Regioselective Suzuki-Miyaura Reactions of the Bis(triflate) of 6,7-Dihydroxy-2,2-dimethylchroman-4-one

Article abstract of DOI:10.1055/s-0035-1561265

6,7-Diarylchromanone derivatives were prepared by Suzuki-Miyaura reactions of the bis(triflate) of 6,7-dihydroxy-2,2-dimethylchroman-4-one. Due to electronic factors the first attack proceeded with very good site selectivity at position 7.

Full text of DOI:10.1055/s-0035-1561265

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© Georg Thieme Verlag Stuttgart · New York
2016, 27, A–D
letter
A
D. Pajtás et al.
Letter
Synlett
Regioselective Suzuki–Miyaura Reactions of the Bis(triflate) of
6,7-Dihydroxy-2,2-dimethylchroman-4-one
Dávid Pajtása,b
O
O
1) Ar1B(OH)2
2) Ar2B(OH)2
Károly Dihena,b
Krisztina Kónyaa,b
Peter Langer*b,c
Ar2
Ar1
OTf
OTf
H3C
H3C
H3C
H3C
O
O
a Department of Organic Chemistry, University of Debrecen,
4032 Debrecen, Egyetem tér 1, Hungary
b Department of Chemistry, University of Rostock, Albert-
Einstein-Str. 3a, 18059 Rostock, Germany
peter.langer@uni-rostock.de
c Leibniz-Institute for Catalysis e.V. at the University of
Rostock (LIKAT), Albert-Einstein-Str. 3a, 18059 Rostock,
Germany
28 examples
16–94%
Pd(PPh3)4 (6 mol%), K3PO4,
1,4-dioxane, 60–110 °C
Dedicated in memory to our dear colleague and friend Professor Tamás Patonay, PhD, DSc
Received: 03.11.2015
Accepted after revision: 06.12.2015
Published online: 21.01.2016
Suzuki coupling has the advantage of mild reaction condi-
tions, easy availability of arylboronic acids, and high func-
tional-group tolerance.21–35 Several catalysts and ligands
have been used in this coupling reaction.36–39 The chemose-
lectivity depends on the type of the leaving groups, the re-
activity follows the next sequence: ArI > ArBr > ArOTf > ArCl
> ArOTs.40–45 In the case of identical leaving groups, the re-
gioselectivity is controlled by steric and electronic fac-
tors.46–49 In the last few years, regioselective Suzuki cou-
pling reactions became a useful approach for synthesizing
new differently substituted benzopyrane derivatives.49–51
2,2-Dimethyl-6,7-dihydroxychroman-4-one (3) was
synthesized by the method of Tímár and Jászberényi.52
Commercially available hydroxyquinol (1) was transformed
into α,β-unsaturated ketone 2 which was transformed,
upon addition of potassium hydroxide, to 3. The reaction of
DOI: 10.1055/s-0035-1561265; Art ID: st-2015-d0863-l
Abstract 6,7-Diarylchromanone derivatives were prepared by Suzuki–
Miyaura reactions of the bis(triflate) of 6,7-dihydroxy-2,2-dimethyl-
chroman-4-one. Due to electronic factors the first attack proceeded
with very good site selectivity at position 7.
Key words Suzuki–Miyaura reaction, regioselectivity, palladium, ca-
talysis, heterocycles
Chromanones (2H-benzopyran-4-ones) are widespread
in nature, for example, as plants metabolites.1–4 They show
versatile biological activities, including antibacterial,5–7 HIV
inhibitor,8 enzyme modulator,9 and insecticidal10 proper-
ties. Besides their pharmacological activity, chromanone
derivatives are valuable precursors of molecules with ben-
zopyrane substructure. The 2,2-dimethyl-2H-1-benzopyran
moiety is represented in many natural products formed by
the polyketide biosynthesis pathway.11 Likewise, related
molecules, such as coumarins, chromenes, chromene glyco-
sides, and flavanoids, occur as natural products or are pres-
ent in biologically relevant synthetic molecules.12 Many
studies and investigations on the syntheses and chemical
transformations of 2,2-dimethyl-2H-benzopyrans have
been performed in the past decades. In fact, the synthesis of
2,2-dimethyl-2H-benzopyran-4-ones13 and 2,2-dimethyl-
2H-benzopyrans14 play a central role in drug discovery.
