Synthesis of multicyclic pyridine and quinoline derivatives via intramolecular C-H bond functionalization

Article abstract of DOI:10.1021/ol101002b

An efficient method is reported for the preparation of multicyclic pyridines and quinolines by a rhodium-catalyzed intramolecular C-H bond functionalization process. The method shows good scope for branched and unbranched alkyl substituents on the pyridine ring and at the R position of the tethered alkene group. Starting materials capable of undergoing olefin isomerization to provide terminal 1,1-disubstituted alkenes also proved to be effective substrates.

Full text of DOI:10.1021/ol101002b

ORGANIC
LETTERS
2010
Vol. 12, No. 13
2978-2981
Synthesis of Multicyclic Pyridine and
Quinoline Derivatives via Intramolecular
C-H Bond Functionalization
Sirilata Yotphan, 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
rbergman@berkeley.edu; jellman@berkeley.edu
Received May 1, 2010
ABSTRACT
An efficient method is reported for the preparation of multicyclic pyridines and quinolines by a rhodium-catalyzed intramolecular C-H bond
functionalization process. The method shows good scope for branched and unbranched alkyl substituents on the pyridine ring and at the R
position of the tethered alkene group. Starting materials capable of undergoing olefin isomerization to provide terminal 1,1-disubstituted
alkenes also proved to be effective substrates.
The synthesis of N-heterocycles is an important area of
research due to their prevalence in natural products and
Scheme 1. Rh(I)-Catalyzed Intermolecular Alkylation of
Quinolines and Pyridines via C-H Bond Activation
drugs.1 Of the N-heterocycles, pyridines are the most
extensively used in pharmaceutical research,2 and much effort
has been devoted to their synthesis.3,4 The functionalization
of C-H bonds provides an atom-economical and direct
approach for the preparation of substituted pyridines.5,6 Our
group has previously developed a method for the Rh(I)-
catalyzed intermolecular alkylation of pyridines and quino-
lines to produce ortho-alkylated products (Scheme 1).6
Significantly, pyridines lacking substitution at the 2-position
(R1 ) H) as well as 2,5-disubstituted pyridines did not
undergo alkylation. Presumably, substituents at the 2- and
5-positions introduce steric interactions that either promote
or attenuate, respectively, the propensity of forming the
(1) Joule, J. A.; Mills, K. Heterocyclic Chemistry, 4th ed.; Blackwell:
Oxford, 2000.
(2) (a) Carey, J. S.; Laffan, D.; Thomson, C.; Williams, M. T. Org.
Biomol. Chem. 2006, 4, 2337–2347. (b) Bashford, K. E.; Burton, M. B.;
Cameron, S.; Cooper, A. L.; Hogg, R. D.; Kane, P. D.; MacManus, D. A.;
Matrunola, C. A.; Moody, C. J.; Robertson, A. B.; Warne, M. R.
Tetrahedron Lett. 2003, 44, 1627.
(3) For recent reviews on pyridine syntheses see: (a) Varela, J.; Saa, C.
Chem. ReV. 2003, 103, 3787. (b) Zeni, G.; Larock, R. L. Chem. ReV. 2006,
106, 4644
.
(4) For recent examples of transition-metal-mediated pyridine syntheses,
see: (a) Parthasarathy, K.; Jeganmohan, M.; Cheng, C.-H. Org. Lett. 2008,
10, 325. (b) Trost, B. M.; Gutierrez, A. C. Org. Lett. 2007, 9, 1473. (c)
Movassaghi, M.; Hill, M. D. J. Am. Chem. Soc. 2006, 128, 4592. (d)
McCormick, M. M.; Duong, H. A.; Zuo, G.; Louie, J. J. Am. Chem. Soc.
2005, 127, 5030. (e) Yamamoto, Y.; Kinpara, K.; Ogawa, R.; Nishiyama,
H.; Itoh, K. Chem.sEur. J. 2006, 12, 5618. (f) Tanaka, R.; Yuza, A.; Watai,
Y.; Suzuki, D.; Takayama, Y.; Sato, F.; Urabe, H. J. Am. Chem. Soc. 2005,
127, 7774. (g) Takahashi, T.; Tsai, F.-Y.; Li, Y.; Wang, H.; Kondo, Y.;
Yamanaka, M.; Nakajima, K.; Kotora, M. J. Am. Chem. Soc. 2002, 124,
5059. (h) Fletchter, M. D.; Hurst, T. E.; Miles, T. J.; Moody, C. J.
(5) (a) Wasa, M.; Worrell, B. T.; Yu, J.-Q. Angew. Chem., Int. Ed. 2010,
49, 1275. (b) Tobisu, M.; Hyodo, I.; Chatani, N. J. Am. Chem. Soc. 2009,
131, 12070. (c) Nakao, Y.; Kanyiva, K. S.; Hiyama, T. J. Am. Chem. Soc.
2008, 130, 2448. (d) Berman, A. M.; Lewis, J. C.; Bergman, R. G.; Ellman,
J. A. J. Am. Chem. Soc. 2008, 130, 14926. (e) Campeau, L.-C.; Rousseaux,
S.; Fagnou, K. J. Am. Chem. Soc. 2005, 127, 18020. (f) Larive´e, A.;
Mousseau, J. J.; Charette, A. B. J. Am. Chem. Soc. 2008, 130, 52. (g) Do,
H.-Q.; Kashif Khan, R. M.; Daugulis, O. J. Am. Chem. Soc. 2008, 130,
15185. (h) Kalyani, D.; Deprez, N. R.; Desai, L. V.; Sanford, M. S. J. Am.
Chem. Soc. 2005, 127, 7330.
(6) Lewis, J. C.; Bergman, R. G.; Ellman, J. A. J. Am. Chem. Soc. 2007,
129, 5332.
Tetrahedron 2006, 62, 5454
.
10.1021/ol101002b  2010 American Chemical Society
Published on Web 06/02/2010

