Palladium-catalyzed cyclocarbonylation of 2-halobenzaldehyde and hydrazines: A facile synthesis of 2-aminoisoindolin-1-ones

Article abstract of DOI:10.1002/cjoc.201200798

An efficient procedure for the synthesis of 2-aminoisoindolin-1-ones via a palladium-catalyzed three-component reaction of 2-halobenzaldehydes, hydrazines and carbon monoxide is reported. This cyclocarbonylation process can be performed smoothly under 1 atmospheric pressure of carbon monoxide to afford 2-aminoisoindolin-1-ones in moderate to excellent yields. An efficient procedure for the synthesis of 2-aminoisoindolin-1-ones via a palladium-catalyzed cyclocarbonylation of 2-halobenzaldehydes, hydrazines and carbon monoxide (balloon) is reported. Copyright

Full text of DOI:10.1002/cjoc.201200798

FULL PAPER
DOI: 10.1002/cjoc.201200798
Palladium-Catalyzed Cyclocarbonylation of
2-Halobenzaldehyde and Hydrazines: A Facile Synthesis
of 2-Aminoisoindolin-1-ones
Chao Han, Yang Shen, Ping Lu,* and Yanguang Wang*
Department of Chemistry, Zhejiang University, Hangzhou, Zhejiang 310027, China
An efficient procedure for the synthesis of 2-aminoisoindolin-1-ones via a palladium-catalyzed three-compo-
nent reaction of 2-halobenzaldehydes, hydrazines and carbon monoxide is reported. This cyclocarbonylation proc-
ess can be performed smoothly under 1 atmospheric pressure of carbon monoxide to afford 2-aminoisoindolin-
1-ones in moderate to excellent yields.
Keywords cyclocarbonylation, 2-aminoisoindolin-1-ones, multicomponent reactions, heterocycles
Introduction
Scheme 1 Approaches to 2-substituted isoindolin-1-ones
Previous work
Isoindolinones (phthalimidines) and their derivatives
are an important class of compounds in organic and
pharmaceutical chemistry, not only as the key structural
units in many natural products and pharmaceuticals but
also as useful building blocks for various biologically
active molecules, such as staurosporine, indoprofen, and
DN-2327.[1,2] Multicomponent reactions (MCRs) have
emerged as powerful tools in organic, combinatorial,
and medicinal chemistry with high bond-forming effi-
ciency.[3] Among them, the transition metal-catalyzed
MCRs have been applied for the preparation of isoin-
dolinones.[4] These reactions involved a palladium-
catalyzed cyclocarbonylation process using carbon
monoxide as the carbonyl resource. A number of
2-aryl/alkyl isoindolin-1-ones were synthesized by this
strategy (Scheme 1). Nevertheless, the approaches to
2-amino isoindolin-1-ones, exhibiting excellent effects
on modulating mGluR function, have seldom been re-
ported.[5]
As a continuation of our efforts to develop novel
MCRs strategies on heterocyclic synthesis,[6,7] herein we
reported a three-component reaction for the synthesis of
2-amino isoindolin-1-ones (Scheme 1). This one-pot
cascade reaction could run under 1 atmospheric pressure
of carbon monoxide in the presence of a catalytic
amount of palladium and afforded 2-amino isoindoli-
nones in moderate to excellent yields from readily
available 2-halobenzaldehydes, carbon monoxide and
hydrazines.
CHO
N
R
+
CO (10 atm)
R
NH2
+
C
X
O
This work
CHO
NH2
Ar
+
+ CO (1 atm)
N
N
O
NH
Ar
H
C
X
Results and Discussion
Primarily, we screened the reaction conditions for
the reaction of 2-bromobenzaldehyde (1a), phenylhy-
drazine (2a), and CO in the presence of palladium cata-
lyst, which gave 2-amino isoindolin-1-one (3a) (Table
1). When the reaction was carried out under palladium
acetate and DPPB in DMF at 120 ℃ for 12 h,[4,8] 3a
was obtained in 83% yield (Table 1, Entry 1). Lowering
the reaction temperature to 90 ℃, the yield could be
reduced down to 16% (Table 1, Entries 1－4). The op-
timal reaction time was found to be 12 h (Table 1, En-
tries 5 and 6). DPPP worked well for the reaction, while
PPh3 did not work at all (Table 1, Entries 7 and 8).
Changing the base additive from Et3N to K2CO3 or
Cs2CO3 led to a remarkable reduction in yield (Table 1,
Entries 9 and 10). Two equivalent amounts of Et3N
were essential to the reaction (Table 1, Entries 11－13).
DMF was selected as the optimal solvent among all of
the screened solvents, such as THF, toluene, 1,4-dioxane,
*
E-mail: pinglu@zju.edu.cn (P. Lu), orgwyg@zju.edu.cn (Y. G. Wang); Fax: 0086-0571-87951512
Received August 4, 2012; accepted October 14, 2012; published online December 11, 2012.
