Palladium-catalyzed benzylation of heterocyclic aromatic compounds

Article abstract of DOI:10.1021/ol901689q

Broadly applicable palladium-catalyzed heteroarene benzylation reactions are described with a focus on the most challenging heterocyclic classes under traditional benzylation techniques such as sulfur-containing heterocycles and those bearing functional groups that would be incompatible with reactions requiring Lewis acids and/or strong bases.

Full text of DOI:10.1021/ol901689q

ORGANIC
LETTERS
2009
Vol. 11, No. 18
4160-4163
Palladium-Catalyzed Benzylation of
Heterocyclic Aromatic Compounds
David Lapointe and Keith Fagnou*
Center for Catalysis Research and InnoVation, Department of Chemistry, UniVersity of
Ottawa, 10 Marie Curie, Ottawa, ON, K1N 6J7, Canada
keith.fagnou@uottawa.ca
Received July 23, 2009
ABSTRACT
Broadly applicable palladium-catalyzed heteroarene benzylation reactions are described with a focus on the most challenging heterocyclic
classes under traditional benzylation techniques such as sulfur-containing heterocycles and those bearing functional groups that would be
incompatible with reactions requiring Lewis acids and/or strong bases.
While Friedel-Crafts or SEAr arene alkylation is a front line
technique in the formation of new arene-alkane C-C
bonds,1 application of this method to many heterocyclic
aromatic compounds can be problematic, particularly when
resonance electron-withdrawing groups are present or when
there are functional groups that are sensitive to strong Lewis/
Bronsted acids. These challenges are further exacerbated with
sulfur-containing heterocycles, which are less nucleophilic
than the corresponding oxa- and aza-homologues.2 In these
instances, arene deprotonation with strong bases (such as
BuLi) followed by electrophilic trapping is the most common
alternative.3 While valuable, this approach necessitates the
protection of all electrophilic and acidic functional groups,
adding chemical steps, waste, and cost.4
Recently, metal-catalyzed cross-couplings of benzyl ha-
lides with aryl organometallics have emerged as alternatives
to the use of strong acids or bases.5 Our interest in the use
of simple arenes as replacements of stoichiometric organo-
metallic reagents6 in cross-coupling reactions led us to
question whether similar reactivity may also be possible with
aliphatic electrophiles. In contrast to the rapid growth in
(4) (a) Carpenter, A. J.; Chadwick, D. J. Tetrahedron 1985, 41, 3803.
(b) Ung, A. T.; Pyne, S. G.; Skelton, B. W.; White, A. H. Tetrahedron
1996, 52, 14069. (c) Zhu, Y.; Zhu, Y.-Z.; Song, H.-S.; Zheng, J.-Y.; Liu,
Z.-B.; Tian, J.-G. Tetrahedron Lett. 2007, 48, 5687. (d) Smith, T. E.; Kuo,
W.-H.; Balskus, E. P.; Bock, V. D.; Roizen, J. L.; Theberge, A. B.; Carroll,
K. A.; Kurihara, T.; Wessler, J. D. J. Org. Chem. 2007, 73, 142. (e)
Garfunkle, J.; Ezzili, C.; Rayl, T. J.; Hochstatter, D. G.; Hwang, I.; Boger,
D. L. J. Med. Chem. 2008, 51, 4392.
(5) For reviews, see: (a) Lie´gault, B.; Renaud, J.-L.; Bruneau, C. Chem.
Soc. ReV. 2008, 37, 290. (b) Kuwano, R. Synthesis 2009, 7, 1049. Recent
publications: (c) Srimani, D.; Sarkar, A. Tetrahedron Lett. 2008, 49, 6304.
(d) Fairlamb, I. J. S.; Sehnal, P.; Taylor, R. J. K. Synthesis 2008, 508.
