Rethinking Hydrolytic Imidazoline Ring Expansion: A Common Approach to the Preparation of Medium-Sized Rings via Side-Chain Insertion into [1.4]Oxa- and [1.4]Thiazepinone Scaffolds

Article abstract of DOI:10.1021/acs.joc.8b02805

The previously reported ring-expansion strategy involving hydrolytically prone imidazoline rings was thought to include the formation of a hydrated imidazoline intermediate. In this work, we accessed the latter via the addition of a 2-aminoethyl side chain onto a lactam moiety. This led to an efficient three-atom ring expansion of diarene-fused [1.4]oxazepines and [1.4]thiazepines and led us to propose to term this common approach the hydrated imidazoline ring expansion (HIRE) reaction. The strategy was extended to the insertion of longer (containing up to five atoms) side chains, and thus, larger (11- to 12-membered) diarene-fused rings were obtained via the homo-HIRE and homo²-HIRE reactions, respectively. This underscores the utility of the HIRE reaction for the preparation of medium-sized rings, an important class of chemical tools for interrogation of various biological targets.

Full text of DOI:10.1021/acs.joc.8b02805

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Featured Article
Re-thinking Hydrolytic Imidazoline Ring Expansion: A Common
Approach to the Preparation of Medium-Sized Rings via Side
Chain Insertion into [1.4]Oxa- and [1.4]Thiazepinone Scaffold
Elena Reutskaya, Angelina Osipyan, Alexander Sapegin, Alexander S. Novikov, and Mikhail Krasavin
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b02805 • Publication Date (Web): 19 Dec 2018
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Re-thinking Hydrolytic Imidazoline Ring Expansion: A Common Approach
to the Preparation of Medium-Sized Rings via Side Chain Insertion into
[1.4]Oxa- and [1.4]Thiazepinone Scaffold
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§
Elena Reutskaya, Angelina Osipyan, Alexander Sapegin, Alexander S. Novikov, and Mikhail
Krasavin*
Saint Petersburg State University, Saint Petersburg 199034, Russian Federation
NHBoc
( )n
NH2
( )n
H N
2
O
O
N
1
Z
OH
LG1
LG2
Z
R1
R1
R2
X
Y
XH
Y
W
R2
W
0% aq. NaOH
MeOH, r. t.
HN
O
( )n
HO
HN
O
( )n
H
HN
Z
H
N
Z
R1
R2
R1
X
Y
W
R2
X
Y
W
2
1 examples
X = O, S, SO2
Hydrated Imidazoline
Ring Expansion (HIRE)
n = 1, 2, 3
ABSTRACT: The earlier reported ring expansion strategy involving hydrolytically prone
imidazoline rings was thought to include the formation of a hydrated imidazoline intermediate.
In this work, we accessed the latter via the addition of a 2-aminoethyl side chain onto a lactam
moiety. This led to an efficient three-atom ring expansion of diarene-fused [1.4]oxazepines and
[1.4]thiazepines and led us to propose to term this common approach the hydrated imidazoline
ring expansion (HIRE) reaction. The strategy was extended to the insertion of longer (containing
up to 5 atoms) side chains and thus larger (11- to 12-membered) diarene-fused rings were
2
obtained via the homo-HIRE and homo -HIRE reactions, respectively. This underscores the
utility of the HIRE reaction for the preparation of medium-sized rings, an important class of
chemical tools for interrogation of various biological targets.
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6
INTRODUCTION
Today, small molecules based on medium-sized (8-to-14-membered) cyclic scaffolds are
recognized preferred tools for interrogation of biological targets, owing to the optimal balance
between conformational rigidity and flexibility present in them, which ultimately enables them to
0
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0
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0
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0
1
adopt a unique bioactive conformation. Medium-sized rings are particularly useful as a small-
2
molecule platform for lead generation against poorly druggable targets. Unfortunately, medium-
sized ring systems are notoriously difficult to prepare via synthesis (due to unfavorable entropy
associated with the ring closing in this case and increased enthalpy present in such systems due
3
do destabilizing transannular interactions ) and hence are severely underrepresented in today’s
4
compound collections intended for biological screening. The more productive (compared to ring
closing approach) synthetic strategies based on expansion of smaller rings can, in principle,
change the current situation for the better and thus are subject of increased dedicated research
efforts in recent years. These strategies broadly fall into one of the following two
(mechanistically interrelated) categories: (A) cleavage of a central bond in a fused bicyclic
system and (B) insertion of a reactive side chain into a smaller cycle. In both cases a larger ring
is formed whose size is the sum of atoms initially present in the two fused rings of in the smaller
ring and the side chain (Figure 1).5
Figure 1. Schematic representation of two principal ring expansion strategies.5
X
(A)
A
B
Y
XH
YH
A
B
HX
(B)
A
B
Y
Recently, we described a ring expansion strategy involving nucleophilic addition of hydroxide
anion to an imidazoline moiety (activated by N-alkylation) in diarene-fused [1.4]oxazepines (1)6
7
or [1.4]thiazepines (2) leading to rare, medium-sized [1,4,7]oxazecines 3 and [1,4,7]thiazecines
4, respectively. Such a ring expansion strategy clearly belongs to type A (Figure 1) as it
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presumably involves the breaking of the central bond in putative intermediate 5 through which
the ring expansion process is thought to proceed. Initially, we termed this approach “hydrolytic
imidazoline ring expansion”.6-7 However, herein we propose to switch to a more general
designation of this methodology from the mechanistic standpoint, namely, by calling it
1
1
1
1
1
1
1
1
1
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9
0
8
“
hydrated imidazoline ring expansion (HIRE)”. We reasoned that the same putative hydrated
imidazoline intermediate 5 can be formed via a possible side chain insertion process involving
precursor 6, which, if successful, would lead to type B ring expansion strategy thereby uniting
the two methodological approaches within the same mechanistic framework (Figure 2). We were
particularly motivated to investigate such a complementary methodology as we anticipated it to
potentially allow involving longer side-chains in a homologous HIRE process which would lead
to the formation of 11-membered rings and larger. Previously, we were not able to test the same
possibility via the hydration of homologs of 1 and 2 as the latter could not be synthesized. In
9
principle, expansion of -lactam rings via the insertion of -aminoalkyl side chains as well as
synthesis of rings as large as 53-membered using the so-called ‘zip reaction’ employing a
1
0
polyamine side chain sequential insertion was documented in the literature. However, in the
absence of a specific driving force (such as relief of the ring strain) similar reactions either
yielded an equilibrium mixture of ring-expanded product and starting material11 or did not
proceed at all.12 In our case, expulsion of the less nucleophilic anilinic amino group was
expected to drive the reaction forward via an irreversible formation of 3-4. Herein, we report our
progress in investigating the unified hydrated imidazoline ring expansion (HIRE) process, as
described above, and its application to the preparation of 10-membered rings. We also
demonstrate the scope and limitations of this methodology with respect to the insertion of longer
x
side chains (“homo -HIRE”).
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5
6
Figure 2. Alternative approaches to the formation of hydrated imidazoline intermediate 5 and
the net result of the unified HIRE reaction.
Earlier work:
R
R
R
N
X
N
X
O
N
HO
H O
NH
0
1
2
3
4
5
6
7
8
9
0
1
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9
0
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0
1
2
3
4
5
6
7
8
9
0
N
N
H
HO
(Het)
Ar
(Het)
Ar
X
(
Het)
(Het)
Ar
(Het)
Ar
(Het)
Ar
Ar
1, X = O
5
3, X = O
2, X = S(O)n
4, X = S(O)n
n = 0, 1, 2
n = 0, 1, 2
HN R
Alternative approach
(this work):
O
N
(Het)
Ar
(Het)
Ar
X
6
RESULTS AND DISCUSSION
The principal substrate type investigated in this work was related to 6, i. e. it possessed -
aminoalkyl side chains of various lengths (from 2 to 5 carbon atoms) where 2-aminoethyl side
chain was envisioned to be eventually involved in the formation of the putative hydrated
imidazoline intermediate 5 while the longer side chains were introduced to test the scope and
limitations of the homologous versions of the HIRE approach. To this end, we activated various
(hetero)aromatic carboxylic acids 7a-e (bearing a hydroxy or sulfhydryl groups in ortho-
position) as respective imidazolides and coupled them to a series of diamines mono-protected
1
3
with a Boc group (8a-d). The amides 9a-j thus obtained were introduced in the reaction with a
range of bis-electrophilic aromatic substrates 10. The latter underwent, in the presence of K CO
2
3
and at temperatures ranging from ambient to 80 ºC depending on the reactivity of 10, a double
nucleophilic aromatic substitution reaction accompanied by an intermittent Smiles rearrangement
1
4
(
which defines the regiochemical result of the overall ring-forming process) to give diarene-
fused [1.4]oxazepines 11a-l and [1.4]thiazepines 12a-h in good to excellent yields (Scheme 1,
Table 1).
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Scheme 1. Preparation of diarene-fused [1.4]oxazepines 11a-l and [1.4]thiazepines 12a-h
bearing a Boc-protected -aminoalkyl side chain.
NHBoc
O
O
NHBoc
H N
( )n
2
(
)n
OH
XH
8a-d (n = 1-4)
N
R1
R1
H
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
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5
5
5
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0
1
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6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
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9
0
1
2
3
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5
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7
8
9
0
1
2
3
4
5
6
7
8
9
0
CDI, DCM or
,4-dioxane
Y
Y
XH
9a-j
K CO
1
7a-e
LG1
LG2
Z
2
3
R2
o
DMF, T( C)
time (h)
W
10
NHBoc
( )n
NHBoc
O
O
X
N
( )n
Z
Z
N
R1
R1
Y
R2
X
R2
Y
W
LG2
W
1
1
1a-l (X = O)
2a-h (X = S)
Table 1. Diarene-fused [1.4]oxazepines 11a-l and [1.4]thiazepines 12a-h prepared in this work.
