Platinum-catalysed synthesis of trichloroamidines

Article abstract of DOI:10.1016/j.tetlet.2013.06.062

A mild platinum-catalysed method for the formation of free amidines from the reaction of amines and trichloroacetonitrile in nonpolar solvents has been developed. This protocol provides access to novel amidines that in some cases (4b-d) cannot be synthesised via the direct reaction of amines and halogenated nitriles.

Full text of DOI:10.1016/j.tetlet.2013.06.062

Tetrahedron Letters 54 (2013) 4522–4523
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Tetrahedron Letters
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Platinum-catalysed synthesis of trichloroamidines
⇑
Jay J. Dunsford, Jason E. Camp
School of Chemistry, University of Nottingham, Nottingham NG7 2RD, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
A mild platinum-catalysed method for the formation of free amidines from the reaction of amines and
trichloroacetonitrile in nonpolar solvents has been developed. This protocol provides access to novel ami-
dines that in some cases (4b–d) cannot be synthesised via the direct reaction of amines and halogenated
nitriles.
Received 14 February 2013
Revised 31 May 2013
Accepted 14 June 2013
Available online 22 June 2013
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Amidine
Nitrile activation
Platinum catalysis
Amidines are a useful class of compounds that have been
exploited in a number of disparate fields including catalysis,1,2
medicinal chemistry,3 materials science4 and as switchable sol-
vents5/surfactants.6 Traditional methods for the synthesis of ami-
dines include nucleophilic addition of an amine to a protic or
Lewis acid activated nitrile.7,8 It has also been shown that nitriles
that are activated by strong electron-withdrawing groups, such
as trifluoro- or trichloroacetonitrile, will react directly with amines
to form amidines.9 This reaction is generally carried out in alco-
holic or aqueous solvents and the product amidines are isolated
as their corresponding hydrochloride salts. Additionally, tris(dim-
ethylphosphinito)platinum hydride was shown to catalytically
activate acetonitrile for the formation of a mixture of mono- and
bis-amidines when reacted with n-propyl amine at 160 °C in
DME.10 Herein, we report the ability of simple platinum salts to
catalytically activate trichloroacetonitrile towards the addition of
amines for the formation of free amidines under mild conditions.
Our preliminary investigation was focused on the ability of sim-
ple platinum salts to activate trichloroacetonitrile 1 towards the
addition of primary and secondary amines 2 in nonpolar solvents
in order to form free amidines 4 directly (Scheme 1). It was envis-
aged that the platinum species would co-ordinate to the nitrile,
thus activating it towards addition of the amine nucleophile to
form an intermediate platinum bound amidine species 3. The
in situ formed trichloroamidine 3 would not be a strong ligand
for the metal due to the electron-withdrawing nature of the halo-
gens, and it would thus undergo ligand exchange with the starting
material, leading to catalyst turnover. In contrast, it has been
shown that more electron-rich platinum–amidine complexes can
be synthesised and isolated via a two-step process.11
Thus, the addition of a range of primary and secondary amines
to trichloroacetonitrile in the presence of platinum(II) chloride was
used to assess the feasibility of this approach (Scheme 2). It was
found that reaction of 2.2 equiv of trichloroacetonitrile with a pri-
mary or secondary amine in the presence of 10 mol % platinum(II)
chloride in dichloromethane at room temperature afforded the de-
sired amidines in good yields after isolation and purification.12 For
example, subjecting diethylamine to the reaction conditions gave
amidine 4a in 67% yield after isolation and purification. Secondary
dialkylamines with longer alkyl chains gave the desired amidines
4b–d as a mixture of geometric isomers in good yields. These re-
sults are in contrast to a previously reported uncatalysed process,
which afforded the product of chlorine substitution.10 Cyclic
amines also gave the desired amidines 4e,f in good yields. Addi-
tionally, the primary amines, benzylamine and t-butylamine, affor-
ded amidines 4g and 4h, respectively. For benzylamidine 4g, the
double bond isomerised to form the more substituted imine.
Unfortunately, no reaction was observed when the less nucleo-
philic amine aniline was used at room temperature. Control exper-
iments in which the platinum species was omitted from the
reaction mixture afforded the desired amidines 4a and 4g in signif-
icantly decreased yields under otherwise identical conditions.13 Fi-
nally, trichloroacetonitrile was reacted with N-allylmethylamine
under the standard conditions to afford allylamidine 4i as a single
geometric isomer, though the configuration of the isomer was not
⇑
Corresponding author. Tel.: +44 115 846 8464.
E-mail address: jason.camp@nottingham.ac.uk (J.E. Camp).
Scheme 1. Proposed platinum-catalysed synthesis of halogenated amidines.
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.06.062

