A versatile approach for the asymmetric synthesis of 3-alkyl-2,3-dihydro- 1H-isoindolin-1-ones

Article abstract of DOI:10.1016/j.tet.2003.11.092

Based on the use of (R)-p-benzyloxyphenylglycinol (10) as a new oxidatively cleavable chiral auxiliary, a flexible approach to (R)-3-alkyl-2,3-dihydro-1H-isoindolin-1-ones via a diastereoselective reductive-alkylation is developed. The oxidative cleavage of the chiral auxiliary by CAN under mild conditions ensured the access to (R)-3-alkyl-2,3-dihydro-1H-isoindolin-1-ones with ee at least 92%.

Full text of DOI:10.1016/j.tet.2003.11.092

Tetrahedron 60 (2004) 1651–1657
A versatile approach for the asymmetric synthesis of
3-alkyl-2,3-dihydro-1H-isoindolin-1-ones
*
Ming-De Chen, Xiang Zhou, Ming-Zhu He, Yuan-Ping Ruan and Pei-Qiang Huang
Department of Chemistry and The Key Laboratory for Chemical Biology of Fujian Province, Xiamen University, Xiamen, Fujian 361005,
People’s Republic of China
Received 12 September 2003; revised 24 October 2003; accepted 25 November 2003
Dedicated to Professor Dr. Khi-Rui Tsai on the occasion of his 90th birthday
Abstract—Based on the use of (R)-p-benzyloxyphenylglycinol (10) as a new oxidatively cleavable chiral auxiliary, a flexible approach to
(R)-3-alkyl-2,3-dihydro-1H-isoindolin-1-ones via a diastereoselective reductive-alkylation is developed. The oxidative cleavage of the chiral
auxiliary by CAN under mild conditions ensured the access to (R)-3-alkyl-2,3-dihydro-1H-isoindolin-1-ones with ee at least 92%.
q 2003 Elsevier Ltd. All rights reserved.
1. Introduction
methyl-isoindolin-1-one (1a), first reported by Oppolzer in
1990,5a and ten years later by Allin and co-workers,7
remained the only 3-alkyl-2,3-dihydro-1H-isoindolin-1-one
(1) so far obtained by asymmetric synthesis with high ee
value.
3-Alkyl-2,3-dihydro-1H-isoindolin-1-ones (isoindolin-1-
ones) 1 are the key structural feature of a number of
synthetic and naturally occurring bioactive molecules. For
example, PD-172938 (2) enantiomers show affinity for
dopamine D4 receptor,1 pazinaclone (DN-2327)2 (3) and
pagoclone3 (4) are anxiolytic drug candidates, while
lennoxamine (5)4 is an alkaloid isolated from barberries
species (Fig. 1). Besides, (S)-3-methyl-isoindolin-1-one has
been shown to be a valuable chiral auxiliary.5 Consequently,
the chemistry of 3-alkyl-isoindolin-1-ones has attracted
much attention currently, and a number of valuable
synthetic methods for such compounds have been
developed.6,7
Figure 1.
However, in contrast to the great progress made in
asymmetric synthesis within the last two decades, the
methodology for the asymmetric synthesis of simple
3-alkyl-2,3-dihydro-1H-isoindolin-1-ones 1 in high ee was
rarely explored. Although a flexible approach to 3-aryl
substituted 2,3-dihydro-1H-isoindolin-1-ones has been
reported recently, to the best of our knowledge, (R)-3-
It is worth mentioning that although four methods7,9,10 have
been reported for the asymmetric synthesis of N-substituted
3-alkyl-isoindolin-1-ones 6 starting from (R)-phenyl-
glycinol, the removal of the N-chiral auxiliary to give 1
could not be achieved in a straightforward and racemiza-
tion-free manner (vide infra).6 Consequently, to develop
versatile and flexible methods for the asymmetric synthesis
of 3-alkyl-2,3-dihydro-1H-isoindolin-1-ones 1 is highly
desirable. We herein report a flexible reductive-alkylation
approach to 3-alkyl-2,3-dihydro-1H-isoindolin-1-ones 1
Keywords: Isoindolin-1-one; Chiral auxiliary; Benzyloxyphenylglycinol;
Asymmetric synthesis.
*
Corresponding author. Tel.: þ86-592-218-0992; fax: þ86-592-218-6400;
e-mail address: pqhuang@xmu.edu.cn
0040–4020/$ - see front matter q 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2003.11.092

1652
M.-D. Chen et al. / Tetrahedron 60 (2004) 1651–1657
featuring the removal of the chiral auxiliary under
racemization free conditions.11
under mild racemization-free conditions. N-p-Alkyloxyben-
zyl group is cleavable under mild oxidative conditions,20,21
and (R)-N-p-hydroxyphenylglycinol is a cheap and com-
mercially available amino acid. Based on the consider-
ations, we decided to test (R)-N-p-benzyloxyl-
phenylglycinol as a new chiral auxiliary for the asymmetric
synthesis of 3-alkylisoindolinones, in hoping that at the end
of the synthesis, the N-p-alkyloxybenzyl group could be
removed under racemization-free oxidative conditions.
