Synthesis of aminomethylated 4-fluoropiperidines and 3-fluoropyrrolidines

Article abstract of DOI:10.1039/c003380d

A short and efficient synthesis of 4-aminomethyl-4-fluoropiperidines and 3-aminomethyl-3-fluoropyrrolidines is described. These fluorinated azaheterocycles are of specific interest as bifunctional building blocks for fluorinated pharmaceutical compounds.

Full text of DOI:10.1039/c003380d

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Synthesis of aminomethylated 4-fluoropiperidines and 3-fluoropyrrolidines†
Guido Verniest,‡a Karel Piron,a Eva Van Hende,a Jan Willem Thuring,b Gregor Macdonald,b Frederik Derooseb
and Norbert De Kimpe*a
Received 22nd February 2010, Accepted 6th April 2010
First published as an Advance Article on the web 21st April 2010
DOI: 10.1039/c003380d
A
short and efficient synthesis of 4-aminomethyl-4-
fluoropiperidines and 3-aminomethyl-3-fluoropyrrolidines is
described. These fluorinated azaheterocycles are of spe-
cific interest as bifunctional building blocks for fluorinated
pharmaceutical compounds. The key step of the synthetic
pathway involves the regioselective bromofluorination of N-
Boc-4-methylenepiperidine and 3-methylenepyrrolidine us-
ing Et3N.3HF and NBS.
Fluorinated azaheterocyclic compounds attract widespread at-
tention as important components of pharmaceutical and agro-
chemical compounds. This is mainly due to the fact that the
replacement of a hydrogen with fluorine often gives rise to
drastic changes in biological activity due to the altered electronic
distribution and changes in conformational properties.1,2 The
research dealing with the synthesis of site-specific fluorinated
azaheterocyclic compounds has intensified considerably during
the last decade and has resulted in numerous new synthetic
approaches and new commercial applications in pharmaceutical
chemistry and agrochemistry.3–7 In particular, fluorinated pyrro-
lidines and piperidines, substituted with amino- or aminomethyl
groups, have become increasingly popular as bifunctional building
blocks towards bioactive compounds.
4-Fluorinated piperidines 1 (Fig. 1) are known as specific
antagonists of T-type calcium channels and can be used for the
treatment of neurological and psychiatric diseases.8 The numerous
papers concerning 4-aminomethyl-4-fluoropiperidines, such as
compound 2, as selective 5-HT1A agonist further emphasize
the possibilities of these compounds in the development of
new antidepressants9 and analgesics.10 In addition, 3-fluoro-3-
aminomethylpyrrolidines have been used in the search for new
bioactive compounds, such as anticancer agents 311 and antibac-
terial compounds, such as 4.12
Fig. 1 Biologically active aminomethylated 4-fluoropiperidines and
3-fluoropyrrolidines.
an excess of HF.pyridine in order to effect a ring open-
ing of the epoxide moiety. This sequence gives rise to 4-
fluoro-4-hydroxymethylpiperidines, which can be used for the
synthesis of the corresponding 4-aminomethyl derivatives via
O-tosylation, followed by a Gabriel synthesis of the amine
moiety.14 A second method makes use of 4-fluoropiperidine-
4-carboxylates, synthesized from piperidine-4-carboxylates via
deprotonation by LDA and subsequent reaction with NFSI
(N-fluorodibenzenesulfonimide).15,16 Functional group transfor-
mation of the ester function finally leads to 4-fluoro-4-
aminomethylpiperidines in 15% to 87% yield depending on the
piperidine N-protecting group.9,17 The main synthetic pathway
towards 3-aminomethyl-3-fluoropyrrolidines, concerns the deox-
ofluorination of the cyanohydrins of N-protected 3-pyrrolidinones
using DAST (diethylaminosulfur trifluoride) at -78 ◦C and subse-
quent reduction of the nitrile function towards the aminomethyl
group.18 As many reported methodologies either require difficult
reaction conditions or make use of sensitive deoxofluorina-
tion reagents, there is a considerable interest in the develop-
ment of generally applicable and efficient large scale synthe-
ses of 4-aminomethyl-4-fluoropiperidines and 3-aminomethyl-3-
fluoropyrrolidines. This paper describes the successful preparation
of both classes of compounds via bromofluorination19 of the
double bonds of easily accessible 4-methylenepiperidines or 3-
methylenepyrrolidines as a key step.
Despite the biological relevance of aminomethylated 4-
fluoropiperidines and 3-fluoropyrrolidines, few synthetic method-
ologies have been developed over the years. Only two methods have
been reported to synthesize 4-aminomethyl-4-fluoropiperidines.
