Rhenium-catalyzed regioselective synthesis of multisubstituted pyridines from β-enamino ketones and alkynes via C-C bond cleavage

Article abstract of DOI:10.1021/ol301273j

A new method is described for the regioselective synthesis of multisubstituted pyridine derivatives. Treatment of N-acetyl β-enamino ketones with alkynes in the presence of the rhenium catalyst, Re ₂(CO)₁₀, gives multisubstituted pyridines regioselectively. In this reaction, the N-acetyl moieties are important for the selective formation of the multisubstituted pyridines. This reaction proceeds via insertion of alkynes into a carbon-carbon single bond of β-enamino ketones, intramolecular nucleophilic cyclization, and elimination of acetic acid.

Full text of DOI:10.1021/ol301273j

ORGANIC
LETTERS
2012
Vol. 14, No. 12
3182–3185
Rhenium-Catalyzed Regioselective
Synthesis of Multisubstituted Pyridines
from β-Enamino Ketones and Alkynes via
CꢀC Bond Cleavage
Shun-ichi Yamamoto, Kana Okamoto, Makiko Murakoso, Yoichiro Kuninobu,*,† and
Kazuhiko Takai*
Division of Chemistry and Biotechnology, Graduate School of Natural Science and
Technology, Okayama University, 3-1-1 Tsushimanaka, Kita-ku, Okayama 700-8530,
Japan
kuninobu@mol.f.u-tokyo.ac.jp; ktakai@cc.okayama-u.ac.jp
Received May 8, 2012
ABSTRACT
A new method is described for the regioselective synthesis of multisubstituted pyridine derivatives. Treatment of N-acetyl β-enamino ketones with
alkynes in the presence of the rhenium catalyst, Re2(CO)10, gives multisubstituted pyridines regioselectively. In this reaction, the N-acetyl moieties
are important for the selective formation of the multisubstituted pyridines. This reaction proceeds via insertion of alkynes into a carbonꢀcarbon
single bond of β-enamino ketones, intramolecular nucleophilic cyclization, and elimination of acetic acid.
Construction of N-heterocycles is one of the most
important areas in synthetic organic chemistry. Among
them, the synthesis of highly substituted pyridines is of
special interest because they are partial structures of many
natural products, pharmaceuticals, and organic functional
materials.1,2 From the 19th century, numerous efficient
synthetic procedures have been developed for the synthesis
of pyridine derivatives.3,4 One common method involving
condensationof aminesand carbonyl compoundshas been
used widely for the synthesis of substituted pyridines, such
asthe Hantzsch, Knoevenagel, and Chichibabin methods.5
† Present address: Graduate School of Pharmaceutical Sciences, The
University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
(1) (a) Jones, G. In Comprehensive Heterocyclic Chemistry II, Vol. 5;
Katrisky, A. R., Rees, C. W., Scriven, E. F. V., McKillop, A., Eds.; Pergamon:
Oxford, 1996; pp 167ꢀ243. (b) Joule, K.; Mills, K. Heterocyclic Chem-
istry, 4th ed.; Blackwell Science: Cambridge, 2000; pp 63ꢀ120. (c) Alford,
P. E. In Progress in Heterocyclic Chemistry, Vol. 22; Gribble, G. W., Joule,
J. A., Eds.; Elsevier: Amsterdam, 2011; pp 349ꢀ392.
ꢀ7
In addition, transition metal catalysts have been used
for the synthesis of pyridine derivatives.8 Recent methods
for the synthesis of multisubstituted pyridine derivatives
have been accomplished via transition-metal-catalyzed
(2) (a) Rama Rao, A. V.; Ravindra Reddy, G.; Venkateswara Rao, B.
J. Org. Chem. 1991, 56, 4545. (b) Beley, M.; Chodorowski-Kimmers, S.;
Collin, J.-P.; Laine., P.; Launay, J.-P.; Sauvage, J. -P. Angew. Chem., Int.
