The preparation of various new heterocyclic compounds via cyclization of substituted derivatives of phenacyl esters of hydrazonoacetic acid

Article abstract of DOI:10.1055/s-0033-1339348

A procedure for the preparation of derivatives of phenacyl hydrazonopropanoates and their application in the synthesis of various heterocycles has been developed. Not only is the preparation of indole derivatives described, but also a new method for the preparation of previously unknown pyridazine derivatives.

Full text of DOI:10.1055/s-0033-1339348

PAPER
▌2447
paper
The Preparation of Various New Heterocyclic Compounds via Cyclization of
Substituted Derivatives of Phenacyl Esters of Hydrazonoacetic Acid
Preparation of Various New Heterocyclic Compounds
Radek Mělnický,a Martin Grepl,a Antonín Lyčka,c,d Valerio Bertolasi,e Lubomír Kvapil,a Barbora Dvořáková,a
Pavel Hradil*a,b
a
Farmak a.s., Na Vlcinci 3, 77117 Olomouc, Czech Republic
Fax +4058231424; E-mail: pavel.hradil@farmak.cz
b
Department of Organic Chemistry, Palacky University, Tr. 17. Listopadu 12, 771 46 Olomouc, Czech Republic
c
Research Institute for Organic Syntheses, Rybitvi 296, 533 54 Pardubice, Czech Republic
d
University of Hradec Kralove, Faculty of Science, Rokitanského 62, 500 03 Hradec Králove 3, Czech Republic
e
Dipartimento di Chimica and Centro di Structturistica Diffrattometrica, University of Ferrara, Via L. Borsari 46, 441 00 Ferrara, Italy
Received: 12.03.2013; Accepted after revision: 10.06.2013
We selected hydrazones 3 as the starting materials, which
Abstract: A procedure for the preparation of derivatives of phen-
are isosteric with the phenacyl esters of anthranilic acid 4
acyl hydrazonopropanoates and their application in the synthesis of
(Figure 2). Various methods of cyclization have been re-
various heterocycles has been developed. Not only is the prepara-
tion of indole derivatives described, but also a new method for the
ported for the preparation of quinolones 1;1 these methods
preparation of previously unknown pyridazine derivatives.
were also tested for the cyclization of hydrazones 3.
Key words: phenacyl esters, hydrazone, cyclization, indoles, pyr-
idazine
O
R2
R3
O
R2
O
O
N
O
Heterocycles are an important class of biologically active
compounds that have enormous potential in medicine.
New synthetic methods for the preparation of these com-
pounds are crucial for the development of new drugs. We
decided to test the applicability of our recently developed
method for the synthesis of 2-aryl-3-hydroxyquinolin-
4(1H)-ones 1 (Figure 1).1–5 This reaction was shown to
have general applicability in the synthesis of different
scaffolds, including naphthyridines,6 and in the prepara-
tion of 3-amino derivatives.7 All these compounds can be
considered as aza analogues of flavones and they are
promising biologically active compounds. These com-
pounds exhibit, in particular, anticancer activity, but also
antiviral and antiprotozoal effects have been observed.8
Based on the interesting biological results from previous-
ly prepared molecules, we wanted to prepare new com-
pounds with one ring. Therefore, we also attempted to
apply this synthetic method to the preparation of pyrida-
zine derivatives 2.
O
NH
NH
R1
R3
3
4
R1
Figure 2
Because the starting materials 3 are relatively complex
and contain several reactive functional groups, the reac-
tions and reaction conditions need to be carefully chosen.
Phenacyl malonates react with diazonium salts to produce
furan derivatives (Scheme 1);9 thus, a different synthetic
route had to be selected.
O
R3
+
N2
O
O
N
+
R3
N
R2
R2
O
R1
O
O
O
R3
OH
OH
R1
N
R1
N
Scheme 1
N
R2
R2
H
Keto acids 8 were selected as the key starting materials.
Compounds 8a–c are commercially available, and
phenylglyoxalic acids 8d–g were prepared by the oxida-
tion of the corresponding cyanohydrins 6d–g as previous-
ly described (Scheme 2, Table 4).10,11
R1
1
2
Figure 1 Original preparation of heterocycle 2
SYNTHESIS 2013, 45, 2447–2457
Advanced online publication: 01.08.2013
DOI: 10.1055/s-0033-1339348; Art ID: SS-2012-Z1009-OP
© Georg Thieme Verlag Stuttgart · New York
The phenacyl esters of hydrazones 3a–x (Scheme 2, Table
1) were synthesized in the next step by reaction of the so-
dium salts of hydrazones 10a–l with phenacyl bromide
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X

2448
R. Mělnický et al.
PAPER
O
NHNH2
R3
Br
O
R2
COO–Na+
R3
O
9
H
11
H
OH
OH
R1
c
R3
COOH
R2
a
b
N
N
O
R3
R3
R3CH=O
e
NH
d
NH
COOH
CN
O
5
7
10
3
6
8
R1
R1
5–8
9
11
a R3 = Mea
b R3 = Bna
c R3 = Eta
d R3 = Ph
a R1 = H
a R2 = H
b R1 = 4-Cl
b R2 = 4-F
c R2 = 4-NO2
c R1 = 2,4-(NO2)2
d R1C6H4 = 6-chloropyridin-2-yl d R2 = 4-NH2-3,5-Cl2
e R3 = 4-MeOC6H4
f R3 = 4-MeC6H4
g R3 = 2-MeOC6H4
e R1 = 3-MeO
f R1 = 4-Et
e R2 = 3-NO2
f R2 = 4-Br
g R1 = 2-MeO
g R2 = 4-MeO
h R2 = 4-Me
i R2 = 3-HO-4-MeO
Scheme 2 Reagents and conditions: (a) NaCN, H2O, Na2S2O5; (b) HCl; (c) NaOH, KMnO4; (d) Na2CO3, EtOH, 25 °C, 1–8 h; (e) DMF,
5–70 °C, 0.5–20 h. a Synthesis started from commercially available compound 8.
derivatives 11a–i in N,N-dimethylformamide (Scheme 2,
Table 5). In another method, the triethylammonium salts
of hydrazone 10 react with phenacyl bromide derivatives
11 in boiling acetone.
