A Practical Two-Step Synthesis of 3-Alkyl-2,3-dihydro-1H-isoindolin-1-ones

Article abstract of DOI:10.1081/SCC-120028358

A flexible approach to 3-alkyl-2,3-dihydro-1H-isoindolin-1-ones via the reductive-alkylation procedure is described. Present method is versatile in scope, allowing the easy introduction of various C-3 carbon-substituents by Grignard addition to phthalimid

Full text of DOI:10.1081/SCC-120028358

w
SYNTHETIC COMMUNICATIONS
Vol. 34, No. 5, pp. 853–861, 2004
A Practical Two-Step Synthesis of 3-Alkyl-
,3-dihydro-1H-isoindolin-1-ones
2
Yuan-Ping Ruan, Ming-De Chen, Ming-Zhu He, Xiang Zhou,
and Pei-Qiang Huang*
Department of Chemistry, Xiamen University, Xiamen, Fujian, China
ABSTRACT
A flexible approach to 3-alkyl-2,3-dihydro-1H-isoindolin-1-ones via the
reductive-alkylation procedure is described. Present method is versatile in
scope, allowing the easy introduction of various C-3 carbon-substituents
by Grignard addition to phthalimide.
Key Words: Isoindolin-1-one; Grignard reaction; Reductive alkylation;
Phthalimide.
Due to the presence of 3-alkyl-2,3-dihydro-1H-isoindolin-1-ones
isoindolin-1-ones) as key structural units in a number of synthetic and
(
[1]
natural bioactive molecules, the chemistry of 3-alkyl-isoindolin-1-ones has
attracted much current attention, and a number of valuable synthetic methods
*
Correspondence: Pei-Qiang Huang, Department of Chemistry, Xiamen University,
Xiamen, Fujian 361005, China; Fax: 86-592-2186400; E-mail: pqhuang@xmu.edu.cn.
8
53
DOI: 10.1081/SCC-120028358
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com
Copyright # 2004 by Marcel Dekker, Inc.

ORDER
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8
54
Ruan et al.
Among them, the most flexible and straightforward
[
2–5]
have been developed.
ones are those where the 3-alkyl groups are introduced directly. This has been
achieved either by the reaction of 3-metalated isoindolin-1-ones with electro-
[
3]
philes; by the reaction of an N-acyliminium equivalent with nucleophiles;
[4]
[5]
by the reaction of methyl o-lithiobenzoate to imines, or by organometallic
[6]
reagents addition to phthalimide followed by reductive deoxygenation. For
[6]
the synthesis of N-unprotected 3-alkyl-2,3-dihydro-1H-isoindolin-1-ones,
recently reported two-step organolithiums addition-reductive deoxygenation
[6a]
procedure is the shortest route.
In connection with a program aimed at the development of asymmetric
synthetic methodology based on the reductive alkylation of chiral nonracemic
[
imides, we have reported recently a versatile asymmetric approach to
7]
[8]
N-substituted 3-alkyl-isoindolin-1-ones, we now wish to report herein that
this two-steps approach is applicable to simple N-unprotected phthalimide.
Scheme 1.
Our method is displayed in Sch. 1. Treatment of commercially available
phthalimide 3 with an excess of methyl magnesium iodide led to the desired
a-hydroxylactam 4a (Table 1, Entry 1) in a yield of 81%. Treatment of 4a with
Table 1. Preparation of 3-alkyl-2,3-dihydro-1H-isoindolin-1-ones 1 via
the reductive alkylation of phthalimide 3.
Addition products
(Yield, %)
Isoindolin-1-ones
(Yield, %)
Entry
RMgX (2)
MeMgI
EtMgBr
1
2
3
4
5
6
7
8
9
4a (81)
4b (85)
4c (92)
4d (97)
4e (77)
4f (94)
4g (96)
4h (97)
4i (88)
1a (65)
1b (96)
1c (75)
1d (97)
1e (55)
1f (91)
1g (96)
1h (88)
1i (90)
n-PrMgBr
n-BuMgBr
i-BuMgBr
n-C
n-C
5
H
H
11MgBr
15MgBr
7
BnMgCl
PhMgBr

