A short synthesis of 3,3-di(hetero)arylpropylamines obtained from bis-(hetero)aryl ketones via palladium catalysis

Article abstract of DOI:10.1016/j.tetlet.2005.12.122

A palladium-catalyzed parallel synthesis of bis-hetero(aryl) ketones is described with two further synthetic steps allowing easy entry to 3,3-di(hetero)arylpropylamines.

Full text of DOI:10.1016/j.tetlet.2005.12.122

Tetrahedron
Letters
Tetrahedron Letters 47 (2006) 1649–1651
A short synthesis of 3,3-di(hetero)arylpropylamines obtained
from bis-(hetero)aryl ketones via palladium catalysis
Domnic Martyres* and Frank Schmiedt
Department of Chemical Research, Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorfer Straße 65,
88397 Biberach an der Riss, Germany
Received 1 December 2005; accepted 20 December 2005
Available online 19 January 2006
Abstract—A palladium-catalyzed parallel synthesis of bis-hetero(aryl) ketones is described with two further synthetic steps allowing
easy entry to 3,3-di(hetero)arylpropylamines.
Ó 2006 Elsevier Ltd. All rights reserved.
3,3-Diarylpropylamines are useful intermediates in the
synthesis of biologically active compounds,1 and display
important biological properties in their own right.2
Recently, palladium-catalyzed cross-coupling reactions
have been described, which utilize thioesters or acid
chlorides with boronic acids. These methods have
proved very useful but in the case of thioesters, involve
an extra synthetic step and stoichiometric amounts of
We were interested in synthesizing a number of 3,3-
diarylpropylamines in which the aromatic rings either
contained fluorine substituents, were heterocyclic, or
possessed a combination of both.
Table 1. Palladium-catalyzed ketone synthesis
No.
Producta
Yield (%)
44
We envisaged such amines to be derived from diaryl
ketones (Scheme 1), and sought a reliable method for
synthesizing such ketones from readily available starting
materials, which could be performed in parallel.
O
1
S
CF3
O
2
3
4
5
46
48
80
53
The efficient synthesis of ketones in general has been a
target of research for many years. Since the reactivity
of ketones is generally greater than that of their carbox-
ylic acid precursors, this reactivity, or that of the react-
ing nucleophile must be suppressed in order to minimize
multiple addition. Popular methods to achieve this
include the use of Weinreb amides with Grignard
reagents,3 or the use of acid chlorides with organometallic
reagents, notably zinc or cadmium compounds.4
S
F
O
S
S
O
O
O
F
O
Ar1
NH2
O
CF3
O
Ar2
Ar1
Ar2
6
38
Scheme 1.
CF3
CF3
Corresponding author. Tel.: +49 (0) 7351 543140; fax: +49 (0) 7351
833140; e-mail: domnic.martyres@bc.boehringer-ingelheim.com
a Aryl groups originating from boronic acids are drawn to the left of
the carbonyl group.
*
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.12.122

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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.

D. Martyres, F. Schmiedt / Tetrahedron Letters 47 (2006) 1649–1651
1651
as a pale yellow solid. 1H NMR (400 MHz, DMSO-d6):
d = 6.79–6.82 (1H, m), 7.38–7.44 (3H, m), 7.99–8.07 (2H,
m), 8.12 (1H, s). LRMS: m/z = 241 [MH+].
isomer b), 6.72 (1H, d, isomer a), 6.82 (1H, d, isomer a),
7.28–7.41 (4H, m, isomers a and b), 7.49–7.59 (4H, m,
isomers a and b), 7.96 (1H, s, isomer b), 8.01 (1H, s,
isomer a). LRMS: m/z = 214 [MH+]. Step 2: The product
from step 1 (1.2 g, 5.6 mmol) was dissolved in methanol
(50 mL) and hydrogenated at rt under 3–4 bar pressure
with Pd on carbon catalyst (0.5 g, 10%) and concd HCl
(aq) (3 mL). After 15 h, the reaction was neutralized with
NaOH (aq) and the organic layer separated and dried over
MgSO4. The solution was concentrated in vacuo and the
crude solid purified by flash chromatography (9:1 DCM/
MeOH) to give the amine (0.5 g, 36%) as a pale yellow
solid. LRMS: m/z = 220 [MH+].
8. Typical procedure (as used for entry 10 in Table 2):
Step 1: To a stirred suspension of sodium hydride (930 mg,
60%, 23.3 mmol) in THF (10 mL) at 0 °C was added a
solution of cyanomethylphosphonic acid ethyl ester
(3.7 mL, 23.5 mmol) dropwise. The reaction was allowed
to warm to rt and then a solution of ketone 10, Table 2
(2.2 g, 11.4 mmol) was added to this dropwise. After 15 h,
the reaction mixture was diluted with ethyl acetate (20 mL)
and washed with NH4Cl (aq) solution (10 mL) and water
(10 mL). The organic phase was separated, dried over
MgSO4 and concentrated in vacuo. Flash chromatography
(9:1 cyclohexane/ethyl acetate) provided the acrylonitrile
as a yellow solid (mixture of cis and trans isomers). 1H
NMR (400 MHz, DMSO-d6): d = 5.81 (1H, s, isomer a),
6.20 (1H, s, isomer b), 6.51 (1H, d, isomer b), 6.68 (1H, d,
9. Transfer hydrogenation utilizing Wilkinson’s catalyst
reported to be compatible with sulfur functional groups10
was also unsuccessful.
10. For example: Donohoe, T. J. Oxidation and Reductions in
Organic Synthesis; 2000, Oxford Science Publications.