Isocyanides and arylacetic acids: synthesis and reactivity of 3-Aryl-2-Acyloxyacrylamides, an example of serendipity-oriented synthesis

Article abstract of DOI:10.1021/ol901512c

Research progress Is often promoted by unexpected results that open the way to new scenarios. In this communication, an unprecedented condensation of arylacetlc acids and isocyanides and the unusual base-mediated rearrangement of the resulting products to

Full text of DOI:10.1021/ol901512c

ORGANIC
LETTERS
2009
Vol. 11, No. 18
4068-4071
Isocyanides and Arylacetic Acids:
Synthesis and Reactivity of
3-Aryl-2-acyloxyacrylamides, an Example
of Serendipity-Oriented Synthesis
Andrea Basso,*,† Luca Banfi,† Andrea Galatini,† Giuseppe Guanti,†
Federico Rastrelli,‡ and Renata Riva†
Dipartimento di Chimica e Chimica Industriale, UniVersita` degli Studi di GenoVa,
GenoVa, Italy, and Dipartimento di Scienze Chimiche, UniVersita` degli Studi di
PadoVa, PadoVa, Italy
andreab@chimica.unige.it
Received July 2, 2009
ABSTRACT
Research progress is often promoted by unexpected results that open the way to new scenarios. In this communication, an unprecedented
condensation of arylacetic acids and isocyanides and the unusual base-mediated rearrangement of the resulting products to give two novel
classes of polysubstituted pyrrolones and pyrrolidinediones are reported.
Isocyanide-based reactions are among the most popular
multicomponent condensations. Such reactions include the
famous Passerini and Ugi ones, both involving a nucleophile
(a carboxylic acid) and an electrophile (an aldehyde or imine,
respectively) reacting with the divalent carbon of the
isocyanide.1
Our research group has been involved for several years
in searching for variations of such multicomponent reactions
leading to molecular scaffolds different from the classic
depsipeptides and peptides.2 In one of our research programs,
we attempted to perform a Passerini reaction with 1H-
pyrrole-2-carboxaldehyde as the carbonyl component. The
reaction was performed with various carboxylic acids and
isocyanides under different conditions but never gave the
desired product, probably confirming the vinylogous amide
character of this aldehyde; however, when the reaction was
conducted with phenylacetic acid and cyclohexyl isocya-
nide under microwave heating (100 °C for 30 min), a
product 1a that did not incorporate the carbonyl derivative
was isolated in high yield. Intrigued by this outcome, we
performed the reaction under the same conditions but
without the aldehyde, and NMR and GC-MS analysis of
the crude showed formation of equimolar amounts of 1a
and N-cyclohexyl formamide. The formula of 1a corre-
sponds to the inclusion of two molecules of phenylacetic
acid and one of isocyanide with the loss of one molecule
of water which is included in the second equivalent of
(2) See, for example: (a) Basso, A.; Banfi, L.; Guanti, G.; Riva, R. Org.
Biomol. Chem. 2009, 7, 253–258. (b) Banfi, L.; Basso, A.; Guanti, G.;
Kielland, N.; Repetto, C.; Riva, R. J. Org. Chem. 2007, 72, 2151–2160.
(c) Basso, A.; Banfi, L.; Riva, R.; Guanti, G. Tetrahedron 2006, 62, 8830–
8837. Basso, A.; Banfi, L.; Guanti, G.; Riva, R.; Riu, A. Tetrahedron Lett.
2004, 45, 6109–6111.
† Universita` degli Studi di Genova.
‡ Universita` degli Studi di Padova.
(1) For reviews, see, for example: (a) Bienayme´, H.; Hulme, C.; Oddon,
G.; Schmitt, P. Chem.sEur. J. 2000, 6, 3321–3329. (b) Do¨mling, A. Chem.
ReV. 2006, 106, 17–89.
10.1021/ol901512c CCC: $40.75
Published on Web 08/25/2009
 2009 American Chemical Society

