Synthesis of tetrasubstituted pyridines by the acid-catalysed Bohlmann-Rahtz reaction

Article abstract of DOI:10.1039/b203397f

New facile experimental procedures for the preparation of 2,3,4,6-tetrasubstituted pyridines in a single synthetic step have been developed. Thus, an enamino ester and alkynone react by Michael addition-cyclodehydration in a heterocyclisation process that is catalysed by acetic acid, Amberlyst 15 ion exchange resin, zinc(II) bromide or ytterbium(III) triflate. The new one-step Bronsted or Lewis acid-catalysed Bohlmann-Rahtz reaction is a simple, direct and highly expedient method for the synthesis of pyridines that proceeds at a lower reaction temperature and avoids the need to isolate reaction intermediates.

Full text of DOI:10.1039/b203397f

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Synthesis of tetrasubstituted pyridines by the acid-catalysed
Bohlmann–Rahtz reaction
Mark C. Bagley,*a Christian Brace,a James W. Dale,a Maren Ohnesorge,a Nathan G. Phillips,a
Xin Xionga and Justin Bowerb
1
a Department of Chemistry, Cardiff University, PO Box 912, Cardiff, UK CF10 3TB.
E-mail: bagleymc@cf.ac.uk; Fax: ϩ44 29 20874030; Tel: ϩ44 29 20874029
b RiboTargets Ltd., Granta Park, Abington, Cambridge, UK CB1 6GB
Received (in Cambridge, UK) 8th April 2002, Accepted 24th May 2002
First published as an Advance Article on the web 18th June 2002
New facile experimental procedures for the preparation of 2,3,4,6-tetrasubstituted pyridines in a single synthetic
step have been developed. Thus, an enamino ester and alkynone react by Michael addition–cyclodehydration in
a heterocyclisation process that is catalysed by acetic acid, Amberlyst 15 ion exchange resin, zinc() bromide or
ytterbium() triflate. The new one-step Brønsted or Lewis acid-catalysed Bohlmann–Rahtz reaction is a simple,
direct and highly expedient method for the synthesis of pyridines that proceeds at a lower reaction temperature and
avoids the need to isolate reaction intermediates.
Introduction
Simple nitrogen-containing heteroaromatic compounds have
received a large amount of attention in the literature over the
years. They are pharmacophores of considerable historical
importance, have exciting biological properties in their own
right and serve as important synthetic building blocks in drug
discovery.1 The pyridine nucleus has attracted a great deal of
interest, mainly concerning the synthesis, reactions and bio-
logical properties of these heterocycles, as this structural
motif appears in a large number of pharmaceutical agents
and natural products.2 Inevitably, with so many different
Scheme 1 The traditional Bohlmann–Rahtz pyridine synthesis.
methods available to the synthetic chemist to prepare pyridine-
uct usually needs purification, yields are good for this trans-
containing heterocycles, some procedures following their dis-
formation and so the method offers considerable potential for
covery will become largely forgotten. Bohlmann and Rahtz first
application in heterocyclic chemistry. However, avoiding the use
reported a new synthesis of trisubstituted pyridines from ethyl
β-aminocrotonate and ethynyl ketones back in 1957.3 Since that
of high cyclodehydration temperatures, extending this proto-
col for use in the synthesis of tetrasubstituted pyridines and
date only a few reports on the use of this transformation have
developing a single one-step experimental procedure would
appeared in the literature. Moody has described the synthesis of
increase the scope and utility of the Bohlmann–Rahtz reaction.
the modified oxazole–thiazole–pyridine core of the promo-
thiocin antibiotics4–6 using a traditional Bohlmann–Rahtz reac-
We set out to realise these goals by investigating the use of
Brønsted and Lewis acid catalysts for the cyclodehydration of
dienone 3a (R = Me). An acid catalyst should promote the
double bond isomerisation of this intermediate, resulting in
tion and a number of related heterocyclisations have been
reported by Baldwin for the synthesis of novel heterocyclic
substituted α-amino acids.7 These reports establish the great
spontaneous cyclodehydration at a lower reaction temperature,
potential of this reaction in natural product and heterocyclic
and thus obviating the need to isolate the conjugate addition
chemistry but, in spite of these developments, no further
product. If successful, this procedure then could be extended to
improvements on the Bohlmann–Rahtz pyridine synthesis
provide a new and facile one-step method for the synthesis of
have appeared since its discovery and this reaction remains in
very little use today.8 This paper will address this shortfall in
tetrasubstituted pyridines.
Aminoheptadienone 3a was prepared by
a standard
the current literature and describe new mild methods for a
facile one-step Bohlmann–Rahtz pyridine synthesis so that
this under-exploited process can find new use in synthetic
chemistry.9,10
Bohlmann–Rahtz reaction,3 from ethyl β-aminocrotonate 1 and
but-3-yn-2-one 2a in ethanol at 50 ЊC to give the pure cyclo-
dehydration precursor in 98% yield following purification.
However, due to shortages in the availability of butynone 2a,
concerns about its volatility and in order to expand the scope of
the traditional Bohlmann–Rahtz process, an alternative route
to intermediate 3a was sought. A mixture of ethyl β-amino-
crotonate 1 and 4-(trimethylsilyl)but-3-yn-2-one 5a, which was
cheaper than 2a, more readily available and less volatile, was
heated to 50 ЊC in a range of different solvents (Table 1). In
most cases only unreacted starting materials were isolated from
the reaction mixture. However, when a solution of crotonate 1
and butynone 5a was stirred in ethanol or DMSO at 50 ЊC for
Results and discussion
The traditional Bohlmann–Rahtz pyridine synthesis is a two-
step process involving, for example, initial Michael addition of
ethyl β-aminocrotonate 1 and an ethynyl carbonyl compound 2
in ethanol at 50 ЊC. The aminodienone intermediate 3 is isol-
ated and subsequently heated to high temperatures to affect
cyclodehydration to pyridine 4 (Scheme 1).3 Although the prod-
DOI: 10.1039/b203397f
J. Chem. Soc., Perkin Trans. 1, 2002, 1663–1671
This journal is © The Royal Society of Chemistry 2002
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Table 1 Conditions investigated for the Michael addition of 1 and
4-(trimethylsilyl)but-3-yn-2-one 5a in various solvents at 50 ЊC
Table 3 Comparing the three Bohlmann–Rahtz heteroannulation
methods
Solvent
Result
Solvent
Result
Alkynone
R
Product
Method
Catalyst
Yield (%)
Acetone
Toluene
DCM
No reaction
No reaction
No reaction
No reaction
Diethyl ether
Neat
DMSO
No reaction
No reaction
Product 3a (59%)
Product 3a (98%)
2a
2a
2a
2b
2b
2b
Me
Me
Me
Ph
Ph
Ph
4a
4a
4a
4b
4b
4b
A
B
C
A
B
C
None
AcOH
ZnBr2
None
AcOH
ZnBr2
85
77
65
80
85
86
Chloroform
Ethanol
Table 2 The Lewis acid catalysed cyclodehydration of aminodienone
3a
yield, showing that a Lewis acid catalysed one-step Bohlmann–
Rahtz reaction was feasible and warranted subsequent
investigation.
Lewis acid
Conditions
Compound
With a range of successful conditions established for
cyclodehydration at lower reaction temperatures, it remained to
investigate whether these procedures were compatible with the
initial Michael addition and so establish a new Bohlmann–
Rahtz pyridine synthesis that proceeded in a single preparative
step. To this end, a solution of ethyl β-aminocrotonate 1 and
but-3-yn-2-one 2a in toluene was stirred at 50 ЊC for 5.5 h in the
presence of acetic acid, or heated at reflux in the presence of
zinc() bromide, conditions that had promoted the cyclo-
dehydration of dienone intermediate 3a. Under both sets of
conditions, pyridine 4a was formed in a single preparative step;
the reaction catalysed by acetic acid and zinc() bromide gener-
ating the product in 77 and 65% yield, respectively. An excess of
the volatile butynone 3a (2.4 equivalents) was essential for
optimising the yield of the one-pot transformations. Since no
aminoheptadienone intermediate 3a had been isolated from any
of these reactions, we concluded that, in the presence of an acid
catalyst, cyclodehydration occurred spontaneously under the
reaction conditions. The success of these two reactions con-
firmed that the Bohlmann–Rahtz reaction could be catalysed
by either a Brønsted or Lewis acid, affected at a lower cyclo-
dehydration temperature and conducted in a single preparative
step.
BF3ؒOEt2
DCM, reflux, 4 h
DCM, reflux, 3.5 h
DCM, reflux, 24 h
DCM, reflux, 24 h
Toluene, reflux, 5 h
3a (no reaction)
3a,4a (3 : 2)
3a,4a (1 : 3)
4a (46%)
FeCl3 (10 mol%)
Sc(OTf )3 (100 mol%)
ZnBr2 (100 mol%)
ZnBr2 (15 mol%)
4a (59%)
Scheme 2 Reagents: i, EtOH, 50 ЊC, 5 h; ii, 140–150 ЊC (87%);
iii, toluene–AcOH (5 : 1), RT, 2.5 h; then 50 ЊC, 1 h (quant.); iv, ZnBr2
(15 mol%), toluene, reflux, 5 h (59%).
