l-Proline catalyzed condensation of salicylaldehydes with ethyl nitroacetate: an efficient access to 3-nitrocoumarins

Article abstract of DOI:10.1007/s00706-016-1736-4

Abstract: l-Proline catalyzed condensation of salicylaldehydes and ethyl nitroacetate afforded 3-nitrocoumarins in good to high yields under mild conditions. This organocatalyzed process offers a much improved yield of 3-nitrocoumarins and well tolerates both electron-donating and electron-withdrawing substituents on the phenyl ring. Graphical abstract: [Figure not available: see fulltext.]

Full text of DOI:10.1007/s00706-016-1736-4

Monatsh Chem
DOI 10.1007/s00706-016-1736-4
ORIGINAL PAPER
L-Proline catalyzed condensation of salicylaldehydes with ethyl
nitroacetate: an efficient access to 3-nitrocoumarins
•
Rajesh Kumar Sharma Priyanka
•
Diksha Katiyar
Received: 1 February 2016 / Accepted: 9 March 2016
Ó Springer-Verlag Wien 2016
Abstract L-Proline catalyzed condensation of salicylalde-
hydes and ethyl nitroacetate afforded 3-nitrocoumarins in
good to high yields under mild conditions. This organocat-
because of their remarkable optical properties [4, 5].
Therefore, the development of synthetic protocols that
enable the synthesis of these compounds has attracted a
great deal of interest; especially over the past decade. The
Pechmann, Perkin, Knoevenagel, and Wittig reactions
involving condensation of phenols with carbonyl com-
pounds are some of the well established classic methods [6,
7] for their synthesis. Recently, a number of transition
metal-catalyzed routes have also been developed for the
obtention of functionalized coumarins [8]. It is well
established that the properties of coumarin compounds
depend largely on the nature and position of substituents [1,
2]. In particular it has been shown that the presence of
nitrogen-containing substituent at 3-position of coumarin
moiety induces specific properties [9–11]. For instance,
coumarins bearing 3-nitro substituent are important scaf-
folds having pharmaceutical and synthetic utility. They
have been reported as an efficient inhibitor of phospholi-
alyzed process offers
a much improved yield of
3-nitrocoumarins and well tolerates both electron-donating
and electron-withdrawing substituents on the phenyl ring.
Graphical abstract
R1
R1
O
R2
R2
N
O2
NO2
O
CHO
OH
OEt
-Proline
L
O
EtOH, rt or 80 oC
R3
R3
68-92%
Keywords Coumarins Á 3-Nitrocoumarins Á L-Proline Á
Organocatalysis Á Salicylaldehyde
pase
C enzyme and as promising antifungal and
antimicrobial agents [10–15]. Moreover, they are also used
as precursors of aminocoumarins and other important
molecules [16–22]. The methods reported in the literature
for the synthesis of 3-nitrocoumarins are commonly based
on direct nitration of unsubstituted coumarin with nitric
acid and condensation reaction of salicylaldehydes with
active methylenes [12, 23–27]. However, these methods
suffer from several drawbacks such as use of strong acids
or bases, long reaction times, complicated purification
process, low functional group tolerance, and low yield
(Scheme 1a). Therefore, it is strongly desirable to
develop improved methodologies for the synthesis of
3-nitrocoumarins.
Introduction
Coumarin is a well-known structural motif found in a
variety of natural products and synthetic molecules. Cou-
marin compounds exhibit a broad range of biological
activities [1–3] and are also widely employed as materials
Electronic supplementary material The online version of this
article (doi:10.1007/s00706-016-1736-4) contains supplementary
material, which is available to authorized users.
R. K. Sharma Á Priyanka Á D. Katiyar (&)
Department of Chemistry, MMV, Banaras Hindu University,
Varanasi 221005, India
L-Proline has been reported as a promising catalyst in
various chemical transformations such as Knoevenagel,
Aldol, and Michael reactions. L-Proline is a bifunctional
e-mail: dikshakatiyar@gmail.com
123

