Modulating reactivity and diverting selectivity in palladium-catalyzed heteroaromatic direct arylation through the use of a chloride activating/blocking group

Article abstract of DOI:10.1021/jo902515z

(Chemical Equation Presented) Through the introduction of an aryl chloride substituent, the selectivity of palladium-catalyzed direct arylation may be diverted to provide alternative regioisomeric products in high yields. In cases where low reactivity is typically observed, the presence of the carbon-chlorine bond can serve to enhance reactivity and provide superior outcomes. From a strategic perspective, the C-Cl bond is easily introduced and can be employed in a variety of subsequent transformations to provide a wealth of highly functionalized heterocycles with minimal substrate preactivation. The impact of the C-Cl functional group on direct arylation reactivity has also been evaluated mechanistically, and the observed reactivity profiles correlate very well with that predicted by a concerted metalation-deprotonation pathway.

Full text of DOI:10.1021/jo902515z

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Modulating Reactivity and Diverting Selectivity in Palladium-Catalyzed
Heteroaromatic Direct Arylation Through the Use of a Chloride
Activating/Blocking Group
†
ꢀ
Benoıˆt Liegault,* Ivan Petrov, Serge I. Gorelsky, and Keith Fagnou
Centre for Catalysis Research & Innovation, Department of Chemistry, University of Ottawa,
10 Marie Curie, Ottawa, Ontario K1N 6N5, Canada. †Prof. Keith Fagnou passed away unexpectedly on
November 11, 2009.
bliegaul@uottawa.ca
Received December 12, 2009
Through the introduction of an aryl chloride substituent, the selectivity of palladium-catalyzed direct
arylation may be diverted to provide alternative regioisomeric products in high yields. In cases where
low reactivity is typically observed, the presence of the carbon-chlorine bond can serve to enhance
reactivity and provide superior outcomes. From a strategic perspective, the C-Cl bond is easily
introduced and can be employed in a variety of subsequent transformations to provide a wealth of
highly functionalized heterocycles with minimal substrate preactivation. The impact of the C-Cl
functional group on direct arylation reactivity has also been evaluated mechanistically, and the
observed reactivity profiles correlate very well with that predicted by a concerted metalation-
deprotonation pathway.
Introduction
along with any problems associated with their synthesis,
stability, and/or functional group compatibility.5 In many
instances, high levels of regioselectivity occur to produce one
biaryl regioisomer in good yield, such as with benzothio-
phenes and benzofurans that react at C2,3q indolizines that
react at C3,3c,q as well as 1,2,3-triazoles3g and 2-substituted
imidazoles,3n thiazoles,3h,p,q and oxazoles3o that react at C5
Direct arylation reactions1-4 are finding increased appli-
cation in the preparation of biaryl molecules since they can
avoid the need for stoichiometric organometallic reagents
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DOI: 10.1021/jo902515z
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(Scheme 1). With other substrates, achieving acceptable
regioselectivity can be problematic.1p For example, C3-
substituted thiophenes and furans react to give mixtures of
C2/C5 monoarylated products as well as a significant
amount of C2,C5-diarylation.6 Attaining uniformly high
C2/C3 selectivity with indoles can also be challenging under
direct arylation protocols employing readily available aryl
halide coupling partners, prompting the establishment of
clever alternatives.2d,e,3e,f,j,k,m,x,4a,b,d,j,7,8
SCHEME 1. Established Regioselectivity in Palladium(0)-Catalyzed
Direct Arylation of Heteroaromatics
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J. Am. Chem. Soc. 2008, 130, 3276–3277. (m) Bellina, F.; Benelli, F.; Rossi, R.
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SCHEME 2. Heterobiaryl Compounds with Regiochemistry That
Is Inaccessible via Established Direct Arylation Techniques
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While the selective formation of only one regioisomer is
desirable, it can also limit the applicability of direct arylation
when the preparation of other isomeric compounds is called
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for (illustrative compounds are included in Scheme 2).9-16
For example, while thiazole C5 direct arylation readily
occurs, achieving direct arylation at the least reactive
C4 position, even in the absence of C4/C5 regioselectivity
issues,3a,l,t is exceedingly rare. In a similar fashion, the
inherent bias for reaction of benzothiophenes and benzofur-
ans atC2 makes this approach problematic when C3arylation
is desired.17,18 For direct arylation to continue to grow as a
synthetic tool in the preparation of biaryl molecules, strategies
that overcome these limitations must be established.
SCHEME 3. Palladium-Catalyzed Direct Arylation of Chlorine-
Containing Heteroaromatics
Herein we describe a solution to several regiochemical
limitations in palladium(0)-catalyzed direct arylation, with a
wide range of heteroaromatic coupling partners, that should
have broader implications as a general synthetic strategy. We
have found that a chlorine atom on the heterocycle not only
improves reactivity but also diverts typical direct arylation
regioselectivity to obtain previously inaccessible direct
arylation outcomes (Scheme 3).19 In this way, the C-Cl
bond becomes an invaluable handle for modulating reacti-
vity, manipulating site selectivity, and greatly expanding
the breadth of potential target compounds that may be
accessible via this approach. From a synthetic perspective,
the use of a chlorine substituent in this role is particularly
useful since C-Cl bonds are typically very easily introduced
on aromatic substrates and may be easily removed or
transformed into a wide range of functional groups via
well-established methods.20 Of equal importance, this chem-
istry has strong mechanistic implications on the nature of
the C-H bond cleavage step21 in palladium-catalyzed
direct arylation. The ability of a non-SEAr,22 concerted
metalation-deprotonation (CMD) pathway23-25 to accu-
rately account for this reactivity and selectivity is supported
by experimental and computational methods.
Results and Discussion
1. Use of a Chlorine Substituent to Improve/Induce Regio-
selectivity. When palladium-catalyzed direct arylation is em-
ployed with substrates possessing two nonidentical reactive
sites, low regioselectivities frequently occur. For example,
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TABLE 1. Chlorine-Induced Regioselectivity. Direct Arylation of 2-Chloro-4-hexylthiophene 2 and 2-Chloro-3-hexylthiophene 3 (Conditions A)
aHetAr/ArBr 1:1. bHetAr/ArBr 1.5:1. cArI was used instead of ArBr.
when employing general conditions for the direct arylation
of heteroaromatics,3q reaction of 3-(n-hexyl)thiophene 1 with
1-bromo-4-nitrobenzene generates an inseparable mixture of
isomers in a poor 1.3:1 ratio (eq 1).26 In cases such as this, the
use of an easily transformable blocking group could become a
valuable tool to enable the regiocontrolled formation of either
isomer at will.
arenes to undergo selective direct arylation. In contrast to the
synthetic difficulties associated with the preparation of aryl
fluorides,29 the aryl chloride functional group may be selec-
tively formed under a variety of reaction conditions. For
example, C3-substituted thiophene 1 may be easily and
regioselectively chlorinated at either the C5 or C2 position,
respectively, via deprotonation with the sterically encum-
bered base LiTMP30 and trapping with C2Cl6 to give 2 in
nearly quantitative yield, or by electrophilic chlorination by
action of sulfuryl chloride31 to give 3 in 82% yield (Table 1).
