Solid-phase synthesis of tertiary N-Methyl amines including tropanes

Full text of DOI:10.1021/cc900108p

J. Comb. Chem. 2010, 12, 5–8
5
gel. We also report results of our approaches to reversible
immobilization of nortropinone on polystyrene type supports
with MOM analogue, BOM analogue, Wang type, PAL-type,
Merrifield, para-C3-T2 triazene, carbamate Wang, and trityl
linkers (Figure 1).
Solid-phase Synthesis of Tertiary N-Methyl
Amines Including Tropanes
Michal Sienkiewicz and Ryszard Lazny*
Institute of Chemistry, UniVersity of Bialystok,
ul. Hurtowa 1, 15-399 Bialystok, POLAND
Reversible Anchoring of the Amino Ketone. The cyclic
secondary amines like nortropinone (1) could, in principle,
be immobilized in a form of a tertiary amine via several
linkers such as REM, Wang, and BAL linkers. The REM
linker could not be used for our purposes because of its
incompatibility with the basic conditions of enolate reactions,
such as the directed aldol reaction. The Wang and BAL type
linkers are typically used for releasing amine derivatives,
usually amides or sulfonamides.37 However, the recent
reports24,25,38 prompted us to investigate their use for
immobilization of amino ketones such as nortropinone. We
found that even though nortropinone could be anchored to
Wang polymer (to give 6) and the 2,6-dimethoxy Wang
polymer (to give 10, PAL type linker)39 very effectively
(87-100%, Table 1, Figure 1), cleavage of this amino ketone
was not feasible. Attempted oxidative cleavage of the Wang
linker 6 (with DDQ26) and simple benzylamine linker 7
derived from Merrifield polymer (with ceric(IV) ammonium
nitrate, CAN27), in our hands, did not provide any amine
products (Figure 1). Therefore, we investigated amino acetal
linkers analogous to MOM and BOM protecting groups40
for amines (8 and 9, Figure 1). Preparation of similar linkers
by two different methods was reported.22,23 Unfortunately,
we were able to obtain only modest loadings of the test
amine, 4-benzylpiperidine or nortropinone 1, via such linkers
prepared by either method (Figure 1). The cleavage provided
poor loadings of released amines (17 and 9%, Table 1)
despite using trifluoroacetic acid (TFA) at different concen-
trations, addition of water, prolonged cleavage times, and
ultrasound. The only practical method for reversible linking
of the amino ketone 1 to polymers in the form of a tertiary
amine was the reactions with Merrifield gel or trityl chloride
gel to form loaded polymers 7 and 3, respectively (Figure
1). The amino ketone could however be cleaved off the
Merrifield support only by the procedure of Leysen et al.28
(action of 1-chloroethyl chloroformate (ACE-Cl) in 1,2-
dichloropropane (DCP), followed by methanolysis) in an
analogy to the known reactions in solution,41-44 albeit with
moderate yield (37% of the theoretical loading). As expected,
nortropinone was very efficiently anchored and cleaved from
supports with trityl linker45 3 and carbamate Wang linker46
4, (ca. 100% of the theoretical loadings). Immobilization and
ReceiVed July 23, 2009
Synthesis on solid phase is one of modern methodologies
especially useful in parallel and combinatorial syntheses.1
Tertiary amine functionalities are found in many important
classes of catalysts, reagents and biologically active com-
pounds. The tertiary N-methyl group is also present in
structures of tropane alkaloids2,3 and majority of synthetic
tropane derivatives with potential biological activity.4 Despite
of well-defined tropane scaffold structure, which is present
in known or potentially bioactive functionalized tropane
derivatives5 only a few approaches to tropanes libraries6-9
and supported synthesis10-12 have been studied. Our ap-
proach to supported synthesis of tropane derivatives is based
on anchoring nortropinone (1, Scheme 1),13,14 a secondary
amine which naturally required a postcleavage N-methylation
with one of the known procedures.15 Although secondary
amines can be anchored reversibly via several well-known
linkers including activated Wang carbonate,16,17 and triazene
T2,18,19 we also looked for other methods. The linkers
preserving the amine character of the anchored nitrogen atom,
such as REM (via Michael addition-Hofmann elimination),20,21
amino acetals (DSEM and POEM),22,23 BAL-type,24,25
BOBA26 and several widely available polymeric gels
(Merrifield,27-29 trityl chloride30), could offer certain ad-
vantages. The motivation for seeking such anchors was an
observation that the reactions of lithium enolates of tropinone
and N-benzylnortropinone (both tertiary amines) in solution
were more stereoselective and higher yielding than reactions
of corresponding N-diazaphenyl (triazene) or carbobenzyloxy
(uretane) derivatives.31 Therefore, we undertook a study on
anchoring, and cleavage of nortopinone (1) on various
polymeric supports with emphasis on methods for conversion
of immobilized nortropane scaffold to tertiary amines such
as tropane (2, Scheme 1).
Solid-phase methods for synthesis of tertiary amines
including N-methyl amines have been reported by Anders-
son.32 Others20,33-35 reported solid-phase alkylation and
cleavage of tertiary amines by Hofmann type elimination
from REM-type resins. An interesting method for debenzy-
lating cleavage of quaternized amines from the Merrifield
support based on nucleophilic displacement was reported by
Cai.36 In our report, we wish to describe a novel method for
preparation of N-methylated tertiary amines, including tro-
panes, based on quaternization and nucleophilic debenzyla-
tion of so formed ammonium salts immobilized via benzyl
amine linkage on a widely available solid support, the Wang
Scheme 1
* lazny@uwb.edu.pl.
10.1021/cc900108p CCC: $40.75  2010 American Chemical Society
Published on Web 10/30/2009

