Generation of aryl(2-lithiophenyl)methanone O-methyl oximes and their use for the synthesis of N-(3-alkyl-1-aryl- or 1,3-diaryl-1H-isoindol-1-yl)-O- methylhydroxylamines via the reaction with nitriles

Article abstract of DOI:10.1002/hlca.201400067

An efficient two-step procedure for the preparation of a new type of 1H-isoindoles, i.e., N-(3-alkyl-1-aryl- or 1,3-diaryl-1H-isoindol-1-yl)-O- methylhydroxylamines 5, from readily available aryl(2-bromophenyl)methanones 1 has been developed. Aryl(2-bromophenyl)methanone O-methyloximes 2, derived from the corresponding ketones, were treated with BuLi in Et₂O at 0° to generate novel lithium compounds, aryl(2-lithiophenyl)methanone O-methyloximes 3, which were allowed to react with nitriles to give the desired products 5 in moderate-to-fair yields. Copyright

Full text of DOI:10.1002/hlca.201400067

Helvetica Chimica Acta – Vol. 97 (2014)
915
Generation of Aryl(2-lithiophenyl)methanone O-Methyl Oximes and Their
Use for the Synthesis of N-(3-Alkyl-1-aryl- or 1,3-diaryl-1H-isoindol-1-yl)-O-
methylhydroxylamines via the Reaction with Nitriles
by Kazuhiro Kobayashi*, Kota Matsumoto, Yuu Shirai, Hiroaki Ishikawa, Hiroki Inouchi,
and Miyuki Tanmatsu
Division of Applied Chemistry, Department of Chemistry and Biotechnology, Graduate School of
Engineering, Tottori University, 4-101 Koyama-minami, Tottori 680-8552, Japan
(phone/fax: þ 81-857-315263; e-mail: kkoba@chem.tottori-u.ac.jp)
An efficient two-step procedure for the preparation of a new type of 1H-isoindoles, i.e., N-(3-alkyl-1-
aryl- or 1,3-diaryl-1H-isoindol-1-yl)-O-methylhydroxylamines 5, from readily available aryl(2-bromo-
phenyl)methanones 1 has been developed. Aryl(2-bromophenyl)methanone O-methyloximes 2, derived
from the corresponding ketones, were treated with BuLi in Et2O at 08 to generate novel lithium
compounds, aryl(2-lithiophenyl)methanone O-methyloximes 3, which were allowed to react with nitriles
to give the desired products 5 in moderate-to-fair yields.
Introduction. – In this article, we report a convenient approach to the synthesis
of a new type of 1H-isoindole derivatives, i.e., N-(3-alkyl-1-aryl- or 1,3-diaryl-1H-
isoindol-1-yl)-O-methylhydroxylamines 5, from readily available aryl(2-bromophen-
yl)methanones 1. We found that corresponding O-methyloximes 2, derived from 1, are
treated with BuLi to generate aryl(2-lithiophenyl)methanone O-methyloximes 3,
which are allowed to react with nitriles to give the desired 1H-isoindole derivatives 5.
Because a number of molecules with the 1H-isoindole structure are known to possess a
variety of biological activities [1][2], several synthetic approaches to 1,1-disubstituted
1H-isoindole derivatives have been developed [1][3]. However, to the best of our
knowledge, there has been only one previous report on the synthesis of 1H-isoindole
with an amino substituent at C(1) [4]. Thus, synthesis of 1,3-bis(1,1-dimethylethyl)-1H-
isoindol-1-amine has been achieved by treatment of a VIIIꢀbenzyne complex, CpV(h2-
C6H4)(Me3P)2, with t-BuNC, followed by acid hydrolysis of the resulting isoindolenine-
substituted VIIIꢀimido complex, CpV[NC(t-Bu)N¼C(t-Bu)C6H4](Me3P)2.
Results and Discussion. – N-(3-Alkyl-1-aryl- or 1,3-diaryl-1H-isoindol-1-yl)-O-
methylhydroxylamines 5 were obtained by the two-step sequence from aryl(2-
bromophenyl)methanones
1 as outlined in Scheme 1. Treatment of 1 with
MeONH3 Clꢀ in the presence of C5H5N in refluxing EtOH/THF gave aryl(2-
bromophenyl)methanone O-methyloximes 2 in satisfactory yields. Compounds 2a,
2c, and 2e were obtained as mixtures of stereoisomers, while stereoisomers of
compound 2b were separable, and only (E)-2d was obtained. Although the
configurations of the stereoisomers could not be determined unambiguously, we
þ
ꢀ 2014 Verlag Helvetica Chimica Acta AG, Zꢁrich

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Helvetica Chimica Acta – Vol. 97 (2014)
Scheme 1
tentatively assigned them based on the concept that the less crowded, thermodynami-
cally more stable stereoisomer must be produced predominantly. A mixture of isomers
was used in the next reaction in each case except 2d.
Initially, we tried to achieve Br/Li exchange between (2-bromophenyl)phenylme-
thanone O-methyloxime (2a) and BuLi in THF at ꢀ 788 to generate (2-lithiophenyl)-
phenylmethanone O-methyloxime (3a). However, none of the desired product 5a was
observed in the mixture after addition of PhCN, followed by usual workup.
