Regioselective ruthenium-catalyzed direct benzylations of arenes through C-H bond cleavages

Article abstract of DOI:10.1021/ol902115f

Highly regioselective ruthenium-catalyzed direct benzylatlons through C-H bond cleavages were accomplished under remarkably mild, nonacidic reaction conditions, for which experimental studies suggested a S_EAr-type mechanism not to be operative.

Full text of DOI:10.1021/ol902115f

ORGANIC
LETTERS
2009
Vol. 11, No. 21
4966-4969
Regioselective Ruthenium-Catalyzed
Direct Benzylations of Arenes through
C-H Bond Cleavages
Lutz Ackermann* and Petr Nova´k
Institut fuer Organische und Biomolekulare Chemie, Georg-August-UniVersitaet,
Tammannstrasse 2, 37077 Goettingen, Germany
lutz.ackermann@chemie.uni-goettingen.de
Received September 12, 2009
ABSTRACT
Highly regioselective ruthenium-catalyzed direct benzylations through C-H bond cleavages were accomplished under remarkably mild, nonacidic
reaction conditions, for which experimental studies suggested a SEAr-type mechanism not to be operative.
The diarylmethane moiety is an indispensable structural motif
in various compounds with biological activities.1 A useful
approach for its preparation is represented by acid-catalyzed
benzylations of arenes through electrophilic aromatic sub-
stitution (SEAr) reactions.2-4 Unfortunately, these valuable
processes are often associated with significant limitations,
such as (i) their restriction to electron-rich arenes, (ii) their
low chemo- and/or regioselectivities, and (iii) their low
tolerance of acid-labile functional groups. A popular alterna-
tive for the selective synthesis of diarylmethane derivatives
relies on nucleophilic additions of organometallic reagents
to benzaldehydes, along with subsequent reductions of the
thus obtained alcohols.1,5 Further, a more redox-economical6
strategy involves transition-metal-catalyzed cross-coupling
reactions between organometallic reagents and benzyl ha-
(3) Representative recent examples: (a) Prades, A.; Corberan, R.;
Poyatos, M.; Peris, E. Chem.sEur. J. 2009, 15, 4610–4613. (b) Stadler,
D.; Bach, T. Angew. Chem., Int. Ed. 2008, 47, 7557–7559. (c) Wang, B.-
Q.; Xiang, S.-K.; Sun, Z.-P.; Guan, B.-T.; Hu, P.; Zhao, K.-Q.; Shi, Z.-J.
Tetrahedron Lett. 2008, 49, 4310–4312. (d) Podder, S.; Choudhury, J.; Roy,
S. J. Org. Chem. 2007, 72, 3129–3132. (e) Rueping, M.; Nachtsheim, B. J.;
Ieawsuwan, W. AdV. Synth. Catal. 2006, 348, 1033–1037. (f) Mertins, K.;
Iovel, I.; Kischel, J.; Zapf, A.; Beller, M. AdV. Synth. Catal. 2006, 348,
691–695. (g) Muhlthau, F.; Stadler, D.; Goeppert, A.; Olah, G. A.; Prakash,
G. K. S.; Bach, T. J. Am. Chem. Soc. 2006, 128, 9668–9675. (h) Choudhury,
J.; Podder, S.; Roy, S. J. Am. Chem. Soc. 2005, 127, 6162–6163. (i) Iovel,
I.; Mertins, K.; Kischel, J.; Zapf, A.; Beller, M. Angew. Chem., Int. Ed.
2005, 44, 3913–3917, and references cited therein.
(1) Representative examples: (a) McPhail, K. L.; Rivett, D. E. A.; Lack,
D. E.; Davies-Coleman, M. T. Tetrahedron 2000, 56, 9391–9396. (b) Juteau,
H.; Gareau, Y.; Labelle, M.; Sturino, C. F.; Sawyer, N.; Tremblay, N.;
Lamontagne, S.; Carriere, M.-C.; Denis, D.; Metters, K. M. Bioorg. Med.
