Mild and efficient syntheses of diverse isoindolinones from ortho-phthaldehydic acid methylthiomethyl ester

Article abstract of DOI:10.1016/j.tet.2010.01.070

A mild and efficient method for the synthesis of diverse isoindolinones from o-phthaldehydic acid methylthiomethyl ester and aliphatic/aromatic amines has been developed. A number of nucleophiles including a hydride ion were successfully added to the intermediate Schiff's base providing isoindolinones, with or without substitution at 3-position. Conditions have also been developed for amines with an integrated nucleophilic group to react in a diverse fashion either to give isoindolinones or tricyclic γ-lactams as single diastereoisomers in very good yield.

Full text of DOI:10.1016/j.tet.2010.01.070

Tetrahedron 66 (2010) 2148–2155
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Mild and efficient syntheses of diverse isoindolinones from ortho-phthaldehydic
acid methylthiomethyl ester
*
Usha Ghosh , Rituparna Bhattacharyya, Ashish Keche
Piramal Life Sciences Limited, 1, Nirlon Complex, Off Western Express Highway, Goregaon (East), Mumbai 400 063, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A mild and efficient method for the synthesis of diverse isoindolinones from o-phthaldehydic acid
methylthiomethyl ester and aliphatic/aromatic amines has been developed. A number of nucleophiles
including a hydride ion were successfully added to the intermediate Schiff’s base providing iso-
indolinones, with or without substitution at 3-position. Conditions have also been developed for amines
with an integrated nucleophilic group to react in a diverse fashion either to give isoindolinones or tri-
Received 30 September 2009
Received in revised form 18 January 2010
Accepted 19 January 2010
Available online 25 January 2010
cyclic g-lactams as single diastereoisomers in very good yield.
Keywords:
Ó 2010 Elsevier Ltd. All rights reserved.
Isoindolinones
Reductive amination
Methylthiomethyl ester
Lactamization
1. Introduction
bioisotere liable to undergo metabolic oxidation, but on substitution,
has shown to posses improved metabolic stability while retaining
functionality.8 Therefore, 3-substituted isoindolinones are also very
important class of molecules. Beside biological activities, a class of
isoindolinone was reported recently to have special fluorescent
properties.9 In addition, the isoindolinone skeleton frequently serves
as an indispensable building block for the synthesis of many natu-
rally occurring bioactive compounds.10
Consequently, the chemistry of isoindolinones has attracted
much attention, and a number of synthetic strategies have been
developed over the past few decades including conversion of
lactones to lactams,11 organometallic addition on imines and/or
reduction of phthalimides,12 amination and cyclization of 2-bro-
momethylbenzoyl esters,13 palladium catalyzed carbonylation of
amines or their derivatives,14 base-induced reaction of 2-halogeno-
N-(phosphorylmethyl)benzamide derivatives15 or 2-hydroxy-
methylbenzamide derivatives,16 and Parham-type cyclization of
isolated benzyl-dicarbamates.17
Isoindolinone (2,3-dihydro-1H-isoindolin-1-one) 1 (Fig. 1) is
a key structural feature found in many drugs of natural and synthetic
origin.1 For example, indoprofen 22 is shown to have anti-in-
flammatory activities while deoxythalidomide 33 is an inhibitor of
tumor necrosis factor production and tricyclic g
-lactam 44 is a non-
nucleosidic HIV reverse transcriptase inhibitor. Isoindolinone de-
rivatives are also known as 5-HT2C antagonists,5 and vasodilators.6
Both (R)- and (S)-3-alkyl substituted isoindolinones have been
shown to be valuable chiral auxiliaries.7 The 3-position of iso-
indolinone ring system is generally regarded as a benzylic alcohol
Isoindolinones of type 5 with heteroatomic substituents at
3-position have also been designed to be potent inhibitors for DNA
gyrase.18a Subsequently, they have been synthesized18 in moderate
to poor yields from o-phthaldehydic acid methyl ester by heating
with an amine and nucleophiles such as thiophenoxide, methoxide,
and HCN at elevated temperatures over a long period. Intramolecular
variation of this reaction to provide tricyclic lactams 6 (Scheme 1)
has also been achieved19 by heating o-phthaldehydic acid with
amino alcohols at elevated temperatures. These harsh conditions are
required to improve the reactivity of intermediate zwitterionic acid 7
(Scheme 1) to undergo condensation with expulsion of a water
Figure 1. Few examples of isoindolinone moiety present in various drugs.
* Corresponding author. Tel.: þ91 22 3081 8311; fax: þ91 22 3081 8036.
E-mail address: usha.ghosh@piramal.com (U. Ghosh).
0040-4020/$ – see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.01.070

U. Ghosh et al. / Tetrahedron 66 (2010) 2148–2155
2149
molecule. The other reason could be the slow rate of imine/imino
acetal formation because o-phthaldehydic acid 8/lactone 9 equi-
librium favors the formation of later. To overcome these drawbacks,
we have been studying a milder route. This can be achieved by tuned
activation of the carboxylic acid group that would stop lactol for-
mation and favor lactam formation. In this paper we describe our
studies toward the syntheses of diverse isoindolinones from
a o-phthaldehydic acid methylthiomethyl (MTM) ester, amines, and
nucleophiles including a hydride ion (Hꢀ) by a sequence of reactions
in one-pot involving amination and lactamization.
Reductive amination of aromatic aldehyde and ketone is well
known, which goes via Schiff’s base formation. Amongst the
plethora of reducing agents capable of reducing Schiff’s base, bo-
rohydride based reagents such as sodium cyanoborohydride and
sodium triacetoxyborohydride are frequently used. When aldehydic
MTM ester 12a was treated with 3,4-dimethoxyaniline (1.2 equiv) in
the presence of catalytic amount of acetic acid (40 mol %), it pro-
vided the intermediate Schiff’s base 13a. This on treatment with
sodium triacetoxyborohydride (1.5 equiv) underwent in situ re-
duction to intermediate amine 14a, which on intramolecular lac-
tamization directly gave the isoindolinone 1a (Scheme 3). Amongst
the various solvents we studied, chloroform gave the best result and
the reaction proceeded well at room temperature (28 ꢁC) to give the
product 1a in 90% yield. As mentioned earlier, isoindolinones of type
5 (Fig. 1) with heteroatom substituents at 3-position have been
synthesized18 from o-phthaldehydic acid methyl ester by heating
with an amine and nucleophiles at elevated temperature. It was,
therefore, necessary to check the efficiency of reductive amination–
lactamizationwith the methyl ester substrate. We prepared methyl-
2-formyl-4,5-dimethoxybenzoate
12b
from
corresponding
2-hydroxymethyl benzoic acid 11 by pyridinium chlorochromate
(PCC) oxidation followed by esterification with iodomethane23 in
the presence of base K2CO3 in 62% overall yield (Scheme 2). To
compare the relative reactivity, MTM ester 12a and methyl ester 12b
were separately reacted with 3,4-dimethoxy aniline (1.2 equiv) in
the presence of catalytic amount of AcOH (40 mol %) in CHCl3
(0.08 M) for 30 min. The resulting Schiff’s bases 13a and 13b
(Scheme 3) were then reacted with sodium triacetoxyborohydride
(1.5 equiv) at room temperature (28 ꢁC). We were gratified to note
that the reaction of MTM ester 12a/1a was complete within
30 min whereas the methyl ester 12b/1a required 6 h for com-
pletion. The isolated yield of isoindolinone 1a from the MTM ester
12a was very good (90%) while from the methyl ester 12b was 78%.