C-bound Rh complex necessary for C-H functionalization
relative to the N-bound form.7 Herein, we report an expansion
of substrate scope for pyridine alkylation to include intramo-
lecular cyclization of pyridines with alkenes tethered to the
5-position of the pyridine substrates. This cyclization method
provides a new reaction pathway for the efficient preparation
of underrepresented classes of complex bicyclic pyridines
and tricylic quinolines that have considerable potential as
useful scaffolds in drug discovery.8
PAd2Bu are optimal (entries 4 and 8-10). Although both
[RhCl(coe)2]2 and [RhCl(cod)]2 precatalysts gave good results
(entries 2 and 8-10), we elected to use [RhCl(cod)]2 for all
subsequent studies due to its air and thermal stability,
commercial availability, and higher reaction yield.
After investigation of other parameters, we found that
optimal reaction conditions are 5% [RhCl(cod)]2 loading with
15% phosphine ligand and 0.8 M of substrate in THF at 165
°C.11 Investigation of substrate scope (Table 2) revealed that
PCy3 in general gives similar or slightly better yields than
PAd2Bu for enol ether tethered substrates (Table 2, entries
1-7). Variation of the R group on the tethered enol ether
Our investigation started with an examination of the enol
ether tethered 2-methylpyridine substrate 1 using the opti-
mized conditions for the intermolecular alkylation of py-
ridines: [RhCl(coe)2]2 as the precatalyst and PCy3·HCl as an
optimal ligand-additive combination (Table 1).9,10 Under
Table 2. Investigation of Substrate Scope
Table 1. Alkylation of Enol-Tethered 2-Methylpyridinea
entry
catalyst
ligandb
yieldc (%)
1
2
3
4
5
6
7
8
9
10
[RhCl(coe)2]2
[RhCl(coe)2]2
PCy3·HCl
70 (24 h)
0
0
70 (15 h)
0
0
31 (24 h)
100 (24 h)
99 (24 h)
99 (24 h)
PCy3·HCl
PCy3
[RhCl(coe)2]2
RhCl(PPh3)3
[RhCl(coe)2]2
[RhCl(coe)2]2
[RhCl(coe)2]2
[RhCl(cod)]2
[RhCl(cod)]2
PPh3
P(t-Bu)3
PAd2Bu
PCy3
PAd2Bu
a Partial screening data are listed. See the Supporting Information for
more details. b coe )cis-cyclooctene, cod ) cyclooctadiene. c Reported
1
yields are NMR yields, determined by H NMR spectroscopy relative to
an internal standard.
these conditions, cyclized product 2 was obtained in 70%
yield (Table 1, entry 1). Thus, the tethered enol ether function
located at the meta position of pyridine substrates does not
block the intramolecular ortho C-H activation. Upon
examination of the effects of other reaction parameters9 (Rh-
catalysts, ligands, additives, solvents, temperatures, and
concentrations), no cyclization was observed in the absence
of phosphine ligand or rhodium (entries 2 and 3). Notably,
the HCl additive does not have a dramatic effect on the
reaction (entry 4), which contrasts with the corresponding
intermolecular reactions where alkylation only occurred in
the presence of the acid catalyst.6 We then undertook
extensive ligand screening (partial ligand screening data are
listed in Table 1, entries 5-10) and found that PCy3 and
(7) Carmona and Esteruelas have provided careful studies of the effect
of steric interactions upon the equilibrium between N- and C-bound
transition-metal complexes. (a) Alvarez, E.; Conejero, S.; Paneque, M.;
Petronilho, A.; Poveda, M. L.; Serrano, O.; Carmona, E. J. Am. Chem. Soc.
2006, 128, 13060. (b) Esteruelas, M. A.; Fernandez-Alvarez, F. J.; Onate,
E. J. Am. Chem. Soc. 2006, 128, 13044.
a NMR yields determined by 1H NMR spectroscopy relative to an
internal standard. Yields in parentheses correspond to isolated yields of
pure product after column chromatography.
Org. Lett., Vol. 12, No. 13, 2010
2979

