The interaction of 4-hydroxymethyl isoindolines with dehydrobenzene. Synthesis of 3-phenylaminomethyldihydrobenzo[c]furanes

Article abstract of DOI:10.1016/j.tet.2015.01.022

2-Alkyl or 2-aryl-substituted 4-hydroxymethylisoindolines smoothly undergo intramolecular recyclization through reaction with arynes to give isobenzofurans with good yields.

Full text of DOI:10.1016/j.tet.2015.01.022

Tetrahedron 71 (2015) 1175e1181
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
The interaction of 4-hydroxymethyl isoindolines with
dehydrobenzene. Synthesis of 3-phenylaminomethyldihydrobenzo
[c]furanes
Alexey V. Varlamova, Natalia I. Guranova a, Tatiana N. Borisova a, Flavien A.A. Toze b,
,
Maxim V. Ovcharovc, Sindi Kristancho a, Leonid G. Voskressensky a
*
a Organic Chemistry Department of Peoples’ Friendship University of Russia, 6, Miklukho-Maklaya St., Moscow 117198, Russia
b Department of Chemistry, University of Douala, Faculty of Sciences, PO Box 24157, Douala, Cameroon
c Bruker Ltd, 50/2-1 Pyatnitskaya St., Moscow 119017, Russia
a r t i c l e i n f o
a b s t r a c t
Article history:
2-Alkyl or 2-aryl-substituted 4-hydroxymethylisoindolines smoothly undergo intramolecular recycliza-
tion through reaction with arynes to give isobenzofurans with good yields.
Ó 2015 Elsevier Ltd. All rights reserved.
Received 12 November 2014
Received in revised form 31 December 2014
Accepted 12 January 2015
Available online 16 January 2015
Keywords:
Phthalans
Isobenzofurans
Dehydrobenzene
Isoindolines
Recyclization
Diarylamines
1. Introduction
antimicrobial, antihistamine, antimycotic,7 anti-HIV,8 and anti-
cancer9 activities. CitalopramÒ and TalopramÒ are registered
Dehydrobenzenes or arynes, which were discovered in the
middle of the twentieth century, nowadays represent a powerful
tool for the creation of a wide range of heterocyclic compounds1
that are hardly accessible via known methods. For arynes, the fol-
lowing types of reactions are known: pericyclic reactions, nucleo-
philic additions, insertion reactions, and transition-metal catalyzed
reactions.2 In this paper we describe the nucleophilic aryne-
induced recyclization of 4-hydroxymethyl isoindolines leading to
substituted isobenzofurans with preparative yields.
trademarks and are widely used in medicine as potent
antidepressants.
R2
R1
OAc
O
O
OMe
CO2Me
O
Membranolide C: R1 = OMe, R2 = H
Membranolide D: R1 = H, R2 = OMe
Aplysulphurine
The 1,3-dihydroisobenzofuran motive is found in natural prod-
ucts such as Aplysulphurin isolated from marine sponge Aplysilla
sulphurea,3 Membranolide C, and Membranolide Ddditerpenes,
which were found in Antarctic sponge Dendrilla membranosa,4 and
show antibiotic activity against G-ve bacteria. The study of some
microorganisms revealed phthalans as secondary metabolites.5,6 In
the last 20 years, isobenzofurans and derivatives thereof were
studied for various types of biological activities including
F
NH
N
O
N
N
O
O
N
Mikonazol-like
Citalopram (Celexa)
Talopram
Cl
antifungal activity
Despite the simple structure of phthalans, methods of synthe-
sizing them are limited. Previously we presented a novel approach
* Correspondingauthor. Tel./fax:þ74959550779; e-mail address: lvoskressensky@
sci.pfu.edu.ru (L.G. Voskressensky).
http://dx.doi.org/10.1016/j.tet.2015.01.022
0040-4020/Ó 2015 Elsevier Ltd. All rights reserved.

1176
A.V. Varlamov et al. / Tetrahedron 71 (2015) 1175e1181
towards dihydroisobenzofurans through the action of activated
alkynes such as DMAD, methyl propiolate, and acetyl acetylene on
substituted isoindolines.10 This route is a peculiar case of a general
transformation of N-heterocycles under the action of electron-
deficient alkynes.11,12 Unfortunately, these reactions have some
limitations and can be applied mostly for compounds with aliphatic
substituents at nitrogen.
TMS
OTf
OH
O
Ph
N
N
Condition
2
20
Scheme 2. Optimization studies.
Arynes can also be considered as activated alkynes due to their
high reactivity caused by the strain induced by the triple bond in
the six-membered ring. In arynes the new
overlapping of sp2-orbitals and is out of the aromatic ring plane.
The HOMO of the side -bond is considerably higher and the LUMO
is significantly lower compared to frontier molecular orbitals of the
-bond in normal alkynes. The triple bond in arynes is significantly
distorted and weak, especially in substituted arynes. These facts
make dehydrobenzene and its derivatives highly reactive
intermediates.
p-bond is formed by side
R1
R1
TMS
OTf
O
OH
p
R
N
R1
R1
N R
p
CsF, MeCN, 20oC
R1=H, OMe
19-33, 35, 36
(28-89%)
1-17
Scheme 3. Synthesis of phthalans.
The present paper reports on unusual transformations of related
dihydroisoindoles 1e18 under the action of dehydrobenzene.
Table 2
The yield of phthalan 20 under various reaction conditions
2. Results and discussion
Conditions
Reaction time
Yield %
Isoindolines 1e18 required for the study were obtained by re-
duction of the corresponding isoindolone carboxylic acids,13 or in
the case of compound 18 N-(4-fluorophenyl) indolone with LiAlH4
in dry Et2O (Scheme 1, Table 1).
CsF, MeCN, 5 ꢀC
5 days
1 h
70
77
73
75
CsF, MeCN, 20 ꢀC
CsF, MeCN, 65 ꢀC
30 min
15 min
5 min
5 days
4 h
SsF, MeCN, 65 ꢀC, MW
SsF, MeCN, 125 ꢀC, MW
KF, MeCN, 20 ꢀC
76
R1
R1
O
No reaction
70
52
TBAT, MeCN, 20 ꢀC
LiAlH4
TBAF (1 N solution in THF), 20 ꢀC 5 days (not completed)
N R
CsF, THF, 25e65 ꢀC
3 days at rt and 3 days at heat 63
N R
abs. Et2O
TBAT¼tetrabutyl ammonium difluoro triphenyl silicate.
1-17 R1=CH2OH
18 R1=H
R1= CO2H or H
Table 3
Yields of phthalans 19e36
Scheme 1. Synthesis of starting material.
Product #
Starting material #
R
R1
Yield %
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
1
2
3
4
5
6
Et
i-Pr
n-Pent
(CH2)3OMe
c-C3H5
H
H
H
H
H
H
H
H
H
H
H
H
H
H
OMe
H
H
69
77
79
62
Table 1
Yields of 4-hydroxymethyl isoindolines 1e17 and 18
Product #
R
Yield %
85
1
Et
61
64
67
62
34
76
83
34
61
76
70
87
67
65
71
25
71
80
c-C5H9
Ph
69
2
i-Pr
7, 15a
8
9
80, 28a
3
n-Pent
2-Me-C6H4
4-i-Pr-C6H4
4-OMe-C6H4
4-F-C6H4
3-CF3-C6H4
2-Cl-C6H4
Bn
78
64
72
67
84
73
64
89
4
5
(CH2)3OMe
c-C3H5
10
11
12
13
14
14
15
16
17
6
c-C5H9
7
Ph
8
9
2-Me-C6H4
4-i-Pr-C6H4
4-OMe-C6H4
4-F-C6H4
3-CF3-C6H4
2-Cl-C6H4
Bn
3,4-(OMe)2C6H3CH2
2,3-(Cl)2C6H3CH2
(CH2)2C6H4
4-F-C6H4, R1¼H
10
11
12
13
14
15
16
17
18
Bn
3,4-(OMe)2C6H3CH2
2,3-(Cl)2C6H3CH2
(CH2)2C6H4
Not formed
64
89
H
a
Phthalan 25 was isolated from the reaction of compound 15 and benzyne with
28% yield.
