Me3SiCl-promoted three-component coupling reaction of a functionalized enamine, an acetal, and an alkyne: An unprecedented approach to the synthesis of tetrasubstituted pyridines via a [3 + 2 + 1] intermolecular cyclization

Article abstract of DOI:10.1021/jo801090h

(Chemical Equation Presented) We have identified a Me₃SiCl- mediated three-component coupling reaction of a functionalized enamine, N,N-dimethylformamide diethyl acetal, and an internal alkyne having an electron-withdrawing group that produces 2,3,4,5-tetra-substituted pyridine derivatives in good to excellent yields via a single-step reaction.

Full text of DOI:10.1021/jo801090h

the product yield. Hence, the development of a novel procedure
for a simple, practical, single-step synthesis of a pyridine
framework is highly desirable. We previously found that
intermolecular cyclization of a multifunctionalized 1-azaallylic
anion7 with several Michael acceptors successfully led to the
synthesis of nitrogen-containing heterocycles, such as polysub-
stituted pyridines,8 pyrroles,9 and pyrimidines.10 We also showed
that a Lewis acid catalyzed cyclization of a functionalized
enamine,11 which is formally equivalent to a 1-azaallyl anion
with cyclic Michael acceptors, produced fused heterocycles.12
Me3SiCl-Promoted Three-Component Coupling
Reaction of a Functionalized Enamine, an Acetal,
and an Alkyne: An Unprecedented Approach to
the Synthesis of Tetrasubstituted Pyridines via a
[3 + 2 + 1] Intermolecular Cyclization
Toshiaki Sasada, Norio Sakai, and Takeo Konakahara*
Department of Pure and Applied Chemistry, Faculty of
Science and Technology, Tokyo UniVersity of Science
(RIKADAI), Noda, Chiba 278-8510, Japan
During ongoing exploration of a novel synthetic process of
nitrogen-containing heterocyclic compounds, we found a new,
practical Me3SiCl-promoted three-component coupling reaction
of a polyfunctionalized enamine, N,N-dimethylformamide di-
ethyl acetal (DMF-DEA), and an internal alkyne having an
electron-withdrawing group, leading to the production of
konaka@rs.noda.tus.ac.jp
ReceiVed May 21, 2008
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2307. (c) Varela, J. A.; Saa´, C. Chem. ReV. 2003, 103, 3787. (d) Maryanoff,
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N.; Yamada, A.; Kakehi, A.; Sakai, N. Heterocycles 2001, 55, 313. (c)
Konakahara, T.; Ogawa, R.; Tamura, S.; Kakehi, A.; Sakai, N. Heterocycles
2001, 55, 1737. (d) Hojahmat, M.; Konakahara, T.; Tamura, S. Heterocycles
2000, 53, 629. (e) Konakahara, T.; Hojahmat, M.; Tamura, S. J. Chem. Soc.,
Perkin Trans. 1 1999, 2803.
We have identified a Me3SiCl-mediated three-component
coupling reaction of a functionalized enamine, N,N-dimeth-
ylformamide diethyl acetal, and an internal alkyne having
an electron-withdrawing group that produces 2,3,4,5-tetra-
substituted pyridine derivatives in good to excellent yields
via a single-step reaction.
The pyridine ring system is one of the most important core
structures and is widely found in naturally occurring compounds,
biologically active substances, and clinical drugs.1 A number
of synthetic approaches have therefore been developed for the
facile synthesis of these central skeletons.1–3 Generally, previous
synthetic routes to the pyridine framework have involved the
dehydrated condensation of aldehydes, ketones, and R,ꢀ-
unsaturated carbonyl compounds with ammonia and its amine
derivatives4 or aza-Diels-Alder reactions of a 1- or 2-azadiene
derivative with a dienophile, such as an alkene and an alkyne.5
In addition, [2 + 2 + 2] cycloaddition reactions of two types
of alkynes with a nitrile have been identified.6 However, most
of these procedures have had restricted use due to complicated
protocols. Moreover, these methods often require a high
temperature, a prolonged reaction time, and expensive additives,
such as transition metal complexes, resulting in a decline in
(1) For selected reviews, see: (a) Bagley, M. C.; Dale, J. W.; Merritt, E. A.;
Xiong, X. Chem. ReV. 2005, 105, 685. (b) Henry, G. D. Tetrahedron 2004, 60,
6043. (c) O’Hagan, D. Nat. Prod. Rep. 1997, 14, 637. (d) Plunkett, A. O. Nat.
Prod. Rep. 1994, 11, 581.
(9) Konakahara, T.; Watanabe, A.; Maehara, K.; Nagata, M.; Hojahmat, M.
Heterocycles 1993, 35, 1171.
(2) For selected books and reviews, see: (a) ComprehensiVe Heterocyclic
Chemistry; Katritzky, A. R., Rees, C. W., Eds.; Pergamon Press: Oxford, 1984;
Vol. 2. (b) ComprehensiVe Heterocyclic Chemistry II; Katritzky, A. R., Rees,
C. W., Scriven, E. F. V., Eds.; Pergamon Press: Oxford, 1996; Vol. 5. (c) Zeni,
G.; Larock, R. C. Chem. ReV. 2004, 104, 2285. (d) Gilchrist, T. L. J. Chem.
Soc., Perkin Trans. 1 2001, 2491.
(10) Sakai, N.; Aoki, Y.; Sasada, T.; Konakahara, T. Org. Lett. 2005, 7,
4705.
(11) Erian, A. W. Chem. ReV. 1993, 93, 1991.
(12) (a) Sakai, N.; Aoki, D.; Hamajima, T.; Konakahara, T. Tetrahedron
Lett. 2006, 47, 1261. (b) Sakai, N.; Hattori, N.; Tomizawa, N.; Abe, N.;
Konakahara, T. Heterocycles 2005, 65, 2799.
10.1021/jo801090h CCC: $40.75
Published on Web 07/29/2008
2008 American Chemical Society
J. Org. Chem. 2008, 73, 6905–6908 6905

