Generation of aryl radicals from arylboronic acids by manganese(III) acetate: Synthesis of biaryls and heterobiaryls

Article abstract of DOI:10.1021/jo026466c

The efficient generation of aryl radicals from arylboronic acids by manganese(III) acetate is described. In aromatic solvents, in situ generated aryl radicals afford the corresponding biaryls in very good yields. This method works selectively, and yields

Full text of DOI:10.1021/jo026466c

Gen er a tion of Ar yl Ra d ica ls fr om Ar ylbor on ic Acid s by
Ma n ga n ese(III) Aceta te: Syn th esis of Bia r yls a n d Heter obia r yls
Ayhan S. Demir,* O¨ mer Reis, and Mustafa Emrullahoglu
Department of Chemistry, Middle East Technical University, 06531 Ankara, Turkey
asdemir@metu.edu.tr
Received September 21, 2002
The efficient generation of aryl radicals from arylboronic acids by manganese(III) acetate is
described. In aromatic solvents, in situ generated aryl radicals afford the corresponding biaryls in
very good yields. This method works selectively, and yields are better than those from similar,
previously described methods. Arylboronic acids carrying sensitive functional groups also work
efficiently.
In tr od u ction
synthesis uses arenediazonium ions in an aqueous het-
erogeneous mixture of the aromatic reactant and base.4
The yields of this classical reaction are low for most cases,
possibly related to the instability of arenediazonium salts
in the reported reaction conditions, where many compet-
ing reactions are probably taking place. Beadle et al.
developed a phase-transfer GB (PTGB) reaction, and
under their conditions the yields are greatly improved.5
Patrick et al. reported that aryltriazenes react with
aromatic solvents in the presence of trifluoroacetic acid
to produce biaryls via aryl radicals.6 Although the yields
approach those of the PTGB reaction in some cases, the
PTGB reaction is far better.
C-C bond-forming reactions leading to biaryls are very
important because this approach is the key step in the
synthesis of many natural and unnatural biaryls. There
are various biaryl coupling methods, and the applications
of these methods are reviewed comprehensively in the
literature.1 In the classical Ullmann reaction, arylhalides
are reacted with copper, forming the corresponding
biaryls. The original Ullmann reaction employs high
temperatures and is greatly affected by the nature of the
substituents and the steric environment. An ambient-
temperature variant of this reaction was developed and
has been used by many researchers.2 Catalytic coupling
reactions are also well-known in biaryl synthesis, the four
most commonly used being the Kharasch, Negishi, Stille,
and Suzuki reactions.1d,3 Today, catalytic coupling reac-
tions are a routine means of access to biaryls in labora-
tories. In these catalytic coupling methods, the course of
the reaction is determined by the position of the func-
tional group specific to the method employed so that
perfect regioselective coupling is possible. Thus, the
selectivity of the coupling site is now reduced to the
introduction of that functional group into the desired
coupling position.
Manganese(III) acetate is a one-electron oxidant, largely
used as a radical generator. Since the pioneering work
of Heiba et al. and Bush et al. in 1968,7 manganese(III)-
mediated oxidations have been extensively studied. Fris-
tad et al. showed that the rate of radical generation with
manganese(III) acetate with bridging acetates correlates
with the enolizability and CH acidity of the substrates.8
Thus, it is this reagent’s ability to generate radicals in
such systems that leads to highly efficient C-C bond-
forming reactions, especially for the construction of cyclic
systems, a topic reviewed by Snider.9 We recently showed
that arylhydrazines can be efficiently oxidized by man-
ganese(III) acetate to produce aryl radicals that afford
biaryls in benzene with very good yields.10 Although the
Another common method for the synthesis of simple
unsymmetrical biaryls is the generation of aryl radicals
in the presence of aromatic solvents. Although the
product range of this approach is somewhat limited, it
provides an easy access to a variety of unsymmetrical
biaryls. The classical Gomberg-Bachmann (GB) biaryl
(4) (a) Gomberg, M.; Bachmann, W. J . Am. Chem. Soc. 1924, 46,
2339. (b) Bachmann, W. E.; Hoffman, R. A. Org. React. (N.Y.) 1944, 2,
224.
(5) Beadle, J . R.; Korzeniowsky, S. H.; Rosenberg, D. E.; Garcia-
Slanga, B. J .; Gokel, G. W. J . Org. Chem. 1984, 49, 1596.
