CuI–Zn(OAc)2 catalyzed C(sp2)–H activation for the synthesis of pyridocoumarins through an uncommon CuI–CuIII switching mechanism: A fast, solvent-free, combo-catalytic, ball milling approach

Article abstract of DOI:10.1016/j.tetlet.2017.05.074

CuI–Zn(OAc)₂ catalyzed, a fast, solvent-free synthetic protocol has been developed for the oxidative C–C and C–N coupling via C(sp²)–H activation. In this work, an aldehyde, terminal alkyne and 3-aminocoumarin were coupled together to form pyridocoumarin framework through a greener ball milling process under very mild condition. In contrast to the frequently used imine-alkyne cyclization reactions, this uncommon mild Cu^I–Cu^III switching combo-catalysis is expected to proceed through the formation of a flexible propargylic amine intermediate, which leads to a rapid C(sp²)–H activation for cyclization involving transient Cu^III species. The in-situ formation of transient Cu^III species was confirmed through ultraviolet–visible spectroscopy (UV–Vis), electrospray ionization mass spectrometry (ESI-MS), and X-ray photoelectron spectroscopy (XPS) analyses of the reaction mixture.

Full text of DOI:10.1016/j.tetlet.2017.05.074

Accepted Manuscript
CuI-Zn(OAc)2 catalyzed C(sp2)-H activation for the synthesis of pyridocou-
marins through an uncommon CuI-CuIII switching mechanism: A fast, solvent-
free, combo-catalytic, ball milling approach
Nazia Kausar, Asish R. Das
PII:
S0040-4039(17)30667-6
DOI:
http://dx.doi.org/10.1016/j.tetlet.2017.05.074
TETL 48967
Reference:
Tetrahedron Letters
To appear in:
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Revised Date:
Accepted Date:
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19 May 2017
21 May 2017
Please cite this article as: Kausar, N., Das, A.R., CuI-Zn(OAc)2 catalyzed C(sp2)-H activation for the synthesis of
pyridocoumarins through an uncommon CuI-CuIII switching mechanism: A fast, solvent-free, combo-catalytic, ball
milling approach, Tetrahedron Letters (2017), doi: http://dx.doi.org/10.1016/j.tetlet.2017.05.074
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Graphical Abstract
CuI-Zn(OAc)2 catalyzed C(sp2)-H activation for the
Synthesis of pyridocoumarins through an uncommon
Cu I-CuIII switching mechanism: A fast, solvent-free
Combo-catalytic, ball milling approach
Leave this area blank for abstract info.
Nazia Kausar, Asish R. Das*

1
Tetrahedron Letters
journal homepage: www.els evier.com
CuI-Zn(OAc)2 catalyzed C(sp2)-H activation for the synthesis of
pyridocoumarins through an uncommon CuI-CuIII switching mechanism: A fast,
solvent-free, combo-catalytic, ball milling approach
Nazia Kausar, Asish R. Das*
Department of Chemistry, University of Calcutta, Kolkata-700009, India
*Corresponding author: Tel.: +913323501014, +919433120265; fax:913323519754;
E-mail address: ardchem@caluniv.ac.in , ardas66@rediffmail.com
ARTICLE INFO
ABSTRACT
Article history:
Received
CuI-Zn(OAc)2 catalyzed, a fast, solvent-free synthetic protocol has been developed for the
oxidative C-C and C-N coupling via C(sp2)-H activation. In this work, an aldehyde, terminal
alkyne and 3-aminocoumarin were coupled together to form pyridocoumarin framework through
a greener ball milling process under very mild condition. In contrast to the frequently used
imine-alkyne cyclization reactions, this uncommon mild CuI-CuIIIswitching combo-catalysis is
expected to proceed through the formation of a flexible propargylic amine intermediate, which
leads to a rapid C(sp2)-H activation for cyclization involving transient CuIII species. The in-situ
formation of transient CuIII species was confirmed through ultraviolet-visible spectroscopy
(UV−Vis), electrospray ionization mass spectrometry (ESI-MS), and X-ray photoelectron
spectroscopy (XPS) analyses of the reaction mixture.