TABLE 2. Optimization of Reaction Conditions
SCHEME 1. New Approach for a Single-Step Synthesis of
Pyridine
TABLE 1. Synthesis of Enamine 1a
run
Me3SiX (equiv)
yield (%)a
1
2
3
4
5
6
7
none
7
98b
13
trace
17
Me3SiCl (2)
Me3SiCl (1)
Me3SiI (1)
Me3SiI (2)
Me3SiOTf (1)
Me3SiOTf (2)
trace
8
a NMR yield. b Isolated yield.
followed by addition of water to the reaction mixture at room
temperature, to produce the desired enamine 1aa in a 90% yield
(run 1). The coupling reaction of prepared enamine 1aa, DMF-
DEA, and dimethyl acetylene dicarboxylate (DMAD) was then
systematically investigated, and the results are outlined in Table
2. When a CH3CN solution of enamine 1aa, 2 equiv of DMF-
DEA 2, and DMAD 3a was stirred at room temperature for 30
min, the tetrasubstituted pyridine 4aa was obtained in only 7%
yield (run 1). The structure of pyridine 4aa was determined by
spectral data and elemental analysis and was unambiguously
confirmed by the X-ray structure analysis of compound 4ab
(see Supporting Information).14 To enhance the yield, the
reaction conditions were optimized with several different
solvents and a Lewis acidic silicon compound as an additive.15
As a result, it was found that the desired product 4aa was
dramatically improved to a nearly quantitative yield when the
reaction mixture, including 2 equiv of trimethylchlorosilane
(Me3SiCl), was vigorously stirred for 10 min before the addition
of enamine 1aa (run 2). In contrast, reducing the amount of
Me3SiCl to 1 equiv drastically decreased the yield to 13% (run
3). Moreover, the use of trimethyliodosilane (Me3SiI) and
trimethylsilyl trifluoromethanesulfonate (Me3SiOTf) instead of
Me3SiCl, even with an increased amount of these silicon
catalysts, was ineffective for the improvement of the yield of
pyridine 4aa (runs 4-7). Consequently, we decided that the
experimental operation using 2 equiv of Me3SiCl in CH3CN
was the best procedure for the ring-forming reaction (run 2).
We then used this procedure to extend the preparation of
polyfunctionalized pyridine derivatives, and the results are
summarized in Table 3. The reaction of enamines 1ab-ad,
containing not only an electron-donating group but also an
electron-withdrawing group on the benzene ring, with acetal
2 and DMAD was conducted in the presence of Me3SiCl to
produce the expected pyridine derivatives 4ab-ad in good
to excellent yields (runs 2-4). Similarly, the use of enamine
1ba and 1ca-cd tethered with other substituted groups, such
as an amide group or a qunolin-2-yl group, gave the
corresponding pyridines 4ba and 4ca-cd in excellent yields
a Isolated yield.
tetrasubstituted pyridines. To our knowledge, this type of
preparation of a pyridine core through a one-pot [3 + 2 + 1]
coupling process, shown in Scheme 1, has not previously been
reported. This paper details the results of this coupling reaction.
On the basis of previous work,13 we first prepared a variety
of functionalized enamines as starting materials, and the results
are summarized in Table 1. For example, the mixture of 3,5-
dimethylisoxazole with benzonitrile was initially treated with
lithium diisopropylamide (LDA) in THF at -70 °C for 1 h,
(14) Crystal data for 4ab: C20H18N2O6, MW ) 382.36, monoclinic, a )
6.7232(10) Å, b ) 24.783(4) Å, c ) 10.9025(16) Å, ꢀ ) 95.596(2)°, U )
1808.0(5) Å3, space group P21/c, Z ) 4, µ(Mo KR) ) 0.105 mm-1, 10719
reflections measured, 4068 independent reflections (Rint ) 0.0379), R1 ) 0.1298,
wR2 ) 0.3149. Also see the details in Supporting Information.
(15) Typical solvents, such as THF, CHCl3, and toluene, and typical Lewis
acids, such as InCl3, ZnBr2, Cu(OTf)2, MgBr2 ·OEt2, BF3 ·OEt2, and AlCl3, were
ineffective or only slightly effective for the reaction.
(13) (a) Akiba, K.; Kashiwagi, K.; Ohyama, Y.; Yamamoto, Y.; Ohkata, K.
J. Am. Chem. Soc. 1985, 107, 2721. (b) Konakahara, T.; Takagi, Y. Heterocycles
1980, 14, 393.
6906 J. Org. Chem. Vol. 73, No. 17, 2008

