An easy approach for the synthesis of N-substituted isoindolin-1-ones

Article abstract of DOI:10.1055/s-0031-1289680

A practical and efficient two-step synthesis of N-substituted isoindolin-1-ones was developed. The one-pot reaction of 2-formylbenzoic acid with amines and dimethyl phosphite proceeds in short time either with conventional heating or microwave irradiation

Full text of DOI:10.1055/s-0031-1289680

PAPER
569
An Easy Approach for the Synthesis of N-Substituted Isoindolin-1-ones
N
-Substituted Isoindol
ain-1-ones rio Ordóñez,* Gaurao D. Tibhe, Angel Zamudio-Medina, José Luis Viveros-Ceballos
Centro de Investigaciones Químicas, Universidad Autónoma del Estado de Morelos, Av. Universidad 1001, 62209 Cuernavaca, Morelos,
México
Fax +52(777)3297997; E-mail: palacios@ciq.uaem.mx
Received 7 November 2011; revised 8 December 2011
2-carbomethoxybenzaldehyde,6h,9 palladium(0)-catalyzed
Abstract: A practical and efficient two-step synthesis of N-substi-
carbonylation–amination,10 synthesis from isocyanates11
tuted isoindolin-1-ones was developed. The one-pot reaction of 2-
and base-induced aryne-mediated cyclization of o-halo-
formylbenzoic acid with amines and dimethyl phosphite proceeds
in short time either with conventional heating or microwave irradi-
N-(phosphinylmethyl)benzamide derivatives;12,13 howev-
ation under catalyst-free conditions to afford the corresponding N- er, despite their potential utility, these procedures typical-
substituted dimethyl 3-oxoisoindolin-1-ylphosphonates in good
ly suffer from one or more disadvantages, such as the use
yield which, by means of a dephosphonylation reaction with lithium
of harsh conditions or tedious multisteps which are neces-
aluminum hydride, give the target N-substituted isoindolin-1-ones
sary for these syntheses. Thus, there is still a need to de-
in moderate to good yield.
velop versatile and flexible methods for the synthesis of
isoindolin-1-ones. In this context, herein we describe an
efficient method for the synthesis of N-substituted isoin-
Key words: amino phosphonates, isoindolinones, C–P cleavage,
microwave irradiation, one-pot reaction
dolin-1-ones. Our synthetic strategy is based upon a one-
pot reaction of 2-formylbenzoic acid with alkyl- or aryl-
amines and dimethyl phosphite using conventional heat-
Isoindolin-1-ones (2,3-dihydro-1H-isoindol-1-ones) have
gained considerable attention recently due to their fasci-
ing or microwave irradiation under catalyst-free
conditions,14 followed by a dephosphonylation reaction.
nating properties and potential applications in many
fields, especially in biology and medicinal science.1 The
interest in these heterocyclic compounds stems mainly
from their diverse biological activities. For example,
isoindolin-1-ones 1–3 (Figure 1) have been tested as anti-
microbial agents,2 while indoprofen (4) has been shown to
have anti-inflammatory activity3,4 and deoxythalidomide
(5) is an inhibitor of tumor necrosis factor production.5
Additionally, the isoindolin-1-one skeleton is a key inter-
mediate for the synthesis of many naturally occurring bio-
active compounds.6
We have recently developed15 an efficient and highly dia-
stereoselective method for the synthesis of 3-oxoisoindo-
lin-1-ylphosphonate 7a by a three-component, one-pot
reaction of 2-formylbenzoic acid (6), (S)-a-methylbenzyl-
amine and dimethyl phosphite under catalyst- and sol-
vent-free conditions (Table 1, entry 1). To establish the
generality of this three-component, one-pot process we
carried out the reaction of 2-formylbenzoic acid (6) with
either alkyl- or arylamines and dimethyl phosphite. Thus,
the reaction of 2-formylbenzoic acid (6) with tert-butyl-
amine or benzhydrylamine and dimethyl phosphite at
80 °C under catalyst- and solvent-free conditions gave the
corresponding 3-oxoisoindolin-1-ylphosphonates 7b,c,
but in low yield. Better results were obtained when the re-
action was carried out in toluene at reflux; under these
conditions, the phosphonates 7b,c were obtained in 69%
and 40% yield, respectively (Table 1, entries 2 and 3). On
the other hand, the reaction of 2-formylbenzoic acid (6),
aniline and dimethyl phosphite at 90 °C produced the de-
sired 3-oxo-2-phenylisoindolin-1-ylphosphonate 7d in
14% yield after five days (Table 1, entry 4). With this re-
sult, we decided to use microwave irradiation as an alter-
native heating source. Thus, the one-pot reaction of 2-
formylbenzoic acid (6) with aniline under catalyst- and
solvent-free conditions was irradiated at 70 °C for five
minutes. After this time, dimethyl phosphite was added
and the reaction mixture was again irradiated at 90 °C for
five minutes, which gave the expected 3-oxoisoindolin-1-
ylphosphonate 7d in 77% yield (Table 1, entry 5). After
the optimization of these experimental conditions, we ex-
plored the generality of this method with other aryl-
amines, such as 4-methoxyaniline, 3,4-dimethoxyaniline,
O
O
N
N
R
CO2H
4
1 R = (S)-CH(Me)Ph
2 R = Bn
3 R = Ph
O
N
O
N
O
H
5
Figure 1
Consequently, the chemistry of isoindolinones has attract-
ed much attention, and a number of synthetic strategies
have been developed over the past few years including the
reduction of phthalimides,7 the condensation of anilines
with o-phthalaldehydes,8 amination and lactamization of
SYNTHESIS 2012, 44, 569–574
x
x
.x
x
.2
0
1
1
Advanced online publication: 26.01.2012
DOI: 10.1055/s-0031-1289680; Art ID: M104611SS
© Georg Thieme Verlag Stuttgart · New York

