Synthesis of dipyrrolo-diazepine derivatives via intramolecular alkyne cyclization

Article abstract of DOI:10.1016/j.tet.2018.06.013

A regioselective approach was developed for the synthesis of dipyrrolo-diazepine derivatives. The synthetic route to dipyrrolo-diazepines first involves the synthesis of dipyrromethanes, followed by reaction of propargyl bromide in the presence of NaH to attach one alkyne functionality to the pyrrole nitrogen atom. Intramolecular heterocyclization with NaH in DMF between the alkyne functionality and pyrrole nitrogen atom gave the desired structures in good yields.

Full text of DOI:10.1016/j.tet.2018.06.013

Accepted Manuscript
Synthesis of dipyrrolo-diazepine derivatives via intramolecular alkyne cyclization
Dılgeş Baskın, Yasin Çetinkaya, Metin Balci
PII:
S0040-4020(18)30684-7
10.1016/j.tet.2018.06.013
TET 29609
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 2 May 2018
Revised Date: 1 June 2018
Accepted Date: 5 June 2018
Please cite this article as: Baskın Dış, Çetinkaya Y, Balci M, Synthesis of dipyrrolo-diazepine derivatives
via intramolecular alkyne cyclization, Tetrahedron (2018), doi: 10.1016/j.tet.2018.06.013.
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Synthesis of dipyrrolo-diazepine derivatives
via intramolecular alkyne cyclization
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Dılgeş Baskın,a Yasin Çetinkaya,a,b Metin Balcia,*
aDepartment of Chemistry, Middle East Technical University, 06800 Ankara, Turkey
bDepartment of Food Technology, Oltu Vocational School, Atatürk University, 25400 Oltu-Erzurum, Turkey

1
ACCEPTED MANUSCRIPT
Tetrahedron
journal homepage: www.elsevier.com
Synthesis of dipyrrolo-diazepine derivatives via intramolecular alkyne
cyclization
Dılgeş Baskın,a Yasin Çetinkaya,a,b Metin Balcia,*
aDepartment of Chemistry, Middle East Technical University, 06800 Ankara, Turkey
bDepartment of Food Technology, Oltu Vocational School, Atatürk University, 25400 Oltu-Erzurum, Turkey
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A regioselective approach was developed for the synthesis of dipyrrolo-diazepine derivatives.
The synthetic route to dipyrrolo-diazepines first involves the synthesis of dipyrromethanes,
followed by reaction of propargyl bromide in the presence of NaH to attach one alkyne
functionality to the pyrrole nitrogen atom. Intramolecular heterocyclization with NaH in DMF
between the alkyne functionality and pyrrole nitrogen atom gave the desired structures in good
yields.
Available online
Keywords:
Pyrrole
2009 Elsevier Ltd. All rights reserved
.
Indole
Dipyrromethane
Diazepine
Alkyne cyclization
1. Introduction
Corresponding author. Tel.: +90 535 388 8276; fax: 90 312 210
3200; e-mail: mbalci@metu.edu.tr
Diazepines are a well-known class of heterocyclic compounds
demonstrating a range of clinically important properties such as
anxiolytic, hypnotic, sedative, anticonvulsant, skeletal, amnestic
and muscle relaxant properties.1-5 In particular, benzodiazepines
are used to treat anxiety disorders. They act on the central
nervous system to produce a calming effect.6-8
Clozapine (1) containing a benzodiazepine structure9 is a drug
effective in decreasing psychopathology, improving some aspects
of cognition, improving quality of life, decreasing
hospitalization, and decreasing suicide attempts and
completions.10,11 Lorazepam (2) is a benzodiazepine used to treat
irritable bowel syndrome, epilepsy, and insomnia and to control
tension caused by alcohol withdrawal. The compound causes a
slowing of activity in the brain and allows relaxation.12 Diazepam
(3), also containing a benzodiazepine structure, is used to treat
anxiety, acute alcohol withdrawal, and seizures. It is also used to
relieve muscle spasms (Figure 1).12,13
Various diazepinone derivatives have been synthesized in which
the benzene ring is replaced by heterocycles such as indole,
pyrrole, pyridine, and quinolone, and their activities have been
studied.14 Thiophene is an isostere of the benzene ring.
Clotiazepam (4)15,16 differs from benzodiazepines in that the
benzene ring has been replaced by a thiophene ring. It is a
marketed drug and possesses anxiolytic, sedative, and muscle
relaxant properties. However, furan- and pyrrole-fused
diazepinone derivatives are not common in the literature. De
Meijere and coworkers17 described the synthesis of new types of
pyrrolo- and furo-condensed perhydro[1,4]diazepine-2,5-diones 5
starting from spiro seven-membered ring compounds. Very
recently, we reported the first synthesis of furo- and thieno-fused
1,3-diazepine-4,6-dione derivatives 6 starting from ethyl 2-(2-
methoxy-2-oxoethyl)-3-furancarboxylate and 2-(2-methoxy-2-
oxoethyl)-3-thiophencarboxylate (Figure 2).18
N
Cl
N
N
Cl
Cl
N
N
Cl
OH
N
N
N
H
H
Me
O
O
Clozapine
Diazepam
Lorazepam
1
2
3
Figure 2. Furan- and thiophene-fused diazepinone derivatives.
Figure 1. Structures of some diazepine drugs.

2
Tetrahedron
ACCEPTED MANUSCRIPT
As a continuation of that work, we decided to synthesize
pyrrole-fused diazepinone derivatives. Synthesis of compound 7
was performed with the reaction of 1H-pyrrole-2-carbaldehyde
and propargyl bromide.19 The reaction of 7 with hydrazine
monohydrate resulted in the formation of 5H-pyrrolo[2,1-
d][1,2,5]-triazepine (9) (Scheme 1).19 Unfortunately, the
oxidation reactions to introduce a carbonyl group into the
molecule 9 failed. Therefore, we turned our attention to the
construction of the desired heterocyclic scaffold by
intramolecular cyclization reaction of a N-propynyl methyl ester
1119,20 with hydrazine monohydrate. Unfortunately, the desired
compound 13 was formed in only 16% yield (Scheme 2).
Furthermore, triazepinone derivate 13 was smoothly rearranged
to the six-membered ring isomer 12 in quantitative yield upon
standing at room temperature in chloroform. Finally, we decided
to synthesize diazepine derivatives fused to pyrrole rings.
Scheme 4. Synthesis of dipyrromethanes (19a-g).
After synthesis of meso-substituted dipyrromethanes, the next
step was the incorporation of propargyl groups into the molecule
which are the key functional groups for final cyclization
reactions. According to the common literature procedures,19,25
19c was first reacted with NaH in DMF, followed by dropwise
addition of a solution of propargyl bromide in dry DMF at 0 °C.
Unfortunately, double propargylated dipyrromethane derivatives
21a-f were formed as the major products. For example, 20c and
21c were formed in yields of 16% and 45%, respectively. To
increase the yield of the mono-propargylated compounds 20,
NaH was added portionwise to a mixture of dipyrromethanes and
propargyl bromide. The yield of 20c was increased up to 55%
(Scheme 5).
Scheme 1. Reaction of N-propynyl carbaldehyde 7 with hydrazine hydrate.
Scheme 2. Reaction of N-propynyl carbaldehyde 7 and ester 10 with
hydrazine hydrate.
2. Results and discussion
Scheme 5. Synthesis mono- and dipropargylated dipyrromethanes 20a-f and
21a-f.
Our planned approach to 14 involved metal-free cyclization of
propargylated dipyrromethane derivatives 15 synthesized by the
reaction of pyrrole with aldehydes, followed by the reaction with
propargyl bromide of dipyrromethane 16. The retrosynthesis is
summarized in Scheme 3.
