Table 2 Reaction with aniline hydrochloride derivatives
Solvent-based
Solvent-free
Entry
1
Product
Reaction conditions
Reaction timea
Reaction timea
Yield (%)
91
[0.39 M] in boiling EtOAcb
3 h
10 min
10 min
30 min
2
3
[0.41 M] in 50 1C NMPc
1 h
93
[0.41 M] in 50 1C NMPc
[0.41 M] in 50 1C NMPc
29 h
82
4
>143 h
3.5 h
78d
a
b
c
d
Reaction time to reach 86% conversion for entry 1 and >90% conversion for entries 2–4. See ref. 8. See ref. 9. From 4-aminobenzonitrile.
to the synthesis of the active pharmaceutical ingredient
Teriflunomide that was obtained in 81% yield in two steps.
Further studies of this complete solvent-free approach to other
reactions are currently underway.
´
CNRS, Universite Montpellier 1 (post-doctoral grant to J.B.)
and Universite Montpellier 2 are gratefully acknowledged for
´
their financial support.
Scheme 2 Multi-gram solvent-free synthesis of N-Benzylbenzamide.
Notes and references
1 C. Jimenez-Gonzalez, C. S. Ponder, Q. B. Broxterman and
J. B. Manley, Org. Process Res. Dev., 2011, 15, 912.
2 B. Rodrıguez, A. Bruckmann, T. Rantanen and C. Bolm, Adv.
´
Synth. Catal., 2007, 349, 2213; A. Stolle, T. Szuppa, S. E.
S. Leonhardt and B. Ondruschka, Chem. Soc. Rev., 2011,
40, 2317; T. Friscic, Chem. Soc. Rev., 2012, 41, 3493.
´
3 S. L. James, C. J. Adams, C. Bolm, D. Braga, P. Collier, T. Friscic
´
,
F. Grepioni, K. D. M. Harris, G. Hyett, W. Jones, A. Krebs,
J. Mack, L. Maini, A. G. Orpen, I. P. Parkin, W. C. Shearouse,
J. W. Steedk and D. C. Waddelli, Chem. Soc. Rev., 2012, 41, 413.
4 G. Kaupp, J. Schmeyers, M. R. Naimi-Jamala, H. Zoz and H. Ren,
Chem. Eng. Sci., 2002, 57, 763; G. Kaupp, M. R. Naimi-Jamal and
V. Stepanenko, Chem.–Eur. J., 2003, 9, 4156; G. Kaupp,
M. R. Naimi-Jamal and J. Schmeyers, Tetrahedron, 2003, 59, 3753;
J. Mokhtari, M. R. Naimi-Jamal, H. Hamzeali, M. G. Dekamin and
G. Kaupp, ChemSusChem, 2009, 2, 248; P. Nun, C. Martin,
J. Martinez and F. Lamaty, Tetrahedron, 2011, 67, 8187.
Scheme 3 Solvent-free synthesis of Teriflunomide.
easily transferred to a round-bottom flask and subjected to
classical stirring. Opening of the isoxazole ring was realised by
adjusting the pH to 1 with concentrated hydrochloric acid
followed by 24 h stirring. Finally, simple filtration of the
suspension afforded Teriflunomide with 81% yield.
5 I. Huskic, I. Halasz, T. Friscic and H. Vancik, Green Chem., 2012,
´ ´
14, 1597.
6 V. Declerck, P. Nun, J. Martinez and F. Lamaty, Angew. Chem.,
Int. Ed., 2009, 48, 9318.
7 S. K. Verma, R. Ghorpade, A. Pratap and M. P. Kaushik, Tetrahedron
Lett., 2012, 53, 2373.
8 P. J. Dunn, W. Hoffmann, Y. Kang, J. C. Mitchell and
M. J. Snowden, Org. Process Res. Dev., 2005, 9, 956.
9 E. K. Woodman, J. G. K. Chaffey, P. A. Hopes, D. R. J. Hose and
J. P. Gilday, Org. Process Res. Dev., 2009, 13, 106.
10 P. O’Connor, J. S. Wolinsky, C. Confavreux, G. Comi, L. Kappos,
T. P. Olsson, H. Benzerdjeb, P. Truffinet, L. Wang, A. Miller and
M. S. Freedman, N. Engl. J. Med., 2011, 365, 1293.
Fast and efficient synthesis of amides could be realised by
activation of carboxylic acids with CDI followed by reaction
with amine hydrochlorides in the complete absence of any organic
solvent. The methodology allowed purification and recovery
of the desired products without solvent except water. Performing
reactions in solvent-free media led to a sharp increase in the speed
of acylation of aniline hydrochlorides compared to reactions
carried out in solution. This approach was efficiently applied
c
This journal is The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 11781–11783 11783