The formation of geometrical isomers was observed in
these reactions. Some isomers were obtained as the by-
product, mostly in low yield, to the major isomers: (Z)-3c
(2%), (Z)-3h (2%), (Z)-3i (6%), (Z)-3j (55%), and (Z)-3l
(19%). Cyclization was not observed on heating (Z)-3m
and (Z)-3r in trifluoroacetic acid or polyphosphoric acid,
instead quantitative formation of isomers (E)-3m and
(E)-3r was observed. Also the quantitative transformation
of isomers (E)-3m and (E)-3r was observed on standing in
ethanolic solution to give isomers (Z)-3m and (Z)-3r.
Figure 3 ORTEP17 views of compound (E)-3a displaying the ther-
mal ellipsoids at 30% probability
The structure of the isomers was proven by X-ray crystal-
lography (Figures 3–6) and can also be determined from
the NMR data.
Crystal data were collected on a Nonius Kappa CCD dif-
fractometer using graphite monochromated MoKα radia-
tion (λ = 0.7107 Å) at room temperature (295 K). The data
sets were integrated with the Denzo-SMN package12 and
corrected for Lorentz polarization effects. The structures
were solved by direct methods (SIR97)13 and refined by
full-matrix least square methods with all non-hydrogen
atoms anisotropic and hydrogens isotropic. All calcula-
tions were performed using SHELXL-9714 and PARST15
implemented in the WINGX16 system of programs.
The most common method for the preparation of quino-
lones 1 is the cyclization of phenacyl ester 4 in the pres-
ence of various acids, typically trifluoroacetic acid or
polyphosphoric acid.3
The cyclization of hydrazones 3 is more complicated be-
cause various reaction pathways are possible, especially
the hydrolysis of either the hydrazone or the ester bond. In
the cases of compounds 3a–i,k,l, there is a possibility of
the formation of indole derivatives 12. In fact, all of these
Figure 4 ORTEP17 views of compound (E)-3j displaying the ther-
mal ellipsoids at 30% probability
Synthesis 2013, 45, 2447–2457
© Georg Thieme Verlag Stuttgart · New York

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Preparation of Various New Heterocyclic Compounds
2449
Figure 5 ORTEP17 views of compound (E)-3r displaying the ther-
mal ellipsoids at 30% probability
Figure 6 ORTEP17 views of compound (Z)-3r displaying the ther-
mal ellipsoids at 30% probability
reactions were observed (Scheme 3). The final product
and course of the reaction depends especially on the sub-
stitution of the starting compound. The R3 substituents are
critically important in determining the course of the reac-
tion and formation of individual heterocyclic systems.
When we started our research, various acids were used as
cyclization agents. Fisher’s type of cyclization was pre-
ferred for compounds 3a–i,k,l. Indole derivatives 12 were
formed at first as the major products after a few minutes
of reflux in trifluoroacetic acid (Scheme 3, Table 2). Lac-
tones 13 and 14 were isolated as the main products if the
reaction time was prolonged. Similar reaction pathways as
observed in the cyclization using trifluoroacetic acid were
also observed in the cyclization of compounds 3a and 3b
using polyphosphoric acid or boron trifluoride–diethyl
ether complex in toluene.
The structures of compounds 12, 13, and 14 were con-
firmed by NMR, and compound 14a was also confirmed
by X-ray crystallography (Figure 7). Using similar cycli-
zation conditions for the cyclization of compounds (Z)-
3m and (Z)-3r produced only (E)-3m and (E)-3r.
Figure 7 ORTEP17 views of compound 14a displaying the thermal
ellipsoids at 30% probability
R4
R1
O
O
R4
O
O
R2
O
R1
R3
R1
O
O
O
N
d
a (b or c)
N
O
+
N
R2
N
H
NH
H
R2
O
R2
3 R3 = Me, Bn, Et
12 R4 = H, Ph, Me
13
14
R1
Scheme 3 Reagents and conditions: (a) TFA, reflux, 5–30 min; (b) PPA, 90 °C, 35 min; (c) BF3·OEt2, reflux, 30 min; (d) TFA, reflux, 5–320 h.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 2447–2457

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R. Mělnický et al.
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In addition to using acids, different methods for the cycli- Products 2 were only obtained in low yields, hence, other
zation of phenacyl ester 4 are known. In particular, ther- reaction conditions were explored including catalytic po-
mal cyclization affords high yields in the cyclization of tassium tert-butoxide in various solvents, the combination
acetonyl derivatives.5 Unfortunately, the formation of tar- of potassium hydroxide with alcohols, diglyme, or tolu-
like product was observed in our case.
ene, and microwave catalysis. However, all of these reac-
tion conditions failed, and only hydrolysis products were
observed.
A complex mixture of compounds was also observed if
the reaction of compound 3 was performed in boiling
phosphoryl chloride or warm 1-methylpyrrolidin-2-one.
Only the combination of sodium, potassium, or lithium
hydroxide in N,N-dimethylformamide, 1-methylpyrro-
lidin-2-one, or dimethyl sulfoxide was successful.
The preparation of quinolone derivatives 1 from anthrani-
lates 4 via cyclization in alkali medium is also known. The
best results were observed if the reaction was performed Moreover, other conditions were examined including po-
in N,N-dimethylformamide, 1-methylpyrrolidin-2-one, tassium tert-butoxide in tetrahydrofuran at 25 °C, potassi-
dimethyl sulfoxide or similar solvents with sodium or po- um tert-butoxide in 1-methylpyrrolidin-2-one under
tassium hydroxide, but the yields of quinolones 1 were microwave catalysis, potassium hydroxide in methanol
low, most likely due to the limited stability of quinolones and tert-butyl alcohol, and potassium tert-butoxide in di-
1 in alkali medium. Because the acid cyclization condi- glyme. All of these conditions led to hydrolyzed products.
tions lead to nearly quantitative product yields, cycliza- This reaction did not proceed when the R1 and R2 substi-
tion in alkali medium is not used for the preparation of tuted derivatives had electron-withdrawing groups, e.g.
quinolone 1. Nevertheless, this method was successfully NO2; in these cases only hydrolysis was observed. At
used for the preparation of isocoumarins 15 from phen- higher temperatures, decarboxylation is possible.
acyl phthalates 16 (Figure 8), whereas other methods
The structure of 5-hydroxy-1,3,6-triphenylpyridazin-
4(1H)-one (2a) was confirmed by X-ray (Figure 9).
failed.18
O
O
O
O
O
COOMe
OH
15
O
16
Figure 8
The expected compounds 2 were prepared by the cycliza-
tion of derivatives 3m–q,s–x in alkali conditions (Scheme
4, Table 3). The best results were obtained using 1-meth-
ylpyrrolidin-2-one in the presence of potassium hydrox-
ide at 110 °C. At lower temperatures, only hydrolysis of
the ester was observed.
