Palladium-catalyzed direct arylation of 4-chromanones: Selective synthesis of racemic isoflavanones and 3,3-diaryl-4-chromanones

Article abstract of DOI:10.1002/ejoc.200901356

For the first time, the synthesis of racemic isoflavanones has been achieved in satisfactory to good yields and with high selectivity by Pd-catalyzed direct C-3 arylation of 3-unsubstituted 4-chromanones with aryl bromides with the aid of a Pd₂(dba)₃/tBu ₃PHBF₄ catalyst system in the presence of KHCO₃ as the base in a dioxane/water mixture (4:1). This catalyst system has also been employed in an unprecedented synthesis of 3,3-diaryl-4-chromanones through direct arylation of 4-chromanones in water.

Full text of DOI:10.1002/ejoc.200901356

FULL PAPER
DOI: 10.1002/ejoc.200901356
Palladium-Catalyzed Direct Arylation of 4-Chromanones: Selective Synthesis
of Racemic Isoflavanones and 3,3-Diaryl-4-chromanones
Fabio Bellina,*[a] Tiziana Masini,[a] and Renzo Rossi*[a]
Keywords: Direct arylation / Palladium / C–C coupling / Chromanones / Synthetic methods / Isoflavanones
For the first time, the synthesis of racemic isoflavanones has
been achieved in satisfactory to good yields and with high
selectivity by Pd-catalyzed direct C-3 arylation of 3-unsubsti-
tuted 4-chromanones with aryl bromides with the aid of a
Pd2(dba)3/tBu3PHBF4 catalyst system in the presence of
KHCO3 as the base in a dioxane/water mixture (4:1). This
catalyst system has also been employed in an unprecedented
synthesis of 3,3-diaryl-4-chromanones through direct aryl-
ation of 4-chromanones in water.
A plausible explanation for the lack of such findings is
that compounds1 might undergo ring-opening to phenolate
anions 5[2] under the strongly basic conditions often re-
quired for the catalyzed direct α-arylation of ketones with
aryl halides (Scheme 2).[3]
Introduction
The catalytic direct α-arylation of substrates containing
sp3-hybridized C–H bonds in positions α to a carbonyl
group of a ketone, an aldehyde, a carboxylic ester, an aza-
lactone, a lactone, a carboxamide, a lactam, a β-oxo ester,
a β-diketone, or ethyl cyanoacetate with aryl halides repre-
sents a very useful and convenient tool for efficient forma-
tion of Csp3–Csp2 bonds with high atom economy.[1] How-
ever, no report focusing on transition-metal-catalyzed direct
arylation of 4-chromanones 1 at the 3-position with aryl
halides 2a–c (Scheme 1) has yet appeared in the literature.
Scheme 2. Base-promoted ring-opening of 4-chromanones.
Moreover, even if it were possible to avoid ring-opening
of compounds 1 by use of a weak base, multiple arylation
might represent a significant side-reaction,[4] and the direct
α-arylation reaction of 1 might produce the required iso-
flavanones 3 together with a significant amount of the α,α-
diarylated derivatives 4. On the other hand, many of the
established procedures for preparation of compounds 3[5]
are severely limited by the use of expensive and/or not read-
ily available starting materials and, in some cases, toxic rea-
gents.
We therefore set out to investigate the Pd-catalyzed direct
C-3 arylation of 4-chromanes 1 with aryl bromides 2a and
to develop effective procedures for the selective preparation
of racemic isoflavanones 3 and 3,3-diaryl-4-chromanones 4.
The influence of factors such as the nature of the base used
in the reactions, the transition metal ligand, the solvent, the
1/2a molar ratio and the reaction temperature was exam-
ined.
Scheme 1. Transition-metal-catalyzed direct α-arylation of 4-
chromanones 1.
[a] Dipartimento di Chimica e Chimica Industriale, University of
Pisa,
Via Risorgimento 35, 56126 Pisa, Italy
Fax: +39-050-2219260
E-mail: bellina@dcci.unipi.it
rossi@dcci.unipi.it
Eur. J. Org. Chem. 2010, 1339–1344
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1339

F. Bellina, T. Masini, R. Rossi,
FULL PAPER
volve treatment of this substrate (2.0 equiv.) with 2aa in a
mixture of dioxane/water (4:1) under reflux for 1.2 h in the
presence of KHCO3 (2.0 equiv.), Pd2(dba)3 (2.5 mol-%) and
tBu3PHBF4 (10 mol-%). Compound 3a was thus obtained
in 71% isolated yield.
Results and Discussion
We began our studies by investigating the reaction between
4-chromanone (1a) and bromobenzene (2aa) in the presence
of various Pd precatalysts, ligands, bases and solvents
(Table 1). Our attention first focused on the catalyst systems
and reaction conditions employed successfully by Buch-
wald[3c] and Nolan[3j] for the arylation of ketone enolates,
so the use of tBuONa as the base in toluene[3c] or THF[3j]
and catalyst systems consisting of mixtures of Pd(OAc)2
and BINAP[3c] or (SIPr)Pd(allyl)Cl[3j] [SIPr = N,NЈ-bis(2,6-
We also observed that the amount of water in the reac-
tion solvent had a significant effect on the selectivity of the
C-3 arylation reaction and the yield of racemic 3a. In fact,
the Pd2(dba)3/tBu3PHBF4-catalyzed reaction between 1a
and 2aa (1.1 equiv.) in a mixture of dioxane/water (1:1) un-
der reflux in the presence of KHCO3 as the base furnished
a 75:25 mixture of racemic 3a/4a from which racemic 3a
was isolated in 45% yield (Entry 11, Table 1). On the other
hand, the Pd2(dba)3/tBu3PHBF4-catalyzed reaction be-
tween 1a and 2aa (1.1 equiv.) in water under reflux in the
presence of KHCO3 provided a mixture of 3a/4a in a 4:96
molar ratio, from which 4a was isolated in 54% yield (En-
try 12, Table 1). Finally, treatment of 1a with 2aa (4 equiv.)
in water under otherwise the same experimental conditions
as Entry 12, Table 1 led us to obtain 4a with high selectivity
and 61% isolated yield (Entry 13, Table 1).[7]
Next, Pd-catalyzed C-3 monoarylation of 4-chrom-
anones 1, including mono- and trisubstituted derivatives,
with a variety of aryl bromides 2a (Figure 1) under the opti-
mized reaction conditions of Entry 10 of Table 1 was inves-
tigated (Table 2).
