Organocatalytic synthesis of highly functionalized pyridines at room temperature

Article abstract of DOI:10.1002/anie.201301519

Amines by all means: A unique aza-Rauhut-Currier/cyclization/desulfonation cascade reaction between allenoates and N-sulfonyl-1-aza-1,3-dienes, catalyzed by the readily available diamine TMEDA, has been developed. This strategy provides facile access to a broad range of valuable highly functionalized pyridines in good yields under very mild reaction conditions. Copyright

Full text of DOI:10.1002/anie.201301519

Angewandte
Chemie
Communications
Heterocycles
Z. Shi, T. P. Loh*
&&&& — &&&&
Organocatalytic Synthesis of Highly
Functionalized Pyridines at Room
Temperature
Amines by all means: A unique aza-
Rauhut–Currier/cyclization/desulfona-
tion cascade reaction between allenoates
and N-sulfonyl-1-aza-1,3-dienes, cata-
lyzed by the readily available diamine
TMEDA, has been developed. This strat-
egy provides facile access to a broad
range of valuable highly functionalized
pyridines in good yields under very mild
reaction conditions.
Angew. Chem. Int. Ed. 2013, 52, 1 – 5
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Communications
DOI: 10.1002/anie.201301519
Heterocycles
Organocatalytic Synthesis of Highly Functionalized Pyridines at Room
Temperature**
Zugui Shi and Teck-Peng Loh*
Substituted pyridines are important building blocks for many
natural products, bioactive molecules, and functional materi-
als.[1] Thus, their synthesis has drawn extensive attention from
the organic community during the past few decades. Accord-
ingly various significant methodologies have been dis-
closed.[2,3] Among them, the traditional thermal condensation
of carbonyl compounds represents a typical method for
pyridine synthesis, while modern synthetic strategies mainly
rely on transition metal catalyzed cycloaddition reactions.
However, these existing methodologies either require high
temperature or toxic metals as catalysts. Thus, the develop-
ment of a more general, operationally simple, and environ-
mentally benign method for pyridine synthesis is highly
desirable.
Scheme 1. Amine-catalyzed synthesis of highly functionalized pyri-
dines.
Table 1: Amine-catalyzed synthesis of tetrasubstituted pyridines.[a]
Entry
Catalyst
Solvent
t [h]
Yield [%][b]
1
DABCO
DABCO
DMAP
pyridine
NEt3
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
MeCN
CH2Cl2
CHCl3
48
48
24
24
24
72
72
72
72
24
24
24
24
24
24
24
24
56
55
n.d.
n.d.
50
39
36
28
36
30
77
69
68
57
37
60
55
2[c]
3
Recently, the Rauhut–Currier reaction has emerged as
ꢀ
a powerful tool for new C C bond formation, and demon-
4
5
6
7
8
9
10
11
12
13
14
15
16[d]
17[e]
strated its high efficiency for the construction of carbocycles
and N-containing heterocycles with good stereocontrol.[4,5]
Among existing methodologies, however, the majority rely on
the use of air-sensitive phosphine catalysts. The alternative
and newly developed thiol catalyst proved to be a promising
catalytic system, albeit still lacking in efficiency.[6] In contrast,
amines are more stable and easier to handle when compared
to phosphines, and has shown its efficiency in numerous
nucleophilic catalysis.[7] Unfortunately, the amine-catalyzed
cross-Rauhut–Currier reactions are rarely documented.[8]
Herein, we report a novel aza-Rauhut–Currier/cyclization/
desulfonation cascade reaction of allenoates with 1-aza-1,3-
dienes by using N,N,N’,N’-tetramethylethane-1, 2-diamine
(TMEDA) as a catalyst, which enables a facile entry into the
synthesis of highly functionalized pyridines (Scheme 1). To
the best of our knowledge, this is the first example of an
amine-catalyzed aza-Rauhut–Currier reaction.