Characterization of compounds 20c and 21c was achieved by
1
1
using H-NMR and 13C-NMR spectra. In the H-NMR spectrum
of compounds 20c the NH proton of the pyrrole unit resonates at
7.91 ppm as a broad singlet and the terminal alkyne proton
resonates at 2.36 ppm as a triplet (J = 2.5 Hz) due to coupling
with methylene protons. The methylene protons appear as a
doublet. Furthermore, the presence of two unequal pyrrole rings
clearly indicates mono-substitution. On the other hand, the
absence of NH proton resonance in the spectra of 21c and the
observed symmetry in the 1H- as well as in the 13C-NMR spectra
also support the symmetrical structure. The methylene protons
are diastereotopic26 and they give rise to an AB-system with
further splitting with the alkyne proton (4J = 2.5 Hz). The A-part
of the AB-system resonates at 4.37 ppm, whereas the B-part of
the AB-system appears at 4.30 ppm. The main coupling of the
AB-system was measured as J = 14.0 Hz which is within the
expected range.26
Scheme 3. Retrosynthesis of dipyrrolo-diazepine derivatives
Many procedures are reported in the literature for the
synthesis of meso-substituted dipyrromethanes. Trifluoroacetic
acid or BF3 O(Et)2 catalyzed reaction of aldehydes with excess
pyrrole afforded meso-substituted dipyrromethanes.21 Temelli
and Unaleroglu reported a new procedure for meso-substituted
dipyrromethanes by the reaction of N-tosyl imines with excess
pyrrole in the presence of metal triflates.22 Singh et al. used
Amberlyst 15 as an efficient catalyst for condensation of
electron-rich heterocycles with a variety of aldehydes to give
dipyrromethanes.23 However, Sobral et al.24 described an efficient
synthesis of dipyrromethanes in water. We also used 0.18 M HCl
for the reaction of freshly distilled excess pyrrole with
benzaldehyde in water at room temperature to give 2,2'-
(phenylmethylene)bis(1H-pyrrole) (19c) in 74% yield. Then, for
testing the scope of further reactions, additional derivatives 19a-g
were synthesized (Scheme 4).
For the synthesis of 20g, dipyrromethane derivative 19g was
submitted to propargylation under the same reaction conditions.
Unexpectedly, instead of the predicted mono-propargylated
product 20g or dipropargylated product, dipyrrin derivative 22
was produced under these reaction conditions (Scheme 6).

3
our attention to a NaH-supported cyclization reaction.31
ACCEPTED MANUSCRIPT
Reaction of 20a-e, 26, and 29 with NaH in DMF at room
temperature exclusively gave 7-exo-dig heterocyclization
products 30a-g in good yields (Scheme 8).
The 1D and 2D NMR (HSQC, COSY, and HMBC) spectra
were used for characterization of cyclization products 30a-g.
When the NMR spectra of 20c and 30c were compared,
disappearance of the alkyne proton, the NH proton, and the
alkyne carbon resonances was very informative in view of the
proposed structure. Furthermore, the appearance of a singlet at
Scheme 6. Attempted synthesis of propargylated dipyrromethane derivative
20g and formation of 22.
When compound 19g was reacted with NaH in DMF in the
absence of propargyl bromide, 22 was formed in just a minute
(Scheme 6). Thus, propargyl bromide does not affect the
reaction. The spectral data (1H-NMR, 13C-NMR, and HRMS) of
compound 22 are fully consistent with the literature data.27 Very
recently, Dolphin et al.27 synthesized compound 22 by oxidation
of 19g with DDQ in high yield.
1
2.15 ppm arising from the CH3 protons in the H-NMR spectrum
of 30c clearly indicated the cyclization reaction. Moreover, the
13C-NMR spectrum with 16 distinct carbon resonances also
supports the formation of product 30c.
Due to the presence of a strong electron-withdrawing group
such as the nitro group in 19g, the acidity of the methine proton
is enhanced. Therefore, the base can easily abstract this proton,
forming an anion that can be stabilized due to delocalization over
the benzene and pyrrole rings. This anion can undergo an
oxidation reaction in the presence of air to form the oxidation
product 22. Similar oxidation did not occur in the case of 19f.
This is probably due to the strong hydrogen bonding between the
NH proton and the nitro group, which probably hinders oxidation
(see Figure 3).
For the synthesis of pyrrole- and indole-substituted
dipyrromethane derivatives 26 and 29 we directly started from
propargylated pyrrole 2519,24a,b,28 and propargylated indole 28,29
which were synthesized upon reaction of pyrrole- and indole-
aldehyde with propargyl bromide in the presence of NaH as
described in the literature (Scheme 7). Reaction of 25 and 28
with pyrrole in the presence of HCl under the same reaction
conditions as described above resulted in the formation of
propargylated dipyrromethane derivatives 26 and 29 in 59% and
72% yields, respectively.
Scheme 8. NaH-supported 7-exo-dig cyclization of propargylated
dipyrromethane derivatives 20a-e, 26, and 29.
Table 1. Structures of diazepine derivatives 30 a-g.
A tentative mechanism for the formation of diazepine
derivatives is outlined in Scheme 9. We propose that the terminal
alkyne group undergoes base-catalyzed isomerization to form the
corresponding allene unit.19 Since the central carbon atom in
allene is much more electropositive, the nitrogen atom of pyrrole
with its increased electron density exclusively attacks the central
carbon atom of allene to form 33 through the intermediates 31
and 32. The exo-cyclic products 33 can easily undergo 1,3-H
shift under the basic conditions to form the thermodynamically
more stable 30.
Scheme 7. Synthesis of pyrrole- and indole-substituted dipyrromethane
derivatives 26 and 29.
After the successful generation of propargylated and meso-
substituted dipyrromethane derivatives, the next step was the
cyclization process. The ability to perform the key carbon-
heteroatom bond formation step, which transforms an acyclic
precursor into the desired cyclic compound is a critical process to
construct heterocycles including a diazepine structure. We first
conducted the gold-catalyzed cyclization30 of 20c. Unfortunately,
we were not able to observe the formation of 8-endo-dig or 7-
exo-dig cyclization products using AuCl, AuCl3 or other metal
catalysts. In every case, the starting material 20c was recovered.
We assume that the nucleophilicity of the pyrrole nitrogen atom
is not sufficient to accomplish cyclization. Therefore, we turned

4
Tetrahedron
ACCEPTED MANUSCRIPT
R
R
R
R
H+
NH
N
NaH
DMF
N
N
N
N
N
N
N
HN
Br
CH2
33
32
CH2
NaH, 0 °C
DMF, 61%
N
N
N
N
31
20/26/29
H-shift
CH3
CH3
R
R
30f
36
H+
Scheme 11. Synthesis of propargylated dipyrrolo-diazepine derivative 36.
N
N
N
N
CH2
CH3
30
Scheme 9. Proposed mechanism for the formation of diazepine derivatives
30.
3. Conclusion
A synthetic methodology was developed for the synthesis of
new pyrrole-fused diazepine derivatives. The methodology starts
with the synthesis of dipyrromethanes. Incorporation of a
propargyl group followed by NaH-supported cyclization resulted
in the construction of a hitherto unknown skeleton, dipyrrolo-
diazepine derivatives. Some of the compounds such as 36 may
provide an entry into the synthesis of interesting compounds by
additional cyclization reactions.
Mono-propargylated derivative 20f having a benzene group
bearing a nitro functionality at the ortho-position was also
submitted to a cyclization reaction. Unfortunately, the expected
cyclization product 34 was not formed from the reaction of 20f
with NaH in DMF even at 90 °C (Scheme 10).
NO2
NO2
NaH, DMF
90 oC
4. Experimental Section
HN
N
N
rt
N
4.1 General Methods
CH3
All reagents were acquired from commercial provider and
additional purification was not done. Melting points are
uncorrected. NMR spectra were recorded on a Bruker instrument
at 400 MHz for 1H and 100 MHz for 13C NMR. IR were recorded
in the range 4000-600 cm-1 on a Perkin Elmer 980 spectrometer.
High resolution mass spectra were recorded by LC-MS TOF
electrospray ionization technique on an Agilent Technologies
6224 TOF LC/MS instrument. Column chromatography was
carried out on silica gel (60-mesh, Merck). TLC was carried out
on Merck 0.2 mm silica gel 60 F254 analytical aluminum plates.
20f
34
Scheme 10. Reaction of structure 20f with NaH.
Strong intramolecular hydrogen-bonding between the pyrrole
NH and the nitro group may be responsible for the failure of this
reaction. We assume that the alkyne unit will first isomerize to
the corresponding allene. Therefore, we optimized the allene
structure 35 in the gas phase with the hybrid density functional
B3LYP32 method using the 6-31+G(d,p) basis set33 to prove the
formation of intramolecular hydrogen-bonding in compound 35.
The distance between the NH hydrogen atom and one of the
oxygen atoms of the nitro group was 2.40 Å (Figure 3).
Hydrogen-bondings are regarded as “strong and mostly covalent”
with donor-acceptor distances of 2.2-2.5 Å; as “moderate and
mostly electrostatic” if the distance is between 2.5 and 3.2 Å and
as “weak and electrostatic” with a distance of 3.2 - 4.0 Å.34 Thus,
the intramolecular hydrogen-bonding in 35 is mostly covalent,
which hinders the cyclization reaction.