Chem. 2001, 9, 1977–1984. (c) Graffner-Nordberg, M.; Kolmodin, K.;
Aqvist, J.; Queener, S. F.; Hallberg, A. J. Med. Chem. 2001, 44, 2391–
2402. (d) Sun, H. H.; Paul, V. J.; Fenical, W. Phytochemistry 1983, 22,
743–735. (e) Hoshina, H.; Maekawa, K.; Taie, K.; Igarashi, T.; Sakurai, T.
Heterocycles 2003, 60, 1779–1786. (f) Manzoni, C.; Lovati, M. R.; Bonelli,
A.; Galli, G.; Sirtori, C. R. Eur. J. Pharmacol. 1990, 190, 39–49. (g) Rose,
C.; Vtoraya, O.; Pluzanska, A.; Davidson, N.; Gershanovich, M.; Thomas,
R.; Johnson, S.; Caicedo, J. J.; Gervasio, H.; Manikhas, G.; Ben Ayed, F.;
Burdette-Radoux, S.; Chaudri-Ross, H. A.; Lang, R. Eur. J. Cancer 2003,
39, 2318–2327. (h) Forsch, R. A.; Queener, S. F.; Rosowsky, A. Bioorg.
Med. Chem. Lett. 2004, 14, 1811–1815.
(4) Ruthenium-catalyzed benzylations through electrophilic aromatic
substitution reactions were achieved at 200 °C with low regioselectivities:
(a) Kondo, T.; Kajiya, S.; Tantayanon, S.; Watanabe, Y. J. Organomet.
Chem. 1995, 489, 83–91. (b) Kondo, T.; Tantayanon, S.; Tsuji, Y.;
Watanabe, Y. Tetrahedron Lett. 1989, 30, 4137–4140.
(5) For recent examples, see: (a) L’Hermite, N.; Giraud, A.; Provot,
O.; Peyrat, J.-F.; Alami, M.; Brion, J.-D. Tetrahedron 2006, 62, 11994–
12002. (b) Long, Y.-Q.; Jiang, X.-H.; Dayam, R.; Sanchez, T.; Shoemaker,
R.; Sei, S.; Neamati, N. J. Med. Chem. 2004, 47, 2561–2573, and references
cited therein.
(2) For selected recent reviews, see: (a) Bandini, M.; Tragni, M. Org.
Biomol. Chem. 2009, 7, 1501–1507. (b) Bandini, M.; Umani-Ronchi, A.
Catalytic Asymmetric Friedel-Crafts Alkylations; Wiley-VCH: Weinheim,
(6) Burns, N. Z.; Baran, P. S.; Hoffmann, R. W. Angew. Chem., Int.
Ed. 2009, 48, 2854–2867.
2009
.
10.1021/ol902115f CCC: $40.75
Published on Web 10/07/2009
 2009 American Chemical Society

lides.7-9 However, these two methodologies require the use
of stoichiometric amounts of organometallic reagents, which
are predominantly prepared through deprotonations with
strong bases.
employing unactivated alkyl halides.18 Given the practical
importance of efficient dirarylmethane syntheses, we con-
sequently became interested in exploring unprecedented
ruthenium-catalyzed direct benzylation reactions under nona-
cidic4 reaction conditions. Herein, we wish to report on the
development of such a protocol, as well as experimental
mechanistic studies providing evidence for a non-SEAr-type
mechanism.
During recent years, metal-catalyzed C-H bond function-
alizations have matured to being increasingly viable alterna-
tives to traditional cross-coupling reactions, which avoid the
use of organometallic reagents in stoichiometric quantities.
