Addition of transiently-generated methyl o-lithiobenzoate to imines. An isoindolone annulation

Article abstract of DOI:10.1021/jo960582w

Addition of phenyllithium to a mixture of an imine, methyl o-iodobenzoate, and BF₃-etherate at -105°C gives good to excellent yields of isoindolones. The transient formation of methyl o-lithiobenzoate is proposed, which is formed by a rapid lithium/iodide exchange reaction of the phenyllithium with methyl o-iodobenzoate in the presence of the imine. The transiently generated anions can then be captured by the BF₃-activated imines to form the isoindolones in good to high yield. The reactions conditions are sufficiently mild, and selective, to permit functional groups such carbmethoxy and aryl bromide, which could otherwise react with the added PhLi, to be tolerated.

Full text of DOI:10.1021/jo960582w

J . Org. Chem. 1996, 61, 6205-6211
6205
Ad d ition of Tr a n sien tly-Gen er a ted Meth yl o-Lith ioben zoa te to
Im in es. An Isoin d olon e An n u la tion
J ames B. Campbell,* Robert F. Dedinas, and Sally A. Trumbower-Walsh
Medicinal Chemistry Department, Zeneca Pharmaceuticals, 1800 Concord Pike,
Wilmington, Delaware 19850-5437
Received March 28, 1996X
Addition of phenyllithium to a mixture of an imine, methyl o-iodobenzoate, and BF3‚etherate at
-105 °C gives good to excellent yields of isoindolones. The transient formation of methyl
o-lithiobenzoate is proposed, which is formed by a rapid lithium/iodide exchange reaction of the
phenyllithium with methyl o-iodobenzoate in the presence of the imine. The transiently generated
anions can then be captured by the BF3-activated imines to form the isoindolones in good to high
yield. The reactions conditions are sufficiently mild, and selective, to permit functional groups
such carbmethoxy and aryl bromide, which could otherwise react with the added PhLi, to be
tolerated.
Sch em e 1
In tr od u ction
Recently, we required a practical synthesis of isoindo-
lones of generic structure 1. Direct annulative ap-
proaches were appealing due to synthetic convergency
and the capacity to more widely vary substituents on the
targeted isoindolone ring. In particular cases, such as
in isoindolone 15, the presence of the two stereogenic
centers necessitated strict synthetic control of both
relative and absolute stereochemistry. Finally, since we
required multigram quantities of the isoindolones, a
synthesis would have to be sufficiently robust for scale-
up.
We considered the addition of an appropriately func-
tionalized ortho-substituted aryl organometallic deriva-
tive to an imine as a synthetic approach to generation of
the isoindolone ring system (Scheme 1).1 We envisioned
that the aryl organometallic derivative (2), an ortho-
metalated benzamide, for example, would add to an imine
(3) to form an intermediate nitrogen-based anion 4. This
intermediate could then directly cyclize onto the ortho-
substituent of the aryl ring to form the isoindolone ring
1. For the case of R-chiral imines as reaction partners,
addition of an aryl organometallic would be predicted to
proceed through a Felkin-Ahn transition state to afford
the syn-diastereoisomer as the major product (Figure 1).2
The use of an enantiomerically enriched imine should
then produce diastereodefined and enantioenriched iso-
indolone, assuming no racemization occurred during the
course of the reaction.
however, the yields of the isoindolones were poor. Fur-
thermore, their procedures could not accommodate imi-
nes with hydrogens R to the imine carbon, due to
suspected competing proton transfer. A related synthetic
strategy, based upon the addition of lithiated N,N-
diethyl-o-toluamide to imines, was used to prepare a
series of dihydroisoquinolones.6 The yields of dihy-
droisoindolones were, however, modest to poor.
In this paper, we describe our investigations of the
addition of o-lithiated benzoates, and the dianion derived
from N-methylbenzamide, to imines. We have found that
The addition of ortho-substituted aryllithium reagents
to imines has been described by Bradsher and Hunt as
a synthetic approach to isoindolones.3 Their procedure
required use of either the very unstable isopropyl o-
lithiobenzoate anion4 or, as an alternative, o-lithioben-
zonitrile5 as a more stable reaction partner. In general,
X Abstract published in Advance ACS Abstracts, August 15, 1996.
(1) For recent examples of addition of organometallics to imines
see: (a) Katritzky, A. R.; Hong, Q.; Yang, Z. J . Org. Chem. 1995, 60,
3405. (b) Higashiyama, K.; Fujikura, H.; Takahashi, H. Chem. Pharm
Bull Tokyo 1995, 43, 722.
(2) (a) Yamamoto, Y.; Komatsu, T.; Maruyama, K. J . Am. Chem.
Soc. 1984, 106, 5031. (b) Wada, M.; Sakurai, Y.; Akiba, K. Tetrahedron
Lett. 1984, 25, 1079. (c) Fujisawa, T.; Nagai, M.; Koike, Y.; Shimizu,
M. J . Org. Chem. 1994, 59, 5865.
(3) Bradsher, C. K.; Hunt, D. A. J . Org. Chem. 1981, 46, 327.
(4) Parham, W. E.; J ones, L. D. J . Org. Chem. 1976, 41, 2704.
(5) Parham, W. E.; J ones, L. D. J . Org. Chem. 1976, 41, 1187.
F igu r e 1.
(6) Clark, R. D.; J ahangir J . Org. Chem. 1987, 52, 5378.
S0022-3263(96)00582-8 CCC: $12.00 © 1996 American Chemical Society

6206 J . Org. Chem., Vol. 61, No. 18, 1996
Campbell et al.
Sch em e 2a
Ta ble 1. Ad d ition of th e N-Meth ylben za m id e Dia n ion (6)
to Im in e 7a
entry
product
R1
R2
% yieldb
1
2
3
4
5
9a
9b
9c
9d
9d
Et
Pr
Ph
Bu
Bu
Ph
Ph
Ph
Pr
79
72
47
12
40c
Pr
a
Reactions conducted at 0 °C using 1.35 equiv of N-methyl-
benzamide and 2.7 equiv of nBuLi to generate the dianion. b Yields
refer to isolated products. See Experimental Section. c Conducted
at -78 °C in the presence of 1.1 equiv of BF3‚OEt2.
in the absence of BF3.9 Heating to 130 °C was required
to cyclize the 1,2-addition product and to give the desired
isoindolone 9d in a 40% overall yield.
Rea ction of Im in es w ith Alk yl or th o-Lith ioben -
zoa tes. During the course of our investigations, we
became intrigued with the possibility of adding alkyl
o-lithiobenzoates, prepared in-situ, to imines. We rea-
soned that alkyl o-lithiobenzoates would exhibit greater
reactivity in the addition to imines relative to the more
extensively, and intramolecularly complexed, dianion 6.
Also, the initially formed imine adduct, derived from a
lithiated benzoate, would be more likely to cyclize onto
the o-carbalkoxy group to afford the isoindolone ring
system.
a
Key: (i) 2 BuLi, THF, -20 to 0 °C; (ii) 0 °C to rt; (iii) -78 °C,
1.1 mmol equiv of BF3‚OEt2; (iv) 130 °C.
alkyl o-lithiobenzoates, generated in the presence of
imines and boron trifluoride diethyl etherate (BF3‚OEt2),
undergo addition to imines to give isoindolones. Fur-
thermore, the addition of alkyl o-lithiobenzoates, gener-
ated in-situ, to imines with R hydrogens proceeds in high
yields without any apparent competing proton transfer.
