Synthesis of 2-Fluoroalkyl 4-Substituted Azepanes

Article abstract of DOI:10.1002/ejoc.201900613

Synthesis of di- and tri-substituted fluoroalkylated azepanes was achieved by ring expansion of pyrrolidines via a regioselective attack of nucleophiles on a bicyclic azetidinium intermediate. A broad scope of azepanes, substituted at C4 and bearing a α-t

Full text of DOI:10.1002/ejoc.201900613

A Journal of
Accepted Article
Title: Synthesis of 2-fluoroalkyl 4-substituted azepanes
Authors: Guillaume Masson, Sarah Rioton, Domingo Gomez Pardo,
and Janine Cossy
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201900613
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10.1002/ejoc.201900613
European Journal of Organic Chemistry
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Synthesis of 2-fluoroalkyl 4-substituted azepanes
Guillaume Masson,[a] Sarah Rioton,[a] Domingo Gomez Pardo,*[a] Janine Cossy*[a]
Abstract: Synthesis of di- or tri-substituted fluoroalkylated azepanes
was achieved by ring-expansion of pyrrolidines via a regioselective
attack of nucleophiles on a bicyclic azetidinium intermediate. A broad
scope of azepanes, substituted at C4 and bearing a α-trifluoromethyl,
α-difluoromethyl or α-perfluorobutyl group, can be synthesized by this
method by using a wide variety of nucleophiles.
Introduction
Seven-membered N-heterocycles, e.g. azepanes, are important
scaffolds present in
a
number of natural products,
pharmaceuticals1 and agrochemicals – Selected examples are
depicted in Figure 1. According to the FDA orange book,2
azepanes are in the top 60 most frequently used ring system in
small molecular drugs.3 It is worth mentioning that the introduction
of a fluoroalkylated group in the α position of an amine can modify
the physico-chemical properties of a compound, such as its
metabolic stability, lipophilicity, pKa,4 while maintaining the
hydrogen bond donor properties. For example, the introduction of
trifluoromethyl groups in the  position of amines was used to
form bio-isosters of amides, improving in some cases the
biological activity of a compound.5 Another interesting fluoroalkyl
group of interest is the difluoromethyl,6,7 due to its capacity to form
hydrogen bonding, for example with a hydroxy or a thiol group
present in proteins.8,9 Furthermore a perfluoroalkyl chain can be
of great value to further increase the lipophilicity of a molecule,
and some marketed drugs contain either a trifluoromethyl,
difluoromethyl or perfluoroalkyl10 motif.
Figure 1. Azepanes in bioactive molecules and drugs containing a trifluoro-, a
difluoro- or a perfluoro-alkyl group.
Different methods can be used to produce α-fluoroalkylated
azepanes, either by cyclization of linear α-fluoroalkylated amines
II,12,13,14 addition of nucleophiles on fluoroalkylated cyclic imines
III,15 or addition of trifluoromethyl anions on cyclic imines IV.16
However, in most cases the methods are dealing with the
preparation of α-trifluoromethylated azepanes, excluding the
other fluoroalkylated groups, and only few examples are reported
for the synthesis of highly enantio-enriched fluoroalkylated
azepanes (Scheme 1).
Due to the importance of azepanes in medicinal chemistry, and
the possibility to modulate the properties of these compounds by
introducing fluorinated groups,11, the development of methods to
access -fluoroalkylated azepanes I is of interest (Figure 1).
[a]
Guillaume Masson, Dr. Sarah Rioton, Dr. Domingo Gomez Pardo,
Prof. Janine Cossy
Molecular, Macromolecular Chemistry and Materials, ESPCI Paris,
CNRS, PSL University
Scheme 1. Previous syntheses of fluoroalkylated azepanes.
10 rue Vauquelin, Paris 75231 Cedex 05, France
E-mail: janine.cossy@espci.fr, domingo.gomez-pardo@espci.fr
https://www.lco.espci.fr/-Home-
In the context of our ring-expansion program,17 we would like to
report the synthesis of optically active α-trifluoromethyl-,
α-difluoromethyl- and α-perfluoroalkyl- substituted azepanes A,
which were envisaged by regioselective ring-opening of an
Supporting information for this article is given via a link at the end of
the document.
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azetidinium intermediates of type B issued from pyrrolidines C.
These latter would be synthesized from L-proline (Scheme 2).
Scheme 2. Strategy to access α-fluoroalkylated azepanes.
Results and Discussion
At first, the ring-expansion of pyrrolidines (±)-6 and (±)-7 was
studied Compounds (±)-6 and (±)-7 were prepared from N-Cbz-L-
proline in 4 steps. Thus, the N-protected proline 1 underwent an
iodo-decarboxylation (PhI(OAc)2, I2, hν) and the resulting iminium
intermediate
was
then
treated
with
2-methyl-
1(trimethylsilyoxy)propene in the presence of a Lewis acid to
produce aldehyde 2 (83%).18 After addition of TMSCF3 (1.6 equiv)
on aldehyde 2, in the presence of CsF (0.4 equiv), the
trifluoromethyl trimethylsily ethers were obtained as a mixture of
two diastereomers (±)-3 and (±)-3’. After treatment of (±)-3 and
(±)-3’ with TBAF, three products were isolated: the desired
pyrrolidine (±)-4 (49%) as a unique diastereomer, and two
diasteromeric bicyclic compounds (±)-5 and (±)-5’. It seems that
the diastereomer (±)-3’ underwent a cyclization to form the bicylic
compound (±)-5’ (40%), while the other diastereoisomer (±)-3
almost did not cyclize as only traces of (±)-5 were detected.
Compounds (±)-4 and (±)-5 were then transformed to the
corresponding N-benzyl pyrrolidines (±)-6 and (±)-7. The
transformation of N-Cbz pyrrolidines to the N-benzyl pyrrolidines
is of importance as the ring-expansion is achieved via an
azetidinium intermediate which is coming from an intramolecular
nucleophilic attack of the nitrogen of the pyrrolidine onto the C4’
of the side chain. Thus, after a hydrogenolysis/N-benzylation
sequence, (±)-4 was transformed to pyrrolidine (±)-6 in 64% yield.
To realize the transformation of (±)-5 to pyrrolidine (±)-7, two
steps were necessary. After treatment of (±)-5 with NaOH, the
pyrrolidine was N-benzylated (BnBr, Et3N, CH2Cl2) leading to the
formation of (±)-7 (Scheme 3).
Scheme 3. Synthesis of the racemic trifluoromethyl pyrrolidines (±)-6 and (±)-7.
Having pyrrolidines (±)-6 and (±)-7 in hand, these latter were
treated under the previously tuned up conditions allowing the
ring-expansion of pyrrolidines to piperidines,17c e.g. with Tf2O (1.1
equiv) in the presence of the 1,8-bis-(dimethylamino)naphthalene
(proton-sponge) (2.0 equiv), in CH2Cl2 followed by the addition of
a nucleophile. After optimization of the conditions, the best yield
in azepane (±)-8 was obtained from (±)-6 when the first step
(formation of the azetidinium) was realized in refluxing CH2Cl2 for
5 h, and the second step (ring-opening of the azetidinium by a
nucleophile) was achieved at room temperature (Scheme 4). By
using sodium phenoxide as the nucleophile, (±)-8a was isolated
with an excellent yield of 81%. n-Tetrabutylammonium azide and
n-tetrabutylammonium fluoride were also used as nucleophiles
and led respectively to the corresponding azepanes (±)-8b and
(±)-8c in 91% and 22% yield respectively. It is worth mentioning
that pyrrolidine (±)-7 was also transformed to azepanes (±)-9a–c
in moderate to excellent yields, by using the same nucleophiles
as for the transformation of (±)-6 to (±)-8a–c. In all cases, the
azepanes were obtained with diastereoselectivities superior to
95:5 (Scheme 4).
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Scheme 5. Synthesis of enantio-enriched trifluoromethyl pyrrolidines.
Starting from 11, we were also able to access the difluoromethyl
and perfluorobutyl derivatives (Scheme 6). Difluoromethyl
pyrrolidines 22 and 22’ were synthetized in 3 steps from 11. The
pyrrolidino-ester 11 was treated with the anion of
diethyl(difluoromethyl)phosphonate generated with LDA (THF, –
78°C).20 The resulting difluoro ketophosphonate 21 was obtained
in 46% yield. After cleavage of the phosphonate (MeOH, MeONa,
0°C)20 and reduction (NaBH4, MeOH, rt), the pyrrolidines 22 and
22’ were formed in a 40:60 ratio. After a hydrogenolysis/
N-benzylation sequence, the N-benzyl pyrrolidines 23 and 24
were isolated in 74% and 78% yield respectively from 22 and 22’
(Scheme 6).
Scheme 4. Ring-expansion of (±)-6 and (±)-7 using different nucleophiles.
As the ring-expansion of pyrrolidines (±)-6 and (±)-7 was
successful in the racemic series, the synthesis of optically active
pyrrolidines
C
was considered using an Arndt-Eistert
homologation of L-proline19 via a diazoketone. To synthesize
diazoketone 10, N-Cbz-proline 1 was treated with oxalyl chloride
(1.3 equiv, CH2Cl2, DMF cat.), and the resulting acyl chloride was
then treated with (trimethylsilyl)diazomethane (2.2 equiv, Et3N,
THF/CH3CN, 0°C, 5 h) to afford the desired diazoketone in 80%
yield. After a Wolff rearrangement, induced by silver benzoate,
the ketene intermediate was trapped with methanol to give the
corresponding methyl ester 11 (90%, 99% ee).19 A first attempt to
synthesize 13 and 14 from 11 was realized but a racemization
was observed, as the ee dropped from 99% to 30% (cf.
Supporting Information). In order to overcome this racemization,
we decided to modify the first sequence of reaction to access
pyrrolidines 13 and 14 from the pyrrolidino-ester 11 (ee > 99%).
The pyrrolidino-ester 11 was directly treated with TMSCF3/TBAF
(toluene, –78°C to rt) and the resulting trifluoromethyl ketone was
reduced by NaBH4 (MeOH, rt). The trifluoromethyl alcohols 12
and 12’ were isolated in 28% and 45% respectively. After a
hydrogenolysis/N-benzylation sequence, the pyrrolidino-alcohols
13 and 14 were isolated in 66% and 82% respectively (dr > 95:5).
We were also able to perform the same sequence starting from
the trans-4-methoxy N-Cbz-L-proline 15 to access the
corresponding pyrrolidines 19 and 20, bearing a methoxy group
at C4 (Scheme 5).
Perfluorobutyl pyrrolidines 26 and 27 were synthetized in 4 steps
from the pyrrolidino-ester 11 (Scheme 6). At first, the pyrrolidino-
ester 11 was reacted with perfluoro butyllithium (perfluorobutyl
iodide, MeLi.LiBr, THF, –78 °C) to form a perfluorobutyl ketone
intermediate, which is subsequently reduced with NaBH421 to form
the two diastereomeric perfluorobutyl alcohols 25 and 25’. After
cleavage of the carbamate by hydrogenolysis and N-benzylation,
the two diastereomes, N-benzyl perfluorobutyl pyrrolidines 26 and
27, were obtained in 62% and 68% yield respectively (Scheme 6).
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Scheme 6. Synthesis of difluoromethyl and perfluorobutyl pyrrolidines.
The ring-expansion was also performed on 13 and 14. When 13
and 14 were treated with Tf2O (1.1 equiv) in the presence of the
proton sponge (2.0 equiv) in refluxing CH2Cl2, followed by the
addition of nucleophiles such as alcoholates, amines, azide,
sodium acetimidate, thiol, hydride, cyanide, malonate, cuprate,
the corresponding azepanes 28 and 29 were isolated in good
yields (52% to 95%).22 The results are reported in Scheme 7.
Scheme 7. Ring-expansion of 13 and 14 using different nucleophiles.
The enantiomeric excess measured by chiral supercritical fluid
chromatography (SFC) for 28f and 29f, revealed to be superior to
99%. As expected, a complete transfer of chirality from the
starting proline to the newly formed azepanes occured. It is worth
mentioning that as 28f and 29f were crystalline, an X-ray
diffraction (CCDC 1850086 and 1850085) was realized
confirming the relative and absolute configuration of the
stereogenic centers (Figure 2).
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33a–c were formed in good to excellent yields, and with excellent
diastereoselectivity and an excellent enantiomeric excess
(Scheme 9).
Figure 2. X-ray diffraction of 28f and 29f.
Pyrrolidines 19 and 20 synthesized from 3-hydroxyproline were
also involved in the ring-expansion. However, by using the initial
reaction conditions (proton-sponge, Tf2O, CH2Cl2, 40 °C) we were
unable to achieve a complete conversion of 19 to the azetidinium.
Fortunately, by switching CH2Cl2 to CH3CN and heating the
reaction up to 60 °C, the complete disappearance of the
pyrrolidines 19 and 20 was observed by TLC. After addition of a
nucleophiles such as an amine, an acetate or a cyanide, the
corresponding azepanes were formed with a good overall yield for
both diastereomers (Scheme 8).
Scheme 9. Ring-expansion of pyrrolidines 23 and 24 using different
nucleophiles.
Perfluorobutyl pyrrolidines 26 and 27 were then involved in the
ring-expansion process. It is worth mentioning that the presence
of a perfluoroalkyl side chain instead of a CF3 or a CF2H group in
the pyrrolidino-alcohols does not alter the rearrangement.
However, due to the presence of a bulky fluorinated group, the
azetidinium intermediate was difficult to form. Thus, acetonitrile
was used as the solvent and the reaction was heated at 60 °C
ensuring a complete formation of the azetidinium intermediate.
After the addition of a nucleophile, the azepanes 34a–c and
35a–c were obtained with excellent yields, diastereoselectivity
and enantiomeric excess (Scheme 10).
Scheme 8. Ring-expansion of pyrrolidines 19 and 20 using different
nucleophiles.
The two diastereomers 23 and 24 bearing a difluoromethyl group
were submitted to the ring-expansion conditions using different
nucleophiles (Tf2O, proton-sponge, then addition of a nucleophile).
Whatever the nucleophiles, the disubstituted azepanes 32a–c,
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a good yield of 70%. The trifluoromethyl analog of azelastine was
obtained in 2 steps from pyrrolidine 12’ with an overall yield of
40.6 % (Scheme 11).
Scheme 11. Synthesis of α-trifluoromethyl azelastine 36.
Conclusion
The ring-expansion of pyrrolidino-alcohols C to azepanes A via a
bicyclic azetidinium intermediate
B showed an excellent
regioselectivity and complete transfer of chirality from L-proline to
the corresponding azepanes. This ring-expansion tolerates
various fluorinated groups such as
a trifluoromethyl, a
Scheme 10. Ring-expansion of pyrrolidines 26 and 27 using different
difluoromethyl as well as a perfluorobutyl group. The 2-fluoroalkyl
4-substituted azepanes were obtained with excellent
diastereoselectivity and excellent enantiomeric excesses and
should be of interest for medicinal chemists.
nucleophiles.
As this ring-expansion allows the access to a wide variety of
enantio-enriched azepanes, the access to biologically active
α-trifluoromethyl azepanes could be of interest. We choose to
synthetize the α-trifluoromethyl analog of azelastine, an
antihistaminic and bronchodilator used in the treatment of allergy
and asthma (Figure 3).
Experimental Section
General : All reactions were run under an argon atmosphere in oven-dried
glassware unless otherwise specified. All commercially available
compounds were purchased from Merck and used as received.Anhydrous
solvents, such as tetrahydrofuran (THF) and diethyl ether (Et2O) were
distilled from sodium/benzophenone. Dichloromethane (CH2Cl2) was
distilled from calcium hydride. The other anhydrous solvents, CH3CN and
DMF, were purchased from Merck and used as received.Analytical thin
layer chromatography (TLC) was performed over silica gel plates (Merck
60F254) visualized either with a UV lamp (254 nm) or by using a solution
of phosphomolybdic acid in ethanol followed by heating. Flash
chromatography was performed over silica gel (230-400 mesh).Infrared
spectra (IR) were recorded on a Bruker TENSOR™ 27 (IR-FT) with
attenuated total reflectance (ATR) and wavenumbers are indicated in
cm–1.1H NMR spectra were recorded on a Bruker AVANCE 400 at 400
MHz in CDCl3 (unless otherwise specified) and the observed signals are
reported as follows: chemical shift in parts per million from
tetramethylsilane with TMS as an internal indicator (TMS δ 0 ppm),
multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet or
overlap of non-equivalent resonances), integration. 13C NMR spectra were
recorded at 100 MHz in CDCl3 (unless otherwise specified) and the
observed signals were reported as follows: chemical shift in parts per
million from tetramethylsilane with the solvent as an internal indicator
Figure 3. Azelastine and its targeted trifluoromethyl analog.
The synthesis of α-trifluoromethyl azelastine 36 started with the
synthesis of N-methyl trifluoromethyl pyrrolidine 37 issued from
the reduction of the N-Cbz pyrrolidine 12’ (LiAlH4, THF, reflux)
(Scheme 11). The N-methyl pyrrolidine 37 was then submitted to
the ring-expansion conditions using 3823 as the nucleophile. The
desired trifluoromethyl azelastine 36 was formed and isolated with
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(CDCl3 δ 77.16 ppm). 19F NMR were recorded at 380 MHz in CDCl3.
Coupling constants (J) are reported in Hertz (Hz). All NMR spectra were
obtained at rt unless otherwise specified. High-resolution mass spectra
(HRMS) were performed by "Groupe de Spectrométrie de masse de
Sorbonne Université campus Pierre et Marie Curie (Paris)". Optical
rotations were determined using a Anton Paar MCP 100 polarimeter. The
enantiomeric excesses were determined by supercritical fluid
chromatography (SFC) analysis on a chiral stationary phase using a
Minigram Berger SFC-Mettler Toledo apparatus.
70.5 (q, 2JC-F = 23.7 Hz), 70.1, 61.8, 47.4, 42.7, 31.3, 28.7, 23.3, 20.1 (q,
4JC-F = 2.3 Hz). HRMS: calcd for C16H22F3N4 (M+H+): 327.1791; Found:
327.1793
(±)-(2S*,4R*)-1-Benzyl-4-fluoro-2-(trifluoromethyl)-3,3-dimethyl
azepane (8c)
Prepared according to the general procedure from (±)-6 (49.1 mg, 0.163
mmol, 1.0 equiv), proton sponge (69.8 mg, 0.326 mmol, 2.0 equiv), Tf2O
(0.030 mL, 0.181 mmol, 1.1 equiv), and n-Bu4NF (1M in THF, 0.410 mL,
0.410 mmol,2.5 equiv). The crude product was then purified by flash
column chromatography (PE/Et2O = 95:05) to afford compound 8c (10.9
mg, 0.036 mmol, 22%). IR (neat): 2926, 1495, 1470, 1455, 1372, 1258,
1214, 1174, 1126, 1091, 1028, 996, 940, 902 cm–1. 1H NMR (CDCl3, 400
MHz): δ 7.39–7.23 (m, 5H), 4.48 (dm, J = 46.8 Hz, 1H), 4.02 (d, JAB = 13.6
Hz, 1H), 3.91 (d, JAB = 13.6 Hz, 1H), 3.15 (q, J = 9.8 Hz, 1H), 2.92 (m, 1H),
2.72 (m, 1H), 2.04–1.85 (m, 2H), 1.75 (m, 1H), 1.47 (m, 1H), 1.17 (br s,
3H), 1.14 (dapp, J = 3.1 Hz, 3H). 13C NMR (CDCl3, 100 MHz): δ 139.4,
129.1 (2C), 128.5 (2C), 127.4, 126.2 (sapp, CF3), 97.7 (d, 1JC-F = 178.7 Hz),
General procedure for the synthesis of 2-trifluoromethylated-3,3-
dimethyl-4-substituted azepanes
To a stirred solution of compound (±)-6 or (±)-7 (1 equiv) and proton
sponge (2 equiv) in CH2Cl2 (0.1 M) was added Tf2O (1.1 equiv) at rt. The
reaction mixture was stirred for 5 h in a sealed tube at 40 °C. After 5 h, the
reaction was stirred at rt and the nucleophile (2.5 equiv) was added. After
5 min the reaction was diluted with H2O, extracted with CH2Cl2 and the
combined organic phases were dried over anhydrous Na2SO4, filtered and
concentrated under reduced pressure. The crude product was then
purified by flash column chromatography (PE/Et2O = 95:05) to obtain the
azepanes.
3
69.9 (qd, J = 24.7, 3.6 Hz), 61.6, 48.1, 42.3 (d, JC-F = 20.3 Hz), 29.4 (d,
3
4
4JC-F = 8.0 Hz), 28.7 (d, JC-F = 22.5 Hz), 20.8 (d, JC-F = 10.3 Hz), 20.2.
HRMS: calcd for C16H22F4N (M+H+): 304.1683; Found: 304.1684
(±)-(2S,4S)-1-Benzyl-2-(trifluoromethyl)-3,3-dimethyl-4-phenoxy
azepane (9a)
(±)-(2S*,4R*)-1-Benzyl-2-(trifluoromethyl)-3,3-dimethyl-4-phenoxy
Prepared according to the general procedure from (±)-7 (41.4 mg, 0.137
mmol, 1.0 equiv), proton sponge (58.9 mg, 0.275 mmol, 2.0 equiv), Tf2O
(0.025 mL, 0.151 mmol, 1.1 equiv), sodium phenoxide (58.4 mg, 0.344
mmol, 2.5 equiv). The crude product was then purified by flash column
chromatography (PE/Et2O = 95:05) to afford compound 9a (45.8 mg, 0.121
mmol, 88 %). IR (neat): 2930, 1598, 1585, 1493, 1453, 1391, 1361, 1327,
1298, 1237, 1194, 1154, 1132, 1098, 1070, 1028, 1010, 955 cm–1.1H NMR
(CDCl3, 400 MHz): δ 7.34–7.15 (m, 7H), 6.93–6.81 (m, 3H), 4.17 (m, 1H),
4.13 (d, JAB = 14.0 Hz), 3.89 (d, JAB = 13.9 Hz, 1H), 3.22 (q, J = 10.1 Hz,
1H), 2.84 (m, 1H), 2.65 (m, 1H), 1.97–1.62 (m, 3H), 1.43 (m, 1H), 1.24 (s,
3H), 1.14 (q, J = 1.6 Hz, 3H). 13C NMR (CDCl3, 100 MHz):24 δ 158.5, 139.8,
129.8 (2C), 128.8 (2C), 128.4 (2C), 127.2, 120.9, 116.0 (2C), 84.7, 71.6
azepane (8a)
Prepared according to the general procedure from (±)-6 (29.4 mg, 0.098
mmol, 1 equiv), proton sponge (41.8 mg, 0.195 mmol, 2 equiv), Tf2O (0.018
mL, 0.107 mmol, 1.1 equiv), sodium phenoxide (41.5 mg, 0.244, 2.5 equiv).
The crude product was then purified by flash column chromatography
(PE/EtOAc = 95:05 to 90:10) to afford compound 8a (30 mg, 0.079 mmol,
81%). IR (neat): 2929, 1598, 1585, 1493, 1454, 1369, 1299, 1240, 1171,
1126, 1089, 1027, 1014, 990, 946, 900 cm–1. 1H NMR (CDCl3, 400 MHz):24
δ 7.39–7.24 (m, 7H), 6.92 (tt, J = 7.3, 1.0 Hz, 1H), 6.87 (br d, J = 8.0 Hz,
2H), 4.25 (m, 1H), 4.11 (d, JAB = 13.6 Hz, 1H), 4.00 (br d, JAB = 12.9 Hz,
1H), 3.21 (q, J = 9.8 Hz, 1H), 2.99 (m, 1H), 2.75 (m, 1H), 2.00-1.86 (m,
2H), 1.70 (m, 1H), 1.46 (m, 1H), 1.25 (q, J =1.9 Hz, 3H), 1.18 (s, 3H). 13
C
2
(dapp, JC-F = 29.0 Hz), 42.6, 26.6, 25.1 (C9), 23.9, 21.3. HRMS: calcd for
NMR (CDCl3, 100 MHz): δ 158.5, 139.8, 129.7 (2C), 129.1 (2C), 128.5
C22H27F3NO (M+H+): 378.2039; Found: 378.2039
1
(2C), 127.8 (dapp, JC-F = 292.4 Hz), 127.4, 120.6, 115.7 (2C), 82.2, 70.7
(±)-(2S*,4S*)-4-Azido-1-benzyl-2-(trifluoromethyl)-3,3-dimethyl
2
(q, JC-F = 23.8 Hz), 48.3 (C7), 43.1, 30.4, 27.3, 22.0, 20.7. HRMS: calcd
for C22H27F3NO (M+H+): 378.2039; Found: 378.2039
azepane (9b)
(±)-(2S*,4R*)-4-Azido-1-benzyl-2-(trifluoromethyl)-3,3-dimethyl
Prepared according to the general procedure from (±)-7 (41.0 mg, 0.136
mmol, 1.0 equiv), proton sponge (58.3 mg, 0.272 mmol, 2.0 equiv), Tf2O
(0.025 mL, 0.151 mmol, 1.1 equiv), and n-Bu4NN3 (98.3 mg, 0.346 mmol,
2.5 equiv). The crude product was then purified by flash column
chromatography (PE/Et2O = 95:05) to afford compound 9b (40.8 mg, 0.125
mmol, 92 %). IR (neat): 2933, 2095, 1470, 1454, 1388, 1366, 1323, 1250,
1192, 1155, 1133, 1099, 1041, 1028, 982, 951, 928 cm–1. 1H NMR (CDCl3,
400 MHz): δ 7.38–7.22 (m, 5H), 4.05 (br d, JAB = 13.6 Hz, 1H), 3.89 (d, JAB
= 13.7 Hz, 1H), 3.49 (m, 1H), 3.14 (q, J = 10.3 Hz, 1H), 2.85 (m, 1H), 2.73
(m, 1H), 1.98–1.77 (m, 3H), 1.61 (m, 1H), 1.16 (br s, 3H), 1.12 (br s, 3H).
13C NMR (CDCl3, 100 MHz):24 δ 139.4, 129.0 (2C), 128.5 (2C), 128.0 (q,
J = 291.6 Hz), 127.4, 71.9 (q, J = 23.7 Hz), 71.3, 62.9, 48.2, 42.1, 27.7,
24.8, 22.7. HRMS: calcd for C16H22F3N4 (M+H+): 327.1791; Found:
327.1793
azepane (8b)
Prepared according to the general procedure from (±)-6 (52.4 mg, 0.174
mmol, 1.0 equiv), proton sponge (74.5 mg, 0.348 mmol, 2.0 equiv), Tf2O
(0.032 mL, 0.193 mmol, 1.1 equiv), and n-Bu4NN3(127 mg, 0.445 mmol,
2.6 equiv). The crude product was then purified by flash column
chromatography (PE/Et2O = 95:05) to afford compound 8b (51.7 mg, 0.158
mmol, 91 %). IR (neat): 2929, 2094, 1454, 1394, 1370, 1339, 1254, 1207,
1125, 1088, 1053, 1028, 981, 934 cm–1. 1H NMR (CDCl3, 400 MHz): δ
7.43–7.20 (m, 5H), 4.04 (d, JAB = 13.5 Hz, 1H), 3.91 (d, JAB = 13.5 Hz, 1H),
3.60 (dd, J = 9.5, 2.3 Hz, 1H), 3.13 (q, J = 9.8 Hz, 1H), 2.90 (m, 1H), 2.72
(ddd, J = 14.2, 5.4, 5.4 Hz, 1H), 1.99 (m, 1H), 1.87 (m, 1H), 1.66 (m, 1H),
1.54 (m, 1H), 1.17 (s, 3H), 1.11 (q, J = 2.0 Hz, 3H). 13C NMR (CDCl3, 100
MHz): δ 139.3, 129.1 (2C), 128.5 (2C), 127.8 (q, 1JC-F = 292.1 Hz), 127.5,
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201900613
European Journal of Organic Chemistry
FULL PAPER
(±)-(2S,4R)-1-Benzyl-4-fluoro-2-(trifluoromethyl)-3,3-dimethyl
38.9, 34.3, 21.4. {1H}19F NMR (376 MHz, CDCl3): δ –73.5 (s, 3F). HRMS:
azepane (9c)
calcd for C17H23F3NO3 (M+H+): 346.1625. Found: 346.1624.
Prepared according to the general procedure from (±)-7 (56.3 mg, 0.187
mmol, 1.0 equiv), proton sponge (80.1 mg, 0.374 mmol, 2.0 equiv), Tf2O
(0.034 mL, 0.205 mmol, 1.1 equiv), and n-Bu4NF (1M in THF, 0.467 mL,
0.467 mmol, 2.5 equiv). The crude product was then purified by flash
column chromatography (PE/Et2O = 95:05) to afford compound 9c (30.8
mg, 0.102 mmol, 54%). IR (neat): 2939, 1495, 1479, 1454, 1370, 1355,
(2S,4S,6R)-1-Benzyl-4-carbonitril-6-methoxy-2-
(trifluoromethyl)azepane (30c)
Prepared according to the general procedure from 19 (35 mg, 0.115 mmol,
1 equiv), proton sponge (50 mg, 0.23 mmol, 2 equiv), Tf2O (0.021 mL, 0.13
mmol, 1.1 equiv), and tetrabutylammonium cyanide (82 mg, 0.29 mmol,
2.5 equiv). The crude product was then purified by flash column
chromatography (PE/EtOAc = 95:05 to 90:10) to afford 30c (31 mg, 0.099,
86%) as a colorless oil. [α]D20 –3.4 (c 0.95, CHCl3) IR (neat): 2931, 1684,
1494, 1455, 1382, 1362, 1257, 1205, 1161, 1098, 1072, 1029, 1006, 965,
1248, 1205, 1155, 1135, 1100, 1076, 1000, 1006, 981, 954, 926 cm–1
.
1H NMR (CDCl3, 400 MHz): δ 7.40–7.20 (m, 5H), 4.47 (ddapp, J = 45.5,
10.0, 1H), 4.04 (d, JAB = 13.7 Hz, 1H), 3.87 (d, JAB = 13.8 Hz, 1H), 3.15
(qd, J = 10.4, 2.9 Hz, 1H), 2.83 (m, 1H), 2.69 (m, 1H), 2.05–1.79 (m, 2H),
1.73 (m, 1H), 1.59 (m, 1H), 1.21–1.14 (m, 6H). 13C NMR (CDCl3, 100
906 cm–1. 1H NMR (400 MHz, CDCl3): δ 7.41–7.25 (m, 5H), 4.28 (d, JAB
=
13.2 Hz, 1H), 3.93 (d, JAB = 13.2 Hz, 1H), 3.40–3.29 (m, 1H), 3.34 (s, 3H),
3.22 (m, 1H), 3.18–3.12 (m, 2H), 3.05 (m, 1H), 2.50–2.35 (m, 2H), 1.87 (m,
1H), 1.69 (ddd, J = 14.9, 11.6, 3.6 Hz, 1H). 13C NMR (101 MHz, CDCl3): δ
MHz):24 δ 139.4, 128.9 (2C), 128.5 (2C), 127.9 (dapp
,
1JC-F = 289.9 Hz),
1
2
127.4, 99.3 (d, JC-F = 173.6 Hz), 70.9, 60.8 (C10), 48.7, 28.6 (d, JC-F
=
19.5 Hz), 23.7, 23.2, 20.8 (d, 3JC-F = 11.9 Hz). HRMS: calcd for C16H22F4N
(M+H+): 304.1683; Found: 304.1685
1
138.9, 129.3 (2C), 128.6 (2C), 127.6, 127.4 (q, JC-F = 294.9 Hz), 122.8,
2
77.8, 60.0, 57.4 (q, JC-F = 26.1 Hz), 56.6, 49.3, 38.1, 32.5, 22.7. {1H}19F
(2S,4S,6R)-4-N,N-Diallylamine-1-benzyl-6-methoxy-2-
NMR (376 MHz, CDCl3): δ –71.9 (s, 3F). HRMS: calcd for C16H20F3N2O
(trifluoromethyl)azepan (30a)
(M+H+): 313.1522. Found: 313.1521.
Prepared according to the general procedure from 19 (35 mg, 0.115 mmol,
1 equiv), proton sponge (50 mg, 0.29 mmol, 2 equiv), Tf2O (0.021 mL, 0.13
mmol, 1.1 equiv), and diallylamine (0.035 mL, 0.288 mmol, 2.5 equiv). The
crude product was then purified by flash column chromatography
(PE/EtOAc = 95:05 to 90:10) to afford 30a (36 mg, 0.084 mmol, 82%) as
a colorless oil. [α]D20 –12.4 (c 2.05, CHCl3) IR (neat): 2932, 1720, 1643,
1603, 1495, 1455, 1365, 1273, 1155, 1114, 1029, 989, 919 cm–1. 1H NMR
(400 MHz, CDCl3): δ 7.38 (d, J = 7.2 Hz, 2H), 7.26 (m, 3H), 5.80 (m, 2H),
5.14 (m, 4H), 4.34 (d, JAB = 13.5 Hz, 1H), 3.90 (d, JAB = 13.4 Hz, 1H), 3.33–
3.31 (m, 1H), 3.31 (s, 3H), 3.28–3.19 (m, 1H), 3.18–2.97 (m, 7H), 2.24–
2.09 (m, 2H), 1.56 (ddd, J = 14.0, 12.0, 9.4 Hz, 1H), 1.41 (ddd, J = 14.0,
11.1, 3.8 Hz, 1H). 13C NMR (100 MHz, CDCl3): δ 139.9, 137.2 (2C), 129.3
(2R,4S,6R)-4-N,N-Diallyl-1-benzyl-6-methoxy-2-
(trifluoromethyl)azepane (31a)
Prepared according to the general procedure from 20 (45 mg, 0.148 mmol,
1 equiv), proton sponge (64 mg, 0.296 mmol, 2 equiv), Tf2O (0.027 mL,
0.163 mmol, 1.1 equiv), and diallylamine (0.046 mL, 0.37 mmol, 2.5 equiv).
The crude product was then purified by flash column chromatography
(PE/EtOAc = 95:05 to 90:10) to afford 31a (40 mg, 0.104, 70%) as a
colorless oil. [α]D20 +5 (c 0.95, CHCl3) IR (neat): 2931, 1727, 1642, 1454,
1364, 1272, 1154, 1111, 1097, 1053, 1028, 990, 918 cm–1. 1H NMR (400
MHz, CDCl3): δ 7.32–7.15 (m, 5H), 5.81 (m, 2H), 5.28–4.99 (m, 4H), 3.95
(d, JAB = 14.0 Hz, 1H), 3.90 (d, JAB = 14.0 Hz, 1H), 3.44–3.28 (m, 3H),
3.17–3.06 (m, 4H), 3.11 (s, 3H) 2.86 (ddapp, J = 15.5, 6.6 Hz, 1H), 2.65
(ddapp, J = 15.5, 3.6 Hz, 1H), 2.06–1.86 (m, 3H), 1.76 (m, 1H). 13C NMR
(2C), 128.3 (2C), 128.1 (q, 1JC-F = 291.6 Hz), 127.1, 117.0 (2C), 78.5, 60.5,
2
58.3 (q, JC-F = 26.5 Hz), 56.5, 53.2 (2C), 51.5, 49.6, 35.9, 32.0. {1H}19
F
(101 MHz, CDCl3): δ 139.8, 136.0 (2C), 128.6 (2C), 128.4 (2C), 127.3 (dapp
1JC-F = 284.8 Hz) 127.2, 117.4 (2C), 77.0, 61.0 (q, JC-F = 27.0 Hz), 56.9,
56.7, 52.7 (2C), 52.0, 50.4, 34.7, 28.3. {1H}19F NMR (376 MHz, CDCl3): δ
–74.1 (s, 3F). HRMS: calcd for C21H30F3N2O (M+H+): 383.2305. Found:
383.2302.
,
NMR (376 MHz, CDCl3): δ –73.0 (s, 3F). HRMS: calcd for C21H30F3N2O
(M+H+): 383.2305. Found: 383.2300.
2
(2S,4S,6R)-4-Acetate-1-benzyl-6-methoxy-2-(trifluoromethyl)azepane
(30b)
(2R,4S,6R)-4-Acetate-1-benzyl-6-methoxy-2-(trifluoromethyl)azepane
Prepared according to the general procedure from 19 (35 mg, 0.115 mmol,
1 equiv), proton sponge (50 mg, 0.23 mmol, 2 equiv), Tf2O (0.021 mL, 0.13
mmol, 1.1 equiv), and tetrabutylammonium acetate (87 mg, 0.29 mmol, 2.5
equiv). The crude product was then purified by flash column
chromatography (PE/EtOAc = 95:05 to 90:10) to afford compound 30b (30
mg, 0.087 mmol, 75%) as a colorless oil.
(31b)
Prepared according to the general procedure from 20 (45 mg, 0.148 mmol,
1 equiv), proton sponge (64 mg, 0.296 mmol, 2 equiv), Tf2O (0.027 mL,
0.163 mmol, 1.1 equiv), and tetrabutylammonium acetate (112 mg, 0.37
mmol, 2.5 equiv). The crude product was then purified by flash column
chromatography (PE/EtOAc = 95:05 to 90:10) to afford 31b (36 mg, 0.104
mmol, 71%) as a colorless oil. [α]D20 +5 (c 0.95, CHCl3) IR (neat): 2942,
1739, 1495, 1454, 1370, 1275, 1240, 1155, 1115, 1074, 1090, 1026 cm–1.
1H NMR (400 MHz, CDCl3): δ 7.33–7.19 (m, 5H), 5.29 (m, 1H), 4.05 (d,
JAB = 13.8 Hz, 1H), 3.87 (d, JAB = 13.8 Hz, 1H), 3.38 (m, 1H), 3.31 (m, 1H),
3.03 (s, 3H), 2.88–2.70 (m, 2H), 2.35 (m, 1H), 2.26 (m, 1H), 2.09 (s, 3H),
[α]D20 –12.4 (c 2.05, CHCl3) IR (neat): 2930, 1735, 1495, 1454, 1366, 1233,
1163, 1115, 1098, 1076, 1025, 942 cm–1. 1H NMR (400 MHz, CDCl3): δ
7.39 (d, J = 7.22 Hz, 2H), 7.32 (t, J = 7.1 Hz, 2H), 7.25 (m; 1H), 5.15 (ttapp
,
J = 10.1, 2.5 Hz, 1H), 4.37 (d, JAB = 13.7 Hz, 1H), 3.93 (d, JAB = 13.7 Hz,
1H), 3.48–3.38 (m, 1H), 3.38–3.32 (m, 1H), 3.28 (s, 3H), 3.13–3.03 (m,
2H), 2.32–2.19 (m, 2H), 2.04 (s, 3H), 1.89 (m, 1H), 1.68 (m, 1H). 13C NMR
(101 MHz, CDCl3): δ 170.2, 139.5, 129.0 (2C), 128.4 (2C), 127.4 (q, 1JC-F
1.93 (m, 1H), 1.44 (ddd, J = 14.1, 10.2, 2.9 Hz, 1H). 13C NMR (101 MHz,
1
CDCl3): δ 170.1, 139.0, 128.8 (2C), 128.5 (2C), 127.5, 127.3 (q, JC-F
=
2
2
= 289.1 H), 127.3, 77.6, 69.0, 60.2, 57.8 (q, JC-F = 26.9 Hz), 56.6, 48.9,
286.10 Hz), 73.5, 67.5, 60.0 (q, JC-F = 27.67 Hz), 59.1, 56.9, 49.4, 38.6,
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201900613
European Journal of Organic Chemistry
FULL PAPER
29.9, 21.3. {1H}19F NMR (376 MHz, CDCl3): δ –75.8 (s, 3F). HRMS: calcd
(2S,4R)-4-Acetate-1-benzyl-2-(difluoromethyl)azepane (32b)
for C17H23F3NO3 (M+H+): 346.1625. Found: 346.1623.
Prepared according to the general procedure from compound 23 (30 mg,
0.117 mmol, 1 equiv), proton sponge (50.4 mg, 0.235 mmol, 2 equiv), Tf2O
(0.021 mL, 0.130 mmol, 1.1 equiv), and tetrabutylammonium acetate (88.6
mg, 0.29 mmol, 2.5 equiv). The crude product was then purified by flash
column chromatography (PE/EtOAc = 95:05 to 90:10) to afford compound
32b (29 mg, 0.097 mmol, 83%) as a colorless oil. [α]D20 –11 (c 0.6, CHCl3)
IR (neat): 2937, 1730, 1495, 1453, 1365, 1241, 1169, 1114 1024, 968,
(2R,4S,6R)-1-Benzyl-4-carbonitril-6-methoxy-2-
(trifluoromethyl)azepane (31c)
Prepared according to the general procedure from 20 (45 mg, 0.148 mmol,
1 equiv), proton sponge (64 mg, 0.296 mmol, 2 equiv), Tf2O (0.027 mL,
0.163 mmol, 1.1 equiv), and tetrabutylammonium cyanide (105 mg, 0.37
mmol, 2.5 equiv). The crude product was then purified by flash column
chromatography (PE/EtOAc = 95:05 to 90:10) to afford compound 31c (35
940, 920 cm–1.1H NMR (400 MHz, CDCl3): δ 7.37–7.21 (m, 5H), 5.56 (tdapp
J = 56.6, 3.2 Hz, 1H), 4.94 (br tt, J = 10.4, 2.8 Hz, 1H), 4.00 (d, JAB = 13.9
Hz, 1H), 3.81 (d, JAB = 13.9 Hz, 1H), 3.11 (m, 1H), 2.96–2.80 (m, 2H),
2.22–1.83 (m, 3H), 2.05 (s, 3H), 1.66 (m, 1H), 1.54 (m, 1H), 1.40 (m, 1H).
13C NMR (101 MHz, CDCl3): δ 170.4, 139.7, 128.7 (2C), 128.5 (2C), 127.4,
,
20
mg, 0.112 mmol, 76%) as a colorless oil. [α]D +78 (c 0.65, CHCl3)
IR (neat): 2934, 1496, 1455, 1385, 1363, 1327, 1256, 1234, 1156, 1115,
1040, 1075, 1029, 1016, 986, 965 cm–1. 1H NMR (400 MHz, CDCl3): δ
7.56–7.41 (m, 2H), 7.39–7.24 (m, 3H), 4.17 (d, JAB = 13.4 Hz, 1H), 3.99 (d,
JAB = 13.3 Hz, 1H), 3.71 (m, 1H), 3.23 (m, 1H), 3.08 (m, 1H), 2.95–2.86
1
2
117.3 (t, JC-F = 247.67 Hz), 73.4, 60.5 (t, JC-F = 21.19 Hz), 59.2, 47.6,
35.0, 33.0, 21.5, 20.9. {1H}19F NMR (376 MHz, CDCl3): δ –121.3 (d, J =
277.4 Hz, 1F), –130.0 (d, J = 277.1 Hz, 1F). HRMS: calcd for C16H22F2NO2
(M+H+): 298.1613. Found: 298.1611
(m, 1H), 2.92 (s, 3H) 2.75 (m, 1H), 2.46 (m, 1H), 2.35 (m, 1H), 1.92 (ddapp
,
J = 14.2, 12.8 Hz, 1H), 1.39 (ddd, J = 13.9, 10.8, 3.9 Hz, 1H). 13C NMR
(101 MHz, CDCl3): δ 138. 6, 129.7 (2C), 128.5 (2C), 127.9 (q, 1JC-F = 290.9
(2S,4R)-1-Benzyl-4-carbonitril-2-(difluoromethyl)azepane (32c)
2
Hz) 127.7, 120.4, 76.3, 61.3 (q, JC-F = 26.8 Hz), 59.80, 56.9, 47.7, 37.4,
29.1, 23.8. {1H}19F NMR (376 MHz, CDCl3): δ –73.1 (s, 3F). HRMS: calcd
for C16H20F3N2O (M+H+): 313.1522. Found: .313.1521
Prepared according to the general procedure from compound 23 (30 mg,
0.117 mmol, 1 equiv), proton sponge (50.4 mg, 0.235 mmol, 2 equiv), Tf2O
(0.021 mL, 0.130 mmol, 1.1 equiv), and tetrabutylammonium cyanide (78.9
mg, 0.29 mmol, 2.5 equiv). The crude product was then purified by flash
column chromatography (PE/EtOAc = 95:05 to 90:10) to afford compound
General procedure for the synthesis of difluoromethylated-4-
substituted azepanes
20
32c (25 mg, 0.094, 80%) as a colorless oil. [α]D –21 (c 0.8, CHCl3) IR
To a stirred solution of compound 23 or 24 (1 equiv) and proton sponge (2
equiv) in CH2Cl2 (0.1 M) was added Tf2O (1.1 equiv) at rt. The reaction
mixture was stirred for 5 h in a sealed tube at 40 °C. After 5 h, the reaction
was cooled to rt and the nucleophile (2.5 equiv) was added. After 5 min
the reaction was diluted with H2O, extracted with CH2Cl2 and the combined
organic phases were dried over anhydrous Na2SO4, filtered and
concentrated under reduced pressure. The crude product was then
purified by flash column chromatography (PE/EtOAc = 95:05 to 90:10) to
obtain the azepanes.
(neat): 2936, 2238, 1494, 1467, 1453, 1377, 1335, 1211, 1173, 1134,
1106, 1041, 1030, 971, 916 cm–1. 1H NMR (400 MHz, CDCl3): δ 7.38–7.24
(m, 5H), 5.63 (tdapp, J = 56.1, 3.3 Hz, 1H), 4.02 (d, JAB = 13.8 Hz, 1H), 3.82
(d, JAB = 13.8 Hz, 1H), 3.08 (m, 1H), 2.97–2.76 (m, 3H), 2.40 (ddapp, J =
15.0, 5.5 Hz, 1H), 2.23 (m, 1H), 1.99 (m, 1H), 1.78–1.45 (m, 3H). 13C NMR
1
(101 MHz, CDCl3): δ 139.3, 128.7 (4C), 127.6, 122.8, 116.8 (t, JC-F
=
249.3 Hz), 62.0 (t, 2JC-F = 20.8 Hz), 59.2, 47.6, 33.7, 30.7 (t, 2JC-F = 3.1 Hz),
28.0, 25.5. {1H}19F NMR (376 MHz, CDCl3): δ –121.0 (d, J = 281.4 Hz,
1F), –129.2 (d, J = 281.8 Hz, 1F). HRMS: calcd for C15H19F2N2 (M+H+):
265.1511. Found: 265.1509
(2S,4R)-4-N,N-diallylamin-1-benzyl-2-(difluoromethyl)azepane (32a)
Prepared according to the general procedure from compound 23 (30 mg,
0.117 mmol, 1 equiv), proton sponge (50.4 mg, 0.235 mmol, 2 equiv), Tf2O
(0.021 mL, 0.130 mmol, 1.1 equiv), and diallylamine (36 μL, 0.29 mmol,
2.5 equiv). The crude product was then purified by flash column
chromatography (PE/EtOAc = 95:05 to 90:10) to afford compound 32a (34
mg, 0.102 mmol, 87%) as a colorless oil. [α]D20 –6 (c 1.9, CHCl3) IR (neat):
2927, 1641, 1494, 1452, 1417, 1374, 1264, 1216, 1170, 1135, 1103, 1042,
993, 917 cm–1. 1H NMR (400 MHz, CDCl3): δ 7.33–7.21 (m, 5H), 5.84 (m,
(2R,4R)-4-N,N-Diallylamin-1-benzyl-2-(difluoromethyl)azepane (33a)
Prepared according to the general procedure from compound 24 (44 mg,
0.17 mmol, 1 equiv), proton sponge (74 mg, 0.34 mmol, 2 equiv), Tf2O
(0.031 mL, 0.190 mmol, 1.1 equiv), and diallylamine (53 μL, 0.43 mmol,
2.5 equiv). The crude product was then purified by flash column
chromatography (PE/EtOAc = 95:05 to 90:10) to afford compound 33a (46
20
mg, 0.138 mmol, 80%) as a colorless oil. [α]D –10 (c 0.95, CHCl3)
IR (neat): 2929, 2810, 1642, 1574, 1494, 1453, 1417, 1378, 1357, 1277,
1150, 1117, 1057, 1035, 995, 984, 918 cm–1. 1H NMR (400 MHz, CDCl3):
δ 7.35–7.20 (m, 5H), 5.85 (m, 2H), 5.68 (tdapp, J = 56.8, 4.7 Hz, 1H), 5.18
(m, 4H), 3.80 (d, JAB = 14.2 Hz, 1H), 3.75 (d, JAB = 14.2 Hz, 1H), 3.26–3.02
(m, 6H), 2.86 (m, 1H), 2.61 (m, 1H), 2.04 (ddd, J = 14.5, 9.4, 4.9 Hz 1H),
1.85–1.73 (m, 2H), 1.70–1.53 (m, 3H). 13C NMR (101 MHz, CDCl3): δ
2H), 5.50 (tdapp, J = 56.9, 3.2 Hz, 1H), 5.22–5.10 (m, 4H), 3.99 (d, JAB
=
13.8 Hz, 1H), 3.76 (d, JAB = 13.8 Hz, 1H), 3.13 (dd, JAB = 14.1, 6.1 Hz, 2H),
3.04 (dd, JAB = 14.1, 6.5 Hz, 2H), 2.94–2.81 (m, 4H), 2.07 (br dd, J = 14.1,
3.9 Hz, 1H), 2.00–1.79 (m, 1H), 1.68–1.54 (m, 2H), 1.44–1.32 (m, 2H).
13C NMR (101 MHz, CDCl3): δ 140.2, 137.5 (2C), 128.8 (2C), 128.5 (2C),
127.2, 117.8 (t, 1JC-F = 246.12 Hz), 116.9 (2C), 62.0 (t, 2JC-F = 21.57 Hz),
59.7, 57.6, 53.1 (2C), 47.9, 32.2, 29.3, 22.5. {1H}19F NMR (376 MHz,
CDCl3): δ –121.1 (d, J = 274.8 Hz, 1F), –130.1 (d, J = 275.1 Hz, 1F).
HRMS: calcd for C20H29F2N2 (M+H+): 335.2293. Found: 335.2285
1
140.1, 137.1 (2C), 128.5 (2C), 128.4 (2C), 127.1, 118.2 (t, JC-F = 245.31
Hz), 116.9 (2C), 61.5 (t, 2JC-F = 22.85 Hz), 56.4, 55.6, 52.7 (2C), 51.9, 30.4,
26.8, 25.4. {1H}19F NMR (376 MHz, CDCl3): δ –120.6 (d, J = 278.5 Hz,
1F), –125.8 (d, J = 278.4 Hz, 1F). HRMS: calcd for C20H29F2N2 (M+H+):
335.2293. Found: 335.2292
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201900613
European Journal of Organic Chemistry
FULL PAPER
(2R,4R)-4-Acetate-1-benzyl-2-(difluoromethyl)azepane (33b)
colorless oil. [α]D20 +4.5 (c 0.65, CHCl3) IR (neat): 3001, 1459, 1425, 1355,
1223, 1165, 1135, 1029 cm–1. 1H NMR (400 MHz, CDCl3): δ 7.33–7.21 (m,
5H), 5.84 (m, 2H), 5.23–5.10 (m, 4H), 4.16 (d, JAB = 13.6 Hz, 1H), 3.87 (d,
JAB = 13.6 Hz, 1H), 3.40 (m, 1H), 3.13 (dd, J = 14.1, 6.1 Hz, 2H), 3.03 (dd,
J = 14.1, 6.5 Hz, 2H), 2.91 (tapp, J = 9.6 Hz, 1H), 2.86–2.70 (m, 2H), 2.20
(m; 1H), 1.91 (m, 1H), 1.78 (m, 1H), 1.67–1.49 (m, 1H), 1.40 (dddapp, J =
Prepared according to the general procedure from compound 24 (44 mg,
0.172 mmol, 1 equiv), proton sponge (74 mg, 0.34 mmol, 2 equiv), Tf2O
(0.031 mL, 0.190 mmol, 1.1 equiv), and tetrabutylammonium acetate (104
mg, 0.34 mmol, 2.5 equiv). The crude product was then purified by flash
column chromatography (PE/EtOAc = 95:05 to 90:10) to afford compound
33b (37 mg, 0.124 mmol, 72%) as a colorless oil. [α]D20 +1.9 (c 1.1, CHCl3)
IR (neat): 2937, 1736, 1495, 1442, 1430, 1371, 1245, 1232, 1166, 1132,
1042, 1026, 990 cm–1. 1H NMR (400 MHz, CDCl3): δ 7.38–7.22 (m, 5H),
5.59 (tdapp, J = 56.8, 3.6 Hz, 1H), 5.29 (m, 1H), 3.95 (d, JAB = 13.9 Hz, 1H),
3.81 (d, JAB = 13.9 Hz, 1H), 3.12 (m, 1H), 2.87 (m, 2H), 2.23–2.11 (m, 1H),
2.14 (s, 3H), 2.09–2.00 (m, 1H), 2.00–1.91 (m, 1H), 1.91–1.79 (m, 1H),
1.63 (m, 1H), 1.45 (m, 1H). 13C NMR (101 MHz, CDCl3): δ 170.3, 139.9,
24.1, 12.6, 4.7 Hz, 1H), 1.22 (m, 1H). 13C NMR (101 MHz, CDCl3):25
δ
139.0, 137.3 (2C), 128.8 (2C), 128.4 (2C), 127.3, 117.0 (2C), 62.5, 59.7,
56.7, 53.2 (2C), 45.4, 32.2, 31.1, 21.3. {1H}19F NMR (376 MHz, CDCl3): δ
–80.84 (dd, J = 10.9, 8.4 Hz, 3F), –118.51 (m, 2F), –121.55 (s, 2F), –
125.50– –126.60 (m, 2F). HRMS: calcd for C23H28F9N2 (M+H+): 503.2103.
Found: 503.2096
(2S,4R)-4-Acetate-1-benzyl-2-(perfluorobutyl)azepane (34b)
1
128.7 (2C), 128.5 (2C), 127.3, 117.8 (t, JC-F = 247.51 Hz), 71.4, 59.8 (t,
Prepared according to the general procedure from compound 26 (35 mg,
0.083 mmol, 1 equiv), proton sponge (35.4 mg, 0.165 mmol, 2 equiv), Tf2O
(0.015 mL, 0.090 mmol, 1.1 equiv), and tetrabutylammonium acetate (104
mg, 0.34 mmol, 2.5 equiv). The crude product was then purified by flash
column chromatography (PE/EtOAc = 95:05 to 90:10) to afford 34b (27 mg,
0.058 mmol, 71%) as a colorless oil. [α]D20 –25.8 (c 1.46, CHCl3) IR (neat):
2941, 1735, 1468, 1454, 1365, 1231, 1215, 1199, 1131, 1104, 1026, 995,
940 cm–1 1H NMR (400 MHz, CDCl3) δ 7.35–7.23 (m, 5H), 4.92 (tapp, J =
14.1, 1H), 4.19 (d, JAB = 13.6 Hz, 1H), 3.93 (d, JAB = 13.6 Hz, 1H), 3.65
(qdapp, J = 12.9, 5.9 Hz, 1H), 2.94–274 (m, 2H), 2.28–2.10 (m, 2H), 2.06
(s, 3H), 2.05–1.98 (m, 1H), 1.72–1.46 (m, 2H), 1.24 (m, 1H). 13C NMR (101
MHz, CDCl3): δ 170.3, 138.6, 128.8 (2C), 128.5 (2C), 127.4, 119.1–115.4
2JC-F = 21.68), 57.6, 49.5, 33.4, 29.6, 21.5, 21.1. {1H}19F NMR (376 MHz,
CDCl3): δ –120.9 (d, J = 276.0 Hz, 1F), –129.4 (d, J = 276.0 Hz, 1F).
HRMS: calcd for C16H22F2NO2 (M+H+): 298.1613. Found: 298.1610
(2R,4R)-1-Benzyl-4-carbonitril -2-(difluoromethyl)azepane (33c)
Prepared according to the general procedure from compound 24 (44 mg,
0.17 mmol, 1 equiv), proton sponge (74 mg, 0.34 mmol, 2 equiv), Tf2O
(0.031 mL, 0.190 mmol, 1.1 equiv), and tetrabutylammonium cyanide (116
mg, 0.43 mmol, 2.5 equiv). The crude product was then purified by flash
column chromatography (PE/EtOAc = 95:05 to 90:10) to afford compound
33c (32 mg, 0.12 mmol, 71%) as a colorless oil. [α]D20 +16 (c 0.84, CHCl3)
IR (neat): 2935, 2237, 1495, 1453, 1377, 1359, 1225, 1159, 1129, 1099,
1050, 1040, 987, 945, 925 cm–1. 1H NMR (400 MHz, CDCl3): δ 7.42–7.22
(m, 5H), 5.58 (tdapp, J = 56.7 Hz, 2.8 Hz, 1H), 4.12 (d, JAB = 14.1 Hz, 1H),
3.95 (d, JAB = 14.1 Hz, 1H), 3.38–3.22 (m, 2H), 2.96–2.82 (m, 2H), 2.30
(m, 1H), 2.11 (m, 1H), 2.02–1.84 (m, 2H), 1.62–1.45 (m, 2H). 13C NMR
(101 MHz, CDCl3): δ 139.9, 128.8 (2C), 128.5 (2C), 127.3, 121.2, 117.2 (t,
1JC-F = 247.6 Hz), 61.5 (dd, 2JC-F = 21.2, 19.8 Hz), 59.0, 47.8, 32.3, 28.3,
28.2, 23.9. {1H}19F NMR (376 MHz, CDCl3): δ –120.9 (d, J = 277.4 Hz,
1F), –131.2 (d, J = 277.3 Hz, 1F). HRMS: calcd for C15H19F2N2 (M+H+):
265.1511. Found: 265.1510
2
(4C), 72.4, 60.8 (t, JC-F = 21.09 Hz), 59.0, 45.0, 35.1, 34.8, 21.5, 19.7.
{1H}19F NMR (376 MHz, CDCl3): δ -80.8 (t, 3F), -117.9 (dm, J = 281.5 Hz,
1F),–-119.3 (dm, J = 286.2 Hz, 1F), –121.5 (m, 2F),–126.1 (tapp, 2F).
HRMS: calcd for C19H21F9NO2 (M+H+): 466.1423. Found: 466.1418
(2S,4R)-1-Benzyl-4-carbonitril-2-(perfluorobutyl)azepane (34c)
Prepared according to the general procedure from 26 (35 mg, 0.083 mmol,
1 equiv), proton sponge (35.4 mg, 0.165 mmol, 2 equiv), Tf2O (0.015 mL,
0.090 mmol, 1.1 equiv), and tetrabutylammonium cyanide (55.5 mg, 0.206
mmol, 2.5 equiv). The crude product was then purified by flash column
chromatography (PE/EtOAc = 95:05 to 90:10) to afford 34c (32 mg, 0.074
mmol, 89%) as a colorless oil. [α]D20 –15.0 (c 1.33, CHCl3) IR (neat): 2939,
2210, 1468, 1455, 1354, 1229, 1214, 1199, 1131, 1079, 1012 cm–1. 1H
NMR (400 MHz, CDCl3): δ 7.39–7.21 (m, 5H), 4.16 (d, JAB = 13.5 Hz, 1H),
3.95 (d, JAB = 13.5 Hz, 1H), 3.58 (m, 1H), 2.95 (ddapp, J = 14.8, 10.3 Hz,
1H), 2.86–2.77 (m, 2H), 2.50 (ddapp, J = 14.8, 6.1 Hz, 1H), 2.24 (m, 1H),
2.15 (m, 1H), 1.72–1.51 (m, 2H), 1.43 (m, 1H). 13C NMR (101 MHz,
CDCl3): δ 138.2, 128.9 (2C), 128.7 (2C), 127.7, 122.5, 121–108.8 (m, 4C),
61.7 (t, 2JC-F = 21.0 Hz), 59.4, 45.9, 33.8, 32.1, 27.5, 24.5. {1H}19F NMR
(376 MHz, CDCl3): δ –80.85 (m, 3F), –116.95 (dm, J = 280.3 Hz, 1F),
–118.93 (dm, J = 282.1 Hz, 1F), –121.85 (m, 2F), –126.06 (m, 2F). HRMS:
calcd for C18H18F9N2 (M+H+): 433.1321. Found: 433.1321
General procedure for the synthesis of perfluorinated substituted
azepanes
To a stirred solution of compound 26 or 27 (1 equiv) and proton sponge (2
equiv) in CH3CN (0.1 M) was added Tf2O (1.1 equiv) at rt. The reaction
mixture was stirred for 5 h in a sealed tube at 60 °C. After 5 h, the reaction
was cooled to rt and the nucleophile (2.5 equiv) was added. After 5 min
the reaction was diluted with H2O, extracted with CH2Cl2 and the combined
organic phases were dried over anhydrous Na2SO4, filtered and
concentrated under reduced pressure. The crude product was then
purified by flash column chromatography (PE/EtOAc = 95:05 to 90:10) to
obtain the azepanes.
(2R,4R)-4-N,N-Diallylamin-1-benzyl-2-(perfluorobutyl)azepane (35a)
(2S,4R)-4-N,N-Diallylamine-1-benzyl-2-(perfluorobutyl)azepane (34a)
Prepared according to the general procedure from 27 (40 mg, 0.094 mmol,
1 equiv), proton sponge (40 mg, 0.185 mmol, 2 equiv), Tf2O (0.017 mL,
0.101 mmol, 1.1 equiv), and diallylamine (29 μL, 0.24 mmol, 2.5 equiv).
The crude product was then purified by flash column chromatography
(PE/EtOAc = 95:05 to 90:10) to afford 35a (34 mg, 0.068 mmol, 72%) as
a colorless oil. [α]D20 +6.3 (c 1.7, CHCl3) IR (neat): 2932, 1642, 1496, 1454,
Prepared according to the general procedure from 26 (35 mg, 0.083 mmol,
1 equiv), proton sponge (35.4 mg, 0.165 mmol, 2 equiv), Tf2O (0.015 mL,
0.090 mmol, 1.1 equiv), and diallylamine (25 μL, 0.20 mmol, 2.5 equiv).
The crude product was then purified by flash column chromatography
(PE/EtOAc = 95:05 to 90:10) to afford 34a (32 mg, 0.064, 77%) as a
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201900613
European Journal of Organic Chemistry
FULL PAPER
1354, 1296, 1231, 1215, 1200, 1185, 1131, 1094, 995, 919 cm–1. 1H NMR
(400 MHz, CDCl3): δ 7.40–7.13 (m, 5H), 5.87 (m, 2H), 5.32–5.07 (m, 4H),
4.05 (d, JAB = 13.8 Hz, 1H), 3.76–3.69 (m, 1H), 3.66 (d, JAB = 13.8 Hz, 1H),
3.24 (m, 1H), 3.12 (m, 4H), 2.88 (m, 1H), 2.51 (m, 1H), 2.24 (m, 1H), 1.93
(m, 1H), 1.79 (m, 1H), 1.74–1.42 (m, 3H). 13C NMR (101 MHz, CDCl3):25
δ 138.9, 136.8 (2C), 128.6 (2C), 128.4 (2C), 127.1, 117.1 (2C), 60.5 (dd,
2JC-F = 24.16, 21.23 Hz), 57.2, 52.8 (2C), 52.2, 51.4, 29.1, 25.9, 24.2.
{1H}19F NMR (376 MHz, CDCl3): δ –80.8 (m, 3F), –112.4 (d, J = 294.2 Hz,
1F), –120.2 (d, J = 294.2 Hz, 1F), –120.4 (dm, J = 311.2 Hz, 1F), –122.7
(dm, J = 310.8 Hz, 1F), –125.0 (dm, J = 298.6 Hz, 1F), –127.3 (d, J = 292.1
Hz, 1F) HRMS: calcd for C23H28F9N2 (M+H+): 503.2103. Found: 503.2100
mmol, 1.1 equiv), and the sodium phtalizinone solution* [*prepared as
follow: phtalizinone (550 mg, 2 mmol, 4 equiv) in DMF (1 mL) was added
dropwise to the stirred suspension of NaH (61 mg, 1.5 mmol, 23 equiv) in
DMF (1 mL) at 0 °C.]. The crude product was then purified by flash column
chromatography (PE/EtOAc = 95:05 to 90:10) to afford compound 36 (160
20
mg, 0.36 mmol, 70%) as a colorless oil. [α]D –10.4 (c 1.4, CHCl3)
IR (neat): 2937, 1647, 1587, 1490, 1452, 1445, 1380, 1322, 1310, 1263,
1223, 1163, 1150, 1114, 1105, 1031, 1016, 966, 912 cm–1. 1H NMR (400
MHz, CDCl3): δ 8.46 (m, 1H), 7.80–7.66 (m, 3H), 7.30–7.25 (m, 2H), 7.22–
7.17 (m, 2H), 5.51 (m, 1H), 4.30 (d, JAB = 15.7 Hz, 1H), 4.26, (d, JAB = 15.7
Hz, 1H), 3.55 (m, 1H), 3.13 (dtapp, J = 10.1, 4.8 Hz, 1H), 2.86 (m, 1H), 2.56
(s, 3H), 2.48 (dddapp, J = 15.2, 11.0, 7.5 Hz, 1H), 2.20 (ddd, J = 15.2, 5.9,
3.7 Hz, 1H), 2.07 (m, 1H), 1.96–1.78 (m, 3H). 13C NMR (101 MHz, CDCl3):
(2R,4R)-4-Acetate-1-benzyl-2-(perfluorobutyl)azepane (35b)
δ 158.4, 145.2, 136.1, 133.1, 132.8, 131.6, 130.2 (2C), 129.0 (2C), 128.8,
Prepared according to the general procedure from 27 (62 mg, 0.15 mmol,
1 equiv), proton sponge (63 mg, 0.2953 mmol, 2 equiv), Tf2O (0.027 mL,
0.162 mmol, 1.1 equiv), and tetrabutylammonium acetate (111 mg, 0.37
mmol, 2.5 equiv). The crude product was then purified by flash column
chromatography (PE/EtOAc = 95:05 to 90:10) to afford 35b (49 mg, 0.105
mmol, 70%) as a colorless oil. [α]D20 +15.8 (c 0.8, CHCl3) IR (neat): 2943,
1740, 1443, 1430, 1420, 1371, 1354, 1228, 1215, 1200, 1130, 1085, 1059,
1023, 996, 947 cm–1. 1H NMR (400 MHz, CDCl3): δ 7.40–7.19 (m, 5H),
5.33 (m, 1H), 4.21 (d, JAB = 13.7 Hz, 1H), 3.79 (d, JAB = 13.7 Hz, 1H), 3.64
(qdapp, J = 26.2, 13.7, 4.9 Hz, 1H), 2.84 (ddd, J = 15.4, 9.0, 2.2 Hz, 1H),
2.72 (ddd, J = 15.5, 6.7, 2.6 Hz, 1H), 2.33 (m, 1H), 2.21 (m, 1H), 2.16 (s,
3H), 2.01 (m, 1H), 1.80 (m, 1H), 1.63 (m, 1H), 1.39 (m, 1H). 13C NMR (101
MHz, CDCl3): δ 170.4, 138.8, 128.8 (2C), 128.5 (2C), 127.2, 121.1–106.1
2
128.2, 127.7, 126.8 (dapp
,
1JC-F = 283.0 Hz), 124.7, 61.4 (q, JC-F = 27.5
Hz), 55.2, 53.5, 39.1, 38.4, 31.6, 29.2, 24.2. {1H}19F NMR (376 MHz,
CDCl3): δ –73.94 (s, 3F). HRMS: calcd for C23H24ClF3N3O (M+H+):
450.1555. Found: 450.1556
Acknowledgments
We thanks Dr. Marie-Noëlle Rager (Chimie ParisTech, PSL
University), for recording the RMN spectra of perfluorobutyl
derivatives.
2
(m, 4C), 71.3, 60.8 (t, JC-F = 20.5 Hz), 56.3, 47.2, 32.9, 30.1, 21.5, 20.0.
Keywords: azepanes • ring-expansion reaction • azetidinium •
regioselective ring-opening • fluoroalkyl group
{1H}19F NMR (376 MHz, CDCl3): δ –80.8 (m, 3F), –116.9 (brd, J = 293.5
Hz, 1F), –118.4 (brd, J = 273.9 Hz, 1F), –120.7 (dm, J = 298.1 Hz, 1F), –
121.9 (dm, J = 295.1 Hz, 1F), –125.6 (dm, J = 292.2 Hz, 1F), –126.7 (dm,
J = 295.1 Hz, 1F) HRMS: calcd for C19H21F9N1 (M+H+): 466.1423. Found:
466.1420
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0.241 mmol, 1.1 equiv), and tetrabutylammonium cyanide (79 mg, 0.295
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JAB = 14.2 Hz, 1H), 3.95 (d, JAB = 14.2 Hz, 1H), 3.83 (m, 1H), 3.29 (m, 1H),
2.95–2.73 (m, 2H), 2.44 (m, 1H), 2.21–2.00 (m, 2H), 1.88 (m, 1H), 1.57 (m,
1H), 1.38 (m, 1H). 13C NMR (101 MHz, CDCl3):25 δ 138.8, 128.8 (2C),
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J = 287.2 Hz, 1F), –120.4 (dm, J = 279.3 Hz, 1F), –121.2 (dm, J = 300.6
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This article is protected by copyright. All rights reserved.

10.1002/ejoc.201900613
European Journal of Organic Chemistry
FULL PAPER
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European Journal of Organic Chemistry
FULL PAPER
FULL PAPER
Ring-expansion
Guillaume Masson, Sarah Rioton,
Domingo Gomez Pardo,* Janine Cossy*
Page No. – Page No.
Synthesis of 2-fluoroalkyl 4-
substituted azepanes
The synthesis of a variety of highly enantio-enriched 2-fluoroalkyl 4-substituted
azepanes was achieved using a ring-expansion of pyrrolidines via an azetidinium
intermediate. This reaction is regioselective and a broad scope of nucleophiles can
be used which gives access to a great diversity of substituted azepanes.
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