J. J. Dunsford, J. E. Camp / Tetrahedron Letters 54 (2013) 4522–4523
NH
CCl3
4523
Supplementary data
NH2
CCl3
R1
H
PtCl2 (10 mol%)
N
R2
R1
Cl3CCN
(2.2 equiv.)
or R1
+
N
R2
N
CH2Cl2 (1 M)
rt, 20 h
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2013.
06.062.
1
2
4a-f, i
4g
HN
NH
NH
CCl3
References and notes
Bu
Hex
Et
N
Bu
CCl3
N
N
Et
CCl3
1. For reviews, see: (a) Baker, J.; Kliner, M. Coord. Chem. Rev. 1994, 133, 219–300;
(b) Edelmann, F. T. Chem. Soc. Rev. 2009, 38, 2253–2268.
Hex
2. For the use of amidines as bases in cross-coupling reactions, see: (a) Mio, M. J.;
Kopel, L. C.; Braun, J. B.; Gadzikwa, T. L.; Hull, K. L.; Brisbois, R. G.; Markworth,
C. J.; Grieco, P. A. Org. Lett. 2002, 4, 3199–3202; For the use of amidines as
ligands for catalysis, see: (b) Forsberg, J. H.; Spaziano, V. T.; Balasubramian, T.
M.; Liu, G. K.; Kinsley, S. A.; Duckworth, C. A.; Poteruca, J. J.; Brown, P. S.; Miller,
J. L. J. Org. Chem. 1987, 52, 1017–1021.
3. (a) Saari, W. S.; Freedman, M. B.; Huff, J. R.; King, S. W.; Raab, A. W.; Bergstrand,
S. J.; Engelhardt, E. L. J. Med. Chem. 1978, 21, 1283–1290; (b) Guile, S. D.;
Alcaraz, L.; Birkinshaw, T. N.; Bowers, K. C.; Ebden, M. R.; Furber, M.; Stocks, M.
J. J. Med. Chem. 2009, 52, 3123–3141.
4a 67% (26%)a
4b 69%
4c 61%
NH
NH
NH
Oct
N
CCl3
N
CCl3
N
CCl3
O
Oct
4. Ikeda, M.; Tanaka, Y.; Hasegawa, T.; Furusho, Y.; Yashima, E. J. Am. Chem. Soc.
2006, 128, 6806–6807.
5. Jessop, P. G.; Heldebrant, D. J.; Li, X.; Eckert, C. A.; Liotta, C. L. Nature 2005, 436,
1102.
6. Liu, Y.; Jessop, P. G.; Cunningham, M.; Eckert, C. A.; Liotta, C. L. Science 2006,
313, 958–960.
7. Dunn, P. J. In Comprehensive Organic Functional Group Transformations In ;
Elsevier: Oxford, U.K., 2005; Vol. 5, pp 665–699.
8. For alternative syntheses of acetamidines, see: (a) Rousselet, G.; Capdevielle, P.;
Maumy, M. Tetrahedron Lett. 1993, 34, 6395–6398; (b) Harjani, J. R.; Liang, C.;
Jessop, P. G. J. Org. Chem. 2011, 76, 1683–1691.
4e
4d 59%
62%
NH
4f 54%
NH
N
NH2
CCl3
CCl3
Ph
N
N
H
CCl3
9. (a) Dachlauer, K. German Patent 671,785, 1939; Chem. Abstr. 1939, 33, 6345.;
(b) Oxley, P.; Partridge, M. W.; Short, F. W. J. Chem. Soc. 1948, 303–309; (c)
Backer, H. J.; Wanmaker, W. L. Recl. Trav. Chim. Pays-Bas 1951, 70, 638–646; (d)
Grivas, J. C.; Taurins, A. Can. J. Chem. 1958, 36, 771–774; (e) Grivas, J. C.; Taurins,
A. Can. J. Chem. 1961, 39, 761–764.
4g 86% (35%)a
4h 72%
4i 56%
a PtCl2 was not added
10. Cobley, C. J.; van der Heuvel, M.; Abbadi, A.; de Vries, J. G. Tetrahedron Lett.
2000, 41, 2467–2470.
Scheme 2. Platinum-catalysed synthesis of trichloroacetamidine.
11. For the formation of platinum bound amidines derived from the addition of
amines to platinum bound nitriles, see: (a) Sbovata, S. M.; Bettio, F.; Marzano,