(6) For reviews, see: (a) Daugulis, O.; Zaitsev, V. G.; Shabashov, D.;
Pham, Q.-N.; Lazareva, A. Synlett 2006, 3382. (b) Campeau, L.-C.; Fagnou,
K. Chem. Commun. 2006, 1253. (c) Alberico, D.; Scott, M. E.; Lautens,
M. Chem. ReV. 2007, 107, 174. (d) Seregin, I. V.; Gevorgyan, V. Chem.
Soc. ReV. 2007, 36, 1173. (e) Satoh, T.; Miura, M. Chem. Lett. 2007, 36,
200. (f) Campeau, L.-C.; Stuart, D. R.; Fagnou, K. Aldrichimica Acta, 2007,
40, 35. (g) Li, B.-J.; Yang, S.-D.; Shi, Z.-J. Synlett 2008, 949. Recent
publications, see: (h) Lie´gault, B.; Lapointe, D.; Caron, L.; Vlassova, A.;
Fagnou, K. J. Org. Chem. 2009, 74, 1826. (i) Campeau, L.-C.; Stuart, D. R.;
Leclerc, J.-P.; Bertrand-Laperle, M.; Villemure, E.; Sun, H.-Y.; Lasserre,
S.; Guimond, N.; Lecavallier, M.; Fagnou, K. J. Am. Chem. Soc. 2009,
131, 3291. (j) Huestis, M. P.; Fagnou, K. Org. Lett. 2009, 11, 1357.
(1) (a) Olah, G. A. Friedel-Crafts and Related Reactions; Wiley-
Interscience: New York, 1964; Vol. II, Part 1. (b) Roberts, R. M.; Khalaf,
A. A. Friedel-Crafts Alkylation Chemistry. A Century of DiscoVery; Marcel
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Angew. Chem., Int. Ed. 2004, 43, 550. (d) Dugger, R. W.; Ragan, J. A.;
Ripin, B. Org. Process Res. DeV. 2005, 9, 253. (e) Carey, J. S.; Laffran,
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B.; Ofial, A. R. Acc. Chem. Res. 2003, 36, 9769.
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791. (b) Chinchilla, R.; Na´jera, C.; Yus, M. Chem. ReV. 2004, 104, 2667.
(c) Slocum, D. W.; Shelton, P.; Moran, K. M. Synthesis 2005, 3477.
10.1021/ol901689q CCC: $40.75
Published on Web 08/17/2009
 2009 American Chemical Society

direct arylation with aryl halide electrophiles,6 the use of
aliphatic electrophiles is rare. Very recently, Yu described
palladium(II)-catalyzed benzoic acid alkylation reactions,7
and Ackermann has reported a directed arene alkylation
employing a ruthenium catalyst where the catalytic cycle
likely involves arene metalation prior to interaction with the
alkyl halide.8 Palladium(0)-catalyzed arene alkylations em-
ploying norbornene have also been described by Catellani9
and Lautens,10 enabling the preparation of a wide range of
alkyl-substituted aromatic compounds.11
With a standard palladium(0) catalytic cycle employing
aliphatic halides, important first steps have been made
establishing intramolecular reactivity. For example, Buch-
wald and Henessy described the cyclization of R-chloroac-
etanilides in the formation of oxindoles,12 and Cheng reported
a cyclization of benzylic halides with a pendent pyrrole to
close a six-membered ring.13 An interesting tandem process
has also been described by Wong involving closure of a six-
membered ring between a benzyl bromide and a furan.14 On
the other hand, the reaction of oxazole with alkyl halides
reported by Hoarau constitutes the only example of inter-
molecular arene alkylation under this reaction paradigm.15
In this letter, we describe the establishment of broadly
applicable palladium-catalyzed heteroarene benzylation reac-
tions (Figure 1). A particular focus is accorded to the most
with palladium catalysis in reactions at unactivated C-H
bonds with sp2 carbon halides6 should also be accessible with
sp3 carbon electrophiles.
