Palladium-catalyzed intramolecular cyclization of 2-iodobenzamides: An efficient synthesis of 3-acyl isoindolin-1-ones and 3-hydroxy-3-acyliso-indolin- 1-ones

Article abstract of DOI:10.1055/s-0033-1339449

Palladium-catalyzed intramolecular cyclization of 2-iodobenzamides with a 2-oxoethyl function group on the nitrogen atom moiety is presented, providing an efficient method for the synthesis of 3-acyl isoindolin-1-ones and 3-hydroxy-3-acylisoindolin-1-ones under mild conditions in moderate yields. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0033-1339449

1856▌
LETTER
letter
Palladium-Catalyzed Intramolecular Cyclization of 2-Iodobenzamides:
An Efficient Synthesis of 3-Acyl Isoindolin-1-ones and 3-Hydroxy-3-acyliso-
indolin-1-ones
Palladium-Catalyzed Intramolecular Cyclization of 2-Iodobenzamides
Wanli Chen,*a Lina Jin,a Yinghong Zhu,*b Xiaoji Cao,a Lebin Zheng,a Weimin Moa
a
Center of Analysis & Measurement, Zhejiang University of Technology, Hangzhou 310014, P. R. of China
Fax +86(571)88320961; E-mail: chenwl@zjut.edu.cn
b
College of Chemical Engineering and Materials Science, Zhejiang University of Technology, Hangzhou 310014, P. R. of China
E-mail: yhzhuchem@zjut.edu.cn
Received: 23.04.2013; Accepted after revision: 20.06.2013
As a consequence, much attention has been paid to the
Abstract: Palladium-catalyzed intramolecular cyclization of 2-iodo-
synthesis of 3-substituted isoindolinone derivatives. Tra-
benzamides with a 2-oxoethyl function group on the nitrogen atom
ditionally, the preparation of 3-substituted isoindolinones
moiety is presented, providing an efficient method for the synthesis
has been carried out by the nucleophilic attack reduction
sequence of phthalimide, which usually involves the use
of active organometallic nucleophiles.7 The deprotonation
reaction of unsubstituted isoindolinone by strong base
represents another conventional strategy in providing dif-
ferent 3-substituted isoindolinones.8 More modern
achievements in the construction of substituted isoindoli-
nones include rhenium-catalyzed reaction of aromatic al-
dimines with isocyanates,9 superacid-catalyzed aza-
Nazarov reaction of N-acyliminium ion salts,10 palladium-
catalyzed aromatic carbonylation of benzylic amines,11
and iodoamination of R-substituted secondary 2-vinyl-
benzamides.12 Recently, substituted isoindolinones could
be readily prepared by the means of Pd-,13 Rh-14 or Ru-
catalyzed15 C–H activation sequences. Despite these well-
established routes in the synthesis of C-3 functionalized
isoindolinones, development of new and efficient meth-
odologies for the synthesis of isoindolinones with differ-
ent substituent groups from simple, readily available
starting materials remains an active research area in or-
ganic chemistry regarding its broad structural diversity.
of 3-acyl isoindolin-1-ones and 3-hydroxy-3-acylisoindolin-1-ones
under mild conditions in moderate yields.
Key words: intramolecular cyclization, palladium-catalyzed,
3-acyl isoindolin-1-ones, 3-hydroxy-3-acylisoindolin-1-ones,
2-iodobenzamides
Isoindolinones with substitution at C-3 is the core struc-
ture of a number of biologically active natural products
and pharmaceutically interesting compounds.1,2 For
example (Figure 1), pagoclone (A) is a commercialized
anxiolytic drug,3 and lennoxamine (B) is a typical alkaloid
isolated from barberries species.4 Pestalachloride A (C) is
a strongly antifungal metabolite isolated from the plant
endophytic fungus Pestalotiopsis adusta,5 while isoindo-
linone D is a potent inhibitor of DNA gyrase, which
shows promising antibacterial activity against Gram-
positive bacterial strains.6
O
N
N
N
Recently, we have succeeded in the construction of iso-
quinolin-1(2H)-ones through DBU-promoted cyclization
of o-(3-hydroxy-1-alkynyl)benzamides with a 2-oxoethyl
function group on the nitrogen atom moiety, which could
be obtained conveniently by a Sonogashira coupling be-
tween propargyl alcohols and 2-iodobenzamides with a 2-
oxoethyl function group on the nitrogen atom moiety.16
We proposed that this kind of 2-iodobenzamides might be
used as efficient substrates in the construction of isoindo-
linones with an acyl group, which have not been accessi-
ble previously (Scheme 1). Retrosynthetically, 3-acyl
isoindolin-1-one derivatives could be prepared by intra-
molecular α-arylation17 of carbonyl derivatives, which in
turn could be obtained conveniently by a reaction between
2-iodobenzoyl chloride and amino ketone. Herein, we re-
port a general and efficient protocol for the preparation of
3-acyl isoindolin-1-ones18 and 3-hydroxy-3-acylisoindo-
lin-1-ones19 through the palladium-catalyzed intramolec-
ular cyclization of 2-iodobenzamides.
