Stereospecific synthesis of syn -α-oximinoamides by a three-component reaction of isocyanides, syn -chlorooximes, and carboxylic acids

Article abstract of DOI:10.1021/ol201397x

A stereospecific multicomponent reaction among isocyanides, syn-chlorooximes, and carboxylic acids provides an efficient synthesis of biologically relevant syn-α-oximinoamides.

Full text of DOI:10.1021/ol201397x

ORGANIC
LETTERS
2011
Vol. 13, No. 14
3734–3737
Stereospecific Synthesis of syn-r-
Oximinoamides by a Three-Component
Reaction of Isocyanides,
syn-Chlorooximes, and Carboxylic Acids
Tracey Pirali,*,† Riccardo Mossetti,† Simona Galli,‡ and Gian Cesare Tron*,†
Dipartimento di Scienze Chimiche, Alimentari, Farmaceutiche e Farmacologiche,
ꢀ
Universita degli Studi del Piemonte Orientale “A. Avogadro”, Via Bovio 6,
28100 Novara, Italy, and Dipartimento di Scienze Chimiche e Ambientali,
ꢀ
Universita dell’Insubria, Via Lucini 3, 22100 Como, Italy
pirali@pharm.unipmn.it; tron@pharm.unipmn.it
Received May 24, 2011
ABSTRACT
A stereospecific multicomponent reaction among isocyanides, syn-chlorooximes, and carboxylic acids provides an efficient synthesis of
biologically relevant syn-R-oximinoamides.
When three or more starting materials react in the same
flask to produce a molecule which contains parts of all the
reactants, a multicomponent reaction (MCR) takes place.1
Scheme 1. Passerini Reaction
In general, MCRs stand out as a powerful tool for the
rapid construction of quite complex molecules, not easily
accessible via the classical two-component chemistry.2
Among them, the Passerini reaction (Scheme 1) is the
oldest MCR in which isocyanides have been used,3 exploit-
ing their propensity to react with nucleophiles and
†
electrophiles at the same carbon atom. Over the past few
decades, this reaction has gained interest as a simple and
practical methodology for the synthesis of novel molec-
ular scaffolds. Besides the post-transformation strategy,4
another tactic to expand the scope of this venerable reac-
tion is to use surrogates of the carboxylic or the carbonyl
partners.
ꢀ
Universita degli Studi del Piemonte Orientale “A. Avogadro”.
‡
ꢀ
Universita dell'Insubria.
ꢀ
(1) Multicomponent reactions; Zhu, J., Bienayme, H., Eds.: Wiley-VCH:
Weinheim, 2005 and references therein. For reviews, see: (b) Domling, A.
€
Chem. Rev. 2006, 106, 17–89. (c) Synthesis of heterocycles via multi-
component reactions I and II; Orru, R. V. A., Ruijeter, E., Eds.; Springer
GmbH: Berlin, 2010 and references therein.
(2) For reviews, see: (a) Akritopoulou-Zanze, I.; Djuric, S. W. Het-
erocycles 2007, 73, 125–147. (b) Zhu, J. Eur. J. Org. Chem. 2003, 7, 1133–
1144. (c) Sunderhaus, J. D.; Martin, S. F. Chem.;Eur. J. 2009, 15, 1300–
1308. (d) D’Souza, D. M.; Muller Thomas, J. J. Chem. Soc. Rev. 2007,
36, 1095–1108. (e) Toure, B. B.; Hall, D. G. Chem. Rev. 2009, 109, 4439–
4486. (f) Domling, A.; Ugi, I. Angew. Chem., Int. Ed. 2000, 39, 3168–
3210.
Successful examples of replacing the carboxylic moiety
with water,5 hydrazoic acid,6 o-nitrophenol,7 silanol,8 and
€
€
(3) (a) Passerini, M. Gazz. Chim. Ital. 1921, 51, 126–129. (b) Riva, R.;
Banfi, L. Org. React. 2005, 65, 1–140. (c) For a novel proposal regarding
the mechanism of the Passerini reaction, see: Maeda, S.; Komagawa,
S.; Uchiyama, M.; Morokuma, K. Angew. Chem., Int. Ed. 2011, 50
644–649.
(4) (a) Marcaccini, S.; Torroba, T. In Multicomponent reactions; Zhu,
ꢁ
J., Bienayme, H., Eds.; Wiley-VCH: Weinheim, 2005; pp 33À75. (b) Banfi,
L.; Basso, A.; Riva, R. In Synthesis of heterocycles via multicomponent
reactions I; Orru, R. V. A., Ruijeter, E., Eds.: Springer GmbH: Berlin, 2010;
pp 1À40.
r
10.1021/ol201397x
Published on Web 06/13/2011
2011 American Chemical Society

