Ring expansion of cyclic β-amino alcohols induced by diethylaminosulfur trifluoride: Synthesis of cyclic amines with a tertiary fluorine at C3

Article abstract of DOI:10.1021/jo300887u

As the replacement of a hydrogen atom by a fluorine atom in a compound can have an important impact on its biological properties, the development of methods allowing the introduction of a fluorine atom is of great importance. The scope and limitations of

Full text of DOI:10.1021/jo300887u

Article
pubs.acs.org/joc
Ring Expansion of Cyclic β-Amino Alcohols Induced by
Diethylaminosulfur Trifluoride: Synthesis of Cyclic Amines with a
Tertiary Fluorine at C3
Bruno Anxionnat,† Benoit Robert,‡ Pascal George,§ Gino Ricci,∥ Marc-Antoine Perrin,‡
Domingo Gomez Pardo,*,† and Janine Cossy*,†
†Laboratoire de Chimie Organique, ESPCI ParisTech, CNRS, 10 rue Vauquelin, 75231 Paris Cedex 05, France
‡Research & Development, LGCR Department 13, Sanofi, quai Jules Guesde, 94403 Vitry-sur Seine France
§Research & Development, Sanofi, 1 avenue Pierre Brossolette, 91385 Chilly-Mazarin Cedex, France
∥Process Development, Sanofi, 45 chemin de Met
́
eline, 04210 Sisteron Cedex, France
S
* Supporting Information
ABSTRACT: As the replacement of a hydrogen atom by a
fluorine atom in a compound can have an important impact on
its biological properties, the development of methods allowing
the introduction of a fluorine atom is of great importance. The
scope and limitations of the ring expansion of cyclic 2-
hydroxymethyl amines induced by diethylaminosulfur trifluoride
(DAST) to produce cyclic β-fluoro amines was studied as well as
the enantioselectivity of the process.
Here, we would like to report that the ring expansion
induced by DAST can be generalized to 2-hydroxymethylaze-
panes, 2-hydroxymethylazocanes, and heterocyclic 2-hydrox-
ymethyl amines such as piperazines H, morpholines I, and
indolines J (Figure 1). Furthermore, an enantioselective ring
expansion leading to optically active cyclic amines bearing a
tertiary fluorine atom at C3 will also be reported.
INTRODUCTION
■
In nature, compounds with fluorine atoms are rare as only 13
compounds have been reported to date.1 The introduction of a
fluorine atom in a molecule can have an important impact on
its physical and biological properties due to the high
electronegativity, the low polarizability, and the small size of
the fluorine atom.2 In the pharmaceutical industry, about 20%
of the prescribed pharmaceuticals and 30% of the leading 30
blockbuster drugs by sales contain a C−F bond.3,4 In addition,
organofluorine compounds have also achieved significant
advances in the area of agrochemicals and materials.5 The
majority of commercially available fluorinated compounds
contains F-aryl and/or CF3-aryl moieties; however, since
compounds possessing a stereogenic center with a fluorine
atom are interesting, chemists have developed new fluorinating
reagents as well as ingenious methods for the enantioselective
introduction of fluorinated functionality in building blocks or
for a late stage fluorination.6
A few years ago, we had reported ring expansion of prolinols
A to the corresponding optically active 3-fluoro piperidines B as
well as the synthesis of racemic 3-fluoro azepanes D from
racemic 2-hydroxymethylpiperidines C. These ring expansions
were achieved by using DAST or Deoxo-Fluor (Scheme 1).6a,7
The ring expansion is supposed to proceed via an intermediate
aziridinium ion F resulting from the anchimeric assistance of
the nitrogen atom, which expells the leaving group in E.
RESULTS AND DISCUSSION
■
Ring Expansion of Racemic Cyclic Amino Alcohols. In
order to determine the scope and the limitation of the ring
expansion induced by DAST, racemic 7- and 8-membered rings
K were synthetized by using a Schmidt rearrangement applied
to cyclic β-keto esters L (Scheme 2).8
The transformation of β-keto esters 1 (n = 1, 2) to the
corresponding cyclic 2-hydroxymethyl amines 4 was achieved.
At first, the alkylation of 1 with different alkyl halides was
performed (K2CO3, RX, acetone, reflux)9 to produce the C-
alkylated products 2 in 82% to quantitative yields (Table 1).
The obtained alkylated β-keto esters 2 were then submitted to a
Schmidt rearrangement using NaN3 under acidic conditions
(H2SO4) to afford 7- and 8-membered ring lactams 3.10 After
reduction (LiAlH4, THF, reflux) and N-benzylation (K2CO3,
Received: May 2, 2012
Published: June 11, 2012
© 2012 American Chemical Society
6087
dx.doi.org/10.1021/jo300887u | J. Org. Chem. 2012, 77, 6087−6099

The Journal of Organic Chemistry
Article
Scheme 1
Table 1. Synthesis of Azepanes and Azocanes
entry
1
n
RX
EtI
2 (yield %)
3 (yield %)
4 (yield %)
1
1
1
2
2
2a (100)
2b (96)
2c (97)
2d (82)
2e (98)
3a (93)
3b (68)
3c (74)
3d (21)
3e (36)
4a (42)
4b (68)
4c (64)
4d (62)
4e (42)
a
2
AllylBr
BnBr
EtI
3
4
5
BnBr
a
For the Schmidt rearrangement, CH3SO3H was used.
Table 2. Ring Expansion of Azepanes and Azocanes Induced
by DAST
entry
4 (R, n)
5 (yield %)
1
2
3
4
5
4a (Et, 1)
4b (Allyl, 1)
4c (Bn, 1)
4d (Et, 2)
4e (Bn, 2)
5a (64)
5b (83)
5c (65)
5d (58)
5e (62)
Figure 1. Amino-alcohols considered for the ring expansion.
Scheme 2
with LDA followed by the addition of allyl bromide (THF, −78
°C to rt), and the resulting C-alkylated piperazine was reduced
by LiAlH4 (THF, rt) to produce 2-hydroxymethylpiperazine 8
(56% for the two chemical steps) (Scheme 3, eq 1).
The synthesis of 2-hydroxymethylmorpholine 12 was
achieved within four steps from aminodiol 9.14 After reductive
amination of 9, N-protected aminodiol 10 was isolated in 56%
yield. The transformation of 10 to morpholine 11 was realized
in two steps, however in low yield14 (14%), using chloroacetyl
chloride (K2CO3, CH2Cl2, rt) followed by a basic treatment (t-
BuOK, t-BuOH, reflux). After reduction by Red-Al in toluene,
morpholine 12 was isolated (75%) (Scheme 3, eq 2).
2-Hydroxymethylindolines 16a−16c were obtained from
indoline carboxylic acid 13 within four steps. After esterification
(SOCl2, MeOH, rt) and N-protection (BnBr, K2CO3, n-Bu4NI,
CH3CN), the indolino-ester 14 was isolated in good yield and
then alkylated by treatment with LDA followed by the addition
of an alkyl halide (EtI, AllylBr, or BnBr) to produce the
corresponding alkylated indolines 15a−15c (60%-88%). The
indolines 15a−15c were then reduced by LiAlH4 (THF, rt) to
access the desired 2-hydroxymethylindolines 16a−16c (84−
100%) (Scheme 3, eq 3).
BnBr, n-Bu4NI, CH3CN, reflux), the corresponding N-benzyl 2-
hydroxymethylazepanes 4a−4c and azocanes 4d and 4e were
isolated (yields over 2 steps 13−52%) (Table 1). Noteworthy,
the Schmidt rearrangement gave lower yield in 8-membered
ring lactams (3d and 3e) than in 7-membered ring lactams
(3a−3c).11−13
Compounds 4a−4e were then treated with DAST (1.4 equiv,
CH2Cl2, 0 °C to rt) to produce the corresponding expanded β-
fluoro amines 5a−5e in good to excellent yields (58−83%).
The best yield was obtained for allylic derivative 5b, which was
isolated in 83% yield. It is worth noting that for a full
conversion of 4, the ring enlargement adducts 5 were the only
isolated compounds obtained, and the 2-fluoromethyl cyclic
amines 5′ were not detected (Table 2).
In order to study the chemoselectivity of the ring expansion
induced by DAST, piperazines, morpholines as well as indolines
were examined as substrates. The synthesis of N-alkyl-2-
hydroxymethylpiperazine 8 was achieved from N-Boc-2-
carboxylic piperazine 6. After esterification and N-protection
(Na2CO3, NaOH, H2O), the corresponding ester 7 was isolated
(55%). The alkylation of 7 was then performed by treatment
Compounds 8, 12, and 16a−16c were then treated with
DAST to obtain respectively and exclusively the ring enlarge-
6088
dx.doi.org/10.1021/jo300887u | J. Org. Chem. 2012, 77, 6087−6099

The Journal of Organic Chemistry
Article
Scheme 3
Scheme 4
Scheme 5
asymmetric intramolecular cyclization involving the memory of
chirality,15 would produce the precursors of M (Scheme 5).
The synthesis of the desired cyclic β-amino alcohols 23a−
23d was achieved from amino ester 20.16 Amino ester 20 was
transformed to the N-Boc, N-bromoalkylamino esters 21a−21d
within three or four steps. After N-alkylation (K2CO3, DMF, 70
°C) followed by treatment with Boc2O (1.5 equiv) and O-
debenzylation (H2, Pd/C), the hydroxy esters were trans-
formed to the corresponding bromo esters 21a and 21b using
CBr4/PPh3 (Scheme 6, eq 1). To introduce the side chain in
compounds 21c and 21d, a reductive amination was realized,
and after the protection of the amine with a Boc group (1.5
equiv), the treatment with CBr4 (1.3 equiv) in presence of PPh3
(1.6 equiv) led to the desired bromo amines 21c and 21d
(Scheme 6, eq 2 and 3). When these bromide derivatives were
treated with potassium hexamethyldisilazide (KHMDS, 1.2
equiv) in DMF at −60 °C for 30 min, the corresponding cyclic
amino esters 22a−22d were isolated in yields which varied
from 22 to 90% but always with excellent enantiomeric excesses
(94−98%).17 After deprotection (TFA, CH2Cl2, rt), N-
benzylation (BnBr, K2CO3, n-Bu4NI, CH3CN, reflux), and
reduction with LiAlH4 (THF, rt), the desired 2-hydroxyme-
thylcyclic amines 23a−23d were isolated in good yields
(Scheme 6, eq 4).
ment adducts 17, 18, and 19a−19c in good to excellent yields.
The results are reported in Scheme 4.
Ring Expansion of Optically Active Cyclic Amino
Alcohols. As previously indicated, we have reported the
enantioselective ring expansion of optically active prolinols A to
the corresponding 3-fluoro piperidines B (Scheme 1). In order
to generalize this ring expansion to produce optically active β-
fluoro pyrrolidines, piperidines, azepanes, and azocanes,
possessing a tertiary fluoride at C3, the corresponding optically
active 2-hydroxymethylazetidines, pyrrolidines, piperidines, and
azepanes were synthetized and treated with DAST. The
synthesis of cyclic β-amino alcohols M was planned from β-
amino ester O via the bromo-amino esters N, which, after an
6089
dx.doi.org/10.1021/jo300887u | J. Org. Chem. 2012, 77, 6087−6099

The Journal of Organic Chemistry
Article
Scheme 6
The cyclic β-amino alcohols 23a−23d were then treated with
DAST (1.4 equiv, CH2Cl2, 0 °C to rt), and the corresponding
3-fluorocyclic amines 24a−24d were isolated in good yields
(61−96%).18 Although the ring expansion of 23a and 23b to
the corresponding β-fluoro pyrrolidine 24a and β-fluoro
piperidine 24b is highly enantioselective, an erosion of the
enantiomeric excess was noticed for the transformation of 23c
(ee = 98%) to 24c (ee = 85%), and this erosion was worse for
the transformation of 23d (ee = 94%) to 24d (ee = 52%)
(Scheme 7).
amines possessing a small ring such as compounds P, the
selective attack of the fluorine anion at the C2 position, leading
exclusively to the ring expansion adduct R, can be explained by
a nonsymmetrical intermediate aziridinium ion Q in which the
C2−N bond is longer than the C2′−N bond (Scheme 8, eq 1).
Moreover, the presence of a quaternary center at C2 results in
the stabilization of a partially positive charge at C2 correlated
with a weakened C2−N bond. Thus, cleavage of the C2−N
bond induced by the nucleophilic attack of the fluorine anion at
the most electrophilic carbon is favored to afford R. When
cyclic 2-hydromethyl amines with larger rings such as S are
involved, the intermediate aziridinium ion T can be in
equilibrium with a stable intermediate carbocation U. As the
C2−N bond is longer than it was previously in eq 1, an
epimerization of the quaternary center can occur (Scheme 8, eq
2).
When the size of the cyclic amines 23 increased, the
enantioselectivity of the ring expansion decreased. This
phenomenon is probably related to the structure of the
intermediate aziridinium ion. For cyclic 2-hydroxymethyl
Scheme 7
To investigate the formation of an intermediate carbocation,
the alkyl group on the quaternary center was replaced by a
phenyl, and the rearrangement of 2-hydroxymethylpyrrolidine
28, which possesses a phenyl substituent at C2, was
investigated. Thus, the synthesis of 2-hydroxymethylpyrrolidine
28 was achieved from phenylglycine ethyl ester 25. After the
introduction of the side chain (3-bromopropanol, K2CO3,
DMF, reflux) and the protection of the amine (Boc2O, DIPEA,
CH2Cl2), amino ester 25 was transformed to the bromide
derivative 26 (CBr4, PPh3, CH2Cl2). When the bromide
derivative was treated with KHMDS (1.2 equiv) in DMF, the
reaction did not go to completion (69% based on resting
starting material brsm) and the cyclized product 27 was isolated
in a modest yield (19%). The pyrrolidino ester 27 was then
transformed within three steps (deprotection, benzylation,
reduction) to the desired prolinol 28 with a modest
enantiomeric excess (ee = 50%). When 28 was treated with
DAST (1.4 equiv) in CH2Cl2, the ring enlargement adduct was
exclusively obtained in an excellent yield (87%) and with a
similar enantiomeric excess than the starting material 28
(Scheme 9). This example showed that the erosion of the
enantiomeric excess is related to the ring size of the cyclic
6090
dx.doi.org/10.1021/jo300887u | J. Org. Chem. 2012, 77, 6087−6099

