Palladium-catalysed convenient synthesis of 3-methyleneisoindolin-1-ones

Article abstract of DOI:10.1081/SCC-120004063

2′-Bromoacetophenone reacts with an array of aliphatic primary amines under carbon monoxide pressure in the presence of a catalytic amount of a palladium catalyst to afford 3-methyleneisoindolin-1-ones in moderate yields.

Full text of DOI:10.1081/SCC-120004063

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PALLADIUM-CATALYSED CONVENIENT SYNTHESIS OF 3-
METHYLENEISOINDOLIN-1-ONES
Chan Sik Cho a , Hyung Sup Shim a , Heung-Jin Choi a , Tae-Jeong Kim a & Sang Chul Shim b
a Department of Industrial Chemistry , College of Engineering , Kyungpook National
University , Taegu, 702-701, Korea
b Department of Industrial Chemistry , College of Engineering , Kyungpook National
University , Taegu, 702-701, Korea
Published online: 17 Oct 2011.
To cite this article: Chan Sik Cho , Hyung Sup Shim , Heung-Jin Choi , Tae-Jeong Kim & Sang Chul Shim (2002) PALLADIUM-
CATALYSED CONVENIENT SYNTHESIS OF 3-METHYLENEISOINDOLIN-1-ONES, Synthetic Communications: An International Journal
for Rapid Communication of Synthetic Organic Chemistry, 32:12, 1821-1827, DOI: 10.1081/SCC-120004063
To link to this article: http://dx.doi.org/10.1081/SCC-120004063
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SYNTHETIC COMMUNICATIONS, 32(12), 1821–1827 (2002)
PALLADIUM-CATALYSED
CONVENIENT SYNTHESIS OF
3-METHYLENEISOINDOLIN-1-ONES
*
Chan Sik Cho, Hyung Sup Shim, Heung-Jin Choi,
*
Tae-Jeong Kim, and Sang Chul Shim
Department of Industrial Chemistry,
College of Engineering, Kyungpook National
University, Taegu 702-701, Korea
ABSTRACT
20-Bromoacetophenone reacts with an array of aliphatic pri-
mary amines under carbon monoxide pressure in the presence
of a catalytic amount of a palladium catalyst to afford
3-methyleneisoindolin-1-ones in moderate yields.
Key Words: Carbon monoxide; Cyclisation; Isoindolinone;
Palladium; Primary amine
Homogeneous palladium-catalysed cyclisation reaction has been
used as convenient and efficient synthetic method for the construction of the
structural core of many pharmacological and biological active
compounds.[1–3] Thus, the formation of isoindolinones also has been
attempted by the catalytic action of transition metals.[4] During the course
of our continuing studies on homogeneous transition metal-catalysed
*Corresponding authors.
1821
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1822
CHO ET AL.
synthesis of N-heterocycles, we recently developed and reported a palladium-
catalysed synthetic approach for the formation of a wide variety of isoindo-
linones.[5–12] It was suggested that all reactions proceed via intra- and inter-
molecular carbopalladative addition across carbon–nitrogen double bonds as
an organometallic key step. Herein, we report another palladium-catalysed
approach for the synthesis of isoindolinones from 20-bromoacetophenone
and an array of aliphatic primary amines via intramolecular
carbopalladative addition across carbon–nitrogen double bond.
We accomplished the three components carbonylative cyclisation of
20-bromoacetophenone (1) with an array of aliphatic primary amines (2) and
carbon monoxide under a similar palladium catalyst system which we intro-
duced for the synthesis of several isoindolinones (Eq. 1).[5–12] Treatment of 1
with two equivalents of 2 in anhydrous acetonitrile in the presence of
bis(triphenylphosphine)palladium(II) chloride [PdCl2(PPh3)2, 5 mol%
based on 1] and triphenylphosphine (10 mol% based on 1) together with
triethylamine and anhydrous sodium sulfate at 100ꢀC for 20 h under carbon
monoxide (20 atm) afforded 3-methyleneisoindolin-1-ones (3) in moderate
yields. Buchwald et al reported that haloarenes are coupled with primary
and secondary amines in the presence of a palladium catalyst to give ami-
noarenes.[13] However, no amination product was observed in the present
reaction.
ð1Þ
The present carbonylative cyclisation was applicable to various
straight and branched aliphatic primary amines, and several representative
results are summarised in Table 1. With aliphatic primary amines which has
no substituent at ꢀ-position the reaction proceeded well toward 3 and the
yield was not affected significantly by the structural nature of the
amine chain (runs 1–6). In the reaction with cyclohexylamine, which bears
ꢀ-substituent, the product yield was similar to that obtained with the amine
described above (run 7). Even in the reaction with allylamine, which has
olefinic site to be activated under Heck arylation conditions,[1–3] the corre-
sponding carbonylative cyclised product 3 was also obtained in a similar
yield (run 8). However, with aniline the reaction was not satisfactory under
the employed reaction conditions.