As shown in Entries 1–9 of Table 2, deactivated, moder-
ately activated and unactivated aryl bromides, including
functionalized derivatives, were used, and racemic 3-aryl-
4-chromanones 3 were generally obtained with selectivities
higher than 90% in satisfactory to good yields.
diisopropylphenyl)-4,5-dihydroimidazol-2-ylidene]
(En-
tries 1 and 2, Table 1) was examined. However, we found
that the resulting reaction mixtures did not contain even
traces of either compound 3a or compound 4a, nor of unre-
acted 1a.
In contrast, the reaction, when performed in a mixture
of dioxane/water (4:1) at reflux with K2CO3 as the base[6]
and a Pd(OAc)2/tBu3PHBF4 catalyst precursor, produced
racemic 3a in 46% isolated yield (Entry 3, Table 1). Interest-
ingly, the selectivity and efficiency of the reaction was in-
creased when Pd(OAc)2 was replaced with Pd2(dba)3, the
1a/2aa molar ratio now being 1:1.5, as can be seen in En-
try 3 in Table 1. In fact, 3a was isolated in 53% yield from
a crude reaction mixture in which the 3a/4a molar ratio was
72:28 (Entry 4, Table 1). On the other hand, the use of a
1:1.1 molar ratio of 1a/2aa allowed us to increase the 3a/
4ab molar ratio in the crude reaction mixture further, but
the C-3 monoarylated derivative was isolated in only 41%
yield (Entry 5, Table 1). Better results were obtained when
Na2CO3 was employed as the base in place of K2CO3 (En-
try 6, Table 1). In contrast, KHCO3 gave better results than
Notable exceptions were the strongly deactivated 4-
NaHCO3 in terms of yields and selectivity (Entries 7 and 9, bromo-1,2-dimethoxybenzene (2ag) (Entry 10, Table 2),
Table 1). The optimal reaction conditions for C-3 mono- which gave the corresponding monoarylated derivative 3k
arylation of 1a were finally found (Entry 10, Table 1) to in- in only 31% isolated yield, and 1-bromo-4-nitrobenzene
Table 1. Screening of reaction conditions.
Entry
Pd compound
[mol-%]
Ligand
[mol-%]
Base
[equiv.]
1a/2aa
molar ratio
Solvent
Reaction conditions[a]
Products
3a, 4a yield
(%)[b] molar ratio
[°C/h]
3a/4a
1
2
3
4
5
6
7
8
9
10
11
12
13
Pd(OAc)2 (10)
(SIPr)Pd(allyl)Cl (1)
Pd(OAc)2 (5)
(Ϯ)-BINAP (12) tBuONa (2.0)
tBuONa (1.05)
1:2
1:1
PhMe
THF
100/2
50/1
–
–
–
–
–
–
tBu3PHBF4 (10)
tBu3PHBF4 (10)
tBu3PHBF4 (10)
K2CO3 (2.0)
K2CO3 (2.0)
K2CO3 (2.0)
1:1.5
1:1.5
1:1.1
1:1.1
1:1.1
1:1.1
1.5:1
2:1
dioxane/H2O (4:1)
dioxane/H2O (4:1)
dioxane/H2O (4:1)
dioxane/H2O (4:1)
dioxane/H2O (4:1)
dioxane/H2O (4:1)
dioxane/H2O (4:1)
dioxane/H2O (4:1)
dioxane/H2O (1:1)
H2O
reflux/17
reflux/17
reflux/19
reflux/24
reflux/24
reflux/24
reflux/2.75
reflux/1.2
reflux/3.5
reflux/24
reflux/24
3a
3a
3a
3a
3a
3a
3a
3a
3a
4a
4a
46
53
41
47
58
46
63
71
45
54
61
63:37
72:28
78:22
80:20
81:19
75:25
83:17
87:13
75:25
4:96
Pd2(dba)3 (2.5)
Pd2(dba)3 (2.5)
Pd2(dba)3 (2.5)
Pd2(dba)3 (2.5)
Pd2(dba)3 (2.5)
Pd2(dba)3 (2.5)
Pd2(dba)3 (2.5)
Pd2(dba)3 (2.5)
Pd2(dba)3 (2.5)
Pd2(dba)3 (2.5)
tBu3PHBF4 (10) Na2CO3 (2.0)
tBu3PHBF4 (10) KHCO3 (2.0)
tBu3PHBF4 (10) NaHCO3 (2.0)
tBu3PHBF4 (10) KHCO3 (2.0)
tBu3PHBF4 (10) KHCO3 (2.0)
tBu3PHBF4 (10) KHCO3 (2.0)
tBu3PHBF4 (10) KHCO3 (2.0)
tBu3PHBF4 (10) KHCO3 (2.0)
1:1.1
1:1.1
1:4
H2O
9:91
[a] The reactions were stopped when the amount of 1a in the reaction mixture was less than 5% (GLC). [b] Isolated yield.
1340 Eur. J. Org. Chem. 2010, 1339–1344
www.eurjoc.org
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Palladium-Catalyzed Direct Arylation of 4-Chromanones
Figure 1. Chemical structures of compounds 1b–d and 2ab–2ah.
Table 2. Pd-catalyzed C-3 arylation of 4-chromanones 1 with aryl
bromides 2a.[a]
Scheme 3. Pd-catalyzed synthesis of 3,3-diaryl-4-chromanones.
Entry
Reagents
Reaction time [h]
Product[b]
Yield (%)[c]
1
2a
3
1
2
3
4
5
6
7
8
9
1a
1a
1a
1a
1a
1b
1c
1d
1c
1d
1a
2ab
2ac
2ad
2ae
2af
2aa
2aa
2aa
2af
2ag
2ah
1.10
1.15
2.20
2.20
2.20
22.5
2.20
2.15
3.30
3.20
3.0
3b
3c
3d
3e
3f
3g
3h
3i
55
40
72
41
44
73
81
58
62
31
–
Conclusions
We describe the first examples of Pd-catalyzed direct C-
3 arylation of 4-chromanones with aryl bromides. The aryl-
ation procedure introduced here, which involves the use of
a Pd2(dba)3/tBu3PHBF4 catalyst system and KHCO3 as the
base, allows the selective synthesis either of racemic isoflav-
anones or of 3,3-diaryl-4-chromanones in satisfactory
yields, the selectivity of the reaction being dependent both
on the reaction solvent and the molar ratio of the reagents.
