Ruthenium-catalyzed isoquinolone synthesis through C-H activation using an oxidizing directing group

Article abstract of DOI:10.1002/chem.201102445

The oxidant directs: A mild, practical, efficient, and regioselective Ru-catalyzed isoquinolone synthesis with a broad substrate scope was reported (see scheme). In this redox neutral process, the aromatic CiH bond functionalization can be performed at room temperature without using any external oxidant. The mechanism of the reaction was probed, and it was found that CiH activation is the turnover-limiting step.

Full text of DOI:10.1002/chem.201102445

COMMUNICATION
DOI: 10.1002/chem.201102445
À
Ruthenium-Catalyzed Isoquinolone Synthesis through C H Activation Using
an Oxidizing Directing Group
Bin Li,*[a] Huiliang Feng,[a] Shansheng Xu,[a] and Baiquan Wang*[a, b]
À
Transition-metal-catalyzed oxidative C H activation pro-
cesses have received significant interest in recent years, be-
cause such approaches eliminate the need for prior steps to
activate the substrate.[1] Consequently, the use of an external
oxidant is generally demanded to regenerate the catalyst. In
the last two years, a new strategy—the use of an oxidizing
directing group that acts as both directing group and (inter-
nal) oxidant—has emerged in this field, which obviates the
need for an external co-oxidant, increases the reactivity and
selectivity under mild reaction conditions, and reduces the
amount of waste formed.[2] This efficient method has been
independently developed in palladium- and rhodium-cata-
wish to disclose our development of the first ruthenium-cat-
À
alyzed C H functionalization using an oxidizing directing
group at room temperature [Eq. (2)]. Similar strategies were
previously used in rhodium catalysis [Eq. (3)].[6a] Moreover,
the lower cost of the ruthenium catalyst[17] in comparison
with rhodium makes this new methodology more valuable
and practical.
À
lyzed C H bond transformation reactions by the research
groups of Cui and Wu,[3] Hartwig,[4] Yu,[5] Guimond and
Fagnou,[6] and Glorius.[7]
In recent work, Miura and Satoh,[8] Fagnou,[9] and Jones[10]
independently reported that rhodium catalysts were compe-
tent catalysts for oxidative annulation reactions of alkynes
[11]
À
through C H bond activation.
As a result, methods for
rhodium-catalyzed isoquinolone[12] syntheses have been de-
veloped during the last four years.[6,13] In contrast, the analo-
gous ruthenium-catalyzed processes[14] were less explored. In
a very recent pioneering and elegant report, the research
group of Ackermann demonstrated the first ruthenium-cata-
lyzed oxidative annulation reaction of alkynes with benza-
mide [Eq. (1)].[15] Nevertheless, a high reaction temperature
(1108C), large excess of the alkyne (2.0 equiv) and an exter-
We initiated our study with the coupling reaction of N-
methoxybenzamide (1a) and diphenylacetylene (2a). After
many trials, we found that treatment of 1a (1.0 equiv) with
nal oxidant [CuACHTUNGTRENNUNG(OAc)2·H2O, 2.0 equiv] were necessary for
this new transformation.
We envisioned using the CONH
(OMe) group of N-me-
2a (1.2 equiv) in the presence of 3.0 mol% of [{RuCl2ACHTUNGTRENNUNG(p-
thoxybenzamides 1[6a,16] as an oxidizing directing group with
cymene)}2] and 20 mol% of NaOAc in CH3OH at room
temperature for 8 h gave the desired isoquinolone product
3aa in 90% yield (Scheme 1). The structure of 3aa was con-
selective formation of the isoquinolone motif by Ru-cata-
À
lyzed C H bond activation under mild reaction conditions
1
in high yield without using any external oxidant. Herein, we
firmed by H and 13C NMR analysis and mass spectrometry.
The addition of metal acetate was essential for the success
of the present catalytic reaction, because the acetate anion
is crucial for the cyclometallation step and the regeneration
of the catalyst (see below). No reaction was observed in the
absence of acetate. Other salts, such as K2CO3, gave low
conversion (see Table S1 in the Supporting Information for
details). The metal cation of the acetate did not affect the
catalytic performance. Therefore, NaOAc and KOAc
showed almost the same catalytic activity as CsOAc. Owing
to the convenience in handling, NaOAc was chosen as co-
catalyst.[18] Interestingly, the catalytic process also proceeded
efficiently at room temperature. Certainly, no desired prod-
[a] Prof. Dr. B. Li, H. Feng, Prof. S. Xu, Prof. Dr. B. Wang
State Key Laboratory of Element-Organic Chemistry
College of Chemistry, Nankai University
Tianjin 300071 (P. R. China)
Fax : (+86)22-2350-4781
E-mail: nklibin@nankai.edu.cn
bqwang@nankai.edu.cn
[b] Prof. Dr. B. Wang
State Key Laboratory of Organometallic Chemistry
Chinese Academy of Sciences, Shanghai 200032 (P. R. China)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201102445.