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Synthesis of 3-Alkyl-2,3-dihydro-1H-isoindolin-1-ones
855
[
8]
triethylsilane in the presence of boron trifluoride etherate afforded the
desired deoxygenated product 3-methyl-2,3-dihydro-1H-isoindolin-1-one 1a
in 64% yield. Extension of the same procedure to other Grignard reagents led
to the corresponding products 4b–h and 1b–h in good to excellent yields,
except in the case of 1e, where some dehydrated side-product was formed
(
40%). The successful preparation of 3-phenyl-2,3-dihydro-1H-isoindolin-1-
one 1i served to demonstrate that the present method can be extended to the
preparation of 3-aryl-2,3-dihydro-1H-isoindolin-1-ones as well.
It is worth-mentioning that although the Grignard reagents addition to
[
6a,10]
N-protected phthalimide is known for a long time, to the best of our
knowledge, the direct Grignard reagents addition to N-unprotected phthali-
mide it-self and leading to the corresponding 3-alkyl-3-hydroxy-2,3-dihydro-
1
phthalimide see Ref. ). Comparing with an analogue method reported
H-isoindolin-1-ones has not been reported (for Grignard addition to
[
11]
[
6b]
recently,
use of more easily available Grignard reagents instead of lithium reagents.
the present method is more practical and versatile in view of the
[6b]
[6b]
In addition, the use of hazardous reagents such as HMPA and NaBH CN is
3
avoided in the present method.
In summary, we have developed a flexible approach to 3-alkyl-2,3-
dihydro-1H-isoindolin-1-ones via the reductive-alkylation procedure. This
method is versatile in scope, since various C-3 carbon substituents can be
introduced easily by Grignard reaction.
EXPERIMENTAL
Melting points were determined on a Yanaco M-500 micro melting point
apparatus and the thermometer was uncorrected. IR spectra were obtained on a
1
Nicholet Avatar 360 FT-IR spectrophotometer. H NMR spectra were taken at
a Varian Unity þ500 spectrometer. Mass spectra were recorded on a Finnigan
MAT-GCQ (direct injection, EI). Column chromatography was performed on
silica gel H (Qingdao, 400 Mesh).
General Procedure for the Preparation of 3-Alkylisoindolin-
1-ones and 3-Arylisoindolin-1-ones 1 by Reductive
Alkylation of Phthalimide
To an ice-bath chilled solution of phthalimide (3) (1 mmol) in CH Cl
2
2
(10 mL) was added, under N , a Grignard reagent (3 mmol). After being stirred
2
under the same temperature for 3 hr, the reaction was quenched by a saturated
aqueous solution of NH Cl (6 mL). The resulting mixture was extracted with
4

ORDER
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8
56
Ruan et al.
CH Cl (3 Â 10 mL). The combined organic phases were washed with brine,
2
2
then dried (Na SO ), filtered and concentrated. A short silica gel column
2
4
filtration of the crude mixture [EtOAc-petroleum ether (60–908C) ¼ 2 : 1 as
eluent] afforded 4.
To a solution of 4 in dry CH Cl (10 mL) was added successively
2
2
triethylsilane (10.0 mmol) and trifluoroboron etherate (3.0 mmol) at 2158C
under N . The mixture was allowed to stir at room temperature overnight. A
saturated aqueous solution of NaHCO (3 mL) was added, which was followed
2
3
by CH Cl extraction (3 Â 6 mL). The combined organic layers were washed
2
2
with brine, dried (Na SO ), filtered and concentrated under reduced pressure.
4
2
The crude was subjected to column chromatography purification on silica gel
to afford 1.
3-Methyl-2,3-dihydro-1H-isoindolin-1-one (1a)
[12]
Yield 65%. White crystal, mp 112–1138C (CH Cl ) [Lit.
mp 112–
2
2
1
2
1
148C (DCM)]. R : 0.39 (AcOEt : PE ¼ 1.5 : 1). IR (KBr, Pellet) nmax: 3243,
f
973, 2929, 1693, 1617, 1593, 1470, 1416, 1355, 1306, 1210, 1140,
2
1 1
099 cm . HNMR (500 MHz, CDCl ) d: 1.51 (d, J ¼ 6.7 Hz, 3H, CH ), 4.54
3
3
(
(
q, J ¼ 6.7 Hz, 1H, CH CH), 6.90 (s, 1H, NH), 7.40–7.60 (m, 3H, Ar), 7.84
3
þ
þ
d, 1H, Ar). MS (ESI, m/z): 148 (M þ H , 100), 170 (M þ Na , 77).
3-Ethyl-2,3-dihydro-1H-isoindolin-1-one (1b)
[13]
Yield 96%. White crystal, mp 105–1068C (CH Cl ) [Lit.
mp 1058C].
2
2
R : 0.31 (AcOEt : PE ¼ 1 : 1). IR (KBr, pellet) n : 3208, 3081, 2968, 2929,
f
max
2
1
1
689, 1615, 1593, 1468, 1423, 1361, 1305, 1206, 1140 cm . H NMR
1
(
500 MHz, CDCl ) d: 0.96 (t, J ¼ 7.4 Hz, 3H, CH ), 1.66–1.78 (m, 1H, CH ),
3
3
2
1
.98–2.08 (m, 1H, CH ), 4.61 (dd, J ¼ 4.9, 6.9 Hz, 1H, NCH), 7.05 (s, 1H,
2
þ
NH), 7.42–7.60 (m, 3H, Ar), 7.84 (m, 1H, Ar). MS (ESI, m/z): 162 (M þ H ,
þ
þ
1
00), 163 [(M þ 2H) , 11], 184 (M þ Na , 7).
3-n-Propyl-2,3-dihydro-1H-isoindolin-1-one (1c)
[14]
Yield 75%. White crystal, mp 135–1368C (ether) [Lit. mp 135–1368C
(
water)]. R : 0.48 (AcOEt : PE ¼ 1 : 1). IR (KBr, pellet) n : 3194, 3077,
f
max
2
962, 2932, 2868, 1685, 1613, 1466, 1361, 1263, 1144 cm . H NMR
1
1
2
(
500 MHz, CDCl ) d: 0.88 (t, J ¼ 7.2 Hz, 3H, CH ), 1.36–1.56 (m, 2H,
3
3
CH CH ), 1.60–1.98 (m, 2H, CH CH CH ), 4.62–4.66 (dd, J ¼ 4.4, 7.7 Hz,
2 3 2 2 3

