Simple and convenient synthesis of 4-unsubstituted-3-(3-oxoalkyl) isocoumarins

Article abstract of DOI:10.1080/00397910801929382

A simple transformation of 2-alkylfurans and 2-formylbenzoic acids into 4-unsubstituted 3-(3-oxoalkyl)isocoumarins is described. It is based on the synthesis of 2-(2-carboxybenzyl)furans followed by their acid-catalyzed recyclization to the target isocoum

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Simple and Convenient Synthesis of
4‐Unsubstituted‐3‐(3‐Oxoalkyl)isocoumarins
Alexander V. Butin a , Artem S. Dmitriev a , Maxim G. Uchuskin a , Vladimir
T. Abaev b & Igor V. Trushkov c
a Research Institute of Heterocyclic Compounds Chemistry, Kuban State
University of Technology, Krasnodar, Russian Federation
b Department of Chemistry, North‐Ossetian State University, Russian
Federation
c Department of Chemistry, M. V. Lomonosov Moscow State University,
Russian Federation
Version of record first published: 24 Apr 2008.
To cite this article: Alexander V. Butin, Artem S. Dmitriev, Maxim G. Uchuskin, Vladimir T. Abaev & Igor V.
Trushkov (2008): Simple and Convenient Synthesis of 4‐Unsubstituted‐3‐(3‐Oxoalkyl)isocoumarins, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry, 38:10,
1569-1578
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Synthetic Communicationsw, 38: 1569–1578, 2008
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910801929382
Simple and Convenient Synthesis
of 4-Unsubstituted-3-
(3-Oxoalkyl)isocoumarins
Alexander V. Butin,1 Artem S. Dmitriev,1 Maxim G.
Uchuskin,1 Vladimir T. Abaev,2 and Igor V. Trushkov3
1Research Institute of Heterocyclic Compounds Chemistry, Kuban State
University of Technology, Krasnodar, Russian Federation
2Department of Chemistry, North-Ossetian State University,
Russian Federation
3Department of Chemistry, M. V. Lomonosov Moscow State University,
Russian Federation
Abstract: A simple transformation of 2-alkylfurans and 2-formylbenzoic acids into
4-unsubstituted 3-(3-oxoalkyl)isocoumarins is described. It is based on the synthesis
of 2-(2-carboxybenzyl)furans followed by their acid-catalyzed recyclization to the
target isocoumarins.
Keywords: Furans, isocoumarins, ring closure, ring opening
Isocoumarins are class of natural products with a broad spectrum of biological
activity.[1] 4-Unsubstituted 3-alkylisocoumarins have been isolated from
fungi,[2] lichens,[3] and high plants.[4] They showed antifungal,[4g,5] antibacter-
ial,[6] antitumor,[7] anti-angiogenic,[8] antidiabetic,[9] phytotoxic,[10] and other
kinds of physiological activity; synthetic isocoumarins being at least equipo-
tent to natural ones. For example, 2-(8-hydroxy-6-methoxy-1-oxo-1H-2-ben-
zopyran-3-yl)propionic acid is a synthetic isocoumarin that is currently
entering phase II clinical trials.[7e] These and other data stimulate the
Received October 2, 2007
Address correspondence to Alexander V. Butin, Research Institute of Heterocyclic
Compounds Chemistry, Kuban State University of Technology, Moskovskaya St. 2,
Krasnodar 350072, Russian Federation. E-mail: alexander_butin@mail.ru
1569

