Practical routes to diacetylenic ketones and their application for the preparation of alkynyl substituted pyridines, pyrimidines and pyrazoles

Article abstract of DOI:10.1016/S0040-4020(03)00244-8

Alkynyl substituted pyridines, pyrimidines and pyrazoles have been synthesised by cyclocondensations of diacetylenic ketones with enamines, amidines and hydrazines, respectively.

Full text of DOI:10.1016/S0040-4020(03)00244-8

Tetrahedron 59 (2003) 2197–2205
Practical routes to diacetylenic ketones and their application
for the preparation of alkynyl substituted pyridines,
pyrimidines and pyrazoles
Mauro F. A. Adamo,a † Robert M. Adlington,a Jack E. Baldwin,a Gareth J. Pritchardb
, ,
*
and Richard E. Rathmella
aThe Dyson Perrins Laboratory, Oxford University, South Parks Road, Oxford OX1 3QY, UK
bDepartment of Chemistry, Loughborough University, Epinal Way, Loughborough, Leicestershire LE11 3TU, UK
Received 4 November 2002; revised 23 January 2003; accepted 13 February 2003
Abstract—Alkynyl substituted pyridines, pyrimidines and pyrazoles have been synthesised by cyclocondensations of diacetylenic ketones
with enamines, amidines and hydrazines, respectively. q 2003 Elsevier Science Ltd. All rights reserved.
Heterocycles are widely utilised compounds in both
pharmaceutical and agricultural fields.1 Consequently, the
development of methodologies useful for the assembly of
molecules containing heterocyclic templates continues to
attract the attention of both the academic and industrial
communities. Due to the increasing demand for a large
number of potentially biologically active compounds, we
have been intrigued in pursuing the synthesis of heterocyclic
containing molecules using a parallel synthesis approach.
Our approach has been to synthesise either families of
analogues or different series of compounds starting from a
common synthon.2–5 Such a strategy involves the synthesis
of a reactive intermediate, which can subsequently be
reacted with a number of polynucleophiles. Indeed in the
recent years we have reported the synthesis of a number of
reactive electrophilic chiral synthons derived from the
natural chiral pool as starting materials and their subsequent
application to make heterocycles.2–5 By this route, families
of pyrimidine and isoxazole containing amino acids,2
C-nucleosides,3 non-proteinogenic aminoacids4and kainic
acid analogues5 have been prepared (Fig. 1).
With the need to synthesise diversely substituted hetero-
cycles, we became interested in polyelectrophilic systems
and their reactivity. Diacetylenic ketones such as 1 represent
a class of polyelectrophiles bearing three electrophilic
centres. We have reasoned that when compounds such as 1
were coupled with polynucleophiles, the similar electro-
philic character of the centres 10 and 50 would lead to a
mixture of regioisomeric products. To obviate this problem,
the bis acetylenic ketone 2–4 bearing an ester group at one
end of the acetylenic terminus were designed. We envisaged
that the presence of a strongly electron withdrawing group
would render the two alkynyl moieties inequivalent towards
nucleophilic attack, leading to high regiochemical control
when coupled with suitable nucleophiles. Symmetrical and
asymmetrical diacetylenic ketones of type 1 have been
reported in the literature6,7 and we have recently described a
synthesis of alkynylketones 2–5.8 The high shielding nature
of the alkynyl moieties is illustrated in compounds 2–4 by
the high field shift of the carbonyl carbons as seen in the 13C
NMR (typically 158–159 ppm). This finding is in line with
data reported for similar compounds6b (Fig. 2).
In our previous route8 the carbethoxyester functionality was
introduced as an orthoester, which was subsequently
transformed to the desired ester by treatment with mild
acid. Thus, commercially available trimethylsilylacetylene
Figure 1.
Keywords: heterocycle; pyrimidine; pyrazoles.
*
Corresponding author. Tel.: þ353-1-402-2208; fax: þ353-1-402-2168;
e-mail: madamo@rcsi.ie
Present address: The Royal College of Surgeons in Ireland, 123 St
Stephen’s Green, Dublin 2, Dublin, Ireland.
†
Figure 2.
0040–4020/03/$ - see front matter q 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4020(03)00244-8

2198
M. F. A. Adamo et al. / Tetrahedron 59 (2003) 2197–2205
with the lithium salt of ethyl propinoate 17 furnished
alcohols 18–20 in moderate yields (Scheme 3). We found
that, in these reactions, the method of quenching was critical
in order to isolate the product in reasonable yield. Indeed
raising the temperature above 2508C prior to acid
quenching caused the almost complete decomposition of
the product. However, when the reaction mixture is
quenched at 2788C, alcohols 18–20 can be isolated in
40–45% yield. Alcohols 18–20 were then oxidised using
the TEMPO/Oxonew procedure developed by Bolm.10
Scheme 1. Reagents and conditions: i, 6, n-BuLi, Et2O, 2788C, (EtO)3CBF4,
80%; ii, 7, n-BuLi, THF, 08C; RCuCCHO, 74–80%.
Hence reacting 18–20 with 2.2 equiv. of Oxonew in the
presence of 10 mol% of TEMPO and 30 mol% of
tetrabutylammonium bromide, gave ketones 2–4 in high
yield, uncontaminated by side products.
6 was firstly converted into the alkynyl orthoester 7.9
Subsequent treatment of 7 with n-butyllithium, in THF,
generates an organolithium which could be reacted with a
range of acetylenic aldehydes to give the diynols 8–10 in
excellent yields (Scheme 1). Oxidation of the diynols 8–10
with freshly prepared manganese dioxide gave the acetyl-
enic ketoorthoesters 11–13 in nearly quantitative yields
(Scheme 2).
We also have revisited our reported route to the symmetric
bis-acetylenic ketone 5 bearing two ester functionalities
(Scheme 4).8
Scheme 2. Reagents and conditions: i, MnO2, benzene, 99%; ii, Amberlyst
15w, benzene, RT, 98%.
The orthoesters could then be converted to the ethyl ester by
stirring with Amberlyst 15w resin, to give the required
ketones 2–4. The facile deprotection reaction gave material
that was essentially homogeneous. Further purification was
unnecessary and, indeed, detrimental due to the highly
reactive nature of the products 2–4.
Scheme 4. Reagents and conditions: i, 7, n-BuLi, THF, 08C; 21, THF, RT,
79%; ii, 7, n-BuLi, THF, 08C; 23, THF, RT, 21%; iii, Amberlyst 15w,
benzene, RT, 98%.
We now report a more direct route to desired products 2–4.
Thus, reaction of aryl or alkyl propargylic aldehydes 14–16
In the current study, compound 5 was prepared in three steps
starting from the double Weinreb amide 2111 (Scheme 4).
Addition of lithium alkynoate orthoester 22, generated in
situ from 7 and n-BuLi, to 21 proceeded smoothly to give
the monoacetylenic amide 23 in good isolated yield.
Subsequent reaction of 23 with a second equivalent of 22 led
to the formation of the desired symmetric bis acetylenic
ketone orthoester 24 in low yield, which upon treatment
with Amberlyst 15w resin in benzene was smoothly
deprotected to give 5 in 98% yield. Along with 24, product
25 was also formed in 71% yield.
We have spent some time trying to optimise this reaction.