DIPEA
4-methylmorpholine
quinine
NBu3
DBU
TMEDA
TMEDA
TMEDA
TMEDA
TMEDA
TMEDA
TMEDA
THF
toluene
toluene
[a] Reaction conditions: 1a (0.1 mmol), 2a (0.05 mmol), and catalyst
(20 mol%) were stirred at room temperature. [b] Yield of isolated
product. [c] N-tosyl-1-aza-1,3-diene was used. [d] Used 10 mol%
TMEDA. [e] Used 5 mol% TMEDA. DBU=1,8-diazabicyclo[5.4.0]undec-
7-ene, DIPEA=, DMAP=4-(N,N-dimethylamino)pyridine, n.d.=not
detected, PMP=para-methoxyphenyl.
Our first trial was conducted with benzyl allenoate and N-
4-methoxybenzenesulfonyl-1-aza-1,3-diene, in the presence
of 20 mol% 1, 4-diazabicyclo[2, 2, 2]octane (DABCO) as the
catalyst (Table 1). To our delight, the pyridine 3a, having
multiple functional groups, was obtained with a modest yield
(entry 1). Different N-protecting groups turned out to have
no significant influence on the reaction outcome (entry 2). To
improve the chemical yield, various amines were then
examined. Trialkylamines proved to be superior to aromatic
ones (entries 5–10), and afforded moderate product yields;
and the aromatic amines did not catalyze this reaction
(entries 3 and 4). Surprisingly, when TMEDA was employed,
the reaction yield was significantly elevated (entry 11).
Subsequent investigation of solvent effects indicated toluene
to be the best choice (entries 12–15). Additionally, the
catalyst loading can be further decreased to 10 mol%,
though slightly lower yield was obtained (entry 16). Using
5 mol% of catalyst is still efficient enough to promote this
reaction (entry 17).
[*] Prof. Dr. T. P. Loh
Hefei National Laboratory for Physical Science at the Microscale
and Department of Chemistry, University of Sciences and Technol-
ogy of China, Hefei, Anhui 230026 (P. R. China)
E-mail: teckpeng@ntu.edu.sg
Dr. Z. Shi, Prof. Dr. T. P. Loh
Division of Chemistry and Biological Chemistry, Nanyang Techno-
logical University, Singapore 637371 (Singapore)
[**] We gratefully acknowledge the Nanyang Technological University,
the Singapore Ministry of Education Academic Research Fund Tier 2
(MOE2010-T2-2-067, and MOE2011-T2-1-013) for financial support.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201301519.
2
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Under the optimized reaction conditions, a variety of
2,3,4,6-tetrasubstituted pyridines and 2,3,4,5,6-pentasubsti-
tuted pyridines were efficiently synthesized in good chemical
yields (Table 2). Generally, aromatic groups, such as the
were also easily prepared (3n–p). Additionally, styryl was
well-incorporated in this pyridine system (3q). A heterotri-
cycle (3r) could also be prepared using this methodology in
modest yield. Moreover, the use of 2,3,4-trisubstituted 1-aza-
1, 3-diene provided a straightforward entry to the pentasub-
stituted pyridine 3s. This protocol could be readily extended
to the synthesis of 6-alkyl-substituted pyridine. To our
surprise, the more sterically hindered 6-tert-butyl-substituted
pyridine could be easily prepared with excellent yield (3t).
Further exploration demonstrated that the size of the 2,3-
butadienoate had no significant influence on the reaction
outcome (3u). Notably, highly unstable 1-phenyl-2,3-buta-
dien-1-one was well tolerated in this transformation (3v).
Unfortunately, g-substituted 2,3-butadienoates could not
participate in this process (3w), possibly because of the
lower electrophilicity of g-substituted 2,3-butadienoates,
compared to simple nonsubstituted 2,3-dienoates. Thus, the
zwitterionic intermediate A could not be formed by nucleo-
philic addition of the amine catalyst (see Scheme 3). Chal-
cone-derived N-sulfonyl-1-aza-1,3-diene could not be
employed in this transformation, probably because of its
lower reactivity.