O
O
R2
Figure 9 ORTEP17 views of compound 2a displaying the thermal el-
lipsoids at 30% probability
R3
OH
R3
O
N
N
O
N
a
R2
NH
In conclusion, we verified that synthetic method used for
the synthesis of 2-aryl-3-hydroxyquinolin-4(1H)-ones 1
fail for the synthesis of 5-hydroxy-1,3,6-triarylpyridazin-
4(1H)-one 2. A new method for the synthesis of these
molecules was developed. Beside these compounds, also
new indole derivatives 12–14 were prepared.
R1
R1
2m–q,s–x
3m–q,s–x
Scheme 4 Reagents and conditions: (a) KOH, NMP, 110 °C, 5–35
min.
Synthesis 2013, 45, 2447–2457
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Preparation of Various New Heterocyclic Compounds
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Table 1 Preparation of Hydrazone Derivatives 3
Entry
Product
(colored solid)
R1
R2
R3
Temp, time
25 °C, 2 h
Yield
Mp (°C)
HRMS
found
(calcd)
(Rf)a
1
(E)-3a
(light yellow)
H
H
Me
Me
Me
Me
2.53 g (54%)
147–148
(0.331)
295.1082
(295.1077)
2
(E)-3b
(light yellow)
H
4-F
25 °C, 0.67 h 4.35 g (88%)
138–140
(0.346)
313.0989
(313.0983)
3
(E)-3c
(yellow)
H
4-NO2
4-NO2
5 °C, 3.5 h
5 °C, 3.5 h
5 °C, 1.5 h
5 °C, 1 h
3.86 g (72%)
0.1 g (2%)b
175–178
(0.278)
340.0932
(340.0928)
4
(Z)-3c
(brown)
H
151–153
(0.586)
340.0927
(340.0928)
5
(E)-3d
(light yellow)
H
4-NH2-3,5-Cl2 Me
5.12 g (86%)
3.66 g (68%)
4.73 g (80%)
3.57 g (69%)
4.89 g (76%)
0.12 g (2%)b
3.46 g (59%)
0.33 g (6%)b
2.34 g (39%)
3.33 g (55%)
0.45 g (8%)b
3.62 g (74%)
0.91 g (19%)b
4.78 g (84%)
4.29 g (86%)c
6.69 g (96%)
5.18 g (84%)
3.12 g (53%)
2.72 g (43%)
172–174
(0.293)
378.0412
(378.0407)
6
(E)-3e
(yellow)
H
3-NO2
4-Br
H
Me
Me
Me
Me
Me
Me
Me
Me
Me
Bn
Et
132–134
(0.195)
340.0931
(340.0928)
7
(E)-3f
(beige)
H
5 °C, 1.5 h
5 °C, 0.5 h
25 °C, 1 h
25 °C, 1 h
25 °C, 1 h
25 °C, 1 h
25 °C, 3 h
25 °C, 3 h
70 °C, 2 h
25 °C, 1.5 h
25 °C, 1.5 h
25 °C, 5.5 h
25 °C, 3 h
25 °C, 20 h
25 °C, 8 h
25 °C, 16 h
70 °C, 16 h
181–183
(0.383)
373.0187
(373.0182)
8
(E)-3g
(beige)
4-Cl
145–147
(0.299)
329.0693
(329.0686)
9
(E)-3h
(beige)
4-Cl
4-Br
4-Br
4-NO2
4-NO2
H
176–179
(0.328)
408.9948
(408.9949)
10
11
12
13
14
15
16
17
18
19
20
21
22
23
(Z)-3h
(yellow)
4-Cl
161–166
(0.704)
408.9949
(408.9949)
(E)-3i
(yellow)
4-Cl
183–186
(0.196)
374.0543
(374.0538)
(Z)-3i
(yellow)
4-Cl
172–176
(0.545)
374.0541
(374.0538)
(E)-3j
(yellow)
2,4-(NO2)2
122–124
(0.290)
385.0781
(385.0779)
(Z)-3j
(yellow)
2,4-(NO2)2
H
212-215
(0.333)
385.0780
(385.0779)
(E)-3k
(brown)
H
H
H
H
H
H
H
H
H
H
153–155
(0.493)
373.1551
(373.1547)
(E)-3l
(beige)
H
140–143
(0.364)
309.1240
(309.1233)
(Z)-3l
(yellow)
H
Et
110–114
(0.678)
311.1388
(311.1390)
(Z)-3m
(yellow)
H
Ph
114–117
(0.386)
359.1389
(359.1390)
(E)-3m
(yellow)
H
Ph
184–186
(0.546)
359.1391
(359.1390)
(Z)-3n
(yellow)
4-NH2-3,5-Cl2 Ph
142–145
(0.370)
440.0567
(440.0563)
(Z)-3o
(yellow)
4-OMe
Ph
Ph
Ph
111–113
(0.348)
389.1493
(389.1496)
(Z)-3p
(brown)
4-Me
114–115
(0.500)
373.1544
(373.1547)
(Z)-3q
(yellow)
3-OH-4-OMe
150–152
(0.196)
403.1290
(403.1289)
© Georg Thieme Verlag Stuttgart · New York
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R. Mělnický et al.