2. Results and discussion
To this end, cheap and easily available (R)-p-hydroxy-
phenylglycine 8 was converted to O-benzylether 9 by a
known procedure.22 The reduction of 9 with lithium
aluminum hydride in refluxing tetrahydrofuran led to the
crude (R)-p-benzyloxyphenylglycinol (10), which was
subjected to react with phthalic anhydride without further
purification, under solvent-free conditions23 (170–180 8C,
14–15 h). In this way, (R)-11 {white crystal, mp 132–
133 8C (ether), [a]2D0¼þ7.4 (c 0.9, CHCl3)} was obtained in
79% yield (Scheme 2).
In chiral auxiliary-based asymmetric synthetic method-
ology, the success of a chiral auxiliary depends, firstly, on
its asymmetric induction, and secondly, on the feasibility of
its smooth removal from the substrate after asymmetric
induction. This is the case of (R)-phenylglycinol, a valuable
chiral auxiliary gained widespread application in asym-
metric syntheses.12,13 The success of this chiral auxiliary is
due partially to the easy cleavage of the benzylic auxiliary
under hydrogenolysis conditions.13 Further development for
its cleavage under non-reductive conditions14–16 has led to
the extension of the scope of this chiral auxiliary.
During the asymmetric synthesis of amides or lactams using
phenylglycinol as a chiral auxiliary, apart from the widely
used dissolving metal reduction method,17 only two
alternative procedures18 have been used for the removal of
benzylic auxiliary group from the nitrogen (e.g., Scheme 1,
6!1). Recently, inspired from the pioneering work of
Meyers,19 we have developed a versatile and flexible
reductive alkylation approach to optically active 3-alkyl-
isoindolin-1-one derivatives (7!6, Scheme 1).10 However,
attempted removal of the chiral auxiliary (2-hydroxy-1-
phenylethyl group) from the nitrogen of 6 (R¼Me, i-Bu) by
above-mentioned procedures18 resulted in extensive race-
mization (Scheme 1). In the recent asymmetric synthesis of
3-aryl-isoindolin-1-ones, Enders and co-workers8 also noted
that attempted cleavage of N–N bond of the chiral auxiliary
SAMP under reductive conditions led to either complex
mixture or racemization.
Scheme 2.
With multi-gram quantities of (R)-11 available, the
reductive-alkylation was investigated. The reaction of
(R)-11 with 2.5 equiv. of methyl magnesium iodide at
215 to 210 8C led smoothly to the formation of a-hydroxy-
lactam 12a (Table 1, entry 1) in 98% yield as a 1.2:1
diastereomeric mixture (the stereochemistry was not
determined). Although the two diastereomers of 12a are
separable by column chromatography on silica gel, they
were unseparated and used in the next step as diastereomeric
mixture, since the subsequent reductive dehydroxylation
was expected to proceed via the N-acyliminium ion
intermediate A.24 Indeed, when the diastereomeric mixture
of 12a was subjected to a boron trifluoride etherate mediated
triethylsilane reduction,25,10 diastereoisomer 13a formed
predominately. The two diastereomers 13a/14a were
separated by flash chromatography on silica gel, from
which the diastereomeric ratio of 13a/14a was determined
as 75:25 (Scheme 3).
Scheme 1.
The stereochemistry of the0 major diastereomer 13a was
tentatively assigned as (3R,1 R) by the comparison of its 1H
NMR spectral data with that of an analogue, de-benzyloxy-
15, whose structure was determined by a single-crystal
X-ray crystallographic analysis.10 This assignment was
The easy racemization of the 3-carbon-subsituted isoindo-
lin-1-one systems under acidic, basic or reductive con-
ditions (vide supra), account for the importance of
developing a new chiral auxiliary, which is cleavable

M.-D. Chen et al. / Tetrahedron 60 (2004) 1651–1657
Table 1. Preparation of 13 via the reductive alkylation of 11
1653
Entry
RMgX
Compounds 12 (yield, %)
Compounds 13/14 (yield, %)
Diastereomeric ratioa (13/14)
1
2
3
4
5
6
7
MeMgI
EtMgBr
n-PrMgBr
n-BuMgBr
i-BuMgBr
n-C5H11MgBr
n-C7H15MgBr
12a (98)
12b (88)
12c (93)
12d (73)
12e (89)
12f (83)
12g (83)
13/14a (98)
13/14b (79)
13/14c (96)
13/14d (98)
13/14e (94)
13/14f (67)
13/14g (79)
75:25
88:12
81:19
81:19
83:17
73:27
70:30
a
Determined by chromatograph separation.
