Palladium-catalyzed intramolecular C-H arylation of arenes using tosylates and mesylates as electrophiles

Article abstract of DOI:10.1021/ol302166n

This paper describes a method for the palladium catalyzed intramolecular C-H arylation using tosylates and mesylates as electrophiles. The transformation is efficient for the synthesis of various heterocyclic motifs including furans, carbazoles, indoles, and lactams. Additionally, a protocol for the one-pot sequential tosylation/arylation of phenol derivatives is presented.

Full text of DOI:10.1021/ol302166n

ORGANIC
LETTERS
2012
Vol. 14, No. 18
4838–4841
Palladium-Catalyzed Intramolecular CÀH
Arylation of Arenes Using Tosylates and
Mesylates as Electrophiles
Christine S. Nervig,§ Peter J. Waller,§ and Dipannita Kalyani*
Department of Chemistry, St. Olaf College, 1520 St. Olaf Avenue, Northfield,
Minnesota 55057, United States
kalyani@stolaf.edu
Received August 3, 2012
ABSTRACT
This paper describes a method for the palladium catalyzed intramolecular CÀH arylation using tosylates and mesylates as electrophiles. The
transformation is efficient for the synthesis of various heterocyclic motifs including furans, carbazoles, indoles, and lactams. Additionally,
a protocol for the one-pot sequential tosylation/arylation of phenol derivatives is presented.
Transition metal catalyzed CÀH arylation reactions are
now well established for the construction of CÀC bonds.1
A vast majority of these reactions utilize aryl halides and
their derivatives as electrophiles. Recently, however, there
has been an increasing demand for the use of phenolic
electrophiles in place of aryl halides.2 This is because such
electrophiles are readily available from inexpensive phenol
derivatives. However, the development of CÀH arylation
protocols using CÀO electrophiles has been relatively slow.
Initial reports toward achieving this goal employed aryl
triflates as electrophiles.3 While this represents a significant
advancement, these reactions are not ideal for use in long
synthetic sequences due to the sensitive and expensive
nature of triflates.4 The use of tosylates and mesylates for
CÀH arylation would constitute a more robust methodol-
ogy because these sulfonates are easy to handle and are
generally stable to hydrolysis. Additionally, these electro-
philes can be accessed using inexpensive sulfonating re-
agents. However, the increased stability of tosylates and
mesylates render them less reactive electrophiles. None-
theless, over the past six years a few sporadic reports
have described their use as substrates for transition metal
catalyzed CÀH arylations. These methods have accom-
plished the direct arylations of heteroarenes5,6 (azoles and
azine N-oxides) as well as fluorinated aromatics.7 To date,
however, there is no general report on the CÀH arylation of
§ These authors contributed equally to this work.
(1) For representative reviews on CÀH arylation, see: (a) Alberico,
D.; Scott, M. E.; Lautens, M. Chem. Rev. 2007, 107, 174. (b) Kakiuchi,
F.; Kochi, T. Synthesis 2008, 3013. (c) McGlacken, G. P.; Bateman,
L. M. Chem. Soc. Rev. 2009, 38, 2447. (d) Chen, X.; Engle, K. M.; Wang,
D.-H.; Yu, J.-Q. Angew. Chem., Int. Ed. 2009, 48, 5094. (e) Ackermann,
L.; Vincente, R.; Kapdi, A. R. Angew. Chem., Int. Ed. 2009, 48, 9792.
(f) Bellina, F.; Rossi, R. Tetrahedron 2009, 65, 10269. (g) Lyons, T. W.;
Sanford, M. S. Chem. Rev. 2010, 110, 1147. (h) Daugulis, O. Top. Curr.
Chem. 2010, 292, 57. (i) Chiusoli, G. P.; Catellani, M.; Costa, M.; Motti,
E.; Della Ca’, N.; Maestri, G. Coord. Chem. Rev. 2010, 254, 456.
(2) (a) Yu, D.-G.; Li, B.-J.; Shi, Z.-J. Acc. Chem. Res. 2010, 43, 1486.
(b) Rosen, B. M.; Quasdorf, K. W.; Wilson, D. A.; Zhang, N.;
Resmerita, A.-M.; Garg, N. K.; Percec, V. Chem. Rev. 2011, 111,
1346. (c) Li, B.-J.; Yu, D.-G.; Sun, C.-L.; Shi, Z.-J. Chem.;Eur. J.
2011, 17, 1728.
(3) For some representative recent reports, see: (a) Brenner, M.;
Mayer, G.; Terpin, A.; Steglich, W. Chem.;Eur. J. 1997, 3, 70.
(b) Kametani, K.; Satoh, T.; Miura, M.; Nomura, M. Tetrahedron Lett.
2000, 41, 2655. (c) Hara, O.; Nakamura, T.; Sato, F.; Makino, K.;
Hamada, Y. Heterocycles 2006, 68, 1. (d) Cruz, A. C. F.; Miller, N. D.;
Willis, M. C. Org. Lett. 2007, 9, 4391. (e) Roger, J.; Doucet, H. Org.
Biomol. Chem. 2008, 6, 169. (f) Schipper, D. J.; El-Salfiti, M.; Whipp,
C. J.; Fagnou, K. Tetrahedron 2009, 65, 4977.
(4) Goossen, L. J.; Rodriguez, N.; Lange, P. P.; Linder, C. Angew.
Chem., Int. Ed. 2010, 49, 1111.
r
10.1021/ol302166n
Published on Web 09/13/2012
2012 American Chemical Society

