Convenient Assembly of Privileged (Hetero)Arene-Fused Benzo[1.4]oxazepines via Two Tandem SNAr Events. Part 1 – On the Importance of the Intermittent Smiles Rearrangement

Article abstract of DOI:10.1002/ejoc.201900263

New bis-nucleophilic precursors to [1.4]oxazepines synthesized via S_NAr-Smiles rearrangement-S_NAr cascade have been designed. Employing them in base-promoted condensation with aromatic bis-electrophiles allowed differentiating between highly and poorly reactive substrates (i.e. those which can and cannot pass through the Smiles rearrangement barrier, respectively). The reactivity toward the desired course of cyclization can be restored by introducing electron-withdrawing substituents in the bis-electrophile precursor. This strongly argues for the importance of the Smiles rearrangement for the successful overall ring formation.

Full text of DOI:10.1002/ejoc.201900263

A Journal of
Accepted Article
Title: Convenient Assembly of Privileged (Hetero)Arene-Fused
Benzo[1.4]oxazepines via Two Tandem SNAr Events. Part 1 - On
the Importance of the Intermittent Smiles Rearrangement
Authors: Alexander Sapegin and Mikhail Krasavin
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201900263
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10.1002/ejoc.201900263
European Journal of Organic Chemistry
Convenient
Assembly
of
Privileged
(Hetero)Arene-Fused
Benzo[1.4]oxazepines via Two Tandem SNAr Events. Part 1 - On the
Importance of the Intermittent Smiles Rearrangement
Alexander Sapegin[a] and Mikhail Krasavin*[a]
[a] Dr. Alexander Sapegin and Prof. Dr. Mikhail Krasavin
Saint Petersburg State University, Saint Petersburg 199034 Russian Federation
http://www.krasavin-group.org
E-mail: m.krasavin@spbu.ru
Abstract: new bis-nucleophilic precursors to [1.4]oxazepines synthesized via SNAr-Smiles
rearrangement-SNAr cascade have been designed. Employing them in base-promoted
condensation with aromatic bis-electrophiles allowed differentiating between highly and poorly
reactive substrates (i. e. those which can and cannot pass through the Smiles rearrangement
barrier, respectively). The reactivity toward the desired course of cyclization can be restored by
introducing electron-withdrawing substituents in the bis-electrophile precursor. This strongly
argues for the importance of the Smiles rearrangement for the successful overall ring formation.
Introduction
Tricyclic (hetero)arene-fused benzo[1,4]oxazepines represent a broad cluster of privileged[1]
tricyclic systems (Fig. 1) that has delivered a wealth of biologically active compounds and drugs
in various therapeutic areas.[2] On top of its well established positions in drug discovery, only in
the recent three years, tricyclic benzo[1,4]oxazepine scaffolds have been explored in the design
of nuclear farnesoid X receptor (FXR) modulators,[3] serine hydroxymethyltransferase 2
(SHMT2) inhibitors,[4] and serotonin receptor 5-HT2B antagonists,[5] and human carbonic
anhydrase (hCA) inhibitors[6] (Fig. 2).
Fig. 1. Privileged tricycles for the drug design.
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10.1002/ejoc.201900263
European Journal of Organic Chemistry
O
O
O
N
HN
N
O
N
O
Cl
Cl
O
O
OH
N
FXR modulator
O
SHMT2 inhibitor
N
O
HN
N
O
N
N
N
Cl
O
O
SO2NH2
5-HT 2B antagonist
hCA inhibitor
Fig. 2. Examples of bioactive tricyclic benzo[1,4]oxazepines from the recent literature.
Recently, we have been developing a generalized strategy to assemble such scaffolds. The
resulting protocols do not employ linear synthetic sequences, are based on a judicial design of
reactivity-matched bifunctional partners and do not require the use of expensive (and
environmentally hazardous) transition metal catalysts. The approach involves the use of phenols
1 substituted at the ortho-position with a moderately acidic functionality which can react, under
mildly basic conditions, with bis-electrophilic aromatic and heteroaromatic partners 2. The
process essentially proceeds via two consecutive SNAr events intermitted by a Smiles
rearrangement. It is triggered by displacement of the most labile leaving group in 2 by the
phenoxide nucleophile and is completed after the phenoxide anion is liberated again, via the
Smile rearrangement, for the substitution of the other, less labile leaving group. Thus, the
intricate interplay of consecutive steps aided by the timely nucleophile switch lays an
energetically favorable path for the reaction and enables efficient overall ring closing process
towards tricylic product 3. The strategy has been realized for such Y-ZH motifs as secondary
amides (3a),[7] pyrazoles (3b),[8] imidazolines (3c),[9] secondary sulfonamides (3d),[10]
and O-alkyl hydroxamic acids (3e)[11] (Scheme 1).
Scheme 1. Synthetic strategy toward tricycles 3 employed to-date.
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10.1002/ejoc.201900263
European Journal of Organic Chemistry
It should be noted that in all cases listed above, the regiochemistry of the tricyclic adducts 3a-e
(as confirmed by X-ray crystallography or correlational NMR spectra) corresponded to the
Smiles rearrangement occurring in between of the two consecutive SNAr events. This led us to
hypothesize that the occurrence (i. e. the kinetic and thermodynamic feasibility) of the Smiles
rearrangement might be a pre-requisite to the successful overall ring-forming even. In order to
test this hypothesis, we aimed to energetically disfavor the Smiles rearrangement and potentially
exclude some of the reactivity-matched bis-electrophiles 2 which have been successfully
involved in the construction of tricyles 3. We noted that all bis-electrophiles 1a-e employed so
far possessed an electro-withdrawing Y-ZH motif in conjugation with the phenol functionality.
