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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5262_Библиотеки_им_академика_М_И_Перельмана.pdf
5 Mechanism Problems from Reactions Give Unexpected, Undesired, or Side Products318
5.3 Formation of Aromatic Compounds
5.3.1 Benzene
Problem 128: Formation of an Undesired Substituted Benzene Side Product
Dolutegravir sodium ( 1), an inhibitor of HIV integrase, is a drug for the treatment of
HIV/AIDS infection. In a process study, the diethyl 3-(benzyloxy)-4-oxo-4 H-pyran-
2,5-dicarboxylate ( 4) was designed as a key intermediate. The initial synthesis of 4 ,
as illustrated below, gave the desired product 4 in low yield (35%) and a side product
5 in considerable amount (8%) [ 15 ].
Please suggest a mechanism for the formation of 5 and propose a solution for solv-
ing the selectivity and low yield problems.
t-Bu
N
O
N
Cl
4
H
=
Ar
t-BuOH
Ar
Cl
4a
Ar
Cl
4
4
KCl
Ar
Ar
Cl
H
t-BuOK
t-BuOH
KCl
Ar
Ar
4b
Ar
Cl
K
+
4a
4a
Ar
Ar
Cl
Ar
KCl
Ar
Ar
Ar
5
K
+
K
+
t-BuO
–
t-BuOK
t-BuO
–
−
−
−
t-Bu
N
O
N
Cl
4
NaH (1.2 eq.)
THF, DMF
rt, 15 h
68%
5
O
O
OBn
4a (35%)
OH
BnO
5 (8%)
+
BnO
O
2a
+
3a
t-BuONa (2 eq.)
DMI, rt
Steps
N
O
ONa
Dolutegravir sodium (1)
N
O
H
H
N
O
FF
DMI = 1,3-dimethyl-2-
imidazolidinone
N
N
O
CO
2
Et
NMe
2
CO
2
Et
CO
2
Et
CO
2
Et
EtO
2
C
CO
2
Et
CO
2
Et
5.3 Formation of Aromatic Compounds 319
Experimental Procedure (from Org. Process Res. Dev. 2019, 23, 565*)
Dimethyl 3-(benzyloxy)-4-oxo-4H-pyran-2,5-dicarboxylate (4c). To 1,3-dimethyl-
2-imidazolidinone (1000 mL) was added 28% methanolic solution of sodium methox-
ide (438 mL, 2.16 mol, 1.4 eq) and cooled to the ice bath temperature. To the solution
was added dimethyl oxalate (3b, 509 g, 4.31 mol, 2.8 eq) portionwise and stirred at
room temperature for 30 min. To this was added crude oil of 2b (430.7 g, 1.55 mmol,
1.0 eq) and stirred at room temperature for 2.5 h. Methanolic solution of sodium
methoxide (29 mL, 0.14 mol) was added and stirred for an additional 1.5 h. The reac-
tion mixture was added to the mixture of ethyl acetate (1600 mL), 2 M aqueous hydro-
chloric acid (2000 mL), and cold water (798 g) and extracted. The organic layer was
washed with 5% aqueous sodium hydrogen carbonate (2000 mL) and 2% aqueous
sodium chloride (2000 mL). The aqueous layer was extracted with ethyl acetate
(2000 mL), and the combined organic layer was dried over magnesium sulfate and
concentrated. To the resultant brown oil was added diisopropyl ether (600 mL) and
n-hexane (400 mL) with stirring, and the precipitated solid was collected by filtration,
washed with diisopropyl ether (200 mL × 3), and dried to give 4c (314.82 g) as a pale
yellow solid. Additional 4c (7.55 g) was obtained from the concentrated mother liquor
by column chromatography (silica gel, chloroform/ethyl acetate = 99:1), yield 65%.
1
HNMR (400 MHz, CDCl
3
) δ 8.30 (s, 1H), 7.49–7.45 (m, 2H), 7.40–7.30 (m, 3H), 5.34
(s, 2H), 3.93 (s, 3H), 3.89 (s, 3H).
13
CNMR (100 MHz, CDCl
3
) δ 172.4, 162.9, 160.2,
159.7, 150.2, 145.2, 135.9, 129.0, 128.6, 128.5, 120.6, 75.1, 53.2, 52.7.
