The Barbier-Grignard-Type Arylation of Ketones and Unexpected Cross-Coupling of Phenolic Ketones using Unactivated Aryl Bromides

Article abstract of DOI:10.1002/adsc.201500743

A novel, highly versatile and efficient method has been developed for the Barbier-Grignard-type arylation of ketones and an unexpected cross-coupling of phenolic ketones was observed using unactivated bromides and magnesium in tetrahydrofuran/toluene at 96°C promoted by multicatalysts of cupric bromide (15 mol%), bismuth chloride (5 mol%) and silver bromide (10 mol%). The substituent and electronic effects on the reaction have been discussed. High yields of arylation and cross-coupling have been attained under mild conditions. A novel reasonable mechanism involving a quinone intermediate is proposed. The high chemical selectivity in the cross-coupling to the hydroxy group of phenolic ketones should help ketones find new applications.

Full text of DOI:10.1002/adsc.201500743

FULL PAPERS
DOI: 10.1002/adsc.201500743
The Barbier–Grignard-Type Arylation of Ketones and Unexpect-
ed Cross-Coupling of Phenolic Ketones using Unactivated Aryl
Bromides
Yunming Wen,+a Guifang Chen,+a Shiqiang Huang,b Yu Tang,a,* Jun Yang,a
and Yuanming Zhanga,*
a
Department of Chemistry, College of Life Science and Technology, Jinan University, Guangzhou 510632, Peopleꢀs
Republic of China
Fax: (+86)-20-8522-5036 (Y.T.) or (+86)-20-8522-2756 (Y.Z,); e-mail: tytang@jnu.edu.cn or tzhangym@jnu.edu.cn
Guangdong Inspection and Quarantine Technology Center, Guangzhou 510632, Peopleꢀs Republic of China
b
+
These authors contributed equally to this work.
Received: August 7, 2015; Revised: January 6, 2016; Published online: March 8, 2016
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201500743.
Abstract: A novel, highly versatile and efficient coupling have been attained under mild conditions.
method has been developed for the Barbier– A novel reasonable mechanism involving a quinone
Grignard-type arylation of ketones and an unexpect- intermediate is proposed. The high chemical selectiv-
ed cross-coupling of phenolic ketones was observed ity in the cross-coupling to the hydroxy group of phe-
using unactivated bromides and magnesium in tetra- nolic ketones should help ketones find new applica-
hydrofuran/toluene at 968C promoted by multicata- tions.
lysts of cupric bromide (15 mol%), bismuth chloride
(5 mol%) and silver bromide (10 mol%). The sub-
stituent and electronic effects on the reaction have Keywords: arylation; Barbier–Grignard-type reac-
been discussed. High yields of arylation and cross- tion; cross-coupling; ketones; unactivated bromides
Introduction
derivatives to aryl Grignard reagents was first report-
ed,[10] which was limited to 2-naphthol derivatives,
The Barbier–Grignard-type reaction is one of the and suffered the sensitive feature of Grignard re-
most important reactions to form carbon-carbon agents. Some other coupling reactions concerning hy-
bonds in organic synthesis.[1,2] Numerous examples droxy groups could also be found, such as Pd- or Pd/
have been reported including allylation,[3,4] benzyla- Cu-catalyzed direct arylation of arylboronic acids or
tion,[5] propargylation,[4e,6] and alkylation[7] of ketones dehydrating cross-coupling of alkynes to tautomeriza-
mediated by different metals and catalysts such as ble heterocycles,[11] Pd-catalyzed cross-coupling of 4-
Mn/Cp2TiCl2, Ga, In, and SmI2. But they are mainly hydroxycoumarins, 4-substituted-pyrones and 2(5H)-
limited to activated halides, expensive metals, or furanones with arylboronic acids.[12] To the best of our
more difficultly obtained materials than halides. Re- knowledge, cross-coupling of other phenol com-
cently, an effective arylation of unactivated aryl io- pounds to aryl bromides mediated by magnesium and
dides to aldehydes in water was revealed,[8] but gener- catalysts, even to Grignard reagents could not be
ated less than 80% yields and proved to be unsuitable found yet. On the basis of our previous reaction re-
for ketones or aryl bromides. Therefore, it is still sults of aryl or alkyl bromides with esters catalyzed
a hard challenge to develop a more efficient and prac- by CuO,[13] we would like herein report the highly ef-
tical method for the Barbier–Grignard-type reaction ficient Barbier–Grignard-type arylation of ketones
of ketones with unactivated aryl bromides. On the and unexpected cross-coupling of phenolic ketones
other hand, Grignard reagents have been widely ap- catalyzed by multimetals using unactivated aryl bro-
plied in coupling reactions.[9] But it was only in 2010 mides. This multicatalyst route demonstrates a novel
that a nickel-catalyzed cross-coupling of 2-naphthol application of the synergistic role of catalysts.[14]
Adv. Synth. Catal. 2016, 358, 947 – 957
ꢁ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
947

FULL PAPERS
Yunming Wen et al.
Results and Discussion
ed to improve the yield of the reaction, but it looked
unsuitable by just using a single catalyst. Then, we
CuO and Cu2O[13] were firstly chosen as catalysts in tried to conduct a multicomponent catalyst of CuBr2,
the reaction of bromobenzene with cyclohexanone, BiCl3 or AgBr, which each exhibited relatively high
which were unfortunately not effective to give the catalytic efficiency when used alone. We were sur-
product (Table 1, entries 1 and 2). The results indicat- prised to gain a better yield of 86% (Table 1,
ed that the reaction of cyclohexanone with bromoben- entry 11) using a mixture of CuBr2 (10 mol%) and
zene was different from that of esters.[13] It was found BiCl3 (10 mol%). But the mixture of CuBr2 and AgBr
that other copper compounds such as CuCl, CuBr, catalyzed the reaction to give a slightly lower yield of
CuI or CuBr2 could afford yields of 48%, 65%, 39% 78% (Table 1, entry 12). The investigation of ratios
or 73% (Table 1, entries 3–6), respectively. Thus, met- between CuBr2 and BiCl3 did not result in a better
allic halides such as AgBr containing an element in yield (Table 1, entries 13 and 14) either. Interestingly,
the same subgroup as Cu and other commonly used further efforts on investigating the ratios of three
Lewis acids AlCl3, ZnCl2 and BiCl3 were also investi- metallic catalysts (Table 1, entries 15–18) afforded an
gated (Table 1, entries 7–10). With them, yields of excellent yield of 95% (Table 1, entry 17). When the
67% and 74% (Table 1, entries 7 and 10) correspond- amount of mixed catalyst was reduced to 15 mol%,
ing to AgBr and BiCl3 were obtained, which were the yield decreased to 80% too (Table 1, entry 18).
close to the result catalyzed by CuBr2. We still expect- Other one- or two-component catalysts at 30 mol%
could only catalyze the reaction to achieve yields of
less than 80% (Table 1, entries 19–22). There is a supe-
Table 1. Effects of metallic catalysts on the reaction.[a]
riority of multi-metal catalysis because a one-pot re-
action often involves multi-step reactions. The opti-
mal catalyst for each step may not be the same. Co-
location of different metals would have more advan-
tages in promoting different processes than using
a single metal.[3a,14,15] In order to understand the role
of each metal in this mixed catalyst, the reactions of
bromobenzene with isobutyraldehyde catalyzed by
BiCl3,[16] AgBr and CuBr2 were carried out, which
generated the addition product in yields of 78%, 35%
and 49%, respectively. Now, let us compare the reac-
tion of cyclohexanone with isobutyraldehyde. The
first stage is the same interaction of bromobenzene
with magnesium, and the second stage involving
ketone or aldehyde is different. The similar yields
gained from reactions of cyclohexanone and isobutyr-
aldehye catalyzed by BiCl3 may indicate that BiCl3
promoted the first stage of the reaction mainly. The
much higher yields obtained from the reactions of cy-
clohexanone than those from isobutyraldehyde cata-
lyzed by AgBr and CuBr2 may reveal the effect of
catalysts on the stage involving cycohexanone critical-
ly. After all, isobutyraldehyde is well known to be
more reactive than cyclohexanone in nucleophilic ad-
dition.
Temperature and ligand are two important factors
in the reaction. In our results, a relatively high tem-
perature could give high yields. Compared with the
yield of 95% at 968C (Table 1, entry 17), lower yields
of 90, 83 or 78% (Table 1, entries 1–3) were obtained
at lower temperatures of 90, 83 or 668C, respectively.