On the one hand, this is mandated by the need to NH-deprotonate this motif (in 4) under the
reaction conditions and to generate a competent internal nucleophile (5) for the Smiles
rearrangement. On the other hand, an electron-withdrawing group in the ortho-position to the
phenolic hydroxyl group in 1 will ultimately stabilize the phenoxide leaving group released in
the course of the Smiles rearrangement (and the formation of 6) and will thermodynamically
facilitate the latter. Since our goal was to perturb this favorable reactivity situation, reduce the
likelihood of the Smiles rearrangement for some substrates 2 and thus confirm the hypothesis on
its importance for the overall ring-forming process, we designed a new type of bis-nucleophiles 7
where the electron-withdrawing carbonyl group would still enable deprotonation of the
secondary amide functionality (in analogy to 1a) but be removed from the conjugation from the
phenoxy group in 6 this changing the energy characteristics of the postulated reactive
intermediates (Fig. 3). Herein, we describe the results obtained in the course of testing the new
reactivity-matched combinations of 7 and 2 in the formation of the respective tricyclic
[1.4]oxazepines.
Fig. 3. Expected impact of replacing 1a with 7 on the course of the reaction.
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10.1002/ejoc.201900263
European Journal of Organic Chemistry
Results and Discussion
A set of seven 2-(N-carbonylamino)methyl phenols 7a-g was prepared in 4-5 straightforward
steps as indicated in Scheme 2.
O
O
CN
CN
OH
iii or iv-v
N
R'
vi
ii
NH2
OBn
N
H
R'
i
R
H
R
R
R
R
OH
7a-g
OBn
OBn
Reagents and Conditions:
i: BnBr, K2CO3, DMF, RT, 12 h; ii: LiAlH4, THF, reflux, 5 h; iii: R'COCl, TEA, DCM, 5-10 oC, 5 h; iv: triphosgene, toluene, reflux, 6 h;
v: HNR''R''', TEA, RT, 12 h; vi: HCO2NH4, 10% Pd/C, MeOH, 8 h, 60 oC.
Scheme 2. Synthesis of bis-nucleophilic synthons 7a-g.
In order to determine optimal conditions (solvent, temperature and base), compound 7a was
cyclocondensed with 2,3-dichloropyrazine to demonstrate that the best yield of tricyclic product
8a was achieved at room temperature in DMSO or DMF using Cs2CO3 as a base (Table 1). All
subsequent reactions were run in DMF due to easier removal of this solvent.
Table 1. Screening of the 7a8a reaction conditions.
T
(ºC)
40
Time
(h)
15
9
Isolated yield of
Entry
Base
Solvent
8a (%)
41
1
2
3
4
5
6
7
8
K2CO3
K2CO3
K2CO3
Cs2CO3
Cs2CO3
Cs2CO3
t-BuOK
NaH
MeCN
DMF
40
56
DMSO
MeCN
DMF
40
9
65
RT
RT
RT
RT
RT
18
4
69
75
DMSO
DMF
4
76
4
48
DMF
3
37
Having identified the optimum solvent and base for the reaction, we proceeded testing bis-
nucleophiles 7a-g in reactions with bis-electrophilic (hetero)aromalic substrates 2 containing
vicinally positioned leaving groups (halogens or nitro groups). The progress of the reaction was
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10.1002/ejoc.201900263
European Journal of Organic Chemistry
monitored by analytical HPLC and the reaction temperature and time indicated represent the
parameters required to achieve full conversion (Table 2).
Table 2. Base-promoted cyclocondensation of reactivity-matched bis-nucleophiles 7a-g with
various bis-electrophilic (hetero)aromatic substrates 2.
T
Time Yield
Entry
1
7
2
Product 8(9)
(ºC)
(h)
(%)
r.t.
4
75
O
N
OMe
H
O
2
100
24
59
Cl
9a
N
Br
3
4
75
50
5
4
63
69
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10.1002/ejoc.201900263
European Journal of Organic Chemistry
5
60
24
51
O
N
OMe
H
O
6
r.t.
24
34
Cl
N
9c
NO2
6
7
40
75
8
8
57
44
8
9
50
7
4
50
79
r.t.
10
75
5
58
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10.1002/ejoc.201900263
European Journal of Organic Chemistry
11
50
75
6
6
71
63
12
13
O
N
H
S
O
45
24
85
NO2
9d
NO2
14
15
50
75
5
9
52
47
16
17
50
50
7
8
63
68
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10.1002/ejoc.201900263
European Journal of Organic Chemistry
18
75
50
6
8
44
53
19
20
O
N
N
H
O
60
24
63
Cl
N
9e
CF3
21
45
24
66
Cl
NH
N
8q
N
22
23
50
75
4
6
41a
38a
O
aThe ethylamino carbonyl group in 8q-r proved to be hydrolytically labile and was lost in the
course of aqueous workup.
As it is evident from the results presented in Table 1, the new type of bis-nucleophilic
condensation partners 7 clearly allows to differentiate between highly reactive bis-electrophilic
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10.1002/ejoc.201900263
European Journal of Organic Chemistry
counterparts (i. e. 2a, 2c, 2d which delivered the anticipated [1.4]oxazepinones 8) and non-
reactive ones (in this case, 2b, 2e and 2f whose reaction stalled after first SNAr event – at
intermediate 10 – and thus delivered only non-cyclized products 9). Notably, this differentiation
has not been observed with substrates 1a-e and was established in this study for the first time. It
is likely due to the absence of stabilization of the phenoxide intermediate 12 by an electron-
withdrawing substituent. Raising the energy of 12 as the final state of the Smiles rearrangement
(101112), in turn, leads to some substrate combinations – particularly those which do not
effectively stabilize Meisenheimer intermediate 11 – not being able to cross the energy barrier
leading to the cyclization (Figure 4).
Fig. 4. Plausible mechanism for the formation of adducts 8(9).
Aiming to test the above mechanistic reasoning for the formation of non-cyclized products 8, we
decided to place electron-withdrawing groups (EWG) within the structure of bis-nucleophiles 7
so that the former are in conjugation with the phenolic hydroxyl group. We reasoned that, if the
proposed mechanism and its interpretation are fundamentally correct, EWG-substituted
substrates 7h-i (whose reaction’s path would be more energetically favorable due to greater
stabilization of intermediate 12) will be able to react with some of the substrates 2 which did not
previously react with partners 7.
