Synthesis of acylnaphthylamines and their applications in the formation of benzoquinazolines

Article abstract of DOI:10.24820/ark.5550190.p010.739

The synthesis of acyl N-Boc-1- And N-Boc-2-naphthylamines and their transformation into alkyl substituted benzoquinazolines and benzoquinazolinones through the reaction with formamide or potassium cyanate in the presence of ammonium acetate is described.

Full text of DOI:10.24820/ark.5550190.p010.739

The Free Internet Journal
for Organic Chemistry
Paper
Archive for
Organic Chemistry
Arkivoc 2018, part vii, 0-0
Synthesis of acylnaphthylamines and their applications
in the formation of benzoquinazolines
a
b
c
d
a
Monika Nowak,* Emilia Fornal, Renata Kontek, Dariusz Sroczyński, Andrzej Jóźwiak,
a
b
c
a
Ewelina Augustowska, Anna Warpas, Marta Adamczyk, and Zbigniew Malinowski*
aUniversity of Lodz, Faculty of Chemistry, Department of Organic Chemistry,
Tamka 12 Str., 91-403 Lodz, Poland
Medical University of Lublin, Department of Pathophysiology, Jaczewskiego 8b Str., 20-090 Lublin, Poland
b
c
University of Lodz, Faculty of Biology and Environmental Protection, Laboratory of Cytogenetics,
Banacha 12/16 Str., 90-237 Lodz, Poland
University of Lodz, Faculty of Chemistry, Department of Inorganic and Analytical Chemistry,
d
Tamka 12 Str., 91-403 Lodz, Poland
Email: monika.nowak@uni.lodz.pl; zbigniew.malinowski@chemia.uni.lodz.pl
Received 08-31-2018
Accepted 09-26-2018
Published on line 10-13-2018
Abstract
The synthesis of acyl N-Boc-1- and N-Boc-2-naphthylamines and their transformation into alkyl substituted
benzoquinazolines and benzoquinazolinones through the reaction with formamide or potassium cyanate in the
presence of ammonium acetate is described. Presented acyl derivatives were obtained from the reactions of
the corresponding lithiated N-Boc naphthylamines with various acetylating agents like AcCl, Ac
PrCOCl and also Wienreb amides. Biological screening of the potential cytotoxicity on the HT29 cell line and
lymphocytes were demonstrated for some benzoquinazoline derivatives.
2
O, AcOEt, PivCl,
i
Keywords: Acylation, benzoquinazoline, benzoquinazolinone, Pd-coupling, Cu-coupling, cytotoxicity
DOI: https://doi.org/10.24820/ark.5550190.p010.739
Page 1
©ARKAT USA, Inc

Arkivoc 2018, vii, 0-0
Nowak, M. et al.
Introduction
1,2
The quinazoline or quinazolinone skeleton is a building block of various alkaloids with diverse biological
3
-5
6-8
activities like for example vasicine and vasicinone (active compounds of Justicia athatoda), asperlicins A-E
9,10
(
fungal metabolite components of Aspergillus alliaceus)
ochraceus). It has been shown that e.g. asperlicin and its analogues can act as antagonists of neurotransmitter
cholecystokinin (CCK). Other quinazolinone alkaloids exhibit also anti-inflammatory,13 antiviral and
or circumdatin H (from the fungus Aspergillus
11
12
14
15,16
antibacterial activity.
Some of quinazoline derivatives have been approved as effective drugs against
Erlotinib or Ispinesib. Additionally, aryl- or alkyl- quinazolin-2(1H)-one derivatives
1
7
18,19
20
21
cancer, e.g. Gefitinib,
22
23
are applied e.g. as nonsteroidal anti-inflammatory drugs (Proquazone) or in the treatment of cardiovascular
diseases (Bemarinone).
24,25
In the present paper we focused on the synthesis of acyl-N-Boc-aminonaphthalenes and their application
for the preparation of new alkylbenzoquinazolines, which constitute a continuation of our work in the field of
26-28
benzoquinazoline derivatives chemistry and their potential cytotoxic activity.
Results and Discussion
The synthesis of acyl-N-Boc-aminonaphthalenes 2a,b and 5a,b based on a two-stage procedure consisting of 1)
t
26,27
in situ generation of lithium carbamates 1a or 4a using BuLi or BuLi
and then 2) their reaction with the
selected acylating agents (Scheme 1). At the beginning of our investigations, the behavior of bis-metalated
i
species 1a and 4a in the reaction with electrophiles like AcCl, Ac
2
O, AcOEt, PivCl and PrCOCl was verified. The
results are summarized in Table 1.
a)
b)
Scheme 1. Synthesis of ketones 2, 5. The reaction conditions for the reaction of 1 with Ac
2
O, for the reaction
c)
i
of 4 with Ac O, for the reaction of 4 with PrCOCl.
2
Page 2
©ARKAT USA, Inc

Arkivoc 2018, vii, 0-0
Nowak, M. et al.
The use of acetic anhydride for the acylation of 1 or 4 at ˗78 °C, turned out to be the most effective for 2a
45%) and 5a (55%), (Table 1, entries 3 and 11). When 1a was treated with Ac O apart from 2a also N-Ac, N-Boc
(
2
derivative 3 was isolated from the post reaction mixture (Table 1, entry 3). Additionally, we have observed that
an increase in the reaction temperature from ˗78 °C up to ˗20 °C, (Table 1, entry 2), resulted in a decrease in
yield of 2a (20%). Likewise ineffective was the use of acetyl chloride at ˗20 °C (2a was separated in only 10%
yield, Table 1, entry 1). As can be seen in Table 1, treatment of bis-lithiated species 4a with acetyl chloride at
˗
78 °C gave 5a (45%, entry 11), with comparable yield to that of acylation with Ac O (55%, entry 11) whereas
2
ethyl acetate shown considerably less reactivity at this temperature (10%, entry 12).
Table 1. Optimization of conditions for the synthesis of acyl derivatives 2, 5
Yield (%) a
Temp.
(oC)
Electrophile
Substarte Products
, 5
Other
2
products
1
2
3
4
5
AcCl
˗20
˗20
˗78
˗20
˗20
2a (10)
2a (20)
2a (45)
2a (30)
2b (60)
–
Ac
2
O
O
–
1
1
Ac
2
3 (20)
AcN(OMe)Me
PivCl
–
–
2b
6
7
8
9
PivCl
˗78
˗78
˗20
–
–
–
(trace)
PivN(OMe)M
2b (0)
e
PivN(OMe)M
2b (30)
e
PivN(OMe)M
0
2b (13)
5a (45)
5a (55)
5a (10)
–
–
e
1
0
1
2
3
AcCl
˗78
˗78
˗78
˗20
6
(8)
1
1
1
2
Ac O
7
(25)
4
4
AcOEt
–
5a
AcN(OMe)Me
7 (60)
(trace)
8
7
(5)
(5)
14
15
16
iPrCOCl
iPrCOCl
˗78
˗20
˗20
5b (20)
5b (40)
5b (2)
8
7
(10)
(12)
iPrCON(OMe)
Me
–
Reaction conditions: organolithium compound (2 hours, ˗20° C), 1 equiv. of electrophile (2 hours, temperature
described in Table 1, entry 1-16).
a
Isolated yield
Page 3
©ARKAT USA, Inc