C.; Mozzon, M.; Bertani, R.; Benetollo, F.; Michelin, R. A. Inorg. Chim. Acta 2008,
361, 3109–3116; (b) Bacchi, A.; Dell’Amico, D. B.; Calderazzo, L.; Pelizzi, G.;
Marchetti, F.; Samaritani, S. Inorg. Chim. Acta 2010, 363, 2467–2473.
determined. Whilst it was hoped that [3,3]-sigmatropic rearrange-
ment process catalysed by PtCl2 would also occur to form a second-
ary amidine (multifaceted catalysis14,15) independent synthesis of
allylamidine 4i under basic conditions confirmed the structural
assignment.
In conclusion, a platinum-catalysed method for the formation of
amidines from the reaction of primary and secondary amines and
trichloroacetonitrile in a nonpolar solvent has been developed.
Importantly, this method allows for the direct catalytic synthesis
of free amidines in nonpolar solvents at room temperature without
the use of corrosive acids, strong bases or stoichiometric additives.
We anticipate that this approach to amidine synthesis will find
wide application due to its utility and operational simplicity. The
further extension of this approach to less activated nitriles is cur-
rently in progress.
12. Typical procedure for the synthesis of amidines 4:
A flame dried 5 mL
microwave vial was charged with PtCl2 (10 mol %), under nitrogen and
evacuated under vacuum for ca. 10 min and backfilled with nitrogen prior to
the addition of CH2Cl2. Trichloroacetonitrile (1, 2.2 equiv) and the primary or
secondary amine 2 (1.0 equiv.) were added sequentially. The vessel was sealed
and the reaction mixture allowed to stir at room temperature for 20 h. The
crude reaction mixture was reduced in vacuo prior to purification by flash
column chromatography (EtOAc/petroleum ether) on silica gel to afford the
desired amidine 4.
13. See Supplementary information for details.
14. For reviews, see: (a) Lu, B.-L.; Dai, L.; Shi, M. Chem. Soc. Rev. 2012, 41, 3318–
3339; (b) Britton, J.; Camp, J. E. Chem. Today 2012, 30, 6–8.
15. For recent examples of multifaceted catalysis, see: (a) Penno, D.; Lillo, V.;
Koshevoy, I. O.; Sanaú, M.; Ubeda, M. A.; Lahuerta, P.; Fernández, E. Chem. Eur. J.
2008, 14, 10648–10655; (b) Blanc, A.; Tenbrink, K.; Weibel, J.-M.; Pale, P. J. Org.
Chem. 2009, 74, 5342–5348; (c) Ngwerume, S.; Camp, J. E. Chem. Commun.
2011, 1857–1859; (d) Ngwerume, S.; Lewis, W.; Camp, J. E. J. Org. Chem. 2013,
78, 920–934; (e) Kern, N.; Hoffmann, M.; Blanc, A.; Weibel, J.-M.; Pale, P. Org.
Lett. 2013, 15, 836–839; (f) Lester, R. P.; Camp, J. E. ACS Sustainable Chem. Eng.
2013, 1, 545–548.
Acknowledgements
This work was supported by the School of Chemistry at the Uni-
versity of Nottingham and the EPSRC (postdoctoral associateship
for J.J.D. through a First-Grant EP/J003298/1).