A General, Selective, High-Yield N-Demethylation Procedure for Tertiary Amines by Solid Reagents in a Convenient Column Chromatography-like Setup

Article abstract of DOI:10.1021/ol036319g

(Equation presented) A traditional preparative chromatographic column can be used to achieve quantitative N-demethylation of tertiary N-methylamines and alkaloids. The filling is the crucial part and is loaded with different solid reagents in three reaction zones. The parent compound is charged on the column, and the neat N-demethylated secondary amine leaves the column some minutes later.

Full text of DOI:10.1021/ol036319g

ORGANIC
LETTERS
2004
Vol. 6, No. 4
541-544
A General, Selective, High-Yield
N-Demethylation Procedure for Tertiary
Amines by Solid Reagents in a
Convenient Column
Chromatography-like Setup
Thomas Rosenau,* Andreas Hofinger, Antje Potthast, and Paul Kosma
Institute of Chemistry, Christian-Doppler Laboratory, UniVersity of Natural Resources
and Applied Life Sciences, Vienna, Austria
thomas.rosenau@.boku.ac.at
Received November 27, 2003
ABSTRACT
A traditional preparative chromatographic column can be used to achieve quantitative N-demethylation of tertiary N-methylamines and alkaloids.
The filling is the crucial part and is loaded with different solid reagents in three reaction zones. The parent compound is charged on the
column, and the neat N-demethylated secondary amine leaves the column some minutes later.
Tertiary N-methyl groups represent key elements in many
natural products, especially in the realm of alkaloids and
related drugs. In drug design, pharmacological developments,
and metabolic studies, the removal or replacement of
N-methyl substituents is a frequently required synthetic step.
While nature is able to accomplish this N-demethylation
elegantly by means of oxidative (P450) enzymes, producing
N-desmethyl compounds from the corresponding tertiary
N-methylamines remains a comparatively intricate task in
organic chemistry, especially in the case of complex natural
products.
N-Methyl groups exhibit superior stability toward many
kinds of reaction conditions, which is an obstacle to cleaving
N-methyl groups in molecules with other functional groups.
Although several procedures are known to effect N-de-
methylation, they are often incompatible with common
requirements for high yields, chemoselectivity, and mild
reaction conditions.1 Especially the standard methods, em-
ploying BrCN (Von Braun reaction)2 or chloroformates,3
suffer from these disadvantages. Later approaches, using for
instance diethyl azodicarboxylate4 or N-iodosuccinimide,5
give excellent yields in special cases but have limited general
applicability. Also, various photochemical approaches avail-
(1) Marson, C. M.; Hobson, A. D. ComprehensiVe Organic Functional
Group Transformations; Katritzky, A. R., Meth-Cohn, O., Rees, C. W.,
Eds.; Pergamon Press: New York, 1995; Vol. 5, p 302.
(2) (a) von Braun, J. Chem. Ber. 1907, 40, 3914. (b) von Braun, J. Chem.
Ber. 1909, 42, 2219. (c) von Braun, J. Chem. Ber. 1911, 44, 1250.
(3) For examples, see: (a) Flynn, E. H.; Murphy, H. W.; McMahon, R.
E. J. Am. Chem. Soc. 1955, 77, 3104. (b) Morimoto, S.; Misawa, Y.; Adachi,
T.; Nagate, T.; Watanabe, Y.; Omura, S. J. Antibiot. 1990, 286. (c)
Watanabe, Y.; Kashimura, M.; Asaka, T.; Adachi, T.; Morimoto, S.
Heterocycles 1993, 36, 761. (d) Campbell, A. L.; Pilipauskas, D. R.; Knanna,
I. K.; Rhodes, R. A. Tetrahedron Lett. 1987, 28, 2331. (e) Peat, A. J.;
Buchwald, S. L. J. Am. Chem. Soc. 1996, 118, 1028.
(4) Fang, Q. K.; Senanayake, C. H.; Han, Z.; Morency, C.; Grover, P.;
Malone, R. E.; Bulter, H.; Wald, S. A.; Cameron, T. S. Tetrahedron:
Asymmetry 1999, 10 (23), 4477.
(5) Stenmark, H. G.; Brazzale, A.; Ma, Z. J. Org. Chem. 2000, 65 (12),
3875.
10.1021/ol036319g CCC: $27.50 © 2004 American Chemical Society
Published on Web 01/23/2004

able6 have a satisfying outcome but require rather specialized
reagents and are mostly applicable to one special alkaloid
only. In general, there is currently no robust, all-purpose
N-demethylation procedure.
Here we would like to communicate a general method for
the selective N-demethylation of tertiary N-methylamines (1)
in near-quantitative yields, on a scale of up to 10 g. The
approach takes the “detour” via the corresponding N-oxides
(Figure 1), as it was elaborated from previous results on
requiring only solid chemicals in a chromatography-like
setup: a column containing the coreactants as fillings is
charged with the tertiary N-methylamine (1), which passes
through the different reaction zones and leaves the column
as neat N-desmethyl compound (5) a few minutes later in
more than 90% yield without any need for further purifica-
tion.
The N-demethylation approach consists of three stages,
corresponding to the three “zones” of the demethylation
column (see Figure 1): first, the intermediate formation of
the tertiary amine N-oxide 2, second, the deoxygenative
demethylation into secondary amine 5 and HCHO,8 and third,
the removal of the latter upon its formation.
The oxidation (step 1) was favorably carried out by sodium
percarbonate Na2CO3‚1.5 H2O2, which converts tertiary
amines quantitatively into the corresponding amine N-oxides,
as previously demonstrated.9 Primary and secondary amines
and hydroxyls remained unchanged. The reagent combined
the oxidative power of hydrogen peroxide as the oxidant of
choice for amine N-oxide generation with the preparative
advantages of a solid reagent10 such as insolubility in all
nonaqueous organic solvents and was thus superior to
comparable reagents such as urea-H2O2 adduct or perbo-
rates. A 5-fold molar excess of the oxidant and reaction times
over 10 min guaranteed quantitative conversion of the tertiary
amine.11
The following deoxygenative demethylation (step 2) of
the N-oxide intermediate 2 is the key step in the N-
demethylation sequence. The autocatalytic degradation of
tertiary N-methylamine N-oxides into secondary amines and
HCHO catalyzed by carbenium-iminium ions12 (Mannich
intermediates) was the optimal choice for this reaction, as it
proceeded in a quantitative and strictly methyl-selective
Figure 1. Column setup for the N-demethylation of tertiary
N-methylamines.
amine N-oxides and their different degradation pathways.7
The main feature is a deceptively simple work routine,
(6) (a) Nelson, A.; Chou, S.; Spencer, T. A. J. Am. Chem. Soc. 1975, 97
(3), 648. (b) Baciocchi, E.; Lanzalunga, O.; Lapi, A.; Manduchi, L. J. Am.
Chem. Soc. 1998, 120 (23), 5783. (c) Sako, M.; Shimada, K.; Hirota, K.;
Maki, Y. J. Am. Chem. Soc. 1986, 108 (19), 6039. (d) Santamaria, J.;
Ouchabane, R.; Rigaudy, J. Tetrahedron Lett. 1989, 30, 2927. (e) For a
review, see: Ripper, J. A.; Tiekink, E. R. T.; Scammells, P. J. Bioorg.
Med. Chem. Lett. 2001, 11 (4), 443.
Figure 2. Mechanism of the deoxygenative demethylation reaction
(step 2). The fate of the starting amine N-oxide through the
conversion is shown by gray shading.
(7) For a review see: Rosenau, T.; Potthast, A.; Sixta, H.; Kosma, P.
Prog. Polym. Sci. 2001, 26 (9), 1763.
542
Org. Lett., Vol. 6, No. 4, 2004

Table 1. N-Demethylation of Tertiary N-Methylamines According to the Column Approach
starting tertiary N-methylamine N-demethylated product
1-methylmorpholine (6)
yield [%]
morpholine
96
89
96
98
98
92
92
91
93
94
94
dibenzylmethylamine (7)
1-methylimidazole (8)
N,N-dibenzylamine
imidazole
N-ethyl-N-methylaniline (9)
1-methylpiperidine (10)
N-ethylaniline
piperidine
N,N-dimethylaniline (11)
N-methylaniline
9-methyl-9H-carbazole (12)
2-dimethylaminoethanol (13)
tert-butyldimethylamine (14)
ethyl 1-methyl-piperidine-3-carboxylate (15)
methyl 1-methyl-1,2,5,6-tetrahydro-pyridine-3-carboxylate
(arecoline, 16)
carbazole
2-methylaminoethanol
tert-butylmethylamine
ethyl piperidine-3-carboxylate (ethyl nipecotate)
methyl 1,2,5,6-tetrahydro-pyridine-3-carboxylate
(()-nicotine (17)
(()-nornicotine
95
manner. The organic-insoluble sodium salt of 4,6-dichloro-
2-hydroxy-[1,3,5]triazine (3) was used to induce the forma-
tion of N-(methylene)iminium ions (4), which then carry the
reaction further, see Figure 2. Larger amounts of inducing
agent, more than 1.5% relative to the starting amine, caused
the reaction to become uncontrollable (which manifested in
an esthetically rewarding, fountain-like discharge of the
column filling, but was otherwise of little value). The
evolving HCl was trapped in situ by pulverized anhydrous
potassium carbonate; also here, the trapping agent and the
trapping product are insoluble in organic solvents. Cyanuric
chloride as the inducer13 as well as stable Mannich inter-
mediates such as Eschenmoser’s salt proved to be overly
reactive (and were moreover soluble) and thus unsuitable.
Yield losses, even though in the low percent range, were
mainly due to the side reaction between the inducer and
already formed 5.
The purification (step 3) brings the N-demethylation
sequence to a close. The HCHO formed from the former
N-methyl group is removed by absorption on a 1/1 mixture
of neutral and basic alumina.14 While other absorbers such
as activated carbon, starch, or cellulose powder also ef-
ficiently absorbed the formaldehyde, they failed to cleave
off and then bind the part of HCHO that was still bound to
the product amine as N-hydroxymethyl compound, and they
might retain larger amounts of product in addition.
interaction between amine N-oxide and cyanuric chloride
derivatives13 so that no N-demethylation occurs. Chloroform
was the eluant of choice. CH2Cl2, Et2O, and other low-boiling
solvents must be avoided because of the exothermicity of
steps 1 and 2, which might cause cavity formation and impair
the smooth passage through the column. The compatibility
of the procedure with different functional groups was
preliminarily checked.15 While double bonds as well as
hydroxy, ester, amide, and epoxide groups did not interfere,
carboxyl groups and primary as well as secondary amines
did. The latter consume the inducer in step 2; the former are
retained by the aluminum oxide used in step 3.
The column technique16 was optimized with regard to a
quick (no clogging of the column) and complete conversion
(no starting material left) as well as minimum retention of
products (no reactions and absorption), employing N-
methylmorpholine (6) and dibenzylmethylamine (7). Several
other tertiary N-methylamines (8-17) were demethylated
according to the present approach, among them some
In the demethylation sequence, the presence of water must
be avoided. First, water lowers the efficiency of the deoxy-
genative demethylation step by quenching the catalytically
active carbenium-iminium ions into N-hydroxymethyl com-
pounds, and second, it changes the mechanism of the
(8) Process thus resembles the metabolic N-dealkylation pathway, which
mostly starts with R-hydroxylation, the leaving group being cleaved in the
aldehyde stage.
(9) Rosenau, T.; Potthast, A.; Kosma, P. Synlett 1999, 1972.
(10) Muzart, J. Synthesis 1995, 11, 1325.
(11) Reaction time refers to the time of contact between the solute and
the respective column filling as the solid coreactant.
(12) Rosenau, T.; Potthast, A.; Kosma, P.; Chen, C. L.; Gratzl, J. S. J.
Org. Chem. 1999, 64, 2166.
(13) Rosenau, T.; Potthast, A.; Kosma, P. Tetrahedron 2002, 58 (49),
9808.
(14) Acidic alumina must be avoided, as it retains amines. See also:
Thompson, A. M. Tellus 1980, 32, 376.
Figure 3. Demethylated tertiary N-methylamines. Cleaved CH3
groups are indicated by an arrow.
Org. Lett., Vol. 6, No. 4, 2004
543

