Rhodium(III)-catalyzed synthesis of pyridines from α,β- unsaturated ketoximes and internal alkynes

Article abstract of DOI:10.1055/s-0031-1289556

A method for the synthesis of highly substituted pyri-dines from ,-unsaturated oximes and internal alkynes has been developed using [Cp*RhCl₂]₂-CsOPiv as the catalyst system. The present transformation is carried out by a redox-neutral sequence of vinylic C-H rhodation, alkyne insertion, and C-N bond formation of the putative vinyl rhodium intermediate with the oxime nitrogen, where the N-O bond of oxime derivatives could work as an internal oxidant to maintain the catalytic cycle. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0031-1289556

LETTER
2789
Rhodium(III)-Catalyzed Synthesis of Pyridines from a,b-Unsaturated
Ketoximes and Internal Alkynes
Synthesisof
Pe
yridines i Chui Too,a Toshiharu Noji,b Ying Jie Lim,a Xingwei Li,*c Shunsuke Chiba*a
a
Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological University,
21 Nanyang Link, 637371 Singapore, Singapore
Fax +6567911961; E-mail: shunsuke@ntu.edu.sg
Graduate School of Pharmaceutical Sciences, Tohoku University, Aramaki, Aoba-ku, Sendai 980-8578, Japan
Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, P. R. of China
E-mail: xwli@dicp.ac.cn
b
c
Received 1 September 2011
Abstract: A method for the synthesis of highly substituted pyri-
dines from a,b-unsaturated oximes and internal alkynes has been
developed using [Cp*RhCl2]2–CsOPiv as the catalyst system. The
present transformation is carried out by a redox-neutral sequence of
vinylic C–H rhodation, alkyne insertion, and C–N bond formation
of the putative vinyl rhodium intermediate with the oxime nitrogen,
where the N–O bond of oxime derivatives could work as an internal
oxidant to maintain the catalytic cycle.
Scheme 1
Key words: pyridines, oximes, alkynes, rhodium, C–H activation
isoquinoline derivatives with internal alkynes
(Scheme 1).7c,e,f
Based on these backgrounds, our attention has been drawn
to the use of readily available a,b-unsaturated ketoximes
for vinylic C–H fission/functionalization. Herein we wish
to report rhodium(III)-catalyzed synthesis of highly func-
tionalized pyridines from a,b-unsaturated ketoximes and
internal alkynes under mild reaction conditions
(Scheme 2).10
Among nitrogen-containing heterocycles (azaheterocy-
cles),1 pyridines are one of the most prevalent motifs in
numerous natural products, potent pharmaceutical drugs,
and synthons for functional materials. Although diverse
approaches toward synthesis of pyridines have been de-
veloped,2,3 there remains a demand for versatile method-
ologies to construct pyridines with selective control of
substitution patterns from readily accessible building
blocks.
Synthetic transformation via C–H bond functionalization
by transition-metal catalysts is an ideal process in organic
synthesis in terms of atom- and step-economical points of
view.4 Commonly, suitable heteroatoms are utilized as a
directing group to activate the specific proximal C–H
bond, where an sp2-imino/amido nitrogen atom has been
employed in numerous examples of the C–H bond activa-
tion.5
Scheme 2
First, we screened the reaction conditions for synthesis of
pyridine 3aa from (E)-4-phenylbut-3-ene-2-one oxime
derivatives 1a and diphenyl acetylene (2a, 1.2 equiv) us-
ing 2.5 mol% of [Cp*RhCl2]2 and 30 mol% of metal car-
boxylates as an additive in MeOH (Table 1). As expected,
the reactions of O-acetyloxime 1a (Table 1, entries 1–3)
proceeded to give desired pyridine 3aa, the highest yield
of which was provided by running with CsOPiv as an ad-
ditive (10 h, 77% yield, Table 1, entry 3). The reaction
with Cu(OAc)2,7c however, did not give the desired pyri-
dine 3aa, resulting in decomposition of oxime acetate 1a
(Table 1, entry 4). Using the [Cp*RhCl2]2–CsOPiv sys-
tem, the effect of the substituent X was next examined.
