Diastereoselective syntheses of (3 R*,4 R*)- and (3 R*,4 S*)-4-Aryl-3-methyl-4-piperidinemethanol and fluoro analogues

Article abstract of DOI:10.1021/jo302303h

Two concise and high-yielding diastereoselective syntheses of 4-aryl-3-methyl-4-piperidinemethanols were realized from 1,3-dimethyl-4- piperidinone. The key reactions to control the C3-C4 relative stereochemistry were the alkoxymethylation of a metalloenamine generated from 4-aryl-3-methyl-1,2,3,6-tetrahydropyridine that afforded the (3R*,4S*)-form and the nucleophilic substitution of a fluoroarene with deprotonated 3-methyl-4-piperidinenitrile giving the (3R*,4R*)- isomer. The corresponding fluoromethyl analogues were subsequently obtained through the fluorination of the piperidinemethanols using DAST.

Full text of DOI:10.1021/jo302303h

Note
pubs.acs.org/joc
Diastereoselective Syntheses of (3R*,4R*)- and (3R*,4S*)‑4-Aryl-3-
methyl-4-piperidinemethanol and Fluoro Analogues
Sebastien Schmitt,†,‡,§ Richard C. D. Brown,∥ and Cecile Perrio*,†,‡,§
́
́
†CNRS, UMR 6301 ISTCT, LDM − TEP, GIP Cyceron, Boulevard Henri Becquerel, BP5229, F-14074 Caen Cedex, France
‡Universite
F-14074 Caen Cedex, France
́
de Caen Basse-Normandie, UMR 6301 ISTCT, LDM − TEP, GIP Cyceron, Boulevard Henri Becquerel, BP5229,
§CEA, DSV/I2BM, UMR 6301 ISTCT, LDM − TEP, GIP Cyceron, Boulevard Henri Becquerel, BP5229, F-14074 Caen Cedex,
France
∥School of Chemistry, University of Southampton, Highfield, Southampton SO17 1BJ, United Kingdom
S
* Supporting Information
ABSTRACT: Two concise and high-yielding diastereoselec-
tive syntheses of 4-aryl-3-methyl-4-piperidinemethanols were
realized from 1,3-dimethyl-4-piperidinone. The key reactions
to control the C3−C4 relative stereochemistry were the
alkoxymethylation of a metalloenamine generated from 4-aryl-
3-methyl-1,2,3,6-tetrahydropyridine that afforded the
(3R*,4S*)-form and the nucleophilic substitution of a
fluoroarene with deprotonated 3-methyl-4-piperidinenitrile giving the (3R*,4R*)-isomer. The corresponding fluoromethyl
analogues were subsequently obtained through the fluorination of the piperidinemethanols using DAST.
pharmacophore when embedded within spirocyclic CCR2
antagonists 73 and 8,6 opioid ligands 9,7 and DPP-4 (dipeptidyl
peptidase IV) inhibitors 108 (Figure 1). In the case of 3,4-
polysubstituted piperidines, the configuration at the C-3 and C-
4 positions can be critical for the intrinsic biological activity.
However, the structural specificity of the antagonist activity has
only been demonstrated for opioid ligands 9.
Considering the biological and synthetic importance of 3-
methylpiperidines on one hand and of 4-aryl-4-piperidineme-
thanols on the other hand, we considered the 4-aryl-3-methyl-
4-piperidinemethanols 11 to represent attractive tools for the
development of original drug analogues (Scheme 2), for
pharmaceutical optimization, and for understanding of binding
mechanisms with the molecular targets. To date, the chemistry
of such a building block remains relatively unexplored. Only
one synthesis is reported in a patent and involves the sequential
alkylation of an arylacetonitrile with the bis-mesylate of (R)-N-
Boc-2-hydroxyethyl-2-hydroxypropylamine.3 This approach led
to a mixture of (3R,4S) and (3R,4R) diastereoisomers in a 7:3
ratio in rather poor yields (<20%).
INTRODUCTION
■
In recent years, 4-aryl-4-piperidinemethanols 1 have become
attractive as versatile molecular frameworks for drug discovery
programs (Scheme 1). The importance of piperidines 1 in
medicinal chemistry is highlighted by their growing utility as
key intermediates for the synthesis of more advanced structures
and also by the presence of these structures in novel patented
pharmaceutical agents targeting central nervous system
disorders and cancers. For illustration, the coupling of
piperidines 1 with a bromocyanopyridinone gave access to N-
substituted piperidines 2 functioning as positive allosteric
modulators of metabotropic glutamate receptors subtype 2
(mGluR2).1 In this series, a further substitution of the hydroxy
group by a fluorine led to compounds with an increased
mGluR2 inhibition. The conversion of alcohols 1 into
appropriate ethers 3 afforded inhibitors of neurokinin-1 and
serotonin (5-hydroxytryptamine 5-HT) reuptake receptors,2
and the transformation of 1 to spirodihydrobenzofurans 4
provided an efficient route to antagonists of CCR2 chemokine
receptors.3 Finally, piperidinemethanols 1 can also be the
subject of other transformations such as a ring contraction to
provide 3-disubstituted pyrrolidines 5 and 6 as a new class of
compounds with potential pharmacotherapeutic interest.4
Derivatives containing a backbone 6 have already been
investigated as selective dopamine D3 receptor antagonists.5
The reported products 1−4 contain a symmetrical 3-
desalkylpiperidine moiety, but SAR studies on other piper-
idine-based drugs identified that methyl substitution at position
3 on the ring improved potency and bioavailability. Typically,
the 3-methylpiperidine unit has been identified as an attractive
Over the course of our program concerning preparation of
3,4-trisubstituted piperidines,9 we set out to develop
straightforward and diastereoselective synthetic routes to
(3R*,4S*)- and (3R*,4R*)-4-aryl-3-methyl-4-piperidinemetha-
nols 11a and 11b (Scheme 2). By analogy with the 4-
arylpiperidine template in opioid ligands 9, a phenol moiety
was selected as the aryl group. Our strategy for the preparation
Received: October 23, 2012
© XXXX American Chemical Society
A
dx.doi.org/10.1021/jo302303h | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
Scheme 1. 4-Aryl-4-piperidinemethanols as Building Blocks for the Synthesis of Pharmacologically Active Molecules
of piperidines 11a,b was based on the use of the commercially
available N-methyl-3-methyl-4-piperidinone 13 as the common
starting material. Construction of the quaternary center at C4
was central to the syntheses of target compounds. The general
approach involved sequential introduction of the aryl moiety
and the hydroxymethyl equivalent, where control of the C3−
C4 relative stereochemistry was directly related to the order of
introduction of these groups. As the addition of fluorine at
specific positions in drug-like molecules has successfully led to
improvements in a variety of properties including enhanced
binding interaction, brain penetration, metabolic stability, and
extended biological half-life,10 we also targeted fluorine-
containing 4-aryl-3,4-dimethypiperidines. Knowing that con-
version of the piperidinemethanol moiety present in mGluR2
inhibitors into their fluoromethyl derivative led to enhanced
potency,1 we focused on the diastereoselective preparation of
fluoro compounds 12a and 12b.
Figure 1. Structures of pharmacologically active 3-methylpiperidines
7−10.
Scheme 2
RESULTS AND DISCUSSION
■
For the synthesis of 11a, we envisioned an approach based on
the alkylation reaction of the metalloenamine generated from
the tetrahydropyridine 14 (Scheme 3).11−14 Tetrahydropyr-
Scheme 3. Synthesis of Piperidine 11a
B
dx.doi.org/10.1021/jo302303h | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
Scheme 4. Synthesis of Piperidine 11b
idine 14 was easily accessed from piperidinone 13 via
aryllitihum addition followed by regioselective dehydration as
described in the literature.12 The metalloenamine alkylation
methodology from 3-alkyl-4-aryltetrahydropyridines was pre-
viously reported with methylating,11,12 propylating,13 and
allylating14 agents in the context of the synthesis of morphinoid
alkaloids. Alkylation was shown to be highly regioselective in
favor of the 3-position and to occur exclusively trans to the C3-
substituent. The trans diastereoselectivity was explained by the
C3-substituent preferentially adopting a pseudoaxial orientation
in the flattened metalloenamine, thus impeding alkylation from
the β-face. Our attention was turned to the introduction of an
alkoxymethyl group as a protected hydroxymethyl equivalent.
