Addition of carbon nucleophiles to aldehyde tosylhydrazones of aromatic and heteroaromatic-compounds: Total synthesis of piperine and its analogs

Article abstract of DOI:10.1016/S0040-4039(00)00219-7

Addition of carbon nucleophiles to aldehyde tosylhydrazones of aromatic and heteroaromatic compounds is reported. New observations have been made wherein alkylative reduction is observed in some cases whereas alkylative fragmentation is noticed in others. These findings are exploited in the synthesis of the useful alkaloid piperine and its analogs. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00219-7

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TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 2667–2670
Addition of carbon nucleophiles to aldehyde tosylhydrazones of
aromatic and heteroaromatic-compounds: total synthesis of
piperine and its analogs†,‡
S. Chandrasekhar,∗ M. Venkat Reddy, K. Srinivasa Reddy and C. Ramarao
Indian Institute of Chemical Technology, Hyderabad 500 007, India
Received 26 November 1999; accepted 3 February 2000
Abstract
Addition of carbon nucleophiles to aldehyde tosylhydrazones of aromatic and heteroaromatic compounds is
reported. New observations have been made wherein alkylative reduction is observed in some cases whereas
alkylative fragmentation is noticed in others. These findings are exploited in the synthesis of the useful alkaloid
piperine and its analogs. © 2000 Elsevier Science Ltd. All rights reserved.
Keywords: toluene-p-sulphonylhydrazine; piperine; anti-feedant; insecticide.
Tosylhydrazones of carbonyl compounds are gaining importance not only as a tool for purification
of unstable aldehydes but also because of their ability to undergo novel nucleophilic additions and
fragmentations.1,2 Our group was the first to discover a new application of aldehyde tosylhydrazones
wherein sugar hydrazones3 and epoxy hydrazones4 undergo alkylative fragmentation to generate chiral
allyl alcohols.5 These chiral allyl alcohols were efficiently utilized by Schmidt et al. for the total
synthesis of sphingosines.6 More recently the Myers group has reported7 the reductive coupling of carbon
nucleophiles to sugar hydrazones. Inspired by all of these reports we have undertaken a programme
to study the reactions between carbon nucleophiles (RMgX and RLi) on aldehyde tosylhydrazones of
aromatic and heteroaromatic scaffolds. New findings pertaining to this study are presented herein.
∗
Corresponding address. Tel: +91 40 7170512; fax: +91 40 7173387; e-mail: srivaric@iict.ap.nic.in (S. Chandrasekhar)
IICT Communication No. 4460.
Dedicated to Dr. A. V. Rama Rao on his 65th birthday.
†
‡
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00219-7
tetl 16499

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2668
(1)
Readily available furfural was derivatized as its hydrazone (toluene-p-sulphonylhydrazine CH3OH,
rt, 15 h) which was treated with PhMgBr (2.5 equiv.) in anhydrous THF to realize 5-phenyl-2E,4E-
pentadienal 2 in 75% isolated yield.
Accordingly hydrazone 1, on treatment with nucleophiles such as p-methoxyphenylmagnesium bro-
mide and 3,4-methylenedioxyphenylmagnesium bromide, furnished the corresponding dienals 3 and 4 in
70 and 80% yields, respectively.8,12d Thus furfuraldehyde has been efficiently utilized as a five-carbon
open chain dienal equivalent. Exposure of the furfural hydrazone to aliphatic nucleophiles (substrate 1),
however, produced the corresponding alkylated products (5, 5a, 6) without any traces of ring-opened
products. This unusual behavior between aromatic and aliphatic nucleophiles made us believe that both
the nucleophilicity and the basicity of the nucleophiles have a direct influence on the outcome of the
reaction.9
Thiophene 2-carboxyaldehyde toluene-p-sulphonylhydrazone 7, on treatment with an excess of BuLi
(5 equiv.), resulted only in the reductive coupling product, 2-pentylthiophene. However, exposure of 7 to
phenylmagnesium bromide produced a complex mixture of products, which could not be characterized.
Benzaldehyde toluene-p-sulphonylhydrazone and naphthaldehyde toluene-p-sulphonylhydrazone when
treated with BuLi, consistently yielded pentylbenzene and 2-pentylnapthalene in good yields (substrate
9, 11).
Using this chemistry the dienal 4 was converted to piperine 14, a bioactive alkaloid (Scheme 1). This
alkaloid is found to possess diverse roles in biology especially related to central nervous system disorders,
anti-inflammatory, antidepressant, insecticidal and anti-feedant activities.10 Aldehyde 4 was oxidized to
the dienoic acid11 13 (75%) on treatment with NaClO2 and NaH2PO4 in t-BuOH, which was amidated
with various amines to produce piperine 14 (72%)12 and its analogs, 14a (69%) and 14b (76%).
Scheme 1.
In conclusion, a highly efficient and novel methodology is developed involving addition of carbon
nucleophiles to various aromatic and heteroaromatic aldehyde tosylhydrazones.13 The products thus

