Stereoselective synthesis of 3-substituted phtalides via asymmetric transfer hydrogenation using well-defined ruthenium catalysts under neutral conditions

Article abstract of DOI:10.1016/S0040-4039(01)00076-4

The asymmetric transfer hydrogenation of methyl 2-acylbenzoates and 2-propyl 3-acetylpyridine-2-carboxylate in 2-propanol, in the absence of base, with presynthesized Ru-{β-amino alcohol} or Ru-{TsDPEN} true catalysts provides 3-alkylphtalides in high yields and 92-97% ee. The procedure is, however, not as efficient for the preparation of optically active 3-phenylphtalide.

Full text of DOI:10.1016/S0040-4039(01)00076-4

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 1899–1901
Stereoselective synthesis of 3-substituted phtalides via
asymmetric transfer hydrogenation using well-defined ruthenium
catalysts under neutral conditions
Kathelyne Everaere, Jean-Luc Scheffler, Andre´ Mortreux and Jean-Franc¸ois Carpentier*
Laboratoire de Catalyse de Lille associe´ au CNRS, Groupe de Chimie Organique Applique´e,
Ecole Nationale Supe´rieure de Chimie de Lille, BP 108-59652 Villeneuve d’Ascq, France
Received 30 November 2000; accepted 10 January 2001
Abstract—The asymmetric transfer hydrogenation of methyl 2-acylbenzoates and 2-propyl 3-acetylpyridine-2-carboxylate in
2-propanol, in the absence of base, with presynthesized Ru-{b-amino alcohol) or Ru-{TsDPEN} true catalysts provides
3-alkylphtalides in high yields and 92–97% ee. The procedure is, however, not as efficient for the preparation of optically active
3-phenylphtalide. © 2001 Elsevier Science Ltd. All rights reserved.
Chiral 1(3H)-isobenzofuranones (phtalides), almost all
of them having an S configured chiral center, feature an
impressive list of applications due to their pharmacolog-
ical effects, e.g. anti-tumor,1,2 anti-convulsant,3 anaesthe-
sia prolongation,4 PGF2h inhibitors,5… They are also key
intermediates for the synthesis of several alkaloids.6,7
Accordingly, many approaches have been developed for
their asymmetric syntheses. Representative examples
involve the use of chiral lithiated oxazolines,8 reaction of
aldehydes with chiral aryllithium reagents,9,10 alkylation
reactions with chiral alkyltitanium reagents11 or using
dialkylzinc compounds in the presence of chiral amino
alcohols.12,13 Asymmetric reduction of alkyl 2-acylben-
zoates using microbial agents,14 Binal-H,15 borane
reagents,16 and by hydrogenation using a Binap-Ru(II)
catalyst17 has also been applied to prepare optically
active 3-alkylphtalides. Catalytic approaches, especially
the highly enantioselective one-step hydrogenation of
2-acylbenzoates,17 are of particular interest because they
do not use stoichiometric amounts of chiral auxiliaries.
Scheme 1.
Keywords: asymmetric transfer hydrogenation; chiral phtalides; chiral Ru catalysts.
* Corresponding author. Tel.: +33 (0)320 436 754; fax: +33 (0)320 436 585; e-mail: carpentier@ensc-lille.fr
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00076-4

