Solvent-free passerini reactions

Article abstract of DOI:10.1080/00397910701863608

The influence of the substrate structure and concentration on the yield of the Passerini reaction was studied. A new, solvent-free methodology for a convenient preparation of α-acyloxyamides 4 was established and compared to the classical methodology. A h

Full text of DOI:10.1080/00397910701863608

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Solvent‐Free Passerini Reactions
Dominik Koszelewski a , Wiktor Szymanski a , Joanna Krysiak a & Ryszard
Ostaszewski a
a Institute of Organic Chemistry, Polish Academy of Sciences , Kasprzaka
44/52, 01‐224, Warsaw, Poland
Published online: 12 Mar 2008.
To cite this article: Dominik Koszelewski , Wiktor Szymanski , Joanna Krysiak & Ryszard Ostaszewski
(2008) Solvent‐Free Passerini Reactions, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 38:7, 1120-1127, DOI: 10.1080/00397910701863608
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Synthetic Communicationsw, 38: 1120–1127, 2008
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910701863608
Solvent-Free Passerini Reactions
Dominik Koszelewski, Wiktor Szymanski, Joanna Krysiak,
and Ryszard Ostaszewski
Institute of Organic Chemistry, Polish Academy of Sciences, Warsaw,
Poland
Abstract: The influence of the substrate structure and concentration on the yield of the
Passerini reaction was studied. A new, solvent-free methodology for a convenient prep-
aration of a-acyloxyamides 4 was established and compared to the classical method-
ology. A higher reaction yield was obtained in shorter time, especially in the case of
aromatic aldehydes.
Keywords: a-acyloxyamides, aromatic aldehydes, Passerini reaction, solvent free
Multicomponent reactions (MCRs) are synthetically useful organic transform-
ations in which three or more different starting materials react together to form
a final product in a one-pot procedure.[1–4] For that reason, the optimization of
MCRs is one of the crucial factors in drug-design development.
One of the most widely used MCRs is the Passerini three-component con-
densation, in which an aldehyde 1, a carboxylic acid 2, and an isocyanide 3
react to form an a-acyloxyamide 4 (Scheme 1).[5]
The Passerini reaction is simple, performed in one pot, gives products in
high yields, and has a 100% atom economy, which nearly satisfies the defi-
nition of an ideal synthesis, as given by P. A. Wender et al.[6] The common
problems in the Passerini reactions are associated with purification of the
product and low reaction yields when aromatic aldehydes are used.[7–9]
Received in the U.K. May 30, 2007
Address correspondence to Ryszard Ostaszewski, Institute of Organic Chemistry,
Polish Academy of Sciences, Kasprzaka 44/52, 01-224 Warsaw, Poland. E-mail:
rysza@icho.edu.pl
1120

Solvent-Free Passerini Reactions
1121
Scheme 1. Passerini reaction.
Several solutions for the latter problem were established: application of water
as a reaction solvent, which makes purification easier, or use of high pressure,
which improves the outcome of the sterically congested Passerini
reactions.[10,11] Sometimes, the use of metal catalysts gives good results.[12]
During our studies, we were interested in an efficient synthesis of the
a-acyloxyamide 4a, derived from benzaldehyde (Scheme 2). This
compound is an important building block in the synthesis of biodegradable
polymers[13,14] and the drugs related to Parkinson’s Disease.[15]
An initial experiment was performed under classic conditions in the
methylene chloride solution, and the desired product was obtained after
24 h in 14% yield. A two-fold increase of the substrate concentrations
doubled the yield. This result encouraged us to study systematically the
influence of the substrate concentrations on the yield of the Passerini reaction.
The results depicted in Fig. 1 show that there is a linear correlation
between the substrate concentrations and the yield of reactions studied. It is
important to note that the product 4a precipitates from the reaction mixture
if the reaction is performed at a concentration of substrates greater than
2.5 mol/L. A simple crystallization of the obtained product yields the analyti-
cally pure compound. The concentration of 3.0 M is the maximum attainable
if a solvent is used.
In the next step, the same reaction was performed without any solvent.
The product was obtained in 86% yield after crystallization, which greatly
improved the efficiency of this synthesis. The same reaction performed in a
DCM solution under the classical conditions led to the desired product in
22% yield (Table 1, entry 1). The concentration of the substrates was
1 mol/L.
Scheme 2. Model reaction.