In order to examine the use of a less volatile alkynone in this
reaction, 1-phenylprop-2-yn-1-one 2b was generated by the
oxidation of 1-phenylprop-2-yn-1-ol with o-iodoxybenzoic acid
(IBX)11–13 and reacted with ethyl β-aminocrotonate 1 by the
traditional two-step procedure3 and both of our new one-step
acid-catalysed methods (Scheme 3). All three reactions gave the
5 hours, aminodienone 3a was produced in 98 or 59% yield,
respectively, after purification. In both of these solvents
desilylation occurred spontaneously under the reaction
conditions. In view of the improvements that this transform-
ation offered over the original procedure, this became the
method of choice for the synthesis of aminodienone 3a
(Scheme 2).
When intermediate 3a was heated in the absence of solvent,
according to the standard Bohlmann–Rahtz cyclodehydration
procedure,3 pyridine 4a was generated in 87% yield. This repre-
sented an overall yield for this transformation of 85% from
crotonate 1, including two chromatographic purifications, and
this highlighted the great potential of the traditional procedure
for the synthesis of trisubstituted pyridines. In order to improve
on this process and reduce the temperature of the cyclo-
dehydration reaction, a solution of intermediate 3a was heated
to 50 ЊC in toluene–acetic acid (5 : 1) to generate pyridine 4a in
quantitative yield and without any need for further purification
(Scheme 2). Spectroscopic analysis of 4a determined that it was
indistinguishable from the product formed under the standard
cyclodehydration conditions, namely heating to 160 ЊC and
subsequent chromatographic purification on silica. This finding
represented a considerable breakthrough in the search for a
one-step Bohlmann–Rahtz protocol and confirmed that our
initial premise was well justified.
In the search for alternative methods to affect the cyclo-
dehydration that were compatible with a range of functional
groups, intermediate 3a was reacted with a number of Lewis
acids under a variety of conditions (Table 2). In general, the
Lewis acid catalysed cyclodehydration appeared to be more
sluggish and less efficient than the corresponding reaction
conducted in acetic acid. However, using zinc() bromide
(15 mol%) in toluene at reflux, pyridine 4a was prepared in 59%
Scheme 3 Reagents: A, EtOH, 50 ЊC, 5 h; then 140–160 ЊC; B, toluene–
AcOH (5 : 1), 50 ЊC, 5.5 h; C, ZnBr2 (15 mol%), toluene, reflux, 5.5 h.
desired product 4b in excellent yield, the least efficient route
being the traditional two-step procedure (Table 3). The zinc()
bromide catalysed process generated pyridine 4b in 86% yield
after 5.5 hours at a lower reaction temperature, highlighting the
advantage of our new procedures over existing methodology.
In these initial studies it was apparent that the one-step reac-
tion using but-3-yn-2-one 2a, although more convenient, was
still not as efficient as the traditional Bohlmann–Rahtz method
for this transformation. In a second study of the Bohlmann–
Rahtz heteroannulation reaction that used a less volatile
alkynone, the experiments were repeated using 4-(trimethyl-
silyl)but-3-yn-2-one 5a. One-pot reactions in the presence of
acetic acid or zinc() bromide gave pyridine 6 in 79 or 90%
yield, respectively (Scheme 4). It was noteworthy that, under
these conditions, desilylation did not occur during the course of
the reaction. In contrast, the traditional Bohlmann–Rahtz
annulation generated pyridine 4a in 85% yield over two steps.
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Table 4 The effect of different Lewis acids on the one-pot heteroan-
β-Ketoesters 8a–c were prepared by the homologation of the
nulation reaction
corresponding acid chloride or mixed anhydride by reaction
with magnesium ethyl malonate,14 generated from potassium
ethyl malonate by treatment with methyl magnesium iodide
(Scheme 6). The formation of the required enamino ester was
Lewis acid
Catalyst (mol%)
Reaction time (t/h)
Yield (%)a
None
ZnBr2
ZnBr2
ZnBr2
ZnBr2
ZnBr2
ZnBr2
ZnBr2
ZnBr2
ZnBr2
ZnCl2
ZnCl2
ZnI2
ZnI2
Sc(OTf )3
Tb(OTf )3
Tb(OTf )3
Yb(OTf )3
Yb(OTf )3
—
10
15
15
20
20
30
40
50
100
20
100
20
100
20
20
100
20
18
18
5
18
5
18
5
5
0a
53
90
68
71
82
59
66
57
44
44
42
66
35
60
45
75
90
70
5
5
18
18
18
18
18
18
18
18
18
Scheme 6 Preparation of enamines 7a–d. Reagents: i, MeMgI, THF
then 2-picolinic acid, EtO2CCl, THF; ii, MeMgI, THF then 2-furoyl
chloride; iii, NH4OAc, toluene or benzene–AcOH (5 : 1), reflux; iv, aq
NH3.
100
a Isolated yield of pyridine 6 after column chromatography. b Only
unreacted starting material 1 was isolated.
facilitated by reaction with ammonium acetate–acetic acid
in toluene15,6 to give 7a, 7b and 7c in 60, 41 or 55% overall
yield, respectively. In the case of tert-butyl acetoacetate, reac-
tion with 35% aqueous ammonia in methanol was found to give
superior results,16 generating enamino ester 7d in 96% yield.
Ethyl 2-oxo-4-(trimethylsilyl)- and ethyl 2-oxo-4-phenylbut-3-
ynoate, 9a and 9b, were prepared by the addition of lithium
(trimethylsilyl)acetylide or lithium phenylacetylide, respectively,
generated from the corresponding alkyne by treatment with
n-butyllithium, to Weinreb amide 10 according to the procedure
of Chiu and Jordan (Scheme 7).17 The Weinreb amide 10 was in
turn generated by the reaction of N,O-dimethylhydroxylamine
and ethyl oxalyl chloride at 0 ЊC to provide alkynones 9a
and 9b in moderate yield. This simple procedure provided us
with a library of five alkynones, with commercially available
4-(trimethylsilyl)but-3-yn-2-one 5a, 4-phenylbut-3-yn-2-one 5b
and hex-3-yn-2-one 5c, in order to investigate the scope of the
acid-catalysed Bohlmann–Rahtz heteroannulation reaction.
Scheme 4 Bohlmann–Rahtz annulation reaction using ethyl β-amino-
crotonate 1 and 4-(trimethylsilyl)but-3-yn-2-one 5a.
In order to establish whether any other Lewis acids were cap-
able of promoting this one-pot heteroannulation reaction, a
solution of ethyl β-aminocrotonate 1 and 4-(trimethylsilyl)but-
3-yn-2-one 5a in toluene was heated at reflux overnight in the
presence of 10–100 mol% of a variety of Lewis acid catalysts
(Scheme 5). No reaction occurred in the absence of a Lewis acid
Scheme 5 The Lewis acid catalysed Bohlmann–Rahtz reaction.
catalyst, but in all of the other experiments pyridine 6 was
formed, indicating that Lewis acids promote both Michael
addition and subsequent spontaneous cyclodehydration.
Pyridine 4a could not be isolated from any of the reactions,
confirming that the trimethylsilyl moiety was stable under
Lewis acid catalysed conditions. The efficiency of reaction
varied considerably depending upon the type and quantity of
Lewis acid that was used and the reaction time (Table 4). Only
ytterbium() trifluoromethanesulfonate gave pyridine 6 in a
yield that compared well with zinc() bromide, which seemed to
give optimum yields when used in 15–20 mol% depending upon
the reaction time.
With the success of this facile one-step annulation reaction
firmly established, it remained to investigate the scope and ver-
satility of the acetic acid and Lewis acid catalysed methods. To
this end, a range of enamino esters were prepared and reacted
with a number of different alkynones using the new conditions.
Scheme 7 Preparation of alkynones 9a and 9b. Reagents: i, Et3N,
MeONHMeؒHCl, CH2Cl2, 0 ЊC; ii, PhCCH or Me3SiCCH, n-BuLi,
THF, Ϫ78 ЊC; then 10.
