Hydroxyl-directed ruthenium-catalyzed C-H bond functionalization: Versatile access to fluorescent pyrans

Article abstract of DOI:10.1021/ol301387t

Hydroxyl-assisted oxidative annulations of alkynes were accomplished with an inexpensive ruthenium(II) complex, delivering fluorescent pyrans via highly site selective as well as chemo- and regioselective C-H/O-H bond functionalizations.

Full text of DOI:10.1021/ol301387t

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Hydroxyl-Directed Ruthenium-Catalyzed
CÀH Bond Functionalization: Versatile
Access to Fluorescent Pyrans
Vedhagiri S. Thirunavukkarasu, Margherita Donati, and Lutz Ackermann*
€
Institut fu€r Organische und Biomolekulare Chemie, Georg-August-Universitat,
€
Tammannstrasse 2, 37077 Gottingen, Germany
Lutz.Ackermann@chemie.uni-goettingen.de
Received May 19, 2012
ABSTRACT
Hydroxyl-assisted oxidative annulations of alkynes were accomplished with an inexpensive ruthenium(II) complex, delivering fluorescent pyrans
via highly site selective as well as chemo- and regioselective CÀH/OÀH bond functionalizations.
Oxidative CÀH bond functionalizations1 provide step-
economical access to important bioactive heteroarenes, the
vastmajorityof which havethusfar beenpreparedwiththe
aid ofpalladium or rhodium catalysts.2 A significant recent
advance in direct CÀH bond functionalizations was re-
presented by the development of palladium and rhodium
catalysts that proved applicable to hydroxyl groups as
versatile Lewis basic directing groups.3 While rather
inexpensive4 ruthenium complexes have very recently
emerged as powerful catalysts for oxidative annulations
of alkynes via CÀH/NÀH or CÀH/CÀO bond cleav-
ages,5À9 ruthenium-catalyzed oxidative10 CÀH bond
functionalizations utilizing ubiquitous hydroxyl groups
have unfortunately as of yet proven elusive. Within our
program on catalyzed direct CÀH bond transformations
for a streamlining of organic synthesis,11 we consequently
became interested in exploring the possibility of control-
ling site selectivity in oxidative CÀH bond functionaliza-
tions through hydroxyl assistance. To this end, we employed
naphthols 1as substrates, which were only recently utilized by
Miura, Satoh and co-workers in elegant rhodium-catalyzed
couplings, however, unfortunately solely with symmetrical
alkynes.12 Considering the importance of unsymmetrically
(2) For representative recent reviews, see: (a) Zhu, C.; Wang, R.; Falck,
J. R. Chem. Asian J. 2012, DOI: 10.1002/asia.201200035. (b) Song, G.; Wang,
F.; Li, X. Chem. Soc. Rev. 2012, 41, 3651–3678. (c) Satoh, T.; Miura, M.
Chem.;Eur. J. 2010, 16, 11212–11222. For selected recent examples, see:
(d) Duttwyler, S.; Lu, C.; Rheingold, A. L.; Bergman, R. G.; Ellman, J. A.
J. Am. Chem. Soc. 2012, 134, 4064–4067. (e) Muralirajan, K.; Parthasarathy,
K.; Cheng, C.-H. Angew. Chem., Int. Ed. 2011, 50, 4169–4172. (f) Hyster,
T. K.; Rovis, T. Chem. Sci. 2011, 2, 1606–1610. (g) Huestis, M. P.; Chan, L.;
Stuart, D. R.; Fagnou, K. Angew. Chem., Int. Ed. 2011, 50, 1338–1341. (h)
Shiota, H.; Ano, Y.; Aihara, Y.; Fukumoto, Y.; Chatani, N. J. Am. Chem.
Soc. 2011, 133, 14952–14955. (i) Patureau, F. W.; Besset, T.; Kuhl, N.;
Glorius, F. J. Am. Chem. Soc. 2011, 133, 2154–2156. (j) Shi, Z.; Ding, S.; Cui,
Y.; Jiao, N. Angew. Chem., Int. Ed. 2009, 48, 7895–7898. (k) Umeda, N.;
Tsurugi, H.; Satoh, T.; Miura, M. Angew. Chem., Int. Ed. 2008, 47, 4019–
4022. (l) Ueura, K.; Satoh, T.; Miura, M. Org. Lett. 2007, 9, 1407–1409 and
references cited therein.