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Table 1 Preparation of Hydrazone Derivatives 3 (continued)
Entry
Product
(colored solid)
R1
R2
R3
Temp, time
Yield
Mp (°C)
HRMS
found
(Rf)a
(calcd)
d
24
25
26
27
28
29
30
31
(Z)-3r
(yellow)
–
H
H
H
H
H
H
H
H
Ph
Ph
Ph
Ph
Ph
25 °C, 8 h
5.55 g (89%)
4.34 g (79%)e
5.04 g (82%)
4.51 g (74%)
5.36 g (87%)
5.08 g (83%)
4.17 g (71%)
0.66 g (11%)b
152–154
(0.420)
394.0950
(394.0953)
d
(E)-3r
(beige)
–
70 °C, 5.5 h
25 °C, 2 h
144–148
(0.304)
394.0958
(394.0953)
(Z)-3s
(yellow)
3-OMe
4-Et
2-OMe
H
117–120
(0.590)
389.1500
(389.1496)
(Z)-3t
(brown)
25 °C, 1.5 h
25 °C, 1.5 h
123–126
(0.676)
387.1699
(387.1703)
(Z)-3u
(yellow)
150–155
(0.589)
389.1494
(389.1496)
(Z)-3v
(yellow)
4-MeOC6H4 25 °C, 3 h
120–124
(0.568)
389.1494
(389.1496)
(Z)-3w
(brown)
H
4-MeC6H4
25 °C, 0.6 h
110–114
(0.653)
373.1545
(373.1547)
(Z)-3x
H
2-MeOC6H4 25 °C, 8 h
90–95
389.1495
(yellow)
(0.474)
(389.1496)
a TLC solvent system: toluene–EtOAc (9:1).
b Purified by column chromatography (toluene–EtOAc, 9: 1).
c Obtained from (Z)-3m (TFA).
d R1C6H4 = 6-chloropyridin-2-yl.
e Obtained from (Z)-3r (PPA).
Table 2 Preparation of Indole Derivatives 12, 13, and 14
Entry
Product
(colored solid)
R1
R2
R4
Temp, time
Yield
Mp (°C)
(Rf)
HRMS
found
(calcd)
1
2
3
4
5
6
7
8
9
10
12a
(beige)
H
H
H
H
H
H
H
H
H
H
H
H
–
90 °C, 35 min
73 °C, 9 h
0.42 g (26%)
0.75 g (47%)
0.68 g (43%)
197–201
(0.100)a
278.0816
(278.0812)
13a
(beige)
H
226–232
(0.294)b
260.0713
(260.0706)
14a
(yellow)
H
H
H
–
73 °C, 9 h
153–156
(0.673)b
262.0861
(262.0863)
12b
(light pink)
4-F
126 °C, 30 min 0.52 g (30%)
208–211
(0.123)a
296.0724
(296.0718)
13b
(white)
4-F
73 °C, 32 h
73 °C, 32 h
73 °C, 35 min
73 °C, 36 h
73 °C, 36 h
73 °C, 30 min
0.29 g (17%)
0.58 g (34%)
1.76 g (93%)
0.12 g (7%)
0.81 g (44%)
0.92 g (44%)
251–253
(0.292)b
280.0768
(280.0768)
14b
(beige)
4-F
H
H
–
153–155
(0.670)b
280.0767
(280.0768)
12c
(brown)
4-NO2
4-NO2
4-NO2
4-NH3-3,5-Cl2
222–226
(0.069)a
323.0668
(323.0663)
13c
(yellow)
332–336
(0.258)b
305.0562
(305.0557)
14c
(yellow)
H
H
266–270
(0.587)b
307.0711
(307.0713)
12d
(light yellow)
224–227
(0.077)a
361.0146
(361.0141)
Synthesis 2013, 45, 2447–2457
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Preparation of Various New Heterocyclic Compounds
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Table 2 Preparation of Indole Derivatives 12, 13, and 14 (continued)
Entry
Product
(colored solid)
R1
R2
R4
Temp, time
Yield
Mp (°C)
(Rf)
HRMS
found
(calcd)
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
13d
(beige)
H
4-NH3-3,5-Cl2
–
73 °C, 28 h
0.36 g (17%)
0.56 g (27%)
1.29 g (68%)
0.22 g (12%)
0.90 g (48%)
0.88 g (42%)
0.40 g (20%)
0.91 g (44%)
0.55 g (30%)
0.22 g (12%)
0.36 g (20%)
0.50 g (22%)
0.24 g (10%)
0.35 g (15%)
0.58 g (28%)
0.23 g (11%)
0.52 g (25%)
0.48 g (23%)
0.35 g (17%)
0.18 g (11%)
1.45 g (86%)
261–264
(0.292)b
345.0192
(345.0192)
14d
(light yellow)
H
4-NH3-3,5-Cl2
3-NO2
3-NO2
3-NO2
4-Br
4-Br
4-Br
H
H
H
–
73 °C, 28 h
190–193
(0.647)b
345.0192
(345.0192)
12e
(light yellow)
H
73 °C, 25 min
73 °C, 26 h
174–176
(0.069)a
323.0668
(323.0663)
13e
(yellow)
H
280–282
(0.253)b
305.0562
(305.0557)
14e
(yellow)
H
H
H
–
73 °C, 26 h
223–225
(0.560)b
307.0711
(307.0713)
12f
(beige)
H
73 °C, 40 min
73 °C, 28 h
218–221
(0.200)a
355.9922
(355.9917)
13f
(beige)
H
291–296
(0.303)b
339.9970
(339.9968)
14f
(beige)
H
H
H
–
73 °C, 28 h
195–198
(0.707)b
339.9969
(339.9968)
12g
(white)
5-Clc
8-Cld
8-Cle
5-Clc
8-Cld
5-Clc
5-Clc
8-Cld
8-Cle
H
73 °C, 40 min
73 °C, 55 h
205–209
(0.130)a
312.0428
(312.0422)
13g
(beige)
H
276–280
(0.275)b
294.0324
(294.0316)
14g
(beige)
H
H
H
–
73 °C, 55 h
203–205
(0.707)b
296.0472
(296.0473)
12h
(light yellow)
4-Br
4-Br
4-Br
4-NO2
4-NO2
4-NO2
H
73 °C, 20 min
73 °C, 320 h
73 °C, 320 h
73 °C, 30 min
73 °C, 190 h
73 °C, 190 h
73 °C, 20 min
73 °C, 3.5 h
73 °C, 5 min
73 °C, 15 min
240–245
(0.212)a
389.9531
(389.9527)
13h
(beige)
317–318
(0.275)b
373.9578
(373.9578)
14h
(beige)
H
H
–
185–188
(0.747)b
373.9578
(373.9578)
12i
218–220
(0.083)a
357.0279
(357.0273)
(light yellow)
13i
(yellow)
336–339
(0.225)b
341.0323
(341.0324)
14i
(beige)
H
Ph
Ph
Me
Me
275–279
(0.588)b
341.0321
(341.0324)
12k
(white)
162–163
(0.144)a
356.1283
(356.1281)
14k
(yellow)
H
H
189–191
(0.700)b
338.1174
(338.1176)
12l
(beige)
H
H
181–188
(0.159)a
294.1124
(294.1125)
14l
(yellow)
H
H
148–150
(0.760)b
276.1017
(276.1019)
a TLC solvent system: n-hexane–EtOAc (7:3).
b TLC solvent system: toluene–EtOAc (9:1).
c Position 5 of the indole system.
d Position 8 of the 4-substituted pyrano[4,3-b]indol-1-one.
e Position 8 of the 4-substituted 1H-[1,4]oxazino[4,3-a]indol-1-one.
