SCHEME 1. Synthesis of the Aryldiazonium
Tetrafluoroborate 7
into the aryldiazonium tetrafluoroborate 7 using a stan-
dard procedure, as indicated in Scheme 1, in 73% yield
after recrystallization.
Next, the N-Boc-3-pyrroline 8 (prepared in 82% yield
according to the protocol of Grubbs)9 was submitted to a
Heck-Matsuda arylation with the aryldiazonium tet-
rafluoroborate salt 7 in the presence of 2 mol % Pd(OAc)2
in CH3CN/H2O (1:1, v/v).8b The reaction proceeded rapidly
(30-45 min) to furnish lactamol 10, which was isolated
and used in the next step without further purification
(Scheme 2). Under the Heck-Matsuda conditions, the
primary product of the Heck arylation was the endocyclic
enecarbamate 9, which quickly underwent hydrolysis due
to the acidity of the reaction medium, to provide lactamol
10.10
SCHEME 2. Heck-Matsuda Reaction Coupling
the Pyrrolidine Ring to the Aromatic Moiety
The crude lactamol 10 was then oxidized with catalytic
tetrapropylammonium perruthenate (TPAP), with N-
methylmorpholine-N-oxide (NMO) as a co-oxidant in CH2-
Cl2, to give lactam 11 (66% yield from 7).11 Oxidation
employing either pyridinium chlorochromate (PCC) in
CH2Cl2 or o-iodoxybenzoic acid (IBX) in EtOAc12 led to
lactam 11 in comparable yields (60-63%). Finally, acidic
hydrolysis of lactam 11 with 6 M HCl in ethyl acetate at
room temperature provided racemic Rolipram 1 in quan-
titative yield (Scheme 3). The physical and spectroscopic
data of Rolipram 1 were in excellent agreement with
those reported in the literature.6
SCHEME 3. Synthesis of Rolipram 1 from the
Heck-Matsuda Adduct 10
Following the protocol described above, racemic Rolip-
ram was synthesized in six steps from commercially
available 5-nitro-2-methoxyphenol 4 in an overall yield
of 45% (average of 87-88% yields per step).13
The Heck-Matsuda approach was flexible enough to
allow the synthesis of the unreported γ-amino butyric
acids (GABA) analogues 13 and 14. Thus, basic hydroly-
sis of lactam 11 with LiOH in THF using Grieco’s
conditions14 produced N-protected γ-amino acid 12 in 85%
yield. Removal of the Boc protecting group occurred
smoothly with 6 M HCl/EtOAc (1:1) at room temperature
to provide the desired γ-amino butyric acid hydrochloride
13 in quantitative yield. The temperature of acidic
hydrolysis significantly affects the type of product ob-
tained. Thus, lactam 11 was hydrolyzed at 95 °C with 6
M HCl for 12 h to cleanly furnish the hydrochloride 14
in 84% yield. On the other hand, when hydrolysis of
lactam 11 was carried out under acidic conditions at
reflux, a hard-to-separate mixture of the γ-amino butyric
Ether 5 was next subjected to catalytic hydrogenation
(H2, Pd-C, EtOAc, 10 h), followed by filtration through
Celite and acidification with 6 M HCl to provide the pure
aniline hydrochloride 6 in 95% yield. Acidification with
HCl caused precipitation of the ammonium salt, which
helped to improve the yields. Moreover, purification of
the hydrochloride 6 was unnecessary; washing the crude
hydrochloride 6 with CH2Cl2 resulted in a white solid of
high purity. The hydrochloride 6 was then transformed
(6) For previous synthesis of Rolipram, see: (a) Mulzer, J.; Zuhse,
R.; Schmiechen, R. Angew. Chem., Int. Ed. Engl. 1992, 31, 870-872.