Compounds 7h-i were obtained in several straightforward steps from substituted
salicylaldehydes 13a-b, one of which, 13a, needed to be synthesized (Scheme 3).
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10.1002/ejoc.201900263
European Journal of Organic Chemistry
N
N
i
O
O
O
OH
OH
13a
EWG
O
NH2
OBn
OH
EWG
EWG
EWG
O
vii-viii
N
OMe
ii-iii
iv-vi
H
OH
13a-b
i: Urotropin, TFA, reflux, 24 h; ii: BnBr, K2CO3, DMF, r.t., 12 h;
OH
OBn
7h, EWG = CON(CH2)4
7i, EWG = NO2
iii: NaBH4, MeOH 5-10 oC, 4 h; iv: PBr3, DCM, 0 oC, 2 h; v: NaN3, MeCN,
12 h, r.t.; vi: PPh3 0 oC, 1h; vii: MeOCOCl, TEA, DCM, 5-10 oC, 5 h;
viii: HCO2NH4, 10% Pd/C, MeOH, 8 h, 60 oC.
Scheme 3. Synthesis of bis-nucleophilic synthons 7h-i.
To our delight, bis-nucleophile 7h was indeed found reactive not only with the highly reactive
substrate 2d (delivering respective cyclic adduct 8s in excellent yield) but also with substrates 2e
and 2f which previously underwent the initial SNAr reaction but failed to cyclize. However, in
case of 7i, no reaction occurred neither with the highly reactive substrate 2a nor with 2f whose
reactivity was shown to be lower (Table 3). The latter experimental observation can be justified
by the overly stable phenoxide anion (conjugate to 7) which is not able to pass even through the
initial SNAr step. Both of these facts strongly support the mechanistic picture for the formation of
[1.4]oxazepines proposed above.
Table 3. Cyclizations involving electron-poor phenolic substrates 7h-i..
T
Time Yield
Entry
EWG
2
Product 8(9)
(ºC)
(h)
(%)
MeO
O
N
N
N
CH3
1
r.t.
3
85
O
N
O
8s
F3C
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10.1002/ejoc.201900263
European Journal of Organic Chemistry
2
60
90
6
8
46
38
3
4
5
NO2
NO2
No reaction
No reaction
In addition to the general mechanistic insight provided by the new variant of the SNAR-Smiles-
SNAr approach to constructing diarene-fused [1.4]oxazepines, the structure of the compounds
obtained was confirmed by single-crystal X-ray analysis (Fig. 5). The method to prepare these
compounds also represents a distinctly short alternative to multistep synthetic sequences
generally carried out to access compounds with similar substitution pattern [12-13].
A
B
Fig. 5. Single-crystal X-ray structures of compounds (A) 8j (CCDC 1584484) and (B) 8p
(CCDC 1855185).
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Conclusions
In conclusion, we employed current mechanistic understanding of the earlier developed approach
to diarene-fused [1.4]oxazepines via consecutive SNAr-Smiles rearrangement-SNAr steps. This
helped design a new type bis-nucleophilic cyclization partners which allow differentiating
between highly and poorly reactive bis-electrophilic counterparts. The experimentally observed
differences ultimately confirm the hypothesis on the importance of the Smiles rearrangement
step for the success of the overall cyclization process. The new variant of [1.4]oxazepine
synthesis presented herein also presents a practically concise alternative to the methods reported
in the literature for the synthesis of similarly substituted tricyclic scaffolds.
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-d6 or in CDCl3 and were referenced to residual solvent
signals (δH = 2.50 and 7.26 ppm respectively) and solvent carbon signals (δC = 39.52 and 77.00
ppm 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.
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. Experimental procedures for the synthesis of bis-
nucleophilic phenols 7a-i is provided in the Electronic Supplementary Information.
General procedure for preparation of compounds 8a-u and 9a-f. A mixture of bis-
inucleophilic phenol 7 (2 mmol), 1,2-dihaloarene 2 (2 mmol) and freshly calcinated Cs2CO3 (829
mg, 6 mmol) in anhydrous DMF (7 mL) was stirred, at a given temperature for 3-24 h. DMF was
removed in vacuo and the residue was treated with water (10 mL), which caused a viscous oil to
separate. It was extracted with CH2Cl2 (5 mL), the organic layer was separated, dried over
anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by column
chromatography on silica gel using an appropriate gradient of ethyl acetate in hexanes as eluent.
Methyl benzo[f]pyrazino[2,3-b][1,4]oxazepine-11(10H)-carboxylate (8a): white solid (386
1
o
mg, 75%); m.p. 67-70 C. H NMR (400 MHz, CDCl3): δ = 8.25 (d, J= 2.4 Hz, 1H, HPyrazine),
8.22 (d, J= 2.4 Hz, 1H, HPyrazine), 7.29- 7.35 (m, 3H, HAr), 7.09-7.18 (m, 1H, HAr), 4.89 (s, 2H,
13
ArCH2N), 3.75 (s, 3H, COOCH3) ppm. C NMR (100 MHz, CDCl3) δ 154.6, 153.5, 152.6,
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10.1002/ejoc.201900263
European Journal of Organic Chemistry
140.6, 139.6, 137.6, 129.6, 129.2, 126.8, 124.3, 120.7, 53.6, 48.7 ppm. HRMS (ESI), m/z calcd
for C13H12N3O3 [M+H]+ 258.0873, found 258.0870.
