Carboxylate-assisted ruthenium-catalyzed direct alkylations of ketimines

Article abstract of DOI:10.1021/ol200366n

The mechanism of carboxylate-assisted ruthenium(II)-catalyzed direct alkylations of ketimines with unactivated alkyl halides was probed through experimental studies. The remarkable chemoselectivity of the broadly applicable catalyst also enabled direct al

Full text of DOI:10.1021/ol200366n

ORGANIC
LETTERS
2011
Vol. 13, No. 7
1875–1877
Carboxylate-Assisted Ruthenium-
Catalyzed Direct Alkylations of Ketimines
ꢀ
Lutz Ackermann,* Nora Hofmann, and Ruben Vicente
€
Institut fu€r Organische und Biomolekulare Chemie, Georg-August-Universitat,
€
Tammannstrasse 2, 37077 Gottingen, Germany
Lutz.Ackermann@chemie.uni-goettingen.de
Received February 8, 2011
ABSTRACT
The mechanism of carboxylate-assisted ruthenium(II)-catalyzed direct alkylations of ketimines with unactivated alkyl halides was probed through
experimental studies. The remarkable chemoselectivity of the broadly applicable catalyst also enabled direct alkylations among others on H2O or
under solvent-free reaction conditions.
Transition-metal-catalyzed direct C-H bond1 alkyla-
tions of arenes under basic reaction conditions have recently
been developed as sustainable alternatives to traditional
cross-coupling reactions between organometallic reagents
and alkyl halides.2 Particularly, ruthenium catalysts3
enabled C-H bond functionalizations with challen-
ging unactivated alkyl halides bearing β-hydrogens.4,5
Despite this recent progress, mechanistic studies on
ruthenium-catalyzed direct alkylations6 have unfortu-
nately thus far not been reported. As a consequence, we
explored the working mode of ruthenium(II) carboxylate
complexes in direct C-H bond functionalizations focusing
particularly on ketimines7 as substrates, because of their
importance as key intermediates in organic synthesis.
Herein, we wish to report on our findings, which include
first direct alkylations on H2O or under solvent-free reac-
tion conditions.
(1) Select recent reviews on metal-catalyzed C-H bond functionali-
zations: (a) Ackermann, L.; Potukuchi, H. K. Org. Biomol. Chem. 2010,
8, 4503–4513. (b) Daugulis, O. Top. Curr. Chem. 2010, 292, 57–84. (c)
Sun, C.-L.; Li, B.-J.; Shi, Z.-J. Chem. Commun. 2010, 46, 677–685. (d)
Colby, D. A.; Bergman, R. G.; Ellman, J. A. Chem. Rev. 2010, 110,
624–655. (e) Fagnou, K. Top. Curr. Chem. 2010, 292, 35–56. (f) Satoh,
T.; Miura, M. Chem.;Eur. J. 2010, 16, 11212–11222. (g) Jazzar, R.;
Hitce, J.; Renaudat, A.; Sofack-Kreutzer, J.; Baudoin, O. Chem.;Eur.
J. 2010, 16, 2654–2672. (h) Lei, A.; Liu, W.; Liu, C.; Chen, M. Dalton
Trans. 2010, 39, 10352–10361. (i) Lyons, T. W.; Sanford, M. S. Chem.
Rev. 2010, 110, 1147–1169. (j) Kulkarni, A. A.; Daugulis, O. Synthesis
2009, 4087–4109. (k) Bellina, F.; Rossi, R. Tetrahedron 2009, 65, 10269–
10310. (l) Ackermann, L.; Vicente, R.; Kapdi, A. Angew. Chem., Int. Ed
2009, 48, 9792–9826. (m) Thansandote, P.; Lautens, M. Chem.;Eur. J.
2009, 15, 5874–5883. (n) Kakiuchi, F.; Kochi, T. Synthesis 2008, 3013–
3039. (o) Satoh, T.; Miura, M. Chem. Lett. 2007, 36, 200–205. (p)
Ackermann, L. Synlett 2007, 507–526. (q) Alberico, D.; Scott, M. E.;
Lautens, M. Chem. Rev. 2007, 107, 174–238 and references cited therein.
(2) Ackermann, L. Chem. Commun. 2010, 46, 4866–4877.
At the outset of our studies, we tested various phos-
phine ligand-free8 reaction conditions for direct alkyla-
tions of ketimines. Among a variety of stoichiometric
bases, KOAc gave promising results in the absence of an
(3) (a) Ackermann, L.; Vicente, R. Top. Curr. Chem. 2010, 292,
211–229. (b) Ackermann, L. Pure Appl. Chem. 2010, 82, 1403–1413.
(6) For experimental mechanistic studies on ruthenium-catalyzed
direct arylations, see: Ackermann, L.; Vicente, R.; Potukuchi, H. K.;
Pirovano,
ꢀ
(4) (a) Ackermann, L.; Novak, P.; Vicente, R.; Hofmann, N. Angew.
ꢀ
V. Org. Lett. 2010, 12, 5032–5035.
Chem., Int. Ed. 2009, 48, 6045–6048. (b) Ackermann, L.; Novak, P. Org.
Lett. 2009, 11, 4966–4969.
(7) For representative recent examples of direct arylations with
imines, see: (a) Tredwell, M. J.; Gulias, M.; Gaunt Bremeyer, N.;
Johansson, C. C. C.; Collins, B. S. L.; Gaunt, M. J. Angw. Chem., Int.
Ed. 2011, 50, 1076–1079. (b) Gao, K.; Yoshikai, N. J. Am. Chem. Soc.
2011, 133, 400–402. (c) Yoshikai, N.; Matsumoto, A.; Norinder, J.;
Nakamura, E. Angew. Chem, Int. Ed. 2009, 48, 2925–2928. (d) Ack-
ermann, L.; Althammer, A.; Born, R. Tetrahedron 2008, 64, 6115–6124.
(e) Oi, S.; Ogino, Y.; Fukita, S.; Inoue, Y. Org. Lett. 2002, 4, 1783–1785
and references cited therein.
(5) For examples of nickel- or palladium-catalyzed direct alkylations
of (hetero)arenes, see: (a) Yao, T.; Hirano, K.; Satoh, T.; Miura, M.
Chem.;Eur. J. 2010, 16, 12307–12311. (b) Shabashov, D.; Daugulis, O.
J. Am. Chem. Soc. 2010, 132, 3965–3972. (c) Vechorkin, O.; Proust, V.;
Hu, X. Angew. Chem., Int. Ed. 2010, 49, 3061–3064. (d) Ackermann, L.;
€
Barfusser, S.; Pospech, J. Org. Lett. 2010, 12, 724–726. (e) Lapointe, D.;
Fagnou, K. Org. Lett. 2009, 11, 4160–4163. (f) Zhang, Y.-H.; Shi, B.-F.;
Yu, J.-Q. Angew. Chem., Int. Ed. 2009, 48, 6097–6100. (g) Rudolph, A.;
Rackelmann, N.; Lautens, M. Angew. Chem., Int. Ed. 2007, 46, 1485–
1488 and references cited therein.
(8) For early direct arylations in the absence of phosphine additives,
see: Ackermann, L.; Althammer, A.; Born, R. Synlett 2007, 2833–2836.
r
10.1021/ol200366n
2011 American Chemical Society
Published on Web 03/09/2011

