Rh(III)-catalyzed C-H bond activation along with "rollover" for the synthesis of 4-azafluorenes

Article abstract of DOI:10.1021/ol302375c

An intramolecular reaction of 3-alkynyl and 3-alkenyl-2-arylpyridines selectively gave 4-azafluorene compounds in the presence of a catalytic amount of [Cp*RhCl₂]₂ and Cu(OAc)₂. Pyridine-directed C-H bond activation along

Full text of DOI:10.1021/ol302375c

ORGANIC
LETTERS
2012
Vol. 14, No. 19
5106–5109
Rh(III)-Catalyzed CꢀH Bond Activation
along with “Rollover” for the Synthesis
of 4‑Azafluorenes
Takanori Shibata,* Satoshi Takayasu, Shun Yuzawa, and Takashi Otani
Department of Chemistry and Biochemistry, School of Advanced Science and
Engineering, Waseda University, Shinjuku, Tokyo, 169-8555, Japan
tshibata@waseda.jp
Received August 27, 2012
ABSTRACT
An intramolecular reaction of 3-alkynyl and 3-alkenyl-2-arylpyridines selectively gave 4-azafluorene compounds in the presence of a catalytic
amount of [Cp*RhCl2]2 and Cu(OAc)2. Pyridine-directed CꢀH bond activation along with “rollover” are likely to be key steps of this transformation.
Transition metal-catalyzed CꢀH bond activation is
currently one of the most active topics in organic chem-
istry, and CꢀH bond cleavage using a directing group is a
reliable strategy for achieving facile and regioselective
CꢀH bond functionalization.1 For example, 2-phenylpyr-
idine is a typical substrate, and the reaction with a transi-
tion metal complex selectively gives an ortho-metalated
intermediate with the help of nitrogen coordination to
the metal. The subsequent intermolecular reaction with
alkyne, alkene and aryl halide leads to carbonꢀcarbon
bondformation (Scheme 1a).2 Asa newuse fora metalated
CꢀH bond, we were inspired by CꢀH bond metalation by
“rollover”: the coordinations of nitrogen to the metal are
switched to carbonꢀmetal bonds by rotation of the pyr-
idine ring in 2,20-bipyridine (Scheme 1b).3,4 We considered
that “rollover” of the ortho-metalated intermediate might
enable coordination to an alkyne or alkene moiety at the
3-position of the pyridine ring, which follows an intra-
molecular cyclization (Scheme 1c).5
We report here an intramolecular reaction of 3-alkynyl
and 3-alkenyl-2-arylpyridines with the use of [Cp*RhCl2]2
as a catalyst and Cu(OAc)2 as a catalytic additive. A new
carbon skeleton of 4-azafluorene was selectively con-
structed. A preliminary mechanistic study, which supports
the “rollover” step, is also addressed.
(1) For recent reviews: (a) Kitamura, T. Eur. J. Org. Chem. 2009,
1111. (b) Giri, R.; Shi, B.-F.; Engle, K. M.; Maugel, N.; Yu, J.-Q. Chem.
Soc. Rev. 2009, 38, 3242. (c) Yu, J.-Q., Shi, Z., Eds. C-H Activation;
Springer-Verlag: Berlin, Germany, 2010. (d) Daugulis, O. Top. Curr. Chem.
2010, 292, 57. (e) Colby, D. A.; Bergman, R. G.; Ellman, J. A. Chem.
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We chose 3-(phenylethynyl)-2-(p-tolyl)pyridine (1a) as a
model compound and subjected it to several reaction
conditions (Table 1). We have developed cationic Ir(I)-
catalyzed reactions initiated by oxidative cleavage of a
CꢀH bond,6 and used an Ir-BINAP complex for this reac-
tion (entry 1). However, the conventional intermolecular
(3) For a review of CꢀH bond cleavage via “rollover”: Butschke, B.;
Schwarz, H. Chem. Sci. 2012, 3, 308.
(4) For examples of CꢀH bond cleavage via “rollover”: (a) Minghetti,
G.; Stoccoro, S.; Cinellu, M. A.; Soro, B.; Zucca, A. Organometallics
€
2003, 22, 4770. (b) Butschke, B.; Schroder, D.; Schwarz, H. Organome-
tallics 2009, 28, 4340. (c) Zucca, A.; Petretto, G. L.; Cabras, M. L.;
Stoccoro, S.; Cinellu, M. A.; Manassero, M.; Minghetti, G. J. Organo-
met. Chem. 2009, 694, 3753. (d) Tyo, E. C.; Castleman, A. W., Jr.;
€
Schroder, D.; Milko, P.; Roithova, J.; Ortega, J. M.; Cinellu, M. A.;
Cocco, F.; Minghetti, G. J. Am. Chem. Soc. 2009, 131, 13009.
(e) Butschke, B.; Schwarz, H. Organometallics 2010, 29, 6002. (f) Petretto,
G. L.; Rourke, J. P.; Maidich, L.; Stoccoro, S.; Cinellu, M. A.;
Minghetti, G.; Clarkson, G. J.; Zucca, A. Organometallics 2012, 31, 2971.
(5) Rh(III)-catalyzed oxidative coupling, which involved C-H bond
cleavage via CꢀN bond rotation of 1-phenylpyrazole, is reported:
Umeda, N.; Hirano, K.; Satoh, T.; Shibata, N.; Sato, H.; Miura, M.
J. Org. Chem. 2011, 76, 13.
r
10.1021/ol302375c
Published on Web 09/17/2012
2012 American Chemical Society