From the onset it was clear that the addition of N-methoxy-
N-methylamine 27 onto the triple bond was taking place
during the neutral work up procedure. Indeed, reaction of
lithium alkynoate 22 with 23 proceeds via the stabilised
lithium adduct 26, which requires a protic aqueous work up
to eliminate amine 27 in the course of liberating the
Scheme 3. Reagents and conditions: i, 17, n-BuLi, THF, 2788C; 14–16,
THF; NH4Cl, 40–45%; ii, 18–20, Oxonew (2.2 equiv.), TEMPO
(10 mol%), NBu4Br (30 mol%), RT, 91–95%.

M. F. A. Adamo et al. / Tetrahedron 59 (2003) 2197–2205
2199
Scheme 7. Reagents and conditions: i, EtOH, NH2NHR·H2O; 2–5, EtOH,
08C, 10 min, then reflux 1 h.
Table 2. Preparation of functionalised pyrazoles
Scheme 5. Reagents and conditions: i, 7, n-BuLi, THF, 08C; 23, THF, RT.
Substrate Compound
R
R2 Yield of a (%) Yield of b (%)
carbonyl functionality (Scheme 5). However acidic work up
conditions are not compatible with the orthoester function-
alities of 24. Indeed, we have tried a number of quenching
procedures including dilute hydrochloric acid in water,
ammonium chloride in water, ammonium chloride powder,
distilled water and found that none of these was efficient.
The use of a strong acidic condition led to product
decomposition whilst the use of ammonium chloride in
water failed to prevent Michael addition of 27 onto the
acetylenic moiety. We speculated that as the Michael
addition was a bimolecular process, dilution prior to
aqueous work up would slow the rate of formation of 25.
The optimised route was thus obtained by diluting the
reaction mixture by a factor of 6.
2
2
3
3
4
4
5
36
37
38
39
40
41
42
Ph
Ph
Ph
H
48
49
60
51
60
52
35
24
20
20
–
–
–
–
C3H7
C3H7
C4H9
C4H9
CO2Et
Ph
H
Ph
H
H
being the most electron deficient, making this the preferen-
tial site for nucleophilic attack of the amidine. Remarkably
when the bis acetylenic ketoester 5 was used, pyrimidines
34 and 35 were obtained in good yields.
Miller has reported that for symmetrical ketones, after the
initial attack of simple nitrogen nucleophiles, the second
acetylene moiety becomes deactivated towards further
nucleophilic attack, resulting in only mono-addition of the
nucleophile.12 The presence of two equivalent electrophilic
centers in this moiety therefore is not detrimental.
Substitution of N,N0-dimethoxy-N,N0-dimethyl urea 21 by
ethyl-N-methoxy-N-methyl-carbamate in the previously
reported work8 led to 24 in reasonable yield (20–25%).
With a range of diacetylenic ketoesters 2–5 in hand we
examined their reactivity with a range of nitrogen
nucleophiles. Our starting point was to apply the conditions
we had developed for the synthesis of heterocyclic
substituted non-proteinogenic a-amino acids.2
We have also observed that diacetylenic ketoesters 2–5
react well with both substituted and unsubstituted hydra-
zines to give the corresponding pyrazoles 36–42 in good
yield (Scheme 7 and Table 2).13
Thus 2–5 were found to react smoothly with amidines to
yield a range of densely functionalised pyrimidines 28–35
in high yields (Scheme 6 and Table 1). It is worth noting that
compounds 28–35 were obtained as single regioisomers,
attributed to the acetylenic carbon bearing the ester group
When phenylhydrazine was used a mixture of regioisomers
a/b was generated in a 3:1 ratio for compounds 38–39.14
When hydrazine hydrate was used as the nucleophile only
regioisomer a was observed, presumably resulting from
intramolecular hydrogen bonding.
We have also explored the condensation of 2–4 and 5 with
enamines 43 (Scheme 8 and Table 3). Bohlmann and Rahtz
Scheme 6. Reagents and conditions: i, MeCN–H2O, K2CO3; 2–5, MeCN–
H2O.
Table 1. Preparation of functionalised pyrimidines
Substrate
Compound
R
R1
Ph
SMe
Ph
SMe
Ph
SMe
Ph
Yield (%)
Scheme 8. Reagents and conditions: i, EtOH, 43, 2–5, EtOH, reflux, 6 h.
Table 3. Preparation of functionalised pyridines
2
2
3
3
4
4
5
5
28
29
30
31
32
33
34
35
Ph
Ph
90
85
92
90
87
90
80
75
Substrate
Compound
R
Yield (%)
C3H7
C3H7
C4H9
C4H9
CO2Et
CO2Et
2
3
4
5
45
46
47
48
Ph
85
75
78
–
C3H7
C4H9
CO2Et
SMe

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M. F. A. Adamo et al. / Tetrahedron 59 (2003) 2197–2205
have described the cyclocondensation of enamines with
alkynyl ketones to give pyridines in good yields.15
aluminium plates. The plates were visualised using alkaline
potassium permanganate and/or irradiation under low-
frequency ultraviolet light. Flash chromatography was
performed using silica gel 60 (35–75 mm, 200–400 mesh)
as the stationary phase. Experimental details for the
procedures described in Schemes 1 and 2 has been
previously reported.8
Thus reacting ketones 2–4 with enaminones in refluxing
ethanol afforded pyridines 45–47 in good isolated yield.
When the symmetric bis acetylenic ester 5 was used, only a
complex mixture of product was obtained.
We also have reported a route to pyridines employing the
condensation between acetylenic ketones and enamines.2 In
our case it was proved that the enamine adds to the triple
bond to give an isolable adduct, which was subsequently
heated to give the desired pyridine.
1.1. General procedure for the preparation of bis
acetylenic alcohols 18–20
To a stirred solution of ethyl propiolate (500 mg, 5.1 mmol)
in dry THF (8 mL) at 2788C kept under an argon
atmosphere, was added n-butyllithium (2.3 mL, 2.2 M in
hexane, 1 equiv.) over 5 min. The reaction mixture was
stirred (15 min) at 2788C before a solution of aldehyde
14–16 (5.1 mmol, 1 equiv.) in THF (10 mL) was added via
slow addition syringe pump (60 mL/h). The red brown
solution so obtained was stirred at 2788C (30 min) and then
quenched by slow addition of saturated aqueous ammonium
chloride (6 mL). The reaction mixture was then allowed to
reach RT, diluted with diethyl ether (20 mL) and washed
with NaHCO3 sat. in water (10 mL), then twice with water
(10 mL). The organic phase was dried (MgSO4) and the
solvent removed in vacuo. The residue was purified by flash
chromatography to give compounds 18–20.
Hence reacting the acetylenic ketone 2 with enamine 43 at
room temperature led to isolation of adduct 44 in 74% yield
(Scheme 9). Adduct 44 was then condensed to pyridine
45 by heating in refluxing ethanol. The isolation and
characterisation of 44 was critical to the assignment of the
correct regiochemistry for pyridines 45–47.
1.1.1. 4-Hydroxy-6-phenyl-hexa-2,5-diynoic acid ethyl
ester 18. Yellow oil (513 mg, 2.25 mmol, 45% yield);
Rf¼0.25 [light petroleum/EtOAc (10:1)]; nmax (film, cm21
)
3480s (OH), 2959m (CH), 2934m (CH), 2202m (CuC),
1713s (CO2Et); dH (200 MHz, CDCl3) 7.50–7.21 (5H, m,
Ar), 5.50 (1H, s, CCHOHC), 4.50–4.40 (1H, broad, OH),
4.29 (2H, q, J¼7 Hz, OCH2CH3), 1.32 (3H, t, J¼7 Hz,
OCH2CH3); dC (50.3 MHz, CDCl3): 153.34 (CvO), 132.09
(CH), 129.26 (CH), 128.43 (CH), 121.51 (C), 85.93 (Cu),
83.98 (Cu), 83.35 (Cu), 75.64 (Cu), 62.53 (CH2), 52.48
(CH), 14.03 (CH3); HRMS found: MNHþ4 246.1130,
C14H16NO3 requires 246.1130; m/z (APCIþ, NH3) 246
(100%, MNHþ4 ).