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/cjoc.201200798 or from the author.
182
© 2013 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2013, 31, 182—186

A Facile Synthesis of 2-Aminoisoindolin-1-ones
acetonitrile, and DMSO (Table 1, Entries 14－18). We
also examined the Pd(0) catalyst Pd(PPh3)4, but a poor
yield was obtained. Structure of 3a was established by
single crystal analysis (Figure 1).[13]
ble 1, Entry 3), the substrate diversity was tested and the
results are summarized in Table 2. Structures of 3a－3p
1
were characterized by H NMR, 13C NMR, IR and
HRMS. Copies of spectra were presented in supporting
information. Electronic effect of the substituents on
phenyl hydrazine was observed. With strong electron-
donating group (2c) or strong electron-withdrawing
group (2f) on 4-position of phenyl hydrazine, apparently
lower yields were obtained in comparison with those
with moderate electron-donating group (2b) or electron-
withdrawing group (2d) (Table 2, Entries 1－7). Re-
markably, 2-tolylhydrazine (2i) afforded 3i in 90% yield,
while 3-tolylhydrazine (2h) gave 3h in 74% yield only.
Similar situation was observed for the pair of 2j and 2k,
which furnished 3j and 3k in 73% and 81% yields, re-
spectively (Table 2, Entries 8－11). Acetohydrazide (2l)
and benzohydrazide (2m) also worked for this trans-
formation and produced 3l and 3m in 53% and 65%
yields, accordingly (Table 2, Entries 12 and 13). Elec-
Table 1 Optimization of reaction conditions for the synthesis of
3aa
CO (balloon)
CHO
Solvent, T, 12 h
+
NH2
Pd(OAc)2, Ligand
Base
Br
N
H
1a
2a
O
N
NH
3a
Entry Ligand (%) Base (equiv.) Solvent T/℃ Yieldb/%
1c
2c
DPPB (4%) Et3N (2.0)
DPPB (4%) Et3N (2.0)
DPPB (2%) Et3N (2.0)
DPPB (2%) Et3N (2.0)
DPPB (2%) Et3N (2.0)
DPPB (2%) Et3N (2.0)
DPPP (2%) Et3N (2.0)
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
120
110
100
90
83
82
Table 2 Scope of the reactiona
3
83
CO (balloon)
DMF, 100 o
CHO
4
5c
6d
16
R2
C
NH2
R1
+
N
H
100
100
100
100
100
100
100
100
100
reflux
100
53
2 mol% Pd(OAc)2
X
C
83
2
1
2 mol% DPPB
2 equiv. Et3N
7
79
R2
NH
R1
N
8
PPh3 (4%)
Et3N (2.0)
trace
7
9
DPPB (2%) K2CO3 (2.0) DMF
DPPB (2%) Cs2CO3 (2.0) DMF
O
10
11
12
13
14e
14e
16e
17e
18e
26
3
Entry
1
1 (R1, X)
2 (R2)b
3/(Yieldc/%)
DPPB (2%) Et3N (3.0)
DPPB (2%) Et3N (1.0)
DMF
DMF
DMF
THF
83
65
1a (H, Br)
2a (Ph)
3a/83
3b/55
3c/47
3d/95
3e/68
3f/38
3g/84
3h/74
3i/90
DPPB (2%)
－
N.R.
trace
17
2
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
2b (4-MeC6H4)
2c (4-MeOC6H4)
2d (4-ClC6H4)
2e (4-FC6H4)
2f (4-NO2C6H4)
2g (4-CF3C6H4)
2h (3-MeC6H4)
2i (2-MeC6H4)
2j (3-CF3C6H4)
2k (2-CF3C6H4)
2l (MeCO)
2m (PhCO)
2a
DPPB (4%) Et3N (2.0)
DPPB (4%) Et3N (2.0)
DPPB (4%) Et3N (2.0)
DPPB (4%) Et3N (2.0)
DPPB (4%) Et3N (2.0)
3
4d
toluene
dioxane 100
MeCN reflux
trace
34
5
6
7d
DMSO
100
messy
a Reaction conditions: 1a (1.05 mmol), 2a (1.0 mmol), Pd(OAc)2
8
(0.02 mmol), ligand, base, solvent (5 mL), CO (1 atm), the indi-
9
b
cated temperature, 12 h. Yield of isolated product. c Reacted for
10d
11d
12
13
14
15
16
17
18
3j/73
3k/81
3l/53
4 h. d Reacted for 18 h. e 4 mol% Pd(OAc)2 was used.