R. K. Sharma et al.
Scheme 1
CHO
(a) Previous works
R
+
N
O2
COOEt
OH
CHO
OH
CHO
OH
R
R
Ac2O, NaH
RT, 3 h
NH2 (1.7 mmol)
EtOH, 11 h
CH3
1 mmol
+
1 mmol
AcONa (1 mmol)
Ac2O, AcOH, 24 h
R = H, 30%; R = Br, 20%
[26]
+
[23]
[25]
N
O2
COOEt
N
O2
CN
R=H, 25 %
1 mmol
1 mmol
NO2
R
CHO
OH
NO2
[12]
O
O
n
C3
H7NH
R
3Cl (1.2 mmol)
R
TiCl4
(2 mmol)
N-methylmorpholine
(4 mmol) 12 h, 17-80%
[24]
Piperidine,
AcOH,
OH or
Et2NH2Cl (1.2 mmol)
Toluene, reflux
1 mmol
1 mmol
[27]
(only electron-rich
salicylaldehyde)
C4H9OH, reflux
(electron-rich and electron-poor
48 h (9-85%)
=
24
R
Et
73%
salicylaldehyde)
+
h,
2N,
+
R
CHO
N
O2
COOEt
N
O2
COOMe
1.2 mmol
+
N
O2
COOEt
1 mmol
OH
(b) This work
simple experimental procedure
short reaction time
NO2
O
O
CHO
OH
L-Proline (30 mol%)
mild reaction conditions
N
O2
+
R
R
OEt EtOH, rt or 80 oC, 1.5-6 h
(68-92 %)
1 mmol
recyclable catalyst
O
good product yields
electron-rich and electron-poor
salicylaldehydes
1 mmol
.
catalyst and its catalytic action mainly involves the easy
and rapid formation of iminium ion and enamine inter-
mediates with carbonyl compounds [28, 29]. To the best of
our knowledge, no example of L-proline catalyzed syn-
thesis of 3-nitrocoumarins has been reported so far. Herein
we wish to report a simple and efficient protocol for the
synthesis of 3-nitrocoumarins via L-proline catalyzed con-
densation of salicylaldehydes and ethyl nitroacetate
(Scheme 1b).
(Table 1, entry 3). Notably, the reaction did not occur
satisfactorily in toluene, THF, and DMF and no product
formation was detected in case of water (Table 1, entries
4–7). Further, the yield of the product 3 remained almost
the same with an increased catalyst loading of 40 mol %
(Table 1, entry 8) and declined remarkably when the
reaction was performed at lower catalyst loadings of 20,
10, and 5 mol % (Table 1, entries 9–11). In addition,
increase in the reaction temperature resulted in the for-
mation of some unidentified side products and low yields
of coumarin 3 (Table 1, entries 12–15).12
Results and discussion
With the optimized reaction conditions in hand, the
substrate scope of this methodology was explored by
varying salicylaldehyde 4 (Table 2). A variety of salicyl-
aldehydes 4a–4h were compatible with the reaction
conditions and the corresponding coumarin products were
obtained in good to excellent yields (68–92 %, 1.5–6 h,
entries 1–8). Electron-donating substitutents such as 6-hy-
droxy (5a), 6-methyl (5b), 8-methoxy (5c), 8-ethoxy (5d)
on the aryl moiety were effectively converted to the cor-
responding 3-nitrocoumarins in good yields. Electron-
withdrawing groups including 6-chloro (5e), 6-bromo (5f),
and 6-nitro (5g) were also well tolerated to afford the
desired coumarins. However, in case of 5c–5g heating was
needed to accelerate the reaction rate. Further, the scope of
this reaction could be expanded from the phenyl to
The commercially available ethyl nitroacetate (2) is very
expensive; we have therefore synthesized it economically
and in much improved yield by modification of earlier
reported method [30]. In an initial investigation, we con-
ducted a model reaction between salicylaldehyde (1) and 2
in the presence of 30 mol % of L-proline in acetonitrile at rt
(40–42 °C) for 6 h to afford desired product 3 in 30 %
yield (Table 1, entry 1). To further improve the reaction
yield, a series of solvents were examined. When the reac-
tion was performed in DCM, 68 % conversion was
observed (6 h; Table 1, entry 2). To our delight, the reac-
tion proceeded well in ethanol in a much shorter reaction
time of 4 h, affording the desired product 3 in 85 % yield
123

L-Proline catalyzed condensation of salicylaldehydes with ethyl nitroacetate: an efficient…
Table 1 Optimization of reaction conditions for the synthesis of 3
CHO
O
NO2
O
L
-Proline
N
O2
+
OEt
Solvent,
temperature
OH
O
3
1
2
Entry
Proline/mol %
Solvent
Temp./°C
Time/h
Yield/%a
1
30
30
30
30
30
30
30
40
20
10
5
CH3CN
DCM
rt
6
6
30
2
rt
68
3
C2H5OH
Toluene
THF
rt
4
85b
Trace
18
4
rt
8
5
rt
8
6
DMF
rt
8
Trace
0
7
Water
rt
8
8
C2H5OH
C2H5OH
C2H5OH
C2H5OH
C2H5OH
C2H5OH
C2H5OH
C2H5OH
rt
4
83
9
rt
8
69
10
11
12
13
14
15
rt
12
20
3
57
rt
35
30
20
10
5
80
80
80
80
75
6
58
5
48
8
32
Reaction conditions: 1 (1 mmol), 2 (1 mmol), L-proline (30 mol %), 3 cm3 ethanol, rt, 4 h
a
Isolated yields
b
o
M.p.: 141–142 C (Ref. [12] M.p.: 141–142 C)
o
Table 2 Synthesis of 3-nitrocoumarin derivatives
NO2
O
CHO
Rn
O
L
30 mol% -Proline
Rn
N
O2
+
EtOH, rt or 80 oC
OEt
O
OH
5a 5h
-
2
4a 4h
-
Entry
Substrate Rn=
Time/h
Prod.