Subsequently, we found that the generation of 3 could be accomplished by treating 2
with BuLi in Et2O at 08. After generation of 3, nitriles were added at the same
temperature. The addition of the carbanion to the nitrile C-atom, followed by
cyclization through attack of the resulting imido anion in intermediate 4 on the
methoxyimino C-atom proceeded smoothly. After aqueous workup, followed by
purification of the crude products by recrystallization (in general), the desired products
5 were obtained in generally moderate-to-fair yields, as compiled in the Table. The
results indicate that 2-methylpropanenitrile carrying an a-H-atom is also usable in this
sequence, and that the corresponding 3-(1-methylethyl) derivatives 5f, 5h, and 5l are
obtained in yields comparable to those obtained with aromatic nitriles (Entries 6, 8, and
12, resp.). Unfortunately, however, propanenitrile proved to be unusable in this
reaction; a considerably complex mixture of products was obtained from the reaction
with 3a.
Next, we turned our attention to the synthesis of 1-hetaryl derivatives to
demonstrate the scope of the present method. As shown in Scheme 2, (2-bromophe-
nyl)(thiophen-2-yl)methanone O-methyloxime (2f), which is accessible by condensa-
tion of (2-bromophenyl)(thiophen-2-yl)methanone (1f) with O-methylhydroxylamine,
furnished N-[1-(thiophen-2-yl)-1H-isoindol-1-yl]-O-methylhydroxylamines 5m and 5n
under the same reaction conditions as described above. The yield of 2f was excellent,
but the yields of the conversion of 2f into 5m and 5n were somewhat lower than those
obtained with 2a – 2e.

Helvetica Chimica Acta – Vol. 97 (2014)
917
Table. Preparation of N-(1,3-Disubstituted 1H-Isoindol-1-yl)-O-methylhydroxylamines 5
Entry
Compound 2
R2
Product
Yielda) [%]
1
2
3
4
5
6
7
8
9
2a (R1 ¼ H, Ar¼ Ph)
Ph
5a
5b
5c
5d
5e
5f
5g
5h
5i
66
62
59
55
61
60
57
64
59
64
61
66
2a
4-MeꢀC6H4
3-ClꢀC6H4
4-ClꢀC6H4
4-MeOꢀC6H4
i-Pr
2a
2a
2a
2a
2b (R1 ¼ H, Ar¼ 4-ClꢀC6H4)
2c (R1 ¼ H, Ar¼ 4-MeOꢀC6H4)
2d (R1 ¼ Cl, Ar¼ Ph)
2e (R1 ¼ MeO, Ar¼ Ph)
2e
4-ClꢀC6H4
i-Pr
4-ClꢀC6H4
3-MeꢀC6H4
4-ClꢀC6H4
i-Pr
10
11
12
5j
5k
5l
2e
a) Yields of isolated products.
Scheme 2
In summary, a convenient procedure to synthesize a new type of 1H-isoindoles,
N-(3-alkyl-1-aryl- or 1,3-diaryl-1H-isoindol-1-yl)-O-methylhydroxylamines 5, based
on the reaction of new lithium compounds, i.e., aryl(2-lithiophenyl)methanone
O-methyloximes 3, with nitriles has been developed. The ready availability of the
starting materials and simplicity of the operations render the present method attrac-
tive.
Experimental Part
General. All of the org. solvents used in this study were dried over appropriate drying agents and
distilled prior to use. TLC: Merck silica gel 60 PF254. Column chromatography (CC): Wako Gel C-200E.
M.p.: Laboratory Devices MEL-TEMP II melting-point apparatus; uncorrected. IR Spectra: Perkin-
1
Elmer Spectrum65 FT-IR spectrophotometer; ˜n in cmꢀ1. H- and 13C-NMR spectra: JEOL ECP500 or
JEOL LA400 FT NMR spectrometer (500 or 400 and 125 or 100 MHz, resp.); d in ppm rel. to Me4Si as
internal standard, J in Hz. HR-MS (DART, pos.): Thermo Scientific Exactive spectrometer; in m/z.
Synthesis of Diarylmethanones 1. (2-Bromophenyl)(4-chlorophenyl)methanone (1b) [5], (2-bromo-
phenyl)(4-methoxyphenyl)methanone (1c) [6], (2-bromo-5-chlorophenyl)(phenyl)methanone (1d) [7],
and (2-bromo-5-methoxyphenyl)(phenyl)methanone (1e) [8] were prepared according to the literature
methods. BuLi was supplied by Asia Lithium Corporation. All other chemicals used were commercially
available.

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Helvetica Chimica Acta – Vol. 97 (2014)
(2-Bromophenyl)(thiophen-2-yl)methanol [9] was prepared by treating 2-bromobenzaldehyde with
(thiophen-2-yl)lithium as described in [5]. Yield: 99%. Pale-yellow oil. Rf (AcOEt/hexane 1:10) 0.33. IR
1
(neat): 3367. H-NMR (500 MHz, CDCl3): 2.52 (d, J ¼ 4.0, 1 H); 6.41 (d, J ¼ 4.0, 1 H); 6.92 – 6.95 (m,
2 H); 7.18 (td, J ¼ 7.4, 1.7, 1 H); 7.27 (dd, J ¼ 4.6, 1.1, 1 H); 7.38 (ddd, J ¼ 8.0, 7.4, 1.1, 1 H); 7.54 (dd, J ¼ 8.0,
1.1, 1 H); 7.71 (dd, J ¼ 8.0, 1.7, 1 H). Anal. calc. for C11H9BrOS (269.16): C 49.09, H 3.37; found: C 49.12,
H 3.52.
