A General Way to Construct Arene-Fused Seven-Membered Nitrogen Heterocycles

Article abstract of DOI:10.1002/ejoc.201701642

Imines react with seven-membered cyclic anhydrides (prepared from the corresponding dicarboxylic acids by a recently discovered in-situ cyclodehydration protocol) by the Castagnoli–Cushman reaction pathway to give privileged seven-membered arene-fused nitrogen-heterocyclic compounds with reagent-controlled diversity of the skeleton and peripheral groups.

Full text of DOI:10.1002/ejoc.201701642

A Journal of
Accepted Article
Title: A Common Way to Construct Arene-Fused Seven-Membered
Nitrogen Heterocycles
Authors: Olga Bakulina, Maria Chizhova, Dmitry Dar'in, and Mikhail
Krasavin
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201701642
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10.1002/ejoc.201701642
European Journal of Organic Chemistry
A Common Way to Construct Arene-Fused Seven-Membered
Nitrogen Heterocycles
Olga Bakulina, Maria Chizhova, Dmitry Dar’in and Mikhail Krasavin*
Saint Petersburg State University, Saint Petersburg, 199034 Russian Federation
ABSTRACT:
Imines reacted with seven-membered cyclic anhydrides (prepared from respective dicarboxylic
acids by recently discovered in situ cyclodehydration protocol) via the Castagnoli-Cushman
reaction pathway to provide privileged seven-membered arene-fused nitrogen heterocylic
compounds with reagent-controlled diversity of the skeleton and peripheral groups.
Keywords: tetrahydroazepines, multicomponent reactions, Castagnoli-Cushman reaction,
cyclodehydration, imines.
Introduction
Seven-membered nitrogen heterocycles fused to a benzene ring can be confidently regarded as
privileged[1] motifs for drug design considering the wide range of biological activities displayed
by the compounds based on such scaffolds. Figure 1 displays only a handful of clinically used as
well as investigational drugs whose vastly differing therapeutic applications[2-13] clearly illustrate
the immense importance of these azaheterocycles in medicinal chemistry. This observation is
perhaps unsurprising, considering that the very concept of privileged structures was coined in a
Merck publication devoted to benzodiazepines.[14] It also justifies development of new synthetic
approaches to ‘tetrahydrobenzo-X-azepines’, particularly those that would permit flexible
periphery group variation as well as undertake, if necessary, scaffold hopping[15] within the same
1
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10.1002/ejoc.201701642
European Journal of Organic Chemistry
reagent space. That such an ambitious goal can be realized, in principle, has already been
eloquently illustrated by the ‘intramolecular’ Ugi reaction of benzene-tethered oxocarboxylic
acids
which
has
delivered
tetrahydro
versions
of
benzo[c]azepines,[16]
benzo[f][1,4]thiazepines,[17] benzo[f][1,4]oxazepines,[18] and benzo[e][1,4]diazepines[19] (i. e. all
four scaffolds shown in Figure 1).
Figure 1. Examples of biologically active compounds based on benzene-fused seven-membered
saturated azaheterocyclic (‘tetrahydrobenzo-X-azepine’) cores.
Heterocyclic
Bioactive compounds reported in the literature
core
2
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10.1002/ejoc.201701642
European Journal of Organic Chemistry
Recently, our team has been actively involved in researching and expanding the scope of another
powerful multicomponent reaction – namely, cyclocondensation of imines 1 (prepared from
respective primary amines and aldehydes) with -C-H cyclic anhydrides known as the
Castagnoli-Cushman reaction (CCR).[20] For a long time (since its discovery in 1969[21]) this
reaction was thought to be applicable to 5- and 6-membered cyclic anhydrides (homophthalic
anhydride, or HPA (2), being one of the most reactive ones[22]), thus providing access only to -
and -lactams (such as 3, usually obtained in the trans-configuration).[23] However, recently
we[24] and others[25] demonstrated that -lactams are also accessible by the CCR of o-
phenylenediacetic acid anhydride (4). The latter can be viewed as an HPA homolog where
enolization of the anhydride (occurring in the course of the CCR according to the current
mechanistic understanding[23]) doesn’t produce a fully conjugated system (as is the case for HPA
itself) and, therefore, is less likely to proceed. Despite this potential obstacle, the CCR toward
seven-membered lactams 5 was found to be rather efficient, albeit offering little skeletal
diversity. Encouraged by this result, we were keen to explore other expanded versions of HPA,
namely, seven-membered cyclic anhydrides 6 which can be viewed as resulting from ‘insertion’
of an additional atom in the methylene bridge of HPA (thereby also destroying the full
conjugation in the respective enolate). We reasoned that reducing this idea to practice would
provide a convenient, unified entry into all the four ‘tetrahydrobenzo-X-azepines’ discussed
above. Moreover, the resulting lactams 7 would have a substitution pattern which has not been
previously described in the literature (Figure 2).[26]
Figure 2. Traditional CCR of HPA and the ‘expanded’ versions of HPA explored earlier and in
this work.
3
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10.1002/ejoc.201701642
European Journal of Organic Chemistry
Herein, we report on a successful realization of this strategy for cyclic anhydrides 6 either
prepared or generated in situ (vide infra) from respective dicarboxylic acids 8a-e (Figure 3).
Figure 3. Dicarboxylic acids 8 employed in this work (as such or as anhydrides 6).
Results and Discussion
Initial experiments were conducted with sulfur-containing anhydride 6a prepared from
dicarboxylic acid 8a via the previously developed cyclodehydration protocol employing oxalyl
chloride.[27] As was expected, the anhydride proved to be significantly less reactive compared to
HPA as no CCR product was obtained in the reaction with a model imine (N-(4-
methylbenzylidene)ethylamine, 1a) in acetonitrile at ambient temperature conducted over 24 h
(the conditions providing excellent CCR yield with HPA).[28] Raising the temperature to reflux
1
for the reaction in acetonitrile led to some conversion (according to H NMR and TLC analysis
of the reaction mixture) was did not warrant preparative isolation. Further screening of
conditions involved mostly solvent variation. Changing the reaction medium to DMF (r. t. to 130
ºC)[20b] or conduction the reaction without solvent[20c] led to either incomplete conversions or
difficult-to-discern product mixtures. A major but not sufficient improvement in terms of
suppressing side-reactions (much in line with the previously reported CCR of heteroatom-
containing cyclic anhydrides[20a]) was observed for the reaction in refluxing toluene (16 h).
Screening of temperature regimens (110-150 ºC over 16 h) in chlorobenzene finally produced the
cleanest and fullest conversion of all (at 150 ºC). It was however, accompanied by a significant
tar formation and this could be the reason for the modest isolated yield (36%) obtained in this
case (Table 1).
While this work was in progress, we have discovered a novel protocol for the CCR which
involved exposure of pre-formed imines to dicarboxylic acids in the presence of acetic anhydride
in chlorobenzene at 150 ºC. The process presumably proceeded via an in situ formation of the
respective cyclic anhydrides and produced the expected CCR product in improved purity and
yields. We had successfully tested this protocol in a combinatorial array of 180 reactions[29] and
4
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10.1002/ejoc.201701642
European Journal of Organic Chemistry
thus sought to apply it toward the reaction of dicarboxylic acids selected for present study. It was
to our utmost delight that the yield of the model reaction discussed above was improved from 36
to 61% when conducted via in situ cyclodehydration of 8a with 1.1 equiv. of acetic anhydride!
Table 1. Screening of the CCR conditions.
Entry
Conditions
Results
No reaction
1
2
Acetonitrile, r. t., 24 h
Acetonitrile, 80 ºC, 16 h
Toluene, reflux, 16 h
Neat, 110 ºC, 16 h
Low conversion
3
Clean but incomplete (~75%) conversion to 7{6a,1a}
Full conversion, complex product mixture
Low conversion
4
5
DMF, r. t., 24 h
6
DMF, 110 ºC, 16 h
Significant decomposition
7
DMF, 130 ºC, 16 h
Significant decomposition
8
Chlorobenzene, 110 ºC, 16 h
Chlorobenzene, 130 ºC, 16 h
Chlorobenzene, 150 ºC, 16 h
Improved but incomplete conversion
Improved but incomplete conversion
Full conversion, 36% isolated yield of 7{6a,1a}
9
10
Notably, additional attempts to further improve the yield of the model CCR by varying the
amount of acetic anhydride from 1.0 equiv. (leading to incomplete conversion) to 2.0 equiv.
(resulting in markedly worse product mixture purity) failed while the 61% yield was perfectly
reproducible. Hence, we concluded that we had identified optimal conditions for the reaction and
the same general protocol - dicarboxylic acid (1 mmol), imine (1 mmol), acetic anhydride (1.1
mmol), chlorobenzene, 150 ºC, 16 h – was applied to all dicarboxylic acids 8a-e and a range of
imines 1a-r (Table 2).
The compounds based on tetrahydrobenzo[f][1,4]thiazepine (entries 1-8) and
tetrahydrobenzo[c]azepine (entries 9-12) cores were isolated by extraction into a basic aqueous
solution (see Experimental Section). When the resulting carboxylate solution was neutralized,
the desired product precipitated from the solution (additional crystallization was required to
obtain these compounds in analytically pure form). However, the formation of compounds
containing
tetrahydrobenzo[f][1,4]oxazepine
(entries
13-19)
and
tetrahydrobenzo[e][1,4]diazepine (entries 20-28) scaffolds was not only characterized by lower
diastereomeric ratios in general but was also accompanied by significant amounts of carboxylic
5
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10.1002/ejoc.201701642
European Journal of Organic Chemistry
acid-containing by-products (vide infra). As a result, the protocol involving basic extraction
followed by neutralization produced impure product mixtures. Therefore, the crude mixtures of
carboxylic acids 7 (entries 13-28) were esterified by treatment with methyl iodide in presence of
potassium carbonate and the resulting methyl esters 9 were purified by column chromatography.