Table 1. Optimization of the Reaction Conditions
Scheme 1. Concept of CꢀH Bond Functionalization via
“Rollover” in 2-Arylpyridine
entry
catalyst
additive (x)
time (h) yield (%)a
1b
2b
3
[IrCl(cod)2]BF4 rac-BINAP (10)
[RhCl(cod)2]BF4 rac-BINAP (10)
14
14
24
24
24
24
24
8
NDc
NDc
30
[Cp*IrCl2]2
[Cp*RhCl2]2
[Cp*RhCl2]2
none
Cu(OAc)2 H2O (100)
3
4
Cu(OAc)2 H2O (100)
36
3
5
none
trace
ND
37
6
Cu(OAc)2 H2O (100)
3
7
[Cp*RhCl2]2
[Cp*RhCl2]2
[Cp*RhCl2]2
Cu(OAc)2 H2O (20)
3
8d
9d
Cu(OAc)2 H2O (20)
67
3
Cu(OAc)2 (20)
NaOAc (20)
KOAc (20)
6
70
10d [Cp*RhCl2]2
11d [Cp*RhCl2]2
12d [Cp*RhCl2]2
13d [Cp*RhCl2]2
14d [Cp*RhCl2]2
24
24
24
24
24
27
52
NaOPiv (20)
KOPiv (20)
CsOPiv (20)
33
30
49
a Z/E ratio of obtained 2a was from 2/1 to 1/1. b Reaction was
examined in chlorobenzene at 100 °C. c No intramolecular adduct was
detected, but a dimer of 1a was obtained by intermolecular reaction.
d Concentration of 1a was 0.05 M.
by intramolecular hydroarylation to alkyne.9ꢀ11 Neither
[Cp*RhCl2]2 nor Cu(OAc)2 H2O was effective by itself
3
alkenylation proceeded to give a dimer of 1a,7 and intra-
molecular adducts including 2a could not be detected. The
rhodium counterpart gave the same results (entry 2). We
next examined the catalysis of the electrophilic metalation
of CꢀH bond by using Ir(III) or Rh(III) complex along
with a stoichiometric amount of copper acetate (entries 3
and 4).8 As a result, we were pleased to detect the forma-
tion of 4-azafluorene 2a as a 5-exo-dig-type cycloadduct
(entries 5 and 6), but the combination ofa catalytic amount
of [Cp*RhCl2]2 and Cu(OAc)2 H2O gave the same yield
3
as in entry 4, which means that the copper salt acts as a
catalytic additive for the promotion of hydrogen abstrac-
tion, rather than as an oxidant (entry 7).6e,12 The yield of
the present intramolecular reaction drastically improved
under more dilute conditions (entry 8)13 and anhydrous
copper salt gave slightly better results (entry 9). A few alkali
metal acetates and pivalates were examined as alternatives
(6) (a) Tsuchikama, K.; Kasagawa, M.; Hashimoto, Y.; Endo, K.;
Shibata, T. J. Organomet. Chem. 2008, 693, 3939. (b) Tsuchikama, K.;
Hashimoto, Y.; Endo, K.; Shibata, T. Adv. Synth. Catal. 2009, 351,
2850. (c) Tsuchikama, K.; Kasagawa, M.; Endo, K.; Shibata, T. Org.
Lett. 2009, 11, 1821. (d) Tsuchikama, K.; Kasagawa, M.; Endo, K.;
Shibata, T. Synlett 2010, 97. (e) Shibata, T.; Hashimoto, Y.; Otsuka, M.;
Tsuchikama, K.; Endo, K. Synlett 2011, 2075. (f) Shibata, T.; Hirashima,
H.; Kasagawa, M.; Tsuchikama, K.; Endo, K. Synlett 2011, 2171. (g) Pan,
S.; Endo, K.; Shibata, T. Org. Lett. 2011, 13, 4692. (h) Takebayashi, S.;
Shibata, T. Organometallics 2012, 31, 4114.
(7) For examples of directed CꢀH alkenylation of 2-phenylpyridine
with alkynes: (a) Lim, Y.-G.; Lee, K.-H.; Koo, B. T.; Kang, J.-B.
Tetrahedron Lett. 2001, 42, 7609. (b) Volpe, E. C.; Chadeayne, A. R.;
Wolczanski, P. T.; Lobkovsky, E. B. J. Organomet. Chem. 2007, 692,
4774. (c) Li, L.; Brennessel, W. W.; Jones, W. D. J. Am. Chem. Soc. 2008,
130, 12414. (d) Cheng, K.; Yao, B.; Zhao, J.; Zhang, Y. Org. Lett. 2008,
10, 5309. (e) Zhang, Z.; Ferrence, G. M.; Lash, T. D. Org. Lett. 2009, 11,
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Lett. 2009, 38, 118. (g) Xie, M.-H.; Wang, M.; Wu, C.-D. Inorg. Chem.
2009, 48, 10477. (h) Gao, K.; Lee, P.-S.; Fujita, T.; Yoshikai, N. J. Am.
Chem. Soc. 2010, 132, 12249.
(9) For pioneering examples of Pd-catalyzed intramolecular hydro-
arylation to alkyne, (a) Jia, C.; Piao, D.; Oyamada, J.; Lu, W.;
Kitamura, T.; Fujiwara, Y. Science 2000, 287, 1992. (b) Jia, C.; Piao,
D.; Kitamura, T.; Fujiwara, Y. J. Org. Chem. 2000, 65, 7516. For a
review of intramolecular hydroarylation to alkyne (c) Nevedo, C.;
Echavarren, A. M. Synthesis 2005, 167.
(10) For FriedelꢀCrafts type cyclizations of o-alkynyl biphenyls in a
€
6-endo-dig fashion: (a) Mamane, V.; Hannen, P.; Furstner, A. Chem.;
Eur. J. 2004, 10, 4556. (b) Nevado, C.; Echavarren, A. M. Chem.;Eur.
J. 2005, 11, 3155. (c) Soriano, E.; Marco-Contelles, J. Organometallics
2006, 25, 4542.
(11) For Pd-catalyzed cyclization of o-alkynyl biphenyls in
a
5-exo-dig fashion for the synthesis of 9-alkylidene-9H-fluorenes:
(a) Chernyak, N.; Gevorgyan, V. J. Am. Chem. Soc. 2008, 130, 5636.
(b) Chernyak, N.; Gevorgyan, V. Adv. Syn. Catal. 2009, 351, 1101.
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Hilton, S. T.; Russell, D. R. Dalton Trans. 2003, 4132. (b) Davies, D. L.;
€
Donald, S. M. A.; Al-Duaij, O.; Macgregor, S. A.; Polleth, M. J. Am.
Chem. Soc. 2006, 128, 4210. (c) Li, L.; Brennessel, W. W.; Jones, W. D.
Organometallics 2009, 28, 3492. (d) Boutadla, Y.; Davies, D. L.;
Macgregor, S. A.; Poblador-Bahamonde, A. I. Dalton Trans. 2009, 5887.
(13) Under further dilute conditions (0.025 M), the yield of 2a
decreased because of low conversion.
(8) For reviews of Rh(III)-catalyzed CꢀH bond activation using a
stoichiometric amount of oxidants: (a) Satoh, T.; Miura, M. Chem.;
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2012, 41, 3651.
Org. Lett., Vol. 14, No. 19, 2012
5107

