One-pot synthesis of functionalized 2H-chromene (=2H-1-benzopyran) derivatives via a three-component reaction between a CH-acid, a dialkyl acetylenedicarboxylate, and methyl chloroglyoxylate or benzyl carbonochloridate mediated by triphenylphosphine

Article abstract of DOI:10.1002/hlca.201000030

An effective route to functionalized 2H-chromene (=2H-1-benzopyran) derivatives 4 is described (Scheme 1). This involves the reaction of a 1,1-diactivated alkene, resulting from the reaction of dimedone (=5,5-dimethylcyclohexane-1,3-dione; 1a) with methyl

Full text of DOI:10.1002/hlca.201000030

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Helvetica Chimica Acta – Vol. 93 (2010)
One-Pot Synthesis of Functionalized 2H-Chromene (¼2H-1-Benzopyran)
Derivatives via a Three-Component Reaction between a CH-Acid, a Dialkyl
Acetylenedicarboxylate, and Methyl Chloroglyoxylate or Benzyl
Carbonochloridate Mediated by Triphenylphosphine
by Mohammad Bayat*a), Nader Zabarjad Shirazb), and Soheila Shafei Asayesha)
a) Chemistry Department, Imam Khomeini International University, Qazvin, Iran
(phone: þ 98-281-3780040; fax: þ 98-281-3780040; e-mail: bayat_mo@yahoo.com)
b) Chemistry Department, Islamic Azad University, Tehran, Iran
An effective route to functionalized 2H-chromene (¼2H-1-benzopyran) derivatives 4 is de-
scribed (Scheme 1). This involves the reaction of a 1,1-diactivated alkene, resulting from the reac-
tion of dimedone (¼ 5,5-dimethylcyclohexane-1,3-dione; 1a) with methyl chloroglyoxylate
(ClC(¼O)COOMe), benzyl carbonochloridate (ClC(¼O)OCH2Ph) or 3,5-dinitrobenzoyl chloride
(3,5-(NO2)2C6H3C(¼O)Cl), and a dialkyl acetylenedicarboxylate (¼dialkyl but-2-ynedioate) in the
presence of Ph3P which undergo intramolecular Wittig reaction to produce 2H-chromene derivatives
(Scheme 1).
Introduction. – The developments of multicomponent reactions have attracted
much attention from the vantage point of combinatorial and medicinal chemistry [1].
The 2H-chromene (¼2H-1-benzopyran) moiety is a common structural feature of
numerous biologically active molecules [2][3] and is widely occurring in many natural
flavonoids and anthocyanins [4] as well as in members of the vitamin E family
(tocopherols and tocotrienes) [5]. Substituted chromenes are a new class of anticancer
compounds [6]. A variety of methods are known for the synthesis of this class of
compounds [3][5][7], typically starting with 2-hydroxyacetophenone derivatives or
directly from phenols via cyclization methods, electrophilic aromatic substitution, or by
relying on Pd-catalyzed processes.
Herein, we report a simple one-pot reaction between a reactive 1,1-diactivated
alkene, derived from the reaction of dimedone (¼ 5,5-dimethylcyclohexane-1,3-dione;
1a) or N,N’-dimethylbarbituric acid (¼1,3-dimethylpyrimidine-2,4,6(1H,3H,5H)-tri-
one; 1b) as CH-acids with active carbonyl compounds 2, such as methyl chloroglyox-
ylate (¼ methyl 2-chloro-2-oxoacetate), benzyl carbonochloridate or 3,5-dinitroben-
zoyl chloride, and a dialkyl acetylenedicarboxylate (¼dialkyl but-2-ynedioate) 3 in the
presence of Ph3P leading to 2H-chromene derivatives 4 (Scheme 1). The reaction
proceeded via a smooth 1:1:1 addition in CH2Cl2 at room temperature, to produce 2H-
chromene derivatives 4a – 4f in 65 – 90% yields.