In a number of cases (entries 13, 15, 18-21, 23-26), we managed to separate and characterized
individually the cis- and trans-diastereomers of compounds 9. The assignment of relative
3
configuration for these compounds was based on much larger (by up to 10.1 Hz) JHH values for
protons at stereogenic centers observed for the trans-isomers compared to their cis-configured
counterparts (see Table S2). This assignment was found to be in line with the single-crystal
structures (ESI) obtained for compounds 7{8b,1a}, 7{8a,1h}, 7{8a,1e}, 7{8a,1a}. Disturbingly,
tetrahydrobenzo[f][1,4]oxazepines (entries 13-19) unlike their diazepine counterparts, were
found to be unstable to chromatography on silica and had to be isolated on neutral alumina.
Table 2. Azaheterocyclic (‘tetrahydrobenzo-X-azepine’) compounds 7(9) prepared in this work.
Isolated
Dicarboxylic
trans:
cisa
Entry
1
Imine 1
Product 7(9) structure
yield,
%
acid 8
61
58
>20:1b
8a
8a
2
>20:1
6
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10.1002/ejoc.201701642
European Journal of Organic Chemistry
3
4
47
45
>20:1
8a
8a
>20:1
5
45
>20:1b
8a
6
7
40
37
>20:1
>20:1
8a
8a
8
34
>20:1b
8a
9
58
49
48
>20:1b
>20:1
>20:1b
8b
8b
8b
10
11
7
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European Journal of Organic Chemistry
12
13
32
>20:1
8b
8c
19
(trans)
16 (cis)
n/a
>20:1
n/a
14
15
8c
8c
25
9
(trans)
5 (cis)
16
17
8c
11
41
2.8:1
8d
>20:1
23
(trans)
4 (cis)
18
19
8d
8d
n/a
n/a
12
(trans)
3 (cis)
30
(trans)
20 (cis)
20
8e
n/a
8
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European Journal of Organic Chemistry
21
(trans)
20 (cis)
21
22
8e
8e
n/a
39
1.1:1c
19 (cis)
17
(trans)
23
24
8e
8e
n/a
n/a
20
(cis)b
12
(trans)b
24
(cis)b
6
25
26
8e
8e
n/a
n/a
(trans)b
19
(trans)
8 (cis)
27
28
8e
8e
25
22
2:1
>20:1
a Ratio of diastereomers of the isolated products 7(9). For intrinsic dr values (generally reflective
1
of those in the isolated pure compounds) determined by H NMR analysis of the crude reaction
mixtures see ESI, TableS1.
b Structure assignment confirmed by single-crystal X-ray analysis. A correlation between relative
3
configuration and JHH-values for protons at stereogenic centers was also observed. For details
see ESI, TableS2.
c Separation of diastereomers failed.
9
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European Journal of Organic Chemistry
One observation is particularly noteworthy and is relevant to the dicarboxylic acid CCR format
employed in this study. For carboxylic acids 8a-d, it was confirmed that exemplary reactions
conducted on respective isolated cyclic anhydrides 6a-d delivered markedly lower yields.
However, anhydride 6e prepared by cyclocdehydration of 8e[27] delivered no appreciable amount
of compounds 7 and was also found to be unstable to storage. Thus, only the protocol involving
the in situ generation of 6e was found productive in terms of the desired CCR.
The universal propensity of the approach presented in this paper to deliver compounds 7(9)
based on four different privileged heterocyclic cores - and the unprecedented use of novel cyclic
seven-membered anhydrides (generated in situ) in the CCR - certainly constitute a
methodological achievement in scaffold-oriented synthesis. However, the low isolated yields
obtained for some of these compounds (particularly tetrahydrobenzo[f][1,4]oxazepines) are quite
disappointing. Although the reaction protocol identified in this study has been thoroughly
optimized, we believe the relatively low reactivity of anhydrides 6a-e and the entropy constraints
associated with the formation of the seven-membered rings (compared to traditional five- an six-
membered CCR products) results in either incomplete conversions at low temperature or in
noticeable tar formation (and a consequent mass balance loss) at the temperature identified as
productive (150 ºC). Additionally, a significant amount of dicarboxylic acid monoamides 10 was
detected in some cases (particularly, for oxa- and aza-variants) which complicated the target
product separation. The origin of monoamides 10 (described by us as CCR by-products[20c]) can
be traced to N-acyl iminium species 11 presumably formed en route to 7.[23] If subsequent
intramolecular Mannich-type cyclization in 11 is suppressed (as is probably the case for seven-
membered cycle formation), the latter would simply lose the former aldehyde component of the
iminium and give 11 (Scheme 1).
Scheme 1. Mechanistic rationale for the formation of monoamides 10.
Conclusions
In conclusion, we have described a unified synthetic approach toward four major heterocyclic
cores that can clearly be regarded as privileged scaffolds for drug design. The reagents employed
10
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10.1002/ejoc.201701642
European Journal of Organic Chemistry
in the preparation of the imine component and the cyclic anhydride determined the periphery and
the scaffold of the molecule, which eloquently illustrates the diversity-oriented synthesis
concept.[30] Notably, significant improvement of the reaction outcome was achieved by relying
on the recently discovered ‘dicarboxylic acid CCR’ protocol involving in situ generation of the
cyclic anhydride. For the nitrogen-linked anhydride 6e, the preparation of the respective
tetrahydrobenzo[e][1,4]diazepines would not be possible if it were not for the in situ
cyclodehydration protocol. Despite the moderate – and in some cases – low yields (attributable
to generally lower reactivity of seven-membered anhydrides studies herein), the methodology
represents the first example of preparing skeletally diverse, arene-fused seven-membered
nitrogen heterocycles via the Castagnoli-Cushman multicomponent reaction.
Experimental Section
General. NMR spectroscopic data were recorded with Bruker Avance 400 spectrometer (400.13
1
13
MHz for H and 100.61 MHz for C) in CDCl3 and DMSO-d6 and were referenced to residual
solvent proton signals (δH = 7.26 and 2.50 ppm, respectively) and solvent carbon signals (δC =
77.0 and 39.5 ppm, respectively). Melting points were determined with a Stuart SMP50
instrument in open capillary tubes. Mass spectra were recorded with a Bruker Maxis HRMS-
ESI-qTOF spectrometer (electrospray ionization mode). Chlorobenzene was distilled from P2O5
and stored over activated molecular sieves 4Å. Dicarboxylic acids 8a-e were prepared according
to published procedures[31-35] (see ESI for details).
General procedure 1 (GP1) for the Castagnoli-Cushman reaction of dicarboxylic acids 8a-
b. To a solution of imines 1a-i (1.0 mmol; prepared from corresponding aldehydes (1.05 mmol)
and amines (1.0 mmol) by stirring with anhydrous MgSO4 (500 mg) at room temperature in
DCM for 24-48h and subsequent filtration and concentration in vacuo) in anhydrous
chlorobenzene (2mL) dicarboxylic acid 8a,b (1 mmol) and acetic anhydride (112 mg, 1.1 mmol)
were added at room temperature in a screw-cap vial. The reaction mixture was placed in a pre-
heated to 150 °C oil bath and stirred for 16h. After cooling to room temperature, the reaction
mixture was concentrated under reduced pressure and the residue was redissolved in DCM (20
mL). This solution was extracted with saturated aqueous NaHCO3 (3×10 mL). The combined
aqueous phase was washed with DCM (15 mL) and the pH was then adjusted to 1 with
concentrated HCl under vigorous stirring at 0 °C. The precipitate formed was collected, washed
with water and dried in air to give crude compounds 7. Crystallization from MTBE-PE (7{8a,1a-
h}) or MeOH-H2O (7{8b,1a,c,d,i,j}) mixtures afforded pure compounds 7.
11
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General procedure 2 (GP2) for the Castagnoli-Cushman reaction of dicarboxylic acids 8c-
e. To a solution of imines 1a-q (1.0 mmol; prepared from corresponding aldehydes (1.05 mmol)
and amines (1.0 mmol) by stirring with anhydrous MgSO4 (500 mg) at room temperature in
DCM for 24-48h and subsequent filtration and concentration in vacuo) in anhydrous
chlorobenzene (2mL) dicarboxylic acid 8c-e (1 mmol) and acetic anhydride (112 mg, 1.1 mmol)
were added at room temperature in a screw-cap vial. The reaction mixture was placed in a pre-
heated to 150 °C oil bath and stirred for 16h. After cooling to room temperature, the reaction
mixture was concentrated under reduced pressure and the residue was redissolved in dry acetone
(15 mL). Methyl iodide (355 mg, 2.5 mmol) and K2CO3 (345 mg, 2.5 mmol) were added to this
solution. The resulting suspension was stirred at room temperature for 24h, concentrated under
reduced pressure. The residue was partitioned between water (15 mL) and DCM (30 mL). The
organic layer was separated, washed with brine, dried over anhydrous Na2SO4 and concentrated
in vacuo to give crude esters 9. Compounds 9{8c,1d,i-k} and 9{8d,1a,f,l} were purified using
column chromatography on neutral alumina eluting with hexane-chloroform mixtures (gradient
from 6:1 to 1:1). Compounds 9{8e,1i,k,h,m-r} were purified using column chromatography on
silica eluting with hexane – ethyl acetate mixtures (gradient from 5:1 to 1:1).
trans-4-Ethyl-5-oxo-3-(p-tolyl)-2,3,4,5-tetrahydrobenzo[f][1,4]-thiazepine-2-carboxylic acid
1
(7{8a,1a}). Yield 208 mg, 61%. White solid, mp 256 − 258 °C (MTBE-PE). H NMR (400
MHz, CDCl3) δ = 7.82 – 7.71 (m, 1H), 7.54 (td, J=7.6, 7.1, 2.3, 1H), 7.48 – 7.38 (m, 2H), 7.21 –
7.12 (m, 4H), 4.91 (d, J=12.1, 1H), 4.42 (d, J=12.1, 1H), 3.55 (dq, J=14.0, 7.0, 1H), 3.09 (dq,
13
J=14.0, 7.0, 1H), 2.37 (s, 3H), 0.97 (t, J=7.0, 13H). C NMR (101 MHz, DMSO-d6) δ 171.5,
168.9, 141.7, 138.7, 135.0, 131.7, 131.6, 130.6, 129.8, 129.7, 129.3, 126.5, 62.1, 51.3, 37.7,
21.1, 14.4. HRMS (ESI/Q-TOF) m/z: [M+Na]+ Calcd for C19H19NO3SNa 364.0978; Found
364.0990.