*The mechanism for the formation of the side product 5 was discussed in the article [15]. However, the
isolation and identification of 5 was not disclosed.
The Mechanism
Under basic (t-BuONa) condition, the C-4 in starting material 2a is deprotonated
and an anion A is generated. The diethyl oxalate 3a is first attacked by A, followed
by cyclization to provide the desired product 4a. Meanwhile, the anion A could be
dimerized by replacing the leaving group NMe
2
in 2a followed by cyclization and
elimination of Me
2
NH to yield the side product 5.
Under basic conditions (t-BuONa), the C-4 position in the starting material 2a
undergoes deprotonation, generating an anion intermediate A. This anion A then
nucleophilically attacks diethyl oxalate 3a, leading to cyclization and formation of
the desired product 4a. Concurrently, anion A can also undergo dimerization by
displacing the leaving group NMe
2
in 2a, followed by cyclization and elimination of
Me
2
NH, resulting in the formation of the side product 5.
Based on this mechanism, the dimerization of 2a and the following cyclization
are just catalyzed by t-BuONa. One equivalent of t-BuONa is consumed only at the
final elimination stage. To suppress the side reaction, increasing both the amount
O
O
OBn
BnO
O
2b
+
3b
MeONa (1.5 eq.)
DMI, rt, 4 h
4c
65%
CO
2
Me
NMe
2
CO
2
Me
CO
2
Me
MeO
2
C
CO
2
Me
5 Mechanism Problems from Reactions Give Unexpected, Undesired, or Side Products320
and the reactivity of the oxalate may be beneficial. For example, dimethyl oxalate
3b is more active than diethyl oxalate 3a. The order of reagent addition is also cru-
cial, such as adding 2b to a pre-mixed solution of 3b and base. To exclude the possi-
bility of transesterification, MeONa could be a substituent of t-BuONa and methyl
ester 2b is a replacement of ethyl ester 2a. With those considerations in mind, the
Japanese chemists performed the following reaction and the desired product 4c was
obtained in high yield [15].
5.4 Formation of Nonaromatic Heterocycles
5.4.1 Aziridine
Problem 129: Formation of an Aziridine-a Neighboring Group Participated
Cyclization
Diamine 2 was developed as a crucial intermediate for the synthesis of the direct
oral anticoagulant (DOAC) edoxaban (1). To achieve this synthesis, researchers at
Daiichi Sankyo chose to utilize compound 3 as a starting material. This compound
features an N-protecting group linked to a tether with a terminal nitrogen, which
BnO
O
2a
H
t-BuO
–
Na
+
t-BuONa
BnO
NMe
2
OBn
O
2a
2
BnO
O
O
OBn
BnO
O
O
OBn
H
Catalyzed by
t-BuONa
BnO
O
O
OBn
ONa
BnO
5 (sodium)
+
O
OBn
O
6
A
3a
EtONa
O
–
Na
+
BnO
O
Catalyzed by
t-BuONa
O
O
OBn
4a
NMe
2
CO
2
Et
t-BuOH
Me
2
N
EtO
2
C
CO
2
Et
CO
2
Et
CO
2
Et
O
–
Na
+
Me
EtO
2
C
2
N
NMe
2
Na
+
Me
2
NH
t-BuONa
t-BuOH
CO
2
Et
CO
2
Et
t-BuONa
CO
2
Et
t-BuO
–
Na
+
Me
2
NH
EtO
2
C
CO
2
Et
NMe
2
EtO
2
C
t-BuO
–
Na
+
EtO
2
C
CO
2
Et
CO
2
Et
CO
2
Et
EtO
2
C
Me
2
NH
NMe
2
−
Cl
O
7
BnOH
t-PentONa
THF
BnO
O
8
MeO N
+
BnO
O
2b
3b (3 eq.)
MeONa (1.6 eq.), MeOH
O
O
OBn
4c
70%, 3 steps
CO
2
Me
CO
2
Me
MeOSO
3
–
Et
3
N, DMI
CO
2
Me
MeO
2
C
CO
2
Me
NMe
2
CO
2
Me
CO
2
Me
5.4 Formation of Nonaromatic Heterocycles 321
acts as a nucleophile. The nucleophilic nitrogen was intended to displace an adja-
cent mesylate group through an intramolecular cyclization. Subsequent removal of
the tether was expected to yield the desired cis-diamine. However, when the reac-
tion was conducted in acetonitrile at 80 °C in the presence of trimethylamine, the
anticipated product 4 was not obtained. Instead, compounds 5 and 6 were identified
as the primary products [16].