Imines with R-chiral centers react with methyl o-lithio-
benzoate, generated in-situ, with high diastereoselective
bias, which is consistent with Felkin-Ahn transition
state models.
Isopropyl and tert-butyl o-lithiobenzoate have been
reported to be modestly stable at -100 °C.4 However,
their synthetic utility has been limited. This is partially
due to their relative instability toward self-condensation.
Thus, warming solutions of these anions to -78 °C
results in their decomposition and/or self-addition. Meth-
yl o-lithiobenzoate, in particular, has been reported to
be too reactive toward self-condensation, even at -100
°C, to be synthetically useful.10 We proposed that BF3-
activated imines might be able to capture the ortho-
lithiated carbalkoxybenzoates if these reactive anions
could be stabilized or could be generated transiently.
We viewed lithium-halogen exchange using a suitable
o-bromo or -iodobenzoate as an attractive approach for
the transient generation of carbalkoxy-substituted aryl-
lithium reagents. Adjusting the rate of addition of an
“inducing” organolithium reagent to the alkyl o-haloben-
zoate would provide a means to control the formation of
the alkyl o-lithiobenzoate, in situ. The rate of formation
of the o-lithiated carbalkoxybenzoates, induced by
lithium-halogen exchange, would have to be exception-
ally fast to avoid unwanted side reactions. Potential
competing processes would include addition of the “in-
ducing” organolithium to the imine, deprotonation of
imine R-or R′-hydrogens, and self-condensation, or de-
composition, of the o-lithiobenzoate. However, we were
encouraged by previous reports that described the prepa-
ration, and trapping, of organolithium reagents in the
presence of nontethered reactive electrophiles.9,11
To test this synthetic approach to isoindolones, a
solution of isopropyl o-bromobenzoate, 7d , and BF3‚OEt2
Resu lts a n d Discu ssion
Rea ction s of Im in es w ith th e N-Meth ylben za m id e
Dia n ion (6). To initiate our investigations, we first
evaluated the addition of o-lithiobenzonitrile to a simple
representative imine, benzylidenethylamine (7a ). Our
use of o-lithiobenzonitrile, while successfully exploited by
Bradsher4 and Parham,5 failed to afford more than traces
of the expected isoindolone. We next focused our atten-
tion on the use of the N-methylbenzamide dianion (6),
which was prepared by the addition of 2 equiv of BuLi
to N-methylbenzamide.7 The N-methylbenzamide dian-
ion (6) reacted effectively at 0 °C with 7a to give a
mixture of two products, the simple imine 1,2-addition
product and the desired isoindolone 9 (Scheme 2). Heat-
ing the reaction mixture to 130 °C for 30 min completed
cyclization of the initially formed addition product to
afford the desired isoindolone (9a ) in excellent yield. The
reaction was shown to be general for producing isoindo-
lones from several other simple benzylideneamines not
containing acidic R hydrogens (Table 1, entries 1-3).
However, in a substrate in which acidic R-hydrogens
were present, 6 was found to not add effectively (Table
1, entry 4). Imines are known to have an increased
propensity to undergo organometallic addition reactions
in the presence of strong Lewis acids.8 We found that
the addition of 6 to butylidenebutylamine (7d ), in the
presence of 1 equiv of BF3‚OEt2, proceeded at -78 °C to
give the imine adduct in 48% yield. The very rapid rate
of addition of 6 to imines at -78 °C, in the presence of
BF3‚OEt2, should be noted in contrast to the same dianion
requiring a temperature of 0 °C to add effectively to 7d
(9) BF3‚OEt2 promotes the addition of perfluoroalkylcarbanions to
imines with acidic R-hydrogens. See: Uno, H.; Shiraishi, Y.; Shimoka-
wa, K.; Suzuki, H. Chem. Lett. 1988, 729. For a discussion of the kinetic
acidity of imine R-hydrogens see: Romesberg, F. E.; Collum, D. B. J .
Am. Chem. Soc. 1995, 117, 2166.
(10) Parham, W. E.; Sayed, Y. A. J . Org. Chem. 1974, 39, 2053.
(11) Perfluoroalkyl carbanions: Reference 8. (a) J ohncock, P. J .
Organomet. Chem. 1969, 19, 257. (b) Gassman, P. G.; O’Reilly, N. J .
Tetrahedron Lett. 1985, 26, 5243. Allyllithiums: (c) Katzenellenbogen,
J . A.; Lenox, R. S. J . Org. Chem. 1973, 38, 326. Alkenyllithiums: (c)
Flann, C. J .; Overman, L. E. J . Am. Chem. Soc. 1987, 109, 6115. Lee,
S. W.; Fuchs, P. L. Tetrahedron Lett. 1993, 34, 5209.
(7) Puterbaugh, W. H.; Hauser, C. R. J . Org. Chem. 1964, 29, 853.
(8) (a) Volkmann, R. A. In Comprehensive Organic Synthesis;
Pergamon Press: Oxford, 1991; Vol. 1, Chapter 1.12.

Isoindolone Annulation
J . Org. Chem., Vol. 61, No. 18, 1996 6207
Sch em e 3a
in THF was cooled to -78 °C. Phenyllithium (1 equiv)
was added dropwise to induce metal-halogen exchange.
After the mixture was stirred at -78 °C for 1 h and for
an additional interval at ambient temperature, the
reaction was quenched with water. Isoindolone 9d was
isolated in a 27% yield. Use of isopropyl o-iodobenzoate
as a reaction partner, under otherwise identical reaction
conditions, afforded a 48% yield of isoindolone 9d . We
suspect the faster rate of lithium-iodide exchange,
compared to lithium-bromide exchange, might be en-
hancing the desired course of reaction, therein obviating
some of the competing side processes.12,13
We also examined the suitability of other alkyl o-
iodobenzoates to function as reaction partners.14 We
were pleased to find that the use of methyl o-iodoben-
zoate, and lowering the reaction temperature to between
-105 and -110 °C, provided a further improvement in
the yield of isoindolone. In light of the reported instabil-
ity of methyl o-lithiobenzoate, this was an unexpected
discovery.10 Thus, conducting the reaction of 7d , BF3‚
OEt2, methyl o-iodobenzoate, and phenyllithium at -110
°C, according to the above-described procedure, afforded
the isoindolone 9d in 65% yield.
Finally, the influence of phenyllithium stoichiometry
on the reaction was briefly evaluated. We found that
increasing the amount of phenyllithium to between 1.3
and 1.4 equiv raised the yield of 9d to 89%.15 The only
byproducts that were identified were iodobenzene, methyl
benzoate, and methyl o-iodobenzoate. Only traces of the
self-condensation products derived from methyl benzoate
and methyl o-iodobenzoate could be detected. No prod-
ucts derived from addition of phenyllithium to the methyl
benzoates were found.
