Metal-Free, Regioselective, Dehydrogenative Cross-Coupling between Formamides/Aldehydes and Coumarins by C–H Functionalization

Article abstract of DOI:10.1002/ejoc.201701764

A highly efficient, single-step, metal-free synthetic approach to the synthesis of coumarin-3-carboxamides has been developed. The protocol employs tert-butyl peroxybenzoate as a radical initiator to achieve the regioselective carboxamidation of coumarins at C-3 in good-to-moderate yields. The established reaction protocol offers a wide substrate scope as it allows the use of both formamides as well as aldehydes as coupling partners with excellent regioselectivity. Furthermore, mechanistic investigations illustrate that the reaction proceeds by a free-radical pathway.

Full text of DOI:10.1002/ejoc.201701764

A Journal of
Accepted Article
Title: Metal-Free, Regioselective, Dehydrogenative Cross Coupling
between Formamides/Aldehydes and Coumarins via C-H
Functionalization
Authors: Mohit Gupta, Prahsant Kumar, Vijay Bahadur, Krishan Kumar,
Virinder S Parmar, and Brajendra Kumar Singh
This manuscript has been accepted after peer review and appears as an
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of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201701764
Link to VoR: http://dx.doi.org/10.1002/ejoc.201701764
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10.1002/ejoc.201701764
European Journal of Organic Chemistry
FULL PAPER
Metal-Free, Regioselective, Dehydrogenative Cross Coupling
between Formamides/Aldehydes and Coumarins via C-H
Functionalization
Mohit Gupta, [a] Prashant Kumar, [a] Vijay Bahadur, [a] Krishan Kumar, [a] Virinder S. Parmar [a],[b] and
Brajendra K. Singh*[a]
Abstract:
A
highly efficient, single-step, metal-free synthetic
remarkable biological importance, coumarins also attract great
attention from the scientific community due to their interesting
chemical framework which enables the regioselective C-H
functionalization at the C-3 position due to the generation of
resonance stabilized benzylic radical.[10] Thus, using the inherent
selectivity of coumarin for its C-3 functionalization, various
regioselective arylation,[11] alkylation,[12] phosphorylation,[13]
aroylation[14] olifination,[15] and trifluoromethylation[16] have been
developed to provide simple and shorter routes for its direct
functionalization. However, to the best of our knowledge there is
no report that discusses the direct carboxamidation of coumarin
to afford coumarin-3-carboxamide derivatives till date (Scheme
1). Nevertheless, methods reported so far include multistep
approaches which involve the coupling between amines and
activated coumarin derivatives.[17] Apart from having several
steps, these approaches suffer from various other shortfalls
such as prefunctionalization of the substrates, harsh reaction
conditions, expensive reagents, long reaction times and
laborious workup. In 2008, Proenca et al. have developed a
Knoevenagel condensation using salicyaldehydes and N-
substituted cynoacetamides.[18] Non-availability of readily
available starting materials, multi steps involved and limited
substrate scope do not allow this approaches for general
application. Recently, Sepay et al. have developed Ni-NiO
nanoparticles mediated one pot three component reaction to
afford coumarin-3-carboxamides,[19] however preparation,
characterization and high toxicity[20] of Ni nanocatalyst restricts
its practical applicability. Limitations of these reported
procedures encouraged us to develop an efficient and
regioselective methodology for the C-3 derivatization of
coumarins.
approach for the synthesis of coumarin-3-carboxamides has been
developed. The protocol employs TBPB (tert-butylperoxybenzoate)
as a radical initiator to achieve regioselective C-3 carboxamidation of
coumarins in good to moderate yields. The established reaction
protocol offers
a wide substrate scope as it employs both
formamides as well as aldehydes as coupling partners with excellent
regioselectivity. Furthermore, mechanistic investigations illustrate
that the reaction proceeds via a free radical pathway.
