Ruthenium-catalyzed oxidative annulation by cleavage of C-H/N-H bonds

Article abstract of DOI:10.1002/anie.201101943

Bond activation in action: Unprecedented ruthenium-catalyzed oxidative annulations of alkynes through cleavage of C-H bonds set the stage for an efficient 1(2H)-isoquinolone synthesis with ample scope (see scheme; tAm=tert-amyl). Mechanistic studies provided strong evidence for a rate-limiting C-H bond metalation through carboxylate assistance. Copyright

Full text of DOI:10.1002/anie.201101943

DOI: 10.1002/anie.201101943
À
C H Bond Activation
À
À
Ruthenium-Catalyzed Oxidative Annulation by Cleavage of C H/N H
Bonds**
Lutz Ackermann,* Alexander V. Lygin, and Nora Hofmann
Dedicated to Professor Dieter Enders on the occasion of his 65th birthday
Oxidative transition-metal-catalyzed C H bond functionali-
zations[1] have attracted significant recent interest, because
these methods avoid the multi-step preparation of preacti-
vated starting materials, and hence allow for an overall
streamlining of organic synthesis. Pioneering reports by the
research groups of Miura and Satoh,[2] Fagnou,[3] and Jones[4]
revealed that particularly rhodium catalysts enabled effective
dehydrogenative annulation reactions of alkynes through
chelation assistance,[5,6] which have set the stage for very
recently developed rhodium-catalyzed isoquinolone[7] synthe-
ses.[8] On the contrary, the use of less-expensive ruthenium[9]
Table 1: Optimization study for the synthesis of isoquinolone 3a.[a]
À
Entry Oxidant
Solvent
T [8C] Conv. into Conv. into
3a [%][b]
4a [%][b]
1
2
Cu(OAc)2·H2O m-xylene 120
m-xylene 120
Cu(OAc)2·H2O m-xylene 120
Cu(OAc)2·H2O nBu2O
Cu(OAc)2·H2O tAmOH
Cu(OAc)2·H2O tAmOH
Cu(OAc)2·H2O tAmOH
58 (40)
19
–
0
–
3[c]
4
0
–
120
120
100
80
100
100
80
32 (27)
32
61 (50)
51
33
8
10
81 (62)
97 (76)
40 (15)
À
catalysts for oxidative annulations through cleavage of C H
5
6
7
–
–
–
–
–
–
–
–
bonds has thus far not been reported. During studies on
oxidative ruthenium-catalyzed homodehydrogenative aryla-
tions,[10] we observed unprecedented ruthenium-catalyzed
direct annulations of alkynes[11] through the chemo- and
8
9
AgOAc
Ag2CO3
Cu(OAc)2·H2O tAmOH
Cu(OAc)2·H2O tAmOH
Cu(OAc)2·H2O tAmOH
tAmOH
tAmOH
10[d]
11[e]
12[e,f]
À
À
site-selective functionalization of both C H and N H bonds,
and we wish to disclose our results herein.
100
100
At the outset of our studies, we explored the effect of
different reaction parameters on the oxidative annulation of
alkyne 2a by amide 1a, which included the use of represen-
tative ruthenium precursors, solvents, oxidants, and additives
(Table 1, and Table S1 in the Supporting Information).
Among a variety of ruthenium complexes, optimal yields of
product 3a were obtained with [{RuCl2(p-cymene)}2], along
with Cu(OAc)2·H2O as the terminal oxidant, and tAmOH
(tAm = tert-amyl) as the solvent. On the contrary, the use of
silver(I) salts as stoichiometric oxidants resulted in decreased
catalytic efficacy. As to the reaction mechanism (see below),
the formation of compound 4a in apolar solvents is note-
worthy.[12]
[a] Reaction conditions: 1a (0.5 mmol), 2a (0.5 mmol), [{RuCl2(p-
cymene)}2] (2.5 mol%), oxidant (2.0 equiv), solvent (2.0 mL). [b] Con-
version determined by GC methods, and yields of isolated product in
parentheses. [c] In the absence of [{RuCl2(p-cymene)}2]. [d] Under air.
