Copper (cat) and phenylboronic acid mediated deformylative C-N coupling of isoindolinone-3-ols with formamides provide C(3) aminoisoindolinones

Article abstract of DOI:10.1007/s12039-018-1474-8

Abstract: Copper(I) iodide efficiently catalyzes deformylative C-N coupling of formamides and isoindolinone-3-ols to provide C(3) primary/secondary amine substituted isoindolinones. The transformation requires a stoichiometric amount of phenylboronic acid as a co-reactant. In the reaction, formamides act as the synthetic equivalent of primary/secondary amines. The method is amenable for the synthesis of a combinatorial library of medicinally relevant C(3) amino substituted isoindolinones. Graphical Abstract: Copper(I) iodide efficiently catalyzes deformylative C-N coupling of formamides and isoindolinone-3-ols in presence of stoichiometric amount of phenylboronic acid (co-reactant) to provide C(3) primary/secondary amine substituted isoindolinones. Here, formamides act as synthetic equivalents of primary/secondary amines. Herein we report synthesis of a combinatorial library of medicinally relevant C(3) amino substituted isoindolinones.

Full text of DOI:10.1007/s12039-018-1474-8

J. Chem. Sci. (2018) 130:74
© Indian Academy of Sciences
https://doi.org/10.1007/s12039-018-1474-8
REGULAR ARTICLE
Special Section on Transition Metal Catalyzed Synthesis of Medicinally Relevant Molecules
Copper (cat) and phenylboronic acid mediated deformylative C-N
coupling of isoindolinone-3-ols with formamides provide C(3)
aminoisoindolinones
H SURYA PRAKASH RAO∗, J PRABHAKARAN, SILAMBARASAN KANNIYAPPAN and
A VEERA BHADRA RAO
Department of Chemistry, Pondicherry University, Puducherry 605 014, India
E-mail: hspr.che@pondiuni.edu.in
MS received 8 January 2018; revised 22 April 2018; accepted 25 April 2018
Abstract. Copper(I) iodide efficiently catalyzes deformylative C-N coupling of formamides and isoindolinone-
3-ols to provide C(3) primary/secondary amine substituted isoindolinones. The transformation requires a
stoichiometric amount of phenylboronic acid as a co-reactant. In the reaction, formamides act as the synthetic
equivalent of primary/secondary amines. The method is amenable for the synthesis of a combinatorial library
of medicinally relevant C(3) amino substituted isoindolinones.
Keywords. Isoindolinones; copper catalysis; deformylative C-N coupling; phenylboronic acid.
1. Introduction
N(2) and C(3) have attracted greater attention (high-
lighted portion in pazinaclone 4, Figure 1).8 Several
efforts were directed towards the synthesis of this core
structure, most of which go through cyclization to form
an isoindolinone nucleus in the final step.9
Isoindole is not as ubiquitous as indole, it is, how-
ever, represented as a part-structure in many bio-active
alkaloids.1 Isoindolinones (1,3-dihydro-2H-isoindole-
1-one;phthalimidines;thehighlightedportioninstachy-
botrysam A 1, Figure 1) form a distinctive sub-group
among isoindoles. Significantly, several alkaloids iso-
lated from marine fungi (e.g., 1) imbibe isoindole core.2
Alkaloids with this heterocyclic core exhibit potent and
varied biological activities and thus isoindole is consid-
ered as a medicinally privileged structure.3 For example,
the potent antifungal agent pestalachloride A 2 (Fig-
ure 1), isolated from the fungus Pestalotiopsis adusta
has an isoindolinone core.4 Over the past few years,
medicinal chemists have been engaged in the synthe-
sis and biological evaluation of a variety heterocyclic
compounds with this core; with an aim to unearth phar-
maceutical compounds.5 Such efforts yielded develop-
ment of anticancer compound lenalidomide 3, used for
treating multiple myeloma,6 and (S)-pazinaclone 4 and
its siblings used for sedative and anxiolytic effects.7
Among the family of isoindolinone heterocyclic com-
pounds, synthesis of those which have a substitution on
For the past few years, we have been engaged in
the copper-mediated synthesis of a variety of hete-
rocyclic compounds via C(sp3)-C(sp2) coupling reac-
tions.10 In the context of the synthesis of C(3) substi-
tuted isoindolinones, we have reported a facile copper-
mediated coupling of 3-hydoxyisoindolinones 5 and
aryl-, heteroaryl- and alkenylboronic acids with con-
comitant removal of boric acid to provide C(3) aryl/
heteroaryl/alkenyl substituted isoindolinones 6 (Equa-
tion 1, Scheme 1).11 Among the various copper cata-
lysts, tried copper(II) trifluoromethanesulfonate
(Cu(OTf)2) worked well in dichloroethane (DCE)
reflux. Both inter- and intra-molecular versions of the
reaction were facile. When we conducted the reaction
of 5 in N,N-dimethylformamide (DMF) medium, unex-
pectedly, it provided C-N coupled product 7 instead
of anticipated C-C coupled product 6 (Equation 2,
Scheme 1). The product 7, obviously did not have the
component of phenylboronic acid, but the reaction did
*
For correspondence
Electronic supplementary material: The online version of this article (https://doi.org/10.1007/s12039-018-1474-8) contains
supplementary material, which is available to authorized users.

74 Page 2 of 13
J. Chem. Sci. (2018) 130:74
Figure 1. Representative examples of natural products (1 and 2) and synthetic drugs (3 and 4) with isoin-
dolinone core.
Scheme 1. Our previous and present work on the synthesis of C(3) substituted isoindolinones 6 and 7.
not take place in the absence of this reagent as well as a variety of coupling reactions conducted under copper
in the absence of copper catalyst. The product forma- catalysis under aerobic/oxidative conditions.14 In our
tion of 7 was evidently going through deformylation reaction, deformylataive C-N coupled product 7 formed
of DMF. Since the reaction was going to completion exclusively. The reaction did not provide even traces
only in the presence of one equivalent of phenylboronic of dehydrative C-C coupled product 8, dehydrogena-
acid, we concluded that it was a co-reactant. Overall, the tive C-O coupled product 9 or methylated product 10
intriguing and surprising result prompted us to explore (Scheme 1). To the best of our knowledge, copper and
the reaction in greater detail and the results are reported phenylboronic acid-mediated deformylative and dehy-
herein. Of late, copper-catalyzed transformations are droxylative C-N coupling as seen in the conversion of
gaining more popularity over palladium catalyzed reac- 3-hydoxyisoindolinone 5 to C(3) N,N-dimethylamino
tions as the copper catalysts are less expensive, less toxic isoindolinone 7 is not known and is being reported for
and biocompatible.12 Recently, Palombi and cowork- the first time.
