Palladium-catalyzed benzylic C-H insertion of 2-substituted N-iminopyridinium ylides

Article abstract of DOI:10.1021/ol800396v

Palladium-catalyzed direct benzylic C-H arylation of 2-alkyl substituted N-iminopyridinium ylides is described. The insertion can be conducted with several electron-poor and electron-rich aryl chlorides in good yields. This work adds to the few examples o

Full text of DOI:10.1021/ol800396v

ORGANIC
LETTERS
2008
Vol. 10, No. 8
1641-1643
Palladium-Catalyzed Benzylic C
Insertion of 2-Substituted
N-Iminopyridinium Ylides
−H
James J. Mousseau, Alexandre Larive´e, and Andre´ B. Charette*
Department of Chemistry, UniVersite´ de Montre´al, P. O. Box 6128, Station Downtown,
Montre´al, Quebec, Canada H3C 3J7
andre.charette@umontreal.ca
Received February 20, 2008
ABSTRACT
Palladium-catalyzed direct benzylic C−H arylation of 2-alkyl substituted N-iminopyridinium ylides is described. The insertion can be conducted
with several electron-poor and electron-rich aryl chlorides in good yields. This work adds to the few examples of sp3
been reported so far.
C−H insertions that have
Pyridine derivatives are found in many bioactive molecules,1
pharmaceuticals,2 organic materials,3 and ligands4 used in
various catalytic chemical transformations. In addition, our
group has shown that pyridines can be readily converted into
polysubstituted and enantioenriched piperidines,5,6 which also
exhibit important biological properties.7 This was achieved
by converting pyridine to a pyridinium ylide (via amination
of pyridine, Figure 1, A) and subjecting these activated
substrates to various reaction conditions (Figure 1, C).5,6
Although this is an effective method for generating pip-
eridines, the reaction is limited by the unavailability of more
Figure 1. Scope of reactivity of pyridinium substrates.
substituted pyridine starting materials. Recently, we have
addressed this issue by exploiting the Lewis basic N-
iminobenzoyl moiety of the ylide by using it as a directing
group8 for the direct arylation at the 2-position of the
pyridinium substrate (Figure 1, B).9 This gave access to a
wide range of substituted pyridinium ylides, which can be
easily converted into the corresponding pyridines (Figure 1,
E)9 or into highly functionalized piperidines (Figure 1, D).10
(1) Borivoj, J.; Elving, P. J. Chem. ReV. 1968, 68, 295.
(2) (a) Laird, T. Org. Process Res. DeV. 2006, 10, 851. (b) Yurovskaya,
M. A.; Karchava, A. V. Chem. Heterocycl. Compd. 1994, 30, 1331.
(3) (a) Baxter, P. N. W.; Lehn, J.-M.; Fischer, J.; Youinou, M.-T. Angew.
Chem., Int. Ed. Engl. 1994, 33, 2284. (b) Lehn, J.-M. Science 2002, 295,
2400.
(4) (a) Desimoni, G.; Faita, G.; Quadrelli, P. Chem. ReV. 2003, 103, 3119.
(b) Gibson, V. C.; Redshaw, C.; Solen, G. A. Chem. ReV. 2007, 107, 1745.
(5) Legault, C. Y.; Charette, A. B. J. Am. Chem. Soc. 2003, 125, 6360.
(6) Legault, C. Y.; Charette, A. B. J. Am. Chem. Soc. 2005, 127, 8966.
(7) For recent reviews on the stereoselective synthesis of piperidines,
see: (a) Buffat, M. G. P. Tetrahedron 2004, 60, 1701. (b) Felpin, F.-X.;
Lebreton, J. M. Eur. J. Org. Chem. 2003, 3693. (c) Weintraub, P. M.; Sabol,
J. S.; Kane, J. M.; Borcherding, D. R. Tetrahedron 2003, 59, 2953.
(8) For an example of palladation of pyridinium ylides, see: Dias, S.
A.; Downs, A. W.; McWhinnie, W. R. J. Chem. Soc., Dalton Trans. 1975,
162.
(9) Larive´e, A.; Mousseau, J. J.; Charette, A. B. J. Am. Chem. Soc. 2008,
130, 52.
(10) This approach has been used in the total synthesis of (()-anabasine.
See ref 9 for details.
10.1021/ol800396v CCC: $40.75
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Published on Web 03/22/2008

