Synthesis of 1,4-Benzodiazepine-2,5-diones by Base Promoted Ring Expansion of 3-Aminoquinoline-2,4-diones

Article abstract of DOI:10.1021/acs.joc.6b01497

An unprecedented reactivity of 3-aminoquinoline-2,4-diones is reported. Under basic conditions, these compounds undergo molecular rearrangement to furnish 1,4-benzodiazepine-2,5-diones. The transformations take place under mild reaction conditions by using 1,1,3,3-tetramethylguanidine, NaOEt, or benzyltrimethylammonium hydroxide as a base. A proposed mechanism of the rearrangement and the conformational equilibrium of 1,4-benzodiazepine-2,5-dione rings are discussed.

Full text of DOI:10.1021/acs.joc.6b01497

Subscriber access provided by CORNELL UNIVERSITY LIBRARY
Note
Synthesis of 1,4-Benzodiazepine-2,5-diones by Base
Promoted Ring Expansion of 3-Aminoquinoline-2,4-diones
Filip K#emen, Martin Gazvoda, Stanislav Kafka, Karel Proisl, Anna
Srholcová, Antonin Klasek, Damijana Urankar, and Janez Košmrlj
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b01497 • Publication Date (Web): 27 Oct 2016
Downloaded from http://pubs.acs.org on October 28, 2016
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a free service to the research community to expedite the
dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts
appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been
fully peer reviewed, but should not be considered the official version of record. They are accessible to all
readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered
to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published
in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just
Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor
changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers
and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors
or consequences arising from the use of information contained in these “Just Accepted” manuscripts.
The Journal of Organic Chemistry is published by the American Chemical Society.
1155 Sixteenth Street N.W., Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 28
The Journal of Organic Chemistry
1
2
3
4
5
6
Synthesis of 1,4-Benzodiazepine-2,5-diones by Base Promoted Ring Expansion of 3-
Aminoquinoline-2,4-diones
7
8
9
Filip Křemen,†,# Martin Gazvoda,‡,# Stanislav Kafka,†,* Karel Proisl,† Anna Srholcová,†
Antonín Klásek,† Damijana Urankar,‡ and Janez Košmrlj‡,*
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
† Department of Chemistry, Faculty of Technology, Tomas Bata University,
76272 Zlín, Czech Republic
‡ Faculty of Chemistry and Chemical Technology, University of Ljubljana, Večna pot 113,
SI 1000 Ljubljana, Slovenia
TOC Graphics
Abstract: An unprecedented reactivity of 3-aminoquinoline-2,4-diones is reported. Under basic
conditions these compounds undergo molecular rearrangement to furnish 1,4-benzodiazepine-
2,5-diones. The transformations take place under mild reaction conditions by using 1,1,3,3-
tetramethylguanidine (TMG), NaOEt, or benzyltrimethylammonium hydroxide (Triton B) as a
base. A proposed mechanism of the rearrangement and the conformational equilibrium of 1,4-
benzodiazepine-2,5-dione rings are discussed.
The 1,4-benzodiazepine-2,5-dione scaffold, a subset of the 1,4-benzodiazepines,
comprises a privileged structure and numerous derivatives have been found to exhibit a diverse
1
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 2 of 28
1
2
3
4
5
6
7
8
9
array of biological activities.1–5 These activities include: histone deacetylase inhibition (Figure 1,
structure I);6 anticholinesterase activity (II, R= H, R’ = Br);7 melanocortin agonist activity;8
endothelin receptor antagonism (III);9 glycoprotein IIb-IIIa antagonism (IV);10,11 antagonism of
the HDM2-p53 interaction (V);12,13 anxiolytic activity;14 anti-leishmanial activity;15 and
herbicidal activity.16 The 1,4-benzodiazepine-2,5-dione motif appears in natural products
including cyclopenin17,18 (II; R = CH3, R' = H, Ar = C6H5), cyclopenol17 (II; R = CH3, R' = H, Ar
= 3-OH-C6H4), and cyclopeptin (VI).19 They were predicted to be biosynthesized by the
condensation of anthranilic acid and an amino acid.20 In addition to diverse biological activities,
1,4-benzodiazepine-2,5-diones found widespread applications as intermediates in the preparation
of products of medicinal interest.21,22
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Figure 1. Selected 1,4-benzodiazepine-2,5-diones of biological relevance.
The synthesis of 1,4-benzodiazepine-2,5-dione has been reviewed.1,23 There are two major
strategies for their preparation. One relies on the condensation of an anthranilic acid or its
2
ACS Paragon Plus Environment

Page 3 of 28
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
derivative, e.g. isatoic anhydride, with -amino acid (Figure 2a). Another versatile route takes
advantage of Ugi reaction, a four component reaction of substituted N-Boc-protected anthranilic
acid with an aldehyde, an amine, and an isonitrile to form bis-amide (Figure 2b).24 Subsequent N-
Boc-deprotection and condensation of the bis-amide Ugi product generates the 1,4-
benzodiazepine-2,5-dione ring skeleton. With some exceptions,25,26 this procedure has been
largely executed to give N1 unsubstituted products (R1 = H). After ring formation, late stage,
selective alkylation (N1/N3) to form the desired product can sometimes be challenging.27 High-
throughput synthetic protocols have been realized by a combinatorial approach.1,8,28–32
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Figure 2. Approaches to 1,4-benzodiazepine-2,5-diones.
Due to the remarkable synthetic and biological relevance of 1,4-benzodiazepine-2,5-
diones and related compounds there is an urge to discover new strategies for their preparation. As
3
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 4 of 28
1
2
3
4
5
6
7
8
9
a part of our interest in the chemistry of quinoline-2,4(1H,3H)-diones,33–42 herein we report a
novel, approach to this scaffold that is based on a rearrangement of 3-aminoquinoline-
2,4(1H,3H)-diones (Figure 2c). In a simple four-step protocol this method employs anilines as
starting substrates. An advantage of the method over those from Figure 2a–b is a broad
availability of aniline derivatives in comparison to anthranilic acids and isatoic anhydrides, both,
synthetically and commercially. It readily provides the 1,4-benzodiazepine-2,5-dione ring
functionalized at N1 and N3 with an alkyl or aryl moiety. Optimization of the reaction conditions
as well as the scope of the reaction is reported.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Differently functionalized starting compounds required for this study were prepared in
three simple steps starting from commercially available anilines and diethyl malonates to initially
afford 4-hydroxy-2(1H)-quinolones (Scheme 1). Chlorination of 4-hydroxy-2(1H)-quinolones
with sulfuryl chloride gave 3-chloroquinolin-2,4(1H,3H)-diones 1,43,44 which subsequently
readily underwent nucleophilic displacement of the chlorine atom with selected primary amines
into 3-aminoquinoline-2,4(1H,3H)-diones 2.45
Scheme 1. Preparation of compounds 1 and 2
4
ACS Paragon Plus Environment

Page 5 of 28
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Investigating the scope of the Wittig olefination at the C-3 carbonyl atom of 3-
aminoquinoline-2,4(1H,3H)-diones, we have previously made a preliminary observation that
these compounds are capable of ring expansion into 1,4-benzodiazepine-2,5-diones.46 In one
instance the treatment of a selected 3-aminoquinoline-2,4(1H,3H)-dione with ethyl
(triphenylphosphoranylidene)acetate (Ph3P=CHCO2Et) in xylene at elevated temperature
unexpectedly resulted in its rearrangement into 1,4-benzodiazepine-2,5-dione instead of the
anticipated olefination.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
It is reasonable to assume that in the presence of Ph3P=CHCO2Et the rearrangement was
47
enabled by the assistance of a relatively basic Wittig reagent (pKa of the conjugated acid,
Ph3P+CH2CO2Et, measured in DMSO = 8.50). To find out whether 3-aminoquinoline-
2,4(1H,3H)-diones are in general susceptible to base mediated transformations into 1,4-
benzodiazepine-2,5-diones, we initially conducted some base screening experiments with
compound 2a as a model substrate. As the above mentioned heating in xylene in the presence of a
phophonium ylide would unlikely find practical applications, we decided to test amine bases
including 4-dimethylaminopyridine (DMAP), triethylamine, piperidine, butylamine and 1,1,3,3-
tetramethylguanidine (TMG) in ethanol as the reaction solvent (Table 1). Whereas DMAP
completely failed to react with 2a, triethylamine resulted in a complex mixture of products, as
judged by TLC analyses of the crude reaction mixtures. In contrast, piperidine, butylamine, and
TMG afforded the desired (3a) in low to moderate yield. Out of these three bases, TMG was the
most effective. It appeared that the efficiency of this rearrangement correlated with its basic
character (pKa data of conjugated acids in water for DMAP = 9.60;48 triethylamine = 10.68;49
piperidine = 11.12;50 butylamine = 10.6;50 TMG (pKa = 13.651, 15.252). We next explored sodium
5
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 28
1
2
3
4
5
6
7
8
9
ethoxide and Cs2CO3 as alternative non-amine bases and found out to perform similarly as TMG.
Finally, benzyltrimethylammonium hydroxide (Triton B), a source of hydroxide ion that is
soluble in organic solvents turned out to be superior. Triton B, TMG and NaOEt were thus
selected for the subsequent substrate scope screening experiments. The results are shown in Table
1.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Table 1. Rearrangements of compounds 2 into 3
Entry
1
2
3
4
5
6
7
8
R1 R2 R3
Base
DMAP
Triethylamine
Piperidine
Butylamine
TMG
TMG
NaOEt
NaOEt
Cs2CO3
Triton B
TMG
TMG
Triton B
NaOEt
Triton B
TMG
Triton B
Triton B
TMG
Equiv.
0.7
1.1
1.0
1.6
1.0
0.3
2.3
0.2
0.2
0.2
2.2
2.2
0.2
2.5
0.2
2.2
0.2
0.2
2.2
0.2
2.2
2.3
2.3
2.3
2.5
2.5
0.2
t (h)
Yielda (%)
2
3
b
Me Ph c-Hex
Me Ph c-Hex
Me Ph c-Hex
Me Ph c-Hex
Me Ph c-Hex
Me Ph c-Hex
Me Ph c-Hex
Me Ph c-Hex
Me Ph c-Hex
Me Ph c-Hex
Me Ph Me
0
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2b
2c
2d
2e
2e
2f
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3b
3c
3d
3e
3e
3f
c
48
b
26
41
46
73
68
35e
46
95
77
76
97
68
94
67
34e
65e
97
90
59
44
58
71
43e
83e
9e
b
72
4d
4
1
f
9
35g
1
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
23
10
1
Me Ph Ph
Me Me c-Hex
Me Bn Bu
30
1
Me Bn Bu
Ph Ph c-Hex
Ph Ph c-Hex
Ph Ph c-Hex
Ph Ph Me
5d
1
2f
2f
2g
2g
2h
2i
3f
3f
3g
3g
3h
3i
4
16
1
Ph Ph Me
Triton B
TMG
H
H
H
H
H
H
H
Ph Me
Ph Bu
Et Bu
Bu Bu
Bu Bu
Bu Bu
Bu Bu
32
NaOEt
NaOEt
NaOEt
Triton B
Triton B
Triton B
12
h
2j
3j
48
24
72
24
2k
2k
2k
2k
3k
3k
3k
3k
6
ACS Paragon Plus Environment