Yield/%a
M.p./°C (obs)
M.p./°C (lit)
1
2
3
4
5
6
7
8
5-OH
4
5a
75
82
81
76
82
78
68
92
208–209
Sticky solid
179–180
180–181
136–137
182–183
174–175
225–226
215–218 [12]
–
5-CH3
5
5b
3-CH3O
3-CH3CH2O
5-Cl
4
5cb
5db
5eb
5fb
5gb
5h
187.5–188.5 [24]
5
–
6
176–177 [24]
200 [25], 207–208 [24]
179.5–180.5 [24]
–
5-Br
6
5-NO2
6
5,6-Benzo
1.5
Reaction conditions: 4 (1 mmol), 2 (1 mmol), L-proline (30 mol %) in 3 cm3 ethanol at rt for given hours
a
Isolated yield
b
Reaction was conducted at 80 °C
123

R. K. Sharma et al.
Scheme 2
NO2
O
CHO
OH
30 mol% -Proline
L
N
O2
+
OEt
EtOH, rt
88% yield
O
O
2
1
3
(2 g, 16.4 mmol) (2.2 g, 16.4 mmol)
.
intermediate D, which undergoes cyclization via interme-
diate E to afford the desired product 3 [32].
Scheme 3
NO2
O
EtO
NO2
COOH
O
N
H
O
2
3
Conclusion
NO2
N
COOH
H
N
In conclusion, we have developed an efficient, mild, and
environmentally benign method for the preparation of
3-nitrocoumarins from salicylaldehydes and ethyl nitroac-
etate using a catalytic amount of L-proline. The method
yielded 3-nitrocoumarins in good to high yields under mild
conditions. Most importantly, both electron rich and elec-
tron deficient salicyaldehydes were well tolerated under the
reaction conditions. The resulting substituted coumarins
can be subjected to different functional group transforma-
tions to produce other compounds of chemical and
biological importance. The biological evaluation of syn-
thesized compounds and the extension of this methodology
to the synthesis of some new bioactive molecules are
currently in progress in our laboratory.
EtO
O
NO2
OH
OH
HOOC
A
-EtOH
E
NO2
N
COOH
N
B
NO2
OH
HO
OH
H
H
2O
OOC
O
NO2
N
-H
2O
D
H
OH
OH
OOC
OH
1
C
.
Experimental
naphthyl system, leading to the formation of benzo-
coumarin 5h in excellent yield (92 %, Table 2, entry 8)
with significantly shorter reaction time than the others.
Notably, benzocoumarins are an important class of com-
pounds found in a variety of naturally occurring molecules
such as arnottin and gilvocarcin [31].
Unless otherwise stated, all common reagents and solvents
were obtained from commercial suppliers (Sigma-Aldrich
and Spectrochem Pvt. Ltd.) and were used without further
purification. Melting points were determined on a Bu¨chi
510 apparatus. Column chromatography was carried on
silica gel (60–120 mesh). Reactions were monitored by
thin-layer chromatography (TLC) using pre-coated, glass-
backed silica gel plates and visualization of the developed
chromatogram was performed by UV absorbance (254 nm)
and by iodine vapors. ESI mass spectra were recorded
using Quattro II (Micromass). IR spectra were recorded on
a JASCO FTIR 5300 in KBr from 400 to 4000 cm-1. NMR
spectra were recorded on JEOL FT-NMR spectrometer
using tetramethylsilane (TMS) as internal standard. The
chemical shift values are on d scale and the coupling
Furthermore, to demonstrate the synthetic utility of the
present protocol, a gram scale synthesis was performed
reacting 1 and 2 under the standard reaction conditions to
afford the desired product 3 in high yield as shown in
Scheme 2.