ers reported access to isoindolinones of the type 7
(N-Mannich bases of 1-isoindolinones) by the reac-
tion of 2-formylbenzonitriles with primary or secondary
2. Experimental
amines under chemical or electrochemical activation.13
In our reaction, DMF (Equation 2, Scheme 1) is a sur-
2.1 General Experimental Methods
rogate and convenient source of dimethyl amine which
is a toxic gas at rt (B.p. = 7 ◦C). Previously, DMF and
The progress of all the reactions was monitored by TLC using
similar formamides have been used as a source of (i)
a suitable mixture of hexanes (a mixture of aliphatic hydro-
carbons that boil between 60–80 ◦C) and ethyl acetate as an
N-acylamines, (ii) amines, (iii) alkyl groups to effect

J. Chem. Sci. (2018) 130:74
Page 3 of 13 74
eluent. Column chromatography was performed on silica gel (400 MHz, CDCl3/CCl4, 1/1) δ 7.86–7.81 (m, 1H), 7.44 (dd,
(100–200 mesh) using increasing percentages of ethyl acetate
in hexanes. 1H NMR (400 MHz), 13C NMR (100 MHz) and
J = 5.7, 2.5 Hz, 2H), 7.40 (d, J = 6.4 Hz, 1H), 7.27 (d,
J = 6.0 Hz, 2H), 7.26–7.22 (m, 2H), 7.19 (dd, J = 5.8,
DEPT-135 spectra were recorded for CDCl3 or CDCl3/CCl4 2.7 Hz, 1H), 5.21 (d, J = 14.7 Hz, 1H), 4.98 (s, 1H), 4.21
(1/1) solutions with a 400 MHz NMR spectrometer with TMS (d, J = 14.6 Hz, 1H), 2.26 (s, 6H); 13C NMR (100 MHz,
astheinternalstandard. Chemicalshifts(inppm)andcoupling CDCl3/CCl4, 1/1) δ 167.3 (C), 142.2 (C), 137.5 (C), 133.0
constants (J in Hz) are given here. IR spectra were recorded (C), 131.3 (CH), 129.1 (CH), 128.7 (CH), 128.5 (CH), 127.5
as KBr pellets with a Nicolet-6700 FT-IR spectrometer. The (CH), 124.0, (CH) 123.5 (CH), 77.3 (CH), 43.6 (CH2), 39.1
melting points were recorded with open-ended capillary tubes (2 x CH3); HRMS (ESI) calcd.. for C17H19N2O (M + H)
with a VEEGO VMP-DS instrument and are uncorrected. 267.1497, found 267.1511.
High-resolution mass spectra were recorded on a quadrupole
time-of-flight (QTOF) mass spectrometer using electro-spray
ionization mode (ESIMS). X-Ray diffraction measurements
were carried out at 298 K on a diffractometer equipped with
2.2b 2-Benzyl-3-(phenylamino)isoindolin-1-one (7b):
α
a graphite monochromator and a Mo-K fine focus sealed
tube (λ = 0.71073 Å). Organic solvents were dried by stan-
dard methods.15 Commercially obtained reagents were used
after purification. Arylboronic acids were purchased from
Sigma-Aldrich and copper salts were purchased from Avra
Chemicals.
2.2 General Procedure for synthesis of N(2)
substituted C(3) aminoisoindolin-1-ones Synthesis of
2-benzyl-3-(dimethylamino)isoindolin-1-one 7a
White solid (103 mg, 78% yield); M.p. 163 ◦C; IR (KBr,
cm−1) 3349, 3033, 2924, 2859, 1683, 1600, 1499, 1261, 1077,
1024, 805, 746, 698; 1H NMR (400 MHz, CDCl3/CCl4, 1/1)
δ 7.80 (dd, J = 6.6, 1.4 Hz, 1H), 7.50–7.44 (m, 2H), 7.44–
7.41 (m, 1H), 7.25 (d, J = 1.7 Hz, 1H), 7.24 (d, J = 0.7 Hz,
1H), 7.22 (d, J = 3.7 Hz, 1H), 7.16–7.13 (m, 2H), 7.11 (d,
J = 1.1 Hz, 1H), 7.11–7.08 (m, 1H), 6.77 (t, J = 7.4 Hz,
1H), 6.55 (dd, J = 8.5, 0.9 Hz, 2H), 5.81 (s, 1H), 5.11 (d,
J = 15.1 Hz, 1H), 4.13 (d, J = 15.1 Hz, 1H); 13C NMR (100
MHz, CDCl3/CCl4, 1/1) δ 167.3 (C), 145.6 (C), 144.0 (C),
137.4 (C), 132.19 (C), 132.12 (CH), 129.6 (CH), 129.5 (CH),
128.7 (CH), 128.3 (CH), 127.6 (CH), 123.8 (CH), 123.2 (CH),
119.5 (CH), 114.4 (CH), 68.8 (CH), 43.2 (CH2); HRMS (ESI)
calcd.. for C21H19N2O (M + H) 315.1497, found 315.1494.
To an oven-dried test tube charged with a mixture of 2-
benzyl-3-hydroxyisoindolin-1-one 5a (100 mg, 1 mmol,),
N,N-dimethylformamide (DMF, 30 mg, 1 mmol), copper
iodide (7.9 mg, 0.1 mmol), phenylboronic acid (50 mg, 1
mmol), N-methylpyrrolidinone (1 mL) were added. The test
tube with the resulting inhomogeneous solution was kept in a
pre-heated (100 ◦C) oil-bath and the contents were stirred.
The progress of the reaction was periodically checked by
TLC for its completion. After the disappearance of the reac-
tants the reaction mixture was cooled to rt and then diluted
with dichloromethane (DCM, 20 mL) and water (20 mL).
The aqueous layer was extracted with (DCM, 20 mL). The
organic layers were mixed and washed with water (2×20 mL)
and brine (1 × 10 mL) sequentially. The organic layer was
dried over Na2SO4. Removal of DCM by under reduced
pressure resulted in a crude product which was purified by
column chromatography (silica gel, gradient elution with
increasing volume of EtOAc in hexanes) to yield pure 2-
benzyl-3-(dimethylamino)isoindolin-1-one as yellow solid.