Introduction
During the past decade, significant achievements have been
made in the field of C-H activation, which allow the formation of
new bonds between unactivated coupling partners without any
prefucntionlization.[1]
Transition
metal
catalyzed
cross
dehydrogenative coupling (CDC) reactions have proven to be a
powerful tool in the recent years for the construction of C-C and
C-heteroatom bonds via the direct functionalization of C-H
bonds.[2] CDC inherently avoids the pre-functionalization of the
substrates and offers the atom economical shorter routes for
important organic transformations.[3] Although transition metal
catalysis has become an indispensable tool for the direct
transformations, yet it suffers from several limitations such as
the use of expensive catalysts, toxicity of catalysts, air and
moisture sensitivity of catalysts, addition of expensive and exotic
ligands and the presence of transition metals as trace impurities
in the final products which restrict its practical applicability in
pharmaceutical industries.[4] Therefore, the development of
metal free strategies for organic transformations is highly
desirable and has become the subject of immense research
among researchers.
Coumarins and their derivatives have gained tremendous
scientific attention due to their wide range of pharmacological
properties such as anti-oxidant activity,[5] HIV protease
inhibition,[6] anti-cancer activity,[7] anti-Alzheimer activity,[8]
Monoamine oxidase (MAO) inhibition,[9] etc. Apart from their
[a]
[b]
Mr. Mohit Gupta, Mr. Prashant Kumar, Mr.Vijay Bahadur, Mr.
Krishan Kumar, Prof. Virinder S. Parmar, Dr. Brajendra Kumar
Singh
Department of chemistry, University of Delhi, Delhi-110007, India
E-mail: singhbk@chemistry.du.ac.in
Prof. Virinder S. Parmar
Institute of Advanced Sciences
86-410 Faunce Corner Mall Road, Dartmouth, MA 02747, USA
Scheme 1. Methods for the Synthesis of coumarin-3-
carboxamides.
Supporting information for this article is given via a link at the end of
the document.
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10.1002/ejoc.201701764
European Journal of Organic Chemistry
FULL PAPER
H2O2
TBPB
TBPB
TBPB
TBPB
TBPB
TBPB
TBPB
TBPB
TBPB
TBPB
TBPB
TBPB
TBPB
TBPB
TBPB
TBPB
-
150
90
90
90
90
90
90
90
90
90
90
90
90
90
90
90
90
DEF
DEF
-
NR
42
8
Thus, in continuation of our research to develop metal-free
protocols[21] to resolve inherent issues and our ongoing efforts
for the functionalization of coumarin,[22] herein we report a metal
free, regioselective cross coupling reaction of coumarins with
formamides to afford industrially and biologically important
coumarin-3-carboxamides (Figure 1).[17], [23], [24a-24f]
-
-
9
-
DEF
-
43
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
-
DEF
-
69
-
DEF
-
31
-
DEF
-
NR
41
AgOAc
Toluene
Benzene
DCE
-
FeCl2.2H2O
-
31
Cu(OAc)2
-
-
NR[d]
26
CuO
CH3CN
Benzene
Benzene
Benzene
Benzene
Benzene
Benzene
Benzene
CuCl2
-
NR[d]
Traces
41
FeCl3
-
Figure 1. Selected biologically active compounds containing
coumarin-3-carboxamide
skeleton.
and
azacoumarin-3-carboxamide
-
-
-
-
-
DABCO
NaOAc
KOAc
CuBr
ZnCl2
61
37
Results and Discussion
24
During the course of our investigation on regioselective C-H
functionalization of coumarin, 7-methoxycoumarin (1a) and N,N-
diethylformamide (DEF) (2a) were taken as model substrates.
Initially regioselective oxidative cross coupled product at C-3
position of coumarin (3a, 27% yield, Entry 1, Table 1) was
obtained when 3 equiv. of tert-butyl hydrogen peroxide (TBHP)
was heated at 150 oC for 24 h with excess of DEF, leaving
majority of coumarin unreacted. Encouraged by these
preliminary results, a variety of solvents, catalysts and additives
were screened but no significant improvement in yields was
observed due to the incomplete conversion (Table S2). However,
a maximum of 35% yield was obtained with 3 equiv. of
anhydrous ZnCl2 (Entry 4, Table 1).
