Efficient N-p-methoxyphenyl amine deprotection through anodic oxidation

Article abstract of DOI:10.1021/jo051867o

A new method of deprotection of N-p-methoxyphenylamines using anodic oxidation in acidic medium is presented. The process furnishes a high yield of amine and is compatible with several oxidable functional groups.

Full text of DOI:10.1021/jo051867o

SCHEME 1. Cleavage of the N-PMP Bond
Efficient N-p-Methoxyphenyl Amine
Deprotection through Anodic Oxidation
Sandra De Lamo Marin,† Thierry Martens,‡
Charles Mioskowski,*,† and Jacques Royer*,‡
Laboratoire de chimie bioorganique, UMR 7514
CNRS-Universite´ Louis Pasteur, Faculty of Pharmacy,
74 route du Rhin, 67401 Illkirch Cedex, France, and
Synthe`se et structure de mole´cules d’inte´reˆt
nitrogen if a clean and efficient deprotection method of
the PMP group is available. The deprotection of the PMP
group is crucial in many cases, and it is then quite
important to have at hand an efficient, selective, and
high-yielding deprotecting method. This is particularly
important in the synthesis of enantiomerically pure
amino acids.
pharmacologique, UMR 8638 CNRS-Universite´ Rene´
Descartes, Faculty of Pharmacy, 4 avenue de l’Observatoire,
75270 Paris Cedex 6, France
charles.mioskowski@pharma.u-strasbg.fr;
jacques.royer@univ-paris5.fr
The cleavage of the N-PMP bond is classically obtained
by oxidation which occurs with formation of quinone and
the corresponding amine (Scheme 1).
Received September 6, 2005
For this transformation, the most widely used reagent
is cerium ammonium nitrate (CAN),4 whereas few pub-
lications reported the use of other reagents such as
hypervalent iodine.2b,3b In most cases, CAN gives the
expected primary amines in good yield. Nevertheless,
there have been some reports in the literature proving
that, in some instances, CAN was poorly effective in
removing the PMP group.5 Modest yields (25-50%) have
been reported, and modified procedures have been pro-
posed. Tomioka, for example, suggested to first acetylate
the NH-PMP group before cleavage or to perform a one-
pot NH-PMP deprotection and N-acetylation to improve
the yield of the oxidative reaction.6 Additionally, it can
be expected that some sensitive functions are not com-
patible with this very powerful oxidative reagent;7 thus,
polyfunctionalized compounds require more selective
oxidation processes. Furthermore, massive quantities of
CAN are needed due to high molecular weight and the
use of several molecular equivalents of reagent.
A new method of deprotection of N-p-methoxyphenylamines
using anodic oxidation in acidic medium is presented. The
process furnishes a high yield of amine and is compatible
with several oxidable functional groups.
In recent years, p-anisidine has emerged as a very
attractive reagent in several synthetic processes and
particularly in the development of new powerful asym-
metric strategies. Its enhanced nucleophilicity and its
effectiveness to form imines with carbonyl compounds
render this reagent quite useful and versatile.1 It was
also proven that the addition of several nucleophiles to
the imines under the control of asymmetric catalysts gave
better stereoselectivity and yields compared to imines
derived from other anilines or alkylamines.2 This was
recently applied to the asymmetric version of some very
well-known reactions such as the Mannich reaction. For
example, the asymmetric Mannich reaction with p-
