Room-temperature photoinduced direct C-H-arylation via base-promoted homolytic aromatic substitution

Article abstract of DOI:10.1021/ol3034687

Conceptually different approach toward biaryl syntheses by photoinduced direct C-H arylation of benzene and thiophene in the presence of t-BuOK is reported. The reaction proceeds through photo- and base-promoted homolytic aromatic substitution. The o-, m- and p- substituted ArI, as well as the electron-donating and electron-withdrawing nature of the substituents were found be good to excellent substrates. Heteroaryl, ArBr, ArCl and double C-H arylation were successfully achieved.

Full text of DOI:10.1021/ol3034687

ORGANIC
LETTERS
2013
Vol. 15, No. 6
1174–1177
Room-Temperature Photoinduced Direct
CꢀH-Arylation via Base-Promoted
Homolytic Aromatic Substitution
ꢀ
Marıa E. Buden, Javier F. Guastavino, and Roberto A. Rossi*
´
´
INFIQC, Departamento de Quımica Organica, Facultad de Ciencias Quımicas,
Universidad Nacional de Cordoba, X5000HUA Cordoba, Argentina
ꢀ
´
ꢀ
ꢀ
rossi@fcq.unc.edu.ar
Received December 18, 2012
ABSTRACT
Conceptually different approach toward biaryl syntheses by photoinduced direct CꢀH arylation of benzene and thiophene in the presence of
t-BuOK is reported. The reaction proceeds through photo- and base-promoted homolytic aromatic substitution. The o-, m- and p- substituted ArI,
as well as the electron-donating and electron-withdrawing nature of the substituents were found be good to excellent substrates. Heteroaryl, ArBr,
ArCl and double CꢀH arylation were successfully achieved.
Biaryl structural motifs are widely available in a variety
of natural products, drugs, and ligands for cross coupling
reactions catalyzed by transition metals. The synthesis of
biarylhas been known for more ofa centuryusing different
transition metal catalyzes. These reactions typically in-
volve either the coupling of an aryl halide or pseudohalide
with an organometallic reagent, or the homocoupling of
two aryl halides or two organometallic reagents.1 Many
transition metals have been successfully applied in the direct
arylation of arenes by CꢀH activation.2 However, these
reactions often require a ligand, base and high temperature.
New cheap, efficient and noncontaminant methodologies to
prepare these motifs are always of great interest.
Over recent years, there have been many reported synthe-
ses of biaryl compounds using homolytic aromatic substitu-
tions (HAS) mediated by Bu3SnH/AIBN, or (Me3Si)3SiH.3,4
Recently, an attractive alternative to the CꢀH arylation
of arenes using base-promoted HAS reactions has been
reported,5 which avoids the use of stoichiometric amounts of
tin or silicon reagents, initiators, or transition metals. In 2008,
it was shown that t-BuOK caused the addition reaction of
ArI and/or ArBr to pyridazine and other electron-poor
aromatic rings under elevated temperatures or MW irradia-
tion.6 Furthermore, the construction of biaryl com-
pounds from unactivated aromatic rings by direct CꢀH
activation using t-BuOK and DMEDA or 1,10-phenan-
throline as ligands was also reported.7 Nowadays, these
(1) (a) de Meijere, A.; Diederich, F. Metal-Catalyzed Cross-Coupling
Reactions, 2nd ed.; Wiley-VCH: Weinheim, 2004. (b) Johansson Seechurn,
C. C.; Kitching, M. O.; Colacot, T. J.; Snieckus, V. Angew. Chem., Int. Ed.
2012, 51, 5062.
(2) (a) Ritleng, V.; Sirlin, C.; Pfeffer, M. Chem. Rev. 2002, 102, 1731.
(b) Alberico, D.; Scott, M. E.; Lautens, M. Chem. Rev. 2007, 107, 174.
(c) Yamaguchi, J.; Yamaguchi, A. D.; Itami, K. Angew. Chem., Int. Ed.
2012, 51, 8960.
(3) For mechanism discussions, see: (a) Studer, A.; Bossart, M. In
Radicals in Organic Synthesis, 1st ed.; Renaud, P., Sibi, M. P., Eds.; Wiley-
VCH Verlag: Weinheim, 2001; Vol. 2, p 62. (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.