TABLE 3. Synthesis of Tetrasubstituted Pyridines 4 and 5a
Experimental Section
General Procedure for Synthesis of Enamine 1. To a THF
solution (50 mL) of diisopropylamine (2.53 g, 25.0 mmol) was
added n-BuLi (27.5 mmol, in hexane) at -70 °C, and the mixture
was stirred at the same temperature. After 30 min, 2-methylquino-
line (3.58 g, 25.0 mmol) was added dropwise, and the mixture was
stirred for 1 h at -70 °C. p-Anisonitrile (3.33 g, 25.0 mmol) was
gradually added to the solution, and the reaction mixture was further
stirred for 1 h at the same temperature and then for 1 h at room
temperature. To quench the reaction, water was added to the
mixture. The mixture was extracted several times with AcOEt, and
the combined organic extracts were dried over Na2SO4, filtered,
and then concentrated under reduced pressure. The residue was
purified by recrystallization (AcOEt-hexane) to give enamine
2-(quinolin-2-yl)-1-(4-methoxyphenyl)-1-ethenamine 1cb (6.22 g,
1
90%) as a yellow crystal: mp 156.7-158.0 °C; H NMR (CDCl3,
500 MHz) δ 3.84 (s, 3H), 5.56 (s, 1H), 6.94 (d, 2H, J ) 8.5 Hz),
7.12 (d, 1H, J ) 8.0 Hz), 7.33 (t, 1H, J ) 8.0 Hz), 7.58 (t, 1H, J
) 8.0 Hz), 7.61 (d, 2H, J ) 8.5 Hz), 7.64 (d, 1H, J ) 8.0 Hz),
7.88 (d, 1H, J ) 8.0 Hz), 7.88 (d, 1H, J ) 8.0 Hz); 13C NMR
(CDCl3, 125 MHz) δ 55.3, 94.7, 114.0, 122.6, 124.0, 125.1, 127.3,
127.4, 127.5, 129.0, 132.0, 134.9, 147.4, 152.4, 159.9, 160.4; MS
(FAB) m/z 276 (M+, 100%). Anal. Calcd for C18H16N2O: C, 78.24;
H, 5.84; N, 10.14, Found: C, 78.40; H, 5.76; N, 10.06.
General Procedure for Synthesis of Tetrasubstituted Pyri-
dine 4. To a MeCN solution (0.6 mL) of N,N-dimethylformamide
diethyl acetal (2, 88 mg, 0.60 mmol) and dimethyl acetylenedicar-
boxylate (3, 85 mg, 0.60 mmol) was added freshly distilled
trimethylchlorosilane (65 mg, 0.60 mmol) at room temperature
under a N2 atmosphere, and the mixture was stirred at the same
temperature. After 10 min, enamine 1 (0.3 mmol) was added to
the resulting solution, and the reaction mixture was further stirred
for 30 min at room temperature. To quench the reaction, a saturated
aqueous solution of NaHCO3 (5 mL) was added to the mixture.
The mixture was extracted several times with CHCl3; the combined
organic extracts were dried over Na2SO4, filtered, and concentrated
under reduced pressure. The crude product was purified by silica
gel column chromatography (AcOEt/hexane) to produce pyridine
4 in the yields shown in Table 3. Dimethyl 3-(3′-Methylisoxazol-
5′-yl)-2-phenylpyridin-4,5-dicarboxylate (4aa): a pale yellow crystal
1
(AcOEt/hexane); mp 94.8-95.7 °C; H NMR (CDCl3, 500 MHz)