570
M. Ordóñez et al.
PAPER
3-(trifluoromethyl)aniline and 2-aminopyridine, which tetrahydrofuran at 0 to 25 °C, whereupon the desired
produced the N-aryl-3-oxoisoindolin-1-ylphosphonates isoindolin-1-ones 1–3 were obtained in moderate to good
7e–h in good yield, except for the 2-aminopyridine deriv- yield (Scheme 1). Other reagents (such as DIBAL-H and
ative (Table 1, entries 6–9).
LiBH4) gave only poor yields of the corresponding isoin-
dolin-1-ones 1–3.
Table 1 Synthesis of 3-Oxoisoindolin-1-ylphosphonates 7a–h
In order to establish the generality of this method, we car-
ried out the synthesis of N-(2-hydroxyethyl)-, N-(3-hy-
droxypropyl)- and N-(4-hydroxybutyl)isoindolin-1-one
(9a–c), which are key intermediates for the preparation of
the piperazine derivatives 10a–c (Scheme 2).6a Thus, the
reaction of 2-formylbenzoic acid (6) with ethanolamine
and dimethyl phosphite under catalyst- and solvent-free
conditions was irradiated at 55 °C for five minutes to give
the corresponding 3-oxoisoindolin-1-ylphosphonate 8a in
very poor yield, while the one-pot reaction of 2-formyl-
benzoic acid (6) with ethanolamine in methanol under mi-
crowave irradiation at 55 °C for five minutes, followed by
addition of dimethyl phosphite and heating at 55 °C/180
W for five minutes, gave the desired phosphonate 8a in
85% yield. Under these conditions, the reaction of 2-
formylbenzoic acid (6), 3-aminopropan-1-ol or 4-amino-
butan-1-ol and dimethyl phosphite provided the corre-
sponding 3-oxoisoindolin-1-ylphosphonates 8b,c in 67%
and 83% yield, respectively (Scheme 2). Finally, the reac-
tion of the 3-oxoisoindolin-1-ylphosphonates 8a–c with
lithium aluminum hydride in anhydrous tetrahydrofuran
afforded the target isoindolin-1-ones 9a–c in good yield.
O
CO2H
H2N
R
N
R
+
CHO
O
6
P(OMe)2
O
P(OMe)2
H
7a–h
Entry
R
Conditions
Yield (%)
1
2
3
4
5
6
7
8
9
7a; (S)-CH(Me)Ph
7b; t-Bu
80 °C, 60 min
toluene, reflux
toluene, reflux
90 °C, 5 d
75
69
40
14
77
82
75
73
22
7c; CHPh2
7d; Ph
7d; Ph
MW, 180 Wa
MW, 180 Wa
MW, 180 Wa
MW, 180 Wa
MW, 180 Wa
7e; 4-MeOC6H4
7f; 3,4-(MeO)2C6H3
7g; 3-F3CC6H4
7h; 2-pyridyl
a Reaction conditions: (i) 70 °C, 5 min; (ii) dimethyl phosphite, 90 °C,
5 min.
