Mechanosynthesis of amides in the total absence of organic solvent from reaction to product recovery

Article abstract of DOI:10.1039/c2cc36352f

The synthesis of various amides has been realised avoiding the use of any organic solvent from activation of carboxylic acids with CDI to isolation of the amides. Mechanochemistry was the key point of the process allowing rapid formation of the amide bond and efficient water-based purification of the final products.

Full text of DOI:10.1039/c2cc36352f

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COMMUNICATION
Mechanosynthesis of amides in the total absence of organic solvent from
reaction to product recoverywz
´
Thomas-Xavier Metro,* Julien Bonnamour, Thomas Reidon, Jordi Sarpoulet, Jean Martinez
and Frederic Lamaty*
´
´
Received 31st August 2012, Accepted 8th October 2012
DOI: 10.1039/c2cc36352f
The synthesis of various amides has been realised avoiding the use
of any organic solvent from activation of carboxylic acids with CDI
to isolation of the amides. Mechanochemistry was the key point of
the process allowing rapid formation of the amide bond and efficient
water-based purification of the final products.
added-value molecules production. Pursuing our interest in
the development of solvent-free amide bond formation,6 we
found that solvent-free synthesis of amides resulting from
activation of carboxylic acids with N,N0-carbonyldiimidazole
(CDI) can be combined with solvent-free purification and recovery.
We built our strategy on the great water solubility difference
between the hydrophobic amides and the hydrophilic side-products
of the reaction, which are amines, carboxylic acids and imidazole.
Among the commonly used coupling reagents, N,N0-carbonyl-
diimidazole (CDI) appeared as the most promising reagent. It is
cheap, readily available in large quantities and produces relatively
benign and easily separable by-products (carbon dioxide and
imidazole). To our knowledge, only one study has been previously
published concerning the solvent-free formation of amide bonds
from carboxylic acids and amines using CDI.7 In this case, mixing
was realised with a spatula, which may raise serious problems in a
scale-up perspective. Additionally, products were recovered using
EtOAc, which is of limited interest as the formation of the studied
products can be easily realised in EtOAc.8
Solvent-free synthesis is probably the most efficient way to improve
the ‘‘greenness’’ of complex organic molecule syntheses as the
solvent is generally the main source of waste.1 Excluding solvent
from the reaction medium has led to an ever-growing use of the
ball-mill as a practical tool for efficient mixing of solid-containing
reaction mixtures.2 Mechanochemistry-based approaches also
proved to be more selective and efficient than the solvent-based
versions in a wide range of reactions.3 Nevertheless, as noticed by
James et al. in a recent review,3 it is ‘‘clearly unrealistic that
mechanochemistry could make all of chemical synthesis completely
solvent-free’’. Indeed, an overwhelming majority of the mechano-
chemistry-based methodologies requires solvent for recovery and
purification of the products, thereby attenuating the interest of
these solvent-free syntheses. A very limited number of mechano-
chemistry-based methodologies describe complete solvent-free
processes.4 Unfortunately, they are limited to inherently simple
reactions such as addition or condensation reactions producing
water as the only by-product, rendering the purification step
unnecessary. Recently, a solvent-free process including solvent-
free synthesis, product recovery and purification was described
by Halasz and coworkers.5 While being a real breakthrough in
the development of complete solvent-free syntheses of high
added-value molecules, the solvent-free purification of this process
was based on sublimation of the products, thereby limiting the
possible extension of this approach to the narrow range of
molecules possessing high vapor pressure properties.
We started our study by treating hydrocinnamic acid with
1.0 eq. CDI for 5 min in a ball-mill, followed by the addition of
0.9 eq. benzylamine hydrochloride and mixing for 10 min
(Scheme 1). Consumption of both the carboxylic acid in the
first step and the acyl-imidazole in the second step was
followed in the solid-state by disappearance of their IR bands
(1692 and 1730 cmꢀ1 respectively). Deionised water was added
into the milling jar and 5 min ball-mill mixing furnished a fine
suspension, which rendered isolation of pure N-benzylhydrocinn-
amide by filtration very easy. As by-products (imidazole, unreacted
carboxylic acid and amine) were more soluble in water than
We would like to detail here the results of our recent studies
in the development of complete solvent-free processes for high
´
Institut des Biomolecules Max Mousseron, UMR 5247 Universite
Montpellier 1 et Universite Montpellier 2-CNRS, Place Eugene
´
´
`
Bataillon, 34095 Montpellier Cedex 05, France.
E-mail: txmetro@um2.fr, frederic.lamaty@univ-montp2.fr
w This article is part of the ChemComm ‘Mechanochemistry’ web
themed issue.
z Electronic supplementary information (ESI) available: General
experimental procedures and characterization data for all compounds.
See DOI: 10.1039/c2cc36352f
Scheme 1 Solvent-free synthesis of N-benzylhydrocinnamide.
Chem. Commun., 2012, 48, 11781–11783 11781
c
This journal is The Royal Society of Chemistry 2012