Although the synthesis of 2,2-dimethylchromanone15–18
is well-known, derivatives containing aryl groups located at
the benzene moiety have, to the best of our knowledge,
only scarcely been reported to date. This prompted us to de-
velop a new synthesis of mono- and diarylated 2,2-dimeth-
ylchromanones by regioselective Suzuki–Miyaura reac-
tions19,20 starting with the corresponding triflate derivative.
As compared to other palladium-catalyzed reactions, the
CH3
O
OH
OH
i
OH
OH
H3C
HO
HO
1
2 (70%)
ii
O
O
O
O
OH
OTf
iii
H3C
H3C
H3C
H3C
OH
OTf
4 (81%)
3 (82%)
Scheme 1 Synthesis of 4. Reagents and conditions: (i) 1 (1.0 equiv), 3-
methylbut-2-enoic acid (1.0 equiv), ZnCl2 (1.5 equiv), POCl3 (8.8 equiv),
r.t., 2 h; (ii) 5% NaOH solution, r.t., 1 h, then pH = 1 with concd HCl solu-
tion; (iii) Tf2O (2.4 equiv), pyridine (4.0 equiv), dry CH2Cl2, –78 °C to r.t.,
2 h.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–D

B
D. Pajtás et al.
Letter
Synlett
3 with trifluoromethanesulfonic anhydride in dry dichloro-
methane in the presence of pyridine provided bis(triflate) 4
(Scheme 1).
tained using 1.1 equivalents of boronic acid with Pd(PPh3)4
(3 mol%) in dry 1,4-dioxane at a temperature of 60 °C or, in
some cases, at 110 °C.
The Suzuki–Miyaura reaction of 4 with arylboronic ac-
ids 5a–j (2.2 equiv) afforded 6,7-diaryl-2,2-dimethylchro-
manones 6a–j in good yields (Scheme 2,Table 1).53 Both
electron-poor and electron-rich arylboronic acids were suc-
cessfully employed. The reactions were carried out in dry
1,4-dioxane at 90–100 °C using Pd(PPh3)4 (6 mol%) as cata-
lyst and K3PO4 (3.0 equiv) as base. However, the first cou-
pling occurred quickly at position 7, the second one went
slower, due to the lower reactivity of position 6 and the ste-
ric hindrance caused by the aryl group introduced in the
first coupling step. In one case (6i) the use of a larger
amount of boronic acid provided a higher yield.
O
O
ArB(OH)2
OTf
Ar
OTf
OTf
5a–j
H3C
H3C
H3C
H3C
i
O
O
7a–j
4
Scheme 3 Synthesis of 7a–j. Reagents and conditions: (i) 4 (1.0 equiv),
5a–j (1.1 equiv), Pd(PPh3)4 (3 mol%), K3PO4 (2.0 equiv), dry 1,4-diox-
ane, 60–110 °C, 5–18 h.
Table 2 Synthesis of 7a–j
5
7
Ar
4-F3CC6H4
T (°C)
t (h)
6.5
Yield of 7 (%)a
O
O
ArB(OH)2
Ar
Ar
OTf
OTf
a
b
c
d
e
f
a
b
c
d
e
f
60
60
34
68
70
77
65
38
76
80
73
59
5a–j
H3C
H3C
H3C
H3C
4-O MeC6H4
4-MeC6H4
Ph
8
9
i
O
O
60
4
6a–j
60
10
18
Scheme 2 Synthesis of 6a–j. Reagents and conditions: (i) 4 (1.0 equiv),
5a–j (2.2 equiv), Pd(PPh3)4 (6 mol%), K3PO4 (3.0 equiv), dry 1,4-diox-
ane.
