A short and efficient synthesis of isoindolin-1-ones

Article abstract of DOI:10.1055/s-2006-933114

Here, we report a short and efficient synthesis of isoindolin-1-ones. Base-induced cyclization of o-hydroxymethyl-benzamides, which was easily prepared from the corresponding phthalides and amines, led predominantly to N-alkylation in good yield. The reaction proceeded under mild conditions and bromine and nitrile substituents were tolerated. The selectivity is explained by HASB theory. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-933114

LETTER
801
A Short and Efficient Synthesis of Isoindolin-1-ones
A
S
hort and Eff
a
icient
S
ynt
k
hesis of Isoin
a
doline-1-on
y
es uki Tsuritani,*a Satoshi Kii,a Atsushi Akao,a Kimihiko Sato,a Nobuaki Nonoyama,a Toshiaki Mase,a
Nobuyoshi Yasudab
a
Process Research, Banyu Pharmaceutical Co. Ltd., 9-1, Kamimutsuna 3-Chome, Okazaki, Aichi 444-0858, Japan
b
Merck Research Laboratories, Department of Process Chemistry, P.O. Box 2000, Rahway, NJ 07065, USA
Fax +81(564)517086; E-mail: takayuki_tsuritani@merck.com
Received 26 December 2005
of 2-halogeno-N-(phosphinylmethyl)benzamide deriva-
tives.8 Among possible methods the simplest route would
be the transformation of lactones to lactams. Späth and
Lintner reported that lactams were formed with primary
Abstract: Here, we report a short and efficient synthesis of iso-
indolin-1-ones. Base-induced cyclization of o-hydroxymethyl-
benzamides, which was easily prepared from the corresponding
phthalides and amines, led predominantly to N-alkylation in good
yield. The reaction proceeded under mild conditions and bromine amines from the corresponding lactones at elevated tem-
perature and under high pressure.9,10 However, under
and nitrile substituents were tolerated. The selectivity is explained
by HASB theory.
these harsh reaction conditions, some functional groups
Key words: lactams, cyclizations, lactones, phosphate, N-selective
alkylation
were not tolerated. For instance, the reaction of 5-bro-
mophthalide (5a) with isopropylamine at 200 °C, 6.0–6.6
MPa provided the desired lactam 1a together with non-
negligible amounts of by-products, which were generated
The class of isoindolin-1-ones (phthalimidines 1) is of from reaction of bromide with amine, or water
great importance in organic chemistry, especially in the (Equation 1). Lowering temperature and pressure did not
field of medicine.1 The interest in these heterobicyclic improve the outcome, preferentially yielding o-hy-
compounds stems mainly from their diverse biological droxymethylbenzamide 6a.
activities; e.g. indoprofen (2, anti-inflammatory agent),2
deoxythalidomide (3, reducer of tumor necrosis factor
production),3 batracyclin (4, neoplasm inhibitor)4
(Figure 1).
O
O
O
NH2
N
O
N
H
200 °C,
6.0–6.6 MPa
2 h
Br
X
Br
5a
OH
X = Br (1a)
OH
O
O
6a
NH-i-Pr
N
R2
N
Equation 1
COOH
R1
1
2
O
Consequently, we have been studying a milder and clean-
er route. We focused on o-hydroxymethylbenzamide 6. If
N-selective cyclization of o-hydroxymethylbenzamide 6
could be achieved, the lactam 1 is obtained. Surprisingly
enough, there have been no reports on transformation of
o-hydroxymethylbenzamides to lactams other than under
relatively extreme thermal conditions.9 Thus, we investi-
gated the transformation of o-hydroxymethylbenzamide
to corresponding lactams under a variety of reaction
conditions. Herein we report a base-induced N-selective
cyclization of o-hydroxymethylbenzamides, which were
easily prepared from the corresponding lactones.