The isoindolone annulation proved to be quite general
using methyl o-iodobenzoate as a reaction partner. Thus,
the reaction of methyl o-iodobenzoate, and several sub-
stituted analogs, with a variety of imines provided good
to excellent yields of the corresponding isoindolones (see
Schemes 2 and 3 and Table 2).
Isoindolones were obtained in good to excellent yields,
even when substituted with reactive functional groups.
Thus, a pendant 4-carbmethoxy group on the methyl
o-iodobenzoate afforded the corresponding isoindolone
11c in a 64% yield (Table 2, entry 11). However, in this
case, only 1.1 equiv of phenyllithium was used to promote
a
Key: (i) BF3‚OEt2, -78 °C; (ii) PhLi, -78 or -105 °C; (iii) H2O,
warm to 50 °C overnight.
Ta ble 2. Syn th esis of Isoin d olon es 9 a n d 11a u sin g
Meth yl O-Lith ioben zoa tes
entry product R1
R2
R3
R4
R5
% yield
1
2
3
4
5
6
7
8
9
10
11
12
13
14
9d
9d
9d
9b
9c
9e
9f
9g
11a
11b
11c
11d
11e
11f
Bu Pr
Bu Pr
Bu Pr
H
H
H
H
H
H
H
H
Me
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Cl
H
H
H
H
H
H
H
H
H
H
H
Me
Br
OMe
89
89b
65c
57d
<5
72
71
0
46
Pr
Ph
Ph Ph
Bn c-hexyl
Pr
2-furyl
iPr Ph
Bu Pr
Bu Pr
Bu Pr
Bu Pr
Bu Pr
Bu Pr
76
CO2Me
H
H
64c
89
84c
72
OMe
a
Unless otherwise specified reactions were conducted at -105
°C ((3 °C) using 1.35 equiv of PhLi and 1.1 equiv each of the
methyl o-iodobenzoates and BF3‚OEt2. Yields are for isolated
b
chromatographed or recrystallized products. 1.45 equiv of PhLi
used. c 1.1 equiv of PhLi used. Reaction conducted at -78 °C.
d
the reaction. As expected, the use of greater amounts of
phenyllithium gave an increase in the formation of
byproducts, especially benzophenones derived from ad-
dition of phenyllithium to the pendent carbmethoxy
group. The excellent yield of isoindolone that was
obtained in the presence of an aryl bromide (Table 2,
entry 13) is exemplary of the remarkable selectivity that
may be achieved in the lithium-iodide exchange-induced
annulation reaction.
The isoindolone annulation reaction does appear to be
subject to certain steric constraints. For example, the
steric demands of the isopropyl group (Table 2, entry 8)
may be preventing adequate coordination of BF3 with the
imine nitrogen. This would prevent activation of the
imine, which may then seriously impede the desired
addition reaction. The poor result obtained with benz-
ylideneaniline as the imine was surprising (Table 2, entry
5). We can only speculate that the extended π system of
the benzylideneaniline may be too good of an electron
acceptor, thereby allowing competing reaction pathways,
e.g., reductive dimerization,16 to supersede the desired
course of addition. In general, however, the reaction
procedure appears to accommodate a variety of sub-
strates and provides access to a number of substituted
isoindolones.
(12) (a) Rogers, H. R.; Houk, J . J . Am. Chem. Soc. 1982, 104, 522.
(b) Reich, H. J .; Phillips, N. H.; Reich, I. L. J . Am. Chem. Soc. 1985,
107, 4101. (c) Bailey, W. F.; Punzalan, E. R. J . Org. Chem. 1990, 55,
5404. (d) Beak, p.; Musick, T. J .; Liu, C.; Cooper, T.; Gallagher, D. J .
J . Org. Chem. 1993, 58, 7330.
(13) The annulation was tried using isopropyl o-(trimethylstannyl)-
benzoate as an alternative precursor to the organolithium reagent.
Thus, reaction of the stannane with 7d , in the presence of BF3‚OEt2,
gave only ca. 20% of isoindolone 9d . Previous attempts to prepare
organolithium reagents from stannanes in the presence of esters failed
unless additional stabilizing groups were present. See: (a) Linderman,
R. J .; Graves, D. M.; Kwochka, W. R.; Ghannam, A. F.; Anklekar, T.
V. J . Am. Chem. Soc. 1990, 112, 7438. (b) Imanieh, H.; MacLeod, D.;
Quayle, P.; Zhao, Y.; Davies, G. M. Tetrahedron Lett. 1992, 33, 405.
(c) Booth, C.; Imanieh, H.; Quayle, P.; Shui-Yu, L. Tetrahedron Lett.
1992, 33, 413.
(14) We also tried to exploit the dianion derived from o-bromobenzoic
acid, especially given the reported stability of the dianion at -78 °C.
Isoindolones could be prepared in 35-45% yield. However, the poor
solubility of the dianion tended to give variable results. See: Parham,
W. E.; Sayed, Y. A. J . Org. Chem. 1974, 39, 2051.
(15) Several other organolithium reagents were evaluated in the
isoindolone annulation process. Both MeLi‚LiBr and tert-butyllithium
proved to be inferior to phenyllithium. nBuLi, when used in a strict
stoichiometry of 1.30 equiv relative to the imine, gave good yields of
isoindolone. However, small variations in the amount of nBuLi, e.g.,
1.2 equiv, gave significantly lower yields.
Ap p lica tion of th e Isoin d olon e An n u la tion Rea c-
tion to th e Syn th esis of 15. We next applied our
(16) Thies, H.; Scho¨nenberger, H. Chem. Ber. 1956, 89, 1918.

6208 J . Org. Chem., Vol. 61, No. 18, 1996
Campbell et al.
Sch em e 4a
analysis established the relative and absolute stereo-
chemistry of 15 to be as predicted (see the supporting
information). Furthermore, despite the very low tem-
peratures employed for the synthesis of isoindolone 15,
we were able to routinely conduct reactions using 50-
60 g of imine 14 as a starting material. The chemical
yields, distereomeric ratios, and enantiomeric purity of
15 all remained consistent with the aforementioned
results.
Con clu sion s
We have described a novel, direct annulation approach
for the synthesis of isoindolones based upon the addition
of methyl o-lithiobenzoate, and the dianion derived from
N-methylbenzamide, to imines activated with BF3. Acidic
imine R-hydrogens are tolerated by the reaction condi-
tions, as is the presence of relatively reactive functional
groups, such as an ester and an aryl bromide. More
importantly, we have demonstrated that the unstable
methyl o-lithiobenzoate19 can be prepared by lithium-
iodide exchange in the presence of reactive acceptor
electrophiles such as the BF3-activated imines. The
transient generation of methyl o-lithiobenzoate, and
related functionalized aryllithium derivatives, in the
presence of imines, and perhaps a range of other elec-
trophiles, should extend the scope of functionally substi-
tuted organometallic reagents.20
a
Key: (i) (COCl)2, cat. DMF, CH2Cl2; (ii) Li(t-BuO)3AlH,
diglyme, -78 °C; (iii) EtNH2, cat. Bu2SnCl2, Na2SO4; (iv) methyl
o-iodobenzoate, BF3‚OEt2, -78 °C; (v) PhLi, -105 °C.
isoindolone synthesis process to the assembly of isoin-
dolone 15, which was of especial interest to us. Previous
work described the preparation of (S)-(-)-2-(3,4-dichlo-
rophenyl)-4-pentenoic acid (12) of 96-97% ee.17 The acid
was easily converted to the sensitive aldehyde 13 as
shown in Scheme 4. The chiral purity of 13 was
determined indirectly. Thus, treatment of 13 with
NaBH4 in ethanol gave the corresponding alcohol. HPLC
analysis of the alcohol, using a chiral stationary phase,
indicated a chiral purity of 92-94% ee. Thus, a slight
erosion in the chiral purity was indicated from the
starting acid 12. Formation of imine 14 required the use
of dibutyltin dichloride as a catalyst to accelerate the
reaction and minimize epimerization of the chiral cen-
ter.18 Significant epimerization of the R-chiral center is
observed when the reaction is conducted in the absence
of the tin catalyst. The very sensitive imine 14 was then
used immediately for the isoindolone annulation.