In the event, treatment of tetrahydropyridine 14 with n-BuLi
(1−1.5 equiv) in THF followed by iodomethoxymethane (1−2
equiv) did not provide an efficient access to the 4-
methoxymethyltetrahydropyridine 15a due to concurrent N-
alkylation giving ammonium 16 and butylation of tetrahy-
dropyridine 14 resulting in 4-butyltetrahydropyridine 17. The
des-alkyltetrahydropyridine 18, formed by protonation of the
metalloenamine was also detected as side product in significant
amounts. Under a variety of conditions, a mixture of products
15a/16/17/18 was obtained in a ratio of about 34:34:21:11
(estimated from the 1H NMR spectrum of the crude products).
Tetrahydropyridines 15a, 17, and 18 were not easily separable
by chromatography, and reduction with NaBH4 was performed
from a mixture enriched in 15a to afford methoxymethylpiper-
idine 19a in only 17% yield from tetrahydropyridine 14.
Changing the hydroxymethylating equivalent to benzylox-
ymethyl chloride (BOM − Cl) proved more rewarding;
treatment of the tetrahydropyridine 14 with n-BuLi in THF
at −20 °C followed by addition of BOM − Cl at −50 °C
afforded the pure benzyloxymethyltetrahydropyridine 20a in
55% yield. No traces of side products 17, 18, and the
The route envisaged for the preparation of hydroxymethyl-
piperidine 11b involved 4-cyano-3-methylpiperidine 24 as the
key intermediate (Scheme 4). Indeed, the α-arylation of a
secondary aliphatic nitriles with aryl halides provides a valuable
entry to tertiary benzylic nitriles, which are precursors of
hydroxymethyl derivatives.15−20 Single-step transformation of
piperidinone 13 to the nitrile intermediate 24 was carried out
using tosylmethyl isocyanide and t-BuOK in DME in 64%
yield,21 giving mixture of diastereoisomers 24a and 24b in a 70/
30 ratio. Structural identification of the major isomer 24a was
achieved through a combination of NMR spectroscopic
analyses (COSY, HSQC, and NOE) from a pure fraction
isolated by chromatography.22 On the basis of the COSY and
HSQC spectra, we were able to assign a well-resolved signal at
2.85 ppm to the C4-H(CN) proton of the product. NOE
experiments further confirmed the stereochemical relationship
between C3 and C4 substituents on the basis of observed
correlation for C3-H/C4-Me (see the Supporting Information).
This result indicated that the newly introduced nitrile and the
methyl group possess a trans relationship.
A variety of methods have been developed to carry out α-
arylation of substituted nitriles with direct nucleophilic aromatic
substitution (SNAr) providing an attractive approach.16,17
Classically, this method suffers from the use of harsh conditions
unless an activated heteroaryl halide is employed.16 The
palladium-catalyzed arylation of nitriles has recently emerged
as a promising methodology.18−20 The applicability of this
method to cyclohexanecarbonitriles has recently been ad-
dressed, but the use of the starting nitrile in excess (nitrile/aryl
halide ratio of 1.5 to 2/1) reduces the attractiveness of the
reported procedure in the present work.20 Although under-
exploited to date, an improved procedure for direct SNAr
arylation of the potassium salts of secondary nitriles with aryl
fluorides has been described by Caron and co-workers.17 The
potassium salts of nitrile derivatives of tropinone were shown to
react with fluoroarenes from a less hindered α-equatorial
direction. However, we are not aware of any reported examples
of SNAr arylation reactions of simple piperidinenitrile
derivatives. From nitrile 24, we anticipated that arylation will
result in the (3R*,4R*) isomer as the major product.
Nucleophilic substitution of (3-isopropoxy)fluorobenzene was
realized using the 70/30 mixture of nitriles 24a and 24b in the
presence of KHMDS in toluene at 120 °C for 24 h to give the
desired benzylic nitrile 25b in 52% yield as a single
diastereoisomer. N-Methylpiperidine 25b was converted to
the phenyl and tert-butyl carbamates 26b (65% yield) and 27b
(60% yield) by reaction with phenyl chloroformate in refluxing
toluene or sequential N-demethylation and Boc protection,
respectively. The crystal structure of N-Boc compound 27b
established the (3R*,4R*) configuration (see the Supporting
Information). The high diastereoselectivity observed for the
1
corresponding ammonium were detected by H NMR analysis
of the crude product, and the diastereoisomer 20a was the sole
alkylation product isolated. Enamine 20a was reduced with
NaBH4 to give piperidine 21a in 95% yield. The anticipated
trans diasteroselectivity of the metalloenamine alkylation was
confirmed by 1H NMR analysis of compound 21a (and also of
19a) with the signal attributed to the methyl group in position
3 in the form of a unique doublet at 0.85 ppm.12 Compound
21a was then subjected to successive deprotection steps to yield
the target product 11a. Treatment of N-methylpiperidine 21a
with phenyl chloroformate in refluxing toluene led to the N-
phenylcarbamate 22a in 82% yield. Basic hydrolysis of
carbamate 22a gave piperidine 23a in 70% yield. Finally,
liberation of the aliphatic alcohol and phenol functionalities was
carried out using BBr3 in DCM to produce hydroxymethylpi-
peridine 11a in 87% yield.
C
dx.doi.org/10.1021/jo302303h | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
Scheme 5. Proposed Mechanism for the Formation of Nitrile 25b
synthesis of nitrile 25b can be rationalized on the basis of the
proposed transition-state arrangement for the fluoroarene
substitution process (Scheme 5). Following formation of the
potassium ketenimine generated by deprotonation of nitriles
24a and 24b, arylation proceeds via potassium coordination
with the developing negative charge on the aromatic ring. As
observed for the alkylation reactions, addition trans to the C3-
methyl is favored due to the steric hindrance of the
pseudoaxially oriented methyl group at the adjacent position.
Heating of both nitriles 26b and 27b in HCl 6 N at reflux for
3 weeks led to N,O-deprotected piperidine carboxylic acid 28b
in quantitative yields. Despite the prolonged reaction time, the
transformation was remarkably selective, although more forcing
conditions such as refluxing H2SO4 (50%) or KOH (1 M) led
to substantial degradation, and reaction with DIBAL afforded
the corresponding aldehyde in less than 20% yield. Reduction
of 28b with borane−dimethyl sulfide in THF at reflux afforded
the key hydroxymethylpiperidine 11b quantitatively.
The targeted fluoromethylpiperidine derivatives 12a and 12b
were synthesized by reaction of (diethylamido)sulfur trifluoride
(DAST)23 with an appropriate piperidinemethanol precursor.
N-Methyl- and N-phenyloxycarbonylpiperidinemethanol failed
to give access to 12a and 12b due to either unsuccessful
fluorination (in case of N-methyl) or deprotection conditions
incompatible with the presence of fluorine (in case of N-
benzyloxycarbonyl, data not shown). Thus, syntheses of
fluoromethylpiperidines 12a and 12b started from the
previously prepared hydroxymethylpiperidines 11a and 11b
(Scheme 6). Piperidines 11a and 11b were converted to N,O-
di-Boc piperidines 29a and 29b, respectively, using (Boc)2O
and Et3N in CH2Cl2 in 88−90% yields. Fluorination of 29a and
29b with DAST afforded the fluoro analogues 30a and 30b in
40−42% yields, and deprotection with TFA produced the
desired fluoromethylpiperidines 12a and 12b quantitatively.24
CONCLUSION
■
In summary, starting from 1,3-dimethyl-4-piperidinone 13,
(3R*,4S*)- and (3R*,4R*)-4-aryl-3-methyl-4-piperidinemetha-
nols 11a and 11b were prepared in high yields and
diastereoselectivities by two straightforward efficient synthetic
protocols. The fluoro analogues 12a and 12b were
subsequently obtained through fluorination with DAST. The
procedures reported here pave the way for the preparation of
novel structures as chemical tools for drug development.