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2669
Table 1
formed, both ring cleaved products as well as reductive coupling products, may find widespread
application in natural product synthesis.
Acknowledgements
Two of us (M.V.R and K.S.R) thank (CSIR, New Delhi) for financial support.
References
1. (a) Chamberlin, R. A.; Steven, H. B. Org. React. 1990, 39, 1–83. (b) Adlington, R. M.; Barrett, A. G. M. Acc. Chem. Res.
1983, 10, 55.
2. Shapiro, R. H. Org. React. 1976, 23, 405.
3. Chandrasekhar, S.; Takhi, M.; Yadav, J. S. Tetrahedron Lett. 1995, 36, 307.
4. Chandrasekhar, S.; Takhi, M.; Yadav, J. S. Tetrahedron Lett. 1995, 36, 5071.
5. (a) Chandrasekhar, S.; Mohapatra, S.; Takhi, M. Tetrahedron Lett. 1996, 37, 759. (b) Chandrasekhar, S.; Reddy, M. V.; Takhi,
M. T. Tetrahedron Lett. 1998, 39, 6535.
6. Schmidt, R. R.; Kumar, P. Synthesis 1998, 33.
7. Myers, A. G.; Movassaghi, M. J. Am. Chem. Soc. 1998, 120, 8891.

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2670
8. General procedure: preformed alkyl magnesium halide (2.5 mmol) in anhydrous THF (15 mL), was added dropwise to a
cold solution of aldehyde toluene-p-sulphonylhydrazone (1 mmol) in anhydrous THF (5 mL) under a nitrogen atmosphere.
After the reaction mixture was stirred at ambient temperature for 2 h, the reaction mixture was quenched with saturated
NH4Cl solution (10 mL) and extracted with ether (2×25 mL). The combined organic layer was washed with water, brine
and dried over Na2SO4. The volatiles were removed under vacuum and the residue was purified by column chromatography
to afford trans-2,4-pentadienal in the yields summarized in Table 1.
9. A free radical mechanism as proposed by Myers (see Ref. 7) may not be ruled out.
10. Parmar, V. S.; Jain, S. C.; Bisht, K. S.; Jain, R.; Taneja, P.; Jha, A.; Tyagi, O. D.; Prasad, A. K.; Wengel, J.; Olsen, C. E.;
Boll, P. M. Phytochemistry 1997, 46, 597.
11. Balkrishna, S. B.; Wayne, E. C.; Pinnick, H. W. Tetrahedron 1981, 37, 2091.
12. (a) Schulze, A.; Oedieger, H. Liebigs Ann. Chem 1981, 1725. (b) Nasker, D.; Chowdhury, S.; Roy, S. Tetrahedron Lett.
1998, 39, 699. (c) Chattergee, A.; Dutta, C. P. Tetrahedron 1967, 1769. (d) Lewis, N.; McKen, P. W.; Taylor, R. J. K. Synlett
1991, 898.
13. Spectral data of compounds: 2: 1H NMR CDCl3 200 MHz: δ 9.6 (d, 1H, J=6 Hz), 7.62–7.2 (m, 6H), 6.95 (d, 1H, J=11.4
Hz), 6.5 (dd, 1H, J=12, 18 Hz), 6.25 (dd, 1H, J=6, 16 Hz); EI MS: m/z 158, 129, 115, 102, 91, 77; 4: 1H NMR CDCl3 200
MHz: δ 9.62 (d, 1H, J=6.9 Hz), 7.25 (dd, 1H, J=9.7, 16.6 Hz), 7.05–6.8 (m, 5H), 6.2 (dd, 1H, J=6.2, 16 Hz), 6.05 (s, 2H);
EI MS: m/z 202, 173, 115, 102, 91, 77; 6: 1H NMR CDCl3 200 MHz: δ 7.55 (s, 1H), 7.15 (d, 1H, J=4 Hz), 6.5 (m, 1H), 2.8
(t, 2H, J=7 Hz), 1.8–1.6 (m, 2H), 1.45–1.2 (m, 4H), 0.9 (t, 3H, J=7 Hz); EI MS: m/z 123 (M+−15), 105, 91, 67, 54.