(2-Bromophenyl)(thiophen-2-yl)methanone (1f) [10] was prepared by the pyridinium chlorochro-
mate (PCC) oxidation of the above alcohol as described in [11]. Yield: 91%. Pale-yellow oil. Rf (AcOEt/
1
hexane 1:12) 0.35. IR (neat): 1650. H-NMR (500 MHz, CDCl3): 7.13 (dd, J ¼ 5.1, 1.1, 1 H); 7.34 – 7.44
(m, 4 H); 7.66 (d, J ¼ 8.6, 1 H); 7.77 (dd, J ¼ 5.1, 1.1, 1 H). Anal. calc. for C11H7BrOS (267.14): C 49.46, H
2.64; found: C 49.46, H 2.65.
Syntheses of Diarylmethanone Oximes 2. Representative Procedure: 1-(2-Bromophenyl)-N-methoxy-
1-phenylmethanimine (¼(2-Bromophenyl)phenylmethanone O-Methyloxime; 2a). To a soln. of
MeONHþ3 Clꢀ (0.30 g, 3.5 mmol) in EtOH (2 ml) and pyridine (2 ml) was added a soln. of 1a (0.37 g,
1.8 mmol) in THF (2 ml). The mixture was heated at reflux for 8 h under stirring. After cooling, aq. sat.
NaHCO3 soln. (10 ml) was added, and the mixture was extracted with Et2O (2 ꢁ 10 ml). The combined
extracts were washed with brine (10 ml), dried (Na2SO4), and concentrated by evaporation. The residue
was purified by CC (SiO2; Et2O/hexane 1:10) to give 2a (0.32 g, 76%). A mixture of stereoisomers (E)/
1
(Z) ca. 9 :1). White solid. M.p. 118 – 1218. IR (KBr): 1602, 1052. H-NMR (500 MHz, CDCl3): 3.99 (s,
2.7 H); 4.04 (s, 0.3 H); 7.17 (dd, J ¼ 8.0, 1.1, 0.9 H); 7.27 – 7.42 (m, 5 H); 7.45 – 7.55 (m, 2.1 H); 7.58 (d, J ¼
8.0, 0.1 H); 7.67 (d, J ¼ 8.0, 0.9 H). Anal. calc. for C14H12BrNO (290.16): C 57.95, H 4.17, N 4.83; found: C
57.90, H 4.18, N 4.70.
1-(2-Bromophenyl)-1-(4-chlorophenyl)-N-methoxymethanimine (¼(2-Bromophenyl)(4-chlorophe-
nyl)methanone O-Methyloxime; 2b).
Data of (E)-2b. Yield: 57%. Pale-yellow oil. Rf (Et2O/hexane 1:10) 0.37. IR (neat): 1603, 1052.
1H-NMR (400 MHz, CDCl3): 3.98 (s, 3 H); 7.15 (dd, J ¼ 7.8, 2.0, 1 H); 7.29 – 7.32 (m, 3 H); 7.39 – 7.42 (m,
3 H); 7.67 (d, J ¼ 7.8, 1 H). Anal. calc. for C14H11BrClNO (324.60): C 51.80, H 3.42, N 4.32; found: C
51.81, H 3.71, N 4.23.
Data of (Z)-2b. Yield: 13%. Pale-yellow oil. Rf (Et2O/hexane 1:10) 0.30. IR (neat): 1589, 1037.
1H-NMR (400 MHz, CDCl3): 4.04 (s, 3 H); 7.28 (dd, J ¼ 7.8, 6.9, 1 H); 7.33 (d, J ¼ 8.8, 2 H); 7.39 (dd, J ¼
7.8, 6.9, 1 H); 7.45 (d, J ¼ 7.8, 1 H), 7.49 (d, J ¼ 8.8, 2 H); 7.59 (d, J ¼ 7.8, 1 H). Anal. calc. for
C14H11BrClNO (324.60): C 51.80, H 3.42, N 4.32; found: C 51.81, H 3.39, N 4.20.
1-(2-Bromophenyl)-N-methoxy-1-(4-methoxyphenyl)methanimine (¼(2-Bromophenyl)(4-methoxy-
phenyl)methanone O-Methyloxime; 2c). A mixture of stereoisomers (E)/(Z) ca. 9 :1). Colorless oil. An
anal. specimen of each isomer was obtained by CC (SiO2).
Data of (E)-2c. Colorless oil. Rf (THF/hexane 1:15) 0.39. IR (neat): 1607, 1052. 1H-NMR (400 MHz,
CDCl3): 3.81 (s, 3 H); 3.96 (s, 3 H); 6.85 (d, J ¼ 8.8, 2 H); 7.16 (dd, J ¼ 7.8, 2.2, 1 H); 7.28 (td, J ¼ 7.8, 2.0,
1 H); 7.38 – 7.42 (m, 3 H); 7.66 (d, J ¼ 7.8, 1 H). Anal. calc. for C15H14BrNO2 (320.18): C 56.27, H 4.41, N
4.37; found: C 55.97, H 4.45, N 4.45.
