Ruthenium-catalyzed oxidative C - H alkenylations of anilides and benzamides in water

Article abstract of DOI:10.1021/ol203251s

A cationic ruthenium(II) complex enabled efficient oxidative alkenylations of anilides in water as a green solvent and proved applicable to double C - H bond functionalizations of (hetero)aromatic amides with ample scope. Detailed studies provided strong support for a change of ruthenation mechanism in the two transformations, with an irreversible metalation as the key step in cross-dehydrogenative alkenylations of benzamides.

Full text of DOI:10.1021/ol203251s

ORGANIC
LETTERS
2012
Vol. 14, No. 3
728–731
Ruthenium-Catalyzed Oxidative CÀH
Alkenylations of Anilides and Benzamides
in Water
Lutz Ackermann,* Lianhui Wang, Ratnakancana Wolfram, and Alexander V. Lygin
€
Institut fu€r Organische und Biomolekulare Chemie, Georg-August-Universitat,
€
Tammannstrasse 2, 37077 Gottingen, Germany
Lutz.Ackermann@chemie.uni-goettingen.de
Received December 6, 2011
ABSTRACT
A cationic ruthenium(II) complex enabled efficient oxidative alkenylations of anilides in water as a green solvent and proved applicable to
double CÀH bond functionalizations of (hetero)aromatic amides with ample scope. Detailed studies provided strong support for a change of
ruthenation mechanism in the two transformations, with an irreversible metalation as the key step in cross-dehydrogenative alkenylations of
benzamides.
Direct oxidative alkenylations of (hetero)arenes via two-
fold CÀH bond cleavages are highly attractive tools for
atom- and step-economical organic syntheses, because they
avoid the preparation and use of prefunctionalized starting
materials.1 Based on early reports by Fujiwara and
Moritani2,3 a wealth of palladium- and rhodium-catalyzed
oxidative alkenylations were developed.4 Conversely, less
expensive ruthenium complexes were as of yet underutilized
for cross-dehydrogenative alkenylations of (hetero)arenes,
with notable exceptions being accomplished only very re-
cently.5,6 Despite this significant recent progress, ruthenium-
catalyzed direct oxidative alkenylations continue to be
limited to (hetero)arenes bearing electron-withdrawing
directing groups.5,6 Given the importance of anilines as
key intermediates for the preparation of bioactive
(1) Selected recent reviews on metal-catalyzed CÀH bond functio-
nalizations: (a) Cho, S. H.; Kim, J. Y.; Kwak, J.; Chang, S. Chem. Soc.
Rev. 2011, 40, 5068–5083. (b) Yeung, C. S.; Dong, V. M. Chem. Rev.
2011, 111, 1215–1292. (c) Willis, M. C. Chem. Rev. 2010, 110, 725–748.
(d) Ackermann, L.; Potukuchi, H. K. Org. Biomol. Chem. 2010, 8, 4503–
4513. (e) Yoo, W.-J.; Li, C.-J. Top. Curr. Chem. 2010, 292, 281–302. (f)
Daugulis, O. Top. Curr. Chem. 2010, 292, 57–84. (g) Colby, D. A.;
Bergman, R. G.; Ellman, J. A. Chem. Rev. 2010, 110, 624–655. (h)
Fagnou, K. Top. Curr. Chem. 2010, 292, 35–56. (i) Giri, R.; Shi, B.-F.;
Engle, K. M.; Maugel, N.; Yu, J.-Q. Chem. Soc. Rev. 2009, 38, 3242–
3272. (j) Ackermann, L.; Vicente, R.; Kapdi, A. Angew. Chem., Int. Ed.
2009, 48, 9792–9826. (k) Thansandote, P.; Lautens, M. Chem.;Eur. J.
2009, 15, 5874–5883 and references cited therein.
(5) (a) Ackermann, L.; Pospech, J. Org. Lett. 2011, 13, 4153–4155.
For oxidative annulations from our laboratories, see: (b) Ackermann,
L.; Lygin, A. V.; Hofmann, N. Angew. Chem., Int. Ed. 2011, 50, 6379–
6382. (c) Ackermann, L.; Lygin, A. V.; Hofmann, N. Org. Lett. 2011, 13,
3278–3281. (d) Ackermann, L.; Fenner, S. Org. Lett. 2011, 13, 6548–
6551. (e) Ackermann, L.; Wang, L.; Lygin, A. V. Chem. Sci. 2012, 3, 177–
ꢀ
180. See also: (f) Ackermann, L.; Novak, P.; Vicente, R.; Pirovano, V.;
Potukuchi, H. K. Synthesis 2010, 2245–2253.
(6) (a) Hashimoto, Y.; Ueyama, T.; Fukutani, T.; Hirano, K.; Satoh,
T.; Miura, M. Chem. Lett. 2011, 40, 1165–1166. (b) Arockiam, P. B.;
Fischmeister, C.; Bruneau, C.; Dixneuf, P. H. Green Chem. 2011, 13,
3075–3078. (c) Padala, K.; Jeganmohan, M. Org. Lett. 2011, 13, 6144–
6147. (d) Ueyama, T.; Mochida, S.; Fukutani, T.; Hirano, K.; Satoh, T.;
Miura, M. Org. Lett. 2011, 13, 706–708. (e) Kwon, K.-H.; Lee, D. W.;
Yi, C. S. Organometallics 2010, 29, 5748–5750. (f) Weissman, H.; Song,
X.; Milstein, D. J. Am. Chem. Soc. 2001, 123, 337–338. For illustrative
examples of ruthenium-catalyzed CÀH bond alkylations, see: (g) Murai,
S.; Kakiuchi, F.; Sekine, S.; Tanaka, Y.; Kamatani, A.; Sonoda, M.;
(2) Moritani, I.; Fujiwara, Y. Tetrahedron Lett. 1967, 8, 1119–1122.
(3) For early studies on rhodium-catalyzed oxidative alkenylations,
see: (a) Matsumoto, T.; Yoshida, H. Chem. Lett. 2000, 29, 1064–1065.
(b) Matsumoto, T.; Periana, R. A.; Taube, D. J.; Yoshida, H. J. Catal.
2002, 206, 272–280.
ꢀ
(4) Selected reviews: [Pd]: (a) Jia, C.; Kitamura, T.; Fujiwara, Y. Acc.
Chem. Res. 2001, 34, 633–639. (b) Wasa, M.; Engle, K. M.; Yu, J.-Q. Isr.
J. Chem. 2010, 50, 605–616. [Rh]: (c) Satoh, T.; Miura, M. Chem.;Eur.
J. 2010, 16, 11212–11222.
Chatani, N. Nature 1993, 366, 529–531. (h) Ackermann, L.; Novak, P.;
Vicente, R.; Hofmann, N. Angew. Chem., Int. Ed. 2009, 48, 6045–6048.
(i) Ackermann, L.; Novak, P. Org. Lett. 2009, 11, 4966–4969. (j) Lee, D.-H.;
ꢀ
Kwon, K.-H.; Yi, C. S. Science 2011, 333, 1613–1616.
r
10.1021/ol203251s
Published on Web 01/20/2012
2012 American Chemical Society

