Synthesis of new pyrrole and pyrrolo[2,3-d]pyrimidine derivatives of potential antioxidant activity

Article abstract of DOI:10.1135/cccc2009566

New 2-amino-3-cyanopyrrole derivatives were prepared and converted to 7-deazapurines. 7-Deazaadenine 6 was synthesized by different methods and alkylated with alkyl iodides to afford the quaternized 3- alkylpyrrolopyrimidinium iodide salts 8. The latter salts were dequaternized to N-alkylpyrrolo[2,3-d]pyrimidin-4-amines 12. Compounds 12 were identical to the products obtained from reactions of 4-chloro-7-(4-fluorophenyl)-5-p-tolyl-7H- pyrrolo-[2,3-d]pyrimidine 11 with methyl- or ethylamine in the presence of a catalyst. The thione 13 and its related 4-methylthio- and 4-ylcarbonothioate derivatives 14a, 14b were obtained. The triazolo- 17a-17e, benzenesulfonamido- 19, and tetrazolopyrrolopyrimidine 21 derivatives were synthesized. Several examples of the synthesized pyrrole- and pyrrolo[2,3-d]pyrimidine derivatives showed high to remarkable antioxidant scavenging activity as measured by their ability to scavenge the 1,1-diphenyl-2-picrylhydrazyl (DPPH) free radical

Full text of DOI:10.1135/cccc2009566

New Pyrrole and Pyrrolo[2,3-d]pyrimidine Derivatives
813
SYNTHESIS OF NEW PYRROLE AND PYRROLO[2,3-d]PYRIMIDINE
DERIVATIVES OF POTENTIAL ANTIOXIDANT ACTIVITY
1,
2
Khairy Abdelhameed Mohsen EL-BAYOUKI *, Wahid Mohmoud BASYOUNI
3
and Eslam Attya MOSTAFA
1
National Research Centre, Dokki, 11111 Cairo, Egypt; e-mail: khelbayouki@yahoo.com,
w_basyouni2002@yahoo.com, atyaeslam@yahoo.com
2
3
Received December 13, 2009
Accepted April 26, 2010
Published online August 17, 2010
New 2-amino-3-cyanopyrrole derivatives were prepared and converted to 7-deazapurines.
7-Deazaadenine 6 was synthesized by different methods and alkylated with alkyl iodides to
afford the quaternized 3-alkylpyrrolopyrimidinium iodide salts 8. The latter salts were
dequaternized to N-alkylpyrrolo[2,3-d]pyrimidin-4-amines 12. Compounds 12 were identical
to the products obtained from reactions of 4-chloro-7-(4-fluorophenyl)-5-p-tolyl-7H-pyrrolo-
[2,3-d]pyrimidine 11 with methyl- or ethylamine in the presence of a catalyst. The thione
13 and its related 4-methylthio- and 4-ylcarbonothioate derivatives 14a, 14b were obtained.
The triazolo- 17a–17e, benzenesulfonamido- 19, and tetrazolopyrrolopyrimidine 21 deriva-
tives were synthesized. Several examples of the synthesized pyrrole- and pyrrolo[2,3-d]pyrim-
idine derivatives showed high to remarkable antioxidant scavenging activity as measured by
their ability to scavenge the 1,1-diphenyl-2-picrylhydrazyl (DPPH) free radical
Keywords: Antioxidant activity; Pyrrole; Pyrrolo[2,3-d]pyrimidine; Quaternization; Triazole;
Tetrazole.