additional sterically hindered carboxylate as a cocata-
lyst (Scheme 1).
Scheme 3. Intramolecular Competition Experiments
Scheme 1. Direct Alkylations with KOAc as the Base
However, the efficacy of this catalytic system proved to
be inferior to the one of a ruthenium catalyst derived from
sterically hindered carboxylic acid 4, as illustrated by the
syntheses of alkylated products 3a and 3c (Scheme 2).
Notably, the carboxylate-assisted C-H bond functionali-
zation proved broadly applicable and allowed for the
direct introduction of the neopentyl group to give access
to compound 3o.
Scheme 2. Direct Alkylations with Acid 4 as a Cocatalyst
These transformations were largely controlled by steric inter-
actions (Scheme 3). However, the presence of a meta-
substituent displaying an electronegative heteroatom led
to the formation of compound 3s as a byproduct and the
selective generation of arene 3t as the sole product.9,10
Scheme 4. Intermolecular Competition Experiments
Given the broad scope of these carboxylate-assisted
C-H bond functionalizations, and since mechanistic stu-
dies on ruthenium-catalyzed direct alkylations have thus far
proven elusive, we subsequently performed intramolecular
competition experiments with meta-substituted arenes 1.
Intermolecular competition experiments clearly high-
lighted electron-deficient arenes to be functionalized pre-
ferentially (Scheme 4). Interestingly, this reactivity profile
contrasts with previously made observationsinruthenium-
catalyzed direct arylations.6
(9) (a) Shen, K.; Fu, Y.; Li, J.-N.; Liu, L.; Guo, Q.-X. Tetrahedron
ꢀ
2007, 63, 1568–1576. (b) Clot, E.; Megret, C.; Eisenstein, O.; Perutz,
R. N. J. Am. Chem. Soc. 2009, 131, 7817–7827. (c) Preliminary experi-
ments on ruthenium-catalyzed direct arylations revealed that C-H
bond functionalizations with 2-{meta-(trifluoromethyl)phenyl}pyridine
are controlled by steric interactions, thus yielding the 6-arylated
products.
(10) Analysis of the crude reaction mixture by GC-MS showed the
mass balance to be mainly unreacted starting material 1.
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Org. Lett., Vol. 13, No. 7, 2011