(4) (a) Bowman, W. R.; Storey, J. M. D. Chem. Soc. Rev. 2007, 36,
1803. (b) Curran, D. P.; Keller, A. I. J. Am. Chem. Soc. 2006, 128, 13706.
(5) (a) Studer, A.; Curran, D. P. Angew. Chem., Int. Ed. 2011, 50,
5018. (b) Shirakawa, E.; Hayashi, T. Chem. Lett. 2012, 41, 130.
(6) Yanagisawa, S.; Ueda, K.; Taniguchi, T.; Itami, K. Org. Lett.
2008, 10, 4673.
(7) (a) Liu, W.; Cao, H.; Zhang, H.; Chung, K. H.; He, C.; Wang,
H.; Kwong, F. Y.; Lei, A. J. Am. Chem. Soc. 2010, 132, 16737.
(b) Shirakawa, E.; Itoh, K.; Higashino, T.; Hayashi, T. J. Am. Chem.
Soc. 2010, 132, 15537. (c) Sun, C. L.; Li, H.; Yu, D. G.; Yu, M.; Zhou, X.;
Lu, X. Y.; Huang, K.; Zheng, S. F.; Li, B. J.; Shi, Z. J. Nat. Chem. 2010,
2, 1044.
r
10.1021/ol3034687
Published on Web 03/06/2013
2013 American Chemical Society

methodologies have been successfully extended to differ-
ent systems by intra8 and inter9 approaches.
(Table 1, expts. 1ꢀ6). Although other bases were also
screened, 1a was recovered quantitatively (Table 1, expts.
7ꢀ9). Moreover, the reaction without DMSO, but with
MeCN or in the presence of different ligands, did not give
3a at all (Table 1, expts. 10ꢀ14).14 PhBr (1b) only gave 30%
yield of 3a after 8 h of irradiation (Table 1, expt. 15).
The proposed base-promoted HAS mechanism is a
chain process with radicals and radical anions as inter-
mediates (Scheme 1). The initiation step is an electron
transfer (ET) to yield an [ArX]ꢀ. radical anion, which then
fragments to produce an [Ar] radical and an Xꢀ ion. The
We suggest that the formation of Ar and radical anions
3
3
[Ar] formed is able to couple to ZH moiety to give radical
are key steps (Scheme 1), which were supported by experi-
ments performed in the presence of the radical scavenger
(TEMPO) and a good acceptor electron such as m-dini-
trobenzene (m-DNB) which inhibited the reactions
(Table 1, expts. 16 and 17). In addition this reaction did
not occur in dark conditions (Table 1, expt. 18).
3
[ArZH] . This radical is deprotonated by the base to gen-
3
eratethe[ArZ]ꢀ. radical anion, and by an ET from [ArZ]ꢀ. to
the ArX provides the ArZ product and the [ArX]ꢀ. to
continue the chain process.10 The deprotonation step of
phenylcyclohexadienyl radical by t-BuOꢀ was calculated by
B3LYP-D/6-31þG* in the presence of a continuum solvent
(benzene) and is exothermic ca. ꢀ2.75 kcal.molꢀ1 11
.
Table 1. Photostimulated Reaction of 1aꢀb and 2a
Scheme 1. Base-Promoted HAS Mechanism
time
3a
Iꢀ
expt
base, additive
t-BuOK, DMSO
(h) (yield %)b (%)c
1d
2e
3
4
5
3
3
3
1
0.5
0.25
1
1
1
1
1
1
1
1
8
1
1
44
76
92
90
68
46
94
100
92
88
77
44
<7
<9
<9
<5
<9
<9
33
13
47
7
As t-BuOK can form [ArX]ꢀ. by ET in photostimulated
t-BuOK, DMSO
t-BuOK, DMSO
t-BuOK, DMSO
t-BuOK, DMSO
t-BuOK, DMSO
t-BuONa, DMSO
Et4N(OH), DMSO
KOH, DMSO
S
RN1 reactions,12 we speculated that the CꢀH arylation of
benzene could be achieved with only t-BuOK and light13 at
room temperature (rt), which would be a very promising
approach for clean, efficient, and cheap synthesis of biaryl
moieties.