Page 7 of 28
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
28
H
Bn Me
NaOEt
2.3
51
40
2l
3l
b
aYield of isolated pure product is given. 24 hours at rt and then heated at 50 °C for 30 h.
cComplex mixture of products. Reflux. Conversion based on H NMR integration. DMF used
as a solvent. g15 h at rt, then 14 h at 80 °C, then 6 h at 90 °C. h24 h at rt, then 4 h at 50 °C, then 4
h at 65 °C.
d
e
1
f
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
In the case of N1 substituted substrates 2a–2g (R1 = alkyl or phenyl) catalytic amounts of
TMG, NaOEt or Triton B could be employed for the rearrangement into 3. However, the
reactions with TMG and NaOEt were too slow and/or resulted in unacceptably low conversions
for practical applications in preparative purposes. For the rearrangement of these substrates
Triton B was found to be superior. It is also noteworthy that the reactions with Triton B were
extremely clean as no side products could be detected by TLC or NMR analyses of the crude
reaction mixtures. A simple extractive workup was only required to isolate pure products that
needed no further chromatographic purification. In contrast, for N1 unsubstituted analogues 2h–
2l (R1 = H) an excess of a base (NaOEt) had to be applied for an efficient rearrangement.
The proposed reaction mechanism that accounts for the rearrangement of 2 into 3 is
shown in Scheme 2. The base assisted intramolecular addition of the 3-amino nitrogen atom to
the C-4 carbonyl group results in the formation of aziridine oxo-anion, which then undergoes
cleavage of C-3/C-4 bond, followed by protonation. It is interesting to note that a reverse
reaction, i.e., ring contraction of some 1,4-benzodiazepine-2,5-diones into the corresponding 3-
aminoquinoline-2,4(1H,3H)-diones, was recently reported by the groups of Dewynter53 and
Carlier.54 The transformation was achieved by using LiHMDS or KHMDS at –78 °C.
7
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 8 of 28
1
2
3
4
Scheme 2. Proposed mechanism
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
The chemical compositions of all the compounds under investigation were confirmed by
standard spectroscopic and analytical methods. Structure elucidation of compounds 3 as well as
the assignments of proton and carbon resonances was performed by using 2D NMR experiments.
1H NMR spectra of C3-alkyl and C3-benzyl derivatives 3d, 3e, 3j–3l, recorded in DMSO-d6 at
296 K, exhibited split signal patterns. This suggested the presence of two conformers that are
slowly interconverting on the NMR time scale and was confirmed by variable-temperature (VT)
1H NMR experiments. VT 1H NMR spectra of compound 3l in the temperature range of 293–353
K are shown in Figure 3. The spectrum at 293 K, in the slow exchange regime, is consistent with
the presence of two isomers of the compound 3l. At increase in the temperature, the broadening
of the resonances occurs with the subsequent appearance of the average resonance above 323 K,
where fast ring inversion takes place. The VT 1H NMR spectra could be rationalized by the 1,4-
benzodiazepine-2,5-dione seven-membered ring interconversion in which the C3 substituent has
either pseudoequatorial or pseudoaxial orientation thus providing two pairs of enantiomers (P)-
(S)-3 / (M)-(R)-3 and (P)-(R)-3 / (M)-(S)-3 in two diastereomeric forms (P)-(R)-3 / (M)-(S)-3 and
(M)-(R)-3 / (P)-(S)-3, respectively (Figure 4). The existence of two conformers in DMSO-d6 at
296 K through the split signal patterns was also evident from 13C NMR spectra and 2D NMR
spectra. In contrast to the C3-benzyl and C3-alkyl derivatives 3d, 3e, 3j–3l the NMR spectra of
8
ACS Paragon Plus Environment

Page 9 of 28
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
the C3-phenyl substituted products 3a–3c, 3f–3i, indicated a single set of resonances. The
conformational behavior is consistent with that observed in related 1,4-benzodiazepine-2,5-
diones.6,11,53–57
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Figure 3. Selected parts of VT 1H NMR spectra of 3l in DMSO-d6.
Figure 4. Conformational equilibrium in 1,4-benzodiazepine-2,5-dione ring at racemic
compounds 3. Conformational assignment (M/P) followed an earlier proposal to designate the
9
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 10 of 28
1
2
3
4
5
6
sense of conformational chirality of the benzodiazepine ring and is based on the sign of the 2–1–
9a–5a dihedral angle (M = minus, P = positive).58,59
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
In conclusion, a novel approach to 1,4-benzodiazepine-2,5-dione scaffold is reported. It is
based on a molecular rearrangement of easily available 3-aminoquinoline-2,4(1H,3H)-diones in
the presence of base, such as benzyltrimethylammonium hydroxide (Triton B), 1,1,3,3-
tetramethylguanidine (TMG) or NaOEt. The transformations proceed under mild reaction
conditions in environmentally-friendly ethanol as a reaction solvent, at room temperature. In
contrast to the known methods, this approach does not require N1/N3 post alkylation of the 1,4-
benzodiazepine-2,5-dione parent ring.
Experimental Section
General Experimental Methods. The reagents and solvents were used as obtained from the
commercial sources. Compounds 1a,43,45 1d,60 1e,61 1f,61 1h,45 1j,43 1k,43,61 and 1l,43,45,61 were
prepared as described in the literature. Column chromatography was carried out on Silica gel 60
(particle size 0.063–0.2 mm, activity acc. Brockmann and Schodder 2–3). Melting points were
determined on the microscope hot stage, and are uncorrected. TLC was carried out on TLC-cards
with a fluorescent indicator, visualization was accomplished with UV light (254 nm). NMR
spectra were recorded with a 500 MHz NMR instrument operating at 500 MHz (1H), 126 MHz
(13C) and 51 MHz (15N) at 300 K. Proton spectra were referenced to TMS as internal standard, in
some cases to the residual signal of DMSO-d6 (at δ 2.50 ppm). Carbon chemical shifts were
determined relative to the 13C signal of DMSO-d6 (39.5 ppm). 15N chemical shifts were extracted
1
from H–15N gs-HMBC spectra (with 20 Hz digital resolution in the indirect dimension and the
10
ACS Paragon Plus Environment