O
MeOH
CO2H
CHO
OH
OH
55 °C
( )n
( )n
N
H2N
+
MW
With the 3-oxoisoindolin-1-ylphosphonates 7a–h in hand,
in the next step we turned our attention to the reduction of
the C–P bond to obtain the desired N-alkyl- and N-aryl-
isoindolin-1-ones 1–3. In this context, Oh and co-
workers16 have reported a method for C–P bond cleavage
in b-oxo phosphonates by dephosphonylation of their lith-
ium enolates with lithium aluminum hydride. Additional-
ly, Amedjkouh and Grimaldi17 have reported the
dephosphonylation of 5-phosphonylpyrrolidines using the
same reducing agent. According to these methods, we car-
ried out the reaction of the 3-oxoisoindolin-1-ylphospho-
nates 7a–h with lithium aluminum hydride in anhydrous
6
O
P(OMe)2
O
H
P(OMe)2
8a n = 1, 85%
8b n = 2, 67%
8c n = 3, 83%
LiAlH4, THF
0 to 25 °C
MeO
O
O
OH
ref. 6a
N
N
( )n
( )n
10a–c
N
N
9a n = 1, 71%
9b n = 2, 70%
9c n = 3, 42%
O
O
Scheme 2
LiAlH4, THF
0 to 25 °C
N
R
N
R
In summary, we have developed a practical and efficient
synthetic approach to N-substituted isoindolin-1-ones.
The synthetic route involves the one-pot reaction of 2-
formylbenzoic acid with amines and dimethyl phosphite,
followed by a dephosphonylation reaction. This two-step
synthetic sequence is very efficient, affording the N-sub-
stituted isoindolin-1-ones in good yield. Considering the
mild reaction conditions, we believe that this methodolo-
gy could be of use in organic synthesis for the preparation
of important isoindolin-1-ones.
P(OMe)2
O
7a–h
1–3
1 R = (S)-CH(Me)Ph; 67%
2a R = t-Bu; 85%
2b R = CHPh2; 60%
3a R = Ph; 90%
3b R = 4-MeOC6H4; 80%
3c R = 3,4-(MeO)2C6H3; 43%
3d R = 3-F3CC6H4; 58%
3e R = 2-pyridyl; 44%
Scheme 1
Synthesis 2012, 44, 569–574
© Thieme Stuttgart · New York

PAPER
N-Substituted Isoindolin-1-ones
571
Hz, 1 H, CHP(OCH3)2], 7.26–7.30 (m, 1 H, Harom), 7.42–7.66 (m, 6
H, Harom), 7.84–7.96 (m, 2 H, Harom).
13C NMR (100 MHz, CDCl3): d = 53.1 [d, J = 6.0 Hz, (CH3O)2P],
54.1 [d, J = 6.0 Hz, (CH3O)2P], 59.2 [d, J = 151.7 Hz,
CHP(OCH3)2], 124.6, 124.7, 125.2, 126.6, 129.0, 129.4, 132.2,
132.4, 137.5, 138.1, 167.6 (C=O).
31P NMR (81 MHz, CDCl3): d = 20.47.
HRMS (CI+): m/z calcd for C16H17NO4P: 318.0817; found:
All commercial materials were used as received without further pu-
rification. Melting points were registered in a Fisher–Johns appara-
tus and are uncorrected. Flash chromatography was performed
using silica gel 60 (230–400 mesh). Thin-layer chromatography
was performed with precoated TLC sheets of silica gel 60 F254
(Merck). Microwave reactions were performed in a CEM Discover
System. NMR spectra were recorded with a Varian System instru-
ment (400 MHz for 1H, 100 MHz for 13C) or a Mercury instrument
(81 MHz for 31P) and calibrated with CDCl3 as solvent and TMS as
internal standard signal. Chemical shifts (d) are reported in parts per
million. Coupling constants (J) are given in Hz. High-resolution
FAB+ and CI+ mass spectra (HRMS) were obtained with a JEOL
HRMStation JHRMS-700 instrument. Compound 7a was prepared
according to the literature procedure.15
318.0886.
Dimethyl 2-(4-Methoxyphenyl)-3-oxoisoindolin-1-ylphospho-
nate (7e)
Yield: 1.38 g (82%); yellow solid; mp 169–172 °C.
1H NMR (400 MHz, CDCl3): d = 3.31 [d, J = 10.8 Hz, 3 H,
(CH3O)2P], 3.50 [d, J = 10.8 Hz, 3 H, (CH3O)2P], 3.83 (s, 3 H,
CH3O), 5.47 [d, J = 12.8 Hz, 1 H, CHP(OCH3)2], 6.98 (AA¢BB¢ sys-
tem, J = 6.8 Hz, 2 H, Harom), 7.40 (AA¢BB¢ system, J = 6.8 Hz, 2 H,
N-Alkyl-3-oxoisoindolin-1-ylphosphonates 7b,c; General Pro-
cedure
A mixture of 2-formylbenzoic acid (6, 1 equiv), an amine (1.06
equiv) and dimethyl phosphite (1.11 equiv) in toluene (7 mL) was
heated under reflux for 4 h. The crude product was purified by sim-
ple column chromatography (EtOAc–hexane, 70:30).