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3-METHYLENEISOINDOLIN-1-ONES
1823
Table 1. Palladium-Catalysed Synthesis of 3-Methyleneisoindolin-
1-onesa
Primary
Amine 2
Isolated
Yield (%)
Run
1
Product 3
42
51
46
40
44
45
42
35
2
3
4
5
6
7
8
aReaction conditions:
1 (1 mmol), 2 (2mmol), PdCl 2(PPh3)2
(0.05 mmol), PPh3 (0.1 mmol), Na2SO4 (10 mmol), Et3N (5 mmol),
acetonitrile (10 ml), 100ꢀC, 20 h, under CO (20 atm).

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1824
CHO ET AL.
In summary, we have demonstrated that 3-methyleneisoindolin-1-ones can
be conveniently synthesized from 20-bromoacetophenone and aliphatic pri-
mary amines in the presence of a palladium catalyst under carbon
monoxide pressure via an intramolecular carbopalladation across carbon–
nitrogen double bond.
EXPERIMENTAL
General procedure for palladium-catalysed synthesis of 3-methylene-iso-
indol-1-ones: 20-bromoacetophenone (0.199 g, 1 mmol), primary amine
(2mmol), PdCl 2(PPh3)2 (0.035 g, 0.05 mmol), PPh3 (0.026 g, 0.1 mmol),
Et3N (0.506 g, 5 mmol), anhydrous Na2SO4 (1.420 g, 10 mmol), and
MeCN (10 ml) were placed in a 50 ml stainless autoclave and allowed to
react under carbon monoxide (20 atm) at 100ꢀC for 20 h. The reaction mix-
ture was filtered through a short silica gel column (ethyl acetate), washed
with brine and dried over Na2SO4. Removal of the solvent left on oil which
was separated by column chromatography (ethyl acetate/hexane ¼ 1/10) to
give the corresponding product.
2-Butyl-3-methylene-2,3-dihydroisoindol-1-one: pale yellow oil;
;
1H NMR (400 MHz, CDCl3) ꢁ 0.96
IR (neat) 1706 (C¼O) cmÀ1
(t, J ¼ 7.3 Hz, 3H), 1.35–1.44 (m, 2H), 1.63–1.70 (m, 2H), 3.78
(t, J ¼ 7.3 Hz, 2H), 4.86 (d, J ¼ 2.5 Hz, 1H, C¼CHEHZ), 5.19 (d,
J ¼ 2.5 Hz, 1H, C¼CHEHZ), 7.48 (t, J ¼ 7.5 Hz, 1H), 7.56 (dt, J ¼ 7.5 and
1.0 Hz, 1H), 7.68 (d, J ¼ 7.5 Hz, 1H), 7.82(d, J ¼ 7.5 Hz, 1H); 13C NMR
(100 MHz, CDCl3) ꢁ 13.8, 20.2, 30.4, 39.2, 88.5, 119.8, 123.0, 129.4, 129.5,
131.7, 136.3, 141.9, 167.1 (C¼O); M/S m/z (relative intensity) 201 (Mþ, 39),
186 (20), 159 (100), 146 (31), 130 (40), 103 (37), 77 (33). Anal. calcd for
C13H15NO: C, 77.58; H, 7.51; N, 6.96. Found: C, 77.29; H, 7.78; N, 7.06.
2-Hexyl-3-methylene-2,3-dihydroisoindol-1-one: pale yellow oil;
IR (neat) 1710 (C¼O) cmÀ1
;
1H NMR (400 MHz, CDCl3) ꢁ 0.88
(t, J ¼ 7.0 Hz, 3H), 1.24–1.39 (m, 6H), 1.63–1.73 (m, 2H), 3.77 (t,
J ¼ 7.0 Hz, 2H), 4.85 (d, J ¼ 2.0 Hz, 1H, C¼CHEHZ), 5.19 (d, J ¼ 2.0 Hz,
1H, C¼CHEHZ), 7.49 (dt, J ¼ 7.5 and 1.0 Hz, 1H), 7.56 (dt, J ¼ 7.5 and
1.0 Hz, 1H), 7.68 (d, J ¼ 7.5 Hz, 1H), 7.82(d, J ¼ 7.5 Hz, 1H); 13C NMR
(100 MHz, CDCl3) ꢁ 14.0, 22.6, 26.7, 28.3, 31.5, 39.5, 88.5, 119.8, 123.0,
129.4, 129.5, 131.7, 136.3, 141.9, 167.1 (C¼O); M/S m/z (relative intensity)
229 (Mþ, 33), 172 (12), 159 (100), 146 (39), 130 (42), 103 (47), 77 (43).
Anal. calcd for C15H19NO: C, 78.56; H, 8.35; N, 6.11. Found: C, 78.31;
H, 8.49; N, 6.20.
3-Methylene-2-phenethyl-2,3-dihydroisoindol-1-one: pale yellow oil; IR
1
(neat) 1708 (C¼O) cmÀ1; H NMR (400 MHz, CDCl3) ꢁ 2.97 (t, J ¼ 7.5 Hz,