Page 11 of 28
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
parameters adjusted for a long-range 1H–15N coupling constant of 5 Hz) determined with respect
to external nitromethane and are corrected to external ammonia by addition of 380.5 ppm.
Nitrogen chemical shifts are reported to one decimal place as measured of the spectrum,
however, the data should not be considered to be more accurate than ±0.5 ppm because of the
digital resolution limits of the experiment. Chemical shifts are given on the δ scale (ppm).
Coupling constants (J) are given in Hz. Multiplicities are indicated as follows: s (singlet), d
(doublet), t (triplet), q (quartet), m (multiplet) or br (broadened). The numbering used for the
assignment of NMR signals is as follows: quinoline-2,4(1H,3H)-dione ring (2) and 1,4-
benzodiazepine-2,5-dione (3), simple figures, R1-substituent primed figures; R2-substituent,
double primed figures; R3-substituent, triple primed figures. NMR peak assignments are based on
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
1
1
1
the analyses of H−1H gs-COSY, H−13C gs-HSQC, H−13C gs-HMBC and H−15N gs-HMBC
2D NMR spectra. Infrared spectra were recorded on a FT-IR spectrometer using samples in
potassium bromide disks and only the strongest/structurally most important peaks are listed.
Electron impact mass spectra (EI) were recorded at 70 eV. High-resolution mass spectra (HRMS)
were obtained with a time-of-flight (TOF) mass spectrometer equipped with an electrospray
source at atmospheric pressure ionization (ESI). Elemental analyses (C, H, N) were performed
with a CHNS/O Analyzer.
Synthesis of 3-aminoquinoline-2,4(1H,3H)-diones 2. 3-Aminoquinoline-2,4(1H,3H)-diones 2
were prepared from 3-chloroquinolin-2,4(1H,3H)-diones 1 according to the procedures described
in the literature.45 Spectroscopic and analytical data for compounds 2a,45 2b,45 2c,45 2e,42 2h,45
2g,45 2i,45 2k,45 and 2l45 were in agreement with the literature data. Spectroscopic and analytical
data of new compounds 2d, 2f, 2g, and 2j are reported below.
11
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 12 of 28
1
2
3
4
5
6
7
8
9
3-(Cyclohexylamino)-1,3-dimethylquinoline-2,4(1H,3H)-dione (2d). Compound 2d (1.67
g, 58.3 mmol, 58%) was prepared from 1d (2.24 g, 10.0 mmol). Beige solid, mp 78–81 °C
(ethanol). 1H NMR (500 MHz, DMSO-d6) δ 0.88–1.09 (m, 5H), 1.32 (s, 3H), 1.40–1.60 (m, 5H),
2.34 (br s, 1H), 2.38–2.45 (m, 1H), 3.21 (s, 3H), 7.24 (dd, 1H, J = 7.4 Hz, 7.4 Hz), 7.40 (d, 1H, J
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
13
= 8.4 Hz), 7.75 (ddd, 1H, J = 8.7, 7.0, 1,6 Hz), 7.91 (dd, 1H, J = 7.7, 1.6 Hz); C NMR (126
MHz, DMSO-d6) δ 24.7, 25.4, 26.6, 29.8, 34.0, 34.5, 52.8, 67.6, 115.8, 119.4, 122.9, 127.4,
136.4, 142.7, 173.1, 195.4; two C resonances are overlapped; IR (cm–1): ν 3326, 2924, 2854,
13
1693, 1658, 1597, 1491, 1468, 1363, 1345, 1298, 1101, 762, 579, 418; MS (EI) m/z (%): 286 (2,
[M]+), 243 (34), 214 (22), 191 (36), 189 (19), 160 (16), 98 (89), 83 (42), 71 (16); HRMS (ESI+):
m/z calcd for C17H23N2O2 [M + H]+ 287.1754, found 287.1751. Anal. calcd for C17H22N2O2
+
(286.37): C, 71.30, H, 7.74, N, 9.78%. Found: C, 71.60, H, 7.99, N, 9.80.
3-(Cyclohexylamino)-1,3-diphenylquinoline-2,4(1H,3H)-dione (2f). Compound 2f (3.91 g,
9.5 mmol, 96%) was prepared from 1f (3.44 g, 9.9 mmol). Beige solid, mp 86–92 °C (benzene);
1H NMR (500 MHz, DMSO-d6) δ 0.98–1.15 (m, 5H), 1.45 (br s, 1H), 1.53–1.64 (m, 3H), 1.77 (d,
1H, J = 10.1 Hz), 2.60–2.67 (m, 1H, H1'''), 6.37 (d, 1H, J = 8.3 Hz, H8), 7.16 (dd, 1H, J = 7.3,
7.2 Hz, H6), 7.29–7.35 (m, 2H, H4', H3'), 7.35–7.40 (m, 2H, H3'', H5''), 7.45–7.53 (m, 4H, H7,
H2'', H6'', H3'), 7.58 (dd, 1H, J = 7.4, 7.4 Hz, H4'), 7.61–7.71 (m, 2H, H2', H6'), 7.86 (dd, 1H, J =
7.8, 1.5 Hz, H5); NH proton not found, probably in fast exchange with HOD; 13C NMR (126
MHz, DMSO-d6) δ 24.97, 25.00, 25.4, 34.5, 34.8, 53.0 (C1'''), 75.7 (C3), 116.7 (C8), 119.9
(C4a), 123.5 (C6), 126.7 (C2'', C6''), 127.8 (C5), 128.6 (C4''), 128.7 (C3' or C5'), 128.9 (C3'',
C5''), 129.0 (C4'), 129.2 (C5' or C3'), 130.3 (C2' or C6'), 130.6 (C6' or C2'), 136.1 (C7), 137.3
15
(C1'), 138.4 (C1''), 143.0 (C8a), 172.2 (C2), 192.7 (C4); N NMR (51 MHz, DMSO-d6) δ 151.4
(N1); IR (cm–1): ν 2924, 2850, 1705, 1672, 1599, 1491, 1461, 1332, 1301, 1240, 757, 717, 695;
12
ACS Paragon Plus Environment

Page 13 of 28
The Journal of Organic Chemistry
1
2
3
4
MS (EI) m/z (%): 411 (4, [M + 1]+), 410 (12, [M]+), 367 (14), 316 (11), 313 (26), 312 (25), 196
5
6
+
(14), 186 (16), 104 (100), 98 (82), 77 (12); HRMS (ESI+): m/z calcd for C27H27N2O2 [M + H]+
7
8
9
411.2067, found 411.2062 Anal. Calcd for C27H26N2O2 (410.51): C 79.00, H 6.38, N 6.82; found:
C 78.92, H 6.44, N 6.99.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
3-(Methylamino)-1,3-diphenylquinoline-2,4(1H,3H)-dione (2g). Compound 2g (1.58 g,
4.6 mmol, 90%) was prepared from 1f (1.79 g, 5.1 mmol). White solid, mp 142–149 °C (ethanol).
1H NMR (500 MHz, DMSO-d6) δ 2.26 (s, 3H, H'''), 2.98 (br s, 1H, NH), 6.34 (d, 1H, J = 8.3 Hz,
H8), 7.14 (dd, 1H, J = 7.5, 7.4 Hz, H6), 7.32 (dd, 1H, J = 7.2, 7.2 Hz, H4''), 7.39 (dd, 2H, J = 7.6,
7.6 Hz, H3'', H5''), 7.40–7.50 (m, 5H, H7, H3', H5', H2'', H6''), 7.57 (dd, 1H, J = 7.4, 7.4 Hz,
H4'), 7.60–7.70 (m, 2H, H2', H6'), 7.82 (dd, 1H, J = 7.8, 1.2 Hz, H5); 13C NMR (126 MHz,
DMSO-d6) δ 31.7 (C'''), 78.0 (C3), 116.6 (C8), 120.6 (C4a), 123.3 (C6), 126,8 (C2'', C6''), 127.5
(C5), 128.7 (C4''), 128.9 (C3'', C5''), 129.0 (C4'), 129.1 (C3', C5'), 130.4 (C2'', C6''), 135.9 (C7),
15
137.3 (C1''), 137.4 (C1'), 143.0 (C8a), 171.2 (C2), 192.7 (C4); N NMR (51 MHz, DMSO-d6) δ
34.2 (NH), 152.1 (N1); IR (cm–1): ν 3342, 3062, 2953, 2853, 2793, 1701, 1670, 1598, 1491,
1461, 1336, 1301, 1247, 763, 735, 690, 598, 537, 518; MS (EI) m/z (%):343 (6, [M + 1]+), 342
(23, [M]+), 313 (14), 312 (11), 119 (11), 118 (100), 104 (12), 77 (19); HRMS (ESI+): m/z calcd
+
for C22H19N2O2 [M + H]+ 343.1441, found 343.1440. Anal. calcd. for C22H18N2O2 (342.39): C,
77.17, H, 5.30, N, 8.18; found: C, 76.89, H, 5.25, N, 8.07.
3-(Butylamino)-3-ethylquinoline-2,4(1H,3H)-dione (2j) Compound 2j (597 mg, 2.3 mmol,
46%) was prepared from 1j (1.12 g, 5.0 mmol). Yellowish solid, mp 86–89 °C (cyclohexane). 1H
NMR (500 MHz, DMSO-d6) δ 0.71 (t, 3H, J = 7.4 Hz), 0.81 (t, 3H, J = 7.2 Hz), 1.20–1.29 (m,
2H), 1.29–1.36 (m, 2H), 1.68–1.82 (m, 2H), 2.17–2.33 (m, 3H), 7.09 (d, 1H, J = 8.0 Hz), 7.11
(dd, 1H, J = 7.6 Hz), 7.60 (dd, 1H, J = 7.6 Hz), 7.75 (d, 1H, J = 7.7 Hz), 10.94 (s, 1H). 13C NMR
13
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 14 of 28
1
2
3
4
5
6
(126 MHz, DMSO-d6) δ 7.8, 13.8, 19.8, 32.2, 32.8, 44.1, 73.5, 116.3, 119.3, 122.6, 126.6, 136.3,
141.7, 172.8, 196.5. IR (cm–1): ν 3305, 2963, 2925, 2872, 1706, 1695, 1670, 1650, 1609, 1593,
7
8
9
+
1485, 1435, 1369, 757, 666. HRMS (ESI+): m/z calcd for C15H21N2O2 [M + H]+ 261.1598,
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
found 261.1596. Anal. Calcd for C15H20N2O2 (260.33): C 69.20, H 7.74, N 10.76; found: C
68.98, H 7.88, N 10.53.
Rearrangement of 3-aminoquinoline-2,4(1H,3H)-diones 2 into 1,4-benzodiazepine-2,5-
diones 3.
General procedure for rearrangement of 2 into 3: A mixture of 3-aminoquinoline-2,4-
(1H,3H)-dione (2, 0.9 mmol) and a base in ethanol (9 mL) was stirred at room temperature for
given time (see Table 1). Details of isolation are described below.
With benzyltrimethylammonium hydroxide (Triton B) as a base: A mixture of 3-
aminoquinoline-2,4-(1H,3H)-dione (2, 0.9 mmol) and Triton B (34 mg, 0.2 mmol; as 84 mg of 40
wt. % solution in methanol) in ethanol (9 mL) was stirred for 1 hour at room temperature. The
reaction mixture was at room temperature concentrated under reduced pressure. The crude
product was dissolved in ethyl acetate (30 mL), washed with water (2 × 15 mL), brine (15 mL),
dried over sodium sulfate and evaporated to dryness to afford pure products 3 in excellent
isolated yield (Table 1, entries 10, 13, 15, 20) or ratio of conversion (Table 1, entries 17, 18, 25–
27) which was determined by 1H NMR integration.
With TMG as base: A mixture of 3-aminoquinoline-2,4-(1H,3H)-dione (2, 0.9 mmol) and
TMG (230 mg, 2.0 mmol) in ethanol (9 mL) was stirred at room temperature until completion as
judged by TLC analysis (Table 1). The precipitated crude product was collected by filtration,
14
ACS Paragon Plus Environment