Alkynones 5a–c and 9a,b were reacted with enamino esters
7a–d according to one of the new one-step heteroannulation
procedures, by heating to 50 ЊC in toluene–acetic acid for 5.5 h
(method B), heating a solution in toluene at reflux in the pres-
ence of 15 mol% of zinc() bromide for 5 h (method C) or by
heating at reflux in the presence of 15 mol% of ytterbium()
triflate overnight (method D) (Scheme 8). A representative
number of reactions was carried out (Table 5) and the different
one-step procedures were compared. In almost all of the cases
investigated, the desired pyridine was produced in reasonable
J. Chem. Soc., Perkin Trans. 1, 2002, 1663–1671
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Table 5 Comparing the four one-step heteroannulation methods for the synthesis of pyridines 11–23
Method B
Yield (%)
Method C
Yield (%)
Method D
Yield (%)
Method E
Yield (%)
Enamine
Alkynone
Product
R2
R3
R4
R6
1
5a
5b
5c
9a
9b
2a
5b
5c
9b
5a
5c
5a
5b
5c
6
Me
Me
Me
Me
Me
Ph
Ph
Ph
EtO2C
EtO2C
EtO2C
EtO2C
EtO2C
EtO2C
EtO2C
EtO2C
EtO2C
EtO2C
EtO2C
tBuO2C
tBuO2C
tBuO2C
Me3Si
Ph
Et
Me3Si
Ph
H
Ph
Et
Ph
Me3Si
Et
Me
Me
Me
CO2Et
CO2Et
Me
Me
Me
CO2Et
Me
Me
Me
Me
79
0
90
—
67
44a
85
70
62
72
65
—
62
—
85
70
90
—
83
33
55
58
68
32
44
—
68
—
32
14
—
71
—
—
—
—
—
—
—
73
—
83b
76
80
1
11
12
13
14
15
16
17
18
19
20
21
22
23
1
85
—
95
73
—
65
—
80
—
0
1
1
7a
7a
7a
7a
7b
7c
7d
7d
7d
Ph
2-Furyl
2-Pyridyl
Me
Me
Me
H
Ph
Et
—
—
Me
a Desilylated pyridine (R4 = H) was also produced. b Desilylation occurred during the course of the reaction.
Scheme 8 Examining the scope of the one-step Bohlmann–Rahtz heteroannulation procedure.
yield. Furthermore, it was evident that these new procedures
were appropriate for the formation of tetrasubstituted prod-
ucts, the introduction of a range of different substituents at the
terminal position of the alkyne seeming not to affect the out-
come of these reactions. Out of the two Lewis acid catalysed
procedures (C and D), it appeared that in most instances the
zinc() bromide catalysed method was superior, increasing the
efficiency of reaction dramatically in a much shorter time.
The use of acetic acid or zinc() bromide as catalyst (method B or
C) seemed to give similar results in the majority of cases, verify-
ing that both of these procedures were valuable new one-step
methods for the facile synthesis of tetrasubstituted pyridines.
In addition, it was decided to explore a new milder method
for conjugate addition–cyclodehydration that would be compat-
ible with acid sensitive substrates and that would lend itself well
to combinatorial methodology. In this procedure (method E), a
solution of the alkynone and enamine in toluene was stirred
overnight at 50 ЊC in the presence of Amberlyst 15 ion exchange
resin. Once the reaction was complete, the resin was filtered and
washed to give the crude pyridine product directly in good
yield, even in reactions that failed or performed poorly using
acetic acid as a catalyst. In all cases, this new method compared
favourably with other procedures and its simplicity made it a
compelling alternative to existing methodology.
chromatography was carried out using Merck Kieselgel 60 H
silica or Matrex silica 60. Analytical thin layer chromatography
was carried out using aluminium-backed plates coated with
Merck Kieselgel 60 GF254 that were visualised under UV light
(at 254 and/or 360 nm).
Fully characterised compounds were chromatographically
homogeneous. Melting points were determined on a Kofler hot
stage apparatus. Infra-red spectra were recorded in the range
4000–600 cmϪ1 on a Perkin–Elmer 1600 series FTIR spectro-
meter using KBr disks for solid samples and thin films between
NaCl plates for liquid samples or as a Nujol mull, and are
reported in cmϪ1. NMR spectra were recorded using a Bruker
DPX 400 instrument operating at 400 MHz for 1H spectra and
100 MHz for 13C spectra; J values were recorded in Hz
and multiplicities are expressed by the usual conventions. Low
resolution mass spectra were determined using a Fisons VG
Platform II Quadrupole instrument using electrospray ioniz-
ation (ES) unless otherwise stated. APcI refers to atmospheric
pressure chemical ionization, CI refers to chemical ionization
(ammonia) and EI refers to electron ionization. High resolu-
tion mass spectra were obtained courtesy of the EPSRC Mass
Spectrometry Service at University College of Wales, Swansea,
UK using the ionization methods specified. Microanalyses were
recorded using a Perkin–Elmer 240C Elemental Analyzer.
New modified conditions for Bohlmann–Rahtz pyridine syn-
thesis were successful using either acetic acid, zinc() bromide,
ytterbium() triflate or an acidic ion exchange resin. The
temperature required to affect this heteroannulation reaction
has been reduced but, more importantly, these procedures can
now be conducted in a single preparative step. With a number
of new experimental procedures established, work is now
underway to apply these novel methods to the synthesis of
heterocyclic natural products to be reported in due course.
1-Phenylprop-2-yn-1-one 2b
A solution of o-iodoxybenzoic acid (IBX) (8.50 g, 30.3 mmol)
in DMSO (230 ml) was stirred for 15 min at room temperature
until homogeneous. A solution of 1-phenylprop-2-yn-1-ol
(1.60 g, 12.1 mmol) in DMSO (5 ml) was added and the mixture
was stirred for 5 h. Water (25 ml) was added and the mixture
was stirred at room temperature for 10 min, cooled in ice and
partitioned between water (200 ml) and ether (150 ml). The
mixture was filtered through Celite® and the aqueous layer was
further extracted with ether (120 ml). The organic extracts were
combined, washed sequentially with water (3 × 120 ml), satur-
ated aqueous sodium hydrogen carbonate solution (160 ml) and
brine (160 ml), dried (Na2SO4) and evaporated in vacuo to
give the title compound as a pale yellow solid (1.56 g, 99%),
mp 49–50 ЊC (methanol) (lit.,18 mp 47–48 ЊC) (Found: Mϩ,
Experimental
Commercially available reagents were used without further
purification; solvents were dried by standard procedures. Light
petroleum refers to the fraction with bp 40–60 ЊC and ether
refers to diethyl ether. Unless otherwise stated, reactions
were performed under an atmosphere of dry nitrogen. Flash
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J. Chem. Soc., Perkin Trans. 1, 2002, 1663–1671

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130.0418. C9H6O requires M, 130.0419); νmax(KBr)/cmϪ1 3232,
2094, 1644, 1596, 1579, 1452, 1315, 1265, 1176, 1007 and 697;
δH(400 MHz; CDCl3) 8.10 (2H, m, o-PhH ), 7.57 (1H, m,
p-PhH ), 7.50 (2H, m, m-PhH ), 3.38 (1H, s, 3-H); δC(100 MHz;
CDCl3) 176.4 (C), 135.0 (C), 133.5 (CH), 128.6 (CH), 127.7
(CH), 80.1 (C) and 79.2 (CH); m/z (EI) 130 (83), 102 (100) and
77 (37).
with toluene (2 × 20 ml) and the combined organic layers were
washed sequentially with saturated aqueous sodium hydrogen
carbonate solution (20 ml) and brine (20 ml), dried (MgSO4)
and evaporated in vacuo to give the pyridine product.
General procedure for the one-step Bohlmann–Rahtz reaction
catalysed by zinc(II) bromide (method C)
A solution of the enamine (∼1 mmol, 1 equiv.), alkynone
(1.2 equiv.) and zinc() bromide (15–20 mol%) in toluene (6 ml)
was heated at reflux for 6 h, allowed to cool, washed sequen-
tially with saturated aqueous sodium hydrogen carbonate
solution (6 ml) and brine (6 ml), dried (MgSO4) and evaporated
in vacuo to give the pyridine product.
(4E )-2-Amino-3-ethoxycarbonylhepta-2,4-dien-6-one 3a
A solution of ethyl β-aminocrotonate 1 (0.2 ml, 1.6 mmol) and
but-3-yn-2-one 2a (0.3 ml, 3.8 mmol) or 4-trimethylsilylbut-3-
yn-2-one 5 (0.52 ml, 3.2 mmol) in ethanol (5 ml) was stirred at
50 ЊC for 5 h, cooled and then evaporated in vacuo. Purification
by flash chromatography on silica, eluting with ethyl acetate–
light petroleum (1 : 1), gave the title compound as a yellow solid
(0.28 g, 98%); mp 125.5–126.4 ЊC (light petroleum) (lit.,3 mp
135 ЊC) (Found: C, 60.9; H, 7.6; N, 7.1. Calc. for C10H15NO3: C,
60.5; H, 7.6; N, 7.0%) (Found: MHϩ, 198.1130. C10H15NO3
requires MH, 198.1129); νmax(Nujol)/cmϪ1 3335, 3194, 2924,
1643, 1548 and 1462; δH(400 MHz; CDCl3) 9.59 (1 H, br s, NH),
7.53 (1 H, d, J 15.5, 4-H), 6.50 (1 H, d, J 15.5, 5-H), 5.57 (1 H,
br s, NH), 4.20 (2 H, q, J 7.1, CH2Me), 2.23 (3 H, s, Me), 2.17
(3 H, s, Me), 1.31 (3 H, t, J 7.1, CH2Me); δC(100 MHz; CDCl3)
199.7 (C), 170.5 (C), 166.5 (C), 140.4 (CH), 122.0 (CH), 95.3
(C), 59.9 (CH2), 29.2 (Me), 23.5 (Me) and 15.3 (Me); m/z (APcI)
198 (MHϩ, 9%), 181 (100), 152 (29) and 107 (9).
