O. Dirat et al. / Tetrahedron Letters 47 (2006) 1729–1731
1731
develop another route for a practical synthesis of 3. An
References and notes
alternative regioselective synthesis is shown in Scheme
3 using an ynone as the coupling partner for the alkyl-
hydrazine. The commercial aldehyde 14 was converted
into alkyne 16 using the Bestmann reagent 15 in good
yield.6 The preparation of the Bestmann reagent nor-
mally requires two steps from readily available starting
materials, as tosyl azide is no longer commercially avail-
able. We report here a true one-step procedure to prepare
the Bestmann reagent, using 4-acetamidobenzenesulfon-
yl azide as the diazo transfer agent.7 This azide has
the advantage of being less hazardous than tosyl azide,
and we prepared >150 g batches of the Bestmann reagent
using this protocol. Ynone 17 is obtained by alkylation
of 16 using N-methoxy-N-methylacetamide. Addition
of ethyl hydrazine to 17 at 60 °C yields a 12/1 mixture
of regioisomeric pyrazoles 7 and 8 in favour of the de-
sired isomer 7. The addition of trifluoroethyl hydrazine
requires more forcing conditions to produce the desired
pyrazole directly, as hydrazone 19 is isolated as the major
product after heating at 60 °C.8 After optimisation, we
found that acetic acid was needed (presumably to facili-
tate the trans to cis isomerisation of the kinetically
formed hydrazone 19), and the optimal temperature pro-
file was three hour microwave9 heating at 150 °C; higher
temperatures result in loss of the Boc protecting group,
and lower temperatures yield mostly hydrazone 19. Grati-
fyingly, these conditions produce 18 as a 13/1 mixture of
regioisomers in 72% isolated yield. A final deprotection
and recrystallisation from 2-propanol gave the desired
pyrazole 3 in good yield and purity. This third route
allows a practical, regioselective synthesis of 3, and a
rapid access to diversely 2,5-disubstituted pyrazole
piperidines in three steps from alkyne 16 using the appro-
priate Weinreb amide and hydrazine combination.
1. (a) Elguero, J. In Comprehensive Heterocyclic Chemistry;
Potts, K. T., Ed.; Pergamon: Oxford, 1984; Vol. 5, p 167;
(b) Elguero, J. In Comprehensive Heterocyclic Chemistry II;
Katritzky, A. R., Rees, C. W., Scriven, E. F. V., Eds.;
Pergamon: Oxford, 1996; Vol. 3, p 1; (c) Bourrain, S.;
Ridgill, M.; Collins, I. Synlett 2004, 795; (d) Dvorak, C. A.;
Rudolph, D. A.; Ma, S.; Carruthers, N. I. J. Org. Chem.
2005, 70, 4188; (e) Calle, M.; Cuadrado, P.; Gonzalez-
Nogal, A. M.; Valero, R. Synthesis 2001, 1949.
2. (a) Shu, M.; Loebach, J. L.; Parker, K. A.; Mills, S. G.;
Chapman, K. T.; Shen, D.-M.; Malkowitz, L.; Springer, M.
S.; Gould, S. L.; DeMartino, J. A.; Siciliano, S. J.; Di
Salvo, J.; Lyons, K.; Pivnichny, J. V.; Kwei, G. Y.; Carella,
A.; Carver, G.; Holmes, K.; Schleif, W. A.; Danzeisen, R.;
Hazuda, D.; Kessler, J.; Lineberger, J.; Miller, M. D.;
Emini, E. A. Bioorg. Med. Chem. Lett. 2004, 14, 947; (b)
Raimundo, B. C.; Oslob, J. D.; Braisted, A. C.; Hyde, J.;
McDowell, R. S.; Randal, M.; Waal, N. D.; Wilkinson, J.;
Yu, C. H.; Arkin, M. J. Med. Chem. 2004, 47, 3111.
1
1
3. By H NMR. H NMR (360 MHz, CD3OD): d 5.97 (s, 1
H); 3.18–3.08 (m, 3H); 2.72–2.64 (m, 2H); 2.15 (s, 3H); 1.82
(m, 2H); 1.61 (m, 11H); 1.45 (s, 9H).
4. Structure of 7 and 8 assigned by NOE experiments.
5. Separation of the regioisomers proved impossible by
crystallisation at any stage of the sequence.
6. Roth, G. J.; Liepold, B.; Mueller, S. G.; Bestmann, H. J.
Synthesis 2004, 59.
7. Dimethyl (2-oxopropyl)phosphonate (50 g, 0.30 mol), THF
(270 mL) and toluene (1.3 L) were charged to a reaction
vessel with stirring under nitrogen. Ice cooling was applied,
and sodium hydride (60% in mineral oil) (13.25 g, 0.33 mol)
was added over 10 min. The turbid yellow mixture was
stirred for one hour with ice water cooling. 4-Acet-
amidobenzenesulfonyl azide (80 g, 0.33 mol) was then
added over 10 min. The turbid orange mixture was stirred
overnight at room temperature under nitrogen. The orange
mixture was filtered on a Celite pad, the resulting cake was
washed with toluene (250 mL), EtOAc (500 mL) and the
filtrate was concentrated in vacuo. Compound 16 (57 g) was
isolated pure as a clear liquid after a filtration on silica gel
(EtOAc) in 98% yield.
8. When the hydrazine addition is performed at 60 °C,
hydrazone 19 is isolated in 50% yield, alongside less than
10% of pyrazole 18. A variety of acidic and basic conditions
were screened to transform 19 into the pyrazole 18
presumably through a trans to cis isomerisation of the
hydrazone. Three equivalents of acetic acid in refluxing
ethanol gave the best reaction profile (with fewer side
products), yielding 18 as a single regioisomer in 25% yield.
9. Microwave heating performed in a SmithSynthesizer in
20 mL vials.
In conclusion, we have developed scaleable and practical
routes to the 4-(pyrazolyl)-piperidines 1, 2 and 3. The
synthesis of 1 relies on a regioselective addition of tert-
butyl hydrazine onto a 1,3-diketone. This high selectiv-
ity is not observed when ethyl or trifluoroethyl hydra-
zines are used. Alternatively,
a Suzuki coupling
between a pyrazole triflate and 4-pyridyl boronic acid
allows the regioselective synthesis of 2 in excellent yield.
Finally, a more flexible route allowing rapid synthesis of
diversely 2,5-disubstituted pyrazole piperidines has been
described using a regioselective addition of an alkyl-
hydrazine to an ynone as the key step. This route
allowed a practical large-scale synthesis of 3.