Synthesis and Intramolecular Azo Coupling of 4-Diazopyrrole-2-carboxylates: Selective Approach to Benzo and Hetero [c]-Fused 6H-Pyrrolo[3,4-c]pyridazine-5-carboxylates

Article abstract of DOI:10.1021/acs.joc.6b01662

A high yield synthesis of fluorescent benzo, thieno, and furo [c]-fused methyl 7-aryl-6H-pyrrolo[3,4-c]pyridazine-5-carboxylates, including unprecedented heterocyclic skeletons, was performed by the transformation of methyl 4-aminopyrrole-2-carboxylate in

Full text of DOI:10.1021/acs.joc.6b01662

Subscriber access provided by Northern Illinois University
Article
Synthesis and intramolecular azo coupling of 4-diazopyrrole-2-
carboxylates: selective approach to benzo and hetero
[c]-fused 6H-pyrrolo[3,4-c]pyridazine-5-carboxylates
Ekaterina E. Galenko, Alexey V. Galenko, Alexander F.
Khlebnikov, Mikhail Sergeevich Novikov, and Julia R. Shakirova
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b01662 • Publication Date (Web): 22 Aug 2016
Downloaded from http://pubs.acs.org on August 23, 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 39
The Journal of Organic Chemistry
1
2
3
Synthesis and intramolecular azo coupling of 4ꢀdiazopyrroleꢀ2ꢀcarboxylates: selective approach to
4
5
benzo and hetero [c]ꢀfused 6Hꢀpyrrolo[3,4ꢀc]pyridazineꢀ5ꢀcarboxylates
6
7
Ekaterina E. Galenko, Alexey V. Galenko, Alexander F. Khlebnikov,* Mikhail S. Novikov,
8
9
Julia R. Shakirova
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
St. Petersburg State University, Institute of Chemistry, 7/9 Universitetskaya nab., St. Petersburg, 199034
Russia
*Corresponding author eꢀmail: a.khlebnikov@spbu.ru
Abstract Graphic
Abstract:
A high yield synthesis of fluorescent benzo, thieno and furo [c]ꢀfused methyl 7ꢀarylꢀ6Hꢀpyrrolo[3,4ꢀ
c]pyridazineꢀ5ꢀcarboxylates, including unprecedented heterocyclic skeletons, was performed by the
transformation of methyl 4ꢀaminopyrroleꢀ2ꢀcarboxylate into the corresponding diazo compound, followed
by intramolecular azo coupling under acid conditions onto a nucleophilic aryl or hetaryl group in the 3ꢀ
position. Azo coupling is completely regioselective and, according to DFT calculations, kinetically
controlled reaction. NꢀMethylation of 1,3ꢀdisubstituted 2Hꢀpyrrolo[3,4ꢀc]cinnolines occurs selectively at
N5 under kinetic control, leading exclusively to 5ꢀmethylꢀ5Hꢀpyrrolo[3,4ꢀc]cinnoline derivatives.
INTRODUCTION
1
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 2 of 39
1
2
3
4
5
6
7
8
9
Diazoazoles have demonstrated high potential for the synthesis of practically useful polynitrogen
compounds.1 Thus, for example, the preparation of temozolomide, 3ꢀmethylꢀ4ꢀoxoimidazo[5,1ꢀ
d][1,2,3,5]tetrazineꢀ8ꢀcarboxamide, which is used as a treatment of some brain cancers,2 involves
reactions of 4ꢀdiazoꢀ4Hꢀimidazoleꢀ5ꢀcarboxamide.3 βꢀAminopyrroles, efficient synthesis of which was
recently described,4 are potentially convenient precursors of βꢀdiazopyrroles 1. Analysis of the literature
showed that while chemistry of βꢀdiazoindoles is developing widely, for example, 6 articles were
published only during 2015,5 the chemistry of βꢀdiazopyrroles was studied only in one work for the same
period.6 Moreover, only about 20 articles were published1d, 7 for the time since the release in 1908 of the
first work7a on βꢀdiazopyrrole chemistry, and this despite the fact that some βꢀdiazopyrroles showed
antimicrobial8 and mutagenic9 activity. One of the reasons for this may be the relative inaccessibility of
the corresponding βꢀaminopyrroles, which are convenient precursors of βꢀdiazopyrroles. With an effective
method for the preparation of alkyl 4ꢀaminopyrroleꢀ2ꢀcarboxylates in hand that allows the introduction of
a variety of aryl and hetaryl substituents at positions 3 and 5,4 we decided to synthesize the corresponding
diazopyrroles 1 with the aim of studying their intramolecular azo coupling. Such azo coupling could
potentially serve as a method for the preparation of 1Hꢀpyrrolo[3,2ꢀc]cinnoline 2, 2Hꢀpyrrolo[3,4ꢀ
c]cinnoline 3, 8Hꢀpyrrolo[3,2ꢀc]thieno[2,3ꢀe]pyridazine 4, 7Hꢀpyrrolo[3,4ꢀc]thieno[2,3ꢀe]pyridazine 5,
7Hꢀfuro[3,2ꢀc]pyrrolo[3,4ꢀe]pyridazine 6, 8Hꢀfuro[3,2ꢀc]pyrrolo[2,3ꢀe]pyridazine 7 and other fused
heterocycles (Scheme 1). It is notable that about thirty substituted 1Hꢀpyrrolo[3,2ꢀc]cinnolines (backbone
2) are known,7e,10 while only three compounds with the skeleton 2Hꢀpyrrolo[3,4ꢀc]cinnoline 3 were
reported: (1,3ꢀdiphenylꢀ, 1,3ꢀdiphenylꢀ2ꢀethylꢀ2Hꢀpyrrolo[3,4ꢀc]cinnoline (8a, 9) and 1,3ꢀdiphenylꢀ5ꢀ
ethylꢀ5Hꢀpyrrolo[3,4ꢀc]cinnoline (10).7a,b,d The remaining mentioned heterocyclic systems are until now
unknown. Meanwhile fused heteroaromatic molecules containing a pyrrole core have a significant
importance in the development of new perspective materials, especially luminophores for bioimaging
applications.11
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
2
ACS Paragon Plus Environment

Page 3 of 39
The Journal of Organic Chemistry
1
2
3
Scheme 1. 4ꢀDiazopyrroleꢀ2ꢀcarboxylates as precursors of fused pyrrolopyridazinecarboxylates
4
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
1,3ꢀDiphenylꢀ2Hꢀpyrrolo[3,4ꢀc]cinnoline 8a was obtained for the first time by prolonged boiling of
diazo compound 11a in 25% sulfuric acid (Scheme 2).7a The formation of the second isomer, 1Hꢀ
pyrrolo[3,2ꢀc]cinnoline 12a as a result of competitive intramolecular azo coupling reaction on the 2ꢀ
phenyl group was not reported.7a,d It has also been shown that compound 8a occurs as the 2Hꢀtautomer,
and its alkylation with EtI/EtONa leads to the formation of only 5ꢀethylꢀ5Hꢀsubstituted tautomer 10
(Scheme 2).7d It is noteworthy that compound 9, 8a, and 10 is yellow, red and blue, respectively.7d Such a
possibility of managing the color of the heterocyclic system by protonation, alkylation, or complexation of
a certain skeletal nitrogen atom of the heterocycle is very useful for their application in modern
technologies.
Scheme 2. Synthesis of pyrrolo[3,4ꢀc]cinnolines 8a, 10
3
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 4 of 39
1
2
3
RESULTS AND DISCUSSION
4
5
6
7
8
9
First we tried to reproduce the intramolecular azo coupling for diazo compound 11a under conditions7a
published in 1908 to make sure that the reaction actually proceeds selectively. The synthesis of
aminopyrrole 14a was carried out according to our method from azirine 15a and the pyridinium salt 16a.4
Aminopyrrole 14a was transformed into diazo compound 11a by treating with excess of sodium nitrite in
acetic acid at about 10 °C for 15 minutes. Diazo compound 11b, without the 5ꢀphenyl group, was
synthesized analogously (Scheme 3).
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 structure of 3ꢀdiazopyrroles has virtually not been investigated by Xꢀray analysis, probably because
of difficulties in obtaining suitable crystals.1d The only, but very inaccurate, structural data was mentioned
in a review1d for 4ꢀacetylꢀ3ꢀdiazoꢀ2,5ꢀdiphenylpyrrole. Moreover, 4ꢀacetylꢀ5ꢀmethylꢀ2ꢀphenylꢀ1Hꢀpyrroleꢀ
3ꢀdiazonium nitrate instead of the corresponding diazopyrrole was obtained under diazotization of 3ꢀ
acetylꢀ4ꢀaminoꢀ2ꢀmethylꢀ5ꢀphenylꢀ1Hꢀpyrrole with NaNO2/AcOH.6 Taking all this into account, crystals
of 11a, suitable for performing a single crystal Xꢀray analysis, were grown and the Xꢀray study was
performed (see Supporting Information) to be sure of the diazopyrrole structure. The selected Xꢀray
structural data for 11a, as well as the corresponding data for the mentioned compounds, available from the
publications1d,6 are listed in Table 1. The N1ꢀC2and C3ꢀN6 bond in diazopyrrole 11a are much shorter than
the corresponding bonds in the 1Hꢀpyrroleꢀ3ꢀdiazonium nitrate, however the N6ꢀN7 in the diazo compound
is much longer. The CNN fragment of diazo compound 11a has linear geometry. The Xꢀray bond length
and angle are in good accordance with the corresponding data from DFT B3LYP/6ꢀ31+g(d,p)
calculations.
Refluxing compound 11a in 25% sulfuric acid for 8 days resulted in the formation of cinnoline 8a
isolated in 72% yield. Analysis of the reaction by TLC and NMR showed the absence of a second possible
isomer.
4
ACS Paragon Plus Environment