General procedure for the one-step Bohlmann–Rahtz reaction
catalysed by ytterbium(III) triflate (method D)
A solution of the enamine (∼1 mmol, 1 equiv.), alkynone
(1.2 equiv.) and ytterbium() triflate (15–20 mol%) in toluene
(6 ml) was heated at reflux for 16 h, allowed to cool and water
(6 ml) was added. The mixture was heated at reflux for 20 min
and extracted with ethyl acetate (2 × 10 ml). The organic layers
were combined, washed with brine (6 ml), dried (MgSO4) and
evaporated in vacuo to give the pyridine product.
General procedure for the one-step Bohlmann–Rahtz reaction
catalysed by Amberlyst 15 ion exchange resin (method E)
A solution of the enamine (∼1 mmol, 1 equiv.), alkynone
(1.2 equiv.) and Amberlyst 15 ion exchange resin (0.1 g) in tolu-
ene (4 ml) was stirred at 50 ЊC for 26 h. The mixture was filtered,
the resin was washed with chloroform (5 ml) and the filtrate was
evaporated in vacuo to give the pyridine product.
Cyclodehydration procedure catalysed by acetic acid
A solution of (4E)-2-amino-3-ethoxycarbonylhepta-2,4-dien-6-
one 3a (0.10 g, 0.56 mmol) in toluene–glacial acetic acid (6 ml)
was stirred at room temperature for 2.5 h and then heated to
50 ЊC for 1 h in a flask fitted with a drying tube. The solution
was allowed to cool and partitioned between saturated aqueous
sodium hydrogen carbonate solution (25 ml) and ethyl acetate
(25 ml). The aqueous layer was further extracted with ethyl
acetate (2 × 15 ml) and the organic extracts were combined,
washed with brine (15 ml), dried (MgSO4) and evaporated
in vacuo to give ethyl 2,6-dimethylpyridine-3-carboxylate 4a as a
brown oil (0.10 g, quantitative).
Ethyl 2,6-dimethylpyridine-3-carboxylate 4a
Ethyl β-aminocrotonate 1 (0.13 g, 1.0 mmol) and but-3-yn-2-
one 2a (0.16 g, 2.4 mmol) were reacted according to the two- or
one-step general procedure (method A or B). Purification by
flash chromatography on silica, eluting with light petroleum–
ethyl acetate (3 : 1), gave the title compound as a pale yellow oil
(Found: MHϩ, 180.1024. C10H13NO2 requires MH, 180.1021);
νmax(film)/cmϪ1 2983, 1724, 1593, 1446 and 772; δH(400 MHz;
CDCl3) 8.03 (1 H, d, J 8.0, 4-H), 6.99 (1 H, d, J 8.0, 5-H), 4.29
(2 H, q, J 7.1, CH2), 2.74 (3 H, s, 6-Me), 2.50 (3 H, s, 2-Me),
1.32 (3 H, t, J 7.1, Me); δC(100 MHz; CDCl3) 167.1 (C), 161.6
(C), 159.8 (C), 139.2 (CH), 123.1 (C), 120.8 (CH), 61.4 (CH2),
25.2 (Me), 25.1 (Me) and 14.7 (Me); m/z (APcI) 180 (MHϩ,
100%).
Cyclodehydration procedure catalysed by zinc(II) bromide
A solution of (4E)-2-amino-3-ethoxycarbonylhepta-2,4-dien-
6-one 3a (0.10 g, 0.56 mmol) and zinc() bromide (20 mg,
0.08 mmol) in toluene (6 ml) was heated at reflux for
5 h, allowed to cool and then water (6 ml) was added. The
mixture was stirred for 10 min and extracted with ethyl acetate
(3 × 10 ml). The organic extracts were combined, washed with
brine (10 ml), dried (MgSO4) and evaporated in vacuo to give
ethyl 2,6-dimethylpyridine-3-carboxylate 4a as a brown oil
(0.10 g, quantitative).
Ethyl 2-methyl-6-phenylpyridine-3-carboxylate 4b
Ethyl β-aminocrotonate 1 (0.13 g, 1.0 mmol) and 1-phenylprop-
2-yn-1-one 2b (0.16 g, 1.2 mmol) were reacted according to
the two- or one-step general procedure (method A, B or C).
Purification by flash chromatography on silica, eluting with
dichloromethane–light petroleum (1 : 1), gave the title com-
pound19 as a pale yellow solid, mp 44–45 ЊC (methanol) (lit.,3
mp 44 ЊC) (Found: MHϩ, 242.1182. C15H15NO2 requires MH,
242.1182); νmax(KBr)/cmϪ1 2980, 2925, 2890, 1717, 1581, 1476,
1277, 1090 and 1022; δH(400 MHz; CDCl3) 8.19 (1 H, d, J 8.2,
4-H), 8.00 (2 H, m, o-PhH ), 7.55 (1 H, d, J 8.2, 5-H), 7.41 (3 H,
m, m,p-PhH ), 4.33 (2 H, q, J 7.1, CH2), 2.85 (3 H, s, 2-Me), 1.35
(3 H, t, J 7.1, Me); δC(100 MHz; CDCl3) 165.7 (C), 159.1 (C),
158.1 (C), 138.5 (CH), 137.6 (C), 128.7 (CH), 128.0 (CH), 126.5
(CH), 122.8 (C), 116.5 (CH), 60.3 (CH2), 24.6 (Me) and 13.5
(Me); m/z (APcI) 241 (Mϩ, 91%), 240 (69), 212 (32), 196 (100),
195 (98), 168 (43) and 167 (40).
General procedure for the traditional two-step Bohlmann–Rahtz
reaction (method A)3
A solution of ethyl β-aminocrotonate 1 (∼1 mmol, 1 equiv.) and
alkynone (2.4 equiv.) in ethanol (5 ml) was stirred at 50 ЊC for
5 h, cooled and then evaporated in vacuo to give dienone inter-
mediate 3 as a yellow solid. The residue was heated at 140–
160 ЊC in a flask fitted with a drying tube for 1–2 h and allowed
to cool to give pyridine 4.
General procedure for the one-step Bohlmann–Rahtz reaction
catalysed by acetic acid (method B)
A solution of the enamine (∼1 mmol, 1 equiv.) and alkynone
(1.2–2.4 equiv.) in toluene–glacial acetic acid (5 : 1) (5 ml) was
stirred at 50 ЊC for 6 h. The mixture was partitioned between
toluene (30 ml) and saturated aqueous sodium hydrogen car-
bonate solution (30 ml), the aqueous layer was further extracted
Ethyl 2,6-dimethyl-4-(trimethylsilyl)pyridine-3-carboxylate 6
Ethyl β-aminocrotonate 1 (0.1 g, 0.79 mmol) and 4-(trimethyl-
silyl)but-3-yn-2-one 5a (0.17 ml, 1.0 mmol) were reacted
J. Chem. Soc., Perkin Trans. 1, 2002, 1663–1671
1667

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according to the one-step general procedure (method B, C or
D). Purification by flash chromatography on silica, eluting with
light petroleum–ethyl acetate (3 : 1), gave the title compound as a
pale yellow oil (0.16 g, 79%) (Found: MHϩ, 252.1420. C13H21-
NO2Si requires MH, 252.1420); νmax(film)/cmϪ1 2956, 2903,
1724, 1529, 1104, 1085 and 1016; δH(400 MHz; CDCl3) 7.12
(1 H, s, PyH ), 4.35 (2 H, q, J 7.2, CH2Me), 2.54 (3 H, s, Me),
2.51 (3 H, s, Me), 1.37 (3 H, t, J 7.2, CH2Me), 0.26 (9 H, s,
SiMe3); δC(100 MHz; CDCl3) 171.1 (C), 158.5 (C), 154.9 (C),
149.4 (C), 131.5 (C), 126.6 (CH), 62.1 (CH2), 30.5 (Me), 24.1
(Me) 14.9 (Me) and 0.0 (Me); m/z (APcI) 252 (MHϩ, 100%) and
236 (2).
malonate in THF. The reaction mixture was stirred overnight
at room temperature. Saturated aqueous ammonium chloride
solution (25 ml) was added and the mixture was concentrated in
vacuo. The residue was partitioned between water (25 ml) and
chloroform (75 ml), the aqueous layer was further extracted
with chloroform (2 × 30 ml) and the combined organic extracts
were washed sequentially with glacial acetic acid (5%; 50 ml),
saturated aqueous sodium hydrogen carbonate solution (50 ml)
and brine (50 ml), dried (MgSO4) and evaporated in vacuo to
give a dark oil (1.0 g). Ammonium acetate (4.1 g, 53.19 mmol)
and toluene–glacial acetic acid (5 : 1) (50 ml) were added and
the solution was heated at reflux for 20 h, allowed to cool
and partitioned between saturated aqueous sodium hydro-
gen carbonate solution (100 ml) and ethyl acetate (50 ml).