finally confirmed by its transformation into known (R)-3-
methyl-isoindolin-1-one 1a (vide infra).
paring with a racemic sample, the enantiomeric excess of 1a
was determined to 97% based on HPLC analysis on a chiral
column (eluent: 2.5% IPA in hexane, l¼270 nm). The
specific rotation of the synthesized (R)-3-methyl-isoindolin-
1-one 1a {[a]2D0¼þ39.1 (c 1.0, MeOH)} is in agreement
with that reported by Stevenson and co-workers
{[a]2D0¼239.8 (c 0.6, EtOH) for (S)-1a},5c but different,
both in the sense and in the magnitude, from that reported by
Allin {[a]2D0¼289.7 (c 1.7, MeOH) for (R)-1a, ca. 96% ee}
(Scheme 4).7
Extension of the same reductive alkylation procedure to
other Grignard reagents led to the corresponding products
13b–g and 14b–g in diastereoselectivity varied from 70:30
to 88:12 (Table 1, entries 2–7). Although the diastereo-
selectivity in this step is not high, the easy separation of the
diastereomers by flash chromatography on silica gel allows
the ready isolation of the diastereomer 13 in pure form.
Next, the key oxidative removal of the chiral auxiliary was
investigated. The treatment of N-substituted 3-methyliso-
indolin-1-one (13a) with four molar equivalents of ceric
ammonium nitrate (CAN)21 in a mixed solvent system
(MeCN–H2O, 3:1, rt, 30 min.) led smoothly to the desired
(R)-3-methylisoindolin-1-one (1a) as white crystals [mp
112–115 8C; lit.5c mp 102–103 8C for (S)-1a]. By com-
Scheme 4.
Following the same procedure as described for 13a, the
oxidative cleavages of 13b–13g by CAN were performed.
The results were listed in Table 2. Except in the case of 13b
(Table 2, entry 2), other 3-substituted isoindolin-1-ones
were obtained in high chemical yield and with ee % value no
less than 92%.
Table 2. Synthesis of (R)-1 by oxidative N-deprotection of 13
Entry
Compounds (R)-1 (yield, %)
ee (%) of (R)-1
1
2
3
4
5
6
7
1a (84)
1b (63)
1c (86)
1d (90)
1e (88)
1f (88)
1g (82)
97
92
97
92
93
94
97
In summary, a versatile and flexible approach to (R)-3-
alkyl-isoindolin-1-ones 1, in high enantiomeric purity
(ee$92%), is developed via a diastereoselective reduc-
tive-alkylation procedure.26 The use of (R)-p-benzyloxy-
phenylglycinol (10) as a new oxidatively cleavable chiral
auxiliary is the key to reach high enantiomeric purity of the
3-alkyl-isoindolin-1-ones 1. This method is versatile in
scope, because various C-3 alkyl substituents can be
introduced easily by Grignard reaction. The application of
present method to the asymmetric synthesis of 3-alkyl-
isoindolin-1-one-based bioactive compounds is in
progress.
Scheme 3.

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M.-D. Chen et al. / Tetrahedron 60 (2004) 1651–1657
3. Experimental
To a cooled (278 8C) solution of diastereomer mixture 12
(1.0 mmol) in dry dichloromethane (10 mL) was added
dropwise triethylsilane (10 mmol) and boron trifluoride
etherate (3.0 mmol) under nitrogen atmosphere. After
stirring at 278 8C for 6 h, the mixture allowed to react at
rt and stirred overnight. The reaction was quenched by
saturated aqueous sodium bicarbonate and extracted with
dichloromethane (3£20 mL). The combined extracts were
washed with brine and dried over anhydrous Na2SO4 then
concentrated in vacuum. The crude was purified by flash
column chromatography on silica gel with ethyl acetate–
petroleum ether (1:2) as eluent to give 13.
3.1. General
All melting points were determined on a Yanaco MP-500
micro melting point apparatus and were uncorrected.
Infrared spectra were measured with a Nicolet Avatar 360
1
FT-IR spectrometer using film KBr pellet techniques. H
NMR spectra were recorded in CDCl3 on a Varian
unityþ500 spectrometer with tetramethylsilane as an
internal standard. Chemical shifts are expressed in d
(ppm) units downfield from TMS. Mass spectra were
recorded by a Bruker Dalton ESquire 3000 plus liquid
chromatography-mass Spectrum (ESI direct injection).