4.2. General procedure for synthesis of 5-substituted
dipyrromethanes (19a-g)
Corresponding aldehydes (18a-g) (5 mmol) were dissolved in
pyrrole (15 mmol) and then HCl (0.18 M, 0.045 mmol, 250 mL)
was added to media and the composition was mixed at room
temperature for 3 hours. The reaction was followed with TLC
and after completion of the reaction. The mixture was extracted
with EtOAc (3 × 50 mL) and dried over MgSO4 and the solvent
was evaporated. The residue was purified with gradient column
chromatography eluting with hexane:ethyl acetate (10:1 to 5:1)
and the product were crystallized from appropriate solvents.
NO2
NH
4.2.1. Synthesis of 2-(1H-pyrrol-2-ylmethyl)-1H-pyrrole
(19a)27
N
Formaldehyde (0.15 g, 5 mmol) and pyrrole (1.005 g, 15
mmol) was reacted in HCl (0.18 M, 0.045 mmol, 250 mL) as
described above to give compound (19g). Colorless needles from
35
1
Figure 3. H bonding of allene structure of compound 35.
EtOAc/hexane, mp 74-75 ºC. (0.50 g, 69 %). H NMR (400
MHz, CDCl3): δ 7.63 (bs, 2H, H-1), 6.56–6.54 (m, 2H, H-5),
6.14–6.12 (m, 2H, H-4), 6.08–5.95 (m, 2H, H-3), 3.89 (s, 2H, H-
1'); 13C NMR (100 MHz, CDCl3): δ 129.2, 117.5, 108.3, 106.6,
26.3.
Some of the compounds such as 30f and 30g have suitable
functionality to introduce further propargyl groups to form the
corresponding propargylated compounds. Furthermore, to show
the presence of a pyrrole unit with a NH functionality in 30f, the
compound was submitted to further reaction with propargyl
bromide in the presence of NaH. The propargylated compound
36 was obtained in a yield of 61% (Scheme 11).
4.2.2. Synthesis of 2-[1-(1H-pyrrol-2-yl)ethyl]-1H-pyrrole
(19b)27
Acetaldehyde (0.22 g, 5 mmol) and pyrrole (1.005 g, 15
mmol) were reacted in HCl (0.18 M, 0.045 mmol, 250 mL) as
described above to give compound (19b). Colorless sticky solid
(0.49 g, 62%). 1H NMR (400 MHz, CDCl3): δ 7.60 (bs, 2H, H-
1), 6.67–6.42 (m, 2H, H-5), 6.08–6.06 (m, 2H, H-4), 5.98 (bs,

5
2H, H-3), 4.06 (q, J = 7.2 Hz, 1H, H-1'), 1.50 (d, J = 7.2 Hz, 3H,
H-2'); 13C NMR (CDCl3): δ 20.6, 31.7, 105.0, 108.0, 117.2,
134.8.
(m, B-part of AA'BB'-system, 2H, H-2''), 6.77–6.74 (m, H-5),
ACCEPTED MANUSCRIPT
6.04 (m, 2H, H-4), 5.82–5.78 (m, 1H, H-3), 5.67 (s, 1H, H-1').
13C NMR (100 MHz, Acetone-d6) δ 152.3, 147.5, 132.6, 130.3,
124.1, 118.4, 108.4, 107.9, 44.7.
4.2.3. Synthesis of 2-[phenyl(1H-pyrrol-2-yl)methyl]-1H-
pyrrole (19c)27
4.3.
General
procedure
for
propargylation
of
dipyrromethanes substituted at C-5 position (19a-f)
Benzaldehyde (18c) (0.5 g, 5 mmol) and pyrrole (1.005 g, 15
mmol) was reacted with HCl (0.18 M, 0.045 mmol, 250 mL) as
described above. 19c was formed as pale yellow crystals (0.82 g,
To a stirred solution of 5-substituted dipyrromethanes (19a-f)
(3 mmol) in DMF (30 mL) was added propargyl bromide (3.6
mmol) in DMF (5 mL). The process was followed by portionwise
addition of NaH (3,6 mmol) at 0 °C over a period of 30 min. The
reaction was monitored with thin-layer chromatography and
completed after 12-17 h. After completion of the reaction, water
(150 mL) was added then the reaction mixture was extracted with
EtOAc (4 × 40 mL). Then, DMF in media was removed with
brine (8 × 50 mL) and mixture dried over MgSO4. The eluent
was removed under reduced pressure and the residue was purified
with gradient column chromatography on silica gel eluting with
hexane:ethyl acetate (20:1 to 7:1) and crystallized from
appropriate solvent.
1
74%), mp 105-106 ºC from EtOAc/hexane. H-NMR (400 MHz,
CDCl3): δ 7.88 (bs, 2H, H-1), 7.22-7.35 (m, 5H, arom), 6.63-6.59
(m, 2H, H-5), 6.15–6.13 (m, 2H, H-4), 5.92 (bs, 2H, H-3), 5.49
(s, 1H, H-1'); 13C NMR (100 MHz, CDCl3): δ 44.1, 107.5, 108.8,
117.1, 127.0, 128.5, 128.7, 132.4, 142.2.
4.2.4.
Synthesis
of
2-[(2-chlorophenyl)(1H-pyrrol-2-
yl)methyl]-1H-pyrrole (19d)
4-Chlorobenzaldehyde (18d) ( 0.70 g, 5 mmol) ) and pyrrole
(1.005 g, 15 mmol) was reacted in HCl (0.18 M, 0.045 mmol,
250 mL) as described above. The product was isolated as pale
1
yellow powder (1.14 g, 89%), mp 108-109 ºC. H NMR (400
4.3.1.1. Synthesis of 1-prop-2-ynyl-2-(1H-pyrrol-2-ylmethyl)-
1H-pyrrole (20a)
MHz, CDCl3): δ 7.96 (bs, 2H, H-1), 7.41–7.31 (m, 1H, H-3''),
7.22–7.16 (m, 2H, H-4'', H-5''), 7.12–7.07 (m, 1H, H-6''), 6.70–
6.68 (m, 2H, H-3), 6.16 (m, 2H, H-4), 5.91 (s, 1H, H-1'), 5.88–
5.85 (m, 2H, H-5); 13C NMR (100 MHz, CDCl3): δ 140.0, 133.7,
131.2, 129.7, 129.6, 128.2, 127.1, 117.3, 108.5, 107.4, 40.6; IR
(ATR, cm-1) 3674, 2986, 2901, 1507, 1456, 1394, 1228, 1066,
1055, 892, 823, 725; HRMS calcd. for C15H13ClN2 [M+H]+:
257.0840, found: 257.0843.
To a stirred solution of 2-(1H-pyrrol-2-ylmethyl)-1H-pyrrole
(19a) (0.50 g, 3,42 mmol) (20a) in DMF (30 mL) was added
propargyl bromide (3.5 mL, 4.1 mmol) in DMF at 0 °C over a
period of 30 min followed by portionwise addition of NaH (0.09
g, 4.1 mmol). The reaction was completed after 11 h and the
further procedure was done as described above. Mono-
propargylated product (20a) was isolated as colorless liquid
(0.12 g, 51%) and dipropargylated product (21g) was isolated as
4.2.5. Synthesis of 2-[(4-methoxyphenyl)(1H-pyrrol-2-
yl)methyl]-1H-pyrrole (19e)27
1
light yellow oil (0.14 g, 24%). H NMR (400 MHz, CDCl3): δ
7.84 (bs, 1H, NH), 6.72-6.70 (m, 1H), 6.61 (dd, J4,3 = 4.0 and J4,5
= 2.5 Hz, 1H), 9.11–6.09 (m,2H), 6.00–5.99 (m, 2H), 4.43 (d, J
= 2.5 Hz, 2H), 3.99 (s, 2H), 2.33 (t, J' = 2.5 Hz, 1H); 13C NMR
(101 MHz, CDCl3): δ 129.3, 128.5, 121.1, 117.0, 108.6, 108.4,
107.5, 106.0, 78.8, 73.2, 36.1, 25.3; IR (ATR, cm-1) 3377, 3282,
1698, 1567, 1482, 1420, 1342, 1311, 1286, 1240, 1205, 1180,
1115, 1088, 1071, 1025, 935, 883, 775, 707, 640; HRMS calcd
for C12H12N2 [M+H]+: 185.1073 found: 185.1079.