The aqueous phase was further extracted with ethyl acetate
(2 × 50 ml) and the combined organic extracts were washed
sequentially with saturated aqueous sodium hydrogen carbon-
ate solution (40 ml) and brine (40 ml), dried (MgSO4) and
evaporated in vacuo. Purification by flash chromatography on
silica, eluting with light petroleum–ethyl acetate (3 : 1), gave the
title compound as a colourless oil (0.84 g, 50%) (Found: MHϩ,
193.0977. C10H12N2O2, requires MH, 193.0977); νmax(film)/cmϪ1
3462, 3333, 2980, 1665, 1613, 1545, 1465, 1363, 1312, 1189,
1152, 1096, 1051, 996, 782 and 751; δH(400 MHz; CDCl3) 8.55
(1 H, m, PyH ), 8.2–7.6 (1 H, br s, NH), 7.66 (2 H, m, PyH ),
7.26 (1 H, m, PyH ), 6.80 (1 H, br s, NH), 5.26 (1 H, s, CH), 4.14
(2 H, q, J 7.2, CH2), 1.24 (3 H, t, J 7.2, Me); δC(100 MHz;
CDCl3) 171.0 (C), 155.9 (C), 151.7 (C), 149.2 (CH), 137.2 (CH),
125.1 (CH), 120.6 (CH), 82.6 (CH), 59.4 (CH2) and 15.0 (Me);
m/z (EI) 192 (Mϩ, 37%), 147 (59), 120 (100), 105 (87) and 79
(82).
Ethyl 3-amino-3-phenylpropenoate 7a
A solution of ethyl benzoylacetate 8a (5 ml, 29.0 mmol) and
ammonium acetate (13.4 g, 0.17 mol) was heated at reflux in
toluene–glacial acetic acid (5 : 1) (40 ml) for 20 h. The mixture
was partitioned between water (100 ml) and diethyl ether
(60 ml), the aqueous layer was further extracted with diethyl
ether (2 × 25 ml) and the combined organic layers were washed
sequentially with saturated aqueous sodium hydrogen carbon-
ate solution (50 ml) and brine (25 ml), dried (MgSO4) and
evaporated in vacuo. Purification by flash chromatography on
silica, eluting with light petroleum–ethyl acetate (3 : 1), gave the
title compound as a pale yellow oil (3.32 g, 60%) (Found: MHϩ,
192.1024. C11H13NO2, requires MH, 192.1025); νmax(film)/cmϪ1
3440, 3326, 3066, 2979, 1663, 1556, 796, 772 and 699; δH(400
MHz; CDCl3) 8.50–6.50 (1 H, br s, NH), 7.48 (2 H, m, o-PhH ),
7.35 (3 H, m, m,p-PhH ), 6.1–3.8 (1 H, br s, NH), 4.90, (1 H, s,
CH), 4.11 (2 H, q, J 7.1, CH2), 1.23 (3 H, t, J 7.1, Me); δC(100
MHz, CDCl3) 170.9 (C), 160.9 (C), 138.1 (C), 130.7 (CH), 129.3
(CH), 126.6 (CH), 85.0 (CH), 59.4 (CH2) and 15.0 (Me); m/z
(APcI) 192 (MHϩ, 100%), 186 (36) and 103 (11).
tert-Butyl ꢀ-aminocrotonate 7d
According to a modified literature procedure,16 a solution
of tert-butyl acetoacetate (2 ml, 1.21 mmol) and aqueous
ammonium hydroxide solution (35%; 20 ml) in methanol
(20 ml) was stirred overnight. The solution was concentrated in
vacuo and partitioned between water (20 ml) and ethyl acetate
(20 ml). The aqueous layer was further extracted with ethyl
acetate (3 × 30 ml) and the combined organic layers were
washed with brine (15 ml), dried (Na2SO4) and evaporated
in vacuo to give the title compound16 as a pale yellow oil (0.18 g,
96%) (Found: MHϩ, 158.1183. C8H15NO2 requires MH,
158.1181); νmax(film)/cmϪ1 3448, 3334, 2977, 2925, 1655, 1620,
1565, 1451, 1365, 1298, 1149, 983, 790 and 757; δH(400 MHz;
CDCl3) 7.78 (1 H, br s, NH), 4.43 (1 H, s, CH), 4.39 (1 H, br s,
NH), 1.80 (3 H, s, Me), 1.40 (9H, s, CMe3); δC(100 MHz;
CDCl3) 170.6 (C), 159.3 (C), 86.2 (CH), 78.5 (C), 29.0 (Me) and
22.7 (Me); m/z (EI) 157 (Mϩ, 11%), 101 (53), 83 (100), 57 (35)
and 41 (82).
Ethyl 3-amino-3-(2-furyl)propenoate 7b
A solution of ethyl 3-(2-furyl)-3-oxopropanoate 8b (1.17 g,
6.44 mmol) and ammonium acetate (3.9 g, 50.6 mmol) was
heated at reflux in benzene–glacial acetic acid (5 : 1) (25 ml) for
25 h. The mixture was partitioned between saturated aqueous
sodium hydrogen carbonate solution (50 ml) and diethyl ether
(50 ml), the aqueous layer was further extracted with diethyl
ether (2 × 20 ml) and the combined organic layers were washed
sequentially with saturated aqueous sodium hydrogen carbon-
ate solution (20 ml) and brine (20 ml), dried (MgSO4) and
evaporated in vacuo. Purification by flash chromatography on
silica, eluting with light petroleum–ethyl acetate (3 : 1), gave the
title compound as a dark oil (0.82 g, 70%) (Found: MHϩ,
182.0814. C9H11NO3 requires MH, 182.0817); νmax(film)/cmϪ1
3446, 3334, 3125, 2980, 1662, 1544, 790 and 751; δH(400 MHz;
CDCl3) 7.42 (1 H, m, FuH ), 6.69 (1 H, m, FuH ), 7.20–5.55
(2 H, br s, NH2), 6.41 (1 H, m, FuH ), 5.07 (1 H, s, CH), 4.10
(2 H, q, J 7.2, CH2), 1.22, (3 H, t, J 7.2, Me); δC(100 MHz;
CDCl3) 170.9 (C), 149.7 (C), 149.2 (C), 144.1 (CH), 112.5 (CH),
109.8 (CH), 81.7 (CH), 59.4 (CH2) and 15.0 (Me); m/z (APcI)
182 (MHϩ, 100%), 117 (18), 107 (11) and 59 (2).
Ethyl 3-(2-furyl)-3-oxopropanoate 8b
A solution of methylmagnesium iodide (3 M; 5.79 ml, 17 mmol)
was added dropwise over 15 min to a stirred suspension of ethyl
potassium malonate (2.95 g, 17 mmol) in dry THF (40 ml) at
0 ЊC. The mixture was stirred for 30 min at 0 ЊC, warmed to
room temperature and stirred for a further 2.5 h. 2-Furoyl
chloride (1.10 ml, 0.011 mol) was added dropwise over 10 min
and the solution was stirred overnight at room temperature.
Saturated aqueous ammonium chloride solution (25 ml) was
added, the mixture was concentrated in vacuo and partitioned
between chloroform (75 ml) and water (75 ml). The aqueous
layer was further extracted with chloroform (2 × 25 ml) and the
combined organic layers were washed sequentially with acetic
acid (5%) (25 ml), saturated aqueous sodium hydrogen carbon-
ate solution (25 ml) and brine (25 ml), dried (MgSO4) and
evaporated in vacuo. Purification by flash chromatography on
silica, eluting with light petroleum–ethyl acetate (3 : 1), gave the
title compound as a colourless oil (1.80 g, 58%) (Found: MHϩ,
Ethyl 3-amino-3-(2-pyridyl)propenoate 7c
A solution of methylmagnesium iodide in THF (3 M; 5.3 ml,
16 mmol) was added dropwise over 10 min to a stirred suspen-
sion of ethyl potassium malonate (2.91 g, 16.51 mmol) in dry
THF (35 ml) at 0 ЊC. The mixture was stirred for 30 min,
warmed to room temperature and stirred for a further 2 h to
give a solution of the magnesium enolate of ethyl hydrogen
malonate in THF. Ethyl chloroformate (0.8 ml, 8.37 mmol)
was added dropwise over 5 min to a solution of picolinic acid
(1.08 g, 8.78 mmol) and triethylamine (1.2 ml, 8.61 mmol) in
dry THF at 0 ЊC. The mixture was stirred for 30 min and added
to the solution of the magnesium enolate of ethyl hydrogen
1668
J. Chem. Soc., Perkin Trans. 1, 2002, 1663–1671

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183.0657. C9H10O4 requires MH, 183.0658); νmax(film)/cmϪ1
3135, 2983, 1739, 1677, 1571, 1468, 1393, 1155, 1084, 1027, 915,
884 and 769; δH(400 MHz; CDCl3) 7.55 (1 H, d, J 0.8, FuH ),
7.20 (1 H, t, J 3.7, FuH ), 6.51 (1 H, m, FuH ), 4.14 (2 H, q,
J 7.2, CH2Me), 3.78 (2 H, s, CH2), 1.19 (3 H, t, J 7.2, Me).