H
arom), 7.54–7.65 (m, 2 H, Harom), 7.82–7.95 (m, 2 H, Harom).
13C NMR (100 MHz, CDCl3): d = 53.2 [d, J = 6.1 Hz, (CH3O)2P],
54.1 [d, J = 6.1 Hz, (CH3O)2P], 55.6 (CH3O), 59.6 [d, J = 151.7 Hz,
CHP(OCH3)2], 114.4, 124.5, 124.7, 126.9, 129.3, 130.3, 132.2,
138.0, 158.4, 167.9 (C=O).
Dimethyl 2-tert-Butyl-3-oxoisoindolin-1-ylphosphonate (7b)
Yield: 682 mg (69%); white solid; mp 120–122 °C.
31P NMR (81 MHz, CDCl3): d = 20.67.
HRMS (CI+): m/z calcd for C17H19NO5P: 348.0923; found:
1H NMR (400 MHz, CDCl3): d = 1.68 [s, 9 H, C(CH3)3], 3.60 [d,
J = 10.4 Hz, 3 H, (CH3O)2P], 3.62 [d, J = 10.8 Hz, 3 H, (CH3O)2P],
5.10 [d, J = 10.4 Hz, 1 H, CHP(OCH3)2], 7.46–7.82 (m, 4 H, Harom).
348.0993.
13C NMR (100 MHz, CDCl3): d = 28.4 [(CH3)3C], 53.6 [d, J = 7.6
Hz, (CH3O)2P], 54.4 [d, J = 7.6 Hz, (CH3O)2P], 56.6 [C(CH3)3],
58.2 [d, J = 151.7 Hz, CHP(OCH3)2], 123.5, 124.3, 128.8, 131.1,
134.2, 139.3, 169.3 (C=O).
31P NMR (81 MHz, CDCl3): d = 22.00.
HRMS (FAB+): m/z calcd for C14H21NO4P: 298.1208; found:
Dimethyl 2-(3,4-Dimethoxyphenyl)-3-oxoisoindolin-1-ylphos-
phonate (7f)
Yield: 0.55 g (75%); yellow solid; mp 110–113 °C.
1H NMR (400 MHz, CDCl3): d = 3.32 [d, J = 10.8 Hz, 3 H,
(CH3O)2P], 3.52 [d, J = 10.8 Hz, 3 H, (CH3O)2P], 3.91 (s, 6 H,
CH3O), 5.52 [d, J = 12.8 Hz, 1 H, CHP(OCH3)2], 6.92–6.99 (m, 2
H, Harom), 7.13 (s, 1 H, Harom), 7.55–7.66 (m, 2 H, Harom), 7.83 (d,
J = 7.2 Hz, 1 H, Harom), 7.94 (d, J = 7.2 Hz, 1 H, Harom).
13C NMR (100 MHz, CDCl3): d = 53.2 [d, J = 7.6 Hz, (CH3O)2P],
54.1 [d, J = 7.6 Hz, (CH3O)2P], 56.2 (2 CH3O), 59.6 [d, J = 154.7
Hz, CHP(OCH3)2], 110.0, 111.3, 117.7, 124.5, 124.6, 129.4, 130.6,
132.1, 132.3, 138.0, 148.0, 149.3, 167.9 (C=O).
298.1203.
Dimethyl2-(Diphenylmethyl)-3-oxoisoindolin-1-ylphosphonate
(7c)
Yield: 214 mg (40%); white solid; mp 130–132 °C.
1H NMR (400 MHz, CDCl3): d = 3.46 [d, J = 10.4 Hz, 3 H,
(CH3O)2P], 3.54 [d, J = 11.2 Hz, 3 H, (CH3O)2P], 4.94 [d, J = 12.8
Hz, 1 H, CHP(OCH3)2], 6.45 (s, 1 H, CHPh2), 7.24–7.85 (m, 14 H,
Harom).
31P NMR (81 MHz, CDCl3): d = 20.80.