1122
D. Koszelewski et al.
Figure 1. Influence of the substrate concentrations on the yield of the model Passerini
reaction.
These results encouraged us to perform a systematic study in which the
yields of the classical and solvent-free approaches were compared (see
Table 1).
The solvent-free procedure resulted in a considerable increase of yield in
the case of both aromatic and aliphatic acids (entries 1–3, Table 1). When an
aromatic isocyanide was used for the reaction (entry 4, Table 1), an increase of
the yield in the solvent-free procedure was also observed, compared to the
classical conditions (55% vs. 36%). On the other hand, the products derived
Table 1. Influence of the substrate structures and the reaction condition on the yield
of the Passerini reaction
Yield (%)
(solvent- Yield (%)
Entry Compound
R1
R2
R3
free)
(DCM)
1
2
4a
4b
4c
4d
4e
4f
Ph
Ph
CH3
CH2Br
Ph
CH2CO2Et
CH2CO2Et
CH2CO2Et
PhCH2
86
56
82
55
89
57
53
65
0
22
30
29
36
90
88
96
89
0
3
Ph
Ph
4
CH3
CH3
CH3
CH3
CH3
5
PhCH2
C2H5
CH2CO2Et
CH2CO2Et
CH2CO2Et
CH2CO2Et
6
7
4g
4h
4i
(CH3)2CHCH2
C7H15
8
9
4-MeO-Ph
4-MeO-Ph
4-NO2-Ph
4-F-Ph
4-F-Ph
4-MeO-Ph CH2CO2Et
4-NO2-Ph CH2CO2Et
4-NO2-Ph CH2CO2Et
4-NO2-Ph CH2CO2Et
4-MeO-Ph CH2CO2Et
10
11
12
13
4j
23
44
55
20
11
42
12
3
4k
4l
4m

Solvent-Free Passerini Reactions
1123
from aliphatic aldehydes were obtained in good yields when the reaction was
performed in dichloromethane (88–90%, entries 6–8, Table 1), although the
purification procedure was much more difficult. Regardless of the protocol
used, the reaction between p-anisaldehyde, p-methoxybenzoic acid, and iso-
cyanoacetic acid ethyl ester failed (entry 9, Table 1).
For aromatic substrates, the influence of the functional group present on
phenyl rings was investigated. The highest yield enhancement was obtained
when one of these substrates bears an electron-withdrawing group, while
the other had an electron-donating group (entries 10 and 13, Table 1).
When the electron densities of the aldehyde and the acid were altered in the
same direction, no yield enhancement was observed (entry 11, Table 1),
although the product purification was very easy in the solvent-free procedure.
CONCLUSIONS
The Passerini reaction, which is widely used in the synthesis of peptidomi-
metics, can be efficiently carried out under solvent-free conditions. Even in
the case of aliphatic aldehydes, for which the reaction proceeds less efficiently,
it is an interesting alternative to the classical approach, simplifying the
isolation and purification of the product. According to the best of our
knowledge, this is the first example of a solvent-free approach to the
Passerini reaction, which is a standard of green chemistry and a characteristic
of an ideal synthesis.
EXPERIMENTAL
General Solvent Procedure
Aldehyde 1 (3.0 mmol) and isocyanide 3 (3.3 mmol) were added to the
solution of a carboxylic acid 2 (3.3 mmol) in methylene chloride (3 mL) at
room temperature. The reaction mixture was stirred at ambient temperature
for 24 h and then concentrated in vacuo. The crude product was purified by
silica-gel flash chromatography using hexane/ethyl octane 6:4 as an eluent
to afford the corresponding product 4.
General Solvent-Free Procedure
Isocyanide 3 (3.3 mmol) was added to the suspension of the carboxylic acid 2
(3.3 mmol) and the aldehyde 1 (3.0 mmol) at room temperature. The reaction
mixture was stirred at ambient temperature for 24 h and then concentrated in
vacuo. The crude product was purified by crystallization from ethyl octane/
hexane to afford the corresponding product 4.