(b) Meyers, A. I.; Snyder, L. J. Org. Chem. 1993, 58, 36-42. (c) Baures,
P. W.; Eggleston, D. S.; Erhard, K. F.; Cieslinski, L. B.; Thorphy, T.
J.; Christensen, S. B. J. Med. Chem. 1993, 36, 3274-3277. (d) Mulzer,
J. J. Prakt. Chem. 1994, 336, 287-291. (e) Braun, M.; Opdenbusch,
K.; Unger, C. Synlett 1995, 11, 1174-1176. (f) Honda, T.; Ishikawa,
F.; Kanai, K.; Sato, S.; Kato, D.; Tominaga, H. Heterocycles 1996, 42,
109-112. (g) Langlois, N.; Wang, H.-S. Synth. Commun. 1997, 27,
3133-3144. (h) Diaz, A.; Siro, J. G.; Garc´ıa-Nav´ıo, J. L.; Vaquero, J.
J.; Alvarez-Builla, J. Synthesis 1997, 559-562. (i) Demnitz, J.; LaVec-
chia, L.; Bacher, E.; Keller, T. H.; Mu¨ller, T.; Schu¨rch, F.; Weber, H.-
P.; Pombo-Villar, E. Molecules 1998, 3, 107-119. (j) Anada, M.; Mita,
O.; Watanabe, H.; Kitagaki, S.; Hashimoto, S. Synlett 1999, 1775-
1777. (k) Barluenga, J.; Ferna´ndez-Rodr´ıguez, M. A.; Aguilar, E.;
Ferna´ndez-Mar´ı, F.; Salinas, A.; Olano, B. Chem. Eur. J. 2001, 7,
3533-3544. (l) Itoh, K.; Kanemasa, S. J. Am. Chem. Soc. 2002, 124,
13394-13395. (m) Barnes, D. M.; Ji, J.; Fickes, M. G.; Fitzgerald, M.
A.; King, S. A.; Morton, H. E.; Plagge, F. A.; Preskill, M.; Wagaw, S.
H.; Wittenberger, S. J.; Zhang, J. J. Am. Chem. Soc. 2002, 124, 13097-
13105. (n) Yoon, C. H.; Nagle, A.; Chen, C.; Gandhi, D.; Jung, K. W.
Org. Lett. 2003, 5, 2259-2262. (o) Chang, M.-Y.; Sun, P.-P.; Chen, S.-
T.; Chang, N.-C. Heterocycles 2003, 60, 1865-1872. (p) Becht, J.-M.;
Meyer, O.; Helmchen, G. Synthesis 2003, 2805-2810.
(7) Rolipram is a very expensive tool for pharmacological investiga-
tions: (()-Rolipram: 10 mg, US$ 55; 50 mg, US$ 245; 10 mg of (R)-
(-)-Rolipram or (S)-(+)-Rolipram: US$ 129. TOCRIS online catalogue
(http://www.tocris.com).
(8) (a) Carpes, M. J. S.; Correia, C. R. D. Synlett 2000, 1037. (b)
Carpes, M. J. S.; Correia, C. R. D. Tetrahedron Lett. 2002, 43, 741. (c)
Severino, E. A.; Costenaro, E. R.; Garc´ıa, A. L. L.; Correia, C. R. D.
Org. Lett. 2003, 5, 305. (d) Garc´ıa, A. L. L.; Correia, C. R. D.
Tetrahedron Lett. 2003, 44, 1553.
(9) Fu, G. C.; Grubbs, R. H. J. Am. Chem. Soc. 1992, 114, 5426-
5427.
(10) For recent results on the mechanism of the Heck-Matsuda
reaction: Sabino, A. A.; Machado, A. H. L.; Correia, C. R. D.; Eberlin,
M. N. Angew. Chem., Int. Ed. 2004, 43, 2514-2518.
(11) For a review on oxidation with TPAP, see: Ley, S. V.; Norman,
J.; Griffith, W. P.; Marsden, S. P. Synthesis 1994, 640.
(12) More, J. D.; Finney, N. S. Org. Lett. 2002, 4, 3001-3003.
(13) Correia, C. R. D.; Garc´ıa, A. L. L. Brazilian Patent BR 204007,
2004.
(14) Flynn, D. L.; Zelle, R. E.; Grieco, P. A. J. Org. Chem. 1983, 48,
2424.
J. Org. Chem, Vol. 70, No. 3, 2005 1051