Triphenylphosphine-catalyzed, novel, one-pot, multicomponent synthesis of functionalized β-acetamido carbonyls

Article abstract of DOI:10.1080/00397911.2013.873939

An efficient triphenylphosphine-catalyzed synthesis of β-acetamido carbonyls via multicomponent reaction of aromatic aldehydes, enolizable ketones or β-keto esters, acid chlorides and acetonitrile at room temperature is described. The process is remarkably simple, environmentally benign, and uses Lewis base for the first time in such type of reaction.

Full text of DOI:10.1080/00397911.2013.873939

This article was downloaded by: [Swinburne University of Technology]
On: 03 September 2014, At: 03:16
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered
office: Mortimer House, 37-41 Mortimer Street, London W1T 3JH, UK
Synthetic Communications: An
International Journal for Rapid
Communication of Synthetic Organic
Chemistry
Publication details, including instructions for authors and
subscription information:
http://www.tandfonline.com/loi/lsyc20
Triphenylphosphine-Catalyzed, Novel,
One-Pot, Multicomponent Synthesis of
Functionalized β-Acetamido Carbonyls
Shyam Babu Singh a , Pankaj Kumar Verma a , Kamleshwar Tiwari a ,
Mandavi Singh a , Preyas Ankit a , Shahin Fatma a , Jagdamba Singh a
& Kamla Prasad Tiwari a
a Environmentally Benign Synthesis Laboratory, Department of
Chemistry , University of Allahabad , Allahabad , India
Published online: 14 May 2014.
To cite this article: Shyam Babu Singh , Pankaj Kumar Verma , Kamleshwar Tiwari , Mandavi Singh ,
Preyas Ankit , Shahin Fatma , Jagdamba Singh & Kamla Prasad Tiwari (2014) Triphenylphosphine-
Catalyzed, Novel, One-Pot, Multicomponent Synthesis of Functionalized β-Acetamido Carbonyls,
Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic
Chemistry, 44:12, 1795-1802, DOI: 10.1080/00397911.2013.873939
To link to this article: http://dx.doi.org/10.1080/00397911.2013.873939
PLEASE SCROLL DOWN FOR ARTICLE
Taylor & Francis makes every effort to ensure the accuracy of all the information (the
“Content”) contained in the publications on our platform. However, Taylor & Francis,
our agents, and our licensors make no representations or warranties whatsoever as to
the accuracy, completeness, or suitability for any purpose of the Content. Any opinions
and views expressed in this publication are the opinions and views of the authors,
and are not the views of or endorsed by Taylor & Francis. The accuracy of the Content
should not be relied upon and should be independently verified with primary sources
of information. Taylor and Francis shall not be liable for any losses, actions, claims,
proceedings, demands, costs, expenses, damages, and other liabilities whatsoever or
howsoever caused arising directly or indirectly in connection with, in relation to or arising
out of the use of the Content.
This article may be used for research, teaching, and private study purposes. Any
substantial or systematic reproduction, redistribution, reselling, loan, sub-licensing,

systematic supply, or distribution in any form to anyone is expressly forbidden. Terms &
Conditions of access and use can be found at http://www.tandfonline.com/page/terms-
and-conditions

Synthetic Communications1, 44: 1795–1802, 2014
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2013.873939
TRIPHENYLPHOSPHINE-CATALYZED, NOVEL,
ONE-POT, MULTICOMPONENT SYNTHESIS OF
FUNCTIONALIZED b-ACETAMIDO CARBONYLS
Shyam Babu Singh, Pankaj Kumar Verma,
Kamleshwar Tiwari, Mandavi Singh, Preyas Ankit,
Shahin Fatma, Jagdamba Singh, and Kamla Prasad Tiwari
Environmentally Benign Synthesis Laboratory, Department of Chemistry,
University of Allahabad, Allahabad, India
GRAPHICAL ABSTRACT
Abstract An efficient triphenylphosphine-catalyzed synthesis of b-acetamido carbonyls via
multicomponent reaction of aromatic aldehydes, enolizable ketones or b-keto esters, acid
chlorides and acetonitrile at room temperature is described. The process is remarkably
simple, environmentally benign, and uses Lewis base for the first time in such type of
reaction.
Keywords b-Acetamido carbonyls; ambient temperature; multicomponent reaction;
triphenylphosphine
INTRODUCTION
Multicomponent reactions (MCRs) have been steadily gaining more importance
in the field of organic and medicinal chemistry, as high degrees of molecular diversity
can be introduced in these reactions in a very fast, efficient, and time-saving manner
without isolation of any intermediates.[1] As a result, considerable attention has been
paid to the development of new and improved one-pot, multicomponent reactions in
topical years.[2] Besides this, the utility of MCRs is well represented in the synthesis of
privileged medicinal scaffolds such as 1,4-dihydropyridines, dihydropyrimidines,
Received October 10, 2013.
Address correspondence to Jagdamba Singh, Environmentally Benign Synthesis Laboratory,
Department of Chemistry, University of Allahabad, Allahabad 211 002, India. E-mail: dr.jdsau@
gmail.com
Color versions of one or more of the figures in the article can be found online at www.tandfonline.
com/lsyc.
1795