EXPERIMENTAL SECTION
■
(3R*,4S*)-4-(Benzyloxymethyl)-4-(3-isopropoxyphenyl)-1,3-
dimethyl-1,2,3,4-tetrahydropyridine (20a). To a solution of
tetrahydropyridine 1412 (5.00 g, 20.4 mmol) in THF (50 mL) was
added dropwise n-BuLi (1.6 M in hexanes, 19.1 mL, 30.6 mmol) while
the temperature was maintained between −10 and −20 °C. When the
addition was complete, the reaction mixture was stirred for 30 min at
−20 °C and then cooled to −50 °C. Benzyloxymethyl chloride (75%,
5.8 mL, 30.6 mmol) was added dropwise to the reaction medium at
−50 °C. The reaction mixture was stirred for 30 min at −50 °C. After
addition of a dilute solution of aqueous NH4OH (6%, 30 mL) and
heptanes (25 mL), the reaction mixture was stirred for 1.5 h at rt and
then concentrated. The residue was purified by chromatography on
silica gel (DCM/MeOH from 100/0 to 96/4) to give the title
compound as an orange oil (4.10 g, 55%): Rf 0.32 (DCM/MeOH 95/
1
3
5); H NMR (CDCl3, 400.0 MHz) δ 0.50 (d, JH−H = 8.1 Hz, 3H),
1.26−1.33 (m, 6H) 2.17−2.22 (m, 1H), 2.44−2.52 (m, 2H), 2.50 (s,
3H), 3.39 and 3.57 (AB, d, 2JA‑B = 7.1 Hz, 2H), 4.21 (sept, 3JH−H = 6.1
Scheme 6. Synthesis of Fluoromethylpiperidines 12a and
12b from Hydroxymethylpiperidines 11a and 11b
Hz, 1H), 4.28 (d, 3JH−H = 10.0 Hz, 1H), 4.30 (s, 2H), 6.01 (d, 3JH−H
=
10.0 Hz, 1H), 6.71−6.75 (m, 2H), 6.93−6.99 (m, 2H), 7.20−7.30 (m,
5H); 13C NMR (CDCl3, 100.6 MHz) δ 15.4, 22.2, 33.8, 42.2, 45.2,
48.5, 65.4, 69.8, 73.3, 109.7, 113.1, 117.7, 121.9, 127.0, 127.6, 128.6,
139.0, 144.6, 157.0; IR (neat) ν 2973, 2930, 1670, 1600, 1485, 1245,
1113. ESI+/MS/MS (m/z) 366.2 ([M(C24H31NO2) + H]+, 100),
288.2 (20), 141.0 (10); ESI+/HRMS (QTOF) calcd for C24H32NO2
366.2433, found 366.2417.
(3R*,4S*)-4-(Benzyloxymethyl)-4-(3-isopropoxyphenyl)-1,3-
dimethylpiperidine (21a). To a solution of tetrahydropyridine 20a
(1.00 g, 2.8 mmol) in MeOH (15 mL) at 0 °C was added NaBH4 (160
mg, 4.4 mmol). When the addition was complete, the reaction mixture
was stirred for 3 h at rt. The reaction was quenched by addition of
acetone (10 mL) and a saturated solution of NaHCO3 (10 mL) then
concentrated. The residue was dissolved in EtOAc (50 mL) and water
(50 mL). After separation and extraction with EtOAc, the combined
organic fractions were washed with water, dried, and concentrated.
The residue was purified by chromatography on silica gel (AcOEt/
D
dx.doi.org/10.1021/jo302303h | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
3
MeOH from 100/0 to 95/5) to give the title compound as a yellow oil
2H), 2.41−2.46 (m, 1H), 3.04 (dd, JH−H = 4.0 Hz, 13.2 Hz, 1H),
3.34−3.38 (m, 2H), 3.38 (dd, 3JH−H = 3.6, 13.2 Hz, 1H), 3.76 and 4.02
(AB, d, 2JA‑B = 11.5 Hz, 2H), 6.68 (dd, 4JH−H = 2.3 Hz, 3JH−H = 8.0 Hz,
1
(955 mg, 95%): Rf 0.26 (AcOEt/MeOH 95/5); H NMR (CDCl3,
3
400.0 MHz) δ 0.85 (d, JH−H = 7.0 Hz, 3H), 1.31−1.33 (m, 6H),
3
2.04−2.08 (m, 2H), 2.16−2.18 (m, 2H), 2.26 (s, 3H), 2.45−2.53 (m,
1H), 6.79−6.84 (m, 2H), 7.19 (t, JH−H = 8.0 Hz, 1H); 13C NMR
2
2H), 2.76−2.81 (m, 1H), 3.57 and 3.79 (AB, d, JA‑B = 9.3 Hz, 2H),
(D2O, 75.5 MHz) δ 13.5, 31.7, 40.0, 42.9, 45.9, 48.8, 65.6, 113.5,
133.8, 118.9, 129.9, 145.2, 155.6; IR (neat) ν 3260, 2852, 1584, 1488,
1443, 1220, 1152, 1018; ESI+/MS/MS (m/z) 464.2 (2[M-
(C13H19NO2) + Na, 40), 222.2 ([M(C13H19NO2) + H]+, 100),
152.2 (30); ESI+/HRMS (QTOF) calcd for C13H20NO2 222.1494,
found 222.1493.
4.29−4.37 (m, 2H), 4.51 (sept, 3JH−H = 6.0 Hz, 1H), 6.73 (dd, 3JH−H
=
3
1.6, 2.2 Hz, 1H), 6.75−6.89 (m, 2H), 7.11 (dd, JH−H = 1.6, 6.2 Hz,
1H), 7.18−7.23 (m, 5H); 13C NMR (CDCl3, 100.6 MHz) δ 15.9, 21.9,
26.3, 34.2, 42.3, 46.5, 52.1, 58.7, 69.5, 72.9, 74.6, 112.5, 115.2, 118.9,
127.0, 127.9, 128.4, 138.5, 147.9, 157.4; IR (neat) ν 2972, 2892, 1601,
1382, 1113, 1028; ESI+/MS/MS (m/z) 368 ([M(C24H33NO2) + H]+,
100), 260 ([M − BnO]+, 80); ESI+/HRMS (QTOF) calcd for
C24H34NO2 368.2590, found 368.2599.