Table 1. Optimization of the Intramolecular CÀH Arylation
Reaction of 1-OTs
Table 2. Substrate Scope for the Pd-Catalyzed CÀH Arylation
for Synthesis of Furans
Cs2CO3
(equiv)
CsOPiv
(equiv)
GC
yielda,b
entry
ligand
1
none
1.5
1.5
1.5
1.5
1.5
none
1.5
1.5
1.5
1.1
1.1
1.1
1.1
1.1
1.1
none
1.1
1.1
3%
2
X-Phos
S-Phos
Ru-Phos
dcype
dcype
dcype
dcype
dcype
12%
4%
3
4
4%
5
92%
0%
6
7
96%
0%
8c
9d
86%
a General conditions: 1-OTs (1 equiv), Pd(OAc)2 (0.10 equiv), dcype
(0.20 equiv), Cs2CO3 (1.5 equiv), CsOPiv (1.1 equiv), toluene (0.25 M
in 1-OTs), 120 °C. b Calibrated GC yields against hexadecane as the
internal standard. c General conditions with no Pd(OAc)2. d General
conditions, but with Pd(OAc)2 (0.05 equiv), dcype (0.10 equiv).
simple arenes using tosylates and mesylates as electrophiles.5a
We report herein a general method for the palladium-
catalyzed intramolecular arylation of diverse arenes with
aryl tosylates as electrophiles. Furthermore, a prelimin-
ary scope for the use of more atom-economical mesylates
for CÀH arylations is also presented.
Our investigations commenced with the optimization of
conditions for the intramolecular arylation of substrate
1-OTs (Table 1). These studies began with the use of some
reaction parameters (e.g., carbonate base and pivalate salt)
known to be essential for Pd-catalyzed CÀH arylations
using aryl halides.8 The initial choice of ligands included
those that have been used in the context of Pd-catalyzed
CÀH arylations using CÀO electrophiles (e.g., X-Phos,
Ru-Phos, S-Phos, Table 1, entries 2À4).5À7 The desired
product 1a was obtained in all three cases albeit in low
yields. Further ligand screening revealed that the use of
1,2-bis(dicyclohexylphosphino)ethane (dcype) led to pro-
duct 1a in excellent yield (92%) (entry 5).9 Notably, the
use of ligand, Cs2CO3, and Pd(OAc)2 is each essential
a General conditions: substrate (1 equiv), Pd(OAc)2 (0.05 equiv),
dcype (0.10 equiv), Cs2CO3 (1.5 equiv), CsOPiv (1.1 equiv), toluene
(0.25 M in substrate), 120 °C. b General conditions but with 7.5 mol %
Pd(OAc)2 and 15 mol % dcype. c Isolated as a 1.5:1 mixture of isomers
favoring 9a as determined by gas chromatographis analysis of the crude
reaction mixture. d General conditions but with xylene at 140 °C.
e General conditions but with 10 mol % Pd(OAc)2 and 20 mol % dcype.
(5) (a) Ackermann, L.; Althammer, A.; Born, R. Angew. Chem., Int.
Ed. 2006, 45, 2619. (b) Ackermann, L.; Mulzer, M. Org. Lett. 2008, 10,
5043. (c) Ackermann, L.; Althammer, A.; Fenner, S. Angew. Chem., Int.
Ed. 2009, 48, 201. (d) Ackermann, L.; Barfuesser, S.; Pospech, J. Org.
Lett. 2010, 12, 724. (e) Ackermann, L.; Pospech, J.; Potukuchi, H. K.
Org. Lett. 2012, 14, 2146. (f) Muto, K.; Yamaguchi, J.; Itami, K. J. Am.
Chem. Soc. 2012, 134, 169.
for catalysis (entries 1, 6, and 8). With substrate 1-OTs,
a slightly higher yield of product was obtained in the
absence of CsOPiv (entry 7). However, the conditions
were more broadly applicable and reproducible in the pre-
sence of CsOPiv. Finally, the catalyst loading could be
lowered (5 mol % Pd(OAc)2, 10 mol % dcype, 1.5 equiv of
Cs2CO3, 1.1 equiv of CsOPiv, toluene, 120 °C) to afford
(6) (a) Ackermann, L.; Fenner, S. Chem. Commun. 2011, 47, 430.
(7) (a) Fan, S.; Yang, J.; Zhang, X. Org. Lett. 2011, 13, 4374.
(b) Chang, J. W. W.; Chia, E. Y.; Chai, C. L. L.; Seayad J. Org. Biomol.
Chem. 2012, 10, 2289.
(8) (a) Campeau, L.-C.; Parisien, M.; Jean, A.; Fagnou, K. J. Am.
Chem. Soc. 2006, 128, 581. (b) Ackermann, L. Chem. Rev. 2011, 111, 1315.
(9) Other bidentate phosphine ligands such as dppf and dppe were
ineffective in these transformations. See Supporting Information
(Table S1) for details.
Org. Lett., Vol. 14, No. 18, 2012
4839