Table 2: TMEDA-catalyzed synthesis of highly substituted pyridines.[a,b]
To further simplify this protocol, a one-pot three compo-
nent strategy was developed. As shown in Scheme 2, in the
presence of TMEDA, the mixture of readily available benzyl
Scheme 2. One-pot synthesis of pyridine.
2-(triphenylphosphoranylidene)acetate, acetic chloride, and
the N-sulfonyl-1-aza-1,3-diene 2a were directly converted
into the pyridine adduct 3a in good yield under mild reaction
conditions.
Although the detailed mechanism of this reaction is not
clear at the current stage, a rational reaction pathway is
proposed [Scheme 3, Eq. (1)]. The reaction is believed to be
initiated by the nucleophilic addition of TMEDA to the 2,3-
butadienoate 1, thus giving the zwetterironic intermediate A.
Subsequent nucleophilic attack of the 1-aza-1,3-diene 2 and
subsequent intramolecular proton transfer within B provides
C, which is believed to exist in equilibrium with the
intermediate D. A second intramolecular proton transfer
then provides E, which undergoes an aza-1,4-addition, thus
affording the tetrahydropyridine adduct F. After expulsion of
the TMEDA catalyst, the dihydropyridine G is formed.
Further desulfonaltion delivers the final pyridine adduct. The
observation of the side-product 4 provides evidence in
support of this mechanism [Scheme 3, Eq. (2)].
[a] Reaction conditions: 1(0.2 mmol), 2 (0.1 mmol), and TMEDA
(20 mol%) in 0.4 mL toluene were stirred at room temperature. [b] Yield
of isolated product. [c] Used 30 mol% TMEDA. Ts=4-toluenesulfonyl.
phenyl ring in 3a, can be readily installed at the 6-position.
Notably, the yield of 3a could be slightly improved to 79%,
but at the expense of a higher catalyst loading. Fluorinated N-
containing heterocycles were frequently found with superior
biological activities. This methodology provided facile access
to the preparation of fluorinated pyridine derivatives, regard-
less of their substitution patterns (3b,c). Both meta- and para-
substituted phenyl moieties, possessing either electron-with-
drawing or electron-donating substituents, were efficiently
introduced at the 6-position of the pyridine ring (3d–h).
Halogenated biaryl systems (3i–k) can also be readily
constructed by this strategy, where the iodo, bromo, and
chloro functionalities enable further transformations such as
coupling. The more bulky 1-naphthyl and 2-naphthyl groups
were well-tolerated in this reaction (3l,m). 6-Furyl-, thio-
phenyl-, and 6-(1-tosyl-1H-indol-3-yl)-substituted pyridines
In conclusion, a mild, environmentally benign protocol for
the synthesis of pyridines has been developed by an amine-
catalyzed aza-Rauhut–Currier/cyclization/desulfonation cas-
cade reaction between 2,3-butadienoate and N-sulfonyl-1-
aza-1,3-dienes. Readily available TMEDA proved to be an
efficient catalyst for this process. In addition, a plausible
Angew. Chem. Int. Ed. 2013, 52, 1 – 5
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dented cascade reaction pathway. A detailed mechanistic
study and application of this strategy to the synthesis of
complex heterocycles are currently underway in our labora-
tory and will be reported in due course.
Experimental Section
General procedure: N,N,N’,N’-tetramethylethane-1, 2-diamine
(TMEDA; 0.02 mmol) was added, under ambient conditions, to
a solution of allenoates (0.2 mmol) and N-sulfonyl-1-aza-1, 3-dienes
(0.1 mmol) in 0.4 mL toluene. The reaction mixture was stirred at
room temperature. After the reaction was completed, it was directly
subjected to column chromatography purification using n-hexane/
ethyl acetate (15:1!10:1) as the eluent.
Received: February 20, 2013
Revised: April 23, 2013
Published online: && &&, &&&&
Keywords: amines · cyclization · heterocycles · organocatalysis ·
.
synthetic methods
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