Conformational regulation of substituted azepanes through mono-, di-, and trifluorination

Article abstract of DOI:10.1002/ejoc.201301811

Substituted azepanes have flexible ring structures and this conformational diversity is important for their bioactivity. We have shown that a single fluorine atom, when installed diastereoselectively on a model azepane ring, can bias its ring to one major conformation. Here the conformational effects of mono-, di-, and trifluorination, as well as hydroxylation, on substituted azepanes have been investigated by ¹H NMR spectroscopy and computational modeling in chloroform. Fluorine substitution was found to be more effective than hydroxyl group substitution in reducing conformational disorder; however, multiple fluorinations may not lead to additive conformational control and can result in complex conformational outcomes. Seven-membered nitrogen heterocycles have flexible ring structures and this conformational diversity is important for their bioactivity. Here the conformational effects of fluorination, as well as hydroxylation, on an azepane model system are investigated by ¹H NMR spectroscopy and computational modeling. Copyright

Full text of DOI:10.1002/ejoc.201301811

Job/Unit: O31811
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Date: 26-02-14 19:00:45
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FULL PAPER
DOI: 10.1002/ejoc.201301811
Conformational Regulation of Substituted Azepanes through Mono-, Di-, and
Trifluorination
Alpesh Ramanlal Patel,[a] Luke Hunter,[b] Mohan M. Bhadbhade,[c] and Fei Liu*[a]
Keywords: Conformation analysis / Medium-ring compounds / Fluorine / Density functional calculations / Nucleophilic
substitution
Substituted azepanes have flexible ring structures and this
conformational diversity is important for their bioactivity. We
have shown that a single fluorine atom, when installed dia-
stereoselectively on a model azepane ring, can bias its ring
to one major conformation. Here the conformational effects
of mono-, di-, and trifluorination, as well as hydroxylation,
spectroscopy and computational modeling in chloroform.
Fluorine substitution was found to be more effective than hy-
droxyl group substitution in reducing conformational disor-
der; however, multiple fluorinations may not lead to additive
conformational control and can result in complex conforma-
tional outcomes.
1
on substituted azepanes have been investigated by H NMR
Introduction
ducers, and sugar mimics,[18] and the introduction of fluor-
ine-based conformatonal control represents an additional
Conformational change is frequently observed in recep-
tor-ligand interactions.[1–4] Various models, such as the “in-
duced-fit” mechanism, or its “conformational selection” al-
ternative, and a combined “induced selection” process, have
been developed to describe such complexity in molecular
recognition.[1] This conformation dynamics, however, ren-
ders theoretical prediction of the productive conformation
in a ligand-receptor pair difficult, and the details of the dy-
namic conformational effects that determine the specificity
of receptor-ligand interactions remain poorly under-
stood.[2–4] As such, experimental approaches that allow
controlled conformational space sampling or manipulation
are highly desirable for the rational discovery of specific
ligand-receptor interactions.
avenue through which to access bioactive azepanes.[17b]
A
series of azepanes with 1,2-trans azidobenzyloxy substitu-
ents were examined because such compounds can be uti-
lized as building blocks for the synthesis of bioactive natu-
ral product analogues with a 1,2-trans aminohydroxy moi-
ety. In our model system (Figure 1), disubstituted azepane
Several strategies, such as steric directing, electronic at-
traction and repulsion, stereoelectronic control, and hydro-
gen-bonding, have been developed to tune the conforma-
tion of a ligand molecule.[5–12] More recently, selective
fluorination has become an important tool in conforma-
tional control, due to the strong and unusual stereoelec-
tronic effects resulting from the C–F bond.[13–16]
We have recently reported the regulatory effects of selec-
tive monofluorination on substituted azepanes.[17] Such mo-
lecules have been extensively studied as prevalent bioactive
epitopes in natural products, or as DNA binders, helix in-
[a] Department of Chemistry and Biomolecular Sciences,
Macquarie University,
Sydney NSW 2109, Australia
E-mail: fei.liu@mq.edu.au
http://www.cbms.mq.edu.au/~fliu/
[b] School of Chemistry, The University of New South Wales,
Sydney NSW 2052, Australia
[c] Analytical Centre, The University of New South Wales,
Sydney NSW 2052, Australia
Figure 1. Structures of azepanes 1–10, and the various stereoelec-
tronic effects that are expected to influence their conformations.
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201301811.
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A. R. Patel, L. Hunter, M. M. Bhadbhade, F. Liu
FULL PAPER
1, with an azido substituent at C3 and an OBn substituent diequatorial vs. pseudo-diaxial preference operates in close
at C4 in a trans relationship, was utilized for selective proximity to the C5–fluorine substitution and is potentially
monofluorination at the C6 position. Two monofluorinated moderated by the C5–fluorine/C4–OBn gauche effect (Fig-
azepanes, 2 and 3, were prepared, with the single fluorine ure 1, inset). Azepanes 5, 6, and 7, which are hydroxyl-sub-
atom in either the 6S or 6R configuration. This was the stituted counterparts of 2, 3, and 4, respectively, in which
first study of fluorine conformational regulation of a seven- an OH group replaces the fluorine, may reveal whether the
membered N-heterocycle, and complemented previous conformational effects of fluorine at C6 are unique.
studies of fluorine conformational effects in four-, five-, Azepane 8 was difluorinated at C6 to examine whether an
six-, and eight-membered N-heterocycles.[19–21]
additional fluorine at C6 would maintain or disrupt the dia-
The substituted azepane systems in 2 and 3 have complex stereospecific conformational bias of azepane 3. Azepane 9,
conformational properties in which the overall conforma- as the C6(=O) counterpart of azepane 8, was prepared so
tional characteristics depend on the interplay of the C3/C4 that the effects of an achiral moiety at C6 could be delin-
pseudo-diequatorial vs. pseudo-diaxial preference (Figure 1, eated. Finally, azepane 10 was trifluorinated with the 6S,
insert), the azido gauche effect,[22] and the fluorine gauche 6R, and 5R configuration to understand the potential limits
effect.[23] For this model system, parameters for potentially of conformational bias imposed by multiple fluorination.
synergistic conformational regulation were investigated and Together, these substituted azepanes form part of an intri-
these studies revealed that monofluorination led to a re- cate conformational landscape controlled by single or mul-
duction in the ring conformational disorder of the parent tiple fluorination.
azepane 1. However, only azepane 3, with the 6R configura-
tion (trans to the C4–OBn group), was able to furnish one
Results and Discussion
major conformation in which the pseudo-diequatorial pref-
erence, the azido gauche effect, and the fluorine gauche ef-
fect were all satisfied concurrently. These results established
the diastereospecificity requirement for synergistic confor-
mational control in these azepanes.
