Fast and efficient solvent-free Passerini reaction

Article abstract of DOI:10.1016/j.tetlet.2011.11.028

A Passerini three component condensation between a carboxylic acid, an aldehyde, and an isocyanide at high temperature under solvent-free conditions was developed. This methodology allows the formation of a broad range of α-acyloxyamides in excellent yields in short reaction times.

Full text of DOI:10.1016/j.tetlet.2011.11.028

Tetrahedron Letters 53 (2012) 306–308
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Fast and efficient solvent-free Passerini reaction
Till Bousquet a,b,c, , Mouhamad Jida a,c,d, Mohamad Soueidan a,b,c, Rebecca Deprez-Poulain a,c,d
,
⇑
Francine Agbossou-Niedercorn a,b,c, Lydie Pelinski a,b,c,
⇑
a Université Lille Nord de France, Lille, France
b UMR CNRS 8181, Unité de Catalyse et de Chimie du Solide, Université de Lille 1, 59655 Villeneuve d’Ascq Cedex, France
c PRIM, Pôle de Recherche Interdisciplinaire sur le Médicament, Lille F-59000, France
d Biostructures and Drug Discovery, INSERM U761, Faculté de Pharmacie, 3 rue du Pr Laguesse, Lille F-59006, France
a r t i c l e i n f o
a b s t r a c t
Article history:
A Passerini three component condensation between a carboxylic acid, an aldehyde, and an isocyanide at
high temperature under solvent-free conditions was developed. This methodology allows the formation
Received 14 October 2011
Revised 28 October 2011
Accepted 4 November 2011
Available online 12 November 2011
of a broad range of
a-acyloxyamides in excellent yields in short reaction times.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Passerini reaction
Solvent free
High temperature
Multicomponent reactions (MCRs) are convergent reactions in
which three or more reagents are combined to react in a one pot
procedure.1 They have been extensively studied over the past
few years, leading to products exhibiting a great structural diver-
sity in an environmentally friendly way with regards to the con-
cept of atom economy.2 Among these processes, the Passerini
reaction is classified as an isocyanide multicomponent reaction
(IMCR) and deals with the condensation of an isocyanide, an alde-
hyde, and a carboxylic acid.3 This reaction is typically carried out
with high concentrations of starting materials in an inert aprotic
solvent (usually methylene chloride).3,4 Depending on the nature
of the substrate, reaction times ranging from hours to several days
are often required.
quite expensive.9 In addition, carrying out a very efficient reaction
followed by an effective isolation of highly functionalized products
from ionic liquids remains still a challenge.
Given our ongoing interest in MCRs10 and considering the high
potential of the Passerini reaction, we wish to report herein a new
green protocol to perform the reaction at high temperature under
solvent-free conditions on a broad range of substrates.
Initial experiments were performed to determine the
temperature and reaction times required to complete the transfor-
mation under solvent-free conditions (Table 1).
Table 1
Optimization of Passerini reaction conditions under solvent-free conditions
In the last decade, several optimizations have been achieved to
improve the yield, reduce the cost, the ecological impact, and the
reaction times of the Passerini reaction. Thus, processes have been
described in aqueous solution,5 ionic liquid,6 without solvent
either at room temperature,7 or under microwave irradiation acti-
vation.8 However, the solvent-free method at room temperature
gives products in low to moderate yields when aliphatic aldehydes
were reacted.7 Although this limitation can be overcome by a
microwave-assisted procedure,8 an alternative could be interesting
since this irradiation process is not easy to scale up. On the other
side, ionic liquids are interesting solvents for organic transforma-
tions, however they are not as green as expected and are usually
O
Ph
O
O
H
N
neat
tBu NC
Ph
O
tBu
Ph
H
Ph
OH
O
1
2
3
4
Entry Temperature
Reaction time
(min)
Conversion
(%)a
Yield
(%)b
(°C)
1
2
3
4
6
7
80
100
120
150
180
200
20
20
15
10
4
88
100
100
100
100
100
70
86
85
84
88
77
2
a
Determined by 1H NMR.
Isolated yields.
⇑
Corresponding authors.
E-mail address: till.bousquet@univ-lille1.fr (T. Bousquet).
b
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.11.028