Our future work will be devoted both to use of the above
arylation procedure for the synthesis of naturally occurring
racemic isoflavanones possessing significant biological
properties[8] and to evaluate the potential for performing
asymmetric direct arylation reactions of 3-unsubstituted 4-
chromanones with aryl bromides. The use of aryl chlorides
and tosylates as alternative electrophiles will be also investi-
gated.
3j
3k
3i
10
11
[a] Aryl bromide 2a (1.0 mmol), 4-chromanone 1 (2.0 mmol),
Pd2(dba)3 (2.5 mol-%), tBu3PHBF4 (10 mol-%), KHCO3
(4.0 mmol), dioxane/H2O (4:1, 5.0 mL). [b] The amount of 3,3-di-
aryl-4-chromanones 4 in the crude reaction mixtures of Entries 1–
10 proved to be less than 10%. [c] Isolated yield.
(2ah, Entry 11, Table 2), which afforded no product. Inter-
estingly, the presence of ortho substituents in the aryl
moieties of compounds 2a did not hinder the reactions (En-
tries 3 and 4, Table 2), and the methodology also allowed
the coupling of 4-bromophenol (2af) with 1a and 1c (En-
tries 5 and 9, Table 2), although only a modest yield was
obtained when this bromide was treated with 1a (Entry 5,
Table 2). It is also interesting to point out that the direct
arylation involving 1b required more that 22 h to go to
completion (Entry 7, Table 2), probably due to a combina-
tion of unfavourable electronic and steric effects.
Experimental Section
General Remarks: Melting points are uncorrected. Precoated
Merck 60 F254 aluminium silica gel sheets were used for TLC analy-
ses. GLC analyses were performed with two types of capillary col-
umns: an Alltech AT-35 bonded FSOT column (30 mϫ0.25 mm
i.d.) and an Alltech AT-1 bonded FSOT column (30 mϫ0.25 mm
i.d.). Purifications by flash chromatography were performed with
silica gel (Merck 60, particle size 0.040–0.063 mm). EI mass spectra
Finally, we tested the reaction conditions of Entry 13 of were measured at 70 eV with a GLC/MS system. NMR spectra
were recorded at room temperature at 200 (1H), 300 (1H), 50.3 (13C)
Table 1 for the selective synthesis of some representative
3,3-diaryl-4-chromanones other than 4a by starting from 3-
and 75.5 MHz (13C) and were referenced to TMS. All reactions
were performed under argon by standard syringe, cannula and
unsubstituted or monosubstituted 4-chromanones.
septa techniques. Chroman-4-one (1a), 6,7-dimethoxy-2,2-dimeth-
As shown in Scheme 3, the reaction between 1a and
ylchroman-4-one (1b), 6-methylchroman-4-one (1c), 6-chlorochro-
bromide 2ac (4 equiv.) in water under reflux for 24 h in the
man-4-one (1d), bromobenzene (2aa), 4-bromoanisole (2ab), 1-
presence of KHCO3 (2 equiv.) and a Pd2(dba)3/tBu3PHBF4
bromo-4-(trifluoromethyl)benzene (2ac), 2-bromoanisole (2ad), 1-
catalyst system led to the required 3,3-diaryl derivative 4b
bromo-2-(trifluoromethyl)benzene (2ae), 4-bromophenol (2af), 4-
in 40% yield. Moreover, the reaction between racemic 3-
phenyl-4-chromanone (3a) and 2ac (2 equiv.) under the
bromo-1,2-dimethoxybenzene
(2ag),
1-bromo-4-nitrobenzene
(2ah), Pd(OAc)2, (SIPr)Pd(allyl)Cl, Pd2(dba)3, (Ϯ)-BINAP and
same experimental conditions gave racemic 4c in 33% yield. tBu3PHBF4 were commercially available.
Eur. J. Org. Chem. 2010, 1339–1344
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1341

F. Bellina, T. Masini, R. Rossi,
FULL PAPER
General Procedure for the Pd-Catalyzed Selective C-3 Monoaryl-
ation of Chroman-4-ones 1 with Aryl Bromides 2a: A chroman-4-
one 1 (2.0 mmol), Pd2(dba)3 (22.9 mg, 0.025 mmol), tBu3PHBF4
H), 4.07 (t, J = 7.0 Hz, 1 H, 3-H) ppm. 13C NMR (50.3 MHz,
CDCl3): δ = 191.3, 161.5, 139.0, 136.4, 129.0 (3 C), 128.2, 127.8 (2
C), 125.8, 121.9, 120.8, 117.9, 71.0, 52.0 ppm. EI-MS: m/z (%) =
(29.0 mg, 0.1 mmol), KHCO3 (200 mg, 2.0 mmol) and, if solid, an 293 (6) [M + 1]+, 292 (32) [M]+, 172 (6), 151 (5), 121 (9), 120 (100),
aryl bromide 2a (1.0 mmol) were placed in a reaction vessel under
a stream of argon. The reaction vessel was fitted with a silicon
septum, evacuated and back-filled with argon, and this sequence
was repeated thrice. A deaerated mixture of dioxane/H2O (4:1 v/v,
5 mL) and, if liquid, an aryl bromide 2a (1.0 mmol) were added by
syringe, and the stirred mixture was heated at reflux under argon
for the period of time given in Tables 1 and 2. After this period of
time, the reaction, which was periodically monitored by GLC,
GLC-MS and TLC analyses of samples treated with a saturated
aqueous NH4Cl solution and extracted with AcOEt, was complete.
The mixture was then allowed to cool to room temperature, diluted
with Et2O (25 mL) and poured into a saturated aqueous NH4Cl
solution (100 mL), and the resulting mixture was extracted with
Et2O (4ϫ25 mL). The combined organic extracts were washed
with brine, dried and concentrated under reduced pressure. The
resulting residue was purified by flash chromatography on silica gel
and/or by recrystallization. This procedure was employed to pre-
pare 3-arylchroman-4-ones 3a–k.