Table 2. Substrate Scope of 3-Alkynyl-2-arylpyridines
Figure 1. Inappropriate substrates for the present Rh(III)-
catalyzed intramolecular reaction.
Scheme 2. Proposed Mechanism Including “Rollover”
to Cu(OAc)2, but the yield was not improved (entries
10ꢀ14).14
As a preliminary mechanistic study, we performed con-
trol experiments using regioisomeric alkynylarylpyridines
3ꢀ5 and nitrogen-free substrate 6 under the optimal reac-
tion conditions listed in entry 9 of Table 1 (Figure 1). The
reaction of these four substrates did not proceed at all,
as expected. These results imply that the coordination
of nitrogen atom to a metal center assists sp2 CꢀH bond
cleavage on the benzene ring. Moreover, the present
intramolecular reaction is not an electrophilic substitution
using an alkyne moiety activated by π-coordination of
the metal.
Based on the above results, we can propose a mechanism
depicted in Scheme 2. Rhodium acetate is the true catalyst,
and acetate facilitates hydrogen abstraction in pyridine-
directed CꢀH bond cleavage. “Rollover” from intermediate
(14) The formation of azafluorene 2a could not be detected under the
heating conditions by using PtCl2, InCl3, or AuCl(PPh3) along with
AgBF4, which is typical catalyst for FriedelꢀCrafts type intramolecular
hydroarylation to alkyne (ref 9c).
a Z/E ratio of product 2 is listed in parentheses. b Reaction was
examined at 100 °C.
5108
Org. Lett., Vol. 14, No. 19, 2012