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The examination of the meta-substituted benzamide scope
revealed that the conversion of meta-substituted 1p and 1t
or the b-naphthyl derivative 1w was largely controlled by
steric interactions, with the first affording isoquinolone 3pa
as sole product (Scheme 1), whereas the last two substrates
yielded 3ta-1 and 3wa-1 as major regioisomers (Scheme 2).
Scheme 2. Intramolecular competition experiments with meta-substituted
amides. Isolated yields are given. Reaction conditions: 1 (0.50 mmol), 2a
(0.60 mmol), [{RuCl2ACTHNUTRGNEUNG(p-cymene)}2] (3.0 mol%), NaOAc (20 mol%), dry
CH3OH (0.2m). [a] Reaction run at RT for 12 h. [b] Reaction run at
608C for 16 h. [c] Reaction run at 608C for 24 h.
In contrast, when substrates 1u and 1v with electronegative
heteroatoms in meta-position were applied, significant
amounts of regioisomers 3ua-2 and 3va-2 were produced
À
through C H bond transformations at the 2-position of the
arenes (Scheme 2). The observed site selectivity of different
Scheme 1. Scope of the ruthenium-catalyzed oxidative annulation with al-
kynes. Isolated yields are given. [a] 5.0 mol% of [{RuCl2A(p-cymene)}2]
were used. [b] Reaction run at 608C for 12 h. [c] Reaction run at 608C
for 24 h. [d] Reaction run at 608C for 30 h. [e] Reaction run at 608C for
48 h.
CTHUNGTRENNUNG
substrates is in agreement with that found by Ackermann[15]
and results from the C H bond acidity or Ru C bond sta-
[21]
À
À
bility.[22]
Moreover, the reaction showed broad substrate tolerance
with internal alkynes (Scheme 1). With other symmetrically
aryl-, or alkyl-substituted alkynes, such as methyl- (2b), me-
thoxy- (2c), and fluoro- (2d) substituted diphenylacetylenes
or 3-hexyne (2e) and 4-octyne (2 f), the reaction proceeded
smoothly and provided the corresponding adducts (3ab–
3af) in excellent yields. It is important to note that when un-
symmetrical alkynes were employed, the insertion of an aryl
alkyl-disubstituted alkyne occurred in high regioselectivity
with the aryl-substituted carbon center being installed at the
3-position (3ag and 3ah).[6,13a,15] Unfortunately, under the
current reaction conditions, terminal alkynes failed to afford
the corresponding cycloadducts.
We then conducted a series of experiments to unveil the
reaction mechanism of this redox neutral process. First, re-
actions with isotopically labeled solvents and substrate 1a
were studied. When the reaction of 1a was conducted in
deuterated CH3OH in the absence of alkyne, 15% deuteri-
um incorporation was observed at the two ortho-positions,
uct was formed in the absence of catalyst, under otherwise
identical conditions.
Under the optimal reaction conditions described above,
various substituted benzamides 1 were treated with 2a and
gave the corresponding isoquinolone derivatives (Scheme 1).
The high reactivity resulted in impressively high yields and a
remarkably broad substrate scope. Likewise, the reaction
could conveniently be run on gram scale.[19] Both electron-
rich and electron-poor N-methoxybenzamides participated
well in this reaction. Many important functional groups on
the aromatic ring of benzamides 1, such as fluoro, chloro,
bromo, iodo, methoxy, nitro, ester, and acetyl substituents
(3ea–3ma) were compatible in the present catalytic reac-
tion. ortho-Methylbenzamide afforded the isoquinolone
product in good yield (3na), whereas ortho-methoxybenza-
mide showed a slightly decreased efficacy (3oa).[20] Further-
more, extension of this reaction to heteroaryl carboxamides
proved to be successful (3qa–3sa).