Optical rotations were measured with Perkin–Elmer 341
automatic polarimeter. Flash column chromatography was
carried out with silica gel (200–300 mesh). Solvent THF
was distilled over sodium, with dichloromethane being
distilled over P2O5.
3.2.1. (3R,10R)-3-Methyl-2-[2-hydroxy-1-(4-benzyloxy-
phenyl)ethyl]-2,3-dihydro-1H-isoindolin-1-one
(13a).
Diastereomeric ratio: 75:25, combined yield 98%.
(3R,10R)-13a (major diastereomer): Rf: 0.27 (AcOEt–
P.E.¼1:2). Colorless oil. [a]2D0¼þ54.4 (c 0.9, CHCl3). IR
(film) nmax: 3366, 2924, 2847, 1664, 1611, 1583, 1510,
1468, 1454, 1468, 1409, 1354, 1300, 1240, 1178, 1079,
3.1.1. (R)-N-[2-Hydroxy-1-(4-benzyloxyphenyl)ethyl]-
phthalimide (11). A mixture of phthalic anhydride
(0.288 g, 1.943 mmol) and (R)-2-hydroxy-1-(4-benzyloxy-
phenyl)- ethylamine (0.45 g, 1.85 mmol), which obtained
by LiAlH4 reduction of known (R)-(4-benzyloxyphenyl)-
glycinol,21 was stirred at 170–180 8C for 15 h. The mixture
was then cooled to rt, before CH2Cl2 was added. The
resulting solution was dried over anhydrous Na2SO4,
filtered and concentrated under reduced pressure. The
crude was purified by flash column chromatography on
silica gel to give 11 (544 mg, yield 79%) as a pale yellow
solid. Rf: 0.29 (AcOEt–P.E.¼1:2). White crystal. Mp
132,133 8C (ether). [a]2D0¼þ7.4 (c 0.9, CHCl3). IR (KBr,
Pellet) nmax: 3461, 3062, 3033, 2926, 1771, 1707, 1610,
1584, 1512, 1463, 1389, 1363, 1331, 1242, 1179, 1111,
1069, 1013 cm21. 1H NMR (500 MHz) d: 2.45 (dd, J¼4.6,
8.2 Hz, 1H, OH), 4.21 (ddd, J¼4.6, 5.0, 11.4 Hz, 1H,
CH2OH), 4.61 (ddd, J¼8.2, 8.6, 11.4 Hz, 1H, CH2OH), 5.03
(s, 2H, OCH2Ph), 5.42 (dd, J¼5.0, 8.6 Hz, 1H, CHCH2OH),
6.88–7.90 (m, 13H, Ar) ppm. MS (ESI, m/z): 375
[(Mþ2H)þ, 34], 374 (MþHþ, 69), 356 [(MþH–H2O)þ,
29], 227 (100), 209 (51). HRESIMS calcd for
[C23H19NO4þH]þ: 374.1392. Found: 374.1391. Anal.
Calcd for C23H19NO: C, 73.97; H, 5.13; N, 3.75. Found:
C, 74.25; H, 5.32; N, 3.55.
1024 cm21 1H NMR (500 MHz, CDCl3) d: 1.45 (d,
.
J¼6.8 Hz, 3H, CH3), 4.08 (ddd, J¼3.4, 7.2, 12.4 Hz, 1H,
CH2OH), 4.35 (q, J¼6.8 Hz, 1H, NCHMe), 4.44 (ddd,
J¼7.2, 7.9, 12.4 Hz, 1H, CH2OH), 4.72 (dd, J¼3.4, 7.9 Hz,
1H, CHCH2OH), 4.85 (dd, J¼7.2, 7.9 Hz, 1H, OH), 5.03 (s,
2H, OCH2Ph), 6.88–7.88 (m, 13H, Ar) ppm. MS (ESI, m/z):
396 (MþNaþ, 6), 375 [(Mþ2H)þ, 25], 374 (MþHþ, 100).
HRESIMS calcd for [C24H23NO3þH]þ: 374.1756. Found:
374.1754.
3.2.2. (3R,10R)-3-Ethyl-2-[2-hydroxy-1-(4-benzyloxy-
phenyl)ethyl]-2,3-dihydro-1H-isoindolin-1-one
(13b).
Diastereomeric ratio: 88:12, combined yield 79%.
