J. J. Powers et al. / Tetrahedron Letters 50 (2009) 1267–1269
1269
pane-1,10-isoindol]-30(20H)-one (8, Scheme 8). Following a previ-
ously reported procedure,12 the 2-cyano-5-methoxy-benzoic acid
methyl ester (10) was treated with titanium(IV) isopropoxide in
ether followed by the addition of 3 M ethyl magnesium bromide
in diethyl ether at 0 °C to obtain the ring-closed 50-methoxy-
spiro[cyclopropane-110-isoindol]-30(20H)-one (40) in 38% yield.
This was then treated with boron tribromide in DCM at 0 °C to ob-
tain 50-hydroxy-spiro[cyclopropane-1,10-isoindol]-30(20H)-one (8)
in 41% yield.
F
Br
F
F
Br
b
a
O
CO2Me
O
CO2H
O
CO2H
30
F
31
32
F
F
CN
CO2Me
c
e
d
NH
O
NH
O
O
HO
O
33
34
6
In summary, a collection of methyl-, fluoro-, and chloro-substi-
tuted 6-hydroxyisoindolin-1-ones were prepared as templates for
drug discovery from a common aryl nitrile-ester intermediate.
Scheme 6. Reagents and conditions: (a) Br2/AcOH, 60 °C, 85%; b) H2SO4/MeOH
93%; (c) CuCN, DMF, 150 °C (3 h), 68%; (d) 10% Pd/C, EtOH, H2 (55 psi), 80%; (e) BBr3
(5.0 equiv), DCM, ꢁ78 °C, 80%.
D,
Acknowledgments
Cl
Cl
Br
Cl
a
b
We would like to acknowledge Andrew White and Michael Stier
for their helpful discussions.
O
CO2Me
O
CO2Me
HO
COOH
35
36
37
7
Supplementary data
Cl
CN
Cl
Cl
c
d
e
NH
NH
O
Supplementary data associated with this article can be found, in
O
CO2Me
O
HO
O
38
39
References and notes
Scheme 7. Reagents and conditions: (a) trimethylsilyl diazomethane, benzene,
0 °C, 80%; (b) Br2/AcOH, 60 °C, 95%; (c) CuCN, DMF, 160 °C, 60%; (d) Raney Ni,
MeOH/EtOAc/NH4OH (40:10:1.0), H2 (45 psi), 76%; (e) BBr3, DCM, 77%.
1. Voshid Fajardo, V.; Elango, V.; Cassels, B. K.; Shamma, M. Tetrahedron Lett. 1982,
23, 39–42.
2. Li, S.; Wong, X.; Guo, H.; Chem, L. Yiyano Gongye 1985, 16, 543 (Chem. Abstr.
1986, 1056378).
3. Belliotti, T. R.; Brink, W. A.; Kesten, S. R.; Rubin, J. R.; Wustrow, D. J.; Zoski, K. T.;
Whetzel, S. Z.; Corbin, A. E.; Pugsley, T. A.; Heffner, T. G.; Wise, L. D. Bioorg. Med.
Chem Lett. 1998, 8, 1499–1502.
CN
a
b
NH
NH
4. Norman, M. H.; Minick, D. J.; Rigdon, G. C. J. Med. Chem. 1996, 39, 149–157.
5. Benzylidenephthalimidines. Jpn. Kokai Tokkyo Koho JP 59046268, 1984.
6. Maugeri, C.; Alisi, M. A.; Apicella, C.; Cellai, L.; Dragone, P.; Fioravanzo, E.;
Florio, S.; Furlotti, G.; Mangano, G.; Ombrato, R.; Luisi, R.; Pompei, R.; Rincicotti,
V.; Russo, V.; Vitiello, M.; Cazzolla, N. Bioorg. Med. Chem. 2008, 16, 3091–3107.
7. Do Minh, T.; Johnson, A. L.; Jones, J. E.; Senise, P. P., Jr. J. Org. Chem. 1977, 42,
4217–4221.
HO
O
CO2Me
O
O
O
10
40
8
Scheme 8. Reagents and conditions: (a) Ti(OCH(CH3)2)4, 3 M EtMgBr/diethyl ether,
0 °C, 38% (b) BBr3, DCM, 0 °C, 41%.