group from methyl (1) to ethyl (3) or isopropyl (5) leads to
the formation of cyclized products in 99% (2 and 4) and
58% (6) yields, respectively (entries 1-3). Variation of the
ortho-pyridine substituent from methyl (1) to ethyl (7) or
isopropyl (9) also results in good conversion to the fused
products in 80% (8) and 58% (10) yields, respectively
(entries 4 and 5). Enol ether tethered quinoline substrate 11
also undergoes cyclization in 80% yield (entry 6). On the
other hand, for the allyl-tethered quinoline substrates (entries
7 and 8), the PAd2Bu ligand was found to minimize the
competitive double-bond isomerization pathway, resulting
in higher cyclization yields. Unfortunately, for allyl-tethered
pyridine substrate 17 only the conjugated pyridine product
18 that resulted from double-bond isomerization was ob-
served (entry 9).
Table 3. Cyclization of Isomerizable Tethered Alkene
Substrates
In contrast to intermolecular pyridine alkylation where
ortho substitution is required for alkylation to proceed,6
substrate 19, which lacks alkyl substitution at the ortho
position, undergoes cyclization under the reaction conditions
(Scheme 2). In the case of substrate 19, using PCy3·HCl as
Scheme 2.
Cyclization of Unsubstituted Pyridinea
a Reported yields are NMR yields, determined by 1H NMR spectroscopy
relative to an internal standard. b E/Z isomerization was observed. c Hydrolysis
of the enol group was observed.
a NMR yields determined by 1H NMR spectroscopy relative to an
internal standard. Yield in parentheses corresponds to isolated yields of
pure product after column chromatography.
however, the bicyclic pyridine products (4 and 6) were
observed as a consequence of olefin isomerization to the less
substituted 1,1-disubstituted regioisomer prior to cyclization
(Scheme 3). Olefin isomerization is well-documented with
a ligand results in a great improvement in yield (PCy3·HCl
gives 38% cyclized product while PCy3 gives <10% product).
It is likely that Rh coordination to the tethered alkene helps
to promote C-H bond functionalization at the proximal site.
In addition to no substitution and alkyl substitution at the
2-position of the pyridine ring, 2-chloro substitution was also
investigated, but no reaction was observed.
Scheme 3
.
[Rh]-Catalyzed Olefin Isomerization Prior to
Cyclization Reaction
We also investigated the effects of different alkyl substit-
uents on the tethered enol ether function (Table 3). Substrates
21-23 (entries 1-3) undergo intramolecular alkylation;
(8) For recent literature on fused pyridines as potent kinase inhibitors,
see the following: (a) Chiou, M.; Samadi, A.; Soriano, E.; Lozach, O.;
Meijer, L.; Marcro-Contelles, J. Bioorg. Med. Chem. Lett. 2009, 19, 4566.
(b) Saavedra, O.; Claridge, S.; Zhan, L.; Raeppel, F.; Granger, M.-C.;
Raeppel, S.; Mannion, M.; Gaudette, F.; Zhou, N.; Isakovic, L.; Bernstein,
N.; De´ziel, R.; Nguyen, H.; Beaulieu, N.; Beaulieu, C.; Dupont, I.; Wang,
J.; Macleod, A. R.; Besterman, J. M.; Vaisburg, A. Bioorg. Med. Chem.
Lett. 2009, 19, 6836. (c) Cusack, K.; Allena, H.; Bischoffa, A.; Clabbersa,
A.; Dixona, R.; Stenzela, S. F.; Friedmana, M.; Gaumonta, Y.; Georgea,
D.; Gordona, T.; Grongsaarda, P.; Janssena, B.; Jiaa, Y.; Moskeya, M.;
Quinna, C.; Salmerona, A.; Thomasa, C.; Wallacea, G.; Wisharta, N.; Yua,
Z. Bioorg. Med. Chem. Lett. 2009, 19, 1722. (d) Wu, J.-P.; Fleck, R.;
Brickwood, J.; Capolino, A.; Catron, K.; Chen, Z.; Cywin, C.; Emeigh, J.;
Foerst, M.; Ginn, J.; Hrapchak, M.; Hickey, E.; Hao, M. H.; Kashem, M.;
Li, J.; Liu, W.; Morwick, T.; Nelson, R.; Marshall, D.; Martin, L.; Nemoto,
P.; Potocki, I.; Liuzzi, M.; Peet, G. W.; Scouten, E.; Stefany, D.; Turner,
M.; Weldon, S.; Zimmitti, C.; Spero, D.; Kelly, T. A. Bioorg. Med. Chem.
Lett. 2009, 19, 5547. (e) Tumey, L. N.; Boschelli, D. H.; Lee, J.; Chaudhary,
D. Bioorg. Med. Chem. Lett. 2008, 18, 4420.
Rh catalysts, including for intramolecular azole alkylation
substrates.12 The observation that 1,2-disubstituted alkenes
(24) do not cyclize is also consistent with the presence of
ꢀ-substituents on the vinyl ether group impeding the cy-
clization rate (entry 4). However, R-substitution on the vinyl
ether group also appears to be required for cyclization
because the unsubstituted vinyl ether 25 was found to be
unreactive (entry 5).
(9) See the Supporting Information for experimental details of substrate
preparation and screening of reaction conditions.
(10) These conditions were also found to be optimal for intermolecular
azole alkylation: Tan, K. L.; Park, S.; Ellman, J. A.; Bergman, R. G. J.
Org. Chem. 2004, 69, 7329.
2980
Org. Lett., Vol. 12, No. 13, 2010