alchools9 have been reported, while acyl cyanides,10
epoxides,11 acylisocyanates,12 and ketenes13 emerged as
electrophilic partners in the Passerini reaction.14 In this
respect, and in connection with our ongoing projects
aiming at the development of multicomponent reactions15
and their applications in medicinal chemistry,16 we became
interested in developing multicomponent processes ex-
ploiting novel electrophilic species. We reasoned that,
as in principle there are no restrictions on the nature of
the electrophile and nucleophile which can react with the
isocyanide forming the so-called R-adduct,17 syn-chlor-
ooximes could be excellent surrogates for the carbonyl
group. Herein, we report a multicomponent reaction
among syn-chloroximes, isocyanides, and carboxylic acids
to afford syn-R-oximinoamides with a high level of stereo-
specificity (Scheme 2).
Scheme 3. Three-Component Reaction of Cyclohexylisocya-
nide 2a, Phenylacetic Acid 3a, and Benzylchloroxime 1a
deprotonate the carboxylic acid. After the addition of syn-
phenylchlorooxime (1a),18,19 the reaction was stirred at
room temperature for 1 h. To our delight, the desired syn-
oximinoamide20 (4a) was formed in 70% yield, along with
a trace of its anti isomer (syn/anti ratio 94:6)21 (Scheme 3).
The use of a base, to avoid the generation of HCl, was
compulsory for the success of this transformation. Indeed,
the reaction carried out in the absence of triethylamine
gave the desired product in only 21% of yield.
Scheme 2. Novel Multicomponent Passerini-Type Reaction
Scheme 4. Proposed Mechanism for the Three-Component
Reaction
To validate our hypothesis, to a solution of cyclohexyl
isocyanide (2a) and phenylacetic acid (3a) in dichloro-
methane as solvent was added 1 equiv of triethylamine to
(5) Seebach, D.; Adam, G.; Gees, T.; Schiess, M.; Weigand, W.
Chem. Ber. 1988, 121, 507–517.
(6) (a) Ugi, I.; Meyr, R. Chem. Ber. 1961, 94, 2229–2233. (b) Nixey,
T.; Hulme, C. Tetrahedron Lett. 2002, 43, 6833–6835. (c) For an
asymmetric version of this reaction, see: Yue, T.; Wang, M. X.; Wang,
D. X.; Zhu, J. Angew. Chem., Int. Ed. 2008, 47, 9454–9457.
(7) El-Kaim, L.; Gizolme, M.; Grimaud, L. Org. Lett. 2006, 8, 5021–
5023.
(8) Soeta, T.; Kojima, Y.; Ukaji, Y.; Inomata, K. Org. Lett. 2010, 12,
4341–4343.
(9) Yanai, H.; Oguchi, T.; Taguchi, T. J. Org. Chem. 2009, 74, 3927–
3939.
(10) Oaksmith, J. M.; Peters, U.; Ganem, B. J. Am. Chem. Soc. 2004,
126, 13606–13607.
(11) (a) Kern, O. T.; Motherwell, W. B. Chem. Commun. 2003, 2988–
2989. (b) Revised structure: Kern, O. T.; Motherwell, W. B. Chem.
Commun. 2005, 1787.
Our proposed mechanism for this reaction is depicted in
Scheme 4. The syn-chlorooxime reacts with the isocyanide,
forming the transient R-adduct, which is in equilibrium
with its nitrilium form. The nitrilium intermediate is
then intercepted by the carboxylate ion. The intermedi-
ate so obtained undergoes an irreversible Mumm-type
(12) Neidlein, R. Naturforsch 1964, 19, 1159–1160.
(13) Ugi, I.; Rosendahl, F. K. Chem. Ber. 1961, 94, 2233–2235.
(14) Replacing of the aldehyde or ketone with an imine leads to the
well-known four-component Ugi reaction.
(15) (a) Giovenzana, G. B.; Tron, G. C.; Di Paola, S.; Menegotto, I.;
Pirali, T. Angew. Chem. 2006, 118, 1117–1120. Angew. Chem., Int. Ed.
2006, 45, 1099–1102. (b) Mossetti, R.; Pirali, T.; Tron, G. C. J. Org.
Chem. 2009, 74, 4890–4892. (c) Pirali, T.; Tron, G. C.; Masson, G.; Zhu,
J. Org. Lett. 2007, 9, 5275–5278. (d) Mossetti, R.; Caprioglio, D.;
Colombano, G.; Tron, G. C.; Pirali, T. Org. Biomol. Chem. 2011, 9,
1627–1631. (e) Mossetti, R.; Pirali, T.; Seggiorato, D.; Tron, G. C.
Chem. Commun. 2011, 47, 6966–6968.
(18) E-Oximes were prepared from the corresponding aldehydes. All
the chlorooximes were preparedfollowing the procedurereported by Liu
and Howe: Liu, K. C.; Shelton, B. R.; Howe, R. K. J. Org. Chem. 1980,
45, 3916–3918. A small amount of E-chlorooximes was always present.
See the experimental part for the general procedures.
(19) Z-Chlorooximes are stable in solution see: Smolikovta, J.;
Exner, O.; Barbaro, G.; Macciantelli, D.; Dondoni, A. J. Chem. Soc.,
Perkin Trans 2 1980, 1051–1056.
(16) (a) Pirali, T.; Faccio, V.; Mossetti, R.; Grolla, A. A.; Di Micco,
S.; Bifulco, G.; Genazzani, A. A.; Tron, G. C. Mol. Diversity 2010, 14,
ꢀ
109–121. (b) Grolla, A. A.; Podesta, V.; Chini, M. G.; Di Micco, S.;
(20) El-Kaim et al. have described the synthesis of a syn/anti mixture
of R-oximinoamides by reacting primary nitro compounds, isocyanides,
Vallario, A.; Genazzani, A. A.; Canonico, P. L.; Bifulco, G.; Tron,
G. C.; Sorba, G.; Pirali, T. J. Med. Chem. 2009, 52, 2776–2785. (c) Pirali,
T.; Callipari, G.; Ercolano, E.; Genazzani, A. A.; Giovenzana, G. B.;
Tron, G. C. Org. Lett. 2008, 10, 4199–4202.
(17) Saegusa, T.; Ito, Y. In Isonitrile Chemistry; Ugi, I., Ed.; Academic
Press: New York, 1971; pp 65À92.
ꢁ
and anhydrides. See: (a) Dumestre, P.; El Kaim, L.; Gregoire, A. Chem.
Commun. 1999, 755–756. (b) Dumestre, P.; El Kaim, L. Tetrahedron
Lett. 1999, 40, 7985–7986.
(21) The ratio was established by H NMR, by integrating the best
1
resolved peaks.
Org. Lett., Vol. 13, No. 14, 2011
3735