Methyl
3-methyl-4-oxo-3,4-dihydrobenzo[f]pyridazino[4,5-b][1,4]oxazepine-11(10H)-
carboxylate (8b): white solid (362 mg, 63%); m.p. 151-153 oC. 1H NMR (400 MHz, CDCl3): δ
= 7.79 (s, 1H, HPyridazine), 7.30-7.35 (m, 2H, HAr), 7.26 (d, J= 7.5 Hz, 1H, HAr), 7.08- 7.14 (m,
13
1H, HAr), 4.81 (s, 2H, ArCH2N), 3.80 (s, 3H, NCH3), 3.77 (s, 3H, COOCH3) ppm. C NMR
(100 MHz, CDCl3): δ = 156.9, 154.6, 154.2, 142.3, 136.4 (2C), 132.7, 129.9, 129.2, 127.4,
124.6, 53.8, 50.5, 40.1 ppm. HRMS (ESI), m/z calcd for C14H14N3O4 [M+H]+ 288.0979, found
288.0975.
Methyl
2-methyl-4-(trifluoromethyl)benzo[f]pyrimido[5,4-b][1,4]oxazepine-11(10H)-
1
o
carboxylate (8c): white solid (467 mg, 69%); m.p. 136-139 C. H NMR (400 MHz, CDCl3): δ
= 7.33-7.38 (m, 1H, HAr), 7.31 (dd, J= 1.7, 7.6 Hz, 1H, HAr), 7.26 (dd, J= 1.7, 7.6 Hz, 1H, HAr),
7.17 (td, J= 1.7, 7.6 Hz, 1H, HAr), 4.99 (s, 2H, ArCH2N), 3.81 (s, 3H, COOCH3), 2.74 (s, 3H,
13
HetCH3) ppm. C NMR (100 MHz, CDCl3): δ = 160.8, 154.5, 154.0, 152.0, 146.7 (t, J= 34.4
Hz), 140.0, 129.9, 128.9, 127.5, 125.1, 120.6 (d, J= 276.5 Hz), 120.4, 53.8, 47.9, 25.1 ppm.
HRMS (ESI), m/z calcd for C15H13F3N3O3 [M+H]+ 340.0904, found 340.0905.
Methyl 6-methylbenzo[f]pyrazino[2,3-b][1,4]oxazepine-11(10H)-carboxylate (8d): light oil
1
(308 mg, 57%). H NMR (400 MHz, CDCl3): δ = 8.23 (d, J= 2.4 Hz, 1H, HPyrazine), 8.20 (d, J=
2.4 Hz, 1H, HPyrazine), 7.21 (d, J= 7.5 Hz, 1H, HAr), 7.15 (d, J= 7.5 Hz, 1H, HAr), 7.03 (t, J= 7.5
13
Hz, 1H, HAr), 4.87 (s, 2H, ArCH2N), 3.76 (s, 3H, COOCH3), 2.47 (s, 3H, ArCH3) ppm. C
NMR (100 MHz, CDCl3): δ = 154.7, 152.2, 140.1, 139.8, 137.4, 131.3, 130.8, 129.9, 127.5,
126.7, 124.1, 53.6, 48.7, 16.7 ppm. HRMS (ESI), m/z calcd for C14H14N3O3 [M+H]+ 272.1030,
found 272.1032.
Methyl 3,6-dimethyl-4-oxo-3,4-dihydrobenzo[f]pyridazino[4,5-b][1,4]oxazepine-11(10H)-
1
o
carboxylate (8e): white solid (265 mg, 44%); m.p. 102-106 C. H NMR (400 MHz, CDCl3): δ
= 7.80 (s, 1H, HPyridazine), 7.17 (d, J= 7.5 H1z, 1H, HAr), 7.08 (d, J= 7.5 Hz, 1H, HAr), 6.98 (t, J=
7.5 Hz, 1H, HAr), 4.78 (s, 2H, ArCH2N), 3.77 (s, 3H, NCH3), 3.75 (s, 3H, COOCH3), 2.43 (s, 3H,
ArCH3) ppm. 13C NMR (100 MHz, CDCl3): δ = 157.1, 154.2, 153.2, 141.9, 136.2, 131.5, 130.5,
127.7, 127.1, 126.6, 124.3, 53.7, 50.1, 39.9, 16.0 ppm. HRMS (ESI), m/z calcd for C15H16N3O4
[M+H]+ 302.1135, found 302.1133.
Methyl
2,6-dimethyl-4-(trifluoromethyl)benzo[f]pyrimido[5,4-b][1,4]oxazepine-11(10H)-
carboxylate (8f): light oil (353 mg, 50%). 1H NMR (400 MHz, CDCl3): δ = 7.21 (dd, J= 1.8, 7.6
Hz, 1H, HAr), 7.13 (dd, J= 1.8, 7.6 Hz, 1H, HAr), 7.03 (t, J= 6.5 Hz, 1H, HAr), 4.89 (s, 2H,
13
ArCH2N), 3.81 (s, 3H, COOCH3), 2.74 (s, 3H, HetCH3), 2.38 (s, 3H, ArCH3) ppm. C NMR
(100 MHz, CDCl3): δ = 159.7, 153.9, 152.5, 151.3, 145.9 (q, J= 34.5 Hz), 140.1, 131.9, 129.9,
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10.1002/ejoc.201900263
European Journal of Organic Chemistry
126.7, 126.6, 124.3, 120.7 (d, J= 276.2 Hz), 53.7, 48.8, 24.9, 16.6 ppm. HRMS (ESI), m/z calcd
for C16H15F3N3O3 [M+H]+ 354.1060, found 354.1058.
Methyl 8-chlorobenzo[f]pyrazino[2,3-b][1,4]oxazepine-11(10H)-carboxylate (8g): white
solid (372 mg, 79%); m.p. 146-148 oC. 1H NMR (400 MHz, CDCl3): δ = 8.25 (d, J= 2.4 Hz, 1H,
HPyrazine), 8.22 (d, J= 2.4 Hz, 1H, HPyrazine), 7.29-7.37 (m, 2H, HAr), 7.10-7.17 (m, 1H, HAr), 4.88
13
(s, 2H, ArCH2N), 3.75 (s, 3H, COOCH3) ppm. C NMR (100 MHz, CDCl3): δ = 154.7, 153.5,
152.6, 140.5, 139.6, 137.6, 129.7, 129.2, 126.8, 124.4, 120.7, 53.6, 48.8 ppm. HRMS (ESI), m/z
calcd for C13H11ClN3O3 [M+H]+ 292.0483, found 292.0485.
