Tert-butoxide-mediated arylation of benzene with aryl halides in the presence of a catalytic 1,10-phenanthroline derivative

Article abstract of DOI:10.1021/ja1080822

Sodium tert-butoxide mediates the coupling of aryl halides with benzene derivatives without the aid of transition metal catalysts but with a catalytic 1,10-phenanthroline derivative.

Full text of DOI:10.1021/ja1080822

Published on Web 10/20/2010
tert-Butoxide-Mediated Arylation of Benzene with Aryl Halides in the
Presence of a Catalytic 1,10-Phenanthroline Derivative
Eiji Shirakawa,* Ken-ichi Itoh, Tomohiro Higashino, and Tamio Hayashi*
Department of Chemistry, Graduate School of Science, Kyoto UniVersity, Kyoto 606-8502, Japan
Received September 7, 2010; E-mail: shirakawa@kuchem.kyoto-u.ac.jp; thayashi@kuchem.kyoto-u.ac.jp
Table 1. Arylation of Benzene with p-Tolyl Iodidea
Abstract: Sodium tert-butoxide mediates the coupling of aryl
halides with benzene derivatives without the aid of transition metal
catalysts but with a catalytic 1,10-phenanthroline derivative.
Homolytic aromatic substitution (HAS) with aryl radicals, namely
addition of aryl radicals to benzene derivatives followed by
elimination of a hydrogen radical, is one of the most straightforward
methods to construct biphenyl frameworks.1 However, its utility
has been hampered by laborious procedures for generation of aryl
radicals. Aromatic compounds such as arenediazonium salts and
diaroyl peroxides having an Ar-X bond that readily undergoes
homolytic cleavage are efficient precursors but are not always easily
accessible.1a,2 Use of readily available aryl halides as aryl radical
precursors requires a stoichiometric amount of a radical source such
as Bu3SnH and (Me3Si)3SiH1d,3 or special conditions such as
irradiation.4 A transition metal catalyst in combination with an aryl
halide has recently been introduced as a radical source.5 Here we
found that the coupling of aryl halides with benzene derivatives is
mediated by sodium tert-butoxide with the aid of a catalytic 1,10-
phenanthroline derivative through an HAS mechanism.6
Treatment of 4-iodotoluene (1a: 1 equiv) with NaOt-Bu (2 equiv)
and 1,10-phenanthroline (phen: 20 mol %) in benzene (2a: 120
equiv) at 155 °C7 for 3 h gave 4-methylbiphenyl (3a) in 72% yield
(entry 1 of Table 1).8 The coupling proceeded at a lower temperature
though a longer reaction period is required (entries 2 and 3). Use
of a reduced amount of NaOt-Bu resulted in a slow rate, and no
reaction took place without a base (entries 4-6). A comparable
yield of 3a was obtained with the more basic KOt-Bu, whereas
weaker bases were much less effective (entries 7-11). No coupling
product was obtained in the reaction with no ligands or other types
of bidentate sp2- or sp3-nitrogen ligands (entries 12-14). Phenan-
throlines that have nitrogen atoms at 1,7- or 4,7-positions were
totally ineffective (entries 15 and 16). Substitution of phen with
two phenyl groups at 4- and 7-positions (Ph-phen) increased the
yield (entry 17), whereas the substitution at 2,9-positions or
introduction of methyl groups resulted in much lower yields with
lower activities (entries 18 and 19). Ph-phen was found to be more
active than phen, and the reaction was completed in 6 h with a
reduced amount (10 mol %) (entries 20-22).9
temp
(°C)
time
(h)
conv
(%)b
yield
(%)b
entry
base (equiv)
ligand (mol %)
1
2
3
4
5
6
7
8
NaOt-Bu (2)
NaOt-Bu (2)
NaOt-Bu (2)
NaOt-Bu (1.5)
NaOt-Bu (1.5)
-
KOt-Bu (2)
LiOt-Bu (2)
NaOH (2)
phen (20)
phen (20)
phen (20)
phen (20)
phen (20)
phen (20)
phen (20)
phen (20)
phen (20)
phen (20)
phen (20)
-
155
130
130
155
155
155
155
155
155
155
155
155
155
155
155
155
155
155
155
155
155
155
3
3
48
3
12
3
3
3
3
3
3
3
3
3
3
3
3
3
3
>99
30
>99
43
>99
2
>99
23
13
8
72
21
73
32
74
<1
67
7
9
2
10
11
12
13
14
15
16
17
18
19
20
21
22
Na2CO3 (2)
Bu3N (2)
<1
<1
<1
1
<1
<1
<1
82
12
22
26
37
80c
3
NaOt-Bu (2)
NaOt-Bu (2)
NaOt-Bu (2)
NaOt-Bu (2)
NaOt-Bu (2)
NaOt-Bu (2)
NaOt-Bu (2)
NaOt-Bu (2)
NaOt-Bu (2)
NaOt-Bu (2)
NaOt-Bu (2)
<1
16
10
10
<5
>99
26
44
40
58
>99
bpy (20)
TMEDA (20)
1,7-phen (20)
4,7-phen (20)
Ph-phen (20)
Ph-phen′ (20)
Me-phen (20)
phen (10)
Ph-phen (10)
Ph-phen (10)
3
3
6
a The reaction was carried out under a nitrogen atmosphere using
4-iodotoluene (1a: 0.225 mmol) and benzene (2a: 2.4 mL, 27 mmol) in
a sealed tube. b Determined by GC. c Isolated yield ) 76%.