1570
A. V. Butin et al.
Scheme 1.
interest in the development of new approaches to the synthesis of 4-unsubsti-
tuted 3-alkylisocoumarins.
At present, some ways to 3-alkylisocoumarins are known. Two of them
(Scheme 1) have the largest scope of applicability. The first method is
based on the electrophilic or transition metal–mediated cyclization of the
alkynes possessing a carboxylate or an equivalent group in proximity to the
triple bond.[11] The second one is the intramolecular cyclization of ortho-(2-
oxoalkyl)benzoic acids that can be prepared by different methods. The last
way is the general approach to construction of the isocoumarin framework.
It has been successfully applied to the synthesis of 3-alkylisocoumarins.[12]
It is well known that under acidic condtions alkylfurans undergo a ring
opening with formation of 1,4-dicarbonyl compounds.[13] It means that ben-
zylfurans can be considered as synthons of benzyl alkyl ketones. Based on
this fact, for the past decade we have developed the general method of
synthesis of benzannelated heterocycles by recyclization of ortho-substituted
benzylfurans (Scheme 2). By varying ortho-substituent in the benzyl
fragment, we have synthesized the different heterocycles including benzofur-
ans, indoles, isochromenes, and isoquinolones.[14] In this work, we applied
this methodology to the synthesis of 4-unsubstituted 3-alkylisocoumarins.
As starting compounds we used available 3-(2-furyl)phthalides 1
(Scheme 3), which are usually synthesized by ortho-lithiation of benzoic
acid derivatives followed by treatment of organolithium intermediates with
the corresponding aldehydes.[15] Here, we applied an alternative method,
acid-catalyzed condensation of 2-formylbenzoic acid with 2-alkylfur-
ans.[14e,16] In spite of lower yields, this method is more convenient because
of its simplicity and the absence of any precautions that are needed during
the work with organolithium compounds.
Scheme 2.

4-Unsubstituted-3-(3-Oxoalkyl)isocoumarins
1571
Scheme 3. a) Zn, NH4OH, reflux; b) HCl, EtOH, reflux.
3-(2-Furyl)phthalides 1a–e were reduced to 2-(2-carboxybenzyl)furans
2a–e by a slightly modified literature procedure[15b,17] with zinc dust in
refluxing aqueous ammonia (Scheme 3, Table 1). Unfortunately, this
method cannot be applied to reduction of phthalides containing bromine,
iodine, or nitro groups in the aromatic ring. In the last case, the complex uni-
dentified mixture was obtained. For bromo- and iodo-substituted phthalides,
dehalogenation products were formed.
The synthesized 2-(2-carboxybenzyl)furans 2a–e were known to transform
into naphtho[2,3-b]furans by treatment with trifluoroacetic anhydride[18] or with
acetic anhydride and acetic acid in the presence of ZnCl2.[15b,17b,19] Under these
aprotic conditions, furan is stable to ring opening. However, it can be expected
that attack on the a-position of 2,5-disubstituted furans should be much faster by
Brønsted acids than by bulky electrophilic species in acylation reaction. Indeed,
we found that heating of 2a–e in ethanolic hydrogen chloride yielded isochro-
mones 3a–e in good yields (Scheme 3, Table 1).
In conclusion, we have developed a simple and convenient method of
synthesis of 4-unsubstituted-3-(3-oxoalkyl)isocoumarins. The presence of
the carbonyl group in the alkyl substituent allows the further modification
of synthesized isocoumarins. For example, isocoumarin 3a can straightfor-
wardly be transformed into an efficient antifungal agent (E)-30-oxoartemi-
din[5c] and its analogs, including capillarin, which has also been used for
treatment of hepatocellular jaundice[20] and showed insect antifeeding
activity.[21] Then, this simple method can be useful for the synthesis of the
broad scope of isocoumarins followed by screening of the synthesized
compounds on different kinds of biological activity.
Table I. Yields of 2-(2-carboxybenzyl)furans 2 and isocoumarins 3
Compound
R
R0
R00
Yield 2 (%)
Yield 3 (%)
a
b
c
H
Cl
H
H
Me
Me
Me
tBu
tBu
51
46
58
55
48
70
72
75
65
68
MeO MeO
d
e
H
Cl
H
H