103 (5), 92 (34), 64 (6), 63 (5). GLC analysis showed that 3c was
chemically pure. C16H11F3O2 (292.25): calcd. C 65.76, H 3.79;
found C 65.92, H 3.81.
3-(2-Methoxyphenyl)chroman-4-one (3d): The crude product ob-
tained from the direct C-3 arylation reaction between chroman-4-
one (1a) and 2-bromoanisole (2ad) (Table 2, Entry 3) was purified
by flash chromatography on silica gel with use of a mixture of
toluene and MeCN (98:2 v/v) as eluent to give 3d (183 mg, 72%)
as a viscous, pale yellow oil. 1H NMR (300 MHz, CDCl3): δ = 7.98
(dd, J = 7.8, 1.5 Hz, 1 H, 5-H), 7.44 (m, 1 H, 7-H), 7.26 (m, 1 H,
6-H), 6.98 (m, 5 H, 8-H, Ar-H) 4.68 (m, 1 H, 2-H), 4.62 (m, 1 H,
2-H), 4.48 (dd, J = 10.6, 5.4 Hz, 1 H, 3-H), 4.34 (dd, J = 12.0,
5.4 Hz, 1 H, 3-H), 3.72 (s, 3 H, OCH3) ppm. 13C NMR (75.5 MHz,
CDCl3): δ = 192.3, 161.8, 157.3, 135.6, 130.3, 129.0, 127.5, 123.4,
121.5, 121.3, 120.8, 117.8, 111.1, 70.6, 55.4, 48.4 ppm. EI-MS: m/z
(%) = 255 (14) [M + 1]+, 254 (75) [M]+, 135 (10), 134 (100), 120
(12), 119 (72), 92 (13), 91 (42). GLC analysis showed that 3d was
99% chemically pure. The spectroscopic data for this compound
were in agreement with those previously reported.[5e]
3-Phenylchroman-4-one (3a): The crude product obtained from the
direct C-3 arylation reaction between chroman-4-one (1a) and bro-
mobenzene (2aa) (Table 1, Entry 8) was purified by flash
chromatography on silica gel with use of toluene as eluent. The
chromatographic fractions containing compound 3a were collected
and concentrated under reduced pressure. The solid residue was
recrystallized from MeOH to give 3a (159 mg, 71%) as a colourless
solid; m.p. 77 °C (ref.[5d] m.p. 77 °C). 1H NMR (200 MHz, CDCl3):
δ = 7.96 (m, 1 H, 5-H), 7.49 (m, 1 H, 7-H), 7.30 (m, 5 H, Ar-H),
7.02 (m, 2 H, 6-H, 8-H), 4.65 (d, J = 7.4 Hz, 2 H, 2-H), 3.98 (t, J
= 7.4 Hz, 1 H, 3-H) ppm. 13C NMR (50.3 MHz, CDCl3): δ = 192.1,
161.6, 136.0, 135.0, 128.9, 128.6 (2 C), 127.8 (2 C), 127.7, 121.6,
121.0, 117.8, 71.4, 52.3 ppm. EI-MS: m/z (%) = 225 (8) [M + 1]+,
224 (49) [M]+, 120 (100), 104 (35), 103 (10), 92 (26). GLC analysis
showed that 3a was 99% chemically pure. The spectral properties of
this compound were in agreement with those previously reported.[9]
3-[2-(Trifluoromethyl)phenyl]chroman-4-one (3e): The crude product
obtained from the direct C-3 arylation reaction between chroman-
4-one (1a) and 1-bromo-2-(trifluoromethyl)benzene (2ae) (Table 2,
Entry 4) was purified by flash chromatography on silica gel with
use of toluene as eluent to give 3e (120 mg, 41%) as a colourless
solid; m.p. 103–105 °C. 1H NMR (300 MHz, CDCl3): δ = 7.99 (dd,
J = 7.8, 1.5 Hz, 1 H, 5-H), 7.73 (d, J = 7.8 Hz, 1 H, Ar-H), 7.53
(m, 2 H, Ar-H), 7.42 (m, 1 H, 7-H), 7.24 (d, J = 7.5 Hz, 1 H, Ar-
H), 7.06 (m, 2 H, 6-H, 8-H), 4.57 (m, 3 H, 2-H, 3-H) ppm. 13C
NMR (75.5 MHz, CDCl3): δ = 191.6, 161.7, 136.2, 133.7, 132.1,
130.7, 127.8, 127.7, 126.3, 126.0, 122.4, 121.7, 121.4, 118.0, 71.8,
49.1 ppm. EI-MS: m/z (%) = 293 (5) [M + 1]+, 292 (39) [M]+, 151
(7), 121 (9), 120 (100), 92 (30), 64 (5). GLC analysis showed that
3e was chemically pure. C16H11F3O2 (292.25): calcd. C 65.76, H
3.79; found C 65.88, H 3.80.
3-(4-Methoxyphenyl)chroman-4-one (3b): The crude product ob-
tained from the direct C-3 arylation reaction between chroman-4-
one (1a) and 4-bromoanisole (2ab) (Table 2, Entry 1) was purified
by flash chromatography on silica gel with use of a mixture of
toluene and AcOEt (95:5 v/v) as eluent to give 3b (140 mg, 55%)
3-(4-Hydroxyphenyl)chroman-4-one (3f): The crude product ob-
tained from the direct C-3 arylation reaction between chroman-4-
one (1a) and 4-bromophenol (2af) (Table 2, Entry 5) was purified
by flash chromatography on silica gel with use of a mixture of
toluene/AcOEt (90:10 v/v) as eluent to give 3f (106 mg, 44%) as a
yellow solid; m.p. 137–140 °C (ref.[2] m.p. 140 °C). 1H NMR
(300 MHz, CDCl3): δ = 7.96 (dd, J = 7.8, 1.7 Hz, 1 H, 5-H), 7.51
(m, 1 H, 7-H), 7.10 (m, 2 H, Ar-H), 7.02 (m, 2 H, 6-H, 8-H), 6.75
(m, 2 H, Ar-H), 5.62 (br. s, 1 H, OH), 4.62 (m, 2 H, 2-H), 3.94 (dd,
J = 8.7, 6.0 Hz, 1 H, 3-H) ppm. 13C NMR (75.5 MHz, CDCl3): δ
= 194.0, 161.9, 155.7, 136.5, 129.9 (2 C), 127.1, 126.4, 121.7, 121.0,
118.0, 116.1 (2 C), 71.7, 51.7 ppm. EI-MS: m/z (%) = 293 (5) [M
+ 1]+, 292 (39) [M]+, 151 (7), 121 (9), 120 (100), 92 (30), 64 (5).
