Palladium-catalyzed chloroimination of imidoyl chlorides to a triple bond: An intramolecular reaction leading to 4-chloroquinolines

Article abstract of DOI:10.1021/ol800512m

(Chemical Equation Presented) In this paper, a new type of effective chloroimination was reported. This reaction afforded 4-chloro-2-perfluoroalkyl quinolines from fluorinated imidoyl chlorides in high yields. This is the first achievement of oxidative addition-reductive elimination type C-Cl bond activation by chloropalladation.

Full text of DOI:10.1021/ol800512m

ORGANIC
LETTERS
2008
Vol. 10, No. 13
2657-2659
Palladium-Catalyzed Chloroimination of
Imidoyl Chlorides to a Triple Bond: An
Intramolecular Reaction Leading to
4-Chloroquinolines
Akira Isobe, Jun Takagi, Toshimasa Katagiri,* and Kenji Uneyama*
Department of Applied Chemistry, Faculty of Engineering, Okayama UniVersity, 3-1-1,
Tsushimanaka, Okayama 700-8530, Japan
uneyamak@cc.okayama-u.ac.jp; tkata@cc.okayama-u.ac.jp
Received April 7, 2008
ABSTRACT
In this paper, a new type of effective chloroimination was reported. This reaction afforded 4-chloro-2-perfluoroalkyl quinolines from fluorinated
imidoyl chlorides in high yields. This is the first achievement of oxidative addition-reductive elimination type C-Cl bond activation by
chloropalladation.
Recently, methods of palladium-catalyzed carbon-carbon
bond formation have been recognized as useful reactions for
advanced organic synthesis.1 Among these techniques, reac-
tions via chloropalladation have the advantage of introducing
both chloride and carbon moieties into a multiple bond
simultaneously, but as of yet only a few such reactions have
been reported.2
Past mechanistic studies of chloropalladation reactions
have suggested that the reaction proceeds via nucleophilic
attack of a chloride moiety of the Pd-Cl catalyst or of a
chloride additive to the Pd(II)-activated multiple bond
forming the chloropalladation intermediate. Electrophilic
activation of the multiple bond by the electron-deficient
Pd(II) catalyst is essential for this process. Reductive
elimination of the catalyst then forms the carbon-carbon
bond, so conventional chloropalladation requires the reoxi-
dation of Pd(0) to Pd(II) to complete the catalytic cycle. This
could potentially be accomplished through the oxidative
addition of a carbon-chlorine bond to Pd(0). As of yet, there
have been no reports of such catalytic chloro-palladations
initiated by the oxidative addition.
(1) (a) Negishi, E.; Meijere, A. D.; Ba¨ckvall, J. E.; Cacchi, S.; Hayashi,
T.; Ito, Y.; Kosugi, M.; Murahashi, S. I.; Oshima, K.; Yamamoto, Y.
Handbook of Organopalladium Chemistry for Organic Synthesis; Wiley-
Interscience: New York, 2002; Vols. 1 and 2. (b) Li, J. J.; Gribble, G. W.
Tetrahedron Organic Chemistry Series 20: Palladium in Heterocyclic
Chemistry: A Guide for the Synthetic Chemist; Pergamon: Amsterdam, The
Netherlands, 2000.
(2) (a) Wiger, G.; Albelo, G.; Rettig, M. F. J. Chem. Soc., Dalton 1974,
2242. (b) Wipke, W. T.; Goeke, G. L. J. Am. Chem. Soc. 1974, 93, 4244.
(c) Mann, B. E.; Bailey, P. M.; Maitlis, P. M. J. Am. Chem. Soc. 1975, 97,
1275. (d) Kaneda, K.; Uchiyama, T.; Fujiwara, Y.; Imanaka, T.; Teranishi,
S. J. Org. Chem. 1979, 44, 55. (e) Ma, S.; Lu, X. J. Chem. Soc., Chem.
Commun. 1990, 733. (f) Ma, S.; Lu, X. J. Org. Chem. 1991, 51, 5120. (g)
Ma, S.; Zhu, G.; Lu, X. J. Org. Chem. 1993, 58, 3692. (h) Ba¨ckvall, J.-E.;
Nilsson, Y. I. M.; Andersson, P. G.; Gatti, R. G. P.; Wu, J. Tetrahedron
Lett. 1994, 35, 5713. (i) Ba¨ckvall, J.-E.; Nilsson, Y. I. M.; Gatti, R. G. P.
Organometallics 1995, 14, 4242. (j) Ji, J.; Wang, Z.; Lu, X. Organometallics
1996, 15, 2821. (k) Huang, X.; Sun, A. J. Org. Chem. 2000, 65, 6561. (l)
Lu, X. In Handbook of Organopalladium Chemistry for Organic Synthesis;
Wiley-Interscience: New York, 2002; Vol. 2, p 2267. (m) Ma, S.; Wu, B.;
Chloroacylation of a multiple bond via chlororhodation
has been reported.3 The reaction was initiated by the
Zhao, S. Org. Lett. 2003, 5, 4429. (n) Zhu, G.; Zhang, Z. J. Org. Chem.
2005, 70, 3339.
(3) (a) Kokubo, K.; Matsumasa, K.; Miura, M.; Nomura, M. J. Org.
Chem. 1996, 61, 6941. (b) Hua, R.; Shimada, S.; Tanaka, M. J. Am. Chem.
Soc. 1998, 120, 12365. (c) Sugihara, T.; Satoh, T.; Miura, M.; Nomura, M.
AdV. Synth. Catal 2004, 346, 1765. (d) Hua, R.; Onozawa, S.; Tanaka, M.
Chem. Eur. J. 2005, 11, 3621. (e) Kashiwabara, T.; Kataoka, K.; Hua, R.;
Shimada, S.; Tanaka, M. Org. Lett. 2005, 7, 2241.
10.1021/ol800512m CCC: $40.75
Published on Web 05/29/2008
2008 American Chemical Society