Page 15 of 28
The Journal of Organic Chemistry
1
2
3
4
5
6
washed with water (2 × 2 mL) and recrystallized from ethanol to afford pure 1,4-benzodiazepine-
2,5-dione 3.
7
8
9
With NaOEt as base: A mixture of 3-aminoquinoline-2,4-(1H,3H)-dione (2, 0.9 mmol)
and 0.5 M solution of NaOEt (4.5 mL, 2.25 mmol) was stirred at room temperature under
exclusion of atmospheric moisture (the flask equipped with drying tube filled with potassium
hydroxide) until completion as judged by TLC analysis (Table 1). The isolation of 1,4-
benzodiazepine-2,5-diones 3 from the reaction mixture was done as follows.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
From 2a or 2e: The reaction mixture was filtered. The filter cake was washed with water (2 mL)
and dried at 50 °C to afford pure 3a (212 mg, 68%) or 3e (206 mg, 68%).
From 2i and 2l: The reaction mixture was acidified with 1M HCl to Congo red and concentrated
in vacuo. The oily residue was triturated with water (1 mL) and the resulting precipitate was
collected by filtration. The filter cake was washed with water and dried at 50 °C to afford pure 3i
(121 mg, 44%) or 3l (100 mg, 40%).
From 2j or 2k: The reaction mixture was acidified with 1M HCl to Congo red and extracted with
dichloromethane (3 × 9 mL). The combined organic layers were dried over Na2SO4 and
evaporated to dryness. The residue was subjected to column chromatography on silica gel using:
(i) benzene as an eluent to isolate product 3j, which was additionally crystallized from a mixture
of hexane and benzene to obtain pure 3j (136 mg, 58%); (ii) chloroform as an eluent to provide
pure 3k (185 mg, 71%).
4-Cyclohexyl-1-methyl-3-phenyl-3,4-dihydro-1H-benzo[e][1,4]diazepine-2,5-dione (3a).
Triton B: 298 mg, 95% yield; TMG: 232 mg, 74% yield; NaOEt: 212 mg, 68% yield. White
1
solid, mp 192–193 °C (benzene/cyclohexane). H NMR (500 MHz, DMSO-d6) δ 1.11–1.22 (m,
15
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 16 of 28
1
2
3
4
5
6
7
8
9
1H, cyclohexyl), 1.32–1.89 (m, 9H, cyclohexyl), 3.37 (s, 3H, H1'), 4.73–4.81 (m, 1H, H1''' of
cyclohexyl), 5.59 (s, 1H, H3), 6.87 (d, 2H, J = 7.7 Hz, H2'', H6''), 6.95 (dd, 1H, J = 7.5, 7.5 Hz,
H7), 6.99 (t, 1H, J = 6.8 Hz, H4''), 7.03 (d, 1H, J = 8.5 Hz, H9), 7.06 (dd, 2H, J = 7.5, 7.5 Hz,
H3'', H5''), 7.21 (ddd, 1H, J = 8.5, 7.0, 1.6 Hz, H8), 7.38 (dd, 1H, J = 7.8, 1.5 Hz, H6); 13C NMR
(126 MHz, DMSO-d6) δ 24.6, 25.3, 25.4, 29.1, 30.4, 35.1 (C1'), 54.3 (C1'''), 61.1 (C3), 120.7
(C9), 124.0 (C2'', C6''), 124.6 (C7), 126.9 (C4''), 128.1 (C3'', C5''), 129.8 (C6), 129.9 (C5a), 131.4
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
15
(C8), 135.0 (C1''), 138.9 (C9a), 165.8 (C5), 170.3 (C2); N NMR (51 MHz, DMSO-d6) δ 124.3
(N1), 143.3 (N4); IR (cm–1): ν 2936, 2856, 1664, 1629, 1601, 1493, 1475, 1457, 1432, 1366,
1246, 1145, 715; MS (EI) m/z (%):349 ([M + 1]+, 12), 348 ([M]+, 49), 291 (48), 266 (43), 251
+
(68), 161 (65), 132 (44), 105 (60), 104 (100), 55 (42); HRMS (ESI+): m/z calcd for C22H25N2O2
[M + H]+ 349.1911, found 349.1907. Anal. Calcd for C22H24N2O2 (348.74): C, 75.83; H, 6.94; N,
8.04%. Found: C, 75.62; H, 6.96; N, 8.07%.
3,4-Dihydro-1,4-dimethyl-3-phenyl-1H-benzo[e][1,4]diazepine-2,5-dione (3b). TMG: 194
mg, 77% yield. White solid, mp 183–186 °C. 1H NMR (500 MHz, DMSO-d6) δ 3.38 (s, 3H, H1'),
3.41 (s, 3H, H1'''), 5.64 (s, 1H, H3), 6.83 (d, 2H, J = 7.8 Hz, H2'', H6''), 6.96 (dd, 1H, J = 7.5, 7.5
Hz, H7), 7.01 (t, 1H, J = 7.3 Hz, H4''), 7.08 (dd, 2H, J = 7.7, 7.7 Hz, H3'', H5''), 7.10 (d, 1H, J =
8.0 H, H9), 7.26 (ddd, 1H, J = 7.7, 7.7, 1.2 Hz, H8), 7.38 (dd, 1H, J = 7.8, 1.0 Hz, H6); 13C NMR
(126 MHz, DMSO-d6) δ 35.3 (C1'), 38.2 (C1'''), 68.0 (C3), 121.0 (C9), 123.9 (C2'', C6''), 124.8
(C7), 127.1 (C4''), 128.3 (C3'', C5''), 129.1 (C5a), 129.6 (C6), 131.6 (C8), 134.6 (C1''), 139.2
(C9a), 166.3 (C5), 169.3 (C2); 15N NMR (51 MHz, DMSO-d6) δ 119.2 (N4), 124.0 (N1); IR (cm–
1): ν 2933, 2852, 1702, 1670, 1602, 1473, 1443, 1356, 1307, 1124, 1098, 765, 704, 647; MS (EI)
m/z (%):281 (8, [M + 1]+, 280 (42, [M]+), 175 (46), 161 (36), 133 (38), 120 (100), 118 (91), 105
+
(46), 104 (45), 78 (23), 77 (27); HRMS (ESI+): m/z calcd for C17H17N2O2 [M + H]+ 281.1285,
16
ACS Paragon Plus Environment