Thus, various protocols for efficient catalytic direct arylations
for versatile biaryl syntheses were established.10 Contrarily,
methods for intermolecular11 direct alkylations with aliphatic
halides are scarce.12 In this context, significant progress was
very recently accomplished by Hoarau13 and Fagnou,14 as
well as by Yu,15 by devising reaction conditions for
palladium-catalyzed direct alkylations of heteroarenes or
benzoic acids, respectively. We, on the contrary, developed
ruthenium catalysts for direct alkylations16,17 of arenes
At the outset, we explored various (pre)ligands and
ruthenium precursors for the direct functionalization of arene
1a with benzyl chloride 2a (Table 1). Representative
Table 1. Optimization of Direct Benzylation of Arene 1aa
(7) For select recent examples, see: (a) Bedford, R. B.; Huwe, M.;
Wilkinson, M. C. Chem. Commun. 2009, 600–602. (b) Chen, Y.-H.; Sun,
M.; Knochel, P. Angew. Chem., Int. Ed. 2009, 48, 2236–2239. (c) Chupak,
L. S.; Wolkowski, J. P.; Chantigny, Y. A. J. Org. Chem. 2009, 74, 1388–
1390. (d) Burns, M. J.; Fairlamb, I. J. S.; Kapdi, A. R.; Sehnal, P.; Taylor,
R. J. K. Org. Lett. 2007, 9, 5397–5400. (e) Molander, G. A.; Elia, M. D.
J. Org. Chem. 2006, 71, 9198–9202. (f) McLaughlin, M. Org. Lett. 2005,
entry
[Ru]
L
solvent
PhMe
yield
1
2
3
4
5
6
7
8
[RuCl2(p-cymene)]2
[RuCl2(p-cymene)]2 PPh3
---
10%b
<5%b
<5%b
<5%b
<5%b
<10%b
26%b
81%
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
7, 4875–4878, and references cited therein
.
[RuCl2(p-cymene)]2 HIMesCl
[RuCl2(p-cymene)]2 HIPrCl
[RuCl2(p-cymene)]2 SHIPrCl
[RuCl2(p-cymene)]2 KOAc
[RuCl2(p-cymene)]2 PhCO2H
[RuCl2(p-cymene)]2 MesCO2H
[RuCl2(p-cymene)]2 i-PrCO2H
[RuCl2(p-cymene)]2 t-BuCO2H
[RuCl2(p-cymene)]2 (1-Ad)CO2H PhMe
[RuCl2(p-cymene)]2 (1-Ad)CO2H NMP
[RuCl2(p-cymene)]2 (1-Ad)CO2H 1,4-dioxane
[RuCl2(PPh3)3]
[RuCl2(cod)]n
(8) Liegault, B.; Renaud, J.-L.; Bruneau, C. Chem. Soc. ReV. 2008, 37,
290–299
.
(9) Kuwano, R. Synthesis 2009, 1049–1061
.
(10) Recent reviews: (a) Chen, X.; Engle, K. M.; Wang, D.-H.; Yu,
J.-Q. Angew. Chem., Int. Ed. 2009, 48, 5094–5115. (b) Thansandote, P.;
Lautens, M. Chem.sEur. J. 2009, 15, 5874–5883. (c) Daugulis, O.; Do,
H.-Q.; Shabashov, D. Acc. Chem. Res. 2009, 42, 1074–1086. (d) Kakiuchi,
F.; Kochi, T. Synthesis 2008, 3013–3039. (e) Li, B.-J.; Yang, S.-D.; Shi,
Z.-J. Synlett 2008, 949–957. (f) Lewis, J. C.; Bergman, R. G.; Ellman, J. A.
Acc. Chem. Res. 2008, 41, 1013–1025. (g) Satoh, T.; Miura, M. Chem.
Lett. 2007, 36, 200–205. (h) Alberico, D.; Scott, M. E.; Lautens, M. Chem.
ReV. 2007, 107, 174–238. (i) Seregin, I. V.; Gevorgyan, V. Chem. Soc.
ReV. 2007, 36, 1173–1193. (j) Pascual, S.; de Mendoza, P.; Echavarren,
A. M. Org. Biomol. Chem. 2007, 5, 2727–2734. (k) Campeau, L.-C.; Stuart,
D. R.; Fagnou, K. Aldrichimica Acta 2007, 40, 35–41. (l) Ackermann, L.
Synlett 2007, 507–526.