Data of (Z)-2c. Colorless oil. Rf (THF/hexane 1:15) 0.34. IR (neat): 1604, 1037. 1H-NMR (400 MHz,
CDCl3): 3.82 (s, 3 H); 4.04 (s, 3 H); 6.87 (d, J ¼ 8.8, 2 H); 7.26 (t, J ¼ 7.8, 1 H); 7.36 (t, J ¼ 7.8, 1 H); 7.43
(dd, J ¼ 7.8, 2.0, 1 H); 7.53 (d, J ¼ 8.8, 2 H); 7.58 (d, J ¼ 7.8, 1 H). Anal. calc. for C15H14BrNO2 (320.18): C
56.27, H 4.41, N 4.37; found: C 56.14, H 4.45, N 4.30.
(E)-1-(2-Bromo-5-chlorophenyl)-N-methoxy-1-phenylmethanimine (¼(E)-(2-Bromo-5-chlorophe-
nyl)phenylmethanone O-Methyloxime; 2d). Colorless oil. Rf (THF/hexane 1:40) 0.47. IR (neat): 1593,
1054. 1H-NMR (400 MHz, CDCl3): 3.99 (s, 3 H); 7.16 (d, J ¼ 2.9, 1 H); 7.26 (dd, J ¼ 7.8, 2.9, 1 H); 7.33 –
7.40 (m, 3 H); 7.46 (dd, J ¼ 7.8, 2.0, 2 H); 7.59 (d, J ¼ 7.8, 1 H). Anal. calc. for C14H11BrClNO (324.60): C
51.80, H 3.42, N 4.32; found: C 51.77, H 3.59, N 4.18.
1-(2-Bromo-5-methoxyphenyl)-N-methoxy-1-phenylmethanimine (¼(2-Bromo-5-methoxyphenyl)-
phenylmethanone O-Methyloxime; 2e; mixture of stereoisomers, (E)/(Z) ca. 9 :1). Colorless oil. An
anal. specimen of each isomer was obtained by CC (SiO2).
Data of (E)-2e. White solid. M.p. 62 – 648 (hexane/THF). Rf (THF/hexane 1:40) 0.43. IR (KBr):
1587, 1054. 1H-NMR (400 MHz, CDCl3): 3.78 (s, 3 H); 3.99 (s, 3 H); 6.70 (d, J ¼ 2.9, 1 H); 6.84 (dd,

Helvetica Chimica Acta – Vol. 97 (2014)
919
J ¼ 8.8, 2.9, 1 H); 7.31 – 7.36 (m, 3 H); 7.49 (dd, J ¼ 7.8, 2.0, 2 H); 7.54 (d, J ¼ 8.8, 1 H). Anal. calc. for
C15H14BrNO2 (320.18): C 56.27, H 4.41, N 4.37; found: C 56.23, H 4.49, N 4.36.
Data of (Z)-2e. White solid. M.p. 87 – 898 (hexane/THF). Rf (THF/hexane 1:40) 0.38. IR (KBr):
1578, 1036. 1H-NMR (400 MHz, CDCl3): 3.82 (s, 3 H); 4.04 (s, 3 H); 6.82 (dd, J ¼ 8.8, 2.9, 1 H); 7.00 (d,
J ¼ 2.9, 1 H); 7.35 – 7.37 (m, 3 H); 7.45 (d, J ¼ 8.8, 1 H); 7.55 – 7.57 (m, 2 H). Anal. calc. for C15H14BrNO2
(320.18): C 56.27, H 4.41, N 4.37; found: C 56.00, H 4.45, N 4.08.
1-(2-Bromophenyl)-N-methoxy-1-(thiophen-2-yl)methanimine (¼(2-Bromophenyl)(thiophen-2-yl)-
methanone O-Methyloxime; 2f, a mixture of stereoisomers (E)/(Z) ca. 7:3). White solid. An anal.
specimen of each isomer was obtained by CC (SiO2).
Data of (E)-2f. White solid. M.p. 51 – 558 (hexane/THF). Rf (THF/hexane 1:30) 0.43. IR (KBr):
1
1575, 1051. H-NMR (500 MHz, CDCl3): 4.18 (s, 3 H); 6.88 (dd, J ¼ 4.0, 1.1, 1 H); 7.00 (dd, J ¼ 5.2, 4.0,
1 H); 7.31 (td, J ¼ 7.4, 1.7, 1 H); 7.40 (td, J ¼ 7.4, 1.1, 1 H); 7.44 (dd, J ¼ 7.4, 1.7, 1 H); 7.57 (dd, J ¼ 5.2, 1.1,
1 H); 7.66 (d, J ¼ 7.4, 1 H). Anal. calc. for C12H10BrNOS (296.18): C 48.66, H 3.40, N 4.73; found: C 48.41,
H 3.22, N 4.82.
Data of (Z)-2f. White solid. M.p. 79 – 818 (hexane/THF). Rf (THF/hexane 1:30) 0.37. IR (KBr):
1564, 1046. 1H-NMR (500 MHz, CDCl3): 3.96 (s, 3 H); 6.70 (d, J ¼ 4.0, 1 H); 6.94 (dd, J ¼ 5.2, 4.0, 1 H);
7.24 (dd, J ¼ 7.4, 1.7, 1 H); 7.29 (ddd, J ¼ 8.0, 7.4, 1.7, 1 H); 7.32 (d, J ¼ 5.2, 1 H); 7.40 (t, J ¼ 7.4, 1 H); 7.67 (d,
J ¼ 8.0, 1 H).