Results and Discussion. – The one-pot three-component condensation, mediated by
Ph3P, of CH-acid 1 with active carbonyl compounds 2 and electron-deficient acetylenic
esters 3 proceeded in anhydrous CH2Cl2 or toluene and was completed after 24 h to
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Helvetica Chimica Acta – Vol. 93 (2010)
2219
Scheme 1
afford corresponding 2H-chromene systems 4a – 4f in moderate to good yields. 1H- and
13C-NMR spectra of the crude products clearly indicated the formation of 4a – 4f. The
structures of 4a – 4f were deduced from their elemental analyses, and IR and 1H- and
13C-NMR spectra. The mass spectra of 4a – 4f displayed the molecular-ion peak at the
expected m/z values. Initial fragmentations involved loss of the side chains and scission
of the heterocyclic system.
1
The H-NMR spectrum of 4a consisted of four s for Me and MeO groups (d 1.05,
1.10, 3.63, and 3.73) and a further s for the CH H-atom (d 4.57). The CH2 H-atoms of
the benzyl group are diastereotopic and exhibited an AB system (JAB ¼ 12.0 Hz, dA 5.23,
1
and dB 5.28). The H-decoupled 13C-NMR spectrum of 4a showed 20 sharp signals in
agreement with the proposed structure. The signal of the CH group of 4a appeared at d
ca. 50. The 1H- and 13C-NMR spectra of 4b – 4e are similar to those of 4a, except for the
activated carbonyl and ester moieties (see Exper. Part). The structural assignments,
1
made on the basis of the H- and 13C-NMR spectra of 4a, are supported by the IR
spectra. The spectrum of 4a showed strong absorption at 1735 and 1681 cmꢀ1
attributable to the C¼O groups.
We also used other CH-acidic compounds such as Meldrumꢂs acid (¼2,2-dimethyl-
1,3-dioxane-4,6-dione), barbituric acid (¼ pyrimidine-2,4,6(1H,3H,5H)-trione), or
indan-1,3-dione for the same reaction sequence, but the yields of the corresponding
2H-chromenes were very low, and in three cases several by-products were observed
(based on TLC).
Although the mechanism of the reaction between Ph3P and dialkyl acetylenedi-
carboxylates 3 in the presence of 1,1-diactivated alkene 6 (derived from C-acylation of

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Helvetica Chimica Acta – Vol. 93 (2010)
dimedone (1a) by 2) has not yet been established unambiguously by experiment, a
possible mechanistic sequence is proposed in Scheme 2. Based on the well-established
chemistry of trivalent phosphorus nucleophiles [8], it is reasonable to assume that
product 4 results from initial addition of Ph3P to the dialkyl acetylenedicarboxylate 3,
leading to 7, which on protonation by the acidic alkene 6 yields the 1:1 adduct 8. Then,
conjugate addition of the resulting O-enolate results in the formation of phosphorane 9,
which is converted to 4 via an intramolecular Wittig-type ring closure.
Scheme 2
From the reaction of dialkyl acetylenedicarboxylate with dimedone and benzyl
carbonochloridate in the presence of Ph3P, in addition to the 2H-chromene derivative 4,
fused 2H-pyran-2-ones 5 were isolated. In fact, the fused 2H-pyran-2-ones 5 are the
major product in the absence of 2. The mechanism for the formation of 5a and 5b is
proposed in Scheme 3. In this case, intermediate 8 is directly attacked by the dimedone
anion to form phosphorane 10. This intermediate undergoes a H-atom transfer to yield
11, which furnishes 12 by loss of Ph3P. Finally, cyclization of 12 leads to compound 5
[8][9].
In conclusion, we developed a convenient one-pot procedure for preparing 2H-
chromenes 4 of potential synthetic interest. The present method offers the advantage
that the reaction proceeds under neutral conditions and, moreover, the substances can
be mixed without any prior activation or modification. The simplicity of the present
procedure makes it an interesting alternative to complex multi-step syntheses.