δC(100 MHz; CDCl3) 181.5 (C), 167.4 (C), 152.4 (C), 147.5
(CH), 118.8 (CH), 113.1 (CH), 61.9 (CH2), 45.9 (CH2) and 14.5
(Me); m/z (EI) 182 (Mϩ, 15%) and 95 (100).
(2 × 10 ml). The filtrate was evaporated in vacuo and distilled
to give the title compound as a colourless oil (1.54 g, 53%), bp
55–60 ЊC (10 mmHg) (Found: MHϩ, 162.0766. C6H11NO4,
requires MH, 162.0761); νmax(film)/cmϪ1 2985, 2943, 1747 and
1682; δH(400 MHz; CDCl3) 4.28 (2 H, J 7.1, q, CH2), 3.69 (3 H,
s, Me), 3.17 (3 H, s, Me), 1.30 (3 H, J 7.1, t, CH2Me); δC(100
MHz; CDCl3) 162.8 (C), 162.4 (C), 62.7 (Me), 62.5 (Me), 31.8
(CH2) and 14.4 (Me); m/z (APcI) 162 (MHϩ, 100%), 134 (14),
106 (52), 88 (92) and 83 (50).
Ethyl 2-oxo-4-(trimethylsilyl)but-3-ynoate 9a
Ethyl 2,6-dimethyl-4-phenylpyridine-3-carboxylate 11
A solution of n-butyllithium in hexanes (2.5 M; 2.36 ml,
5.9 mmol) was added dropwise over 10 min to a stirred solu-
tion of (trimethylsilyl)acetylene (1.2 ml, 8.5 mmol) in dry
THF (10 ml) at Ϫ78 ЊC. The solution was stirred for 30 min
and added dropwise to a solution of monoethyloxalic acid
N-methoxy-N-methylamide 10 (0.64 g, 4.0 mmol) in dry THF
(10 ml) at Ϫ78 ЊC. The mixture was stirred for 1 h, warmed to
0 ЊC and stirred for a further 2 h. The solution was poured over
ice (30 g), concentrated in vacuo and partitioned between phos-
phoric acid (20%; 60 ml) and diethyl ether (120 ml). The aque-
ous layer was further extracted with diethyl ether (2 × 40 ml)
and the combined organic extracts were washed sequentially
with phosphoric acid (10%; 30 ml), saturated aqueous sodium
hydrogen carbonate solution (20 ml) and brine (20 ml), dried
(MgSO4) and evaporated in vacuo. Purification by flash chrom-
atography on silica, eluting with light petroleum–diethyl ether
(9 : 1) gave the title compound as a dark oil (1.01 g,
60%) (Found: MNH4ϩ, 216.1056. C9H14O3Si requires MNH4,
216.1057); νmax(film)/cmϪ1 2984, 2904, 2149, 1742, 1686, 1447,
1370, 1254, 1101, 1014, 847, 763 and 716; δH(400 MHz; CDCl3)
4.13 (2 H, q, J 7.1, CH2Me), 1.15 (3 H, t, J 7.1, CH2Me), 0.06
(9 H, s, SiMe3); δC(100 MHz; CDCl3) 170.3 (C), 160.0 (C), 107.8
(C), 101.2 (C), 64.3 (CH2), 14.9 (Me) and 0.0 (Me); m/z (CI) 216
(MNH4ϩ, 100%), 123 (19), 96 (13), 90 (42), 52 (64).
Ethyl β-aminocrotonate 1 (0.1 ml, 0.79 mmol) and 4-phenylbut-
3-yn-2-one 5b (0.15 ml, 1.03 mmol) were reacted according to
the one-step general procedure (method E). Purification by
flash chromatography on silica, eluting with light petroleum–
ethyl acetate (3 : 1), gave the title compound as a pale yellow oil
(0.14 g, 71%) (Found: MHϩ, 256.1337. C16H17NO2 requires
MH, 256.1334); νmax(film)/cmϪ1 2978, 2926, 1725, 1587, 1548,
1266, 1206, 1083, 870, 767 and 701; δH(400 MHz; CDCl3) 7.30
(5 H, m, PhH ), 6.94 (1 H, s, PyH ), 4.01 (2 H, q, J 7.1, CH2),
2.54 (3 H, s, Me), 2.50 (3 H, s, Me), 0.90 (3 H, t, J 7.1, CH2Me);
δC(100 MHz; CDCl3) 169.5 (C), 159.1 (C), 155.5 (C), 148.9 (C),
139.2 (C), 128.9 (CH), 128.8 (CH), 128.2 (CH), 126.1 (C), 121.6
(CH), 61.7 (CH2), 24.9 (Me), 23.2 (Me) and 14.0 (Me);
m/z (APcI) 256 (MHϩ, 100%) and 252 (2).
Ethyl 2,6-dimethyl-4-ethylpyridine-3-carboxylate 12
Ethyl β-aminocrotonate 1 (0.1 ml, 0.79 mmol) and hex-3-yn-2-
one 5c (0.1 ml, 0.92 mmol) were reacted according to the one-
step general procedure (method B, C or D). Purification by
flash chromatography on silica, eluting with light petroleum–
ethyl acetate (3 : 1), gave the title compound as a pale yellow oil
(Found: MHϩ, 208.1337. C12H17NO2 requires MH, 208.1335);
δmax(film)/cmϪ1 2975, 2937, 1726, 1595, 1561, 1190 and 1089;
δH(400MHz; CDCl3) 6.85 (1 H, s, PyH ), 4.32 (2 H, q, J 7.1,
OCH2Me), 2.50 (2 H, q, J 7.6, CH2Me), 2.44 (3 H, s, Me), 2.42
(3 H, s, Me), 1.30 (3 H, t, J 7.1, CH2Me), 1.12 (3 H, t, J 7.6,
CH2Me); δC(100 MHz; CDCl3) 169.5 (C), 158.9 (C), 154.7 (C),
151.1 (C), 126.7 (C), 120.7 (CH), 61.6 (CH2), 26.6 (CH2), 24.7
(Me), 23.2 (Me), 15.0 (Me) and 14.5 (Me); m/z (APcI) 208
(MHϩ, 100%).
Ethyl 2-oxo-4-phenylbut-3-ynoate 9b17
A solution of n-butyllithium in hexanes (2.5 M; 2.48 ml, 6.2
mmol) was added dropwise over 10 min to a stirred solution
of phenylacetylene (0.68 ml, 6.2 mmol) in dry THF (15 ml) at
Ϫ78 ЊC. The solution was stirred for 35 min and added drop-
wise to a solution of monoethyloxalic acid N-methoxy-N-
methylamide 10 (1.00 g, 6.21 mmol) in dry THF (30 ml) at
Ϫ78 ЊC. The mixture was stirred for 20 min, poured over ice
(10 g), and partitioned between phosphoric acid (20%; 30 ml)
and diethyl ether (30 ml). The aqueous layer was further
extracted with diethyl ether (2 × 25 ml) and the combined
organic extracts were washed sequentially with phosphoric acid
(10%; 25 ml) and brine (25 ml), dried (MgSO4) and evaporated
in vacuo. Purification by flash chromatography on silica, eluting
with light petroleum–ethyl acetate (6 : 1) gave the title compound
as a yellow oil (1.0 g, 80%) (Found: MNH4ϩ, 220.0974.
C12H10O3 requires MNH4, 220.0967); νmax(film)/cmϪ1 2985,
2204, 1738, 1678, 858, 761 and 688; δH(400 MHz; CDCl3) 7.60
(2 H, J 7.0, d, o-PhH ), 7.45 (1 H, m, p-PhH ), 7.35 (2 H, m,
m-PhH ), 4.34 (2 H, q, J 7.2, CH2), 1.35 (3 H, t, J 7.2, Me);
δC(100 MHz; CDCl3) 170.0 (C), 159.6 (C), 134.2 (CH), 132.3
(CH), 129.2 (CH), 119.4 (C), 98.5 (C), 87.6 (C), 63.7 (CH2) and
14.4 (Me); m/z (CI) 203 (MHϩ, 6%), 176 (8), 175 (100), 105 (22)
and 105 (58).
Diethyl 2-methyl-4-(trimethylsilyl)pyridine-3,6-dicarboxylate 13
Ethyl β-aminocrotonate 1 (0.1 g, 0.79 mmol) and ethyl 2-oxo-4-
(trimethylsilyl)but-3-ynoate 9a (0.2 g, 1.01 mmol) were reacted
according to the one-step general procedure (method C or D).