4-HOC6H4
4-ClC6H4
110
60
6.5
g
h
i
g
h
i
4-FC6H4
60
6.5
5
3-vinylC6H4
3,4-(MeO)2C6H3
5-F-2-MeOC6H3
60
Table 1 Synthesis of 6a–j
110
60
18
6.5
j
j
5
6
Ar
4-F3CC6H4
T (°C)
t (h)
1,5
Yield of 6 (%)a
a Isolated yields.
a
b
c
d
e
f
a
b
c
d
e
f
90
90
90
90
90
90
90
90
90
100
83
68
71
57
49
56
78
16
75b
61
4-MeOC6H4
4-MeC6H4
Ph
2,5
2,5
6
The Suzuki–Miyaura reaction of monoarylated products
7b,d,e,g,j with arylboronic acids 5b,d,e,g,j (2.2 equiv) af-
forded 2,2-dimethyl-6,7-diarylchromanones 8a–h (Scheme
4, Table 3).55 The reactions were carried out at 90 °C in 1,4-
dioxane and resulted in high yields.
4-HOC6H4
4-ClC6H4
6
10
g
h
i
g
h
i
4-FC6H4
24
24
24
24
Table 3 Synthesis of 8a–h
3-vinylC6H4
3,4-(MeO)2C6H3
5-F-2-MeOC6H3
5
7
8
Ar1
4-HOC6H4
Ar2
Ph
Yield of 8 (%)a
j
j
d
e
j
e
d
e
j
a
b
c
94
82
89
71
91
82
83
72
a Isolated yields.
b Conditions: 4.4 equiv boronic acid.
Ph
4-HOC6H4
5-F-2-MeOC6H3
4-HOC6H4
4-FC6H4
4-HOC6H4
5-F-2-MeOC6H3
4-HOC6H4
4-FC6H4
e
g
e
e
b
d
e
f
The Suzuki–Miyaura reaction of 4 with arylboronic ac-
ids 5a–j (1.1 equiv) afforded the 7-aryl-2,2-dimethyl-6-tri-
flyloxychromanones 7a–j in moderate to good yields
(Scheme 3,Table 2).54 The reactions proceeded with very
good site selectivity. The first coupling occurred at position
7. Isomeric byproducts were not formed. Both electron-
poor and electron-rich arylboronic acids were successfully
used. During the optimization, the best yields were ob-
e
g
b
e
4-HOC6H4
4-HOC6H4
4-MeOC6H4
g
h
4-MeOC6H4
4-HOC6H4
a Isolated yields.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–D

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D. Pajtás et al.
Letter
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O
O
O
O
Ar2B(OH)2
5b,d,e,g,j
H3C
Ar2
Ar1
OTf
Ar1
H3C
H3C
i
H3C
7b,d,e,g,j
8a–h
Scheme 4 Synthesis of 8a–h. Reagents and conditions: (i) 7b,d,e,g,j
(1.0 equiv), 5b,d,e,g,j (2.2 equiv), Pd(PPh3)4 (6 mol%), K3PO4 (3.0
equiv), dry 1,4-dioxane, 90 °C, 2–4 h.
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troscopic methods. The structure of products 7a–j was
proved by 2D NMR experiments (HMBC, NOESY). Figure 1
shows the example of 7e. All structures were also con-
firmed by GC–MS, HRMS, and IR analysis.
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Figure 1 NOESY measurement of 7e
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In conclusion, we have reported the synthesis of a vari-
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Miyaura reactions of 6,7-ditriflyloxy-2,2-dimethylchro-
man-4-one. The first attack occurred at the position 7. The
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Acknowledgement
Financial support by the Alexander-von-Humboldt Foundation (Insti-
tute partnership program) and by the State of Mecklenburg-Vorpom-
mern (scholarships for D.P. and K.D.) is gratefully acknowledged.
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argon. The reaction mixture was stirred and heated in an alu-
minium heating block. The solvent was evaporated in vacuum,
then the solid mixture was submitted to adsorptive filtration on
silica gel using acetone as eluent removing the inorganic com-
pounds. Silica was added to the solution, the acetone was evap-
orated, and the mixture was purified by column chromatogra-
phy (eluent: heptane–EtOAc mixture, the ratio is given below)
giving the monosubsituted product.
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D.; Stanetty, P. Eur. J. Org. Chem. 2006, 3283.
7-(4-Methoxyphenyl)-2,2-dimethyl-6-(triflyloxy)chroman-
4-one
Starting with 4 (150 mg, 0.32 mmol), K3PO4 (135 mg, 0.64
mmol), Pd(PPh3)4 (11 mg, 3 mol%), (4-methoxyphenyl)boronic
acid (5b, 53 mg, 0.35 mmol), and 1,4-dioxane (4 mL), 7b was
isolated as a yellow oil (93 mg 68%), eluent: toluene–heptane
(47) Wang, R.; Manabe, K. Synthesis 2009, 1405.