59[c]
[a] Reaction conditions: a mixture of 7-methoxycoumarin (1a) (1 equiv.), DEF
(2a) (3 equiv.), catalyst (20 mol-%), oxidant (3 equiv.) and additive (1 equiv.)
was heated at indicated temperature for 24 h; [b] Isolated yield of product was
calculated using coumarin as limiting reagent; [c] equiv. of ZnCl2 was used;
dCross coupled product of DEF and oxidant was formed.
Further, different oxidants other than TBHP were screened
(Entry 5-8, Table 1), interestingly TBPB and DTPB afforded
24 % and 23 % yields, respectively without the addition of any
additive (Entries 5 and 6, Table 1), however no product
formation was observed when hydrogen peroxide was used as
an oxidant (Entry 8, Table 1). Improvement in the product yields
was observed when the reaction temperature was changed from
150 oC to 90 oC using TBPB as the oxidant. Under these
conditions, various solvents were screened (Entries 10-13,
Table 1). TBPB in benzene furnished gratifying results by
delivering the desirable product in 69 % yields (Entry 11, Table
1). Next, different catalysts and additives were investigated
(Entries 16-24, Table 1), unfortunately all these catalysts and
additives exhibited a deteriorating effect on the product yields. It
is worth mentioning here that in the cases where Cu(OAc)2 and
CuCl2 were used as catalysts, a cross coupled product of TBPB
and DEF was obtained[25] without any formation of the desired
product even in traces (Entries 16 and 18, Table 1). After
several permutations and combinations, the optimized reaction
conditions were established as 1.0 equiv. of coumarin, 3.0 equiv.
of TBPB, 3.0 equiv. of formamide in benzene as solvent at 90 oC
for 24 h.
Table 1. Optimisation of the reaction conditions.[a]
Sr.
No
Temp.
0C
Oxidant
TBHP
Catalyst
Solvent
DEF
Additives
-
Yields[b]
27
-
150
150
90
1
2
3
-
-
-
-
-
-
Benzene
DEF
-
NR
32
35[c]
24
23
5
TBHP
TBHP
-
90
DEF
ZnCl2
4
5
6
7
TBHP
TBPB
150
150
150
DEF
-
-
-
Further, the substrate scope of this optimized protocol was
evaluated. During the investigations, 7-methoxycoumarin was
first treated with different disubstituted aliphatic, alicyclic and
aromatic formamides (Table 2). The reactions went smoothly
DTBP
Benzene
DEF
K2S2O8
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10.1002/ejoc.201701764
European Journal of Organic Chemistry
FULL PAPER
and delivered the regioselective C-3 functionalized products in
moderate to good yields with aliphatic as well as alicyclic
formamides (Entries 3a-3e, Table 2). However, no product was
observed with diphenylformamide, probably due to steric
reasons[24] (Entry 3f, Table 2).
Next, various aliphatic, aromatic and heterocyclic aldehydes
were screened with coumarin under optimized reaction
conditions and all the screened aldehydes yielded desired
products in moderate to good yields (Table 3). Better yields were
observed with those aldehydes having electron donating groups
on benzene ring whereas electron withdrawing groups present
on the aromatic ring of aldehyde provided lower yields. It is
worth mentioning here that halogen atoms at ortho- and para-
positions to aldehyde moiety were also tolerated well and
yielded the desired products in good yields (Entries 5d-5g, Table
3). However, no product was obtained with p-nitrobenzaldehyde
as it was completely converted into p-nitrobenzoic acid (Entry 5h,
Table 3). Moreover, with iso-butraldehyde, the desired product
was obtained in 41 % yield (Entry 5a, Table 3).
Table 2. Direct formimidation of coumarins.[a],[b]
Substrate scope was further investigated with of N-methyl
quinolone. Both benzaldehyde and DEF afforded the coupling
products in moderate yields (Entries 8a and 8b Table 4).
Table 4: Formamidation and aroylation of quinolone.[a]
[a] Reaction conditions: a mixture of 7-methoxycoumarin (1) (0.17 mmol),
formamides 2 (0.51 mmol) and TBPB (0.51 mmol) was heated at 90 oC for 24
h; [b] CCDC access number for 3c is 1563897.[27]
Subsequently, several differently substituted coumarins were
treated with DEF to investigate the role of electronic factors of
the functional groups on the product yields. It was found that the
coumarins with electron donating groups (such as -OCH3, -CH3)
afford the desired product in better yields (Entries 3a and 3j,
Table 2) as compared to those carrying the electron withdrawing
groups (such as -Br) (Entry 3l, Table 2). However, no product
formation was observed with coumarins having the -OCOCH3
and -NO2 as electron withdrawing groups (Entries 3h and 3k,
Table 2).