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Synthesis of 3-Alkyl-2,3-dihydro-1H-isoindolin-1-ones
857
1
H, NCH), 7.42–7.58 (m, 3H, Ar), 7.64–7.92 (brs, 1H, NH), 7.85 (m, 1H, Ar)
þ
þ
ppm. MS (ESI, m/z): 176 (M þ H , 100), 177 [(M þ 2H) , 14], 198
þ
þ
þ
(
M þ Na , 51), 351 [(2M þ H) , 7], 373 [(2M þ Na) , 17].
3-n-Butyl-2,3-dihydro-1H-isoindolin-1-one (1d)
[
6a]
Yield 97%. White crystal, mp 86–878C (CH Cl ) [Lit. mp 88–898C].
2
2
R : 0.31 (AcOEt : PE ¼ 1 : 1.5). IR (KBr, pellet) nmax: 3226, 2956, 2931, 2861,
f
2
1 1
696, 1616, 1468, 1418, 1359, 1310, 1141 cm . H NMR (500 MHz, CDCl3)
1
d: 0.90 (t, J ¼ 7.1 Hz, 3H, CH ), 1.22–1.50 (m, 4H, 2CH ), 1.60–1.70 (m, 1H,
3
2
CH Pr), 1.92–2.00 (m, 1H, CH Pr), 4.61 (dd, 1H, J ¼ 4.6, 7.7 Hz, NCH), 6.90
2
2
(
s, 1H, NH), 7.40–7.62 (m, 3H, Ar), 7.85 (m, 1H, Ar) ppm. MS (ESI, m/z):
þ
þ
þ
1
90 (M þ H , 100), 191 [(M þ 2H) , 12], 212 (M þ Na , 4), 379
þ
[
(2M þ H) , 8].
3-iso-Butyl-2,3-dihydro-1H-isoindolin-1-one (1e)
[15]
Yield 55%. White crystal, mp 176–1778C (CH Cl ) [Lit.
mp 1538C
2
2
(
EtOH)]. R : 0.45 (AcOEt : PE ¼ 1 : 1). IR (KBr, pellet) n : 3192, 3074,
f
max
21 1
957, 2922, 2863, 1683, 1613, 1469, 1363, 1268, 1209, 1142 cm . H NMR
2
(
CH ), 1.46–1.53 (m, 1H, CHCH ), 1.72–1.78 (m, 1H, CHCH ), 1.79–1.88
500 MHz, CDCl ) d: 1.00 (d, J ¼ 6.5 Hz, 3H, CH ), 1.06 (d, J ¼ 6.5 Hz, 3H,
3 2 2
3
3
(
m, 1H, CH(CH ) ), 4.65 (dd, J ¼ 4.1, 9.6 Hz, 1H, NCH), 6.64 (s, 1H, NH),
3
2
þ
7
.42–7.60 (m, 3H, Ar), 7.84 (m, 1H, Ar) ppm. MS (ESI, m/z): 190 (M þ H ,
þ þ
1
00), 191 [(M þ 2H) , 13], 212 (M þ Na , 4).
3-n-Pentyl-2,3-dihydro-1H-isoindolin-1-one (1f)
Yield 91%. White crystal, mp 85–868C (CH Cl ). Rf: 0.48
2
2
(
AcOEt : PE ¼ 1 : 1). IR (KBr, pellet) n : 3208, 3081, 2854, 2930, 1698,
max
21 1
616, 1593, 1468, 1427, 1359, 1309, 1199, 1141 cm . HNMR (500 MHz,
1
CDCl ) d: 0.88 (t, J ¼ 6.9 Hz, 3H, CH ), 1.24–1.38 (m, 5H, CH ), 1.41–1.52
3
3
2
(
m, 1H, CH ), 1.58–1.70 (m, 1H, CH Bu), 1.90–1.98 (m, 1H, CH ), 4.62 (dd,
2 2 2
J ¼ 4.4, 7.7 Hz, 1H, NCH), 7.01 (s, 1H, NH), 7.41–7.58 (m, 3H, Ar), 7.84
þ
þ
(
m, 1H, Ar) ppm. MS (ESI, m/z): 204 (M þ H , 100), 205 [(M þ 2H) , 16],
þ
4
07 [(2M þ H) , 5].