Arkivoc 2018, vii, 0-0
Nowak, M. et al.
In case of the synthesis of acyl derivatives 2b, 5b the best results were achieved employing pivaloyl or 2-
methylpropanoyl chloride at ˗20 °C (2b (60%), 5b (40%), Table 1, entries 5, 15). When the reaction temperature
was decreased from ˗20 °C to ˗78 °C, yields of both acetyl derivatives 2b, 5b were lower (Table 1, entries 6, 14).
Additionally, the decrease in the reaction temperature resulted also in reduced yields of side products 7, 8
accompanying the formation of 5b, from 12% (7), 10% (8) at ˗20 °C to about 5% (7, 8) at ˗78 °C (Table 1, entries
1
4, 15).
Weinreb amides are alternative acylating agents to classical ones.29-31 On account of that fact, we decided
to examine the effectiveness of N-methoxy-N-methylacetamide (AcN(OMe)Me), N-methoxy-N,2,2-
i
trimethylpropanamide (PivN(OMe)Me) and N-methoxy-N,2-dimethylpropanamide ( PrCON(OMe)Me) in the
32
reactions with naphthalene derivatives 1a or 4a. We noticed that bis-lithiated species 1a reacted with
AcN(OMe)Me as well as PivN(OMe)Me at ˗20 °C giving corresponding 2a and 2b in merely moderate 30% yield
i
(
Table 1, entries 4, 8). Surprisingly, the effectiveness of Weinreb amides (AcN(OMe)Me, PrCON(OMe)Me) in the
acylation of 4a was very low and the desired products 5a,b were formed in trace amounts (Table 1, entries 13,
6). Besides products 2 or 5 and mentioned above N-acetyl carbamate 3 (as an effect of the reaction of 1a with
Ac O, Table 1, entry 3), from the post reaction mixture some amounts of starting carbamates 1 or 4 (10-50%),
ketoamide 6 (8%), N-Boc 2-naphthylamine 7 (5-60%) and naphtho[2,1-d][1,3]oxazin-3-one 8 (5-10%) were also
1
2
1
13
isolated (confirmed by H, C NMR, HRMS, Table 1, entries 11, 13-15). The formation of ketoamide 6, appears
to result from the C-acylation of lithiated N-(naphthalen-2-yl)acetamide 9 by Ac O, followed by quenching with
methanol. The generation of 9 was most probably due to the ability of N-Boc-2-naphthylamine derivatives to
2
27
cleave the Boc protecting group under basic conditions accompanied by N-acylation with Ac O (Scheme 2).
2
Scheme 2. Possible pathways for the formation of 6 and 8.
33
This type of acetamide aldolization for the first time has been reported by Hauser and Gay. They observed
that acetanilide can be efficiently deprotonated by BuLi to produce the corresponding dianion, which is able to
34
react with diverse electrophiles. In turn, the formation of 8 seems to result from BuLi addition (excess of BuLi)
to the carbonyl group of the emerging keto derivative which subsequently transforms into adduct 10 and finally
to 8 via an the intramolecular cyclization (Scheme 2).
Page 4
©ARKAT USA, Inc

Arkivoc 2018, vii, 0-0
Nowak, M. et al.
We have observed the formation of systems similar to 8 in the reaction of the bis-lithium derivative
t
1
generated from N-Boc-2-naphthylamine 7 ( BuLi/TMEDA) and acetaldehyde (Scheme 3). The H NMR spectrum
of the post reaction complex mixture indicated signals belonging to methyl-1,4-dihydronaphto-1,3-oxazinones
1
1
3 and 14 (the ratio ca. 3:5, H NMR) Ultimately, from the crude material only compound 14 was isolated in the
pure form (40% yield).
t
Schemat 3. Reaction of N-Boc-2-naphthylamine 7 with BuLi / acetaldehyde.
In the literature several strategies have been described for the construction of a quinazoline skeleton, e.g.
35
36
37,38
using aromatic nitroaldehydes, imido amides or amines,
as substrates. There are some procedures for
the preparation of functionalized benzoquinazolines from naphthylamine derivatives like e.g. amidines
3
9
38
(
reactions with DMFA) or anilides (reactions with ammonium formate). However, there are few examples of
38,40,41
the synthesis of benzoquinazoline systems with simple alkyl substituents.
In this work alkylbenzoquinazoline derivatives were synthesized by the thermal condensation (170 °C) of
acylnaphthyl)carbamates 2a,b, 18 or their derivatives 15a, 19 with HCONH /AcONH (Scheme 4).
(
2
4
Transformation of aminoketones 15a, 19 provided the desired products 16a, 20 in moderate yields (35%, 30%,
respectively). Much better results were obtained from the direct reaction of N-Boc derivatives 2a, 2b or 18 with
formamide/AcONH . The corresponding alkylbenzoquinazolines 16a,b and 20 were obtained in 50-60% yields.
4
Attempts to modify the reaction conditions for N-Boc derivatives, e.g. by the replacement of ammonium acetate
by formic acid or the use only of formamide, led to a substantial decrease in yield (e.g. 16a, 10-20% by use of
HCONH
2
/HCOOH or 25-35% via reaction with HCONH ).
2
In our opinion, the formation of quinazolines 16a,b and 20 from ketones (2a,b and 18, Scheme 4) by
condensation with formamide runs through the formation of arylamidine type intermediate 17a and then the
ring closure reaction with a subsequent elimination of water. This can be supported by the fact that the N-Boc
derivatives 2a,b and 18 during the reaction with formamide, underwent deprotection to their parent
ketoamines (isolated yields 6-15%) in any case.
Page 5
©ARKAT USA, Inc

Arkivoc 2018, vii, 0-0
Nowak, M. et al.
Scheme 4. Synthesis of benzoquinazolines 16, 20 from acyl derivatives of N-Boc-1-naphthylamine 2.
Next, we employed naphthalene ketone 19 in the synthesis of formamido quinazoline 21 via the one-pot
type reaction comprising 1) condensation of amine 19 with HCONH
of formamide in the presence of PdCl (PPh (30 mol%). Nonetheless, this way of synthesis did not give the
expected product 21 (Scheme 5). The H NMR (DMSO-d ) spectrum of isolated compound did not show signals
2
and 2) cross coupling reaction with excess
2
1
)
3 2
6
belonging to protons of the –NHCHO group at position 6 of benzoquinazoline skeleton. The obtained spectrum
was identical to the one observed for compound 16a. Thereby, in the course of this reaction the β-hydride
elimination dominated in the last stage of the catalytic cycle and in consequence led to the formation of 16a
42
(
50%) instead 21. Finally, the target product 21 was obtained by the Cu(II) mediated coupling reaction of
quinazoline 20 with an excess of formamide with access to air (52%, Scheme 5). The spectroscopic analysis
indicated that N-arylformamide derivative 21 existed as a mixture of two rotamers (≈ 2:1), favoring the Z form.
Page 6
©ARKAT USA, Inc