(3R,10R)-13b (major diastereomer): Rf: 0.51 (AcOEt–
P.E.¼1:1). White solid. Mp 111–113 8C. [a]2D0¼þ51.0 (c
0.7, CHCl3). IR (KBr, Pellet) nmax: 3366, 3083, 3058, 3027,
2967, 2934, 2878, 1664, 1616, 1491, 1469, 1454, 1421,
1361, 1332, 1301, 1066 cm21. 1H NMR (500 MHz, CDCl3)
(: 0.56 (t, J¼7.5 Hz, 3H, CH3), 1.92–2.12 (m, 2H, CH2Me),
4.10 (ddd, J¼3.4, 7.1, 12.4 Hz, 1H, CH2OH), 4.40 (dd,
J¼5.1, 7.1 Hz, 1H, OH), 4.45 (ddd, J¼5.1, 7.9, 12.4 Hz, 1H,
CH2OH), 4.57 (dd, J¼3.4, 7.9 Hz, 1H, CHCH2OH), 4.98 (t,
J¼7.2 Hz, 1H, NCH), 5.02 (s, 2H, OCH2Ph), 6.84–6.88 (m,
2H, Ar), 7.22–7.60 (m, 10H, Ar), 7.80–7.88 (m, 1H,
Ar) ppm. MS (ESI, m/z): 389 [(Mþ2H)þ, 26], 388 (MþHþ,
100). HRESIMS calcd for [C25H25NO3þH]þ: 388.1913.
Found: 388.1909.
3.2. General procedure for the reductive alkylation of
(R)-phthalimide derivative (11)
3.2.3. (3R,10R)-3-n-Propyl-2-[2-hydroxy-1-(4-benzyloxy-
To a cooled (215 to 210 8C) solution of 11 (1.0 mmol)
in anhydrous CH2Cl2 (10 mL) was added dropwise a
Grignard reagent (3.0 mmol) in diethyl ether under
nitrogen atmosphere. After stirred at the same temperature
for 4 h, the reaction was quenched with saturated
aqueous solution of ammonium chloride (6 mL) and
extracted with dichloromethane (3£30 mL). The combined
extracts were dried with anhydrous Na2SO4 and concen-
trated in vacuum. Filtration with a short pad of column
eluting with ethyl acetate-petroleum ether (1:1) yielded
a mixture of two diastereomers 12. The diastereomeric
ratio could be obtained either from flash chromatographic
separation or from 1H NMR spectra of the crude
mixture.
phenyl)ethyl]-2,3-dihydro-1H-isoindolin-1-one
(13c).
Diastereomeric ratio: 81:19, combined yield 96%.
(3R,10R)-13c (major diastereomer): Rf: 0.32 (AcOEt–
PE¼1:2). Colorless oil. [a]2D0¼þ42.4 (c 1.0, CHCl3). IR
(film) nmax: 3378, 3039, 2954, 2871, 1667, 1611, 1510,
1
1462, 1411, 1237, 1176, 1023 cm21. H NMR (500 MHz,
CDCl3) (: 0.80 (t, J¼6.8 Hz, 3H, CH3), 1.08–1.20 (m, 1H,
(CH2)2Me), 1.82–2.00 (m, 3H, (CH2)2Me), 4.08 (ddd,
J¼3.5, 6.0, 12.3 Hz, 1H, CH2OH), 4.38 (dd, J¼6.0, 7.8 Hz,
1H, OH), 4.45 (ddd, J¼7.8, 8.1, 12.3 Hz, 1H, CH2OH), 4.62
(dd, J¼3.5, 8.1 Hz, 1H, CHCH2OH), 4.96 (t, J¼7.2 Hz,
1H, NCH), 5.02 (s, 2H, OCH2Ph), 6.88–6.95 (m, 2H, Ar),
7.18–7.22 (m, 2H, Ar), 7.25–7.60 (m, 8H, Ar), 7.80–7.83
(m, 1H, Ar) ppm. MS (ESI, m/z): 403 [(Mþ2H)þ, 27], 402

M.-D. Chen et al. / Tetrahedron 60 (2004) 1651–1657
1655
(MþH, 100). HRESIMS calcd for [C26H27NO3þH]þ:
PE¼1:2). White crystal. Mp 104,105 8C (ether).
[a]2D0¼þ31.7 (c 0.9, CHCl3). IR (KBr, Pellet) nmax: 3371,
3037, 2929, 2858, 1668, 1612, 1511, 1462, 1409, 1238,
402.2069. Found: 402.2058.
3.2.4. (3R,10R)-3-n-Butyl-2-[2-hydroxy-1-(4-benzyloxy-
1177, 1024 cm21. H NMR (500 MHz, CDCl3) d: 0.85 (t,
1
phenyl)ethyl]-2,3-dihydro-1H-isoindolin-1-one
(13d).
