Isocyanide-mediated multicomponent synthesis of C-oximinoamidines

Article abstract of DOI:10.1021/ol403062m

By capitalizing on the different reactivity of nitrile N-oxides with isocyanides and amine, α-oximinoamidines, a so far elusive class of compounds, have been synthesized in a straightforward way by reacting isocyanides, syn-chlorooximes, and amines in a multicomponent fashion.

Full text of DOI:10.1021/ol403062m

ORGANIC
LETTERS
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Vol. XX, No. XX
000–000
Isocyanide-Mediated Multicomponent
Synthesis of C‑Oximinoamidines
Valentina Mercalli,† Fiorella Meneghetti,‡ and Gian Cesare Tron*,†
ꢀ
Dipartimento di Scienze del Farmaco, Universita degli Studi del Piemonte Orientale
“A. Avogadro”, Largo Donegani 2, 28100 Novara, Italy, and Dipartimento di Scienze
ꢀ
Farmaceutiche, Universita degli Studi di Milano, Via L. Mangiagalli 25, 20133 Milano, Italy
giancesare.tron@unipmn.it
Received October 24, 2013
ABSTRACT
By capitalizing on the different reactivity of nitrile N-oxides with isocyanides and amine, R-oximinoamidines, a so far elusive class of compounds,
have been synthesized in a straightforward way by reacting isocyanides, syn-chlorooximes, and amines in a multicomponent fashion.
The identification of novel domino multicomponent
reactions1 (MCRs) is a hard and challenging task for
organic chemists but it can be extremely rewarding; it is
possible to gain access with simplicity to chemical frame-
works which are unknown or would be otherwise difficult
to achieve.2 Because of their unique reactive nature, iso-
cyanides are a versatile class of chemical compounds and
have been used as pivotal reagents in multicomponent
reactions,3 thanks to the their well-known ability to react
with various electrophilic partners to form the so-called
R-adduct4 (Figure 1).
Figure 1. Selected examples of electrophilic partners for
isocyanides.
A major challenge in the search for novel isocyanide-
mediated MCRs is to select suitable electrophilic partners
capable of generating adducts sufficiently reactive to continue
the reaction. In this case, a third player, until that moment an
inert spectator, can react in an irreversible manner with them,
eventually leading to a domino multicomponent reaction.
Recently, we unveiled the role of syn-chlorooximes (also
named hydroximoyl chlorides) as suitable partners for
isocyanides, and we discovered a novel multicomponent
reaction by adding a carboxylic acid to the isocyanide-syn-
chlorooxime mixture to give syn-R-oximinoamides in a
stereospecific manner.5
To rationalize the course of this reaction, we suggested
the formationof anR-adductbetween the syn-chlorooxime
and the isocyanide, ruling out the participation of a nitrile
N-oxide species, since, in an independent experiment,
among syn-phenylchlorooxime (1), phenylacetic acid (2),
and triethylamine (3), the formation of the nitrile N-oxide
dimerization products diphenylfuroxan (4) and/or 3,6-
dipheyl-1,4,2,5-dioxadiazine (5) was not detected.6 Later,
we realized that the formation of these dimerization
†
ꢀ
ꢀ
Universita degli Studi del Piemonte Orientale “A. Avogadro”.
‡
Universita degli Studi di Milano.
(1) Three- or four-component reactions can be divided in three main
groups: domino, sequential, and consecutive multicomponent reacions.
€
See: Muller, J. J. Top. Heterocycl. Chem 2010, 25, 25–94.
ꢁ
(2) Multicomponent Reactions; Zhu, J., Bienayme, H., Eds.; Wiley-
VCH: Weinheim, 2005 and references cited therein.
€
(3) (a) Domling, A.; Ugi, I. Angew. Chem., Int. Ed. 2000, 39, 3168–
€
€
3210. (b) Domling, A. Chem. Rev. 2006, 106, 17–89. (c) Domling, A.;
Wang, W.; Wang, K. Chem. Rev. 2012, 112, 3083–3135.
