Manganese(III) acetate-mediated synthesis of biaryls under microwave irradiation

Article abstract of DOI:10.1016/j.tet.2009.12.018

Manganese(III) acetate (Mn(OAc)₃)-mediated synthesis of biaryls and heterobiaryls starting from arylboronic acid was developed under microwave irradiation in high yields. Microwaves were also used for the synthesis of Mn(OAc)₃ from KMnO₄ and acetic acid. Additional irradiation of this in situ generated Mn(OAc)₃ with arylboronic acids, which in turn furnished the biaryls in high yields in a one pot reaction. This is superior from the point of view of yield, short reaction time, sensitive functional group toleration, and more environmentally friendly than the reported methods with a minimum amount of benzene and thiophene as a reagent but not as a solvent.

Full text of DOI:10.1016/j.tet.2009.12.018

Tetrahedron 66 (2010) 1308–1312
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Manganese(III) acetate-mediated synthesis of biaryls under microwave irradiation
,
a
b
a
Ayhan S. Demir a , Hamide Findik , Nezire Saygili , N. Tuna Subasi
*
a Department of Chemistry, Middle East Technical University, Inonu Bulvari, 06531 Ankara, Turkey
b Faculty of Pharmacy, Hacettepe University, 06100 Ankara, Turkey
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 3 June 2009
Received in revised form 16 November 2009
Accepted 4 December 2009
Available online 22 December 2009
Manganese(III) acetate (Mn(OAc)3)-mediated synthesis of biaryls and heterobiaryls starting from aryl-
boronic acid was developed under microwave irradiation in high yields. Microwaves were also used for
the synthesis of Mn(OAc)3 from KMnO4 and acetic acid. Additional irradiation of this in situ generated
Mn(OAc)3 with arylboronic acids, which in turn furnished the biaryls in high yields in a one pot reaction.
This is superior from the point of view of yield, short reaction time, sensitive functional group toleration,
and more environmentally friendly than the reported methods with a minimum amount of benzene and
thiophene as a reagent but not as a solvent.
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
In our previous work, we developed a general method for the
synthesis of biaryls starting from arylhydrazines/aromatic solvents
Metal-promoted radical reactions have found widespread use in
organic synthesis, in which one of the well-known examples of this
application is the Mn(OAc)3-mediated reaction.1 Manganese(III)
acetate dihydrate (Mn(OAc)32H2O)-mediated free-radical reactions
have emerged as important synthetic methods for a new bond
formation as well as bond breaking. The application of Mn(OAc)3
promoted free-radical reactions in numerous regio-, chemo-, and
stereoselective carbon–carbon, carbon–heteroatom bond forma-
tions have been developed in both inter- and intramolecular reac-
tions.2a–c
Biaryls are an important class of organic compounds, since the
biaryl unit is represented in natural products, advanced materials,
and molecules of medicinal interest. There are various biaryl cou-
pling methods, in which the applications of these methods have
been reviewed comprehensively in the literature.3 Catalytic cou-
pling reactions3c,4 are commonly used methods for the formation of
C–C bonds in turn leading to biaryls. The Suzuki–Miyaura pro-
tocol4,5 is one of those catalytic methods wherein arylboronic acids
are used as a reaction partner and where the position of the boronic
acid functional group determines the course of the reaction
regioselectively in order to yield aryl- and heterobiaryls.6
Another common method for the synthesis of simple un-
symmetrical biaryls is the generation of aryl radicals in the pres-
ence of aromatic solvents. Mn(OAc)3 is a one-electron oxidant and
is generally used to generate radicals that lead to C–C bond forming
reactions.2c
and arylboronic acids/aromatic solvents in the presence of
Mn(OAc)3. We showed, for the first time, that Mn(OAc)3 is a versa-
tile reagent for the generation of aryl radicals from arylhydrazines
and arylboronic acids.7
The potassium permanganate and acetic acid method were also
developed for aryl coupling reactions. The reaction of arylboronic
acids and arylhydrazines in benzene with potassium permanganate
and acetic acid in turn furnished biaryls in 85–96% yield. We have
shown that the potassium permanganate/carboxylic acid/organic
solvent combination behaves as manganese(III)acetate. This system
is also applied to an aryl coupling reaction, in which aryl coupling
products are obtained in good yield (Scheme 1).7
Mn(OAc)3, C6H6
OH
OH
B
heat
R
R
or
2
1
KMnO4/AcOH,C6H6
heat
Scheme 1.