However, a 91% yield was gained at a reaction tem-
perature of 1008C (Table 2, entry 4). The yield decre-
ment is supposed to be caused by adding toluene in
THF to raise the temperature. In the process of the
reaction, THF will volatilize at temperatures higher
than its boiling point, whereas too little THF is ad-
Entry
Catalyst
(mol%)
Yield
[%][b]
1
2
3
4
5
6
7
8
CuO (15 mol%)
Cu2O (15 mol%)
CuCl (15 mol%)
CuBr (15 mol%)
CuI (15 mol%)
CuBr2 (15 mol%)
AgBr (15 mol%)
AlCl3 (15 mol%)
trace
trace
48
65
39
73
67
59
41
74
86
78
88
88
85
9
ZnCl2 (15 mol%)
BiCl3 (15 mol%)
10
11
12
13
14
15
CuBr2 (10 mol%)+BiCl3 (10 mol%)
CuBr2 (10 mol%)+AgBr (10 mol%)
CuBr2 (5 mol%)+BiCl3 (15 mol%)
CuBr2 (15 mol%)+BiCl3 (5 mol%)
CuBr2 (10 mol%)+BiCl3 (10 mol%)
+AgBr(10 mol%)
CuBr2 (5 mol%)+BiCl3 (15 mol%)
+AgBr (10 mol%)
CuBr2 (15 mol%)+BiCl3 (5 mol%)
+AgBr(10 mol%)
CuBr2 (7.5 mol%)+BiCl3 (2.5 mol%)
+AgBr (5 mol%)
CuBr2 (30 mol%)
BiCl3 (30 mol%)
CuBr2 (15 mol%)+BiCl3 (15 mol%)
CuBr2 (15 mol%)+AgBr (15 mol%)
16
17
18
88
95
80
19
20
21
22
73
55
78
77
[a]
Reaction conditions: PhBr (15 mmol), Mg (15 mmol), cy-
clohexanone (5 mmol), catalyst (x mol% of cyclohexa-
none), in THF (5 mL)+toluene (20 mL) at 968C for
12 h.
[b]
Isolated yield based on at least 2 runs.
948
asc.wiley-vch.de
ꢁ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2016, 358, 947 – 957

FULL PAPERS
The Barbier–Grignard-Type Arylation of Ketones
Table 2. Effects of temperature and ligands on the reacti-
(Table 3, 3). Bearing electron-donating groups, p-me-
thoxy- and p-methylbromobenzenes generated excel-
lent yields of 91% and 92% (Table 3, 3a, 3c), respec-
tively. The steric hindrance in o-methoxy- and o-
methylbromobenzenes caused slightly decreasing but
still high yields of 88% and 86%, respectively
(Table 3, 3b, 3d). The weak deactivating effect of 3-
methoxy-, 3-fluoro- and 4-chlorobromobenzenes obvi-
ously decreased the yields to 65–78% (Table 3, 3e–g).
Interestingly, these yields could be improved to 73–
86% using ligand l-cysteine (Table 3, 3e–g). A good
yield of 81% was obtained using heterocyclic 2-bro-
mothiophene (Table 3, 3h). Benzyl bromide or 1-bro-
monaphthalene could only give medium yield of 65%
or 56% (Table 3, 3i, 3j), respectively, which could not
be improved by l-cysteine. Further studies are expect-
ed to reveal the role of l-cysteine in the bromides
on.[a]
Entry Temperature [8C] Ligand
Yield [%][b]
1
2
3
4
5
6
7
8
66[c]
83[d]
90[e]
100[f]
110[g]
96
96
96
96
96
none
none
none
none
none
PPh3
(C2H5)3N
2,2-dipyridyl
PMDETA
l-vitamin C
78
83
90
91
ND
67
60
72
67
82
9
10
11
12
13
96
96
96
l-phenylalanine 69
l-valine
l-cysteine
78
94
Table 3. The reactions of cyclohexanone with aryl bro-
mides.[a]
[a]
Reaction conditions: PhBr (15 mmol), Mg (15 mmol), cy-
clohexanone (5 mmol), CuBr2 (15 mol%)+BiCl3
(5 mol%)+AgBr (10 mol%), ligand (15 mol% of cyclo-
hexanone), in THF (5 mL)+toluene (20 mL) at 968C for
12 h.
Isolated yield based on at least 2 runs.
THF (25 mL).
THF (10 mL)+toluene (15 mL).
THF (7.5 mL)+toluene (17.5 mL).
THF (2.5 mL)+toluene (22.5 mL).
Toluene (25 mL).
[b]
[c]
[d]
[e]
[f]
[g]
verse to the formation of the magnesium reagent of
bromobenzene. This effect becomes stronger in the
case of too little THF to cause a slight yield decre-
ment when reacting at 1008C in 2.5 mL of THF and
22.5 mL of toluene. This could be further proven
from the result that reaction did not occur in toluene
(Table 2, entry 5). On the other hand, this effect re-
sulted in yield fluctuations of parallel reactions too,
which could be overcome by connecting a small bal-
loon on the top of condenser. The used N or P con-
taining ligands mostly displayed unfavorable effects
on the reaction to decrease the yields to 60–82%
(Table 2, entries 6–12). Although containing activated
hydrogen, l-cysteine could still result in 94% yield
(Table 2, entry 13). Thus, the optimal reaction condi-
tions could be given as: catalyzed by CuBr2
(15 mol%)+BiCl3 (5 mol%)+AgBr (10 mol%), cy-
clohexanone (5 mmol, 1 equiv.) was reacted with Mg
(3 equiv.) and bromobenzene (3 equiv.) in 5 mL of
THF and 20 mL of toluene at 968C for 12 h.
[a]
Reaction conditions: RBr (15 mmol), Mg (15 mmol), cy-
clohexanone
(5 mmol),
CuBr2
(15 mol%)+BiCl3
(5 mol%)+AgBr (10 mol%), in THF (5 mL)+toluene
(20 mL) at 968C for 12 h, isolated yield based on at least
2 runs.
15 mol% l-cysteine was used.
Iodobenzene.
Chlorobenzene.
Under the optimal conditions, a variety of aryl bro-
mides was examined to react with cyclohexanone.
Other phenyl halides such as iodobenzene or chloro-
benzene afforded traces or no product, respectively
[b]
[c]
[d]
Adv. Synth. Catal. 2016, 358, 947 – 957
ꢁ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
949

FULL PAPERS
Yunming Wen et al.
with weak electron-withdrawing groups. Other alkyl tions with bromobenzene, p-methyl- or p-methoxy-
bromides such as allyl, n-butyl and cyclohexyl bro- bromobenzene to generate good yields of 87%, 75%
mides could not yield the desired addition products.
or 72% (Table 4, 3r–t), respectively. When n-butyl
Then the reactions of bromobenzene with various bromide was reacted with benzophenone, the product
ketones were carried out. Linear ketones, butanone was a mixture of diphenylmethanol (major, 67%) and
and 3-pentanone, afforded the products in good yields
of about 82% (Table 4, 3k, 3l), which was still lower
than the 95% obtained from cyclohexanone. Probably
because of the steric hindrance, a moderate yield of
68% was generated from 4-methyl-2-pentanone
Table 5. Cross-coupling reactions of 4-hydroxybenzophe-
none with aryl bromides.[a]
(Table 4, 3m). The aromatic acetophenone gave
a good yield of 78% (Table 4, 3n). We were surprised
to find that the reactions of bromobenzene with di-
phenyl ketone or 9-fluorenone, and 3,5-dimethoxybro-
mobenzene with 9-fluorenone afforded excellent
yields higher than 90% (Table 4, 3o–q), although
these ketones should be less reactive than alkyl ke-
tones when considering conjugated electronic and
steric hindered effects. With a similar structure and
activated hydrogen, 2-amino-5-chlorobenzophenone
also displayed relatively high reactivity in the reac-
Table 4. The reactions of aryl bromides with different ke-
tones.[a]
[a]
Reaction conditions: RBr (15 mmol), Mg (15 mmol), 4-
hydroxybenzophenone (5 mmol), CuBr2 (15 mol%)+
BiCl3 (5 mol%)+AgBr (10 mol%), in THF (5 mL)+tol-
uene (20 mL) at 968C for 12 h, isolated yield based on at
least 2 runs.
New compound.
Addition of 1 equiv. of phenylmagnesium bromide in ad-
vance, then 2 equiv. of bromobenzene and magnesium
were added.
[a]
Reaction conditions: RBr (15 mmol), Mg (15 mmol),
ketone (5 mmol), CuBr2 (15 mol%)+BiCl3 (5 mol%)+
AgBr (10 mol%), in THF (5 mL)+toluene (20 mL) at
968C for 12 h, isolated yield based on at least 2 runs.
New compound.
[b]
[c]
[b]
[c]
[d]
24 h.
Using chlorobenzene or iodobenzene to react.
950
asc.wiley-vch.de
ꢁ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2016, 358, 947 – 957

FULL PAPERS
The Barbier–Grignard-Type Arylation of Ketones
Table 6. Cross-coupling reactions of aryl bromides with dif-
a trace of addition product of benzophenone to butyl
bromide.
ferent phenolic ketones.[a]
Beyond our expectations, a novel reaction was ob-
served between activated hydrogen-containing 4-hy-
droxybenzophenone and bromobenzene. Instead of
arylation of the carbonyl group, a cross-coupling
product was obtained in an excellent 92% yield
(Table 5, 5a). Without the addition product being gen-
erated, the reaction displayed a very high chemical se-
lectivity. Even when the separated coupling product
was reacted with magnesium and bromobenzene
under the same conditions, the addition would not
occur. Thus, the remaining carbonyl group could be
applied to react with other compounds in one pot.