HRMS (CI+): m/z calcd for C18H21NO6P: 378.1128; found:
13C NMR (100 MHz, CDCl3): d = 53.3 [d, J = 7.6 Hz, (CH3O)2P],
54.4 [d, J = 7.6 Hz, (CH3O)2P], 59.0 [d, J = 156.3 Hz,
CHP(OCH3)2], 63.9 (CHPh2), 124.3, 124.6, 127.5, 127.7, 128.3,
128.6, 128.7, 129.2, 129.3, 132.0, 132.9, 138.7, 139.0, 139.4, 169.5
(C=O).
378.1120.
Dimethyl 3-Oxo-2-[3-(trifluoromethyl)phenyl]isoindolin-1-
ylphosphonate (7g)
Yield: 0.50 g (73%); yellow solid; mp 124–128 °C.
1H NMR (400 MHz, CDCl3): d = 3.31 [d, J = 11.2 Hz, 3 H,
(CH3O)2P], 3.51 [d, J = 11.2 Hz, 3 H, (CH3O)2P], 5.63 [d, J = 12.0
Hz, 1 H, CHP(OCH3)2], 7.49–7.57 (m, 3 H, Harom), 7.62–7.66 (m, 1
H, Harom), 7.76–7.84 (m, 3 H, Harom), 7.92 (d, J = 7.6 Hz, 1 H, Harom).
31P NMR (81 MHz, CDCl3): d = 21.60.
HRMS (FAB+): m/z calcd for C23H23NO4P: 408.1365; found:
408.1398.
13C NMR (100 MHz, CDCl3): d = 53.2 [d, J = 6.0 Hz, (CH3O)2P],
N-Aryl-3-oxoisoindolin-1-ylphosphonates 7d–h; General Pro-
cedure
54.2 [d, J = 6.0 Hz, (CH3O)2P],
58.8 [d, J = 151.7 Hz,
CHP(OCH3)2], 121.4, 122.9, 123.9 (d, J = 270.0 Hz), 124.7, 124.8,
128.1, 129.5, 129.6, 131.2, 131.7, 132.8, 137.9, 138.1 (d, J = 30.4
Hz), 167.5 (C=O).
31P NMR (81 MHz, CDCl3): d = 20.06.
HRMS (CI+): m/z calcd for C17H16F3NO4P: 386.0769; found:
386.0777.
A mixture of 2-formylbenzoic acid (6, 1 equiv) and an amine (1
equiv) was irradiated using a CEM microwave at 70 °C/180 W for
5 min. After this time, dimethyl phosphite (1.1 equiv) was added
and the reaction mixture was again irradiated at 90 °C/180 W for 5
min. The crude product was purified by column chromatography
(EtOAc–hexane, 50:50).
Dimethyl 3-Oxo-2-phenylisoindolin-1-ylphosphonate (7d)
Yield: 1.3 g (77%); yellow solid; mp 145–147 °C.
1H NMR (400 MHz, CDCl3): d = 3.28 [d, J = 10.8 Hz, 3 H,
(CH3O)2P], 3.47 [d, J = 10.8 Hz, 3 H, (CH3O)2P], 5.58 [d, J = 12.4
Dimethyl 3-Oxo-2-(2-pyridyl)isoindolin-1-ylphosphonate (7h)
Two rotamers were observed for this compound.
Yield: 385 mg (22%); yellow solid; mp 105–108 °C.
© Thieme Stuttgart · New York
Synthesis 2012, 44, 569–574

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M. Ordóñez et al.
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1H NMR (400 MHz, CDCl3): d = 3.36 [d, J = 11.0 Hz, 3 H,
(CH3O)2P], 3.60 [d, J = 10.4 Hz, 3 H, (CH3O)2P], 3.65 [d, J = 11.0
Hz, 3 H, (CH3O)2P], 3.92 [d, J = 10.4 Hz, 3 H, (CH3O)2P], 5.73 (d,
J = 11.2 Hz, 1 H, CHP(OCH3)2], 6.36 (d, J = 13.6 Hz, 1 H,
CHP(OCH3)2], 7.12–7.15 (m, 2 H, Harom), 7.53–7.95 (m, 10 H,
Harom), 8.23–8.24 (d, J = 8.4 Hz, 2 H, Harom), 8.44–8.46 (m, 2 H,
Dimethyl2-(4-Hydroxybutyl)-3-oxoisoindolin-1-ylphosphonate
(8c)
Yield: 1.70 g (83%); colorless oil.
1H NMR (400 MHz, CDCl3): d = 1.54–1.61 (m, 2 H, CH2), 1.69–
1.76 (m, 1 H, CH2), 1.84–1.91 (m, 1 H, CH2), 2.75 (br s, 1 H, OH),
3.57–3.64 (m, 5 H), 3.66–3.69 (m, 1 H, CH2), 3.72 [d, J = 10.4 Hz,
3 H, (CH3O)2P], 4.07–4.15 (m, 1 H, CH2), 4.94 [d, J = 13.6 Hz, 1 H,
CHP(OCH3)2], 7.50–7.60 (m, 2 H, Harom), 7.72–7.74 (m, 1 H, Harom),
7.85–7.87 (m, 1 H, Harom).