HCl (0.18 M, 0.045 mmol, 250 mL) was added to a mixture of
4-methoxybenzaldehyde (18e) (0.75 g, 5 mmol) and pyrrole
(1.005 g, 15 mmol). Then, procedure was continued as described
above. 19e was obtain as pale yellow powder (0.88 g, 70%), mp
1
102-103 ºC. H-NMR (400 MHz, CDCl3): δ 7.82 (bs, 2H, H-1'),
7.14 (quasi d, J = 8.6, 2H, H-2''), 6.85 (quasi d, J = 8.6, 2H, H-
3''), 6.65–6.67 (m, 2H, H-5), 6.15–6.13 (m, 2H, H-4), 5.90-5.92
(m, 2H, H-3), 5.42 (s, 1H, H-1'), 3.82 (s, 3H, H-1'''). 13C NMR
(100 MHz CDCl3): δ 158.6, 134.3, 132.8, 129.4, 117.0, 114.0,
108.7, 107.3, 55.2, 43.2.
4.3.1.2.
1-Prop-2-ynyl-2-[(1-prop-2-ynyl-1H-pyrrol-2-
yl)methyl]-1H-pyrrole (21a)
4.2.6. Synthesis of 2-[(2-nitrophenyl)(1H-pyrrol-2-yl)methyl]-
1H NMR (400 MHz, CDCl3); δ 6.73–6.71 (m, 2H, H-5), 6.08–
6.06 (m, 2H, H-4), 5.92–5.89 (m, 2H, H-3), 4.55 (d, J = 2.5 Hz,
4H), 4.05 (s, 2H), 2.38 (t, J = 2.5 Hz, 1H); 13C NMR (101 MHz,
CDCl3): δ 128.9, 120.9, 108.6, 107.5, 78.4, 73.2, 36.3, 24.3; IR
(ATR, cm-1) 3247, 2917, 2849, 1660, 1480, 1424, 1336, 1290,
1283, 1204, 1182, 1137, 1071, 1016, 930, 882, 800, 707, 693,
655, 629, 614; HRMS calcd for C15H14N2 [M+H]+: 223.1230
found: 223.1240.
1H-pyrrole (19f)35
2-Nitrobenzaldehyde (18f) (0.75 g, 5 mmol) and pyrrole
(1.005 g, 15 mmol) were reacted in HCl (0.18 M, 0.045 mmol,
250 mL) as described above to give compound 19f. Yellow
1
needles from CH2Cl2 (1.05 g, 79%), m.p. 145-147 ºC. H NMR
(400 MHz, CDCl3): δ 8.16 (bs, 2H, H-1), 7.90 (dd, J = 8.1 and
1.2 Hz, 1H, H-3''), 7.54 (td, J = 7.7 and = 1.2 Hz, 1H, H-4'')
7.46 – 7.35 (m, 1H-5''), 7.30 (dd, J = 8.1 and 1.5 Hz, 1H, H-6''),
6.75–6.71 (m, 2H, H-5), 6.22 (s, 1H, H-1'), 6.16-6.18 (m, 1H, H-
4), 5.89–5.84 (m, 1H, H-3); 13C NMR (100 MHz, CDCl3) δ
148.8, 137.2, 133.0, 131.0, 130.7, 127.8, 124.5, 117.6, 108.6,
107.4, 38.9.
4.3.2.1. Synthesis of 1-prop-2-ynyl-2-[1-(1H-pyrrol-2-
yl)ethyl]-1H-pyrrole (20b)
To a stirred solution of 2-[1-(1H-pyrrol-2-yl)ethyl]-1H-pyrrole
(0.49 g, 3.05 mmol) (19b) in DMF (30 mL) was added propargyl
bromide (0.31 g, 3.66 mmol) in DMF at 0 °C over a period of 30
min followed by portionwise addition of NaH (0.08 g, 3.6 mmol).
After 10 h reaction was completed. The further procedure was
done as described above. Mono-propargylated product (20b) was
isolated as colorless liquid (0.08 g, 45%) and di-propargylated
compound (21b) was isolated as colorless liquid (0.26 g, 33%).
1H NMR (400 MHz, CDCl3) δ 7.72 (bs, 1H, NH), 6.75–6.74 (m,
1H, H-5), 6.59 (dd, J4,3 = 4.1 and J4,5 = 2.5 Hz, 1H, H-4), 6.14–
6.12 (m, 1H, H-4''), 6.12–6.10 (m, 1H, H-5''), 6.10–6.08 (m, 1H,
H-3), 6.02–6.00 (m, 1H, H-3''), 4.41 (dd, A-part of AB-system,
4.2.7. Synthesis of 2-[(4-nitrophenyl)(1H-pyrrol-2-yl)methyl]-
1H-pyrrole (19g)
4-Nitrobenzaldehyde (18g) ( 0.75 g, 5 mmol) and pyrrole
(1.005 g, 15 mmol) ) were reacted in HCl (0.18 M, 0.045 mmol,
250 mL) as described above to give compound (19g) as light
yellow needles from hexane/ethyl acetate, m.p. 160-161 ºC. (1.08
1
g, 81%). H NMR (400 MHz, Acetone-d6): δ 9.84 (bs, 1H, H-1),
8.28–8.08 (m, A-part of AA'BB'-system, 2H, H-3''), 7.54–7.43

6
Tetrahedron
ACCEPTED MANUSCRIPT
Jgem = 17.7 and J = 2.5 Hz, 1H, HCH), 4.38 dd, B-part of AB-
mL) was added propargyl bromide (0.46 mL 5.3 mmol) in DMF
system, Jgem = 17.7 and J = 2.5 Hz, 1H, HCH), 4.27 (q, J = 7.1
Hz, 1H, H-1'), 2.32 (t, J = 2.5 Hz, 1H), 1.61 (d, J = 7.1 Hz, 3H,
CH3); 13C NMR (101 MHz, CDCl3); δ 134.5, 134.5, 121.1, 116.6,
108.2, 107.3, 106.5, 104.7, 78.4, 73.1, 35.9, 30.5, 21.3; IR
(ATR, cm-1) 3383, 3284, 2971, 2930, 1682, 1561, 1481, 1372,
1343, 1283, 1242, 1116, 1071, 1027, 936, 882, 789, 763, 710,
641, 561. HRMS calcd for C13H14N2 [M+H]+: 199.1230 found:
199.1239.
at 0 °C over a period of 30 min followed by portionwise addition
of NaH (0.10 g, 5.3 mmol). The reaction was completed after 16
h. The further procedure was applied as described above. Mono-
propargylated (20d) product was isolated as colorless oil (0.35 g,
44 %) and di- propargylated (21d) product was isolated as light
yellow needles from EtOAc/hexane (0.21 g, 18%). 1H NMR (400
MHz, CDCl3): δ 7.94 (bs, 1H, NH), 7.40–7.35 (m, 1H, arom.),
7.22–7.15 (m, 2H, arom.), 7.01–6.96 (m, 1H, arom.), 6.81–6.77
(m, 1H, H-5), 6.70 (dd, J = 4.2 and 2.6 Hz, 1H), 6.15–6.13 (m,
1H), 6.11–6.07 (m, 1H), 5.93 (s, 1H, CH), 5.81–5.80 (m, 1H),
5.68– 5.61 (m, 1H), 4.41 (d, J = 2.5 Hz, 2H, CH2), 2.33 (t, J' =
2.5 Hz, 1H, C≡CH); 13C NMR (101 MHz, CDCl3): δ 139.5,
133.7, 132.3, 130.4, 130.0, 129.5, 128.2, 127.0, 121.2, 117.2,
109.4, 108.8, 107.7, 107.4, 77.9, 73.5, 39.9, 36.2; IR (ATR, cm-1)
3376, 3291, 1723, 1571, 1468, 1434, 1285, 1235, 1115, 1072,
1046, 1029, 936, 884, 847, 751, 712, 663, 609; HRMS calcd for
C18H15ClN2 [M+H]+: 295.0996 found: 295.0979.
4.3.2.2.
1-Prop-2-ynyl-2-[1-(1-prop-2-ynyl-1H-pyrrol-2-
yl)ethyl]-1H-pyrrole (21b)
1H NMR (400 MHz, CDCl3): δ 6.66–6.63 (m, 2H, H-5), 6.04–
6.01 (m, 2H, H-4), 5.83–5.81 (m, 2H, H-3), 4.39 (d, J = 2.5 Hz,
4H, CH2), 4.24 (q, J = 6.9 Hz, 1H, CH), 2.29 (t, J = 2.5 Hz,
C≡CH), 1.55 (d, J = 6.9 Hz, 3H, CH3); 13C NMR (101 MHz,
CDCl3): δ 134.6, 120.9, 107.4, 107.0, 78.7, 73.13, 36.0, 29.5,
20.8; IR (ATR, cm-1) 2927, 2851, 1712, 1479, 1420, 1373, 1340,
1283, 1234, 1202, 1128, 1077, 1011, 934, 789, 759, 706, 637,
572; HRMS calcd for C16H16N2 [M+H]+: 237.1386 found:
237.1396.