2.2c 2-Benzyl-3-(cyclohexylamino)isoindolin-1-one
(7c):
2.2a 2-Benzyl-3-(dimethylamino)isoindolin-1-one
(7a):
White solid (103 mg, 77% yield); M.p. 104 ◦C; IR (KBr,
cm−1); 3347, 2928, 2845, 1670, 1510, 1467, 1391, 1354,
1306, 1235, 1176, 1121, 1090, 1035, 964, 842, 746, 694, 624,
520; 1H NMR (400 MHz, CDCl3/CCl4, 1/1) δ 7.84–7.82 (m,
1H), 7.49–7.47 (m, 2H), 7.44 (dd, J = 8.8, 2.1 Hz, 1H), 7.28
(s, 2H), 7.27 (s, 2H), 7.20 (dd, J = 8.6, 4.5 Hz, 1H), 5.22 (d,
J = 15.0 Hz, 1H), 5.16 (s, 1H), 4.29 (d, J = 15.0 Hz, 1H),
Yellow solid (92 mg, 80% yield); M.p. 105 ◦C; IR (KBr, 2.43 (dd, J = 8.6, 4.7 Hz, 1H), 1.68–1.63 (m, 2H), 1.60–
cm−1) 3343, 3035, 2926, 2846, 2787, 1690, 1425, 1358, 1279, 1.56 (m, 1H), 1.50 (d, J = 4.4 Hz, 1H), 1.48 – 1.43 (m, 1H),
1210, 1124, 1059, 976, 936, 796, 747, 700, 600, 523; 1H NMR 1.12 (d, J = 8.0 Hz, 2H), 1.09–1.02 (m, 2H), 1.00 – 0.92

74 Page 4 of 13
J. Chem. Sci. (2018) 130:74
(m, 1H); 13C NMR (100 MHz, CDCl3/CCl4, 1/1) δ 167.4 NMR (100 MHz, CDCl3/CCl4, 1/1) δ 167.3 (C), 143.2 (C),
(C), 145.1 (C), 137.7 (C), 132.4 (C), 131.6 (CH), 128.9 (CH), 139.5(C), 137.1(C),132.7(C), 131.5(CH), 128.8(CH), 128.7
128.7 (CH), 128.2 (CH), 127.5 (CH), 123.6 (CH), 123.3 (CH), (CH), 128.6 (CH), 128.4 (CH), 128.0 (CH), 127.3 (CH), 126.3
71.2 (CH), 51.9 (CH), 43.0 (CH2), 35.3 (CH2), 35.0 (CH2), (CH), 123.3 (CH), 123.0 (CH), 71.8 (CH), 42.6 (CH2), 41.7
25.8 (CH2), 25.0 (CH2), 24.93(CH2); HRMS (ESI) calcd. for (CH2), 36.0 (CH2); HRMS (ESI) calcd. for C23H23N2O (M
C21H25N2O (M + H) 321.1967, found 321.1968.
+ H) 343.1810, found 343.1847.
2.2d 2-Benzyl-3-(benzylamino)isoindolin-1-one (7d):
2.2f 3-(Benzo[d]thiazol-2-ylamino)-2-
benzylisoindolin-1-one (7f):
Yellow liquid (110 mg, 80% yield); IR (KBr, cm−1); 3331,
3032, 2914, 1762, 1689, 1461, 1404, 1361, 1300, 1210, 1139,
1078, 966, 794, 741, 701, 519; 1H NMR (400 MHz, CDCl3)δ
7.85 (d, J = 7.3 Hz, 1H), 7.50 (d, J = 0.9 Hz, 1H), 7.49
(s, 1H), 7.46–7.41 (m, 1H), 7.32 (dd, J = 8.0, 1.2 Hz, 2H),
7.28 (d, J = 1.6 Hz, 1H), 7.27–7.24 (m, 2H), 7.23 (s, 1H),
7.21 (d, J = 0.7 Hz, 1H), 7.18 (d, J = 7.0 Hz, 1H), 7.15–
7.10 (m, 2H), 5.29 (s, 1H), 5.11 (d, J = 15.0 Hz, 1H), 4.35
(d, J = 15.0 Hz, 1H), 3.31 (d, J = 13.1 Hz, 1H), 3.21 (d,
J = 13.1 Hz, 1H), 2.28 (d, J = 7.6 Hz, 1H); 13C NMR (100
MHz, CDCl3) δ 167.7 (C), 143.4 (C), 139.7 (C), 137.5 (C),
132.8 (C), 131.9 (CH), 129.1 (CH), 128.8 (CH), 128.4 (CH),
128.3 (CH), 128.1 (CH), 127.6 (CH), 127.1 (CH), 123.4 (CH),
123.3 (CH), 72.4 (CH), 45.5 (CH2), 43.2 (CH2); HRMS (ESI)
calcd. for C22H21N2O (M + H) 329.1654, found 329.1648.
White solid (125 mg, 80% yield); M.p. 170 ◦C; IR (KBr,
cm−1) 3256, 3037, 2926, 1754, 1693, 1603, 1538, 1443,
1261, 1208, 1127, 1065, 804, 749, 700; 1H NMR (400
MHz, CDCl3/CCl4, 1/1) δ 7.77 (dd, J = 6.7, 1.0 Hz, 1H),
7.61–7.55 (m, 2H), 7.54–7.45 (m, 3H), 7.35–7.26 (m, 3H),
7.24–7.19 (m, 3H), 7.17–7.11 (m, 1H), 6.48 (s, 1H), 4.92 (d,
J = 14.9 Hz, 1H), 4.28 (d, J = 14.9 Hz, 1H);13C NMR (100
MHz, CDCl3/CCl4, 1/1) δ 167.6 (C), 165.3 (C), 151.6 (C),
142.6 (C), 137.1 (C), 132.5 (C), 132.1 (C), 131.1 (CH), 130.0
(CH), 128.7 (CH), 128.7 (CH), 127.8 (CH), 126.3 (CH), 123.8
(CH), 123.6 (CH), 122.6 (CH), 121.0 (CH), 119.7 (CH), 68.4
(CH), 43.8 (CH2); HRMS (ESI) calcd. for C22H18N3OS (M
+ H) 372.1171, found 372.1162.
2.2g 2-Benzyl-3-(piperidin-1-yl)isoindolin-1-one(7g):
2.2e 2-Benzyl-3-(phenethylamino)isoindolin-1-one
(7e):
Yellow solid (104 mg, 81% yield); M.p. 115 ◦C; IR (KBr,
cm−1) 3422, 2934, 2803, 1677, 1623, 1594, 1399, 1354, 1121,
1
White solid (108 mg, 75% yield); M.p. 105 ◦C; IR (KBr, 1081, 986, 862, 750, 698, 631, 511; H NMR (400 MHz,
cm−1) 3335, 3029, 2924, 2856, 1762, 1685, 1459, 1407, CDCl3/CCl4, 1/1) δ 7.85–7.79 (m, 1H), 7.48–7.34 (m, 3H),
1360, 1141, 1080, 1020, 745, 700, 557; 1H NMR (400 MHz, 7.29 (t, J = 5.5 Hz, 3H), 7.25–7.10 (m, 2H), 5.17 (d, J =
CDCl3/CCl4, 1/1) δ 7.71 (d, J = 7.2 Hz, 1H), 7.34 (dd, 14.4 Hz, 1H), 4.90 (s, 1H), 4.25 (d, J = 13.6 Hz, 1H), 2.54
J = 7.4, 1.3 Hz, 1H), 7.31 (dd, J = 7.3, 1.3 Hz, 1H), 7.25 (s, 2H), 2.37 (s, 2H), 1.52 (s, 4H), 1.44 (s, 2H); 13C NMR (100
(d, J = 7.1 Hz, 1H), 7.15 (dd, J = 11.9, 4.5 Hz, 2H), 7.09 MHz, CDCl3/CCl4, 1/1) δ 167.2 (C), 142.8 (C), 137.8 (C),
(d, J = 6.7 Hz, 4H), 6.97 (d, J = 7.0 Hz, 4H), 5.00 (s, 133.1 (C), 131.1 (CH), 128.7 (CH), 128.7 (CH), 127.4 (CH),
1H), 4.95 (d, J = 14.9 Hz, 1H), 3.76 (d, J = 14.9 Hz, 1H), 124.0 (CH), 123.4 (CH), 115.6 (CH), 77.9 (CH), 48.6 (CH2),
2.57–2.48 (m, 1H), 2.45–2.36 (m, 1H), 2.35–2.27 (m, 1H), 43.2 (CH2), 26.5 (CH2), 24.6 (CH2); HRMS (ESI) calcd. for
2.17 (dt, J = 11.8, 6.1 Hz, 1H), 2.02–1.86 (m, 1H); 13C C20H23N2O (M + H) 307.1810, found 307.1823.