compounds and functional materials,7 we hence set out to
develop the first ruthenium-catalyzed cross-dehydrogenative
alkenylations of anilines, on which we wish to report herein.
Notably, the most efficient catalysis was achieved with a
cationic6c,e ruthenium(II) complex in water8,9 as a green
solvent, which allowed for efficient cross-dehydrogenative
alkenylations of benzamides10 as well.
cationic ruthenium(II) complexes.11 Water proved to be
the solvent of choice (entries 4 and 7), and an aerobic
oxidative alkenylation with cocatalytic amounts of Cu-
(OAc)2 H2O was viable, albeit with reduced efficacy (entry 8).
3
The use of silver(I) salts as terminal oxidants provided less
satisfactory results but indicated a strong dependence of
the catalyst’s performance on the presence of acetates12
(entries 9 and 10).
With an optimized catalytic system in hand, we explored
its scope in the intermolecular oxidative alkenylation of
anilides 1 (Scheme 1). Thus, the catalytic CÀH bond
functionalization in water allowed for the efficient conver-
sion of para-substitutedsubstrates 1bÀd and parent anilide
1e via chemoselective monoalkenylations.
Table 1. Optimization of Alkenylation with Acetanilide 1aa
Scheme 1. Oxidative Alkenylations with Anilides 1
additive
entry
oxidant
(mol %)
yield
b
1
2
3
4
5
6
7
8
Cu(OAc)2 H2O
KPF6 (10)
À
À
3
Cu(OAc)2 H2O
2%c
3
Cu(OAc)2 H2O
AgSbF6 (10)
KPF6 (10)
KPF6 (5.0)
KPF6 (10)
KPF6 (10)
KPF6 (10)
54%
3
Cu(OAc)2 H2O
87%
3
Cu(OAc)2 H2O
80%
3
Cu(OAc)2 H2O
77%d
54%e
48%c,d,f
3
Cu(OAc)2 H2O
3
Cu(OAc)2 H2O
3
(10 mol %)
Ag2CO3
AgOAc
9
KPF6 (10)
KPF6 (10)
À
10
40%c
a Reaction conditions: 1a (0.50 mmol), 2a (0.75 mmol), [RuCl2(p-
cymene)]2 (2.5 mol %), additive (10 mol %), oxidant (0.5 mmol), H2O
(2.0 mL), 120 °C, 20 h, under N2, isolated yields. b Without [RuCl2(p-
cymene)]2. c GC conversion. d 100 °C. e t-AmOH (2.0 mL). f Under air.
Intramolecular competition experiments with meta-sub-
stituted anilides 1 site selectively delivered the products 3
through alkenylation in position C-6, likely due to steric
interactions (Scheme 2). Notably, this reactivity pattern
was not observed when using meta-fluoro-substituted
anilide 1i, as was previously noted for ruthenium-catalyzed
CÀH bond functionalization with organic electrophiles.13
Interestingly, intermolecular competition experiments
revealed electron-rich anilides 1 to be preferentially func-
tionalized (Scheme 3),14 which is in good agreement with
an electrophilic activation manifold.
At the outset of our studies, we optimized reaction
conditions for the oxidative alkenylation of acetanilide
1a with alkene 2a (Table 1). In the absence of an additive,
only trace amounts of the desired product 3aa were formed
(entries 1 and 2). Yet, high catalytic efficiency was ensured
by a complex generated in situ from [RuCl2(p-cymene)]2
and cocatalytic amounts of KPF6 (entries 3À6), reaction
conditions previously established for the generation of
(7) Ricci, A., Ed. Amino Group Chemistry; Wiley-VCH: Weinheim,
2008.
(8) For recent reviews on transition-metal-catalyzed coupling reac-
tions in or on water, see: (a) Simon, M.-O.; Li, C.-J. Chem. Soc. Rev.
2011, DOI: 10.1039/C1CS15222J. (b) Li, C.-J. Acc. Chem. Res. 2010, 43,
581–590. (c) Lipshutz, B. H.; Abela, A. R.; Boskovic, Z. V.; Nishikata,
T.; Duplais, C.; Krasovskiy, A. Top. Catal. 2010, 53, 985–990. (d) Butler,
R. N.; Coyne, A. G. Chem. Rev. 2010, 110, 6302–6337 and references
cited therein.
(9) For examples of ruthenium-catalyzed CÀH bond functionaliza-
tions with water: (a) Ackermann, L.; Hofmann, N.; Vicente, R. Org.
Lett. 2011, 13, 1875–1877. (b) Arockiam, P. B.; Fischmeister, C.;
Bruneau, C.; Dixneuf, P. H. Angew. Chem., Int. Ed. 2010, 49, 6629–
6632. (c) Ackermann, L. Org. Lett. 2005, 7, 3123–3125. (d) Ackermann,
L. Chem. Commun. 2010, 46, 4866–4877.
Additionally, the cationic ruthenium(II) complex led to
ortho-selective H/D exchange on anilide 1j, when employ-
ing D2O as the solvent (Scheme 4), thereby indicating a
reversible cycloruthenation event.
However, the chemoselectivity was found to be signifi-
cantly altered when using N-benzoyl anilines 1k and 1l as
the substrates, solely leading to CÀH bond alkenylation at
the benzamide moiety (Scheme 5).
(10) For very recent examples of oxidative alkenylations with benza-
mides in organic solvents, see refs 6a,6e.
(12) Ackermann, L. Chem. Rev. 2011, 111, 1315–1345.
(13) (a) Ackermann, L.; Vicente, R.; Althammer, A. Org. Lett. 2008,
10, 2299–2302. (b) Ackermann, L.; Vicente, R.; Potukuchi, H. K.;
Pirovano, V. Org. Lett. 2010, 12, 5032–5035. (c) See also ref 9a.
(14) For detailed information see the Supporting Information.
(11) (a) Bennett, M. A.; Smith, A. K. J. Chem. Soc., Dalton Trans.
ꢀ
Organometallics 1999, 18, 2390–2394. (c) Ackermann, L.; Vicente, R.
Top. Curr. Chem. 2010, 292, 211–229.
1974, 233–241. (b) Fernandez, S.; Pfeffer, M.; Ritleng, V.; Sirlin, C.
Org. Lett., Vol. 14, No. 3, 2012
729