We began this investigation with the reaction of PhI (1a)
with benzene (2), as a model system for the synthesis of
biphenyl 3a (Table 1).
6
7f
8g
9g
10g t-BuOK, none
11
12
13
14
t-BuOK, 19 equiv MeCN
t-BuOK, 0.2 equiv DMEDA
t-BuOK, 0.3 equiv 1,10-phenanthroline
t-BuOK, 0.4 equiv ethylene glycol
23
8
30
The best result was obtained in the photostimulated
reaction of 1a (1 equiv) with 2 (150 equiv), t-BuOK (3 equiv)
and DMSO (13 equiv), which after 1 h gave 90% yield of 3a
15h t-BuOK, DMSO
16g t-BuOK, DMSO, 0.3 equiv TEMPO
17g t-BuOK, DMSO, 0.3 equiv m-DNB
18g,i t-BuOK, DMSO
<5
<5
1
(8) (a) De, S.; Ghosh, S.; Bhunia, S.; Sheikh, J. A.; Bisai, A. Org. Lett.
2012, 14, 4466. (b) Roman, D. S.; Takahashi, Y.; Charette, A. B. Org.
Lett. 2011, 13, 3242. (c) Sun, C. L.; Gu, Y. F.; Huang, W. P.; Shi, Z. J.
Chem. Commun. 2011, 47, 9813. (d) Rueping, M.; Leiendecker, M.; Das,
A.; Poisson, T.; Bui, L. Chem. Commun. 2011, 47, 10629. (e) Bhakuni,
B. S.; Kumar, A.; Balkrishna, S. J.; Sheikh, J. A.; Konar, S.; Kumar, S.
Org. Lett. 2012, 14, 2838. (f) Wu, Y.; Wong, S. M.; Mao, F.; Chan, T. L.;
Kwong, F. Y. Org. Lett. 2012, 14, 5306.
(9) (a) Qiu, Y.; Liu, Y.; Yang, K.; Hong, W.; Li, Z.; Wang, Z.; Yao,
Z.; Jiang, S. Org. Lett. 2011, 13, 3556. (b) Yong, G. P.; She, W. L.;
Zhang, Y. M.; Li, Y. Z. Chem. Commun. 2011, 47, 11766. (c) Castro, S.;
Fernandez, J. J.; Vicente, R.; Fananas, F. J.; Rodriguez, F. Chem.
Commun. 2012, 48, 9089. (d) Chen, W. C.; Hsu, Y. C.; Shih, W. C.;
Lee, C. Y.; Chuang, W. H.; Tsai, Y. F.; Chen, P. P.; Ong, T. G. Chem.
Commun. 2012, 48, 6702. (e) Shirakawa, E.; Zhang, X.; Hayashi, T.
Angew. Chem., Int. Ed. 2011, 50, 4671. (f) Sun, C. L.; Gu, Y. F.; Wang,
B.; Shi, Z. J. Chem.;Eur. J. 2011, 17, 10844. (g) Ng, Y. S.; Chan, C. S.;
Chan, K. S. Tetrahedron Lett. 2012, 53, 3911. (h) Vakuliuk, O.;
Koszarna, B.; Gryko, D. T. Adv. Synth. Catal. 2011, 353, 925. (i) Liu,
H.; Yin, B.; Gao, Z.; Li, Y.; Jiang, H. Chem. Commun. 2012, 48, 2033.
(10) Stable biaryls radical anions transfer electrons to aryl halides
Cohen, T.; Bhupathy, M. Acc. Chem. Res. 1989, 22, 152.
a The photostimulated reaction was carried out under N2 atmo-
sphere using 1a (1 equiv, 0.5 mmol), t-BuOK (3 equiv), DMSO (0.5 mL,
13 equiv), and 2 (6.7 mL, 150 equiv) in a sealed tube. b Yields were
determined by GC (internal standard method). c Iꢀ ions were determined
potentiometrically. d 50 equiv of 2 and 70 equiv of DMSO were used.
e 100 equiv of 2 was used. f The substrate was recovered in 97% yield.
g The substrate was recovered quantitatively. h 1 equiv of PhBr
(1b, 0.25 mmol), 44 equiv of DMSO, and 5 equiv of t-BuOK were used.
i The reaction was carried out under dark conditions.
