Effects of Base for the Efficient Synthesis of 4-Formylcoumarins and 4-Formylcarbostyrils

Article abstract of DOI:10.1080/00397911.2014.981754

(Chemical Presented). The first efficient transformation of 4-bromomethylcoumarins and 4-bromomethylcarbostyrils to 4-formylcoumarins and 4-formylcarbostyril under aqueous conditions has been achieved by modifying the Kornblum method, resulting in excelle

Full text of DOI:10.1080/00397911.2014.981754

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Effect of Base for the Efficient Synthesis of 4-
Formylcoumarins and 4-Formylcarbostyrils
Megharaja Holiyachia, Samundeeswari L. Shastria, Bahubali M. Chougalaa & Lokesh A.
Shastria
a Department of Chemistry, Karnatak University, Dharwad
Accepted author version posted online: 15 Dec 2014.
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Effect of Base for the Efficient Synthesis of 4-Formylcoumarins and 4-Formylcarbostyrils, Synthetic Communications: An
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EFFECT OF BASE FOR THE EFFICIENT SYNTHESIS OF 4-
FORMYLCOUMARINS AND 4-FORMYLCARBOSTYRILS
Megharaja Holiyachi1, Samundeeswari L. Shastri1, Bahubali M. Chougala1, Lokesh A.
Shastri1
1Department of Chemistry, Karnatak University, Dharwad
Corresponding author. Lokesh A. Shastri, Email: drlashastri@kud.ac.in
Abstract
The first efficient transformation of 4-bromomethylcoumarins and 4-
bromomethylcarbostyrils to 4-Formylcoumarins and 4-Formylcarbostyril under aqueous
condition has been achieved by modifying novel ‘Kornblum’ method in excellent yield.
Hence, the experimental method is very simple and more economic, no further
purification required and the experimental conditions have been optimized. All the
isolated compounds were characterized by IR, NMR, mass and some of the compounds
by single crystal X-ray analysis.
CHO
CH2Br
DMSO - NaCO3 (aqu.)
110 oC, 6-16 hr
R
R
X
O
X
O
(X = O; NH)
KEYWORDS: 4-Formylcoumarins; 4-Formylcarbostyril; 4-bromomethylcoumarins; 4-
bromomethylcarbostyrils; Kornblum
INTRODUCTION
1

A numerous methods have been reported in the literature for the preparation of aromatic
and aliphatic aldehydes from aromatic alkyl halides and aliphatic alkyl halides with very
limited scope. Aromatic aldehydes are prepared by various methods such as using carbon
monoxide,[1] in presence of catalyst at low and high pressure(Gattermann-Koch),
Gattermann reaction using hydrogen cyanide,[2] formylation of phenols or amines,[3] with
hexamine (Duff reaction) in presence of boric acid, hexamine and glycerol mixture at
high temperature results low yield, hydroformylation,[4] of unsaturated compounds using
cobalt catalyst, Sommalet,[5] formylation of halo methyl compounds in presence of
hexamine, ortho and para-formylation of phenols via Reimer- Teimann reaction,[6]
aromatic methyl halides interaction with sodium 2-propenenitrate,[7] decomposition of
arylosulphonohydrazides,[8] followed by base treatment at elevated temperature but the
method fails in case of aliphatic sulphonohydrazides. Controlled oxidation of side
chain,[9] and primary alcohols,[10] leads to aromatic aldehydes.
The best known method for the transformation of aryl/alkyl halides to corresponding
aryl/alkyl aldehydes in presence of dimethylsulphoxide (DMSO) is an oxidizing agent in
Kornblum reaction.[11] In this reaction DMSO acts as nucleophile and it undergo SN2
followed by E1CB to give the desired aldehydes. Hence, recently the conversion of
aryl/alkyl halides to corresponding aryl/alkyl aldehyde have been attempted under
microwave irradiation,[12] using heterogeneous catalyst, such as Mg-Al hydrotalcites,[13]
and dihalomethylaranes.[14] In view of the above literature reports we thought to
synthesize 4-formylcoumarins and 4-formylcarbostyrils from 4-bromomethylcoumarins
2

and 4-bromethylcarbostyrils. Thus, the aldehydic functional group is most potent for the
verity of heterocyclic molecule synthesis.
RESULTS AND DISCUSSION
The methods which are reported for 4-methyl coumarins to 4-fromylcoumarins by
Krohnke oxidation,[15] using p-nitrosodimethylaniline as oxidizing agent at room
temperature under basic condition followed by acid hydrolysis resulting to desired
product. Thus, the known method for the synthesis of 4-methyl coumarins to 4-
formylcoumarins,[16] have been achieved in good yield by using oxidizing agent [16,17]
(reported data were presented in table 3 at supporting file). Whereas, Sommelet and other
methods have tried to complete the desired product, but we did not observed the products,
it may be due to insolubility of the starting materials in chloroform and other non-polar
solvents. Here, we applied the modified “Kornblum oxidation” method to 4-
bromomethylcoumarins for achieving the desired aldehydes. The Kornblum oxidation is
carried with 4-bromomethy coumarins using excesses DMSO in presence of base (TEA /
Na2CO3) under heating condition. The conversion of product was observed about 60-65%
and isolated product is only 20 -25%. Thus, the removing of excesses DMSO from
reaction mixture is difficult and water workup most of the product going with DMSO
water. Therefore, the development of excellent methodology for such functional group
transformations is of continued interest, hence, we thought optimization of the procedure.
3