Our initial attempts to prepare isoindolone 15 from
imine 14 using the dianion derived from N-methylbenz-
amide, in the presence of BF3‚OEt2, gave only small
quantities of the desired product, which was accompanied
by numerous byproducts. However, application of the
procedure using methyl o-iodobenzoate and phenyl-
lithium at -105 °C, with imine 14, afforded a mixture of
the isoindolone diastereomers 15 and 16 in a combined
yield of 69%. We were gratified to find that the diaster-
eomeric ratio was 18:1, favoring formation of the desired
syn isomer 15. Thus, the addition of the lithiated
benzoate to imine 14 was consistent with that predicted
by the Felkin-Ahn transition state model (Figure 1).
Also, examination of the major diastereomer 15 by HPLC,
using a chiral support phase, indicated a chiral purity of
92-94% ee. Thus, there was no loss of the chiral
integrity from the starting aldehyde (and imine) during
the isoindolone annulation step. Isoindolone 15 was
found to be highly crystalline, so enantiomeric enrich-
ment could be achieved by simple recrystallization to give
purified product of >99.3% ee. Single-crystal X-ray
Exp er im en ta l Section
Gen er a l In for m a tion . Unless otherwise noted, materials
were obtained from commercial suppliers and used without
further purification. Methyl o-iodobenzoate (Lancaster Syn-
thesis) was redistilled under argon, wrapped with aluminum
foil to protect from the light, and stored refrigerated. Imines
were prepared using standard literature procedures using
commercially available amines and aldehydes.21 Volatile
aldehydes were purified by distillation prior to imine forma-
tion. In most cases the imines were distilled and stored
refrigerated. Boron trifluoride diethyl etherate was distilled
from CaH2 and stored refrigerated in an ampule fitted with a
Teflon stopcock. Phenyllithium was purchased from Alfa and
transferred under argon to a storage ampule surmounted with
a Teflon stopcock. The phenyllithium was titrated periodically
using diphenylacetic acid as the titrant and the acid dianion
color as the endpoint.22 Ambiguous titers were obtained using
the procedure of Watson and Eastham23 and related proce-
dures using different indicators.24 THF was distilled from
sodium benzophenone ketyl immediately prior to use. HPLC
analyses were performed using a Chiracel OD column (4.6 ×
250 mm) with 10% 2-propanol/hexanes as the mobile phase.
TLC analyses were performed on silica gel GHLF. All reac-
tions were performed under a nitrogen or argon atmosphere
using standard techniques for manipulation of air- and
moisture-sensitive reagents.25 Internal reaction temperatures
(19) We have chosen to formally designate the reactive species
generated by the PhLi-induced lithium-iodide exchange on methyl
o-iodobenzoate as the o-lithiated benzoate derivative. However, we have
no structural evidence that confirms the lithio-derivative as the
reactive intermediate. An alternative reactive intermediate might be
a hypervalent “ate” complex. See: Reich, H. J .; Green, D. P.; Phillips,
N. H. J . Am. Chem. Soc. 1989, 111, 3444.
(20) We have also added phenyllithium to a mixture of isopropyl
o-iodobenzoate and trimethylsilyl chloride, at -78 °C, to produce
isopropyl o-(trimethylsilyl)benzoate in a 72% yield.
(21) (a) Sandler, S. R.; Karo, W. Organic Functional Group Prepara-
tions; Academic Press: New York, 1972; Vol. II, Chapter 12. (b)
Anderson, W. K.; Milowsky, A. S. J . Med. Chem. 1986, 29, 2241.
(22) Kofron, W. G.; Baclawski, L. M. J . Org. Chem. 1976, 41, 1879.
(23) Watson, S. C.; Eastham, J . F. J . Organomet. Chem. 1967, 9,
165.
(17) Hale, J . J .; Finke, P. E.; MacCoss, M. Biorg.Med. Chem. Lett.
1993, 3, 319.
(18) Stetin, C.; de J eso, B.; Pommier, J . C. Synth. Commun. 1982,
12, 495.
(24) Bergbreiter, D. E.; Pendergrass, E. J . Org. Chem. 1981, 46, 219.
(25) Brown, H. C.; Kramer, G. W.; Levy, A. B.; Midland, M. M. In
Organic Synthesis via Boranes; J ohn Wiley & Sons, Inc.: New York,
1975; Chapter 9.

Isoindolone Annulation
J . Org. Chem., Vol. 61, No. 18, 1996 6209
were monitored using a Fluke 52K/J thermocouple, with
digital readout. The thermocouple probe was inserted into a
glass well containing ethanol, which was immersed into the
reaction solution. Ambient temperature refers to 23 °C ((3
°C). Melting points were taken on a capillary apparatus. 1H
NMR spectra were obtained at 300 or 400 MHz. 13C NMR
spectra were recorded at 75 MHz. Mass spectra were recorded
on an atmospheric pressure chemical ionization platform.
Elemental analyses were performed by the departmental
analytical laboratory at Zeneca Pharmaceuticals, Inc.
BF3‚OEt2 was added, by cannula, to the -78 °C solution of 6.
The reaction mixture was stirred at -78 °C for 1 h and then
was allowed to warm slowly to ambient temperature. After
the mixture was stirred for 1 h at ambient temperature, water
was added. The mixture was extracted three times with
diethyl ether. The combined extracts were washed with brine,
dried (Na2SO4), and concentrated. The resulting gum was
heated in an oil bath at 150 °C for 1 h. After being cooled to
ambient temperature, the crude product was purified by flash
chromatography using ethyl acetate:hexanes (1:3) to afford 9d
as an oil, 0.183 g (0.79 mmol, 40%).