rearrangement mediated by the syn-oxime driving all the
equilibria to the final syn-R-oximinoamide.
Under these buffered conditions (1 equiv of carboxylic
acid and 1 equiv of TEA), no generation of nitrile N-oxides
and the subsequent formation of the corresponding furox-
ans from chloroximes were detected, as confirmed in
separate experiments, ruling out a direct involvement of
nitrile N-oxides in the reaction.22
Scheme 5. Proposed Mechanism for the Formation of the syn
and anti Isomers of R-Oximinoamides
Figure 2. Building blocks.
With the anti isomer of chloroximes, it is the lone pair of
the nitrogen atom which captures the acyl group to give an
acylimide23 and finally the anti-oximinoamide (Scheme 5).
Figure 1. X-ray crystal structure of 4a.
As shown in Figure 1, the syn stereochemistry for the
majorstereoisomerofcompound4awas furtherconfirmed
by X-ray diffraction analysis.
The scope and limitation of this MCR were next exam-
ined. Different chlorooximes (1aÀh), isocyanides (2aÀe),
and carboxylic acids (3aÀi) were chosen (Figure 2).
(22) Reaction between isocyanides and nitrile N-oxides to give iso-
cyanates and nitriles has been reported: (a) Vita Finzi, P.; Arbasino, M.
Tetrahedron Lett. 1965, 6, 4645–4646. (b) Alpoim, C. M.; Barrett,
A. G: M.; Barton, D. H. R.; Hiberty, P. C. New J. Chim. 1980, 4, 127–
129. (c) El Kaim, L.; Gacon, A. Tetrahedron Lett. 1997, 38, 3391–3394.
(23) Acylimides have been reported. See: Ziegler, E.; Belegratis, K.
Monatsh. Chem. 1968, 99, 995–998.
Figure 3. Synthesized R-oximinoamides.
As it is possible to see in Figure 3, this transformation
proved to be highly versatile, and the level of stereospecificity
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Org. Lett., Vol. 13, No. 14, 2011

