Palladium-catalyzed alkylation of ortho-C(sp2)-H bonds of benzylamide substrates with alkyl halides

Article abstract of DOI:10.1021/ol201930e

A highly efficient and generally applicable method has been developed to functionalize the ortho-C(sp²)-H bonds of picolinamide (PA)-protected benzylamine substrates with a broad range of β-H-containing alkyl halides. Sodium triflate has been identified as a critical promoter for this reaction system. The PA group can be easily installed and removed under mild conditions. This method provides a new strategy to prepare highly functionalized benzylamines for the synthesis of complex molecules.

Full text of DOI:10.1021/ol201930e

ORGANIC
LETTERS
2011
Vol. 13, No. 18
4850–4853
Palladium-Catalyzed Alkylation of
ortho-C(sp2)ÀH Bonds of Benzylamide
Substrates with Alkyl Halides
Yingsheng Zhao and Gong Chen*
Department of Chemistry, The Pennsylvania State University, University Park,
Pennsylvania 16802, United States
guc11@psu.edu
Received July 16, 2011
ABSTRACT
A highly efficient and generally applicable method has been developed to functionalize the ortho-C(sp2)ÀH bonds of picolinamide (PA)-protected
benzylamine substrates with a broad range of β-H-containing alkyl halides. Sodium triflate has been identified as a critical promoter for this
reaction system. The PA group can be easily installed and removed under mild conditions. This method provides a new strategy to prepare highly
functionalized benzylamines for the synthesis of complex molecules.
Synthetic methods based on the catalytic arylation of
CÀH bonds of arenes and heteroarenes have become
readily available in the past decade.1 The development of
CÀH alkenylation of arenes is also rapidly advancing.2 In
keeping with this trend, CÀH alkylation reactions, espe-
cially using easily accessible alkyl halides, represents the
next significant challenge in the CÀH activation field.3
Despite difficulties associated with the inherent resis-
tance of alkyl halides toward oxidative addition and the
tendency toward β-H elimination,4 several metal-catalyzed
CÀH alkylation reactions have emerged during the past
few years.5À9 However, in order to move this CÀH alkyla-
tion conceppt into the mainstream of organic synthesis,
many features of these reaction systems need to be sig-
nificantly improved, including broader arene and alkyl
(5) For selected examples of Pd-catalyzed CÀH alkylation reactons,
see: (a) Tremont, S. J.; Rahmen, H. U. J. Am. Chem. Soc. 1984, 106,
5759–5760. (b) Hennessy, E.; Buchwald, S. L. J. Am. Chem. Soc. 2003,
125, 12084–12085. (c) Chen, X.; Li, J.-J.; Hao, X.-S.; Goodhue, C. E.;
Yu, J.-Q. J. Am. Chem. Soc. 2006, 128, 78–79. (d) Rudolph, A.;
Rackelmann, N.; Lautens, M. Angew. Chem., Int. Ed. 2007, 46, 1485–
1488. (e) Hwang, S. J.; Cho, S. H.; Chang, S. J. Am. Chem. Soc. 2008,
130, 16158–16159. (f) Zhang, Y.-H.; Yu, J.-Q. Angew. Chem., Int. Ed.
2009, 48, 6097–6100. (g) Lapointe, D.; Fagnou, K. Org. Lett. 2009, 11,
4160–4263. (h) Shabashov, D.; Daugulis, O. J. Am. Chem. Soc. 2010,
132, 3965–3972. (i) Mukai, T.; Hirano, K.; Satoh, T.; Miura, M. Org.
Lett. 2010, 12, 1360–1363.
(1) For selected reviews on CÀH arylation reactions of arene and
heteroarenes, see: (a) Miura, M.; Nomura, M. Top. Curr. Chem. 2002,
219, 211–241. (b) Campeau, L.-C.; Fagnou, K. Chem. Commun. 2006,
1253–1264. (c) Alberico, D.; Scott, M. E.; Lautens, M. Chem. Rev. 2007,
107, 174–238. (d) Lewis, J. C.; Bergman, R. G.; Ellman, J. A. Acc. Chem.