Page 17 of 28
The Journal of Organic Chemistry
1
2
3
4
5
6
found 281.1283. Anal. Cald. for C17H16N2O2 (280.33): C 72.84, H 5.75, N 9.99, found C 72.76,
H 5.77, N 10.04.
7
8
9
3,4-Diphenyl-1-methyl-3,4-dihydro-1H-benzo[e][1,4]diazepine-2,5-dione (3c). TMG: 234
mg, 76% yield. White solid, mp 202–204 °C. 1H NMR (500 MHz, DMSO-d6) δ 3.48 (s, 3H, H1'),
5.78 (s, 1H, H3), 7.03 (dd, 1H, J = 7.6, 7.6 Hz, H7), 7.06 (d, 2H, J = 7.8 Hz, H2'', H3''), 7.07 (t,
1H, J = 7.8 Hz, H4''), 7.14 (dd, 2H, J = 7.5, 7.5 Hz, H3'', H5''), 7.16 (d, 1H, J = 8.3 Hz, H9), 7.32
(ddd, 1H, J = 8.5, 7.0, 1.4 Hz, H8), 7.36–7.41 (m, 1H, H4'''), 7.46 (dd, 1H, J = 7.8, 1.2 Hz, H6),
7.49–7.54 (m, 4H, H2''', H3''', H5''', H6'''); 13C NMR (126 MHz, DMSO-d6) δ 35.4 (C1'), 69.9
(C3), 121.3 (C9), 124.0 (C2'', C6''), 125.0 (C7), 126.1 (C2''', C6'''), 127.3 (C4'''), 127.4 (C4''),
128.5 (C3'', C5''), 129.4 (C5a, C3''', C5''), 129.9 (C6), 132.1 (C8), 134.2 (C1''), 139.2 (C9a), 143.8
(C1'''), 165.7 (C5), 169.1 (C2); 15N NMR (51 MHz, DMSO-d6) δ 124.1 (N1), 139.2 (N4); IR (cm–
1): ν 3064, 1667, 1654, 1600, 1494, 1473, 1458, 1417, 1369, 1243, 764, 712, 698, 614, 545, 524;
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
+
HRMS (ESI+): m/z calcd for C22H19N2O2 [M + H]+ 343.1441, found 343.1441. Anal. Calcd for
C22H18N2O2 (342.40) C, 77.17; H, 5.30; N, 8.18%. Found: C, 77.47; H, 5.35; N 8.22.
4-Cyclohexyl-1,3-dimethyl-3,4-dihydro-1H-benzo[e][1,4]diazepine-2,5-dione (3d). Triton
B: 250 mg, 97% yield; White solid, mp 120–124 °C (hexane). Major isomer : minor isomer = 88
: 12. Major isomer: 1H NMR (500 MHz, DMSO-d6) δ 0.89 (d, 3H, 7.5 Hz, 3-H''), 1.00–1.83 (m,
10H, H2''', H3''', H4''', H5''', H6'''), 3.30 (s, 3H, H1'), 4.41 (q, 1H, J = 7.5 Hz, H3), 4.53–4.60 (m,
1H, H1'''), 7.31 (dd, 1H, J = 7.4 Hz, H7), 7.38 (d, 1H, J = 8.2 Hz, H9), 7.60 (ddd, 1H, J = 7.8,
7.7, 1.3 Hz, H8), 7.68 (dd, 1H, J = 7.8, 1.3 Hz, H6); 13C NMR (126 MHz, DMSO-d6) δ 16.0
(C1''), 24.7, 25.2, 25.3, 29.3, 29.8, 35.2 (C1'), 53.6 (C3), 54.2 (C1'''), 121.1 (C9), 125.1 (C7),
15
129.4 (C5a), 130.2 (C6), 132.0 (C8), 139.2 (C9a), 164.7 (C5), 170.9 (C2); N NMR (51 MHz,
DMSO-d6) δ 123.0 (N1), 146.9 (N4); Minor isomer: 1H NMR (500 MHz, DMSO-d6) δ 1.00–1.83
17
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 18 of 28
1
2
3
4
5
6
7
8
9
(m, 10H, H2''', H3''', H4''', H5''', H6'''), 1.36 (d, 3H, J = 6.8 Hz, H''), 3.26–3.31 (m, 1H, H1'''), 3.31
(s, 3H, H1'), 4.23 (q, 1H, J = 6.8 Hz, H3), 7.29 (dd, 1H, J = 7.4 Hz, H7), 7.38 (d, 1H, J = 8.2 Hz,
H9), 7.57 (ddd, 1H, J = 7.8, 7.7, 1.3 Hz, H8), 7.68 (dd, 1H, J = 7.8, 1.3 Hz, H6); 13C NMR (126
MHz, DMSO-d6) δ 12.5 (C1''), 25.0, 25.8, 28.5, 30.7, 34.1 (C1'), 51.0 (C3), 55.0 (C1'''), 121.0
(C9), 124.9 (C7), 129.7 (C5a), 130.1 (C6), 131.7 (C8), 140.4 (C9a), 167.4 (C5), 170.5 (C2), one
resonance belonging to cyclohexane ring not visible; 15N NMR (51 MHz, DMSO-d6) δ 142.0
(N4); IR (cm–1): ν 2931, 2918, 2850, 1678, 1636, 1601, 1454, 1423, 1377, 1368, 1318, 1248,
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
+
1138, 794, 766, 713; HRMS (ESI+): m/z calcd for C17H23N2O2 [M + H]+ 287.1754, found
287.1753. Anal. calcd for C17H22N2O2 (286.37): C, 71.30, H, 7.74, N, 9.78%. Found: C, 71.10, H,
8.00, N, 9.69%.
3-Benzyl-4-butyl-3,4-dihydro-1-methyl-1H-benzo[e][1,4]diazepine-2,5-dione (3e). Triton
B: 286 mg, 94% yield; NaOEt: 206 mg, 68% yield. Pale yellow solid, mp 135–136 °C. Major
isomer : minor isomer = 53 : 47. Major isomer: 1H NMR (500 MHz, DMSO-d6) δ 0.87 (t, 3H, J =
7.3 Hz, H4'''), 1.11–1.26 (m, 2H, H3'''), 1.39–1.49 (m, 1H, H2'''), 1.49–1.59 (m, 1H, H2'''), 3.13
(ddd, 1H, J = 13.9, 8.8, 4.5 Hz, H1'''), 3.22 (dd, 1H, J = 14.5, 7.3 Hz, PhCH2), 3.32–3.38 (m,
1H, PhCH2), 3.31 (s, 3H, H1'), 3.89 (ddd, 1H, J = 14.0, 8.2, 8.1 Hz, H1'''), 4.46 (t, 1H, J = 7.5 Hz,
H3), 7.15–7.20 (m, 1H, H4''), 7.20–7.29 (m, 4H, H2'', H3'', H5'', H6''), 7.34 (dd, 1H, J = 7.5, 7.5
Hz, H7), 7.40 (d, 1H, J = 8.3 Hz, H9), 7.59 (ddd, 1H, J = 7.7, 7.7, 1.4 Hz, H8), 7.71 (dd, 1H, J =
13
7.7, 1.5 Hz, H6); C NMR (126 MHz, DMSO-d6) δ 13.6 (C4'''), 19.4 (C3'''), 29.9 (C2'''), 31.8
(PhCH2), 34.4 (C1'), 41.3 (C1'''), 55.8 (C3), 121.4 (C9), 125.3 (C7), 126.5 (C4''), 128.4 (C3'',
C5''), 128.9 (C2'', C6''), 129.1 (C5a), 129.7 (C6), 132.0 (C8), 137.2 (C1''), 140.4 (C9a), 167.2
15
1
(C5), 169.7 (C2); N NMR (51 MHz, DMSO-d6) δ 125.6 (N1), 132.0 (N4); Minor isomer: H
NMR (500 MHz, DMSO-d6) δ 0.82 (t, 3H, J = 7.3 Hz, H4'''), 1.11–1.26 (m, 2H, H3'''), 1.28–1.39
18
ACS Paragon Plus Environment

Page 19 of 28
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
(m, 2H, H2'''), 2.44 (dd, 1H, J =13.4, 9.3 Hz, PhCH2), 2.49–2.55 (m, 1H, PhCH2), 2.99 (ddd, 1H,
J = 13.4, 8.1, 5.6 Hz, H1'''), 3.31 (s, 3H, H1'), 3.68 (ddd, 1H, J = 13.3, 7.8, 7.5 Hz, H1'''), 4.41 (t,
1H, J = 8.9 Hz, H3), 6.96 (d, 2H, J = 7.1 Hz, H2''), 7.20–7.29 (m, 3H, H3'', H4'', H5''), 7.41 (dd,
1H, J = 7.5, 7.5 Hz, H7), 7.50 (d, 1H, J = 8.2 Hz, H9), 7.70 (ddd, 1H, J = 7.4, 7.4, 1.4 Hz, H8),
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
13
7.79 (dd, 1H, J = 7.7, 1.3 Hz, H6); C NMR (126 MHz, DMSO-d6) δ 13.6 (C4'''), 19.2 (C3'''),
29.1 (C2'''), 34.3 (PhCH2), 35.4 (C1'), 49.5 (C1'''), 66.0 (C3), 121.5 (C9), 125.4 (C7), 126.9 (C4''),
128.5 (C3'', C5''), 128.9 (C2'', C6''), 129.3 (C5a), 130.1 (C6), 132.4 (C8), 136.0 (C1''), 139.4
(C9a), 165.0 (C5), 169.2 (C2); 15N NMR (51 MHz, DMSO-d6) δ 124.4 (N1), 131.8 (N4); IR (cm–
1): ν 2951, 2866, 1676, 1640, 1629, 1602, 1459, 1408, 1384, 760, 707; HRMS (ESI+): m/z calcd
for C21H25N2O2 [M + H]+ 337.1911, found 337.1909. Anal. Calcd for C21H24N2O2 (336.43): C,
+
74.97; H, 7.19; N, 8.33%. Found: C, 74.67; H, 7.43; N, 8.26%.
4-Cyclohexyl-1,3-diphenyl-3,4-dihydro-1H-benzo[e][1,4]diazepine-2,5-dione (3f). TMG:
1
247 mg, 67% yield. Yellow solid, mp 224–227 °C (ethanol). H NMR (DMSO-d6, 500 MHz):
1.10–1.21 (m, 1H, cyclohexyl), 1.31–1.48 (m, 2H, cyclohexyl), 1.50–1.84 (m, 6H, cyclohexyl),
1.84–1.92 (m, 1H, cyclohexyl), 4.81–4.89 (m, 1H, H1'''), 5.72 (s, 1H, H3), 6.32 (d, 1H, J = 8.1
Hz, H9), 6.94 (dd, 1H, J = 7.5, 7.5 Hz, H7), 7.01–7.06 (m, 2H, H8, H4''), 7.08–7.15 (m, 4H, H2'',
H3'', H5'', H6''), 7.31 (d, 2H, J = 7.4 Hz, H2', H6'), 7.40 (t, 1H, J = 7.4 Hz, H4'), 7.47 (dd, 1H, J =
7.9, 1.5 Hz, H6), 7.50 (dd, 2H, J = 7.9, 7.6 Hz, H3', H5'); 13C NMR (DMSO-d6, 126 MHz) 24.6,
25.3, 25.4, 29.0, 30.4, 54.6 (C1'''), 61.3 (C3), 123.2 (C9), 124.1 (C2'', C6''), 125.0 (C7), 127.1
(C4''), 127.8 (C4'), 128.3 (C3'', 5''), 128.5 (C2', C6'), 129.5 (C3', C5'), 130.1 (C6), 130.6 (C5a),
15
131.3 (C8), 134.8 (C1''), 138.5 (C9a), 140.7 (C1'), 165.6 (C5), 169.2 (C2); N NMR (51 MHz,
DMSO-d6) δ 142.0 (N4), 145.3 (N1); IR (cm–1): ν 2918, 2848, 1668, 1640, 1602, 1493, 1456,
1426, 1353, 1238, 1149, 765, 708, 693, 568; MS (EI) m/z (%): (411 5, [M + 1]+), (410 (16, [M]+),
19
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 20 of 28
1
2
3
4
328 (32), 327 (19), 313 (34), 305 (19), 291 (65), 223 (34), 196 (23), 195 (100), 167 (37), 132
5
6
+
(25), 77 (19); HRMS (ESI+): m/z calcd for C27H27N2O2 ([M + H]+) 411.2067, found 411.2065.
7
8
9
Anal. Calcd for C27H26N2O2 (410.52): C 79.00, H 6.38, N 6.82, found: C 79.11, H 6.29, N 6.76.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1,3-Diphenyl-4-methyl-3,4-dihydro-1H-benzo[e][1,4]diazepine-2,5-dione (3g). Triton B:
276 mg, 90% yield; TMG: 298 mg, 97% yield. Yellow solid, mp 84–89 °C. 1H NMR (500 MHz,
DMSO-d6) δ 3.47 (s, 3H, H1'''), 5.77 (s, 1H, H3), 6.36 (d, 1H, J = 8.2 Hz, H9), 6.96 (dd, 1H, J =
7.5, 7.5 Hz, H7), 7.03–7.10 (m, 4H, H8, H2'', H4'', H6''), 7.15 (dd, 2H, J = 7.6, 7.6 Hz, H3'', H5''),
7.33 (d, 2H, J = 7.5 Hz, H2', H6'), 7.40 (t, 1H, J = 7.5 Hz, H4'), 7.47 (dd, 1H, J = 7.9, 1.4 Hz,
13
H6), 7.50 (dd, 2H, J = 7.5 Hz, H3', H5'); C NMR (126 MHz, DMSO-d6) δ 38.2 (C1'''), 68.1
(C3), 123.4 (C9), 123.9 (C2'', C6''), 125.1 (C7), 127.3 (C4''), 127.8 (C4'), 128.5 (C3'', C5''), 128.6
(C2', C6'), 129.5 (C3', C5'), 129.8 (H6), 129.9 (C5a), 131.5 (C8), 134.4 (C1''), 138.8 (C9a), 140.8
(C1'), 166.2 (C5), 168.0 (C2); 15N NMR (51 MHz, DMSO-d6) δ 118.4 (N4), 145.8 (N1); IR (cm–
1): ν 3061, 2929, 1678, 1643, 1601, 1492, 1450, 1396, 1352, 1243, 1162, 758, 711, 695 595, 529;
MS (EI) m/z (%): (8, [M + 1]+), 342 (34, [M]+), 237 (40), 223 (40), 196 (24), 195 (100), 167 (32),
+
118 (16), 77 (22); HRMS (ESI+): m/z calcd for C22H19N2O2 ([M + H]+) 343.1441, found
343.1439.
3,4-Dihydro-4-methyl-3-phenyl-1H-benzo[e][1,4]diazepine-2,5-dione (3h). TMG: 142
1
mg, 59% yield. White solid, mp 249–252 °C; mp62 242–244 °C (DMF/water). H NMR (500
MHz, DMSO-d6) δ 3.46 (s, 3H, H1'''), 5.55 (s, 1H, H3), 6.93 (d, 1H, J = 8.1 Hz, H9), 6.98 (dd,
1H, J = 7.5, 7.5 Hz, H7), 7.00–7.08 (m, 2H, H2'', H6''), 7.14 (t, 1H, J = 7.2 Hz, H4''), 7.22 (dd,
2H, J = 7.6, 7.6 Hz, H3'', H5''), 7.28 (dd, 1H, J = 7.4, 7.4 Hz, H8), 7.54 (d, 1H, J = 7.7 Hz, H6),
10.80 (br s, 1H, H1); 13C NMR (126 MHz, DMSO-d6) δ 38.6 (br, C1'''), 67.5 (br, C3), 119.9 (C9),
123.6 (C7), 124.3 (br, C2'', C6''), 126.7 (C5a), 127.4 (C4''), 128.4 (C3'', C5''), 130.3 (C6), 131.7
20
ACS Paragon Plus Environment

