An Alternative Approach to the Hydrated Imidazoline Ring Expansion (HIRE) of Diarene-Fused [1.4]Oxazepines

Article abstract of DOI:10.1002/ejoc.202000789

A four-step approach to the “hydrated imidazoline ring expansion” (HIRE) is presented. In most cases, the ring expansion was the sole process. However, for the first time, an alternative course of the hydrated imidazoline evolution was discovered which gave N-aminoethyl derivatives. These can, in principle, be converted into the target HIRE products under sufficiently forcing conditions. The approach offers improved flexibility with respect to the peripheral substituents and is also applicable to the synthesis of eleven-membered lactams. We observed that the latter can exist in two stable isomeric forms due to lactam–amide bond isomerization. The latter finding further demonstrates the value of medium-sized rings as multiple-conformer probes for biological target interrogation.

Full text of DOI:10.1002/ejoc.202000789

European Journal of Organic Chemistry
Accepted Article
Accepted Article
Title: An alternative approach to the hydrated imidazoline ring
expansion (HIRE) of diarene-fused [1.4]oxazepines
Authors: Sergey Grintsevich, Alexander Sapegin, Elena Reutskaya,
Stefan Peintner, Máté Erdélyi, and Mikhail Krasavin
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.202000789
Link to VoR: https://doi.org/10.1002/ejoc.202000789
01/2020

10.1002/ejoc.202000789
European Journal of Organic Chemistry
An alternative approach to the hydrated imidazoline ring expansion (HIRE)
of diarene-fused [1.4]oxazepines
Sergey Grintsevich,[a] Dr. Alexander Sapegin,[a] Elena Reutskaya,[a] Stefan Peintner,[b] Prof. Dr.
Máté Erdélyi[b] and Prof. Dr. Mikhail Krasavin*[a]
[a] Institute of Chemistry, Saint Petersburg State University, Saint Petersburg 199034 Russia
[b] Department of Chemistry − BMC, Uppsala University, SE-751 23 Uppsala, Sweden
E-mail: m.krasavin@spbu.ru
http://www.krasavin-group.org/
Supporting information and ORCID(s) from the author(s) for this article are available on the
WWW under http://dx.doi.org/10.1002/ejoc.xxxxxxxxx.
Abstract: A four-step approach to the ‘hydrated imidazoline ring expansion’ (HIRE) is
presented. In most cases, the ring expansion was the sole process. However, for the first time, an
alternative course of the hydrated imidazoline evolution was discovered which gave N-
aminoethyl derivatives. These can, in principle, be converted to the target HIRE products under
sufficiently forcing conditions. The approach offers improved flexibility with respect to the
peripheral substituents, and is also applicable to the synthesis of eleven-membered lactams. We
observed that the latter can exist in two stable isomeric forms due to lactam amide bond
isomerization. The latter finding further demonstrates the value of medium-sized rings as
multiple-conformer probes for biological target interrogation.
Introduction
Medium-sized, 8-11-membered, rings represent a scarcely populated area of synthetically
accessible chemical space, largely due to the known difficulty associated with constructing such
scaffolds via ring-closing approaches. This is to a large extent due to unfavorable transannular
interactions leading to large activation enthalpies.1 The scarcity of such compounds in screening
collections for drug discovery may be a valid reason for the absence of medium-sized cyclic
compounds among the 200 top-selling pharmaceuticals.2 However, medium-sized carbo- and
heterocycles are found in numerous natural products3 with selected illustrative examples shown
in Figure 1. Considering the success rates of natural products as drug leads,4 such cyclic
frameworks have emerged as a privileged platform on which synthetic compound libraries can
be built for lead generation in drug discovery.5 Their particular suitability for interrogation of
protein targets could intuitively be rationalized, on one hand, by their higher degree of
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10.1002/ejoc.202000789
European Journal of Organic Chemistry
conformational flexibility compared to the smaller-sized counterparts, and, therefore, higher
chances of adopting a protein-binding conformation. On the other hand, the conformational
restriction still imposed by their cyclic character is an advantage, in comparison to overly
flexible linear scaffolds. This intermediate flexibility ensures such important drug characteristics
as bioavailability and cell permeability.6
Figure 1. Examples of natural products containing medium-sized rings.
Strategies that are based on expansion of smaller cycles have emerged as the preferred way of
constructing medium-sized cyclic scaffolds.7 Recently, we developed a protocol for an n+3 ring
expansion of diarene [1.4]oxazepines 1 additionally fused to an imidazoline ring (Scheme 1). As
such, these compounds were resistant to basic or acidic hydrolysis. However, when ‘quaternized’
by alkylation at the imidazoline nitrogen atom, treatment of the resulting imidazolinium salts 2
with 0.1% w/v aqueous K2CO3 solution rapidly converted them to ring-expanded 1,4,7-
oxadiazecines 3.8 Since the formation of a putative ‘hydrated imidazoline’ (HI) intermediate was
evoked, with the energetically favored7c breakage of the central a bond leading to 3, the approach
was dubbed the ‘hydrated imidazoline ring expansion’ (HIRE).8-11 The reversible breakage of the
other C-N bond (b)12 in HI could, in principle, lead to N-(2-aminoethyl) [1.4] oxazepinones 4,
which was not observed over the formation of 3. On the contrary, primary and secondary amines
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European Journal of Organic Chemistry
4 smoothly underwent ring expansion in aqueous alkaline acetonitrile to give 3. Under
dehydrative conditions, primary amines 4 gave respective imidazolines 1 which could not
undergo the HIRE process without being activated by alkylation.10
Unfortunately, the alkylation of 1 could only be achieved upon treatment with methyl or ethyl
sulfate under microwave-promoted conditions.8 This limited the diversity of the R′ substituents
on the lactam nitrogen atom of ring-expanded products 3. At the same time, obtaining secondary
amines 4 entailed lengthy synthesis.10 This prompted us to consider an alternative approach to
constructing imidazolinium salts 2, which would allow for a much greater flexibility of the R′
substituents as well as a shorter route to ring-expanded products 3 obtained upon hydration of 2.
We reasoned that NH-lactams 5 could be coupled with secondary 2-hydroxyethylamines 6 in a
stepwise fashion via amidine formation13 followed by intramolecular nucleophilic substitution
(SN2′) of suitably activated hydroxyl group, thus delivering the amidinium salts 2 ready for the
HIRE (Scheme 1). Herein, we describe the results obtained in the course of exploring such an
approach.
Scheme 1. (a) Previously reported approaches to the hydrated imidazoline ring expansion
(HIRE) of diarene-fused [1.4]oxazepines; (b) Alternative HIRE approach explored in this work.
Results and Discussion
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To access a series of benzo[f][1,4]oxazepin-5(2H)-ones 5, we employed the earlier developed
double aromatic nucleophilic substitution-based cyclization protocol.14 To this end, secondary
amide 6 (prepared via amidation of salicylic acid) was reacted with a series of bis-electrohilic
(hetero)aromatic substrates 7a-f to afford benzo[f][1,4]oxazepin-5(2H)-ones 8 bearing a 2,4-
dimethoxybenzyl (DMB) group on the lactam nitrogen atom. Without purification, crude
products 8 were deprotected using TFA and the resulting NH-lactams 5a-f were obtained in good
to excellent yields over two steps without a need for chromatographic purification. As it had
been established earlier,14-15 the cyclocondensation of 6 with 7a-f was accompanied by a Smiles
rearrangement, which governed the regiochemistry of products 5a-f (Scheme 2). Usubstituted
salicylamide did not react with any of the substrates 7a-f.
Scheme 2. Synthesis of benzo[f][1,4]oxazepin-5(2H)-ones 5a-f.
Compounds 5a-f are electronically biased in the sense that the aromatic ring originating from
substrates 7 is electron-deficient (which enables the construction of these compounds via the
double SNAr cyclocondensation). In order to increase the substrate scope of the synthetic strategy
explored in this work, we additionally synthesized three benzo[f][1,4]oxazepin-5(2H)-ones 5g-i
as described in the literature.16 Amino phenols 9 were acylated with 2-fluorobenzoyl chloride
and the intermediate amides 10 were treated with powdered NaOH which triggered an
intramolecular SNAr reaction to give compounds 5g-i in good yields (Scheme 3).
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10.1002/ejoc.202000789
European Journal of Organic Chemistry
Scheme 3. Synthesis of benzo[f][1,4]oxazepin-5(2H)-ones 5g-i.
With the eleven benzo[f][1,4]oxazepin-5(2H)-one substrates 5a-i, we selected a number of
secondary 2-hydroxy ethylamines 6a-h and one homologous variant, 6i. Some of these amines
(6f-i) were prepared by reductive alkylation of respective primary amino alcohols with suitable
aromatic aldehydes17 (see Experimental section) while others were available commercially
(Figure 2).
Figure 2. Secondary hydroxyalkyl amines 6a-i employed in this study.
The initial results obtained with substrates 5a and 6a were promising and surprising at the same
time. After substantial preliminary experimentation, we arrived at the following four-step
protocol which allowed coupling some steps in succession and required chromatographic
purification only at the final step. [1.4]Oxazepine 5a was converted to imidoyl chloride 11a on
treatment with PCl5 in refluxing POCl3. After brief aqueous workup, 11a was treated with amine
6a in acetonitrile in the presence of DIPEA which led, after 18 h at reflux, to the formation of
amidine 12a (according to TLC analysis). At this point, excess thionyl chloride was added to the
cooled reaction mixture and the reaction continued at ambient temperature, presumably leading
to the activation of the alkanol side chain as a respective chloride and the formation of
imidazolinium chloride 2a (the intermediacy of the imidazolinium salts was confirmed by their
isolation and full characterization in one instance, vide infra). The scene was set for the HIRE
step; however, the process proved inefficient in acetonitrile. So, the solvent was changed to
methanol whereupon addition of 0.2% aqueous solution of K2CO3 led to the anticipated
conversion to the ring-expanded products 3a (isolated in 20% yield) accompanied by 10% 2-
(methylamino)ethyl derivative 4a (Scheme 4).
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10.1002/ejoc.202000789
European Journal of Organic Chemistry
Scheme 4. Initial attempt at ring-expansion of 5a with 2-hydroxy ethylamine 6a.
The formation of N-aminoalkyl derivative 4a, though never observed in the HIRE reactions
before, can be rationalized by the competing directions (a and b) for the evolution of the putative
‘hydrated imidazoline’ (HI) intermediate (Scheme 1). Indeed, if the N-linked aromatic ring is not
sufficiently electron-poor (i. e. it does not provide enough of an ‘electron sink’ for the aniline
leaving group in the HI evolution path a), the competing process of the aminoalkyl side chain
expulsion (path b) manifests itself in the formation of 4a. Thus, we reasoned that the propensity
of lactams 5 to undergo ring expansion towards 3 rather than ‘aminoalkylation’ towards 4 will be
higher in the case of more electron-poor N-linked aromatic rings. In order to verify this
hypothesis, we set off to explore the reaction scope for other partner pairs of substrates 5 and 6.
