Synthesis of linked heterocycles via use of bis-acetylenic compounds

Article abstract of DOI:10.1016/j.tetlet.2006.03.052

Linked bis-pyrazoles, a pyrazolyl-isoxazole, a pyrazolyl-pyrimidine and a pyrazolyl-triazole were synthesized starting with commercially available 1,4-bis(trimethylsilyl)-1,3-butadiyne 1 or readily available bis-acetylenic diketone 22. A stepwise approach

Full text of DOI:10.1016/j.tetlet.2006.03.052

Tetrahedron Letters 47 (2006) 3209–3212
Synthesis of linked heterocycles via use of bis-acetylenic compounds
Christopher D. Smith, Kirill Tchabanenko, Robert M. Adlington* and Jack E. Baldwin
Department of Chemistry, University of Oxford, Chemistry Research Laboratory, Mansfield Road,
Oxford OX1 3TA, United Kingdom
Received 31 January 2006; revised 28 February 2006; accepted 9 March 2006
Available online 29 March 2006
Abstract—Linked bis-pyrazoles, a pyrazolyl-isoxazole, a pyrazolyl-pyrimidine and a pyrazolyl-triazole were synthesized starting
with commercially available 1,4-bis(trimethylsilyl)-1,3-butadiyne 1 or readily available bis-acetylenic diketone 22. A stepwise
approach based on the use of 1 allowed the synthesis of nonsymmetrically substituted bis-pyrazoles and linked heterocycles with
two different cores whereas a symmetric approach based on the use of 22 allowed a very short synthesis of symmetric bis-pyrazoles.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
2. Symmetric approach
HO
1. Stepwise approach
TMS
The synthesis of linked small ring heterocycles has
attracted much attention in recent years due to their inter-
esting biological properties.1,2 Substituted pyrazoles and
isoxazoles play key pharmacophore functions in many
pharmaceuticals.3–5 Moreover, linked heterocycles have
found application in asymmetric catalysis.6,7 Previous
approaches to C–C linked heterocycles were predomi-
nantly based on cross-coupling strategies.7,8 Our previ-
ous experience in the use of 1,4-bis(trimethylsilyl)-1,
3-butadiyne 1 in the synthesis of 1H-pyrazolo[4,3-c]pyri-
dines9 has prompted us to investigate alternative appli-
cations of bis-acetylenic compounds for the synthesis
of new heterocycles.
4
1
R1
TMS
Glazer
coupling
Friedel-
Crafts
HO
R1
TMS
O
HO
3
R1
X-Y-R2
R1
[O]
R2
Y
TMS
O
X
R1
R1
2
O
Two strategies were originally proposed. The first
(Scheme 1), allowed the synthesis of nonsymmetric
linked heterocycles and envisaged stepwise formation
of the first ring, possessing the acetylenic substituent 2,
followed by condensation of the second ring. The sec-
ond strategy was based on the use of the bis-acetylenic
diketone 3, which on condensation with hydrazines or
hydroxylamines would give symmetric bis-pyrazoles or
bis-isoxazoles. The first pathway, although longer than
the second, would provide access to previously unknown
pyrrazolyl-isoxazoles, pyrazolyl-pyrimidines and pyrazol-
yl-triazoles. It was proposed to access the diketone 3
R1
R2
Y
O
X-Y-R2
X
X
R3
R2
R2
R1
X
Y
X-Y-R4
R4
X
Y
R1
R1
R2
Y
X
Y
R3
R1
Scheme 1. Proposed approaches to linked heterocycles.
*
Corresponding author. Tel.: +44 (0) 1865 275 626; fax: +44 (0) 1865
275 626; e-mail addresses: kirill.tchabanenko@chem.ox.ac.uk; Robert.
Adlington@chem.ox.ac.uk
via Glazer type oxidative coupling10 of propargylic alco-
hols 4.
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.03.052