J. Chem. Sci. (2018) 130:74
Page 5 of 13 74
2.2h 2-Benzyl-3-morpholinoisoindolin-1-one (7h):
25.0 (CH), 24.7 (CH); HRMS (ESI) calcd. for C23H23N2O
(M + H) 343.1810, found 343.1817.
2.2j 2-Benzyl-3-(R)-1-phenylethyl)amino)isoindolin-
1-one (7j):
White solid (94 mg, 73% yield); M.p. 129 ◦C; IR (KBr,
cm−1) 3217, 2924, 2703, 1670, 1438, 1306, 1211, 1115,
1057, 969, 919, 743, 698, 633, 600, 519; 1H NMR (400
MHz, CDCl3/CCl4, 1/1) δ 7.80 (dd, J = 5.8, 2.3 Hz, 1H),
7.46–7.39 (m, 2H), 7.36 (d, J = 7.7 Hz, 1H), 7.25–7.22 (m,
3H), 7.22–7.13 (m, 2H), 5.14 (d, J = 14.5 Hz, 1H), 4.87 (s,
1H), 4.24 (d, J = 14.5 Hz, 1H), 3.56 (t, J = 4.5 Hz, 4H),
2.63–2.49 (m, 2H), 2.43–2.29 (m, 2H); 13C NMR (100 MHz,
CDCl3/CCl4, 1/1) δ 167.2 (C), 141.7 (C), 137.3 (C), 132.8
(CH), 131.3 (C), 129.1 (CH), 128.6 (CH), 128.4 (CH), 127.4
(CH), 123.9 (CH), 123.4 (CH), 77.2 (CH), 67.2 (CH2), 47.6
(CH2), 43.5 (CH2); HRMS (ESI) calcd. for C19H21N2O2 (M
+ H) 309.1603, found 309.1594.
Yellow liquid (90 mg, 62% yield); IR (KBr, cm−1) 3452,
3335, 3028, 2970, 2924, 1758, 1690, 1459, 1407, 1359, 1280,
1211, 1078, 839, 746, 700;1HNMR(400MHz, CDCl3/CCl4,
1/1) δ 7.75 (d, J = 7.5 Hz, 1H), 7.70 (d, J = 7.5 Hz, 1H),
7.43 (d, J = 7.3 Hz, 1H), 7.41–7.39 (m, 1H), 7.37 (d, J =
6.7 Hz, 1H), 7.27 (s, 1H), 7.24 (s, 1H), 7.22 (s, 2H), 7.19
(d, J = 5.4 Hz, 3H), 7.17 (d, J = 3.4 Hz, 3H), 7.14 (d,
J = 4.7 Hz, 2H), 7.11 (s, 3H), 7.10 (s, 2H), 7.08 (s, 2H),
7.06 (s, 2H), 7.05 (s, 2H),), 5.10 (d, J = 14.9 Hz, 1H), 5.02
(s, 1H), 4.99 (s, 1H), 4.85 (d, J = 15.3 Hz, 1H), 4.27 (d,
J = 14.9 Hz, 1H), 3.89 (d, J = 15.3 Hz, 1H), 3.78 (q, J =
6.6 Hz, 1H), 3.63 (q, J = 6.6 Hz, 1H), 1.89 (s, 2H), 1.20 (d,
J = 6.6Hz, 3H), 1.12 (d, J = 6.6 Hz, 3H); 13C NMR (100
MHz, CDCl3/CCl4, 1/1) δ 167.5 (C), 167.3 (C), 145.9 (C),
145.5 (C), 144.6 (C), 144.5 (C), 137.78 (C), 137.71(C), 132.5
(C), 132.2 (C), 131.7 (CH), 131.2 (CH), 130.0 (CH), 129.1
(CH), 128.82 (CH), 128.80 (CH), 128.7 (CH), 128.4 (CH),
128.3 (CH), 127.9 (CH), 127.5 (CH), 127.1 (CH), 126.8 (CH),
126.5 (CH), 126.0 (CH) 123.58 (CH), 123.56 (CH), 123.54
(CH), 123.3 (CH), 122.1 (CH), 71.6 (CH), 71.0 (CH), 54.0
(CH), 53.0 (CH), 43.2 (CH2), 43.0 (CH2), 25.3 (CH), 24.9
(CH); HRMS (ESI) calcd. for C23H23N2O (M + H) 343.1810,
found 343.1801.