Arkivoc 2018, vii, 0-0
Nowak, M. et al.
Scheme 5. The formamidation reaction of benzoquinazoline derivatives 19, 20.
The second part of the presented work concerned the investigation of the behavior of acyl derivatives 2
or/and 5 in the synthesis of benzo[f]quinazolin-3(4H)-ones 22 and benzo[h]quinazolin-2(1H)-ones 23 (Scheme
6
). Heterocycles containing a quinazolin-2(1H)-one scaffold are a relatively little-studied class. Some studies
25,43,44
reported that quinazolin-2(1H)-ones can be obtained by cyclization reactions using amino acetophenones
45
or aminobenzonitriles. Our studies on the construction of benzoquinazolinone systems using N-Boc 2-
naphthylamine derivatives showed that, when a solution of 5a in acetic acid was treated with a large excess of
potassium cyanate, the methylbenzoquinazolinone (22a) can be produced in a satisfactory yield (50%, Scheme
6
). In addition, when ammonium acetate was added to the reaction mixture, the yield of lactam 22a increased
up to 65%. In accordance with this methodology, when the isopropyl derivative 5b was treated with a mixture
of KOCN, AcONH the desired product 22b was obtained in 40% yield (Scheme 6).
4
The transformation of N-Boc 1-naphthylamine derivatives 2a and 2b into lactams 23a (23%) and 23b (15%)
1
was less efficient. H NMR spectra of post reaction mixtures, showed that the main ingredients were the starting
carbamates 2. Furthermore, proton signals for the aminoketone generated by Boc group cleavage from 2b were
also observed. The analysis of obtained results gives a ground for conclusion that the conversion of acyl
carbamates 2 or 5 into corresponding benzoquinazolinones 22, 23 runs through the acidic deprotection of the
amino group, as the first step and then condensation of the resulting ketoamine with potassium cyanate giving
finally benzoquinazolinones (see supplementary material, Scheme S1, Path A: IVVIVIIII). On the other
hand, the presence of AcONH , which can act as a source of nitrogen (ammonium) implies the possibility to
4
include the alternative pathway by the formation of an imidoyl derivative VIII (see supplementary material,
Scheme S1, Path B: IVIIIIXII).
Page 7
©ARKAT USA, Inc

Arkivoc 2018, vii, 0-0
Nowak, M. et al.
Scheme 6. The synthesis of alkyl 4-alkylbenzo[h]quinazolin-2(1H)-ones 22 and 1-alkylbenzo [f]quinazolin-
a)
b) 1
3
(4H)-ones 23; isolated yield; H NMR yield.
In the case of quinazolinones the lactam-lactim tautomerism is possible, wherein amide is the major form.
Additionally, in quinazolinone systems containing a methyl group at position 4 or 2, the tautomerism effect can
1
13
extend to include the methylidene form. The spectroscopic analysis ( H, C NMR) of compounds 22a,b showed
that methylquinazolinone 22a in DMSO-d solution exist in equilibrium with its tautomeric form 24 (Scheme 6)
see supplementary material, Fig. S1). The series of spectra recorded within 7 days demonstrated that the
6
(
concentration of the methylidene form 24 increase till to ≈14%. Compound 22b remained in this form. Crucial
1
for the identification of tautomers 22a and 24 were the H NMR signals of the NH protons observed as a broad
singlet at 12.11 ppm for the lactam form 22a (at 12.06 ppm for 22b) and as two singlets at 9.94 and 9.48 ppm
2
for methylidene derivative 24. Also, methylidene proton signals (C=CH ) of 24 observed as two singlets at 4.86
and 4.74 ppm as well as a singlet of methyl protons of 22a at 3.04 ppm, had the essential diagnostic value. By
13
contrast, in the interpretation of C NMR spectrum of a mixture of 22a  24 the significant role is played by
the resonance signals for C=N and C=O carbon atoms of 22a located at 174.0 and 154.1 ppm, respectively (lit. ≈
4
6,47,48
1
77-180.5 ppm (C=N), ≈ 158 ppm (C=O))
and the carbon atom signal of an alkyl group at 30.0 ppm (lit. ≈
46,47,48
13
22.9 ppm).
A similar image was observed in the C NMR spectrum of compound 22b. The corresponding
carbon atom signals of C=N and C=O moiety were located at 181.7 and 154.4 ppm, respectively. For the
identification of compound type 24, useful were also signals of the methylidene carbon (C=CH ) situated at 91.7
ppm (lit. ≈ 84-88 ppm) and C=CH , C=O at 138.5 and 151.1 ppm (lit. ≈ 150-159 ppm), respectively.
comparison of C NMR spectroscopic data for both quinazolinones 22a and 22b with carbon chemical shifts
was calculated using GIAO method at the B3LYP/6-311++G(d,p) level of theory in DMSO-d solution (IEF-PCM
implicit solvation model) and allowed to signals identify and next their assignment to the corresponding carbon
2
46,47,48
2
The
13
6
13
atoms (see supplementary material, Table S1). The calculated C NMR shifts of atoms C4a-C10b of the
naphthalene system 22b, as was shown in Table S1 (entries 4, 7, 10-12, 14, 17, 18, 21, 23) were located in the
range 117.7-151.6 ppm and they have been assigned to ten experimental signals observed in NMR spectrum at
Page 8
©ARKAT USA, Inc

Arkivoc 2018, vii, 0-0
Nowak, M. et al.
144.8, 136.8, 129.9, 129.8, 128.8, 128.4, 125.1, 124.8, 116.3 and 109.4 ppm. In the case of 22a chemical shifts
of carbon atoms C4a-C10b indicated similar values. Slightly greater differences were visible for C=N (C1) and
13
C=O (C3) carbons. The comparison between theoretical and experimental C NMR shifts for C1 and C3 carbon
atoms were as follows: signals of 22b were found at 193.5 and 181.7 ppm for C=N, and at 161.1 and 154.4 ppm
13
for C=O, while for 22a at 185.8 and 174.0 ppm, and at 160.4 and 154.1 ppm, respectively. The calculated C
2
NMR shift values correlated well with their experimental counterparts with the correlation coefficient (r ) of
0.9992 (22a), 0.9996 (22b) and 0.9913 (24).
In our previous work we demonstrated that a morpholine substituent attached to the
benzo[h]quinazolinone scaffold can be responsible for increased cytotoxicity properties. In the last part of this
2
6,27
work 3-substituted-6-bromobenzo[h]quinazolin-4(3H)ones 26a,b
were subjected to the Cu(II) catalyzed
42
formamidation and Pd
2 3 2
(dba) /Binap/Cs CO
3
catalyzed Buchwald-Hartwig amination reaction (Scheme 7).
According this, target formamides 27a,b were obtained in 60% and 40% yield, respectively, in turn the
1
morpholine products 28a,b were isolated in 55% and 68% yields. H NMR spectra of the new formamides 27
possess a double set of resonance signals, which points out that compounds 27a and 27b, similarly as 21 exist
in two rotameric forms in DMSO-d solution, and the cis form is dominant (cis:trans ≈ 3:1).
6
Scheme 7. The formamidation reaction of benzoquinazolinone derivatives 26.
The cytotoxic activity of the tested quinazoline, quinazolinonene derivatives were evaluated against HT29
human colorectal adenocarcinoma cell line using the MTT test and additionally towards the normal human
Page 9
©ARKAT USA, Inc

Arkivoc 2018, vii, 0-0
Nowak, M. et al.
lymphocytes. The obtained IC50 values were collected in Table 2. In addition, in order to interpret more fully the
26,27
results obtained, the cytotoxicity values of compounds 30-33, evaluated in our earlier papers
cisplatin were also added to Table 2.
and also
49
Table 2. IC50 values of compounds 21, 27-33
IC50 (µM)
Entry
Compound
HT29
80.0
44.0
80.0
16.7
70.0
60.7
30.0
201.0
169.0
4.12
8.47
Lymphocytes
>350
1
2
3
4
5
6
7
8
9
21
27a
>350
27b
>350
28a
279.0
>350
28b
2927
3027
3127
3227
3326
>350
49.0
532.5
501.7
178.11
6.83
10
1
1
Cisplatin49
29
30
31
32
33
The tested new synthesized derivatives 21, 27, 28 showed different activity. Out of these compounds the
most interesting results were obtained for morpholine benzoquinazolinone 28a (IC50 16.7 μM), formamido
benzoquinazolinone 27a (IC50 44.0 μM) and formamido benzoquinoline 29 (IC50 60.7 μM), which exhibited the
highest cytotoxicity against HT29 cell line. As it can be seen from Table 2, N-benzyl-benzoquinazolinone 28a (IC50
16.7 μM) showed a greater toxicity than N-benzyl-benzoquinazolinone 30 (IC50 30.0 μM) and N-dimethoxybenzyl
derivative 28b (IC50 70.0 μM). Regarding the activity of presented morpholine benzo[h]quinazolinones,
compounds 28a, 28b were less active than methoxybenzyl derivative 33 (IC50 4.12 μM). It might be suggested
that cytotoxic activity for tested morpholine benzo[h]quinazolin-4(3H)-ones was dependent on the substituent
at the lactam nitrogen atom and the trend of increasing antitumor activity for these compounds was
PMB>Bn>DMB. Generally, the introduction of the morpholine moiety into the 3,4-dimethoxybenzyl
benzoquinazolinone skeleton in return of the 4-(4-fluorophenyl)piperazin-1-yl (for 32, IC50 169.0 μM) moiety,
had an impact on the increase of activity (for 28b, IC50 70.0 μM). However, the fluorophenylpiperazin-1-yl
derivative 32 showed greater activity than their benzo[f]- analogue 31 (IC50 201.0 μM).
Page 10
©ARKAT USA, Inc