trans-3-(2-Bromophenyl)-4-(4-methoxybenzyl)-5-oxo-2,3,4,5-tetrahydro-
benzo[f][1,4]thiazepine-2-carboxylic acid (trans-7{8a,1b}). Yield 288 mg, 58%. White solid,
1
mp 253 − 255 °C (MTBE-PE). H NMR (400 MHz, DMSO-d6) δ 12.83 (s, 1H), 7.75 (dd, J =
7.5, 1.5 Hz, 1H), 7.69 – 7.60 (m, 1H), 7.60 – 7.55 (m, 2H), 7.55 – 7.49 (m, 1H), 7.46 – 7.31 (m,
2H), 7.23 – 7.12 (m, 1H), 6.90 – 6.81 (m, 2H), 6.71 – 6.61 (m, 2H), 5.01 (d, J = 12.0 Hz, 1H),
4.69 (d, J = 12.0 Hz, 1H), 4.49 (d, J = 15.2 Hz, 1H), 4.27 (d, J = 15.2 Hz, 1H), 3.68 (s, 3H). 13C
NMR (126 MHz, DMSO-d6) δ 171.2, 170.4, 158.3, 141.4, 135.1, 133.6, 133.5, 131.9, 131.1,
130.7, 130.2, 129.9, 129.3, 129.3, 128.2, 126.8, 126.1, 113.5, 61.9, 55.4, 50.7, 45.4. HRMS
(ESI/Q-TOF) m/z: [M+Na]+ Calcd for C24H20BrNO4SNa 520.0189; Found 520.0211.
12
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European Journal of Organic Chemistry
trans-4-Isopropyl-3-(4-methoxyphenyl)-5-oxo-2,3,4,5-tetrahydrobenzo[f][1,4]thiazepine-2-
carboxylic acid (trans-7{8a,1c}). Yield 174 mg, 47%. White solid, mp 243 − 246 °C (MTBE-
PE). 1H NMR (400 MHz, DMSO-d6) δ = 12.64 (s, 1H), 7.68 (d, J=6.8, 1H), 7.59 (td, J=7.4, 1.6,
1H), 7.55 – 7.41 (m, 2H), 7.34 (d, J=8.2, 2H), 7.02 – 6.87 (m, 2H), 4.82 (d, J=12.0, 1H), 4.71 (d,
13
J=12.0, 1H), 3.75 (s, 3H), 1.44 (d, J=6.7, 3H), 3.44 – 3.33 (m, 1H), 0.90 (d, J=6.7, 3H). C
NMR (101 MHz, DMSO-d6) δ 171.6, 169.1, 159.6, 142.4, 135.0, 131.6, 131.1, 130.5, 129.4,
126.69, 126.64, 114.3, 63.0, 55.6, 50.6, 48.4, 21.1, 20.2. HRMS (ESI/Q-TOF) m/z: [M+Na]+
Calcd for C20H21NO4SNa 394.1083; Found 394.1098.
trans-4-(4-Methoxybenzyl)-5-oxo-3-(p-tolyl)-2,3,4,5-tetrahydrobenzo-[f][1,4]thiazepine-2-
carboxylic acid (trans-7{8a,1d}). Yield 195 mg, 45%. White solid, mp 215 − 217 °C (MTBE-
PE). 1H NMR (400 MHz, DMSO-d6) δ 12.71 (s, 1H), 7.75 – 7.69 (m, 1H), 7.67 – 7.58 (m, 1H),
7.58 – 7.51 (m, 1H), 7.51 – 7.44 (m, 1H), 7.10 (s, 4H), 6.92 (d, J = 8.6 Hz, 2H), 6.73 (d, J = 8.7
Hz, 2H), 4.82 (d, J = 11.9 Hz, 1H), 4.70 (t, J = 15.1 Hz, 1H), 4.31 (d, J = 11.9 Hz, 1H), 3.97 (d, J
= 15.1 Hz, 2H), 3.71 (s, 4H), 2.26 (s, 5H). 13C NMR (101 MHz, DMSO-d6) δ 171.2, 169.6,
158.5, 141.4, 138.6, 135.0, 131.8, 131.2, 130.7, 130.5, 129.7, 129.5, 129.4, 129.1, 126.3, 113.6,
62.2, 55.5, 51.4, 45.2, 21.1. HRMS (ESI/Q-TOF) m/z: [M+Na]+ Calcd for C25H23NO4SNa
456.1240; Found 456.1258.
trans-3-(4-Chlorophenyl)-5-oxo-4-propyl-2,3,4,5-tetrahydrobenzo[f][1,4]thiazepine-2-
carboxylic acid (trans-7{8a,1e}). Yield 169 mg, 45%. White solid, mp 270 − 272 °C (MTBE-
PE). 1H NMR (400 MHz, DMSO-d6) δ 12.77 (s, 1H), 7.66 (t, J = 7.4 Hz, 1H), 7.61 (t, J = 7.3 Hz,
1H), 7.58 – 7.41 (m, 6H), 4.89 (d, J = 11.9 Hz, 1H), 4.76 (d, J = 11.9 Hz, 1H), 3.31 – 3.18 (m,
1H), 3.06 – 2.90 (m, 1H), 1.46 – 1.29 (m, 1H), 0.95 – 0.80 (m, 1H), 0.64 (t, J = 7.3 Hz, 3H). 13C
NMR (101 MHz, DMSO-d6) δ 171.4, 169.2, 141.6, 135.0, 133.96, 133.95, 131.7, 130.6, 129.45,
129.43, 129.2, 126.3, 61.8, 50.9, 44.7, 22.1, 11.9. HRMS (ESI/Q-TOF) m/z: [M+H]+ Calcd for
C19H19ClNO3S 376.0769; Found 376.0782.
trans-4-Methyl-5-oxo-3-phenyl-2,3,4,5-tetrahydrobenzo[f][1,4]-thiazepine-2-carboxylic
1
acid (trans-7{8a,1f}). Yield 125 mg, 40%. White solid, mp 250 − 252 °C (MeOH-H2O). H
NMR (400 MHz, DMSO-d6) δ 12.73 (s, 1H), 7.72 – 7.65 (m, 1H), 7.62 (td, J = 7.3, 1.6 Hz, 1H),
7.56 – 7.48 (m, 2H), 7.44 – 7.33 (m, 5H), 4.99 (d, J = 11.9 Hz, 1H), 4.78 (d, J = 11.9 Hz, 1H),
2.63 (s, 3H). 13C NMR (101 MHz, DMSO-d6) δ 171.6, 169.1, 141.6, 135.1, 134.7, 131.8, 130.6,
129.6, 129.4, 129.2, 129.1, 126.6, 62.2, 49.8, 29.1. HRMS (ESI/Q-TOF) m/z: [M+H]+ Calcd for
C17H16NO3S 314.0845; Found 314.0856.
13
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trans-3-(4-Chlorophenyl)-4-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-5-oxo-2,3,4,5-
tetrahydrobenzo-[f][1,4]thiazepine-2-carboxylic acid (trans-7{8a,1g}). Yield 173 mg, 37%.
1
White solid, mp 260 − 262 °C (MTBE-PE). H NMR (400 MHz, DMSO-d6) δ 12.80 (s, 1H),
7.74 (d, J = 7.2 Hz, 1H), 7.66 (td, J = 7.2, 1.9 Hz, 1H), 7.58 (dt, J = 13.4, 4.6 Hz, 2H), 7.26 (d, J
= 8.6 Hz, 2H), 7.10 (d, J = 8.3 Hz, 2H), 6.69 (d, J = 8.5 Hz, 1H), 6.48 (d, J = 2.2 Hz, 1H), 6.41
(dd, J = 8.5, 2.2 Hz, 1H), 5.03 (d, J = 12.0 Hz, 1H), 4.79 (d, J = 12.0 Hz, 1H), 4.26 – 4.13 (m, J
13
= 8.1, 4.4 Hz, 4H). C NMR (101 MHz, DMSO-d6) δ 171.2, 169.4, 143.5, 143.2, 141.1, 135.3,
133.5, 133.4, 132.1, 131.8, 131.4, 130.8, 129.8, 128.6, 126.6, 123.2, 119.1, 117.2, 64.5, 64.3,
63.5, 51.5. HRMS (ESI/Q-TOF) m/z: [M+Na]+ Calcd for C24H18ClNO5SNa 490.0486; Found
490.0509.
trans-4-(4-Chlorophenyl)-5-oxo-3-(p-tolyl)-2,3,4,5-tetrahydrobenzo-[f][1,4]thiazepine-2-
carboxylic acid (trans-7{8a,1h}). Yield 143 mg, 34%. White solid, mp 275 − 277 °C (MTBE-
PE). 1H NMR (400 MHz, DMSO-d6) δ 12.72 (s, 1H), 7.76 (dd, J = 7.4, 1.4 Hz, 1H), 7.70 – 7.64
(m, 1H), 7.64 – 7.54 (m, 2H), 7.32 – 7.24 (m, 2H), 7.04 – 6.84 (m, 6H), 5.05 (d, J = 12.0 Hz,
13
1H), 4.86 (d, J = 12.0 Hz, 1H), 2.18 (s, 3H). C NMR (101 MHz, DMSO-d6) δ 171.2, 169.3,
140.9, 138.3, 137.7, 135.4, 132.4, 132.3, 132.2, 130.9, 130.8, 129.9, 129.7, 129.3, 129.1, 126.7,
63.9, 51.6, 21.1. HRMS (ESI/Q-TOF) m/z: [M+Na]+ Calcd for C23H18ClNO3SNa 446.0588;
Found 446.0608.
trans-2-Isopropyl-3-(4-methoxyphenyl)-1-oxo-2,3,4,5-tetrahydro-1H-benzo[c]azepine-4-
carboxylic acid (trans-7{8b,1c}).Yield 204 mg, 58%. Colorless solid, mp 233–234 °C (MeOH-
H2O). 1H NMR (400 MHz, DMSO-d6, 80 °C) δ 12.32 (br.s, 1H), 7.46 (dd, J = 7.6, 1.5 Hz, 1H),
7.30 (td, J = 7.4, 1.6 Hz, 1H), 7.25 (td, J = 7.4, 1.2 Hz, 1H), 7.17 – 7.07 (m, 3H), 6.79 (d, J = 8.7
Hz, 2H), 4.98 (d, J = 7.2 Hz, 1H), 4.10 (br.s, 1H), 3.71 (s, 3H), 3.72 – 3.65 (m, 1H), 3.12 (dd, J =
13.9, 6.6 Hz, 1H), 3.01 (dd, J = 13.9, 6.6 Hz, 1H), 1.34 (d, J = 6.8 Hz, 3H), 1.11 (d, J = 6.8 Hz,
13
3H). C NMR (100 MHz, DMSO-d6) δ 174.1, 170.4, 158.8, 137.7, 135.4, 131.5, 130.7, 129.3,
129.2, 128.7, 127.4, 114.1, 59.7, 55.6, 50.2, 48.0, 33.8, 21.1, 20.8. HRMS (ESI/Q-TOF) m/z:
[M+H]+ Calcd for C21H24NO4 354.1700; Found 354.1697.
trans-2-Сyclopropyl-1-oxo-3-phenyl-2,3,4,5-tetrahydro-1H-benzo[c]-azepine-4-carboxylic
1
acid (trans-7{8b,1i}). Yield 158 mg, 49%. Colorless solid, mp 213–215 °C (MeOH-H2O). H
NMR (400 MHz, DMSO-d6) δ 12.57 (br.s, 1H), 7.57 (d, J = 7.2 Hz, 1H), 7.39 (td, J = 7.4, 1.6
Hz, 1H), 7.36 – 7.19 (m, 6H), 7.17 (dd, J = 7.4, 1.1 Hz, 1H), 4.93 (d, J = 9.5 Hz, 1H), 3.82 (ddd,
J = 9.6, 7.0, 4.3 Hz, 1H), 3.08 (dd, J = 13.8, 7.0 Hz, 1H), 2.96 (dd, J = 13.8, 4.3 Hz, 1H), 2.08
(br.s, 1H), 0.85 – 0.71 (m, 2H), 0.71 – 0.61 (m, 1H), 0.38 (br.s, 1H). 13C NMR (100 MHz,
14
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European Journal of Organic Chemistry
DMSO-d6) δ 174.2, 171.8, 136.1, 135.9, 131.4, 129.9, 129.3, 128.7, 128.6, 127.9, 127.7, 62.7,
48.6, 34.4, 29.0, 9.7, 8.8. HRMS (ESI/Q-TOF) m/z: [M+Na]+ Calcd for
C20H19NO3Na 344.1257; Found 344.1255.
trans-2-Ethyl-1-oxo-3-(p-tolyl)-2,3,4,5-tetrahydro-1H-benzo[c]-azepine-4-carboxylic
acid
1
(trans-7{8b,1a}). Yield 156 mg, 48%. Colorless solid, mp 245−246 °C (MeOH-H2O). H NMR
(400 MHz, DMSO-d6) δ 12.43 (br.s, 1H), 7.57 – 7.51 (m, 1H), 7.43 – 7.34 (m, 2H), 7.22 (d, J =
7.8 Hz, 2H), 7.18 – 7.11 (m, 3H), 4.78 (d, J = 10.9 Hz, 1H), 3.85 (ddd, J = 10.7, 7.8, 2.6 Hz,
1H), 3.50 (dq, J = 14.2, 7.1 Hz, 1H), 3.15 (dd, J = 14.1, 7.8 Hz, 1H), 3.02 – 2.91 (m, 2H), 2.27
13
(s, 3H), 0.87 (t, J = 7.0 Hz, 3H). C NMR (100 MHz, DMSO-d6) δ 173.9, 169.7, 137.8, 136.6,
135.1, 133.7, 130.9, 129.7, 129.5, 129.3, 128.3, 127.8, 61.4, 48.4, 38.4, 34.1, 21.1, 14.8. HRMS
(ESI/Q-TOF) m/z: [M+Na]+ Calcd for C20H21NO3Na 346.1414; Found 346.1409.
trans-3-(4-Chlorophenyl)-1-oxo-2-propyl-2,3,4,5-tetrahydro-1H-benzo[c]azepine-4-
carboxylic acid (trans-7{8b,1d}). Yield 114 mg, 32%. Colorless solid, mp 235–236 °C (MeOH-
1
H2O). H NMR (400 MHz, DMSO-d6) δ 12.57 (br.s, 1H), 7.49 (d, J = 7.2 Hz, 1H), 7.42 – 7.27
(m, 6H), 7.17 (dd, J = 7.3, 1.4 Hz, 1H), 4.86 (d, J = 9.8 Hz, 1H), 3.87 (ddd, J = 10.0, 7.5, 3.8 Hz,
1H), 3.40 (ddd, J = 13.8, 10.6, 5.3 Hz, 1H), 3.14 (dd, J = 14.0, 7.5 Hz, 1H), 2.99 (dd, J = 14.0,
3.8 Hz, 1H), 2.96 (br.s, 1H), 1.52 – 1.36 (m, 1H), 1.27 – 1.10 (m, 1H), 0.70 (t, J = 7.4 Hz, 3H).
13C NMR (100 MHz, DMSO-d6) δ 173.9), 170.1, 136.5, 135.1, 132.9, 131.0, 130.9, 129.6, 128.8,
128.5, 127.8, 61.2, 48.5, 46.3, 33.9, 22.4, 11.9. HRMS (ESI/Q-TOF) m/z: [M+H]+ Calcd for
C20H20ClNO3 358.1204; Found 358.1203.
Methyl
trans-4-cyclohexyl-3-(4-fluorophenyl)-5-oxo-2,3,4,5-tetrahydro-
1
benzo[f][1,4]oxazepine-2-carboxylate (trans-9{8c,1j}). Yield 75 mg, 19%. Colorless oil. H
NMR (400 MHz, CDCl3) δ 8.1 (dd, J = 8.1, 1.8 Hz, 1H), 7.3 – 7.2 (m, 1H), 7.1 – 7.1 (m, 2H),
7.1 – 7.0 (m, 1H), 6.9 – 6.9 (m, 2H), 6.7 (dd, J = 8.2, 1.2 Hz, 1H), 5.4 (d, J = 4.8 Hz, 1H), 5.3 (d,
J = 4.8 Hz, 1H), 4.7 – 4.6 (m, 1H), 3.8 (s, 3H), 2.0 – 1.0 (m, 10H). 13C NMR (101 MHz, CDCl3)
δ 168.7, 167.2, 161.9 (d, J = 247.2 Hz), 153.2, 132.9, 132.8 (d, J = 3.3 Hz), 132.6, 128.1 (d, J =
8.2 Hz), 123.0, 121.8, 119.1, 115.4 (d, J = 21.8 Hz), 81.6, 58.0, 57.0, 52.8, 31.0, 30.2, 26.0, 25.8,
25.4. HRMS (ESI/Q-TOF) m/z: [M+Na]+ Calcd for C23H24FNO4Na 420.1582; Found 420.1599.
Methyl
cis-4-cyclohexyl-3-(4-fluorophenyl)-5-oxo-2,3,4,5-tetrahydro-
benzo[f][1,4]oxazepine-2-carboxylate (cis-9{8c,1j}). Yield 64 mg, 16%. Colorless oil. 1H NMR
(400 MHz, CDCl3) δ 8.31 (dd, J = 8.2, 1.8 Hz, 1H), 7.37 – 7.27 (m, 1H), 7.12 – 7.03 (m, 1H),
7.01 – 6.90 (m, 2H), 6.92 – 6.79 (m, 3H), 5.55 (d, J = 0.8 Hz, 1H), 4.90 (d, J = 0.8 Hz, 1H), 4.86
– 4.68 (m, 1H), 4.00 (s, 3H), 2.08 – 1.05 (m, 10H). 13C NMR (101 MHz, CDCl3) δ 168.8, 166.5,
15
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European Journal of Organic Chemistry
162.1 (d, J = 247.0 Hz), 153.3, 133.9, 132.9, 131.2 (d, J = 3.2 Hz), 128.3 (d, J = 8.1 Hz), 121.9,
121.6, 119.1, 115.3 (d, J = 21.6 Hz), 81.5, 59.0, 57.0, 53.4, 30.9, 29.5, 25.8, 25.5, 25.4. HRMS
(ESI/Q-TOF) m/z: [M+Na]+ Calcd for C23H24FNO4Na 420.1582; Found 420.1597.
Methyl trans-3,4-Bis(4-methoxyphenyl)-5-oxo-2,3,4,5-tetrahydro-benzo[f][1,4]oxazepine-2-
1
carboxylate (trans-9{8c,1k}). Yield 108 mg, 25%. Beige foam. H NMR (400 MHz, CDCl3) δ
8.03 (dd, J = 7.9, 1.7 Hz, 1H), 7.47 – 7.37 (m, 1H), 7.21 – 7.14 (m, 1H), 7.08 – 6.94 (m, 5H),
6.89 – 6.78 (m, 2H), 6.76 – 6.67 (m, 2H), 5.50 (d, J = 8.0 Hz, 1H), 5.47 (d, J = 8.0 Hz, 1H), 3.80
13
(s, 3H), 3.75 (s, 3H), 3.66 (s, 3H). C NMR (101 MHz, CDCl3) δ 168.7, 167.9, 159.5, 158.6,
153.2, 134.6, 133.1, 131.9, 129.6, 129.1, 125.2, 123.5, 121.3, 114.4, 113.9, 82.1, 64.2, 55.4,
55.2, 52.4. HRMS (ESI/Q-TOF) m/z: [M+H]+ Calcd for C25H25NO6 434.1598; Found 434.1621.