1900
K. E6eraere et al. / Tetrahedron Letters 42 (2001) 1899–1901
Table 1. Ruthenium-catalyzed asymmetric transfer hydrogenation of 2-acylarylcarboxylates 3 in 2-propanola
Entry
Ketone
Catalystb
Temp. (°C)
Timec (h)
Conv.d (%)
Sel. 4d (%)
eee (%)
1
3a
3a
3a
3a
3a
3a
3a
3b
3b
3b
3c
3c
3c
3c
3d
3d
Ru-1 in situ
20
20
20
50
20
50
20
50
50
20
20
50
20
50
50
20
18
16
23
3.5
16
16
3
92
61
93
96
65
32f
96f
99
97 (S)
97 (S)
97 (S)
94 (S)
84 (S)
73 (S)
83 (S)
94 (−)
96 (−)
23 (−)
92 (S)
80 (S)
72 (S)
66 (S)
15 (S)
10 (S)
2g
3
Ru-1 in situg
Ru-1 preformed
Ru-1 preformed
Ru-2 in situ
Ru-2 in situ
Ru-2 preformed
Ru-1 in situ
Ru-1 preformed
Ru-2 preformed
Ru-1 preformed
Ru-1 preformed
Ru-2 preformed
Ru-2 preformed
Ru-1 preformed
Ru-2 preformed
4
5
6
7
8
9
10
11
12
13
14
15
16
\99
41f
75
96
47f
\99
96
\99
\99
98
98
\99
98
2h
1
65h
100
99
3
18i
22
18
1.5
48
18
80i
91
99
97
23
\99
\99
99
a The reaction was carried out using 2.0 mmol of 3 and 0.02 mmol of Ru in a 0.1 M 2-propanol solution.
b Unless otherwise noted in situ catalysts were generated as follows: A solution of [RuCl2(h6-p-cymene)]2 (6.2 mg, 0.01 mmol) and the appropriate
chiral ligand (0.04 mmol) in dry freshly distilled 2-propanol (5 mL) was heated under nitrogen at 80°C for 20 min. After cooling down the orange
solution to room temperature, a solution of 3 (2.0 mmol) in 2-propanol (14 mL) and 2-PrOK (1.0 mL, 0.12 M in 2-propanol, 0.12 mmol) were
added. The resulting solution was stirred at the desired temperature and the reaction was monitored by GLC.
c Reaction time was not necessarily optimized.
d Conversions of 3 and selectivities for 4/5 were determined by quantitative GLC analysis using a BPX5 column and by 1H NMR.
e ee’s Were determined by chiral GLC analysis using a Chirasil-DEX CB column and H2 as a carrier gas. Absolute configuration of the major
enantiomer was determined from the sign of rotation of the isolated product.14,16
f Compound 5 accounts for the balance.
g 2 equiv. (versus Ru) of base were used.
h 65% Conv. and 95% ee after 24 h of reaction.
i 94% Conv. and 90% ee after 43 h of reaction.
Ruthenium-catalyzed asymmetric transfer hydrogena-
tion of 2-propanol to ketones has recently emerged as a
convenient and viable tool for the synthesis of chiral
alcohols.18,19 This process is achieved using combina-
tions of a chlororuthenium(II)arene complex with a
chiral monoaryl-sulfonylated-1,2-diamine, e.g. TsD-
PEN,19,20 or simple chiral b-amino alcohol ligands21 in
the presence of a base, usually present in excess. The
true catalysts for these systems, e.g. Ru cat 1 and Ru
cat 2 (Scheme 1), have been isolated and characterized
by Noyori et al.22 and by us,23 respectively. Herein we
report the application of transfer hydrogenation to the
synthesis of chiral 3-substituted phtalides in high yield
and enantiomeric excess (ee) and demonstrate the possi-
bility of performing selectively the reaction with the
true catalysts under neutral conditions (Scheme 1,
Table 1).
tively in 59% yield with the same ee (entry 2). The
reaction carried out using the preformed true catalyst
Ru-1 without any added 2-PrOK gave comparable
results; lactone 4 was obtained after 23 h in 93% yield
and 97% ee (entry 3). These results show that the
presence of a slight excess of the base necessary for the
generation of the active catalyst from its precursors
favours the formation of side-product 5a, most likely
via lactonization of the hemiacetal of 4a.24 The same
improvement in the chemoselectivity of the reaction
was observed by using preformed catalyst Ru-2 in pure
2-propanol in place of the equivalent in situ combina-
tion in the presence of 6 equiv. (versus Ru) of base
(entries 5–7). The b-amino alcohol catalyst Ru-2 was
found to be more active, although significantly less
enantioselective, than the TsDPEN catalyst Ru-1. With
the latter catalyst, increasing the reaction temperature
to 50°C allowed us to reduce the completion time with
a slight decrease in the enantioselectivity from 97 to
94% ee (entry 4). The results of this study revealed that
over the reaction time studied (typically 2–24 h), only
limited erosion of the ee (52%) was observed.
Treatment of methyl 2-acetylbenzoate (3a) with the in
situ catalytic combination [RuCl2(h6-p-cymene)]2/(S,S)-
TsDPEN (1:4) in 2-propanol in the presence of 6 equiv.
(versus Ru)18,20 of 2-PrOK at 20°C for 18 h provided a
mixture of 3-methylphtalide (4a) and 3-(2-propoxy)-3-
methylphtalide (5a) in 30 and 62% yields, respectively.
The analysis of lactone 4a by chiral GLC showed an ee
of 97% (entry 1). When the same reaction was per-
formed with only 2 equiv. (versus Ru) of base, i.e. the
stoichiometric amount, lactone 4a was recovered selec-
The synthesis of other 3-substituted phtalides was next
investigated using preformed catalysts Ru-1 and Ru-2.
The reduction of 2-propyl 3-acetylpyridine-2-carboxy-
late (3b) (available from Lancaster Co.) using Ru-1 in
neutral 2-propanol afforded pyridinyl lactone 4b in

K. E6eraere et al. / Tetrahedron Letters 42 (2001) 1899–1901
1901
virtually quantitative yield and 96% ee (entry 9).† The
References
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† In a typical experiment, a solution of 2-propyl 3-acetylpyridine-2-
carboxylate (3b) (414 mg, 2.0 mmol; previously recrystallized from
petroleum ether) in dry freshly distilled 2-propanol (20 mL) was
transfered via canula under nitrogen in a Schlenk tube containing
complex Ru-122 (12 mg, 0.02 mmol). The resulting solution was
placed in an oil bath at 50°C and stirred with a magnetic bar; the
solution initially purple red turned progressively yellow. After 1 h,
the reaction mixture was exposed to air and cooled to room
temperature. GLC analysis using a BPX5 and a Chirasil-DEX CB
capillary column showed complete conversion of 3b to 4b with an
enantiomeric excess of 96%. After evaporation of volatiles under
vacuum the crude product was purified by column chromatography
(silica, Et2O–heptane) to provide 269 mg (90%) of a white powder;
[h]2D0 −46 (c 0.35, CHCl3); 1H NMR (CDCl3) l 8.87 (d, J=3.7 Hz,
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(q, J=6.7 Hz, 1H), 1.66 (d, J=6.7 Hz, 3H); 13C NMR (CDCl3) l
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.