(3R*,4S*)- and (3R*,4R*)-1,3-Dimethylpiperidine-4-carbon-
itrile (24a and 24b). To a solution of 1,3-dimethylpiperidin-4-one 13
(1 mL, 7.46 mmol) and tosylmethyl isocyanide (1.67 g, 14.9 mmol) in
DME (24 mL) was added dropwise at 0 °C a solution of t-BuOK (1.67
g) in DME (12 mL) and t-BuOH (12 mL). The reaction mixture was
stirred for 45 min at 0 °C then for 2 h at rt, and water (20 mL) was
added. After extraction with diethyl ether, the combined organic
fractions were dried and concentrated. The residue was purified by
chromatography on silica gel (DCM/MeOH 100/0 to 95/5) to give a
first fraction containing a mixture of 24a and 24b in a 7/3 ratio as a
yellow oil (1.10 g, 55%) and a second fraction as pure 24a (30 mg,
2%), Rf 0.32 for 24b and 0.28 for 24a (DCM/MeOH 94/6). Analysis
(3R*,4S*)-Phenyl-4-(benzyloxymethyl)-4-(3-isopropoxy-
phenyl)-3-methylpiperidine-1-carboxylate (22a). To a solution
of N-methylpiperidine 21a (500 mg, 1.36 mmol) in toluene (5 mL)
was added dropwise phenyl chloroformate (200 μL, 1.56 mmol) at 85
°C. The mixture was refluxed for 3 h. After the mixture was cooled to
45 °C, aqueous NaOH (5%, 1.7 mL) was added, and the mixture was
allowed to cool to rt under stirring. After separation, the organic layer
was washed three times with MeOH/HCl (1 N) 1:1, then once with
MeOH/NaOH (1 N) 1:1, and finally with water. The solvent was
removed under reduced pressure. The residue was purified by
chromatography on silica gel (pentane/diethyl ether from 90/10 to
70/30) to give the title compound as a yellow oil (526 mg, 82%): Rf
0.35 (pentane/diethyl ether 70/30); 1H NMR (CDCl3, 400.0 MHz): δ
0.76−0.80 (m, 3H), 1.32−1.34 (m, 6H), 2.08−2.16 (m, 2H), 2.25−
2.30 (m, 1H), 3.15−3.47 (m, 2H), 3.66−3.70 (m, 1H), 3.86−3.97 (m,
2H), 4.21−4.26 (m, 1H), 4.36−4.38 (m, 2H), 4.53 (sept, J = 6.1 Hz,
1
of the mixture of 24a and 24b: H NMR (CDCl3, 400.0 MHz) δ
1.08−1.09 (m, 4.3H, 2a, 2b), 1.58 (t, 3JH−H = 10.8 Hz, 1H, 2a), 1.82−
2.07 (m, 8.1H, 2a, 2b), 2.24 (s, 3H, 2a), 2.28−2.31 (m, 1.6H, 2b),
2.67−2.86 (m, 3.3H, 2a, 2b); 13C NMR (CDCl3, 100.4 MHz)
attributed to 24b δ 17.8, 29.2, 34.2, 34.3, 46.1, 54.3, 62.3, 121.5; ESI+/
MS/MS m/z 139.2 ([M(C8H14N2) + H]+, 100), 122.1 (10), 112.2
([M − CN]+, 5), 107.1 (20); ESI+/HRMS (QTOF) calcd for
C8H15N2 139.1235, found 139.1230. Analysis for 24a: 1H NMR
4
3
1H), 6.78 (dd, JH−H = 1.3 Hz, JH−H = 7.8 Hz, 1H), 6.80−6.90 (m,
2H), 7.07−7.33 (m, 11H); 13C NMR (CDCl3, 100.6 MHz) δ 14.2,
22.2, 25.5, 34.3, 40.9, 43.3, 46.9, 69.8, 73.3, 74.3, 113.0, 115.0, 118.7,
121.8,125.2, 127.5, 128.3, 128.9, 129.3, 138.4, 151.6, 154.4, 157.8; IR
(neat) ν 1713, 1595, 1488, 1426, 1198, 1114; ESI+/MS/MS (m/z)
474.4 ([M(C30H35NO4) + H]+, 100), 456.4 (30), 432.4 (50), 414.3
([M − OiPr]+, 35), 366.3 ([M − BnO]+, 40), 324.3 (20), 320.3 (20),
272.3 (30), 246.3 ([M − BnOCO2Ph + H]+, 20), 230.2 (40%); ESI+/
HRMS (QTOF) calcd for C30H36NO4 474.2644, found 474.2624.
(3R*,4S*)-4-(Benzyloxymethyl)-4-(3-isopropoxyphenyl)-3-
methylpiperidine (23a). A mixture of phenyl carbamate 22a (1.5 g,
3.17 mmol) and KOH (800 mg, 14.3 mmol) in toluene (50 mL) was
refluxed for 24 h and then cooled to rt. After addition of water (50
mL) followed by extraction with EtOAc, the organic layer was washed
with NaOH (1 N) and then with water, dried, and concentrated to
give the title compound as a yellow oil which was used without further
purification (800 mg, 70%): 1H NMR (MeOD, 300.0 MHz) δ 0.75 (d,
3
(CDCl3, 400.0 MHz) δ 1.09 (d, JH−H = 6.4 Hz, 3H), 1.94−2.08 (m,
4H), 2.28−2.33 (4H), 2.70−2.80 (m, 2H), 2.83−2.86 (m, 1H); 13C
NMR (CDCl3, 100.6 MHz) δ 17.1, 28.2, 32.1, 32.3, 46.1, 51.4, 59.2,
119.8; IR (neat) ν 2934, 2787, 2337, 1059.
(3R*,4R*)-1,3-Dimethyl-4-(3-isopropoxyphenyl)piperidine-
4-carbonitrile (25b). To a 7/3 mixture of nitriles 24a and 24b (460
mg, 2.98 mmol) and fluoro-3-isopropoxybenzene (1.7 g, 11.9 mmol)
was added dropwise a solution of KHMDS (0.5 M in toluene, 11.9
mL, 5.96 mmol) at rt. The reaction mixture was stirred at 120 °C for
24 h and cooled to rt. After addition of saturated aqueous solution of
NH4Cl and then extraction with EtOAc, the resulting organic layer was
washed with water, dried, and concentrated. The residue was purified
by chromatography on silica gel (DCM/MeOH from 100/0 to 98/2)
to give the title compound as a brown oil (430 mg, 52%): Rf 0.29
(DCM/MeOH 96/4); 1H NMR (CDCl3, 400.0 MHz) δ 0.81 (d,
3JH−H = 6.5 Hz, 3H), 1.33 (d, JH−H = 6.0 Hz, 6H), 2.03 (dt, JH−H
=
3
3
3
3JH−H = 7.3 Hz, 3H), 1.28 (d, JH−H = 5.9 Hz, 6H), 1.97−2.12 (m,
2.5, 13.8 Hz), 2.17−2.30 (m, 3H), 2.38 (s, 3H), 2.47 (dt, 3JH−H = 2.2,
12.0 Hz), 2.86−2.96 (m, 2H), 4.55 (sept, 3JH−H = 6.0 Hz, 1H), 6.82−
3
3H), 2.64−2.69 (m, 1H), 2.79−2.99 (m, 2H), 3.07 (dd, JH−H = 3.7
2
3
Hz, 13.5 Hz, 1H), 3.65 and 3.94 (AB, d, JA‑B = 9.1 Hz, 2H), 4.28−
6.83 (m, 1H), 7.02−7.05 (m, 2H), 7.23 (t, JH−H = 4.2 Hz, 1H); 13C
3
4.38 (m, 2H), 4.54 (sept, JH−H = 5.9 Hz, 1H), 6.74−6.77 (m, 1H),
NMR (CDCl3, 100.6 MHz) δ 14.7, 22.0, 38.4, 39.1, 45.9, 49.4, 52.9,
60.1, 70.0, 114.0, 115.2, 118.0, 120.1, 130.0, 140.3, 158.3; IR (neat) ν
2973, 2791, 1603, 1581, 1466, 1254, 1114; ESI+/MS/MS (m/z) 273.2
([M(C17H24N2O) + H]+, 100); ESI+/HRMS (QTOF) calcd for
C17H25N2O 273.1967, found 273.1974. Anal. Calcd for C17H24N2O C,
74.96; H, 8.88; N, 10.28. Found: C, 74.92; H, 9.11; N, 10.15.
6.86−6.90 (m, 2H), 7.09−7.11 (m, 2H), 7.17−7.26 (m, 4H); 13C
NMR (MeOD, 75.5 MHz) δ 13.4, 20.8, 20.9, 33.6, 41.3, 42.8, 49.3,
69.4, 72.5, 74.4, 112.6, 114.7, 118.5, 126.9, 127.1, 127.7, 128.3, 138.4,
147.9, 157.6; IR (neat) ν 3028, 2931, 1601, 1579, 1486, 1452, 1187,
1145, 1027; ESI+/MS/MS (m/z) 354.3 ([M(C23H31NO2) + H]+, 20),
246.2 ([M − BnO]+, 100), 187.1 ([M − BnOOiPr]+, 10), 159.1 (10),
96.1 (15); ESI+/HRMS (QTOF) calcd for C23H32NO2 354.2433,
found 354.2431.