(4) (a) Saegusa, T.; Ito, Y. In Isonitrile Chemistry; Ugi, I., Ed.;
Academic Press: New York, 1971; pp 65À92. (b) Sadjadi, S.; Heravi,
M. M. Tetrahedron 2011, 67, 2707–2752.
(5) Pirali, T.; Mossetti, R.; Galli, S.; Tron, G. C. Org. Lett. 2011, 13,
3734–3737.
r
10.1021/ol403062m
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products is actually not as easy as we thought6 and cannot
be considered as a marker for the involvement of nitrile
N-oxides. Indeed, when we carried out the reaction in the
presence of phenylacetylene (4), the corresponding isoox-
azole (7) was obtained in 40% yields, pointing out that,
even under these buffered conditions (TEA, carboxylic
acid), nitrile N-oxides can, indeed, be generated (Scheme 1).
dichloromethane at room temperature, after 6 h, the
TLC analysis revealed a complex mixture.
However, this disappointing scenario dramatically
changed when in the third experiment an amine (2 equiv)
waspresentintheflask. Indeed, wecouldobserve, after3 h,
the neat formation of a novel product (11) which incorpo-
rated all of the reactants. Spectroscopic analyses deter-
mined the formation of an R-oximinoamidine in 71%
yield, a novel chemical moiety never reported before to
the best of our knowledge (Scheme 3).
Scheme 1. Experiments To Demonstrate the Direct Involvement
of the nitrile N-Oxide Species
Scheme 3. Three-Component Synthesis of C-Oximinoamidines
Having showed the ability of isocyanides to directly
react with the nitrile N-oxides,7 we hypothesized we could
introduce a novel level of complexity by using an amine as
a third component. In principle, in this case several scenar-
ios are possible as reactions between chlorooximes and
amines, via nitrile N-oxide, are well-known in literature for
giving amidoximes.8 This fact could increase the chaos in
the round-bottomed flask aborting the multicomponent
reaction pathway (Figure 2).
The proposed mechanism for this new multicomponent
transformation is depicted in Scheme 4. The syn-phenyl-
chlorooxime (1) reacts with a base (8), forming the corre-
sponding nitrile N-oxide (12), rapidly intercepted by
pentylisocyanide (10) to give a nitrilium ion intermediate
(13), eventuallystereospecifically trapped by the amine,9 to
afford the final product (14).
Scheme 4. Proposed Mechanism for the Three-Component
Reaction
Figure 2. Possible scenario in the reaction between syn-chloro-
oximes and amines.
Unlike those of most amidines,10 the 1H and 13C spectra
of the final adducts recorded at 80 °C reveal, in most cases,
However, initial experiments revealed that the reaction
between 1 equiv of syn-phenylchlorooxime (1) and 2 equiv
of N,N-dibenzylamine (8) was sluggish and not clean,
requiring at least 10 h to go to completeness to give 9 in
60% yield (Scheme 2).
(6) For an example of compound formed by dimerization of benzo-
nitrile N-oxide according to the reaction conditions, see: Marinone
Albini, F.; De Franco, R.; Bandiera, T.; Grunanger, P.; Caramella, P.
Gazz. Chim. Ital. 1990, 120, 1–6.
On the other hand, when pentyl isocyanide (10)
was reacted with the syn-phenylchlorooxime (1) in
(7) Only a two-component reaction between isocyanides and nitrile
N-oxides to give isocyanates and nitriles has been disclosed to date. See:
Vita Finzi, P.; Arbasino, M. Tetrahedron Lett. 1965, 6, 4645–4646.
(8) (a) Johnson, J. E.; Carvallo, C.; Dolliver, D. D.; Sanchez, N.;
Garza, V.; Cansexo, D. C.; Eggleton, G. L.; Fronczek, F. R. Aust. J.