T. Bousquet et al. / Tetrahedron Letters 53 (2012) 306–308
307
First, 1.1 equiv of benzoic acid 1, 1 equiv of benzaldehyde 2, and
1 equiv of tert-butyl isocyanide 3 were combined and reacted at
Thus, this optimization has highlighted a range of temperatures
where the target product 4 can be isolated in good yields. For the
following experiments, the temperature was set to 180 °C and
the reaction time to 4 min.12
The scope of the process has been demonstrated by the evalua-
tion of a large array of reagents by varying the isocyanide, the car-
boxylic acid, and the aldehyde.
In the first series of experiments, tert-butyl isocyanide was con-
densed with various carboxylic acids and aldehydes bearing elec-
tron-donating or -withdrawing groups (Table 2).
In all cases, the desired products 7a–j were isolated in good
yields ranging from 76 to 92% (Table 2). When compared to the lit-
erature data, the reaction promoted by microwave irradiation pro-
vided product 7b in a 70% yield at 120 °C,8 while the classical
thermal heating procedure applied here allowed a significant
improvement of the yield (86% vs 70%) (entry 2). Thus, although
microwave–assisted organic synthesis has been demonstrated to
usually increase the rate of MCR with the reduction of reaction
times and improvement of the yields,13 the protocol described
herein seems to be more efficient for the Passerini reaction. Addi-
tionally, it is noteworthy that the reactions were successfully per-
formed with heterocyclic aldehydes as well (entries 13 and 14).
80 °C11 for 10 min providing the
a-acyloxy amide 4 with 88% con-
version and in a 70% yield (entry 1, Table 1). Increasing the temper-
ature to 100 °C for 20 min resulted in higher conversion (100%) and
yield (86%) (entry 2). Although these reaction conditions are al-
ready interesting, we have investigated the limits of the method
by increasing further the temperature. As expected, shorter reac-
tion times were required to reach full conversions (180 °C, 2 min,
100% conversion, entry 6) At 200 °C, the product was isolated in
lower yield (77%) suggesting degradation due to overheating
(entry 7).
Table 2
Passerini reaction under solvent-free conditions with tert-butyl isocyanide
O
R2
O
O
H
N
neat
tBu NC
R1
O
tBu
R1
OH
R2
H
O
5
6
3
7
Entry
1
R1
R2
Product
Yields (%)a
Table 3
Scope of the Passerini reaction under solvent-free conditions with benzyl and
cyclohexyl isocyanide
7a
80
O
R2
O
O
H
N
neat
Bn NC
or
2
3
6
7b
7c
7d
86 (70b)
R1
O
Bn
R2
H
R1
OH
Cy NC
180°C
Cl
O
6
7
8
82
Entry R1
R2
Isocyanide Product Yields
(%)a
F
MeO
O2N
88
1
2
Bn-NC
Bn-NC
Bn-NC
8a
8b
8c
86
81
80
F3C
7
8
7e
7f
83
86
i
Me
Ph
Pr
OMe
MeO
3
4
Bn-NC
8d
93
75
9
7g
7h
92
85
O2N
OMe
5
6
7
Bn-NC
Bn-NC
Cy-NC
8e
8f
10
64
Cl
Me
(36b)
(55c)
11
12
13
7i
83
90
78
Cl
Br
MeO
8g
85
85
7j
Ph
8
Cy-NC
8h
7k
Cl
N
O
Cl
9
Cy-NC
Cy-NC
8i
8j
88
79
14
7l
76
10
Br
a
b
c
Isolated yields.
In CH2Cl2 at room temperature for 24 h.
Under solvent-free conditions at room temperature for 24 h.
a
Isolated yields.
b
Under microwave irradiation at 120 °C for 1 min (40 W).

308
T. Bousquet et al. / Tetrahedron Letters 53 (2012) 306–308
A second set of experiments with benzyl and cyclohexyl isocy-
References and notes
anide is reported in Table 3. Once again, whatever the nature of the
aldehydes and carboxylic acids used, products 8a–j were obtained
in excellent yields (64–93%). When the reaction involving sub-
strates of entry 6 was performed in dichloromethane at room tem-
perature, product 8f was obtained in a 36% yield.7 The yield rises
up to 55% when the reaction is achieved under solvent free condi-
tions.7 The present system provided 8f in a 64% yield highlighting
the higher efficiency of our protocol.
In conclusion, a convenient and efficient Passerini multicompo-
nent reaction under solvent-free conditions at high temperature
was achieved with a broad range of reagents. Additionally, this
procedure is interesting as it shows that microwave heating is
not always necessary to reach high conversions and excellent
yields. In this work, whatever the reagent used, the yields were
all over 75%. Possible adjustments of the temperature would allow
the extension of scope of this protocol.
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11.
A
regular silicon oil bath was used for heating with
a thermocouple
temperature control.
12. General experiment procedure: the reaction vessel containing a mixture of
isocyanide (0.5 mmol, 1 equiv), aldehyde (0.55 mmol, 1.1 equiv) and carboxylic
acid (0.55 mmol, 1.1 equiv) is placed in a preheated oil bath at 180 °C for 4 min.
After being diluted in dichloromethane/MeOH (90:10), the organic layer was
washed twice with a saturated aqueous solution of NaHCO3, dried over MgSO4
and concentrated in vacuo. The crude product was dissolved in ethanol (3 mL)
before being poured into water. The resulting thick precipitate was collected
by filtration furnishing the Passerini product. As an example, product 7j was
obtained as an off-white solid in 90% yield (Table 2, entry 12); mp = 136–
138 °C; Purity >99% (measured by LC/MS); 1H NMR (300 MHz, DMSO) d 8.10 (d,
J = 8.7 Hz, 2H), 7.99 (br s, 1H, NH), 7.85 (d, J = 8.7 Hz, 2H), 7.74 (d, J = 6.9 Hz,
2H), 7.61 (d, J = 8.7 Hz, 2H), 7.51 (t, J = 7.8 Hz, 2H), 7.46–7.36 (m, 4H), 6.09 (s,
1H), 1.22 (s, 9H); 13C NMR (75 MHz, DMSO) d 167.50, 165.24, 145.44, 139.29,
136.73, 130.54, 129.59, 128.92, 128.64, 127.66, 127.48, 75.96, 50.94, 28.83; rt
(LCMS) = 3.19 min; (M+H+) = 388.
Acknowledgments
The authors thank Pr B. Deprez for fruitful discussions. We want
to thank institutions supporting our laboratories (Centre National
de la Recherche Scientifique and Université de Lille Nord de
France). This project was supported by the Conseil Régional
Nord-Pas de Calais, DRRT PRIM 2008-07 PRIM-SP.
Supplementary data
Supplementary data (typical reaction procedure, spectral data
and copies of NMR data of compounds 7j,k,g and 8a,d,h) associated
with this article can be found, in the online version, at doi:10.1016/
j.tetlet.2011.11.028.
13. (a) Kappe, C. O. Chem. Soc. Rev. 2008, 37, 1127; (b) Kappe, C. O. Angew. Chem.,
Int. Ed. 2004, 43, 6250; (c) Lidström, P.; Tierney, J.; Wathey, B.; Westman, J.
Tetrahedron 2001, 57, 9225.