Antus, Sándor

Kerti, Gábor

Kurtán, Tibor

ARKIVOC

University of Debrecen Electronic Archive

Issue in Honor of Prof Henk C. van der Plas ARKIVOC 2009 (vi) 103-110 
ISSN 1551-7012 Page 103 ©ARKAT USA, Inc. 
Study on the reaction mechanism of Heck-oxyarylation of  
2H-chromenes 
 
Gábor Kerti,a Tibor Kurtán,a and Sándor Antusa,b* 
 
aDepartment of Organic Chemistry, University of Debrecen,  
P.O.Box 20, H-4010 Debrecen, Hungary 
bResearch Group for Carbohydrates of the Hungarian Academy of Sciences, 
P.O.Box 94, H-4010 Debrecen, Hungary 
E-mail: antuss@tigris.unideb.hu  
 
Dedicated to Professor Henk van der Plas on his 80th birthday 
 
 
Abstract 
The Heck-oxyarylation reaction of deuterium labeled 2H-chromenes (12,15) has been studied 
whose synthesis was achieved in four steps starting from the readily available 7-
benzyloxychromane (9). Since the deuterium label was not affected in the course of the 
oxyarylation, the formation of the neutral achiral intermediate 7 could be ruled out as a possible 
reaction pathway and a reason for the lack of enantioselectivity in asymmetric Heck-
oxyarylations. This also allowed the simple synthesis of 6a- and 11a-deutero-3-
benzyloxypterocarpanes (13a,b).  
 
Keywords: Pterocarpan, Heck-oxyarylation, mechanism 
 
 
 
Introduction 
 
Pterocarpans are naturally occurring plant products carrying a cis-fused benzofuranyl-
benzopyran ring system. Many of them are phytoalexins, which are produced in plants during 
infections by fungi, bacteria or viruses and subsequently act as protective agents for plants1. 
While some pterocarpans have antifungal2 and oestrogenic activity3 others have been reported to 
inhibit HIV-1 in cell cultures4 and to possess significant snake or spider inhibition venom 
activity5.  
 Among the wide variety of synthetic routes to pterocarpans,6-14 one of the most commonly 
used approaches14 involves the Heck-oxyarylation of 2H-chromenes (1) with 2-
chloromercuriophenols (2a) using equimolar amount of Li2[PdCl4] as catalyst (Scheme 1). 
 
Issue in Honor of Prof Henk C. van der Plas ARKIVOC 2009 (vi) 103-110 
ISSN 1551-7012 Page 104 ©ARKAT USA, Inc. 
O OH
X
catalyst precursor
ligand/base
solvent
1 X
2a
2b
HgCl
I
O
O
3
H
H
BnOBnO
+
1
2
3
4 5
6
6a
7
8
910
11
11a
 
 
Scheme 1 
 
 Recently, we have described a convenient modification of this Heck-oxyarylation step by 
the replacement of the toxic chloromercuriophenol derivatives (2a) with 2-iodophenols (2b), 
which allowed to considerably decrease the amount of the expensive palladium (II) salt (from 
100 mol% to 10 mol%) in the presence of triphenylphosphine and silver carbonate in acetone15 
or in ionic liquids such as 1-butyl-3-methylimidazolium hexafluorophosphate [[bmim] [PF6]]16. 
We have also published17 that the extension of this reaction to a practical asymmetric Heck-
oxyarylation affording enantiomerically enriched pterocarpans using different chiral bidentate 
phosphins or (+)-α-pinene as a ligand as well as a chiral ionic liquid could not be accomplished.  
 
Pd(II)
nL activation
Pd(0)L2
Pd
OH
R''
L X
L
OH
R''
X
oxidative insertion
O
O
H
H
R'
R''
O
R'
base
base*HX
syn-addition
2a,b
4
1
5
3
displacement
O
PdL
X
L
HR'
HO R''
 
 
Figure 1. Proposed sequence of Pd-catalyzed oxyarylation. 
Issue in Honor of Prof Henk C. van der Plas ARKIVOC 2009 (vi) 103-110 
ISSN 1551-7012 Page 105 ©ARKAT USA, Inc. 
 Although intramolecular Heck-oxyarylation is widely used in the synthesis of racemic 
pterocarpans,14,18-22 in contrast to the conventional Heck reaction,23-25 its mechanism is not fully 
understood.  
 It presumably also proceeds via the generation of active Pd(0), oxidative addition of 
aryliodide (2b) or chloromercuriophenol (2a) to Pd(0), followed by regioselective syn-addition 
of 4 to 2H-chromenes (1) and palladium displacement by phenolic oxygen whose details are not 
known (Figure 1).  
 On the basis of data published in the literature,26 the displacement step may take place via (i) 
cationic (5→6) (ii) neutral (5→7) or a palladium containing cyclic intermediate (5→8) as shown 
in Figure 2. 
 