6
Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 1
Reports
Figure 1
Table 1. Loadings of Nortropinone on Tested Polymeric Supports
loading of immobilized
nortropinone [mmol/g] (%)a
resin
anchoring
cleavage
based on Et3N · HClb
based on nortropinonec
3
4
trityl chloride resin, 1, DMF, 80 °C
(i) Wang resin, 4-NO2PhO(CO)Cl, Py,
DCM, rt, (ii) 1, DCM, rt
20% TFA/DCM
20% TFA/DCM
d
d
1.55 (100)
0.87 (100)
5
(i) triazene resin, 10% TFA, -10 °C, (ii) 1, DCM,
10% TFA/DCM
d
0.71 (78)
-10 °C, (iii) 1, DCM, rt
6
7
8
Wang resin, SOCl2, DCM, rt
50% TFA/DCM
i) ACE-Cl/ DCP, ii) MeOH
50-95% TFA/DCM
0.79 (87)
1.07 (99)
1.0 (44)
0.79 (87)e
0.40 (37)
0.39 (17)
Merrifield resin, 1, DMF, 80 °C
(i) hydroxybutyl resin; (HCHO)n, HCl,
DME, 0 °C (or (1) t-BuOK, ClCH2SMe, THF;
(2) SO2Cl2), (ii) 1, DME
9
(i) Wang resin; (HCHO)n, HCl,
DME, 0 °C (or (1) t-BuOK, ClCH2SMe, THF;
(2) SO2Cl2), (ii) 1, DME
50-95% TFA/DCM
50-90% TFA/DCM
0.40 (35)
0.10 (9)
0
10
NaBH3CN, 1 · HCl, AcOH, EtOH
1.06 (100)
a % of theoretical value. b Loading determined from mass of triethylamine · HCl obtained after washing of the gel with HCl solution followed by
washing with triethylamine.47 c Loading determined from mass of nortropinone · HCl obtained after cleavage and conversion to hydrochloride. d Method
not suitable for determination of loading of bound amines. e When accounted for released linker bound to nortropinone after “bind and release” process
(Scheme 2).
Scheme 2
synthesis based on enolate chemistry the cleaved nortropanes
needed additional post cleavage N-methylation. Thus we
turned our attention to the Wang resin that has been used
for binding amines and releasing them after modification as
sulfonamides37 or even primary amines.38 Unfortunately, our
attempts to release unchanged secondary amines especially
nortropane derivatives were only partially successful and
complicated by byproduct of linker cleavage (Scheme 2).
Cleavage of nortropinone and even a simple test amine,
morpholine, from the Wang polymer with TFA resulted in a
mixture of cleaved amine e.g., 1 and its N-(para-hydro-
xybenzyl) derivative 11 in ∼1:1 ratio (Scheme 2, Table 1, resin
6).51
cleavage of the amino ketone under previously optimized
conditions13 from the para-C3-T2 triazene support 5 (the
optimal triazene linker for the aldol reaction14) was slightly
less efficient (61% of the theoretical loading).
To allow for application of highly reactive and basic
conditions of enolate chemistry, which have been success-
fully used for synthesis of various tropane derivatives in
solution,48-50 to reactions of immobilized nortropinone the
linker should be sufficiently robust. Although our initial
studies14,51 showed that triazene T2,14,18 and Wang carbam-
ate46 anchored nortropinone could be used in supported
To directly obtain the N-methylated tropane derivatives
we investigated a possibility of quaternization of supported
nortropane followed by cleavage by debenzylation. W
reasoned that some known from solution synthesis deben-
zylations of quaternary ammonium salts such as thermal