The Journal of Organic Chemistry
Article
Scheme 8
Scheme 9
amino alcohols and not to the stability of a possible
intermediate carbocation.
Scheme 10
It is worth noting that the absolute configuration of the
stereogenic center in 24b·HCl was determined by X-ray
diffraction and confirmed the expected absolute configuration
of the stereogenic center, which is R (see ORTEP in the
Supporting Information).
We have to point out that the deprotection of the cyclic β-
fluoro amines was investigated. When racemic β-fluoro azepane
30 was submitted to classical hydrogenolysis conditions (H2,
Pd/C, MeOH, rt), the deprotected fluoroazepane 31 was
obtained with an excellent yield of 91% (Scheme 10). This
method could be generalized for the deprotection of other β-
fluoro amines.
In summary, the ring expansion of cyclic 2-hydroxymethyl
amines possessing a quaternary center at C2 induced by DAST
is a general and highly selective method allowing the formation
of cyclic amines with a tertiary fluoride at C3. Furthermore, the
ring expansion is highly enantioselective when applied to 2-
hydroxymethylazetidines and prolinols, but when applied to
cyclic 2-hydroxymethyl amines with larger ring, the enantiose-
lectivity is decreasing. The obtained 3-fluoro cyclic amines can
be useful building blocks, as they can be deprotected and then
involved in the synthesis of biologically active compounds.
EXPERIMENTAL SECTION
■
The synthesis of compounds 2a−2c, 2e, 14, 22a−22d, and 30 has
been already described in the literature.7,14,19
1
All reactions were run under an atmosphere of argon. H NMR
spectra were recorded on a NMR apparatus at 400 MHz and data are
reported as follows: chemical shift in ppm from tetramethylsilane as
internal standard, multiplicity (s = singlet, d = doublet, t = triplet, q =
quartet, m = multiplet or overlap of nonequivalent resonances,
integration). 13C NMR spectra were recorded on a NMR apparatus at
100 MHz and data are reported as follows: chemical shift in ppm from
tetramethylsilane with the solvent as internal standard (CDCl3, δ 77.0
6091
dx.doi.org/10.1021/jo300887u | J. Org. Chem. 2012, 77, 6087−6099

The Journal of Organic Chemistry
Article
ppm or DMSO-d6, δ 40.4 ppm), multiplicity with respect to proton
(deduced from DEPT experiments, s = quaternary C, d = CH, t =
CH2, q = CH3). Mass spectra with electronic impact (MS-EI) were
recorded a tandem GC apparatus (12 m capillary column) MS
apparatus (70 eV). Infrared (IR) spectra were recorded on an IR
apparatus (IRFT); wavenumbers are indicated in cm−1. TLC was
performed on 60F254 silica gel plates and visualized with a UV lamp
(254 nm) or by using solutions of KMnO4/K2CO3/AcOH in water
followed by heating. Column chromatography was performed with
silica gel (40−63 μm). High resolution mass spectra (HRMS) were
performed by an orbitrap mass spectrometer using a positive
electrospray ionization.
General Procedure 1. To a solution of cyclic β-keto ester of type
1 (1 equiv) and alkyl halide (2 equiv) in acetone was added K2CO3.
After refluxing for 12 h, the reaction media was cooled, filtered
through Celite, and washed with CH2Cl2. The solvents were removed
under reduced pressure, and the crude was purified by flash
chromatography on silica gel using a mixture of PE and EtOAc
leading to the desired compound of type 2.
General Procedure 2. To a solution of cyclic β-keto ester of type
2 (1 equiv) and concentrated sulfuric acid in excess (50 equiv) in
CHCl3 was added per portions over 2 h NaN3 (2 equiv). The reaction
media was vigorously stirred at rt for 3 h before iced water was added.
The layers were separated, and the aqueous layer was extracted with
CHCl3. The organic layers were combined, dried over MgSO4, and
concentrated under reduced pressure. The crude was purified by flash
chromatography on silica gel using a mixture of CH2Cl2 and EtOAc to
obtain the desired lactam of type 3.
General Procedure 3. To a solution of lactam of type 3 (1 equiv)
in THF was added LiAlH4 (5 equiv) at 0 °C. The reaction media was
refluxing for 2 h before being hydrolyzed at 0 °C successively by water
(10.5 equiv), a 0.15 M aqueous solution of NaOH (10.5 equiv), and
water (26.25 equiv). The residue was then filtered over Celite and
washed with CH2Cl2. The filtrate was concentrated under reduced
pressure leading to the desired amino alcohol. To a solution of this
alcohol (1 equiv) in CH3CN were successively added BnBr (1.1
equiv), K2CO3 (1.5 equiv), and n-Bu4NI (0.15 equiv). The reaction
media was refluxed for 4 h before being concentrated under reduced
pressure. The crude was diluted with water/EtOAc 1/1, the layers
were separated, and the aqueous layer was extracted with EtOAc. The
organic layers were combined, dried over MgSO4, and concentrated
under reduced pressure. The residue was purified by flash
chromatography on silica gel with a mixture of PE and EtOAc
affording the N-benzylamino alcohol of type 4.
General Procedure 4. To a solution of β-amino alcohol (1 equiv)
in CH2Cl2 was slowly added DAST (1.4 equiv) at 0 °C. The reaction
media was stirred 1 h at 0 °C followed by 1 h at rt before a saturated
aqueous solution of Na2CO3 was added. The layers were separated.
The aqueous layer was extracted with CH2Cl2. The organic layers were
combined, dried over Na2SO4, and concentrated under reduced
pressure. The crude was purified by flash chromatography on silica gel
using a mixture of PE and Et2O to obtain the fluorinated compound.
General Procedure 5. To a solution of amino ester (1 equiv) in
THF was added at −78 °C LDA (1.1 equiv). The reaction media was
stirred at this temperature for 20 min. Alkyl halide (1.2 equiv) was
added in the reaction media. The temperature was risen slowly at rt
over 4 h and water was added. The layers were separated, and the
aqueous layer was extracted with CH2Cl2. The organic layers were
combined, dried over MgSO4, and concentrated under reduced
pressure. The crude was purified by flash chromatography on silica gel
using a mixture of PE and EtOAc leading to the desired compound.
General Procedure 6. To a solution of ester (1 equiv) in THF
was added LiAlH4 (2 equiv) at 0 °C. The reaction media was stirred
for 2 h at rt before being hydrolyzed at 0 °C successively by water (4.2
equiv), a 0.15 M aqueous solution of NaOH (4.2 equiv), and water
(10.5 equiv). The residue was then filtered over Celite and washed
with CH2Cl2. The filtrate was concentrated under reduced pressure
leading to the desired amino alcohol.
at rt before a saturated aqueous solution of NaHCO3 was added at 0
°C. The layers were separated, and the aqueous layer was extracted
with CH2Cl2. The organic layers were combined, dried over MgSO4,
and concentrated under reduced pressure to afford the desired
compound.
General Procedure 8. To a solution of the amine (1 equiv) in
CH3CN were successively added BnBr (1.1 equiv), K2CO3 (1.5
equiv), and n-Bu4NI (0.5 equiv). The reaction media was stirred under
reflux for 8 h before being cooled. Water was added, and the mixture
was extracted with EtOAc. The organic layers were combined, dried
over MgSO4, and concentrated under reduced pressure. The crude was
purified by flash chromatography on silica gel using a mixture of PE
and EtOAc to afford the desired compound.
Methyl 1-Ethyl-2-oxocycloheptanecarboxylate (2d). Prepared
according to General Procedure 1, 1d (0.92 mL, 5.9 mmol, 1 equiv)
was alkylated by ethyl iodide (0.94 mL, 11.7 mmol, 2 equiv) in acetone
(15 mL). The crude was purified by flash chromatography on silica gel
(PE/EtOAc 95/5) leading to the desired compound 2d (958 mg, 4.8
mmol, 82%), isolated as a colorless oil: IR (neat) 2933, 2861, 1734,
1
1702, 1454, 1224, 1145, 1002 cm−1; H NMR (400 MHz, CDCl3) δ
3.60 (s, 3H), 2.50 (m, 1H), 2.36 (m, 1H), 2.02 (m, 1H), 1.90 (m, 2H),
1.66−1.30 (m, 7H), 0.73 (t, 3H, J = 8.4 Hz) ppm; 13C NMR (100
MHz, CDCl3) δ 209.2 (s), 172.8 (s), 63.1 (s), 51.8 (q), 41.9 (t), 32.2
(t), 29.7 (t), 28.2 (t), 25.4 (t), 24.7 (t), 8.9 (q) ppm; MS m/z (%) 198
(M+., 1), 170 (28), 166 (22), 141 (18), 139 (21), 138 (51), 137 (29),
115 (14), 110 (20), 109 (20), 102 (21), 98 (78), 97 (19), 96 (18), 95
(26), 87 (30), 83 (47), 81 (32), 69 (44), 67 (27), 59 (48), 55 (100),
53 (16); HRMS (ESI) Calcd. for C11H18O3Na (MNa)+, 221.1148,
found 221.1146.
Methyl 2-Ethyl-7-oxoazepane-2-carboxylate (3a). Prepared
according to General Procedure 2, 2a16 (470 mg, 2.55 mmol, 1 equiv)
was rearranged in CHCl3 (5 mL). The crude was purified by flash
chromatography on silica gel (CH2Cl2/EtOAc 80/20) affording 3a
(470 mg, 2.36 mmol, 93%), isolated as a white solid: mp 122−124 °C;
IR (neat) 3216, 3082, 2937, 1735, 1651, 1435, 1411, 1233, 1205, 1182,
1
1158, 1119, 1077 cm−1; H NMR (400 MHz, CDCl3) δ 6.06 (s br,
NH), 3.75 (s, 3H), 2.49 (m, 1H), 2.32 (m, 1H), 2.16 (m, 1H), 1.93−
1.63 (m, 4H), 1.81 (q, 2H, J = 7.6 Hz), 1.56 (m, 1H), 0.87 (t, 3H, J =
7.3 Hz) ppm; 13C NMR (100 MHz, CDCl3) δ 177.8 (s), 173.6 (s),
63.6 (s), 52.6 (q), 37.8 (t), 37.4 (t), 33.4 (t), 26.1 (t), 22.9 (t), 8.1 (q)
ppm; MS m/z (%) 170 (M+ − C2H5·, 1), 142 (16), 140 (100), 97
(42), 95 (32), 82 (20), 67 (11), 56 (28), 55 (61), 54 (12); HRMS
(ESI) Calcd. for C10H17NO3Na (MNa)+, 222.1101, found 222.1099.
Methyl 2-Allyl-7-oxoazepane-2-carboxylate (3b). To a
solution of 2b16 (1.21 g, 6.1 mmol, 1 equiv) in CHCl3 (30 mL)
were added at 0 °C CH3SO3H (3.95 mL, 61 mmol, 10 equiv) and
NaN3 (1.56 g, 24 mmol, 4 equiv). The reaction media was refluxed for
2 h before iced water was added. The media was neutralized by an
aqueous solution of ammonia 35% (5 mL). The layers were separated;
the aqueous layer was extracted with Et2O (3 × 10 mL). The organic
layers were combined, dried over Na2SO4, and concentrated under
reduced pressure. The crude was purified by flash chromatography on
silica gel (CH2Cl2/EtOAc 80/20) affording 3b (807 mg, 3.82 mmol,
68%), isolated as a white solid: mp 111−113 °C; IR (neat) 3216, 3079,
2953, 2921, 1736, 1648, 1447, 1405, 1268, 1200, 1172, 1148, 1099,
1058, 993 cm−1; 1H NMR (400 MHz, CDCl3) δ 5.85 (s br, 1H), 5.60
(m, 1H), 5.23 (m, 2H), 3.78 (s, 3H), 2.61 (dddd, 1H, J = 14.1, 6.2, 6.2,
and 1.4 Hz), 2.54 (m, 1H), 2.44−2.25 (m, 3H), 1.91 (m, 1H), 1.78−
1.67 (m, 2H), 1.60−1.50 (m, 2H) ppm; 13C NMR (100 MHz, CDCl3)
δ 177.4 (s), 173.2 (s), 130.7 (d), 121.5 (t), 62.4 (s), 52.6 (q), 45.5 (t),
38.5 (t), 37.7 (t), 26.4 (t), 22.8 (t) ppm; MS m/z (%) 170 (M+.−
Allyl·, 25), 152 (51), 142 (100), 110 (43), 109 (41), 107 (11), 83
(10), 82 (99), 81 (13), 79 (15), 68 (28), 67 (83), 55 (53), 54 (30), 53
(11); HRMS (ESI) Calcd. for C11H17NO3Na (MNa)+, 234.1101, found
234.1099.
Methyl 2-Benzyl-7-oxoazepane-2-carboxylate (3c). Prepared
according to General Procedure 2, 2c16 (500 mg, 2.03 mmol, 1 equiv)
was rearranged in CHCl3 (5 mL). The crude was purified by flash
chromatography on silica gel (CH2Cl2/EtOAc 80/20) affording 3c
(386 mg, 1.48 mmol, 74%), isolated as a beige solid: mp 128−130 °C;
General Procedure 7. To a solution of the amino ester (1 equiv)
in CH2Cl2 was added TFA (10 equiv) at 0 °C. The mixture was stirred
6092
dx.doi.org/10.1021/jo300887u | J. Org. Chem. 2012, 77, 6087−6099

The Journal of Organic Chemistry
Article
IR (neat) 3198, 3079, 2947, 2865, 1733, 1661, 1440, 1415, 1361, 1267,
1198, 1177, 1094 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.27−6.98 (m,
5H), 5.83 (s br, 1H), 3.67 (s, 3H), 3.14 (d, 1H, J = 13.1 Hz), 2.89 (d,
1H, J = 13.2 Hz), 2.48 (dd, 1H, J = 15.8 and 7.9 Hz), 2.35−2.22 (m,
2H), 1.88 (m, 1H), 1.79 (m, 1H), 1.65 (m, 1H), 1.58−1.46 (m, 2H)
ppm; 13C NMR (100 MHz, CDCl3) δ 177.2 (s), 173.2 (s), 136.8 (s),
130.2 (d, 2C), 129.7 (d, 2C), 127.8 (d), 63.8 (s), 52.5 (q), 46.4 (t),
38.8 (t), 37.7 (t), 26.0 (t), 22.8 (t) ppm; MS m/z (%) 261 (M+., 1),
202 (13), 170 (41), 142 (100), 110 (28), 92 (8), 91 (67), 82 (60), 81
(14), 65 (14), 55 (24), 54 (15); HRMS (ESI) Calcd. for C15H19NO3Na
(MNa)+, 284.1257, found 284.1259.
3110, 2914, 2821, 1498, 1448, 1414, 1258, 1173, 1048, 1021 cm−1; 1H
NMR (400 MHz, CDCl3) δ 7.49−7.19 (m, 10H), 4.07 (d, 1H, J = 14.2
Hz), 3.85 (d, 1H, J = 10.5 Hz), 3.75 (d, 1H, J = 9.2 Hz), 3.53 (d, 1H, J
= 10.5 Hz), 2.95 (d, 1H, J = 12.0 Hz), 2.88 (d, 1H, J = 12.5 Hz), 2.77
(m, 2H), 1.94−1.22 (m, 8H) ppm; 13C NMR (100 MHz, CDCl3) δ
141.5 (s), 138.1 (s), 130.5 (d, 2C), 128.7 (d, 2C), 128.4 (d, 2C), 128.1
(d, 2C), 126.9 (d), 126.2 (d), 67.7 (t), 63.0 (s), 54.2 (t), 47.0 (t), 40.1
(t), 38.1 (t), 31.2 (t), 29.7 (t), 23.2 (t) ppm; MS m/z (%) 309 (M+.,
1), 278 (8), 218 (27), 92 (8), 91 (100), 65 (9); HRMS (ESI) Calcd.
for C21H28NO (MH)+, 310.2165, found 310.2166.
(1-Benzyl-2-ethylazocan-2-yl)methanol (4d). Prepared accord-
ing to General Procedure 3, 3d (101 mg, 0.47 mmol, 1 equiv) was
transformed into 4d (62%). 4d was isolated as a yellow oil: IR (neat)
3373, 2922, 2851, 1452, 1376, 1207, 1119, 1043 cm−1; 1H NMR (400
MHz, CDCl3) δ 7.32−7.12 (m, 5H), 3.79 (d, 1H, J = 12.5 Hz), 3.60
(d, 1H, J = 10.8 Hz), 3.50 (d, 1H, J = 10.8 Hz), 3.39 (d, 1H, J = 13.3
Hz), 2.98 (m, 1H), 2.56 (ddd, 1H, J = 15.6, 4.6, and 4.6 Hz), 1.84−
0.88 (m, 12H), 0.84 (t, 3H, J = 7.8 Hz) ppm; 13C NMR (100 MHz,
CDCl3) δ 140.8 (s), 129.4 (d, 2C), 128.2 (d, 2C), 126.9 (d), 67.0 (t),
62.3 (s), 55.1 (t), 47.8 (t), 30.3 (t), 29.7 (t), 27.5 (t), 26.7 (t), 25.8 (t),
24.9 (t), 8.9 (q) ppm; MS m/z (%) 261 (M+., 1), 232 (9), 230 (43),
92 (8), 91 (100), 55 (8); HRMS (ESI) Calcd. for C17H28NO (MH)+,
262.21654, found 262.21646.
(1,2-Dibenzylazocan-2-yl)methanol (4e). Prepared according to
General Procedure 3, 3e (146 mg, 0.53 mmol, 1 equiv) was
transformed into 4e (42%). 4e was isolated as a yellow oil: IR (neat)
3429, 3026, 2921, 2850, 1493, 1451, 1357, 1249, 1204, 1115, 1041,
1017 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.35−7.09 (m, 10H), 4.00
(d, 1H, J = 13.5 Hz), 3.82 (d, 1H, J = 11.3 Hz), 3.52 (d, 1H, J = 13.5
Hz), 3.49 (d, 1H, J = 10.7 Hz), 3.19 (s br, OH), 2.93 (m, 1H), 2.81 (d,
1H, J = 13.5 Hz), 2.70 (d, 1H, J = 14.2 Hz), 2.50 (m, 1H), 1.80−0.57
(m, 10H) ppm; 13C NMR (100 MHz, CDCl3) δ 140.7 (s), 138.3 (s),
130.5 (d, 2C), 129.4 (d, 2C), 128.3 (d, 2C), 128.1 (d, 2C), 127.1 (d),
126.1 (d), 67.1 (t), 63.5 (s), 55.9 (t), 48.4 (t), 39.6 (t), 34.7 (t), 30.5
(t), 27.3 (t), 25.8 (t), 25.1 (t) ppm; MS m/z (%) 323 (M+., 1), 292
(10), 232 (35), 92 (7), 91(100), 65 (7); HRMS (ESI) Calcd. for
C22H30NO (MH)+, 324.2322, found 324.2317.
Methyl 2-Ethyl-8-oxoazocane-2-carboxylate (3d). Prepared
according to General Procedure 2, 2d (594 mg, 3.0 mmol, 1 equiv)
was rearranged in CHCl3 (5 mL). The crude was purified by flash
chromatography on silica gel (CH2Cl2/EtOAc 50/50) affording 3d
(135 mg, 0.63 mmol, 21%), isolated as a white solid: mp 128−130 °C;
IR (neat) 3203, 3082, 2927, 1730, 1655, 1450, 1400, 1231, 1159, 1131,
1
1075 cm−1; H NMR (400 MHz, CDCl3) δ 6.49 (s br, 1H), 3.71 (s,
3H), 2.40−2.18 (m, 3H), 1.85−1.38 (m, 9H), 0.80 (t, 3H, J = 7.2 Hz)
ppm; 13C NMR (100 MHz, CDCl3) δ 176.0 (s), 173.6 (s), 64.1 (s),
52.5 (q), 38.5 (t), 35.1 (t), 32.3 (t), 25.7 (t), 24.9 (t), 22.5 (t), 8.2 (q)
ppm; MS m/z (%) 213 (M+., 2), 156 (51), 154 (100), 124 (33), 116
(25), 111 (18), 109 (40), 99 (18), 96 (39), 84 (18), 81 (30), 69 (79),
56 (56), 55 (66), 54 (21); HRMS (ESI) Calcd. for C11H20NO3 (MH)+,
214.1438, found 214.1437.
Methyl 2-Benzyl-8-oxoazocane-2-carboxylate (3e). Prepared
according to General Procedure 2, 2e16 (520 mg, 2.0 mmol, 1 equiv)
was rearranged in CHCl3 (5 mL). The crude was purified by flash
chromatography on silica gel (CH2Cl2/EtOAc 50/50) affording 3e
(200 mg, 0.72 mmol, 36%), isolated as a beige solid: mp 141−143 °C;
IR (neat) 3190, 3067, 2933, 1741, 1659, 1453, 1404, 1265, 1227, 1195,
1165, 1099, 1043 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.24−6.99 (m,
5H), 6.39 (s br, 1H), 3.63 (s, 3H), 2.95 (s, 2H), 2.37 (m, 1H), 2.14
(m, 2H), 1.98 (m, 1H), 1.78−1.34 (m, 6H) ppm; 13C NMR (100
MHz, CDCl3) δ 175.5 (s), 173.5 (s), 134.4 (s), 130.4 (d, 2C), 128.5
(d, 2C), 127.3 (d), 64.9 (s), 52.8 (q), 47.5 (t), 36.6 (t), 33.4 (t), 25.6
(t), 24.8 (t), 22.8 (t) ppm; MS m/z (%) 275 (M+., 1), 216 (9), 184
(42), 157 (9), 156 (100), 124 (53), 96 (54), 91 (64), 81 (19), 79 (12),
69 (10), 65 (12), 55 (28), 54 (14); HRMS (ESI) Calcd. for
C16H21NO3Na (MNa)+, 298.1414, found 298.1413.
(1-Benzyl-2-ethylazepan-2-yl)methanol (4a). Prepared accord-
ing to General Procedure 3, 3a (300 mg, 1.51 mmol, 1 equiv) was
transformed into 4a (40%). 4a was isolated as a colorless oil: IR (neat)
3404, 2924, 2851, 1451, 1355, 1134, 1028 cm−1; 1H NMR (400 MHz,
CDCl3) δ 7.34−7.14 (m, 5H), 3.81 (d, 1H, J = 13.1 Hz), 3.53 (d, 1H, J
= 10.3 Hz), 3.48 (d, 1H, J = 10.0 Hz), 3.42 (d, 1H, J = 13.9 Hz), 2.74
(dd, 1H, J = 13.4 and 9.7 Hz), 2.55 (dd, 1H, J = 14.3 and 6.7 Hz),
1.90−1.80 (m, 2H), 1.65−1.41 (m, 6H), 1.17 (m, 2H), 0.86 (t, 3H, J =
7.6 Hz) ppm; 13C NMR (100 MHz, CDCl3) δ 140.9 (s), 128.7 (d,
2C), 128.4 (d, 2C), 126.9 (d), 67.9 (t), 65.4 (s), 53.7 (t), 47.1 (t), 37.6
(t), 31.2 (t), 29.8 (t), 27.1 (t), 23.3 (t), 8.7 (q) ppm; MS m/z (%) 247
(M+., 1), 216 (38), 91 (100), 65 (9); HRMS (ESI) Calcd. for
C16H26NO (MH)+, 248.20089, found 248.20086.
(2-Allyl-1-benzylazepan-2-yl)methanol (4b). Prepared accord-
ing to General Procedure 3, 3b (547 mg, 2.59 mmol, 1 equiv) was
transformed into 4b (68%). 4b was isolated as a yellow oil: IR (neat)
3410, 2923, 2850, 1493, 1451, 1354, 1320, 1144, 1056, 1027 cm−1; 1H
NMR (400 MHz, CDCl3) δ 7.32−7.14 (m, 5H), 5.80 (m, 1H), 5.04
(m, 2H), 3.84 (d, 1H, J = 14.2 Hz), 3.60 (d, 1H, J = 10.7 Hz), 3.48 (d,
1H, J = 13.6 Hz), 3.47 (d, 1H, J = 10.9 Hz), 2.73 (m, 1H), 2.54 (dd,
1H, J = 15.4 and 7.1 Hz,), 2.31 (dd, 1H, J = 14.2 and 7.1 Hz), 2.19
(dd, 1H, J = 13.6 and 7.6 Hz), 1.87−1.13 (m, 8H) ppm; 13C NMR
(100 MHz, CDCl3) δ 140.6 (s), 134.5 (d), 128.7 (d, 2C), 128.4 (d,
2C), 126.9 (d), 117.9 (t), 68.2 (t), 60.4 (s), 54.1 (t), 47.3 (t), 39.4 (t),
38.3 (t), 31.4 (t), 29.8 (t), 23.3 (t) ppm; MS m/z (%) 259 (M+., 1),
228 (15), 218 (22), 92 (8), 91 (100), 65 (8); HRMS (ESI) Calcd. for
C17H25NO (MH)+, 260.2009, found 260.2008.
1-Benzyl-3-ethyl-3-fluoroazocane (5a). Prepared according to
General Procedure 4, 4a (100 mg, 0.40 mmol, 1 equiv) was
rearranged in CH2Cl2 (5 mL) by DAST (75 μL, 0.56 mmol, 1.4
equiv). The residue was purified by flash chromatography on silica gel
(PE/Et2O 90/10) affording 5a (64 mg, 0.25 mmol, 64%), isolated as a
yellow oil: IR (neat) 2921, 2854, 2790, 1452, 1364, 1270, 1124, 1070,
1
1011 cm−1; H NMR (400 MHz, CDCl3) δ 7.29−7.11 (m, 5H), 3.71
(d, 1H, J = 13.7 Hz), 3.60 (d, 1H, J = 13.6 Hz), 2.78 (dd, 1H, J = 15.1
and 15.1 Hz), 2.53 (m, 1H), 2.42 (m, 1H), 2.31 (m, 1H), 2.07 (m,
1H), 1.80−1.66 (m, 2H), 1.60−1.14 (m, 7H), 0.86 (t, 3H, J = 7.2 Hz)
ppm; 13C NMR (100 MHz, CDCl3) δ 140.4 (s), 128.7 (d, 2C), 128.1
(d, 2C), 126.7 (d), 100.3 (ds, J = 169 Hz), 64.1 (t), 59.4 (dt, J = 25
Hz), 54.8 (t), 33.6 (dt, J = 24 Hz), 29.9 (dt, J = 23 Hz), 27, 3 (t), 27.2
(t), 22.7 (dt, J = 10 Hz), 7.28 (dq, J = 5 Hz) ppm; MS m/z (%) 249
(M+., 5), 174 (8), 160 (15), 158 (16), 147 (7), 146 (8), 134 (20), 98
(10), 92 (10), 91 (100), 84 (7), 65 (10); HRMS (ESI) Calcd. for
C16H25FN (MH)+, 250.1966, found 250.1968.
3-Allyl-1-benzyl-3-fluoroazocane (5b). Prepared according to
General Procedure 4, 4b (317 mg, 1.22 mmol, 1 equiv) was
rearranged in CH2Cl2 (10 mL) by DAST (226 μL, 1.71 mmol, 1.4
equiv). The residue was purified by flash chromatography on silica gel
(PE/Et2O 95/5) affording 5b (264 mg, 1.01 mmol, 83%), isolated as a
yellow oil: IR (neat) 2921, 2854, 2791, 1452, 1347, 1197, 1134, 1070,
1
1021 cm−1; H NMR (400 MHz, CDCl3) δ 7.55−7.31 (m, 5H), 6.03
(m, 1H), 5.23 (m, 2H), 3.91 (d, 1H, J = 13.2 Hz), 3.82 (d, 1H, J = 13.3
Hz), 3.00 (dd, 1H, J = 14.0 and 14.0 Hz), 2.79 (m, 1H), 2.67−2.49
(m, 3H), 2.46 (ddd, 1H, J = 7.2, 1.3, and 1.3 Hz), 2.27 (m, 1H), 2.06−
1.93 (m, 2H), 1.79−1.55 (m, 5H) ppm; 13C NMR (100 MHz, CDCl3)
δ 140.4 (s), 133.2 (d), 128.9 (d, 2C), 128.3 (d, 2C), 127.0 (d), 118.2
(t), 99.5 (ds, J = 179 Hz), 64.2 (t), 59.4 (dt, J = 43 Hz), 55.0 (t), 42.4
(dt, J = 24 Hz), 34.5 (dt, J = 24 Hz), 27.2 (t), 26.9 (t), 22.5 (dt, J = 9
Hz) ppm; MS m/z (%) 261 (M+., 5), 170 (16), 160 (12), 134 (18), 98
(1,2-Dibenzylazepan-2-yl)methanol (4c). Prepared according
to General Procedure 3, 3c (97 mg, 0.37 mmol, 1 equiv) was
transformed into 4c (64%). 4c was isolated as a colorless oil: IR (neat)
6093
dx.doi.org/10.1021/jo300887u | J. Org. Chem. 2012, 77, 6087−6099

The Journal of Organic Chemistry
Article
(11), 92 (11), 91 (100), 84 (7), 65 (11); HRMS (ESI) Calcd. for
C17H24FN (MH)+, 262.1966, found 262.1967.
tert-Butyl 3-Allyl-4-benzyl-3-(hydroxymethyl)piperazine-1-
carboxylate (8). 7 (902 mg, 2.2 mmol, 1 equiv) was alkylated by
LDA 1 M (2.4 mL, 2.4 mmol, 1.1 equiv) with allyl bromide (228 μL,
2.6 mmol, 1.2 equiv) in THF (10 mL) following General Procedure
5. The crude was purified by flash chromatography on silica gel (PE/
EtOAc 90/10) affording the intermediate piperazine (557 mg, 1.2
mmol, 56%). This intermediate piperazine (494 mg, 1.1 mmol, 1
equiv) was reduced in THF (10 mL) by LiAlH4 (166 mg, 4.4 mmol, 4
equiv) following General Procedure 6. Piperazine 8 (387 mg, 1.1
mmol, 100%) was isolated as a yellow oil: IR (neat) 3240, 2975, 1701,
1,3-Dibenzyl-3-fluoroazocane (5c). Prepared according to
General Procedure 4, 4c (155 mg, 0.50 mmol, 1 equiv) was
rearranged in CH2Cl2 (5 mL) by DAST (92 μL, 0.70 mmol, 1.4
equiv). The residue was purified by flash chromatography on silica gel
(PE/Et2O 90/10) affording 5c (101 mg, 0.32 mmol, 65%), isolated as
a yellow oil: IR (neat) 2918, 2854, 2790, 1452, 1347, 1138, 1076, 1025
1
cm−1; H NMR (400 MHz, CDCl3) δ 7.29−7.10 (m, 10H), 3.69 (d,
1H, J = 13.5 Hz), 3.56 (d, 1H, J = 13.8 Hz), 2.88−2.55 (m, 4H), 2.36
(m, 2H), 1.95 (m, 1H), 1.84−1.35 (m, 7H) ppm; 13C NMR (100
MHz, CDCl3) δ 140.3 (s), 136.7 (s), 130.6 (d, 2C), 128.8 (d, 2C),
128.2 (d, 2C), 128.1 (d, 2C), 126.8 (d), 126.4 (d), 99.9 (ds, J = 173
Hz), 64.1 (t), 59.6 (dt, J = 26 Hz), 54.6 (t), 43.7 (dt, J = 21 Hz), 34.0
(dt, J = 23 Hz), 27.1 (t), 27.0 (t), 22.6 (dt, J = 9 Hz) ppm; MS m/z
(%) 311 (M+., 3), 220 (12), 160 (13), 134 (15), 120 (9), 92 (10), 91
(100), 65 (10); HRMS (ESI) Calcd. for C21H27FN (MH)+, 312.2122,
found 312.2121.
1
1473, 1245, 1153, 1025 cm−1; H NMR (400 MHz, DMSO-d6 100
°C) δ 7.42−7.18 (m, 5H), 5.98 (m, 1H), 5.09 (m, 2H), 4.78 (m, 1H),
4.52 (m, 1H), 4.12 (m, 1H), 3.85 (d, 1H, J = 14.6 Hz), 3.72 (d, 1H, J =
14.2 Hz), 3.62 (dd, 1H, J = 11.4 and 5.0 Hz), 3.55 (dd, 1H, J = 11.4
and 3.9 Hz), 3.40−3.18 (m, 4H), 2.48−2.31 (m, 2H), 1.42 (s, 9H)
ppm; 13C NMR (100 MHz, CDCl3) δ 154.9 (s), 138.4 (s), 133.5 (d),
128.6 (d, 2C), 127.5 (d, 2C), 126.9 (d), 118.9 (t), 80.1 (s), 68.0 (t),
65.1 (t), 59.5 (s), 52.7 (t), 47.5 (t), 45.0 (t), 31.0 (t), 28.4 (q, 3C)
ppm; MS m/z (%) 315 (M+.-CH2OH, 18), 259 (25), 231 (20), 218
(17), 92 (10), 91 (100), 57 (24); HRMS (ESI) Calcd. C20H31N2O3
(MH)+, 347.2256, found 347.2258.
1-Benzyl-3-ethyl-3-fluoroazonane (5d). Prepared according to
General Procedure 4, 4d (72 mg, 0.28 mmol, 1 equiv) was rearranged
in CH2Cl2 (4 mL) by DAST (51 μL, 0.39 mmol, 1.4 equiv). The
residue was purified by flash chromatography on silica gel (PE/Et2O
98/2) affording 5d (43 mg, 0.16 mmol, 58%), isolated as a yellow oil:
IR (neat) 2929, 2792, 1453, 1365, 1265, 1192, 1109, 1063, 1027, 1004
2-(Benzylamino)-2-methylpropane-1,3-diol (10). To a solu-
tion of 9 (2.10 g, 20 mmol, 1 equiv) in methanol (20 mL) was added
benzaldehyde (2.03 mL, 20 mmol, 1 equiv) at 0 °C. The reaction
medium was stirred at rt for 2 h before being cooled at 0 °C. NaBH4
(1.18 g, 32 mmol, 1.6 equiv) was added per portions in the medium,
which was stirred 10 min before being hydrolyzed by the addition of a
1 M aqueous solution of NaOH (10 mL). The layers were separated,
and the aqueous layer was extracted with EtOAc (3 × 10 mL). The
organic layers were combined, dried over MgSO4, and concentrated
under reduced pressure. The crude was purified by flash chromatog-
raphy on silica gel (EtOAc/MeOH 90/10) leading to 10 (2.18 g, 11.2
mmol, 56%), isolated as a white solid: mp 133−135 °C; IR (neat)
1
cm−1; H NMR (400 MHz, CDCl3) δ 7.31−7.12 (m, 5H), 3.86 (d,
1H, J = 14.2 Hz), 3.46 (d, 1H, J = 12.7 Hz), 2.59−2.55 (m, 2H), 2.30−
2.17 (m, 3H), 1.74−1.04 (m, 11H), 0.89 (t, 3H, J = 6.9 Hz) ppm; 13C
NMR (100 MHz, CDCl3) δ 140.4 (s), 129.1 (d, 2C), 128.1 (d, 2C),
126.7 (d), 102.4 (ds, J = 170 Hz), 63.1 (dt, J = 4 Hz), 56.0 (dt, J = 22
Hz), 53.7 (t), 28.8 (dt, J = 22 Hz), 28.4 (dt, J = 23 Hz), 27.3 (t), 22.5
(t), 19.7 (t), 18.2 (dt, J = 11 Hz), 7.1 (dq, J = 4 Hz) ppm; MS m/z
(%) 263 (M+., 3), 172 (27), 160 (9), 134 (20), 120 (20), 92 (10), 91
(100), 65 (11); HRMS (ESI) Calcd. C17H26FN (MH)+, 264.2122,
found 264.2124.
1
3255, 2925, 1451, 1077, 1053 cm−1; H NMR (400 MHz, CDCl3) δ
7.35−7.24 (m, 5H), 3.67 (s, 2H), 3.50 (s, 4H), 2.78 (s br, 3H), 1.03
(s, 3H) ppm; 13C NMR (100 MHz, CDCl3) δ 140.1 (s), 128.6 (d,
2C), 128.4 (d, 2C), 127.2 (d), 67.0 (t), 57.0 (s), 46.0 (t, 2C), 18.3 (q)
ppm; HRMS (ESI) Calcd. C11H18NO2 (MH)+, 196.1332, found
196.1330.
1,3-Dibenzyl-3-fluoroazonane (5e). Prepared according to
General Procedure 4, 4e (50 mg, 0.15 mmol, 1 equiv) was rearranged
in CH2Cl2 (3 mL) by DAST (28 μL, 0.21 mmol, 1.4 equiv). The
residue was purified by flash chromatography on silica gel (PE/Et2O
98/2) affording 5e (43 mg, 0.09 mmol, 62%), isolated as a yellow oil:
4-Benzyl-5-(hydroxymethyl)-5-methylmorpholin-3-one (11).
To a solution of 10 (485 mg, 2.5 mmol, 1 equiv) in CH2Cl2 (10 mL)
were successively added at 0 °C K2CO3 (513 mg, 3.7 mmol, 1.5 equiv)
and 2-chloroacetyl chloride (239 μL, 3.0 mmol, 1.2 equiv). The
reaction media was stirred at rt for 5 h, and water (10 mL) was added.
The layers were separated, and the aqueous layer was extracted with
CH2Cl2 (2 × 10 mL). The organic layers were combined, washed
successively with water (10 mL), 1 M aqueous solution of HCl (10
mL), and brine (10 mL), dried over MgSO4, and concentrated under
reduced pressure. The crude was dissolved in t-BuOH (5 mL), and t-
BuOK (277 mg, 2.5 mmol, 1 equiv) was added to the medium. After
refluxing for 3 h, the media was cooled, and a mixture of EtOAc/H2O
50:50 was added. The layers were separated, and the aqueous layer was
extracted with EtOAc (2 × 5 mL). The organic layers were combined,
dried over MgSO4, and concentrated under reduced pressure. The
crude was purified by flash chromatography on silica gel (EtOAc,
100%) affording 11 (83 mg, 0.35 mmol, 14%), isolated as a colorless
1
IR (neat) 2928, 2793, 1494, 1453, 1364, 1137, 1063, 1022 cm−1; H
NMR (400 MHz, CDCl3) δ 7.32−7.10 (m, 10H), 3.91 (d, 1H, J = 13.8
Hz), 3.41 (d, 1H, J = 13.8 Hz), 2.84−2.53 (m, 4H), 2.30−2.15 (m,
3H), 1.66−1.09 (m, 9H) ppm; 13C NMR (100 MHz, CDCl3) δ 140.3
(s), 136.5 (s), 130.5 (d, 2C), 129.1 (d, 2C), 128.1 (d, 2C), 128.0 (d,
2C), 126.7 (d), 126.4 (d), 102.1 (ds, J = 173 Hz), 63.1 (dt, J = 3 Hz),
56.1 (dt, J = 20 Hz), 53.5 (t), 42.4 (dt, J = 20 Hz), 28.3 (dt, J = 23
Hz), 27.4 (t), 22.3 (t), 19.3 (t), 18.4 (dt, J = 11 Hz) ppm; MS m/z
(%) 325 (1), 234 (20), 172 (6), 160 (6), 134 (13), 120 (16), 92 (9),
91 (100), 65 (10); HRMS (ESI) Calcd. C22H29FN (MH)+, 326.2278,
found 326.2275.
3-Benzyl 1-tert-Butyl 4-Benzylpiperazine-1,3-dicarboxylate
(7). To a suspension of amino acid 6 (1.00 g, 4.3 mmol, 1 equiv) in
water (10 mL) were successively added at 0 °C benzyl bromide (1.54
mL, 13.0 mmol, 3 equiv), Na2CO3 (920 mg, 8.7 mmol, 2 equiv), and
NaOH (347 mg, 8.7 mmol, 2 equiv). The reaction media was refluxed
for 3 h and then cooled and extracted with Et2O (3 × 10 mL). The
organic layers were combined, dried over MgSO4, and concentrated
under reduced pressure. The crude was purified by flash chromatog-
raphy on silica gel (PE/EtOAc 90/10) to afford 7 (985 mg, 2.4 mmol,
55%), isolated as a colorless oil: IR (neat) 2975, 1735, 1693, 1454,
1421, 1365, 1286, 1243, 1146, 1123, 1025 cm−1; 1H NMR (400 MHz,
CDCl3) δ 7.42−7.23 (m, 10H), 5.22 (d, 1H, J = 12.2 Hz), 5.15 (d, 1H,
J = 12.4 Hz), 3.90 (m, 1H), 3.86 (d, 1H, J = 13.1 Hz), 3.60 (d, 1H, J =
13.7 Hz), 3.56 (m, 2H), 3.22 (m, 2H), 3.08 (m, 1H), 2.36 (m, 1H),
1.44 (s, 9H) ppm; 13C NMR (100 MHz, CDCl3) δ 171.1 (s), 154.4
(s), 137.7 (s), 135.6 (s), 129.1 (d, 2C), 128.6 (d, 2C), 128.3 (d, 2C),
128.2 (d, 2C), 127.5 (d), 127.3 (d), 79.9 (s), 66.4 (t), 61.5 (t), 59.6
(t), 47.8 (t), 46.4 (t), 36.1 (t), 28.3 (q, 3C) ppm; HRMS (ESI) Calcd.
C24H31N2O4 (MH)+, 411.2278, found 411.2289.
1
oil: IR (neat) 3275, 2967, 1685, 1452, 1277, 1172 cm−1; H NMR
(400 MHz, CDCl3) δ 7.25−7.11 (m, 5H), 4.65 (d, 1H, J = 12.1 Hz),
4.47 (d, 1H, J = 11.9 Hz), 4.18 (s, 2H), 3.87 (d, 1H, J = 9.0 Hz), 3.55
(d, 1H, J = 8.8 Hz), 3.43 (d, 1H, J = 9.0 Hz), 3.32 (d, 1H, J = 8.6 Hz),
3.04 (s br, 1H), 1.00 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3) δ
168.8 (s), 138.5 (s), 128.6 (d, 2C), 127.1 (d, 2C), 127.0 (d), 71.5 (t),
68.0 (t), 65.0 (t), 59.8 (s), 44.6 (t), 18.7 (q) ppm; MS m/z (%) 235
(M+., 1), 204 (24), 91 (100), 65 (10); HRMS (ESI) Calcd. C13H18NO3
(MH)+, 236.1208, found 236.1211.
(4-Benzyl-3-methylmorpholin-3-yl)methanol (12). To a sol-
ution of 11 (146 mg, 0.62 mmol, 1 equiv) in toluene (2 mL) was
added at 0 °C a 3.31 M solution of Red-Al in toluene (563 μL, 1.86
mmol, 1 equiv). The reaction media was stirred at rt for 1 h before
being cooled to 0 °C. EtOH (2 mL) and then a 1 M aqueous solution
6094
dx.doi.org/10.1021/jo300887u | J. Org. Chem. 2012, 77, 6087−6099

The Journal of Organic Chemistry
Article
of NaOH were added until pH = 12. The layers were separated, and
the aqueous layer was extracted with EtOAc (2 × 5 mL). The organic
layers were combined and acidified with a 1 M aqueous solution of
HCl (pH 3). The aqueous layer was separated, and a 1 M aqueous
solution of NaOH was added (pH 12). The aqueous layer was
extracted with EtOAc (2 × 5 mL). The organic layers were combined,
dried over MgSO4, and concentrated under reduced pressure. The
crude was purified by flash chromatography on silica gel (PE/EtOAc
70/30) affording 12 (102.6 mg, 0.46 mmol, 75%), isolated as a
ppm; MS m/z (%) 357 (M+., 1), 265 (36), 91 (100), 65 (9); HRMS
(ESI) Calcd. C24H23NO2Na (MNa)+, 380.1621, found 380.1626.
(1-Benzyl-2-ethylindolin-2-yl)methanol (16a). Prepared ac-
cording to General Procedure 6, 15a (1.75 g, 5.93 mmol, 1 equiv)
in THF (15 mL) was reduced by LiAlH4 (451 mg, 11.86 mmol, 2
equiv). 16a (1.58 g, 5.93 mmol, 100%) was isolated as a yellow oil: IR
(neat) 3415, 3026, 2965, 2933, 2875, 1604, 1485, 1452, 1354, 1314,
1274, 1142 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.44−7.26 (m, 5H),
7.10 (d, 1H, J = 7.4 Hz), 7.01 (dd, 1H, J = 7.4 and 7.4 Hz), 6.68 (dd,
1H, J = 6.9 and 6.9 Hz), 6.28 (d, 1H, J = 7.9 Hz), 4.38 (s, 2H), 3.60 (d,
1H, J = 11.7 Hz), 3.53 (d, 1H, J = 11.7 Hz), 3.31 (d, 1H, J = 15.9 Hz),
3.01 (d, 1H, J = 16.4 Hz), 1.81 (s br, OH), 1.79 (qd, 1H, J = 14.9 and
7.5 Hz), 1.55 (qd, 1H, J = 14.8 and 7.4 Hz), 0.88 (t, 3H, J = 7.8 Hz)
ppm; 13C NMR (100 MHz, CDCl3) δ 152.4 (s), 139.9 (s), 130.5 (d),
128.9 (d, 2C), 127.3 (d, 2C), 127.1 (s), 126.6 (d), 123.9 (d), 117.3
(d), 106.0 (d), 71.9 (s), 66.3 (t), 46.9 (t), 35.4 (t), 27.0 (t), 8.2 (q)
ppm; MS m/z (%) 267 (M+., 5), 236 (37), 9 (100), 65 (10); HRMS
(ESI) Calcd. C18H21NONa (MNa)+, 290.1515, found 290.1518.
(2-Allyl-1-benzylindolin-2-yl)methanol (16b). Prepared ac-
cording to General Procedure 6, 15b (1.62 g, 5.27 mmol, 1 equiv)
in THF (15 mL) was reduced by LiAlH4 (461 mg, 12.13 mmol, 2
equiv). 16b (1.41 g, 5.05 mmol, 95%) was isolated as a yellow oil: IR
(neat) 3415, 3026, 2918, 1604, 1485, 1452, 1353, 1270, 1141, 1027
1
colorless oil: IR (neat) 3412, 2961, 2852, 1450, 1126, 1041 cm−1; H
NMR (400 MHz, CDCl3) δ 7.28−7.17 (m, 5H), 3.87 (d, 1H, J = 9.9
Hz), 3.73−3.64 (m, 3H), 3.43 (m, 1H), 3.39 (d, 1H, J = 9.1 Hz), 3.12
(d, 1H, J = 8.4 Hz), 3.10 (d, 1H, J = 9.6 Hz), 2.51−2.46 (m, 2H), 1.04
(s, 3H) ppm; 13C NMR (100 MHz, CDCl3) δ 138.3 (s), 128.9 (d,
2C), 128.5 (d, 2C), 127.3 (d), 74.0 (t), 67.6 (t), 63.8 (t), 57.1 (s), 53.3
(t), 45.8 (t), 12.9 (q) ppm; MS m/z (%) 221 (M+., 1), 190 (35), 91
(100), 65 (10); HRMS (ESI) Calcd. C13H20NO2 (MH)+, 222.1489,
found 222.1485.
Methyl 1-Benzyl-2-ethylindoline-2-carboxylate (15a). Pre-
pared according to General Procedure 5, 14 (2.36 g, 8.8 mmol, 1
equiv) was alkylated by LDA 1 M (9.5 mL, 9.5 mmol, 1.1 equiv) with
ethyl iodide (832 μL, 10.4 mmol, 1.2 equiv) in THF (20 mL). The
residue was purified by flash chromatography on silica gel (PE/EtOAc
98/2) affording 15a (1.78 g, 6.0 mmol, 68%), isolated as an orange oil:
IR (neat) 3028, 2950, 1729, 1606, 1485, 1452, 1353, 1233, 1194, 1157
1
cm−1; H NMR (400 MHz, CDCl3) δ 7.40−7.25 (m, 5H), 7.10 (d,
1H, J = 7.6 Hz), 7.00 (dd, 1H, J = 7.6 and 7.6 Hz), 6.68 (dd, 1H, J =
7.4 and 7.4 Hz), 6.25 (d, 1H, J = 7.6 Hz), 5.74 (dddd, 1H, J = 14.2,
7.1, 7.1, and 6.5 Hz), 5.16 (m, 1H), 5.09 (m, 1H), 4.45 (d, 1H, J =
16.7 Hz), 4.37 (d, 1H, J = 16.7 Hz), 3.66 (d, 1H, J = 12.2 Hz), 3.58 (d,
1H, J = 11.6 Hz), 3.25 (d, 1H, J = 16.2 Hz), 3.07 (d, 1H, J = 16.2 Hz),
2.53 (dd, 1H, J = 14.2 and 7.1 Hz), 2.33 (dd, 1H, J = 14.2 and 7.6 Hz)
ppm; 13C NMR (100 MHz, CDCl3) δ 151.8 (s), 139.7 (s), 133.0 (d),
128.9 (d), 127.4 (d, 2C), 127.3 (d, 2C), 127.1 (s), 126.6 (d), 124.1
(d), 118.7 (t), 117.6 (d), 106.4 (d), 71.3 (s), 66.0 (t), 47.1 (t), 38.6
(t), 35.7 (t) ppm; MS m/z (%) 279 (M+., 4), 248 (11), 237 (19), 208
(10), 91 (100), 65 (10); HRMS (ESI) Calcd. C19H22NO (MH)+,
280.1696, found 280.1700.
(1,2-Dibenzylindolin-2-yl)methanol (16c). Prepared according
to General Procedure 6, 15c (2.65 g, 7.43 mmol, 1 equiv) in THF (15
mL) was reduced by LiAlH4 (565 mg, 14.87 mmol, 2 equiv). 16c (2.05
g, 6.23 mmol, 84%) was isolated as a yellow oil: IR (neat) 3430, 3026,
2919, 1604, 1483, 1353, 1275, 1138, 1027 cm−1; 1H NMR (400 MHz,
CDCl3) δ 7.46−7.18 (m, 10H), 7.11 (d, 1H, J = 7.1 Hz), 7.02 (dd, 1H,
J = 7.5 and 7.5 Hz), 6.70 (dd, 1H, J = 7.1 and 7.1 Hz), 6.30 (d, 1H, J =
8.0 Hz), 4.58 (d, 1H, J = 16.4 Hz), 4.45 (d, 1H, J = 16.5 Hz), 3.79 (d,
1H, J = 10.8 Hz), 3.62 (d, 1H, J = 12.0 Hz), 3.10 (d, 1H, J = 15.5 Hz),
3.06 (d, 1H, J = 12.3 Hz), 3.00 (d, 1H, J = 15.9 Hz), 2.90 (d, 1H, J =
13.3 Hz) ppm; 13C NMR (100 MHz, CDCl3) δ 151.3 (s), 139.6 (s),
136.7 (s), 130.5 (d), 128.9 (d, 2C), 128.3 (d, 2C), 127.4 (d, 2C),
127.3 (s), 127.1 (d, 2C), 126.6 (d), 126.5 (d), 124.3 (d), 117.8 (d),
107.1 (d), 72.8 (s), 64.9 (t), 47.4 (t), 38.7 (t), 34.7 (t) ppm; MS m/z
(%) 329 (M+., 1), 238 (27), 208 (11), 91 (100), 65 (10); HRMS (ESI)
Calcd. C23H23NONa (MNa)+, 352.1672, found 352.1673.
tert-Butyl 6-Allyl-4-benzyl-6-fluoro-1,4-diazepane-1-carbox-
ylate (17). Prepared according to General Procedure 4, 8 (387 mg,
1.12 mmol, 1 equiv) was rearranged in CH2Cl2 (10 mL) by DAST
(206 μL, 1.56 mmol, 1.4 equiv). The residue was purified by flash
chromatography on silica gel (PE/EtOAc 90/10) affording 17 (220
mg, 0.63 mmol, 56%), isolated as a colorless oil: IR (neat) 2921, 2854,
2791, 1695, 1452, 1347, 1197, 1134, 1070, 1021 cm−1; 1H NMR (400
MHz, DMSO-d6 100 °C) δ 7.36−7.21 (m, 5H), 5.76 (m, 1H), 5.07
(m, 2H), 3.76−3.66 (m, 3H), 3.58−3.45 (m, 2H), 3.26 (m, 1H), 2.80
(m, 1H), 2.76 (m, 1H), 2.66 (m, 2H), 2.46−2.27 (m, 2H), 1.42 (s,
9H) ppm; 13C NMR (100 MHz, CDCl3) δ 154.1 (s), 138.9 (s), 131.9
(d), 128.6 (d, 2C), 128.1 (d, 2C), 127.0 (d), 118.9 (t), 98.1 (ds, J =
177 Hz), 78.8 (s), 62.3 (t), 62.0 (dt, J = 28 Hz), 55.5 (t), 55.4 (dt, J =
34 Hz), 52.9 (dt, J = 31 Hz), 49.0 (dt, J = 33 Hz), 27.9 (q, 3C) ppm;
MS m/z (%) 348 (M+., 1), 291 (12), 230 (15), 91 (100), 65 (9), 57
(37); HRMS (ESI) Calcd. C20H30N2O2F (MH)+, 349.22858, found
349.22856.
1
cm−1; H NMR (400 MHz, CDCl3) δ 7.39−7.22 (m, 5H), 7.09 (d,
1H, J = 7.5 Hz), 6.97 (d, 1H, J = 7.5 Hz), 6.66 (ddd, 1H, J = 7.3, 7.3
and 1.0 Hz), 6.15 (d, 1H, J = 7.6 Hz), 4.52 (d, 1H, J = 17.8 Hz), 4.44
(d, 1H, J = 17.1 Hz), 3.65 (s, 3H), 3.58 (d, 1H, J = 16.4 Hz), 3.20 (d,
1H, J = 16.5 Hz), 2.03 (m, 2H), 0.96 (t, 3H, J = 7.1 Hz) ppm; 13C
NMR (100 MHz, CDCl3) δ 174.5 (s), 151.0 (s), 139.2 (s), 129.8 (d),
129.0 (d, 2C), 128.4 (d, 2C), 127.5 (d), 126.6 (s), 123.6 (d), 117.5
(d), 106.4 (d), 74.7 (s), 52.1 (q), 48.6 (t), 37.7 (t), 28.0 (t), 8.5 (q)
ppm; MS m/z (%) 295 (M+., 1), 236 (39), 91 (100), 65 (8); HRMS
(ESI) Calcd. C19H21NO2Na (MNa)+, 318.1465, found 318.1466.
Methyl 2-Allyl-1-benzylindoline-2-carboxylate (15b). Pre-
pared according to General Procedure 5, 14 (2.36 g, 8.8 mmol, 1
equiv) was alkylated by LDA 1 M (9.5 mL, 9.5 mmol, 1.1 equiv) with
allyl bromide (898 μL, 10.4 mmol, 1.2 equiv) in THF (20 mL). The
crude was purified by flash chromatography on silica gel (PE/EtOAc
98/2) affording 15b (1.65 g, 5.4 mmol, 61%), isolated as an orange oil:
IR (neat) 3028, 2950, 1730, 1605, 1485, 1434, 1352, 1250, 1196, 1164
1
cm−1; H NMR (400 MHz, CDCl3) δ 7.39−7.24 (m, 5H), 7.07 (d,
1H, J = 7.0 Hz), 6.97 (dd, 1H, J = 7.7 and 7.7 Hz), 6.67 (dd, 1H, J =
7.6 and 7.6 Hz), 6.16 (d, 1H, J = 7.6 Hz), 5.78 (m, 1H), 5.15 (m, 2H),
4.55 (d, 1H, J = 16.5 Hz), 4.43 (d, 1H, J = 16.6 Hz), 3.67 (s, 3H), 3.52
(d, 1H, J = 15.9 Hz), 3.28 (d, 1H, J = 16.5 Hz), 2.81 (dd, 1H, J = 14.2
and 7.5 Hz), 2.72 (dd, 1H, J = 14.3 and 6.8 Hz) ppm; 13C NMR (100
MHz, CDCl3) δ 174.1 (s), 150.9 (s), 139.0 (s), 132.6 (d), 128.5 (d,
2C), 127.5 (d, 2C), 126.7 (d), 126.6 (s), 126.4 (d), 123.7 (d), 119.3
(t), 117.7 (d), 106.6 (d), 73.7 (s), 52.1 (q), 49.0 (t), 39.6 (t), 38.2 (t)
ppm; MS m/z (%) 307 (M+., 1), 265 (22), 248 (9), 91 (100), 65 (9);
HRMS (ESI) Calcd. C20H21NO2Na (MNa)+, 330.1464, found
330.1465.
Methyl 1,2-Dibenzylindoline-2-carboxylate (15c). Prepared
according to General Procedure 5, 1416 (2.36 g, 8.8 mmol, 1 equiv)
was alkylated by LDA 1 M (9.5 mL, 9.5 mmol, 1.1 equiv) with benzyl
bromide (1.24 mL, 10.4 mmol, 1.2 equiv) in THF (20 mL). The crude
was purified by flash chromatography on silica gel (PE/EtOAc 98/2)
affording 15c (2.79 g, 7.8 mmol, 88%), isolated as an orange oil: IR
(neat) 3028, 2949, 1728, 1605, 11484, 1452, 1352, 1268, 1237, 1195,
1
1081, 1028 cm−1; H NMR (400 MHz, CDCl3) δ 7.39−7.17 (m,
10H), 7.08 (d, 1H, J = 6.8 Hz), 6.98 (dd, 1H, J = 7.5 and 7.5 Hz), 6.69
(ddd, 1H, J = 7.4, 7.4, and 1.0 Hz), 6.19 (d, 1H, J = 7.8 Hz), 4.67 (d,
1H, J = 17.1 Hz), 4.59 (d, 1H, J = 16.9 Hz), 3.66 (s, 3H), 3.54 (d, 1H,
J = 13.3 Hz), 3.53 (d, 1H, J = 15.7 Hz), 3.30 (d, 1H, J = 16.0 Hz), 3.16
(d, 1H, J = 13.5 Hz) ppm; 13C NMR (100 MHz, CDCl3) δ 173.5 (s),
150.4 (s), 139.1 (s), 136.0 (s), 130.4 (d), 128.5 (d, 2C), 128.3 (d, 2C),
127.5 (d, 2C), 126.9 (d, 2C), 126.7 (d), 126.6 (s), 126.5 (d), 123.7
(d), 117.9 (d), 107.1 (d), 75.3 (s), 52.1 (q), 49.0 (t), 40.6 (t), 37.7 (t)
6095
dx.doi.org/10.1021/jo300887u | J. Org. Chem. 2012, 77, 6087−6099

The Journal of Organic Chemistry
Article
4-Benzyl-6-fluoro-6-methyl-1,4-oxazepane (18). Prepared ac-
cording to General Procedure 4, 12 (100 mg, 0.45 mmol, 1 equiv)
was rearranged in CH2Cl2 (5 mL) by DAST (83.6 μL, 0.63 mmol, 1.4
equiv). The residue was purified by flash chromatography on silica gel
(PE/EtOAc 90/10) affording 18 (67 mg, 0.30 mmol, 67%), isolated as
a colorless oil: IR (neat) 2938, 1454, 1125, 1067 cm−1; 1H NMR (400
MHz, CDCl3) δ 7.28−7.15 (m, 5H), 3.90 (dd, 1H, J = 13.9 and 10.0
Hz), 3.79 (ddd, 1H, J = 9.2, 3.7, and 2.9 Hz), 3.64 (d, 1H, J = 13.3
Hz), 3.58 (d, 1H, J = 13.3 Hz), 3.56 (dd, 1H, J = 25.8 and 13.3 Hz),
3.51 (ddd, 1H, J = 16.0, 3.8, and 3.8 Hz), 2.90 (dd, 1H, J = 13.0 and
10.3 Hz), 2.73−2.56 (m, 3H), 1.13 (d, 3H, J = 16.1 Hz) ppm; 13C
NMR (100 MHz, CDCl3) δ 139.1 (s), 129.0 (d), 128.3 (d), 127.3 (d),
98.0 (ds, J = 169 Hz), 78.7 (dt, J = 28 Hz), 74.4 (t), 65.0 (dt, J = 30
Hz), 63.7 (t), 59.5 (t), 23.1 (dq, J = 25 Hz) ppm; MS m/z (%) 223
(M+., 5), 162 (30), 133 (25), 132 (24), 91 (100), 65 (21); HRMS
(ESI) Calcd. C13H19NOF (MH)+, 224.1445, found 224.1442.
91 (100), 65 (13); HRMS (ESI) Calcd. C23H23NF (MH)+, 332.1809,
found 332.1807.
(R)-(1,2-Dibenzylazetidin-2-yl)methanol (23a). Prepared ac-
cording to General Procedure 7, 22a14 (64.2 mg, 0.20 mmol, 1 equiv)
was deprotected by TFA in CH2Cl2. The β-amino ester obtained was
protected by BnBr in CH3CN following General Procedure 8. The β-
amino ester was then reduced by LiAlH4 in THF following General
Procedure 6 affording 23a (44%), isolated as a white solid: mp 119−
20
121 °C; [α]D = −4.1 (c 1, CHCl3); IR (neat) 3241, 2925, 2853,
1494, 1453, 1310, 1238, 1153, 1063, 1044 cm−1; 1H NMR (400 MHz,
CDCl3) δ 7.29−7.06 (m, 10H), 3.72 (d, 1H, J = 12.9 Hz), 3.54 (d, 1H,
J = 13.0 Hz), 3.21 (d, 1H, J = 12.9 Hz), 3.19−3.06 (m, 4H), 2.77 (d,
1H, J = 13.0 Hz), 2.06 (m, 1H), 1.87 (m, 1H) ppm; 13C NMR (100
MHz, CDCl3) δ 138.4 (s), 136.9 (s), 130.0 (d, 2C), 128.5 (d, 2C),
128.4 (d, 2C), 128.3 (d, 2C), 126.5 (d), 125.5 (d), 70.0 (t), 64.2 (s),
53.8 (t), 48.8 (t), 37.0 (t), 22.7 (t) ppm; MS m/z (%) 249 (M+.-H2O,
29), 248 (10), 247 (6), 172 (10), 158 (6), 131 (21), 129 (6), 115 (5),
92 (9), 91 (100), 65 (16); HRMS (ESI) Calcd. for C18H22NO (MH)+,
268.1696, found 268.1701.
1-Benzyl-3-ethyl-3-fluoro-1,2,3,4-tetrahydroquinoline (19a).
Prepared according to General Procedure 4, 16a (534 mg, 2.0 mmol,
1 equiv) was rearranged in CH2Cl2 (20 mL) by DAST (369 μL, 2.8
mmol, 1.4 equiv). The residue was purified by flash chromatography
on silica gel (PE/Et2O 98/2) affording 19a (440 mg, 1.6 mmol, 81%),
isolated as a yellow oil: IR (neat) 3027, 2970, 2937, 1602, 1507, 1451,
(S)-(1,2-Dibenzylpyrrolidin-2-yl)methanol (23b). Prepared
according to General Procedure 7, 22b14 (97 mg, 0.29 mmol, 1
equiv) was deprotected by TFA in CH2Cl2. The β-amino ester
obtained was protected by BnBr in CH3CN following General
Procedure 8. The β-amino ester was then reduced by LiAlH4 in THF
following General Procedure 6 affording 23b (77%), isolated as a
1
1354, 1327, 1288, 1247, 1168 cm−1; H NMR (400 MHz, C6D6) δ
7.33−7.00 (m, 7H), 6.82 (ddd, 1H, J = 7.3, 7.3, and 1.0 Hz), 6.63 (d,
1H, J = 8.3 Hz), 4.27 (s, 2H), 3.22 (m, 1H), 3.06−2.95 (m, 2H), 2.69
(dd, 1H, J = 19.2 (H−F) and 16.0 Hz), 1.53 (qd, 2H, J = 20.6 (H−F)
and 7.3 Hz), 0.93 (t, 3H, J = 7.4 Hz) ppm; 13C NMR (100 MHz,
C6D6) δ 144.6 (s), 138.8 (s), 129.9 (d), 128.3 (d), 128.0 (d, 2C),
127.8 (d, 2C), 126.9 (d), 119.3 (s), 117.3 (d), 111.5 (d), 91.7 (ds, J =
175 Hz), 56.3 (dt, J = 25 Hz), 54.9 (t), 37.6 (dt, J = 24 Hz), 30.5 (dt, J
= 25 Hz), 7.2 (dq, J = 6 Hz) ppm; MS m/z (%) 269 (M+., 35), 192
(10), 178 (7), 158 (7), 92 (12), 91 (100), 65 (14); HRMS (ESI)
Calcd. C18H21NF (MH)+, 270.1652, found 270.1659.
20
beige solid: mp 85−87 °C; [α]D = −3.6 (c 1, CHCl3); IR (neat)
3165, 3029, 2929, 2854, 1492, 1461, 1370, 1320, 1268, 1201, 1149,
1
1119, 1069 cm−1; H NMR (400 MHz, CDCl3) δ 7.43−7.18 (m,
10H), 4.05 (d, 1H, J = 12.8 Hz), 3.69 (d, 1H, J = 10.1 Hz), 3.52 (d,
1H, J = 12.5 Hz), 3.47 (d, 1H, J = 10.6 Hz), 3.03 (m, 1H), 2.80 (s,
2H), 2.64 (m, 1H), 1.96−1.65 (m, 4H) ppm; 13C NMR (100 MHz,
CDCl3) δ 139.5 (s), 137.8 (s), 130.3 (d, 2C), 128.6 (d, 2C), 128.5 (d,
2C), 128.3 (d, 2C), 127.1 (d), 126.3 (d), 67.4 (s), 63.2 (t), 52.1 (t),
50.1 (t), 37.1 (t), 30.3 (t), 21.3 (t) ppm; MS m/z (%) 281 (M+., 0.1),
250 (9), 190 (29), 92 (8), 91 (100), 65 (10); HRMS (ESI) Calcd. for
C19H24NO (MH)+, 282.1853, found 282.1855.
3-Allyl-1-benzyl-3-fluoro-1,2,3,4-tetrahydroquinoline (19b).
Prepared according to General Procedure 4, 16b (558 mg, 2 mmol, 1
equiv) was rearranged in CH2Cl2 (20 mL) by DAST (369 μL, 2.8
mmol, 1.4 equiv). The residue was purified by flash chromatography
on silica gel (PE/Et2O 98/2) affording 19b (441 mg, 1.6 mmol, 78%),
isolated as a yellow oil: IR (neat) 3017, 2894, 1600, 1508, 1498, 1451,
(S)-(1,2-Dibenzylpiperidin-2-yl)methanol (23c). Prepared ac-
cording to General Procedure 7, 22c14 (300 mg, 0.86 mmol, 1 equiv)
was deprotected by TFA in CH2Cl2. The β-amino ester obtained was
protected by BnBr in CH3CN following General Procedure 8. The β-
amino ester was then reduced by LiAlH4 in THF following General
Procedure 6 affording 23c (81%), isolated as a white solid: mp 103−
1
1289, 1247 cm−1; H NMR (400 MHz, C6D6) δ 7.32−7.00 (m, 7H),
6.81 (ddd, 1H, J = 7.3, 7.3, and 0.9 Hz), 6.63 (d, 1H, J = 8.0 Hz), 5.90
(m, 1H), 5.11 (d, 1H, J = 10.3 Hz), 5.03 (d, 1H, J = 17.1 Hz), 4.30 (d,
1H, J = 16.9 Hz), 4.24 (d, 1H, J = 17.0 Hz), 3.23 (ddd, 1H, J = 11.8,
10.5, and 2.3 Hz), 3.06 (ddd, 1H, J = 25.6 (H−F), 12.3 and 1.6 Hz),
2.99 (ddd, 1H, J = 16.2, 13.6, and 2.4 Hz), 2.75 (dd, 1H, J = 28.7 (H−
F) and 12.3 Hz), 2.33 (dd, 1H, J = 7.3 and 1.0 Hz), 2.28 (dd, 1H, J =
7.3, 1.1 Hz) ppm; 13C NMR (100 MHz, C6D6) δ 144.5 (s), 138.7 (s),
132.1 (dd, J = 4.8 Hz), 129.9 (d), 128.8 (d), 128.0 (d, 2C), 127.8 (d,
2C), 126.9 (d), 119.1 (t), 119.1 (s), 117.4 (d), 111.6 (d), 91.2 (ds, J =
176 Hz), 56.3 (dt, J = 25 Hz), 54.9 (t), 42.2 (dt, J = 22 Hz), 37.9 (dt, J
= 24 Hz) ppm; MS m/z (%) 281 (M+., 5), 280 (28), 237 (10), 148
(10), 92 (12), 91 (100), 65 (13); HRMS (ESI) Calcd. C19H21NF
(MH)+, 282.1652, found 282.1659.
20
104 °C; [α]D = −6.7 (c 1, CHCl3); IR (neat) 3387, 3029, 2935,
2850, 2812, 1495, 1447, 1412, 1365, 1303, 1133, 1050, 1030 cm−1; 1H
NMR (400 MHz, CDCl3) δ 7.44−7.18 (m, 10H), 4.21 (d, 1H, J = 13.7
Hz), 3.94 (d, 1H, J = 10.8 Hz), 3.28 (d, 1H, J = 13.7 Hz), 3.23 (d, 1H,
J = 13.2 Hz), 3.17 (d, 1H, J = 10.1 Hz), 2.85 (m, 1H), 2.75 (d, 1H, J =
13.5 Hz), 2.54 (ddd, 1H, J = 12.1, 3.0, and 3.0 Hz), 1.78−1.39 (m,
6H) ppm; 13C NMR (100 MHz, CDCl3) δ 139.3 (s), 137.7 (s), 130.1
(d, 2C), 129.5 (d, 2C), 129.1 (d, 2C), 128.5 (d, 2C), 126.5 (d), 126.3
(d), 65.2 (t), 60.6 (s), 53.0 (t), 46.3 (t), 37.1 (t), 29.7 (t), 25.8 (t),
20.6 (t) ppm; MS m/z (%) 264 (M+.−CH2OH·, 8), 204 (33), 92 (8),
91 (100), 65 (10); HRMS (ESI) Calcd. for C20H26NO (MH)+,
296.2009, found 296.2007.
1,3-Dibenzyl-3-fluoro-1,2,3,4-tetrahydroquinoline (19c). Pre-
pared according to General Procedure 4, 16c (455 mg, 1.38 mmol, 1
equiv) was rearranged in CH2Cl2 (15 mL) by DAST (255 μL, 1.93
mmol, 1.4 equiv). The residue was purified by flash chromatography
on silica gel (PE/Et2O 98/2) affording 19c (299 mg, 0.90 mmol,
65%), isolated as a yellow oil: IR (neat) 3027, 2916, 1602, 1495, 1452,
(S)-(1,2-Dibenzylazepan-2-yl)methanol (23d). Prepared ac-
cording to General Procedure 7, 22d14 (190 mg, 0.52 mmol, 1
equiv) was deprotected by TFA in CH2Cl2. The β-amino ester
obtained was reduced by LiAlH4 in THF following General
Procedure 6. The β-amino alcohol was then protected by BnBr in
CH3CN following General Procedure 8 affording 23d (20%), isolated
1
1353, 1288, 1247, 1079, 1028 cm−1; H NMR (400 MHz, C6D6) δ
7.31−7.06 (m, 11H), 6.93 (d, 1H, J = 7.5 Hz), 6.78 (dd, 1H, J = 7.0
and 7.0 Hz), 6.63 (d, 1H, J = 8.3 Hz), 4.26 (d, 1H, J = 17.1 Hz), 4.18
(d, 1H, J = 16.8 Hz), 3.24 (ddd, 1H, J = 11.8, 9.3, and 2.3 Hz), 3.08
(ddd, 1H, J = 22.0 (H−F), 12.0 and 2.0 Hz), 2.96 (m, 1H), 2.84 (d,
2H, J = 22.8 (H−F) Hz), 2.79 (dd, 1H, J = 24.6 (H−F) and 15.8 Hz)
ppm; 13C NMR (100 MHz, C6D6) δ 144.4 (s), 138.7 (s), 136.0 (s),
130.8 (d), 130.1 (d), 128.8 (d, 2C), 128.5 (d, 2C), 128.3 (d, 2C),
127.9 (d, 2C), 127.1 (d), 127.0 (d), 119.0 (s), 117.4 (d), 111.7 (d),
91.4 (ds, J = 177 Hz), 56.5 (dt, J = 25 Hz), 54.9 (t), 43.6 (dt, J = 22
Hz), 38.0 (dt, J = 24 Hz) ppm; MS m/z (%) 331 (M+., 28), 148 (7),
20
as a colorless oil: [α]D = −8.5 (c 1, CHCl3); IR (neat) 3110, 2914,
2821, 1498, 1448, 1414, 1258, 1173, 1048, 1021 cm−1; 1H NMR (400
MHz, CDCl3) δ 7.49−7.19 (m, 10H), 4.07 (d, 1H, J = 14.2 Hz), 3.85
(d, 1H, J = 10.5 Hz), 3.75 (d, 1H, J = 9.2 Hz), 3.53 (d, 1H, J = 10.5
Hz), 2.95 (d, 1H, J = 12.0 Hz), 2.88 (d, 1H, J = 12.5 Hz), 2.77 (m,
2H), 1.94−1.22 (m, 8H) ppm; 13C NMR (100 MHz, CDCl3) δ 141.5
(s), 138.1 (s), 130.5 (d, 2C), 128.7 (d, 2C), 128.4 (d, 2C), 128.1 (d,
2C), 126.9 (d), 126.2 (d), 67.7 (t), 60.4 (s), 54.2 (t), 47.0 (t), 40.1 (t),
38.1 (t), 31.2 (t), 29.7 (t), 23.2 (t) ppm; MS m/z (%) 309 (M+., 1),
6096
dx.doi.org/10.1021/jo300887u | J. Org. Chem. 2012, 77, 6087−6099

The Journal of Organic Chemistry
Article
278 (8), 218 (27), 92 (8), 91 (100), 65 (9); HRMS (ESI) Calcd. for
C21H28NO (MH)+, 310.2165, found 310.2162.
1H, J = 13.5 Hz), 3.56 (d, 1H, J = 13.8 Hz), 2.88−2.55 (m, 4H), 2.36
(m, 2H), 1.95 (m, 1H), 1.84−1.35 (m, 7H) ppm; 13C NMR (100
MHz, CDCl3) δ 140.3 (s), 136.7 (s), 130.6 (d, 2C), 128.8 (d, 2C),
128.2 (d, 2C), 128.1 (d, 2C), 126.8 (d), 126.4 (d), 99.9 (ds, J = 173
Hz), 64.1 (t), 59.6 (dt, J = 26 Hz), 54.6 (t), 43.7 (dt, J = 21 Hz), 34.0
(dt, J = 23 Hz), 27.1 (t), 27.0 (t), 22.6 (dt, J = 9 Hz) ppm; MS m/z
(%) 311 (M+., 3), 220 (12), 160 (13), 134 (15), 120 (9), 92 (10), 91
(100), 65 (10); HRMS (ESI) Calcd. for C21H27FN (MH)+, 312.2122,
found 312.2121.
(S)-1,3-Dibenzyl-3-fluoropyrrolidine (24a). Prepared according
to General Procedure 4, 23a (18 mg, 0.07 mmol, 1 equiv) was
rearranged in CH2Cl2 (3 mL) by DAST (12 μL, 0.09 mmol, 1.4
equiv). The residue was purified by flash chromatography on silica gel
(PE/Et2O 80/20) affording 24a (18 mg, 0.30 mmol, 96%), isolated as
a colorless oil: ee = 94% determined by supercritical fluid
chromatography on Daicel chiralcel AD-H column (MeOH 3%, flow
20
rate 5 mL/min, tmaj = 2.4 min, tmin = 2.7 min); [α]D = −3.1 (c 1,
(R)-Methyl 2-((3-Bromopropyl)(tert-butoxycarbonyl)amino)-
2-phenylacetate (26). To a solution of 25 (3.84 g, 19.09 mmol, 1
equiv) in DMF (25 mL) were added 3-bromopropanol (2.57 mL, 28.6
mmol, 1.5 equiv), NaI (248 mg, 1.91 mmol, 0.1 equiv), and K2CO3
(5.80 g, 42 mmol, 2.2 equiv). The media was stirred at 70 °C for 2 h
before being hydrolyzed by iced water (100 mL). The mixture was
extracted with EtOAc (3 × 20 mL). The organic layers were
combined, washed successively with water and brine, dried over
Na2SO4, and concentrated under reduced pressure. The crude was
purified by flash chromatography on silica gel (EtOAc/MeOH 90/10)
leading to the desired amino alcohol (1.26 g, 5.70 mmol, 30%). To a
solution of this alcohol (1.14 g, 5.10 mmol, 1 equiv) in CH2Cl2 (10
mL) were successively added Boc2O (1.33 g, 6.12 mmol, 1.2 equiv)
and DIPEA (978 μL, 5.61 mmol, 1.1 equiv). The solution was stirred
at rt for 24 h before being hydrolyzed by the addition of a 1 M
aqueous solution of hydrochloric acid (10 mL). The layers were
separated, and the aqueous layer was extracted with CH2Cl2 (3 × 10
mL). The organic layers were combined, dried over MgSO4, and
concentrated under reduced pressure. To a solution of the crude in
CH2Cl2 (10 mL) were added at 0 °C CBr4 (2.19 g, 6.63 mmol, 1.3
equiv) and PPh3 (2.13 g, 8.13 mmol, 1.6 equiv). The mixture was
stirred at rt for 2 h before being hydrolyzed by the addition of a
saturated aqueous solution of NaHCO3 (10 mL). The layers were
separated. The aqueous layer was extracted with CH2Cl2 (3 × 10 mL).
The organic layers were combined, dried over Na2SO4, and
concentrated under reduced pressure. The crude was purified by
flash chromatography on silica gel (PE/EtOAc 90/10 to 80/20)
leading to 26 (1.38 g, 3.50 mmol, 70% over to steps), isolated as a
CHCl3); IR (neat) 2969, 2924, 2793, 1454, 1379, 1300, 1261, 1122,
1
1073, 1028 cm−1; H NMR (400 MHz, CDCl3) δ 7.28−7.11 (m,
10H), 3.55 (s, 2H), 2.94 (d, 2H, J = 24.8 (H−F) Hz), 2.74−2.65 (m,
2H), 2.63 (dd, 1H, J = 15.5 and 11.9 Hz), 2.53 (m, 1H), 1.92 (ddd,
2H, J = 25.9 (H−F), 6.8 and 6.8 Hz) ppm; 13C NMR (100 MHz,
CDCl3) δ 138.5 (s), 136.5 (s), 130.1 (d, 2C), 128.8 (d, 2C), 128.3 (d,
2C), 128.2 (d, 2C), 127.1 (d), 126.7 (d), 103.4 (ds, J = 179 Hz), 64.0
(dt, J = 25 Hz), 60.3 (t), 52.8 (t), 44.3 (dt, J = 24 Hz), 37.0 (dt, J = 23
Hz) ppm; MS m/z (%) 269 (M+., 21), 268 (11), 192 (7), 191 (6), 178
(11), 133 (16), 132 (18), 92 (13), 91 (100), 65 (17); HRMS (ESI)
Calcd. C18H21FN (MH)+, 270.16525, found 270.16523.
(R)-1,3-Dibenzyl-3-fluoropiperidine (24b). Prepared according
to General Procedure 4, 23b (48 mg, 0.17 mmol, 1 equiv) was
rearranged in CH2Cl2 (3 mL) by DAST (31 μL, 0.24 mmol, 1.4
equiv). The residue was purified by flash chromatography on silica gel
(PE/Et2O 90/10) affording 24b (34 mg, 0.12 mmol, 71%), isolated as
a colorless oil: ee = 98% determined by supercritical fluid
chromatography on Daicel chiralcel AD-H column (i-PrOH 3%,
flow rate 5 mL/min, tmaj = 2.8 min, tmin = 3.4 min); [α]D20 = +13.2 (c
1.1, CHCl3); IR (neat) 3028, 2942, 2801, 1494, 1453, 1346, 1300,
1114, 1078, 1028 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.46−7.23 (m,
10H), 3.62 (d, 1H, J = 12.9 Hz), 3.56 (d, 1H, J = 13.6 Hz), 3.10 (dd,
1H, J = 24.8 (H−F) and 14.3 Hz), 3.02 (dd, 1H, J = 25.5 (H−F) and
14.7 Hz), 2.56−2.43 (m, 4H), 1.89−1.59 (m, 4H) ppm; 13C NMR
(100 MHz, CDCl3) δ 138.0 (s), 136.3 (s), 130.6 (d, 2C), 129.2 (d,
2C), 128.3 (d, 2C), 128.1 (d, 2C), 127.1 (d), 126.5 (d), 93.8 (ds, J =
175 Hz), 62.8 (t), 60.5 (dt, J = 24 Hz), 53.0 (t), 43.5 (dt, J = 21 Hz),
33.4 (dt, J = 21 Hz), 22.3 (dt, J = 6 Hz) ppm; MS m/z (%) 283 (M+.,
23), 282 (13), 206 (8), 192 (11), 191 (7), 172 (5), 146 (6), 134 (11),
92 (11), 91 (100), 65 (11); HRMS (ESI) Calcd. C19H23FN (MH)+,
284.1809, found 284.1812.
20
yellow oil: [α]D = +54.2 (c 1, CHCl3); IR (neat) 2958, 1743, 1698,
1
1482, 1054, 1012 cm−1; H NMR (400 MHz, CDCl3) mixture of
rotamers δ 7.49−7.20 (m, 5H), 6.01−5.21 (m, 1H), 3.82 (m, 3H),
3.45−3.12 (m, 3H), 2.02−1.32 (m, 12H); 13C NMR (100 MHz,
DMSO at 395 K) δ 170.1 (s), 142.2 (s), 134.1 (s), 128.9 (d, 2C),
128.5 (d, 2C), 128.3 (d), 66.5 (s), 62.9 (d), 51.8 (q), 42.6 (t), 28.1 (q,
3C), 23.5 (t), 22.0 (t) ppm; HRMS (ESI) Calcd. for C17H25BrNO4
(MH)+, 396.0967, found 396.0921.
(R)-1,3-Dibenzyl-3-fluoroazepane (24c). Prepared according to
General Procedure 4, 23c (163 mg, 0.55 mmol, 1 equiv) was
rearranged in CH2Cl2 (10 mL) by DAST (102 μL, 0.77 mmol, 1.4
equiv). The residue was purified by flash chromatography on silica gel
(PE/Et2O 90/10) affording 24c (134 mg, 0.45 mmol, 82%), isolated
as a colorless oil: ee = 85% determined by supercritical fluid
chromatography on Daicel chiralcel AD-H column (MeOH 10%, flow
(S)-1-tert-Butyl 2-Methyl 2-phenylpyrrolidine-1,2-dicarbox-
ylate (27). To a solution of 26 (1.31 g, 3.4 mmol, 1 equiv) in DMF
(32 mL) was slowly added at −60 °C a 0.5 M solution of KHMDS in
toluene (8.16 mL, 4.1 mmol, 1.2 equiv). The media was stirred at this
temperature for 30 min before being hydrolyzed by the addition of a
saturated aqueous solution of NH4Cl (100 mL). The layers were
separated, and the aqueous layer was extracted with EtOAc (3 × 30
mL). The organic layers were combined, washed successively with a
saturated aqueous solution of NaHCO3 (30 mL) and brine (30 mL),
dried over Na2SO4, and concentrated under reduced pressure. The
crude was purified by flash chromatography on silica gel (PE/Et2O 80/
20 to 70/30) leading to 27 (298 mg, 0.98 mmol, 19%), isolated as a
colorless oil: [α]D20 = +14.3 (c 1, CHCl3); IR (neat) 3012, 2958, 1734,
20
rate 5 mL/min, tmaj = 1.7 min, tmin = 2.3 min); [α]D = +8.2 (c 1,
CHCl3); IR (neat) 2927, 1494, 1452, 1350, 1106, 1078, 1008 cm−1;
1H NMR (400 MHz, CDCl3) δ 7.45−7.18 (m, 10H), 3.73 (s, 2H),
3.04−2.82 (m, 4H), 2.78 (m, 1H), 2.59 (m, 1H), 1.97−1.47 (m, 6H)
ppm; 13C NMR (100 MHz, CDCl3) δ 139.8 (s), 136.7 (s), 130.7 (d,
2C), 128.9 (d, 2C), 128.3 (d, 2C), 128.0 (d, 2C), 127.1 (d), 126.4 (d),
99.2 (ds, J = 172 Hz), 64.0 (t), 63.9 (dt, J = 30 Hz), 57.8 (t), 45.2 (dt,
J = 22 Hz), 38.0 (dt, J = 23 Hz), 30.9 (t), 21.4 (dt, J = 4 Hz) ppm; MS
m/z (%) 297 (M+., 12), 296 (3), 191 (7), 206 (5), 186 (11), 160 (17),
147 (6), 146 (7), 134 (20), 132 (6), 120 (15), 115 (6), 92 (9), 91
(100), 84 (8), 70 (6), 65 (12); HRMS (ESI) Calcd. C20H25FN (MH)+,
298.1965, found 298.1963.
1
1702, 1461, 1238, 1143, 1045 cm−1; H NMR (400 MHz, CDCl3) δ
7.38−7.23 (m, 5H), 3.76 (s, 3H), 3.74−3.68 (m, 2H), 2.60 (m, 1H),
2.27 (m, 1H), 1.89 (m, 1H), 1.65 (m, 1H), 1.24 (s, 9H) ppm; 13C
NMR (100 MHz, CDCl3) δ 173.3 (s), 153.9 (s), 140.3 (s), 127.4 (d,
2C), 127.1 (d, 2C), 126.9 (d), 80.2 (s), 71.5 (s), 52.4 (q), 47.8 (t),
43.4 (t), 28.4 (q, 3C), 22.6 (t) ppm; MS m/z (%) 248 (M+.−t-Bu·, 1),
246 (M+.−CO2Me·, 20), 190 (35), 147 (11), 146 (100), 117 (15), 77
(7), 57 (93); HRMS (ESI) Calcd. for C17H23NO4Na (MNa)+,
328.1519, found 328.1515.
1,3-Dibenzyl-3-fluoroazocane (24d). Prepared according to
General Procedure 4, 23d (14 mg, 0.045 mmol, 1 equiv) was
rearranged in CH2Cl2 (2 mL) by DAST (12 μL, 0.11 mmol, 1.4
equiv). The residue was purified by flash chromatography on silica gel
(PE/Et2O 90/10) affording 24d (8.5 mg, 0.027 mmol, 61%), isolated
as a yellow oil: ee = 52% determined by supercritical fluid
chromatography on Daicel chiralcel AD-H column (MeOH 10%,
flow rate 5 mL/min, tmaj = 2.4 min, tmin = 3.0 min); [α]D20 = +2.1 (c 1,
CHCl3); IR (neat) 2918, 2854, 2790; 1452, 1347, 1138, 1076, 1025
(S)-(1-Benzyl-2-phenylpyrrolidin-2-yl)methanol (28). Pre-
pared according to General Procedure 7, 27 (242 mg, 0.79 mmol,
1 equiv) was deprotected by TFA in CH2Cl2. The β-amino ester was
1
cm−1; H NMR (400 MHz, CDCl3) δ 7.29−7.10 (m, 10H), 3.69 (d,
6097
dx.doi.org/10.1021/jo300887u | J. Org. Chem. 2012, 77, 6087−6099

The Journal of Organic Chemistry
Article
then protected by BnBr in CH3CN following General Procedure 8.
The β-amino ester obtained was reduced by LiAlH4 in THF following
General Procedure 6 to afford 28 (85%), isolated as a colorless oil: ee
= 50% determined by supercritical fluid chromatography on Daicel
chiralcel OD-H column (MeOH 15%, flow rate 5 mL/min, tmaj = 3.4
ACKNOWLEDGMENTS
■
Sanofi is greatly acknowledged for financial support (B.A.).
Mireille Sevrin and Yannick Evanno from Sanofi Research &
Development, Chilly Mazarin, France, are acknowledged for
scientific discussions.
20
min, tmin = 4.1 min); [α]D = +10.3 (c 1, CHCl3); IR (neat) 3414,
3026, 2944, 1494, 1445, 1406, 1363, 1053, 1028 cm−1; 1H NMR (400
MHz, CDCl3) δ 7.44−7.23 (m, 10H), 4.09 (d, 1H, J = 10.1 Hz), 3.91
(d, 1H, J = 10.4 Hz), 3.60 (d, 1H, J = 13.5 Hz), 3.16 (d, 1H, J = 13.5
Hz), 3.10 (ddd, 1H, J = 9.3, 7.9, and 3.7 Hz), 2.90 (m, 1H), 2.45 (ddd,
1H, J = 13.1, 9.9, and 5.5 Hz), 2.16 (ddd, 1H, J = 13.3, 9.1, and 7.1
Hz), 1.95 (m, 2H) ppm; 13C NMR (100 MHz, CDCl3) δ 143.6 (s),
140.1 (s), 128.5 (d, 2C), 128.4 (d, 2C), 128.3 (d, 2C), 127.0 (d, 2C),
126.9 (d), 126.6 (d), 69.2 (s), 63.4 (t), 53.8 (t), 52.4 (t), 37.3 (t), 22.8
(t) ppm; HRMS (ESI) Calcd. for C18H22NO (MH)+, 268.1696, found
268.1699.
REFERENCES
■
(1) (a) Harper, D. B.; O’Hagan, D. Nat. Prod. Rep. 1994, 11, 123−
133. (b) O’Hagan, D. B. J. Fluorine Chem. 1999, 100, 127−133.
(2) (a) Smart, B. J. Fluorine Chem. 2001, 109, 3−11. (b) Lemal, D.
M. J. Org. Chem. 2004, 69, 1−11. (c) Bolm, H.-J.; Banner, D.; Bendels,
̈
S.; Kansy, M.; Kuhn, B.; Muller, K.; Obst-Sander, U.; Stahl, M.
̈
ChemBioChem 2004, 5, 637−643. (d) Muller, K.; Fach, C.; Diederich,
̈
F. Science 2007, 317, 1881−1886. (e) O’Hagan, D. Chem. Soc. Rev.
2008, 37, 308−319. (f) Purser, S.; Moore, P. R.; Swallow, S.;
Gouverneur, V. Chem. Soc. Rev. 2008, 37, 320−330. (g) Kirsch, P.
Modern Fluoroorganic Chemistry: Synthesis, Reactivity, Application;
Wiley-VCH: Weinheim, 2004. (h) Uneyamo, K. Organofluorine
(R)-1-Benzyl-3-fluoro-3-phenylpiperidine (29). Prepared ac-
cording to General Procedure 4, 28 (72 mg, 0.26 mmol, 1 equiv) was
rearranged in CH2Cl2 (3 mL) by DAST (49 μL, 0.37 mmol, 1.4
equiv). The residue was purified by flash chromatography on silica gel
(PE/Et2O 85/15) affording 29 (61 mg, 0.22 mmol, 87%), isolated as a
beige solid: ee = 50% determined by supercritical fluid chromatog-
raphy on Daicel chiralcel OJ-H column (MeOH 5%, flow rate 5 mL/
́ ́
Chemistry; Blackwell Publishing Ltd: Oxford, 2006. (i) Begue, J.-P.;
Bonnet-Delpon, D. Bioorganic and Medicinal Chemistry of Fluorine;
Wiley: New York, 2008.
(3) (a) Jeschke, P. ChemBioChem 2004, 5, 570−589. (b) Hagmann,
W. K. J. Med. Chem. 2008, 51, 4359−4369.
20
min, tmaj = 6.3 min, tmin = 7.1 min); [α]D = +8.6 (c 1, CHCl3); mp
121−123 °C; IR (neat) 2948, 2917, 1447, 1348, 1237, 1160, 1100,
1074, 1030, 1008 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.39−7.13 (m,
10H), 3.57 (d, 1H, J = 13.2 Hz), 3.51 (d, 1H, J = 13.3 Hz), 2.91 (m,
1H), 2.81 (m, 1H), 2.34 (dd, 1H, J = 30.4 (H−F) and 12.5 Hz), 2.12
(m, 1H), 2.03−1.91 (m, 2H), 1.76 (m, 1H), 1.56 (m, 1H) ppm; 13C
NMR (100 MHz, CDCl3) δ 143.2 (ds, J = 21 Hz), 137.6 (s), 129.1 (d,
2C), 128.3 (d, 2C), 128.2 (d, 2C), 127.7 (dd, J = 1.5 Hz), 127.1 (d),
124.6 (dd, J = 9.6 Hz, 2C), 94.1 (ds, J = 177 Hz), 62.8 (t), 62.0 (dt, J =
22 Hz), 52.6 (t), 35.0 (dt, J = 23 Hz), 21.6 (dt, J = 1 Hz) ppm; MS m/
z (%) 269 (M+., 7), 249 (M+.-HF, 17), 134 (34), 131 (17), 129 (12),
115 (8), 92 (10), 91 (100), 65 (16); HRMS (ESI) Calcd. for C18H21NF
(MH)+, 270.16525, found 270.16523.
(4) O’Hagan, D. J. Fluorine Chem. 2010, 131, 1071−1081.
(5) (a) Tressaud, A. Fluorine and the Environment: Agrochemicals,
Archaeology, Green Chemistry and Water; Elsevier: Amsterdam, 2006.
(b) Thayer, A. M. Chem. Eng. News 2006, 84, 15−24.
(6) (a) Al-Maharik, N.; O’Hagan, D. Aldrichimica Acta 2011, 44, 65−
75. (b) Brunet, V. A.; O’Hagan, D. Angew. Chem., Int. Ed. 2008, 47,
1179−1182. (c) Kirk, K. L. Org. Process Res. Dev. 2008, 12, 305−321.
́
(7) (a) For a review, see: Ferret, H.; Dechamps, I.; Gomez Pardo,
D.; Van Hijfte, L.; Cossy, J. ARKIVOC 2010, 8, 216−259.
(b) Dechamps, I.; Gomez Pardo, D.; Cossy, J. Synlett 2007, 263−
267. (c) Dechamps, I.; Gomez Pardo, D.; Cossy, J. Eur. J. Org. Chem.
́
́
2007, 4224−4234. (d) For related work, see: Jarvis, S. B. D.; Charette,
3-Ethyl-3-fluoroazepane (31). To a solution of 307 (62.8 mg,
0.26 mmol, 1 equiv) in methanol (10 mL) was added Pd/C (6.28 mg,
10%). The reaction media was stirred overnight under hydrogen
atmosphere (1 bar) at rt. The mixture was filtered through Celite and
washed with CH2Cl2 (2 × 10 mL). The solvents were removed under
reduced pressure to afford 31 (34.6 mg, 0.24 mmol, 91%), isolated as a
colorless oil: IR (neat) 3407, 2835, 1610, 1511, 1247, 1174, 1033
cm−1; 1H NMR (400 MHz, CDCl3) δ 2.89 (dd, 1H, J = 15.0 and 15.0
Hz), 2.78 (m, 1H), 2.71−2.60 (m, 2H), 1.86 (s br, 1H), 1.81 (m, 1H),
1.65−1.28 (m, 7H), 0.79 (t, 3H, J = 7.5 Hz) ppm; 13C NMR (100
MHz, CDCl3) δ 100.2 (ds, J = 169 Hz), 57.1 (dt, J = 26 Hz), 50.5 (t),
37.3 (dt, J = 24 Hz), 32.1 (dt, J = 24 Hz), 31.7 (t), 21.4 (dt, J = 5 Hz),
7.4 (dq, J = 5 Hz) ppm; MS m/z (%) 145 (M+., 14), 125 (16), 116
(20), 110 (14), 96 (26), 84 (16), 82 (12), 70 (100), 68 (13), 59 (17),
57 (31), 56 (44), 55 (21), 53 (10); HRMS (ESI) Calcd. for C8H17NF
(MH)+, 146.1339, found 146.1337.
A. B. Org. Lett. 2011, 13, 3830−3833.
(8) (a) Georg, G. I.; Guan, X.; Kant, J. Tetrahedron Lett. 1988, 29,
403−406. (b) Biaggio, F. C.; Barreiro, E. J. J. Heterocycl. Chem. 1989,
26, 725−728.
(9) Matsumoto, K.; Tsustumi, S.; Ihori, T.; Ohta, H. J. Am. Chem.
Soc. 1990, 112, 9614−9619.
(10) Caution! Since HN3 was formed in the medium, this step was
carefully realized.
(11) Other acidic conditions were tested. Beckmann rearrangement
was also investigated but without success.
(12) When 2b was treated by H2SO4, the dihydroxylation of the
double bond was observed; see: Zukerman-Schpector, J.; Biaggio, F.
C.; Rufino, A. R.; Caracelli, I. Acta Crystallogr., Sect. C: Cryst. Struct.
Commun. 1999, 55, 416−419.
(13) There is no explanation for the lower yield for the Schmidt
rearrangement to provide 8-membered ring lactams. Moreover, the
Schmidt rearrangement of 7-membered cyclic ketones did not work
with the allylic derivative.
(14) Hiroshi, M.; Kazuhiko, T.; Shinji, S.; Hidenori, A.; Hiroshi, S.;
Yoshiteru, E.; Kazuo, N.; Junya, I.; Takashi, M.; Nobukiyo, K.;
Tadashi, T. Patent: US2003/114668A1 2003.
(15) See for example: (a) Kawabata, T.; Yahiro, K.; Fuji, K. J. Am.
Chem. Soc. 1991, 113, 9694−9696. (b) Schmalz, H.-G.; Konig, C. B.;
Bernicke, D.; Siegel, S.; Pflectschinger, A. Angew. Chem., Int. Ed. 1999,
ASSOCIATED CONTENT
■
S
* Supporting Information
1H NMR and 13C NMR of compounds described, and
crystallographic data (CIF). This material is available free of
charge via the Internet at http://pubs.acs.org.
38, 1620−1623. (c) Giese, B.; Wettstein, P.; Stahelin, C.; Barbosa, F.;
̈
Neuburger, M.; Zehnder, M.; Wessig, P. Angew. Chem., Int. Ed. 1999,
38, 2586−2587. (d) Yashima, E.; Maeda, K.; Okamoto, Y. Nature
1999, 399, 449−451. (e) Mizuno, Y.; Aida, T.; Yamaguchi, K. J. Am.
Chem. Soc. 2000, 122, 5278−5285.
(16) (a) Kawabata, T.; Kawakami, S.; Majumdar, S. J. Am. Chem. Soc.
2003, 125, 13012−13013. (b) Kawabata, T.; Matsuda, S.; Kawakami,
S.; Monguchi, D.; Moriyama, K. J. Am. Chem. Soc. 2006, 128, 15394−
15395.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: domingo.gomez-pardo@espci.fr; janine.cossy@espci.
fr.
Notes
The authors declare no competing financial interest.
6098
dx.doi.org/10.1021/jo300887u | J. Org. Chem. 2012, 77, 6087−6099

The Journal of Organic Chemistry
Article
(17) The racemic synthesis was done from racemic β-amino esters,
and the enantiomeric excesses were determined by supercritical fluid
chromatography (SFC).
(18) For recent synthesis of 3-fluorinated azaheterocycles, see for
example: (a) Van Hende, E.; Verniest, G.; Thuring, J.-W.; Macdonald,
G.; Deroose, F.; De Kimpe, N. Synlett 2009, 11, 17651768.
(b) Surmont, R.; Verniest, G.; Thuring, J.-W.; ten Holte, P.;
Deroose, F.; De Kimpe, N. Org. Biomol. Chem. 2010, 8, 45144517.
(c) Piron, K.; Verniest, G.; Van Hende, E.; De Kimpe, N. ARKIVOC
2012, v, 615.
(19) (a) Umemura, K.; Matsuyama, H.; Watanabe, N.; Kobayashi,
M.; Kamigata, N. J. Org. Chem. 1989, 54, 2374−2383. (b) Ando, K.;
Takemasa, Y.; Tomioka, K.; Koga, K. Tetrahedron 1993, 49, 1579−
1588. (c) Hashimoto, T.; Naganawa, Y.; Maruoka, K. J. Am. Chem. Soc.
2011, 133, 8834−8837. (d) Andersson, F.; Hedenstroem, E.
Tetrahedron: Asymmetry 2006, 17, 1952−1957.
6099
dx.doi.org/10.1021/jo300887u | J. Org. Chem. 2012, 77, 6087−6099