In order to investigate the influence of solvents and fluorine
source on reaction time and efficiency, we carried out some opti-
mization studies to find the best reaction conditions (Table 2). The
N-isopropyl substituted isoindoline 2 was chosen as a model
starting material for these studies (Scheme 2).
The model experiments with 4-hydroxymethyl isoindolines 2e4
and 11 showed that the reaction with dehydrobenzene proceeded
smoothly at room temperature in dry acetonitrile in the presence of
CsF as catalyst to give the corresponding phthalans 20e22 and 29
as the sole products in good yields (Scheme 3, Table 3). It is worth
noting that NeAr substituted isoindoline 11, which was inert in
reactions with activated alkynes, rapidly interacted with dehy-
drobenzene to form phthalan 29 with 67% yield.
It was shown that variation of temperature from 5 to 65 ꢀC did
not significantly affect the reaction yield. The lower temperature
dramatically increased the reaction time, while elevated tempera-
ture obviously resulted in its decrease. In order to evaluate the
influence of microwave irradiation on the course of the reaction,
the interaction was repeated in a microwave reactor from Anton

A.V. Varlamov et al. / Tetrahedron 71 (2015) 1175e1181
1177
Paar. Although in this case the reaction time was minimized, the
4. Experimental section
4.1. General information
higher temperature caused self-condensation of benzyne and the
formation of byproducts of unidentified structure that complicated
the isolation of the desired product. Using TBAT as a fluorine source
resulted in an increased reaction time, and it was very difficult to
wash out from this catalyst. Changing the solvent to THF led to
lower yields due to the fact that the reaction failed to be completed;
even on heating at 65 ꢀC with an excess of aryne precursor, the
starting isoindoline still remained in the reaction mixture. As Table
2 shows, a better result was obtained with CsF in acetonitrile at
room temperature. Therefore the rest of the experiments were
carried out under these conditions.
To find the scope and limitation of the reaction, the interaction
of 4-hydroxymethyl isoindolines 1, 5e10, and 12e17 with arynes
was performed. The reaction proceeded smoothly at room tem-
perature and finished within 0.5e5 h, giving the corresponding
phthalan derivatives 19e33, 35, and 36 with preparative yields
(Scheme 3, Table 3).
Surprisingly, isoindoline 15 did not give the corresponding
product of pyrrolidine ring recyclization 34, and the only product
isolated after the column chromatography was phthalan 25.
We presume that the reaction starts with the Michael addition
of the aryne to the tertiary N-atom of the starting compound fol-
lowed by abstraction of Hþ from the hydroxy group in intermediate
A. The resulting zwitterion B undergoes intramolecular recycliza-
tion to yield the corresponding phthalan derivatives (Scheme 4).
The aryne precursors were purchased from SigmaeAldrich and
TCI and were used without additional purification. 1H NMR and 13
C
NMR were recorded on a Bruker AMX-400 (400 MHz for 1O and
100.6 MHz for 13C) and a JEOL JNM ECA (600 MHz and 150.9 MHz,
respectively). Proton chemical shifts are reported relative to the
residual solvent peak (CDCl3 at
are reported relative to CDCl3 at
d
7.26 ppm). Carbon chemical shifts
77.2 ppm. Mass spectra were
d
recorded by Bruker MicroTOF-QII (Germany), ESI, collision-induced
dissociation (argon, 17 eV), direct injection, and a Finnigan MAT 95
XL mass spectrometer (electron ionization, 70 eV). IR spectra were
recorded on FT spectrometer Infralum FT-801. For the elemental
analyses, a Carlo Erba 1106 was used. Melting points were mea-
sured on SMP 10 in open capillaries. TLC on Sorbfil plates was used
for the monitoring of reactions. Kieselgel from MachereyeNagel
ꢀ
GmbH&Co (0.04e0.06 mm/230e400 mesh), 60 A, was used for
column chromatography. All solvents were dried according to
standard procedures.14
4.2. General procedure for the synthesis of isoindolines
(1e18)
To a suspension of LiAlH4 (3 equiv) in absolute ether (150 mL),
the corresponding isoindoline acid (1 equiv) [in the case of indoline
18, the isoindolinone was used] was added in portions. The mixture
was stirred at reflux for 3e4 h (TLC monitoring). After the reaction
was completed, the mixture was cooled to room temperature, and
then 25 mL of EtOAc (cooled with an ice-bath) was added dropwise.
The resulting mixture was poured out into 200 mL of cold water
and extracted with EtOAc (3*100 mL). The combined organic layer
was dried over MgSO4. The solvent was removed under reduced
pressure. The resulting powder was recrystallized from the mixture
of hexane-EtOAc to give corresponding isoindoline.
OH
R1
R1
TMS
OTf
O
R
N
N R
R1
R1
CsF, MeCN
1-17
19-33, 35, 36
R1
R1
R1
R1
OH
O
The spectra of compounds 2e4, 11, 14, and 15 correspond to
literature data.10
N
N
R
R
4.2.1. (2-Ethyl-2,3-dihydro-1H-isoindol-4-yl)methanol (1). From N-
ethyl isoindolone acid (1.0 g, 5 mmol). Yellow powder (523 mg,
61%); mp 75e76 ꢀC; [Found: C, 74.38; H, 8.27; N, 8.10. S11H15NO
requires C, 74.54; H, 8.53; N, 7.90%]; nmax(KBr) 3142, 2974, 2809,
B
A
Scheme 4. Proposed mechanism.
1451, 1389, 1077, 781 cmꢁ1
; dH (600 MHz, CDC13) 7.28 (1H, d, J
The formation of isobenzofuran 25 in the reaction of 15 with
benzyne could presumably be explained by the elimination of the
dimethoxybenzyl cation from the initially formed zwitterion A, and
the obtained O-anion reacts further with the next molecule of aryne.
Non-substituted isoindoline 18, which was also inert in the case
of activated alkynes, gave quaternary salt 37 with moderate yield
under these conditions (Scheme 5).
7.5 Hz, Ar), 7.20 (1H, t, J 7.5 Hz, Ar), 7.09 (1H, d, J 7.5 Hz, Ar), 4.23 (2H,
s, CH2OH), 3.89 (2H, s, 3-CH2), 3.58 (2H, s, 1-CH2), 2.75 (2H, q, J
6.7 Hz, CH2Me), 1.21 (3H, t, J 7.2 Hz, CH2Me); dC (100.6 MHz, CDCl3)
139.3, 136.6, 136.3, 127.1, 124.1, 120.7, 61.4, 58.2, 56.2, 49.7, 13.4. m/z
EI (70 eV), (Irel,%): 177 (23) [Mþ], 176 (71), 159 (74), 158 (100), 146
(21), 130 (28), 117 (47), 103 (25), 91 (49), 77 (40), 65 (19), 42 (18).
