Synthesis of 4-substituted 3,3-difluoropiperidines

Article abstract of DOI:10.1021/jo902164z

Synthetic strategies toward 4-substituted 3,3-difluoropiperidines were evaluated. 4-Alkoxymethyl- and 4-aryloxymethyl-3,3-difluoropiperidines were synthesized via 1,4-addition of ethyl bromodifluoroacetate to 3-substituted acrylonitriles in the presence o

Full text of DOI:10.1021/jo902164z

pubs.acs.org/joc
in organofluorine chemistry. This is reflected by the numer-
Synthesis of 4-Substituted 3,3-Difluoropiperidines
ous papers in this area as an answer to the increased need for
new fluorinated building blocks for applications in agro-
chemistry and pharmaceutical chemistry.1 Recently, we
published convenient routes for the preparation of 3-amino-
methyl-3-fluoropiperidines2 and 3-alkoxy-4,4-difluoro-
piperidines,3 and we introduced new entries toward valuable
2-substituted 3,3-difluoropiperidines via electrophilic R-fluori-
nation of imines using N-fluorodibenzenesulfonimide (NFSI).4
4-Substituted 3,3-difluoropiperidines showed already their
importance in medicinal chemistry; however, only limited
synthetic pathways are available.5 Focus was directed to a
general synthetic route toward 4-substituted 3,3-difluoro-
piperidines with application to the synthesis of 3,3-difluoro-
isonipecotic acid, a new γ-amino acid and potential GABAA
agonist.6 Also 3,3-difluoro-4-piperidinone is a promising
building block because 4-piperidones serve an important
role as intermediates of bioactive piperidines.7 In contrast
to 3-fluoro-4-piperidinone,8 only one synthetic route to 3,3-
difluoro-4-piperidinone has been described recently via a
Reformatsky reaction of ethyl bromodifluoroacetate, zinc,
and ethyl 3-(benzotriazol-1-ylmethylbenzylamino)pro-
pioniate, followed by cyclization.9 Deoxofluorination of
3-piperidinones is the most obvious way to synthesize
4-substituted 3,3-difluoropiperidines, although DAST
((diethylamino)sulfur trifluoride) is a reagent with limited
stability and functional group tolerance and can induce re-
arrangements. Moreover, low yields were reported for the
deoxofluorination of 4-substituted 3-piperidinones.10 Highly
substituted 3,3-difluoropiperidines have been synthesized for
the preparation of anti-Alzheimer’s agents and glycosidase
inhibitors.11,12 Earlier work from Beeler et al. resulted in a
,^
Riccardo Surmont, ,§ Guido Verniest,
Jan Willem Thuring,z Gregor Macdonald,z
Frederik Deroose,z and Norbert De Kimpe*,
Department of Organic Chemistry, Faculty of Bioscience
Engineering, Ghent University, Coupure Links 653, B-9000
Gent, Belgium and Johnson & Johnson Pharmaceutical
z
Research & Development, a Division of Janssen
Pharmaceutica NV, Turnhoutseweg 30, B-2340 Beerse,
Belgium. §Aspirant of the Research Foundation-Flanders
(FWO-Vlaanderen, Belgium). ^Postdoctoral Fellow of the
Research Foundation-Flanders (FWO-Vlaanderen,
Belgium).
norbert.dekimpe@ugent.be
Received October 8, 2009
Synthetic strategies toward 4-substituted 3,3-difluoro-
piperidines were evaluated. 4-Alkoxymethyl- and 4-aryloxy-
methyl-3,3-difluoropiperidines were synthesized via 1,4-
addition of ethyl bromodifluoroacetate to 3-substituted
acrylonitriles in the presence of copper powder, followed
by borane reduction of the cyano substituent, lactamiza-
tion, and reduction of the lactam. This method was applied
to establish the synthesis of N-protected 3,3-difluoroiso-
nipecotic acid, a fluorinated γ-amino acid. 4-Benzyloxy-
3,3-difluoropiperidine was prepared using an analogous
methodology and was converted to N-protected 3,3-di-
fluoro-4,4-dihydroxypiperidine, a compound with high po-
tential as a building block in medicinal chemistry.
