Synthesis of aminocarbonyl N-Acylhydrazones by a three-component reaction of isocyanides, hydrazonoyl chlorides, and carboxylic acids

Article abstract of DOI:10.1021/ol502515b

A novel one-pot multicomponent synthesis of α-aminocarbonyl N-acylhydrazones starting from readily available hydrazonoyl chlorides, isocyanides, and carboxylic acids is reported. The strategy exploits the ability of the carboxylic acid as a third component to suppress all competing reactions between nitrile imines and isocyanides, channeling the course of the reaction toward the formation of this novel class of compounds. (Chemical Equation Presented).

Full text of DOI:10.1021/ol502515b

Letter
pubs.acs.org/OrgLett
Synthesis of Aminocarbonyl N‑Acylhydrazones by a Three-
Component Reaction of Isocyanides, Hydrazonoyl Chlorides, and
Carboxylic Acids
Mariateresa Giustiniano,† Fiorella Meneghetti,‡ Valentina Mercalli,§ Monica Varese,§
Francesco Giustiniano,∥,⊥ Ettore Novellino,*,† and Gian Cesare Tron*,§
†Dipartimento di Farmacia, Universita
̀
di Napoli “Federico II”, via D. Montesano 49, 80131 Napoli, Italy
degli Studi di Milano, Via L. Mangiagalli 25, 20133 Milano, Italy
degli Studi del Piemonte Orientale “A. Avogadro”, Largo Donegani 2, 28100
‡Dipartimento di Scienze Farmaceutiche, Universita
̀
§Dipartimento di Scienze del Farmaco, Universita
̀
Novara, Italy
⊥
∥Department of Physics and Graphene Research Center, National University of Singapore, Singapore, 117542, Singapore
S
* Supporting Information
ABSTRACT: A novel one-pot multicomponent synthesis of α-amino-
carbonyl N-acylhydrazones starting from readily available hydrazonoyl
chlorides, isocyanides, and carboxylic acids is reported. The strategy exploits
the ability of the carboxylic acid as a third component to suppress all
competing reactions between nitrile imines and isocyanides, channeling the
course of the reaction toward the formation of this novel class of
compounds.
ioneering work on the reactions between nitrile imines and
isocyanides by Professor Moderhack has shown that,
according to the experimental conditions and the steric and
electronic nature of the isocyanides and hydrazonoyl chlorides
used, at least four competing reactions can take place (Scheme
1).1 This simple two-component reaction affords four different
conditions and with the reagents used drastically reduces the
generality of these transformations. This chaotic result is due to
the formation of a reactive nitrilium intermediate (from the
isocyanide attack to the nitrile imine) which can follow different
paths, none being preferred over the others. Aware of this
situation, we wondered whether the presence of a third
component2 could change the anarchic situation typical of the
two-component reaction between nitrile imines and isocyanides
and render the method more suitable for the creation of
libraries of compounds useful from a medicinal chemistry point
of view. We therefore tested the three-component reaction (3-
CR) between a hydrazonoyl chloride (1), cyclohexylisocyanide
(2), and benzoic acid (3) as the third component, in
dichloromethane (0.2 M) at room temperature overnight,
and with 2 equiv of triethylamine (one needed to generate the
nitrile imine, and the other to form the carboxylate). We were
pleased to observe the formation of the multicomponent
adduct α-aminocarbonyl N-acylhydrazone 4 in 37% yield, along
with the adduct 5 in 42% yield deriving from a two-component
reaction between the hydrazonoyl chloride 1 and the carboxylic
acid 3 (Scheme 2).
P
Scheme 1. Products of the Reaction between Nitrile Imines
and Isocyanides
To explain the formation of these two products the following
mechanistic scenario is proposed. The hydrazonoyl chloride 1,
under basic conditions, forms the ephemeral nitrilimine species
63 bearing an electrophilic carbon suitable for the isocyanide
attack. At this point, the generated nitrilium ion 7 would be
ready to undergo the transformations reported by Moderack.