Due to the inherent instability of the strained ring system, aziridine 5 could not
be isolated in pure form. Its structure was tentatively characterized based on liquid
chromatography mass spectrometry (LCMS) and NMR data obtained from the
crude reaction mixture. As the reaction progressed, the formation of compound 6
increased, suggesting its role as a major product under the given conditions.
When an ethyl ester 7 was employed as starting material under the cyclization
conditions, the corresponding aziridine 8 was also formed. However, 8 remained
unchanged and cyclic sulfamides 9 and 10 were not observed. In addition, 8 was
stable enough to be isolated by silica gel column chromatography.
NO
N
H
Boc
NO
N
H
HN
O
N
S
N
N
H
N
Cl
O
O
2
Edoxaban (1)
NO
HN
OMs
NO
3
S
NH
O
O
Cbz
Et
3
N
CH
3
CN
80 °C
HN
S
N
O
O
Cbz
4
NO
5
NO
N
S
NH
O
O
6
N
S
O
O
N
H
Cbz
Cbz
Reaction time 1 h Not detected 78% 9%
Reaction time 8 h Not detected Not detected 71%
NH
2
OEtO
HN
OMs
OEtO
7
S
NH
O
O
Cbz
HN
S
N
O
O
Cbz
9 (not detected)
OEtO
8 (94%)
OEtO
N
S
NH
O
O
10 (not detected)
N
S
O
O
N
H
Cbz
Cbz
Et
3
N
CH
3
CN
80 °C, 4 h
5 Mechanism Problems from Reactions Give Unexpected, Undesired, or Side Products322
The goal of this research was to develop a process to produce isolable intermediates,
such as mono-Boc-protected diamine 2. Based on the findings of the Cbz-protected
analog 3, switch the Cbz to Boc-protected substrate 11, the key reaction proceeded
smoothly to produce 12 in 86% yield with excellent regio- and stereoselectivity.
Further desulfonylation of 12 to 2 was achieved by employing pyridine-H
2
O. After
optimization, it was shown that the four-step cyclization sequence and desulfonyl-
ation reactions (11 to 2) could be conducted in one pot and 2 was isolated in 85%
yield as the oxalate salt with >99% purity [16].
Please provide mechanism for the transformation from 3 to 5 and 6 (or from
11 to 12).
Experimental Procedure (from Org. Process Res. Dev., 2019, 23, 524*)
tert-Butyl{(1R,2S,5S)-2-amino-5-[(dimethylamino)-carbonyl]cyclohexyl}
carbamate Oxalate (2) from 11. Mesylate 11 (1430 kg, 3.224 kmol) was charged to
a reactor, followed by the addition of acetonitrile (6435 L) and triethylamine (503 L,
3.579 kmol). The mixture was stirred at 70 °C for 2 h. After the reaction completion,
water (358 L) and pyridine (1287 L, 15.98 kmol) were added, and the mixture was
stirred at 75 °C for 5 h. NaCl aqueous solution (20%, 1430 L), water (200 L), toluene
(14 300 L), and NaOH aqueous solution (25%, 2145 L) were added, and the mixture
was stirred at 50 °C; then the layers were separated. The organic layer was washed
with NaCl aqueous solution (20%, 1430 L) and NaOH aqueous solution (25%, 286 L).
The organic layer was concentrated under reduced pressure to a volume of 4290 L,
and then acetonitrile (8580 L) was added and filtered to give the solution of 2. Oxalic
acid (406 kg, 4.510 kmol), water (601 L), and acetonitrile (10 100 L) were charged to
another reactor, followed by the addition of 2 solution at 35 °C for 2 h. The mixture
was stirred at 50 °C for 2 h, then cooled to 25 °C, and filtrated. The cake was washed
with an aqueous acetonitrile solution (93%, 5434 L) to give the crude crystalline 2 as
a hydrate. Then the crude 2 was charged into acetonitrile (10 010 L), and the mixture
was concentrated under reduced pressure to remove most of the water. The slurry
was filtrated at 30 °C and then dried under full vacuum at 60 °C to give 2 (1010.8 kg,
2.692 kmol, 83.5% yield) as a white crystalline solid.