Gen er a l P r oced u r e for th e Ad d ition of th e N-Meth yl-
ben za m id e Dia n ion 6 to Im in es. The procedure for the
preparation of 2-ethyl-3-phenyl-2,3-isoindol-1-one (9a ) is rep-
resentative. A solution of N-methylbenzamide (0.184 g, 1.36
mmol) in THF was cooled to -20 °C. BuLi (1.19 mL, 2.40 M
in hexanes, 2.73 mmol) was then added dropwise. The
resulting yellow-orange solution was stirred for a few minutes
at -20 °C followed by placing in an ice bath and stirring for 1
h. Imine 7a (0.143 mL, 0.133 g, 1.0 mmol) in THF (1 mL)
was then added dropwise. The resulting red solution was
stirred for 30 min in the ice bath. After removal of the ice
bath, the solution was warmed to ambient temperature and
stirred for an additional 30 min. Water was added and the
mixture extracted several times with ethyl acetate. The
combined extracts were washed once with brine and then dried
(Na2SO4) and concentrated to leave an oil. TLC analysis
revealed the presence of N-methylbenzamide and two new
additional components. Mass spectral analysis suggested the
identity of the three major components as follows: N-meth-
ylbenzamide (m/ z ) 136, [M + H]), the imine adduct (m/ z )
269, [M + H]), and 9a (m/ z ) 238, [M + H]). The mixture
containing the crude reaction products was then heated in an
oil bath at 130 °C for 1 h. TLC analysis revealed N-
methylbenzamide and one other component. Purification of
the crude product by flash chromatography using ethyl acetate:
hexanes (3:7) as the eluent afforded 0.187 g (0.79 mmol, 79%)
of the product as a white solid: mp 97-98 °C; 1H NMR (CDCl3)
1.14 (t, 3H, J ) 7.3 Hz), 2.98 (dq, 1H, J ) 7.2 ,14.1 Hz), 3.99
(dq, 1H, J ) 7.3, 14.1 Hz), 5.47 (s, 1H) 7.16 (m, 4H), 7.33 (m,
2H), 7.45 (m, 2H), 7.89 (m, 1H); 13C (CDCl3)13.49, 34.95, 63.96,
122.99, 123.42, 127.53, 128.24, 128.60, 129.06, 131.59, 131.77;
MS (m/ z) ) 238 [M + H]. Anal. Calcd for C16H15NO: C,
80.98; H, 6.37; N, 5.90. Found: C, 80.78; H, 6.46; N, 5.93.
2-P r op yl-3-p h en yl-2,3-d ih yd r oisoin d ol-1-on e (9b): mp
92-93 °C; 1H NMR (CDCl3) 0.88 (t, 3H, J ) 7.4 Hz), 1.58 (m,
2H), 2.84 (m, 1H), 3.88 (dt, 1H, J ) 7.4, 13.7 Hz), 5.45 (s, 1H),
7.14 (m, 3H), 7.34 (m, 3H), 7.45 (m, 2H), 7.89 (m, 1H); 13C NMR
(CDCl3) 11.34, 21.52, 41.79, 64.36, 122.99, 123.50, 127.52,
128.24, 128.59, 129.06, 131.58, 131.72, 137.17, 146.22, 168.59;
MS (m/ z) ) 252 [M + H]. Anal. Calcd for C17H17NO: C,
81.24; H, 6.81; N, 5.57. Found: C, 80.87; H, 6.85; N, 5.68.
2,3-Dip h en yl-2,3-d ih yd r oisoin d ol-1-on e (9c): mp 190-
Gen er a l P r oced u r e for Im in e Isoin d olon e An n u la tion
Usin g Meth yl o- Iod oben zoa te, BF 3‚OEt2, a n d P h en yl-
lith iu m . To a -78 °C solution of the imine (1 mmol equiv)
and methyl o-iodobenzoate (1.1 mmol equiv) in THF (3.5 mL/
mmol of imine) was added dropwise BF3‚OEt2 (1.1 mmol
equiv). The internal temperature was maintained below -73
°C during the addition of the BF3‚OEt2. Following the addi-
tion, the reaction was then cooled to -105 °C ( 3 °C using a
methanol:ethanol (1:1) bath with liquid nitrogen as the coolant.
A solution of phenyllithium (1.3 mmol equiv, typically 1.8-
1.9 M in diethyl ether/cyclohexane) was diluted in THF (25%
of the volume of phenyllithium used). This solution was then
added dropwise to the reaction mixture while the temperature
was maintained at -105 °C. (Note: The dilution of the
phenyllithium with THF is necessary to prevent precipitation
of the phenyllithium during the addition) Following the
addition of the phenyllithium, the reaction was cooled to -110
( 3 °C and stirred for 1 h. The cooling bath was removed,
and the reaction was placed in a dryice/acetone bath (ca. -78
°C). After being stirred at -78 °C for 1 h, the cooling bath
was removed and the reaction again allowed to warm. Upon
reaching -25 to -30 °C, internal temperature, water was
added. The reaction mixture was allowed to warm to ambient
temperature, after which it was placed in a heating bath. The
reaction mixture was heated overnight (15-18 h) at 45-50
°C. After the mixture was cooled to ambient temperature, the
pH was adjusted to 2-3, if necessary. The mixture was
extracted several times with diethyl ether or ethyl acetate. The
combined extracts were dried (Na2SO4 and then MgSO4),
filtered, and concentrated. Products were typically purified
by flash chromatography or recrystallization. Physical and
spectroscopic data for the additional isoindolones listed in
Table 2 are given below.
2-B e n zy l-3-c y c lo h e x y l-2,3-d ih y d r o is o in d o l-1-o n e
1
(9e): mp 163-164.5 °C; H NMR (CDCl3) 0.42 (m, 1H), 1.06
(m, 2H), 1.26 (m, 2H), 1.43 (m, 2H), 1.68 (m, 2H), 2.03 (m,
1H), 4.20 (d, 1H, J ) 15.2 Hz), 4.26 (d, 1H, J ) 3.1 Hz), 5.40
(d, 1H, J ) 15.2 Hz), 7.35 (m, 5H), 7.45 (m, 3H), 7.90 (d, 1H,
J ) 6.45 Hz); 13C NMR (CDCl3) 25.76, 25.95, 26.35, 26.90,
29.69, 39.38, 43.98, 63.57, 123.27, 123.77, 127.46, 127.93,
128.06, 128.66, 128.90, 130.92, 132.82, 137.17, 144.09, 168.68;
MS (m/ z) ) 306 [M + H]. Anal. Calcd for C21H23NO: C,
82.58; H, 7.59; N, 4.85. Found: C, 82.11; H, 7.53; N, 5.14.
2-P r op yl-3-(2-fu r yl)-2,3-d ih yd r oisoin d ol-1-on e (9f): mp
1
192 °C; H NMR (CDCl3) 6.10 (s, 1H), 7.10 (m, 1H), 7.20 (m,
4H), 7.50 (m, 2H), 7.61 (m, 2H), 7.98 (m, 1H); 13C NMR (CDCl3)
65.60, 122.48, 122.96, 124.09, 124.92, 126.87, 128.32, 128.54,
128.83, 129.07, 131.08, 132.44, 137.57, 145.62, 167.50; MS (m/
z) ) 286 [M + H]. Anal. Calcd for C20H15NO‚2H2O: C, 83.13;
H, 5.37; N, 4.87. Found: C, 83.00; H, 5.33; N, 5.27.
1
101-102 °C; H NMR (CDCl3) 0.90 (t, 3H, J ) 7.40 Hz), 1.57
(m, 2H), 3.08 (m, 1H), 3.8 (dt, 1H, J ) 7.4, 12.2 Hz), 5.60 (s,
1H), 6.31 (d, 1H, J ) 3.2 Hz), 6.37 (dd, 1H, J ) 3.2, 1.6 Hz),
7.35 (m, 1H), 7.47 (d, 1H, J ) 1.6 Hz), 7.50 (m, 2H), 7.88 (m,
1H); 13C NMR (CDCl3) 11.29, 21.47, 42.27, 57.80, 109.33,
110.50, 122.84, 123.62, 128.67, 131.51, 132.28, 142.85, 143.33;
MS (m/ z) ) 242 [M + H]. Anal. Calcd for C15H15NO2‚H2O:
C, 74.39; H, 6.28; N, 5.78. Found: C, 74.33; H, 6.28; N, 5.72.