Received in revised form
Accepted
Available online
Keywords:
3-aminocoumarin
Pyridocoumarin
C-C, C-N coupling
C-H activation
combo-catalysis(CuI-CuIII switching)
2009 Elsevier Ltd. All rights reserved
.
ball milling
solvent-free
1. Introduction
Among the various 3-aminocoumarin scaffold containing
molecules, pyridocoumarin derivatives are an important class of
naturally occurring molecules and they exhibit a wide range of
pharmacological activities such as CNS depressant,7 anti-
inflammatory,8 anti-tumor9and antimicrobial activities.10 They
also exhibit interesting photochemical properties and have been
used as laser dye stuffs,11 luminescence intensifiers,12 and
spasmolytics.13 From the literature it is found that only a few
methods are reported for the synthesis of pyrido[2,3-c] coumarin
derivatives. Majumdar et al. devised a synthetic protocol for the
synthesis of pyrido[2,3-c]coumarins14 through the palladium
catalyzed Heck reaction followed by dehydrogenation with
palladium charcoal. Bodwell and co-workers reported the
synthesis of pyrido[2,3-c]coumarin derivatives using Yb(OTf)3
catalyst through the Povarov reaction followed by oxidation with
Br2.15Later on, the same group devised a synthetic protocol
(Scheme 1, c) for the synthesis of pyrido[2,3-c]coumarins
involving the intramolecular Povarov reaction of 3-
aminocoumarin and 2-(propargyloxy)benzaldehyde. This
synthetic protocol afforded the product in 45% yield after 9 days.
16Recently, similar Povarov-type 3-component reaction was
reported by McNulty17a and co-workers. In that work, a Bronsted
acid catalyst, TFA (trifluoroacetic acid) in dichloromethane was
used to accomplish the desired transformation. Khan et al17b
described a three-component reaction to access pyrido[2,3-
c]coumarins using molecular iodine in acetonitrile solvent under
refluxing condition. The main disadvantages of the above
mentioned protocols are low yield, requirement of expensive
Metal catalyzed activation of the carbon–hydrogen (C–H)
bond for the formation of carbon–carbon (C–C) bond is a fast
and economic approach for the development of biologically
significant compounds and natural products1. It is a useful
strategy of synthetic organic chemistry because it can be used for
efficient functionalization of arenes without the use of hazardous
precursors 2. On the other hand, ‘combo-catalysis’ is an emerging
area in modern organic synthesis for diverse cyclization reaction
through C(sp2)-H activation3; for example, CuBr−ZnI2-catalyzed
N−N/C−N
reactions,3dPd(I)−Ru(I)-mediated
reactions3e
and
coupling
for
oxidative
Suzuki
cyclization
cross-coupling
[IrCuCl2]2−AgNTf2-promoted
amination
reaction3h. The combo-catalytic strategy is also found to be an
efficient tool for direct N-C and C-C coupling of amine with
aldehyde and terminal alkyne4. Taking the advantages of the
combo-catalysis, we targeted to synthesize a wide range of
pyridocoumarin derivatives through the oxidative C-C and C-N
coupling employing 3-aminocoumarin, aldehyde and terminal
alkyne.
3-aminocoumarin and its derivatives are one of the most active
classes of compounds possessing a wide range of biological
activity.5Due to their wide spectrum of biological activities,
various research groups have put their efforts to synthesize
compounds containing 3-aminocoumarin structural core6.

2
Tetrahedron
metal catalysts, prolonged reaction time, use of higher thermal
entry 1). After several unsuccessful attempts using Zn(OAc)2,
ZnI2, Cu(OAc)2 catalysts (Table 1, entries 2-4), we have designed
a combo-catalyst CuBr/ZnI2(10 mol % each) for this three-
component recation in CH3CN solvent at 70 oC. Interestingly, we
got 52% yield of the product after heating for 4h (Table 1, entry
5).Then we employed another combo-catalyst, CuI/Zn(OAc)2(10
mol % each) for the desired transformation.To our delight, yield
of the reaction (70%) as well as the reaction rate (3h) were
significantly improved under the identical reaction condition
(Table 1, entry 6). It was found that the said reaction was unable
to proceed at room temperature in CH3CN medium under similar
catalyst loading (CuI/Zn(OAc)2, 10 mol % each). Different
solvents such as PhMe, THF (tetrahydrofuran) were also
screened for this reaction, but in each case compound 4b was
obtained in comparatively low yield and after a much longer
period of time (Table 1, entries 8-9).Few other reactions (4a, 4d)
were also performed in these solvent systems (THF,PhMe) which
provided relatively lower yields of the corresponding products
(Table 1, entries 10-13).
