New entry to alicyclic amines via alkylative fragmentation of cyclic aminoaldehyde tosylhydrazones

Article abstract of DOI:10.1016/S0040-4039(00)01807-4

Tosylhydrazones of cyclic aminoaldehydes when exposed to aromatic and aliphatic Grignard reagents produce ring-opened acyclic unsaturated primary carbamates and carbamate alcohols in good yields. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)01807-4

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 10131–10134
New entry to alicyclic amines via alkylative fragmentation
of cyclic aminoaldehyde tosylhydrazones†
S. Chandrasekhar,* M. Venkat Reddy and G. Rajaiah
Indian Institute of Chemical Technology, Hyderabad 500 007, India
Received 23 May 2000; revised 10 July 2000; accepted 11 October 2000
Abstract
Tosylhydrazones of cyclic aminoaldehydes when exposed to aromatic and aliphatic Grignard reagents
produce ring-opened acyclic unsaturated primary carbamates and carbamate alcohols in good yields.
© 2000 Elsevier Science Ltd. All rights reserved.
Keywords: p-toluenesulfonyl hydrazine; amine; proline; hydroxyproline.
Amines and amino alcohols containing an alkene double bond are very important building
blocks in organic synthesis.1 This class of compounds have multiple functionality for further
manipulation towards the synthesis of natural products and designed pharmaceutically valuable
compounds.2 Our group has been engaged in the development of this class of compounds over
the past few years.3 As part of an ongoing project4 on the exploitation of our newly discovered
methodology on alkylative fragmentation of aldehyde tosylhydrazones having a-heteroatom
functionality, we have observed that both five- and six-membered nitrogen heterocycles with the
aldehyde tosylhydrazone functionality at C2 undergo alkylative fragmentation to result in acyclic
amines and aminols having unsaturation (between C4–C5 or C5–C6). The results pertaining to
this study are reported herein (Eq. (1)).
(1)
Initially, pyrrolidine-2-carboxaldehyde was protected with di-tert-butyl dicarbonate and
derivatized with p-toluenesulfonyl hydrazine to afford the prerequisite hydrazone 1 (entry 1,
Table 1). This was subjected to phenyl magnesium bromide (2.5 equiv.) in anhydrous THF for
* Corresponding author. Tel: +91 40 7170512; fax: +91 40 7173387; e-mail: srivaric@iict.ap.nic.in
†
IICT Communication No. 4571.
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01807-4

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4 h to afford 5-phenyl-4-pentenyl amine derivative5 2 in 75% yield. However, when the same
reaction was carried out with unprotected pyrrolidine hydrazone, a complex and an uncharac-
terizable mixture of products was obtained. Thus, it is anticipated that the acidic NꢀH is better
off being protected (Eq. (2), Scheme 1).
Table 1

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Scheme 1.
(2)
To check generality of this method, 1 was subjected to 4-methoxyphenylmagnesium bromide
under identical reaction conditions to give Boc-protected 4-methoxyphenyl-pentenyl amine in
65% yield. Hydrazone 1 was also treated with 3,4-methylenedioxy phenylmagnesium bromide
and propylmagnesium bromide to provide ring-opened products in moderate yields (entry 3 and
4). The tosylhydrazone 6, which is obtained from 4-hydroxyproline, when exposed to PhMgBr,
4-MeO-PhMgBr, and 3,4 methylenedioxyphenylmagnesium bromide gave the corresponding
amino alcohols (7, 8, 9).6 Identical results were drawn from tosylhydrazone 10 (entry 8, Table
1) to afford the ring-opened acyclic amines having unsaturation between C5–C6 (entries 8, 9, 10).
In conclusion, a facile and convenient method for the synthesis of double bond containing
terminal carbamates and carbamate alcohols has been developed, which should find use in
organic synthesis.
Acknowledgements
Two of us (M.V.R. and G.R.) thank (CSIR New Delhi) for financial support.
References
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5. General procedure: Preformed arylmagnesium bromide (2.5 mmol) in (15 mL) anhydrous THF was added
dropwise to a cold aminoaldehyde p-toluenesulfonyl hydrazone (1 mmol) in (5 mL) anhydrous THF under a
nitrogen atm, then stirred at ambient temperature for 4 h. The reaction mixture was quenched with saturated
NH4Cl solution (10 mL) and extracted with ether (2×25 mL). The combined organic layers were 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-Boc-protected compounds (see Table 1).
6. Spectroscopic data of compounds: compound 2. 1H NMR CDCl3 200 MHz: l 7.4–7.15 (m, 5H), 6.40 (d, 1H,
J=15 Hz), 6.25–6.10 (m, 1H), 4.50 (bs, 1H), 3.25–3.15 (m, 2H), 2.35–2.20 (m, 2H), 1.75–1.6 (m, 2H), 1.45 (s, 9H);
1
IR (neat): 3325, 1687, 1280, 1150 cm−1; EI MS: m/z 205 (M+−56), 144, 105, 77, 57: compound 7. H NMR CDCl3
200 MHz: l 7.40–7.20 (m, 10H), 6.55 (d, 1H, J=15 Hz), 5.80–5.65 (m, 1H), 4.80 (bs, 1H), 4.70–4.65 (m, 1H),
4.62–4.50 (dd, 2H, J=9.6, 19.2 Hz), 3.62–3.05 (m, 2H), 2.72–2.45 (m, 2H), 1.45 (s, 9H); IR (neat): 3306, 1685,
1
1282, 1103 cm−1; EI MS: m/z 311 (M+−56) 204, 107, 57: compound 12. H NMR CDCl3 200 MHz: l 7.25 (d, 2H,
J=8.3 Hz), 6.80 (d, 2H, J=8.3 Hz), 6.30 (d, 1H, J=16 Hz), 6.10–5.95 (m, 1H), 4.50 (bs, 1H), 3.80 (s, 3H),
3.10–2.90 (m, 2H), 2.30–2.10 (m, 2H), 2.0–1.65 (m, 4H), 1.45 (s, 9H). IR (neat): 3320, 1685, 1280, 1175 cm−1; EI
MS: m/z 249 (M+−56), 188, 147, 121, 57.
.
.