3m/65
3n/85
3o/90
3p/81
3a/85
3d/49
1b (4-Me, Br)
1c (5-F, Br)
1d (5-MeO, Br)
1e (H, I)
2a
2a
2a
1f (H, OTf)
2d
a Reaction conditions: 1 (1.05 mmol), 2 (1.0 mmol), Pd(OAc)2
(0.02 mmol), DPPB (0.02 mmol), Et3N (2.0 mmol), DMF (5 mL),
CO (1 atm), 100 ℃, 12 h. b If 2 was in its hydrochloride form,
Et3N (3.0 equiv) was added. c Yield of isolated products. d The
reaction completed in 4 h.
Figure 1 Ellipsoid plot of 3a with the thermal ellipsoid drawn
at the 50% probability level.
With the optimized reaction conditions in hand (Ta-
Chin. J. Chem. 2013, 31, 182—186
© 2013 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
183

Han et al.
FULL PAPER
tron-withdrawing substituent on 2-halobenzal-dehyde
(1c) favored the reaction and gave the highest yield
among those with electron-donating groups (Table 2,
Entries 14－16). Slightly higher yield was observed for
2-iodobenzaldehyde (1e) as compared to 2-bromo-ben-
zaldehyde (1a) (Table 2, Entries 1 and 17), while lower
yield was observed for 1f that contains C-OTf bond
(Table 2, Entries 4 and 18).
Based on these results, we proposed a plausible
mechanism for this Pd-catalyzed carbonylation cycliza-
tion (Scheme 2). Initially, the condensation of 1a with
2a generates A. In the presence of the palladium catalyst,
an oxidative addition occurs over C－Br bond of A and
leads to the formation of B, which subsequently coordi-
nates with CO under its atmosphere to form C. Assisted
by the lone-pair electrons of the nitrogen, intermediate
D is formed via the migratory insertion of CO.[9] Addi-
tion of acyl palladium D to imine intramolecularly[10]
leads to cyclization to form E. Then, E undergoes a
metal-H exchange[12] to produce the final product 3a
cellent yields with high atom efficiency, and the sub-
strates are readily available.
Experimental
General information
Infrared spectra were obtained on a FTIR spec-
trometer. 1H NMR spectra were recorded on 500 or 400
MHz spectrometer unless noted otherwise and the
chemical shifts were reported relative to internal stan-
dard TMS (δ 0) or DMSO-d6 (δ 2.50). The following
abbreviations are used to describe peak patterns where
appropriate: b＝broad, s＝singlet, d＝doublet, t＝triplet,
q＝quartet, m＝multiplet. Coupling constants are re-
ported in Hertz (Hz). 13C NMR were recorded on 100 or
125 MHz unless noted otherwise and referenced to the
internal solvent signals (central peak is δ 77.0 for CDCl3
or δ 40.0 for DMSO-d6). MS and HRMS were obtained
using EI ionization. Melting points were measured with
micro melting point apparatus. Infrared spectra were
obtained on an FTIR spectrometer.
and Pd(II), which can be reduced back by either the in
[4d,11]
situ generated H2
or DMF[12] to Pd(0) for catalytic
DMF was distilled from CaH2, while THF, dioxane,
toluene were distilled from Na/benzophenone respec-
tively.
cycle.
Scheme 2 Possible mechanism for the formation of 3
General procedure for the synthesis of isoindolinones
3
1a + 2a
H2O
To a solution of Pd(OAc)2 (0.02 mmol), DPPB (0.02
mmol), 1 (1.05 mmol), and 2 (1.0 mmol) in DMF (5 mL)
in Schlenk tube was added Et3N (2.0 mmol) slowly via
a syringe under carbon monoxide atmosphere. The reac-
tion mixture was stirred at 100 ℃ for 12 h. After the
completion of the reaction, the solvent was removed
under reduced pressure. The residue was subjected to
flash chromatography on silica gel (petroleum ether/
ethyl acetate, 2∶1 to 1∶1) to afford pure 3.
H
N
N
Ph
Br
Ph
NH
A
N
[H]
Pd(0)
L
3a
O
Pd(II)
L
H
N
N
Ph
L
2-(Phenylamino)isoindolin-1-one (3a)
White
Br
1
L
solid; m.p. 186－187 ℃; H NMR (DMSO-d6, 500
MHz) δ: 4.64 (s, 2H ), 6.64 (d, J＝8.0 Hz, 2H), 6.77 (t,
J＝7.5 Hz, 1H), 7.18 (t, J＝7.5 Hz, 2H), 7.55 (t, J＝7.0
Hz, 1H), 7.62 (d, J＝7.5 Hz, 1H), 7.68 (t, J＝7.5 Hz,
1H), 7.78 (d, J＝7.5 Hz, 1H), 8.35 (s, 1H); 13C NMR
(125 MHz, DMSO-d6) δ: 50.6, 112.1, 119.1, 123.1,
123.8, 128.0, 129.1, 131.0, 131.9, 140.3, 147.5, 166.3;
ATR-FTIR v: 3252, 1689, 1600, 1523, 1495, 1468,
1397, 755, 734, 691, 669 cm−1; HRMS (EI) calcd for
C14H12N2O ([M]＋) 224.0950, found 224.0948.