The results of this investigation are presented in Table 1.
Table 1. Results of the HIRE reactions of substrates 5a-i and 6a-i.
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European Journal of Organic Chemistry
Starting
materials
Products
Entry
5
6
3
4
1
5a
5b
6a
2
3
4
6b
6a
6f
–
–
5b
5b
5
6
–
–
5c
5c
6b
6d
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7a
–
5c
6e
6g
6h
8
9
–
–
5c
5c
10
–
5c
6i
11
12
13
–
–
–
5d
5d
5d
6e
6c
6a
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European Journal of Organic Chemistry
14
15
–
5d
5e
6f
–
6e
16
–
5e
6i
17
18
19
–
–
–
5f
5f
5f
6b
6a
6f
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European Journal of Organic Chemistry
20
21
22
23
24
25
–
–
–
–
–
–
5g
5g
5h
5h
5h
5i
6e
6b
6e
6b
6a
6a
26
5i
6c
a Imidazolinium salt 2g was isolated and characterized (see Experimental section).
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Fortunately, among the substrates 5a-f containing electron-poor N-linked aromatic ring the ring
expansion was the only observable result (except for 5b+6b pair, entry 2). Despite the seemingly
modest yields (15-55%), we were pleased with the outcome as for the four-step synthetic
transformation, these results translate into an average yield of 62-86% per chemical step.
However, the yield at the HIRE step per se (triggered by the addition of 0.2% aq. K2CO3) was
probably very high as the yield of the imidazolinium salt involved in this step isolated in one
case, 2g (28%) was nearly identical to the yield of the ring-expanded product 3g (25%) obtained
in four-step sequence. Not unexpectedly, the highest yields over four steps were obtained with
pyridine- and pyrazine-containing substrates 5d-f (Table 1, Entries 11-19). Also notable is the
fact the ring expansion approach was found applicable not only to the n+3 ring expansion
(delivering 10-membered [1,4,7]oxadiazecin-9-ones, Figure 3) but also to the n+4 ring
expansion in a process we termed ‘homo-HIRE’10 (Table 1, Entries 10 and 16). The formation of
the resulting [1]oxa[4,8]diazacycloundecin-10-ones 3j and 3p likely occurs with the
intermediacy of the respective ‘hydrated tetrahydropyrimidines’ (in analogy to the HI
intermediates postulated in all other cases).
Figure 3. Single-crystal X-ray crystallographic structures of compounds (a) 3a (CCDC
1993159), (b) 3c (CCDC 1993156), (c) 3l (CCDC 1993158) and (d) 3q (CCDC 1993157);
thermal ellipsoids are shown at 50% probability.
Much in line with the initial hypothesis on the relationship between the electronic character of
the N-linked aromatic ring in substrates 5 and the competing formation of HIRE products 3 and
aminoalkyl derivatives 4, substrates 5g-h only delivered the latter (Table 1, Entries 20-24).
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Interestingly, even the small electron-withdrawing influence of the chlorine substituent in 5i
manifested itself in the competing formation of ring-expanded product 3z in one case, albeit with
a mediocre yield (Table 1, Entry 26).
Since in most cases ring-expanded products 3 were favored over aminoalkyl derivatives 4 (as
summarized in Table 1), under sufficiently forcing conditions, it should be possible, under
sufficient actvation, to force an amino alkyl dibenzo[b,f][1,4]oxazepin-11-one such as 4y to
overcome two energy barriers – 4yHI-y3y – and undergo the ring expansion to give 3y. To
our utmost delight, heating 4y at 60 °C in aqueous methanol in the presence of a four-fold excess
of sodium hydroxide led to a smooth conversion to ring-expanded product 3y isolated in 63%
yield (Scheme 5).
Scheme 5. Forced ring expansion of 2-aminoethyl derivative 4y.
According to DFT calculations conducted at B3LYP/6-31G* level of theory10, 18 (see Supporting
information), evolution of HI-y into 4y is marginally different in energy effect from an
alternative pathway HI-y3y (G -15.7 kcal/mol and -14.9 kcal/mol, respectively). However,
the formation of 3y is probably irreversible, despite its being nearly equal in free energy to 4y.
Indeed, the reverse conversion of 3y into HI-y would be most likely accompanied not only by an
unfavorable entropy loss but also require that the lactam carbonyl group is attacked by the
relatively non-nucleophilic anilinic nitrogen.
Overcoming the same energy barriers (4HI3) turned out not feasible for aminoalkyl
derivatives 4t-x and, accordingly, these compounds remained unchanged under even more
prolonged (up to 3 days) heating at 60 °C with NaOH in aqueous methanol. Achieving such a
HIRE-type translactamization is a goal of our current endeavors.
In the course of the present study, we encountered four examples of amino alkyl derivatives 4
matched in pairs to the respective HIRE products 3, which allowed us noting some
1
distinguishing features in the H NMR spectra of these compounds (Table 2, Figure 4). For
instance, the anilinic nitrogen-bound proton in ring-expanded compounds 3 appear as a sharp
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10.1002/ejoc.202000789
European Journal of Organic Chemistry
triplet between 5.0 and 6.0 ppm while the aliphatic amine NH in compounds 4 appear as broad
signal at lower frequency. -Protons of the substituent on the nitrogen atom also differ in
chemical shift: these protons of 3 are deshielded and loose equivalency, most likely, due to
complex conformational behavior of the ten-membered ring.
Table 2. Characteristic 1H NMR signals of matching products 3 and 4 obtained in this work.
H, ppm (multiplicity)
Compound
N–H
6.04 (t)
1.95 (br s)
5.73 (t)
1.95 (br s)
5.34 (t)
N–CH2R′
4.50 (ABq)
3.82 (s)
3.45 (m)
2.50 (q)
3a
4a
3b
4b
3y
4y
3z
4z
2.82 (s)
2.70 (br s)
5.40 (t)
2.38 (br s)
2.26 (s)
4.52 (ABq)
3.69 (s)
Figure 4. Characteristic 1H NMR signals of compounds 3z and 4z.
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An especially complex conformational behavior was observed for the 11-membered rings of 3j
and 3p, which displayed two sets of NMR signals suggesting these compounds to exist in
solution as a mixture of two unequally populated stable conformers at room temperature. In
order to confirm this, compound 3p was assessed by NMR in DMSO-d6 solution. Whereas no
1
exchange peaks between the two sets of H NMR signals has been observed by EXSY at 25 °C
(tmix = 500 ms), these were detected at 55 °C (Figure S6, Supporting Information) suggesting a
relatively high barrier of interconversion. The ∆δ/T = 2.1 ppb/K (25 °C – 105 °C) amine
temperature coefficient of the major isomer (Figure 5) revealed it to be solvent shielded by an
intramolecular hydrogen bond, presumably to the carbonyl oxygen across the macrocycle. In
contrast, the 5.5 ppb/K temperature coefficient of the anilinic amine of the minor form indicated
it to be solvent exposed.19-20 The line-broadening of the 1H NMR signals of the major form at 25
°C (Figure 5) suggest this isomer to be involved into a dynamic process. Accordingly, the signals
of the major isomer sharpen at increased temperatures, whereas those of the minor form broaden
and coalesce into the corresponding signals of the major conformer. The energy barrier of the
exchange process was estimated for coalescence of proton H18 to be ∆G‡ ~ 154 kJ/mol (see
Supporting Information for details), corroborating that the interconversion of the two isomers
required overcoming a relatively high energy barrier. The large difference of the amine
temperature coefficients of the two forms along with the vastly dissimilar chemical shift
difference of the diastereotopic CH2-4 protons of the major (∆δCH2a/b = 1.7 ppm) and the minor
(∆δCH2a/b = 0.2 ppm) isomers revealed the vastly different flexibility of the macrocycle of the two
forms, with an intramolecular N-H…O=C hydrogen bond presumably playing an important role
in the stabilization of the major conformation. This also suggested the two sets of NMR signals
to originate from the cis and the trans isomers of the lactam amide bond, promoting distinctly
different carbonyl orientations. This was corroborated by a Monte Carlo conformational search
(see Supporting Information for details) yielding 2.49 Å and 5.64 Å Boltzmann population
averaged (N-)H…O(=C) interatomic distances for the trans and the cis amide
isomers, respectively. These computationally predicted interatomic distances are in excellent
agreement with the experimentally detected presence of the major isomer possessing a strong
intramolecular N-H…O=C hydrogen bond, whereas the minor isomer lacking such stabilization.
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1
Figure 5. Variable temperature H NMR spectra of compound 3p. (A) The signals of the major
isomer sharpen, whereas those of the minor broaden at higher temperatures. (B) The amine
temperature coefficients of the two forms indicate the anilinic amine of the major isomer (blue)
to be involved into an intramolecular hydrogen bond, whereas that of the minor form (red) to be
solvent exposed. (C) The large chemical shift difference of diastereotopic protons of CH2-4 of
the major isomer, 1.7 ppm, indicates this to be locked into a rigidified macrocycle conformation,
whereas the smaller difference, 0.2 ppm, of these protons of the minor isomer to be
conformationally more flexible. (D) Shown are the lowest energy conformers for the cis (red)
and trans (blue) isomer. The experimental observations are corroborated by the major trans
isomer being intramolecularly hydrogen bonded whereas the minor cis isomer to lack this
stabilizing secondary chemical interaction.
Conclusions
We have described a fundamentally new approach to the construction of diversely substituted
imidazolinium-fused diarene [1,4]oxazepines previously shown to undergo a facile ‘hydrated
imidazoline ring expansion’ (HIRE) to produce ten-membered lactams. The approach relies on
the respective NH-lactams and secondary 2-hydroxyethylamines. We have shown for the first
time that insufficient electron deficiency of the nitrogen-bound aromatic ring in these systems
may change the course of the putative ‘hydrated imidazoline’ evolution and to deliver N-
aminoalkyl derivatives as a second or the sole product. While we are in the quest for a universal
approach to direct these unwanted products towards the ring-expanded products, we have shown
that in some cases, it is possible to obtain the latter on simple heating of the N-aminoalkyl
derivatives in alkaline aqueous methanol solution. The new approach was also found applicable
to the use of secondary 3-hydroxypropylamines which delivered eleven-membered products via
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the process termed ‘homo-HIRE’. The latter lactams displayed a rather pronounced complex
conformational behavior. One of the eleven-membered lactams was shown to exist in two rather
stable isomeric forms with the energy barrier for their coalescence estimated as ∆G‡ ~ 154
kJ/mol. Based on the Monte-Carlo conformational search, the more populated form was shown
to be the lactam amide bond trans-isomer supported by an intramolecular hydrogen bond while
the other form was the cis-isomer in which no such hydrogen bonding was present.