Time dependent 1H NMR experiment24 at 25 ꢁC also suggested that
in case of MTM ester 12a, the rate determining step is the reduction
of the imine 13a while the slowest step in case of methyl ester 12b is
the intramolecular lactamization of the intermediate benzylamine
14b. It is worthwhile to note that the rate of lactamization of benzyl
amine MTM ester 14a is >50 times24 faster than the corresponding
methyl ester 14b.
Scheme 1. Reaction of o-phthaldehydic acid with amino alcohols via zwitterionic acid
intermediate 7.
2. Results and discussion
We have recently reported20 an efficient method for the syn-
thesis of MTM esters from the corresponding acids under Swern
oxidation conditions wherein substituted 2-hydroxymethyl ben-
zoic acid2111, obtained from corresponding lactone 10, gave meth-
ylthiomethyl-2-formyl-4,5-dimethoxy benzoate 12a in 72% yield
(Scheme 2). We anticipated that this ester would be ideal starting
material for isoindolinone synthesis by carrying out a reductive
amination on the aldehyde functionality, which would then un-
dergo intramolecular cyclization with the MTM ester group. The
MTM group has double advantages because it is known to be
a moderately activating group for amidation of acids and also
compatible with mild reducing agent22 needed for reductive ami-
nation to give the lactam 1.
Scheme 3. Proposed mechanism for the preparation of isoindolinones from corre-
sponding aniline and MTM/methyl esters 12a/12b via reductive amination.
To establish the generality of the MTM ester mediated re-
ductive amination–lactamization process, a few substituted ani-
lines were reacted with the aldehyde MTM ester 12a under
reductive amination conditions in chloroform to give the
Scheme 2. Preparation of MTM and methyl esters of 2-formyl-4,5-dimethoxybenzoic
acid.

2150
U. Ghosh et al. / Tetrahedron 66 (2010) 2148–2155
corresponding isoindolinones as shown in Table 1. In few cases
with anilines having electron withdrawing substituents (Table 1,
entries 2–5), the Schiff’s base formation was very slow at room
temperature hence required heating at 40 ꢁC. The reaction is not
restricted to aniline derivatives. Aliphatic amine such as cyclo-
hexylamine or phenylalanine (Table 1, entries 6, 7) reacted at
a much faster rate at room temperature to give the desired
product in excellent yield.
We next turned our attention to the synthesis of 3-hetero-
atom substituted isoindolinone derivatives. In the reductive
amination–lactamization sequence as described above, the hy-
dride (Hꢀ) nucleophile added to the imine bond (C]N) of the
Schiff’s base 13a. We were therefore curious to know if other
nucleophiles can be engaged for this purpose. We first tried with
a thiol nucleophile. Therefore, when a mixture of MTM ester 12a
and 3-chloro-4-methylaniline was stirred at 40 ꢁC in the
presence of catalytic amount of acetic acid in chloroform fol-
lowed by addition of 2-mercaptophenol and heating at 40 ꢁC for
1 h provided the 3-thioaryl substituted isoindolinone 5a in
moderate yield (Scheme 4). The reaction took place smoothly
even with electronically deactivated 4-cyanoaniline to give
3-subsituted isoindolinone 5b, although slightly longer (3 h) re-
action time was needed. The cyanide ion (CNꢀ) also underwent
smooth nucleophilic addition. When the Schiff’s base was made
by the reaction of MTM ester 12a with 3,4-dimethoxybenzyl-
amine at room temperature and reacted with aqueous-THF
solution of sodium cyanide at 60 ꢁC, it gave the 3-cyanosubsi-
tuted isoindolinone 5c (Scheme 4) in good yield.
Table 1
Synthesis of isoindolin-1-ones from MTM ester 12a and aminesa
Entry Amine (1.2 equiv)
Product
Tempb Yieldc
(ꢁC)
(%)
1
28d
90e
2
3
40f
40f
79g
Scheme 4. Synthesis of 3-substituted isoindolinones using various nucleophiles.
We intended to apply our strategy with MTM ester 12a and
amines with an integrated nucleophile to make tricyclic lactams
of type 6. As mentioned earlier, synthesis of such lactams has
been achieved19,25 by heating o-phthaldehydic acid with amino
alcohols at high temperatures over long time. When MTM ester
12a was treated with 1,2-ethylenediamine (1.2 equiv) at room
temperature, a clean reaction took place to give the tricyclic
88g
4
40f
96h
g
-lactam 6a in excellent yield (Table 2, entry 1). Thiol containing
nucleophiles viz. 2-aminothioethanol, (R)-cysteine ethyl ester
(Table 2, entries 2 and 3) also gave the tricyclic heterocycles 6b
and 6c with great ease at 0 ꢁC. Interestingly, 6c was formed as
a single diastereoisomer only. Amino alcohols derived from chiral
amino acids viz. (S)-leucinol and (S)-phenylalaninol also reacted
intramolecularly to give the tricyclic lactams 6d and 6e (Table 2,
entries 4 and 5) again as single diastereoisomers as confirmed by
HPLC analyses as well as 1H NMR of the crude products. Slightly
higher temperature (60 ꢁC) was required for these amino alco-
hols to drive the reaction to completion because of relatively
lower nucleophilicity of the OH group compared to NH2 or SH
groups. The trans stereochemistry of the (S)-leucinol derived
product 6d (Table 2, entry 4) was confirmed from 1H–1H NOESY
interactions.
5
6
40f
85h
28d
88e
7
28d
75e
a
The reaction of aldehyde 12a with the amine containing an in-
tegrated nucleophile first forms the intermediate imine 15
(Scheme 5). Intramolecular addition of the nucleophilic group to
the imine then results in the reversible formation of iminoacetals
trans-16 and cis-16. The exclusive formation19a of single di-
astereoisomeric tricyclic lactams 6 can be explained on the basis of
easy ring formation for the thermodynamically favored trans
The reactions were carried out in chloroform.
Temperature for the formation of the Schiff’s base.
Yield of the isolated product after chromatography/crystallization.
Schiff’s base formation time 0.5 h.
Reduction and cyclization time 0.5 h.
Schiff’s base formation time 2 h.
b
c
d
e
f
g
h
Reduction and cyclization time 4 h.
Reduction and cyclization time 6 h.

U. Ghosh et al. / Tetrahedron 66 (2010) 2148–2155
2151
Table 2
Synthesis of tricyclic
nucleophilesa
where the reactive functional groups (–CO2CH2SMe and –NH–) can
come closer. The reversibility of the iminoacetal cis-16 to imine 15
then follows Curtin–Hammett principle thus channelizes imino-
acetal cis-16 to trans-16 and finally to the trans product 6 (Scheme
5) as a single diastereoisomer.
g-lactams from MTM ester 12a and amines integrated with
At this stage, we were keen to see if we can make 3-
unsubstituted isoindolinones with amines containing a nucleo-
philic substituent under reductive amination conditions. We
were delighted to note that when MTM ester 12a was treated
with ethanolamine at room temperature followed by sodium
triacetoxyborohydride, a clean reaction took place to give the 3-
unsubstituted isoindolinone 1h in good yield (Table 3, entry 1).
Similarly, (S)-leucinol and (S)-phenylalaninol also gave the de-
sired products 1i and 1j, respectively. Amines with another
amino substituent such as ethylene diamine gave an interesting
product 1k due to reaction with two molecules of 12a at 0 ꢁC.
The formation of the dimer 1k even took place in the presence
of excess of ethylene diamine. The optimized conditions were to
use 2 equiv of MTM ester 12a per diamine that gave 1k in ex-
cellent yield (Table 3, entry 4). It is imperative to mention that
for the ethylene diamine case, low temperature (0 ꢁC) is critical.
Above this, variable amount of 6a formation was observed.