Pd
Pd
H
N
L
L
N
Ph
B
CO
Ph
O
E
Br-
H
N
Ph
N
CO
NH
N
Pd
L
L
L
Pd
L
O
D
C
2-(p-Tolylamino)isoindolin-1-one (3b)
White
1
solid; m.p. 184－185 ℃; H NMR (CDCl3, 500 MHz)
δ: 2.23 (s, 3H), 4.57 (s, 2H), 6.54 (s, 1H), 6.65 (d, J＝
8.0 Hz, 2H), 6.98 (d, J＝8.0 Hz, 2H), 7.43 (d, J＝8.0 Hz,
1H), 7.48 (t, J＝7.5 Hz, 1H), 7.58 (t, J＝7.5 Hz, 1H),
7.88 (d, J＝7.0 Hz, 1H); 13C NMR (CDCl3, 125 MHz) δ:
20.7, 51.3, 113.9, 123.2, 124.2, 128.4, 129.9, 130.8,
131.4, 132.2, 140.0, 144.3, 167.8; ATR-FTIR v: 3245,
1686, 1610, 1509, 1471, 1395, 738, 711 cm−1; HRMS
(EI) calcd for C15H14N2O ([M] ＋ ) 238.1106, found
238.1107.
Conclusions
In summary, we developed an efficient synthesis of
2-aminoisoindolin-1-ones via a palladium-catalyzed
carbonylation reaction of 2-halobenzaldehydes, aryl
hydrazines and carbon monoxide. The presented
three-component reaction can be run smoothly under 1
atmospheric carbon monoxide. Furthermore, the proce-
dure furnishes the desired products in moderate to ex-
184
www.cjc.wiley-vch.de
© 2013 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2013, 31, 182—186

A Facile Synthesis of 2-Aminoisoindolin-1-ones
2-((4-Methoxyphenyl)amino)isoindolin-1-one (3c)
White solid; m.p. 162－163 ℃; H NMR (CDCl3, 500
(m, 2H), 6.60 (s, 1H), 6.69 (d, J＝7.5 Hz, 1H), 7.07 (t,
J＝7.5 Hz, 1H), 7.45 (d, J＝7.0 Hz, 1H), 7.49 (t, J＝7.0
Hz), 7.59 (t, J＝7.0 Hz, 1H), 7.90 (d, J＝7.5 Hz, 1H);
13C NMR (CDCl3, 125 MHz) δ: 21.5, 51.2, 110.5, 114.1,
122.1, 123.1, 124.1, 128.2, 129.1, 131.1, 132.1, 139.2,
139.8, 146.6, 167.7; ATR-FTIR v: 3241, 1684, 1595,
1448, 985, 772, 735 cm−1; HRMS (EI) calcd for
C15H14N2O ([M]＋) 238.1106, found 238.1108.
1
MHz) δ: 3.71 (s, 3H), 4.55 (s, 2H), 6.60－6.62 (m, 1H),
6.71－6.75 (m, 4H), 7.42 (d, J＝7.5 Hz, 1H), 7.47 (t,
J＝7.5 Hz, 1H), 7.57 (t, J＝7.5 Hz, 1H), 7.87 (d, J＝7.5
Hz, 1H); 13C NMR (CDCl3, 125 MHz) δ: 51.0, 55.6,
114.7, 115.5, 123.0, 124.0, 128.2, 131.2, 131.9, 139.8,
140.1, 154.7, 167.7; ATR-FTIR v: 3236, 1684, 1504,
1451, 1396, 1289, 1245, 1167, 1034, 782, 739, 710 cm−1;
HRMS (EI) calcd for C15H14N2O2 ([M]＋) 254.1055,
found 254.1058.
2-(o-Tolylamino)isoindolin-1-one (3i)
White
1
solid; m.p. 167－168 ℃; H NMR (CDCl3, 500 MHz)
δ: 2.24 (s, 3H), 4.61 (s, 2H), 6.44 (s, 1H), 6.54 (d, J＝
8.0 Hz, 1H), 6.83 (t, J＝7.5 Hz, 2H), 7.09 (d, J＝7.5 Hz,
1H), 7.45 (t, J＝7.5 Hz, 1H), 7.49 (t, J＝7.5 Hz, 1H),
7.59 (t, J＝7.5 Hz, 1H), 7.89 (d, J＝7.5 Hz, 1H); 13C
NMR (CDCl3, 125 MHz) δ: 17.2, 51.5, 111.9, 121.2,
123.2, 123.5, 124.3, 127.1, 128.4, 131.0, 131.3, 132.2,
140.0, 167.8; ATR-FTIR v: 3240, 1684, 1605, 1506,
1478, 1447, 1397, 753, 732 cm−1; HRMS (EI) calcd for
C15H14N2O ([M]＋) 238.1106, found 238.1103.