Scheme 9. Reagents and conditions: i, EtOH, 2, 43, RT, 2 h, 74%; ii, EtOH,
reflux, 6 h, 84%.
In summary we have shown that it is possible to prepare a
range of highly functionalised pyrimidines 28–35, pyra-
zoles 36–42 and pyridines 45–47 in good yields by reaction
of highly reactive diacetylenic ketones with nitrogen
nucleophiles. As ethyl esters and alkynes are versatile
groups for synthetic manipulation, we believe these
products will be of interest for further synthetic application.
1.1.2. 4-Hydroxy-nona-2,5-diynoic acid ethyl ester 19.
Yellow oil (397 mg, 2.04 mmol, 41% yield); Rf¼0.2 [light
petroleum/EtOAc (10:1)]; nmax (film, cm21) 3438s (OH),
2967m (CH), 2875m (CH), 2237m (CuC), 1716s (CO2Et);
dH (200 MHz, CDCl3) 5.20 (1H, s, CCHOHC), 4.21 (2H, q,
J¼7 Hz, OCH2CH3), 3.70–3.50 (1H, broad, OH), 2.17–
2.11 (2H, m, CH2C2H5), 1.54– 1.32 (2H, m, CH2CH2 CH3),
1.27 (3H, t, J¼7 Hz, OCH2CH3), 0.94 (3H, t, J¼7 Hz,
CH2CH2CH3); dC (50.3 MHz, CDCl3): 153.35 (CvO),
86.93 (Cu), 84.18 (Cu), 73.61 (Cu), 74.84 (Cu), 64.41
(CH2), 51.95 (CH), 21.62 (CH2), 20.06 (CH2), 14.03 (CH3),
13.40 (CH3); HMRS found: MNHþ4 212.1297, C11H18NO3
requires 212.1287; m/z (APCIþ, NH3) 212 (100%, MNH4þ).
1. Experimental
Anhydrous diethyl ether and tetrahydrofuran were freshly
distilled from sodium benzophenone ketyl. Petrol refers to
light petroleum (bp 30–408C). All other solvents used in
reactions were spectroscopic grade and used as received.
Infrared (IR) spectra of thin films or KBr discs were
recorded on a Perkin–Elmer 1750 Fourier transform
spectrometer. Absorption maxima are recorded in wave-
numbers (cm21 s, m, w) relative to a polystyrene standard.
1H NMR spectra were recorded on a Bru¨ker AM20
(200 MHz). Chemical shifts (dH) are reported in parts per
million (ppm) downfield from tetramethylsilane. Coupling
constants (J) are reported in hertz (Hz). 13C NMR spectra
were recorded on a Bru¨ker AM200 (50.3 MHz). Chemical
shifts (dC) are reported in parts per million (ppm) downfield
from tetramethylsilane. Mass spectra were run on a V. G.
Micromass ZAB 1F, V. G. Masslab 20–250 and V.G. Bio-Q
instruments as appropriate. Thin layer chromatography (tlc)
was performed on Merck silica gel 60 F254 0.25 mm
1.1.3. 4-Hydroxy-deca-2,5-diynoic acid ethyl ester 20.
Yellow oil (447 mg, 2.15 mmol, 43% yield); Rf¼0.2 [light
petroleum/EtOAc (10:1)]; nmax (film, cm21) 3417s (OH),
2968m (CH), 2873m (CH), 2240m (CuC), 1715s (CO2Et);
dH (200 MHz, CDCl3) 5.19 (1H, s, CCHOHC), 4.23 (2H, q,
J¼7 Hz, OCH2CH3), 3.40–3.20 (1H, broad, OH), 2.25–
2.15 (2H, m, C3H7CH2), 1.52– 1.31 (4H, m, CH3CH2CH2),
1.26 (3H, t, J¼7 Hz, OCH2CH3), 0.85 (3H, t, J¼7 Hz,

M. F. A. Adamo et al. / Tetrahedron 59 (2003) 2197–2205
2201
CH2CH2CH3); dC (50.3 MHz, CDCl3): 153.35 (CvO),
87.10 (Cu), 84.18 (Cu), 75.41 (Cu), 74.81 (Cu), 62.41
(CH2), 51.93 (CH), 30.20 (CH2), 21.09 (CH2), 18.31 (CH2),
13.98 (CH3), 13.49 (CH3); HRMS found: MNHþ4 226.1441,
C12H20NO3 requires 226.1443; m/z (APCIþ, NH3) 226
(100%, MNHþ4 ).
dry THF (10 mL) and kept at 08C, was added n-butyllithium
(1.05 mL, of a 1.9 M solution in hexanes, 2.0 mmol,
1 equiv.). The resultant solution was allowed to warm to
RT and stir for a further hour before being transferred via
cannular into a solution of N,N0-dimethoxy-N,N0-dimethyl
urea 2111 (270 mg, 2 mmol, 1 equiv.) in dry THF (20 mL) at
2788C. The resultant solution was allowed to stir at this
temperature for 30 min before being allowed to warm to RT
and stirred for a further hour. The mixture was diluted with
ether (20 mL) and washed with water (4£10 mL). The
organic phase was dried (MgSO4) and the solvent removed
in vacuo. The residue was purified by flash chromatography
[30% ethyl acetate in petrol] to give 23 as a colourless liquid
(410 mg, 79% yield). Rf¼0.6 [30% ethyl acetate in petrol];
nmax (film, cm21) 2978m (CH), 2873w (CH), 2239m
(CuC), 1655s (CvO); dH (200 MHz, CDCl3) 3.74 (3H,
s), 3.68 (6H, q, J¼7 Hz, O–CH2CH3), 3.20 (3H, s), 1.21
(9H, t, J¼7 Hz, O–CH2CH3); dC (50.3 MHz, CDCl3)
153.12 (CvO), 108.72 [C(OCH2CH3)3], 84.15 (Cu),
74.61 (Cu), 62.17 (CH2), 59.28 (CH3), 32.23 (CH3),
14.75 (CH3); HMRS found: MNaþ 282.1314,
C12H21NO5Na requires 282.1317; m/z (APCIþ, Na) 282
(100%, MNaþ).
1.2. General procedure for the preparation of bis
acetylenic ketones 2–4
To a stirred solution of bis acetylenic alcohols 18–20
(3 mmol) in toluene (5 mL) were added Oxonew
(2.2 equiv.), tetrabutylammonium bromide (30 mol%) and
TEMPO (10 mol%). The reaction mixture was stirred at RT
for 5 h, then the solids filtered and the solvent removed in
vacuo. The product was then purified by flash chroma-
tography [light petroleum/EtOAc (10:1)] to give compounds
2–4.
1.2.1. 4-Oxo-6-phenyl-hexa-2,5-diynoic acid ethyl ester
2. Colourless oil (644 mg, 2.84 mmol, 95% yield); Rf¼0.5
[light petroleum/EtOAc (10:1)]; nmax (film, cm21) 2984m
(CH), 2204m (CuC), 1720s (CO2Et), 1631s (CvO); dH
(200 MHz, CDCl3) 7.67–7.42 (5H, m, Ar), 4.32 (2H, q,
J¼7 Hz, OCH2CH3), 1.33 (3H, t, J¼7 Hz, OCH2CH3);
dC (50.3 MHz, CDCl3) 159.81 (CvO), 151.99 (CvO),
133.61 (CH), 131.92 (CH), 128.75 (CH), 118.65 (C), 99.93
(Cu), 88.69 (Cu),80.79 (Cu), 78.01 (Cu), 63.17 (CH2),
13.79 (CH3); HMRS found: MHþ 227.0630, C14H11O3
requires 227.0708); m/z (APCIþ, NH3) 182 (100%,
MHþ2OC2H5).