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3-METHYLENEISOINDOLIN-1-ONES
1825
2H), 3.99 (t, J ¼ 7.5 Hz, 2H), 4.82 (d, J ¼ 2.0 Hz, 1H, C¼CHEHZ), 5.18
(d, J ¼ 2.0 Hz, 1H, C¼CHEHZ), 7.22–7.31 (m, 5H), 7.49 (dt, J ¼ 7.5 and
1.0 Hz, 1H), 7.57 (dt, J ¼ 7.5 and 1.0 Hz, 1H), 7.68 (d, J ¼ 7.5 Hz, 1H),
7.82(d, J ¼ 7.5 Hz, 1H); 13C NMR (100 MHz, CDCl3) ꢁ 34.6, 41.0, 88.6,
119.8, 123.1, 126.6, 128.6, 128.8, 129.3, 129.5, 131.9, 136.3, 138.6, 141.7,
166.9. (C¼O); M/S m/z (relative intensity) 249 (Mþ, 51), 158 (100), 129
(14), 104 (36), 77 (30).
2-Isoamyl-3-methylene-2,3-dihydroisoindol-1-one: pale yellow oil;
;
1H NMR (400 MHz, CDCl3) ꢁ 0.98
IR (neat) 1715 (C¼O) cmÀ1
(t, J ¼ 6.4 Hz, 6H), 1.53–1.59 (m, 2H), 1.63–1.68 (m, 1H), 3.79
(t, J ¼ 7.6 Hz, 2H), 4.85 (d, J ¼ 2.0 Hz, 1H, C¼CHEHZ), 5.19 (d,
J ¼ 2.0 Hz, 1H, C¼CHEHZ), 7.48 (t, J ¼ 7.2Hz, 1H), 7.56 (dt, J ¼ 7.2and
0.8 Hz, 1H), 7.68 (d, J ¼ 7.6 Hz, 1H), 7.81 (d, J ¼ 7.6 Hz, 1H); 13C NMR
(100 MHz, CDCl3) ꢁ 22.9, 26.5, 37.4, 38.2, 88.9, 120.1, 123.4, 129.8, 132.1,
134.2, 136.7, 142.2, 167.4 (C¼O); M/S m/z (relative intensity) 215 (Mþ, 17),
172 (8), 159 (100), 146 (24), 130 (32), 103 (28), 77 (26). Anal.
calcd for C14H17NO: C, 78.10; H, 7.96; N, 6.51. Found: C, 77.86; H, 8.09;
N, 6.60.
2-Isobutyl-3-methylene-2,3-dihydroisoindol-1-one: pale yellow oil;
;
1H NMR (400 MHz, CDCl3) ꢁ 0.96
IR (neat) 1713 (C¼O) cmÀ1
(d, J ¼ 7.0 Hz, 6H), 2.09–2.22 (m, 1H), 3.60 (d, J ¼ 7.5 Hz, 2H), 4.85 (d,
J ¼ 2.0 Hz, 1H, C¼CHEHZ), 5.20 (d, J ¼ 2.0 Hz, 1H, C¼CHEHZ), 7.49
(dt, J ¼ 7.5 and 1.0 Hz, 1H), 7.57 (dt, J ¼ 7.5 and 1.0 Hz, 1H), 7.68
(d, J ¼ 7.5 Hz, 1H), 7.83 (d, J ¼ 7.5 Hz, 1H); 13C NMR (100 MHz, CDCl3)
ꢁ 20.3, 27.8, 46.9, 88.8, 119.7, 123.1, 129.3, 129.4, 131.8, 136.3, 142.4, 167.5
(C¼O); M/S m/z (relative intensity) 201 (Mþ, 53), 186 (8), 158 (100), 146
(62), 130 (21), 103 (44), 89 (14), 77 (35). Anal. calcd for C13H15NO: C, 77.58;
H, 7.51; N, 6.96. Found: C, 77.20; H, 7.68; N, 7.01.
2-Benzyl-3-methylene-2,3-dihydroisoindol-1-one: pale yellow oil;
;
1H NMR (400 MHz, CDCl3) ꢁ 4.79
IR (neat) 1706 (C¼O) cmÀ1
(d, J ¼ 2.0 Hz, 1H, C¼CHEHZ), 5.01 (s, 2H), 5.15 (d, J ¼ 2.0 Hz, 1H,
C¼CHEHZ), 7.24–7.31 (m, 5H), 7.52 (dt, J ¼ 7.5 and 1.0 Hz, 1H), 7.59
(dt, J ¼ 7.5 and 1.0 Hz, 1H), 7.67 (d, J ¼ 7.5 Hz, 1H), 7.89 (d, J ¼ 7.5 Hz,
1H), 13C NMR (100 MHz, CDCl3) ꢁ 43.2, 90.0, 119.9, 123.4, 127.1, 127.4,
128.7, 129.2, 129.5, 132.1, 136.4, 136.8, 141.6, 167.3 (C¼O); M/S m/z (rela-
tive intensity) 235 (Mþ, 46), 104 (29), 91 (100), 77 (29).
2-Cyclohexyl-3-methylene-2,3-dihydroisoindol-1-one: white solid; m.p.
;
1H NMR (400 MHz, CDCl3)
118–120ꢀC; IR (KBr) 1705 (C¼O) cmÀ1
ꢁ 1.21–1.46 (m, 4H), 1.71–1.92 (m, 4H), 2.17–2.30 (m, 2H), 4.09
(t, J ¼ 12.1 Hz, 1H), 5.00 (d, J ¼ 2.0 Hz, 1H, C¼CHEHZ), 5.22 (d, J ¼ 2.0 Hz,
1H, C¼CHEHZ), 7.47 (dt, J ¼ 7.5 and 1.0 Hz, 1H), 7.55 (dt, J ¼ 7.5 and
1.0 Hz, 1H), 7.65 (d, J ¼ 7.5 Hz, 1H), 7.79 (d, J ¼ 7.5 Hz, 1H); 13C NMR

