Ruthenium-catalyzed oxidative C-H bond alkenylations in water: Expedient synthesis of annulated lactones

Article abstract of DOI:10.1021/ol201563r

Ruthenium-catalyzed cross-dehydrogenative C-H bond alkenylations occurred efficiently in environmentally benign water, which was exploited for an oxidative phthalide synthesis with ample scope. Mechanistic studies provided strong evidence for the oxidativ

Full text of DOI:10.1021/ol201563r

ORGANIC
LETTERS
2011
Vol. 13, No. 16
4153–4155
Ruthenium-Catalyzed Oxidative CÀH
Bond Alkenylations in Water: Expedient
Synthesis of Annulated Lactones
Lutz Ackermann* and Jola Pospech
€
Institut fu€r Organische und Biomolekulare Chemie, Georg-August-Universitat,
€
Tammannstrasse 2, 37077 Gottingen, Germany
Lutz.Ackermann@chemie.uni-goettingen.de
Received June 10, 2011
ABSTRACT
Ruthenium-catalyzed cross-dehydrogenative CÀH bond alkenylations occurred efficiently in environmentally benign water, which was exploited
for an oxidative phthalide synthesis with ample scope. Mechanistic studies provided strong evidence for the oxidative alkenylation to proceed by
an irreversible CÀH bond metalation via acetate assistance.
Cross-dehydrogenative CÀH bond functionalizations1
have attracted significant recent attention, because these
methods avoid the tedious, multistep preparation of pre-
functionalized starting materials and, hence, enable a
streamlining of organic synthesis.2 Particularly, pioneering
studies by Fujiwara and Moritani3 as well as Matsumoto4
have set the stage for a plethora of oxidative palladium-
and rhodium-catalyzed alkenylations, respectively.1,2 Yet,
less expensive ruthenium catalysts have thus far been
underutilized for cross-dehydrogenative CÀH bond
alkenylations,5,6 withnotable exceptionsbeing represented
by elegant contributions from Milstein5a as well as Miura
and Satoh.5b
(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, 174À238 and references cited therein.
(4) (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. A comprehensive review: (c) Satoh, T.; Miura, M.
Chem.;Eur. J. 2010, 16, 11212–11222.
(5) For a pioneering report, see: (a) Weissman, H.; Song, X.; Mil-
stein, D. J. Am. Chem. Soc. 2001, 123, 337–338. (b) For alkenylations of
heteroarenes in DMF, see: Ueyama, T.; Mochida, S.; Fukutani, T.;
Hirano, K.; Satoh, T.; Miura, M. Org. Lett. 2011, 13, 706–708. See also:
(c) Kwon, K.-H.; Lee, D. W.; Yi, C. S. Organometallics 2010, 29, 5748–
5750.
(6) For oxidative couplings of boronic acids with alkenes, see:
(a) Farrington, E. J.; Barnard, C. F. J.; Rowsell, E.; Brown, J. M. Adv.
Synth. Catal. 2005, 347, 185–195. (b) Farrington, E. J.; Brown, J. M.;
Barnard, C. F. J.; Rowsell, E. Angew. Chem., Int. Ed. 2002, 41, 169–171.
(7) For pertinent examples of palladium-catalyzed CÀH bond func-
tionalizations in or on water, see: (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.
(2) Representative recent reviews: (a) Cho, S. H.; Kim, J. Y.; Kwak,
J.; Chang, S. Chem. Soc. Rev. 2011, DOI: 10.1039/C1CS15082K.
(b) Yeung, C. S.; Dong, V. M. Chem. Rev. 2011, 111, 1215–1292.
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1824. (d) Yoo, W.-J.; Li, C.-J. Top. Curr. Chem. 2010, 292, 281À302 and
references cited therein.
(3) For early examples, see: (a) Moritani, I.; Fujiwara, Y. Tetrahedron
Lett. 1967, 8, 1119–1122. (b) Fujiwara, Y.; Moritani, I.; Danno, S.;
Asano, R.; Teranishi, S. J. Am. Chem. Soc. 1969, 91, 7166–7169.
A
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633–639.
r
10.1021/ol201563r
2011 American Chemical Society
Published on Web 07/12/2011

