Novel copper-catalyzed multicomponent cascade synthesis of iminocoumarin aryl methyl ethers

Article abstract of DOI:10.1021/ol4014359

A copper(I)-catalyzed one-pot synthesis of iminocoumarin aryl methyl ethers has been developed from ynal, phenol, and sulfonyl azide at ambient conditions via a cascade [3 + 2]-cycloaddition, 1,3-pseudopericyclic ketenimine rearrangement, 1,4-conjugate addition, and aldol-type condensation. This protocol provides a potential route for the construction of a library of iminocoumarin aryl methyl ethers in good yields.

Full text of DOI:10.1021/ol4014359

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Novel Copper-Catalyzed Multicomponent
Cascade Synthesis of Iminocoumarin Aryl
Methyl Ethers
Govindarasu Murugavel and Tharmalingam Punniyamurthy*
Department of Chemistry, Indian Institute of Technology Guwahati, Guwahati-781039,
India
tpunni@iitg.ernet.in
Received May 21, 2013
ABSTRACT
A copper(I)-catalyzed one-pot synthesis of iminocoumarin aryl methyl ethers has been developed from ynal, phenol, and sulfonyl azide at ambient
conditions via a cascade [3 þ 2]-cycloaddition, 1,3-pseudopericyclic ketenimine rearrangement, 1,4-conjugate addition, and aldol-type con-
densation. This protocol provides a potential route for the construction of a library of iminocoumarin aryl methyl ethers in good yields.
The transformation of simple substrates into a library of
complex molecules with structural diversity constitutes a
great challenge in organic synthesis. The use of a one-pot
multicomponent reaction (MCR) with cascade processes
offers an extremely powerful tool for this strategy.1ꢀ6
Iminocoumarins are privileged structural frameworks ex-
hibiting widespread biological, medicinal, and material
applications. For example, iminocoumarins exhibit anti-
tumor,7a anticancer,7b and antimicrobial properties.7c In
addition, they serve as inhibitors of protein-tyrosine kinase
p56lck,7d dynamins I and II GTPase,7e and HIV-1
integrase.7f Furthermore, iminocoumarins are widely
used as dyes8a and fluorescent sensors for the estimation
of metal ions in micromolar concentrations.8b Whereas the
common methods for the synthesis of iminocoumarins
take advantage of the Knoevenagel reaction,9 some diffi-
culties are often encountered such as the limited substrate
scope and harsh reaction conditions. Development of
effective methods for the synthesis of iminocoumarin
(5) For examples of copper-catalyzed MCR via ketenimine, see: (a)
Lu, P.; Wang, Y. Chem. Soc. Rev. 2012, 41, 5687. (b) Kim, S. H.; Park,
S. H.; Choi, J. H.; Chang, S. Chem.;Asian J. 2011, 6, 2618. (c) Yoo,
E. J.; Chang, S. Curr. Org. Chem. 2009, 13, 1766. (d) Yoo, E. J.; Ahlquist,
M.; Kim, S. H.; Bae, I.; Fokin, V. V.; Sharpless, K. B.; Chang, S. Angew.
Chem., Int. Ed. 2007, 46, 1730. (e) Yoo, E. J.; Ahlquist, M.; Bae, I.;
Folkin, V. V.; Sharpless, K. B.; Chang, S. J. Org. Chem. 2008, 73, 5520.
(f) Whiting, M.; Fokin, V. V. Angew. Chem., Int. Ed. 2006, 45, 3157. (g)
Xu, X.; Cheng, D.; Li, J.; Guo, H.; Yan, J. Org. Lett. 2007, 9, 1585. (h)
Cui, S. L.; Wang, J.; Wang, Y. G. Org. Lett. 2007, 9, 5023. (i) Kim, J.;
Lee, Y.; Do, Y.; Chang, S. J. Org. Chem. 2008, 73, 9454. (j) Lu, W.; Song,
W. Z.; Hong, D.; Lu, P.; Wang, Y.-G. Adv. Synth. Catal. 2009, 351, 1768.
(k) Shang, Y.; He, X.; Hu, J.; Wu, J.; Zhang, M.; Yu, S.; Zhang, Q. Adv.
Synth. Catal. 2009, 351, 2709. (l) Yao, W.; Pan, L.; Zhang, Y.; Wang, G.;
Wang, X.; Ma, C. Angew. Chem., Int. Ed. 2010, 49, 9210. (m) Namitharan,
K.;Pitchumani, K.Org. Lett. 2011, 13, 5728. (n)Chen, Z.;Ye, C.; Gao, L.;
Wu, J. Chem. Commun. 2011, 47, 5623. (o) Li, S.; Luo, Y.; Wu, J. Org.
