Efficient Pd-catalyzed direct arylations of heterocycles with unreactive and hindered aryl chlorides

Article abstract of DOI:10.1021/ol302635e

A highly electron-rich Pd complex can efficiently catalyze the direct arylation of heteroaromatics with unreactive and sterically congested aryl chlorides.

Full text of DOI:10.1021/ol302635e

ORGANIC
LETTERS
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Vol. XX, No. XX
000–000
Efficient Pd-Catalyzed Direct Arylations
of Heterocycles with Unreactive and
Hindered Aryl Chlorides
Debalina Ghosh and Hon Man Lee*
Department of Chemistry, National Changhua University of Education,
Changhua 50058, Taiwan, ROC
leehm@cc.ncue.edu.tw
Received September 24, 2012
ABSTRACT
A highly electron-rich Pd complex can efficiently catalyze the direct arylation of heteroaromatics with unreactive and sterically congested aryl
chlorides.
Heteroaromatic biaryls are important motifs in numerous
products and pharmaceutical drugs.1 The most commonly
used synthetic route to these biaryls, metal-catalyzed
Suzuki-type cross-coupling,2 requires stoichiometric orga-
nometallic substrates, which give rise to problems of metal
waste and extra synthetic steps. Recently, CÀH arylation3
has emerged as an effective approach for biaryl synthesis,
and successive improvements allow for the use of this
method to synthesize a broad range of heteroaromatic
biaryls.4 Nevertheless, one of the drawbacks of the existing
procedures is that the aryl halides (coupling partners) used
are limited to bromides and iodides; the less reactive but
inexpensive aryl chlorides have come into use only
recently.5 Most of these recently developed strategies
effectively aid the synthesis of heterocyclic biaryls from
aryl chlorides, but the established reaction conditions
are applicable only to certain heterocycle classes. In his
impressive work, Daugulis demonstrated the Pd-catalyzed
direct arylation of indoles, pyrroles, and furans with
electron-rich and electron-deficient aryl chlorides using
the Buchwald phosphine ligand.5c However, extensive
efforts had to be devoted to optimize the reaction condi-
tions for each substrate class, and high Pd (5 mol %) and
phosphine loading (10 mol %) was required. More re-
cently, Doucet reported that the use of a ferrocenyl dipho-
sphine ligand allows for the direct arylation of numerous
heteroaromatics, including oxazoles, benzofurans, indoles,
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r
10.1021/ol302635e
XXXX American Chemical Society

and pyrazoles, with aryl chlorides.6 While a low Pd loading
of 0.5 mol % is sufficient for this reaction, only activated
aryl chlorides can be used as coupling partners. The other
notable drawback of the existing biaryl synthesis method
based on direct arylation with aryl chlorides is that only a
small amount of steric bulk is tolerated on the chlorides.
That is, ortho-, meta- or 3,5-disubstituted chlorobenzenes
were successfully utilized in several cases,5aÀf but there
is hardly any report on the use of highly hindered aryl
chloride substrates as coupling partners, except for one
case where 2,6-dimethylchlorobenzene was successfully
made to react with a 1,2,3-triazole.5d Therefore, the search
for a catalyst system that helps in addressing these pro-
blems would be advantageous for industrial applications
of heteroaromatic biaryl synthesis.
products in moderate-to-excellent yields (Scheme 1). The
coupling reactions were highly regioselective, and in al-
most all the cases, only C5 arylated products were formed.
Hardly any modification of the reaction conditions was
required for different classes of heterocyclic substrates.
2-Acetylfuran bearing a C2 electron-withdrawing group
reacted with various aryl chlorides to afford the corre-
sponding 2-arylfurans in moderate-to-good yields (entries
1À7). In general, electron-rich aryl chlorides give higher
yields than do electron-deficient chlorides. Further, highly
electron deficient haloarenes bearing a nitro, cyano, or
acetyl group typically give low product yields.9 As shown
in entries 1À6, even such haloarenes readily reacted with
2-acetylfuran to afford the corresponding products in
synthetically useful yields. When using the electron-rich
3-chlorotoluene as the coupling partner, 2ag was obtained
in very good yield (89%, entry 7).
The coupling reactions also proceeded smoothly when
an electron-rich furan was used as the substrate (entries
9À12). The reaction of 2-n-butylfuran with the electron-
deficient 4-chlorotrifluoromethylbenzene and 4-chloro-
acetophenone afforded the coupled products 2ba and 2bd
in 62 and 48% yield, respectively (entries 9 and 10). These
yields, however, were markedly lower than those of 2aa
Herein, we discuss the Pd-catalyzed direct arylation of
heteroaromatics with aryl chlorides using a Pd(II) complex
1 bearing a functionalized N-heterocyclic carbene (NHC)
and a tricyclohexylphosphine (Figure 1).
Scheme 1. Direct Arylation of Heterocycles with Aryl Chloridesa
Figure 1. Pd(II) Complex 1 for CÀH arylation.
We chose 1 as the precatalyst because this robust and
highly electron-rich Pd(II) complex actively promotes aryl
CÀCl bond cleavage, thus showing excellent catalytic
activity in traditional CÀC cross-coupling reactions.7 For
aryl CÀH bond activation, we employed catalytic amounts
of pivalic acid, which has been shown to function as
a proton shuttle in the bond cleavage step.8 In the presence
of the aforementioned catalyst system and at a mild 2%
Pd loading, the reaction has broad substrate scope and
most notably, highly hinderedaryl chlorides can furnishthe
desired heteroaromatic biaryls in moderate-to-excellent
yields.
By considering Fagnou’s direct arylation procedure8
and screening the reaction parameters, we decided the
optimum reaction conditions: 1, 2 mol %; PivOH, 30 mol
%; K2CO3, 1.5 equiv; aryl chloride, 1.0 equiv; heterocycle,
1.2 equiv; solvent, DMAc; reaction temperature, 110 °C;
reaction time, 12À15 h. Under the optimized conditions, a
series of heterocyclic substrates reacted with aryl chlorides
having different electronic properties to furnish the biaryl
a Conditions (unless otherwise specified): heterocycle (1.2 mmol),
ArCl (1.0 mmol), K2CO3 (1.5 equiv), DMAc (2.5 mL), cat. (2.0 mol %),
PivOH (30 mol %), 110 °C, 12 h, isolated yield. b15 h.
(6) Roy, D.; Mom, S.; Royer, S.; Lucas, D.; Hierso, J.-C.; Doucet, H.
ACS Catal. 2012, 2, 1033.
(7) Liao, C.-Y.; Chan, K.-T.; Tu, C.-Y.; Chang, Y.-W.; Hu, C.-H.;
Lee, H. M. Chem.;Eur. J. 2009, 15, 405.
(8) (a) Lafrance, M.; Fagnou, K. J. Am. Chem. Soc. 2006, 128, 16496.
(b) Lapointe, D.; Fagnou, K. Chem. Lett. 2010, 39, 1118. (c) Ackermann,
L. Chem. Rev. 2011, 111, 1315.
ꢀ
(9) Liegault, B.; Lapointe, D.; Caron, L.; Vlassova, A.; Fagnou, K.
J. Org. Chem. 2009, 74, 1826.
B
Org. Lett., Vol. XX, No. XX, XXXX