1
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1639.
(52) Tímár, T.; Jászberényi, J. C. J. Heterocycl. Chem. 1988, 25, 871.
(53) Procedure for Synthesizing 6,7-Diaryl-2,2-dimethylchro-
man-4-one Derivatives
(6:1). H NMR (300 MHz, 298 K, DMSO-d6): δ = 7.71 (s, 1 H, 5-
H), 7.47 (d, 2 H, J= 8.7 Hz, 2′,6′-H), 7.06 (d, 2 H, J= 8.7 Hz, 3′,5′-H),
3.82 (s, 3 H, OCH3), 2.92(s, 2 H, 3-H), 1.44 (s, 6 H, CH3). 13C NMR
(75 MHz, 298 K, DMSO-d6): δ = 190.7 (C-4), 160.0 (C-4′), 158.6
(C-8a), 142.1 (C-6), 140.1 (C-7), 130.5 (C-2′,6′), 126.1 (C-1′),
120.9 (C-5), 118.9 (C-8), 118.8 (C-4a), 114.2 (C-3′,5′), 80.6 (C-2),
55.3 (OCH3), 47.3 (C-3), 26.0 (CH3). IR (ATR): υ = 2978, 2839,
1696, 1607, 1518, 1423, 1205, 1136, 1097, 1030, 915, 890, 832,
613, 564, 513 cm–1. GC–MS (EI, 70 eV): m/z = 430 [M+∙], 297,
255, 241 (100%), 215, 185, 157, 83. HRMS: m/z calcd for
To a mixture of 2,2-dimethyl-6,7-ditriflyloxychroman-4-one
(150 mg, 0.318 mmol), K3PO4 (202 mg, 0,95 mmol), and boronic
acid (0.70 mmol) in dry 1,4-dioxane (4 mL) was added Pd(PPh3)4
(22 mg, 0.019 mmol) in a dried pressure tube under argon. The
reaction mixture was stirred and heated in an aluminium
heating block. The solvent was evaporated in vacuum, and the
solid mixture was submitted to adsorptive filtration on silica
gel using acetone as eluent removing the inorganic compounds.
Silica was added to the solution, the acetone was evaporated,
and the mixture was purified by column chromatography (elu-
ent: heptane–EtOAc, the ratio is given below) giving the diary-
lated product.
6,7-Bis(4-methoxyphenyl)-2,2-dimethylchroman-4-one
Starting with 4 (150 mg, 0.32 mmol), K3PO4 (202 mg, 0.95
mmol), Pd(PPh3)4 (22 mg, 6 mol%), (4-methoxyphenyl)boronic
acid (5b, 106 mg, 0.70 mmol), and 1,4-dioxane (4 mL), 6b was
isolated as a white solid (84 mg 68%), mp 150–152.5 °C. 1H NMR
(300 MHz, 298 K, CDCl3): δ = 7.61 (s, 1 H, 5-H), 7.05 (d, J= 10.5
Hz, 2 H, 2′,6′′-H) 6.98 (d, J= 10.5 Hz, 2 H, 2′,6′-H), 6.93 (s, 1 H, 8-
H), 6.81 (m, 4 H, 3′,5′-H, 3′′,5′′-H), 3.72 (s, 3 H, 4′′-OCH3), 3.71 (s,
3 H, 4′-OCH3), 2.83 (s, 2 H, 3-H), 1.44 (s, 6 H, 2-CH3). 13C NMR
(75 MHz, 298 K, CDCl3): δ = 191.7.7 (C-4), 158.6 (C-8a), 158.3
(C-4′′), 157.9 (C-4′), 147.5 (C-7), 132.5 (C-1′′), 132.3 (C-1′), 132.0
(C-6), 130.4 (C-2′,6′, C-2′′,6′′), 127.4 (C-5), 119.3 (C-8), 118.5 (C-
4a), 113.6 (C-3′,5′, C-3′′5′′), 79.6 (C-2), 55.0 (OCH3), 48.0 (C-3),
26.2 (CH3). IR (ATR): υ = 2994, 2954, 2835, 1683, 1606, 1512,
1466, 1430, 1403, 1296, 1243, 1167, 1109, 1025, 951, 831, 655,
564, 549 cm–1. GC–MS (EI, 70 eV): m/z = 388 [M+∙, 100%], 373,
333, 261, 189. HRMS: m/z calcd for C25H24O4: 388.16691; found:
388.16649.