4.2.2. (2-Cyclopropyl-2,3-dihydro-1H-isoindol-4-yl)methanol
(5). From N-cyclopropyl isoindolone acid (1.0 g, 5 mmol). Almost
white powder (295 mg, 34%); mp 128e130 ꢀC; [Found: C, 75.94; H,
7.83; N, 7.55. S12H15NO requires C, 76.16; H, 7.99; N, 7.40%];
TMS
OTf
OTf
N
N
F
CsF, MeCN
nmax(KBr) 3171, 2938, 2814, 1451, 1348, 1074, 774 cmꢁ1
; dH
18
37 (47%)
(400 MHz, CDC13) 7.31e7.20 (2H, m, Ar), 7.14 (1H, d, J 6.9 Hz, Ar),
4.34 (2H, s, CH2OH), 4.07 (2H, s, 3-CH2), 3.86 (2H, s, 1-CH2),
2.10e1.99 (1H, m, CH), 0.66e0.49 (4H, m, CH2); dC (100.6 MHz,
CDCl3) 140.3, 137.6, 135.9, 127.3, 124.8, 121.5, 62.6, 58.8, 57.1, 35.7,
5.8 (2C); m/z EI (70 eV), (Irel,%): 189 (26) [Mþ], 174 (100), 156 (100),
144 (26), 117 (20), 103 (32), 91 (50), 77 (44), 65 (18), 51 (16), 41 (61),
39 (66).
F
Scheme 5. Interaction of unsubstituted isoindoline with aryne.
3. Conclusion
We have reported a novel synthetic approach to 4-amino-
methyl-substituted dihydroisobenzofuran derivatives, based on
aryne-induced recyclization of easily available 4-hydroxymethyl
isoindolines.
4.2.3. (2-Cyclopentyl-2,3-dihydro-1H-isoindol-4-yl)methanol
(6). From N-cyclopentyl isoindolone acid (2.0 g, 8 mmol). Light

1178
A.V. Varlamov et al. / Tetrahedron 71 (2015) 1175e1181
yellow powder (1.34 g, 76%); mp 142e143 ꢀC; [Found: C, 77.23; H,
8.71; N, 6.68. S14H19NO requires C, 77.38; H, 8.81; N, 6.45%];
(2.0 g, 6 mmol). Orange powder (1.53 g, 87%); mp 122e123 ꢀC;
[Found: C, 65.37; H, 4.67; N, 4.91. S16H14F3NO requires C, 65.52; H,
4.81; N, 4.78%]; nmax(KBr) 3319, 3233, 2864, 2828, 1613, 1507, 1457,
nmax(KBr) 3140, 2955, 2801, 1453, 1347, 1078, 790 cmꢁ1
; dH
(600 MHz, CDC13) 7.36 (1H, d, J 7.6 Hz, Ar), 7.24 (1H, t, J 7.6 Hz, Ar),
7.12 (1H, d, J 7.6 Hz, Ar), 4.09 (2H, s, CH2OH), 3.92 (2H, s, 3-CH2), 3.49
(2H, s, 1-CH2), 2.93e2.81 (1H, m, CH), 1.94e1.76 (4H, m, CH2),
1.71e1.53 (4H, m, CH2); dC (100.6 MHz, CDCl3) 139.5, 137.0, 136.1,
127.1, 123.6, 120.6, 66.6, 61.0, 58.1, 55.9, 31.6 (2C), 23.9 (2C); m/z EI
(70 eV), (Irel,%): 217 (39) [Mþ], 199 (14), 188 (59), 174 (69), 156 (54),
131 (16), 130 (72), 118 (40), 91 (51), 77 (38), 65 (19), 41 (100).
1389,1311,1161,1103, 774, 693 cmꢁ1
; dH (600 MHz, CDC13) 7.36 (1H,
t, J 7.6 Hz, Ar), 7.33e7.22 (3H, m, Ar), 6.98 (1H,d, J 7.6 Hz, Ar), 6.84 (1H,
s, Ar), 6.79 (1H, d, J 8.2 Hz, Ar), 4.70 (2H, s, CH2OH), 4.64 (2H, br s, 3-
CH2), 4.61 (2H, br s,1-CH2); dC (150.9 MHz, CDCl3) 147.1,138.0,135.8,
135.3, 131.8, 131.6, 129.8, 128.0, 126.0, 122.1, 114.6, 112.6, 107.9, 63.5,
53.7, 52.6; m/z EI (70 eV), (Irel,%): 293 (56) [Mþ], 275 (100), 262 (32),
145 (100),104 (26),103 (50), 91 (60), 77 (71), 75 (34), 63 (33), 51 (30).
4.2.4. (2-Phenyl-2,3-dihydro-1H-isoindol-4-yl)methanol (7). From
N-phenyl isoindolone acid (2.0 g, 8 mmol). Beige powder (1.48 g,
83%); mp 95e97 ꢀC; [Found: C, 79.85; H, 6.51; N, 6.32. S15H15NO
requires C, 79.97; H, 6.71; N, 6.22%]; nmax(KBr) 3370, 2822, 1597,
4.2.9. (2-(2-Chlorophenyl)-2,3-dihydro-1H-isoindol-4-yl)methanol
(13). From N-(2-chlorophenyl) isoindolone acid (2.0 g, 7 mmol).
Orange powder (1.2 g, 67%); mp 68e69 ꢀC; [Found: C, 69.51; H,
5.63; N, 5.51. S15H14ClNO requires C, 69.36; H, 5.43; N, 5.39%];
nmax(KBr) 3285, 2862, 1679, 1594, 1482, 1360, 1055, 1033, 747,
1506, 1372, 743, 688 cmꢁ1
; dH (600 MHz, CDC13) 7.36e7.23 (5H, m,
Ar), 6.76 (1H, t, J 7.6 Hz, Ar), 6.70 (2H,d, J 7.6 Hz, Ar), 4.72 (2H, s,
CH2OH), 4.66 (2H, br s, 3-CH2), 4.62 (2H, br s,1-CH2); dC (100.6 MHz,
CDCl3) 146.8, 138.1, 135.9, 135.2, 129.3 (2C), 127.6, 125.6, 121.7, 116.7,
111.9 (2C), 63.1, 53.9, 52.7; m/z EI (70 eV), (Irel,%): 225 (42) [Mþ], 207
(42), 206 (59), 194 (27), 165 (12), 130 (12), 104 (25), 91 (28), 77
(100), 65 (14), 51 (40).
737 cmꢁ1
; dH (600 MHz, CDC13) 7.35 (1H, d, J 7.6 Hz, Ar), 7.31e7.23
(3H, m, Ar), 7.20 (1H, t, J 6.9 Hz, Ar), 7.06 (1H, d, J 7.6 Hz, Ar), 6.85
(1H, t, J 7.2 Hz, Ar), 4.85 (4H, br s, 3-CH2,CH2OH), 4.71 (2H, s, 1-CH2);
dC (100.6 MHz, CDCl3) 145.5, 138.6, 136.2, 134.8, 131.7, 127.5, 127.4,
125.5, 123.1, 121.4, 120.7, 118.0, 63.1, 56.0, 54.7; m/z EI (70 eV),
(Irel,%): 261 (13), 260 (16), 259 (40) [Mþ], 258 (57), 241 (100), 240
(70), 228 (32), 192 (12), 178 (14), 165 (30), 138 (24), 116 (26), 111
(61), 91 (62), 77 (100), 75 (80), 63 (44), 51 (50).