O
HO
HR'
R"
O
R'
R"
OH
PdX
O
PdXL
L
O R''
R'
L
L
5
6 7 8
3
(i)
(ii)
(iii)
 
 
Figure 2. Possible pathways of the displacement step. 
 
 Since no or very moderate (ee%<10) asymmetric induction could be observed by us17 in the 
presence of chiral bidentate phosphine ligands, such as CHIRAPHOS, NORPHOS, TRIPHOS 
and R-(+)-BINAP, it could be assumed that this reaction takes place through parallel pathways 
and the main pathway involves an achiral intermediate 7, where the chirality introduced by chiral 
ligands of Pd(0) is lost. 
 In order to obtain aunambiguous evidence about this assumption, 2H-chromenes (12,15) 
labeled with deuterium at C-3 or C-4 have been synthesized and their transformation to the 
corresponding pterocarpans were studied. 
 
 
Results and Discussion 
 
According to the proposed mechanism shown in Figure 1 and 2, it seemed reasonable to prepare 
compounds in which a D atom was introduced at C-3 or at C-4 of the 2H-chromene skeleton (1).  
Issue in Honor of Prof Henk C. van der Plas ARKIVOC 2009 (vi) 103-110 
ISSN 1551-7012 Page 106 ©ARKAT USA, Inc. 
O
O
BnO
i
O
O
BnO
10a
vi O
OH
BnOO
O
BnO
D
14
D
D
ii
10b (D 99%)
iii
iv
O
OH
BnO
D
D
11
iv
BnO O
D
12 (D 75%)
BnO O
D
15 (D 100%)
v
BnO O
OR
2
R1v
R1 R2
D
H
H
D
13a
13b
9
1
2
3
4 5
6
6a
7
8
9
1011
11a
D%
75
100  
 
Scheme 2. (i) LAH/THF, Et2O, -60 °C, (ii) CDCl3/TBD, r.t, (iii) LAH/Et2O, r.t, (iv) acetone, 
10% HCl, 56 °C, (v) Pd(C6H5CN)2Cl2, Ag2CO3, Ph3P/THP, 65 °C or [bmim] [PF6], 100 °C or 
Li2[PdCl4] in acetone, r. t. Deuterium abundance is indicated in brackets as determined by 1H-
NMR. 
 
 For this purpose 7-benzyloxychromone (9) was reduced by lithium aluminium hydride in 
tetrahydrofuran at – 60 ºC resulting in 7-benzyloxychromanone (10a)18 in 70% yield, whose 
hydrogens at C-3 could be exchanged (10a→10b) using the method published by Mioskowski et 
al27 (Scheme 2). Since the 1H NMR monitoring of 10a in CDCl3 at room temperature has clearly 
indicated that in the presence 10 mol% triazabicyclo [4.4.0] dec-5-ene (TBD) the deuterium 
incorporation has reached 99% in 12h, then the target molecule (10b) could be simply isolated in 
88% yield. Subsequently, 10b was reduced by lithium aluminium hydride in ether at room 
temperature resulting in the corresponding chromane-4-ol (11), whose dehydratation was 
performed by some drops of diluted hydrochloric acid in acetone at 56 ºC affording the C-3 
deuterium labeled 2H-chromene 12 in an overall yield 46%. The deuterium content of 12 has 
been determined by 1H NMR as 75%. The Heck-oxyarylation of 12 was performed with 2a or 2b 
Issue in Honor of Prof Henk C. van der Plas ARKIVOC 2009 (vi) 103-110 
ISSN 1551-7012 Page 107 ©ARKAT USA, Inc. 
under the standard conditions [in case of 2a: PdCl2/LiCl, acetone, r.t.; in case of 2b: 
Pd(C6H6CN)2Cl2, Ag2CO3, Ph3P, THF, at 65 ºC or [bmim] [PF6], at 100 ºC] to result in 3-
benzyloxypterocarpan (13a) in 30-40% yield whose 1H NMR spectrum has clearly indicated the 
presence of the C-6a deuterium with 75% abundance. Since the deuterium incorporation of the 
chromene ring did not change in the course of the oxyarylation, contrast to our earlier 
assumption, the formation of the neutral achiral intermediate 7 must have been ruled out as a 
possible reaction pathway. It is also noteworthy that the oxyarilation of C-4 labeled 15 
possessing 100% deuterium incorporation with 2a or 2b (R’=H) took place in a similar manner 
to give 13b with unchanged deuterium incorporation. The 1H NMR spectra of 13a and 13b has 
also been found identical with those of compounds prepared by us in different synthetic route.28 
Since the absence of an asymmetric Heck-oxyarylation can not be attributed to the formation of 
achiral intermediate 7, further efforts are required to find suitable chiral inductor and to optimize 
circumstances. It is also noteworthy that our efforts to increase the yield of the oxyarylation 
carried out in DMF or NMP in the presence of a palladacycle, such as trans-di(µ-acetato)-bis[o-
(di-o-tolylphosphino)benzyl]dipalladium(II) prepared according to the literature29 were 
unsuccessful. Surprisingly, no transformation could be observed in these solvents, although 
palladacycletes have been found highly efficient catalysts for Heck vinylation of aryl halides 
under these conditions.30 Moreover the yield of the oxyarylation described in general procedure b 
of the experimental section could not be improved by microwave irradiation either. Work on this 
project is in progress in our laboratory. 
 