À
and no cleavage of the N O bond was observed [Eq. (4)]. If
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Isoquinolone Synthesis
COMMUNICATION
the same reaction was conducted in the presence of 2a, no
deuterium incorporation was detected in both unreacted 1a
and the product 3aa [Eq. (5)]. These experiments suggest
[Eq. (9)]. This finding suggests that tolane is favored in the
insertion step. A competition experiment between tolane
derivatives 2c and 2d revealed that the product favors iso-
quinolone 3ad derived from the more electron-deficient
tolane derivative [Eq. (10)]. This observation is consistent
with the reported ruthenium-catalyzed oxidative annulations
procedure,[15] but distinctly different from the rhodium-cata-
lyzed process.[13]
À
that, under the reaction conditions, the C H bond metala-
tion step is probably irreversible.[13a,15] Furthermore, a kinet-
ic isotope effect (KIE) of kH/kD ꢀ 3.0 was observed in the
intermolecular isotopic study [Eq. (6)], indicating that the
À
cleavage of the C H bond was most likely involved in the
rate-determining step.
Competition experiments between different substrates
were performed to gain further support for the irreversible
step mentioned above. The reaction of benzamides 1i and
1k with a single equivalent of alkyne under the standard
conditions indicated that the product formation favors iso-
quinolone 3ka derived from the more electron-deficient
À
benzamide [Eq .(7)]. It implied that either N H activation
À
or C H activation could be the first irreversible step. We
then conducted another competition experiment between
benzamides 1g and 1k, in which two para-substituents have
disparate sp values but similar sm values, to distinguish these
À
two possibilities. If N H activation was the first irreversible
step, a greater difference in product distribution should be
shown, given the increased acidity of amide 1k relative to
1g. Indeed, isoquinolone products 3ga and 3ka were ob-
tained in nearly equal amounts [Eq. (8)]. These results re-
Based on the above information, a potential mechanism is
À
proposed (Scheme 3). The first step is an irreversible C H
bond activation process to yield a five-membered ruthenacy-
À
vealed that C H bond activation is the first irreversible
cle A with concomitant formation of acetic acid. Then, the
step.[13a]
alkyne can insert into the Ru C or Ru N bond of A to
form seven-membered ruthenacycle intermediates B or C,
respectively. In both cases, this is followed by a reductive
À
À
Finally, we conducted competition experiments between
alkynes to unveil the subsequent steps in the catalytic cycle.
Reaction of 1a, diphenylacetylene (2a), and 3-hexyne (or 4-
octyne) afforded product 3aa as the major product
À
elimination/N O bond cleavage step to afford the desired
product 3 and the catalyst is released to facilitate the cata-
Chem. Eur. J. 2011, 17, 12573 – 12577
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12575

B. Li, B. Wang et al.
À
Keywords: alkynes · C H activation · directing group ·
homogeneous catalysis · ruthenium
À
[1] For select recent reviews about C H bond functionalizations, see:
a) D. A. Colby, R. G. Bergman, J. A. Ellman, Chem. Rev. 2010, 110,
624–655; b) T. W. Lyons, M. S. Sanford, Chem. Rev. 2010, 110,
1147–1169; c) M. C. Willis, Chem. Rev. 2010, 110, 725–748; d) C.-L.
Sun, B.-J. Li, Z.-J. Shi, Chem. Commun. 2010, 46, 677–685; e) R.
Jazzar, J. Hitce, A. Renaudat, J. Sofack-Kreutzer, O. Baudoin,
Chem. Eur. J. 2010, 16, 2654–2672; f) A. Lei, W. Liu, C. Liu, M.
Chen, Dalton Trans. 2010, 39, 10352–10361; g) L. Ackermann,
Chem. Commun. 2010, 46, 4866–4877; h) A. S. Dudnik, V. Gevorgy-
an, Angew. Chem. 2010, 122, 2140–2142; Angew. Chem. Int. Ed.
À
2010, 49, 2096–2098; i) Topics in Current Chemistry, Vol. 292, C H
Activation (Eds.: J.-Q. Yu, Z.-J. Shi), Springer, Berlin, 2010; j) R.
Giri, B.-F. Shi, K. M. Engle, N. Maugel, J.-Q. Yu, Chem. Soc. Rev.
2009, 38, 3242–3272; k) L. Ackermann, R. Vicente, A. R. Kapdi,
Angew. Chem. 2009, 121, 9976–10011; Angew. Chem. Int. Ed. 2009,
48, 9792–9826; l) 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; m) A. A. Kulkarni, O. Daugulis, Synthesis 2009,
4087–4109; n) P. Thansandote, M. Lautens, Chem. Eur. J. 2009, 15,
5874–5883; o) O. Daugulis, H.-Q. Do, D. Shabashov, Acc. Chem.