Synthesis of (1H-Isoindol-1-yl)hydroxylamines 5. Representative Procedure: N-Methoxy-1,3-diphen-
yl-1H-isoindol-1-amine (¼ N-(1,3-Diphenyl-1H-isoindol-1-yl)-O-methylhydroxylamine; 5a). To a stirred
soln. of 2a (0.29 g, 1.0 mmol) in Et2O (4 ml) at 08 was added, dropwise BuLi (1.6m in hexane; 1.0 mmol).
After 5 min, PhCN (0.10 g, 1.0 mmol) was added, and stirring was continued at the same temp. for an
additional 15 min, before sat. aq. NH4Cl soln. (10 ml) was added. The mixture was extracted with AcOEt
(3 ꢁ 10 ml), and the combined extracts were washed with brine (10 ml) and dried (Na2SO4). After
evaporation of the solvent, the residual solid was recrystallized from hexane/Et2O to afford 5a (0.21 g,
1
66%). Colorless needles. M.p. 118 – 1218. IR (KBr): 3185, 1603. H-NMR (500 MHz, CDCl3): 3.38 (s,
3 H); 6.43 (s, 1 H); 7.28 – 7.34 (m, 3 H); 7.40 – 7.43 (m, 2 H); 7.54 – 7.55 (m, 3 H); 7.70 – 7.75 (m, 4 H);
8.06 – 8.08 (m, 2 H). 13C-NMR (125 MHz, CDCl3): 63.17; 94.67; 123.03; 124.03; 126.57; 128.33; 128.41;
128.54; 128.55; 128.64; 128.84; 130.55; 134.02; 137.79; 138.29; 153.06; 171.55. HR-MS: 315.1495 ([M þ
H]þ, C21H19N2Oþ; calc. 315.1497). Anal. calc. for C21H18N2O (314.38): C 80.23, H 5.77, N 8.91; found:
C 79.94, H 5.87, N 8.83.
N-Methoxy-3-(4-methylphenyl)-1-phenyl-1H-isoindol-1-amine (¼O-Methyl-N-[3-(4-methylphenyl)-
1-phenyl-1H-isoindol-1-yl]hydroxylamine; 5b). White solid. M.p. 136 – 1388 (hexane/Et2O). IR (KBr):
1
3225, 1614, 1601. H-NMR (500 MHz, CDCl3): 2.46 (s, 3 H); 3.38 (s, 3 H); 6.41 (s, 1 H); 7.23 – 7.41 (m,
7 H); 7.69 – 7.74 (m, 4 H); 7.98 (d, J ¼ 8.2, 2 H). 13C-NMR (125 MHz, CDCl3): 21.53; 63.16; 94.52; 123.05;
123.97; 126.56; 128.26; 128.37; 128.48; 128.51; 128.74; 129.32; 131.23; 137.90; 138.45; 140.78; 153.05;
171.35. HR-MS: 329.1650 ([M þ H]þ, C22H21N2Oþ; calc. 329.1654). Anal. calc. for C22H20N2O (328.41): C
80.46, H 6.14, N 8.53; found: C 80.19, H 6.30, N 8.56.
3-(3-Chlorophenyl)-N-methoxy-1-phenyl-1H-isoindol-1-amine (¼ N-[3-(3-Chlorophenyl)-1-phenyl-
1H-isoindol-1-yl]-O-methylhydroxylamine; 5c). Pale-yellow solid. M.p. 112 – 1148 (hexane/Et2O). IR
(KBr): 3179, 1601. 1H-NMR (500 MHz, CDCl3): 3.37 (s, 3 H); 6.43 (s, 1 H); 7.30 – 7.35 (m, 3 H); 7.43 – 7.44
(m, 2 H); 7.48 (t, J ¼ 8.0, 1 H); 7.53 (dd, J ¼ 8.0, 1.1, 1 H); 7.68 – 7.71 (m, 3 H); 7.75 (d, J ¼ 8.0, 1 H); 7.95
(dd, J ¼ 8.0, 1.1, 1 H); 8.07 (d, J ¼ 1.1, 1 H). 13C-NMR (100 MHz, CDCl3): 63.20; 94.80; 122.78; 124.14;
126.50; 126.63; 128.21; 128.47; 128.61; 128.67; 129.08; 129.93; 130.61; 134.77; 135.65; 137.28; 137.87;
152.98; 170.32. HR-MS: 349.1096 ([M þ H]þ, C21H18ClN2Oþ; calc. 349.1107). Anal. calc. for
C21H17ClN2O (348.83): C 72.31, H 4.91, N 8.03; found: C 72.13, H 5.07, N 7.81.