4.3.4.2.
2-[(2-chlorophenyl)(1-prop-2-ynyl-1H-pyrrol-2-
yl)methyl]-1-prop-2-ynyl-1H-pyrrole (21d)
1H NMR (400 MHz, CDCl3): δ 7.41–7.37 (m, 1H, arom.),
7.23–7.16 (m, 2H, arom.), 7.00–6.95 (m, 1H, arom), 6.79–6.77
(m, 2H, H-5), 6.07–6.05 (m, 2H, H-4), 6.01 (s, 1H, CH), 5.52–
5.49 (m, 2H, H-3), 4.45 (dd, A-part of AB-system, Jgem = 17.5
4.3.3.1. Synthesis of 2-[phenyl(1H-pyrrol-2-yl)methyl]-1-
prop-2-ynyl-1H-pyrrole (20c)
To a stirred solution of 2-[phenyl(1H-pyrrol-2-yl)methyl]-1H-
pyrrole (19c) (0.82 g, 3.9 mmol) in DMF (30 mL) was added
propargyl bromide (0.384 mL, 4.6 mmol) in DMF at 0 °C over a
and J = 2.5 Hz, 1H, HCH), 4.40 dd, B-part of AB-system, Jgem
=
17.5 and J = 2.5 Hz, 1H, HCH), 2.37 (t, J= 2.5 Hz, 2H, C≡CH).
13C NMR (101 MHz, CDCl3); δ 138.2, 133.9, 131.6, 130.4,
129.5, 128.2, 126.9, 121.2, 110.0, 107.4, 78.2, 73.4, 37.0, 36.3;
IR (ATR, cm-1) 3295, 1475, 1434, 1339, 1306, 1291, 1254, 1233,
1130, 1071, 1044, 1029, 1016, 936,846, 819, 787, 777, 734, 706,
666, 628, 607, 574; HRMS calcd for C21H17ClN2 [M+H]+:
333.1153 found: 333.1169.
period of 30 min followed by portionwise addition of NaH (0.112
g, 4.6 mmol). The reaction was completed after 12 h. Further
procedure was applied as described above. Mono-propargylated
product (20c) was isolated as light yellow oil (0.49 g, 55%) and
di-propargylated product (21c) was isolated as light yellow solid
(0.20 g, 22%) mp 73-74 °C from EtOAc/ hexzane. 1H NMR (400
MHz, CDCl3): δ 7.91 (bs, 1H, NH), 7.39–7.10 (m, 5H, arom),
6.79– 6.72 (m, 1H, H-5), 6.68 (dd, J = 4.1 and 2.5 Hz, 1H, H-4),
6.14–6.12 (m, 1H, H-4''), 6.10–6.06 (m, 1H, H-5''), 5.83–5.82 (m,
1H, H-3), 5.70–5.68 (m, 1H, H-3''), 5.56 (s, 1H, H-1'), 4.44 –
4.33 (m, 2H, CH2), 2.35 (t, J = 2.5 Hz, 1H, C≡CH); 13C NMR
(101 MHz, CDCl3): δ 141.5, 133.5, 131.8, 128.5, 128.4, 126.9,
121.2, 117.1, 109.5, 108.3, 107.4, 107.3, 78.3, 73.4, 36.3, 29.6;
IR (ATR, cm-1) 3390, 1662, 1510, 1416, 1381, 1342, 1287, 1272,
1252, 1118, 1094, 1043, 1002, 935, 909, 845, 808, 773, 714, 638,
593, 575. HRMS calcd for C18H16N2 [M+H]+: 261.1386 found:
261.1390.
4.3.5.1. Synthesis of 2-[(4-Methoxyphenyl)(1H-pyrrol-2-
yl)methyl]-1-prop-2-ynyl-1H-pyrrole (20e)
To a stirred solution of 2-[(4-methoxyphenyl)(1H-pyrrol-2-
yl)methyl]-1H-pyrrole (19e) (0.88 g, 3.48 mmol) in DMF (30
mL) was added propargyl bromide (0,36 mL, 4.18 mmol) in
DMF at 0 °C over a period of 30 min and the reaction was
followed by portionwise addition of NaH (0.10 g, 4.18 mmol).
After 10 h reaction was completed. The further procedure was
applied as described above. Mono-propargylated product (20e)
was isolated as yellow oil (0.15 g, 48%) and di-propargylated
product (21e) was isolated as yellow needles (0.12 g, 24%) from
1
EtOAc/ hexane, mp 72-73 °C. H NMR (400 MHz, CDCl3): δ
7.90 (bs, 1H, NH), 7.13–7.11 (quasi d, A-part of AA'BB' system,
2H, arom.) 6.82–6.80 (m, B-part of AA'BB' system, 2H-arom),
6.78–6.74 (m, 1H, H-5), 6.69 (dd, J = 4.1 and 2.6 Hz, 1H, H-4),
6.14–6.12 (m, 1H), 6.08 (t, J = 3.2 Hz, 1H), 5.82-5.81 (m, 1H),
5.71–5.69 (m, 1H), 5.51 (s, 1H), 4.38 (bd, J = 2.5 Hz, 2H, CH2),
3.79 (s, 3H, OMe), 2.36 (t, J = 2.5 Hz, 1H, C≡CH); 13C NMR
(101 MHz, CDCl3) δ 158.5, 133.8, 133.6, 133.5, 132.2, 129.4,
121.1, 117.0, 113.9, 109.3, 108.3, 107.2, 78.4, 73.3, 55.2, 41.7,
36.2; IR (ATR, cm-1) 3372, 3289, 1681, 1607, 1583, 1508, 1479,
1463, 1439, 1342, 1300, 1284, 1243, 1173, 1108, 1090, 1072,
1028, 936, 884, 842, 790, 707, 667,645, 592; HRMS calcd for
C19H18N2O [M+H]+: 291.1492 found: 291.1508.
4.3.3.2. 2-[Phenyl(1-prop-2-ynyl-1H-pyrrol-2-yl)methyl]-1-
prop-2-ynyl-1H-pyrrole (21c)
1H NMR (400 MHz, CDCl3): δ 7.28–7.06 (m, 5H, arom.),
6.71–6.66 (m, 2H, H-5), 6.03–5.94 (m, 2H, H-4), 5.54 (s, 1H, H-
1'), 5.50–5.41 (m, 2H, H-3), 4.36 (dd, A-part of AB-system, Jgem
= 17.9 and J = 2.5 Hz, 2H, HCH), 4.30 dd, B-part of AB-system,
Jgem = 17.9 and J = 2.5 Hz, 2H, HCH), 2.33 (t, J = 2.5 Hz, 2H,
C≡CH); 13C NMR (101 MHz, CDCl3): δ 140.6, 132.9, 128.7,
128.5, 126.9, 121.1, 109.9, 107.3, 78.7, 73.3, 41.2, 36.3; IR
(ATR, cm-1) 3025, 2116, 1704, 1598, 1477, 1449, 1434, 1340,
1226, 1197, 1124, 1071, 1027, 1016, 962, 933, 896, 821, 789,
778, 751, 710, 697, 656, 609; HRMS calcd for C21H18N2 [M+H]+:
299.1543 found: 299.1553.
4.3.5.2.
2-[(4-Methoxyphenyl)(1-prop-2-ynyl-1H-pyrrol-2-
yl)methyl]-1-prop-2-ynyl-1H-pyrrole (21d)
1H NMR (400 MHz, CDCl3): δ 7.08–7.05 (m, 2H, arom.),
6.85 6.82 (m, 2H, arom.), 6.76–6.74 (m, 2H, H-5), 6.06–6.04 (m,
2H, H-4), 5.55 (s, 1H, CH), 5.52–5.49 (m, 2H, H-3), 4.43 (dd, A-
part of AB-system, Jgem = 17.6 and J = 2.5 Hz, 2H, HCH), 4.37
(dd, B-part of AB-system, Jgem = 17.6 and J = 2.5 Hz, 2H, HCH),
4.3.4.1. Synthesis of 2-[(2-chlorophenyl)(1H-pyrrol-2-
yl)methyl]-1-prop-2-ynyl-1H-pyrrole (20d)
To a stirred solution of 2-[(2-chlorophenyl)(1H-pyrrol-2-
yl)methyl]-1H-pyrrole (19d) (1.14 g, 4.44 mmol) in DMF (30

7
3.79 (s, 3H, OMe), 2.39 (t, J = 2.5 Hz, 2H, C≡CH); 13C NMR
(101 MHz, CDCl3): δ 158.5, 133.2, 132.6, 129.7, 121.0, 113.9,
109.7, 107.3, 78.7, 73.2, 55.2, 40.4, 36.3; IR (ATR, cm-1) 3289,
3256, 1680, 1603, 1577, 1507, 1478, 1454, 1420, 1390, 1341,
1319, 1299, 1281, 1256, 1242, 1196, 1172, 1159, 1127, 1104,
1072, 1028, 956, 936, 898, 856, 826, 732, 721, 707, 687, 668,
644, 610, 571; HRMS calcd for C22H20N2O [M+H]+: 329.1648
found: 329.1684.