(3R*,4R*)-Phenyl-4-cyano-4-(3-isopropoxyphenyl)-3-meth-
ylpiperidine-1-carboxylate (26b). To a solution of N-methylpiper-
idine 25b (1.8 g, 6.60 mmol) in toluene (20 mL) was added dropwise
phenyl chloroformate (1 mL, 7.92 mmol) at 85 °C, and the mixture
was refluxed for 3 h. After cooling to 45 °C and addition of aqueous
NaOH (5%, 4.5 mL), the mixture was cooled to rt under stirring. The
organic and aqueous layers were separated, and the organic layer was
washed three times with MeOH/HCl (1 N) 1:1 and then once with
MeOH/NaOH (1 N) 1:1 and finally with water. The solvent was
removed under reduced pressure. The residue was purified by
chromatography on silica gel (pentane/diethyl ether from 100/0 to
70/30) to give the title compound as a yellow oil (1.6 g, 65%): Rf 0.67
(3R*,4S*)-4-Hydroxymethyl-4-(3-hydroxyphenyl)-3-methyl-
piperidine Hydrochloride (11a). To a solution of diether 23a (580
mg, 1.64 mmol) in DCM (6 mL) at −78 °C was added BBr3 (1 M in
DCM, 16.4 mL, 16.4 mmol). The reaction mixture was stirred at −78
°C for 3 h, and EtOH (2 mL) was added dropwise. The mixture was
warmed to rt and concentrated. The residue was dissolved in wate, and
the pH was adjusted to 8 with NaOH (1 N). After the residue was
washed with ethyl acetate, the aqueous layer was concentrated. The
resulting residue was purified by chromatography on silica gel (DCM/
MeOH 85/15) to give the title compound as a yellow solid (315 mg,
1
(pentane/diethylether 70/30); H NMR (CDCl3, 400.0 MHz) δ 0.90
1
87%): Rf 0.24 (DCM/MeOH 85/15); mp 320−330 °C; H NMR
(d, 3JH−H = 6.8 Hz, 3H), 1.37 (d, 3JH−H = 6.0 Hz, 6H), 2.12−2.16 (m,
2H), 2.21−2.27 (m, 1H), 3.97−3.15 (m, 1H), 3.32−3.47 (m, 1H),
3
(MeOD, 300.0 MHz) δ 0.81 (d, JH−H = 7.3 Hz, 3H), 2.22−2.27 (m,
E
dx.doi.org/10.1021/jo302303h | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
4.33−4.47 (m, 2H), 4.61 (sept, 3JH−H = 6.0 Hz, 1H), 6.89 (dd, 4JH−H
=
2.95 mmol). The mixture was stirred overnight at rt and then
concentrated. The residue was dissolved in DCM (2 mL) and water (2
mL). After separation and extraction with DCM, the combined organic
fractions were washed with water, dried, and concentrated to give the
title compound as a beige solid (223 mg, 90%): mp 50−55 °C; Rf 0.43
1.8 Hz, 3JH−H = 7.8 Hz, 1H), 7.03−7.07 (m, 2H), 7.15−7.17 (m, 2H),
7.24−7.27 (m, 1H), 7.33 (t, 3JH−H = 8.0 Hz, 1H), 7.38−7.42 (m, 2H);
13C NMR (CDCl3, 100.6 MHz) (doubling of some signals due to
rotamers) δ 14.1, 22.0, 37.8, 38.4, 38.9, 39.4, 41.8, 42.3, 59.1, 70.1,
114.3, 114.9, 117.9, 119.5, 121.7, 125.5, 129.4, 130.2, 139.6, 151.3,
153.4, 158.5; IR (neat) ν 2976, 1715, 1581, 1228, 1114, 1070; ESI+/
MS/MS (m/z) 401.1 (100). ESI+/HRMS (QTOF) calcd for
C23H26N2O3Na 401.1841, found 401.1856.
1
(pentane/EtOAc 70/30); H NMR (MeOD, 400.0 MHz) δ 0.66 (d,
3JH−H = 7.0 Hz, 3H), 1.45 (s, 9H), 1.52 (s, 9H), 1.92−2.02 (m, 2H),
2.15−2.19 (m, 1H), 3.09−3.34 (m, 2H), 3.77−3.82 (m, 2H), 4.03−
4.09 (m, 2H), 6.97−6.99 (m, 1H), 7.07−7.09 (m, 1H), 7.21 (d, 3JH−H
= 8.0 Hz, 1H), 7.34 (t, 3JH−H = 8.0 Hz, 1H); 13C NMR (MeOD, 100.6
MHz) δ 14.6, 27.5, 28.6, 35.2, 40.3, 41.3, 45.5, 47.2, 66.7, 80.8, 84.2,
119.8, 120.8, 125.2, 129.9, 149.1, 152.6, 153.6, 56.9; IR (neat) ν 3450,
1755, 1686, 1609, 1584, 1246, 1137; ESI+/MS/MS (m/z) 444.5
([M(C23H35NO6) + Na]+, 30), 388.4 (40), 344.4 ([M − Boc+Na]+,
100), 288.3 (30); ESI+/HRMS (QTOF) calcd for C23H35NO6Na
444.2362, found 444.2362.
(3R*,4R*)-tert-Butyl 4-Cyano-4-(3-isopropoxyphenyl)-3-
methylpiperidine-1-carboxylate (27b). To a solution of N-
methylpiperidine 25b (1.5 g, 5.5 mmol) in CHCl3 (20 mL) was
added dropwise 1-chloroethyl chloroformate (1.2 mL, 11.0 mmol) at
rt. The reaction mixture was refluxed for 4.5 h, cooled to rt, and
concentrated under vacuum. The residue was dissolved in MeOH (20
mL). The solution was refluxed for 2 h, cooled to rt, and concentrated
under vacuum. The residue was dissolved in DCM (25 mL), and Et3N
(1.3 mL, 8.8 mmol) and di-tert-butyl dicarbonate (1.8 g, 8.3 mmol)
were added. The reaction mixture was stirred at rt for 4 h and then
washed with brine. The organic layer was dried and concentrated. The
residue was purified by chromatography on silica gel (hexane/diethyl
ether from 80/20 to 70/30) to give the title compound as a white solid
(1.2 g, 60%): mp 85−86 °C; Rf 0.47 (hexane/diethyl ether 70/30); 1H
(3R*,4R*)-1-(tert-Butoxycarbonyl)-4-(3-tert-butoxycarbony-
loxyphenyl)-4-(hydroxymethyl)-3-methylpiperidine (29b). To a
solution of alcohol 11b (200 mg, 0.78 mmol) and Et3N (0.40 mL, 2.95
mmol) in DCM (5 mL) was added di-tert-butyl dicarbonate (643 mg,
2.95 mmol). The mixture was stirred overnight at rt, and then water (5
mL) was added. After separation and extraction with DCM, the
combined organic fractions were washed with water, dried, and
concentrated. The residue was purified by chromatography on silica
gel (pentane/EtOAc from 90/10 to 70/30) to give the title compound
as a beige solid (223 mg, 68%): mp 60−65 °C; Rf 0.48 (pentane/
3
NMR (DMSO, 300.0 MHz) δ 0.69 (d, JH−H = 6.6 Hz, 3H), 1.26 (d,
3JH−H = 5.9 Hz, 6H), 1.43 (s, 9H), 1.96−2.10 (m, 2H), 2.18−2.26 (m,
1H), 2.51−2.66 (m, 1H), 2.89−3.07 (m, 1H), 4.04−4.14 (m, 2H),
1
3
EtOAc 70/30); H NMR (MeOD, 400.0 MHz) δ 0.95 (m, 3H), 1.45
4.66 (sept, JH−H = 5.9 Hz, 1H), 6.89−6.93 (m, 1H), 7.02−7.08 (m,
3
2H), 7.33 (t, JH−H = 6.1 Hz, 1H); 13C NMR (CDCl3, 75.5 MHz) δ
(s, 9H), 1.53 (s, 9H), 1.88−1.93 (m, 2H), 2.40−2.42 (m, 1H), 3.19−
3.22 (m, 1H), 3.44−3.48 (m, 1H), 3.64−3.79 (m, 3H), 6.99−7.01 (m,
1H), 7.24−7.5 (m, 1H), 7.37−7.38 (m, 2H); 13C NMR (MeOD,
100.6 MHz) δ 13.5, 27.9, 28.7, 34.8, 36.1, 38.3, 41.2, 46.2, 70.8, 80.9,
84.3, 120.1, 121.9, 126.1, 130.3, 152.8, 153.7, 157.0; IR (neat) ν 3452,
1727, 1691, 1608, 1583, 1251, 1148. ESI+/MS/MS (m/z) 444.5
([M(C23H35NO6) + Na]+, 25), 388.4 (40), 344.4 ([M − Boc + Na]+,
100), 288.3 (40); ESI+/HRMS (QTOF) calcd for C23H35NNaO6
444.2362, found 444.2358.
