Medium-Sized-Ring Analogues of Dibenzodiazepines by a Conformationally Induced Smiles Ring Expansion

Article abstract of DOI:10.1002/anie.201708991

Analogues of dibenzodiazepines, in which the seven-membered nitrogen heterocycle is replaced by a 9–12-membered ring, were made by an unactivated Smiles rearrangement of five- to eight-membered heterocyclic anthranilamides. The conformational preference of the tertiary amide in the starting material leads to intramolecular migration of a range of aryl rings, even those lacking electron-withdrawing activating groups, and provides a method for n→n+4 ring expansion. The medium-ring products adopt a chiral ground state with an intramolecular, transannular hydrogen bond. The rate of interconversion of their enantiomeric conformers depends on solvent polarity. Ring size and adjacent steric hindrance modulate this hidden hydrophilicity, thus making this scaffold a good candidate for drug development.

Full text of DOI:10.1002/anie.201708991

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Accepted Article
Title: Medium-ring analogues of dibenzodiazepines by conformationally
induced Smiles ring expansion
Authors: Romain Costil, Quentin Lefebvre, and Jonathan Clayden
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Angewandte Chemie International Edition
10.1002/anie.201708991
COMMUNICATION
Medium-ring analogues of dibenzodiazepines by
conformationally induced Smiles ring expansion
[
a]
Romain Costil, Quentin Lefebvre, and Jonathan Clayden*
Abstract: Analogues of dibenzodiazepines in which the 7-
membered nitrogen heterocycle is replaced by a 9-12 membered
ring were made by an unactivated Smiles rearrangement of 5-8
membered heterocyclic anthranilamides. The conformational
O
N
NH
O
N
S
N
N
preference of the tertiary amide in the starting material leads to
intramolecular migration of a range of aryl rings, even those lacking
electron-withdrawing activating groups, and provides a method for
n→n+4 ring expansion. The medium-ring products adopt a chiral
ground state with an intramolecular, transannular hydrogen bond.
The rate of interconversion of their enantiomeric conformations
depends on solvent polarity. Ring-size and adjacent steric hindrance
enables the modulation of this ‘hidden hydrophilicity’, making this
scaffold a good candidate for drug development.
N
N
O
N
N
imipramine
dibenzepin
telenzepine
Ar2
( )n–4
O
H
N
n
O
N
2
O
N
H
(
)n–4
( )n–4
base
n+4
O
N
n
Ar1
Ar1
Ar1
Ring
N
Ar2
O
NH
Ar2
expansion
by Smiles
rearrangement
1
3
4
Approaches to drug design have recently started employing
shape-based 3D molecular descriptors in an effort to “escape
Scheme 1. Prototypical tricyclic antidepressants and our approach to their
medium-ring analogues.
[
1]
from flatland”, with good success in the prediction of the
[
1b,1c]
likeliness of clinical success.
Medium-sized rings (with 8 to
1
2 atoms) present promising scaffolds for the development of
Ring expansion provides an appealing way to make medium-
small-molecule drugs with an extended three-dimensional shape. sized heterocyclic rings, because transannular strain is to some
The limited flexibility of these rings is beneficial for enhanced
binding affinity, while their well-defined conformations ameliorate
physicochemical properties such as bioavailability or cell
extent mitigated in the transition state leading to the medium
[
2b,10]
ring,
and because heterocycles of rings sizes 5-7 are readily
available. In this paper we report the use of an unconventional
[
2]
[11]
permeability.
unfavourable transannular interactions increase the enthalpy of
Nonetheless it is well established that
variant of the Smiles rearrangement to generate medium rings
from much simpler benzo-fused nitrogen heterocycles by n→n+4
[
3]
[12]
[13]
transition states of reactions leading to medium rings. This
ring expansion. The work builds on our observation that the
usual electron-withdrawing activating substituents are not
necessary for the Smiles rearrangement of tertiary anilides,
[
4]
makes their synthesis difficult, and consequently medium rings
[
2b,5]
are under-represented in screening libraries.
some medium-ring lactams have been found active against
Only recently,
[
14]
because conformational preorganization
about the N–CO
[
6a]
myelogenous leukemia,
while trapoxins and apicidins, two
bond is sufficient to place the nucleophilic migration terminus
and the electrophilic aromatic ring in close proximity. Scheme 1
shows the overall strategy, and illustrates the similarity of the
reaction products to ring-expanded analogues of the biologically
active dibenzodiazepines.
classes of cyclotetrapeptides isolated from fungi, are anti-
protozoal agents that function by inhibition of histone
[
6b,6c]
deacetylase.
Dibenzodiazepine
Scheme 1) are widely prescribed for the treatment of depression,
tricyclic
antidepressants
(TCAs,
Anthranilamides 3 were made efficiently by condensation
of isatoic anhydride derivatives 1 with nitrogen heterocycles 2
[
7]
schizophrenia, or nocturnal enuresis.
possess a pair of rigid but rapidly interconverting enantiomeric
butterfly” conformations, arising from the strain in the dibenzo-
Dibenzodiazepines
[
15]
(See the Supporting Information for details).
Compound 3b,
“
for example, was obtained in one step from a mixture of N-
methyl isatoic anhydride and tetrahydroquinoline in THF in the
presence of a base. On treatment with NaHMDS in refluxing
THF, 3b rearranged to the migration product 4b, having a ten-
membered ring, in 40% yield (Table 1, entry 1). Increasing the
temperature to 100 °C (in a sealed tube) improved the yield of
the product (entry 2), but also led to decomposition to the
corresponding N-methyl anthranilic acid and tetrahydroquinoline
[
8]
fused 7-membered heterocycle. This interconversion is locked
in telenzepine, of which one of the two atropisomers is 500 times
[
9]
more active than the other.
(
THQ, Table 1, final column). Microwave heating promoted a
cleaner reaction, giving the product in 72% yield after only 15
min (entry 3). KHMDS gave comparable results (entry 5), but
there was negligible conversion with LiHMDS. Silazide bases
seem particularly suited for this ring expansion as other bases
investigated were either too weak, leaving the starting material
untouched, or too nucleophilic, leading to decomposition (entry
[a]
R. Costil, Dr. Q. Lefebvre, Prof. Dr. J. Clayden
School of Chemistry, University of Bristol, Cantock’s Close, Bristol,
BS8 1TS, UK
E-mail: j.clayden@bristol.ac.uk
Supporting information for this article is given via a link at the end of
the document
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Angewandte Chemie International Edition
10.1002/anie.201708991
COMMUNICATION
O
H
N
6
). 2-Methyl THF provided a good alternative solvent, giving the
O
NaHMDS
(1.1 equiv)
product in 67% isolated yield (entry 4), whereas toluene and
MTBE led to decomposition (see Supporting Information).
( )n–4
N
n
( )n–4
n+4
Ar1
Ar1
THF, 15 min,
µw, 100 °C
NH
N
Ar2
Table 1. Optimisation of the reaction conditions.
3
4
H
N
O
H
N
O
H
N
HN
O
O
O
1
0
N
6
base
THF
11
9
10
N
N
N
N
NH
3
b
4b
4
a, 70%
4
b, 72%, 79%[a]
4c, 82%
(
4 h, 120 °C)
Isolated yield
b / %
Recovered
Entry
Base
T / °C
t
[a]
[b]
H
N
HN
HN
4
THQ /%
O
O
O
1
2
[
b]
11
1
2
3
4
5
6
NaHMDS
NaHMDS
NaHMDS
NaHMDS
KHMDS
66
16 h
40
38
22
<5
<5
<5
<5
10
N
N
N
[
c]
d]
d]
d]
d]
100
100
100
100
100
15 min
66
72
F
F
[
[
[
[
15 min
15 min
15 min
15 min
4d, quant.
4e, 45%; 80%[b]
4f, 78%
(
45 min)
[e]
67
62
H
N
H
N
H
N
O
O
O
[b]
1
0
10
F
Br
10
[b],[f]
LiHMDS
2
N
N
N
Cl
Reaction conditions: 3b (0.11 mmol, 1.0 eq.), with base (1.1 eq.) in THF (0.2
4h, 52%; 66%[b]
4i, 44%; 53%[b]
4
g, 78%
1
M). [a] THQ = 1,2,3,4-tetrahydroquinoline. [b] H NMR yields determined using
HN
HN
O
HN
O
1
,3,5-trimethoxybenzene as internal standard. [c] Using a sealed tube. [d]
O
Using a microwave reactor. [e] 2-MeTHF as solvent. [f] No product obtained
1
1
11
11
4
with Phosphazene base P -tBu, 1,5,7-Triazabicyclo[4.4.0]dec-5-ene (TDB) or
F3CO
Cl
KOtBu as base.
N
N
N
Having identified the optimal conditions for rearrangement of 4b,
we explored the scope of the reaction. Ring-expansion of the 5-
membered indoline derivative 3a required more forcing
conditions (4 hours at 120 °C), but yielded the corresponding 9-
membered product 4a in excellent yield. Rearrangements of
larger rings (6- to 8-membered) were even cleaner, providing the
corresponding 10- to 12-membered compounds 4b-d in
excellent yields after short reaction times. The reaction showed
good tolerance to halogen substituents, with fluoro-, bromo-, and
chloro-substituted products 4e-j formed without dehalogenation.
The reaction conditions were fully compatible with the
4l, 57%; 73%[b]
4
j 84%
4k, 82%
(1 h)
H
N
HN
HN
O
O
O
N
11
11
1
0
NH
N
N
N
o, 54%[c]
1 h)
4m 98%
4n, 91%
4
Cl
(
Me
[
16]
H
N
metabolically stable, lipophilic trifluoromethoxy group of 4k.
O
O
N
Moderate steric hindrance around the reactive centers was
tolerated, as demonstrated by products 4e, 4f and 4l. Products
with functionalized rings were made by rearrangement of staring
materials containing alternative heterocycles. Ring opening of
dibenzazepine leads to benzop-fused product 4m in near-
quantitative yield. Heterocycles containing an additional nitrogen
atom, namely benzodiazepane and quinoxaline, also
successfully rearranged, yielding the triaza ring systems of 4n
and 4o.
NaHMDS, MeI
THF, r.t., 2 h
1
0
10
N
N
Me
4
Me
, 77%
b
5
H HN
HN
O
BH .SMe2
3
H
THF, 80 °C, 18 h
12
12
N
N
Me
6, 50%
Me
4
d
Scheme 2. Scope of the ring expansion. Yields of isolated products. [a] 3
mmol scale. [b] Based on recovered starting material.
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Angewandte Chemie International Edition
10.1002/anie.201708991
COMMUNICATION
Further transformations of the amide function of the medium-ring
products were possible. Alkylation of the amide nitrogen with
methyl iodide gave 5 in 77% yield, and reduction of the carbonyl
with a solution of borane dimethyl sulfide in THF, gave the more
compound 4d displayed
a
moderate upfield shift. These
observations suggest that the transannular intramolecular
hydrogen bond evident in the solid state persists in solution,
[
20]
increasing in strength with larger rings.
1
lipophilic diamine 6.
Table 2. Crystal structures of 4a-d, and selected structural data.
H NMR of compounds 4a-l showed diastereotopic signals
for the methylene groups within the ring, indicating that these
heterocycles adopt chiral ground states whose enantiomeric
[
21,22]
conformations interconvert slowly on the NMR time scale.
We determined the rate constants of enantiomerisation of
compounds 4a-d and 4l by Variable Temperature Exchange
Spectroscopy (VT-EXSY), as summarized in Table 3 (See SI for
details). Apart from 4a, with its distorted amide, larger rings were
significantly more flexible: 12-membered ring 4d inverted more
3
than 2000 times faster than 10-membered 4b in CDCl , which
may even exist as two atropisomeric enantiomers at
temperatures around 0 °C. The rates to enantiomerisation were
6
up to tenfold faster in polar solvents such as DMSO-d , with
barriers to enantiomerisation in larger rings 4c and 4d being
more sensitive to solvent polarity than in 4b.
Table 3. Rates of conformational enantiomerisation of 4a-d in various
solvents.
–
1
Cpd.
d
N-H-N / Å
2.42ꢀ
2.72ꢀ
2.47ꢀ
1.95ꢀ
θ
Ar–CO / °
54ꢀ
δ
NH / ppm
5.87ꢀ
ΔδNH/%DMSO / ppm %
0.025ꢀ
‡
ꢀ
–1ꢀ[a]
[b]ꢀ
Cpd.ꢀ
Solventꢀ
k
enantꢀ/ꢀsꢀ
ΔG /ꢀkJꢀmol
ꢀ
τ
1/2ꢀ/ꢀsꢀ
–
[
c]
4a
4b
4c
4d
4a
DMSO-d6/CD OD
–
–
3
Toluene-d8
0.0082
0.0074
0.0019
0.16
84.9
42.3
47.1
58ꢀ
6.46ꢀ
0.031ꢀ
4b
4c
4d
DMSO-d6
85.1
42ꢀ
7.72ꢀ
0.004ꢀ
CDCl
3
88.5
180.9
2.1
1.3ꢀ
9.10ꢀ
-0.014ꢀ
DMSO-d6
77.5
CDCl3
0.016
30.7
83.2
21.6
0.011
0.076
7.0
The conformation and dynamics of the medium-ring products
were investigated in the solid state and in solution. Crystals
suitable for X-ray analysis were obtained for each ring size,
revealing the solid-state conformation of compounds 4a-d and 4l
CD
3
OD
64.5
CDCl
3
4.6
69.2
4
l
DMSO-d6
CDCl
0.049
0.031
80.4
[
17]
(
Table 2). The relative difficulty of synthesizing compound 4a
3
81.6
11.1
can be explained by the deviation from planarity in its amide
[
a]ꢀ Freeꢀ energyꢀ ofꢀ enantiomerisationꢀ calculatedꢀ atꢀ 298ꢀ K.ꢀ [b]ꢀ Half-lifeꢀ forꢀ
group: the sum of the bond angles at nitrogen (344.4°) and its
racemisationꢀatꢀ298ꢀK.ꢀ[c]ꢀPeakꢀoverlapꢀprecludesꢀcalculationꢀinꢀeitherꢀsolvent.ꢀ
3
pyramidalization (χ
N
= 47.8°) indicate significant sp character at
[
18]
1
the amide nitrogen.
Moreover, while the C–N bond torsion
H NMR indicated another distinctive feature of 4a: it exists as a
angle is moderate (τ = 23.4°), the dihedral angle between the
amide group and the adjacent aromatic ring (θAr–CO = 54°)
restricts delocalization.
pair of inequivalent diastereoisomeric conformers whose
proportions vary with the solvent, with less of the minor
conformer in toluene-d or CDCl
8
3
(ratios of 7:1 and 6:1) than in
A clear trend was observed as the ring size increased from
CD OD and DMSO-d (ratios of 3:1). Cross-peaks for the
3
6
1
0 to 11 to 12. The N-H-N distance shortened from 2.72 to 1.95
Å with larger rings, with the Ar–CO dihedral angle approaching
° in the 12-membered ring, permitting conjugation between the
amide and the aromatic ring. This behavior suggested
transannular hydrogen bond, a characteristic of interest for the
interconversion of the diastereoisomeric conformers were
evident by EXSY NMR, and the barriers to their interconversion
0
3 8
in both CD OD and toluene-d were calculated using the Eyring
a
equation (Table 4). While the rate at which the minor
diastereomer converts to the major shows little dependence on
solvent, the rate of the reverse process is strongly solvent-
development
hydrophilicity’.
of
bioactive
molecules
with
‘hidden
[
5c,19]
3
dependent, and is three times as fast in CD OD. This suggests
1
The downfield shift of the N-H signal in the H NMR
spectra of the products 4 in CDCl from 6.46 to 9.10 ppm with
that the major conformer owes its relative stability to an
additional intramolecular hydrogen bond which is destabilised by
hydrogen bonding solvents.
3
increasing ring size also indicated a progressively stronger
hydrogen bond. Titration with DMSO-d6 of solutions of
These diastereoisomeric conformers probably arise from
the two alternative relative orientations of Ar–CO and Ar–N
bonds of the adjacent secondary amide and tertiary amine
groups. Clear evidence that twisting in these bonds can lead to
diastereoisomeric conformers came from 11-membered ring 4l,
1
compounds 4a-d in CDCl
3
shifted the N-H signal in the H NMR
spectrum of 9- and 10-membered compounds 4a and 4b
strongly downfield (Table 2, final column). Hardly any shift was
observed for 11-membered compound 4c; 12-membered
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Angewandte Chemie International Edition
10.1002/anie.201708991
COMMUNICATION
1
which also displays two diastereoisomeric conformers in its
H
3
coplanar. In non-hydrogen bonding solvent such as CDCl , the
[
23,24]
NMR spectrum.
Scheme 3) shows a more or less perpendicular arrangement in
the amide Ar—CO bond, and a strong downfield shift of the N-H
signal from 6.12 ppm in CDCl to 7.84 ppm in DMSO-d6
The crystal structure of compound 4l
barrier to diastereomerisation is lowered by transient
transannular hydrogen bonding between the amide proton and
(
the diarylamine nitrogen. In DMSO-d
transition state becomes less favorable, decreasing the rate of
exchange by 10-fold. Unlike compound 4a, for which
enantiomerisation occurs through stepwise bond rotation, these
higher values for diastereomerisation compared to
6
, the relative energy of
3
indicates that the intramolecular hydrogen bond in the ground
a
state of 4l is weaker than in 4c. However, EXSY NMR shows
that compound 4l possesses
enantiomerisation as compound 4c. The similarity of the rates of
exchange for enantiomerisation in CDCl and DMSO-d6
suggests that compound 4l adopts in solution a conformation
a
similar barrier to
enantiomerisation suggest that racemisation of compound 4l
occurs through geared rotation of the Ar—CO and the Ar—N
bonds (Scheme 3).
3
similar to the one observed in the solid state, with
a
To conclude, we used Smiles rearrangement of
anthranilamides to yield medium-size heterocyclic analogues of
dibenzodiazepines. Microwave heating reduces reaction time to
15 minutes, providing 9- to 12-membered rings in excellent
yields. The reaction tolerates sensitive functional groups, and
can be performed in a ‘green solvent’. A transannular hydrogen
bond in the products provides the structures with ‘hidden
hydrophilicity’. The strength of this hydrogen bond, which
governs the stereodynamic properties of the medium-ring
heterocycles, is modulated either by ring size or introduction of
steric hindrance close to the amide group, making this class of
compounds a versatile tool of drug development.
perpendicular Ar—CO bond.
1
H
NMR of compound 4l revealed
a
mixture of
diastereoisomeric atropisomers in ratios of 3:1 in toluene-d8, 4:1
in CDCl and 10:1 in CD OD. This trend, opposed to compound
a, shows that despite the perpendicular twist in the amide of 4l,
3
3
4
the flexibility of the 11-membered ring allows an intramolecular
hydrogen bond in solution, but only in the minor conformer. The
rate of interconversion of the diastereomers was calculated
using EXSY NMR at higher temperatures (Table 4).
Table 4. Diastereomerisation parameters of compounds 4a and 4l.
[
a]
[b]
‡
[a]
‡
[b]
Cpd.
Solvent
k
min-maj
k
maj-min
ΔG min-maj
ΔG maj-min
-
1
-1
–1
–1
/
s
/ s
/ kJ mol
75.8ꢀ
/ kJ mol
78.7ꢀ
Acknowledgements
4
aꢀ
CD
3
ODꢀ
0.326ꢀ
0.306ꢀ
0.099ꢀ
0.035ꢀ
ꢀ
Toluene-d8ꢀ
DMSO-d6ꢀ
75.9ꢀ
81.3ꢀ
4
lꢀ
0.00052ꢀ
0.0083ꢀ
0.00022ꢀ
0.0026ꢀ
91.7ꢀ
93.9ꢀ
We thank Craig Butts for assistance with EXSY NMR and Hazel
Sparkes and Natalie Pridmore for X-ray crystallographic
assistance. The work was supported by the Deutsche
Forschungsgemeinschaft (research fellowship LE 3853/1-1 to
QL), the EPSRC and the University of Bristol.
ꢀ
CDCl
3
ꢀ
84.8ꢀ
87.8ꢀ
Rates and free energies of activation for conversion of [a] minor to major and
b] major to minor conformer, at 298 K.
[
Keywords: dibenzodiazepinone • chiral heterocycles • medium-
size ring • transannular hydrogen bonding • tricyclic
antidepressant
[
1]
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(
3
27; (c) W. H. B. Sauer, M. K. Schwarz, J. Chem. Inf. Comput. Sci.,
003, 43, 987.
2
[
2]
(a) A. Hussain, S. K. Yousuf, D. Mukherjee, RSC Adv., 2014, 4, 43241;
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(
Unsworth, Chem. Eur. J., 2017, 23, 2225.
[
[
3]
4]
G. Illuminati, L. Mandolini, Acc. Chem. Res., 1981, 14, 95.
For reviews, see: (a) U. Nubbemeyer, Top. Curr. Chem., 2001, 216, 12;
(
b) A. Sharma, P. Appukkuttan, E. Van der Eycken, Chem. Commun.,
012, 48, 1623.
Scheme 3. X-ray crystal structure and conformational dynamics of 4l.
2
[
5]
The ZINC database contains examples of azepanes, azocanes and
azonanes in numbers one, three and four orders of magnitude fewer
than piperidines. (a) R. D. Taylor, M. MacCoss, A. D. G. Lawson, J.
Med. Chem., 2014, 57, 5845; (b) E. Vitaku, D. T. Smith, J. T.
Njardarson, J. Med. Chem., 2014, 57, 10257; (c) R. Madhavachary, E.
M. M. Abdelraheem, A. Rossetti, A. Twarda-Clapa, B. Musielak, K.
Katarzyna, K.-T. Justyna, T. A. Holak, A. Dömling, Angew. Chem. Int.
Ed., 2017, 56, 1.
Unlike compound 4a, diastereomerisation of compound 4l is
slower than enantiomerisation by a factor of almost 4 in CDCl
and up to 100 in DMSO-d . The rates of diastereomerisation of
compound 4l (unlike those of enantiomerisation) is strongly
solvent-dependent. In this case, DMSO-d raised the free energy
of both the forward and reverse exchange relative to CDCl
3
6
6
3
.
[
6]
(a) G. Ding, F. Liu, T. Yang, Y. Jiang, H. Fu and Y. Zhao, Bioorg. Med.
Chem., 2006, 14, 3766; (b) S. B. Singh, D. L. Zink, J. M. Liesch, R. T.
Mosley, A. W. Dombrowski, G. F. Bills, S. J. Darkin-Rattray, D. M.
Because the amide group and the adjacent aromatic ring are
perpendicular in the ground state, diastereomerisation must
occur through a transition state in which these two groups are
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Angewandte Chemie International Edition
10.1002/anie.201708991
COMMUNICATION
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[
[
7]
8]
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1
977, 54, 35.
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Hargrave, J. Adams, J. Med. Chem., 1992, 35, 201; (c) M. Simonyi,
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[
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[
[
1
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[
[
[
21] For application of a planar-chiral medium-size nitrogen heterocycle,
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ring in 4a may adopt a cis amide conformation.
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Angewandte Chemie International Edition
10.1002/anie.201708991
COMMUNICATION
Table of Contents
COMMUNICATION
Ar2
Ring
expansion
by Smiles
H
N
Medium Ring Heterocycles
O
n
O
O
N
H
R. Costil, Q. Lefebvre, J. Clayden*
rearrangement
n+4
n
N
O
Ar1
Ar1
Ar1
base
Page No. – Page No.
N
Ar2
Ar2
N
O
NH
Medium-ring analogues of
dibenzodiazepines by
•
electron-rich and -poor rings • ring sizes 9-12 • conformationally restricted products
Smiles rearrangement of readily prepared amide derivatives of benzo-fused nitrogen
heterocycles requires no electronic activation to give medium ring analogues of the
dibenzodiazepine tricyclic antidepressants.
conformationally induced Smiles ring
expansion
This article is protected by copyright. All rights reserved.