[a] Reaction conditions: a mixture of N-methyl quinolone 5 (0.17 mmol),
compound 7 (0.51 mmol) and TBPB (0.51 mmol) was heated at 90 oC for 24 h.
To get the insight into the reaction mechanism, some control
experiments were carried out (Scheme 2). Firstly, the
regioselectivity of reaction was studied by treating 3-methyl-7-
methoxycoumarin (9a) with DEF (2a) under optimal reaction
conditions (Scheme 2a). Absence of the desired product 3a as
well as C-4 functionalized coumarin derivative, even after
Table 3. Direct Aroylation of coumarins with aldehydes.[a]
exposing the reaction contents for 48
regioselectivity of the reaction.
h confirms the
R
R
O
O
O
O
O
O
4
TBPB
+
R1
H
R1
Benzene, 24 h
90 o
C
5
1
O
O
O
O
O
O
O
Cl
O
O
O
O
O
O
O
O
O
O
Cl
5c, 75%
5d, 69%
O
5a, 41%
O
5b, 68%
O
O
O
O
O
NO2
O
Br O
O
O
O
O
O
Br
O
O
O
F
5h, 0%
5g, 64%
O
5e, 55%
O
5f, 56%
O
O
O
O
Br
O
O2N
O
O
O
O
5k, 64%
5j, 60%
O
5i, 70%
5l, 0%
O
O
O
O
N
O
O
5m, 38%
O
5n, 60%
Scheme 2. Control experiments.
[a] Reaction conditions: a mixture of coumarin 1 (0.17 mmol), aldehyde 4 (0.51
mmol) and TBPB (0.51mmol) was heated at 90 oC for 24 h.
Next, when 7-methoxycoumarin (1a) and DEF (2a) were reacted
in the presence of 3 equiv. of TEMPO and 3 equiv. of BHT under
the standard reaction conditions, the desired product was also
not obtained (Scheme 2b and 2c). The complete suppression of
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10.1002/ejoc.201701764
European Journal of Organic Chemistry
FULL PAPER
desired product in presence of TEMPO and BHT confirms the
involvement of a radical intermediate in the reaction pathway.
Authors acknowledge the financial assistance from the
University of Delhi for providing a grant under the strengthening
of R&D Doctoral Research Programme and the DST-DU Purse
Grant Phase-II from India. M.G. is thankful to the CSIR (Council
of Scientific and Industrial Research) Delhi, India for providing
Junior Research Fellowship and Senior Research Fellowship.
Hence, on the basis of these results and literature reports,[10-14]
possible mechanism for the reaction has been proposed
(Scheme 3).
a
Initially, the radical initiator TBPB (10) undergoes thermal
homolytic cleavage to generate radicals 11 and 12. Thereafter,
these radicals selectively abstract hydrogen atom from DEF (2)
to generate radical 13, followed by its addition across the C-3
and C-4 C=C bond of coumarin (1a) to afford the intermediate
15. Subsequently, the intermediate 15 undergoes hydrogen
abstraction by tert-butyl radical (12) to afford the final product 3a
along with the formation of tert-butyl alcohol (14), a useful
reagent.
Keywords: Coumarin-3-carboxamide • Regioselective • Direct
amidation • Direct aroylation • Cross dehydrogenative coupling
.
[1]
a) L. Yang, H. Huang, Chem. Rev. 2015, 115, 3468-3517; b) T. Gensch,
M. N. Hopkinson, F. Glorius, J. Wencel-Delord, Chem. Soc. Rev. 2016,
45, 2900-2936; c) X. Chen, K. M. Engle, D-H. Wang, J-Q. Yu, Angew.
Chem. Int. Ed. 2009, 48, 5094-5115; d) S. H. Cho, J. Y. Kim, J. Kwak,
S. Chang, Chem. Soc. Rev. 2011, 40, 5068-5083.
[2]
a) Metal-catalyzed Cross-Coupling Reactions (Eds.: F. Diederich, P. J.