(1) Recent illustrative reviews on CÀH bond functionalizations: (a)
Engle, K. M.; Mei, T.-S.; Wasa, M.; Yu, J.-Q. Acc. Chem. Res. 2012,
DOI: 10.1021/ar200185g. (b) Hickman, A. J.; Sanford, M. S. Nature 2012, 484,
177–185. (c) Yeung, C. S.; Dong, V. M. Chem. Rev. 2011, 111, 1215–1292.
(d) McMurray, L.; O’Hara, F.; Gaunt, M. J. Chem. Soc. Rev. 2011, 40,
€
1885–1898. (e) Wencel-Delord, J.; Droge, T.; Liu, F.; Glorius, F. Chem.
Soc. Rev. 2011, 40, 4740–4761. (f) Ackermann, L.; Potukuchi, H. K. Org.
Biomol. Chem. 2010, 8, 4503–4513. (g) Daugulis, O. Top. Curr. Chem. 2010,
292, 57–84. (h) Sun, C.-L.; Li, B.-J.; Shi, Z.-J. Chem. Commun. 2010, 46, 677–
685. (i) Colby, D. A.; Bergman, R. G.; Ellman, J. A. Chem. Rev. 2010, 110,
624–655. (j) Fagnou, K. Top. Curr. Chem. 2010, 292, 35–56. (k) Boutadla, Y.;
Davies, D. L.; Macgregor, S. A.; Poblador-Bahamonde, A. I. Dalton Trans.
2009, 5820–5831. (l) Ackermann, L.; Vicente, R; Kapdi, A. Angew. Chem.,
Int. Ed. 2009, 48, 9792–9826. (m) Thansandote, P.; Lautens, M. Chem.;Eur.
J. 2009, 15, 5874–5883 and references cited therein.
r
10.1021/ol301387t
XXXX American Chemical Society

substituted naphtha[1,8-bc]pyrans as key structural motifs
of bioactive compounds13 and in optoelectronics,14 we
particularly became attracted by the use of unsymmetrical
alkynes for oxidative annulations with inexpensive ruthe-
nium catalysts.
utilized as the oxidant, provided that NaOAc was present
as an additive (entries 16À19), hence highlighting carbox-
ylate assistance to be of key importance.15,16
At the outset, we probed various reaction conditions
for the envisioned oxidative annulation of alkyne 2a by
R-naphthol (1a) (Table 1). Among a set of representative
solvents, t-AmOH, 1,4-dioxane, and toluene furnished
promising results, while optimal yields were obtained with
m-xylene (entries 1À11). Interestingly, an increase of the
reaction temperature led to a decreased yield of the desired
product 3aa (entries 11 and 12), and an aerobic oxidative
annulation under an atmosphere of ambient air proved
viable (entries 13À15). Furthermore, CuBr2 could be
Table 1. Hydroxyl Assistance for Oxidative Annulationa
T
yield
(%)
entry
solvent
DMSO
oxidant
(°C)
1
Cu(OAc)2 H2O
80
80
80
80
80
80
80
80
80
80
80
110
80
80
80
À
3
(3) For pertinent examples, see: (a) Simmons, E. M.; Hartwig, J. F.
Nature 2012, 483, 70–73. (b) Lu, Y.; Leow, D.; Wang, X.; Engle, K. M.;
Yu, J.-Q. Chem. Sci. 2011, 2, 967–971. (c) Wei, Y.; Yoshikai, N. Org.
Lett. 2011, 13, 5504–5507. (d) Xiao, B.; Gong, T.-J.; Liu, Z.-J.; Liu,
J.-H.; Luo, D.-F.; Xu, J.; Liu, L. J. Am. Chem. Soc. 2011, 133, 9250–
9253. (e) Wang, X.; Lu, Y.; Dai, H.-X.; Yu, J.-Q. J. Am. Chem. Soc.