Entry
Amine/
nucleophile
(1.2 equiv)
Product
Temp
(ꢁC)/
time
Yieldb
(%)
1
28/1 h 94
2
3
4
0/2 h
0/3 h
92
79
Table 3
Synthesis of 3-unsubstituted isoindolinones from MTM ester 12a and amines con-
taining a nucleophilic substituenta
60/4.5 h 86
60/4.5 h 80
Entry
Amine
Product
Tempb Yieldc
(ꢁC)
(%)
5
1
28d
78e
a
The reactions were carried out in chloroform.
Yield of the isolated product after chromatography/crystallization.
b
product. The simple molecular model building shows that the
trans-diastereoisomer 6 adopts a ‘bowl-like’ shape, with the bulky
alkyl substituent disposed on the less hindered convex face of the
fused 5,5-bicyclic system. On the other hand, the cis-diaster-
oisomer 17 where the alkyl substituent has to be disposed on the
congested concave face won’t allowa transition state conformation
2
3
28f
74g
28f
74h
4
0d
56e,i
a
The reactions were carried out in chloroform.
b
c
d
e
f
Temperature for the formation of the Schiff’s base.
Yield of the isolated product after chromatography/crystallization.
Schiff’s base formation time 15 min.
Reduction time 2 h.
Schiff’s base formation time 0.5 h.
Reduction time 3 h.
g
h
i
Reduction time 4 h.
Yield 94% when 2 equiv of MTM ester 12a was used.
Scheme 5. Proposed synthetic steps for synthesis of tricyclic g-lactams using amines
with integrated nucleophiles.

2152
U. Ghosh et al. / Tetrahedron 66 (2010) 2148–2155
3. Conclusion
dissolved in ether and washed with water. The organic extract was
dried over anhydrous sodium sulfate and evaporated under re-
duced pressure. The residue was purified by silica gel column
chromatography (10% EtOAc/hexane) to give 12b (0.325 g, 85%; 62%
overall) as solid. Mp 99–101 ꢁC; dH (300 MHz, CDCl3) 10.67 (1H, s),
7.53 (1H, s), 7.48 (1H, s), 4.02 (3H, s), 4.01 (3H, s), 3.99 (3H, s); dC
(75 MHz, CDCl3) 191.4, 166.5, 152.6, 152.2, 131.5, 126.2, 112.8, 109.8,
56.6, 56.5, 52.8; m/z (ESI): 247 [MþNa]þ.
We have developed a new, mild, and efficient method for the
synthesis of diversely substituted isoindolinones based on readily
available precursors. The synthetic potential of this method is fur-
ther demonstrated by the synthesis of 3-unsubstituted iso-
indolinones and fused tricyclic
in very good yield.
g-lactams as single diastereoisomers
4. Experimental section
4.4. GeneralprocedureI. Preparationofisoindolin-1-one(1a–1g)
4.1. Materials and methods
In a typical procedure, the amine (2.4 mmol) was added to
a solution of MTM ester 12a (0.541 g, 2.0 mmol) in chloroform
(25 mL) under N2 atmosphere. Acetic acid (0.05 mL, 0.85 mmol)
was added to the reaction mixture and stirred at 28 ꢁC/40 ꢁC for
0.5–2 h followed by addition of sodium triacetoxyborohyride
(0.636 g, 3.0 mmol). After 0.5–6 h at 28 ꢁC, the reaction mixture
was quenched with water (25 mL) and extracted with chloroform
(100 mL). The combined extract was washed with water (50 mL)
and with brine (50 mL), dried (Na2SO4) and evaporated. The residue
was purified by silica gel column chromatography (20% EtOAc/
hexane)/crystallization to give pure 1a–1g.
All reactions were performed in oven-dried (120 ꢁC) or flame-
dried glass apparatus under dry N2 or argon atmosphere. Solvents
were obtained from commercial sources and purified further by
distillation before use. Reagents were purchased from Aldrich/
Fluka and used as such. The column chromatography was per-
formed on silica gel (200–300 mesh). 1H NMR and 13C NMR spectra
were recorded with Bruker 200/300 MHz spectrometers. 1H–1H
NOESY spectra were recorded with Bruker 500 MHz spectrometer.
Spectra were referenced to residual chloroform (d
7.25 ppm, 1H;
77.16 ppm, 13C). High resolution mass spectra were recorded at with
Bruker Daltonics Micro TOF-Q spectrometer (ESI, N2). Melting
points (mp) were determined on a LABINDIA melting range appa-
ratus MR-VIS and are uncorrected. Optical rotations were taken
relative to sucrose on Perkin Elmer 341 Polarimeter. Methyl 2-for-
myl-4,5-dimethoxybenzoate 12b was prepared following the lit-
erature procedure.23
4.4.1. 2-(3,4-Dimethoxyphenyl)-5,6-dimethoxyisoindolin-1-one
(1a). Yield: 0.59 g, 90%; Rf (50% EtOAc/hexane) 0.32; solid, mp 171–
173 ꢁC; dH (300 MHz, CDCl3) 7.83 (1H, d, J¼2.1 Hz, Ar), 7.35 (1H, s,
Ar), 6.99 (1H, dd, J¼2.1, 8.7 Hz, Ar), 6.96 (1H, s, Ar), 6.88 (1H, d,
J¼8.7 Hz, Ar), 4.74 (2H, s, NCH2–), 3.97 (3H, s, OMe), 3.96 (3H, s,
OMe), 3.94 (3H, s, OMe), 3.89 (3H, s, OMe); dC (75 MHz, CDCl3)
167.8, 153.2, 150.1, 149.3, 146.0, 133.9, 133.6, 125.7, 111.4, 111.0, 105.5,
104.8 (2C), 56.4, 56.4, 56.2, 56.1, 51.0; HRMS (ESI): MHþ, found
330.1311. C18H20NO5 requires 330.1336.
4.2. Methylthiomethyl-2-formyl-4,5-dimethoxy-
benzoate (12a)
This compound was also prepared from 12b and 3,4-dime-
thoxyaniline as follows. 3,4-Dimethoxyaniline (0.368 g, 2.4 mmol)
was added to a solution of methyl ester 12b (0.448 g, 2.0 mmol) in
chloroform (25 mL) under N2 atmosphere. Acetic acid (0.05 mL,
0.85 mmol) was added to the reaction mixture and stirred at 28 ꢁC
for 0.5 h followed by addition of sodium triacetoxyborohyride
(0.636 g, 3.0 mmol). After 6 h at 28 ꢁC, the reaction mixture was
quenched with water (25 mL) and extracted with chloroform
(100 mL). The combined extract was washed with water (50 mL)
and with brine (50 mL), dried (Na2SO4) and evaporated. The residue
was purified by silica gel column chromatography (20% EtOAc/
hexane) to give pure 1a (0.515 g, 78%).
A solution of DMSO (8.5 mL, 120.6 mmol) in dichloromethane
(150 mL) was added drop-wise to a stirred solution of oxalyl
chloride (7.2 mL, 83 mmol) in dichloromethane (150 mL) at ꢀ60 to
ꢀ65 ꢁC under nitrogen. After 5 min, solid 2-(hydroxymethyl)-4,5-
dimethoxybenzoic acid21 (8.0 g, 37.7 mmol) was added to the
reaction mixture and stirring was continued for 15 min. Triethyl-
amine (26.0 mL, 188.5 mmol) was added drop-wise to the reaction
mixture and was allowed to attain room temperature. The reaction
mixture was diluted with dichloromethane (250 mL), washed with
water (100 mL) and with brine (75 mL). The organic extract was
dried over anhydrous sodium sulfate and evaporated under re-
duced pressure. The residue was purified by silica gel column
chromatography (10% EtOAc/hexane) to give 12a (7.3 g, 72%) as
solid. Mp 90–92 ꢁC; dH (300 MHz, CDCl3) 10.68 (1H, s, CHO), 7.53
(1H, s, Ar), 7.49 (1H, s, Ar), 5.46 (2H, s, –OCH2SMe), 4.02 (3H, s,
OMe), 4.01 (3H, s, OMe), 2.35 (3H, s, SMe); dC (75 MHz, CDCl3) 191.0,
165.5, 152.4, 152.2, 131.4, 125.6, 112.6,109.7, 69.8, 56.4, 56.3, 15.9; m/z
(ESI): 271 [MþH]þ.
