PdI2-catalyzed regioselective cyclocarbonylation of 2-allyl phenols to dihydrocoumarins

Article abstract of DOI:10.1021/ol5029157

A simple, efficient, and regioselective synthesis of 3-methyl-3,4-dihydrocoumarins is reported. The reaction of 2-allyl phenols with synthesis gas was catalyzed by PdI₂, and 1,3,5,7-tetramethyl-6-phenyl-2,4,8-trioxa-6-phosphaadamantane (L1) and 1,3,5,7-tetramethyl-6-tetradecyl-2,4,8-trioxa-6-phosphaadamantane (L2) were effective as ligands, affording good product selectivity in all cases.

Full text of DOI:10.1021/ol5029157

Letter
pubs.acs.org/OrgLett
PdI2‑Catalyzed Regioselective Cyclocarbonylation of 2‑Allyl Phenols
to Dihydrocoumarins
Manuel Amezquita-Valencia and Howard Alper*
́
Centre for Catalysis Research and Innovation, Department of Chemistry, University of Ottawa, 10 Marie Curie, Ottawa, Ontario K1N
6N5, Canada
S
* Supporting Information
ABSTRACT: A simple, efficient, and regioselective synthesis
of 3-methyl-3,4-dihydrocoumarins is reported. The reaction of
2-allyl phenols with synthesis gas was catalyzed by PdI2, and
1,3,5,7-tetramethyl-6-phenyl-2,4,8-trioxa-6-phosphaadaman-
tane (L1) and 1,3,5,7-tetramethyl-6-tetradecyl-2,4,8-trioxa-6-
phosphaadamantane (L2) were effective as ligands, affording
good product selectivity in all cases.
oumarins and their derivatives are compounds that occur
in a number of natural products and are key intermediates
C
for the synthesis of biologically active molecules.1 As an
important subset, 3,4-dihydrocoumarins exhibit some interest-
ing biological activities; their therapeutic properties include
inhibition of sir2 as well as immunomodulatory and estrogenic
activity.2 Owing to the importance of these molecules, different
synthetic approaches have been reported which include
enzymatic synthesis,3 [4 + 2] cycloaddition using silyl ketene
acetals,4 organocatalysts,5 and transition-metal-catalyzed reac-
tions.6 Despite these examples, there are few methods to
synthesize 3-methyl-3,4-dihydrocoumarins.3b,6a,7 Metal-cata-
lyzed cyclocarbonylation is an attractive approach for the
preparation of a variety of cyclic compounds,8 such as five-, six-,
or seven-membered ring lactones and lactams.9
Figure 1. CYTOP ligands used. 1,3,5,7-Tetramethyl-6-phenyl-2,4,8-
trioxa-6-phosphaadamantane (L1) and 1,3,5,7-tetramethyl-6-tetradec-
yl-2,4,8-trioxa-6-phosphaadamantane (L2).
optimal reaction conditions (Table 1). As a starting point,
intramolecular cyclocarbonylation experiments were performed
with a 1:1 H2/CO mixture (600 psi) for 20 h at 90 °C, using 2
mol % of different palladium precursors and CYTOP 292 (L1)
as the ligand in dichloromethane (DCM). Although the
cyclocarbonylation reaction is effective with different palladium
sources such as Pd(OAc)2, Pd(tfa)2, Pd(cod)2Cl2, Pd-
(MeCN)2Cl2, and Pd(acac)2, giving 100% conversion, our