Res. 2008, 41, 1013–1025. (e) Chen, X.; Engle, K. M.; Wang, D.-H.; Yu,
J.-Q. Angew. Chem., Int. Ed. 2009, 48, 5094–5115. (f) Lyons, T. W.;
Sanford, M. S. Chem. Rev. 2010, 110, 1147–1169.
(6) For selected examples of Ru-catalyzed CÀH alkylation reactons,
(2) For selected examples of CÀH alkenylation reactions, see:
(a) Boele, M. D. K.; van Strijdonck, G. P. F.; de Vries, A. H. M.; Kamer,
P. C. J.; de Vries, J. G.; van Leeuwen, P. W. N. M. J. Am. Chem. Soc.
2002, 124, 1586–1587. (b) Zaitsev, V. G.; Daugulis, O. J. Am. Chem. Soc.
2005, 127, 4156–4157. (c) Cai, G.; Fu, Y.; Li, Y.; Wan, X.; Shi, Z. J. Am.
Chem. Soc. 2007, 129, 7666–7673. (d) Nishikata, T.; Lipshutz, B. H. Org.
Lett. 2010, 12, 1972–1975. (e) Wang, D.-H.; Engle, K. M.; Shi, B.-F.; Yu,
J.-Q. Science 2010, 327, 315–319.
ꢀ
see: (a) Ackermann, L.; Novak, P.; Vicente, R.; Hofmann, N. Angew.
Chem., Int. Ed. 2009, 48, 6045–6048. (b) Ackermann, L.; Hofmann, N.;
Vicente, R. Org. Lett. 2011, 13, 1875–1977.
(7) For a selected example of the Ni-catalyzed CÀH alkylation
reacton, see: Vechorkin, O.; Proust, V.; Hu, X. Angew. Chem., Int. Ed.
2010, 49, 3061–3064.
(8) For a selected example of the Cu-catalyzed CÀH alkylation
reacton, see: Dieu, L.; Daugulis, O. Org. Lett. 2010, 12, 4277–4279.
(9) For a selected example of the Co-catalyzed CÀH alkylation
reacton, see: Chen, Q.; Ilies, L.; Nakamura, E. J. Am. Chem. Soc. 2011,
133, 428–429.
(3) Ackermann, L. Chem. Commun. 2010, 46, 4866–4877.
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1525–1532. (b) Rudolph, A; Lautens, M. Angew. Chem., Int. Ed. 2009,
48, 2656–2670.
r
10.1021/ol201930e
Published on Web 08/19/2011
2011 American Chemical Society

halide substrate scope, use of low-cost catalysts and re-
agents, and convenient and mild operating conditions
(e.g., no strong bases or acids).10 Herein, we report a highly
efficient and generally applicable method to selectively
functionalize the ortho-CÀH bonds of benzyl picolinamide
substrates with a broad range of β-H-containing alkyl
halides under palladium-catalyzed conditions.
The chemistry of Pd-catalyzed picolinamide (PA)-direc-
ted arylation of C(sp3)ÀH bonds with aryl halides was first
introduced in a seminal paper by Daugulis in 2005.11 Our
recent reinvestigation of this system has significantly ex-
panded the substrate scope and improved the synthetic
utility of this chemistry.12 Prompted by this success, we
wanted to explore whether the PA directing group could
also facilitate the CÀH alkylation reactions with alkyl
halides.13 Because of the γ-regioselectivity controlled by
the five-membered palladacycle intermediate, we expected
that ortho-CÀH bonds of benzylamides could be sele-
ctively functionalized to provide the corresponding ortho-
alkylated benzylamides, which could then be readily
transformed to privileged structures such as the tetrahy-
droisoquinoline (THIQ) scaffolds (Table 1A).14
Accordingly, the alkylation of PA-protected benzyl-
amine substrate 1 with 1-iodopropane (3 equiv) was
examined under various palladium-catalyzed conditions
(Table 1B). The initial trials under the original Pd(OAc)2/
AgOAc conditions provided only trace amounts of prod-
uct 2 even with a large excess of iodopropane (entry 1).15
Replacing AgOAc with a carboxylic acid additive gave no
improvement. Addition of 2 equiv of K2CO3 increased the
yield of 2 to 43% (entry 4). Interestingly, a much-improved
reaction was achieved with 2 equiv of K2CO3 and 3 equiv
of NaOAc in t-amylalcohol at 125 °C for 24 h (entry 11).