As we have described in our previous papers,8 microwave irra-
diation has been widely used as a powerful and easily controllable
heating source for organic reactions. Furthermore, the use of mi-
crowave ovens in organic synthesis is an alternative green tech-
nology for heating. Reactions conducted under microwave usually
have short reaction times, high yields and better selectivities.9 The
heating effect, that is, utilized in microwave-assisted organic
transformations is due to the dielectric constant of the solvent. It is
particularly convenient that, qualitatively, the larger the dielectric
constant of the reaction medium, the greater the coupling with
microwaves.10
* Corresponding author. Tel.: þ90 312 210 3242; fax: þ90 312 210 3200.
E-mail address: asdemir@metu.edu.tr (A.S. Demir).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.12.018

A.S. Demir et al. / Tetrahedron 66 (2010) 1308–1312
1309
In the course of our studies on biaryl systems,6,7 we decided to
Table 1
Mn(OAc)3-mediated synthesis of biaryls
investigate the reaction of arylboronic acids with Mn(OAc)3 and
benzene as well as the KMnO4/acetic acid system under microwave
irradiation. Herein, we report the microwave-assisted synthesis of
a variety of unsymmetrical biaryls with in situ generated aryl rad-
icals from arylboronic acids/Mn(OAc)3 system.
Product
Yield (%)
Yield (%) lit., mp ꢀC (lit.)
Mn(OAc)3 KMnO4/AcOH/
benzene system
96, 69–73 (69–72)7a
2. Results and discussion
91
90
1a
In an initial reaction, which is shown in Scheme 2, to a mixture
of Mn(OAc)3 and 500 mg of zeolite (montmorilloite K10) in 5 mL
benzene was added to arylboronic acid. This solution was stirred
under different microwave conditions, such as 200-, 400-, 600-,
and 800-W irradiation, in which the reaction is monitored by TLC.
After all of the starting material is consumed (30 min), the product
is isolated after a work up procedure. The best yield (91%) is
obtained under the 600–800-W conditions (30 min). We examined
a variety of aryl- and hetero-arylboronic acids and observed that
biaryls 1–18 can be prepared in very good yields by the reaction of
arylboronic acid with manganese(III) acetate in benzene under
microwave irradiation (Scheme 2). These microwave yields are in
some cases better than those from similar reactions that were
reported previously.7
F
85
78
90
84
99, 56–5812
F
2a
95, oil7a
F3CO
3a
Mn(OAc)3, C6H6
OH
OH
B
MW
R
R
or
84
87
100, 91–93 (92–93)13,14
2
1
KMnO4/AcOH,C6H6
MW
Br
4a
Scheme 2.
The same reaction was also performed with the KMnO4/AcOH/
benzene system. First, the KMnO4/AcOH/benzene mixture was
mixed with zeolite and irradiated under microwave (20–30 min).
After the purple color of the mixture transformed into brown,
arylboronic acid is added and the irradiation is continued (30 min).
The products are obtained with similar yields with the Mn(OAc)3
case as summarized in Table 1. Formylphenylboronic acids were
reacted similarly to other arylboronic acids with careful monitoring
of the reaction mixture by TLC. We observed that the corresponding
formylbiphenyls were formed in good yields. Therefore, we showed
that aryl radicals can be generated efficiently from for-
mylphenylboronic acids for the synthesis of the formylbiphenyls,
which are valuable starting materials for a variety of important
targets, such as benzoins or pinacols,11 most of the compounds are
protected. We also examined the reaction of arylboronic esters.