Arkivoc 2018, vii, 0-0
Nowak, M. et al.
Conclusions
We have presented a method to prepare of acylnaphthalenecarbamates 2a,b, 5a,b as precursors in the synthesis
of alkyl substituted benzo[f]quinazolin-3(4H)-ones 22a,b, benzo[h]quinazolin-2(1H)-ones 23a,b and also
benzoquinazolines 16a,b, 20. New benzoquinazolinyl formamides 21, 28a,b achieved via copper catalyzed
coupling reaction can constitute a suitable starting point for further modifications.
Experimental Section
1
13
General. Melting points were determined on a Boetius hot stage apparatus and were uncorrected. H, C NMR
spectra were recorded on a Bruker Advance III spectrometer at 600 MHz, 150 MHz respectively. The residual
1
CDCl
CDCl
3
or DMSO-d
at 77.0 ppm or DMSO-d
6
signal was used for reference (CDCl
3
at 7.26 ppm or DMSO-d
6
at 2.54 ppm for H NMR and
13
3
6
at 39.0 ppm for C NMR). IR spectra were recorded on a Nexus FT-IR
spectrometer. LC/HRMS analyses were performed using an Agilent Technologies HPLC 1290 coupled to an
Agilent Technologies 6550 Accurate Mass Q-TOF LC-MS mass spectrometer equipped with a JetStream
Technology ion source housed in the Department of Pathophysiology, Medical University of Lublin, Poland.
Internal mass calibration was enabled, reference ions of m/z 121.0509 and 922.0098 were used. The analytical
thin layer chromatography tests (TLC) were carried out on Sigma Aldrich (Supelco) silica gel plates (Kiselgel 60
F254, layer thickness 0.2 mm) and the spots were visualized using UV lamp. The flash column chromatography
purifications were performed on Fluka silica gel (Silica gel 60, 0.040-0.063 mm).
t
Butyllithium (BuLi) solution in hexanes (Aldrich), tert-butyllithium ( BuLi) solution in pentane (Aldrich) were each
26
time titrated before use. All reactions with organolithium and organopalladium compounds were performed
under an argon atmosphere using standard Schlenk technique. Diethyl ether, THF and 1,4-dioxane were distilled
from sodium benzophenone ketyl prior to use. Commercially available solvents and reagents: acetyl chloride
i
(
AcCl), acetic anhydride (Ac
acetaldehyde (AcH), 1-naphthylamine, formamide, Boc
dimethoxybenzyl bromide (DMBBr), N-bromosuccinimide (NBS), CuSO
acetic acid (AcOH 80%aq.), potassium cyanate (KOCN), ammonium acetate (AcONH
acetonitrile were purchased from Sigma‒Aldrich, Flucka or POCh and were used without further purification.
2
O), ethyl acetate (AcOEt), pivaloyl chloride (PivCl), isobutyryl chloride ( PrCOCl),
2
O, ethyl chloroformate, benzyl bromide (BnBr), 3,4-
×5H O, binap, Pd (dba) , PPh PdCl PPh
), 1,4-dioxane, THF, Et O,
4
2
2
3
3
2
3
,
4
2
N-Boc-1-naphthylamine (2), N-Boc-1-bromo-2-naphthylamine (4), N-Boc-2-naphthylamine (8), N-methoxy-N-
methylacetamid (AcN(OMe)Me), N-methoxy-N,2,2-trimethylpropanamide (PivN(OMe)Me), N-methoxy-N,2-
i
dimethylpropanamide ( PrCON(OMe)Me), 3-benzyl-6-bromobenzo[h]quinazolin-4(3H)-one (26a), 6-bromo-3-
[
(3,4-dimethoxyphenyl)methyl]benzo[h]quinazolin-4(3H)-one
(26b),
N-(3-methylbenzo[h]quinolin-6-
26,27,32
yl)formamide (29) were prepared by a procedure similar to that in the literature.
General procedure for the preparation of compounds 2,5. Under argon, to a solution of N-Boc-1-
t
naphthylamine (1) or N-Boc-1-bromo-2-naphthylamine (4) (2.1 mmol) in dry Et
2
O (20 mL), at ‒20 °C, BuLi
solution in pentane or BuLi solution in hexanes (2.2 equiv.) was added dropwise. The reaction mixture was
stirred at this temperature for 2 hours. After this time, 1 equiv. of electrophile at ‒78 °C (for Ac
2
O) or at ‒20 °C
i
(for PrCOCl or PivCl) was added dropwise and whole was further stirred at appropriate temperature for next 2
hours. Next, to the reaction mixture 20 mL of methanol was added. Evaporation of solvents and purifications of
the crude residue by flash chromatography gave the desired product 2 or 5. In the case of the reaction of 1 with
Page 11
©ARKAT USA, Inc