Synthesis of Azepanes 1–10
Azepanes 1 were synthesized by following a reported
procedure.[17] Azepanes 2–7 were synthesized from the key
Several new lines of enquiry are addressed here to further intermediate
tert-butyl
(3R,4R)-3-azido-4-benzyloxy-
understand the complex conformational properties of this 2,3,4,7-tetrahydro-1H-azepine-1-carboxylate (14) by hydro-
azepane system in the solvent chloroform. Because seven- boration–oxidation (azepanes 5–7) followed by deoxyfluor-
membered nitrogen heterocycles are inherently highly flexi- ination (azepanes 2–4) by following our methods.[17a]
ble and difficult to control conformationally, this study fo- Azepane 9 was prepared from azepane 11 by oxidation
cused on the conformational outcomes of several fluorine using pyridinium chlorochromate to provide azepane 12,
substitution patterns on the same substituted azepane Boc deprotection of which furnished azepane 9 in quantita-
model system to establish the first full profile of the fluorine tive yield. Fluorination of 12 with Deoxofluor furnished
stereoelectroinc effects on such a ring system. Azepane 4, azepane 13 in 64% yield and the Boc-deprotected azepane
in which the fluorine atom is positioned at C5 rather than was characterized as 8 (Scheme 1).
C6 while maintaining the configuration trans to the C4–
Trifluoroazepane 10 was synthesized from 14 in five
OBn substituent, is controlled by a different combination steps, starting from dihydroxylation of 14 to give a mixture
of conformational factors. In this case, the C3/C4 pseudo- of syn-dihydroxy azepanes 15 and 16 for separation by
Scheme 1. Synthesis of azepanes 2–10. Reagents and conditions: (a) i. BH3·DMS, THF, 25 °C, 14 h; ii. EtOH, 6 n NaOH, H2O2, 50 °C,
1 h (all four diastereomers); 11 (32%);[17a] (b) PCC (1.1 equiv.), MS (4 Å), anhydrous CH2Cl2, 25 °C, 1.5 h; (c) TFA, neat, 5 min; (d) De-
oxofluor (2.2 equiv.), anhydrous CH2Cl2, 0 °C, 10 h; (e) NMO, OsO4, (CH3)2CO/H2O, room temp., 5 h, 15/16 (62:38); (f) imidazole,
TBSCl, anhydrous DMF, 25 °C, 10 h; (g) Deoxofluor, anhydrous CH2Cl2, 0 °C, 8 h; (h) TBAF, anhydrous THF, 45 min.
2
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Conformational Regulation of Fluorinated Azepanes
chromatography. Regioselective TBS monoprotection led to benzyl protection group and reduce the azido group, fol-
azepane 17 in 70% yield, the fluorination of which afforded lowed by amidation to install a p-benzyloxy benzoyl group
its 5R-fluoro analogue 18 with inversion of stereochemistry. to promote crystalization.[24]
Azepane 18 then underwent TBS deprotection to furnish
fluorohydroxy azepane 19, followed by oxidation to fluoro-
keto azepane 20 in excellent yield. Treatment of azepane
20 with Deoxofluor gave the desired trifluoro azepane inter-
Conformational Analysis and Comparison of Azepanes 2–10
mediate 21 and then azepane 10 after Boc deprotection. All
The conformational analysis of azepanes 2–9 was based
1
azepanes were prepared and analyzed as their trifluoro- on experimental J values obtained from H NMR spectra
acetic acid (TFA) salts in CDCl3. The stereochemistry of (Table 1).[25] This J-based analysis was coupled with mo-
azepanes 8–10 was unambiguously assigned on the basis of lecular modeling and DFT geometry optimizations. Con-
HSQC, HMBC, COSY and NOESY 2D NMR experi- formers within 3–5 kcal/mol for each azepane were clus-
ments, which were analogous to those used for the structure tered to identify unique ring conformations, as im-
elucidation of azepanes 1–7 as described previously.[24] The plemented in the program MOE.[26] All of the conformers
stereochemical structure assignment was further supported were subjected to DFT geometry optimization (Turbo-
by an X-ray crystal structure of 22 (see Figure 4). Azepane mole),[27] followed by general J calculations as described
22 was prepared from 21 by hydrogenation to remove the previously.[25] The experimental J values were compared
3
3
Table 1. Experimental JH,H and JH,F values for azepanes 1–9.
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Figure 2. Conformations of azepanes 2–7. Only the major conformer of azepane 3 simultaneously satisfies the C3/C4 pseudo-diequatorial
preference, the azido gauche effect and the fluorine gauche effect.
with the calculated values to identify matching conform- configuration trans to the C4–OBn group to investigate its
ers.[24]
positional dependence. It was found that azepane 4 adopted
two low-energy geometries (4a and 4b, Figure 2) in a ratio
of approximately 3:2. The two geometries of 4 are quite
similar; in each case the benzyloxy and azido groups are
pseudo-equatorial, as expected, whereas perhaps surpris-
ingly the azido group is positioned anti to the ring nitrogen
in both cases. The major difference between the low-energy
geometries of 4 is that the fluorine is anti to the benzyloxy
group in 4a but gauche in 4b. This highlights a new influ-
ence on the azepane conformation; C–F bonds are known
to have a preference for aligning gauche to vicinal C–O
bonds (Figure 1, inset), due to favorable σCHǞσ*CF hyper-
conjugation.[28] However, this preference is very slight and
is thus easily overridden in 4a (Figure 3). This also explains
why azepane 4 is more disordered than azepane 3; a strong
F···N+ interaction is lost whereas only a weak F···OBn in-
teraction is gained. The comparison between the conforma-
tional labilities of the major conformers of azepanes 3 and
4 seems to suggest that in azepane 3, there is synergistic
conformational reinforcement between the fluorine gauche
Comparison of Azepanes 2 and 3
As described in our preliminary communication,[17]
azepane 1 is conformationally disordered, with many con-
tributing conformers. Azepanes 2 and 3 are more confor-
mationally ordered but have dramatically different confor-
mations (Figure 2). Azepane 2 still exhibits considerable
disorder in solution, with three low-energy geometries (2a–
c) contributing in a 1:1:1 ratio. In contrast, azepane 3 has
one dominant conformer 3a and one minor conformer 3b
in a 4:1 ratio. Further highlighting the greater extent of con-
formational biasing in azepane 3, the two low-energy geo-
metries 3a and 3b are quite similar, with the major differ-
ence being only a slight change in the C4–C5 dihedral an-
gle, whereas the three low-energy geometries of 2 are very
different from one another.
Several factors contribute to the observed conformations
of azepanes 2 and 3; first, a pseudo-diequatorial preference
of the benzyloxy and azido substituents (Figure 1, inset);
second, an electrostatic charge–dipole interaction between
the C–F bond and the ring nitrogen; and third, the azido
gauche effect. These three conformational effects can act
either in synergy or in competition with one another de-
pending on the stereochemistry, and this leads to different
conformational outcomes in azepanes 2 and 3. For exam-
ple, in azepane 2 the fluorine and the azido groups cannot
be simultaneously gauche to the ring nitrogen (hence disor-
der), whereas this is possible for azepane 3 (hence order).
