Directed C-H alkenylation of quinoline N-oxides at the C-8 position using a cationic rhodium(I) catalyst

Article abstract of DOI:10.1002/adsc.201400223

The cationic rhodium-catalyzed alkenylation proceeds at the C-8 position of quinoline N-oxides. Regioselective C-H bond activation was achieved by the directing effect of the anionic oxygen of an N-oxide moiety, which can be readily removed by reductive treatment. A variety of 8-alkenylated quinoline N-oxides was obtained in moderate to high yields.

Full text of DOI:10.1002/adsc.201400223

COMMUNICATIONS
DOI: 10.1002/adsc.201400223
À
Directed C H Alkenylation of Quinoline N-Oxides at the C-8
Position Using a Cationic Rhodium(I) Catalyst
Takanori Shibataa,b,* and Yusuke Matsuoa
a
Department of Chemistry and Biochemistry, School of Advanced Science and Engineering, Waseda University, Shinjuku,
Tokyo 169-8555, Japan
Fax : (+81)-3-5286-8098; e-mail: tshibata@waseda.jp
JST, ACT-C, 4-1-8 Honcho, Kawaguchi, Saitama 332-0012, Japan
b
Received: February 28, 2014; Published online: && &&, 0000
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201400223.
Abstract: The cationic rhodium-catalyzed alkenyla-
tion proceeds at the C-8 position of quinoline N-
oxides. Regioselective C H bond activation was
achieved by the directing effect of the anionic
oxygen of an N-oxide moiety, which can be readily
removed by reductive treatment. A variety of 8-al-
kenylated quinoline N-oxides was obtained in mod-
erate to high yields.
ing, since it can be prepared and removed by oxida-
tion and reduction, and the only loss is an oxygen
À
atom. We report here Rh
alkenylation of quinolines with alkynes using N-oxide
as a directing group.[6]
ACHTUNGTNER(NUNG III)-catalyzed C-8 selective
ACHTUNGTRENNUNG
The 2-position of pyridine N-oxide is more elec-
À
tron-rich and transition metal-catalyzed C C bond
formation initiated by cleavage of the C-2 H bond is
À
a well-established protocol.[7] Pd-catalyzed oxidative
arylation and alkenylation are representative exam-
ples and quinoline N-oxide is often used as a substrate,
whereby 2-substituted quinoline N-oxides are ob-
tained.[7,8] In these reactions, electrophilic aromatic
À
Keywords: alkenylation; C H activation; directing
group; N-oxides; rhodium catalysts
À
substitution was proposed as a mechanism of C H
bond cleavage, and the directing effect of N-oxide
Transition metal-catalyzed C H bond activation has was not considered.[7d] We assumed that the Rh(I)-
À
been shown to be an important strategy in organic catalyzed reaction using N-oxide as a directing group
synthesis.[1] Many efficient C C bond-forming reac- could be realized for a new regioselectivity in C-8 H
tions initiated by C H bond cleavage have been de- bond activation via a 5-membered metallacycle inter-
À
À
À
scribed, which were proposed but not yet realized ten mediate (Scheme 1, bottom).[9–11]
years ago.[2] The trick for cleavage of an inactive C H
We examined the reaction of quinoline N-oxide
À
bond is the use of a directing group, which brings the (1a) with diphenylacetylene (2a) under various reac-
À
metal catalyst to the desired C H bond by coordina-
tion of a heteroatom of the directing group to the
metal center, and which stabilizes the metallacycle in-
À
termediate after C H bond cleavage. The carbonyl,
imino, and pyridyl groups are major players. Howev-
er, the directing group sometimes imposes synthetic
limitations, since it has to be introduced into the sub-
strate and remains in the product. One way out of
this dilemma is through further use of the directing
À
group. C H alkenylation and alkylation along with in-
tramolecular cyclization by reaction with the directing
group are successful examples of this approach.[3] An-
other method involves the use of easily removable di-
recting groups. Ackermann used the carbamoyl group
in the Ru-catalyzed alkenylation of phenols,[4] and
Huang developed a diazoamino group in the Rh-cata-
À
Scheme 1. Conventional C-2 H bond activation of pyridine
N-oxide derivatives and the present C-8 H bond activation
lyzed alkenylation of benzene.[5] From an atom-eco-
À
nomical perspective, the N-oxide moiety is fascinat- of quinoline N-oxide (this work).
Adv. Synth. Catal. 0000, 000, 0 – 0
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1
ÞÞ
These are not the final page numbers!

