N-tert-butoxycarbonylaminophthalimide, a versatile reagent for the conversion of alcohols into alkylated tert-butylcarbazates or hydrazines via the Mitsunobu protocol

Article abstract of DOI:10.1016/S0040-4039(99)02038-9

An efficient two-step method has been developed for the conversion of alcohols to substituted hydrazines. The use of N-tert- butoxycarbonylaminophthalimide as an acid partner in Mitsunobu reactions with a variety of alcohols permits the synthesis of the corresponding monoalkylated tert-butylcarbazates and hydrazines.

Full text of DOI:10.1016/S0040-4039(99)02038-9

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 205–207
N-tert-Butoxycarbonylaminophthalimide, a versatile reagent for
the conversion of alcohols into alkylated tert-butylcarbazates or
hydrazines via the Mitsunobu protocol
Nicolas Brosse, Maria-Fatima Pinto and Brigitte Jamart-Grégoire ∗
MAEM UMR mixte CNRS-UHP no. 7567, Faculté des Sciences, Université H. Poincaré Nancy I, Bld des Aiguillettes BP 239,
F-54506 Vandoeuvre les Nancy, France
Received 12 October 1999; accepted 27 October 1999
Abstract
An efficient two-step method has been developed for the conversion of alcohols to substituted hydrazines. The
use of N-tert-butoxycarbonylaminophthalimide as an acid partner in Mitsunobu reactions with a variety of alcohols
permits the synthesis of the corresponding monoalkylated tert-butylcarbazates and hydrazines. © 1999 Elsevier
Science Ltd. All rights reserved.
Keywords: Mitsunobu reactions; hydrazines; alkylation.
The Mitsunobu reaction, which performs O- and N-alkylation under mild conditions, has been used
for the conversion of alcohols into a wide range of derivatives including esters, amines, imides, azides,
etc.1 The reaction proceeds via condensation of an alcohol ROH with an acid HA aided by the use
of diethylazodicarboxylate (DEAD) and triphenylphosphine.1a It has been reported2 that the success
of the Mitsunobu reaction is highly dependent upon the nature of the acid partner which must be
strong enough to be easily deprotonated and not be too hindered to allow nucleophilic attack with
inversion of configuration in the SN2 step. As a result, cyclic or acyclic imides,1a,2 oxamates3 and
sulfonylcarbamates4 have been successfully used as nitrogen nucleophiles to yield amine derivatives.
Ragnarsson and colleagues2a reported that imidodicarbonates can be used to prepare amino acids in
synthetic protocols that utilize the Mitsunobu reaction and also confirmed that the yield from the reaction
is clearly dependent upon the electronic and steric nature of the acid partner.
As a part of our studies aimed at developing a synthetic method for producing monolabelled
isoniazide,5 we performed the synthesis of 1,1-bis(tert-butoxycarbonyl) aminophthalimide 2 using N-
aminophthalimide 1 as a starting material. We also showed that 2 could be easily mono deprotected thus
producing N-tert-butoxycarbonylaminophthalimide 35b (Scheme 1).
∗
Corresponding author. Tel/fax: 33(0)3/83/91/27/48; e-mail: Brigitte.Jamart@maem.uhp-nancy.fr (B. Jamart-Grégoire)
0040-4039/00/$ - see front matter © 1999 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(99)02038-9
tetl 15966