(71%, entry 1) and 2ad (65%, entry 5) obtained from
2-acetylfuran. Entries 13À16 demonstrated that when
using the present catalyst system, protection/deprotection
of the hydroxyl group on the furan moiety can be
avoided.10 Thus, 2ci and 2ck could be obtained from the
corresponding hydroxy furans in much higher yields (71
and 68%, respectively) than those reported by Doucet (10
and 15%), who used simple Pd(OAc)2 and aryl bromides
as substrates.10
Direct arylation of 2-methylthiophene bearing a C2
electron-donating group followed essentially the same
trend. Both electron-rich and electron-deficient aryl chlo-
rides could be employed as coupling partners to furnish
2-arylthiophene in moderate-to-excellent yields (entries
17À24).
between benzothiophene with 4-bromobenzonitrile re-
sulted in poor yield with only a 15% conversion of the
starting material (entry 1). Under our optimized reaction
conditions and with the chloride analogue as the coupling
partner, the desired product 5b was obtained in 69%
isolated yield. Similarly, 5c and 5g were successfully pro-
duced from aryl chlorides (entries 2 and 3). The present
catalyst system was much more effective for the prepara-
tion of biheteroaryl motifs from chloropyridines than was
Fagnou’s protocol (entries 4À6). It should be noted that
equally effective catalyst systems for the Pd-catalyzed
direct arylation of heterocycles with nonsterically hindered
aryl chlorides have also been reported by Mori5i and
Daugulis.5b For example, Mori reported the same yield
of 5g using 2 mol % Pd(Pt-Bu)3 as catalyst. A biheteroaryl
compound similar to 5m was obtained in 72% yield from
the catalyst system reported by Daugulis using 5 mol %
Pd(OAc)2/P(Ad)2Bu (1:2) as catalyst.5b
The catalyst system was also highly effective for the
coupling reaction of sterically hindered aryl chlorides
(Table 1). 2-Acetylfuran, 2-n-butylfuran, 2-methyl thio-
phene and benzothiophene reacted smoothly with 2,6-
dimethylchlorobenzene to afford the biaryl products in
good-to-excellent yields (77À91%, entries1, 2, 4, 8). Under
our optimized reaction conditions, 2bo, which was pre-
viously prepared in relatively low yield (40%) by Doucet
via the Pd-catalyzed direct arylation with the more reactive
bromo analogue, was obtained in 84% yield.12 As opposed
to this, under our conditions, 2-methylthiophene and
2-chloro-1,3-dimethylbenzene, which bears two ortho
In the direct arylation of 1-methyl-2-formylpyrrole with
aryl chlorides, the aldehyde group was well tolerated, and
the coupled products 4ei and 4ek were obtained in good
yields (entries 26 and 27). The coupling procedure could
also be applied to produce biheteroaryl motifs. Thus, the
reaction between 2-acetylfuran and the heterocyclic aryl
chloride, 3-chloropyridine, proceeded smoothly to afford
2ah in 51% (entry 7). Similarly, coupling of 2-methylthio-
phene with 2-chloropyridine afforded 3dm in reasonable
yield (41%, entry 25).
The generality of the catalyst system for the coupling of
different heterocyclic substrates with aryl chlorides was
further manifested by its efficiency in the production of
challenging coupled products reported in the literature.
Preparation of several heteroaromatic biaryls by Fagnou’s
direct arylation protocol is well-known to be difficult.9
Scheme 2 shows some benzothiophene-based biaryls
Table 1. Direct Arylation of Heterocycles with Hindered Aryl
Chloridesa
Scheme 2. Direct Arylation of Benzothiophene with Aryl Halidesa
a Conditions (unless otherwise specified): same as Scheme 1. bConver-
sion of the limiting starting material, ref 9. c15 h.
producedinlow yieldsinpreviousstudies butinreasonable
yields in the present study. Kappe recently reported the
successful arylation of some of these unreactive hetero-
cyclic substrates with aryl bromides and heteroaryl
bromides.11 However our catalyst system allows for the
use of aryl chlorides as coupling partners in place of
bromide substrates. Fagnou reported that coupling
a Conditions (unless otherwise specified): same as Scheme 1. b 15 h.
ꢁ
(10) Roger, J.; Pozgan, F.; Doucet, H. Adv. Synth. Catal. 2010, 352,
696.
(11) Baghbanzadeh, M.; Pilger, C.; Kappe, C. O. J. Org. Chem. 2011,
76, 8138.
(12) Roy, D.; Mom, S.; Lucas, D.; Cattey, H.; Hierso, J.-C.; Doucet,
H. Chem.;Eur. J. 2011, 17, 6453.
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C

