Bronsted acidity of substrates influences the outcome of passerini three-component reactions

Article abstract of DOI:10.1021/jo900831n

(Chemical Equation Presented) Passerini three-component reactions of aldehydes, isocyanides, and strong carboxylic acids (i.e., pK_a < 2) yield R-acyloxycarboxamides and/or α-acylaminocarboxamides, the characteristic products of Ugi four-compone

Full text of DOI:10.1021/jo900831n

SCHEME 1. Proposed Mechanisms of the Passerini 3CR
and the Ugi 4CR
Brønsted Acidity of Substrates Influences the
Outcome of Passerini Three-Component
Reactions
Babajide O. Okandeji and Jason K. Sello*
Department of Chemistry, Brown UniVersity, 324 Brook
Street, ProVidence, Rhode Island 02912
jason_sello@brown.edu
ReceiVed April 23, 2009
TABLE 1. Dependence of r-Acylaminocarboxamide Formation on
the Carboxylic Acid Identitya
Passerini three-component reactions of aldehydes, isocya-
nides, and strong carboxylic acids (i.e., pKa < 2) yield
R-acyloxycarboxamides and/or R-acylaminocarboxamides,
the characteristic products of Ugi four-component reactions.
We propose that R-acylaminocarboxamide formation with
these substrates is a consequence of in situ Brønsted acid-
catalyzed reaction of the isocyanide and aldehyde to yield
an imine that participates in an Ugi-type reaction. The
apparent transfer of the isocyanide R-carbon to protic solvents
as a formyl group during imine formation is indicative of
new isocyanide reactivity.
Isocyanide-based multicomponent reactions are used exten-
sively in targeted oriented and diversity oriented organic
synthesis.1 These one-pot reactions are known for the ease with
which they are performed, their high yields, and their predictable
outcomes. The most widely known and best characterized of
the isocyanide-based multicomponent reactions are the Passerini
three-component reaction (Passerini 3CR) and the Ugi four-
component reaction (Ugi 4CR).1 In the Passerini 3CR, an
isocyanide, a carboxylic acid, and either an aldehyde or a ketone
react with one another to yield an R-acyloxycarboxamide
(Scheme 1).2 In contrast, an isocyanide, a carboxylic acid, an
amine, and either an aldehyde or a ketone react to yield an
R-acylaminocarboxamide in the Ugi 4CR (Scheme 1).3 Gener-
ally, the Passerini 3CR and Ugi 4CR have these characteristic
outcomes regardless of the identities of the substrates.1 Curi-
ously, we found that under typical Passerini conditions, car-
boxylic acids with a pKa < 2 reacted with aldehydes and
isocyanides to yield varying amounts of R-acylaminocarboxa-
mides, the characteristic products of the Ugi 4CR. Our observa-
tions are reminiscent of those reported by Dai and Li where
a All reactions were performed in methanol at 1.0 M for 12 h at room
temperature. The stoichiometry of aldehyde:isocyanide:acid was 1:2:1.
Products were isolated by flash chromatography. Yields were calculated
based on the carboxylic acid.
Lewis acids catalyze the formation of Ugi 4CR products from
Passerini 3CR substrates.4 We propose that this unanticipated
reaction outcome is a consequence of in situ Brønsted acid-
catalyzed generation of imines from isocyanides and aldehydes
via transfer of the isocyanide R-carbon to protic solvents as a
formyl group.
(1) Do¨mling, A. Chem. ReV. 2006, 106, 17.
(2) (a) Passerini, M.; Simone, L. Gazz. Chim. Ital. 1921, 51, 126. (b) Passerini,
M.; Ragni, G. Gazz. Chim. Ital. 1931, 61, 964.
(3) (a) Ugi, I.; Meyr, R.; Fetzer, U.; Steinbru¨ckner, Angew. Chem. 1959, 71,
386. (b) Ugi, I.; Rosendahl, F. K.; Bondesheim, F. Liebigs Ann. Chem. 1963,
666, 54.
(4) Dai, W.-M.; Li, H. Tetrahedron 2007, 63, 12866–12876.
10.1021/jo900831n CCC: $40.75  2009 American Chemical Society
Published on Web 05/28/2009
J. Org. Chem. 2009, 74, 5067–5070 5067