the product (1a) in good yield (86%) as determined by gas
chromatographic analysis of the crude reaction mixture
(entry 9).10
Table 3. Scope of Pd-Catalyzed CÀH Arylation for Synthesis of
Diverse Heterocycles
Having the optimal conditions in hand for the arylation
of 1-OTs, we next examined the generality of this trans-
formation with respect to varied substitution patterns on
the tethered aryl rings. As shown in Table 2, the method
is compatible with electron-donating (entries 3, 6, and 10)
and -withdrawing substituents (entries 7 and 11) on both
aryl rings to afford the corresponding furan products in
good to excellent yields. Substrates bearing benzylic methyl
groups (entries 2 and 8) as well as halides (entries 4 and 5)
effectively participated in these reactions.11 Importantly,
product 5a is amenable to further structural elabora-
tion by transition metal catalyzed cross-couplings of aryl
chlorides.12 Substrates such as 6-OTs, 7-OTs, and 9-OTs
bear two different aromatic CÀH bonds that could under-
go arylation (entries 6, 7, and 9). While products 6a and 7a
form via functionalization of the less sterically hindered
CÀH bond, a 1.5:1 mixture of isomers was obtained from
the reaction of naphthyl substrate 9-OTs. These selectivities
are consistent with those previously documented for known
Pd-catalyzed CÀH arylation reactions.8a,13
We next explored the scope of these arylations toward
the synthesis of diverse heterocycles. As shown in Table 3,
carbazoles, fused indoles, and lactams could be obtained
in good yields from the palladium-catalyzed reaction of
substrates 12À16. Importantly, these heterocyclic motifs
are widely prevalent in bioactive molecules and pharma-
ceutical targets.8a
a General conditions: substrate (1 equiv), Pd(OAc)2 (0.10 equiv),
dcype (0.20 equiv), Cs2CO3 (1.5 equiv), CsOPiv (1.1 equiv), toluene
(0.25 M in substrate), 120 °C. b General conditions but at 145 °C in
xylene. c Substrate (1 equiv), Pd(OAc)2 (0.15 equiv), dcype (0.30 equiv),
Rb2CO3 (1.5 equiv), xylene (0.25 M in 16), 140 °C. d The isolated product
contained a small amount of protodeoxygenated substrate (16:1).
Our next efforts focused on the development of reaction
conditions for the one-pot sequential tosylation/arylation
starting from phenol derivatives.5b,c We were pleased to
find that this could be accomplished using a sequence
involving (1) the reaction of phenolic substrates such as
1-OH with Cs2CO3 (1.5 equiv) and TsCl (1.02 equiv) in
toluene for 1 h at 120 °C and (2) the addition of Pd(OAc)2
(10 mol %), dcype (20 mol %), and CsOPiv (1.1 equiv) to
the reaction mixture. This procedure allowed the reaction
of 1-OH to lead to the desired product 1a in good yield
(Table 4, entry 1). As depicted in Table 4, the one-pot
tosylation/arylation sequence was general with respect to
different substrates and led to products in good isolated
yields. Importantly, the sequential arylation obviates the
isolation and purification of the intermediate tosylates
and effectively leads to the desired products from readily
accessible phenol derivatives.
In order to gain preliminary insight into the mechanism
of the CÀH activation step of the newly developed intra-
molecular arylation, we conducted the reaction with sub-
strate 17. As illustrated in Scheme 1, this reaction pro-
ceeded to afford a mixture of products 17a and 17b in 61%
isolated yield. Importantly, the major product 17a was
obtained via the preferential functionalization of the elec-
tron-rich aryl ring. Although further studies are needed to
elucidate the detailed mechanism, the modest selectivity
for 17a is consistent with the CÀH activation step proceed-
ing via a concerted metalationÀdeprotonation (CMD)
pathway.8b,14,15
(10) Although the reaction was optimized with Cs2CO3, other bases
(e.g., K3PO4 and K2CO3) also lead to good yields of product 1a (see
Supporting Information for details).
(11) Gas chromatographic analysis of the crude reaction mixture
obtained from the reaction of 5-OTs did not show any trace of products
derived from intermolecular arylation.
(12) Upon a reviewers suggestion, the reaction of 18-OTs was also
conducted to study the direct competition between the reaction of aryl
chloride versus aryl tosylate. The reaction of 18-OTs afforded product
18 via selective oxidative addition into the CÀO bond albeit in a low
yield (22%). The mass balance is accounted for by the low conversion of
subtrate 18-OTs and trace protodechlorination.
(14) (a) Ryabov, A. D.; Sakodinskaya, I. K.; Yatsimirsky, A. K.
J. Chem. Soc., Dalton Trans. 1985, 2629. (b) Jia, C.; Lu, W.; Oyamada,
J.; Kitamura, T.; Matsuda, K.; Irie, M.; Fujiwara, Y. J. Am. Chem. Soc.
2000, 122, 7252. (c) Tunge, J. A.; Foresee, L. N. Organometallics 2005,
24, 6440. (d) Davies, D. L.; Donald, S. M. A.; Macgregor, S. A. J. Am.
Chem. Soc. 2005, 127, 13754.
(13) For some representative recent reports on furan synthesis via
CÀH activation, see: (a) Wang, C.; Piel, I.; Glorius, F. J. Am. Chem. Soc.
2009, 131, 4194. (b) Xiao, B.; Gong, T.-J.; Liu, Z.-J.; Liu, J.-H.; Luo, D.-
F.; Xu, J.; Liu, L. J. Am. Chem. Soc. 2011, 133, 9250.
(15) (a) Lafrance, M.; Fagnou, K. J. Am. Chem. Soc. 2006, 128,
16496. (b) Garcia-Cuadrado, D.; de Mendoza, P.; Braga, A. A. C.;
Maseras, F.; Echavarren, A. M. J. Am. Chem. Soc. 2007, 129, 6880.
(c) Gorelsky, S. I.; Lapointe, D.; Fagnou, K. J. Org. Chem. 2012, 77, 658.
4840
Org. Lett., Vol. 14, No. 18, 2012

