Rh(I)-catalyzed alkylation of quinolines and pyridines via C-H bond activation

Article abstract of DOI:10.1021/ja070388z

The scope of heterocycle ortho-alkylation has been dramatically expanded to include pharmaceutically important pyridines and quinolines, which contain only a single nitrogen. The reactions, which are conducted at a high concentration (0.8 M), can be performed with catalyst loadings as low as 1% Rh. Substitution ortho to the heterocycle ring nitrogen is required for efficient alkylation and is consistent with the intermediacy of a Rh-carbene intermediate similar to those proposed in our earlier work. Copyright

Full text of DOI:10.1021/ja070388z

Published on Web 04/06/2007
Rh(I)-Catalyzed Alkylation of Quinolines and Pyridines via C-H Bond
Activation
Jared C. Lewis, Robert G. Bergman,* and Jonathan A. Ellman*
Department of Chemistry, UniVersity of California, and DiVision of Chemical Sciences, Lawrence Berkeley National
Laboratory, Berkeley, California 94720
Received January 18, 2007; E-mail: jellman@berkeley.edu; rbergman@berkeley.edu
Table 1. Alkylation of 2-Methylpyridinea
Elaboration of heterocycles through the application of carbon-
carbon bond forming reactions via C-H bond activation constitutes
a powerful approach for the preparation of functional molecules
ranging from ligands for biomolecular targets to electroactive
materials.1 Our group developed a general method for the ortho-
alkylation of nitrogen-containing heterocycles with olefins using a
Rh(I)-phosphine catalyst2 and gathered extensive evidence sup-
porting the intermediacy of substrate-based N-heterocyclic carbene
(NHC) complexes (eq 1).3
entry
phosphine
additive
conc (M)b
yield (%)c
1
2
3
4
5
6
7
PCy3
PCy3
PCy3
PCy3
PCy3‚HCl
PCy3‚HCl
PCy3‚HCl
none
0.1
0.1
0.1
0.1
0.1
0.4
0.8
0
0
MgBr2
LutBr
LutCl
none
none
none
16
20
17
42
64
a coe ) cis-cyclooctene; Lut ) lutidinium. b Concentration of heterocycle
1
in total reaction volume. c Determined by H NMR spectroscopy relative
to internal standard.
Consistent with this mechanism, the catalytic alkylation reaction
to date has been reported only for heterocycles with two heteroatoms
adjacent to and thereby capable of stabilizing the carbene center
of the proposed intermediates.4 Herein, we report dramatic expan-
sion of substrate scope for this reaction by demonstrating the
catalytic alkylation of heterocycles containing a single nitrogen,
specifically pyridines and quinolines, which are extensively used
in the pharmaceutical industry.5 The alkylation of these electron-
deficient heterocycles marks a significant departure from other direct
functionalization methods,6 which typically require directing groups7
or electron-rich (hetero)arenes and proceed via electrophilic meta-
lation.8
We recently conducted a detailed kinetic analysis of the
conversion of heterocycle complex 1 to NHC complex 2 (eq 2)
and utilized the acquired data, along with DFT calculations, to
propose a reaction coordinate.9 This work provided strong evidence
that coordination of the heterocycle to the catalytically active RhCl-
(PCy3)2 fragment precedes an intramolecular C-H activation step,
which provides a Rh-H intermediate that ultimately tautomerizes
to the observed carbene complex.
Table 2. Investigation of Heterocycle Scope
a Isolated yield of pure product.
could be used to not only activate but also alkylate these
heterocycles, presumably via an NHC intermediate.11
Our investigation commenced with an examination of catalysts
and additives to affect the coupling of 2-methylpyridine and 3,3-
dimethylbutene (eq 3, Table 1).12 No conversion was observed when
no additive or Lewis acids such as MgBr2 were used. However,
we were pleased to find that the use of the Rh/PCy3 catalyst system
in combination with a Brønsted acid provided the desired alkylated
product, 3. PCy3‚HCl was found to be the optimal acid additive as
was previously observed for azoles.2b Notably, increasing the
substrate concentration to 0.8 M greatly improved the yield of 3 to
64%.
The scope of heterocycles compatible with the optimized
alkylation conditions was next investigated (eq 4, Table 2).
Increasing the bulk of the group located ortho to the pyridine ring
nitrogen from methyl to isopropyl led to an increase in both
alkylation rate and isolated yield of alkylated product 4. o-
Triisopropylsilyl (TIPS)-substituted pyridine was also an effective
substrate (entry 3). This has significant synthetic utility because
the silyl group can be removed, enabling additional transformations
(vide infra). Consistent with the findings of Carmona and Esteruelas
The Carmona and Esteruelas groups have since reported the
synthesis of (2-substituted)-pyridine- and quinoline-based Os, Ru,
and Ir-NHC complexes directly from the corresponding hetero-
cycles and a late transition metal complex.10 The authors propose
mechanisms analogous to that shown in eq 2, with substitution ortho
to the heterocycle ring nitrogen being necessary to drive the
equilibrium from an N-bound to the desired NHC complexes. We
therefore sought to determine whether our Rh/PCy3 catalyst system
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J. AM. CHEM. SOC. 2007, 129, 5332-5333
10.1021/ja070388z CCC: $37.00 © 2007 American Chemical Society