1.2.5. Synthesis of 1,1,1,7,7,7-hexaethoxy-hepta-2,5-diyn-
4-one 24. To a stirred solution of trimethylsilyl ortho-
propiolate triethylester 79 (250 mg, 1.0 mmol) in dry THF
(5 mL) at 08C, was added n-butyllithium (0.55 mL, of a
1.9 M solution in hexanes, 1.0 mmol, 1 equiv.). The
resultant solution was allowed to warm to RT and stirred
for a further hour before being transferred via cannular into
a solution of 4,4,4-triethoxybut-2-ynoic acid methoxy-
methyl-amide 23 (260 mg, 1.0 mmol, 1 equiv.) in dry THF
(10 mL) at 2788C. The resultant solution was allowed to
stir at this temperature for 30 min before being allowed to
warm to RT and stirred for a further hour. The mixture
was diluted with ether (100 mL) and washed with water
(4£20 mL). The organic phase was dried (MgSO4) and the
solvent removed in vacuo. The residue was purified by flash
chromatography [3% diethyl ether in petrol] to give 24 as a
colourless liquid (79 mg, 21% yield). Rf¼0.2 [3% diethyl
ether in petrol]; nmax (film, cm21) 2928m (CH), 2211m
(CuC), 1747m (CvO); dH (200 MHz, CDCl3) 3.67
(12H, q, J¼7 Hz, OCH2CH3), 1.24 (18H, t, J¼7 Hz,
OCH2CH3); dC (50.3 MHz, CDCl3) 158.88 (CvO),
108.56 [C(OCH2CH3)3], 85.77 (Cu), 81.03 (Cu), 59.42
(CH2), 14.66 (CH3); HMRS found: MHþ 371.1991,
C19H31O7 requires 371.2069; m/z (APCIþ, NH3) 194
(100%).
1.2.2. 4-Oxo-nona-2,5-diynoic acid ethyl ester 3. Colour-
less oil (524 mg, 2.72 mmol, 91% yield); Rf¼0.5 [light
petroleum/EtOAc (10:1)]; nmax (film, cm21) 2969m (CH),
2211m (CuC), 1723s (CO2Et), 1635s (CvO); dH
(200 MHz, CDCl3) 4.33 (2H, q, J¼7 Hz, OCH2CH3), 2.42
(2H, t, J¼7 Hz, CH2Cu), 1.63 (2H, sextet, J¼7 Hz,
CH3CH2), 1.30 (3H, t, J¼7 Hz OCH2CH3), 0.99 (3H, t,
J¼7 Hz, CH3CH2 CH2); dC (50.3 MHz, CDCl3) 158.89
(CvO), 151.98 (CvO), 99.41 (Cu), 81.57 (Cu), 80.90
(Cu), 76.98 (Cu), 63.15 (CH2), 21.12 (CH2), 20.87 (CH2),
13.86 (CH3), 13.86 (CH3); HMRS found: MNHþ4 210.1137;
C11H16NO3 requires 210.1130; m/z (APCIþ, NH3) 148
(100%, MHþ2OC2H5).
1.2.3. 4-Oxo-deca-2,5-diynoic acid ethyl ester 4. Colour-
less oil (574 mg, 2.78 mmol, 93% yield); Rf¼0.5 [light
petroleum/EtOAc (10:1)]; nmax (film, cm21) 2928m (CH),
2211m (CuC), 1721s (CO2Et), 1636s (CvO); dH
(200 MHz, CDCl3) 4.33 (2H, q, J¼7 Hz, OCH2CH3), 2.42
(2H, t, J¼7 Hz, CH2Cu), 1.63–1.24 (7H, m, CH3CH2CH2,
OCH2CH3), 0.91 (3H, t, J¼7 Hz, CH3CH2CH2); dC
(50.3 MHz, CDCl3) 158.95 (CvO), 152.02 (CvO), 99.69
(Cu), 81.47 (Cu), 80.93 (Cu), 77.41 (Cu), 63.09 (CH2),
29.28 (CH2), 21.90 (CH2), 18.32 (CH2), 13.95 (CH3), 13.42
(CH3); HMRS found: MNHþ 224.1292, C12H18NO3
requires 224.1287; m/z (APCIþ, NH3) 162 (100%,
MHþ2OC2H5).
1.2.6. 1,1,1,7,7,7-Hexaethoxy-2-(N-methoxy-N-methyl-
amino)-hept-2-en-5-yn-4-one 25. Yellow oil (306 mg,
0.71 mmol, 71% yield); Rf¼0.5 [50% ethyl acetate in
petrol]; nmax (film, cm21) 2970m (CH), 2897m (CH),
2221m (CuC), 1710s (CvO); dH (200 MHz, CDCl3) 5.72
(1H, s, CHvC), 3.68 (6H, q, J¼7 Hz, OCH2CH3), 3.58 (3H,
s, OCH3), 3.49 (6H, q, J¼7 Hz, OCH2CH3), 3.30 (3H, s,
NCH3), 1.18 (18H, t, J¼7 Hz, OCH2CH3); dC (50.3 MHz,
CDCl3): 172.31 (CvO), 151.05 (Cv), 111.06 (CHv),
109.15 (C), 84.32 (Cu), 80.09 (Cu), 59.18 (CH2), 58.41
(CH2), 41.84 (OCH3), 32.25 (NCH3), 14.51 (CH3), 14.26
(CH3); HMRS found: MHþ 432.2596, C21H38NO8 requires
432.2597; m/z (APCIþ) 432 (MHþ, 100%).
1.2.4. Synthesis of 4,4,4-triethoxy-but-2-ynoic acid meth-
oxy-methyl-amide 23. To a stirred solution of trimethyl-
silyl orthopropiolate triethylester 79 (500 mg, 2.0 mmol) in

2202
M. F. A. Adamo et al. / Tetrahedron 59 (2003) 2197–2205
1.2.7. Synthesis of 4-oxo-hepta-2,5-diynedioic acid
diethyl ester 5. Amberlyst 15w (120 mg) was added in
one portion to a stirred solution of 24 (75 mg) in benzene
(10 mL). The resultant suspension was stirred at RT for
15 min before the solids were removed by filtration and the
solvent removed in vacuo to yield a yellow oil (48 mg,
1.3.4. 2-Methylthio-6-pent-1-ynyl-pyrimidine-4-carb-
oxylic acid ethyl ester 31. Yellow oil (47 mg,
0.178 mmol, 90% yield); Rf¼0.5 [light petroleum/EtOAc
(10:1)]; nmax (film, cm21) 2964m (CH), 2930m (CH),
2231m (CuC), 1749s (CO2Et); dH (200 MHz, CDCl3) 7.56
(1H, s, CH), 4.41 (2H, q, J¼7 Hz, OCH2CH3), 2.59 (3H, s,
SCH3), 2.49 (2H, t, J¼7 Hz, CH2–Cu), 1.64 (2H, m,
CH2–CH2–Cu), 1.40 (3H, t, J¼7 Hz, OCH2CH3), 1.04
(3H, t, J¼7 Hz, CH3); dC (50.3 MHz, CDCl3) 173.92
(CvO), 153.18 (C), 152.11 (C), 117.95 (CH), 98.07 (Cu),
83.00 (Cu), 62.49 (CH2), 44.96 (CH2), 21.44 (CH2), 18.65
(CH3), 14.24 (CH2), 14.10 (CH3), 13.58 (CH3); HMRS
found: MHþ 265.0932, C13H17SN2O2 requires 265.1011;
m/z (EI) 265 (100%, MHþ).