studies show that Pd2(dba)3 and PdI2 are more selective than
other palladium catalysts to form the six-membered ring 2,3-
dihydrocoumarin 3a (Table 1, entries 1−8). The best solvent is
toluene (entry 13). The use of coordinating solvents such as
tetrahydrofuran (THF) and acetonitrile (MeCN) resulted in
reduced reactivity (entries 9−12). The analogous reaction with
Pd2(dba)3 gave only traces of the desired products 2/3/4
(entry 14). When the reaction temperature was increased to
120 °C the selectivity increased (entries 15−20).
We have previously reported that the regioselectivity for the
cyclocarbonylation of 2-allyl phenols is dependent on the
reaction conditions. Our earlier publication noted that using
[Pd(PCy3)2(H)(H2O)]+BF4 or [Pd(OAc)2] as the catalyst
−
and the bidentate ligand (dppb) gave fine selectivity for the
formation of seven-membered ring heterocycles from 2-allyl
phenols.9 Similar results were observed using immobilized
palladium catalysts such as Pd-clays and a recyclable system in
ionic liquids.10 In general, the product distribution was related
to the extent of isomerization of the allyl substrate, and the
selectivity was influenced by the metal precursor, solvent
relative pressures of gases, and the ligand. Bidentate ligands are
excellent for the cyclocarbonylation reactions. We reasoned that
the use of an appropriate monodentate ligand could change the
selectivity of this reaction. This concept is supported by the
good results obtained working with a monodentate ligand for
the cyclocarbonylation of 2-vinylphenol and allyl aniline.9
Herein we report a highly selective process to form six-
membered ring 3-methyl-3,4-dihydrocoumarins. The cyclo-
isomerization of allyl phenols proceeded by employing PdI2
and CYTOP ligands (L1 and L2, Figure 1).
Finally, the best results were obtained using PdI2 in toluene
at 120 °C for 20 h to form the corresponding 3-methyl-3,4-
dihydrocoumarin 3a in 82% selectivity (entry 21), accompanied
by smaller amounts of five- and seven-membered ring lactones
(2a and 4a). In contrast, poor selectivity was obtained using
PdCl2 under the same reaction conditions (entry 22). No
Initially, 2-allyl phenol 1a was chosen as the model substrate,
and extensive investigations were carried out to define the
Received: October 2, 2014
© XXXX American Chemical Society
A
dx.doi.org/10.1021/ol5029157 | Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Table 1. Screening of Reaction Conditions
Table 3. Cyclocarbonylation of Different Allyl Phenols Using
PdI2 and L1 or L2 as the Ligand
a
b
b
entry
[Pd]
solvent
conv (%)
2a:3a:4a (%)
1
Pd2(dba)3
Pd(OAc)2
Pd(tfa)2
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
THF
100
100
100
100
100
100
100
100
12:39:49
20:20:60
18:30:52
26:26:48
24:38:38
21:36:43
31:35:34
16:54:30