O
N
N
O
N
NH
O
O
4
3
Figure 1
With this background, we have been investigating concise
and versatile syntheses for a variety of phthalides starting
from commercially available compounds. A number of
synthetic routes to phthalimidine have been reported: (i)
bromination of 2-methylbenzoyl ester followed by amina-
tion and cyclization,5 (ii) reduction of phthalimides,6 (iii)
Pd(0)-catalyzed carbonylation of 2-halogeno-aminometh-
ylbenzene derivatives,7 and (iv) base-induced cyclization
The first facet, elaboration of the required o-hydroxy-
methylbenzamides 6 was readily accomplished by amina-
tion of lactones 5 in the presence of MsOH or AlCl3 at
mild temperature (Equation 2).11,12 Aminolysis with tert-
butylamine proceeded efficiently under the action of
AlCl3, while no reaction occurred with MsOH. Interest-
ingly, when an excess of MsOH (2.0 equiv) was em-
ployed, lactone 5 was recovered quantitatively as a result
of hydrolysis of imino ester 7.
SYNLETT 2006, No. 5, pp 0801–0803
1
7.
0
3.
2
0
0
6
Advanced online publication: 09.03.2006
DOI: 10.1055/s-2006-933114; Art ID: U31905ST
© Georg Thieme Verlag Stuttgart · New York

802
T. Tsuritani et al.
LETTER
MsOH or AlCl3
(1.2 equiv)
R2NH2 (5.0 equiv)
Phosphate, a soft electrophile, prefers to react with the
softer nitrogen atom than the oxygen atom. Indeed, the
selectivity of N-alkylation decreased with the hard
electrophile mesylate (Scheme 2).
O
R2
O
R2
N
N
O
H
DMI or
ClCH2CH2Cl
R1
O
R1
R1
5
OH
6
imino ester 7
1) i-PrMgCl /
THF (2.25 equiv)
solvent, 0 °C to r.t.
O
O
O
Equation 2
R2
N
NR2
O
H
R1
R1
R1
2) Cl–X (1.3 equiv)
0 °C to r.t.
1
5
6
With o-hydroxymethylbenzamides 6 in hand, we then
focused on N-selective alkylation of amide under a variety
of reaction conditions. As described above, only acid-
catalyzed O-intramolecular substitution takes place.
Mesylation of o-hydroxymethylbenzamide 6a with Et3N
and MsCl (neutral conditions) also spontaneously gener-
ated the O-cyclized product, imino ester 7a, in 33% yield.
However, under basic conditions, N-cyclization proceed-
ed preferentially (entry 1). In general, the selectivity of N-
alkylation vs. O-alkylation is dominated by leaving group,
solvent and counter cation.13 So we screened various
leaving groups and solvents. The results are summarized
in Table 1. As a leaving group, ClP(O)(NMe2)2 or
ClP(O)(OEt)2 was found to be suitable for N-cyclization.
O-Protected compound 8 was obtained in moderate yield
when sec-butoxy carbonyl chloride or pivaloyl chloride
was employed (Scheme 1).14 The more polar the solvent,
the higher the observed selectivity for N-cyclization.
OH
H
N-cyclization
R2
N
O
R2
O-cyclization
N
O
H
R1
R1
7
8
OX
Scheme 1
O
O
R2
1) i-PrMgCl/THF (2.25 equiv), DMI
N
H
NR2
R1
2) ClP(O)(NMe2)2 (1.3 equiv)
0 °C to r.t.
R1
6
OH
1
Scheme 2
Having optimized the conditions, we next examined the
scope and limitation of this procedure (Table 2). o-Hy-
droxymethylbenzamides afforded the lactam in good se-
lectivity and yield even with secondary and tertiary
amines. In the case of the phenyl substituent (entry 10), a
higher temperature was required to obtain the correspond-
ing lactam. Bromine and nitrile groups were tolerated un-
der the reaction conditions. This procedure was found to
be adaptable to kilogram-scale synthesis (Table 2, entry
2). The selectivity can be explained by the HASB theory.
In conclusion, we have developed a concise transforma-
tion from lactones to lactams in two steps: aminolysis and
N-selective cyclization. The reaction proceeds under
milder reaction condition than conventional methods,
which require elevated temperature and high pressure.
The procedure is suitable for large-scale synthesis without
any modification.
Table 1 Effect of Leaving Group and Solvent
Entry
Solvent
X
Conversion (%)
Yield (%)a
Selectivity
(N/O)
1
5
1
2
3
4
5
6
7
8
THF
Ms
75
80
80
75
99
99
83
65
50
43
45
59
96
92
<1
16
25
37
35
14
3
2.00
1.16
1.29
4.26
32.3
24.0
<1
DMIb
Toluene
THF
Ms
Ms
P(O)(NMe2)2
P(O)(NMe2)2
P(O)(OEt)2
C(O)O-s-Bu
C(O)-t-Bu
DMI
DMI
DMI
DMI
4
56
9
1.78
a Determined by HPLC analysis.
b DMI: 1,3-dimethyl-2-imidazolidinone.