Stang) Wiley-VCH: Weinheim, 2008; b) Handbook of C-H
Transformations: Applications in Organic Synthesis (Eds.: G., Dyker)
Wiley-VCH: Weinheim, 2005.
[3]
[4]
a) C-J. Li, Acc. Chem. Res. 2009, 42, 335-344; b) S. A. Girard, T.
Knauber, C-J Li, Angew. Chem. Int. Ed. 2014, 53, 74-100; c) L. Lv, Z. Li,
Top. Curr. Chem. 2010, 38, 374.
a) Guideline on the Specification for Residues of Metal Catalysts or
Metal Reagents, Doc. Ref. EMEA/CHMP/SWP/4446/2000, European
Medicines Agency, London, 2008;
http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_gui
deline/2009/09/WC500003586.pdf; b) G. Li, D. Schoneker, K. L. Ulman,
J. J. Sturm, L. M. Thackery, J. F. Kauffman, J. Pharm. Sci. 2015, 104,
4197-4206; c) S. B. Bari, B. R. Kadam, Y. S. Jaiswal, A. A. Shirkhedkar,
Eurasian J. Anal. Chem. 2007, 2, 32-53
a) F. Pérez-Cruz, S. Vazquez-Rodriguez, M. J. Matos, A. Herrera-
Morales, F. A. Villamena, A. Das, B. Gopalakrishnan, C. Olea-Azar, L.
Santana, E. Uriarte, J. Med. Chem. 2013, 56, 6136-6145; b) M.
Giuseppa, T. Domenico, B. K. Singh, A. K. Prasad, V. S. Parmar, C.
Naccari, M. Ferdinando, S. Antonina, C. Mariateresa, F. Omidreza, S.
Luciano, Biochimie, 2010, 92, 1101-1107.
Scheme 3: Plausible mechanisum for the carboxamidation of
coumarin
[5]
Conclusions
In summary, we have successfully described
a general
methodology for the regioselective C-3 functionlization of
coumarins and aza-coumarin with formamides and aldehydes
using radical initiator TBPB in single step. This methodology not
only provides a convenient, cost effective and shorter route to
access useful products but also includes some characteristic
features such as single step reaction, metal free approach, wide
substrate scope and excellent regioselectivity, thus making the
present methodology superior to the literature precedents.
[6]
[7]
a) D. Yu, M. Suzuki, L. Xie, S. L. Morris-Natschke, K-H. Lee, Med. Res.
Rev. 2003, 23, 322-345; b) I. Kostova, S. Raleva, P. Genova, R.
Argirova, Bioinorg. Chem. Appl. 2006, 1-9.
(a) M. A. Musa, J. S. Cooperwood, M. O. F. Khan, Curr. Med. Chem.
2008, 15, 2664-2679; b) I. Kempen, D. Papapostolou, N. Thierry, L.
Pochet, S. Counerotte, B. Masereel, J-M. Foidart, M. Reboud-Ravaux,
A. Noel, B. Pirotte, Br. J. Cancer, 2003, 88, 1111-1118.
P. Anand, B. Singh, N. Singh, Bioorg. Med. Chem. 2012, 20, 1175-
1180.
a) M. J. Matos, D. Viña, E. Quezada, C. Picciau, G. Delogu, F. Orallo, L.
Santana, E. Uriarte, Bioorg. Med. Chem. Lett. 2009, 19, 3268-3270; b)
M. J. Matos, D. Viña, C. Picciau, F. Orallo, L. Santana, E. Uriarte,.
Bioorg. Med. Chem. Lett. 2009, 19, 5053-5055.
[8]
[9]
Experimental Section
[10] M. Kojima, K. Oisaki, M. Kanai, Chem. Commun. 2015. 51. 9718-9721.
[11] a) P. Chauhan, M. Ravi, S. Singh, P. Prajapati, P. P. Yadav, RSC Adv.
2016, 6, 109-118; b) F. Jafarpour, S. Zarei, M. B. A. Olia, N.