Lett. 2011, 13, 4312. (p) Jiang, Z.; Lu, P.; Wang, Y. Org. Lett. 2012, 14,
6266. (q) Li, S.; Wu, J. Chem. Commun. 2012, 48, 8973. (r) Li, B.-S.; Yang,
B.-M.; Wang, S.-H.;Zhang, Y.-Q.;Cao, X.-P.;Tu, Y.-Q. Chem. Sci. 2012,
3, 1975. (s) Namitharan, K.; Pitchumani, K. Adv. Synth. Catal. 2013, 355,
93. (t) Bae, I.; Han, H.; Chang, S. J. Am. Chem. Soc. 2005, 127, 2038. (u)
Cho, S. H.; Yoo, E. J.; Bae, I.; Chang, S. J. Am. Chem. Soc. 2005, 127,
16046. (v) Yoo, E. J.; Bae, I.; Cho, S. H.; Han, H.; Chang, S. Org. Lett.
2006, 8, 1347. (w) Cui, S.-L.; Lin, X.-F.; Wang, Y.-G. Org. Lett. 2006, 8,
4517. (x) Shen, Y.; Cui, S.; Wang, J.; Chen, X.; Lu, P.; Wang, Y. Adv.
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(1) For examples of a book and reviews of MCR, see: (a) Multi-
€
component Reactions; Zhu, J., Gopel, W., Hesse, J., Eds.; WILEY-VCH:
€
Weinheim, 2005. (b) Domling, A.; Ugi, I. Angew. Chem., Int. Ed. 2000, 45,
ꢀ
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(d) Domling, A. Chem. Rev. 2006, 106, 17. (e) Toure, B. B.; Hall, D. G.
Chem. Rev. 2009, 109, 4439. (f) Ganem, B. Acc. Chem. Res. 2009, 42, 463.
(g) Sunderhaus, J. D.; Martin, S. F. Chem.;Eur. J. 2009, 15, 1300.
(2) For reviews on applications of MCR in biological and medicinal
€
sciences, see: (a) Domling, A.; Wang, W.; Wang, K. Chem. Rev. 2012,
112, 3083. (b) Slobbe, P.; Ruijter, E.; Orru, R. V. A. Med. Chem.
Commun. 2012, 3, 1189.
(3) Hulme, C.; Gore, V. Curr. Med. Chem. 2003, 10, 51.
(4) For books and reviews on transition-metal-catalyzed MCR, see:
(a) Balme, G.; Bouyssi, D.; Monteiro, N. Metal-Catalyzed Multicom-
ꢀ
ponent Reactions. In Multicomponent Reactions; Zhu, J., Bienayme, H.,
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r
10.1021/ol4014359
XXXX American Chemical Society

derivatives is thus attractive and challenging. Recently, Wang
and co-workers reported the copper(I)-catalyzed synthesis of
iminocoumarins from an alkyne and sulfonyl azide with
either salicylaldehyde5t or 2-ethynylphenol5u (Scheme 1). In
continuation of our studies on heterocycle syntheses,10 we
report herein the synthesis of iminocoumarin aryl methyl
ethers 4 from the coupling of ynals 1, phenols 2, and sulfonyl
azides 3 using copper(I) catalysis via a cascade [3 þ 2]-
cycloaddition, ketenimine rearrangement,11 1,4-conjugate
addition, and aldol condensation. This protocol provides a
potential route for the synthesis of the target products using
the rearrangement of the ketenimine as a key step.
Scheme 1. Multicomponent Syntheses of Iminocoumarins
First, our investigation started with ynal 1a, phenol 2a,
and p-toluenesulfonyl azide (TsN3) 3a as the model sub-
strates for the scrutinization of the reaction conditions,
which was carried out using different Cu(I) sources, bases,
additives, and solvents at room temperature under air
(Table 1). Gratifyingly, the reaction proceeded to afford
the iminocoumarin aryl methyl ether 4a in 30% yield when
the substrates 1a, 2a, and 3a were reacted with 10 mol %
CuI and 2.2 equiv of K2CO3 in CH2Cl2 under ambient
conditions (entry 2). Surprisingly, the use of tetrabutylammo-
nium iodide (TBAI) as an additive led to an increase in the
yield to 83%, whereas tetrabutylammonium bromide
(TBAB) and tetrabutylammonium chloride (TBAC) af-
forded a 76% and 71% yield, respectively.12 In a set of
bases screened, K2CO3 furnished the best results, while
Na2CO3 resulted in a moderate yield. In contrast, Cs2CO3,
K3PO4, and Et3N showed no effect for the target reaction.