1796
S. B. SINGH ET AL.
Scheme 1. Lewis base–catalyzed one-pot synthesis of b-acetoamido carbonyls.
decahydroquinolin-4-ones, substituted indoles, and b-acetamido carbonyls.[3,4] The
preparation of b-acetamido carbonyls have attracted considerable attention in
organic synthesis because of their importance as valuable building blocks for the
synthesis of 1,3-amino alcohols and alpha-amino acids[5,6] as well as for the synthesis
of various bioactive molecules such as antibiotics (e.g., nikkomycins, neopolyox-
ines).[7,8] Although, several synthetic protocols have been developed to access
b-acetamido carbonyls using Lewis or Brønsted acid catalysts such as CoCl2,[9,10]
montmorillonite K-10 clay,[11] silica sulfuric acid,[12] BiCl3 (generated from BiOCl),[13]
ZrOCl2 Á 8H2O,[14] heteropolyacids,[15] sulfuric acid absorbed on silica gel,[16]
Sc(OTf)3,[17] silica-supported H3PW12O4,[18] H6P2W18O62,[19] and FeCl3 Á 6H2O.[20]
Recently, Selectfluor[21] and Fe(ClO4)3 Á 6H2O[22] were also employed to promote
this reaction. However, some of these catalysts are toxic, difficult to prepare, and
expensive. We sought to develop a mild synthesis of these biologically interesting
b-acetamido carbonyl compounds using PPh3, a Lewis base catalyst. This method
is very flexible and makes possible the preparation of a large number of b-acetamido
carbonyls. In continuation of our work,[23] we have found that this reaction occurs
very smoothly in the presence of PPh3 as compared to previously reported toxic Lewis
acid catalyst (Scheme 1).
RESULTS AND DISCUSSION
To demonstrate the merits of this method in comparison to previously reported
methods,[24] we compared the results of the synthesis of b-acetamido-b-phenyl-
propiophenone in the presence of silica sulfuric acid, Bi(OTf)3, Sc(OTf)3, Montmor-
illonite K-10, FeCl3 Á 6H2O, and Fe(ClO4)3 Á 6H2O, with respect to the catalyst
amounts, reaction times and temperatures, and yields of the products (Table 1, entries
1–6). It seems that Lewis base (triphenylphosphine) catalyzes the reaction better than
Brønsted acids with respect to yield, time, and temperature (Table 1, entry 7). It could
be due to the activation of aldehyde with triphenylphosphine.
Initially, benzaldehyde has been used to react with acetophenone and acetyl
chloride over different catalytic amounts of PPh3 in acetonitrile, at 25 ꢀC. The best
catalytic activity of PPh3 was optimized to be 10 mol% and any excess of the catalyst,
beyond this proportion (20%), did not show any further increase in the conversion
and yield. Thus, in a model experiment, when benzaldehyde (1.1 mmol) was reacted
with acetophenone (1 mmol) and acetyl chloride (3 mmol) in the presence of PPh3
(10 mol%) in acetonitrile (3 mL, which acts as reagent as well as solvent) at room
temperature, the corresponding b-acetamido ketone was obtained after 6 h in 94%

FUNCTIONALIZED b-ACETAMIDO CARBONYLS
1797
Table 1. Evaluation of catalyst effect on the synthesis of b-acetamido-b-phenyl-propiophenone
Entry
Catalyst (mol %)
Time (h)
Temp (ꢀC)
Yielda(%)
Ref.
1
2
3
4
5
6
7
Silica sulfuric acid (78)
Bi(OTf)3 (10)
Sc(OTf)3(10)
65 min
80
25
25
70
25
80
25
91
69
82
80
88
77
94
11
11
30
30
7
12
Montmorillonite K-10 (2 g)
FeCl3 Á 6H2O(10)
Fe(ClO4)3 Á 6H2O(1)
PPh3 (10)
10
20
8
3.5
6
22
This work
aYields of the isolated pure compounds.
yield (Table 1, entry 7). We also examined the efficiency of benzoyl chloride instead
of acetyl chloride in this reaction, but our attempts were failed to generate the
corresponding b-acetamido ketones even after 24 h.
The mechanism may be involving the formation of an enolate, which attacks the
activated aldehyde to provide the corresponding b-acetoxy ketone, which can be con-
verted in to final product by treatment with acetonitrile (Scheme 2); therefore acetyl
group of the products has been derived from MeCN. Under optimized conditions, a
variety of aromatic aldehydes, enolizable ketones or b-keto esters, acid chlorides,
have been utilized for the preparation of b-acetamido ketones=esters and all products
were obtained in good to excellent yields, averaging 72–94% (Table 2). The more
stability of its enolate than those related to the acetophenone derivatives (Table 2,
entries 9 and 12).
Scheme 2. Mechanistic pathway for the progress of reaction.