Compound
Cyclocondensation
product 11 or 12
Time
(h)
T
(ºC)
Yield
(%)
Entry
1
Compound 9
1
0
NHBoc
O
Cl
O N
2
N
11a
12
12
12
RT
RT
50
89
82
98
O
NO2
NO2
NHBoc
Cl
NHBoc
O
O
O
Cl
Br
N
N
11b
N
2
3
N
H
OH
9a
O
CF3
Cl
CF3
NHBoc
N
N
11c
N
O
NO2
NO2
NHBoc
NHBoc
O
O
Cl
Cl
N
N
N
11d
N
N
4
5
16
12
80
49
54
H
9
b
OH
O
N
CH3
CH3
NHBoc
NHBoc
11e
O
Cl
N
O
Cl
N
N
H
RT
N
9
c
Cl
OH
O N
2
O
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5
5
5
5
5
5
5
6
NHBoc
11f
Cl
O
O N
2
N
6
7
8
12
12
12
RT
50
50
87
84
97
O
NO2
NO2
NHBoc
Cl
0
1
2
3
4
5
6
7
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9
0
1
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0
1
2
3
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9
0
O
Cl
11g
N
N
N
NHBoc
O
CF3
O
CF3
NHBoc
N
H
OH
Cl
O
Br
9d
11h
N
N
N
O
NO2
CN
NO2
NHBoc
O
F
CN
9
18
12
50
60
86
N
11i
Cl
O
BocHN
Cl
O N
2
O
11j
N
1
0
RT
BocHN
O
NO2
Cl
O
NO2
BocHN
N
H
OH
9e
Br
O
N
N
11k
11
12
50
92
N
NO2
O
NO2
NHBoc
BocHN
O
N
Cl
Cl
N
N
O
11l
1
1
2
3
16
5
80
81
83
N
N
H
9f
O
OH
N
NHBoc
Cl
O
O N
2
N
12a
RT
NHBoc
O
S
NO2
N
NO2
N
H
NHBoc
9g
SH
Cl
O
12b
N
1
4
18
50
39
N
O N
2
S
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NHBoc
2c
CN
O
1
N
1
5
3
RT
86
O N
2
S
Cl
CN
NHBoc
NHBoc
Cl
N
O
1
2d
O
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
N
1
1
6
7
12
24
50
64
40
N
N
N
O N
2
H
9
h
S
SH
NHBoc
O
Cl
N
N
RT
12e
O N
2
S
N
N
NHBoc
Cl
NHBoc
O
O N
2
N
12f
O
1
8
8
RT
89
N
S
H
SO NMe
2
2
SO NMe2
2
9
i
N
SH
NHBoc
Cl
O
O N
2
N
12g
1
2
9
0
12
18
RT
50
70
49
S
N
CF3
CF3
BocHN
O
BocHN
Cl
N
O
N
12h
N
N
H
O N
2
9j
SH
S
Additionally, we synthesized sulfoxide (13) and sulfone (14) substrates for further testing in the
ring expansion process, by oxidation of compound 12a with m-CPBA and NaIO /RuCl (cat.),
4
3
respectively (Scheme 2).
Scheme 2. Oxidation of compound 12a.
NHBoc
NHBoc
NO2
NHBoc
NO2
O
O
NaIO4
O
m-CPBA
N
N
N
cat. RuCl3
(3 equiv.)
o
H2O/CCl4
rt, 18 h
S
S
S
DCM, 0 C
NO2
O O
O
4
h
1
3, 71%
12a
14, 63%
Having prepared the diverse set of starting materials for potential hydrated imidazoline ring
expansion (HIRE) reactions and its homologous variants, we proceeded to identify the optimal
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2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
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4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
workable conditions to conduct this process. To this end, the Boc protecting group in 11a was
removed (by treatment with 4M solution of HCl in 1,4-dioxane), the resulting hydrochloride salt
1
5a was isolated by simple filtration and used in the ring expansion reactions under a range of
conditions which included the variation of the base (thought to promote the scission of the
0
1
2
3
4
5
6
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9
0
1
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7
central bond in the putative hydrated imidazoline intermediate 16a ), its quantity as well as
solvent system (Table 2).
Table 2. Optimization studies for the HIRE reaction of 15a prepared from 11a.
O
R
B:
H
HN
O
O
NH
H
N
conditions
N
O
NH
O
O
NO2
NO2
1
1a, R = NHBoc
O N
2
4
M HCl in
1,4-dioxane
16a
17a
+
5a, R = NH Cl
3
-
1
rt, 18 h
#
of base
equiv.
Reaction
time (h)
Entry
Solvent system
Base
Yield (%)
a
1
2
3
4
5
6
7
8
9
NaOH
LiOH
K CO
1
1
2
18
4
68
66
62
30
58
43
62
41
62
64
65
68
44
48
45
48
48
50
16
H O-MeOH (1:1)
4.0
4.0
2
2
3
b
Et N
3
H O-MeCN (1:1)
2
b
H O-THF (1:1)
24
2
NaOH
H O-DMF (1:1)
5
18
24
6
3
3
2
2
4
8
2
H O-acetone (1:1)
2
1.0
1.5
2.0
3.0
1
1
0
1
H O-MeOH (1:1) NaOH
2
12
13
H O-MeOH (3:1)
2
1
1
1
4
5
6
H O-MeOH (2:1)
2
H O-MeOH (1:2)
2
H O-MeOH (1:3) NaOH
3.0
2
17
18
H O-MeOH (1:4)
24
48
72
2
H O-MeOH (1:5)
2
1
9
MeOH
a
b
Time to maximum conversion (by TLC analysis).
Reaction was run at 50 ºC.
To our delight, the ring-expanded product which we had expected to arise via the formation of
intermediate 16a, was indeed isolated in all cases studied (this was particularly reassuring since
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previously, we were not able to trigger the hydration of imidazoline substrates to form
6-7
intermediate such as 16a without activating the imidazoline by N-alkylation ). In principle, the
use of the base was not critical for achieving the full conversion of the reaction: by using only 1
equiv. of NaOH (which will only liberate the primary amino group from the salt form) a yield
comparable (62%, entry 9) to the optimum yield (68%, entries 1 or 12) was obtained. However,
employing additional equivalents of base (up to 3.0) significantly accelerated the reaction (very
much in line with the likely participation of the base in the evolution of intermediate 16a). Other
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
inorganic bases gave comparable results while using Et N led to poorer yield and longer reaction
3
time (entry 4). The outcome of the reaction was not sensitive to the concentration of the base
(data not shown) but was strongly dependent on the solvent system. Particularly noteworthy is
the importance of using 1:1 MeOH-H O mixture and the rapid decrease in both the yield and the
2
rate of conversion on going from 25% to 20% H O in MeOH and to pure MeOH (Table 1,
2
entries 16-19). Overall, the optimal conditions subsequently employed in all HIRE reactions and
their homologous variants described below were identified as using 3.0 equiv. of NaOH in
MeOH-H O (1:1) as 10 wt. % solution, ambient temperature.
2
These conditions were applied to other N-aminoethyl-substituted 7-membered lactams prepared
by Boc group removal from compounds 11a-e, 12a-c and 13-14 (Scheme 3). The yields of ten-
membered lactams 17 were generally good except for sulfoxide 17i which was not detected in
the complex product mixture obtained after exposing 13 to the same reaction conditions.
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1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Scheme 3. The HIRE reaction of primary amines generated from compounds 11a-e, 12a-c, 13-
1
4.
O
X
NHBoc
1) 4M HCl in
1,4-dioxane, rt, 18 h
NH
R1
O
N
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Z
NH
R1
2) NaOH (3 equiv.)
W
X
R2
MeOH-H O (1:1)
W
2
Z
rt, 3 h
R2
1
1a-e, 12a-c, 13-14
17a-j
O
O
O
O
O
NH
NH
NH
NH
O
O
O
NH
NH
NH
NH
N
N
N
N
F3C
O N
2
O N
2
7a, 68%a
17b, 60%a
17c, 67%
17d, 42%a
1
O
O
O
O
Cl
NH
NH
S
NH
S
NH
O
S
NH
NH
NH
NH
N
N
O N
2
NC
1
7e, 67%a
17f, 65%
17g, 44%
17h, 42%
O
O
NH
S
NH
S
O
O
O
NH
NH
O N
2
O N
2
17i, 0%
17j
, 67%
a
Structure confirmed by single-crystal X-ray analysis.
Encouraged by the successful realization of our strategy to re-construct the hydrated imidazoline
intermediate we postulated earlier6-7 in the hydrolytic imidazoline ring expansion (and thus
arriving at a unified hydrated imidazoline ring expansion process), we were keen to explore the
homologous variants of the three-atom side-chain substrates under the same conditions.
Previously, we were not able to achieve such a ring expansion process for cyclic amidines larger
than imidazoline due to our inability to prepare the respective substrates. With the current ‘-
aminoalkyl side chain’ approach, we reasoned, these ‘homologous imidazolines’ would be also
formed, already in the hydrated form, and would be rapidly evolved into respective ring-
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expanded products. To our delight, this proved to be true. While the respective homologous
x
hydrated imidazoline ring expansion (‘homo -HIRE’) reactions were markedly slower and took
2
4-36 h to complete, the respective 11- and 12-lactams were successfully obtained from the
2
respective homo-HIRE and homo -HIRE reactions in moderate to good yields. Unfortunately,
the same process envisioned for the 6-atom side chain (present in the compound obtained after
Boc group removal from 11l) was not effective, thus defining applicability of the present
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
methodology to 3- to 5-atom lactam ring expansion (Scheme 4).
Scheme 4. Deprotection of substrates 11f-11l, 12d-12h and subsequent homo-HIRE, homo2-
3
HIRE and attempted homo -HIRE reactions (for n = 2, 3 and 4, respectively).
O
NHBoc
1
) 4M HCl in
1,4-dioxane, rt, 18 h
NH
O
( )n
R1
N
Y
X
( )n
Z
NH
2) NaOH (3 equiv.)