9
60%
76%
81%
10
11
12
13
14
15
<5%b
46%b
32%b
<10%b
(1-Ad)CO2H PhMe
(1-Ad)CO2H PhMe
a Reaction conditions: 1a (0.50 mmol), 2a (0.75 mmol), [Ru] (5.0 mol
%), L (30 mol %), K2CO3 (1.00 mmol), PhMe (2.0 mL), 100 °C, 20 h.
b GC-conversion; HIMes ) N,N′-bis-(2,4,6-trimethylphenyl)imidazolium,
(S)HIPr ) N,N′-bis-(2,6-di-iso-propylphenyl)imidazol(in)ium.
(11) For palladium-catalyzed intramolecular alkylations with activated
alkyl halides, see: (a) Hennessy, E. J.; Buchwald, S. L. J. Am. Chem. Soc.
2003, 125, 12084–12085. (b) Hwang, S. J.; Cho, S. H.; Chang, S. J. Am.
Chem. Soc. 2008, 130, 16158–16159.
(12) For reviews on palladium-catalyzed sequential reactions involving
alkylations through the use of norbornene, see: (a) Catellani, M.; Motti, E.;
Della Ca, N. Acc. Chem. Res. 2008, 41, 1512–1522. (b) Catellani, M. Synlett
2003, 298–313. (c) Refs.10b and h
phosphines or N-heterocyclic carbene precursors19 did not
enable the desired transformation (entries 1-5). However,
when employing carboxylic acids20 as additives, more
satisfactory results were obtained (entries 6-11), with
sterically demanding derivatives providing the highest yields
(entries 8 and 11).
(13) Verrier, C.; Hoarau, C.; Marsais, F. Org. Biomol. Chem. 2009, 7,
647–650.
(14) Lapointe, D.; Fagnou, K. Org. Lett. 2009, 11, 4160–4163.
(15) Zhang, Y.-H.; Shi, B.-F.; Yu, J.-Q. Angew. Chem., Int. Ed. 2009,
48, 6097–6100.
(16) For select recent examples of ruthenium-catalyzed direct arylations,
see: (a) Kitazawa, K.; Kochi, T.; Sato, M.; Kakiuchi, F. Org. Lett. 2009,
11, 1951–1954. (b) Ackermann, L.; Born, R.; Vicente, R. ChemSusChem
2009, 2, 546–549. (c) Ackermann, L.; Mulzer, M. Org. Lett. 2008, 10, 5043–
(18) Ackermann, L.; Novak, P.; Vicente, R.; Hofmann, N. Angew.
Chem., Int. Ed. 2009, 48, 6045–6048.
¨
5045. (d) Ozdemir, I.; Demir, S.; Cetinkaya, B.; Gourlaouen, C.; Maseras,
F.; Bruneau, C.; Dixneuf, P. H. J. Am. Chem. Soc. 2008, 130, 1156–1157.
(e) Ackermann, L.; Althammer, A.; Born, R. Tetrahedron 2008, 64, 6115–
6124. (f) Oi, S.; Funayama, R.; Hattori, T.; Inoue, Y. Tetrahedron 2008,
64, 6051–6059. (g) Ackermann, L.; Althammer, A.; Born, R. Synlett 2007,
2833–2836. (h) Ackermann, L.; Althammer, A.; Born, R. Angew. Chem.,
Int. Ed. 2006, 45, 2619–2622. (i) Oi, S.; Aizawa, E.; Ogino, Y.; Inoue, Y.
J. Org. Chem. 2005, 70, 3113–3119. (j) Kakiuchi, F.; Matsuura, Y.; Kan,
S.; Chatani, N. J. Am. Chem. Soc. 2005, 127, 5936–5945, and references
cited therein. Reviews: (k) Ackermann, L. Modern Arylation Methods;
Wiley-VCH: Weinheim, 2009. (l) Ackermann, L.; Born, R.; Spatz, J. H.;
(19) For examples of direct arylations catalyzed by ruthenium complexes
generated from N-heterocyclic carbenes, see: (a) Ackermann, L.; Born, R.;
´
Alvarez-Bercedo, P. Angew. Chem., Int. Ed. 2007, 46, 6364–6367. (b)
Ackermann, L. Org. Lett. 2005, 7, 3123–3125.
(20) Ackermann, L.; Vicente, R.; Althammer, A. Org. Lett. 2008, 10,
2299–2302.