Synlett 2006, No. 5, 801–803 © Thieme Stuttgart · New York

LETTER
A Short and Efficient Synthesis of Isoindoline-1-ones
803
Table 2 Synthesis of Lactams 115
(7) Orito, K.; Horibata, A.; Nakamura, T.; Ushito, H.; Nagasaki,
H.; Yuguchi, M.; Yamashita, S.; Tokuda, M. J. Am. Chem.
Soc. 2004, 126, 14342.
(8) Hoarau, C.; Couture, A.; Deniau, E.; Grandclaudon, P.
Synthesis 2000, 655.
(9) (a) Späth, E.; Lintner, J. Ber. Dtsch. Chem. Ges. B 1936, 69,
2727. (b) Barrios, I.; Camps, P.; Comes-Franchini, M.;
Muñoz-Torrero, D.; Ricci, A.; Sánchez, L. Tetrahedron
2003, 59, 1971.
(10) See for mechanical study: Decker, M.; Nguyen, T. T. H.;
Lehmann, J. Tetrahedron 2004, 60, 4567.
(11) Lesimple, P.; Bigg, D. C. H. Synthesis 1991, 306.
(12) See ref. 6 for preparation of 6i.
(13) Kornblum, N.; Smiley, R. A.; Blackwood, R. K.; Iffland, D.
C. J. Am. Chem. Soc. 1955, 77, 6269.
(14) When 1 equiv of Grignard reagent was employed, O-
protected compound 8 was obtained predominantly in entry
5.
Entry
R1
Br
Br
Br
Br
Br
Br
Ph
CN
H
R2
Yield (%)a
90 (1a)
88 (1a)
86 (1b)
83 (1c)
82 (1d)
83 (1e)
81 (1f)
82 (1g)
77 (1h)
70 (1i)
Selectivityb
32.3
1
2c
3
i-Pr
i-Pr
n-Pr
PMBd
t-Bu
Me
6a
6a
23.8
6b
6c16
6d
6e
24.0
4
10.1
5
9.00
6
>50
7
i-Pr
i-Pr
i-Pr
Ph
6f16
6g16
6h
6i
24.0
8
30.4
9
>50
(15) Typical Experimental Procedure.
To a three-necked 50-mL round-bottomed flask equipped
with dropping funnel were charged DMI (15 mL) and o-
hydroxymethylbenzamide 6a (1.35 g, 5.00 mmol). The
resulting solution was cooled to 0 °C, and then 1.98 M of
i-PrMgCl–THF (5.63 mL, 11.15 mol, 2.23 equiv to 6a) was
added dropwise. The resulting solution was warmed to
ambient temperature and stirred for 0.5 h. The solution was
cooled to 0 °C, and then ClP(O)(NMe2)2 (0.94 mL, 6.50
mmol, 1.3 equiv to 6a) was added dropwise. The mixture
was warmed to ambient temperature, and stirred for 14 h.
The resulting solution was quenched by 2 N aq HCl (10 mL).
The mixture was extracted with i-PrOAc (3 × 10 mL), and
the combined i-PrOAc extracts were washed with H2O (2 ×
10 mL) and dried over anhyd Na2SO4. Removal of the
solvent and subsequent silica gel chromatography (heptane
and EtOAc) afforded the corresponding lactam 1a in a pure
form.
10e
H
11.2
a Isolated yield.
b Determined by HPLC analysis.
c ClP(O)(OEt)2 was employed instead of ClP(O)(NMe2)2. The reac-
tion was performed on an 8.0 kg scale.
d PMB: p-methoxybenzyl.
e The reaction was carried out at 50 °C.
References and Notes
(1) (a) Luzzio, F. A.; Piatt Zachert, D. Tetrahedron Lett. 1998,
39, 2285. (b) Campbell, J. B.; Dedinas, R. F.; Trumbower-
Walsh, S. A. J. Org. Chem. 1996, 61, 6205. (c) Decroix, B.;
Pigeon, P. . Tetrahedron Lett. 1996, 37, 7707. (d) Decroix,
B.; Pigeon, P.; Othman, M. Tetrahedron 1997, 53, 2495.