2-((4-Chlorophenyl)amino)isoindolin-1-one (3d)
1
White solid; m.p. 184－185 ℃; H NMR (CDCl3, 500
MHz) δ: 4.56 (s, 2H), 6.62 (d, J＝8.5 Hz, 2H), 7.08 (t,
J＝8.0 Hz, 3H), 7.44 (d, J＝7.5 Hz, 1H), 7.49 (t, J＝7.0
Hz, 1H), 7.60 (t, J＝7.5 Hz), 7.86 (d, J＝7.5 Hz, 1H);
13C NMR (CDCl3, 125 MHz) δ: 5.2, 114.5, 123.1, 124.1,
125.7, 128.4, 129.1, 130.9, 132.3, 139.8, 145.3, 167.9;
ATR-FTIR v: 3252, 1682, 1592, 1486, 1442, 1389, 831,
773, 731 cm−1; HRMS (EI) calcd for C14H11ClN2O
258.0560 ([M]＋ ) and 260.0530 ([M＋2]＋ ), found
258.0563 and 260.0532, respectively.
2-((3-(Trifluoromethyl)phenyl)amino)isoindolin-
1
1-one (3j) White solid; m.p. 189－190 ℃; H NMR
(CDCl3, 500 MHz) δ: 4.62 (s, 2H), 6.83－6.84 (m, 1H),
6.92 (s, 1H), 7.06－7.07 (m, 1H), 7.20－7.27 (m, 2H),
7.46－7.53 (m, 2H), 7.62 (t, J＝7.0 Hz, 1H), 7.89 (d,
J＝7.5 Hz, 1H); 13C NMR (CDCl3, 125 MHz) δ: 51.6,
109.8, 109.9, 116.3, 117.7, 123.4, 124.2 (q, J＝271 Hz),
128.7, 130.0, 130.9, 131.9 (q, J＝32.5 Hz), 132.7, 140.1,
147.5, 168.3; ATR-FTIR v: 3255, 1679, 1617, 1393,
1334, 1174, 1126, 797, 734 cm−1; HRMS (EI) calcd for
C15H11F3N2O ([M]＋) 292.0823, found 292.0821.
2-((4-Fluorophenyl)amino)isoindolin-1-one (3e)
1
White solid; m.p. 173－174 ℃; H NMR (CDCl3, 400
MHz) δ: 4.60 (s, 2H), 6.68－6.71 (m, 3H), 6.86－6.90
(m, 2H), 7.45－7.52 (m, 2H), 7.58－7.61 (m, 1H), 7.88
(d, J＝8.0 Hz, 1H); 13C NMR (CDCl3, 100 MHz) δ:
51.4, 115.0 (d, J＝7.8 Hz), 116.0 (d, J＝23 Hz), 123.2,
124.3, 128.5, 131.1, 132.3, 139.9, 142.8, 158.1 (d, J＝
238 Hz), 167.9; ATR-FTIR v: 3260, 1684, 1612, 1502,
1444, 1388, 1210, 977, 865, 731, 708 cm−1; HRMS (EI)
calcd for C14H11FN2O ([M]＋) 242.0855, found 242.0857.
2-((2-(Trifluoromethyl)phenyl)amino)isoindolin-
1
1-one (3k) White solid; m.p. 138－139 ℃; H NMR
2-((4-Nitrophenyl)amino)isoindolin-1-one
(3f)
(CDCl3, 500 MHz) δ: 4.60 (s, 2H), 6.68 (d, J＝8.5 Hz,
2H), 7.33 (d, J＝8.5 Hz, 2H), 7.46 (d, J＝8.0 Hz, 1H),
7.51 (t, J＝7.5 Hz, 1H), 7.54 (s, 1H), 7.62 (t, J＝7.5 Hz,
1H), 7.88 (d, J＝8.0 Hz); 13C NMR (CDCl3, 125 MHz)
δ: 51.2, 113.6, 115.2 (q, J＝30 Hz), 120.6, 123.2, 124.4,
124.5 (q, J＝270 Hz), 126.8 (q, J＝5.0 Hz), 128.5,
130.7, 132.4, 133.3, 139.7, 144.3, 167.5; ATR-FTIR v:
3297, 1693, 1613, 1584, 1508, 1451, 1100, 758, 728
cm−1; HRMS (EI) calcd for C15H11F3N2O ([M] ＋ )
292.0823, found 292.0824.