R1
W
X
MeOH-H O (1:1)
Y
W
R2
2
Z
rt, 24 h (n = 2) or
36 h (n = 3)
R2
1
1f-11l, 12d-12h
1
7k-v
homo-HIRE:
O
O
O
O
NH
NH
NH
NH
O
O
O
O
NH
NH
NH
CN
NH
F3C
O N
2
O N
2
N
N
17k, 54%
7l, 69%a
17m
, 54%
17n, 70%a
1
O
O
O
O
NH
NH
NH
NH
N
N
S
N
S
S
N
S
N
NH
NH
NH
NH
Me NO S
F3C
2
2
17q, 63%
17r, 69%
17p, 26%
17o, 38%
2
3
homo -HIRE:
O
homo -HIRE:
O
O
O
O
N
N
H
N
H
N
H
H
O
S
O
H
NH
NH
NH
N
N
N
N
N
O N
2
O N
2
17s, 49%
17t, 22%
17u, 23%
17v, 0%
a
Structure confirmed by single-crystal X-ray analysis.
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1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
We further reasoned that elaboration of primary -aminoalkyl side chain (present in substrates
obtained by deprotection of compounds 11-14) into a secondary one should not preclude such
x
systems from undergoing a (homo -)HIRE process. The latter was envisioned to furnish ring-
expanded lactam products containing an additional substituent (potentially useful as a periphery
diversity element for medicinal chemistry optimization).
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Scheme 5. Preparation of N-substituted (homo-)HIRE lactam products 18a-f via reductive
alkylation.
1
2
3
) 4M HCl in
,4-dioxane, rt, 18 h
) Na CO
1
2
3
O
X
o
DCM/H O, 0 C
2
NHBoc
2
R2
) R CHO, toluene
N
Z
O
( )n
p-TsOH, reflux, 48 h
N
( )n
NH
Z
4) NaBH , THF/MeOH
4
X
R1
o
0 C, 3 h
R1
5) K CO (3 equiv.)
2
3
1
1b, 11g, 11i, 12d
18a-f
MeOH/H O, rt, 2-24 h
2
O
N
O
N
O
N
N
O
O
O
NH
NH
NH
N
F3C
N
F3C
F3C
N
18a, 27%
18b, 39%
18c, 42%
OMe
O
O
N
O
OMe
N
OMe
N
S
O
O
S
NH
NH
NH
N
CN
18d, 29%
CN
18e, 33%
18f, 38%
We tested and confirmed this possibility for compounds 11b, 11g, 11i and 12d. Without
intermittent purification, these compounds were subjected to Boc group removal, Schiff base
formation (which, surprisingly, turned out to be particularly sluggish in this case), reduction of
the latter with sodium borohydride and triggering the (homo-)HIRE event. The latter, again, was
found to be markedly slower for the formation of 11-membered lactams 18b-f compared to their
1
0-membered counterpart 18a (24 h vs. 2 h to achieve a complete conversion, respectively). The
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target compounds 18a-f were isolated in 27-42% yields, which we consider rather efficient
taking into account the number chemical events involved in this syntheses (Scheme 5).
x
Aiming to better understand the structural factors influencing the rate of the (homo -)HIRE
process, we compared the initial rates of conversion observed UV-spectrophotometrically for the
HIRE reactions (performed in solutions 1000-fold more dilute compared to the preparative
reactions described above) for five similarly substituted substrates (generated by deprotection of
11a, 11f, 11j, 12a and 14).
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
x
Figure 3. Comparative initial rates of conversion for (homo -)HIRE substrates obtained by
deprotection of 11a, 11f, 11j, 12a and 14.
BocHN
NHBoc
NHBoc
1f
NHBoc
NHBoc
O
O
O
O
O
N
11a
N
1
N
12a
N
14
11j
N
O
S
S
O O
O
NO2
O
NO2
NO2
NO2
NO2
As it is evident form the data plotted in Figure 3, the rates of conversion were virtually
insensitive to the nature of the linker atom (group) between the two aromatic rings (cf.
deprotected 11a, 12a and 14). This finding is contrast to our earlier observations made for the
7
hydrolytic imidazoline ring expansion reaction and suggests that the electrophilicity of the
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1
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1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
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3
3
3
3
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5
5
5
5
5
5
6
lactam carbonyl carbon atom (which is influenced by the nature of the X group, being in direct
conjugation with it) in present case has no significant bearing on the rate of reaction. On the
contrary, what does have a substantial effect on the reaction rate is the length of the side chain
(cf. significant slowing of the conversion for deprotected 11a11f11j).
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
x
Figure 4. Energy diagram for the (homo )-HIRE reaction proceeding via the formation of
hydrated imidazoline and its homologs.
B3LYP/6-31G* level of theory
G, kcal/mol
HI
25
24.0 (n = 3)
1.0 (n = 2)
20.4 (n = 1)
2
20
15
10
5
0
5
-
3.6 (n = 1)
5.0 (n = 2)
SM
-
-
-6.7 (n = 3)
-10
P
NH2
HN
HO
HN
n
n
O
O
n
N
HN
O
N
O
O
NO2
NO2
NO2
Hydrated
imidazoline (HI)
n = 1 (16a)
n = 2 (homo-16a)
n = 3 (homo -16a)
Product (P)
n = 1 (17a)
n = 2 (homo-17k)
Starting material (SM)
n = 1 (deBoc-11a)
n = 2 (deBoc-11f)
n = 3 (deBoc-11j)
2
2
n = 3 (homo -17s)
Theoretical calculations performed at the B3LYP/6-31G* theory level confirmed that elongation
of the side chain in deprotected starting material (11a11f11j) led to a substantial increase of
x
the energy level of the respective hydrated imidazoline intermediate and its homologs ((homo )-
1
6a). Increase entropy loss associated with the formation of the latter is the likely reason for the
observed reactivity trend (also corroborated by the energy calculations) rather than the relative
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energy levels of the reactions products which were calculated to decrease in the same order
(17a17k17s). The energy diagram summarizing the results of the theoretical calculations is
presented in Figure 4. Interestingly, in this case, calculations gave more reliable results
compared to the M06-2X/6-31G* theory level (Tables S3-S4). The computational results and the
resulting conclusions obtained in present work are similar to those described in two recent
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
5
16
conceptually related publications by Yudin and Unsworth on ring expansion (also using the
B3LYP/6-31G* theory level calculations). Additionally, the ring expansions described in this
paper are also related to other methodologies recently described by Unsworth and co-workers.17
The intermediacy of the hydrated imidazoline and its homologs in the reactions described herein
suggests that if these reactions are conducted in aprotic, dehydrating medium in the absence of
base, the hydrated imidazoline can be dehydrated to form stable imidazoline product. This was
indeed observed for deprotected compounds 11a and 12a on reflux in toluene with azeotropic
6
7
removal of water (Scheme 6). Interestingly, that previously described compounds 19a and 19b
need to be activated by N-alkylation in order to form the hydrated imidazoline intermediate and,
as the result, undergo the HIRE process, as we observed earlier.6-7
Scheme 6. Formation of imidazolines 19a-b from deprotected 11a and 12a under dehydrative
conditions.
1) 4M HCl in
NHBoc
NO2
1,4-dioxane, rt, 18 h
N
O
2
) Na CO
2
3
N
N
o
DCM/H O, 0 C
2
X
X
3) toluene, reflux, 48 h
NO2
19a, X = O, 60%
9b, X = S, 54%
11a, X = O
1
12a, X = S
CONCLUSION
In summary, we have presented a novel ring expansion strategy involving insertion of an -
aminoalkyl side chain in [1.4]oxazepinone and [1.4]thiazepinone nucleus. The reaction of 2-
aminoethyl derivatives is thought to proceed via a hydrated imidazoline intermediate and thus
has a common mechanistic foundation with the earlier described expansion of imidazoline rings
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1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
activated by alkylation. We therefore propose to term this common ring expansion approach the
hydrated imidazoline ring expansion or HIRE. This methodology was found applicable to
insertion of longer side chains (up to 5 atoms) and thus can also furnish 11- to 12-membered
x
medium-sized rings via a “homo -HIRE” approach. The HIRE reaction itself was found to be
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
markedly faster compared to its homologous variant which, according to theoretical calculations
of the respective energy profiles, has to do with the least entropy loss associated with the
formation of hydrated imidazoline among its homologs. The new approach to the construction of
medium-sized cycles will add significantly to the modern arsenal of methods to assemble such
rings. The development of common mechanistic view on the ring expansion process will
significantly facilitate our ongoing quest for yet unexplored opportunities for three-atom ring
expansion via the HIRE reaction. The results of these studies will be reported as they become
available.
EXPERIMENTAL SECTION
1
General. NMR spectroscopic data were recorded with a 400 spectrometer (400.13 MHz for H
13
and 100.61 MHz for C) in DMSO-d or in CDCl and were referenced to residual solvent
6
3
signals (δ = 2.50, 7.26 ppm respectively) and solvent carbon signals (δ = 39.52, 77.00 ppm
H
C
respectively). Mass spectra were recorded on microTOF spectrometers (ESI ionization). Melting
points were determined in open capillary tubes on Stuart SMP50 Melting Point Apparatus.
Single crystal X-ray data were obtained using an Agilent Technologies SuperNova Atlas and an
Agilent Technologies Xcalibur Eos diffractometers at a temperature of 100 K.
Spectrophotometric measurements were performed on a UV-1800 Shimadzu double beam
spectrophotometer (Japan) using 10.00 mm quartz cells. Column chromatography was carried
out with silica gel grade 60 (0.040–0.063 mm) 230–400 mesh. HPLC preparative
chromatography was performed with Agilent PrepHT XDB-C18 preparative cartridge 21.2x150
mm 5-micron. All commercial reagents and solvents were used without further purification,
unless otherwise noted. DMF for the synthesis was distilled over CaH and stored under nitrogen
2
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o
over freshly activated molecular sieves 4Å. Potassium carbonate was dried at 200 C for 5 hours
prior to use.