GLC analysis showed that 3f was 99% chemically pure. The spec-
troscopic data for this compound were in agreement with those
previously reported.[9]
1
as a yellow solid; m.p. 93–95 °C (ref.[10] m.p. 91–93 °C). H NMR
(300 MHz, CDCl3): δ = 7.95 (m, 1 H, 5-H), 7.48 (m, 1 H, 7-H),
7.19 (m, 2 H, Ar-H), 7.00 (m, 2 H, 6-H, 8-H), 6.88 (m, 2 H, Ar-
H), 4.62 (m, 2 H, 2-H), 3.93 (t, J = 7.2 Hz, 1 H, 2-H), 3.77 (s, 3
H, OCH3) ppm. 13C NMR (75.5 MHz, CDCl3): δ = 192.4, 161.5,
159.1, 135.9, 129.6 (2 C), 127.7, 126.9, 121.5, 121.0, 117.8, 114.3 (2
C), 71.5, 55.2, 51.5 ppm. EI-MS: m/z (%) = 255 (3) [M + 1]+, 254
(15) [M]+, 135 (10), 134 (100), 119 (13), 92 (4), 91 (9), 65 (4). GLC
analysis showed that 3b was 99% chemically pure. The spectral
properties of this compound were in agreement with those pre-
viously reported.[10]
3-[4-(Trifluoromethyl)phenyl]chroman-4-one (3c): The crude product
obtained from the direct C-3 arylation reaction between chroman-
4-one (1a) and 1-bromo-4-(trifluoromethyl)benzene (2ac) (Table 2,
Entry 2) was purified by flash chromatography on silica gel with
use of toluene as eluent to give 3c (117 mg, 40%) as a colourless
solid; m.p. 137–139 °C. 1H NMR (200 MHz, CDCl3): δ = 7.96 (dd,
J = 8.0, 1.9 Hz, 1 H, 5-H), 7.62 (m, 2 H, Ar-H), 7.53 (m, 1 H, 7-
6,7-Dimethoxy-2,2-dimethyl-3-phenylchroman-4-one (3g): The crude
product obtained from the direct C-3 arylation reaction between
6,7-dimethoxy-2,2-dimethylchroman-4-one (1b) and 1-bromoben-
zene (2aa) (Table 2, Entry 6) was purified by flash chromatography
on silica gel with use of a mixture of toluene and AcOEt (80:20 v/
v) as eluent to give 3g (228 mg, 73%) as a pale yellow solid; m.p.
1
170–173 °C. H NMR (300 MHz, CDCl3): δ = 7.24 (m, 6 H, 5-H,
H), 7.42 (m, 2 H, Ar-H), 7.06 (m, 2 H, 6-H, 8-H), 4.68 (m, 2 H, 2- Ar-H), 6.49 (s, 1 H, 8-H), 3.94 (s, 3 H, OCH3), 3.87 (s, 3 H, OCH3),
1342
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© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 1339–1344

Palladium-Catalyzed Direct Arylation of 4-Chromanones
3.60 (s, 1 H, 3-H), 1.49 (s, 3 H, CH3), 1.28 (s, 3 H, CH3) ppm. 13C
2 H, 2-H), 3.92 (t, J = 7.1 Hz, 1 H, 3-H), 3.86 (s, 3 H, OCH3), 3.85
NMR (75.5 MHz, CDCl3): δ = 191.1, 156.5, 155.8, 144.3, 135.6, (s, 3 H, OCH3) ppm. EI-MS: m/z (%) = 319 (5) [M + 1]+, 318
129.4 (2 C), 128.6 (2 C), 127.5, 112.0, 107.1, 100.6, 81.8, 62.0, 56.2,
56.1, 26.7, 24.7 ppm. EI-MS: m/z (%) = 313 (16) [M + 1]+, 312
(73), 298 (11), 297 (53), 181 (74), 180 (100), 165 (17), 137 (11), 117
(13), 91 (9). GLC analysis showed that 3g was chemically pure.
C19H20O4 (312.36): calcd. C 73.06, H 6.45; found C 73.22, H 6.47.
(30) [M]+, 165 (11), 164 (100), 149 (17), 91 (6), 77 (6). 13C NMR
(75.5 MHz, CDCl3): δ = 191.3, 160.0, 149.3, 148.9, 135.9, 127.2,
126.8, 121.7, 120.7, 119.7, 111.8 (2 C), 111.6, 71.6, 56.0 (2 C),
51.6 ppm. GLC analysis showed that 3k was chemically pure.
C17H15ClO4 (318.75): calcd. C 64.06, H 4.74; found C 64.25, H
4.76.
6-Methyl-3-phenylchroman-4-one (3h): The crude product obtained
from the direct C-3 arylation reaction between 6-methylchroman-
4-one (1c) and 1-bromobenzene (2aa) (Table 2, Entry 7) was puri-
fied by flash chromatography on silica gel with use of a mixture of
toluene and AcOEt (98:2 v/v) as eluent to give 3h (193 mg, 81%)
as a pale yellow solid; m.p. 42–43 °C. 1H NMR (200 MHz, CDCl3):
δ = 7.70 (s, 1 H, 5-H), 7.24 (m, 6 H, 7-H, Ar-H), 6.86 (d, J =
8.4 Hz, 1 H, 8-H), 4.53 (d, J = 7.2 Hz, 2 H, 2-H), 3.87 (t, J =
7.2 Hz, 1 H, 3-H), 2.24 (s, 3 H, CH3) ppm. 13C NMR (75.5 MHz,
CDCl3): δ = 192.1, 159.5, 136.9, 135.2, 130.8, 128.7, 128.5 (2 C),
127.5 (2 C), 127.1, 120.5, 117.5, 71.3, 52.2, 20.3 ppm. EI-MS: m/z
(%) = 239 (9) [M + 1]+, 238 (48) [M]+, 135 (10), 134 (100), 106
(14), 105 (12), 78 (15), 77 (9). GLC analysis showed that 3h was
chemically pure. C16H14O2 (238.28): calcd. C 80.65, H 5.92; found
C 80.94, H 5.93.