Scheme 2. Alkenylations with Meta-Substituted Substrates 1
Scheme 5. Intramolecular Competition Experiment
Scheme 6. Oxidative CÀH Bond Alkenylation of Benzamides
Scheme 3. Intermolecular Competition Experiment
Scheme 4. Ruthenium-Catalyzed H/D Exchange in D2O
For the oxidative alkenylations of benzamides 1 the
previously optimized reaction conditions (vide supra) were
found to be superior as compared to numerous variations of
the solvent (DMF, NMP, MeCN, ortho-xylene, t-AmOH),
the oxidant (CuBr2, Ag2CO3, AgOAc), or the cocatalytic
additive (PPh3,NH4PF6,NaBF4,NH4BF4,NaBPh4,BARF,
NH4OTf).14
Scheme 7. Oxidative Alkenylation of Benzamide 4
Importantly, the cationic ruthenium(II) complex was
broadly applicable and enabled the conversion of differently
substituted benzamides 1 by chemoselective monoalkenyla-
tions (Scheme 6). The site selectivity within intramolecular
competition experiments with meta-substituted benzamides
1uÀ1w was largely governed by steric interactions. How-
ever, meta-fluoro-substituted arene 1x was functionalized at
its C-2 position. N-Pentafluorophenyl benzamide (4) was a
viable substrate as well and delivered lactams 5 and 6 via a
reaction sequence consisting of oxidative alkenylation and
intramolecular aza-Michael addition (Scheme 7).
730
Org. Lett., Vol. 14, No. 3, 2012