Arkivoc 2018, vii, 0-0
Nowak, M. et al.
°
Ac
2
O at ‒78 C from post-reaction mixture also substrate and compound 3 were isolated. On the other hand
i
from reaction of 4 with Ac
2
O and PrCOCl compounds 6, 7, 8 and a small amount of substrate were isolated.
tert-Butyl (2-acetylnaphthalen-1-yl)carbamate (2a). Light yellow solid, yield 45%, 270 mg, mp 150−152 °C; R
f
-1
1
(Hex/AcOEt 5:1) = 0.22. FTIR (KBr, νmax, cm ) 3257, 3055, 3003, 2979, 2928, 1709, 1689. H NMR (CDCl
3
): δ 9.26
(
1H, s, NH), 8.07 (1H, d, J 8.4 Hz, Ar‒H), 7.82 (1H, d, J 8.4 Hz, Ar‒H), 7.78 (1H, d, J 8.6 Hz, Ar‒H), 7.70 (1H, d, J 8.7
1
3
Hz, Ar‒H), 7.56 (2H, m, Ar‒H), 2.71 (3H, s, Me), 1.52 (9H, s, Boc‒Me). C NMR (CDCl
3
): δ 202.0, 154.5, 136.6,
1
C
36.1, 129.1, 128.6, 127.9, 126.7, 126.7, 126.4, 125.5, 125.1, 81.0, 29.6, 28.4. HRMS (ESI) m/z calcd for
+
17
H
20NO : 286.1438; found [M+H] : 286.1441.
3
tert-Butyl (1-acetylnaphthalen-2-yl)carbamate (5a). Beige solid, yield 55%, 243 mg, mp 119−121°C; R
f
-
1
1
(Hex/AcOEt 5:1) 0.55. FTIR (KBr, νmax, cm ) 3274, 3103, 3066, 3002, 2978, 2929, 1711, 1687. H NMR (CDCl
3
): δ
8
.31 (1H, s, NH), 8.26 (1H, d, J 9.1 Hz, Ar‒H), 7.87 (1H, d, J 9.1 Hz, Ar‒H), 7.82 (1H, d, J 8.1 Hz, Ar‒H), 7.76 (1H, d,
13
J 8.5 Hz, Ar‒H), 7.54‒7.49 (1H, m, Ar‒H), 7.46‒7.41 (1H, m, Ar‒H), 2.69 (3H, s, Me), 1.53 (9H, s, Boc‒Me). C
NMR (CDCl
3
): δ 206.0, 153.2, 134.7, 132.0, 130.3, 130.2, 128.8, 127.4, 125.1, 124.7, 120.8, 81.2, 33.0, 28.5. HRMS
+
(ESI) m/z calcd for C17
H20NO
3
: 286.1438; found [M+H] : 286.1435.
4
-Methyl-1,4-dihydro-2H-naphtho[2,3-d][1,3]oxazin-2-one (14). Under argon, to a solution of N-Boc-2-
t
naphthylamine (8) (4.11 mmol) in dry THF (20 mL), at ‒20 °C, TMEDA (2.2 equiv.) and next BuLi solution in
pentane (2.2 equiv.) was added dropwise. The reaction mixture was stirred at this temperature for 2 hours.
After this time, at ‒20 °C, 6.5 equiv. of acetaldehyde was added dropwise and whole was further stirred at ‒20
°C for next 1 hour. Next, to the reaction mixture 20 mL of methanol was added. Evaporation of solvents and
purification of the crude residue by flash chromatography gave 14. White solid, yield 40%, 350 mg, mp 204−206
-
1
1
°
(
C; R
1H, dd, J 8.1, 0.4 Hz, Ar-H), 7.73 (1H, dd, J 8.1, 0.4 Hz, Ar-H), 7.57 (1H, s, Ar-H), 7.46 (1H, ddd, J 8.1, 6.9, 1.2 Hz,
Ar-H), 7.39 (1H, ddd, J 8.1, 6.8, 1.2 Hz, Ar-H), 7.28 (1H, s, Ar-H), 5.67 (1H, qd, J 6.6, 1.2 Hz, CH), 1.84 (3H, d, J 6.6
f
(Hex/AcOEt 4:3) = 0.34. FTIR (KBr, νmax, cm ) 3432, 1713, 1296. H NMR (CDCl
3
): δ 9.54 (1H, s, NH), 7.77
13
Hz, Me). C NMR (CDCl
HRMS (ESI) m/z calcd for C13
3
): δ 154.1, 133.9, 133.1, 130.3, 128.1, 127.2, 127.0 125.1, 124.0, 123.3, 110.3, 75.9, 20.4.
+
H12NO
2
: 214.0863; found [M+H] : 214,0866.
Bromo carbamate 18.To a solution of the appropriate carbamate 2a (0.86 mmol) in acetonitrile (10 mL) at 0 °C,
a solution of NBS (1.3 mmol) in acetonitrile (10 mL) was added dropwise. Next, the resulting mixture was allowed
to warm to ambient temperature. The reaction was continued under these conditions until TLC analysis of the
reaction mixture indicated the absence of starting material 2a (≈ 3-6 hours). After the reaction was completed,
acetonitrile was removed under reduced pressure and the bromo derivative 18 was separated by flash
-
chromatography. Beige solid, yield 80%, 251 mg, mp 161−163 °C; R (Hex/AcOEt 10:1) = 0.20. FTIR (KBr, νmax, cm
f
1
1
)
3279, 3002, 2964, 2924, 2854, 1723, 1681. H NMR (CDCl
3
): δ 9.09 (1H, s, NH), 8.22 (1H, d, J 8.4 Hz, Ar‒H),
8
.11–8.05 (2H, m, Ar‒H), 7.72–7.66 (1H, m, Ar‒H), 7.63–7.56 (1H, m, Ar‒H), 2.70 (3H, s, Me), 1.51 (9H, s, Boc‒
13
Me). C NMR (CDCl
3
): δ 200.7, 154.3, 136.3, 134.4, 130.3, 130.0, 128.9, 127.4, 127.2, 127.1, 122.7, 119.6, 81.4,
+
29.5, 28.4. HRMS (ESI) m/z calcd for C17
H19BrNO
3
: 364.0543; found [M+H] : 364.0541.
Procedure for the preparation of aminoketone 15a. To a mixture of HClaq (0.5 M) and 1,4-dioxane in the ratio
2:3 (v/v), at room temperature ketone 2a (0.48 mmol) was added. The resulting mixture was then heated at 50-
60 °C (oil bath) for about 3-4 hours, until TLC analysis of the reaction mixture indicated the absence of starting
material 2a. After the reaction was completed, all the volatile materials were removed under reduced pressure
and water (5-10 mL) was added to residue. The mixture was adjusted to pH 8-10 with saturated NaHCO and
then extracted with chloroform (320 mL). The combined extracts were dried over MgSO , concentrated under
3
4
reduced pressure. A crude residue was subjected to column chromatography to give amine 15a.
Page 12
©ARKAT USA, Inc