4.2.5. (2-(2-Methylphenyl)-2,3-dihydro-1H-isoindol-4-yl)methanol
(8). From N-(2-methyl)phenyl isoindolone acid (2.5 g, 9 mmol).
Yellow powder (753 mg, 34%); mp 78e79 ꢀC; [Found: C, 80.23; H,
7.11; N, 5.94. S16H17NO requires C, 80.30; H, 7.16; N, 5.85%];
4.2.10. (2-(2,3-Dichlorobenzyl)-2,3-dihydro-1H-isoindol-4-yl)meth-
anol (16). From N-(2,3-dichlorobenzyl) isoindolone acid (2.0 g,
6 mmol). White powder (428 mg, 25%); mp 120e121 ꢀC; [Found: C,
62.41; H, 5.01; N, 4.67. S16H15Cl2NO requires C, 62.35; H, 4.91; N,
4.54%]; nmax(KBr) 3149, 2850, 2800, 1450, 1421, 1072, 785,
nmax(KBr) 3274, 2872, 2819, 1597, 1492, 1456, 759, 727 cmꢁ1
; dH
(600 MHz, CDC13) 7.31e7.22 (3H, m, Ar), 7.21e7.16 (2H, m, Ar), 7.10
(1H, d, J 8.2 Hz, Ar), 6.95e6.91 (1H, m, Ar), 4.69 (2H, s, CH2OH), 4.66
(2H, br s, 3-CH2), 4.63 (2H, br s, 1-CH2), 2.45 (3H, s, Me); dC
(100.6 MHz, CDCl3) 147.9, 139.2, 136.9, 134.9, 132.1, 129.4, 127.3,
126.7, 125.5, 121.4 (2C), 117.4, 63.1, 56.6, 55.3, 20.7; m/z EI (70 eV),
(Irel,%): 239 (43) [Mþ], 238 (48), 220 (62), 218 (26), 208 (20), 204
(16), 178 (12), 130 (16), 118 (30), 103 (24), 91 (100), 77 (36), 65 (80),
63 (20), 39 (28).
771 cmꢁ1
; dH (600 MHz, CDC13) 7.48 (1H, d, J 7.6 Hz, Ar), 7.40 (1H, d,
J 7.6 Hz, Ar), 7.22 (1H, t, J 7.6 Hz, Ar), 7.19e7.15 (2H, m, Ar), 7.12 (1H,
d, J 6.9 Hz, Ar), 4.48 (2H, s, CH2OH), 4.07 (2H, s, CH2Ph), 4.02 (2H, s,
3-CH2), 3.97 (2H, s, 1-CH2); dC (100.6 MHz, CDCl3) 139.9, 138.5,
137.4, 135.4, 133.1, 132.1, 129.1, 128.6, 127.2, 127.1, 124.8, 121.3, 62.6,
58.8, 57.3, 57.2; m/z EI (70 eV), (Irel,%): 308 (15) [Mþ], 306 (20), 289
(22), 288 (13), 163 (12), 162 (20), 161 (100), 148 (21), 130 (84), 123
(38), 91 (55), 89 (64), 77 (38), 63 (28), 39 (18).
4.2.6. (2-(4-Isopropylphenyl)-2,3-dihydro-1H-isoindol-4-yl)metha-
nol (9). From N-(4-isopropyl)phenyl isoindolone acid (1.0 g,
3 mmol). Yellow powder (488 mg, 61%); mp 98e100 ꢀC; [Found: C,
80.78; H, 8.13; N, 5.41. S18H21NO requires C, 80.86; H, 7.92; N,
4.2.11. (2-(2-Phenethyl)-2,3-dihydro-1H-isoindol-4-yl)methanol
(17). From N-(phenethyl) isoindolone acid (2.0 g, 7 mmol). White
powder (1.27 g, 71%); mp 110e111 ꢀC; [Found: C, 80.52; H, 7.41; N,
5.77. S17H19NO requires C, 80.60; H, 7.56; N, 5.53%]; nmax(KBr) 3399,
5.24%]; nmax(KBr) 3293, 2956, 2863, 1615, 1520, 1375, 812 cmꢁ1
; dH
(600 MHz, CDC13) 7.33e7.26 (3H, m, Ar), 7.18 (2H, d, J 8.2 Hz, Ar),
6.66 (2H, d, J 8.2 Hz, Ar), 4.74 (2H, s, SO2PO), 4.67 (2H, br s, 3-SO2),
4.63 (2H, br s, 1-SO2), 2.86 (1H, m, eCHMe2), 1.25 (6H, d, J 6.9 Hz,
eCHMe2); dC (100.6 MHz, CDCl3) 145.2, 138.5, 136.6, 136.2, 135.2,
127.5, 127.2 (2C), 125.5, 121.7, 111.6 (2C), 63.1, 53.8, 52.5, 33.1, 24.2
(2C); m/z EI (70 eV), (Irel,%): 267 (63) [Mþ], 252 (100), 248 (28), 232
(23), 220 (19), 204 (12),132 (14), 130 (24), 117 (42),103 (57), 91 (64),
77 (64), 65 (20), 51 (15), 39 (22).
3168, 2922, 2810, 1461, 1449, 1134, 1079, 778, 735, 700 cmꢁ1
; dH
(600 MHz, CDC13) 7.33e7.29 (2H, m, Ar), 7.26 (3H, d, J 8.9 Hz, Ar),
7.22 (2H, t, J 7.6 Hz, Ar), 7.13 (1H, d, J 6.9 Hz, Ar), 4.40 (2H, s, CH2OH),
3.99 (2H, s, 3-CH2), 3.82 (2H, s,1-CH2), 3.05e2.81 (4H, m, (CH2)2Ph);
dC (100.6 MHz, CDCl3) 139.7, 139.5, 136.6, 136.4, 128.6 (2C), 128.4
(2C), 127.2, 126.2, 124.3, 120.9, 61.8, 58.7, 57.7, 56.8, 35.2; m/z EI
(70 eV), (Irel,%): 253 (<10) [Mþ], 163 (11), 162 (100), 144 (12), 117
(14), 105 (15), 91 (54), 77 (18), 65 (16).
4.2.7. (2-(4-Methoxyphenyl)-2,3-dihydro-1H-isoindol-4-yl)metha-
nol (10). From N-(4-methoxy)phenyl isoindolone acid (1.0 g,
3.5 mmol). Yellow powder (680 mg, 76%); mp 143e144 ꢀC; [Found:
C, 75.10; H, 6.80; N, 5.57. S16H17NO2 requires C, 75.27; H, 6.71; N,
4.2.12. (2-(4-Fluorophenyl)isoindoline (18). From N-fluorophenyl
isoindolone (4.3 g, 20 mmol). Beige powder (3.4 g, 80%). Mp
143e145ꢀS. [Found: S, 78.94, O, 5.53, N, 6.65. S14H12FN requires C,
78.85; H, 5.67; N, 6.57%]; nmax(KBr) 3429, 3055, 2843, 1519, 1374,
5.49%]; nmax(KBr) 3274, 2932, 2834,1517,1250,1035, 816, 775 cmꢁ1
;
dH (600 MHz, CDC13) 7.35e7.19 (3H, m, Ar), 6.90 (2H, d, J 8.9 Hz, Ar),
6.64 (2H, d, J 8.9 Hz, Ar), 4.71 (2H, s, CH2OH), 4.61 (2H, br s, 3-CH2),
4.58 (2H, br s, 1-CH2), 3.77 (3H, s, OMe); dC (150.9 MHz, CDCl3)
154.5, 145.1, 141.8, 139.5, 138.1, 130.5, 128.6, 124.7, 118.4 (2C), 115.5
(2C), 66.3, 58.9, 57.2, 56.0; m/z EI (70 eV), (Irel,%): 255 (69) [Mþ], 253
(100), 236 (54), 222 (41), 192 (22), 180 (44), 165 (33), 152 (32), 119
(28), 103 (28), 92 (36), 91 (51), 77 (76), 63 (54), 39 (29).