4.4.2. 4-(5,6-Dimethoxy-1-oxoisoindolin-2-yl)benzonitrile
(1b). Yield: 0.464 g, 79%; Rf (50% EtOAc/hexane) 0.35; solid, mp
238–239 ꢁC; dH (300 MHz, CDCl3) 8.00 (2H, d, J¼8.7 Hz, Ar), 7.68
(2H, d, J¼8.7 Hz, Ar), 7.34 (1H, s, Ar), 6.97 (1H, s, Ar), 4.77 (2H, s,
NCH2–), 3.96 (3H, s, OMe), 3.98 (3H, s, OMe); dC (75 MHz, CDCl3)
168.4, 154.2, 150.4, 143.7, 133.9, 133.5 (2C), 124.8, 119.1, 118.3 (2C),
106.6, 105.7, 104.7, 56.5, 50.0, 29.8; HRMS (ESI): MHþ, found
295.1082. C17H15N2O3 requires 295.1077.
4.3. Methyl 2-formyl-4,5-dimethoxybenzoate (12b)
Solid 2-(hydroxymethyl)-4,5-dimethoxybenzoic acid21 (0.5 g,
2.35 mmol) was added to a stirred suspension of pyridinium
chlorochromate (PCC) (0.8 g, 3.7 mmol) in dichloromethane
(10 mL) at room temperature. After 1 h, the reaction mixture was
diluted with ether and the reaction mixture was passed through
a Celite column. The eluent was evaporated to give the crude al-
dehydic acid (0.360 g, 73%) as an unstable material. Following the
literature procedure,23 a solution of this acid (0.360 g, 1.7 mmol)
and iodomethane (0.2 mL, 3.2 mmol) in acetone (6 mL) was stirred
over anhydrous potassium carbonate (0.71 g, 5.1 mmol) at room
temperature over 3 h. The reaction mixture was filtered and the
filtrate was evaporated under reduced pressure. The residue was
4.4.3. 2-(4-Acetylphenyl)-5,6-dimethoxyisoindolinon-1-one
(1c). Yield: 0.545 g, 88%; Rf (2% MeOH/CHCl3) 0.35; solid, mp 245–
247 ꢁC; dH (300 MHz, CDCl3) 7.94–8.02 (4H, m, Ar), 7.33 (1H, s, Ar),
6.96 (1H, s, Ar), 4.78 (2H, s, NCH2–), 3.98 (3H, s, OMe), 3.96 (3H, s,
OMe), 2.59 (3H, s, MeCO); dC (75 MHz, CDCl3) 197.1, 168.2, 153.9,
150.3, 144.1, 134.0, 132.4, 129.9 (2C), 125.1, 117.8 (2C), 105.6, 104.7,
56.5, 56.4, 50.2, 26.6; HRMS (ESI): MHþ, found 312.1225. C18H18NO4
requires 312.1230.
4.4.4. 4-(5,6-Dimethoxy-1-oxoisoindolin-2-yl) benzoic acid (1d). Yield:
0.601 g, 96%; Rf (5% MeOH/CHCl3) 0.21; solid, mp 315–318 ꢁC
(decomp.); dH (300 MHz, CDCl3) 12.77 (1H, s, CO2H), 7.94–8.02 (4H,

U. Ghosh et al. / Tetrahedron 66 (2010) 2148–2155
2153
m, Ar), 7.23 (1H, s, Ar), 7.22 (1H, s, Ar), 4.92 (2H, s, NCH2–), 3.87 (3H,
s, OMe), 3.83 (3H, s, OMe); dC (75 MHz, CDCl3) 167.9, 167.5, 153.98,
150.2, 144.2, 135.5, 131.0 (2C), 125.8, 124.4, 118.3 (2C), 106.3, 105.6,
56.7, 56.4, 50.4; HRMS (ESI): MHþ, found 314.1032. C17H16NO5 re-
quires 314.1023.
MeOH/CHCl3) 0.48; solid, mp 192–197 ꢁC; dH (300 MHz, CDCl3):
7.87 (2H, d, J¼8.4 Hz, Ar), 7.75 (2H, d, J¼8.4 Hz, Ar), 7.16 (1H, t,
J¼7.5 Hz, Ar), 7.12 (1H, s, Ar), 7.09 (1H, s, Ar), 6.75–6.71 (2H, m,
Ar), 6.61 (1H, t, J¼7.5 Hz, Ar), 6.23 (1H, s, OH), 5.89 (1H, s, SCHN),
4.03 (3H, s, OMe), 3.91 (3H, s, oMe); dC (75 MHz, CDCl3) 166.6,
157.9, 154.2, 151.1, 140.8, 136.7, 135.4, 133.2 (2C), 132.9, 123.5,
121.7 (2C), 120.7, 118.9, 115.4, 111.5, 108.0, 105.1 (2C), 65.7, 56.7,
56.5; HRMS (ESI): MHþ, found 419.1019. C23H19N2O4S requires
419.1060.
4.4.5. 2-(3-Chloro-4-methylphenyl)-5,6-dimethoxyisoindolin-1-one
(1e). Yield: 0.541 g, 85%; Rf (50% EtOAc/hexane) 0.23; Solid, mp 212–
214 ꢁC; dH (300 MHz, CDCl3) 7.81 (1H, d, J¼2.1 Hz, Ar), 7.67 (1H, dd,
J¼2.1, 8.4 Hz, Ar), 7.32 (1H, s, Ar), 7.23 (1H, d, J¼8.4 Hz, Ar), 6.94 (1H,
s, Ar), 4.69 (2H, s, NCH2–), 3.97 (3H, s, OMe), 3.95 (3H, s, OMe), 2.35
(3H, s, Me); dC (75 MHz, CDCl3) 167.8,153.5,150.2,138.7,134.8,133.9,
131.6, 131.3, 125.3, 119.5, 117.4, 105.6, 104.7, 56.4 (2C), 50.4, 19.6;
HRMS (ESI): MHþ, found 318.0873. C17H17ClNO3 requires 318.0891.
4.5.3. 2-(3,4-Dimethoxybenzyl)-5,6-dimethoxy-3-oxoisoindoline-1-
carbonitrile (5c). 3,4-Dimethoxy benzylamine (0.198 g, 1.2 mmol)
was added to a solution of MTM ester 12a (0.27 g, 1.0 mmol) in
chloroform (10 mL) under N2 atmosphere. Acetic acid (25 mL,
0.42 mmol) was added to the reaction mixture and stirred at
28 ꢁC for 1 h. The reaction mixture was concentrated under re-
duced pressure and a solution of NaCN (0.059 g, 1.2 mmol) in 1/1
THF/H2O (30 mL) was added into it. After 3 h at 60 ꢁC, THF was
evaporated under reduced pressure and the reaction mixture was
quenched with dil HCl (0.3 M, 10 mL). The mixture was extracted
with chloroform (150 mL) and the extract was washed with
water (50 mL) and with brine (50 mL), dried (Na2SO4), and
evaporated. The residue was purified by silica gel column chro-
matography (40% EtOAc/hexane) to give pure 5c (0.265 g, 72%) as
solid; Rf (5% MeOH/CHCl3) 0.51; mp 127–129 ꢁC; dH (300 MHz,
CDCl3) 7.32 (1H, s, Ar), 7.28 (1H, s, Ar), 6.92 (2H, d, J¼8.1 Hz, Ar),
6.82 (1H, dd, J¼1.8, 8.1 Hz, Ar), 5.65 (1H, s, CHCN), 4.89 (1H, d,
J¼15.0 Hz, ArCHaHb), 4.44 (1H, d, J¼15.3 Hz, ArCHaHb), 3.90 (3H, s,
OMe), 3.85 (3H, s, OMe), 3.72 (3H, s, OMe), 3.71 (3H, s, OMe); dC
(75 MHz, CDCl3) 166.9, 153.3, 150.8, 148.9, 148.5, 131.2, 128.5,
122.7, 120.4, 116.3, 111.9 (2C), 106.1, 105.4, 56.2, 56.0, 55.5, 55.5,
49.1, 44.8; HRMS (ESI): MNaþ, found 391.1247. C20H20N2O5Na
requires 391.1264.
4.4.6. 2-Cyclohexyl-5,6-dimethoxyisoindolin-1-one
(1f). Yield:
0.487 g, 88%; Rf (50% EtOAc/hexane) 0.14; Solid, mp 136–138 ꢁC; dH
(300 MHz, CDCl3) 7.31 (1H, s, Ar), 6.91 (1H, s, Ar), 4.26 (2H, s, NCH2-
), 4.17–4.21 (1H, m, NCH), 3.93 (6H, s, 2ꢂOMe), 1.84–1.86 (4H, m,
cyclohexyl), 1.67–1.74 (1H, m, cyclohexyl), 1.38–1.53 (4H, m,
cyclohexyl),1.16–1.21 (1H, m, cyclohexyl); dC (75 MHz, CDCl3) 167.7,
151.8, 149.1, 134.3, 125.2, 104.8, 104.5, 55.8 (2C), 50.1, 45.2, 31.1 (2C),
25.2 (3C); HRMS (ESI): MHþ, found 276.1611. C16H22NO3 requires
276.1594.
4.4.7. (S)-Methyl-2-(5,6-dimethoxy-1-oxoindolin-2-yl)-3-phenyl-
propanoate (1g). Yield: 0.53 g, 75%; Rf (50% EtOAc/hexane) 0.34;
20
Solid, mp 138–139 ꢁC; [
a
]
ꢀ72.17 (c 2.3, CHCl3); dH (300 MHz,
D
CDCl3) 7.35 (1H, s, Ar), 7.22–7.14 (5H, m, Ph), 6.86 (1H, s, Ar), 5.36
(1H, dd, J¼5.7, 10.5 Hz, PhCH2CH), 4.42 (1H, d, J¼16.2 Hz, NCHaHb),
4.26 (1H, d, J¼16.2 Hz, NCHaHb), 3.91 (3H, s, OMe), 3.90 (3H, s,
OMe), 3.71 (3H, s, CO2Me), 3.47 (1H, dd, J¼5.7, 14.7 Hz, PhCHaHb),
3.17 (1H, dd, J¼10.5, 14.7 Hz, PhCHaHb); dC (75 MHz, CDCl3) 171.1,
168.8, 152.3, 149.2, 136.0, 134.9, 128.2 (2C), 128.1 (2C), 126.5, 123.6,
105.0, 104.5, 55.7 (2C), 54.2, 51.9, 46.8, 35.4; HRMS (ESI): MHþ,
found 356.1478. C20H22NO5 requires 356.1492.
4.6. General procedure III. Preparation of tricyclic
g-lactams (6a–6e)
4.5. General procedure II. Preparation of 3-substituted
isoindolinones (5a and 5b)
In a typical procedure, the required nucleophile attached amine
(2.4 mmol) was added to a solution of MTM ester 12a (0.541 g,
2.0 mmol) in chloroform (25 mL) under N2 atmosphere. Acetic acid
(0.05 mL, 0.85 mmol) was added to the reaction mixture and stirred
at 0–28 ꢁC for 1–3 h. In the case of (S)-leucinol and (S)-phenyl-
alaninol, the reaction mixture was refluxed at 60 ꢁC for 4–5 h. The
reaction mixture was quenched with water (25 mL) and extracted
with chloroform (100 mL). The combined extract was washed with
water (50 mL) and with brine (50 mL), dried (Na2SO4), and evapo-
rated. The residue was purified by silica gel column chromatogra-
phy (EtOAc/hexane) to give pure 6a–6e.
In a typical procedure, the required amine (2.4 mmol) was
added to a solution of MTM ester 12a (0.541 g, 2.0 mmol) in chlo-
roform (25 mL) under N2 atmosphere. Acetic acid (0.05 mL,
0.85 mmol) was added to the reaction mixture and stirred at 40 ꢁC
for 1–3 h followed by addition of the required thiol (3.0 mmol).
After 6 h at 40 ꢁC, the reaction mixture was quenched with water
(25 mL) and extracted with chloroform (100 mL). The combined
extract was washed with water (50 mL) and with brine (50 mL),
dried (Na2SO4), and evaporated. The residue was purified by silica
gel column chromatography (EtOAc/hexane) to give pure 5a and 5b.
4.6.1. 7,8-Dimethoxy-[1,2,3,9b]-tetrahydro-imidazo-[2,1-a]-isoindol-
5-one (6a). Yield: 0.44 g, 94%; Rf (5% MeOH/CHCl3) 0.23; solid, mp
212–217 ꢁC; dH (300 MHz, CDCl3) 7.24 (1H, s, Ar), 7.08 (1H, s, Ar),
5.24 (1H, s, NCHN), 3.95 (3H, s, OMe), 3.93 (3H, s, OMe), 3.72–3.62
(1H, m, NCHaHb), 3.59–3.54 (1H, m, NCHaHb), 3.51–3.42 (1H, m,
NHCHaHb), 3.34–3.28 (1H, m, NHCHaHb), 2.16 (1H, s, NH); dC
(75 MHz, CDCl3) 166.1, 146.0, 143.9, 129.9, 119.1, 98.7, 98.6, 71.9, 49.2
(2C), 44.4, 35.8; HRMS (ESI): MHþ, found 235.1089. C12H15N2O3
requires 235.1077.
4.5.1. 2-(3-Chloro-4-methyl-phenyl)-3-(2-hydroxy-phenylsulfanyl)-
5,6-dimethoxy-2,3-dihydro-isoindol-1-one (5a). Yield: 0.601 g, 68%;
Rf (5% MeOH/CHCl3) 0.45; solid, mp 169–171 ꢁC; dH (300 MHz,
CDCl3) 7.62 (1H, d, J¼1.5 Hz, Ar), 7.47 (1H, dd, J¼1.5, 8.4 Hz, Ar), 7.31
(1H, d, J¼8.4 Hz, Ar), 7.15 (1H, d, J¼7.8 Hz, Ar), 7.13 (1H, s, Ar), 7.06
(1H, s, Ar), 6.84 (1H, d, J¼7.5 Hz, Ar), 6.75 (1H, d, J¼8.1 Hz, Ar), 6.62
(1H, t, J¼7.5 Hz, Ar), 6.15 (1H, s, OH), 6.03 (1H, s, SCHN), 4.00 (3H, s,
OMe), 3.89 (3H, s, OMe), 2.40 (3H, s, Me); dC (75 MHz, CDCl3) 166.4,
157.8, 153.6, 150.8, 136.7, 135.4, 135.3, 134.8, 133.3, 132.6, 131.3,
124.0, 123.2, 121.1, 120.6, 115.3, 112.3, 105.3, 105.1, 66.7, 56.6, 56.4,
19.8; HRMS (ESI): MHþ, found 442.0846. C23H21ClNO4S requires
442.0874.