Compound 2,
1
HNMR (CDCl
3
) 4.10 (br, 1H), 3.32 (d, J = 12.2 Hz, 1H), 2.96
(m, 3H), 2.80 (t, J = 12.4 Hz, 1H), 2.77 (s, 3H), 1.72–1.83 (m, 3H), 1.63 (t, J = 22.7 Hz,
1H), 1.37–1.49 (m, 2H), 1.30 (s, 9H).
NMR spectra of aziridine 8:
1
HNMR (CDCl
3
) 7.35–7.39 (m, 5H), 5.22 (s, 2H), 4.16
(q, J = 7.0 Hz, 2H), 3.21–3.23 (m, 1H), 3.10–3.13 (m, 1H), 2.41–2.45 (m, 1H), 1.91–1.98
(m, 2H), 1.80–1.86 (m, 1H), 1.72–1.75 (m, 1H), 1.34–1.45 (m, 1H), 1.26 (t, J = 7.0 Hz, 3H).
NO
HN
OMs
11
S
NH
O
O
Boc
NO
N
S
NH
O
O
12
Boc
86%
Pyridine
H
2
O, CH
3
CN
NO
N
H
2
Boc
Et
3
N
CH
3
CN
NH
2
5.4 Formation of Nonaromatic Heterocycles 323
*The mechanism for the formation of 5 and 6 was discussed in the article [16]. It is stated that the
structure of 6 was assigned by
1
H−
1
H COSY spectra. However, the isolation and identification of 6
was not disclosed.
The Mechanism
Deprotonation of the sulfonamide from the cyclohexane side generates anion A. Then
cyclization occurs to form aziridine 5. The aziridine ring is opened by the pendant
dimethylamide group to afford B. After proton transfer, the anion C recyclizes to form 6.
Under the cyclization conditions, the corresponding aziridine 8 was produced from
ethyl ester 7. The corresponding cyclic sulfamides 9 and 10 were not observed. The
result supports the participation of the dimethylamide group in the formation of 6.
5.4.2 Pyrrolidine
Problem 130: Formation of Ring-contracted Side Product During
Fluorination
Compound 1 was identified as a highly potent and selective inhibitor of
estrogen-related receptor 1 (ERR1) for the treatment of hyperglycemia in patients
with type 2 diabetes mellitus. In a process synthesis of 1, fluorination of intermediate
2 with Deoxo-Fluor provided the desired product 3 and a ring-contracted side
product 4 [17]. Reducing the amount of Deoxo-Fluor from 1.35 equiv to 1.1 equiv,
led to a ~4.3/1 3/4 mixture with <1% of starting 2. Triturating the crude 3/4 in
EtOAc provided >98% purity 3 with an isolated yield 55%. The structure of the
ring-contracted side product 4 was elucidated by HNMR and confirmed by X-ray
diffraction studies.
Please suggest a mechanism for the formation of 4.
NO
N
OMs
3
S
NH
O
O
Cbz
NO
5
NO
N
S
NH
O
O
6
N
S
O
O
N
H
Cbz
Cbz
H
Et
3
N
NO
OMs
S
NH
O
O
Cbz
N
S
O
O
H
N
Cbz
N
O
5
S
O
O
O
N
Cbz
H
O
NH
S
O
O
Cbz
A
B
C
Et
3
N
+
H
N
–
Et
3
N
+
HMsO
–
N
+
N
+
N
–
N
–
N
N
Cl
F
3
C
S
N
O
O
N
F
.HCl
1
N
N
S
OO
OH
Boc
Deoxo-Fluor
DCM
N
N
S
OO
F
Boc
2
3 (60–67%)
N
S
OO
4 (11–20%)
N
F
Boc
Steps
5 Mechanism Problems from Reactions Give Unexpected, Undesired, or Side Products324
Experimental Procedure (from Org. Process Res. Dev. 2014, 18, 321*)
tert-Butyl 4-(2,4-dioxothiazolidin-3-yl)-3-fluoropiperidine-1-carboxylate (3).