1124
D. Koszelewski et al.
Data
Compound 4a: mp 95–97 8C. 1H NMR (200 MHz, CDCl3): d ¼ 1.28
(t, J ¼ 7.1 Hz, 3H), 2.19 (s, 3H), 4.06 (d, J ¼ 5.1 Hz, 2H), 4.22
(q, J ¼ 7.1 Hz, 2H), 6.13 (s, 1H), 6.72 (s, 1H), 7.33–7.497 (m, 5H). 13C
NMR (50 MHz, CDCl3): d ¼ 14.7, 21.6, 41.8, 62.3, 75.9, 128.0, 129.3,
129.4, 129.6, 135.8, 168.9, 169.6, 170.0. Anal. calcd. for C14H17NO5: C,
60.21; H, 6.14; N, 5.01. Found: C, 60.14; H, 6.22; N, 5.12, HRMS (ESI):
m/z calcd. for C14H17NO5Na [M þ Na]þ: 302.1004, Found: 302.0999.
Compound 4b: mp 94–95 8C. 1H NMR (200 MHz, CDCl3): d ¼ 1.28
(t, J ¼ 7.1 Hz, 3H), 3.95 (s, 2H), 4.06 (dd, J ¼ 3.0 Hz, J ¼ 5.7 Hz, 2H),
4.21 (q, J ¼ 7.1 Hz, 2H), 6.17 (s, 1H), 6.80 (s, 1H), 7.36–7.48 (m, 5H). 13C
NMR (50 MHz, CDCl3): d ¼ 14.7, 25.9, 41.9, 62.3, 76.7, 127.9, 129.1,
129.7, 134.9, 165.6, 167.9, 169.6. Anal. calcd. for C14H16BrNO5: C, 46.95;
H, 4.50; N, 3.91. Found: C, 46.94; H, 4.62; N, 3.78. HRMS (ESI): m/z
calcd, for C14H16BrNO5Na [M þ Na]þ: 380.0109, Found: 380.0104.
Compound 4c: mp 101–103 8C. 1H NMR (200 MHz, CDCl3): d ¼ 1.26
(t, J ¼ 7.1 Hz, 3H), 4.08 (dd, J ¼ 5.3 Hz; J ¼ 7.1 Hz, 2H), 4.21
(q, J ¼ 7.1 Hz, 2H), 6.39 (s, 1H), 6.80 (s, 1H), 7.25–8.14 (m, 10H). 13C
NMR (50 MHz, CDCl3): d ¼ 14.4, 41.6, 62.0, 76.1, 127.8, 128.9, 129.1,
129.4, 130.1, 134.0, 135.6, 165.3, 168.7, 169.7. Anal. calcd. for
C19H19NO5: C, 66.85; H, 5.61; N, 4.10. Found: C, 66.61; H, 5.82; N, 4.11.
HRMS (ESI): m/z calcd. for C19H19NO5Na [M þ Na]þ: 364.1160. Found:
364.1155.
Compound 4d: mp 88–90 8C. 1H NMR (200 MHz, CDCl3): d ¼ 2.13 (s, 3H),
4.43 (d, J ¼ 5.6 Hz, 2H), 6.09 (s, 1H), 6.55 (s, 1H), 7.17–7.44 (m, 10H). 13
C
NMR (50 MHz, CDCl3): d ¼ 21.6, 43.9, 76.2, 127.9, 128.1, 129.2, 129.3,
129.5, 136.0, 138.2, 168.8, 169.7. Anal. calcd. for C17H17NO3: C, 72.07; H,
6.05; N, 4.95. Found: C, 72.07; H, 6.16; N, 4.91. HRMS (ESI): m/z calcd.
for C17H17NO3 [M þ Na]þ: 306.1106, Found: 306.1101.
1
Compound 4e: H NMR (200 MHz, CDCl3): d ¼ 1.28 (t, J ¼ 7.1 Hz, 3H),
2.08 (s, 3H), 3.04–3.34 (m, 2H), 3.99 (dd, J ¼ 3.6 Hz, J ¼ 5.1 Hz, 2H),
4.21 (q, J ¼ 7.1 Hz, 2H), 5.42 (dd, J ¼ 4.7 Hz, J ¼ 7.5 Hz, 1H), 6.48
(s, 1H), 7.13–7.35 (m, 5H). 13C NMR (50 MHz, CDCl3): d ¼ 14.7, 21.4,
38.3, 41.6, 62.2, 74.7, 127.5, 128.9, 129.9, 130.0, 136.4, 169.7, 169.9,
171.1. Anal. calcd. for C15H19NO5: C, 61.42; H, 6.53; N, 4.78. Found: C,
61.62; H, 6.64; N, 4.81. HRMS (ESI): m/z calcd. for C15H19NO5Na
[M þ Na]þ: 316.1161. Found: 316.1155.
1
Compound 4f: H NMR (200 MHz, CDCl3): d ¼ 0.89 (t, J ¼ 7.4 Hz, 3H),
1.23 (t, J ¼ 7.1 Hz, 3H), 1.84–2.08 (m, 2H), 2.12 (s, 3H), 3.98 (dd,
J ¼ 2.5 Hz, J ¼ 5.1 Hz, 2H), 4.16 (q, J ¼ 7.1 Hz, 2H), 5.07–5.13 (m, 1H),
6.59 (s, 1H). 13C NMR (50 MHz, CDCl3): d ¼ 8.9, 14.1, 20.9, 25.0, 40.9,