3210
C. D. Smith et al. / Tetrahedron Letters 47 (2006) 3209–3212
We present the initial results of our investigation of both
pathways in this letter.
lowed by lithiation and quench of the acetylides with
acetic or benzoic anhydrides led to formation of ketones
12, 13, 14 and 15 (Scheme 2).
2. The stepwise approach
Heating of the acetylenic ketones 12 and 14 with phenyl
hydrazine hydrochloride and potassium carbonate in
methanol led to formation of bis-pyrazoles 16 and 17
in moderate yields. The structure of 16 was confirmed
by single crystal X-ray diffraction (Fig. 1). It is interest-
ing to note that the two phenyl rings appear to be p-
bonded, thus influencing the dihedral angle between
the pyrazole nitrogens.
The initial acylation of the 1,4-bis(trimethylsilyl)-1,3-
butadiyne 1 was carried out according to the literature
procedure11 resulting in near quantitative isolation of
the acetylenic ketones 5 and 6. Direct formation of the
pyrazoles on treatment of ketones 5 and 6 with methyl
and phenyl hydrazines in refluxing ethanol12 in the pres-
ence of molecular sieves led to compounds 7, 8, 9 and 10
in varying yields.13 It was observed that condensations
with methyl hydrazine proceeded in higher yields and
regioselectivity. Reaction of phenyl hydrazine with
ketone 6 gave a significant amount of the regioisomeric
pyrazole 11, formation of which was attributed to stabi-
lizing p-stacking of the two phenyl rings in 11. Attempts
to perform Friedel–Crafts acylation of the alkyne in
either ketones 5 and 6 or acetylenic pyrazoles 7, 8 or 9
were unsuccessful. Alternatively, cleavage of the TMS
group in 8 or 9 with methanolic sodium hydroxide14 fol-
Next, we attempted formation of a pyrazolyl-isoxazole.
The acetylenic ketone 12 was treated with hydroxyl-
amine hydrochloride in acetonitrile.15 The reaction took
two days to reach completion and the linked heterocycle
18 was isolated in satisfactory yield as a single regio-
isomer (Scheme 3).16
Treatment of 12 with benzamidine hydrogen chloride
salt in acetonitrile17 produced a linked pyrazolyl-pyrimi-
dine 19, whereas treatment of the acetylenic pyrazole 20
TMS
TMS
AcCl or BzCl,
AlCl3
O
TMS
DCM, 0 oC
R1
1
R1 = Me : 5 80%
Ph : 6 95%
MeNHNH2 or
PhNHNH2
EtOH, Δ,
4Å mol. sieves
R2
N
Ph
N
TMS
TMS
N
N
+
R1
Ph
R1 = Me, R2 = Me : 7 82%
Me
Ph
Ph
Ph : 8 22%
Me : 9 85%
Ph : 10 15%
11 11%
BuLi, THF, -78 oC
then Ac2O or Bz2O
R2
N
R2
N
NaOH,
MeOH
O
R3
N
N
8 or 9
quant.
R1
R1
R1 R2
R3
12 : Me Ph
13 : Me Ph
Me 65%
Ph 61%
14 : Ph Me Me 59%
15 : Ph Me Ph 60%
PhNHNH2 (1.1 eq.)
K2CO3 (2 equiv.)
MeOH, reflux
R4
N
R2
N
N
N
R3
12 or 14
R1
R1 = Me, R2 = Ph, R3 = Me, R4 = Ph : 16 44%
R1 = Ph, R2 = Me, R3 = Me, R4 = Ph : 17 41%
Scheme 2. Stepwise approach to bis-pyrazoles.

C. D. Smith et al. / Tetrahedron Letters 47 (2006) 3209–3212
3211
OH
Ph
CuCl (1 eq.)
TMEDA,
O2, acetone
HO
Ph
HO
80%
Ph
24
23
DMP,
DCM,
0 oC
O
Ph
O
22
Ph
Me
Me
N
MeNHNH2 (2.2 eq.)
DCM
N
N
N
Ph
Ph
22
Figure 1. X-ray structure of bis-pyrazole 16.
Ph
75%
23
Ph
Ph
N
O
Ph
N
Ph
N
NH2OH HCl,
MeCN, 2 days
N
N
O
N
N
Me
N
N
Me
Me
Me
Ph
65%
24
18
12
Ph
NH
NH2 HCl
PhNHNH2 (2.1 eq.)
EtOH, 4Å mol. sieves
N
N
Ph
Ph
Ph
N
N
Ph
25
Ph
22
Ph
K2CO3, MeCN,
reflux
N
N
81%
N
N
12
Me
Ph
31%
Me
N
N
19
Ph
N
N
Ph
Ph
BnN3, (2 equiv.),
26
H2O/tBuOH (1 : 1),
24 : 25 : 26 = 1 : 1.5 : 0.5
Ph
Ph
N
sodium ascorbate (10 mol%)
CuSO4 (1 mol%)
N
N
N
N
N
N
Scheme 4. Symmetric synthesis of bis-pyrazoles.
Bn
Me
Me
81%
21
20
On treatment with methyl hydrazine in DCM diketone
22 gave symmetric bis-pyrazole 23 in a satisfying yield.
Reaction of 22 with phenyl hydrazine, on the other
hand, produced a mixture of regioisomeric bis-pyrazoles
24, 25 and 26 tentatively assigned in a 1:1.5:0.5 ratio as
judged by integration of resonances in the crude 1H
NMR. The low regioselectivity in this case follows our
observation of poor control in the case of formation
of 10 and 11 as discussed previously. Due to their similar
polarity the three regioisomeric bis-pyrazoles were never
fully separated and were characterised as major compo-
nents in mixtures with the isomeric analogues.
Scheme 3. Synthesis of novel linked heterocycles.
derived from 8 with benzyl azide in the presence of a
copper catalyst, following the method published by
Sharpless and co-workers18 resulted in formation of a
pyrazolyl-triazole 21 in a satisfactory yield as a single
regioisomer. The structure of 21 was assigned according
to the published mechanism for the copper catalysed
Huisgen cycloaddition.18
3. The symmetric approach
In conclusion, we have demonstrated the application of
bis-acetylenic compounds 1 and 24 in syntheses of
linked heterocycles. Two strategies—stepwise and sym-
metrical were investigated producing six substituted
bis-pyrazoles and three novel pyrazolyl derivatives 18,
19 and 21. Further investigation will be focussed on
Next, we investigated the symmetric approach to linked
heterocycles. According to our original strategy the bis-
acetylenic diketone 22 was synthesised via Glazer-type
coupling10 of propargylic alcohol 23 followed by mild
Dess–Martin oxidation19 of the diol 24 (Scheme 4).