Comparison of Azepanes 3 and 4
Having observed the diastereospecificity requirement for
the fluorine atom to exert a greater conformational biasing
effect in azepane 3, azepane 4 was prepared with the fluor-
ine atom at the C5 position while maintaining the relative Figure 3. Main conformers of azepanes 8 and 9.
4
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Conformational Regulation of Fluorinated Azepanes
effect and the azido gauche effect, which together dominate and 3, respectively. However, azepanes 5 and 6 are more
the C3/C4 pseudo-diequatorial preference. When this al- conformationally disordered than azepanes 2 and 3.
liance is lost in azepane 4 and replaced by a relatively weak
C5–fluorine/C4–OBn gauche effect, the C3/C4 pseudo-di- Comparison of Azepanes 4 and 7
equatorial preference becomes dominant.
As described above, fluorinated azepane 4 exhibits some
conformational biasing, with two closely-related geometries
(4a and 4b) dominating in a 3:2 ratio (Figure 2). However
the case is quite different for hydroxy derivative 7. The
3JH,H values of 7 are mostly intermediate in magnitude
(Table 1) and, consistent with this, several low-energy geo-
metries of 7 were identified by molecular modeling. A rea-
Comparison of Azepanes 2 and 5
Thus far, some striking differences in conformational be-
havior have been observed between the fluorinated
azepanes 2–4 (Figure 2). To investigate whether the various
conformational biases are uniquely products of fluorine
substitution, or could be reproduced with other electro-
negative substituents, azepanes 5–7, in which the fluorine
atoms were replaced by hydroxy groups, were prepared for
investigation.
3
sonably close match to the experimental JH,H values was
found by averaging the geometries 7a and 7b. Geometry 7a
has gauche N+···N3 and OH···OBn alignments, but does not
have pseudo-diequatorial benzyloxy/azido groups. The sec-
ond low-energy geometry, 7b, differs from 7a in its pseudo-
diequatorial benzyloxy/azido groups and its anti N+···N3
alignment. Interestingly, the geometry of 7a closely re-
sembles that of 4a, suggesting some level of similarity in
the effects of fluorine and hydroxy groups in this position.
However, a caveat is that no weighted average of 7a and 7b
actually gave a very good match with the experimental
3JH,H values of 7,[24] suggesting that at least one other ge-
ometry of 7 is involved. Hence, the analysis of 4 and 7 indi-
cates that conformational biasing is enhanced with fluorine
at C5 compared with hydroxy group substitution at the
same position.
Conformer 7b was analogous to the minor conformer 4b
with the C3/C4 pseudo-diequatorial preference. The azido
gauche effect was again not satisfied. The other conformer,
7a, was not analogous to either 4a or 4b. In 7a, the C3/C4
pseudo-diequatorial preference was not met, and the C5–
OH/C4–OBn was gauche while satisfying the azido gauche
effect. The OH group presented a conformational profile
that was clearly different to that of fluorine, possibly due to
lower levels of electronic repulsion with C5–OH/C4–OBn
gauche vs. C5–F/C4–OBn gauche.
As discussed above, azepane 2 exhibits some conforma-
tional disorder, with three low-energy geometries identified
in a 1:1:1 ratio (2a–c; Figure 2). A similar level of disorder
3
emerged for azepane 5; most of the JH,H values for which
(Table 1) were intermediate in magnitude, suggesting signifi-
cant levels of conformational averaging. Consistent with
this, multiple low-energy geometries of 5 were identified by
molecular modeling, and no single geometry seemed to
dominate in solution. Taken together, the results obtained
with azepanes 2 and 5 suggest that placing an electronega-
tive substituent in the S configuration at C6 is not particu-
larly effective at reducing conformational disorder because
the various conformational influences (Figure 1, inset) are
in competition with one another.
Comparison of Azepanes 3 and 6
Azepane 3 has one dominant conformation in solution
(Figure 2). Therefore, it was interesting to examine its OH-
counterpart, azepane 6, to determine whether the confor-
mational biasing effect of the fluorine atom could be repro-
duced with a hydroxyl group. It emerged that azepane 6
does indeed show evidence of significant conformational
biasing (Figure 2); in this case, two major geometries (6a
and 6b) were observed in a 3:2 ratio. It is noteworthy that
the major geometry of azepane 6 (i.e., 6a) is nearly identical
to the major geometry of azepane 3 (i.e., 3a), with pseudo-
Comparison of Azepanes 3 and 8
Among all the azepanes examined thus far (2–7; Fig-
diequatorial benzyloxy/azido groups, gauche N+···N3 align- ure 2), the monofluorinated azepane 3 clearly experiences
ments, and gauche N+···F/OH alignments. This suggests a the strongest conformational bias. This brings forward the
strong similarity between the fluorine and hydroxyl groups next question of whether incorporating a second fluorine at
of 3 and 6. However, the hydroxyl group is somewhat less C6 would further reduce the conformational disorder. To
effective than fluorine at biasing the ring conformation, for this end, azepane 8 (Figure 3), which was gem-difluorinated
two reasons. First, the conformer ratio of azepane 3 is much at C6, was prepared. Interestingly, incorporation of the sec-
more strongly biased than that of azepane 6 (4:1 vs. 3:2 ond fluorine atom actually has a disruptive effect rather
ratio). Second, the two major geometries of azepane 3 are than a reinforcing effect, and two equally dominant confor-
very similar to one another, whereas the two major geome- mations, 8a and 8b, were found in a 1:1 ratio. These two
tries of azepane 6 are quite different from one another. In geometries differ from each other by the nitrogen pucker-
6b, the C3/C4 pseudo-diequatorial preference is maintained ing, “down” in 8a and “up” in 8b. Structure 8a is highly
whereas the azido gauche preference became anti. The syn- reminiscent of the structure of 3a (Figure 2), but 8b is not
ergy between the fluorine gauche and azido gauche effects seen in any of the main contributors of azepane 3. In fact,
seems to be exclusive to fluorine (azepane 3) and is not the conformational disorder in azepane 8 can be readily
reproduced in the case of an OH substitution (azepane 6).
explained by the F···N+ gauche effect; this preference is sat-
Overall, the diastereospecific preference is reproduced in isfied in both observed ring puckers of 8, due to the pres-
azepanes 5 and 6, as the 6-OH counterparts of azepanes 2 ence of two fluorine atoms.
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A. R. Patel, L. Hunter, M. M. Bhadbhade, F. Liu
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Comparison of Azepanes 8 and 9
that successive introduction of fluorine atoms at different
positions of the azepane ring leads to nonadditive confor-
mational outcomes.[29]
The gem-difluorinated azepane 8 (Figure 3) offered the
opportunity to explore another conformational effect of
fluorination, which is that the difluoromethylene moiety is
often regarded as an isoster of the carbonyl group.[13b] The
CF2 carbon atom can be thought of as having partial sp2
character, and difluoromethylene-containing compounds
typically have C–CF2–C angles of around 117°. Thus, the
gem-difluorinated azepane 8 was compared to the “iso-
steric” carbonyl-containing azepane 9. It was somewhat dif-
ficult to fully elucidate the NMR solution structure of 9
3
because there are fewer JH,H values available (Table 1),
nevertheless, two geometries (9a and 9b) were identified
that, when combined in a 4:1 ratio, provided a good match
with this limited set of experimental 3JH,H values. Geometry
9a features a gauche N3···N+ alignment and pseudo-diaxial
benzyloxy/azido groups, whereas geometry 9b features an
anti N3···N+ alignment and pseudo-diequatorial benzyloxy/
azido groups; thus, it appears that these two preferences are
in competition with one another in azepane 9. The ring
geometry 9a is not observed in any of the previous
azepanes, but there is a striking similarity between 9b and
8b. The latter observation reinforces the concept of the gem-
difluoro moiety as an effective isoster of the carbonyl
group.
Figure 4. X-ray structure of 22.
Conclusions
A series of mono-, di-, and tri-fluorinated azepanes were
examined with respect to their conformational properties.
Hydroxy-substituted counterparts were also investigated to
determine whether the conformational effects were unique
to fluorine. As illustrated by the comparison between
azepanes 3 and 4, the synergy between the fluorine gauche
effect and the other conformational factors is position-de-
pendent, in addition to the diastereospecificity noted ear-
lier.[17b] The OH substitution, while able to follow the same
diastereospecificity requirement for reducing conforma-
tional disorder, has different and also weaker bias effects
that lead to different mixtures of conformational popula-
tions. Finally, multiple fluorination may not offer ad-
ditional conformational bias compared to that of mono-
fluorination, because the introduction of additional fluor-
ine atoms also introduces more opportunities for conflicting
conformational effects. Although able to reduce conforma-
tional disorder, neither the fluorine nor OH group reduced
ring mobility, and variant temperature studies of azepanes
1–10 suggested shallow barriers for conformational mo-
bility on the NMR time-scale.[24,30]
Azepane 10
Azepane 10 incorporates fluorine atoms at all three sites
previously examined in isolation (Figure 1). This molecule
was successfully synthesized as described in Scheme 1, how-
ever, the NMR solution structure of 10 was too complex
for reliable J value extraction due to overlapping 1H/19F
NMR signals (see the Supporting Information). Therefore,
as an alternative measure, the solid-state structure of a crys-
talline derivative, 22, was solved (Figure 4). Azepane 22 dif-
fers from 10 in several respects: the ring nitrogen is Boc-
protected, the benzyl group is absent, and the azido group
is replaced with an amide. However, the trifluorination
pattern remains intact. The crystal structure of 22 (Fig-
ure 4) features a ring geometry that clearly corresponds
with our prior expectations. There is a gauche alignment
between the two nitrogen atoms (dihedral angle 73°), and
there is also the maximum possible number of F···N, F···F
and F···O gauche alignments (one, two and one, respec-
tively, with dihedral angles of 66°, 70°, 44°, and 51°). The
particularly small value of 44° for one of the difluoro
gauche alignments is partially explained by the widened C–
CF2–C angle of 117°, which also fully accords with our ex-
pectation. The orientations of the vicinal hydroxy and
amide groups are noteworthy; the unusual dihedral angle of
101° seems indicative of some strain, and this accords with
our previous observations with azepane 3 (Figure 2) in
which competition exists between the azido gauche effect
and the pseudo-diequatorial preference of the C3/C4 sub-
stituents. Overall, the crystal structure of 22 is highly remi-
niscent of structures 3a (Figure 2) and 8a (Figure 3), but it
does not resemble either of the low-energy geometries of
Experimental Section
General: All reactions were conducted under an N2 atmosphere.
Unless otherwise specified, all reagents were purchased from
Sigma–Aldrich and used without further purification. Deoxofluor
was obtained from Matrix Scientific and used without further puri-
fication. CH2Cl2 was obtained from a solvent purification system
(Innovative Technology SPS400) and stored over 4 Å MS beads.
Ethyl acetate and petroleum ether (60–80 °C) were distilled before
use. THF was distilled from Na/benzophenone and stored over 4 Å
MS beads. Anhydrous DMF was obtained from Sigma–Aldrich
and used without further purification.
1H NMR spectra were recorded at 25 °C with either a Bruker
DRX600 K or a DPX400 NMR spectrometer and are reported in
parts per million (ppm) using the specified solvent as the internal
azepane 4 (Figure 2). This result supports the conclusion standard (CDCl3 at δ = 7.26 ppm). 13C NMR spectra are reported
6
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Conformational Regulation of Fluorinated Azepanes
in ppm using the specified solvent as the internal standard (CDCl3
at δ = 77.16 ppm). Computational investigations were performed
using programs MOE (Molecular Operating Environment 2011.10;
Chemical Computing Group), and Turbomole (version 6.3).
= 23.83 Hz), 28.3 ppm. HRMS (ESI): m/z calcd. for C18H25F2N4O3
[M + H]+ 383.1895; found 383.1900.
(5R,6R)-6-Azido-5-benzyloxy-3,3-difluoroazepane (8): Yield 96%
from 13; colorless oil; [α]2D0 = –53.7 (c = 1.2, CH2Cl2). IR (film):
ν
max = 2392, 2331, 2110, 1700, 1681, 1678, 1550, 1544, 1511, 1486,
˜
Synthesis of Azepanes 1–22: Synthesis of disubstituted tetra-
hydroazepine 14 was achieved as described previously. Azepanes 1–
7 and 11 were synthesized from 14 by using our recently reported
methods.[17a]
1190 cm–1. H NMR (600 MHz, CDCl3): δ = 7.39–7.30 (m, 5 H),
4.69 (d, J = 11.17 Hz, 1 H), 4.56 (d, J = 11.17 Hz, 1 H), 3.78–3.73
(m, 2 H), 3.29–3.20 (m, 3 H), 3.00 (dd, J = 15.02, 4.60 Hz, 1 H),
2.58–2.41 (m, 2 H) ppm. 13C NMR (150 MHz, CDCl3): δ = 137.0,
1
1
3
128.4, 128.0, 127.9, 122.3 (d, JC,F = 244.5 Hz), 75.5 (d, JC,F
=
tert-Butyl (3R,4R)-3-Azido-4-benzyloxy-6-oxoazepane-1-carboxyl-
ate (12): Pyridinium chlorochromate (119.6 mg, 0.555 mmol) was
added to a well-stirred suspension of 11 (67.0 mg, 0.185 mmol) and
4 Å MS (95.5 mg) in anhydrous CH2Cl2 (8.20 mL) under an N2
atmosphere at 25 °C. The mixture was stirred at the same tempera-
ture until the reaction reached completion (50 min; TLC). The re-
action mixture was evaporated to dryness and the crude mixture
was subjected to flash chromatography (petroleum ether/EtOAc,
2
2
7.07 Hz), 71.8, 65.0, 50.7, 56.0 (d, JC,F = 32.9 Hz), 36.7 (d, JC,F
= 25.5 Hz) ppm. HRMS (ESI): m/z calcd. for C13H17F2N4O [M +
H]+ 283.1370; found 283.1378.
tert-Butyl
(3R,4S,5S,6S)-3-Azido-4-benzyloxy-5,6-dihydroxyaz-
epane-1-carboxylate (15) and tert-Butyl (3R,4S,5R,6R)-3-Azido-4-
benzyloxy-5,6-dihydroxyazepane-1-carboxylate (16): To a solution
of azepane 14 (344.4 mg, 1 mmol) in acetone/water (8:1, 2.45 mL)
was added N-methyl morpholine-N-oxide (351.6 mg, 3 mmol) and
OsO4 (4% w/w in H2O, 318 μL, 0.05 mmol). The solution was
stirred at room temperature for 5 h before addition of EtOAc
(15 mL) and a saturated solution of Na2S2O3 (5 mL). The organic
layer was separated and the aqueous layer was extracted with
EtOAc (2ϫ 5 mL). The combined organic extracts were evaporated
to obtain a light-yellow oil, which was subjected to flash column
chromatography (EtOAc/petroleum ether, 2:3) to give 15 (211.2 mg,
56%, Rf = 0.22) and 16 (129.4 mg, 34%, Rf = 0.16) as colorless
oils.
4:1) to give 12 (62 mg, 93%; Rf = 0.40) as a colorless oil. [α]2D0
–47.4 (c = 1.0, CH Cl ). IR (film): ν = 2369, 2347, 2133, 1725,
=
˜
max
2
2
1695, 1672, 1559, 1544, 1413, 1147 cm–1. 1H NMR (600 MHz,
CDCl3): δ = 7.38–7.28 (m, 5 H), 4.68 (d, J = 10.87 Hz, 1 H), 4.48
(d, J = 10.87 Hz, 1 H), 4.28 (br. d, J = 18.11 Hz, 1 H), 3.84 (br. s,
1 H), 3.81–3.70 (m, 2 H), 3.64 (dd, J = 7.10, 6.76 Hz, 1 H), 3.58–
3.50 (m, 1 H), 3.02 (d, J = 13.52 Hz, 1 H), 2.85–2.78 (m, 1 H), 1.53
(s, 9 H) ppm. 13C NMR (150 MHz, CDCl3): δ = 208.3, 155.1,
136.8, 128.6, 128.2, 128.1, 81.5, 75.3, 71.4, 63.4, 57.9, 47.3, 42.3,
28.2 ppm. HRMS (ESI): m/z calcd. for C18H25N4O4 [M + H]+
361.1876; found 361.1885.
Compound 15: [α]2D0 = +48.6 (c = 1.8, CHCl ). IR (film): ν
=
max
˜
3
3600–3130 (br), 2997, 2933, 2365, 2114, 1680, 1411, 1157, 1088,
(3R,4R)-3-Azido-4-benzyloxy-6-oxoazepane (9): Compound 12
(7.2 mg, 19.9 μmol) was dissolved in TFA (500 μL) at 25 °C and
the solution was stirred for 5 min before TFA was evaporated under
an N2 flow. The reaction flask was kept under high vacuum
(0.005 Torr, 25 °C) for 3 h to remove traces of TFA and the color-
less, oily residue obtained was characterized as 9 (5.0 mg, 97%).
1
1045 cm–1. H NMR (600 MHz, CDCl3): δ = 7.40–7.31 (m, 5 H),
4.95 (d, J = 10.80 Hz, 1 H), 4.62 (d, J = 10.80 Hz, 1 H), 4.33–4.26
(m, 1 H), 4.10–4.00 (m, 1 H), 3.82–3.71 (m, 1 H), 3.64–3.55 (m, 1
H), 3.21 (dd, J = 14.68, 9.84 Hz, 1 H), 3.15 (dd, J = 14.70, 3.82 Hz,
1 H), 1.47 (s, 9 H) ppm. 13C NMR (150 MHz, CDCl3): δ = 154.9,
137.3, 128.9, 128.5, 128.4, 81, 80.9, 75.7, 72.9, 69.6, 64.5, 49.6, 47.6,
28.5 ppm. HRMS (ESI): m/z calcd. for C18H27N4O5 [M + H]+
379.1981; found 379.1982.
[α]2D0 = –32.1 (c = 0.8, CH Cl ). IR (film): νmax = 3581, 2349, 1742,
˜
2
2
1715, 1690, 1673, 1646, 1550, 1161, 1133 cm–1. 1H NMR
(600 MHz, CDCl3): δ = 7.39–7.32 (m, 5 H), 4.72 (d, J = 11.43 Hz,
1 H), 4.48 (d, J = 11.43 Hz, 1 H), 4.10–4.06 (m, 1 H), 3.91 (d, J =
18.25 Hz, 1 H), 3.90 (t, J = 7.39, 5.38 Hz, 1 H), 3.54 (dd, J = 14.37,
4.05 Hz, 1 H), 3.53 (d, J = 18.22 Hz, 1 H), 3.51 (dd, J = 14.78,
1.2 Hz, 1 H), 3.43 (dd, J = 14.58, 2.02 Hz, 1 H), 3.07 (dd, J =
14.78, 7.39 Hz, 1 H) ppm. 13C NMR (150 MHz, CDCl3): δ = 201.3,
136.2, 128.9, 128.7, 128.2, 72.5, 71.8, 60.0, 56.4, 47.5, 41.7 ppm.
HRMS (ESI): m/z calcd. for C13H17N4O2 [M + H]+ 261.1273;
found 261.1273.
Compojund 16: [α]2D0 = –24.8 (c = 1.6, CHCl ); IR (film): ν
=
max
˜
3
3600–3130 (br), 2997, 2933, 2365, 2114, 1680, 1411, 1157, 1088,
1
1045 cm–1. H NMR (600 MHz, CDCl3): δ = 7.40–7.31 (m, 5 H),
4.66 (d, J = 4.13 Hz, 2 H), 4.18–4.15 (m, 1 H), 4.00–3.96 (m, 1 H),
3.93–3.88 (m, 1 H), 3.74–3.67 (m, 1 H), 3.61 (dd, J = 15.15,
5.25 Hz, 1 H), 3.54 (d, J = 7.68 Hz, 1 H), 3.45 (dd, J = 15.15,
5.46 Hz, 1 H), 3.29 (dd, J = 14.43, 7.26 Hz, 1 H), 1.47 (s, 9 H) ppm.
13C NMR (150 MHz, CDCl3): δ = 156.0, 137.2, 128.8, 128.4, 128.3,
83.1, 81.1, 73.4, 72.4, 70.4, 61.4, 51.1, 49.7, 28.4 ppm. HRMS
(ESI): m/z calcd. for C18H27N4O5 [M + H]+ 379.1981; found
379.1984.
tert-Butyl (5R,6R)-6-Azido-5-benzyloxy-3,3-difluoroazepane-1-carb-
oxylate (13): Bis(2-methoxyethyl)aminosulfur trifluoride (Deox-
ofluor; 83.7 mg, 0.379 mmol) was added to a solution of 12
(62.0 mg, 0.172 mmol) in anhydrous CH2Cl2 (5.1 mL) under an N2
atmosphere at 0 °C. The mixture was stirred at the same tempera-
ture for 10 h, then evaporated to dryness and the crude mixture
was subjected to flash chromatography (petroleum ether/EtOAc,
9:1) to give 12 (42.1 mg, 64%, Rf = 0.43) as a colorless oil. It is
noteworthy that 13 was obtained exclusively and unreacted 12 was
tert-Butyl (3R,4S,5S,6R)-3-Azido-4-benzyloxy-6-(tert-butyldimeth-
ylsilyl)oxy-5-hydroxyazepane-1-carboxylate (17): A solution of tert-
butyldimethylsilyl chloride (96.5 mg, 0.641 mmol) in DMF
(3.25 mL) was added dropwise by using a syringe to a well-stirred
solution of 16 (220 mg, 0.583 mmol) and imidazole (43.6 mg,
0.641 mmol) in DMF (3.25 mL) at 25 °C under an N2 atmosphere.
The reaction mixture was stirred at the same temperature for 10 h,
recovered. [α]2D0 = –44.1 (c = 1.5, CH Cl ). IR (film): ν
= 2363,
˜
max
2
2
2347, 2109, 1716, 1533, 1520, 1478, 1450, 1419, 1109 cm–1. 1H then the reaction was quenched by addition of water (5 mL). The
NMR (600 MHz, CDCl3): δ = 7.39–7.29 (m, 5 H), 4.68 (d, J =
11.18 Hz, 1 H), 4.57 (d, J = 11.18 Hz, 1 H), 4.05–3.54 (m, 5 H),
3.24–3.14 (m, 1 H), 2.53–2.42 (m, 1 H), 2.28–2.16 (m, 1 H), 1.46
mixture was extracted with EtOAc (3ϫ 10 mL) and the combined
organic extracts were washed with water (2ϫ 5 mL) and brine
(5 mL) to remove DMF residues and dried (MgSO4) before evapo-
(s, 9 H) ppm. 13C NMR (150 MHz, CDCl3): δ = 154.5, 137.1, ration under reduced pressure to give the crude mixture, which was
1
3
128.7, 128.3, 128.2, 123.0 (d, JC,F = 249 Hz), 81.4, 76.2 (d, JC,F
subjected to flash chromatography (petroleum ether/EtOAc, 9:1) to
give 17 (201.0 mg, 70%, Rf = 0.32) as a colorless oil. It is note-
= 7.40 Hz), 72.0, 63.8, 55.1 (d, 2JC,F = 36.0 Hz), 48.6, 36.9 (d, 2JC,F
Eur. J. Org. Chem. 000, 0–0
© 000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
7

Job/Unit: O31811
/KAP1
Date: 26-02-14 19:00:45
Pages: 11
A. R. Patel, L. Hunter, M. M. Bhadbhade, F. Liu
FULL PAPER
worthy that 17 was obtained exclusively and unreacted 16 was reco-
10.45 Hz, 1 H), 1.47 (s, 9 H) ppm. 13C NMR (100 MHz, CDCl3):
2
vered. [α]2D0 = –42.8 (c = 0.8, CH Cl ). IR (film): νmax = 3600–3130
δ = 201.9 (d, JC,F = 17.08 Hz), 154.2, 136.9, 128.9, 128.7, 128.5,
˜
2
2
1
2
(br), 2997, 2933, 2365, 2114, 1680, 1411, 1157, 1088, 1045,
95.6 (d, JC,F = 190.8 Hz), 82.5, 81.6 (d, JC,F = 19.15 Hz), 76.1,
990 cm–1. 1H NMR (600 MHz, CDCl3): δ = 7.40–7.27 (m, 5 H), 62.7 (d, JC,F = 6.84 Hz), 55.4, 47.9, 28.3 ppm. HRMS (ESI): m/z
4.67 (d, J = 11.71 Hz, 1 H), 4.63 (d, J = 11.71 Hz, 1 H), 4.07 (br. s, calcd. for C18H23FN4NaO4 [M + Na]+ 401.1601; found 401.1602.
1 H), 4.00–3.84 (m, 3 H), 3.77–3.67 (m, 1 H), 3.42–3.36 (m, 2 H),
3
tert-Butyl (4R,5S,6R)-6-Azido-5-benzyloxy-3,3,4-trifluoroazepane-
2.83 (dd, J = 10.58, 3.43 Hz, 1 H), 2.42 (br. s, 1 H), 1.47 (s, 9 H),
1-carboxylate (21): Yield 54% from 20; colorless oil; Rf = 0.54 (pe-
0.88 (s, 9 H), 0.08 (d, J = 13.93 Hz, 6 H) ppm. 13C NMR
troleum ether/EtOAc, 4:1); [α]2D0 = –26.9 (c = 1.1, CH2Cl2). IR
(150 MHz, CDCl3): δ = 155.2, 137.5, 128.6, 128.3, 128.1, 80.6, 80.5,
(film): νmax = 2366, 2335, 2109, 1716, 1531, 1529, 1478, 1457, 1415,
˜
75.4, 73.0, 70.1, 63.4, 49.6, 49.3, 28.3, 25.8, –4.52, –4.85 ppm.
HRMS (ESI): m/z calcd. for C24H41N4O5Si [M + H]+ 493.2846;
found 493.2847.
1
1111 cm–1. H NMR (600 MHz, CDCl3): δ = 7.43–7.36 (m, 5 H),
4.87–4.60 (m, 3 H), 4.47 (dd, J = 29.2, 15.93 Hz, 1 H), 3.86 (d, J
= 15.18 Hz, 1 H), 3.81–3.63 (m, 2 H), 3.50–3.33 (m, 1 H), 2.89 (dd,
tert-Butyl (3R,4S,5R,6R)-3-Azido-4-benzyloxy-6-(tert-butyldimeth-
ylsilyl)oxy-5-fluoroazepane-1-carboxylate (18): A solution of De-
oxofluor (89.8 mg, 0.406 mmol) was added dropwise by using a sy-
ringe to a well-stirred solution of 17 (200.0 mg, 0.406 mmol) in
anhydrous CH2Cl2 (5.5 mL) under an N2 atmosphere at 0 °C. The
J = 14.66, 10.85 Hz, 1 H), 1.49 (s, 9 H) ppm. 13C NMR (100 MHz,
1
CDCl3): δ = 154.3, 136.8, 128.7, 128.7, 128.5, 119.5 (dd, JC,F
=
2
1
2
244, JC,F = 21.88 Hz), 91.4 (dt, JC,F = 187.46, JC,F = 27.87 Hz),
2
82.3, 81.2 (br. s), 75.3, 64.1, 48.8 (t, JC,F = 32.9 Hz), 46.5,
28.3 ppm. HRMS (ESI): m/z calcd. for C18H23F3N4O3 [M + H]+
mixture was stirred at the same temperature for 8 h, then evapo- 401.1722; found 401.1716.
rated under reduced pressure to give the crude mixture, which was
(4R,5S,6R)-6-Azido-5-benzyloxy-3,3,4-trifluoroazepane (10): Yield
97% from 21; colorless oil; [α]2D0 = –29.4 (c = 1.3, CH2Cl2). IR
subjected to flash chromatography (petroleum ether/EtOAc, 9:1) to
give 18 (138.5 mg, 69%, Rf = = 0.52) as a colorless oil. [α]2D0 = –52.1
(film): νmax = 2396, 2330, 2116, 1709, 1688, 1678, 1557, 1541, 1525,
˜
(c = 0.6, CH Cl ). IR (film): ν = 2997, 2933, 2365, 2114, 1680,
˜
max
2
2
1
1480, 1194 cm–1. H NMR (600 MHz, CDCl3): δ = 7.44–7.34 (m,
1521, 1473, 1456, 1411, 1157, 1088, 1045, 990 cm–1. 1H NMR
5 H), 4.93 [dd, J = 44.19 (1JH,F), 14.7 Hz, 1 H], 4.80 (d, J =
11.44 Hz, 1 H), 4.73 (d, J = 11.44 Hz, 1 H), 4.08 (dd, J = 8.71,
8.68 Hz, 1 H), 3.89–3.82 (m, 1 H), 3.67–3.57 (m, 2 H), 3.48 (d, J
= 14.0 Hz, 1 H), 3.10 (dd, J = 14.0, 9.70 Hz, 1 H) ppm. 13C NMR
(600 MHz, CDCl3): δ = 7.41–7.32 (m, 5 H), 4.76 (d, J = 11.49 Hz,
1
1 H), 4.65 (d, J = 11.49 Hz, 1 H), 4.60 (br. d, JH,F = 45.02 Hz, 1
H), 4.09–4.02 (m, 1 H), 3.83–3.76 (m, 1 H), 3.68–3.50 (m, 3 H),
3.40 (br. d, J = 14.17 Hz, 1 H), 3.30–3.20 (m, 1 H), 1.48 (s, 9 H),
0.87 (s, 1 H), 0.12 (s, 6 H) ppm. 13C NMR (150 MHz, CDCl3): δ
= 155.1, 137.4, 128.6, 128.4, 128.2, 95.0 (d, 1JC,F = 180.74 Hz), 82.8
1
(150 MHz, CDCl3): δ = 135.7, 129.0, 128.5, 128.5, 118.4 (dd, JC,F
2
1
2
= 247.66, JC,F = 28.07 Hz), 90.2 (ddd, JC,F = 186.03, JC,F
=
2
2
3
34.98, JC,F = 27.82 Hz), 79.6 (dd, JC,F = 24.93, JC,F = 7.20 Hz),
2
2
(d, JC,F = 25.05 Hz), 80.6, 74.0, 70.8 (d, JC,F = 25.02 Hz), 63.9
2
2
73.9, 60.6, 45.8 (dd, JC,F = 39.76, JC,F = 25.66 Hz), 45.6 ppm.
HRMS (ESI): m/z calcd. for C13H16F3N4O [M + H]+ 301.1276;
found 301.1278.
3
3
(d, JC,F = 3.79 Hz), 47.2 (d, JC,F = 4.06 Hz), 46.8, 28.5, 25.9,
–4.89, –5.03 ppm. HRMS (ESI): m/z calcd. for C24H39FN4NaOSi
[M + Na]+ 517.2622; found 517.2623.
tert-Butyl (4R,5S,6R)-6-[4-(Benzyloxy)benzamido]-3,3,4-trifluoro-5-
hydroxyazepane-1-carboxylate (22): A solution of 21 (23.3 mg,
58.1 μmol) and trifluoromethanesulfonic acid (4 μL, 58.1 μmol) in
MeOH (1.21 mL) was treated with Pd/C (5% w/w). The resulting
suspension was stirred under H2 (1 atm) for 14 h, then the reaction
mixture was filtered through a pad of Celite, which was rinsed with
MeOH (5ϫ 1 mL). The solvent was evaporated under reduced
pressure to give the desired primary amine for use in the next step
without further purification. 4-Benzyloxybenzoyl chloride
(15.6 mg, 68.1 μmol) was added to the solution of amine and Et3N
(64 μL, 681 μmol) in anhydrous CH2Cl2 (0.81 mL) under an N2
atmosphere. The reaction mixture was stirred for 2 h at 25 °C, then
quenched by the addition of MeOH (0.15 mL) and pyridine
(0.15 mL). The volatiles were evaporated under vacuum and the
residue was dissolved in EtOAc. The organic phase was successively
extracted with aqueous 2 n HCl, water, aqueous saturated
NaHCO3, and brine. The organic layer was dried (Na2SO4) and
evaporated under vacuum to give the crude mixture, which was
purified by flash chromatography (petroleum ether/ethyl acetate,
1:1) to afford azepane 22 (14.9 mg, 52% over both steps, Rf = 0.37)
as white crystals (CCDC-966288). [α]2D0 = –11.4 (c = 1.0, CHCl3);
tert-Butyl (3R,4S,5S,6R)-3-Azido-4-benzyloxy-5-fluoro-6-hydroxy-
azepane-1-carboxylate (19): A solution of tetrabutylammonium
fluoride (TBAF; 1 m in THF, 80 μL, 80.1 μmol) was added drop-
wise by using a syringe to a well-stirred solution of 18 (36.0 mg,
72.8 μmol) in anhydrous THF (1 mL) under an N2 atmosphere at
25 °C. The mixture was stirred at the same temperature until the
reaction reached completion (45 min; TLC), then evaporated to
dryness and the crude mixture was subjected to flash chromatog-
raphy (petroleum ether/EtOAc, 4:1) to give 19 (20.8 mg, 75%, Rf
= 0.25) as a colorless oil. [α]2D0 = –18.2 (c = 1.7, CH2Cl2). IR (film):
ν
= 3600–3130 (br), 2990, 2963, 2365, 2134, 1684, 1526, 1479,
˜
max
1466, 1419, 1167, 1081, 1042 cm–1. 1H NMR (600 MHz, CDCl3):
δ = 7.42–7.30 (m, 5 H), 4.82 (d, J = 11.20 Hz, 1 H), 4.69 (d, J =
11.20 Hz, 1 H), 4.56 [ddd, J = 47.34 (1JH,F), 7.04, 6.84 Hz, 1 H],
4.12–4.00 (m, 1 H), 3.84–3.50 (m, 4 H), 3.44 (br. d, J = 15.16 Hz,
1 H), 3.09 (dd, J = 14.83, 9.53 Hz, 1 H), 1.48 (s, 9 H) ppm. 13C
NMR (150 MHz, CDCl3): δ = 156.0, 137.1, 128.7, 128.6, 128.4,
1
2
96.2 (d, JC,F = 175.24 Hz), 81.6 (d, JC,F = 21.87 Hz), 81.5, 74.9,
2
3
3
71.4 (d, JC,F = 23.97 Hz), 62.9 (d, JC,F = 6.07 Hz), 48.7 (d, JC,F
=
6.59 Hz), 47.9, 28.4 ppm. HRMS (ESI): m/z calcd. for
C18H26FN4O4 [M + H]+ 381.1938; found 381.1945.