[e] [{RuCl2(p-cymene)}2] (5.0 mol%). [f] 1a (0.5 mmol), 2a (1.0 mmol).
such as fluoro, chloro, or ester substituents. Furthermore,
amides 1 bearing different groups on the nitrogen atom,[13]
such as N-alkyl, N-benzyl, or N-aryl derivatives, were
efficiently reacted, with the latter being chemoselectively
converted into isoquinolones 3k and 3l, without the forma-
tion of any indole[3] by-products.[14] Likewise, the successful
use of a heteroaromatic benzamide turned out to be viable.
The catalytic system was not restricted to the use of tolane
(2a), but also allowed for efficient oxidative annulations of
aryl-, alkenyl- or alkyl-substituted alkynes 2 (Scheme 2).
Importantly, the annulation process occurred with high
regioselectivity even when using unsymetrically substituted
aryl/alkyl or alkenyl/alkyl[6a] alkynes 2.[15]
Given the remarkable activity of the novel catalytic
system, we became interested in understanding its mode of
action. Thus, intramolecular competition experiments with
meta-substituted substrates were largely controlled by steric
interactions, thus delivering isoquinolones 3m and 3n as the
sole products (Scheme 1). In contrast, the use of substrates 1b
and 1c, which have electronegative heteroatoms in meta-
position, gave significant amounts of products 3w and 3y,[16]
With an optimized catalytic system in hand, we explored
À
its scope in C H bond functionalizations by employing
differently substituted benzamides 1 (Scheme 1). Owing to
its remarkable chemoselectivity the ruthenium catalyst
proved tolerant of valuable electrophilic functional groups,
[*] Prof. Dr. L. Ackermann, Dr. A. V. Lygin, Dipl.-Chem. N. Hofmann
Institut fꢀr Organische und Biomolekulare Chemie
Georg-August-Universitꢁt
Tammannstrasse 2, 37077 Gꢂttingen (Germany)
Fax: (+49)551-39-6777
E-mail: lutz.ackermann@chemie.uni-goettingen.de
Homepage: http://www.org.chemie.uni-goettingen.de/ackermann/
[**] Support by the CaSuS PhD program (fellowship to N.H.), and the
DFG is gratefully acknowledged.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201101943.
À
respectively, through C H bond functionalizations at the 2-
Angew. Chem. Int. Ed. 2011, 50, 6379 –6382
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
6379

Communications
Scheme 2. Scope of the ruthenium-catalyzed oxidative annulation with
alkynes 2.
Scheme 1. Scope of ruthenium-catalyzed oxidative annulation.
position of the arenes (Scheme 3). These observations can
[17]
À
À
be rationalized with the C H bond acidity
or Ru C
Scheme 3. Intramolecular competition experiments with meta-substituted
amides.
bond stability[18,19] governing the site selectivity of the
overall annulation process within a carboxylate-assisted[20]
ruthenation manifold.
Moreover, intermolecular competition experiments
revealed electron-deficient benzamides 1 to be functionalized
good agreement with a concerted acetate-assisted metalation
transition state.[20,21]
Based on our mechanistic studies we propose the ruthe-
nium-catalyzed oxidative annulation to proceed by an initial
intermolecular carboruthenation of alkyne 2 via rate-limiting
À
preferentially, hence rendering an electrophilic C H bond
activation less likely to be operative (Scheme 4a). Further,
benzamides 1 with less electron-rich nitrogen substituents
were found to be more efficiently converted to the corre-
sponding isoquinolones 3 (Scheme 4b).
À
acetate-assisted C H bond ruthenation, and subsequent
À
Intermolecular competition experiments with differently
substituted alkynes 2 showed that electron-deficient tolane
derivatives reacted preferentially (Scheme 5), a notable
difference to a rhodium-catalyzed oxidative annulation
process.[8]
Finally, we performed studies with isotopically labeled
solvents and substrates 1 (Scheme 6, and the Supporting
Information). These experiments were suggestive of an
intramolecular oxidative C N bond formation (Scheme 7).