Remarkable practical progress in catalyzed functionali-
zations of unreactive CÀH bonds was recently accom-
plished by the use of water as an environmentally benign,
nonflammable, and nontoxic reaction medium.7,8 Based
on recent studies directed toward the ruthenium-catalyzed
oxidative annulations of alkynes9 we developed first ruthe-
nium-catalyzed oxidative CÀH bond alkenylations in
water,10 on which we wish to report herein. Specifically,
benzoic acids11 underwent a reaction sequence comprising
an intermolecular oxidative alkenylation and a subsequent
oxa-Michael reaction. Thereby, diversely substituted
phthalides were obtained, which constitute valuable inter-
mediates in organic synthesis and indispensable structural
motifs of bioactive molecules.12 It is noteworthy that
related palladium- or rhodium-catalyzed cascade reactions
have thus far only been realized in organic solvents.13
At the outset of our studies, we probed the effect of
representative oxidants, additives, and solvents on the
ruthenium-catalyzed cross-dehydrogenative alkenylation
Table 1. Optimization of Ruthenium-Catalyzed Oxidative Al-
kenylationsa
entry
oxidant
additive
---
solvent
yield
1
2
3
4
5
6
7
---
H2O
H2O
H2O
H2O
H2O
H2O
H2O
---
PhI(OAc)2
benzoquinone
AgNO3
---
---
---
25%
---
---
AgOAc
---
<5%
---
CuBr2
---
CuBr2
LiOAc
(3.0 equiv)
NaOAc
(3.0 equiv)
---
66%
8
CuBr2
H2O
86%
9
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
H2O
95%
90%b
28%
34%
---
(8) 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, 2546À2562 and references cited therein.
10
11
12
13
14
---
H2O
---
MeOH
t-AmOH
m-xylene
H2O
---
---
TEMPO
(20 mol %)
95%
(9) (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) For oxidative aryla-
a Reaction conditions: 1a (1.0 mmol), 2a (2.0 mmol), [RuCl2(p-
cymene)]2 (2.0 mol %), oxidant (2.0 equiv), H2O (5.0 mL), 80 °C, 16 h;
isolated yields. b [RuCl2(p-cymene)]2 (1.0 mol %).
ꢀ
tions, see also: Ackermann, L.; Novak, P.; Vicente, R.; Pirovano, V.;
Potukuchi, H. K. Synthesis 2010, 2245–2253.
(10) For ruthenium-catalyzed direct arylations and alkylations in the
presence of water, see: (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.
(11) For a review on CÀH bond functionalizations with benzoic
acids, see: (a) Satoh, T.; Miura, M. Synthesis 2010, 3395–3409. (b) For a
representative recent example of palladium-catalyzed oxidative CÀH
bond functionalizations with acids, see: Wang, D.-H.; Yu, J.-Q. J. Am.
Chem. Soc. 2011, 133, 5767–5769 and references cited therein.
(12) For select reviews, see: (a) Willis, M. C. Angew. Chem., Int. Ed.
2010, 49, 6026–6027. (b) Beck, J. J.; Chou, S.-C. J. Nat. Prod. 2007, 70,
891–900 and references cited therein. Recent examples: (c) Tianpanich,
K.; Prachya, S.; Wiyakrutta, S.; Mahidol, C.; Ruchirawat, S.; Kittakoop,
P. J. Nat. Prod. 2011, 74, 79–81. (d) Yoshikawa, K.; Kokudo, N.;
Hashimoto, T.; Yamamoto, K.; Inose, T.; Kimura, T. Biol. Pharm. Bull.
2010, 33, 1355–1359. (e) Ye, Z.; Lv, G.; Wang, W.; Zhang, M.; Cheng, J.
Angew. Chem., Int. Ed. 2010, 49, 3671–3674. (f) Singh, M.; Argade, N. P.
J. Org. Chem. 2010, 75, 3121–3124 and references cited therein.
(13) (a) Satoh, T.; Ueura, K.; Miura, M. Pure Appl. Chem. 2008, 80,
1127–1134. (b) Ueura, K.; Satoh, T.; Miura, M. Org. Lett. 2007, 1407–
1409. (c) Ueura, K.; Satoh, T.; Miura, M. J. Org. Chem. 2007, 72, 5362–
5367. (d) Miura, M.; Tsuda, T.; Satoh, T.; Pivsa-Art, S.; Nomura, M.
J. Org. Chem. 1998, 63, 5211–5215. See also: (e) Mochida, S.; Hirano,
K.; Satoh, T.; Miura, M. J. Org. Chem. 2011, 76, 3024–3033.
of benzoic acid 1a employing olefin 2a (Table 1). Notably,
the desired product 3aa was not formed in the absence of a
sacrificial oxidant (entry 1). Yet, particularly Cu(OAc)2
proved to be effective among various terminal oxidants
(entries 2À10). Interestingly, CuBr2 could be employed as
well, provided that superstoichiometric amounts of an
acetate salt were present (entries 6À8), thus indicating
carboxylate assistance.14,15 Among representative sol-
vents, H2O turned out to be the most suitable (entries
9À13). With respect to the reaction mechanism, it is
notable that TEMPO as an additive did not inhibit the
catalytic activity (entry 14).16
Subsequently, we explored the scope of the ruthe-
nium-catalyzed oxidative phthalide synthesis in water
(Scheme 1). We were delighted to observe that differ-
ently substituted benzoic acids 1 were converted with
high efficacy. For instance, the catalytic system tolerated
valuable electrophilic functional groups, such as fluoro
or bromo substituents. Further, sterically hindered
ortho-substituted acids 1aÀ1h proved to be viable
(14) For examples of carboxylate-assisted ruthenium-catalyzed di-
rect arylations and alkylations, see: (a) Ackermann, L.; Lygin, A. Org.
Lett. 2011, 13, 3332–3335. (b) Ouellet, S. G.; Roy, A.; Molinaro, C.;
Angelaud, R.; Marcoux, J.-F.; O’Shea, P. D.; Davies, I. W. J. Org.
Chem. 2011, 76, 1436–1439. (c) Ackermann, L.; Vicente, R.; Potukuchi,
H. K.; Pirovano, V. Org. Lett. 2010, 12, 5032–5035. (d) Ackermann, L.
Pure Appl. Chem. 2010, 82, 1403–1413. (e) Ackermann, L.; Vicente, R.
Top. Curr. Chem. 2010, 292, 211–229. (f) Pozgan, F.; Dixneuf, P. H. Adv.
Synth. Catal. 2009, 351, 1737–1743. (g) Ackermann, L.; Vicente, R. Org.
Lett. 2009, 11, 4922–4925. (h) Arockiam, P.; Poirier, V.; Fischmeister,
C.; Bruneau, C.; Dixneuf, P. H. Green Chem. 2009, 11, 1871–1875.
(15) A review: (a) Ackermann, L. Chem. Rev. 2011, 111, 1315–1345.
For early examples of acetate-assisted stoichiometric cyclometalations,
see: (b) Duff, J. M.; Shaw, B. L. J. Chem. Soc., Dalton Trans. 1972, 2219–
2225. (c) Duff, J. M.; Mann, B. E.; Shaw, B. L.; Turtle, B. J. Chem. Soc.,
Dalton Trans. 1974, 139–145. (d) Davies, D. L.; Al-Duaij, O.; Fawcett,
J.; Giardiello, M.; Hilton, S. T.; Russell, D. R. Dalton Trans. 2003, 4132–
4138.
ꢀ
(i) Ackermann, L.; Novak, P. Org. Lett. 2009, 11, 4966–4969.
ꢀ
(j) Ackermann, L.; Novak, P.; Vicente, R.; Hofmann, N. Angew. Chem.,
Int. Ed. 2009, 48, 6045–6048. (k) Ackermann, L.; Mulzer, M. Org. Lett.
2008, 10, 5043–5036. (l) Ackermann, L.; Vicente, R.; Althammer, A.
Org. Lett. 2008, 10, 2299–2302.
(16) Reactions in the presence of 3 wt % of surfactant PTS/H2O
(polyoxyethanyl R-tocopheryl sebacate) did not provide improved yields
in a set of representative transformations.
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Org. Lett., Vol. 13, No. 16, 2011