Scheme 8. Oxidative Alkenylation of Heteroaromatic Sub-
strates
Scheme 9. Direct Alkenylation with Labeled Substrate [D]1-1m
rates.14 Mechanistic studies with isotopically labeled sub-
strate [D]1-1m indicated the cycloruthenation to be irre-
versible, with an intramolecular kinetic isotope effect16 of
kH/kD ≈ 5.4 (Scheme 9).
In summary, we have reported on the first ruthenium-
catalyzed oxidative alkenylations of anilides. Detailed
optimization studies revealed a cationic ruthenium(II)
complex to be the catalyst of choice in water as a green
solvent. The cationic catalyst also set the stage for efficient
twofold CÀH bond alkenylations with various benza-
mides. Mechanistically, the two transformations were
found to display different rate-limiting steps, with an
irreversible CÀH bond metalation in cross-dehydrogena-
tive alkenylations of benzamides. Further studies on ruthe-
nium-catalyzed oxidative CÀH bond functionalizations
are ongoing in our laboratories and will be reported in due
course.
Acknowledgment. Support by the DFG and the Chi-
nese Scholarship Council (fellowship to L.W.) is gratefully
acknowledged.
Further, direct CÀH bond functionalization of
heteroaromatic15 amides 7, 9, and 12aÀc occurred with high
catalytic efficacy and excellent site selectivity (Scheme 8).
As to the catalyst’s working mode, intermolecular com-
petition experiments indicated electron-deficient benza-
mides 1 to be converted with higher relative reaction
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.
(15) For ruthenium-catalyzed direct arylations of heteroarenes with
aryl halides, see: Ackermann, L.; Lygin, A. V. Org. Lett. 2011, 13, 3332–
3335.
ꢀ
(16) Gomez-Gallego, M.; Sierra, M. A. Chem. Rev. 2011, 111, 4857–4963.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 3, 2012
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