Although the yield of pyridine 3aa from oxime pivalate
1a¢ was moderate (Table 1, entry 5), the reactions of oxy-
gen-free oxime 1a¢¢ resulted in the smooth reaction, af-
fording pyridine 3aa in 79% yield within seven hours
(Table 1, entry 6). The reaction under a N2 atmosphere
Recently, redox-neutral catalytic strategies using the N–O
bond attached in the nitrogen directing group have been
developed for the synthesis of azaheterocycles via the se-
quence of ortho C–H activation and C–N bond formation,
where the N–O bond works as an internal oxidant to main-
tain catalytic turnover.6,7 For example, Guimond and
Fagnou disclosed the synthesis of isoquinolones from
benzhydroxamic acid derivatives and internal alkynes cat-
alyzed by the [Cp*RhCl2]2–CsOAc system.7a,g,8,9 It was
also reported by us that the N–O bond of aryl ketoximes
could be used for the rhodium(III)-catalyzed synthesis of
SYNLETT 2011, No. 19, pp 2789–2794
x
x
.x
x
.2
0
1
1
Advanced online publication: 25.10.2011
DOI: 10.1055/s-0031-1289556; Art ID: B16911ST
© Georg Thieme Verlag Stuttgart · New York

2790
P. C. Too et al.
LETTER
was found to be sluggish, indicating that the presence of
air (oxygen) has a crucial role to maintain and accelerate
the catalytic turnover (Table 1, entry 7). Use of 1.5 equiv-
alents of oxime 1a'' with diphenyl acetylene (2a) gave
86% yield of pyridine 3a (based on acetylene 2a), while
longer reaction time (24 h) was required (Table 1, entry
8).
[Cp*RhCl2]2 (5 mol%)
OH
Me
CsOPiv (30 mol%)
N
+
Ph
Ph
MeOH, 60 °C
under air, 54 h
Ph
2a
(5 equiv)
1a"
Ph
Ph
Ph
Ph
Ph
Table 1 Optimization of Reaction Conditionsa,b
N
Ph
+
Ph
Ph
Ph
N
Ph
Me
Ph
[Cp*RhCl2]2 (2.5 mol%)
additive (30 mol%)
OX
Me
3aa 32%
Ph
Ph
N
N
Me
4aa 56%
+
MeOH, 60 °C
under air
Ph
Me
Ph
Scheme 3
1a
2a
3aa
Entry
X
Additive Time (h) Yield of 3aa (%)b
The present process showed wide substrate tolerance with
a,b-unsaturated oxime derivatives 1 by the reactions with
alkynes 2a or 2e (Table 3). By varying the substituent on
the b-carbon, benzene rings bearing electron-donating
groups (Table 3, entries 1–3) and a bromine atom
(Table 3, entry 4) as well as naphthyl and thienyl groups
(Table 3, entries 5–8) could be introduced, leading to the
formation of the corresponding pyridines 3 in good to
moderate yields. The reaction of dibenzylideneacetone
oxime (1i) with diphenyl acetylene (2a) proceeded
smoothly to give 6-styrylpyridine 3ia in 81% yield
(Table 3, entry 9). When the substituent of R1 of oxime
1a¢¢ was replaced from methyl to isopropyl, the stere-
ochemistry of the N–O bond of oxime 1j became a mix-
ture of E- and Z-isomers in a 55:45 ratio. The reaction of
oxime 1j afforded pyridine 3ja in 40% yield with 25% re-
covery of Z-isomer (Table 3, entry 10).13 Pentasubstituted
pyridines 3ka and 3la could be synthesized smoothly in
good yields (Table 3, entries 11 and 12). When 3-benzyl-
but-3-en-2-one oxime (1m) without the b-substituent was
employed, the reaction took place in a shorter reaction
time (2 h), affording 2,3,5,6-tetrasubstituted pyridine 3ma
in 88% yield (Table 3, entry 13).