1233,1220, 810, 743, 623 cmꢁ1
; dH (600 MHz, CDC13) 7.20e7.07 (4H,
m, Ar), 6.85 (2H, t, J 7.9 Hz, Ar), 6.43e6.40 (2H, m, Ar), 4.45 (4H, s,
CH2); dC (100.6 MHz, CDCl3) 162.4,157.5,149.1 (2S),136.7 (2S),128.7
(2S), 121.3 (2S), 117.8 (2C), 63.4 (2S). ESI MS 214 [MþH]. (213.25).
4.3. General procedure for the synthesis of phthalans (19e32,
35, 36)
4.2.8. (2-(3-(Trifluoromethyl)phenyl)-2,3-dihydro-1H-isoindol-4-yl)
methanol (12). From N-(3-trifluoromethyl)phenyl isoindolone acid
To a suspension of CsF (3 equiv) in 5e7 mL of dry acetonitrile,
the corresponding 4-hydroxymethyl isoindoline (1 equiv) was

A.V. Varlamov et al. / Tetrahedron 71 (2015) 1175e1181
1179
added, and after the dissolution of starting material 2-(trime-
3081, 3005, 2849, 1599, 1504, 1362, 1335, 1257, 1041, 748, 692 cmꢁ1
;
thylsilyl)phenyl trifluoromethanesulfonate (1.2 equiv) was added
into the flask. The mixture was stirred at room temperature for
1e3 h with TLC monitoring. Upon completion, the solvent was re-
moved under reduced pressure, 10 mL of CHCl3 was added, the
white precipitate of CsOTf was filtrated and washed 2 times with
CHCl3, the filtrate was evaporated, and the resulting crude oil was
then purified by column chromatography (glass column,
H¼100 mm, d¼15 mm, mobile phase: EtOAc-hexane, 1:5) to give
the corresponding isobenzofurans (19e32, 35, 36).
dH (600 MHz, CDC13) 7.25e7.17 (3H, m, Ar), 7.13 (1H, d, J 7.6, Ar), 7.03
(1H, d, J 7.6 Hz, Ar), 6.91 (2H, d, J 8.3 Hz, Ar), 6.79 (1H, t, J 7.2 Hz, Ar),
5.15 (2H, s, 1-CH2), 5.11 (2H, s, 3-CH2), 4.51 (2H, s, CH2), 2.68e2.59
(1H, m, CH), 0.89e0.82 (2H, m, CH2), 0.74e0.68 (2H, m, CH2); dC
(100.6 MHz, CDCl3) 149.6, 139.4, 136.3, 129.0 (4C), 127.9, 125.3,
119.3, 118.2, 114.3, 73.7, 72.6, 54.7, 33.2, 8.9 (2C); HRMS (ESIþ):
[MþH]þ, found 266.1544 S18H19NO calcd 266.1539., MS2 (m/z
266.1544): m/z 133.0683, 105.0707.
4.3.6. N-Cyclopentyl-N-(1,3-dihydro-2-benzofuran-4-ylmethyl) ani-
line (24). From isoindoline 6 (100 mg, 0.46 mmol). Almost white
powder (94 mg, 69%); mp 121e123 ꢀC; nmax(KBr) 3500e3300 (br),
3051, 2961, 2864, 1597, 1504, 1393, 1335, 194, 1046, 900, 777, 751,
4.3.1. N-(1,3-Dihydro-2-benzofuran-4-ylmethyl)-N-ethylaniline
(19). From isoindoline 1 (70 mg, 0.4 mmol). Light yellow viscous oil
(68 mg, 67%); Rf (EtOAc/Hexane,1:3) 0.81; [Found: C, 80.51; H, 7.39;
N, 5.71. S17H19NO requires C, 80.60; H, 7.56; N, 5.53%]; nmax(liquid
film) 3397, 2968e2853 (br), 1598, 1499, 1350, 1049, 904, 747,
700 cmꢁ1
; dH (400 MHz, CDC13) 7.32e7.07 (5H, m, Ar), 6.85e6.70
(3H, m, Ar), 5.19 (4H, s, 1-CH2), 4.43e4.28 (3H, m, 3-CH2, CH),
2.12e2.01 (2H, m, CH2), 1.83e1.46 (6H, m, CH2); dC (100.6 MHz,
CDCl3) 150.0, 139.2, 136.2, 135.6, 134.4, 129.0 (2C), 127.8, 125.1, 119.0,
117.1, 113.9, 73.5, 72.4, 59.8, 48.6, 29.4 (2C), 24.0 (2C); HRMS (ESIþ):
[MþH]þ, found 294.1858 S20H23NO calcd 294.1852, MS2 (m/z
294.1858): m/z 226.1225, 208.1117, 161.1197, 133.0662, 105.0702.
691 cmꢁ1
; dH (600 MHz, CDC13) 7.29e7.20 (3H, m,Ar), 7.17 (2H, t, J
6.2 Hz, Ar), 6.78e6.66 (3H, m, Ar), 5.16 (2H, s, 1-CH2), 5.14 (2H, br s,
3-CH2), 4.43 (2H, s, CH2), 3.50 (2H, q, J 6.9 Hz, CH2Me), 1.23 (3H, t, J
7.2 Hz, CH2Me); dC (100.6 MHz, CDCl3) 148.2, 139.5, 136.5, 133.1,
129.2 (2C), 127.7, 125.3, 119.3, 116.6, 112.6 (2C), 73.4, 72.6, 52.2, 45.3,
11.7; ESI MS 254 [MþH] (253.34).
4.3.7. N-(1,3-Dihydro-2-benzofuran-4-ylmethyl)-N-phenylaniline
(25). From isoindoline 7 (100 mg, 0.44 mmol). White powder
(106 mg, 80%); From isoindoline 15 (200 mg, 0.67 mmol) as
byproduct (55 mg, 28%); mp 121e122 ꢀC; nmax(KBr) 3500e3300
(br), 3034, 2847, 1587, 1493, 1371, 1227, 1044, 899, 778, 748, 690,
4.3.2. N-(1,3-Dihydro-2-benzofuran-4-ylmethyl)-N-isopropylaniline
(20). From isoindoline 2 (105 mg, 0.55 mmol). Colorless trans-
parent viscous oil (108 mg, 77%); Rf (EtOAc/Hexane, 1:5) 0.83;
nmax(liquid film) 3397, 3318, 2970, 2856, 1598, 1499, 1390, 1046,
905, 746, 691 cmꢁ1
;
dH (600 MHz, CDC13) 7.31e7.20 (4H, m, Ar), 7.15
592 cmꢁ1
; dH (600 MHz, CDC13) 7.30 (1H, d, J 7.6 Hz, Ar), 7.26e7.19
(1H, d, J 6.9 Hz, Ar), 6.80e6.73 (3H, m, Ar), 5.22 (2H, br s, 1-CH2),
5.19 (2H, s, 3-CH2), 4.34e4.27 (3H, m, CHMe2, CH2), 1.27 (6H, d, J
6.2 Hz, CHMe2); dC (100.6 MHz, CDCl3)149.1,139.1,135.7,134.3,129.1
(2C), 127.7, 125.2, 118.9, 117.0, 113.9 (2C), 73.5, 72.5, 48.8, 46.3, 19.7
(2S); HRMS (ESIþ): [MþH]þ, found 268.1695 S18H21NO calcd
268.1995, MS2 (m/z 268.1695): m/z 133.0656, 120.0815, 105.0707.