We were pleased to find that when subjected to direct
arylation, both 2-chloro-4-hexylthiophene 2 and 2-chloro-
3-hexylthiophene 3 react smoothly with various aryl halides
to give products 4a-c and 5a-c as single regioisomers and in
good yields (Table 1). For instance, when 2 is treated with 1
equiv of aryl halide in the presence of Pd(OAc)2 (2 mol %),
Based on our previous work in direct arylation with aryl
fluoride substrates,23c,27,28 we reasoned that an aryl chloride
functional group might also serve as an activating group for
reactions at nearby C-H bonds. Less clear, however, was
whether a chloride substituent might be able to transmit this
activation over greater distances to enable a broad range of
PCy3 HBF4 (4 mol %), PivOH (30 mol %), and K2CO3 (1.5
3
equiv) in DMA at 100 °C (conditions A),3q the exclusive site
of direct arylation is adjacent to both the sulfur atom and the
hexyl side chain. Illustrative examples include the use of
4-bromotoluene and 1-bromo-4-nitrobenzene which pro-
vided the corresponding thiophenes 4a and 4b in 72% and
85% isolated yields, respectively (entries 1 and 2). When
3-bromoanisole is used as the coupling partner, however, the
desired aryl thiophene is isolated in only 13% yield (entry 3).
Reasoning that with this more electron-rich aryl bro-
mide competitive and undesired oxidative insertion of the
(26) The ratio of products was determined by 1H NMR analysis of the
crude reaction mixture; see the Supporting Information for details.
(27) Lafrance, M.; Shore, D.; Fagnou, K. Org. Lett. 2006, 22, 5097–5100.
(28) For other related metal-catalyzed transformations involving poly-
fluorinated arenes, see: (a) Do, H.-Q.; Daugulis, O. J. Am. Chem. Soc. 2008,
130, 1128–1129. (b) Johnson, S. A.; Huff, C. W.; Mustafa, F.; Saliba, M.
J. Am. Chem. Soc. 2008, 130, 12278–12280. (c) Nakao, Y.; Kashihara, N.;
Kanyiva, K. S.; Hiyama, T. J. Am. Chem. Soc. 2008, 130, 16170–16171. See
also ref 4k.
(30) TMP=2,2,6,6-tetramethylpiperidine. See the Supporting Informa-
tion for detailed preparation of 2.
ꢀ
(31) Bidan, G.; De Nicola, A.; Enee, V.; Guillerez, S. Chem. Mater. 1998,
10, 1052–1058.
(29) (a) Watson, D. A.;Su, M.;Teverovskiy, G.;Zhang, Y.;Garcıa-Fortanet,
J.; Kinzel, T.; Buchwald, S. L. Science 2009, 325, 1661–1664. (b) Brown, J. M.;
Gouverneur, V. Angew. Chem., Int. Ed. 2009, 48, 8610–8614.
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TABLE 2. Chlorine-Induced Regioselectivity. Direct Arylation of 3-Chloro-N-methylindole 9 and 2-Chloro-N-methylindole 11 (Conditions A)
aHetAr/ArBr 1.5:1. bHetAr/ArBr 1:1. cArI was used instead of ArBr.
palladium catalyst into the aryl chloride bond of 2 may
occur, the reaction was instead performed with the corre-
sponding aryl iodide, for which oxidative insertion should be
favored. Indeed, substituting 3-bromoanisole for 3-iodoani-
sole led to the formation of thiophene 4c in an improved 66%
yield (entry 4).
ling partners. For example, when N-methylindole 8 is
reacted with sterically encumbered aryl halides, such as
2-bromotoluene, a mixture of C3 and C2 isomers is produced
in a poor 1.2:1 ratio (eq 2).26,33
In a similar vein, when the isomeric chlorothiophene
starting material 3 was employed, arylation can be induced
to occur exclusively at a position remote to the hexyl group.
By employing conditions A and the corresponding aryl
bromide coupling partner, products 5a, 5b, and 5c were
formed in 88%, 64%, and 81% isolated yields, respectively
(entries 5-7).
Importantly (and in addition to several other uses of the
Ar-Cl bond in substrate diversification), the chlorine atom
can simply be removed by treatment with catalytic Pd/C
under a hydrogen atmosphere32 to provide the C2 and C5
monoarylated 3-hexylthiophenes 6 and 7 in very good yields
(Table 1). In this way, the preparation and use of stoichio-
metric organoboron, tin, and other organometallic reagents
can be avoided in the cross-coupling step while preserving
the aryl chloride functionality for use in other valuable
diversity-introducing transformations (vide infra).20
Indole direct arylation can also be used to illustrate the
utility of the chloride functional group in cases where pro-
blematic regioselectivity may occur. While a wide range of
indole direct arylation reactions have been established,7
some substrate combinations remain problematic, particu-
larly with the palladium(0)-catalyzed processes employing
inexpensive and readily available aryl bromide coup-
By employing a strategy similar to that described for
3-substituted thiophenes, an aryl chloride substituent may
be introduced to enforce the desired regiochemical outcome.
For example, 2-bromotoluene reacts efficiently with
3-chloro-N-methylindole 9, prepared via electrophilic chlori-
nation of 8, to provide the C2 arylation product 10a in 73%
yield as a single regioisomer (Table 2, entry 1). 1-Bromo-4-
chlorobenzene and 4-bromobenzotrifluoride may also be
employed to provide indoles 10b and 10c in 80% and 89%
yield, respectively (entries 2 and 3). As previously found,
when an electron-rich aryl bromide is employed, in this case
4-bromoanisole, lower yields of the C2 arylated indole 10d
are obtained. Again, by changing to the corresponding aryl
iodide, improved outcomes are observed (entries 4 and 5).
In an analogous manner, 2-chloro-N-methylindole 11,
prepared from commercially available (or easily prepared)
N-methyloxindole 12 and POCl3 in 38% yield (91% brsm),
can also be employed to induce arylation at C3 with a range
(32) Monguchi, Y.; Kume, A.; Hattori, K.; Maegawa, T.; Sajiki, H.
Tetrahedron 2006, 62, 7926–7933.
(33) It has also been previously reported that ratios can be strongly
affected by steric hindrance of the aryl halide. See ref 3e.
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SCHEME 4. Typical Metal-Catalyzed Synthesis of 4-Aryl-5H-
the greater stability of these reagents.5,38 Considering a direct
arylation solution to this problem, we also recognized that a
similar reactivity profile disfavoring reaction at C4 is pre-
sent. In this instance, we sought to evaluate the ability of a
chloride functional group to not only block reaction at C5
but also to enhance reactivity at C4 toward direct arylation.