(m, 2H, H-5), 7.62–7.59 (m, B-part of AA'BB' system, 2H,
ACCEPTED MANUSCRIPT
arom), 6.41 (dd, J = 4.2 and 1.0 Hz, 2H, H-3), 6.36 (dd, J = 4.2
and 1.5 Hz, 2H, H-4); 13C NMR (101 MHz, CDCl3) δ 148.2,
144.6, 143.8, 139.8, 139.7, 131.5, 128.6, 122.9, 118.3.
4.3.8. Synthesis of 2-[di(1H-pyrrol-2-yl)methyl]-1-prop-2-
ynyl-1H-pyrrole (26)
24a,c27
1-(Prop-2-yn-1-yl)-1H-pyrrole-2-carbaldehyde (25)
(0.665 g, 5 mmol) and pyrrole (1.005 g, 15 mmol) was reacted in
HCl (0.18 M, 0.045 mmol, 250 mL) as described above to give
compound 26. Yellow solid (0.89 g, 72%), mp 92-93 ºC. H
4.3.6.1.
Synthesis
of
2-[(2-nitrophenyl)(1H-pyrrol-2-
yl)methyl]-1-prop-2-ynyl-1H-pyrrole (20f)
1
To a stirred solution of 2-[(2-nitrophenyl)(1H-pyrrol-2-
yl)methyl]-1H-pyrrole (19f) (1.05 g, 3.9 mmol) in DMF (20 mL)
was added propargyl bromide (0.384 mL, 4.6 mmol) in DMF (5
mL) at 0 °C over a period of 30 min followed by portionwise
addition of NaH (0.112 g, 4.6 mmol). The reaction was
completed after 12 h. Further procedure was applied as described
above. Mono-propargylated (20f) product was isolated as yellow
sticky solid (0.24 g, 44%) and di- propargylated product (21f)
was isolated as colorless cubic crystals (0.10 g, 12%) from
NMR (400 MHz, CDCl3): δ 7.93 (bs, 2H, NH), 6.77 (dd, J = 2.6,
2.0 Hz, 1H, H-5), 6.69–6.66 (m, 2H, H-5''), 6.16–6.14 (m, 2H, H-
4''), 6.12–6.09 (m, 1H, H-4), 6.00–5.97 (m, 2H, H-3''), 5.91–5.88
(m, 1H, H-3), 5.64 (s, 1H, H-1'), 4.44 (d, J = 2.6 Hz, 2H, CH2),
2.36 (t, J = 2.6 Hz, 1H, C≡CH); 13C NMR (100 MHz, CDCl3): δ
132.1, 130.5, 121.5, 117.2, 108.7, 108.4, 107.4, 106.9, 78.3, 73.4,
36.2, 36.0; IR (ATR, cm-1) 3285, 1651, 1528, 1475, 1402, 1368,
1337, 1314, 1282, 1246, 1218, 1075, 1030, 953, 939, 890, 785,
741, 641, 605; HRMS calcd. for C16H15N3 [M+H]+: 250,1339,
found: 250.1353.
1
CHCl3, mp 143-144 ºC from EtOAc/ hexane. H NMR (400
MHz, CDCl3) δ 7.98 (bs, 1H, NH), 7.93 (dd, J = 8.1 and 1.2 Hz,
1H, arom.), 7.51 (dt, J = 7.6 and 1.2 Hz, 1H, arom.) 7.41 – 7.39
(m, 1H, arom.), 7.13 (dd, J = 7.8 and 1.0 Hz, 1H, arom.), 6.82–
6.81 (m, 1H), 6.73–6.71 (m, 1H), 6.38 (s, 1H), 6.17–6.15 (m,
1H), 6.09–6.03 (m, 1H), 5.85 (bs, 1H), 5.61–5.59 (m, 1H), 4.49
(dd, A-part of AB-system, Jgem = 17.8 and J = 2.6 Hz, 2H, HCH),
4.47 (dd, B-part of AB-system, Jgem = 17.8 and J = 2.6 Hz, 2H,
HCH), 2.33 (t, J = 2.6 Hz, 1H, C≡CH); 13C NMR (101 MHz,
CDCl3) δ 148.6, 136.8, 133.0, 131.5, 130.9, 129.7, 127.8, 124.8,
121.6, 117.6, 109.3, 108.8, 107.9, 107.4, 77.2, 73.7, 37.5, 36.2;
IR (ATR, cm-1) 3286, 2914, 2849, 1669, 1605, 1520, 1472, 1423,
1397, 1342, 1285, 1183, 1117, 1073, 1028, 937, 883, 834, 784,
713, 657, 604; HRMS calcd for C18H15N3O2 [M+H]+: 306.1237
found: 306.1238
4.3.9. Synthesis of 2-[di(1H-pyrrol-2-yl)methyl]-1-prop-2-
ynyl-1H-indole (29)
1-(Prop-2-yn-1-yl)-1H-indole-2-carbaldehyde (28)31 (0.916 g,
5 mmol) and pyrrole (1.005 g, 15 mmol) ) were reacted in HCl
(0.18 M, 0.045 mmol, 250 mL) as described above to give
1
compound 29. Yellow oil (0.88 g, 59%). H NMR (400 MHz,
CDCl3); δ 7.90 (bs, 2H, NH), 7.45 (bd, J = 7.8 Hz, 1H, arom.),
7.29 (bd, J = 8.2 Hz, 1H, arom.), 7.18–7.14 (m, 1H, arom.), 7.08–
7.01 (m, 1H, arom.), 6.62– 6.60 (m, 2H, H-5), 6.17 (s, 1H, H-3''),
6.11–6.09 (m, 2H, H-4), 6.0 –5.95 (m, 2H, H-3), 5.74 (s, 1H,
CH), 4.63 (d, J' = 2.5 Hz, 2H, CH2), 2.16 (t, J' = 2.5 Hz, 1H,
C≡CH); 13C NMR (100 MHz, CDCl3) δ 139.7, 137.1, 129.7,
127.6, 122.0, 120.6, 120.2, 117.6, 109.2, 108.6, 107.3, 102.5,
78.3, 72.4, 36.5, 32.5; IR (ATR, cm-1) 3403, 2987, 1715, 1507,
1459, 1402, 1339, 1311, 1249, 1182, 1162, 1106, 1085, 1027,
907, 884, 770, 726, 646, 603; HRMS calcd. for C20H17N3
[M+H]+: 300.1495 found: 300.1510.
4.3.6.2.
2-[(2-nitrophenyl)(1-prop-2-ynyl-1H-pyrrol-2-
yl)methyl]-1-prop-2-ynyl-1H-pyrrole (21f)
1H NMR (400 MHz, CDCl3): δ 7.96 (dd, J' = 8.1 and 1.2 Hz,
1H, arom.), 7.51 (dt, J' = 7.6 and 1.2 Hz, 1H, arom.) 7.47–7.37
(m, 1H, arom.), 7.15 (dd, J' = 7.6 and 1.2 Hz, 1H, arom.), 6.81–
6.75 (m, 2H), 6.50 (s, 1H, CH), 6.08–6.02 (m, 2H), 5.50– .48
(m, 2H), 4.49 (dd, A-part of AB-system, Jgem = 17.7 and J = 2.5
Hz, 2H, HCH), 4.33 (dd, B-part of AB-system, Jgem = 17.6 and J
= 2.5 Hz, 2H, HCH), 2.36 (t, J = 2.5 Hz, 2H, C≡CH); 13C NMR
(101 MHz, CDCl3) δ 148.8, 135.5, 133.0, 131.3, 131.0, 128.0,
124.9, 121.5, 110.3, 107.5, 77.8, 73.7, 36.3, 36.0; IR (ATR, cm-1)
3300, 3281, 1519, 1477, 1355, 1301, 1288, 1253, 1131, 1071,
1017, 937, 864, 836, 819, 742, 719, 687, 638, 606, 572. HRMS
calcd for C21H17N3O2 [M+H]+: 344.1394 found: 344.1419.