2-Bu t yl-3-p r op yl-4-m et h yl-2,3-d ih yd r oisoin d ol-1-on e
(11a ): 1H NMR (CDCl3) 0.60 (m, 1H), 0.77 (t, 3H, J ) 7.0 Hz),
0.87 (m, 1H), 0.95 (t, 3H, J ) 7.4 Hz), 1.37 (m, 2H), 1.62 (m,
2H), 2.04 (m, 2H), 2.41 (s, 3H), 3.05 (m, 1H), 4.05 (dt, 1H, J )
8.2, 13.9 Hz), 4.66 (t, 1H, J ) 3.5 Hz), 7.26-7.37 (m, 2H), 7.67
(d, 1H, J ) 7.7 Hz); 13C NMR (CDCl3) 13.84, 13.97, 14.94,
18.46, 20.21, 30.17, 30.39, 39.14, 58.69, 121.11, 128.11, 132.13,
132.71, 133.19, 143.00, 168.66; MS (m/ z) ) 246 [M + H]. Anal.
Calcd for C16H23NO: C, 78.32; H, 9.45; N, 5.71. Found: C,
77.94; H, 9.29; N, 5.84.
2-Bu t yl-3-p r op yl-2,3-d ih yd r oisoin d ol-1-on e (9d ): 1H
NMR (CDCl3) 0.82 (m, 4H), 0.95 (t, 3H, J ) 7.3 Hz), 1.08 (m,
1H), 1.37 (m, 2H), 1.60 (m, 2H), 1.93 (m, 2H), 3.08 (m, 1H),
4.02 (dt, 1H, J ) 8.0, 13.9 Hz), 4.59 (t, 1H, J ) 3.8 Hz), 7.46
(m, 3H), 7.83 (d, 1H, J ) 7.4); 13C NMR (CDCl3) 13.72, 13.96,
15.67, 20.09, 30.38, 32.60, 39.36, 58.87, 121.90, 123.41, 127.85,
131.03, 132.76, 145.16, 168.36; MS (m/ z) ) 232 [M + H]. Anal.
Calcd for C15H21NO‚0.25H2O: C, 76.39; H, 9.19; N, 5.93.
Found: C, 76.20; H, 8.82; N, 55.95.
Ad d ition of th e N-Meth ylben za m id e Dia n ion 6 to
Im in e 7d in th e P r esen ce of BF 3‚OEt2. A solution of 6 was
prepared as described above using N-methylbenzamide (0.36
g, 2.6 mmol) and BuLi (2.26 mL of a 2.40 M solution in
hexanes, 5.46 mmol) in THF (8 mL). The solution was cooled
to -78 °C. In a separate flask, 7d (0.34 mL, 2.0 mmol) was
dissolved in THF (1 mL) and cooled to -25 °C. BF3‚OEt2 (0.24
mL, 2.0 mmol) was then added dropwise to the solution of 7d .
After being stirred for 5 min, the solution containing 7d and
2-Bu t yl-3-p r op yl-5-ch lor o-2,3-d ih yd r oisoin d ol-1-on e
(11b): 1H NMR (CDCl3) 0.85 (m, 4H), 0.95 (t, 3H, J ) 7.4 Hz),
1.09 (m, 1H), 1.36 (m, 2H), 1.60 (m, 2H), 1.93 (m, 2H), 3.08

6210 J . Org. Chem., Vol. 61, No. 18, 1996
Campbell et al.
(m, 1H), 4.0 (dt, 1H, J ) 8.3, 14.2 Hz), 4.58 (t, 1H, J ) 4.4
Hz), 7.40 (s, 1H), 7.42 (d, 2H, J ) 7.7 Hz), 7.75 (d, 1H, J ) 7.7
Hz); 13C NMR (CDCl3) 13.71, 13.92, 15.71, 20.10, 30.32, 32.52,
39.51, 58.62, 122.41, 124.67, 128.50, 131.36, 137.42, 146.82,
cooled on ice to slow decomposition of the crude aldehyde until
filtered. When all the hexane had been removed, the residual
oil was set under high vacuum for 30 min. There was obtained
27.5 g (97%) of 13 as a pale yellow oil. Aldehyde 13 was stored
under argon at -78 °C (on dry ice): 1H NMR (CDCl3) 2.47 (m,
1H), 2.83 (m, 1H), 3.60 (m, 1H), 5.02-5.09 (m, 2H), 5.68 (m,
1H), 7.04 (dd, 1H, J ) 2.2, 8.2 Hz), 7.30 (d, 1H, J ) 2.2 Hz),
7.45 (d, 1H, J ) 8.2 Hz), 9.67 (d, 1H, J ) 1.6); MS (m/ z) )
229 (80/231 (53) [M + H].
167.30; MS (m/ z) ) 266 [M + H]. Anal. Calcd for C17H23
-
NO3: C, 67.79; H, 7.58; N, 5.27. Found: C, 67.55; H, 7.48; N,
5.31.
2-Bu tyl-3-p r op yl-5-ca r bom eth oxy-2,3-d ih yd r oisoin d ol-
1-on e (11c): mp 62-64 °C; 1H NMR (CDCl3) 0.85 (m, 4H),
0.96 (t, 3H, J ) 7.3 Hz), 1.08 (m, 1H), 1.38 (m, 2H), 1.62 (m,
2H), 1.98 (m, 1H), 3.11 (m, 1H), 3.96 (s, 3H), 4.03 (dt, 1H, J )
8.3, 14 Hz), 4.65 (t, 1H, J ) 4.3 Hz), 7.88 (d, 1H, J ) 7.8 Hz),
8.10 (s, 1H), 8.15 (d, 1H, J ) 7.8 Hz); 13C NMR (CDCl3) 13.72,
13.92, 15.70, 20.13, 30.32, 32.44, 39.64, 52.43, 59.00, 123.33,
123.45, 129.47, 132.60, 136.83, 145.11, 166.60, 167.30; MS (m/
z) ) 290 [M + H]. Anal. Calcd for C17H23NO3: C, 70.56; H,
8.01; N, 4.84. Found: C, 70.53; H, 8.01; N, 4.98.
2-Bu t yl-3-p r op yl-6-m et h yl-2,3-d ih yd r oisoin d ol-1-on e
(11d ): 1H NMR (CDCl3) 0.85 (m, 4H), 0.94 (t, 3H, J ) 7.4 Hz),
1.08 (m, 1H), 1.36 (m, 2H), 1.60 (m, 2H), 1.90 (m, 2H), 2.43 (s,
3H), 3.07 (m, 1H), 4.01 (dt, 1H, J ) 8.2, 13.9 Hz), 4.55 (t, 1H,
J ) 3.7 Hz), 7.27-7.34 (m, 2H), 7.63 (d, 1H); 13C NMR (CDCl3)
13.77, 14.01, 15.77, 20.15, 21.27, 30.44, 32.77, 39.39, 58.70,
121.69, 123.71, 132.01, 133.00, 137.87, 142.45, 168.48; MS (m/
z) ) 246 [M + H]. Anal. Calcd for C16H23NO: C, 78.32; H,
9.45; N, 5.71. Found: C, 77.96; H, 9.48; N, 5.76.