General Procedure for the Preparation of Amides 9a-j
To a suspension of 7 (35 mmol) in CH Cl (9a-f) or 1,4-dioxane (9g-j) (25 mL) CDI (5.83 g, 36
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
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7
8
9
0
1
2
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6
7
8
9
0
2
2
mmol) was added. The mixture was stirred at room temperature for 1.5-2 h. Mono-Boc-protected
diaminoalkane 8 (35 mmol) was added at 0 ˚C. The resulting mixture was stirred at 0 ºC for 2 h
and then at room temperature overnight. The reaction mixture was washed with sat. aq. K CO
2
3
(3×20 mL), water, dried over Na SO and concentrated under reduced pressure. Compounds 9a,
2
4
9
e, 9f were purified by column chromatography. Compounds 9h-i were crystallized from EtOAc.
All other compounds were sufficiently pure to be used in the step without further purification.
tert-Butyl (2-(2-hydroxybenzamido)ethyl)carbamate (9a)
1
Yield 6.48 g, 66%; white solid; mp 75-78 ˚C. H NMR (400 MHz, CDCl ) δ 12.51 (br s, 1H),
3
7
6
9
.89 – 7.68 (br s, 1H), 7.49 (d, J = 8.0 Hz, 1H), 7.39 (t, J = 8.0 Hz, 1H), 6.98 (d, J = 8.4 Hz, 1H),
.86 (t, J = 8.4 Hz, 1H), 5.04 (s, 1H), 3.56 (td, J = 6.0, 4.6 Hz, 2H), 3.50 – 3.39 (m, 2H), 1.46 (s,
1
3
1
H) ppm. C{ H} NMR (101 MHz, CDCl ) δ 170.6, 161.5, 158.1, 134.0, 126.0, 118.6, 118.3,
3
+
114.2, 80.4, 42.4, 39.5, 28.3(3C) ppm. HRMS (ESI), m/z calcd for C H N NaO [M+Na]
1
4
20
2
4
3
03.1315, found 303.1326.
tert-Butyl (2-(2-hydroxy-3-methylbenzamido)ethyl)carbamate (9b)
1
Yield 5.15 g, 50%; white solid; R (Hexane/EtOAc = 4/1): 0.19; mp 118-120 ˚C. H NMR (400
f
MHz, CDCl ) δ 12.89 – 12.71 (br s, 1H), 7.73 – 7.60 (br s, 1H), 7.34 (d, J = 8.0 Hz, 1H), 7.26 (d,
3
J = 7.3 Hz, 1H), 6.76 (t, J = 7.7 Hz, 1H), 5.13 – 4.96 (br s, 1H), 3.59 – 3.50 (m, 2H), 3.48-3.41
1
3
1
(
m, 2H), 2.28 (s, 3H), 1.46 (s, 9H) ppm. C{ H} NMR (101 MHz, CDCl ) δ 171.0, 160.0,
3
158.0, 134.8, 127.3, 123.4, 117.9, 113.3, 80.4, 42.3, 39.6, 28.3 (3C), 15.7 ppm. HRMS (ESI),
+
m/z calcd for C H N NaO [M+Na] 317.1472, found 317.1471.
1
5
22
2
4
tert-Butyl (2-(5-chloro-2-hydroxybenzamido)ethyl)carbamate (9c)
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5
5
5
6
1
Yield 5.73 g, 42%; white solid; R (Hexane/EtOAc = 2/1): 0.27; mp 159-161 ˚C. H NMR (400
f
MHz, CDCl ) δ 12.57 – 12.36 (br s, 1H), 8.11 – 7.96 (br s, 1H), 7.51 (d, J = 2.5 Hz, 1H), 7.32
3
(
dd, J = 8.9, 2.5 Hz, 1H), 6.92 (d, J = 8.9 Hz, 1H), 5.19 – 5.01 (br s, 1H), 3.58 – 3.50 (m, 2H),
1
3
1
3.50 – 3.41 (m, 2H), 1.48 (s, 9H) ppm. C{ H} NMR (101 MHz, CDCl ) δ 169.4, 160.1, 158.4,
3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
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7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
33.8, 125.7, 123.3, 119.7, 115.1, 80.8, 42.8, 39.3, 28.3(3C) ppm. HRMS (ESI), m/z calcd for
+
C H ClN O [M+H] 315.1106, found 315.1097.
1
4
20
2
4
tert-Butyl (3-(2-hydroxybenzamido)propyl)carbamate (9d)
1
Yield 7.21 g, 70%; white solid; mp 87-90 ˚C. H NMR (400 MHz, CDCl ) δ 12.64 (br s, 1H),
3
7
1
.95 – 7.78 (br s, 1H), 7.59 (d, J = 8.0 Hz, 1H), 7.40 (td, J = 7.2, 1.6 Hz, 1H), 6.99 (dd, J = 8.3,
.3 Hz, 1H), 6.89 (td, J = 7.6, 1.3 Hz, 1H), 4.86 (s, 1H), 3.52 (q, J = 6.1 Hz, 2H), 3.29 (q, J = 6.3
1
3
1
Hz, 2H), 1.78 – 1.68 (m, 2H), 1.49 (s, 9H) ppm. C{ H} NMR (101 MHz, CDCl ) δ 170.1,
3
1
61.6, 157.4, 133.9, 125.9, 118.7, 118.3, 114.5, 79.9, 36.9, 35.4, 30.1, 28.4(3C) ppm. HRMS
+
(
ESI), m/z calcd for C H N NaO [M+Na] 317.1472, found 317.1480.
1
5
22
2
4
tert-Butyl (4-(2-hydroxybenzamido)butyl)carbamate (9e)
Yield 2.91 g, 27%; white solid; R (CH Cl /EtOAc = 9/1): 0.33; mp 100-102 ˚C. H NMR (400
1
f
2
2
MHz, CDCl ) δ 12.65 – 12.47 (br s, 1H), 7.54 (d, J = 7.9 Hz, 1H), 7.39 (td, J = 7.2, 1.6 Hz, 1H),
3
7
3
.18 – 7.04 (br s, 1H), 6.98 (dd, J = 8.3, 1.2 Hz, 1H), 6.83 (td, J = 7.3, 1.2 Hz, 1H), 4.74 (s, 1H),
1
3
.50 (q, J = 6.4 Hz, 2H), 3.18 (q, J = 6.6 Hz, 2H), 1.72 – 1.56 (m, 4H), 1.47 (s, 9H) ppm. C
NMR (101 MHz, CDCl ) δ 170.2, 161.5, 156.4, 134.0, 125.8, 118.5, 118.4, 114.4, 79.4, 39.8,
3
+
3
9.2, 28.4(3С), 27.9, 27.4 ppm. HRMS (ESI), m/z calcd for C H N NaO [M+Na] 331.1628,
1
6
24
2
4
found 331.1635.
tert-Butyl (5-(2-hydroxybenzamido)pentyl)carbamate (9f)
1
Yield 8.38 g, 75%; white solid; mp 105-107 ˚C. H NMR (400 MHz, CDCl ) δ 12.63 – 12.47 (br
3
s, 1H), 7.53 (d, J = 7.4 Hz, 1H), 7.39 (td, J = 7.2, 1.6 Hz, 1H), 6.99 (dd, J = 8.3, 1.2 Hz, 1H),
7
.02 – 6.84 (br s, 1H), 6.88 – 6.82 (m, 1H), 4.69 – 4.57 (br s, 1H), 3.45 (q, J = 6.6 Hz, 2H), 3.15
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9
1
3
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(q, J = 6.4 br Hz, 2H), 1.69-1.59 (m, 2H), 1.53 – 1.35 (m, 13H) ppm. C{ H} NMR (101 MHz,
CDCl ) δ 207.0, 170.0, 161.5, 156.3, 133.9, 125.7, 118.5, 114.6, 79.2, 39.8, 38.9, 30.9, 30.1,
3
+
2
8.4(3C), 25.7 ppm. HRMS (ESI), m/z calcd for C H N NaO [M+Na] 345.1785, found
1
7
26
2
4
345.1788.
1
1
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0
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8
9
0
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7
8
9
0
1
2
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4
5
6
7
8
9
0
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8
9
0
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4
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7
8
9
0
tert-Butyl (2-(2-mercaptobenzamido)ethyl)carbamate (9g)
1
Yield 7.88 g, 76%; white solid; mp 185-188 ˚C. H NMR (400 MHz, DMSO-d ) δ 8.59 (t, J =
6
5
.6 Hz, 1H), 7.68 (d, J = 7.7 Hz, 1H), 7.64 (d, J = 8.1 Hz, 1H), 7.45 (td, J = 7.7, 1.4 Hz, 1H),
7.30 (t, J = 7.4 Hz, 1H), 6.90 (t, J = 5.8 Hz, 1H), 3.32 (q, J = 6.3 Hz, 2H), 3.15 (q, J = 6.3 Hz,
13
1
2
1
H), 1.39 (s, 9H) ppm. C{ H} NMR (101 MHz, DMSO-d ) δ 167.4, 156.2, 137.2, 134.2,
6
31.5, 128.5, 126.3, 126.1, 78.2, 40.4, 39.8, 28.7(3C) ppm. HRMS (ESI), m/z calcd for
+
C H N NaO S [M+Na] 319.1087, found 319.1084.
1
4
20
2
3
tert-Butyl (3-(2-mercaptobenzamido)propyl)carbamate (9h)
1
Yield 5.87 g, 54%; white solid; mp 164-165 ˚C. H NMR (400 MHz, DMSO-d ) δ 8.58 (t, J =
6
5
.7 Hz, 1H), 7.69 – 7.60 (m, 2H), 7.45 (td, J = 7.7, 1.5 Hz, 1H), 7.30 (t, J = 7.4 Hz, 1H), 6.82 (t,
J = 5.9 Hz, 1H), 3.28 (q, J = 6.7 Hz, 2H), 3.02 (q, J = 6.6 Hz, 2H), 1.72 – 1.62 (m, 2H), 1.39 (s,
13
1
9
1
H) ppm. C{ H} NMR (101 MHz, DMSO-d ) δ 167.3, 156.1, 137.1, 134.5, 131.5, 128.3,
6
26.4, 126.2, 78.0, 38.2, 37.5, 30.0, 28.7(3C) ppm. HRMS (ESI), m/z calcd for C H N NaO S
1
5
22
2
3
+
[
M+Na] 333.1243, found 333.1250.
tert-Butyl (3-(2-mercaptonicotinamido)propyl)carbamate (9i)
1
Yield 6.21 g, 57%; yellow solid; mp 125-127 ˚C. H NMR (400 MHz, CDCl ) δ 13.23 – 12.84
3
(
br s, 1H), 10.98 – 10.74 (br s, 1H), 8.81 (dd, J = 7.7, 1.9 Hz, 1H), 7.77 (d, J = 6.1 Hz, 1H), 6.95
(t, J = 7.7 Hz, 1H), 5.19 – 5.07 (br s, 1H), 3.59 (q, J = 6.3 Hz, 2H), 3.27 (q, J = 6.4 Hz, 2H), 1.99
13
1
–
1
1.71 (m, 2H), 1.45 (s, 9H) ppm. C{ H} NMR (101 MHz, CDCl ) δ 174.7, 164.1, 156.2,
3
43.3, 139.3, 133.7, 113.9, 79.1, 37.9, 37.0, 29.8, 28.5(3C) ppm. HRMS (ESI), m/z calcd for
+
C H N O S [M+H] 312.1376, found 312.1380.
14 22
3
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tert-Butyl (4-(2-mercaptobenzamido)butyl)carbamate (9j)
1
Yield 2.95 g, 26%; white solid; mp 193-195 ˚C. H NMR (400 MHz, DMSO-d ) δ 8.59 (t, J =
6
5
.6 Hz, 1H), 7.68 – 7.59 (m, 2H), 7.44 (td, J = 6.2, 1.5 Hz, 1H), 7.29 (td, J = 7.4, 1.2 Hz, 1H),
6.80 (t, J = 5.8 Hz, 1H), 3.27 (q, J = 5.8 Hz, 2H), 2.96 (q, J = 6.4 Hz, 2H), 1.59 – 1.41 (m, 4H),
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
13
1
1
1
.38 (s, 9H) ppm. C{ H} NMR (101 MHz, DMSO-d ) δ 167.2, 156.1, 137.1, 134.6, 131.4,
6
28.3, 126.3, 126.2, 77.8, 40.0, 39.4, 28.8(3C), 27.5, 26.9 ppm. HRMS (ESI), m/z calcd for
+
C H N NaO S [M+Na] 347.1400, found 347.1395.
1
6
24
2
3
General Procedure for Preparation of [1.4]Oxazepinones 11 and [1.4]Thiazepinones 12
To a solution of amide 9 (0.70 mmol) in anhydrous DMF (5 mL) the respective 1,2-dihaloarene
or 1-halo-2-nitroarene 10 (0.70 mmol) and freshly calcinated K CO (290 mg, 2.10 mmol) were
2
3
added. The mixture was stirred the appropriate temperature (Table 1) overnight. DMF was
removed in vacuo and the residue was partitioned between water (5 mL) and CH Cl (5 mL).
2
2
The organic layer was separated, washed with water (3 x 5 mL), dried over anhydrous Na SO ,
2
4
filtered and concentrated in vacuo.
Compounds 11a, 11c, 11d, 11e, 11k, 12c, 12e, 12f were purified by column chromatography.
Compound 11g was crystallized from Hexane/EtOAc = 4/1.
tert-Butyl (2-(7-nitro-11-oxodibenzo[b,f][1,4]oxazepin-10(11H)-yl)ethyl)carbamate (11a)
1
Yield 248.8 mg, 89%; green solid; R (CH Cl /Acetone = 20/1): 0.21; mp 159-161 ˚C. H NMR
f
2
2
(400 MHz, CDCl ) δ 8.15 (d, J = 2.5 Hz, 1H), 8.12 (dd, J = 8.9, 2.5 Hz, 1H), 7.85 (dd, J = 7.7,
3
1
4
.7 Hz, 1H), 7.65 (d, J = 8.6 Hz, 1H), 7.54 (td, J = 7.8, 1.7 Hz, 1H), 7.32 – 7.25 (m, 2H), 5.04 –
1
3
1
.84 (br s, 1H), 4.25 (t, J = 6.6 Hz, 2H), 3.57 (q, J = 6.2 Hz, 2H), 1.40 (s, 9H) ppm. C{ H} (101
MHz, CDCl ) δ 166.1, 159.7, 156.0, 153.5, 145.0, 141.6, 134.3, 132.2, 126.1, 125.9, 123.6,
3
1
21.5, 119.8, 117.5, 79.7, 49.6, 39.0, 28.3(3C) ppm. HRMS (ESI), m/z calcd for C H N NaO
20 21 3 6
+
[
M+Na] 422.1323, found 422.1319.
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tert-Butyl
(2-(10-oxo-3-(trifluoromethyl)benzo[f]pyrido[3,2-b][1,4]oxazepin-11(10H)-
yl)ethyl)carbamate (11b)
1
Yield 243.0 mg, 82%; white solid; mp 106-108 ˚C. H NMR (400 MHz, CDCl ) δ 8.56 (d, J =
3
0.9 Hz, 1H), 7.90 (dd, J = 7.8, 1.6 Hz, 1H), 7.80 (d, J = 1.8 Hz, 1H), 7.54 (td, J = 8.0, 1.6 Hz,
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
5
H), 7.31 (td, J = 7.7, 0.9 Hz, 1H), 7.25 (d, J = 8.1 Hz, 1H), 5.37 – 5.19 (br s, 1H), 4.48 (t, J =
1
3
1
.7 Hz, 2H), 3.60 (q, J = 5.7 Hz, 2H), 1.40 (s, 9H) ppm. C{ H} NMR (101 MHz, CDCl ) δ
3
165.9, 158.8, 155.9, 151.1, 147.7, 141.7 (q, J = 4.1 Hz), 134.3, 132.7, 127.2, 126.2, 125.8, 124.5,
1
22.7 (d, J = 272.5 Hz), 119.5, 79.1, 46.7, 39.8, 28.3(3C) ppm. HRMS (ESI), m/z calcd for
+
C H F N O [M+H] 424.1479, found 424.1486.
2
0
21
3
3
4
tert-Butyl (2-(3-nitro-10-oxobenzo[f]pyrido[3,2-b][1,4]oxazepin-11(10H)-yl)ethyl)carbamate
(11c)
1
Yield 274.7 mg, 98%; yellow solid; R (CH Cl ): 0.18; mp 179-181 ˚C. H NMR (400 MHz,
f
2
2
CDCl ) δ 9.14 (d, J = 2.2 Hz, 1H), 8.35 (d, J = 2.3 Hz, 1H), 7.89 (dd, J = 7.8, 1.4 Hz, 1H), 7.56
3
(td, J = 6.9, 1.4 Hz, 1H), 7.33 (t, J = 7.5 Hz, 1H), 7.28 (d, J = 6.9 Hz, 1H), 5.21 – 5.03 (br s, 1H),
1
3
1
4
.51 (t, J = 5.9 Hz, 2H), 3.59 (q, J = 5.9 Hz, 2H), 1.39 (s, 9H) ppm. C{ H} NMR (101 MHz,
CDCl ) δ 165.7, 158.3, 155.9, 152.9, 147.1, 141.1, 140.5, 134.6, 132.7, 126.4, 125.6, 125.1,
3
+
1
19.6, 79.3, 46.8, 39.5, 28.3(3C) ppm. HRMS (ESI), m/z calcd for C H N NaO [M+Na]
19 20 4 6
423.1275, found 423.1270.
tert-Butyl
(2-(6-methyl-10-oxobenzo[f]pyrazino[2,3-b][1,4]oxazepin-11(10H)-
yl)ethyl)carbamate (11d)
1
Yield 127.1 mg, 49%; white solid; R (CH Cl /EtOAc = 40/1): 0.13; mp 159-161 ˚C. H NMR
f
2
2
(400 MHz, CDCl ) δ 8.31 (d, J = 2.5 Hz, 1H), 8.08 (d, J = 2.5 Hz, 1H), 7.69 (dd, J = 7.8, 1.6 Hz,
3
1
5
H), 7.41 (dd, J = 7.6, 1.5 Hz, 1H), 7.19 (t, J = 7.6 Hz, 1H), 5.29 – 5.01 (br s, 1H), 4.43 (t, J =
1
3
1
.9 Hz, 2H), 3.57 (q, J = 5.8 Hz, 2H), 2.59 (s, 3H), 1.40 (s, 9H) ppm. C{ H} NMR (101 MHz,
CDCl ) δ 166.2, 155.9, 155.1, 153.5, 144.7, 139.9, 137.8, 135.3, 130.4, 129.7, 125.8, 125.7, 79.2,
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+
46.4, 39.6, 28.4(3C), 16.3 ppm. HRMS (ESI), m/z calcd for C H N NaO [M+Na] 393.1533,
1
9
22
4
4
found 393.1540.
tert-Butyl
(2-(8-chloro-10-oxobenzo[f]pyrido[3,2-b][1,4]oxazepin-11(10H)-
yl)ethyl)carbamate (11e)
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
Yield 147.4 mg, 54%; yellow solid; R (Hexane/EtOAc = 2/1): 0.27; mp 159-161 ˚C. H NMR
f
(
400 MHz, CDCl ) δ 8.31 (dd, J = 4.6, 1.5 Hz, 1H), 7.85 (d, J = 2.6 Hz, 1H), 7.58 (dd, J = 7.9,
3
1
.5 Hz, 1H), 7.43 (dd, J = 8.6, 2.6 Hz, 1H), 7.18 – 7.12 (m, 2H), 5.54 (t, J = 5.6 Hz, 1H), 4.41 (t,
1
3
1
J = 5.9 Hz, 2H), 3.59 (q, J = 5.7 Hz, 2H), 1.41 (s, 9H) ppm. C{ H} NMR (101 MHz, CDCl ) δ
3
1
64.9, 157.9, 156.0, 148.5, 147.6, 145.0, 133.6, 132.2, 131.2, 129.8, 127.6, 121.7, 121.0, 79.0,
+
4
6.9, 39.8, 28.4(3C) ppm. HRMS (ESI), m/z calcd for C H ClN NaO [M+Na] 412.1035,
1
9
20
3
4
found 412.1042.