m.p. 169–172 °C. IR (film): ν
= 3500–3100 (br), 2360, 1716,
˜
max
tert-Butyl (3R,4S,5R)-3-Azido-4-benzyloxy-5-fluoro-6-oxoazepane-
1-carboxylate (20): Yield 92% from 19; colorless oil; Rf = 0.42 (pe-
troleum ether/EtOAc, 4:1); [α]2D0 = –17.8 (c = 0.9, CH2Cl2). IR
1683, 1652, 1630, 1613, 1518, 1249, 1210, 1171, 1139, 1049, 840,
1
793, 726, 608 cm–1. H NMR (600 MHz, CDCl3): δ = 8.44 (d, J =
4.87 Hz, 1 H), 7.82 (d, J = 8.66 Hz, 2 H), 7.45–7.32 (m, 5 H), 7.03
(d, J = 8.59 Hz, 2 H), 5.45 (s,1 H), 5.12 (s, 2 H), 4.68 [dddd, J =
(film): νmax = 2365, 2349, 2119, 1710, 1547, 1527, 1467, 1448, 1424,
˜
1
1109 cm–1. H NMR (600 MHz, CDCl3): δ = 7.45–7.30 (m, 5 H), 46.57 (1JH,F), 18.31, 9.42, 1.57 Hz, 1 H], 4.47–4.39 (m, 1 H), 4.30–
5.25 [dd, J = 48.98 (1JH,F), 8.38 Hz, 1 H], 4.89 (d, J = 10.12 Hz, 1
H), 4.71 (d, J = 10.12 Hz, 1 H), 4.08 (br. d, J = 15.47 Hz, 1 H),
4.24 (m, 1 H), 4.21–4.10 (m, 2 H), 4.34–4.23 (m, 2 H), 1.51 (s, 9
H) ppm. 13C NMR (150 MHz, CDCl3): δ = 168.6, 162.0, 156.7,
3.94–3.85 (m, 1 H), 3.67–3.50 (m, 3 H), 2.60 (dd, J = 14.85, 136.4, 129.3, 128.8, 128.4, 127.6, 125.4, 121.7 [dd, J = 252.11
8
www.eurjoc.org
© 000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 000, 0–0

Job/Unit: O31811
/KAP1
Date: 26-02-14 19:00:45
Pages: 11
Conformational Regulation of Fluorinated Azepanes
(1JC,F), 18.99 (3JC,F) Hz], 114.9, 90.3 [dt, J = 193.17 (1JC,F), 22.29
[13]
a) X.-G. Hu, L. Hunter, Beilstein J. Org. Chem. 2013, 9, 2696–
2708; b) L. Hunter, Beilstein J. Org. Chem. 2010, 6, 38; c) D.
O’Hagan, Chem. Soc. Rev. 2008, 37, 308–319; d) R. Filler, R.
Saha, Future Med. Chem. 2009, 1, 777–791; e) E. Ilardi, E.
Vitaku, J. Njardarson, J. Med. Chem. 2013, ASAP.
a) D. O’Hagan, J. Org. Chem. 2012, 77, 3689–3699; b) D.
O’Hagan, Y. Wang, M. Skibinski, A. M. Z. Slawin, Pure Appl.
Chem. 2012, 84, 1587–1595.
2
3
(2JC,F) Hz], 82.9, 73.2 (d, JC,F = 16.55 Hz), 70.3, 57.6 (d, JC,F
=
5.71 Hz), 52.4 [dd, J = 37.68 (2JC,F), 27.76 (2JC,F) Hz], 48.9,
28.3 ppm. HRMS (ESI): m/z calcd. for C25H30F3N2O5 [M + H]+
495.2107; found 495.2104. CCDC-966288 contains the supplemen-
tary crystallographic data for this paper. These data can be ob-
tained free of charge from The Cambridge Crystallographic Data
Centre via www.ccdc.cam.ac.uk/data_request/cif.
[14]
[15]
a) M. A. Massa, D. P. Spangler, R. C. Durley, B. S. Hickory,
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Conformational Analysis: The conformational analysis was based
on the observed J values, which were extracted from the H NMR
1
spectra of azepanes in chloroform, in conjunction with computa-
tional modeling in chloroform. The conformational search for each
azepane was performed as implemented in the program MOE.[26]
Conformers were generated by the stochastic method and mini-
mized in the MMFF94X force field with chloroform as the solvent.
Conformers within 3–5 kcal/mol in energy were grouped to identify
different azepane ring conformations. All representative conform-
ers were subjected to DFT calculations as implemented in the pro-
gram Turbomole.[27] A DFT geometry optimization [SV(P) basis
set at the B3LYP level in COSMO solvent CHCl3] was performed
3
for each conformer.[24] The JH,H values were calculated for each
conformer ring geometry as described by Haasnoot et al.[25a] The
calculated spin–spin coupling constants for each conformer were
compared with the experimentally determined values (extracted by
simulation with program Bruker TopSpin 3.2) to exclude conform-
ers that were in clear violation and identify valid contributing con-
formers.
Supporting Information (see footnote on the first page of this arti-
cle): Copies of NMR spectra and conformational analysis details.
Acknowledgments
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Pages: 11
A. R. Patel, L. Hunter, M. M. Bhadbhade, F. Liu
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1
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mational interchange.
Received: December 5, 2013
Published Online: ᭿
10
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© 000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 000, 0–0

Job/Unit: O31811
/KAP1
Date: 26-02-14 19:00:45
Pages: 11
Conformational Regulation of Fluorinated Azepanes
Conformation Analysis
Seven-membered nitrogen heterocycles
have flexible ring structures and this con-
formational diversity is important for their
bioactivity. Here the conformational effects
of fluorination, as well as hydroxylation,
on an azepane model system are investi-
A. R. Patel, L. Hunter, M. M. Bhadbhade,
F. Liu* ............................................ 1–11
Conformational Regulation of Substituted
Azepanes through Mono-, Di-, and Tri-
fluorination
1
gated by H NMR spectroscopy and com-
putational modeling.
Keywords: Conformation analysis / Me-
dium-ring compounds / Fluorine / Density
functional calculations / Nucleophilic sub-
stitution
Eur. J. Org. Chem. 000, 0–0
© 000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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11