Ed. Engl. 1994, 33, 1775. (c) Jayasinghe, L.; Jayasooriya, C.-P.; Hara,
N.; Fujimoto, Y. Tetrahedron Lett. 2003, 44, 8769. (d) Henry, G. D.
Tetrahedron 2004, 60, 6043. (e) Michael, J. P. Nat. Prod. Rep. 2005, 22,
627. (f) Kubota, T; Nishi, T.; Fukushi, E.; Kawabata, J.; Fromont, J.;
Kobayashi, J. Tetrahedron Lett. 2007, 48, 4983.
(4) For recent reviews, see: (a) Hill, M. D. Chem.;Eur. J. 2010, 16,
12052. (b) Trost, B. M.; Gutierrez, A. C. Org. Lett. 2007, 9, 1473. (c)
Yamamoto, Y.; Kinpara, K.; Ogawa, R.; Nishiyama, H.; Itoh, K.
Chem.;Eur. J. 2006, 12, 5618. (d) Zeni, G.; Larock, R. C. Chem. Rev.
2004, 104, 2285.
(5) Hantzsch, A. Liebigs Ann. Chem. 1882, 215, 1.
(6) Colonge, J.; Dreux, J.; Thiers, M. Bull. Soc. Chim. Fr. 1959, 1461.
(7) Chichibabin, A. E.; Zeide, O. A. J. Russ. Phys. Chem. Soc. 1914,
46, 1212.
(8) (a) Roesch, K. R.; Zhang, H.; Larock, R. C. J. Org. Chem. 2001,
66, 8042. (b) Roesch, K. R.; Larock, R. C. J. Org. Chem. 2002, 67, 86. (c)
Ingebrigtsen, T.; Helland, I.; Lejon, T. Heterocycles 2005, 65, 2593. (d)
Korivi, R. P.; Cheng, C.-H. Org. Lett. 2005, 7, 5179.
(3) For recent synthesis of multisubstituted pyridines, see: (a) Wang,
Y. -F.; Toh, K. K.; Ng, E. P. J.; Chiba, S. J. Am. Chem. Soc. 2011, 133,
6411. (b) Chun, Y.-S.; Lee, H.-J.; Kim, J.-H.; Ko, Y.-O.; Lee, S.-g. Org.
Lett. 2011, 13, 6390. (c) Donohoe, T. J.; Basutto, J. A.; Bower, J. F.;
Rathi, A. Org. Lett. 2011, 13, 1036. (d) Coffinier, D.; Kaim, L. E.;
Grimaud, L.; Hadrot, S. Tetrahedron Lett. 2010, 51, 6186.
r
10.1021/ol301273j
Published on Web 05/31/2012
2012 American Chemical Society

CꢀH bond activation and subsequent CꢀC bond forma-
tion. For example, EllmanꢀBergman,9 Cheng,10 Chiba,11
and Rovis12 have reported the rhodium-catalyzed synthesis
of highly substituted pyridines from R,β-unsaturated imines
(or oximes) and internal alkynes via insertion of alkynes into
an olefinic CꢀH bond of the R,β-unsaturated imines and
successive electrocyclization. In these reactions, nonpolar
internal alkynes can be introduced into the pyridine rings. In
contrast, only a few examples have been reported for the
catalytic synthesis of pyridine derivatives via CꢀC bond
cleavage.13 These reactions were sometimes limited by re-
gioselectivity and product selectivity. In particular, the use of
unsymmetrical alkynes (e.g., 1-phenyl-1-propyne and
1-hexyne) gave a mixture of regioisomers.
Treatment of 1a with 1-phenyl-1-propyne (2a) in the
presence of a catalytic amount of Re2(CO)10 in octane at
180 °C for 24 h gave multisubstituted pyridine 3a in 76%
yield as a single regioisomer (Scheme 1).17ꢀ20 In this
reaction, the N-acetyl moiety was important for formation
of pyridine derivatives. Using β-enamino ketones with
other functional groups, such as N-isopropylcarbonyl,
benzoyl, pentafluorobenzoyl, trichloroacetyl, trifluoroace-
tyl, and pentafluoroethylcarbonyl, produced multisubsti-
tuted pyridine 3a in low yields.