tert-Butyl (3-(7-nitro-11-oxodibenzo[b,f][1,4]oxazepin-10(11H)-yl)propyl)carbamate (11f)
1
Yield 256.3 mg, 87%; yellow solid; mp 129-131 ˚C. H NMR (400 MHz, CDCl ) δ 8.16 (d, J =
3
2
.6 Hz, 1H), 8.10 (dd, J = 9.0, 2.6 Hz, 1H), 7.85 (dd, J = 7.7, 1.8 Hz, 1H), 7.63 – 7.48 (m, 1H),
7.46 (d, J = 9.0 Hz, 1H), 7.33 – 7.24 (m, 2H), 4.91 (br s, 1H), 4.24 (t, J = 7.0 Hz, 2H), 3.34 –
13
1
3
.21 (m, 2H), 2.05 – 1.87 (m, 2H), 1.44 (s, 9H) ppm. C{ H} NMR (101 MHz, CDCl ) δ 166.0,
3
1
59.7, 154.2, 145.0, 140.9, 134.1, 132.2, 126.0(2С), 125.9, 123.2, 121.3, 119.7, 117.1, 77.3,
+
5
3.4, 46.5, 30.9, 28.3(3C) ppm. HRMS (ESI), m/z calcd for C H N NaO [M+Na] 436.1479,
21 23
3
6
found 436.1472.
tert-Butyl
(3-(10-oxo-3-(trifluoromethyl)benzo[f]pyrido[3,2-b][1,4]oxazepin-11(10H)-
yl)propyl)carbamate (11g)
Yield 257.2 mg, 84%; white solid; mp 122-124 ˚C. H NMR (400 MHz, CDCl ) δ 8.56 (s, 1H),
1
3
7
.89 (d, J = 7.1 Hz, 1H), 7.80 (s, 1H), 7.54 (t, J = 7.3 Hz, 1H), 7.31 (t, J = 7.7 Hz, 1H), 7.25 (d, J
8.1 Hz, 1H), 5.23 – 5.07 (br s, 1H), 4.42 (t, J = 6.4 Hz, 2H), 3.24 (q, J = 5.7 Hz, 2H), 2.05 –
=
1
3
1
1
.94 (m, 2H), 1.46 (s, 9H) ppm. C{ H} NMR (101 MHz, CDCl ) δ 165.8, 158.8, 156.0, 151.1,
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147.8, 141.7 (q, J = 4.2 Hz), 134.2, 132.6, 127.2, 126.2, 126.0, 124.4, 122.7 (d, J = 267.7 Hz),
1
19.5, 79.1, 44.4, 37.8, 30.9, 28.4(3С) ppm. HRMS (ESI), m/z calcd for C H F N NaO
21 22 3 3 4
+
[
M+Na] 460.1455, found 460.1461.
tert-Butyl
(3-(3-nitro-10-oxobenzo[f]pyrido[3,2-b][1,4]oxazepin-11(10H)-
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
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0
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0
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7
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0
1
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8
9
0
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4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
yl)propyl)carbamate (11h)
1
Yield 281.4 mg, 97%; yellow solid; mp 141-143 ˚C. H NMR (400 MHz, CDCl ) δ 9.13 (d, J =
3
2
.4 Hz, 1H), 8.35 (d, J = 2.4 Hz, 1H), 7.88 (dd, J = 7.8, 1.7 Hz, 1H), 7.57 (td, J = 7.8, 1.7 Hz,
1H), 7.33 (td, J = 8.1, 1.8 Hz, 1H), 7.28 (d, J = 8.1 Hz, 1H), 5.13 – 4.97 (br s, 1H), 4.43 (t, J =
13
1
6
.8 Hz, 2H), 3.24 (q, J = 6.0 Hz, 2H), 2.07 – 1.97 (m, 2H), 1.46 (s, 9H) ppm. C{ H} NMR (101
MHz, CDCl ) δ 165.6, 158.3, 156.0, 152.9, 147.1, 141.1, 140.6, 134.5, 132.6, 126.4, 125.7,
3
125.1, 119.5, 79.2, 44.8, 37.8, 28.7, 28.4(3C) ppm. HRMS (ESI), m/z calcd for C H N O
6
2
0
23
4
+
[
M+H] 415.1612, found 415.1620.
tert-Butyl (3-(9-cyano-11-oxodibenzo[b,f][1,4]oxazepin-10(11H)-yl)propyl)carbamate (11i)
Yield 165.2 mg, 60%; beige solid; crystallized from 20% ethyl acetate in hexane; mp 172-174
1
˚C. H NMR (400 MHz, CDCl ) δ 7.86 (dd, J = 7.7, 1.5 Hz, 1H), 7.58 – 7.51 (m, 2H), 7.47 (td, J
3
=
8.1, 1.7 Hz, 1H), 7.34 – 7.25 (m, 2H), 7.20 (d, J = 8.1 Hz, 1H), 4.92 (dt, J = 14.0, 6.8 Hz, 1H),
4
1
1
1
4
.91 – 4.83 (br s, 1H), 3.91 – 3.81 (m, 1H), 3.35 – 3.21 (m, 1H), 3.08 (td, J = 12.7, 6.0 Hz, 1H),
1
3
1
.98 – 1.88 (m, 1H), 1.76 – 1.68 (m, 1H), 1.41 (s, 9H) ppm. C{ H} NMR (101 MHz, CDCl ) δ
3
66.4, 160.9, 157.6, 155.8, 137.8, 133.8, 132.2, 131.5, 127.8, 126.6, 126.2, 126.1, 119.7, 116.1,
+
09.8, 79.1, 47.6, 37.3, 28.5, 28.4(3C) ppm. HRMS (ESI), m/z calcd for C H N NaO [M+Na]
2
2
23
3
4
16.1581, found 416.1575.
tert-Butyl (4-(7-nitro-11-oxodibenzo[b,f][1,4]oxazepin-10(11H)-yl)butyl)carbamate (11j)
1
Yield 86% (264.7 mg, 0.62 mmol); yellow solid; mp 101-105 ˚C. H NMR (400 MHz, CDCl ) δ
3
8
.16 (d, J = 2.5 Hz, 1H), 8.11 (dd, J = 9.0, 2.5 Hz, 1H), 7.86 (dd, J = 7.8, 1.6 Hz, 1H), 7.53 (td, J
=
7.9, 1.7 Hz, 1H), 7.45 (d, J = 8.9 Hz, 1H), 7.34 – 7.25 (m, 1H), 4.71 – 4.46 (br s, 1H), 4.19 (t, J
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5
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= 7.2 Hz, 2H), 3.25 – 3.07 (m, 2H), 1.88 – 1.75 (m, 2H), 1.67 – 1.53 (m, 2H), 1.44 (s, 9H) ppm.
13
1
C{ H} NMR (101 MHz, CDCl ) δ 165.7, 159.7, 155.9, 154.0, 144.9, 141.1, 134.0, 132.3,
3
1
26.0(2С), 123.34, 121.2, 119.6, 117.7, 79.2, 53.4, 48.7, 28.3, 27.3, 25.1(3C) ppm. HRMS (ESI),
+
m/z calcd for C H N NaO [M+Na] 450.1636, found 450.1632.
2
2
25
3
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
tert-Butyl
yl)butyl)carbamate (11k)
(4-(3-nitro-10-oxobenzo[f]pyrido[3,2-b][1,4]oxazepin-11(10H)-
1
Yield 275.9 mg, 92%; yellow solid; mp 115-118˚C. H NMR (400 MHz, CDCl ) δ 9.12 (d, J =
3
2.4 Hz, 1H), 8.32 (d, J = 2.4 Hz, 1H), 7.87 (dd, J = 7.8, 1.6 Hz, 1H), 7.54 (td, J = 8.0, 1.6 Hz,
1
2
H), 7.30 (t, J = 8.0 Hz, 1H), 7.25 (d, J = 7.2 Hz, 1H), 4.80 – 4.65 (br s, 1H), 4.39 – 4.28 (m,
H), 3.18 (q, J = 6.0 Hz, 2H), 1.94 – 1.77 (m, 2H), 1.68 – 1.49 (m, 2H), 1.43 (s, 9H) ppm.
1
3
1
C{ H} NMR (101 MHz, CDCl ) δ 165.2, 158.3, 155.9, 153.0, 146.9, 141.9, 140.6, 134.4,
3
1
32.7, 126.4, 125.7, 125.0, 119.5, 79.1, 46.9, 40.0, 28.4(3C), 27.3, 25.4 ppm. HRMS (ESI), m/z
+
calcd for C H N O [M+H] 429.1769, found 429.1773.
2
1
25
4
6
tert-Butyl
(5-(10-oxobenzo[f]pyrazino[2,3-b][1,4]oxazepin-11(10H)-yl)pentyl)carbamate
(11l)
1
Yield 226.8 mg, 81%; pink solid; mp 83-86 ˚C. H NMR (400 MHz, CDCl ) δ 8.33 (d, J = 2.4
3
Hz, 1H), 8.07 (d, J = 2.4 Hz, 1H), 7.94 – 7.87 (m, 1H), 7.57 – 7.51 (m, 1H), 7.37 (d, J = 8.0 Hz,
1
H), 7.34 – 7.27 (m, 1H), 4.54 (br s, 1H), 4.33 – 4.24 (m, 2H), 3.15 – 3.07 (m, 2H), 1.88 – 1.63
1
3
1
(
m, 2H), 1.53 – 1.32 (m, 13H) ppm. C{ H} NMR (101 MHz, CDCl ) δ 165.1, 156.8, 156.0,
3
1
2
53.4, 144.4, 140.2, 137.6, 134.1, 132.3, 126.1, 125.8, 120.5, 79.0, 46.8, 40.5, 28.4(3C), 28.0,
+
6.6, 26.4 ppm. HRMS (ESI), m/z calcd for C H N NaO [M+Na] 421.1846, found 421.1849.