Given the increased hydrolytic stability of pyridine di-
recting groups, we thus probed unprecedented ruthe-
nium-catalyzed direct alkylations with substrate 1f on
H2O. Interestingly, when using MesCO2H as a cocatalyst
we observed the formation of byproduct 3w being func-
tionalized in the meta-position12 with respect to the
2-pyridyl substituent (Scheme 7). Notably, compound
3w was also generated under solvent-free13 reaction
conditions.
Scheme 5. Direct Alkylations with Isotopically Labeled Starting
Materials
Scheme 7. Meta-Selectivity in Direct Alkylations
Experiments with isotopically labeled starting materials
revealed a D/H-exchange reaction (Scheme 5a). Further,
potential mechanisms involving the formation of ruthe-
nium alkylidenes were shown unlikely to be operative,
since the transformation of substrate 2a-[D2] occurred
without the detectable loss of its isotopic labels (b).
In summary, we have reported on broadly applicable
ruthenium-catalyzed direct alkylations of ketimines
through carboxylate assistance. Mechanistic studies re-
vealed these reactions to proceed through an initial cyclo-
metalation, and a subsequent activation of the alkyl halide.
Notably, electron-deficient arenes were preferentially
functionalized, thereby supporting a nonelectrophilic
C-H bond metalation event. The catalytic system dis-
played an excellent chemoselectivity, which was exploited
for first direct alkylations on H2O or under solvent-free
reaction conditions.
Scheme 6. Proposed Mechanism of Ruthenium-Catalyzed Di-
rect Alkylations
Acknowledgment. Support by the State of Lower
Saxony within the CaSuS (Catalysis for Sustainable
Synthesis) PhD program (fellowship to N.H.) and the
DFG is gratefully acknowledged. Further, we thank
Dr. S. I. Kozhushkov for preliminary experiments and
Dipl.-Chem. R. Machinek for 2D-NMR experiments
€
(both Georg-August-Universitat).
Supporting Information Available. Experimental pro-
1
cedures, characterization data, and H and 13C NMR
spectra for new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
Based on these mechanistic studies, we propose the
catalytic cycle depicted in Scheme 6, which involves an
initial reversible cyclometalation, along with a subse-
quent activation of alkyl halide 2 and a reductive
elimination.
Previously, we studied ruthenium-catalyzed direct
C-H bond functionalizations in the presence of H2O.11
(12) For examples of meta-selective C-H bond functionalizations,
see: (a) Duong, H. A.; Gilligan, R. E.; Cooke, M. L.; Phipps, R. J.;
Gaunt, M. J. Angew. Chem., Int. Ed. 2011, 50, 463–466. (b) Phipps, R. J.;
Gaunt, M. J. Science 2009, 323, 1593–1597. (c) Yue, W.; Li, Y.; Jiang,
W.; Zhen, Y.; Wang, Z. Org. Lett. 2009, 11, 5430–5433. (d) Zhang, Y.-
H.; Shi, B.-F.; Yu, J.-Q. J. Am. Chem. Soc. 2009, 131, 5072–5074 and
references cited therein.
(13) For recent examples of palladium-catalyzed direct arylations in
the absence of solvent, see: (a) Bedford, R. B.; Mitchell, C. J.; Webster,
R. L. Chem. Commun. 2010, 46, 3095–3097. (b) Bedford, R. B.;
Engelhart, J. U.; Haddow, M. F.; Mitchell, C. J.; Webster, R. L. Dalton
Trans 2010, 39, 10464–10472.
(11) For ruthenium-catalyzed direct arylations in the presence of
H2O, see: (a) Ackermann, L. Org. Lett. 2005, 7, 3123–3125. See also:
(b) Arockiam, P. B.; Fischmeister, C.; Bruneau, C.; Dixneuf, P. H.
Angew. Chem., Int. Ed. 2010, 49, 6629–6632.
Org. Lett., Vol. 13, No. 7, 2011
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