(6) Patrick, T. B.; Willaredt, P. R.; DeGonia, D. J . J . Org. Chem.
1985, 50, 2232.
(7) (a) Bush, J . B.; Finkenbeiner, H. J . Am. Chem. Soc. 1968, 90,
5903. (b) Heiba, E. I.; Dessau, R. M.; Koehl, W. J . J . Am. Chem. Soc.
1968, 90, 5905.
(8) (a) Fristad, W. E.; Peterson, J . R. J . Org. Chem. 1985, 50, 10.
(b) Fristad, W. E.; Hershberger, S. S. J . Org. Chem. 1985, 50, 1026.
(c) Fristad, W. E.; Peterson, J . R.; Ernst, A. B. J . Org. Chem. 1985,
50, 3143.
* To whom correspondence should be addressed. Phone: +90-312-
2103242. Fax: +90-312-2101280.
(1) (a) Bringman, G.; Weirich, R.; Walter, R. Angew. Chem., Int. Ed.
Engl. 1990, 29, 977. (b) Sainsbury, M. Tetrahedron 1980, 36, 3327. (c)
Lloyd-Williams, P.; Giralt, E. Chem. Soc. Rev. 2001, 30, 145. (d)
Hassan, J .; Sevignon, M.; Gozzi, C.; Schulz, E.; Lemaire, M. Chem.
Rev. 2002, 102, 1359.
(2) (a) Miyano, S.; Shimizu, K.; Sato, S.; Hashimoto, H. Bull. Chem.
Soc. J pn. 1985, 58, 1346. (b) Ziegler, F. E.; Fowler, K. W. J . Org. Chem.
1976, 41, 1564. (c) Zhang, S.; Zhang, D.; Liebiskind, L. S. J . Org. Chem.
1997, 62, 2312.
(9) Snider, B. B. Chem. Rev. 1996, 96, 339.
(10) Demir, A. S.; Reis, O¨ .; O¨ zgu¨l-Karaaslan, E. J . Chem. Soc.,
Perkin Trans. 1 2001, 30, 3042.
(3) Stanforth, S. P. Tetrahedron 1998, 54, 263.
10.1021/jo026466c CCC: $25.00 © 2003 American Chemical Society
Published on Web 12/14/2002
578
J . Org. Chem. 2003, 68, 578-580

Synthesis of Biaryls and Heterobiaryls
TABLE 1. Yield s of Bia r ylsa
arylboronic
acid, R
biaryl,
yield (%)
PTGB
yield (%)
arylhydrazine
yield (%)
mp
(°C)
lit. mp
(°C)
entry
solvent
1
2
3
4
5
6
7
8
1a , H
1b, 2-Br
1c, 3-Br
1d , 4-Br
1e, 2-OMe
1f, 3-OMe
1g, 4-OMe
1h , 2-CHO
1i, 3-CHO
1j, 4-CHO
1a , H
1b, 2-Br
1c, 3-Br
1d , 4-Br
1e, 2-OMe
1f, 3-OMe
1g, 4-OMe
1h , 2-CHO
1i, 3-CHO
1j, 4-CHO
1a , H
1b, 2-Br
1c, 3-Br
1d , 4-Br
1e, 2-OMe
1f, 3-OMe
1g, 4-OMe
1h , 2-CHO
1i, 3-CHO
1j, 4-CHO
benzene
benzene
benzene
benzene
benzene
benzene
benzene
benzene
benzene
benzene
thiophene
thiophene
thiophene
thiophene
thiophene
thiophene
thiophene
thiophene
thiophene
thiophene
furan
2a , 95
2b, 90
2c, 89
2d , 80
2e, 82
2f, 85
2g, 84
2h , 40
2i, 60
2j, 80
6a , 73
6b, 74
6c, 77
6d , 75
6e, 70
6f, 55
6g, 66
6h , 50
6i, 67
6j, 73
7a , 62
7b, 55
7c, 63
7d , 67
7e, 36
7f, 32
7g, 34
7h , 19
7i, 24
7j, 27
62
81
75
70
73
81
NR
NR
83
NR
NR
NR
70
65
68
54
NR
NR
62
NR
NR
NR
60
53
60
65
NR
NR
30
NR
NR
NR
68-69
oil
oil
695
NR
81
NR
NR
80
NR
NR
73
90
905
895
oil
oil14a
90
oil14b
oil14c
58-59
42
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
6013a
43
42-435
NR
NR
56
oil14d
oil11
99
99-1005
106-10710
67-6813b
NR
NR
NR
NR
NR
NR
NR
NR
NR
55
NR
NR
NR
NR
NR
NR
oil14e
oil14f
105
oil14g
oil14h
66
oil14i
oil11
oil14j
85
furan
furan
furan
furan
furan
furan
furan
furan
85-865
oil
oil14f
36
37-3810
41-4213b
oil14k
oil
furan
40-41
a
Yields are isolated except for 7e. The presence and yield of compound 7e were determined by GC-MS, but we were unable to isolate
the pure compound from the complex crude mixture. New compound 7i gave satisfactory analytical data (Experimental Section). All
other compounds are known (2b, 2c, and 2e are commercially available), and all analytical data are in agreement with previously reported
data.14 NR: not reported.