2010, 132, 12203–12205. (f) Morimoto, K.; Hirano, K.; Satoh, T.;
Miura, M. J. Org. Chem. 2011, 76, 9548–9551. (g) Lewis, J. C.; Wu, J.;
Bergman, R. G.; Ellman, J. A. Organometallics 2005, 24, 5737–5746. (h)
Bedford, R. B.; Coles, S. J.; Hursthouse, M. B.; Limmert, M. E. Angew.
Chem., Int. Ed. 2003, 42, 112–114. (i) Kawamura, Y.; Satoh, T.; Miura,
M.; Nomura, M. Chem. Lett. 1999, 961–962. (j) Satoh, T.; Kawamura,
Y.; Miura, M.; Nomura, M. Angew. Chem., Int. Ed. Engl. 1997, 36,
1740–1742 and references cited therein.
2
NMP
Cu(OAc)2 H2O
À
3
3
DCE
Cu(OAc)2 H2O
18
11
5
3
4
H2O
Cu(OAc)2 H2O
3
5
AcOH
Cu(OAc)2 H2O
3
6
DMF
Cu(OAc)2 H2O
26
33
59
42
66
89
55
3
7
DME
Cu(OAc)2 H2O
3
8
t-AmOH
1,4-dioxane
PhMe
Cu(OAc)2 H2O
3
9
Cu(OAc)2 H2O
3
10
11
12
13
14
15
Cu(OAc)2 H2O
3
m-xylene
m-xylene
m-xylene
m-xylene
m-xylene
Cu(OAc)2 H2O
3
Cu(OAc)2 H2O
3
b
Cu(OAc)2 H2O
À
(4) [{Cp*RhCl2}2]: h 638 versus [{RuCl2(p-cymene)}2]: h 77 (2.0 g,
SigmaÀAldrich, 19.05.2012).
3
c
Cu(OAc)2 H2O
À
3
Cu(OAc)2 H2O
45d
(5) Amides: (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) Hashimoto, Y.;
Ueyama, T.; Fukutani, T.; Hirano, K.; Satoh, T.; Miura, M. Chem.
Lett. 2011, 40, 1165–1166.
3
(20 mol %)
16
17
18
19
m-xylene
m-xylene
m-xylene
m-xylene
CuBr2
80
80
80
80
À
CuBr2/NaOAce
41
89f
74g
(6) Acids: (a) Ackermann, L.; Pospech, J. Org. Lett. 2011, 13, 4153–
4155. (b) Ackermann, L.; Pospech, J.; Graczyk, K.; Rauch, K. Org. Lett.
2012, 14, 930–933. (c) Chinnagolla, R. K.; Jeganmohan, M. Chem.
Commun. 2012, 48, 2030–2032. See also: (d) Ueyama, T.; Mochida, S.;
Fukutani, T.; Hirano, K.; Satoh, T.; Miura, M. Org. Lett. 2011, 13, 706–
708. (e) Ketones: Chinnagolla, R. K.; Jeganmohan, M. Eur. J. Org.
Chem. 2012, 417–423.
(7) (a) (NH)-Azoles: Ackermann, L.; Wang, L.; Lygin, A. V. Chem.
Sci. 2012, 3, 177–180. (b) Anilides: Ackermann, L.; Lygin, A. V. Org.
Lett. 2012, 14, 764–767.
Cu(OAc)2•H2O
Cu(OAc)2 H2O
3
a Reaction conditions: 1a (1.0 mmol), 2a (0.5 mmol), oxidant
(1.0 mmol), [RuCl2(p-cymene)]2 (5.0 mol %), solvent (3.0 mL); isolated
yields. b Without [RuCl2(p-cymene)]2. c Without Cu(OAc)2 H2O.
3
d Under air (1 atm), GC-conversion. e NaOAc (1.5 mmol). f [RuCl2(p-
cymene)]2 (2.0 mol %). g 1a (0.5 mmol), 2a (1.0 mmol).
(8) N-Methoxybenzamides: (a) Ackermann, L.; Fenner, S. Org. Lett.
