Sequential multicomponent synthesis of α-ketoimides, from acyl chlorides, isocyanides, and silver salts of carboxylic acids

Article abstract of DOI:10.1016/j.tetlet.2014.10.135

A sequential multicomponent synthesis among acyl chlorides, isocyanides, and silver salts of carboxylic acids was developed to synthesize α-ketoimides. The latter undergo an intramolecular aza-Wittig reaction to afford 2-acylquinazolinones.

Full text of DOI:10.1016/j.tetlet.2014.10.135

Accepted Manuscript
Sequential Multicomponent Synthesis of α-Ketoimides, from Acyl chlorides,
Isocyanides and Silver Salts of Carboxylic Acids
Fabio La Spisa, Gian Cesare Tron
PII:
S0040-4039(14)01853-X
DOI:
http://dx.doi.org/10.1016/j.tetlet.2014.10.135
TETL 45364
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
2 October 2014
20 October 2014
27 October 2014
Please cite this article as: Spisa, F.L., Tron, G.C., Sequential Multicomponent Synthesis of α-Ketoimides, from Acyl
chlorides, Isocyanides and Silver Salts of Carboxylic Acids, Tetrahedron Letters (2014), doi: http://dx.doi.org/
10.1016/j.tetlet.2014.10.135
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers
we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and
review of the resulting proof before it is published in its final form. Please note that during the production process
errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Graphical Abstract
Leave this area blank for abstract info.
Sequential Multicomponent Synthesis of α-
ketoimides, from Acyl chlorides, Isocyanides
and Silver Salts of Carboxylic Acids.
Fabio La Spisa, Gian Cesare Tron

1
Tetrahedron Letters
jo u rn al h ome p ag e : w ww .e lse vie r .c om
Sequential Multicomponent Synthesis of α-Ketoimides, from Acyl chlorides,
Isocyanides and Silver Salts of Carboxylic Acids
Fabio La Spisaa and Gian Cesare Trona∗
a
Dipartimento di Scienze del Farmaco, Università del Piemonte Orientale “A. Avogadro”, Largo Donegani 2, 28100 Novara, Italy
ARTICLE INFO
ABSTRACT
Article history:
Received
A sequential multicomponent synthesis among acyl chlorides, isocyanides and silver salts of
carboxylic acids was developed to synthesize α-ketoimides. The latter undergo an intramolecular
aza-Wittig reaction to afford 2-acylquinazolinones.
Received in revised form
Accepted
2009 Elsevier Ltd. All rights reserved.
Available online
Keywords:
Isocyanides
Multicomponent reaction
Nef Reaction
Acyl Chlorides
Discovered by Nef in 1892, the reaction between acyl chlorides
(1) and isocyanides (2) to give α-ketoimidoyl chlorides1 (3) is
generally referred as isocyanide Nef-reaction.2 α-Ketoimidoyl
chlorides can be considered interesting precursors for further
chemical manipulations, but the presence of two different
electrophilic sites complicates the situation. Indeed, one
electrophilic site is productive (path A) and allows the disclosure
for a series of novel chemical transformations, among which,
stands out the formation of medicinally important α-ketoamides,3
while the other one (path B) is unproductive forming an acylated
adduct (5) and regenerating the isocyanide.4 (Figure 1)
Summarizing, until now, it has been demonstrated that
nucleophiles like water,3 alcohols,3 hydrazoic acid,3 tetrazoles,5
hydrogen sulfide,6 follow the path A, while anilines,7 primary,
secondary and tertiary amines,7 trialkylphosphites,8 urea
derivatives9 react according to the path B.
With the aim to discover novel transformations using the α-
ketoimidoyl chlorides as pivotal reagents, we decided to screen
for novel nucleophiles. Our initial attempts to use the
nucleophilic carbon of isocyanoacetamides (6) or isocyanoesters
(7) under base conditions (e.g. DBU) were disappointing as only
path B was detected, giving 4-acyl-1,3-oxazole derivatives (8 and
9), a class of compounds already described.10 (Scheme 1)
Figure 1. Synthetic paths for the nucleophilic attack to α-
ketoimidoyl chlorides.
Scheme 1. Isocyanoacetamides and isocyanoesters follow the
unproductive path B.
———
∗
Corresponding author. Tel: +390321375857; fax: +390321375621; e-mail: giancesare.tron@unipmn.it;