The optimized conditions and yields were presented by using required volume DMSO
along with aqueous base to achieve the desired product in good yield (Table 1).
Here, we have synthesized 4-formylcoumarins 2 from 4-bromomethylcoumarins[18] 1,
under aqueous condition. The reaction gives clear observations, when 4-
bromomethylcoumarins 1 is warmed with DMSO at 70 oC followed by addition of equal
volume of dilute (5%) sodium carbonate and heated at 100-110 oC for 6-16 hrs (Scheme
1). Cool the reaction mixture at room temperature and obtained solid was filtered out as
desired product around 85-90% yields (Table 2). As in case of excess of aqueous base the
yields were dramatically decreased. The experimental and isolation procedure was good
without loss of product, when camper with other reported methods. All the isolated
products have been characterized by IR, 1H NMR, 13C NMR, and mass analysis, and
some of them by single X-ray crystal analysis study (Fig. 1 and Fig. 2). In 1H NMR the
characteristic signal of aldehydic proton appeared around 10.12 δppm, and down filed
shift of C3-H proton of coumarin was observed, ie around 6.3 to 7.12 δppm. Whereas,
13C NMR two down filed shift carbon signal are appeared due to the lactone carbonyl
carbon and aldehydic carbonyl carbon. The reaction also extended to 4-
bromomethylcarbostyrils,[19] 3 to 4-formylcarbostyrils 4 and achieved the similar results,
but less yields, longer time (Table 2) for the completion of reaction and higher the
concentration (20%) of base is required, compared to coumarin systems. Therefore, this
comparative yields, base concentration and longer reaction time may be due to
heteroatom present in the ring system. In case of coumarin ring system formation of
4

anion is faster and stabilization via enolates is more favorable (structure A in Scheme 2)
compared with carbostyrile ring system (structure B in Scheme 2).
CONCLUSION
In summary we have achieved successful synthesis of 4-formylcoumarins 2 and 4-
formylcarbostyrils 4 via simple experimental methods by using aqueous mild base. The
simplicity of methods makes more advantage in the transformation of alkyl halides to
corresponding aldehydic group, which is more powerful functional group in the synthesis
of different biologically active heterocycles. The purity and higher yields are advantages
of this method.
EXPERIMENTAL
General Experimental Information
Melting points were recorded on a Sheetal Scientific instrument and presented in degrees
centigrade. IR spectra were recorded on a Nicolet 410 Fourier transform (FT) infrared
spectrometer. The NMR was recorded on Bruker 400-MHz FT NMR spectrometers in
DMSO-d6. 1H and 13C chemical shifts were represented as δppm values relative to the
internal standard tetramethylsilane.
General procedure for the synthesis of 2 and 4: The substituted 4-
bromomethylcoumarins/4-bromomethylcarbostyrils 1/3 (0.5gm; 1.0 equiv.) was heated
with dimethylsulphoxide (2 mL) for 30 min at 70 0C, it forms clear solution. Cooled the
reaction at room temperature and added 5% sodium carbonate solution (2 mL) into the
5

reaction mixture, continue the heating at 110 0C on oil bath for 6–16 h and reaction was
monitored by TLC. After completion, the reaction was cooled and diluted with ice cooled
water (20 mL), the solid separated was filtered, and washed with water, and no further
purification is required.
Synthesis of 4-Formyl-6-methylcoumarin 2a: Isolated compound light yellow solid;
mp: 164-166 oC; IR (KBr) ν 1736, 1703 cm-1; 1HNMR (400MHz, DMSO-d6) δ10.14
(s,1H), 8.27 (s,1H) 7.50 (dd, 1H, J =1.6 Hz and 8.8 Hz), 7.37(d, 1H, J = 8.8 Hz),
7.13(s,1H), 2.38(s, 3H); 13C NMR (100 MHz, DMSO-d6) δ 193, 160.08, 151.99, 143.36,
134.14, 133.20, 125.45, 124.77, 116.48, 114.65, 20.48; m/z (GC-MS) 188 (Calcd 188).
Synthesis of 4-Formylcarbostyril 4a: Isolated compound yellow solid; mp: 214-216 oC
IR(KBr) ν 3404, 1709, 1663 cm-1; 1H NMR(400MHz, DMSO-d6) δ 12.14 (br s, 1H, NH),
10.17 (s. 1H), 8.56 (d, 1H, J = 8.0 Hz), 7.58(t, 1H), 9.39(d, 1H, J = 7.6 Hz), 7.27 (t, 1H),
7.71(s, 1H); NMR (100MHz, DMSO-d6) δ194.69, 161.32, 141.15, 139.58, 130.98,
130.40, 130.17, 125.98, 124.62, 115.39; m/z (GC-MS) 207 (Calcd 207).
ACKNOWLEDGMENTS
We acknowledge the University Grant Commission (UGC) and Department of Science
and Technology (DST) and also UGC-UPE New Delhi, for the financial support. Authors
also thank to USIC KU Dharwad for single crystal X-ray analysis.
SUPPORTING INFORMATION
6