Methyl trans-3-(4-chlorophenyl)-5-oxo-4-propyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-
1
2-carboxylate (trans-9{8c,1d}). Yield 34 mg, 9%. Colorless oil. H NMR (400 MHz, CDCl3) δ
8.11 (dd, J = 8.1, 1.8 Hz, 1H), 7.37 – 7.29 (m, 1H), 7.29 – 7.20 (m, 2H), 7.15 – 7.09 (m, 2H),
7.11 – 7.02 (m, 1H), 6.83 (dd, J = 8.2, 1.2 Hz, 1H), 5.50 (d, J = 5.8 Hz, 1H), 5.27 (d, J = 5.8 Hz,
1H), 3.76 (s, 3H), 3.66 – 3.53 (m, 1H), 3.46 – 3.35 (m, 1H), 1.62 – 1.48 (m, 2H), 0.91 (t, J = 7.4
13
Hz, 3H). C NMR (126 MHz, CDCl3) δ 168.4, 166.8, 153.2, 134.1, 133.6, 133.0, 132.7, 128.9,
128.2, 122.7, 122.3, 119.9, 80.8, 62.5, 52.8, 51.9, 21.3, 11.4. HRMS (ESI/Q-TOF) m/z: [M+Na]+
Calcd for C20H20ClNO4Na 396.0973; Found 396.0992.
Methyl cis-3-(4-chlorophenyl)-5-oxo-4-propyl-2,3,4,5-tetrahydrobenzo-[f][1,4]oxazepine-2-
carboxylate (cis-9{8c,1d}). Yield 19 mg, 5%. Colorless oil. 1H NMR (400 MHz, CDCl3) δ 8.50
(dd, J = 8.3, 1.8 Hz, 1H), 7.50 – 7.34 (m, 1H), 7.26 – 7.21 (m, 2H), 7.20 – 7.08 (m, 1H), 7.05 –
6.88 (m, 3H), 5.34 (d, J = 1.1 Hz, 1H), 5.01 (d, J = 1.1 Hz, 1H), 3.92 (s, 3H), 3.90 – 3.82 (m,
13
1H), 3.22 – 3.07 (m, 1H), 1.80 – 1.68 (m, 2H), 0.97 (t, J = 7.4 Hz, 3H). C NMR (126 MHz,
CDCl3) δ 168.1, 164.8, 154.7, 134.5, 134.5, 133.4, 133.3, 128.8, 128.6, 122.6, 120.7, 119.6, 80.7,
64.8, 53.3, 52.6, 20.7, 11.5. HRMS (ESI/Q-TOF) m/z: [M+Na]+ Calcd for C20H20ClNO4Na
396.0973; Found 396.0989.
Methyl
4-cyclopropyl-5-oxo-3-phenyl-2,3,4,5-tetrahydro-benzo[f][1,4]-oxazepine-2-
1
carboxylate (9{8c,1i}). Yield 37 mg, 11% (dr 2.8:1). White solid. trans-isomer (major): H
NMR (400 MHz, CDCl3) δ 8.05 (dd, J = 8.1, 1.8 Hz, 1H), 7.27 – 7.17 (m, 4H), 7.16 – 7.08 (m,
2H), 7.07 – 6.99 (m, 1H), 6.78 (dd, J = 8.2, 1.2 Hz, 1H), 5.57 (d, J = 5.9 Hz, 1H), 5.45 (d, J = 5.9
Hz, 1H), 3.80 (s, 3H), 2.95 – 2.85 (m, 1H), 1.02 – 0.92 (m, 1H), 0.88 – 0.77 (m, 2H), 0.69 – 0.57
13
(m, 1H). C NMR (101 MHz, CDCl3) δ 168.8, 168.3, 153.5, 135.7, 132.8, 132.6, 128.6, 127.8,
1
126.2, 122.8, 122.0, 119.5, 80.8, 64.0, 52.8, 33.9, 8.3, 7.2. cis-isomer: H NMR (400 MHz,
16
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European Journal of Organic Chemistry
CDCl3) δ 8.38 (dd, J = 8.2, 1.8 Hz, 1H), 7.39 – 7.33 (m, 2H), 7.27 – 7.19 (m, 3H), 6.98 – 6.91
(m, 3H), 5.53 (d, J = 1.1 Hz, 1H), 5.05 (d, J = 1.1 Hz, 1H), 3.95 (s, 3H), 3.16 – 3.08 (m, 1H),
13
1.02 – 0.92 (m, 1H), 0.89 – 0.76 (m, 2H), 0.69 – 0.55 (m, 1H). C NMR (101 MHz, CDCl3) δ
168.8, 167.9, 154.4, 135.7, 134.0, 133.1, 128.6, 128.2, 126.6, 122.2, 121.3, 119.5, 80.9, 66.7,
53.2, 34.6, 8.1, 6.5. HRMS (ESI/Q-TOF) m/z: [M+Na]+ Calcd for C20H19NO4Na 360.1206;
Found 360.1214.
Methyl
trans-4-cyclopropyl-5-oxo-3-(3,4,5-trimethoxyphenyl)-2,3,4,5-
tetrahydronaphtho[2,1-f][1,4]oxazepine-2-carboxylate (trans-9{8d,1l}). Yield 196 mg, 41%.
1
Colorless foam. H NMR (400 MHz, CDCl3) δ 8.18 (dd, J = 8.5, 1.2 Hz, 1H), 8.04 (d, J = 8.8
Hz, 1H), 7.74 (dd, J = 8.3, 0.9 Hz, 1H), 7.56 – 7.49 (m, 1H), 7.49 – 7.40 (m, 2H), 6.31 (s, 2H),
5.73 (d, J = 5.6 Hz, 1H), 5.47 (d, J = 5.6 Hz, 1H), 3.79 (s, 3H), 3.72 (s, 3H), 3.61 (s, 6H), 3.05 –
13
2.92 (m, 1H), 1.08 – 0.95 (m, 1H), 0.93 – 0.78 (m, 2H), 0.76 – 0.64 (m, 1H). C NMR (101
MHz, CDCl3) δ 169.3, 168.6, 153.1, 150.3, 137.4, 135.8, 131.4, 128.2, 127.6, 127.2, 126.0,
125.8, 123.5, 121.8, 117.4, 103.6, 81.8, 64.4, 60.7, 56.0, 52.9, 34.0, 8.5, 7.2. HRMS (ESI/Q-
TOF) m/z: [M+Na]+ Calcd for C27H27NO7Na 500.1680; Found 500.1701.
Methyl
trans-4-ethyl-5-oxo-3-(p-tolyl)-2,3,4,5-tetrahydronaphtho[2,1-f][1,4]oxazepine-2-
1
carboxylate (trans-9{8d,1a}). Yield 89 mg, 23%. Colorless foam. H NMR (400 MHz, CDCl3)
δ 8.19 – 8.15 (m, 1H), 8.13 (d, J = 8.9 Hz, 1H), 7.79 – 7.73 (m, 1H), 7.55 – 7.48 (m, 2H), 7.46 –
7.37 (m, 1H), 7.11 (d, J = 8.1 Hz, 2H), 7.04 (d, J = 8.1 Hz, 2H), 5.76 (d, J = 6.2 Hz, 1H), 5.37 (d,
J = 6.2 Hz, 1H), 3.73 – 3.61 (m, 5H), 2.24 (s, 3H), 1.22 (t, J = 7.1 Hz, 3H). 13C NMR (101 MHz,
CDCl3) δ 168.3, 167.0, 150.0, 138.0, 135.9, 131.7, 129.5, 127.9, 127.9, 127.2, 126.8, 126.3,
125.8, 123.7, 121.9, 117.7, 82.0, 62.4, 52.7, 44.4, 21.0, 13.3. HRMS (ESI/Q-TOF) m/z: [M+Na]+
Calcd for C24H23NO4Na 412.1519; Found 412.1531.
Methyl
cis-4-ethyl-5-oxo-3-(p-tolyl)-2,3,4,5-tetrahydronaphtho[2,1-f][1,4]oxazepine-2-
1
carboxylate (cis-9{8d,1a}). Yield 15 mg, 4%. Colorless foam. H NMR (400 MHz, CDCl3) δ
8.52 (d, J = 9.0 Hz, 1H), 8.45 – 8.38 (m, 1H), 7.80 (d, J = 8.0 Hz, 1H), 7.61 – 7.54 (m, 2H), 7.51
– 7.39 (m, 1H), 7.09 – 6.95 (m, 4H), 5.41 (d, J = 1.2 Hz, 1H), 5.16 (d, J = 1.2 Hz, 1H), 4.08 –
3.98 (m, 1H), 3.97 (s, 3H), 3.31 (dq, J = 14.0, 7.0 Hz, 1H), 2.27 (s, 3H), 1.32 (t, J = 7.1 Hz, 3H).
13C NMR (101 MHz, CDCl3) δ 168.3, 164.8, 152.1, 138.2, 135.9, 132.0, 129.3, 129.1, 128.6,
127.3, 126.9, 126.0, 125.8, 124.5, 121.7, 115.3, 81.4, 64.9, 53.2, 45.6, 21.1, 12.6. HRMS
(ESI/Q-TOF) m/z: [M+Na]+ Calcd for C24H23NO4Na X 412.1519; Found 412.1533.