 
Experimental Section 
 
General Procedures. All reagents and organic compounds were purchased from Sigma Aldrich. 
7-Benzyloxychromane (9), trans-di(µ-acetato)-bis[o-(di-o-tolylphosphino)benzyl]- dipalladium 
(II) and 2-chloromercuriophenol (2a, R’=H) were prepared according to the known 
procedures.29,31,32 
 
7-Benzyloxychromanone (10a) 
To a stirred solution of 9 (2 g, 7.9 mmol) in 40 ml dry THF and Et2O (1:1) at –60 °C a solution 
of LiAlH4 (600 mg, 15.8 mmol) in dry THF (15 ml) was added under N2 atmosphere. After 3 
hours the reaction was quenched by addition of saturated aqueous NH4Cl (20 ml) and extracted 
with Et2O (3x20 ml). The organic layer was washed with brine, water, dried (Na2SO4), filtered 
and concentrated. The resulting product was purified by column chromatography on silica gel 
resulting in 10a of m.p.101-103 °C (1.41 g, 70%) as a colorless solid. Lit.33 m.p 102-103 °C. 1H-
NMR: δ 2.69 (t, J = 6.6 Hz, 2H, 3-H), 4.44 (t, J = 6.6 Hz, 2H, 2-H), 5.03 (s, 2H, OCH2Ph), 6.44 
(d, J = 2.4 Hz, 1H, 8-H), 6.61 (dd, J = 8.8, 2.4 Hz, 1H, 6-H), 7.25-7.40 (m, 5H, Ph), 7.80 (d, J = 
8.8 Hz, 1H, 5-H). 
 
Issue in Honor of Prof Henk C. van der Plas ARKIVOC 2009 (vi) 103-110 
ISSN 1551-7012 Page 108 ©ARKAT USA, Inc. 
7-Benzyloxy-3,3-dideutero-chromanone (10b) 
To the stirred solution of TBD (33 mg, 0.24 mmol) in deutero chloroform (8 ml) 10a (388 mg, 
1.53 mmol) was added at room temperature. After 12 h the reaction mixture was quenched with 
1N HCl (2 ml). The organic layer was washed with water (2x15 ml), brine (15 ml), dried 
(Na2SO4) and filtered. Evaporation of the solvent afforded 10b, whose deuterium incorporation 
has been found as 99% by 1H-NMR. 1H-NMR: δ 4.51 (s, 2H, 2-H), 5.09 (s, 2H, OCH2Ph), 6.49 
(d, J = 2.4 Hz, 1H, 8-H), 6.66 (dd, J = 8.8, 2.4 Hz, 1H, 6-H), 7.25-7.40 (m, 5H, Ph). 7.85 (d, J = 
8.8 Hz, 1H, 5-H). 
7-Benzyloxy-4-deutero-2H-chromene (15) 
To stirred solution of 10a (132 mg, 0.52 mmol) in dry Et2O (10 ml) LiAlD4 (28 mg, 0.66 mmol) 
was added at 0 °C. After 30 min. the reaction mixture was quenched with sat. aqueous NH4Cl 
(20 ml) and the organic layer was separated and the water phase was extracted with Et2O (3x10 
ml). The combined organic phase was washed with brine and dried (Na2SO4), whose evaporation 
resulted in 14 as a colorless solid (132 mg). It was dissolved in acetone (5 ml) and heated in the 
presence of one drop 10% HCl for 3 hours. After neutralization with Et3N, the reaction mixture 
was diluted with water and extracted with dichloromethane (3x5 ml). The organic layer was 
washed with brine and dried (Na2SO4). Evaporation of the solvent gave an oil (70 mg), which 
was purified by preparative TLC (n-hexane:ethyl acetate = 3:1) to give 15 of m.p. 59-60 °C (55 
mg, 44%), as a colorless solid incorporation has been determination by 1H-NMR to be 99%.1H-
NMR: δ 4.77 (d, J = 3.2 Hz, 2H, 2-H), 5.01 (s, 2H, OCH2Ph), 5.61 (t, J = 3.2 Hz, 1H, 3-H), 6.44 
(d, J = 2.2 Hz, 1H, 8-H), 6.48 (dd, J = 8.2, 2.2 Hz, 1H, 6-H), 6.86 (d, J = 8.2 Hz, 1H, 5-H), 7.25-
7.40 (m, 5H, Ph). 
7-Benzyloxy-3-deutero-2H-chromene (12) 
Starting from 10b (170 mg, 0.66 mmol) 12 (73 mg, 46%) was obtained by a similar procedure 
described for 15. On the basis of its 1H-NMR the deuterium incorporation is 75%.  
1H-NMR: δ 4.78 (d, J = 1.8 Hz, 2H, 2-H), 5.02 (s, 2H, OCH2Ph), 6.30-6.40 (m, 1H, 4-H), 6.44 
(d, J = 2.4 Hz, 1H, 8-H), 6.49 (dd, J = 8.2, 2.4 Hz, 1H, 6-H), 6.86 (d, J = 8.2 Hz, 1H, 5-H), 7.30-
7.45 (m, 5H, Ph). 
 