97%); Rf¼0.3 [3% diethyl ether in petrol]; nmax (film, cm21
)
2928m (CH), 2223m (CuC), 1725s (CO2Et), 1655s
(CvO); dH (200 MHz, CDCl3) 4.32 (4H, q, J¼7 Hz,
OCH2CH3), 1.35 (6H, t, J¼7 Hz, OCH2CH3); this com-
pound gave unsatisfactory mass spectral data and rapidly
decomposed after being generated.
1.3. General procedure for the preparation of
pyrimidines 28–35
1.3.5. 6-Hex-1-ynyl-2-phenyl-pyrimidine-4-carboxylic
acid ethyl ester 32. Yellow oil (53 mg, 0.172 mmol, 87%
yield); Rf¼0.5 [light petroleum/EtOAc (10:1)]; nmax (film,
cm21) 2959m (CH), 2934m (CH), 2234m (CuC), 1749s
(CO2Et); dH (200 MHz, CDCl3) 8.54–8.49 (2H, m, Ar),
7.86 (1H, s, CH), 7.50–7.45 (3H, m, Ar), 4.49 (2H, q,
J¼7 Hz, OCH2CH3), 2.57 (2H, t, J¼7 Hz, CH2–Cu),
1.86–1.43 (7H, m, CH2CH2CH2–Cu, OCH2CH3), 0.97
(3H, t, J¼7 Hz, CH3); dC (50.3 MHz, CDCl3) 165.39
(CvO), 164.24, 155.49, 136.51, 131.21, 128.64, 128.47,
120.61, 97.68 (Cu), 79.78 (Cu), 62.45 (CH2), 44.96
(CH2), 30.00 (CH2), 22.02 (CH2), 14.15 (CH3), 13.54
(CH3); HMRS found: MHþ 309.1542, C19H21N2O2 requires
309.1603; m/z (EI) 309 (100%, MHþ).
A solution of freshly prepared ketone 2–5 (1.0 equiv.) in
MeCN–H2O [10:1] (50 mg/3 cm3) was added to a stirred
solution of the amidine (1.5 equiv.) and K2CO3 (3.0 equiv.)
in MeCN–H2O [10:1] (100 mg/10 cm3). The resultant deep
red solutions were stirred at room temperature for 30 min
before being absorbed onto silica gel and purified by flash
chromatography [light petroleum/EtOAc (10:1)].
1.3.1. 2-Phenyl-6-phenylethynylpyrimidine-4-carboxylic
acid ethyl ester 28. Yellow oil (56 mg, 0.170 mmol, 85%
yield); Rf¼0.5 [light petroleum/EtOAc (10:1)]; nmax (film,
cm21) 2981m (CH), 2930m (CH), 2217m (CuC), 1749s
(CO2Et); dH (200 MHz, CDCl3) 8.59–8.54 (2H, m, Ar),
7.56 (1H, s, CH), 7.70–7.66 (3H, m, Ar), 7.46–7.41 (5H, m,
Ar), 4.41 (2H, q, J¼7 Hz, O–CH2CH3), 1.49 (3H, t, J¼
7 Hz, OCH2CH3); dC (50.3 MHz, CDCl3) 165.59 (CvO),
164.15, 155.72, 153.13, 136.48, 132.45, 131.35, 130.02,
128.75, 128.58, 120.66, 97.77 (Cu), 87.09 (Cu), 62.55
(CH2), 14.18 (CH3); HMRS found: MHþ 329.1221,
C21H17N2O2 requires 329.1290; m/z (EI) 329 (100%, MHþ).
1.3.6. 6-Hex-1-ynyl-2-methylthio-pyrimidine-4-carb-
oxylic acid ethyl ester 33. Yellow oil (47 mg,
0.169 mmol, 85% yield); Rf¼0.5 [light petroleum/EtOAc
(10:1)]; nmax (film, cm21) 2994m (CH), 2930m (CH),
2232m (CuC), 1749s (CO2Et); dH (200 MHz, CDCl3) 7.55
(1H, s, CH), 4.41 (2H, q, J¼7 Hz, OCH2CH3), 2.58 (3H, s,
SCH3), 2.49 (2H, t, J¼7 Hz, CH2–Cu), 1.66–1.36 (7H, m,
CH2CH2CH2–Cu, OCH2CH3), 0.94 (3H, t, J¼7 Hz, CH3);
dC (50.3 MHz, CDCl3) 173.70 (CvO), 155.04, 153.18,
117.93, 98.25 (Cu), 77.02 (Cu), 62.47 (CH2), 44.11
(CH3), 29.93 (CH2), 21.93 (CH2), 19.18 (CH2), 14.07 (CH3),
13.48 (CH3); HMRS found: MHþ 279.0199, C14H19SN2O2
requires 279.01167; m/z EI) 279 (100%, MHþ).
1.3.2. 2-Methylthio-6-phenylethynyl pyrimidine-4-carb-
oxylic acid ethyl ester 29. Yellow oil (51 mg, 0.170 mmol,
85% yield); Rf¼0.5 [light petroleum/EtOAc (10:1)]; nmax
(film, cm21) 2984m (CH), 2928m (CH), 2215m (CuC),
1727s (CO2Et); dH 7.73 (1H, s, CH), 7.65–7.60 (2H, m, Ar),
7.44–7.39 (3H, m, Ar), 4.45 (2H, q, J¼7 Hz, OCH2CH3),
2.64 (3H, s, SCH3), 1.43 (3H, t, J¼7 Hz, OCH2CH3); dC
(50.3 MHz, CDCl3) 163.65 (CvO), 155.24, 152.76, 132.45,
130.14, 128.53, 121.1, 118.01, 94.66 (Cu), 89.44 (Cu),
62.59 (CH2), 44.96 (SCH3), 14.13 (CH3); HMRS found:
MHþ 299.0790, C16H15SN2O2 requires 299.0854; m/z (EI)
299 (100%, MHþ).
1.3.7. 6-Ethoxycarbonylethynyl-2-phenyl-pyrimidine-4-
carboxylic acid ethyl ester 34. Yellow oil (52 mg,
0.160 mmol, 80% yield); Rf¼0.30 [light petroleum/EtOAc
(10:1)]; nmax (film, cm21) 3019m (CH), 2938m (CH),
2234m (CuC), 1719s (CO2Et); dH (200 MHz, CDCl3)
8.56–8.51 (2H, m, Ar), 8.01 (1H, s, CH), 7.56–7.40 (3H, m,
Ar), 4.53 (2H, q, J¼7 Hz, OCH2CH3), 4.36 (2H, q, J¼7 Hz,
O–CH2CH3), 1.48 (3H, t, J¼7 Hz, CH3), 1.39 (3H, t, J¼
7 Hz, CH3); dC (50.3 MHz, CDCl3) 165.86 (CvO), 163.56
(CvO), 156.40, 152.69, 150.44, 135.86, 131.81, 128.79,
128.63, 121.25, 82.66 (Cu), 80.99 (Cu), 62.88 (CH2),
62.81 (CH2), 14.16 (CH3), 13.99 (CH3); HMRS found:
MHþ 325.1188, C18H17N2O4 requires 325.1188; m/z (EI)
325 (100%, MHþ).