4.6.2. 7,8-Dimethoxy-2,3-dihydrothiazolo[2,3-a]isoindol-5(9bH)-one
(6b). Yield: 0.462 g, 92%; Rf (50%EtOAc/hexane) 0.20; solid, mp
123–128 ꢁC; dH (300 MHz, DMSO-d6) 7.26 (1H, s, Ar), 7.16 (1H, s, Ar),
5.92 (1H, s, SCHN), 4.17–4.09 (1H, m, NCHaHb), 3.85 (3H, s, OMe),
3.83 (3H, s, OMe), 3.44–3.33 (3H, m, NCH2, NCHaHb); dC (75 MHz,
DMSO-d6) 171.2, 153.6, 150.6, 139.9, 122.8, 107.0, 105.8, 66.1, 56.5,
4.5.2. 4-[1-(2-Hydroxy-phenylsulfanyl)-5,6-dimethoxy-3-oxo-1,3-di-
hydro-isoindol-2-yl]-benzonitrile (5b). Yield: 0.544 g, 65%; Rf (5%

2154
U. Ghosh et al. / Tetrahedron 66 (2010) 2148–2155
56.3, 44.9, 36.5; HRMS (ESI): MHþ, found 252.0689. C12H14NO3S
requires 252.0689.
CDCl3) 7.28 (1H, s, Ar), 6.89 (1H, s, Ar), 4.44–4.40 (1H, m, NCH), 4.37
(1H, d, J¼16.8 Hz, ArCHaHbN), 4.24 (1H, d, J¼16.8 Hz, ArCHaHbN),
3.93 (3H, s, OMe), 3.92 (3H, s, OMe), 3.83 (1H, dd, J¼3.9, 11.4 Hz,
CHaHbOH), 3.75–3.68 (1H, dd, J¼3.9, 11.4 Hz, CHaHbOH), 2.86 (1H, s,
OH), 1.60–1.69 (1H, m, Me2CH), 1.40–1.57 (2H, m, Me2CHCH2), 0.96
(3H, d, J¼6.0 Hz, MeCH), 0.92 (3H, d, J¼6.3 Hz, MeCH); dC (75 MHz,
CDCl3) 170.2, 152.6, 149.7, 135.1, 125.1, 105.4, 105.0, 64.8, 56.3 (2C),
52.7, 47.0, 38.2, 25.0, 23.4, 22.2; HRMS (ESI): MHþ, found 294.1711.
C16H24NO4 requires 294.1700.
4.6.3. (3R)-Ethyl 7,8-dimethoxy-5-oxo-[2,3,5,9b]-tetrahydrothiazolo-
[2,3-a]-isoindole-3-carboxylate (6c). Yield: 0.51 g, 79%; Rf (50%
27
EtOAc/hexane) 0.26; Thick gum; [
a
]
ꢀ259.1 (c 1.02, CHCl3); dH
D
(300 MHz, CDCl3) 7.28 (1H, s, Ar), 6.95 (1H, s, Ar), 6.03 (1H, s, SCHN),
5.23 (1H, dd, J¼4.5, 6.9 Hz, NCHCO), 4.33 (1H, dd, J¼1.5, 7.2 Hz,
SCHaHb), 4.28 (1H, dd, J¼1.5, 7.2 Hz, SCHaHb), 3.99 (3H, s, OMe), 3.95
(3H, s, OMe), 3.62 (2H, q, J¼7.2 Hz, CO2CH2Me), 1.33 (3H, t, J¼7.2 Hz,
CO2CH2Me); dC (75 MHz, CDCl3) 171.2, 170.3, 154.0, 150.8, 139.5,
122.7,106.0,105.3, 66.4, 62.2, 58.1, 56.5, 56.4, 39.7,14.3; HRMS (ESI):
MNaþ, found 346.0715. C15H17NO5SNa requires 346.0720.
4.7.3. (S)-2-(1-Hydroxy-3-phenylpropan-2-yl)-5,6-dimethoxy-
isoindolin-1-one (1j). Yield: 0.485 g, 74%; Rf (5% MeOH/CHCl3) 0.30;
20
solid, mp 163–165 ꢁC; [
a]
ꢀ113.4 (c 2.0, CHCl3); dH (300 MHz,
D
CDCl3)7.23–7.13(5H, m, Ph), 7.11(1H, s,Ar), 7.06(1H, s, Ar), 4.90(1H, t,
J¼5.4 Hz, OH), 4.49–4.39 (1H, m, NCH), 4.32 (1H, d, J¼17.4 Hz,
ArCHaHbN), 4.23 (1H, d, J¼17.4 Hz, ArCHaHbN), 3.79 (3H, s, OMe), 3.76
(3H, s, OMe), 3.66–3.56 (2H, m, CH2OH), 3.01–2.83 (2H, m, PhCH2); dC
(75 MHz, CDCl3) 167.8,152.0,149.1,138.7,135.3,128.7 (2C),128.2 (2C),
126.1,124.5,106.0,104.7, 62.0, 55.8, 55.7, 54.4, 46.4, 34.9; HRMS (ESI):
MHþ, found 328.1524. C19H22NO4 requires 328.1543.
4.6.4. (3S)-3-Isobutyl-7,8-dimethoxy-2,3-dihydro-9bH-oxazolo[2,3-
a]isoindol-5-one (6d). Yield: 0.5 g, 86%; Rf (50% EtOAc/hexane)
24
0.32; solid, mp 102–104.5 ꢁC; [
a
]
þ63.5 (c 0.95, CHCl3); dH
D
(300 MHz, CDCl3) 7.23 (1H, s, Ar), 7.07 (1H, s, Ar), 5.81 (1H, s,
OCHN), 4.45 (1H, dd, J¼6.9, 8.4 Hz, OCHaCHb), 4.21–4.16 (1H, m,
NCH), 3.97 (3H, s, OMe), 3.95 (3H, s, OMe), 3.84 (1H, dd, J¼6.3,
8.4 Hz, OCHaCHb), 1.89–1.84 (1H, m, Me2CH), 1.74–1.65 (1H, m,
NCHCHaCHb), 1.42–1.33 (1H, m, NCHCHaCHb), 1.08 (3H, d, J¼6.3 Hz,
MeCH), 1.01 (3H, d, J¼6.6 Hz, MeCH); dC (75 MHz, CDCl3) 174.7,
153.9, 151.8, 136.8, 126.0, 106.3, 106.2, 90.8, 56.8, 56.8, 54.1 (2C),
44.1, 26.2, 23.6, 22.7; HRMS (ESI): MNaþ, found 314.1354.
C16H20NO4 Na requires 314.1363.