13C NMR (100 MHz, CDCl3): d = 24.4, 29.7, 41.7, 53.7 [d, J = 7.6
Hz, (CH3O)2P], 53.9 [d, J = 6.0 Hz, (CH3O)2P], 57.2 [d, J = 154.7
Hz, CHP(OCH3)2], 61.9, 124.0, 124.4, 129.2, 131.8, 132.4, 138.4,
169.0.
Harom).
13C NMR (100 MHz, CDCl3): d = 53.7 [d, J = 6.0 Hz, (CH3O)2P],
53.8 [d, J = 6.0 Hz, (CH3O)2P], 54.2 [d, J = 6.0 Hz, (CH3O)2P], 54.5
[d, J = 6.0 Hz, (CH3O)2P], 56.3 [d, J = 151.7 Hz, CHP(OCH3)2],
75.3 [d, J = 163.8 Hz, CHP(OCH3)2], 117.2, 120.5, 123.7, 124.6,
124.8, 125.2, 125.3, 126.1, 129.1, 130.0, 132.0, 132.9, 134.6, 137.9,
139.1, 143.7, 147.6, 150.8, 167.7 (C=O), 169.6 (C=O).
31P NMR (81 MHz, CDCl3): d = 21.40.
HRMS (CI+): m/z calcd for C15H16N2O4P: 319.0848; found:
31P NMR (81 MHz, CDCl3): d = 21.14.
HRMS (CI+): m/z calcd for C14H21NO5P: 314.1079; found:
319.0853.
314.1154.
N-(w-Hydroxyalkyl)-3-oxoisoindolin-1-ylphosphonates 8a–c;
General Procedure
N-Substituted Isoindolin-1-ones 1–3 and 9a–c; General Proce-
dure for the Dephosphonylation of 7a–h and 8a–c
A mixture of 2-formylbenzoic acid (6, 6.6 mmol) and an amine (6.6
mmol) in MeOH (1 mL) was irradiated using a CEM microwave at
55 °C/180 W for 5 min. After this time, dimethyl phosphite (7.3
mmol) was added and the reaction mixture was again irradiated at
55 °C/180 W for 5 min. The crude product was purified by column
chromatography (EtOAc).
To a suspension of LiAlH4 (3 equiv) in anhyd THF (5 mL) at 0 °C
was added slowly a 3-oxoisoindolin-1-ylphosphonate (1 equiv) in
anhyd THF (5 mL). The reaction mixture was allowed to warm to
r.t. and was stirred for 30 min. EtOAc (5 mL) and H2O (5 mL) were
added, and the resulting mixture was refluxed for 1 h. The reaction
mixture was extracted with EtOAc (3 × 5 mL), and the combined
organic layer was washed with H2O (5 mL), dried (Na2SO4) and
concentrated under reduced pressure. The residue was purified by
column chromatography (hexane–EtOAc, 50:50).
Dimethyl 2-(2-Hydroxyethyl)-3-oxoisoindolin-1-ylphosphonate
(8a)
Yield: 1.59 g (85%); white solid; mp 92–94 °C.
1H NMR (400 MHz, CDCl3): d = 3.58 [d, J = 11.2 Hz, 3 H,
(CH3O)2P], 3.71 [d, J = 10.8 Hz, 3 H, (CH3O)2P], 3.74–3.82 (m, 1
H, CH2N), 3.86 (br s, 1 H, OH), 3.88–3.90 (m, 2 H, CH2), 4.13–4.19
(m, 1 H, CH2OH), 5.19 [d, J = 13.2 Hz, 1 H, CHP(OCH3)2], 7.47–
7.51 (m, 1 H, Harom), 7.55–7.59 (m, 1 H, Harom), 7.70–7.72 (m, 1 H,
2-[(S)-1-Phenylethyl]isoindolin-1-one (1)
Yield: 135 mg (67%); white solid; mp 143–145 °C (Lit.10e 142–
144 °C for the R-enantiomer).
[a]D –161.3 (c 1.33, CHCl3) [Lit.10e [a]D +144 (c 1.33, CHCl3) for
the R-enantiomer].
Harom), 7.82–7.84 (m, 1 H, Harom).