Phenylboronic acid is converted to the corresponding esters with
1,3-propanediol with the azeotropic removal of water in benzene.
The reaction of phenylboronic acid ester furnished biphenyl in 5–
6% yield. Therefore, the boronic acid esters seem to be unreactive
toward MW assisted manganese(III) acetate 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 manganese(III) acetate-mediated synthesis as a pro-
tection or deprotection tool and for the controlled generation of
aryl radicals from arylboronic acids, which is not easily applicable
by using other methods.
81
80
95 (oil)13,15
Br
5a
89
91
90 (oil)13,14
Br
6a
87
93
61 (oil)16
CH3
7a
76
75
90 (oil)7a
OCH3
8a
For the synthesis of biaryls under microwave irradiation heter-
oaromatic compounds were also tried, such as furan, thiophene,
and pyrimidine. Among these aromatic compounds, thiophene and
pyrimidine gave biaryls with high yields but in the furan case,
significant amounts of side products were formed and we could not
obtain the desired product in acceptable yields.
92
98
85 (oil)17
OCH3
9
The reaction proceeds independent of the substituents of the
arylboronic acid and hetero-arylboronic acids. Both arylboronic
(continued on next page)

1310
A.S. Demir et al. / Tetrahedron 66 (2010) 1308–1312
acids with electron withdrawing and electron donating groups at
Table 1 (continued)
the ortho-, para- and meta- positions gave corresponding biaryls in
excellent yields. This method tolerates sensitive groups and no
isomerization in the arylboronic acid part is detected, but the
changing of the benzene to substituted derivatives furnished
a mixture of isomeric products. Similar results were also obtained
with heating methods.7d
Product
Yield (%)
Yield (%) lit., mp ꢀC (lit.)
Mn(OAc)3 KMnO4/AcOH/
benzene system
The progress of the reaction under microwave irradiation was so
rapid that all of the reactions went to completion in a short time.
71
77
60, 53–54 (semisolid)18
CHO
3. Conclusion
10a
A rapid and efficient method for the manganese(III) acetate-
mediated synthesis of biaryls and heterobiaryls has been developed
under microwave irradiation. Microwaves are also used for the
synthesis of Mn(OAc)3 from KMnO4 and acetic acid, and additional
irradiation with arylboronic acids, which in turn furnished biaryls
in high yields. This is superior from the point of view of yield, short
reaction time, tolerates sensitive functional groups, and is more
environmentally friendly than the reported methods. The boronic
acid esters seem to be unreactive toward MW assisted Mn(OAc)3
oxidation. Benzene and thiophene are not used as a solvent but
rather as a reagent in very low amounts.
81
88
87 (oil)17
11
N
75
91
73
95
56, semisolid (54)19,20
N
4. Experimental section
4.1. General
12
S
1H and 13C NMR spectra were obtained on Bruker Avance DPX
400 spectrometers at 300 MHz. All of the resonances are referenced
to the residual solvent signals (CDCl3 for 1H NMR; CDCl3 for 13C
NMR). Elemental analyses: Leco CHNS 932 Analyzer (Central lab-
oratory from Hacettepe university and METU). The IR spectra were
obtained on Bruker IFS 66/s. Column chromatography was con-
ducted on silica gel 60 (40–63 mm). TLC was carried out on alu-
minum sheets that were pre-coated with silica gel 60F254 (Merck),
79, oil20,21
CH3
13
S
92
82
92
90
88
95
70, oil (34–35)22,23
in which the spots were visualized with UV light (l 254 nm). Mi-
crowave reactions are carried out with Milestone start MW.
