The reactions of diacetylenic ketones with nitrogen nucleophiles; facile preparation of alkynyl substituted pyrimidines and pyrazoles

Article abstract of DOI:10.1039/b108645f

Alkynyl substituted pyrimidines and pyrazoles have been synthesized by cyclocondensations of diacetylenic ketones with amidines and hydrazines.

Full text of DOI:10.1039/b108645f

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The reactions of diacetylenic ketones with nitrogen nucleophiles;
facile preparation of alkynyl substituted pyrimidines and pyrazoles
Jack E. Baldwin,*a Gareth J. Pritchardb and Richard E. Rathmella
1
a The Dyson Perrins Laboratory, Oxford University, South Parks Road, Oxford, UK OX1 3QY
b Department of Chemistry, Loughborough University, Epinal Way, Loughborough,
UK LE11 3TU. E-mail: jack.baldwin@chem.ox.ac.uk
Received (in Cambridge, UK) 27th September 2001, Accepted 15th October 2001
First published as an Advance Article on the web 26th October 2001
Alkynyl substituted pyrimidines and pyrazoles have been
synthesized by cyclocondensations of diacetylenic ketones
with amidines and hydrazines.
As part of an ongoing program to develop novel routes to
various heterocyclic structures, we describe here the facile
preparation of alkynyl substituted pyrimidines and pyrazoles.
We recently reported a range of reactive electrophiles, which
undergo facile reactions with various nucleophiles to form a
heterocycle.1–6 Initial work has been on a novel route to hetero-
cyclic, substituted non-proteinogenic α-amino acids. The route
made use of the reaction of α-amino acid substituted alkynyl
ketones with a range of nucleophiles to form the hetero-
cyclic ring system.1,2 We have also reported the use of similar
chemistry to generate a range of novel C-nucleosides.3 Other
related work makes use of vicinal tricarbonyls as the reactive
core permitting the synthesis of novel non-proteinogenic α-
amino acids.4 Two new approaches to novel C-4 heteroaromatic
Scheme 2 Reagents and conditions: i, MnO2, benzene, RT, 90 min,
kainoid analogues have also been reported, both routes make
use of key reactive precursors to introduce a variety of hetero-
aromatic rings.5,6
99%; ii, Amberlyst 15, benzene, RT, 98%.
ketones 9–11. The facile deprotection reaction gives material
that is essentially homogeneous. Further purification was
unnecessary and unreliable due to the highly reactive nature of
the products 9–11.
With a range of diacetylenic ketoesters in hand we were now
able to examine reactions 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 α-amino acids.1,2 Thus diacetylenic ketoesters
9–11 reacted smoothly with amidines to yield a range of densely
functionalised pyrimidines 12–18 in excellent yields (Scheme 3
and Table 1).
We now wish to describe our related studies on diacetylenic
ketones 9–11. We have recently reported a route to unsym-
metrical diacetylenic ketoesters.7 The chemistry reported makes
use of orthoesters, which can be removed under very mild con-
ditions to give ethyl esters.8 Our route makes use of chemistry
developed by Boche.9 Thus treatment of (trimethylsilyl)acetyl-
ene 1 with n-butyllithium in diethyl ether at low temperature
and reaction with triethoxycarbenium tetrafluoroborate gave 2
in good yield.10 Treatment of 2 with n-butyllithium, in THF,
generates the organolithium which can be reacted with a range
of acetylenic aldehydes to give the diynols 3–5 in excellent
yields (Scheme 1).
Scheme 1 Reagents and conditions: i, n-BuLi, Et2O, Ϫ78 ЊC; (EtO)3-
CBF4, 80%; ii, n-BuLi, THF, Ϫ0 ЊC; RCCCHO, 74–80%.
With a good route established to alcohols 3–5 we now looked
at oxidation routes to the ketones. We found, after some
experimentation, that freshly prepared manganese dioxide gave
the optimum yields and product purity of the ketones 6–8
(Scheme 2). The orthoesters could then be converted to the ethyl
ester by stirring with Amberlyst resin, to give the required
Scheme 3 Reagents and conditions: i, R1C(NH)NH2, MeCN–H2O,
55–90%.
2906
J. Chem. Soc., Perkin Trans. 1, 2001, 2906–2908
This journal is © The Royal Society of Chemistry 2001
DOI: 10.1039/b108645f