1
Yellow solid; m.p. 241－242 ℃; H NMR (DMSO-d6,
400 MHz) δ: 4.71 (s, 2H), 6.78 (d, J＝8.5 Hz, 2H), 7.56
(t, J＝7.5 Hz, 1H), 7.65 (d, J＝7.5 Hz, 1H), 7.71 (t, J＝
8.0 Hz, 1H), 7.79 (d, J＝8.0 Hz, 1H), 8.09 (d, J＝8.5 Hz,
1H), 9.52 (s, 1H); 13C NMR (DMSO-d6, 100 MHz) δ:
51.1, 111.4, 123.7, 124.2, 126.4, 128.6, 130.6, 132.8,
139.2, 140.9, 153.9, 166.6; ATR-FTIR v: 3273, 1692,
1594, 1500, 1472, 1383, 1329,1278, 835, 773, 737 cm−1;
HRMS (EI) calcd for C14H11N3O3 ([M]＋) 269.0800,
found 269.0802.
2-(Acetylamino)isoindoline-1-one (3l)
White
1
2-((4-(Trifluoromethyl)phenyl)amino)isoindolin-
solid; m.p. 196－197 ℃; HNMR (DMSO-d6, 500
MHz) δ: 1.97 (s, 3H), 4.56 (s, 2H), 7.53 (t, J＝7.5 Hz,
1H), 7.59 (d, J＝7.5 Hz, 1H), 7.66 (t, J＝7.5 Hz, 1H),
7.75 (t, J＝7.5 Hz, 1H), 10.38 (s, 1H); 13C NMR
(DMSO-d6, 125 MHz) δ: 20.5, 51.0, 123.3, 123.7, 128.1,
130.4, 132.2, 140.7, 166.1, 168.8; ATR-FTIR v: 3199,
3012, 1710, 1666, 1523, 1452, 1290, 729 cm−1; HRMS
(EI) calcd for C10H10N2O2 ([M]＋ ) 190.0742, found
190.0746.
1
1-one (3g) White solid; m.p. 195－196 ℃; H NMR
(CDCl3, 500 MHz) δ: 4.63 (s, 2H), 6.74－6.78 (m, 2H),
6.97 (t, J＝8.0 Hz, 1H), 7.36 (t, J＝8.0 Hz, 1H), 7.52－
7.55 (m, 3H), 7.61－7.64 (m, 1H), 7.92 (d, J＝7.5 Hz,
1H); 13C NMR (CDCl3, 125 MHz) δ: 51.3, 112.3, 122.5
(q, J＝32.4 Hz), 123.2, 124.2, 124.5 (q, J＝271 Hz),
126.6 (q, J＝3.4 Hz), 128.5, 130.7, 132.5, 139.8, 149.5,
168.1; ATR-FTIR v: 3257, 1690, 1613, 1525, 1471,
1397, 1321, 1153, 1103, 1058, 823, 767, 735 cm−1;
HRMS (EI) calcd for C15H11F3N2O ([M]＋) 292.0823,
found 292.0820.
2-(Benzamido)isoindoline-1-one (3m)
White
1
solid; m.p. 247－248 ℃; H NMR (DMSO-d6, 500
MHz) δ: 4.69 (s, 2H), 7.54－7.58 (m, 3H), 7.63－7.65
(m, 2H), 7.71 (t, J＝7.5 Hz, 1H), 7.81 (d, J＝7.5 Hz,
1H), 7.97 (t, J＝8.0 Hz, 2H); 13CNMR (DMSO-d6, 125
MHz) δ: 51.2, 123.3, 123.8, 127.6, 128.2, 128.7, 130.4,
2-(m-Tolylamino)isoindolin-1-one (3h)
White
1
solid; m.p. 177－178 ℃; H NMR (CDCl3, 500 MHz)
δ: 2.23 (s, 3H), 4.60 (s, 2H), 6.44 (s, 1H), 6.52－6.54
Chin. J. Chem. 2013, 31, 182—186
© 2013 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
185

Han et al.
FULL PAPER
353.
131.7, 132.4, 140.8, 165.6, 166.5; ATR-FTIR v: 3244,
2921, 2852, 1694, 1670, 1520, 1469, 1286, 1255, 887,
770, 722, 686 cm−1; HRMS (EI) calcd for C15H12N2O2
([M]＋) 252.0899, found 252.0895.
[3] (a) Multicomponent Reactions, Eds.: Zhu, J.; Bienayme, H.,
Wiley-VCH, Weinheim, Germany, 2005; (b) Domling, A. Chem. Rev.
2006, 106, 17; (c) Tejedor, D.; Garcia-Tellado, F. Chem. Soc. Rev.
2007, 36, 484; (d) Ramon, D. J.; Miguel, Y. Angew. Chem., Int. Ed.