C19H17F3O6S: 430.06979; found: 430.06967.
(55) Procedure for Synthesizing Differently Substituted 6,7-
Diaryl-2,2-dimethylchroman-4-one Derivatives
To a mixture of 7-aryl-2,2-dimethyl-6-triflyloxychroman-4-one
(0.120 mmol), K3PO4 (76 mg, 0,360 mmol), and boronic acid
(0.264 mmol) in dry 1,4-dioxane (4 mL) was added Pd(PPh3)4
(8.3 mg, 0.0072 mmol) in a dried pressure tube under argon.
The reaction mixture was stirred and heated in an aluminium
heating block. The solvent was evaporated in vacuum, and then
the solid mixture was submitted to adsorptive filtration on
silica gel using acetone as eluent removing the inorganic com-
pounds. Silica was added to the solution, the acetone was evap-
orated, and the mixture was purified by column chromatogra-
phy (eluent: heptane–EtOAc mixture, the ratio is given below)
giving the differently substituted product.
6-(4-Hydroxyphenyl)-7-(4-methoxyphenyl)-2,2-dimethyl-
chroman-4-one
Starting with 7b (50 mg, 0.12 mmol), K3PO4 (76 mg, 0.36
mmol), Pd(PPh3)4 (8.1 mg, 6 mol%), (4-hydroxyphenyl)boronic
acid (5e, 35 mg, 0.264 mmol), and 1,4-dioxane (4 mL), 8g was
isolated as a light yellow solid (36 mg 83%), mp 182.5–185°C,
1
eluent: heptane–EtOAc (2:1). H NMR(300 MHz, 298 K, CDCl3):
δ = 9.37 (s, 1 H, 5-H), 7.59 (s, 1 H, 8-H), 7.06 (d, J= 8.7 Hz, 2 H,
2′′,6′′-H), 6.86 (d, J= 8.7 Hz, 2 H, 2′,6′-H), 6.82 (d, J= 8.7 Hz, 2 H,
3′′,5′′-H), 6.62 (d, J= 8.7 Hz, 2 H, 3′,5′-H), 6.55 (s, 1 H, OH), 3.73
(s, 3 H, OCH3), 2.82 (s, 2 H, 3-H), 1.44 (s, 6 H, CH3). 13C NMR (75
MHz, 298 K, CDCl3): δ = 191.7 (C-4), 158.6 (C-8a), 158.1 (C-4′′),
156.1 (C-4′), 147.5 (C-7), 132.9 (C-1′′), 132.1 (C-1′), 130.6 (C-6),
130.4 (C-2′,6′, C-2′′,6′′), 127.2 (C-5), 119.2 (C-8), 118.4 (C-4a),
115.0 (C-3′,5′), 113.5 (C-3′′,5′′), 79.6 (C-2), 55.0 (OCH3), 48.0 (C-
3), 26.2 (CH3). IR (ATR): υ = 3299, 2921, 2847, 1737, 1668, 1602,
(54) Procedure for Synthesizing 7-Aryl-2,2-dimethyl-6-triflyloxy-
chroman-4-one Derivatives
1512, 1406, 1243, 1163, 1109, 1026, 950, 834, 654, 560 cm–1
.
To a mixture of 2,2-dimethyl-6,7-ditriflyloxychroman-4-one
(150 mg, 0.318 mmol), K3PO4 (135 mg, 0,64 mmol), and boronic
acid (0.349 mmol) in dry 1,4-dioxane (4 mL) was added
Pd(PPh3)4 (11 mg, 0.0095 mmol) in a dried pressure tube under
GC–MS (EI, 70 eV): m/z = 374 [M+∙, 100%], 359, 319, 290, 247,
219, 202, 179, 152. HRMS: m/z calcd for C24H22O4: 374.15126;
found: 374.15110.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–D