Methyl trans-4-methyl-5-oxo-3-phenyl-2,3,4,5-tetrahydronaphtho[2,1-f][1,4]oxazepine-2-
1
carboxylate (trans-9{8d,1f}). Yield 43 mg, 12%. Colorless foam. H NMR (400 MHz, CDCl3)
17
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δ 8.20 – 8.15 (m, 1H), 8.07 (d, J = 8.8 Hz, 1H), 7.77 (d, J = 8.0 Hz, 1H), 7.57 – 7.50 (m, 2H),
7.48 – 7.41 (m, 1H), 7.27 – 7.18 (m, 5H), 5.79 (d, J = 6.7 Hz, 1H), 5.41 (d, J = 6.7 Hz, 1H), 3.70
13
(s, 3H), 3.22 (s, 3H). C NMR (126 MHz, CDCl3) δ 168.3, 167.6, 150.0, 136.0, 134.2, 128.9,
128.3, 128.1, 127.6, 127.3, 126.9, 126.3, 126.0, 123.6, 122.3, 118.0, 81.7, 63.7, 52.8, 36.8.
HRMS (ESI/Q-TOF) m/z: [M+Na]+ Calcd for C22H19NO4Na 384.1206; Found 384.1223.
Methyl
cis-4-methyl-5-oxo-3-phenyl-2,3,4,5-tetrahydronaphtho[2,1-f][1,4]oxazepine-2-
1
carboxylate (cis-9{8d,1f}). Yield 11 mg, 3%. Colorless foam. H NMR (400 MHz, CDCl3) δ
8.53 (d, J = 9.0 Hz, 1H), 8.46 – 8.39 (m, 1H), 7.81 (d, J = 8.1 Hz, 1H), 7.63 – 7.54 (m, 2H), 7.52
– 7.43 (m, 1H), 7.31 – 7.22 (m, 3H), 7.17 – 7.08 (m, 2H), 5.36 (d, J = 1.4 Hz, 1H), 5.25 (d, J =
1.4 Hz, 1H), 3.94 (s, 3H), 3.24 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 168.0, 165.1, 152.7,
136.0, 134.9, 129.1, 128.7, 128.70, 128.69, 127.5, 126.9, 126.2, 125.9, 124.5, 122.0, 115.3, 81.1,
67.4, 53.1, 38.0. HRMS (ESI/Q-TOF) m/z: Calcd for C22H19NO4Na [M+Na]+ 384.1206; Found
384.1225.
Methyl
trans-3,4-bis(4-methoxyphenyl)-5-oxo-1-tosyl-2,3,4,5-tetrahydro-1H-
benzo[e][1,4]diazepine-2-carboxylate (trans-9{8e,1k). Yield 70 mg, 30%. Pale yellow foam.
1H NMR (400 MHz, CDCl3): δ 7.86 – 7.81 (m, 1H), 7.74 (d, J = 8.3 Hz, 2H), 7.59 – 7.51 (m,
2H), 7.43 – 7.39 (m, 1H), 7.32 (d, J = 8.0 Hz, 2H), 6.76 (d, J = 8.2 Hz, 2H), 6.61 – 6.56 (m, 4H),
6.28 (d, J = 8.9 Hz, 2H), 5.42 (d, J = 11.6 Hz, 1H), 5.06 (d, J = 11.6 Hz, 1H), 3.72 (s, 3H), 3.70
13
(s, 3H), 3.42 (s, 3H), 2.43 (s, 3H). C NMR (101 MHz, CDCl3): δ 169.3, 168.6, 160.0, 125.9,
144.5, 136.8, 135.2, 134.0, 132.0, 131.9, 131.7. 131.1, 130.4, 130.2, 130.1, 129.5, 128.1, 123.0,
114.2, 113.6, 65.8, 64.6, 55.4, 55.2, 21.7. HRMS (ESI/Q-TOF) m/z: [M+H]+ Calcd for
C32H31N2O7S 587.1846; Found 587.1844.
Methyl
cis-3,4-bis(4-methoxyphenyl)-5-oxo-1-tosyl-2,3,4,5-tetrahydro-1H-
1
benzo[e][1,4]diazepine-2-carboxylate (cis-9{8e,1k). Yield 48 mg, 20%. Pale yellow foam. H
NMR (400 MHz, CDCl3): δ 7.65 (d, J = 7.8 Hz, 1H), 7.61 (d, J = 8.3 Hz, 2H), 7.36 (ddd, J = 8.0,
6.3, 2.8 Hz, 1H), 7.24 (br.s., 1H), 7.17 – 7.11 (m, 2H), 6.98 (d, J = 9.0 Hz, 2H), 6.90 (d, J = 9.0
Hz, 2H), 6.69 (d, J = 8.9 Hz, 2H), 6.46 (d, J = 8.9 Hz, 2H), 5.70 (d, J = 6.7 Hz, 1H), 5.60 (d, J =
13
6.7 Hz, 1H), 3.85 (s, 3H), 3.68 (s, 3H), 3.65 (s, 3H), 2.40 (s, 3H). C NMR (101 MHz, CDCl3):
δ 170.3, 168.0, 158.5, 158.2, 144.4, 136.7, 136.4, 136.1, 134.5, 132.3, 131.6, 130.4. 130.0, 129.4,
129.2, 128.1, 127.9, 127.2, 114.7, 113.6, 65.7, 64.5, 55.7, 55.2, 53.0, 21.5. HRMS (ESI/Q-TOF)
m/z: [M+H]+ Calcd for C32H31N2O7S 587.1846; Found 587.1866.
Мethyl
trans-4-(4-chlorophenyl)-5-oxo-3-(p-tolyl)-1-tosyl-2,3,4,5-tetrahydro-1H-
1
benzo[e][1,4]diazepine-2-carboxylate (trans-9{8e,1h). Yield 123 mg, 21%. Beige foam. H
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NMR (400 MHz, CDCl3): δ 7.86 – 7.81 (m, 1H), 7.73 (d, J = 8.3 Hz, 2H), 7.60 – 7.53 (m, 2H),
7.36 – 7.34 (m, 1H), 7.32 (d, J = 8.3 Hz, 2H), 7.04 (d, J = 8.6 Hz, 2H), 6.89 (d, J = 7.9 Hz, 2H),
6.75 (d, J = 7.8 Hz, 2H), 6.37 (s, J = 8.6 Hz, 2H), 5.51 (d, J = 11.6 Hz, 1H), 5.10 (d, J = 11.6 Hz,
1H), 3.43 (s, 3H), 2.44 (s, 3H), 2.22 (s, 3H). 13C NMR (101 MHz, CDCl3): δ 169.0, 168.5, 144.6,
139.5, 136.8, 136.5, 135.0, 133.9, 133.7, 132.2, 131.6, 131.5, 130.5, 130.3, 130.1, 129.7, 129.2,
129.0, 128.1, 127.6, 65.5, 64.6, 52.3, 21.7, 21.2. HRMS (ESI/Q-TOF) m/z: [M+Na]+ Calcd for
C31H27ClN2O5SNa 597.1221; Found 597.1217.
Мethyl
cis-4-(4-chlorophenyl)-5-oxo-3-(p-tolyl)-1-tosyl-2,3,4,5-tetrahydro-1H-
benzo[e][1,4]diazepine-2-carboxylate (cis-9{8e,1h). Yield 114 mg, 20%. Beige foam. 1H NMR
(400 MHz, CDCl3): δ 7.62 - 7.57 (m, 3H), 7.40 – 7.33 (m, 1H), 7.36 (d, J = 8.7 Hz, 2H), 7.25 (d,
J = 8.4 Hz, 2H), 7.11 (d, J = 4.0 Hz, 2H), 7.03 (d, J = 8.7 Hz, 2H), 6.74 (d, J = 8.2 Hz, 2H), 6.63
13
(d, J = 8.2 Hz, 2H), 5.66 (s, 2H), 3.70 (s, 3H), 2.42 (s, 3H), 2.13 (s, 3H). C NMR (101 MHz,
CDCl3): δ 170.1, 167.9, 144.5, 141.8, 136.9, 136.5, 136.1, 134.4, 134.2, 132.7, 132.4, 131.8,
130.4, 130.0, 129.6, 129.3, 129.0, 128.1, 127.2, 126.2, 65.5, 64.3, 53.2, 21.8, 20.9. HRMS
(ESI/Q-TOF) m/z: [M+Na]+ Calcd for C31H27ClN2O5SNa 597.1221; Found 597.1242.
Methyl
4-(2-methoxyethyl)-3-(3-methoxyphenyl)-5-oxo-1-tosyl-2,3,4,5-tetrahydro-1H-
benzo[e][1,4]diazepine-2-carboxylate (9{8e,1m). Yield 210 mg, 39% (dr 1.1:1). Beige foam.
1H NMR (400 MHz, CDCl3), signals of major (trans-): δ 7.72 (dd, J = 5.8, 3.4 Hz, 1H), 7.58 (d, J
= 8.1 Hz, 1H), 7.51 (d, J = 8.5 Hz, 2H), 7.31 (dd, J = 5.8, 3.4 Hz, 1H), 7.22 (d, J = 7.8 Hz, 2H),
7.03 (dt, J = 7.4, 1.0 Hz, 1H), 6.79 (t, J = 8.1 Hz, 1H), 5.73 (d, J = 11.7 Hz, 1H), 4.86 (d, J = 11.7
Hz, 1H), 4.09 (ddd, J = 14.0, 4.9, 2.1 Hz, 1H), 3.78 (s, 3H), 3.54 (s, 3H), 3.24 (s, 3H), 2.83 –
2.75 (m, 2H), 2.40 (s, 3H); signals of minor (cis-): δ 7.55 (d, J = 8.3 Hz, 2H), 6.98 (dd, J = 7.7,
1.8 Hz, 1H), 6.46 – 6.42 (m, 1H), 6.29 (d, J = 7.3 Hz, 2H), 5.88 (d, J = 6.1 Hz, 1H), 5.49 (d, J =
6.1 Hz, 1H), 3.75 (s, 3H), 3.55 (s, 3H), 3.48 (s, 3H), 2.40 (s, 3H). 13C NMR (101 MHz, CDCl3):
signals of major: δ 169.2, 168.3, 144.2, 136.4, 132.1, 131.7, 129.8, 129.7, 128.9, 127.8, 118.6,
70.1, 64.9, 62.9, 58.8, 55.4, 52.3, 55.1, 42.2, 21.7; signals of minor: δ 170.8, 168.3, 144.1, 136.5,
127.9, 122.7, 116.3, 112.5, 71.8, 65.2, 62.3, 59.0, 55.4, 53.0, 50.0, 21.7. HRMS (ESI/Q-TOF)
m/z: [M+H]+ Calcd for C28H31N2O7S 539.1846; Found 539.1848.