During the course of our work on the direct arylation
reactions of these pyridinium ylides,9 we discovered that a
methyl group at the 2-position led to a marked decrease in
the yield for the formation of the expected product 4.
Interestingly, we observed arylation on the benzylic methyl
group as the major product, in a 2.7:1 ratio with the sp2
arylation product (3a:4). Although direct arylation reactions
on sp2 centers are relatively well-known,11 little has been
reported about the direct arylation of sp3 centers. The
functionalization of sp3 C-H bonds remains a challenge in
organic synthesis.12 Herein, we report the optimization and
scope of the selective arylation of the benzylic carbon of
2-alkyl substituted N-iminopyridinium ylides, underlining
another novel reactivity of these ylides giving more func-
tionalized pyridines.
Table 1. Palladium-Catalyzed sp3 Arylation of
N-Iminopyridinium Ylide with Aryl Chloride Derivativesa
Several phosphine ligands were screened and DavePHOS
proved to be the most effective.13 Dimethylformamide (DMF)
was the optimal solvent. It was found, as with sp2 aryla-
tion, that carbonate bases were required and subsequently
Cs2CO3 gave the best yields. At 125 °C, the reaction was
found to work equally well with aryl bromides and aryl
chlorides, whereas aryl iodides gave slightly poorer results.
The reaction temperature using aryl chlorides could be
lowered to 70 °C without a significant effect on the yield.
Indeed, it was found that at 70 °C the results with aryl iodides
were improved, although aryl chlorides remained the best
substrates. In addition, under the optimized conditions no
sp2 arylation was observed via NMR.
The scope of the reaction was next investigated using
various aryl chlorides (Table 1). Under the optimized reaction
conditions [1a (1.1 equiv), Pd(OAc)2 (5 mol %), DavePHOS
(11) (a) Alberico, D.; Scott, M. E.; Lautens, M. Chem. ReV. 2007, 107,
174. (b) Ellman, J. Science 2007, 316, 1131. (c) Seregin, I. Y.; Gevorgyan,
V. Chem. Soc. ReV. 2007, 36, 1173. (d) LeClerc, J.-P.; Fagnou, K. Angew.
Chem., Int. Ed. 2006, 45, 7781. (e) Garcia-Cuadrado, D.; Braga, A. A. C.;
Maseras, F.; Echavarren, A. M. J. Am. Chem. Soc. 2006, 128, 1066. (f)
Miura, M.; Satoh, T. Top. Organomet. Chem. 2005, 14, 55. (g) Wolfe, J.
P.; Thomas, J. S. Curr. Org. Chem. 2005, 9, 625. (h) Kakiuchi, F.; Chatani,
N. AdV. Synth. Catal. 2003, 345, 1077. (i) Miura, M.; Nomura, M. Top.
Curr. Chem. 2002, 219, 211. (j) Dyker, G. Angew. Chem., Int. Ed. 1999,
38, 1698.
a Reaction conditions: 1a (1.1 equiv), 2 (1.0 equiv), Pd(OAc)2 (5 mol
%), DavePHOS (12 mol %), Cs2CO3 (3 equiv), DMF (0.8 M), 70 °C, 16
h. b Yield of isolated product.
(12) For selected examples of sp3 arylation, see: (a) Lafrance, M.;
Gorelsky, S. I.; Fagnou, K. J. Am. Chem. Soc. 2007, 129, 14570. (b) Niwa,
T.; Yorimitsu, H.; Oshiwa, K. Org. Lett. 2007, 9, 2373. (c) Hull, K. L.;
Sanford, M. S. J. Am. Chem. Soc. 2007, 129, 11904. (d) Niwa, T.; Yorimitsu,
H.; Oshima, K. Angew. Chem., Int. Ed. 2007, 46, 2643. (e) Giri, R.; Maugel,
N.; Li, J.-J.; Wang, D.-H.; Breazzano, S. P.; Sanders, L. B.; Yu, J.-Q. J.
Am Chem. Soc. 2007, 129, 3510. (f) Pastine, S. J.; Gribkov, D. V.; Sames,
D. J. Am. Chem. Soc. 2006, 128, 14220. (g) Kalyani, D.; Dick, A. R.; Anani,
W. Q.; Sanford, M. S. Tetrahedron 2006, 62, 11483. (h) Chen, X.; Goodhue,
G. E.; Yu, J.-Q. J. Am. Chem. Soc. 2006, 128, 12634. (i) Tobisu, M.;
Chatani, N. Angew. Chem., Int. Ed. 2006, 45, 1683. (j) Thu, H.-Y.; Yu,
W.-Y.; Che, C.-M. J. Am. Chem. Soc. 2006, 128, 9048. (k) Kalyani, D.;
Deprez, N. R.; Desai, L. V.; Sanford, M. S. J. Am. Chem. Soc. 2005, 127,
7330. (l) Zaitsev, V. G.; Shabashov, D.; Daugulis, O. J. Am. Chem. Soc.
2005, 127, 13154. (m) Hamada, T.; Chieffi, A.; Ahman, J.; Buchwald, S.
L. J. Am. Chem. Soc. 2002, 124, 1261.
(12 mol %), Cs2CO3 (3 equiv), DMF, 70 °C] chlorobenzene
(1 equiv), afforded the 2-benzyl-N-iminopyridinium ylide 1a
in 86% isolated yield. Both electron-rich (entries 2-5) and
most electron-poor (entries 6-11) substrates are compatible
under the reaction conditions. 2-Chlorotoluene (2b) gave a
good yield of the arylated product showing that sterically
hindered aryl chlorides do not inhibit the reaction. However,
lower yields are observed with an electron-withdrawing
substituent ortho to the halide (entry 6). The lower yields
are attributed to unreacted starting material and not side
(13) See Supporting Information for selected optimization.
1642
Org. Lett., Vol. 10, No. 8, 2008