1
2
1a X = Ac
1a X = Ac
1a X = Ac
1a X = Ac
NaOAc
CsOAc
24
24
10
14
19
7
49
62
77
0
3
CsOPiv
Cu(OAc)2
CsOPiv
CsOPiv
CsOPiv
CsOPiv
4
5
1a¢ X = Piv
1a¢¢ X = H
1a¢¢ X = H
1a¢¢ X = H
55
79
78
86
6
7c
8d
24
24
a Unless otherwise noted, reactions were carried out using 0.5 mmol
of oxime 1a and 1.2 equiv of alkyne 2a with 2.5 mol% of [Cp*RhCl2]2
and 30 mol% of additive in MeOH at 60 °C under an air atmosphere.
b Isolated yields were recorded above.
c The reaction was conducted under a N2 atmosphere.
d The reaction was conducted using 0.5 mmol of alkyne 2a and 1.5
equiv of oxime 1a¢¢, and the yield of 3aa was calculated based on
alkyne 2a.
During optimization of the reaction conditions (Table 1),
in addition to the desired pyridine 3aa generated via 1:1
coupling of oxime 1a and alkyne 2a, the formation of 2-
naphthylpyridine 4aa (1:3 coupling of 1a and 2a) was ob-
served as a minor side product (less than 10% yield) in
most of the entries. The naphthyl moiety of 4aa was pre-
sumably constructed from 3aa via catalytic multiple C–H
bond cleavage and insertion of two more equivalents of
alkyne 2a.11,12 Indeed, treatment of oxime 1a¢¢ with excess
amounts (5 equiv) of alkyne 2a under the present reaction
conditions delivered 2-naphthylpyridine 4aa in 56% yield
after 54 hours along with 32% yield of 3aa (Scheme 3).
A proposed catalytic reaction pathway of the present py-
ridine formation was outlined in Scheme 4. It commences
with vinylic C–H activation of a,b-unsaturated oxime 1a¢¢
with the aid of the oxime sp2-nitrogen to give vinyl rhod-
ium intermediate A. Insertion to alkynes 2a with A affords
seven-membered-ring rhodacyclic iminium cation inter-
mediate B, which undergoes concerted redox processes of
C–N reductive elimination and regeneration of rhodi-
um(III) species to give pyridine 3aa.
With the optimized reaction conditions using oxygen-free
oxime 1a¢¢ (Table 1, entry 6), generality of the substitu-
ents on internal alkynes 2 was investigated (Table 2).
Symmetrical diaryl acetylenes 2 bearing various substitu-
ents reacted smoothly, affording the corresponding py-
ridines 3 in good yields (Table 2, entries 1–3). Similarly,
the reactions of dialkyl acetylenes 2e and 2f also proceed-
ed smoothly (Table 2, entries 4 and 5). Insertion of un-
symmetrical alkynes 2g–i occurred somehow in
regioselective manner, albeit in moderate selectivity
(Table 2, entries 6–8).
OH
[RhIII]
– H+
OH
Me
Ph
Ph
[RhIII]
Pe
N
H
N
2a
Ph
Ph
Me
– H+
1a"
A
Ph
[RhIII]
Ph
H+
– [RhIII]OH
O–
Ph
Ph
N
N
Ph
Me
Me
3aa
B
Scheme 4 A proposed catalytic pathway
Synlett 2011, No. 19, 2789–2794 © Thieme Stuttgart · New York

LETTER
Synthesis of Pyridines
2791
Table 2 Scope of Internal Alkynesa
R5
[Cp*RhCl2]2 (2.5 mol%)
OH
Me
R4
Ph
N
CsOPiv (30 mol%)
N
R4
R5
+
MeOH, 60 °C
under air
Ph
Me
1a"
2
3
Entry
Alkyne
2b
R4
R5
Time (h)
Yield of 3 (%)b
1
2
3
4
5
6
7
8
4-MeOC6H4
4-TMSC6H4
3-BrC6H4
n-Pr
4-MeOC6H4
4-TMSC6H4
3-BrC6H4
n-Pr
24
10
10
8
3ab
3ac
3ad
3ae
3af
3ag
3ah
3ai
61
2c
60c
2d
77
2e
75
2f
TBSOCH2
Me
TBSOCH2
Ph
30
8
69
2g
97 (60:40)
45 (60:40)
87 (70:30)
2h
CO2Et
Ph
24
24
2i
4-MeOC6H4
4-F3CC6H4
a Unless otherwise noted, reactions were carried out using 0.5 mmol of oxime 1a¢¢ and 1.2 equiv of alkyne 2 with 2.5 mol%
of [Cp*RhCl2]2 and 30 mol% of CsOPiv in MeOH at 60 °C under an air atmosphere.
b Isolated yields were recorded above.
c Oxime 1a¢¢ was recovered in 32% yield.