CuI provided a superior yield compared to the other
copper(I) salts such as CuBr, CuCl, and Cu2O that were
tested. Consequently, CH2Cl2 was found to be the solvent
of choice. Other solvents such as toluene, THF, CH3CN,
and 1,2-dichloroethane has no appreciable effect on 4a, as
it resulted in a sluggish conversion. A control experiment
Table 1. Optimization of the Reaction Conditionsa
entry
catalyst
base
Et3N
additive
solvent
yield (%)b
1
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuBr
CuCl
Cu2O
ꢀ
ꢀ
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH3CN
(CH2Cl)2
THF
n.d.
30
2
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
Na2CO3
Cs2CO3
K3PO4
K2CO3
K2CO3
K2CO3
K2CO3
ꢀ
3
TBAB
TBAC
TBAI
TBAI
TBAI
TBAI
TBAI
TBAI
TBAI
TBAI
TBAI
TBAI
TBAI
TBAI
76
4
71
5
83
6
42
7
74
8
28
(7) For examples, see: (a) O’Challaghan, C. N.; Conalty, M. L. Proc. R.
Ir. Acad., Sec. B 1979, 79B, 87. (b) Al-Said, M. S.; El-Gazzar, M. G.;
Ghorab, M. M. Eur. J. Chem. 2012, 3, 228. (c) Costa, M.; Areias, F.;
9
toluene
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
60
10
11
12
13
14
15
16
35
n.d.
n.d.
67
^
Abrunhosa, L.; Vanancio, A.; Proenc-a, F. J. Org. Chem. 2008, 73, 1954. (d)
Burke, T. R., Jr.;Lim, B.; Marquez, V. E.;Li, Z. H.; Bolen, J. B.; Stefanova,
I.; Horak, I. D. J. Med. Chem. 1993, 36, 425. (e) Hill, T. A.; Mariana, A.;
Gordon, C. P.;Odell, L. R.;Robertson, M. J.; McGeachie, A. B.;Chau, N.;
Daniel, J. A.; Gorgani, N. N.; Robinson, P. J.; McCluskey, A. J. Med.
Chem. 2010, 53, 4094. (f) Burke, T. R., Jr.; Fesen, M.; Mazumder, A.; Yung,
J.; Wang, J.; Carothers, A. M.; Grunberger, D.; Driscoll, J.; Pommier, Y.;
Kohn, K. J. Med. Chem. 1995, 38, 4171.
(8) For examples, see: (a) Guo, D.; Chen, T.; Ye, D.; Xu, J.; Jiang, H.;
Chen, K.; Wang, H.; Liu, H. Org. Lett. 2011, 13, 2884. (b) Komatsu, K.;
Urano, Y.; Kojima, H.; Nagano, T. J. Am. Chem. Soc. 2007, 129, 13447.
(9) (a) Freeman, F. Chem. Rev. 1969, 69, 591. (b) Volmajer, J.;
Toplak, R.; Leban, I.; Le Marechal, A. M. Tetrahedron 2005, 61,
7012. (c) Borisov, A. V.; Dzhavakhishvili, S. G.; Zhuravel, I. O.;
Kovalenko, S. M.; Nikitchenko, V. M. J. Comb. Chem. 2007, 9, 5.
(10) For examples, see: (a) Saha, P.; Ramana, T.; Purkait, N.; Ali,
M. A.; Paul, R.; Punniyamurthy, T. J. Org. Chem. 2009, 74, 8719. (b) Guru,
M. M.; Ali, M. A.; Punniyamurthy, T. J. Org. Chem. 2011, 76, 5295. (c)
Guru, M. M.; Ali, M. A.; Punniyamurthy, T. Org. Lett. 2011, 13, 1194. (d)
Sengoden, M.; Punniyamurthy, T. Angew. Chem., Int. Ed. 2013, 52, 572.
(11) For ketenimine rearrangement, see: (a) Nguyen, M. T.; Landuyt,
L.; Nguyen, H. M. T. Eur. J. Org. Chem. 1999, 401. (b) Finnerty, J. J.;
Wentrup, C. J. Org. Chem. 2004, 69, 1909. (c) Finnerty, J. J.; Wentrup,
C. J. Org. Chem. 2005, 70, 9735.
71
41
n.d.
a Ynal 1a (0.5 mmol), phenol 2a (0.6 mmol), azide 3a (0.6 mmol),
catalyst (10 mol %), base (1.1 mmol), additive (10 mol %), solvent
(3.0mL), 8h, air. b Determined by 400 MHz 1HNMR. n.d. =not detected.
confirmed that, without the Cu source, the target reaction
was not observed.