© Georg Thieme Verlag Stuttgart · New York
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2454
R. Mělnický et al.
PAPER
Table 3 Preparation of Pyridazine Derivatives 2
Entry
Product
(colored solid)
R1
R2
H
R3
Ph
Temp, time
Yield
Mp (°C)
HRMS found
(calcd)
(Rf)a
1
2m
(beige)
H
20 min, 110 °C
20 min, 110 °C
20 min, 110 °C
35 min, 110 °C
5 min, 110 °C
15 min, 110 °C
30 min, 110 °C
15 min, 110 °C
20 min, 110 °C
25 min, 110 °C
30 min, 110 °C
0.13 g (15%) 274–275
(0.157)
341.1289
(341.1285)
2
2n
(beige)
H
4-NH2-3,5-Cl2 Ph
0.15 g (13%) 245–250
(0.183)
424.0611
(424.0614)
3
2o
(white)
H
4-OMe
4-Me
Ph
Ph
0.28 g (29%) 242–243
(0.099)
371.1396
(371.1390)
4
2p
(white)
H
0.21 g (23%) 267–269
(0.155)
355.1439
(355.1441)
5
2q
(white)
H
3-OH-4-OMe Ph
0.11 g (11%) 174–180
(0.099)
387.1326
(387.1339)
6
2s
(beige)
3-OMe
4-Et
2-OMe
H
H
H
H
H
H
H
Ph
0.19 g (19%) 230–232
(0.147)
371.1396
(371.1390)
7
2t
(beige)
Ph
0.07 g (7%) 203–205
(0.324)
369.1591
(369.1596)
8
2u
(beige)
Ph
0.22 g (22%) 288–292
(0.077)
371.1392
(371.1390)
9
2v
(brown)
4-MeOC6H4
4-MeC6H4
2-MeOC6H4
0.08 g (9%) 247–255
(0.139)
371.1392
(371.1390)
10
11
2w
(beige)
H
0.16 g (17%) 271–273
(0.111)
355.1436
(355.1441)
2x
(white)
H
0.14 g (15%) 245–249
(0.028)
371.1393
(371.1390)
a TLC solvent system: n-hexane–EtOAc (7:3).
Table 4 Preparation of Phenylglyoxalic Acid Derivatives 8
Table 5 Preparation of Sodium Salts 10
Enry Producta R1
R3
Time (h) Yield
Enry
Producta
R3
Yieldb
1
2
3
4
8d
8e
8f
Ph
27.0 g (90%)
7.9 g (22%)
19.0 g (58%)
11.2 (31%)
1
10a
10b
10c
10d
10e
10f
10g
10h
10i
H
Me
Me
1
8.9 g (98%)
4-MeOC6H4
4-MeC6H4
2-MeOC6H4
2
4-Cl
1.5
1
10.4 g (98%)
11.9 g (98%)
10.4 g (90%)
5.5 g (63%)
7.0 g (64%)
5.6 g (46%)
8.2 g (67%)
6.4 g (52%)
6.9 g (56%)
10.8 g (94%)
3.8 g (31%)
3
2,4-(NO2)2 Me
8g
4
H
Bn
1
a 8d–g were all yellowish oils.
5
H
Et
1.5
2
b Yield was calculated based on compound 5.
6
H
Ph
7
3-MeO
4-Et
2-MeO
H
Ph
1.5
1
8
Ph
NMR measurements: 1H and 13C NMR spectra were recorded on a
Bruker Avance 500 spectrometer (500.13 MHz for 1H, 125.76 MHz
for 13C) in DMSO-d6. The central signals of the solvent [δ = 2.55
(1H) and δ = 39.6 (13C)] were used as the reference signals. All 2D
experiments (gradient-selected (gs)-COSY, gs-TOCSY, gs-
HMQC, gs-HMBC) were performed using the manufacturer’s soft-
ware.
9
Ph
1
10
11
12
10j
10k
10l
4-MeOC6H4
4-MeC6H4
1
H
8
H
2-MeOC6H4 1.5
a Products 10a–l were all yellow solids.
LCMS measurements: LCMS were measured with a Thermo Exac-
tive instrument (Thermo Scientific, USA). The chromatographic
apparatus consisted of an Accela 1250 LC pump, autosampler, and
column thermostat. The separation was performed using the follow-
Synthesis 2013, 45, 2447–2457
© Georg Thieme Verlag Stuttgart · New York

PAPER
Preparation of Various New Heterocyclic Compounds
2455
ing conditions: (1) Luna C18, 3 um, 50 × 2 mm i.d. column (Phe-
nomenex, USA), isocratic elution; mobile phase: MeCN–H2O
(50:50) + 0.1% HCO2H; flow rate: 250 μL/min; column tempera-
ture: 30 °C. (2) Luna C18, 3 um, 4 × 2 mm i.d. column (Phe-
nomenex, USA), isocratic elution; mobile phase: MeCN–H2O
(70:30) + 0.1% HCO2H; flow rate: 150 μL/min; column tempera-
ture: 30 °C. The samples were prepared using the following proce-
dure: sample (1 mg) was dissolved in MeCN–H2O (1:1, 10 mL) (1
min sonication), and then a portion of this soln (30 μL) and MeCN–
H2O (1:1, 970 μL) were added to a vial and mixed as a final dilution
before injection of 5 μL.
1H NMR: δ = 8.24 (m, 2 H), 7.49 (m, 3 H), 7.43 (m, 2 H), 7.35 (m,
3 H), 7.25 (m, 2 H), 7.16 (m, 2 H), 2.29 (s, CH3).
13C NMR: δ = 162.3, 147.9, 147.1, 144.0, 137.0, 134.6, 127.0 (all
C), 130.3 (2 C), 128.9, 128.8 (2 C), 128.6 (2 C), 128.4, 128.3 (2 C),
128.0 (2 C), 126.9 (2 C) (all CH), 20.9 (CH3).
2q
White solid; yield: 0.11 g (11%).
1H NMR: δ = 8.23 (m, 2 H), 7.33–7.52 (m, 8 H), 6.86 (d, J = 1.9 Hz,
1 H), 6.82 (dd, J = 8.1, 1.9 Hz, 1 H), 6.74 (d, J = 8.1 Hz, 1 H), 3.56
(s, OCH3).
HRMS measurements: An Exactive spectrometer with an orbitrap
mass analyzer was equipped with heated electrospray ionization
(HESI) or atmospheric pressure chemical ionization (APCI). The
spectrometer was tuned to obtain a maximum response for m/z 70–
1000. The source parameters were set to the following values: HESI
temperature: 250 °C; spray voltage: ±3.5 kV; transfer capillary tem-
perature: 300 °C; sheath gas/auxiliary gas (N2) flow rates: 35/10.
APCI temperature: 400 °C; spray voltage: ±3.5 kV; transfer capil-
lary temperature: 330 °C; sheath gas/aux gas (N2) flow rates: 25/10.
The separated compounds were observed by recording the TIC (to-
tal ion current)/time signal. The HRMS spectra of target peaks al-
lowed for evaluation of their elemental composition due to high
intensities of their protonated/deprotonated molecules. The identifi-
cation of the respective structures was performed with less than 3
ppm difference between the experimental and theoretically calculat-
ed values.
13C NMR: δ = 162.3, 147.9, 147.1, 147.0, 144.3, 137.2, 134.6, 120.5
(all C), 128.9, 128.7 (2 C), 128.3 (2 C), 128.2, 128.1 (2 C), 126.8 (2
C), 123.7, 115.1, 114.8 (all CH), 55.7 (OCH3).
2s
Beige solid; yield: 0.19 g (19%).
1H NMR: δ = 8.24 (m, 2 H), 7.50 (m, 3 H), 7.37 (m, 5 H), 7.25 (t,
J = 8.1 Hz, 1 H), 7.05 (m, 1 H), 7.00 (dd, J = 7.9, 1.9 Hz, 1 H), 6.90
(dd, J = 8.4, 2.5 Hz, 1 H), 3.67 (s, OCH3).
13C NMR: δ = 162.4, 159.2, 147.8, 147.2, 144.8, 136.9, 134.6, 130.1
(all C), 130.4 (2 C), 129.5, 128.9, 128.8, 128.3 (2 C), 128.1 (2 C),
119.1, 114.3, 112.9 (all CH), 55.5 (OCH3).
2t
Beige solid; yield: 0.07 g (7%).
1H NMR: δ = 8.25 (m, 2 H), 7.49 (m, 3 H), 7.34 (d, J = 8.5 Hz, 7 H),
7.18 (m, 2 H), 2.58 (q, J = 7.6 Hz, CH2), 1.15 (t, J = 7.6 Hz, CH3).
13C NMR: δ = 162.3, 147.9, 147.2, 144.1, 141.7, 137.0, 134.6, 130.1
(all C), 130.4, (2 C), 128.9, 128.8, 128.3 (2 C), 128.1 (2 C), 128.0
(2 C), 126.7 (2 C) (all CH), 27.7 (CH2), 15.4 (CH3).
1,3,6-Triaryl-5-hydroxypyridazin-4(1H)-ones 2; General Pro-
cedure
Acetates 3m–q and 3s–x (2.65 mmol) were dissolved in NMP (6.0
mL). The mixture was heated to 110–120 °C, and KOH (31.9 mmol,
12 equiv) was added. The mixture was stirred at this temperature for
5–35 min (Table 3, entries 1–11). When the starting material was
not observed by TLC (n-hexanes–EtOAc, 7:3), the mixture was
poured onto ice (100 g). The mixture was acidified by HCl to pH 1.
The crude solid product was filtered off, washed with H2O, and
dried in a vacuum drier at 60 °C. Then, the solid product 2 was sus-
pended in EtOAc and heated to reflux for 5 min, and the undis-
solved product was filtered off. The filter cake was washed with
EtOAc and dried in vacuo at 60 °C. If the crude product 2 was sol-
uble in EtOAc, then it was crystallized (EtOH), see Table 3.
2u
Beige solid; yield: 0.22 g (22%).
1H NMR: δ = 8.19 (m, 2 H), 7.61 (m, 1 H), 7.46–7.53 (m, 3 H),
7.31–7.37 (m, 6 H), 7.00 (t, J = 7.7 Hz, 1 H), 6.96 (d, J = 8.4 Hz, 1
H), 3.64 (s, OCH3).
13C NMR: δ = 162.5, 153.2, 147.6, 147.4, 138.4, 134.5, 132.4, 129.6
(all C), 130.9, 129.9 (2 C), 129.0, 128.9, 128.8, 128.3 (2 C), 128.1
(2 C), 127.6 (2 C), 120.4, 112.2 (all CH), 55.6 (OCH3).
2m
2v
Beige solid; yield: 0.13 g (15%).
Brown solid; yield: 0.08 g (9%).
1H NMR: δ = 8.27 (m, 2 H), 7.29–7.42 (m, 10 H), 7.06 (m, 2 H),
3.85 (s, OCH3).
13C NMR: δ = 162.3, 159.9, 147.4, 146.9, 143.9, 136.8, 130.1, 127.0
(all C), 130.5 (2 C), 129.8 (2 C), 128.9, 128.8 (2 C), 128.4, 128.1,
126.9 (2 C), 113.5 (all CH), 55.3 (OCH3).
1H NMR: δ = 8.25 (m, 2 H), 7.37–7.54 (m, 13 H).
13C NMR: δ = 162.3, 147.8, 147.2, 143.8, 136.9, 134.5, 130.0 (all
C), 130.4 (2 C), 128.9, 128.8, 128.7 (2 C), 128.4, 128.3, 128.0 (2 +
2 C), 126.8 (2 C) (all CH).
2n
Beige solid; yield: 0.15 g (13%).
2w
1H NMR: δ = 8.24 (m, 2 H), 7.37–7.52 (m, 8 H), 7.25 (s, 2 H), 5.84
Beige solid; yield: 0.16 g (17%).
(s, NH2).
1H NMR: δ = 8.16 (m, 2 H), 7.30–7.43 (m, 12 H), 2.40 (s, CH3).
13C NMR: δ = 162.3, 148.1, 147.1, 143.9, 141.6, 135.1, 134.6,
117.9, 117.1 (2 C) (all C), 130.1 (2 C), 128.9 (2 C), 128.6, 128.3 (2
C), 128.1 (2 C), 126.9 (2 C) (all CH).
13C NMR: δ = 162.4, 147.7, 147.2, 143.9, 138.5, 136.9, 131.8, 130.1
(all C), 130.5 (2 C), 128.9, 128.8 (2 C), 128.7 (2 C), 128.4, 128.2 (2
C), 128.1 (2 C), 126.9 (2 C) (all CH), 21.1 (CH3).
2o
2x
White solid; yield: 0.28 g (29%).
White solid; yield: 0.14 g (15%).
1H NMR: δ = 7.48 (m, 1 H), 7.27–7.39 (m, 11 H), 7.18 (d, J = 8.3
Hz, 1 H), 7.07 (t, J = 7.4 Hz, 1 H), 3.76 (s, OCH3).
13C NMR: δ = 162.2, 157.9, 150.5, 146.4, 143.7, 137.1, 130.1, 124.4
(all C), 130.9, 130.5 (2 C), 130.2, 128.9, 128.8 (2 C), 128.3, 128.1
(2 C), 126.9 (2 C), 120.3, 111.8 (all CH), 55.7 (OCH3).
1H NMR: δ = 8.25 (m, 2 H), 7.28–7.54 (m, 10 H), 6.91 (m, 2 H),
3.77 (s, OCH3).
13C NMR: δ = 162.2, 159.4, 148.0, 144.0, 143.9, 136.8, 134.6, 122.0
(all C), 131.9 (2 C), 128.8, 128.7 (2 C), 128.3 (2 C), 128.0 (2 C),
126.8 (2 C), 113.5 (all CH), 55.2 (OCH3).
2p
White solid; yield: 0.21 g (23%).
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 2447–2457

2456
R. Mělnický et al.
PAPER
2-Aryl-2-oxoethyl (2E)-(2-Arylhydrazono)propanoates and 2-
Aryl-2-oxoethyl (2Z)-(2-Arylhydrazono)propanoates 3; Gener-
al Procedure
Sodium (2E)-(2-Arylhydrazono)propanoates 10a–e and (2Z)-
Sodium Aryl(arylhydrazono)acetates 10f–l; General Procedure
Derivatives 8a–g (45.4 mmol) were dissolved in EtOH (30.0 mL).
Arylhydrazine derivatives 9a–g (45.4 mmol) were added, and the
mixture was stirred at 25 °C for 1–8 h (Table 5) (TLC monitoring,
n-hexanes–EtOAc, 7:3). Then Na2CO3 (2.4 g, 22.7 mmol) was add-
ed and the mixture was stirred at 25 °C for 2 h. The solid precipitate
was filtered off, washed with EtOH, and dried in a vacuum drier.
Compounds 10a–g were obtained as yellow solids and used in the
next step without purification.
Sodium (2E)-(2-arylhydrazono)propanoate 10–c (17.5 mmol) or
sodium (2Z)-aryl(arylhydrazono)acetate 10d–g (17.5 mmol) was
dissolved in DMF (30 mL). 1-Aryl-2-bromoethanone 11a–i (15.8
mmol, 0.9 equiv) was added, and the mixture was stirred for 0.5–20
h at 5–70 °C (TLC monitoring, toluene–EtOAc, 9:1). The mixture
was poured onto ice (300 g). The product was filtered off, washed
with H2O, and dried to give 3a–x in 40–90% yields.
The crude product was purified by dissolving it in acetone and fil-
tering it over charcoal. The acetone was evaporated, and EtOH was
added. The mixture was cooled to 0 °C, and the precipitated product
was filtered off and dried in a vacuum drier, see Table 1 and Table
6 (Supporting Information).
2-Aryl-2-oxoethyl 1H-Indole-2-carboxylates 12;
General Procedure
2-Aryl-2-oxoethyl (2E)-(2-arylhydrazono)propanoate 3a–i,k,l
(5.86 mmol) was dissolved in TFA (20 mL), PPA, or BF3·OEt2 in
toluene. The mixture stirred at 100 °C for 20–40 min. When the re-
action was complete (TLC monitoring, n-hexanes–EtOAc, 7:3), the
mixture was poured onto ice (500 g). The precipitated solid was fil-
tered off, washed with H2O, and dried in vacuo at 60 °C. The isolat-
ed compounds 12a–i,k,l were purified by crystallization (EtOH) or
by column chromatography (n-hexanes–EtOAc, 7:3), see Table 2
and Table 7 (Supporting Information).
The isomers of esters 3 were isolated as impurities from the mother
liquor by crystallization (3j) or by column chromatography (tolu-
ene–EtOAc, 9:1) (3c,h,i,k,l,x).
2-Oxo-2-phenylethyl (2E)-Phenyl(phenylhydrazono)acetate
[(E)-3m]
2-Oxo-2-phenylethyl (2Z)-phenyl(phenylhydrazono)acetate [(Z)-
3m, 13.9 mmol] was dissolved in TFA (50.0 mL). The mixture was
stirred for 3 h at 25 °C (Table 1, entry 19). Then, the mixture was
poured into a mixture of ice and H2O (500 g). The precipitated solid
was filtered off, washed with H2O, and dried. The isolated product
was recrystallized (EtOH), see Table 1 (entry 19) and Table 6
(Supporting Information).
4-Arylpyrano[4,3-b]indole-1(5H)-ones 13 and 4-Aryl-1H-
[1,4]oxazino[4,3-a]indole-1-ones 14; General Procedure
Propanoate 3a–i,k,l (6.1 mmol) was dissolved in TFA (40.0 mL),
and the mixture was heated to reflux until consumption of the start-
ing material (HPLC monitoring). When the reaction was complete,
the mixture was poured onto ice (500 g). The precipitated solid was
filtered off, washed with H2O, and dried. The products were sepa-
rated by column chromatography (silica gel, toluene–EtOAc, 9:1).
The isolated products 13 and 14 were then crystallized (EtOH), see
13a–i and 14a–i,k,l (Table 2), and 13a–i (Table 8) and 14a–i,k,l
(Table 9) (Supporting Information).
2-Oxo-2-phenylethyl (2E)-[(6-Chloropyridin-2-yl)hydrazo-
no]phenylacetate [(E)-3r]
2-Oxo-2-phenylethyl (2Z)-[(6-chloropyridin-2-yl)hydrazono]phen-
ylacetate [(Z)-3r, 13.9 mmol] was dissolved in PPA (50.0 g). The
mixture was stirred for 5.5 h at 70 °C (Table 1, entry 25). Then, the
mixture was poured into a mixture of ice and H2O (500 g). The pre-
cipitated solid was filtered off, washed with H2O, and dried. The
isolated product was recrystallized (EtOH), see Table 1 (entry 25)
and Table 6 (Supporting Information).
Acknowledgment
This project was supported in part by the Ministry of Education,
Youth and Sport of the Czech Republic (grants MSM6198959216
and ME09057) and FM EEA/Norska (A/CZ0046/1/0022).
Arylglyoxalic Acid Derivatives 8d–g; General Procedure9,10
NaCN (9.8 g, 200 mmol) was dissolved in H2O (34 mL). Aldehyde
derivative 5d–g (200 mmol) and ice (50.0 g) were added, and the
mixture stirred for 5 min at r.t. Then, a mixture of sodium disulfite
(19.0 g, 200 mmol) in H2O (50 mL) was added, and the mixture
stirred for 1 h at this temperature. Cyanohydrin derivatives 6d–g
were filtered off or the organic layer was separated, and the deriva-
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.SnoIufproi
m
tgioSrantnugIifoop
r
itmnatr
tives were used in the next step without purification. Cyanohydrin References
6d–g was dissolved in aq 36% HCl (120.0 mL) and stirred for 12 h
(1) Hradil, P.; Vaněček, J.; Hlaváč, J.; Ševčík, J. Collect. Czech.
Chem. Commun. 1999, 64, 257.
(2) Hradil, P.; Krejčí, P.; Hlaváč, J.; Wiedermannová, I.; Lyčka,
A.; Bertolasi, V. J. Heterocycl. Chem. 2004, 41, 375.
(3) Hradil, P.; Jirman, J. Collect. Czech. Chem. Commun. 1995,
60, 1375.
(4) Soural, M.; Hlaváč, J.; Hradil, P.; Fryšová, I.; Hajdúch, M.;
Bertolasi, V.; Maloň, M. Eur. J. Med. Chem. 2006, 41, 467.
(5) Hradil, P.; Hlaváč, J.; Lemr, K. J. Heterocycl. Chem. 1999,
36, 141.
(6) Lopez, S. E.; Rosales, M. E.; Salazar, J.; Urdaneta, N.;
Ferrer, R.; Angel, J. E. Heterocycl. Commun. 2003, 9, 345.
(7) Hradil, P.; Grepl, M.; Hlavac, J.; Soural, M.; Malon, M.;
Bertolasi, V. J. Org. Chem. 2006, 71, 819.
at 25 °C. Then, the mixture was concentrated in vacuo. The residue
was extracted into hot toluene (3 × 100 mL). The toluene layer was
evaporated in vacuo, and the oily residue containing hydroxy acid
derivative 7d–g was used in the next step without purification. The
oily residue was suspended in H2O (18.0 mL), and NaOH (3.95 g,
98.75 mmol) in H2O (18 mL) and ice (70.0 g) were added. The mix-
ture was cooled in an ice–salt bath and KMnO4 (31.6 g, 200 mmol)
was added in small portions over a period of 0.5 h at –4 to –2 °C.
Then, the reaction was kept at 0 °C for 1.5 h. At the end of the reac-
tion, the excess KMnO4 was destroyed with sodium sulfite. The
mixture was filtered off, and the filtrate was acidified to pH 1 using
aq 36% HCl. The filtrate was extracted into Et2O (3 × 100 mL),
dried (Na2SO4) and concentrated using a rotary evaporator. Phenyl-
glyoxalic acids 8d–g were obtained as yellowish oils and were used
in the next step without purification (Table 4).
(8) Hradil, P.; Hlaváč, J.; Soural, M.; Hajdúch, M.; Kolář, M.;
Večeřová, R. Mini-Rev. Med. Chem. 2009, 9, 696.
(9) Mělnický, R.; Kvapil, L.; Šlézar, P.; Grepl, M.; Hlaváč, J.;
Lyčka, A.; Hradil, P. J. Heterocycl. Chem. 2008, 45, 1.
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(10) Corson, B. B.; Dodge, A.; Harris, S. A.; Yeaw, J. S. Org.
Synth. Coll. Vol. I; John Wiley & Sons: London, 1941, 336.
(11) Corson, B. B.; Dodge, A.; Harris, S. A.; Yeaw, J. S. Org.
Synth. Coll. Vol. I; John Wiley & Sons: London, 1941, 241.
(12) Otwinowski, Z.; Minor, Z. In Methods in Enzymology; Vol.
276, Part A; Carter, C. W.; Sweet, R. M., Eds.; Academic
Press: London, 1977, 307–326.
(13) Altomare, A.; Burla, M. C.; Camalli, M.; Cascarano, G. L.;
Giacovazzo, C.; Guagliardi, A.; Moliterni, A. G.; Polidori,
G.; Spagna, R. J. Appl. Crystallogr. 1999, 32, 115.
(14) Sheldrick, G. M. SHELXL97, Program for Crystal Structure
Refinement; University of Göttingen: Göttingen, 1997.
(15) Nardelli, M. J. Appl. Crystallogr. 1995, 28, 659.
(16) Farrugia, L. J. J. Appl. Crystallogr. 1999, 32, 837.
(17) Burnett, M. N.; Johnson, C. K. ORTEP-III: Oak Ridge
Thermal Ellipsoids Plot Program for Crystal Structure
Illustrations, Oak Ridge National Laboratory Report ORNL-
6895; Oak Ridge National Laboratory: Oak Ridge (TN,
USA), 1996.
(18) Hradil, P.; Mělnický, R.; Grepl, M.; Koristek, K.; Hlaváč, J.;
Bertolasi, V. Heterocycles 2006, 68, 9.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 2447–2457