When 4-hydroxybenzophenone was reacted with
3 equiv. of phenylmagnesium bromide prepared be-
forehand under the optimal conditions, along with
a large part of 4-hydroxybenzophenone, only an 8%
GC yield of carbonyl group-reduced coupling product
was obtained, which indicated that this protocol was
unique. When adding slowly 3 equiv. of phenylmagne-
sium bromide to 4-hydroxybenzophenone, the prod-
uct was not observed either. After adding 1 equiv. of
phenylmagnesium bromide in advance to remove the
activated hydrogen of the hydroxy group, 2 equiv. of
bromobenzene and magnesium were involved in the
reaction, but the cross-coupling yield was decreased
to 51% (Table 5, 5a). Thus, the excess bromobenzene
and magnesium have not been consumed by the acti-
vated hydrogen of the hydroxy group to improve the
yield. On the other hand, the yield could not been im-
proved by further increasing bromobenzene and mag-
nesium to 4 equiv. Other phenyl halides such as iodo-
benzene or chlorobenzene afforded no product
[a]
Reaction conditions: RBr (15 mmol), Mg (15 mmol), phe-
nolic ketone (5 mmol), CuBr2 (15 mol%)+BiCl3
(5 mol%)+AgBr (10 mol%), in THF (5 mL)+toluene
(20 mL) at 968C for 12 h, isolated yield based on at least
2 runs.
25 mL THF (658C).
New compound.
[b]
[c]
(Table 5, 5a), although aryl bromides with electron- tive reactions, while the less steric hindered 2’-
donating groups, methyl and methoxy, resulted in de- hydroxyacetophenone would be favorable to addition.
creasing yields (Table 5, 5b–e). Except for p-methyl- To prove this assumption, the more sterically hin-
bromobenzene, the yields of 80-85% are still good, dered 2’-hydroxy-3-phenylpropiophenone was em-
which exhibits almost complete independence of elec- ployed in the reaction. As expected, cross-coupling
tronic and steric effects (Table 5, 5b–d). Bromonaph- products in good yields of 72% to 92% (Table 6, 5l–q)
thalene, the less reactive reactant in the addition reac- were obtained from some aryl bromides. Further-
tion, could also give a yield of 72% (Table 5, 5f). more, coupling products 5l–q could tautomerize to
With weak electron-withdrawing groups, m-methoxy-, the enol form more easily and display NMR shifts of
3-fluoro- and p-chlorobromobenzenes gave lower the enol form because of the increased conjugation
yields of 75–78% (Table 5, 5g–i) than bromides with on the benzene ring, whereas 2’-hydroxy-3-phenylpro-
electron-donating groups.
piophenone did not display NMR shifts of the enol
Bromobenzene reacted with (2-hydroxy-4-methoxy- form. Compared with other compounds in coupling
phenyl)phenylmethanone to give 65% of the coupling reactions, phenolic ketones may be easier to be syn-
product (Table 6, 5j). But the reaction of bromoben- thesized because of the activating role of the hydroxy
zene with 2’-hydroxyacetophenone was an addition group on the benzene ring. The method presented
and generated the dehydrated alkene in a high yield herein has made a large improvement in expanding
of 88% (Table 6, 5k), which offered a new way to reactants compared with the cross-coupling of 2-naph-
form aryl-alkenes without the addition of other dehy- thol derivatives.[10]
drated agents such as acid. Even when the reaction
In order to expand the scope of this coupling reac-
temperature was decreased to 658C in THF, the tion, other phenolic compounds such as 2-methoxy-
alkene product was still formed in 75% yield (Table 6, phenol, 2,4-dichlorophenol, 1-naphthalenol, 4-
5k). Cross-coupling and addition may be two competi- trifluoromethylphenol were also employed in the re-
Adv. Synth. Catal. 2016, 358, 947 – 957
ꢁ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
951

FULL PAPERS
Yunming Wen et al.
action. Unfortunately, they all could not undergo the
reaction, irrespective of bearing electron-donating or
electron-withdrawing groups on the reactants. For
similar phenolic compounds containing carbonyl
groups such as salicylaldehyde or ethyl 4-hydroxyben-
zoate, addition or no reaction was observed, respec-
tively. It is well known that an electron is initially
transferred from magnesium to halide to give a radi-
cal, then to form the Grignard reagent which will
change to a carbanion. Although the Grignard re-
agent is sensitive to activated hydrogen, the proposed
protonation is with the carbanion formed from the or-
ganometallic reagent.[17] The formation of a carbanion
and addition of phenyl bromide to the carbonyl group
via radicals or Grignard reagent are competitive.
With the aid of catalyst, the addition would be faster,
and therefore the cross-coupling products could be
formed. Actually, without adding catalyst or ketone,
the reaction and formation of Grignard reagent will
not proceed in the used solvent. Besides, our experi-
ments revealed that only very small amounts or no
cross-coupling product could be observed when using
the phenyl-Grignard reagent prepared in advance to
replace bromobenzene and magnesium, which may in-
dicate that addition to the carbonyl group is a radical
process and not phenylmagnesium bromide. This
could be further supported by the obviously retarded
cross-coupling reaction observed when adding
1 equiv. of phenylmagnesium bromide to the mixture
Scheme 1. A possible mechanism for the cross-coupling re-
action.
after the reaction had proceeded for half an hour, compounds without carbonyl group or with a carbonyl
which gave 24% UV yield after adding phenyl- group of the ester type, the quinone intermediate
Grignard reagent for 9 h, whereas 92% UV yield was could not be formed either, and thus the coupling re-
obtained after reacting for 9 h without Grignard re- action could not occur. On the other hand, this pro-
agent (see the Supporting Information). On the other cess is different from the classic hydroxy group cou-
hand, aqueous Barbier–Grignard-type reactions have pling mechanism,[10–12] which offers a possibility for
been extensively studied, the formation of a radical or other groups to react with such phenolic ketones via
a covalent carbon-metal bond in water is also one of quinone intermediates. However, it still needs further
the suggested mechanisms depending on the condi- investigation to understand how the metallic magnesi-
tions.[4e] The addition of radicals to carbonyl com- um reagent is formed and reacted with the carbonyl
pounds was also proposed as a mechanism.[4e,15d] Thus, group, which would a topic for our further consider-
a reasonable mechanism for the coupling reaction is ation.
proposed (Scheme 1). Initially, the metal halide cata-
lysts interact with the oxygen atom of the carbonyl
group and help the corresponding double bond of the Conclusions
carbonyl group to break when the lone pair electrons
on oxygen of the hydroxy group shift to the carbon We have successfully achieved the Barbier–Grignard-
on benzene, which forms the intermediate quinone type arylation of ketones and found an unexpected
(1!2). Then the formed radial from bromobenzene cross-coupling with the hydroxy group in phenolic ke-
and magnesium in situ attacks the carbonyl group of tones using unactivated aryl bromides for the first
quinone to furnish addition radical intermediate (3) time. The reactions proceed under mild conditions
which is reduced to result in intermediate (4). Subse- and exhibit good tolerance of substrate functionality,
quent proton transfer (5) and bond breakage between furnishing good yields of 56–95% in arylations of ke-
carbon and oxygen of the phenolic hydroxy group re- tones and high yields of 65–92% in cross-coupling of
store the stable aromatic structure of benzene and phenolic ketones. Most yields are in the range 70–
generate the cross-coupling product. Thus, only those 90%. The high chemical selectivity in cross-coupling
ketones which are difficult to be added at the carbon- of phenolic ketones is also another advantage, which
yl group could undergo the coupling reaction. For would allow the remaining carbonyl group to form
952
asc.wiley-vch.de
ꢁ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2016, 358, 947 – 957

FULL PAPERS
The Barbier–Grignard-Type Arylation of Ketones
1H NMR (300 MHz, CDCl3): d=7.46 (d, J=7.9 Hz, 2H),
6.94 (d, J=7.7 Hz, 2H), 3.83 (s, 3H), 1.57 (s, 9H), 1.25 (s,
1H); IR (KBr): n=3352, 3060, 2928, 2855, 1592, 1481, 1466,
1310, 1025, 755 cmÀ1; GC-MS: m/z=206.
more complex species. This finding should prompt
more active investigation and development of phenol-
ic ketone reactions, which could provide a faster,
safer, more economic and atom economic as well as
eco-friendly approach for the design and preparation
of complex scaffolds. The protocol of mixing catalysts
has extended the catalytic scope. A novel but reason-
able mechanism involving a quinone intermediate is
proposed, which offers a possibility for other groups
to react with such phenolic ketones via quinone inter-
mediates.