COMMUNICATIONS
Takanori Shibata and Yusuke Matsuo
Table 1. Optimization of the reaction conditions.
Table 2. Substrate scope of diarylacetylenes.
Entry R
2
Conditions Time [h] Yield [%][a] E/Z
Entry X
Ligand[a]
Time
[h]
Conv.
[%][b]
Yield
[%][c]
1
2
H
H
2a A
2a B
1
5
1
5
3
1
8
3
82 (3aa)
89 (3aa)
75 (3ab)
80 (3ab)
88 (3ab)
47 (3ac)
41 (3ac)
43 (3ad)
7/1
11/1
14/1
1/1
3/1
>20/1
9/1
1
2
3
4
5
BF4
BINAP
BINAP
BINAP
BINAP
24
9
1
5
5
1
18
3
>95
ca. 80
>95
94
>95
–
74
90
>95
>95
90
34
47
72
38
55
NR
13
51
81
3
OMe 2b A
OMe 2b B
OMe 2b B
CF3 2c
CF3 2c
BF4
OTf
PF6
4
5[b]
6
BARF[d] BINAP
A
B
7
6
7
8
9
OTf
OTf
OTf
OTf
OTf
none
DPPP
8
Cl
2d B
>20/1
BIPHEP
tolBINAP
xylylBINAP 1
xylylBINAP 12
xylylBINAP 6
[a]
[b]
The total yield of isolated E- and Z-isomers.
1,4-Dioxane was used as a solvent.
1
10
>95
79
>95
11[e] OTf
12[e,f] OTf
>95
[a]
BINAP=rac-2,2’-bis(diphenylphosphino)-1,1’-binaphthyl,
DPPP=1,3-bis(diphenylphosphino)propane, BIPHEP=
10). The high reaction temperature of 1358C was es-
sential for efficient transformation in chlorobenzene
(entry 11), but a comparable yield was achieved at
1108C with the use of cyclopentyl methyl ether
(CPME) as a solvent (entry 12).
We examined several diarylacetylenes as coupling
partners under the reaction conditions of entry 10
(method A) and entry 12 (method B) in Table 2. In
the reactions of diphenylacetylene (2a) and bis(4-me-
thoxyphenyl)acetylene (2b), the corresponding alken-
2,2’-bis(diphenylphosphino)biphenyl,
tolBINAP=(S)-
xylylBI-
2,2’-bis[di(4-tolyl)phosphine]-1,1’-binaphthyl,
ACHTUNGTRENNUNG
NAP =(S)-2,2’-bis[di(3,5-xylyl)phosphine]-1,1’-binaphth-
yl.
[b]
[c]
1
Conversion of 1a was determined by H NMR integra-
tion relative to 1,1,2,2-tetrachloroethane as an internal
standard.
1
Yield was determined by H NMR integration relative to
1,1,2,2-tetrachloroethane as an internal standard.
TetrakisACHTUNGTRENNUNG[3,5-bis(trifluoromethyl)phenyl]borate.
The reaction was examined at 1108C.
CPME was used as a solvent.
[d]
[e]
[f]
AHCTUNGTREGUNyNN lated products 3aa and 3ab were obtained in good to
high isolated yields, but the E/Z ratio changed with
the solvent (entries 1–5). The electron-withdrawing
groups on the aryl moiety lowered the reactivity of
the alkyne and the yield was moderate (entries 6–
tion conditions using cationic Rh catalysts (Table 1). 8).[13]
When BINAP was used as a ligand and BF4 was used
We next investigated the scope of substituted quin-
as a counter anion of the cationic Rh catalyst in oline N-oxides in the reaction of diphenylacetylene
chloroACHTUNGTRENNUNGbenzene, the complete consumption of 1a re- (2a) (Table 3). 2-, 3-, 4-, and 6-methylquinoline N-
quired 24 h, and formation of the desired C-8 alkeny- oxides 1b–1e were transformed into alkenylated prod-
lated product 3aa in 34% yield was ascertained by ucts 3ba–3ea in moderate to good yield (entries 1–4).
NMR, but the reaction gradually became messy 2,6-Dimethylquinoline 1f was a good substrate and
(entry 1).[12] A shorter reaction time resulted in a high yield was achieved (entry 5). Both electron-do-
a better yield (entry 2). Screening of the counter nating and electron-withdrawing groups were tolerat-
anion showed that triflate gave favorable results: N- ed at the 6-position (entries 6–8).
oxide 1a was completely consumed within 1 h and
In addition to a quinoline skeleton, phenanthridine
a good NMR yield of 72% was achieved (entries 3–5). N-oxide 1j and quinoxaline N-oxide 1k were subject-
The reaction did not proceed in the absence of a phos- ed to the reaction, and the expected products were
phine ligand (entry 6). When several diphosphine li- obtained, albeit in low yields (Scheme 2).
gands were investigated, xylylBINAP gave the best
We examined the further transformation of the al-
results; i.e., complete conversion and almost perfect kenylated product (E)-3aa (Scheme 3). Reduction
NMR yield within a short reaction time (entries 7– using trichlorophosphine gave the corresponding
2
asc.wiley-vch.de
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 0000, 000, 0 – 0
ÝÝ
These are not the final page numbers!