anisidine and using L-proline as catalyst was reported
with ee’s as high as 99%. Asymmetric synthesis of amino
acids, â-lactams, and saturated N-heterocycles was also
described via this strategy.3
We were also confronted with difficulties in the depro-
tection of p-methoxyphenyl with CAN. In the course of
the optimization of the CAN oxidation, we decided to try
(3) (a) Cordova, A.; Watanabe, S.-I.; Tanaka, F.; Notz, W.; Barbas,
C. F., III. J. Am. Chem. Soc. 2002, 124, 1866-1867. (b) Cordova, A.;
Notz, W.; Zhong, G.; Betancort, J. M.; Barbas, C. F., III. J. Am. Chem.
Soc. 2002, 124, 1842-1843. (c) Watanabe, S.-I.; Cordova, A.; Tanaka,
F.; Barbas, C. F., III. Org. Lett. 2002, 4, 4519-4522. (d) Chowdari, N.
S.; Suri, J. T.; Barbas, C. F., III. Org. Lett. 2004, 6, 2507-2510. (e)
Mu¨nch, A.; Wendt, B.; Christmann, M. Synlett 2004, 15, 2751-2755.
(4) (a) Sakai, T.; Korenaga, T.; Washio, N.; Nishio, Y.; Minami, S.;
Ema, T. Bull. Chem. Soc. Jpn. 2004, 77, 1001-1007. (b) Hata, S.;
Iguchi, M.; Iwasawa, T.; Yamada, K.; Tomioka, K. Org. Lett. 2004, 6,
1721-1723. (c) Overman, L. E.; Owen, C. E.; Pavan, M. P. Org. Lett.
2003, 5, 1809-1812. (d) Chi, Y.; Zhou, Y.-G.; Zhang, X. J. Org. Chem.
2003, 68, 4120-4122. (e) Fustero, S.; Garcia Soler, J.; Bartolome´, A.;
Sanchez Rosello, M. Org. Lett. 2003, 5, 2707-2710. (f) Fustero, S.;
Bartolome, A.; Sanz-Cervera, J. F.; Sanchez-Rosello, M.; Soler, J. G.;
Ramirez de Arellano, C.; Fuentes, A. S. Org. Lett. 2003, 5, 2523-2526.
(g) Cordova, A. Synlett 2003, 1651-1654.
(5) (a) Shimizu, M.; Kimura, M.; Watanabe, T.; Tamaru, Y. Org. Lett.
2005, 7, 637-640. (b) Di Fabio, R.; Alvaro, G.; Bertani, B.; Donati, D.;
Giacobbe, S.; Marchioro, C.; Palma, C.; Lynn, S. M. J. Org. Chem. 2002,
67, 7319-7328. (c) Haak, E.; Bytschkov, I.; Doye, S. Eur. J. Org. Chem.
2002, 457-463. (d) Gittins (ne´e Jones), C. A.; North, M. Tetrahedron:
Asymmetry 1997, 8, 3789-3799. (e) Taniyama, D.; Hasegawa, M.;
Tomioka, K. Tetrahedron Lett. 2000, 41, 5533-5536.
Eventually the possibility to cleave the p-methoxyphe-
nyl (PMP) group through oxidative process constitutes a
further advantage contributing to the usefulness of
p-anisidine. It thus constitutes a very good source of
† Universite´ Louis Pasteur.
‡ Universite´ Rene´ Descartes.
(1) (a) Hagiwara, E.; Fujii, A.; Sodeoka, M. J. Am. Chem. Soc. 1998,
120, 2474-2475. (b) Nishiwaki, N.; Knudsen, K. R.; Gothelf, K. V.;
Jorgensen, K. A. Angew. Chem., Int. Ed. 2001, 40, 2992-2995. (c) Ji,
J.-X.; Au-Yeung, T. T.-L.; Wu, J.; Yip, C. W.; Chan, A. S. C. Adv. Synth.
Catal. 2004, 346, 42-44. (d) Notz, W.; Watanabe, S.-I.; Chowdari, N.
S.; Zhong, G.; Betancort, J. M.; Tanaka, F.; Barbas, C. F., III. Adv.
Synth. Catal. 2004, 346, 1131-1140. (e) Hata, S.; Iguchi, T.; Iwasawa,
T.; Yamada, K.-I.; Tomioka, K. Org. Lett. 2004, 6, 1721-1723.
(2) (a) List, B.; Pojarliev, P.; Biller, W. T.; Martin, H. J. J. Am. Chem.
Soc. 2002, 124, 827-833. (b) Ibrahem, I.; Casas, J.; Cordova, A. Angew.
Chem., Int. Ed. 2004, 43, 6528-6531.
(6) (a) Inoue, I.; Shindo, M.; Koga, K.; Tomioka, K. Tetrahedron
1994, 50, 4429-4438. (b) Hasegawa, M.; Taniyama, D.; Tomioka, K.
Tetrahedron 2000, 56, 10153-10158.
(7) Ho, T.-L. In Encyclopedia of Reagents for Organic Synthesis;
Paquette, L. A., Ed.; Wiley: Chichester, 1995; Vol. 2, pp 1026-1028.
10.1021/jo051867o CCC: $30.25 © 2005 American Chemical Society
Published on Web 10/29/2005
10592
J. Org. Chem. 2005, 70, 10592-10595