Cl
O
O
MeO
N
pagoclone (A)
MeO
O
OH
O
O
lennoxamine (B)
NH
O
N
OMe
Cl
HO
MeO
HO
N
Cl
pestalachloride A (C)
O
OH
(D)
Figure 1
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DOI: 10.1055/s-0033-1339449; Art ID: ST-2013-W0374-L
© Georg Thieme Verlag Stuttgart · New York

LETTER
Palladium-Catalyzed Intramolecular Cyclization of 2-Iodobenzamides
1857
O
N
O
O
Cl
R1
R2
R1
R2
N
R1
N
+
H
I
R2
I
O
O
O
Scheme 1
In our primary investigations, we selected the intramolec- ing Pd2(dba)3 as the catalyst and Xantphos as the ligand, a
ular cyclization of 2-iodo-N-(2-oxo-2-phenylethyl)-N- much better yield could be obtained (Table 1, entry 14),
phenylbenzamide (1a) as the model reaction (Table 1). while others gave a lower yield (Table 1, entries 10–13).
After workup and isolation, the desired product 2a was
obtained in 54% yield using PdCl2(PPh3)2 as the catalyst
With the optimized reaction conditions in hand (Table 1,
entry 14), we further examined the scope of the reaction20
(Table 1, entry 1). In order to optimize the reaction condi-
and the results are summarized in Table 2. From the re-
tions, several solvents and bases were examined. A lower
sults in Table 2, we can see that the reaction proceeded
yield was obtained when i-Pr2NH was used as the base
(Table 1, entry 4). i-PrOH was found to be the suitable sol-
smoothly to afford 3-acyl isoindolin-1-ones in moderate
to good yields. Lower yields were obtained when R2 was
vent for this transformation in comparison with others,
a methyl group relative to the aryl group (Table 2, entries
such as MeCN, dioxane, ClCH2CH2Cl, DMF and EtOH
10 and 11), and the reactions also needed more time to
(Table 1, entries 3–9). Then, we further examined the ef-
complete.
fect of Pd catalyst and ligand choice on this reaction. Us-
Table 1 Optimization of Reaction Conditions for the Pd-Catalyzed Cyclization of 1aa
O
O
Ph
Ph
Ph
O
catalyst
solvent
N
N
O
Ph
I
1a
2a
Entry
Catalyst
Temp (°C)
Solvent
Base
Yield (%)b
1
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(dppe)
PdCl2(dppf)
70
100
70
70
70
70
70
70
70
70
70
70
70
70
MeCN
DMF
Et3Nc
Et3Nc
Et3N
i-Pr2NH
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
54d
68
81
52
67
64
68
85
88
11
65
54
0
2
3
MeCN
MeCN
dioxane
DCE
4
5
6
7
DMF
8
EtOH
9
i-PrOH
i-PrOH
i-PrOH
i-PrOH
i-PrOH
i-PrOH
10
11
12
13
14
Pd2(dba)3–P(o-MeC6H4)3
Pd2(dba)3–BINAP
Et3N
Et3N
Pd2(dba)3–Xantphos
96
a The reaction was carried out using 1a (0.3 mmol) in solvent (1 mL) and amine (1 mL) with Pd catalyst (5 mol%).
b Isolated yields.
c Et3N (1.5 equiv) was added.
d Amide 1a (34%) was recovered.
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 1856–1860

1858
W. Chen et al.
LETTER
Table 2 Synthesis of 3-Acyl Isoindolin-1-ones 2
Where did the oxygen atom come from? The first reaction
step was run under nitrogen, thus the possibility of the ox-
ygen introduced at the cyclization stage was excluded. So
we thought that the hydroxy isoindolin-1-one product 3a
may come from the reaction between isoindolin-1-one
and oxygen in the air.21 Therefore we conducted the con-
trol experiments which might be helpful for supporting
the above points (Scheme 3).