These conditions were further improved by carrying
out the reaction under an O2 atmosphere (entry 13).16
Although efficient alkylation of 1 was observed under this
set of conditions, undesired alkylation of the OAc anion
with iodopropane was a side reaction, which not only
consumed a significant amount of the halide substrate
but also caused the incomplete alkylation of the benzyl-
amide substrate. In the presence of AgOAc, this esterifica-
tion reaction significantly competed with the desired CÀH
alkylation process (entry 8). To overcome this problem, a
non-nucleophilic ligand for palladium was needed. To our
surprise, though the OAc ligand is known to facilitate both
CÀH activation and catalyst regeneration, the CÀH alky-
lation takes place in the absence of OAc (entry 6).17
Further screening revealed that sodium triflate (NaOTf,
3 equiv) worked as a superior surrogate for NaOAc to
completely avoid the side esterification reaction and pro-
mote a highly efficient CÀH alkylation reaction even with
reduced loading of Pd(OAc)2 under an O2 atmosphere
(entry 15). Product 2 was obtained in nearly quantitative
yield after simple filtration through a short silica gel plug
(entry 15, 36 h). LiOTf and KOTf gave considerably lower
Table 1. Pd-Catalyzed C(sp2)ÀH Alkylation Reactionsa
yields than NaOTf (entries 17 and 18). Pd(OTf)2 2H2O
3
(10) For selected examples of CÀH activation in natural product
synthesis, see: (a) Godula, K.; Sames, D. Science 2006, 312, 67–72.
(b) Davies, H. M.; Manning, J. R. Nature 2008, 451, 417–424.
(c) Gutekunst, W. R.; Baran, P. S. Chem. Soc. Rev. 2011, 40, 1976–
1991. (d) Hinman, A.; Du Bois, J. J. Am. Chem. Soc. 2003, 125, 11510–
11511. (e) O’Malley, S. J.; Tan, K. L.; Watzke, A.; Bergman, R. G.;
Ellman, J. A. J. Am. Chem. Soc. 2005, 127, 13496–13497. (f) Beck, E. M.;
Hatley, R.; Gaunt, M. J. Angew. Chem., Int. Ed. 2008, 47, 3004–3007.
(g) Chaumontet, M.; Piccardi, R.; Baudoin, O. Angew. Chem., Int. Ed.
2009, 48, 179–182. (h) Chen, M. S.; White, M. C. Science 2010, 327, 566–
571. (i) Feng, Y. Q.; Chen, G. Angew. Chem., Int. Ed. 2010, 49, 958–961.
(j) Wang, D.-H.; Yu, J.-Q. J. Am. Chem. Soc. 2011, 133, 5767–5769.
(11) Zaitsev, V. G.; Shabashov, D.; Daugulis, O. J. Am. Chem. Soc.
2005, 127, 13154–13155.
(12) He, G.; Chen, G. Angew. Chem., Int. Ed. 2011, 50, 5192–5196.
(13) (a) Canty, A. J. Acc. Chem. Res. 1992, 25, 83–90. (b) Hull, K. L.;
Lanni, E. L.; Sanford, M. S. J. Am. Chem. Soc. 2006, 128, 14047–14049.
(c) Xu, L.; Li, B.; Yang, Z.; Shi, Z. Chem. Soc. Rev. 2010, 39, 712–733.
(14) Bentley, K. Nat. Prod. Rep. 2006, 23, 444–463.
(15) (a) See ref 11. (b) Chiong, H. A.; Pham, Q.-N.; Daugulis, O.
J. Am. Chem. Soc. 2007, 127, 9879–9884.
(16) O2 is crititial to the high yield of these alkylation reactions when
low loading of Pd(OAc)2 (<10%) and/or β-H-containing alkyl halides
are employed. It presumably reoxidizes Pd0 generated from the unde-
sired side reactions to PdII and increases the catalytic turnover number
of Pd(OAc)2. O2 has no effect on the Pd-catalyzed methylation reaction
with MeI.