4.4. General procedure for NaH-supported cyclization
reactions of N-propargyl dipyrromethane derivatives
To
a stirred solution of N-propargyl dipyrromethane
derivatives 20a-f, 26, and 29 (1 mmol) in DMF (10 mL) was
added solid NaH (3.0 mmol) portionwise at room temperature
and the reaction mixture was stirred at room temperature for 1
h. After completion of the reaction, water was added, and then
the mixture was extracted with EtOAc (3 × 50 mL). Afterwards,
DMF in media was removed with brine (3 × 25 mL) and the
mixture was dried over MgSO4. After evaporation of solvent, the
residue was purified with gradient column chromatography
eluting with hexane:ethyl acetate (10:1 to 4:1) and the
compounds 30a-9 were crystallized from appropriate solvent.
4.3.7. Synthesis of (Z)-2-((4-nitrophenyl)(2H-pyrrol-2-
ylidene)methyl)-1H-pyrrole (22)
To a stirring solution of 2-[(4-nitrophenyl)(1H-pyrrol-2-
yl)methyl]-1H-pyrrole (19g) (0.5 g, 1.8 mmol) in DMF (10 mL),
sodium hyride was added (0.04 g mL, 2 mmol) portionwise and
stirred for 2-3 minutes at room temperature. After completion of
the reaction which was monitored by using TLC, solvent was
removed and water (30 mL) was added. The resulting mixture
was extracted with ethyl acetate (3 × 20 mL). The organic
mixture dried over MgSO4, then filtered. After evaporation of the
solvent, the residue was chromatographed on silica gel column
eluting with hexane/EtOAc (7:1) to give (Z)-2-((4-
nitrophenyl)(2H-pyrrol-2-ylidene)methyl)-1H-pyrrole (22) (0.32
4.4.1. Synthesis of 5-methyl-11H-dipyrrolo[1,2-d:2',1'-
g][1,4]diazepine (30a)
A stirred solution of 1-prop-2-ynyl-2-(1H-pyrrol-2-ylmethyl)-
1H-pyrrole (20a) (0.12 g, 0.65 mmol) in DMF (15 mL) was
reacted with NaH (43.0 mg, 1.95 mmol) as described above to
give cyclization product 30a. Light yellow solid (0.09 g, 81%)
1
mp 58-60 °C. H NMR (400 MHz, CDCl3); δ 6.80 (dd, J = 3.0
and 1.7 Hz, 1H), 6.58 (dd, J = 2.7 and 1.7 Hz, 1H), 6.47 (bs,
1H), 6.19 (t, J = 3.2 Hz, 1H), 6.13 (t, J = 3.1 Hz, 1H), 5.94 (bs,
1H), 5.88 (bs, 1H), 3.85 (s, 2H, CH2), 2.29 (s, 3H, CH3); 13C
NMR (101 MHz, CDCl3); δ 132.8, 132.6, 123.2, 119.4, 117.5,
112.7, 109.7 (2C), 105.3, 104.4, 26.0, 19.9; IR (ATR, cm-1) 2916,
1
g, 64%) as yellow sticky solid. H NMR (400 MHz, CDCl3): δ
8.27–8.24 (m, A-part of AA'BB' system, 2H, arom.), 7.63–7.62

8
Tetrahedron
ACCEPTED MANUSCRIPT
2849, 1715, 1507, 1480, 1417, 1378, 1331, 1235, 1180, 1114,
MHz, CDCl3); δ 6.86–6.84 (m, 1H), 6.83– 6.81(m, 2H, arom.),
1024, 885, 826, 747, 695, 610, 546; HRMS calcd for C12H12N2
6.75–6.73 (m, 2H, arom.), 6.59 (dd, J = 2.8 and 1.4 Hz, 1H),
6.26–6.23 (m, 2H), 6.20–6.16 (m, 1H), 6.05–6.03 (m, 1H), 6.02–
6.00 (m, 1H), 5.32 (s, 1H, CH), 3.73 (s, 3H, OCH3), 2.07 (s, 3H,
CH3); 13C NMR (101 MHz, CDCl3); δ 158.2, 135.0, 134.9, 132.5,
128.5, 123.8, 120.2, 118.2, 113.4, 113.0, 109.6, 109.5, 107.6,
106.9, 55.2, 41.5, 19.7; IR (ATR, cm-1) 2922, 1693, 1605, 1507,
1481, 1424, 1379, 1348, 1333, 1281, 1243, 1199, 1175, 1114,
1082, 1028, 889, 829, 789, 766, 700, 635, 609, 585, 562; HRMS
calcd for C19H18N2O [M+H]+: 291.1492 found: 291.1508.
[M+H]+: 185.1073 found: 185.1085.
4.4.2. Synthesis of 5,11-dimethyl-11H-dipyrrolo[1,2-d:2',1'-
g][1,4]diazepine (30b)
A
stirred solution of 1-prop-2-ynyl-2-[1-(1H-pyrrol-2-
yl)ethyl]-1H-pyrrole (20b) (0.08 g, 0.4 mmol) in DMF (15 mL)
was reacted with NaH (27.0 mg, 1.2 mmol) as described above to
give cyclization product (30b) as colorless liquid (0.06 g, 85%).
1H NMR (400 MHz, CDCl3); δ 6.81 (dd, J = 2.7 and 1.7 Hz, 1H),
6.60–6.58 (m, 1H), 6.52 (s, 1H), 6.22–6.21 (m 1H), 6.15–6.14
(m, 1H), 5.92–5.91 (m, 1H), 5.84–5.85 (m, 1H), 3.85 (q, J = 7.0
Hz, 1H, CH), 2.29 (d, J = 1.0 Hz, 3H, CH3), 1.69 (d, J = 7.0 Hz,
3H, CH3); 13C NMR (101 MHz, CDCl3); δ 138.0, 137.8, 123.7,
119.2, 117.3, 113.0, 109.4 (2C), 103.2, 102.5, 30.1, 19.8, 15.0;
IR (ATR, cm-1) 3100, 2973, 1686, 1556, 1482, 1454, 1432, 1418,
1379, 1344, 1300, 1261, 1223, 1186, 1170, 1157, 1114, 1087,
1051, 1038, 1022, 971, 884, 791, 730, 691, 622, 591, 579;
HRMS calcd for C13H14N2 [M+H]+: 199.1230 found: 199.1236.
4.4.6. Synthesis of 5-methyl-11-(1H-pyrrol-2-yl)-11H-
dipyrrolo[1,2-d:2',1'-g][1,4]diazepine (30f)
A stirred solution of 2-[di(1H-pyrrol-2-yl)methyl]-1-prop-2-
ynyl-1H-pyrrole (26) (0.89 g, 3.6 mmol) in DMF (15 mL) was
reacted with NaH (240.0 mg, 10.8 mmol) as described above to
give cyclization product 30f. Brown solid (0.5 g, 65%) mp 130-
1
131 °C. H NMR (400 MHz, CDCl3); δ 7.73 (s, 1H, NH), 6.87
(dd, J = 3.1 and 1.8 Hz, 1H), 6.66–6.59 (m, 2H), 6.30 (s, 1H),
6.24 (t, J = 3.2 Hz, 1H), 6.18 (t, J = 3.1 Hz, 1H), 6.07 – 6.03 (m,
3H), 5.59– 5.57 (m, 1H), 5.43 (s, 1H), 2.15 (s, 3H, CH3); 13C
NMR (101 MHz, CDCl3); δ 133.5, 133.3, 130.3, 122.9, 120.6,
118.5, 116.7, 112.6, 109.5, 109.5, 108.3, 107.3, 106.4, 105.9,
36.9, 19.8; IR (ATR, cm-1) 3285, 1651, 1528, 1475, 1402, 1368,
1337, 1314, 1282, 1246, 1218, 1075, 1030, 953, 939, 890, 785,
741, 641, 605; HRMS calcd for C16H15N3 [M+H]+: 250.1339
found: 250.1350.