Page 5 of 39
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Table 1. The selected structural data for 3ꢀdiazopyrrole derivatives
Bond
length, Å;
bond
11a
[B3LYP/6ꢀ
31+g(d,p)]
angle,
grad
l1ꢀ2
l2ꢀ3
l3ꢀ4
l4ꢀ5
l5ꢀ1
l3ꢀ6
l6ꢀ7
a3ꢀ6ꢀ7
1.315(2)
1.442(2)
1.437(2)
1.385(2)
1.400(1)
1.324(2)
1.129(2)
179.3(1)
1.315
1.459
1.452
1.390
1.395
1.313
1.136
179.3
ꢀ
1.352(3)
1.381(3)
1.433(3)
1.366(3)
1.375(3)
1.353(3)
1.101(3)
179.1(3)
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
ꢀ
ꢀ
ꢀ
ꢀ
1.31(3)
1.13(3)
171(1)
Use of 20% aq HBF4 or glacial acetic acid in place of 25% aq sulfuric acid did not lead to a reduction of
the reaction time or to an increase of the reaction yield (55 and 57%, respectively).
Scheme 3. Synthesis and reactivity of diazopyrroles 11a,b
An attempt to synthesize the 1ꢀunsubstituted analogue 8b by intramolecular azo coupling of diazo
compound 11b under the same conditions resulted in the formation of a complex mixture of unidentified
products and significant resinification of the reaction mixture. To clarify the reasons for the selectivity of
cyclization of diazo compound 11a and the failure in the synthesis of pyrrolocinnoline 8b the DFT
5
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 39
1
2
3
4
5
6
7
8
9
calculations of cyclization of the corresponding diazonium cations 11’ were performed (Fig. 1). According
to the calculation results the barrier for the cyclization of the diazonium cation 11’a, generated from diazo
compound 11a, on the 4ꢀPh group, leading eventually to the formation of compound 8a, is 4.8 kcal/mol
lower than the barrier for the cyclization on the 2ꢀPh group (product 12a). This difference is large enough
to provide complete selectivity of the intramolecular azo coupling. The minimal barrier for the cyclization
of diazonium cation 11’b (from diazo compound 8b) is 1.7 kcal/mol higher than that of diazonium cation
11’a. This should result in a relatively lower rate of intramolecular reaction of diazo compound 8b, but it
should not principally change the reactivity. At the same time, unlike compound 8a, compound 8b is able
to enter into intermolecular azo coupling on the unsubstituted position of the pyrrole ring. For example,
the intermolecular reaction of 2,5ꢀdiphenylpyrroleꢀ3ꢀdiazonium chloride with αꢀunsubstituted pyrroles,
leading to the corresponding azo compounds, have been implemented by Kreutzberg and Kalter.7c
Formation of a complex mixture of products and resinification of the reaction mixture in the case of
compound 11b is therefore most likely due to the occurrence of intermolecular azo coupling leading to
oligomeric products.
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
Fig. 1. Energy profiles for the intramolecular azo coupling of diazonium cations 11’. Relative free Gibbs
energies (in kcal mol–1, 298 K, PCM model for H2O) computed at the B3LYP/6ꢀ31+g(d,p) level.
6
ACS Paragon Plus Environment

Page 7 of 39
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
From this standpoint, the use of diazo compounds 1, containing substituents in the 2,3,5ꢀpositions, as
starting material for intramolecular azo coupling is promising. The presence of a methoxycarbonyl group
could potentially preclude the implementation of the intramolecular azo coupling in the harsh reaction
conditions mentioned above, due to hydrolysis or decarboxylation of the ester group. To outline the ways
of rational choice of diazo compounds 1 for selective intramolecular azo coupling, we performed DFT
calculations for the cyclization of diazonium cations 1’ (Fig. 2).
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
Fig. 2. Energy profiles for the intramolecular azo coupling of diazonium cations 1’. Relative free Gibbs
energies (in kcal mol–1, 298 K, PCM model for H2O) computed at the B3LYP/6ꢀ31+g(d,p) level.
According to the calculation the barrier for cyclization of diazonium cation 1', generated from diazo
compound 1a (R = Ph), on the 3ꢀPh group, leading to intermediate 17, is 5.1 kcal/mol lower than the
barrier for cyclization on the 5ꢀPh group (intermediate 21). This difference should provide the selective
cyclization onto the 3ꢀPh exclusively. On the other hand, the barrier for the formation of intermediate 17
from 1'a is little higher than that for the cyclization of diazonium cation 11’a into 8’a. From the latter it
follows that the diazonium cation 1'a needs even harsher conditions for the cyclization than 11'a. This
may make it impossible the intramolecular azo coupling starting from compound 1a, which is potentially
7
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 8 of 39
1
2
3
4
5
6
7
8
9
less stable in boiling acid due to the ester group. Since the azo coupling is an electrophilic reaction, an
introduction of an electron donating group into the respective benzene ring or replacement of the phenyl
group with a more nucleophilic group should lead to a reduction of the cyclization barrier, thus decreasing
the reaction time and increasing the probability of obtaining the desired products. According to the
calculation, the introduction of a metaꢀmethoxy group into the 3ꢀphenyl substituent or replacing the 3ꢀ
phenyl group with the thiopheneꢀ2ꢀyl or furꢀ2ꢀyl group significantly reduces the cyclization barrier.
Similar changes with the 5ꢀphenyl substituent also lead to lowering the respective barriers, which
however, are still higher than that for the cyclization on the identical aryl/hetaryl substituent at the 3ꢀ
position of diazo compound 1. Then diazo compounds 25a,b were synthesized (vide infra) and introduced
into the azo coupling reaction in order to check reliability of our theoretical predictions for the rational
design of pyrrolo[3,4ꢀc]pyridazine systems.
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
Scheme 4. Intramolecular azo coupling of diazopyrroles 25a,b
Refluxing of the solution of diazo compound 25a in 25% aqueous sulfuric acid during 4 d was required
for the complete consumption of the starting material. This was accompanied by intensive resinification of
1
the reaction mixture and afforded only trace amounts of cinnoline 26a (according to H NMR
spectroscopy of the reaction mixture). In contrast, cyclization of diazo 25b proceeded 5 times faster than
the cyclization of diazo compound 11a under the same conditions and cinnoline 26b was isolated in
80%yield (Scheme 4).
Based on the above theoretical and experimental results, we synthesized a series of diazo pyrroles 25
(Table 2), containing 3ꢀarylꢀ and hetarylꢀsubstituents which are suitable for intramolecular azo coupling.
8
ACS Paragon Plus Environment

Page 9 of 39
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Pyrroles 28aꢀj were prepared in oneꢀpot mode by the reaction of 5ꢀmethoxyisoxazoles 27aꢀd with
pyridinium ylides 16aꢀd under relay catalysis with FeCl2/Et3N leading to 1ꢀ(5ꢀmethoxycarbonylꢀ1Hꢀ
pyrrolꢀ3ꢀyl)pyridinium salts, followed by hydrazinolysis, according to published procedure (Table 2).4 All
new compounds were characterized by 1H and 13C NMR, IR spectroscopy, and massꢀspectrometry.
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 2. Synthesis of 4ꢀaminopyrroles 28aꢀj and 4ꢀdiazopyrroles 25aꢀj
Entry R1
R2
27+16
28, yield %
25, yield %
a, 89
1
Ph
Ph
a, 63
27a+16a
2
3ꢀMeOC6H4
3ꢀMeOC6H4
3ꢀMeOC6H4
3ꢀMeOC6H4
thiophenꢀ2ꢀyl
thiophenꢀ2ꢀyl
thiophenꢀ2ꢀyl
thiophenꢀ2ꢀyl
benzofuranꢀ2ꢀyl
Ph
b, 67
c, 78
d, 47
e, 58
f, 47
g, 52
h, 71
i, 15
j, 44
b, 76
c, 98
d, 88
e, 99
f, 94
g, 92
h, 79
i, 99
j, 84
27b+16a
27b+16b
27b+16c
27b+16d
27c+16a
27c+16b
27c+16c
27c+16d
27d+16a
3
4ꢀBrC6H4
4ꢀMeOC6H4
4ꢀNO2C6H4
Ph
4
5
6
7
4ꢀBrC6H4
4ꢀMeOC6H4
4ꢀNO2C6H4
Ph
8
9
10
The oneꢀpot procedure for the preparation of 4ꢀaminopyrrolole 28k having a benzo[b]thiophenꢀ2ꢀyl
substituent at the C3 atom gave unsatisfactory results, and therefore this compound was synthesized in a
stepwise manner (Scheme 5).4,12
9
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 10 of 39
1
2
3
Scheme 5. Stepwise synthesis of diazopyrrole 28k
4
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
Aminopyrroles 28 were easily converted into diazopyrroles 25 by the reaction with sodium nitrite in
acetic acid (Table 3). The reaction is completed within 15 minutes at a temperature of about 10 °C to give
3ꢀdiazopyrroles 25aꢀj in high yields. Diazopyrroles are usually bright orange crystals that are stable in the
solid state in the absence of light. Compound 25k with 3ꢀ(benzo[b]thiophenꢀ2ꢀyl) substituent was not
isolated in pure form. According to NMR, the reaction mixture along with the diazotization product
contained a significant amount of the intramolecular azo coupling product. Apparently the activation
barrier for the azo coupling reaction in this case is sufficiently low and the reaction proceeds already in
acetic acid at low temperature.
The cyclization of diazopyrroles 25 to pyrrolo[3,4ꢀc]pyridazines 26cꢀk was performed by refluxing
solutions of the diazopyrroles in 25% sulfuric acid. Typically, the reaction requires 30ꢀ36 h, except the
synthesis of compound 26k, which requires only 0.5 h. Compounds 26bꢀk were isolated in good yields by
a simple workup: the sulphate salt of the product was filtered off, converted to free base by suspending in
an aqueous sodium bicarbonate solution, the base obtained was filtered, washed with water and dried
(Table 3). Pyrrolo[3,4ꢀc]pyridazines 26 are solid, coloured, highꢀmelting compounds .
10
ACS Paragon Plus Environment