the isocyanide, and its structure was the captodative olefine
not evolve via a 1,3-acyl shift to give b as described by
Danishefsky but reacts with an additional molecule of isocya-
nide to form c and anionic formamide d (Scheme 2), neutralized
by the excess acid, in analogy with the Nef reaction11 where
an acyl chloride undergoes an R-addition on an isocyanide.
Formation of intermediate c in our case should be favored by
the equilibrium with tautomer e, stabilized by extensive
conjugation with the aromatic ring; formation of e has already
been described by Robertson in the reaction of a molecule of
ketene with one of isocyanide. Compound e then reacts with
another molecule of phenylacetate to give f and finally 1 via a
sort of Mumm rearrangement. According to this hypothesis,
the different outcome of arylacetic acids compared to other
carboxylic compounds should be related to the higher tendency
to give intermediate e. It is worth noting that other acetic acid
derivatives, lacking a conjugating substituent, failed to give this
reaction, behaving mostly as described by Danishefsky. In
principle, other mechanisms could not be ruled out, for example,
the direct formation of a ketene from a with a E1cb elimination
and its subsequent reaction with a molecule of acid and one of
isocyanide, in a way similar to that reported by Ugi, although
the absence of a base catalysis makes this hypothesis less
likely.12 Also, formation of a symmetrical anhydride13 from a
and an additional molecule of acid could be in principle possible,
and indeed when we investigated the reaction of phenylacetic
anhydride with 0.5 equiv of cyclohexyl isocyanide compound
1 was isolated (in this case, without formation of the formamide)
although in lower yields.
1a (Scheme 1).3,4
Scheme 1
.
Reaction between Phenylacetic Acid and
Cyclohexylisocyanide
Danishefsky recently reported the sequential concerted
rearrangement mechanism occurring in the coupling between
isocyanides and carboxylic acids, leading to N-formyla-
mides.5 The different outcome observed when the carboxylic
derivative is a phenylacetic acid prompted us to disclose our
results.
Compounds with general formula 1 (Figure 1) are very
rarely reported in the literature, if we exclude their synthesis
starting from R-acetoxycinnamoyl chloride6 and a report by
I. Ugi7 where compound 3 is obtained by treatment of
compound 2 with concentrated HCl. Compound 2, on the
other hand, is obtained by reaction of an isocyanide with 2
equiv of diphenylketene. The reactivity of isocyanides with
ketenes, investigated for the first time by Ugi8 and reported
also by Moore9 and Robertson,10 gave us some hints about
the mechanism of this novel reaction.
We have also investigated the influence of the relative ratio
of reagents, the temperature, and the solvent, as outlined in Table
1. These experiments clearly indicated that the stoichiometry
of the reaction involves 2 equiv of acid and 2 equiv of
isocyanide to give 1 equiv of 1 and 1 equiv of formamide. It is
worth noting that under the same conditions described by
Danishefsky (entry d) the reaction was complete after 1 min,
while formation of N-formylamides usually required 30 min.
Moreover, the reaction proceeded well also with conventional
heating (entry g), although being much slower.
Table 1. Analysis of Different Reaction Conditions
Figure 1. Early report by I. Ugi.
isocyanide/
acid ratio
entry
temp (°C)
solvent
yielda
a
b
c
d
e
f
1:1
1:2
2:1
1:1
1:1
1:1
1:1
100 (30 min)
100 (30 min)
100 (30 min)
150 (1 min)
100 (30 min)
100 (30 min)
reflux, o/nb
DCM
DCM
DCM
DCM
THF
85
45
78
94
75
50
84
In our hypothesis, phenylacetic acid and isocyanide react to
give R-addition adduct a; however, this mixed anhydride does
(3) Several years ago, in our group, adducts with a similar formula had
been detected after reaction of phenylacetic acid with isocyanides but were
not examined with much attention, and a wrong cyclic structure was assigned
t-BuOH
DCE
at that time and reported in ref 4 at page 14
(4) Banfi, L.; Riva, R. Org. React. 2005, 65, 1
.
g
.
a Based on the amount of acid. b Conventional heating in an oil bath.
(5) (a) Li, X. C.; Danishefsky, S. J. J. Am. Chem. Soc. 2008, 130, 5446–
5448. (b) Jones, G. O.; Li, X. C.; Hayden, A. E.; Houk, K. N.; Danishefsky,
S. J. Org. Lett. 2008, 10, 4093–4096. (c) Li, X. C.; Yuan, Y.; Berkowitz,
W. F.; Todaro, L. J.; Danishefsky, S. J J. Am. Chem. Soc. 2008, 130, 13222–
13224. (d) Li, X. C.; Yuan, Y.; Kan, C.; Danishefsky, S. J. J. Am. Chem.
Soc. 2008, 130, 13225–13227.
We subsequently explored the reactivity of various isocya-
nides and arylacetic acid derivatives under the standard condi-
(6) Chigira, Y.; Masaki, M.; Ota, M. Bull. Chem. Soc. Jpn. 1969, 42,
228–232.
(7) El Gomati, T.; Firl, J.; Ugi, I. Chem. Ber. 1977, 110, 1603–1605.
(8) Ugi, I.; Rosendahl, K. Chem. Ber. 1961, 94, 2233–2235.
(9) Moore, H. W.; Yu, C.-C. J. Org. Chem. 1981, 46, 4935–4938.
(10) Robertson, J.; Bell, S. J.; Krivokapic, A. Org. Biomol. Chem. 2005,
3, 4246–4251.
(11) Ugi, I.; Fetzer, U. Chem. Ber. 1961, 94, 1116.
Org. Lett., Vol. 11, No. 18, 2009
4069