J¼7.2 Hz, 3H, CH3), 1.06–1.20 (m, 7H, (CH2)6Me), 1.20–
1.30 (m, 2H, (CH2)6Me), 1.66–1.78 (m, 1H, (CH2)6Me),
1.86–1.98 (m, 2H, (CH2)6Me), 4.12 (ddd, J¼3.7, 6.8,
11.7 Hz, 1H, CH2OH), 4.40 (dd, J¼6.8, 7.8 Hz, 1H, OH),
4.46 (ddd, J¼7.8, 7.8, 11.7 Hz, 1H, CH2OH), 4.62 (dd,
J¼3.7, 7.8 Hz, 1H, CHCH2OH), 4.98 (t, J¼7.0 Hz, 1H,
NCH), 5.04 (s, 2H, OCH2Ph), 6.88–6.95 (m, 2H, Ar), 7.18–
7.22 (m, 2H, Ar), 7.25–7.45 (m, 6H, Ar), 7.55–7.60 (m, 2H,
Ar), 7.84 (d, 1H, Ar) ppm. MS (ESI, m/z): 480 (MþNaþ, 7),
459 [(Mþ2H)þ, 29], 458 (MþHþ, 100). HRESIMS calcd
for [C30H35NO3þH]þ: 458.2695. Found: 458.2695.
Diastereomeric ratio: 81:19, combined yield 98%.
(3R,10R)-13d (major diastereomer): Rf: 0.63 (AcOEt–
PE¼1:1). White solid. Mp 88–90 8C. [a]2D0¼þ38.0 (c 1.1,
CHCl3). IR (KBr, Pellet) nmax: 3345, 2921, 2852, 1659,
1577, 1540, 1511, 1462, 1421, 1376, 1303, 1241, 1175,
1
1098, 1019 cm21. H NMR (500 MHz, CDCl3) d: 0.80 (t,
J¼7.3 Hz, 3H, CH3), 1.04–1.28 (m, 4H, (CH2)3Me), 1.84–
2.00 (m, 2H, (CH2)3Me), 4.10 (ddd, J¼3.4, 5.1, 12.4 Hz,
1H, CH2OH), 4.39 (dd, J¼3.0, 5.1 Hz, 1H, OH), 4.44 (ddd,
J¼3.0, 8.0, 12.4 Hz, 1H, CH2OH), 4.60 (dd, J¼3.4, 8.0 Hz,
1H, CHCH2OH), 4.98 (t, J¼7.4 Hz, 1H, NCH), 5.04 (s, 2H,
OCH2Ph), 6.88–6.96 (m, 2H, Ar), 7.16–7.60 (m, 10H, Ar),
7.82–7.84 (m, 1H, Ar) ppm. MS (ESI, m/z): 438 (MþNaþ,
5), 417 [(Mþ2H)þ, 31], 416 (MþHþ, 100). HRESIMS
calcd for [C27H29NO3þH]þ: 416.2226. Found: 416.2224.
3.3. General procedure for the oxidative deprotection of
N-substituted 3-alkyl-isoindolin-1-ones (13)
To a solution of diastereomeric mixture 13 (1.0 mmol) in a
mixed MeCN–H2O solvent system (3:1, 4 mL) was added
ceric ammonium nitrate (2.192 g, 4.0 mmol) at rt. After
stirred at the same temperature for 30 min, H2O (10 mL)
was added. The resulting mixture was extracted with ethyl
acetate (3£10 mL). The combined extracts were washed
with saturated aqueous sodium bicarbonate and brine, then
dried over anhydrous Na2SO4. The crude was purified by
flash column chromatography on silica gel with ethyl
acetate-petroleum ether (2:1) as eluent to give 1.
3.2.5. (3R,10R)-3-iso-Butyl-2-[2-hydroxy-1-(4-benzyloxy-
phenyl)ethyl]-2,3-dihydro-1H-isoindolin-1-one
(13e).
Diastereomeric ratio: 83:17, combined yield, 94%.
(3R,10R)-13e (major diastereomer): Rf: 0.60 (AcOEt–
PE¼1:1). Colorless oil. [a]2D0¼þ34.2 (c 1.2, CHCl3). IR
(film) nmax: 3367, 3033, 2955, 2925, 2868, 1666, 1611,
1583, 1510, 1468, 1454, 1413, 1334, 1239, 1177, 1114,
1
1061, 1024 cm21. H NMR (500 MHz, CDCl3) d: 0.70 (d,
J¼6.4 Hz, 3H, CH3), 0.92 (d, J¼6.4 Hz, 3H, CH3), 1.66–
1.88 (m, 3H, CH2CHMe2), 4.10 (ddd, J¼3.4, 7.0, 12.4 Hz,
1H, CH2OH), 4.33 (dd, J¼3.2, 7.0 Hz, 1H, OH), 4.43 (ddd,
J¼3.2, 7.8, 12.4 Hz, 1H, CH2OH), 4.66 (dd, J¼3.4, 7.8 Hz,
1H, CHCH2OH), 5.02 (s, 2H, OCH2Ph), 5.04 (t, J¼7.9 Hz,
1H, NCH), 6.85–6.90 (m, 2H, Ar), 7.15–7.21 (m, 2H, Ar),
7.28–7.58 (m, 8H, Ar), 7.82–7.84 (m, 1H, Ar) ppm. MS
(ESI, m/z): 438 (MþNaþ, 36), 417 [(Mþ2H)þ, 24], 416
(MþHþ, 100). HRESIMS calcd for [C27H29NO3þH]þ:
416.2226. Found: 416.2220.
3.3.1. (R)-Methyl-2,3-dihydro-1H-isoindolin-1-one (1a).