depends on the syn/anti ratio of the starting R-chlorooximes.
The reaction was tolerant to primary, secondary, and
tertiary isocyanides but failed with aromatic isocyanides.
Both aliphatic and aromatic carboxylic acids participated
well in the reaction. The presence of electron-withdrawing
or electron-releasing groups on the benzoic acid did not
affect the course of the reaction.
The R-oximinoamide motif occupies a relevant role in
the core of numerous pharmaceuticals and natural pro-
ducts. It can be found in its syn configuration in most of the
second- and third-generation cephalosporins, either as
such or as the oximino ether (e.g., cefmatilen, cefixime,
cefdinir, and cefditoren) and β-lactamase inhibitors (e.g.,
aztreonam),24 as well as in some natural products such as
the antibacterial nocardicin A. The anti form is displayed
in marine natural products such as verongamine, basta-
dines, and psammaplin A.25
Very recently, R-oximinoamides have been reported as
an effective zinc chelating moiety in a series of potent
HDAC inhibitors.26
In conclusion, we have successfully developed a MCR
where chlorooximes are involved to produce syn-R-oximi-
noamides in a stereospecific manner. The reaction is
effective across a range of structures in each component,
producing diverse oximinoamides in a single step.
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Acknowledgment. Financial support from Universita
del Piemonte Orientale is gratefully acknowledged.
(24) Foye’s principles of medicinal chemistry; Foye, W. O., Lemke, T. L.,
Williams, D. A. Wolters Kluver: the Netherlands, 2008; p 1057.
(25) Hentschel, F.; Lindel, T. Synthesis 2010, 2, 181–204.
(26) Botta, C. B.; Cabri, W.; Cini, E.; De Cesare, L.; Fattorusso, C.;
Giannini, G.; Persico, M.; Petrella, A.; Rondinelli, F.; Rodriquez, M.;
Russo, A.; Taddei, M. J. Med. Chem. 2011, 54, 2165–2182.
Supporting Information Available. Experimental pro-
cedures and characterization data for all new com-
pounds synthesized. This material is available free of
charge via the Internet at http://pubs.acs.org.
Org. Lett., Vol. 13, No. 14, 2011
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