Scheme 2. Postulated Mechanism for the Formation of 1
tions (30 min at 100 °C), finding that the scope of the reaction
was quite general and that conversions were generally good
(Table 2). The correct assignment of the Z configuration of the
double bond was made possible by the observation that
compounds 1f, 1g, 1i, and 1j showed NOE between the amidic
and the olefinic hydrogens, only possible when the aryl group
and the amide are trans. However, generalization to all
compounds 1 was not possible with this technique since NOEs
were not clearly observed for other derivatives (the olefinic
hydrogen was often buried within the aromatic region). At this
purpose, we analyzed the signal belonging to the carbonyl amide
in the coupled 13C NMR spectrum: this was always a triplet,
due to the 2J coupling wih the hydrogen NH and the 3J coupling
with the olefinic proton, both being constantly between 3 and
4 Hz, consistent with a cis configuration between the olefinic
hydrogen and the carbonyl amide.14
oxides, or diazocompounds in 1,3-dipolar cycloadditions
failed. However, when the conditions described by Lasri were
employed to generate in situ the nitrile oxide, a main product
5b was formed whose structure derived from the rearrange-
ment of compound 1b, without inclusion of the nitrile oxide.
Postulating that the rearrangement had occurred for the
presence of the base used to generate the nitrile oxide,
compound 1b was simply reacted with triethylamine under
the same solvent and temperature conditions: indeed the same
outcome was observed. We also investigated whether
stronger bases would give the same rearrangement at lower
temperatures; however, reacting 1b with NaH or t-BuONa
at room temperature, a different rearranged product 6b was
isolated. NMR analysis of both compounds highlighted the
absence of the amidic hydrogen and the appearance of two
diastereotopic benzylic hydrogens, an aliphatic OH, and a
quaternary aliphatic carbon. In addition, compound 5b
showed an aliphatic CH and two carbonyls, while compound
6b showed a tetrasubstituted double bond, an additional OH,
more acidic, and only one carbonyl. On the basis of this
evidence, the structures of 5b and 6b were devised as
illustrated in Scheme 3. The coherence between these
structures and the observed 13C NMR chemical shifts was
first examined by DFT calculations:17 a linear fit of experi-
mental vs calculated data provided strong correlations with
no significant outliers. Additional HMBC experiments were
also run, showing crosspeaks due to 2JCH and 3JCH couplings
consistent with the proposed structures. Finally, NOE experi-
ments established the relative configuration of 5b (see
Supporting Information for details).
Table 2. Investigation of the Scope of the Reaction
entry
isocyanide
acid
yield (1)
a
b
c
d
e
f
g
h
i
cyclohexyl
n-butyl
t-butyl
4-MeO-phenyl
phenylacetic
phenylacetic
phenylacetic
phenylacetic
85%
90%
76%
53%
54%
90%
88%
51%
64%
58%
62%
75%
methyl isocyanopropionate phenylacetic
t-butyl
t-butyl
n-pentyl
benzyl
n-butyl
n-pentyl
t-butyl
3-MeO-phenylacetic
4-Cl-phenylacetic
1-naphthylacetic
4-Cl-phenylacetic
4-Cl-phenylacetic
2-NO2-phenylacetic
2-thiophenylacetic
j
k
l
We postulated that compound 1b, treated with a base,
could give a transacylated adduct that, according to the
particular reaction conditions, would cyclize via the aldol
condensation of the R-carbon of the phenylacetimide to the
carbonyl group in 4b (to give 5b) or the attack of the enolate
Compounds of formula 1 can be classified as captodative
olefins, which are often employed in cycloaddition reac-
tions.15,16
Preliminary attempts to react compound 1b either with
dienes in a Diels-Alder reaction or with nitrones, nitrile
(15) For Diels-Alder reactions: Herrera, R.; Jime´nez-Va`zquez, H. A.;
Modelli, A.; Jones, D.; So¨derberg, B. C.; Tamariz, J. Eur. J. Org. Chem.
2001, 4657.
(16) For 1,3-dipolar cycloadditions: (a) Herrera, R.; Nagarajan, A.;
Morales, M. A.; Mendez, F.; Jime´nez-Va`zquez, H. A.; Zepeda, L. G.;
Tamariz, J. J. Org. Chem. 2001, 66, 1252–1263. (b) Lasri, J.; Mukho-
padhyay, S.; Charmier, M. A. J. J. Heterocycl. Chem. 2008, 45, 1385–
1389. (c) Nagarajan, A.; Zepeda, G.; Tamariz, J. Tetrahedron Lett. 1996,
37, 6835–6838.
(12) (a) Cho, B. R.; Kim, N. S.; Kim, Y. K.; Son, K. H. J. Chem. Soc.-
Perkin Trans. 2000, 2, 1419–1423. (b) Cho, B. R.; Kim, Y. K.; Seung,
Y. J.; Kim, J. C.; Pyun, S. Y. J. Org. Chem. 2000, 65, 1239–1242.
(13) Gautier, A. Ann. Chim. (Paris) 1869, 17, 222.
(14) Rulev, A. Y.; Ushakov, I. A.; Nenajdenko, V. G. Tetrahedron 2008,
64, 8073–8077.
(17) See, for example: Bagno, A.; Rastrelli, F.; Saielli, G. Chem.sEur.
J. 2006, 12, 5514–5525.
4070
Org. Lett., Vol. 11, No. 18, 2009