Res. 2009, 42, 1074–1086; p) B.-J. Li, S.-D. Yang, Z.-J. Shi, Synlett
2008, 949–957, and references therein.
Scheme 3. Proposed mechansim (Cy = p-cymene).
lytic cycle. It should be noted that either a concerted
(path A, Scheme 3) or a stepwise (path B, Scheme 3) process
is likely to occur in the last catalytic step, although a step-
wise process was favored by Guimond in the rhodium-cata-
lyzed annulation process.[6b]
In summary, we have developed a mild, practical, efficient
and regioselective Ru-catalyzed isoquinolone synthesis with
a broad substrate scope. In this reaction, the aromatic C H
bond functionalization can be performed at room tempera-
ture. This redox neutral strategy circumvents the use of
wasteful metal oxidants and leads to a clean process. The re-
action also adds to the rapidly expanding repertoire of inter-
[2] For a highlight, see: F. W. Patureau, F. Glorius, Angew. Chem. 2011,
123, 2021–2023; Angew. Chem. Int. Ed. 2011, 50, 1977–1979.
[3] J. Wu, X. Cui, L. Chen, G. Jiang, Y. Wu, J. Am. Chem. Soc. 2009,
131, 13888–13889.
[4] Y. Tan, J. F. Hartwig, J. Am. Chem. Soc. 2010, 132, 3676–3677.
[5] K.-H. Ng, A. S. C. Chan, W.-Y. Yu, J. Am. Chem. Soc. 2010, 132,
12862–12864.
[6] a) N. Guimond, C. Gouliaras, K. Fagnou, J. Am. Chem. Soc. 2010,
132, 6908–6909; b) N. Guimond, S. I. Gorelsky, K. Fagnou, J. Am.
Chem. Soc. 2011, 133, 6449–6457.
[7] S. Rakshit, C. Grohmann, T. Besset, F. Glorius, J. Am. Chem. Soc.
2011, 133, 2350–2353.
[8] 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.
[9] D. R. Stuart, M. Bertrand-Laperle, K. M. N. Burgess, K. Fagnou, J.
Am. Chem. Soc. 2008, 130, 16474–16475.
À
[2–7]
À
nal oxidant directed C H bond activation reactions.
In
addition, the mechanism of the reaction was investigated
À
and we found that C H activation is the turnover-limiting
step. Further studies to explore this new method and clearly
understand the nature of the catalytic process are in prog-
ress.
[10] a) L. Li, W. W. Brennessel, W. D. Jones, J. Am. Chem. Soc. 2008,
130, 12414–12419; b) L. Li, W. W. Brennessel, W. D. Jones, Organo-
metallics 2009, 28, 3492–3500.
Experimental Section
[11] For recent reviews, see: a) T. Satoh, M. Miura, Chem. Eur. J. 2010,
16, 11212–11222; b) T. Satoh, M. Miura, Synthesis 2010, 3395–3409;
for examples of recent experimental work, see: [Pd]: c) J. Wu, X.
Cui, X. Mi, Y. Li, Y. Wu, Chem. Commun. 2010, 46, 6771–6773;
d) 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; [Rh]: e) K. Muralirajan, K. Parthasarathy, C.-H. Cheng,
Angew. Chem. 2011, 123, 4255–4258; Angew. Chem. Int. Ed. 2011,
50, 4169–4172; f) M. P. Huestis, L. Chan, D. R. Stuart, K. Fagnou,
Angew. Chem. 2011, 123, 1374–1377; Angew. Chem. Int. Ed. 2011,
50, 1338–1341; g) F. Wang, G. Song, Z. Du, X. Li, J. Org. Chem.
2011, 76, 2926–2932; h) F. W. Patureau, T. Besset, N. Kuhl, F. Glo-
rius, J. Am. Chem. Soc. 2011, 133, 2154–2156; i) D. R. Stuart, P. Al-
sabeh, M. Kuhn, K. Fagnou, J. Am. Chem. Soc. 2010, 132, 18326–
18339; j) N. Umeda, K. Hirano, T. Satoh, N. Shibata, H. Sato, M.
Miura, J. Org. Chem. 2011, 76, 13–24; k) P. C. Too, Y.-F. Wang, S.
Chiba, Org. Lett. 2010, 12, 5688–5691; l) F. Wang, G. Song, X. Li,
Org. Lett. 2010, 12, 5430–5433; m) J. Chen, G. Song, C.-L. Pan, X.