energy, hazardous solvent and low substrate scope. Thus, a mild
and competent strategy to access pyrido[2,3-c]coumarins is still
challenging and highly desirable.
Figure. 1 Bioactive and naturally occurring molecules
containing pyridocoumarin moiety
In recent years, solvent-free, ball-milling process has been
emerged as a powerful tool for greener reactions.18High Speed
Ball-Milling (HSBM) is
a
sustainable mechanochemical
technique, which is used in synthetic organic chemistry to
promote reactions under solvent-free conditions.18a,19This
technique has been applied to a variety of organic reactions such
as Knoevenagel condensation reactions,20Heck-type cross-
couplings,21Baylis Hillman reactions,22Michael additions,20
functionalization of fullerenes23and Sonogashira coupling24.
Analyzing the literature reports, we have opted this ball milling
technique and planned to materialize the oxidative C-C and C-N
bond formation through C(sp2)-H activation. In continuation of
our recent effort to synthesize biologically relevant
heterocycles,25 we wish to report a solvent-free, greener ball
milling synthetic protocol for the synthesis of a wide range of
pyridocoumarin derivatives starting from 3-aminocoumarin,
aldehyde and phenyl acetylene, catalyzed by CuI-Zn(OAc)2
involving a propargylic amine intermediate and CuI -CuIII
switching mechanism.
Table 1.Optimization of reaction condition to synthesize
pyridocoumarinderivativesa
Catalyst
(mol %)
Reaction
condition
Temperature
o C)
time
yieldb
(%)
Entry
(
(min)
1
2
CuI (10 mol%)
Zn(OAc)2(10
mol%)
CH3CN
CH3CN
70 o
C
C
8 h
8 h
-
-
70 o
3
4
5
ZnI2(10 mol%)
Cu(OAc)2(10mol%)
CuBr-ZnI2 (10
mol% each)
CuI-Zn(OAc)2
(10 mol% each)
CuI-Zn(OAc)2 (10
mol% each)
CuI-Zn(OAc)2 (10
mol% each)
CuI-Zn(OAc)2 (10
mol% each)
CuI-Zn(OAc)2 (10
mol% each)
CuI-Zn(OAc)2 (10
mol% each)
CuI-Zn(OAc)2 (10
mol% each)
CuI-Zn(OAc)2 (10
mol% each)
CuBr-
Zn(OAc)2(10mol%
each)
CuI (7mol
%)/Zn(OAc)2(9mol
%)
CuI-
Zn(OAc)2(5mol%
each)
CuBr-ZnI2(10
mol% each)
CH3CN
CH3CN
CH3CN
70 o
70 o
70 o
C
C
C
8 h
8 h
4 h
-
-
52
6
7
CH3CN
CH3CN
PhMe
THF
70 o
r.t.