reaction is very efficient in benzene, it generally produces
the corresponding heterobiaryls in furan and thiophene
with moderate to good yields.11
stirred at room temperature, and the reaction was
monitored by GC-MS and TLC. The progress of the
reaction was so slow that only a small amount of product
could be detected after 24 h. Refluxing of the same
reaction mixture quickly furnished the biphenyl in 30
min with an almost quantitative yield (Table 1, entry 1).
We examined a variety of arylboronic acids 1a -j (Table
1, entries 1-10) and observed that biaryls 2a -j can be
prepared in very good yields by the reaction of arylboronic
acids with manganese(III) acetate in benzene (eq 1). The
yields are generally better than those from similar
reactions reported previously. This shows that arylbo-
ronic acids are suitable substrates for the generation of
aryl radicals. Products were obtained as a single isomer
showing that the initial radical that forms does not
isomerize as reported previously for the PTGB reaction5
and the oxidation of arylhydrazines:10 the unpaired
electron is attached to the carbon that originally bore the
leaving functionality.
This drawback of arylhydrazines prompted us to find
a more suitable substrate as the source of aryl radicals.
A suitable candidate for this reaction should be much
more reactive than arylhydrazinium salts under the
reaction conditions yet stable enough to handle easily and
not prone to side reactions. It is known that arylboronic
acids decompose to aryl radicals in the presence of some
oxidants.12 Arylboronic acids are widely used as the
organometallic counterpart in the Suzuki reaction. They
are stable under atmospheric and aqueous conditions
such that Suzuki coupling can be carried out with
aqueous organic solvents.
Therefore, we decided to investigate the oxidation of
arylboronic acids with manganese(III) acetate in aromatic
solvents. Herein we report the synthesis of a variety of
unsymmetrical biaryls with in situ generated aryl radi-
cals from arylboronic acids with manganese(III) acetate.
Resu lts a n d Discu ssion
First, we examined the reaction of various arylboronic
acids with manganese(III) acetate in benzene. A mixture
of manganese(III) acetate and phenylboronic acid was
Formylphenylboronic acids were reacted similarly to
other arylboronic acids with careful monitoring of the
reaction mixture by TLC and GC-MS. We observed that
the corresponding formylbiphenyls 2h -j were formed in
very good yields (Table 1, entries 8-10) without any
oxidation products. Therefore, we showed that aryl
(11) Demir, A. S.; Reis, O¨ .; Emrullahoglu, M. Tetrahedron 2002, 58,
8055.
(12) Riant, O.; Samuel, O.; Flessner, T.; Taudien, S.; Kagan, H. B.
J . Org. Chem. 1997, 62, 6733.
J . Org. Chem, Vol. 68, No. 2, 2003 579

Demir et al.
radicals can be generated efficiently from formylphenyl-
boronic acids for the synthesis of the formylbiphenyls 3,
which are valuable starting materials for a variety of
important targets such as benzoins or pinacols.
boronic acid in bromobenzene afforded 49%, 30%, and
21% isomers, results very similar to those obtained from
the oxidation of phenylhydrazinium chloride in bromo-
benzene where the O isomer predominates, but there is
no substantial selectivity. 4-OMe-phenylboronic acid in
bromobenzene shows a very similar distribution of iso-
mers: 54%, 29%, and 17%. This observation is in agree-
ment with the product distribution of the formation of
aryl radicals by a substitution reaction of aryl radicals
with arenes.
We also examined the reaction of arylboronic esters.
Phenylboronic acid and 2-formylphenylboronic acid were
converted to the corresponding esters with 1,3-pro-
panediol with the azeotropic removal of water in benzene.