3,3-Diphenylchroman-4-one (4a, Entry 13, Table 1): Chroman-4-one
(1a, 148 mg, 1.0 mmol), Pd2(dba)3 (22.9 mg, 0.025 mmol),
tBu3PHBF4 (29.0 mg, 0.1 mmol) and KHCO3 (200 mg, 2.0 mmol)
were placed in a reaction vessel under a stream of argon. The reac-
tion vessel was fitted with a silicon septum, evacuated and back-
filled with argon, and this sequence was repeated thrice. Deaerated
water (5 mL) and 4-bromobenzene (2aa, 0.42 mL, 628 mg,
4.0 mmol) were added by syringe, and the mixture was stirred un-
der reflux under argon for 24 h. The reaction mixture was then
allowed to cool to room temperature, diluted with Et2O (25 mL)
and poured into a saturated aqueous NH4Cl solution (100 mL),
and the resulting mixture was extracted with Et2O (4ϫ25 mL). The
combined organic extracts were dried and concentrated under re-
duced pressure, and the residue was purified by flash chromatog-
raphy on silica gel with use of a mixture of toluene/petroleum ether
(60:40 v/v) as eluent to give 4a (183 mg, 61%) as a pale yellow solid;
m.p. 128–130 °C (ref.[5d] m.p. 129–131 °C). 1H NMR (200 MHz,
CDCl3): δ = 8.02 (dd, J = 7.6, 1.8 Hz, 1 H, 5-H), 7.39 (m, 1 H, 7-
H), 7.28 (m, 10 H, Ar-H), 6.95 (m, 2 H, 6-H, 8-H), 4.88 (s, 2 H,
2-H) ppm. 13C NMR (50.3 MHz, CDCl3): δ = 193.2, 160.6, 138.4
(2 C), 135.8, 128.8 (4 C), 128.5 (4 C), 128.3, 127.7 (2 C), 121.4,
121.0, 117.6, 73.8, 59.5 ppm. EI-MS: m/z (%) = 301 (8) [M + 1]+,
300 (33) [M]+, 223 (17), 181 (16), 180 (100), 179 (37), 178 (28), 165
(45). GLC analysis showed that 4a was chemically pure. C21H16O2
(300.35): calcd. C 83.98, H 5.37; found C 84.49, H 5.39.
6-Chloro-3-phenylchroman-4-one (3i): The crude product obtained
from the direct C-3 arylation reaction between 6-chlorochroman-
4-one (1d) and 1-bromobenzene (2aa) (Table 2, Entry 8) was puri-
fied by flash chromatography on silica gel with use of toluene as
eluent to give 3i (151 mg, 58%) as a pale yellow solid; m.p. 99–
101 °C. 1H NMR (200 MHz, CDCl3): δ = 7.89 (d, J = 2.6 Hz, 1
H, 5-H), 7.33 (m, 6 H, 7-H, Ar-H), 6.96 (d, J = 8.8 Hz, 1 H, 8-H),
4.65 (d, J = 7.2 Hz, 2 H, 2-H), 3.96 (t, J = 7.2 Hz, 1 H, 3-H) ppm.
13C NMR (75.5 MHz, CDCl3): δ = 191.0, 160.0, 135.8, 134.5,
128.9, 128.5 (2 C), 127.9 (2 C), 127.1, 126.9, 121.8, 119.6, 71.5,
51.9 ppm. EI-MS: m/z (%) = 259 (11) [M + 1]+, 258 (49) [M]+, 156
(32), 155 (9), 154 (100), 126 (19), 104 (55), 103 (15), 78 (11), 63
(10). GLC analysis showed that 3i was chemically pure.
C15H11ClO2 (258.70): calcd. C 69.64, H 4.29; found C 69.87, H
4.31.
3,3-Bis[4-(trifluoromethyl)phenyl]chroman-4-one (4b): Chroman-4-
one (1a, 148 mg, 1.0 mmol), Pd2(dba)3 (22.9 mg, 0.025 mmol),
tBu3PHBF4 (29.0 mg, 0.1 mmol) and KHCO3 (200 mg, 2.0 mmol)
were placed in a reaction vessel under a stream of argon. The reac-
tion vessel was fitted with a silicon septum, evacuated and back-
filled with argon, and this sequence was repeated thrice. Deaerated
water (5 mL) and 1-bromo-4-(trifluoromethyl)benzene (2ac,
0.56 mL, 900 mg, 4.0 mmol) were added by syringe, and the mix-
ture was stirred under reflux under argon for 24 h. The reaction
mixture was then allowed to cool to room temperature, diluted with
Et2O (25 mL) and poured into a saturated aqueous NH4Cl solution
(100 mL), and the resulting mixture was extracted with Et2O
(4ϫ25 mL). The combined organic extracts were dried and con-
centrated under reduced pressure, and the residue was purified by
flash chromatography on silica gel with use of a mixture of toluene/
petroleum ether (20:80 v/v) as eluent to give 4b (175 mg, 40%) as
3-(4-Hydroxyphenyl)-6-methylchroman-4-one (3j): The crude prod-
uct obtained from the direct C-3 arylation reaction between 6-
methylchroman-4-one (1c) and 4-bromophenol (2af) (Table 2, En-
try 9) was purified by flash chromatography on silica gel with use
of a mixture of toluene/AcOEt (85:15 v/v) as eluent to give 3j
1
(158 mg, 62%) as a viscous, pale yellow oil. H NMR (300 MHz,
CDCl3): δ = 7.73 (d, J = 1.7 Hz, 1 H, 5-H), 7.31 (dd, J = 1.7,
8.4 Hz, 1 H, 7-H), 7.03 (m, 2 H, Ar-H), 6.90 (d, J = 8.4 Hz, 1 H,
8-H), 6.70 (m, 2 H, Ar-H), 4.56 (m, 2 H, 2-H), 3.89 (dd, J = 9.0,
6.0 Hz, 1 H, 3-H), 2.30 (s, 3 H, CH3) ppm. 13C NMR (75.5 MHz,
CDCl3): δ = 194.1, 160.0, 155.7, 137.6, 131.2 (2 C), 129.8, 127.4,
126.6, 120.6, 117.8 (2 C), 116.1, 71.7, 51.8, 20.5 ppm. EI-MS: m/z
(%) = 255 (18) [M + 1]+, 254 (100) [M]+, 253 (26), 239 (29), 225
(39), 207 (49), 135 (54), 119 (51), 108 (20), 91 (16), 79 (21), 44
(19). GLC analysis showed that 3j was chemically pure. C16H14O3
(254.28): calcd. C 75.57, H 5.55; found C 75.74, H 5.56.