It is well known that pyrrolic compounds such as polypyrroles, poly- or
heteroarylpyrroles present an electronic delocalization, conferring to these
molecules electric conductor and oxidizable properties1, also, other
2-aminopyrrole-3-carbonitrile derivatives having β-enaminonitrile moiety
are well known to be highly reactive and were used as intermediates for the
synthesis of new pyrrolo[2,3-d]pyrimidine derivatives2. 7-Deazapurine
(pyrrolo[2,3-d]pyrimidine) is a heterobicyclic system bearing structural
analogy both to purine and indole and as such might be expected to have
pharmacological interest and perhaps clinical value. This heterosystem is
widely distributed in nature, being the part of antibiotics: tubercidin,
toyocamycin, sangivamycin, cadeguomycin, rigidin alkaloids3. Moreover,
some 2,4-diaminopyrrolo[2,3-d]pyrimidine derivatives were identified to
have a much greater blood brain barrier (BBB) penetration capacity and
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© 2010 Institute of Organic Chemistry and Biochemistry
doi:10.1135/cccc2009566

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El-Bayouki, Basyouni, Mostafa:
high-lipophilic antioxidant activity with protective effects4. For example,
some 2,4-diaminopyrrolo[2,3-d]pyrimidines and 6,7-dimethyl-2,4-di-
pyrrolidin-1-yl-7H-pyrrolo[2,3-d]pyrimidine were reported for their anti-
oxidant, neuroprotective, and antiasthma properties5. Furthermore, it is
well known that organofluorine compounds display a variety of interesting
pharmacological and agrochemical properties. A series of fluoro-substituted
4-(dialkylamino)pyrrolo[2,3-d]pyrimidines has been synthesized and re-
ported for their binding affinity for corticotrophin releasing hormone
type 1 receptor (CRHR1) and some other compounds were presented as
promising candidates for the development of 18F-containing non-peptide
6
PET radioligands for CRHR1
.
Therefore, it was intended to synthesize new pyrrole- and pyrrolo-
[2,3-d]pyrimidine derivatives bearing fluorophenyl and p-tolyl moieties for
their potential antioxidant activity.
RESULTS AND DISCUSSION
2-Amino-1-(4-fluorophenyl)-4-p-tolyl-1H-pyrrole-3-carbonitrile (1) was pre-
pared under mild Gewald reaction condition7, from 2-(4-fluorophenyl-
amino)-1-p-tolylethanone (prepared from 2-bromo-1-p-tolylethanone and
p-fluoroaniline) upon reaction with malononitrile in the presence of so-
dium ethoxide.
When the pyrrole-3-carbonitrile 1 was treated with chloroacetyl chloride
at room temperature, the desired monoacetyl derivative 2 was obtained in
86% yield. Heating of 1 in a mixture of acetic acid–acetic anhydride for
a short time afforded the unexpected diacetyl product 3 in 79% yield.
1
Structural elucidation of products 2 and 3 was based on IR, H NMR and
mass spectroscopic determinations (see Experimental).
Hot treatment of 1 with trimethyl orthoformate or triethyl orthoformate
provided the formimidates 4a and 4b in 79 and 86% yield, respectively.
1
IR and H NMR spectra accorded well the proposed structure of products 4
(Scheme 1).
The latter formimidates when reacted with saturated ethanolic ammonia
solution at room temperature gave the (pyrrol-2-yl)formimidamide 5 in
1
85% yield, rather than the expected 7-deazaadenine 6. H NMR spectrum of
5 revealed NH2 proton signals (broad) at δ ~ 2.38 ppm (D2O-exchangeable)
which is absent in the spectra of their parents 4. Mass spectrum of 5
showed a molecular ion peak m/z at 318 (100%). Noteworthy to mention
that such method for the synthesis of product 5 has been previously re-
ported for preparation of (E)-N′-(4-(3-(benzyloxy)phenyl)-3-cyano-1H-
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New Pyrrole and Pyrrolo[2,3-d]pyrimidine Derivatives
815
pyrrol-2-yl)formimidamide form 2-amino-4-(3-(benzyloxy)phenyl)-1H-
pyrrole-3-carbonitrile8.
The 7-deazaadenine 6 was synthesized smoothly in 86% yield upon heat-
ing the pyrrolecarbonitrile 1 in formamide solution. Also, the interesting
feature of N-arylidenamine fragment was used instead of the amino group
of the pyrrole 1 to synthesize product 6. Thus, when the corresponding
2-arylideneamino-1-(4-fluorophenyl)-4-p-tolyl-1H-pyrole-3-carbonitrile de-
rivatives 7b (prepared from reaction of 1 with the desired aldehyde in 92
and 78.5% yield, respectively) were heated with formamide until formation
of a precipitate and disappearance of the colored Schiff base afforded the
Reagents and conditions: a) chloroacetyl chloride, stirring at r.t., (86%); b) acetic acid/acetic anhydride mixture
(1:1), heat, (79%); c) trimethyl- or triethyl orthoformate, heating, (79.9%); d) ethanolicammonia stirring for ~10 h
at r.t., (85%)
SCHEME 1
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816
El-Bayouki, Basyouni, Mostafa:
N′-(3-cyano-1-(4-fluorophenyl)-4-p-tolyl-1H-pyrrol-2-yl)formimidamide (5)
(m.p. and mixed m.p., 85% yield). Upon heating product 5 for 1 h in etha-
nol in the presence of alkaline catalyst, the 7-deazaadenine 6 was obtained
(m.p. and mixed m.p., 67% yield) (Scheme 2).
