A new mild method for the one-pot synthesis of pyridines

Article abstract of DOI:10.1016/j.tetlet.2004.06.061

Polysubstituted pyridines are prepared in good yield and with total regiocontrol by the one-pot reaction of an alkynone, 1,3-dicarbonyl compound and ammonium acetate in alcoholic solvents. This new three-component heteroannulation reaction proceeds under mild conditions in the absence of an additional acid catalyst and has been used in the synthesis of dimethyl sulfomycinamate, the acidic methanolysis degradation product of the sulfomycin family of thiopeptide antibiotics.

Full text of DOI:10.1016/j.tetlet.2004.06.061

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 6121–6124
A new mild method for the one-pot synthesis of pyridines
*
Xin Xiong, Mark C. Bagley and Krishna Chapaneri
School of Chemistry, Cardiff University, PO Box 912, Cardiff CF10 3TB, UK
Received 6 May 2004; revised 7 June 2004; accepted 15 June 2004
Abstract—Polysubstituted pyridines are prepared in good yield and with total regiocontrol by the one-pot reaction of an alkynone,
,3-dicarbonyl compound and ammonium acetate in alcoholic solvents. This new three-component heteroannulation reaction
1
proceeds under mild conditions in the absence of an additional acid catalyst and has been used in the synthesis of dimethyl sulfo-
mycinamate, the acidic methanolysis degradation product of the sulfomycin family of thiopeptide antibiotics.
Ó 2004 Elsevier Ltd. All rights reserved.
1
In our recent synthesis of dimethyl sulfomycinamate 1,
the acidic methanolysis degradation product of the
ceeds by Michael addition, typically at 50 °C, to give an
aminodienone intermediate 4 that is cyclodehydrated at
high temperature or under acidic conditions to tetra-
2
thiopeptide antibiotic sulfomycin I, we described a
3
4
Bohlmann–Rahtz strategy (Scheme 1) for the prepa-
ration of the oxazole–thiazole–pyridine central domain
substituted pyridine 5. Our 13 step total synthesis of
dimethyl sulfomycinamate 1, which proceeded in 8%
overall yield, used 1-(oxazol-4-yl)enamine 3a, obtained
from the corresponding b-ketoamide 2a, and methyl 4-
(trimethylsilyl)-2-oxobut-3-ynoate 6a in a multistep
heteroannulation reaction to give pyridine 5a in 93%
yield as a single regioisomer (Scheme 2). Curiously, this
reaction occurred at room temperature in alcoholic
solvent and did not give any trace of the Bohlmann–
Rahtz intermediate 4a; conditions, which appeared
remarkably facile for spontaneous cyclodehydration to
the pyridine.
(
Scheme 2). This heteroannulation of an enamine 3,
often derived from a 1,3-dicarbonyl compound 2 by
reaction with ammonium acetate, and alkynone 6 pro-
O
O
NH2 O
NH4OAc
-H2O
R2
R3
R2
R3
2
3
O
NH4OAc
Michael
addition
R4
(
acid cat.)5
We recently reported a one-pot method for the synthesis
of pyridines from a b-ketoester, ammonia and an alky-
none using a Brønsted or Lewis acid catalyst (Scheme
R6
6
5
1
) and wanted to apply this methodology to the syn-
NH2 O
R4
thesis of dimethyl sulfomycinamate 1 in order to shorten
the number of steps to this target. However, in all of the
three-component reactions that we investigated acid-
catalyzed degradation of the highly sensitive 2-(2-pro-
penyl)oxazole unit prevented the isolation of the oxa-
zole–pyridine product 5a. In view of the facility of the
Bohlmann–Rahtz pyridine synthesis in alcoholic sol-
cyclo-
dehydration
3
R2
R3
O
R OC
R4
R2
N
R6
R6
5
4
Scheme 1. Bohlmann–Rahtz and three-component pyridine 5 synthe-
sis.
6;7
vent, and the surprising ease with which the hetero-
annulation of enamine 3a and alkynone 6a gave the
required pyridine 5a, we set out to explore a new mul-
tistep three-component condensation process for the
synthesis of pyridine heterocycles that would be com-
patible with these precursors and that avoided the use of
an acid catalyst (Scheme 1).
Keywords: Pyridines; Multicomponent reactions; Heterocycles; Sulfo-
mycin; Bohlmann–Rahtz.
*
Corresponding author. Tel.: +44-29-2087-4029; fax: +44-29-2087-
030; e-mail: bagleymc@cf.ac.uk
4
0
040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.06.061