Finally, recycling experiments carried out during the
synthesis of 3 showed that the catalyst can be reused in up
to three runs without any appreciable loss of activity.
A plausible mechanism of the reaction is shown in
Scheme 3. We assume that the initial interaction of L-
proline with 2 generates an enamine intermediate B, which
undergoes nucleophilic addition to the aldehyde 1 to pro-
duce intermediate C. Subsequent dehydration provides an
1
constant (J) are in Hertz (Hz). The data of H NMR was
reported in the order: chemical shift, multiplicity
123

L-Proline catalyzed condensation of salicylaldehydes with ethyl nitroacetate: an efficient…
References
(s = singlet, d = doublet, t = triplet, m = multiplet and
br = broad), coupling constant, and integration.
1. Riveiro ME, De KN, Moglioni A, Vazquez R, Monczor F, Shayo
C, Davio C (2010) Curr Med Chem 17:1325
2. Hault JRS, Paya M (1996) Gen Pharmacol 27:713
3. Mishra S, Singh LK, Priyanka, Gupta J, Misra-Bhattacharya S,
Katiyar D (2015) Eur J Med Chem 94:211
4. Trenor SR, Shultz AR, Love BJ, Long TE (2004) Chem Rev
104:3059
5. Sheng R, Wang P, Gao Y, Wu Y, Liu W, Ma J, Li H, Wu S
(2008) Org Lett 10:5015
6. Symeonidis T, Chamilos M, Hadjipavlou-Litina DJ, Kallitsakis
M, Litinas KE (2009) Bioorg Med Chem Lett 19:1139
7. Garazd MM, Garazd YL, Khilya VP (2005) Chem Nat Compd
41:245
8. Zhang X-S, Li Z-W, Shi Z-J (2014) Org Chem Front 1:44
9. Galm U, Heller S, Shapiro S, Page M, Li S-M, Heide L (2004)
Antimicrob Agents Chemother 48:1307
General procedure for the synthesis of 3-nitrocoumarins
3 and 5
To the solution of salicylaldehyde (1 mmol) and ethyl
nitroacetate (1 mmol) in 3 cm3 ethanol, L-proline
(30 mol %) was added. The reaction mixture was stirred
for an appropriate time. After completion of the reaction
(as monitored by TLC), the solvent was evaporated and the
product so obtained was dissolved in 12 cm3 CHCl3 and
washed with water (3 9 10 cm3). The organic layer was
washed with 10 cm3 brine, dried over anhydrous NaSO4,
and evaporated under reduced pressure. The residue was
recrystallized from ethanol (3, 5a, 5b, and 5h) or purified
by silica gel column using chloroform/methanol (9:1) as
eluent (5c–5g). The combined aqueous layers, containing
L-proline, were evaporated, washed with ether, dried at
45 °C, and reused for next run.
10. Xie J-W, Wang Z, Yang W-J, Kong L-C, Xu D-C (2009) Org
Biomol Chem 7:4352
ˇ
11. Debeljak Z, Krbo S, Jasprica AI, Mornar A, Plecko V, Banjanac
^
ˆ
ˇ
´
´
M, Medic-Saric MJ (2007) Chem Inf Model 47:918
12. Perrella FW, Chen S-F, Behrens DL, Kaltenbach RF III, Seitz SP
(1994) J Med Chem 37:2232
6-Methyl-3-nitrocoumarin (5b, C10H7NO4)
13. Bergsma JCT, Kasri NN, Donaton MCV, Wever VD, Tisi R,
Winde JHD, Martegani E, Thevelein JM, Wera S (2001) Bio-
chem J 359:517
14. Tisi R, Coccetti P, Banfi S, Martegani E (2001) Cell Biochem
Funct 19:229
Light yellow sticky solid; Rf = 0.36 (20 % ethyl acetate/
hexane); IR (KBr): V = 3083, 2929, 1742, 1620, 1345,
851 cm-1; ESI MS: m/z = 206 ([M ? H]?); 1H NMR
(300 MHz, CDCl3): d = 8.54 (s, 1H), 7.34 (m, 3H), 2.47
(s, 3H) ppm; 13C NMR (75 MHz, CDCl3): d = 154.0,
145.3, 140.6, 136.1, 129.6, 129.3, 123.1, 120.1, 118.6,
19.2 ppm.