B gives alkyne-metal complex C, and subsequent intra-
molecular carborhodation affords cyclic adduct D. Proto-
nation by acetic acid gives (Z)-2a along with regeneration
of the catalyst. We ascertained that isomerization from
the (Z)- to (E)-isomer of isolated 2a did not occur under
either thermal or Rh-catalyzed conditions. In contrast,
the reaction at a lower temperature predominantly gave
the (Z)-isomer, but in moderate yield due to low conver-
sion (eq 1). These results imply that Z/E isomerization
of intermediate D proceeds at a higher temperature
(120 °C).
We next investigated 2-aryl-3-vinylpyridines as sub-
strates (eq 2). The reactions of 7a and 7b proceeded under
the same reaction conditions to give methyl-substituted
azafluorenes 8a and 8b in moderate yield.
In summary, we have described a Rh(III)-catalyzed
transformation from 3-alkynyl and 3-alkenyl-2-arylpyri-
dines into 4-azafluorene compounds using Cu(OAc)2 as a
catalytic additive. Pyridine-directed CꢀH bond cleavage
along with “rollover” realizes an intramolecular reaction
for the new construction of a nitrogen-containing multi-
cyclic skeleton. Further studies on CꢀH bond function-
alization via “rollover” in synthetic chemistry and the
further mechanistic studyare in progress inour laboratory.
Under the optimal reaction conditions, we examined the
substrate scope of 3-alkynyl-2-arylpyridine for the syn-
thesis of 9-alkylidene-9H-4-azafluorenes (Table 2).15 We
first screened the substituents (R1) on the benzene ring.
2-Phenyl-3-(phenylethynyl)pyridine (1b) was efficiently
transformed into the corresponding azafluorene (2b)
(entry 1). The yield of 2c was moderate, probably because
the steric bulkiness of the ortho methyl group (entry 2).
Electron-donating and -withdrawing groups includ-
ing a fluoro group can be installed at the para position
(entries 3ꢀ6). With regard to the substituents (R2) at the
alkyne terminus, either an aryl group possessing an electron-
donating or -withdrawing group or an alkyl group is
suitable (entries 7ꢀ10).
Acknowledgment. This research was supported by
Grant-in-Aid for Scientific Research on Innovative Areas,
“Molecular Activation Directed toward Straightforward
Synthesis,” MEXT, Japan, and Global COE program
“Practical Chemical Wisdom,” Waseda University, Japan.
Supporting Information Available. Experimental pro-
cedure and physical property of new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(15) Pd-catalyzed intermolecular coupling of 3-iodopyridine with an
alkyne gave regioisomeric mixture of 9-alkylidene-9H-2-azafluorenes
and 4-azafluorenes: (a) Tian, Q.; Larock, R. C. Org. Lett. 2000, 2, 3329.
(b) Larock, R. C.; Tian, Q. J. Org. Chem. 2001, 66, 7372.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 19, 2012
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