Page 11 of 39
The Journal of Organic Chemistry
1
2
3
Table 3. Synthesis of pyrrolo[3,4ꢀc]pyridazines 26
4
5
6
7
8
9
10
11
12
13
OMe
R1
S
O
S
N
N
N
N
N
N
N
N
25% H2SO4
reflux
,
N2
CO2Me
,
,
CO2Me
CO2Me
CO2Me
CO2Me
N
R2
NH
26b e
NH
NH
NH
R2
R2
R2
R2
25a k
26f i
26j
26k
Entry R1
Ph
R2
25
26, yield %
a, 0
1
Ph
a
b
c
d
e
f
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
2
3ꢀMeOC6H4
3ꢀMeOC6H4
3ꢀMeOC6H4
3ꢀMeOC6H4
thiophenꢀ2ꢀyl
thiophenꢀ2ꢀyl
thiophenꢀ2ꢀyl
thiophenꢀ2ꢀyl
benzofuranꢀ2ꢀyl
Ph
b, 80
c, 85
3
4ꢀBrC6H4
4ꢀMeOC6H4
4ꢀNO2C6H4
Ph
4
d, 73
e, 84
5
6
f, 70
7
4ꢀBrC6H4
4ꢀMeOC6H4
4ꢀNO2C6H4
Ph
g, 89
h, 61
i, 82
g
h
i
8
9
10
11
j, 94
j
benzo[b]thiophenꢀ2ꢀyl 4ꢀBrC6H4
k, 79
k
Compounds 26 may in principle exist in the three tautomeric forms, as shown in the scheme 6.
Scheme 6. Tautomeric forms of compounds 26b,f,j
According to calculations (Table 4) the tautomer with hydrogen at the pyrrole nitrogen is much more
stable than the other two tautomers in solution. The most stable tautomers (26bꢀ2H, 26fꢀ7H, 26jꢀ2H) have
11
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 12 of 39
1
2
3
4
5
also a longꢀwave maximum at ~400 nm in the visible absorption spectra whereas tautomers 26bꢀ4H, 26fꢀ
4H, 26jꢀ4H and 26bꢀ5H, 26fꢀ2H, 26jꢀ5H have a maximum at ~550 and ~ 530 nm, respectively (Table 4).
6
7
8
9
Table 4. Relative free Gibbs energies (298K), the longꢀwave maximums and the oscillator strengths
of tautomers 26b,f,j, (DFT and TDꢀDFT B3LYP/6ꢀ31+g(d,p), PCM model for the corresponding
solvents)
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
EtOH
λmax, nm; f
MeOH
λmax, nm; f
CH2Cl2
λmax, nm; f
rel ꢁG,
kcal/mol
0.0
rel ꢁG,
kcal/mol
0.0
rel ꢁG,
kcal/mol
0.0
392; 0.478
569; 0.089
527; 0.254
403; 0.317
563; 0.044
533; 0.165
404; 0.356
540; 0.075
524; 0.269
392; 0.468
568; 0.088
525; 0.250
402; 0.309
562; 0.043
527; 0.163
404; 0.349
539; 0.074
522; 0.269
393; 0.509
578; 0.090
534; 0.260
402; 0.338
569; 0.044
534; 0.169
405; 0.374
546; 0.075
533; 0.281
26bꢀ2H
26bꢀ4H
26bꢀ5H
26fꢀ7H
26fꢀ5H
26fꢀ4H
26jꢀ2H
26jꢀ4H
26jꢀ5H
9.6
5.3
0.0
7.5
4.0
0.0
6.2
4.8
9.5
5.2
0.0
7.5
3.9
0.0
6.2
4.8
9.8
5.4
0.0
7.7
4.6
0.0
6.4
4.7
UVꢀVIS spectra in the region 230ꢀ700 nm for dichloromethane solutions of compounds 26b,f,j are
shown in Fig. 3. The longꢀwave absorption band maxima of compounds 26b,f,j are at 392, 401, 403 nm,
respectively (Table 5). This is in accordance with the results of TDꢀDFT B3LYP/6ꢀ31+g(d,p) calculations
for the electronic transition from the HOMO to the LUMO of the most stable tautomers 26bꢀ2H, 26fꢀ7H,
26jꢀ2H in dichloromethane (Table 4).
12
ACS Paragon Plus Environment

Page 13 of 39
The Journal of Organic Chemistry
1
2
3
4
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
Fig. 3. UVꢀVIS spectra of compounds 26b,f,j in dichloromethane.
The compounds 26 are luminescent in solution. The photophysical data are given in Table 5 and
representative examples of excitation and emission spectra are depicted in Fig. 4. Typically small values
of Stokes shifts, together with excited state lifetime in nanosecond domain, clearly indicate that the
emission observed originates from the singlet excited state, i.e. fluorescence.
Fig. 4. Room temperature excitation and emission spectra of 26b,f,j in dichloromethane.
13
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 14 of 39
1
2
3
4
5
6
7
8
9
It was found that the fluorescence properties of 26b,c,d,e are sensitive to the substituent in the para
position of the phenyl group (Fig. 5, Table 5). The Brꢀsubstituent does not change the position of the
emission maxima but increases the fluorescence quantum yield. The MeO and NO2 substituents shift
emission to redder wavelengths by 29 or 74 nm, respectively, and increase the fluorescence quantum yield
more than an order of magnitude.
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
Fig. 5. Room temperature excitation and emission spectra of 26b,c,d,e in dichloromethane.
Table 5. Photophysical characteristics of 26b,c,d,e,f,j and 26bꢀ5Me in dichloromethane solutions at
room temperature, λex = 383ꢀ415 nm (corresponds to the most wavelength maximum of excitation
spectrum). Lifetimes (τ) were measured at λmax of the emission bands
Compound Absorbance,
Emission Excitation
λmax, nm λmax, nm
τ,
ns
QY,
%
λ
max, nm (ε, 103·M−1·cm−1)
271 (29), 297 (16), 353 (12), 475
272, 297, 350, 363, 2.23
2.07
26b
26c
26d
26e
364 (13), 392 (12)
390
276 (34), 302 (17), 346 (12), 475
365 (14), 395 (14)
274, 298, 349, 364, 0.58
11.37
28.23
26.19
393
277 (27), 302 (15), 356 (11), 504
370 (12), 401 (11)
275, 298, 356, 367, 6.10
400
298 (15), 371 (11), 413 (22), 549
436 (18)
295, 375, 415
2.44
14
ACS Paragon Plus Environment

Page 15 of 39
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
272 (17), 293(19), 335 (6),
350 (5), 401 (6)
478
273, 292, 333, 344, 2.13
11.05
16.72
1.86
26f
403
260 (22), 290 (25), 299 (26), 473
331 (8), 347 (6), 403 (5)
291, 297, 336, 348, 3.36
26j
408
257 (29), 281 (21), 297 (18), 482
335 (10), 345 (13), 371 (5),
397 (4), 533 (6)
268, 291, 341, 359, 2.71
383
26bꢀ5Me
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
Fixing other tautomeric forms of the compounds 26, which should have significantly different VIS
properties from the most stable, may be realized by alkylation of the nitrogens of the pyridazine fragment
of 26. Alkylation of pyrrolocinnoline 8a, existing in 2Hꢀtautomeric form, proceeded selectively under the
action of EtI/EtONa in EtOH and led to the formation of the 5ꢀethylꢀ5Hꢀtautomer 10.7a To understand the
reasons for this selectivity and to evaluate the prospects of the selective alkylation of compounds 26, we
performed DFT calculations for the model compounds listed in the Table 6.
Table 6. Relative free Gibbs energies (298K) of tautomers 8a, 26b, their Meꢀderivatives 8aꢀnMe,
26bꢀnMe (DFT B3LYP/6ꢀ31+g(d,p), PCM for MeOH) and barrier for nucleophilic substitution of
Br in MeBr with anion derived from 8a or 26b (DFT B3LYP/6ꢀ31+g(d,p){CNH}/LANL2DZ{Br},
298K, PCM for MeOH)
Compound
rel ꢁG,
kcal/mol
0.0
Compound
rel ꢁG,
kcal/mol
0.0
rel ꢁG#,
kcal/mol
33.3
2Hꢀtautomer
4Hꢀtautomer
5Hꢀtautomer
2Hꢀtautomer
4Hꢀtautomer
5Hꢀtautomer
8aꢀ2H
8aꢀ2Me
8aꢀ4Me
8aꢀ5Me
26bꢀ2Me
26bꢀ4Me
26bꢀ5Me
10.7
3.7
0.0
9.5
5.2
8.1
0.3
2.2
5.2
0
34.6
31.1
34.4
34.9
30.6
8aꢀ4H
8aꢀ5H
26bꢀ2H
26bꢀ4H
26bꢀ5H
The existence of pyrroloсinnoline 8a as 2Hꢀtautomer corresponds to its greater stability compared with
5Hꢀ and 4Hꢀ tautomers (Table 6). Since the relative thermodynamic stabilities of 2ꢀmethylꢀ1,3ꢀdiphenylꢀ
2Hꢀpyrrolo[3,4ꢀc]cinnoline 8aꢀ2Me and 5ꢀmethylꢀ1,3ꢀdiphenylꢀ5Hꢀpyrrolo[3,4ꢀc]cinnoline 8aꢀ5Me are
15
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 16 of 39
1
2
3
4
5
6
7
8
9
almost equal (Table 6), the selective alkylation the cinnoline N5 atom is a kinetically controlled process.
The DFT calculations of the thermodynamic parameters for the reaction of MeBr with the anion, formed
from pyrroloсinnoline 8a under deprotonation, showed that the free Gibbs energies of the transition states
for N2 and N4 alkylation were by 2.2 and 3.5 kcal/mol greater than for N5 alkylation and ensures the
dominant alkylation of the N5 atom of the backbone (Table 6). This result can be explained by steric
hindrances for attack of the alkylating agent caused by the Phꢀgroups in the case of N2 attack and by the
3ꢀPhꢀgroup in the case of N4 attack (Table S8, Supporting Information). In accordance with the
calculation results methylation of 8a by MeI/MeONa in MeOH gave 8aꢀ5Me as the only product (Scheme
7).
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
Scheme 7. Methylation of cinnolines 8a, 26b,c
Replacing the 1ꢀPh group with a CO2Me group when passing from compound 8a to compounds 26 can
potentially alter the selectivity of the alkylation. The DFT calculation showed, however, that the free
Gibbs energy of the transition states of N2ꢀ and N4ꢀmethylation of the anion, formed by deprotonation of
26b, with MeBr are 3.8 and 4.3 kcal/mol greater than that for N5ꢀmethylation and that ensures complete
selectivity of the reaction. Increasing energy of the transition states under the attack N2 and N4 on MeBr
is caused by obstacles for the approach of the alkylating agent, created by the Ph and the MeO2C groups in
the case of N2, and the 3ꢀPhꢀgroup in the case of N4 (Table S8, Supporting Information). Methylation of
16
ACS Paragon Plus Environment