Scheme 1. Rhenium-Catalyzed Synthesis of Pyridine 3a from
N-Acetyl β-Enamino Ketone 1a and Alkyne 2a
The rhenium-catalyzed regioselective insertion of termi-
nal alkynes into a CꢀC single bond of cyclic and acyclic
1,3-dicarbonyl compounds has already been reported
(Figure 1a).14 In this reaction, a mixture of regio- and
stereoisomers was formed. In contrast, only a single pro-
duct was obtained from β-enamino ketones instead of 1,3-
dicarbonyl compounds (Figure 1b). This report describes
the first rhenium-catalyzed regioselective synthesis of mul-
tisubstituted pyridine derivatives from β-enamino ketones
as well as terminal and internal alkynes.15,16
Next, several β-enamino ketones (Table 1) were exam-
ined. These reactions produced the corresponding pyri-
dines as a single product. Regioselective synthesis of pyri-
dines 3b and 3c also can be accomplished using β-enamino
ketones, 1b and 1c, which have a phenyl group at the R1 or
R3 position, respectively, of the β-enamino ketones (entries
1 and 2). These results indicate that a CꢀC single bond was
cleaved between the carbonyl and R-carbons of the β-
enamino ketones. The β-enamino ketone with phenyl
groups at the R1 and R3 positions, 1d, provided the corres-
ponding pyridine 3d in 60% yield (entry 3). Moreover,
treatment of 2a with N-acetyl β-enamino ketone 1e with a
methyl group at the R-position gave the desired pyridine 3e
in 57% yield (entry 4). The reaction of cyclic β-enamino
ketone 1f produced tetrahydroquinoline derivative 3f in
69% yield (entry 5).21
The scope and limitations of several internal alkynes
were also investigated (Table 2).22 The use of the aryl alkyne
with an electron-donating group at the para-position, 2b,
Figure 1. Rhenium-catalyzed insertion of alkynes into a CꢀC
single bond.
(15) For reactions of β-enamino carbonyl compounds, see: (a)
Breitmaier, E.; Bayer, E. Tetrahedron Lett. 1970, 11, 3291. (b) Bagley,
M. C.; Brace, C.; Dale, J. W.; Ohnesorge, M.; Phillips, N. G.; Xiong, X.;
Bower, J. J. Chem. Soc., Perkin Trans. 1 2002, 1663.
(16) For reactions of N-acyl enamino carbonyl compounds, see: (a)
Movassaghi, M.; Hill, M. D.; Ahmad, O. K. J. Am. Chem. Soc. 2007,
129, 10096. (b) Dash, J.; Reissig, H.-U. Chem.;Eur. J. 2009, 15, 6811.
(17) A side reaction occurred when using phenyl acetylene, which is
described in Table 2, entry 9.
(9) (a) Colby, D. A.; Bergman, R. G.; Ellman, J. A. J. Am. Chem. Soc.
2008, 130, 3645. (b) Martin, R. M.; Bergman, R. G.; Ellman, J. A. J. Org.
Chem. 2012, 77, 2501.
(10) Parthasarathy, K.; Jeganmohan, M.; Cheng, C.-H. Org. Lett.
2008, 10, 325.
(18) This reaction did not proceed when using MnBr(CO)5, ReBr-
(11) Too, P. C.; Noji, T.; Lim, Y. J.; Li, X.; Chiba, S. Synlett 2011,
2789.
(CO)5, [ReBr(CO)3(thf)]2, [ReH(CO4)]n, W(CO)6, Mn2(CO)10, Fe3(CO)12
Ru3(CO)12, Ir4(CO)12, and Rh4(CO)12. Dimerization of β-enamino ketone
occurred upon using Rh4(CO)12
,
(12) Hyster, T. K.; Rovis, T. Chem. Commn. 2011, 47, 11846.