In summary, we have developed the first ruthenium-
catalyzed oxidative annulation reaction of alkynes, which
gave efficient access to isoquinolones with ample scope. A
valuable asset of the inexpensive catalytic system is repre-
sented by its remarkably high chemo- and regioselectivity.
À
À
Mechanistic studies on this novel C H/N H bond-function-
alization process provided strong evidence for a rate-limiting
À
À
irreversible C H bond metalation with a kinetic isotope
effect (KIE) of kH/kD ꢀ 2.6. A KIE of this magnitude is in
C H bond metalation through carboxylate assistance, a
striking difference to a rhodium-catalyzed isoquinolone
6380 www.angewandte.org
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2011, 50, 6379 –6382

Scheme 6. Experiments with isotopically labeled compounds.
Scheme 4. Intermolecular competition experiments with
benzamides 1.
Scheme 7. Proposed catalytic cycle.
Experimental Section
Representative procedure for ruthenium-catalyzed oxidative annu-
lation. Synthesis of 3a (Table 1, entry 12): A mixture of 1a (67.5 mg,
0.50 mmol), 2a (178 mg, 1.00 mmol), [{RuCl2(p-cymene)}2] (15.3 mg,
5.0 mol%), and Cu(OAc)2·H2O (200 mg, 1.00 mmol) in tAmOH
(2.0 mL) was stirred at 1008C under nitrogen for 22 h. After cooling
the reaction mixture to ambient temperature, it was diluted with aq
NH3 (75 mL, 1.0 wt%) and extracted with EtOAc (3 ꢀ 75 mL). The
combined organic phase was washed with brine (50 mL) and dried
over Na2SO4. After filtration and evaporation of the solvents in
vacuum, the crude product was purified by column chromatography
on silica gel (n-hexane/EtOAc: 4:1) to yield 3a as a colorless solid
(118 mg, 76%).
Scheme 5. Intermolecular competition experiments with alkynes 2.
Received: March 18, 2011
Revised: April 18, 2011
Published online: May 24, 2011
synthesis.[8a] Furthermore, it is noteworthy that the ruthenium
catalyst converts electron-deficient alkynes with increased
efficacy and leads to improved isolated yields when using N-
benzyl-substituted benzamides as substrates. Further appli-
À
Keywords: annulation · C H activation · heteroarenes ·
.
oxidation · ruthenium
À
cations of ruthenium-catalyzed oxidative C H bond func-
tionalizations are ongoing in our laboratories, and will be
reported in due course.
À
[1] Select recent reviews on metal-catalyzed C H bond functional-
izations: a) M. C. Willis, Chem. Rev. 2010, 110, 725 – 748; b) O.
Angew. Chem. Int. Ed. 2011, 50, 6379 –6382
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
6381

Communications
Daugulis, Top. Curr. Chem. 2010, 292, 57 – 84; c) C.-L. Sun, B.-J.
related studies, see: j) Y. Tan, J. F. Hartwig, J. Am. Chem. Soc.
2010, 132, 3676 – 3677; k) C. E. Houlden, C. D. Bailey, J. G. Ford,
M. R. Gagne, G. C. Lloyd-Jones, K. I. Booker-Milburn, J. Am.
Chem. Soc. 2008, 130, 10066 – 10067.
Li, Z.-J. Shi, Chem. Commun. 2010, 46, 677 – 685; d) D. A. Colby,
R. G. Bergman, J. A. Ellman, Chem. Rev. 2010, 110, 624 – 655;
e) K. Fagnou, Top. Curr. Chem. 2010, 292, 35 – 56; f) R. Jazzar, J.
Hitce, A. Renaudat, J. Sofack-Kreutzer, O. Baudoin, Chem. Eur.