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C. D. Smith et al. / Tetrahedron Letters 47 (2006) 3209–3212
8. Murakami, Y.; Yamamoto, T. Inorg. Chem. 1997, 36,
5826.
9. Commeiras, L.; Woodcock, S. C.; Baldwin, J. E.; Adling-
ton, R. M.; Cowley, A. R.; Wilkinson, P. J. Tetrahedron
2004, 60, 939.
10. Yadav, J. S.; Reddy, B. V. S.; Reddy, K. B.; Gayathri, K.
U.; Prasad, A. R. Tetrahedron Lett. 2003, 44, 6493.
11. Walton, D. R. M.; Waugh, F. J. Orgonomet. Chem. 1972,
37, 45.
synthesis of a wider range of linked heterocycles as well
as further optimisation of reaction conditions.
Acknowledgements
We would like to thank Drs. Andrew Cowley (X-ray)
and Barbara O’Dell (NMR), for their help.
12. Bowden, K.; Jones, E. R. H. J. Chem. Soc. 1946, 953;
Coispeau, G.; Elguero, J.; Jacquier, R. Bull. Soc. Chim. Fr.
1970, 689.
References and notes
13. Our study was originally based on a stepwise pyrazole
formation, which included isolation of the intermediate
hydrazones. Cyclisation of these hydrazones upon heating
proceeded with selective formation of single 1,3,5-trisub-
stituted pyrazoles 7, 8, 9 and 10 (although in lower overall
yields from acetylenic ketones). All further structure
assignments were based on correlation of the spectro-
scopic data of novel compounds with these cases.
14. Ford, M. F.; Walton, D. R. M. Synthesis 1973, 47.
15. Adlington, R. M.; Baldwin, J. E.; Catterick, D.; Pritchard,
G. J.; Tang, L. T. J. Chem. Soc., Perkin Trans. 1 2000,
2311.
16. The isoxazole structure was assigned based on the high
ppm value (159.7) of the C-5 carbon of the isoxazole in
the 13C NMR. This follows the general pattern described
by Comprehensive Heterocyclic Chemistry; Katritzky,
A. R., Rees, C. W., Eds.; Pergamon Press: Oxford, 1984;
Vol. 3, p 226.
1. Tavares, F. X.; Deaton, D. N.; Miller, L. R.; Wright, L. L.
J. Med. Chem. 2004, 47, 5057; Jang, S.-Y.; Ha, Y. H.; Ko,
S. W.; Lee, W.; Lee, J.; Kim, S.; Kim, Y. W.; Lee, W. K.;
Ha, H.-J. Bioorg. Med. Chem. Lett. 2004, 3881; Somei, M.;
Yamada, Y.; Kitagawa, K.; Sugaya, K.; Tomita, Y.;
Yamada, F.; Nakagawa, K. Heterocycles 1997, 45, 435.
2. Sammes, M. P.; Lai, T. F.; Katritzky, A. R.; Murugan, R.;
Luce, H. J. Chem. Soc., Perkin Trans. 2 1985, 573, and
citations therein.
3. Kloner, R. A.; Jarow, J. P. Am. J. Cardiol. 1999, 83, 576;
Fries, R. W.; Bohlken, D. P.; Plapp, B. V. J. Med. Chem.
1979, 22, 356; Tso, J. Y.; Bower, S. G.; Zalkin, H. J. Biol.
Chem. 1980, 255, 6734.
4. The Merck Index; 12th ed.; Budavari, S., Ed.; Merck &
Co.: New Jersey, 1996; p 529, p 807, 880.
5. Comprehensive Heterocyclic Chemistry; Katritzky, A. R.,
Rees, C. W., Eds.; Pergamon Press: Oxford, 1984; Vol. 5,
p 782.
6. Benincori, T.; Piccolo, O.; Rizzo, S.; Sannicolo, F. J. Org.
Chem. 2000, 65, 8340.
7. Rist, O.; Begtrup, M. J. Chem. Soc., Perkin Trans. 1 2001,
1566.
17. Adlington, R. M.; Baldwin, J. E.; Catterick, D.; Pritchard,
G. J.; Spencer, K. C. Tetrahedron Lett. 2000, 41, 2596.
18. Rostovtsev, V. V.; Green, L. G.; Fokin, V. V.; Sharpless,
K. B. Angew. Chem., Int. Ed. 2002, 41, 2596.
19. Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4156.