To determine whether a C5 chloride functionality could
divert the site of direct arylation to C4, 5-chloro-2-phenyl-
thiazole 17 was employed as a model substrate. While the use
of conditions A failed to induce useful yields of C4 arylation
product, we found that under modified conditions, i.e.,
thiazole Derivatives36h
Pd(OAc)2 (5 mol %), P(t-Bu)2Me HBF4 (10 mol %), PivOH
3
of aryl bromide coupling partners (Table 2). For example, 3-
bromotoluene, 1-bromo-3-chlorobenzene, and 1-bromo-3-
nitrobenzene may be employed as direct arylation coupling
partners with 11 to provide the C3 arylated indoles 13a-c in
yields of 79%, 66%, and 80%, respectively (entries 6-8).
Given the prevalence of the indole core in materials and
medicinal chemistry, the frequent need to introduce func-
tionality in a site selective manner at both the C2 and C3
positions,7 and the ease with which the aryl chloride func-
tional group may be modified, these transformations should
find wide application when the selective functionalization of
both of these positions is called for.
2. Use of a Chlorine Substituent to Divert Direct Arylation
away from Normal Site Selectivity. Despite the advances in
direct arylation, regiocontrolled carbon-carbon bond for-
mation at some positions of heteroaromatic compounds
remains a challenging goal. This limitation can be illustrated
by the reactivity of thiazoles. While useful reactivity has been
achieved at C23a,l,r,t,34 and C5,3a,h,l,p,t,34a,35 direct arylation at
C4,3a,l,t even in the absence of C4/C5 regioselectivity issues, is
extremely rare. Even with conventional metal-catalyzed
cross-coupling processes, forming a C4 biaryl bond is an
inefficient task due to the circuitous routes required to install
a C4 activating group in the presence of a C5 C-H bond.36
For example, electrophilic bromination of 2-phenylthiazole
14 at C5 can be followed by a C5 to C4 migration under a
“halogen dance” process (Scheme 4).36h,37 If an organo-
metallic is required at this position to enable cross-coupling
with another aryl halide, the resulting 4-bromothiazole 15 is
most commonly transformed into an arylstannane 16 due to
(30 mol %), and Cs2CO3 (2 equiv) in mesitylene at 140 °C
(conditions B, see the Supporting Information for an opti-
mization table), good yields of C4 arylation could be
achieved for the first time with a diverse set of coupling
partners (Table 3). For example, 5-chlorothiazole substrates
17-19 (prepared by deprotonation/electrophilic chlorina-
tion in good yields, see the Supporting Information), bearing
either an aryl (17-18) or an isobutyl group (19) at the C2
position, underwent direct arylation at C4 with various
electron-rich and electron-poor aryl bromides to provide
the corresponding products 20-22, in good yields ranging
from 61% to 75% (entries 1-6). 5-Chloro-2-phenyloxazole
23 also participated well in these transformations to provide
the C4-arylated oxazoles 24a and 24b in 58% and 56% yield,
respectively (entries 7 and 8). To illustrate how this method
might be applied to the preparation of functionalized 5H-
thiazoles, hydrodechlorination32 of 21b was performed to
provide 25 in an excellent yield (Table 3).
The direct arylation of benzothiophenes can also be used
to illustrate the utility of the chloride functional group in
diverted site selectivity. Benzothiophenes are excellent sub-
strates in palladium-catalyzed direct arylation, providing C2
regioselectivity in high yields.3q By installing a C2 chlorine
atom via deprotonation and electrophilic trapping (com-
pound 26, 91% yield), this methodology may also be used to
access the C3 direct arylation regioisomers in good yields.
Both electron-poor and electron-rich aryl bromides may
be employed under these conditions to generate 3-aryl-2-
chlorobenzothiophenes 27a-c in 56-77% yields (conditions
B, Table 4, entries 1-3). Likewise, 3-arylbenzofuran deriva-
tives, usually prepared via elaborate routes,18 can also be
accessed from 2-chlorobenzofuran 28 in moderate to good
yields (compounds 29a,b, entries 4 and 5). As previously
described, the products may be easily deprotected,32 as
illustrated by the reaction of 27a which gave 3-(4-tolyl)-
benzothiophene 30 in 98% yield.
3. Additional Examples Where the C-Cl Bond May Im-
prove Reactivity. Even in cases where a deviation in site
selectivity is not imparted by the presence of a chlorine
functional group, performing direct arylation reaction in
its presence may still be beneficial. Commercially available
2-chlorothiophene 31, for instance, can be employed in these
transformations with various electron-neutral and electron-
poor 4-substituted aryl bromides to give the corresponding
coupling products 32a-d in good yields (conditions A, Table 5,
entries 1-4). Sterically encumbered substrates provided
(34) For additional examples of palladium(0)-catalyzed C2 direct aryla-
tion of thiazoles, see: (a) Mori, A.; Sekiguchi, A.; Masui, K.; Shimada, T.;
Horie, M.; Osakada, K.; Kawamoto, M.; Ikeda, T. J. Am. Chem. Soc. 2003,
125, 1700–1701. (b) Martin, T.; Verrier, C.; Hoarau, C.; Marsais, F. Org.
Lett. 2008, 10, 2909–2912.
(35) For additional examples of palladium(0)-catalyzed C5 direct aryla-
tion of thiazoles, see: (a) Parisien, M.; Valette, D.; Fagnou, K. J. Org. Chem.
2005, 70, 7578–7584. (b) Gottumukkala, A. L.; Doucet, H. Eur. J. Inorg.
ꢁ
Chem. 2007, 3629–3632. (c) Pozgan, F.; Roger, J.; Doucet, H. ChemSusChem
2008, 1, 404–407. (d) Primas, N.; Bouillon, A.; Lancelot, J.-C.; El-Kashef, H.;
Rault, S. Tetrahedron 2009, 65, 5739–5746.
(36) For the preparation of 4-metallathia(oxa)zoles, see: (a) Nicolaou,
K. C.; He, Y.; Roschangar, F.; King, N. P.; Vourloumis, D.; Li, T. Angew.
Chem., Int. Ed. 1998, 37, 84–87. (b) Smith, A. B. III; Verhoest, P. R.;
Minbiole, K. P.; Schelhaas, M. J. Am. Chem. Soc. 2001, 123, 4834–4836.
(c) Smith, A. B. III; Razler, T. M.; Meis, R. M.; Pettit, G. R. J. Org. Chem.
2008, 73, 1201–1208. (d) Araki, H.; Katoh, T.; Inoue, M. Synlett 2006, 555–
558. (f) Nakashima, T.; Atsumi, K.; Kawai, S.; Nakagawa, T.; Hasegawa, Y.;
€
Kawai, T. Eur. J. Org. Chem. 2007, 3212–3218. (g) Hammerle, J.; Schnurch,
M.; Stanetty, P. Synlett 2007, 2975–2978. (h) Hammerle, J.; Spina, M.;
€
€
€
Schnurch, M.; Mihovilovic, M. D.; Stanetty, P. Synthesis 2008, 3099–3107.