[(S)-(-)-2-(3,4-Dich lor op h en yl)-4-p en ten ylid en ]eth yl-
a m in e (14). To a solution of dibutyltin dichloride (1.94 g, 6.39
mmol) in methylene chloride (100 mL) was added Na2SO4 (55
g, anhydrous). The stirred mixture was cooled in an ice bath,
and a solution containing freshly-prepared (S)-(-)-2-(3,4-
dichlorophenyl)-4-pentenal (13) (28.39 g, 123.9 mmol) in dry
methylene chloride (50 mL) was added. Additional methylene
chloride (2 × 25 mL) was used to wash in residual aldehyde.
The mixture was stirred for 5 min, and then a solution
containing ethylamine (32.0 mL, 4.06 M in methylene chloride,
129.9 mmol) was slowly added. The slightly-yellowish mixture
was stirred for 75 min and then cooled to -78 °C. After the
mixture was stirred for 5 min at -78 °C, the mixture was
filtered through an in-line glass frit to remove Na2SO4 while
maintaining strictly anhydrous conditions. The solids were
washed with additional dry methylene chloride (100 mL total,
in portions). The combined filtrates and washings were
concentrated without external heating. The remaining residue
was placed under high vacuum (∼100 mTorr) until a stable
pressure reading was obtained (5-10 min). The recovered
viscous liquid residue weighed 33.1 g (or 31.2 g, 98%, after
the weight of Bu2SnCl2 was subtracted). The material was
used immediately or was cooled (-78 °C) and stored under an
argon atmosphere until needed: 1H NMR (CDCl3) 1.12 (t, 3H,
J ) 7.1 Hz), 2.43 (m, 1H), 2.62 (m, 1H), 3.35 (dt, 2H, J ) 5.3,7.1
Hz), 3.43 (m, 1H), 4.91-4.97 (m, 2H), 5.61 (m, 1H), 6.98 (dd,
1H, J ) 2.1,8.3 Hz), 7.23 (d, 1H, J ) 2.1 Hz), 7.32 (d, 1H, J )
8.3 Hz), 7.57 (d, 1H, J ) 5.3 Hz); MS (m/ z) ) 256 (100)/258
(65) [M + H].
(3R)-3-[(1S)-1-(3,4-Dich lor op h en yl)-3-bu ten yl]-2-eth yl-
2,3-d ih yd r oisoin d ol-1-on e (15). A flask was charged with
THF (200 mL) and then cooled to -78 °C. A solution
containing freshly-prepared imine 14 (31.2 g, 122 mmol) in
dry THF (50 mL) was rapidly added and washed in with
additional THF (2 × 25 mL). Methyl o-iodobenzoate (19.9 mL,
35.0 g, 133.7 mmol) was added, and the solution was allowed
to reequilibrate to -78 °C (internal temperature). BF3‚OEt2
(16.5 mL, 19.0 g, 134 mmol) was added dropwise, while the
internal temperature was maintained below -75 °C. The
solution was then cooled to -105 ( 3 °C. Phenyllithium (69.8
mL, 1.92 M in diethyl ether/hexanes, 134 mmol) was then
added dropwise over approximately 1 h, during which the
internal temperature was maintained between -103 and -106
°C. When the addition was completed, the reaction was cooled
to approximately -110 °C and maintained between -110 and
-113 °C for 1 h. The low-temperature cooling bath was then
replaced with a dry ice-acetone bath, and the reaction was
stirred for an additional 1 h. The cooling bath was then
removed and the reaction allowed to warm. When the internal
temperature reached -25 to -30 °C, ice-water (250 mL) was
added. The mixture was allowed to warm slowly to ambient
temperature, after which time it was heated at 55-60 °C, with
stirring, for 16 h. The mixture was allowed to cool to ambient
temperature. The pH of the mixture was adjusted (to pH ∼
2) with 6 N aqueous hydrochloric acid (∼10 mL) after which
diethyl ether (200 mL) was added. The organic layer was
separated, and the aqueous layer was extracted with diethyl
ether (2 × 150 mL). The organic extracts were combined,
stirred over anhydrous Na2SO4 for 10 min, and then stirred
with added anhydrous MgSO4 for an additional 10 min. After
standing briefly the combined Na2SO4-MgSO4 solids were
removed by filtration and washed with additional diethyl
ether. The filtrates and washings were combined and con-
centrated. The red-orange, oily residue (75.2 g) was dissolved
in a minimum amount of methylene chloride and then applied
to a chromatography column (500 g of silica gel 60) in 3:1
hexane-ethyl acetate. The column was eluted with hexane:
2-Bu t yl-3-p r op yl-6-b r om o-2,3-d ih yd r oisoin d ol-1-on e
(11e): 1H NMR (CDCl3) 0.84 (m, 4H), 0.95 (t, 3H, J ) 7.5 Hz),
1.08 (m, 1H), 1.36 (m, 2H), 1.61 (m, 2H), 1.92 (m, 2H), 3.08
(m, 1H), 4.00 (dt, 1H, J ) 8.0, 13.9 Hz), 4.56 (t, 1H, J ) 3.7
Hz), 7.29 (d, 1H, J ) 8.1 Hz), 7.63 (d, 1H, J ) 8.1 Hz), 7.96 (s,
1H); 13C NMR (CDCl3) 13.76, 13.97, 15.70, 20.13, 30.35, 32.45,
39.57, 58.75, 122.00, 123.61, 126.69, 134.04, 134.91, 143.84,
166.90; MS (m/ z) ) 310, 312 [M + H]. Anal. Calcd for C15H20
-
NO: C, 58.07; H, 6.50; N, 4.51. Found: C, 57.76; H, 6.47; N,
4.60.
2-Bu tyl-3-p r op yl-5,6-d im eth oxy-2,3-d ih yd r oisoin d ol-1-
on e (11f): 1H NMR (CDCl3) 0.85 (m, 4H), 0.95 (t, 3H, J ) 7.3
Hz), 1.07 (m, 1H), 1.36 (m, 2H), 1.60 (m, 2H), 1.90 (m, 2H),
3.06 (m, 1H), 3.94 (s, 3H), 3.96 (s, 3H), 3.99 (m, 1H), 4.52 (t,
1H, J ) 4.2 Hz), 6.86 (s, 1H), 7.30 (s, 1H); 13C NMR (CDCl3)
13.72, 13.98, 15.53, 20.06, 30.15, 32.68, 39.41, 56.10, 56.16,
58.46, 104.16, 105.08, 125.12, 138.58, 149.43, 152.20, 168.55;
MS (m/ z) ) 292 [M + H]. Anal. Calcd for C17H25NO3‚
0.15H2O: C, 69.43; H, 8.67; N, 4.76. Found: C, 69.46; H, 8.64;
N, 4.90.
