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J. B. Campbell et al.
LETTER
(6) (a) Reich, H. J.; Green, D. P.; Phillips, N. H. J. Am. Chem.
Soc. 1989, 111, 3444. (b) Reich, H. J.; Green, D. P.; Phillips,
N. H. J. Am. Chem. Soc. 1991, 113, 1414. (c) Beak, P.;
Musick, T. J.; Liu, C.; Cooper, T.; Gallagher, D. J. J. Org
Chem. 1993, 58, 7330.
dried (Na2SO4), concentrated and chromatographed by flash
chromatography. The isolated products were typically
obtained as viscous oils. Several of the products (designated
in Table 1) were distilled in a bulb-to-bulb short path
(Kugelrohr) distillation apparatus. [Note: Imines were
prepared by one of two procedures. For volatile imines, a
procedure using K2CO3 reported by Stork et al.19b was
followed. Imines were distilled and then stored under a
nitrogen atmosphere at 0 °C prior to use. For non-volatile
imines, the procedure using dibutyltin dichoride and Na2SO4
as described by Stetin et al.19c was followed. The imines
were isolated and used immediately without further
(7) Bailey, W. F.; Gagnier, R. P.; Patricia, J. J. J. Org. Chem.
1984, 49, 2098.
(8) Campbell, J. B.; Dedinas, R. F.; Trumbower-Walsh, S. A.
J. Org. Chem. 1996, 61, 6205.
(9) (a) Enders, D.; Braig, V.; Raabe, G. Can. J. Chem. 2001, 79,
1528. (b) Enders surveys the literature by systematically
considering multiple retrosynthetic disconnects for
assembling isoindolones. Using his nomenclature from the
aforementioned citation, Method II and Method VIII would
involve the formation of a bond between the carbon a to
nitrogen and the ortho-C-aryl carbon (red bond designated in
Scheme 1, structure 5).
purification] (b) Stork, G.; Dowd, S. R. Org. Synth. 1974,
54, 46. (c) Stetin, C.; de Jeso, B.; Pommier, J. C. Synth.
Commun. 1982, 12, 495.
(20) Spectroscopic and characterization data for selected
products: 2-Butyl-3-propyl-2,3-dihydroisoindol-1-one (5a):
1H NMR (300 MHz, CDCl3): d = 0.82 (m, 4 H), 0.95 (t, 3 H,
J = 7.3 Hz), 1.08 (m, 1 H), 1.37 (m, 2 H), 1.60 (m, 2 H), 1.93
(m, 2 H), 3.08 (m, 1 H), 4.02 (dt, 1 H, J = 8.0, 13.9 Hz), 4.59
(t, 1 H, J = 3.8 Hz), 7.46 (m, 3 H), 7.83 (d, 1 H, J = 7.4 Hz).
13C NMR (75 MHz, CDCl3): d = 13.72, 13.96, 15.76, 20.09,
30.38, 32.60, 39.36, 58.87, 121.90, 123.41, 127.41, 127.85,
131.03, 132.76, 145.16, 168.36. MS: m/z = 232 [M + H].
Anal. Calcd for C15H21NO·0.25 H2O: C, 76.39; H, 9.19; N,
5.93. Found: C, 76.20; H, 8.82; N, 5.95. 2-Butyl-3-propyl-6-
bromo-2,3-dihydroisoindol-1-one (5b): 1H NMR (300 MHz,
CDCl3): d = 0.85 (m, 4 H), 0.94 (t, 3 H, J = 7.4 Hz), 1.08 (m,
1 H), 1.36 (m, 2 H), 1.61 (m, 2 H), 1.92 (m, 2 H), 3.08 (m, 1
H), 4.00 (dt, 1 H, J = 8.0, 13.9 Hz), 4.56 (t, 1 H, J = 3.7 Hz),
7.29 (d, 1 H, J = 8.1 Hz), 7.63 (d, 1 H, J = 8.1 Hz), 7.96 (s,
1 H). 13C NMR (75 MHz, CDCl3): d = 13.76, 13.97, 15.70,
20.13, 30.35, 32.45, 39.57, 58.75, 122.00, 123.61, 126.69,
134.04, 134.91, 143.84, 166.90. MS: m/z = 310, 312 [M +
H]. Anal. Calcd for C15H20NOBr: C, 58.07; H, 6.50; N, 4.51.
Found: C, 57.76; H, 6.47; N, 4.60. 2-Benzyl-3-cyclohexyl-
2,3-dihydroisoindol-1-one (5e): mp 163–164.5 °C (methyl
tert-butyl ether–hexanes). 1H NMR (300 MHz, CDCl3): d =
0.42 (m, 1 H), 1.06 (m, 2 H), 1.26 (m, 2 H), 1.43 (m, 2 H),
1.68 (m, 2 H), 2.03 (m, 1 H), 3.10 (m, 1 H), 4.20 (d, 1 H, J =
15.2, 13.9 Hz), 4,26 (d, 1 H, J = 3.1 Hz), 5.40 (d, 1 H, J =
15.2 Hz), 7.35 (m, 5 H), 7.45 (m, 3 H), 7.90 (d, 1 H, J = 6.45
Hz). 13C NMR (75 MHz, CDCl3): d = 25.76, 25.95, 26.35,
26.90, 29.69, 39.38, 43.98, 63.57, 123.27, 123.77, 127.46,
127.93, 128.06, 128.66, 128.90, 130.92, 132.82, 137.17,
144.09, 168.68. MS: m/z = 306 [M + H]. Anal. Calcd for
C21H23NO: C, 82.58; H, 7.59; N, 4.85. Found: C, 82.11; H,
7.53; N, 5.14. 2-[2-(1,3-Dioxolan-2-yl)ethyl]-3-
(10) At –78 °C formation of the acid chloride/imine adduct was
considerably slower with the yields of isoindolone 4
dropping significantly.