products, usually with modest yields: 1,2,3- and 1,2,4-triazolium
salts, dihydrotriazolyl pyrazolamines, and the unstable 1,2-
diazetimines. While the diversity of obtainable products has to
be considered a bonus of this chemistry, the impossibility of
limiting the course of the reaction to a single product, or
controlling the ratio of the various adducts, under the
Received: August 26, 2014
Published: September 26, 2014
© 2014 American Chemical Society
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Letter
Scheme 2. Three-Component Reaction between a
Hydrazonoyl Chloride (1), Cyclohexylisocyanide (2), and
Benzoic Acid (3)
Instead the presence of the carboxylate ion prevents the other
reaction pathways by generating, in a stereoselective way,4 the
iminoanhydride intermediate 8, which affords the desired
product by undergoing a Mumm type rearrangement thanks to
the properly positioned hydrazine nitrogen atom (Scheme 3).
Scheme 3. Proposed Mechanism for the Three-Component
Reaction
Figure 1. Building blocks used.
Additionally, nitrile imines are highly reactive species which
can react directly with carboxylic acids5 and undergo an acyl
migration to generate the byproduct compound 5. It is
important to highlight that we did not observe any of the
compounds described by Moderack, proving that the use of the
carboxylate as a third component suppresses all the competing
reactions between nitrile imines and isocyanides. Stimulated by
this early result and with the goal to suppress/reduce the
formation of the product 5, we decided to screen the reaction
conditions in order to improve the 4:5 ratio and increase the
yield of α-aminocarbonyl N-acylhydrazones. The results are
shown in Table 1 (see Supporting Information).
To our delight, solvent-free reaction conditions with
equimolar amounts of hydrazonoyl chloride, isocyanide, and
carboxylic acid, and 2 equiv of TEA gave the α-aminocarbonyl
N-acylhydrazone 4 in 52% yield and compound 5 in 18% yield,
increasing the desired/undesired product ratio. With these
optimized conditions in hand, we planned to explore the scope
and the limitations of this novel multicomponent process by
randomly combining one of six hydrazonoyl chlorides (1, 9−
13) with one of five isocyanides (2, 14−17) and one of ten
carboxylic acids (18−27) (Figure 1).
The starting hydrazonoyl chlorides (1, 9−13) were readily
synthesized in two steps with quite good yields (43−77%) (see
Supporting Information). A library of 14 α-aminocarbonyl N-
acylhydrazones was thus generated (28−40, Figure 2), with
yields ranging from 83% to 27%, indicating the generality and
the versatility of the process. In particular we observed that the
Figure 2. Synthesized α-aminocarbonyl N-acylhydrazones. Yields in
parentheses refer to the competing reaction between nitrile imines and
carboxylic acids.
reaction proceeded well when the carboxylic acids were solid.
When they were liquid (e.g., cyclopentancarboxylic acid) the
formation of the undesired product was preponderant (86%
yield). In this case prior salification to afford a solid was used
with success affording the desired 3-CR product in 67% yield.
Although the reaction stereoselectively generates the Z isomer,
we observed that these acylhydrazones are not always
geometrically stable and, on standing, some of them undergo
an isomerization process to afford a mix of E and Z isomers
(see Supporting Information for more details). In order to
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provide a detailed structure assignment of the proposed
structures, a single crystal X-ray diffraction analysis on
derivative 4 has been carried out. The established solid state
structure is represented in Figure 3, together with the relative
arbitrary atom-numbering scheme.
To our satisfaction the reaction was clean, and we observed a
marked increase in yield in the presence of solvent. Whereas
the desired α-aminocarbonylhydrazone 44 was produced in
67% yield in the presence of CH2Cl2 (Scheme 5), under neat
Scheme 5. Multicomponent Synthesis of α-
Aminocarbonylhydrazone Using the Sacrificial Acid 43
conditions the yield was only 18%. A possible reaction
mechanism accounting for the formation of 47 is depicted in
Scheme 6. Here the α-adduct 45 could in principle follow two
Figure 3. ORTEP6 view of 4 and the relative arbitrary atom-
Scheme 6. Possible Paths of 3-CR with “Sacrificial Acid”
numbering scheme (thermal ellipsoids at 40% probability).