Page 17 of 39
The Journal of Organic Chemistry
1
2
3
4
5
6
7
pyrroloсinnoline 26b by MeI/MeONa in MeOH in accordance with the theoretical prediction led to the
isolation of compound 26bꢀ5Me as the only product (Scheme 7). The structure of the alkylation product
was proven by 2DꢀNOESY.
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
Fig. 6. UVꢀVIS spectra of compounds 26b and 26bꢀ5Me in dichloromethane.
Since the alkylation of compound 26b occurs at the N5, a substantial change of the electronic structure
takes place. This is reflected in the difference between both the structure and the energies of HOMO and
LUMO of the compounds 26b and 26bꢀ5Me. Fixing the 5Hꢀtautomer of compound 26b via methylation
increases the energy of the HOMO and lowers the LUMO energy in the compound 26bꢀ5Me, the latter
changes larger than the former. From a comparison of FMO energies of compounds 26bꢀ5H and 26bꢀ5Me
(Table S9, Supporting Information) it can be concluded, that this change is not an effect of a methyl
group. As a result, the alkylation should lead to a large bathochromic shift of the longꢀwave band in the
absorption spectrum (Table 4), which is observed experimentally (533 nm 26bꢀ5Me compared to 392 nm
26b) (Fig. 6).
17
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 18 of 39
1
2
3
In conclusion:
4
5
6
7
8
9
Methyl 4ꢀaminopyrroleꢀ2ꢀcarboxylates are excellent precursors of methyl 4ꢀdiazopyrroleꢀ2ꢀcarboxylates.
According to DFT calculations cyclization of the diazonium cations derived from 4ꢀdiazopyrroleꢀ2ꢀ
carboxylates in acid should proceed selectively on the nucleophilic 3ꢀaryl/heteroaryl group rather than on
the same group in the 5ꢀposition of the pyrrole ring. This led to the easy performing high yield synthesis
of benzo, thieno and furo [c]ꢀfused 7ꢀarylꢀ6Hꢀpyrrolo[3,4ꢀc]pyridazineꢀ5ꢀcarboxylates, including first
representatives of new heterocyclic systems, from the corresponding 4ꢀdiazopyrroleꢀ2ꢀcarboxylates. The
synthesised derivatives of pyrrolo[3,4ꢀc]pyridazine fluoresce in solutions. NꢀMethylation of 1,3ꢀ
disubstituted 2Hꢀpyrrolo[3,4ꢀc]cinnolines, which occurs selectively at N5 under kinetic control, leads to a
large bathochromic shift of the longꢀwave band in the VIS absorption spectra.
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
EXPERIMENTAL SECTION
General Information and Methods. Melting points were determined on a capillary melting point
1
apparatus. H (400 MHz) and 13C (100 MHz) NMR spectra were determined in CDCl3 and DMSOꢀd6.
Chemical shifts (δ) are reported in parts per million downfield from tetramethylsilane (TMS δ = 0.00). 1H
NMR spectra were calibrated according to the residual peak of CDCl3 (7.26 ppm) or DMSOꢀd6 (2.50
13
13
ppm). For all new compounds C{1H} and C DEPT135 were recorded and calibrated according to the
peak of CDCl3 (77.00 ppm) or DMSOꢀd6 (39.51 ppm). Mass spectra were recorded on a HRMSꢀESIꢀ
QTOF, electrospray ionization, positive mode. IRꢀspectra were recorded for tablets in KBr, only
characteristic absorption is indicated. The photophysical measurements in solution were carried out using
CH2Cl2, which was distilled prior to use. UV/Vis spectra were recorded on a UVꢀspectrophotometer
Emission and excitation spectra in solution were recorded on a spectrofluorimeter. The absolute emission
quantum yield in solutions was determined by a comparative method. Fluorescence lifetimes were
determined by the TCSPC (TimeꢀCorrelated Single Photon Counting) method. The lifetime data were fit
18
ACS Paragon Plus Environment

Page 19 of 39
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
using the JobinꢀYvon software package. Direct quantum yield measurements of the samples were
performed at room temperature with an integrating sphere. Single crystal Xꢀray diffraction experiment
was performed on diffractometer at 100K using monochromated CuKα radiation. Thinꢀlayer
chromatography (TLC) was conducted on aluminium sheets with 0.2 mm silica gel with fluorescent
indicator. Synthesis of 3ꢀsubstitutedꢀ3ꢀoxopropanoates was performed according to published procedure.13
Methyl 3ꢀ(benzo[b]thiophenꢀ2ꢀyl)ꢀ3ꢀoxopropanoate (30). A hexane solution of BuLi (2.5 М, 20.8 mL,
52 mmol) was added to a solution of DIPA (3.85 g, 52 mmol) in absolute THF (10 mL) at ꢀ78 °С under an
argon atmosphere and the mixture was stirred for 10 min. Methyl acetate (3.85 g, 52 mmol), and then,
after an additional 10 min, a solution of methyl benzo[b]thiophenꢀ2ꢀcarboxylate (5.00 g, 26 mmol) in
absolute THF (20 mL) was added. The reaction mixture was stirred for 30 min and quenched by saturated
aqueous NH4Cl. The organic layer was separated and the water layer extracted with ether (30 mL). The
combined organic solution was washed with brine and dried over Na2SO4. The solvents were evaporated
and the residue purified by column chromatography on silica gel (light petroleum/EtOAc 6:1). Light
yellow oil, 4.21 g (69%, 97% on consumed methyl benzo[b]thiophenꢀ2ꢀcarboxylate). 1Н NMR (CDCl3): δ
= 3.76 (s, 3Н), 4.03 (s, 2Н), 7.39ꢀ7.46 (m, 1Н), 7.46ꢀ7.50 (m, 1Н), 7.85ꢀ7.91 (m, 2Н), 7.98 (s, 1Н).
Spectrum demonstrated the presence of about 8 % of the enol form with characteristic signals δ = 5.65 (s,
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
1H) и 12.35 (s, 1H) – СH and ОH. C NMR (CDCl3): δ = 46.1 (СН2), 52.6 (СН3), 122.9 (СН), 125.2
(СН), 126.2 (СН), 127.9 (СН), 130.6 (СН), 138.9 (С), 142.5 (С), 142.9 (С), 167.2 (С), 186.2 (С).
ESI/HRMS (m/z): 235.0423 calcd for C12Н11O3S [M + H]+, found 235.0419. IR (KBr, cmꢀ1): ν 3469,
2557, 1744, 1667.
General method for 3ꢀarylisoxazolꢀ5ꢀones synthesis.14 A mixture of alkyl 3ꢀarylꢀ3ꢀoxopropanoate (1.00
mol) and H2NOH·HCl (2.50ꢀ3.00 mol, 2.50ꢀ3.00 eq.) in water (100 mL) was brought to boiling while
stirring and boiled for 5 minutes. The mixture was diluted with ethanol (100 mL), and boiled for 40ꢀ60
minutes. After cooling, the precipitate was filtered, washed with a mixture EtOH/H2O 1:1 and dried.
19
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 20 of 39
1
2
3
4
5
6
7
3ꢀ(3ꢀMethoxyphenyl)isoxazolꢀ5(4H)ꢀone (31a). Compound 31a (6.10 g , 87%) was obtained from ethyl
3ꢀ(3ꢀmethoxylphenyl)ꢀ3ꢀoxopropanoate (8.17 g, 36.76 mmol) and H2NOH·HCl (7.70 g, 110.00 mmol).
Colorless solid, mp 112ꢀ113 °С (EtOHꢀH2O). 1Н NMR (CDCl3): δ = 3.78 (s, 2Н), 3.85 (s, 3Н), 7.05ꢀ7.08
8
9
13
(m, 1Н), 7.16ꢀ7.18 (m, 1Н), 7.25ꢀ7.26 (m, 1Н), 7.36ꢀ7.40 (m, 1Н). C NMR (CDCl3): δ = 34.1 (СН2),
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
55.5 (СН3), 111.0 (СН), 118.4 (СН), 119.3 (СН), 128.8 (С), 130.2 (СН), 160.0 (С), 163.0 (С), 174.6 (С).
ESI/HRMS (m/z): 214.0480 calcd for C10Н9NNaO3 [M + Na]+, found 214.0485. IR (KBr, cmꢀ1): ν 2924,
1806.
3ꢀ(Benzofuranꢀ2ꢀyl)isoxazolꢀ5(4H)ꢀone (31b). Compound 31b (1.64 g, 25%) was obtained from ethyl 3ꢀ
(3ꢀbenzofuranꢀ2ꢀyl)ꢀ3ꢀoxopropanoate (7.30 g, 31.4 mmol) and H2NOH·HCl (6.95 g, 100.0 mmol).
1
Colorless solid, mp 140ꢀ165°С (dec.) (EtOH). Н NMR (DMSOꢀd6): δ = 4.33 (br s, 0.6Н), 5.72 (br s,
0.6Н), 7.32ꢀ7.36 (m, 1Н), 7.43ꢀ7.45 (m, 1Н), 7.53ꢀ7.55 (m, 1Н), 7.68ꢀ7.70 (m, 1Н), 7.75ꢀ7.77 (m, 1Н),
13.13 (br s, 0.3Н); tautomer ratio: 1:2. 13С NMR spectrum consisted of very wide signals due to the
tautomeric equilibrium. ESI/HRMS (m/z): 202.0499 calcd for C11Н8NO3 [M + Н]+, found 202.0495. IR
(KBr, cmꢀ1): ν 3108, 1794, 1607.
3ꢀ(Benzo[b]thiophenꢀ2ꢀyl)isoxazolꢀ5(4Н)ꢀone (31c). Compound 31c (2.33 g, 66%) was obtained from
compound 30 (3.90 g, 16.6 mmol) and H2NOH·HCl (3.06 g, 44 mmol) in ethanol (without addition of
water). Colorless solid, mp > 188 °С (dec) (EtOH). 1Н NMR (DMSOꢀd6): δ = 4.41 (br s, 0.95Н), 5.79 (br
s, 0.44Н), 7.45ꢀ7.46 (m, 2Н), 7.95 (pseudoꢀs, 2Н), 8.03ꢀ8.05 (m, 1Н), 13.35 (br s, 0.32Н); tautomer ratio:
1:1. 13С NMR spectrum consisted of very wide signals due to the tautomeric equilibrium. ESI/HRMS
(m/z): 240.0090 calcd for C11Н7NO2S [M + Na]+, found 240.0096. IR (KBr, cmꢀ1): ν 1809, 1792.
General method of 5ꢀmethoxyisoxazoles 27.14 Isoxazolone (1.00 mmol) was added in small portions to a
stirred solution of diazomethane in ether, prepared by reaction of N,Nꢀnitrosomethylcarbamide (2.50ꢀ3.00
mmol, 2.50ꢀ3.00 eq) with KОН (40% water solution). The reaction mixture was stirred for 30 min and
20
ACS Paragon Plus Environment