Reagents and conditions: i) the desired aldehyde, dilute KOH solution (1–2 drops), warming for 5 min, (92 and
78.5%); ii) formamide, heating for ~1 h, (85%); iii) ethanol dilute NaOH, heat for 1 h, (67%)
SCHEME 2
1
Structure of compound 6 was confirmed by studying of its IR, H NMR
and mass spectral determinations. Preparation of some 4-amino-6-aryl-
5-cyanopyrrolo[2,3-d]pyrimidine derivatives has been reported from
2-(N-arylideneamino)-5-aryl-3,4-dicyanopyrrole and formamide at reflux
temperature9.
When the 7-deazaadenine 6 was treated with either methyl or ethyl io-
dide in hot DMF solution, the corresponding 3-alkylpyrrolopyrimidinium
iodide salts 8a and 8b were afforded (62 and 50% yield, respectively), rather
than the probable 1-alkylpyrrolopyrimidinium salts 9 (Scheme 3).
Comparison of the 13C NMR spectra of 8 with that of the non-alkylated
product 6 cleared that the signals due to C-2 and C-4 were down-field
shifted (de-shielded). For example, these signals appeared in the case of
compounds 8b at 160.82 and 162.77 ppm, respectively (in case of com-
pound 6 these signals were revealed, shielded at 152.30 and 157.52 ppm,
respectively). Presumably, such noticeable shielding can be explained as be-
ing due to incorporation of the alkyl substituent at the N3-position of the
pyrrolo-pyrimidine ring, thus, supporting the proposed structure of type 8
rather than the probable structure of type 9.
This finding accorded well with the previously reported observation for
the 13C NMR of some pyrimidinium and 1-methylpyrimidinium salts as
well for some purinium and furo[2,3-d]pyrimidinium salts10.
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New Pyrrole and Pyrrolo[2,3-d]pyrimidine Derivatives
817
Reagents and conditions: a) alkyl halide, DMF, heating for 8 h, (62 and 50%)
SCHEME 3
In order to confirm and support the structure of the pyrroloprimidinium
salts 8, their dequaternization was tried. Thus, upon warming the iodide
salts 8 in an ethanolic sodium hydroxide solution, their dequaternized and
rearranged products N-alkylpyrrolo[2,3-d]pyrimidin-4-amines 12a and 12b
1
were afforded in 49 and 79% yield, respectively. H NMR and mass spectra
of 12a agreed its structure. The latter products were found to be identical
(m.p. and mixed m.p.) with the products obtained from reactions of
4-chloro-7-(4-fluorophenyl)-5-p-tolyl-7H-pyrrolo[2,3-d]pyrimidine (11) with
methyl- or ethylamines in the presence of triethylamine as a catalyst. Prod-
uct 11 was obtained in 81% yield from hot reaction of POCl3 with
pyrrolo[2,3-d]pyrimidin-4H-(7H)-one 10 (prepared in the present work via
heating the starting pyrrolecarbonitrile 1 with formic acid, through a reac-
tion believed to proceed through the formation of the corresponding
2-amino-3-carboxamidopyrrole followed by cyclization) (Scheme 4).
Mass spectra of the salts 8a and 8b exhibited molecular ion peaks m/z at
335 (25%) and 349 (13%), respectively, which corresponds to M+ – HI. This
observation suggested the splitting of HI in the mass spectrometer11.