O
O
Ar
O
Ar
Pd2(dba)3⋅CHCl3 (2.5mol%)
N
N
R1
R1
Xantphos (5 mol%)
R2
R2
I
i-PrOH–Et3N (1:1), 70 °C, N2
O
2
1
Entry R1, R2, Ar
Time (h) Product Yield (%)a
O
Pd2(dba)3⋅CHCl3 (2.5 mol%)
Xantphos (5 mol%)
i-PrOH–Et3N (1:1), 70 °C, O2
1
H, Ph, Ph; 1a
2
2
2
2
5
5
2
2
2
5
5
24
2a
2b
2c
2d
2e
2f
96
95
95
87
94
87
96
66
82
72
58
0b
Ph
O
N
2
H, Ph, p-MeC6H4; 1b
H, Ph, p-ClC6H4; 1c
H, p-FC6H4, Ph; 1d
H, p-MeC6H4, Ph; 1e
H, p-ClC6H4, p-MeC6H4; 1f
5-Cl, Ph, Ph; 1g
no reaction
Ph
I
3
4
1a
O
O
5
Ph
Ph
Ph
N
O2 balloon
N
O
6
O
i-PrOH–Et3N (1:1)
7
2g
2h
2i
HO
Ph
8
5-Me, Ph, Ph; 1h
4-Cl, Ph, Ph; 1i
2a
3a
9
Scheme 3
10
11
12
H, Me, Ph; 1j
2j
When we ran the cyclization reaction under bubbled O2,
only the starting material 1a was recovered due to the pre-
cipitation of palladium black. When isoindolin-1-one 2a
was stirred under O2 at 70 °C, it was completely trans-
formed into the hydroxy product 3a. Further screening
demonstrated that the reaction could be run in a one-pot,
sequential procedure. Using N2 for the first cyclization
step and O2 for the second step, we obtained 3a in 80%
yield. Then, a variety of similar compounds (1b–k) were
also reacted under the same conditions22 and the corre-
sponding 3-hydroxy-3-acylisoindolin-1-ones (3b–k) were
obtained in moderate yields (Table 3, entries 2–11).
H, Me, p-ClC6H4; 1k
H, OEt, Ph; 1l
2k
2l
a Isolated yields based on 1.
b Compound 1l was recovered.
Interestingly, it was surprising to find the formation of the
hydroxy product 3a took place if the reaction mixture was
left overnight under air without any precautions taken af-
ter the cyclization reaction (Scheme 2).
O
O
Pd2(dba)3⋅CHCl3 (2.5 mol%)
In summary, we have developed an efficient method for
the synthesis of 3-acyl isoindolin-1-ones and 3-hydroxy-
3-acylisoindolin-1-ones in moderate to good yields under
mild conditions. Further studies on the scope, mechanism,
and synthetic applications of this transformation are being
carried out in our laboratory.
Ph
Ph
O
Xantphos (5 mol%)
N
O
N
i-PrOH–Et3N (1:1), 70 °C, N2
Ph
HO
Ph
I
air, overnight
3a
1a
Scheme 2
Table 3 Synthesis of 3-Hydroxy-3-acylisoindolin-1-ones 3
O
O
1. Pd2(dba)3⋅CHCl3 (2.5 mol%)
Xantphos (5 mol%)
i-PrOH–Et3N (1:1), 70 °C, N2
Ar
Ar
O
N
O
N
R1
R1
R2
R2
I
HO
2. O2
1
3
Entry
R1, R2, Ar
Time (h)
Product
Yield (%)a
1
2
3
H, Ph, Ph; 1a
24
24
24
3a
3b
3c
80
75
71
H, Ph, p-MeC6H4; 1b
H, Ph, p-ClC6H4; 1c
Synlett 2013, 24, 1856–1860
© Georg Thieme Verlag Stuttgart · New York

LETTER
Palladium-Catalyzed Intramolecular Cyclization of 2-Iodobenzamides
1859
Table 3 Synthesis of 3-Hydroxy-3-acylisoindolin-1-ones 3 (continued)
O
O
1. Pd2(dba)3⋅CHCl3 (2.5 mol%)
Ar
Ar
O
Xantphos (5 mol%)
i-PrOH–Et3N (1:1), 70 °C, N2
N
O
N
R1
R1
R2
I
HO
R2
2. O2
1
3
Entry
R1, R2, Ar
Time (h)
Product
Yield (%)a
4
H, p-FC6H4, Ph; 1d
H, p-MeC6H4, Ph; 1e
24
24
24
24
24
24
24
24
3d
3e
3f
77
79
68
72
62
60
67
51
5
6
H, p-ClC6H4, p-MeC6H4; 1f
5-Cl, Ph, Ph; 1g
7
3g
3h
3i
8
5-Me, Ph, Ph; 1h
4-Cl, Ph, Ph; 1i
9
10
11
H, Me, Ph; 1j
3j
H, Me, p-ClC6H4; 1k
3k
a Isolated yields based on 1.