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Compounds 12–18 were formed as single regioisomers,
attributed to the acetylenic carbon bearing the ester group
being the most electron deficient, making this the initial site
for nucleophilic attack of the amidine. Miller has reported that
on symmetrical ketones after initial attack of simple nitrogen
nucleophiles the second acetylene moiety becomes deactiv-
ated towards further nucleophilic attack, resulting in only
mono-addition of the nucleophile.11
We have also observed that diacetylenic ketoesters 9–11 react
well with both substituted and unsubstituted hydrazines to give
the corresponding pyrazoles 19–24 in good yield (Scheme 4 and
Table 2). When phenylhydrazine was used a mixture of regio-
isomers a/b was generated in approximately 3 : 2 ratio. When
hydrazine hydrate was used as the nucleophile only regioisomer
Experimental
General experimental details are as previously published.1
General procedure for the preparation of pyrimidines
A solution of freshly prepared ketone (1.0 eq.) in MeCN–H2O
[10 : 1] (3 cm3/50 mg) was added to a stirred solution of the
amidine (1.5 eq.) and K2CO3 (3.0 eq.) in MeCN–H2O [10 : 1]
(10 cm3/100 mg). The resultant deep red solutions were stirred
at room temperature for 30 min before being absorbed onto
silica gel and purified by flash chromatography.
2-Phenyl-6-phenylpropargyl pyrimidine-4-carboxylic acid
ethyl ester 12.† νmax (Film)/cmϪ1 2981 (CH), 2930 (CH), 2217
᎐
(C᎐C), 1749 (CO Et); δH (200 MHz, CDCl3) 8.59–8.54 (2H, m,
᎐
2
Ar), 7.56 (1H, s, CH), 7.70–7.66 (3H, m, Ar), 7.46–7.41 (6H, m,
Ar), 4.41 (2H, q, J = 7 Hz, O-CH2CH3), 1.49 (3H, t, J = 7 Hz,
O-CH2-CH3); δC (50.3 MHz, CDCl3) 165.59, 164.15, 155.72,
153.13, 136.48, 132.45, 131.35, 130.02, 128.75, 128.58, 120.66,
97.77, 87.09, 62.55, 14.18 (Found: MHϩ 329.1222, C21H16N2O2
requires M, 328.1211); m/z 329 (100%, MHϩ).
General procedure for the preparation of pyrazoles
Phenylhydrazine or hydrazine (1.5 eq.) was added to a stirred
solution of the respective freshly prepared ketone (1.0 eq.) in
EtOH (10 cm3/50 mg). The resultant deep red solutions were
stirred at room temperature for 90 min before being absorbed
onto silica gel and purified by flash chromatography.
2-Phenyl-5-phenylpropargyl-2H-pyrazole-3-carboxylic acid
ethyl ester 19a. Rf = 0.4 [light petroleum–EtOAc (10 : 1)]; νmax
(Film)/cmϪ1 2985 (CH), 2932 (CH), 2244 (C᎐C), 1732 (CO Et);
᎐
᎐
2
Scheme 4 Reagents and conditions: i, R2NHNH2, EtOH, RT, 55–90%.
δH (200 MHz, CDCl3) 7.59–7.34 (11H, m, Ar and CH), 4.48
(2H, q, J = 7 Hz, O-CH2CH3), 1.43 (3H, t, J = 7 Hz, O-CH2-
CH3); δC (50.3 MHz, CDCl3) 165.49 (C), 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 (C), 78.12 (C), 59.16 (CH2), 13.48 (CH3) (Found:
MHϩ 317.1233, C20H16N2O2 requires M, 316.1211); m/z 316
(100%, MHϩ).
a was isolated, presumably due to hydrogen bonding to the
ethyl ester group.
In summary we have shown that it is possible to prepare a
range of functionalised pyrimidines 12–18 and pyrazoles 19–24
in good yield by reaction of highly reactive diacetylenic ket-
ones with nitrogen nucleophiles. Both ethyl ester and alkyne are