4.7.4. 2,20-(Ethane-1,2-diyl)bis(5,6-dimethoxyisoindolin-1-one)
(1k). Yield: 0.231 g, 56%; Rf (5% MeOH/CHCl3) 0.25; solid, mp
265.5–273 ꢁC; dH (300 MHz, CDCl3) 7.19 (2H, s, Ar), 6.92 (2H, s, Ar),
4.44 (4H, s, ArCH2N), 3.94 (4H, s, CCH2CH2N), 3.92 (6H, s, 2ꢂOMe),
3.89 (6H, s, 2ꢂOMe); dC (75 MHz, CDCl3) 168.8 (2C),152.1 (2C),149.1
(2C), 134.6 (2C), 123.9 (2C), 104.7 (4C), 55.7 (4C), 49.1 (2C), 39.9
(2C); HRMS (ESI): MHþ, found 413.1723. C22H25N2O6 requires
413.1707. This compound was also prepared using 2 equiv of MTM
4.6.5. (3S)-3-Benzyl-7,8-dimethoxy-2,3-dihydro-9bH-oxazolo[2,3-
a]isoindol-5-one (6e). Yield: 0.522 g, 80%; Rf (50% EtOAc/hexane)
23
0.31; solid, mp 184–186 ꢁC;
[a
]
þ61.8 (c 1.03, CHCl3); dH
ester 12a as follows. Ethylenediamine (125 mL, 2 mmol) was added
D
(300 MHz, CDCl3) 7.36–7.27 (5H, m, Ph), 7.25 (1H, s, Ar),7.05 (1H, s,
Ar), 5.72 (1H, s, OCHN), 4.49–4.41 (1H, m, NCH), 4.31 (1H, dd, J¼6.9,
8.7 Hz, OCHaHb), 4.00 (1H, dd, J¼6.0, 8.7 Hz, OCHaHb), 3.97 (3H, s,
OMe), 3.95 (3H, s, OMe), 3.20 (1H, dd, J¼5.4,13.8 Hz, PhCHaHb), 2.98
(1H, dd, J¼8.1, 13.8 Hz, PhCHaHb); dC (75 MHz, CDCl3): 174.7, 154.0,
151.8, 137.5, 137.0, 130.0 (2C), 129.1 (2C), 127.3, 125.9, 106.3, 106.2,
91.3, 75.4, 56.8 (2C), 56.0, 40.3; HRMS (ESI): MNaþ, found 348.1213.
C19H19NO4 Na requires 348.1206.
to a solution of MTM ester 12a (1.08 g, 4.0 mmol) in chloroform
(40 mL) under N2 atmosphere. Acetic acid (0.1 mL, 1.7 mmol) was
added to the reaction mixture and stirred at 0 ꢁC for 30 min fol-
lowed by addition of sodium triacetoxyborohyride (1.28 g,
6.0 mmol). After 2 h at room temperature, the reaction mixture was
quenched with water (25 mL) and extracted with chloroform
(150 mL). The combined extract was washed with water (50 mL)
and with brine (50 mL), dried (Na2SO4), and evaporated. The resi-
due was purified by silica gel column chromatography (30% EtOAc/
hexane) to give pure 1k (0.775 g, 94%).
4.7. General procedure IV. Preparation of isoindolin-
1-one (1h–1k)
Acknowledgements
In a typical procedure, the amine (2.4 mmol) was added to
a solution of MTM ester 12a (0.541 g, 2.0 mmol) in chloroform
(25 mL) under N2 atmosphere. Acetic acid (0.05 mL, 0.85 mmol)
was added to the reaction mixture and stirred at 0–28 ꢁC for 15–
30 min followed by addition of sodium triacetoxyborohyride
(0.636 g, 3.0 mmol). After 2–4 h at room temperature, the reaction
mixture was quenched with water (25 mL) and extracted with
chloroform (100 mL). The combined extract was washed with wa-
ter (50 mL) and with brine (50 mL), dried (Na2SO4), and evaporated.
The residue was purified by silica gel column chromatography (10%
EtOAc/hexane) to give pure 1h–1k.
The authors would like to acknowledge analytical department,
Piramal Life Sciences Limited for providing spectral services.
Supplementary data
Copies of 1H and 13C of all new products, 2D-NOESY of 6d, 6e,
and the study of the rate of formation of 1a from 12a/12b by 1H
NMR are provided. Supplementary data associated with this article
can be found in the online version, at doi:10.1016/j.tet.2010.01.070.
4.7.1. 2-(2-Hydroxyethyl)-5,6-dimethoxyisoindolin-1-one
(1h). Yield: 0.37 g, 78%; Rf (50% EtOAc/hexane) 0.21; solid, mp 147–
152 ꢁC; dH (300 MHz, CDCl3) 7.32 (1H, s, Ar), 6.92 (1H, s, Ar), 4.44
(2H, s, ArCH2N), 3.96 (3H, s, OMe), 3.95 (3H, s, OMe), 3.92 (2H, t,
J¼4.8 Hz, CH2OH), 3.77 (2H, t, J¼4.8 Hz, CH2CH2N), 3.21 (1H, br s,
OH); dC (75 MHz, CDCl3) 169.6, 152.1, 149.2, 134.6, 124.3, 104.7,
104.4, 61.4, 55.7 (2C), 51.0, 45.9; HRMS (ESI): MHþ, found 238.1080.
C12H16NO4 requires 238.1074.
References and notes
1. (a) Kundu, N. G.; Khan, M. W.; Mukhopadhyay, R. J. Indian Chem. Soc. 2001, 671–
´
688; (b) Blasko, G.; Gula, D. J.; Shamma, M. J. Nat. Prod. 1982, 45, 105–122; (c)
Aboudi, A. F.; Al-Eisawi, D. M.; Sabri, S. S.; Zarga, M. H. A. J. Nat. Prod. 1986, 49
370-370; (d) Hussain, S. F.; Minard, R. D.; Freyer, A. J.; Shamma, M. J. Nat. Prod.
1981, 44, 169–178; (e) Norman, M. H.; Minick, D. J.; Rigdon, G. C. J. Med. Chem.
1996, 39, 149–157; (f) Jagtap, P. G.; Southan, G. J.; Baloglu, E.; Ram, S.; Mabley, J.
´
G.; Marton, A.; Salzman, A.; Szabo, C. Bioorg. Med. Chem. Lett. 2004, 14, 81–85.
2. (a) Takahashi, I.; Hirano, E.; Kawakami, T.; Kitajima, H. Heterocycles 1996, 43,
2343–2346; (b) Nannini, G.; Giraldi, P. N.; Molgora, G.; Biasoli, G.; Spinelli, F.;
Logemann, W.; Dradi, E.; Zaanni, G.; Buttinoni, A.; Tommasini, R. Arzneim.-
Forsch. 1973, 23, 1090–1100.
3. Muller, G. W.; Chen, R.; Huang, S.-Y.; Corral, L. G.; Wong, L. M.; Patterson, R. T.;
Chen, Y.; Kaplan, G.; Stirling, D. I. Bioorg. Med. Chem. Lett. 1999, 9, 1625–1630.
4.7.2. (S)-2-(1-Hydroxy-4-methylpentan-2-yl)-5,6-dimethoxy-
isoindolin-1-one (1i). Yield: 0.435 g, 74%; Rf (5% MeOH/CHCl3) 0.28;
20
solid, mp 135–138 ꢁC; [
a
]
ꢀ18.2 (c 2.0, CHCl3); dH (300 MHz,
D

U. Ghosh et al. / Tetrahedron 66 (2010) 2148–2155
2155
4. (a) Scha¨fer, W.; Friebe, W.-G.; Leinert, H.; Mertens, A.; Poll, T.; von der Saal, W.;
Zilch, H.; Nuber, B.; Ziegler, N. L. J. Med. Chem. 1993, 36, 726–732; (b) Mertens,
A.; Zilch, H.; Ko¨nig, B.; Scha¨fer, W.; Poll, T.; Kampe, W.; Seidel, H.; Leser, U.;
Leinert, H. J. Med. Chem. 1993, 36, 2526–2535.
5. Hamprecht, D.; Micheli, F.; Tedesco, G.; Checchia, A.; Donati, D.; Petrone, M.;
Terreni, S.; Wood, M. Bioorg. Med. Chem. Lett. 2007, 17, 428–433.