Page 21 of 28
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
(C8), 134.3 (br, C1''), 135.2 (C9a), 166.4 (C5), 170.3 (C2); 15N NMR (51 MHz, DMSO-d6) δ
116.4 (N4), 135.7 (N1); IR (cm–1): ν 3143, 2920, 1687, 1618, 1488, 1448, 1396, 1373, 1246,
1168, 795, 760, 728, 693, 495; MS (EI) m/z (%):267 (15, [M + 1]+), 266 (81, [M]+), 161 (100),
146 (13), 120 (60), 119 (43), 118 (44), 92 (32), 91 (14), 77 (12), 42 (21); HRMS (ESI+): m/z
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
+
calcd for C16H15N2O2 [M + H]+ 267.1128, found 267.1129. Anal Calcd for C16H14N2O2
(266.29): C 72.17, H 5.30, N 10.52%, found C 72.02, H 5.26, N 10.59.
4-Butyl-3-phenyl-3,4-dihydro-1H-benzo[e][1,4]diazepine-2,5-dione (3i). NaOEt: 121 mg,
44% yield. Brownish solid, mp 166–170 °C (ethyl acetate); mp46 159–163 °C (benzene/hexane)
1H NMR (500 MHz, DMSO-d6) δ 0.92 (t, 3H, J = 7.3 Hz, H4'''), 1.34 (tq, 2H, J = 7.3, 7.3 Hz,
H3'''), 1.58–1.71 (m, 2H, H2'''), 3.53 (ddd, 1H, J = 13.7, 7.7, 5.4 Hz, H1'''a), 4.07–4.17 (m, 1H,
H1'''b), 5.47 (s, 1H, H3), 6.83 (d, 1H, J = 8.0 Hz, H9), 6.90 (dd, 1H, J = 7.5, 7.5 Hz, H7), 6.96 (br
d, 2H, J = 6.9 Hz, H2'', H6''), 7.05 (t, 1H, J = 7.1, H4''), 7.14 (dd, 2H, J = 7.5, 7.5 Hz, H3'', H5''),
13
7.19 (dd, 1H, J = 7.5, 7.5 Hz, H8), 7.46 (d, 1H, J = 7.7 Hz, H6), 10.70 (s, 1H, H1); C NMR
(126 MHz, DMSO-d6 δ 13.7 (C4'''), 19.4 (C3'''), 29.9 (C2'''), 49.7 (C1'''), 66.1 (C3), 119.9 (C9),
123.6 (C7), 124.2 (br, C2'', C6''), 127.3 (C4'', C5a), 128.4 (C3'', C5''), 130.3 (C6), 131.6 (C8),
15
134.5 (C1''), 135.1 (C9a), 166.1 (C5), 170.8 (C2); N NMR (51 MHz, DMSO-d6) δ 128.5 (N4),
135.5 (N1); IR (cm–1): ν 3206, 3085, 2955, 2926, 2859, 1675, 1630, 1606, 1484, 1461, 1450,
1434, 1400, 765, 735; HRMS (ESI+): m/z calcd for C19H21N2O2 [M + H]+ 309.1598, found
+
309.1594. Anal. Calcd for C19H20N2O2 (308.38): C, 74.00; H, 6.54; N, 9.08%. Found: C, 73.70;
H, 6.67; N, 9.01%.
4-Butyl-3-ethyl-3,4-dihydro-1H-benzo[e][1,4]diazepine-2,5-dione (3j). NaOEt: 136 mg,
58% yield. Colorless solid, mp 98–104 °C (benzene/hexane). Major isomer : minor isomer = 59 :
41. Major isomer: 1H NMR (500 MHz, DMSO-d6) δ 0.76 (t, 3H, J = 7.4 Hz, H2''), 0.89 (t, 3H, J
21
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 22 of 28
1
2
3
4
5
6
7
8
9
= 7.3 Hz, H4'''), 1.23–1.31 (m, 2H, H3'''), 1.31–1.42 (m, 2H, H1''), 1.49–1.56 (m, 2H, H2'''), 3.19–
3.27 (m, 1H, H1'''a), 3.90–4.01 (m, 2H, H3, H1'''b), 7.08 (d, 1H, J = 8.1 Hz, H9), 7.17 (dd, 1H, J
= 7.5, 7.5 Hz, H7), 7.47 (dd, 1H, J = 7.7, 7.7 H, H8), 7.73 (d, 1H, J = 7.8 Hz, H6), 10.50 (br s,
1H, H1); 13C NMR (126 MHz, DMSO-d6) δ 10.3 (C2''), 13.7 (C4'''), 19.3 (C3'''), 21.9 (C1''), 29.7
(C2'''), 49.8 (C1'''), 65.4 (C3), 119.9 (C9), 123.7 (C7), 126.6 (C5a), 130.7 (C6), 132.2 (C8), 135.5
(C9a), 164.9 (C5), 171.2 (C2); Minor isomer: 1H NMR (500 MHz, DMSO-d6) δ 0.84 (t, 3H, J =
7.1 Hz, H2''), 0.89 (t, 3H, J = 7.3 Hz, H4'''), 1.16–1.23 (m, 2H, H3'''), 1.41–1.49 (m, 2H, H2'''),
1.74–1.84 (m, 1H, H1''a), 1.92–2.03 (m, 1H, H1''b), 3.00–3.09 (m, 1H, H1'''a), 3.83 (t, 1H, J = 7.2
Hz, H3), 3.90–4.01 (m, 1H, H1'''b), 7.08 (d, 1H, J = 8.1 Hz, H9), 7.21 (dd, 1H, J = 7.6, 7.6 Hz,
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
13
H7), 7.49 (dd, 1H, J = 7.8, 7.8 Hz, H8), 7.73 (d, 1H, J = 7.8 Hz, H6), 10.50 (br s, 1H, H1); C
NMR (126 MHz, DMSO-d6) δ 10.9 (C2''), 13.6 (C4'''), 19.1 (C1''), 19.5 (C3'''), 30.2 (C2'''), 41.0
(C1'''), 56.3 (C3), 120.5 (C9), 123.9 (C7), 127.3 (C5a), 130.7 (C6), 131.8 (C8), 136.7 (C9a),
167.4 (C5), 170.9 (C2); IR (cm–1): ν 3223, 3169, 2956, 2930, 2871, 1709, 1616, 1604, 1482,
+
1414, 1391, 1220, 767, 757; HRMS (ESI+): m/z calcd for C15H21N2O2 [M + H]+ 261.1598,
found 261.1601. Anal. Calcd. for C15H20N2O2 (260.33): C, 69.20; H, 7.74; N, 10.76%. Found: C,
69.13; H, 7.73; N, 10.62%.
3,4-Dibutyl-3,4-dihydro-1H-benzo[e][1,4]diazepine-2,5-dione (3k). NaOEt: 185 mg, 71%
1
yield, colorless oil. Major isomer : minor isomer = 61 : 39. Major isomer: H NMR (500 MHz,
DMSO-d6) δ 0.69 (t, 3H, J = 7.1 Hz, H4''), 0.89 (t, 3H, J = 7.4 Hz, H4'''), 1.05–1.57 (m, 10H,
H3'', H2'', H1'', H3''', H2'''), 3.16–3.26 (m, 1H, H1'''), 3.94 (dd, 1H, J = 7.6, 7.6 Hz, H1'''), 4.00
(dd, 1H, J = 8.5, 8.5 Hz, H3), 7.08 (d, 1H, J = 7.9 Hz, H9), 7.18 (ddd, 1H, J = 7.2, 7.2, 0.6 Hz,
H7), 7.48 (ddd, 1H, J = 7.4, 7.4, 1.4 Hz, H8), 7.72 (d, 1H, J = 7.9 Hz, H6, H6), 10.49 (s, 1H, H1);
13C NMR (126 MHz, DMSO-d6) δ 13.5 (C4''), 13.7 (C4'''), 19.3 (C3'''), 21.5 (C3''), 27.6 (C2''),
22
ACS Paragon Plus Environment