Methyl
8-chloro-3-methyl-4-oxo-3,4-dihydrobenzo[f]pyridazino[4,5-b][1,4]oxazepine-
1
o
11(10H)-carboxylate (8h): white solid (372 mg, 58%); m.p. 189-192 C. H NMR (400 MHz,
CDCl3): δ = 7.79 (s, 1H, HPyridazine), 7.22-7.30 (m, 2H, HAr), 7.06-7.13 (m, 1H, HAr), 4.80 (s, 2H,
13
ArCH2N), 3.79 (s, 3H, COOCH3), 3.76 (s, 3H, NCH3) ppm. C NMR (100 MHz, CDCl3): δ =
156.9, 154.6, 154.2, 142.3, 136.4, 129.8, 129.2, 127.4, 124.6, 121.1, 53.8, 50.5, 40.1 ppm.
HRMS (ESI), m/z calcd for C14H13ClN3O4 [M+H]+ 322.0589, found 322.0587.
Benzo[f]pyrazino[2,3-b][1,4]oxazepin-11(10H)-yl(thiophen-2-yl)methanone (8i): white solid
1
o
(438 mg, 71%); m.p. 155-158 C. H NMR (400 MHz, CDCl3): δ = 8.26 (d, J= 2.4 Hz, 1H,
HPyrazine), 8.08 (d, J= 2.4 Hz, 1H, HPyrazine), 7.30-7.40 (m, 4H, 3HAr+1HThiophene), 7.15 (dd, J= 1.2,
7.0 Hz, 1H, HAr), 6.95 (dd, J= 1.2, 3.8 Hz, 1H, HThiophene), 6.88 (t, J= 3.8, 1H, HThiophene), 5.19 (s,
13
2H, ArCH2N) ppm. C NMR (100 MHz, CDCl3): δ = 162.6, 152.9, 152.7, 141.5, 141.3, 138.0,
137.1, 132.0, 130.9, 129.5, 129.5, 126.8, 125.5, 124.4, 120.7, 47.9 ppm. HRMS (ESI), m/z calcd
for C16H12N3O2S [M+H]+ 310.0645 found 310.0641.
3-Methyl-11-(thiophene-2-carbonyl)-10,11-dihydrobenzo[f]pyridazino[4,5-b][1,4]oxazepin-
4(3H)-one (8j): white solid (427 mg, 63%); m.p. 183-186 oC. 1H NMR (400 MHz, CDCl3): δ =
7.52 (dd, J= 1.3, 5.0 Hz, 1H, HAr), 7.40 (dd, J= 1.3, 8.3 Hz, 1H, HAr), 7.31-7.37 (m, 2H,
HThiophene+HPyridazine), 7.20-7.26 (m, 2H, HThiophene+HAe), 7.10 (dt, J= 1.3, 7.3 Hz, 1H, HAr), 6.98
13
(dd, J= 3.8, 5.0 Hz, 1H, HThiophene), 5.13 (s, 2H, ArCH2N), 3.81 (s, 3H, NCH3) ppm. C NMR
(100 MHz, CDCl3): δ = 161.4, 156.8, 153.7, 142.6, 136.3, 135.9, 132.4, 131.9, 129.9, 129.6,
128.1, 127.4, 126.2, 124.7, 121.1, 50.8, 40.3 ppm. HRMS (ESI), m/z calcd for C17H14N3O3S
[M+H]+ 340.0750, found 340.0746.
1-(6-Methylbenzo[f]pyrazino[2,3-b][1,4]oxazepin-11(10H)-yl)propan-1-one (8k): light oil
1
(279 mg, 52%). H NMR (400 MHz, CDCl3): δ = 8.20 (d, J= 2.4 Hz, 1H, HPyrazine), 8.15 (d, J=
2.4 Hz, 1H, HPyrazine), 7.16-7.24 (m, 2H, HAr), 7.02 (t, J= 7.5 Hz, 1H, HAr), 4.96 (s, 2H,
ArCH2N), 2.55 (q, J= 7.4 Hz, 2H, CH2CH3), 2.46 (s, 3H, ArCH3), 1.06 (t, J= 7.4 Hz, 3H,
13
CH2CH3) ppm. C NMR (100 MHz, CDCl3): δ = 173.6, 152.0, 151.7, 140.8, 140.0, 136.6,
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10.1002/ejoc.201900263
European Journal of Organic Chemistry
131.0, 129.4, 127.5, 127.2, 124.2, 46.5, 28.8, 16.6, 9.2 ppm. HRMS (ESI), m/z calcd for
C15H16N3O2 [M+H]+ 270.1237, found 270.1239.
3,6-Dimethyl-11-propionyl-10,11-dihydrobenzo[f]pyridazino[4,5-b][1,4]oxazepin-4(3H)-one
(8l): white solid (215 mg, 47%); m.p. 107-110 oC. 1H NMR (400 MHz, CDCl3): δ = 7.72 (s, 1H,
HPyridazine), 7.18 (d, J= 7.5 Hz, 1H, HAr), 7.06 (d, J= 7.5 Hz, 1H, HAr), 6.99 (t, J= 7.5 Hz, 1H,
HAr), 4.83 (s, 2H, ArCH2N), 3.80 (s, 3H, NCH3), 2.38-2.52 (m, 5H, ArCH3+CH2CH3), 1.10 (t, J=
7.3 Hz, 3H, CH2CH3) ppm. 13C NMR (100 MHz, CDCl3): δ = 172.9, 157.1, 152.1, 143.1, 136.2,
131.6, 130.6, 127.6, 126.5 (2C), 124.2, 50.5, 40.0, 27.7, 16.3, 8.9 ppm. HRMS (ESI), m/z calcd
for C16H18N3O3 [M+H]+ 230.1343, found 230.1341.