Scheme 1. Scope of Ruthenium-Catalyzed Oxidative CÀH
Scheme 2. Oxidative CÀH Bond Functionalization with para-
Substituted Acids 1 in Watera
Bond Functionalization in Watera
a Reaction conditions: 1 (1.0 mmol), 2 (2.0 mmol), [RuCl2(p-cymene)]2
(2.0 mol %), Cu(OAc)2•H2O (2.0 mmol), H2O (5.0 mL), 80 °C, 16À24 h;
isolated yields. b 48 h.
In summary, we have disclosed the first ruthenium-
catalyzed oxidative CÀH bond alkenylation with water
as an environmentally benign, nontoxic reaction medium.
Thus, a highly chemoselective ruthenium catalyst enabled
a versatile phthalide synthesis with ample scope through a
reaction sequence consisting of cross-dehydrogenative
alkenylation and subsequent intramolecular oxa-Michael
reaction. Experimental mechanistic studiesweresuggestive
of a kinetically relevant, irreversible CÀH bond ruthena-
tion through acetate assistance.
a Reaction conditions: 1 (1.0 mmol), 2 (2.0 mmol), [RuCl2(p-cymene)]2
(2.0 mol %), Cu(OAc)2•H2O (2.0 mmol), H2O (5.0 mL), 80 °C, 16À
24 h; isolated yields. b 3,5-Dimethoxyphenylacrylic acid butyl ester (4db)
was also isolated in 29% yield. c [RuCl2(p-cymene)]2 (4.0 mol %). d 48 h.
Scheme 3. Oxidative CÀH Bond Functionalizations with Sub-
strate 1l-[D5]
starting materials. The protocol was not restricted to
acrylic acid esters 2 as olefinic substrates, but also
allowed for the conversion of acrylonitrile 2c. Notably,
more sterically demanding R-substituted alkene 2d furn-
ished desired product 3bd in a comparably high isolated
yield. Interestingly, the cross-dehydrogenative reaction
between benzoic acid 1d and alkene 2b delivered desired
lactone 3db, along with significant amounts of product
4db through a direct alkenylation/decarboxylation cas-
cade reaction.
The ruthenium catalyst turned out to be broadly applic-
able, and thus also enabled the selective conversion of
benzoic acids 1iÀ1l not bearing an ortho-substituent
(Scheme 2).
Considering the remarkably broad scope and high che-
moselectivity of the ruthenium catalysis in water, we there-
after probed its working mode through the use of
isotopically labeled substrates. Hence, reactions with start-
ing material 1l-[D5] highlighted that a reversible H/D
exchange was not operative (Scheme 3a). Moreover, an
intermolecular competition experiment was indicative of
an irreversible ruthenation event with a kinetic isotope
effect (KIE) of kH/kD ≈ 3.6 (Scheme 3b).
Acknowledgment. Support by the DFG is gratefully
acknowledged.
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. 16, 2011
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