(2) Van Hende, E.; Verniest, G.; Thuring, J. W.; Macdonald, G.;
Deroose, F.; De Kimpe, N. Synlett 2009, 1765.
(3) Surmont, R.; Verniest, G.; De Weweire, A.; Thuring, J. W.;
Macdonald, G.; Deroose, F.; De Kimpe, N. Synlett 2009, 1933.
(4) Verniest, G.; Surmont, R.; Van Hende, E.; De Weweire, A.; Deroose,
F.; Thuring, J. W.; De Kimpe, N. J. Org. Chem. 2008, 73, 5458 and references
cited therein.
(5) (a) Masuya, K.; Yokokawa, F.; Irie, O.; Nihonyanagi, A.; Toyao, A.; Ehara,
T.; Konishi, K.; Kanazawa, T.; Suzuki, M. PCT Int. Appl. WO 2006094763, 2006;
Chem. Abstr. 2006, 145, 335938. (b) Castro Pineiro, J. L.; Dinnell, K.; Elliot,
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Johnston, G. A. R.; Chebib, M. Neurochem. Int. 2003, 42, 561. (b) Antane,
S. Synth. Commun. 2003, 33, 2145 and references cited therein. (c) Fan, J.; Fahr,
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Morrison, D.; Moyes, C. R.; O’Connor, D.; Pike, A.; Rowley, M.; Russel,
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J. L. J. Med. Chem. 1999, 42, 2087.
The unique properties of fluorine as a substituent in
organic compounds have an undisputed effect on their
bioactivity and have dramatically intensified the research
*Corresponding author. Phone: þ32 (0)9 264 59 51. Fax: þ32 (0)9 264 62
(9) Marmsaeter, F. P.; Munson, M. C.; Rizzi, J. P.; Robinson, J. E.;
Schlachter, S. T.; Topalov, G. T.; Zhao, Q.; Lyssikatos, J. P. PCT Int. Appl.
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DOI: 10.1021/jo902164z
r
Published on Web 01/05/2010
J. Org. Chem. 2010, 75, 929–932 929
2010 American Chemical Society

Surmont et al.
JOCNote
SCHEME 1. Synthesis of 3,3-Difluoro-2-piperidinone 4
bromodifluoroacetate 1 and copper gave rise to complex
mixtures. For the selective reduction of nitriles 6a-c, the use
of borane in THF was preferred over the PtO2-catalyzed
hydrogenation to avoid hydrogenolysis of the benzyloxy
substituent of 6a. After reduction of the nitrile of 6 at room
temperature, spontaneous cyclization occurred, affording
3,3-difluoro-2-piperidinones 7 in 63-76% yields. The crys-
talline δ-lactams 7 were further reduced using 2 equiv of
borane in THF at reflux temperature for 3 h, resulting in
4-alkyl-3,3-difluoropiperidines 8. To cleave the obtained
borane-amine complexes, compounds 8 were treated
with Pd/C in methanol at room temperature before the
final purification via flash chromatography or acid/base
extraction.
Having in hand a good method for the synthesis of
4-benzyloxymethyl-3,3-difluoropiperidine 8a, this compound
was used to synthesize 3,3-difluoroisonipecotic acid. At first,
N-H piperidine 8a was protected at nitrogen with a trifluor-
acetyl group resulting in piperidine 9, which was subsequently
O-debenzylated via Pd/C-catalyzed hydrogenolysis to give
3,3-difluoro-4-hydroxymethyl-1-(trifluoroacetyl)piperidine
10. In contrast to various unsuccessful attempts to oxidize
the hydroxymethyl group of 10 using ruthenium(IV) oxide,
the use of CrO3 afforded 3,3-difluoro-1-(trifluoroacetyl)-
piperidine-4-carboxylic acid 11 in 55% yield.
synthesis of 4-hydroxy-4-phenyl-3,3-difluoropiperidine, a
proneurotoxin, via a SmI2-induced Reformatsky reaction of
ethyl bromodifluoroacetate with 3-(N-methyl-N-benzylamino)-
propiophenone, followed by cyclization to the 2-piperidinone
and reduction of the lactam.13 In the present report, ethyl
bromodifluoroacetate was used as starting material to develop
a general synthetic route to 4-substituted 3,3-difluoropiperi-
dines, which is clearly lacking in the literature.
As a model study, the use of ethyl 4-cyano-2,2-difluorobu-
tanoate 3 as a starting material for the synthesis of 3,3-difluoro-
piperidines was investigated. Ethyl 4-cyano-2,2-difluoro-
butanoate 3 was synthesized from ethyl bromodifluoroacetate
1 and acrylonitrile in the presence of copper in DMSO14 or in
THF in the presence of TMEDA (Scheme 1).15 At first, various
methods were evaluated to reduce selectively the nitrile func-
tion of compound 3. Hydrogenation on Pd/C in ethanol did
not result in any reduction of 3, while the use of NaBH4/
CoCl2 6H2O, LiAlH4, or BH3 Me2S gave complex mixtures.
In order to extend this methodology to 4-alkoxy-3,3-
difluoropiperidines, which can serve as good precursors for
the synthesis of the interesting 3,3-difluoro-4-piperidinone,
ethyl bromodifluoroacetate was reacted with 2-chloroacry-
lonitrile 12 in the presence of copper in DMSO at 60 ꢀC
(Scheme 3). This reaction nicely gave rise to ethyl 4-cyano-
2,2-difluoro-3-butenoate 13, which occurred as a mixture of
E- and Z-isomers (ratio 1:1). For spectroscopic purposes,
these isomers were separated by column chromatography.
The Michael acceptor ethyl 4-cyano-2,2-difluoro-3-buteno-
ate 13 was considered as a good substrate for the synthesis of
the target 3,3-difluoro-4-piperidinone. Because it is known
that DBU efficiently catalyzes the 1,4-addition of alcohols to
simple acrylonitriles under mild conditions,17 it was decided
to treat compound 13 with benzyl alcohol and a catalytic
amount of DBU. The ideal catalytic load of DBU was found
to be 0.2 equiv, affording 3-benzyloxy-4-cyano-2,2-difluoro-
butanoate 14 in 64% yield. Analogous to the synthesis of 4-
alkoxymethyl-3,3-difluoropiperidines 8, nitrile 14 was re-
duced using borane in THF, cyclized to 2-piperidinone 15,
and further reduced to 4-benzyloxy-3,3-difluoropiperidine
16 in good yields. Subsequently, the N-unsubstituted piper-
idine 16 was trifluoroacetylated toward difluoropiperidine
17 and O-debenzylated to give 3,3-difluoro-4-hydroxy-
1-(trifluoroacetyl)piperidine 18. Subsequently, alcohol 18
was oxidized using Dess-Martin periodinane to the corre-
sponding 3,3-difluoro-4-piperidinone, which occurred as a
hydrate 19, in 56% yield. It was proven that this seven-step
procedure is a convenient route for a multigram synthesis of
3,3-difluoro-4,4-dihydroxypiperidinone 19. It should be
noted that compound 19 cannot be synthesized via fluorina-
tion of 4-piperidinone, in contrast to the easily accessible
3-fluoro-4-piperidinone, which can be obtained via fluorina-
tion of the trimethylsilylenol ether of 4-piperidinone using
3
3
Upon platinum-catalyzed hydrogenation of nitrile 3 in ethanol
for 3 days, spontaneous cyclization occurred to afford 3,3-
difluoro-2-piperidinone 4 in 81% yield. Fortunately, a faster
reduction was observed using 2 equiv of borane in THF at room
temperature, resulting in piperidinone 4 in 72% yield after 24 h.
Having in hand an efficient method to access 3,3-difluoro-
piperidinone 4, the above-described methodology was
extended toward the synthesis of 4-alkoxymethyl-3,3-di-
fluoro-2-piperidinones 7, using 3-(alkoxymethyl)- and
3-(aryloxymethyl)acrylonitriles 5a-d16 as starting materials
(Scheme 2). 3-Substituted acrylonitriles 5 were treated with
ethyl bromodifluoroacetate 1 and copper in THF with
TMEDA as an additive. In contrast to acrylonitrile 2, the
reaction of 3-alkyl-substituted acrylonitriles 5a-c required
reflux temperatures to complete the 1,4-addition reaction. In
the case of the allyloxy derivative 5d, the treatment with
(12) Wang, R.-W.; Qiu, X.-L.; Bols, M.; Ortega-Caballero, F.; Qing,
F.-L. J. Med. Chem. 2006, 49, 2989.
(13) Beeler, A. B.; Gadepalli, R. S. V. S.; Steyn, S.; Castagnoli, N.;
Rimoldi, J. M. Bioorg. Med. Chem. 2003, 11, 5229.
(14) (a) Sato, K.; Tamura, M.; Tamoto, K.; Omote, M.; Ando, A.;
Kumadaki, I. Chem. Pharm. Bull. 2000, 48, 1023. (b) Laurent, S.; Chen,
H.; Bedu, S.; Ziarelli, F.; Peng, L.; Zhang, C.-C. Proc. Natl. Acad. Sci. U.S.A.
2005, 102, 9907.
(15) Sato, K.; Nakazato, S.; Enko, H.; Tsujita, H.; Fujita, K.;
Yamamoto, T.; Omote, M.; Ando, A.; Kumadaki, I. J. Fluorine Chem.
2003, 121, 105.
(16) (a) Kikuchi, H.; Satoh, H.; Fukutomi, R.; Inomata, K.; Suzuki, M.;
Hagihara, K.; Arai, T.; Mino, S.; Eguchi, H. PCT Int. Appl. WO 9531442, 1995;
Chem. Abstr. 1995, 124, 232479. (b) Kuwamura, T.; Takahashi, H. Bull. Chem.
Soc. Jpn. 1969, 42, 1345. (c) Julia, M.; Tchernoff, G. Bull. Soc. Chim. Fr. 1954,
474. (d) Iranpoor, N.; Shekarriz, M. Synth. Commun. 1999, 29, 2249. (e) Itadani,
S.; Hashimoto, K.; Shirahama, H. Heterocycles 1998, 49, 105.
(17) Murtagh, J. E.; McCooey, S. H.; Connon, S. Chem. Commun. 2005,
227.
930 J. Org. Chem. Vol. 75, No. 3, 2010

Surmont et al.
JOCNote
SCHEME 2. Synthesis of 4-Substituted 3,3-Difluoropiperidines 8 and Derivatization toward N-Protected 3,3-Difluoroisonipecotic
Acid 11
SCHEME 3. Synthesis of 3,3-Difluoro-4,4-dihydroxypiperidine 19
Selectfluor.8 A second fluorination of 3-fluoro-4-piperidi-
SCHEME 4. Reductive Amination of Hydrate 19
none at the 3-position is problematic and results in mixtures
of regioisomers.
To demonstrate the synthetic utility of difluoropiperidi-
none 19, the synthesis of 4-amino-3,3-difluoropiperidine 21
was carried out. A one-step reductive amination of 3,3-
difluoro-4,4-dihydroxypiperidinone 19 with benzylamine
using NaBH(OAc)3 resulted in a complex mixture contain-
ing starting material, 3-hydroxypiperidine 18, and the corre-
sponding N-deprotected derivatives (Scheme 4).
This is due to the lowered reactivity of the hydrate with
benzylamine compared to the corresponding ketone and the
presence of a labile N-trifluoroacetyl group. Therefore, the
N-deprotected imine 20 was prepared through a Dean-Stark
reaction in toluene, followed by reduction of the imine using
NaCNBH3 to obtain 4-benzylaminopiperidine 21 in good yield.
In conclusion, it can be stated that new entries toward new
substituted fluorinated piperidines, a class of compounds
This method was used to synthesize the new N-protected
3,3-difluoroisonipecotic acid 11. In addition, 4-cyano-
2,2-difluoro-3-butenoate was obtained via reaction of ethyl
bromodifluoroacetate and 2-chloroacrylonitrile in the pre-
sence of copper. The 1,4-addition of benzyl alcohol to the
obtained butenoate, followed by reduction, provided a new
4-benzyloxy-3,3-difluoro-2-piperidine which could be con-
verted to 3,3-difluoro-4,4-dihydroxypiperidine 19.
with considerable potential as building blocks in medicinal
chemistry, were developed. 3-Alkoxymethyl- and 3-aryloxy-
methyl-4-cyano-2,2-difluorobutanoates 6 were synthesized
via reaction of ethyl bromodifluoroacetate with 3-substituted
acrylonitriles as Michael acceptors in the presence of copper
powder. The cyano substituent of these 1,4-addition adducts
was successfully reduced to induce lactamization toward new
3,3-difluoro-2-piperidinones, which were further reduced to the
corresponding 4-alkyl-3,3-difluoropiperidines in good yields.
Experimental Section
Synthesis of 3,3-Difluoro-2-piperidinones 4, 7, and 15.
Typical procedure for 4: In a flask of 50 mL, 0.50 g of ethyl
4-cyano-2,2-difluorobutanoate 3 (2.82 mmol, 1 equiv) was
dissolved in 20 mL of dry tetrahydrofuran. The solution
was cooled to 0 ꢀC, and 5.6 mL of BH3 THF (1 M in THF)
(5.64 mmol, 2 equiv) was slowly added under nitrogen atmo-
sphere. The reaction mixture was allowed to warm up to room
temperature and stirred for 24 h. The reaction mixture was
3
J. Org. Chem. Vol. 75, No. 3, 2010 931

Surmont et al.
JOCNote
þ
quenched with 5 mL of methanol and poured in 20 mL of
water and 20 mL of ethyl acetate. The separated aqueous
phase was extracted twice with 20 mL of ethyl acetate, and
the combined organic phases were dried over MgSO4. After
filtration, the solvent was evaporated in vacuo and the residue
was crystallized in 9:1 Et2O/MeOH, yielding 0.27 g of
3,3-difluoro-2-piperidinone 4 (2.03 mmol, 72% yield) as
984; MS (ESþ) m/z (%) 136 (M þ Hþ, 13), 153 (M þ NH4
,
100). Anal. Calcd for C5H7F2NO: C, 44.45; H, 5.22; N, 10.37.
Found: C, 44.79; H, 5.19; N, 10.39.
Acknowledgment. The authors are indebted to the Re-
search Foundation-Flanders (FWO-Flanders), Ghent
University (GOA, BOF), and Janssen Pharmaceutica
(Johnson & Johnson) for financial support.
1
white crystals: mp = 105.1 ꢀC (Et2O); H NMR (CDCl3) δ
1.97-2.07 (2H, m, CH2), 2.21-2.37 (2H, m, CH2CF2), 3.40
(2H, t, J = 5.4 Hz, NCH2), 7.92 (1H, br s, NH); 19F NMR
(CDCl3) δ -102.2 (2F, t, J = 14.5 Hz, CF2); 13C NMR
(CDCl3) δ 19.3 (t, J = 4.6 Hz), 31.7 (t, J = 22.5 Hz), 41.6,
112.5 (t, J = 244.0 Hz), 163.9 (t, J = 30.0 Hz); IR (ATR,
cm-1) ν = 3218 (NH), 3099, 1688 (CdO), 1340, 1195, 1146,
Supporting Information Available: General experimental
methods, 1H NMR and 13C NMR spectra of all new com-
pounds. This material is available free of charge via the Internet
at http://pubs.acs.org.
932 J. Org. Chem. Vol. 75, No. 3, 2010