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