1798
S. B. SINGH ET AL.
a
Table 2. One-pot synthesis of b-acetamido carbonyls using catalytic amount of PPh3
No.
R1
R2
X
H
Productb,c
1
C6H5
C6H5
2
4-CH3C6H4
C6H5
H
3
4
5
6
4-F C6H4
4-Cl C6H4
4-Br C6H4
4-OMe C6H4
C6H5
C6H5
C6H5
C6H5
H
H
H
H
7
2-NO2 C6H4
C6H5
H
(Continued )

FUNCTIONALIZED b-ACETAMIDO CARBONYLS
Table 2. Continued
1799
No.
R1
R2
X
Productb,c
8
3-NO2 C6H4
C6H5
H
9
10
11
12
H C6H4
4-CH3 C6H4
4-F C6H4
CH3
CH3
CH3
CH3
COCH3
COCH3
COCH3
COCH3
4-Cl C6H4
13
4-OMe C6H4
CH3
COCH3
14
15
H C6H4
CH3
COOC2H5
4-CH3 C6H4
CH3
COOC2H5
(Continued )

1800
S. B. SINGH ET AL.
Table 2. Continued
No.
R1
R2
X
Productb,c
16
4-F C6H4
CH3
COOC2H5
17
18
19
4-Cl C6H4
4-OMe C6H4
C6H5CHCH
CH3
CH3
C6H5
COOC2H5
COOC2H5
H
aProduct were characterized by comparison of their mp, TLC, IR, and 1H NMR data with those of
authentic samples.
bYields of the isolated pure compounds.
cReaction conditions: Benzaldehyde=cynnamaldehyde (1.1 mmol), ethyl acetoacetate=enolizable ketones
or b-keto esters (1.0 mmol), acetonitrile (3 mL), and acetylchloride (3 mmol).
dSyn=anti ratio of product was reported.
Electron-rich aromatic aldehydes afforded the desired products in relatively
good yield in short time as compared with aromatic aldehydes bearing electron-
withdrawing group (Table 2, entries 2–8).
CONCLUSION
Conclusively, we have reported triphenylphosphine-catalyzed, efficient, mild,
one-pot synthesis of b-acetamido carbonyls at ambient temperature in good to excel-
lent yield. The present method is a remarkably improved synthesis of b-acetamido
carbonyls and also applicable to a wide range of substrates. This methodology offers
several advantages such as reduced reaction times, milder conditions, elevated
product yields, compatibility with various functional groups, and economic viability
of the catalyst, compared with conventional methods and other catalyst.

