One-pot selective cleavage of prenyl carbamates using iodine in methanol followed by zinc

Article abstract of DOI:10.1016/j.tetlet.2003.10.058

The prenyloxycarbonyl (Preoc) moiety was efficiently removed from carbamates to provde the corresponding amines in good to excellent yields (63-88 percent) by using iodine in methanol followed by treatment of the resulting β-methoxyiodides by zinc powder. The reaction conditions are compatible with the presence of a number of functional groups such as Boc and Cbz carbamates, sulfides, double bonds, indoles and aromatic methyl ethers.

Full text of DOI:10.1016/j.tetlet.2003.10.058

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 9127–9129
One-pot selective cleavage of prenyl carbamates using iodine in
methanol followed by zinc
Jean-Michel Vate`le*
Laboratoire de Chimie Organique 1, UMR 5181 CNRS, Universite´ Claude Bernard, CPE, 43 Boulevard du 11 Novembre 1918,
69622 Villeurbanne, France
Received 18 September 2003; revised 7 October 2003; accepted 8 October 2003
Abstract—The prenyloxycarbonyl (Preoc) moiety was efficiently removed from carbamates to provide the corresponding amines
in good to excellent yields (63–88%) by using iodine in methanol followed by treatment of the resulting b-methoxyiodides by zinc
powder. The reaction conditions are compatible with the presence of a number of functional groups such as Boc and Cbz
carbamates, sulfides, double bonds, indoles and aromatic methyl ethers.
© 2003 Elsevier Ltd. All rights reserved.
Amines, because of their high reactivity, must be pro-
tected before synthetic operations. Very often, these
protecting groups have the function of negating the
amine’s basicity, a task realized by acylation. However,
the deprotection of resulting amides or carbamates
requires conditions that may damage the natural
product or functionalities thereon. For these reasons,
an impressive arsenal of amino protecting groups and
of techniques of cleavage of these latter have been
developed.1 Nevertheless, because of the increasing
complexity of the molecules synthesized and also only
very few amino protecting groups have found wide
applications, new protecting groups with modulated
reactivity and new cleavage techniques of existing pro-
tecting groups are still needed.
In preliminary experiments, the two protocols that we
developed for the deprotection of prenyl ethers,2 were
tested for the cleavage of the carbamate derived from
2-phenylethylamine 1b. In both cases, after stirring for
24 h at room temperature, the carbamate 1b remained
unchanged. In methanol, on the other hand, iodine
Scheme 1.
In an ongoing project aimed to develop the uses of
prenyl group in the protection of alcohols and amines,
we have recently reported that deprotection of prenyl
ethers could be carried out chemoselectively, at room
temperature, with iodine in dichloromethane or with
dichlorodicyanoquinone (DDQ) in
a
mixture of
dichloromethane and water.2
In this report, we wish to present a one-pot procedure
for the cleavage of prenyl carbamates by first iodoether-
ification with iodine in methanol followed by reductive
b-elimination with zinc (Scheme 1).
Keywords: amines; carbamates; iodine; deprotection; zinc.
* Fax: 33.4.72.43.12.14; e-mail: vatele@univ-lyon1.fr
Scheme 2.
0040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.10.058

9128
J.-M. Vate`le / Tetrahedron Letters 44 (2003) 9127–9129
Table 1. One-pot deprotection of prenyl carbamates with I2 in MeOH followed by Zna
reacted smoothly with 1b to afford the b-methoxyiodide
3 (Scheme 2).
3. This addition led almost instantaneously to the dis-
coloration of the solution (ZnI2 formation) with con-
comitant bubbling due to decarboxylation and heat
formation. Thus, under the same reaction conditions,
the liberation of the amine took place very readily
without the need for heating. The reasons for the
acceleration of the release of amine 1b with zinc in the
presence of iodine are uncertain. It is possible that
iodine, present in the medium, transforms zinc into an
active species, as it does with magnesium,5 achieving its
rapid oxidative insertion to the CꢀI bond.6 It is admit-
This compound bears a 2-haloalkoxycarbonyl system
(a2d)3 which is known to fragment easily in the pres-
ence of a metal.4 Indeed, treatment of 3 with 2 equiva-
lents of zinc in refluxing methanol for 30 min furnished
the 2-phenylethylamine 2b in 70% yield (not optimized).
In order to simplify the process, zinc was directly added
to the reaction mixture containing the b-methoxyiodide