Arkivoc 2018, vii, 0-0
Nowak, M. et al.
Procedure for the preparation of amino ketone 19. To the solution of N-Boc-amino keton 18 (0.88 mmol) in
DCM (4.8 mL) at 0°C, TFA (8.8 mmol, 0.67 mL) was added. The resulting mixture was allowed to warm to ambient
temperature and stirring in these conditions until the completion of reaction (TLC analysis). After this time, all
the volatile materials were removed under reduced pressure and to residue water (5 mL) was added. The whole
lot was adjusted to pH=8-10 (saturated solution of NaHCO
combined extracts were dried over MgSO and concentrated under reduce pressure. The crude residue was
purified via flash chromatography to give the appropriate amine 19. Yellow solid, yield 85%, 198 mg, mp
3
) and next extracted with DCM (320 mL). The
4
-1
1
134−136 °C; R
f
(Hex/AcOEt 5:1) = 0.32. FTIR (KBr, νmax, cm ) 3439, 3288, 3027, 3000, 1634, 1602. H NMR (CDCl
3
):
δ 8.15 (1H, d, J 8.4 Hz, Ar‒H), 7.97 (1H, s, Ar‒H), 7.91 (1H, d, J 8.4 Hz, Ar‒H), 7.72–7.48 (4H, m, NH
2
, Ar‒H), 2.64
13
(3H, s, Me). C NMR (CDCl
3
): δ=199.4, 148.8, 134.5, 131.0, 130.2, 128.1, 126.3, 124.7, 122.2, 112.5, 107.7, 28.5.
+
HRMS (ESI) m/z calcd for C12H11BrNO: 264.0019; found [M+H] : 264.0016.
Synthesis of benzoquinazolines 16, 20
Method A (from amino ketones) and Method B (from carbamates). To a mixture of amino ketone (Method A)
1
5a or 19 (0.31 mmol) or carbamate (Method B) 2a or 2b or 18 (0.31 mmol) in 10 mL of formamide, MeCOONH
4
(0.52 mmol) was added. The whole mixture was stirred and heated at 170 °C (oil bath). After completion of the
reaction, as indicated by TLC (7-15 hours), the resulting solution was cooled to room temperature and 40 mL of
water was added. Then mixture was extracted with chloroform (3x10 mL). The organic layer was dried over
MgSO and concentrated under reduced pressure. A crude residues was purified by column chromatography to
4
afford products 16a, 16b, 20.
Method C (β-hydrogen elimination). To a mixture of amino ketone 19 (0.38 mmol) in 10 mL of formamide,
MeCOONH
60 °C (oil bath) with 3Å molecular sieves. After completion of the reaction, as indicated by TLC (25 hours), the
resulting solution was cooled to room temperature and 40 mL of water was added. Then mixture was extracted
with chloroform (3x10 mL). The organic layer was dried over MgSO and concentrated under reduced pressure.
A crude residue was purified by column chromatography to afford product 16a. Light yellow solid, yield: 35%
4
(0.66 mmol), PPh
3
PdCl
2
PPh
3
(0.11 mmol) was added. The whole mixture was stirred and heated at
1
4
(
0
Method A), 21 mg, 52% (Method B), 31 mg, 55% (Method C), 41 mg, mp 136−138 °C; R
f
(DCM/AcOEt 10:1) =
-1
1
.16. FTIR (KBr, νmax, cm ) 3070, 3042, 2925, 2854, 1621. H NMR (CDCl
3
): δ 9.32 (1H, s, Ar‒H), 9.30–9.26 (1H,
13
m, Ar‒H), 7.95–7.87 (3H, m, Ar‒H), 7.82–7.75 (2H, m, Ar‒H), 2.99 (3H, s, Me). C NMR (CDCl
3
): δ 166.5, 154.8,
1
1
49.9, 135.2, 130.6, 130.1, 128.7, 128.0, 127.8, 125.2, 122.3, 121.1, 22.1. HRMS (ESI) m/z calcd for C13 11BN :
95.0917; found [M+H] : 195.0914.
H
2
+
Synthesis of benzoquinazolinones 22, 23. A solution of the appropriate carbamate 2a or 2b or 5a or 5b (0.52
mmol) in 5 mL of 80% acetic acid was stirred at 130 °C (oil bath) for 2 hours. Then KOCN (4.44 mmol) and
MeCOONH
4
(9.86 mmol) in water (1-2 mL) was added to the mixture. After 30 min. next portion of KOCN (8.86
(9.86 mmol) in water (1-2 mL) was added. The resulting mixture was further heated at
30 °C (oil bath) for 2.5 hours. After that to the stirring mixture the last portion of KOCN (2.7 mmol) and
mmol) and MeCOONH
1
4
MeCOONH (9.1 mmol) in water (1-2 mL) was added. The reaction mixture was held at this conditions for next
4
3
hours. After cooling, 40 mL water was added. The precipitated solid was filtered and purified by flash
chromatography.
1
-Methylbenzo[f]quinazolin-3(4H)-one (22a). Gray solid, yield 65%, 72 mg, mp decomposition above 280 °C; R
f
1
(acetone/MeOH/Hex 2:1:1) = 0.76. HNMR (DMSO-d
6
): δ 12.11 (1H, s, NH), 8.60 (1H, d, J 8.7 Hz, Ar-H), 8.21 (1H,
d, J 8.9 Hz, Ar-H), 8.01 (1H, d, J 7.9 Hz, Ar-H), 7.78–7.71 (1H, m, Ar-H), 7.62–7.55 (1H, m, Ar-H), 7.43 (1H, d, J 8.9
+
Hz, Ar-H), 3.04 (3H, s, Me). HRMS (ESI) m/z calcd for C13
11
H N
2
O: 211.0866; found [M+H] : 211.0870.
Page 13
©ARKAT USA, Inc

Arkivoc 2018, vii, 0-0
Nowak, M. et al.
Mixture of 1-methylbenzo[f]quinazolin-3(4H)-one (22a) and 1-methylidene-1,4-dihydrobenzo[f]quinazolin-
-1
1
3
(
8
(2H)-one (24) in ratio 1:0.16*. FTIR (KBr, νmax, cm ) 3437, 3003, 2973, 2858, 2822, 2753, 1663, 1621. H NMR
DMSO-d ): δ 12.11 (1H, br s, NH), 9.94 (1H, s, NH*), 9.58 (1H, s, NH*), 8.60 (1H, d, J 8.7 Hz, Ar-H), 8.44 (1H, d, J
.6 Hz, Ar-H*), 8.21 (1H, d, J 8.9 Hz, Ar-H), 8.01 (1H, dd, J 7.9, 1.2 Hz, Ar-H), 7.85 (1H, d, J 8.2 Hz, Ar-H*), 7.82
6
(1H, d, J 8.7 Hz, Ar-H*), 7.78–7.71 (1H, m, J 8.5, 7.0, 1.4 Hz, Ar-H), 7.62–7.55 (1H, m, Ar-H), 7.54–7.50 (1H, m, Ar-
H*), 7.43 (1H, d, J 8.9 Hz, Ar-H), 7.40–7.35 (1H, m, J 7.4 Hz, Ar-H*), 7.12 (1H, d, J 8.7 Hz, Ar-H*), 4.86 (1H, s,
13
CH
2
*), 4.74 (1H, s, CH
2
*), 3.04 (3H, s, Me). C NMR (DMSO-d ): δ 174.0, 154.1, 151.1, 144.8, 138.4, 138.5, 136.9,
6
1
9
36.7, 130.8, 129.8, 129.7, 129.2, 128.9, 128.7, 127.5, 125.0, 124.9, 123.8, 123.1, 116.3, 115.8, 110.2, 110.2
1.7, 30.0.
Preparation of 21 or 27 via copper-mediated N-formamidation. To the bromo derivative 20 or 26 (0.27mmol)
suspended in formamide (15 mL) CuSO x5H O (0.68 mmol) and K CO (1.35 mmol) was added. Whole mixture
4
2
2
3
was heated with magnetic stirring at 150 °C (oil bath) for about 15-25 hours. After completion the reaction, as
indicated by TLC the mixture was cooled and poured into crushed ice with water (20-30 mL). After 30 min.
mixture was extracted with DCM. The combined extracts were dried over MgSO and concentrated in vacuo.
4
The residue was next subjected to flash chromatography to afford the pure product 21 or 27.
*
N-(4-Methylbenzo[h]quinazolin-6-yl)formamide (21). Mixture of rotamers 2:1 , light yellow solid, yield 47%, 30
-
1
1
mg, mp 299−301 °C; R
0.71 (1H, s, NH*), 10.59 (1H, s, NH), 9.32–9.20 (3H, m, 2Ar-H, Ar-H*), 8.83 (1H, d, J 9.4 Hz, CHO*), 8.68 (1H, s,
Ar-H), 8.62 (1H, s, CHO), 8.37 (1H, d, J 8.3 Hz, Ar-H), 8.32 (1H, d, J 8.1 Hz, Ar-H*), 8.01–7.91 (2H, m, Ar-H, Ar-H*),
f
(AcOEt/DCM 5:1) = 0.38. FTIR (KBr, νmax, cm ) 3223, 3075, 1719. H NMR (DMSO-d ): δ
6
1
1
3
7
1
1
.91–7.86 (3H, m, Ar-H, 2Ar-H*), 2.96 (3H, s, Me*), 2.90 (3H, s, Me). C NMR (DMSO-d ): δ 165.8, 164.3, 160.9,
58.5, 153.8, 153.7, 146.2, 135.9, 132.3, 130.3, 130.2, 129.8, 128.8, 128.2, 127.9, 124.9, 123.1, 122.1, 121.5,
6
+
11.8, 111.4, 21.8, 21.6. HRMS (ESI) m/z calcd for C14
12
H N
3
O: 238.0975; found [M+H] : 238.0974.
Preparation of benzoquinazolinone derivatives 28 via Pd cross-coupling reaction. An oven dried resealable
Schlenk flask which was equipped with a magnetic stirring bar was charged with Pd (dba) (0.062 mmol), Binap
0.062 mmol) and freshly distilled toluene (4 mL). The vessel was evacuated and backfilled with argon, which
was repeated of 3 times. After that Cs CO (0.62 mmol), bromo derivative 28a or 28b (0.42 mmol) dissolved in
2
3
(
2
3
toluene (6 ml) and morpholine (1.2 mmol) was added. The whole mixture was stirred and heated at 100 °C (oil
bath) for 30 hours. After this time the reaction mixture was cooled and diluted with chloroform (5 mL). The solid
was filtered off, washed with chloroform (2 mL) and the filtrate concentrated in vacuo. The crude product was
purified by flash chromatography.
3
-Benzyl-6-(morpholin-4-yl)benzo[h]quinazolin-4(3H)-one (28a). White solid, yield: 55%, 86 mg, mp 165−166
-1
°
C; R
f
(DCM/AcOEt 1:1) = 0.72. FTIR (KBr, νmax, cm ) 3081, 3066, 3032, 2968, 2917, 2915, 2889, 2853, 2826, 1678.
H NMR (CDCl ): δ 8.99 (1H, d, J 8.2 Hz, Ar‒H), 8.28 (1H, d, J 8.2 Hz, Ar‒H), 8.25 (1H, s, Ar‒H), 7.80 (1H, s, Ar‒H),
.74–7.66 (2H, m, Ar‒H), 7.43–7.27 (5H, m, Bn), 5.28 (2H, s, CH ), 4.04–3.96 (4H, m, Morf), 3.25–3.11 (4H, m,
1
3
7
2
13
Morf). C NMR (CDCl
3
): δ 161.2, 149.3, 145.2, 143.7, 135.9, 132.1, 131.5, 129.2, 129.0, 128.5, 128.3, 127.2,
+
125.7, 123.8, 119.2, 109.5, 67.5, 53.6, 50.1. HRMS (ESI) m/z calcd for C23
22
H N
3
O
2
: 372.1707; found [M+H] :
372.1702.
Acknowledgements
This work was partially supported by the University of Lodz.
Page 14
©ARKAT USA, Inc

Arkivoc 2018, vii, 0-0
Nowak, M. et al.
Supplementary Material
Copies of selected H and 13C NMR spectra of new compounds, Biology section information (general),
Computational details and additional compounds characterization data, Schemes, Tables, Figures can be found
in supplementary material in the online version of this article.
1
References
1. Michael, J. P. Nat. Prod. Rep. 2007, 24, 223‒246.
http://dx.doi.org/10.1039/B612168N
2. Shang, X-F.; Morris-Natschke, S. L.; Liu, Y-Q.; Guo, X.; Xu, X-S.; Goto, M.; Li, J-C.; Yang, G-Z.; Lee, K-H. Med.
Res. Rev. 2017, 1‒54.
http://dx.doi.org/10.1002/med.21466
3
4
5
. Salvam, T. P.; Kumar, P. V. Res. Pharma. 2011,1 , 1‒21.
Online ISSN: 2231-539X
. Asif, M. Int. J. Med. Chem. 2014, ID 395637, 1‒27.
http://dx.doi.org/10.1155/2014/395637
. Rakesh, K. P.; Darshini, N.; Shubhavathi, T.; Mallesha, N. Organic&Medicinal Chem. IJ. 2017, 2, 1‒5.
http://dx.doi.org/10.19080/OMCIJ.2017.02.555585
6
7
. Basu Sujata, T.; Mamta, P.; Priyanka, K. M.; Sonam, S. Indo Glob. J. Pharm. Sci. 2011, 1, 85‒98.
. Duraipandiyan, V.; Al-Dhabi, N. A.; Balachandran, C.; Ignacimuthu, S.; Sankar, C.; Balakrishana, K. BioMed.
Res. Int. 2015, ID 727304, 1‒7.
http://dx.doi.org/10.1155/2015/727304
8
9
1
1
1
. Singh, S. K.; Patel, J. R.; Dangi, A.; Bachle, D.; Kataria, R. A. J. Med. Plants Stud. 2017, 5, 175‒180.
Online ISSN: 2320-3362
. Houck, J.; Ondeyka, D. R.; Zink, D. L.; Inamine, E.; Goetz, M. A.; Hensens, O. D. J. Antibiot. 1988, XLI, 882‒
891.
0. Haynes, S. W.; Gao, X.; Tang, Y.; Walsh, Ch. T. J. Am. Chem. Soc. 2012, 134, 17444‒17447.
http://dx.doi.org/10.1021/ja308371z
1. Bose, D. S.; Chary, W. V. Synthesis, 2010, 4, 0643‒0650.
http://dx.doi.org/10.1055/s-0029-1218606
2. Bock, R. M. G.; DiPardo, M.; Rittle, K. E.; Evans, B. E.; Freidinger, R. M.; Veber, D. F.; Chang, R. S. L.; Chen, T-
B.; Keegan, M. E.; Lotti, V. J. J. Med. Chem. 1986, 29, 1941‒1945.
http://dx.doi.org/10.1021/jm00160a024
1
1
1
3. Kumar, A.; Sharma, S.; Kiran Bajaj, A.; Sharma, S.; Panwar, H.; Singh, T.; Srivastava, V. K. Bioorg. Med. Chem.
2003, 11, 5293‒5299.
http://dx.doi.org/10.1016/S0968-0896(03)00501-7
4. Selvam, P.; Vijayalakshimi, P.; Smee, D. F.; Gowen, B. B.; Julander, J. G.; Day, C. W.; Barnard, D. L. Antivir.
Chem. Chemother. 2007, 18, 301‒305.
http://dx.doi.org/10.1177/095632020701800506
5. Pandeya, S. N.; Sriram, D.; Nath, G.; De Clercq, E. Pharm. Acta Helv. 1999, 74, 11‒17.
http://dx.doi.org/10.1016/S0031-6865(99)00010-2
Page 15
©ARKAT USA, Inc

Arkivoc 2018, vii, 0-0
Nowak, M. et al.
16. Raju, G. N.; Sai, K. B.; Resshma, V.; Sudarshini, N.; Sowmya, P. L.; Nalini, Y.; Nadendla, R. R. J. Chem. Pharm.
Res. 2015, 7, 1279‒1287.
Online ISSN: 0975-7384
1
1
1
2
2
2
7. Marzaro, G.; Guiotto, A.; Chilin, A. Expert Opin. Ther. Patents, 2012, 22, 223‒252.
http://dx.doi.org/10.1517/13543776.2012.665876
8. Tamura, K.; Fukuoka, M. Expert Opin. Pharmacother. 2005, 6, 985‒993.
http://dx.doi.org/10.1517/14656566.6.6.985
9. Nurwidya, F.; Takahashi, F.; Takahashi, K. J. Nat. Sc. Biol. Med. 2016, 7, 119‒123.
http://dx.doi.org/10.4103/0976-9668.184695
0. Schettino, C.; Bareschino, M. A.; Ricci, V.; Ciardiello, F. Expert Rev. Resp. Med. 2008, 2, 167‒178.
http://dx.doi.org/10.1586/17476348.2.2.167
1. Marzo, I.; Naval, J. Biochem. Pharmacol. 2013, 86, 703‒710.
http://dx.doi.org/10.1016/j.bcp.2013.07.010
2. Coombs, R. V.; Denzer, D. M.; Hardtmann, G. E.; Huegi, B.; Koletar, G.; Koletar, J.; Ott, H.; Junkiewicz, E.;
Perrine, J. W.; Takesue, E. I.; Trapold, J. H. J. Med. Chem. 1973, 16, 1237‒1245.
http://dx.doi.org/10.1021/jm00269a006
23. Clissold, S. P.; Beresford, R. Drugs 1987, 33, 478‒502.
http://dx.doi.org/10.2165/00003495-198733050-00004
24. Falotico, R.; Moore, J. B.; Bandurco, V.; Bell, S. C.; Levine, S. D.; Tobia, A. J. Drug Dev. Res. 1988, 12, 241‒
257.
http://dx.doi.org/10.1002/ddr.430120307
25. Bandurco, V. T.; Schwender, Ch. F.; Bell, S. C.; Combs ,D. W.; Kanoija, R. M.; Levine, S. D.; Mulvey, D. M.;
Appollina, M. A.; Reed, M. S.; Malloy, E. A.; Falotico, R.; Moore, J. B.; Tobia, A. J. J. Med. Chem. 1987, 30,
1421‒1426.
http://dx.doi.org/10.1021/jm00391a026
26. Nowak, M.; Malinowski, Z.; Jóźwiak, A.; Fornal, E.; Błaszczyk, A.; Kontek, R. Tetrahedron, 2014, 70, 5153‒
5160.
http://dx.doi.org/10.1016/j.tet.2014.05.117
27. Nowak, M. ; Malinowski, Z. ; Fornal, E. ; Jóźwiak, A. ; Parfieniuk, E. ; Gajek, G. ; Kontek, R. Tetrahedron, 2015,
50, 9463‒9473.
http://dx.doi.org/10.1016/j.tet.2015.10.049
2
2
3
8. Malinowski, Z.; Fornal, E.; Sierocińska, B.; Czeczko, R.; Nowak, M. Tetrahedron, 2016, 72, 7942‒7951.
http://dx.doi.org/10.1016/j.tet.2016.10.022
9. Turnbull, K.; Sun, C.; Krein, D. M. Tetrahedron Lett. 1998, 39, 1509‒1512.
http://dx.doi.org/10.1016/S0040-4039(98)00069-0
0. Clark, R. D.; Muchowski, J. M.; Fisher, L. E.; Flippin, L. A.; Repke, D. B.; Souchet, M. Synthesis, 1991, 10, 871‒
878.
http://dx.doi.org/10.1055/s-1991-26597
31. Pace, V.; Holzer, W.; Olofsson, B. Adv. Synth. Catal. 2014, 356, 3697‒3736.
http://dx.doi.org/10.1002/adsc.201401093
32. Diehl, J.; Brückner, R. Eur. J. Org. Chem. 2017, 2, 278‒286.
http://dx.doi.org/10.1002/ejoc.201601202
Page 16
©ARKAT USA, Inc

Arkivoc 2018, vii, 0-0
Nowak, M. et al.
3
3
3
3
3
3. Gay, R. L.; Hauser, Ch, R. J. Am. Chem. Soc. 1967, 89, 1647‒1651.
http://dx.doi.org/10.1021/ja00983a021
4. Kern, N.; Hoffmann, M.; Weibel, J-M.; Pale, P.; Blanc, A. Tetrahedron, 2014, 70, 5519‒5531.
http://dx.doi.org/10.1016/j.tet.2014.06.106
5. Ostrowski, S.; Wolniewicz, A. M. Chem. Heterocycl. Compd. 2000, 36, 705‒713.
http://dx.doi.org/10.1007/BF02297680
6. Cheng, X.; Wang, H.; Xiao, F.; Deng, G-J. Green Chem. 2016, 18, 5773‒5776.
http://dx.doi.org/10.1039/C6GC02319C
7. Conconi, M. T.; Marzaro, G.; Urbani, L.; Zanusso, I.; Di Liddo, R.; Castagliuolo, I.; Brun, P.; Tonus, F.; Ferrarese,
A.; Guiotto, A.; Chilin, A. Eur. J. Med. Chem. 2013, 67, 373‒383.
http://dx.doi.org/10.1016/j.ejmech.2013.06.057
3
3
4
4
4
4
8. Ferrini, S.; Ponticelli, F.; Taddei, M. Org. Lett. 2007, 9, 69‒72.
http://dx.doi.org/10.1021/ol062540s
9. Robev, S. K. Tetrahedron Lett. 1983, 24, 4351‒4354.
http://dx.doi.org/10.1016/S0040-4039(00)88339-2
0. Breukink, K. W.; Krol, L. H.; Verkade, P. E.; Webster, P. M. Recl. Trav. Chim. Pazs-Bas. 1957, 76, 401‒414.
http://dx.doi.org/10.1002/recl.19570760505
1. Ramanathan, M.; Liu, S-T. J. Org. Chem. 2017, 82, 8290‒8295.
http://dx.doi.org/10.1021/acs.joc.7b01325
2. Komati, R.; Jursic, S. Tetrahedron Lett. 2014, 55, 1523‒1527.
http://dx.doi.org/10.1016/j.tetlet.2014.01.046
3. Press, J. B.; Bandurco, V. T.; Wong, E. M.; Hajos, Z. G.; Kanoija, R. M.; Mallory, R. A.; Deegan, E. G.; McNelly,
J. J.; Roberts, J. R.; Cotter, M. L.; Graden, D. W.; Lloyd, J. R. J. Heterocyclic Chem. 1986, 23, 1821‒1828.
http://dx.doi.org/10.1002/jhet.5570230643
4
4. Conley, R. A.; Barton, D. L.; Stefanick, S. M.; Lam, M. M.; Lindabery, G. C.; Kasulanis, Ch, F.; Cesco-Concian,
S.; Currey, S.; Fabian, A. C.; Levine, S. D. J. Heterocyclic Chem. 1995, 32, 761‒770.
http://dx.doi.org/10.1002/jhet.5570320312
4
5. Pham, T. T.; Walden, M.; Butler, Ch.; Diaz-Gonzalez, R.; Perez-Moreno, G.; Ceballoz-Perez, G.; Gomez-Perez,
V.; Garcia-Hernandez, R.; Zecca, H.; Krakoff, E.; Kopec, B.; Ichire, O.; Mackenzie, C.; Pitot, M.; Ruiz, M. L.;
Gamarro, F.; Gonzalez-Pacanowska, D.; Navarro, M.; Dounay, A. B. Bioorg. Med. Chem. 2017, 27, 3629‒
3635.
http://dx.doi.org/10.1016/j.bmcl.2017.07.032
46. Gimeno, A.; Medio-Simon, M.; Ramirez, C.; De Arellano, R.; Asensio, G.; Cuenca, A. B. Org. Lett. 2010, 12,
1900‒1903.
http://dx.doi.org/10.1021/ol100595s
47. Wang, H.; Liu, L.; Wang, Y.; Peng, Ch.; Zhang, J.; Zhu, Q. Tetrahedron Lett. 2009, 50, 6841‒6843.
http://dx.doi.org/10.1016/j.tetlet.2009.09.130
48. Barthel, A.; Trieschmann, L.; Strӧhl, D.; Kluge, R.; Bӧhm, G.; Csuk, R. Arch. Pharm. Chem. Life Sci. 2009, 342,
445‒452.
http://dx.doi.org/10.1002/ardp.200800196
49. Kontek, R.; Matławska-Wasowska, K.; Kalinowska-Lis, U.; Kontek, B.; Ochocki, J. Acta Pol. Pharm. Drug Res.
2011, 68, 127‒136.
Online ISSN: 0001-6837; PMID: 21485711
Page 17
©ARKAT USA, Inc