To the cold solution of compound 2 (700.0 g, 2.18 mol) in DCM (11.0 L) at 0 °C, was
added dropwise a solution of bis(2-methoxyethylaminosulfur trifluoride) (426.0 mL,
2.31 mol) in DCM (1.0 L) over 1 h. The resulting mixture was stirred at 0 °C for 2 h and
then stirred at 20 °C for 20 h. The progress of the reaction was monitored by HPLC
and LCMS. The reaction was cooled to 0 °C with fast agitation, and a solution of 2 N
NaOH (2.0 L) was carefully added. (Caution: Addition of the first 500 mL of 2 N NaOH
solution is very exothermic; the internal temperature was maintained between 0 and
10 °C by adjusting the addition rate.) The resulting suspension was allowed to stir for
1 h at 0 to 10 °C. After phase separation, the organic phase was washed with saturated
NaHCO
3
(2.0 L) and D.I. H
2
O (2.0 L) and then was dried over Na
2
SO
4
. The solvent was
concentrated to dryness under house vacuum to give the crude 3 as an oily material.
This crude 3 was triturated with EtOAc (1.0 L) at 25 °C for 30 min, the solid was col-
lected by filtration, and the filter cake was washed with heptanes (300 mL × 3) and
dried in a vacuum oven at 50 °C for 20 h to afford 382.0 g (55% isolated yield; 94.1% of 3,
3.9% of 4, 1.9% of 2; HPLC area%) of compound 3 as a slightly yellow solid. The filtrate
was concentrated to give 116.0 g of an oily, yellowish solid, which was recrystallized
in EtOAc (116 mL) to afford an additional 81.5 g (12% isolated yield; 98.0% of 3, 2.0%
of 4; HPLC area%) of compound 3 as a yellowish solid. Mp = 151–152 °C.
1
HNMR
(300 MHz, CDCl
3
) δ 1.47 (s, 9 H, 3 CH
3
), 1.75–1.65 (m, 1 H), 2.38 (ddd, J = 4.40, 4.65,
12.71 Hz, 1 H), 2.62–2.83 (m, 2H), 3.97 (s, 2H), 4.08–4.26 (m, 1H), 4.28–4.38(m, 1H),
4.41–4.66 (m, 1H), 5.15 (ddd, J = 5.6, 10.27, 50.13 Hz, 1H).
13
CNMR (400 MHz, CDCl
3
)
δ 171.65, 171.36, 154.10, 84.00, 80.70, 57.07, 47.03, 42.57, 33.27, 28.37 (3 C), 26.50. LC/
MS m/z 319.4 ((MH)
+
not detected), 341.1 (MNa)
+
, and 219.1 [M─Bo c]
+
. Calcd for
C
13
H
19
FN
2
O
4
S (MW = 318.36): C, 49.09; H, 6.02; N, 8.80; F, 5.97; S, 10.07. Found: C,
49.15; H, 6.33; N, 8.78; F, 5.93; S, 10.37.
*The mechanism for the formation of 4 was discussed in the article [17]. It is stated that the structure
of 4 was confirmed by
1
H NMR and by X-ray diffraction. However, the isolation and identification of
4 was not disclosed.
The Mechanism
Direct reaction of the hydroxyl group in compound 2 with Deoxo-Fluor gener-
ates intermediate A. In pathway a, fluoride (F
−
) then attacks the activated C-3
leading to the desired product 3. Alternatively, the nearby oxygen of the thiazoli-
dine ring can participate in an intramolecular attack, forming cyclic intermediate B.
Subsequent attack by F
−
at C-3 in intermediate B also yields product 3. However,
the Boc-protected amine on the piperidine ring can further react by attacking C-3 to
form aziridium intermediate C. Finally, F
−
attacks C-2 of the aziridine ring, result-
ing in the ring-contracted product 4.
The formation of aziridium intermediate C does not necessarily proceed via
intermediate B. It may also be generated directly from intermediate A through
N-Boc attacking the sulfonate-bearing carbon.
Ring contraction caused by neighboring group participation was also reported during
a diethylaminosulfur trifluoride (DAST)-mediated fluorination in the following case
[18]. When compound 5 was treated with DAST, a mixture of 6 and 7 was obtained.