6122
X. Xiong et al. / Tetrahedron Letters 45 (2004) 6121–6124
O
NH2
HN
O
acidic methanolysis
O
NH
HN
O
O
N
N
HO
OH
HN
MeO2C
O
S
N
H
N
N
O
N
hydrolysis
S
N
O
MeOH
O
N
HN
H+
N
CO2Me
O
O
O
N
O
dimethyl sulfomycinamate 1
HN
NH
N
H
MeO
O
O
6 steps
24%)
S
1
(
sulfomycin I
CO2Me
NH
tBuO
CO2Me
t
O Bu
Me3Si
NH2
O
O
N
6
a
O
N
O
N
H
CO2Me
MeOH, RT
(93%)
N
2
CO Me
1
3
a
O
5a
Scheme 2. Degradation of sulfomycin I and synthesis of dimethyl sulfomycinamate 1 via a Bohlmann–Rahtz heteroannulation strategy.
In order to examine if a one-step three-component het-
EtO2C
eroannulation reaction was possible under mild condi-
tions without an acid catalyst, a mixture of ethyl
acetoacetate 2b, 1-phenylprop-2-yn-1-one 6b, and
ammonium acetate was stirred in ethanol for up to
+
Me
O
Ph
O
2b
6b
3
days (Scheme 3). Reactions conducted at room tem-
NH4OAc
one-pot EtOH, reflux
perature or at reflux with up to 4 equiv of ammonium
acetate did not go to completion, giving mixtures of
pyridine 5b, aminodienone 4b and/or enamine 3b (Table
(95%)
EtO2C
Me
1
). However, when the reaction was carried out at reflux
with a large excess of ammonium acetate, pyridine 5b
was isolated as the only product in excellent yield, cyc-
lodehydration occurring spontaneously under the reac-
tion conditions without the use of an acid catalyst.
Optimally, heating an excess of ethyl acetoacetate 2b
N
Ph
5b
Scheme 3. One-pot synthesis of pyridine 5b under mild conditions.
(1.7 equiv) and ammonium acetate (10 equiv with respect
to 2b) with 6b for 24 h gave pyridine 5b as a single
regioisomer in 95% yield after purification on silica
8
In order to investigate the scope of this reaction, a range
of different 1,3-dicarbonyl compounds 2b–e and alky-
(
Table 1, entry 5).
Table 1. Optimizing the one-pot synthesis of ethyl 2-methyl-6-phenylpyridine-3-carboxylate 5b
a
b
Entry
Ratio of 6b/2b
NH
4
OAc equivalents
Temperature
Time (h)
Product (Yield %)
1
2
3
4
5
6
0.6
1.0
1.0
1.0
0.6
1.7
5
2
Room temperature
Reflux
Reflux
72
24
24
24
24
24
4b (70) and 5b (23)
3b and 5b (1:1)
3b and 5b (1.4:1)
5b (89)
4
10
10
10
Reflux
Reflux
Reflux
5b (95)
5b (91)
a
Equivalents of NH
Isolated yield after purification on silica.
4
OAc with respect to b-ketoester 2b.
b