Collectively, these findings expand the arsenal of synthetic approaches to the comparably scarce
medium-sized heterocyclic scaffolds as well as our knowledge base of the HIRE reactions at the
mechanistic level. Additionally, the insight gained into the conformational behavior of the
eleven-membered lactams resulting from the homo-HIRE reaction underscores the value of
medium-sized rings in being able to interrogate protein targets in multiple binding modes which
can significantly aid in early drug lead generation.
Experimental Section
General. NMR spectra were recorded on a Bruker Avance III 400 spectrometer (1H: 400.13
13
MHz; C: 100.61 MHz; chemical shifts are reported as parts per million (δ, ppm)); the residual
solvent peaks were used as internal standards: 7.28 and 2.50 ppm for 1H in CDCl3 and DMSO-d6
13
respectively, 40.01 and 77.02 ppm for C in DMSO-d6 and CDCl3 respectively. Mass spectra
were recorded on a Bruker Maxis HRMS-ESI-qT spectrometer (ESI ionization). Melting points
were determined in open capillary tubes on Stuart SMP30 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. Column chromatography
was carried out with silica gel grade 60 (0.040–0.063 mm) 230–400 mesh. All commercial
reagents and solvents were used without further purification, unless otherwise noted. DMF for
the synthesis was distilled over CaH2 and stored under nitrogen over freshly activated molecular
sieves 4Å. Potassium carbonate was dried at 200 oC for 5 hours prior to use.
N-(2,4-Dimethoxybenzyl)-2-hydroxybenzamide (6)
To a suspension of salicylic acid (5.00 g, 36.2 mmol, 1.00 equiv.) in CH2Cl2 (50 mL) CDI (6.16
g, 38.0 mmol, 1.05 equiv.) was added. The mixture was stirred at r. t. for 1 h. (2,4-
Dimethoxyphenyl)methanamine (6.05 g, 36.2 mmol, 1.00 equiv.) was added at 0 °C. The
resulting mixture was stirred at the same temperature for 2 h and then at r. t. overnight. The
reaction mixture was washed with sat. aq. K2CO3 (3×20 mL), water (1×20 mL), dried over
Na2SO4 and filtered. The solvent was removed under reduced pressure to afford analytically pure
title compound. Yield 77%, 8.00 g; light oil; 1H NMR (400 MHz, CDCl3) δ 12.45 (s, 1H), 7.43 –
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European Journal of Organic Chemistry
7.35 (m, 1H), 7.31 (dd, J = 8.0, 1.6 Hz, 1H), 7.26 (d, J = 8.1 Hz, 1H), 6.99 (dd, J = 8.3, 1.2 Hz,
1H), 6.88 – 6.79 (m, 1H), 6.80 (s, 1H), 6.54 – 6.43 (m, 2H), 4.58 (d, J = 5.7 Hz, 2H), 3.90 (s,
13
3H,), 3.83 (s, 3H,) ppm. C{1H} NMR (101 MHz, CDCl3) δ 169.5, 161.7, 160.9, 158.7, 134.0,
130.8, 125.3, 118.6, 118.5, 118.0, 114.5, 104.2, 98.8, 55.5, 55.5, 39.3 ppm. HRMS (ESI), m/z
calcd for C16H17NNaO4 [M+Na]+ 310.1050, found 310.1053.
General procedure for the preparation of diarene-fused [1.4]oxazepines 5a-5f.
To a solution of 6 (500 mg, 1.74 mmol, 1 equiv.) in anhydrous DMF (10 mL) 1,2-dihaloarene or
1-halo-2-nitroarene 7a-f (1.74 mmol, 1 equiv.) was added followed by freshly calcinated K2CO3
(721 mg, 5.22 mmol, 3 equiv.). The mixture was stirred at 70 °C for 18 h. DMF was removed in
vacuo and the residue was taken up to water (10 mL) and extracted with CH2Cl2 (10 mL). The
organic layer was separated, washed with water (3×10 mL), dried over anhydrous Na2SO4 and
filtered. CH2Cl2 was evaporated in vacuo. The resulting oil was dissolved in mixture of CH2Cl2
(5 mL) and CF3COOH (5 mL) at 0 °C. The mixture was stirred at the same temperature for 2 h
and then at r. t. for 18 h. After completion of the reaction, the mixture was concentrated in vacuo,
and diluted with water (15 mL). The crystals formed were filtered off, washed with Et2O (5 ml ×
2) and air-dried to afford desired product 5a-f.
11-Oxo-10,11-dihydrodibenzo[b,f][1,4]oxazepine-7-carbonitrile (5a)
Yield 95%, 390 mg; white solid; mp > 250 °C; 1H NMR (400 MHz, DMSO-d6) δ 10.67 (s, 1H),
13
7.87 – 7.79 (m, 2H), 7.69 – 7.59 (m, 2H), 7.42 – 7.31 (m, 3H) ppm. C{1H} NMR (101 MHz,
DMSO-d6) δ 165.8, 158.5, 150.0, 136.7, 135.3, 132.0, 130.7, 126.3, 125.9, 125.7, 122.7, 121.1,
118.3, 107.5 ppm. HRMS (ESI), m/z calcd for C14H8N2NaO2 [M+Na]+ 259.0478, found
259.0480.
N,N-Dimethyl-11-oxo-10,11-dihydrodibenzo[b,f][1,4]oxazepine-7-sulfonamide (5b)
Yield 85%, 471 mg; white solid; mp > 250 °C; 1H NMR (400 MHz, DMSO-d6) δ 10.92 (s, 1H),
7.81 (dd, J = 7.7, 1.8 Hz, 1H), 7.72 (d, J = 2.1 Hz, 1H), 7.70 – 7.64 (m, 1H), 7.59 (dd, J = 8.4,
2.1 Hz, 1H), 7.50 (dd, J = 8.2, 1.1 Hz, 1H), 7.42 – 7.34 (m, 2H), 2.63 (s, 6H) ppm. 13C{1H}
NMR (101 MHz, DMSO-d6) δ 166.0, 158.7, 150.0, 136.2, 135.4, 132.0, 131.4, 126.4, 126.1,
125.7, 122.4, 121.4, 121.4, 38.0 (2C) ppm. HRMS (ESI), m/z calcd for C15H14N2NaO4S
[M+Na]+ 341.0566, found 341.0562.
7-Nitrodibenzo[b,f][1,4]oxazepin-11(10H)-one (5c)
Yield 92%, 410 mg; yellow solid; mp > 250 °C; 1H NMR (400 MHz, DMSO-d6) δ 10.81 (s, 1H),
8.19 (d, J = 2.6 Hz, 1H), 8.07 (dd, J = 8.8, 2.6 Hz, 1H), 7.83 (dd, J = 7.8, 1.8 Hz, 1H), 7.70 –
7.63 (m, 1H), 7.48 (dd, J = 8.2, 1.2 Hz, 1H), 7.42 – 7.34 (m, 2H) ppm. 13C{1H} NMR (101 MHz,
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10.1002/ejoc.202000789
European Journal of Organic Chemistry
DMSO-d6) δ 165.7, 158.4, 149.5, 144.3, 138.5, 135.4, 132.0, 126.4, 125.5, 122.1, 122.0, 121.3,
117.7 ppm. HRMS (ESI), m/z calcd for C13H8F3N2O2 [M+H]+ 281.0532, found 281.0530.
3-(Trifluoromethyl)benzo[f]pyrido[3,2-b][1,4]oxazepin-10(11H)-one (5d)
Yield 90%, 439 mg; white solid; mp > 250 °C; 1H NMR (400 MHz, DMSO-d6) δ 11.08 (s, 1H),
8.57 (dd, J = 2.3, 1.1 Hz, 1H), 8.19 (d, J = 2.1 Hz, 1H), 7.85 (dd, J = 7.8, 1.8 Hz, 1H), 7.73 –
13
7.63 (m, 1H), 7.50 – 7.33 (m, 2H) ppm. C{1H} NMR (101 MHz, DMSO-d6) δ 165.3, 157.9,
149.5, 144.8, 142.7 (q, J = 3.5 Hz), 135.6, 132.2, 127.9 (q, J = 3.0 Hz), 126.6, 125.4, 123.6 (q, J
= 272.1 Hz), 122.4 (q, J = 33.2 Hz), 121.2 ppm. HRMS (ESI), m/z calcd for C13H8F3N2O2
[M+H]+ 281.0532, found 281.0530.
3-(Pyrrolidin-1-ylsulfonyl)benzo[f]pyrido[3,2-b][1,4]oxazepin-10(11H)-one (5e)
1
Yield 90%, 541 mg; white solid; mp 230-232 °C; H NMR (400 MHz, DMSO-d6) δ 11.46 (s,
1H), 8.59 (d, J = 2.1 Hz, 1H), 8.23 (d, J = 2.2 Hz, 1H), 7.83 (dd, J = 7.8, 1.7 Hz, 1H), 7.74 –
7.66 (m, 1H), 7.52 (d, J = 8.1 Hz, 1H), 7.39 (t, J = 7.6 Hz, 1H), 3.29 – 3.17 (m, 4H), 1.75 – 1.63
13
(m, 4H) ppm. C{1H} NMR (101 MHz, DMSO-d6) δ 165.3, 157.9, 149.4, 144.7, 144.2, 135.7,
132.2, 129.8, 129.3, 126.6, 125.3, 121.4, 48.3 (2C), 25.2 (2C) ppm. HRMS (ESI), m/z calcd for
C13H8F3N2O2 [M+H]+ 281.0532, found 281.0530.
Benzo[f]pyrazino[2,3-b][1,4]oxazepin-10(11H)-one (5f)
Yield 65%, 352 mg; white solid; mp > 250 °C; 1H NMR (400 MHz, DMSO-d6) δ 10.99 (s, 1H),
8.33 (d, J = 3.0 Hz, 1H), 8.11 (d, J = 3.0 Hz, 1H), 7.92 – 7.85 (m, 1H), 7.73 – 7.64 (m, 1H), 7.43
13
– 7.35 (m, 2H) ppm. C{1H} NMR (101 MHz, DMSO-d6) δ 164.9, 156.3, 151.0, 141.9, 141.1,
137.8, 135.5, 132.2, 126.5, 125.1, 121.5 ppm. HRMS (ESI), m/z calcd for C11H7N3NaO2
[M+Na]+ 236.0430, found 236.0426.