1-(2,6-Dimethyl-4-(trifluoromethyl)benzo[f]pyrimido[5,4-b][1,4]oxazepin-11(10H)-yl)
1
propan-1-one (8m): light oil (442 mg, 63%). H NMR (400 MHz, CDCl3): δ = 7.17-7.23 (m,
2H, HAr), 7.03 (t, J= 7.5 Hz, 1H, HAr), 5.00 (s, 2H, ArCH2N), 2.74 (q, J= 7.4 Hz, 2H, CH2CH3),
13
2.70 (s, 3H, HetCH3), 2.38 (s, 3H, ArCH3), 1.15 (t, J= 7.4 Hz, 3H, CH2CH3) ppm. C NMR
(100 MHz, CDCl3): δ = 173.4, 159.0, 152.6, 151.9, 145.5 (q, J= 34.4 Hz), 138.9, 131.7, 129.5,
127.2, 127.0, 124.4, 120.7 (d, J= 276.2 Hz), 46.1, 29.5, 24.7, 16.6, 9.4 ppm. HRMS (ESI), m/z
calcd for C17H17F3N3O2 [M+H]+ 352.1267, found 352.1265.
Benzo[f]pyrazino[2,3-b][1,4]oxazepin-11(10H)-yl(pyrrolidin-1-yl)methanone (8n): white
solid (402 mg, 68%); m.p. 116-119 oC. 1H NMR (400 MHz, CDCl3): δ = 8.03 (d, J= 2.6 Hz, 1H,
HPyrazine), 7.96 (d, J= 2.6 Hz, 1H, HPyrazine), 7.29-7.36 (m, 2H, HAr), 7.22 (d, J= 8.4 Hz, 1H, HAr),
7.08-7.14 (m, 1H, HAr), 4.93 (s, 2H, ArCH2N), 3.12-3.32 (m, 4H, HPyrrolidine), 1.69-1.89 (m, 4H,
13
HPyrrolidine) ppm. C NMR (100 MHz, CDCl3): δ = 156.3, 153.7, 149.7, 143.9, 137.4, 136.4,
129.4, 128.8, 127.2, 124.3, 120.4, 49.0 (2C), 47.4, 25.1 (2C) ppm. HRMS (ESI), m/z calcd for
C16H17N4O2 [M+H]+ 297.1346, found 297.1345.
3-Methyl-11-(pyrrolidine-1-carbonyl)-10,11-dihydrobenzo[f]pyridazino[4,5-b][1,4]oxazepin
-4(3H)-one (8o): white solid (286 mg, 44%); m.p. 186-188 oC. 1H NMR (400 MHz, CDCl3): δ =
7.53 (s, 1H, HPyridazine), 7.27-7.34 (m, 2H, HAr), 7.14 (dd, J= 1.5, 7.5 Hz, 1H, HAr), 7.06 (td, J=
1.5, 7.8 Hz, 1H, HAr), 4.93 (s, 2H, ArCH2N), 3.79 (s, 3H, NCH3), 3.19-3.26 (m, 4H, HPyrrolidine),
1.73-1.85 (m, 4H, HPyrrolidine) ppm. 13C NMR (100 MHz, CDCl3): δ = 157.3, 156.5, 154.1, 139.9,
134.2, 130.5, 129.6, 128.9, 126.9, 124.2, 120.9, 50.8 (2C), 48.3, 40.1, 25.3 (2C) ppm. HRMS
(ESI), m/z calcd for C17H19N4O3 [M+H]+ 327.1452, found 326.1456.
(2-Methyl-4-(trifluoromethyl)benzo[f]pyrimido[5,4-b][1,4]oxazepin-11(10H)-yl)(pyrrolidin-
1
o
1-yl)methanone (8p): white solid (400 mg, 53%); m.p. 124-127 C. H NMR (400 MHz,
CDCl3): δ = 7.38 (td, J= 1.7, 7.9 Hz, 1H, HAr), 7.25-7.35 (m, 2H, HAr), 7.20 (td, J= 1.3, 7.9 Hz,
1H, HAr), 4.92 (s, 2H, ArCH2N) 3.36 (s, 4H, HPyrrolidine), 2.50 (s, 3H, ArCH3), 1.89 (s, 4H,
HPyrrolidine) ppm. 13C NMR (100 MHz, CDCl3): δ = 161.7, 156.4, 155.4, 153.9, 144.6 (q, J= 33.4
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10.1002/ejoc.201900263
European Journal of Organic Chemistry
Hz), 135.1, 130.3, 129.3, 128.5, 125.7, 121.0 (d, J= 276.0 Hz), 120.3, 116.9, 48.3 (2C), 47.1,
25.2 (2C) ppm. HRMS (ESI), m/z calcd for C18H18F3N4O2 [M+H]+ 379.1376, found 379.1371.
8-Chloro-10,11-dihydrobenzo[f]pyrazino[2,3-b][1,4]oxazepine (8q): white solid (247 mg,
41%); m.p. 144-147 oC. 1H NMR (400 MHz, CDCl3): δ = 8.15 (d, J= 2.6 Hz, 1H, HPyrazine), 8.00
(d, J= 2.6 Hz, 1H, HPyrazine), 7.42-7.51 (m, 2H, HAr), 7.34 (td, J= 1.3, 7.5 Hz, 1H, HAr), 7.20 (dd,
J = 1.3, 8.0 Hz, 1H, HAr), 6.89-7.02 (br.s, 1H, NH), 4.55 (d, J= 5.7 Hz, 2H, ArCH2NH) ppm. 13C
NMR (100 MHz, CDCl3): δ = 155.8, 151.3, 139.2, 138.5, 138.2, 130.8, 130.1, 128.4, 126.7,
122.2, 39.5 ppm. HRMS (ESI), m/z calcd for C11H9ClN3O [M+H]+ 234.0426 found 234.0425.