2011, 13, 6548–6551. (b) Li, B.; Ma, J.; Wang, N.; Feng, H.; Xu, S.;
Wang, B. Org. Lett. 2012, 14, 736–739.
With an optimized catalytic system in hand, we tested its
scope in the oxidative annulation of alkynes 2 by naphthol
derivatives 1 (Scheme 1). The ruthenium(II) catalyst al-
lowed for the efficient conversion of decorated substrates 1
and displayed a remarkable tolerance of valuable electrophilic
(9) Selected oxidative alkenylations: (a) Ackermann, L.; Wang, L.;
Wolfram, R.; Lygin, A. V. Org. Lett. 2012, 14, 728–731. (b) Arockiam,
P. B.; Fischmeister, C.; Bruneau, C.; Dixneuf, P. H. Green Chem. 2011,
13, 3075–3078. (c) Hashimoto, Y.; Hirano, K.; Satoh, T.; Kakiuchi, F.;
Miura, M. Org. Lett. 2012, 14, 2058–2061. (d) Kwon, K.-H.; Lee, D. W.;
Yi, C. S. Organometallics 2010, 29, 5748–5750. (e) Weissman, H.; Song,
X.; Milstein, D. J. Am. Chem. Soc. 2001, 123, 337–338 and references
cited therein.
(10) For recent dehydrative (non-oxidative) direct alkylations, see:
Lee, D.-H.; Kwon, K.-H.; Yi, C. S. J. Am. Chem. Soc. 2012, 134, 7325–
7328.
(11) Recent reviews: (a) Ackermann, L. Pure Appl. Chem. 2010,
82, 1403–1413. (b) Ackermann, L. Isr. J. Chem. 2010, 50, 652–663.
(c) Ackermann, L.; Vicente, R. Top. Curr. Chem. 2010, 292, 211–229.
(12) Mochida, S.; Shimizu, M.; Hirano, K.; Satoh, T.; Miura, M.
Chem.;Asian J. 2010, 5, 847–851.
(13) Representative examples: (a) Shin, D.-Y.; Kim, S. N.; Chae,
J.-H.; Hyun, S.-S.; Seo, S.-Y.; Lee, Y.-S.; Lee, K.-O.; Kim, S.-H.; Lee,
Y.-S.; Jeong, J. M.; Choi, N.-S.; Suh, Y.-G. Bioorg. Med. Chem. Lett.
2004, 14, 4519–4523. (b) Suh, Y.-G.; Shin, D.-Y.; Min, K.-H.; Hyun,
S.-S.; Jung, J.-K.; Seo, S.-Y. Chem. Commun. 2000, 1203–1204.
(14) Selected examples: (a) Tyson, D. S.; Fabrizio, E. F.; Panzner,
M. J.; Kinder, J. D.; Buisson, J.-P.; Christensen, J. B.; Meador, M. A.
J. Photochem. Photobiol. A 2005, 172, 97–107. (b) Christensen, J. B.;
Johannsen, I.; Bechgaard, K. J. Org. Chem. 1991, 56, 7055–7058.
(15) Examples of carboxylate-assisted ruthenium-catalyzed aryla-
tions and alkylations: (a) Ackermann, L.; Pospech, J.; Potukuchi,
H. K. Org. Lett. 2012, 14, 2146–2149. (b) Ackermann, L.; Diers, E.;
Manvar, A. Org. Lett. 2012, 14, 1154–1157. (c) Ackermann, L.; Lygin,
A. Org. Lett. 2011, 13, 3332–3335. (d) 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. (e) Ackermann, L.; Vicente, R.; Potukuchi,
H. K.; Pirovano, V. Org. Lett. 2010, 12, 5032–5035. (f) Arockiam, P.;
Poirier, V.; Fischmeister, C.; Bruneau, C.; Dixneuf, P. H. Green Chem.
2009, 11, 1871–1875. (g) Ackermann, L.; Vicente, R. Org. Lett. 2009, 11,
ꢀ
4922–4925. (h) Ackermann, L.; Novak, P. Org. Lett. 2009, 11, 4966–
4969. (i) Ackermann, L.; Vicente, R.; Althammer, A. Org. Lett. 2008, 10,
2299–2302.