oxidative addition of acyl chlorides to rhodium, followed
by the chlororhodation of the multiple bond. This reaction
could be a useful synthetic tool because it simultaneously
introduces both the acyl moiety and the chloride into the
multiple bond. Nevertheless, elevated reaction temperatures
and a prolonged reaction time were required because the
rhodium catalyst possessed less reducing ability than the
palladium catalyst.
Like chloroacylation, chloroimination of a multiple bond
would also be a useful tool for synthesizing multifunctional
nitrogen-containing compounds, especially nitrogen-contain-
ing heterocycles. Although the imidoyl halides need strong
electron withdrawing groups for their preparation, such
methods would be of particular synthetic merit, because the
chloride present in the product could be converted into a
variety of other functional groups via nucleophilic substitu-
tion. Presently, there are no literature reports of transition
metal-catalyzed chloroimination.
We hypothesized that the high electrophilicity of the
C-Pd(II)-X species, which is formed via oxidative addition
of imidoyl halides to Pd(0),1 would facilitate the reaction
with the multiple bond under mild conditions to give the
chloropalladation adduct. Reductive elimination from the Pd
catalyst would then yield the desired chloroimination product
inamannersimilartothatofrhodium-catalyzedchloroacylation.3
In the present study, we demonstrate the first palladium-
catalyzed intramolecular chloroimination reactions, in which
the triple bond of N-(2-ethynylphenyl)-2,2,2-trifluoroetha-
nimidoyl chloride was reacted to yield 4-chloro-2-polyfluo-
roalkylquinolines. The reactions were initiated by the
oxidative addition of imidoyl chloride to Pd(0). The resulting
4-chloro-2-polyfluoroalkylquinolines could serve as synthetic
precursors to quinolone carboxylic acid antibiotics.
Pd2(dba)3/CHCl3 (entries 3-5). While the addition of base
was not essential, it does improve the reaction rate and
selectivity (a similar reaction to entry 5 without AcONa
resulted in 50% conversion with 13% yield of the product).
The exact role of base has not yet been revealed, but the
combination of BINAP and AcONa was found to be the best
combination examined (entry 5).
Additives were examined in an attempt to reduce the
harshness of the reaction conditions to 80 °C for 12 h.
Although the previously reported PdCl2-mediated chloro-
palladation reaction proceeded with cis selectivity and the
chloride was derived from PdCl2,2b–d the present chloroimi-
nation proceeded via trans addition onto the triple bond,
forming a six-membered ring. A trans chloropalladation
would require nucleophilic attack from an exogenous chloride
source rather than from the catalytic Pd-Cl species.2h,i
A
variety of chloride sources were surveyed, and the effects
on the rate and yield of chloropalladation were analyzed
(Table 2). The addition of a chloride source accelerated the
Table 2. Examination of Chloride Source
equiv
of
equiv
of
time temp
convn yield
entry (h)
(°C)
additive additive AcONa (%)a (%)a
1
2
3
4
5
1
1
1
1
5
80
1.0
1.0
1.0
1.0
0.25
37
52
79
>99
>99
23
32
34
66
84
80 LiCl
80 Et3BnNCl
80 TBAC
30 TBAC
2.0
2.0
2.0
1.0
First, the intramolecular chloroimination reaction was
optimized in terms of the Pd catalyst, the phosphine ligand,
and the base employed (Table 1). The bidentate ligand dppf
was found to be superior to the monodentate ligand PPh3
(entries 1 and 2). Thus, a variety of catalysts were generated
by reacting different bidentate phosphine ligands with
a Determined by 19F NMR with 1,3-(bistrifluoromethyl)benzene as an
internal standard.
reaction (entries 2-5), especially, TBAC (n-tetrabutylam-
monium chloride). With this additive, complete consumption
of the starting material was observed within 1 h at 80 °C.
Nevertheless, the yield was slightly lower than other previ-
ously tested reaction conditions (Table 1, entry 5). Further
experiments were conducted to optimize the amounts of
additive and base, the temperature, and the reaction time.
Ultimately, the best product yield was attained under very
mild conditions, reaction at 30 °C for 5 h (entry 5).
Table 1. Examination of Catalytic Conditions
entry
catalyst
ligand
base
yield (%)a
A series of experiments were conducted to assess the
substrate scope of the reaction (Table 3). Substituted quino-
lines were obtained in high yields, which demonstrated
1
2
3
4
5
6
7
8
PdCl2(PPh3)2
PdCl2(dppf)
AcONa
AcONa
AcONa
AcONa
AcONa
AcOK
0
38
7
47
84
82
50
42
Pd2(dba)3·CHCl3
Pd2(dba)3·CHCl3
Pd2(dba)3·CHCl3
Pd2(dba)3·CHCl3
Pd2(dba)3·CHCl3
Pd2(dba)3·CHCl3
dppe
dppf
BINAP
BINAP
BINAP
BINAP
(4) See the Supporting Information [Spectroscopic Data and Experi-
mental methods for 4-chloro-2-polyfluoroalkyl quinolines and the sub-
strates].
NaHCO3
NaOH
(5) Schlosser, M.; Cottet, F.; Heiss, C.; Lefebvre, O.; Marull, M.;
Masson, E.; Scopelliti, R. Eur. J. Org. Chem. 2006, 729.
(6) (a) Uneyama, K.; Watanabe, H. Tetrahedron Lett. 1991, 32, 1459.
(b) Watanabe, H.; Hashizume, Y.; Uneyama, K. Tetrahedron Lett. 1992,
33, 4333. (c) Amii, H.; Kishikawa, Y.; Kageyama, K.; Uneyama, K. J.
Org. Chem. 2000, 65, 3404.
a Determined by 19F NMR with 1,3-(bistrifluoromethyl)benzene as an
internal standard.
2658
Org. Lett., Vol. 10, No. 13, 2008

