New entries toward 3,3-difluoropiperidines

Article abstract of DOI:10.1021/jo800768q

(Chemical Equation Presented) Difluoropiperidines attract considerable interest from organic and medicinal chemists, but their synthesis is often problematic. This paper describes a new synthetic pathway toward valuable 3,3-difluoropiperidines starting fr

Full text of DOI:10.1021/jo800768q

New Entries toward 3,3-Difluoropiperidines
Guido Verniest,†,§ Riccardo Surmont,† Eva Van Hende,† Arvid Deweweire,†
Frederik Deroose,‡ Jan Willem Thuring,‡ and Norbert De Kimpe*,†
Department of Organic Chemistry, Faculty of Bioscience Engineering, Ghent UniVersity,
Coupure Links 653, B-9000 Ghent, Belgium, and Johnson & Johnson Pharmaceutical Research &
DeVelopment, a DiVision of Janssen Pharmaceutica NV, Turnhoutseweg 30, B-2340 Beerse, Belgium
norbert.dekimpe@ugent.be
ReceiVed April 7, 2008
Difluoropiperidines attract considerable interest from organic and medicinal chemists, but their synthesis
is often problematic. This paper describes a new synthetic pathway toward valuable 3,3-difluoropiperidines
starting from suitable δ-chloro-R,R-difluoroimines. The latter imines can be synthesized via electrophilic
fluorination of the corresponding δ-chloroimines using NFSI (N-fluorodibenzenesulfonimide) in acetonitrile.
After hydride reduction of the imino bond and subsequent intramolecular substitution of the chloride
atom, new 3,3-difluoropiperidines were obtained in good yields. In addition, this methodology was applied
to establish the first synthesis of N-protected 3,3-difluoropipecolic acid, a new fluorinated amino acid.
Introduction
rinated compounds.11,12 In that respect, various fluorinated
azaheterocyclic compounds have been used as building blocks
in drug design to fine-tune bioactivity and therapeutic efficacy,
as evidenced by numerous papers in this area.13 Of special
interest in this research area are 3,3-difluorinated piperidines,
which have been used successfully to synthesize anticonvul-
sant,14 anticancer,15 antiobesity,16 and anti-Alzheimer com-
pounds.17 Unfortunately, only limited synthetic pathways are
available to synthesize substituted 3,3-difluoropiperidines. The
majority of 3,3-difluoropiperidines are synthesized via deoxof-
The specific properties of fluorine as a substituent in organic
compounds has resulted in a steadily growing interest in
organofluorine chemistry, which proved to be a research area
with numerous applications in agrochemistry and pharmaceutical
chemistry.1–10 In addition, the commercialization of safe and
efficient fluorinating agents has paved the way for the develop-
ment of a wide scope of synthetic pathways to various fluo-
† Ghent University.
‡ Johnson & Johnson Pharmaceutical Research & Development.
§ Postdoctoral Fellow of the Research Foundation-Flanders (FWO-Vlaan-
deren).
(11) Nyffeler, P. T.; Duron, S. G.; Burkart, M. D.; Vincent, S. P.; Wong,
C.-H. Angew. Chem., Int. Ed. 2005, 44, 192.
(1) Welch, J. T.; Eswarakrishnan, S. Fluorine in Bioorganic Chemistry; John
Wiley & Sons: New York, 1991.
(2) Dolbier, W. R. J. Fluorine Chem. 2005, 126, 157.
(3) Organofluorine Chemistry; Uneyama, K., Ed.; Blackwell: Oxford,
2006.
(12) Baasner, B.; Hageman, H. Tatlow, J. Organo-fluorine compounds In
Houben-Weyl Methods of Organic Chemistry; Georg Thieme-Verlag: Stuttgart,
New York, 1999; E10a-c, additional and supplementary volume to the 4th ed.
(13) (a) Edmondson, S. D.; Mastracchio, A.; Mathvink, R. J.; He, J.; Harper,
B.; Park, Y.-J.; Beconi, M.; Di Salvo, J.; Eiermann, G. J.; He, H.; Leiting, B.;
Leone, J. F.; Levorse, D. A.; Lyons, K.; Patel, R. A.; Patel, S. B.; Petrov, A.;
Scapin, G.; Shang, J.; Roy, R. S.; Smith, A.; Wu, J. K.; Xu, S.; Zhu, B.;
Thornberry, N. A.; Weber, A. E. J. Med. Chem. 2006, 49, 3614. (b) Celanire,
S.; Quere, L.; Denonne, F.; Provins, L. PCT Int. Appl. WO 2007048595 A1
20070503, 2007. (c) Keith, J. M.; Gomez, L. A.; Letavic, M. A.; Ly, K. S.;
Jablonowski, J. A.; Seierstad, M.; Barbier, A. J.; Wilson, S. J.; Boggs, J. D.;
Fraser, I. C.; Mazur, C.; Lovenberg, T. W.; Carruthers, N. I. Bioorg. Med. Chem.
Lett. 2007, 17, 702. (d) Parker, J. C.; Hulin, B. US Pat. Appl. US 2005043292
A1 24/02/2005; Chem. Abstr. 2005, 142, 261783.
(4) Thayer, A. M. Chem. Eng. News 2006, 84, 15.
(5) Park, B. K.; Kitteringham, N. R.; O’Neill, P. M. Annu. ReV. Pharmacol.
Toxicol. 2001, 41, 443, and references therein.
(6) Ja¨ckel, C.; Koksch, B. Eur. J. Org. Chem. 2005, 4483.
(7) O’Hagan, D. Chem. Soc. ReV. 2008, 37, 308.
(8) Purser, S.; Moore, P. R.; Swallow, S.; Gouverneur, V. Chem. Soc. ReV.
2008, 37, 320.
(9) Kirk, K. L. Org. Process Res. DeV. 2008, 12, 305.
(10) Mu¨ller, K.; Faeh, C.; Diederich, F. Science 2007, 317, 1881.
5458 J. Org. Chem. 2008, 73, 5458–5461
10.1021/jo800768q CCC: $40.75 2008 American Chemical Society
Published on Web 06/12/2008

New Entries toward 3,3-Difluoropiperidines
SCHEME 1
luorination of suitable 3-piperidinones using DAST ((diethy-
lamino)sulfur trifluoride) or Deoxofluor ((bis(2-methoxyethyl)-
amino)sulfur trifluoride).14,15,18 Another strategy makes use of
ethyl bromodifluoroacetate as the starting material to synthesize
3,3-difluoro-2-piperidinones, which can be reduced to 3,3-
difluoropiperidines.19 3,3-Difluorinated azasugars have been
synthesized via [2,3]-Wittig rearrangements of difluoroallylic
ethers, which were synthesized from trifluoroethanol.20 3,3-
Difluoropipecolic acid is a particularly interesting difluoropip-
eridine but has never been synthesized before, in contrast to
4,4- or 5,5-difluoropipecolic acid.21,22 In the viewpoint of the
various applications of the latter amino acids in medicinal
chemistry, also 3,3-difluoropipecolic acid derivatives are con-
sidered as promising compounds. Despite the interest in
substituted 3,3-difluorinated piperidines, their synthesis remains
often problematic. Halogenated imines are good substrates for
the synthesis of a variety of azaheterocyclic compounds,23,24
and hence a study was performed recently to synthesize
fluorinated imines as starting materials for the synthesis of new
fluorinated azaheterocyclic compounds.25 The present research
focuses on the use of R,R-difluorinated imines in the synthesis
of new 2-aryl-3,3-difluoropiperidines and the application of the
methodology in the first synthesis of 3,3-difluoropipecolic acid.
SCHEME 2
Results and Discussion
In a first strategy toward new N-substituted 2-aryl-3,3-difluo-
ropiperidines, N-(2,2-difluoro-1-phenylethylidene)alkylamines 2
were used as starting materials for further R-functionalization.
Difluoroimines 2 were synthesized from R,R-difluoroacetophenone
1 by reaction with primary amines and titanium(IV) chloride
(Scheme 1). Subsequently, fluorinated imines 2 were deprotonated
at the R-position using LDA at -100 °C, giving rise to the
(14) Castro Pineiro, J. L.; Dinnell, K.; Elliot, J. M.; Hollingworth, G. J.;
Shaw, D. E.; Swain, C. J. PCT Int. Appl. WO 2001087838 A1 20011122, 2001;
Chem. Abstr. 2001, 136, 5907.
(15) Li, Y.; Zhou, J.; Burns, D.; Yao, W. PCT Int. Appl. WO 2005037826
A1 20050428, 2005; Chem. Abstr. 2005, 142, 430307.
(16) Nagase, T.; Sato, N.; Kanatani, A.; Tokita, S. US Patent. US 2005182045
A1 20050818, 2005; Chem. Abstr. 2006, 143, 211923.
(17) Collins, I. J.; Cooper, L. C.; Harrison, T.; Keown, L. E.; Madin, A.;
Ridgill, M. P. PCT Int. Appl. WO 2003093252 A1 20031113, 2003; Chem. Abstr.
2003, 139, 381490.
corresponding difluorinated 1-azaallylic anions, which were im-
mediately brought into reaction with 1-chloro-3-iodopropane. While
this reaction resulted in the formation of δ-chloroimine 3a when
R,R-difluoroimine 2a was used, the same procedure using 2b only
gave complex reaction mixtures. When an inverse procedure was
used, in which a solution of LDA in THF was added to a mixture
of imine 2b and 1-chloro-3-iodopropane, δ-chloro-R,R-difluor-
oimine 3b could be isolated, albeit in low yield. The formed imines
3a,b were successfully reduced using sodium cyanoborohydride
in methanol in the presence of acetic acid toward the respective
trihalogenated amines, which cyclized spontaneously under the used
reaction conditions, i.e., reflux for 4 h. This short reaction sequence
directly provided new N-alkylated 3,3-difluorinated piperidines 4.
(18) Golubev, A. S.; Schedel, H.; Radics, G.; Fioroni, M.; Thust, S.; Burger,
K. Tetrahedron Lett. 2004, 45, 1445.
(19) Beeler, A. B.; Gadepalli, R. S. V. S.; Steyn, S.; Castagnoli, N., Jr.;
Rimoldi, J. M. Bioorg. Med. Chem. 2003, 11, 5229.
(20) (a) Wang, R.-W.; Qing, F.-L. Org. Lett. 2005, 7, 2189. (b) Wang, R.-
W.; Qing, F.-L. J. Med. Chem. 2006, 49, 2989.
(21) Golubev, A. S.; Schedel, H.; Radics, G.; Sieler, J.; Burger, K.
Tetrahedron Lett. 2001, 42, 7941.
(22) Golubev, A. S.; Schedel, H.; Radics, G.; Fioroni, M.; Thust, S.; Burger,
K. Tetrahedron Lett. 2004, 45, 1445.
The above-described methodology was extended toward the
synthesis of N-unsubstituted 3,3-difluoropiperidine 7 (Scheme 2).
For this purpose, imine 2a was transformed into δ-azidoimine 5
via deprotonation and reaction with 1-azido-3-iodopropane. Treat-
ment of the azide 5 with tin(II) chloride in methanol yielded a
new 3,3-difluorotetrahydropyridine 6 in 22% isolated yield over
two steps. Finally, this cyclic imine was easily reduced toward the
envisaged 3,3-difluoropiperidine 7 in nearly quantitative yield.
Although the synthetic pathways described above yielded new
3,3-difluoropiperidines (4 and 7), the reactions of the 1-azaallylic
anions derived from imines 2 with electrophiles proceeded rather
sluggishly and were difficult to scale up to gram scale. To
overcome the problems associated with the reduced stability of
fluorinated azaallylic anions, a second synthetic strategy was
(23) (a) Abbaspour Tehrani, K.; De Kimpe, N. Sci. Synth. 2004, 27, 245.
(b) De Kimpe, N.; Schamp, N.; Verhe´, R. Synth. Commun. 1975, 5, 403. (c) De
Kimpe, N.; Verhe´, R.; De Buyck, L.; Schamp, N. Synth. Commun. 1975, 5,
269. (d) De Kimpe, N.; Sulmon, P.; Verhe´, R.; De Buyck, L.; Schamp, N. J.
Org. Chem. 1983, 48, 4320. (e) De Kimpe, N.; Keppens, M.; Fonck, G. J. Chem.
Soc., Chem. Commun. 1996, 635. (f) De Kimpe, N.; Abbaspour Tehrani, K.;
Stevens, C.; De Cooman, P. Tetrahedron 1997, 53, 3693. (g) De Kimpe, N.;
Aelterman, W.; De Geyter, K.; Declercq, J.-P. J. Org. Chem. 1997, 62, 5138.
(h) Aelterman, W.; De Kimpe, N.; Tyvorskii, V.; Kulinkovich, O. J. Org. Chem.
2001, 66, 53. (i) Stevens, C.; De Kimpe, N. J. Org. Chem. 1996, 61, 2174. (j)
Mangelinckx, S.; Giubellina, N.; De Kimpe, N. Chem. ReV. 2004, 104, 2353.
(24) (a) Van Hende, E.; Verniest, G.; Surmont, R.; De Kimpe, N. Org. Lett.
2007, 9, 2935. (b) Guo, Y.; Fujiwara, K.; Amii, H.; Uneyama, K. J. Org. Chem.
2007, 72, 8523. (c) Chaume, G.; Van Severen, M.-C.; Marinkovic, S.; Brigaud,
T. Org. Lett. 2006, 8, 6123. (d) Suzuki, A.; Mae, M.; Amii, H.; Uneyama, K. J.
Org. Chem. 2004, 69, 5132. (e) Osipov, S. N.; Tsouker, P.; Hennig, L.; Burger,
K. Tetrahedron 2004, 60, 271.
(25) Verniest, G.; Van Hende, E.; Surmont, R.; De Kimpe, N. Org. Lett.
2006, 8, 4767.
J. Org. Chem. Vol. 73, No. 14, 2008 5459

Verniest et al.
SCHEME 3
a n.p. ) not purified, purity 87-92%.
evaluated to access 3,3-difluoropiperidines. N-(1-Arylethylide-
ne)alkylamines 8 (R1 ) alkyl, R2 ) aryl) were first transformed
to the corresponding δ-chloroimines 9 via deprotonation with
LDA and reaction with 1-chloro-3-bromopropane (Scheme 3).26
The resulting imines 9 were used directly as substrates for
electrophilic fluorination because it was observed that the latter
imines tended to cyclize and decompose when stored at room
temperature. Reaction of crude imines 9 with 3 equiv of
N-fluorodibenzenesulfonimide (NFSI) in dry acetonitrile in the
presence of potassium carbonate and molecular sieves yielded
the corresponding difluoroimines 3a and 10. The best results
were obtained when commercial NFSI was dried at 0.01 mmHg
at 40 °C for 2 h prior to use. In this way, suitable δ-chloro-
R,R-difluoroimines can be prepared on a multigram scale. It
should be noted, however, that the fluorination of more electron-
rich substrates 9d,e proceeded much more slowly and could
not be driven to completion. In the latter experiments, 10-20%
of monofluorinated imines were present and could not be
separated via chromatography. In these cases, the following
transformations were carried out on the crude reaction mixtures
(and purified in the next step). The reduction of imines 3a, 10b,c
using sodium cyanoborohydride and acetic acid in refluxing
methanol resulted nicely in new 3,3-difluoropiperidines 4a and
13a,b (Scheme 3). The low yields of compounds 13a and 13b
are due to the difficult purification by chromatography on
silicagel. Analysis of the 1H NMR spectra of the crude reaction
mixture after difluorination revealed that in the latter cases, at
best, 10-15% of hydrolysis products (i.e., the corresponding
ketones) of both imines 9 and 10 were present. Because of the
presence of these ketones, the chromatographic separation of
difluoropiperidines 13a,b after treatment of the reaction mixture
with hydride was further complicated and resulted in a lower
overall yield.
thus provide a way for further ring functionalization, attempts
were performed to synthesize the corresponding N-benzyl-3,3-
difluoropiperidines 13c-e. Because N-benzylimines derived
from acetophenone cannot be alkylated at the R-position because
of a preferential deprotonation by LDA at the benzylic position,
isopropylimines 3a, 10d, and 10e were hydrolyzed and subse-
quently reconverted into imines using benzylamine in the
presence of titanium(IV) chloride. The resulting N-benzylimines
12 smoothly gave rise to new N-benzyl-3,3-difluoropiperidines
13c-e after reduction of the imino bond and subsequent
cyclization. Having in hand a good method for the synthesis of
N-benzyl-3,3-difluoropiperidines, these compounds were used
in the development of the first synthesis of 3,3-difluoropipecolic
acid. Fluorinated piperidines 13c,e were hydrogenated toward
N-H piperidines 7 and 14e and were subsequently reacted with
an excess of trifluoroacetic anhydride to give new difluoropi-
peridines 15 bearing an electron-withdrawing group at nitrogen
(Scheme 4). Because further experiments to oxidize the phenyl
group of 15d with ruthenium(IV) oxide did not result in any
piperidine-2-carboxylic acid, piperidine 15e was chosen as a
starting material because of its substitution with the more
electron-rich 3,5-dimethoxyphenyl group. In this case, the
oxidative cleavage of the aromatic moiety could be ac-
complished and resulted in the envisaged N-protected 3,3-
difluoropipecolic acid 16, which was separated from the reaction
mixture by chromatography on silica gel. No byproduct could
be isolated and characterized because of the difficult chromato-
graphic separation, and therefore no further attempts were
undertaken to identify possible side reactions that could be
responsible for the low yield.
Conclusions
In conclusion, it can be stated that new entries were developed
toward new fluorinated piperidines, a class of compounds with
considerable potential as building blocks in medicinal chemistry.
δ-Chloro-R,R-difluoroimines were synthesized via 3-chloropropy-
To synthesize 3,3-difluoropiperidines bearing a protecting
group at the nitrogen atom which could be easily removed and
(26) Sulmon, P.; De Kimpe, N.; Schamp, N. Synthesis 1989, 8.
5460 J. Org. Chem. Vol. 73, No. 14, 2008

New Entries toward 3,3-Difluoropiperidines
SCHEME 4
of the solids and evaporation of the solvent yielded almost pure
3,3-difluoro-1-isopropyl-2-phenylpiperidine 4a, which could be
further purified by flash chromatography (hexane/EtOAc 98:2, Rf
1
) 0.14), yield 70%. Mp 55 °C. H NMR (CDCl3): δ 0.73 (3H, d,
J ) 6.7 Hz, CH3); 1.02 (3H, J ) 6.7 Hz, CH3); 1.61-1.75 (1H, m,
C(H)HCF2); 1.77-1.85 (2H, m, CH2); 2.18-2.31 (2H, m, C(H)H-
CF2, NC(H)H); 2.84 (1H, sept, J ) 6.7 Hz, CH(CH3)2); 2.98-3.06
(1H, m, NC(H)H); 3.55 (1H, dd, J ) 21.1 Hz, 3.4 Hz, CHCF2);
7.31-7.37 (3H, m, 3 × CHar); 7.40-7.45 (2H, m, 2 × CHar). 19F
NMR (CDCl3): δ -94.9 (dd, J ) 240.3 Hz, 2.2 Hz, C(F)F); -111.0
(dddd, J ) 240.3 Hz, 43.9 Hz, 21.1 Hz, 9.9 Hz, C(F)F). 13C NMR
(CDCl3): δ 11.7 (CH3); 21.3 (CH3); 21.7 (d, J ) 10.4 Hz, CH2);
33.7 (dd, J ) 25.4 Hz, 21.9 Hz, CH2CF2); 42.9 (NCH2); 48.0 (CH);
70.4 (dd, J ) 26.5 Hz, 20.8 Hz, CHCF2); 119.8 (dd, J ) 248.6 Hz,
239.4 Hz, CF2); 127.8 (2 × CHar); 128.0 (CHar); 130.3 (2 × CHar);
135.0 (Car). IR (KBr): νmax 1172 cm-1. MS (ES+) m/z (%): 240
(M + H+, 100). HRMS calcd for C14H19NF2 (M + H+) 240.15583,
found 240.15606. Anal. Calcd for C14H19NF2: C, 70.27; H, 8.00;
N, 5.85. Found: C, 69.42; H, 7.75; N, 6.12.
3. Oxidation of Piperidine 15e toward 3,3-Difluoro-1-(trifluo-
roacetyl)piperidine-2-carboxylic Acid 16. In a 25 mL flask was
dissolved 0.23 g of 3,3-difluoro-2-(3,5-dimethoxyphenyl)-1-(trif-
luoroacetyl)piperidine 15e was dissolved in a mixture of 4 mL of
distilled tetrachloromethane, 4 mL of distilled acetonitrile, and 6
mL of distilled water. To this solution was added 2.92 g of sodium
periodate (13.65 mmol; 15.00 equiv) during 5 min at 0 °C. After
stirring 30 min at 0 °C, 0.010 g of ruthenium(III) chloride trihydrate
(0.046 mmol; 0.05 equiv) was added. The temperature was raised
to room temperature, and the mixture was stirred for 15 h. After
filtration, the solids were rinsed three times with 20 mL of
dichloromethane. The filtrate was evaporated under vacuum, and
the residual oil was purified via flash chromatography resulting in
0.05 g of 3,3-difluoro-1-(trifluoroacetyl)piperidine-2-carboxylic acid
16 (0.192 mmol; 21%). Flash chromatography (hexane/EtOAc 67:
33, Rf ) 0.24), yield 21%. Ratio rotamers 83:17. 1H NMR (CDCl3):
lation of R,R-difluoroimines or better via electrophilic fluorination
of the corresponding δ-chloroimines. Treatment of the obtained
difluoroimines with sodium cyanoborohydride in the presence of
acetic acid yielded new 3,3-difluorpiperidines in good yields.
Second, N-(5-chloro-2,2-difluoropentylidene)benzylamines were
obtained via hydrolysis of the corresponding isopropylimines and
reimination with benzylamine. The hydride induced cyclization of
the former imines provided new N-benzyl-3,3-difluoropiperidines,
which were used to synthesize N-protected 3,3-difluoropipecolic
acid, a new fluorinated amino acid.
δminor rotamer 1.85-1.91 (2H, m, CH2); 2.03-2.42 (2H, m, CH2CF2);
Experimental Section
3.26 (1H, td, J ) 13.1 Hz, 3.9 Hz, NC(H)H); 4.57 (1H, d, J )
13.9 Hz, NC(H)H); 4.89 (1H, d, J ) 11.6 Hz, NCH); 9.20-9.70
(1H, m, COOH); δmajor rotamer 1.85-1.91 (2H, m, CH2); 2.03-2.42
(2H, m, CH2CF2); 3.49-3.67 (1H, m, NC(H)H); 4.02 (1H, d, J )
13.8 Hz, NC(H)H); 5.47 (1H, d, J ) 12.1 Hz, NCH); 9.20-9.70
(1H, m, COOH). 19F NMR (CDCl3): δminor rotamer -67.9 (s, CF3);
-97.2 (ddt, J ) 254.5 Hz, 31.6 Hz, 11.5 Hz, C(F)F); -99.0 (d, J
) 254.5 Hz, C(F)F); δmajor rotamer -69.2 (s, CF3); -97.2 (ddt, J )
254.5 Hz, 31.6 Hz, 11.5 Hz, C(F)F); -99.0 (d, J ) 253.2 Hz,
C(F)F) 13C NMR (CDCl3): δ 21.5 (d, J ) 6.9 Hz, CH2); 29.7 (t, J
) 22.5 Hz, CH2CF2); 42.3 (d, J ) 3.5 Hz, NCH2); 58.5 (t, J )
32.3 Hz, NCH) and 61.6 (t, J ) 28.3 Hz, NCH); 116.3 (q, J )
287.3 Hz, CF3); 118.0 (dd, J ) 255.0 Hz, 242.3 Hz, CF2); 157.7
(q, J ) 37.3 Hz, CdO); 170.5 (d, J ) 11.5 Hz, COOH). IR (NaCl):
1. Difluorination of δ-Chloroimines 9. N-((1E)-5-Chloro-2,2-
difluoro-1-phenylpentylidene)isopropylamine 3a. In a flame-dried
100 mL flask was vigorously stirred a heterogeneous mixture of
7.96 g of NFSI (N-fluorobenzenesulfonimide; 25.27 mmol; 3 equiv),
1.72 g (25.27 mmol; 3 equiv) of K2CO3, and 4 g of freshly activated
4Å molecular sieves in 50 mL of acetonitrile under N2 atmosphere
for 15 min at room temperature. Subsequently, 2.00 g (8.42 mmol)
of N-(5-chloro-1-phenylpentylidene)isopropylamine 9a was added
dropwise via a syringe at 0 °C. The mixture was warmed to room
temperature and stirred for 15 h. Subsequently, an excess of
triethylamine (5 mL) was added at 0 °C, and stirring was continued
for 2 min. The reaction mixture was filtered over Celite, and the
solids were washed three times with 20 mL of diethyl ether.
Subsequently, the filtrate was poured in 100 mL of aqueous 0.5 M
NaOH. After separation of the organic layer, the aqueous phase
was extracted three times with 25 mL of diethyl ether and dried
over MgSO4/K2CO3 (10:1). Filtration of the drying agents and
evaporation of the solvents in vacuo yielded crude N-((1E)-5-chloro-
2,2-difluoro-1-phenylpentylidene)isopropylamine 3a (yield 92%).
2. Reduction of r,r-Difluoro-δ-chloroimines 3, 10, and 12
toward Piperidines 4 and 13. 3,3-Difluoro-1-isopropyl-2-phenylpi-
peridine 4a. To a solution of 0.5 g (1.65 mmol) of N-((1E)-5-chloro-
2,2-difluoro-1-phenylpentylidene)isopropylamine 3a in 25 mL of
absolute methanol were added 0.11 g (1.81 mmol, 1.1 equiv) of
acetic acid and 0.11 g (1.81 mmol, 1.1 equiv) of sodium cy-
anoborohydride at 0 °C. The mixture was heated at reflux for 4 h.
After completion of the reaction, the mixture was poured into 50
mL of a saturated aqueous NaHCO3 solution and was subsequently
extracted with diethyl ether (3 × 50 mL). The combined organic
layers were washed with brine and dried over MgSO4. Filtration
ν
max 3202; 1695; 1194; 1156 cm-1. MS (ES-) m/z (%): 260 (M -
H+, 100). Anal. Calcd for C8H8NO3F5: C, 36.79; H, 3.09; N, 5.36.
Found: C, 37.01; H, 3.33; N, 5.27.
Acknowledgment. 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.
Supporting Information Available: General experimental
1
methods and H NMR and 13C NMR spectra of compounds
2b, 3a,b, 4a,b, 6, 7, 8b, 8d,e, 9e, 11a-c, 12a, 12c, 13a-e,
14e, 15d,e, and 16. This material is available free of charge via
the Internet at http://pubs.acs.org.
JO800768Q
J. Org. Chem. Vol. 73, No. 14, 2008 5461