(17) For discussions of the role of the carboxylate ligands in CÀH
activation, see: (a) Davies, D. L.; Donald, S. M. A.; Macgregor, S. A.
J. Am. Chem. Soc. 2005, 127, 13754–13755. (b) Lafrance, M.; Fagnou,
K. J. Am. Chem. Soc. 2006, 128, 16496–16497. (c) Feng, Y.; Wang, Y.;
Landgraf, B.; Liu, S.; Chen, G. Org. Lett. 2010, 12, 3414–3417.
a All screening reactions were carried out in a 10 mL glass vial with a
PETF-lined cap on a 0.2 mmol scale without strict exclusion of moisture.
1
b Yields are based on H NMR analysis of the reaction mixture. c The
reaction vial was flushed with O2 (1 atm) and then sealed with a PETF-
lined cap. d Isolated yield.
Org. Lett., Vol. 13, No. 18, 2011
4851

Table 2. Substrate Scope of Alkyl Halides
Scheme 1. Substrate Scope of Benzylamides
a All yields are based on isolated products on a 0.2 mmol scale without
strict exclusion of moisture or air. b Condition B is similar to condition A
except using 5 equiv of n-PrI. c Condition Cis similar to condition Aexcept
using 10 mol % of Pd(OAc)2, 3-methyl-3-pentanol as solvent, 135 °C.
(commercially unavailable) was a slightly less effective
catalyst for this reaction (entry 19).18
With an optimized set of conditions in hand (condition
A), we next explored the benzylamine substrate scope
(Scheme 1). The electronic property of the benzylamine
substrates used has a strong effect on its reactivity toward
alkylation. In general, electron-rich substrates (e.g., 3)
could be readily alkylated in excellent yield while elec-
tron-deficient substrates (e.g., 4, 5 and 6) gave lower
yields. The alkylation reactions of the latter could be im-
proved using slightly more forcing conditions (condition
C: 10 mol % of Pd(OAc)2, 3-methyl-3-pentanol solvent,
135 °C, 36 h). Bis-alkylation usually predominates in the
reaction of substrates with two equivalent ortho-CÀH
bonds (e.g., 7 and 8). However, highlyregioselectivemono-
alkylation can be achieved with substrates bearing para-
directing substituents (e.g., 6, 9, 10 and 14); steric factors
may also play a role in the high regioselectivity observed in
these substrates. Furthermore, both bromine and alkene
substituents on the benzylamine substrates (e.g., 10 and
14) are conserved under these conditions. Finally, R-sub-
stituted benzylamine substrates also alkylate well (e.g.,
8 and 11).
The substrate scope of the alkyl halides has also been
explored (Table 2). A broad range of primary alkyl iodides
were readily incorporated. Most common functional groups
including CO2Me, CbzNH, cyclic ketals, benzyl ethers,
and alkenes are well-tolerated (entries 1À6). Steric hin-
drance usually retards the reactivity as evidenced by the
low yield obtained in alkylations with secondary alkyl
a Yields are based on isolated products on a 0.2 mmol scale with 3
equiv of alkyl halides. b Under condition C. c Condition D is similar to
condition A except the addition of 2 equiv of NaI. d Condition E is
similar to condition A except using 10 mol % of Pd(OAc)2.
(18) For a selected example of OTf ligand used in Pd-catalyzed CÀH
activations, see: (a) Wang, X.; Mei, T.-S.; Yu, J.-Q. J. Am. Chem. Soc.
2009, 131, 7520–7521. (b) Xiao, B.; Gong, T.-J.; Xu, J.; Liu, Z.-J.; Liu, L.
J. Am. Chem. Soc. 2010, 133, 1466–1474.
iodides (entry 9). Compared to alkyl iodides, primary
alkyl bromides and chlorides only gave trace amount of
products under the standard conditions. However, the
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Org. Lett., Vol. 13, No. 18, 2011

Scheme 2. Preliminary Mechanistic Studies
Scheme 3. Synthetic Utilities of the CÀH Alkylation Methoda
reactions could be dramatically improved by the addition
of 2 equiv of NaI (condition D, entries 11À13). More
electrophilic halides such as benzyl chloride (39), R-bromo
acetic ester (42), and Weinreb amide (44) could also be
effectively employed; the NaOTf additive was critical to
the success of these more reactive substrates. Finally, it is
noteworthy that N-alkylated products were not observed
in any of the reactions.