C
3 h
3 h
4 h
4 h
4 h
4 h
4 h
4 h
1
70
-
8
70 o
70 o
70 o
70 o
70 o
70 o
r.t
C
C
C
C
C
C
69
65
49
59
60
61
82
9
10c
11 d
12 c
13 d
14e
THF
THF
PhMe
PhMe
Solvent-
free Ball-
milling
Solvent-
free Ball-
milling
Solvent-
free Ball-
milling
Solvent-
free Ball-
milling
Solvent-
free Ball-
milling
15e
16e
17e
18e
19e
r.t
r.t
r.t
r.t
r.t
35
min
89
85
77
-
1 h
1h
2h
1h
-
Scheme 1: Various synthetic strategies involving amine/3-
aminocoumarin, aldehyde and terminal alkyne
TFA (10 mol%)
Solvent-
free Ball-
milling
-
2. Results and Discussion
20
21
TFA (10 mol%)
DCM
r.t
r.t
2h
-
To study the possibility of our hypothesis for the synthesis of
pyridocoumarin
CuI (7mol
%)/Zn(OAc)2
(9mol%)
Solvent-
free Ball-
milling
50min
85
derivatives,
3-aminocoumarin(1),4-
methylbenzaldehyde (2) and phenyl acetylene (3) were chosen as
the model substrate. Initially, 3-aminocoumarin (1),4-
methylbenzaldehyde (2) and phenyl acetylene (3) were taken in
aIn
each
case 3-aminocoumarin
(1.0
mmol),
4-
methylbenzaldehyde (1.2 mmol) and phenyl acetylene (1 mmol)
b
and 3 mL of solvent were taken in a 25 mL rb flask. Yield of
the isolated product. cbenzaldehyde (1.2 mmol) was used. d4-
o
CH3CN solvent and treated with 10 mol % of CuI at 70 C but
reaction did not proceed even after prolonged heating (Table 1,
e
cyanobenzaldehyde (1.2 mmol) was used. Reactions performed

3
in a stainless steel jar under solvent-free ball-milling technique,
internal temperature based on friction is 65oC
Table 2: Substrate scope for the synthesis of
pyridocoumarinsa
Next we focused our attention to perform the reaction under
solvent-free condition. In this regard, 3-aminocoumarin (1), 4-
methylbenzaldehyde
(2),
phenyl
acetylene
(3) and
(CuI/Zn(OAc)2, 10 mol % each) were placed in high vibrational
ball milling apparatus and grinded at 30 Hz. Surprisingly, we
obtained 82 % yield of the product within 1h (Table 1, entry 14).
Lowering of the catalyst loading (CuI/Zn(OAc)2, 5 mol % each)
under ball-milling process decreases the yield of the product
(Table 1, entry 16). Finally, it was established that employment
of CuI/Zn(OAc)2,@ 7 mol % and 9 mol % respectively provided
the desired product (4b) within 35 min giving 89% yield (Table
1, entry 15).It was also noticed that on continuation of the
optimized reaction for a longer time (50 min) under ball-milling
technique has resulted in slightly lowering of the yield (4b).At
the end of the experiment, all the contents were taken out for
column chromatographic separation directly using ethyl acetate/
petroleum ether (1:4).
C-C coupling
C-C coupling
C(sp2)-H activation
H
C-N coupling
O
R2
R2
R2
H
NH2
O
CuI / Zn(OAc) 2
Ball milling
2
N
O
N
O
+
+
+
O
R1
O
O
Ph
H
R1
R1
1
3
4
5
Not found
Scheme 2. Combo-catalysis for C(sp2)-H activation and
cyclization
Achieving the optimized reaction condition for our protocol to
synthesize pyridocoumarins, we have investigated the substrate
scope for this chemical transformation. A wide range of aromatic
aldehydes, heteroaromatic aldehydes and substituted 3-
aminocoumarins were employed for this reaction.However,
desired transformation became unsuccessful under imposed
reaction condition when disubstituted alkyne (Diethyl
acetylenedicarboxylate) was employed.
a
In each case 3-aminocoumarin derivatives (1.0 mmol),
substituted aldehyde (1.2 mmol) and phenyl acetylene (1
mmol) were taken in a stainless steel ball milling vial with
b
two stainless steel ball (d= 5.0 mm). Yield of the isolated
product
This synthetic protocol was found to be extremely facile to
access a library of pyridocoumarin derivatives under solvent-free
condition (Table 2, entry 4a-4r). It is noteworthy to mention that
the reaction was very clean producing only pyridocoumarin as
the sole isolable product and no other side products were detected
(Scheme 2). All the synthesized pyridocoumarin derivatives have
been well characterized by spectral analysis (1H NMR, 13C NMR,
IR) and finally the structural motif of the pyridocoumarin
scaffold was established through X-ray crystallographic analysis
of single crystal of one representative compound 4c (CCDC
1540607, Figure 2).
Figure 2. Single Crystal Structure of compound 4c
dehydrogenation
R2
R2
A plausible mechanism for this reaction is depicted in scheme 3.