21 26
4
4
tert-Butyl (2-(7-nitro-11-oxodibenzo[b,f][1,4]thiazepin-10(11H)-yl)ethyl)carbamate (12a)
1
Yield 241.4 mg, 83%; yellow solid; mp 125-127 ˚C. H NMR (400 MHz, CDCl ) δ 8.50 (d, J =
3
2
7
.6 Hz, 1H), 8.19 (dd, J = 8.9, 2.6 Hz, 1H), 7.73 – 7.66 (m, 1H), 7.56 (d, J = 8.9 Hz, 1H), 7.53 –
.48 (m, 1H), 7.41 – 7.35 (m, 2H), 4.99 (t, J = 6.3 Hz, 1H), 4.66 (dt, J = 13.3, 5.2 Hz, 1H), 3.98
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9
1
3
1
(dt, J = 13.8, 6.7 Hz, 1H), 3.62 – 3.37 (m, 2H), 1.32 (s, 9H) ppm. C{ H} NMR (101 MHz,
CDCl ) δ 168.3, 155.7, 149.7, 144.7, 137.4, 137.2, 137.1, 131.5 (2C), 131.2, 129.3, 128.2, 126.4,
3
+
1
24.9, 79.4, 51.4, 39.2, 28.2(3C) ppm. HRMS (ESI), m/z calcd for C H N NaO S [M+Na]
20 21 3 5
438.1094, found 438.1095.
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1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
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0
1
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5
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7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
tert-Butyl (2-(10-oxobenzo[f]pyrido[3,2-b][1,4]thiazepin-11(10H)-yl)ethyl)carbamate (12b)
1
Yield 101.4 mg, 39%; yellow solid; mp 159-161 ˚C. H NMR (400 MHz, CDCl ) δ 8.43 (dd, J =
3
4
.7, 1.8 Hz, 1H), 7.93 (dd, J = 7.6, 1.8 Hz, 1H), 7.74 – 7.68 (m, 1H), 7.48 – 7.43 (m, 1H), 7.39 –
7.33 (m, 2H), 7.10 (dd, J = 7.6, 4.7 Hz, 1H), 5.57 – 5.41 (br s, 1H), 4.53 (dt, J = 13.7, 5.5 Hz,
13
1
1
H), 4.40 (dt, J = 13.6, 5.8 Hz, 1H), 3.61 – 3.46 (m, 2H), 1.39 (s, 9H) ppm. C{ H} NMR (101
MHz, CDCl ) δ 168.7, 155.9, 148.8, 141.8, 138.1, 137.1, 131.8, 131.2(2C), 130.7, 130.1, 129.0,
3
+
121.4, 78.9, 48.6, 39.6, 28.4(3C) ppm. HRMS (ESI), m/z calcd for C H N NaO S [M+Na]
1
9
21
3
3
3
94.1196, found 394.1202.
tert-Butyl (2-(7-cyano-11-oxodibenzo[b,f][1,4]thiazepin-10(11H)-yl)ethyl)carbamate (12c)
1
Yield 238.1 mg, 86%; yellow solid; R (CH Cl /EtOAc = 4/1): 0.25; mp 159-161 ˚C. H NMR
f
2
2
(400 MHz, CDCl ) δ 7.93 (d, J = 2.0 Hz, 1H), 7.75 – 7.68 (m, 1H), 7.63 (dd, J = 8.4, 2.0 Hz,
3
1
1
H), 7.53 – 7.45 (m, 2H), 7.42 – 7.34 (m, 2H), 5.09 – 4.91 (br s, 1H), 4.64 (dt, J = 13.6, 5.1 Hz,
1
3
1
H), 3.95 (dt, J = 14.0, 6.6 Hz, 1H), 3.59 – 3.47 (m, 2H), 1.34 (s, 9H) ppm. C{ H} NMR (101
MHz, CDCl ) δ 168.4, 155.7, 148.2, 137.5, 137.3, 137.2, 136.7, 133.4, 131.6, 131.5, 131.2,
3
1
29.3, 126.7, 117.2, 110.2, 79.5, 51.4, 39.2, 28.3(3C) ppm. HRMS (ESI), m/z calcd for
+
C H N NaO S [M+Na] 418.1196, found 418.1201.
2
1
21
3
3
tert-Butyl
(3-(10-oxobenzo[f]pyrido[3,2-b][1,4]thiazepin-11(10H)-yl)propyl)carbamate
(12d)
1
Yield 172.7 mg, 64%; yellow solid; mp 159-161 ˚C. H NMR (400 MHz, CDCl ) δ 8.43 (dd, J =
3
4
.7, 1.8 Hz, 1H), 7.93 (dd, J = 7.7, 1.8 Hz, 1H), 7.69 (dd, J = 7.3, 2.0 Hz, 1H), 7.45 (dd, J = 7.2,
.8 Hz, 1H), 7.47 – 7.29 (m, 2H), 7.09 (dd, J = 7.7, 4.7 Hz, 1H), 4.62 – 4.34 (m, 2H), 3.43 – 3.13
1
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5
5
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6
1
3
1
(m, 2H), 2.01 – 1.69 (m, 2H), 1.45 (s, 9H) ppm. C{ H} NMR (101 MHz, CDCl ) δ 169.0,
3
1
56.0, 155.5, 148.8, 141.9, 138.4, 137.2, 131.5, 131.1, 130.7, 130.6, 129.0, 121.3, 78.9, 45.7,
+
3
7.5, 28.6, 28.5(3C) ppm. HRMS (ESI), m/z calcd for C H N NaO S [M+Na] 408.1352,
2
0
23
3
3
found 408.1344.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
tert-Butyl
(3-(10-oxodipyrido[3,2-b:3',2'-f][1,4]thiazepin-11(10H)-yl)propyl)carbamate
(12e)
1
Yield 108.2 mg, 40%; yellow solid; R (CH Cl /EtOAc = 4/1): 0.25; mp 159-161 ˚C. H NMR
f
2
2
(400 MHz, CDCl ) δ 8.49 – 8.38 (m, 2H), 8.02 – 7.96 (m, 2H), 7.30 (dd, J = 7.8, 4.8 Hz, 1H),
3
7
.13 (dd, J = 7.7, 4.7 Hz, 1H), 5.18 (d, J = 6.4 Hz, 1H), 4.58 – 4.32 (m, 2H), 3.40 – 3.09 (m, 2H),
1
3
1
1
.96 – 1.67 (m, 2H), 1.41 (s, 9H) ppm. C{ H} NMR (101 MHz, CDCl ) δ 167.0, 157.1, 155.9,
3
154.6, 151.1, 149.2, 142.9, 140.0, 134.3, 127.8, 123.8, 121.8, 78.9, 45.8, 41.1, 37.6, 28.4(3C)
+
ppm. HRMS (ESI), m/z calcd for C H N NaO S [M+Na] 409.1305, found 409.1301.
1
9
22
4
3
tert-Butyl (3-(9-(N,N-dimethylsulfamoyl)-5-oxobenzo[b]pyrido[3,2-f][1,4]thiazepin-6(5H)-
yl)propyl)carbamate (12f)
1
Yield 306.9 mg, 89%; yellow solid; R (CH Cl /EtOAc = 4/1): 0.21; mp 159-161 ˚C. H NMR
f
2
2
(
400 MHz, CDCl ) δ 8.50 (dd, J = 4.8, 1.9 Hz, 1H), 8.14 (d, J = 2.1 Hz, 1H), 8.01 (dd, J = 7.8,
3
1
1
1
.8 Hz, 1H), 7.79 (dd, J = 8.5, 2.1 Hz, 1H), 7.56 (d, J = 8.5 Hz, 1H), 7.34 (dd, J = 7.8, 4.8 Hz,
H), 5.03 – 4.84 (br s, 1H), 4.79 (dt, J = 14.4, 7.4 Hz, 1H), 3.84 – 3.74 (m, 1H), 3.41 – 3.25 (m,
H), 3.28 – 3.14 (m, 1H), 2.77 (s, 6H), 2.04 – 1.81 (m, 1H), 1.77 (dt, J = 13.6, 6.6 Hz, 1H), 1.44
1
3
1
(
s, 9H) ppm. C{ H} NMR (101 MHz, CDCl ) δ 167.0, 157.6, 156.0, 151.3, 146.1, 139.9,
3
1
35.0, 134.8, 133.8, 133.4, 129.3, 126.1, 123.9, 79.3, 48.7, 37.8(2C), 37.7, 28.6, 28.4(3C) ppm.
+
HRMS (ESI), m/z calcd for C H N NaO S [M+Na] 515.1393, found 515.1393.