further transformations. Quinoline 2a was successfully
converted to quinolone carboester equivalent 4, which
possesses the carbon skeleton of a quinolone antibiotic
(Scheme 1).5
Table 3. Scope of Substrates
A plausible mechanism for this catalytic reaction is
proposed in Scheme 2. The first step is the oxidative addition
entry
R1
R2
Rf
product
yield (%)
Scheme 2. Plausible Mechanism
1
2
3
4
H
H
H
H
Cl
CO2Et
F
H
H
H
H
H
H
F
CF3 (1aa)
C3F7 (1ab)
CF2Cl (1ac)
CHF2 (1ad)
CF3 (1b)
2aa
2ab
2ac
2ad
2b
84
80
88
81
87
77
82
5a
6a
7a,b
CF3 (1c)
CF3 (1d)
2c
2d
a 2,2′-Dipyridyl was used as a ligand. b Catalyst and ligand used were
5 mol % and 10 mol %, respectively.
tolerance for an array of functional groups at Rf ) CF3, C3F7,
CHF2, CF2Cl, as well as at R1 ) H, F, Cl, CO2Et and R2 )
H, F. Preparation of nonfluorinated alkyl or aryl imidoyl
halides was unsuccessful. These imidoyl halides decompose
easily due to their labile nature.
Previous studies have shown that application of a Pd(II)
chloropalladation catalyst4 to our substrate (1a) resulted in
near complete recovery of a combination of the substrate
and trifluoroacetamide, a hydrolysis product (ca. 75%). This
suggested that the present chloropalladation was initiated by
the oxidative addition of the C-Cl bond of 1a to the Pd(0)
species, and this represents a significant difference between
the present method and the conventional Pd(II)-catalyzed
chlorocarbonations.2
of the C-Cl bond of imidoyl chloride6 1aa to the Pd(0)
species (path A). Next, a chloride from an exogenous source
attacks the triple bond, which is intramolecularly activated
by the activated Pd(II) catalyst to generate the seven-
membered trans-chloropalladation palladacycle intermediate
(paths B and C). Finally, the reductive elimination of Pd(0)
from the palladacycle yields quinoline 2aa and regenerates
the Pd(0) species (path D).
In conclusion, we have developed the first intramolecular
chloroimination of a triple bond initiated via the oxidative
addition of the imidoyl chloride C-Cl bond to the Pd(0)
species, followed by chloropalladation and reductive elimina-
tion. The reaction proceeded under mild conditions and gave
the desired quinoline products in high yields. This novel Pd-
catalyzed chloroimination reaction expands the scope of
palladium chemistry.
The products of chloropalladation, 4-chloro-2-polyfluo-
roalkylquinolines, have a reactive C-Cl bond that allows
Scheme 1. Transformation of Quinoline (2a) to Quinoline (4)
Supporting Information Available: Experimental pro-
cedures and spectroscopic data and charts for all products.
This material is available free of charge via the Internet at
http://pubs.acs.org.
OL800512M
Org. Lett., Vol. 10, No. 13, 2008
2659