Lithiation-Substitution of N -Boc-2-phenylazepane

Article abstract of DOI:10.1055/s-0036-1590857

Preparation of 2,2-disubstituted azepanes was accomplished from N - tert -butoxy(N -Boc)-2-phenylazepane by treatment with butyllithium then electrophilic quench. The lithiation was followed by in situ ReactIR spectroscopy and the rate of rotation of the carbamate was determined by variable temperature (VT)-NMR spectroscopy and by DFT studies. Most electrophiles add α to the nitrogen atom but cyanoformates and chloroformates gave ortho -substituted products. Cyclic carbamates were formed from an aldehyde or ketone electrophile. Kinetic resolution with sparteine was only poorly selective. Removal of the Boc group promoted cyclization to a homoindolizidine or an isoindolinone.

Full text of DOI:10.1055/s-0036-1590857

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© Georg Thieme Verlag Stuttgart · New York
2017, 28, A–D
letter
A
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T. Aeyad et al.
Letter
Synlett
Lithiation–Substitution of N-Boc-2-phenylazepane
Tahani Aeyad
Jason D. Williams
React-IR, VT-NMR
spectroscopy
n-BuLi
THF, –5 °C
10 min
then E+
E
DFT studies
N
N
ΔG‡
Ph
Ph
Anthony J. H. M. Meijer
rot
Boc
Boc
Iain Coldham*
67–93%
for
example:
Ph
N
Department of Chemistry, University of Sheffield,
Brook Hill, Sheffield, S3 7HF, UK
i.coldham@sheffield.ac.uk
Ph
Ph
N
N
Ph
O
E+ = Br(CH2)3Br
then TMSCl, NaI
O
Boc
E+ = allyl bromide
+ = PhCHO
Dedicated to Victor Snieckus on the occasion of
his 80th birthday
E
Received: 31.05.2017
Accepted: 06.07.2017
Published online: 17.08.2017
DOI: 10.1055/s-0036-1590857; Art ID: st-2017-r0412-l
dines,3 tetrahydroisoquinolines,4 and tetrahydro-β-carbo-
lines.5 Considering the importance of substituted azepanes
in natural products and drug compounds we wanted to ex-
plore the lithiation–substitution of the 2-phenylazepane
ring system and describe here our efforts with this chemis-
try.
The desired 2-phenylazepane framework was prepared
according to a method reported in the literature (Scheme
1).6,7 Treatment of caprolactam with Boc2O gave the lactam
1 which was partially reduced with DIBAL-H and converted
into the benzotriazole adducts 2. Displacement of the ben-
zotriazole group with phenylmagnesium bromide gave the
desired N-Boc-2-phenylazepane 3.
Abstract Preparation of 2,2-disubstituted azepanes was accomplished
from N-tert-butoxy(N-Boc)-2-phenylazepane by treatment with butyl-
lithium then electrophilic quench. The lithiation was followed by in situ
ReactIR spectroscopy and the rate of rotation of the carbamate was de-
termined by variable temperature (VT)-NMR spectroscopy and by DFT
studies. Most electrophiles add α to the nitrogen atom but cyanofor-
mates and chloroformates gave ortho-substituted products. Cyclic car-
bamates were formed from an aldehyde or ketone electrophile. Kinetic
resolution with sparteine was only poorly selective. Removal of the Boc
group promoted cyclization to a homoindolizidine or an isoindolinone.
Key words alkylation, heterocycles, lithiation, lithium
1. DIBAL-H
PhMgBr
Azepanes form the basis of a number of pharmaceuti-
cals and natural products, and two examples are shown in
Figure 1. These include important bioactive compounds
such as fenoldopam which acts on the dopamine receptor,1
and stemona alkaloids such as stenine.2
Et2O
0 °C
THF, –78 °C
2. benzotriazole
PhMe, 110 °C
70%
N
N
N
O
Bt
Ph
Boc
1
Boc
2
Boc
3
54%
Scheme 1 Preparation of azepane 3 (Bt = benzotriazolyl)
OH
To determine the optimum conditions for reaction of
the azepane 3, we followed its lithiation by using in situ IR
spectroscopy. It was apparent that the lithiation with n-bu-
tyllithium was incomplete at low temperatures (e.g., –78 °C
in THF). Complete reaction did, however, occur when the
temperature was raised to –5 °C (Figure 2). The azepane 3
has νC=O at 1690 cm–1 and on addition of n-butyllithium this
is replaced within minutes by a carbonyl stretch at 1644
cm–1, corresponding to the lithiated intermediate.
Cl
OH
H
H
N
H
O
H
N
H
OH
O
H
fenoldopam
stenine
Figure 1 Examples of azepanes
Of particular importance in medicinal chemistry are
aryl-substituted saturated and partially saturated cyclic
amines, so methods to access aryl-substituted azepanes are
of interest. Our research group has reported the ability to
prepare aryl-substituted cyclic amines by lithiation α to a
nitrogen atom then electrophilic quench with 2-arylpiperi-
The partial lithiation at low temperatures is due to the
presence of both rotamers that are interconverting ex-
tremely slowly, with only one rotamer able to undergo re-
action through a complex induced proximity effect.8 The ra-
tio of rotamers is approximately 1:1 from the NMR spectra
and variable-temperature NMR spectroscopy was used to-
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–D

B
T. Aeyad et al.
Letter
Synlett
group, with the lowest Gibbs energy barrier (at 298 K) in
DMSO of 72.9 kJ/mol (74.1 kJ/mol in THF), which is in rea-
sonable agreement with the Gibbs energy barrier at 298 K
determined by VT-NMR spectroscopy in DMSO of 70.3
kJ/mol.
Figure 2 3D ReactIR spectrum for lithiation of 3 with n-BuLi in THF at
–5 °C (complete lithiation occurs within minutes)
gether with line-shape analysis to determine the activation
1
parameters for the rotation of the Boc group. The H NMR
spectra showing coalescence of signals in the region δ =
5.50–2.00 ppm in DMSO-d6 is given in Figure 3. Analysis led
to approximate values of ΔH‡ 73 kJ/mol and ΔS‡ 9 J/K mol.
The solvent DMSO was chosen for this study due to its abil-
ity to reach the elevated temperatures required for coales-
cence of these signals and the values in THF may of course
be different. Nonetheless it is clear that the half-life for ro-
tation is many hours at low temperatures such as –78 °C
but only seconds at –5 °C, thereby allowing complete lithia-
tion at higher temperatures.
Figure 4 Minimum energy structures for the azepane 3 by DFT [6-
311G(d,p) basis set with B3LYP functional in DMSO (see Supporting In-
formation)]. The relative Gibbs energies (in kJ/mol) are: (a) 0.00; (b)
0.20; (c) 2.14; (d) 2.40, meaning relative populations of
1.0:0.82:0.12:0.09.
The spectroscopic and DFT studies indicated that the
optimum conditions for lithiation of azepane 3 would be at
temperatures of at least –10 °C as this would allow for rota-
tion of the Boc group and therefore subsequent higher
yields after electrophilic quench. We therefore allowed a
lithiation period of several minutes at –5 °C in THF prior to
adding an electrophile. We were pleased to find that this
method allowed the formation of 2,2-disubstituted azepane
products 4a–f with good to excellent yields (Scheme 2).9 In
the case of the carbonyl electrophiles acetone and benzal-
dehyde, the products were the cyclic carbamates 4e and 4f
where the intermediate alkoxide had cyclized on to the Boc
n-BuLi
E
THF, –5 °C
10 min
then E+
N
N
Figure 3 1H NMR spectra of azepane 3 in DMSO-d6
Ph
Ph
Boc
3
Boc
4a–f
The rate of rotation of the Boc group differs significantly
from the corresponding five- and six-membered ring ana-
logues.3a The pyrrolidine has a slightly lower barrier to rota-
tion (about 64.5 kJ/mol at 46 °C) but the piperidine has a
considerably lower barrier (about 50 kJ/mol at –28 °C). To
probe this further, we carried out density functional calcu-
lations (using the methodology from ref. 3a; see Supporting
Information for full details) in both THF and DMSO (PCM)
solvent. For both solvents we found two similar energy
minima for each rotamer, indicating a more complex ar-
rangement than in the smaller ring systems (Figure 4).
Transition states were found between these structures after
studying clockwise and anticlockwise rotation of the Boc
SnBu3
Me
Ph
N
N
N
Boc
82% 4c
Ph
Ph
Boc
Boc
75% 4a
E+ = Bu3SnCl
76% 4b
E+ = MeI
E+ = allyl bromide
Br
Ph
Ph
Ph
N
Boc
88% 4d
N
N
Ph
O
O
O
67% 4e
E+ = acetone
O
93% 4f dr 3:1
E+ = Br(CH2)4Br
E+ = PhCHO
Scheme 2 Lithiation–substitution of azepane 3 to give products 4
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–D

C
T. Aeyad et al.
Letter
Synlett
group. In the latter case, a separable mixture of diastereo-
mers (dr 3:1) was isolated and the stereochemistry of the
major isomer (trans-phenyl groups) was determined by
single-crystal X-ray analysis (Figure 5).
epane 3 is less amenable to the kinetic resolution than the
corresponding piperidine, presumably due to greater flexi-
bility of the larger ring size.3b
Finally, treating the azepane 3 with n-butyllithium in
THF at –5 °C followed by addition of 1,3-dibromopropane
gave the azepane 4g (Scheme 4). Initial attempts to remove
the Boc group with trifluoroacetic acid (TFA) gave a mixture
of products that lacked the Boc group but contained alkene
protons in the 1H NMR spectrum, possibly arising from
ready E1 elimination through a tertiary benzylic cation. We
therefore treated the carbamate 4g with TMSI, generated
from TMSCl and NaI to remove the Boc group and promote
in situ cyclization to give the desired bicyclic product 6
(Scheme 4). In addition, we treated the azepane 5a with
TFA, which did not suffer from the same problem, possibly
due to the lack of full substitution adjacent to the nitrogen
atom, and we were able to isolate the desired lactam (isoin-
dolinone) product 7 (Scheme 4).
Figure 5 Crystal structure of the major isomer of product 4f
In addition to the electrophiles shown in Scheme 2, we
investigated substitution of the organolithium intermediate
with alkyl cyanoformates. We were surprised to find that
the ortho-substituted products 5a–c were formed exclu-
sively in these cases (Scheme 3). The same products were
also formed by using alkyl chloroformates as the electro-
philes. We speculate that these products arise from a pref-
erence for reaction at the ortho position (rather than α to
the nitrogen atom) followed by re-aromatization. The initial
deprotonation α to the nitrogen atom should give an organo-
lithium intermediate that will be coordinated to the car-
bonyl oxygen atom but which could also be η3-coordinated
due to the phenyl ring and could therefore lead to the ortho-
substituted product. We are currently investigating this re-
activity aspect further.10
n-BuLi
Br
THF, –5 °C
10 min
N
N
Ph
Ph
Boc
3
Boc
then Br(CH2)3Br
92% 4g
TMSCl, NaI
Ph
MeCN, heat, 2 h
N
78%
6
CO2Me
TFA, CH2Cl2
r.t., 2 h
N
N
Boc
O
86%
5a
7
n-BuLi
CO2R
Scheme 4 Preparation of bicyclic products 6 and 7
THF, –5 °C
10 min
N
N
Ph
Boc
3
Boc
5a–c
then ROCOCN
In conclusion, a range of 2,2-disubstituted azepanes has
been prepared by lithiation–substitution reactions. Rela-
tively high temperatures (–5 °C) are required for effective
lithiation to allow for the slow rate of rotation of the Boc
group, as verified by VT-NMR spectroscopy and DFT stud-
ies. A selection of substituted products can be prepared
with different carbon-based electrophiles although cyano-
formate electrophiles provide aryl-substituted products
and the reason for the change in regiochemistry requires
further investigation. The increase in the conformational
freedom of the larger ring in comparison with the piperi-
dine presumably accounts for the reduced selectivity in the
kinetic resolution with sparteine as the chiral ligand. The
products are amenable to further transformation, such as
removal of the Boc group and cyclization to give bicyclic
ring systems.
R = Me
R = Et
R = Bn
65%
64%
64%
Scheme 3 Lithiation–substitution of azepane 3 to give products 5
The azepane 3 is chiral but racemic and it is possible
that a kinetic resolution could be achieved by conducting
the lithiation in the presence of a chiral ligand such as
sparteine.3b,11 However, we were disappointed to find that
poor enantiomeric ratios were obtained on treating aze-
pane 3 with BuLi/(+)-sparteine in PhMe at various tempera-
tures and times after electrophilic quench. For example,
treatment of azepane 3 with 1.5 equivalents (+)-sparteine
in PhMe at –5 °C followed by addition of 1.2 equivalents n-
BuLi then, after three hours, addition of tri-n-butyltin chlo-
ride gave recovered 3 (40%, er 59:41), together with the
product 4a (40%, er not determined). It appears that the az-
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–D

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T. Aeyad et al.
Letter
Synlett
Acknowledgment
(5) Cochrane, E. J.; Hassall, L. A.; Coldham, I. J. Org. Chem. 2015, 80,
5964.
We are grateful for support from the Libyan Embassy and the Univer-
sity of Sheffield. We thank Dr. C. Robertson (University of Sheffield)
for single crystal X-ray analysis for 4f, CCDC 1550480.
(6) Madan, S.; Milano, P.; Eddings, D. B.; Gawley, R. E. J. Org. Chem.
2005, 70, 3066.
(7) For alternative syntheses of compound 3, see: (a) Chen, F.; Ding,
Z.; Qin, J.; Wang, T.; He, Y.; Fan, Q.-H. Org. Lett. 2011, 13, 4348.
(b) Coldham, I.; Leonori, D. Org. Lett. 2008, 10, 3923.
(8) (a) Gallagher, D. J.; Beak, P. J. Org. Chem. 1995, 60, 7092.
(b) Bertini Gross, K. M.; Beak, P. J. Am. Chem. Soc. 2001, 123, 315.
(9) Typical Conditions
Supporting Information
Experimental details and spectroscopic data, including NMR spectra
and X-ray crystal structure, together with DFT data, are provided in the
Supporting information available online at https://doi.org/10.1055/s-
n-BuLi (0.19 mL, 0.45 mmol, 2.4 M in hexanes) was added to the
azepane 3 (100 mg, 0.36 mmol) in dry THF (2 mL) at –5 °C under
nitrogen. After 10 min, the electrophile (1.09 mmol) was added,
and the mixture was allowed to warm to r.t. After 18 h, MeOH (1
mL) was added. The solvent was evaporated and the residue was
purified by column chromatography, eluting with PE–EtOAc, see
Supporting Information.
0036-1590857.
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References and Notes
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© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–D