The present work was directed to probe reaction of 4-chloro-7-(4-fluoro-
phenyl)-5-p-tolyl-7H-pyrrolo[2,3-d]pyrimidine (11) with thiourea. Thus,
when the 4-chloro product 11 was heated with thiourea in absolute etha-
nol, the thione 13 was readily obtained in 71% yield (see Experimental for
structure confirmation data). Previously some thiopurine derivatives were
obtained by treating chloropurines with thiourea12 (Scheme 5).
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El-Bayouki, Basyouni, Mostafa:
Reagents and conditions: a) POCl , heat, (82%); b) desired aliphatic amine, ethanol, heat, (49 and 79%); c)
3
ethanolic NaOH, warming
SCHEME 4
Reagents and conditions: i) thiourea, ethanl, short time heating, (71%); ii) dimethyl sulfate, alcoholic KOH,
stirring at r.t. (72%); iii) ethyl chloroformate, benzene, KOH, stirring at r.t. (79%)
SCHEME 5
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New Pyrrole and Pyrrolo[2,3-d]pyrimidine Derivatives
819
Reaction of the thione 13 with dimethyl sulfate in ethanol–KOH at room
temperature provided the corresponding methylthio derivative 14a in 72%
yield. Meanwhile, its treatment with ethyl chloroformate in benzene at
room temperature afforded the pyrrolo[2,3-d]pyrimidin-4-ylcarbonothioate
14b in 79% yield.
In the present investigation, it was found that the formimidates 4a or 4b
upon condensation with hydrazine hydrate–ethanol solution at room tem-
perature ring closure occurred and the 4-iminopyrrolo[2,3-d]pyrimidin-
3-amine 15 was obtained in 84% yield. Also, when the same reaction was
repeated under the same conditions using either methyl- or ethylamine
ring closure and alkylation at N-3 position of the pyrimidine ring of 4
occurred, affording 7-(4-fluorophenyl)-3-substituted-5-p-tolyl-3H-pyrrolo-
[2,3-d]pyrimidin-4-(7H)-imines 16a and 16b in 80 and 60% yield, respec-
tively. Worthy to note that only in the case of reaction of 4b with
ethylamine, the open chain product N′-(3-cyano-1-(4-fluorophenyl)-
4-p-tolyl-1H-pyrrol-2-yl)-N-ethylformimidamide (16c) was separated and
purified as a minor product (40% yield), which upon heating in sodium
ethoxide–absolute ethanol solution for 5 h afforded product 16b (m.p. and
mixed m.p.) (Scheme 6).
Reagents and conditions: a) hydrazine hydrate/ethanol, stirring at r.t., (84%); b) methyl- or ethyl amine,
ethanol, stirring at r.t., (60%); c) heating in NaOEt in absolute EtOH, 5 h
SCHEME 6
Structure of compounds 15 and 16 was elucidated on the basis of correct
elemental analyses and spectral data (see Experimental).
Triazolo- and tetrazolopyrimidines are well known for their biological
activities and exhibited in particular antitumor, hypotensive, antiseptic,
antiarrhythmic and antiasthmatic properties, high affinity and selectivity
for human adenosine A3 receptor antagonists, and antibacterial and anti-
fungal activities13–15. It has also been reported16 that [1,2,4]triazolo-
[4,3-c]pyrimidine derivatives could not be isolated even when the reaction
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820
El-Bayouki, Basyouni, Mostafa:
mixture was heated at a low temperature and can isomerize under different
suitable conditions to the thermodynamically more stable [1,2,4]tri-
azolo[1,5-c]. This isomerization can occur when [1,2,4]triazolo[4,3-c]pyrimi-
dine derivative was treated with an acid or base, or thermally.
Therefore, the pyrrolo[3,2-e][1,2,4]triazolo[1,5-c]pyrimidines 17a–17e
were synthesized (81–62% yield) in the present work, when the imino com-
pound 15 was left to react with some desired aldehydes in hot ethanol.
Structure elucidation of products 17 based on correct elemental analyses
and careful studying for their PMR and mass spectral determinations (see
Experimental).
In the case of benzaldehyde reaction with the imino product 15, the ex-
pected N-benzylidene derivative 18 was separated as by-product in 24%
yield and identified. Structure of product 18 was confirmed from its IR and
mass spectral determinations. Its UV spectrum indicated the presence of
unsaturated chromophoric N=CH-Ph moiety in its structure. Also, when a
pure sample of product 18 was heated in ethanol for 5 h, the imino product
17a was afforded (m.p. and mixed m.p.). Some N-arylidene derivatives have
been synthesized and characterized previously17 from 6-amino-3-benzyl-
7-imino-5-methyl-2,3,6,7-tetrahydrothiazolo[4,5-d]pyrimidin-2-thione.
Due to the fact that the sulfonamide partial structure appears to belong
to the so-called “privileged structures” in medicinal chemistry and it exhib-
its favorable pharmacokinetic properties including metabolic stability18. So,
it was interesting to synthesize newer pyrrolo[2,3-d]pyrimidine derivatives
incorporating sulfonamide moiety in their structure. Thus, when the imino
product 15 reacted with either benzenesulfonyl- or 4-methylbenzenesulfo-
nyl chloride in dry benzene, the corresponding benzene sulfonamides 19a
and 19b were afforded in 73 and 79% yield, respectively, leaving the
N-(3-amino) group intact (Scheme 7).
Structural assignment of the sulfonamides 19a and 19b was based on cor-
rect elemental analyses and spectroscopic determinations. IR spectra of the
latter products exhibited NH2 (amino and imino) stretching vibrations.
1H NMR spectra of 19a and 19b (DMSO-d6) displayed proton signals for
CH3, NH2 and C2-H, beside the aromatic proton signals and their mass spec-
tra accorded well the proposed structures (see Experimental).
In the present work, synthesis of 7-(4-fluorophenyl)-9-p-tolyl-7H-pyrrolo-
[3,2-e]tetrazolo[1,5-c]pyrimidine (21) was tried by two different routes. In
the first route, the reaction between the chloro compound 11 and sodium
azide in the presence of ammonium chloride and DMSO as a solvent af-
forded the tetrazolopyrimidine 21 in 90% yield. Ammonium chloride was
used for in situ generation of ammonium azide. In the second route, the
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New Pyrrole and Pyrrolo[2,3-d]pyrimidine Derivatives
821
Reagents and conditions: a) desired aldehyde, ethanol, heating for 12 h, (81–62%); b) ethanol, heating for
5 h; c) desired benzenesulfonyl chloride, dry benzene, stirring at r.t. (73 and 79%)
SCHEME 7
same tetrazole product 21 can also be obtained in 66% yield by
diazotization of the hydrazide 20 (prepared from 11 and hydrazine hydrate
in 93% yield) upon reaction with sodium nitrite in acetic acid while cool-
ing (0–5 °C).
As the reactive cleavage of the tetrazole moiety constituted a syntheti-
cally important way for the preparation of amines, it was found that the
7-deazaadenine
6
was synthesized in 67% yield from the
pyrrolotetrazolopyrimidine 21 employing activated zinc dusts in acetic acid
as a reducing agent under boiling conditions. The amine 6 was identical
with that obtained from reactions of either 2-amino-3-cyanopyrrole 1 or
2-arylideneamino-1-(4-fluorophenyl)-4-p-tolyl-1H-pyrrole-3-carbonitrile (4)
with formamide (Scheme 8).
The absence of absorption in IR spectrum of 21 near 2100 cm–1 can ex-
clude the possibility of the azide structure 21A formation19. Also formation
of the tetrazole 21 from the hydrazide 20 was supported by the absence of
NHNH2 functional group in its IR spectrum, which is clearly noticed in the
spectrum of the hydrazide 20. Mass spectrum of the tetrazole 21 showed
regular fragmentation pattern giving a molecular ion peak m/z at 344 (35%)
with the fragments at 316, 289 and 288, resulting due to successive elimina-
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822
El-Bayouki, Basyouni, Mostafa:
tion of nitrogen and hydrogen cyanide or subsequent elimination of two
nitrogen molecules. 1H NMR spectrum of 21 (DMSO-d6) displayed reso-
nances due to aromatic protons, CH3 and C2-H proton signals, respectively.
Also, the spectrum revealed the absence of NH proton signals which were
clearly displayed in the spectrum of the hydrazide 20.