The spectroscopic data were identical with those reported in the lit-
13C NMR (100 MHz, CDCl3): d = 45.4, 53.8 [d, J = 7.6 Hz,
(CH3O)2P], 54.0 [d, J = 6.0 Hz, (CH3O)2P], 58.7 [d, J = 154.7 Hz,
CHP(OCH3)2], 61.6, 123.9, 124.3, 129.0, 131.9, 132.0, 138.9,
169.8.
31P NMR (81 MHz, CDCl3): d = 21.51.
HRMS (CI+): m/z calcd for C12H17NO5P: 286.0769; found:
erature for the R-enantiomer.10e
2-tert-Butylisoindolin-1-one (2a)
Yield: 136 mg (85%); white solid; mp 62–63 °C.
The spectroscopic data were identical with those reported in the lit-
erature.18
286.0852.
2-(Diphenylmethyl)isoindolin-1-one (2b)
Yield: 108 mg (60%); white solid; mp 115–117 °C.
1H NMR (400 MHz, CDCl3): d = 4.22 (s, 2 H, CH2N), 6.91 (s, 1 H,
NCHPh2), 7.21–7.92 (m, 14 H, Harom).
Dimethyl 2-(3-Hydroxypropyl)-3-oxoisoindolin-1-ylphospho-
nate (8b)
Yield: 1.37 g (67%); colorless oil.
1H NMR (400 MHz, CDCl3): d = 1.78–1.88 (m, 1 H, CH2), 1.93–
2.00 (m, 1 H, CH2), 3.36 (br s, 1 H, OH), 3.50–3.56 (m, 1 H, CH2),
3.60 [d, J = 11.2 Hz, 3 H, (CH3O)2P], 3.60–3.65 (m, 1 H, CH2), 3.75
[d, J = 10.8 Hz, 3 H, (CH3O)2P], 3.82–3.88 (m, 1 H, CH2), 4.05–
4.12 (m, 1 H, CH2), 4.94 [d, J = 13.6 Hz, 1 H, CHP(OCH3)2], 7.51–
7.55 (m, 1 H, Harom), 7.58–7.62 (m, 1 H, Harom), 7.75–7.77 (m, 1 H,
13C NMR (100 MHz, CDCl3): d = 47.6 (CH2N), 58.8 (NCHPh2),
123.0, 124.2, 127.8, 128.2, 128.7, 128.8, 131.6, 132.5, 139.4, 141.6,
168.6 (C=O).
HRMS (FAB+): m/z calcd for C21H18NO: 300.1388; found:
300.1382.
H
arom), 7.85–7.87 (m, 1 H, Harom).
2-Phenylisoindolin-1-one (3a)
13C NMR (100 MHz, CDCl3): d = 31.0, 39.0, 53.9 [d, J = 7.6 Hz,
(CH3O)2P], 54.0 [d, J = 6.0 Hz, (CH3O)2P], 57.8 [d, J = 154.7 Hz,
CHP(OCH3)2], 59.0, 124.0, 124.5, 129.2, 132.0, 132.1, 138.5,
170.1.
Yield: 178 mg (90%); yellow solid; mp 160–163 °C (Lit.10c,19 mp
162–163 °C).
The spectroscopic data were identical with those reported in the lit-
erature.10c,19
31P NMR (81 MHz, CDCl3): d = 21.14.
HRMS (CI+): m/z calcd for C13H19NO5P: 300.0923; found:
2-(4-Methoxyphenyl)isoindolin-1-one (3b)
300.0970.
Yield: 100 mg (80%); yellow solid; mp 130–134 °C.
1H NMR (400 MHz, CDCl3): d = 3.81 (s, 3 H, CH3O), 4.79 (s, 2 H,
CH2), 6.93–6.97 (m, 2 H, Harom), 7.47–7.50 (m, 2 H, Harom), 7.55–
Synthesis 2012, 44, 569–574
© Thieme Stuttgart · New York

PAPER
N-Substituted Isoindolin-1-ones
573
7.59 (m, 1 H, Harom), 7.70–7.75 (m, 2 H, Harom), 7.89–7.91 (m, 1 H,
Acknowledgment
Harom).
The authors thank the CONACYT of Mexico for financial support
(via projects 62271, 126793). We thank Victoria Labastida-Galván
and Selene Lagunes for their technical assistance. Two of us,
G.D.T. and J.L.V.-C., also thank the CONACYT for Graduate
Scholarships.
13C NMR (100 MHz, CDCl3): d = 51.4 (CH3O), 55.7 (CH2), 114.6,
121.7, 122.7, 124.2, 128.5, 131.9, 132.9, 133.5, 140.4, 156.9, 167.4
(C=O).
