Diastereodivergent addition of allenylzincs to aryl glyoxylates

Article abstract of DOI:10.1021/ol900494g

A diastereodivergent addition of allenylzincs to aryl glyoxylates was observed depending on the method used for the preparation of the allenylzinc reagent. The allenylzincs were prepared from propargylic benzoates in the presence of a palladium catalyst o

Full text of DOI:10.1021/ol900494g

ORGANIC
LETTERS
2009
Vol. 11, No. 11
2397-2400
Diastereodivergent Addition of
Allenylzincs to Aryl Glyoxylates
Thomas Hameury,† Je´roˆme Guillemont,‡ Luc Van Hijfte,‡ Ve´ronique Bellosta,*,†
and Janine Cossy*,†
Laboratoire de Chimie Organique, ESPCI ParisTech, 10 rue Vauquelin 75231 Paris
Cedex 05, France, and Tibotec, a DiVision of Janssen-Cilag SAS, Janssen-Cilag
Research Center, Campus de Maigremont, 27106 Val de Reuil, France
Veronique.bellosta@espci.fr; janine.cossy@espci.fr
Received March 9, 2009
ABSTRACT
A diastereodivergent addition of allenylzincs to aryl glyoxylates was observed depending on the method used for the preparation of the
allenylzinc reagent. The allenylzincs were prepared from propargylic benzoates in the presence of a palladium catalyst or by metalation of
alkynes.
The addition of allenylmetals to aldehydes and imines has
been used extensively to synthesize homopropargylic alco-
Scheme 1
.
Addition of Allenyl/Propargylmetals to Imines and
Aldehydes
hols and amines, respectively.1 When aldehydes or imines
A are treated with allenylmetals, a mixture of homopropar-
gylic and allenic products D and E is observed, due to an
equilibrium between allenylmetal of type B and propargyl-
metal C (Scheme 1). The ratio between D and E depends
on the metal. It is worth noting that the addition of
allenylzincs to aldehydes proceeds with high regioselectivity
to afford homopropargylic alcohols.
Whereas R-ketoesters have been frequently transformed
to the corresponding R-hydroxyesters when treated with
organometallic reagents, the addition of allenylmetals to
R-ketoesters has been rarely studied.2 Here, we would like
to report that tertiary homopropargylic alcohols of type H
can be obtained in good yields from aryl glyoxylates F by
addition of 3-phenylallenylzinc G generated either from
propargylic benzoate using Pd(OAc)2·PPh3/Et2Zn or by
metalation of 1-(trimethylsilyl)-3-phenylprop-1-yne (Scheme
† ESPCI ParisTech.
‡ Tibotec, a Division of Janssen-Cilag SAS.
(1) (a) Yamamoto, H. In ComprehensiVe Organic Synthesis; Trost, B. M.,
Fleming, I., Eds.; Pergamon: London, 1991; Vol. 2, 81. (b) Marshall, J. A.
Chem. ReV. 2000, 100, 3163. (c) Marshall, J. A. In The Chemistry of
Organozinc Compounds; Rappoport, Z., Marek, I., Eds.; Wiley: New York,
2006; Vol. 1, 421. (d) Marshall, J. A. J. Org. Chem. 2007, 72, 8153.
10.1021/ol900494g CCC: $40.75
Published on Web 05/07/2009
 2009 American Chemical Society