Table 3 Scope of a,b-Unsaturated Oximesa
Ph
Ph
Ph
n-Pr
OH
R1
[Cp*RhCl2]2 (2.5 mol%)
CsOPiv (30 mol%)
2a
N
Ph
R3
n-Pr
N
N
or
or
+
R3
MeOH, 60 °C
under air
R1
R3
R1
n-Pr
n-Pr
R2
R2
R2
2e
1
3
Entry
1
Oximes 1
Alkynes 2a or 2e Time (h)
Pyridines 3
Yield (%)b
n-Pr
OH
N
n-Pr
N
2e
20
3be 60
Me
Me
MeO
MeO
1b
n-Pr
OH
Me
OMe
N
n-Pr
MeO
N
2
3
4
2e
2a
2a
30
30
12
3ce 63
3da 68
3ea 87
Me
1c
Ph
OH
N
Ph
N
Me
Me
Me
Me
1d
Ph
OH
Me
N
Ph
N
Me
Br
Br
1e
Synlett 2011, No. 19, 2789–2794 © Thieme Stuttgart · New York

2792
P. C. Too et al.
LETTER
Table 3 Scope of a,b-Unsaturated Oximesa (continued)
Ph
Ph
Ph
R2
n-Pr
OH
R1
[Cp*RhCl2]2 (2.5 mol%)
CsOPiv (30 mol%)
2a
N
Ph
R3
n-Pr
N
N
or
or
+
R3
MeOH, 60 °C
under air
R1
R3
R1
n-Pr
n-Pr
R2
R2
2e
1
3
Entry
Oximes 1
Alkynes 2a or 2e Time (h)
Pyridines 3
Yield (%)b
R
OH
N
R
5
6
2a
2e
24
24
3fa R = Ph, 87
3fe R = n-Pr, 77
N
Me
Me
1f
Ph
OH
Me
N
Ph
N
7
2a
24
3ga 74
Me
1g
Ph
OH
Me
N
Ph
S
N
8
2a
2a
24
7
3ha 53
3ia 81
Me
S
1h
Ph
Ph
OH
N
N
9c
Ph
Ph
N
Ph
Ph
Ph
1i
OH
Me
Ph
Ph
10
2a
24
3ja 40d
N
Ph
Me
Me
1j
Me
Me
E/Z = 55:45
Ph
OH
Me
N
Ph
Ph
N
N
11
12
2a
2a
7
3ka 66
3la 68
Ph
Me
1k
Me
Ph
OH
N
Ph
Ph
10
Me
Me
1l
Ph
OH
N
N
13
2a
2
3ma 88
Me
Me
Ph
Ph
1m
a Unless otherwise noted, reactions were carried out using 0.5 mmol of oxime 1 and 1.2 equiv of alkyne 2 with 2.5 mol% of [Cp*RhCl2]2 and
30 mol% of CsOPiv in MeOH at 60 °C under an air atmosphere.
b Isolated yields were recorded above.
c The reaction was conducted using 1 equiv of alkyne 2a.
d The Z isomer of oxime 1j was recovered in 25% yield.
Synlett 2011, No. 19, 2789–2794 © Thieme Stuttgart · New York

LETTER
Synthesis of Pyridines
2793
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In summary, we have developed a synthetic method of
highly substituted pyridines from a,b-unsaturated oximes
and internal alkynes using [Cp*RhCl2]2–CsOPiv as the
catalyst system.14 Further investigation on application of
this methodology for the synthesis of other types of het-
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Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
Acknowledgment
This work was supported by funding from Nanyang Tech nological
University and Singapore Ministry of Education, and Science & En-
gineering Research Council (A*STAR Grant No. 082 101 0019).