2.2i 2-Benzyl-3-(S)-1-phenylethyl)amino)isoindolin-
1-one (7i):
Yellow liquid (95 mg, 66% yield); IR (KBr, cm−1) 3493,
3335, 3032, 2968, 2923, 1764, 1688, 1460, 1409, 1360, 1276,
1
1212, 1081, 975, 747, 700; H NMR (400 MHz, CDCl3)δ
7.82–7.75 (m, 2H), 7.51–7.47 (m, 1H), 7.46–7.40 (m, 2H),
7.34–7.30 (m, 2H), 7.28 (t, J = 4.1 Hz, 2H), 7.24 (s, 1H),
7.22 (d, J = 1.8Hz, 2H), 7.21–7.20 (m, 2H), 7.19 (d, J =
1.4 Hz, 2H), 7.18 (s, 3H), 7.16 (d, J = 2.8 Hz, 2H), 7.14 (t,
J = 2.7 Hz, 2H), 7.13–7.11 (m, 5H), 5.16 (d, J = 14.9 Hz,
1H), 5.09 (s, 1H), 5.05 (s, 1H), 4.91 (d, J = 15.3 Hz, 1H),
4.34 (d, J = 15.0 Hz, 1H), 3.98 (d, J = 15.4 Hz, 1H), 3.83
(q, J = 6.6 Hz, 1H), 3.70 (t, J = 6.6 Hz, 1H), 2.08 (s, 2H),
1.24 (d, J = 6.6 Hz, 3H), 1.18 (d, J = 6.7 Hz, 3H); 13C
NMR (100 MHz, CDCl3)δ 167.6 (C), 167.4 (C), 145.7 (C),
2.2k 3-(Dimethylamino)-2-(4-methoxybenzyl)
isoindolin-1-one (7k):
145.4 (C), 144.49 (C), 144.40 (C), 137.56 (C), 137.53 (C), White solid (102 mg, 92% yield); M.p. 115 ◦C; IR (KBr,
132.3 (C), 131.9 (C), 131.7 (CH), 131.2 (CH), 129.0 (CH), cm−1) 3480, 2939, 2836, 2791, 1763, 1691, 1614, 1512, 1464,
128.7 (CH), 128.67 (CH), 128.62 (CH), 128.60 (CH), 128.3 1411, 1361, 1248, 1180, 1100, 1038, 836, 746, 692, 595, 534;
(CH), 128.2 (CH), 128.1 (CH), 127.8 (CH), 127.35 (CH), 1H NMR (400 MHz, CDCl3/CCl4, 1/1) δ 7.82 (dd, J = 5.8,
127.30 (CH), 126.9 (CH), 126.7 (CH), 126.4 (CH), 123.4 2.7 Hz, 1H), 7.47–7.40 (m, 2H), 7.38 (d, J = 1.9 Hz, 1H),
(CH), 123.3 (CH), 123.28 (CH), 123.24 (CH), 71.5 (CH), 7.21 (d, J = 8.6Hz, 2H), 6.78 (d, J = 8.7Hz, 2H), 5.15 (d,
71.0 (CH), 53.8 (CH), 52.8 (CH), 42.9 (CH2), 42.8 (CH2),
J = 14.5 Hz, 1H), 4.95 (s, 1H), 4.13 (d, J = 14.5 Hz, 1H),

74 Page 6 of 13
J. Chem. Sci. (2018) 130:74
Table 1. Crystallographic data and structure refinement for 7.50–7.44 (m, 2H), 7.43 (d, J = 2.0 Hz, 1H), 7.14 (dd,
7k.
J = 8.5, 7.4 Hz, 2H), 7.08 (d, J = 8.6 Hz, 2H), 6.84–6.78
(m, 1H), 6.78–6.75 (m, 2H), 6.61 (d, J = 1.0 Hz, 1H), 6.59
Empirical Formula
Formula Weight
Bond precision
Wavelength
a, Å
C18H20N2O2
296.37
(d, J = 0.9 Hz, 1H), 5.80 (s, 1H), 5.05 (d, J = 14.9 Hz,
1H), 4.06 (d, J = 14.9 Hz, 1H), 3.76 (s, 3H); 13C NMR
(100 MHz, CDCl3/CCl4, 1/1) δ 167.1 (C), 159.1 (C), 145.7
(C), 144.1 (C), 132.1 (C), 132.0 (CH), 129.7 (C), 129.6 (CH),
129.49 (CH), 129.46 (CH), 123.7 (CH), 123.2 (CH), 119.5
(CH), 114.5 (CH), 114.1 (CH), 68.64 (CH), 55.24 (CH),
42.58 (CH2); HRMS (ESI) calcd. for C22H21N2O2 (M + H)
345.1603, found 345.1610.
C-C 0.0026 Å
0.71073
11.8224(9)
6.2257(5)
21.7641(17)
90
b, Å
c, Å
◦
α
,
β, ◦◦
90.456(7)
90
γ
,
2.2m 3-(Cyclohexylamino)-2-(4-methoxybenzyl)
isoindolin-1-one (7m):
Temperature
Volume
Space group
Hall group
Mr
295 K
1601.9 (2)
P 21/c
-P 2ybc
296.36
Dx, g cm-3
Z
Mu (mm-1)
F000
1.229
4
0.081
632.0
F000’
h,k,lmax
Nref
632.26
16,8,29
4287
White solid (113 mg, 86% yield); M.p. 113 ◦C; IR (KBr,
cm−1) 3337, 2928, 2847, 1679, 1510, 1467, 1391, 1352,
1306, 1236, 1176, 1121, 1090, 1032, 964, 842, 746, 694,
Tmin,Tmax
Tmin’
0.975, 0.992
0.941
Correction method:
TminTmax
Data completeness
Theta(max)
R(reflections)
wR2(reflections)
S
1
0.707, 0.922
0.774
620, 520; H NMR (400 MHz, CDCl3/CCl4, 1/1) δ 7.82
(d, J = 6.9 Hz, 1H), 7.46 (dt, J = 8.8, 3.5 Hz, 3H), 7.21
(d, J = 8.6 Hz, 2H), 6.80 (d, J = 8.6 Hz, 2H), 5.18 (d,
J = 14.8 Hz, 1H), 5.14 (s, 1H), 4.20 (d, J = 14.8 Hz, 1H),
3.76 (s, 3H), 2.48–2.40 (m, 1H), 1.75–1.71 (m, 1H), 1.70–
1.63 (m, 2H), 1.62–1.57 (m, 1H), 1.54–1.45 (m, 2H), 1.15 (d,
J = 7.4 Hz, 2H), 1.12–1.06 (m, 2H), 1.00 (dd, J = 11.1, 8.3
Hz, 1H);13C NMR (100 MHz, CDCl3/CCl4, 1/1) δ 167.3 (C),
159.1 (C), 145.2 (C), 132.6 (C), 131.6 (CH), 129.8 (C), 129.5
(CH), 129.0 (CH), 123.6 (CH), 123.3 (CH), 114.2 (CH), 71.1
(CH), 55.2 (CH), 51.8 (CH), 42.4 (CH2), 35.4 (CH2), 35.1
(CH2), 25.9 (CH2), 25.1 (CH2), 24.9 (CH2); HRMS (ESI)
calcd. for C22H27N2O2 (M + H) 351.2073, found 351.2099.
29.060
0.0466 (2295)
0.1332 (3320)
1.086
Npar
201
3.73 (s, 3H), 2.25 (s, 6H);13C NMR (100 MHz, CDCl3/CCl4,
1/1) δ 167.1 (C), 158.9 (C), 142.2 (C), 132.9 (C), 131.1 (CH),
129.7 (CH), 129.5 (C), 128.9 (CH), 123.7 (CH), 123.3 (CH),
113.9 (CH), 77.1 (CH), 55.0 (CH), 42.7 (CH2), 38.9 (CH);
HRMS (ESI) calcd. for C18H21N2O2 (M + H) 297.1603,
found 297.1600 (Table 1).