J. 2010, 16, 2654 – 2672; g) A. Lei, W. Liu, C. Liu, M. Chen,
Dalton Trans. 2010, 39, 10352 – 10361; h) L. Ackermann, Chem.
Commun. 2010, 46, 4866 – 4877; i) T. W. Lyons, M. S. Sanford,
Chem. Rev. 2010, 110, 1147 – 1169; j) A. S. Dudnik, V.
Gevorgyan, Angew. Chem. 2010, 122, 2140 – 2142; Angew.
Chem. Int. Ed. 2010, 49, 2096 – 2098; k) R. Giri, B.-F. Shi,
K. M. Engle, N. Maugel, J.-Q. Yu, Chem. Soc. Rev. 2009, 38,
3242 – 3272; l) A. A. Kulkarni, O. Daugulis, Synthesis 2009,
4087 – 4109; m) L. Ackermann, R. Vicente, A. Kapdi, Angew.
Chem. 2009, 121, 9976 – 10011; Angew. Chem. Int. Ed. 2009, 48,
9792 – 9826; n) X. Chen, K. M. Engle, D.-H. Wang, J.-Q. Yu,
Angew. Chem. 2009, 121, 5196 – 5217; Angew. Chem. Int. Ed.
2009, 48, 5094 – 5115; o) P. Thansandote, M. Lautens, Chem. Eur.
J. 2009, 15, 5874 – 5883; p) O. Daugulis, H.-Q. Do, D. Shabashov,
Acc. Chem. Res. 2009, 42, 1074 – 1086; q) F. Kakiuchi, T. Kochi,
Synthesis 2008, 3013 – 3039; r) T. Satoh, M. Miura, Chem. Lett.
2007, 36, 200 – 205; s) D. Alberico, M. E. Scott, M. Lautens,
Chem. Rev. 2007, 107, 174 – 238, and references therein.
[2] a) K. Ueura, T. Satoh, M. Miura, J. Org. Chem. 2007, 72, 5362 –
5367; b) K. Ueura, T. Satoh, M. Miura, Org. Lett. 2007, 9, 1407 –
1409.
[3] D. R. Stuart, M. Bertrand-Laperle, K. M. N. Burgess, K. Fagnou,
J. Am. Chem. Soc. 2008, 130, 16474 – 16475.
[4] L. Li, W. W. Brennessel, W. D. Jones, J. Am. Chem. Soc. 2008,
130, 12414 – 12419.
[5] Recent reviews: a) T. Satoh, M. Miura, Chem. Eur. J. 2010, 16,
11212 – 11222; b) T. Satoh, M. Miura, Synthesis 2010, 3395 –
3409.
[6] For important recent progress, see: [Rh]: a) M. P. Huestis, L.
Chan, D. R. Stuart, K. Fagnou, Angew. Chem. 2011, 123, 1374 –
1377; Angew. Chem. Int. Ed. 2011, 50, 1338 – 1341; b) D. R.
Stuart, P. Alsabeh, M. Kuhn, K. Fagnou, J. Am. Chem. Soc. 2010,
132, 18326 – 18339; c) S. Rakshit, F. W. Patureau, F. Glorius, J.
Am. Chem. Soc. 2010, 132, 9585 – 9587; d) K. Morimoto, K.
Hirano, T. Satoh, M. Miura, Org. Lett. 2010, 12, 2068 – 2071; e) N.
Guimond, K. Fagnou, J. Am. Chem. Soc. 2009, 131, 12050 –
12051; f) N. Umeda, H. Tsurugi, T. Satoh, M. Miura, Angew.
Chem. 2008, 120, 4083 – 4086; Angew. Chem. Int. Ed. 2008, 47,
4019 – 4022; [Cu]: g) R. Bernini, G. Fabrizi, A. Sferrazza, S.
Cacchi, Angew. Chem. 2009, 121, 8222 – 8225; Angew. Chem. Int.