Мethyl
trans-3-(4-fluorophenyl)-5-oxo-4-(p-tolyl)-1-tosyl-2,3,4,5-tetrahydro-1H-
benzo[e][1,4]diazepine-2-carboxylate (trans-9{8e,1n). Yield 95 mg, 17%. Pale yellow foam.
1H NMR (400 MHz, CDCl3): δ 7.86 – 7.81 (m, 1H), 7.73 (d, J = 8.3 Hz, 2H), 7.60 – 7.51 (m,
2H), 7.45 – 7.41 (m, 2H), 7.31 (d, J = 8.0 Hz, 2H), 6.87 (d, J = 7.9 Hz, 2H), 6.85 – 6.83 (m, 2H),
6.76 (t, J = 8.6 Hz, 2H), 6.25 (d, J = 8.2 Hz, 2H), 5.45 (d, J = 11.6 Hz, 1H), 5.11 (d, J = 11.6 Hz,
19
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1H), 3.43 (s, 3H), 2.43 (s, 3H), 2.24 (s, 3H). . 13C NMR (101 MHz, CDCl3): δ 169.2, 168.4,
162.8 (d, J = 249.6 Hz), 144.6, 137.9, 136.6, 135.0, 134.8, 133.9, 132.5 (d, J = 8.4 Hz), 132.0,
131.7, 130.2, 130.1, 129.73, 129.65, 129.57, 128.1, 127.0 (d, J = 3.4 Hz), 115.3 (d, J = 21.6 Hz),
65.7, 64.2, 52.3, 21.7, 21.2. HRMS (ESI/Q-TOF) m/z: [M+Na]+ Calcd for C31H27FN2O5SNa
581.1517; Found 581.1506.
Мethyl
cis-3-(4-fluorophenyl)-5-oxo-4-(p-tolyl)-1-tosyl-2,3,4,5-tetrahydro-1H-
1
benzo[e][1,4]diazepine-2-carboxylate (cis-9{8e,1n). Yield 106 mg, 19%. Yellow foam. H
NMR (400 MHz, CDCl3): δ 7.65 (d, J = 7.9 Hz, 1H), 7.58 (d, J = 8.3 Hz, 2H), 7.40 – 7.34 (m,
1H), 7.24 (d, J = 8.0 Hz, 2H), 7.20 (d, J = 8.1 Hz, 2H), 7.14 – 7.09 (m, 2H), 6.95 (d, J = 8.4Hz,
2H), 6.80 (dd, J = 8.6, 5.1 Hz, 2H), 6.63 (t, J =8.6 Hz, 2H), 5.70 (d, J = 6.6 Hz, 1H), 5.67 (d, J =
6.6 Hz, 1H), 3.71 (s, 3H), 2.40 (s, 3H), 2.39 (s, 3H). 13C NMR (101 MHz, CDCl3): δ 170.2,
167.7, 161.2 (d, J = 248.0 Hz), 144.5, 140.6, 137.3, 136.6, 135.9, 134.4, 133.4 (d, J = 3.6 Hz),
132.4, 131.8, 130.3, 130.1, 130.0, 129.3, 128.3 (d, J = 8.0 Hz), 128.1, 125.5, 115.2 (d, J = 21.5
Hz), 65.6, 63.9, 53.1, 21.7, 21.2. HRMS (ESI/Q-TOF) m/z: [M+H]+ Calcd for C31H28FN2O5S
559.1697; Found 559.1673.
Мethyl
trans-4-cyclopropyl-5-oxo-3-phenyl-1-tosyl-2,3,4,5-tetrahydro-1H-
benzo[e][1,4]diazepine-2-carboxylate (trans-9{8e,1i). Yield 59 mg, 12%. Pale yellow foam. 1H
NMR (400 MHz, CDCl3): δ 7.91 (dd, J = 7.6, 1.7 Hz, 1H), 7.54 (d, J = 8.3 Hz, 2H), 7.52 – 7.43
(m, 2H), 7.39 – 7.32 (m, 5H), 7.25 (d, J = 7.1 Hz, 2H), 7.12 (dd, J = 7.8, 1.2 Hz, 1H), 5.69 (d, J
= 12.0 Hz, 1H), 4.94 (d, J = 12.0 Hz, 1H), 3.55 (s, 3H), 2.41 (s, 3H), 1.66 (ddd, J = 15.8, 6.7, 4.6
Hz, 1H), 0.75 (ddd, J = 13.0, 9.4, 6.9 Hz, 1H), 0.63 (ddd, J = 15.8, 6.7, 4.6 Hz, 1H), 0.40 – 0.32
(m, 1H), 0.29 – 0.21 (m, 1H). 13C NMR (101 MHz, CDCl3): δ 169.8, 169.0, 144.3, 136.8, 135.5,
133.4, 132.1, 131.7, 131.6, 130.8, 130.3, 129.9, 129.7, 128.6, 127.6, 65.2, 63.5, 52.4, 26.9, 21.7,
9.5, 8.3. HRMS (ESI/Q-TOF) m/z: [M+Na]+ Calcd for C27H26N2O5SNa 513.1455, Found
513.1472.
Мethyl
cis-4-cyclopropyl-5-oxo-3-phenyl-1-tosyl-2,3,4,5-tetrahydro-1H-
1
benzo[e][1,4]diazepine-2-carboxylate (cis-9{8e,1i). Yield 98 mg, 20%. Pale yellow foam. H
NMR (400 MHz, CDCl3): δ 7.65 (d, J = 7.9 Hz, 1H), 7.47 (d, J = 8.3 Hz, 2H), 7.35 (ddd, J = 8.1,
5.9, 3.2 Hz, 1H), 7.24 (s, 1H), 7.12 – 7.04 (m, 2H), 6.95 – 6.85 (m, 3H), 6.61 (d, J = 7.3 Hz, 2H),
5.43 (d, J = 7.0 Hz, 1H), 5.40 (d, J = 7.0 Hz, 1H), 3.70 (s, 3H), 3.01 – 2.93 (m, 1H), 2.42 (s, 3H),
13
0.95 – 0.83 (m, 2H), 0.81 – 0.73 (m, 1H), 0.30 – 0.20 (m, 1H). C NMR (101 MHz, CDCl3): δ
170.2, 169.9, 144.3, 137.9, 136.3, 136.1, 134.5, 132.6, 131.7, 130.4, 130.0, 129.1, 128.1, 127.6,
20
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126.8, 126.2, 66.8, 62.7, 53.1, 33.6, 21.7, 9.0, 6.0. HRMS (ESI/Q-TOF) m/z: [M+Na]+ Calcd for
C27H26N2O5SNa 513.1455; Found 513.1475.
Мethyl
trans-3-(4-methoxyphenyl)-4-methyl-5-oxo-1-tosyl-2,3,4,5-tetrahydro-1H-
1
benzo[e][1,4]diazepine-2-carboxylate (trans-9{8e,1o). Yield 30 mg, 6%. Pale yellow foam. H
NMR (400 MHz, CDCl3): δ 7.72 (dd, J = 7.4, 1.7 Hz, 1H), 7.61 – 7.47 (m, 5H), 7.26 (d, J = 8.1
Hz, 2H), 7.17 (d, J = 8.7 Hz, 2H), 6.85 (d, J = 8.8 Hz, 2H), 5.41 (d, J =11.9 Hz, 1H), 4.83 (d, J =
11.9 Hz, 1H), 3.79 (s, 3H), 3.56 (s, 3H), 2.40 (s, 3H), 2.15 (s, 3H). 13C NMR (101 MHz, CDCl3):
δ 169.0, 168.0, 160.4, 144.3, 136.1, 134.8, 133.24, 133.19, 133.1, 132.1, 131.3, 130.1, 130.0,
129.7, 127.4, 123.2, 114.3, 64.4, 62.1, 55.4, 52.5, 29.3, 21.7. HRMS (ESI/Q-TOF) m/z: [M+Na]+
Calcd for C26H26N2O6SNa 517.1404; Found 517.1416.
Мethyl
cis-3-(4-methoxyphenyl)-4-methyl-5-oxo-1-tosyl-2,3,4,5-tetrahydro-1H-
benzo[e][1,4]diazepine-2-carboxylate (cis-9{8e,1o). Yield 119 mg, 24%. Pale yellow foam. 1H
NMR (400 MHz, CDCl3): δ 7.78 (dd, J = 8.0, 0.8 Hz, 1H), 7.45 (d, J = 8.3 Hz, 2H), 7.40 (dt, J =
7.8, 1.6 Hz, 1H), 7.25 (d, J = 8.1 Hz, 2H), 7.11 (dt, J = 7.6, 1.1 Hz, 1H), 6.99 (dd, J = 7.7, 1.5
Hz, 1H), 6.49 (d, J = 8.8Hz, 2H), 6.40 (d, J = 8.9 Hz, 2H), 5.53 (d, J = 6.9 Hz, 1H), 5.18 (d, J =
13
6.9 Hz, 1H), 3.72 (s, 3H), 3.62 (s, 3H), 3.00 (s, 3H), 2.42 (s, 3H). C NMR (101 MHz, CDCl3):
δ 170.2, 168.1, 158.1, 144.3, 135.9, 135.5, 134.4, 133.1, 131.6, 130.0, 129.8, 129.5, 129.3, 127.5,
127.4, 113.4, 65.1, 62.8, 55.2, 53.1, 37.5, 21.7. HRMS (ESI/Q-TOF) m/z: [M+H]+ Calcd for
C26H27N2O6S 495.1584; Found 495.1587.