1572
A. V. Butin et al.
EXPERIMENTAL
Melting points are uncorrected. 1H NMR and 13C NMR spectra were
recorded in CDCl3 on a Bruker AC 200 and Bruker DPX 300 spectrometers.
Chemical shifts are reported in parts per million (ppm) relative to tetra-
methylsilane as an internal standard, and coupling constants (J ) are given
in Hertz. Mass spectra were recorded on a Kratos MS-30 instrument with
70 eV electron impact ionization at 200 8C. IR spectra were measured as
KBr plates on InfraLUM FT-02 and InfraLUM FT-801 instruments.
Compounds 3 were purified by column chromatography using silica gel
KSK (5–40 mm), manufactured by LTD Sorbpolymer.
General procedure for the synthesis of compounds 1a–e was reported
earlier.[16] Analytical data of compounds 1a,b,d,e were given in previous
publications.[14e,16]
5,6-Dimethoxy-3-(5-methyl-2-furyl)-1,3-dihydro-1-isobenzofuranone (1c).
Mp 163–164 8C (CH2Cl2/petroleum ether). IR (KBr): 1758, 1605, 1503,
1
1461, 1325, 1274, 1220, 1123, 1052, 936, 872, 811, 762 cm21. H NMR
(300 MHz, CDCl3): dH 2.23 (s, 3H, CH3), 3.91 (s, 3H, OCH3), 3.93 (s, 3H,
OCH3), 5.93 (d, J ¼ 3.3 Hz, 1H, HFur), 6.21 (d, J ¼ 3.3 Hz, 1H, HFur), 6.27
(s, 1H, CH), 6.81 (s, 1H, HAr), 7.30 (s, 1H, HAr). Anal. calcd. for C15H14O5:
C, 65.69; H, 5.15; found: C, 65.78; H, 5.19.
General Procedure for the Synthesis of Compounds 2a–e
.
The mixture of phthalide 1 (0.01 mol), zinc dust (30 g), and CuSO4 5H2O
(1 g) in aqueous ammonia (300 ml) was refluxed under stirring for 6–10 h
until reaction was complete (thin-layer chromatography, TLC, monitoring).
Hot solution was filtered off; filtrate was cooled and neutralized with conc.
hydrochloric acid to pH 5–6. The product was extracted with AcOEt
(3 ꢀ 20 ml). Extract was heated with activated charcoal, filtered, and evapor-
ated to dryness. The residue was recrystallized from CH2Cl2/petroleum ether.
2-[(5-Methyl-2-furyl)methyl]benzoic acid (2a). Yield 51%. White solid. Mp
99–100 8C. IR (KBr): 1682, 1573, 1312, 1293, 1273, 1080, 1018, 924, 780,
1
735 cm21. H NMR (200 MHz, CDCl3): dH 2.26 (s, 3H, CH3), 4.23 (s, 2H,
CH2), 5.87 (s, 2H, HFur), 7.28–7.37 (m, 2H, HAr), 7.47–7.55 (m, 1H, HAr),
8.06–8.10 (m, 1H, HAr). Anal. calcd. for C13H12O3: C, 72.21; H, 5.59;
found: C, 72.31; H, 5.68.
5-Chloro-2-[(5-methyl-2-furyl)methyl]benzoic acid (2b). Yield 46%. White
solid. Mp 113–114 8C. IR (KBr): 1684, 1570, 1302, 1250, 1021, 909, 868,
1
778, 705 cm21. H NMR (200 MHz, CDCl3): dH 2.25 (s, 3H, CH3), 4.38
(s, 2H, CH2), 5.88 (s, 2H, HFur), 7.25 (d, J ¼ 8.4 Hz, 1H, HAr), 7.46 (dd,
J ¼ 2.3, 8.4 Hz, 1H, HAr), 8.05 (d, J ¼ 2.3 Hz, 1H, HAr). Anal. calcd. for
C13H11ClO3: C, 62.29; H, 4.42; found: C, 62.33; H, 4.40.