Jalalimanesh, S. Rahiminejadan, J. Org. Chem. 2013, 78, 2957-2964;
c) F. Jafarpour, M. B. A. Olia, H. Hazrati, Adv. Synth. Catal. 2013, 355,
3407-3412. (d) M. Min, S. Hong, Chem. Commun. 2012, 48, 9613-
9615; (e) M. Khoobi, M. Alipour, S. Zarei, F. Jafarpour, A. Shafia, Chem.
Commun. 2012, 48, 2985-2987; (f) F. Jafarpour, H. Hazrati, N.
Mohasselyazadi, M. Khoobi, A. Shafiee, Chem. Commun. 2013, 49,
10935-10937.
General procedure for the cross coupling reaction of coumarins with
formamides/aldehydes.
To an oven-dried screw cap reaction tube charged with magnetic bead,
0.17 mmol of coumarin was added to it. Subsequently, 0.51 mmol of
TBPB, 0.51 mmol of formamides/aldehyde and 2 mL of benzene were
added using micro litre pipette, the reaction mixture was then allowed to
heat at 90 oC for 24 h on a preheated oil bath. After the completion of
reaction as monitored by TLC, the reaction mixture was allowed to cool.
The solvent present in the reaction mixture was evaporated under
vaccum and the residue thus obtained was extracted with ethyl acetate
and water (3x50 mL), the combined organic layers were dried over
anhydrous Na2SO4 and evaporated to dryness to yield crude product
which was further purified by column chromatography using ethyl acetate
and hexane as eluents.
[12] A. Banerjee, S. K. Santra, N. Khatun, W. Ali, B. K. Patel, Chem.
Commun. 2015, 51, 15422-15425.
[13] a) X. Mi, M. Huang, J; Zhang, C. Wang, Y. Wu, Org. Lett. 2013, 15,
6266-6269; b) S. Guo, J. Gong, Z. Zhu, L. Yu, Y. Wang, L. Huang, H.
Cai, Chem. Lett. 2016, 45, 825-827; c) I. Kim, M. Min, D. Kang, K. Kim,
S. Hong, Org. Lett. 2017, 19, 1394-1397; d) X. Mia, M. Huang, J. Wang,
Y. Wu, Org. Lett. 2013, 15, 6266-6269.
[14] a) F. Jafarpour, M. Abbasnia, J. Org. Chem. 2016, 81, 11982-11986; b)
W. Zhao, L. Xu, Y. Ding, B. Niu, P. Xie, Z. Bian, D. Zhang, A. Zhou, Eur.
J. Org. Chem. 2016, 325-330; c) J-W. Yuan, Q-Y. Yin, L-R. Yang, W-P.
Mai, P. Mao, Y-M. Xiao, L-B Qu, RSC Adv. 2015, 5, 88258-88265.
[15] M. Min, Y. Kin, S. Hong, Chem. Commun. 2013, 49, 196-198.
Acknowledgements
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[16] X-H. Cao, X. Pan, P-J. Zhou, J-P. Zou, O. T. Asekun, Chem. Commun.
2014, 50, 3359-3362.
[17] F. Chimenti, D. Secci, A. Bolasco, P. Chimenti, B. Bizzarri, A. Granese,
S. Carradori, M. Yáñez, F. Orallo, F. Ortuso, S. Alcaro, J. Med. Chem.
2009, 52, 1935-1942.
[18] F. Proenca, M. Costa, Green Chem. 2008, 10, 995-998.
[19] N. Sepay, C. Guha, A. Kool, A. K. Mallik, RSC Adv. 2015, 87, 70718-
70725.
[20] a) K. Ada, M. Turk, S. Oguztuzun, M. Kilic, M. Demirel, N. Tandogan, E.
Ersayar, O. Latif, Folia Histochem. Cytobiol. 2010, 48, 524-529; b) S.
Latvala, J. Hedberg, S. D. Bucchianico, L. Möller, I. O. Wallinder, K.
Elihn,
H.
L.
Karlsson,
PLOS
ONE.
2016,
DOI:10.1371/journal.pone.0159684.