In conclusion, cyclization of tethered pyridines and quino-
lines produces multicyclic derivatives via C-H activation.
The cyclization reactions show good scope for branched and
unbranched alkyl substituents on the pyridine ring and at
the R-position of the vinyl ether group. Morever, isomer-
ization of the double bond on the alkene tether enables
cyclization to be accomplished via isomerization of trisub-
stituted enol ether substrates. Expansion of the synthetic
utility of this method, including exploration of enantiose-
lective catalytic cyclizations, is currently in progress.
Acknowledgment. This work was supported by NIH
Grant No. GM069559 (to J.A.E.) and by the Director, Office
of Energy Research, Office of Basic Energy Sciences,
Chemical Sciences Division, US Department of Energy under
contract DE-AC02-05CH11231 (to R.G.B.).
(11) Lowering catalyst loading, effective concentration of substrate and
temperature result in much lower yield and slower rate of reaction. See the
Supporting Information for more details.
(12) (a) Tan, K. L.; Bergman, R. G.; Ellman, J. A. J. Am. Chem. Soc.
2001, 123, 2685. (b) Rech, J. C.; Yato, M.; Duckett, D.; Ember, Brian;
LoGrasso, P. V.; Bergman, R. G.; Ellman, J. A. J. Am. Chem. Soc. 2007,
129, 490. (c) Crabtree, R. H. The Organometallic Chemistry of the Transition
Metals, 5th ed.; Wiley: Hoboken, 2009; pp 229-230.
Supporting Information Available: Full experimental
details and characterization for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL101002B
Org. Lett., Vol. 12, No. 13, 2010
2981