Supplemental data for this article can be accessed on the publisher’s website.
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7

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9

Table 1. Optimizations of experimental conditions.
Conditions (v/v)
Time (hrs)
Isolated Yield (%)
DMSO
11
10
10
6
10
DMSO+ Aqu.NaCO3 (3:1)
DMSO+ Aqu.NaCO3 (3:2)
DMSO+ Aqu.NaCO3 (1:1)
DMSO+ Aqu.NaCO3 (1:3)
20
30
>84
15
20
10

Table 2. Physical data of compounds (2a-2i and 4a-4d)
Entry
2a
2b
2c
R
X
Time (hrs)
Yield (%)
91
6-CH3
7-CH3
6-OCH3
6-Cl
O
6
O
6
92
O
6
90
O
7
87
2d
2e
6-Br
O
8
84
5,6-Benzo
7,8-Benzo
5,7-Dimethyl
7-OH
O
8
85
2f
O
8
88
2g
2h
2i
O
6
92
O
8
86
H
NH
NH
NH
NH
14
16
16
12
55
4a
4b
4c
6- Cl
54
6- Br
52
6- CH3
56
4d
11

Table 3. Melting points of Compounds (2a to 2i and 4a to 4d)
Entry Mp (oC) *Our report Mp (oC) Literature reported (ChemSpider)
172.385
Mp (oC) Literature reported (Scifinder)
168-169
164-166
2a
Data Source: J. Heterocycl. Chem. 2006, 43(5), 1367- Data Sources: Ind. J. Chem. B: 1982, V21B 5, 399
1369
402.
181-183
174.072
201-202 ; 185-187
2b
Data Sources: J. Heterocycl. Chem. 2006, 43(5),
1367-1369
Data Sources: (1) Eur. J. Org. Chem. 2007, 26, 4301-
4304; (2) Ind. J. Chem. Section B:1982, V21B 5,
399-402.
168-170
180-184
-
192.7±28.8
2c
Data Sources:
184-186
192.4±27.7
2d
Data Sources: Cambridge Crystallographic data centre Data Sources: Cryst. Eng. Comm. 2003, V5, 507-
513.
196-198
112-114
-
209.3±28.7
2e
2f
Data Sources:
215.1±27.4
-
Data Sources:
12

200-202
138-134
215.102
215.1±27.4
2g
2h
Data Sources: J. Heterocycl. Chem. 2006, 43(5),
Data Sources:
1367-1369
152
165-166
Data Source:
-
Data Sources: J. Heterocycl. Chem.1988, 25, 6,
1681.
128-130
214-216
223-225
2i
Data Sources: Eur. J. Org. Chem. 2007, 26, 4301-
4304.
203.231
267, 261-262, 257
4a
Data Sources: ABI Chemicals, External id;
Data Sources: (1) AIST: Integrated Spectral Database
System of Organic Compounds. (Data were obtained
from the National Institute of Advanced Industrial
Science and Technology (Japan)). (2) Indiana
Academy of Science 1961, V70, P115-18. (3)
Monatshefte fuer Chemie 1966, V97 (2), P409-16.
AC2A03D96, Biochemistry 1996, 35, 4457-4467
220-222
228.374
228.4±28.7
4b
13

Data Sources: J. Heterocycl. Chem. 1972, 9(1), 175-
176.
Data Sources:(1) Calculated using Advanced
Chemistry Development (ACD/Labs) Software
V11.02 (© 1994-2014 ACD/Labs).(2) Predicted
NMR data calculated using Advanced Chemistry
Development, Inc. (ACD/Labs) Software V11.01 (©
1994-2014 ACD/Labs).
198-200
-
235.6±28.7
4c
Data Sources: (1) Calculated using Advanced
Chemistry Development (ACD/Labs) Software
V11.02 (© 1994-2014 ACD/Labs). (2) Predicted
NMR data calculated using Advanced Chemistry
Development, Inc. (ACD/Labs) Software V11.01 (©
1994-2014 ACD/Labs).
175-177
210.314
193.8±28.9
4d
Data Sources: AKOs, External ID;AKI-BBV-
Data Sources:
00014126, Innovapharm, External id; BBV-00014126.
* Note: Melting points were recorded on a Sheetal Scientific instrument (hot plate system)
14

Scheme 1.
15

Scheme 2.
16

Figure 1. ORTEP diagram of compound (2a)
17

Figure 2. ORTEP diagram of compound (2c)
18