medicinally important alkaloids.17 Table 1 and the corre-
sponding Figure 3 give illustrative examples. In all cases,
the N-desmethyl compound was obtained in analytical purity
simply by passing through the demethylation column,
followed by conversion into the hydrochloride and evapora-
tion of CHCl3 as the eluant. The astonishing selectivity of
the dealkylation allowed methyl cleavage in the presence of
other alkyl groups, which appeared to be completely inert
under the reaction conditions. This behavior can be explained
with the transition state geometry of the deoxygenative
demethylation step, in which the reaction centers, the C-N
of the attacking carbenium-iminium ion 4 and the O-N-
C-H structure of the amine N-oxide 2, assemble in a six-
membered, chairlike arrangement.18 Here, a methyl group
is sterically much more readily accommodated than any
larger substituent.
Weighing the pros and cons of the procedure, the limitation
to N-methyl groups can be regarded as a drawback but also
as a bonus because it means complete methyl selectivity.
Moreover, demethylation occurs strictly just once in di-
methylamino structures. The limitation to tertiary amines is
a clear shortcoming, as is the requirement of an oxidation
step, which might interfere with oxidant-sensitive structures,
although this was not reflected in yield losses so far. The
exclusive use of solid and cheap, mostly inorganic reagents
is positive with regard to environmental concerns, as it limits
the use of organic solvents and the production of related
waste. The broad applicability along with good yields, but
most notably the quick and easy protocol, are the main
benefits of the method, which is currently being applied to
candidates out of the atropine and amaryllidaceae alkaloid
group.
(15) Functional groups were contained either in the amines to be
demethylated or in non-amine test compounds, of which the clear passage
through the column without yield loss was taken as indication of minimum
interference with the column fillings.
(16) Preparation of Column. Four different column fillings (mixtures
A-D) were prepared as suspensions of the solids in the eluant CHCl3
(mixture A, silica gel; mixture B, a 1/1 mixture of neutral and basic alumina
(Brockmann grade 1); mixture C, a 3/1/1 mixture of silica gel, pulverized
anhydrous K2CO3 and neutral alumina (Brockmann grade 1); mixture D, a
1/3 mixture of pulverized sodium percarbonate and silica gel. A standard
chromatography column (i.d. 2.4 cm) is loaded successively with the fillings;
filling heights given in the following refer to the settled solid material and
are calculated for 10 mmol of amine to be N-demethylated. The following
solids are charged from the bottom: sea sand (∼1 cm), mixture A (∼2
cm), mixture B (10 cm), mixture C containing 0.1 mmol of freshly prepared
and dried 3 (4 cm), a mixture of 3 (0.05 mmol) and 2 g of silica gel, mixture
A (∼2 cm), mixture D (10 cm), and sea sand (∼3 cm).
Acknowledgment. This work was supported by the
Austrian Science Fund (FWF) Grant P14687.
(17) N-Demethylation Procedure. Tertiary N-methylamine (10 mmol)
was dissolved in CHCl3 (2 mL) and applied to the column. Chloroform
(30 mL) was added on top, and 30 mL of eluant was withdrawn from the
bottom; the flow was stopped for 10 min (contact time between amine and
mixture D, which can be extended without problems). An eluant reservoir
was added, and elution was resumed at 2 mL/min until no more amine left
the column (TLC control). The eluate fractions were combined, and the
solvents were evaporated in vacuo to give the pure N-demethylated amine.
In the case of low-boiling amines, the combined eluate fractions were treated
with ethereal HCl prior to solvent evaporation to give the product amines
as hydrochlorides (for examples and yields, see Table 1).
Supporting Information Available: Typical experimen-
tal procedure, proof of purity (elemental analyses), and
typical NMR spectra of N-demethylated amines. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL036319G
(18) This is also supported by DFT computations.
544
Org. Lett., Vol. 6, No. 4, 2004