(i) Martin, T.; Laguerre, C.; Hoarau, C.; Marsais, F. Org. Lett. 2009, 11,
3690–3693.
€
(37) For a review on “halogen dance” reactions, see: Schnurch, M.;
(38) For selected reviews on the Stille cross-coupling, see: (a) Stille, J. K.
Angew. Chem., Int. Ed. 1986, 25, 508–524. (b) Espinet, P.; Echavarren, A. M.
Angew. Chem., Int. Ed. 2004, 43, 4704–4734.
Spina, M.; Khan, A. F.; Mihovilovic, M. D.; Stanetty, P. Chem. Soc. Rev.
2007, 36, 1046–1057.
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TABLE 3. Chlorine-Diverted Regioselectivity. Direct Arylation of
2-Substituted 5-Chlorothiazoles 17-19 and 5-Chlorooxazole 23 (Conditions B)
TABLE 4. Chlorine Diverted Regioselectivity. Direct Arylation of
2-Chlorobenzothiophene 26 and 2-Chlorobenzofuran 28 (Conditions B)
(58% vs 13%) and 32h (59% vs 37%) (entries 7-10).
Analogous reactivity was also observed with N-benzyl-2-
chloropyrrole 33, easily prepared by electrophilic chlorina-
tion,39 providing exclusive regioisomers 34a-c in good
compounds 32e-f without loss of reactivity (entries 5 and
6). In cases where unactivated electron-rich aryl halides
were employed, the use of more reactive aryl iodides was
found to result in improved yields for compounds 32g
(39) Cordell, G. A. J. Org. Chem. 1975, 40, 3161–3169.
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TABLE 5. C5 Direct Arylation of 2-Chlorothiophene 31, N-Benzyl-2-chloropyrrole 33 (Conditions A), and C2 Direct Arylation of N-Methyl-5-chloro-
imidazole 35 and N-Benzyl-4,5-dichloroimidazole 36, in the Presence of a Copper Additive (Conditions A0)
aArI was used instead of ArBr. bChlorine-free N-methylimidazole was used as starting material.
yields (entries 11-13). With imidazole substrates (entries
15-22), synthetically useful yields of C2 arylation products
can be obtained in the presence of C5-chloride or C4,C5-
dichloride substituents (compounds 35 and 36, respectively).
In these instances, superior outcomes were observed when
the reactions were performed in the presence of one equivalent
of CuI (conditions A0, Table 5).40 When these same reac-
tions were conducted on N-methylimidazole lacking chlorine
substituents, no reaction was observed (entry 14), illustrating
the activating effect of the remote chlorine substituent for such
transformations.
4. Subsequent Transformations. A key benefit associated
with the use of a C-Cl bond to divert direct arylation
reactivityis not only its ease of installationbut alsoitscapacity
to be employed in a wide range of subsequent transforma-
tions.20 To demonstrate the utility of this strategy, 2,4-diary-
lated 5-chlorothiazole 21b was subjected to various
palladium-catalyzed transformations (Scheme 5), including
a Heck reaction with butyl acrylate following Fu’s condi-
tions41 providing alkene 39 in 68% yield,42 and a Suzuki
coupling with p-tolylboronic acid in the presence of Pd2(dba)3
and phosphine ligand X-Phos43 to give tris-arylated thiazole
(40) The role of copper additives in palladium-catalyzed direct arylation
of heteroaromatics has not been definitively elucidated. For selected exam-
ples, see: (a) Leclerc, J.-P.; Fagnou, K. Angew. Chem., Int. Ed. 2006, 45,
7781–7786. (b) Bellina, F.; Cauteruccio, S.; Rossi, R. J. Org. Chem. 2007, 72,
8543–8546. (c) Storr, T. E.; Firth, A. G.; Wilson, K.; Darley, K.; Baumann,
ꢂ
C. G.; Fairlamb, I. J. S. Tetrahedron 2008, 64, 6125–6137. (d) Besselievre, F.;
Mahuteau-Betzer, F.; Grierson, D. S.; Piguel, S. J. Org. Chem. 2008, 73,
(41) Littke, A. F.; Fu, G. C. J. Am. Chem. Soc. 2001, 123, 6989–7000.
(42) Reaction conditions not optimized.
(43) Billingsley, K.; Buchwald, S. L. J. Am. Chem. Soc. 2007, 129, 3358–
3366.
ꢁ
ꢁ
3278–3280. (e) Cerna, I.; Pohl, R.; Klepetarova, B.; Hocek, M. J. Org. Chem.
2008, 73, 9048–9054. (f) Cernova, M.; Pohl, R.; Hocek, M. Eur. J. Org. Chem.
ꢀꢁ
ꢀ
ꢁ
ꢁ
ꢀ
2009, 3698–3701. See also refs 3a, 3l, and 3t.
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SCHEME 5. Subsequent Transformations of Thiazoles 21b and 25
40 in 52% yield.42 Deprotected thiazole 25 (see Table 3) may
also be subjected to a C5 direct arylation reaction (conditions
A) to give compound 40 in 98% yield. This final approach
may be an attractive alternative for the synthesis of such
polyarylated azoles in cases where the requisite boronic acid
coupling partners are expensive or not readily accessible.
5. Mechanistic Studies: Competition Experiments. To in-
vestigate the influence of a chlorine substituent in palladium-
catalyzed direct arylation, competition experiments were per-
formed and the results compared to the outcomes of SEAr-type
processes (Schemes 6 and 7). For example, when an equimolar
mixture of 2-methylthiophene 41 and 2-chlorothiophene 31
was subjected to a direct arylation competition reaction with
0.2 equivalents of 2-bromotoluene (conditions A, Scheme 6),
preferential reaction occurred at the more electron-deficient
chlorothiophene 31 in an 11:1 ratio. A similar but less pro-
nounced effect was observed for experiments performed with
pyrroles 45 and 33, where the chlorinated substrate 33 reacted
preferentially in a 1.2:1 ratio. In stark contrast, when Vils-
meier-Haack formylation (known to proceed via an electro-
philic aromatic substitution pathway)44 competition
experiments were performed with the same substrate combina-
tions, the more electron-rich nonchlorinated heterocycles 41
and 45 reacted preferentially in 17:1 and 19:1 ratios, respec-
tively.
Under Vilsmeier-Haack formylation conditions where
the natural site for electrophilic attack at C3 is blocked,
reaction took place almost exclusively at the nonchlorinated
indole 8.
Competition experiments were also performed with 8 and
2-chloro-N-methylindole 11. Despite the fact that the site of
arylation is diverted from C2 to C3, chlorinated indole 11
still reacts preferentially in a 1.6:1 ratio over the nonchlori-
nated indole 8 (that undergoes arylation at C2). Under
Friedel-Crafts acylation conditions, both substrates may
undergo reaction at the natural C3 position. In this case, a
less pronounced preference is observed for reaction at non-
chlorinated substrate 8 (in a 2.3:1 ratio), in accord with
electrophilic aromatic substitution chemistry. These experi-
ments underline the different reactivity profiles observed for
palladium-catalyzed direct arylation compared to electro-
philic aromatic substitution. These results also provide a
valuable experimental reference point against which compu-
tational work may be calibrated.