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1826
CHO ET AL.
(100 MHz, CDCl3) ꢁ 25.5, 26.3, 29.8, 52.4, 89.4, 119.5, 122.9, 129.3, 129.4,
131.6, 136.6, 141.4, 167.3 (C¼O); M/S m/z (relative intensity) 227 (Mþ, 4),
146 (17), 132(100), 104 (13), 77 (17). Anal. calcd for C 15H17NO: C, 79.26;
H, 7.54; N, 6.16. Found: C, 78.95; H, 7.78; N, 6.30.
2-Allyl-3-methylene-2,3-dihydroisoindol-1-one: pale yellow oil; IR (neat)
1
1712(C ¼O) cmÀ1; H NMR (400 MHz, CDCl3) ꢁ 4.42–4.44 (m, 2H), 4.86
(d, J ¼ 2.5 Hz, 1H, C¼CHEHZ), 5.15–5.20 (m, 2H), 5.19 (d, J ¼ 2.5 Hz, 1H,
C¼CHEHZ), 5.81–5.91 (m, 1H), 7.50 (dt, J ¼ 7.5 and 1.0 Hz, 1H), 7.58
(dt, J ¼ 7.5 and 1.0 Hz, 1H), 7.69 (d, J ¼ 7.5 Hz, 1H), 7.85 (d, J ¼ 7.5 Hz,
1H), 13C NMR (100 MHz, CDCl3) ꢁ 41.8, 89.5, 116.8, 119.8, 123.2,
129.3, 129.5, 132.0, 132.4, 136.4, 141.6, 166.8 (C¼O); M/S m/z (relative
intensity) 185 (Mþ, 100), 156 (46), 129 (30), 115 (26), 102 (34), 77 (36).
Anal. calcd for C12H11NO: C, 77.81; H, 5.99; N, 7.56. Found: C, 77.50;
H, 6.11; N, 7.62.
ACKNOWLEDGMENT
This work was supported by the Basic Research Program of the Korea
Science and Engineering Foundation (2000-2-12200-001-3) and grant of
Post-Doc. (C.S.C.) Program from Kyungpook National University (2000).
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3-METHYLENEISOINDOLIN-1-ONES
1827
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Received in the UK April 26, 2001