(11) Johnson, C. D. Acc. Chem. Res. 1993, 26, 476.
(12) The stilbene is thought to arise from nucleophilic attack at
the benzylic chloride of the acid chloride/imine adduct by
another molecule of adduct which has been deprotonated at
the a-chlorobenzylic position. Elimination of chloride from
the resulting chloro-substituted 1,2-diphenylethane would
then afford the stilbene. See: Kobrich, G. Angew. Chem., Int.
Ed. Engl. 1972, 11, 473.
(13) (a) Mehta, G.; Rao, H. S. In The Chemistry of Alkanes and
Cycloalkanes; Patai, S.; Rappoport, Z., Eds.; John Wiley and
Sons: New York, 1992, 583–584. (b) Billington, D. C.
Coupling Reactions Between sp3 Carbon Centers, In
Comprehensive Organic Synthesis, Vol. 3; Trost, B. M., Ed.;
Pergamon Press: Oxford, 1991, Chap. 2.1, 414.
(c) Billington, D. C. Coupling Reactions Between sp3Carbon
Centers, In Comprehensive Organic Synthsis, Vol. 3; Trost,
B. M., Ed.; Pergamon Press: Oxford, 1991, Chap. 2.1, 422.
(d) Kwa, T. L. Tetrahedron 1969, 25, 5771.
(14) (a) Fukagawa, T.; Fujiwara, Y.; Yokoo, K.; Taniguchi, H.
Chem. Lett. 1981, 10, 1771. (b) Yokoo, K.; Fukagawa, T.;
Yamanaka, Y.; Taniguchi, H.; Fujiwara, Y. J. Org. Chem.
1984, 49, 3237.
(15) Girard, P.; Namy, J. L.; Kagan, H. B. J. Am. Chem. Soc.
1980, 102, 2693.
(16) Matsumoto, H.; Inaba, S.; Rieke, R. D. J. Org. Chem. 1983,
48, 840.
(17) (a) Semmelhack, M. F.; Helquist, P.; Jones, L. D.; Keller, L.;
Mendelson, L.; Speltz Ryono, L.; Gorzynski Smith, J.;
Stauffer, R. D. J. Am. Chem. Soc. 1981, 103, 6460.
(b) Tsou, T. T.; Kochi, J. K. J. Am. Chem. Soc. 1979, 101,
7547.
propylisoindolin-1-one (5g): 1H NMR (300 MHz, CDCl3):
d = 0.83 (m, 4 H), 1.07 (m, 1 H), 1.98 (m, 4 H), 3.25 (m, 1
H), 3.85 (m, 2 H), 3.99 (m, 2 H), 4.12 (m, 1 H), 4.64 (m, 1
H), 4.93 (m, 1 H), 7.42 (m, 3 H), 7.81 (d, 1 H, J = 7.4 Hz).
13C NMR (75 MHz, CDCl3): d = 13.95, 15.67, 32.41, 32.57,
35.09, 59.17, 64.89, 102.57, 121.96, 123.39, 127.84, 131.12,
132.64, 145.26, 168.38. MS: m/z = 276 [M+]. Anal. Calcd
for C16H21NO3: C, 69.79; H, 7.69; N, 5.09. Found: C, 69.52;
H, 7.57; N, 5.30. 2-Propyl-3-(2-furyl)-2,3-dihydroisoindol-
1-one (5h): 1H NMR (300 MHz, CDCl3): d = 0.90 (t, 3 H,
J = 7.4 Hz), 1.57 (m, 2 H), 3.08 (m, 1 H), 3.80 (dt, 1 H, J =
7.4, 12.2 Hz), 5.60 (s, 1 H), 6.31 (d, 1 H, J = 3.2 Hz), 6.37
(dd, 1 H, J = 3.2, 1.6 Hz), 7.35 (m, 1 H), 7.47 (d, 1 H, J = 1.6
Hz), 7.50 (m, 2 H), 7.88 (m, 1 H). MS: m/z = 242 [M + H].
(21) By comparison the procedure described in this manuscript
provides isoindolones in comparable yields and purity to our
previously described work.8 For larger scale reactions, the
present work is more practical to conduct requiring
(18) Chen, Y.-H.; Knochel, P. Angew. Chem. Int. Ed. 2008, 47,
7569.
(19) (a) General Procedure for the Synthesis of Isoindolones 5
from o-Iodobenzoyl Chlorides 1 and Imines 2: Neat 2-
iodobenzoyl chloride (1 mmol) was added dropwise to a
solution of the corresponding imine (1 mmol) as a solution
in THF at –25 °C. After stirring for 10 min, the reaction was
cooled to –78 °C and stirred for an additional 30 min.
Phenyllithium (1.1 mmol, typically about 1.8 M in Et2O–
hexanes) was added dropwise to the solution over 5 min
followed by stirring the reaction for 1 h at –78 °C. The
cooling bath was removed, the reaction warmed to ambient
temperature, then stirred for 1 h. The reaction was quenched
slowly at ambient temperature by the addition of H2O. The
mixture was stirred for about 30 min, followed by extraction
of the mixture with CH2Cl2. The combined extracts were
temperatures no lower than –78 °C.
Synlett 2010, No. 20, 3008–3010 © Thieme Stuttgart · New York