FUNCTIONALIZED b-ACETAMIDO CARBONYLS
1801
EXPERIMENTAL
Benzaldehydes 1 (1.1 mmol) was allowed to react with ethyl acetoacetate=
enolizable ketones or b-keto esters 2 (1.1 mmol), and acetyl chloride 3 (1.5 mmol)
in the presence of PPh3 (10 mol%) in acetonitrile (3 mL) at room temperature. The
progress of reaction was monitored by thin-layer reaction (TLC). The corresponding
b-acetamido ketones 4 were obtained after 5–7 h in 74–94% yield. The mixture was
extracted with ethyl acetate (3 Â 10 ml), washed with water (3 Â 10 ml), and dried
over Na2SO4. Then the solvent was removed in vacuo and the crude product was
recrystallized from ethyl acetate–hexane to afford product. The product was charac-
terized by NMR and mass spectroscopy. Syn=anti ratio of product was established
1
by H NMR studies. The spectral data of all compounds match fairly with that
reported in literature.[14,20,24(d),25]
ACKNOWLEDGMENT
We sincerely thank SAIF, Punjab University, Chandigarh, for providing spectra.
FUNDING
We thank the University Grants Commission, New Delhi, for financial
support.
SUPPLEMENTAL MATERIAL
Supplementary information contain full experimental details and melting
1
points, H NMR, 13C NMR, and HRMS data of compounds 4a–4r. Supplemental
data for this article can be accessed on the publisher’s website.
REFERENCES
1. Terret, N. K.; Gardner, M.; Gordon, D. W.; Kobylecki, R. J.; Steele, J. Tetrahedron, 1995,
51, 8135.
2. Armstrong, R. W.; Combs, A. P.; Tempest, P. A.; Brown, S. D.; Keating, T. A. Acc.
Chem. Res. 1996, 29, 123.
3. Thomson, L. A.; Ellman, J. A. Chem. Rev. 1996, 96, 555.
4. Do¨mling, A.; Ugi, I. Angew. Chem. Int. Ed. 2000, 39, 3168.
5. Barluenga, J.; Viado, A. L.; Aguilar, E.; Fustero, S.; Olano, B. J. Org. Chem. 1993, 58,
5972.
6. Enders, D.; Moser, M.; Geibel, G.; Laufer, M. C. Synthesis 2004, 2040.
7. Kobinata, K.; Uramoto, M.; Nishii, M.; Kusakabe, H.; Nakamura, G.; Isono, K. Agric.
Biol. Chem. 1980, 44, 1709.
8. Da¨hn, U.; Hagenmaier, H.; Ho¨hne, H.; Ko¨nig, W. A.; Wolf, G.; Za¨hner, H. Arch. Microbiol.
1976, 107, 143.
9. Mukhopadhyay, M.; Bhatia, B.; Iqbal, J. Tetrahedron Lett. 1997, 38, 1083.
10. Bhatia, B.; Reddy, M. M.; Iqbal, J. J. Chem. Soc. Chem. Commun. 1994, 713.
11. Bahulayan, D.; Das, S. K.; Iqbal, J. J. Org. Chem. 2003, 68, 5735.
12. Khodaei, M. M.; Khosropour, A. R.; Fattahpour, P. Tetrahedron Lett. 2005, 46, 2105.

1802
S. B. SINGH ET AL.
13. Ghosh, R.; Maity, S.; Chakraborty, A. Synlett 2005, 115.
14. Ghosh, R.; Maity, S.; Chakraborty, A.; Chakraborty, S.; Mukherjee, A. K. Tetrahedron
2006, 62, 4059.
15. Rafiee, E.; Tork, F.; Joshaghani, M. Bioorg. Med. Chem. Lett. 2006, 16, 1221.
16. Yakaiah, T.; Reddy, G.; Lingaiah, B. P. V.; Narsaiah, B.; Rao, P. S. Synth. Commun.
2005, 35, 1307.
17. Pandey, G.; Singh, R. P.; Garg, A.; Singh, V. K. Tetrahedron Lett. 2005, 46, 2137.
18. Rafiee, E.; Shahbazi, F.; Joshaghani, M.; Tork, F. J. Mol. Catal. A: Chem. 2005, 242, 129.
19. Heravi, M. M.; Ranjbar, L.; Derikvand, F.; Bamoharram, F. F. Catal. Commun. 2007,
8, 289.
20. Khan, A. T.; Parvin, T.; Choudhury, L. H. Tetrahedron 2007, 63, 5593.
21. Shinu, V. S.; Sheeja, B.; Purushothaman, E.; Bahulayan, D. Tetrahedron Lett. 2009, 50,
4838.
22. Majid, M. K.; Heravi, F.; Behbahani, D. M. H.; Oskooie, A. Mol. Divers. 2009, 13, 375.
23. (a) Singh, J.; Verma, P. K.; Tiwari, K.; Singh, S. B. J. Kor. Chem. Soc. 2011, 55 (2), 153;
(b) Verma, P. K.; Tiwari, K.; Singh, S. B.; Singh, J. Synth. Commun. 2012, 42, 3021;
(c) Singh, S. B.; Verma, P. K.; Tiwari, K.; Srivastava, M.; Singh, J.; Tiwari, K. P.
Supramol. Chem. 2013, 25, 255.
24. (a) Stapp, P. R. J. Org. Chem. 1973, 38, 1433; (b) Maki, T.; Ishihara, K.; Yamamoto, H.
Org. Lett. 2005, 7, 5047; (c) Sarvan, J.; Jonnalagadda, C.; Mereddy, R. Tetrahedron. Lett.
2010, 51, 779; (d) Hui, M.; Jieping, W.; Yuanjiang, P. Tetrahedron 2009, 65, 1026.
25. (a) Khan, A. T.; Choudhury, L. H.; Parvin, T.; Ali, M. A. Tetrahedron Lett. 2006, 47,
8137; (b) Nagarapu, L.; Kantevari, S.; Cheemalapati, V. N.; Apuri, S.; Kumari, N. V.
J. Mol. Catal. A: Chem. 2007, 264, 22; (c) Das, B.; Krishnaiah, M.; Laxminarayana,
K.; Reddy, K. R. J. Mol. Catal. A: Chem. 2007, 270, 284.