Yield 84%. White crystal. Mp 112–115 8C (CH2Cl2) [lit.5c
mp 102–103 8C for (S)-1a; lit.6e mp 118–119 8C for
racemic 1a]. [a]D20¼þ39.1 (c 1.0, MeOH) {lit.5c
[a]2D0¼239.8 (c 1.0, MeOH) for (S)-enantiomer; lit.7
[a]2D0¼289.7 (c 1.7, MeOH) for (R)-enantiomer}. IR
(KBr, Pellet) nmax: 3193, 3079, 3021, 2923, 1688, 1655,
1540, 1454, 1416, 1260, 1206, 1138, 1084, 1024 cm21. 1H
NMR (500 MHz, CDCl3) d: 1.51 (d, J¼6.8 Hz, 3H, CH3),
4.54 (q, J¼6.8 Hz, 1H, CHMe), 6.90 (s, 1H, NH), 7.40–
7.60 (m, 3H, Ar), 7.84 (d, J¼7.50 Hz, 1H, Ar) ppm. MS
(ESI, m/z): 170 (MþNaþ, 77), 148 (MþHþ, 100).
HRESIMS calcd for [C9H9NOþH]þ: 148.0762. Found:
148.0755.
3.2.6. (3R,10R)-3-n-Pentyl-2-[2-hydroxy-1-(4-benzyloxy-
phenyl)ethyl]-2,3-dihydro-1H-isoindolin-1-one
(13f).
Diastereomeric ratio: 73:27, combined yield 67%.
(3R,10R)-13f (major diastereomer): Rf: 0.63 (AcOEt–
P.E.¼1:1). White crystal. Mp 104–108 8C. [a]2D0¼þ32.1
(c 1.0, CHCl3). IR (KBr, Pellet) nmax: 3369, 3034, 2928,
2862, 1665, 1611, 1510, 1465, 1409, 1303, 1240, 1177,
3.3.2. (R)-Ethyl-2,3-dihydro-1H-isoindolin-1-one (1b).
Yield 63%. White crystal. Mp 128–131 8C (CH2Cl2)
[lit.27 mp 105 8C for racemic 1b]. [a]2D0¼þ52.0 (c 0.6,
MeOH). IR (KBr, Pellet) nmax: 3209, 2961, 2925, 2855,
1690, 1654, 1462, 1421, 1312, 1209, 1143 cm21. 1H NMR
(500 MHz, CDCl3) d: 0.96 (t, J¼7.4 Hz, 3H, CH3), 1.66–
1.76 (m, 1H, CH2Me), 1.98–2.06 (m, 1H, CH2Me), 4.60
(dd, J¼4.9, 7.6 Hz, 1H, NCH), 7.10 (br s, 1H, NH), 7.42–
7.61 (m, 3H, Ar), 7.84 (m, 1H, Ar) ppm. MS (ESI, m/z): 184
(MþNaþ, 7), 163 [(Mþ2H)þ, 11], 162 (MþHþ, 100).
HRESIMS calcd for [C10H11NOþH]þ: 162.0919. Found:
162.0918.
1
1114, 1021 cm21. H- NMR (500 MHz, CDCl3) d: 0.80 (t,
J¼6.9 Hz, 3H, CH3), 0.68–0.74 (m, 1H, (CH2)4Me), 1.08–
1.22 (m, 5H, (CH2)4Me), 1.86–2.00 (m, 2H, (CH2)4Me),
4.10 (ddd, J¼3.4, 6.1, 12.4 Hz, 1H, CH2OH), 4.39 (dd,
J¼3.1, 6.1 Hz, 1H, OH), 4.44 (ddd, J¼3.1, 7.9, 12.4 Hz, 1H,
CH2OH), 4.60 (dd, J¼3.4, 7.9 Hz, 1H, CHCH2OH), 4.95 (t,
J¼7.4 Hz, 1H, NCH), 5.04 (s, 2H, OCH2Ph), 6.88–6.92 (m,
2H, Ar), 7.18–7.22 (m, 2H, Ar), 7.38–7.60 (m, 8H, Ar),
7.88 (m, 1H, Ar) ppm. MS (ESI, m/z): 431 [(Mþ2H)þ, 40],
430 (MþHþ, 100). HRESIMS calcd for [C28H31NO3þH]þ:
430.2382. Found: 430.2381.
3.3.3. (R)-n-Propyl-2,3-dihydro-1H-isoindolin-1-one
(1c). Yield 86%. White crystal. Mp 108–109 8C (CH2Cl2)
[lit.28 mp 135–136 8C (H2O) for racemic 1c]. [a]2D0¼þ57.2
(c 0.7, MeOH). Rf: 0.48 (AcOEt–PE¼1:1). IR (KBr, Pellet)
3.2.7. (3R,10R)-3-n-Heptyl-2-[2-hydroxy-1-(4-benzyloxy-
phenyl)ethyl]-2,3-dihydro-1H-isoindolin-1-one
Diastereomeric ratio: 70:30, combined yield 79%
(13g).
(3R,10R)-13g (major diastereomer): Rf: 0.59 (AcOEt–
nmax: 3211, 2958, 2927, 2869, 1680, 1465, 1423, 1306,

1656
M.-D. Chen et al. / Tetrahedron 60 (2004) 1651–1657
745 cm21
.
1H NMR (500 MHz, CDCl3) d: 0.97 (t,
J¼4.6, 7.5 Hz, 1H, NCH), 7.40–7.60 (m, 3H, Ar), 7.70 (br
s, 1H, NH), 7.82 (m, 1H, Ar) ppm. MS (ESI, m/z): 485
[(2MþNa)þ, 3], 232 (MþHþ, 100). HRESIMS calcd for
[C15H21NOþH]þ: 232.1701. Found: 232.1691.
J¼7.3 Hz, 3H, CH3), 1.36–1.44 (m, 2H, (CH2)2Me),
1.48–1.56 (m, 1H, (CH2)2Me), 1.59–1.68 (m, 1H,
(CH2)2Me), 4.64 (dd, J¼4.4, 7.7 Hz, 1H, NCH), 7.40–
7.60 (m, 3H, Ar), 7.60 (br s, 1H, NH), 7.83 (m, 1H, Ar) ppm.
MS (ESI, m/z): 373 [(2MþNa)þ, 17], 351 [(2MþH)þ, 7],
198 (MþNaþ, 51), 177 [(Mþ2H)þ, 14], 176 (MþHþ, 100).
HRESIMS calcd for [C11H13NOþH]þ: 176.1075. Found:
176.1068.
Acknowledgements
The authors are grateful to the National Science Fund for
Distinguished Young Investigators, the NNSF of China
(29832020; 20072031; 20272048; 203900505), and the
Specialized Research Fund for the Doctoral Program of
Higher Education for financial support.
3.3.4. (R)-n-Butyl-2,3-dihydro-1H-isoindolin-1-one (1d).
Yield 90%. White crystal. Mp 69–71 8C (CH2Cl2) [Lit.6e
mp 88–89 8C for racemic 1d]. [a]2D0¼þ53.0 (c 0.8, MeOH).
IR (KBr, Pellet) nmax: 3270, 3078, 2955, 2922, 2852, 1695,
1576, 1540, 1465, 1376, 1203, 1137, 1098 cm21. 1H NMR
(500 MHz, CDCl3) d: 0.90 (t, J¼7.1 Hz, 3H, CH3), 1.22–
1.50 (m, 4H, (CH2)3Me), 1.60–1.70 (m, 1H, (CH2)3Me),
1.9–2.0 (m, 1H, (CH2)3Me), 4.61 (dd, 1H, J¼4.5, 7.6 Hz,
NCH), 6.90 (br s, 1H, NH), 7.20–7.30 (m, 2H, Ar), 7.55 (m,
1H, Ar), 7.85 (m, 1H, Ar) ppm. MS (ESI, m/z): 379
[(2MþH)þ, 8], 212 (MþNaþ, 4), 191 [(Mþ2H)þ, 12], 190
(MþHþ, 100). HRESIMS calcd for [C12H15NOþH]þ:
190.1232. Found: 190.1229. Anal. Calcd for C12H15NO:
C, 76.16; H, 7.99; N, 7.40. Found: C, 76.49; H, 7.99; N,
7.68.
References and notes
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2863, 1686, 1608, 1467, 1363, 1269, 1203, 1142,
1019 cm21 1H NMR (500 MHz, CDCl3) d: 1.00 (d,
.
J¼6.6 Hz, 3H, CH3), 1.06 (d, J¼6.6 Hz, 3H, CH3), 1.46–
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M.-D. Chen et al. / Tetrahedron 60 (2004) 1651–1657
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