À
COMMUNICATIONS
Directed C H Alkenylation of Quinoline N-Oxides
Table 3. Substrate scope of quinoline N-oxides.
Entry
R’
1
Time [h]
Yield [%][a]
E/Z
1
2
3
4
5
6
7
8
2-Me
3-Me
4-Me
6-Me
2,6-Me2
6-OMe
6-Cl
1b
1c
1d
1e
1f
1g
1h
1i
2
4
3
3
3
4
1
1
64 (3ba)[b]
60 (3ca)
50 (3da)
84 (3ea)
86 (3fa)[b]
61 (3ga)
84 (3ha)
67 (3ia)
6/1[c]
>20/1
>20/1
7/1
Scheme 3. Reduction and Pd-catalyzed arylation of 3aa.
5/1[c]
10/1
20/1
6/1
6-NO2
[a]
The total yield of isolated E- and Z-isomers, unless other-
wise noted.
The yield of the mixture of E- and Z-isomers.
The E/Z ratio was determined by the NMR analysis.
[b]
[c]
Scheme 4. Reaction of quinoline N-oxide (1a) and pyridine
N-oxide (6) in the presence of D2O.
Scheme 2. Reaction of other N-oxides with diphenylacety-
lene (2a).
quinoline 4 in excellent yield.[8] Pd-catalyzed arylation
Scheme 5. Plausible reaction mechanism.
proceeded at the C-2 position, which means that the
À
N-oxide moiety could realize regioselective C H
bond activation depending on the choice of the cata-
Based on these results, we can propose a possible
reaction mechanism (Scheme 5). C H bond cleavage
lyst.[7e]
À
As a preliminary mechanistic study, we examined occurs at both the C-2 and C-8 positions to give inter-
the reaction of 1a in the presence of D2O and in the mediates A and B. However, alkyne insertion pro-
absence of alkyne (Scheme 4, upper). Surprisingly, ceeds from A and the stable 5-membered metallacyle
both the C-2 and C-8 positions were deuterated with C is generated.[15] Subsequent reductive elimination
the same ratio. In fact, deuteration of pyridine N- affords alkenylated product 3.
oxide (6) also proceeded under the same reaction
In conclusion, we have developed a cationic Rh(I)-
catalyzed C-8 alkenylation of quinoline N-oxides in
conditions (Scheme 4, bottom).[14]
Adv. Synth. Catal. 0000, 000, 0 – 0
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
3
ÞÞ
These are not the final page numbers!