General procedures for the Heck-oxyarylation reaction 
a) Palladium chloride (89 mg, 0.48 mmol) and lithium chloride (45 mg, 1.06 mmol) were 
stirred in dry acetone (5 ml) for 15 min, 7-benzyloxy-2H-chromene (12 or 15) (120 mg, 0.50 
mmol) was added, stirred further for 15 min, followed by dilution of the mixture with dry 
acetone (15 ml) and addition of o-chloromercuriophenol (2a) (181 mg, 0.55 mmol). Stirring was 
continued for 14 hours and then the reaction mixture was poured on brine (50 ml), extracted with 
dichloromethane, dried, and concentrated in vacuo to give a viscous crude product (180 mg), 
whose purification by column chromatography on silica gel (n-hexane:ethyl acetate = 7:1) 
resulted in (±)-13a or 13b respectively (60-66 mg, 36-40%) as colorless prisms, m.p. 146-148 °C 
(MeOH). 
Issue in Honor of Prof Henk C. van der Plas ARKIVOC 2009 (vi) 103-110 
ISSN 1551-7012 Page 109 ©ARKAT USA, Inc. 
b) To a stirred solution of 12 or 15 (100 mg, 0.42 mmol) in dry acetone or THF (6 ml), 2-
iodophenol (93 mg, 0.42 mmol), silver carbonate (350 mg, 1.26 mmol), PPh3 as ligand (220 mg, 
0.84 mmol) and Pd(C6H5CN)2Cl2 palladium catalyst (16 mg, 0.042 mmol) were added at room 
temperature, and then the reaction mixture was stirred at 65 °C. After filtration, the solution was 
evaporated, and 13a or 13b respectively (40-45%) was isolated as given above. 
c) 4.2 x 10–3 mmol Pd(II) catalyst and 8.4 x 10–3 mmol PPh3 were stirred in [bmim][PF6] (1 g) 
at 80 °C for 5 min, respectively. Then 100 mg (0.42 mmol) 12 or 15, 93 mg (0.42 mmol) 2b and 
Ag2CO3 (348 mg, 1.26 mmol) were added. Stirring was continued at 100 °C for 5 hours and then 
the reaction mixture was cooled, extracted with toluene and concentrated in vacuo. The crude 
product was purified by preparative TLC (dichloromethane:n-hexane=1:2) to give rac-13a or 
13b respectively (34-36 mg, 36-38%). 
 
 
Acknowledgements 
 
Authors thank the Hungarian Scientific Research Fund (OTKA, T-049436, NI-61336), National 
Office for Research and Technology (NKTH, K-68429), Bolyai János Foundation, and Pázmány 
Péter Programme (NKTH, RET 006/2004) for financial support.  
 
 
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Study on the reaction mechanism of Heck-oxyarylation of 2H-chromes

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Study on the reaction mechanism of Heck-oxyarylation of 2H-chromes

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