Solvent-Free Passerini Reactions
1125
61.6, 74.7, 169.5, 169.5, 169.8. Anal. calcd. for C10H17NO5: C, 51.94; H, 7.41;
N, 6.06. Found: C, 51.82; H, 7.46; N, 5.91, HRMS (ESI): m/z calcd. for
C10H17NO5Na [M þ Na]þ: 254.1004. Found: 254.0999.
Compound 4g: mp 44–46 8C. 1H NMR (200 MHz, CDCl3): d ¼ 0.94
(d, J ¼ 3.9 Hz, 6H), 1.29 (t, J ¼ 7.1 Hz, 3H), 1.71–1.98 (m, 3H), 2.16
(s, 3H), 4.01–4.05 (m, 2H), 4.22 (q, J ¼ 7.1 Hz, 2H), 5.25–5.52 (m, 1H),
6.71 (s, 1H). 13C NMR (50 MHz, CDCl3): d ¼ 14.6, 17.4, 19.2, 31.2, 41.5,
62.1, 78.4, 170.1, 170.2, 176.0. Anal. calcd. for C12H21NO5: C, 55.58; H,
8.16; N, 5.40. Found: C, 55.57; H, 8.34; N, 5.38. HRMS (ESI): m/z calcd.
for C12H21NO5Na [M þ Na]þ: 282.1317. Found: 282.1312.
1
Compound 4h: H NMR (200 MHz, CDCl3): d ¼ 0.87 (t, J ¼ 7.0 Hz, 3H),
1.25–1.32 (m, 15H), 1.85–2.05 (m, 2H), 2.17 (s, 3H), 4.01–4.07 (m, 2H),
4.22 (q, J ¼ 7.1 Hz, 2H), 5.20–5.37 (m, 1H), 6.61 (s, 1H). 13C NMR
(50 MHz, CDCl3): d ¼ 14.6, 14.6, 21.4, 23.1, 25.2, 29.5, 29.7, 32.2, 32.4,
41.5, 62.1, 74.4, 170.0, 170.1, 170.6. Anal. calcd. for C15H27NO5: C, 59.78;
H, 9.03; N, 4.65. Found: C, 59.61; H, 8.95; N, 4.63. HRMS (ESI): m/z
calcd. for C15H27NO5Na [M þ Na]þ: 324.1787. Found: 324.1798.
Compound 4i: The substrates were recovered instead.
1
Compound 4j: H NMR (200 MHz, CDCl3): d ¼ 1.28 (t, J ¼ 7.2 Hz, 3H),
3.81 (s, 3H), 4.08 (dd, J ¼ 3.6 Hz, J ¼ 4.9 Hz, 2H), 4.22 (q, J ¼ 7.1 Hz,
2H), 6.32 (s, 1H), 6.54 (s, 1H), 6.94 (d, J ¼ 8.8 Hz, 2H), 7.49
(d, J ¼ 8.8 Hz, 2H), 8.15–8.45 (m, 4H). 13C NMR (200 MHz, CDCl3):
d ¼ 14.5, 41.7, 55.7, 62.1, 76.6, 114.7, 123.9, 126.8, 129.7, 131.2, 163.6,
168.3, 169.7. Anal. calcd. for C20H20N2O8: C, 57.69; H, 4.84; N, 6.73.
Found: C, 57.72; H, 4.71; N, 6.73. HRMS (ESI): m/z calcd. for
C20H20N2O8Na [M þ Na]þ 439.1117. Found: 439.1126.
Compound 4k: 1H NMR (200 MHz, CDCl3 þ DMSO): d ¼ 1.16
(t, J ¼ 7.0 Hz, 3H), 3.96–4.02 (m, 2H), 4.16 (q, J ¼ 7.4 Hz, 2H), 6.51
(s, 1H), 7.9 (d, J ¼ 8.8 Hz, 2H), 8.26 (d, J ¼ 8.8 Hz, 2H), 8.30–8.38
(m, 4H). 13C NMR (200 MHz, CDCl3 þ DMSO): d ¼ 13.8, 60.9, 65.3,
74.8, 123.2, 123.3, 128.2, 130.8, 134.0, 141.7, 147.6, 150.3, 162.9, 167.0,
168.8. Anal. calcd. for C19H17N3O9: C, 52.90; H, 3.97; N, 9.74. Found: C,
53.05; H, 4.16; N, 9.53. HRMS (ESI): m/z calcd. for C19H17N3O9Na
[M þ Na]þ: 454.0862. Found: 454.0879.
1
Compound 4l: H NMR (200 MHz, CDCl3): d ¼ 1.28 (t, J ¼ 7.2 Hz, 3H),
4.09 (dd, J ¼ 4.0 Hz, J ¼ 4.9 Hz, 2H), 4.22 (q, J ¼ 7.1 Hz, 2H), 6.35
(s, 1H), 6.72 (s, 1H), 7.06–7.15 (m, 2H), 7.50–7.63 (m, 2H), 8.30–8.36
(m, 4H). 13C NMR (200 MHz, CDCl3): d ¼ 14.5, 41.7, 62.2, 76.1, 116.1,
116.6, 124.0, 130.0, 130.1, 130.7, 130.7, 131.2, 134.6, 151.1, 163.4, 167.9,
169.6. Anal. calcd. for C19H17FN2O7: C, 56.44; H, 4.24; N, 6.93. Found: C,
55.99; H, 4.56; N, 6.54. HRMS (ESI): m/z calcd. for C19H17FN2O7Na
[M þ Na]þ: 427.0917. Found: 427.0906.