14
S
4.2. General procedure for the synthesis of biaryls with
Mn(OAc)3
d
F3CO
To a solution of Mn(OAc)3 (680 mg, 0.3 mmol) and 500 mg of
zeolite in 5 mL benzene–AcOH (20:1) or thiophene–AcOH was
added to 0.1 mmol of arylboronic acid. This solution was stirred
under 800-W microwave radiation (30 min). The reaction is mon-
itored by TLC. After all the starting material is consumed, the re-
action mixture was diluted with 50 mL ether and neutralized with
NaHCO3 (10% solution). The resulting organic phase was dried over
MgSO4 and concentrated under vacuum. If necessary, the crude
products were purified by column chromatography by using
EtOAc–hexane as an eluent. In most cases, the direct filtering of the
reaction mixture was conducted through a pad of silica provided
pure products.
15
S
F
d
F
16
S
N
N
78
81
92, 77–79 (77–78)24,25
4.3. General procedure for the synthesis of biaryl via the
KMnO4/acetic acid system under microwave radiation
17
KMnO4 (47 mg, 0.3 mmol) and 500 mg of zeolite in 5 mL ben-
zene–AcOH (20:1) or thiophene–AcOH was stirred under 800-W
microwave radiation until the color of the solution turned brown.
To this solution 0.1 mmol of arylboronic acid was added and stirred
under 800-W microwave radiation (30 min). The reaction was
monitored by TLC. After all of the starting material was consumed,
the reaction mixture was diluted with ether (50 mL) and neutral-
ized with NaHCO3 (10% solution). The resulting organic phase was
S
62
65
d
MeO
H
O
18
a
Commercially available compound.

A.S. Demir et al. / Tetrahedron 66 (2010) 1308–1312
1311
dried over MgSO4 and concentrated under vacuum. If necessary, the
crude products were purified by column chromatography by using
flash silica gel, EtOAc–hexane (1:10) as an eluent.
J¼7.5 Hz, 2H), 7.56–7.67 (m, 1H), 8.96 (s, 2H), 9.21 (s, 1H); dC
(100 MHz CDCl3) 126.8, 129.1, 129.5, 134.2, 134.3, 154.8, 157.3.
4.3.13. 2-o-Tolylthiophene (13)20,21. Yield (16.5 mg, 95%), colorless
oil. dH (400 MHz CDCl3) 2.45 (s, 3H), 7.06–7.10 (m, 1H), 7.08–7.12 (m,
1H), 7.24–726 (m, 3H), 7.33–7.37 (m, 1H), 7.39–7.44 (m, 1H); dC
(100 MHz CDCl3) 21.1, 124.09, 125.8, 126.6, 127.2, 127.9, 130.6, 134.2,
136.1, 143.2.
4.3.1. Biphenyl (1)7a. Yield (13.8 mg, 90%), white solid; mp 69–
73 ꢀC (lit. 69–72 ꢀC). dH (400 MHz CDCl3) 7.31–7.36 (m, 2H), 7.42–
7.47 (m, 4H), 7.55–7.60 (d, 4H); dC (100 MHz CDCl3) 127.2, 127.3,
128.8, 141.2.
4.3.2. 3,5-Difluorobiphenyl (2)12. Yield (19.1 mg, 90%), yellow oil. dH
(400 MHz CDCl3) 6.76 (1H, tt, J¼8.8, 2.0 Hz), 7.14 (2H, dd, J¼8.8,
2.4 Hz), 7.41 (1H, t, J¼7.2 Hz), 7.47 (2H, t, J¼7.2 Hz), 7.54 (2H, d,
J¼7.2 Hz); dC (100 MHz CDCl3) 102.5 (t, J¼100 Hz), 110.1 (dd, J¼18,
6 Hz), 127.1, 128.6, 129.2, 139.2, 144.6 (t, J¼10 Hz), 163.5 (dd, J¼247,
13 Hz).
4.3.14. 2-Phenylthiophene (14)22,23. Yield (14.4 mg, 90%), yellow oil
(lit.17 mp 34–35 ꢀC). dH (400 MHz CDCl3) 7.12–7.14 (m, 1H), 7.28–
7.34 (m, 1H), 7.35–7.38 (m, 1H), 7.42–7.46 (m, 3H), 7.69–7.71 (m,
2H); dC (100 MHz CDCl3) 123.1, 124.6, 125.7, 127.5, 128.2, 128.7,
134.2, 144.4.