Although the reaction sequence involves several steps, the preparation can be carried
out in only one practical step (one-pot preparation).

Helvetica Chimica Acta – Vol. 93 (2010)
2221
Scheme 3
Experimental Part
General. Methyl chloroglyoxylate (¼ methyl 2-chloro-2-oxoacetate), benzyl carbonochloridate,
N,N’-dimethylbarbituric acid, and other reagents and solvents used in this work were obtained from
Fluka (Buchs, Switzerland) and used without further purification. Column chromatography ¼ CC. M.p.:
Gallenkamp-9100 electrothermal apparatus; uncorrected. IR Spectra: Bruker-Tensor-27 spectrometer;
KBr pellets; ˜n in cmꢀ1 1H- and 13C-NMR Spectra: Bruker-DRX-300-Avance instrument; CDCl3 as
.
solvent; d in ppm rel. to Me4Si as internal standard, J in Hz. MS: Shimadzu-QP-GC Mass-1100-EX
spectrometer operating at an ionization potential of 70 eV; in m/z (rel. %). Elemental analyses:
Heraeus-CHN-O-Rapid analyzer; exper. values in agreement with calc. values.
General Procedure, Exemplified for Dimethyl 4-(Benzyloxy)-5,6,7,8-tetrahydro-7,7-dimethyl-5-oxo-
2H-1-benzopyran-2,3-dicarboxylate (4a). To a soln. of dimedone (1a; 0.140 g, 1 mmol) and benzyl
carbonochloridate (0.170 g, 1 mmol) in dry CH2Cl2 (5 ml), magnetically stirred for 8 h, PPh3 (0.262 g,
1 mmol) was added, followed by dropwise addition of a soln. of dimethyl but-2-ynedioate (0.142 g,
1 mmol) in dry CH2Cl2 (3 ml) at r.t. over 10 min. The mixture was stirred for 24 h. The solvent was
evaporated and the residue separated by CC (silica gel (Merck 230 – 240 mesh), hexane/AcOEt 8 :2): 4a
(0.360 g, 90%). Orange oil. IR: 2929 (CꢀH), 1735 and 1681 (C¼O), 1199 (CꢀO). 1H-NMR: 1.05, 1.10
(2s, Me2C); 2.26 (AB q, 2J ¼ 16.2, CH2); 2.30 (AB q, 2J ¼ 17.7, CH2); 3.63, 3.73 (2s, 2 MeO); 4.57 (s, CH);
5.25 (AB q, 2J ¼ 12.0, PhCH2O); 7.29 – 7.40 (m, 5 arom. H). 13C-NMR: 27.33, 28.98 (Me2C); 32.50, 36.45 (2
CH2); 40.28 (Me2C); 50.46 (CH); 51.63, 52.53 (2 MeO); 71.74 (CH2O); 84.05 (CHC¼C); 117.73
(OC¼C); 127.67, 128.58, 128.66, 135.12 (arom. C); 159.25 (OC¼C); 163.47 (CHC¼C); 165.52, 172.68
(2 C¼O ester); 195.84 (C¼O). EI-MS: 400 (1, Mþ), 277 (100), 262 (48), 199 (16), 183 (37), 152 (17), 119
(34), 91 (41), 77 (24), 51 (20). Anal. calc. for C22H24O7 (400.43): C 65.99, H 6.04; found: C 65.9, H 6.1.