Page 21 of 39
The Journal of Organic Chemistry
1
2
3
4
5
excess of diazomethane was quenched with acetic acid. The solvent was removed in vacuo and the residue
was purified by column chromatography (light petroleum/EtOAc 6:1 – 4:1).
6
7
8
9
5ꢀMethoxyꢀ3ꢀ(3ꢀmethoxyphenyl)isoxazole (27b). Compound 27b (2.95 g, 74%) was obtained from
compound 31a (3.71 g, 19.40 mmol) and N,Nꢀnitrosomethylcarbamide (6.00 g, 58.00 mmol). Light yellow
oil. 1Н NMR (CDCl3): δ = 3.84 (s, 3Н), 4.03 (s, 3Н), 5.51 (s, 1Н), 6.96ꢀ6.99 (m, 1Н), 7.26ꢀ7.36 (m, 3Н).
13C NMR (CDCl3): δ = 55.3 (СН3), 58.8 (СН3), 75.5 (СН), 111.3 (СН), 116.1 (СН), 119.0 (СН), 129.8
(СН), 130.8 (С), 159.8 (С), 164.1 (С), 174.4 (С). ESI/HRMS (m/z): 228.0632 calcd for C11Н11NNaO3 [M
+ Na]+, found 228.0626. IR (KBr, cmꢀ1): ν 2950, 1615.
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
5ꢀMethoxyꢀ3ꢀ(thiophenꢀ2ꢀyl)isoxazole (27c). Compound 27c (2.98 g, 81%), was obtained from 3ꢀ
(thiophenꢀ2ꢀyl)isoxazolꢀ5(4Н)ꢀone (3.39 g, 20.29 mmol) and N,Nꢀnitrosomethylcarbamide (5.44 g, 53.00
1
mmol). Colorless solid, mp 64ꢀ65 °C (hexaneꢀEtOAc). Н NMR (CDCl3): δ = 4.03 (s, 3Н), 5.47 (s, 1Н),
13
7.08ꢀ7.10 (m, 1Н), 7.39ꢀ7.41 (m, 2Н). C NMR (CDCl3): δ = 58.9 (СН3), 75.6 (СН), 127.2 (СН), 127.4
(СН), 127.5 (СН), 131.3 (С), 159.4 (С), 174.3 (С). ESI/HRMS (m/z): 182.0271 calcd for C8Н8NO2S [M +
H]+, found 182.0269. IR (KBr, cmꢀ1): ν 3134, 1612.
3ꢀ(Benzofuranꢀ2ꢀyl)ꢀ5ꢀmethoxyisoxazole (27d). Compound 27d (535 mg, 99%) was obtained from
compound 31b (503 mg, 2.50 mmol), suspended in THF, and N,Nꢀnitrosomethylcarbamide (620 mg, 6.00
mmol). Colorless solid, mp 92ꢀ95 °C (MeOH). 1Н NMR (CDCl3): δ = 4.07 (s, 3Н), 5.65 (s, 1Н), 7.21ꢀ7.22
(m, 1Н), 7.26ꢀ7.29 (m, 1Н), 7.34ꢀ7.38 (m, 1Н), 7.54ꢀ7.56 (m, 1Н), 7.62ꢀ7.64 (m, 1Н). 13C NMR (CDCl3):
δ = 59.0 (СН3), 75.7 (СН), 106.2 (СН), 111.6 (СН), 121.7 (СН), 123.4 (СН), 125.7 (СН), 127.9 (С),
146.1 (С), 155.1 (С), 156.8 (С), 174.5(С). ESI/HRMS (m/z): 216.0657 calcd for C12Н10NO3 [M + Н]+,
found 216.0660. IR (KBr, cmꢀ1): ν 3121, 2924, 1737, 1621, 1600.
3ꢀ(Benzo[b]thiophenꢀ2ꢀyl)ꢀ5ꢀmethoxyisoxazole (27e). Compound 27e (1.21 g, 86%) was obtained from
compound 31c (1.30 g, 6.00 mmol), suspended in THF, and N,Nꢀnitrosomethylcarbamide (1.61 g, 15.6
1
mmol). Colorless solid, mp 125ꢀ126 °С (MeOH). Н NMR (CDCl3): δ = 4.05 (s, 3Н), 5.58 (s, 1Н), 7.35ꢀ
21
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 22 of 39
1
2
3
4
5
6
7
8
7.40 (m, 2Н), 7.63 (s, 1Н), 7.78ꢀ7.82 (m, 1Н), 7.84ꢀ7.87 (m, 1Н). 13C NMR (CDCl3): δ = 58.9 (СН3), 75.8
(СН), 122.5 (СН), 124.1 (СН), 124.1 (СН), 124.7 (СН), 125.6 (СН), 131.5 (С), 139.2 (С), 140.1 (С),
159.7 (С), 174.5 (С). ESI/HRMS (m/z): 232.0427 calcd for C12Н10NO2S [M + H]+, for 232.0431. IR
(KBr, cmꢀ1): ν 3132, 1614, 1601.
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
Methyl 3ꢀ(benzo[b]thiophenꢀ2ꢀyl)ꢀ2Hꢀazirineꢀ2ꢀcarboxylate (15c) was prepared according to the
published procedure.15 A mixture of compound 27e (880 mg, 3.80 mmol), FeCl2·4H2O (152 mg, 0.76
mmol, 20 mol.%) in absolute acetonitrile (25 mL) was stirred for 20h at room temperature under Ar, then
filtered and the solvent removed in vacuo. The residue was purified by column chromatography (light
1
petroleum/EtOAc 6:1). Colorless solid, 598 mg (68%), mp 101ꢀ102 °С (pentane). Н NMR (CDCl3): δ =
2.97 (s, 1Н), 3.77 (s, 3Н), 7.16ꢀ7.54 (m, 2Н), 7.93 (s, 1Н), 7.93ꢀ7.95 (m, 2Н). 13C NMR (CDCl3): δ = 30.8
(СН), 52.4 (СН3), 122.9 (СН), 124.3 (С), 125.5 (СН), 125.8 (СН), 127.7 (СН), 133.3 (СН), 138.3 (С),
143.5 (C), 153.3 (С), 171.5 (С). ESI/HRMS (m/z): 232.0427 calcd for C12Н10NO2S [M + H]+, found
232.0432. IR (KBr, cmꢀ1): ν 1767, 1721.
Oneꢀpot synthesis of 4ꢀaminopyrroles 28.4 A mixture of isoxazole 27 (1.2ꢀ1.5 mmol),
phenacylpyridinium bromide 16 (1.0 mmol), FeCl2·4H2O (0.06–0.08 mmol, 5 mol.% on isoxazole) and
NEt3 (3.0 mmol, 3 eq) in absolute acetonitrile (4 mL) was stirred at 45 °C for 6ꢀ7 h. (monitoring by TLC).
Hydrazine hydrate (10.0 mmol, 10 eq) was added to the reaction mixture when bromide 16 was
consumed. The mixture was stirred at 45 °C for 6ꢀ7 h until the completion of the reaction (monitoring by
TLC). The solvent was removed in vacuo and the residue was purified by column chromatography
(CH2Cl2 or CH2Cl2/MeOH 40:1).
Methyl 4ꢀaminoꢀ3ꢀ(3ꢀmethoxyphenyl)ꢀ5ꢀphenylꢀ1Нꢀpyrroleꢀ2ꢀcarboxylate (28b). Compound 28b (498
mg, 67%) was obtained from compounds 27b (513 mg, 2.50 mmol), 16a (639 mg, 2.30 mmol),
FeCl2·4H2O (26 mg, 0.13 mmol, 5 mol.%), Et3N (700 mg, 6.90 mmol) and NH2NH2·H2O (1150 mg,
1
23.00 mmol). Light yellow solid, mp 57ꢀ58 °C (hexane). Н NMR (CDCl3): δ = 3.29 (br s, 2Н), 3.72 (s,
22
ACS Paragon Plus Environment

Page 23 of 39
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
3Н), 3.84 (s, 3Н), 6.89ꢀ6.92 (m, 1Н), 7.02ꢀ7.06 (m, 2Н), 7.28ꢀ7.31 (m, 1Н), 7.34ꢀ7.38 (m, 1Н), 7.44ꢀ7.48
(m, 2Н), 7.61ꢀ7.63 (m, 2Н), 8.87 (br s, 1Н). 13C NMR (CDCl3): δ = 51.2 (CH3), 55.3 (CH3), 113.1 (CH),
115.6 (CH), 116.6 (С), 120.7 (С), 121.8 (С), 122.6 (CH), 125.5 (CH), 126.9 (CH), 129.1 (С), 129.16
(CH), 129.22 (CH), 131.7 (С), 134.4 (С), 159.5 (С), 161.5 (С). ESI/HRMS (m/z): 323.1390 calcd for
C19H19N2O3 [M + H]+, found 323.1391. IR (KBr, cmꢀ1): ν 3304, 2952, 1712, 1670, 1604.
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
Methyl
4ꢀaminoꢀ5ꢀ(4ꢀbromophenyl)ꢀ3ꢀ(3ꢀmethoxyphenyl)ꢀ1Hꢀpyrroleꢀ2ꢀcarboxylate
(28c).
Compound 28c (624 mg, 78%) was obtained from compounds 27b (472 mg, 2.30 mmol), 16b (714 mg,
2.00 mmol), FeCl2·4H2O (24 mg, 0.12 mmol, 5 mol.%), Et3N (400 mg, 6.00 mmol) and NH2NH2·H2O
1
(1150 mg, 23.00 mmol). Colorless solid, mp 177ꢀ178 °C (CH2Cl2). Н NMR (DMSOꢀd6): δ = 3.62 (s,
3Н), 3.72 (s, 2Н), 3.77 (s, 3Н), 6.89ꢀ6.92 (m, 3Н), 7.31ꢀ7.35 (m, 1Н), 7.58 (d, J = 8.6 Hz, 2Н), 7.74 (d, J
= 8.6Hz, 2Н), 11.44 (s, 1Н). 13C NMR (DMSOꢀd6): δ = 50.7 (CH3), 55.0 (CH3), 112.4 (CH), 115.7 (CH),
116.7 (С), 118.8 (С), 119.9 (С), 121.2 (С), 122.4 (CH), 128.1 (CH), 128.9 (CH), 130.0 (С), 131.0 (С),
131.2 (CH), 134.8 (С), 158.9 (С), 160.7 (С). ESI/HRMS (m/z): 401.0495 calcd for C19H18BrN2O3 [M +
H]+, found 401.0502. IR (KBr, cmꢀ1): ν 3314, 1665, 1603.
Methyl
4ꢀaminoꢀ3ꢀ(3ꢀmethoxyphenyl)ꢀ5ꢀ(4ꢀmethoxyphenyl)ꢀ1Нꢀpyrroleꢀ2ꢀcarboxylate
(28d).
Compound 28d (414 mg, 47%) was obtained from compounds 27b (606 mg, 2.95 mmol), 16c (770 mg,
2.50 mmol), FeCl2·4H2O (30 mg, 0.15 mmol, 5 mol.%), Et3N (758 mg, 7.50 mmol) and NH2NH2·H2O
1
(1150 mg, 23.00 mmol). Colorless solid, mp 61ꢀ64 °C (hexane). Н NMR (CDCl3): δ = 3.21 (br s, 2Н),
3.71 (s, 3Н), 3.84 (s, 3Н), 3.85 (s, 3Н), 6.88ꢀ6.91 (m, 1Н), 6.99 (d, J = 8.8 Hz, 2Н), 7.02ꢀ7.06 (m, 2Н),
13
7.33ꢀ7.37 (m, 1Н), 7.55 (d, J = 8.8 Hz, 2Н), 8.80 (br s, 1Н). C NMR (CDCl3): δ = 51.2 (CH3), 55.3
(CH3), 55.4 (CH3), 113.0 (CH), 114.7 (CH), 115.6 (CH), 115.9 (С), 121.0 (С), 121.9 (С), 122.6 (CH),
124.3 (С), 127.1 (CH), 128.2 (С), 129.1 (CH), 134.5 (С), 158.7 (С), 159.4 (С), 161.6 (С). ESI/HRMS
(m/z): 375.1315 calcd for C20H20N2NaO4 [M + Na]+, found 375.1311. IR (KBr, cmꢀ1): ν 3309, 2949, 1709,
1669, 1610.
23
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 24 of 39
1
2
3
4
5
6
7
8
9
Methyl 4ꢀaminoꢀ3ꢀ(3ꢀmethoxyphenyl)ꢀ5ꢀ(4ꢀnitrophenyl)ꢀ1Нꢀpyrroleꢀ2ꢀcarboxylate (28e). Compound
28e (322 mg (58%) was obtained from compounds 27b (369 mg, 1.80 mmol), 16d (484 mg, 2.50 mmol),
FeCl2·4H2O (18 mg, 0.09 mmol, 5 mol.%), Et3N (455 mg, 4.50 mmol) and NH2NH2·H2O (751 mg, 15.00
mmol). Red solid, mp 208 °C. (CH2Cl2). 1Н NMR (DMSOꢀd6): δ = 3.65 (s, 3Н), 3.78 (s, 3Н), 4.07 (s, 2Н),
6.89ꢀ6.91 (m, 3Н), 7.32ꢀ7.38 (m, 1Н), 8.05(d, J = 8.9 Hz, 2Н), 8.23 (d, J = 8.9 Hz, 2Н), 11.64 (br s, 1Н).
13C NMR (DMSOꢀd6): δ = 51.0 (CH3), 55.0 (CH3), 112.6 (CH), 115.6 (CH), 118.6 (С), 119.1 (С), 120.9
(С), 122.4 (CH), 123.7 (CH), 125.9 (CH), 129.0 (CH), 132.8 (С), 134.2 (С), 138.5 (С), 144.1 (С), 159.0
(С), 160.6 (С). ESI/HRMS (m/z): 368.1241 calcd for C19H18N3O5 [M + H]+, found 368.1247. IR (KBr,
cmꢀ1): ν 3318, 1671.
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
Methyl 4ꢀaminoꢀ5ꢀphenylꢀ3ꢀ(thiopenꢀ2ꢀyl)ꢀ1Hꢀpyrroleꢀ2ꢀcarboxylate (28f). Compound 28f (135 mg,
47%) was obtained compounds 27c (208 mg, 1.15 mmol), 16a (271 mg, 0.97 mmol), FeCl2·4H2O (20 mg,
0.10 mmol, 5 mol.%)), Et3N (300 mg, 3.00 mmol) and NH2NH2·H2O (500 mg, 10.00 mmol). Colorless
1
solid, mp 153ꢀ154 °C (Et2Oꢀhexane). Н NMR (DMSOꢀd6): δ = 3.67 (s, 3Н), 3.82 (s, 2Н), 7.12ꢀ7.14 (m,
2Н), 7.24ꢀ7.27 (m, 1Н), 7.40ꢀ7.43 (m, 2Н), 7.56ꢀ7.57 (m, 1Н), 7.73ꢀ7.75 (m, 2Н), 11.50 (s, 1Н). 13C NMR
(DMSOꢀd6): δ = 50.8 (CH3), 113.2 (С), 116.8 (С), 120.9 (С), 125.9 (CH), 126.2 (CH), 126.3 (CH), 126.9
(CH), 127.4 (CH), 128.4 (CH), 130.3 (С), 131.6 (С), 134.1 (С), 160.4 (С). ESI/HRMS (m/z): 299.0849
calcd for C16H15N2O2S [M + H]+, found 299.0857. IR (KBr, cmꢀ1): ν 3303, 1670, 1604.
Methyl 4ꢀaminoꢀ5ꢀ(4ꢀbromophenyl)ꢀ3ꢀ(thiopenꢀ2ꢀyl)ꢀ1Hꢀpyrroleꢀ2ꢀcarboxylate (28g). Compound 28g
(429 mg, 52%) was obtained from compounds 27c (453 mg, 2.50 mmol), 16b (785 mg, 2.20 mmol),
FeCl2·4H2O (25 mg, 0.13 mmol, 5 mol.%), Et3N (668 mg, 6.60 mmol) and NH2NH2·H2O (1100 mg,
1
22.00 mmol). Colorless solid, mp 168 °C (CH2Cl2). Н NMR (DMSOꢀd6): δ = 3.67 (s, 3Н), 3.88 (s, 2Н),
7.10ꢀ7.14 (m, 2Н), 7.56ꢀ7.57 (m, 1Н), 7.59 (d, J = 8.5 Hz, 2Н), 7.72 (d, J = 8.5 Hz, 2Н), 11.59 (br s, 1Н).
13C NMR (DMSOꢀd6): δ = 50.8 (СН3), 113.3 (С), 117.3 (С), 119.0 (С), 119.8 (С), 126.0 (СН), 126.9
24
ACS Paragon Plus Environment