The 2-formylphenylboronic acid ester was unreactive in
our reaction conditions, but the reaction of phenylboronic
acid furnished biphenyl in 15% yield after 72 h of reflux.
Therefore, the boronic acid esters seem to be unreactive
toward manganese(III) acetate-mediated oxidation. The
low-yield conversion of the phenylboronic acid ester to
the biphenyl can be attributed to the slow hydrolysis of
the ester, which in turn yields the reactive phenylboronic
acid. This observation may find application in manga-
nese(III) acetate-mediated synthesis as a protection or
deprotection tool and for the controlled generation of aryl
radicals from arylboronic acids.
As seen in Table 1, the generation and subsequent
trapping of aryl radicals in heterobiaryl solvents have
been reported to give lower yields than the corresponding
reactions in benzene. Therefore, we examined the oxida-
tion of arylboronic acids 1a -j in thiophene (4; entries
11-20) or furan (5; entries 20-30). The arylation of furan
and thiophene occurred with moderate to good yields and
exclusively in the 2 position to furnish 6a -j and 7a -j
(eq 2). Yields were lower than those for the reactions
In conclusion, we showed that a variety of radicals can
be generated from the corresponding arylboronic acids.
In the presence of organic solvents, these radicals afford
the monosubstituted biaryls with yields generally higher
than those from similar previously reported reactions.
Reactions in benzene gave higher yields than those in
thiophene or furan; the former was better in terms of
yield. Possible applications and extensions of this study
are now under investigation.
Exp er im en ta l Section
Typ ica l P r oced u r e for Bia r yls. To a mixture of manga-
nese(III) acetate15 (330 mg, 1.24 mmol Mn(OAc)3‚2H2O) in 10
mL of benzene was added phenylboronic acid (50 mg, 0.41
mmol), and the resulting mixture was refluxed for 30 min
(formation of the products was monitored by TLC and GC-
MS). After the completion of the reaction, the mixture was
filtrated through a pad of silica using hexane or petroleum
ether as the eluent. Concentration under reduced pressure
furnished the biphenyl 2a (62 mg, 95%, solid), confirmed by
NMR, IR, and GC-MS.
2-(3-F or m ylp h en yl)fu r a n (7i): yield 24%, colorless oil; 1H
NMR (400 MHz, CDCl3) δ 6.49 (1H, dd, J ) 3.3, 1.7 Hz), 6.74
(1H, d, J ) 3.3 Hz), 7.49 (1H, d, J ) 1.7 Hz), 7.53 (1H, dd, J
) 7.7, 7.6 Hz), 7.74 (1H, d, J ) 7.6 Hz), 7.90 (1H, d, J ) 7.7
Hz), 8.14 (1H, s), 10.1 (1H, s); 13C NMR (100 MHz, CDCl3) δ
106.6, 112.2, 125.2, 128.6, 129.5, 129.7, 132.2, 137.3, 143.0,
152.9, 191.8. Anal. Calcd for C11H8O2: C, 76.73; H, 4.68.
Found: C, 76.64; H, 4.61.
Ack n ow led gm en t . Financial support from the
Middle East Technical University (BAP-2002), the
Scientific and Technical Research Council of Turkey
(TUBITAK), the Turkish Academy of Science, and the
Turkish State Planning Organization (DPT) is gratefully
acknowledged.
carried out in benzene, as expected, based on previous
reports by us and others.5,6,10 Although there was a good
improvement of the yields in thiophene with the use of
arylboronic acids instead of arylhydrazines, they were
just comparable for the furan and below satisfactory.
That shows us that, although arylboronic acids are more
suitable for the generation of aryl radicals, furan is not
as compatible as thiophene in the manganese(III) acetate-
mediated synthesis that results in comparable or lower
yields in furan. However, arylboronic acids furnished the
corresponding heterobiaryls with higher yields than did
PTGB. Formylphenylboronic acids were also studied
under the same reaction conditions, and it was observed
that they gave the corresponding formylheterobiaryls but
the yields were lower than those of benzene and below
satisfactory for furan.
J O026466C
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(15) The manganese(III) acetate used in this study is commercially
available or, alternatively, can be synthesized from manganese(II)
nitrate/acetic anhydride and dried over P2O5 under vacuum prior to
use.
To clarify the radical nature of the reaction, phenyl-
boronic acid and 4-OMe-phenylboronic acid were reacted
with manganese(III) acetate in bromobenzene. Phenyl-
580 J . Org. Chem., Vol. 68, No. 2, 2003