−Vis data26
N
N
H
On the basis of the controlled experiments, UV
data27 and literature reports28, we proposed
, XPS
plausible
O
O
O
O
4
a
V
C-C
coupling
H
Ph
CuI
3
mechanism for this chemical transformation (scheme 3). At first,
CuI activated the terminal C−H of the alkyne to produce
−C and C−N bond
(II, Scheme 3). The C
Reductive
elimination
H
III
I
Cu
R2
formation between 3-aminocoumarin (1), aldehyde (2), and
intermediate II generated propargylic amine intermediate III.29
Zn(OAc)2 might act as Lewis Acid catalyst to polarize C=O
during C-C and C-N coupling to form III. The intermediate III
containing the flexible C-C triple bond allowed CuI to activate
NH
CuI
Ph
II
O
O
IV
Zn(OAc)2
O
C-H activated
H
N
Oxidative insertion
NH2
O
R2
+
CuI
H
R2
O
1
O
O
2
H2
O
III
Ph
−H and π
the aromatic C
−H insertion with
-bonds for oxidative C
C-C and C-N coupling
C−C coupling30 to form a seven-membered intermediate IV. This
CuIII containing seven-membered intermediate IV was then
Scheme 3. Combo-catalysis cycle

4
Tetrahedron
transformed into a transient intermediate V by reductive
elimination of IV. Then intermediate V immediately transformed
into desired product 4 involving the aromatization of V 31(scheme
3).
CuI-catalyzed C(sp2)-H activation and functionalization involving
in-situgenerated aryl-CuIII species. UV-Vis, XPS, ESI-MS, and
control experiments were successfully carried out to establish the
reaction mechanism which clearly depictsthat the reaction
proceeds through a mechanistic pathway of CuI-CuIII switching.
To establish the reaction mechanism, we conducted several
control experiments. In this regard, reaction was performed under
catalyst-free condition but it was unable to proceed even after
prolonged grinding (Table 1, entries 18). We also performed two
separate control experiments with CuI and Zn(OAc)2 (Table 1,
entries 1-2) and the reaction did not proceed. Formation of
copper acetylide is supported by the fact that the reaction was
completely plugged when internal alkyne was employed.The
cyclization reaction was ineffective upon using the imine
(generated from 3-aminocoumarin and benzaldehyde) and
phenylacetylene under imposed reaction condition which justifies
that the reaction proceeded without the formation of an imine
intermediate.Moreover, application of catalytic amount (10
mol%) of Bronsted acid catalyst17b (trifluoroacetic acid) could not
trigger the reaction under solvent-free ball milling condition
(Table 1, entry 19) and also in DCM medium (Table 1, entry
20).The formation of the transient CuIII-species (IV) was
confirmed and established by analyzingUV−Vis26 spectra of the
reaction mixture of 4p at different time interval (15 min, 30 min,
60 min) of the reaction(Figure 3), XPS27 (Figure 4)and
electrospray ionization mass spectrometry (ESI-MS) (for IV; e/z
541.9675 [M + H]) of the reaction mixture (4p) after 15 min of
the reaction.
4. Acknowledgments
We acknowledge the financial support from the centre of
CAS-V (Synthesis and functional materials) of department of
Chemistry, University of Calcutta for financial support. N.K.
thanks
DST,
New
Delhi,
India for
DST-inspire
fellowship.Crystallography was performed at the DST-FIST,
India-funded Single Crystal Diffractometer Facility at the
Department of Chemistry, University of Calcutta.
5. References and notes
1. Yamaguchi J, Yamaguchi AD, Itami K. Angew Chem Int Ed.
2012;51:8960.
2. (a) Coperet C. Chem Rev. 2010;110:656-690; (b) Lyons TW, Sanford
MS. Chem Rev. 2010;110:1147-1169; (c) Campbell AN, Stahl SS. Acc Chem
Res.2012;45:851-863; (d) Engle KM, Mei T-S, Wasa M, Yu J-Q. Acc Chem
Res.2012;45:788-802; (e) Li B, Dixneuf, PH. Chem Soc Rev.2013;42:5744-
5767; (f) Ackermann L. Acc Chem Res.2014;47:281-295.