1-(2-Methoxyphenyl)cyclohexanol (3b):[20] TLC (petrole-
um ether/ethyl acetate=10:1); yield: 88%; mp 54–558C;
1H NMR (300 MHz, CDCl3): d=7.32 (d, J=7.7 Hz, 1H),
7.26–7.20 (m, 1H), 6.94 (dd, J=12.6, 7.6 Hz, 2H), 3.90 (s,
3H), 2.05 (d, J=11.1 Hz, 2H), 1.82 (tt, J=22.9, 11.3 Hz,
6H), 1.60 (d, J=11.8 Hz, 2H), 1.26 (d, J=9.0 Hz, 1H); IR
(KBr): n=3349, 3066, 2929, 2855, 1599, 1488, 1460, 1317,
1027, 754 cmÀ1; GC-MS: m/z=206.
1-p-Tolylcyclohexanol (3c):[19] TLC (petroleum ether/ethyl
acetate=10:1); yield: 92%; mp 57–588C; 1H NMR
(300 MHz, CDCl3): d=7.38 (d, J=7.9 Hz, 2H), 7.14 (d, J=
7.6 Hz, 2H), 2.33 (s, 3H), 1.76 (d, J=14.2 Hz, 6H), 1.58 (s,
4H), 1.25 (s, 1H); IR (KBr): n=3450, 2931, 2860, 1450,
1267, 1131, 1035, 969, 727 cmÀ1; GC-MS: m/z=190.
1-o-Tolylcyclohexanol (3d):[19] TLC (petroleum ether/
ethyl acetate=10:1); yield: 86%; colorless oil; 1H NMR
(300 MHz, CDCl3): d=7.41 (s, 1H), 7.14 (s, 3H), 2.62 (s,
3H), 1.98–1.84 (m, 4H), 1.75 (d, J=14.1 Hz, 2H), 1.56 (s,
4H), 1.25 (s, 1H); IR (KBr): n=3441, 3059, 2930, 2857,
1449, 1261, 1130, 1039, 966, 756, 727 cmÀ1; GC-MS: m/z=
190.
Experimental Section
General Information
1H NMR (300 MHz) and 13C NMR (75 MHz) spectra were
recorded in CDCl3 solutions. Chemical shifts are reported in
parts per million (ppm, d) relative to CDCl3 (d=7.26 for
1H NMR or d=77.1 for 13C NMR). Multiplicities are indi-
cated as s (singlet), d (doublet), t (triplet), q (quartet), m
(multiplet), and br (broad). IR spectra were measured with
an Eqinox 55 FT-IR spectrometer. Mass spectra were mea-
sured on a TRACE METM GC/MS. High resolution mass
spectra were measured on an AB SCIEX TripleTOF 5600
HR/MS. UV-Vis spectra were measured using a TU1810.
Most of the reagents were purchased at the highest commer-
cial quality (aladdin) and were used without further purifica-
tion, unless otherwise noted. Reactions were monitored by
thin-layer chromatography (TLC) carried out on 0.25 mm
Merck silica gel plates (60F-254) using UV light, and iodine
for visualization.
1-(3-Methoxyphenyl)cyclohexanol (3e):[21] TLC (petrole-
um ether/ethyl acetate=10:1); yield: 78/86%; colorless oil;
1H NMR (300 MHz, CDCl3): d=7.25 (d, J=6.8 Hz, 1H),
7.07 (d, J=9.8 Hz, 2H), 6.78 (d, J=7.9 Hz, 1H), 3.82 (s,
3H), 1.77 (d, J=15.4 Hz, 6H), 1.64 (d, J=10.7 Hz, 4H),
1.31 (d, J=9.2 Hz, 1H); IR (KBr): n=3437, 2998, 2934,
2854, 1603, 1486, 1247, 1170, 1045, 972, 780, 700 cmÀ1; GC-
MS: m/z=206.
1-(3-Fluorophenyl)cyclohexanol (3f):[22] TLC (petroleum
ether/ethyl acetate=10:1); yield: 72/80%; colorless oil;
1H NMR (300 MHz, CDCl3): d=7.34–7.22 (m, 3H), 6.95
(ddd, J=9.8, 4.1, 2.1 Hz, 1H), 1.72 (ddd, J=28.4, 13.3,
3.4 Hz, 10H), 1.32–1.24 (m, 1H); IR (KBr): n=3402, 3034,
2934, 2856, 1613, 1587, 1484, 1440, 1266, 1159, 973, 782,
699 cmÀ1; GC-MS: m/z=194.
General Procedure for the Barbier–Grignard-Type
Arylation and Cross-Coupling of Ketones
THF (5 mL), toluene (20 mL), RBr (15 mmol), ketone or
phenolic ketone (5 mmol), magnesium turnings (0.36 g,
15 mmol), CuBr2 (0.16 g, 0.75 mmol), BiCl3 (0.08 g,
0.25 mmol), and AgBr (0.10 g, 0.5 mmol) were added into
a 50-mL, three-necked flask equipped with thermometer
and condenser connected with a small balloon on top. The
mixture was heated under stirring vigorously at 968C for
12 h. After reaction, the mixture was cooled to room tem-
perature and 15 mL of saturated aqueous NH4Cl were
added under stirring. Then, the mixture was extracted with
ethyl acetate three times (20 mL”3). The oil residue ob-
tained after the extraction was dried over anhydrous magne-
sium sulfate, filtered, and evaporated. The product could be
purified by TLC eluting with petroleum ether (volume):
ethyl acetate (volume)=10:1 or 4:1.
1-(4-Chlorophenyl)cyclohexanol (3g):[23] TLC (petroleum
ether/ethyl acetate=10:1); yield: 65/73%; mp 778C;
1H NMR (300 MHz, CDCl3): d=7.43 (d, J=8.3 Hz, 2H),
7.29 (d, J=8.5 Hz, 2H), 1.75 (d, J=13.2 Hz, 6H), 1.64 (d,
J=16.1 Hz, 4H), 1.28 (s, 1H); IR (KBr): n=3049, 2934,
2855, 1494, 1446, 1381, 1133, 975, 823, 661 cmÀ1; GC-MS: m/
z=210.
1-Thiophen-2-ylcyclohexanol (3h):[24] TLC (petroleum
ether/ethyl acetate=10:1); yield: 81%; light yellow oil;
1H NMR (300 MHz, CDCl3): d=7.07 (dd, J=4.8, 1.2 Hz,
1H), 6.92 (q, J=3.5 Hz, 2H), 6.25–6.08 (m, 1H), 2.43–2.36
(m, 2H), 2.16 (qd, J=6.2, 3.1 Hz, 2H), 1.74 (ddd, J=12.1,
6.2, 2.4 Hz, 2H), 1.64–1.59 (m, 2H), 1.21 (d, J=7.0 Hz, 2H);
IR (KBr): n=3420, 3100, 2929, 2858, 1518, 1415, 1236, 1056,
726 cmÀ1; GC-MS: m/z=182.
1-Phenylcyclohexanol (3):[18] TLC (petroleum ether/ethyl
acetate=10:1); yield: 95%; mp 63.58C; H NMR (300 MHz,
1
CDCl3): d=7.51 (d, J=7.6 Hz, 2H), 7.35 (t, J=7.4 Hz, 2H),
7.25 (d, J=5.4 Hz, 1H), 1.78 (d, J=13.6 Hz, 6H), 1.64 (d,
J=13.6 Hz, 4H), 1.31 (d, J=9.1 Hz, 1H); IR (KBr): n=
3358, 3058, 3027, 2920, 2854, 1599, 1492, 1381, 1260, 1208,
1033, 755, 696 cmÀ1; GC-MS: m/z=176.
1-Benzylcyclohexanol (3i):[25] TLC (petroleum ether/ethyl
1
acetate=10:1); yield: 65%; mp 338C; H NMR (300 MHz,
CDCl3): d=7.32–7.18 (m, 5H), 2.76 (s, 2H), 1.50 (t, J=
15.2 Hz, 10H), 1.27 (s, 1H); IR (KBr): n=3432, 3026, 2918,
2850, 1494, 1450, 1260, 1148, 1084, 976, 700 cmÀ1; GC-MS:
m/z=190.
1-(4-Methoxyphenyl)cyclohexanol (3a):[19] TLC (petrole-
um ether/ethyl acetate=10:1); yield: 91%; mp 388C;
Adv. Synth. Catal. 2016, 358, 947 – 957
ꢁ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
953

FULL PAPERS
Yunming Wen et al.
