Transition-metal-free one-pot synthesis of biaryls from grignard reagents and substituted cyclohexanones

Article abstract of DOI:10.1002/chem.201300491

A new strategy for the construction of biaryls by a transition-metal-free process is presented. A sequence of a Grignard reaction, dehydration, and oxidative aromatization affords the desired products in a one-pot fashion. Copyright

Full text of DOI:10.1002/chem.201300491

FULL PAPER
DOI: 10.1002/chem.201300491
Transition-Metal-Free One-Pot Synthesis of Biaryls from Grignard Reagents
and Substituted Cyclohexanones
Feng Zhou, Marc-Oliver Simon, and Chao-Jun Li*[a]
Dedicated to Professor Irina Petrovna Beletskaya
Abstract: A new strategy for the construction of biaryls by a transition-metal-free
process is presented. A sequence of a Grignard reaction, dehydration, and oxida-
tive aromatization affords the desired products in a one-pot fashion.
Keywords: biaryls · cyclohexanone ·
Grignard reaction · one-pot pro-
AHCTUNGTERGcNNUN ess · transition-metal free
Introduction
The synthesis of biaryl scaf-
folds, which are widely occur-
ring subunits in a variety of
compounds such as biologically
active
molecules,[1]
natural
products,[2] polymers, advanced
materials, and liquid crystals
(LCD),[3] has attracted persis-
tent interest from the chemistry
community. Over the past dec-
ACHTUNGTRENNUNGades, a large number of meth-
ods[4] have been developed,
among which the most reliable
and widely applicable are the
transition-metal-catalyzed
cross-coupling
reactions
[Eq. (1), Scheme 1]. These reac-
tions include the Kumada,[5]
Suzuki,[6] Negishi,[7] and Stille
couplings,[8] along with further
refinements thereof. Alterna-
tive methods, such as arylation
À
through C H bond activation
Scheme 1. Strategies for the synthesis of biaryls.
[Eq. (2), Scheme 1],[9] have
emerged in the past few years.
In such processes, the regiose-
both install the directing group into the substrate and to ma-
nipulate it after the functionalization. A third interesting ap-
proach involving a decarboxylative step between an aryl
halide and an arene carboxylic acid [Eq. (3), Scheme 1] has
recently been established.[10] However, for all of the meth-
ods mentioned above, it is essential to utilize transition
metals to catalyze the transformations, which may be unde-
sirable. We are particularly interested in exploring the po-
tential of transition-metal-free systems, which might provide
an alternative approach for the construction of biaryls.
Recently, our group reported the synthesis of aromatic
ethers[11] and amines[12] from non-aromatic precursors by ox-
À
lectivity of C H bond functionalization is the primary chal-
lenge. Although this may be accomplished by using a direct-
ing group, additional synthetic steps are often required to
[a] Dr. F. Zhou, M.-O. Simon, Prof. Dr. C.-J. Li
Department of Chemistry, McGill University
Montreal, QC, H3A 0B8 (Canada)
Fax : (+1)514-398-3797
E-mail: cj.li@mcgill.ca
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201300491.
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idative aromatization, for which the copper and palladium,
respectively, were used as the catalysts. We envisaged that
the even more valuable biaryls might also be accessed by
using a similar strategy.[13] Herein, we describe a transition-
metal-free oxidative aromatization based on a sequential
process in one pot, employing a Grignard reagent as the nu-
cleophile, cyclohexanone as the source of one aromatic ring,
and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) as a
hydrogen abstractor [Eq. (4), Scheme 1].
results demonstrated that the amount of DDQ had not been
sufficient in our initial studies (Table 1, entries 1 and 2), and
presumably one equivalent of DDQ was decomposed[15b,17]
by each equivalent of water formed during the reaction. We
next examined the reaction at a lower temperature of 508C,
whereupon the yield was reduced to 81% (Table 1, entry 4).
When the reaction was attempted at room temperature,
none of the desired product 3aa was detected and only the
alkene byproduct 4aa was obtained in 13% yield (Table 1,
entry 5). Thus, para-tolylmagnesium bromide 1a (1.1 equiv),
cyclohexanone 2a (1 equiv), and DDQ (3.5 equiv) in tol-
uene at 1008C under a nitrogen atmosphere were identified
as the optimized reaction conditions.
Results and Discussion
We started the investigation by examining the reaction of
para-tolylmagnesium bromide (1a) with cyclohexanone
(2a). Toluene was selected as the reaction medium because
it has been shown to be the most effective solvent for aero-
bic aromatization.[11,12] DDQ is a well-known oxidant in or-
ganic chemistry.[14] For many years, it has been used for the
oxidation of allylic and benzylic alcohols[15] as well as allylic
ethers[16] to the corresponding carbonyl compounds. There-
fore, we decided to use it as the oxidant in the present stud-
ies.
The reaction of 1a and 2a in the presence of DDQ
(2.2 equiv) under a nitrogen atmosphere afforded the ex-
pected product 3aa in 60% yield. Furthermore, an alkene
byproduct, 4aa, which is the hypothetical reaction inter-
mediate (see the Supporting Information), was generated in
30% yield (Table 1, entry 1). We suspected that the dehy-
dration step might not have been efficient enough under
these reaction conditions. In an attempt to overcome this,
we added 5 mol% p-TsOH to improve the efficiency of the
dehydration; however, no clear improvement was observed
(Table 1, entry 2). Indeed, the yield of byproduct 4aa de-
creased to 17%. We then focused our attention on the dehy-
drogenation and increased the amount of DDQ to 3.5 equiv-
alents. Under these conditions, the desired product 3aa was
obtained in almost quantitative yield (Table 1, entry 3). The
Having established the optimal conditions, the generality
of this one-pot biaryl synthesis was explored and the results
are summarized in Table 2. The biaryls were obtained very
efficiently from the reactions of para-tolylmagnesium bro-
mide (1a) or phenylmagnesium bromide (1b) with substitut-
ed cyclohexanones. With cyclohexanone, the reaction gener-
ated a 99% yield (Table 2, entry 1). The 4-methyl- and 3-
methyl-substituted cyclohexanones (2b,c) also reacted
smoothly to afford the corresponding products in 76–80%
yields (Table 2, entries 2, 3, and 8). In the case of 2-methyl-
substituted cyclohexanone 2d, the yield dramatically de-
creased to 34%, presumably due to steric hindrance
(Table 2, entry 4). The reaction of 2e, bearing a 4-tert-butyl
group, proceeded efficiently to furnish the product in 94%
yield (Table 2, entry 5). Even better reactivity was observed
when 4-phenyl-substituted substrate 2 f was used, and an
almost quantitative yield of the product was obtained
(Table 2, entry 6). However, 2,6-dimethylcyclohexanone 2g
did not afford the corresponding biaryl product, possibly be-
cause of the high degree of steric hindrance (Table 2,
entry 7).
To further broaden the scope of the reaction, we turned
our attention to various Grignard reagents generated in situ.
Halogen–metal exchange[18] is a powerful tool for the prepa-
ration of functionalized organometallic species; therefore,
we decided to prepare Grignard reagents with various func-
tionalities by an iodine–magnesium exchange strategy.[19] It
was anticipated that this strategy would be easier and more
convenient than using pre-synthesized Grignard reagents.
Thus, various aryl and heteroaryl iodides 1c’–k’ were con-
verted into the corresponding organomagnesium compounds
by treatment with 1.05 equivalents of iPrMgCl (2m in THF)
for 1 h at the indicated temperature (Table 2, entries 9–18).
When cyclohexanone (2a) was added dropwise to a solution
of the Grignard reagent generated in situ at À308C, it react-
ed rapidly to produce the corresponding intermediate. The
respective intermediates then underwent the sequential
process in the presence of DDQ to afford a range of func-
tionalized biaryls 3ca–ia, 3ka, and 3ih. Substrates with
either an electron-withdrawing group (1c’) or an electron-
donating group (1d’–f’) reacted smoothly to provide the ex-
pected products in good to excellent yields (Table 2, en-
tries 9–12). A 92% yield was obtained when a methoxy
group was present at the ortho-position of the benzene ring
Table 1. Reaction optimization for the transition-metal-free synthesis of
biaryls from a Grignard reagent and cyclohexanone.[a]
Entry
DDQ
[equiv]
Additive
Temp.
[8C]
Yield [%][b]
(3aa/4aa)
G
1
2
3
4
5
2.2
2.2
3.5
3.5
3.5
–
100
100
100
50
60:30
61:17
99:0
81:0
0:13
p-TsOH (5 mol%)
–
–
–
RT
[a] The reaction was conducted under the following conditions: 1a
(0.22 mmol, 1.0m in THF), 2a (0.2 mmol), and DDQ in toluene (1.0 mL)
under N2 were heated in a sealed tube at the indicated temperature for
40 h (DDQ=2,3-dichloro-5,6-dicyano-1,4-benzoquinone; p-TsOH=para-
toluenesulfonic acid). [b] Yield of the isolated product.
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Transition-Metal-Free Biaryl Synthesis
FULL PAPER
Table 2. Substrate scope of the transition-metal-free one-pot synthesis of
biaryls.[a]
Table 2. (Continued)
Entry 1 or 1’
2
3
Yield
[%][b]
11[e]
2a
73
92
Entry 1 or 1’
2
3
Yield
[%][b]
12[e]
2a
2a
2a
2a
1
99
80
13[f]
14[d]
15[e]
78
79
60
2
1a
3
4
1a
1a
76
34
16[d,g]
2a
2a
0
66
28
17[f]
5[c]
1a
94
99
18[e]
1i’
6
1a
1a
[a] Reaction conditions: 1a,b (0.22 mmol, 1.0m in THF) and 2a–g
(0.20 mmol; entries 1–8) or 1c’–k’ (0.2 mmol), iPrMgCl (0.21 mmol, 2.0m
in THF), and 2a,h (0.22 mmol; entries 9–18) with DDQ (3.5 equiv) in tol-
uene (1.0 mL) at 1008C under N2 for 40 h. For entries 1–8, Grignard re-
actions were carried out at room temperature for 0.5 h by using para-tol-
ylmagnesium bromide (1a) or phenylmagnesium bromide (1b) directly;
for entries 9–18, iPrMgCl was used to generate Grignard reagents in situ
and the Grignard reactions were carried out at À308C for 2 h. [b] Yield
of the isolated product. [c] 4.0 Equivalents of DDQ were used. [d] The
Grignard reagents were generated in situ at À308C. [e] The Grignard re-
agents were generated in situ at room temperature. [f] The Grignard re-
agents were generated in situ at 08C. [g] The Grignard reagent was gen-
erated in situ at À788C.
7
8
0
2b
76
9[d]
2a
2a
86
90
(Table 2, entry 12), suggesting that once the Grignard re-
agent had been generated in situ, its addition to the cycloke-
tone was very efficient. Halogenated substrates, bearing
fluoro (1g’) or bromo substituents (1h’), were tolerated in
this sequential process, furnishing the desired products in
yields of 78 and 79%, respectively (Table 2, entries 13 and
14). When 1-iodonaphthalene (1i’) and cyclohexanone (2a)
were subjected to the optimized reaction conditions, the cor-
10[e]
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C.-J. Li et al.
Scheme 2. Tentative mechanism for the transition-metal-free formation of biaryls from Grignard reagents and cyclohexanones.
responding product was obtained in 60% yield (Table 2,
entry 15). No reaction occurred in the case of 2-iodopyridine
(1j’), presumably owing to the competitive homo-coupling[20]
reaction of the pyridine Grignard reagent (Table 2,
entry 16). Subjecting 1-iodothiophene (1k’) to the same re-
action conditions gave the product in 66% isolated yield
(Table 2, entry 17). Finally, the reaction of 1-iodonaphtha-
lene (1i’) with 1-tetralone (2h) afforded 1,1’-binaphthalene
in 28% yield (Table 2, entry 18).
A tentative mechanism that accounts for the formation of
the biaryls is illustrated in Scheme 2. The Grignard reagent
1 was generated in situ by iodine–magnesium exchange[18]
from the corresponding precursor aryl iodide 1’ and
iPrMgCl, and then reacted with the requisite substituted cy-
clohexanone 2 to furnish the intermediate A. Subsequent
elimination of MgXOH afforded the aryl-substituted alkene
intermediate B. Transfer of a hydride ion from B to the
oxygen atom of DDQ generated the intermediate C.[21] Ab-
straction of a proton by the resulting anionic oxygen of
DDQ then provided the diene intermediate D, with reduc-
tion of DDQ to hydroquinone. The product was formed
from the diene species D by using another equivalent of
DDQ, which underwent the same process.
alkyl Grignard reagents and its synthetic application are
under investigation in our laboratory.
Experimental Section
Typical procedure for the synthesis of biaryls by using para-tolylmagne-
AHCTUNGERTGsNNUN ium bromide and substituted cyclohexanones: An oven-dried Biotage
round-bottomed reaction vessel (10 mL) was charged with a magnetic
stirring bar, evacuated, and refilled with nitrogen gas three times. Under
an atmosphere of nitrogen, toluene (1.0 mL) was added, followed by
para-tolylmagnesium bromide (1a; 0.22 mL, 0.22 mmol, 1.0m in THF).
Cyclohexanone (2a; 19.6 mg, 0.2 mmol) was then added dropwise to the
solution at room temperature. The reaction mixture was stirred at room
temperature for 0.5 h. DDQ (160 mg, 3.5 equiv) was then loaded into the
vessel, which was sealed and placed in an oil bath. The reaction mixture
was gradually heated from room temperature to 1008C under vigorous
stirring over a period of 40 h. After cooling to room temperature, it was
filtered through a short column of silica gel, which was washed with ethyl
acetate. The solvent was removed under vacuum, and the residue was pu-
rified by column chromatography on silica gel eluting with hexanes to
afford the product 1-methyl-4-phenylbenzene 3aa (33.2 mg, 99%) as a
white solid. 1H NMR (500 MHz, CDCl3): d=7.63 (d, J=8.5 Hz, 2H),
7.55 (d, J=8.0 Hz, 2H), 7.48 (t, J=8.0 Hz, 2H), 7.37 (t, J=8.0 Hz, 1H),
7.30 (d, J=7.5 Hz, 2H), 2.45 ppm (s, 3H); 13C NMR (125 MHz, CDCl3):
d=141.1, 138.3, 137.0, 129.5, 128.7, 127.0, 126.9, 21.1 ppm.
Typical procedure for the synthesis of biaryls by reacting Grignard re-
agents bearing functionalities (generated in situ) with cyclohexanone: An
oven-dried Biotage round-bottomed reaction vessel (10 mL) was charged
with a magnetic stirring bar, evacuated, and refilled with nitrogen gas
three times. Under an atmosphere of nitrogen, a solution of methyl 4-
Conclusion
iodo
benzoate (1c’; 0.2 mmol) in toluene (1.0 mL) was cooled to À308C,
An efficient method for the construction of biaryls by a
DDQ-mediated sequential process has been developed. This
new method has several advantages: 1) no transition metal
is needed, 2) the reaction is conducted in one pot, in which
the Grignard reagent and cyclohexanone are either commer-
cially available or easily prepared and 3) no additional re-
agent is required. An extension of this method to vinyl and
whereupon iPrMgCl (0.11 mL, 0.21 mmol, 2.0m in THF) was added drop-
wise. After the addition, the iodine–magnesium exchange reaction was
kept at À308C for 1 h. Cyclohexanone (2a; 23 mL, 0.22 mmol) was then
added dropwise to the reaction mixture, and stirring was continued for a
further 2 h at À308C. After warming to room temperature, DDQ
(160 mg, 3.5 equiv) was added and then the vessel was sealed and placed
in an oil bath at 1008C, stirring the contents vigorously for 40 h. After
cooling to room temperature, the reaction mixture was filtered through a
short column of silica gel, which was washed with ethyl acetate. The sol-
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Transition-Metal-Free Biaryl Synthesis
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vent was removed under vacuum, and the residue was purified by
column chromatography on silica gel eluting with hexanes/EtOAc (30:1)
to give the product methyl 4-phenylbenzoate 3ca (36.3 mg, 86%) as a
white solid. 1H NMR (400 MHz, CDCl3): d=8.11 (dd, J=6.4, 1.6 Hz,
2H), 7.68–7.62 (m, 4H), 7.47 (t, J=8.0 Hz, 2H), 7.40 (t, J=7.6 Hz, 1H),
3.94 ppm (s, 3H); 13C NMR (125 MHz, CDCl3): d=167.0, 145.6, 140.0,
130.1, 128.9, 128.8, 128.1, 127.3, 127.0, 52.1 ppm.
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Acknowledgements
We are grateful to the Canada Research Chair (Tier 1) Foundation (to
C.-J. Li) and the NSERC for their support of our research.
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Received: February 7, 2013
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C.-J. Li et al.
Biaryl synthesis
F. Zhou, M.-O. Simon,
C.-J. Li* ........................ &&&& — &&&&
Transition-Metal-Free One-Pot
Synthesis of Biaryls from Grignard
Reagents and Substituted Cyclohexa-
nones
One-pot biaryl synthesis: An efficient
method for the construction of biaryls
based on a transition-metal-free proc-
ess is presented (see scheme). Various
functionalities are tolerated in this
transformation, and the products can
be generated in a one-pot fashion by a
sequence of Grignard reaction, dehy-
dration, and oxidative aromatization.
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Chem. Eur. J. 0000, 00, 0 – 0
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