Given their challenging use under Friedel-Crafts reaction
conditions, sulfur-containing heterocycles2 were selected for
reaction development and optimization. From these studies,
we determined that treatment of the heterocycle with a benzyl
17
chloride (1.5 equiv) in the presence of Pd(OPiv)2 (2 mol
%), 2-Ph2P-2′-(Me2N)biphenyl18 (4 mol %), PivOH (20 mol
%), and Cs2CO3 (1.5 equiv) in toluene (0.5 M) at 110 °C
were optimal conditions. Choice of the appropriate electro-
phile is crucial (Table 1). While reactions with bromide,
Table 1. Effect of the Benzylic Leaving Group on Reactivity
entry
X
% GC yield
1
2
3
4
5
6
7
Cl (2a)
OP(O)OEt2
Br
O2CCF3
OAc
81(78b)
51
6
11
0
0
OPiv
O2COMe
0
a Conditions: benzyl chloride (0.75 mmol), heteroarene (0.50 mmol),
Pd(OPiv)2 (0.01 mmol), 2-Ph2P-2′-(Me2N)biphenyl (0.02 mmol), PivOH
(0.10 mmol), Cs2CO3 (0.75 mmol), toluene (1.0 mL), 110 °C, 16-20 h.
b Isolated yield.
Figure 1. Palladium-catalyzed heteroarene benzylation.
acetate, pivalate, trifluoroacetate, and carbonate electrophiles
provide little (less than 10%) or none of the desired cross-
coupling product, use of benzylic chloride or phosphonate
substrates generates 3 in 81% and 51% GC yields, respec-
tively (Table 1, entries 1 and 2). The importance of the
leaving group is interesting and merits further consideration.
From a convenience and cost effectiveness perspective, the
fact that the inexpensive, readily available benzyl chlorides
perform best is a desirable outcome. For this reason, we opted
to evaluate the scope with this class of electrophile. It is
important to note, however, that the use of the benzyl phos-
phonate electrophiles may have particular utility since they may
be easily prepared form the corresponding benzyl alcohol.
Illustrative examples with a range of sulfur-containing
heterocycles are included in Table 2. Thiazole substrates,
which are problematic under SEAr benzylation conditions
or necessitate deprotonation with strong bases followed by
electrophilic trapping,19 are ideal substrates for palladium-
challenging heterocycles of traditional benzylation tech-
niques, such as sulfur-containing heterocycles and those
bearing functional groups that would be incompatible with
Lewis acids and/or strong bases. The reactions are highly
regioselective and form industrially important diarylmethane
compounds.16 Furthermore, the establishment of generally
applicable Csp2-Csp3 direct benzylation reactions provides
compelling evidence that the wealth of reactivity uncovered
(7) Zhang, Y.-H.; Shi, B.-F.; Yu, J.-Q. Angew. Chem., Int. Ed. 2009,
48, 6097.
(8) Ackermann, L.; Novak, P.; Vicente, R.; Hofmann, N. Angew. Chem.,
Int. Ed. 2009, 48, 6045.
(9) (a) Catellani, M.; Frignani, F.; Rangoni, A. Angew. Chem., Int. Ed.
Engl. 1997, 36, 119. (b) Catellani, M.; Cugini, F. Tetrahedron 1999, 55,
6595. (c) Catellani, M.; Motti, E.; Minari, M. Chem. Commun. 2000, 157.
(10) (a) Rudolph, A.; Rackelmann, N.; Turcotte-Savard, M.-O.; Lautens,
M. J. Org. Chem. 2009, 74, 289. (b) Martins, A.; Lautens, M. Org. Lett.
2008, 10, 5095.
(11) For reviews, see: (a) Frisch, A. C.; Beller, M. Angew. Chem., Int.
Ed. 2005, 44, 674. (b) Catellani, M.; Motti, E.; Della Ca′, N. Acc. Chem.
Res. 2008, 41, 1512.