In a first strategy, 4-piperidones are transformed into (1-oxa-6-
azaspiro[2.5]oct-6-yl)phenylmethanones13 and then treated with
aDepartment of Organic Chemistry, Faculty of Bioscience Engineer-
ing, Ghent University, Coupure Links 653, B-9000 Ghent, Belgium.
E-mail: norbert.dekimpe@ugent.be; Fax: +32 (0)9 264 62 43
bJohnson & Johnson, Pharmaceutical Research & Development, a Division
of Janssen Pharmaceutica NV, Turnhoutseweg 30, B-2340 Beerse, Belgium
† Electronic supplementary information (ESI) available: Experimental
procedures and spectroscopic data for compounds 6–8, 10, and 17–20
is available. See DOI: 10.1039/c003380d
‡ Postdoctoral Fellow of the Research Foundation–Flanders (FWO-
Vlaanderen, Belgium)
To establish
a
short and efficient synthesis of 4-
aminomethyl-4-fluoropiperidines, commercially available 1-Boc-
4-methylenepiperidine 5 was treated with N-bromosuccinimide
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(NBS) and triethylamine trihydrofluoride in dry dichloromethane
at room temperature during 3 h (Scheme 1). This bromoflu-
orination reaction conveniently gave tert-butyl 4-bromomethyl-
4-fluoropiperidine-1-carboxylate 6 in high yield, without the
removal of the acid sensitive N-protecting group. It should be
noted that the use of equimolar amounts of NBS and Et3N.3HF
with respect to the starting material 5, resulted in an incomplete
conversion even after reaction for 15 h. Although the subsequent
neopentylic displacement of bromine by ammonia in methanol
(7 N) was not successful, even under pressure or under microwave
conditions, an alternative route via substitution of the bromine
atom by using sodium azide in the presence of sodium iodide in
DMSO proceeded very smoothly and resulted in 4-azidomethyl-
4-fluoropiperidine 7 in 91% yield. The obtained azide 7 was used
without further purification in the Pd/C catalyzed hydrogenation
reaction in methanol and gave rise to the desired 4-aminomethyl-
1-Boc-4-fluoropiperidine 8 in 67% yield after purification via
acid/base extraction. This three-step synthesis efficiently gives
access to the desired 4-aminomethyl-4-fluoropiperidine 8 in 56%
overall yield without the need for chromatographic purification
of the intermediate bromomethyl- and azidomethylpiperidines 6
and 7. The efficiency and ease of the reaction sequence clearly
makes this an attractive route for the large scale preparation of
8, which is of specific pharmaceutical interest. Next to the above
described synthetic pathway to 4-aminomethyl-4-fluoropiperidine
8, other routes towards aminomethylated 4-fluoropiperidines
were also evaluated. At first, commercially available 1-Boc-4-
cyanopiperidine 9 was deprotonated with LDA in THF at 0 ◦C and
quenched with NFSI, yielding 1-Boc-4-cyano-4-fluoropiperidine
10 in a disappointing 22% yield (Scheme 2). In addition, also the
subsequent reduction of the cyano function to the 4-aminomethyl
group proceeded in low yield with either LiAlH4 or NaBH4 in
the presence of NiCl2. Obviously, this deprotonation/fluorination
sequence is not suitable for the large scale preparation of
piperidine 8.
Scheme 2 Synthesis of 4-fluoropiperidine 8 via electrophilic fluorination.
To verify if a deoxofluorination strategy of 4-hydroxypiperidines
could be used to synthesize 4-aminomethyl-4-fluoropiperidines,
known compounds 12 and 13,20,21 which can be synthesized from
piperidinone 11, were subjected to reaction with DAST, mor-
phDAST or di(2-methoxyethyl)amidosulfur trifluoride (Deoxo-
fluorTM) (Scheme 3). Unfortunately, all reaction conditions gave
rise to complex reaction mixtures. These studies (Schemes 2 and
3) clearly demonstrate the value of the synthesis of piperidine 8
via bromofluorination of 4-methylenepiperidine 6 (Scheme 1).
Scheme 3 Attempted synthesis of fluoropiperidines via deoxofluorination
of piperidinone 11.
In addition to the synthesis of aminomethylated 4-
fluoropiperidine 8, the bromofluorination methodology was ap-
plied to synthesize various 3-aminomethyl-3-fluoropyrrolidines
as important building blocks for bioactive compounds. For
this purpose, 3-methylenepyrrolidine 16, which can easily be
obtained from 3-pyrrolidinone 15,22 was used as a starting
material. The treatment of pyrrolidine 16 with triethylamine
trihydrofluoride in the presence of NBS in dichloromethane at
Scheme 1 Synthesis of 4-aminomethyl-4-fluoropiperidine 8.