2.2n 3-(Benzylamino)-2-(4-methoxybenzyl)isoindolin-
1-one (7n):
2.2l 2-(4-Methoxybenzyl)-3-(phenylamino)isoindolin-
1-one (7l):
Colorless liquid (119 mg, 89% yield); IR (KBr, cm−1) 3333,
White solid (108 mg, 85% yield); M.p. 150 ◦C; IR (KBr, 2915, 2841, 1690, 1611, 1510, 1458, 1401, 1356, 1245, 1176,
cm−1); 3315, 2924, 2839, 1689, 1604, 1512, 1407, 1301, 1086, 1033, 967, 903, 836, 746, 699, 587;1HNMR(400MHz,
1
1249, 1173, 1098, 1030, 972, 902, 824, 749, 694, 546; H CDCl3/CCl4, 1/1) δ 7.86 (d, J = 7.3 Hz, 1H), 7.51 (s, 2H),
NMR (400 MHz, CDCl3/CCl4, 1/1) δ 7.81–7.76 (m, 1H), 7.47 (dd, J = 7.9, 5.1 Hz, 1H), 7.28 (s, 1H), 7.24 (s, 2H),

J. Chem. Sci. (2018) 130:74
Page 7 of 13 74
7.21 (d, J = 7.0 Hz, 2H), 7.15 (d, J = 6.9 Hz, 2H), 6.82 (d,
J = 7.9 Hz, 1H), 7.26 (d, J = 1.5 Hz, 1H), 7.24 (s, 1H),
J = 8.6 Hz, 2H), 5.31 (s, 1H), 5.10 (d, J = 14.8 Hz, 1H), 6.82 (d, J = 2.0 Hz, 1H), 6.81 (d, J = 2.1 Hz, 1H), 5.15
4.27(d, J = 14.8 Hz, 1H), 3.75(s, 3H), 3.35(d, J = 13.0 Hz, (d, J = 14.3 Hz, 1H), 4.90 (s, 1H), 4.19 (d, J = 14.3 Hz,
1H), 3.24 (d, J = 13.0 Hz, 1H), 2.14 (s, 1H); 13C NMR 1H), 3.77 (s, 3H), 2.62–2.51 (m, 2H), 2.39 (d, J = 5.0 Hz,
(100 MHz, CDCl3/CCl4, 1/1) δ 167.7 (C), 159.1 (C), 143.3 2H), 1.54 (d, J = 5.0 Hz, 4H), 1.46 (d, J = 4.2 Hz, 2H);13C
(C), 139.7 (C), 132.9 (C), 131.8 (CH), 129.6 (C), 129.5 (CH), NMR (100 MHz, CDCl3/CCl4, 1/1) δ 167.2 (C), 159.0 (C),
129.2 (CH), 128.4 (CH), 128.1 (CH), 127.2 (CH), 123.5 (CH), 142.9 (C), 133.2 (C), 131.1 (CH), 130.0 (CH), 129.9 (CH),
123.2 (CH), 114.2 (CH), 72.2 (CH), 55.3 (CH), 45.6 (CH2), 128.9 (CH), 123.9 (CH), 123.5 (CH), 114.0 (CH), 77.8 (CH),
42.7 (CH2); HRMS (ESI) calcd. for C23H23N2O2 (M + H) 55.3 (CH), 48.6 (CH2), 42.8 (CH2), 26.6 (CH2), 25.0 (CH2);
359.1760, found 359.1747.
HRMS (ESI) calcd. for C21H25N2O2 (M + H) 337.1916,
found 337.1921.
2.2o 2-(4-Methoxybenzyl)-3-(phenethylamino)
isoindolin-1-one (7o):
2.2q 2-(4-Methoxybenzyl)-3-morpholinoisoindolin-1-
one (7q):
White solid (99 mg, 79% yield); M.p. 130 ◦C; IR (KBr,
Viscous solid (116 mg, 84% yield); IR (KBr, cm−1) 3446, cm−1); 3240, 2923, 2703, 1670, 1440, 1307, 1211, 1118,
2923, 2837, 1685, 1610, 1463, 1406, 1247, 1177, 1089, 1031, 1058, 960, 919, 791, 742, 698, 633, 600, 520; 1H NMR (400
808, 750, 696, 464; 1H NMR (400 MHz, CDCl3/CCl4, 1/1) MHz, CDCl3/CCl4, 1/1) δ 7.88–7.83 (m, 1H), 7.51–7.45 (m,
δ 7.75 (dd, J = 6.5, 1.1 Hz, 1H), 7.43–7.35 (m, 2H), 7.32– 2H), 7.42 (dd, J = 5.9, 2.5 Hz, 1H), 7.26 (s, 1H), 7.24 (d,
7.28 (m, 1H), 7.23 (dd, J = 6.1, 1.3 Hz, 1H), 7.18 (d, J =
J = 1.9 Hz, 1H), 6.84–6.82 (m, 1H), 6.82–6.79 (m, 1H), 5.17
6.5 Hz, 2H), 7.08–7.03 (m, 2H), 6.91 (d, J = 8.6 Hz, 2H), (d, J = 14.4 Hz, 1H), 4.92 (s, 1H), 4.23 (d, J = 14.4 Hz,
6.68 (d, J = 8.7 Hz, 2H), 5.02 (s, 1H), 4.95 (d, J = 14.8 Hz, 1H), 3.78 (s, 3H), 3.66 (t, J = 4.6Hz, 4H), 2.71–2.60 (m,
1H), 3.70 (d, J = 16 Hz, 1H), 3 .68 (s, 3H), 2.65–2.56 (m, 2H), 2.49–2.41 (m, 2H); 13C NMR (100 MHz, CDCl3/CCl4,
1H), 2.53 – 2.43 (m, 1H), 2.38 (ddd, J = 11.1, 8.4, 5.8 Hz, 1/1) δ 167.3 (C), 159.2 (C), 142.0 (C), 133.1 (C), 131.4 (C),
1H), 2.27–2.20 (m, 1H), 1.72 (s, 1H); 13C NMR (100 MHz, 130.0 (CH), 129.6 (CH), 129.3 (CH), 124.1 (CH), 123.5 (CH),
CDCl3/CCl4, 1/1) δ 167.5 (C), 159.2 (C), 143.3 (C), 139.7 114.1 (CH), 77.3 (CH), 67.4 (CH2), 55.3 (CH), 47.8 (CH2),
(C), 133.1 (C), 131.7 (CH), 129.6 (C), 129.3 (CH), 129.1 43.1 (CH2) HRMS (ESI) calcd. for C20H23N2O3 (M + H)
(CH), 129.0 (CH), 128.7 (CH), 126.6 (CH), 123.6 (CH), 123.2 339.1709, found 339.1709.
(CH), 114.2 (CH), 71.9 (CH), 55.3 (CH), 42.4 (CH2), 41.8
(CH2), 36.2 (CH2); HRMS (ESI) calcd. for C24H25N2O2 (M
+ H) 373.1916, found 373.1904.