(e) Allin, S. M.; Northfield, C. J.; Page, M. I.; Slawin, A. M.
Z. Tetrahedron Lett. 1997, 38, 3627. (f) Kundu, N. G.;
Khan, M. W. Tetrahedron Lett. 1997, 38, 6937.
(g) Kitching, M. S.; Clegg, W.; Elsewood, M. R. J.; Griffin,
R. J.; Golding, B. T. Synlett 1999, 997.
(2) (a) Nannin, G.; Griraldi, P. N.; Molgora, G.; Biasoli, G.;
Spinelli, F.; Logemann, L.; Dradi, E.; Zanni, G.; Buttinoni,
A.; Tommasini, R. Arzneim. Forsch. 1973, 23, 1090.
(b) Hisamitsu Pharmaceutical Co., Inc. Japan Kokai Tokyo
Koho 149257, 1980; Chem. Abstr. 1981, 94, 174879;
address: P. J. Kocienski, School of Chemistry, Univerity of
Leeds, Leeds LS2 9JT, UK.
(16) Spectroscopic Data for New Compounds.
Compound 6c: IR (neat): 1673, 1608, 1510, 1451, 1411,
1356, 1308, 1274, 1242, 1175, 1033, 1007, 837, 813, 768,
673 cm–1. 1H NMR (300 MHz, CDCl3): d = 3.79 (s, 3 H),
4.22 (s, 2 H), 4.72 (s, 2 H), 6.86 (d, J = 8.5 Hz, 2 H), 7.24 (d,
J = 8.5 Hz, 2 H), 7.53 (s, 1 H), 7.60 (d, J = 8.1 Hz, 1 H), 7.74
(d, J = 8.1 Hz, 1 H). 13C NMR (CDCl3): d = 45.82, 48.77,
55.27, 114.18, 125.21, 125.93, 126.12, 128.75, 129.50,
131.47, 131.72, 142.97, 159.21, 167.38.
Compound 6f: IR (neat): 1658, 1460, 1409, 1367, 1303,
1234, 1057, 764, 737, 686 cm–1. 1H NMR (300 MHz,
CDCl3): d = 4.86 (s, 2 H), 7.18–7.21 (m, 1 H), 7.41–7.46 (m,
2 H), 7.48–7.53 (m, 2 H), 7.58–7.60 (m, 1 H), 7.86–7.89 (m,
2 H), 7.92–7.94 (m, 1 H). 13C NMR (CDCl3): d = 50.71,
119.46, 122.59, 124.15, 124.46, 128.37, 129.14, 132.05,
133.24, 139.50, 140.09, 167.49.
(3) Schmahl, H.-J.; Denker, L.; Plum, C.; Chahoud, I.; Nau, H.
Arch. Toxicol. 1996, 11, 749.
Compound 6g: IR (neat): 2227, 1677, 1610, 1447, 1409,
1230, 1060, 877, 839, 770, 677 cm–1. 1H NMR (300 MHz,
CDCl3): d = 1.32 (d, J = 6.8 Hz, 6 H), 4.41 (s, 2 H), 4.69
(sept, J = 6.8 Hz, 1 H), 7.76 (d, J = 8.2 Hz, 1 H), 7.77 (s, 1
H), 7.94 (d, J = 8.2 Hz, 1 H). 13C NMR (CDCl3): d = 20.75,
43.12, 44.90, 114.56, 118.31, 124.45, 126.75, 132.09,
137.32, 141.51, 165.88.
(4) Plowman, J.; Paull, K. D.; Atassi, G.; Harrison, S.; Dykes,
D.; Kabbe, N.; Narayan, V. L.; Yoder, O. Invest. New Drugs
1988, 6, 147.
(5) (a) Ganesan, A.; Wang, H. Tetrahedron Lett. 1998, 39,
9097. (b) Anzani, M.; Capelli, A.; Vomero, S. Heterocycles
1994, 38, 103.
(6) Horii, Z.; Iwata, C.; Tamura, Y. J. Org. Chem. 1961, 26,
2273.
Synlett 2006, No. 5, 801–803 © Thieme Stuttgart · New York