T.N. thanks JSPS (Japan Society for the Promotion of Science) for
a predoctoral fellowship.
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2794
P. C. Too et al.
LETTER
(9) For selected reports on rhodium(III)-catalyzed oxidative
C–H bond functionalization–C–N bond formation with
alkynes, see: (a) Stuart, D. R.; Alsabeh, P.; Kuhn, M.;
Fagnou, K. J. Am. Chem. Soc. 2010, 132, 18326. (b) Chen,
J.; Song, G.; Pan, C.-L.; Li, X. Org. Lett. 2010, 12, 5426.
(c) Su, Y.; Zhao, M.; Han, K.; Song, G.; Li, X. Org. Lett.
2010, 12, 5462. (d) Hyster, T. K.; Rovis, T. J. Am. Chem.
Soc. 2010, 132, 10565. (e) Rakshit, S.; Patureau, F. W.;
Glorius, F. J. Am. Chem. Soc. 2010, 132, 9585.
(11) Umeda, N.; Tsurugi, H.; Satoh, T.; Miura, M. Angew. Chem.
Int. Ed. 2008, 47, 4019.
(12) The formation of 4aa could result in generation of
rhodium(I) species, which should be re-oxidized to
rhodium(III) by air (O2) to maintain the catalytic turnover.
(13) Although E/Z isomerization of the N–O bond of oxime 1k
might be possible in the present reaction conditions, we are
not certain whether the Z-isomer of 1k was converted into
pyridine via its isomerization to E-isomer during this
reaction. For isomerization of the oxime N–O bonds, see:
Johnson, J. E.; Silk, N. M.; Nalley, E. A.; Arfan, M. J. Org.
Chem. 1981, 46, 546.
(f) Morimoto, K.; Hirano, K.; Satoh, T.; Miura, M. Org. Lett.
2010, 12, 2068. (g) Mochida, S.; Umeda, N.; Hirano, K.;
Satoh, T.; Miura, M. Chem. Lett. 2010, 39, 744.
(h) Guimond, N.; Fagnou, K. J. Am. Chem. Soc. 2009, 131,
12050. (i) Fukutani, T.; Umeda, N.; Hirano, K.; Satoh, T.;
Miura, M. Chem. Commun. 2009, 5141. (j) Stuart, D. R.;
Bertrand-Laperle, M.; Burgess, K. M. N.; Fagnou, K. J. Am.
Chem. Soc. 2008, 130, 16474.
(14) General Procedure (Table 1, Entry 6)
To a MeOH solution (2.5 mL) of (2E,3E)-4-phenylbut-3-
en-2-one oxime (1a, 80.5 mg, 0.50 mmol) and diphenyl-
acetylene (2a, 106.9 mg, 0.60 mmol) were added
[Cp*RhCl2]2 (7.7 mg, 0.0125 mmol) and CsOPiv (35.1 mg,
0.15 mmol), and the reaction mixture was stirred at 60 °C
under air for 7 h. After cooled to r.t., the solvent was
removed in vacuo, and the resulting crude material was
subjected to flash column chromatography (hexane–
EtOAc = 90:10) to afford 6-methyl-2,3,4-triphenylpyridine
(3aa, 126.4 mg, 0.393 mmol) in 79% yield.
(10) For synthesis of pyridine derivatives by utilization of
6p-electrocyclization of azatrienes generated by ortho-
vinylation, see: (a) Parthasarathy, K.; Cheng, C.-H. J. Org.
Chem. 2009, 74, 9359. (b) Colby, D. A.; Bergman, R. G.;
Ellman, J. A. J. Am. Chem. Soc. 2008, 130, 3645.
(c) Yotphan, S.; Bergman, R. G.; Ellman, J. A. J. Am. Chem.
Soc. 2008, 130, 2452. (d) Parthasarathy, K.; Jeganmohan,
M.; Cheng, C.-H. Org. Lett. 2008, 10, 325. (e) Lim, S.-G.;
Lee, J. H.; Moon, C. W.; Hong, J.-B.; Jun, C.-H. Org. Lett.
2003, 5, 2759.
Synlett 2011, No. 19, 2789–2794 © Thieme Stuttgart · New York

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