Scheme 3. Two Alternative Rearrangement Reactions of Compound 1b
In conclusion, we have reported a novel outcome of the
reaction between isocyanides and carboxylic acids, when the
latter is an arylacetic derivative, and we have also investi-
gated the unprecedented reactivity of such enolamide deriva-
tives when treated with bases, leading to two interesting
classes of five-membered heterocycles. Further developments
will be reported in due course.
Table 3. Results for the Base-Mediated
Rearrangement-Cyclization of Compounds 1
entry
substrate
type of product
yield
a
b
c
d
e
f
1b
1b
1e
1i
1j
1a
5
6
6
6
6
5
60%
84%
85%
65%
72%
63%
Acknowledgment. The authors acknowledge MiUR and
Fondazione San Paolo for financial support.
Supporting Information Available: General experimental
procedures, full characterization of compounds 1, 5, and 6,
DFT analysis, and NMR prediction for compounds 5b and
6b. This material is available free of charge via the Internet
at http://pubs.acs.org.
to the imidic carbonyl in 4b′ (to give 6b). The two alternative
mechanisms are exclusive, and formation of 4b′ could be
favored by the presence of a chelating metal ion, although
more detailed studies will be carried out in due course.
The same reactions were performed with other substrates,
to prove the generality of the two methods, and the results
are summarized in Table 3.
OL901512C
Org. Lett., Vol. 11, No. 18, 2009
4071