Selectfluor-promoted fluorination of piperidinyl olefins

Article abstract of DOI:10.1016/j.tetlet.2010.08.090

A simple and straightforward synthesis of 1-substituted-4-aryl-5-fluoro-1, 2,3,6-tetrahydropyridine (3) or 1-substituted 4-diarylmethanoyl-4- fluoropiperidine (6) by the treatment of piperidinyl exo- or endo-olefin with 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate (Selectfluor) is reported. Two transformations from endo-olefin 1 to allylic fluoride 3 and from exo-olefin 2 to fluorohydrin 6 proceed via allylic fluorination and fluorohydroxylation in moderate yields. It presents two novel reactions promoted by Selectfluor and broadens the scope of application.

Full text of DOI:10.1016/j.tetlet.2010.08.090

Tetrahedron Letters 51 (2010) 5900–5903
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Selectfluor-promoted fluorination of piperidinyl olefins
⇑
Meng-Yang Chang , Nien-Chia Lee, Ming-Fang Lee, Yu-Ping Huang, Chung-Han Lin
Department of Medicinal and Applied Chemistry, Kaohsiung Medical University, Kaohsiung 807, Taiwan
a r t i c l e i n f o
a b s t r a c t
Article history:
A simple and straightforward synthesis of 1-substituted-4-aryl-5-fluoro-1,2,3,6-tetrahydropyridine (3) or
1-substituted 4-diarylmethanoyl-4-fluoropiperidine (6) by the treatment of piperidinyl exo- or endo-ole-
fin with 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate (Selectfluor) is
reported. Two transformations from endo-olefin 1 to allylic fluoride 3 and from exo-olefin 2 to fluorohy-
drin 6 proceed via allylic fluorination and fluorohydroxylation in moderate yields. It presents two novel
reactions promoted by Selectfluor and broadens the scope of application.
Received 14 July 2010
Revised 19 August 2010
Accepted 31 August 2010
Available online 6 September 2010
Keywords:
Selectfluor
Ó 2010 Elsevier Ltd. All rights reserved.
Allylic fluorination
Fluorohydroxylation
1. Introduction
Ar
O
Ar
CHO
Notably, Selectfluor™ has been reviewed for reactions involving
carbon-fluoride formation.1 Due to the numerous advantages asso-
ciated with this mild, stable, and eco-friendly compound, recent
investigations have explored its applications as an effective re-
agent for some interesting reactions. Some representative exam-
Ar
MCPBA, BF , DCM
3
N
R
or
N
R
ref. 7
Ar
Ar
Ar
ples include oxidation,2
a
-fluorination,3 rearrangement,4
Ar
Ar
OMe
OH
or
N
R
N
R
Ar
deprotection5 etc. Especially, the reaction of olefins with electro-
philic fluorinating agents in the presence of nucleophiles was well
documented.6 Recently, we investigated some interesting reactions
related to the structures of 4-aryl-1,2,3,6-tetrahydropyridine 1 and
4-diarylmethylenepiperidine 2 by a combination of m-chloroper-
oxybenzoic acid/boron trifluoride etherate-promoted ring-contrac-
tion and ring-expansion7 or selenium dioxide-mediated
methoxyhydroxylation8 (Scheme 1). To explore the synthetic
application of two frameworks, a simple strategy for Selectfluor-
mediated allylic fluorination of 1 and fluorohydroxylation of 2
was developed.
OMe
SeO , H O
2 2(MeOH)
2
HO
endo-olefin 1 exo-olefin 2
ref. 8
or
N
R
N
R
Scheme 1. Reactions of skeletons 1 and 2.
Br
H
N
F
F
N
The unique structural feature of fluoropiperidine prompted
many strategies from synthetic chemists.9 Indeed, the molecular
framework of fluoropiperidine has been used as a core template
to design unique ligands binding to various molecular targets
(Fig. 1).10 Several research groups have examined the pharmaco-
logical activities for these fluorinated piperidines. For instance, 3-
arylfluoropiperidne derivatives had been identified the high-
throughput assay for important resistance patterns in the Gram-
negative pathogens by Thorarensen group.10g Stanton et al. had
Bn
N
N
N
Cl
N
H
CH
3
N
10g
9e
potential antibacterial agent
affinity agent for 5-HT
1D
CO H
F
F
2
F
F
F
N
F C
3
CF
3
N
N
CH
CH
3
3
9a
10h
⇑
Corresponding author. Tel.: +886 7 3121101x2220; fax: +886 7 3125339.