14.0, 21.9, 28.4, 33.5, 38.1, 38.9, 47.5, 70.0, 80.1, 114.1, 114.8, 117.9,
119.6, 130.0, 139.9, 154.4, 158.3; IR (neat) ν 1691, 1608, 1581, 1448,
1244, 1133; ESI+/MS/MS (m/z) 381.2 ([M(C21H30N2O3) + Na]+,
30), 325 (100); ESI+/HRMS calcd for C21H30N2NaO3 381.2154,
found 381.2156. Anal. Calcd for C21H30N2O3: C, 70.36; H, 8.44; N,
7.81. Found: C, 70.79; H, 8.65; N, 7.96.
(3R*,4R*)-4-(3-Hydroxyphenyl)-3-methylpiperidine-4-car-
boxylic Acid Hydrochloride (28b). A solution of nitrile 27b (600
mg, 1.68 mmol) in HCl (6 N, 6 mL) was refluxed for 4 weeks, cooled
to rt, and then concentrated to give the title compound as beige solid
(455 mg, quant) which was used without further purification: mp
(3R*,4S*)-1-(tert-Butoxycarbonyl)-4-(3-tert-butoxycarbony-
loxyphenyl)-4-(fluoromethyl)-3-methylpiperidine (30a). To a
solution of alcohol 29a (50 mg, 0.11 mmol) in DCM (0.5 mL) at −50
°C was added DAST (23 μL, 0.19 mmol). The mixture was stirred at
−50 °C for 2 h and then at rt overnight and cooled to −78 °C. After
addition of saturated aqueous solution of NaHCO3 (0.5 mL) at −78
°C, the mixture was allowed to warm to rt. After extraction with DCM,
the organic layer was washed with water, dried, and concentrated. The
residue was purified by chromatography on silica gel (pentane/diethyl
ether from 95/5 to 90/10) to give the title compound as a colorless oil
(20 mg, 40%): Rf 0.60 (pentane/diethyl ether 80/20); 1H NMR
(CDCl3, 400.0 MHz) δ 1.05−1.08 (m, 3H), 1.42 (s, 9H), 1.52 (s, 9H),
1.72−1.87 (m, 2H), 2.73−2.97 (m, 2H), 3.20−3.23 (m, 1H), 3.57−
3.84 (m, 2H), 6.99−7.04 (m, 2H), 7.09−7.15 (m, 1H), 7.28−7.30 (m,
1H); 13C NMR (CDCl3, 100.6 MHz) (some doubling of signals due
to rotamers) δ 11.8, 27.7, 28.5, 31.4, 33.8, 38.4, 43.5, 47.4, 80.9 and
1
3
280−285 °C; H NMR (MeOD, 400.0 MHz) δ 0.89 (d, JH−H = 6.7
Hz, 3H), 2.37−2.48 (m, 2H), 2.58−2.61 (m, 1H), 3.16−3.30 (m, 4H),
6.75 (ddd, 4JH−H = 0.8 Hz, 4JH−H = 2.3 Hz, 4JH−H = 3.1 Hz, 1H), 6.83−
6.87 (m, 2H), 7.23 (t, JH−H = 8.0 Hz); 13C NMR (MeOD, 100.6
3
MHz) δ 145, 36.6, 42.9, 47.9, 51.2, 53.8, 114.8, 115.3, 118.5, 130.7,
142.7, 158.8, 175.7; IR (neat) ν 3350, 2794, 1713, 1584, 1496, 1447,
1272, 1103; ESI+/MS/MS 236.2 ([M(C13H17NO3) + H]+, 30), 190.2
(100); ESI+/HRMS (QTOF) calcd for C13H18NO3 236.1287, found
236.1293.
(3R*,4R*)-4-Hydroxymethyl-4-(3-hydroxyphenyl)-3-methyl-
piperidine Hydrochloride (11b). To a solution of carboxylic acid
28b (440 mg, 1.68 mmol) in THF (5 mL) was added dropwise
BH3·SMe2 (1 M in THF, 10.1 mL, 10.1 mmol). The mixture was
refluxed for 3 h. After cooling to rt and addition of MeOH (2 mL), the
solvent was removed under reduced pressure. The residue was
dissolved in a 1:1 MeOH/HCl (6 N) mixture (10 mL) and the
solution refluxed for 1 h. The solvent was removed under reduced
pressure to give the title compound as a beige solid (203 mg, 48%):
2
81.0, 84.1, 97.6 (d, JC−F = 174.1 Hz), 120.3, 120.4, 124.3, 124.4,
128.9, 129.0, 129.8, 129.9, 138.7, 139.0, 152.2, 152.3, 153.23, 153.3,
156.2, 156.7; 19F NMR (CDCl3) δ -(154.9−155.5) (m); IR (neat) ν
1755, 1689, 1613, 1588, 1235, 1138, 1046; ESI+/MS/MS (m/z) 446.4
([M(C23H34FNO5) + Na]+, 35), 390.3 (100), 346.3 (60), 326.3 (20),
290.2 (20), 270.2 (10); ESI+/HRMS (QTOF) calcd for
C23H34FNNaO5 446.2319, found 446.2300.
(3R*,4R*)-1-(tert-Butoxycarbonyl)-4-(3-tert-butoxycarbony-
loxyphenyl)-4-(fluoromethyl)-3-methylpiperidine (30b). To a
solution of alcohol 29b (100 mg, 0.22 mmol) in DCM (1 mL) at −50
°C was added DAST (46 μL, 0.38 mmol). The mixture was stirred at
−50 °C for 2 h, then at rt for 20 h, and cooled to −78 °C. After
addition of saturated aqueous solution of NaHCO3 (1 mL) at −78 °C,
the mixture was allowed to warm to rt. After extraction with DCM, the
organic layer was washed with water, dried, and concentrated. The
residue was purified by chromatography on silica gel (pentane/diethyl
ether from 95/5 to 90/10) to give the title compound as a colorless oil
(40 mg, 40%): Rf 0.38 (pentane/diethyl ether 90/10); 1H NMR
1
3
mp 110−115 °C; H NMR (MeOD, 400.0 MHz) δ 0.96 (d, JH−H
=
7.2 Hz, 3H), 2.13−2.15 (m, 2H), 2.57−2.62 (m, 1H), 3.13−3.20 (m,
4H), 3.83 and 3.94 (AB, d, JA‑B = 11.4 Hz, 2H), 6.38 (ddd, JH−H
2
4
=
3
3
0.9 Hz, JH−H = 2.2 Hz, JH−H = 8.1 Hz), 6.92−6.96 (m, 2H), 7.18−
7.23 (m, 1H); 13C NMR (acetone-d6, 100.6 MHz) δ 13.0, 26.3, 35.4,
41.4, 41.5, 44.0, 46.8, 62.4, 113.9, 115.3, 118.7, 130.1, 147.3, 158.4; IR
(neat) ν 3056, 1672, 1587, 1455, 1200, 1136; ESI+/MS/MS (m/z)
222.2 ([M(C13H19NO2 + H)]+, 100), 204.2 ([M − H2O]+, 30); ESI+/
HRMS (QTOF) calcd for C13H20NO2 222.1494, found 222.1489.