General procedure for the preparation of dibenzo[b,f][1,4]oxazepin-11(10H)-ones 5g-5i.
The 2-fluorobenzoyl chloride (344 mg, 2.28 mmol, 1.05 equiv.) was added dropwise to a
solution of 2-aminophenol 9 (2.17 mmol, 1.00 equiv.) and Et3N (363 μL, 2.60 mmol, 1.10
equiv.) in dry DMF (5 mL) at 0 °C. After the addition of the acid chloride, the mixture was
allowed to warm up to room temperature overnight while stirring under a nitrogen atmosphere.
After that, the freshly powdered NaOH (183 mg, 3.26 mmol, 1.50 equiv.) was added. The
resulting mixture was heated at reflux for 5 h. After cooling to room temperature, the mixture
was diluted with water (100 mL), and the precipitated product was filtered over a glass filter and
washed with 5% NaOH and then water to remove the unreacted starting material. The solid
residue was dried overnight under vacuum to afford analytically pure compounds 5g-i.
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10.1002/ejoc.202000789
European Journal of Organic Chemistry
Dibenzo[b,f][1,4]oxazepin-11(10H)-one (5g)
1
Yield 70%, 320 mg; white solid; mp 210-212 °C; H NMR (400 MHz, DMSO-d6) δ 10.53 (s,
1H), 7.79 (dd, J = 7.7, 1.8 Hz, 1H), 7.65 – 7.57 (m, 1H), 7.38 – 7.27 (m, 3H), 7.21 – 7.09 (m,
3H) ppm. 13C{1H} NMR (101 MHz, DMSO-d6) δ 166.3, 159.4, 150.9, 134.8, 131.9, 131.7,
126.4, 126.2, 125.9, 125.7, 122.1, 121.8, 121.1 ppm. HRMS (ESI), m/z calcd for C13H10NO2
[M+H]+ 212.0706, found 212.0710.
8-Chlorodibenzo[b,f][1,4]oxazepin-11(10H)-one (5h)
Yield 54%, 287 mg; white solid; mp > 250 °C; 1H NMR (400 MHz, DMSO-d6) δ 10.60 (s, 1H),
7.79 (dd, J = 7.7, 1.7 Hz, 1H), 7.68 – 7.61 (m, 1H), 7.41 – 7.31 (m, 3H), 7.23 – 7.16 (m, 2H)
13
ppm. C{1H} NMR (101 MHz, DMSO-d6) δ 166.0, 159.0, 149.5, 135.1, 133.1, 132.0, 130.0,
126.1, 125.8, 125.2, 123.4, 121.4, 121.1 ppm. HRMS (ESI), m/z calcd for C13H8ClNNaO2
[M+Na]+ 268.0136, found 268.0136.
8-Methyldibenzo[b,f][1,4]oxazepin-11(10H)-one (5i)
1
Yield 65%, 317 mg; white solid; mp 233-234 °C; H NMR (400 MHz, DMSO-d6) δ 10.46 (s,
1H), 7.77 (dd, J = 7.7, 1.8 Hz, 1H), 7.65 – 7.57 (m, 1H), 7.35 – 7.27 (m, 2H), 7.20 (d, J = 8.1 Hz,
1H), 6.99 – 6.89 (m, 2H), 2.24 (s, 3H) ppm. 13C{1H} NMR (101 MHz, DMSO-d6) δ 166.4,
159.5, 148.8, 135.7, 134.8, 131.8, 131.2, 126.2, 126.1, 125.8, 122.2, 121.4, 121.0, 20.8 ppm.
HRMS (ESI), m/z calcd for C14H12NO2 [M+H]+ 226.0863, found 226.0866.
General procedure for the preparation of hydroxyalkyl amines 6f-i
A solution of amino alcohol (8.92 mmol, 1.0 equiv.) and aldehyde (8.92 mmol, 1.0 equiv.) in
MeOH (15 mL) was stirred at r. t. for 36 h. Sodium borohydride (505 mg, 13.38 mmol, 1.5
equiv.) was added in one portion and the resulting mixture was stirred at 50 °C for 4 h. MeOH
was distilled off under reduced pressure and the residue was purified by column chromatography
on SiO2 by using EtOAc as eluent to give the title compound.
2-((Thiophen-2-ylmethyl)amino)ethan-1-ol (6f)
Yield 62%, 869%; light oil; 1H NMR (400 MHz, CDCl3) δ 7.23 (dd, J = 4.9, 1.3 Hz, 1H), 6.99 –
13
6.93 (m, 2H), 4.03 (s, 2H), 3.72 – 3.64 (m, 2H), 2.89 – 2.80 (m, 2H) ppm; C{1H} NMR (101
MHz, CDCl3) δ 143.7, 126.7, 125.1, 124.5, 61.0, 50.4, 48.0 ppm; HRMS (ESI), m/z calcd for
C7H12NOS [M+H]+ 158.0634, found 158.0640.
2-((Thiophen-3-ylmethyl)amino)ethan-1-ol (6g)
Yield 63%, 869 mg; light oil; 1H NMR (400 MHz, CDCl3) δ 7.31 (dd, J = 5.0, 2.9 Hz, 1H), 7.16
(dd, J = 2.9, 1.2 Hz, 1H), 7.07 (dd, J = 5.0, 1.3 Hz, 1H), 3.86 (s, 2H), 3.73 – 3.65 (m, 2H), 2.89 –
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10.1002/ejoc.202000789
European Journal of Organic Chemistry
13
2.80 (m, 2H) ppm; C{1H} NMR (101 MHz, CDCl3) δ 141.2, 127.5, 125.9, 121.6, 61.0, 50.5,
48.4 ppm; HRMS (ESI), m/z calcd for C7H12NOS [M+H]+ 158.0634, found 158.0638.
2-((3,4-Dimethoxybenzyl)amino)ethan-1-ol (6h)
Yield 83%, 1562 mg; light oil; 1H NMR (400 MHz, CDCl3) δ 6.91 – 6.82 (m, 3H), 3.91 (s, 3H),
13
3.89 (s, 3H), 3.77 (s, 2H), 3.71 – 3.65 (m, 2H), 2.87 – 2.80 (m, 2H) ppm; C{1H} NMR (101
MHz, CDCl3) δ 149.1, 148.2, 132.8, 120.2, 111.4, 111.1, 61.0, 56.0, 55.9, 53.3, 50.5 ppm;
HRMS (ESI), m/z calcd for C11H18N3O [M+H]+ 212.1281, found 212.1277.
3-(Benzylamino)propan-1-ol (6i)
1
Yield 56%, 825 mg; light oil; H NMR (400 MHz, CDCl3) δ 7.38 – 7.28 (m, 5H), 3.87 – 3.79
13
(m, 4H), 2.96 – 2.89 (m, 2H), 1.79 – 1.71 (m, 2H) ppm; C{1H} NMR (101 MHz, CDCl3) δ
139.6, 128.5 (2C), 128.2 (2C), 127.2, 64.3, 54.0, 49.4, 30.8 ppm; HRMS (ESI), m/z calcd for
C10H16NO [M+H]+ 166.1226, found 166.1228.
1-Benzyl-7-nitro-2,3-dihydrodibenzo[b,f]imidazo[1,2-d][1,4]oxazepin-1-ium chloride (2g)
A mixture of 5c (85 mg, 0.35 mmol, 1.0 equiv.), PCl5 (109 mg, 0.53 mmol, 1.5 equiv.) and
POCl3 (5 mL) was heated at reflux for 8 hours. The volatiles were removed in vacuo, the residue
was diluted with ice-cold water and extracted with CH2Cl2. The organic layer was washed with
water, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The resulting oil, 6e
(105 mg, 0.70 mmol, 2.0 equiv) and DIPEA (0.07 mL, 0.38 mmol, 1.1 equiv.) were dissolved in
MeCN (5 mL). The mixture was stirred at ambient temperature for 12 h, whereupon SOCl2 (76.3
μL, 1.05 mmol, 3.0 equiv.) was slowly added. The reaction mixture was stirred at r. t. for 12 h.
The solvent was removed in vacuo, the resulting oil was suspended in Et2O (3 mL) and left to
stand at r. t. overnight. The precipitate formed was filtered off, rinsed with Et2O (2x1 mL), and
dried in vacuo. Yield 28%, 41 mg; yellow solid; 1H NMR (400 MHz, DMSO-d6) δ 8.12 (dd, J =
8.5, 1.9 Hz, 1H), 8.05 (td, J = 7.7, 1.3 Hz, 1H), 7.97 – 7.90 (m, 2H), 7.88 – 7.76 (m, 5H), 7.69
(td, J = 7.6, 1.2 Hz, 1H), 4.94 – 4.86 (m, 2H), 4.37 – 4.24 (m, 1H), 4.17 – 4.06 (m, 2H) ppm.
13C{1H} NMR (101 MHz, DMSO-d6) δ 168.1, 154.2, 138.4, 137.9, 136.7, 133.3 (2C), 130.9,
130.2 (2C), 129.4 (2C), 128.5 (2C), 127.5, 127.7, 127.3, 119.2, 114.8, 51.1, 47.5, 44.6 ppm.
HRMS (ESI), m/z calcd for C22H18N3O3 [M+H]+ 372.1343, found 372.1340.
General procedure for the preparation of diarene-fused 10-11-membered heterocyclic
compounds 3a-z
A mixture of [1.4]oxazepines (0.35 mmol, 1.0 equiv.), PCl5 (109 mg, 0.53 mmol, 1.5 equiv.) and
POCl3 (5 mL) was heated at reflux for 8 hours. The volatiles were removed in vacuo, the residue
was diluted with ice-cold water and extracted with CH2Cl2. The organic layer was washed with
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10.1002/ejoc.202000789
European Journal of Organic Chemistry
water, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The resulting oil, amino
alcohol (0.70 mmol, 2.0 equiv) and DIPEA (0.07 mL, 0.38 mmol, 1.1 equiv.) were dissolved in
MeCN (5 mL) and the solution was heated at reflux for 18 h. Upon cooling to r. t., SOCl2 (76.3
μL, 1.05 mmol, 3.0 equiv.) was slowly added and the reaction mixture was stirred at r. t. for an
additional 12 h. The solvent was removed in vacuo, the residue was dissolved at MeOH (3 mL),
0.2% aq. K2CO3 (3 mL) was added and the mixture was stirred at r. t. for 24 h. The mixture was
extracted with EtOAc (2 x 5 mL). The organic layer was separated by centrifugation, washed
with water, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. Column
chromatography on silica gel using ethyl acetate (or DCM → EtOAc) as eluent afforded the title
compounds and/or amino alkyl [1.4]oxazepine derivatives 4.