Table 4. Scope of Sequential Tosylation/Arylation
Table 5. Pd-Catalyzed Intramolecular Arylation Using
Mesylates
a General conditions: substrate (1 equiv), Pd(OAc)2 (0.10 equiv),
dcype (0.20 equiv), Rb2CO3 (1.5 equiv), CsOPiv (1.0 equiv), toluene,
(0.25 M in substrate), 120 °C. b General conditions but with xylene at
140 °C. c The isolated products contained trace amounts of protode-
oxygenated substrate. The ratio of the desired product to the proto-
deoxygenated substrate was generally >20:1.
a General conditions: (1) substrate (1 equiv), Cs2CO3 (1.5 equiv),
TsCl (1.02 equiv), toluene (0.25 M in substrate), 1 h, 120 °C; (2)
Pd(OAc)2 (0.10 equiv), dcype (0.20 equiv), CsOPiv (1.1 equiv), toluene
(0.25 M in substrate), 120 °C. b The isolated products contained trace
amounts of protodeoxygenated substrate. The ratio of desired product
to the protodeoxygenated substrate was generally >20:1.
the base in place of Cs2CO3 significantly attenuated the
hydrolysis and led to the desired products in good yields.
The results in Table 5 depict a preliminary scope of the
arylations using mesylate substrates.
In summary, this paper describes the development of
palladium-catalyzed intramolecular CÀH arylation of
arenes and heteroarenes using tosylates and mesylates as
electrophiles. The transformation is general and efficient
with respect to diverse substrates. Further studies will
focus on broadening the scope of the current transforma-
tion. Additionally, detailed mechanistic studies will be
conducted and reported in due course.
Scheme 1. Electronic Effect for Pd-Catalyzed CÀH Arylation
Acknowledgment. This work was supported by St. Olaf
College. The authors would also like to thank the CURI
(Collaborative Undergraduate Research and Inquiry) pro-
gram at St. Olaf College for financial support of this work.
The successful achievement of the Pd-catalyzed intra-
molecular arylation using tosylates set the stage for the use
of more challenging mesylates as electrophiles. The opti-
mized conditions for the CÀH arylation using tosylates led
to significant hydrolysis of the mesylates. We were pleased
to find, however, that the use of less soluble Rb2CO3 as
Supporting Information Available. Experimental de-
tails and spectroscopic and analytical data for new com-
pounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 18, 2012
4841