(3R*,4S*)-1-(tert-Butoxycarbonyl)-4-(3-tert-butoxycarbony-
loxyphenyl)-4-(hydroxymethyl)-3-methylpiperidine (29a). To a
solution of alcohol 11a (130 mg, 0.59 mmol) and Et3N (0.40 mL, 2.95
mmol) in DMF (1.5 mL) was added di-tert-butyl dicarbonate (643 mg,
F
dx.doi.org/10.1021/jo302303h | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
(MeOD, 400.0 MHz) δ 1.02−1.06 (m, 3H), 1.42 (s, 9H), 1.52 (s,
9H), 1.71−1.83 (m, 2H), 2.73−3.15 (m, 3H), 319−3.23 (m, 2H),
3.57−3.80 (m, 2H), 6.99−7.03 (m, 2H), 7.09−7.15 (m, 1H), 7.28−
7.32 (m, 1H); 13C NMR (MeOD, 100.6 MHz) (some doubling of
REFERENCES
■
(1) Cid-Nunez, J. M.; Trabanco-Suarez, A. A.; McDonald, G. J.;
Duvey, G. A. J.; Lutjens, R. J. PCT WO2008/107479, September 12,
2008.
(2) Schmitz, W. D.; Whitney, I. E.; Degnan, A. P.; Bronson, J. J. PCT
WO2009/009633, Jan 15, 2009.
(3) Budzik, B. W.; Haile, P. A.; Hughes, T. V.; Sehon, C. A.; Wang,
G. Z. PCT WO2009/061881, May 14, 2009.
(4) Bandarage, U. K.; Davies, R. J. Tetrahedron Lett. 2010, 51, 6415−
6417.
(5) (a) Micheli, F.; Arista, L.; Bertani, B.; Braggio, S.; Capelli, A. M.;
Cremonesi, S.; Di-Fabio, R.; Gelardi, G.; Gentile, G.; Marchioro, C.;
Pasquarello, A.; Provera, S.; Tedesco, G.; Tarsi, L.; Terreni, S.; Worby,
A.; Heidbreder, C. J. Med. Chem. 2010, 53, 7129−7139. (b) Bertani,
B.; Di-Fabio, R.; Micheli, F.; Pasquarello, A.; Tarsi, L.; Terreni, S. PCT
WO2007/125061, Nov 8, 2007.
(6) (a) Pasternak, A.; Marino, D.; Vicario, P. P.; Ayala, J. M.;
Cascierri, M. A.; Parsons, W.; Mills, S. G.; MacCoss, M.; Yang, L. J.
Med. Chem. 2006, 49, 4801−4804. (b) Yang, L.; Butora, G.; Jiao, R. X.;
Pasternak, A.; Zhou, C.; Parsons, W. H.; Mills, S. G.; Vicario, P. P.;
Ayala, J. M.; Cascieri, M. A.; MacCoss, M. J. Med. Chem. 2007, 50,
2609−2611.
signals due to rotamers) δ 12.0, 27.9, 28.6, 31.7, 38.6, 38.7 (d, 2JC−F
=
1
46.3 Hz), 43.4, 81.0, 81.1, 84.2, 84.3, 96.2 (d, JC−F = 178.8 Hz), 97.7
1
(d, JC−F = 178.8 Hz), 120.5, 124.5, 129.0, 129.2, 129.9, 130.1, 138.8,
139.2, 152.4, 152.4, 153.4, 153.5, 156.3, 156.9; 19F NMR (MeOD,
376.5 MHz) δ -(150.9−151.6) (m); IR (neat) ν 1755, 1688, 1612,
1587, 1234, 1137, 1046; ESI+/MS (m/z) 224.2 ([M − 2Boc]+, 100),
204.2 ([M − 2Boc-F]+, 70); ESI+/HRMS (QTOF) calcd for
C23H34FNNaO5 446.2319, found 446.2306.
(3R*,4R*)-4-Fluoromethyl-4-(3-hydroxyphenyl)-3-methylpi-
peridinium Trifluoroacetate (12a). A solution of piperidine 30a
(20 mg, 0.05 mmol) in TFA (0.5 mL) was stirred for 30 min at rt and
then concentrated to give the title compound as an orange oil (16 mg,
1
95%): H NMR (MeOD, 400.0 MHz) δ 1.17−1.20 (m, 3H), 1.75−
2.23 (m, 3H), 2.77−2.97 (m, 2H), 3.08−3.13 (m, 1H), 3.17−3.22 (m,
2H), 3.35−3.38 (m, 1H), 6.68−6.74 (m, 3H), 7.09−7.14 (m, 1H); 13C
NMR (MeOD, 100.6 MHz) δ 13.5, 29.0 (d, 3JC−F = 22.7 Hz), 36.3 (d,
2
2
3JC−F = 23.5 Hz), 41.5 (d, JC−F = 64.4 Hz), 47.4, 95.6 (d, JC−F
=
176.2 Hz), 114.9, 118.5, 122.8, 130.3, 137.5, 158.4; 19F NMR (MeOD,
376.5 MHz) δ −(151.8−152.9) (m, 1F), −76.8 (s, 3F); IR (neat) ν
3400, 1670, 1587, 1456, 1184, 1133, 1041; ESI+/MS/MS (m/z) 224.3
([M(C13H18NOFN) + H]+, 10), 204.3 ([M − F]+, 100), 159.2 (10),
96.1 (10); ESI+/HRMS (QTOF) calcd for C13H19FNO 224.1451,
found 224.1456.
(7) (a) Zimmerman, D. M.; Nickander, R.; Horng, J. S.; Wong, D. T.
Nature 1978, 275, 332−334. (b) Caroll, F. I. J. Med. Chem. 2003, 46,
1775−1794. (c) Mitch, C. H.; Leander, J. D.; Mendelsohn, L. G.;
Shaw, W. N.; Wong, D. T.; Cantrell, B. E.; Johnson, B. G.; Reel, J. K.;
Snoddy, J. D.; Takemori, A. E.; Zimmerman, D. J. Med. Chem. 1993,
36, 2842−2850. (d) Emmerson, P. J.; McKinzie, J. H.; Surface, P. L.;
Suter, T. M.; Mitch, C. H.; Statnick, M. A. Eur. J. Pharmacol. 2004,
494, 121−130. (e) Zimmerman, D. M.; Gidda, J. S.; Cantrell, B. E.;
Schoepp, D. D.; Johnson, B. G.; Leander, J. D. J. Med. Chem. 1994, 37,
2262−2265. (f) Thomas, J. B.; Atkinson, R. N.; Vinson, N. A.;
Catanzaro, J. L.; Perretta, C. L.; Fix, S. E.; Mascarella, S. W.; Rothman,
R. B.; Xu, H.; Dersch, C. M.; Cantrell, B. E.; Zimmerman, D. M.;
Carroll, F. I. J. Med. Chem. 2003, 46, 3127−3137. (g) Carroll, I.;
Thomas, J. B.; Dykstra, L. A.; Granger, A. L.; Allen, R. M.; Howard, J.
L.; Pollard, G. T.; Aceto, M. D.; Harris, L. S. Eur. J. Pharmacol. 2004,
501, 111−119. (h) Thomas, J. B.; Fall, M. J.; Cooper, J. B.; Rothman,
R. B.; Mascarella, S. W.; Xu, H.; Partilla, J. S.; Dersch, C. M.;
McCullough, K. B.; Cantrell, B. E.; Zimmerman, D. M.; Caroll, F. I. J.
Med. Chem. 1998, 41, 5188−5197. (i) Le Bourdonnec, B.; Belanger, S.;
Cassel, J. A.; Stabley, G. J.; DeHaven, R. N.; Dolle, R. E. Bioorg. Med.
Chem. Lett. 2003, 13, 4459−4462.
(3R*,4R*)-4-Fluoromethyl-4-(3-hydroxyphenyl)-3-methylpi-
peridinium Trifluoroacetate (12b). A solution of piperidine 30b
(30 mg, 0.07 mmol) in TFA (0.5 mL) was stirred for 30 min at rt then
concentrated to give the title compound as an orange oil (15 mg,
1
quantitative yield): H NMR (MeOD, 400.0 MHz) δ 1.14−1.71 (m,
3H), 1.75−2.17 (m, 3H), 2.74−2.94 (m, 2H), 3.03−3.10 (m, 1H),
3.14−3.23 (m, 2H), 3.31−3.37 (m, 1H) 6.65−6.71 (m, 3H), 7.07−
7.10 (m, 1H); 13C NMR (acetone-d6, 100.6 MHz) δ 13.5, 31.1 (d,
3JC−F = 30.6 Hz), 35.8 (d, 3JC−F = 24.4 Hz), 40.8 (d, 2JC−F = 73.3 Hz),
43.1, 46.8, 114.6, 118.3, 122.4, 30.0, 137.6, 158.1; 19F NMR (MeOD,
376.5 MHz) δ -(152.9−153.3) (m, 1F), −77.3 (s, 3F); IR (neat) ν
2989, 1669, 1587, 1459, 1198, 1132, 1041; ESI+/MS (m/z) 446.4
([2M(C13H18FNO]+, 80), 158.1 (100); ESI+/HRMS (QTOF) calcd
for C13H19FNO 224.1451, found 224.1446.