8-Benzyl-9-oxo-6,7,8,9-tetrahydro-5H-dibenzo[b,i][1,4,7]oxadiazecine-2-carbonitrile (3a)
1
Yield 20%, 26 mg; light oil; H NMR (400 MHz, DMSO-d6) δ 7.64 (d, J = 1.8 Hz, 1H), 7.46
(dd, J = 8.5, 1.9 Hz, 1H), 7.43 – 7.26 (m, 7H), 7.14 (t, J = 7.2 Hz, 1H), 7.02 (d, J = 8.5 Hz, 1H),
6.92 (d, J = 8.3 Hz, 1H), 6.04 (t, J = 6.5 Hz, 1H), 4.85 (d, J = 14.9 Hz, 1H), 4.14 (d, J = 14.9 Hz,
1H), 3.55 – 3.36 (m, 2H), 3.31 – 3.26 (m, 2H) ppm. 13C{1H} NMR (101 MHz, DMSO-d6) δ
168.0, 153.1, 148.3, 140.8, 137.9, 131.3, 131.0, 129.9, 129.2, 129.0 (2C), 128.2 (2C), 127.7,
125.2, 123.2, 119.8, 119.1, 115.7, 99.1, 51.0, 47.9, 46.5 ppm. HRMS (ESI), m/z calcd for
C23H20N3O2 [M+H]+ 370.1550, found 370.1555.
8-Ethyl-N,N-dimethyl-9-oxo-6,7,8,9-tetrahydro-5H-dibenzo[b,i][1,4,7]oxadiazecine-2-
sulfonamide (3b)
Yield 14%, 19 mg; dark oil; 1H NMR (400 MHz, DMSO-d6) δ 7.45 – 7.36 (m, 2H), 7.32 (d, J =
2.1 Hz, 1H), 7.15 – 7.05 (m, 3H), 6.99 (d, J = 8.4 Hz, 1H), 5.73 (t, J = 6.7 Hz, 1H), 3.54 – 3.35
(m, 4H), 3.31 – 3.21 (m, 1H), 2.95 – 2.82 (m, 1H), 2.58 (s, 6H), 1.06 (t, J = 7.0 Hz, 3H) ppm.
13C{1H} NMR (101 MHz, DMSO-d6) δ 167.2, 152.8, 148.0, 141.1, 131.0, 129.8, 126.6, 125.3,
124.2, 123.0, 122.9, 118.1, 116.8, 50.7, 46.0, 40.7, 38.1 (2C), 12.9 ppm. HRMS (ESI), m/z calcd
for C19H24N3O4S [M+H]+ 390.1482, found 390.1480.
8-Benzyl-N,N-dimethyl-9-oxo-6,7,8,9-tetrahydro-5H-dibenzo[b,i][1,4,7]oxadiazecine-2-
sulfonamide (3c)
Yield 18%, 28 mg; white solid (28 mg, 18%); 1H NMR (400 MHz, DMSO-d6) δ 7.47 – 7.41 (m,
2H), 7.39 – 7.33 (m, 3H), 7.31 – 7.25 (m, 3H), 7.20 – 7.11 (m, 3H), 7.05 (d, J = 8.3 Hz, 1H),
5.68 (t, J = 6.8 Hz, 1H), 4.75 (d, J = 15.0 Hz, 1H), 4.06 – 3.95 (m, 1H), 3.62 – 3.48 (m, 1H),
13
3.44 – 3.34 (m, 2H), 3.26 – 3.14 (m, 1H), 2.60 (s, 6H) ppm. C{1H} NMR (101 MHz, DMSO-
d6) δ 168.0, 152.7, 147.9, 141.2, 137.9, 131.1, 129.7, 129.1 (2C), 128.0 (2C), 127.7, 126.7,
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10.1002/ejoc.202000789
European Journal of Organic Chemistry
124.6, 124.2, 123.1, 123.1, 118.1, 117.3, 51.0, 47.4, 45.4, 38.1 (2C) ppm. HRMS (ESI), m/z
calcd for C24H26N3O4S [M+H]+ 452.1639, found 452.1640.
N,N-Dimethyl-9-oxo-8-(thiophen-2-ylmethyl)-6,7,8,9-tetrahydro-5H-dibenzo[b,i][1,4,7]
oxadiazecine-2-sulfonamide (3d)
1
Yield 15%, 24 mg; white solid; mp 215-216 °C; H NMR (400 MHz, DMSO-d6) δ 7.47 – 7.39
(m, 3H), 7.35 (d, J = 2.1 Hz, 1H), 7.16 – 7.07 (m, 4H), 7.06 – 7.01 (m, 1H), 6.98 (dd, J = 5.1, 3.4
Hz, 1H), 5.75 (t, J = 6.8 Hz, 1H), 4.77 (d, J = 15.1 Hz, 1H), 4.27 (d, J = 15.0 Hz, 1H), 3.58 –
13
3.41 (m, 2H), 3.31 – 3.27 (m, 2H), 2.60 (s, 6H) ppm. C{1H} NMR (101 MHz, DMSO-d6) δ
167.6, 152.8, 147.9, 141.1, 140.4, 131.3, 129.6, 127.3, 127.1, 126.7, 126.5, 124.4, 124.2, 123.1,
123.1, 118.0, 117.2, 50.8, 45.5, 42.9, 38.1 (2C) ppm. HRMS (ESI), m/z calcd for
C22H23N3NaO4S2 [M+Na]+ 480.1022, found 480.1026.
8-Ethyl-2-nitro-5,6,7,8-tetrahydro-9H-dibenzo[b,i][1,4,7]oxadiazecin-9-one (3e)
1
Yield 29%, 33 mg; dark oil; H NMR (400 MHz, DMSO-d6) δ 7.93 (dd, J = 9.0, 2.6 Hz, 1H),
7.87 (d, J = 2.6 Hz, 1H), 7.41 (ddd, J = 8.7, 7.3, 1.8 Hz, 1H), 7.25 (dd, J = 7.6, 1.8 Hz, 1H), 7.15
(td, J = 7.4, 1.0 Hz, 1H), 7.07 – 7.01 (m, 1H), 6.97 (d, J = 9.0 Hz, 1H), 6.63 (t, J = 6.5 Hz, 1H),
3.77 – 3.63 (m, 1H), 3.59 – 3.40 (m, 3H), 3.32 – 3.21 (m, 1H), 3.03 – 2.89 (m, 1H), 1.08 (t, J =
7.1 Hz, 3H) ppm. 13C{1H} NMR (101 MHz, DMSO-d6) δ 167.1, 153.1, 150.2, 140.2, 137.3,
131.3, 130.3, 125.9, 123.6, 123.0, 121.0, 117.4, 116.5, 49.9, 46.0, 40.7, 12.7 ppm. HRMS (ESI),
m/z calcd for C17H17N3NaO4 [M+Na]+ 350.1111, found 350.1114.
12-Nitro-1,2,3,15,16,16a-hexahydro-5H-dibenzo[b,i]pyrrolo[2,1-f][1,4,7]oxadiazecin-5-one
(3f)
Yield 31%, 37 m; dark oil; 1H NMR (400 MHz, DMSO-d6) δ 7.90 (dd, J = 9.1, 2.6 Hz, 1H), 7.70
(d, J = 2.6 Hz, 1H), 7.51 – 7.43 (m, 1H), 7.26 – 7.13 (m, 3H), 6.97 (d, J = 9.1 Hz, 1H), 6.50 (s,
1H), 3.87 – 3.68 (m, 2H), 3.53 – 3.40 (m, 1H), 3.28 – 3.15 (m, 1H), 2.94 – 2.81 (m, 1H), 2.14 –
1.98 (m, 1H), 1.96 – 1.80 (m, 2H), 1.76 – 1.65 (m, 1H) ppm. 13C{1H} NMR (101 MHz, DMSO-
d6) δ 165.7, 152.4, 149.5, 141.2, 137.0, 131.2, 130.1, 126.3, 123.7, 123.0, 119.5, 119.4, 116.1,
61.0, 49.5, 45.3, 31.7, 21.7 ppm. HRMS (ESI), m/z calcd for C18H18N3O4 [M+H]+ 340.1292,
found 340.1297.
8-Benzyl-2-nitro-5,6,7,8-tetrahydro-9H-dibenzo[b,i][1,4,7]oxadiazecin-9-one (3g)
Yield 25%, 34 mg; yellow solid; m.p. 181-183 °C; 1H NMR (400 MHz, DMSO-d6) δ 7.99 – 7.90
(m, 2H), 7.48 – 7.40 (m, 1H), 7.40 – 7.26 (m, 6H), 7.22 – 7.15 (m, 1H), 7.05 (dd, J = 13.3, 8.7
Hz, 2H), 6.60 (t, J = 6.7 Hz, 1H), 4.88 (d, J = 15.1 Hz, 1H), 4.11 (d, J = 14.8 Hz, 1H), 3.66 –
13
3.42 (m, 2H), 3.38 – 3.26 (m, 2H) ppm. C{1H} NMR (101 MHz, DMSO-d6) δ 167.9, 153.1,
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10.1002/ejoc.202000789
European Journal of Organic Chemistry
150.2, 140.2, 137.8, 137.4, 131.5, 130.3, 129.1 (2C), 128.1 (2C), 127.7, 125.4, 123.7, 123.1,
121.1, 117.4, 116.6, 50.2, 48.0, 45.7 ppm. HRMS (ESI), m/z calcd for C22H20N3O4 [M+H]+
390.1448, found 390.1445.
2-Nitro-8-(thiophen-3-ylmethyl)-5,6,7,8-tetrahydro-9H-dibenzo[b,i][1,4,7]oxadiazecin-9-one
(3h)
Yield 39%, 54 mg; yellow solid; mp 180-182 °C; 1H NMR (400 MHz, DMSO-d6) δ 7.95 (dd, J =
9.0, 2.6 Hz, 1H), 7.91 (d, J = 2.6 Hz, 1H), 7.52 (dd, J = 5.0, 3.0 Hz, 1H), 7.46 – 7.38 (m, 2H),
7.30 (dd, J = 7.6, 1.8 Hz, 1H), 7.20 – 7.12 (m, 1H), 7.11 – 6.99 (m, 3H), 6.72 – 6.63 (m, 1H),
4.78 (d, J = 14.9 Hz, 1H), 4.17 (d, J = 14.9 Hz, 1H), 3.71 – 3.56 (m, 1H), 3.53 – 3.40 (m, 1H),
13
3.36 – 3.28 (m, 2H) ppm. C{1H} NMR (101 MHz, DMSO-d6) δ 167.6, 153.2, 150.2, 140.1,
138.4, 137.4, 131.5, 130.3, 128.2, 127.2, 125.4, 123.6, 123.5, 123.1, 121.1, 117.4, 116.5, 50.1,
45.8, 43.7 ppm. HRMS (ESI), m/z calcd for C20H18N3O4S [M+H]+ 396.1013, found 396.1010.