4.3.15. 2-(4-Trifluoromethoxyphenyl)thiophene (15). Yield (19.5 mg,
88%), brown solid; mp¼72.5–75.3 ꢀC. IR (CHCl3): 3120–3080, 1620,
4.3.3. 4-Trifluoromethoxybiphenyl (3)7a. Yield (20 mg, 84%), white
solid; mp 57–59 ꢀC (lit. 56–58 ꢀC). dH (400 MHz CDCl3), 7.18 (d,
J¼8.6 Hz, 2H, CH), 7.27 (t, J¼7.4 Hz, 1H, CH), 7.33 (d, J¼7.4 Hz, 2H,
CH, CH), 7.45 (t, J¼7.4 Hz, 2H, CH, CH), 7.48 (t, J¼8.6 Hz, 2H, CH, CH);
dC (100 MHz CDCl3) 121.2, 127.2, 127.6, 128.5, 128.8, 139.9, 140.2,
148.6.
1525 cmꢁ1
.
dH (400 MHz CDCl3) 6.98 (t, J¼4.2 Hz, 1H, CH), 7.13–7.32
(m, 4H, CH), 7.52 (d, J¼8.6, 2H,); dC (100 MHz CDCl3) 121.3, 121.4,
123.6, 125.3, 126.1, 127.2, 127.7, 128.0, 133.3, 142.8, 148.5. Anal. Calcd
for C11H7F3OS (244.23): C, 54.09; H, 2.89. Found: C, 54.27; H, 3.12.
4.3.16. 2-(3,5-Difluorophenyl)thiophene (16). Yield (95, 18.6 mg),
4.3.4. 4-Bromobiphenyl (4)13,14. Yield (20.2 mg, 87%), white solid;
mp 91–93 ꢀC (lit. 92–93 ꢀC). dH (400 MHz CDCl3) 7.35–7.39 (m, 1H),
7.42–7.51 (m, 2H), 7.60–7.68 (m, 6H); dC (100 MHz CDCl3) 121.6,
126.9, 127.6, 128.7, 128.8, 131.9, 140.1, 140.3.
brown oil; IR (CHCl3): 3118–3092, 1616, 1522 cmꢁ1
. dH (400 MHz
CDCl3) 6.57–6.63 (m, CH, 1H), 6.95–7.02 (m, CH, 3H,), 7.20 (2H, d,
J¼5.2 Hz, CH); dC (100 MHz CDCl3) 102.5 (t, JCF¼24.7 Hz), 108.8 (dd,
JCF1¼7.5, JCF2¼18.5 Hz), 121.7, 124.4, 126.0, 126.7, 128.1, 137.5 (t,
JCF¼9.9 Hz), 141.9, 163.4 (dd, JCF1¼247, JCF2¼12.6 Hz). Anal. Calcd for
C10H6F2S (196.22): C, 61.21; H, 3.08. Found: C, 61.11; H, 3.22.
4.3.5. 2-Bromobiphenyl (5)13,15. Yield (18.6 mg, 80%), colorless oil.
dH (400 MHz CDCl3)
d 7.12 (m, 1H, Ar), 7.26 (m, 2H, Ar), 7.33 (t,
J¼7.0 Hz,1H, Ar), 7.36 (m, 4H, Ar), 7.59 (d, J¼7.2 Hz,1H); dC (100 MHz
4.3.17. 5-(Thiophen-2-yl)pyrimidine (17)24,25. Yield (13.1 mg, 81%),
white solid; mp 77–79 ꢀC (lit.18 77.2–78.1 ꢀC). dH (400 MHz CDCl3)
7.16–7.20 (m, 1H), 7.42–7.44 (m, 1H), 7.45–7.47 (m, 2H), 8.97 (s, 1H),
9.14 (s, 1H); dC (100 MHz CDCl3) 125.3, 127.1, 128.5, 128.6, 136.1,
153.5, 157.3.