8-Chloro-3-methyl-10,11-dihydrobenzo[f]pyridazino[4,5-b][1,4] oxazepin-4(3H)-one (8r):
white solid (199 mf, 38%); m.p. 166-168 oC. 1H NMR (400 MHz, DMSO-d6): δ = 7.52 (d, J= 2.7
Hz, 1H, HAr), 7.38 (dd, J= 2.7, 8.6 Hz, 1H, HAr), 7.35 (s, 1H, HPyridazine), 7.08-7.16 (m, 2H,
13
HAr+NH), 4.50 (d, J = 4.0 Hz, 2H, ArCH2NH), 3.51 (s, 3H, NCH3) ppm. C NMR (100 MHz,
DMSO-d6): δ + 157.2, 157.1, 137.9, 133.2, 131.7, 129.9, 129.7, 129.1, 128.6, 122.9, 43.8, 39.3
ppm. HRMS (ESI), m/z calcd for C12H11ClN3O2 [M+H]+ 264.0534, found 264.0530.
Methyl
2-methyl-8-(pyrrolidine-1-carbonyl)-4-(trifluoromethyl)benzo[f]pyrimido[5,4-
1
o
b][1,4]oxazepine-11(10H)-carboxylate (8s): white solid (462 mg, 85%); m.p. 162-165 C. H
NMR (400 MHz, CDCl3): δ = 7.78-7.84 (m, 2H, HAr), 7.38 (d, J= 8.3 Hz, 1H, HAr), 5.02 (s, 2H,
ArCH2N), 3.81 (s, 3H, COOCH3), 3.19-3.32 (m, 4H, HPyrrolidine), 2.76 (s, 3H, ArCH3), 1.74-1.84
13
(m, 4H, HPyrrolidine) ppm. C NMR (100 MHz, CDCl3): δ = 172.2, 166.5, 156.4, 155.4, 154.0
144.7 (q, J= 34.3 Hz), 135.0, 130.3, 129.3, 128.5, 125.7, 120.9 (d, J= 276.1 Hz), 120.4, 116.9,
53.0, 48.4 (2C), 47.1, 25.2 (2C) ppm. HRMS (ESI), m/z calcd for C20H20F3N4O4 [M+H]+
437.1431, found 437.1435.
Methyl
3-nitro-8-(pyrrolidine-1-carbonyl)benzo[f]pyrido[3,2-b][1,4]oxazepine-11(10H)-
carboxylate (8t): yellow solid (366 mg, 46%); m.p. 177-180 oC. 1H NMR (400 MHz, CDCl3): δ
= 9.09 (d, J= 2.4 Hz, 1H, HPy), 8.40 (d, J= 2.4 Hz, 1H, HPy), 7.76-7.86 (m, 2H, HAr), 7.36 (d, J=
8.4 Hz, 1H, HAr), 4.98 (s, 2H, ArCH2N), 3.80 (s, 3H, COOCH3), 3.23-3.36 (m, 4H, HPyrrolidine),
1.74-1.88 (m, 4H, HPyrrolidine) ppm. 13C NMR (100 MHz, CDCl3): δ = 172.2, 162.8, 155.4, 154.6,
150.6 141.7, 141.1, 138.8, 134.3, 131.4, 126.4, 124.3, 121.6, 52.3, 49.9 (2C), 36.2, 24.9 (2C)
ppm. HRMS (ESI), m/z calcd for C19H19N4O6 [M+H]+ 399.1299, found 399.1295.
Methyl
8-(pyrrolidine-1-carbonyl)-3-(trifluoromethyl)benzo[f]
pyrido[3,2-
1
o
b][1,4]oxazepine-11(10H)-carboxylate (8u): white solid (319 mg, 38%); m.p. 132-135 C. H
NMR (400 MHz, CDCl3): δ = 8.56 (d, J= 2.2 Hz, 1H, HPy), 7.87 (d, J= 2.2 Hz, 1H, HPy), 7.75-
7.83 (m, 2H, HAr), 7.33 (d, J = 8.4 Hz, 1H, HAr), 4.96 (s, 2H, ArCH2N), 3.79 (s, 3H, COOCH3),
3.24-3.34 (m, 4H, HPyrrolidine), 1.77-1.86 (m, 4H, HPyrrolidine) ppm. 13C NMR (100 MHz, CDCl3): δ
= 165.8, 158.7, 156.0, 151.0, 147.7, 141.7, 134.2, 132.5 (2C), 127.2 (q, J= 34.3 Hz), 126.0,
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10.1002/ejoc.201900263
European Journal of Organic Chemistry
125.9, 124.3, 120.9 (d, J= 276.1 Hz), 44.4 (2C), 40.4, 37.8, 28.4 (2C) ppm. HRMS (ESI), m/z
calcd for C20H19F3N3O4 [M+H]+ 422.1322, found 422.1324.
Methyl (2-((5-bromo-3-chloropyridin-2-yl)oxy)benzyl)carbamate (9a): yellow solid (435 mg,
59%); m.p. 146-148 oC. 1H NMR (400 MHz, CDCl3): δ = 8.55 (d, J= 2.1 Hz, 1H, HPy), 8.47 (d,
J= 2.1 Hz, 1H, HPy), 7.54 (dd, J= 1.9, 7.7 Hz, 1H, HAr), 7.35 (td, J= 1.9, 7.7 Hz, 1H, HAr), 7.27-
7.34 (m, 1H, HAr), 7.10 (dd, J= 1.3, 8.0 Hz, 1H, HAr), 5.12 (t, J= 5.9 Hz, 1H, NH), 4.37 (d, J= 5.9
13
Hz, 2H, ArCH2NH), 3.74 (s, 3H, COOCH3) ppm. C NMR (100 MHz, DMSO-d6): δ = 166.0,
156.2, 150.9, 142.6, 140.3, 137.8, 132.0, 130.5, 128.7, 126.7, 122.2, 107.3, 53.1, 45.5 ppm.