to reproduce the deprotection of N-p-methoxyphenyl
N-methylbenzylamine (1a) described in the literature
with 81% yield:8 in our hands, under the same reaction
conditions, we could not detect the formation of 2a.
However, a tedious optimization of the reaction condi-
tions by varying temperature, reagent equivalents, sol-
vent, and acidic medium allowed us to attain an accept-
able but hardly reproducible 70% yield.
According to these observations, we developed an
alternative method based on anodic oxidation to achieve
this goal. This method exhibits several advantages since
electrochemical approaches permit us to adjust the
oxidative potential to the exact value required for the
deprotection and therefore are respectful of other oxidable
functional groups.
To the best of our knowledge, no data are available in
the literature concerning the electrochemical deprotection
of N-PMP amines.9
Herein we report the first successful N-p-methoxy-
phenyl cleavage of amines (mainly secondary amines)
using anodic oxidation and show that it represents an
interesting alternative to oxidative reagents since high-
yielding deprotection was observed in all cases we
examined even in the presence of sensitive functional
groups present on the structure.
Anodic R-oxidation of amines and particularly N-
arylamines has been broadly described in the literature.10
This latter reaction has to be circumvented to avoid
possible side reactions. Furthermore, it is noteworthy
that N-p-methoxyphenyl oxidative cleavage leads to
primary amine 2, which is at least as easily oxidable as
the starting material 1. This constitutes, a priori, a
serious drawback. Nevertheless, we thought that we
could take advantage of the difference in basicity between
secondary N-p-methoxyphenylamine 1 and primary amine
2 resulting from the desired cleavage reaction. N-p-
Methoxyphenylamines 1, which are substituted anilines,
are less basic than corresponding alkylamines formed
during the reaction. The latter are therefore selectively
protonated by addition of at least 1 equiv of acid and
consequently protected against further oxidation by
protonation.
After some trials, the anodic oxidation of several N-p-
methoxyphenylamines 1 (Table 1) was found to be quite
efficient, leading to the primary amines 2 in high yields.
The reaction was conducted at a controlled potential (i.e.,
0.85 V versus saturated calomel electrode, SCE) at a
platinum electrode in CH3CN/H2O 9:1 mixture and in the
presence of 2 equiv of HClO4 to give a clean deprotection
of the p-methoxyphenyl group in all examples shown in
Table 1. The given yields are those of isolated products,
while HPLC analysis of the crude reaction mixture
showed the complete disappearance of the starting mate-
rial and the formation of only two new products: the
quinone and the expected amine 2, which was easy to
separate from the quinone by simple acid/base extraction
and to isolate. The regioselectivity of this oxidation is
complete since no product resulting from oxidation at the
R-position of nitrogen was detected. We also compared
our results with deprotection with CAN: the yields were
generally found to be lower with this chemical reagent
and are those obtained after optimization (Table 1).
Several functional groups are compatible with the
electrochemical process: olefin (1b), ester (1e,f), ketone
(1e), and phenol (1f) are not affected. The method is
respectful of chiral centers if present: the anodic oxida-
tion of 1e led to the corresponding primary amine 2e
isolated in a good 87% yield without loss of enantiomeric
purity.
The N-p-methoxyphenyl cleavage was also found to be
efficient in the case of tertiary amines: N-methyl meth-
ylbenzylamine 2d was obtained from its N-p-methoxy-
phenyl parent 1d in 76% isolated yield.
As shown in entry 7, the 2,4-dimethoxyphenyl group
of compound 1g is also easily removed by this procedure.
In our hands, CAN was found totally ineffective in this
case.
Deprotection of the phenylglycine derivative 1f was
performed in an excellent 94% yield by the electrochemi-
cal process without oxidation of the phenol group and in
sharp contrast with the CAN method that gave a low
conversion (entry 6).
To emphasize the interest of controlled oxidation
potentials, we investigated the behavior of 1,3-dithiane
and p-methoxybenzyl groups in anodic oxidative condi-
tions. A mixture of 1a and a thioketal 3 was electrolyzed
at 0.85 V versus SCE (Scheme 2). The latter was
recovered unchanged, while a clean deprotection of
p-methoxyphenyl was observed. This result is noteworthy
since thioketals are classically cleaved by CAN or under
anodic oxidation using upper potential values.11 A com-
plete disappearance of the thioketal compound 3 was
noticed in the presence of the strong oxidant CAN.
Since no oxidation R to nitrogen was observed even at
benzylic position (entries 1, 4, and 7), we anticipated that
N-p-methoxybenzyl groups (-N-PMB) should be resistant
to the anodic oxidation conditions we used. Indeed, under
these conditions, amine 1h was recovered totally un-
changed, whereas this classical protecting group was
cleaved using CAN oxidation.12 To demonstrate that this
selectivity could be quite useful to perform orthogonal
deprotection, we studied the selective electrochemical
N-PMP deprotection of two compounds, 1i and 1j, bearing
both the PMP and the PMB groups. As shown in Table
1 (entries 10 and 11), the PMP groups of secondary amine
1i and amide 1j were easily cleaved via that anodic
oxidation without altering the PMB group.
In summary, we have shown in a series of various
examples that anodic oxidation realized at fixed potential
constitutes an alternative method to the CAN procedure
for removal of N-p-methoxyphenyl group. The method is
(8) Chi, Y.; Zhou, Y.-G.; Zhang, X. J. Org. Chem. 2003, 68, 4120-
4122.
(9) (a) Only one example of cleavage of N-p-methoxyphenyl amides
(namely â-lactames derivatives) is reported: Corley, E. G.; Karady,
S.; Abramson, N. L. Tetrahedron Lett. 1988, 29, 1497-1500. (b) General
anodic oxidation study of p-methoxyanilides was described to give
quinone imine ketals: Swenton, J. S.; Bonke, B. R.; Chen, C.-P.; Chou,
C.-T. J. Org. Chem. 1989, 54, 51-58. (c) Ikenoya, S.; Masui, M.;
Ohmori, H.; Sayao, H. J. Chem. Soc., Perkin Trans. 2 1974, 571-576.
(10) (a) Malassene, R.; Toupet, L.; Hurvois, J.-P.; Moinet, C. Synlett
2002, 895-898. (b) Malassene, R.; Vanquelef, E.; Toupet, L.; Hurvois,
J.-P.; Moinet, C. Org. Biomol. Chem. 2003, 1, 547-551.
(11) (a) Cristau, H. J.; Chabaud, B.; Christol, H. J. Org. Chem. 1984,
49, 2023-2025. (b) Tsai, Y.-M.; Nieh, H.-C.; Cherng, C.-D. J. Org.
Chem. 1992, 57, 7010-7012.
(12) (a) Adams, H.; Anderson, J. C.; Peace, S.; Pennell, A. M. K. J.
Org. Chem. 1998, 63, 9932-9934. (b) Hanrahan, J. R.; Taylor, P. C.;
Errington, W. J. Chem. Soc., Perkin Trans. 1 1997, 493-502.
J. Org. Chem, Vol. 70, No. 25, 2005 10593

