Neighboring group participation of the indole nucleus: An unusual DAST-mediated rearrangerment reaction

Article abstract of DOI:10.1021/jo0004759

A rearrangement reaction involving the indole nucleus was investigated using stereochemical markers and low-temperature NMR experiments. Treatment of(3S,4S)-3-hydroxy-4-(2-phenyl-1H-indol-3-yl)-piperidine-1-carboxylic acid benzyl ester (> 90% ee) with diethylaminosulfur trifluoride gave stereospecifically (3S,4S)-4-fluoro-3-(2-phenyl-1H-indol-3-yl)-piperidine-1-carboxylic acid benzyl ester (> 90% ee) with complete regioselectivity. The initial formation of a reactive spirocyclopropyl-3H-indole intermediate is believed to be responsible for the stereo- and regiochemical outcome of the reaction.

Full text of DOI:10.1021/jo0004759

4984
J . Org. Chem. 2000, 65, 4984-4993
Neigh bor in g Gr ou p P a r ticip a tion of th e In d ole Nu cleu s: An
Un u su a l DAST-Med ia ted Rea r r a n gem en t Rea ction
David J . Hallett,* Ute Gerhard,* Simon C. Goodacre, Laure Hitzel, Timothy J . Sparey,
Steven Thomas, and Michael Rowley
Merck Sharp & Dohme Research Laboratories, Neuroscience Research Centre,
Terlings Park, Eastwick Road, Harlow, Essex CM20 2QR, United Kingdom
Richard G. Ball
Merck & Co., Inc., 126 East Lincoln Avenue, Rahway, New J ersey 07065
david_hallett@merck.com
Received March 29, 2000
A rearrangement reaction involving the indole nucleus was investigated using stereochemical
markers and low-temperature NMR experiments. Treatment of (3S,4S)-3-hydroxy-4-(2-phenyl-1H-
indol-3-yl)-piperidine-1-carboxylic acid benzyl ester (>90% ee) with diethylaminosulfur trifluoride
gave stereospecifically (3S,4S)-4-fluoro-3-(2-phenyl-1H-indol-3-yl)-piperidine-1-carboxylic acid benzyl
ester (>90% ee) with complete regioselectivity. The initial formation of a reactive spirocyclopropyl-
3H-indole intermediate is believed to be responsible for the stereo- and regiochemical outcome of
the reaction.
In tr od u ction
Over 30 years ago, two groups of researchers1 demon-
strated that the indole nucleus could exert a large neigh-
boring-group effect on the rate of solvolysis of derivatives
of tryptophol (Scheme 1). They speculated that this
process occurred via the reactive 3,3-spirocyclopropyl-3H-
indole 1 whose structure was more rigorously established
some years later.2
Spirocyclic and related 3,3-disubstituted intermediates
similar to 1 occur throughout indole chemistry and
demonstrate the strong preference in indole for electro-
philic attack to occur at C-3, even when that position
carries a substituent. For example, the Pictet-Spengler
type cyclization that gives rise to tetrahydro-â-carbolines
is believed to take place via a 3H-indolinium ion 23
(Figure 1), while the Plancher rearrangement4 of 3,3-
dialkyl-3H-indolinium ions such as 3 is one of the
accepted intermediates along the pathway to 2,3-dialkyl-
indoles.5 We now wish to report a similar pattern of
reactivity that was observed unexpectedly during at-
tempts to synthesize fluoropiperidine 4 as part of a
medicinal chemistry program.
F igu r e 1.
Sch em e 1
Resu lts a n d Discu ssion
It was envisaged that the target fluorinated piperidine
4 might be accessed by reaction of a suitably protected
alcohol with diethylaminosulfur trifluoride (DAST).6 To
this end, racemic alcohol 8 was constructed as outlined
in Scheme 2. Condensation of 2-phenyl-1H-indole 5 with
4-piperidone under acidic conditions7 gave tetrahydro-
pyridine 6 which was protected as its N-benzyl carbamate
7. Hydroboration8 with borane-dimethyl sulfide followed
by oxidative workup afforded the desired trans alcohol
(1) (a) Closson, W. D.; Roman, S. A.; Kwiatkowski, G. T.; Corwin D.
A. Tetrahedron Lett. 1966, 2271. (b) J ulia M.; Igolen H.; Lenzi, J . Bull.
Soc. Chim. Fr. 1966, 2291. (c) J ulia, M.; Sliwa, H.; Caube`re, P. Bull.
Soc. Chim. Fr.. 1966, 3359.
(2) J ohansen, J . E.; Christie, B. D.; Rapoport, H. J . Org. Chem. 1981,
46, 4914.
(3) J ackson, A. H.; Smith, A. E. Tetrahedron 1968, 24, 403.
(4) (a) Ciamician, G.; Plancher, G. Chem. Ber. 1896, 29, 2475. (b)
J ackson, A. H.; Smith, P. Tetrahedron 1968, 24, 2227.
(5) Direct attack at C-2 can and does occur: (a) Casnati, G.; Dossena,
A.; Pochini, A. Tetrahedron Lett. 1972, 5277. (b) Iyer, R.; J ackson, A.
H.; Shannon, P. V. R.; Naidoo, B. J . Chem. Soc., Chem. Commun. 1972,
461.
(6) Hudlicky, M. Org. React. 1988, 35, 513.
(7) Freter, K.; Fuchs, V. J . Heterocycl. Chem. 1982, 19, 377.
(8) Pelter, A.; Smith, K.; Brown, H. C. Borane Reagents; Academic
Press: London 1988.
10.1021/jo0004759 CCC: $19.00 © 2000 American Chemical Society
Published on Web 07/19/2000

Unusual DAST-Mediated Rearrangement Reaction
J . Org. Chem., Vol. 65, No. 16, 2000 4985
Sch em e 2a
the piperidine ring system was apparent from the
proton-proton coupling of the proton geminal to the
fluorine atom (H3), which is coupled to the ring protons
H5 centered at 1.51 and 2.13 ppm, respectively. The
chemical shifts of H5 indicate these protons are not
attached to a nitrogen-bound carbon. Furthermore, the
methylene protons H5 are also coupled to a methylene
group (H6) at lower field (2.72 and 2.92 ppm), proving
the substitution pattern of piperidine 10. The relative
stereochemistry of this 4-fluoro isomer was determined
on the basis of the proton assignment and the coupling
pattern of proton H4. This proton showed a large 2J
fluorine coupling (ca. 49 Hz) and two further 3J axial-
3
axial couplings (ca. 10 Hz), as well as a J axial/equatorial
coupling of ca. 2 Hz. This was consistent with the indole
residue and the fluorine atom both residing in the
equatorial positions of the ring systems.
In contrast, the methylene protons H2 in structure 4
at ca. 2.5 and 3.3 ppm (overlap with residual d6-DMSO
and H2O signals) are coupled only to proton H3 at 5.03
ppm (Figure 2, B). This indicates that the H2 protons
are indeed attached to the nitrogen-bound carbon. The
entire spin system can be traced around the ring sys-
tem and is consistent with the 3-fluoro isomer. The
relative stereochemistry of the fluoropiperidine ring
system present in 4 was again determined on the basis
of the coupling pattern of proton H3. This showed one
large geminal fluorine coupling (ca. 49 Hz), two 3J
axial-axial couplings (ca. 10 Hz each) and a smaller 3J
axial/equatorial coupling of ca. 5 Hz. When taken with
the corresponding coupling constants this coupling pat-
tern is consistent with both the indole residue and the
fluorine atom residing in equatorial positions on the ring
system.
a
Key: (i) 4-piperidone monohydrate hydrochloride, HOAc,
H3PO4, 95 °C; (ii) benzyl chloroformate, CHCl3, K2CO3, reflux; (iii)
BH3‚DMS, THF then NaOH, H2O2; (iv) DAST, EtOAc, -50 °C to
ambient temperature; (v) HCO2H, EtOAc, 10% Pd-C.
Sch em e 3a
An enantioenriched sample of alcohol 8 was prepared
to investigate the stereochemical course of the DAST
reaction. Treatment of tetrahydropyridine 7 at -20 °C
with monoisopinocampheylborane (IpcBH2)11 derived from
(-)-R-pinene (Scheme 4), followed by oxidative workup,
produced alcohol 12 in good chemical yield but only a
modest 56% ee as determined by chiral HPLC. Repeating
the reaction with (+)-diisopinocampheylborane (Ipc2BH)12
gave a similar result (52% ee) but at the expense of
reaction rate (70 h at ambient temperature for complete
reaction as compared with 4 h at -20 °C for IpcBH2.)
Ultimately the practical ease of synthesizing large quan-
tities of Ipc2BH made this the reagent of choice.