Reports
Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 1 7
Scheme 3
Table 2. Results of Amines Quaternization and Cleavage from
the Wang Polymer
decomposition,52-55 or better, nucleophilic displacement with
amines (e.g., with morpholine),36 thiophenol,56,57 triph-
enylphosphine58 or sodium acetate in glacial acetic acid,59
could perhaps be combined with N-methylation to get access
to N-methylated tertiary amines including tropinone or other
tropane derivatives. Thus two amines, nortropinone and
4-benzyl piperidine, were effectively anchored on the Mer-
rifield gel and the Wang resin activated by thionyl chloride
(Wang resin chloride). The immobilized amines were N-
methylated (quaternized) using methyl iodide or methyl
triflate. Interestingly, an acidolitic (50% TFA/DCM) cleavage
of the quaternized nortropinone from the Wang gel provided
tropinone 2 (in ∼80% purity) admixed with products of
linker release. As we expected the polymer bound benzylic
quaternary salts were susceptible to nucleophilic attack at
the benzylic position with concomitant releasing of the
tertiary amine as a nucleofuge. Four nucleophiles were tested:
triphenylphosphine in THF, sodium thiophenolate in metha-
nol, sodium acetate in acetic acid and neat morpholine. The
thiophenolate, sodium acetate and morpholine were quite
effective for cleavage of N-methylpiperidine 14 but failed
except for sodium acetate and the Wang polymer for tropinone
2 (Scheme 3). The reaction with sodium acetate and the Wang
support gave no cleavage in other polar solvents like methanol
or DMF. The triphenylphosphine and thiophenolate-based
cleavages were complicated by excess reagents, phosphine
oxidation, and thiophenolate oxidation byproduct.
theoretical found loading of
yield of cleaved
loading amine [mmol/g] N-methylated amine
of amine (% of theoretical
[mmol/g]
(% of theoretical
yield)b
amine
loading)a
dibutylamine
phenethylamine
piperidine
benzylamine
4-benzylpiperidine
0.90
0.91
0.94
0.92
0.86
0.87
0.90 (quantitative)
0.88 (97)
0.94 (quantitative)
0.78 (85)
0.86 (quantitative)
0.87 (quantitative)
49
quantitativec
95
quantitativec
98
phenylglycine
methyl ester
proline benzyl ester
nortropinone
0.84
0.88
0.84 (quantitative)
0.88 (quantitative)
quantitative
a Loading determined from mass of triethylamine · HCl obtained after
washing of the gel with HCl solution followed by washing with tri-
ethylamine.47 b Yields based on experimentally found loadings of starting
1
amines, determined from mass of the crude products. Purities ∼90% by H
NMR and GC-MS. c Loading based on a sum of mono and dimethyl
derivatives.
Scheme 4
The sodium acetate method was then checked on other
selected secondary and primary amines (Table 2). In the
typical procedure the amines were immobilized on the Wang
resin activated by thionyl chloride (Wang resin chloride).
The resulting polymer supported benzylic amines were
methylated with methyl iodide in DCM solution. Cleavage
from polymer to free the tertiary amines was effected by
heating the resin to 100 °C with 5 equiv of dry sodium
acetate in glacial acetic acid (Scheme 3, Table 2).
Primary amine, phenethylamine, and benzylamine, gave
as major products N,N-dimethyl derivatives admixed with a
few percent of monomethyl derivatives. Unfortunately the
method failed for proline benzyl ester and phenylglycine
methyl ester. Clearly the harsh condition of cleavage may
result in, ester hydrolysis or transesterification. On the other
hand, the cleavage conditions could be used for one step
cleavage and hydroxyl acetylation. Accordingly, the method
was used to acetylate, a model compound, nortropine 16
(Scheme 4). During cleavage the hydroxyl group of im-
mobilized nortropine underwent effective acetylation giving
crude O-acetyltropine60 (19, Scheme 4) in quantitative yield
(based on nortropine loading) and reasonable purity (>85%).
The distillation purified product 19 was obtained in 69%
yield. Obviously the stability of ester, hydroxyl, and other
functionalities sensitive to the cleavage conditions will be a
limitation for wider applicability of the procedure. Nonethe-
less the procedure may be useful for solid-phase synthesis

8
Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 1
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CC900108P