CDCl3) 122.5,127.3,127.5,127.8,128.9,129.2,131.3,133.1,141.1,142.3.
4.3.6. 3-Bromobiphenyl (6)13,14. Yield (21.2 mg, 91%), colorless oil.
dH (400 MHz CDCl3) 7.28–7.69 (m, 8H), 7.77 (s, 1H); dC (100 MHz
CDCl3) 122.9, 125.8, 127.1, 127.9, 128.9, 130.2, 130.3, 139.7, 143.4.
4.3.18. 2-Methoxy-5-thiophene-2-yl-benzaldehyde (18). Yield
4.3.7. 2-Methylbiphenyl (7)16. Yield (15.6 mg, 93%), colorless oil. dH
(400 MHz CDCl3), 2.34 (s, 3H), 7.28–7.32 (m, 4H), 7.36–7.41 (m, 3H),
7.46–7.51 (m, 2H); dC (100 MHz CDCl3) 20.4, 125.8, 126.6, 127.1,
128.1, 128.8, 129.1, 129.6, 130.3, 135.2, 141.8.
(14.18 mg, 65%), green oil; IR (CHCl3): 3210–3075, 1695, 1616,
1533 cmꢁ1
. dH (400 MHz CDCl3) 3.89 (3H, s, CH3), 6.90–6.98
(2H, m, CH), 7.15–7.19 (2H, m, CH), 7.67 (1H, dd, J1¼2.5,
J2¼8.7 Hz, CH), 7.96 (1H, d, J¼2.5 Hz, CH), 10.39 (1H, s, CH); dC
(100 MHz CDCl3) 54.4, 110.9, 121.8, 123.5, 123.9, 124.6, 126.6,
126.9, 131.9, 141.7, 159.9, 187.6. Anal. Calcd for C12H10O2S
(218.27): C, 66.03; H, 4.62. Found: C, 66.19; H, 4.44.
4.3.8. 2-Methoxybiphenyl (8)7a. Yield (13.8 mg, 75%), colorless oil.
dH (400 MHz CDCl3) 3.86 (s, 3H), 7.04 (d, J¼8.6 Hz, 1H), 7.08 (t,
J¼7.5 Hz, 1H), 7.41–7.35 (m, 3H), 7.47 (t, J¼8.0 Hz, 2H), 7.59 (d,
J¼7.9 Hz, 2H); dC (100 MHz CDCl3)
d 55.6, 111.3, 120.8, 126.7, 127.8,
128.6, 129.6, 130.8, 130.9, 138.5, 156.5.
Acknowledgements
The financial support from the Scientific and Technical Research
Council of Turkey (TUBITAK), the Turkish Academy of Sciences
(TUBA), the Turkish State Planning Organization, and the Middle
East Technical University is gratefully acknowledged.
4.3.9. 3-Methoxybiphenyl (9)17. Yield (15.7 mg, 85%), colorless oil.
dH (400 MHz CDCl3) 3.84 (s, 1H), 6.90–6.93 (m, 1H), 7.15–7.23 (m,
2H), 7.35–7.49 (m, 4H), 7.61–7.65 (m, 2H); dC (100 MHz CDCl3) 55.5,
112.6, 113.1, 119.6, 127.2, 127.4, 128.8, 129.8, 141.1, 142.8, 161.0.
References and notes
4.3.10. Biphenyl-3-carbaldehyde (10)18. Yield (12.3 mg, 77%), col-
orless semisolid (lit.7d mp 53–54 ꢀC). dH (400 MHz CDCl3) 7.22(m,
1H), 7.34 (m, 2H), 7.51 (m, 3H), 7.77 (m, 2H), 8.03 (m, 1H), 9.88 (s,
1H); dC (100 MHz CDCl3) 127.2, 127.8, 128.6, 129.3, 129.4, 129.7,
133.4, 136.5, 137.2, 137.3, 191.2.
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(100 MHz CDCl3) 125.5, 125.8, 126.1, 127.2, 127.5, 127.9, 128.4, 130.2,
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