Page 25 of 39
The Journal of Organic Chemistry
1
2
3
4
5
(СН), 127.5 (СН), 128.2 (СН), 130.7 (С), 130.8 (С), 131.2 (СН), 133.9 (С), 160.4 (С). ESI/HRMS (m/z):
376.9959 calcd for C16H14BrN2O2S [M + H]+, found 376.9961. IR (KBr, cmꢀ1): ν 3300, 1679.
6
7
8
9
Methyl 4ꢀaminoꢀ5ꢀ(4ꢀmethoxyphenyl)ꢀ3ꢀ(thiopenꢀ2ꢀyl)ꢀ1Hꢀpyrroleꢀ2ꢀcarboxylate (28h). Compound
28h (515 mg, 71%) was obtained from compounds 27c (453 mg, 2.50 mmol), 16c (678 mg, 2.20 mmol),
FeCl2·4H2O (25 mg, 0.13 mmol, 5 mol.%), Et3N (668 mg, 6.60 mmol) and NH2NH2·H2O (1100 mg,
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
22.00 mmol). Colorless solid, mp 156 °C (CH2Cl2). Н NMR (DMSOꢀd6): δ = 3.66 (s, 3Н), 3.72 (s, 2Н),
3.79 (s, 3Н), 6.99 (d, J = 8.7 Hz, 2Н), 7.11ꢀ7.12 (m, 2Н), 7.56ꢀ7.57 (m, 1Н), 7.68 (d, J = 8.7 Hz, 2Н),
11.43 (br s, 1Н). 13C NMR (DMSOꢀd6): δ = 50.7 (СН3), 55.1 (СН3), 113.5 (С), 113.9 (СН), 115.9 (С),
121.4 (С), 124.1 (С), 125.8 (СН), 126.8 (СН), 127.3 (СН), 127.8 (СН), 129.4 (С), 134.3 (С), 157.9 (С),
160.5 (С). ESI/HRMS (m/z): 329.0960 calcd for C17H17N2O3S [M + H]+, found 329.0962. IR (KBr, cmꢀ1):
ν 3290, 1672, 1614.
Methyl 4ꢀaminoꢀ5ꢀ(4ꢀnitrophenyl)ꢀ3ꢀ(thiopenꢀ2ꢀyl)ꢀ1Hꢀpyrroleꢀ2ꢀcarboxylate (28i). Compound 28i
(115 mg, 15%) was obtained from compounds 27c (453 mg, 2.50 mmol), 16d (710 mg, 2.20 mmol),
FeCl2·4H2O (25 mg, 0.13 mmol, 5 mol.%), Et3N (668 mg, 6.60 mmol) and NH2NH2·H2O (1100 mg,
1
22.00 mmol). Orange solid, mp 201ꢀ202 °C (CH2Cl2). Н NMR (DMSOꢀd6): δ = 3.69 (s, 3Н), 4.22 (s,
2Н), 7.09ꢀ7.10 (m, 1Н), 7.15ꢀ7.16 (m, 1Н), 7.60ꢀ7.61 (m, 1Н), 8.04 (d, J = 8.9 Hz, 2Н), 8.23 (d, J = 8.9
Hz, 2Н), 11.79 (s, 1Н). 13C NMR (DMSOꢀd6): δ = 51.1 (СН3), 113.0 (С), 118.5 (С), 119.7 (С), 123.7
(СН), 126.0 (СН), 126.3 (СН), 127.0 (СН), 127.8 (СН), 133.2 (С), 133.5 (С), 138.2 (С), 144.3 (С), 160.3
(С). ESI/HRMS (m/z): 344.0700 calcd for C16H14N3O4S [M + H]+, found 344.0705. IR (KBr, cmꢀ1): ν
3338, 1679.
Methyl 4ꢀaminoꢀ3ꢀ(benzofuranꢀ2ꢀyl)ꢀ5ꢀphenylꢀ1Hꢀpyrroleꢀ2ꢀcarboxylate (28j). Compound 28j (220
mg, 44%) was obtained from compounds 27d (405 mg, 1.88 mmol), 16a (417 mg, 1.50 mmol),
FeCl2·4H2O (20 mg, 0.10 mmol, 5 mol.%), Et3N (450 mg, 4.50 mmol) and NH2NH2·H2O (751 mg, 15.00
1
mmol). Colorless solid, mp 174ꢀ175 °C (CH2Cl2). Н NMR (DMSOꢀd6): δ = 3.76 (s, 3Н), 4.38 (s, 2Н),
25
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 26 of 39
1
2
3
4
5
6
7
8
9
7.25ꢀ7.30 (m, 4Н), 7.43ꢀ7.46 (m, 2Н), 7.59ꢀ7.61 (m, 1Н), 7.64ꢀ7.7.66 (m, 1Н), 7.73ꢀ7.75 (m, 2Н), 11.73
(s, 1Н). 13C NMR (DMSOꢀd6): δ = 51.1 (СН3), 105.1 (СН), 108.9 (С), 110.8 (СН), 116.6 (С), 120.6
(СН), 120.7 (С), 122.7 (СН), 123.6 (СН), 126.4 (СН), 126.6 (СН), 128.5 (СН), 128.7 (С), 131.0 (С),
131.3 (С), 150.7 (С), 153.6 (С), 160.2 (С). ESI/HRMS (m/z): 333.1234 calcd for C20H17N2O3 [M + H]+,
found 333.1240. IR (KBr, cmꢀ1): ν 3315, 1666.
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
Methyl 4ꢀaminoꢀ3ꢀ(benzo[b]thiophenꢀ2ꢀyl)ꢀ5ꢀ(4ꢀbromophenyl)ꢀ1Hꢀpyrroleꢀ2ꢀcarboxylate (28k).
Hydrazine hydrate (165 mg, 3.3 mmol) was added to a suspension of salt 29 (190 mg, 0.33 mmol) in
MeCN/DMSO (20:1, 5 mL) and the reaction mixture was stirred for 10 h at 45ꢀ50 °C. The solvents were
removed in vacuo, and the residue was purified by column chromatography (CH2Cl2) to give compound
1
28k (80 mg, 56%). Light yellow solid, mp 184ꢀ185 °C (CH2Cl2). Н NMR (DMSOꢀd6): δ = 3.68 (s, 3Н),
4.04 (s, 2Н), 7.32ꢀ7.40 (m, 3Н), 7.60 (d, J = 8.6 Hz, 2Н), 7.73 (d, J = 8.6 Hz, 2Н), 7.84ꢀ7.87 (m, 1Н),
7.94ꢀ7.96 (m, 1Н), 11.74 (s, 1Н). 13C NMR (DMSOꢀd6): δ = 51.0 (СН3), 113.2 (С), 117.6 (С), 119.2 (С),
120.1 (С), 122.0 (СН), 123.4 (СН), 123.9 (СН), 124.0 (СН), 124.1 (СН), 128.3 (СН), 130.5 (С), 130.5
(С), 131.3 (СН), 134.8 (С), 139.7 (С), 139.8 (С), 160.2 (С). ESI/HRMS (m/z): 427.0110 calcd for
C20H16BrN2O2S [M + H]+, found 427.0108. IR (KBr, cmꢀ1): ν 3309, 1680.
1ꢀ(4ꢀ(Benzo[b]thiophenꢀ2ꢀyl)ꢀ2ꢀ(4ꢀbromophenyl)ꢀ5ꢀ(methoxycarbonyl)ꢀ1Hꢀpyrroleꢀ3ꢀyl)pyridineꢀ1ꢀ
ium bromide (29). A mixture of azirine 15с (200 mg, 0.86 mmol), salt 16b (268 mg, 0.75 mmol) and
NEt3 (152 mg, 1.50 mmol) in CH2Cl2 (5 mL) was stirred for 2 days at room temperature. Precipitate was
filtered, washed with CH2Cl2, and dried on air to give compound 29 (245 mg, 57%). Light yellow solid,
mp 292 °C (dec.) (CH2Cl2). 1Н NMR (DMSOꢀd6): δ = 3.61 (s, 3Н), 7.06 (d, J = 8.6 Hz, 2Н), 7.15 (s, 1Н),
7.23ꢀ7.28 (m, 2Н), 7.38 (d, J = 8.6 Hz, 2Н), 7.67ꢀ7.68 (m, 1Н), 7.76ꢀ7.78 (m, 1Н), 8.07ꢀ8.10 (m, 2Н),
8.58ꢀ8.62 (m, 1Н), 9.01ꢀ9.03 (m, 2Н). 13C NMR (DMSOꢀd6): δ = 50.0 (CН3), 118.1 (С), 118.5 (С), 121.8
(СН), 123.00 (СН), 123.03 (СН), 123.5 (СН), 124.0 (СН), 125.5 (С), 127.6 (СН), 128.1 (С), 128.2 (СН),
131.2 (СН), 134.0 (С), 134.8 (С), 136.2 (С), 139.5 (С), 139.7 (С), 145.8 (СН), 147.3 (СН), 164.5 (С).
26
ACS Paragon Plus Environment