5.4 Formation of Nonaromatic Heterocycles 325
It can also be predicted that the following side product 8 is almost impossible to
produce since the nitrogen is not a nucleophile due to the conjugation to an extra
carbonyl.
N
N
S
OO
OH
Boc
Deoxo-Fluor
DCM
2
S N
F
F
F OMe
OMe
Deoxo-Fluor
N
S
OO
O
Boc
S
NR
2
F
F
F
H
a
b
a
S
F
O
N
N
S
OO
F
Boc
3
+HF
N
Boc
O
S
O
S
F
O
+HF
b
N
S
OO
Boc
N
S
OO
4
N
F
Boc
A
B
C
NR
2
N
+
F
–
F
–
NR
2
N
+
N
N
N
S
OO
O
Boc
S
F
F
N
S
OO
Boc
N
S
OO
4
N
F
Boc
A
C
O
S
F
NR
2
NR
2
N
+
F
–
N
OH
O
1. DAST, DCM
2. HCl
NH
F
O
5
6
NH
O
F
+
7
3:1
DAST
N
O
O
S
F
F
NEt
2
F
–
N
O
+
F
–
then
HCl
then
HCl
de-Boc
F
–
Boc
Boc
Boc
5 Mechanism Problems from Reactions Give Unexpected, Undesired, or Side Products326
5.4.3 Piperidine
Problem 131: An Unusual DAST-Mediated Rearrangement
During attempts to synthesize 3-(3-fluoropiperidin-4-yl)-2-phenyl-1H-indole (3b) as
part of a medicinal chemistry program, [19] chemists from Merck discovered an
unusual DAST-mediated rearrangement [20]. Treatment of compound 1 with DAST
at low temperature did not yield the desired Cbz-protected product 3a; instead,
while the rearranged product 2a was afforded in 99% yield. After removal of the Cbz
group by transfer hydrogenolysis, the 4-fluoro-3-indolyl isomer 2b was obtained in
excellent yield. To support the structural assignment of 2b, a genuine sample of the
3-fluoro-4-indolyl substituted piperidine 3b was needed for comparison. Reaction
of 2-phenyl-1H-indole 4 with 3-fluoro-4-oxo-piperidine-1-carboxylic acid tert-butyl
ester 5 furnished tetrahydropyridine 6 as a single isomer. Ionic reduction with tri-
fluoroacetic acid/triethylsilane gave the trans-fluoropiperidine 3b. The structure of
2b and 3b were determined by double quantum filtered correlation spectroscopy
experiments.
Please provide a mechanism for the transformation from 1 to 2a.
N
O
O
F
F
NEt
2
O
then
HCl
Boc
Boc
NH
O
F
8
N
OH
O
5
Boc
OH
–
O
5
Boc
DAST
N
+
F
–
N
+
N
H
Cbz
N
HO
DAST, EtOAc
− 50 °C to rt
99%
N
H
NR
F
Ph
Ph
1
2a, R
=
Cbz
2b, R
=
H
N
H
R
N
F
Ph
3a, R
=
Cbz, not obtained
3b, R
=
H
HCO
2
H, EtOAc
10% Pd-C
yield 90%
N
H
Ph
4
Boc
N
F
O
+
5
HOAc, H
3
PO
4
90 °C
N
H
H
N
F
Ph
91%
6
Et
3
SiH
TFA
66%
3b
5.4 Formation of Nonaromatic Heterocycles 327
Experimental Procedure (from J. Org. Chem., 2000, 65, 4984)
(3RS,4RS)-4-Fluoro-3-(2-phenyl-1H-indol-3-yl)-piperidine-1-carboxylic Acid
Benzyl Ester (2a). A cooled (−50 °C) solution of racemic alcohol 1 (1.0 g, 2.3 mmol)
in anhydrous ethyl acetate (20 mL) was treated with DAST (350 μL, 2.6 mmol).