HRMS (CI+): m/z calcd for C15H14NO2: 240.1025; found: 240.1015.
2-(3,4-Dimethoxyphenyl)isoindolin-1-one (3c)
Yield: 73 mg (43%); white solid; mp 138–140 °C.
References
1H NMR (400 MHz, CDCl3): d = 3.88 (s, 3 H, CH3O), 3.94 (s, 3 H,
CH3O), 4.81 (s, 2 H, CH2), 6.88 (d, J = 8.8 Hz, 1 H, Harom), 7.03 (d,
J = 8.4 Hz, 1 H, Harom), 7.49 (m, 2 H, Harom), 7.57 (m, 1 H, Harom),
7.88 (m, 2 H, Harom).
13C NMR (100 MHz, CDCl3): d = 51.4 (CH2), 56.2 (CH3O), 56.3
(CH3O), 105.3, 111.4, 111.8, 122.7, 124.2, 128.5, 132.0, 133.5,
140.2, 146.5, 149.6, 167.5.
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HRMS (CI+): m/z calcd for C16H16NO3: 270.1052; found: 270.1126.
2-[3-(Trifluoromethyl)phenyl]isoindolin-1-one (3d)
Yield: 200 mg (58%); white solid; mp 158–160 °C.
1H NMR (400 MHz, CDCl3): d = 4.88 (s, 2 H, CH2), 7.40–7.43 (m,
1 H, Harom), 7.50–7.56 (m, 3 H, Harom), 7.60–7.64 (m, 1 H, Harom),
7.91–7.93 (m, 1 H, Harom), 8.11–8.18 (m, 2 H, Harom).
13C NMR (100 MHz, CDCl3): d = 50.8 (CH2), 115.7 (q, J = 0.46
Hz), 121.0 (q, J = 3.1 Hz), 122.3, 122.9, 124.5, 128.8, 129.9, 131.7
(d, J = 31.8 Hz), 132.7, 132.9, 139.9, 140.0, 167.9 (C=O).
HRMS (CI+): m/z calcd for C15H11F3NO: 278.0714; found:
278.0790.
2-(2-Pyridyl)isoindolin-1-one (3e)
Two rotamers were observed for this compound.
Yield: 40 mg (44%); yellow solid; mp 128–130 °C.
1H NMR (400 MHz, CDCl3): d = 5.08 (s, 2 H, CH2), 7.04–7.07 (m,
1 H, Harom), 7.47–7.62 (m, 3 H, Harom), 7.74 (t, J = 8.0 Hz, 1 H,
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Harom), 7.91 (d, J = 8.0 Hz, 1 H, Harom), 8.38 (s, 1 H, Harom), 8.65 (d,
J = 8.8 Hz, 1 H, Harom).
13C NMR (100 MHz, CDCl3): d = 50.0 (CH2), 114.4, 119.6, 123.1,
124.4, 128.4, 132.7, 133.2, 138.0, 141.2, 147.9, 152.1, 168.9.
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2-(2-Hydroxyethyl)isoindolin-1-one (9a)
Yield: 222 mg (71%); white solid; mp 116–118 °C (Lit.1k 117–
119 °C).
(b) Alessio Moriconi, A.; Cesta, M. C.; Cervellera, M. N.;
Aramini, A.; Coniglio, S.; Colagioia, S.; Beccari, A. R.;
Bizzarri, C.; Cavicchia, M. R.; Locati, M.; Galliera, E.;
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The spectroscopic data were identical with those reported in the lit-
erature.1k
2-(3-Hydroxypropyl)isoindolin-1-one (9b)
Yield: 89 mg (70%); colorless oil.
The spectroscopic data were identical with those reported in the lit-
erature.1k
2-(4-Hydroxybutyl)isoindolin-1-one (9c)
Yield: 122 mg (42%); colorless oil.
1H NMR (400 MHz, CDCl3): d = 1.58–1.65 (m, 2 H, CH2), 1.75–
1.82 (m, 2 H, CH2), 2.31 (br s, 1 H, OH), 3.66–3.72 (m, 4 H, CH2),
4.39 (s, 2 H, CH2), 7.43–7.47 (m, 2 H, Harom), 7.50–7.54 (m, 1 H,
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13C NMR (100 MHz, CDCl3): d = 25.2 (CH2), 29.7 (CH2), 42.3
(CH2), 50.1 (CH2), 62.5 (CH2), 122.8, 123.9, 128.2, 131.4, 133.1,
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© Thieme Stuttgart · New York
Synthesis 2012, 44, 569–574

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Synthesis 2012, 44, 569–574
© Thieme Stuttgart · New York