Page 23 of 28
The Journal of Organic Chemistry
1
2
3
4
28.2 (C1''), 29.7 (C2'''), 49.8 (C1'''), 64.2 (C3), 120.0 (C9), 123.8 (C7), 126.7 (C5a), 130.7 (C6),
5
6
15
132.2 (C8), 135.6 (C9a), 165.0 (C5), 171.3 (C2); N NMR (51 MHz, DMSO-d6) δ 129.2 (N4),
7
8
9
135.5 (N1); Minor isomer: 1H NMR (500 MHz, DMSO-d6) δ 0.85 (t, 6H, J = 7.3 Hz, H4'', H4'''),
1.05–1.57 (m, 10H, H3'', H2'', H3''', H2'''), 1.69–1.81 (m, 1H, H1''), 1.88–2.00 (m, 1H, H1''),
2.98–3.08 (m, 1H, H1'''), 3.88 (dd, 1H, J = 7.3, 7.3 Hz, H3), 3.97 (dd, 1H, J = 7.5, 7.5 Hz, H1'''),
7.07 (d, 1H, J = 8.0 Hz, H9), 7.21 (dd, 1H, J = 7.8, 7.8 Hz, H7), 7.49 (ddd, 1H, J = 7.4, 7.4, 1.3
Hz, H8), 10.49 (s, 1H, H1); 13C NMR (126 MHz, DMSO-d6) δ 13.6 (C4'''), 13.8 (C4''), 19.5
(C3'''), 22.1 (C3''), 25.4 (C1''), 28.1 (C2''), 30.2 (C2'''), 41.1 (C1'''), 54.9 (C3), 120.5 (C9), 124.0
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
15
(C7), 127.3 (C5a), 130.7 (C6), 131.9 (C8), 136.7 (C9a), 167.5 (C5), 171.0 (C2); N NMR (51
MHz, DMSO-d6) δ 137.4 (N1); IR (cm–1): ν 3221, 2958, 2930, 2871, 1689, 1636, 1620, 1484,
+
1437, 1380, 1164, 760, 703, 526; HRMS (ESI+): m/z calcd for C17H25N2O2 [M + H]+ 289.1911,
found 289.1909.
3-Benzyl-4-methyl-3,4-dihydro-1H-benzo[e][1,4]diazepine-2,5-dione (3l). NaOEt: 100
mg, 40% yield. Brownish solid, mp 121–124 °C; mp63 100.5–103 °C (acetone/hexane). Major
1
isomer : minor isomer = 62 : 38. Major isomer: H NMR (500 MHz, DMSO-d6) δ 2.95 (s, 3H,
H1'''), 3.21 (dd, 1H, J = 14.4, 7.5 Hz, PhCH2), 3.29 (dd, 1H, J = 14.4, 7.6 Hz, PhCH2), 4.33 (t,
1H, J = 7.4 Hz, H3), 7.08 (d, 1H, J = 8.1 Hz, H9), 7.16–7.32 (m, 6H, H7, H2'', H3'', H4'', H5'',
H6''), 7.50 (dd, 1H, J = 7.3, 7.3 Hz, H8), 7.73 (d, 1H, J = 7. 6 Hz, H6), 10.51 (br s, 1H, H1); 13C
NMR (126 MHz, DMSO-d6) δ 28.7 (C1'''), 31.4 (PhCH2), 56.0 (PhCH2), 120.7 (C9), 124.1,
15
126.5, 127.0, 128.4, 129.0, 130.7 (C6), 132.0 (C8), 136.6 (C9a), 137.4, 167.6, 169.2 (C2). N
1
NMR (51 MHz, DMSO-d6) δ 117.3 (N4), 136.9 (N1). Minor isomer: H NMR (500 MHz,
DMSO-d6) δ 2.62 (dd, 1H, J = 13.2, 10.2 Hz, PhCH2), 2.72 (dd, 1H, J = 13.3 H, 7.8 Hz, PhCH2),
2.88 (s, 3H, H1'''), 4.32 (t, 1H, J = 7.8 Hz, H3), 7.02 (d, 2H, J = 7.2 Hz, H2'', H6''), 7.16–7.32 (m,
23
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 24 of 28
1
2
3
4
5H, H7, H9, H3'', H4'', H5''), 7.58 (dd, 1H, J = 7.4, 7.4 Hz, H8), 7.86 (d, 1H, J = 7.7 Hz, H6),
5
6
13
10.65 (br s, 1H, H1); C NMR (126 MHz, DMSO-d6) δ 33.7 (PhCH2), 38.7 (C1'''), 67.1 (C3),
7
8
9
120.2 (C9), 124.0, 126.4, 126.9, 128.5, 128.9, 131.0 (C6), 132.5 (C8), 135.6 (C9a), 136.0, 165.2,
15
169.8 (C2). N NMR (51 MHz, DMSO-d6) δ 115.5 (N4), 136.6 (N1); IR (cm–1): ν 3602, 3084,
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
2904, 1691, 1613, 1607, 1482, 1454, 1436, 1396, 755, 700, 525, 499; HRMS (ESI+): m/z calcd
for C17H17N2O2 [M + H]+ 281.1285, found 281.1283. Anal. Calcd for C17H16N2O2 (280.32): C,
+
72.84; H, 5.75; N, 9.99%. Found: C, 72.58; H, 5.98; N, 9.83%.
Associated Content
Supporting Information: The Supporting Information is available free of charge on the ACS
Publications website at DOI: ___.
Copies of 1H and 13C NMR spectra for new products 2 and 3.
Author Information
Corresponding Authors:
*E-mail (SK): kafka@ft.utb.cz (SK)
*E-mail (JK): janez.kosmrlj@fkkt.uni-lj.si (JK)
# These authors contributed equally.
Notes: The authors declare no competing financial interest.
Acknowledgements
This work was financed by TBU in Zlín (internal grants No. IGA/FT/2016/004, funded from the
resources of specific university research) and the Ministry of Education, Science and Sport,
Republic of Slovenia, the Slovenian Research Agency (Grant: P1-0230). The authors are grateful
24
ACS Paragon Plus Environment