(21) Catalytic or (over-)stoichiometric amounts of typical Lewis acids,
such as FeCl3 or AlCl3, did not provide benzylated products under otherwise
identical reaction conditions.
(22) Preliminary experiments indicated that the formation of N-benzyl
pyridinium salts was not of relevance for ruthenium-catalyzed direct
benzylations of pyridine derivatives.
(23) This product ratio could also be the result of a steric effect exerted
by the ortho-methyl substituent in substrate 4a.
Althammer, A.; Gschrei, C. J. Pure Appl. Chem. 2006, 78, 209–214
(17) Recently, ruthenium-catalyzed amino- or alkoxycarbonylations were
reported: Kochi, T.; Urano, S.; Seki, H.; Mizushima, E.; Sato, M.; Kakiuchi,
.
F. J. Am. Chem. Soc. 2009, 131, 2792–2793
.
Org. Lett., Vol. 11, No. 21, 2009
4967

With an optimized catalytic system in hand, we explored
its scope in the direct benzylation of arenes 1 under
nonacidic reaction conditions (Scheme 1). Interestingly,
the synthesis of diarylmethane 3b. Due to the mild reaction
conditions, important functional groups, such as esters or
enolizable ketones on the aromatic moieties of chlorides
2, were well tolerated by the catalytic system. Further-
more, electrophiles displaying both benzyl and aryl
chlorides were coupled chemoselectively at the former
functionality, a valuable asset for further catalytic func-
tionalization chemistry.
Scheme 1. Direct Benzylations of Oxazoline Derivatives 1
Direct benzylations through C-H bond cleavages were
not restricted to oxazoline-substituted arenes 1. Indeed,
pyridine-substituted arenes or alkenes 4 were functionlized
regioselectively, delivering diarylmethanes 5a-5h and
alkene 5i, again with a useful functional group tolerance
(Scheme 2).21,22
Likewise, the ruthenium complex derived from carboxylic
acid (1-Ad)CO2H allowed for a highly regioselective direct
benzylation of pyrazolyl-substituted arene 6a (Scheme 3).
Scheme 3. Direct Benzylation of Pyrazol Derivative 6a
benzyl chlorides 2 gave rise to more efficient catalysis
than did the corresponding bromides, as illustrated with
Despite the recent significant impact of ruthenium-catalyzed
direct C-H bond functionalizations with aryl16b-i,20 or alkyl18
halides, experimental studies on their mechanism are very
rare. To gain insight into the working mode of the present
catalytic system, we conducted intermolecular competition
experiments, which indicated a slight preference for more
electron-deficient benzyl chloride 2c (Scheme 4).
Scheme 2. Direct Benzylations of Pyridine Derivatives 4
Scheme 4
.
Intermolecular Competition Experiment between
Chlorides 2b and 2c
Moreover, inter- and intramolecular competition experi-
ments between differently substituted arenes highlighted that
(i) less nucleophilic pyridine derivative 4b was benzylated
preferentially23 and that (ii) meta-fluoro-substituted arene 6b
4968
Org. Lett., Vol. 11, No. 21, 2009

was functionalized regioselectively at its more C-H acidic
ortho-position (Scheme 5). On the basis of these experimental
observations, a simple SEAr-type mechanism seems less
likely to be operative. On the contrary, the acidities of the
C-H bonds to be functionalized appear to be of relevance,
which is in good agreement with a concerted cyclometalation/
deprotonation mechanism.
Scheme 5
.
Inter- and Intramolecular Competition Experiments
between Substituted Arenes
In conclusion, we have developed a broadly applicable
ruthenium catalyst for highly regioselective direct benzyla-
tions of various arenes under remarkably mild, nonacid
reaction conditions. Further, experimental mechanistic studies
provided evidence for a non-SEAr-type catalytic manifold.
Acknowledgment. Financial support by the DFG is
gratefully acknowledged.
Supporting Information Available: Experimental pro-
cedures, characterization data, and 1H and 13C NMR spectra
for new compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
OL902115F
Org. Lett., Vol. 11, No. 21, 2009
4969