2
Tetrahedron
In the search of unreported nucleophiles able to follow the path
A, we were intrigued by the hydrolysis of α-ketoimidoyl
chlorides to α-ketoamides in presence of acetic acid or formic
acid reported by Ugi.3,11 This result was again confirmed by us
when the imidoyl chloride deriving from cyclohexylisocyanide
and benzoyl chloride was reacted with acetic acid. We speculated
on an active role carried out by the carboxylic acid, acting as
nucleophile and not only as proton source, hypothesizing the
following scenario: after protonation of the imine nitrogen, the
carboxylic anion attacks the imidoyl chloride (10) to give a
protonated imino anhydride (11) which is rapidly hydrolyzed to
ketoamide (12) by water. (Scheme 2)
Scheme 4. Silver benzoate reacts in a productive way with the
imidoyl chloride affording the keto-iminoanhydride and then the
ketoimide.
A search for the literature revealed us the presence of only one
example where a stable keto-iminoanhydride was isolated.13 The
moderate stability of these intermediates with respect those
generated with the Ugi reaction both with primary and secondary
amines14 can be explained in the following manner. At first, the
carboxylate attacks the nitrilium ion in a stereoselective way,
affording the acyl-iminoanhydride with the lone pair and the
carboxylate trans from each other.15 In this situation no Mumm
rearrangement can occur and the intermediate, in absence of
nucleophiles, can be isolated. Its reluctance to undergo a fast
isomerization process is due to two factors: a) a lower internal
energy compared with the iminoanhydride intermediate which
originates from Ugi reaction (see supporting information); b) the
neutrality of the medium which requires that the isomerization
takes place via nitrogen inversion. As soon as the E isomer (21)
is formed, it undergoes a fast Mumm rearrangement giving the α-
ketoimide. (Scheme 5)
Scheme 2. Proposed reaction mechanism for the formation of
ketoamides in the presence of acetic acid.
We, therefore, reasoned that removing the acidity, using a salt of
the carboxylic acid, we could allow the isocyanide nitrogen atom
to participate in a 1,3(O,N) acyl transfer, also known as Mumm
rearrangement,12 to give an acylimide. Disappointingly, the α-
ketoimidoyl chloride (13), deriving from pentylisocyanide and
pivaloyl chloride, in the presence of sodium benzoate (14)
afforded again the ketoamide (16). The only plausible reaction
mechanism considers the chlorine ion as the culprit of this
transformation. (Scheme 3)
Scheme 5. Z,E interconvertion of the iminoanhydride
intermediate 18.
Scheme 3. Proposed reaction mechanism for the formation of α-
ketoamides in the presence of sodium benzoate.
We next examined the generality of the method by using
different acyl chlorides, isocyanides, and silver salt of carboxylic
acids (see supporting information) always observing the
formation of the acyl-iminoanhydrides followed by the formation
of the corresponding α-ketoimides (22-27) (Figure 2).
Removing the chlorine ion off the medium should eventually
allow the Mumm rearrangement to take place. With our delight
when silver benzoate (17) was used, we noticed the immediate
formation of silver chloride and we were able to isolate a novel
product different from the α-ketoamide. This compound was
enough stable to be purified by column chromatography and for
registering proton and carbon NMR spectra, but on standing it
converts in a different and more stable compound. Spectroscopic
analyses (see supporting information) revealed that the first
compound was the keto-iminoanydride (18) which then
undergoes a Mumm rearrangement to give the desired α-
ketoimide (19). (Scheme 4)
It is important to highlight that when benzoic acid was used and a
source of silver was added (e.g. silver tetrafluoroborate) the only
isolated compound was again the α-ketoamide.
Figure 2. Synthesized α-ketoimides. Yields are referred over two
synthetic steps.