Page 25 of 28
The Journal of Organic Chemistry
1
2
3
4
to anonymous reviewer pointing out Triton B, and Mrs. H. Geržová (Faculty of Technology,
5
6
Tomas Bata University in Zlín) for technical assistance.
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
References
(1) Horton, D. A.; Bourne, G. T.; Smythe, M. L. Chem. Rev. 2003, 103, 893–930.
(2) Gill, R. K.; Kaushik, S. O.; Chugh, J.; Bansal, S.; Shah, A.; Bariwal, J. Mini-Rev. Med.
Chem. 2014, 14, 229–256.
(3) Smith, S. G.; Sanchez, R.; Zhou, M. M. Chem. Biol. 2014, 21, 573–583.
(4) Vitaku, E.; Smith, D. T.; Njardarson, J. T.; J. Med. Chem. 2014, 57, 10257–10274.
(5) Azzarito, V.; Long, K.; Murphy, N. S.; Wilson, A. J.; Nat. Chem. 2013, 5, 161–173.
(6) Loudni, L.; Roche, J.; Potiron, V.; Clarhaut, J.; Bachmann, C.; Gesson, J.-P.; Tranoy-
Opalinski, I. Bioorg. Med. Chem. Lett. 2007, 17, 4819–4823.
(7) Mohamed, L. W.; El-yamany, M. F. Arch. Pharm. Res. 2012, 35, 1369–1377.
(8) Joseph, C. G.; Wilson, K. R.; Wood, M. S.; Sorenson, N. B.; Phan, D. V.; Xiang, Z.; Witek,
R. M.; Haskell-Luevano, C. J. Med. Chem. 2008, 51, 1423–1431.
(9) Cheng, M.-F.; Yu, H.-M.; Ko, B.-W.; Chang, Y.; Chen, M.-Y.; Ho, T.-I.; Tsai, Y.-M.;
Fang, J.-M. Org. Biomol. Chem, 2006, 4, 510–518.
(10) McDowell, R. S.; Blackburn, B. K.; Gadek, T. R.; McGee, L. R.; Rawson, T.; Reynolds, M.
E.; Robarge, K. D.; Somers, T. C.; Thorsett, E. D.; Tischler, M.; Webb II, R. R.; Venutil,
M. C. J. Am. Chem. Soc. 1994, 116, 5077–5083.
(11) Blackburn, B. K.; Lee, A.; Baier, M.; Kohl, B.; Olivero, A. G.; Matamoros, R.; Robarge, K.
D.; McDowell, R. S. J. Med. Chem. 1997, 40, 717–729.
(12) Parks, D. J.; LaFrance, L. V.; Calvo, R. R.; Milkiewicz, K. L.; Gupta, V.; Lattanze, J.;
Ramachandren, K.; Carver, T. E.; Petrella, E. C.; Cummings, M. D.; Maguire, D.;
Grasberger, B. L.; Lu, T. Bioorg. Med. Chem. Lett. 2005, 15, 765–777.
(13) Grasberger, B. L.; Lu, T.; Schubert, C.; Parks, D. J.; Carver, T. E.; Koblish, H. K.;
Cummings, M. D.; LaFrance, L. V.; Milkiewicz, K. L.; Calvo, R. R.; Maguire, D.;
Lattanze, J.; Franks, C. F.; Zhao, S.; Ramachandren, K.; Bylebyl, G. R.; Zhang, M.;
Manthey, C. L.; Petrella, E. C.; Pantoliano, M. W.; Deckman, I. C.; Spurlino, J. C.;
25
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 26 of 28
1
2
3
4
5
6
Maroney, A. C.; Tomczuk, B. E.; Molloy, C. J.; Bone, R. F. J. Med. Chem. 2005, 48,
909−912.
7
8
9
(14) Wright, W. B.; Brabander, H. J.; Greenblatt, E. N.; Day, I. P.; Hardy, R. A. J. Med. Chem.
1978, 21, 1087–1089.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(15) Clark, R. L.; Carter, K. C.; Mullen, A. B.; Coxon, G. D.; Owusu-Dapaah, G.; McFarlane,
E.; Thi, M. D. D.; Grant, M. H.; Tettey, J. N. A.; Mackay, S. P. Bioorg. Med. Chem. Lett.
2007, 17, 624–627.
(16) Karp, G. M., J. Org. Chem. 1995, 60, 5814–5819.
(17) Mohammed Y. S.; Luckner, M.; Tetrahedron Lett. 1963, 1953–1958.
(18) Smith, H.; Wegfahrt, P.; Rapoport, H. J. Am. Chem. Soc. 1968, 90, 1668–1669.
(19) Afiyatullov, Sh. Sh.; Leshchenko, E. V.; Sobolevskaya, M. P.; Gerasimenko, A. V.;
Khudyakova, Yu. V.; Kirichuk, N. N.; Mikhailov, V. V. Chemistry of Natural Compounds
2015, 51, 111–115.
(20) Ishikawa, N.; Tanaka, H.; Koyama, F.; Noguchi, H.; Wang, C. C. C.; Hotta, K.; Watanabe,
K. Angew. Chem. Int. Ed. 2014, 53, 12880–12884.
(21) Kaur, N. Int. J. Pharma Bio Sci. 2013, 4, 485–513.
(22) Yin, W.-B.; Cheng, J.; Li, S.-M.; Org. Biomol. Chem. 2009, 7, 2202–2207.
(23) Kaur, N.; Kishore, D. Synth. Commun. 2014, 44, 1375–1413.
(24) Ugi, I. Angew. Chem. Int. Ed. Engl. 1962, 1, 8–20.
(25) Keating, T. A; Armstrong, R. W. J. Org. Chem. 1996, 61, 8935–8939.
(26) Hulme, C.; Peng, J.; Tang, S.-Y.; Burns, C. J.; Morize, I.; Labaudiniere, R. J. Org. Chem.
1998, 63, 8021–8023.
(27) Blass, B. E.; Burt, T. M.; Liu, S.; Portlock, D. E.; Swing, E. M. Tetrahedron Lett. 2000, 41,
2063–2066.
(28) Boojamra, C. G.; Burrow, K. M.; Thompson, L. A.; Ellman, J. A. J. Org. Chem. 1997, 62,
1240–1256.
(29) Liu, A.; Zhou, H.; Su, G.; Zhang, W.; Yan, B. J. Comb. Chem. 2009, 11, 1083–1093.
(30) Ellman, J. A. Acc. Chem. Res. 1996, 29, 132–143.
(31) Cheng, M.-F.; Fang, J.-M. J. Comb. Chem. 2004, 6, 99–104.
(32) Mayer, J. P.; Zhang, J.; Bjergarde, K.; Lenz, D. M.; Gaudino, J. J. Tetrahedron Lett. 1996,
37, 8081–8084.
26
ACS Paragon Plus Environment

Page 27 of 28
The Journal of Organic Chemistry
1
2
3
4
5
6
(33) Proisl, K.; Kafka, S.; Urankar, D.; Gazvoda, M.; Kimmel, R.; Košmrlj, J. Org. Biomol.
Chem. 2014, 12, 9650–9664.
7
8
9
(34) Kafka, S.; Proisl, K.; Kašpárková, V.; Urankar, D.; Kimmel, R.; Košmrlj, J. Tetrahedron
2013, 69, 10826–10835.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(35) Kafka, S.; Hauke, S.; Salcinovic, A.; Soidinsalo, O.; Urankar, D.; Košmrlj, J. Molecules
2011, 16, 4070–4081.
(36) Kafka, S.; Košmrlj, J.; Klásek, A.; Pevec, A. Tetrahedron Lett. 2008, 49, 90–93.
(37) Klásek, A.; Lyčka, A.; Mikšík, I.; Růžička, A. Helv. Chim. Acta 2009, 92, 689–708.
(38) Prucková, Z.; Klásek, A.; Lyčka, A.; Mikšík, I.; Růžička, A. Tetrahedron 2009, 65, 9103–
9115.
(39) Klásek, A.; Mrkvička, V.; Lyčka, A.; Mikšík, I.; Růžička, A. Tetrahedron 2009, 65, 4908–
4916.
(40) Klásek, A.; Lyčka, A.; Mikšík, I.; Růžička, A. Tetrahedron 2010, 66, 2015–2025.
(41) Mrkvička, V.; Lyčka, A.; Rudolf, O.; Klásek, A. Tetrahedron 2010, 66, 8441–8445.
(42) Mrkvička, V.; Rudolf, O.; Lyčka, A.; Klásek, A. Tetrahedron 2011, 67, 2407–2413.
(43) Stadlbauer, W.; Laschober, R.; Lutschounig, H.; Schindler, G.; Kappe, T. Monatsh. Chem.
1992, 123, 617–636.
(44) Klásek, A.; Kořistek, K.; Lyčka, A.; Holčapek, M. Tetrahedron 2003, 59, 5279–5288.
(45) Kafka, S.; Klásek, A.; Polis, J.; Košmrlj, J. Heterocycles 2002, 57, 1659–1682.
(46) Kafka, S.; Klásek, A.; Polis, J.; Rosenbreierová, V.; Palík, C.; Mrkvička, V.; Košmrlj, J.
Tetrahedron 2008, 64, 4387–4402.
(47) Zbang, X.-M.; Bordwell, F. G. J. Am. Chem. Soc. 1994, 116, 968–972.
(48) Kaljurand, I.; Kütt, A.; Sooväli, L.; Rodima, T.; Mäemets, V.; Leito, I.; Koppel, I. A. J.
Org. Chem. 2005, 70, 1019–1028.
(49) Frenna, V.; Vivona, N.; Consiglio, G.; Spinelli, D. J. Chem. Soc., Perkin Trans. 2 1985,
1865–1868.
(50) Gervasini, A,; Auroux, A. J. Phys. Chem. 1993, 97, 2628–2639.
(51) Angual, S. J.; Warburton, W. K. J. Chem. Soc. 1951, 2492–2494.
(52) Margetic D. Physico-Chemical Properties of Organosuperbases In Superbases for Organic
Synthesis: Guanidines, Amidines, Phosphazenes and Related Organocatalysts; Ishikawa,
T., Ed.; John Wiley & Sons: Chichester, 2009; p. 25.
27
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 28 of 28
1
2
3
4
5
6
(53) Farran, D.; Archirel, P.; Toupet, L.; Martinez, J.; Dewynter, G. Eur. J. Org. Chem. 2011,
2043–2047.
7
8
9
(54) Antolak, S. A.; Yao, Z.-K.; Richoux, G. M.; Slebodnick, C.; Carlier, P. R. Org. Lett. 2014,
16, 5204–5207.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(55) A. M. Van den Bogaert, J. Nelissen, M. Ovaere, L. Van Meervelt, F. Compernolle, W. M.
De Borggraeve, Eur. J. Org. Chem. 2010, 5397–5401.
(56) A. C. Araújo, F. Nicotra, C. Airoldi, B. Costa, G. Giagnoni, P. Fumagalli, L. Cipolla, Eur.
J. Org. Chem. 2008, 635–639.
(57) P. R. Carlier, H. Zhao, S. L. MacQuarrie-Hunter, J. C. DeGuzman, D. C. Hsu, J. Am.
Chem. Soc. 2006, 128, 15215–15220.
(58) Konowal, A.; Snatzke, G.; Alebić-Kolbah, T.; Kajfež, F.; Rendić, S.; Šunjić, V. Biochem.
Pharm. 1979, 28, 3109–3113.
(59) D. C. Hsu, P. C.-H. Lam, C. Slebodnick, P. R. Carlier, J. Am. Chem. Soc. 2009, 131,
18168–18176.
(60) Bowman, R. E.; Grey, T. F.; Huckle, D.; Lockhart, I. M.; Wright, M. J. Chem. Soc. 1964,
3350–3353.
(61) Rudolf, O.; Mrkvička, V.; Lyčka, A.; Rouchal, M.; Klásek, A. J. Heterocycl. Chem. 2013,
50 (S1), E100–E110.
(62) Mohrbacher, R. J.; Grous, P. P. U.S. 1977, US 4002610 A; Chem. Abstr. 1977, 86, 155710.
(63) Ishikura, M.; Mori, M.; Ikeda, T.; Terashima, M.; Ban, Y. J. Org. Chem. 1982, 47, 2456–
2461.
28
ACS Paragon Plus Environment