2.2r 2-(4-Methoxybenzyl)-3-(4-phenylpiperazin-1-yl)
isoindolin-1-one (7r):
2.2p 2-(4-Methoxybenzyl)-3-(piperidin-1-yl)
isoindolin-1-one (7p):
Yellow solid (102 mg, 82% yield); M.p. 120 ◦C; IR (KBr, Viscous solid (120 mg, 78% yield); IR (KBr, cm−1) 2933,
cm−1); 3451, 2933, 2845, 1767, 1693, 1612, 1511, 1459, 2833, 1701, 1603, 1507, 1452, 1394, 1344, 1302, 1244, 1152,
1408, 1246, 1172, 1095, 1038, 1003, 835, 744, 695, 520, 1095, 1018, 967, 836, 752, 527, 479;1H NMR (400 MHz,
1
449; H NMR (400 MHz, CDCl3/CCl4, 1/1) δ 7.84 (dd, CDCl3/CCl4, 1/1) δ 7.89–7.87 (m, 1H), 7.50–7.47 (m, 2H),
J = 5.8, 2.6 Hz, 1H), 7.45 (t, J = 2.8 Hz, 2H), 7.39 (d, 7.44 (dd, J = 5.8, 2.8 Hz, 1H), 7.37 (d, J = 8.6 Hz, 1H),

74 Page 8 of 13
J. Chem. Sci. (2018) 130:74
7.27 (s, 1H), 7.22 (d, J = 7.4 Hz, 2H), 6.88 (d, J = 7.8 Hz, 3. Results and Discussion
2H), 6.84–6.81 (m, 3H), 5.21 (d, J = 14.4 Hz, 1H), 5.02 (s,
1H), 4.24 (d, J = 14.4 Hz, 1H), 3.78 (s, 3H), 3.15 (t, J = 4.8 As a first attempt, we conducted the reaction of C(3)-
Hz, 4H), 2.80 (dd, J = 10.4, 5.1 Hz, 2H), 2.64–2.60 (m, 2H);
hydroxy isoindolinone 5a with phenylboronic acid
13C NMR (100 MHz, CDCl3/CCl4, 1/1) δ 167.3 (C), 159.2
under Cu(OTf)2 catalysis in DMF medium under the
(C), 151.5 (C), 142.2 (C), 133.9 (C), 133.1 (CH), 131.4 (CH),
optimized conditions worked out for the conversion of
130.0 (CH), 129.7 (C), 129.3 (CH), 124.1 (CH), 123.6 (CH),
5a to 6a (Previous work, Scheme 1). The reaction, how-
ever, provided C-N coupled product 7a exclusively in
120.3 (CH), 116.6 (CH), 114.2 (CH), 77.0 (CH) 55.3 (CH),
50.1 (CH2), 47.4 (CH2), 41.2 (CH2); HRMS (ESI) calcd. for
56%yield(Presentwork, Scheme1). Structureof7awas
C26H28N3O2 (M + H) 414.2182, found 414.2213.
confirmed on the basis of spectroscopic (IR, 1H NMR,
13C NMR, DEPT-135, HSQC and HMBC 2D NMR)
and analytical (ESIMS HRMS) data. Particularly, the 1H
2.2s 3-(Dimethylamino)-2-(2-nitrobenzyl)isoindolin-
1-one (7s):
NMR spectrum of 7a displayed the characteristic singlet
for C(3)H at δ 4.98 ppm, which was located between two
doublets for diastereomeric benzylic hydrogens (δ 5.21
and 4.21 ppm). As anticipated from the structure, the
signal for C(3)H of 7a moved to up-field by about δ
0.54 ppm when compared to its location (δ 5.52 ppm) in
the parent isoindolinone 5a.16 A signal for C(3) located
at δ 77.3 ppm (CH type in DEPT-135) and HMBC 2D
NMR correlation between C(3)H and NMe supported
White solid (59 mg, 54% yield); M.p. 105 ◦C; IR (KBr,
the assigned structure.
cm−1) 2937, 2867, 2784, 1701, 1611, 1528, 1461, 1410, 1352,
1290, 1036, 979, 856, 791, 743, 568; H NMR (400 MHz,
Next, we have taken up optimization of reaction
conditions to increase the yield of 7a. We conducted
a series of reactions by changing the Cu catalysts.
We tried Cu(II) catalysts like Cu(OOCCF3)2(27%),
Cu(OAc)2.H2O (47%) and CuBr2(41%) followed by
Cu(I) catalysts like CuI (Scheme 2 and Figure 2, 80%),
1
CDCl3/CCl4, 1/1) δ 7.99–7.95 (m, 1H), 7.87 (dd, J = 6.3,
1.5 Hz, 1H), 7.56–7.52 (m, 1H), 7.51 (dd, J = 2.9, 1.8
Hz, 2H), 7.50–7.46 (m, 1H), 7.46–7.42 (m, 1H), 7.40 (dd,
J = 8.3, 2.2 Hz, 1H), 5.26 (d, J = 16.4 Hz, 1H), 5.10 (s,
1H), 4.95 (d, J = 16.4 Hz, 1H), 2.16 (s, 6H);13C NMR (100
MHz, CDCl3/CCl4, 1/1) δ 167.8 (C), 148.9 (C), 142.1 (C), CuBr (64%), CuCl (61%) and copper(I) thiophene-2-
133.23 (C), 133.21 (CH), 132.3 (C), 131.5 (CH), 130.3 (CH),
129.1 (CH), 127.9 (CH), 124.6 (CH), 123.9 (CH), 123.3 (CH),
78.9 (CH), 40.2 (CH2), 38.7 (CH); HRMS (ESI) calcd. for
C17H18N3O3 (M + H) 312.1348, found 312.1345.
carboxylate (CuTc; 43%). These set of experiments
clearly showed that CuI is the best catalyst for the
transformation. We found that the reaction works in
open air and does not proceed under a blanket of dry
N2 indicating oxygen is involved in the regeneration
of the catalyst. Alternate oxidizing agents like t-butyl
hydroperoxide (TBHP, 12%) or 30% hydrogen peroxide
(8%) did not promote the reaction which showed their
lower efficiency. By varying mol% of CuI from 0.1
mol% to 1 equivalent, we found that the transforma-
tion is best achieved with 10 mol% of CuI. The reaction
did not take place in the presence of radical initia-
tors like azobisisobutyronitrile (AIBN) or stable radical
like (2,2,6,6-tetramethylpiperidin-1-yl)oxyl (TEMPO)
which indicate that radical chain reactions may not be
driving the reaction. Reaction worked less efficiently in
presence of one equivalent of 4-ClC6H4B(OH)2 (50%)
or 4-MeC6H4B(OH)2(48%) compared to C6H5B(OH)2
(80%). Unlike the transformation of isoindolinol 5 to
C-C coupled product 6 (Scheme 1, Equation 1) which
required Na2CO3, the reaction of 5 with DMF did not
require any base.