2). Furthermore, depending on the experimental conditions
used for the generation of allenylzinc G, a divergent
diastereoselectivity was observed in providing compound H.
diethylzinc, leading to 2-aryl-2-hydroxyacetates 6 as signifi-
cant byproducts (29% and 16%) (Table 1).5 It is worth
mentioning that decreasing the quantity of diethylzinc or the
temperature to 0 °C did not provide better yields in 5, and
these latter conditions did not prevent the formation of
compound 6.
Scheme 2. Addition of 3-Phenylallenylzincs to Aryl Glyoxylates
Table 1. Reactivity of Allenylzinc Prepared from 4 Using
Pd(PPh3)4/Et2Zn
Aryl glyoxylates 2a-d were synthesized by addition of
Grignard reagents to (imidazoyl)glyoxylate 1.3 The aryl
glyoxylates 2a-d were isolated in 48-79% yields (Scheme
3, eq 1). Glyoxylate 2e was obtained by nucleophilic attack
of N-methylindole 3 to oxalyl chloride, followed by the
transformation of the acyl chloride intermediate to tert-butyl
ester 2e by addition of t-BuOK (Scheme 3, eq 2).
2
Ar
5 (dr, yield %)
6 (yield %)
2a
2b
1-naphthyl
Ph
5a
5b
75/25
89/11
54
65
29
16
The addition of the allenylzinc, generated from propargylic
benzoate 4 according to the procedure described by Marshall
et al.,6 to aryl glyoxylates 2 was then examined. Thus, the
addition of the allenylzinc generated by treatment of
propargylic benzoate 4 (3 equiv) with Pd(OAc)2·PPh3 in a
1:1 ratio (10 mol %) and diethylzinc (6 equiv) to compounds
2a-c and 2e afforded the corresponding homopropargylic
alcohols 5a-c and 5e in good yields (68-88%) with
diastereomeric ratios ranging from 85/15 to 89/11. We have
to point out that no traces of the reduction products 6 were
detected by using these conditions (Table 2).7 However,
Scheme 3. Synthesis of Aryl Glyoxylates
Table 2. Reactivity of Allenylzinc Prepared from 4 Using
Pd(OAc)2·PPh3/Et2Zn
The addition of an allenylzinc to compounds 2a-e was
then examined. The preparation of 3-phenylallenylzinc of
type G (R3 ) H) has been described by Tamaru et al. from
benzoate 4 (1.2 equiv) by treatment with Pd(PPh3)4
(5 mol %) in the presence of diethylzinc (3.6 equiv).4
Following this procedure, the addition of the allenylzinc,
generated from 4, to aryl glyoxylates 2a and 2b provided
compounds 5a (54%) and 5b (65%) with a diastereomeric
ratio of 75/25 and 89/11, respectively. The moderate yields
of 5 were due to the reduction of aryl glyoxylates 2 by
Ar
5
dr
yield (%)
1-naphthyl
Ph
4-(MeO)C6H4
3-N-Me-indolyl
5a
5b
5c
5e
87/13
85/15
89/11
87/13
88
80
86
68
treatment of aryl glyoxylate 2d led to a complex mixture of
products.
As allenylzincs can also be formed by metalation of
alkynes, compound 7 was first treated with n-BuLi, and then
(2) (a) Yamamoto, Y.; Maruyama, K.; Komatsu, T.; Ito, W. J. Org.
Chem. 1986, 51, 886. (b) McPherson, D. W.; Lambert, C. R.; Jahn, K.;
Sood, V.; McRee, R. C.; Zeeberg, B.; Reba, R. C.; Knapp, F. F., Jr. J. Med.
Chem. 1995, 38, 3908. (c) Clive, D. L. J.; Zhou, Y.; Pires de Lima, D.
Chem. Commun. 1996, 1463. (d) McCluskey, A.; Muderawan, I. W.;
Muntari; Young, D. J. J. Org. Chem. 2001, 66, 7811.
(5) Fennie, M. W.; DiMauro, E. F.; O’Brien, E. M.; Annamalai, V.;
Kozlowski, M. C. Tetrahedron 2005, 61, 6249.
(3) Nimitz, J. S.; Mosher, H. S. J. Org. Chem. 1981, 46, 211.
(4) Tamaru, Y.; Goto, S.; Tanaka, A.; Shimizu, M.; Kimura, M. Angew.
Chem., Int. Ed. Engl. 1996, 35, 878.
(6) (a) Marshall, J. A.; Adams, N. D. J. Org. Chem. 1998, 63, 3812. (b)
Marshall, J. A.; Adams, N. D. J. Org. Chem. 1999, 64, 5201.
2398
Org. Lett., Vol. 11, No. 11, 2009