6. Mechanistic Studies: Computational Results. Density
functional theory (DFT) calculations have been performed
using the Gaussian 03 program.45 In all calculations, the
spin-restricted method was employed. Wave function stabi-
lity calculations were carried out to confirm that the calcu-
lated wave functions corresponded to the electronic ground
The influence of the chlorine substituent in direct arylation
and SEAr reactions was also evaluated with indole substrates
where the reaction occurs at both typical and atypical
sites (Scheme 7). For instance, when N-methylindole 8 and
3-chloro-N-methylindole 9 were subjected to direct aryla-
tion reaction conditions, natural C2-arylation occurred
preferentially at the chlorinated indole 9 in a 9:1 ratio.
(45) Gaussian 03, Revision C.02: Frisch, M. J.; Trucks, G. W.; Schlegel, H.
B.; Scuseria, G. E.; Robb, M. A.; Cheeseman, J. R.; Montgomery, J. A., Jr.;
Vreven, T.; Kudin, K. N.; Burant, J. C.; Millam, J. M.; Iyengar, S. S.;
Tomasi, J.; Barone, V.; Mennucci, B.; Cossi, M.; Scalmani, G.; Rega, N.;
Petersson, G. A.; Nakatsuji, H.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda,
R.; Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.;
Klene, M.; Li, X.; Knox, J. E.; Hratchian, H. P.; Cross, J. B.; Bakken, V.;
Adamo, C.; Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev, O.;
Austin, A. J.; Cammi, R.; Pomelli, C.; Ochterski, J. W.; Ayala, P. Y.;
Morokuma, K.; Voth, G. A.; Salvador, P.; Dannenberg, J. J.; Zakrzewski,
V. G.; Dapprich, S.; Daniels, A. D.; Strain, M. C.; Farkas, O.; Malick, D. K.;
Rabuck, A. D.; Raghavachari, K.; Foresman, J. B.; Ortiz, J. V.; Cui, Q.;
Baboul, A. G.; Clifford, S.; Cioslowski, J.; Stefanov, B. B.; Liu, G.;
Liashenko, A.; Piskorz, P.; Komaromi, I.; Martin, R. L.; Fox, D. J.; Keith,
T.; Al-Laham, M. A.; Peng, C. Y.; Nanayakkara, A.; Challacombe, M.; Gill,
P. M. W.; Johnson, B.; Chen, W.; Wong, M. W.; Gonzalez, C.; Pople, J. A.
Gaussian, Inc., Wallingford CT, 2004.
(44) (a) Vilsmeier, A.; Haack, A. Ber. Dtsch. Chem. Ges. 1927, 60, 119–
122. (b) Linda, P.; Marino, G.; Santini, S. Tetrahedron Lett. 1970, 48, 4223–
4224. (c) Alunni, S.; Linda, P.; Marino, G.; Santini, S.; Savelli, G. J. Chem.
Soc., Perkin Trans. 2 1972, 2070–2073. (d) Linda, P.; Lucarelli, A.; Marino,
G.; Savelli, G. J. Chem. Soc., Perkin Trans. 2 1974, 1610–1612. (e) Mayr, H.;
Ofial, A. R. Tetrahedron Lett. 1997, 38, 3503–3506. (f) Jones, G.; Stanforth,
S. P. Org. React. 1997, 49, 1–330.
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SCHEME 6. “Direct Arylation” and “Vilsmeier-Haack Formylation” Competition Experiments between Non-Chlorinated and
Chlorinated Thiophenes 41 and 31 and Pyrroles 45 and 33a
aRatios of products (red numbers) determined by 1H NMR analysis of the crude reaction mixture (see the Supporting Information for detailed reaction
conditions and NMR spectra).bConditions A were used, with 0.2 equiv of the aryl bromide.cA small amount of product arising from formylation at the
C3 position of 45 was also detected.
SCHEME 7. “Direct Arylation”, “Vilsmeier-Haack Formylation”, and “Friedel-Crafts Acylation” Competition Experiments between
Non-Chlorinated and Chlorinated Indoles 8 and 9 and 8 and 11a
aRatios of products (in red) determined by 1H NMR analysis of the crude reaction mixture (see the Supporting Information for detailed reaction
conditions and NMR spectra).bConditions A were used, with 0.2 equiv of the aryl bromide.cA small amount of product arising from an intermolecular
reaction between 8 and 11 was also detected.dNot detected.
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state. The structures of all species were optimized using the
B3LYP exchange-correlation functional46 with the mixed
basis set (DZVP47 on Pd and TZVP48 on all other atoms).
The Pd catalyst was modeled with PMe3 ligands and an
acetate base. Tight SCF convergence criteria (10-8 au) were
used for all calculations. Harmonic frequency calculations
with the analytic evaluation of force gradients (OPT =
CalcAll) were used to determine the nature of the stationary
points. Intrinsic reaction coordinate (IRC)49 calculations
were used to confirm the reaction pathways through the
CMD transition states (TSs). Free energies of species were
evaluated at 298 K and 1 atm. Mayer bond orders50 were
calculated using the AOMix program.51
TABLE 6. Reaction Pathway Analysis for Direct Arylation and Elec-
trophilic Aromatic Substitution of Non-Chlorinated and Chlorinated
Heteroaromaticsa
Gibbs Free Energy of Activation ΔGq. The reaction path-
ways for both direct arylation and SEAr reactions were
evaluated with nonchlorinated and chlorinated thiophenes
41 and 31 and indoles 8, 9, and 11. By first considering a
concerted metalation-deprotonation (CMD) pathway for
the direct arylation reactions, the Gibbs free energy of
activation ΔG‡ was determined (Table 6). In accord with
experimental outcomes, the ΔGq for the CMD pathway was
found to be significantly lower for substrates bearing a
chlorine atom, with gaps of 1.4 kcal mol-1 for thiophenes
41 and 31 (entries 1 and 2) and 2.3 kcal mol-1 for indoles 8
and 9 (entries 3 vs 4) and 8 and 11 (entries 5 vs 6).
Proton Affinity. To evaluate the impact of the chlorine
functional group on electrophilic aromatic substitution
(SEAr) pathways, the proton affinity (ΔEPA) of the reactive
sites was calculated. In accord with known SEAr reactivity
and experimental observations, the relative proton affinities
correlate well with experimental SEAr outcomes (Schemes 6
and 7) and follow an opposite trend to the CMD pathway
calculated for direct arylation reactions. With thiophenes for
example, values of 212.5 and 205.2 kcal mol-1 were deter-
mined for 2-methylthiophene 41 and 2-chlorothiophene 31,
respectively (entries 1 and 2). On the other hand, the addition
of a chlorine atom at C2 appears to have little impact on the
C3-nucleophilicity of indole 11, with a decrease of ΔEPA of
only 1.2 kcal mol-1 when compared to indole 8 (226.8 vs
225.6 kcal mol-1, entries 5 vs 6), in agreement with the low
experimental ratio observed for the Friedel-Crafts acylation
competition experiment (Scheme 7).