206
Scheme 1. (a) (BOC)2O, DMAP, Et3N, THF, rt, 2 h, 65%; (b) CF3COOH, CH2Cl2, rt, 48 h, 75%
Compound 3 may be considered as a triprotected hydrazine, since one could envisage that both the
phthaloyl and the tert-butoxycarbonyl groups may potentially be removed. In addition, the presence
of three electron-withdrawing acyl groups increases the acidity of the hydrazinyl proton whilst the
incorporation of two of the three acyl groups into the phthaloyl moity reduces steric hindrance. In light
of the above we postulated that compound 3 could act as a good acid partner in a Mitsunobu reaction for
a mild and stereospecific means of converting alcohols to substituted hydrazines. The latter are generally
obtained by reduction of the corresponding hydrazones,6 or by using triprotected hydrazines under PTC
conditions as recently described,7 or even by direct alkylation8 of the hydrazine itself.
Here we report, for the first time, the rapid and efficient syntheses of monoalkylated tert-
butylcarbazates 6 and hydrazines 7, in only two steps, respectively, by using alcohols 4 as starting
materials in a Mitsunobu reaction (as specified in Scheme 2).
Scheme 2. Reagents: (a) Compound 3, 1 equiv.; DEAD, 1.5 equiv.; PPh3, 1.5 equiv., 0.5 h; (b) MeNHNH2, 1.5 equiv., THF; (c)
(1) MeNHNH2, 1.5 equiv., THF; (2) filtration; (3) HCl gas, anhydride Et2O
Using this methodology, as summarized in Table 1 (step a), when a range of alcohols 4 were subjected
to the usual Mitsunobu conditions1a for 0.5 hours in the presence of 3, the corresponding products 5 were
obtained with good yields regardless of the nature of the starting alcohol (methanol, primary, secondary,
benzylic or allylic). Dephthaloylation reactions (step b) were performed by treating a solution of 5 in
THF with 1.5 equiv. of methylhydrazine over 0.5 hours at −20°C. Reaction mixtures were then brought
to room temperature until completion (monitored by TLC). The use of methylhydrazine, employed to
avoid the formation of a complex with the free amine,11 as reported elsewhere, resulted in a very clean
reaction compared to hydrazine hydrate or phenylhydrazine which gave poor results in these studies.
Following filtration to remove N-methylphthalhydrazide which precipitates as a by-product, the desired
N-alkylated tert-butylcarbazates 6 were isolated and purified by column chromatography on neutral
alumina gel. Removal of the BOC group can be performed without purification of 6 (step c) using HCl gas
in anhydrous ether. Under these conditions, monoalkylated hydrazines could be isolated as hydrochloride
salts 7.
In summary, we have shown that alcohols can be efficiently converted into substituted hydrazines 7
utilizing N-tert-butoxycarbonylaminophthalimide 3. These substituted hydrazines can also be isolated
in a BOC-protected form as compounds 6 that subsequently may be used in other multistep synthetic
protocols. Moreover, using the strategy we have developed to obtain compound 3,5b singly labelled
substituted hydrazines could be obtained using commercially available potassium [15N]phthalimide as

207
Table 1
a starting material. The use of N-tert-butoxycarbonylaminophthalimide 3 in other synthetic applications
is currently under investigation.
Acknowledgements
Financial support from the European Communities Commission under contract no. BMH4-CT96-1492
is gratefully acknowledged.
References
1. (a) For a review, see: Mitsunobu, O. Synthesis 1981, 1–28. For recent applications of the Mitsunobu reaction, see: (b) Dodd,
D. S.; Kozikowski, A. P. Tetrahedron Lett. 1994, 35, 977–980. (c) Berrée, F.; Michelot, G.; Le Gorre, M. Tetrahedron Lett.
1998, 39, 8275–8276. (d) Kim, T. H.; Lee, G. J.; Cha, M. H. Synth. Commun. 1999, 29, 2753–2758.
2. (a) Degerbeck, F.; Fransson, B.; Grehn, L.; Ragnarsson, U. J. Chem. Soc., Perkin Trans. 1 1992, 245–253. (b) Koppel, I.;
Koppel, J.; Leito, I.; Deberbeck, F.; Ragnarsson, U. J. Org. Chem. 1991, 56, 7172–7174. (c) Chong, J. M.; Park, S. B. J. Org.
Chem. 1993, 58, 7300–7303.
3. Maurer, P. J.; Miller, M. J. J. Am. Chem. Soc. 1982, 104, 3096–3101.
4. Campbell, J. A.; Hart, D. J. J. Org. Chem. 1993, 58, 2900–2903.
5. (a) Brosse, N.; Pinto, M. F.; Jamart-Grégoire, B. J. Chem. Soc., Perkin Trans. 1 1998, 3685–3688. (b) Jamart-Grégoire, B.;
Brosse, N.; Bodiguel, J. Synthesis, 1998, 269–270.
6. Ghali, N. I.; Venton, D. L.; Hung, S. C.; Le Breton, G. C. J. Org. Chem. 1981, 46, 5413–5414.
7. (a) Mäeorg, U.; Ragnarsson, U. Tetrahedron Lett. 1998, 39, 681–684. (b) Grehn, L.; Nyasse, B.; Ragnarsson, U. Synthesis
1997, 1429–1432.
8. Stroh, H. H.; Scharnow, H. G. Chem. Ber. 1965, 98, 1588–1597.
9. Hammick, D. L.; Voaden, D. J. J. Chem. Soc. 1961, 3303–3309.
10. Mlotkowska, B.; Zwierzak, A. Tetrahedron Lett. 1978, 19, 4731–4734.
11. Kukolja, S.; Lammert, S. R. J. Am. Chem. Soc. 1975, 97, 5582–5583.