Diethyl 4-(Benzyloxy)-5,6,7,8-tetrahydro-7,7-dimethyl-5-oxo-2H-1-benzopyran-2,3-dicarboxylate
(4b): Yield 0.364 g (85%). Yellow oil. IR: 2925 (CH), 1735, 1671 (C¼O), 1197 (CꢀO). 1H-NMR:
3
2
2
1.10, 1.15 (2s, Me2C); 1.20, 1.31 (2t, J ¼ 7.0, 2 MeCH2O); 2.25 (AB q, J ¼ 15.0, CH2); 2.45 (AB q, J ¼
3
2
15.5, CH2); 4.11 (q, J ¼ 7.0, 1 MeCH2O); 4.15 – 4.30 (m, 1 MeCH2O); 4.56 (s, CH); 5.28 (AB q, J ¼
12.0, PhCH2O); 7.25 – 7.45 (m, 5 arom. H). 13C-NMR: 14.10, 14.29 (2 MeCH2O); 27.24, 29.07 (Me2C);
32.67, 36.67 (2 CH2); 40.32 (Me2C); 60.34, 61.24 (2 MeCH2O); 71.71 (PhCH2O); 84.99 (CHC¼C); 111.73
(OC¼C); 127.73, 128.53, 128.61, 135.18 (arom. C); 158.91 (OC¼C); 163.40 (CHC¼C); 165.02, 172.68 (2
ester C¼O); 195.90 (C¼O). EI-MS: 400 (1.5, Mþ), 355 (13), 307 (6), 277 (27), 219 (6), 91 (100), 83 (7).
Anal. calc. for C24H28O7 (428.48): C 67.28, H 6.59; found: C 67.1, H 6.7.
Trimethyl 5,6,7,8-Tetrahydro-7,7-dimethyl-5-oxo-2H-1-benzopyran-2,3,4-tricarboxylate (4c): Yield
0.264 g (75%). Orange oil. IR: 2957 (CꢀH), 1736, 1671 (C¼O), 1204 (CꢀO). 1H-NMR: 1.11, 1.13

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Helvetica Chimica Acta – Vol. 93 (2010)
2
(2s, Me2C); 2.34 (AB q, J ¼ 16.2, CH2); 2.47 (br. s, CH2); 3.68, 3.80, 3.86 (3s, 3 MeO); 4.47 (s, CH).
13C-NMR: 27.13, 29.07 (Me2C); 32.39, 36.76 (2 CH2); 40.56 (Me2C); 50.25 (CH); 52.78, 53.18, 53.52
(3 MeO); 108.76 (CHC¼C); 112.11 (OC¼C); 144.70 (OC¼C); 161.20 (CHC¼C); 164.69, 165.33, 170.34
(3 ester C¼O); 195.82 (C¼O). Anal. calc. for C17H20O8 (352.34): C 57.95, H 5.72; found: C 57.8, H 5.6.
2,3-Diethyl 4-Methyl 5,6,7,8-Tetrahydro-7,7-dimethyl-5-oxo-2H-1-benzopyran-2,3,4-tricarboxylate
1
(4d): Yield 0.304 g (80%). Yellow oil. IR: 2960 (CꢀH), 1736, 1672 (C¼O), 1198 (CꢀO). H-NMR:
3
2
2
1.10, 1.14 (2s, Me2C); 1.19, 1.32 (2t, J ¼ 6.9, 2 MeCH2O); 2.25 (AB q, J ¼ 16.0, CH2); 2.45 (AB q, J ¼
15.5, CH2); 3.81 (s, MeO); 4.10 – 4.25 (m, 2 MeCH2O); 4.46 (s, CH). 13C-NMR: 13.90, 13.97
(2 MeCH2O); 26.90, 29.62 (Me2C); 32.46, 36.93 (2 CH2); 40.52 (Me2C); 50.34 (CH); 52.98 (MeO);
61.72, 61.80 (2 MeCH2O); 108.81 (CHC¼C); 112.55 (OC¼C); 144.29 (OC¼C); 161.20 (CHC¼C);
164.18, 164.80, 169.65 (3 ester C¼O); 196.19 (C¼O). Anal. calc. for C19H24O8 (380.39): C 59.99, H 6.36;
found: C 60.1, H 6.4.
Dimethyl 4-(3,5-Dinitrophenyl)-5,6,7,8-tetrahydro-7,7-dimethyl-5-oxo-2H-1-benzopyran-2,3-dicar-
boxylate (4e): Yield 0.322 g (70%). Yellow paste. IR: 2960 (CH), 1738, 1680 (C¼O), 1212 (CꢀO).