2
3
4
Pd(cod)Cl2
Pd(MeCN)2Cl2
Pd(acac)2
PdCl2
5
6
7
8
PdI2
c
9
Pd2(dba)3
Pd2(dba)3
PdI2
NR
NR
NR
NR
c
c
c
10
11
12
13
14
MeCN
MeCN
THF


PdI2

PdI2
PhMe
PhMe
DCM
DCM
DCM
DCM
PhMe
PhMe
PhMe
PhMe
PhMe
100
20:58:22

c
Pd2(dba)3
Pd2(dba)3
Pd(OAc)2
Pd(cod)Cl2
Pd(MeCN)2Cl2
Pd(MeCN)2Cl2
Pd(cod)Cl2
PdI2
NR
NR
98
d
c
15

d
16
16:50:34
36:48:16
23:45:32
9:44:47
27:28:45
10:82:8
35:32:33

d
17
99
d
18
99
d
19
100
100
100
100
0
d
20
d
21
d
22
PdCl2
de
,
23
PdI2
a
Reactions were carried out with 1a (3.8 mmol), 2 mol % [Pd] (0.076
mmol), ligand L1 (0.152 mmol), CO (300 psi), and H2 (300 psi) at 90
b
°C in 10 mL of solvent. The conversion and the ratio of 2/3/4 were
1
determined by H NMR spectroscopy of the crude reaction mixture.
c
d
e
No reaction. Reaction at 120 °C. Reaction without ligand.
a
Table 2. Cyclocarbonylation of 1a Using Different Ligands
b
c
b
entry
ligand (L)
conversion (%)
2a:3a:4a:5a (%)
a
Reactions were carried out with 1 (3.8 mmol), 2 mol % of PdI2
1
2
3
4
5
6
PPh3
100
100
0
14:48:15:23
6:40:10:44
−
(0.076 mmol), and CYTOP 292 (L1) or L2 ligand (0.152 mmol) in
b
(p-Tolyl)3P
PCy3
10 mL of toluene at 120 °C for 20 h. The product distribution and
the ratio of 2/3/4 were determined by 1H NMR analysis of the crude
c
reaction mixture. The isolated yield after column chromatography is
dppp
5
traces
shown in brackets.
dppb
3
traces
L2
100
10:80:10:0
a
Reactions were carried out with 1a (3.8 mmol), 2 mol % PdI2 (0.076
to isomerization of the double bond in the substrate (entries 1
and 2). Moreover, no catalytic activity was observed using PCy3
(entry 3). The use of dppp or dppb as ligands gave only 5% and
3% conversion, respectively, with traces of the desired products
(entries 4 and 5). However, another ligand with the
phosphaadamantane framework (L2) afforded similar results
to that of L1 (entry 6).
Having established the optimal reaction conditions, the
intramolecular cyclocarbonylation was then applied to a variety
of 2-allyl phenols. All reactions proceeded to full conversion
with excellent regioselectivity, giving the six-membered ring 3-
methyl-3,4-dihydrocoumarins as major products (from 73% to
82% yields), and the results are summarized in Table 3. The
electronic nature of the substituent on the aryl ring of the
mmol), ligand L (0.152 mmol), CO (300 psi), and H2 (300 psi) at 120
b
°C in 10 mL of toluene. The conversion and the ratio of 2/3/4/5
were determined by 1H NMR spectroscopy of the crude reaction
c
mixture. Isomerization product.
products were observed without added ligand and the starting
material was recovered (entry 23).
To explore the efficiency of the PdI2/CYTOP 292 catalytic
system further, we worked with different commercial phosphine
ligands (Table 2). Under the above optimized conditions, the
use of monodentate phosphines such as PPh3 or (p-Tolyl)3P
resulted in excellent conversion, but poor selectivity, and also
included the formation of 5a in some instances, corresponding
B
dx.doi.org/10.1021/ol5029157 | Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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substrates had little influence on the product selectivity. For
example, substrates bearing both para-substituted electron-
donating and -withdrawing substituents gave comparable
selectivity for the six-membered ring heterocycles (3a−c)
(entries 1−3). An allyl phenol bearing a sterically bulky p-tert-
butyl group (1d) gave the desired product (3d) in good
selectivity (entry 4), as did substrates with an α-naphthyl group
(entries 5 and 6).
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reactants forming six-membered ring dihydrocoumarins in
good yields (entry 7). The same selectivity occurred when the
reaction was carried out with o-methoxy and o-methyl groups
on the aromatic ring (entries 8 and 9). Substrates with two
different substituents (1j−k) also experienced cyclocarbonyla-
tion to form six-membered ring lactones in excellent
regioselectivity (entries 10 and 11). Clearly, these results
show that the cyclocarbonylation using the PdI2/L1 or L2
catalytic system is not sensitive to electronic or steric effects.
In conclusion, we have developed an efficient regioselective
cyclocarbonylation of 2-allyl phenols using a combination of
PdI2 as the metal catalyst source and 1,3,5,7-tetramethyl-6-
phenyl-2,4,8-trioxa-6-phosphaadamantane (L1) or 1,3,5,7-tetra-
methyl-6-tetradecyl-2,4,8-trioxa-6-phosphaadamantane (L2) as
a ligand. This method provides facile access to a variety of 3-
methyl-3,4-dihydrocoumarins in excellent regioselectivity and
good yields.
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ASSOCIATED CONTENT
■
S
* Supporting Information
Experimental procedures, characterization data, and NMR
spectra. This material is available free of charge via the Internet
at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: howard.alper@uottawa.ca.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful to Cytec Canada, Inc. and to the Natural
Sciences and Engineering Research Council (NSERC) for
support of this work. This paper is dedicated to the memory of
Prof. Dr. Armando Cabrera (1944−2014).
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dx.doi.org/10.1021/ol5029157 | Org. Lett. XXXX, XXX, XXX−XXX