J.-M. Vate`le / Tetrahedron Letters 44 (2003) 9127–9129
9129
ted that magnesium halides initiate the formation of
Grignard reagents,7 zinc iodide, formed by reaction of
zinc with iodine in excess, maybe play the same role in
the formation of the organozinc intermediate.
3. Ho, T. L. Heterocyclic Fragmentation of Organic
Molecules; Wiley: New York, 1993; p. 49.
4. For a good example of this fragmentation, see the depro-
tection of trichloroethylcarbamates: Mineno, T.; Choi,
S.-R.; Avery, M. A. Synlett 2002, 883–886 and references
cited therein.
In order to examine the generality of the method of
prenyl carbamates deprotection, diversely functional-
ized prenyl carbamates8 were prepared and the results
of this study are presented in Table 1. As depicted in
Table 1,9,10 amines 2a–k were obtained in acceptable to
excellent yields (53–88%). Commonly used amino pro-
tecting groups such as Boc and Cbz groups are stable
under our conditions of Preoc deprotection (entries 10,
11). In view of the oxidative nature of the medium,11
deprotection of the methionine derivative (entry 8)
emphasizes the mildness of the method. Compound 1d
bearing a double bond, in the presence of 4 equivalents
of iodine and 8 equivalents of zinc, was deprotected in
an excellent yield (88%, entry 4). As seen in entry 5, the
N-Preoc group could be removed chemoselectively in
the presence of a prenyl ether in an acceptable yield
(63%). The release of the tetrahydroisoquinoline alka-
loid 2c occurred in good yield without affecting the two
methoxy groups (entry 3). In the case of N-Preoc
proline benzyl ester 1g, removal of the carbamate hap-
pened with complete transesterification by methanol
(entry 7). As no transesterication of the benzyl ester of
the isonipecotic acid derivative 1f was observed, in the
same reaction conditions, we assume that the easy
formation of the methyl ester 2g is very likely the result
of an intramolecular delivery of the methoxide anion to
the carbonyl site of the ester by zinc, coordinated to the
nitrogen of the pyrolidine ring of the proline deriva-
tive.12 Surprisingly, in the presence of iodine in
5. Rieke, R. D.; Sell, M. S. In Handbook of Grignard
Reagents; Rakta, G. S.; Rakta, P. E., Eds.; Silverman,
Marcel Dekker, 1996; p. 53.
6. Activation of zinc by iodine is precedented, see for exam-
ple: (a) Palmer, M. H.; Reid, J. A. J. Chem. Soc. 1960,
931–938; (b) Huo, S. Org. Lett. 2003, 5, 423–425.
7. Garst, J. F.; Ungvary, F. In Grignard Reagents: New
Developments; Richey, H. G., Ed.; John Wiley, 2000; Vol.
7, p. 185.
8. Prenyl carbamates 1a–k were prepared from the corre-
sponding amines and prenyl p-nitrophenyl carbonate in
the presence of a catalytic amount of DMAP.
9. All new compounds gave satisfactory physical and ana-
lytical data.
10. Typical procedure for the cleavage of the N-Preoc of
compound 1h. To a solution of N-Preoc-L-methionine
methyl ester 1h (0.25 g, 0.9 mmol) in methanol (6 mL)
was added, at room temperature, iodine (0.46 g, 1.8
mmol). After stirring 7 h, zinc14 (0.24 g, 3.6 mmol) was
added and the stirring was continued for 30 min. After
evaporation to dryness, CH2Cl2 and saturated Na2CO3
solution were added and the formed precipitate and zinc
in excess were filtered through a funnel. The aqueous
layer was extracted once with CH2Cl2. The combined
organic layers were washed with brine, dried (Na2SO4)
and evaporated. The residue was purified by chromato-
graphy on silica gel (CH2Cl2–MeOH, 95:5) to give pure
L
-methionine methyl ester as an oil (0.123 g, 83%). It was
methanol, the liberation of the amine of N-Preoc-L-
characterized as its hydrochloride salt: mp 145–149°C;
[h]D=+23.4 (c 1.25, H2O), (lit.15 [h]D=+25.2 (c 5.1,
H2O); mp 147–150°C). 1H NMR (CDCl3, 200 MHz): 2.14
(s, 3H, Me), 2.29 (sextuplet, 2H, J=7.16 and 6.33 Hz),
2.72 (t, 2H, J=7.16 Hz), 3.88 (s, 3H), 4.34 (t, 1H, J=6.33
Hz).13C NMR (CDCl3, 50 MHz): 14.4, 28.9, 29.2, 52.2,
54.2, 171.0.
tryptophan methyl ester 2i occurred directly after stir-
ring for 24 h at room temperature (entry 9). In this
case, the b-methoxyiodide intermediate was not seen by
TLC. We have no mechanistic rationale to explain this
result.
In summary, we have developed a mild and efficient
method for the chemoselective deprotection of prenyl
carbamates using zinc and iodine, two cheap reagents.
Because of its simplicity and chemoselectivity, this pro-
cedure will undoubtedly extend the use of prenyl carba-
mates for the protection of a variety of amine
compounds.13
11. For a study of the iodine oxidation of methionine, see:
Young, P. R.; Hsieh, L. S. J. Am. Chem. Soc. 1978, 100,
7121–7122.
12. This Zn-mediated intramolecular transesterification is
reminiscent of the intramolecular cleavage of phosphodi-
esters catalyzed by Zn(II) coordinated to amines: (a)
Mollenveld, P.; Engbersen, J. F. J.; Reinhoudt, D. N.
Chem. Soc. Rev. 2000, 29, 75–86; (b) Bonfa`, L.; Gatos,
M.; Mancin, F.; Teulla, P.; Tonellato, U. Inorg. Chem.
2003, 42, 3943–3949.
References
13. Until now, only one method to deprotect the N-Preoc
group has been described: Lemaire-Audoire, S.; Savignac,
M.; Pourcelot, G.; Geneˆt, J.-P.; Bernard, J.-M. J. Mol.
Cat. A: Chem. 1997, 116, 247–258.
1. (a) Kocienski, P. J. Protecting Groups; Thieme: Stuggart,
1994; Chapter 6; (b) Greene, T. W.; Wuts, P. G. M.
Protecting Groups in Organic Synthesis; 3rd ed., John
Wiley and Sons Inc.: New York, 1999; Chapter 7.
2. (a) Vate`le, J.-M. Synlett 2001, 1989–1991; (b) Vate`le,
J.-M. Synlett 2002, 507–509; (c) Vate`le, J.-M. Tetra-
hedron 2002, 58, 5689–5698.
14. Aldrich Chemical Company, zinc dust <10 micron Cata-
log c 20,998-8.
15. Rachele, J. R. J. Org. Chem. 1963, 28, 2898.