COMMUNICATIONS
Takanori Shibata and Yusuke Matsuo
[3] Transition metal-catalyzed cyclizations, which involve
the reaction of diarylacetylenes. This is a rare exam-
ple of the use of an N-oxide as a directing group and
provides a new protocol for regioselective functionali-
zation of the C-8 position of quinolines. Further stud-
ies on the use of an N-oxide as a directing group and
the precise mechanism are underway in our laborato-
ry.
À
À
the C C bond forming reactions initiated by C H
bond cleavage along with intramolecular reaction of
the directing groups: a) Y. Kuninobu, A. Kawata, K.
Takai, J. Am. Chem. Soc. 2005, 127, 13498–13499; b) K.
Tsuchikama, M. Kasagawa, K. Endo, T. Shibata, Synlett
2010, 97–100; c) N. Umeda, K. Hirano, T. Satoh, N. Shi-
bata, H. Sato, M. Miura, J. Org. Chem. 2011, 76, 13–24;
d) Z. Shi, M. Boultadakis-Arapinis, F. Glorius, Chem.
Commun. 2013, 49, 6489–6491.
Experimental Section
[4] J. Li, C. Kornhaab, L. Ackermann, Chem. Commun.
2012, 48, 11343–11345.
Typical Experimental Procedure for Products 3
[5] C. Wang, H. Chen, Z. Wang, J. Chen, Y. Huang,
Angew. Chem. 2012, 124, 7354–7357; Angew. Chem. Int.
Ed. 2012, 51, 7242–7245.
[RhACHTUNGTRENNUNG(cod)2]OTf (0.01 mmol), (S)-xylylBINAP (0.01 mmol),
quinoline N-oxide (1, 0.10 mmol), and diarylacetylene (2,
0.10 mmol) were placed in a Schlenk tube, which was then
evacuated and backfilled with argon (ꢁ3). To the reaction
vessel was added chlorobenzene (0.5 mL, pretreated by
argon bubbling for 30 sec) before the solution was stirred at
1358C. After the reaction was complete, the resultant mix-
ture was cooled to room temperature. After evaporation of
the solvent, the crude products were purified by thin-layer
chromatography to give analytically pure product 3.
À
[6] In the Rh
G
aniline N-oxides, anionic oxygen was proposed to act
as a directing group as well as an oxidant; X. Huang, J.
Huang, C. Du, X. Zhang, F. Song, J. You, Angew.
Chem. 2013, 125, 13208–13212; Angew. Chem. Int. Ed.
2013, 52, 12970–12974.
[7] a) L.-C. Campeau, S. Rousseaux, K. Fagnou, J. Am.
Chem. Soc. 2005, 127, 18020–18021; b) J.-P. Leclerc, K.
Fagnou, Angew. Chem. 2006, 118, 7945–7950; Angew.
Chem. Int. Ed. 2006, 45, 7781–7786; c) L.-C. Campeau,
D. J. Schipper, K. Fagnou, J. Am. Chem. Soc. 2008, 130,
3266–3267; d) L.-C. Campeau, M. Bertrand-Laperle, J.-
P. Peclerc, E. Villemure, S. Gorelsky, K. Fagnou, J. Am.
Chem. Soc. 2008, 130, 3276–3277; e) L.-C. Campeau,
D. R. Stuart, J.-P. Leclerc, M. Bertrand-Laperle, E. Vil-
lemure, H.-Y. Sun, S. Lasserre, N. Guimond, M. Leca-
vallier, K. Fagnou, J. Am. Chem. Soc. 2009, 131, 3291–
3306; f) D. J. Schipper, M. El-Salfiti, C. J. Whipp, K.
Fagnou, Tetrahedron 2009, 65, 4977–4983; g) P. Xi, F.
Yang, S. Qin, D. Zhao, J. Lan, G. Gao, C. Hu, J. You, J.
Am. Chem. Soc. 2010, 132, 1822–1824; h) L. Acker-
mann, S. Fenner, Chem. Commun. 2011, 47, 430–432;
i) S. Duric, C. C. Tzschucke, Org. Lett. 2011, 13, 2310–
2313; j) D. Lapointe, T. Markeiwicz, C. J. Whipp, A. To-
derian, K. Fagnou, J. Org. Chem. 2011, 76, 749–759;
k) D. Mandal, A. D. Yamaguchi, J. Yamaguchi, K.
Itami, J. Am. Chem. Soc. 2011, 133, 19660–19663; l) K.
Li, D. Zhao, J. Lan, J. You, Angew. Chem. 2011, 123,
5477–5481; Angew. Chem. Int. Ed. 2011, 50, 5365–5369;
m) X. Gong, G. Song, H. Xhang, X. Li, Org. Lett. 2011,
13, 1766–1769; n) W. Liu, Y. Li, Y. Wang, C. Kuang,
Org. Lett. 2013, 15, 4682–4685.
Acknowledgements
This work was supported by Grand-in-Aid for Scientific Re-
search on Innovative Areas, “Molecular Activation Directed
toward Straightforward Synthesis,” MEXT, JST, ACT-C, and
Grants for Excellent Graduate School (Practical Chemical
Wisdom), Waseda University, MEXT, Japan.
References
[1] For recent reviews, see: a) G. Dyker, (Ed.), Handbook
À
of C H Transformations, Wiley-VCH, Weinheim, Ger-
many, 2005; b) D. Alberico, M. E. Scott, M. Lautens,
Chem. Rev. 2007, 107, 174–238; c) T. Kitamura, Eur. J.
Org. Chem. 2009, 1111–1125; d) R. Giri, B.-F. Shi,
K. M. Engle, N. Maugel, J.-Q. Yu, Chem. Soc. Rev.
À
2009, 38, 3242–3272; e) J.-Q. Yu, Z. Shi, (Eds.), C H
Activation, Springer-Verlag, Berlin, Germany, 2010;
f) O. Daugulis, Top. Curr. Chem. 2010, 292, 57–84;
g) D. A. Colby, R. G. Bergman, J. A. Ellman, Chem.
Rev. 2010, 110, 624–655.
[8] Ni-catalyzed alkenylation of pyridine N-oxides with al-
kynes: K. S. Kanyiva, Y. Nakao, T. Hiyama, Angew.
Chem. 2007, 119, 9028–9030; Angew. Chem. Int. Ed.
2007, 46, 8872–8874.
[2] For selected reviews, see: a) V. Ritleng, C. Sirlin, M.
Pfeffer, Chem. Rev. 2002, 102, 1731–1770; b) F. Kaki-
ACHTUNGTRENNUNGuchi, N. Chatani, Adv. Synth. Catal. 2003, 345, 1077–
À
[9] For C H arylation of the C-8 position of quinolines
1101; c) K. Godula, D. Sames, Science 2006, 312, 67–72;
d) H. M. L. Davis, J. R. Manning, Nature 2008, 451,
417–424; e) X. Chen, K. M. Engle, D. H. Wang, J.-Q.
Yu, Angew. Chem. 2009, 121, 5196–5217; Angew. Chem.
Int. Ed. 2009, 48, 5094–5115; f) T. W. Lyons, M. S. San-
ford, Chem. Rev. 2010, 110, 1147–1169; g) C.-L. Sun,
B.-J. Li, Z.-J. Shi, Chem. Commun. 2010, 46, 677–685;
h) C. S. Yeung, V. M. Dong, Chem. Rev. 2011, 111,
1215–1292; i) S. H. Cho, J. Y. Kim, J. Kwak, S. Chang,
Chem. Soc. Rev. 2011, 40, 5068–5083.
using a dinuclear Rh catalyst, see: J. Kwak, M. Kim, S.
Chang, J. Am. Chem. Soc. 2011, 133, 3780–3783.
[10] Hydroxy-directed C-8 alkenylation of 1-naphthol: a) T.
Satoh, Y. Nishinaka, M. Miura, M. Nomura, Chem.
Lett. 1999, 615–616; b) S. Mochida, M. Shimizu, K.
Hirano, T. Satoh, M. Miura, Chem. Asian J. 2010, 5,
847–851; c) V. S. Thirunavukkarasu, M. Donati, L. Ac-
kermann, Org. Lett. 2012, 14, 3416–3419.
4
asc.wiley-vch.de
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 0000, 000, 0 – 0
ÝÝ
These are not the final page numbers!