E-mail addresses: mychang@kmu.edu.tw, mychang624@yahoo.com.tw (M.-Y.
potency against the γ-secretase complex
MPTP-analogs for MAO-B catalysis
Chang).
Figure 1. Biological active fluoropiperidines.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.08.090

M.-Y. Chang et al. / Tetrahedron Letters 51 (2010) 5900–5903
5901
Ar
identified that a novel series of fluorinated piperidine acetic acid is
the modulator of
-secretase.9a van Niel et al. had found that a no-
vel series of 3-fluoro-4-aminopiperidines have high affinity for 5-
Ar
HO
Ph
HO
F
HO
N
3
c
1) NaN , acetone
3
H , Pd/C
2
HO
NH
2
2) OsO , NMO,
4
t-BuOH/THF = 1/1
(two steps)
EA
(for 4a)
9e
N
Bs
N
Bs
N
HT1D
.
Rimoldi et al. had reported that b-fluoro-4-phenyl-
Bs
1,2,3,6-tetrahydropyridine analogs can evaluate the contribution
of electronic parameters to monoamine oxidase (MAO-B).10h
3a, Ar = Ph
4a, Ar = Ph (62%) X-Ray
4b, Ar = 2-MeOPh (48%)
4c, Ar = 4-FPh (54%)
5 (79%)
3i, Ar = 2-MeOPh
3k, Ar = 4-FPh
2. Results and discussion
3l, Ar = 4-Cl-3-CF Ph
4d, Ar = 4-Cl-3-CF Ph (42%)
3
3
Our initial investigation focused on the reaction of piperidinyl
endo-olefin 1 or piperidinyl exo-olefin 2 with fluorinating reagents,
such as Deoxo-Fluor or (diethylamino)sulfur trifluoride (DAST).
However, trace amount of the fluoroproduct was isolated and the
major starting material 1 or 2 was recovered. When N-fluoroben-
zenesulfonimide (NFSI) or fluoropyridinium salt was chosen as
the reagent, complex fluoro-containing product was yielded under
a number of reaction conditions. Interestingly, a significant amount
of allylic fluorination product or fluorohydroxylation product was
observed when Selectfluor was used as a fluorinating reagent un-
der the general condition usually used in this literature. Selectflu-
or-mediated allylic fluorination of 1 was shown in Table 1. We first
applied the condition to a diverse range of endo-olefin 1a. Com-
pared with entries 1–4, the yield of compound 3a was decreasing
under the condition of the prolonged time and elevated tempera-
ture. This might be due to the fact that compound 3a is easily aro-
matized to the major fluoropyridine product. The optimized
reaction system was the reaction of 1 with Selectfluor (1.1 equiv)
in the co-solvent of acetonitrile (10 mL) and water (1 mL) at 40–
50 °C for 4–5 h.11
Scheme 2. Synthesis of 3-azidopiperidin-4,5-diols 4.
(X = O) with Selectrfluor yielded 3m in only 8% or 23% yield. The
characteristic structural framework of 3b and 3d was determined
by single-crystal X-ray analysis.12 The mechanism proposed for
the allylic fluorination of 1 by Selectfluor involves the formation
of a benzylic carbocation intermediate I. Skeleton 3 is afforded
from intermediate I via hydrogen abstraction.
To further explore the application of 3, synthesis of 3-azidopi-
peridine-4,5-diol 4 was shown in Scheme 2. Hydroxylated piperi-
dines have demonstrated their utility in the treatment of
carbohydrate-mediated diseases.13,14 Azidodiol 4a was easily gen-
erated by a two-step methodology of nucleophilic substitution of
compound 3b with sodium azide in acetone and subsequently by
osmylation of the corresponding allylic azide in 62% yield.15 The
total synthetic procedure could be monitored by TLC until the reac-
tion was complete. Noticeably, allylic azide is unstable. With the
results in hand, treatment of compound 3i, 3k, or 3l produced com-
pound 4b–d by the above protocols. Further, hydrogenation was
accomplished by treatment of compound 4a with hydrogen on
10% palladium-activated carbon to yield aminodiol 5. It presents
a new methodology for synthesizing 4-arylazasugar analogs.