2.2t 2-Allyl-3-(dimethylamino)isoindolin-1-one (7t):
Yellow solid (83 mg, 72% yield); M.p. 55 ◦C; IR (KBr, cm−1
)
3032, 2933, 2790, 1695, 1610, 1463, 1409, 1363, 1283, 1205,
1143, 1037, 977, 794, 743, 700, 609, 526;1H NMR (400 MHz,
CDCl3/CCl4, 1/1) δ 7.83 (d, J = 6.8 Hz, 1H), 7.46 (dd, J =
10.3, 3.8 Hz, 3H), 5.94–5.76 (m, 1H), 5.20 (t, J = 11.2 Hz,
3H), 4.57 (dd, J = 15.3, 4.4 Hz, 1H), 3.77 (dd, J = 15.3, 7.4
Hz, 1H), 2.31 (s, 6H); 13C NMR (100 MHz, CDCl3/CCl4,
1/1) δ 167.3 (C), 142.6 (C), 133.6 (C), 133.2 (CH), 131.3
(CH), 129.1 (CH), 123.9 (CH), 123.5 (CH), 117.7 (CH2),
77.9 (CH), 42.7 (CH2), 39.2 (CH); HRMS (ESI) calcd. for
C13H17N2O (M + H) 217.1341, found 217.1329.
To be a successful synthetic scheme for the devel-
opment of medicinal drugs, products should be derived

J. Chem. Sci. (2018) 130:74
Page 9 of 13 74
Scheme 2. Copper and phenylboronic acid mediated deformylative amination of isoindolinols 5 with
N-formyl amines 8 to form C(3)amino isoindolinins 7.
from the reactants which have readily variable domains. Furthermore, PMB group is amenable for removal
In the reactants of the present scheme (Scheme 2), under oxidative conditions. The series of reactions of
namely isoindolinone 5 and amines 8, we envisage 5b conducted with N-formylamides 8a–h consistently
possibilities of changes in three domains, that is, sub- provided a better yield of the products 7k–q indicat-
stituents on (i) amines 8, (ii) N(2) and (iii) aromatic ing that electron donating substituents on the benzyl
ring of 5. For the present work, we varied substituents ring promote substitution at C(3). Finally, in the series
in two domains, namely amines 8 and N(2) of isoin- we reacted 5b with N(4)phenyl N(1)formylpiperizine
dolinones 5 to generate a combinatorial library of twenty 8k under optimized reaction conditions to get isoin-
isoindolinones 7 (Scheme 2 and Figure 2). In the first dolinone 7r which has many structural similarities
instance, we employed formamides derived from pri- of the developmental drug, a dopamine D4 antag-
mary (8b–f) and secondary amines (8g–h) and reacted onist (S)-PD172938.17 Next, we sought to evaluate
each of them with 5a, in N-methylpyrrolidone (NMP) if an electron-withdrawing group (e.g., NO2) in the
medium in the presence of CuI (cat) and phenylboronic N(2) benzyl substituent would reduce the reactivity of
acid (stoichiometric). The reactions provided a very isoindolinone 5 with DMF. Accordingly, we reacted
good yield of the isoindolinones 7b-f. The products 7e 5c with DMF 8a under optimized reaction conditions
and 7f are noteworthy as they respectively have medici- and realized 7s, albeit, in lower yield. The N(2) 2-
nallyprivilegedphenylethylaminoandbenzo[d]thiozol- nitrobenzyl group on isoindolinone 5c was selected
2-ylamino moieties. Next, we employed formamides because of photo-labile nature of 2-nitrobenzyl substi-
derivedfromsecondaryamineslike N-formylpiperidine tution. Thus, the set of reactions of DMF with 5a–c
8g and N-formylmorpholine 8h. The reactions pro- showed that electron-donating groups on N(2) ben-
vided corresponding isoindolinones 7g–h in good yield. zyl promote deformylative amino-substitution whereas
We reasoned that the reaction with optically active [S] electron-withdrawing groups impede. Finally, in the
or [R] 1-phenylethylamine could provide one of the present series, we conducted the reaction of isoin-
two possible diasteromers in excess. Regrettably, how- dolinone with N-allyl substitution 5d with DMF and
ever, the reactions conducted with [S] 8i and [R] 8j realized 7t without any difficulty. Structures of the isoin-
N-formyl-1-phenylethylamines provided diasteromeric dolinones 7b–t were confirmed by spectroscopic (IR,
mixtures 7i–j in which the diasteromers were present NMR) and analytical (ESIMS HRMS) data. In the case
in 1:1 ratio; as evidenced by 13C NMR spectra. Next, of 7k, we recorded single crystal X-ray structure data
we changed benzyl group on N(2) to 4-methoxybenzyl and the out-put confirmed the assigned structure (see
(PMB) to evaluate the influence of electron donating experimental section and supplementary information)
OMe in the outcome of the deformylative amination. (Figure 3).

74 Page 10 of 13
J. Chem. Sci. (2018) 130:74
Figure 2. Structures of N(2) and C(3) substituted isoindolinones 7a–t with time taken for the reaction and yield.
Based on the above results we propose a speculative
mechanism as given in Scheme 3. We believe that in
the first step Cu(I) reacts with phenylboronic acid to
form Cu(III) transmetallated product 9. Highly reactive
Cu(III) intermediate 9 then reacts with isoindolinone 5
to form stable boric acid and organo-copper(III) inter-
mediate 10. Reaction of 10 with formamides 8 leads
to benzene and 11. Loss of carbon-monoxide gener-
ates 12. Final step in the sequence is the generation of
C-N coupled product 7 and Cu(I) species. The intere-
mediate 10 or even 9 can generate biphenyl as the
side product. Indeed, we have isolated biphenyl as a
minor side product (about 20%) in each of the reactions
given in Scheme 2. In the presence of copper-chelating
formamides, the reaction does not follow the path where
C-C bond formation (Equation 1, Scheme 1) takes
Figure 3. ORTEP diagram for 3-(dimethylamino)-2-
(4-methoxybenzyl)isoindolin-1-one 7k.

J. Chem. Sci. (2018) 130:74
Page 11 of 13 74
Scheme 3. Proposed mechanism for the copper and phenylboronic acid mediated
deformylative amination of isoindolinones.
place; instead it goes through C-N bond formation AVR thanks CSIR, and S.K thanks PU for fellowships. We
thank CIF, Pondicherry University for recording some of the
spectra.
(Scheme 3).
4. Conclusions
References
In conclusion, we have demonstrated an unprecedented
Cu(I) catalyzed and phenylboronic acid-mediated trans-
formation of isoindolinone-3-ols into C(3) substituted
amino isoindolinones. The reaction goes through a
deformylativeC-Ncoupling. Wehavedemonstratedthat
DMF is a synthetic equivalent of foul smelling, toxic
and gaseous N,N-dimethylamine. The transformation
has wide scope and can be applied for the synthesis of a
combinatoriallibraryofmedicinallyrelevantmolecules.
1. (a) Review: Speck K and Magauer T 2013 The chemistry
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Supplementary Information (SI)
Characterization data, details of the NMR structural deter-
mination of all new compounds and copies of 1H, 13C NMR,
DEPT-135 and HRMS spectra for all the compounds are given
in the supplementary information. Supplementary informa-
tion is available at www.ias.ac.in/chemsci.
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H S P R thanks UGC, UGC-SAP, and DST-FIST for financial
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