Two approaches to boost the optical purity of the
hydroboration product 12 were performed. On a small
scale (<1 g) formation of diastereomeric esters, separa-
tion by column chromatography, and hydrolysis seemed
most appropriate. After screening several chiral deriva-
tizing reagents, the esters derived from camphanic acid
were found to have the largest difference in Rf. When
larger quantities of material were required, however, this
approach proved time-consuming and so another method
was needed. Initial recrystallization of 12 (52% ee) from
diethyl ether furnished crystalline material that was
shown to be racemic by chiral HPLC but whose mother
liquor was enriched with the major enantiomer. With this
knowledge it was possible to assay the supernatant as
a
Key: (i) 3-fluoro-4-oxo-piperidine-1-carboxylic acid tert-butyl
ester, HOAc, H3PO4, 90 °C; (ii) triethylsilane, TFA.
8, which was anticipated to give a 3-fluoro-4-indolyl
substituted piperidine upon treatment with DAST. To our
surprise, the low-temperature reaction of DAST with 8
followed by removal of the Cbz group by hydrogen-
transfer hydrogenolysis furnished the 4-fluoro-3-indolyl
isomer 10 as the exclusive product in excellent yield.
To support the structural assignment of 10 a genuine
sample of the 3-fluoro-4-indolyl substituted piperidine
was needed for comparison (Scheme 3). Reaction of
2-phenyl-1H-indole with 3-fluoro-4-oxo-piperidine-1-car-
boxylic acid tert-butyl ester9 furnished tetrahydropyridine
11 as a single isomer. Initial attempts to reduce the
trisubstituted double bond in 11 by catalytic hydrogena-
tion were hampered by concomitant hydrogenolysis of the
C-F bond. To circumvent this problem, ionic reduction
with trifluoroacetic acid/triethylsilane10 was utilized and
gave the trans fluoropiperidine 4 containing only trace
amounts of the des-fluoro material.
The structures of 4 and 10 were determined by DQF-
COSY experiments (Figure 2). In the 4-fluoro-3-indolyl
isomer 10 (Figure 2A) the substitution pattern around
(9) Van Niel, M. B.; Collins, I.; Beer, M. S.; Broughton, H. B.; 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.; Russell,
M. G. N.; Sohal, B.; Stanton, J . A.; Thomas, S.; Verrier, H.; Watt, A.
P.; Castro, J . L. J . Med. Chem. 1999, 42, 2087.
(10) Kursanov, D. N.; Parnes, Z. N.; Loim, N. M. Synthesis 1974,
633.
(11) Brown, H. C.; Singaram, B. J . Am. Chem. Soc. 1984, 106, 1797.
(12) Brown, H. C.; Desai, M. C.; J adhav, P. K. J . Org. Chem. 1982,
47, 5065.

4986 J . Org. Chem., Vol. 65, No. 16, 2000
Hallett et al.
F igu r e 2. DQF-COSY spectra of 4-fluoro-3-(2-phenyl-1H-indol-3-yl)-piperidine 10 (A) and 3-fluoro-4-(2-phenyl-1H-indol-3-yl)-
piperidine 4 (B).
Sch em e 4a
Sch em e 5a
a
Key: (i) diethylazodicarboxylate, Ph3P, 4-nitrobenzoic acid,
THF; (ii) K2CO3, MeOH; (iii) DAST, EtOAc, -50 °C to ambient
temperature.
by X-ray crystallography. Subsequent treatment of 12
(91% ee) with DAST afforded a fluorinated product 14
(ca. 95% ee by HPLC analysis of the crude reaction
mixture). Removal of the nitrogen protecting group from
14 and reaction with (R)-(+)-R-methylbenzylisocyanate
yielded urea 16 as the major diastereoisomer containing
(3S,4S) absolute stereochemistry as determined by X-ray
crystallography. The stereochemical information provided
by 13 and 16 together with the ee measurements of 12
and 14 indicate that the DAST reaction with alcohol 12
is completely stereospecific and that both stereogenic
centers in 12 are inverted during the reaction.
Further insight into the DAST reaction was obtained
when racemic hydroxypiperidine 8 was subjected to
Mitsunobu conditions (Scheme 5) and the rearranged
nitrobenzoate 17 then hydrolyzed to reveal alcohol 18,
an isomer of 8. When 18 was treated with DAST, a
fluorinated product was obtained, identical in all respects
to piperidine 9 from Scheme 2.
a
Key: (i) (+)-Ipc2BH, THF, ambient temperature then NaOH,
H2O2; (ii) recrystallize and retain mother liquors; (iii) (1S)-(-)-
camphanic chloride, pyridine, DMAP; (iv) DAST, EtOAc, -50 °C
to ambient temperature; (v) HCO2H, EtOAc, 10% Pd-C; (vi) (R)-
(+)-R-methylbenzylisocyanate, DCE.
the crystallization process progressed and in this way
material of 91% ee was obtained from the mother liquors.
Alcohol 12 (91% ee) was then reacted with (1S)-(-)-
camphanic chloride, and the major diastereoisomer 13
was shown to possess (3S,4S) absolute stereochemistry
This result indicates that alcohols 8 and 18 react with
DAST via a common intermediate 1913 as shown in
Figure 3. Two possible conformations of 19 allow trans-

Unusual DAST-Mediated Rearrangement Reaction
J . Org. Chem., Vol. 65, No. 16, 2000 4987
F igu r e 3. Proposed mechanism for the reaction of hydroxy-
piperidine 8 with DAST.
diaxial ring-opening; pathway A gives rise to the observed
fluoropiperidine 9 while pathway B (not observed) pro-
duces the isomer 20. A possible reason for the regiose-
lectivity is that conformer 19b is destabilized relative to
19a as a result of steric congestion caused by the group
endo to the piperidine ring.
F igu r e 4. Comparison of the 1-D proton spectra of hydroxy-
piperidine 8 before DAST addition (A) and the spirocyclopro-
pyl-3H-indole 19 (B) at -50 °C.
The reaction of racemic alcohol 8 with DAST was
observed by NMR spectroscopy at -50 °C in order to
characterize the reaction intermediates further. The
assignment of the proton spectrum of hydroxypiperidine
8 at -50 °C (Figure 4A) was complicated by the presence
of two stable conformers from the restricted rotation of
the benzyloxycarbamate group. On addition of DAST, an
equilibration process was observed by proton NMR
spectroscopy that appeared to be complete after ca. 15
min. The initially formed derivative 8a was converted
into a major species existing as two stable conformers
(Figure 4B). This intermediate remained stable at -50
°C allowing acquisition of DQF-COSY and HMQC
experiments (Figure 5) and assignment of the aliphatic
proton and carbon resonances. The coupling pattern of
the piperidine spin system in the form of a major and a
minor conformer was traced around the ring and is
consistent with the spirocyclopropyl-3H-indole struc-
ture 19.
When comparing the spectra of 8 and 19 the most
dramatic changes could be seen in the chemical shift of
proton H3 and carbon C3. H3 (major conformer) moved
from 4.44 ppm in the starting alcohol 8 to 3.22 ppm in
the intermediate. Likewise, C3 in the intermediate moved
upfield by ca. 35 ppm (Table 1). This showed C3 was not
oxygen bound in 19. The similarity of the chemical shifts
of H3, H4 and C3, C4 in the intermediate 19 is evidence
for a similar chemical environment of these atoms. This
further supports the spirocyclopropyl-3H-indole struc-
ture.
The mechanistic details presented so far predict that
electronic modification of the indole nitrogen should affect
its ability to participate in the formation of 19. With this
in mind we attempted to protect the indole nitrogen in 8
as its N-alkyl carbamate but failed, presumably as a
result of the 2-phenyl substituent. An indole lacking a
2-substituent would overcome this problem, and the
synthesis of such a compound 23 is shown in Scheme 6.
The reaction of alcohol 23 with DAST (Scheme 6) gave
two major fluorinated products together with several
minor alkene-containing materials not isolated in pure
form. The fluoropiperidine 24 (the structure of which was
assigned from a 2-D 1H NMR spectrum of indole 26)
presumably arises from a SN1 type reaction with fluoride
anion attacking the transient carbocation anti to the
indole nucleus. The formation of 24, together with the
olefin mixture (produced by an elimination process) is not
unusual for reactions involving DAST.6 The second major
component isolated from the reaction mixture was dif-
1
ficult to identify by H NMR due to rotamers but was
tentatively assigned as fluoropiperidine 25. To confirm
the structural assignment of this unexpected product and
examine the role that the indole 2-substituent played in
the selectivity of the DAST mediated process, an authen-
tic sample of 25 was prepared as depicted in Scheme 7.