(5) (a) Li, E.; Jiang, L.; Guo, L.; Zhang, H.; Che, Y. Bioorg.
Med. Chem. 2008, 16, 7894. (b) Slavov, N.; Cvengros, J.;
Neudoerfl, J. M.; Schmalz, H. G. Angew. Chem. Int. Ed.
2010, 49, 7588.
(6) Lubbers, T.; Angehrn, P.; Gmunderb, H.; Herzig, S. Bioorg.
Med. Chem. Lett. 2007, 17, 4708.
Acknowledgment
The Foundation of Zhejiang Province (Y4100662, LY13B020014)
and the Opening Foundation of Zhejing Provincial Top Key Disci-
pline are greatly appreciated.
(7) (a) Beak, P.; Kerrick, S. T.; Donald, J. G. J. Am. Chem. Soc.
1993, 115, 10628. (b) Bousquet, T.; Fleury, J.-F.; Daich, A.;
Netchitailo, P. Tetrahedron 2006, 62, 706. (c) Pearson, W.
H.; Dietz, A.; Stoy, P. Org. Lett. 2004, 6, 1005.
(8) (a) Guo, Z.; Schultz, A. G. J. Org. Chem. 2001, 66, 2154.
(b) Pérard-Viret, J.; Prangé, T.; Tomas, A.; Royer, J.
Tetrahedron 2002, 58, 5103. (c) Wang, E. C.; Chen, H. F.;
Feng, P. K.; Lin, Y. L.; Hsu, M. K. Tetrahedron Lett. 2002,
43, 9163.
(9) Kuninobu, Y.; Tokunaga, Y.; Kawata, A.; Taka, K. J. Am.
Chem. Soc. 2006, 128, 202.
(10) Klumpp, D. A.; Zhang, Y.; O’Connor, M. J.; Esteves, P. M.;
Almeid, L. S. Org. Lett. 2007, 9, 3085.
(11) 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.
(12) Kobayashi, K.; Hase, M.; Hashimoto, K.; Fujita, S.;
Tanmatsu, M.; Morikawa, O.; Konishi, H. Synthesis 2006,
2493.
(13) (a) Zhu, C.; Falck, J. R. Org. Lett. 2011, 13, 1214.
(b) Wrigglesworth, J. W.; Cox, B.; Lloyd-Jones, G. C.;
Booker-Milburn, K. I. Org. Lett. 2011, 13, 5326. (c) Li, D.-
D.; Yuan, T. T.; Wang, G. W. Chem. Commun. 2011, 12789.
(14) (a) Wang, F.; Song, G.; Li, X. Org. Lett. 2010, 12, 5430.
(b) Patureau, F. W.; Besset, T.; Glorius, F. Angew. Chem.
Int. Ed. 2011, 50, 1064. (c) Zhu, C.; Falck, J. R. Tetrahedron
2012, 68, 9192. (d) Zhu, C.; Xie, W.; Falck, J. R. Chem. Eur.
J. 2011, 17, 12591. (e) Zhu, C.; Falck, J. R. Chem. Commun.
2012, 48, 1674.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.SnoIufproig
m
iotSrat
maotrin
r
t
References and Notes
(1) (a) Kundu, N. G.; Khan, M. W.; Mukhopadhyay, R. J. Indian
Chem. Soc. 2001, 78, 671. (b) Bhandari, A.; Boros, E. E.;
Cowan, D. J.; Handlon, A. L.; Hyman, C. E.; Oplinger, J. A.;
Rabinowitz, M. H.; Turnbull, P. S. Int. Pat. Appl.
WO03076440, 2003; Chem. Abstr. 2003, 139, 261291.