4.4.3. Synthesis of 5-methyl-11-phenyl-11H-dipyrrolo[1,2-
d:2',1'-g][1,4]diazepine (30c)
A stirred solution of 2-[phenyl(1H-pyrrol-2-yl)methyl]-1-
prop-2-ynyl-1H-pyrrole (20c) (0.49 g, 1.88 mmol) in DMF (20
mL) was reacted with NaH (125.0 mg, 5.64 mmol) as described
above to give cyclization product 30c. White tiny needles (0.37
1
g, 76%) from EtOAc/hexane, (mp 106-107 °C). H NMR (400
4.4.7. Synthesis of 5-methyl-13-(1H-pyrrol-2-yl)-13H-
MHz, CDCl3); δ 7.24–7.15 (m, 4H, arom), 6.90–6.88 (m, 1H,
arom.), 6.87 (s, 1H), 6.64 –6.60 (m, 1H), 6.29–6.25 (m, 1H), 6.23
(bs, 1H), 6.23–6.18 (m, 1H-9), 6.10–6.07 (m, 1H), 6.06–6.05 (m,
1H), 5.40 (s, 1H), 2.08 (s, 3H, CH3); 13C NMR (101 MHz,
CDCl3); δ 140.4, 134.6, 134.5, 128.0, 127.3, 126.3, 123.2, 120.2,
118.2, 113.0, 109.5, 109.5, 107.7, 107.0, 42.1, 19.6; IR (ATR,
cm-1) 3095, 1689, 1599, 1480, 1445, 1424, 1377, 1348, 1279,
12475, 1198, 1169, 1074, 1031, 1023, 713, 704, 694, 611, 591.
HRMS calcd for C18H16N2 [M+H]+: 261.1386 found: 261.1398.
pyrrolo[1',2':4,5][1,4]diazepino[1,7-a]indole (30g)
A stirred solution of 2-[di(1H-pyrrol-2-yl)methyl]-1-prop-2-
ynyl-1H-indole (29) (0.91 g, 3.0 mmol) in DMF (20 mL) was
reacted with NaH (200.0 mg, 9 mmol) as described above to give
1
cyclization product 30g. Yellow sticky oil (0.61 g, 72%). H
NMR (400 MHz, CDCl3); δ 7.79 (s, 1H, NH), 7.57 (bd, J = 7.6
Hz, 1H, arom.), 7.32 (d, J = 8.1 Hz, 1H, arom.), 7.23–7.18 (m,
1H, arom.), 7.17–7.12 (m, 1H, arom.), 6.92–6.89 (m, 1H), 6.68–
6.66 (m, 1H'), 6.53 (bs, 1H), 6.44 (s, 1H), 6.29–6.24 (m, 1H),
6.14 (s, 1H), 6.08 (dd, J = 5.6 and 2.7 Hz, 1H), 5.66 (bs, 1H),
5.58 (bs, 1H), 2.24 (s, 3H, CH3); 13C NMR (101 MHz, CDCl3) δ
136.2, 128.4, 128.3, 123.8, 122.0, 121.9, 120.8, 120.6, 118.8,
116.9, 110.1, 109.7, 109.4, 109.3, 108.5, 107.8, 106.3, 100.3,
37.6, 19.9; IR (ATR, cm-1) 3396, 2917, 1715, 1556, 1480, 1458,
1426, 1373, 1350, 1314, 1243, 1175, 1087, 1024, 937, 884, 767,
746, 735, 707, 666, 604. HRMS calcd for C20H17N3 [M+H]+:
300.1495 found: 300.1510.
4.4.4. Synthesis of 11-(2-chlorophenyl)-5-methyl-11H-
dipyrrolo[1,2-d:2',1'-g][1,4]diazepine (30d)
A
stirred solution of 2-[(2-chlorophenyl)(1H-pyrrol-2-
yl)methyl]-1-prop-2-ynyl-1H-pyrrole (20d) (0.35 g, 1.2 mmol) in
DMF (15 mL) was reacted with NaH (80.0 mg, 3.6 mmol) as
described above to give cyclization product 30d. Light orange
liquid (0.21 g, 61%). 1H NMR (400 MHz, CDCl3); δ 7.63 (dd, J =
7.6 and 1.8 Hz, 1H, arom.), 7.41 (dd, J = 7.7 and 1.6 Hz, 1H,
arom.), 7.32–7.21 (m, 2H, arom.), 6.87 (dd, J = 2.9 and 1.8 Hz,
1H), 6.64 (dd, J = 2.9 and 1.8 Hz, 1H), 6.54 (bs, 1H), 6.16 (t, J =
3.3 Hz, 1H), 6.11 (dd, J = 3.3 and 3.1 Hz, 1H), 5.77 (s, 1H),
5.74–5.68 (m, 2H), 2.33 (s, 3H, CH3); 13C NMR (101 MHz,
CDCl3); δ 136.5, 134.7, 134.4, 133.8, 131.3, 129.9, 128.4, 126.3,
123.4, 120.3, 118.3, 113.2, 109.4, 109.4, 107.5, 106.9, 39.1, 20.1;
IR (ATR, cm-1) 2924, 1732, 1694, 1570, 1474, 1434, 1418, 1380,
1347, 1316, 1288, 1242, 1160, 1197, 1115, 1084, 1041, 895, 857,
808, 782, 748, 698, 641, 607, 562. HRMS calcd for C18H15ClN2
[M+H]+: 295.0996 found: 295.1001.
4.5. Synthesis of 5-methyl-11-(1-(prop-2-yn-1-yl)-1H-pyrrol-
2-yl)-11H-dipyrrolo[1,2-d:2',1'-g][1,4]diazepine (36)
To a stirred solution of 5-methyl-11-(1H-pyrrol-2-yl)-11H-
dipyrrolo[1,2-d:2',1'-g][1,4]diazepine (30f) (0.5 g, 1.7 mmol) in
DMF (20 mL) was added propargyl bromide (0.170 mL, 2.04
mmol) in DMF (5 mL) at 0 °C over a period of 30 min and the
reaction was followed by portionwise addition of NaH (91.0 mg,
4.08 mmol). The reaction was completed after 12 h. After
addition of water the mixture was extracted with EtOAc (3 × 50
mL). Then the organic extracts were washed with brine (8 × 50
mL) and dried over MgSO4. The eluent was removed under
reduced pressure and the residue was purified with gradient
column chromatography eluted with hexane:ethyl acetate (20:1 to
7:1).Compound 36 product was isolated as brown sticky solid
4.4.5. Synthesis of 11-(4-methoxyphenyl)-5-methyl-11H-
dipyrrolo[1,2-d:2',1'-g][1,4]diazepine (30e)
1
A stirred solution of 2-[(4-methoxyphenyl)(1H-pyrrol-2-
yl)methyl]-1-prop-2-ynyl-1H-pyrrole (20e) (0.15 g, 0.5 mmol) in
DMF (15 mL) was reacted with NaH (33.0 mg, 1.5 mmol) as
described above to give cyclization product 30e. Yellow needles
(0.44 g, 61 %). H NMR (400 MHz, CDCl3): δ 6.96 – 6.84 (m,
1H), 6.78 – 6.70 (m, 1H), 6.67 – 6.60 (m, 1H), 6.44 (s, 1H), 6.30
– 6.22 (m, 1H), 6.22 – 6.17 (m, 1H), 6.11 – 6.02 (m, 3H), 5.69
(bs, 1H), 5.61 (s, 1H), 4.60 (dd, A-part of AB-system, Jgem = 17.7
1
(0.12 g, 87%) from EtOAc/hexane, m. 65-68 °C. H NMR (400
and J = 2.3 Hz, 1H, HCH), 4.54 dd, B-part of AB-system, Jgem
=

9
19. Menges, N.; Sari, O.; Abdullayev, Y.; Erdem, S. S.; Balci, M. J.
17.7 and J = 2.3 Hz, 1H, HCH), 2.43 (t, J = 2.3 Hz, C≡CH), 2.27
(s, 3H, CH3); 13C NMR (101 MHz, CDCl3) δ 133.8, 133.2, 129.5,
123.3, 121.4, 120.3, 118.3, 113.0, 109.7, 109.6, 109.1, 107.1,
107.1, 106.4, 78.6, 73.5, 37.0, 36.1, 19.9. IR (ATR, cm-1) 3264,
1698, 1480, 1424, 1394, 1266, 1250, 1237, 1225, 1184, 1163,
1120, 1087, 1075, 1033, 1019, 938, 909, 886, 852, 793, 771, 714,
701, 647, 617, 609; HRMS calcd for C19H17N3 [M+H]+: 288.1495
found: 288.1514.
ACCEPTED MANUSCRIPT
Org. Chem. 2013, 78, 5184−5195.
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Acknowledgements
Financial support from the Scientific and Technological
Research Council of Turkey (TUBITAK, grant no. TBAG-112
T360), the Turkish Academy of Sciences (TUBA), and the
Middle East Technical University (METU) is gratefully
acknowledged.
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Supplementary Material
18. (a) Ozer, M. S.; Koza, G.; Sahin, E.; Balci, M. Tetrahedron Lett.
2013, 54, 6553–6556.
Supplementary data (1D and 2D) NMR spectra (35 pages) can
be found in the online version, at http://dx.doi.org/...
(b) Balci, M. Synthesis 2018, 50, 1373–1401.