Ed. 2009, 48, 8078 – 8081; [Pd]: h) J. Wu, X. Cui, X. Mi, Y. Li, Y.
Wu, Chem. Commun. 2010, 46, 6771 – 6773; i) Z. Shi, S. Ding, Y.
Cui, N. Jiao, Angew. Chem. 2009, 121, 8035 – 8038; Angew.
Chem. Int. Ed. 2009, 48, 7895 – 7898, and references therein; for
[7] For recent examples of metal-catalyzed isoquinolone syntheses,
see: a) Y. Kajita, S. Matsubara, T. Kurahashi, J. Am. Chem. Soc.
2008, 130, 6058 – 6059; b) C.-C. Liu, K. Parthasarathy, C.-H.
Cheng, Org. Lett. 2010, 12, 3518 – 3521, and references therein.
[8] a) T. K. Hyster, T. Rovis, J. Am. Chem. Soc. 2010, 132, 10565 –
10569; b) S. Mochida, N. Umeda, K. Hirano, T. Satoh, M. Miura,
Chem. Lett. 2010, 39, 744 – 746; c) G. Song, D. Chen, C.-L. Pan,
R. H. Crabtree, X. Li, J. Org. Chem. 2010, 75, 7487 – 7490; for an
isohypsic approach, see: d) N. Guimond, C. Gouliaras, K.
Fagnou, J. Am. Chem. Soc. 2010, 132, 6908 – 6909; e) N.
Guimond, S. I. Gorelsky, K. Fagnou, J. Am. Chem. Soc. 2011,
133, 6449 – 6457.
[9] [{Cp*RhCl2}2]: E2545 versus [{RuCl2(p-cymene)}2]: E257 (5.0 g,
Sigma–Aldrich, 17.03.2011). A review on ruthenium-catalyzed
À
direct C H bond arylations: L. Ackermann, R. Vicente, Top.
Curr. Chem. 2010, 292, 211 – 229.
[10] L. Ackermann, P. Novꢁk, R. Vicente, V. Pirovano, H. K.
Potukuchi, Synthesis 2010, 2245 – 2253.
[11] For a pioneering ruthenium-catalyzed cross-dehydrogenative
coupling with alkenes, see: a) H. Weissman, X. Song, D. Milstein,
J. Am. Chem. Soc. 2001, 123, 337 – 338; see also: b) T. Ueyama, S.
Mochida, T. Fukutani, K. Hirano, T. Satoh, M. Miura, Org. Lett.
2011, 13, 706 – 708.
[12] Independently prepared amide 4a was not converted into
isoquinolone 3a under the optimized reaction conditions.
[13] The use of a primary amide as substrate yielded only trace
amounts of polycyclic amides. For a recent rhodium-catalyzed
transformation, see Ref. [8c].
[14] ortho-Methyl-substituted benzamide delivered the correspond-
ing isoquinolone in 33% yield of isolated product.
[15] The use of a terminal alkyne provided only unsatisfactory results.
[16] For
a related observation in rhodium-catalyzed oxidative
coupling reactions, see: N. Umeda, K. Hirano, T. Satoh, N.
Shibata, H. Sato, M. Miura, J. Org. Chem. 2011, 76, 13 – 24.
[17] K. Shen, Y. Fu, J.-N. Li, L. Liu, Q.-X. Guo, Tetrahedron 2007, 63,
1568 – 1576.
[18] E. Clot, C. Megret, O. Eisenstein, R. N. Perutz, J. Am. Chem.
Soc. 2009, 131, 7817 – 7827.
[19] D. Balcells, E. Clot, O. Eisenstein, Chem. Rev. 2010, 110, 749 –
823.
[20] L. Ackermann, Chem. Rev. 2011, 111, 1315 – 1345, and refer-
ences therein.
[21] A representative early example: A. D. Ryabov, I. K. Sakodin-
skaya, A. K. Yatsimirsky, Dalton Trans. 1985, 2629 – 2638.
6382
www.angewandte.org
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2011, 50, 6379 –6382