(16) A review: (a) Ackermann, L. Chem. Rev. 2011, 111, 1315–1345.
Examples of acetate-assisted stoichiometric cyclometalations: (b) Duff,
J. M.; Shaw, B. L. J. Chem. Soc., Dalton Trans. 1972, 2219–2225. (c)
Davies, D. L.; Al-Duaij, O.; Fawcett, J.; Giardiello, M.; Hilton, S. T.;
Russell, D. R. Dalton Trans. 2003, 4132–4138.
B
Org. Lett., Vol. XX, No. XX, XXXX

functional groups, such as chloro, bromo, or ester sub-
stituents. The catalytic system was not restricted to tolan
derivatives but proved applicable to the conversion of
dialkyl alkyne 2i as well,17 thereby furnishing desired
product 3ai.
Scheme 2. Scope with Unsymmetrical Alkynes 2
Scheme 1. Ruthenium-Catalyzed Annulation with Naphthols 1
Scheme 3. Annulation with Coumarin 4 and Quinolin-2-one 6
Given the importance of unsymmetrically substituted
naphtha[1,8-bc]pyrans 3 in bioactive compounds and func-
tional materials, we subsequently tested differently substituted
alkynes 2in the oxidative annulation (Scheme 2). Fortunately,
the ruthenium(II) catalyst delivered the desired products
3ajÀ3ap with high chemical yields and excellent regioselec-
tivities. Interestingly, the novel annulated pyrans 3 and 5
showed remarkable fluorescence in a range of 430À560 nm.
The catalytic system was not limited to CÀH bond
functionalizations on naphthol derivatives 1. Indeed,
highly effective annulations of alkynes 2 also proved viable
with 4-hydroxycoumarin 4 (Scheme 3). The ruthenium(II)
catalystshoweda useful functionalgroup toleranceand led
to excellent regioselectivities with unsymmetrical alkynes
2. Additionally, 4-hydroxy-substituted quinolin-2-one 6
was found to be a suitable substrate, which allowed for
thestep-economicalpreparationofannulatedproduct7aa.
Given the high catalytic efficacy and excellent site
selectivity and regioselectivity of our ruthenium catalyst,
we became interested in its mode of action. To this end, we
performed intermolecular competition experiments be-
tween differently substituted acetylenes, which revealed
electron-deficient alkynes to be preferentially converted
(Scheme 4 and the Supporting Information).
(17) Terminal alkyne 1-octyne provided thus far only unsatisfactory
results.
Org. Lett., Vol. XX, No. XX, XXXX
C

Scheme 4. Competition Experiment with Alkynes 2
Scheme 6. Proposed Mechanism
Furthermore, a catalytic CÀH bond transformation in
the presence of D2O employing an excess of substrate 1b
resulted in a significant D/H exchange in the peri-position
of the recovered starting material [D1]-1b (Scheme 5),
thereby providing evidence for a reversible CÀH bond
ruthenation step.
Scheme 5. Hydroxyl-Directed CÀH Bond Functionalization
hydroxyl assistance. Thus, a ruthenium(II) catalyst al-
lowed for the efficient annulation of alkynes by naphthols
to yield fluorescent annulated pyrans and gave step-
economical access to diversely decorated coumarins and
quinolin-2-ones with ample scope. Mechanistic studies
provided evidence for a carboxylate-assisted reversible
CÀH bond ruthenation.
with D2O
Acknowledgment. We thank Prof. Dr. Ulf Diederichsen
€
€
(Georg-August-Universitat Gottingen) for providing
access to a fluorescence spectrometer. Support by the
Alexander von Humboldt Foundation (fellowship to V.S.T.)
is gratefully acknowledged.
Based on our mechanistic studies we propose a catalytic
cycle involving initial reversible cycloruthenation to form
complex 8 (Scheme 6). Subsequent migratory insertion of
alkyne 2 and reductive elimination furnish desired product
3, while reoxidation regenerates the catalytically active
species [Ru(O2CMe)2(p-cymene)] (9).
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.
In summary, we have reported on the first ruthenium-
catalyzed oxidative CÀH bond functionalization through
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX