2 as major products, for the first time, as depicted in
Scheme 1. Herein, we present the results of this reaction.
Addi-
tional
ligand
Ratio
X of
Yield
Entry BuMgX Catalyst
Solvent (%)b
2a
3a
1
2
3
4
5
6
7
Cl
Br
Cl
Cl
Cl
Cl
Cl
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)2
Pd(PPh3)4
Pd(PPh3)4
–
–
THF
THF
THF
THF
THF
Et2O
67 (67) 91
9
—
12
17
11
25
20
c
—
—
dpppd
dppbd
—
56 (44) 88
48 83
62 (68) 89
e
—
51
61
75
80
dioxanef THF
a Reactions of 1 (50–100 mg) and n-BuMgX (3 equiv.) were carried out
with a palladium catalyst (10 mol%) at 0 °C in THF until all of 1 was
consumed (usually 1 h). b Calculated by 1H NMR spectroscopy using
pyridine as an internal standard which was added after the reaction. Isolated
yields are indicated in parentheses. c A complex mixture of products was
obtained. d 10 mol%. e Prepared from Pd2(dba)3·CHCl3 (5 mol%) and PPh3
(20 mol%). f 20 equiv.
Table 2 Palladium-catalyzed reaction of monoacetate 1 with RMgCla
Products
R for 2,3,
and RMgCl
Entry
No.
Yield (%)b
Ratio 2:3
1
2
3
4
5
6
7
8
Ph(CH2)3
2b,3b
2c,3c
2d,3d
2e,3e
2f,3f
2g,3g
2h,3h
2i,3i
62 (60)
62 (52)
(87)
37
59
39
57 (64)
(41)
90:10
90:10
81:19
79:21
88:12
85:15
85:15
86:14
MOMO(CH2)6
c
c-C6H11
t-Bu
Ph
C6H4(OMe)-o
C6H4(OMe)-p
C6H4(F)-p
Scheme 1 Palladium-catalyzed reaction of monoacetate 1 and RMgCl
giving cis-1,2-isomers 2. R for 2 and 3: a, n-Bu; b, (CH2)3Ph; c,
(CH2)6OMOM (MOM = MeOCH2); d, c-C6H11; e, t-Bu; f, Ph; g, o-MeO-
C6H4; h, p-MeO-C6H4; i, p-F-C6H4.
a Reactions were carried out with RMgCl (3 equiv.) and Pd(PPh3)4 (10
mol%) at 0 °C in THF. b Calculated by 1H NMR spectroscopy using
pyridine as an internal standard which was added after the reaction. Isolated
yields are indicated in parentheses. c The prefix ‘c-’ denotes a cyclo
group.
† Electronic supplementary information (ESI) available: typical procedure
for the palladium-catalyzed reaction, determination of the structures and
spectral data of products. See http://www.rsc.org/suppdata/cc/b3/
b316596e/
884
C h e m . C o m m u n . , 2 0 0 4 , 8 8 4 – 8 8 5
T h i s j o u r n a l i s © T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 4

butylation, thus producing cis-1,2-isomers 2b and 2c as the major
products (entries 1 and 2). The cyclohexyl group, selected as a
representative example of the secondary alkyl group, was also
installed efficiently (entry 3). However, t-BuMgCl afforded cis-
1,2-product 2e in low yield, though stereospecificity and good
regioselectivity were maintained as well (entry 4). Similar
selectivity was also observed in arylation to give cis-1,2-isomers
2f–i as major products (entries 5–8 of Table 2). However, yields
varied much depending on the substitution on the aromatic ring.
Thus, good yields were recorded with Ph- and p-(MeO)C6H4-
MgCl, while lower yields were obtained with o-(MeO)C6H4- and p-
(F)C6H4-MgCl, probably due to steric and electronic reasons,
respectively.
(2)
The structures of most of the products 2a–c,f,g were determined
unambiguously by the method described in the ESI.†
In summary, the palladium-catalyzed reaction of monoacetate 1
with RMgCl was found to produce cis-1,2-isomers 2, which were
previously inaccessible by other methods. This reaction is applica-
ble to alkyl as well as aryl Grignard reagents. We believe that cis-
1,2-isomers 2 would open up a new strategy for the synthesis of
biologically active cyclopentanoids.
In order to obtain information on the stereo- and regio-
selectivities disclosed above, the following reactions were exam-
ined under the conditions used for the production of cis-
1,2-isomers. As shown in eqn. (1),
This research work was supported by Grant-in-Aid for Scientific
Research from the Ministry of Education, Culture, Sports, Science
and Technology, Japan.
Notes and references
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(1)
reaction of 1 with the magnesium anion 6a derived from t-BuMgCl
and dimethyl malonate produced a mixture of products, while
sodium and potassium anions 6b and 6c furnished 7 in 69 and 93%
yields, respectively. On the other hand, reaction of the MEM ether
8 with n-BuMgCl afforded alcohol 9.
3 B. M. Trost and P. E. Strege, J. Am. Chem. Soc., 1977, 99, 1649; B. M.
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On the basis of these results, we consider a pathway illustrated in
Scheme 2, in which complex B derived from A is a key complex
leading to the cis-1,2-product 2. Thus, RMgCl and the Pd(0)
catalyst react with the substrate 1 to provide complex A. Further
reaction with RMgCl takes place preferentially on the magnesium
rather than on the palladium to furnish an advanced complex B,
which undergoes intramolecular delivery of the R group from the
Mg atom to the p-allyl moiety, thus producing the cis-1,2-product
2. In the literature, the 1,4-addition of g-hydroxy-a,b-unsaturated
ketones and nitriles with RMgX is controlled by the hydroxy group
at the g-position by forming (alkoxy)MgR followed by intra-
molecular delivery of the R group to the b-position.12,13 These
reports indirectly support the mechanism proposed in Scheme 2. In
addition, potency of the hydroxy group to arrest the R group by
forming alkoxy oxygen–Mg–R was revealed to be stronger than
that of the MEM group working through chelation14 to RMgCl.
7 Y. Kobayashi, M. G. Murugesh, M. Nakano, E. Takahisa, S. B. Usmani
and T. Ainai, J. Org. Chem., 2002, 67, 7110.
8 Review: Y. Kobayashi, Curr. Org. Chem., 2003, 7, 133.
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Commun., 1999, 807.
10 M. Ito, M. Matsuumi, M. G. Murugesh and Y. Kobayashi, J. Org.
Chem., 2001, 66, 5881.
11 Other attempts using zinc reagents such as n-BuZnCl·LiCl, n-
BuZnCl·MgCl2 produced a mixture of unidentified products.
12 J. C. Saddler, P. C. Conrad and P. L. Fuchs, Tetrahedron Lett., 1978, 51,
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Scheme 2 A probable pathway leading to cis-1,2-isomers 2.
Finally, we examined a similar reaction with cyclohexenyl
monoacetate 10, which afforded the cis-1,2-product 11 as a major
product [eqn. (2)].
C h e m . C o m m u n . , 2 0 0 4 , 8 8 4 – 8 8 5
885