8. Stajer, G.; Csende, F. Curr. Org. Chem. 2005, 9, 1277–1286.
9. Kundu, N. G.; Khan, M. W.; Mukhopadhyay, R. J. Ind. Chem. Soc. 2001, 78, 671–
688.
10. Koltunov, K. Y.; Prakash, G. K. S.; Rasul, G.; Olah, G. A. Eur. J. Org. Chem. 2006, 21,
4861–4866.
11. (a) Klaubert, D. H.; Sellstedt, J. H.; Guinosso, C. J.; Capetola, R. J.; Bell, S. C. J. Med.
Chem. 1981, 24, 742–748; (b) Harris, N. V.; Smith, C.; Bowden, K. J. Med. Chem.
1990, 33, 434–444; (c) Fujiwara, K.; Kudo, M. Jpn. Kokai Tokkyo Koho JP
nitrile and cyclization to afford 34 was accomplished using 10% Pd/
C in ethanol. Finally, the removal of the methoxy group was
accomplished using boron tribromide in DCM to generate 5-flu-
oro-6-hydroxy-2,3-dihydro-isoindol-1-one (6) in 80% yield.
In a similar manner as 5 and 6, the synthesis of previously unre-
ported 5-chloro-6-hydroxy-2,3-dihydro-isoindol-1-one (7) is
found in Scheme 7. Commercially available 35 was treated with
trimethylsilyldiazomethane in benzene to form the ester 36. Bro-
mination of the ester with bromine/AcOH in water afforded 37 in
95% yield. The nitrile 38 was formed by reacting the bromide with
CuCN in DMF. Reduction of the nitrile with Raney Nickel in a
MeOH/EtOAc/NH4OH mixture yielded 39. 5-Chloro-6-hydroxy-
2,3-dihydro-isoindol-1-one (7) was obtained in 77% yield by treat-
ment of 39 with boron tribromide in DCM.
07173125
A 19950711, 1995.; (d) Ratilainen, J.; Toermaekangas, O.;
Karjalainen, A.; Huhtala, P. PCT Int. Appl. WO 2007099200 A1, 2007.; (e)
Hangeland, J. J.; Quan, M. L.; Smallheer, J. M.; Bisacchi, G. S.; Corte, J. R.; Friends,
T. J.; Sun, Z.; Rossi, K. A.; Cavallaro, C. L. U.S. Pat. Appl. Publ. US 2005282805 A1
20051222, 2005.; f Bayrakdarian, M.; Berggren, K.; Davidsson, O.; Fjellstroem,
O.; Gustafsson, D.; Hanessian, S.; Inghardt, T.; Nilsson, I.; Nagard, M.; Simard,
D.; Therrien, E. PCT Int. Appl. WO 2005075424 A1 20050818, 2005.; (g) Nelson,
T. D.; LeBlond, C. R.; Frantz, D. E.; Matty, L.; Mitten, J. V.; Weaver, D. G.; Moore,
J. C.; Kim, J. M.; Boyd, R.; Kim, P.; Gbewonyo, K.; Brower, M.; Sturr, M.;
McLaughlin, K.; McMasters, D. R.; Kress, M. H.; McNamara, J. M.; Dolling, U. H. J.
Org. Chem. 2004, 69, 3620–3627; (h) Park, H.-G.; Choi, J.-Y.; Choi, S.-H.; Park,
M.-K.; Lee, J.; Suh, Y.-G.; Cho, H.; Oh, U.; Kim, H.-D.; Joo, Y. H.; Kim, S.-Y.; Park,
Y.-H.; Jeong, Y. S.; Choi, J. K.; Kim, J. K.; Jew, S.-S. Bioorg. Med. Chem. Lett. 2004,
14, 1693–1696.
Alkylation of these 6-hydroxyisoindolin-1-ones can occur using
the common cyano ester intermediate. This is exemplified by the
synthesis of previously unreported 50-hydroxy-spiro[cyclopro-
12. (a) Bertus, P.; Szymoniak, J. J. Org. Chem. 2003, 68, 7133–7136; (b) Strassert, C.
A.; Awruch, J. Monatsh Chem. 2006, 137, 1499–1503.