3-(4-Chlorophenyl)-N-methoxy-1-phenyl-1H-isoindol-1-amine (¼ N-[3-(4-Chlorophenyl)-1-phenyl-
1H-isoindol-1-yl]-O-methylhydroxylamine; 5d). White solid. M.p. 88 – 928 (hexane/Et2O). IR (KBr):
1
3161, 1597. H-NMR (500 MHz, CDCl3): 3.37 (s, 3 H); 6.42 (s, 1 H); 7.23 – 7.25 (m, 1 H); 7.30 – 7.36 (m,
3 H); 7.42 – 7.44 (m, 2 H); 7.52 (d, J ¼ 8.6, 2 H); 7.67 – 7.69 (m, 2 H); 7.74 – 7.76 (m, 1 H); 8.02 (d, J ¼ 8.6,
2 H). 13C-NMR (125 MHz, CDCl3): 63.16; 94.71; 122.76; 124.11; 127.09; 128.02; 128.20; 128.42; 128.62;
128.91; 128.99; 132.37; 136.69; 137.38; 137.98; 152.98; 170.42. HR-MS: 349.1094 ([M þ H]þ,

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Helvetica Chimica Acta – Vol. 97 (2014)
C21H18ClN2Oþ; calc. 349.1107). Anal. calc. for C21H17ClN2O (348.83): C 72.31, H 4.91, N 8.03; found: C
72.24, H 5.04, N 8.01.
N-Methoxy-3-(4-methoxyphenyl)-1-phenyl-1H-isoindol-1-amine (¼ N-[3-(4-Methoxyphenyl)-1-phe-
nyl-1H-isoindol-1-yl]-O-methylhydroxylamine; 5e). Isolated by CC (SiO2). Pale-yellow amorphous
1
powder. Rf (THF/hexane 1:4) 0.23. IR (neat): 3179, 1610. H-NMR (500 MHz, (D6)DMSO): 3.24 (s,
3 H); 3.86 (s, 3 H); 7.14 (d, J ¼ 8.7, 2 H); 7.25 – 7.31 (m, 3 H); 7.42 – 7.46 (m, 2 H); 7.58 (dd, J ¼ 8.0, 1.8,
2 H); 7.73 – 7.75 (m, 1 H); 7.79 – 7.81 (m, 1 H); 8.04 (d, J ¼ 8.6, 2 H); 9.14 (br. s, 1 H). 13C-NMR
(125 MHz, (D6)DMSO): 55.40; 62.34; 94.29; 114.25; 122.78; 123.89; 126.27; 126.61; 127.94; 128.14;
128.51; 128.60; 129.89; 137.22; 139.14; 153.68; 161.21; 168.58. HR-MS: 345.1599 ([M þ H]þ, C22H21N2O2þ ;
calc. 345.1603). Anal. calc. for C22H20N2O2 (344.41): C 76.72, H 5.85, N 8.13; found: C 76.64, H 5.94, N
8.00.
N-Methoxy-3-(1-methylethyl)-1-phenyl-1H-isoindol-1-amine (¼O-Methyl-N-[3-(1-methylethyl)-1-
phenyl-1H-isoindol-1-yl]hydroxylamine; 5f). Pale-yellow solid. M.p. 106 – 1098 (hexane). IR (KBr):
3177, 1610. 1H-NMR (500 MHz, CDCl3): 1.47 (d, J ¼ 6.9, 3 H); 1.48 (d, J ¼ 6.9, 3 H); 3.29 (sept., J ¼ 6.9,
1 H); 3.35 (s, 3 H); 6.28 (s, 1 H); 7.26 – 7.38 (m, 5 H); 7.49 (d, J ¼ 6.9, 1 H); 7.62 – 7.64 (m, 3 H). 13C-NMR
(125 MHz, CDCl3): 20.27; 20.53; 30.04; 63.14; 94.25; 121.35; 123.55; 126.31; 128.10; 128.28; 128.33;
128.67; 138.05; 138.56; 152.46; 179.33. HR-MS: 281.1629 ([M þ H]þ, C18H21N2Oþ; calc. 281.1654). Anal.
calc. for C18H20N2O (280.36): C 77.11, H 7.19, N 9.99; found: C 77.06, H 7.26, N 9.92.
1,3-Bis(4-chlorophenyl)-N-methoxy-1H-isoindol-1-amine (¼ N-[1,3-Bis(4-chlorophenyl)-1H-isoin-
dol-1-yl]-O-methylhydroxylamine; 5g). White solid. M.p. 123 – 1258 (hexane/CH2Cl2). IR (KBr): 3214,
1597. 1H-NMR (500 MHz, CDCl3): 3.38 (s, 3 H); 6.33 (s, 1 H); 7.29 (d, J ¼ 8.6, 2 H); 7.43 – 7.45 (m, 2 H);
7.53 (d, J ¼ 8.6, 2 H); 7.63 (d, J ¼ 8.6, 2 H); 7.69 – 7.71 (m, 2 H); 8.01 (d, J ¼ 8.6, 2 H). 13C-NMR (125 MHz,
CDCl3): 63.20; 94.20; 122.93; 124.01; 127.98; 128.57; 128.86; 128.98; 129.19; 129.84; 132.20; 134.32;
136.69; 136.89; 137.27; 152.60; 170.81. HR-MS: 383.0708 ([M þ H]þ, C21H17Cl2N2Oþ; calc. 383.0718).
Anal. calc. for C21H16Cl2N2O (383.27): C 65.81, H 4.21, N 7.31; found: C 65.76, H 4.28, N 7.45.