With the optimal conditions in hand, the scope of the
procedure was next explored for the reactions of a series of
substituted phenols 2aꢀn with ynal 1a and azide 3a as
standard substrates (Table 2). The reactions occurred
readily to afford the target heterocycles in good yields.
For example, the reactions of the substituted phenols 2aꢀe
with phenyl, 2-iodo, 3-bromo, and 2-methyl groups fur-
nished the iminocoumarin aryl methyl ethers 4aꢀe in
55ꢀ79% yields, while the phenols 2fꢀh with 4-fluoro,
(12) For use of TBAI as an additive, see: (a) Kofink, C. C.; Knochel,
P. Org. Lett. 2006, 8, 4121. (b) Kim, S.; Sohn, D. W.; Kim, Y. C.; Kim,
S.-A.; Lee, S. K.; Kim, H. S. Arch. Pharm. Res. 2007, 30, 18. (c) Sio,
V. D.; Massa, A.; Scettri, A. Org. Biomol. Chem. 2010, 8, 3055.
B
Org. Lett., Vol. XX, No. XX, XXXX

4-bromo, and 4-chloro groups reacted to give the target
products 4fꢀh in 60ꢀ63% yields. Similar results were
observed with the phenols 2iꢀk containing 4-CHO,
4-methoxy, and 4-methyl substituents affording 4iꢀk in
49ꢀ66% yields, whereas the disubstituted phenols 2lꢀn
with dimethyl groups gave the iminocoumarin aryl methyl
ethers 4lꢀn in 72ꢀ77% yields. Phenols containing elec-
tron-donating groups exhibited greater reactivity in com-
parison to bearing-electron withdrawing groups. The
crystallization of 4j in a 1:1 mixture of CH2Cl2 and MeOH
gave crystals whose structure was confirmed by a single
crystal X-ray analysis (Figure 1).
The reaction of the substituted ynals 1bꢀg was further
studied with phenols 2a, 2f, and 2j and p-toluenesulfonyl
azide 3a (Table 3). As above, the reactions took place to
provide the iminocoumarin aryl methyl ethers in good
yields. The ynals 1bꢀc bearing a methoxy group underwent
reactions with phenol 2a to give the target products 4oꢀp in
70% and 62% yield, respectively. Likewise, the ynal 1d with
the 5-bromo substituent proceeded to react with phenols
2a and 2j to furnish the desired heterocycles 4qꢀr in 57%
and 65% yield, respectively, while the ynal 1e having a
5-methoxy group reacted with 2a and 2f to provide 4sꢀt in
65%ꢀ71% yield. Similarly, the ynals 1fꢀg with 5-methyl
and di-tert-butlyl groups proceeded to react with 2a to give
the iminocoumarin aryl methyl ethers 4uꢀv in 63%ꢀ77%
yield.
Table 2. Reaction of Ynal 1a, p-Toluene Sulfonyl Azide 3a with
Finally, the reaction of sulfonyl azides 3bꢀd was
examined with ynal 1a and phenol 2a (Table 4). These
substrates proceeded to react in moderate to good yields.
For example, the reactions of methanesulfonyl azide 3b
Different Substituted Phenolsa
Table 3. Reaction of p-Toluene Sulfonyl Azide with Different
Substituted Ynals and Phenolsa
entry
2
R
4
yield (%)b
1
2a
2b
2c
2d
2e
2f
H
4a
4b
4c
4d
4e
4f
79
60
78
55
64
61
60
63
49
66
65
72
77
74
2
2-I
3
2-Me
4
3-Br
5
3-Me
6
4-Br
entry
1
R
2
R0
4
yield (%)b
7
2g
2h
2i
4-Cl
4g
4h
4i
8
4-F
1
2
3
4
5
6
7
8
1b
1c
1d
1d
1e
1e
1f
3-MeO
4-MeO
5-Br
2a
2a
2a
2j
H
H
H
4o
4p
4q
4r
4s
4t
70
62
57
65
65
71
77
63
9
4-CHO
4-MeO
4-Me
10
11
12
13
14
2j
4j
2k
2l
4k
4l
5-Br
4-MeO
H
2,3-Me2
3,4-Me2
3,5-Me2
5-MeO
5-MeO
5-Me
2a
2f
2m
2n
4m
4n
4-Br
H
2a
2a
4u
4v
1g
3,5-t-Bu2
H
a Ynal 1a (0.5 mmol), phenol 2 (0.6 mmol), azide 3a (0.6 mmol), CuI
(10 mol %), K2CO3 (1.1 mmol), TBAI (10 mol %), CH2Cl2 (3.0 mL), 8 h,
air. b Isolated yield.