ASSOCIATED CONTENT
■
S
* Supporting Information
(8) Nishio, Y.; Kimura, H.; Tosaki, S.; Sugaru, E.; Sakai, M.;
Horiguchi, M.; Masui, Y.; Ono, M.; Nakagawa, T.; Nakahira, H. Bioorg.
Med. Chem. Lett. 2010, 20, 7246−7249.
1H and 13C NMR spectra of all new compounds, chiral HPLC
chromatograms for 12a,b, and X-ray crystallographic data for
27b (CIF). This material is free of charge via the Internet at
http://pubs.acs.org.
́
(9) Oueslati, F.; Perrio, C.; Dupas, G.; Barre, L. Org. Lett. 2007, 9,
153−156.
(10) Hagmann, W. K. J. Med. Chem. 2008, 51, 4359−4368 and
references therein.
AUTHOR INFORMATION
(11) Evans, D. A.; Mitch, C. H.; Thomas, R. C.; Zimmerman, D. M.;
Robey, R. L. J. Am. Chem. Soc. 1980, 102, 5955−5956.
(12) Werner, J. A.; Cerbone, L. R.; Franck, S. A.; Ward, J. A.; Labib,
P.; Tharp-Taylor, R. W.; Ryan, C. W. J. Org. Chem. 1996, 61, 587−597.
(13) Barnett, C. J.; Copley-Merriman, C. R.; Maki, J. J. Org. Chem.
1989, 54, 4795−4800.
■
Corresponding Author
*E-mail: perrio@cyceron.fr.
Notes
The authors declare no competing financial interest.
(14) Liras, S.; Allen, M. P.; Blake, J. F. Org. Lett. 2001, 3, 3483−3486.
(15) For examples, see: (a) Sun, D.; Wang, Z.; Caille, S.;
DeGraffenreid, M.; Gonzalez-Lopez de Turiso, F.; Hungate, R.; Jaen,
J. C.; Jiang, B.; Julian, L. D.; Kelly, R.; McMinn, D. L.; Kaizerman, J.;
Rew, Y.; Sudom, A.; Tu, H.; Ursu, S.; Walker, N.; Willcockson, M.;
Yan, X.; Ye, Q.; Powers, J. P. Bioorg. Med. Chem. Lett. 2011, 21, 405−
410. (b) Zacheis, D.; Dhar, A.; Lu, S.; Madler, M. M.; Klucik, J.;
Brown, C. W.; Liu, S.; Clement, F.; Subramanian, S.; Weerasekare, G.
M.; Berlin, K. D.; Gold, M. A.; Houck, J. R., Jr.; Fountain, K. R.;
Benbrook, D. M. J. Med. Chem. 1999, 42, 4434−4445.
ACKNOWLEDGMENTS
■
Financial support for this research from the MERNT
(Minister
̀
e de la Recherche et des Nouvelles Technologies),
CNRS (Centre National de la Recherche Scientifique), CEA
(Commissariat a l’Energie Atomique), the “CRUNCH” Net-
work (Pole Universitaire Normand de Chimie Organique), the
“Region Basse-Normandie”, and the European Union (FEDER
̀
̂
́
funding) and for a studentship from the European Regional
Development Fund (ERDF, ISCE-Chem & INTERREG IVa
program 4061) is acknowledged.
(16) For examples, see: (a) Sperber, N.; Papa, D.; Schwenk, E.;
Sherlok, M.; Fricano, R. J. Am. Chem. Soc. 1951, 73, 5752−5759.
(b) Carver, D. R.; Greenwood, T. D.; Hubbard, J. S.; Komin, A. P.;
G
dx.doi.org/10.1021/jo302303h | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
Sachdeva, Y. P.; Wolfe, J. F. J. Org. Chem. 1983, 48, 1180−1185.
(c) Sleevi, M. C.; Cale, A. D.; Gero, T. W.; Jacques, L. W.; Welstead,
W. J.; Johnson, A. F.; Kilpatrick, B. F.; Demian, I.; Nolan, J. C.;
Jenkins, H. J. Med. Chem. 1991, 34, 1314−1328. (d) Skerlj, R. T.;
Bogucki, D.; Bridger, G. J. Synlett 2000, 1488−1490. (e) Klapars, A.;
Waldman, J. H.; Campos, K. R.; Jensen, M. S.; McLaughlin, M.;
Chung, J. Y. L.; Cvetovich, R. J.; Chen, C.-Y. J. Org. Chem. 2005, 70,
10186−10189.
(17) (a) Caron, S.; Vazquez, E.; Wojcik, J. M. J. Am. Chem. Soc. 2000,
122, 712−713. (b) Yang, S.-W.; Ho, G.; Tulshian, D.; Greenlee, W. J.;
Anthes, J.; Fernandez, X.; McLeod, R. L.; Hey, J. A.; Xu, X. J. Med.
Chem. 2009, 52, 5323−5329. (c) Yang, S.-W.; Ho, G.; Tulshian, D.;
Greenlee, W. J.; Fernandez, X.; McLeod, R. L.; Eckel, S.; Anthes, J.
Bioorg. Med. Chem. Lett. 2008, 18, 6340−6343.
(18) For reviews, see: (a) Bellina, F.; Rossi, R. Chem. Rev. 2010, 110,
1082−1146. (b) Johansson, C. C. C.; Colacot, T. J. Angew. Chem., Int.
Ed. 2010, 49, 676−707. (c) Culkin, D. A.; Hartwig, J. F. Acc. Chem.
Res. 2003, 36, 234−245.
(19) (a) Satoh, T.; Inoh, J.-I.; Kawamura, Y.; Kawamura, Y.; Miura,
M.; Nomura, M. Bull. Chem. Soc. Jpn. 1998, 71, 2239−2246.
(b) Culkin, D. A.; Hartwig, J. F. J. Am. Chem. Soc. 2002, 124,
9330−9331. (c) You, J.; Verkade, J. G. J. Org. Chem. 2003, 68, 8003−
8007. (d) You, J.; Verkade, J. G. Angew. Chem., Int. Ed. 2003, 42,
5051−5053. (e) Wu, L.; Hartwig, J. F. J. Am. Chem. Soc. 2005, 127,
15824−15832.
(20) Mycka, R. J.; Duez, S.; Bernhardt, S.; Heppekausen, J.; Knochel,
P.; Fleming, F. F. J. Org. Chem. 2012, 77, 7671−7671.
(21) (a) Elmer, J. R.; Rosen, G. M.; Abou-Donia, M. B. J. Org. Chem.
1976, 41, 564−565. (b) Oldenziel, O. H.; van Leusen, D.; van Leusen,
A. M. J. Org. Chem. 1977, 42, 3114−3118.
(22) Attribution of 1H NMR characteristic signals for C3-H, C3-Me,
and C4-H in isomer 14b was carried out from 2D NMR analyses
(COSY and HSQC) of the 7/3 mixture 14a/14b.
(23) (a) Hudlicky, M. Org. React. 1988, 35, 513−637. (b) Singh, R.
P.; Shreeve, J. M. Synthesis 2002, 2561−2578.
(24) The fluoromethylpiperidines 12a and 12b (obtained in the
racemic form) were analyzed by chiral HPLC (see the Supporting
Information). Results demonstrate that enantiomerically enriched
material can be provided for further developments.
H
dx.doi.org/10.1021/jo302303h | J. Org. Chem. XXXX, XXX, XXX−XXX