Distortion and Interaction Energies EDist and EInt. To
further evaluate and begin to explain the impact of the
C-Cl bond on direct arylation reactivity, the elementary
contributions to free energy of activation ΔGq were calcu-
lated using the charge and energy decomposition analyses. In
this approach, the distortion energy EDist, associated with
distortion of both the heteroarene (HetAr) and the catalyst
(PdLn), and the electronic interaction energy EInt, between
PdLn and the substrate in the CMD transition state, were
aEnergies expressed in kcal mol-1
.
bEDist = EDist(HetAr) þ EDist
-
(PdLn). cPdLn = Pd(Ph)(PMe3)(OAc). dPd-C bond order. eElectronic
component of proton affinity at the corresponding carbon site.
evaluated (Table 6).23i Clear trends emerged from these
studies. In each case, the presence of a chlorine substituent
results in a decrease in EDist(HetAr) by 2.8 kcal mol-1 for
thiophenes 41 and 31 (entries 1 vs 2) and 5.3 and 2.7 kcal
mol-1 for indoles 8 and 9 (entries 3 vs 4) and 8 and 11 (entries
5 vs 6), respectively. On the other hand, EDist(PdLn) showed
much less variation for reactions of substrates with and
without chlorine substituents (between 0.4 and 0.8 kcal
mol-1), indicating that the presence of the C-Cl bond
does not affect the structure of the PdLn fragment in the
CMD TS.
(46) (a) Lee, C.; Yang, W.; Parr, R. G. Phys. Rev. B 1988, 37, 785–789. (b)
Becke, A. D. J. Chem. Phys. 1993, 98, 5648–5652.
(47) Godbout, N.; Salahub, D. R.; Andzelm, J.; Wimmer, E. Can. J.
Chem. 1992, 70, 560–571.
(48) Schafer, A.; Huber, C.; Ahlrichs, R. J. Chem. Phys. 1994, 100, 5829–
5835.
(49) (a) Gonzalez, C.; Schlegel, H. B. J. Chem. Phys. 1989, 90, 2154–2161.
(b) Gonzalez, C.; Schlegel, H. B. J. Phys. Chem. 1990, 94, 5523–5527.
(50) Mayer, I. Chem. Phys. Lett. 1983, 97, 270–274.
(51) (a) Gorelsky, S. I.; Basumallick, L.; Vura-Weis, J.; Sarangi, R.;
Hedman, B.; Hodgson, K. O.; Fujisawa, K.; Solomon, E. I. Inorg. Chem.
2005, 44, 4947–4960. (b) Gorelsky, S. I.; Version 6.43 ed.; University of Ottawa:
Ottawa, Canada, 2009; http://www.sg-chem.net.
The presence of a chorine substituent was also found to
influence the interaction energy EInt (Table 6). Here, sub-
strates bearing a chlorine substituent exhibit decreased EInt
values, with gaps of 1.9 kcal mol-1 for thiophenes 41 and 31
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TABLE 7. C3/C2 Regioselectivity in the Palladium-Catalyzed Direct Arylation of N-Methylindole 8 with 4-Bromotoluene
entry
ArBr (equiv)
K2CO3 (equiv)
time (h)
ratio of productsa
1
2
1.0
0.2
1.5
0.5
14
4
1
1
5.5
2.6
0.9
ndb
aRatios of products determined by 1H NMR analysis of the crude reaction mixture (see Supporting Information for detailed reaction conditions and
NMR spectra). bNot detected.
SCHEME 8. C3/C2 Migration Pathway for C3/C2 Selectivity in the Direct Arylation of Indoles According to the SEAr Pathway
(Neutral Atom Donor Ligands on Palladium Are Omitted for Clarity) and Calculated C3 Proton Affinity Values for Indoles 8 and 9
(entries 1 vs 2) and 3.3 and 1.7 kcal mol-1 for indoles 8 and 9
(entries 3 vs 4) and 8 and 11 (entries 5 vs 6), respectively. An
electronic structure analysis of the covalent interactions in
the CMD TSs indicates that the Pd-C bond order decreases
with the presence of a chlorine substituent by 0.038 for
thiophenes 41 and 31 (entries 1 vs 2) and by 0.066 and
0.034 for indoles 8 and 9 (entries 3 vs 4) and 8 and 11
(entries 5 vs 6), respectively.
These studies begin to paint a more accurate picture of the
underlying factors governing palladium(0)-catalyzed direct
arylation. Since the positive influence of the chlorine substi-
tuent on the magnitude of EDist(HetAr) is larger than its
negative influence on EInt, the improved reactivity associated
with these substrates is predominantly a consequence of this
effect. Ongoing efforts are directed at using this knowledge in
the establishment of a set of guidelines that may be employed
to predict and understand this type of reactivity with the
broadest set of aromatic coupling partners possible.
Indole C3/C2 Selectivity. A more detailed discussion on
the C3/C2 selectivity of N-alkylindole arylation is war-
ranted.52 According to the CMD pathway, the calculated
values of the Gibbs free energies of activation ΔGq for C2-
and C3-arylation of indole 8 are strikingly similar (28.2 and
28.0 kcal mol-1, respectively). To establish an experimental
reference point, reactions employing N-methylindole 8
with 4-bromotoluene were carried out (Table 7). Under
conditions A, a mixture of three products was obtained,
C3-arylindole 49, C2-arylindole 50, and C2,C3-diarylindole
59, in a 1:5.5:0.9 ratio and a combined yield of 65% (entry 1).
To better establish the inherent C3/C2 selectivity, the same
reaction was performed with only 0.2 equiv of 4-bromoto-
luene, thereby minimizing the potential for diarylation. In
this case, a 1:2.6 ratio of 49 and 50 was obtained (entry 2).
Given the ease with which C3/C2 selectivity can be influ-
enced experimentally by changing the reaction parameters
and aryl halide substitution patterns (see also eq 2),3e,53
reaction pathways leading to both outcomes must be en-
ergetically accessible. In this light, the similarity of the
calculated values of the Gibbs free energies of activation
ΔGq (Table 6, entries 3 and 5) should be anticipated. With
(52) It is important to distinguish between reactions involving N-alkyl
and N-H indoles that may become deprotonated under the basic reaction
conditions employed for palladium(0)-catalyzed direct arylation. Such an-
ionic species should exhibit different reactivity and behave much more like
typical nucleophiles in palladium-catalyzed cross-coupling processes. See:
(a) Zhang, Z.; Hu, Z.; Yu, Z.; Lei, P.; Chi, H.; Wang, Y.; He, R. Tetrahedron
Lett. 2007, 48, 2415–2419. (b) Wang, X.; Gribkov, D. V.; Sames, D. J. Org.