1-Naphthalen-1-yl-cyclohexanol (3j):[26] TLC (petroleum
ether/ethyl acetate=10:1); yield: 56%; mp 66–688C;
1H NMR (300 MHz, CDCl3): d=8.92 (dd, J=7.8, 5.8 Hz,
1H), 7.88–7.80 (m, 1H), 7.75 (d, J=8.1 Hz, 1H), 7.56 (d, J=
7.3 Hz, 1H), 7.49–7.35 (m, 3H), 2.26 (d, J=11.7 Hz, 2H),
1.97 (tdd, J=12.7, 9.4, 3.4 Hz, 4H), 1.77–1.64 (m, 4H), 1.35
(tt, J=17.3, 6.0 Hz, 1H); IR (KBr): n=3443, 3047, 2928,
CDCl3): d=145.06, 129.84, 128.74, 128.50, 127.94, 127.83,
120.31, 82.37; IR (KBr): n=3377, 3058, 3026, 2929, 1613,
1486, 1446, 1405, 1297, 1154, 1011, 882, 758 cmÀ1; GC-MS:
m/z=290; ESI-HR-MS: m/z=332.0816, calcd. for
C19H16NClO [M+Na]+: 332.0813.
(2-Amino-5-chlorophenyl)-phenyl-p-tolylmethanol
(3s):
TLC (petroleum ether/ethyl acetate=10:1); yield: 75%; mp
84–858C; 1H NMR (300 MHz, CDCl3): d=7.38–7.28 (m,
5H), 7.20–7.14 (m, 4H), 7.11 (dd, J=8.4, 2.4 Hz, 1H), 6.66
(d, J=8.4 Hz, 1H), 6.51 (d, J=2.4 Hz, 1H), 3.73 (d, J=
7.0 Hz, 1H), 2.39 (s, 3H), 1.27 (d, J=7.2 Hz, 1H); 13C NMR
(75 MHz, CDCl3): d=145.22, 143.05, 142.14, 134.70, 129.20,
128.44, 127.85, 127.80, 127.70, 124.02, 120.09, 82.28, 21.29;
IR (KBr): n=3382, 3026, 2921, 1613, 1448, 1304, 1404, 1154,
1021, 811, 701 cmÀ1; GC-MS: 304; ESI-HR-MS: m/z=
324.1150, calcd. for C20H18NClO [M+H]+: 324.1150.
2855, 1598, 1507, 1446, 1348, 1257, 1130, 1041, 801, 776 cmÀ1
;
GC-MS: m/z=226.
2-Phenylbutan-2-ol (3k):[27] TLC (petroleum ether/ethyl
acetate=10:1); yield: 82%; colorless oil; 1H NMR
(300 MHz, CDCl3): d=7.44–7.37 (m, 2H), 7.35–7.26 (m,
3H), 1.85–1.77 (m, 1H), 1.53 (s, 2H), 1.22 (dd, J=8.3,
5.7 Hz, 3H), 0.82–0.71 (m, 2H); IR (KBr): n=3393, 3059,
2967, 2924, 2854, 1599, 1493, 1450, 1378, 1284, 1126, 1058,
912, 760, 701 cmÀ1; GC-MS: m/z=150.
3-Phenylpentan-3-ol (3l):[28] TLC (petroleum ether/ethyl
acetate=10:1); yield: 82%; colorless oil; 1H NMR
(300 MHz, CDCl3): d=7.43–7.32 (m, 4H), 7.29–7.23 (m,
1H), 1.97–1.75 (m, 4H), 0.78 (t, J=7.4 Hz, 6H); IR (KBr):
n=3390, 3027, 2964, 2924, 2853, 1598, 1451, 1283, 1130,
1070, 968, 760, 701 cmÀ1; GC-MS: m/z=164.
(2-Amino-5-chlorophenyl)-(4-methoxyphenyl)phenylme-
thanol (3t): TLC (petroleum ether/ethyl acetate=10:1);
yield: 72%; mp 110–1128C; 1H NMR (300 MHz, CDCl3):
d=7.38–7.28 (m, 5H), 7.23–7.18 (m, 2H), 7.11 (dd, J=8.4,
2.4 Hz, 1H), 6.92–6.86 (m, 2H), 6.65 (d, J=8.4 Hz, 1H),
6.50 (d, J=2.4 Hz, 1H), 3.84 (s, 3H); 13C NMR (75 MHz,
CDCl3): d=159.12, 145.32, 143.07, 134.80, 129.10, 127.75,
120.09, 113.72, 82.12, 55.45; IR (KBr): n=3376, 3059, 3026,
4-Methyl-2-phenyl-pentan-2-ol (3m):[29] TLC (petroleum
ether/ethyl acetate=10:1); yield: 68%; colorless oil;
1H NMR (300 MHz, CDCl3): d=7.51–7.42 (m, 2H), 7.36 (t,
J=7.6 Hz, 2H), 7.27 (dd, J=7.1, 1.9 Hz, 1H), 1.87–1.73 (m,
2H), 1.58 (s, 3H), 0.90 (d, J=6.6 Hz, 3H), 0.78 (d, J=
6.6 Hz, 3H); IR (KBr): n=3460, 3027, 2956, 2927, 2870,
2932, 1606, 1508, 1405, 1249, 1178, 1031, 883, 757, 702 cmÀ1
;
GC-MS: m/z=339; ESI-HR-MS: m/z=322.1002, calcd. for
C20H18NClO2 [MÀOH]+: m/z=322.0993.
Biphenyl-4-ylphenylmethanone (5a):[31] TLC (petroleum
1600, 1492, 1463, 1363, 1266, 1166, 1072, 1029, 763, 701 cmÀ1
;
ether/ethyl acetate=4:1); yield: 92%; mp 1028C; H NMR
1
GC-MS: m/z=178.
(300 MHz, CDCl3): d=7.84–7.74 (m, 4H), 7.62–7.44 (m,
5H), 7.29 (q, J=7.0 Hz, 2H), 6.96 (d, J=8.6 Hz, 2H); IR
(KBr): n=2805, 1775, 1629, 1508, 1443, 1286, 1147, 846, 740,
689 cmÀ1; GC-MS: m/z=258.
1,1-Diphenylethanol (3n):[21] TLC (petroleum ether/ethyl
acetate=10:1); yield: 78%; mp 81–828C; 1H NMR
(300 MHz, CDCl3): d=7.51–7.43 (m, 4H), 7.41–7.34 (m,
4H), 7.30 (ddd, J=7.2, 3.6, 1.2 Hz, 2H), 2.21 (s, 1H), 2.00
(s, 3H); IR (KBr): n=3404, 3058, 2922, 2853, 1600, 1449,
1100, 800, 755, 698 cmÀ1; GC-MS: m/z=198.
(4’-Methoxybiphenyl-4-yl)phenylmethanone (5b):[32] TLC
(petroleum ether/ethyl acetate=4:1); yield: 82%; mp
1
1668C; H NMR (300 MHz, CDCl3): d=7.54–7.44 (m, 4H),
Triphenylmethanol (3o):[20] TLC (petroleum ether/ethyl
acetate=10:1); yield: 91%; mp 164.28C; 1H NMR
(300 MHz, CDCl3): d=7.29 (s, 15H), 1.28 (s, 1H); IR
(KBr): n=3473, 3060, 3028, 2923, 1597, 1498, 1443, 1180,
1006, 891, 759, 689 cmÀ1; GC-MS: m/z=260.
7.27–7.17 (m, 4H), 6.97 (dd, J=6.6, 5.5 Hz, 3H), 6.55 (d, J=
9.3 Hz, 2H), 3.91 (s, 3H); IR (KBr): n=3058, 2922, 2845,
1593, 1508, 1462, 1252, 1169, 1028, 831, 700 cmÀ1; GC-MS:
m/z=288.
(2’-Methoxybiphenyl-4-yl)phenylmethanone (5c):[33] TLC
(petroleum ether/ethyl acetate=4:1); yield: 80%; mp 50–
9-Phenyl-9H-fluoren-9-ol (3p):[30] TLC (petroleum ether/
1
1
ethyl acetate=10:1); yield: 99%; mp 108–1108C; H NMR
518C; H NMR (300 MHz, CDCl3): d=7.55–7.36 (m, 3H),
(300 MHz, CDCl3): d=7.67 (d, J=7.4 Hz, 2H), 7.36 (dd, J=
16.2, 7.5 Hz, 6H), 7.26 (d, J=7.1 Hz, 5H), 2.49 (s, 1H); IR
(KBr): n=3352, 3061, 2922, 2853, 1601, 1488, 1182, 1039,
917, 751, 696 cmÀ1; GC-MS: m/z=258.
7.31–7.23 (m, 4H), 7.16–7.02 (m, 2H), 6.97 (ddd, J=8.7, 3.7,
2.8 Hz, 1H), 6.88–6.75 (m, 1H), 6.59–6.42 (m, 1H), 3.65 (d,
J=22.4 Hz, 3H); IR (KBr): n=3059, 2938, 2840, 1592, 1509,
1485, 1361, 1234, 1165, 1019, 832, 756, 700 cmÀ1; GC-MS:
m/z=288.
