Ring expansion induced by DAST: Synthesis of substituted 3-fluoropiperidines from prolinols and 3-fluoroazepanes from 2-hydroxymethylpiperidines

Article abstract of DOI:10.1002/ejoc.200700237

Optically active prolinols can be converted into optically active 3-fluoropiperidines by treatment with DAST. The reaction often produces 2-fluoromethylpyrrolidines as byproducts. The ring expansion was also applied to 2-hydroxypiperidines to produce 3-fl

Full text of DOI:10.1002/ejoc.200700237

FULL PAPER
DOI: 10.1002/ejoc.200700237
Ring Expansion Induced by DAST: Synthesis of Substituted
3-Fluoropiperidines from Prolinols and 3-Fluoroazepanes from 2-Hydroxy-
methylpiperidines
Ingrid Déchamps,[a] Domingo Gomez Pardo,[a] and Janine Cossy*[a]
Keywords: Ring expansion / Rearrangement / Fluorine / Aziridinium / Nitrogen heterocycles
Optically active prolinols can be converted into optically
active 3-fluoropiperidines by treatment with DAST. The reac-
tion often produces 2-fluoromethylpyrrolidines as byprod-
idines to produce 3-fluoroazepanes. The rearrangement pro-
ceeds via an aziridinium intermediate.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
ucts. The ring expansion was also applied to 2-hydroxypiper- Germany, 2007)
newly formed good leaving group in D.[7] The selectivity of
the rearrangement, B versus C, depends on the substitution
on the pyrrolidine ring and the steric hindrance at the nitro-
gen atom (Scheme 1).
Introduction
The introduction of a fluorine atom in organic molecules
strongly modifies their physical, chemical and biological
properties.[1] For the past few decades, a variety of fluori-
nating reagents and methodologies have been developed to
fulfil the increasing demand for selective fluorination of or-
ganic compounds,[2] among them, N,N-bis(2-methoxy-
ethyl)aminosulfur
trifluoride,
(CH3OCH2CH2)2NSF3
(Deoxofluor)[3] and N,N-diethylaminosulfur trifluoride
(DAST)[4] have emerged as very useful reagents to convert
simple alcohols into the corresponding monofluorinated
product.[5] The fluorination of optically active alcohols by
using these reagents generally proceeds with inversion of
configuration (SN2 mechanism). Furthermore, these rea-
gents are known to initiate rearrangements through anch-
imeric assistance of an electron-rich group (methoxy,[6]
amine,[7] thioester,[8] epoxide,[9] azide,[10] double bond,[11]
aromatic ring,[12] ester,[13] amide[14]) present at a vicinal po-
sition of the reacting alcohol. These rearrangements can be
explained in terms of neighbouring group participation as
a result of the formation of a very good leaving group re-
sulting from the reaction of an alcohol moiety with DAST
or Deoxofluor. As part of our study of ring expansion of
prolinols to piperidines,[15] we would like to report here the
rearrangement of optically active prolinols of type A into
Scheme 1. Ring expansion.
Results and Discussion
Our study started with N-benzylprolinol (1).[17] This
compound was treated with DAST (1.4 equiv.) in THF at
0 °C for 1 h and then for 1 h at room temp. Under these
conditions, prolinol 1 was transformed into an inseparable
mixture of 3-fluoropiperidine 2 and 2-fluoromethylpyrrol-
idine 3 in a 57:43[18] ratio in favour of the ring-expanded
product 2 with a yield of 60% (Table 1, Entry 1).[7g] To fav-
our the formation of 3-fluoropiperidine 2, a number of dif-
ferent experimental procedures were examined, and the re-
sults are summarized in Table 1. Whatever the solvent used
(THF, CH2Cl2, cyclohexane or acetone), the ratio 2/3 did
not change (Table 1, Entries 1–4). It is worth noting that
the use of cyclohexane or acetone led to the formation of
byproducts, whereas the reaction was clean in THF and
CH2Cl2. Modifications of the reaction mixture temperature
optically active piperidines of type B by using DAST.[16]
A
nonrearranged product of type C can also be obtained. The
ring expansion is supposed to proceed via an aziridinium
intermediate of type E resulting from the intramolecular
nucleophilic substitution of the nitrogen atom onto the
[a] Laboratoire de Chimie Organique associé au CNRS, Ecole Sup-
érieure de Physique et de Chimie Industrielles de la Ville de
Paris (E.S.P.C.I.) – ParisTech, C.N.R.S.
10, rue Vauquelin, 75231 Paris Cedex 05, France
Fax: +33-0140-794-660
E-mail: janine.cossy@espci.fr.
4224
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Ring Expansion Induced by DAST
FULL PAPER
did not change the proportions of 2/3 and byproducts were
also formed under these conditions (Table 1, Entries 5 and
6). It is worth noting that an experiment was carried out in
the presence of Et3N (3.0 equiv.) to prevent the eventual
protonation of the prolinol during the ring-expansion pro-
cess. However, no significant evolution of the ratio 2/3 was
observed (Table 1, Entry 7).
Scheme 3. Rearrangement of prolinol 5.
Table 1. Influence of the experimental conditions on the ratio of
2/3.
As the presence of a silyl ether group seems to influence
the selectivity of the rearrangement, the rearrangement of
prolinols 8a–f,[19] in which the hydroxy group at C-3 or C-
4 is protected, was examined, and the results are reported
in Table 2. At first, the substitution by a tert-butyldimethyl-
silyl ether at C-4 with a trans relative relationship (prolinol
8a[15m]) was studied and, interestingly, the observed ratio
9a/10a increased to 80:20 in favour of the ring-expansion
product. The fluorinated products could be separated and
isolated in 53 and 8% yield, respectively (Table 2, Entry 1).
It is worth noting that when replaced in the ring-expansion
conditions (DAST, 1.4 equiv., 1 h at 0 °C then 1 h at room
temp.), the isolated ring-expansion product 9a was not
transformed into isomer 10a. This result shows that there
is no equilibrium between the two fluoro products in the
presence of DAST and that the reaction is controlled by
Entry Solvent
Conditions
Ratio 2/3
1
2
3
4
5
6
7
THF
1 h at 0 °C, then 1 h at room temp. 57:43
1 h at 0 °C, then 1 h at room temp. 58:42
1 h at 0 °C, then 1 h at room temp. 59:41
1 h at 0 °C, then 1 h at room temp. 55:45
CH2Cl2
Cyclohexane
Acetone
THF
1 h at 0 °C, then 4 h at 65 °C
3 h from –78 °C to room temp.
55:45
58:42
THF
THF + Et3N[a] 1 h at 0 °C, then 1 h at room temp. 56:44
[a] 3.0 equiv. of Et3N were added.
To prove that an aziridinium intermediate of type D was kinetics under these conditions.[15n] When the tert-butyldi-
involved in the formation of 2 and 3, piperidin-3-ol 4[15g] methylsilyl ether group was substituted at C-3 with a trans
was treated with DAST in THF. After 1 h at 0 °C and 1 h at relationship, as in prolinol 8b,[20] an equimolar inseparable
room temp., compounds 2 and 3 were obtained with similar mixture of 3-fluoropiperidine 9a and 2-fluoromethylpyrrol-
ratios (2/3, 57:43) and yields (55%) compared to those ob- idine 10a was obtained with a global yield of 55% (Table 2,
tained when the reaction was performed on prolinol 1. Entry 2). This result suggests that the presence of the C-
These results suggest that, in the presence of DAST, both 3 substituent does not favour the formation of the ring-
substrates were converted into the same intermediate, aziri- expansion product. To test the importance of the presence
dinium EЈ, which was previously postulated in the literature of a silyl ether group at C-4, prolinol 8c and 8d were treated
(Scheme 2).[7]
with DAST. An important decrease in the selectivity was
observed when a methoxy group is present at C-4, as pro-
linol 8c was converted into an inseparable mixture of 9c/10c
with a ratio of 55:45 and with a 55% global yield (Table 2,
Entry 3). The replacement of the methoxy group by a bulky
trityloxy group at C-4 induced an important improvement
in the selectivity, since a 75:25 ratio of 9d/10d was obtained
and 9d and 10d could be isolated in 33 and 5% yield,
respectively (Table 2, Entry 4). The presence of a silyl pro-
tecting group on the hydroxy at C-4 seems to lead to better
selectivity in favour of the rearranged fluoropiperidines
than the use of an alkyl ether group. As an increase in the
steric hindrance induced by the protecting group seems to
improve the selectivity in favour of the ring expansion, pro-
linols 8e[15m] and 8f[15m] possessing bulky silyl ether groups
at C-4 were tested under the ring-expansion conditions.
Scheme 2. Mechanism via an aziridinium intermediate.
The effect of the substituents on the prolinol ring was When triisopropylsilyloxyprolinol 8e was examined, an im-
tested and after treatment with DAST (1.4 equiv., THF, 1 h proved selectivity was obtained with a 89:11 ratio of 9e/10e
at 0 °C then 1 h at room temp.), prolinol 5 substituted by a in 75 and 9% yield, respectively (Table 2, Entry 5). The bet-
tert-butyldimethylsilyl ether at C-4 with a cis relative rela- ter result was obtained with a tert-butyldiphenylsilyl group
tionship, was converted into an inseparable mixture of 3- at C-4, as a ratio of 91:9 for 9f/10f was obtained in favour
fluoropiperidine 6 and 2-fluoromethylpyrrolidine 7 in a of the fluoropiperidine (Table 2, Entry 6). It is worth noting
75:25 ratio and in 73% yield (Scheme 3).
that similar results were obtained with Deoxofluor.
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I. Déchamps, D.Gomez Pardo, J. Cossy
FULL PAPER
Table 2. Influence of substitution at C-3 and C-4 of the pyrrolidine piperidines 9a and 9e–f were obtained as the only dia-
ring.
stereomer; this result is in favour of an aziridinium interme-
diate hypothesis.
Entry Prolinol Substituent
DAST
Ratio 9/10,
Yield [%]
Deoxofluor
Ratio 9/10,
Yield [%]
1
2
3
4
5
6
8a
8b
8c
8d
8e
8f
R1 = H
9a/10a:
9a/10a:
80:20, 53/8
60:40, 58/14
Scheme 4. Aziridinium intermediate and stereochemistry.
R2 = OTBDMS
R1 = OTBDMS 9b/10b:
50:50, 55[a]
As it seems that the rearrangement of prolinols into 3-
fluoropiperidines is sensitive to steric hindrance, the varia-
tion of the N-alkyl substituent of the prolinol was exam-
ined. The results are reported in Table 3. The presence of
the N-tert-butylmethyl group has little effect on the ring
expansion, as an inseparable mixture of fluoropiperidine
12a and fluoropyrrolidine 13a was obtained in a ratio of
60:40, which is similar to the one observed with N-benzyl-
prolinol 1 and in 54% yield (Table 3, Entry 1). In the case
of a N-methyldiphenyl substituent, prolinol 11b was trans-
formed into a mixture of 12b and 13b in a ratio of 76:24 in
favour of the ring-expanded product 12b in 71% yield
(Table 3, Entry 2). As an increase in the steric hindrance on
the nitrogen atom seems to improve the selectivity of the
reaction, N-tritylprolinol 11c[22] was treated with DAST
and N-trityl-3-fluoropiperidine 12c was obtained as the
only observed product, which was isolated in 64% yield
(Table 3, Entry 3).
R2 = H
R1 = H
9c/10c:55:45,
55[a]
R2 = OMe
R1 = H
9d/10d:
75:25, 33/5
R2 = OTr
R1 = H
9e/10e: 89:11,
75/9
R2 = OTIPS
R1 = H
9f/10f: 91:9,
61/4
9f/10f: 91:9,
53/6
R2 = OTBDPS
[a] Combined yield.
