1134
D. A. Price et al.
LETTER
Scheme 3 Conditions: a. POCl3, CHCl3, pyridine, r.t. then acetic hydrazide, CHCl3, reflux; b. PhMe, reflux 59%.
Further examination of the chlorination conditions were further modified to give biologically active molecules for
conducted and phosphorous pentachloride gave the most potential drug development. The reaction conditions are
reproducible high yields using dichloromethane as sol- milder than those previously reported in the literature and
vent. With the iminoyl chloride formation and cyclisation do not require special handling techniques or disposal of
conditions optimised we were now in a position to prepare hazardous mercuric residues. The range of substitutions is
the required range of substituted piperidines and tropanes limited by their compatibility with the use of the chlorina-
(Table 1).
tion conditions rather than any steric considerations.
We were pleased to find that these conditions worked
across a range of piperidine and tropane substitution pat-
terns. Comparing entries 2 and 3 there is essentially no
change in yield regardless of whether the amide is an axial
or equatorial disposition in the tropane structure. Also in
entry 4 with both the tropane bridge and the t-butyl group
hindering the reaction the yield remained consistent with
the other less sterically demanding analogues. Entry 3 has
also been prepared in similar yield in the ‘reversed fash-
ion’ using the tropane acetamide and isobutyric acid
hydrazide. All these examples were debenzylated in high
yield using transfer hydrogenation conditions.9
References
(1) (a) Wermuth, C. G. In The Practice of Medicinal Chemistry;
Wermuth, C. G., Ed.; Academic Press: San Diego, 2001.
(b) Patani, G. A.; LaVoie, E. J. Chem. Rev. 1996, 96, 3147.
(2) Wadsworth, H. J.; Jenkins, S. M.; Orlek, B. S.; Cassidy, F.;
Clark, M. S. G.; Brown, F.; Riley, G. J.; Graves, D.;
Hawkins, J.; Naylor, C. B. J. Med. Chem. 1992, 35, 1280.
(3) Stocks, M. J.; Cheshire, D. R.; Reynolds, R. Org. Lett. 2004,
6, 2969.
(4) (a) Boeglin, D.; Cantel, S.; Heitz, A.; Martinez, J.; Fehrentz,
J. A. Org. Lett. 2003, 5, 4465. (b) Jagodzinski, T. S. Chem.
Rev. 2003, 103, 197.
(5) (a) Clausen, K.; Thorsen, M.; Lawesson, S. O. Tetrahedron
1981, 37, 3635. (b) Voss, J. In Encyclopedia of Reagents for
Organic Synthesis, Vol. 1; Paquette, L. A., Ed.; John Wiley
and Sons: Chichester, 1995.
The main limitation in this methodology is ensuring the
amide substituents are compatible with the use of phos-
phorous pentachloride for iminoyl chloride formation.
(6) Barrett, A. G. M.; Lee, A. C. J. Org. Chem. 1992, 57, 2818.
(7) (a) Klingsberg, E. J. Am. Chem. Soc. 1958, 80, 5786. (b)
See examples contained within patent GB670,480.
(c) Garrat, P. J. In Comprehensive Heterocyclic Chemistry
II, Vol. 4; Storr, R. C., Ed.; Elsevier: Oxford, 1996.
(8) Atkinson, M. R.; Polya, J. B. J. Chem. Soc. 1954, 141.
(9) (a) Protective Groups in Organic Synthesis, 3rd ed.; Greene,
T. W.; Wuts, P. G. M., Eds.; John Wiley and Sons:
Chichester, 1999. (b) Ram, S.; Spicer, L. D. Tetrahedron
Lett. 1987, 28, 515.
In conclusion we have demonstrated an efficient method-
ology for the multigram preparation of 1,2,4-triazoles and
their linkage to synthetically/medicinally useful pipe-
ridines and tropanes. After debenzylation these can be
Table 1 Triazoles prepared.
Entry Amide precursor
Product
Yield
(%)
110
50
65
(10) Preparation of Entry 1.
PCl5 (20.5 g, 98 mmol) was added portionwise to a stirred
CH2Cl2 (200 mL) solution of the amide (19.7 g, 76 mmol) at
0 °C. After 2 h stirring at 0 °C acetic hydrazide (16.8 g, 227
mmol) and t-amylalcohol (195 mL) were added and the
reaction was stirred for 12 h and then allowed to warm to r.t.
The solvent was removed in vacuo and toluene (200 mL) and
p-TsOH (474 mg, 2.5 mmol) were added and the reaction
was heated under reflux for 6 h. The reaction was cooled to
r.t., the solvent was decanted, and CH2Cl2 (200 mL) and H2O
(200 mL) were added with stirring; 1 N aq NaOH was slowly
added to take the pH to >9. The organic layer was separated
and the aqueous was washed with CH2Cl2 (2 × 100 mL), the
organics were combined and washed with H2O (2 × 200
mL), brine (200 mL) and dried (MgSO4) and the solvent was
removed in vacuo. The residue was purified by flash column
chromatography on silica gel eluting with 10% MeOH in
EtOAc to give the product of entry 1 (11.0 g, 50%) as a white
solid. 1H NMR (400 MHz, CD3OD): d = 7.30 (5 H, m), 4.13
(1 H, m), 3.58 (2 H, s), 3.23 (1 H, sept, J = 7.0 Hz), 3.08 (2
H, m), 2.54 (3 H, s), 2.23 (4 H, m), 1.84 (2 H, m), 1.38 (6 H,
d, J = 7.0 Hz). LRMS: m/z = 299 [MH+].
2
3
4
61
60
Synlett 2005, No. 7, 1133–1134 © Thieme Stuttgart · New York