Chem. 2007, 72, 1476–1479. (c) Cusati, G.; Djakovitch, L. Tetrahedron Lett.
2008, 49, 2499–2502. See also refs 2d and 3m, 3x.
(53) The influence of the nature of the halide substituent on regioselec-
tivity has previously been noticed. See: (a) Campeau, L.-C.; Parisien, M.;
Jean, A.; Fagnou, K. J. Am. Chem. Soc. 2006, 128, 581–590. (b) Caron, L.;
Campeau, L.-C.; Fagnou, K. Org. Lett. 2008, 10, 4533–4536.
1058 J. Org. Chem. Vol. 75, No. 4, 2010

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continued refinement and additional advances in our under-
standing of the important reaction variables that influence
this type of reactivity, the precision of this mechanistic
rationale will continue to grow.
SCHEME 9. Proposed Catalytic Cycle for the Palladium-Catalyzed
Direct Arylation of Heteroaromatics in the Presence of a Co-Catalytic
Amount of Pivalic Acid (Neutral Atom Donor Ligands on Palladium
Are Omitted for Clarity)
Another mechanistic hypothesis has also been proposed
that does not involve direct C2 or C3 metalation and instead
involves an initial C3 electrophilic palladation followed by a
C3/C2 palladium migration (Scheme 8).3e This C3/C2
migration pathway, which has also been documented in the
broader indole literature,54 is supported experimentally by
the detection of a secondary kinetic isotope effect (KIE) of
1.6 at C3 when arylation is occurring at C2 (under slightly
different conditions than those described herein). A similar
hypothesis has also been advanced for other palladium(II)-
and copper(I/III)-catalyzed indole functionalization proces-
ses.4d,55 To probe the compatibility of this hypothesis with
the experimental outcomes from the competition experi-
ments involving the chlorinated and nonchlorinated indoles,
the C3 proton affinity ΔEPA of 3-chloro-N-methylindole 9
was determined as a means of approximating the relative
propensity of this indole to undergo electrophilic palladation
at this site compared to the nonchlorinated indole 8
(Scheme 8). These calculations revealed a C3 proton affinity
of 219.0 kcal mol-1 for 9 which is 7.8 kcal mol-1 lower than
the corresponding value for indole 8. This result indicates
that unsubstituted indole 8 should exhibit enhanced reactiv-
ity compared to 9 under an SEAr-like reaction profile, a trend
that is not supported by the direct arylation competition
experiment outcomes (that do correlate well with calculated
CMD-type reactivity, Table 6). What is difficult to reconcile
with the CMD pathway is the previously observed secondary
KIE at C3 for a reaction occurring at C2.3e Our ability to
evaluate this feature under the conditions employed herein is
complicated by the formation of significant amounts of C3
monoarylation and C2/C3 diarylation products - processes
that may exhibit significant primary kinetic isotope effects.
More mechanistic work will be required before a more
definitive statement can be made on the attributes of this
particular substrate class, the first to be successfully em-
ployed in these reactions more than 20 years ago,2e and its
responsiveness to subtle changes in reaction variables.
General Discussion and Implications in Reaction Develop-
ment. Several mechanistic scenarios have been proposed to
explain palladium(0)-catalyzed direct arylation outcomes
including oxidative C-H insertion,56 SEAr,22 Heck-like
additions,57,58 and CMD.23,59 One hypothesis that may
rationalize the breadth of palladium-catalyzed direct aryla-
tion reactivity and the seemingly divergent outcomes is the
presence of flat direct arylation reaction energetics allowing
for mechanistic promiscuity and the involvement of both
SEAr and CMD pathways (and potentially others) depend-
ing on subtle differences in the substrate combinations and
reaction conditions.1f,23i The ability of the CMD pathway to
accurately explain and predict reaction outcomes across a
broad and chemically very diverse set of aromatic coupling
partners leads us to favor a second hypothesis where a CMD
pathway is operative in the majority of cases. This mode of
reactivity in palladium(0)-catalyzed direct arylation has the
power to explain reaction outcomes that might appear
anomalous under a simple SEAr paradigm. It can also
explain the important base effects that have been documen-
ted in these transformations, such as the common use of
acetate and carbonate bases,2 the improvements due to the
use of stoichiometric pivalate salts by the groups of Larock60
and Sames61 in palladium(0)- and rhodium(I)-catalyzed
direct arylation, respectively, and later the use of catalytic
(54) For example, see: (a) Jackson, A. H.; Smith, P. Chem. Commun.
1967, 264–266. (b) Jackson, A. H.; Smith, A. E. Tetrahedron 1968, 24, 403–
413. (c) Jackson, A. H.; Naidoo, B.; Smith, P. Tetrahedron 1968, 24, 6119–
6129. (d) Saulnier, M. G.; Gribble, G. W. J. Org. Chem. 1982, 47, 757–761. (e)
Jackson, A. H.; Lynch, P. P. J. Chem. Soc., Perkin Trans. 2 1987, 1215–1219.
(f) Biswas, K. M.; Jackson, A. H.; Kobaisya, M. M.; Shannon, P. V. R. J.
Chem. Soc., Perkin Trans. 1 1992, 461–467. (g) Ganesan, A.; Heathcock, C.
H. Tetrahedron Lett. 1993, 34, 439–440.
(55) Grimster, N. P.; Gauntlett, C.; Godfrey, C. R. A.; Gaunt, M. J.
Angew. Chem., Int. Ed. 2005, 44, 3125–3129.
(56) For reactions where an oxidative C-H insertion pathway has been
proposed; see: Campo, M. A.; Huang, Q.; Yao, T.; Tian, Q.; Larock, R. C.
J. Am. Chem. Soc. 2003, 125, 11506–11507.
(57) For reactions where a Heck-like addition pathway has been pro-
posed, see: (a) Toyota, M.; Ilangovan, A.; Okamoto, R.; Masaki, T.;
Arakawa, M.; Ihara, M. Org. Lett. 2002, 4, 4293–4296. (b) Wang, J.-X.;
McCubbin, J. A.; Jin, M.; Laufer, R. S.; Mao, Y.; Crew, A. P.; Mulvihill, M.
J.; Snieckus, V. Org. Lett. 2008, 10, 2923–2926. See also ref 3b.
(58) For reactions where a Heck-like addition pathway seems to be less
likely to occur, see: (a) McClure, M. S.; Glover, B.; McSorley, E.; Millar, A.;
Osterhout, M. H.; Roschangar, F. Org. Lett. 2001, 3, 1677–1680. (b) Hughes,
C. C.; Trauner, T. Angew. Chem., Int. Ed. 2002, 41, 1569–1572.
(59) Given the pronounced “non-electrophilic substitution”-like influ-
ences on these arylation reactions, description as an electrophilic process
does not reflect reactivity. Furthermore, only placing emphasis on the
deprotonation step does not reflect that in some instances there can be
important electronic parameters that may contribute to the energetics of the
transition state. Consequently, we prefer the use of “concerted metala-
tion-deprotonation” since it underlines the fact that there are two key
processes that occur simultaneously and that exert important influences on
the overall reactivity.