(16) (a) Graffner-Nordberg, M.; Kolmodin, K.; Åqvist, J.; Queener, S. F.;
Hallberg, A. J. Med. Chem. 2001, 44, 2391. (b) Guile, S. D.; Bantick, J. R.;
Cooper, M. E.; Donald, D. K.; Eyssade, C.; Ingall, A. H.; Lewis, R. J.;
Martin, B. P.; Mohammed, R. T.; Potter, T. J.; Reynolds, R. H.; St-Gallay,
S. A.; Wright, A. D. J. Med. Chem. 2007, 50, 254. (c) Izumi, K.; Kabaki,
M.; Uenaka, M.; Shimizu, S. Org. Process Res. DeV. 2007, 11, 1059.
(17) Bancroft, D. P.; Cotton, F. A.; Falvello, L. R.; Schwotzer, W.
Polyhedron 1988, 7, 615.
(12) Hennessy, E. J.; Buchwald, S. L. J. Am. Chem. Soc. 2003, 125,
12084.
(13) Hwang, S. J.; Cho, S. H.; Chang, S. J. Am. Chem. Soc. 2008, 130,
16158.
(14) Song, Z. Z.; Wong, H. N. C. J. Org. Chem. 1994, 59, 33.
(15) Verrier, C.; Hoarau, C.; Marsais, F. Org. Biomol. Chem. 2009, 7,
647.
(18) Harris, M. C.; Geis, O.; Buchwald, S. L. J. Org. Chem. 1999, 64,
6019.
Org. Lett., Vol. 11, No. 18, 2009
4161

the sulfur atom (Table 2, entries 10-13). A variety of other
heterocycles also undergo regioselective palladium-catalyzed
benzylation, as illustrated in Table 3, including indolizines
imidazopyrimidine, 1,2,3-triazoles, oxazoles, and electron-
deficient furans. It is important to note that under these
conditions the palladium selectively reacts at the benzylic
C-Cl bond rather than the aryl-Cl bond (Table 2, entries
1, 3, 6, and 10 and Table 3, entry 2). In this way, substrates
bearing useful functional groups may be employed that can
subsequently be applied in other metal-catalyzed function-
alization processes.22
Table 2. Benzylation of Sulfur-Containing Heterocyclesa b
,
Table 3. Additional Examples of Heterocycle Benzylationa b
,
a Conditions: benzyl chloride (0.75 mmol), heteroarene (0.50 mmol),
Pd(OPiv)2 (0.01 mmol), 2-Ph2P-2′-(Me2N)biphenyl (0.02 mmol), PivOH
(0.10 mmol), Cs2CO3 (0.75 mmol), toluene (1.0 mL), 110 °C, 16-20 h.
b Isolated yield. c Benzyl chloride (1.00 mmol), heteroarene (0.50 mmol),
Pd(OPiv)2 (0.025 mmol), 2-Ph2P-2′-(Me2N)biphenyl (0.05 mmol), PivOH
(0.10 mmol), Cs2CO3 (0.75 mmol), toluene (1.0 mL), 110 °C, 16-20 h.
a Conditions: benzyl chloride (0.75 mmol), heteroarene (0.50 mmol),
Pd(OPiv)2 (0.01 mmol), 2-Ph2P-2′-(Me2N)biphenyl (0.02 mmol), PivOH
(0.10 mmol), Cs2CO3 (0.75 mmol), toluene (1.0 mL), 110 °C, 16-20 h.
b Isolated yield. c Benzyl chloride (1.00 mmol), heteroarene (0.50 mmol),
Pd(OPiv)2 (0.025 mmol), 2-Ph2P-2′-(Me2N)biphenyl (0.05 mmol), PivOH
(0.10 mmol), Cs2CO3 (0.75 mmol), toluene (1.0 mL), 110 °C, 16-20 h.