TABLE 2. Dependence of r-Acylaminocarboxamide Formation on
TABLE 3. Dependence of Product Distribution on the Isocyanide
Identitya
the Identity of Carbonyl Substratea
a All reactions were performed in methanol at 1.0 M for 12 h at room
temperature. The stoichiometry of aldehyde:isocyanide:acid was 1:2:1.
Products were isolated by flash chromatography. Yields were calculated
based on the carboxylic acid.
a All reactions were performed in methanol at 1.0 M for 12 h at room
temperature. The stoichiometry of aldehyde:isocyanide:acid was 1:2:1.
Products were isolated by flash chromatography. Yields were calculated
based on the carboxylic acid.
acid substrates with a pKa higher than 2 (Table 1, entries a-c).
Furthermore, Passerini 3CRs with propiolic acids and trifluo-
roacetic acid (carboxylic acids with a pKa < 2) as substrates
yielded R-acylaminocarboxamides (Table 1, entries d-f).
In an analysis of the correlation between the rate of the
Passerini 3CR and the pKa of the carboxylic acid substrate, we
found that reaction of phenyl propiolic acid (pKa ≈ 1.8),5
p-nitrobenzaldehyde, and benzyl isocyanide in methanol yielded
two distinct products in significant quantities. NMR spectro-
scopic and mass analyses of the minor product confirmed its
identity as the expected R-acyloxycarboxamide, the Passerini
3CR product. On the basis of several spectral features including
the presence of two sets of benzylic protons and its molecular
mass, we hypothesized that the major product of the reaction
was an R-acylaminocarboxamide. The identity of the major
product in this reaction was confirmed by its independent
synthesis via an Ugi 4CR employing phenyl propiolic acid,
p-nitrobenzaldehyde, benzyl amine, and benzyl isocyanide. The
1H NMR spectra of both products were superimposable and their
masses were identical.
The formation of an R-acylaminocarboxamide from substrates
of a Passerini 3CR is novel. Because R-acylaminocarboxamides
and R-acyloxylcarboxamides cannot interconvert under the
reaction conditions, we suspected that the products result from
distinct reaction pathways. We hypothesized that the result of
the low pKa of phenyl propiolic acid played a critical role in
R-acylaminocarboxamide formation. Its pKa is 2 to 3 orders of
magnitude lower than those of the carboxylic acids generally
used as substrates in Passerini 3CRs. Consistent with this
hypothesis was our observation that only R-acyloxycarboxam-
ides were isolated from Passerini 3CRs that used carboxylic
To gain further insights into R-acylaminocarboxamide forma-
tion under Passerini 3CR conditions, we reacted phenyl propiolic
acid with a variety of isocyanides and carbonyl compounds.
Significant quantities of R-acylaminocarboxamides were isolated
from reactions of phenyl propiolic acid, benzyl isocyanide, and
various aldehydes or a ketone (Table 2). The yields of
R-acylaminocarboxamides were notably higher in reactions with
aromatic and conjugated aldehydes than those with aliphatic
aldehydes. These observation suggest that aliphatic aldehydes
are better substrates in the competing Passerini 3CR than
aromatic aldehydes (Table 2, entries c-f). In the reactions of
phenyl propiolic acid and p-nitrobenzaldehyde with different
isocyanides, there was a correlation between the degree of
substitution of the isocyanide and the product distribution (Table
3). Specifically, the proportion of R-acylaminocarboxamide in
the products decreased as a function of the substitution of the
isocyanide. For instance, the R-acylaminocarboxamide was
isolated in 68% yield from a reaction with benzyl isocyanide
(Table 3, entry a), while the yields of the R-acyloxycarboxa-
mide and the R-acylaminocarboxamide from the reaction with
tert-butyl isocyanide were 29% and 10%, respectively (Table
3, entry d).6
(6) Substituents are known to influence the reactivity of isocyanides via sterics
and/or inductive effects. See: Portal, C.; Launay, D.; Merritt, A.; Bradley, M.
J. Comb. Chem. 2005, 7, 554.
(5) CRC Handbook of Chemistry and Physics, 85th ed.; Lide, D. R. Editor-
in-Chief; CRC Press: Boca Raton, FL, 2004-2005.
5068 J. Org. Chem. Vol. 74, No. 14, 2009