versatile groups for further synthetic steps and manipulation.
1-Phenyl-5-phenylpropargyl-2H-pyrazole-3-carboxylic acid
ethyl ester 19b. Rf = 0.6 [light petroleum–EtOAc (10 : 1)]; νmax
(Film)/cmϪ1 2985 (CH), 2932 (CH), 2244 (C᎐C), 1732 (CO Et);
᎐
᎐
2
δH (200 MHz, CDCl3) 7.59–7.34 (11H, m, Ar and CH), 4.28
(2H, q, J = 7 Hz, O-CH2CH3), 1.22 (3H, t, J = 7 Hz, O-CH2-
CH3); δC (50.3 MHz, CDCl3) 159.51 (C), 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 (C), 89.86 (C), 59.10 (CH2), 13.60 (CH3) (Found:
MHϩ 317.1233, C20H16N2O2 requires M, 316.1211); m/z 316
(100%, MHϩ).
Table 1 Preparation of functionalised pyrimidines
Substrate
Compound
R
R1
Yielda
9
9
10
10
11
11
11
12
13
14
15
16
17
18
Ph
Ph
C3H7
C3H7
C4H9
C4H9
C4H9
Ph
SMe
Ph
SMe
Ph
SMe
Me
90
85
92
90
87
90
55
Acknowledgements
a Isolated yields after chromatography.
We thank F. Hoffmann-La Roche for financial support to RER.
Table 2 Preparation of functionalised pyrazoles
Substrate
Compound
R
R2
Yield of aa(%)
Yield of ba(%)
9
9
10
10
11
11
19a/b
20a
21a/b
22a
23a/b
24a
Ph
Ph
C3H7
C3H7
C4H9
C4H9
Ph
H
Ph
H
Ph
H
24
89
20
51
20
52
48
—
60
—
60
—
1
a Isolated yields after chromatography. The structures a and b were assigned on the basis of H NMR three bond correlation (HMBC) and NOE
experiments.
J. Chem. Soc., Perkin Trans. 1, 2001, 2906–2908
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Baldwin, D. Catterick and G. J. Pritchard, J. Chem. Soc., Perkin
Trans. 1, 2001, 668.
5 J. E. Baldwin, A. M. Fryer and G. J. Pritchard, Bioorg, Med. Chem.
Lett., 2000, 10, 309; J. E. Baldwin, A. M. Fryer and G. J. Pritchard,
J. Org. Chem., 2001, 66, 2588.
6 J. E. Baldwin, G. J. Pritchard and D. S. Williamson, Bioorg, Med.
Chem. Lett., 2000, 10, 1927; J. E. Baldwin, G. J. Pritchard and D. S.
Williamson, Tetrahedron, 2001, 57, 7991.
Notes and references
† The IUPAC name for propargyl is prop-2-ynyl.
1 R. M. Adlington, J. E. Baldwin, D. Catterick and G. J. Pritchard,
J. Chem. Soc., Chem. Commun., 1997, 1757; R. M. Adlington, J. E.
Baldwin, D. Catterick and G. J. Pritchard, J. Chem. Soc., Perkin
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2 R. M. Adlington, J. E. Baldwin, D. Catterick, G. J. Pritchard and
L. T. Tang, J. Chem. Soc., Perkin Trans. 1, 2000, 303; R. M.
Adlington, J. E. Baldwin, D. Catterick, G. J. Pritchard and L. T.
Tang, J. Chem. Soc., Perkin Trans. 1, 2000, 2311.
3 R. M. Adlington, J. E. Baldwin, G. J. Pritchard and K. C. Spencer,
Tetrahedron Lett., 2000, 40, 575.
7 J. E. Baldwin, G. J. Pritchard and R. E. Rathmell, Synth. Commun.,
2000, 30, 3833.
8 For a review see R. H. DeWolfe, Synthesis, 1974, 679.
9 G. Boche and J. Bigalke, Tetrahedron Lett., 1983, 25, 955.
10 For the preparation of triethoxycarbenium tetrafluoroborate see
H. Meerwein, P. Borner, O. Fuchs, H. J. Sasse, H. Schrodt and
J. Spille, Chem. Ber., 1956, 89, 2060.
4 R. M. Adlington, J. E. Baldwin, D. Catterick and G. J. Pritchard,
J. Chem. Soc., Perkin Trans. 1, 2000, 299; R. M. Adlington, J. E.
11 S. I. Miller, Tetrahedron, 1968, 24, 4285.
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J. Chem. Soc., Perkin Trans. 1, 2001, 2906–2908