1.3.3. 6-Pent-1-ynyl-2-phenyl-pyrimidine-4-carboxylic
acid ethyl ester 30. Yellow oil (54 mg, 0.183 mmol, 92%
yield); Rf¼0.5 [light petroleum/EtOAc (10:1)]; nmax (film,
cm21) 2964m (CH), 2930m (CH), 2231m (CuC), 1747s
(CO2Et); dH 8.54–8.29 (2H, m, Ar), 7.56 (1H, s, CH), 7.52–
7.27 (3H, m, Ar), 4.48 (2H, q, J¼7 Hz, OCH2CH3), 2.50
(2H, t, J¼7 Hz, CH2–Cu), 1.70 (2H, m, CH2–Cu), 1.47
(3H, t, J¼7 Hz, O–CH2CH3), 1.09 (3H, t, J¼7 Hz, CH3); dC
(50.3 MHz, CDCl3) 165.39 (CvO), 164.24, 153.55, 136.51,
131.24, 128.68, 128.50, 120.64, 97.51 (Cu), 79.94 (Cu),
62.47 (CH2), 44.96 (CH2), 21.52 (CH2), 14.15 (CH3), 13.59
(CH3); HMRS found: MHþ 295.1638, C18H19N2O2 requires
295.1447; m/z (EI) 295 (100%, MHþ).
1.3.8. 6-Ethoxycarbonylethynyl-2-methylsulfanyl-pyrimi-
dine-4-carboxylic acid ethyl ester 35. Yellow oil (47 mg,
0.160 mmol, 80% yield); Rf¼0.30 [light petroleum/EtOAc
(10:1)]; nmax (film, cm21) 3018m (CH), 2933m (CH),

M. F. A. Adamo et al. / Tetrahedron 59 (2003) 2197–2205
2203
2235m (CuC), 1719s (CO2Et); dH (200 MHz, CDCl3) 7.75
(1H, s, CH), 4.43 (2H, q, J¼7 Hz, OCH2CH3), 4.34 (2H, q,
J¼7 Hz, OCH2CH3), 2.61 (3H, s, SCH3), 1.43 (3H, t, J¼
7 Hz, CH3), 1.36 (3H, t, J¼7 Hz, CH3); dC (50.3 MHz,
CDCl3) 174.88 (CvO), 163.04 (CvO), 155.90, 152.54,
150.08, 118.49, 82.96 (Cu), 80.47 (Cu), 62.87 (CH2),
62.81 (CH2), 14.16 (CH3), 13.94 (CH3); HMRS found:
MHþ 295.0754, C13H15N2O4S requires 295.0753; m/z (EI)
295 (100%, MHþ).
yield); Rf¼0.6 [light petroleum/EtOAc (10:1)]; nmax (film,
cm21) 2985m (CH), 2932m (CH), 2244m (CuC), 1732s
(CO2Et); dH (200 MHz, CDCl3) 7.43 (5H, m, Ar), 7.04 (1H,
s, CH), 4.21 (2H, q, J¼7 Hz, OCH2CH3), 2.43 (2H, t,
J¼7 Hz, CH2–Cu), 1.71–1.24 (5H, m, CH2CH2–Cu,
OCH2CH3), 0.94 (3H, t, J¼7 Hz, CH3); dC (50.3 MHz,
CDCl3) 158.46 (CvO), 139.84 (C), 135.82 (C), 133.48 (C),
128.54 (CH), 128.26 (CH), 125.83 (CH), 115.22 (CH),
92.08 (Cu), 72.16 (Cu), 61.04 (CH2), 21.65 (CH2), 21.12
(CH2), 13.73 (CH3), 13.31 (CH3); HMRS found: MHþ
283.1572, C17H19N2O2 requires 283.1447; m/z (EI) 283
(100%, MHþ).
1.4. General procedure for the preparation of pyrazoles
36–42
Phenylhydrazine or hydrazine hydrate (1.5 equiv.) was
slowly added to a cooled (08C) solution of the respective
freshly prepared ketone (1.0 equiv.) in EtOH (50 mg/
10 cm3). The resultant solutions were stirred at this
temperature for 10 min, then heated at reflux for 1 h before
being absorbed onto silica gel and each regioisomer a and b
purified by flash chromatography [light petroleum/EtOAc
(10:1) or light petroleum/EtOAc (1:1)].
1.4.5. 5-Pent-1-ynyl-1-phenyl-1H-pyrazole-3-carboxylic
acid ethyl ester 38b. Yellow oil (11 mg, 0.04 mmol, 20%
yield); Rf¼0.4 [light petroleum/EtOAc (10:1)]; nmax (film,
cm21) 2985m (CH), 2932m (CH), 2244m (CuC), 1732s
(CO2Et); dH (200 MHz, CDCl3) 7.78–7.74 (2H, m, Ar),
7.47–7.42 (3H, m, Ar), 7.03 (1H, s, CH), 4.41 (2H, q, J¼
7 Hz, OCH2CH3), 2.39 (2H, t, J¼7 Hz, CH2–Cu), 1.59–
1.24 (5H, m, CH2CH2–Cu, OCH2CH3), 0.94 (3H, t, J¼
7 Hz, CH3); dC (50.3 MHz, CDCl3) 161.75 (CvO), 143.87
(C), 139.17 (C), 129.34 (C), 128.50 (CH), 128.09 (CH),
126.89 (CH), 113.75 (CH), 98.88 (Cu), 69.12 (Cu), 60.92
(CH2), 21.31 (CH2), 21.25 (CH2), 14.12 (CH3), 13.80
(CH3); HMRS found: MHþ 283.1572, C17H19N2O2 requires
283.1447; m/z (EI) 283 (100%, MHþ).
1.4.1. 2-Phenyl-5-phenylethynyl-2H-pyrazole-3-carboxylic
acid ethyl ester 36a. Yellow oil (30 mg, 0.09 mmol, 48%
yield); Rf¼0.6 [light petroleum/EtOAc (10:1)]; nmax (film,
cm21) 2985m (CH), 2932m (CH), 2244m (CuC), 1732s
(CO2Et); dH (200 MHz, CDCl3) 7.59–7.34 (11H, m, Ar and
CH), 4.28 (2H, q, J¼7 Hz, OCH2CH3), 1.22 (3H, t, J¼7 Hz,
OCH2CH3); dC (50.3 MHz, CDCl3) 159.51 (CvO), 148.6
(C), 139.71 (C), 132.71 (CH), 129.15 (CH), 128.22 (CH),
128.10 (CH), 126.11 (C), 126.00 (CH), 122.98 (C), 118.23
(CH), 110.00 (CH), 92.73 (Cu), 89.68 (Cu), 59.10 (CH2),
13.61 (CH3); HMRS found: MHþ 317.1233, C20H17N2O2
requires 317.1290; m/z (EI) 317 (100%, MHþ).
1.4.6. 5-Pent-1-ynyl-2H-pyrazole-3-carboxylic acid ethyl
ester 39. Yellow oil (21 mg, 0.102 mmol, 51% yield);
Rf¼0.5 [light petroleum/EtOAc (1:1)]; nmax (film, cm21
)
3343m (NH), 2985m (CH), 2932m (CH), 2234m (CuC),
1725s (CO2Et); dH (200 MHz, CDCl3) 6.87 (1H, s, CH),
4.36 (2H, q, J¼7 Hz, OCH2CH3), 2.41 (2H, t, J¼7 Hz,
CH2Cu), 1.58–1.24 (5H, m, CH2CH2Cu, OCH2CH3),
0.91 (3H, t, J¼7 Hz, CH3); dC (50.3 MHz, CDCl3) 158.65
(CvO), 139.92 (C), 135.95 (C), 115.39 (CH), 92.48 (Cu),
72.11 (Cu), 61.28 (CH2), 30.39 (CH2), 19.01 (CH2), 13.95
(CH3), 13.59 (CH3); HMRS found: MHþ 207.1055,
C11H15N2O2 requires 207.1134; m/z (EI) 207 (100%, MHþ).