(S)-(-)-2-(3,4-Dich lor op h en yl)-4-p en ten a l (13). A mag-
netically stirred solution of (S)-(-)-2-(3,4-dichlorophenyl)-4-
pentenoic acid (12) (30.4 g, 124 mmol)17 in methylene chloride
(375 mL) was cooled in an ice bath and treated with oxalyl
chloride (13 mL, 149 mmol) in one portion, followed by the
addition of DMF (1 mL), also in one portion. The mixture was
stirred in the ice bath for an additional 10 min. The cooling
bath was removed and the mixture allowed to stir at ambient
temperature overnight. The solvent was then removed, with-
out heating, on the rotary evaporator. The residue was
dissolved in anhydrous diglyme (375 mL) and added to a
round-bottom flask equipped with a mechanical stirrer and a
500 mL dropping funnel. The solution of the acid chloride was
cooled to -78 °C. The dropping funnel was charged with
lithium tri-tert-butoxyaluminohydride (262 mL, 0.49 M solu-
tion in diglyme, 0.128 mol). The hydride solution was added
to the rapidly stirring acid chloride solution at such a rate that
the temperature was kept mostly below -72 °C. The addition
took 75 min. When the addition was complete the reaction
mixture was stirred at -78 °C for an additional 45 min and
then poured into a 4 L beaker containing a mechanically
stirred mixture of ice (1200 g), hexane (1200 mL), and a
solution of L-tartaric acid (39 g, 0.26 mol) in water (100 mL).
This mixture was stirred for 10 min. The aqueous phase was
separated and extracted with additional hexane. The com-
bined hexane extracts were washed with ice-water (3 × 1 L)
and saturated brine solution (200 mL) and dried (Na2SO4).
After 10 min a portion of the mixture was filtered and the
volatiles removed by rotary evaporation with no heat applied
to the bath. The unfiltered portion of the hexane solution was

Isoindolone Annulation
J . Org. Chem., Vol. 61, No. 18, 1996 6211
ethyl acetate (3:1). The fractions containing the syn-15 and
anti-16 isoindolone diastereoisomers were combined and con-
centrated. The residue was placed under high vacuum (warm-
ing occasionally) until residual solvent was completely re-
moved. The recovered material weighed 30.4 g (69% of theory).
Evaluation by HPLC indicated that the ratio of syn-15 to anti-
16 diastereoisomers was approximately 18:1. The syn-15
diastereoisomer consisted of >97% of the desired S,R enanti-
omer (ca. 94% ee). The material was dissolved in hot methyl
tert-butyl ether (∼90 mL), diluted with an equal volume of
hexanes, and briefly reheated to boiling. The solution was
stirred and allowed to cool to room temperature. When cool,
several “seed” crystals were added, and the mixture was stirred
at room temperature overnight. The solid was recovered by
suction filtration and was washed twice with hexanes:methyl
tert-butyl ether (10:1). The recovered solid, mp 77-78 °C,
weighed 20.2 g (46%). Reprocessing the mother liquors
returned an additional 2.50 g (5.7%) of solid, mp 77-79 °C.
The mother liquors (from second crop) were concentrated and
rechromatographed using 5%-10% 2-propanol/hexane as the
eluent. Fractions containing the lower Rf diastereoisomer were
combined and concentrated. The residue was recrystallized
(as previously noted) to return an additional 1.10 g (2.5%) of
white solid, mp 77-79 °C. Evaluation by HPLC indicated that
the recovered solid 15 was >99.6% chemically pure and
essentially a single enantiomer (99.4% ee). Total recovery was
23.8 g or 54.2% of theory from acid 12: TLC, Rf ) 0.20 (silica,
5:95, 2-propanol:hexane); 1H NMR (CDCl3) 1.20 (t, 3H, J )
7.3 Hz), 2.75 (m, 2H), 3.15 (m, 1H), 3.40 (m, 1H), 4.16 (m, 1H),
4.83 (d, 1H, J ) 3.7 Hz), 5.10-5.20 (m, 2H), 5.76 (m, 1H), 6.50
(dd, 1H, J ) 2.2, 8.3 Hz), 6.76 (d, 1H, J ) 2.2 Hz), 7.09 (d, 1H,
J ) 8.3 Hz), 7.44-7.58 (m, 2H), 7.65 (d, 1H, J ) 7.5 Hz), 7.70
(d, 1H, J ) 7.5 Hz); 13C NMR (CDCl3) 13.21, 34.66, 35.67,
45.59, 61.24, 117.93, 122.91, 123.75, 127.40, 128.50, 129.63,
130.0, 130.85, 130.89, 131.71, 133.26, 134.90, 137.90, 142.49,
167.61; MS (m/ z) ) 360 (100)/362 (65) [M + H]; [R]25D ) +84.4°
(c ) 1.54 × 10-3 g/mL, ethanol). Anal. Calcd for C20H19Cl2-
NO: C, 66.68; H, 5.32; N, 3.89. Found: C, 66.60; H, 5.41; N,
3.89.
The mother liquors from the first recrystallization were
concentrated and chromatographed on silica gel using 2-pro-
panol:hexane (5:95) as the eluent. An analytical sample of the
minor diastereomer (3S)-3-[(1S)-1-(3,4-d ich lor op h en yl)-3-
bu ten yl]-2-eth yl-2,3-d ih yd r oisoin d ol-1-on e (16) was ob-
tained (no yield): TLC, Rf ) 0.25 (silica, 5:95/2-propanol:
hexane); 1H NMR (CDCl3) 1.36 (t, 3H, J ) 7.2 Hz), 1.93-2.04
(m, 2H), 3.51 (m, 1H), 4.20 (m, 1H), 4.75 (d, 1H, J ) 3.5 Hz),
4.90-4.96 (m, 2H), 5.58 (m, 1H), 6.69 (d, 1H, J ) 7.5 Hz), 7.12
(dd, 1H, J ) 8.4, 2.1 Hz), 7.35-7.50 (m, 4H), 7.82 (m, 1H); MS
(m/ z) ) 360 (100)/362 (68) [M + H].
HPLC analysis of the diastereomers was conducted on a
Chiracel OD column eluting with 2-propanol:hexane (1:9) at
a flow rate of 0.5 mL/min (detector wavelength, 254 nm).
Using these conditions, the retention time was 19.8 min for
the R,S enantiomer and 24.1 min for the S,R enantiomer. The
retention time for the anti diastereoisomers was 17.4 min
(enantiomers not resolved).
Ack n ow led gm en t . We grateful to Dr. Cy J .
Ohnmacht and Mr. Reed W. Smith for their experimen-
tal contributions and to Mr. J im M. Hulsizer for the
provision of acid 12. We would also like to thank Dr.
Ashok Shenvi for providing us with authentic samples
of isoindolones 15 and 16 and to thank Ms. Margaret
Lin for the X-ray structural determination of isoindolone
15.
Su p p or tin g In for m a tion Ava ila ble: The experimental
data for the sample preparation, X-ray diffraction, collection,
and solution of the structure of isoindolone 15 are presented
(3 pages). This material is contained in libraries on microfiche,
immediately follows this article in the microfilm version of the
journal, and can be ordered from the ACS; see any current
masthead page for ordering information.
J O960582W