Scheme 3. Twofold CÀH Bond Arylation
Scheme 4. Competitive Experiments
methyl groups, could be coupled in the presence of 1 to
afford 3do in excellent yield (91%). To the best of our
knowledge, this is the first report on the use of 2,6-dimethyl-
chlorobenzene for the preparation of biaryls with furan and
thiophene. Entries 4À6 and 8À9 also indicated that 1 was
more effective than the preformed [IMesPd(OAc)(κ2-OAc)]
or in situ Pd(OAc)2/IMesHCl catalyst systems derived
from the typical NHC ligand of IMes.3h,i Other hindered
aryl chloride substrates such as 2-chloroanisole and 2-chloro-
toluene could also be employed in the coupling reaction
(entries 3, 7, 10).
Scheme 5. Kinetic Isotope Experiments
The new protocol could be extended to the synthesis of
triaryl compounds 6 and 7 from the unreactive 1,4-dichloro-
benzene (Scheme 3) as well. However, a higher Pd loading
of 5 mol % and higher reaction temperature (130 °C) were
required, and 6 and 7 were furnished in 67 and 63% yields,
respectively. This result was definitely encouraging since
previously, the extended system of 6 could be obtained
from only the expensive 1,4-diiodobenzene by Ir-catalyzed
direct arylation.13
Mechanistic investigations were performed to shed light
on the catalytic pathway. Although both 2aa and 2ba can
be obtained in good yields in individual reactions (vide
supra), the competitive experiment reveals that electron-
deficient heterocycle reacts preferentially over electron-
rich substrate, affording 2aa and 2ba in the ratio of 94:6
(Scheme 4a). Similarly, a product ratio of 68:32 in favor
of the electron-deficient heterocycle was obtained with the
sterically hindered 2-chloro-1,3-dimethylbenzene as cou-
pling partner (Scheme 4b). Using chloride substrates with
different electronic and steric properties, the kinetic iso-
tope experiments reveal similar kH/kD values of 3.1 and 3.4
(Scheme 5). These results support the possible involvement
of a concerted metalationÀdeprotonation (CMD) path-
way rather than electrophilic aromatic substitution or
radical process and the CÀH bond cleavage being the
rate-determining step.8
In summary, the catalyst system based on complex 1 was
highly effective for the regioselective CÀH arylation of
heteroaromatics by aryl chlorides. The general reaction
conditions developed allowed for the use of a wide range
of heterocycles, including thiophene, furan, and pyrrole, as
substrates and aryl halides withdifferent electronic proper-
ties as coupling partners. In almost all the cases, the desired
coupled products could be obtained in moderate-to-
excellent yields. The catalyst system allows the general
use of nonactivated and highly congested aryl chlorides in
heteroaromatic biaryl synthesis via direct arylation.
Acknowledgment. We thank the National Science
Council of Taiwan for supporting this work.
Supporting Information Available. Detailed experimen-
tal procedures and characterization data for all com-
pounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
(13) Join, B.; Yamamoto, T.; Itami, K. Angew. Chem., Int. Ed. 2009,
48, 3644.
The authors declare no competing financial interest.
D
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