reactivity of aryl halides: p-phenylphenyl bromide and p-
cyanophenyl chloride underwent the coupling in 12 and 6 h,
respectively (entries 12 and 13). p-Bromo(iodo)benzene was
selectively phenylated at the iodo moiety (entry 14). A chloro
moiety was intact under standard conditions (entry 15). p-
Diiodobenzene underwent double phenylation (entry 16).10
In HAS, which consists of aryl radical generation, its addition
to an arene, and hydrogen radical (or H+ + e-) abstraction, both
electron-donating and -withdrawing substituents on a benzene
ring accelerate the addition of aryl radicals especially to its ortho-
positions.1 The result that regioisomeric mixtures with a high
ortho ratio were obtained in the reaction of 1a with substituted
benzenes (entries 17-19 of Table 2)11 prompted us to consider
The arylation of arenes is applicable to various aryl and
heteroaryl halides (Table 2). Aryl and heteroaryl iodides of
various electronic character reacted with benzene to give biaryls
in moderate to high yields (entries 1-8). p-Tolyl bromide (1a′)
reacted slower than iodide 1a but scored a comparable yield
(entries 9 and 10). The reaction of 1a′ using KOt-Bu instead of
NaOt-Bu proceeded much faster, but the yield of 3a was lower
(50%) due to coproduction of 3- and 4-(tert-butoxy)toluenes
derived from the aryne intermediate (entry 11). Introduction of
a conjugating or electron-withdrawing group enhanced the
9
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C O M M U N I C A T I O N S
Table 2. Arylation of Arenes with Aryl Halidesa
Scheme 1. Competition Reaction between Arenes
temp
(°C)
time
(h)
yield
(%)b
ratio of
o/m/pc
entry
Ar-X (1)
R in 2
prod
1
2
3
4
5
6
7
8
Ph-I
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
155
155
155
155
155
155
155
155
155
155
155
155
155
155
155
155
182
182
6
6
6
6
6
6
6
6
6
48
6
12
6
6
6
12
6
6
65
82
76
80
71
75
72
69
13d
80
50f
79
75
73h
80
77j
73
68
51
s
3b
3c
3d
3e
3f
3g
3h
3i
3a
3a
3a
3j
p-MeOC6H4-I
m-MeOC6H4-I
p-CF3C6H4-I
p-NCC6H4-I
3-pyridyl-I
s
s
s
s
s
s
s
s
s
s
s
s
s
s
s
Scheme 2. Involvement of Aryl Radical Intermediates
2-pyridyl-I
3-thienyl-I
9
p-MeC6H4-Br
p-MeC6H4-Br
p-MeC6H4-Br
p-PhC6H4-Br
p-NCC6H4-Cl
p-BrC6H4-I
p-ClC6H4-I
10
11e
12
13
14g
15
16i
17i
18i
19
3f
3k
3l
p-IC6H4-I
3j
p-MeC6H4-I
p-MeOC6H4-I
p-MeC6H4-I
CN
CN
OMe 178
58/17/25 3m
56/16/28
59/26/15
3n
3o
6
a The reaction was carried out under a nitrogen atmosphere using an
aryl halide (1: 0.225 mmol), an arene (2: 27 mmol), NaOt-Bu (0.450
mmol), and 4,7-diphenyl-1,10-phenanthroline (Ph-phen: 0.023 mmol) in
15 and 16 of Table 1) also implies the importance of chelate
coordination.