catalyzed benzylation. A variety of aliphatic and aromatic
substituents are tolerated including chloride, ester, ketone,
and nitro functional groups (Table 2, entries 1-8). Ben-
zothiophene also undergoes clean C2 benzylation, which is
complementary to standard SEAr-type benzylation outcomes
that produce the C3 isomer preferentially (Table 2, entry 9).20
Similarly, electron-deficient thiophenes, which are particu-
larly challenging under Friedel-Crafts reactivity,21 undergo
regioselective palladium-catalyzed benzylation adjacent to
The utility of palladium-catalyzed arene benzylation
compared to traditional techniques may be illustrated by the
successful formation of 14 and 15 (Table 2, entries 11 and
12). In addition to low nucleophilicity that is problematic
for SEAr-like reactivity, the 2-acetylthiophene starting ma-
(19) For examples, see: (a) Hamana, H.; Sugasawa, T. Chem. Lett. 1982,
333. (b) Evans, D. A.; Cee, V. J.; Smith, T. E.; Santiago, K. J. Org. Lett.
1999, 1, 87. (c) Deng, S.; Taunton, J. Org. Lett. 2005, 7, 291. (d) Teng,
P.-F.; Tsang, C.-S.; Yeung, H.-L.; Wong, W.-L.; Kwong, H.-L.; Williams,
I. D. J. Organomet. Chem. 2006, 691, 2237.
(21) Friedel-Crafts additions of electrophiles to thiophenes bearing
EWG are exceedingly rare. For examples involving thiophene deprotonation
using a strong base, see: (a) Slocum, D. W.; Gierer, P. L. Chem. Commun.
1971, 305. (b) Shilai, M.; Kondo, Y.; Sakamoto, T. J. Chem. Soc., Perkin
Trans. 1 2001, 442. See also ref.4a
(20) Clark, P. D.; Mesher, S. I. Phosphorus, Sulfur Silicon Relat. Elem.
1995, 105, 157.
(22) Littke, A. F.; Fu, G. C. Angew. Chem., Int. Ed. 2002, 41, 4176.
4162
Org. Lett., Vol. 11, No. 18, 2009

terial required in the formation of 14 would be incompatible
with the strong alkyl-lithium bases required for arene
deprotonation, due to the presence of more acidic protons
on the acetyl moiety. This example highlights the inherent
preference of the palladium catalyst to induce sp2 C-H bond
cleavage under the conditions described herein compared to
similar reactions on the same substrate that result in ketone
R-arylation when performed in the presence of a stronger
base.23,24 Similarly, the formation of 15 would be equally
problematic under traditional techniques due to the presence
of the resonance electron-withdrawing and electrophilic
aldehyde group that would necessitate the use of additional
protection/deprotection steps.4
range of diarylmethane compounds. Importantly, the ability
to achieve useful reactivity with some of the most problem-
atic cases of traditional techniques should be invaluable when
the preparation of these types of molecules is called for.
Finally, the establishment of broadly applicable intermo-
lecular cross-couplings between simple heteroarenes (without
organometallic preactivation) and aliphatic electrophiles
should prompt a much wider examination of this chemistry.
Acknowledgment. We thank NSERC, the University of
Ottawa, Eli Lilly, Amgen, Astra Zeneca, and the Sloan
Foundation (fellowship, K.F.). D.L. thanks NSERC for a
graduate student scholarship.
These palladium-catalyzed heterocycle benzylation reac-
tions should find application in the preparation of a wide
Supporting Information Available: Experimental pro-
cedures and characterization data for all compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(23) This tendency was also observed with picoline N-oxide substrates.
See: (a) Campeau, L.-C.; Schipper, D. J.; Fagnou, K. J. Am. Chem. Soc.
2008, 130, 3266. (b) Schipper, D. J.; Campeau, L.-C.; Fagnou, K.
Tetrahedron 2009, 65, 3155.
(24) For ketone R-arylation, see: Hamann, B. C.; Hartwig, J. F. J. Am.
Chem. Soc. 1997, 119, 12382.
OL901689Q
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