a Ynal 1 (0.5 mmol), phenol 2 (0.6 mmol), azide 3a (0.6 mmol), CuI
(10 mol %), K2CO3 (1.1 mmol), TBAI (10 mol %), CH2Cl2 (3.0 mL), 8 h,
air. b Isolated yield.
Table 4. Reaction of Ynal 1a, Phenol 2a with Different Sulfonyl
Azidesa
entry
3
R
4
yield (%)b
1
2
3
3b
3c
3d
Me
Ph
4w
4x
4y
70
67
39
4-NO2C6H4
Figure 1. ORTEP diagram of (Z)-N-(3-((4-methoxyphenoxy)-
methyl)-2H-chromen-2-ylidene)-4-methylbenzenesulfonamide
4j. Thermal ellipsoids are drawn at the 50% probability level.
Hydrogen atoms have been omitted for clarity.
a Ynal 1a (0.5 mmol), phenol 2a (0.6 mmol), azide 3 (0.6 mmol), CuI
(10 mol %), K2CO3 (1.1 mmol), TBAI (10 mol %), CH2Cl2 (3.0 mL), 8 h,
air. b Isolated yield.
Org. Lett., Vol. XX, No. XX, XXXX
C

dehydration of E could yield the target product 4. The
absence of the formation of 5 suggests that this protocol
involves the rearrangement of the ketenimine B to afford D
compared to the direct intermolecular reaction of the
ketenimine B with the phenoxide ion that could lead to 5.
Scheme 2
Scheme 3. Proposed Catalytic Cycle
and phenylsulfonyl azide 3c could be accomplished in 70%
and 67% yield, respectively, while the azide 3d with a nitro
group exhibited moderate reactivity affording the imino-
coumarin aryl methyl ether 4y in 39% yield. This study
revealed that the reaction is not limited to only tosyl azide,
but other types of sulfonyl azide such as methane sulfonyl
azide, benzenesulfonyl azide, and p-nitrobenzenesulfonyl
azide can also be utilized. The substrates with an electron-
donating group exhibited greater reactivity compared to
those having electron-withdrawing groups.
The protocol was further examined for the reaction of
ynal 1h with phenol 2a and sulfonyl azide 3a (Scheme 2).
The reaction occurred to give the iminocoumarin aryl
methyl ether 4z in 67% yield. Under these conditions, the
use of methanol in place of phenol 2a was less effective
affording the iminocoumarin methyl methyl ether 4aa in
10% yield. Futhermore, the reaction of ketone 1i was
studied with phenol 2a and sulfonyl azide 3a. However,
the substrate 1i underwent decomposition and the target
product 4ab was not obtained.
The proposed catalytic cycle is shown in Scheme 3. The
Cu(I)-catalyzed azideꢀalkyne cycloaddition (CuAAC) of
alkyne 1 with azide 2 may generate ketenimine5 B via
intermediate A, which may undergo the pseudopericyclic
[1,3]-migration11 of 2-formylaryloate through the four-
membered cyclic zwitterionic transition state C to give
the intermediate D. The 1,4-conjugate addition of the
phenoxide ion with D may lead to the formation of the
intermediate E. The aldol-type condensation followed by
In summary, we have developed a copper-catalyzed
three-component synthesis of iminocoumarin aryl methyl
ethers from ynal 1, phenols 2, and sulfonyl azide 3 at room
temperature under air. The reaction takes place via a
cascade [3 þ 2]-cycloaddition, ketenimine rearrangement,
1,4-conjugate addition, and aldol-type condensation.
This protocol allows us to rapidly generate a series of
functionalized iminocoumarin aryl methyl ethers that are
of tremendous importance in medicinal and material
sciences. Further studies on the precise mechanism and
application to other reactions are currently underway.
Acknowledgment. We thank the Department of Science
and Technology, New Delhi, and Council of Scientific and
Industrial Research, New Delhi for financial support.
Supporting Information Available. Experimental pro-
cedure, characterization data, and NMR spectra (1H and
13C) of the products 4aꢀ4aa. This material is available
free of charge via the Internet at http://pubs.acs.org.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX