Metal-free synthesis of sterically crowded biphenyls by direct Ar-H substitution in alkyl benzenes

Article abstract of DOI:10.1002/anie.200701462

(Chemical Equation Presented) Four's definitely a crowd: The chemoselective activation of Ar-H bonds in methylbenzenes by treatment with photogenerated phenyl cations allowed the synthesis of sterically crowded biphenyl compounds, including tetra-ortho-substituted biphenyls, by intermolecular cross-coupling (see scheme). This method is an appealing metal-free alternative to widely used transition-metal catalysis. TFE = 2,2,2-trifluoroethanol.

Full text of DOI:10.1002/anie.200701462

Angewandte
Chemie
DOI: 10.1002/anie.200701462
Photochemical Synthesis
À
Metal-Free Synthesis of Sterically Crowded Biphenyls by Direct Ar H
Substitution in Alkyl Benzenes**
Valentina Dichiarante, Maurizio Fagnoni,* and Angelo Albini
A biaryl moiety is a common structural component of many
pharmaceutically and biologically active compounds.[1] There-
fore, the synthesis of asymmetric or crowded biaryl com-
pounds is a significant challenge. In recent decades, tradi-
tional methods, such as the Ullmann and Gomberg reactions,
have been supplanted by novel transition-metal-catalyzed
processes.[2] These reactions involve the coupling of a
examples was the palladium-catalyzed arylation of isoxa-
zoles.[4] Until now, most reported coupling reactions of this
type have been intramolecular reactions. Successful intermo-
lecular coupling required the presence of a group R’’ (R’’ =
= À
OH, CONR2, COR, C N R, or a pyridyl nitrogen atom) in
the nucleophilic component, placed at a position ortho with
respect to the attack site that ensured binding to the metal
catalyst.[5]
À
nucleophilic organometallic derivative Ar M (M = SnR3:
Stille reaction; M = MgX: Kumada reaction; M = B(OH)2:
As nonfunctionalized aromatic compounds are deemed to
be unreactive, benzene and xylene can be used as solvents for
the coupling of functionalized aromatic compounds.[6] To the
best of our knowledge, the only exceptions to this rule are a
few reactions that occur in moderate yield under severe
conditions: the arylation of azulene (at the 1-position) by 4-
nitrochlorobenzene under palladium catalysis at 1408C in a
sealed tube[7] and the arylation of benzene both by aryl
iodides in the presence of iridium complexes[8a] and by aryl
bromides under palladium catalysis in the presence of pivalic
acid (30 mol%) at 1208C.[8b] A novel arylation method that
does not involve metal catalysis was described recently.[9] In
this method, phenyl cations generated by photoheterolysis of
À
Suzuki reaction) with an electrophilic reagent Ar X (X =
halogen or triflate; see Scheme 1a).
À
À
the Ar X or Ar O bond of aryl halides (chlorides and
fluorides)[10] and esters (mesylates, triflates, and phos-
phates)[11] with an electron-donating substituent undergo
selective addition to p nucleophiles with no interference by
the solvent, even when the solvent is a nucleophile, such as an
alcohol. The reaction is distinguished by the mild conditions
required and in preliminary studies was demonstrated to offer
viable access to biphenyl compounds (Scheme 1b).[9]
The importance of the synthetic target encouraged us to
explore the scope of the reaction. The photochemistry of a
variety of aryl halides and sulfonate/phosphate esters with an
electron-donating substituent (R’C6H4X, 1–11, Table 1) was
investigated in the presence of symmetrical methylbenzenes
C6H6Àn(CH3)n, namely, p-xylene, 1,3,5-trimethylbenzene
(mesitylene), and 1,2,4,5-tetramethylbenzene (durene).
These methyl-substituted benzenes were not only chosen to
tune the degree of steric hindrance involved, but also to allow
Scheme 1. Synthesis of biaryl compounds by a)metal catalysis and
b)the proposed photochemical method.
The main limitation of these methods is that activating
groups must be present on both arene coupling partners. The
process is therefore inherently unfavorable from the point of
view of atom economy. The replacement of one (or both) of
À
these functionalized reagents by a simple Ar H derivative is
thus a key goal in the attempt to develop “greener” methods
and of particular appeal with respect to the organometallic
reagent, which is often the less stable component and the
more difficult to prepare. As the organometallic reagent acts
as the nucleophile, electron-rich (hetero)aromatic com-
pounds have been used in this role:[3] One of the first
À
us to assess whether benzylic C H bond activation competed
[12]
À
with Ar H bond activation under these conditions. The
electron-donating group R’ and the leaving group X in the
component R’C6H4X were varied as much as possible to test
the generality of the method.
[*] V. Dichiarante, Dr. M. Fagnoni, Prof. A. Albini
Department of Organic Chemistry
University of Pavia
We found that the desired coupling took place satisfac-
torily: A variety of bulky biaryl compounds were formed in
yields greater than 50% (mostly > 70%; Table 1). Direct
irradiation at 310 nm was effective for compounds that
absorbed sufficiently at this wavelength, whereas sensitization
by acetone was successful in the other cases. Arylation yields
were higher in the solvent 2,2,2-trifluoroethanol (TFE), but
Via Taramelli 10, 27100 Pavia (Italy)
Fax: (+39)0382-987-323
E-mail: fagnoni@unipv.it
[**] Partial support of this research by Murst, Rome is gratefully
acknowledged.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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Table 1: Photoarylation of alkyl benzenes.
cheaper acetonitrile was a conven-
ient alternative in some cases. A
large excess of the methylbenzene
(1m) was used; the concentration of
the aryl-cation precursor was 0.05m.
However, reasonable yields were
also observed at a lower concentra-
tion of the methylbenzene (ꢀ 0.5m;
see below). Triethylamine (0.05m)
was added in all cases to buffer the
acid liberated in the reaction.
Entry Alkyl
Aryl halide
tirr [h] Product
Yield [%][a]
benzene (1m) or ester (0.05m)
1
2
7
7
76
52
Specifically, p-xylene was aryl-
ated smoothly to give the biphenyl
12 (Table 1, entries 1 and 2) upon
irradiation in the presence of the
N,N-dimethylaminophenyl mesy-
late 1a or phosphate 1b in 76 and
52% yield, respectively. The course
of the reaction was not affected by
the presence of a methyl group
adjacent to X or when the elec-
tron-donating group R’ was in the
ortho position with respect to X. In
this way, the 2,2’-disubstituted
biphenyls 13 and 14 were obtained
from the chloride 2 and triflate 3a,
respectively (Table 1, entries 3 and
4). In the former case, the protec-
tion of the OH group in the parent
compound as a silyl ether led to a
significant improvement in the
yield. In the reaction of 3a, sensiti-
zation with acetone was required.
Mesitylene, which is more
crowded than p-xylene, underwent
arylation with the same efficiency.
Thus, the irradiation of 4-chloro-
thioanisole (4) in the presence of
mesitylene gave the 2,6-dimethylbi-
phenyl 15 in a yield comparable to
those observed with p-xylene
(Table 1, entry 5; 70% with 1m
mesitylene, 58% with 0.5m mesity-
lene). The meta-methoxy triflate 5
also underwent successful arylation
to give 16 in 71% yield, despite the
fact that photosolvolysis has been
shown to be effective with this
derivative.[13] The more sterically
3
7
7
56
77
4[b]
5
8
70
71
77[c]
62
84
77
6[b]
7[b]
8
7
7
5
9[d]
7
crowded
tri-ortho-substituted
biaryl compounds 17 and 18 were
prepared by the irradiation of
ortho-methoxy mesylate (3b) and
the methylchloroaniline 6 in 77 and
62% yield, respectively (Table 1,
entries 7 and 8). In the former
case, acetonitrile could be used
conveniently in place of TFE.
10[b,e]
1.5
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Table 1: (Continued)
by elimination of HX. The func-
tional groups OH, NH2, OR, NR2,
SR, and OSiR3 were found to be
Entry Alkyl
Aryl halide
tirr [h] Product
Yield [%][a]
benzene (1m) or ester (0.05m)
suitable
as
electron-donating
11[f]
12[f]
4
4
58
46
groups R’, mostly in the ortho or
para position. As demonstrated by
the experiments with 6, 9a,b, and 10
(see Table 1), the protection of the
acidic hydrogen atoms in anilines
and phenols is unnecessary in some
cases, despite the fact that the
corresponding phenyl cation can
undergo deprotonation to give a 4-
iminocyclohexa-2,5-dienylidene
carbene (in the case of 6 and
9a,b)[14a] or 4-oxocyclohexa-2,5-
dienylidene carbene (in the case of
10).[14b–d] Apparently, the trapping
of the phenyl cation by a (suffi-
ciently concentrated) p nucleophile
is faster,[15] and deprotonation is a
minor process, if it occurs at all:
Benzoquinone (the diagnostic prod-
uct of the trapping of the corre-
13[f,g]
7
7
60
76
14[f,g]
[a] Yield of the isolated compound. [b] Acetone (0.9m)was added as a sensitizer. [c] Compound 17 was
formed in 71% yield with MeCN as the solvent. [d] Cesium carbonate was used as the base. [e] Two
equivalents of Et3N were used. [f] Durene: 0.2m. [g] Aryl chloride: 0.02m. Ms=methanesulfonyl, Tf=
trifluoromethanesulfonyl.
Most interestingly, the arylation took place smoothly with
the aryl halides 7 and 8, in which two methyl groups flank the
leaving chlorine atom (Table 1, entries 9 and 10). The
corresponding tetra-ortho-substituted biaryl compounds 19
and 20 were formed in high yields of 84 and 77%,
respectively. (Compound 20 was formed in 63% yield when
mesitylene was used at a concentration of 0.5m.) Cesium
carbonate was used in place of triethylamine in the reaction
with compound 7, and the amount of triethylamine used was
doubled with 8 to avoid desilylation during the irradiation.
The extension of the coupling reaction to the substrate
durene was limited by the low solubility of this aromatic
compound in polar solvents. It was necessary to carry out the
irradiation at a durene concentration of 0.2m. Gratifyingly,
biaryl compounds were again formed as the main products by
far, although the yields were somewhat lower (Table 1,
entries 11–14). Thus, the aminobiphenyl 21 was synthesized
from both chloro- (9a) and fluoroaniline (9b) in 58 and 46%
yield, respectively. Despite the moderate yield, the reaction of
9b is noteworthy because the use of an aryl fluoride in a
coupling reaction with a non-activated aromatic compound
has no precedent under thermal conditions. Furthermore, 4-
chlorophenol (10; Table 1, entry 13) underwent successful
arylation with durene, as did the benzo[1,3]dioxole 11, which
was transformed into 23 in 76% yield (Table 1, entry 14). The
aryl halide was used at a lower concentration (0.02m) in these
last two reactions.
sponding carbene by oxygen) was not formed when 10 was
irradiated under oxygen.
We can conclude from this series of experiments that this
method for the synthesis of biaryl compounds has broad scope
and that steric hindrance presents no significant limitation.
Products of the type shown in Table 1 can be obtained by
metal-mediated syntheses with an activating functional group,
such as SnBu3 or B(OH)2.[16] However, for the present method
simple aromatic compounds rather than organometallic
aromatic compounds are required (see Scheme 1), and mild,
practical conditions are used: Moisture has no effect, no labile
or toxic reagent is required, there is no metal residue to
collect and dispose of after the reaction, and the reactions are
carried out at room temperature.
Nevertheless, there is a mechanistic analogy with metal-
catalyzed reactions, particularly with respect to the electro-
philic component. The present reactions involve the gener-
À
ation of a cation by heterolytic cleavage of the Ar X bond.
This process can be likened to the weakening of such bond by
donation from the metal catalyst to the antibonding orbital of
the halide:[9a] Thus, the aryl–metal complex has some
carbocationic character.[3]
The photochemical arylation reactions were strictly
chemoselective. No functionalization was observed at ben-
zylic positions despite the statistical predominance of benzylic
hydrogen atoms over aryl hydrogen atoms (6:1 in the case of
durene). Furthermore, clean monoarylation was always
observed, and other possible competitive pathways, such as
the reduction of the starting halides or sulfonate/phosphate
esters, were in most cases negligible. (Such by-products were
usually formed in 2–5% yield, except in two cases in which
the product of reduction was formed in 9% yield; see the
Supporting Information.) Furthermore, this method is more
versatile than traditional methods with respect to the range of
possible aryl-cation precursors, as the photochemical reaction
These results show that direct hydrogen-atom substitution
of simple arenes (such as alkyl benzenes) is possible in a
metal-free process in which phenyl cations are generated
photochemically under mild conditions. Thus, twelve increas-
ingly congested biaryl compounds, from 2,6- or 2,2’-dimethyl-
substituted to tetra-ortho-methyl-substituted biphenyls, were
prepared by photoinduced coupling between an aryl halide
(or sulfonate/phosphate ester) R’C6H4X and an arene R’’ArH
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Communications
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is more effective than metal-catalyzed activation of the ArX
bond. Indeed, ArX derivatives that are usually less reactive
under palladium catalysis,[5b] such as aryl chlorides and even
aryl fluorides and phosphates, can be used conveniently.
Finally, a large variety of substituents can be present in the
ortho, meta, or para position of the aryl-cation precursor. In
conclusion, this novel photochemical synthesis of biaryl
compounds represents a convenient alternative to organo-
metallic processes.
Experimental Section
General procedure: A solution of an aryl sulfonate ester, phosphate
ester, or halide (1.5 mmol, 0.05m), triethylamine (0.05m), and a
methylbenzene (1m) in TFE (30 mL) was poured into two quartz
tubes and purged with argon for 10 min. The tubes were closed with
serum caps and the solution was irradiated with six 15-W phosphor-
coated lamps (emission centered at 310 nm). The photolyzed solution
was concentrated under reduced pressure and purified by column
chromatography (cyclohexane/ethyl acetate). For the reactions of
compounds 3a,b, 5, and 8, acetone (3 mL, 0.9m) was added to the
reaction mixture.
[12] Cationic PtII complexes were found to activate preferentially
benzylic hydrogen atoms, rather than aryl hydrogen atoms, in
both mesitylene and p-xylene; see: A. F. Heyduk, T. G. Driver,
J. A. Labinger, J. E. Bercaw, J. Am. Chem. Soc. 2004, 126,
15034 – 15035; H. A. Zhong, J. A. Labinger, J. E. Bercaw, J. Am.
Chem. Soc. 2002, 124, 1378 – 1399.
[13] V. Dichiarante, D. Dondi, S. Protti, M. Fagnoni, A. Albini, J. Am.
Chem. Soc. 2007, 129, 5605 – 5611.
Received: April 4, 2007
Revised: May 25, 2007
Published online: July 24, 2007
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Grabner, C. Richard, G. Köhler, J. Am. Chem. Soc. 1994, 116,
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[15] The diagnostic reaction for 4-oxocyclohexa-2,5-dienylidene (or
4-iminocyclohexa-2,5-dienylidene) is trapping by oxygen to form
a carbonyl oxide[14a,b,d] and ultimately benzoquinone (or benzo-
quinone imine). The present reactions are affected to only a
small extent by oxygen, the presence of which leads to a
moderate decrease in the yield (ꢀ 20%), at least when the
concentration of the nucleophile is 1m. No benzoquinone is
formed.
Keywords: aryl cations · arylation · cross-coupling ·
.
methylbenzenes · photochemistry
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