δ 2.26 (s, 3H), 3.86 (s, 3H), 3.98 (s, 3H), 6.00 (s, 1H), 7.33-7.42
(m, 5H), 9.35 (s, 1H); 13C NMR (CDCl3, 125 MHz) δ 11.4, 53.0,
53.1, 106.9, 119.8, 120.7, 128.3, 128.8, 129.6, 138.1, 144.2, 151.9,
159.7, 162.3, 164.0, 164.5, 166.2; MS (FAB) m/z 353 (M + H,
100%). Anal. Calcd for C19H16N2O5: C, 64.77; H, 4.58; N, 7.95,
Found: C, 64.76; H, 4.53; N, 8.12.
(16) Reviewers suggested a reaction route via a hetero Diels-Alder reaction
of a 2-aza-1,3-diene that was generated from an enamine and acetal, with DMAD.
However, when the reaction of enamine 1a with acetal 2a was carried out in the
presence of Me3SiCl, the starting material 1a was recovered in 99% NMR yield
(eq 1).
a Isolated yield.
(runs 6-10). Surprisingly, when enamine 1da having a
pyridin-2-yl group was employed, the yield of the product
4da was moderate (run 11). Also, when diethyl acetylene-
dicarboxylate (3b) was used instead of DMAD, the desired
pyridine 5aa was obtained in a 70% yield (run 12).
Unfortunately, an alternative activated alkyne, such as ethyl
propiolate, and a less-activated alkyne, such as dipheny-
lacetylene, yielded no product.16
Additionally, when hetero Diels-Alder reaction between 2-azadiene 6, which
was synthesized by the other method, and DMAD in the presence of Me3SiCl
was run, the desired reaction barely proceeded, resulting in recovery (83%) of
2-azadiene 6 (eq 2).
In conclusion, we have developed a novel Me3SiCl-promoted
three-component coupling reaction of a polyfunctionalized
enamine, DMF-DEA, and an internal alkyne having a strong
electron-withdrawing group, via a single step. This reaction
proceeds cleanly in a short time to produce a variety of
tetrasubstituted pyridines in good to excellent yields.
The above results implied the existence of another reaction route for the three-
component coupling reaction of enamine, acetal, and alkyne.
J. Org. Chem. Vol. 73, No. 17, 2008 6907

Acknowledgment. We thank Mr. Fuminori Kobayashi for
his experimental assistance. This work was partially supported
by Grant-in-Aid for Scientific Research from MEXT (16550148),
2004-2005, a grant from the Japan Private School Promotion
Foundation, and a fund for the “High-Tech Research Center”
Project for Private Universities: a matching fund subsidy from
MEXT, 2000-2004, and 2005-2007.
Supporting Information Available: Detailed experimental
procedures and characterization data for novel compounds,
ORTEP diagram of 4ab, X-ray data for 4ab in CIF format, and
1
copies of H and 13C NMR spectra of novel products were
prepared. This material is available free of charge via the Internet
at http://pubs.acs.org.
JO801090H
6908 J. Org. Chem. Vol. 73, No. 17, 2008