A few preliminary mechanistic studies have been carried
out to probe the details of this CÀH alkylation reaction.
Although the entire process likely proceeds through a
palladation/cross-coupling sequence, our efforts to obtain
the putative palladacycle intermediate have been unsucces-
sful. However, the ortho-CÀH bond of substrate 1 could
be completely deuterated under the catalysis of Pd-
(OAc)2 and AcOD (10 equiv) to provide product 46
(Scheme 2). A primary kinetic isotope effect (∼3) was
observed for the alkylation of 1 and 46 with n-PrI. The
nature of the subsequent cross-coupling remains elusive.
Although a PdII/IV cycle via the oxidative addition of alkyl
halide might be operative, a σ metathesis mechanism
cannot be ruled out.5a,e
Due to their low cost19 and high stability, PA could be
employed as an amide-linked protecting group for benzyl-
amine substrates. For example, PA could be easily intro-
duced in 15 by reacting 3-methoxybenzylamine with
2-picolinyl chloride or by standard amide coupling with
2-picolinic acid (Scheme 3A). Regioselective alkylation of
15 could be achieved under the standard conditions with
only 1.5 equiv of octyl iodide. Unlike the PA-protected
aliphatic amine substrates with bulky R-substituents,12 the
PA of 35 could be activated with Boc2O and cleaved by
LiOH/H2O2 to give the Boc-protected amine product 47 in
high yield.
a Reagents and conditions: (a) octyl iodide (1.5 equiv), condition A,
87%; (b) Boc2O, DMAP, CH3CN, rt, 92%; (c) LiOH, H2O2, H2O/THF,
rt, 90%; (d) 22 (3 equiv), condition E, 93%; (e) (i) Pd/C, HCl/MeOH,
rt, 76%; (ii) TsCl, pyridine, 0 °C; (iii) NaH, THF, 78% over two steps;
(iv) NaOMe, MeOH, 100 °C, 84%. All yields were based on isolation.
available amineprecursor, could be alkylatedtoprovide 48
in high yield. The OBn group of 48 could be converted to
OTs, followed by intramolecular N-alkylation and clea-
vage of the tertiary picolinamide, to give the THIQ 49 in
good yield (Scheme 3B). We expect that this CÀH alkyla-
tion/cyclization strategy, especially with easily accessible
chiral R-substituted benzylamine substrates, provides an
attractive complement to the classical PictetÀSpengler
synthesis of complex THIQs.20
In summary, we have developed a generally applicable
method to alkylate the ortho-CÀH bonds of picolinamide-
protected benzylamines with β-H-containing alkyl halides.
The non-nucleophilic promoter NaOTf is critical for this
reaction. Excellent product yields and selectivities were
obtained with a broad range of benzylamides and primary
alkyl halides, including chlorides. The alkylation reaction
is silver-free and does not require expensive ligands or
reagents. The PA directing group can be easily exchanged
for a Boc group under mild conditions. Further mechanis-
tic studies and applications of this CÀH alkylation meth-
odology in the synthesis of complex THIQ natural pro-
ducts are currently under investigation.
Acknowledgment. We would like to dedicate this paper
to Professor Steven M. Weinreb on the occasion of his 70th
birthday. This work was supported by a startup fund from
The Pennsylvania State University and an NSF CAREER
Award (CHE-1055795).
To further demonstrate the synthetic utility of this CÀH
alkylation chemistry, 41, prepared from the commercially
Supporting Information Available. Experimental pro-
cedures and spectroscopic data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(19) The price for 2-picolinic acid (99%, Aldrich) is $40 for 100 g.
(20) In contrast with the PictetÀSpengler route, the key stereochem-
istry at the C1 position of THIQ could be readily and reliably established
in the chiral benzylamine precursors in the early stage of synthesis, e.g.,
via asymmetric reduction of corresponding imines.
Org. Lett., Vol. 13, No. 18, 2011
4853