Use of KOt-Bu having a higher basicity than NaOt-Bu in the
reduction of 1a (Scheme 2) scored a comparable yield, whereas 4
was not obtained at all using the less electron-rich LiOt-Bu, showing
a correlation with the base effect in the coupling reaction. The
coupling of p-tolyl bromide (1a′) proceeded much faster with KOt-
Bu than NaOt-Bu though with a lower yield (cf. entries 9 and 11
of Table 1). These results are consistent with the SET mechanism,
where a tert-butoxide as a single electron donor shows higher ability
with higher electron density.
According to the mechanism involving aryl radical generation
through SET, more electron-deficient aryl halides must have higher
reactivities.13a A competition reaction of aryl iodides described in
Scheme 3 shows that a more electron-deficient aryl iodide
selectively reacts with benzene. Conjugating and electron-
withdrawing substituents make aryl bromides and even chlorides
sufficiently reactive in the coupling reaction (entries 12 and 13 of
Table 2).
c
a sealed tube. b Isolated yield based on 1. Determined by H NMR and
GC. d Conv ) 18%. e KOt-Bu was used instead of NaOt-Bu. f A 1:1
mixture of 3- and 4-(tert-butoxy)toluene was produced in 18% yield.
g NaOt-Bu (0.338 mmol) was used. h p-Terphenyl also was produced in
2% yield. i NaOt-Bu (0.675 mmol) was used. j The yield of p-terphenyl.
The yield of 4-iodobiphenyl was estimated by GC to be less than 1%.
1
that the coupling proceeds through HAS. The result that both
benzonitrile and anisole coupled with p-tolyl iodide (1a)
preferentially over benzene in a competition reaction between
these arenes (Scheme 1) is consistent with the HAS mecha-
nism.12
Aryl halides are known to be transformed to aryl radicals via
radical anions [Ar-X]•- upon reaction with a single electron
donor,13 whereas metal tert-butoxides are reported to act as
single electron donors toward alkyl iodides, ketones, and
polynuclear aromatic hydrocarbons.14 Treatment of 1a with
NaOt-Bu (20 equiv) and Ph-phen (1 equiv) at 100 °C for 20 h
in THF-d8 gave a 79% yield of 4-deuteriotoluene (4) (Scheme
2), implying that a tolyl radical is generated by reaction of 1a
with NaOt-Bu to abstract a deuterium radical from THF-d8. The
low conversion (2%) in the absence of Ph-phen indicates that
Ph-phen is essential for the radical generation. Phenanthroline
derivatives, which are highly conjugated and thus have a low-
lying LUMO, are known to accept single electron transfer
(SET).15 Assuming that they act as SET mediators that receive
an electron to form radical anions and then pass the electron to
aryl halides, we can understand the marked difference in
efficiency in the coupling reaction between 1,10-phenanthroline
(phen) and 2,2′-bipyridyl (bpy) in spite of their structural
similarity (cf. entries 1 and 13 of Table 1) in addition to the
improvement of the ability of phen with the introduction of two
phenyl groups (cf. Table 1: entries 1 and 17; entries 20 and 21).
The large decrease in efficiency by the introduction of phenyl
groups to 2- and 9-positions of phen is possibly ascribed to
insufficient complexation with NaOt-Bu for steric reasons.16 The
result that 1,7- and 4,7-phenanthrolines, which have similar
reduction potentials to phen,15 were totally ineffective (entries
A plausible mechanism is shown in Scheme 4.17 SET from NaOt-
Bu-Ph-phen complex 5 to Ar-I (1) gives radical anion 6, which
is transformed to aryl radical 7 to add to benzene, giving
cyclohexadienyl radical 8. Single electron oxidation of 8 by radical
cation 9 gives cation 10, which is deprotonated by t-BuO- to give
coupling product 3 and t-BuOH.18 Complex 11 (or free phen) reacts
with NaOt-Bu to regenerate complex 5.