8-(3,4-dimethoxybenzyl)-2-nitro-5,6,7,8-tetrahydro-9H-dibenzo[b,i][1,4,7]oxadiazecin-9-one
(3i)
Yield 20%, 31 mg; yellow solid; mp 176-178 °C; 1H NMR (400 MHz, DMSO-d6) δ 8.03 – 7.87
(m, 2H), 7.47 – 7.13 (m, 3H), 7.08 – 6.82 (m, 5H), 6.63 (s, 1H), 4.80 (d, J = 14.6 Hz, 1H), 4.06
(d, J = 14.6 Hz, 1H), 3.80 – 3.70 (m, 6H), 3.64 – 3.53 (m, 1H), 3.52 – 3.42 (m, 1H), 3.33 – 3.25
13
(m, 2H) ppm. C{1H} NMR (101 MHz, DMSO-d6) δ 167.8, 153.1, 150.3, 149.3, 148.6, 140.1,
137.4, 131.4, 130.2 (2C), 125.5, 123.7, 123.1, 121.1, 120.5, 117.5, 116.5, 112.3, 112.2, 56.0,
55.9, 50.0, 47.7, 45.8 ppm. HRMS (ESI), m/z calcd for C24H23N3NaO6 [M+Na]+ 472.1479,
found 472.1480.
9-Benzyl-2-nitro-6,7,8,9-tetrahydrodibenzo[b,j][1]oxa[4,8]diazacycloundecin-10(5H)-one
(3j)
1
Yield 23%, 31 mg (as a 5:2 mixture of rotamers); light oil; H NMR (400 MHz, DMSO-d6) δ
7.95 – 8.00 (m, 1Hmajor + 1Hminor), 7.87 (d, J = 2.6 Hz, 1Hminor), 7.77 – 7.85 (m, 2Hmajor), 7.53 –
7.59 (m, 1Hmajor), 7.23 – 7.41 (6Hmajor + 5Hminor), 7.18 (t, J = 7.2 Hz, 1Hminor), 7.11 – 7.05 (m,
2Hmajor), 7.04 (d, J = 8.9 Hz, 1Hminor), 7.00 (d, J = 9.1 Hz, 2Hminor), 6.78 (d, J = 8.2 Hz, 1Hminor),
6.23 (t, J = 6.9 Hz, 1Hmajor), 6.11 (t, J = 7.6 Hz, 1Hminor), 5.11 (d, J = 15.1 Hz, 1Hminor), 4.51 –
4.31 (m, 1Hmajor), 4.19 (d, J = 15.1 Hz, 1Hminor), 4.10 – 3.87 (m, 1Hmajor + 1Hminor), 3.74 – 3.84
(m, 1Hmajor), 3.63 – 3.48 (m, 1Hminor), 3.33 – 3.45 (m, 2Hmajor + 2Hminor), 2.90-2.97 (m, 1Hminor),
2.83 – 2.63 (m, 1Hmajor), 2.51 (p, J = 1.9 Hz, 5H), 1.95 – 2.14 (m, 1Hmajor), 1.51 – 1.68 (m,
13
1Hmajor), 1.30 – 1.42 (m, 1Hminor) ppm. C{1H} NMR (101 MHz, DMSO-d6) δ 168.9 (Cmajor),
168.7 (Cminor), 153.9 (Cmajor), 153.6 (Cminor), 150.4 (Cmajor), 147.3 (Cminor), 145.8 (Cmajor + Cminor),
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10.1002/ejoc.202000789
European Journal of Organic Chemistry
143.2 (Cmajor + Cminor), 139.1 (Cmajor), 137.6 (Cmajor), 136.5 (Cmajor), 136.3 (Cminor), 131.7 (Cminor),
131.2 (Cmajor), 129.2 (2Cmajor), 129.1 (2Cminor), 128.7 (Cmajor), 127.6 (Cminor), 127.5 (Cminor), 127.0
(2Cmajor), 126.7 (2Cminor), 123.9 (Cminor), 123.7 (Cminor), 122.9 (Cminor), 122.6 (Cmajor), 120.8
(Cmajor), 120.4 (Cminor), 115.7 (Cminor), 115.1 (Cmajor), 112.7 (Cmajor), 50.8 (Cmajor), 50.7 (Cmajor),
45.1 (Cminor), 45.0 (Cmajor), 43.7 (Cmajor), 43.6 (Cminor), 27.3 (Cmajor), 27.2 (Cminor) ppm. HRMS
(ESI), m/z calcd for C23H21N3O4 [M+H]+ 404.1615, found 404.1614.
8-Methyl-2-(trifluoromethyl)-5,6,7,8-tetrahydro-9H-benzo[i]pyrido[3,2-b][1,4,7]
oxadiazecin-9-one (3k)
1
Yield 32%, 38 mg; light oil; H NMR (400 MHz, CDCl3) δ 8.29 (s, 1H), 7.62 (d, J = 2.1 Hz,
1H), 7.43 – 7.36 (m, 1H), 7.21 (dd, J = 7.6, 1.8 Hz, 1H), 7.16 – 7.05 (m, 2H), 4.47 (t, J = 6.9 Hz,
1H), 4.22 – 4.08 (m, 1H), 3.78 – 3.62 (m, 1H), 3.52 – 3.40 (m, 1H), 3.35 – 3.24 (m, 1H), 2.85 (s,
3H) ppm. 13C{1H} NMR (101 MHz, CDCl3) δ 167.9, 155.9, 151.4, 142.0 (q, J = 4.4 Hz), 136.7,
130.9, 129.3, 127.9 (q, J = 3.3 Hz), 123.9, 123.5 (q, J = 271.3 Hz), 123.3, 118.30 (q, J = 33.5
Hz), 117.6, 54.1, 44.0, 33.4 ppm. HRMS (ESI), m/z calcd for C16H15F3N3O2 [M+H]+ 338.1111,
found 338.1110.
8-Isopropyl-2-(trifluoromethyl)-5,6,7,8-tetrahydro-9H-benzo[i]pyrido[3,2-b][1,4,7]
oxadiazecin-9-one (3l)
Yield 31%, 40 mg; white solid; mp 156-158 °C; 1H NMR (400 MHz, CDCl3) δ 8.31 (dd, J = 2.2,
1.1 Hz, 1H), 7.99 (d, J = 2.3 Hz, 1H), 7.25 (dd, J = 7.6, 1.8 Hz, 1H), 7.17 – 7.11 (m, 1H), 6.82 (t,
J = 6.5 Hz, 1H), 6.70 (d, J = 8.3 Hz, 1H), 4.48 (hept, J = 6.8 Hz, 1H), 3.65 – 3.45 (m, 3H), 3.27
13
– 3.10 (m, 1H), 1.22 – 1.11 (m, 6H) ppm. C{1H} NMR (101 MHz, CDCl3) δ 167.7, 158.0,
152.8, 142.4 (q, J = 3.8 Hz), 135.8, 131.1, 130.1 (q, J = 2.8 Hz), 129.9, 127.0, 124.4 (q, J =
270.9 Hz), 123.5, 115.5 (q, J = 32.8 Hz), 114.6, 48.1, 47.7, 45.8, 20.8, 20.2 ppm. HRMS (ESI),
m/z calcd for C18H18F3N3NaO2 [M+Na]+ 388.1243, found 388.1240.
8-Benzyl-2-(trifluoromethyl)-5,6,7,8-tetrahydro-9H-benzo[i]pyrido[3,2-b][1,4,7]
oxadiazecin-9-one (3m)
Yield 40%, 58 mg; light oil; 1H NMR (400 MHz, CDCl3) δ 8.37 – 8.31 (m, 1H), 7.67 (d, J = 2.1
Hz, 1H), 7.43 – 7.22 (m, 7H), 7.18 – 7.11 (m, 1H), 7.07 (dd, J = 8.3, 1.0 Hz, 1H), 5.08 (d, J =
14.9 Hz, 1H), 4.46 (t, J = 7.0 Hz, 1H), 4.21 – 4.08 (m, 1H), 3.82 (d, J = 14.5 Hz, 1H), 3.61 –
3.47 (m, 1H), 3.38 – 3.20 (m, 2H) ppm. 13C{1H} NMR (101 MHz, CDCl3) δ 168.1, 156.1, 151.4,
142.1 (q, J = 4.5 Hz), 136.9, 136.6, 131.0, 129.4, 128.8 (2C), 128.3 (q, J = 3.3 Hz), 128.2 (2C),
127.7, 123.8, 123.5 (q, J = 271.3 Hz), 123.3, 118.3 (q, J = 33.4 Hz), 117.3, 50.6, 47.4, 44.1 ppm.
HRMS (ESI), m/z calcd for C22H18F3N3NaO2 [M+Na]+ 436.1243, found 436.1240.
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10.1002/ejoc.202000789
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8-(Thiophen-2-ylmethyl)-2-(trifluoromethyl)-5,6,7,8-tetrahydro-9H-benzo[i]pyrido[3,2-
b][1,4,7]oxadiazecin-9-one (3n)
Yield 47%, 69 mg; light oil; 1H NMR (400 MHz, CDCl3) δ 8.31 (d, J = 2.2 Hz, 1H), 7.82 (d, J
= 2.2 Hz, 1H), 7.50 – 7.41 (m, 2H), 7.19 – 7.10 (m, 3H), 7.06 (d, J = 8.4 Hz, 1H), 6.98 (dd, J =
5.2, 3.4 Hz, 1H), 6.50 (t, J = 6.7 Hz, 1H), 4.86 – 4.72 (m, 1H), 4.31 – 4.19 (m, 1H), 3.91 – 3.74
13
(m, 1H), 3.53 – 3.41 (m, 1H), 3.37 – 3.34 (m, 2H) ppm. C{1H} NMR (101 MHz, CDCl3) δ
167.5, 157.2, 152.1, 142.4 (q, J = 4.5 Hz), 140.4, 136.4, 131.3, 129.5, 128.4 (q, J = 3.3 Hz),
127.4, 127.1, 126.5, 124.4 (q, J = 271 Hz), 124.3, 123.5, 117.8, 115.3 (q, J = 33 Hz), 50.7, 43.7,
43.0 ppm. HRMS (ESI), m/z calcd for C20H16F3N3NaO2S [M+Na]+ 442.0808, found 442.0810.