6. Kato, Y.; Takemoto, M.; Achiwa, K. Chem. Pharm. Bull. 1993, 41, 2003–2006.
7. (a) McAlonan, H.; Murphy, J. P.; Nieuwenhuyzen, M.; Reynolds, K.; Sarma, P. K.
S.; Stevenson, P. J.; Thompson, N. J. Chem. Soc., Perkin Trans. 1 2002, 69–79; (b)
Oppolzer, W.; Wills, M.; Kelly, M. J.; Signer, M.; Blagg, J. Tetrahedron Lett. 1990,
31, 5015–5018.
8. Belliotti, T. R.; Brink, W. A.; Kesten, S. R.; Rubin, J. R.; Wustrow, D. J.; Zoski, K. T.;
Whetzel, S. Z.; Corbin, A. E.; Pugsley, T. A.; Heffner, T. G.; Wise, L. D. Bioorg. Med.
Chem. Lett. 1998, 8, 1499–1502.
9. (a) Ford, J.A.; Stenberg, J.F. Def. Publ. U.S. Patent. Off. 887,030, 1971; Chem. Abstr.
1971, 75, P89330b; (b) Azumaya, I.; Kagechika, H.; Fujiwara, Y.; Itoh, M.;
Yamaguchi, K.; Shudo, K. J. Am. Chem. Soc. 1991, 113, 2833–2838; (c) Tsuruta, Y.;
Date, Y.; Kohashi, K. J. Chromatogr. 1990, 502, 178–183; (d) Das, S.; Fro¨hlich, R.;
Pramanik, A. Org. Lett. 2006, 8, 4263–4266.
10. (a) Bishop, A. C.; Ubersax, J. A.; Petsch, D. T.; Matheos, D. P.; Gray, N. S.;
Blethrow, J.; Shimizu, E.; Tsien, J. Z.; Schultz, P. G.; Rose, M. D.; Wood, J. L.;
Morgan, D. O.; Shokat, K. M. Nature 2000, 407, 395–401; (b) McGovern, S. L.;
Shoichet, B. K. J. Med. Chem. 2003, 46, 1478–1483.
11. (a) Spa¨th, E.; Lintner, J. Chem. Ber. 1936, 69, 2727–2731; (b) Barrios, I.; Camps, P.;
Comes-Franchini, M.; Munoz-Torrero, D.; Ricci, A.; Sanchez, L. Tetrahedron 2003,
59, 1971–1979.
12. (a) Horii, Z.-I.; Iwata, C.; Tamura, Y. J. Org. Chem. 1961, 26, 2273–2276; (b) Wang,
E.-C.; Chen, H.-F.; Feng, P.-K.; Lin, Y.-L.; Hsu, M.-K. Tetrahedron Lett. 2002, 43,
9163–9165; (c) Pierce, J. G.; Waller, D. L.; Wipf, P. J. Organomet. Chem. 2007, 692,
4618–4629; (d) Deniau, E.; Enders, D. Tetrahedron Lett. 2000, 41, 2347–2350; (e)
Chen, M.-D.; Zhou, X.; He, M.-Z.; Ruan, Y.-P.; Huang, P.-Q. Tetrahedron 2004, 60,
1651–1657; (f) Wang, Z.-Q.; Feng, C.-G.; Xu, M.-H.; Lin, G.-Q. J. Am. Chem. Soc.
2007, 129, 5336–5337; (g) Sun, X.-W.; Liu, M.; Xu, M.-H.; Lin, G.-Q. Org. Lett.
2008, 10, 1259–1262.
B.; Jun, J.-G.; Zhou, P. J. Org. Chem. 1997, 62, 5392–5403; (c) Wang, H.; Ganesan,
A. Tetrahedron Lett. 1998, 39, 9097–9098.
14. (a) Grigg, R.; Zhang, L.; Collard, S.; Keep, A. Tetrahedron Lett. 2003, 44, 6979–
6982; (b) Orito, K.; Miyazawa, M.; Nakamura, T.; Horibata, A.; Ushito, H.;
Nagasaki, H.; Yuguchi, M.; Yamashita, S.; Yamazaki, T.; Tokuda, M. J. Org. Chem.
2006, 71, 5951–5958; (c) Campbell, J. B.; Dedinas, R. F.; Trumbower-Walsh, S. A.
J. Org. Chem. 1996, 61, 6205–6211; (d) Cho, C. S.; Ren, W. X. Tetrahedron Lett.
2009, 50, 2097–2099; (e) Cho, C. S.; Jiang, L. H.; Shim, S. C. Synth. Commun. 1998,
28, 849–857.
15. Hoarau, C.; Couture, A.; Deniau, E.; Grandclaudon, P. Synthesis 2000, 655–660.
16. Tsuritani, T.; Kii, S.; Akao, A.; Sato, K.; Nonoyama, N.; Mase, T.; Yasuda, N. Synlett
2006, 801–803.
17. (a) Lamblin, M.; Couture, A.; Deniau, E.; Grandclaudon, P. Tetrahedron 2007, 63,
2664–2669; (b) Lorion, M.; Couture, A.; Deniau, E.; Grandclaudon, P. Synthesis
2009, 1897–1903; (c) Deniau, E.; Couture, A.; Grandclaudon, P. Tetrahedron:
Asymmetry 2008, 19, 2664–2669.
18. (a) Lu¨ bbers, T.; Angehrn, P.; Gmu¨nder, H.; Herzig, S. Bioorg. Med. Chem. Lett.
2007, 17, 4708–4714; (b) Zhuang, Z.-P.; Kung, M.-P.; Mu, M.; Kung, H. F. J. Med.
Chem. 1998, 41, 157–166; (c) Barum, J. S.; Staveski, M. M. Synth. Commun. 1989,
19, 2283–2291.
19. (a) Allin, S. M.; Northfield, C. J.; Page, M. I.; Slawin, A. M. Z. Tetrahedron Lett.
1997, 38, 3627–3630; (b) Allin, S. M.; Northfield, C. J.; Page, M. I.; Slawin, A. M. Z.
J. Chem. Soc., Perkin Trans.1 2000, 1715–1721; (c) Ferraz, R.; Gomes, J. R. B.;
de Oliveira, E.; Moreira, R.; Gomes, P. J. Org. Chem. 2007, 72, 4189–4197.
20. Jadhav, S. B.; Ghosh, U. Tetrahedron Lett. 2007, 48, 2485–2487.
21. Edwards, G. A.; Perkin, W. H., Jr.; Stoyle, F. W. J. Chem. Soc., Trans. 1925, 127,
195–199.
22. Ho, T.-L.; Wong, C. M. J. Chem. Soc., Chem. Commun. 1973, 224–225.
23. Briard, E.; Zoghbi, S. S.; Imaizumi, M.; Gourley, J. P.; Shetty, H. U.; Hong, J.;
Cropley, V.; Fujita, M.; Innis, R. B.; Pike, V. W. J. Med. Chem. 2008, 51, 17–30.
24. For the detail NMR study and relative rate calculations, see ‘Supplementary
data’.
25. For other methods, see: (a) Medimagh, R.; Marque, S.; Prim, D.; Marrot, J.;
Chatti, S. Org. Lett. 2009, 11, 1817–1820; (b) Pace, V.; Martinez, F.; Nova, C. I.;
Fernandez, M.; Sinisterra, J. V.; Alcantara, A. R. Tetrahedron Lett. 2009, 50, 3050–
3053.
13. (a) Pendergast, W.; Dickerson, S. H.; Dev, I. K.; Ferone, R.; Duch, D. S.; Smith, G.
K. J. Med. Chem. 1994, 37, 838–844; (b) Taylor, E. C.; Jennings, L. D.; Mao, Z.; Hu,