Page 27 of 39
The Journal of Organic Chemistry
1
2
3
4
ESI/HRMS (m/z): 489.0267 calcd for C25H18BrN2O2S [M ꢀ Br]+, found 489.0258. IR (KBr, cmꢀ1): ν
1693,1618.
5
6
7
8
9
Synthesis of 4ꢀaminopyrroles from 2Hꢀazirines and phenacylpyridinium salts. A mixture of
phenacylpyridinium salts 16 (1.00 mmol), azirine (1.20ꢀ1.50 mmol, 1.2ꢀ1.5 eq) and NEt3 (3.00 mmol, 3.0
eq). in absolute acetonitrile (8 mL) was stirred at 45ꢀ50 °C for 6ꢀ8 h until complete consumption of the
starting salt (monitoring by TLC). Hydrazine hydrate (10.00 mmol, 10.0 eq) was added to the reaction
mixture and stirring continued at 45ꢀ50 °C for 6ꢀ8 h until the pyridylpyridinium salt (monitoring by TLC)
was consumed. The solvent was removed in vacuo and the residue was purified by column
chromotography (CH2Cl2).
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
3ꢀAminoꢀ2,4,5ꢀtriphenylꢀ1Hꢀpyrrole (14a). Compound 14a (750 mg, 55%) was obtained from azirine
15a (971 mg, 5.03 mmol), bromide 16a (1224 mg, 4.40 mmol), Et3N (1333 mg, 13.20 mmol) and
NH2NH2·H2O (2200 mg, 44.00 mmol). Light yellow solid, mp 178ꢀ180 °C (EtOHꢀH2O) (lit.7c data 182ꢀ
183 °C (benzene)). 1Н NMR (CDCl3): δ = 3.42 (br. s, 2H), 7.15ꢀ7.32 (m, 7H), 7.35ꢀ7.40 (m, 4H), 7.41ꢀ
13
7.46 (m, 2H), 7.57ꢀ7.61 (m, 2H), 7.85 (s, 1H). C NMR (CDCl3): δ =115.4 (C), 116.6 (C), 124.5 (CH),
125.3 (CH), 126.5 (CH), 126.6 (CH), 128.2 (C), 128.6 (CH), 128.8 (CH), 129.2 (CH), 130.2 (CH), 132.8
(C), 133.0 (C), 134.4 (C). ESI/HRMS (m/z): 311.1534 calcd for C22Н19N2 [M + H]+, found 311.1531. IR
(KBr, cmꢀ1): ν 3416, 3357, 1598, 1503.
3ꢀAminoꢀ2,4ꢀdiphenylꢀ1Hꢀpyrrole (14b). Compound 14b (355 mg, 70%) was obtained from azirine 15b
(470 mg, 4.00 mmol), bromide 16a (600 mg, 2.15 mmol), Et3N (780 mg, 7.70 mmol) and NH2NH2·H2O
1
(1500 mg, 30.00 mmol). Light yellow solid, mp 176ꢀ177 °C (EtOHꢀH2O) (lit.16 data 181°C (EtOH)). Н
NMR (CDCl3): δ = 3.41 (br. s, 2H), 6.79 (d, J = 3.0 Hz, 1H), 7.19ꢀ7.22 (m, 1H), 7.25ꢀ7.29 (m, 1H), 7.39ꢀ
13
7.45 (m, 4H), 7.49ꢀ7.57 (m, 4H), 7.87 (br. s, 1H). C NMR (CDCl3): δ = 115.4 (СH), 116.9 (С), 118.2
(С), 124.7 (СH), 125.3 (СH), 125.9 (СH), 126.6 (С), 127.5 (СH), 128.8 (СH), 129.1 (СH), 133.3 (С),
27
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 28 of 39
1
2
3
4
135.1 (С). ESI/HRMS (m/z): 235.1226 calcd for C16Н15N2 [M + H]+, found 235.1230. IR (KBr, cmꢀ1): ν
3391, 3163, 3046, 1603, 1568.
5
6
7
8
9
Synthesis βꢀdiazopyrroles. Aminopyrrole (1.00 mmol) was dissolved (or suspended) in minimal volume
of acetic acid, the mixture cooled to 10 °C and saturated aqueous NaNO2 (2.00ꢀ3.00 mmol, 2.0ꢀ3.0 eq)
was added dropwise. The mixture was stirred for 15ꢀ20 min at room temperature, and then diluted with
water (20 mL). The precipitate was filtered, washed with water and dried in vacuo. If the product did not
crystallize, it was extracted with ether, the organic layer was washed with saturated aqueous NaHCO3 and
brine, dried over Na2SO4 and the solvent removed in vacuo.
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
3ꢀDiazoꢀ2,4,5ꢀtriphenylꢀ3Hꢀpyrrole (11a). Compound 11a (325 mg, 86%) was obtained from compound
14a (360 mg, 1.20 mmol) and NaNO2 (166 mg, 2.40 mmol) in 4 mL of AcOH. Orange solid, mp 151ꢀ153
1
°C (EtOH, dec.) (lit.7c data 157ꢀ158°C (ether, dec.)). Н NMR (CDCl3): δ = 7.19ꢀ7.33 (m, 3H), 7.34ꢀ7.50
(m, 6H), 7.51ꢀ7.62 (m, 4H), 7.85ꢀ7.89 (m, 2H). 13C NMR (CDCl3): δ = 122.5 (С), 126.1 (СH), 127.0
(СH), 127.7 (СH), 127.9 (СH), 128.2 (СH), 128.7 (СH), 129.1 (СH), 129.1 (СH), 129.2 (СH), 131.9 (С),
133.4 (С), 135.3 (С), 139.2 (С), 156.0 (С). ESI/HRMS (m/z): 322.1339 calcd for C22H17N3 [M + H]+,
found 322.1341. IR (KBr, cmꢀ1): ν 2089.
3ꢀDiazoꢀ2,4ꢀdiphenylꢀ3Hꢀpyrrole (11b). Compound 11b (290 mg, 78%) was obtained from compound
14b (350 mg, 1.50 mmol) and NaNO2 (210 mg, 3.00 mmol) in 4 mL of AcOH. Brickꢀred solid, mp 171ꢀ
1
172 °C (Et2Oꢀhexane) (lit.17 data 170 (dec) °C). Н NMR (CDCl3): δ = 3.85 (s, 3Н), 7.41ꢀ7.51 (m, 8Н),
7.77ꢀ7.80 (m, 2Н). 13C NMR (CDCl3): δ = 51.8 (CH3), 126.7 (СН), 128.6 (СН), 128.9 (СН), 129.1 (СН),
129.2 (СН), 129.8 (СН), 130.3 (С), 131.1 (С), 132.8 (С), 132.8 (С), 136.1 (С), 156.0 (С), 163.1 (С).
ESI/HRMS (m/z): 246.1026 calcd for C16H13N3 [M + H]+, found 246.1015. IR (KBr, cmꢀ1): ν 2105.
Methyl 3ꢀdiazoꢀ2,4ꢀdiphenylꢀ3Hꢀpyrroleꢀ5ꢀcarboxylate (25a). Compound 25a (427 mg, 89%) was
obtained from compound 28a (464 mg, 1.59 mmol) and NaNO2 (276 mg, 4.00 mmol) in 4 mL of AcOH.
28
ACS Paragon Plus Environment

Page 29 of 39
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
Orange solid, mp 134ꢀ134 °C (AcOHꢀH2O). 1Н NMR (CDCl3): δ = 3.85 (s, 3Н), 7.41ꢀ7.51 (m, 8Н), 7.77ꢀ
7.80 (m, 2Н). 13C NMR (CDCl3): δ = 51.8 (CH3), 126.7 (СН), 128.6 (СН), 128.9 (СН), 129.1 (СН), 129.2
(СН), 129.8 (СН), 130.3 (С), 131.1 (С), 132.8 (С), 132.8 (С), 136.1 (С), 156.0 (С), 163.1 (С). ESI/HRMS
(m/z): 326.0900 calcd for C18H13N3NaO2 [M + Na]+, found 326.0906. IR (KBr, cmꢀ1): ν 2115, 1712.
Methyl 3ꢀdiazoꢀ4ꢀ(3ꢀmethoxyphenyl)ꢀ2ꢀphenylꢀ3Hꢀpyrroleꢀ5ꢀcarboxylate (25b). Compound 25b (335
mg, 76%) was obtained from compound 28b (424 mg, 1.32 mmol) and NaNO2 (228 mg, 3.30 mmol) in 3
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
1
mL of AcOH. Orange solid, mp 116ꢀ118 °C (AcOHꢀH2O). Н NMR (CDCl3): δ = 3.85 (pseudoꢀs, 6Н),
6.95ꢀ6.98 (m, 1Н), 7.05ꢀ7.06 (m, 2Н), 7.37ꢀ7.42 (m, 1Н), 7.44ꢀ7.50 (m, 3Н), 7.77ꢀ7.79 (m, 2Н). 13C
NMR (CDCl3): δ = 51.8 (CH3), 55.3 (CH3), 114.5 (CH), 115.0 (CH), 121.4 (CH), 126.7 (CH), 129.1 (CH),
129.6 (CH), 129.8 (CH), 131.1 (С), 131.5 (С), 132.8 (С), 135.7 (С), 156.0 (С), 159.6 (С), 163.1 (С).
ESI/HRMS (m/z): 356.1006 calcd for C19H15N3NaO3 [M + Na]+, found 356.1012. IR (KBr, cmꢀ1): ν 2115,
1708.
Methyl 2ꢀ(4ꢀbromophenyl)ꢀ3ꢀdiazoꢀ4ꢀ(3ꢀmethoxyphenyl)ꢀ3Hꢀpyrroleꢀ5ꢀcarboxylate (25c). Compound
25c (511 mg (98%) was obtained from compound 28c (507 mg, 1.26 mmol) and NaNO2 (276 mg, 4.40
1
mmol) in 6 mL of AcOH. Orange solid, mp 88ꢀ93 °C (AcOHꢀH2O). Н NMR (CDCl3): δ = 3.87 (s, 3Н),
3.88 (s, 3Н), 6.96ꢀ6.99 (m, 1Н), 7.03ꢀ7.05 (m, 2Н), 7.37ꢀ7.41 (m, 1Н), 7.60ꢀ7.69 (m, 4Н). 13C NMR
(CDCl3): δ = 51.9 (CH3), 55.4 (CH3), 114.6 (CH), 115.0 (CH), 121.4 (CH), 124.2 (С), 124.2 (С), 128.1
(CH), 129.7 (CH), 131.3 (С), 131.4 (С), 131.6 (С), 132.3 (CH), 136.0 (С), 154.5 (С), 159.6 (С), 163.0
(С). ESI/HRMS (m/z): 434.0111 calcd for C19H14BrN3NaO3 [M + Na]+, found 434.0120. IR (KBr, cmꢀ1):
ν 2157, 1723, 1699.
Methyl
3ꢀdiazoꢀ4ꢀ(3ꢀmethoxyphenyl)ꢀ2ꢀ(4ꢀmethoxyphenyl)ꢀ3Hꢀpyrroleꢀ5ꢀcarboxylate
(25d).
Compound 25d (345 mg, 88%) was obtained from compound 28d (380 mg, 1.08 mmol) and NaNO2 (150
mg, 2.20 mmol) in 5 ml of AcOH. Orange solid, dec. > 115 °C (AcOHꢀH2O). 1Н NMR (DMSOꢀd6): δ =
3.74 (m, 3Н), 3.81 (m, 3Н), 3.87 (m, 3Н), 7.06ꢀ7.08 (m, 1Н), 7.17ꢀ7.19 (m, 3Н), 7.23 (s, 1Н), 7.43ꢀ7.7.47
29
ACS Paragon Plus Environment