Li, Org. Lett. 2010, 12, 5426–5429; n) S. Rakshit, F. W. Patureau, F.
Glorius, J. Am. Chem. Soc. 2010, 132, 9585–9587; o) K. Morimoto,
K. Hirano, T. Satoh, M. Miura, Org. Lett. 2010, 12, 2068–2071; p) N.
General procedure for the ruthenium-catalyzed synthesis of isoquinolone
derivatives: A mixture of N-methoxybenzamide 1 (0.50 mmol, 1.0 equiv),
the alkyne
2 (if solid) (0.60 mmol, 1.2 equiv), [{RuCl2ACHTUNGTERNUGN(p-cymene)}2]
(9.2 mg, 0.015 mmol, 3.0 mol%) and NaOAc (8.2 mg, 0.10 mmol,
20.0 mmol%) were placed in a Schlenk tube equipped with a stir bar.
Dry CH3OH (2.5 mL) was added (followed by the alkyne if it is a liquid)
and the mixture was stirred at room temperature for 8 h under an argon
atmosphere. Afterwards, the mixture was diluted with CH2Cl2 and trans-
ferred to a round-bottomed flask. Silica was added to the flask and vola-
tiles were evaporated under reduced pressure. The purification was per-
formed by flash column chromatography on silica gel (eluent: EtOAc/pe-
troleum ether=1:5 to 1:1, typically) to give the corresponding pure prod-
uct 3.
Acknowledgements
Support of this work by NSFC (21072097, 21072101, 20872066) is grate-
fully acknowledged.
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Isoquinolone Synthesis
COMMUNICATION
Guimond, K. Fagnou, J. Am. Chem. Soc. 2009, 131, 12050–12051;
q) T. Fukutani, N. Umeda, K. Hirano, T. Satoh, M. Miura, Chem.
Commun. 2009, 5141–5143; r) N. Umeda, H. Tsurugi, T. Satoh, M.
Miura, Angew. Chem. 2008, 120, 4083–4086; Angew. Chem. Int. Ed.
2008, 47, 4019–4022; [Cu]: s) R. Bernini, G. Fabrizi, A. Sferrazza, S.
Cacchi, Angew. Chem. 2009, 121, 8222–8225; Angew. Chem. Int. Ed.
2009, 48, 8078–8081.
H. Wang, M. Wasa, R. Giri, J.-Q. Yu, J. Am. Chem. Soc. 2008, 130,
7190–7191; b) M. Wasa, J.-Q. Yu, J. Am. Chem. Soc. 2008, 130,
14058–14059.
[17]
A
2ACHTUNGRTEN(NUNG p-cymene)}2]: $57.7 (1.0 g,
[18] Catalytic amounts of NaOAc have a strong influence on the catalyt-
ic efficacy in ruthenium-catalyzed direct arylations and direct alkyla-
tions, see: L. Ackermann, Chem. Rev. 2011, 111, 1315–1345.
[19] A sample of 1a (6.60 mmol, 0.998 g) with 2a (7.92 mmol ,1.41 g) was
subjected to the standard reaction conditions to afford the cycload-
duct 3aa in 85% yield just by washing the product with cold
CH3OH. For details, see the Supporting Information.
[20] Under these conditions, N-methoxy-1-naphthamide afforded the cy-
cloadduct in approximately 10% yield.
[21] K. Shen, Y. Fu, J.-N. Li, L. Liu, Q.-X. Guo, Tetrahedron 2007, 63,
1568–1576.
[12] For a review of isoquinolone synthesis, see: V. A. Glushkov, Y. V.
Shklyaev, Chem. Heterocycl. Compd. 2001, 37, 663–687; 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.
[13] 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.
[14] L. Ackermann, R. Vicente, Top. Curr. Chem. 2010, 292, 211–229.
[15] L. Ackermann, AV. Lygin, N Hofmann, Angew. Chem. 2011, 123,
6503–6506; Angew. Chem. Int. Ed. 2011, 50, 6379–6382.
[22] a) D. Balcells, E. Clot, O. Eisenstein, Chem. Rev. 2010, 110, 749–
823; b) E. Clot, C. Megret, O. Eisenstein, R. N. Perutz, J. Am.
Chem. Soc. 2009, 131, 7817–7827.
[16] For the pioneering use of O-methyl hydroxamic acids [CONH-
À
Received: August 6, 2011
Published online: September 29, 2011
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