ORDER
REPRINTS
8
58
Ruan et al.
3-n-Heptyl-2,3-dihydro-1H-isoindolin-1-one (1g)
Yield 96%. White crystal, mp 71–728C (ether). R : 0.52 (AcOEt : PE ¼
f
1
1
3
.5 : 1). IR (KBr, pellet) n : 3206, 3080, 2926, 2857, 1691, 1617, 1464,
max
21 1
361, 1310, 1141 cm . HNMR (500 MHz, CDCl ) d: 0.86 (t, J ¼ 7.0 Hz,
3
H, CH ), 1.22–1.34 (m, 9H, (CH ) ), 1.42–1.48 (m, 1H, CH ), 1.60–1.68
3
2 5
2
(
NCH), 7.40–7.60 (m, 3H, Ar), 7.60–7.80 (brs, 1H, NH), 7.82 (m, 1H, Ar)
m, 1H, CH ), 1.92–1.94 (m, 2H, CH ), 4.60–4.64 (dd, J ¼ 4.6, 7.5 Hz, 1H,
2
2
þ
þ
ppm. MS (ESI, m/z): 232 (M þ H , 100), 233 [(M þ 2H) , 17], 463
þ
þ
[
(2M þ H) , 10], 485 [(2M þ Na) , 3].
3-Benzyl-2,3-dihydro-1H-isoindolin-1-one (3h)
[16]
Yield 88%. White crystal, mp 134–1358C (CH Cl ) [Lit.
mp 135–
2
2
1
368C (ether)]. R : 0.33 (AcOEt : PE ¼ 1 : 1). IR (KBr, pellet) n : 3202,
f
max
1 1
2
079, 2917, 1693, 1615, 1557, 1359, 1274, 1141, 1074, 1022 cm . HNMR
3
(
500 MHz, CDCl ) d: 2.80 (dd, 1H, J ¼ 9.3, 13.6 Hz, CH ), 3.26 (dd, 1H,
2 2
3
2
J ¼ 5.0, 13.6 Hz, CH ), 4.80 (dd, 1H, J ¼ 5.0, 9.3 Hz, CHCH ), 6.50 (s, 1H,
NH), 7.20–7.38 (m, 6H, Ar), 7.44–7.60 (m, 2H, Ar), 7.84 (m, 1H, Ar)
ppm. MS (ESI, m/z): 224 (M þ H , 100), 225 [(M þ 2H) , 17], 246
þ
þ
þ
(
M þ Na , 3).
3-Phenyl-2,3-dihydro-1H-isoindolin-1-one (3i)
[
17]
Yield 90%. White crystal, mp 206–2088C (CH Cl ) [Lit.
mp 2128C
2
2
[
18]
(
EtOH); Lit.
KBr, pellet) nmax: 3445, 3209, 3062, 2922, 2851, 1694, 1635, 1615, 1452,
mp 218–2208C (EtOH)]. R : 0.53 (AcOEt : PE ¼ 1.5 : 1). IR
f
(
2
356, 1260, 1129, 1108, 1060, 1021 cm . HNMR (500 MHz, CDCl ) d: 5.62
1 1
1
3
(
s, 1H, NCHPh), 6.72 (s, 1H, NH), 7.20–7.40 (m, 6H, Ar), 7.45–7.66 (m, 2H,
þ
Ar), 7.88 (m, 1H, Ar) ppm. MS (ESI, m/z): 210 (M þ H , 100), 211
þ
þ
[
(M þ 2H) , 15], 232 (M þ Na , 5).
ACKNOWLEDGMENT
We are grateful to the NNSC for financial support.

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Synthesis of 3-Alkyl-2,3-dihydro-1H-isoindolin-1-ones
859
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Synthesis of 3-Alkyl-2,3-dihydro-1H-isoindolin-1-ones
861
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Received in the USA August 21, 2003

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