products. In addition, no sp2 arylation was observed in any
case.
We next explored the scope of the 2-substituted N-imino-
pyridinium ylide coupling partner 1 (Table 2). Although the
encumbrance of the 2,3-dimethyl substrate. Furthermore,
2-ethyl pyridinium ylides were found to undergo selective
arylation at the benzylic position in good yields, again with
no noticeable arylation at the sp2 center. This can be reasoned
due to the higher relative acidity of these benzylic protons
as well as the kinetic preference for the formation a
5-membered palladacycle intermediate involving the ylide
nitrogen during the course of the reaction.
It was also possible to arylate twice at the sp3 center.14
Upon the addition of 2.2 equiv of chlorobenzene the di-sp3
arylated product was obtained in 72% yield.
Table 2. Arylation of Other N-Iminopyridinium Ylidesa
In conclusion, we have developed a new method for the
selective sp3 arylation of 2-substituted-N-iminopyridinium
ylides with various aryl chlorides. This further demonstrates
the synthetic use of these pyridinium ylides. Applications
and mechanistic insights to the novel sp3 C-H insertion will
be reported in due course.
Acknowledgment. This work was supported by the
Natural Science and Engineering Research Council of
Canada (NSERC), Merck Frosst Canada Ltd., Boehringer
Ingelheim (Canada), Ltd., the Canada Research Chairs
Program, the Canadian Foundation for Innovation, and the
Universite´ de Montre´al.
a Reaction conditions: 1a (1.1 equiv), 2 (1.0 equiv), Pd(OAc)2 (5 mol
%), DavePHOS (12 mol %), Cs2CO3 (3 equiv), DMF (0.8 M), 70 °C, 16
h. b Yield of isolated product.
Supporting Information Available: Experimental pro-
cedures, sample spectra and compound characterization data.
This material is available free of charge via the Internet at
http://pubs.acs.org.
2,3- and 2,5-dimethyl pyridines are electronically equivalent,
the 2,3-dimethyl substrate resulted in significantly higher
yield of product. This was surprising due to the extra steric
OL800396V
(14) The di-arylated product is formed as a side-product in some cases.
Org. Lett., Vol. 10, No. 8, 2008
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