(13) Chiba demonstrated palladium-catalyzed synthesis of pyridine
from azidocyclopentenol via chelate-assisted intramolecular CꢀC bond
cleavage. See: Chiba, S.; Xu, Y. -J.; Wang, Y. -F. J. Am. Chem. Soc.
2009, 131, 12886–12887.
(14) (a) Kuninobu, Y.; Kawata, A.; Takai, K. J. Am. Chem. Soc.
2006, 128, 11368. (b) Kuninobu, Y.; Takata, H.; Kawata, A.; Takai, K.
Org. Lett. 2008, 10, 3133. (c) Kuninobu, Y.; Kawata, A.; Nishi, M.;
Takata, H.; Takai, K. Chem. Commun. 2008, 47, 6360. (d) Kuninobu, Y.;
Kawata, A.; Nishi, M.; Yudha, S. S.; Chen, J.; Takai, K. Chem.;Asian
J. 2009, 4, 1424. (e) Kuninobu, Y.; Matsuzaki, H.; Nishi, M.; Takai, K.
Org. Lett. 2011, 13, 2959.
.
(19) Investigation of several solvents: Toluene 73%, MeCN 47%,
DMF 0%, 1,2-dichloroethane 0%, neat 15%.
(20) In this reaction, small amounts of several products by hydrolysis
of 1a (for example, 1,3-diketone and acetic acid) were detected by
GCMS. In addition, polymerization of internal alkyne 2a also occurred.
(21) o-Acetylacetanilide and five-membered cyclic β-enamino ketone
bearing an N-acetyl group at an external ring position did not promote
the formation of pyridine derivatives.
(22) The reaction of N-acetyl enamino ketone 1a with cis-stylbene
(or trans-4-octene) did not proceed except for the decomposition of 1a.
Org. Lett., Vol. 14, No. 12, 2012
3183

Table 1. Reactions between Several β-Enamino Ketones 1 and
1-Phenyl-1-propyne (2a)a
Table 2. Reactions between N-Acetyl β-Enamino Ketone 1a and
Several Alkynes 2a
a 1 (1.7 equiv). b Isolated yield. Yield determined by 1H NMR is
reported in parentheses. c 1f (1.0 equiv), Re2(CO)10 (10 mol %).
produced only one regioisomer 3g in 85% yield (entry 1).
Regioselectivity was not affected by the steric hindrance at
the ortho-position of alkyne 2c, and the corresponding
pyridine derivative 3h was produced in 60% yield (entry 2).
However, an aryl alkyne with an electron-withdrawing
group at the para-position, 2d, led to a decrease in reactiv-
ity and regioselectivity (entry 3). The reaction of enyne 2e
with 1a provided a mixture of 3j and 3j0 in 47% yield (3j and
3j0 = 97:3, entry 4). Internal alkynes with two alkyl or
aromatic groups 2fꢀ2i were transformed to the correspond-
ing multisubstituted pyridines 3kꢀ3n in 59ꢀ72% yields
(entries 5ꢀ8). Use of phenylacetylene (2j) produced the
desired pyridine 3o and unexpected acetylpyridine 5a in
42% and 18% yields, respectively (entry 9).23
a 1a (1.7 equiv). b Isolated yield. Yield determined by 1H NMR is
reported in parentheses. c The regioselectivity was determined by 1H
NMR. d 1a (1.0 equiv), Re2(CO)10 (10 mol %). e 1a (1.0 equiv), 2j (2.0
equiv), toluene, 180 °C, 24 h.
aliphatic alkyne; treatment of enamino ketone 4 with
1-dodecyne (2k) gave the corresponding pyridine (3p) in
41% yield. In contrast, the reaction of N-acetyl β-enanino
ester 6 with phenylactylene (2j) gave multisubstituted
ethoxycarbonylpyridine5bin29%yieldasasingleproduct
(Scheme 2).24
The structures of the pyridine derivatives 3 demonstrated
that the alkynes 2 insert between the carbonyl and
R-carbons of β-enamino ketones 1. The proposed mechanism
for the formation of the pyridine derivatives is shown in
Changing the N-acetyl moiety of β-enamino ketone 1a
to a methoxycarbonyl group yielded multisubstituted pyr-
idine 3o in 43% yield without side products (Scheme 2).