2
2
28
4
5 2
tert-Butyl
(3-(5-oxo-9-(trifluoromethyl)benzo[b]pyrido[3,2-f][1,4]thiazepin-6(5H)-
yl)propyl)carbamate (12g)
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9
1
Yield 222.2 mg, 70%; yellow solid; mp 159-161 ˚C. H NMR (400 MHz, CDCl ) δ 8.49 (dd, J =
3
4
1
.8, 1.8 Hz, 1H), 8.05 – 7.97 (m, 2H), 7.64 (dd, J = 8.4, 2.3 Hz, 1H), 7.53 (dd, J = 8.4, 1.0 Hz,
H), 7.33 (dd, J = 7.8, 4.8 Hz, 1H), 5.07 – 4.86 (br s, 1H), 4.93 – 4.77 (m, 1H), 3.79 – 3.64 (m,
1H), 3.35 (q, J = 8.2, 7.4 Hz, 1H), 3.28 – 3.01 (m, 1H), 1.90 (dt, J = 13.9, 7.2 Hz, 1H), 1.80 –
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
13
1
1
1
.67 (m, 1H), 1.43 (s, 9H) ppm. C{ H} NMR (101 MHz, CDCl ) δ 167.1, 157.9, 155.9, 151.1,
3
45.4, 139.8, 134.8, 133.9, 131.5 (q, J = 3.7 Hz), 129.2, 127.1, 126.0, 123.9, 123.0 (d, J = 272.6
Hz), 79.2, 77.2, 48.4, 37.6, 28.4(3C) ppm. HRMS (ESI), m/z calcd for C H F N NaO S
2
1
22
3
3
3
+
[
M+Na] 476.1226, found 476.1221.
tert-Butyl (4-(10-oxobenzo[f]pyrido[3,2-b][1,4]thiazepin-11(10H)-yl)butyl)carbamate (12h)
1
Yield 137.0 mg, 49%; yellow solid; mp 159-161 ˚C. H NMR (400 MHz, CDCl ) δ 8.43 (dd, J =
3
4.7, 1.9 Hz, 1H), 7.91 (dd, J = 7.7, 1.8 Hz, 1H), 7.75 – 7.66 (m, 1H), 7.48 – 7.40 (m, 1H), 7.47 –
7
.21 (m, 2H), 7.07 (dd, J = 7.7, 4.7 Hz, 1H), 4.77 – 4.62 (br s, 1H), 4.49 (dt, J = 14.3, 7.3 Hz,
H), 4.27 (dt, J = 13.5, 6.9 Hz, 1H), 3.14 (q, J = 6.6 Hz, 2H), 1.80 – 1.68 (m, 2H), 1.64 – 1.55
1
1
3
1
(
m, 2H), 1.44 (s, 9H) ppm. C{ H} NMR (101 MHz, CDCl ) δ 168.3, 155.9, 148.8, 141.7,
3
1
38.4, 137.2, 131.8, 131.0, 130.6, 130.3, 128.9(2C), 121.2, 48.2, 40.2, 28.4(3C), 28.0, 27.3, 25.7
+
ppm. HRMS (ESI), m/z calcd for C H N NaO S [M+Na] 422.1509, found 422.1503.
2
1
25
3
3
Preparation of tert-Butyl (2-(7-nitro-5-oxido-11-oxodibenzo[b,f][1,4]thiazepin-10(11H)-
yl)ethyl)carbamate 13
To a solution of thiazepine 12a (278.0 mg, 0.67 mmol) in CH Cl (10 mL) m-CPBA (289.4 mg,
2
2
1
.68 mmol) was added at 0°C. This solution was stirred for 4 hours at room temperature. After
completion of the reaction, the mixture was concentrated in vacuo, diluted with Et O (3 ml). The
2
crystals formed were filtered and dried in air afford desired product 13.
1
Yield 205.3 mg, 71%; yellow solid; mp 141-143 ˚C. H NMR (400 MHz, DMSO-d6) δ 8.34 (dd,
J = 8.8, 2.7 Hz, 1H), 8.27 (d, J = 2.6 Hz, 1H), 7.93 (d, J = 8.7 Hz, 1H), 7.81 – 7.67 (m, 3H), 7.60
(
td, J = 7.5, 1.5 Hz, 1H), 6.97 (t, J = 5.9 Hz, 1H), 4.76 – 4.58 (m, 1H), 3.95 – 3.81 (m, 1H), 3.31
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– 3.10 (m, 2H), 1.29 (s, 9H) ppm. C{ H} NMR (101 MHz, DMSO-d6) δ 164.5, 155.9, 147.2,
1
2
46.9, 146.1, 141.3, 133.1, 131.7, 131.5, 129.3, 128.6, 128.1, 126.6, 119.5, 78.3, 49.3, 38.5,
+
8.5(3C) ppm. HRMS (ESI), m/z calcd for C H N NaO S [M+Na] 454.1043, found 454.1047.
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0
21
3
6
Preparation of tert-Butyl (2-(7-nitro-5,5-dioxido-11-oxodibenzo[b,f][1,4]thiazepin-10(11H)-
0
1
2
3
4
5
6
7
8
9
0
1
2
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7
8
9
0
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8
9
0
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9
0
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8
9
0
yl)ethyl)carbamate 14
To a stirred solution of thiazepine 12a (299.5 mg, 0.720 mmol) in a mixture of carbon
tetrachloride (4 mL), acetonitrile (4 mL), and water (8 mL), NaIO (462 mg, 2.160 mmol) was
4
added. Once all of the NaIO had dissolved, RuCl (0.4 mg, 0.036 mmol) was added, and the
4
3
reaction mixture was stirred vigorously at room temperature overnight. It was extracted with
CH Cl ; the combined organic extracts were dried over Na SO , filtered and concentrated. The
2
2
2
4
crude product was purified by crystallization from MeOH.
1
Yield 203.0 mg, 63%; white solid; mp 179-125 ˚C. H NMR (400 MHz, DMSO-d6) δ 8.59 –
8
1
1
.51 (m, 2H), 8.10 (d, J = 8.8 Hz, 1H), 7.98 – 7.92 (m, 1H), 7.92 – 7.84 (m, 2H), 7.83 – 7.77 (m,
H), 6.78 (t, J = 5.9 Hz, 1H), 4.46 (dt, J = 13.8, 7.0 Hz, 1H), 4.17 – 3.95 (m, 1H), 3.37 (dd, J =
1
3
1
3.3, 7.1 Hz, 2H), 3.19 (dd, J = 13.7, 7.4 Hz, 1H), 1.32 (s, 9H) ppm. C{ H} NMR (101 MHz,
DMSO-d6) δ 166.2, 155.9, 144.9, 144.5, 140.0, 137.3, 135.7, 132.8, 132.6, 131.3, 130.1, 128.9,
+
1
4
23.9, 122.0, 78.4, 51.0, 28.5(3C) ppm. HRMS (ESI), m/z calcd for C H N3NaO S [M+Na]
20 21 7
70.0992, found 470.0994.
General Procedure for the Preparation of Compounds 17
Boc-protected amine 11-14 (0.20 mmol) was dissolved in 4M solution of HCl in 1,4-dioxane (2
mL) and stirred at room temperature overnight. Volatiles were removed in vacuo and the residue
was triturated with diethyl ether (2 mL). The solid formed was filtered off and washed with
diethyl ether (1 mL). The ammonium hydrochloride salt thus obtained was suspended in water
(
0.5 mL) and methanol (0.5 mL) was added. 10% aq. NaOH (0.60 mmol) was added and the
resulting mixture was stirred at room temperature: for 3 hours (17a-j), 24 hours (17k-r) or 36
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hours (17s-u) as the progress of the reaction was monitored by TLC analysis. Volatiles were
removed in vacuo and the residue was treated with water (1 mL), the solid formed was filtered
off and washed with diethyl ether (0.5 mL).
Products 17s-u were purified by HPLC eluting with H O-MeCN with addition of 0.1% TFA
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(elution gradient MeCN: 15→95 %); flow rate 10mL/min, column temperature 40°C.
2
-Nitro-5,6,7,8-tetrahydro-9H-dibenzo[b,i][1,4,7]oxadiazecin-9-one (17a)
1
Yield 40.7 mg, 68%; yellow solid; mp 173-175 ˚C. H NMR (400 MHz, DMSO-d6) δ 7.92 (dd, J
=
9.0, 2.6 Hz, 1H), 7.96 – 7.74 (br s, 1H), 7.62 – 7.46 (m, 3H), 7.32 – 7.18 (m, 3H), 5.80 – 5.67
1
3
1
(
br s, 1H), 3.55 (t, J = 7.1 Hz, 2H), 3.39 – 3.21 (m, 2H) ppm. C{ H} NMR (101 MHz, DMSO-
d6) δ 167.4, 155.2, 149.8, 148.7, 140.0, 131.4, 131.0, 129.8, 125.5, 122.8, 121.8, 119.4, 116.1,
+
4
4.8, 37.8 ppm. HRMS (ESI), m/z calcd for C H N NaO [M+Na] 322.0798, found 322.0810.
15 13
3
4
2-(Trifluoromethyl)-5,6,7,8-tetrahydro-9H-benzo[i]pyrido[3,2-b][1,4,7]oxadiazecin-9-one
17b)
Yield 38.8 mg, 60 %; white solid; mp 167-170 ˚C. H NMR (400 MHz, DMSO-d6) δ 8.39 – 8.26
m, 1H), 8.16 – 7.96 (br s, 1H), 7.67 – 7.40 (m, 3H), 7.28 (d, J = 4.4 Hz, 2H), 6.18 – 6.01 (br s,
(
1
(
1
3
1
1H), 3.83 – 3.42 (m, 3H), 3.14 (s, 1H) ppm. C{ H} NMR (101 MHz, DMSO-d6) δ 169.5,
1
68.1, 158.8, 155.1, 143.9, 141.6, 136.0, 131.2, 129.8, 129.0, 125.6 (d, J = 223.9 Hz), 124.6 (q, J
+
=
4.8 Hz), 123.0, 43.5, 37.8 ppm. HRMS (ESI), m/z calcd for C H F N O [M+H] 324.0954,
1
5
13
3
3
2
found 324.0944.
2
-Nitro-5,6,7,8-tetrahydro-9H-benzo[i]pyrido[3,2-b][1,4,7]oxadiazecin-9-one (17c)
1
Yield 40.2 mg, 67 %; yellow solid; mp 194-196 ˚C. H NMR (400 MHz, DMSO-d6) δ 8.87 (dd,
J = 13.1, 2.4 Hz, 1H), 8.16 – 8.00 (br s, 1H), 7.91 (d, J = 11.9 Hz, 1H), 7.76 – 7.50 (m, 1H), 7.50
– 7.10 (m, 3H), 6.74 – 6.58 (br s, 1H), 3.72 (d, J = 77.5 Hz, 3H), 3.25 – 3.09 (m, 1H) ppm.
13
1
C{ H} NMR (101 MHz, DMSO-d6) δ 167.3, 157.1, 150.7, 141.9 (2С), 136.8, 136.1, 131.1,
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