C O M M U N I C A T I O N S
Table 3. Investigation of Olefin Scopea
was alkylated with 3,3-dimethylbutene in 91% yield using only
1% of the Rh catalyst (eq 7).
In summary, we have developed a method for the Rh(I)-catalyzed
alkylation of pyridines and quinolines. Consistent with the work
of Carmona and Esteruelas, steric interactions provided by the ortho-
substituent presumably increase the equilibrium from an N-bound
to a C-bound Rh complex. We are currently investigating this
hypothesis by undertaking efforts to isolate intermediate complexes
and by performing DFT calculations on model structures. Continued
expansion of the catalytic alkylation process to new classes of
heterocycle and alkene inputs is also in progress.
Acknowledgment. This work was supported by the NIH
GM069559 to J.A.E. and by the Director and Office of Energy
Research, Office of Basic Energy Sciences, Chemical Sciences
Division, U.S. Department of Energy, under Contract DE-AC03-
76SF00098 to R.G.B.
a Unless specified, only the linear isomer was observed in cases where
linear and branched products were possible. b Isolated yield of pure product.
c A ca. 2:1 mixture of diastereomers. d 0.1 equiv of [RhCl(coe)2]2 and 0.3
equiv of PCy3‚1HCl used.
Note Added after ASAP Publication. A production error in
Table 1, column 2, entry 5 was corrected after this paper was
published ASAP on April 6, 2007. The corrected version was
published ASAP on April 10, 2007.
for carbene formation,10 pyridine itself was alkylated in less than
5% yield when heated in the presence of excess olefin and catalyst.
A variety of quinolines were also alkylated under the reaction
conditions. Parent quinoline provided nearly quantitative conversion
to the corresponding alkylated quinoline (entry 5). Both ether and
ester substitution were tolerated in the quinoline 6-position (entries
4 and 6). On the other hand, isoquinoline was not alkylated, which
again supports the fact that ortho substitution, not simply the
differing electronics of the benzo-fused heterocycle, is responsible
for alkylation.
We next investigated the scope of olefins compatible with the
reaction conditions (eq 5, Table 3). The isomerizable olefin,
n-hexene, coupled to quinoline to provide quantitative conversion
to the alkylated quinoline (entry 2). An 80:14 mixture of linear to
branched isomers was observed which, in addition to providing a
synthetically useful yield of the linear isomer, also indicated the
feasibility of using disubstituted olefins as coupling partners. Indeed,
cyclohexene could be used to alkylate quinoline in extremely high
yield (entry 3). 1,1-Disubstituted olefins, including 2-methylpropene
and camphene, were also effective coupling partners (entries 4 and
5). In a very preliminary investigation of functional group tolerance,
both esters and phthalimides were found to be compatible with the
reaction conditions (entries 6-8); however, styrene was not.
While substitution ortho to the pyridine nitrogen was required
to obtain high yields of alkylated products, an ortho-silyl group
serves as a suitable blocking group that can readily be removed to
provide monoalkylated pyridines. For example, treatment of 5 with
aqueous HF in refluxing THF provided the monoalkylated pyridine
product 17 in good yield (eq 6).
Supporting Information Available: Experimental details, including
analytical data for all compounds described, are included. This material
is available free of charge via the Internet at http://pubs.acs.org.
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