Regioselective fluorohydroxylation of piperidinyl exo-olefin 2
with Selectfluor was shown in Table 2. The optimized reaction sys-
tem should be the reaction of exo-olefin 2 with Selectfluor
(1.1 equiv) in the co-solvent of acetonitrile (10 mL) and water
(1 mL) at reflux temperature.16 During the process, reaction of ole-
fin 2 was only affected by elevated temperature. Under the reflux
temperature, reaction of compound 2a was achieved completely
to generate fluorohydrin 6a without the starting material recov-
ered (entries 1–4). In entries 5–16, the resulting fluorohydrins
6a–j were obtained in 61–93% yields.11 Further, fluorohydroxyla-
tion of compound 2k with cyclopentane ring or 2l with acyclic pro-
pane unit was transformed to compound 6k or 6l and the reaction
of compound 2m with 3-diphenylmethylenyl group was also con-
ducted to the 3-fluoropiperidine skeleton 6m.
The resulting products 3 were obtained in 33–65% yields (en-
tries 5–18). The typical experimental procedure offers a general
and efficient alternative to the typical allylic monofluorination
reaction of 1. In entry 7, the dr value of (S,S)-3d is determined as
the ratio of 94:6 by chiral phase HPLC. But, treatment of 1m
Table 1
Allylic monofluorination of endo-olefins 1a,b
Ar
Ar
Ar
X
F
F
H
Selectfluor (1.1 equiv)
MeCN / H O = 1 / 1
2
X
X
1a-1m
3a-3m
intermediate I
Based on the above results, we examined the fluoroalkoxylation
of compound 2b. Treatment of compound 2b with several alcohols
(e.g., methanol, ethanol, and isopropanol) as the solvent by the
similar protocol produced fluoroalkoxides 7a–c in 72–87% yields
as shown in Scheme 3. It was also interesting to evaluate the com-
patibility of fluorinating reagent with nucleophilic reagents. But,
no reaction between Selectfluor and TMSCN in dry acetonitrile
was noted. In contrast, the combination might cause rapid decom-
position of TMSCN to form TMSF.
On the basis of the above-mentioned results, four fluorohydrins
6b, 6d, 6e, and 6g with piperidinyl and tetrahydropyranyl frame-
works were applied to examine the interesting pinacol-type rear-
rangement as shown in Scheme 4. When compound 6b was
treated with boron trifluoride etherate in dichloromethane, the
sole compound 8a was isolated in 78% yield. The conversion of flu-
Entry
Ar, X group
Temp/time (h)
Product 3/yield (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
1a, Ph, NMs
40 °C/4
40 °C/8
40 °C/20
Reflux/1
40 °C/4
40 °C/4
40 °C/4
40 °C/4
50 °C/5
50 °C/5
50 °C/5
50 °C/5
40 °C/4
40 °C/4
40 °C/4
40 °C/4
40 °C/4
50 °C/5
3a (61)
3a (30)
3a (trace)
3a (trace)
3b (65)
3c (58)
3d (49)
3e (30)
3e (51)
3f (43)
3g (48)
3h (45)
3i (51)
1b, Ph, NBs
1c, Ph, NTs
1d, Ph, (1S)-NSO2Camphor
1e, Ph, NBz
1f, Ph, N-4-FBz
1g, Ph, N-4-MeOBz
1h, Ph, N-2-COthiophene
1i, 2-MeOPh, NBs
1j, 3-CF3Ph, NBs
1k, 4-FPh, NBs
1l, 4-Cl-3-CF3Ph, NBs
1m, 3-MeOPh, O
3j (61)
3k (60)
3l (65)
3m (23)
3m (8)
orohydrin 6 to a-aryl arylketone 8 is the type of pinacol to pinaco-
lone rearrangement.7b Especially, the aryl group could displace the
tertiary fluoride atom during the intramolecular pinacol-type reac-
tion process. Arylketones 8b–d were also prepared in 69–82%
yields.
a
Reactions were performed in the co-solvent of MeCN (10 mL) and water (1 mL)
using the following mole ratios: 1/Selectfluor = 1:1.1.
The isolated products are >95% pure as judged by 1H NMR analysis.
b

5902
M.-Y. Chang et al. / Tetrahedron Letters 51 (2010) 5900–5903
Table 2
Ph
Ph
F
OH
Fluorohydroxylation of exo-olefins 2a,b
F
F
Selectfluor or NFSI
(2.0 equiv), MeCN
Ph
Ph
Ar
Ar
Ar
OH
N
N
F
Bs
Bs
Ar
Selectfluor (1.1 equiv)
for Selectfluor (86%)
for NFSI (72%)
6b
9
MeCN / H O = 1 / 1
2
X
X
Scheme 5. Fluorination of 6b with Selectfluor or NFSI.