(c) Wood, J. L.; Petsch, D. T.; Stoltz, B. M.; Hawkins, E. M.;
Elbaum, D.; Stover, D. R. Synthesis 1999, 1529. (d) Comins,
D. L.; Schilling, S.; Zhang, Y. Org. Lett. 2005, 7, 95.
(e) 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. (f) Honma, T.; Hayashi, K.;
Aoyama, T.; Hashimoto, N.; Machida, T.; Fukasawa, K.;
Iwama, T.; Ikeura, C.; Ikuta, M.; Suzuki-Takahashi, I.;
Iwasawa, Y.; Hayama, T.; Nishimura, S.; Morishima, H.
J. Med. Chem. 2001, 44, 4615.
(2) Substituted 3-methyleneisoindolinones also constitute an
important class of biologically active products; see: Reyes-
González, M. A.; Zamudio-Medina, A.; Ordóñez, M.
Tetrahedron Lett. 2012, 53, 5756; and references therein.
(3) (a) Sorbera, L. A.; Leeson, P. A.; Silvestre, J.; Castaner, J.
Drugs Future 2001, 26, 651. (b) Stuk, T. L.; Assink, B. K.;
Bates, R. C. Jr.; Erdman, D. T.; Fedij, V.; Jennings, S. M.;
Lassig, J. A.; Smith, R. J.; Smith, T. L. Org. Process Res.
Dev. 2003, 7, 851.
(15) Ackermann, L.; Wang, L.; Wolfram, R.; Lygin, A. V. Org.
Lett. 2012, 14, 728.
(4) Fuchs, J. R.; Funk, R. L. Org. Lett. 2001, 3, 3923.
(16) Chen, W.; Cui, J.; Zhu, Y.; Hu, X.; Mo, W. J. Org. Chem.
2012, 77, 1585.
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 1856–1860

1860
W. Chen et al.
LETTER
(17) Recently, Sole and Serrano have reported the synthesis of
isoindoline derivatives through palladium-catalyzed
intramolecular α-arylation reactions of α-amino acid esters.
See: Solé, D.; Serrano, O. J. Org. Chem. 2010, 75, 6267.
(18) For the synthesis of 3-acyl isoindolin-1-one derivatives, see:
(a) Nieto, S.; Sayago, F. J.; Laborda, P.; Soler, T.; Cativiela,
C.; Urriolabeitia, E. P. Tetrahedron 2011, 67, 4185.
(b) Huang, X.; Xu, J. J. Org. Chem. 2009, 74, 8859.
(c) Schmitt, G.; An, N. D.; Poupelin, J. P.; Vebrel, J.; Laude,
B. Synthesis 1984, 758.
(19) For the synthesis of 3-hydroxy isoindolin-1-one derivatives,
see: (a) Dempster, R. K.; Luzzio, F. A. Tetrahedron Lett.
2011, 52, 4992. (b) Colquhoun, H. M.; Zhu, Z.; Cardin, C. J.;
White, A. J. P.; Drew, M. G. B.; Gan, Y. Org. Lett. 2010, 12,
3756. (c) Kise, N.; Isemoto, S.; Sakurai, T. Tetrahedron
2012, 68, 8805. (d) Wang, E. C.; Chen, H. F.; Feng, P. K.;
Lin, Y. L.; Hsu, M. K. Tetrahedron Lett. 2002, 43, 9163.
(e) Kitching, M. S.; Clegg, W.; Elsegood, M. R. J.; Griffin,
R. J.; Golding, B. T. Synlett 1999, 997.
(21) It has been reported that carbonyl compounds can react with
molecular oxygen under basic conditions: (a) Doering, W.
E.; Haines, R. M. J. Am. Chem. Soc. 1954, 76, 482.
(b) Gardner, J. N.; Carlona, F. E.; Gnoj, O. J. Org. Chem.
1968, 33, 3294. (c) Paquette, L. A.; DeRussy, D. T.; Pegg,
N. A.; Taylor, R. T.; Zydowsky, T. M. J. Org. Chem. 1989,
54, 4576. (d) Konen, D. A.; Silbert, L. S.; Pfeffer, P. E. J.
Org. Chem. 1975, 40, 3253. (e) Gardner, J. N.; Popperf, L.;
Carlon, E.; Gnoj, O.; Herzog, H. L. J. Org. Chem. 1968, 33,
3695. (f) Lubin, H.; Tessier, A.; Chaume, G.; Pytkowicz, J.;
Brigaud, T. Org. Lett. 2010, 12, 1496. (g) Yang, Y.;
Moinodeen, F.; Chin, W.; Ma, T.; Jiang, Z.; Tan, C. H. Org.