a transmetalation was achieved using zinc bromide to
produce the desired 3-phenylallenylzinc 7′, which was then
added to glyoxylates 2a-e.8 The desired R-hydroxyesters 8
were isolated, but a dramatic change in the diastereoselec-
tivity was observed as the major isomer obtained under these
conditions corresponds to the minor isomer obtained by using
the conditions developed by Tamaru et al. or Marshall et al.
Compounds 8 were obtained in good yields (80-99%) and
with diastereomeric ratios ranging from 64/36 (Ar ) 3,4-
F2C6H3) to 88/12 (Ar ) 1-naphthyl) (Table 3). Desilylation
of compounds 8 (K2CO3, MeOH, rt) and comparison of the
spectral data of the resulting desilylated alkynes with those
of 5 showed that compounds 5 and 8 had the opposite relative
stereochemistry.
mopropargylic alcohols 10a-c in good yields and with
diastereomeric ratios from 78/22 to 96/4 (Table 4). As
expected, the diastereomeric ratios were better with 2,6-
dimethylphenyl esters 9 than with tert-butyl esters 2.
Table 4. Addition of Allenylzinc 7′ to 2,6-Dimethylphenyl Aryl
Glyoxylates
Ar
10
dra
yield (%)
85
1-naphthyl
10a
96/4
(88/12)
78/22
(65/35)
92/8
Table 3. Reactivity of Allenylzinc Generated by Metalation of 7
Ph
10b
10c
82
63
4-(MeO)C6H4
(71/29)
a dr in parentheses refer to the corresponding tert-butyl ester 8.
In order to explain the divergent diastereoselectivity in
the propargylation of aryl glyoxylates, two different transition
states can be proposed. When the allenylzinc reagent is
prepared by metalation of alkyne 7, a coordination of
allenylzinc bromide to the ketone and a stabilizing π-stacking
interaction between the aromatic groups can take place in a
cyclic transition state TS1 leading to compounds 8 and 10
(Scheme 4).1,10 In TS1, an increase of the steric hindrance
Ar
8
dr
yield (%)
1-naphthyl
Ph
4-(MeO)C6H4
3,4-F2C6H3
3-N-Me-indolyl
8a
8b
8c
8d
8e
88/12
65/35
71/29
64/36
73/27
88
92
95
80
99
Scheme 4. Proposed Transition States
It is worth noting that for the addition of 3-phenylalle-
nylzinc, generated by metalation of 7, to ethyl 2-(naphthalen-
1-yl)-glyoxylate resulted in a poor diastereoselectivity as a
diastereomeric ratio of 1/1 was observed. The diastereose-
lectivity was therefore sensitive to the steric hindrance of
the ester group. Bulky 2,6-dimethylphenyl esters 9a-c were
then examined. These latter compounds were obtained by
hydrolysis of tert-butyl esters 2a-c and esterification of the
resulting carboxylic acids with 2,6-dimethylphenol (DCC,
DMAP, CH2Cl2, rt).9 Treatment of 9a-c with the allenylzinc
generated by metalation of 7 (n-Buli, ZnBr2) led to ho-
(7) The relative configuration of compound 5b was unambiguously
ascertained by its transformation into (2S*,3R*)-2,3-diphenylpent-4-ene-
1,2-diol which has been described in the literature: (a) Yasuda, M.; Hirata,
K.; Nishino, M.; Yamamoto, A.; Baba, A. J. Am. Chem. Soc. 2002, 124,
13442. The relative configuration of the other compounds 5a, 5c, and 5e
was assigned by analogy.
(8) Poisson, J.-F.; Normant, J. F. J. Org. Chem. 2000, 65, 6553.
(9) Synthesis of 2,6-dimethylphenyl glyoxylates 9:
of the ester group would increase the diastereoselectivity
which is in accordance with the obtained experimental
(10) (a) Saniere-Karila, M.; Capmau, M. L.; Chodkiewicz, W. Bull. Soc.
Chim. Fr. 1973, 3371. (b) Favre, E.; Gaudemar, M. J. Organomet. Chem.
1975, 92, 17.
Org. Lett., Vol. 11, No. 11, 2009
2399

results. On the other hand, an open transition state TS2 could
account for the diastereoselectivity observed in compounds
5, issued from the addition of the allenylzinc generated with
Pd(OAc)2·PPh3/Et2Zn to aryl glyoxylates 2.11
these allenylzincs to synthesize biologically active compounds
is under investigation and will be reported in due course.
Acknowledgment. Tibotec, a Division of Janssen-Cilag
SAS, is gratefully acknowledged for financial support and
for a grant to T. H.
Depending on the conditions used to generate the allenylzincs,
the addition of these latter to aryl glyoxylates produced
diastereomeric tertiary homopropargylic alcohols. The use of
Supporting Information Available: Experimental pro-
cedures and full spectroscopic data for all new compounds.
This material is available free of charge via the Internet
at http://pubs.acs.org.
(11) For examples of open transition states with allenylzincs, see: (a)
Bernaud, F.; Vrancken, E.; Mangeney, P. Synlett 2004, 1080. (b) Ferreira,
F.; Denichoux, A.; Chemla, F.; Bejjani, J. Synlett 2004, 2051.
OL900494G
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