We next examined the substrate scope for this reaction,
and the best results obtained are shown in Table 2.11 The
o-, m- and p- substituted ArI with electron-donating and
electron-withdrawing groups were found be good to ex-
cellent substrates for the arylation and provided biaryls in
44ꢀ97% yields (Table 2, expts. 1ꢀ13). However, a prolonged
reaction time was necessary for o-substituted ArI (Table 2,
(11) For a full description, see the Supporting Information.
~ꢀ~
(12) (a) Rossi, R. A.; Pierini, A. B.; Penenory, A. B. Chem. Rev. 2003,
€
~ꢀ~
103, 71. (b) Schmidt, L. C.; Arguello, J. E.; Penenory, A. B. J. Org.
(14) It is proposed that DMSO solvates the t-BuOK and affords the
solvent-separated ion pair to act as an electron donor. However, it is
worth noting that a larger amount of DMSO gives lower yields due to
H-abstraction; see the Supporting Information.
Chem. 2007, 72, 2936.
(13) Irradiation was conducted in a photochemical reactor equipped
with two HPI-T 400 W lamps (cooled with water).
Org. Lett., Vol. 15, No. 6, 2013
1175

Table 2. Photostimulated Reaction of Substituted ArX with 2a
a The photostimulated reaction was carried out under N2 atmosphere using ArX (1, 1 equiv, 0.5 mmol), t-BuOK (3 equiv), DMSO (0.5 mL, 13 equiv)
and 2 (6.7 mL, 150 equiv) in a sealed tube. b Yields were determined by GC (internal standard method). c Isolated yield. d Xꢀ ions were determined
potentiometrically. e The substrate was recovered in 21% yield. f 1.2 equiv of t-BuOK was used. g 6 equiv of t-BuOK and 0.8 mL of DMSO were
used. h Naphthalene was obtained in 16% yield. i 0.7 mL of DMSO and 200 equiv of 2 were used and naphthalene was obtained in 10% yield. j 1 mL of
DMSO was used. k Phenanthrene was obtained in 23% yield. l 6 equiv of t-BuOK was used. m 0.7 mL of DMSO was used.
expts. 4 and 6). The photostimulated reaction of 2- (1p) and
3-iodopyridine (1q) gave excellent yields of the phenyl pyr-
idines 3p and 3q (Table 2, expts. 14 and 15).
benzo[b]thiophene (1v) and 6-chloroquinoline (1w), afforded
3v and 3w in 59% and 63% yields, respectively.
The behavior of the 1,3- and 1,4-halo-iodobenzenes
(4aꢀe) in a photostimulated reaction with 2 was studied
(Table 3). For 4-haloiodobenzene (4aꢀc), the arylation
product 3c was obtained in 60ꢀ74% yields (Expts. 1ꢀ4).
Although a similar result was obtained with 4d, in the case
of 4e the main product was 3-chlorobiphenyl (1y) with
71% of isolated yield, with 15% yield of m-terphenyl,
(5) (Expts. 5 and 6). It is remarkable that with these
halo-iodobenzenes bromide and chloride were as good
In contrast, ArBr and ArCl, which have π extended
systems, were reactive for CꢀH arylation. For example,
PhBr (1b) gave 30% yield of 3a in 8 h of irradiation
(Table 1, expt. 15), whereas 4-bromobiphenyl (1r), 1-bro-
monaphthalene (1s), 2-bromonaphthalene (1t), 9-bromo-
phenanthrene (1u) and 1-chloronaphthalene (1x) provided
the arylation product in very good yields under mild
conditions (Table 2, expts. 16ꢀ19 and 22). Finally, 3-bromo-
1176
Org. Lett., Vol. 15, No. 6, 2013

Table 3. Photostimulated Reaction of 4aꢀf with 2a
Scheme 2. Competing ET for the Radical Anions
Scheme 3. Photostimulated Reaction of ArX with Thiophene
a The photostimulated reaction was carried out for 1 h under a
N2 atmosphere using haloiodobenzenes (4, 1 equiv, 0.5 mmol), t-BuOK
(3 equiv), DMSO (0.6 mL), and2 (9 mL, 200 equiv) in a sealed tube. b Yields
were determined by GC (internal standard method). c Xꢀ ions were deter-
mined potentiometrically. d With 4 equiv of t-BuOK. e 21% yield of 1c and
9% yield of 3a were obtained. f Considering two iodines per mole. g Reaction
time: 3 h. h 3-Chlorobiphenyl (1y) was obtained in 71% isolated yield.