TABLE 1. Deprotection of the PMP Group by Anodic and CAN Oxidation
a At 0.85 V in the presence of 2 equiv of HClO4 (see General Anodic Oxidation Method). b Optimized conditions with CAN at controlled
temperature (°C). c Isolated yields. d 100% conversion, cleavage products (anisaldehyde) as well as imine were found to be formed.
10594 J. Org. Chem., Vol. 70, No. 25, 2005

SCHEME 2. Selective Deprotection of the PMP Group in the Presence of the 1,3-Dithiane
potential was maintained at a constant value of 0.85 V. The
highly selective, allowing the presence of several sensitive
functional groups. The experimental procedure is very
simple, and a clean reaction allows the isolation of
deprotected amines in high yield.
Furthermore, this method is applicable to large amounts
of material with cheap and environmentally friendly
reagents and conditions. It is noticeable that this process
is very easy to perform with basic electrochemical equip-
ment.
electrolysis was stopped when the current was lowered to
residual value (about 1-5 mA compared to an initial value of
40-50 mA) classically after 2 or 3 h. Most of the organic solvent
was then evaporated under vacuum, and a 0.1 N HCl solution
(50 mL) was added before the solution to be extracted with
diethyl ether to remove the quinone. The aqueous mixture was
made alkaline (0.1 N NaOH) and then extracted with diethyl
ether. The ethereal solution was dried (Na2SO4), and the solvent
was removed in vacuo to furnish amine 2.
Experimental Section
Supporting Information Available: Preparation of start-
ing materials and copies of 1H and 13C NMR spectra of
unknown compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
General Anodic Oxidation Method. Protected amine 1 (0.5
mmol) was dissolved in a mixture of CH3CN (90 mL) and water
(10 mL) that contained NaClO4 (5 mmol) and HClO4 (1 mmol).
The electrolysis was conducted at 0 °C, under nitrogen, in a
divided glass cell equipped with two platinum electrodes. The
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