(60) (a) Huang, Q.; Fazio, A.; Dai, G.; Campo, M. A.; Larock, R. C.
J. Am. Chem. Soc. 2004, 126, 7460–7461. (b) Huang, Q.; Campo, M. A.; Yao,
T.; Tian, Q.; Larock, R. C. J. Org. Chem. 2004, 69, 8251–8257. (c) Zhao, J.;
Campo, M.; Larock, R. C. Angew. Chem., Int. Ed. 2005, 44, 1873–1875. (d)
Zhao, J.; Yue, D.; Campo, M. A.; Larock, R. C. J. Am. Chem. Soc. 2007, 129,
5288–5295.
(61) Wang, X.; Lane, B. S.; Sames, D. J. Am. Chem. Soc. 2005, 127, 4996–
4997.
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quantities of pivalate salts in conjunction with a stoichio-
metric and insoluble carbonate.3l,q,t,u,23d,f,i,24a,53b,62 In con-
trast to true SEAr-like mechanisms, arene nucleophilicity is
only one component of CMD reactivity and in many instances
may not be the primary governing influence.23i Importantly,
this mindset is likely to inspire different lines of thought in
reaction development and substrate selection.
6. Proposed Catalytic Cycle. In agreement with experi-
mental and theoretical studies described above, the catalytic
cycle can be depicted as previously proposed by our group
and others (Scheme 9).23 Initial oxidative addition of the
palladium(0) species into the aryl halide bond is followed by
a bromide/pivalate ligand exchange, the latter being gener-
ated in situ from the catalytic pivalic acid and the insoluble
stoichiometric carbonate base. Approach of the hetero-
aromatic partner leads to a concerted metalation-deprotona-
tion (CMD) transition state, enabled by the pivalate ligand.
Subsequent reductive elimination produces the biaryl product
and regenerates the active catalytic species.
aryl bromide were added at this point if liquids. The reaction was
then vigorously stirred at 100 °C for the indicated time. The
solution was then cooled to rt, diluted with EtOAc, washed with
H2O, dried over MgSO4, filtered, and evaporated under reduced
pressure. The crude residue was purified by silica gel column
chromatography to afford the desired product. 2-Chloro-4-(n-
hexyl)-5-(p-tolyl)thiophene (4a): yellow oil; Rf 0.6 (petroleum
ether); 1H NMR (400 MHz, CDCl3) δ 7.25 (d, J=8.0 Hz, 2H),
7.19 (d, J=8.0 Hz, 2H), 6.77 (s, 1H), 2.54 (m, 2H), 2.38 (s, 3H),
1.54 (m, 2H), 1.31-1.20 (m, 6H), 0.85 (t, J=7.0 Hz, 3H); 13C
NMR (100 MHz, CDCl3) δ 138.0, 137.5, 136.5, 130.8, 129.3,
129.2, 128.3, 127.5, 31.6, 30.8, 29.0, 28.7, 22.6, 21.2, 14.0; IR
(νmax) 2957, 2929, 2859, 1510, 811 cm-1; HRMS calcd for
C17H21ClS (Mþ) 292.1052, found 292.1045.
General Procedure for the Direct Arylation of Chlorine-
Containing Heteroaromatics: Conditions B (See the Supporting
Information for Optimization). Pd(OAc)2 (5 mol %),
P(t-Bu)2Me HBF4 (10 mol %), PivOH (30 mol %), and Cs2CO3
3
(2 equiv) were weighed to air and placed in a 2 mL screw-cap vial
equipped with a magnetic stir bar. The heterocycle (0.5-1 mmol)
and the aryl bromide (1.5 equiv, unless otherwise specified) were
added at this point if solids. The vial was purged with argon, and
mesitylene (0.3 M) was added. The heterocycle and the aryl
bromide wereadded at thispoint if liquids. The reaction was then
vigorously stirred at 140 °C over the indicated time. The solution
was then cooled to rt, diluted with EtOAc, washed with H2O,
dried over MgSO4, filtered, and evaporated under reduced
pressure. The crude residue was purified by silica gel column
chromatography to afford the corresponding product. 5-Chloro-
2-phenyl-4-(p-tolyl)thiazole (20a): white solid; mp 72-74 °C;
Conclusion
In summary, we described the palladium-catalyzed direct
arylation of chlorine-containing heteroaromatics with var-
ious aryl halides. The chlorine atom, which remains intact
under the reaction conditions, not only enhances reactivity
but also allows arylation to occur at usually unreactive
positions. The resulting chlorine-containing biaryl products
may also be used for further functionalization, a feature that
should find application in the synthesis of more complex
targets. These aspects as well as more detailed mechanistic
studies are currently being investigated by our group and will
be reported in due course.
1
Rf 0.25 (petroleum ether/toluene 80/20); H NMR (400 MHz,
CDCl3) δ 7.94 (d, J=8.0 Hz, 2H), 7.93-7.89 (m, 2H), 7.47-7.41
(m, 3H), 7.28 (d, J = 8.0 Hz, 2H), 2.41 (s, 3H); 13C NMR
(100 MHz, CDCl3) δ 163.8, 150.5, 138.4, 133.2, 130.4, 130.2,
129.1, 129.0, 128.2, 126.2, 119.6, 21.4; IR (νmax) 928, 831, 746,
724 cm-1; HRMS calcd for C16H12ClNS (Mþ) 285.0379, found
285.0364.
Experimental Section
General Procedure for the Direct Arylation of Chlorine-Con-
Acknowledgment. We thank NSERC, the University of
Ottawa, Astra Zeneca, Amgen, and Eli Lilly for financial support.
taining Heteroaromatics: Conditions A3q. Pd(OAc)2 (2 mol %),
PCy3 HBF4 (4 mol %), PivOH (30 mol %), and K2CO3 (1.5
3
equiv) were weighed to air and placed in a 2 mL screw-cap vial
equipped with a magnetic stir bar. The heterocycle (0.5-1
mmol) and the aryl bromide (1 equiv, unless otherwise specified)
were added at this point if solids. The vial was purged with
argon, and DMA (0.3 M) was added. The heterocycle and the
Supporting Information Available: General considerations;
optimization table (conditions B); competition experiments
details; synthesis, characterization, and NMR spectra of
all new starting materials and all coupling products; optimized
geometries of substrates and the corresponding CMD transition
states. This material is available free of charge via the Internet at
http://pubs.acs.org.
(62) Schipper, D. J.; El-Salfiti, M.; Whipp, C. J.; Fagnou, K. Tetrahedron
2009, 65, 4977–4983.
1060 J. Org. Chem. Vol. 75, No. 4, 2010