N-Methoxy-1-(4-methoxyphenyl)-3-(1-methylethyl)-1H-isoindol-1-amine (¼ N-[1-(4-methoxyphen-
yl)-3-(1-methylethyl)-1H-isoindol-1-yl]-O-methylhydroxylamine; 5h). White solid. M.p. 138 – 1408 (hex-
ane/CH2Cl2). IR (KBr): 3167, 1610. 1H-NMR (500 MHz, CDCl3): 1.45 (d, J ¼ 6.9, 3 H); 1.46 (d, J ¼ 6.9,
3 H); 3.27 (sept., J ¼ 6.9, 1 H); 3.33 (s, 3 H); 3.76 (s, 3 H); 6.24 (s, 1 H); 6.82 (d, J ¼ 8.6, 2 H); 7.34 – 7.37
(m, 2 H); 7.48 (dd, J ¼ 6.9, 2.3, 1 H); 7.57 (d, J ¼ 8.6, 2 H); 7.64 (dd, J ¼ 6.9, 2.3, 1 H). 13C-NMR (125 MHz,
CDCl3): 17.02; 17.26; 32.83; 55.37; 62.89; 96.30; 113.95; 122.64; 123.36; 126.78; 128.17; 128.24; 129.94;
139.28; 151.72; 161.97; 169.97. HR-MS: 311.1743 ([M þ H]þ, C19H23N2O2þ ; calc. 311.1759). Anal. calc. for
C19H22N2O2 (310.39): C 73.52, H 7.14, N 9.03; found: C 73.32, H 7.18, N 8.80.
6-Chloro-3-(4-chlorophenyl)-N-methoxy-1-phenyl-1H-isoindol-1-amine (¼ N-[6-Chloro-3-(4-chloro-
phenyl)-1-phenyl-1H-isoindol-1-yl]-O-methylhydroxylamine; 5i). White solid. M.p. 136 – 1398 (hexane/
1
CH2Cl2). IR (KBr): 3185, 1597. H-NMR (500 MHz, CDCl3): 3.38 (s, 3 H); 6.42 (s, 1 H); 7.33 – 7.35 (m,
3 H); 7.40 (dd, J ¼ 8.0, 1.7, 1 H); 7.52 (d, J ¼ 8.6, 2 H); 7.59 (d, J ¼ 8.6, 2 H); 7.64 (dd, J ¼ 8.0, 1.7, 1 H); 7.70
(d, J ¼ 1.7, 1 H); 7.99 (d, J ¼ 8.6, 2 H). 13C-NMR (125 MHz, CDCl3): 63.26; 94.51; 123.51; 124.60; 126.38;
128.61; 128.73; 128.97; 129.04; 129.78; 131.96; 135.87; 135.90; 137.00; 137.33; 155.18; 169.60. HR-MS:
383.0705 ([M þ H]þ, C21H17Cl2N2Oþ; calc. 383.0718). Anal. calc. for C21H16Cl2N2O (383.27): C 65.81, H
4.21, N 7.31; found: C 65.53, H 4.24, N 7.10.
N,6-Dimethoxy-3-(3-methylphenyl)-1-phenyl-1H-isoindol-1-amine (¼ N-[6-Methoxy-3-(3-methyl-
phenyl)-1-phenyl-1H-isoindol-1-yl]-O-methylhydroxylamine; 5j). White solid. M.p. 103 – 1048 (hexane/
1
CH2Cl2). IR (KBr): 3174, 1613, 1599. H-NMR (500 MHz, CDCl3): 2.54 (s, 3 H); 3.42 (s, 3 H); 3.91 (s,
3 H); 6.40 (s, 1 H); 6.94 (dd, J ¼ 8.6, 2.3, 1 H); 7.23 (d, J ¼ 2.3, 1 H); 7.29 – 7.35 (m, 4 H); 7.42 (t, J ¼ 7.4,
1 H); 7.63 (d, J ¼ 8.6, 1 H); 7.68 (dd, J ¼ 7.2, 1.1, 2 H); 7.82 (d, J ¼ 8.0, 1 H); 7.88 (s, 1 H). 13C-NMR
(125 MHz, CDCl3): 21.43; 55.66; 63.15; 93.95; 110.06; 114.07; 123.96; 125.53; 126.44; 128.23; 128.42;
129.07 (2 overlapped Cs); 130.87; 131.25; 134.04; 138.44; 138.56; 155.61; 160.76; 171.29. HR-MS: 359.1750
([M þ H]þ, C23H23N2Oþ2 ; calc. 359.1759). Anal. calc. for C23H22N2O2 (358.43): C 77.07, H 6.19, N 7.82;
found: C 77.00, H 6.25, N 7.56.
3-(4-Chlorophenyl)-N,6-dimethoxy-1-phenyl-1H-isoindol-1-amine (¼ N-[3-(4-Chlorophenyl)-6-me-
thoxy-1-phenyl-1H-isoindol-1-yl]-O-methylhydroxylamine; 5k). White solid. M.p. 147 – 1498 (hexane/
1
AcOEt). IR (KBr): 3142, 1607. H-NMR (500 MHz, CDCl3): 3.41 (s, 3 H); 3.87 (s, 3 H); 6.39 (s, 1 H);

Helvetica Chimica Acta – Vol. 97 (2014)
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6.92 (dd, J ¼ 8.8, 2.0, 1 H); 7.25 (d, J ¼ 2.0, 1 H); 7.29 – 7.33 (m, 3 H); 7.50 (d, J ¼ 7.8, 2 H); 7.58 (d, J ¼ 8.8,
1 H); 7.66 (dd, J ¼ 7.8, 2.0, 2 H); 8.00 (d, J ¼ 7.8, 2 H). 13C-NMR (125 MHz, CDCl3): 55.67; 63.17; 94.07;
110.24; 114.17; 123.68; 126.42; 128.36; 128.47; 128.88; 129.82; 130.41; 132.55; 136.58; 138.25; 155.63;
160.90; 170.03. HR-MS: 379.1198 ([M þ H]þ, C22H20ClN2Oþ2 ; calc. 379.1213). Anal. calc. for
C22H19ClN2O2 (378.85): C 69.75, H 5.05, N 7.39; found: C 69.52, H 5.19, N 7.30.
