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D. Martyres, F. Schmiedt / Tetrahedron Letters 47 (2006) 1649–1651
expensive reagents.5 More recently, a palladium-catal-
yzed synthesis of aryl ketones has been described inde-
pendently by Gooßen and Yamamoto, utilizing
carboxylic and boronic acids as starting materials.6
Requiring Palladium acetate as the source of Pd(0)
and dimethylcarbonate to generate in situ the mixed
anhydride for oxidative addition, we chose to carry
out this method in a parallel synthesis array.7 The
results are summarized in Table 1.
In conclusion, we have shown that the synthesis of 3,3-
di(hetero)arylpropylamines can be achieved by conden-
sation of bis-(hetero)aryl ketones with an acetonitrile
equivalent and that such ketones can be conveniently
prepared in parallel via palladium catalysis. A limitation
of this three-step method is the incompatibility of
thiophenes in the transfer hydrogenation reaction, and
current efforts are directed at overcoming this.
Acknowledgements
As can be seen in the table, yields are moderate to good,
and we found the reaction to be very amenable to paral-
lel synthesis. The conversion of ketones to 3,3-di(hetero)-
We gratefully acknowledge the services of the analytical
chemistry department for NMR and mass spectral
analyses.
arylpropylamines was achieved using
a two-step
procedure8 involving Horner–Wadsworth–Emmons
(HWE) olefination employing a cyanomethylphosph-
onate followed by hydrogenation (Scheme 2).
References and notes
The HWE olefination proceeded smoothly to provide
acrylonitriles in good yields. Hydrogenation was more
problematic, however, and was found to be successful
with substrates not containing a thiophene moiety
(Table 2).9
1. (a) Buschauer, A. J. Med. Chem. 1989, 32, 1963–1970; (b)
Buschauer, A.; Friese-Kimmel, A.; Baumann, G.;
Schunack, W. Eur. J. Med. Chem. Chim. Ther. 1992, 27,
321–330; (c) Ho, I.; James, G. Tetrahedron 1970, 26, 4277–
4286.
2. (a) As antimuscarinic agents: Sparf, B.; Meese, C. Eur.
Pat. Appl., 1999 (EP957073); (b) Johansson, R.; Moses,
P.; Nilverbant, L.; Sparf, B. PCT Int. Appl., 1994
(WO9411337); (c) As calmodulin antagonists: Joensson,
N.; Sparf, B.; Mikiver, L; Moses, P.; Nilvebrant, L.; Glas,
G. Eur. Pat. Appl., 1989 (EP325571); (d) As cardio-
vascular agents: (i) Jpn. Kokai Tokkyo Koho, 1988
(JP63072657). (ii) Korbonits, D.; Szekeres, L.; Kovacs,
G.; Santa, A.; Udvari, E.; Bata, I.; Marmarosi, K.;
Tardos, L.; Kormoczy, P.; Gergely, V. Eur. Pat. Appl.,
1988 (EP253327). (iii) Ibanez-Paniello, A. An. Quim.
(1968–1979) 1975, 810–814; (e) As CNS agents: (i) Pliai,
K.; Prasad, C.; Kapil, R., Ind. J. Chem., Sect. B 1976, 14B,
714–716. (ii) Jones, G. US Patent US3446901, 1969.
3. (a) Ghosh, A. K.; Bilcer, G.; Schiltz, G. Synthesis 2001,
2203; (b) List, B.; Castello, C. Synlett 2001, 1687.
4. Irgolic, K. J. In Houben-Weyl; 4th ed. Klamann, D., Ed.;
Thieme: Stuttgart, 1990; Vol. E12b, p 150.
N
NH2
O
ii.
i.
Ar1
Ar2
Ar1
Ar2
Ar1
Ar2
Scheme 2. Conditions: (i) cyanomethylphosphonic acid ethyl ester,
NaH, THF, 15 h, 0 °C to rt; (ii) H2, Pd on carbon, methanol, rt.
Table 2. Synthesis and hydrogenation of acrylonitriles
No.
Acrylonitrile
Yield (%)a
Yield (%)b
—
CN
7
83
S
CF3
5. (a) Liebeskind, L. S.; Srogl, J. J. Am. Chem. Soc. 2000,
122, 11260–11261; (b) Wittenberg, R.; Srogl, J.; Egi, M.;
Liebeskind, L. S. Org. Lett. 2003, 5, 3033–3035.
CN
8
9
76
76
86
—
—
36
6. (a) Gooßen, L. J.; Ghosh, K. Angew. Chem., Int. Ed. 2001,
40, 3458–3460; (b) Gooßen, L. J.; Ghosh, K. Eur. J. Org.
Chem. 2002, 3254–3267; (c) Gooßen, L. J.; Winkel, L.;
Do¨hring, A.; Ghosh, K.; Pa¨tzold, J. Synlett 2002, 8, 1237–
1240; (d) Kakino, R.; Narahashi, H.; Shimizu, I.;
Yamamoto, A. Chem. Lett. 2001, 1242–1243; (e) Kakino,
R.; Yasumi, S.; Shimizu, I.; Yamamoto, A. Bull. Chem.
Soc. Jpn. 2002, 75, 137–148; (f) Kakino, R.; Narahashi,
H.; Shimizu, I.; Yamamoto, A. Bull. Chem. Soc. Jpn. 2002,
75, 1333–1345.
S
F
CN
S
S
CN
10
O
7. Typical procedure (as used for entry 4 in Table 1):
The reaction was carried out in parallel on a Mettler-
Toldeo Miniblock-XTÒ parallel synthesizer. To a reaction
vial was added 4-fluorobenzoic acid (2 g, 14 mmol), 2-
furylboronic acid (1.9 g, 17 mmol), Pd(OAc)2 (100 mg,
0.4 mmol) and tris(4-methoxyphenyl)phosphine (350 mg).
F
CN
11
12
65
40
40
57
O
CF3
CN
A
suspension containing dimethylcarbonate (3.8 g,
29 mmol), water (0.6 mL) and THF (25 mL) was added
to this mixture, and the reaction vial flushed with Argon.
The reaction mixture was stirred at 40 °C for 1 day. After
this time, the contents were filtered through a plug of silica
followed by flash chromatography (4:1 cyclohexane/ethyl
acetate) to give the product of entry 4, Table 1 (2.2 g, 80%)
CF3
CF3
a Yield of HWE olefination.
b Yield of hydrogenation.