9-(3,5-Dimethoxyphenyl)-9H-fluoren-9-ol (3q): TLC (pe-
troleum ether/ethyl acetate=10:1); yield: 95%; mp 108–
(2’-Methyl-biphenyl-4-yl)phenylmethanone (5d):[33] TLC
(petroleum ether/ethyl acetate=4:1); yield: 85%; mp 102–
1
1098C; H NMR (300 MHz, CDCl3): d=7.70–7.66 (m, 2H),
1
7.41–7.37 (m, 3H), 6.58 (d, J=2.3 Hz, 2H), 6.36 (t, J=
2.3 Hz, 1H), 3.74 (s, 6H); 13C NMR (75 MHz, CDCl3): d=
160.82, 150.27, 145.95, 139.77, 129.36, 128.65, 124.84, 120.32,
104.03, 99.17, 83.81, 55.47; IR (KBr): 3463, 3013, 2969, 2837,
1597, 1451, 1198, 1147, 1058, 918, 769 cmÀ1; GC-MS: m/z=
318; ESI-HR-MS: m/z=287.1065, calcd. for C21H18O3
[MÀOCH3]+: 287.1067.
1048C; H NMR (300 MHz, CDCl3): d=7.57 (d, J=10.0 Hz,
1H), 7.47–7.39 (m, 3H), 7.36 (d, J=7.8 Hz, 1H), 7.27 (d, J=
6.9 Hz, 4H), 7.14 (d, J=7.4 Hz, 1H), 7.08 (dd, J=10.0,
1.9 Hz, 1H), 6.51 (d, J=10.1 Hz, 1H), 6.40 (d, J=10.0 Hz,
1H), 2.03 (s, 3H); IR (KBr): n=3058, 2923, 1626, 1590,
1507, 1444, 1160, 865, 756, 700 cmÀ1; GC-MS: m/z=272.
(4’-Methylbiphenyl-4-yl)phenylmethanone (5e):[34] TLC
(petroleum ether/ethyl acetate=4:1); yield: 70%; mp 128–
(2-Amino-5-chlorophenyl)diphenylmethanol (3r): TLC
(petroleum ether/ethyl acetate=10:1); yield: 87%; mp 112–
1
1298C; H NMR (300 MHz, CDCl3): d=7.81–7.75 (m, 2H),
1
1138C; H NMR (300 MHz, CDCl3): d=7.41–7.29 (m, 10H),
7.59–7.44 (m, 4H), 7.28 (t, J=3.9 Hz, 3H), 7.15 (dd, J=7.5,
5.2 Hz, 2H), 7.00–6.96 (m, 1H), 6.57 (d, J=9.8 Hz, 1H),
2.41 (d, J=32.9 Hz, 3H); IR (KBr): n=3058, 2920, 1598,
7.12 (dd, J=8.4, 2.3 Hz, 1H), 6.68 (d, J=8.4 Hz, 1H), 6.49
(d, J=2.3 Hz, 1H), 3.77–3.22 (m, 2H); 13C NMR (75 MHz,
954
asc.wiley-vch.de
ꢁ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2016, 358, 947 – 957

FULL PAPERS
The Barbier–Grignard-Type Arylation of Ketones
1508, 1443, 1280, 1238, 1171, 826, 700 cmÀ1; GC-MS: m/z=
272.
1-(4’-Methylbiphenyl-2-yl)-3-phenylpropan-1-one
(5m):
TLC (petroleum ether/ethyl acetate=10:1); yield: 78%;
1
(4-Naphthalen-1-ylphenyl)phenylmethanone (5f):[35] TLC
(petroleum ether/ethyl acetate=4:1); yield: 72%; light red
oil; 1H NMR (300 MHz, CDCl3): d=7.99 (d, J=8.3 Hz,
1H), 7.93 (d, J=8.1 Hz, 1H), 7.71 (dd, J=10.0, 2.7 Hz, 1H),
7.56 (dd, J=5.1, 3.0 Hz, 1H), 7.51–7.47 (m, 2H), 7.42 (dd,
J=8.4, 1.5 Hz, 3H), 7.39–7.35 (m, 3H), 7.09–6.95 (m, 2H),
6.61 (dd, J=10.0, 2.0 Hz, 1H), 6.36 (dd, J=10.0, 2.0 Hz,
1H); IR (KBr): n=3054, 1625, 1505, 1441, 1277, 1170, 777,
696 cmÀ1; GC-MS: m/z=308.
yellow brown oil; H NMR (300 MHz, CDCl3): d=12.09 (s,
1H), 7.32 (d, J=7.3 Hz, 3H), 7.23 (dd, J=4.9, 3.2 Hz, 4H),
7.15 (dd, J=12.4, 4.9 Hz, 3H), 7.08–7.01 (m, 2H), 6.55 (t,
J=7.5 Hz, 1H), 5.08 (s, 0.78H), 3.54 (s, 0.24H), 3.42 (t, J=
6.4 Hz, 2H), 2.36 (s, 3H); 13C NMR (75 MHz, CDCl3): d=
153.09, 140.16, 137.77, 137.12, 136.09, 130.89, 130.72, 130.47,
130.05, 129.51, 129.37, 129.32, 129.17, 129.05, 128.97, 128.63,
128.49, 128.24, 127.03, 126.51, 126.22, 125.44, 120.70, 115.56,
36.13, 21.11; IR (KBr): n=3030, 2855, 1762, 1661, 1603,
1483, 1451, 1294, 1240, 1117, 934, 752 cmÀ1; GC-MS: m/z=
300; ESI-HR-MS: m/z=301.1588, calcd. for C22H20O [M+
H]+: m/z=301.1587.
(3’-Methoxybiphenyl-4-yl)phenylmethanone (5g): TLC
(petroleum ether/ethyl acetate=4:1); yield: 78%; light red
oil; 1H NMR (300 MHz, CDCl3): d=7.52–7.02 (m, 9H),
6.91–6.76 (m, 3H), 6.50 (d, J=10.0 Hz, 1H), 3.83–3.75 (m,
3H); 13C NMR (75 MHz, CDCl3): d=159.44, 155.48, 148.96,
140.05, 132.36, 130.49, 129.59, 128.62, 128.47, 128.01, 127.36,
124.94, 120.69, 117.83, 115.85, 114.96, 114.03, 112.53, 81.90,
55.61, 55.38; IR (KBr): n=3025, 2933, 2836, 1595, 1509,
1486, 1442, 1247, 1173, 1041, 876, 806, 701 cmÀ1; GC-MS:
m/z=288; ESI-HR-MS: m/z=289.1229, calcd. for C20H16O2
[M+H]+: 289.1223.
1-(2’-Methoxybiphenyl-2-yl)-3-phenylpropan-1-one (5n):
TLC (petroleum ether/ethyl acetate=10:1); yield: 72%;
1
yellow brown oil; H NMR (300 MHz, CDCl3): d=12.32 (s,
1H), 7.41–7.22 (m, 9H), 7.22–6.83 (m, 6H), 6.53 (d, J=
7.6 Hz, 1H), 6.20 (td, J=7.4, 2.3 Hz, 1H), 3.89 (s, 1.47H),
3.84 (d, J=5.3 Hz, 0.73H), 3.80 (d, J=3.4 Hz, 1.53H), 3.44
(dd, J=11.2, 7.4 Hz, 2H); 13C NMR (75 MHz, CDCl3): d=
202.25, 163.00, 156.62, 156.19, 155.58, 153.50, 153.27, 140.32,
140.29, 136.60, 135.04, 134.69, 134.18, 134.11, 133.87, 132.32,
131.95, 131.56, 130.37, 130.12, 130.07, 129.53, 129.50, 129.05,
128.91, 128.85, 128.82, 128.72, 128.58, 128.46, 128.41, 127.85,
126.85, 126.14, 121.47, 121.12, 120.60, 120.44, 120.24, 119.91,
118.81, 118.16, 115.75, 115.72, 111.52, 110.99, 110.91, 55.70,
55.67, 55.58, 35.81, 35.63; IR (KBr): n=3030, 2924, 1727,
1626, 1601, 1487, 1457, 1245, 1024, 935, 754 cmÀ1; GC-MS:
316; ESI-HR-MS: m/z=317.1539, calcd. for C22H20O2 [M+
H]+: 317.1536.
(3’-Fluorobiphenyl-4-yl)phenylmethanone (5h):[36] TLC
(petroleum ether/ethyl acetate=4:1); yield: 75%; mp 144–
1
1458C; H NMR (300 MHz, CDCl3): d=7.53–7.37 (m, 3H),
7.35–7.17 (m, 5H), 7.11–7.04 (m, 2H), 7.01–6.94 (m, 1H),
6.83 (t, J=5.8 Hz, 1H), 6.56–6.48 (m, 1H); IR (KBr): n=
3060, 1596, 1513, 1481, 1438, 1234, 1173, 996, 870, 787,
699 cmÀ1; GC-MS: m/z=276.
