Atropisomerism in the 2,3,4,5-Tetrahydro-1 H -1,5-benzodiazepine Nucleus: Effects of Central Chirality at C3 on the N-Mesylation Reaction

Article abstract of DOI:10.1055/s-0037-1609868

The mesylation reaction of the 1,3-dimethyl-2,3,4,5-tetrahydro-1 H -1,5-benzodiazepine nucleus was investigated in detail. Two diastereomers (A and B) of 5-mesyl-1,3-dimethyl-2,3,4,5-tetrahydro-1 H -1,5-benzodiazepines, originating from chirality at C3 and at the Ar-N(SO ₂) axis were formed, among which isomers of the derivative with a methyl group at C6 (R = CH ₃) were separable at room temperature. A and B had chair-like and boat-like conformations, respectively, in which the C3-methyl group adopts a pseudoequatorial arrangement. Furthermore, A and B were shown to be the thermodynamically and kinetically controlled products, respectively.

Full text of DOI:10.1055/s-0037-1609868

SYNLETT
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
© Georg Thieme Verlag Stuttgart · New York
2018, 29, A–F
cluster
A
en
H. Tabata et al.
Cluster
Synlett
Atropisomerism in the 2,3,4,5-Tetrahydro-1H-1,5-benzodiazepine
Nucleus: Effects of Central Chirality at C3 on the N-Mesylation
Reaction
H3CSO2
Hidetsugu Tabata*a
Yuka Tsujia
ps.eq.
N
N5
S*
Tetsuya Yonedaa
Tomohiko Tasakab
Tetsuta Oshitaria
Hideyo Takahashi*c
Hideaki Natsugari*a,b,1
3
6
concave
aS*
H
H
chair-like
3
6
CH3SO2Cl
base
A
N
thermodynamic
H
H
H
HN
a Faculty of Pharma Sciences, Teikyo University, 2-11-1 Kaga,
Itabashi-ku, Tokyo 173-8605, Japan
h-tabata@pharm.teikyo-u.ac.jp
boat-like
convex
ps.eq.
S*
6
natsu@pharm.teikyo-u.ac.jp
b Affinity Science Corporation, 1-11-1 Nishigotanda, Shinagawa-
ku, Tokyo 141-0031, Japan
3
N
aR*
CH3SO2Cl
c Faculty of Pharmaceutical Sciences, Tokyo University of Sci-
ence, 2641 Yamazaki, Noda, Chiba 278-8510, Japan
hide-tak@rs.tus.ac.jp
N
5
boat-like
H3CSO2
from less hindered side
B
Published as part of the Cluster Atropisomerism
kinetic
Received: 28.04.2018
Accepted after revision: 29.05.2018
Published online: 12.07.2018
(VP) receptor ligands. Although the conformational change
in molecules without a substituent in the ortho-position of
the benzene ring (R = H) was too rapid for isolation of the
isomers at room temperature, molecules with a substituent
(R = CH3) at this position were conformationally ‘frozen’
and could be separated into the relatively stable (aS)- and
(aR)-axial isomers5 by chiral HPLC. That study revealed that
the (aS)-isomer is the active structure (eutomer) in exert-
ing the VP antagonistic activity.4d,4h,4j
In addition to the N-benzoyl derivatives of 2,3,4,5-tetra-
hydro-1H-1,5-benzodiazepines I, we recently investigated
the congeneric N-p-tosyl and N-mesyl derivatives II and III,
respectively (Figure 1).4g Although the sulfonamide group is
an important functional moiety in various biologically
active compounds,6 its chemical nature is not well under-
stood. Our study revealed atropisomeric properties of IIa/b
and IIIa/b caused by the Ar–N(SO2) axis.7 Here again, the
atropisomers for the b-series (R = CH3) were stable and
could be separated, although their chemical nature differed
from that of the corresponding N-benzoyl compounds Ib.
The 5-mesyl-3-methyl-2,3,4,5-tetrahydro-1H-1,5-benzo-
diazepines 1 and 2, which possess a stereogenic center at C3
in addition to the chirality due to the axis at Ar–N(SO2), can
theoretically exist as diastereomers. Here, we describe the
N-mesylation reaction of 1,3-dimethyl-2,3,4,5-tetrahydro-
1H-1,5-benzodiazepines, especially the effects of the cen-
tral chirality at C3 on the reaction, and the detailed stereo-
chemistry of the products 1 and 2.
DOI: 10.1055/s-0037-1609868; Art ID: st-2018-d0269-c
Abstract The mesylation reaction of the 1,3-dimethyl-2,3,4,5-tetra-
hydro-1H-1,5-benzodiazepine nucleus was investigated in detail. Two
diastereomers (A and B) of 5-mesyl-1,3-dimethyl-2,3,4,5-tetrahydro-
1H-1,5-benzodiazepines, originating from chirality at C3 and at the
Ar–N(SO2) axis were formed, among which isomers of the derivative
with a methyl group at C6 (R = CH3) were separable at room tempera-
ture. A and B had chair-like and boat-like conformations, respectively, in
which the C3-methyl group adopts a pseudoequatorial arrangement.
Furthermore, A and B were shown to be the thermodynamically and
kinetically controlled products, respectively.
Key words benzodiazepines, mesylation, atropisomerism, conforma-
tion, chirality
Benzo-fused seven-membered-ring nitrogen hetero-
cycles (e.g., 2,3,4,5-tetrahydro-1H-1,5-benzodiazepines) are
found as important scaffolds in many biologically active
molecules.2 Because these heterocycles possess relatively
flexible rings, the seven-membered ring often changes its
conformation so as to exert biological activity. Although of-
ten overlooked, atropisomerism2b,3 is latent in these hetero-
cycles. In our previous papers, we have described the atrop-
isomeric properties of these heterocycles in relation to their
biological activities.4 We first studied atropisomerism
based on the Ar–N(CO) (sp2–sp2) axis in 5-benzoyl-2,3,4,5-
tetrahydro-1H-1,5-benzodiazepines I, which constitute a key
core structure of the vaptan class of arginine–vasopressin
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–F

B
H. Tabata et al.
Cluster
Synlett
O
H
N
methacrylic acid
H2SO4
Zn
H3PO4
NO2
NO2
NH2
N
2
N
N
1
*
3
3
3
aR/aS
6
aR/aS
axis
CO2H
6
6
6
N
H
axis
axis N5
N5
N
H
4
N5
1,4-dioxane
110 °C
80 °C
R
R
R
R
R
R
S
S
X
X
O
4a8: 76%
4b: 30%
O
O
5a8: 51%
5b: 68%
3a: R = H
3b: R = CH3
O
O
Ia,b
IIa,b : X = p-Tolyl
IIIa,b: X = CH3
1 : R = H
2 : R = CH3
LiAlH4
AlCl3
MsCl, DMAP
pyridine, rt
NaH
CH3I
O
2
N
N
N
1
(this paper)
a : R = H, b : R = CH3
3
axis
6
4
N5
THF
80 °C
DMF
–10 °C
Figure 1 2,3,4,5-Tetrahydro-1H-1,5-benzodiazepines with an N-ben-
zoyl group (Ia,b), an N-p-tosyl group (IIa,b), an N-mesyl group (IIIa,b),
or both an N-mesyl group and a 3-methyl group (1, 2; X = Me), all of
which possess axial chirality
N
H
N
H
R
R
R
S
O
O
6a: 74%
6b: 80%
7a: 90%
7b: 92%
1: R = H (78 %)
2: R = CH3 (66 %)
5-Mesyl-1,3-dimethyl-2,3,4,5-tetrahydro-1H-1,5-benzo-
diazepines 1 and 2 (X = Me) theoretically exist as diastereo-
mers A (aS*,S*) and B (aR*,S*) as a result of chiralities at C3
and at the Ar–N(SO2) axis, as shown in Figure 2. Compounds
2 (R = CH3), which has a methyl group at C6 on the benzene
ring, should provide a higher rotational barrier for the axis
and thereby freeze the conformation of the molecule.
Scheme 1 Preparation of 5-mesyl-1,3-dimethyl-2,3,4,5-tetrahydro-
1H-1,5-benzodiazepine (1) and 5-mesyl-1,3,6-trimethyl-2,3,4,5-tetra-
hydro-1H-1,5-benzodiazepine (2).
First, the conformations of the N-mesyl derivative 1
1
(R = H) were examined in detail. In the H NMR (CD2Cl2)
spectrum of 1, each of the two methylene protons and the
methine proton of the diazepine ring were observed as sep-
arated broad peaks (Figure 3a), indicating that the protons
are diastereotopic due to the presence of the C3 central chi-
rality. However, the presence of the signals due to the dia-
stereomers A and B arising from the additional chirality at
the Ar–N(SO2) axis could not be detected, which suggests
that at room temperature (295 K), rotation around the axis
is too rapid on the NMR timescale to permit the observa-
N1
N
2
N
S*
S*
S*
3
axis
6
aS*
aR*
+
4
N
N
N
5
R
R
R
S
S
S
O
O
O
O
O
O
A
B
1 : R = H
2 : R = CH3
(aS*, S*)
(aR*, S*)
1
tion of the diastereomers. A variable-temperature H NMR
Figure 2 Plausible diastereomers originating from the (3S*) central
(VT NMR) study of 1 at lower temperatures (295–183 K in
CD2Cl2) revealed interesting conformational aspects of 1
(Figure 3b): On lowering the temperature, each diastereo-
topic proton signal split into paired signals showing the ap-
pearance of the diastereomers A and B in a ratio of ~5.3:1 at
183 K. From this ratio at 183 K, the energy difference (ΔG)
between 1A and 1B was estimated to be ~2.9 kJ/mol by con-
sidering the Boltzmann distribution.10 The activation free-
energy barrier to rotation (ΔG‡) between 1A and 1B was
also estimated by using VT NMR: the coalescence spectra
(Tc 243 K, C3 methyl) gave a ΔG‡ value11 of ~49 kJ/mol.
On the other hand, the crystal structure of 1 revealed a
relative stereochemistry of (aS*,3S*), which also showed
that the 1,5-benzodiazepine ring exists in a chair-like form
and that the C3 methyl group adopts a pseudoequatorial
orientation (Figure 4: 1). The relative stereochemistry of the
diastereomers of 1 in solution observed at lower tempera-
chirality and (aR*)/(aS*) axial chirality, i.e., (aS*,3S*) (A) and (aR*,3S*)
(B).
5-Mesyl-1,3-dimethyl-2,3,4,5-tetrahydro-1H-1,5-benzo-
diazepine (1; X = Me) and 5-mesyl-1,3,6-trimethyl-2,3,4,5-
tetrahydro-1H-1,5-benzodiazepine (2; X = Me) were pre-
pared starting from the corresponding o-nitroanilines 3a,b
as shown in Scheme 1. 3-Methyl-1,3,4,5-tetrahydro-2H-
1,5-benzodiazepin-2-one (5a), lacking a methyl substituent
at C6 (R = H), is a known compound8 and was prepared
from o-nitroaniline (3a) by N-alkylation with methacrylic
acid in the presence of sulfuric acid, followed by reduction
of the nitro group with zinc. 3,6-Dimethyl-1,3,4,5-tetra-
hydro-2H-1,5-benzodiazepin-2-one (5b, R = CH3) with a
methyl substituent at C6 was similarly prepared from 2-
methyl-6-nitroaniline (3b) via 4b. N-Methylation of the lac-
tams 5a,b with methyl iodide, followed by reduction of the
lactam moiety with LiAlH4 in the presence of AlCl3, gave the
corresponding methyl derivatives 7a,b. Mesylation9 of 7a,b
with mesyl chloride in the presence of DMAP in pyridine at
room temperature afforded the 3-mesylated compounds 1
and 2.
1
tures was determined by comparison of the H NMR spec-
trum (CD2Cl2) at 185 K with that of the separated diastereo-
mers A and B of compound 2 (R = CH3) with a methyl group
at C6 on the benzene ring, which is described below. Thus
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–F

C
H. Tabata et al.
Cluster
Synlett
(a) 1H NMR (CD2Cl2)
SO2·CH3
N-CH3
H2a
H2b
H3
A
B
C3-CH3
N
(aR*,3S*)
(aS*,3S*)
axis
6
H4a
H4b
N
SO2CH3
1
H2b
H2a
H3
H4a
H4b
(b) 1H VT NMR (CD2Cl2)
295 K
263
253
243
Tc
233
223
213
203
193
183
A/B=5.3:1
B
A
A
A
B
B
B
A
B
A
A B
Figure 3 1H NMR (CD2Cl2) spectra (a), and VT 1H NMR (CD2Cl2) spectra (b) of 1.
ration at room temperature. Actually, the mesylation prod-
uct 2 was obtained as a mixture of the diastereomers 2A
and 2B, in a ratio of 1:2.6;12 these were separated at room
temperature by column chromatography on silica gel to
afford 2A and 2B as colorless crystals. Both isomers were
subjected to X-ray structural analysis18,20 to reveal that the
tetrahydrodiazepine nuclei of A and B exist in a chair-like
and boat-like form, respectively, and that the C3 methyl
group of both isomers adopts a pseudoequatorial orienta-
tion (Figure 4; 2A, 2B). The 1H NMR spectra of 2A and 2B in
CD2Cl2 are shown in Figure 5 and they reveal that structures
similar to those demonstrated by the X-ray crystal analysis
also exist in solution. Through detailed inspection of the
2D NMR spectra (NOESY, COSY, and HMQC), the methylene
and methine protons were assigned as shown in Figure 5
and the stereochemistries of 2A and 2B in solution were de-
duced to be (aS*,S*) and (aR*,S*), respectively.
Figure 4 X-ray crystal structures of 5-mesyl-1,3-dimethyl-2,3,4,5-tetra-
hydro-1H-1,5-benzodiazepines 1, 2A, and 2B. The crystal structures
with 3S stereochemistry were extracted from the CIF data of the race-
mate.18,20
The diagnostic protons are H4a and H3, with the chemi-
cal shift of H4a of 2A being observed at a lower field
(δ = 4.25 ppm) than that of 2B (δ = 3.4 ppm). The markedly
lower shift in 2A can be explained as due to the H4a atom
being located within the deshielding cone of the sulfonyl
group, whereas the chemical shift of H3 of 2B is observed at
a higher field (δ = 1.6 ppm) compared with that of 2A
(δ = 2.3 ppm). The markedly higher shift in 2B can be ex-
the 1H NMR spectrum of 1 shown in Figure 3a was shown to
correspond to that of the equilibrium state between the
diastereomers 1A and 1B.
As described above, the A and B diastereomers of 2 were
presumed to have a higher stability, permitting their sepa-
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–F

D
H. Tabata et al.
Cluster
Synlett
the lower (convex) side of the boat-like form (7bB). Thus,
the reaction proceeded by following the bold red line in the
bracketed section of Figure 6, affording 2B as the major
product.
N-CH3
C6-CH3
1H NMR (CD2Cl2)
SO2-CH3
H3C O2S
H2a
H3
N
N
ps.eq.
C3-CH3
To estimate the activation free-energy barrier to rota-
tion (ΔG‡) between the diastereomers 2A and 2B,12 inter-
conversion of the separated diastereomers was examined at
37 °C in toluene. The isomerization profile in Figure 7
shows that, upon heating, both isomers reach an equilibri-
um state in a ratio of 2A/2B = 1.9:1. From this ratio, the
energy difference (ΔG) between 2A and 2B is estimated to
be 1.6 kJ/mol,10 whereas the ΔG‡ values calculated from the
isomerization profile are 104 kJ/mol (from 2A to 2B) and
101 kJ/mol (from 2B to 2A),13 giving a ΔG value of 3 kJ/mol,
which suggests an equilibrium ratio of 3.4:1.10
3
6
H4a
H2b
H4b
2A
H4a
H2a
H4b
2b
H3
H
1H NMR (CD2Cl2)
H3
N-CH3
C6-CH3
SO2-CH3
ps.eq.
H2a
3
6
C3-CH3
N
H4a
N
H2b
2B
H4b
H3C SO2
ΔG‡
N
N
H4a H4b
H2b
H2a
H3
S*
S*
104 kJ/mol
aS*
aR*
N
N
101 kJ/mol
S
S
O
O
Figure 5 1H NMR (CD2Cl2) spectra of diastereomers 2A and 2B
O
O
equilibrium ratio
2A:2B = 1.9:1
2A
2B
plained as due to H3 being located over the fused benzene
ring.
2A
2B
100
80
60
40
20
0
Interestingly, the ratio of 2A to 2B was reversed by
mesylation at elevated temperatures or on heating of the
crude product mixture of 2A and 2B (e.g., at 100 °C in tolu-
ene) to afford 2A in preference to 2B (Figure 6). These re-
sults indicate that the mesylation of 7b proceeds by a kinet-
ically controlled reaction to form 2B in preference to 2A,
but the isomer 2A is the thermodynamically more stable
than 2B. The preferred approach of the mesyl chloride to
the diazepine ring of 7b, in which the chair-like form 7bA
and boat-like form 7bB are in equilibrium, is presumed to
be from the sterically less hindered side. In these forms
(7bA and 7bB), the sterically less hindered side is evidently
2A
2B
37 °C
37 °C
20
40
(%)
(%)
60
80
0
100
0
1
2
3
4
5
6
7
8
9
(h)
Figure 7 Interconversion between the diastereomers 2A and 2B at
37 °C in toluene
CH3SO2Cl
H3CSO2
H
H
N
N
S*
3
ps.eq.
minor
N
N
aS*
3
6
H
H
6
2A
H
MsCl
DMAP
chair-like
H
major
chair-like
Pyridine
rt, 6 h
N
1
7bA
3
2A
heat
ca. 2
1
6
thermodynamic
concave
N
H
H
66%
2.6
3
6
H
N
7b
S*
ps.eq.
2B
6
H
H
HN
N
3
minor
boat-like
aR*
H
major
convex
N
boat-like
7bB
H3CSO2
2B
kinetic
CH3SO2Cl
from less hindered side
Figure 6 N-Mesylation of 3,5,7-trimethyl-1,5-benzodiazepine (7b); mesylation of 7b proceeds preferentially from the convex side of 7bB (boat-like
form) to form 2B predominantly.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–F

E
H. Tabata et al.
Cluster
Synlett
For comparison, the ΔG value between the atropisomer-
ic diastereomers A and B was also estimated by density
functional theory (DFT) calculations.14 Fourteen conform-
ers for 2 were generated, starting from 2D chemical struc-
tures, among which the lowest-energy conformer was 2A
(aS*, S*) and the second-lowest was 2B (aR*, S*). The struc-
tures for A and B obtained by calculation are in good agree-
ment with the X-ray structures. Accurate analyses of the
stabilities at the RB3LYP/6-31+G(d,p) level were performed
both in the gas phase and in solution (toluene) at 310 K,
revealing that the calculated ΔG values for 2A versus 2B are
4.98 and 2.37 kJ/mol, respectively; these data correspond to
equilibrium ratios of 6.9:1and 2.5:1,10 respectively. It is in-
teresting to note that the ΔG values obtained in solution are
smaller than those in the gas phase,15 and that the data in
solution have similar values to those obtained experimen-
tally as described above.
In summary, the N-mesylation reaction of the 1,3-di-
methyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine nucleus,
especially the effects of C3 central chirality on this reaction,
has been clarified. Diastereomers A and B of the 5-mesyl-
1,3-dimethyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepines 1
and 2, originating from the chirality at C3 and the Ar–N(SO2)
axis, were formed, among which the isomers of 2 (R = CH3)
could be separated as stable forms at room temperature.
Accompanied by rotation around the Ar–N(SO2) axis, the
1,3-dimethyl-1,5-diazepine ring adopts chair-like and boat-
like conformations A and B, respectively, in which the C3
methyl group is in a pseudoequatorial arrangement. Fur-
thermore, structures A and B were shown to be the thermo-
dynamically and kinetically controlled products, respec-
tively. The knowledge regarding the conformation of 5-
mesyl-1,3-dimethyl-1,5-benzodiazepines obtained here
provides useful information, not only for sulfonamide
chemistry, but also for future drug design. Currently, con-
formations of 1,3-dimethyl-2,3,4,5-tetrahydro-1H-1,5-benzo-
diazepines with 5-benzoyl and 5-tosyl groups are also
being examined, and the application of the results to the
synthesis of biologically active compounds is underway.
These results will be reported later.
References and Notes
(1) New address: H. Natsugari, Faculty of Pharmaceutical Sciences,
The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 112-
0033, Japan.
(2) For recent review articles on seven-membered-ring heterocy-
cles, see: (a) Ryan, J. H.; Hyland, C.; Meyer, A. G.; Smith, J. A.;
Yin, J.-X. Prog. Heterocycl. Chem. 2012, 24, 493. (b) Ramig, K. Tet-
rahedron 2013, 69, 10783.
(3) For recent review articles on the relationship between atrop-
isomerism and biological activity, see: (a) Clayden, J.; Moran,
W. J.; Edwards, P. J.; LaPlante, S. R. Angew. Chem. Int. Ed. 2009,
48, 6398. (b) LaPlante, S. R.; Edwards, P. J.; Fader, L. D.; Jakalian,
A.; Hucke, O. ChemMedChem 2011, 6, 505. (c) LaPlante, S. R.;
Fader, L. D.; Fandrick, K. R.; Fandrick, D. R.; Hucke, O.; Kemper,
R.; Miller, S. P. F.; Edwards, P. J. J. Med. Chem. 2011, 54, 7005.
(d) Zask, A.; Murphy, J.; Ellestad, G. A. Chirality 2013, 25, 265.
(e) Kumarasamy, E.; Raghunathan, R.; Sibi, M. P.; Sivaguru, J.
Chem. Rev. 2015, 115, 11239.
(4) (a) Lee, S.; Kamide, T.; Tabata, H.; Takahashi, H.; Shiro, M.;
Natsugari, H. Bioorg. Med. Chem. 2008, 16, 9519. (b) Tabata, H.;
Akiba, K.; Lee, S.; Takahashi, H.; Natsugari, H. Org. Lett. 2008, 10,
4871. (c) Tabata, H.; Suzuki, H.; Akiba, K.; Takahashi, H.;
Natsugari, H. J. Org. Chem. 2010, 75, 5984. (d) Tabata, H.;
Nakagomi, J.; Morizono, D.; Oshitari, T.; Takahashi, H.;
Natsugari, H. Angew. Chem. Int. Ed. 2011, 50, 3075. (e) Tabata,
H.; Wada, N.; Takada, Y.; Nakagomi, J.; Miike, T.; Shirahase, H.;
Oshitari, T.; Takahashi, H.; Natsugari, H. Chem. Eur. J. 2012, 18,
1572. (f) Tabata, H.; Yoneda, T.; Oshitari, T.; Takahashi, H.;
Natsugari, H. J. Org. Chem. 2013, 78, 6264. (g) Yoneda, T.; Tabata,
H.; Nakagomi, J.; Tasaka, T.; Oshitari, T.; Takahashi, H.;
Natsugari, H. J. Org. Chem. 2014, 79, 5717. (h) Yoneda, T.; Tabata,
H.; Tasaka, T.; Oshitari, T.; Takahashi, H.; Natsugari, H. J. Med.
Chem. 2015, 58, 3268. (i) Tabata, H.; Yoneda, T.; Ito, S.; Tasaka, T.;
Oshitari, T.; Takahashi, H.; Natsugari, H. J. Org. Chem. 2016, 81,
3136. (j) Tabata, H.; Yoneda, T.; Oshitari, T.; Takahashi, H.;
Natsugari, H. J. Med. Chem. 2017, 60, 4503.
(5) The terms aS and aR (chiral axis nomenclature) correspond to P
and M (helix nomenclature), respectively.
(6) For examples of sulfonamide compounds [biological activity (a
and b) and chemistry] see: (a) Watanabe, M.; Koike, H.; Ishiba,
T.; Okada, T.; Seo, S.; Hirai, K. Bioorg. Med. Chem. 1997, 5, 437.
(b) Nishida, H.; Hasuoka, A.; Arikawa, Y.; Kurasawa, O.; Hirase,
K.; Inatomi, N.; Hori, Y.; Sato, F.; Tarui, N.; Imanishi, A.; Kondo,
M.; Takagi, T.; Kajino, M. Bioorg. Med. Chem. 2012, 20, 3925.
(c) Parkin, A.; Collins, A.; Gilmore, C. J.; Wilson, C. C. Acta Crys-
tallogr., Sect. B 2008, 64, 66.
(7) For recent publications from the Merck group on N-sulfonyl
derivatives of pyrido- and benzo-fused tricyclic diazepine (MK-
7725) as a bombesin receptor subtype 3 agonist in which atrop-
isomerism was first disclosed as an interesting unusual chiral-
ity: see (a) Welch, C. J.; Gong, X.; Schafer, W. A.; Chobanian, H.
R.; Lin, L. S.; Biba, M.; Liu, P.; Guo, Y.; Beard, A. Chirality 2009,
21, 105. (b) Liu, P.; Lanza, T. J. Jr.; Chioda, M.; Jones, C.;
Chobanian, H. R.; Guo, Y.; Chang, L.; Kelly, T. M.; Kan, Y.; Palyha,
O.; Guan, X.-M.; Marsh, D. J.; Metzger, J. M.; Ramsay, K.; Wang,
S.-P.; Strack, A. M.; Miller, R.; Pang, J.; Lyons, K.; Dragovic, J.;
Ning, J. G.; Schafer, W. A.; Welch, C. J.; Gong, X.; Gao, Y.-D.;
Hornak, V.; Ball, R. G.; Tsou, N.; Reitman, M. L.; Wyvratt, M. J.;
Nargund, R. P.; Lin, L. S. ACS Med. Chem. Lett. 2011, 2, 933.
(c) Chobanian, H. R.; Guo, Y.; Liu, P.; Lanza, T. J. Jr.; Chioda, M.;
Chang, L.; Kelly, T. M.; Kan, Y.; Palyha, O.; Guan, X.-M.; Marsh, D.
J.; Metzger, J. M.; Raustad, K.; Wang, S.-P.; Strack, A. M.; Gorski,
Funding Information
This work was supported in part by Grants-in-Aid for Scientific
Research (C) (25460154 and 16K08326) and a Grant-in-Aid for Young
Scientists (B) (25860091) from the Japan Society for the Promotion of
Science. H.T. thanks the MEXT-Supported Program for the Strategic
Research Foundation at Private Universities (2013–2017) for financial
support.
)(
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0037-1609868.
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© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–F

F
H. Tabata et al.
Cluster
Synlett
J. N.; Miller, R.; Pang, J.; Lyons, K.; Dragovic, J.; Ning, J. G.;
Schafer, W. A.; Welch, C. J.; Gong, X.; Gao, Y.-D.; Hornak, V.;
Reitman, M. L.; Nargund, R. P.; Lin, L. S. Bioorg. Med. Chem. 2012,
20, 2845.
2.41 (dd, J = 12.1, 14.0 Hz, 1 H), 2.86 (s, 3 H), 2.92 (s, 3 H), 3.04
(ddd, J = 1.6, 3.6, 13.3 Hz, 1 H), 4.25 (ddd, J = 1.6, 3.5, 14.0 Hz, 1
H), 6.92 (d, J = 7.8 Hz, 1 H), 6.94 (d, J = 7.8 Hz, 1 H), 7.18 (dd,
J = 7.8, 7.8 Hz, 1 H). 13C NMR (150 MHz, CDCl3): δ = 19.0, 34.3,
34.9, 39.3, 50.3, 120.5, 129.1, 129.4, 130.1, 142.0, 143.2, 170.8.
HRMS (ESI): m/z [M + H]+ calcd for C13H21N2O2S: 269.1318;
found: 269.1319.
(8) Cohen, V. I.; Jin, B.; Reba, R. C. J. Heterocycl. Chem. 1993, 30, 835.
(9) Note that, according to nomenclature rules, the atom number-
ing for 5–7 differs from for 1 and 2.
(10) Estimated from the Boltzmann equation.
(aR*,3S*)-5-Mesyl-1,3,6-trimethyl-2,3,4,5-tetrahydro-1H-
1,5-benzodiazepine (2B)
(11) For determination of ΔG‡ values by VT NMR, see: Boiadjiev, S.
E.; Lightner, D. A. Tetrahedron 2002, 58, 7411.
Colorless crystals; yield: 9.4 mg (18.3%); mp 127–130 °C; TLC:
Rf = 0.31 [silica gel, 25% EtOAc–hexane]. IR (ATR): 2876, 1324
(12) Although compound 2B is the major product in the mesylation
reaction at r.t. for 6 h in pyridine, the ratio of 2A/2B (1:2.6)
might not reflect the exact product ratio of the reaction
because, presumably, 2B was partially converted into 2A during
the reaction.
cm–1 1H NMR (600 MHz, CD2Cl2): δ = 0.92 (d, J = 6.7 Hz, 3 H),
.
1.59–1.66 (m, 1 H), 2.34 (s, 3 H), 2.65 (ddd, J = 1.5, 4.0, 10.9 Hz, 1
H), 2.75 (s, 3 H), 2.89 (s, 3 H), 2.91 (dd, J = 10.9, 12.4 Hz, 1 H),
3.40 (dd, J = 11.9, 12.4 Hz, 1 H), 3.47 (ddd, J = 1.5, 4.2, 12.4 Hz, 1
H), 6.80 (d, J = 7.8 Hz, 1 H), 6.89 (d, J = 7.7 Hz, 1 H), 7.18 (dd,
J = 7.7, 7.8 Hz, 1 H). 13C NMR (150 MHz, CDCl3): δ = 15.3, 18.3,
30.0, 37.8, 39.8, 52.1, 60.6, 123.7, 128.5, 140.5, 147.5, 155.5.
HRMS (ESI): m/z [M + H]+ calcd for C13H21N2O2S: 269.1318;
found: 269.1319.
(13) For determination of ΔG‡ values, see: Petit, M.; Lapierre, A. J. B.;
Curran, D. P. J. Am. Chem. Soc. 2005, 127, 14994.
(14) For detailed computational studies on 2A/2B, see the Support-
ing Information.
(15) A similar tendency was reported in the conformational analysis
of methyl (S)-lactate by DFT calculations in the gas phase and
solution (methanol); see: (a) Foresman, J. B.; Frisch, Æ. Exploring
Chemistry with Electronic Structure Methods; Gaussian Inc:
Wallingford, 2015. The SMD solvation model was used to
predict the free energy in solution; see: (b) Marenich, A. V.;
Cramer, C. J.; Truhlar, D. G. J. Phys. Chem. B 2009, 113, 6378.
(16) For general experimental methods, see the Supporting Informa-
tion.
(18) Crystal Data for 1, 2A, and 2B
All measurements were made on a RIGAKU RAXIS RAPID
imaging-plate area detector with graphite monochromated
Cu Kα radiation. The data were collected at a temperature of
–100 °C. The structure was solved by the SIR92 direct method
and expanded by using Fourier techniques. The nonhydrogen
atoms were refined anisotropically. All calculations were per-
formed by using the CrystalStructure crystallographic software
package except for the refinement, which was performed by
using SHELXL97 (See Ref. 19).
(17) 5-Mesyl-1,3-Dimethyl-2,3,4,5-tetrahydro-1H-1,5-benzodiaz-
epine (1)
DMAP (21 mg, 0.17 mmol) and MsCl (0.13 mL, 1.72 mmol) were
added to a stirred solution of 7a (61 mg, 0.35 mmol) in pyridine
(3.5 mL) at 0 °C under argon. The mixture was stirred at 25 °C
for 18 h and then the solvent was evaporated at 25 °C. H2O (6.0
mL) and EtOAc (10 mL) were added to the residue, and the
mixture was extracted with EtOAc (10 × 3 mL). The extracts
were t washed with water, dried, and concentrated. The concen-
trate was purified by column chromatography [silica gel,
EtOAc–hexane (1:5)] to give colorless crystals; yield: 68 mg
Crystal data of 1 (see Ref. 20): C12H18N2O2S; mp 92–94 °C,
Mr = 254.35, Cu Kα (λ = 1.54187 Å), monoclinic, P21/n, colorless
prism: 0.25 × 0.20 × 0.05 mm, crystal dimensions: a = 7.83330(14)
Å, b = 9.04486(16) Å, c = 18.1712(3) Å, β = 91.5053(10)°, T = 173
K, Z = 4, V = 1287.01(4) Å3, Dcalc = 1.313 g/cm3, μCu Kα = 21.802
cm–1
, F000 = 544.00, GOF = 1.063, Rint = 0.0376, R1 = 0.0389,
wR2 = 0.1016.
Crystal data of 2A (see Ref. 20): C13H20N2O2S: mp 133–135 °C,
Mr = 268.37, Cu Kα (λ = 1.54187 Å), monoclinic, P21/n, colorless
prism: 0.40 × 0.35 × 0.20 mm, crystal dimensions: a = 8.38672(15)
Å, b = 8.82991(16) Å, c = 18.4671(4) Å, β = 92.8791(13)°, T = 173
K, Z = 4, V = 1365.84(4) Å3, Dcalc = 1.305 g/cm3, μCu Kα = 20.811
(78%); mp 92–94 °C. IR (ATR): 2897, 1327 cm–1 1H NMR (600
.
MHz, CD2Cl2): δ = 0.86 (d, J = 6.6 Hz, 3 H), 2.15 (br s, 1 H), 2.51
(br s, 1 H), 2.74–2.90 (m, 1 H), 2.85 (s, 3 H), 2.88 (s, 3 H), 2.97–
2.99 (m, 1 H), 4.08 (br s, 1 H), 6.98–7.02 (m, 2 H), 7.26–7.30 (m,
1 H), 7.41 (dd, J = 1.0, 7.7 Hz, 1 H). 13C NMR (150 MHz, CDCl3):
δ = 15.6, 32.9, 40.0, 42.5, 54.0, 62.1, 117.9, 122.2, 129.2, 131.3,
cm–1
, F000 = 576.00, GOF = 1.014, Rint = 0.0410, R1 = 0.0348,
wR2 = 0.0906.
Crystal data of 2B (see Ref. 20): C13H20N2O2S: mp 127–130 °C,
Mr = 268.37, Cu Kα (λ = 1.54187 Å), triclinic, P-1, colorless
prism: 0.35 × 0.20 × 0.08 mm, crystal dimensions a = 8.33(4) Å,
b = 8.71(6) Å, c = 9.82(5) Å, α = 96.87(11)°, β = 106.76(8)°, γ =
94.85(14)°, T = 173 K, Z = 4, V = 672(7) Å3, Dcalc = 1.325 g/cm3,
μCu Kα = 21.137 cm–1, F000 = 288.00, GOF = 0.950, Rint = 0.1560,
R1 = 0.0719, wR2 = 0.1790.
131.9. HRMS (ESI): m/z [M
+
H]+ calcd for C12H19N2O2S:
255.1162; found: 255.1164.
5-Mesyl-1,3,6-trimethyl-2,3,4,5-tetrahydro-1H-1,5-benzodi-
azepine (2)
In a similar manner to the synthesis of 1 from 7a described
above, compound 2 was prepared from 7b, except that the reac-
tion was conducted for 6 h at 25 °C instead of 18 h at 25 °C and
gave separable diastereomers of 2 (2A and 2B) in a ratio of 1:2.6
in 66% yield. These diastereomers were separated by column
chromatography [silica gel, EtOAc–hexane (1:5)].
(19) Sheldrick, G. M. SHELX97 [Includes SHELXS97, SHELXL97 and
CIFTAB]: Programs for Crystal Structure Analysis (Release 97-2);
Institüt für Anorganische Chemie der Universität: Göttingen,
1998.
(aS*,3S*)-5-Mesyl-1,3,6-trimethyl-2,3,4,5-tetrahydro-1H-
1,5-benzodiazepine (2A)
(20) CCDC 1837601, 1837602 and 1837601 contain the supplemen-
tary crystallographic data for compounds 1, 2A, and 2B, respec-
tively. The data can be obtained free of charge from The
Colorless crystals; yield: 24.5 mg (47.7%); mp 133–135 °C; TLC:
Rf = 0.38 (silica gel, 25% EtOAc–hexane). IR (ATR): 2892, 1322
Cambridge
Crystallographic
Data
Centre
via
cm–1 1H NMR (600 MHz, CD2Cl2): δ = 0.77 (d, J = 6.3 Hz, 3 H),
.
www.ccdc.cam.ac.uk/getstructures.
2.25 (dd, J = 10.9, 13.3 Hz, 1 H), 2.35–2.40 (m, 1 H), 2.37 (s, 3 H),
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–F