Chem. 2007, 60, 685–690. (b) Kunz, R. K.; Rumfelt, S.; Chen, N.; Zhang,
Scheme 2. Synthesis of Amidoxime 9
€
D.; Tasker, A. S.; Burli, R.; Hungate, R.; Yu, V.; Nguyen, Y.;
Whittington, D. A.; Meagher, K. L.; Plant, M.; Tudor, Y.; Schrag,
M.; Xu, Y.; Ng, G. Y.; Essa Hu, E. Bioorg. Med. Chem. Lett. 2008, 18,
5115–5117. (c) Thipyapong, K.; Uehara, T.; Tooyama, Y.; Braband, H.;
Alberto, R.; Arano, Y. Inorg. Chem. 2011, 50, 992–998. (d) Exner, O.;
Motekov, N. Collect. Czech. Chem. Commun. 1982, 47, 814–827.
(9) It has been well established by Professor Hegarty that nitriulium
species react with nucleophiles is a stereospecific way with the entering
nucleophile and the lone pair trans from each other. See: Hegarty, A. F.
Acc. Chem. Res. 1980, 13, 448–454.
B
Org. Lett., Vol. XX, No. XX, XXXX

the lack of geometrical isomerism pointing to a fast
equilibrium between the two geometrical isomers.
Remarkably, the use of syn-chlorooximes makes it
possible to overcome the lack of reactivity of the isocyanideÀ
Nef adduct11 with amines, owing to a higher reactivity of
the carbonyl.12,13 The syn-chlorooximes can therefore be
considered excellent surrogates for acyl chlorides in the
reaction with isocyanides (Scheme 5).
Scheme 5. Isocyanide Nef Reaction and Reaction between
Imidoyl Chlorides and Amines
Figure 3. Building blocks.
Thisnovel multicomponent reactionwas next examined.
Different syn-chlorooximes (1, 14À18), isocyanides (10,
19À22), and amines (8, 23À29) were chosen (Figure 3).
syn-Chlorooximes were readily prepared by reacting oxi-
mes with N-chlorosuccinimide in DMF.14 When R is an
aryl group, syn-chlorooximes can be purified by column
chromatography and stored at 4 °C over a long period of
time without noticeable decomposition. On the other
hand, aliphatic hydroximoyl chlorides are unstable and
should be directly used. E/Z isomerism of the starting
oximes is not relevant to the reaction outcome,15 as it gets
lost during the chlorination step, in accordance with pre-
vious reports.16 Furthermore, precedent works indicated
that only the Z geometrical isomer of hydroximoyl chlo-
ride is formed during the reaction.17
reduced nucleophilicity of aromatic isocyanides.18 Both
primary and secondary amines were good partners for the
reaction, and even aniline reacted, although in low yield.
The presence of electron-withdrawing or electron-donating
groups on the phenyl ring of arylchlorooximes does not
seem to alter the course of the reaction.
As shown in Figure 4, the reaction is quite general.
Yields vary from 80% to 26%; this result depends on the
purification step, since these compounds are extremely
polar. The reaction was tolerant to primary, secondary
and tertiary isocyanides, but failed with aromatic isocya-
nides. Indeed, reaction of phenylchlorooxime (1) with
phenylisocyanide (22) and morpholine (26) only gave the
adduct between the chlorooxime and the morpholine in
61% yield. This result is not surprising in the light of the
Figure 4. Synthesized C-oximinoamidines.
(10) (a) Neilson, D. G. In The Chemistry of Amidines and Imidates;
Patai, S., Rappoport, Z., Eds.; John Wiley and Sons: New York, 1991; Vol. 2.
The structure and the stereochemistry of 30 was unam-
biguously established by a single-crystal X-ray diffraction
analysis.
Figure 5 shows the molecular structure of 30, disordered
at C14 and C16 of the morpholine moiety. The two
alternate conformations of the ring show a site occupancy
of 75% and 25% for the a labeled atoms, respectively.