2005, 44, 1602; (e) Wasilke, J. C.; Obrey, S. J.; Baker, R. T.; Bazan,
G. C. Chem. Rev. 2005, 105, 1001; (f) Tietze, L. F. Chem. Rev. 1996,
96, 115; (g) Jiang, B.; Rajale, T.; Wever, W.; Tu, S. J.; Li, G. Chem.
Asian J. 2010, 2318; (h) Bello, D.; Ramon, R.; Lavilla, R. Curr. Org.
Chem. 2010, 14, 332; (i) Zhu, Y. G.; Zhai, C. W.; Hu, W. H. Prog.
Chem. 2010, 22, 1380.
[4] (a) Cho, C. S.; Jiang, L. H.; Lee, D. Y.; Shim, S. C.; Lee, H. S.; Cho,
S. D. J. Heterocyclic Chem. 1997, 34, 1371; (b) Cho, C. S.; Wu, X.;
Jiang, L. H.; Shim, S. C.; Choi, H. J.; Kim, T. J. J. Heterocyclic
Chem. 1998, 35, 265; (c) Cho, C. S.; Wu, X.; Jiang, L. H.; Shim, S.
C.; Kim, H. R. J. Heterocyclic Chem. 1999, 36, 297; (d) Cho, C. S.;
Ren, W. X. Tetrahedron Lett. 2009, 50, 2097; (e) Cho, C. S.; Chu, D.
Y.; Lee, D. Y.; Shim, S. C.; Kim, T. J.; Lim, W. T.; Heo, N. H. Synth.
Commun. 1997, 27, 4141; (f) Grigg, R.; Zhang, L. X.; Collard, S.;
Keep, A. Tetrahedron Lett. 2003, 44, 6979; (g) Gai, X. J.; Grigg, R.;
Khamnaen, T.; Rajviroongit, S.; Sridharan, V.; Zhang, L. X.; Collard,
S.; Keep, A. Tetrahedron Lett. 2003, 44, 7441.
6-Methyl-2-(phenylamino)isoindolin-1-one (3n)
Yellow solid; m.p. 230－231 ℃; HNMR (DMSO-d6,
1
500 MHz) δ: 2.42 (s, 3H), 4.57 (s, 2H), 6.61－6.62 (m,
2H), 6.76－6.77 (m, 1H), 7.15－7.16 (m, 2H), 7.48 (s,
2H), 7.57 (s, 1H), 8.33 (s, 1H); 13C NMR (DMSO-d6,
125 MHz) δ: 20.9, 50.4, 112.1, 119.1, 123.2, 123.5,
129.0, 131.1, 132.8, 137.4, 137.6, 147.6, 166.4;
ATR-FTIR v: 3248, 1690, 1618, 1512, 1452, 1325,
1282, 831, 752 cm−1; HRMS (EI) calcd for C15H14N2O
([M]＋) 238.1106, found 238.1105.
5-Fluoro-2-(phenylamino)isoindolin-1-one
(3o)
1
White solid; m.p. 175－176 ℃; H NMR (CDCl3, 500
MHz) δ: 4.56 (s, 2H), 6.67－6.71 (m, 3H), 6.87 (t, J＝
7.5 Hz, 1H), 7.13－7.20 (m, 4H), 7.85－7.87 (m, 1H);
13C NMR (CDCl3, 125 MHz) δ: 50.9 (d, J＝1.6 Hz),
110.6 (d, J＝24 Hz), 113.4, 116.2 (d, J＝23 Hz), 121.3,
126.3 (d, J＝10 Hz), 127.2 (d, J＝2 Hz), 129.4, 142.2 (d,
J＝10.6 Hz), 146.4, 165.5 (d, J＝250.1 Hz), 166.9;
ATR-FTIR v: 3262, 1685, 1626, 1598, 1478, 1443,
1391, 1249, 749 cm−1; HRMS (EI) calcd for
C14H11FN2O ([M]＋) 242.0855, found 242.0848.
[5] (a) Grigg, R.; Sridharan, V.; Shah, M.; Mutton, S.; Kilner, C.;
MacPherson, D.; Milner, P. J. Org. Chem. 2008, 73, 8352; (b) Egle,
I.; Slassi, A.; Isaac, M.; Ma, F.; Clayton, J.; Joseph, B. WO
2008130853, 2008 [Chem. Abstr. 2008, 149, 513692].
[6] (a) Cui, S. L.; Wang, J.; Wang, Y. G. Org. Lett. 2008, 10, 13; (b) Su,
Y.; Jiang, Z.; Hong, D.; Lu, P.; Wang, Y. G.; Lin, X. F. Tetrahedron
2010, 66, 2427.
5-Methoxy-2-(phenylamino)isoindolin-1-one (3p)
[7] (a) Cui, S. L.; Wang, J.; Wang, Y. G. J. Am. Chem. Soc. 2008, 130,
13526; (b) Hong, D.; Chen, Z.; Lin, X. F.; Wang, Y. G. Org. Lett.