2510 | Org. Biomol. Chem., 2010, 8, 2509–2512
0
◦C for 2.5 h resulted in a regioselective bromofluorination
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Table 1 Synthesis of various 3-aminomethyl-3-fluoropyrrolidines 20
R1
R2
Reaction conditions
Yield
1)
2)
3)
4)
Boc
Boc
Boc
Bn
H
H2 (4.9 bar), 10% Pd/C, MeOH, rt, 4.5 h
20a (90%)
20b (82%)
20c (56%)
20d (35%)
Ac
Cbz
Ac
1) H2 (4.9 bar), 10% Pd/C, MeOH, rt, 4.5 h; 2) excess Ac2O, rt, 16 h
1) H2 (4.9 bar), 10% Pd/C, MeOH, rt, 4.5 h; 2) 1 equiv CbzCl, THF, rt, 4.5 h
1) H2 (4.9 bar), 10% Pd/C, MeOH, rt, 4.5 h; 2) excess Ac2O, rt, 16 h; 3) excess TFA,
CH2Cl2, 0 ◦C, 7 h; 4) 1.2 equiv BnBr, 4 equiv Et3N, CH2Cl2, rt, 5 h
1) H2 (4.9 bar), 10% Pd/C, MeOH, rt, 4.5 h; 2) excess TFA, CH2Cl2, 0 ◦C, 7 h
5)
H
H
20e (47%)a
a Compound 20e was isolated as the double trifluoroacetic acid salt.
towards 3-bromomethyl-3-fluoropyrrolidine 17 in 68% after silica
gel chromatography (Scheme 4). The nucleophilic substitution
of the bromine atom was next evaluated using various nucle-
ophiles. While the reaction of 17 with sodium methoxide resulted
in complex mixtures due to dehydrofluorination, the reaction
with the less basic sodium acetate yielded 3-acetoxymethyl-
3-fluoropyrrolidine 18, which can be regarded as a N- and
O-protected 3-fluoro-3-hydroxymethylpyrrolidine, which is of
interest in medicinal chemistry. For the synthesis of the cor-
responding 3-aminomethylpyrrolidines 20, pyrrolidine 17 was
treated with sodium azide in the presence of sodium iodide
towards azidomethylpyrrolidine 19 and subsequently subjected
to hydrogenation over Pd/C. This reaction sequence yielded the
envisioned 3-aminomethyl-3-fluoropyrrolidine 20a in 90% yield.
To enable the selective introduction of additional functionalities
at both nitrogen atoms and to broaden the scope of reactions
in which 3-aminomethyl-3-fluoropyrrolidine can be used as a
building block, different N-protecting groups were introduced at
both nitrogen atoms of pyrrolidines 20 (see Table 1). At first, the
reaction of pyrrolidine 20a with an excess of acetic anhydride
or CbzCl resulted in the corresponding N,N-bisprotected pyrro-
lidines 20b and 20c (Table 1, entries 2 and 3). In addition, the
reaction of N-Bocpyrrolidine 20b with an excess of trifluoroacetic
acid and subsequent standard N-benzylation gave rise to the
corresponding N-benzylpyrrolidine 20d. Fully N,N-deprotected
3-aminomethyl-3-fluoropyrrolidine 20e was synthesized from 20a
via reaction with trifluoroacetic acid. The obtained pyrrolidine
was precipitated from the reaction mixture as a double TFA
salt, as evidenced by elementary analysis. It should be noted that
1
in contrast to N,N-unprotected pyrrolidine 20e, the H NMR
analysis of fluoropyrrolidines 20a–d is complicated due to the
hindered rotation of the carbamate or amide bonds in combination
with H–F coupling causing extensive signal broadening.
Conclusions
In conclusion,
fluoropiperidine
a
8
new synthesis of 4-aminomethyl-4-
and 3-aminomethyl-3-fluoropyrrolidines
20 via a bromofluorination reaction of the corresponding exo-
methylene substituted piperidine or pyrrolidine was developed.
Nucleophilic displacement of the bromine atom with sodium
azide and subsequent azide reduction, smoothly resulted in the
titled compounds in good overall yields. The efficiency and easy
setup of the reaction sequence enables a large scale preparation
of these building blocks, which are of considerable interest in
pharmaceutical chemistry.
Acknowledgements
The authors are indebted to the Research Foundation – Flanders
(FWO-Flanders), Ghent University (GOA, BOF) and Johnson &
Johnson Pharmaceutical Research & Development, a Division of
Janssen Pharmaceutica NV, for financial support.
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