Both imino groups show a Z-conformation in the solid
€
(b) Komber, H.; Limbach, H. H.; Bohme, F.; Kunert, C. J. Am. Chem.
Soc. 2002, 124, 11955–11963.
(11) Nef, J. U. Justus Liebigs Ann. Chem. 1892, 270, 267–335.
(12) (A) Ugi, I.; Beck, F.; Fetzer, U. Ber. 1962, 95, 126–135. (b) El
Kaım, L.; Grimaud, L.; Wagschal, S. Synlett 2009, 1315–1317.
¨
(13) C-Acylamidines have never been synthesized starting from
R-keto imidoyl chlorides and amines.
(14) All the syn-chlorooximes were prepared according to this pro-
cedure: Liu, K. C.; Shelton, B. R.; Howe, R. K. J. Org. Chem. 1980, 45,
3916–3918.
(15) All the oximes used are known compounds, and their stereo-
chemistry was confirmed by comparison of their melting points, 1H and
13C NMR.
(16) Kanemasa, S.; Matsuda, H.; Kamimura, A.; Kakimani, T.
Tetrahedron 2000, 56, 1057–1064.
(17) (a) Hegarty, A. F.; Mullane, M. J. Chem. Soc., Perkin Trans. 2
1986, 995–1001. (b) Jeong, H. J.; Park, Y. D.; Park, H. Y.; Jeong, Y.;
Jeong, T. S.; Lee, W, S. Bioorg. Med. Chem. Lett. 2006, 16, 5576–5579.
(c) DeClercq, P. J.; Germain, G.; Van Meerssche, M. Acta Cryst B 1975,
31, 2894–2895.
(18) Mironov, M. A. General Aspects of Isocyanide Reactivity. In
Isocyanide Chemistry; Nenajdenko, V. G., Ed.; Wiley-VCH: Weinheim,
2012; pp 35À73.
(19) Only three multistep methods for the synthesis of symmetrical
C-acylamidines have been reported. See: (a) Seyferth, D.; Hui, R. C.
J. Org. Chem. 1985, 50, 1985–1987. (b) Corriu, R. J. P.; Lanneau, G. F.;
Perrot-Petta, M. Synthesis 1991, 954–958. (c) Zhang, C.; Zhang, L.; Jiao,
N. Adv. Synth. Catal. 2012, 354, 1293–1300.
Org. Lett., Vol. XX, No. XX, XXXX
C

As described above, C-oximinoamidine are a novel class
of previously unreported compounds, which could be used
as starting materials for further elaborations taking
advantage of the presence of the oxime.
In conclusion, we developed a novel multicomponent
reaction that generates to R-oximinoamidines, a class of
previously unreported compounds whose reactivity de-
serves further investigation.19 An additional important
advantage of this reaction is the synthesis of oximes of
known configuration (Z). Furthermore, we pointed out
the ease of reactivity between isocyanides and nitrile
N-oxide species paving the way for the discovery of novel
multicomponent transformations. Considerations of atom
economy and practicability compensate for the moderate
yields observed in some cases.
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Acknowledgment. Financial support from Universita
del Piemonte Orientale is gratefully acknowledged. V.M.
acknowledges a grant for the Lagrange ProjectÀCrt
Foundation.
Figure 5. ORTEP19 view of 30 and the relative arbitrary atom-
numbering scheme (thermal ellipsoids at 40% probability).
Supporting Information Available. Experimental pro-
cedures and characterization data for all new compounds
synthesized. X-ray data for 30 (CIF). This material is
available free of charge via the Internet at http://pubs.acs.org.
state. The two rings are almost perpendicularly ori-
ented, as shown by the N3ÀC8ÀC7ÀC4 are linked
through strong hydrogen bond interactions between
O1ÀH1a N2, forming chains running in the a axis
3 3 3
direction.
The authors declare no competing financial interest.
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