If the rearrangement of prolinol 8f proceeds via the
opening of aziridinium EЉ, a relative trans configuration be-
tween the tert-butyldiphenylsilyl ether at C-5 and the fluor-
ine at C-3 should be obtained in 9f (Scheme 4). To confirm
the configuration of the created centre, the relative relation-
ship between the silyloxy group and the fluorine atom was
established by analyzing the 1H NMR spectra of piperidine
9f and by determining the value of the coupling constants
between 3-H and the vicinal protons present at C-2 and C-
4, and by determining the value of the coupling constants
between 5-H and the vicinal protons present at C-4 and C-
6. The equatorial position of the silyl group was confirmed
Table 3. Influence of the substituent on the nitrogen.
Entry Prolinol
R
Ratio 12/13
Yield of 12+13
[%]
1
1
2
3
11a[15g]
11b
11c
CH2tBu
CHPh2
CPh3
12a+13a: 60:40
12b+13b: 76:24
12c: 100:0
54
71
64
by the signal of 5-H in the H NMR spectra, a doublet of
doublet of doublet of doublet (dddd) with two rather large
coupling constants of 8.0 and 8.0 Hz (typical of
H
axial–Haxial couplings) and two medium coupling con-
stants of 4.0 and 4.0 Hz, which correspond to the
axial–Hequatorial constants; in consequence 5-H is axial. DAST, the ring expansion was very selective as only N-
When N-alkyl-2-alkylprolinols 14a–e were treated with
H
The signal that corresponds to 3-H can be described as a alkyl-3-fluoro-3-alkylpiperidines were observed. The op-
“ddddd” with a large coupling constant of 47.7 Hz, which tically active N-tert-butylmethylprolinols 14a–c[23] were
results from the coupling of 3-H with the fluorine atom and converted into the optically active 3-fluoropiperidines 15a–
smaller coupling constants of 5.0, 5.0, 2.5, 2.5 Hz that are c, respectively (Table 4, Entries 1–3). It is worth noting that
due to Hequatorial–Haxial and Hequatorial–Hequatorial couplings. when treated with DAST in THF, prolinol 14a was con-
This analysis allowed us to attribute the (R) configuration verted into fluoropiperidine 15a in a rather low yield of
to the C-3 stereogenic centre. It is worth noting that in the 43% as a result of the volatility of fluoropiperidine 15a.
case of piperidine 9a and 9e–f, the coupling constants for When the reaction was carried out in CH2Cl2 and the distil-
the 3-H proton are too small to be calculated. Moreover, lation of the solvent was carried out at room temp., the
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Eur. J. Org. Chem. 2007, 4224–4234

Ring Expansion Induced by DAST
FULL PAPER
yield was improved to 76% (Table 4, Entry 1). Similar re- dride.[24] However, the possibility of the participation of the
sults were obtained with fluoropiperidine 15b, which could neighbouring allyl or benzyl groups cannot be excluded in
be prepared in 89% yield by using CH2Cl2 as the reaction the case of 3-fluoropiperidines 15b–d.[25]
solvent (Table 4, Entry 2). The use of Deoxofluor was also
The selective attack of the fluorine anion at the C-2 posi-
investigated on these prolinols and compounds 15a–c were tion of substituted prolinols, which leads exclusively to 3-
obtained with the same selectivity and in comparable yields fluoropiperidines, can be explained by an increase in the
(68–93%). The replacement of the N-tert-butylmethyl by an length of the C-2–N bond in the aziridinium intermediate;
N-benzyl group did not affect the selectivity as the N-ben- moreover, the presence of a quaternary centre at C-2 results
zyl-3-fluoropiperidine 15d could be obtained in 30% yield in the stabilization of a partial positive charge at C-2 corre-
as the unique product of the reaction, when prolinol 14d lated with a weakened C-2–N bond. In consequence, the
was treated with DAST (Table 4, Entry 4). After treatment cleavage of the C-2–N bond induced by the nucleophilic
of prolinol 14e[15i] with DAST, the fluorinated N-methylpi- attack of the fluoride at the more electrophilic carbon is
peridine 15e was formed in 72% yield (Table 4, Entry 5). It favoured (Scheme 5). The selectivity of the rearrangement
1
is worth noting that in each case, the H NMR spectra of when the nitrogen atom is substituted by a bulky protecting
the crude material did not show the presence of any elimi- group (Table 3, Entry 3), can also be explained in terms of
nation products. The enantiomeric purity of 3-fluoropiperi- lengthening of the C-2–N bond due to steric constraints.
dine 15c was determined by chiral HPLC. Piperidine 15c
was formed with an enantiomeric excess of 99% when the
ring expansion was realized with DAST and with an enan-
tiomeric excess of 93%, when the rearrangement was
achieved with Deoxofluor. We have to point out that we
were not able to determine the absolute configuration of
the stereogenic centres in compounds 15a–e despite our ef-
forts to crystallize the ammonium salts issued from CSA or
tartaric acid, or to functionalize 3-fluoropiperidine 15b to
obtain single crystals for X-ray diffraction. The absolute
configuration of the 3-fluoropiperidines was postulated ac-
cording to our previous results on the rearrangement of
amino alcohols in the presence of trifluoroacetic anhy-
Scheme 5. Selectivity of the ring expansion.
This ring expansion was also tested to synthesize substi-
tuted 3-fluoroazepanes from racemic 2-hydroxymethylpi-
peridines.[26] The results are reported in Table 5. When N-
benzyl-2-hydroxymethylpiperidine 16a[27] was treated with
DAST, a mixture of 3-fluoroazepane 17a and 2-fluorometh-
ylpiperidine 18a was obtained in a ratio of 70:30 with 51
and 12% yield, respectively (Table 5, Entry 1). By analogy
with the prolinols, the 2-hydroxymethylpiperidines substi-
tuted by an alkyl group at C-2 were investigated. 2-Alkyl-
2-hydroxymethylpiperidines 16b–d were transformed with
high selectivity to 3-fluoroazepanes 17b, 17c and 17d, which
were isolated, respectively, in 63, 76 and 76% yield (Table 5,
Entries 2–4).
Table 4. Influence of the substituent at C-2 of the pyrrolidine ring.
Table 5. Ring expansion applied to 2-hydroxymethylpiperidines.
Entry Prolinol
Substituents DAST
Yield [%]
(ee [%])[c]
Deoxofluor
Yield [%]
(ee [%])[c]
1
2
3
4
5
14a
14b
14c
14d
14e
R = CH2tBu 43[a]
R1 = Et
R2 = H
76[b]
68[b]
85[b]
Entry
Starting
Material
R
Ratio 17/18 Yield [%]
R = CH2tBu 66[a]
R1 = Allyl
R2 = H
89[b]
1
2
3
4
16a
16b
16c
16d
H
Et
Allyl
Bn
70:30
100:0
100:0
100:0
17a/18a: 51/12
R = CH2tBu 87[a]
93
(93)
17b: 63
17c: 76
17d: 76
R1 = Bn
R2 = H
R = Bn
R1 = Bn
R2 = H
R = Me
R1 = Et
R2 =
(99)
30[a]
72[a]
Conclusions
We have shown that DAST and Deoxofluor can induce
a stereo- and enantioselective rearrangement of prolinols to
3-fluoropiperidines with modest-to-good yield. The pres-
ence of a bulky protecting group on the nitrogen atom was
shown to improve the selectivity of the rearrangement to
OTBDMS
[a] Conditions: 1 h at 0 °C, then 1 h at room temp., THF. [b] Owing
to the volatility of the fluorinated product, CH2Cl2 was preferred
to THF. [c] The ee values were determined by comparison with the
racemate on Chiral HPLC: OJ-H, hexane, 0.3 mL/min.
Eur. J. Org. Chem. 2007, 4224–4234
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4227

I. Déchamps, D.Gomez Pardo, J. Cossy
FULL PAPER
1 H, CH2OH), 3.44 (br. s, 1 H, OH), 3.60 (d, J = 10.3 Hz, 1 H,
favour the formation of the piperidine. Selective ring expan-
sions were also observed with C-2-alkyl-substituted prolin-
ols and piperidine methanols to produce 3-alkyl-3-fluoropi-
peridines and 3-alkyl-3-fluoroazepanes.
CH2OH), 3.88 (d, J = 13.6 Hz, 1 H, CH2Ph), 7.13–7.27 (5 H, HAr
)
ppm. 13C NMR (100 MHz, CDCl3): δ = 8.2 (q, CH2CH3), 19.0 (t),
20.3 (t), 25.9 (t), 29.0 (t, C-3, C-4, C-5 and CH2CH3), 46.1 (t, C-
6), 52.7 (t, CH2Ph), 59.5 (s, C-2), 65.1 (t, CH2OH), 126.8 (d), 128.4
(d), 128.6 (d), 139.1 (s, C ) ppm. IR (film): ν = 3424, 2932, 2863,
˜
ar
1494, 1451, 1414, 1363, 1311, 1242, 1122, 1065 cm–1. MS (EI,
70 eV): m/z (%) = 233 (1) [M]+·, 203 (16), 202 (100), 112 (3), 110
(3), 92 (7), 91 (82), 65 (5), 55 (4).
Experimental Section
(N-Benzyl-2-allylpiperidin-2-yl)methanol (16c): Yield: 31% (global).
1H NMR (400 MHz, CDCl3): δ = 1.24–1.60 (5 H), 1.67 (m, 1 H,
3-H, 4-H and 5-H), 2.04 (dd, J = 13.7, 7.4 Hz, 1 H, CH2CH=CH2),
2.26 (ddd, J = 11.9, 11.9, 2.7 Hz, 1 H, 6-H), 2.56 (dd, J = 13.5,
7.8 Hz, 1 H, CH2CH=CH2), 2.62 (m, 1 H, 6-H), 3.02 (d, J =
13.6 Hz, 1 H, CH2Ph), 3.22 (d, J = 10.6 Hz, 1 H, CH2OH), 3.67
(d, J = 10.6 Hz, 1 H, CH2OH), 3.92 (d, J = 13.6 Hz, 1 H, CH2Ph),
4.97–5.06 (2 H, CH=CH2), 5.63 (dddd, J = 17.1, 9.7, 7.5, 7.5 Hz,
1 H, CH=CH2), 7.13–7.26 (5 H, HAr) ppm. 13C NMR (100 MHz,
CDCl3): δ = 20.2 (t), 25.9 (t), 30.1 (t), 31.7 (t, C-3, C-4, C-5 and
CH2CH=CH2), 46.3 (t, C-6), 52.9 (t, CH2Ph), 59.5 (s, C-2), 65.5
(t, CH2OH), 117.9 (t, CH=CH2), 126.9 (d), 128.4 (d), 128.5 (d,
General Procedures: DAST and Deoxofluor are commercially avail-
able from Aldrich and were used as received. Solvents were dis-
tilled. Dry THF and Et2O were obtained by distillation from so-
dium and benzophenone; CH2Cl2 was dried by distillation from
CaH2. TLC was performed on Merck 60F254 silica gel plates and
visualized either with a UV lamp (254 nm) or by using a solution
of KMnO4/K2CO3/NaOH in water followed by heating. Flash
chromatography was performed with Merck Geduran Si60 silica
gel (40–63 µm). Infrared (IR) spectra were recorded with a Bruker
TENSOR 27 (IRFT). 1H NMR spectra at 400 MHz and 13C NMR
at 100 MHz were recorded with a Bruker AVANCE 400. 1H NMR
spectra at 300 MHz and 13C NMR at 75 MHz were recorded with
a Bruker AC 300. 1H NMR data are reported as follows: chemical
shift in ppm from SiMe4 as an internal standard, multiplicity (s =
singlet, d = doublet, t = triplet, q = quartet, m = multiplet or
overlap of nonequivalent resonances) and integration. 13C NMR
data are reported as follows: chemical shift in ppm from SiMe4
with the solvent as an internal indicator (CDCl3 δ 77.0 ppm), multi-
plicity with respect to proton (deduced from DEPT experiments, s
= quaternary C, d = CH, t = CH2, q = CH3). Mass spectra with
electronic impact (EI) were recorded with a Hewlett–Packard tan-
dem 5890A GC (12 m capillary column) – 5971 MS (70 eV). Mass
spectra with chemical ionization (CI) and high resolution mass
spectra (HRMS) were performed by the Centre de Spectrochimie
Organique de l’Ecole Normale Supérieure Ulm (Paris). Optical ro-
tations were measured with a Perkin–Elmer 343 polarimeter in a
10-cm cell.
CAr), 133.8 (d, CH=CH ), 139.5 (s, C ) ppm. IR (film): ν = 3424,
˜
2
ar
2931, 2861, 2800, 1637, 1603, 1493, 1450, 1413, 1311, 1122,
1051 cm–1. MS (EI, 70 eV): m/z (%) = 244 (1) [M – 1]+, 215 (9),
214 (53), 205 (10), 204 (69), 92 (8), 91 (100), 65 (6), 55 (3). HRMS:
calcd. for C17H24O2N [M + H]+ 246.1852; found 246.1852.
(N-Benzyl-2-benzylpiperidin-2-yl)methanol (16d): Yield: 12%
1
(global). H NMR (400 MHz, CDCl3): δ = 1.36–1.52 (2 H), 1.58–
1.74 (4 H, 3-H, 4-H and 5-H), 2.49 (ddd, J = 12.2, 12.2, 2.3 Hz, 1
H, 6-H), 2.70 (d, J = 13.2 Hz, 1 H, CH2Ph), 2.79 (m, 1 H, 6-H),
3.10 (d, J = 10.5 Hz, 1 H, CH2OH), 3.18 (d, J = 13.2 Hz, 1 H,
CH2Ph), 3.22 (d, J = 13.5 Hz, 1 H, N-CH2Ph), 3.90 (d, J = 10.5 Hz,
1 H, CH2OH), 4.16 (d, J = 13.5 Hz, 1 H, N-CH2Ph), 7.13–7.37 (10
H, Har) ppm. 13C NMR (100 MHz, CDCl3): δ = 20.6 (t), 25.9 (t),
29.1 (t, C-3, C-4, C-5), 32.9 (t, CH2Ph), 46.3 (t, C-6), 52.9 (t, N-
CH2Ph), 60.5 (s, C-2), 65.3 (t, CH2OH), 126.3 (d), 127.0 (d), 128.2
(d), 128.5 (d), 128.6 (d), 130.1 (d), 137.7 (s), 139.4 (s, CAr) ppm. IR
General Procedure for the Synthesis of N-Benzyl-2-hydroxymethyl-
piperidines 16b-d: To a solution of N-benzylpiperidine-2-carboxylic
acid methyl ester (4.3 mmol, 1.0 equiv.) in THF (20 mL), cooled to
–78 °C, was added LDA (1 , 4.7 mL, 4.7 mmol, 1.1 equiv.) drop-
wise, followed by, after 20 min, the alkyl halide. The mixture tem-
perature was then allowed to rise slowly over 3 h till room temp.,
and the reaction was quenched by the addition of water (20 mL).
The aqueous phase was extracted with AcOEt (2ϫ40 mL). The
organic phase was dried with Na2SO4, and the solvents were evapo-
rated in vacuo. After purification by flash chromatography (cyclo-
hexane/AcOEt, 90:10), the obtained alkylated piperidines in a solu-
tion of THF (10 mL) were added cautiously at 0 °C to a suspension
of LiAlH4 (2 equiv.) in THF (10 mL). After 2 h at room temp., the
reaction mixture was cooled to 0 °C and quenched cautiously with
a saturated solution of sodium potassium tartrate (10 mL). The
aqueous phase was extracted with Et2O (3ϫ20 mL). The organic
phase was dried with Na2SO4, and the solvents were evaporated in
vacuo. After purification by flash chromatography (cyclohexane/
AcOEt, 90:10), piperidine methanols 16b–d were isolated as colour-
less oil.
(film): ν = 3389, 3028, 2931, 2853, 1492, 1448, 1305, 1127,
˜
1037 cm–1. MS (EI, 70 eV): m/z (%) = 277 (16), 264 (19) [M –
CH2OH]+, 263 (7), 205 (11), 204 (77), 186 (22), 92 (10), 91 (100),
65 (8). HRMS: calcd. for C20H26ON [M + H]+ 296.2008; found
296.2008.
General Procedure for the Ring Expansion Induced by DAST: To a
solution of prolinol (0.5 mmol) in THF or CH2Cl2 (5 mL), cooled
to 0 °C, was added DAST (0.7 mmol, 1.4 equiv.) dropwise. After
1 h at 0 °C and 1 h at room temp., the reaction mixture was cooled
to 0 °C and quenched with a saturated solution of NaHCO3
(10 mL). The aqueous phase was extracted with AcOEt
(2ϫ20 mL). The organic phase was dried with Na2SO4, and the
solvents were evaporated in vacuo.
(R)-N-Benzyl-3-fluoropiperidine (2)[7g] and (S)-N-Benzyl-2-fluoro-
methylpyrrolidine (3):[7g] Following the general procedure, prolinol
1[17] {100 mg, 0.52 mmol, 1.0 equiv., [α]2D0 = –57.4 (c = 1.56,
CHCl3)} was treated with DAST (96 µL, 0.78 mmol, 1.4 equiv.) in
THF (5 mL). After purification by flash chromatography on silica
gel (cyclohexane/AcOEt, 95:5), fluoro compounds 2 and 3 (60 mg,
0.31 mmol, 60%) were obtained as an inseparable mixture. Data
(N-Benzyl-2-ethylpiperidin-2-yl)methanol (16b): Yield: 21%
(global). 1H NMR (400 MHz, CDCl3): δ = 0.76 (dd, J = 7.7,
7.7 Hz, 3 H, CH2CH3), 1.22–1.40 (3 H), 1.42–1.55 (3 H), 1.61 (m,
1
for a mixture of 2+3: H NMR (400 MHz, CDCl3): δ = 1.46–1.98
(4 H2 and 4 H3, 4-H2, 5-H2, 3-H3, and 4-H3), 2.19–2.32 (1 H2 and
1 H, 3-H, 4-H, 5-H and CH2CH3), 1.83 (dq, J = 13.8, 7.7 Hz, 1 H, 1 H3, 5-H3 and 6-H2), 2.36 (ddd, J = 8.1, 7.0, 7.0 Hz, 1 H2, 2-H),
CH2CH3), 2.26 (ddd, J = 11.8, 11.8, 3.0 Hz, 1 H, 6-H), 2.60 (m, 1
H, 6-H), 3.00 (d, J = 13.6 Hz, 1 H, CH2Ph), 3.28 (d, J = 10.3 Hz,
2.49 (m, 1 H2, 6-H), 2.78 (m, 1 H2, 2-H), 2.88 (m, 1 H3, 2-H), 2.94
(m, 1 H3, 5-H), 3.48 (d, J = 13.1 Hz, 1 H3, CH2-Ph), 3.54 (s, 2 H2,
4228
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© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 4224–4234

Ring Expansion Induced by DAST
FULL PAPER
N-CH2-Ph), 4.03 (d, J = 13.1 Hz, 1 H3, CH2-Ph), 4.20–4.40 (2 H3,
2Ј-H3), 4.60 (ddddd, J = 48.1, 7.7, 7.7, 3.8, 3.8 Hz, 1 H2, 3-H2),
(100 MHz, CDCl3): δ = –4.8 (q, Si-Me), –4.8 (q, Si-Me), 18.1 (s,
Si-CMe3), 25.8 (q, Si-CMe3), 38.8 (dt, J = 20.2 Hz, C-4), 56.1 (dt,
J = 20.2 Hz, C-2), 60.2 (t, C-6), 62.3 (t, CH2Ph), 65.1 (d, C-5), 87.9
(dd, J = 171.2 Hz, C-3), 127.1 (d), 128.2 (d), 129.0 (d), 137.5 (s,
7.20–7.27 (1 H2 and 1 H3, HAr), 7.27–7.35 (4 H2 and 4 H3, HAr
)
ppm. 13C NMR (100 MHz, CDCl3): δ = 22.2 (dt, J = 8 Hz, C2-5),
23.1 (t, C3-4), 27.3 (dt, C3-3), 30.2 (dt, J = 19 Hz, C2-4), 52.9 (t,
CAr) ppm. IR (neat): ν = 2921, 1460, 1252, 1153, 1090 cm–1. MS
˜
C3-5), 54.7 (t, C2-6), 57.6 (dt, J = 23 Hz, C2-2), 59.7 (t, CH2 -Ph),
(EI, 70 eV): m/z (%) = 323 (2) [M]+·, 308 (3), 266 (31), 246 (4), 191
3
62.6 (dd, J = 20 Hz, C3-2), 62.9 (t, CH2 -Ph), 86.1 (dt, J = 169 Hz, (4), 134 (11), 92 (9), 91 (100), 75 (4), 73 (10). HRMS: calcd. for
2
C3-2Ј), 88.3 (dd, J = 170 Hz, C2-3), 127.0 (d), 127.1 (d), 128.2 (d), C18H31NFOSi [M + H]+ 324.2154; found 324.2151. Data for 10a:
[α]2D0 = –16.8 (c = 0.62, CHCl3). H NMR (400 MHz, CDCl3): δ =
0.00 (s, 6 H, SiMe), 0.85 (s, 9 H, tBu), 1.81–1.88 (2 H, 3-H), 2.30
(m, 1 H, 5-H), 3.06–3.20 (2 H, 2-H and 5 H), 3.52 (m, 1 H, CH2Ph),
4.00 (m, 1 H, CH2Ph), 4.21–4.38 (3 H, 4-H, 2Ј-H), 7.19–7.32 (5 H,
1
128.9 (d), 129.1 (d), 137.9 (s), 139.5 (s, CAr) ppm. IR (film): ν =
˜
3028, 2945, 2799, 1495, 1453, 1375, 1349, 1263, 1156, 1105, 1073,
1018, 988 cm–1. Data for 2: MS (EI, 70 eV): m/z (%) = 193 (44)
[M]+·, 192 (42), 172 (2), 160 (2), 146 (6), 132 (4), 117 (6), 116 (54),
102 (45), 92 (19), 91 (100), 89 (4), 73 (3), 65 (16), 55 (5), 51 (3). HAr) ppm. 13C NMR (100 MHz, CDCl3): δ = –4.8 (q, SiMe), 18.0
Data for 3: MS (EI, 70 eV): m/z (%) = 193 (13) [M]+·, 192 (9), 161
(9), 160 (65), 146 (2), 130 (2), 116 (14), 102 (10), 92 (11), 91 (100), 61.8 (dd, J = 19 Hz, C-2), 62.5 (t, C-5), 70.3 (d, C-4), 85.8 (dt, J =
(s, CMe3), 25.8 (q, CMe3), 37.5 (dt, J = 4 Hz, C-3), 59.9 (t, CH2Ph),
89 (3), 74 (3), 65 (13), 59 (2), 51 (3).
169 Hz, C-2Ј), 127.0 (d), 128.3 (d), 128.8 (d), 139.3 (s, CAr) ppm.
IR (film): ν = 2954, 2929, 2857, 1471, 1455, 1381, 1255, 1119, 1030,
˜
(3S,5R)-N-Benzyl-5-(tert-butyldimethylsilanyloxy)-3-fluoropiper-
idine (6) and (2R,4R)-N-Benzyl-4-(tert-butyldimethylsilanyloxy)-2-
fluoromethylpyrrolidine (7): Following the general procedure, proli-
nol 5[21] {150 mg, 0.47 mmol, 1.0 equiv., [α]2D0 = +42.3 (c = 1.22,
CHCl3)} was treated with DAST (86 µL, 0.65 mmol, 1.4 equiv.) in
THF (5 mL). After purification by flash chromatography on silica
gel (cyclohexane/Et2O, 98:2), fluoro compounds 6 and 7 were ob-
1008, 913 cm–1. MS (EI, 70 eV): m/z (%) = 308 (3), 292 (6), 291
(24), 290 (100) [M – CH2F]+, 266 (8), 158 (11), 92 (6), 91 (86), 75
(12), 74 (14), 56 (8). HRMS: calcd. for C18H31NFOSi [M + H]+
324.2154; found 324.2154.
(3S,4S)-N-Benzyl-4-(tert-butyldimethylsilanyloxy)-3-fluoropiper-
idine (9b) and (2S,3S)-N-Benzyl-3-(tert-butyldimethylsilanyloxy)-2-
fluoromethylpyrrolidine (10b): Following the general procedure,
tained as an inseparable mixture (100 mg, 0.31 mmol, 73%). Data
for a mixture of 6+7: H NMR (400 MHz, CDCl3): δ = –0.03 (3 prolinol 8b[19] {24 mg, 0.07 mmol, 1.0 equiv., [α]2D0 = –9.3 (c = 1.22,
1
H7, Si-Me), –0.01 (3 H7, Si-Me), 0.00 (3 H6, Si-Me), 0.02 (3 H6, CHCl3)} was treated with DAST (15 µL, 0.10 mmol, 1.4 equiv.) in
Si-Me), 0.80–0.86 (9 H6 and 9 H7, tBu6 and tBu7), 1.10 (dd, J =
THF (5 mL). After purification by flash chromatography on silica
14.8, 7.1 Hz, 1 H7, 3-H), 1.39 (m, 1 H6, 4-H), 1.60 (m, 1 H7, 3-H), gel (cyclohexane/AcOEt, 95:5), fluoro compounds 9b and 10b were
1.80–1.95 (2 H6, 4-H and 6-H), 2.15 (m, 1 H7, 5-H), 2.35 (m, 1 H6,
2-H), 2.48 (m, 1 H7, 5-H), 2.81–2.88 (1 H6 and 1 H7, 6-H6 and 2-
H7), 3.00 (m, 1 H7, 4-H), 3.05 (m, 1 H6, 2-H), 3.50 (d, J = 13.2 Hz,
1 H6, CH2Ph), 3.53 (d, J = 13.5 Hz, 1 H7, CH2Ph), 3.62 (d, J =
obtained as an inseparable mixture (12 mg, 0.38 mmol, 55%). Data
for a mixture of 9b+10b: 1H NMR (400 MHz, CDCl3): δ = –0.01–
0.02 (6 H9b and 6 H10b, Si-Me9b and Si-Me10b), 0.81–0.84 (9 H9b
and 9 H10b, tBu9b and tBu10b), 1.49–1.64 (1 H9b and 1 H10b, 5-H9b
13.2 Hz, 1 H6, CH2Ph), 3.72 (m, 1 H6, 5-H), 4.01 (d, J = 13.6 Hz, and 4-H10b), 1.76–1.88 (1 H9b and 1 H10b, 5-H9b and 4-H10b), 2.06
1 H7, CH2Ph), 4.24–4.62 (1 H6 and 2 H7, 3-H6 and 2Ј-H7), 7.18– (ddd, J = 10.8, 10.8, 3.0 Hz, 1 H9b, 6-H), 2.16 (m, 1 H9b, 2-H), 2.54
7.34 (5 H6 and 5 H7, HAr) ppm. 13C NMR (100 MHz, CDCl3): δ (m, 1 H10b, 5-H), 2.69–2.58 (1 H9b and 1 H10b, 6-H9b and 2-H10b),
6
7
= –4.8 (q, Si-Me7), –4.8 (q, Si-Me6), 18.1 (s, CMe3 and CMe3 ),
2.83 (m, 1 H10b, 5-H), 2.91 (m, 1 H9b, 2-H), 3.46 (d, J = 13.1 Hz,
1 H9b, CH2Ph), 3.49 (d, J = 13.1 Hz, 1 H9b, CH2Ph), 3.52 (d, J =
25.8 (q, CMe3 ), 25.8 (q, CMe3 ), 37.8 (dt, J = 5 Hz, C7-3), 41.1
6
7
(dt, J = 18 Hz, C6-4), 56.6 (dt, J = 26 Hz, C6-2), 59.3 (t), 60.3 (t), 13.1 Hz, 1 H10b, CH2Ph), 3.58 (m, 1 H9b, 4-H), 3.93 (d, J = 13.1 Hz,
61.8 (dd, J = 61.8 Hz, C7-2), 62.1 (t), 62.3 (t), 66.3 (dd, J = 15 Hz,
C6-5), 71.0 (d, C7-4), 86.6 (dt, J = 169 Hz, -C7-2Ј), 86.8 (dd, J =
171 Hz, C6-3), 126.8 (d), 127.2 (d), 128.2 (d), 128.3 (d), 128.6 (d),
1 H10b, CH2Ph), 4.37–4.08 (1 H9b and 3 H10b, 3-H9b, 3-H10b and
2Ј-H10b), 7.15–7.29 (5 H9b and 5 H10b, HAr) ppm. 13C NMR
(100 MHz, CDCl3): δ = –4.8 (q), –4.7 (q), –4.7 (q), –4.6 (q, Si-
9b
128.9 (d), 137.6 (s), 139.3 (s, CAr) ppm. IR (film): ν = 2954, 2929,
Me9b and Si-Me10b), 18.0 (s), 18.1 (s, CMe3 and CMe310b), 25.8
˜
9b
2857, 1471, 1383, 1256, 1178, 1148, 1105, 1020 cm–1. Data for 6:
(q, CMe3 and CMe310b), 32.0 (t, C9b-5), 33.5 (t, C10b-4), 50.3 (t,
MS (EI, 70 eV): m/z (%) = 323 (2), 267 (7), 266 (35), 246 (5), C9b-6), 51.9 (t, C10b-5), 54.8 (dt, J = 23 Hz, C9b-2), 59.9 (t, CH2
-
10b
134 (11), 92 (9), 91 (100), 73 (9). Data for 7: m/z (%) = 323 (1), Ph), 62.4 (t, CH29b-Ph), 70.4 (d, C10b-2), 72.0 (dd, J = 19 Hz, C9b-
291 (15), 290 (58), 266 (21), 158 (7), 92 (8), 91 (100), 74 (8),
73 (8).
4), 73.8 (d, C10b-3), 83.4 (dt, J = 171 Hz, C10b-2Ј), 91.9 (dd, J =
171 Hz, C9b-3), 127.0 (d), 127.1 (d), 127.9 (d), 128.3 (d), 128.9 (d),
129.0 (d), 138.0 (s), 139.3 (s, CAr) ppm. IR (film): ν = 3057, 2935,
˜
(3R,5R)-N-Benzyl-5-(tert-butyldimethylsilanyloxy)-3-fluoropiper-
idine (9a) and (2S,4R)-N-Benzyl-4-(tert-butyldimethylsilanyloxy)-2-
fluoromethylpyrrolidine (10a): Following the general procedure,
prolinol 8a[15m] {500 mg, 1.56 mmol, 1.0 equiv., [α]2D0 = – 51.1 (c =
1.14, CHCl3)} was treated with DAST (245 µL, 2.18 mmol,
1.4 equiv.) in THF (15 mL). After purification by preparative TLC
on silica gel (cyclohexane/AcOEt, 95:5), fluoropiperidine 9a
(265 mg, 0.82 mmol, 53 %) and fluoromethylpyrrolidine 10a
(39 mg, 0.12 mmol, 8%) were isolated as a white solid and a yellow
oil, respectively. Data for 9a: M.p. 43 °C. [α]2D0 = –6.7 (c = 0.135,
CHCl3). 1H NMR (400 MHz, CDCl3): δ = 0.01 (s, 3 H, Si-Me),
0.03 (s, 3 H, Si-Me), 0.83 (s, 9 H, tBu), 1.51 (m, 1 H, 4-H), 1.99–
1596, 1490, 1448, 1375, 1213, 1185, 1070, 1035, 1004 cm–1. Data
for 9b: MS (EI, 70 eV): m/z (%) = 323 (4) [M]+·, 302 (4), 290 (4),
267 (10), 266 (48), 232 (9), 172 (8), 147 (12), 92 (9), 91 (100), 77
(8), 75 (5). Data for 10b: MS (EI, 70 eV): m/z (%) = 323 (3) [M]+·,
291 (14), 290 (58), 267 (7), 266 (30), 232 (7), 172 (6), 147 (9), 92
(9), 91 (100), 77 (8), 75 (8), 74 (13), 75 (6).
(3R,5R)-N-Benzyl-3-fluoro-5-methoxypiperidine (9c) and (2S,4S)-N-
Benzyl-2-fluoromethyl-4-methoxypyrrolidine (10c): Following the
general procedure, prolinol 8c {11 mg, 0.05 mmol, 1.0 equiv., [α]2D0
= +33.5 (c = 1.34, CHCl3)} was treated with DAST (9 µL,
0.07 mmol, 1.4 equiv.) in THF (3 mL). After purification by flash
2.29 (m, 3 H, 2-H, 4-H and 6-H), 2.79–2.92 (m, 2 H, 2-H and 6- chromatography on silica gel (cyclohexane/AcOEt, 95:5), fluoro
H), 3.52 (d, J = 13.4 Hz, 1 H, CH2Ph), 3.64 (d, J = 13.4 Hz, 1 H, compounds 9c and 10c were obtained as an inseparable mixture
1
CH2Ph), 4.06 (dddd, J = 9.5, 9.5, 4.5, 4.5 Hz, 1 H, 5-H), 4.80 (dm, (6 mg, 0.03 mmol, 55%). Data for a mixture of 9c+10c: H NMR
J = 47.2 Hz, 1 H, 3-H), 7.15–7.40 (5 H, HAr) ppm. 13C NMR (400 MHz, CDCl3): δ = 1.57–1.70 (1 H9c and 1 H10c, 4-H9c and 3-
Eur. J. Org. Chem. 2007, 4224–4234
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4229

I. Déchamps, D.Gomez Pardo, J. Cossy
FULL PAPER
H10c), 1.83 (dd, J = 10.3, 9.7 Hz, 1 H9c, 6-H), 2.00 (ddd, J = 9.9,
(400 MHz, CDCl3): δ = 0.95–1.09 (21 H, CHMe3 and CHMe3),
9.9, 5.4 Hz, 1 H9c, 4-H), 2.15 (m, 1 H10c, 3-H), 2.30 (dd, J = 10.8, 1.53 (m, 1 H, 4-H), 2.02 (dd, J = 9.6, 9.6 Hz, 1 H, 6-H), 2.16–2.32
5.2 Hz, 1 H10c, 5-H), 2.43 (m, 1 H10c, 5-H), 2.80–3.03 (1 H10c and (2 H, 2-H and 4-H), 2.87–2.96 (2 H, 2-H and 6-H), 3.60 (s, 2 H,
3 H9c, 2-H9c, 6-H9c and 2-H10c), 3.17 (s, 3 H10c, OMe), 3.22–3.31
(4 H9c, 5-H9c and OMe9c), 3.41 (d, J = 13.3 Hz, 1 H10c, CH2Ph),
3.51 (d, J = 13.2 Hz, 1 H9c, CH2Ph), 3.56 (d, J = 13.2 Hz, 1 H9c,
CH2Ph), 4.16 (dddd, J = 8.9, 8.9, 4.3, 4.3 Hz, 1 H, 5-H), 4.84 (dm,
J = 47.5 Hz, 1 H, 3-H), 7.22–7.34 (5 H, HAr) ppm. 13C NMR
(100 MHz, CDCl3): δ = 12.2 (d, CHMe3), 18.0 (q, CH-Me), 39.1
(dt, J = 20 Hz, C-4), 56.1 (dt, J = 20 Hz, C-2), 60.4 (t, C-6), 62.3
(t, CH2Ph), 65.1 (d, C-5), 88.0 (dd, J = 170 Hz, C-3), 127.1 (d),
CH2Ph), 3.75 (m, 1 H10c, 4-H), 4.00 (d, J = 13.3 Hz, 1 H10c
,
CH2Ph), 4.32 (ddd, J = 47.4, 9.4, 5.3 Hz, 1 H10c, 2Ј-H), 4.38 (m, 1
H10c, 2Ј-H), 4.51 (dm, J = 48.8 Hz, 1 H9c, 3-H), 7.14–7.29 (5 H9c 128.2 (d), 129.1 (d), 137.6 (s, CAr) ppm. IR (film): ν = 2942, 2865,
˜
and 5 H10c, HAr) ppm. 13C NMR (100 MHz, CDCl3): δ = 33.2 (t, 2800, 1462, 1383, 1248, 1155, 1102, 1068, 975 cm–1. MS (EI, 70 eV):
C10c-3), 36.0 (dt, J = 18 Hz, C9c-4), 55.5 (q, OMe9c and OMe10c),
m/z (%) = 365 (10) [M]+·, 322 (48), 192 (14), 172 (6), 134 (8), 120
(5), 92 (9), 91 (100). HRMS: calcd. for C28H35NFOSi [M + H]+,
366.2623; found 366.2623. Data for 10e: [α]2D0 = –40.7 (c = 0.27,
CHCl3). 1H NMR (400 MHz, CDCl3): δ = 1.01–1.04 (21 H,
CHMe3 and CHMe3), 1.88–1.93 (2 H, 3-H), 2.38 (dd, J = 9.8,
5.5 Hz, 1 H, 5-H), 3.11–3.24 (2 H, 2-H and 5-H), 3.57 (d, J =
13.2 Hz, 1 H, CH2Ph), 4.03 (d, J = 13.2 Hz, 1 H, CH2Ph), 4.24–
4.43 (3 H, 4-H, 2Ј-H), 7.21–7.34 (5 H, HAr) ppm. 13C NMR
55.7 (t, C10c-5 or C9c-6), 55.8 (dt, J = 14 Hz, C9c-2), 56.1 (t, C10c
-
5 or C9c-6), 58.1 (t, CH2 -Ph), 60.8 (dd, J = 20 Hz, C10c-2), 61.3
10c
9c
(t, CH2 -Ph), 73.2 (dd, J = 13 Hz, C9c-5), 78.3 (d, C10c-4), 85.9
(dt, J = 169 Hz, C10c-2Ј), 85.8 (dd, J = 172 Hz, C9c-3), 126.0 (d),
126.3 (d), 127.2 (d), 127.3 (d), 127.9 (d), 128.0 (d), 136.5 (s), 137.6
(s) (CAr) ppm. IR (film): ν = 2944, 2818, 1495, 1454, 1381, 1263,
˜
1179, 1149, 1102, 1028 cm–1. MS (EI, 70 eV): m/z (%) = 223 (5)
[M]+·, 222 (4), 208 (4), 193 (6), 190 (13), 178 (6), 146 (7), 134 (8), (100 MHz, CDCl3): δ = 11.9 (d, CHMe3), 17.8 (q, CHMe3), 37.8
132 (7), 120 (9), 92 (10), 91 (100), 65 (10).
(dt, J = 5 Hz, C-3), 59.8 (t, CH2Ph), 61.7 (dd, J = 19 Hz, C-2),
62.8 (t, C-5), 70.4 (d, C-4), 85.7 (dt, J = 170 Hz, C-2Ј), 126.8 (d),
(3R,5R)-N-Benzyl-3-fluoro-5-trityloxypiperidine (9d) and (2S,4R)-
N-Benzyl-4-trityloxy-2-fluoromethylpyrrolidine (10d): Following the
general procedure, prolinol 8d {134 mg, 0.30 mmol, 1.0 equiv.,
[α]2D0 = –14.4 (c = 0.65, CHCl3)} was treated with DAST (56 µL,
0.42 mmol, 1.4 equiv.) in CH2Cl2 (10 mL). After purification by
preparative TLC on silica gel (cyclohexane/AcOEt, 95:5), fluoropi-
peridine 9d (40 mg, 0.09 mmol, 33%) and fluoromethylpyrrolidine
10d (9 mg, 0.02 mmol, 5%) were isolated. Data for 9d: [α]2D0 = +26.5
(c = 0.26, CHCl3). 1H NMR (400 MHz, CDCl3): δ = 1.34 (m, 1 H,
4-H), 1.45 (m, 1 H, 4-H), 1.59 (m, 1 H, 6-H), 2.06 (m, 1 H, 6-H),
2.19 (ddd, J = 32.1, 12.5, 2.0 Hz, 1 H, 2-H), 2.66 (ddd, J = 11.5,
11.5, 4.0 Hz, 1 H, 2-H), 3.30 (s, 2 H, CH2Ph), 3.89 (dddd, J = 8.0,
8.0, 4.0, 4.0 Hz, 1 H, 5-H), 4.66 (dm, J = 46.8 Hz, 1 H, 3-H), 7.09–
7.24 (14 H, HAr), 7.34–7.41 (6 H, HAr) ppm. 13C NMR (100 MHz,
CDCl3): δ = 36.8 (dt, J = 20 Hz, C-4), 56.3 (dt, J = 21 Hz, C-2),
58.2 (t), 62.2 (t, C-6 and CH2Ph), 66.9 (d, C-5), 77.3 (s, CPh3), 87.9
(dd, J = 175 Hz, C-3), 127.0 (d), 127.8 (d), 128.2 (d), 128.7 (d),
128.2 (d), 128.7 (d), 139.1 (s, CAr) ppm. IR (film): ν = 2942, 2865,
˜
1495, 1463, 1382, 1246, 1119, 1053, 1013 cm–1. MS (EI, 70 eV):
m/z (%) = 365 (3) [M]+·, 333 (6), 332 (25), 323 (8), 322 (27), 192
(9), 134 (6), 92 (8), 91 (100), 77 (5), 75 (6). HRMS: calcd. for
C13H25NF [M + H]+ 366.2620; found 366.2620.
(3R,5R)-N-Benzyl-3-(tert-butyldiphenylsilanyloxy)-5-fluoropiper-
idine (9f) and (2S,4R)-N-Benzyl-4-(tert-butyldiphenylsilanyloxy)-2-
fluoromethylpyrrolidine (10f): Following the general procedure, pro-
linol 8f[15m] {129 mg, 0.29 mmol, 1.0 equiv., [α]2D0 = –6.8 (c = 0.81,
CHCl3)} was treated with DAST (57 µL, 0.41 mmol, 1.4 equiv.) in
THF (10 mL). After purification by preparative TLC on silica gel
(cyclohexane/AcOEt, 90:10), fluoropiperidine 9f (78 mg,
0.18 mmol, 61 %) and fluoromethylpyrrolidine 10f (6 mg,
0.013 mmol, 4%) were isolated. Data for 9f: [α]2D0 = +37.6 (c = 0.35,
1
CHCl3). H NMR (400 MHz, CDCl3): δ = 1.04 (s, 9 H, tBu), 1.67
(m, 1 H, 4-H), 1.98 (m, 1 H, 4-H), 2.15 (m, 1 H, 6-H), 2.40 (ddd,
J = 29.1, 12.1, 2.0 Hz, 1 H, 2-H), 2.58–2.74 (m, 2 H, 2-H and 6-
H), 3.50 (s, 2 H, CH2Ph), 4.13 (dddd, J = 8.0, 8.0, 4.0, 4.0 Hz, 1
H, 5-H), 4.83 (ddddd, J = 47.7, 5.0, 5.0, 2.5, 2.5 Hz, 1 H, 3-H),
7.21–7.43 (11 H, HAr), 7.65–7.58 (4 H, HAr) ppm. 13C NMR
(100 MHz, CDCl3): δ = 19.2 (s, CMe3), 27.0 (q, CMe3), 38.5 (dd,
J = 20 Hz, C-4), 56.3 (dt, J = 21 Hz, C-2), 59.6 (t, C-6), 62.2 (t,
CH2Ph), 66.2 (dd, J = 3 Hz, C-5), 87.7 (dd, J = 170 Hz, C-3), 127.1
(d), 127.6 (d), 127.7 (d), 128.2 (d), 129.0 (d), 129.6 (d), 129.7 (d),
128.8 (d), 129.0 (d), 137.6 (s), 144.9 (s) (CAr) ppm. IR (film): ν =
˜
2921, 2852, 1597, 1491, 1448, 1151, 1059, 1029 cm–1. MS (CI,
CH4): m/z (%) = 452 (100) [M + H]+, 432 (20), 271 (9), 244 (23),
244 (86), 210 (19), 208 (14), 192 (28), 167 (17), 127 (9). HRMS:
calcd. for C31H31NFO [M + H]+ 452.2390; found 452.2392. Data
for 10d: [α]2D0 = –40.7 (c = 0.27, CHCl3). 1H NMR (400 MHz,
CDCl3): δ = 1.54–1.66 (2 H, 3-H), 2.14 (dd, J = 9.7, 6.9 Hz, 1 H,
5-H), 2.50 (dd, J = 9.7, 6.2 Hz, 1 H, 5-H), 2.96 (m, 1 H, 2-H), 3.38
(d, J = 13.0 Hz, 1 H, CH2Ph), 3.92 (d, J = 13.0 Hz, 1 H, CH2Ph),
4.06–4.26 (3 H, 4-H and 2Ј-H), 7.15–7.30 (14 H, HAr), 7.40–7.48
(6 H, HAr) ppm. 13C NMR (100 MHz, CDCl3): δ = 34.9 (dt, J =
5 Hz, C-3), 59.2 (t), 60.3 (t, C-5 and CH2Ph), 61.3 (dd, J = 19 Hz,
C-2), 71.9 (d, C-4), 85.6 (dt, J = 169 Hz, C-2Ј), 87.1 (s, CPh3), 126.9
(d), 127.0 (d), 127.8 (d), 128.1 (d), 128.7 (d), 128.9 (d), 138.7 (s),
134.2 (s), 134.0 (s), 135.7 (d), 137.6 (s, CAr) ppm. IR (film): ν =
˜
3069, 2930, 2856, 2800, 1588, 1471, 1427, 1360, 1154, 1105,
1027 cm–1. MS (EI, 70 eV): m/z (%) = 447 (1) [M]+·, 392 (7), 391
(27), 390 (82), 201 (8), 199 (10), 192 (7), 191 (6), 183 (9), 181 (6),
170 (5), 135 (7), 92 (8), 91 (100). HRMS: calcd. for C28H35NFOSi
[M + H]+ 448.2472; found 448.2473. Data for 10f: [α]2D0 = –3.2 (c
= 0.16, CHCl3). 1H NMR (400 MHz, CDCl3): δ = 1.05 (s, 9 H,
CMe3), 1.68 (m, 1 H, 3-H), 1.92 (ddd, J = 12.8, 8.2, 4.4 Hz, 1 H,
3-H), 2.48 (dd, J = 10.0, 5.0 Hz, 1 H, 5-H), 3.03 (dd, J = 10.0,
144.8 (s, CAr) ppm. IR (film): ν = 3059, 3028, 2942, 2799, 1597,
˜
1492, 1449, 1379, 1219, 1153, 1058, 1029 cm–1. HRMS: calcd. for
C31H31NFO [M + H]+ 452.2384; found 452.2384.
(3R,5R)-N-Benzyl-3-fluoro-5-triisopropylsilanyloxypiperidine (9e) 5.5 Hz, 1 H, 5-H), 3.22 (m, 1 H, 2-H), 3.60 (d, J = 13.2 Hz, 1 H,
and (2S,4R)-N-Benzyl-4-triisopropylsilanyloxy-2-fluoromethylpyr-
rolidine (10e): Following the general procedure, prolinol 8e[15m]
{232 mg, 0.64 mmol, 1.0 equiv., [α]2D0 = –26.4 (c = 0.73, CHCl3)}
was treated with DAST (116 µL, 0.89 mmol, 1.4 equiv.) in CH2Cl2
(10 mL). After purification by preparative TLC on silica gel (cyclo-
hexane/Et2O, 90:10), fluoropiperidine 9e (175 mg, 0.48 mmol, 75%)
and fluoromethylpyrrolidine 10e (21 mg, 0.06 mmol, 9%) were iso-
lated. Data for 9e: [α]2D0 = +16.5 (c = 1.20, CHCl3). 1H NMR
CH2Ph), 4.02 (d, J = 13.2 Hz, 1 H, CH2Ph), 4.14–4.36 (3 H, 4-H,
2Ј-H), 7.20–7.44 (12 H, HAr), 7.57–7.65 (3 H, HAr) ppm. 13C NMR
(100 MHz, CDCl3): δ = 19.1 (s, CMe3), 26.9 (q, CMe3), 37.4 (dt, J
= 5 Hz, C-3), 59.9 (t, CH2Ph), 61.8 (dd, J = 19 Hz, C-2), 62.3 (t,
C-5), 71.4 (d, C-4), 85.9 (dt, J = 169 Hz, C-2Ј), 127.0 (d), 127.6 (d),
128.2 (d), 128.8 (d), 129.7 (d), 134.0 (s), 133.9 (s), 135.7 (d, CAr
)
ppm. IR (film): ν = 3070, 2930, 2856, 1472, 1428, 1380, 1112,
˜
1009 cm–1. MS (EI, 70 eV): m/z (%) = 447 (1) [M]+·, 392 (5), 391
4230
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© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 4224–4234

Ring Expansion Induced by DAST
FULL PAPER
(20), 390 (67), 201 (11), 199 (14), 192 (6), 191 (5), 135 (7), 92 (8), 1.4 equiv.) in THF (15 mL). After recrystallization (CH2Cl2), fluo-
91 (100). HRMS: calcd. for C13H25NF [M + H]+ 448.2470; found
448.2470.
ropiperidine 12c (706 mg, 2.0 mmol, 64%) was isolated as a white
solid. M.p. 179 °C (CH2Cl2). [α]2D0 = +7.6 (c = 0.23, CHCl3). 1H
NMR (400 MHz, [D6]DMSO, 100 °C): δ = 1.49 (m, 1 H), 1.66 (m,
1 H), 1.72–1.93 (2 H), 2.03 (m, 1 H, 4-H, 5-H and 6-H), 2.14–2.29
(2 H, 2-H and 6-H), 2.54 (m, 1 H, 2-H), 4.83 (ddddd, J = 48.7, 7.1,
7.1, 3.5, 3.5 Hz, 1 H, 3-H), 7.18 (t, J = 7.3 Hz, 3 H, HAr), 7.30 (t,
J = 7.7 Hz, 6 H, HAr), 7.43 (d, J = 7.9 Hz, 6 H, HAr) ppm. 13C
NMR (100 MHz, [D6]DMSO, 100 °C): δ = 22.4 (dt, J = 6 Hz, C-
5), 29.0 (dt, J = 20 Hz, C-4), 48.7 (t, C-6), 53.2 (dt, J = 23 Hz, C-
2), 77.3 (s, CPh3), 87.9 (dd, J = 172 Hz, C-3), 126.5 (d), 128.0 (d),
(R)-N-(2,2-Dimethylpropyl)-3-fluoropiperidine (12a) and (S)-N-(2,2-
Dimethylpropyl)-2-fluoromethylpyrrolidine (13a): Following the ge-
neral procedure, prolinol 11a {55 mg, 0.32 mmol, 1.0 equiv., [α]2D0
= –48.2 (c = 0.57, CHCl3)} was treated with DAST (59 µL,
0.48 mmol, 1.4 equiv.) in THF (5 mL). After purification by flash
chromatography on silica gel (cyclohexane/AcOEt, 95:5), fluoro
compounds 12a and 13a were obtained as an inseparable mixture
(30 mg, 0.17 mmol, 54 %). Data for a mixture of 12a + 13a: 1H
NMR (400 MHz, CDCl3): δ = 0.85 (s, 9 H12a, CMe3), 0.88 (s, 9
129.3 (d), 142.7 (s) ppm. IR (neat): ν = 2932, 1594, 1486, 1447,
˜
1183, 1065, 1031, 1003, 971 cm–1. HRMS: calcd. for C24H24NFNa
[M + Na]+ 368.1785; found 368.1785.
H13a, CMe3), 1.39–1.95 (4 H12a and 4 H13a, 4-H12a, 5-H12a, 3-H13a
4-H13a), 2.06 (s, 2 H12a, CH2tBu), 2.26 (d, J = 13.5 Hz, 1 H13a
CH2tBu), 2.26–2.37 (1 H12a and 1 H13a), 2.43 (m, 1 H12a, 2-H12a
,
,
,
(R)-N-(2,2-Dimethylpropyl)-3-ethyl-3-fluoropiperidine (15a): Fol-
6-H12a and 5-H13a), 2.47 (d, J = 13.5 Hz, 1 H13a, CH2tBu), 2.53 lowing the general procedure, prolinol 14a {256 mg, 1.29 mmol,
(m, 1 H12a, CH2tBu), 2.79 (m, 1 H13a, 5-H), 2.88 (m, 1 H12a, 2-H),
3.20 (m, 1 H13a, 2-H), 4.18 (ddd, J = 47.9, 9.0, 6.2 Hz, 1 H13a, 2Ј-
H), 4.33 (ddd, J = 47.5, 9.0, 4.9 Hz, 1 H13a, 2Ј-H), 4.56 (ddddd, J =
1.0 equiv., [α]2D0 = –31.7 (c = 1.23, CHCl3)} was treated with DAST
(236 µL, 1.80 mmol, 1.4 equiv.) in CH2Cl2 (15 mL). After purifica-
tion by flash chromatography (pentane/Et2O, 95:5), fluoropiperi-
48.8, 12.3, 4.1, 4.1, 4.1 Hz, 1 H12a, 3-H) ppm. 13C NMR (100 MHz, dine 15a (196 mg, 0.975 mmol, 76%) was isolated as a colourless
CDCl3): δ = 22.4 (dt, J = 8 Hz, C12a-5), 24.1 (t, C13a-4), 27.3 (dt,
oil. [α]2D0 = +12.6 (c = 1.42, CHCl3). 1H NMR (400 MHz, CHCl3):
J = 6 Hz, C13a-3), 27.6 (q, CMe312a), 28.4 (q, CMe313a), 30.1 (dt, J δ = 0.88 (s, 9 H, CCH3), 0.93 (t, J = 7.5 Hz, 3 H, CH2CH3), 1.65–
= 19 Hz, C12a-4), 32.7 (s, CMe313a), 33.2 (s, CMe312a), 42.3 (t, C13a
5), 55.6 (t, C12a-6), 58.1 (t, CH213atBu), 60.6 (dt, J = 23 Hz, C12a
-
-
1.43 (3 H, 4-H and 5-H), 1.66–1.79 (3 H, 5-H, CH2CH3), 2.02 (d,
J = 13.7 Hz, 1 H, CH2tBu), 2.07 (d, J = 13.8 Hz, 1 H, CH2tBu),
2), 65.6 (dd, J = 20 Hz, C13a-2), 69.7 (t, CH212atBu), 86.1 (dt, J = 2.41–2.55 (4 H, 2-H and 6-H) ppm. 13C NMR (100 MHz, CHCl3):
169 Hz, C13a-2Ј), 88.8 (dd, J = 170 Hz, C12a-3) ppm. IR (film): ν = δ = 7.0 (dq, J = 4 Hz, CH2CH3), 22.9 (t, C-5), 27.7 (q, CCH3), 29.8
˜
2951, 2927, 2856, 1465, 1360, 1261, 1206, 1152, 1104, 1027 cm–1.
(dt, J = 23.0 Hz, CH2CH3), 32.7 (dt, J = 22.0 Hz, C-4), 33.2 (s,
CCH3), 56.1 (t, C-6), 63.5 (dt, J = 24.0 Hz, C-2), 69.8 (t, CH2tBu),
Data for 12a: MS (EI, 70 eV): m/z (%) = 173 (2) [M]+·, 158 (9), 117
(7), 116 (100), 96 (4), 73 (3), 55 (4). Data for 13a: MS (EI, 70 eV): 94.8 (ds, J = 171.0 Hz, C-3) ppm. IR (film): ν = 2948, 2865, 2792,
˜
m/z (%) = 173 (3) [M]+·, 158 (10), 117 (7), 116 (100), 110 (2), 102 1463, 1359, 1126 cm–1. MS (EI, 70 eV): m/z (%) = 201 (1) [M]+·,
(3), 96 (2), 70 (3), 55 (4).
186 (7), 145 (10), 144 (100), 124 (12), 116 (2), 102 (3), 55 (4).
HRMS: calcd. for C12H25NF [M + H]+ 202.1971; found 202.1957.
(R)-N-Benzhydryl-3-fluoropiperidine (12b) and (S)-N-Benzhydryl-2-
fluoromethylpyrrolidine (13b): Following the general procedure,
prolinol 11b {80 mg, 0.30 mmol, 1.0 equiv., [α]2D0 = +28.9 (c = 0.28,
(S)-N-(2,2-Dimethylpropyl)-3-allyl-3-fluoropiperidine (15b): Follow-
ing the general procedure, prolinol 14b {256 mg, 1.21 mmol,
CHCl3)} was treated with DAST (55 µL, 0.41 mmol, 1.4 equiv.) in 1.0 equiv., [α]2D0 = –7.9 (c = 1.02, CHCl3)} was treated with DAST
CH2Cl2 (5 mL). After purification by flash chromatography on sil-
ica gel (cyclohexane/AcOEt, 95:5), fluoro compounds 12b and 13b
were obtained as an inseparable mixture (57 mg, 0.21 mmol, 71%).
Data for a mixture of 12b+13b: 1H NMR (400 MHz, CDCl3): δ =
(220 µL, 1.70 mmol, 1.4 equiv.) in CH2Cl2 (10 mL). After purifica-
tion by flash chromatography (pentane/Et2O, 95:5), fluoropiperi-
dine 15b (229 mg, 1.05 mmol, 89%) was isolated as a colourless oil.
[α]2D0 = +11.6 (c = 1.65, CHCl3). 1H NMR (400 MHz, CDCl3): δ =
1.47–1.95 (4 H12b and 4 H13b, 4-H12b, 5-H12b, 3-H13b and 4-H13b), 0.86 (9 H, CCH3), 1.49 (m, 1 H, 5-H), 1.56–1.62 (2 H, 4-H), 1.71
2.16 (m, 1 H12b, 6-H), 2.26–2.41 (1 H12b and 1 H13b, 2-H12b and 5- (m, 1 H, 5-H), 2.03 (d, J = 14.8 Hz, 1 H, CH2tBu), 2.07 (d, J =
H13b), 2.45 (m, 1 H12b, 6-H), 2.74 (m, 1 H12b, 2-H), 2.92 (m, 1 H13b
5-H), 3.11 (m, 1 H13b, 2-H), 3.98 (ddd, J = 47.3, 8.9, 4.7 Hz, 1 H13b
,
,
14.8 Hz, 1 H, CH2 tBu), 2.38–2.54 (6 H, 2-H, 6-H and
CH2CH=CH2), 5.10 (m, 2 H, CH2CH=CH2), 5.86 (dddd, J = 17.1,
2Ј-H), 4.02 (ddd, J = 47.9, 8.9, 7.1 Hz, 1 H13b, 2Ј-H), 4.34 (s, 1 10.1, 7.0, 7.0 Hz, 1 H, CH2CH=CH2) ppm. 13C NMR (100 MHz,
H12b, CHPh2), 4.63 (ddddd, J = 48.2, 7.7, 7.7, 3.8, 3.8 Hz, 1 H12b
,
)
-
CDCl3): δ = 22.7 (dt, J = 6 Hz, C-5), 27.8 (q, CCH3), 33.9 (dt, J
= 21 Hz, C-4), 33.2 (s, CCH3), 41.7 (dt, J = 22 Hz, CH2CH=CH2),
56.0 (t, C-6), 63.7 (dt, J = 23 Hz, C-2), 69.8 (t, CH2tBu), 94.1 (ds,
3-H), 4.74 (s, 1 H13b, CHPh2), 7.14–7.44 (10 H12b and 10 H13b, HAr
ppm. 13C NMR (100 MHz, CDCl3): δ = 22.4 (dt, J = 7 Hz, C12b
5), 23.6 (t, C13b-4), 27.6 (t, C13b-3), 30.5 (dt, J = 21 Hz, C12b-4), J = 173 Hz, C-3), 118.3 (t, CH2CH=CH2), 132.7 (dd, J = 4 Hz,
51.6 (t, C12b-6), 53.0 (t, C13b-5), 56.2 (dt, J = 24 Hz, C12b-2), 60.1 CH CH=CH ) ppm. IR (film): ν = 2950, 2865, 2787, 1643, 1466,
˜
2
2
(dd, J = 24 Hz, C13b-2), 73.4 (d, CH13bPh2), 75.7 (d, CH12bPh2), 1360, 1115, 1023 cm–1. MS (EI, 70 eV): m/z (%) = 213 (1) [M]+·,
85.5 (dt, J = 169 Hz, -C13b-2Ј), 88.7 (dd, J = 170 Hz, C12b-3), 126.9
198 (7), 157 (11), 156 (100), 136 (6), 115 (13), 114 (11), 76 (3).
(d), 127.0 (d), 127.2 (d), 128.0 (d), 128.3 (d), 128.5 (d), 142.3 (s),
HRMS: calcd. for C13H25NF [M + H]+ 214.1971; found 214.1960.
142.4 (s, CAr) ppm. IR (film): ν = 3060, 3025, 2944, 2801, 1598,
˜
(S)-N-(2,2-Dimethylpropyl)-3-benzyl-3-fluoropiperidine (15c): Fol-
lowing the general procedure, prolinol 14c {25 mg, 0.10 mmol,
1.0 equiv., [α]2D0 = –16.1 (c = 0.99, CHCl3)} was treated with DAST
(18 µL, 0.13 mmol, 1.4 equiv.) in THF (5 mL). After purification
by flash chromatography (cyclohexane/AcOEt, 90:10), fluoropiper-
idine 15c (22 mg, 0.084 mmol, 87%) was isolated as a colourless
1491, 1451, 1336, 1304, 1263, 1187, 1154, 1106, 1074, 1015 cm–1.
Data for 12b: MS (EI, 70 eV): m/z (%) = 269 (19) [M]+·, 193 (11),
192 (78), 168 (18), 167 (100), 166 (12), 165 (35), 152 (18), 102 (6),
91 (4). Data for 13b: MS (EI, 70 eV): m/z (%) = 269 (6) [M]+·, 236
(18), 193 (5), 192 (34), 168 (17), 167 (100), 166 (9), 165 (29), 152
(15), 91 (4).
1
oil. [α]2D0 = –4.3 (c = 1.75, CHCl3). H NMR (400 MHz, CDCl3):
(R)-N-Trityl-3-fluoropiperidine (12c): Following the general pro-
cedure, prolinol 11c {1.11 g, 3.2 mmol, 1.0 equiv., [α]2D0 = +40.0 (c
= 1.31, CHCl3)} was treated with DAST (480 µL, 3.6 mmol,
δ = 0.87 (s, 9 H, CMe3), 1.44–1.58 (3 H, 4-H and 5-H), 1.69 (m, 1
H, 5-H), 2.04 (d, J = 13.8 Hz, 1 H, CH2tBu), 2.08 (d, J = 13.8 Hz,
1 H, CH2tBu), 2.38–2.58 (m, 4 H, 2-H and 6-H), 2.95 (dd, J =
Eur. J. Org. Chem. 2007, 4224–4234
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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4231

I. Déchamps, D.Gomez Pardo, J. Cossy
FULL PAPER
19.8, 14.4 Hz, 1 H, CH2Ph), 3.11 (dd, J = 30.6, 14.4 Hz, 1 H,
3.66 (d, J = 13.6 Hz, 1 H, CH2Ph), 4.61 (dm, J = 47.9 Hz, 1 H, 3-
CH2Ph), 7.21–7.31 (5 H, HAr) ppm. 13C NMR (100 MHz, CDCl3): H), 7.13–7.30 (5 H, HAr) ppm. 13C NMR (100 MHz, CDCl3): δ =
δ = 21.8 (dt, J = 7 Hz, C-5), 26.8 (q, CMe3), 31.2 (dt, J = 28 Hz, 20.6 (dt, J = 9 Hz, C-5), 29.3 (t, C-6), 33.5 (dt, J = 21 Hz, C-4),
C-4), 32.2 (s, CMe3), 42.4 (dt, J = 28 Hz, CH2Ph), 55.0 (t, C-6), 56.4 (t, C-7), 59.5 (dt, J = 27 Hz, C-2), 63.1 (t, CH2Ph), 92.6 (dd,
63.3 (dt, J = 31 Hz, C-2), 68.8 (t, CH2tBu), 93.3 (ds, J = 232 Hz,
J = 181 Hz, C-3), 127.0 (d), 128.2 (d), 128.7 (d), 132.7 (s, CAr) ppm.
C-3), 125.4 (d), 127.0 (d), 129.5 (d), 135.5 (s) (CAr) ppm. IR (film):
IR (film): ν = 3026, 2928, 2860, 1494, 1452, 1353, 1066, 1025 cm–1.
˜
ν = 2945, 2862, 2785, 1605, 1454, 1358, 1112, 1020 cm–1. MS (EI,
MS (EI, 70 eV): m/z (%) = 207 (30) [M]+·, 206 (14), 174 (45), 160
˜
70 eV): m/z (%) = 263 (1) [M]+·, 248 (6), 207 (15), 206 (100), 186 (16), 146 (6), 130 (17), 116 (28), 92 (11), 91 (100), 84 (6), 65 (12).
(13), 115 (5), 96 (12), 91 (28). C17H26FN (263.19): C 77.52, H 9.95,
N 5.32; found C 77.13, H 9.73, N 5.34.
HRMS: calcd. for C13H25NF [M + H]+ 208.1496; found 208.1496.
1
Data for 18a: H NMR (400 MHz, CDCl3): δ = 1.27–1.57 (4 H),
1.65–1.74 (2 H, 3-H, 4-H and 5-H), 2.04 (ddd, J = 11.6, 10.3,
3.2 Hz, 1 H, 6-H), 2.61 (m, 1 H, 2-H), 2.77 (ddd, J = 11.5, 4.2,
4.2 Hz, 1 H, 6-H), 3.34 (d, J = 13.7 Hz, 1 H, CH2Ph), 4.08 (d, J =
13.7 Hz, 1 H, CH2Ph), 4.48 (ddd, J = 48.3, 9.9, 3.5 Hz, 1 H, 2Ј-
H), 4.61 (ddd, J = 47.4, 9.9, 5.5 Hz, 1 H, 2Ј-H), 7.20–7.38 (5 H,
HAr) ppm. 13C NMR (100 MHz, CDCl3): δ = 20.8 (t), 23.5 (t, C-
4, C-5), 28.3 (dt, J = 8 Hz, C-3), 52.0 (t, C-6), 59.9 (t, CH2Ph),
60.0 (dd, J = 18 Hz, C-2), 86.4 (dt, J = 169 Hz, C-2Ј), 126.8 (d),
(S)-N-Benzyl-3-benzyl-3-fluoropiperidine (15d): Following the gene-
ral procedure, prolinol 14d {43 mg, 0.15 mmol, 1.0 equiv., [α]2D0
=
+3.6 (c = 0.70, CHCl3)} was treated with DAST (26 µL, 0.18 mmol,
1.4 equiv.) in THF (5 mL). After purification by flash chromatog-
raphy (cyclohexane/AcOEt, 90:10), fluoropiperidine 15d (13 mg,
0.045 mmol, 30%) was isolated as a colourless oil. [α]2D0 = –3.9 (c
1
= 0.41, CHCl3). H NMR (400 MHz, CDCl3): δ = 1.51–1.80 (4 H,
4-H and 5-H), 2.36–2.47 (m, 4 H, 2-H and 6-H), 2.95 (dd, J = 24.8,
14.2 Hz, 1 H, CH2Ph), 3.02 (dd, J = 24.6, 14.2 Hz, 1 H, CH2Ph),
3.48 (d, J = 13.2 Hz, 1 H, N-CH2Ph), 3.54 (d, J = 13.2 Hz, 1 H,
N-CH2Ph), 7.16–7.20 (2 H, HAr), 7.21–7.29 (4 H, HAr), 7.30–7.33
(4 H, HAr) ppm. 13C NMR (100 MHz, CDCl3): δ = 21.3 (dt, J =
7 Hz, C-5), 32.4 (dt, J = 22 Hz, C-4), 42.4 (dt, J = 23 Hz, CH2Ph),
51.4 (t, C-6), 59.5 (dt, J = 23 Hz, C-2), 61.8 (t, N-CH2Ph), 93.0 (ds,
J = 174 Hz, C-3), 125.5 (d), 126.0 (d), 127.1 (d), 127.2 (d), 128.1
128.2 (d), 128.9 (d), 139.4 (s, CAr) ppm. IR (film): ν = 3028, 2934,
˜
2857, 2797, 1494, 1452, 1372, 1339, 1131, 1116, 1082, 1055,
1015 cm–1. MS (EI, 70 eV): m/z (%) = 207 (4) [M]+·, 175 (15), 174
(100), 130 (3), 92 (7), 91 (85), 65 (7), 55 (3). HRMS: calcd. for
C13H25NF [M + H]+ 208.1496; found 208.1496.
N-Benzyl-3-ethyl-3-fluoroazepane (17b): Following the general pro-
cedure, piperidinol 16b (111 mg, 0.48 mmol, 1.0 equiv.) was treated
with DAST (87 µL, 0.67 mmol, 1.4 equiv.) in CH2Cl2 (6 mL). After
purification by flash chromatography on silica gel (pentane/Et2O,
90:10), fluoroazepane 17b (70 mg, 0.30 mmol, 63%) was isolated
as a colourless oil. 1H NMR (400 MHz, CDCl3): δ = 0.70 (m, 3 H,
CH2CH3), 1.34–1.92 (8 H, 4-H, 5-H, 6-H and CH2CH3), 2.45 (m,
1 H, 7-H), 2.58 (m, 1 H, 7-H), 2.67–2.73 (2 H, 2-H), 3.57 (d, J =
13.5 Hz, 1 H, CH2Ph), 3.62 (d, J = 13.5 Hz, 1 H, CH2Ph), 7.13–
7.19 (1 H, HAr), 7.16–7.28 (4 H, HAr) ppm. 13C NMR (100 MHz,
CDCl3): δ = 7.1 (dq, J = 5 Hz, CH2CH3), 21.6 (dt, J = 5 Hz, C-5),
30.9 (t, C-6), 31.0 (dt, J = 23 Hz), 37.5 (dt, J = 24 Hz, C-4 and
CH2CH3), 57.8 (t, C-7), 63.6 (dt, J = 30 Hz, C-2), 64.0 (t, CH2Ph),
99.8 (ds, J = 168 Hz, C-3), 126.9 (d), 128.1 (d), 128.9 (d), 139.9 (s)
(d), 129.5 (d), 135.3 (s), 137.0 (s, CAr) ppm. IR (film): ν = 3029,
˜
2943, 2802, 1495, 1354, 1346, 1301, 1116, 1079, 1029 cm–1. MS (EI,
70 eV): m/z (%) = 283 (36) [M]+·, 282 (24), 263 (42), 206 (12), 192
(15), 191 (12), 186 (11), 172 (38), 115 (10), 92 (10), 91 (100), 65 (10).
HRMS: calcd. for C13H25NF [M + H]+ 284.1815; found 284.1815.
(3R,5R)-N-Methyl-5-(tert-butyldiphenylsilanyloxy)-3-ethyl-3-fluoro-
piperidine (15e): Following the general procedure, prolinol 14e[15m]
{50 mg, 0.13 mmol, 1.0 equiv., [α]2D0 = +2.4 (c = 1.36, CHCl3)} was
treated with DAST (23 µL, 0.19 mmol, 1.4 equiv.) in THF (5 mL).
After purification by flash chromatography (cyclohexane/AcOEt,
80:20), fluoropiperidine 15e (36 mg, 0.09 mmol, 72%) was isolated
as a yellow oil. [α]2D0 = +6.6 (c = 0.35, CHCl3). 1H NMR (400 MHz,
CDCl3): δ = 0.89 (t, J = 7.5 Hz, 3 H, CH2CH3), 1.06 (s, 9 H,
CMe3), 1.51–1.63 (3 H, 4-H and CH2CH3), 1.78–2.00 (2 H, 2-H
and 6-H), 2.07 (m, 1 H, 4-H), 2.22 (s, 3 H, N-Me), 2.75 (m, 1 H,
2-H), 2.87 (m, 1 H, 6-H), 4.12 (dddd, J = 10.1, 10.1, 5.0, 5.1 Hz, 1
H, 5-H), 7.33–7.42 (m, 6 H, HAr), 7.63–7.67 (m, 4 H, HAr) ppm.
13C NMR (100 MHz, CDCl3): δ = 7.1 (q, CH2CH3), 19.2 (s,
CMe3), 27.0 (q, CMe3), 31.4 (dt, J = 23 Hz, CH2CH3), 41.4 (dt, J
= 22 Hz, C-4), 45.8 (q, N-Me), 61.7 (dt, J = 21 Hz, C-2), 62.3 (t,
C-6), 66.4 (d, C-5), 95.1 (ds, J = 172 Hz, C-3), 127.6 (d), 129.7 (d),
ppm. IR (film): ν = 2926, 1494, 1452, 1351, 1111, 968, 910 cm–1.
˜
MS (EI, 70 eV): m/z (%) = 235 (40) [M]+·, 215 (16), 200 (17), 186
(10), 174 (11), 160 (47), 158 (11), 146 (13), 144 (15), 134 (25), 120
(19), 92 (11), 91 (100), 65 (11). HRMS: calcd. for C13H25NF [M +
H]+ 236.1809; found 236.1809.
N-Benzyl-3-allyl-3-fluoroazepane (17c): Following the general pro-
cedure, piperidinol 16c (110 mg, 0.45 mmol, 1.0 equiv.) was treated
with DAST (83 µL, 0.63 mmol, 1.4 equiv.) in CH2Cl2 (6 mL). After
purification by flash chromatography on silica gel (pentane/Et2O,
90:10), fluoroazepane 17c (85 mg, 0.34 mmol, 76%) was isolated as
a yellow oil. 1H NMR (400 MHz, CDCl3): δ = 1.35–1.52 (2 H),
1.56–1.92 (4 H, 4-H, 5-H, 6-H), 2.26 (ddd, J = 21.5, 7.2, 6.5 Hz, 2
H, CH2CH=CH2), 2.45 (ddd, J = 12.5, 8.2, 4.4 Hz, 1 H, 7-H), 2.60
(m, 1 H, 7-H), 2.73 (d, J = 15.7 Hz, 2 H, 2-H), 3.67 (s, 2 H,
CH2 P h ) , 4 . 9 9 ( m , 1 H , C H 2 CH =C H2 ) , 5 . 0 6 ( m , 1 H ,
CH2CH=CH2), 5.77 (dddd, J = 17.2, 10.1, 7.2, 7.2 Hz, 1 H,
134.1 (s), 135.7 (d, CAr) ppm. IR (film): ν = 2930, 2856, 2786, 1460,
˜
1427, 1384, 1252, 1180, 1106, 1083, 1048 cm–1. MS (EI, 70 eV):
m/z (%) = 399 (2) [M]+·, 379 (12), 343 (28), 342 (100), 322 (15), 201
(11), 199 (13), 183 (18), 144 (18), 124 (30), 122 (23), 94 (11), 58
(12). HRMS: calcd. for C31H31NFO [M + H]+ 400.2467; found
400.2467.
N-Benzyl-3-fluoroazepane (17a) and N-Benzyl-2-fluoromethylpiper- CH2CH=CH2), 7.21–7.35 (5 H, HAr) ppm. 13C NMR (100 MHz,
idine (18a): Following the general procedure, piperidine methanol CDCl3): δ = 21.5 (dt, J = 4 Hz, C-5), 30.8 (t, C-6), 38.1 (dt, J =
16a[27] (120 mg, 0.58 mmol, 1.0 equiv.) was treated with DAST 23 Hz, CH2CH=CH2), 43.9 (dt, J = 23 Hz, C-4), 57.6 (t, C-7), 63.7
(107 µL, 0.82 mmol, 1.4 equiv.) in CH2Cl2 (10 mL). After purifica-
tion by preparative TLC on silica gel (cyclohexane/AcOEt, 90:10),
fluoroazepane 17a (61 mg, 0.29 mmol, 51%) and fluoromethylpyr-
rolidine 18a (15 mg, 0.07 mmol, 12%) were isolated as yellow oils.
Data for 17a: 1H NMR (400 MHz, CDCl3): δ = 1.43 (m, 1 H),
1.50–1.70 (3 H, 5-H and 6-H), 1.71–2.10 (2 H, 4-H), 2.57 (2 H),
2.70–2.95 (2 H, 2-H and 7-H), 3.60 (d, J = 13.6 Hz, 1 H, CH2Ph),
(dt, J = 28 Hz, C-2), 63.8 (t, CH2Ph), 98.3 (ds, J = 170 Hz, C-3)
118.3 (t, CH2CH=CH2), 127.0 (d), 128.2 (d), 128.8 (d, CAr), 133.0
(dd, J = 5 Hz, CH2CH=CH2), 139.8 (s, CAr) ppm. IR (film): ν =
˜
2928, 1641, 1494, 1452, 1351, 1268, 1106, 993 cm–1. MS (EI, 70 eV):
m/z (%) = 247 (12) [M]+·, 246 (10), 227 (21), 170 (11), 160 (15), 158
(18), 146 (10), 134 (13), 120 (14), 92 (11), 91 (100), 65 (12). HRMS:
calcd. for C13H25NF [M + H])+ 248.1809; found 248.1809.
4232
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© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 4224–4234

Ring Expansion Induced by DAST
FULL PAPER
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N-Benzyl-3-benzyl-3-fluoroazepane (17d): Following the general
procedure, piperidinol 16d (47 mg, 0.16 mmol, 1.0 equiv.) was
treated with DAST (29 µL, 0.22 mmol, 1.4 equiv.) in THF (4 mL).
After purification by flash chromatography on silica gel (cyclohex-
ane/AcOEt, 95:5), fluoroazepane 17d (32 mg, 0.30 mmol, 76%) was
isolated as a yellow oil. 1H NMR (400 MHz, CDCl3): δ = 1.35–
1.53 (2 H), 1.56–1.67 (2 H), 1.70 (m, 1 H), 1.76 (m, 1 H, 4-H, 5-H
and 6-H), 2.43 (ddd, J = 12.5, 8.3, 4.5 Hz, 1 H, 7-H), 2.62 (m, 1
H, 7-H), 2.67–2.88 (4 H, 2-H and CH2Ph), 3.58 (s, 2 H, N-CH2Ph),
7.04–7.29 (10 H, HAr) ppm. 13C NMR (100 MHz, CDCl3): δ = 21.4
(dt, J = 5 Hz, C-5), 30.8 (t, C-6), 30.9 (dt, J = 23 Hz, C-4), 45.2
(dt, J = 21 Hz, CH2Ph), 57.7 (t, C-7), 63.9 (t, N-CH2Ph), 64.0 (dt,
J = 30 Hz, C-2), 99.2 (ds, J = 171 Hz, C-3), 126.4 (d), 127.0 (d),
[9]
[10]
[11]
[12]
128.0 (d), 128.2 (d), 128.9 (d), 130.7 (d), 136.7 (s), 139.8 (s, CAr
)
ppm. IR (film): ν = 3027, 2926, 1603, 1495, 1453, 1263, 1107, 1077,
˜
1009 cm–1. MS (EI, 70 eV): m/z (%) = 297 (7) [M]+·, 278 (9), 277
(41), 186 (48), 160 (11), 129 (8), 120 (16), 115 (11), 92 (9), 91 (100),
65 (10). HRMS: calcd. for C13H25NF [M + H]+ 298.1965; found
298.1965.
Acknowledgments
Johnson & Johnson is greatly acknowledged for financial support
(Focus Giving Grant to J. C.)
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1
[18]
[19]
The ratios were calculated after examination of the H NMR
spectra of the crude material.
These prolinols were prepared by using classical esterification,
benzylation, protection and reduction steps. For example of
preparation, see ref.[15m]
C. Herdeis, H. P. Hubmann, H. Lotter, Tetrahedron: Asym-
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[20]
Eur. J. Org. Chem. 2007, 4224–4234
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4233

I. Déchamps, D.Gomez Pardo, J. Cossy
FULL PAPER
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[27] B. Weber, J. Schwerdtfeger, R. Fröhlich, A. Göhrt, D. Hoppe,
Synthesis 1999, 1915.
Received: March 15, 2007
Published Online: July 30, 2007
[25] Benzyl and allyl neighbouring groups are reported to partici-
pate in DAST reactions in the absence of an internal nucleo-
4234
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© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 4224–4234