À
COMMUNICATIONS
Directed C H Alkenylation of Quinoline N-Oxides
À
[11] Amide-directed C H alkenylation using a cationic
Rh(I) catalyst: Y. Shibata, Y. Otake, M. Hirano, K.
Tanaka, Org. Lett. 2009, 11, 689–692.
the corresponding alkenylated products could not be
detected under the same reaction conditions.
[14] The C-2 alkenylation of pyridine N-oxide (6) with di-
phenylacetylene (2a) did not proceed at all under the
present reaction conditions.
[12] The iridium counterpart was almost ineffective in this
reaction (<5% NMR yield).
[13] Other alkynes, such as 1-phenylprop-1-yne, dec-5-yne,
and dimethyl acetylenedicarboxylate, were inactive and
[15] The pathway of carborhodation cannot be excluded.
Adv. Synth. Catal. 0000, 000, 0 – 0
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
5
ÞÞ
These are not the final page numbers!

COMMUNICATIONS
À
6 Directed C H Alkenylation of Quinoline N-Oxides at the
C-8 Position Using a Cationic Rhodium(I) Catalyst
Adv. Synth. Catal. 2014, 356, 1 – 6
Takanori Shibata,* Yusuke Matsuo
6
asc.wiley-vch.de
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 0000, 000, 0 – 0
ÝÝ
These are not the final page numbers!