2
2
1H-NMR: 1.15, 1.16 (2s, Me2C); 2.39 (AB q, J ¼ 16.5, CH2); 2.50 (AB q, J ¼ 16.5, CH2); 3.67, 3.74 (2s,
2 MeO); 4.75 (s, CH); 8.62 (d, 3J ¼ 1.2, 2 Ho); 9.08 (t, 3J ¼ 1.2, Hp). Anal. calc. for C21H20N2O10 (460.4): C
54.78, H 4.38, N 6.08; found: C 54.8, H 4.3, N 6.2.
6,7-Diethyl 5-Methyl 1,3,4,7-Tetrahydro-1,3-dimethyl-2,4-dioxo-2H-pyrano[2,3-d]pyrimidine-5,6,7-
tricarboxylate (4f): Yield 0.257 g (65%). Yellow oil. IR: 2924 (CꢀH), 1717, 1681 (C¼O), 1200
(CꢀO). 1H-NMR: 1.33, 1.41 (2t, 2 MeCH2O); 3.45, 3.61 (2s, 2 MeN); 3.95 (s, MeO); 4.28 – 4.32 (m,
2 MeCH2O); 4.47 (s, CH). 13C-NMR: 14.33, 14.42 (2 MeCH2O); 39.16, 39.59 (2 MeN); 53.04 (CH); 53.79
(MeO); 62.75, 63.79 (2 MeCH2O); 85.59 (OC¼C); 116.09 (CHC¼C); 143.50 (CHC¼C); 152.60, 157.71
(C¼O); 160.17 (OC¼C); 161.38, 164.55, 169.79 (3 ester C¼O). Anal. calc. for C17H20N2O9 (396.35): C
51.52, H 5.09, N 7.07; found: C 51.6, H 5.2, N 7.1.
Methyl 5,6,7,8-Tetrahydro-7,7-dimethyl-2,5-dioxo-2H-1-benzopyran-4-carboxylate (5a): Yield 0.02 g
(8%). White powder. M.p. 95 – 978. IR: 2925 (CꢀH), 1760, 1725 (C¼O). 1H-NMR: 1.18 (2s, Me2C); 2.42,
2.70 (2s, 2 CH2); 3.92 (s, MeO); 6.21 (s, ¼CH). 13C-NMR: 28.12, 28.14 (Me2C); 32.48, 36.50 (2 CH2);
42.15 (Me2C); 53.24 (MeO); 111.32 (OC¼C); 111.75 (¼CH); 145.54 (C¼CH); 159.10 (OC¼C); 165.75,
174.19 (2 ester C¼O); 192.35 (C¼O). Anal. calc. for C13H14O5 (250.25): C 62.39, H 5.64; found: C 62.4, H
5.6.
Ethyl 5,6,7,8-Tetrahydro-7,7-dimethyl-2,5-dioxo-2H-1-benzopyran-4-carboxylate (5b): Yield 0.026 g
(10%). Pale yellow paste. IR: 2928 (CꢀH), 1758, 1720 (C¼O). 1H-NMR: 1.16 (2s, Me2C); 1.38 (t, 3J ¼
7.2, MeCH2O); 2.45, 2.76 (2s, 2 CH2); 4.41 (q, 3J ¼ 7.2, MeCH2O); 6.19 (s, ¼CH). 13C-NMR: 14.12
(MeCH2O); 28.13, 28.115 (Me2C); 32.47, 36.49 (2 CH2); 42.17 (Me2C); 61.45 (MeCH2O); 111.30
(OC¼C); 111.74 (¼CH); 145.53 (C¼CH); 159.14 (OC¼C); 165.72, 174.16 (2 ester C¼O); 192.30
(C¼O). Anal. calc. for C14H16O5 (264.27): C 63.63, H 6.10; found: C 63.7, H 6.1.
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Received January 22, 2010