In HAS with aryl radicals, the addition step giving relatively
stable 8 is considered to be fast and irreversible.1b Scheme 1
Scheme 3. Competition Reaction between Aryl Iodides
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C O M M U N I C A T I O N S
shows that substituted benzenes more readily accept the addition
of aryl radicals than benzene but their overall reaction rates are
lower,19 showing that the addition step is not the rate-determining
step. The aryl radical generation step also is unlikely to be the
rate-determining step except in the reaction of aryl halides of
low reactivity such as p-tolyl bromide (1a′) because the overall
reaction rates are not reflected by the reactivities of aryl iodides
as shown in Scheme 3. To clarify which is the rate-determining
step among the last two steps, we conducted the competition
reaction between C6H6 (60 equiv) and C6D6 (60 equiv) in Scheme
5. The observed low KH/KD value (1.07) implies that the rate-
determining step does not contain C-H bond cleavage. Thus,
the rate-determining step is the single electron oxidation from
8 to 10 but not deprotonation from 10 to give 3. This result
excludes an alternative pathway, which involves C-H bond
cleaving hydrogen radical abstraction as a single step transfor-
mation from 8 to 3.
References
(1) For reviews of HAS with aryl radicals, see: (a) Bolton, R.; Williams, G. H.
Chem. Soc. ReV. 1986, 15, 261–289. (b) Fossey, J.; Lefort, D.; Sorba, J.
Free Radicals in Organic Chemistry; John Wiley and Sons: Chichester,
1995; Chapter 14, pp 166-180. (c) Studer, A.; Bossart, M. In Radicals in
Organic Synthesis; Renaud, P.; Sibi, M. P., Eds.; Wiley-VCH; Weinheim,
2001; Vol. 2, Chapter 1.4, pp 62-80. (d) Bowman, W. R.; Storey, J. M. D.
Chem. Soc. ReV. 2007, 36, 1803–1822.
(2) (a) Smith, M. B.; March, J. March’s AdVanced Organic Chemistry, 6th
ed.; John Wiley and Sons: Hoboken, NJ, 2007; Chapter 13, pp 924-926
(arenediazonium salts) and Chapter 14; pp 980-981 (diaroyl peroxides).
Arenediazonium salts are effectively used as aryl radical precursors for
arylation of arenes having various substituents under mild conditions. (b)
Wetzel, A.; Ehrhardt, V.; Heinrich, M. R. Angew. Chem., Int. Ed. 2008,
47, 9130–9133.
(3) Curran, D. P.; Keller, A. I. J. Am. Chem. Soc. 2006, 128, 13706–13707.
(4) For a review, see: Sharma, R. K.; Kharasch, N. Angew. Chem., Int. Ed.
Engl. 1968, 7, 36–44.
(5) (a) Fujita, K.; Nonogawa, M.; Yamaguchi, R. Chem. Commun. 2004, 1926–
1927. For a review, see: (b) Alberico, D.; Scott, M. E.; Lautens, M. Chem.
ReV. 2007, 107, 174–238.
(6) The coupling of aryl halides with π-deficient N-heteroarenes but not with
benzene derivatives has been reported to be promoted by KOt-Bu under
microwave irradiation. Yanagisawa, S.; Ueda, K.; Taniguchi, T.; Itami, K.
Org. Lett. 2008, 10, 4673–4676.
Scheme 4. A Plausible Mechanism
(7) The reaction was conducted in a 35 mL oven-dried pressure-resistant tube
(Ace Pressure Tube, Ace Glass 864807, available via Aldrich). Heating
the reaction mixture at a temperature (bath temperature ) 185 °C) above
the boiling point of the solvent (benzene: 80 °C) causes some pressure
and, consequently, reduces the temperature in the tube to 155 °C.
(8) As byproducts, toluene (7%) and five isomers of dimethylterphenyls (5%)
resulting from the tolylation of 3a were formed. The formation of 4,4′-
dimethylbiphenyl was not observed. The reaction using a reduced amount
(10 equiv) of benzene gave 3a (25%), toluene (18%), the dimethylterphenyls
(five isomers: 10%), and 4,4′-dimethylbiphenyl (3%) with full conversion
of 1a. All the yields were determined by GC, GC-MS, and 1H NMR.
(9) Recently, Charette reported the same type of reaction catalyzed by Fe(II)
at a lower temperature (80 °C). Valle´e, F.; Mousseau, J. J.; Charette, A. B.