1.4.2. 1-Phenyl-5-phenylethynyl-1H-pyrazole-3-carboxylic
acid ethyl ester 36b. Yellow oil (15 mg, 0.05 mmol, 24%
yield); Rf¼0.4; nmax (film, cm21) 2985m (CH), 2932m
(CH), 2244m (CuC), 1732s (CO2Et); dH (200 MHz,
CDCl3) 7.59–7.34 (11H, m, Ar and CH), 4.48 (2H, q, J¼
7 Hz, OCH2CH3), 1.43 (3H, t, J¼7 Hz, OCH2CH3); dC
(50.3 MHz, CDCl3) 165.49 (CvO), 140.92 (C), 139.18 (C),
134.87 (C), 132.70 (CH), 129.30 (CH), 128.25 (CH), 127.03
(CH), 126.22 (CH), 122.76 (C), 118.30 (CH), 110.73 (CH),
84.96 (Cu), 78.12 (Cu), 59.16 (CH2), 13.48 (CH3); HMRS
found: MHþ 317.1233, C20H17N2O2 requires 317.1229;
m/z(EI) 317 (100%, MHþ).
1.4.7. 5-Hex-1-ynyl-2-phenyl-2H-pyrazole-3-carboxylic
acid ethyl ester 40a. Yellow oil (35 mg, 0.120 mmol,
60% yield); Rf¼0.6 [light petroleum/EtOAc (10:1)]; nmax
(film, cm21) 2985m (CH), 2932m (CH), 2244m (CuC),
1732s (CO2Et); dH (200 MHz, CDCl3) 7.43 (5H, m, Ar),
7.04 (1H, s, CH), 4.21 (2H, q, J¼7 Hz, OCH2CH3),
2.43 (2H, t, J¼7 Hz, CH2Cu), 1.71–1.24 (7H, m,
CH2CH2CH2Cu, OCH2CH3), 0.94 (3H, t, J¼7 Hz, CH3);
dC (50.3 MHz, CDCl3) 158.52 (CvO), 139.81 (C), 135.84
(C), 133.46 (C), 128.67 (CH), 128.37 (CH), 125.88 (CH),
115.29 (CH), 92.35 (Cu), 72.03 (Cu), 61.18 (CH2), 30.28
(CH2), 21.87 (CH2), 18.90 (CH2), 13.85 (CH3), 13.50
(CH3); HMRS found: MHþ 297.1542, C18H21N2O2 requires
297.1603; m/z (EI) 297 (100%, MHþ).
1.4.3. 5-Phenylethynyl-2H-pyrazole-3-carboxylic acid
ethyl ester 37. Yellow oil (23 mg, 0.09 mmol, 49%
yield); Rf¼0.5 [light petroleum/EtOAc (1:1)]; nmax (film,
cm21) 3343m (NH), 2985m (CH), 2932m (CH), 2234m
(CuC), 1725s (CO2Et); dH (200 MHz, CDCl3) 7.61–7.41
(5H, m, Ar), 7.34 (1H, s, CH), 4.41 (2H, q, J¼7 Hz,
OCH2CH3), 1.49 (3H, t, J¼7 Hz, OCH2CH3); dC
(50.3 MHz, CDCl3) 165.85 (CvO), 141.33 (C), 133.95
(C), 132.09 (CH), 128.11 (CH), 128.01 (CH), 122.92 (C),
105.39 (CH), 84.36 (Cu), 78.11 (Cu), 61.28 (CH2), 13.59
(CH3); HMRS found: MHþ 241.0899, C14H13N2O2 requires
241.0977; m/z (EI) 241 (100%, MHþ).
1.4.8. 5-Hex-1-ynyl-2-phenyl-1H-pyrazole-3-carboxylic
acid ethyl ester 40b. Yellow oil (12 mg, 0.04 mmol, 20%
yield); Rf¼0.4 [light petroleum/EtOAc (10:1)]; nmax (film,
cm21) 2985m (CH), 2932m (CH), 2244m (CuC), 1732s
(CO2Et); dH (200 MHz, CDCl3) 7.78–7.74 (2H, m, Ar),
7.47–7.42 (3H, m, Ar), 7.03 (1H, s, CH), 4.41 (2H, q,
J¼7 Hz, OCH2CH3), 2.39 (2H, t, J¼7 Hz, CH2Cu),
1.4.4. 5-Pent-1-ynyl-2-phenyl-2H-pyrazole-3-carboxylic
acid ethyl ester 38a. Yellow oil (34 mg, 0.120 mmol, 60%

2204
M. F. A. Adamo et al. / Tetrahedron 59 (2003) 2197–2205
1.59–1.24 (7H, m, CH2CH2CH2Cu, OCH2CH3), 0.94 (3H,
t, J¼7 Hz, CH3); dC (50.3 MHz, CDCl3) 161.90 (CvO),
143.84 (C), 139.20 (C), 128.65 (C), 128.26 (CH), 127.03
(CH), 124.15 (CH), 113.85 (CH), 99.18 (Cu), 69.06 (Cu),
61.11 (CH2), 29.97 (CH2), 21.78 (CH2), 19.07 (CH2), 14.29
(CH3), 13.44 (CH3); HMRS found: MHþ 297.1542,
C18H21N2O2 requires 297.1603; m/z (EI) 297 (100%, MHþ).
solutions were heated at reflux for 6 h before being absorbed
onto silica gel and purified by flash chromatography [light
petroleum/EtOAc (10:1)].
1.5.1. 2-Methyl-6-phenylethynyl-pyridine-3,4-dicarb-
oxylic acid 4-ethyl ester 3-methyl ester 45. Colourless
oil (55 mg, 0.170 mmol, 85% yield); Rf¼0.8 [light petro-
leum/EtOAc (10:1)]; nmax (film, cm21) 3020m (CH), 2968m
(CH), 2230m (CuC), 1730s (CO2R); dH (200 MHz, CDCl3)
7.85 (1H, s, CH), 7.70–7.55 (2H, m, Ar), 7.50–7.30 (3H, m,
Ar), 4.43 (2H, q, J¼7 Hz, OCH2CH3), 3.95 (3H, s, OCH3),
2.61 (3H, s, CH3Cv), 1.43 (3H, t, J¼7 Hz, OCH2CH3); dC
(50.3 MHz, CDCl3) 168.48 (CvO), 164.44 (CvO), 157.02
(C), 144.39, 136.67, 132.41, 129.62, 128.63, 127.43,
124.01, 121.82, 91.36 (Cu), 87.82 (Cu), 62.44 (CH2),
52.85 (OCH3), 22.50 (CH3Cv), 13.91 (CH3); HMRS
found: MHþ 324.1230, C19H18NO4 requires 324.1236; m/z
(EI) 324 (100%, MHþ).