4-Unsubstituted-3-(3-Oxoalkyl)isocoumarins
1573
4,5-Dimethoxy-2-[(5-methyl-2-furyl)methyl]benzoic acid (2c). Yield 58%.
White solid. Mp 139–140 8C. IR (KBr): 1686, 1573, 1523, 1459, 1415, 1354,
1
1299, 1270, 1221, 1170, 1073, 931, 879, 772 cm21. H NMR (300 MHz,
CDCl3): dH 2.24 (s, 3H, CH3), 3.88 (s, 3H, OCH3), 3.91 (s, 3H, OCH3),
4.38 (s, 2H, CH2), 5.84 (s, 2H, HFur), 6.74 (s, 1H, HAr), 7.63 (s, 1H, HAr).
Anal. calcd. for C15H16O5: C, 65.21; H, 5.84; found: C, 65.23; H, 5.86.
2-[(5-tert-Butyl-2-furyl)methyl]benzoic acid (2d). Yield 55%. White solid.
Mp 108–109 8C. IR (KBr): 1696, 1572, 1486, 1410, 1306, 1257, 1167,
1
1124, 1078, 1013, 933, 829, 794, 732 cm21. H NMR (200 MHz, CDCl3):
dH 1.26 (s, 9H, t-Bu), 4.44 (s, 2H, CH2), 5.85 (s, 2H, HFur), 7.25–7.37
(m, 2H, HAr), 7.46–7.54 (m, 1H, HAr), 8.06–8.10 (m, 1H, HAr). Anal.
calcd. for C16H18O3: C, 74.40; H, 7.02; found: C, 74.47; H, 6.98.
5-Chloro-2-[(5-tert-butyl-2-furyl)methyl]benzoic acid (2e). Yield 48%.
White solid. Mp 103–104 8C. IR (KBr): 1692, 1558, 1483, 1401, 1300,
1
1243, 1014, 868, 772, 706 cm21. H NMR (200 MHz, CDCl3): dH 1.25
(s, 9H, t-Bu), 4.38 (s, 2H, CH2), 5.84 (d, J ¼ 3.2 Hz, 1H, HFur), 5.87
(d, J ¼ 3.2 Hz, 1H, HFur), 7.20 (d, J ¼ 8.3 Hz, 1H, HAr), 7.45 (dd, 1H,
J ¼ 2.2, 8.3 Hz, 1H, HAr), 8.05 (d, J ¼ 2.2 Hz, 1H, HAr). Anal. calcd. for
C16H17ClO3: C, 65.64; H, 5.85; found: C, 65.75; H, 5.91.
General Procedure for the Synthesis of Compounds 3a–e
Compound 2 (0.01 mol) was refluxed for 5 min in ethanolic hydrogen chloride
(50 ml, 30% by weight). The solution was poured into H2O. The mixture was
extracted with CH2Cl2 (2 ꢀ 20 ml). The combined extract was washed with
H2O and dried (Na2SO4). Petroleum ether was added to the extract, and the
mixture was filtered through small pad of silica gel. The purified solution
was evaporated to dryness. Residue was recrystallized from CH2Cl2/
petroleum ether.
3-(3-Oxobutyl)-1H-1-isochromenone (3a). Yield 70%. White solid. Mp 83–
1
84 8C. IR (KBr): 1717, 1164, 855, 767, 689 cm21. H NMR (300 MHz,
CDCl3): dH 2.17 (s, 1H, CH3), 2.75–2.80 (m, 2H, CH2), 2.85–2.90 (m, 2H,
CH2), 6.30 (s, 1H, HHet), 7.31–7.34 (m, 1H, HAr), 7.40–7.46 (m, 1H, HAr),
7.62–7.68 (m, 1H, HAr), 8.19–8.22 (m, 1H, HAr). 13C NMR (75 MHz,
CDCl3): dC 27.4, 30.0, 40.2, 103.7, 120.0, 125.2, 127.8, 129.4, 134.8, 137.3,
156.2, 162.8, 206.5. MS (IE): m/z 216 (24, Mþ), 174 (25), 173 (100), 155
(25), 145 (31), 131 (38), 127 (33), 117 (67), 103 (27), 91 (28), 89 (72), 77
(45), 63 (38), 59 (44), 55 (47), 43 (45). Anal. calcd. for C13H12O3: C,
72.21; H, 5.59; found: C, 72.31; H, 5.64.
7-Chloro-3-(3-oxobutyl)-1H-1-isochromenone (3b). Yield 72%. White
solid. Mp 87–88 8C. IR (KBr): 1718, 1651, 1484, 1390, 1354, 1319, 1252,
1
1153, 1045, 953, 894, 867, 795, 695 cm21. H NMR (300 MHz, CDCl3):
dH 2.17 (s, 3H, CH3), 2.75–2.80 (m, 2H, CH2), 2.84–2.89 (m, 2H, CH2),

1574
A. V. Butin et al.
6.29 (s, 1H, HHet), 7.29 (d, J ¼ 8.4 Hz, 1H, HAr), 7.59 (dd, J ¼ 2.1, 8.4 Hz, 1H,
HAr), 8.16 (d, J ¼ 2.1 Hz, 1H, HAr). 13C NMR (75 MHz, CDCl3): dC 27.3,
29.9, 40.0, 103.1, 121.2, 126.7, 128.9, 133.4, 135.1, 135.7, 156.6, 161.6,
206.3. MS (IE): m/z 250 (24, Mþ), 209 (22), 207 (100), 189 (14), 179 (14),
165 (18), 151 (24), 123 (41), 55 (22), 43 (42). Anal. calcd. for C13H11ClO3:
C, 62.29; H, 4.42; found: C, 62.24; H, 4.45.
6,7-Dimethoxy-3-(3-oxobutyl)-1H-1-isochromenone (3c). Yield 75%.
White solid. Mp 167–168 8C. IR (KBr): 1711, 1654, 1608, 1508, 1470,
1393, 1269, 1237, 1044, 871, 777 cm21 1H NMR (300 MHz, CDCl3):
.
dH 2.14 (s, 3H, CH3), 2.72–2.77 (m, 2H, CH2), 2.82–2.87 (m, 2H, CH2),
3.92 (s, 3H, OCH3), 3.93 (s, 3H, OCH3), 6.21 (s, 1H, HHet), 6.69 (s, 1H,
HAr), 7.55 (s, 1H, HAr). 13C NMR (75 MHz, CDCl3): dC 27.3, 30.0, 40.3,
56.2 (2C), 103.4, 105.8, 109.2, 113.0, 133.0, 149.3, 155.0, 155.1, 162.7,
206.6. MS (IE): m/z 276 (21, Mþ), 233 (52), 149 (11), 119 (12), 63 (36),
43 (100). Anal. calcd. for C15H16O5: C, 65.21; H, 5.84; found: C, 65.28;
H, 5.88.
3-(4,4-Dimethyl-3-oxopentyl)-1H-1-isochromenone (3d). Yield 65%.
White solid. Mp 77–78 8C. IR (KBr): 1729, 1659, 1480, 1389, 1166,
1099, 997, 963, 759, 688 cm21 1H NMR (300 MHz, CDCl3): dH 1.12
.
(s, 9H, t-Bu), 2.75–2.81 (m, 2H, CH2), 2.88–2.94 (m, 2H, CH2), 6.30
(s, 1H, HHet), 7.31–7.34 (m, 1H, HAr), 7.40–7.46 (m, 1H, HAr), 7.62–7.68
(m, 1H, HAr), 8.20–8.23 (m, 1H, HAr). 13C NMR (75 MHz, CDCl3): dC
26.3 (3C), 27.9, 33.8, 44.1, 103.7, 120.0, 125.1, 127.7, 129.4, 134.8, 137.4,
156.7, 162.9, 214.0. MS (IE): m/z 258 (37, Mþ), 201 (17), 174 (81), 173
(100), 159 (76), 131 (44), 129 (31), 117 (24), 115 (29), 103 (29), 89 (43),
57 (70). Anal. calcd. for C16H18O3: C, 74.40; H, 7.02; found: C, 74.52; H,
7.07.
7-Chloro-3-(4,4-dimethyl-3-oxopentyl)-1H-1-isochromenone (3e). Yield
68%. White solid. Mp 91–92 8C. IR (KBr): 1723, 1656, 1481, 1153,
1098, 968, 871, 780, 694 cm21 1H NMR (300 MHz, CDCl3): dH 1.13
.
(s, 9H, t-Bu), 2.76–2.80 (m, 2H, CH2), 2.90–2.94 (m, 2H, CH2), 6.30
(s, 1H, HHet), 7.30 (d, J ¼ 8.4 Hz, 1H, HAr), 7.61 (dd, J ¼ 2.1, 8.4 Hz,
1H, HAr), 8.19 (d, J ¼ 2.1 Hz, 1H, HAr). 13C NMR (75 MHz, CDCl3): dC
26.3 (3C), 27.9, 33.6, 44.1, 103.1, 121.3, 126.7, 129.0, 133.4, 135.1 (2C),
135.8, 157.1, 214.1. MS (IE): m/z 292 (40, Mþ), 209 (36), 207 (100),
192 (19), 173 (22), 165 (35), 145 (16), 101 (22), 89 (20), 86 (31), 59
(32), 57 (86). Anal. calcd. for C16H17ClO3: C, 65.64; H, 5.85; found: C,
65.73; H, 5.91.
ACKNOWLEDGMENT
Financial support was provided by the Russian Foundation of Basic Research
(Grant 07-03-00352) and Bayer HealthCare AG (Germany).

4-Unsubstituted-3-(3-Oxoalkyl)isocoumarins
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