3
There are very few papers on the preparation of α-ketoimides
which reflect their difficult preparation16 most probably due to
their reactive nature. This reactive nature has indeed been
exploited to render them useful intermediates in organic
synthesis.16,17 Here, we would like to demonstrate, for the first
time, the use of an aza-Wittig18 post-transformation reaction
which, exploiting the increased electrophilic nature of the
carbonyl of the imide, with respect to a carbonyl of amides, can
give access to 2-acyl quinazolinones19 with yields ranging from
20 to 45 % (28-33) (Figure 3).
2
3
4
La Spisa, F.; Tron, G. C.; El Kaïm, L. Synthesis, 2014, 46,
829.
a) Ugi, I.; Fetzer, U. Ber. 1961, 94, 1116; b) Chen, J. J.;
Deshpande, S. V. Tetrahedron Lett. 2003 44, 8873.
different situation has been reported when alkyl
chlorooxalate have been used. See for example: Yavari, I.;
,
A
Pashazadeh, R.; Hosseinpour, R. Helv. Chim. Acta 2012, 95,
169.
5
El Kaïm, L.; Grimaud, L.; Wagschal, S. Synlett 2009, 1315.
a) Walter, W.; Bode, K.D. Liebigs 1966 698, 131; b) Walter,
W.; Bode, K.D. Angew. Chem. Int. Ed. 1962 , 510.
Ugi, I.; Beck, F.; Fetzer, U. Ber. 1962, 95, 126.
Coffinier, D.; El Kaïm, L.; Grimaud, L. Org. Lett
1825.
Ripka, A. S.; Diaz, D. D.; Sharpless, K. B.; Finn, M. G. Org.
Lett. 2003 , 1531.
10 a) Suzuki, M.; Iwasaki, T.; Matsumoto, K.; Okumura, K.
Synthetic Commun 1972 , 237; b) Gentile, G.; Merlo, G.;
6
,
O
N
O
, 1
7
8
N
N
.
2009, 11,
Cl
N
O
O
29 (26 %)
28 (35 %)
9
O
O
N
,
5
N
.
, 2
N
N
30 (20 %)
(40 %)
Pozzan, A.; Bernasconi, G.; Bax, B.; Bamborough, P.; Bridges,
A.; Carter, P.; Neu, M.; Yao, G.; Brough, C.; Cutler, G.;
31
O
O
Coffin, A.; Belyanskaya, S. Biorg. Med. Chem. Lett. 2012, 22,
O
O
N
1989.
N
N
11 It has been demonstrated that the Nef adduct obtained between
acyl chlorides and -isocyanimine triphenylphosphorane is
N
N
(32 %)
33
O
O
32 (45 %)
attacked by carboxylic acids immediately followed by an aza-
Wittig reaction. See: Cui, L.; Liu, Q.; Yu, J.; Ni, C.; Yu, H.
Figure 3. Synthesized 2-acylquinazolinones. Yields are referred over
three synthetic steps.
Tetrahedron Lett. 2011
12 a) Mumm, O.; Hesse, H.; Volquartz, H. Ber. 1915
Mossetti, R.; Pirali, T.; Saggiorato, D.; Tron, G. C. Chem.
Commun. 2011 47, 6966; c) Basavanag, U. M. V.; Dos
Santos, A.; El Kaïm, L.; Gámez-Montaño, R.; Grimaud, L.
Angew. Chem. Int. Ed. 2013 52, 7194.
, 52, 5530-5544.
,
48, 379; b)
As shown in Scheme 6, yields are referred over three synthetic
steps (an isocyanide Nef reaction, an acylimide formation and an
aza-Wittig reaction), indicating an average yield of 60−75% for
each synthetic step.
,
,
13 Peet, N. P.; Sunder, S.; Barbuch, R. J. J. Heter. Chem. 1980
17, 1513.
,
14 a) Dömling, A.; Ugi, I. Angew. Chem. Int. Ed. 2000
b) Tron, G. C. Eur. J. Org. Chem. 2013 10, 1849; c) The first
NMR observable α-amino isoamide has been reported in this
paper: Quast, H.; Aldenkort, S. Chem. Eur. J. 1996 , 462.
15 Hegarty, A. F. Acc. Chem. Res. 1980 13, 448; Hegarty A. F.;
Tynan, N. M.; Fergus, S. J. Chem. Soc. Perkin Trans. 2 2002
, 1328-1334.
16 Haddain, M. J.; Tannus, H. T. Heterocycles 1984
, 39, 3168;
,
,
2
,
Scheme 6. α-ketoimide–quinazolinone conversion via an
intramolecular aza-Wittig reaction.
,
7
,
22, 773.
17 a) Nishio, T.; Tokunaga, N.; Kondo, M.; Omote, Y. J. Chem.
Soc. Perkin Trans 1 1988, 2921; b) Sakamoto, M.; Takahashi,
M.; Fujita, T.; Watanabe, S.; Iida, I.; Nishio, T.; Aoyama, H. J.
In conclusion, in this manuscript we demonstrated that the
silver salt of carboxylic acid attacks, in a stereoselective
way, the nitrilium ion, generated by α-ketoimidoyl
Org. Chem. 1993, 58, 3476.
chlorides, to afford (Z)-acyl-iminoanhydrides. The latter
18 For an useful review see: Molina, P.; Vilaplana, J. Synthesis
1994, 1197.
,
show a weak stability and, after isomerization, undergo a
fast Mumm rearrangement to afford α-ketoimides, a class of
reactive compounds difficult to synthesize in other ways.
Finally, due to their reactive nature, we demonstrated that α-
ketoimides can be excellent partners for an intramolecular
aza-Wittig reaction to afford 2-acylquinazolinones.20
19 For a recent example of synthesis of 2-acylquinazolinines see:
Zhu, Y.; Fei, Z.; Liu, M.; Jia, F.; Wu, A. Org. Lett. 2013, 15,
378-381.
20 Full experimental procedures and characterization of all
compounds are given in the supplementary material to this
publication.
Acknowledgements
Financial support from Università del Piemonte Orientale is
gratefully acknowledged.
Supplementary data
References and notes
Supplementary data associated with this article can be
found, in the online version, at DOI: xxxxxxxxxxxxxxxxx
1
Nef, J. U. Justus Liebigs Ann. Chem. 1892, 270, 267.

4
Tetrahedron
HIGHLIGHTS
-
Silver salts of carboxylic acids are able to
give a novel three component reaction with
isocyanides and acyl chlorides
-
-
This is a new route for the synthesis of α-
keto-imides
The α-keto-imides can be further transformed
in 2-acylquinazolinones