[21] a) P. Kumar, A. K. Singh, V. Bahadur, C. Len, G. J. Nigel, V. S. Parmar,
E. V. Van der Eycken, B. K. Singh, ACS Sustain. Chem. Eng. 2016, 4,
2206-2210; b) P. Kumar, A. Matta, S. Singh, J. Van der Eycken, C. Len,
V. S. Parmar, E. V. Van der Eycken, B. K. Singh, Synth. Commun.
2017, 47, 756-763.
[22] a) A. Matta, V. Bahadur, T. Taniike, J. Van der Eycken, B. K. Singh,
Dyes and Pigments. 2017, 140, 250-260; b) S. Kumar, B. K. Singh, N.
Kalra, V. Kumar, A. Kumar, A. K. Prasad, H. G. Raj, V. S. Parmar, B.
Ghosh, Bioorg. Med. Chem. 2005, 13, 1605-1613; c) A. Kumar, B. K.
Singh, R. Tyagi, S. K. Jain, S. K. Sharma, A. K. Prasad, H. G. Raj, R. C.
Rastogi, A. C. Watterson, V. S. Parmar, Bioorg. Med. Chem. 2005, 13,
4300-4305; d) P. Mladenka, K. Macakova, L. Zatloukalova, Z.
Rehakova, B. K. Singh, A. K. Prasad, V. S. Parmar, L. Jahodar, R.
Hrdina, L. Saso, Biochimie 2010, 92, 1108-1114.
[23] D. Guo, T. Chen, D. Ye, J. Xu, H. Jiang, K. Chen, H. Wang. H. Liu, Org.
Lett. 2011, 13, 2884-2887.
[24] a) Z-X. Pan, X. He, Y-Y. Chen, W-J. Tang, J-B. Shi, Y-L. Tang, B-A.
Song, J. Li, X-H. Liu, Eur. J. Med. Chem. 2014, 80, 278-284; b) A.
Asadipour, M. Alipour, M. Jafari, M. Khaoobi, S. Emami, H. Nadri, A.
Sakhteman, A. Moradi, V. Sheibani, F. H. Moghadam, A. Shafiee, A.
Foroumadi, Eur. J. Med. Chem. 2013, 70, 623-630; c) F. Areias, M.
Costa, M. Costro, J. Brea, E. Gregori-puigjane, M. F. Proenca. J.
Mestres, M. I. Loza, Eur. J. Med. Chem. 2012, 54, 303-310; d) S.
Robert, C. Bertolla, B. Masereel, J-M Dongne, L. Pochet, J. Med. Chem.
2008, 51, 3077-3080; e) A. R. Mehta, A. J. Armstrong, Ther. Adv. Urol.
2016, 8, 9-18; f) N. F. Kirillov, R. R. Makhmudov, E. A. Nikiforova, L. G.
Mardanova, Pharm. Chem. J. 2015, 49,13-15.
[25] P. S. Kumar, G. S. Kumar, R. A. Kumar, N. V. Reddy, K. R. Reddy, Eur.
J. Org. Chem. 2013, 1218-1222.
[26] M-Z. Zhang, Q-H. Guo, W-B. Sheng, C-C. Guo, Adv. Synth. Catal.
2015, 357, 2855-2861.
[27] CCDC 1563897 (3c) contains the supplementary crystallographic data
for this paper. The data could be obtained free of charge from The
Cambridge
Crystallographic
Data
Centre
via
www.ccdc.cam.ac.uk/data_request/cif.
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10.1002/ejoc.201701764
European Journal of Organic Chemistry
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A general methodology for the
regioselective C-3 functionlization
of coumarins and aza-coumarin
with formamides and aldehydes
has been achieved in single step
using TBPB as a radical initiator.
Key Topic Regioselective
carboxamidation of coumarins
Mohit Gupta, Prashant Kumar, Vijay
Bahadur, Krishan Kumar, Virinder S.
Parmar and Brajendra K. Singh*
This methodology provides
a
Page No. – Page No.
convenient and cost effective
route to access the products
under metal-free conditions with
excellent regioselectivity and wide
substrate scope.
Metal-Free, Regioselective,
Dehydrogenative Cross Coupling
between Formamides/Aldehydes
and Coumarins via C-H
Functionalization
This article is protected by copyright. All rights reserved.