(4’-Chlorobiphenyl-4-yl)phenylmethanone (5i):[37] TLC
(petroleum ether/ethyl acetate=4:1); yield: 75%; light red
oil; 1H NMR (300 MHz, CDCl3): d=7.52–7.36 (m, 4H),
7.31–7.20 (m, 6H), 7.09 (d, J=8.7 Hz, 1H), 6.82 (d, J=
8.7 Hz, 1H), 6.53 (d, J=10.8 Hz, 1H); IR (KBr): n=3055,
1586, 1488, 1158, 1010, 824, 760 cmÀ1; GC-MS: m/z=292.
(5-Methoxybiphenyl-2-yl)phenylmethanone (5j):[38] TLC
(petroleum ether/ethyl acetate=10:1); yield: 65%; mp 81–
1-(3’-Fluorobiphenyl-2-yl)-3-phenylpropan-1-one
(5o):
TLC (petroleum ether/ethyl acetate=10:1); yield: 92%;
1
yellow brown oil; H NMR (300 MHz, CDCl3): d=11.93 (s,
1H), 7.35–7.31 (m, 2H), 7.27 (dd, J=8.3, 2.2 Hz, 2H), 7.23–
7.19 (m, 2H), 7.16–6.97 (m, 6H), 6.62 (t, J=7.5 Hz, 1H),
5.03 (s, 0.94H), 3.60 (s, 0.08H), 3.43 (d, J=7.5 Hz, 2H);
13C NMR (75 MHz, CDCl3): d=164.72, 161.46, 153.06,
142.53, 142.44, 139.74, 135.38, 132.49, 130.93, 130.77, 130.06,
129.95, 129.72, 129.40, 128.74, 128.53, 126.40, 124.80, 122.27,
122.24, 120.95, 115.79, 114.73, 114.45, 113.63, 113.33, 36.23;
IR (KBr): n=3028, 2923, 1660, 1607, 1582, 1486, 1448, 1236,
1032, 867, 754 cmÀ1; GC-MS: m/z=304; ESI-HR-MS: m/z=
305.1345, calcd. for C21H17FO [M+H]+: 305.1336.
1
848C; H NMR (300 MHz, CDCl3): d=8.31 (s, 1H), 7.37–
7.21 (m, 9H), 6.50 (d, J=2.5 Hz, 1H), 6.43 (d, J=8.6 Hz,
1H), 6.32 (dd, J=8.7, 2.5 Hz, 1H), 3.78 (s, 3H); IR (KBr):
n=3166, 2921, 1616, 1592, 1519, 1382, 1300, 1198, 1116,
1037, 756, 698 cmÀ1; GC-MS: m/z=288.
2-(1-Phenylvinyl)phenol (5k):[39] TLC (petroleum ether/
1
ethyl acetate=10:1); yield: 88/75%; colorless oil; H NMR
1-(4’-Chlorobiphenyl-2-yl)-3-phenylpropan-1-one
(5p):
(300 MHz, CDCl3): d=7.44–7.36 (m, 5H), 7.30 (ddd, J=8.4,
5.6, 1.7 Hz, 1H), 7.18 (dd, J=7.5, 1.7 Hz, 1H), 6.97 (ddd,
J=8.6, 5.6, 1.9 Hz, 2H), 5.91 (d, J=1.2 Hz, 1H), 5.46 (d, J=
1.1 Hz, 1H), 5.23 (s, 1H); IR (KBr): n=3507, 3029, 2927,
1603, 1486, 1449, 1238, 1112, 909, 756 cmÀ1; GC-MS: m/z=
196.
1-Biphenyl-2-yl-3-phenylpropan-1-one (5l): TLC (petrole-
um ether/ethyl acetate=4:1); yield: 80%; yellow brown oil;
1H NMR (300 MHz, CDCl3): d=12.18 (s, 1H), d 7.40–7.32
(m, 8H), 7.30–7.26 (m, 2H), 7.22 (dd, J=7.5, 1.6 Hz, 1H),
7.15–7.07 (m, 2H), 6.65 (t, J=7.5 Hz, 1H), 5.20 (s, 0.90H),
3.57 (s, 0.11H), 3.50 (d, J=7.5 Hz, 2H); 13C NMR (75 MHz,
CDCl3): d=161.46, 140.47, 136.60, 131.46, 130.84, 129.53,
128.73, 128.68, 128.59, 127.90, 126.69, 126.34, 125.39, 36.26;
IR (KBr): n=3029, 2924, 1758, 1664, 1602, 1483, 1449, 1242,
1115, 755, 699 cmÀ1; GC-MS: m/z=286; ESI-HR-MS: m/z=
287.1433, calcd. for C21H18O [M+H]+: 287.1430.
TLC (petroleum ether/ethyl acetate=10:1); yield: 80%;
yellow brown oil; H NMR (300 MHz, CDCl3): d=11.96 (s,
1
1H), d 7.43–7.30 (m, 6H), 7.29–7.26 (m, 5H), 7.25–7.18 (m,
3H), 7.15 (dd, J=7.5, 1.7 Hz, 1H), 7.06 (dd, J=7.8, 3.0 Hz,
2H), 6.58 (t, J=7.5 Hz, 1H), 5.12 (s, 1H), 3.68 (d, J=
7.8 Hz, 0.34H), 3.60 (s, 0.24H), 3.44 (d, J=7.5 Hz, 2H);
13C NMR (75 MHz, CDCl3): d=153.02, 139.78, 138.57,
135.30, 133.62, 131.80, 131.23, 130.71, 130.15, 129.66, 129.35,
128.80, 128.70, 128.63, 128.50, 127.86, 127.33, 126.36, 125.94,
124.85, 123.15, 120.92, 115.73, 40.85, 36.23; IR (KBr): n=
3022, 2926, 1661, 1580, 1481, 1439, 1233, 1031, 866, 752 cmÀ1
;
GC-MS: m/z=320; ESI-HR-MS: m/z=321.1049, calcd. for
C21H17ClO [M+H]+: 321.1041.
1-(3’-Methoxybiphenyl-2-yl)-3-phenylpropan-1-one (5q):
TLC (petroleum ether/ethyl acetate=10:1); yield: 91%;
1
yellow brown oil; H NMR (300 MHz, CDCl3): d=7.38–7.32
(m, 3H), 7.29–7.23 (m, 3H), 7.19 (dd, J=7.5, 1.7 Hz, 1H),
Adv. Synth. Catal. 2016, 358, 947 – 957
ꢁ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
955

FULL PAPERS
Yunming Wen et al.
7.10–7.01 (m, 2H), 6.95 (dd, J=7.8, 0.7 Hz, 1H), 6.91 (t, J=
2.0 Hz, 1H), 6.86 (dd, J=8.1, 2.5 Hz, 1H), 6.62 (t, J=
7.5 Hz, 1H), 5.13 (s, 1H), 3.80 (s, 3H), 3.46 (d, J=7.5 Hz,
2H); 13C NMR (75 MHz, CDCl3): d=159.81, 153.11, 141.56,
140.00, 136.18, 131.66, 130.76, 129.60, 129.50, 128.67, 128.53,
126.29, 125.26, 120.77, 119.23, 115.67, 112.99, 112.62, 55.27,
36.20; IR (KBr): n=3030, 2933, 1721, 1620, 1609, 1481,
1452, 1242, 1020, 930, 751 cmÀ1; GC-MS: m/z=316; ESI-
HR-MS: m/z=317.1540, calcd. for C22H20O2 [M+H]+:
317.1536.
[9] a) M. Jin, L. Adak, M. Nakamura, J. Am. Chem. Soc.
2015, 137, 7128–7134; b) G. Cahiez, A. Moyeux, J.
Cossy, Adv. Synth. Catal. 2015, 357, 1983–1989; c) R.
Agata, T. Iwamoto, N. Nakagawa, K. Isozaki, T. Hata-
keyama, H. Takaya, M. Nakamura, Synthesis 2015, 47,
1733–1740; d) K. Graczyk, T. Haven, L. Ackermann,
Chem. Eur. J. 2015, 21, 8812–8815; e) A. M. Gregson,
S. M. Wales, S. J. Bailey, P. A. Keller, J. Organomet.
Chem. 2015, 785, 77–83; f) G. Cahiez, C. Chaboche, C.
Duplais, A. Giulliani, A. Moyeux, Adv. Synth. Catal.
2008, 350, 1484–1488; g) D. Haas, J. M. Hammann, A.
Moyeux, G. Cahiez, P. Knochel, Synlett 2015, 26, 1515–
1519.
[10] D.-G. Yu, B.-J. Li, S.-F. Zheng, B.-T. Guan, B.-Q. Wang,
Z.-J. Shi, Angew. Chem. 2010, 122, 4670–4674; Angew.
Chem. Int. Ed. 2010, 49, 4566–4570.
[11] a) F.-A. Kang, Z. Sui, W. V. Murray, J. Am. Chem. Soc.
2008, 130, 11300–11302; b) F.-A. Kang, J. C. Lanter, C.