(5H, m, Ar), 7.11 (1H, d, J 7.6 Hz, Ar), 7.04 (4H, d, J 7.6 Hz, Ar), 6.95
(2H, t, J 7.2 Hz, Ar), 5.12 (4H, br s, 1-CH2, 3-CH2), 4.86 (2H, s, CH2); dC
(100.6 MHz, CDCl3) 148.2, 139.5, 136.4, 132.9, 129.4 (4C), 127.9,
125.4, 121.8, 121.1, 120.9 (4C), 119.4, 117.9, 73.6, 72.7, 54.6; HRMS
(ESIþ): [MþH]þ, found 302.1534 S21H19NO calcd 302.1539, MS2
(m/z 302.1534): m/z 284.1421, 169.0880, 133.0654, 105.0702.
4.3.3. N-(1,3-Dihydro-2-benzofuran-4-ylmethyl)-N-pentylaniline
(21). From isoindoline 3 (150 mg, 0.68 mmol). Yellow oil (160 mg,
79%); Rf (EtOAc/Hexane, 1:5) 0.7; [Found: S, 81.25, O, 8.39, N, 4.86.
S20H25NO requires C, 81.31; H, 8.53; N, 4.74%]; nmax(liquid film)
4.3.8. N-(1,3-Dihydro-2-benzofuran-4-ylmethyl)-2-methyl-N-phe-
nylaniline (26). From isoindoline 8 (100 mg, 0.42 mmol). Orange
powder (103 mg, 78%); mp 90 ꢀC; [Found: S, 83.63, O, 6.57, N, 4.60.
S22H21NO requires C, 83.78; H, 6.71; N, 4.44%]; nmax(KBr)
3500e3300 (br), 3064, 3021, 2847, 1595, 1499, 1373, 1229, 1045,
3397, 2930, 2858, 1598, 1508, 1459, 1367, 1052, 905, 747, 691 cmꢁ1
;
dH (600 MHz, CDC13) 7.29e7.19 (3H, m, Ar), 7.15 (2H, t, J 6.9 Hz, Ar),
6.79e6.62 (3H, m, Ar), 5.16 (2H, s, 1-CH2), 5.13 (2H, s, 3-CH2), 4.45
(2H, s, CH2), 3.47e3.33 (2H, m, N-CH2(SO2)3Me), 1.70 (2H, q, J
774, 748, 691 cmꢁ1
; dH (600 MHz, CDC13) 7.44 (1H, d, J 7.6 Hz, Ar),
7.34 (1H, d, J 6.2 Hz, Ar), 7.31e7.22 (4H, m, Ar), 7.21e7.12 (3H, m, Ar),
6.77 (1H, t, J 7.2 Hz, Ar), 6.56 (2H, d, J 8.2 Hz, Ar), 5.17 (2H, s, 1-CH2),
5.13 (2H, s, 3-CH2), 4.75 (2H, s, CH2), 2.20 (3H, s, Me); dC (100.6 MHz,
CDCl3) 148.4,145.9,139.2,136.8,136.3,132.5,131.7,129.0 (2C),128.9,
127.8, 127.5, 126.7, 125.6, 119.3, 117.6, 113.7 (2C), 73.6, 72.4, 53.8,
18.4; ESI MS 316 [MþH] (315.41).
7.6 Hz,
N-CH2CH2(SO2)2Me),
1.46e1.27
(4H,
m,
N-
(CH2)2SH2SH2Me), 0.96 (3H, t, J 6.9 Hz, Me); dC (150.9 MHz, CDCl3)
148.4, 139.7, 136.6, 133.1, 129.5 (2C), 128.1, 125.5, 119.5, 116.6, 112.6
(2C), 73.6, 72.8, 52.9, 51.6, 29.4, 26.6, 22.7,14.2; ESI MS 296 [MþH]
(295.42).
4.3.9. N-(1,3-Dihydro-2-benzofuran-4-ylmethyl)-4-isopropyl-N-phe-
nylaniline (27). From isoindoline 9 (108 mg, 0.40 mmol). Light
yellow oil (88 mg, 64%); Rf (EtOAc/Hexane, 1:5) 0.77; nmax(liquid
film) 3397, 2958, 2865, 1596, 1510, 1365, 1049, 905, 837, 752, 697,
4.3.4. N-(1,3-Dihydro-2-benzofuran-4-ylmethyl)-N-(3-
methoxypropyl)aniline (22). From isoindoline
4
(100 mg,
0.45 mmol). Orange oil (83 mg, 62%); Rf (EtOAc/Hexane, 1:3) 0.58;
[Found: S, 76.61, O, 7.73, N, 4.85. S19H23NO2 requires C, 76.73; H,
7.80; N, 4.71%]; nmax(liquid film) 3397, 3000e2800 (br), 1598, 1351,
613 cmꢁ1
; dH (600 MHz, CDC13) 7.33 (1H, d, J 7.6 Hz, Ar), 7.24e7.18
(3H, m, Ar), 7.15 (2H, d, J 8.9 Hz, Ar), 7.12 (1H, d, J 7.6 Hz, Ar), 7.06
(2H, d, J 8.9 Hz, Ar), 6.96 (2H,d, J 8.2 Hz, Ar), 6.88 (1H, t, J 7.2 Hz, Ar),
5.13 (2H, m, 1-CH2), 5.12 (2H, s, 3-CH2), 4.85 (2H, s, CH2), 2.96e2.80
(1H, m, CHMe2), 1.30e1.20 (6H, d, J 6.9 Hz, CHMe2); dC (150.9 MHz,
CDCl3) 148.4, 145.9, 143.3, 139.5, 136.4, 135.2, 129.2 (2C), 127.9,
127.4, 125.4,122.4 (2C),120.5,119.4,119.1 (2C),117.2, 73.6, 72.7, 54.8,
33.5, 24.2 (2C); HRMS (ESIþ): [MþH]þ, found 344.2009 S24H25NO
calcd 344.2009, MS2 (m/z 344.2009): m/z 211.1354, 196.1124,
133.0651, 105.0703.
1049, 904, 748, 691 cmꢁ1
; dH (600 MHz, CDC13) 7.25e7.17 (3H, m,
Ar), 7.14 (1H, d, J 7.6 Hz, Ar),7.10 (1H, d, J 7.6 Hz, Ar), 6.74e6.66 (3H,
m, Ar), 5.13 (2H, s, 1-CH2), 5.11 (2H, s, 3-CH2), 4.44 (2H, s, SO2), 3.54
(2H, t, J 7.2 Hz, N-(CH2)2SO2OMe), 3.44 (2H, t, J 5.8 Hz, N-
CH2(SO2)2OMe), 3.35 (3H, s, PNf), 1.98e1.87 (2H, m, N-
CH2CH2SO2OMe); dC (150.9 MHz, CDCl3) 151.2, 142.5, 139.5, 135.9
(2C), 132.3, 130.8, 128.2, 122.3, 119.5, 115.4, 76.5, 75.6, 73.1, 61.6 (2C),
55.6, 51.2, 30.2; ESI MS 298 [MþH] (297.39).