J. Am. Chem. Soc. 2010, 132, 1514–1516. Our reaction system (entry 22
of Table 1) did not promote the coupling of 1a with 2a at 80 °C. ICP-AES
and/or -MS analysis showed that the contents of transition metals (Fe, Co,
Ni, Cu, Ru, Rh, Pd, Ag, Ir, Pt, Au) in NaOt-Bu and Ph-phen are less than
0.05 ppm except for Fe (1.0 ppm) and Cu (0.18 ppm) in NaOt-Bu.
(10) The reaction of 1a with pyrazine (30 equiv) and NaOt-Bu (2 equiv) in the
presence (10 mol%) or absence of Ph-phen at 100 °C for 12 h gave 2-(p-
tolyl)pyrazine in a yield (conv) of 63% (>99%) or 7% (16%), respectively.
(11) For the coupling of benzonitrile, an increased amount of NaOt-Bu was
used to compensate loss from its reaction with the nitrile moiety.
(12) Similar selectivities were observed also in competition reactions between
2a and 2b as well as 2a and 2c. For details, see Supporting Information.
(13) (a) Fossey, J.; Lefort, D.; Sorba, J. Free Radicals in Organic Chemistry;
John Wiley and Sons: Chichester, 1995; Chapter 15, pp 181-189. (b)
Bunnett, J. F. Acc. Chem. Res. 1978, 11, 413–420.
Scheme 5. KIE Experiment
(14) (a) Ashby, E. C.; Goel, A. B.; DePriest, R. N. J. Org. Chem. 1981, 46,
2429–2431. (b) Ashby, E. C.; Argyropoulos, J. N. J. Org. Chem. 1986,
51, 3593–3597.
(15) Millefiori, S. J. Heterocycl. Chem. 1970, 7, 145–149.
(16) Upon mixing of Ph-phen and NaOt-Bu (1:4) in C6D6, changes (ppm) of
1
their chemical shifts in H NMR were observed: for Ph-phen, H2/9.13 to
9.06, H3/7.07 to 7.14, and H5/7.63 to 7.61; for NaOt-CMe3/1.28 to 1.45.
(17) After the reaction giving 3a under similar conditions of entry 22 of Table
1, 74% of Ph-phen was recovered, implying that it acts as a catalyst rather
than an initiator. See Supporting Information for details.
(18) t-BuO• is considered to oxidize cyclohexadienyl radicals to arenes. (a)
Bowman, W. R.; Bridge, C. F.; Brookes, P.; Cloonan, M. O.; Leach, D. C.
J. Chem. Soc., Perkin Trans. 1 2002, 58-68. (b) Beckwith, A. L. J.; Bowry,
V. W.; Bowman, W. R.; Mann, E.; Parr, J.; Storey, J. M. D. Angew. Chem.,
Int. Ed. 2004, 43, 95–98.
(19) The reaction of 1a (1.0 equiv) with 2b or 2c (120 equiv) under the same
conditions as entry 20 of Table 1 (155 °C, 6 h) gave 3m or 3o in 40% or
5% yield (85% or 19% conversion of 1a), respectively.
(20) Very recently, a report on KOt-Bu-mediated arylation of benzene with aryl
iodides in the presence of a catalytic N,N'-dimethylethylenediamine
appeared. Liu, W.; Cao, H.; Zhang, H.; Zhang, H.; Chung, K. H.; He, C.;
Wang, H.; Kwong, F. Y.; Lei, A. J. Am. Chem. Soc. doi: 10.1021/ja103050x.
In conclusion, we have disclosed that the coupling of aryl halides
with benzene derivatives is mediated by NaOt-Bu with the aid of
a catalytic phenanthroline derivative through a homolytic aromatic
substitution mechanism involving aryl radical intermediates.20
Acknowledgment. We are grateful to Ms. Yuki Yamamoto,
Mr. Mitsuru Harada, Dr. Kenji Kitayama, and Mr. Ikuo Takahashi
(Daicel Chemical Industries, Ltd.) for ICP analysis.
Supporting Information Available: Experimental procedures and
characterization data for all the products. This material is available free
of charge via the Internet at http://pubs.acs.org.
JA1080822
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J. AM. CHEM. SOC. VOL. 132, NO. 44, 2010 15539