being obtained at excellent yields (Scheme 3). In this case,
4-iodoanisole (1g), 4-bromoiodobenzene (4b) and 2-bro-
monaphthalene (1t) were all successful.17
In summary, we have developed a conceptually different
approach toward the biaryl syntheses metal-free photo-
induced direct CꢀH arylation. Previous known catalysts
were not successful. This environmentally friendly metho-
dology effectively promoted the arylation of unactivated
arenes, suchasbenzene and thiophene, using a broadrange
of aryl and heteroaryl halides, including ArI, ArBr and
even ArCl at room temperature. Moreover, double CꢀH
bond arylation was successfully achieved to construct ex-
tended πꢀelectron systems. On the basis of our results, a
plausible chain mechanism with radicals and radical anions
as intermediates for this photoinduced reaction is proposed.
This reaction proceeds via photo ET to initiate the forma-
tion of an aryl radical. Due to the high reactivity of this a
large excess (150 equiv) of benzene (or arene) is required.
Further investigations to expand this novel method to a
broad number of substrates are underway in our laboratory.
leaving groups as iodine, except 4e. Moreover, 1,4-diiodo-
biphenyl (4f) reacted with 2 to provide the diarylation
product 6 in 61% isolated yield (Expt 7).
Taking into account these results and the mechanisms
illustrated in Scheme 1, the radical anion 7 was formed as
the intermediate (Scheme 2). This radical anion has two
possible ways. One of these is an ET intermolecular to give
halobiphenyl 8 (Path A). The other possibility is an ET
intramolecular to the C-X bond that after fragmentation
gives aryl radical 9, which finally provides 3c or 5 (Path B).
Indeed, the radical 9 can also be formed by a second ET
and fragmentation from 8 (Path C).
To demonstrate if 8 is an intermediate in the formation
of 9, we carried out the reaction at lower conversion.15
Even at short reaction times (15 min), at which the dihalo-
benzene is but partially reacted, only low percentages of
monosubstitution product 8 is observable alongside pre-
dominant disubstitution. Moreover, when 8 is p-bromobi-
phenyl (1r) only gives 31% yields of 3c after 60 min11
(compare with Table 3, expt. 3, 74% yield). These results
suggest that the rate of fragmentation in producing 9 was
faster than the intermolecular ET reaction to give 8, for all
the substrates, except 4e.16
Acknowledgment. This work was supported in part by
ꢀ
Agencia Cordoba Ciencia, CONICET, SeCyT, and FON-
CyT. M.E.B. and J.F.G. acknowledge receipt of fellow-
ships from CONICET.
Supporting Information Available. Experimental pro-
cedures, sample spectra, and compound characterization
data. This material is available free of charge via the
Internet at http://pubs.acs.org.
The metal-free photoinduced CꢀH arylation was also
effective for thiophene, with the corresponding products
(17) We tested the feasibility of CꢀH arylation of thiophene using a
known thermal transition-metal-free system. We observed a lower
reactivity and similar regioisomeric preference, favoring the CꢀH
coupling at the 2 position of thiophene; see the Supporting Information.
(15) Bunnett, J. F.; Creary, X. J. Org. Chem. 1974, 39, 3611.
(16) The rate of bond fragmentation of radical anions depends on the
nature of the halogen and on the spin density on the C-X. It is known
that 3-position of the biphenyl has a lower spin density than the
4-position. See: Pierini, A. B.; Vera, M. A. J. Org. Chem. 2003, 68, 9191.
The authors declare no competing financial interest.
Org. Lett., Vol. 15, No. 6, 2013
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