Ruthenium-catalyzed C-H/N-O bond functionalization: Green isoquinolone syntheses in water

Article abstract of DOI:10.1021/ol202861k

Ruthenium-catalyzed isoquinolone syntheses with ample scope were accomplished through carboxylate assistance in environmentally benign water as a reaction medium. The high chemoselectivity of the ruthenium(II) carboxylate complex also set the stage for th

Full text of DOI:10.1021/ol202861k

ORGANIC
LETTERS
2011
Vol. 13, No. 24
6548–6551
Ruthenium-Catalyzed CÀH/NÀO Bond
Functionalization: Green Isoquinolone
Syntheses in Water
Lutz Ackermann* and Sabine Fenner
€
Institut fu€r Organische und Biomolekulare Chemie, Georg-August-Universitat,
€
Tammannstrasse 2, 37077 Gottingen, Germany
Lutz.Ackermann@chemie.uni-goettingen.de
Received October 24, 2011
ABSTRACT
Ruthenium-catalyzed isoquinolone syntheses with ample scope were accomplished through carboxylate assistance in environmentally benign
water as a reaction medium. The high chemoselectivity of the ruthenium(II) carboxylate complex also set the stage for the direct use of free
hydroxamic acids for annulations of alkynes.
Oxidative transition-metal-catalyzed annulations of al-
kynes by CÀH bond cleavages1 are increasingly viable
tools for atom- and step-economical syntheses of bioactive
heterocycles.2,3 These transformations usually require
stoichiometric amounts of external, mostly metallic oxi-
dants, which results inthe generationof undesiredwaste.2,3
Notable recent progress was accomplished by Guimond,
Fagnou and co-workers through the use of hydroxamic
acid esters4 as valuable substrates for rhodium-catalyzed
annulations of alkynes in MeOH as the solvent.5 Thus, the
NÀO bond of N-methoxybenzamides served as a handle
(1) Select recent reviews on metal-catalyzed CÀH bond functionali-
zations: (a) Hartwig, J. F. Chem. Soc. Rev. 2011, 40, 1992–2002.
(b) Willis, M. C. Chem. Rev. 2010, 110, 725–748. (c) Ackermann, L.;
Potukuchi, H. K. Org. Biomol. Chem. 2010, 8, 4503–4513. (d) Daugulis,
O. Top. Curr. Chem. 2010, 292, 57–84. (e) Sun, C.-L.; Li, B.-J.; Shi, Z.-J.
Chem. Commun. 2010, 46, 677–685. (f) Colby, D. A.; Bergman, R. G.;
Ellman, J. A. Chem. Rev. 2010, 110, 624–655. (g) Fagnou, K. Top. Curr.
Chem. 2010, 292, 35–56. (h) Jazzar, R.; Hitce, J.; Renaudat, A.; Sofack-
Kreutzer, J.; Baudoin, O. Chem.;Eur. J. 2010, 16, 2654–2672. (i) Lyons,
T. W.; Sanford, M. S. Chem. Rev. 2010, 110, 1147–1169. (j) Dudnik,
A. S.; Gevorgyan, V. Angew. Chem., Int. Ed. 2010, 49, 2096–2098.
(k) Giri, R.; Shi, B.-F.; Engle, K. M.; Maugel, N.; Yu, J.-Q. Chem.
Soc. Rev 2009, 38, 3242–3272. (l) Bellina, F.; Rossi, R. Tetrahedron 2009,
65, 10269–10310. (m) Ackermann, L.; Vicente, R; Kapdi, A. Angew.
Chem., Int. Ed 2009, 48, 9792–9826. (n) Thansandote, P.; Lautens, M.
Chem.;Eur. J. 2009, 15, 5874–5883. (o) Kakiuchi, F.; Kochi, T.
Synthesis 2008, 3013–3039. (p) Satoh, T.; Miura, M. Chem. Lett. 2007,
36, 200–205. (q) Alberico, D.; Scott, M. E.; Lautens, M. Chem. Rev.
2007, 107, 174–238 and references cited therein.
(4) For the elegant use of hydroxamic acid derivatives as powerful
directing groups in palladium-catalyzed CÀH bond transformations,
see: (a) Wang, D.-H.; Wasa, M.; Giri, R.; Yu, J.-Q. J. Am. Chem. Soc.
2008, 130, 7190–7191. (b) Wasa, M.; Yu, J.-Q. J. Am. Chem. Soc. 2008,
130, 14058–14059.
(5) (a) Guimond, N.; Gorelsky, S. I.; Fagnou, K. J. Am. Chem. Soc.
2011, 133, 6449–6457. (b) Guimond, N.; Gouliaras, C.; Fagnou, K.
J. Am. Chem. Soc. 2010, 132, 6908–6909. Direct alkenylations:(c) Rakshit,
S.; Grohmann, C.; Besset, T.; Glorius, F. J. Am. Chem. Soc. 2011, 133,
2350–2353. (d) Willwacher, J.; Rakshit, S.; Glorius, F. Org. Biomol. Chem.
2011, 9, 4736–4740 and references cited therein. Related reactions with
oximes:(e) Parthasarathy, K.; Jeganmohan, M.; Cheng, C.-H. Org. Lett.
2008, 10, 325–328. (f) Too, P. C.; Wang, Y.-F.; Chiba, S. Org. Lett. 2010,
12, 5688–5691.
(2) Representative recent reviews on oxidative 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) Chao, L.; Hua, Z.; Wei, S.; Aiwen, L. Chem.
Rev. 2011, 111, 1780–1824. (d) Yoo, W.-J.; Li, C.-J. Top. Curr. Chem.
2010, 292, 281–302 and references cited therein.
(6) For recent reviews on transition-metal-catalyzed coupling reac-
tions in or on water, see: (a) Li, C.-J. Handbook Of Green Chemistry:
Reactions In Water; Wiley-VCH: Weinheim, 2010; Vol. 5. (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. (e) Herrerias, C. I.; Yao, X.; Li, Z.; Li, C.-J. Chem. Rev. 2007,
107, 2546–2562 and references cited therein.
(3) A review: Satoh, T.; Miura, M. Chem.;Eur. J. 2010, 16, 11212–
11222.
r
10.1021/ol202861k
Published on Web 11/11/2011
2011 American Chemical Society

for the reoxidation of rhodium(I) intermediates, thereby
preventing the use of additional external oxidants.
Water is a nonflammable, nontoxic, green solvent,6 which
has attracted considerable recent attention as a reaction
medium for sustainable CÀH bond functionalizations.7
Given our interest in employing water as a user-friendly
solvent for catalyzed CÀH bond transformations,8,9 we
thus became attracted by devising first metal-catalyzed
direct annulations10 of alkynes by benzamides in water,11
on which we report herein. Intriguingly, the remarkable
chemoselectivity of the optimized ruthenium(II) carboxy-
late catalyst allowed for the use of N-methoxybenzamides
aswellasmoreatom-economicalfreehydroxymic acidsfor
syntheses of isoquinolones, indispensable structural motifs
in bioactive compounds of importance to medicinal
chemistry.12
At the outset of our studies, we probed the effect of a set
of cocatalytic additives for the envisioned coupling of
N-methoxybenzamide (1a) withalkyne 2ainwater asgreen
solvent (Table 1). Unfortunately, the use of KPF6 did not
provide a satisfactory rate acceleration (entries 1 and 2).
Yet, among different carboxylate additives, sterically hin-
dered KO2CMes provided optimal yields of the desired
product 3aa (entries 3À7). Furthermore, it is noteworthy
that water compared favorably with respect to representa-
tive organic solvents (entries 7À12).
Table 1. Optimization of Isoquinolone Synthesisa
entry
additive
solvent
yield
1
À
H2O
17%
25%
11%
17%
46%b
58%
81%
19%
65%
3%
2
KPF6
H2O
3
KOAc
H2O
4
NaOAc
H2O
5
CsOAc
H2O
6
KOPiv
H2O
7
KO2CMes
KO2CMes
KO2CMes
KO2CMes
KO2CMes
KO2CMes
(10 mol %)
H2O
8
t-AmOH
MeOH
DMF
PhMe
H2O
9
10
11
12
26%b
76%
a Reaction conditions: 1a (0.5 mmol), 2a (1.0 mmol), [RuCl2(p-
cymene)]2 (2.5 mol %), additive (30 mol %), solvent (2.0 mL), 16 h;
isolated yields. b GC-conversion.
With optimized reaction conditions in hand, we ex-
plored the scope of the ruthenium-catalyzed annulation
of alkynes 2 by differently substituted N-methoxybenza-
mides 1 with water as a reaction medium (Scheme 1).
Notably, the catalytic system proved broadly applicable,
thus enabling the efficient conversion of both electron-rich
arenes 1bÀ1d as well as electron-deficient derivatives
1eÀ1h displaying valuable functionalities, such as nitro-
or halo-substituents.
Scheme 1. Scope of CÀH/NÀO Bond Functionalization in
Water
Moreover, alkyl-substituted alkynes 2 were converted
with high catalytic efficacy as well (Scheme 2), while
(7) Select examples of palladium-catalyzed CÀH bond functionali-
zations in or on water: (a) Ohnmacht, S. A.; Culshaw, A. J.; Greaney,
M. F. Org. Lett. 2010, 12, 224–226. (b) Nishikata, T.; Lipshutz, B. H.
Org. Lett. 2010, 12, 1972–1975. (c) Nishikata, T.; Abela, A. R.; Lipshutz,
B. H. Angew. Chem., Int. Ed. 2010, 49, 781–784. (d) Ohnmacht, S. A.;
Mamone, P.; Culshaw, A. J.; Greaney, M. F. Chem. Commun. 2008,
1241–1243. (e) Turner, G.; Morris, J. A.; Greaney, M. F. Angew. Chem.,
Int. Ed. 2007, 46, 7996–8000 and references cited therein.
(8) (a) Ackermann, L.; Pospech, J. Org. Lett. 2011, 13, 4153–4155.
(b) Ackermann, L.; Hofmann, N.; Vicente, R. Org. Lett. 2011, 13, 1875–
1877. (c) Ackermann, L. Org. Lett. 2005, 7, 3123–c. A review:
(d) Ackermann, L. Chem. Commun. 2010, 46, 4866–4877.
(9) See also: Arockiam, P. B.; Fischmeister, C.; Bruneau, C.; Dixneuf,
P. H. Angew. Chem., Int. Ed. 2010, 49, 6629–6632 and references cited
therein..
(10) For ruthenium-catalyzed oxidative annulations of alkynes
with stoichiometric or cocatalytic amounts of external oxidants, see:
(a) Ackermann, L.; Lygin, A. V.; Hofmann, N. Angew. Chem., Int. Ed.
2011, 50, 6379–6382. (b) Ackermann, L.; Lygin, A. V.; Hofmann, N.
Org. Lett. 2011, 13, 3278–3281. (c) Ackermann, L.; Wang, L.; Lygin,
A. V. Chem. Sci. 2011, 2, DOI:10.1039/C1SC00619C.
(11) During the preparation of our manuscript a ruthenium-cata-
lyzed annulation with hydroxamic acid esters in MeOH as the solvent
was reported: Li, B.; Feng, H.; Xu, S.; Wang, B. Chem.;Eur. J. 2011, 17,
DOI: 10.1002/chem.201102445.
(12) (a) Eicher, T.; Hauptmann, S. The Chemistry of Heterocycles,
2nd ed.; Wiley-VCH: Weinheim, 2003. (b) Joule, J. A.; Mills, K. Hetero-
cyclic Chemistry, 4th ed.; Blackwell Science Ltd.: Oxford, 2000, and
references cited therein.
unsymmetrical alkynes 2dÀ2f provided the desired pro-
ducts 3adÀ3af with excellent regioselectivities.
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Org. Lett., Vol. 13, No. 24, 2011

Scheme 2. Reaction Scope with Alkyl-Alkynes 2 in Water
Scheme 4. Site Selectivity with Meta-Substituted Arenes
Scheme 5. Intermolecular Competition Experiment
As to the catalyst’s working mode it is noteworthy that
well-defined ruthenium(II) carboxylate complex 413 dis-
played an efficacy comparable to the one observed when
using the in situ generated catalytic system (Scheme 3).
Scheme 3. Well-Defined Complex 4 As Catalyst
Scheme 6. Competition Experiment between Alkynes 2a and 2c
Intramolecular competition experiments with substrates
1iand 1jbearing heteroatom-containing substituentsinthe
meta-position occurred with a significantly altered site
selectivity (Scheme 4) as compared to a meta-methyl-
substituted N-methoxybenzamide (1d) (3da, Scheme 1).
This observation can be rationalized with the key cyclo-
ruthenation step depending on the kinetic CÀH bond
acidity.14
Additionally, intermolecular competition experiments
indicated electron-deficient arenes to be preferentially
functionalized(Scheme5), hence renderinganelectrophilic
activation manifold less likely to be operative.
Further, annulations with differently substituted diaryl-
alkynes highlighted electron-deficient derivatives to be
converted with higher relative reaction rates.15
Experiments with isotopically labeled solvent and sub-
strate [D5]-1a were suggestive of an irreversible CÀH bond
metalation (Scheme 7), which constitutes a notable differ-
ence to rhodium-catalyzed CÀH bond functionalizations
with N-methoxybenzamides.5b Moreover, the kinetic iso-
tope effect (KIE) was determined to be kH/kD ≈ 3.0,15
which can be rationalized with a working mode involving
carboxylate-assisted ruthenation as the rate-limiting step.
Intermolecular competition experiments between differ-
ently substituted alkynes 2a and 2c revealed tolane (2a) to
be predominantly reacted (Scheme 6).
ꢀ
(13) (a) Ackermann, L.; Novak, P.; Vicente, R.; Hofmann, N. Angew.
Chem., Int. Ed. 2009, 48, 6045–6048. (b) Ackermann, L.; Vicente, R.;
Potukuchi, H. K.; Pirovano, V. Org. Lett. 2010, 12, 5032–5035.
(14) Ackermann, L. Chem. Rev. 2011, 111, 1315–1345.
(15) See the Supporting Information for further details.
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Org. Lett., Vol. 13, No. 24, 2011

Scheme 7. Studies with D2O and Labeled Substrate [D5]-1a
Scheme 8. Free Hydroxamic Acids 5 as Substrates
N-methoxybenzamides. Moreover, the extraordinary ro-
bustness and chemoselectivity of the ruthenium(II) car-
boxylate catalyst allowed for the direct use of free
hydroxamic acids in annulations of alkynes. Further ap-
plications of inexpensive ruthenium complexes to cata-
lyzed oxidative CÀH bond functionalizations are ongoing
in our laboratories and will be reported in due course.
Finally, we were intrigued by the possibility of directly
using significantly more atom-economical free hydroxa-
mic acids 5 for ruthenium-catalyzed annulations ofalkynes
by CÀH/NÀO bond cleavages. Thus, we were pleased to
observe that isoquinolones 3 were efficiently accessible
from user-friendly acids 5 in water (Scheme 8), thereby
further illustrating the remarkable robustness of the in-
expensive ruthenium catalyst.
Acknowledgment. Support by the DFG is gratefully
acknowledged.
In summary, we have reported on first catalyzed annula-
tions of alkynes by benzamides through CÀH bond clea-
vages with water as a green reaction medium. Thus,
carboxylate assistance set the stage for a broadly applic-
able ruthenium-catalyzed isoquinolone synthesis from
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.
Org. Lett., Vol. 13, No. 24, 2011
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