Table 1 Exemplification of the solvent-free CDI-mediated mechanosynthesis of amidesa
a
e
b
Realised on the 1.35 mmole scale. Completed within 6 h. Determined by chiral HPLC. See ESI for details. Completed within 30 min.
c
d
Starting from free amine. Determined by H and 13C NMR. No signal corresponding to the diastereoisomer was observed.
f
1
the resulting amide, the latter could be recovered in a pure
form in 94% yield. Under these optimised conditions, various
amides could be synthesised and isolated without the use of
any organic solvent (Table 1).
the product 18 times faster, within 10 min only (Table 2, entry 1).
The difference is even more pronounced when using a less
reactive substrate such as 4-(trifluoromethyl)aniline hydro-
chloride. In this case, benzoylation of the latter aniline was
completed after 29 h at 50 1C in NMP. Repeating the same
reaction without this toxic solvent furnished the same compound
58 times faster, in 30 min only (Table 2, entry 3). These results
clearly showed that under solvent-free conditions combined
with ball-mill induced mixing, possible mass transfer limita-
tions related to solid-containing viscous or sticky reaction
media were not significant compared to the sharp increase
in the reaction speed caused by the substantially higher con-
centrated reaction mixture.
Non-substituted carboxylic acids could be transformed into their
corresponding N-benzyl amides with excellent yields (Table 1,
compounds 1–3). High steric hindrance was not an obstacle as
bulky 1-adamantane carboxylic acid could be easily activated with
CDI to furnish the corresponding N-benzyl amide in good yield
(Table 1, compound 4). Heteroatom-containing N-benzyl amides
such as compounds 5 and 6 could be isolated with high yield.
Differently substituted amines could also be benzoylated with high
yields (Table 1, compounds 7–9). This methodology was not limited
to the acylation of primary amine hydrochlorides because O-benzyl
hydroxylamine, phenylhydrazine and dibenzylamine hydro-
chlorides were easily acylated (Table 1, compounds 10–12). In the
latter case the process is less efficient, compound 12 was obtained in
44% yield after 6 h reaction. Finally, it is worth noting that no
racemisation was observed when using either enantiopure amines
or enantiopure carboxylic acids indicating that this process was
highly stereoselective (Table 1, compounds 13–16).
We then decided to study the scalability of this solvent-free
methodology. To address this point, the synthesis of N-benzyl-
benzamide was performed on a 4.5 g scale (Scheme 2). When
mixing 25 mmol of benzoic acid with 25 mmol of CDI in a
250 mL stainless steel jar containing 50 balls (10 mm diameter), the
reaction finished within 5 min, and subsequent consumption of
22.5 mmol of benzylamine hydrochloride was completed within
10 min, affording 4.5 g of N-benzylbenzamide (96% yield). This
result clearly showed that this methodology was applicable at
the multi-gram scale.
Anilines are known to be slow-reacting substrates considering
the addition on acyl-imidazole intermediates.8 As the speed of
reaction increases with concentration, removing the solvent from
the reaction media could have an accelerating effect, as long as the
presence of solids in the reaction media may not lead to mass
transfer limitations. In order to address this point, we carefully
examined aniline substrates and compared the results obtained
with and without solvent (Table 2).
With these results in hand, we decided to apply the methodol-
ogy to the synthesis of Teriflunomide (also known as A77 1726),
an active pharmaceutical ingredient recently approved by the
FDA for multiple sclerosis therapy.10 The amide bond of
Teriflunomide was first synthesised by solvent-free treatment
of 5-methyl-4-isoxazolecarboxylic acid with CDI for 20 min,
followed by reaction with 4-(trifluoromethyl)aniline hydro-
chloride for 5 h (Scheme 3). Addition of deionised water and
5 min mixing in the ball-mill yielded a fine suspension that was
While 3 h in boiling EtOAc was necessary to transform
86% of 2-phenylpropanoic acyl-imidazole into N-phenyl-2-
phenylpropanoic amide,8 the solvent-free procedure could deliver
c
11782 Chem. Commun., 2012, 48, 11781–11783
This journal is The Royal Society of Chemistry 2012

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.,
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7 S. K. Verma, R. Ghorpade, A. Pratap and M. P. Kaushik, Tetrahedron
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8 P. J. Dunn, W. Hoffmann, Y. Kang, J. C. Mitchell and
M. J. Snowden, Org. Process Res. Dev., 2005, 9, 956.
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J. P. Gilday, Org. Process Res. Dev., 2009, 13, 106.
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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