HRMS (ESI), m/z calcd for C14H13BrClN2O3 [M+H]+ 370.9793, found 370.9790.
Methyl (2-((3-chloro-5-(trifluoromethyl)pyridin-2-yl)oxy)benzyl)carbamate (9b): yellow
solid (367 mg, 51%); m.p. 91-93 oC. 1H NMR (400 MHz, CDCl3): δ = 8.51 (s, 1H, HPy), 8.22 (s,
1H, HPy), 7.27-7.36 (m, 2H, HAr), 7.19 (d, J= 7.9 Hz, 1H, HAr), 7.08 (t, J= 7.9 Hz, 1H, HAr), 5.17
13
(t, J= 5.5 Hz, 1H, NH), 4.93 (d, J= 5.5 Hz, 2H, ArCH2NH), 3.71 (s, 3H, COOCH3) ppm. C
NMR (100 MHz, CDCl3): δ = 154.6, 153.9, 146.7, 146.5, 139.2, 129.4, 129.2, 128.7, 127.3 (q,
J= 34.3 Hz), 126.0, 124.1, 120.9 (d, J= 276.1 Hz), 120.4, 53.6, 48.9 ppm. HRMS (ESI), m/z
calcd for C15H13ClF3N2O3 [M+H]+ 361.0563, found 361.0561.
N-(2-(2,4-dinitrophenoxy)benzyl)thiophene-2-carboxamide (9c): yellow solid (678 mg, 85%);
1
o
m.p. 199-201 C. H NMR (400 MHz, DMSO-d6): δ = 9.19 (t, J= 6.1 Hz, 1H, NH), 8.85 (d, J=
2.7 Hz, 1H, HAr), 8.20 (ddd, J= 0.6, 2.7, 9.6 Hz, 1H, HAr), 8.10 (dd, J= 1.3, 5.0 Hz, 1H, HAr),
8.06 (dd, J= 1.3, 3.8 Hz, 1H, HAr), 7.39-7.48 (m, 2H, HAr+HThiophene), 7.27-7.39 (m, 3H,
HAr+HThiophene), 7.04 (d, J= 9.6 Hz, 1H, HThiophene), 4.75 (d, J= 6.1 Hz, 2H, ArCH2NH) ppm. 13C
NMR (100 MHz, DMSO-d6): δ = 160.2, 148.8, 148.4, 135.9 (2C), 135.8, 131.9, 130.9, 130.3,
129.6, 129.4, 129.2, 129.1, 127.0, 123.8, 123.4, 115.7, 42.6 ppm. HRMS (ESI), m/z calcd for
C18H14N3O6S [M+H]+ 400.0598, found 400.0594.
N-(2-((3-Chloro-5-(trifluoromethyl)pyridin-2-yl)oxy)benzyl)pyrrolidine-1-carboxamide
(9b): yellow solid (502 mg, 63%); m.p. 159-161 oC. 1H NMR (400 MHz, CDCl3): δ = 8.49 (d, J=
2.0 Hz, 1H, HPy), 8.21 (d, J= 2.0 Hz, 1H, HPy), 7.51 (d, J = 8.1 Hz, 1H, HAr), 7.39 (t, J = 8.0 Hz,
1H, HAr), 7.31 (t, J= 8.0 Hz, 1H, HAr), 7.12 (d, J= 8.1 Hz, 1H, HAr), 4.62 (br.s, 1H, NH), 4.31 (d,
J= 4.5 Hz, 2H, ArCH2NH), 3.25-3.31 (m, 4H, HPyrrolidine), 1.76-1.97 (m, 4H, HPyrrolidine) ppm. 13C
NMR (100 MHz, DMSO-d6): δ = 165.3, 156.7, 143.4, 140.5, 131.8, 129.9, 129.2, 126.3, 124.9
(d, J= 276.1 Hz), 124.0, 121.6 (q, J= 34.3 Hz), 114.4, 114.1, 43.1 (2C), 35.7, 25.6 (2C) ppm.
HRMS (ESI), m/z calcd for C18H18ClF3N2O3 [M+H]+ 400.1030, found 400.1034.
8-Chloro-3-methyl-10,11-dihydrobenzo[f]pyridazino[4,5-b][1,4] oxazepin-4(3H)-one (9e):
yellow solid (496 mg, 66%); m.p. 185-188 oC. 1H NMR (400 MHz, CDCl3): δ = 8.87 (d, J= 2.5
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10.1002/ejoc.201900263
European Journal of Organic Chemistry
Hz, 1H, HPy), 8.74 (d, J= 2.5 Hz, 1H, HPy), 7.52 (dd, J= 1.8, 7.7 Hz, 1H, HAr), 7.37 (td, J= 1.8,
7.7 Hz, 1H, HAr), 7.27-7.34 (m, 1H, HAr), 7.12 (dd, J= 1.3, 8.0 Hz, 1H, HAr), 4.61 (t, J= 5.7 Hz,
1H, NH), 4.36 (d, J= 5.7 Hz, 2H, ArCH2NH), 3.18-3.34 (m, 4H, HPyrrolidine), 1.78-1.95 (m, 4H,
13
HPyrrolidine) ppm. C NMR (100 MHz, DMSO-d6): δ = 162.8, 156.3, 150.9, 142.5, 140.3, 137.6,
131.9, 130.4, 128.8, 126.8, 122.1, 107.2, 45.5 (2C), 39.9, 25.5(2C) ppm. HRMS (ESI), m/z calcd
for C17H18ClN4O4 [M+H]+ 377.1011, found 377.1014.
Acknowledgement
This research was supported by the Russian Science Foundation (grant no. 17-73-20185). 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.
Keywords: nucleophilic aromatic substitution; Smiles rearrangement; [1.4]oxazepines;
privileged structures; reactivity-matched synthons
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Graphical Abstract:
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