4.3.5. N-Cyclopropyl-N-(1,3-dihydro-2-benzofuran-4-ylmethyl) ani-
line (23). From isoindoline 5 (109 mg, 0.58 mmol). Light yellow
powder (130 mg, 85%); mp 116e117 ꢀC; nmax(KBr) 3500e3300 (br),
4.3.10. N-(1,3-Dihydro-2-benzofuran-4-ylmethyl)-4-methoxy-N-
phenylaniline (28). From isoindoline 10 (200 mg, 0.78 mmol).
White powder (187 mg, 72%); mp 94e96 ꢀC; nmax(KBr) 3500e3300,

1180
A.V. Varlamov et al. / Tetrahedron 71 (2015) 1175e1181
3004, 2850, 1595, 1503, 1344, 1220, 1045, 751 cmꢁ1
;
dH (600 MHz,
(300 mg, 0.84 mmol). White powder (228 mg, 76%); mp 68e69 ꢀC;
nmax(KBr) 3600e3300 (br), 2916, 2854, 1521, 1240, 1021, 776 cmꢁ1
CDC13) 7.32 (1H, d, J 7.6 Hz, Ar), 7.23 (1H, t, J 7.6 Hz, Ar), 7.20e7.08
(5H, m, Ar), 6.88 (2H, d, J 8.9 Hz, Ar), 6.83e6.75 (3H, m, Ar), 5.13 (4H,
s, 1-CH2, 3-CH2), 4.80 (2H, s, CH2), 3.81 (3H, s, OMe); dC (100.6 MHz,
CDCl3) 156.5, 149.1, 141.2, 139.5, 136.5, 133.1, 129.1 (2C), 127.9, 126.5
(2C), 125.6, 119.4, 119.1, 116.6 (2C), 115.0 (2C), 73.7, 72.7, 55.6, 55.0;
HRMS (ESIþ): [MþH]þ, found 332.1636 S22H21NO calcd 332.1645,
MS2 (m/z 332.1636): m/z 330.1632, 199.0987, 184.0755.
;
dH (600 MHz, CDC13) 7.34e7.27 (2H, m, Ar), 7.26e7.19 (4H, m, Ar),
7.17 (1H, d, J 7.6 Hz, Ar), 7.13 (1H, d, J 7.6 Hz, Ar), 6.71 (1H, d, J 8.3 Hz,
Ar), 6.36 (1H, br s, Ar), 6.26 (1H, d, J 8.3 Hz, Ar), 5.10 (2H, s, 1-CH2),
5.05 (2H, br s, 3-CH2), 4.52 (2H, s, CH2), 4.40 (2H, s, CH2), 3.78 (3H, s,
OMe), 3.69 (3H, s, OMe); dC (150.9 MHz, CDCl3) 149.8, 144.2, 141.9,
139.8, 138.6, 137.1, 132.9, 128.7 (2C), 127.9 (2C), 127.3, 127.1, 125.9,
119.6, 113.0, 105.9, 100.4, 73.6, 72.9, 56.6, 55.9, 55.8, 53.7; HRMS
(ESIþ): [MþH]þ, found 376.1909 S24H25NO3 calcd 376.1907, MS2 (m/
z 376.1909): m/z 285.1358, 243.1256, 228.1021, 153.0783, 132.0576.
4.3.11. N-(1,3-Dihydro-2-benzofuran-4-ylmethyl)-4-fluoro-N-phe-
nylaniline (29). From isoindoline 11 (150 mg, 0.62 mmol). Red
powder (132 mg, 67%); mp 63e64 ꢀC; nmax(KBr) 3500e3300 (br),
3066, 2845, 1593, 1504, 1211, 1045, 750, 691 cmꢁ1
;
dH (600 MHz,
4.3.16. N-(2,3-Dichlorobenzyl)-N-(1,3-dihydro-2-benzofuran-4-
ylmethyl)-aniline (35). From isoindoline 16 (100 mg, 0.34 mmol).
Pale yellow powder (83 mg, 64%); mp 178e180 ꢀC; nmax(KBr)
3600e3300 (br), 3058, 2847,1599,1507,1420,1349,1236,1192,1047,
CDC13)7.30e7.26(1H, d,J7.6 Hz, Ar), 7.24e7.19(3H,m, Ar),7.13(1H,d,
J 6.9 Hz, Ar), 7.08 (2H, m, Ar), 6.97 (2H, m, Ar), 6.93e6.87 (3H, m, Ar),
5.12 (4H, s, 3-CH2, 1-CH2), 4.81 (2H, s, CH2); dC (100.6 MHz, CDCl3)
160.1, 157.7, 148.5, 144.2, 141.1, 139.6, 136.5, 132.7, 129.3, 128.0, 125.5,
124.4, 124.5, 120.8, 119.6, 118.8, 116.3, 116.1, 73.6, 72.7, 54.9; HRMS
(ESIþ): [MþH]þ, found 320.1445 S21H18FNO calcd 320.1445, MS2 (m/
z 320.1433): m/z 302.1354, 200.0872, 187.0784, 133.0652, 105.0703.
749 cmꢁ1
; dH (600 MHz, CDC13) 7.39 (1H, d, J 7.6 Hz, Ar), 7.28e7.23
(1H, m, Ar), 7.21e7.13 (5H, m, Ar), 7.12e7.09 (1H, m, Ar), 6.75 (1H, t, J
7.2 Hz, Ar), 6.62 (2H, d, J 8.2 Hz, Ar), 5.14 (2H, s,1-CH2), 5.09 (2H, s, 3-
CH2), 4.70 (2H, s, CH2), 4.56 (2H, s, CH2); dC (150.9 MHz, CDCl3) 148.1,
139.9, 137.7, 136.6, 133.5, 131.9, 131.1, 129.5 (2C), 129.1, 128.2, 127.5,
125.8, 125.0, 119.7, 117.6, 112.4 (2C), 73.7, 72.6, 53.4, 52.7; HRMS
(ESIþ): [MþH]þ, found 384.0914 S22H19Cl2NO calcd 385.0994, MS2
(m/z 384.0914): m/z 250.0187, 133.0650, 105.0701.