2a-2j
6a-6j
pound 1b. The expected Beckmann amide product was not
observed during the process. When repeated treatment of com-
pound 6b with Selectfluor (2.0 equiv) or NFSI (2.0 equiv), difluoro-
piperidine 9 was provided in 86% or 72% yield, respectively, during
the fluorination (Scheme 5). The structural framework of com-
pounds 6a, 6h, 7a, and 8b was determined by single-crystal X-
ray analysis.17
Entry
Ar, X group
Temp/time (h)
Product 6 or 2/yield (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
2a, Ph, NMs
40 °C/20
40 °C/60
Reflux/1
Reflux/4
Reflux/4
Reflux/4
Reflux/4
Reflux/4
Reflux/4
Reflux/4
Reflux/4
Reflux/4
Reflux/4
6a (31) + 2a (48)
6a (73) + 2a (11)
6a (63) + 2a (25)
6a (93)
6b (88)
6c (83)
6d (85)
6e (79)
6f (82)
6g (88)
2b, Ph, NBs
2c, Ph, NTs
2d, 4-MeOPh, NBs
2e, 4-FPh, NBs
2f, Ph, O
2g, 4-MeOPh, O
2h, 4-FPh, O
2i, Ph, CH2
3. Conclusion
In summary, we have successfully presented a synthetic meth-
odology for producing a series of the novel 3- and 4-fluoropiperi-
dine involving Selectfluor-mediated allylic fluorination and
fluorohydroxylation. Under the Selectfluor-promoted fluorination
system, a wide range of 4-aryl-1,2,3,6-tetrahydropyridines and
diarylmethylenyl heterocycles was well studied. Several structures
of the target products were nicely confirmed by X-ray crystal anal-
ysis. The structure–activity studies of desulfonated compound 3 or
6 in the MAO-B studies will be investigated in following work.
6h (85)
6i (70)
6j (72)
2j, 4-MeOPh, CH2
Ph
Ph
HO
Ph
F
Ph
14
15
Reflux/4
Reflux/4
2k,
2l,
6k (64)
Ph Ph
Ph
Ph
OH
6l (61)
F
Ph
OH
Acknowledgments
F
Ph
Ph
Ph
16
Reflux/4
The authors would like to thank the National Science Council of
the Republic of China for its financial support (NSC 99-2113-M-
037-006-MY3). The project is also supported by a grant from the
Kaohsiung Medical Research Foundation (KMU-Q099003).
N
Bs
N
Bs
6m (76)
2m,
a
Reactions were performed in the co-solvent of MeCN (10 mL) and water (1 mL)
using the following mole ratios: 2/Selectfluor = 1:1.1.
The isolated products are >95% pure as judged by 1H NMR analysis.
b
References and notes
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Ph
Ph
Ph
OR
1
F
Ph
Selectfluor (1.1 equiv)
R OH
1
N
Bs
N
Bs
2b
7a, R = Me (87%) X-Ray
1
7b, R = Et (80%)
1
7c, R = CHMe (72%)
1
2
Scheme 3. Fluoroalkoxylation of exo-olefin 2b.
O
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Ph
Ar
F
Ar
Ar
BF -OEt ,
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Hende, E.; Verniest, G.; Thuring, J. W.; Macdonald, G.; Deroose, F.; De Kimpe, N.
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Cheng, S. K. F.; Goodacre, S. C.; Heald, A.; Locker, K. L.; MacLeod, A. M.;
Morrison, D.; Moyes, C. R.; O’Connor, D.; Pike, A.; Rowley, M.; Russel, N.; Sohal,
1) NH OH, EtOH
3
2
2
DCM
2) BF -OEt , DCM
3
2
X
N
Bs
X
(for 8a)
6b, Ar = Ph, X = NBs
8a (78%)
1b (41%)
6e, Ar = 4-FPh, X = NBs 8b (82%) X-Ray
6f, Ar = Ph, X = O
6h, Ar = 4-FPh, X = O
8c (71%)
8d (69%)
Scheme 4. Degradation of skeletons 2 to 1.
Next, condensation of compound 8a with hydroxylamine and
subsequently by boron trifluoride etherate-mediated rearrange-
ment of the corresponding oxime yielded phenylnitrile and com-

M.-Y. Chang et al. / Tetrahedron Letters 51 (2010) 5900–5903
5903
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11. A representative procedure of skeleton 3 or 6 is as follows: A mixture of endo-
olefin 1 or exo-olefin 2 (0.3 mmol) and Selectfluor (0.33 mmol) in the co-
solvent of acetonitrile (10 mL) and water (1 mL) was stirred at 40 °C, 50 °C or
reflux temperature for 4–5 h. The material was cooled to 25 °C, and after
addition of water the mixture was stirred for 5 min. The reaction mixture was
concentrated under reduced pressure. The residue was extracted with ethyl
acetate (3 Â 30 mL). The combined organic layers were washed with brine,
dried, filtered and evaporated to afford crude product under reduced pressure.
