Such BHAS type biarylations can be conducted inter-7
and intramolecularily.8 Herein, we wish to report that
phenyl hydrazine can efficiently initiate the BHAS of
unactivated arenes under relatively mild reaction condi-
tions at a low initiator loading.
its derivatives are valuable candidates. Phenyl hydrazines
were chosen as initiators for the following two reasons: (a)
due to the R-effect exerted by the lone pairs of the adjacent
nitrogen atoms hydrazines are good electron transfer
agents and (b) the hydrazinyl radicals resulting from the
initial electron transfer are stabilized via a two-center
three-electron bond configuration (compare with the sta-
bility of a N-oxyl radical).
The reaction between m-iodotoluene (1a) and benzene
(2a) was chosen as a model cross-coupling for our inves-
tigations (Table 1). The initial experiment using 10 mol %
ofPhNHNH2 (I-1) asthe initiatorand t-BuOK (3 equiv) as
the base afforded the desired product 3a in an encouraging
42% yield along with 31% of unreacted starting material
1a (entry 1). The yield did not improve upon increasing the
amount of hydrazine to 40 mol % (entries 2, 3). Interest-
ingly, GC-MS analysis of the crude reaction mixture
revealed the formation of toluene and at a higher initiator
loading formation of this side product became even more
prominent.
Scheme 1. Base Promoted Biaryl Synthesis via Homolytic
Aromatic Substitution
BHAS reactions are generally performed at high tem-
perature using a large amount of a ligand. The amine
ligand is supposed to be involved in the initiation step
which is currently not well understood. A possibility is that
the ligated t-BuOK acts as an SET reducing reagent in the
initiation step. However, it is obvious that such a species is
not an ideal SET reducing reagent. A challenge in this field
is therefore to find a reagent that allows initiating the BHAS
reaction by single electron transfer (SET) to an aryl halide
ideally at low temperature and at low initiator loading.
Along these lines, we decided to investigate alcoholates
other than t-BuOK as initiators for the BHAS reaction
between m-iodotoluene (1a) and benzene (for details see
Supporting Information (SI)). These studies revealed that
the structure ofthe K-alcoholate does indeedhave aneffect
on the reaction outcome, but the tested alcoholates deliv-
ered similar or worse results than the well-established
t-BuOK (see SI).9
We hypothesized that reduction of the initially formed
aryl radical by H-abstraction from initiator I-1 to be
responsible for toluene formation. In order to suppress
this side reaction, we added the initiator I-1 (20 mol %)
within 6 h in four equal portions to keep its concentration
low. To our delight, the yield of 3a improved to 84%
(entry 4). A further increase in yield (88%) was achieved
upon adding the initiator I-1 over 6 h via syringe pump
(entry 5). The yield remained unaffected by decreasing the
initiator loading to 10 mol % (entry 6). We then screened
other phenyl hydrazine derivatives I-2, I-3, and I-4 as
initiators. While I-4 delivered 3a in a slightly lower yield
(78%, entry 9) as compared to the I-1-initiated reaction,
the reaction was not efficiently initiated with I-2 and I-3
(entries 7, 8). A further decrease in the amount of I-1 led to
an incomplete reaction, although the yield remained al-
most unaffected (entries 10, 11). Attempts to lower the
reaction temperature and decrease the amount of t-BuOK
were not fruitful (entries 12, 13). Moreover, extending
the time for phenyl hydrazine addition (slower addition
by syringe pump) also did not provide a better result
(entries 14, 15). Reaction in the absence of phenylhydra-
zine provided only 3% of biphenyl 3a documenting the
important role of the hydrazine for this transformation
(entry 16). To investigate the importance of the hydrazine
structural motif, we also tested diphenylamine as an
initiator and obtained only 6% of 3a under otherwise
identical conditions (not shown in the Table 1).
We therefore continued our studies by looking at other
potential initiators and assumed that phenyl hydrazine and
(7) (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.;
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With optimized conditions in hand (Table 1, entry 6),
we explored the scope of the process by reacting several
electronically and structurally diverse aryl iodides 1
with benzene (Table 2). Simple iodobenzene 1c, m- and
p-tolyl iodides (1a and 1b), p-phenyl-iodobenzene 1d,
and m-iodoxylene 1e underwent efficient coupling with
benzene to give the corresponding biaryls 3aÀe in high
yields (entries 1À5). Pleasingly, aryl iodides containing
both electron-donating and -withdrawing substituents
(9) During our studies an interesting report demonstrating that
simple alcohols such as n-BuOH act as efficient promoters for direct
BHAS-type CÀH arylations was disclosed (see ref 7j). However, in our
hands n-BuOH showed only a small positive effect (see SI).
(10) Bunnett, J. F.; Creary, X. J. Org. Chem. 1974, 39, 3611.
Org. Lett., Vol. XX, No. XX, XXXX
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