8-Methyl-2-(pyrrolidin-1-ylsulfonyl)-5,6,7,8-tetrahydro-9H-benzo[i]pyrido[3,2-
b][1,4,7]oxadiazecin-9-one (3o)
Yield 55%, 77 mg, light oil; 1H NMR (400 MHz, DMSO-d6) δ 8.31 (d, J = 2.1 Hz, 1H), 7.60 (d,
J = 2.1 Hz, 1H), 7.45 (ddd, J = 8.7, 7.1, 1.9 Hz, 1H), 7.19 (d, J = 8.4 Hz, 1H), 7.16 – 7.06 (m,
2H), 6.28 (s, 1H), 4.01 – 3.85 (m, 1H), 3.59 – 3.44 (m, 1H), 3.43 – 3.35 (m, 1H), 3.31 – 3.24 (m,
13
1H), 3.20 – 3.06 (m, 4H), 2.67 (s, 3H), 1.83 – 1.67 (m, 4H) ppm. C{1H} NMR (101 MHz,
DMSO-d6) δ 167.7, 156.9, 151.6, 144.6, 137.0, 131.0, 129.4, 128.8, 124.3, 123.4, 121.8, 119.5,
53.7, 48.3 (2C), 43.0, 33.3, 25.1(2C) ppm. HRMS (ESI), m/z calcd for C19H23N4O4S [M+H]+
403.1435, found 403.1436.
9-Benzyl-2-(pyrrolidin-1-ylsulfonyl)-6,7,8,9-tetrahydrobenzo[j]pyrido[3,2-b][1]oxa[4,8]
diazacycloundecin-10(5H)-one (3p)
1
Yield 32%, 48 mg (as a 5:1 mixture of rotamers); light oil; H NMR (400 MHz, DMSO-d6) δ
8.29 (d, J = 1.8 Hz, 1Hmajor), 8.23 (d, J = 1.8 Hz, 1Hminor), 7.82 (d, J = 6.2 Hz, 1Hmajor), 7.51 –
7.57 (m, 1Hmajor), 7.45 – 7.50 (m, 2Hminor), 7.22 – 7.42 (m, 6Hmajor + 8Hminor), 7.08 (d, J = 7.2 Hz,
2H), 6.98 (t, J = 1.8 Hz, 1Hminor), 6.69 (t, J = 1.9 Hz, 1Hminor), 4.95 (d, J = 15.0 Hz, 1Hminor), 4.31
– 4.44 (m, 1Hmajor), 3.51 – 4.06 (m, 4Hmajor + 3Hminor), 3.34 – 3.41 (m, 2Hminor), 2.98-3.16 (m,
4Hmajor + 4Hminor), 2.90 – 2.96 (m, 2.70, 1Hminor), 2.70 (dd, J = 13.8, 3.9 Hz, 1Hmajor), 2.08 –
2.28 (m, 1Hmajor + 4Hminor), 1.64 – 1.76 (m, 1Hmajor), 1.48 – 1.63 (m, 4Hmajor + 4Hminor) ppm.
13C{1H} NMR (101 MHz, DMSO-d6) δ 168.5 (Cminor), 168.2 (Cmajor), 155.7 (Cminor), 155.5
(Cmajor), 154.2 (Cmajor), 152.2 (Cminor), 143.9 (Cminor), 143.6 (Cmajor), 138.1 (Cmajor), 137.4 (Cminor),
136.1 (Cminor + Cminor), 133.5 (Cmajor), 131.3 (Cminor), 131.1 (Cmajor), 129.6 (Cminor), 129.3 (2Cmajor
+ 2Cminor), 129.1 (Cmajor), 128.2 (Cmajor), 128.1 (Cmajor + Cminor), 127.7 (Cmajor), 127.2 (2Cmajor
+
2Cminor), 126.7 (Cminor + Cminor), 124.7 (Cminor), 124.6 (Cmajor), 123.6 (Cmajor + Cminor), 120.2 (Cmajor
+ Cminor), 60.2 (Cmajor), 50.4 (Cminor), 48.2 (Cmajor + Cminor), 44.6 (Cminor), 42.2 (Cmajor), 25.2
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10.1002/ejoc.202000789
European Journal of Organic Chemistry
(2Cminor), 25.1 (Cmajor), 21.2 (Cmajor), 14.5 (Cmajor + Cminor) ppm. HRMS (ESI), m/z calcd for
C26H28N4O4S [M+H]+ 493.6015, found 493.6011.
8-Ethyl-5,6,7,8-tetrahydro-9H-benzo[i]pyrazino[2,3-b][1,4,7]oxadiazecin-9-one (3q)
1
Yild 23%, 23 mg; white solid; mp 178-180 °C; H NMR (400 MHz, DMSO-d6) δ 7.93 (d, J =
2.7 Hz, 1H), 7.54 (d, J = 2.7 Hz, 1H), 7.43 (t, J = 7.1 Hz, 1H), 7.29 – 7.22 (m, 1H), 7.22 – 7.11
(m, 2H), 6.44 (t, J = 6.8 Hz, 1H), 3.70 – 3.54 (m, 2H), 3.52 – 3.37 (m, 2H), 3.27 – 2.77 (m, 2H),
1.06 (t, J = 7.1 Hz, 3H) ppm. 13C{1H} NMR (101 MHz, DMSO-d6) δ 167.2, 151.9, 150.0, 145.3,
140.1, 131.2, 130.4, 130.0, 125.9, 123.9, 118.2, 49.6, 43.12, 40.7, 12.5 ppm. HRMS (ESI), m/z
calcd for C15H17N4O2 [M+H]+ 285.1346, found 285.1345.
8-Benzyl-5,6,7,8-tetrahydro-9H-benzo[i]pyrazino[2,3-b][1,4,7]oxadiazecin-9-one (3r)
Yield 26%, 32 mg; white solid; mp 164-166 °C; 1H NMR (400 MHz, DMSO-d6) δ 7.99 (s, 1H),
7.58 (s, 1H), 7.46 (t, J = 7.9 Hz, 1H), 7.42 – 7.25 (m, 6H), 7.25 – 7.14 (m, 2H), 6.43 (t, J = 6.7
Hz, 1H), 5.15 – 3.88 (m, 2H), 3.61 (s, 2H), 3.45 – 3.26 (m, 2H) ppm. 13C{1H} NMR (101 MHz,
DMSO-d6) δ 168.0, 151.8, 150.0, 145.3, 140.3, 137.8, 131.4, 130.3, 130.3, 129.0 (2C), 128.1
(2C), 127.7, 125.3, 124.0, 118.4, 49.8, 47.9, 42.8 ppm. HRMS (ESI), m/z calcd for C20H19N4O2
[M+H]+ 347.1503, found 347.1503.
8-(Thiophen-2-ylmethyl)-5,6,7,8-tetrahydro-9H-benzo[i]pyrazino[2,3-b][1,4,7]oxadiazecin-
9-one (3s)
1
Yield 30%, 37 mg; white solid; mp 167-169 °C; H NMR (400 MHz, DMSO-d6) δ 7.96 (d, J =
2.7 Hz, 1H), 7.56 (d, J = 2.7 Hz, 1H), 7.50 – 7.39 (m, 2H), 7.30 – 7.15 (m, 3H), 7.11 (d, J = 3.4
Hz, 1H), 6.98 (t, J = 4.3 Hz, 1H), 6.51 (t, J = 6.8 Hz, 1H), 4.75 – 4.27 (m, 2H), 3.77 – 3.55 (m,
2H), 3.42 – 3.36 (m, 2H) ppm. 13C{1H} NMR (101 MHz, DMSO-d6) δ 167.6, 152.0, 150.0,
145.3, 140.3, 140.1, 131.6, 130.3, 130.2, 127.5, 127.0, 126.7, 125.1, 124.1, 118.4, 49.5, 43.4,
42.7 ppm. HRMS (ESI), m/z calcd for C18H17N4O2S [M+H]+ 353.1062, found 353.1060.
8-Benzyl-3-chloro-5,6,7,8-tetrahydro-9H-dibenzo[b,i][1,4,7]oxadiazecin-9-one (3z)
Yield 6%, 8 mg; light oil; 1H NMR (400 MHz, DMSO-d6) δ 7.41 – 7.25 (m, 7H), 7.19 – 7.08 (m,
2H), 6.99 (d, J = 2.6 Hz, 1H), 6.87 – 6.82 (m, 1H), 6.76 (dd, J = 8.5, 2.5 Hz, 1H), 5.40 (t, J = 6.4
Hz, 1H), 4.85 (d, J = 14.9 Hz, 1H), 4.18 (d, J = 15.1 Hz, 1H), 3.45 – 3.33 (m, 1H), 3.30 – 3.19
13
(m, 3H) ppm. C{1H} NMR (101 MHz, DMSO-d6) δ 168.1, 153.5, 145.2, 140.6, 138.0, 131.2,
130.5, 129.6, 129.0 (2C), 128.2 (2C), 127.7, 126.7, 125.4, 122.8, 118.5, 118.4, 115.1, 51.7, 47.8,
47.3 ppm. HRMS (ESI), m/z calcd for C22H20ClN2O2 [M+H]+ 379.1208, found 379.1208.
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10.1002/ejoc.202000789
European Journal of Organic Chemistry
10-(2-(Benzylamino)ethyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]oxazepine-7-carbonitrile
(4a)
Yield 10%, 13 mg; light oil; 1H NMR (400 MHz, CDCl3): δ 7.85 (dd, J = 7.8, 1.7 Hz, 1H), 7.59
– 7.45 (m, 4H), 7.35 – 7.21 (m, 7H), 4.24 (t, J = 6.3 Hz, 2H), 3.82 (s, 2H), 3.05 (t, J = 6.3 Hz,
2H) ppm. 13C{1H} NMR (101 MHz, CDCl3): δ = 166.0, 159.9, 154.2, 139.8, 139.7, 134.0, 132.3,
129.8, 128.5 (2C), 128.1 (2C), 127.1, 126.1, 126.0, 125.6, 124.6, 119.7, 117.5, 109.6, 53.5, 49.6,
46.8 ppm. HRMS (ESI), m/z calcd for C23H20N3O2 [M+H]+ 370.1550, found 370.1553.
10-(2-(Ethylamino)ethyl)-N,N-dimethyl-11-oxo-10,11-dihydrodibenzo[b,f][1,4]oxazepine-7-
sulfonamide (4b)
1
Yield 6%, 8 mg; light oil; H NMR (400 MHz, DMSO-d6): δ 7.92 (d, J = 8.5 Hz, 1H), 7.79 –
7.72 (m, 2H), 7.66 – 7.58 (m, 2H), 7.49 (dd, J = 8.1, 1.1 Hz, 1H), 7.37 – 7.31 (m, 1H), 4.15 (t, J
= 6.6 Hz, 2H), 2.82 (t, J = 6.5 Hz, 2H), 2.64 (s, 6H), 2.50 (q, 2H), 0.93 (t, J = 7.1 Hz, 3H) ppm.