´
´
´ ´
15. Dekic B, Dekic V, Radulovic N, Vukicevic R, Palic R (2010)
´
´
Chem Pap 64:354
16. Marcu MG, Schulte TW, Neckers L (2000) J Natl Cancer Inst
92:242
17. Melagraki G, Afantitis A, Igglessi-Markopoulou O, Detsi A,
Koufaki M, Kontogiorgis C, Hadjipavlou-Litina DJ (2009) Eur J
Med Chem 44:3020
8-Ethoxy-3-nitrocoumarin (5d, C11H9NO5)
Light yellow solid; Rf = 0.32 (20 % ethyl acetate/hexane);
IR (KBr): V = 3081, 2940, 1746, 1567, 1456, 1341,
863 cm-1; ESI MS: m/z = 236 ([M ? H]?); 1H NMR
(300 MHz, CDCl3): d = 8.63 (s, 1H), 7.72 (m, 2H), 7.41
(d, J = 9.6 Hz, 1H), 4.16 (q, J = 6.8 Hz, 2H), 1.51 (s, 3H)
ppm; 13C NMR (75 MHz, CDCl3): d = 154.4, 150.9,
144.3, 138.9, 137.1, 128.6, 121.2, 117.5, 115.0, 64.9,
14.8 ppm.
18. Das AR, Medda A, Singha R (2010) Tetrahedron Lett 51:1099
19. Ganguly N, Sukai AK, De S (2001) Synth Commun 31:301
20. Zhou Y, Chu K, Zhen H, Fang Y, Yao C (2013) Spectrochim
Acta Part A 106:197
21. Nishizono N, Oda K, Ohno K, Minami M, Machida M (2001)
Heterocycles 55:1897
22. Prasanna B, Kavitha S (2015) Heteroletters 5:53
23. Dean FM, Park BK (1976) J Chem Soc Perkin Trans 1:1260
24. Dauzonne D, Royer R (1983) Synthesis 10:836
25. Gavrilova NA, Semichenko ES, Korotchenko OS, Suboch GA
(2008) Russ J Org Chem 44:624
26. Matos MJ, Santana L, Serra S, Uriarte E, Corda M, Fadda MB,
Era B, Fais A (2012) J Pharm Pharmacol 64:742
27. Sivakumar K, Xie F, Cash BM, Long S, Barnhill HN, Wang Q
(2004) Org Lett 6:4603
28. List B (2002) Tetrahedron 58:5573
29. Shi CL, Shi DQ, Kim SH, Huang ZB, Ji SJ, Ji M (2008) Tetra-
hedron 64:2425
30. Shestakova TS, Khalymbadzha IA, Deev SL, Eltsov OS, Rusinov
VL, Shenkarev ZO, Arseniev AS, Chupakhina ON (2011) Russ
Chem Bull Int Ed 60:729
31. Lv H-N, Wang S, Zeng KW, Li J, Guo X-Y, Ferreira D, Zjawiony
JK, Tu P-F, Yong J (2015) J Nat Prod 78:279
32. Rankin KN, Gauld JW, Boyd RJ (2002) J Phys Chem A 106:5155
2-Nitro-3H-benzo[f]chromen-3-one (5h, C13H7NO4)
Yellow solid; Rf = 0.41 (20 % ethyl acetate/hexane); IR
(KBr): V = 3065, 1757, 1598, 1560, 1511, 1345,
822 cm-1; ESI MS: m/z = 242 ([M ? H]?); 1H NMR
(300 MHz, CDCl3): d = 9.58 (s, 1H), 8.31 (d, J = 8.4 Hz,
1H), 8.24 (d, J = 9.3 Hz, 1H), 7.99 (d, J = 7.8 Hz, 1H),
7.84 (t, J = 7.5 Hz, 1H), 7.69 (m, 1H), 7.53 (d,
J = 9.0 Hz, 1H) ppm; 13C NMR (125 MHz, CDCl3): d =
155.3, 151.4, 138.7, 137.9, 137.6, 129.5, 129.1, 126.4,
121.5, 115.5, 107.1 ppm.
Acknowledgments The authors thank BHU, Varanasi for financial
support. Priyanka is thankful to CSIR, New Delhi, India for Senior
Research Fellowship.
123