X. Xiong et al. / Tetrahedron Letters 45 (2004) 6121–6124
6123
Table 2. Examining the scope of a one-pot three-component reaction for the synthesis of pyridines 5b–k
R4
R4
one-pot
4
3
R OC
NH OAc, EtOH
3
R OC
+
reflux, 24 h
R2
O
(
38-98%)
R2
R6
R6
N
O
2b-d
6b-g
5b-k
2
3
4
6
b
Entry
1,3-Dicarbonyl
compound 2
Alkynone 6
R
R
R
R
NH
4
OAc
equivalents
Product
Yield (%)
a
c
1
2
3
4
5
6
7
8
9
2b
2b
2b
2b
2b
2b
2b
2c
2c
2c
2c
2d
6b
6c
6d
6e
6f
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
OEt
OEt
OEt
OEt
OEt
OEt
OEt
H
Ph
0
10
10
10
10
1
5b
5c
5d
5e
5f
5f
5g
5h
5i
95
84
c
H
4 -C
0
6
H
H
4
Cl
OMe
c
H
4 -C
6
4
90
Et
Me
Me
Me
Me
Ph
38
90
d
TMS
TMS
Ph
H
d
6f
10
1
90
6g
6b
6e
6e
6f
51
89
71
63
t
O Bu
t
10
1
O Bu
t
Et
Et
Me
Me
Me
Ph
10
11
12
O Bu
t
10
1
5i
d
O Bu
NH
TMS
H
5j
5k
98
98
6b
2
1
a
b
c
4
Equivalents of NH OAc with respect to 1,3-dicarbonyl compound 2.
Isolated yield of pyridine 5 after purification on silica.
An excess (1.7 equiv) of the b-ketoester 2 was employed.
d
4
Only protodesilylated pyridine (R ¼ H) was produced.
nones 6b–g were heated in ethanol at reflux in the
presence of one or 10 equiv of ammonium acetate. In
most experiments (Table 2), pyridine 5b–k was gener-
ated in moderate to excellent yield (entries 1–12, 38–98%
yield) as the only regioisomeric product. When 4-
three-component reaction had failed for ethyl benzoyl-
acetate 2e, the reaction of b-ketoamide 2a (in equilib-
rium with its enol tautomer) prepared by our established
1
route with methyl 4-(trimethylsilyl)-2-oxobut-3-ynoate
6a in the presence of 10 equiv of ammonium acetate was
successful and gave pyridine 5a in 81% yield (Scheme
(trimethylsilyl)but-3-yn-2-one 6f was used, only pro-
todesilylated pyridines 5f and 5j were obtained. Unfor-
9
4). Employing this new multistep process, the total
tunately, reactions carried out using a mixture of ethyl
synthesis of dimethyl sulfomycinamate 1 is now com-
plete in only 12 preparative steps and proceeds in 9%
overall yield.
2
benzoylacetate 2e (R ¼ Ph), ammonium acetate and 1-
arylprop-2-ynones 6b–d did not give the desired pyr-
idines and instead produced the corresponding enamine,
ethyl 3-amino-3-phenylpropenoate, and a number of
side products with degradation of the alkynone. In spite
of this limitation, the reaction was successful for a wide
variety of substrates (entries 1–12), and constitutes a
mild method for the synthesis of polysubstituted pyr-
idines 5b–k.
In conclusion, we have developed a novel one-pot three-
component condensation for the synthesis of pyridines
that combines a 1,3-dicarbonyl compound, ammonia
and an alkynone without the use of an additional acid
catalyst. The resulting polysubstituted pyridines are
isolated in modest to excellent yield and as single
regioisomers. The advantages that this methodology
offers, in particular for the synthesis of acid-sensitive
targets, have been highlighted by its application in the
total synthesis of dimethyl sulfomycinamate 1 and now
will be extended to prepare components of other thio-
peptide antibiotics.
Having established a one-pot three-component con-
densation method that operates under mild conditions,
this methodology was applied to the synthesis of pyr-
idine 5a, the acid-sensitive intermediate in our total
synthesis of dimethyl sulfomycinamate 1. Although the
MeO2C
O
CO2Me
NH
tBuO
N
t
6a
O Bu
6 steps1
CO2Me
S
N
O
O
NH OAc
4
O
N
N
N
H
CO2Me (81%)
N
CO2Me
N
O
O
O
2
a + tautomer
5a
dimethyl sulfomycinamate 1
9
Scheme 4. Synthesis of pyridines 5a under mild conditions by a one-pot three-component condensation reaction.

6124
X. Xiong et al. / Tetrahedron Letters 45 (2004) 6121–6124
Acknowledgements
8. In a typical procedure, a solution of ethyl acetoacetate 2b
0.13 g, 1.0 mmol), 1-phenylprop-2-yn-1-one 6b (80 mg,
.6 mmol) and ammonium acetate (0.77 g, 10.0 mmol) in
(
0
We are grateful to the Great Britain-China Educational
Trust and Henry Lester Trust Ltd. for their generous
support (award to X.X.) and the E.P.S.R.C. Mass
Spectrometry Service, Swansea for high resolution
spectra.
ethanol (10 mL) was stirred at reflux for 24 h, allowed to
cool and evaporated in vacuo. The residue was partitioned
between saturated aqueous sodium hydrogencarbonate
solution (30 mL) and ethyl acetate (30 mL) and the aqueous
layer was further extracted with ethyl acetate (20 mL). The
combined organic extracts were washed sequentially with
saturated aqueous sodium hydrogencarbonate solution
(20 mL) and brine (20 mL), dried (Na SO ) and evaporated
References and notes
2
4
in vacuo. Purification by column chromatography on silica,
eluting with dichloromethane–light petroleum (1:1) gave
pyridine 5b (0.14 g, 95%), as a pale yellow solid whose
characterization data agreed with literature reports (Ref. 4).
9. A solution of b-ketoamide 2a (35 mg, 0.1 mmol), methyl 4-
(trimethylsilyl)-2-oxobut-3-ynoate 6a (49 mg, 0.25 mmol)
and ammonium acetate (77 mg, 1.0 mmol) in methanol
(10 mL) was stirred at reflux for 5 h, allowed to cool and
evaporated in vacuo. The residue was partitioned between
saturated aqueous sodium hydrogencarbonate solution
(5 mL) and ethyl acetate (8 mL) and the aqueous layer
was further extracted with ethyl acetate (5 mL). The
combined organic extracts were washed sequentially with
saturated aqueous sodium hydrogencarbonate solution
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7
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in vacuo. Purification by column chromatography on silica,
eluting with ethyl acetate–light petroleum (2:1) gave pyri-
dine 5a (36 mg, 81%), as a pale yellow oil whose charac-
terization data agreed with the literature (Ref. 1).