1.4.9. 5-Hex-1-ynyl-2H-pyrazole-3-carboxylic acid ethyl
ester 41. Yellow oil (23 mg, 0.104 mmol, 52% yield);
Rf¼0.5 [light petroleum/EtOAc (1:1)]; nmax (film, cm21
)
3343m (NH), 2985m (CH), 2932m (CH), 2234m (CuC),
1725s (CO2Et); dH (200 MHz, CDCl3) 6.87 (1H, s, CH),
4.36 (2H, q, J¼7 Hz, OCH2CH3), 2.41 (2H, t, J¼7 Hz,
CH2–Cu), 1.58–1.24 (7H, m, CH2CH2CH2–Cu,
OCH2CH3), 0.91 (3H, t, J¼7 Hz, CH3); dC (50.3 MHz,
CDCl3) 158.65 (CvO), 139.92 (C), 135.95 (C), 115.39
(CH), 92.48 (Cu), 72.11 (Cu), 61.28 (CH2), 30.39 (CH2),
21.97 (CH2), 19.01 (CH2), 13.95 (CH3), 13.59 (CH3);
HMRS found: MHþ 221.1232, C12H17N2O2 requires
221.1290; m/z (EI) 221 (100%, MHþ).
1.5.2. 2-Methyl-6-pent-1-ynyl-pyridine-3,4-dicarboxylic
acid 4-ethyl ester 3-methyl ester 46. Colourless oil (43 mg,
0.148 mmol, 75% yield); Rf¼0.5 [light petroleum/EtOAc
(10:1)]; nmax (film, cm21) 3020m (CH), 2968m (CH),
2233m (CuC), 1731s (CO2R); dH (200 MHz, CDCl3) 7.68
(1H, s, CH), 4.36 (2H, q, J¼7 Hz, OCH2CH3), 3.91 (3H, s,
OCH3), 2.57 (3H, s, CH3Cv), 2.43 (2H, t, J¼7 Hz,
CH2Cu), 1.65 (2H, sextet, J¼7 Hz, J¼7 Hz,
CH3CH2CH2Cu), 1.37 (3H, t, J¼7 Hz, CH3CH2O),
1.08–1.01 (3H, t, J¼7 Hz, CH3CH2 CH2); dC (50.3 MHz,
CDCl3) 168.37 (CvO), 164.34 (CvO), 156.74 (C), 144.78
(C), 136.41 (C), 126.86 (C), 123.41 (CH), 93.54 (Cu),
79.83 (Cu), 62.49 (CH2), 52.94 (OCH3), 22.62 (CH3Cv),
21.72 (CH2), 21.47 (CH2), 14.13 (CH3), 13.71 (CH3);
HMRS found: MHþ 290.1391, C16H20NO4 requires
290.1392; m/z (EI) 290 (100%, MHþ).
1.4.10. 5-Ethoxycarbonylethynyl-2H-pyrazole-3-carb-
oxylic acid ethyl ester 42. Yellow oil (16 mg,
0.067 mmol, 35% yield); Rf¼0.51 [light petroleum/EtOAc
(1:1)]; nmax (film, cm21) 3264m (NH), 2981m (CH),
2934m (CH), 2235m (CuC), 1712s (CO2Et); dH
(200 MHz, CDCl3) 7.11 (1H, s, CH), 4.43 (2H, q, J¼
7 Hz, OCH2CH3), 4.32 (2H, q, J¼7 Hz, OCH2CH3),
1.7–1.6 (1H, broad, NH), 1.42 (3H, t, J¼7 Hz, CH3), 1.37
(3H, t, J¼7 Hz, CH3); dC (50.3 MHz, CDCl3) 159.15
(CvO), 153.30 (CvO), 131.02 (C), 128.22 (C), 114.19
(CH), 97.03 (Cu), 82.95 (Cu), 62.36 (CH2), 61.79 (CH2),
14.10 (CH3), 13.91 (CH3); HMRS found: MHþ 237.0870,
C11H13N2O4 requires 237.0875; m/z (EI) 237 (100%, MHþ).
1.4.11. Synthesis of 2-(1-amino-ethylidene)-3-(2-oxo-4-
phenyl-but-3-ynylidene)-succinic acid 4-ethyl ester
1-methyl ester 44. 3-Amino-but-2-enoic acid methyl ester
43 (27 mg, 0.24 mmol, 1.2 equiv.) was added to a stirred
solution freshly prepared ketone 2 (45 mg, 0.20 mmol,
1.0 equiv.) in EtOH (5 cm3). The resultant solution was
stirred for 2 h at RT before being absorbed onto silica gel
and purified by flash chromatography [light petroleum/
EtOAc (10:1)]. Yellow oil (53 mg, 0.170 mmol, 85% yield);
1.5.3. 6-Hex-1-ynyl-2-methyl-pyridine-3,4-dicarboxylic
acid 4-ethyl ester 3-methyl ester 47. Colourless oil
(47 mg, 0.155 mmol, 78% yield); Rf¼0.5 [light petroleum/
EtOAc (10:1)]; nmax (film, cm21) 3020m (CH), 2968m
(CH), 2233m (CuC), 1731s (CO2R); dH (200 MHz, CDCl3)
7.68 (1H, s, CH), 4.35 (2H, q, J¼7 Hz, OCH2CH3), 3.93
(3H, s, OCH3), 2.61 (3H, s, CH3Cv), 2.46 (2H, t, J¼Hz,
CH2Cu), 1.73–1.44 (4H, m, CH3CH2CH2), 1.37 (3H, t,
J¼7 Hz, CH3CH2O), 0.95 (3H, t, J¼7 Hz, CH3CH2CH2);
dC (50.3 MHz, CDCl3) 168.3 (CvO), 164.3 (CvO), 156.6
(C), 144.7 (C), 136.4 (C), 126.8 (C), 123.4 (CH), 93.7 (Cu),
79.7 (Cu), 62.4 (CH2), 52.8 (OCH3), 30.3 (CH2), 22.6
(CH3), 22.1 (CH2), 19.2 (CH2), 14.1 (CH3), 13.6 (CH3).
HMRS found: MHþ 304.1549, C17H22NO4 requires
304.1549; m/z (EI) 304 (100%, MHþ).
Rf¼0.6 [light petroleum/EtOAc (1:1)]; nmax (film, cm21
)
3090s (NH), 2975m (CH), 2901m (CH), 2215m (CuC),
1730s (CO2R); dH (200 MHz, CDCl3) 8.85 (1H, s, NH),
7.60–7.50 (2H, m, Ar), 7.40–7.20 (3H, m), 6.95 (1H, s,
CH), 5.45 (1H, s, NH), 4.27 (2H, q, J¼7 Hz, OCH2CH3),
3.62 (3H, s, CH3O), 1.83 (3H, s, CH3Cv), 1.25 (3H, t, J¼
7 Hz, OCH2CH3); dC (50.3 MHz, CDCl3) 177.90 (CvO),
168.54 (CvO), 168.10 (CvO), 142.39 (C), 135.37 (CH),
133.61 (CH), 130.82 (CH), 128.63 (CH), 120.03 (C), 93.20
(C), 90.90 (Cu), 88.52 (Cu), 61.84 (CH2), 50.95 (OCH3),
20.80 (CH3Cv), 14.21 (CH3); HMRS found: MHþ 342.1342,
C19H20NO5 requires 342.1341; m/z (EI) 342 (MHþ).
Acknowledgements
We thank F. Hoffmann-La Roche (Basle) for financial
support to R. E. R. and M. F. A. A.
1.5. General preparation of pyridines 45–47
3-Amino-but-2-enoic acid methyl ester 43 (1.2 equiv.) was
added to a stirred solution of the respective freshly prepared
ketone (1.0 equiv.) in EtOH (50 mg/5 cm3). The resultant
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