Addition of 1.0 equiv of methyl carbamate increased the
yield of 3o to 56%. The reaction also proceeded with an
(24) Treatment of (Z)-methyl (4-oxo-2-penten-2-yl)carbamate
(N-methoxycarbonyl β-enamino ketone, 4) with 1-phenyl-1-propyne
(2a) at 150 °C for 24 h produced a mixture of pyridines 3a and 3a0 in
55% yield (3a:3a0 = 72:28).
(23) Multisubstituted acetylpyridine 5a is generated via rhenium-
catalyzed nucleophilic addition of β-enamino ketone 1a to alkyne 2j and
successive cyclization. For examples of rhenium-catalyzed addition of
active methylene compounds to terminal alkynes (or β-enamino esters to
allenes), see: (a) Kuninobu, Y.; Kawata, A.; Takai, K. Org. Lett. 2005, 7,
4823. (b) Kuninobu, Y.; Yamashita, A.; Yamamoto, S.-i.; Yudha, S. S.;
Takai, K. Synlett 2009, 20, 3027.
3184
Org. Lett., Vol. 14, No. 12, 2012

Scheme 2. Selective Synthesis of Multisubstituted Pyridines with
Terminal Alkynes
Scheme 3. Proposed Mechanism for the Formation of Multi-
substituted Pyridines
a 1g (1.0 equiv), 2j (2.0 equiv), dioxane. b Methyl carbamate (1.0 equiv)
was added as an additive. c 1g (1.0 equiv), 2k (2.0 equiv), methyl
carbamate (1.0 equiv), dioxane. d 6 (2.0 equiv), 2j (1.0 equiv), toluene.
Scheme 3: (1) oxidative cycloaddition of an enol form of β-
enamino ketone 1, alkyne 2, and the rhenium catalyst; (2)
reductive elimination to give a cyclobutene intermediate
and regenerate the rhenium catalyst;25 (3) CꢀC bond
cleavage by the retro-aldol-type reaction (N-acyl group
works as an electron acceptor); (4) intramolecular nucleo-
philic cyclization; (5) elimination of acetic acid to give
pyridine derivative 3. In this reaction, the direction of
insertion of the alkyne is similar to rhenium-catalyzed
insertion of alkynes into a CꢀC bond of a β-keto ester.14
Insummary, the rhenium-catalyzed regioselectivesynth-
esis of multisubstituted pyridines was accomplished suc-
cessfully by the reaction of an N-acetyl β-enamino ketone
with an internal alkyne. This reaction proceeded via
regioselective insertion of alkynes into a CꢀC single bond
of β-enamino ketones. As a result, two substituents from
the alkynes were introduced at the 3- and 4-positions of
the pyridine derivatives regioselectively. For reactions
between N-acetyl β-enamino ketones and a terminal al-
kyne, two pyridines were generated. In contrast, the selec-
tivity of the product improved and only one pyridine was
formed when using an N-methoxycarbonyl β-enamino
ketone. This reaction may become a useful method for
synthesizing multisubstituted pyridines regioselectively.
Acknowledgment. Financial support from the Ministry
of Education, Culture, Sports, Science, and Technology of
Japan is gratefully acknowledged.
Supporting Information Available. General experimen-
tal procedures and characterization data for pyridine
derivatives 3 and 5. This material is available free of
charge via the Internet at http://pubs.acs.org.
(25) The reason for the regioselectivity is not clear; however, the steric
hindrance between the substituents of alkynes and ligands of the
rhenium catalyst may be responsible for the regioselectivity.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 12, 2012
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