N,6-Dimethoxy-3-(1-methylethyl)-1-phenyl-1H-isoindol-1-amine (¼ N-[6-Methoxy-3-(1-methyleth-
yl)-1-phenyl-1H-isoindol-1-yl]-O-methylhydroxylamine; 5l). White solid. M.p. 105 – 1078 (hexane/
1
CH2Cl2). IR (KBr): 3133, 1614. H-NMR (500 MHz, CDCl3): 1.448 (d, J ¼ 6.9, 3 H); 1.451 (d, J ¼ 6.9,
3 H), 3.24 (sept., J ¼ 6.9, 1 H); 3.39 (s, 3 H); 3.83 (s, 3 H); 6.26 (s, 1 H); 6.87 (dd, J ¼ 8.6, 2.3, 1 H); 7.14 (d,
J ¼ 2.3, 1 H); 7.28 – 7.31 (m, 3 H); 7.39 (d, J ¼ 8.6, 1 H); 7.60 (d, J ¼ 6.9, 2 H). 13C-NMR (100 MHz,
CDCl3): 20.32; 20.59; 30.10; 55.60; 63.11; 93.69; 109.69; 113.91; 122.18; 126.26; 128.04; 128.30; 131.17;
138.79; 155.01; 160.66; 178.98. HR-MS: 311.1749 ([M þ H]þ, C19H23N2O2þ ; calc. 311.1759). Anal. calc. for
C19H22N2O2 (310.39): C 73.52, H 7.14, N 9.03; found: C 73.36, H 7.18, N 8.97.
3-(3-Chlorophenyl)-N-methoxy-1-(thiophen-2-yl)-1H-isoindol-1-amine (¼ N-[3-(3-Chlorophenyl)-
1-(thiophen-2-yl)-1H-isoindol-1-yl]-O-methylhydroxylamine; 5m). White solid. M.p. 90 – 928 (hexane/
CH2Cl2). IR (KBr): 3157, 1606. 1H-NMR (500 MHz, CDCl3): 3.36 (s, 3 H); 6.40 (s, 1 H); 6.96 (dd, J ¼ 5.2,
3.4, 1 H); 7.23 (dd, J ¼ 3.4, 1.1, 1 H); 7.27 (dd, J ¼ 5.2, 1.1, 1 H); 7.45 – 7.53 (m, 4 H); 7.70 (dd, J ¼ 6.9, 1.7,
1 H); 7.88 (dd, J ¼ 6.9, 1.7, 1 H); 7.92 (d, J ¼ 7.4, 1 H); 8.04 (s, 1 H). 13C-NMR (125 MHz, CDCl3): 63.30;
92.99; 122.96; 123.95; 125.75; 125.77; 126.64; 126.68; 128.67; 129.00; 129.30; 129.95; 130.75; 134.78;
135.42; 137.20; 140.19; 152.31; 170.46. HR-MS: 355.0660 ([M þ H]þ, C19H16ClN2OSþ; calc. 355.0672).
Anal. calc. for C19H15ClN2OS (354.85): C 64.31, H 4.26, N 7.89; found: C 64.26, H 4.19, N 7.86.
N-Methoxy-3-(1-methylethyl)-1-(thiophen-2-yl)-1H-isoindol-1-amine (¼O-Methyl-N-[3-(1-methyl-
ethyl)-1-(thiophen-2-yl)-1H-isoindol-1-yl]hydroxylamine; 5n). White solid. M.p. 97 – 998 (hexane/
CH2Cl2). IR (KBr): 3157, 1607. 1H-NMR (500 MHz, CDCl3): 1.43 (d, J ¼ 6.9, 3 H); 1.46 (d, J ¼ 6.9,
3 H); 3.23 – 3.28 (m, 1 H); 3.35 (s, 3 H); 6.27 (s, 1 H); 6.92 (dd, J ¼ 4.6, 4.0, 1 H); 7.17 (d, J ¼ 4.0, 1 H); 7.21
(d, J ¼ 4.6, 1 H); 7.39 – 7.40 (m, 2 H); 7.49 (dd, J ¼ 8.0, 2.8, 1 H); 7.76 (dd, J ¼ 8.0, 2.8, 1 H). 13C-NMR
(125 MHz, CDCl3): 20.17; 20.37; 29.97; 63.22; 92.64; 121.53; 123.39; 125.24; 125.31; 126.51; 128.61; 128.89;
137.87; 141.11; 151.81; 179.68. HR-MS: 287.1214 ([M þ H]þ, C16H19N2OSþ; calc. 287.1218). Anal. calc. for
C16H18N2OS (286.39): C 67.10, H 6.33, N 9.78; found: C 67.04, H 6.44, N 9.62.
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Received February 27, 2014