Purification by flash chromatography on silica, eluting with
light petroleum–ethyl acetate (3 : 1), gave the title compound as a
dark oil (Found: MHϩ, 310.1474. C15H23NO4Si requires MH,
310.1473); νmax(film)/cmϪ1 2982, 1724, 1531, 1447, 1269, 1153,
1026, 955, 847 and 759; δH(400 MHz; CDCl3) 7.94 (1 H, s,
PyH ), 4.31 (2 H, q, J 7.1, CH2), 4.24 (2 H, q, J 7.1, CH2), 2.50
(3 H, s, Me), 1.28 (6 H, app t, J 7.1, Me), 0.17 (9 H, s, SiMe3);
δC(100 MHz; CDCl3) 170.5 (C), 166.3 (C), 155.9 (C),150.6 (C),
147.8 (C), 138.0 (C), 128.4 (CH), 63.1 (CH2), 62.8 (CH2), 24.3
(Me), 15.3 (Me), 15.1 (Me) and 0.0 (Me); m/z (APcI) 310
(MHϩ, 100%).
Diethyl 2-methyl-4-phenylpyridine-3,6-dicarboxylate 14
Ethyl β-aminocrotonate 1 (0.1 ml, 0.79 mmol) and ethyl 2-oxo-
4-phenylbut-3-ynoate 9b (0.21 g, 1.29 mmol) were reacted
according to the one-step general procedure (method B, C or
D). Purification by flash chromatography on silica, eluting with
light petroleum–ethyl acetate (85 : 15), gave the title compound
as a colourless solid, mp 85–86 ЊC (light petroleum) (Found:
C, 69.0; H, 6.1; N, 4.5. C18H19NO4 requires C, 69.4; H, 6.3;
N, 4.6%) (Found: MHϩ, 314.1392. C18H19NO4 requires MH,
314.1388); νmax(Nujol)/cmϪ1 2982, 1730, 1582, 1552, 1148, 1081
Monoethyloxalic acid-N-methoxy-N-methylamide 1017
Triethylamine (5.0 ml, 35.9 mmol) was added over 10 min to a
solution of N,O-dimethylhydroxlamine hydrochloride (1.76 g,
19.9 mmol) and ethyl oxalyl chloride (2 ml, 18.05 mmol) in dry
DCM (30 ml) at 0 ЊC and the mixture was stirred for 40 min.
Methanol (5 ml, 0.12 M) was added and the mixture was
evaporated in vacuo. Tetrahydrofuran (20 ml) was added and
the precipitate was filtered under suction, washing with THF
J. Chem. Soc., Perkin Trans. 1, 2002, 1663–1671
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and 1024; δH(400 MHz; CDCl3) 7.93 (1 H, s, PyH ), 7.36 (5 H,
m, PhH ), 4.42 (2 H, q, J 7.1, CH2), 4.08 (2 H, q, J 7.1, CH2),
2.65 (3 H, s, Me), 1.36 (3 H, t, J 7.1, CH2Me), 0.95 (3 H, t, J 7.1,
CH2Me); δC(100 MHz; CDCl3) 168.6 (C), 165.2 (C), 156.6 (C),
149.4 (C), 148.3 (C), 138.0 (C), 131.7 (C), 129.4 (CH), 129.1
(CH), 128.4 (CH), 123.7 (CH), 62.6 (CH2), 62.2 (CH2), 23.5
(Me), 14.7 (Me) and 14.1 (Me); m/z (APcI) 314 (MHϩ, 100%)
and 268 (1).
title compound as a colourless solid, mp 111–112 ЊC (light
petroleum–ethyl acetate) (Found: C, 73.6; H, 5.7; N, 3.7.
C23H21NO4 requires C, 73.6; H, 5.6; N, 3.4%) (Found: MHϩ,
376.1549. C23H21NO4 requires MH, 376.1550); νmax(Nujol)/
cmϪ1 2925, 1739, 1706, 1246, 1136, 1055, 906, 847, 782, 745 and
700; δH(400 MHz; CDCl3) 8.03 (1 H, s, PyH), 7.59 (2 H, m,
o-PhH), 7.33 (8 H, m, m,p-PhH), 4.41 (2 H, q, J 7.1, OCH2),
3.89 (2 H, q, J 7.1, OCH2), 1.34 (3 H, t, J 7.1, Me), 0.78 (3 H, t,
J 7.1, Me); δC(100 MHz; CDCl3) 168.3 (C), 165.2 (C), 157.7 (C),
150.1 (C), 148.6 (C), 139.4 (C), 137.8 (C), 131.5 (C), 129.5
(CH), 129.5 (CH), 129.1 (CH), 128.8 (CH), 128.5 (CH), 124.5
(CH), 124.5 (CH), 124.5 (CH), 62.6 (CH2), 62.1 (CH2), 14.7
(Me) and 13.8 (Me); m/z (APcI) 376 (MHϩ, 100%), 375 (1) and
270 (2).
Ethyl 6-methyl-2-phenylpyridine-3-carboxylate 15
Ethyl 3-amino-3-phenylpropenoate 7a (0.11 ml, 0.58 mmol)
and but-3-yn-2-one 2a (0.06 ml, 0.77 mmol) were reacted
according to the one-step general procedure (method B, C or
D). Purification by flash chromatography on silica, eluting with
light petroleum–ethyl acetate (3 : 1), gave the title compound as
a pale yellow oil (Found: MHϩ, 242.1181. C15H15NO2 requires
MH, 242.1181); νmax(film)/cmϪ1 2981, 2926, 1718, 1589, 1137,
1052, 838 and 766; δH(400 MHz; CDCl3) 7.93 (1 H, d, J 8.0,
PyH ), 7.37 (5 H, m, PhH), 7.10 (1 H, d, J 8.0, PyH ), 4.03 (2 H,
q, J 7.2, CH2), 2.56 (3 H, s, Me), 0.94 (3 H, t, J 7.2, CH2Me);
δC(100 MHz; CDCl3) 168.6 (C), 161.2 (C), 159.1 (C), 141.0 (C),
138.7 (CH), 129.2 (CH), 128.9 (CH), 128.5 (CH), 124.8 (C),
121.6 (CH), 61.7 (CH2), 27.8 (Me) and 14.0 (Me); m/z (APcI)
242 (MHϩ, 100%) and 214 (1).
Ethyl 2-(2-furyl)-6-methyl-4-(trimethylsilyl)pyridine-3-
carboxylate 19
Ethyl 3-amino-3-(2-furyl)propenoate 7b (0.10 ml, 0.55 mmol)
and 4-(trimethylsilyl)but-3-yn-2-one 5a (0.12 ml, 0.73 mmol)
were reacted according to the one-step general procedure
(method B or E). Purification by flash chromatography on sil-
ica, eluting with light petroleum–ethyl acetate (4 : 1), gave the
title compound as a dark oil (Found: MHϩ, 304.1369.
C16H21NO3Si requires MH, 304.1370); νmax(film)/cmϪ1 2962,
2898, 1727, 1520, 1165, 1087, 1015, 836 and 757; δH(400 MHz;
CDCl3) 7.37 (1 H, m, FuH ), 7.13 (1 H, s, PyH ), 6.90 (1 H, m,
FuH ), 6.43 (1 H, m, FuH ), 4.25 (2 H, q, J 7.1, CH2), 2.52 (3 H,
s, Me), 1.20 (3 H, t, J 7.1, CH2Me), 0.25 (9 H, s, SiMe3); δC(100
MHz; CDCl3) 169.2 (C), 156.9 (C), 147.9 (C), 142.3 (CH), 125.9
(CH), 110.8 (CH), 109.5 (CH), 60.5 (CH2), 23.6 (Me), 13.0 (Me)
and 0.0 (Me); other quaternary carbons not observed; m/z
(APcI) 304 (MHϩ, 1%), 141 (2), 117 (100), 107 (26), 90 (8) and
59 (2).
Ethyl 2,4-diphenyl-6-methylpyridine-3-carboxylate 16
Ethyl 3-amino-3-phenylpropenoate 7a (0.1 g, 0.63 mmol) and
4-phenylbut-3-yn-2-one 5b (0.11 ml, 0.76 mmol) were reacted
according to the one-step general procedure (method C or D).
Purification by flash chromatography on silica, eluting with
light petroleum–ethyl acetate (3 : 1), gave the title compound as
a colourless solid, mp 99–100 ЊC (light petroleum) (Found:
C, 79.5; H, 6.0; N, 4.4. C21H19NO2 requires C, 79.9; H, 6.3; N,
4.4%) (Found: MHϩ, 318.1494. C21H19NO2 requires MH,
318.1496); νmax(Nujol)/cmϪ1 2928, 1722, 1543, 1269, 1205, 1110,
1053, 770, 746 and 701; δH(400 MHz; CDCl3) 7.53 (2 H, m,
PhH ), 7.30 (8 H, m, PhH ), 7.07 (1 H, s, PyH), 3.83 (2 H, q,
J 7.2, CH2), 2.57 (3 H, s, Me), 0.75 (3 H, t, J 7.2, CH2Me);
δC(100 MHz; CDCl3) 169.7 (C), 157.9 (C), 155.5 (C), 147.8 (C),
138.9 (C), 137.3 (C), 127.5 (CH), 127.4 (CH), 127.4 (CH), 127.3
(CH), 127.0 (CH), 124.9 (C), 121.2 (CH), 60.2 (CH2), 23.6 (Me)
and 12.4 (Me); m/z (APcI) 319 (MHϩ, 100%), 305 (1) and
263 (1).