SCHEME 2. Proposed Mechanism for the Brønsted Acid-Catalyzed Formation of an Imine from an Isocyanide
TABLE 4. Solvent Dependence of r-Acylaminocarboxamide
Information). The most likely source of the formyl group is the
isocyanide R-carbon.
Formationa
The formation of an R-acylaminocarboxamide and a formate
ester from substrates of a Passerini 3CR is indicative of an
atypical reaction of isocyanides. There are two main possibilities.
One possibility is hydrative conversion of an isocyanide into a
formamide, followed by formyl transfer to an alcohol yielding
a formyl ester and an amine that participates in an Ugi 4CR.
We rule out this possibility because hydration of isocyanides
typically requires aqueous mineral acids and the Passerini 3CRs
with phenyl propiolic acid yielding R-acylaminocarboxamides
were performed in anhydrous solvents under inert atmosphere.
A mechanism involving hydrative consumption of isocyanides
is further ruled out because benzyl formamide is absolutely
stable in the presence of alcohols and phenyl propiolic acid.8
In the alternative possibility, a C-protonated isocyanide and the
aldehyde undergo a formal [2+2] cycloaddition followed by
cycloreversion and alcoholysis yielding an imine and a formate
ester (Scheme 2). The imine intermediate subsequently reacts
with a molecule of isocyanide and phenyl propiolic acid to yield
an R-acylaminocarboxamide, as in the Ugi 4CR (Schemes 1
and 2). There are many reports of cycloadditions involving
isocyanides in the heterocycle literature,9 but this is the first
proposal of a [2+2] cycloaddition involving an isocyanide and
an aldehyde. A [2+2] cycloaddition between an isocyanide and
a carboxylic acid was considered by Danishefsky, Houk, and
co-workers to explain the formation of N-formyl amides.10,11
The proposed mechanism is an alternative to that invoked by
Dai and Li (i.e., conversion of the nitrilium intermediate into
an aziridine that rearranges to yield an imine) to explain a related
observation.4
yields (%)
entry
solvent
7
8
a
b
c
d
e
CH2Cl2
CHCl3
CH3CN
MeOH
76
75
69
24
46
0
0
0
68
34
CH2Cl2 + 2 equiv MeOH
a All reactions were performed in methanol at 1.0 M for 12 h at room
temperature. The stoichiometry of aldehyde:isocyanide:acid was 1:2:1.
Products were isolated by flash chromatography. Yields were calculated
based on the carboxylic acid.
Because the rate of the Passerini 3CR is reported to differ in
protic and aprotic solvents,7 the outcome of the reaction of
phenyl propiolic acid, p-nitrobenzaldehyde, and benzyl isocya-
nide was assessed in a variety of solvents. Interestingly, the
reactions in aprotic, organic solvents exclusively yielded the
canonical products whereas reactions in protic solvents yielded
mixtures of R-acyloxycarboxamides and R-acylaminocarboxa-
mides (Table 4, entries a-c). The inclusion of stoichiometric
quantities of methanol in the reaction of phenyl propiolic acid,
p-nitrobenzaldehyde, and benzyl isocyanide in CH2Cl2 resulted
in the formation of a significant amount of R-acylaminocar-
boxamide. These observations suggested that a nucleophilic
alcohol participates in the reaction pathway that yields R-acy-
laminocarboxamides. Indeed, p-nitrobenzyl formate and R-acy-
laminocarboxamide were formed in a 1.2:1 molar ratio in the
reaction of phenylpropiolic acid, p-nitrobenzaldehyde, benzyl
isocyanide, and p-nitrobenzyl alcohol (see the Supporting
In conclusion, the inclusion of carboxylic acids with low pKa
values as substrates in Passerini three-component reactions
results in the formation of Ugi four-component reaction products
through a peculiar transformation of isocyanides. This trans-
formation is another addition to a growing list of new reactions
of isocyanides.4,10-12
(8) Benzyl formamide and phenyl propiolic acid were stirred in methanol
overnight. GC-MS of the solution showed no significant degradation of benzyl
formamide. Only benzyl formamide and phenyl propiolic acid were detected.
(9) Marcaccini, S.; Torroba, T. Org. Prep. Proced. Int. 1993, 25, 141.
(10) Li, X.; Danishefsky, S. J. J. Am. Chem. Soc. 2008, 108, 5446.
(11) Jones, G. O.; Li, X.; Hayden, A. E.; Houk, K. N.; Danishefsky, S. J.
Org. Lett. 2008, 10, 4093.
(12) Shaabani, A.; Soleimani, E.; Rezayan, A. H. Tetrahedron Lett. 2007,
48, 2185.
(7) Ugi, I.; Meyr, R. Angew. Chem., Int. Ed. Engl. 1962, 1, 8.
J. Org. Chem. Vol. 74, No. 14, 2009 5069

136.1, 128.9, 128.1, 127.9, 127.8, 123.9, 116.2, 74.4, 43.5, 33.3, 28.6;
Experimental Section
LRMS calcd for C20H20N2O5 368.38, obsd 391.5 [M + Na]+.
General Procedure for Passerini 3CRs. The aldehyde (0.125
mmol, 1 equiv), isocyanide (0.25 mmol, 2 equiv), and carboxylic
acid (0.125 mmol, 1 equiv) were added to 125 µL of the solvent in
a half dram glass vial and stirred overnight. After removal of solvent
in vacuo, the reaction products were purified by flash column
chromatography. In reactions where an alcohol was included, 2
equiv of the alcohol was added along with the starting materials at
the start of the reaction.
Acknowledgment. We thank Dr. Tun-Li Shen for mass
spectrometric analyses. This work was generously supported
by funds from Brown University and a 2009 Salomon Award
sponsored by the Office of Vice President of Research at
Brown.
Supporting Information Available: Detailed experimental
procedures, compound characterization data, spectra, and
expanded discussion of peripheral findings. This material is
available free of charge via the Internet at http://pubs.acs.
org.
1
Isolation and characterization of compound 1a (Table 1): H
NMR (400 MHz; CDCl3) δ 8.23 (d, J ) 8.8 Hz, 2H), 7.65 (d, J ) 8.8
Hz, 2H), 7.38-7.32 (m, 3H), 7.25 (d, J ) 5 Hz, 2H), 6.71 (br, 1H),
6.23 (s, 1H), 5.83-5.74 (m, 1H), 5.06-5.95 (m, 2H), 4.48 (d, J )
5.8 Hz, 2H), 2.60 (td, J ) 7.26, 2.76 Hz, 2H), 2.42 (q, J ) 6.9 Hz,
2H); 13C NMR (100 MHz; CDCl3) δ 170.9, 167.0, 148.1, 142.5, 137.3,
JO900831N
5070 J. Org. Chem. Vol. 74, No. 14, 2009