Methyl
trans-4-benzyl-5-oxo-3-(p-tolyl)-1-tosyl-2,3,4,5-tetrahydro-1H-
1
benzo[e][1,4]diazepine-2-carboxylate (trans-9{8e,1p). Yield 105 mg, 19%. Yellow foam. H
NMR (400 MHz, CDCl3): δ 7.81 – 7.78 (m, 1H), 7.57 – 7.52 (m, 4H), 7.47 – 7.44 (m, 1H),7.26
(d, J = 8.0 Hz, 2H), 7.01 – 6.93 (m, 5H), 6.85 (d, J = 7.8 Hz, 2H), 6.66 (d, J = 6.6 Hz, 2H), 5.55
(d, J = 11.8 Hz, 1H), 4.89 (d, J = 11.8 Hz, 1H), 4.26 (d, J = 15.2 Hz, 1H), 3.71 (d, J = 15.2 Hz,
1H), 3.52 (s, 3H), 2.38 (s, 3H), 2.21 (s, 3H). 13C NMR (101 MHz, CDCl3): δ 169.0, 168.6, 144.4,
139.5, 138.3, 136.2, 135.2, 133.2, 132.5, 132.1, 130.1, 129.7, 129.1, 127.7, 127.7, 127.5, 126.4,
64.7, 62.3, 52.5, 46.6, 21.8, 21.2. HRMS (ESI/Q-TOF) m/z: [M+K]+ Calcd for C32H30N2O5SK
597.1217;Found 597.1221.
Methyl cis-4-benzyl-5-oxo-3-(p-tolyl)-1-tosyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine-
1
2-carboxylate (cis-9{8e,1p). Yield 45 mg, 8%. Yellow foam. H NMR (400 MHz, CDCl3): δ
7.69 (d, J = 8.0 Hz, 1H), 7.52 – 7.32 (m, 9H), 7.26 (d, J = 8.2 Hz, 2H), 7.09 – 7.02 (m, 2H), 6.50
(d, J = 8.2 Hz, 2H), 6.07 (d, J = 8.2, 2H), 5.45 (d, J = 6.5 Hz, 1H), 5.25 (d, J = 6.5 Hz, 1H), 4.75
(d, J = 14.2 Hz, 1H), 4.09 (d, J = 14.2 Hz, 1H), 3.67 (s, 3H), 2.41 (s, 3H), 2.01 (s, 3H). 13C NMR
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European Journal of Organic Chemistry
(101 MHz, CDCl3): δ 170.2, 168.0, 144.3, 136.7, 136.2, 136.1, 135.7, 134.4, 133.8, 132.6, 131.4,
130.1, 130.0, 129.9, 129.1, 129.0, 128.5, 128.4, 127.7, 126.3, 65.0, 59.6, 53.0, 52.5, 31.7, 22.7,
21.7, 20.1, 14.2. HRMS (ESI/Q-TOF) m/z: [M+H]+ Calcd for C32H31N2O5S 555.1948; Found
555.1978.
Methyl
4-butyl-3-(3,4-dimethoxyphenyl)-5-oxo-1-tosyl-2,3,4,5-tetrahydro-1H-
1
benzo[e][1,4]diazepine-2-carboxylate (9{8e,1q). Yield 142 mg, 25% (dr 2:1). Beige foam. H
NMR (400 MHz, CDCl3) δ 7.73 – 7.70 (m, 1H), 7.54 (d, J = 8.3 Hz, 1.4H), 7.52 – 7.49 (m,
1.4H), 7.45 (d, J = 8.2 Hz, 0.6H), 7.42 (dd, J = 6.4, 1.5 Hz, 0.7H), 7.33 (td, J = 8.2, 1.6 Hz,
0.6H), 7.23 (m, 2H), 7.08 (td, J = 7.5, 1.0 Hz, 0.3H), 7.01 (dd, J = 7.8, 1.6 Hz, 0.3H), 6.91 (br. d,
J = 8.1 Hz, 0.7H), 6.81 (d, J = 8.4 Hz, 0.7H), 6.68 (br.s, 0.7H), 6.41 (d, J = 8.5 Hz, 0.3H), 6.28
(dd, J = 8.5, 2.2 Hz, 0.3H), 6.20 (d, J = 1.9 Hz, 0.3H), 5.43 (d, J = 6.4 Hz, 0.3H), 5.38 (d, J =
11.8 Hz, 0.7H), 5.21 (d, J = 6.4 Hz, 0.3H), 4.79 (d, J = 11.8 Hz, 0.7H), 3.87 (s, 2.1H), 3.82 (s,
2.1H), 3.75 (s, 0.9H), 3.69 (s, 0.9H), 3.56 (s, 0.9H), 3.54 (s, 2.1H), 3.35 – 3.21 (m, 0.6H), 2.91
(ddd, J = 13.5, 11.7, 4.7 Hz, 0.7H), 2.52 (ddd, J = 13.5, 11.4, 5.1 Hz, 0.7H), 2.40 (s, 0.9H), 2.39
(s, 2.1H), 1.70 – 1.57 (m, 0.3H), 1.49 - 1.33 (m, 0.9 H), 1.17 – 1.06 (m, 0.7H), 0.98 (t, J =7.3 Hz,
13
0.9H), 0.97 – 0.87 (m, 1.4H), 0.63 (t, J = 7.3 Hz, 2.1H), 0.58 – 0.48 (m, 0.7H). C NMR (101
MHz, CDCl3): signals of major (trans-): δ 169.2, 167.8, 150.0, 149.2, 141.3, 136.3, 135.3, 133.2,
132.4, 131.8, 130.0, 129.8, 129.6, 127.7, 123.5, 113.7, 110.9, 65.3, 62.5, 56.2, 56.0, 52.5, 42.9,
30.8, 21.7, 20.2, 13.5; signals of minor (cis-): δ 170.4, 167.9, 148.0, 147.4, 144.3, 136.4, 135.6,
134.4, 132.4, 131.2, 130.0, 129.9, 129.89, 129.2, 128.2, 119.3, 110.7, 109.9, 65.8, 60.9, 55.8,
55.7, 53.1, 49.5, 20.4, 13.9. HRMS (ESI/Q-TOF) m/z: [M+Na]+ Calcd for C30H34N2O7SNa
589.1979; Found 589.1952.
Methyl
trans-8-oxo-13-tosyl-5,6,8,13,14,14a-hexahydrobenzo[5,6][1,4]diazepino[2,1-
1
a]isoquinoline-14-carboxylate (trans-9{8e,1r). Yield 104 mg, 22%. Light grey foam. H NMR
(400 MHz, CDCl3): δ 7.71 (dd, J = 7.6, 1.5 Hz, 1H), 7.66 – 7.54 (m, 4H), 7.51 (d, J = 8.3 Hz,
2H), 7.30 (d, J = 8.1 Hz, 2H), 7.26 (dd, J = 7.3, 1.1 Hz, 1H), 7.22 (d, J = 6.9 Hz, 1H), 7.12 (dt, J
= 7.5, 1.0 Hz, 1H), 6.79 (d, J = 7.5 Hz, 1H), 4.72 (d, J = 11.1 Hz, 1H), 4.63 (d, J = 11.1 Hz, 1H),
3.55 (s, 3H), 3.44 (ddd, J = 12.4, 4.5, 2.5 Hz, 1H), 2.92 (dt, J = 12.5, 4.5 Hz, 1H), 2.83 – 2.73
13
(m, 2H), 2.45 (s, 3H) ppm. C NMR (101 MHz, CDCl3): δ 169.5, 168.5, 144.3, 136.3, 136.2,
134.2, 133.7, 133.6, 132.3, 130.14, 130.07, 130.0, 129.7, 129.1, 128.5, 127.6, 127.5, 127.0, 69.5,
58.8, 52.2, 41.9, 27.9, 21.8. HRMS (ESI/Q-TOF) m/z: [M+Na]+ Calcd for C26H24N2O5SNa
499.1298; Found 499.1319.
Supporting Information
22
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10.1002/ejoc.201701642
European Journal of Organic Chemistry
1
Synthetic procedures for preparation of dicarboxylic acids 8a-e. Copies of H and 13C NMR
spectra, X-ray crystallographic data of selected compounds 7 and 9. Supporting information and
ORCID(s) from the author(s) for this article are available on the WWW under https://. CCDC
1561867 (7{8a,1a}), 1561868 (7{8a,1e}), 1561866 (7{8a,1h}), 1573585 (7{8b,1a}), 1573586
(7{8b,1e}), 1573584 (trans-9{8e,1i}), 1573582 (cis-9{8e,1i}), 1573581 (trans-9{8e,1o}),
1573583 (cis-9{8e,1o}) contain the supplementary crystallographic data for this paper. These
data can be obtained free of charge from The Cambridge Crystallographic Data Centre via
http://www.ccdc.cam.ac.uk.
Corresponding Author
* E-mail: m.krasavin@spbu.ru. URL: http://www.krasavin-group.org.
ORCID: Olga Bakulina: 0000-0002-4930-0739; Dmitry Dar’in: 0000-0002-0413-7413; Mikhail
Krasavin: 0000-0002-0200-4772.
Acknowledgements
This research was supported by the Russian Scientific Fund (project grant 14-50-00069). NMR,
mass spectrometry and X-ray diffraction studies were performed at the Research Centre for
Magnetic Resonance, the Centre for Chemical Analysis and Materials Research and the Center
for X-ray Diffraction Methods of Research park of Saint Petersburg State University.
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