1
a colourless solid; m.p. 115–117 °C. H NMR (200 MHz, CDCl3):
δ = 8.02 (dd, J = 7.8, 1.7 Hz, 1 H, 5-H), 7.60 (m, 4 H, Ar-H), 7.48
(m, 1 H, 7-H), 7.39 (m, 4 H, Ar-H), 7.01 (m, 2 H, 6-H, 8-H), 4.90
(s, 2 H, 2-H) ppm. 13C NMR (50.3 MHz, CDCl3): δ = 191.9, 160.5,
141.9 (2 C), 136.6, 129.3 (6 C), 128.4 (4 C), 126.6, 125.7 (2 C),
122.0, 121.2, 120.5, 117.8, 73.4, 59.4 ppm. EI-MS: m/z (%) = 437
(3) [M + 1]+, 436 (11) [M]+, 417 (8), 297 (6), 247 (6), 227 (6), 178
(10), 121 (9), 120 (100), 92 (23). GLC analysis showed that 4b was
chemically pure. C23H14F6O2 (436.35): calcd. C 63.31, H 3.23;
found C 63.68, H 3.24.
6-Chloro-3-(3,4-dimethoxyphenyl)chroman-4-one (3k): The crude
product obtained from the direct C-3 arylation reaction between 6-
chlorochroman-4-one (1d) and 4-bromo-1,2-dimethoxybenzene
(2ag) (Table 2, Entry 10) was purified by flash chromatography on
silica gel with use of a mixture of toluene/AcOEt (90:10 v/v) as
eluent to give 3k (98 mg, 31%) as a yellow solid; m.p. 106–108 °C.
1H NMR (300 MHz, CDCl3): δ = 7.89 (d, J = 2.7 Hz, 1 H, 5-H), 3-Phenyl-3-[4-(trifluoromethyl)phenyl]chroman-4-one (4c): 3-Phen-
7.43 (dd, J = 8.9, 2.7 Hz, 1 H, 7-H), 6.97 (d, J = 8.9 Hz, 1 H, 8-
H), 6.83 (m, 2 H, Ar-H), 6.77 (s, 1 H, Ar-H), 4.66 (d, J = 7.1 Hz,
ylchroman-4-one (3a, 224 mg, 1.0 mmol), Pd2(dba)3 (22.9 mg,
0.025 mmol), tBu3PHBF4 (29.0 mg, 0.1 mmol) and KHCO3
Eur. J. Org. Chem. 2010, 1339–1344
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1343

F. Bellina, T. Masini, R. Rossi,
FULL PAPER
see: a) Y. Terao, T. Satoh, M. Miura, M. Nomura, Bull. Chem.
Soc. Jpn. 1999, 72, 2345–2350; b) Y. Terao, Y. Kametani, H.
Wakui, T. Satoh, M. Miura, M. Nomura, Tetrahedron 2001,
57, 5967–5974; c) T. Satoh, M. Miura, M. Nomura, J. Or-
ganomet. Chem. 2002, 653, 161–164; d) A. Ehrentraut, A. Zapf,
M. Beller, Adv. Synth. Catal. 2002, 344, 209–217.
(200 mg, 2.0 mmol) were placed in a reaction vessel under a stream
of argon. The reaction vessel was fitted with a silicon septum, evac-
uated and back-filled with argon, and this sequence was repeated
thrice. Deaerated water (5 mL) and 1-bromo-4-(trifluoromethyl)-
benzene (2ac, 0.28 mL, 450 mg, 2.0 mmol) were added by syringe,
and the mixture was stirred at reflux under argon for 24 h. The
reaction mixture was then allowed to cool to room temperature,
diluted with Et2O (25 mL) and poured into a saturated aqueous
NH4Cl solution (100 mL), and the resulting mixture was extracted
with Et2O (4ϫ25 mL). The combined organic extracts were dried
and concentrated under reduced pressure, and the residue was puri-
fied by flash chromatography on silica gel with use of a mixture of
toluene and petroleum ether (60:40 v/v) as eluent to give 4c
(122 mg, 33%) as a colourless solid; m.p. 151–153 °C. 1H NMR
(200 MHz, CDCl3): δ = 8.02 (dd, J = 8.0, 1.8 Hz, 1 H, 5-H), 7.57
(m, 2 H, Ar-H), 7.36 (m, 10 H, 7-H, Ar-H), 6.98 (m, 2 H, 6-H, 8-
H), 4.89 (s, 1 H, 2-H), 4.88 (s, 1 H, 2-H) ppm. 13C NMR
(75.5 MHz, CDCl3): δ = 192.5, 160.6, 142.7, 137.6, 136.1, 129.3 (2
C), 128.71 (2 C), 128.67, 128.3 (2 C), 128.1, 125.8 (2 C), 125.4,
122.2, 121.7, 120.8, 117.7, 73.6, 59.4 ppm. EI-MS: m/z (%) = 369
(7) [M + 1]+, 368 (28) [M]+, 291 (12), 248 (48), 233 (13), 223 (13),
179 (26), 178 (27), 120 (100), 92 (20). GLC analysis showed that 4c
was chemically pure. C22H15F3O2 (368.35): calcd. C 71.74, H 4.10;
found C 72.36, H 4.12.