Base-mediated removal of the indole protecting group
in 23 revealed alcohol 27 (60% ee by HPLC), whose
optical purity could be increased using the same recrys-
tallization protocol developed for 12. In contrast to Boc-
indole 23 the reaction of 27 (88% ee) with DAST afforded
fluoropiperidine 28 as the sole product and in good
chemical yield. The indole nitrogen in 28 was then
reprotected to furnish fluoropiperidine 25 identical in all
(13) For the sake of clarity, only one diastereoisomer at the indole
3-position of 19a and 19b are shown. The curly arrows in Figure 3
imply a concerted mechanism to account for the formation of 19. One
of the referees correctly pointed out that since cyclopropanes can only
be cis-1,2-disubstituted when fused to a second ring 19 may be formed
via an SN1 type process.

4988 J . Org. Chem., Vol. 65, No. 16, 2000
Hallett et al.
Sch em e 6a
a
Key: (i) 4-piperidone monohydrate hydrochloride, MeOH,
KOH, ∆; (ii) di-tert-butyl dicarbonate, DMAP, Et3N, CH2Cl2; (iii)
(-)-Ipc2BH, THF, ambient temperature then NaOH, H2O2; (iv)
DAST, EtOAc, -50 °C to ambient temperature; (v) TFA, DCM.
Sch em e 7a
F igu r e 5. Partial DQF-COSY and HMQC spectra of the
spirocyclopropyl-3H-indole 19 at -50 °C.
a
Key: (i) NaOMe, MeOH; (ii) recrystallize and retain mother
Ta ble 1. Ch em ica l Sh ifts (p p m ) of th e Ma jor Con for m er s
of 8 a n d 19
liquors; (iii) DAST, EtOAc, -50 °C to ambient temperature; (iv)
Di-tert-butyl dicarbonate, DMAP, Et3N, CH2Cl2.
H3
H4
C3
C4
Sch em e 8
starting material 8
intermediate 19
4.44
3.22
3.00
3.45
68.1
33.7
42.0
34.2
respects (except optical purity) to that obtained in
Scheme 6. These results indicate that the indole nitrogen
is an important element of the rearrangement mecha-
nism and a hydrogen atom alone at the 2-position of the
indole is sufficient to control the regiochemical outcome
of the reaction.
The success of the Mitsunobu reaction (Scheme 5)
prompted us to examine the possibility of intercepting
intermediate 19 with other reagents. This required the
development of a general protocol in which 19 could be
generated in the absence of a nucleophile. To this end,
racemic alcohol 8 was first reacted at low tempera-
ture with trifluoromethanesulfonic anhydride before
subsequent treatment with a nucleophile (Scheme 8).
The results of our brief foray into this area are shown in
Table 2.
The intermediate 19 was successfully reacted with a
number of heteroatom-centered nucleophiles to afford
products 29-31 in moderate to good yield (not optimized).
The structure of 29 was confirmed by removing the
acetate group to reveal an alcohol identical in all respects
to 18 (Scheme 5). Our attempts to react carbon-centered
nucleophiles, e.g. cyanide or the anion of diethyl mal-
onate, were not productive.
Ta ble 2. Rea ction of In ter m ed ia te 19 w ith Oth er
Nu cleop h iles
nucleophile
acetic acid
benzylamine
benzyl mercaptan
product
R
yield (%)
29
30
31
AcO
BnNH
BnS
74
55
56
Con clu sion
Using the combined tools of X-ray crystallography,
low-temperature NMR, and chiral HPLC, we have probed
the stereo- and regiochemical outcome of an unusual
reaction of indoles. We have demonstrated that a spiro-
cyclic indole is the reactive intermediate and that this
species reacts with nucleophiles in a completely stereo-
and regioselective manner. We have also shown that this
intermediate can be generated using several methods and
then trapped with a variety of heteroatom-centered
nucleophiles.

Unusual DAST-Mediated Rearrangement Reaction
J . Org. Chem., Vol. 65, No. 16, 2000 4989
ethyl acetate (2 × 150 mL). The organics were combined and
washed with water (250 mL) and brine (250 mL) to give the
title compound (2.69 g, 99%) as a white powder: mp 147-149
Exp er im en ta l Section
Gen er a l. All reactions involving air- and/or water-sensitive
reagents were carried out under an atmosphere of N2 using
oven-dried glassware. Unless otherwise noted, starting materi-
als were obtained from commercial suppliers and used without
further purification. Unless otherwise indicated, organic ex-
tracts were dried over anhydrous sodium sulfate and concen-
trated at aspirator pressure using a rotary evaporator. Puri-
fication by column chromatography was performed according
to the method of Still, Kahn, and Mitra14 using silica gel
(particle size 40-63 µm) as the stationary phase. Melting
points are uncorrected. Optical rotations were measured at
ambient temperature. Enantiomeric excess measurements
were determined by analytical HPLC using either a Chiralcel
OD-H column (250 mm × 4.6 mm) or a Chiralcel OJ -R column
(150 mm × 4.6 mm).
1
°C (Et2O); H NMR (360 MHz, CDCl3) δ 1.76-1.86 (m, 2 H),
2.20-2.40 (m, 1 H), 2.62-2.86 (m, 2 H), 3.00-3.10 (m, 1 H),
4.18-4.38 (m, 2 H), 4.50-4.64 (m, 1 H), 5.20 (s, 2 H), 7.11 (dt,
J ) 8 and 1, 1 H), 7.23 (dt, J ) 7 and 1, 1 H), 7.35-7.48 (m,
9 H), 7.60 (d, J ) 7, 2 H), 7.68 (d, J ) 8, 1 H), 8.15 (s, 1 H);
MS (ES+) m/z 427 (M + H)+. Anal. Calcd for C27H26N2O3‚
0.4H2O: C, 74.77; H, 6.23; N, 6.46. Found: C, 74.76; H, 5.94;
N, 6.31.
(3RS,4RS)-4-F lu or o-3-(2-p h en yl-1H-in d ol-3-yl)-p ip er i-
d in e-1-ca r boxylic Acid Ben zyl Ester (9). A cooled (-50 °C)
solution of racemic alcohol 8 (1.0 g, 2.3 mmol) in anhydrous
ethyl acetate (20 mL) was treated with diethylaminosulfur
trifluoride (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 resulting 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); 1H NMR (360 MHz, CDCl3) δ 1.70-1.85 (m, 1 H),
2.20-2.30 (m, 1 H), 2.90-3.10 (m, 1 H), 3.20-3.30 (m, 1 H),
3.40-3.50 (m, 1 H), 4.20-4.50 (m, 2 H), 5.10 (s, 2 H), 5.24
(dtd, J ) 54, 11 and 5, 1 H), 7.12 (t, J ) 7, 1 H), 7.18 (t, J )
7, 1 H), 7.20-7.43 (m, 9 H), 7.52-7.56 (m, 2 H), 7.67 (d, J )
8, 1 H), 8.15 (s, 1 H); MS (ES+) m/z 429 (M + H)+. Anal. Calcd
for C27H25FN2O2: C, 75.68; H, 5.88; N, 6.54. Found: C, 75.45;
H, 5.80; N, 6.34.
NMR experiments were performed using a 5 mm inverse
broadband probe equipped with Z-gradients. Unless otherwise
stated, spectra were recorded at 300 K in either d6-DMSO or
CD2Cl2; coupling constants are given in hertz.
2-P h e n yl-3-(1,2,3,6-t e t r a h yd r o-p yr id in -4-yl)-1H -in -
d ole (6). A 2 L three-necked flask was charged with 2-phen-
ylindole (70 g, 0.36 mol), 4-piperidone monohydrate hydro-
chloride (100 g, 0.65 mol), glacial acetic acid (700 mL), and 1
M phosphoric acid (150 mL). The resulting suspension was
magnetically stirred and heated at 95 °C for 16 h (complete
solution is obtained after approximately 1 h at the elevated
temperature). The reaction was cooled to ambient temperature
and poured into ammonia (5 L of a 15 wt % aqueous solution),
the excess 4-piperidone being soluble in aqueous ammonia.
After the resulting suspension had cooled to ambient temper-
ature, the cream-colored solid was collected by filtration. The
solid was washed with water (2 L) and then dried at 60 °C
under vacuum for 16 h. Trituration with diethyl ether afforded
the title compound (96 g, 97%) as a pale yellow solid, which
was used without further purification: 1H NMR (360 MHz,
d6-DMSO) δ 2.03-2.14 (m, 2 H), 2.89 (t, J ) 5, 2 H), 3.36-
3.45 (m, 2 H), 5.79 (s, 1 H), 7.00 (t, J ) 8, 1 H), 7.08 (t, J ) 8,
1 H), 7.31-7.37 (m, 2 H), 7.44-7.52 (m, 3 H), 7.69 (d, J ) 7,
2 H), 11.31 (s, 1 H); MS (ES+) m/z 275 (M + H)+, 246 (M -
H2CdNH)+.