It is noteworthy that we could only find in the literature one
example of α-aminocarbonyl N-acylhydrazone, produced by a
two-step reaction involving hydrazonoyl chloride 1, cyclohexyl-
isocyanide 2, and sodium acetate (Scheme 4).1b This reaction is
Scheme 4. Only Two-Step Synthesis of α-Aminocarbonyl N-
Acylhydrazones Reported to Date
different reaction pathways: path A, which via a Mumm-type
rearrangement gives a six-membered transition state leading to
compound 46, and path B, which following the intramolecular
attack of the hydroxyl function on the iminoanhydride gives the
adduct 44 (via a five-membered transition state) and phtalide
47. Since only 44 is obtained we speculate that the formation of
the five-membered intermediate has a lower activation energy
than in the six-membered case.8
To further prove the generality of such a mechanism and the
selectivity toward path B, the synthesis of a small collection of
α-aminocarbonylhydrazones was attempted. In all cases the α-
aminocarbonylhydrazone (48−52) was the only reaction
product and medium-high yields were obtained (Figure 4).
Some of them undergo a rapid isomerization (see Supporting
Information). It is important to highlight that the “sacrificial
acid” 43 is not able to accomplish the formal addition of water
when an Ugi-type reaction with a primary amine is attempted,
due to the higher nucleophilicity of the secondary amine
formed in situ, which leads to Mumm rearrangement.
We were therefore enthusiastic in discovering the possibility,
in our new 3-CR, to tune the reactivity of the nitrilimine
nitrogen atom. Additionally the presence of the NH group in
the final adduct 44 enables further derivatization, opening up
the way to a variety of post-MCR modifications and thus
enlarging the scope of the reaction.
In conclusion, starting from an erratic two-component
reaction between nitrile imines and isocyanides, we discovered
a novel 3-CR between nitrile imines, isocyanides, and carboxylic
however conceptually different from the one reported here, as it
involves first the attack of isocyanide 2 to the hydrazonoyl
chloride 1 to form a 1,2,3-triazolium salt 41, followed by a
challenging purification step consisting of several recrystalliza-
tions. The purified intermediate then undergoes a ring opening
reaction with 3.7 equiv of sodium acetate at 125−130 °C to
give the α-aminocarbonyl N-acylhydrazones 42 in 33% yields
(overall yield after a further purification step). Therefore, such a
two-component reaction is not deemed suitable for the fast and
efficient synthesis of libraries of α-aminocarbonyl N-acylhy-
drazone due to the low yield of product, the formation of
several byproducts, and the need for several purification steps.
In order to widen the scope of this novel 3-CR and to further
explore the reactivity of the nitrilimine nitrogen atom toward a
Mumm-type rearrangement we decided to react nitrilimine 1,
tert-butylisocyanide 14, and 2-hydroxymethylbenzoic acid 43.
The use of the substituted benzoic acid has been already
reported by us7 for the synthesis of unsymmetrical bis(β-
aminoamides). The presence of a hydroxymethyl function at
the ortho position of benzoic acid engenders an alternative
reaction path leading to the formation of phthalide and a formal
addition of water to the final compound. It should be noted
that water itself would not be nucleophilic enough to intercept
the nascent nitrilium ion.
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Figure 4. α-Aminocarbonyl N-acylhydrazones synthesized.
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acids and applied it to the synthesis of the first reported library
of α-aminocarbonyl N-acylhydrazones and some related α-
aminocarbonylhydrazones. The compounds obtained could
also be seen as aza-homologues of the Ugi scaffold. Indeed,
although obtained in a completely different way, the novel 3-
CR molecular scaffold shows the atom connectivity NCCNNC
and an evident peptidomimetic nature similar to the four-
component Ugi scaffold with a NCCNC connectivity. Addi-
tionally, the different chemical functionalities present (hydra-
zone, amide, and acyl groups) enable a potentially large number
of post-transformation reactions, similar to the Ugi adducts.9
Finally, we reckon that other 1,3 dipolar species lay dormant,
since their multicomponent reaction with isocyanides have not
yet been investigated and they are ready to be successfully used
for the discovery of novel multicomponent reactions.10
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures and characterization data for all new
compounds synthesized. Cif file of 4 (CCDC number:
1025235). This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: giancesare.tron@unipmn.it.
*E-mail: ettore.novellino@unina.it.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
Financial support from Universita
gratefully acknowledged. M.G. acknowledges “Progetto Strain-
Regione Campania” for a fellowship.
■
̀
del Piemonte Orientale is
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