[5]
For established synthetic approaches to racemic isoflavanones,
see: a) R.-I. Saito, T. Izumi, A. Kasahara, Bull. Chem. Soc.
Jpn. 1973, 46, 1776–1779; b) R. Gandhisadan, S. Neelakantan,
P. V. Raman, Synthesis 1982, 1110; c) H. G. Krishnamurty, S.
Sathyanaryana, Synth. Commun. 1986, 16, 1657–1663; d)
D. H. R. Barton, D. M. X. Donnelly, J.-P. Finet, P. M. Stenson,
Tetrahedron 1988, 44, 6387–6396; e) D. M. X. Donnelly, J.-P.
Finet, P. H. Stenson, Heterocycles 1989, 28, 15–19; f) A. C.
Jain, A. Kumar, N. K. Sharma, Indian J. Chem. Sect. B 1991,
30, 290–291; g) D. M. X. Donnelly, J.-P. Finet, B. A. Rattigar,
J. Chem. Soc. Perkin Trans. 1 1993, 1729–1735; h) D. M. X.
Donnelly, B. M. Fitzpatrick, B. A. O’Reilly, J.-P. Finet, Tetrahe-
dron 1993, 49, 7967–7976; i) P. Valenti, F. Belluti, A. Rampa,
A. Bisi, Synth. Commun. 1999, 29, 3895–3899; j) R. Skouta,
C.-J. Li, Angew. Chem. Int. Ed. 2007, 46, 1117–1119; k) T.
Skouta, C.-J. Li, Tetrahedron Lett. 2007, 48, 8343–8346.
For an example of the use of a mild base for the α-arylation
of carbonyl derivatives, see: Y. Terao, Y. Fukuoka, T. Satoh,
M. Miura, M. Nomura, Tetrahedron Lett. 2002, 43, 101–104.
For leading references on Pd-catalyzed reactions in water, see:
a) A. Chanda, V. V. Fokin, Chem. Rev. 2009, 109, 725–748; b)
B. H. Lipshutz, A. R. Abela, Org. Lett. 2008, 10, 5329–5332;
c) S. A. Ohnmacht, P. Mamone, A. J. Culshaw, M. F. Greaney,
Chem. Commun. 2008, 1241–1243; d) E. Alacid, C. Najera,
Org. Lett. 2008, 10, 5011–5014; e) G. L. Turner, J. A. Morris,
M. F. Greaney, Angew. Chem. Int. Ed. 2007, 46, 7996–8000; f)
C.-J. Li, Chem. Rev. 2005, 105, 3095–3165; g) B. Liang, M.
Huang, Z. You, Z. Xiong, K. Lu, R. Fathi, J. Chen, Z. Yang,
J. Org. Chem. 2005, 70, 6097–6100; h) B. H. Lipshutz, T. B.
Petersen, A. R. Abela, Org. Lett. 2008, 10, 1333–1336; i) C.
Wolf, R. Lerebours, Org. Biomol. Chem. 2004, 2, 2161–2164; j)
J. P. Genet, M. Savignac, J. Organomet. Chem. 1999, 576, 305–
317.
[6]
[7]
[1] For reviews, see: a) M. Miura, M. Nomura, Top. Curr. Chem.
2002, 219, 212–237; b) D. A. Culkin, J. F. Hartwig, Acc. Chem.
Res. 2003, 36, 234–245; c) G. C. Lloyd-Jones, Angew. Chem.
Int. Ed. 2002, 41, 953–956; d) F. Bellina, R. Rossi, Chem. Rev.,
DOI: 10.1021/cr9000836.
[2] R. K. Akuamoah, P. E. Brown, W. Y. Marcus, J. E. Steele, J.
Chem. Soc. Perkin Trans. 1 1995, 197–201.
[3] For leading references, see: a) M. Palucki, S. L. Buchwald, J.
Am. Chem. Soc. 1997, 119, 11108–11109; b) B. C. Hamann,
J. F. Hartwig, J. Am. Chem. Soc. 1997, 119, 12382–12383; c) J.
Aahman, J. P. Wolfe, M. V. Troutman, M. Palucki, S. L. Buch-
wald, J. Am. Chem. Soc. 1998, 120, 1918–1919; d) G. A. Grasa, [8] Most of the natural isoflavanones isolated to date have been
T. J. Colacot, Org. Lett. 2007, 9, 5489–5492; e) M. Kawatsura,
J. F. Hartwig, J. Am. Chem. Soc. 1999, 121, 1473–1478; f) J. M.
Fox, X. Huang, A. Chieffi, S. L. Buchwald, J. Am. Chem. Soc.
2000, 122, 1360–1370; g) M. Limbeck, H. Wamhoff, T. Roelle,
N. Griebenow, Tetrahedron Lett. 2006, 47, 2945–2948; h) M. S.
Viciu, R. F. Germaneau, S. P. Nolan, Org. Lett. 2002, 4, 4053–
4056; i) K. Matsubara, H. Okazaki, M. Senju, J. Organomet.
Chem. 2006, 691, 3693–3699; j) M. S. Viciu, R. A. Kelly III,
E. D. Stevens, F. Naud, M. Studer, S. P. Nolan, Org. Lett. 2003,
5, 1479–1482.
obtained in racemic form, which has been interpreted in terms
of a racemization side-process during their isolation: a) T. Fu-
kai, L. Zeng, J. Nishizawa, Y.-H. Wang, T. Nomura, Phyto-
chemistry 1996, 41, 951–955; b) J. L. Vicario, D. Badia, L. Car-
rillo, Tetrahedron: Asymmetry 2003, 14, 489–495.
[9] A.-R. Ibrahim, Y. J. Abul-Hajj, J. Nat. Prod. 1990, 53, 644–
656.
[10] W. Vaccaro, C. Amore, J. Berger, R. Burrier, J. Clader, H. Davis,
M. Domalski, T. Fevig, B. Salisbury, R. Sher, J. Med. Chem.
1996, 39, 1704–1719.
[4] For examples of direct α-arylation reactions of ketones that
result in significant amounts of multiple arylation products,
Received: November 24, 2009
Published Online: January 28, 2010
1344
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Eur. J. Org. Chem. 2010, 1339–1344