resistant to Heck arylations resulting in low conversion or
yields of the desired adduct. From a synthetic standpoint,
this is a considerable limitation to the Heck arylation process
and poses a challenge to be addressed.6
Table 1. Heck Arylation of Acyclic-Substituted Acrylates
Because of the higher reactivity of the arenediazonium
salts in the Heck reaction, we decided to investigate the
feasibility of applying the Heck arylation to the more
challenging substituted acrylate derivatives. Our planning
also included the application of these results in the total
synthesis of pharmacologically active compounds to highlight
the versatility of the procedure. One of the objectives of this
initial investigation was the synthesis of 4-arylpiperidines,
of which the antidepressant drug paroxetine 1, femoxetine
2, and the new renin inhibitor 3 are illustrative examples
(Figure 1).7 Paroxetine helps to maintain the neuronal levels
T
(°C)
t
(h)
yield
(%)c
a
entry R1
R2
R3
solventb
1
2
3
4
5
C6H5
H
H
H
H
H
MeO AC
reflux
AC-H2O 60
8
24
40d
43e
71f
67g
50h
64i
59j
66j
31k
C6H5
C6H5
C6H5
C6H5
F
MeO MeOH
reflux
reflux
rt
2
2
8
8
7
2
F
MeOH
MeO MeOH
6
7
8
CH3 CH3
CH3 CH3
CH3 CH3
F
F
AC-H2O 60
AC-H2O 60
MeO MeOH
MeO MeOH
reflux
9
CH3 CO2Me
reflux 5.5
10
11
H
H
CH2CO2Me
F
MeOH
reflux 0.25 91l
reflux 0.25 86l
CH2CO2Me MeO MeOH
a 1.0-1.2 equiv of arenediazonium salts. b AC ) acetonitrile; AC-H2O
refers to a 1:1 mixture of acetonitrile/water. c Isolated yields. d Diastereo-
selectivity (ds, capillary GC) ) 36:64. e ds ) 95:5. f ds ) 26:74. g ds )
93:7. h ds ) 85:15. i Double-arylated product 5; ds ) 47:53. j Yields for
the corresponding isomerized Heck adduct 6. k Double-arylation product 7
also isolated in ∼5% yield. l (E)-Stereoisomer only.
Figure 1. Representative 4-arylpiperidines.
corresponding â,â-diaryl propionic esters in good yields with
the diastereoselectivity depending on the arenediazonium
used. Interestingly, diastereoselectivity was much higher with
p-fluorobenzenediazonium salts than with the p-methoxyl-
benzenediazonium salts. Evidence for thermodynamic control
in this latter case is observed when comparing entries 3 and
5 or when following the reaction by GC. Changes in the
diastereomeric ratio are observed as the reaction proceeds,
probably due to equilibration. Also somewhat surprising was
the fact that no reaction was observed when using Pd2(dba)3
as catalyst. Some of the â,â-diaryl propionic esters prepared
here are key intermediates in the synthesis of many important
drugs.9
of the endogenous neurotransmitter serotonin. This drug acts
by selectively inhibiting the serotonin reuptake system on
the presynaptic neurons, making the so-called SSRI drugs.8
Arenediazonium tetrafluoroborates bearing substituents
with differing electronic affinity were evaluated. 4-Methoxy
and 4-fluorobenzenediazonium tetrafluoroborates were cho-
sen as the main arylating agents because of their exceptional
thermostability and to allow introduction of an electron-rich
aryl group, which is considerably more difficult to introduce
when employing traditional Heck protocols. Some selected
examples are presented in Table 1.
Arylations of methyl cinnamate were screened using CH3-
CN, CH3CN-H2O (1:1), EtOH, and MeOH as solvent (Table
1, entries 1-5) without addition of bases. Arylations were
observed in all solvents tested. However, these were more
efficient and faster in refluxing MeOH. Heck arylations in
ethanol resulted in more complex mixtures due to transes-
terification. Arylations were completed in 2 h to provide the
Heck arylation of methyl tiglate (entries 6-8) resulted in
the double-arylated adduct 5 as the only observed adduct in
64% yield (Figure 2, R ) F). This was not surprising in
(5) (a) Gurtler, C.; Buchwald, S. L. Chem.-Eur. J. 1999, 5, 3107. (b)
Calo`, V.; Nacci, A.; Monopoli, A.; Laera, S.; Cioffi, N. J. Org. Chem.
2003, 68, 2929. Calo`, V.; Nacci, A.; Monopoli, A.; Detomaso, A.; Iliade,
P. Organometallics 2003, 22, 4193. (c) Littke, A. F.; Fu, G. C. J. Am. Chem.
Soc. 2001, 123, 6989.
(6) Part of this work was presented at the XXVIII Annual Meeting of the
Brazilian Chemical Society, May 2005, and at the XI Brazilian Meeting on
Organic Synthesis, Canela, Brazil, August/September 2005.
(7) Renin inhibitors: (a) Oefner, C.; Binggeli, A.; Breu, V.; Bur, D.;
Clozel, J.-P.; D’Arcy, A.; Dorn, A.; Fischli, W.; Gruninger, F.; Guller, R.;
Hirth, G.; Marki, H. P.; Mathews, S.; Muller, M.; Ridley, R. G.; Stadler,
H.; Vieira, E.; Wilhelm, M.; Winkler, F. K.; Wostl, W. Chem. Biol. 1999,
6, 127. (b) Bursavich, M. G.; West, C. W.; Rich, D. H. Org. Lett. 2001, 3,
2317.
Figure 2. Heck adducts from the double and monoarylation of
acyclic acrylates.
view of the formation of a reactive R-substituted acrylate as
the primary Heck adduct. Nevertheless, formation of the
(8) (a) Wagstaff, A. J.; Cheer, S. M.; Matheson, A. J.; Ormrod, D.; Goa,
K. L. CNS Drugs 2002, 16, 425-434. (b) Bourin, M.; Chue, P.; Guillon,
Y. CNS Drug ReV. 2001, 7, 25.
(9) Almansa, C.; Go´mez, L. A.; Cavalcanti, F. L.; de Arriba, A. F.;
Rodr´ıguez, R.; Carceller, E.; Garcia-Rafanell, J.; Forn, J. J. Med. Chem.
1996, 39, 2197.
1658
Org. Lett., Vol. 8, No. 8, 2006