1126
D. Koszelewski et al.
1
Compound 4 m: H NMR (200 MHz, CDCl3): d ¼ 1.28 (t, J ¼ 7.1 Hz, 3H),
3.87 (s, 3H), 4.09 (dd, J ¼ 5.2 Hz, J ¼ 11.7 Hz, 2H), 4.22 (q, J ¼ 7.1 Hz,
2H), 6.35 (s, 1H), 6.85–7.20 (m, 5H), 7.50–7.63 (m, 2H), 8.20–8.40
(m, 2H). 13C NMR (200 MHz, CDCl3): d ¼ 14.5, 41.6, 55.8, 62.0, 75.0,
114.2, 115.8, 116.2, 121.4, 129.6, 129.7, 129.8, 129.9, 131.8, 132.2, 132.6,
164.2, 168.8, 169.9. Anal. calcd. for C20H20FNO6: C, 61.69; H, 5.18; N,
3.60. Found: C, 61.40; H, 5.17; N, 3.74. HRMS (ESI): m/z calcd. for
C20H20FNO6Na [M þ Na]þ: 412.1172. Found: 412.1181.
ACKNOWLEDGMENT
This work was supported by the grants from the Polish State Committee for
Scientific Research, No. PBZ-KBN-126/T09/07, PBZ-MIN-007/P04/2003.
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