4-(2-P h en yl-1H-in d ol-3-yl)-2,3-d ih yd r o-6H-p yr id in e-1-
ca r boxylic Acid Ben zyl E st er (7). A solution of indole 6
(10.0 g, 36.5 mmol) in chloroform (175 mL) was treated with
solid potassium carbonate (7.5 g, 54.3 mmol) and then with
benzyl chloroformate (5.9 mL, 41.3 mmol). The resulting
suspension was heated at reflux for 14 h, cooled to ambient
temperature, and treated with N,N-diethylethylenediamine
(1.5 mL, 10.7 mmol). After stirring at ambient temperature
for 1 h, the majority of the solvent was removed in vacuo and
the resulting residue was partitioned between ethyl acetate
(500 mL) and water (500 mL). The organic phase was then
washed with 0.1 N hydrochloric acid (2 × 500 mL), water (500
mL), and brine (500 mL) to furnish the title compound
(14.8 g, 99%) as a pale orange foam: 1H NMR (360 MHz,
CDCl3) δ 2.20-2.40 (m, 2 H), 3.66 (t, J ) 5.5, 2 H), 4.18-4.24
(m, 2 H), 5.19 (s, 2 H), 5.80-5.95 (m, 1 H), 7.16 (t, J ) 7, 1 H),
7.21 (dt, J ) 7 and 1, 1 H), 7.23-7.41 (m, 9 H), 7.56 (d, J ) 7,
2 H), 7.63 (d, J ) 8, 1 H), 8.17 (s, 1 H); MS (ES+) m/z 409 (M
+ H)+.
(3RS,4RS)-3-(4-F lu or o-p ip er id in -3-yl)-2-p h en yl-1H-in -
d ole (10). A solution of racemic fluoropiperidine 9 (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 dichloromethane/methanol/
concentrated ammonia (93:7:1) gave the title compound (603
mg, 90%) as white needles: mp 134-136 °C (MeOH); 1H NMR
(400 MHz, d6-DMSO) δ 1.42-1.58 (m, 1 H, piperidine H-5ax),
2.08-2.18 (m, 1 H, piperidine H-5eq), 2.72 (dd, J ) 12.5 and
12.5, 1 H, piperidine H-6ax), 2.90-2.94 (m, 1 H, piperidine H-2),
2.98-3.15 (m, 3 H, piperidine H-6eq, piperidine H-2′ and
piperidine H-3ax), 5.20 (1 H, dddd, J ) 49, 10, 10 and 2,
piperidine H-4ax), 6.99 (dd, J ) 8.0 and 7.5, 1 H, indole H-5),
7.09 (dd, J ) 8.0 and 7.5, 1 H, indole H-6), 7.37 (d, J ) 8.0, 1
H, indole H-7), 7.41 (dd, J ) 7.5 and 7.5, 1 H, phenyl H-4),
7.52 (dd, J ) 7.5 and 7.5, 2 H, phenyl H-3), 7.59 (d, J ) 7, 2
H, phenyl H-2), 7.77 (d, J ) 8.0, 1 H, indole H-4), 11.21 (s, 1
H, indole NH); MS (ES+) m/z 295 (M + H)+. Anal. Calcd for
C
19H19FN2.CH4O: C, 73.59; H, 7.10; N, 8.58. Found: C, 73.66;
H, 7.05; N, 8.62.
3-(4-F lu or o-1,2,3,6-tetr a h yd r o-p yr id in -4-yl)-2-p h en yl-
1H-in d ole (11). A hot (90 °C) solution of 2-phenylindole (1.5
g, 7.8 mmol) in glacial acetic acid (20 mL) was treated with
3-fluoro-4-oxo-piperidine-1-carboxylic acid tert-butyl ester9 (1.7
g, 7.8 mmol) and then with 1 M phosphoric acid (4 mL), and
the resulting suspension heated at 90 °C for 14 h. The resulting
green solution was poured into ammonia (150 mL of a 15 wt
% aqueous solution), and the product was extracted into ethyl
acetate (150 mL). The organic phase was washed with water
and brine, dried over anhydrous sodium sulfate, filtered, and
then preadsorbed directly onto silica. Purification by flash
chromatography eluting with dichloromethane containing 1%
concentrated ammonia on a gradient of methanol (1-5%) gave
a pale orange solid. This solid was triturated with ether then
with methanol to afford the title compound (2.07 g, 91%) as
white powder: mp 212-214 °C dec (MeOH); 1H NMR (360
(3RS,4RS)-3-Hyd r oxy-4-(2-p h en yl-1H-in d ol-3-yl)-p ip e-
r id in e-1-ca r boxylic Acid Ben zyl Ester (8). A cooled (-25
°C) solution of carbamate 7 (2.6 g, 6.4 mmol) in anhydrous
tetrahydrofuran (50 mL) was treated with borane-methyl
sulfide complex (650 µL of a 10 M solution, 6.5 mmol), and
this mixture was stirred to ambient temperature over 16 h.
The reaction was then cooled to -10 °C and treated with 3 N
sodium hydroxide solution (2 mL) followed by hydrogen
peroxide (1 mL of a 30 wt % solution in water), and this
mixture was stirred to ambient temperature over 24 h. The
reaction mixture was poured into a saturated aqueous solution
of sodium hydrogencarbonate (250 mL) and extracted with
(14) Still, W. C.; Kahn, M.; Mitra, A. J . Org. Chem. 1978, 43, 2923.

4990 J . Org. Chem., Vol. 65, No. 16, 2000
Hallett et al.
MHz, d6-DMSO) δ 2.35 (br, 1 H), 2.94-3.19 (m, 2 H), 3.24-
3.46 (m, 2 H), 4.91 (dm, J ) 50, 1 H), 6.08-6.10 (m, 1 H), 7.02
(t, J ) 7, 1 H), 7.12 (t, J ) 7, 1 H), 7.32-7.40 (m, 2 H), 7.44-
7.53 (m, 3 H), 7.70 (d, J ) 8, 2 H), 11.41 (s, 1 H); MS (ES+)
m/z 293 (M + H)+, 264 (M - H2CdNH)+. Anal. Calcd for
containing the minor diastereoisomer: mp 236-238 °C (EtOAc/
1
heptane); H NMR (360 MHz, CDCl3) δ 0.01 (s, 3 H), 0.63 (s,
3H), 0.93 (s, 3 H), 1.52-1.58 (m, 1 H), 1.71-1.87 (m, 3 H),
2.18-2.26 (m, 1 H), 2.28-2.40 (m, 1 H), 2.74-2.88 (br m, 2
H), 3.33 (td, J ) 11 and 4, 1 H), 4.20-4.36 (br m, 1 H), 4.60-
4.70 (br m, 1 H), 5.20 (d, J ) 12, 1 H), 5.24 (d, J ) 12, 1 H),
5.52-5.64 (br m, 1 H), 7.10 (t, J ) 7, 1 H), 7.17 (t, J ) 7, 1 H),
7.31-7.45 (m, 7 H), 7.53 (t, J ) 8, 2 H), 7.62 (d, J ) 7, 2 H),
7.64-7.70 (m, 1 H), 7.98 (s, 1 H).
C
19H17FN2: C, 78.06; H, 5.86; N, 9.58. Found: C, 78.39; H,
5.80; N, 9.29.
(3RS,4RS)-3-(3-F lu or o-p ip er id in -4-yl)-2-p h en yl-1H-in -
d ole (4). A solution of allylic fluoride 11 (500 mg, 1.7 mmol)
in trifluoroacetic acid (10 mL) was treated with triethylsilane
(500 µL, 3.1 mmol) and then stirred at ambient temperature
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 com-
pound (330 mg, 66%) as a white solid: oxalate salt, colorless
needles, mp 206-208 °C (EtOH); 1H NMR (400 MHz, d6-
DMSO, free base) δ 1.67-1.78 (m, 1 H, piperidine H-5eq), 2.12-
2.26 (m, 1 H, piperidine H-5ax), 2.34-2.48 (m, 2 H, piperidine
H-6ax and piperidine H-2ax), 2.90 (broad d, J ) 12, 1 H,
piperidine H-6eq), 3.03-3.13 (m, 1 H, piperidine H-4ax), 3.32
(obscured by H2O, 1 H, piperidine H-2eq), 5.03 (dddd, J ) 49,
10, 10 and 5, 1 H, piperidine H-3ax), 7.01 (dd, J ) 8.0 and 7.5,
1 H, indole H-5), 7.10 (dd, J ) 8.0, 7.5, 1 H, indole H-6), 7.38
(d, J ) 8.0, 1 H, indole H-7), 7.40-7.43 (m, 1 H, phenyl H-4),
7.49-7.55 (m, 2 H, phenyl H-3), 7.56-7.60 (m, 2 H, phenyl
H-2), 7.80 (d, J ) 8.0, 1 H, indole H-4), 11.18 (s, 1 H, indole
(3S*,4S*)-4-Flu or o-3-(2-ph en yl-1H-in dol-3-yl)-piper idin e-
1-ca r boxylic Acid Ben zyl Ester (14). The title compound
was prepared using the same procedure as that described for
compound 9 using alcohol 12 (1.3 g, 3.0 mmol, 91% e.e.) and
diethylaminosulfur trifluoride (500 µL, 3.8 mmol) to afford a
cream-colored solid (1.1 g, 84%). Spectral data as for the
racemate 9: HPLC (OD-H column, 4:1 iso-hexane/ethanol, 1
mL min-1, UV, 300 nM) 7.9 min (97.5%), 9.6 min (2.5%).
(3S ,4S )-3-(4-F lu or o-p ip e r id in -3-yl)-2-p h e n yl-1H -in -
d ole (15). The title compound was prepared using the same
procedure as that described for compound 10 using fluoropi-
peridine 14 (1.1 g, 2.6 mmol) to give a white solid (748 mg,
99%). A single recrystallization afforded colorless needles.
Spectral data as for the racemate 10: [R]D -17.5 (c 1.2 in
DMF); mp 124-126 °C (MeOH); HPLC (OD-H column, 4:1 iso-
hexane/ethanol, 1 mL min-1, UV, 300 nM) 7.0 min (<0.5%),
8.5 min (>99.5%). Anal. Calcd for C19H19FN2‚CH4O: C, 73.59;
H, 7.10; N, 8.58. Found: C, 73.82; H, 6.85; N, 8.55.
(3S,4S)-4-F lu or o-3-(2-p h en yl-1H-in d ol-3-yl)-p ip er id in e-
1-ca r boxylic Acid [(R)-1-p h en yl-eth yl]-a m id e (16). A sus-
pension of fluoropiperidine 15 (100 mg, 0.34 mmol, 95% ee) in
1,2-dichloroethane (5 mL) was treated with (R)-(+)-R-meth-
ylbenzylisocyanate (1.7 mL of a 0.5 M solution in 1,2-dichlo-
roethane, 0.85 mmol), and this mixture was heated at 50 °C
for 90 min. The reaction was cooled to ambient temperature
then treated with N,N-dimethylethylenediamine (500 µL) and
stirring continued at ambient temperature for 30 min. The
reaction was diluted with ethyl acetate (25 mL) and washed
with 0.1 N hydrochloric acid (2 × 20 mL), water (20 mL), and
brine (20 mL) to afford the title compound as a white solid
(133 mg, 89%). A single recrystallization gave colorless
needles: mp 250-252 °C (9:1 EtOAc/MeOH); 1H NMR (360
MHz, d6-DMSO) δ 1.30 (d, J ) 7, 3 H), 1.40-1.56 (m, 1 H),
2.10-2.19 (br m, 1 H), 3.00-3.18 (m, 2 H), 3.39 (t, J ) 12, 1
H), 4.08-4.24 (br m, 2 H), 4.81 (quintet, J ) 7, 1 H), 5.30
(dddd, J ) 54, 10, 10 and 5, 1 H), 6.88 (d, J ) 8, 1 H), 7.01 (t,
J ) 7, 1 H), 7.12 (t, J ) 7, 1 H), 7.16-7.24 (m, 5 H), 7.38-7.48
(m, 4 H), 7.61 (d, J ) 7, 2 H), 7.85 (d, J ) 8, 1 H), 11.31 (s, 1
H).
(3RS,4RS)-4-(4-Nitr o-ben zoyloxy)-3-(2-ph en yl-1H-in dol-
3-yl)-p ip er id in e-1-ca r boxylic Acid Ben zyl Ester (17). To
a cooled (0 °C) solution of racemic alcohol 8 (5.0 g, 11.7 mmol)
in anhydrous tetrahydrofuran (400 mL) was added triph-
enylphosphine (9.2 g, 35.1 mmol) followed by 4-nitrobenzoic
acid (5.9 g, 35.3 mmol). Diethyl azodicarboxylate (5.5 mL, 34.9
mmol) was then added dropwise over 10 min, and the resulting
mixture was stirred to ambient temperature over 16 h. The
solvent was removed on a rotary evaporator, and the residue
was suspended in water (400 mL) and extracted with diethyl
ether (500 mL). The organics were washed with 1 N sodium
hydroxide (2 × 500 mL), 1 N hydrochloric acid (500 mL), water
(500 mL), and brine (500 mL), dried over anhydrous sodium
sulfate, filtered, and preadsorbed onto silica. Purification by
chromatography on silica gel eluting with dichloromethane on
a gradient of methanol (0-1.5%) gave the title compound (6.21
g, 76%) as a yellow solid: mp 175-176 °C (Et2O/iso-hexane);
1H NMR (360 MHz, d6-DMSO measured at 340 K) δ 1.61 (qd,
J ) 13 and 4, 1 H), 2.20-2.28 (m, 1 H), 3.30-3.45 (m, 2 H),
3.66 (t, J ) 13, 1 H), 4.19 (dd, J ) 14 and 4, 2 H), 5.08 (d, J
) 13, 1 H), 5.13 (d, J ) 13, 1 H), 5.78 (td, J ) 11 and 5, 1 H),
6.99 (t, J ) 8, 1 H), 7.05 (t, J ) 8, 1 H), 7.27-7.56 (m, 10 H),
7.75 (d, J ) 9, 2 H), 7.88 (d, J ) 8, 1 H), 8.13 (d, J ) 8, 2 H),
11.03 (s, 1 H). Anal. Calcd for C34H29N3O6: C, 70.94; H, 5.08;
N, 7.30. Found: C, 70.87; H, 5.04; N, 7.24.
NH); MS (ES+) m/z 295 (M + H)+. Anal. Calcd for C19H19
-
FN2.C2H2O4: C, 65.62; H, 5.51; N, 7.29. Found: C, 66.01; H,
5.44; N, 7.20.
(3S*,4S*)-3-Hyd r oxy-4-(2-p h en yl-1H-in d ol-3-yl)-p ip er i-
d in e-1-ca r boxylic Acid Ben zyl Ester (12). A cooled (-10
°C) suspension of (+)-diisopinocampheylborane12 (9.8 g, 34
mmol) in anhydrous tetrahydrofuran (30 mL) was treated with
a solution of 4-(2-phenyl-1H-indol-3-yl)-2,3-dihydro-6H-pyri-
dine-1-carboxylic acid benzyl ester (7.0 g, 17 mmol) in anhy-
drous tetrahydrofuran (40 mL), and this mixture was stirred
to ambient temperature over 70 h giving a pale yellow solu-
tion. The reaction was then cooled to -10 °C and treated
with 4 N sodium hydroxide solution (20 mL) followed by
hydrogen peroxide (12 mL of a 30 wt % solution in water),
and this mixture was stirred to ambient temperature over 16
h. The reaction mixture was poured into a saturated aque-
ous solution of sodium hydrogencarbonate (400 mL) and
extracted with ethyl acetate (2 × 250 mL). The organics were
combined and washed with water (400 mL) and brine (400
mL) to give a yellow oil. Purification by chromatography on
silica gel eluting with iso-hexane on a gradient of ethyl ace-
tate (0%-40%) gave the title compound (6.4 g, 88%) as a white
solid whose spectral data were identical to the racemate 8:
HPLC (OD-H column, 4:1 iso-hexane/ethanol with 0.1% di-
ethylamine, 1 mL min-1, UV, 212 nM) 6.4 min (24%), 7.8 min
(76%). Recrystallization from diethyl ether over 72 h gave
colorless needles (2.8 g, racemic by HPLC) and a mother liquor
enriched in the major enantiomer. Concentration of the mother
liquor in vacuo gave a pale yellow foam (3.6 g, 91% ee by
HPLC).
(3S,4S)-4-(2-P h en yl-1H -in d ol-3-yl)-3-{(1S)-3-oxo-4,7,7-
tr im eth yl-2-oxa bicyclo[2.2.1]h ep ta n e-1-ca r bon yloxy}-p i-
p er id in e-1-ca r boxylic Acid Ben zyl Ester (13). A solution
of alcohol 12 (1.0 g, 2.3 mmol, 91% ee) in anhydrous pyridine
(10 mL) was treated with (1S)-(-)-camphanic chloride (770 mg,
3.6 mmol) then with 4-(dimethylamino)pyridine (10 mg), and
this mixture was stirred at ambient temperature for 40 h. The
reaction mixture was poured into 1 N hydrochloric acid (200
mL) and extracted with ethyl acetate (100 mL). The organic
layer was washed with 1 N hydrochloric acid (100 mL), water
(100 mL), and brine (100 mL), dried over anhydrous sodium
sulfate, filtered, and preadsorbed on to silica. Purification by
chromatography on silica gel eluting with iso-hexane on a
gradient of ethyl acetate (10-40%) gave the title compound
(1.25 g, 88%) as a white powder followed by mixed fractions
(3RS,4RS)-4-Hyd r oxy-3-(2-p h en yl-1H-in d ol-3-yl)-p ip e-
r id in e-1-ca r boxylic Acid Ben zyl Ester (18). A suspension

Unusual DAST-Mediated Rearrangement Reaction
J . Org. Chem., Vol. 65, No. 16, 2000 4991
of nitrobenzoate 17 (2.0 g, 3.5 mmol) in methanol (75 mL) was
treated with potassium carbonate (5.0 g, 36 mmol), and this
mixture was stirred at ambient temperature for 3 h. The
reaction was filtered, the filtrate was evaporated to dryness,
and the residue was suspended in water (150 mL) and
extracted with ethyl acetate (150 mL). The organic phase was
then washed with water (100 mL) and brine (100 mL), dried
over anhydrous sodium sulfate, filtered, and preadsorbed on
to silica. Purification by chromatography on silica gel eluting
with iso-hexane on a gradient of ethyl acetate (10-30%) gave
the title compound (1.4 g, 95%) as a white foam: 1H NMR (360
MHz, CDCl3) δ 1.50-1.63 (m, 1 H), 1.82 (d, J ) 2, 1 H), 2.08-
2.14 (m, 1 H), 2.94-3.12 (m, 2 H), 3.38-3.51 (m, 1 H), 4.22-
4.46 (m, 3 H), 5.11 (s, 2 H), 7.12 (t, J ) 8, 1 H), 7.18-7.48 (m,
10 H,), 7.50-7.60 (m, 2 H), 7.73 (d, J ) 8, 1 H), 8.23 (s, 1 H).
Anal. Calcd for C27H26N2O3: C, 76.03; H, 6.14; N, 6.57.
Found: C, 75.83; H, 6.22; N, 6.30.
A cooled (-50 °C) solution of alcohol 18 (1.3 g, 3.0 mmol) in
anhydrous ethyl acetate (25 mL) was treated with diethylami-
nosulfur trifluoride (500 µL, 3.8 mmol). Stirring at -50 °C was
continued for 1 h before the solution was allowed to warm to
ambient temperature. The reaction mixture was then poured
into saturated aqueous sodium hydrogencarbonate (100 mL)
and the product extracted into ethyl acetate (100 mL). The
organic phase was washed with water (100 mL) and brine (100
mL) to give a yellow foam. Purification by column chromatog-
raphy eluting with iso-hexane on a gradient of ethyl acetate
(0-20%) afforded a white foam (1.1 g, 85%) whose spectral
data were identical to fluoropiperidine 9.
3-(1-ter t-Bu toxyca r bon yl-1,2,3,6-tetr a h yd r o-p yr id in -4-
yl)-6-flu or o-in d ole-1-ca r b oxylic Acid ter t-Bu t yl E st er
(22). A cooled (0 °C) solution of potassium hydroxide (73 g,
1.3 mol) in methanol (900 mL) was treated with 6-fluoroindole
(46 g, 0.34 mol) and then with 4-piperidone monohydrate
hydrochloride (138 g, 0.90 mol). The resulting suspension was
magnetically stirred and heated under reflux for 60 h. The
reaction was cooled to ambient temperature, poured into water
(8 L), and the resulting gummy solid was stirred for 16 h to
furnish a fine suspension. The solid was collected by filtration,
washed with water and dried under vacuum to afford 6-fluoro-
3-(1,2,3,6-tetrahydro-pyridin-4-yl)-1H-indole (74 g, 100%) as
a pale yellow powder, which was used without further puri-
fication: 1H NMR (360 MHz, d6-DMSO) δ 2.30-2.40 (m, 2 H),
2.92 (t, J ) 6, 2 H), 3.38-3.45 (m, 2 H), 6.15-6.20 (m, 1 H),
6.86 (td, J ) 9 and 2, 1 H), 7.13 (dd, J ) 9 and 2, 1 H), 7.35 (d,
J ) 2, 1 H), 7.78 (dd, J ) 9 and 6, 1 H), 11.13 (s, 1 H); MS
(ES+) m/z 217 (M + H)+, 188 (M - H2CdNH)+.
A suspension of 6-fluoro-3-(1,2,3,6-tetrahydropyridin-4-yl)-
1H-indole (74 g, 0.34 mol) in dichloromethane (1 L) was treated
with triethylamine (142 mL, 1.02 mol) and then stirred and
cooled to 0 °C. Di-tert-butyl dicarbonate (163 g, 0.75 mol) was
then added portionwise over 15 min followed by 4-(dimethyl-
amino)pyridine (50 g, 0.41 mol), and the resulting solution was
stirred at ambient temperature for 90 min. The reaction was
treated with N,N-dimethylethylenediamine (17 mL, 0.16 mol),
and stirring was continued at ambient temperature for 30 min.
The majority of the solvent was removed on a rotary evapora-
tor, and the residue was dissolved in ethyl acetate (2.5 l). This
was washed with 0.01 N hydrochloric acid (2 × 1.5 L), water
(1.5 L), and brine (1.5 L). Filtration through a pad of Florisil
followed by concentration in vacuo gave the title compound
as a viscous yellow oil (109 g, 77% over 2 steps): 1H NMR (360
MHz, CDCl3) δ 1.50 (s, 9 H), 1.67 (s, 9 H), 2.45-2.50 (m, 2 H),
3.67 (t, J ) 6, 2 H), 4.15-4.20 (m, 2 H), 6.10-6.15 (m, 1 H),
7.00 (td, J ) 9 and 2, 1 H), 7.49 (s, 1 H), 7.70 (dd, J ) 9 and
5, 1 H), 7.85-7.90 (m, 1 H).
mL) followed by hydrogen peroxide (50 mL of a 30 wt %
solution in water), and this mixture was stirred to ambient
temperature over 24 h. The majority of the tetrahydrofuran
was removed on a rotary evaporator, and the residue was
partitioned between ethyl acetate (750 mL) and water (500
mL). The organic phase was then washed with saturated
aqueous sodium hydrogen carbonate (2 × 500 mL), water (500
mL), and brine (500 mL), dried over anhydrous sodium sulfate,
filtered, and preadsorbed on to silica. Purification by chroma-
tography on silica gel eluting with iso-hexane on a gradient of
ethyl acetate (0-25%) gave the title compound (16.9 g, 83%)
as a colorless, viscous oil: 1H NMR (360 MHz, CDCl3) δ 1.50
(s, 9 H), 1.67 (s, 9 H), 1.80 (d, J ) 3, 1 H), 1.80-1.85 (m, 1 H),
1.90-1.95 (m, 1 H), 2.64-2.74 (m, 1 H), 2.76-2.84 (m, 2 H),
3.75-3.84 (m, 1 H), 4.15-4.26 (m, 1 H), 4.35-4.45 (m, 1 H),
6.99 (td, J ) 9 and 2, 1 H), 7.44 (s, 1 H), 7.53 (dd, J ) 9 and
5, 1 H), 7.85-7.90 (m, 1 H).
(3R*,4R*)-3-(1-ter t-Bu toxyca r bon yl-3-flu or o-p ip er id in -
4-yl)-6-flu or o-in d ole-1-ca r boxylic Acid ter t-Bu tyl Ester
(24) and (3R*,4R*)-3-(1-ter t-Bu toxyca r bon yl-4-flu or o-p i-
p er id in -3-yl)-6-flu or o-in d ole-1-ca r boxylic Acid ter t-Bu tyl
Ester (25). A cooled (-78 °C) solution of alcohol 23 (1.3 g, 3
mmol) in anhydrous ethyl acetate (25 mL) was treated with
diethylaminosulfur trifluoride (400 µL, 3.3 mmol). Stirring at
-78 °C was continued for 1 h before the solution was allowed
to warm to ambient temperature. The reaction mixture was
then poured into saturated aqueous sodium hydrogencarbon-
ate (100 mL), and the product extracted into ethyl acetate (100
mL). The organic phase was washed with water (100 mL) and
brine (100 mL), dried over anhydrous sodium sulfate, filtered,
and preadsorbed on to silica. Purification by chromatography
on silica gel eluting with iso-hexane on a gradient of ethyl
acetate (0-10%) gave 3-fluoropiperidine 24 (260 mg, 20%) as
a white foam: 1H NMR (360 MHz, CDCl3) δ 1.49 (s, 9 H), 1.67
(s, 9 H), 1.75-1.87 (br m, 1 H), 2.01-2.10 (br m, 1 H), 2.82-
2.98 (br m, 2 H), 3.01-3.10 (m, 1 H), 4.08-4.20 (br m, 1 H),
4.40-4.50 (br m, 1 H), 4.55 (dddd, J ) 48, 10, 10 and 5, 1 H),
7.00 (td, J ) 7 and 2, 1 H), 7.42 (br s, 1 H), 7.50 (dd, J ) 9 and
5, 1 H), 7.85-7.87 (br m, 1 H). Anal. Calcd for C23H30F2N2O4.0.2-
(H2O): C, 62.77; H, 6.96; N, 6.37. Found: C, 62.76; H, 6.78;
N, 6.10.
Further elution gave 4-fluoropiperidine 25 (390 mg, 30%)
as a white foam: 1H NMR (400 MHz, CDCl3) δ 1.47 (s, 9 H),
1.66 (s, 9 H), 1.74-1.86 (m, 1 H), 2.10-2.22 (m, 1 H), 3.04-
3.20 (m, 3 H), 4.00-4.11 (m, 1 H), 4.15-4.31 (m, 1 H), 4.82
(dddd, J ) 48, 10, 10 and 4, 1 H), 7.00 (td, J ) 9 and 2,1 H),
7.47 (s, 1 H), 7.51 (dd, J ) 9 and 5, 1 H), 7.81-7.90 (m, 1 H).
Anal. Calcd for C23H30F2N2O4: C, 63.29; H, 6.93; N, 6.42.
Found: C, 63.68; H, 7.13; N, 6.29.
(3R*,4R*)-3-(3-F lu or o-p ip er id in -4-yl)-6-flu or o-1H -in -
d ole (26). A solution of fluoro-indole 24 (71 mg, 0.16 mmol)
in dichloromethane (2 mL) was treated with trifluoroacetic
acid (500 µL), and this mixture was stirred at ambient
temperature for 18 h. The reaction mixture was poured
carefully into a saturated aqueous solution of sodium hydrogen
carbonate (20 mL), and the product was extracted into ethyl
acetate (20 mL). The organics were washed with water (20
mL) and then brine (20 mL) to give an oil. This oil was purified
by preparative TLC eluting with dichloromethane/methanol/
concentrated ammonia (90:10:1) to furnish the title compound
(31 mg, 80%) as a white foam: 1H NMR (400 MHz, CDCl3) δ
1.78-1.89 (m, 1 H, piperidine H-5ax), 2.07-2.13 (m, 1 H,
piperidine H-5eq), 2.70-2.83 (m, 2 H, piperidine H-2ax and
piperidine H-6ax), 3.05-3.15 (m, 2 H, piperidine H-2eq and
piperidine H-4ax), 3.42-3.48 (m, 1 H, piperidine H-6eq), 4.58
(dddd, J ) 49, 10, 10 and 5, 1 H, piperidine H-3ax), 6.89 (t, J
) 9, 1 H, indole), 7.03 (d, J ) 9, 1 H, indole), 7.05 (s, 1 H,
indole H-2), 7.59 (dd, J ) 9 and 5, 1 H, indole), 8.04 (br s, 1 H,
indole NH); MS (ES+) m/z 237 (M + H)+. Anal. Calcd for
(3R*,4R*)-3-(1-ter t-Bu toxycar bon yl-3-h ydr oxy-piper idin -
4-yl)-6-flu or o-in d ole-1-ca r boxylic Acid ter t-Bu tyl Ester
(23). A cooled (-10 °C) suspension of (-)-diisopinocampheyl-
borane12 (21.2 g, 74 mmol) in anhydrous tetrahydrofuran (50
mL) was treated with a solution of tetrahydropyridine 22 (19.5
g, 47 mmol) in anhydrous tetrahydrofuran (75 mL) and the
resulting suspension was stirred at ambient temperature for
72 h to give a yellow solution. The reaction was then cooled to
-10 °C and treated with 4 N sodium hydroxide solution (75
C
13H14F2N2: C, 66.09; H, 5.97; N, 11.06. Found: C, 65.71; H,
6.06; N, 11.70.
(3R*,4R*)-4-(6-F lu or o-1H-in d ol-3-yl)-3-h yd r oxy-p ip er i-
d in e-1-ca r boxylic Acid ter t-Bu tyl Ester (27). A solution
of alcohol 23 (16 g, 37 mmol) in methanol (200 mL) was treated
with sodium methoxide (12 g, 0.22 mol), and the resulting

4992 J . Org. Chem., Vol. 65, No. 16, 2000
Hallett et al.
yellow solution was heated at 60 °C for 7 h. After cooling to
ambient temperature, water (400 mL) was added, the majority
of the methanol was removed on a rotary evaporator, and the
residue was partitioned between ethyl acetate (500 mL) and
water (500 mL). The organic phase was then washed with 0.01
N hydrochloric acid (2 × 500 mL), water (2 × 500 mL), and
brine (500 mL) to afford the title compound (11.6 g, 94%) as a
white foam: HPLC (OJ -R column, 32% MeCN in 0.1 M
perchloric acid, 1 mL min-1, UV, 210 nM) 21.0 min (80%), 22.9
min (20%); 1H NMR (360 MHz, CDCl3) δ 1.50 (s, 9 H), 1.86 (d,
J ) 2, 1 H), 1.82-1.90 (m, 1 H), 1.90-1.98 (m, 1 H), 2.64-
2.74 (m, 1 H), 2.78-2.86 (m, 2 H), 3.68-3.78 (m, 1 H), 4.16-
4.26 (m, 1 H), 4.38-4.46 (m, 1 H), 6.90 (td, J ) 9 and 2, 1 H),
7.02-7.08 (m, 2 H), 7.59 (dd, J ) 9 and 5, 1 H), 8.22 (br s, 1
H). Anal. Calcd for C18H23FN2O3: C, 64.65; H, 6.93; N, 8.38.
Found: C, 64.63; H, 6.92; N, 8.32.
This foam was dissolved in ethyl acetate (30 mL) and heated
to 65 °C. iso-Hexane was slowly added until the solution
became turbid, and the heat source was removed. After
standing at ambient temperature for 16 h the solid was
removed by filtration and shown to be racemic by HPLC. The
filtrate was evaporated to dryness, and the above procedure
was repeated, giving a second crop of racemic solid (3.6 g,
combined mass). Concentration of the filtrate afforded a yellow
foam (8.0 g, 88% ee by HPLC).
CDCl3, major rotamer) δ 1.52-1.62 (br m, 1 H), 1.76 (s, 3 H),
2.20-2.24 (br m, 1 H), 2.96-3.11 (br m, 1 H), 3.23-3.32 (br
m, 1 H), 3.48-3.52 (br m, 1 H), 4.18-4.41 (br m, 2 H), 5.09
(br s, 2 H), 5.47-5.56 (m,1 H), 7.11 (t, J ) 8, 1 H), 7.17 (t, J
) 8, 1 H), 7.29-7.50 (m, 9 H), 7.52-7.62 (br m, 2 H), 7.23 (d,
J ) 8, 1 H), 8.07 (s, 1 H). Anal. Calcd for C29H28N2O4.0.2-
(H2O): C, 73.77; H, 6.06; N, 5.93. Found: C, 73.69; H, 6.13;
N, 5.71.
A solution of acetate 29 (275 mg, 0.59 mmol) in methanol
(7 mL) was treated with potassium carbonate (810 mg, 5.9
mmol), and this suspension was stirred at ambient tempera-
ture for 16 h. The reaction was filtered and the filtrate
evaporated in vacuo to give an oil. This oil was purified by
chromatography on silica gel eluting with iso-hexane on a
gradient of ethyl acetate (10-30%) to afford a white foam (223
mg, 89%) whose spectral data were identical to alcohol 18.
(3RS,4RS)-4-Ben zyla m in o-3-(2-p h en yl-1H-in d ol-3-yl)-
p ip er id in e-1-ca r boxylic Acid Ben zyl Ester (30). Using the
procedure described for 29 with benzylamine (500 µL of a 10
M solution in ethyl acetate, 5 mmol) as the nucleophile
afforded the title compound (567 mg, 55%) as a white solid:
mp 127-129 °C (EtOAc/iso-hexane); 1H NMR (360 MHz,
CDCl3, mixture of rotamers) δ 1.30-1.46 (br m, 1 H), 2.04-
2.18 (br m, 1 H), 2.86-3.04 (br m, 1 H), 3.08-3.20 (m, 1 H),
3.29-3.45 (br m, 2 H), 3.49 (d, J ) 14, 1 H), 3.68 (d, J )
14, 1 H), 4.20-4.42 (br m, 2 H), 5.12 (br s, 2 H), 6.89-6.93
(m, 2 H), 7.04 (t, J ) 8, 1 H), 7.10-7.18 (m, 3 H), 7.21 (t, J )
8, 1 H), 7.29-7.40 (m, 9 H), 7.54-7.62 (m, 3 H), 8.11-8.29 (br
m, 1 H); MS (ES+) m/z 516 (M + H)+. Anal. Calcd for
(3R*,4R*)-4-Flu or o-3-(6-flu or o-1H-in dol-3-yl)-piper idin e-
1-ca r boxylic Acid ter t-Bu tyl Ester (28). A cooled (-78 °C)
solution of alcohol 27 (8 g, 24 mmol, 88% ee) in anhydrous
ethyl acetate (125 mL) was treated with diethylaminosulfur
trifluoride (3.3 mL, 27 mmol). Stirring at -78 °C was continued
for 1 h before the solution was allowed to warm to ambient
temperature over 90 min. The reaction mixture was then
poured into saturated aqueous sodium hydrogen carbonate
(300 mL) and then diluted with ethyl acetate (175 mL). The
organic phase was then washed with 0.1 N hydrochloric acid
(300 mL), water (300 mL), and brine (300 mL) to afford an
orange foam. This foam was purified by chromatography on
silica gel eluting with iso-hexane on a gradient of ethyl acetate
(0-20%) to give the title compound (6.9 g, 86%) as a white
foam: 1H NMR (400 MHz, CDCl3) δ 1.47 (s, 9 H), 1.75-1.90
(m, 1 H), 2.05-2.20 (m, 1 H), 3.13-3.30 (m, 3 H), 3.90-4.05
(m, 1 H), 4.10-4.24 (m, 1 H), 4.75-4.95 (m,1 H), 6.96 (td, J )
9 and 2, 1 H), 7.00-7.13 (m, 2 H), 7.57 (dd, J ) 9 and 5, 1 H),
8.09 (br s, 1 H). Anal. Calcd for C18H22F2N2O2: C, 64.27; H,
6.59; N, 8.33. Found: C, 64.13; H, 6.63; N, 8.22.
A solution of indole 28 (6.0 g, 18 mmol) in dichloromethane
(100 mL) was treated with triethylamine (5.0 mL, 36 mmol),
di-tert-butyl dicarbonate (4.9 g, 22 mmol), and 4-(dimethyl-
amino)pyridine (2.5 g, 20 mmol), and the resulting mixture
was stirred at ambient temperature for 16 h. The reaction was
treated with N,N-dimethylethylenediamine (2.5 mL), and
stirring was continued at ambient temperature for 1 h. The
majority of the solvent was removed on a rotary evaporator,
and the residue was dissolved in ethyl acetate (300 mL). This
was washed with 0.01 N hydrochloric acid (2 × 300 mL), water
(300 mL), and brine (300 mL) to give an oil. Purification of
this oil by column chromatography eluting with iso-hexane on
a gradient of ethyl acetate (0-15%) gave a white foam (7.2 g,
92%) whose spectral data were identical to fluoropiperidine
25.
(3RS,4RS)-4-Acetoxy-3-(2-p h en yl-1H-in d ol-3-yl)-p ip er i-
d in e-1-ca r boxylic Acid Ben zyl Ester (29). A cooled (-78
°C) solution of racemic alcohol 8 (853 mg, 2 mmol) in ethyl
acetate (20 mL) was treated with 2,6-lutidine (300 µL, 2.6
mmol) and then with trifluoromethanesulfonic anhydride (370
µL, 2.2 mmol), and this mixture was stirred at -78 °C for 1 h
before adding acetic acid (500 µL of a 10 M solution in ethyl
acetate, 5 mmol). Stirring at -78 °C was continued for 30 min
before the reaction mixture was allowed to warm to ambient
temperature. The reaction was diluted with ethyl acetate (30
mL) and washed with 0.1 N hydrochloric acid (50 mL), water
(50 mL), and brine (50 mL) to give a yellow oil. This oil was
purified by chromatography on silica gel eluting with iso-
hexane on a gradient of ethyl acetate (0-20%) to give the title
compound (693 mg, 74%) as a white foam: 1H NMR (400 MHz,
C
34H33N3O2: C, 79.19; H, 6.45; N, 8.15. Found: C, 79.03; H,
6.54; N, 7.99.
(3RS,4RS)-4-Ben zylsu lfa n yl-3-(2-p h en yl-1H-in d ol-3-yl)-
p ip er id in e-1-ca r boxylic Acid Ben zyl Ester (29). Using the
procedure described for 29 with benzylmercaptan (500 µL of
a 10 M solution in ethyl acetate, 5 mmol) as the nucleophile
afforded the title compound (597 mg, 56%) as a cream-colored
solid: mp 135-137 °C (EtOAc/iso-hexane); 1H NMR (360 MHz,
CDCl3, mixture of rotamers) δ 1.53-1.68 (br m, 1 H), 2.04-
2.13 (br m, 1 H), 2.80-2.93 (br m, 1 H), 3.10-3.21 (br m, 1
H), 3.23 (d, J ) 13,1 H), 3.34 (d, J ) 13, 1 H), 3.40 (td, J ) 12
and 4, 2 H), 4.19-4.37 (br m, 2 H), 5.09 (br s, 2 H), 6.90-6.96
(m, 2 H), 7.07 (t, J ) 8, 1 H), 7.13-7.16 (m, 3 H), 7.18 (t, J )
8, 1 H), 7.26-7.35 (br m, 6 H), 7.37-7.48 (m, 3 H), 7.52 (d, J
) 8, 1 H), 7.54-7.68 (br m, 2 H), 8.11 (br s, 1 H). Anal. Calcd
for C34H32N2O2S.0.5(H2O): C, 75.39; H, 6.14; N, 5.17. Found:
C, 75.46; H, 6.14; N, 5.03.
Low -Tem p er a tu r e NMR Exp er im en ts. The reaction
intermediate 19 was generated in an NMR tube by treating a
cooled (-78 °C) solution of the racemic alcohol 8 in CD2Cl2
with ca. 3 equiv of DAST. The tube was then shaken to effect
mixing and transferred immediately into the magnet.
Partial assignment of the proton and carbon spectra of
racemic alcohol 8 (where separate assignments for both
rotamers were possible, the major isomer is listed first): 1H
NMR (500 MHz, CD2Cl2, 223 K) δ 1.72-1.84 (m, 1 H,
piperidine H-5eq), 1.98 and 1.92 (s, 1 H, OH), 2.20-2.34 (m, 1
H, piperidine H-5eq), 2.57-2.85 (m, 2 H, piperidine H-2ax
,
piperidine H-6ax), 3.00 (m, 1 H, piperidine H-4ax), 4.11-4.26
(m, 2 H, piperidine H-2eq, piperidine H-6eq), 4.44 (m, 1 H,
piperidine H-3ax), 5.04-5.14 (m, 2 H, PhCH2O), 7.04 (dd, J )
8.0 and 7.5, 1 H, ArH), 7.16 (dd, J ) 8.0 and 7.5, 1 H, ArH),
7.27-7.44 (m, 7 H, ArH), 7.48 (dd, J ) 7.5 and 7.5, 2 H), 7.60
(dd, J ) 8.5 and 9.0, 2 H), 7.68 (d, J ) 8.0, 1 H), 8.39 (s, 1 H,
indole NH); 13C NMR (100 MHz, d6-DMSO) δ 30.9 (CH2), 42.0
(C-4), 44.2 (CH2), 51.3 (CH2), 66.4 (CH2), 68.1 (C-3), 111.7 (CH),
112.4 (C), 118.8 (CH), 120.3 (CH), 121.3 (CH), 126.8 (C), 127.6
(CH), 127.7 (CH), 128.0 (CH), 128.6 (2xCH), 129.2 (CH), 133.4
(C), 136.1 (C), 137.3 (C), 154.6 (CO).
Partial assignment of the proton spectrum of 3,3-spirocy-
clopropyl indolenine 19 at 223 K (where separate assignments
for both rotamers were possible, the major isomer is listed
first): 1H NMR (500 MHz, CD2Cl2) δ 2.01-2.14 (m, 1 H,
piperidine H-5), 2.25-2.38 (m, 1 H, piperidine H-5′), 2.85 and
2.90 (m, 1 H, piperidine H-6ax), 3.22 and 3.29 (m, 1 H,
piperidine H-3), 3.45 and 3.39 (m, 1 H, piperidine H-4), 3.78

Unusual DAST-Mediated Rearrangement Reaction
J . Org. Chem., Vol. 65, No. 16, 2000 4993
and 3.71 (dd, J ) 15.5 and 5.5, 1 H, piperidine H-2), 4.14 and
4.20 (d, J ) 15.5, 1 H, piperidine H-2′), 4.38 and 4.34 (dd, J )
13.5 and 4.5, 1 H, piperidine H-6eq), 5.05, 5.28, 5.17 and 5.31
(AB systems, J ) 12, 2 H, PhCH2O), 7.05-7.90 (m, 13 H, ArH),
7.97 (dd, J ) 8.0 and 7.5, 1 H, ArH).
Su p p or tin g In for m a tion Ava ila ble: Crystal structure
data for 13 and 16. The atomic coordinates have also been
deposited with the Cambridge Crystallographic Data Center,
12 Union Road, Cambridge, CB2 1EZ, U.K. (deposition num-
bers 139374 and 139375). This material is available free of
charge via the Internet at http://pubs.acs.org.
Ack n ow led gm en t. We would like to Nancy Tsou for
the X-ray crystal structure determinations.
J O0004759