2010, 12, 4608; (c) Hong, D.; Lin, X. F.; Zhu, Y.; Lei, M.; Wang, Y.
G. Org. Lett. 2010, 12, 4608; (d) Cui, S. L.; Lin, X. F.; Wang, Y. G.
Org. Lett. 2006, 8, 4517; (e) Wang, Y. G.; Cui, S. L.; Lin, X. F. Org.
Lett. 2006, 8, 1241; (f) Cui, S. L.; Wang, J.; Lin, X. F.; Wang, Y. G. J.
Org. Chem. 2007, 72, 7779.
[8] (a) Zeng, F. L.; Alper, H. Org. Lett. 2010, 12, 5567; (b) Cao, H.;
Vieira, T. O.; Alper, H. Org. Lett. 2011, 13, 11; (c) Vieria, T. O.;
Meaney, L. A.; Shi, Y. L.; Alper, H. Org. Lett. 2008, 10, 4899; (d)
Cao, H.; McNamee, L.; Alper, H. Org. Lett. 2008, 10, 5281; (e)
Grigg, R.; Sridharan, V.; Suganthan, S.; Bridge, A. W. Tetrahedron
1995, 51, 295; (f) Bocelli, G.; Catellani, M.; Cugini, F.; Ferraccioli,
R. Tetrhedron Lett. 1999, 40, 2623; (g) Grigg, R.; MacLachlan, W.
S.; MacPherson, D. T.; Sridharan, V.; Suganthan, S.; Thornton, P. M.;
Zhang, J. Tetrahedron 2000, 56, 6585; (h) Marosvölgyi-Haskó, D.;
Takács, A.; Riedl, Z.; Kollár, L. Tetrahedron 2011, 67, 1036; (i) Lu,
S. M.; Alper, H. J. Am. Chem. Soc. 2008, 130, 6451.
1
White solid; m.p. 199－200 ℃; H NMR (CDCl3, 500
MHz) δ: 3.85 (s, 3H), 4.57 (s, 2H), 6.61 (d, J＝8.0 Hz,
2H), 6.75 (t, J＝7.5 Hz, 1H), 7.08－7.09 (m, 1H), 7.15
－7.18 (m, 3H), 7.67 (d, J＝8.5 Hz, 1H), 8.26 (s, 1H);
13C NMR (CDCl3, 125 MHz) δ: 50.4, 55.6, 108.3, 112.0,
115.1, 119.0, 123.3, 124.6, 129.0, 142.6, 147.6, 162.6,
166.2; ATR-FTIR v: 3271, 1683, 1607, 1488, 1452,
1393, 1303, 1263, 1090, 1021, 756, 735, 702 cm−1;
HRMS (EI) calcd for C15H14N2O2 ([M]＋) 254.1055,
found 254.1054.
Acknowledgement
This work was supported by the National Natural
Science Foundation of China (21032005).
[9] Negishi, E.; Copéret, C.; Ma, S.; Liou, S. Y.; Liu, F. Chem. Rev.
1996, 96, 365.
References
[10] Roesch, K. R.; Larock, R. C. J. Org. Chem. 2001, 66, 412.
[11] Yu, J. Y.; Schreiner, S.; Vaska, L. Inorg. Chim. Acta 1990, 170, 145.
[12] Cho, C. S.; Kim, J. U.; Choi, H. J. J. Organomet. Chem. 2008, 693,
3677.
[13] CCDC 832672 contains the supplementary crystallographic data for
this paper. These data can be obtained free of charge from The
Cambridge Crystallographic Data Center via www.ccdc.cam.ac.uk/
data_request/cif.
[1] (a) Omura, S.; Iwai, Y.; Hirano, A.; Nakagawa, A.; Awaya, J.; Tsu-
chiya, H.; Takahashi, Y.; Matsuma, R. J. Antibiot. 1977, 30, 275; (b)
Link, J. T.; Raghavan, S.; Danishefsky, S. J. J. Am. Chem. Soc. 1995,
117, 552; (c) Funato, N.; Takayanagi, H.; Konda, Y.; Toda, Y.; Hai-
gaya, Y. Tetrahedron Lett. 1994, 35, 1251.
[2] (a) Kametani, T.; Kigasawa, K.; Hiiragi, M.; Ishimaru, H.; Haga, S.;
Shirayama, K. J. Heterocycl. Chem. 1978, 15, 369; (b) Takahashi, I.;
Kawakami, T.; Hirano, E.; Yokota, H.; Kitajima, H. Synlett 1996,
(Pan, B.; Fan, Y.)
186
www.cjc.wiley-vch.de
© 2013 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2013, 31, 182—186