4.3.12. N-(1,3-Dihydro-2-benzofuran-4-ylmethyl)-N-phenyl-3-(tri-
fluoromethyl)aniline (30). From isoindoline 12 (200 mg,
0.68 mmol). Yellow powder (212 mg, 84%); mp 75e76 ꢀC; nmax(KBr)
3500e3300 (br), 2853, 1612, 1499, 1457, 1383, 1326, 1123, 1073, 791,
701 cmꢁ1
;
dH (600 MHz, CDC13) 7.33 (2H, t, J 7.2 Hz,Ar), 7.30e7.25
4.3.17. N-(1,3-Dihydro-2-benzofuran-4-ylmethyl)-N-(2-phenylethyl)
aniline (36). From isoindoline 17 (100 mg, 0.39 mmol). Colorless
transparentoil(118 mg, 89%);Rf (EtOAc/Hexane,1:5)0.75;nmax(liquid
film) 3600e3400 (br), 3024, 2852, 1603, 1505, 1350, 1046, 904, 743,
(2H, m, Ar), 7.23 (1H, t, J 7.2 Hz, Ar), 7.17 (3H, d, J 7.6 Hz, Ar), 7.14 (1H,
d, J 7.6 Hz, Ar), 7.11 (2H, t, J 6.5 Hz, Ar), 7.05 (1H, dd, J 8.3, 2.1 Hz, Ar),
5.12 (4H, s, 3-CH2, 1-CH2), 4.88 (2H, s, SO2); dC (100.6 MHz, CDCl3)
148.6, 147.3, 139.8, 136.5, 132.1, 131.5, 129.9 (2C), 129.7, 128.1, 125.3,
124.1, 123.5 (2C), 121.2, 120.5, 119.7, q 116.8e116.7 (J 12.6 Hz), q
114.7e114.6 (J 12.6 Hz), 73.6, 72.6, 54.6; HRMS (ESIþ): [MþH]þ,
found 370.1409 S22H18F3NO calcd 370.1413, MS2 (m/z 370.1409):
m/z 352.1321, 133.0650, 105.0705.
700, 689 cmꢁ1
; dH (400 MHz CDC13) 7.38e7.31 (2H, m, Ar), 7.31e7.20
(6H, m, Ar), 7.16 (1H, d, J 7.3 Hz, Ar), 7.11 (1H, d, J 7.3 Hz, Ar), 6.84e6.74
(3H, m, Ar), 5.15 (2H, s, 3-CH2), 5.07 (2H, s, 1-CH2), 4.37 (2H, s, CH2),
3.67 (2H, t, J 7.6 Hz, CH2), 2.97 (2H, t, J 7.6 Hz, CH2); dC (100.6 MHz,
CDCl3) 147.8, 139.5, 139.4, 136.6, 132.7, 129.3 (2C), 128.7 (2C), 128.5
(2C), 127.8, 126.3, 125.2, 119.3, 116.8, 112.5 (2C), 73.4, 72.5, 53.0, 52.8,
33.2; HRMS (ESIþ): [MþH]þ, found 330.1870 S23H23NO calcd
330.1852, MS2 (m/z 330.1870): m/z 196.1119, 133.0653, 105.0707.
4.3.13. (2-Chlorophenyl)(1,3-dihydro-2-benzofuran-4-ylmethyl)-N-
phenylaniline (31). From isoindoline 13 (105 mg, 0.38 mmol). Yel-
low oil (93 mg, 73%); Rf (EtOAc/Hexane, 1:3) 0.63; nmax(liquid film)
3600e3400 (br), 3057, 2857,1580,1495,1478,1365,1190,1054, 758,
4.3.18. 2-(4-Fluorophenyl)-2-phenylisoindolinium trifluoromethane-
sulfonate (37). From isoindoline 18 (108 mg, 0.51 mmol). The re-
action was heated at 50 ꢀC during 1.5 h. Yellow powder (105 mg,
47%); mp 185e186 ꢀC; [Found: C, 57.36; H, 3.71; N, 3.21.
749, 698 cmꢁ1
; dH (600 MHz, CDC13) 7.52 (1H, dd, J 7.6, 1.4 Hz, Ar),
7.46 (1H, d, J 6.9 Hz, Ar), 7.37 (1H, dd, J 8.2, 1.4 Hz, Ar), 7.30 (1H, td, J
7.6, 1.4 Hz, Ar), 7.28e7.22 (2H, m, Ar), 7.21e7.13 (3H, m, Ar), 6.81
(1H, t, J 7.2 Hz, Ar), 6.58 (2H, d, J 8.2 Hz, Ar), 5.15 (4H, s, 3-CH2, 1-
CH2), 4.78 (2H, s, CH2); dC (100.6 MHz, CDCl3) 147.9, 144.1, 139.2,
136.3, 133.7, 132.2, 131.1, 130.8, 128.9 (2C), 128.1, 127.8, 127.6, 125.6,
119.4, 118.5, 114.3 (2C), 73.6, 72.4, 53.7; HRMS (ESIþ): [MþH]þ,
found 336.1141 S21H18ClNO calcd 336.1149, MS2 (m/z 336.1121): m/
z 318.1025, 203.0495, 133.0651, 105.0706.
C21H17F4NO3S requires C, 57.40; H, 3.90; N, 3.19%]; nmax(KBr) 2962,
1667, 1446, 1386, 1260, 1172, 1074, 759; dH (400 MHz, DMSO-d6)
6.09 (4H, s, 1-SO2, 3-SO2), 7.50e7.40 (4H, m, Ar), 7.56e7.50 (3H, m,
Ar), 7.59 (2H, t, J 7.9 Hz, Ar), 7.82 (2H, d, J 8.3 Hz, Ar), 7.90 (2H, dd, J
9.5, 4.4 Hz, Ar); dC (100.6 MHz, CDCl3) 192.3, 162.8 (d, J 253.1 Hz),
147.3, 142.9, 132.3, 131.0 (3C), 130.7, 130.2 (3C), 124.7 (d, J 9.0 Hz),
123.6 (3C), 122.1 (3C), 117.8 (d, J 23.3 Hz), 72.6 (2C).
4.3.14. N-Benzyl-N-(1,3-dihydro-2-benzofuran-4-ylmethyl)aniline
(32). From isoindoline 14 (100 mg, 0.42 mmol).White powder
(84 mg, 64%); mp 64e65 ꢀC; nmax(KBr) 3500e3300 (br), 2922, 2852,
Acknowledgements
1598, 1506, 1359, 1233, 1046, 750, 694 cmꢁ1
; dH (600 MHz, CDC13)
This work was supported by the RF President grant for young
scientists MK-2367.2013.03 and RFBR grant N 14-03-00311.
7.34 (2O, t, J 7.6 Hz, Ar), 7.30e7.22 (3H, m, Ar), 7.22e7.14 (4O, m, Ar),
7.06 (1H, d, J 8.2 Hz, Ar), 6.74 (3O, d, J 6.9 Hz, Ar), 5.14 (2H, br s, 1-
CH2), 5.06 (2O, br s, 3-CH2), 4.66 (2H, s, CH2), 4.53 (2H, s, CH2); dC
(100.6 MHz, CDCl3) 147.7, 139.6, 136.6, 134.7, 130.6, 129.2 (2C), 128.6
(2C), 127.8 (2C), 126.9, 126.8, 125.2, 121.6, 120.6, 119.4, 112.9, 73.4,
72.5, 54.4, 52.4; HRMS (ESIþ): [MþH]þ, found 316.1718 S22H21NO
calcd 316.1695, MS2 (m/z 316.1703): m/z 298.1590, 224.1069,
196.1118, 183.1036, 133.0654, 105.0706, 91.0545.
ꢀ
Supplementary data
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.tet.2015.01.022.
References and notes
4.3.15. N-Benzyl-N-((1,3-dihydro-2-benzofuran-4-yl)methyl)-3,4-
dimethoxybenzenamine (33). From isoindoline 14 (200 mg,
0.84 mmol), CsF (362 mg, 2.4 mmol), 7 mL of dry acetonitrile, and
4,5-dimethoxy-2-(trimethylsilyl)phenyl trifluoromethanesulfonate
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