Lett. 2012, 14, 4762. (h) At present, the mechanism for the
aerobic oxidation of 3-acylisoindoline is not clear. We think
that this transformation could be a radical reaction between
isoindolin-1-one and oxygen because the reaction could be
blocked when 2,2,6,6-tetramethyl-1-piperidinyloxy
(TEMPO) was added.
(22) General Procedure for the Synthesis of 3:
(20) General Procedure for the Synthesis of 2:
2-Iodobenzamides 1 (0.3 mmol), Pd2(dba)3·CHCl3 (0.0075
mmol), Xantphos (0.015 mmol), and i-PrOH (1 mL) were
added into a Schlenk tube at r.t. under N2. After stirring for
5 min, Et3N (1 mL) was added. The reaction mixture was
stirred at 70 °C until the reaction was complete, as monitored
by TLC (usually 2–5 h). Then the reaction mixture was
stirred continuously under O2 for 24 h. The reaction mixture
was cooled and the solvent was removed under reduced
pressure. Saturated NaCl (15 mL) was added, the aqueous
layer was extracted with EtOAc (3 × 15 mL) and dried over
MgSO4. After filtration and removal of the solvent in vacuo,
the residues were purified by flash chromatography (silica
gel; PE–EtOAc, 5:1 → 4:1) to afford 3.
2-Iodobenzamide 1 (0.3 mmol), Pd2(dba)3·CHCl3 (0.0075
mmol), Xantphos (0.015 mmol), and i-PrOH (1 mL) were
added into a Schlenk tube at r.t. under N2. After stirring for
5 min, Et3N (1 mL) was added. The reaction mixture was
stirred at 70 °C until the reaction was complete, as monitored
by TLC (usually 2–5 h). Then the reaction mixture was
cooled and the solvent was removed under reduced pressure.
Dilute HCl (15 mL) was added, the aqueous layer was
extracted with EtOAc (3 × 15 mL) and dried over MgSO4.
After filtration and removal of the solvent in vacuo, the
residues were purified by flash chromatography (silica gel;
PE–EtOAc, 5:1 → 4:1) to afford 2.
3-Benzoyl-2-phenylisoindolin-1-one (2a): solid (mp 178–
180 °C). 1H NMR (500 MHz, CDCl3): δ = 7.99 (d, J = 7.4
Hz, 1 H), 7.95 (d, J = 7.5 Hz, 2 H), 7.69 (d, J = 8.0 Hz, 2 H),
7.64 (t, J = 7.5 Hz, 1 H), 7.47–7.54 (m, 4 H), 7.33 (t, J = 8.2
Hz, 2 H), 7.29 (d, J = 7.5 Hz, 1 H), 7.13 (d, J = 7.4 Hz, 1 H),
6.65 (s, 1 H). 13C NMR (125 MHz, CDCl3): δ = 193.3, 167.7,
138.8, 138.1, 135.1, 134.2, 132.4, 132.3, 129.4, 129.2,
129.1, 128.7, 125.1, 124.8, 122.5, 121.0, 67.0. IR: 3056,
1687, 1372, 752 cm–1. HRMS (ESI): m/z [M + H]+ calcd for
C21H16NO2: 314.1181; found: 314.1177.
3-Benzoyl-3-hydroxy-2-phenylisoindolin-1-one (3a):
solid (mp 124–126 °C). 1H NMR (500 MHz, CDCl3): δ =
8.05–8.07 (m, 1 H), 7.61–7.67 (m, 2 H), 7.47–7.51 (m, 3 H),
7.40–7.41 (m, 1 H), 7.24–7.29 (m, 5 H), 7.19–7.21 (m, 2 H),
6.02 (br s, 1 H). 13C NMR (125 MHz, CDCl3): δ = 195.7,
167.8, 144.1, 134.7, 134.2, 133.6, 132.4, 131.4, 130.8,
129.3, 129.0, 128.8, 127.6, 126.8, 124.8, 122.7, 91.8. IR:
3254, 1684, 1386, 741 cm–1. HRMS (ESI): m/z [M + H]+
calcd for C21H16NO3: 330.1130; found: 330.1142.
Synlett 2013, 24, 1856–1860
© Georg Thieme Verlag Stuttgart · New York