Ethyl 6-methyl-2-(2-pyridyl)-4-ethylpyridine-3-carboxylate 20
Ethyl 3-amino-3-(2-pyridyl)propenoate 7c (0.1 g, 0.52 mmol)
and hex-3-yn-2-one 5c (0.7 ml, 0.64 mmol) were reacted accord-
ing to the one-step general procedure (method C or D). Purifi-
cation by flash chromatography on silica, eluting with light
petroleum–ethyl acetate (3 : 1), gave the title compound as a pale
orange oil (Found MHϩ, 271.1442. C16H18N2O2 requires MH,
271.1447); νmax(film)cmϪ1 2975, 2936, 2876, 1729, 1584, 1474,
1384, 1278, 1086, 777, 745 and 687; δH(400 MHz; CDCl3) 8.50
(1 H, d, J 3.8, 6Ј-PyH ), 8.14 (1 H, d, J 8.0, 3Ј-PyH ), 7.72 (1 H,
t, J 8.0, 4Ј-PyH ), 7.19 (1 H, dd, J 3.8, 8.0, 5Ј-PyH), 7.01 (1 H, s,
5-PyH ), 4.22 (2 H, q, J 7.1, OCH2), 2.65 (2 H, q, J 7.6, CH2),
2.54 (3 H, s, Me), 1.20 (3 H, t, J 7.6, CH2Me), 1.12 (3 H, t, J 7.1,
OCH2Me); δC(100 MHz; CDCl3) 169.8 (C), 158.9 (C), 156.9
(C), 153.8 (C), 152.3 (C), 148.5 (CH), 137.2 (CH), 126.4 (C),
123.7 (CH), 123.2 (CH), 123.1 (CH), 61.5 (CH2), 26.4 (CH2),
24.9 (Me), 15.1 (Me) and 14.4 (Me); m/z (APcI) 271 (MHϩ,
87%), 226 (13) and 225 (100).
Ethyl 4-ethyl-6-methyl-2-phenylpyridine-3-carboxylate 17
Ethyl 3-amino-3-phenylpropenoate 7a (0.1 ml, 0.6 mmol) and
hex-3-yn-2-one 5c (0.08 ml, 0.73 mmol) were reacted according
to the one-step general procedure (method B, C or D). Purifi-
cation by flash chromatography on silica, eluting with light
petroleum–ethyl acetate (3 : 1), gave the title compound as a pale
yellow oil (Found: MHϩ, 270.1494. C17H19NO2 requires MH,
270.1495); νmax(film)/cmϪ1 2976, 2937, 1723, 1555, 1145, 1086,
1015, 918, 870 and 768; δH(400 MHz; CDCl3) 7.48 (2 H, m,
o-PhH ), 7.30 (3 H, m, m,p-PhH ), 6.96 (1 H, s, PyH ), 4.00 (2 H,
q, J 7.6, OCH2Me), 2.63 (2 H, q, J 7.1, CH2Me), 2.52 (3 H, s,
Me), 1.18 (3 H, t, J 7.6, OCH2Me), 0.88 (3 H, t, J 7.1, CH2Me);
δC(100 MHz; CDCl3) 169.5 (C), 159.4 (C), 156.8 (C), 151.9 (C),
140.8 (C), 128.8 (CH), 128.7 (CH), 128.7 (CH), 126.5 (C), 121.8
(CH), 61.7 (CH2), 26.6 (CH2), 25.0 (Me), 15.1 (Me) and
14.0 (Me); m/z (APcI) 270 (MHϩ, 100%), 107 (4), 77 (4) and 59
(49).
tert-Butyl 2,6-dimethylpyridine-3-carboxylate 21
tert-Butyl β-aminocrotonate 7d (0.14 g, 0.89 mmol) and
4-(trimethylsilyl)but-3-yn-2-one 5a (0.19 ml, 1.19 mmol) were
reacted according to the one-step general procedure (method
E). Purification by flash chromatography on silica, eluting with
light petroleum–ethyl acetate (4 : 1), gave the title compound
as a pale yellow oil (0.15 g, 83%) (Found: MHϩ, 208.1337.
C12H17NO2 requires MH, 208.1337); νmax(film)/cmϪ1 2977, 2930,
2856, 1720, 1592, 1568, 1127 and 1083; δH(400 MHz; CDCl3)
7.95 (1 H, d, J 8.0, 4-PyH ), 6.97 (1 H, d, J 8.0, 5-PyH ), 2.71
(3 H, s, Me), 2.51 (3 H, s, Me), 1.53 (9 H, s, CMe3); δC(100 MHz;
CDCl3) 167.0 (C), 161.4 (C), 159.6 (C), 139.5 (CH), 125.2
(C), 121.2 (CH), 82.4 (C), 29.0 (Me), 25.8 (Me) and 25.5 (Me);
m/z (APcI) 208 (MHϩ, 5), 182 (5), 153 (9), 152 (100) and 84
(5).
Diethyl 2,4-diphenylpyridine-3,6-dicarboxylate 18
Ethyl 3-amino-3-phenylpropenoate 7a (0.1 g, 0.63 mmol)
and ethyl 2-oxo-4-phenylbut-3-ynoate 9b (0.12 ml, 0.75 mmol)
were reacted according to the one-step general procedure
(method C or D). Purification by flash chromatography on
silica, eluting with light petroleum–ethyl acetate (3 : 1), gave the
1670
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tert-Butyl 2,6-dimethyl-4-phenylpyridine-3-carboxylate 22
their contribution on an ERASMUS programme. We also
thank Pfizer Limited for their generous support of our research
programmes and the EPSRC Mass Spectrometry Service at the
University of Wales, Swansea for mass spectra.
tert-Butyl β-aminocrotonate 7d (0.1 g, 0.64 mmol) and 3-phenyl-
but-3-yn-2-one 5b (0.1 ml, 0.76 mmol) were reacted according
to the one-step general procedure (method C, D or E). Purifi-
cation by flash chromatography on silica, eluting with light
petroleum–ethyl acetate (4 : 1), gave the title compound as a pale
yellow oil (Found: MHϩ, 284.1650. C18H21NO3 requires MH,
284.1647); νmax(film)/cmϪ1 2976, 2928, 1722, 1588, 1551, 1138,
1089 and 1031; δH(400 MHz; CDCl3) 7.32 (5 H, m, PhH ), 6.91
(1 H, s, PyH ), 2.53 (3 H, s, Me), 2.50 (3 H, s, Me), 1.22 (9 H, s,
CMe3); δC(100 MHz; CDCl3) 168.4 (C), 158.4 (C), 155.0 (C),
148.4 (C), 139.2 (C), 128.7 (CH), 128.7 (CH), 128.6 (CH), 127.5
(C), 121.5 (CH), 82.5 (C), 28.1 (Me), 24.8 (Me) and 23.2 (Me);
m/z (APcI) 284 (MHϩ, 100%) and 250 (1).
References
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tert-Butyl 2,6-dimethyl-4-ethylpyridine-3-carboxylate 23
tert-Butyl β-aminocrotonate 7d (0.1 g, 0.64 mmol) and hex-3-
yn-2-one 5c (0.08 ml, 0.73 mmol) were reacted according to the
one-step general procedure (method C, D or E). Purification by
flash chromatography on silica, eluting with light petroleum–
ethyl acetate (4 : 1), gave the title compound as a pale yellow oil
(Found: MHϩ, 236.1650. C14H21NO2 requires MH, 236.1651);
νmax(film)/cmϪ1 2974, 2932, 1721, 1594, 1562, 1162 and 1092;
δH(400 MHz; CDCl3) 6.83 (1 H, s, PyH ), 2.54 (2 H, q, J 7.6,
CH2Me), 2.45 (3 H, s, Me), 2.44 (3 H, s, Me), 1.53 (9 H, s,
CMe3), 1.14, (3 H, t, J 7.6, CH2Me); δC(100 MHz; CDCl3) 171.2
(C), 160.7 (C), 156.5 (C), 152.6 (C), 130.4 (C), 123.1 (CH), 85.0
(C), 30.8 (Me), 28.8 (CH2), 27.1 (Me), 25.4 (Me) and 17.4 (Me);
m/z (APcI) 236 (MHϩ, 100%), 181 (5) and 180 (60).
17 C. C. Chiu and F. Jordan, J. Org. Chem., 1994, 59, 5763.
18 J. Fetter, I. Nagy, L. T. Giang, M. Kajtár-Peredy, A. Rockenbauer,
L. Korecz and G. Czira, J. Chem. Soc., Perkin Trans. 1, 2001, 1131
and references cited therein.
Acknowledgements
We thank the EPSRC (studentship award to J. W. D.) for
support of this work and Clausthal University Germany for
19 K. Singh, J. Singh and H. Singh, Tetrahedron, 1998, 54, 935.
J. Chem. Soc., Perkin Trans. 1, 2002, 1663–1671
1671