3.(a) Maiti DK, Halder S, Pandit P, et al.J Org Chem. 2009;74:8086-
8097; (b) Roy D, Sarkar S, Laha RM, Pramanik N, Maiti DK. RSC Adv.
2015;5:73346-73351; (c) Pramanik N, Sarkar S, Roy D, et al. RSC Adv.
2015;5:101959-101964; (d) Ueda S, Nagasawa H.
J Am Chem Soc.
2009;131:15080-15081; (e) Das RK, Saha B, Rahaman SMW, Bera JK.
Chem Eur J. 2010;16:14459-14468; (f) Carreras J ,Gopakumar G, GuL,
Gimeno A, et al. J Am Chem Soc. 2013;135:18815-18823; (g) Liu S, Motta
A, Delferro M, Marks TJ. J Am Chem Soc.2013;135:8830-8833; (h) PiC, Cui
X, Wu Y. J Org Chem.2015;80:7333-7339.
4. (a) Wei C, Li C-J. J. Am Chem Soc. 2002; 124:5638-5693; (b)
Gommermann N, Koradin C, Polborn K, Knochel P. Angew Chem Int Ed.
2003; 42:5763-5766; (c) Aschwanden P, Stephenson CRJ ,Carreira EM. Org
Lett. 2006;8:2437-2440; (d) Matsubara S, Okamura T, Asano K. Synlett.2010;
3053-3056; (e) Meyet CE ,Pierce CJ, Larsen CH. Org. Lett.2012;14: 964-
967; (f) Cardoso FSP, Abboud KA, Aponick A.
Soc.2013;135:14548-14551.
J
Am Chem
5. (a) Kumar A, Verma M, Saxena AK, Shanker K. Indian J Chem. 1987;
26B:378-380; (b)Burlison JA, Neckers L, Smith AB, Maxwell A, Blagg BSJ.
J Am Chem Soc. 2006; 128:15529.
6. (a) Chen Z, Hu L, Peng F. Synlett. 2016; DOI: 10.1055/s-0035-
1561610; (b) Kadhum AAH, Mohamad AB, Al-Amiery AA, Takriff MS.
Molecules 2011; 16:6969-6984.
7. Kulkarni YD, Srivastava D, Bishnoi A, Dua PR. J Indian Chem
Soc.1996;73:173.
Figure 3.UV-Visible study for detection of aryl-CuIII species
8. Melagraki G, Afantitis A, Igglessi-MarkopoulouO, et al.Eur J Med
Chem.2009;44:3020.
9. Marcu MG, Schulte TW, NeckersL. J Natl Cancer Inst. 2000;92: 242.
10. Rodighiero G,Antonello C. Boll Chim Farm.1958;97:592.
11. (a) Hammond PR, Atkins RL. J Heterocycl Chem. 1978;12:1061; (b)
Atkins RL, Bliss DE. J Org Chem. 1978;43:1975; (c) Grandberg II, Denisov
LK, Popova OA. Khim Geterotsikl Soedin.1987;2:147.
12. Fujimoto A, Sakurai A, Iwase E. Bull Chem Soc Jpn. 1976;49:809.
13. Mohanty N, Rath PC, Rout KK. J Indian Chem Soc. 1967;44:1001.
14. Majumdar KC, Chattopadhyay B, Taher A. Synthesis 2007; 3647-
3652.
15. Kudale AA, Kendall J, Miller DO, Collins JL, Bodwell GJ. J Org
Chem. 2008;73:8437-8447.
16. Kudale AA, Miller DO, Dawe LN, Bodwell GJ. Org Biomol Chem.2
011;9:7196.
17. (a) Brown CE, McNulty J, Bordón C, et al. Org Biomol Chem. 2016;
14: 5951–5955; (b) Khan AT, Das DK, Islam K, Das P. Tetrahedron Lett.
2012;53:6418-6422.
Figure 4. XPS study for detection of CuI-CuIII species
18. (a) Stolle A, Szuppa T, Leonhardt SES, Ondruschka B.Chem Soc Rev.