13C{1H} NMR (101 MHz, DMSO-d6): δ 165.5, 160.0, 154.0, 139.4, 134.7, 132.8, 132.2, 126.6,
126.5, 125.9, 125.6, 121.1, 120.4, 49.4, 47.2, 43.6, 38.0 (2C), 15.7 ppm. HRMS (ESI), m/z calcd
for C19H24N3O4S [M+H]+ 390.1482, found 390.1485.
10-(2-(Methylamino)ethyl)dibenzo[b,f][1,4]oxazepin-11(10H)-one (4t)
Yield 45%, 42 mg; light oil; 1H NMR (400 MHz, CDCl3) δ 7.86 (dd, J = 7.8, 1.7 Hz, 1H), 7.49 –
7.43 (m, 1H), 7.38 (dd, J = 7.8, 1.9 Hz, 1H), 7.30 – 7.14 (m, 5H), 4.27 (s, 2H), 2.97 (t, J = 6.5
Hz, 2H), 2.45 (s, 3H) ppm. 13C{1H} NMR (101 MHz, CDCl3) δ 166.5, 160.8, 154.9, 134.9,
133.4, 132.1, 126.8, 126.7, 125.9, 125.3, 123.7, 121.6, 119.7, 49.6, 48.8, 36.2 ppm. HRMS
(ESI), m/z calcd for C16H16N2NaO2 [M+Na]+ 291.1104, found 291.1105.
10-(2-(Ethylamino)ethyl)dibenzo[b,f][1,4]oxazepin-11(10H)-one (4u)
Yield 36%, 36 mg; light oil; 1H NMR (400 MHz, CDCl3) δ 7.86 (dd, J = 7.8, 1.8 Hz, 1H), 7.50 –
7.43 (m, 1H), 7.38 (dd, J = 7.8, 1.8 Hz, 1H), 7.31 – 7.13 (m, 5H), 4.26 (s, 2H), 3.02 (t, J = 6.6
Hz, 2H), 2.67 (q, J = 7.1 Hz, 2H), 1.09 (t, J = 7.1 Hz, 3H) ppm. 13C{1H} NMR (101 MHz,
CDCl3) δ 166.5, 160.8, 154.9, 134.8, 133.4, 132.0, 126.8, 126.7, 125.9, 125.3, 123.7, 121.6,
119.7, 49.0, 47.3, 43.7, 15.2 ppm. HRMS (ESI), m/z calcd for C17H18N2NaO2 [M+Na]+
305.1260, found 305.1265.
8-Methyl-10-(2-(methylamino)ethyl)dibenzo[b,f][1,4]oxazepin-11(10H)-one (4v)
Yield 31%, 38 mg; light oil; 1H NMR (400 MHz, CDCl3) δ 7.82 (dd, J = 7.7, 1.8 Hz, 1H), 7.44 –
7.37 (m, 1H), 7.21 – 7.11 (m, 4H), 6.93 (dd, J = 8.2, 2.0 Hz, 1H), 4.24 (s, 2H), 2.94 (t, J = 6.5
Hz, 2H), 2.42 (s, 3H), 2.30 (s, 3H) ppm. 13C{1H} NMR (101 MHz, CDCl3) δ 166.6, 161.0,
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10.1002/ejoc.202000789
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152.8, 135.8, 134.3, 133.3, 132.0, 127.2, 126.9, 125.2, 124.1, 121.2, 119.6, 49.7, 48.7, 36.2, 21.0
ppm. HRMS (ESI), m/z calcd for C17H19N2O2 [M+H]+ 283.1441, found 283.1440.
10-(2-(Ethylamino)ethyl)-8-methyldibenzo[b,f][1,4]oxazepin-11(10H)-one (4w)
Yield 24%, 25 mg; light oil; 1H NMR (400 MHz, CDCl3) δ 7.83 (dd, J = 7.7, 1.8 Hz, 1H), 7.46 –
7.38 (m, 1H), 7.22 – 7.12 (m, 4H), 6.95 (d, J = 2.0 Hz, 1H), 4.24 (s, 2H), 2.99 (t, J = 6.6 Hz,
13
2H), 2.66 (q, J = 7.1 Hz, 2H), 2.31 (s, 3H), 1.07 (t, J = 7.1 Hz, 3H) ppm. C{1H} NMR (101
MHz, CDCl3) δ 166.6, 161.0, 152.8, 135.7, 134.4, 133.3, 132.0, 127.2, 126.9, 125.2, 124.1,
121.1, 119.6, 49.0, 47.4, 43.8, 21.0, 15.3 ppm. HRMS (ESI), m/z calcd for C18H21N2O2 [M+H]+
297.1598, found 297.1599.
10-(2-(Benzylamino)ethyl)-8-methyldibenzo[b,f][1,4]oxazepin-11(10H)-one (4x)
Yield 19%, 15 mg; light oil; 1H NMR (400 MHz, CDCl3: δ 7.85 (dd, J = 7.8, 1.8 Hz, 1H), 7.47 –
7.40 (m, 1H), 7.34 – 7.13 (m, 9H), 6.95 (dd, J = 8.2, 2.0 Hz, 1H), 4.28 (s, 2H), 3.82 (s, 2H), 3.03
13
(t, J = 6.5 Hz, 2H), 2.31 (s, 3H) ppm. C{1H} NMR (101 MHz, CDCl3) δ 166.7, 161.0, 152.9,
140.2, 135.7, 134.3, 133.3, 132.0, 128.4 (2C), 128.0 (2C), 127.2, 126.9 (2C), 125.2, 124.1,
121.2, 119.6, 53.5, 48.9, 47.0, 21.0 ppm. HRMS (ESI), m/z calcd for C23H23N2O2 [M+H]+
359.1754, found 359.1753.
8-Chloro-10-(2-(methylamino)ethyl)dibenzo[b,f][1,4]oxazepin-11(10H)-one (4y)
1
Yield 57%, 60 mg; light oil; H NMR (400 MHz, DMSO-d6) δ 7.82 (d, J = 2.5 Hz, 1H), 7.72
(dd, J = 7.8, 1.8 Hz, 1H), 7.60 – 7.53 (m, 1H), 7.40 (d, J = 8.6 Hz, 1H), 7.36 – 7.24 (m, 3H), 4.12
13
(t, J = 6.7 Hz, 2H), 2.74 (t, J = 6.5 Hz, 2H), 2.70 (br s, 1H), 2.26 (s, 3H) ppm. C{1H} NMR
(101 MHz, DMSO-d6) δ 165.6, 160.3, 153.4, 136.3, 134.4, 132.2, 130.4, 126.9, 126.8, 126.2,
124.7, 123.3, 120.2, 49.6, 48.7, 36.3 ppm. HRMS (ESI), m/z calcd for C16H16ClN2O2 [M+H]+
303.0895, found 303.0896.
10-(2-(Benzylamino)ethyl)-8-chlorodibenzo[b,f][1,4]oxazepin-11(10H)-one (4z)
1
Yield 14%, 19 mg; light oil; H NMR (400 MHz, DMSO-d6) δ 7.86 (d, J = 2.5 Hz, 1H), 7.71
(dd, J = 7.8, 1.7 Hz, 1H), 7.61 – 7.54 (m, 1H), 7.41 (d, J = 8.6 Hz, 1H), 7.37 – 7.16 (m, 8H), 4.15
(t, J = 6.4 Hz, 2H), 3.69 (s, 2H), 2.79 (t, J = 6.4 Hz, 2H) ppm. 13C{1H} NMR (101 MHz, DMSO-
d6) δ 165.6, 160.3, 153.4, 141.1, 136.3, 134.4, 132.2, 130.4, 128.5 (2C), 128.2 (2C), 127.0,
126.9, 126.8, 126.2, 124.8, 123.3, 120.2, 53.1, 49.0, 46.7 ppm. HRMS (ESI), m/z calcd for
C22H20ClN2O2 [M+H]+ 379.1208, found 379.1210.
3-Chloro-8-methyl-5,6,7,8-tetrahydro-9H-dibenzo[b,i][1,4,7]oxadiazecin-9-one (3y)
This article is protected by copyright. All rights reserved.

10.1002/ejoc.202000789
European Journal of Organic Chemistry
To a solution of 4y (60 mg, 0.2 mmol) in a 1:1 mixture MeOH/H2O (2 mL) solid KOH (45 mg,
o
0.8 mmol, 4 equiv.) was added. The reaction was stirred at 60 C for 12 h, then poured into
water (10 mL) and extracted into EtOAc (2 x 5 mL). The organic layer was washed with water,
dried over anhydrous Na2SO4, filtered and concentrated in vacuo. Column chromatography on
silica gel using ethyl acetate as eluent afforded the title compound. Yield 63%, 38 mg; light oil;
1H NMR (400 MHz, DMSO-d6) δ 7.39 – 7.32 (m, 1H), 7.20 (dd, J = 7.5, 1.8 Hz, 1H), 7.14 –
7.05 (m, 2H), 6.98 (d, J = 2.6 Hz, 1H), 6.87 (dd, J = 8.4, 1.0 Hz, 1H), 6.73 (dd, J = 8.5, 2.5 Hz,
1H), 5.34 (t, J = 6.4 Hz, 1H), 3.49 – 3.38 (m, 1H), 3.35 – 3.31 (m, 3H), 2.82 (s, 3H) ppm.
13C{1H} NMR (101 MHz, DMSO-d6) δ 167.5, 153.5, 145.0, 140.7, 130.9, 130.4, 129.5, 126.4,
125.5, 122.7, 118.4 (2C), 115.4, 54.2, 46.9, 33.1 ppm. HRMS (ESI), m/z calcd for C16H16ClN2O2
[M+H]+ 303.0895, found 303.0890.
Acknowledgement
This research was supported by the Russian Foundation for Basic Research (grant no. 19-33-
90010). We thank the Research Centre for Magnetic Resonance, the Center for Chemical
Analysis and Materials Research, and the Centre for X-ray Diffraction Methods of Saint
Petersburg State University Research Park for obtaining the analytical data. The project made
use of the NMR Uppsala infrastructure, which is funded by the Department of Chemistry - BMC
and the Disciplinary Domain of Medicine and Pharmacy.
Keywords: medium-sized rings; hydrated imidazoline ring expansion; imidazolinium salt
synthesis; cis/trans amide bond isomerism; intramolecular hydrogen bond.
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