Cai, Z. Sui, W. V. Murray, Chem. Commun. 2010, 46,
1347–1349.
Acknowledgements
We are grateful to National Natural Science Foundation of
China (Grant No. 21276104) and Fundamental Research
Funds for the Central Universities (Grant No. 21612403) for
financial support.
[12] a) Y. Luo, J. Wu, Tetrahedron Lett. 2009, 50, 2103–2105;
b) Y. Hu, Q. Ding, S. Ye, Y. Peng, J. Wu, Tetrahedron
2011, 67, 7258–7262.
References
[13] F. Gao, X.-J. Deng, Y. Tang, J.-P. Tang, J. Yang, Y.-M.
Zhang, Tetrahedron Lett. 2014, 55, 880–883.
[1] a) Z. L. Shen, H. L. Cheong, T. P. Loh, Chem. Eur. J.
2008, 14, 1875–1880; b) C.-J. Li, Y. Meng, J. Am. Chem.
Soc. 2000, 122, 9538–9539; c) G. J. Sormunen, D. E.
Lewis, Synth. Commun. 2004, 34, 3473–3480; d) V.
Pace, W. Holzer, B. Olofsson, Adv. Synth. Catal. 2014,
356, 3697–3736.
[2] a) M. Hatano, S. Suzuki, K. Ishihara, J. Am. Chem. Soc.
2006, 128, 9998–9999; b) S. E. Denmark, J.-P. Fu, Chem.
Rev. 2003, 103, 2763–2793; c) K. Ishihara, M. Hatano,
Synthesis 2008, 1647–1675; d) M. Yus, J. C. Gonzalez-
Gomez, F. Foubelo, Chem. Rev. 2011, 111, 7774–7854;
e) E. Fernµndez-Mateos, B. Maciµ, M. Yus, Adv. Synth.
Catal. 2013, 355, 1249–1254.
[3] a) B. D. Jadhav, S. K. Pardeshi, Tetrahedron Lett. 2014,
55, 4948–4952; b) R.-Y. Chen, A. P. Dhondge, G.-H.
Lee, C. Chen, Adv. Synth. Catal. 2015, 357, 961–966;
c) H. Li, F. Dong, M. Xiong, H. Li, P. Li, X. Zhou, Adv.
Synth. Catal. 2011, 353, 2131–2136.
[4] a) K.-H. Wu, Y.-Y. Kuo, C.-A. Chen, Y.-L. Huang, H.-
M. Gau, Adv. Synth. Catal. 2013, 355, 1001–1008; b) S.
Li, J.-X. Wang, X. Wen, X. Ma, Tetrahedron 2011, 67,
849–855; c) K. Takai, Y. Ikawa, Org. Lett. 2002, 4,
1727–1729; d) C.-J. Li, W.-C. Zhang, J. Am. Chem. Soc.
1998, 120, 9102–9103; e) C.-J. Li, Tetrahedron 1996, 52,
5643–5668.
[5] a) W. Deng, X.-H. Tan, L. Liu, Q.-X. Guo, Chin. J.
Chem. 2004, 22, 747–750; b) A. Di Scala, S. Garbacia,
F. Helion, M. I. Lannou, J. L. Namy, Eur. J. Org. Chem.
2002, 2989–2995.
[6] a) S. H. Kim, E. H. Han, Tetrahedron Lett. 2000, 41,
6479–6482; b) J. MuÇoz-Bascón, I. Sancho-Sanz, E. l-
varez-Manzaneda, A. Rosales, J. E. Oltra, Chem. Eur.
J. 2012, 18, 14479–14486; c) J. Justicia, I. Sancho-Sanz,
E. lvarez-Manzaneda, J. E. Oltra, J. M. Cuerva, Adv.
Synth. Catal. 2009, 351, 2295–2300.
[14] a) L. Zhang, L. Sonaglia, J. Stacey, M. Lautens, Org.
Lett. 2013, 15, 2128–2131; b) J. T. Binder, S. F. Kirsch,
Org. Lett. 2006, 8, 2151–2153.
[15] a) C. C. K. Keh, C.-M. Wei, C.-J. Li, J. Am. Chem. Soc.
2003, 125, 4062–4063; b) L. W. Bieber, E. C. Storch, I.
Malvestiti, M. F. da Silva, Tetrahedron Lett. 1998, 39,
9393–9396; c) K. Smith, S. Lock, G. A. El-Hiti, M.
Wada, N. Miyoshi, Org. Biomol. Chem. 2004, 2, 935–
938; d) Z. L. Shen, Y. L. Yeo, T. P. Loh, J. Org. Chem.
2008, 73, 3922–3924; e) Y. Kawamura, Y. Kawano, T.
Matsuda, Y. Ishitobi, T. Hosokawa, J. Org. Chem. 2009,
74, 3048–3053.
[16] Y.-M. Wen, G.-F. Chen, Y. Tang, J. Chen, J. Yang, Y.-
M. Zhang, Chin. J. Org. Chem. 2015, 35, 2545–2551.
[17] C.-L. Zhou, Z.-Y. Wang, Synthesis 2005, 1649–1655.
[18] C. S. A. Antunes, M. Bietti, O. Lanzalunga, M. Sala-
mone, J. Org. Chem. 2004, 69, 5281–5289.
[19] L. J. Rono, H. G. Yayla, D. Y. Wang, M. F. Armstrong,
R. R. Knowles, J. Am. Chem. Soc. 2013, 135, 17735–
17738.
[20] C. Berini, O. Navarro, Chem. Commun. 2012, 48, 1538–
1540.
[21] T. Korenaga, A. Ko, K. Uotani, Y. Tanaka, T. Sakai,
Angew. Chem. 2011, 123, 10891–10895; Angew. Chem.
Int. Ed. 2011, 50, 10703–10707.
[22] A. Balsamo, C. Battistini, P. Crotti, B. Macchia, F. Mac-
chia, Gazz. Chim. Ital. 1976, 106, 77–83.
[23] E. Riva, S. Gagliardi, M. Martinelli, D. Passarella, D.
Vigo, A. Rencurosi, Tetrahedron 2010, 66, 3242–3247.
[24] V. V. Meshkovaya, A. V. Yudashkin, Y. N. Klimochkin,
Dyes Pigments 2015, 113, 435–446.
[25] I. Dokli, M. Gredicak, Eur. J. Org. Chem. 2015, 2727–
2732.
[26] L. F. Fieser, J. Szmuszkovicz, J. Am. Chem. Soc. 1948,
70, 3352–3355.
[7] W. J. Evans, P. S. Workman, N. T. Allen, Org. Lett.
2003, 5, 2041–2042.
[8] F. Zhou, C.-J. Li, Nat. Commun. 2014, 5, 4254.
956
asc.wiley-vch.de
ꢁ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2016, 358, 947 – 957

FULL PAPERS
The Barbier–Grignard-Type Arylation of Ketones
[27] J.-C. Wu, L.-B. Gong, Y. Xia, R.-J. Song, Y.-X. Xie, J.-
H. Li, Angew. Chem. 2012, 124, 10047–10051; Angew.
Chem. Int. Ed. 2012, 51, 9909–9913.
[33] R. Gerber, C. M. Frech, Chem. Eur. J. 2011, 17, 11893–
11904.
[34] X. Yang, Z.-X. Wang, Organometallics 2014, 33, 5863–
5873.
[35] C. M. So, C. C. Yeung, C. P. Lau, F. Y. Kwong, J. Org.
Chem. 2008, 73, 7803–7806.
[36] R. Bolton, R. E. Burley, J. Chem. Soc. Perkin Trans. 2
[28] X. Feng, Y.-Q. Yuan, H.-L. Cui, K. Jiang, Y.-C. Chen,
Org. Biomol. Chem. 2009, 7, 3660–3662.
[29] N. Santschi, C. Matthey, R. Schwenk, E. Otth, A.
Togni, Eur. J. Org. Chem. 2015, 1925–1931.
[30] J. Mao, K. Eberle, J. Zhang, C. Rodriguez-Escrich, Z.
Xi, M. A. Pericas, P. J. Walsh, Tetrahedron Lett. 2015,
56, 3604–3607.
1977, 426–429.
[37] F. Wang, J. Hu, Chin. J. Chem. 2009, 27, 93–98.
[38] B. Schmidt, N. Elizarov, U. Schilde, A. Kelling, J. Org.
Chem. 2015, 80, 4223–4234.
[39] S. Agasti, U. Sharma, T. Naveen, D. Maiti, Chem.
Commun. 2015, 51, 5375–5378.
[31] K. Nakamura, K. Yasui, M. Tobisu, N. Chatani, Tetra-
hedron 2015, 71, 4484–4489.
[32] D. Wu, Z.-X. Wang, Org. Biomol. Chem. 2014, 12,
6414–6424.
Adv. Synth. Catal. 2016, 358, 947 – 957
ꢁ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
957