2011;40:2317-2329; (b) Rodríguez B, Bruckmann A, Rantanen T, Bolm C.
Adv Synth Catal. 2007; 349:2213-2233; (c) Chauhan P, Chimni, SS. Beilstein
J Org Chem. 2012; 8:2132-2141.
3. Conclusions
19. (a) Li Z, Jianga Z, Su W.Green Chem. 2015; 17:2330-2334.
20. Kaupp G, Naimi-Jamal MR, Schmeyers J. Tetrahedron 2003; 59:
3753-3760.
In conclusion, a combo-catalytic, rapid, solvent-free, ball-
milling process has been developed for the synthesis of
pyridocoumarins starting from 3-aminocoumarin, aldehyde and
phenyl acetylene. This method describes a proper example of
21. Tullberg E, Peters D, Frejd, T. J Organomet Chem. 2004; 689:3778-
3781.
22. Mack J, Shumba M. Green Chem. 2007; 9:328-330.

5
23. Komatsu K. Top Curr Chem. 2005; 254:185-206.
24. Thorwirth R,Stolle A.Ondruschka B. Green Chem. 2010; 12:985-991.
25. (a) Das AR, Medda, A ,Singha R. Tetrahedron Lett. 2010; 51:1099-
1102; (b) Bhattacharyya P, Medda A, Das AR, et al. J Indian Chem Soc.
2012; 89:623-629; (c) Kausar N, Mukherjee P, Das AR.RSC Adv. 2016;
6:88904-88910; (d) Kausar N, Masum AA, Islam MM, Das AR. Mol Divers.
2017; DOI: 10.1007/s11030-017-9728-9.
26. King AE, Huffman LM, Casitas A, et al. J Am Chem Soc. 2010; 132:
12068-12073.
27. Kim MS, Yang JB, Medvedeva J, et al. J Phys: Condens Matter 2008;
20:255228.
28. Deng X, Liang J, Allison BB, et al.J Org Chem. 2015; 80:11003-
11012.
29. Rotstein BH, Zaretsky S, Rai V, Yudin AK. Chem Rev. 2014; 114:
8323-8359.
30. Arockiam PB, Bruneau C, Dixneuf PH. Chem Rev. 2012; 112:5879-
5918.
31. Jana R, Paul S, Biswas A, Ray JK. Tetrahedron Lett.2010; 51:273-
276.
General Procedure for the Synthesis of pyridocoumarins: A mixture of 3-
aminocoumarin (1, 1 mmol), aldehyde (2, 1.2 mmol), phenylacetylene (3, 1
mmol), catalyst CuI (0.013 mg, 7 mol %) and Zn(OAc)2 (0.017 mg, 9 mol %)
were taken in a stainless steel ball milling vial with two stainless steel ball
(d= 5.0 mm). Then the vial was placed in a vibrational micromill, and grinded
at 30 Hz for 35-90 min. A pause was added after every 10 minutes of
grinding until the vial cool down. The progress of the reaction was monitored
using TLC. At the end of the experiment, all the contents were taken out for
column chromatographic separation directly using ethyl acetate/ petroleum
ether (1:4).Characterization data of 4c:White solid (0.341g, 90%); Mp: 206-
208 oC; 1H NMR (300 MHz; CDCl3; Me4Si): δ 3.79 (s, 3H), 6.79-6.81 (m,
1H), 6.91-6.96 (m, 3H), 7.26-7.28 (m, 2H), 7.34-7.38 (m, 2H), 7.47-7.49 (m,
3H), 7.81 (s, 1H), 8.05 (d, J= 8.7 Hz, 2H); 13C NMR (75 MHz; CDCl3;
Me4Si): δ 55.28, 114,16, 117.12, 117.60, 123,51, 126.64, 127.39, 128.03,
128.11, 128.73, 128.91, 129.36, 129.59, 139.07, 139.79, 148.62, 150. 69,
-1;
157.02, 159.06, 161.37; IR (KBr): 2936, 1759, 1607cm ESI-MS Calcd. for
C25H17NO3: [M+Na]+, 402.1101; Found: m/z 402.1103 (See Supplementary
Information).