Stirring at −50 °C was continued for 1 h before the solution was allowed to warm to
ambient temperature over 3 h. The reaction mixture was then poured into saturated
aqueous sodium hydrogencarbonate (100 mL), and the product was extracted into
ethyl acetate (100 mL). The organic phase was washed with water (100 mL) and
brine (100 mL) and then dried over anhydrous sodium sulfate. This solution was
filtered, treated with decolorizing charcoal (0.5 g), and filtered again. The result-
ing pale yellow filtrate was then treated with Raney nickel (1 mL of a 50% slurry in
water). After standing at ambient temperature for 2 h, the solution was filtered and
evaporated to dryness to afford the title compound (995 mg, 99%) as a white solid:
mp 199–201 °C (EtOH);
1
HNMR (360 MHz, CDCl
3
) δ 1.70–1.85 (m, 1H), 2.20–2.30
(m, 1H), 2.90–3.10 (m, 1H), 3.20–3.30 (m, 1H), 3.40–3.50 (m, 1H), 4.20–4.50 (m, 2H),
5.10 (s, 2H), 5.24 (dtd, J = 54, 11 and 5 Hz, 1H), 7.12 (t, J = 7 Hz, 1H), 7.18 (t, J =
7 Hz, 1H), 7.20–7.43 (m, 9H), 7.52–7.56 (m, 2H), 7.67 (d, J = 8 Hz, 1H), 8.15 (s, 1H);
MS (ES
+
) m/z 429 (M + H)
+
. Anal. Calcd for C
27
H
25
FN
2
O
2
: C, 75.68; H, 5.88; N, 6.54.
Found: C, 75.45; H, 5.80; N, 6.34.
(3RS,4RS)-3-(4-Fluoro-piperidin-3-yl)-2-phenyl-1H-indole (2b). A solu-
tion of racemic fluoropiperidine 2a (975 mg, 2.3 mmol) in ethyl acetate (50 mL)
was treated with 99% formic acid (5 mL) and then with 10% palladium on
activated carbon (120 mg), and the resulting suspension was stirred at ambient
temperature for 4 h. The reaction mixture was filtered and then preadsorbed
directly onto silica. Purification by flash chromatography eluting with dichlo-
romethane/methanol/concentrated ammonia (93:7:1) gave the title compound
(603 mg, 90%) as white needles: mp 134–136 °C (MeOH);
1
H NMR (400 MHz,
d
6
-DMSO) δ 1.42–1.58 (m, 1H, piperidine H-5
ax
), 2.08–2.18 (m, 1H, piperidine
H-5
eq
), 2.72 (dd, J = 12.5 and 12.5 Hz, 1H, piperidine H-6
ax
), 2.90–2.94 (m, 1H,
piperidine H-2), 2.98–3.15 (m, 3H, piperidine H-6
eq
, piperidine H-2′ and piperi-
dine H-3
ax
), 5.20 (1H, dddd, J = 49, 10, 10, and 2 Hz, piperidine H-4
ax
), 6.99 (dd,
J = 8.0 and 7.5 Hz, 1H, indole H-5), 7.09 (dd, J = 8.0 and 7.5 Hz, 1H, indole H-6),
7.37 (d, J = 8.0 Hz, 1H, indole H-7), 7.41 (dd, J = 7.5 and 7.5 Hz, 1H, phenyl
H-4), 7.52 (dd, J = 7.5 and 7.5 Hz, 2H, phenyl H-3), 7.59 (d, J = 7 Hz, 2H, phenyl H-2),
7.77 (d, J = 8.0 Hz, 1H, indole H-4), 11.21 (s, 1H, indole NH); MS (ES
+
) m/z 295
(M + H)
+
. Anal. Calcd for C
19
H
19
FN
2
.CH
4
O: C, 73.59; H, 7.10; N, 8.58. Found: C,
73.66; H, 7.05; N, 8.62.
(3RS,4RS)-3-(3-Fluoro-piperidin-4-yl)-2-phenyl-1H-indole (3b). A solu-
tion of allylic fluoride 6 (500 mg, 1.7 mmol) in trifluoroacetic acid (10 mL) was
treated with triethylsilane (500 μL, 3.1 mmol) and then stirred at ambient temper-
ature for 3 h. The reaction mixture was poured carefully into a saturated aqueous
solution of sodium hydrogen carbonate (100 mL), and the product was extracted
into ethyl acetate (100 mL). The organics were washed with water (75 mL) and
then brine (75 mL) to give an oil. This oil was purified by flash chromatography
eluting with dichloromethane/methanol/concentrated ammonia (95:4.5:0.5) to
furnish the title compound (330 mg, 66%) as a white solid: oxalate salt, colorless