Purification on silica gel (hexane/ethyl acetate = 4:1–2:1) afforded skeleton 3
or 6. Representative data for 3a: Mp = 140–141 °C; HRMS (ESI, M++1) calcd for
Anal. Calcd for C12H14FNO2S: C, 56.45; H, 5.53; N, 5.49. Found: C, 56.67; H,
5.81; N, 5.62. For 6a: Mp = 173–174 °C; HRMS (ESI, M++1) calcd for
C
19H23FNO3S 364.1383, found 364.1384; 1H NMR (400 MHz): d 7.58–7.55 (m,
4H), 7.35–7.25 (m, 6H), 3.70–3.66 (m, 2H), 3.00–2.93 (m, 2H), 2.77 (s, 3H), 2.66
(br s, 1H), 2.09–1.93 (m, 4H); 13C NMR (100 MHz): d 142.70 (2Â), 128.01 (4Â),
127.64 (2Â), 127.59 (2Â), 127.50 (2Â), 97.83 (d, J = 182.7 Hz), 80.15 (d,
J = 21.2 Hz), 41.68, 41.66, 34.46, 30.50, 30.30; Anal. Calcd for C19H22FNO3S: C,
62.79; H, 6.10; N, 3.85. Found: C, 63.01; H, 6.39; N, 4.17.
12. CCDC 773596 (3b) and 783492 (3d) contain the supplementary
crystallographic data for this Letter. This data can be obtained free of charge
via www.ccdc.cam.ac.uk/conts/retrieving.html (or from the CCDC, 12 Union
Road, Cambridge CB2 1EZ, UK; fax: 44-1223-336033; e-mail:
deposit@ccdc.cam.ac.uk).
13. For recent reviews, see: (a) Pearson, M. S. M.; Mathe-Allainmat, M.; Fargeas, V.;
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14. (a) Concellon, J. M.; Rivero, I. A.; Rodrıguez-Solla, H.; Concellon, C.; Espana, E.;
Garcıa-Granda, S.; Dıaz, M. R. J. Org. Chem. 2008, 73, 6048; (b) Swaleh, S.;
Liebscher, J. Tetrahedron Lett. 1999, 40, 2099.
15. CCDC 769430 (4a) contains the supplementary crystallographic data for this
Letter. This data can be obtained free of charge via www.ccdc.cam.ac.uk/conts/
retrieving.html (or from the CCDC, 12 Union Road, Cambridge CB2 1EZ, UK;
fax: 44-1223-336033; e-mail: deposit@ccdc.cam.ac.uk).
16. (a) Zupan, M.; Iskra, J.; Stavber, S. J. Org. Chem. 1995, 60, 259; (b) Stavber, G.;
Zupan, M.; Jereb, M.; Stavber, S. Org. Lett. 2004, 6, 4973; (c) Pacheco, M. C.;
Gouverneur, V. Org. Lett. 2005, 7, 1267.
C
12H15FNO2S 256.0808, found 256.0809; 1H NMR (400 MHz): d 7.49–7.46 (m,
2H), 7.43–7.32 (m, 3H), 6.40 (dt, J = 2.8, 5.2 Hz, 1H), 5.40 (ddd, J = 2.0, 4.0,
48.0 Hz, 1H), 4.37–4.26 (m, 2H), 3.95 (dd, J = 11.6, 18.0 Hz, 1H), 3.40 (ddd,
J = 2.4, 10.4, 34.0 Hz, 1H), 2.96 (s, 3H); 13C NMR (100 MHz): d 137.34, 133.97 (d,
J = 15.1 Hz), 128.78 (2Â), 128.29, 126.33 (d, J = 7.6 Hz), 125.47 (2Â), 83.93 (d,
J = 172.1 Hz), 47.48 (d, J = 24.5 Hz), 44.50 (d, J = 3.0 Hz), 38.22 (d, J = 3.8 Hz);
17. CCDC 776257 (6a), 783738 (6h), 783739 (7a), and 776259 (8b) contain the
supplementary crystallographic data for this Letter. This data can be obtained
free of charge via www.ccdc.cam.ac.uk/conts/retrieving.html (or from the
CCDC, 12 Union Road, Cambridge CB2 1EZ, UK; fax: 44-1223-336033; e-mail:
deposit@ccdc.cam.ac.uk).