Reagents and conditions: a) hydrazine hydrate, ethanol, heat, (93%); b) sodium nitrite, acetic acid, cooling
at 0–5 °C, (90%); c) sodium azide, ammonium chloride, DMSO, heat at 90 °C, (66%); d) acetic acid/Zn, boiling,
(67%)
SCHEME 8
ANTIOXIDANT ACTIVITY
There is an increasing interest in antioxidants, particularly in those in-
tended to prevent the presumed deleterious effects of free radicals in
the human body, and to prevent the deterioration of fats and other constit-
uents of foodstuffs. Antioxidants are defined as substances that when pres-
ent at low concentrations compared with those of an oxidizable substrate
significantly delay or prevent oxidation of that substrate. 1,1-Diphenyl-
2-picrylhydrazyl (DPPH) is a stable free radical often used as a substance to
evaluate the antioxidant capacity of an oxidant20,21
.
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New Pyrrole and Pyrrolo[2,3-d]pyrimidine Derivatives
823
Results of Antioxidant Screening by DPPH Assay
The antioxidant activity of some selected pyrrole- and pyrrolo[2,3-d]-
pyrimidine derivatives as measured by their ability to scavenge DPPH free
radical is represented in Table I and Fig. 1. The obtained data showed that:
1) 2-Amino-1-(4-fluorophenyl)-4-p-tolyl-1H-pyrrole-3-carbonitrile (1) showed
the best and highest scavenging activity (SA) (100%) at the concentration
of 0.2 mg/ml as compared with ascorbic acid followed by the pyrrole-
formimidate 4a which showed SA 53.37%. Two other tested pyrrole deriva-
tives 2 and 3 exhibited weak scavenging activity (27.10 and 7.28%).
Apparently, the high SA gained by the pyrrolocarbonitrile 1 can be attrib-
uted to the presence and ability of the free NH2 group to reduce free radical
formation and to scavenge free radicals, meanwhile it is obvious that any
substitution for this group lowers the gained antioxidant activity.
2) Pyrrolopyrimidine derivatives 7-(4-fluorophenyl)-5-p-tolyl-3H-pyrrole-
[2,3-d]pyrimidin-4(7H)-one 10, 7-(4-fluorophenyl)-4-hydrazinyl-5-p-tolyl-
7H-pyrrolo[2,3-d]pyrimidine 20 and 7-(4-fluorophenyl)-9-p-tolyl-7H-pyrrolo-
[3,2-e]tetrazole[1,5-c]pyrimidine 21 were of similar high SA activity (100%)
as ascorbic acid. Meanwhile, 7-(4-fluorophenyl)-4-(methylthio)-5-p-tolyl-
7H-pyrrolo[2,3-d]pyrimidine (14a) gained 52.34% SA activity. The tested
pyrrolo[2,3-d]pyrimidine derivatives 8b and 15 exhibited antioxidant activ-
ity lower than 50% (31.33–2.14%). Presumably, the remarkable antioxidant
activities gained by products 10, 20 and 21 could be perhaps due to the
presence of NH (or NH2) grouping in their structures.
FIG. 1
Screening of antioxidant activity by the DPPH assay
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824
El-Bayouki, Basyouni, Mostafa:
TABLE I
Antioxidant activity of some pyrrole- and pyrrolopyrimidine derivatives
Scavenging
Double integration
area
Compound
DPPH
Concentration
activity, %
0
10–3 M of
832413
1 mM ethanol
Pyrrole derivatives
1
2
0.2
0.2
0.2
0.2
100
0
27.1
7.28
53.37
606772
771850
3881218
3
4a
Pyrrolopyrimidine derivatives
8b
0.2
0.2
0.2
0.2
0.2
0.2
2.14
100
814562
10
0
14a
52.34
7.18
397742
15
772659
20
21
100
0
0
0
100
100
Ascorbic acid
10–3 M/
1 mM ethanol
So, the pyrrole 1 as well as the pyrrolo[2,3-d]pyrimidine derivatives 10,
20 and 21 can be presented as potential “antioxidant candidate(s)”, after
carrying out, in the future, further necessary applications and precautions
regarding to human health safety.
CONCLUSION
New pyrrole- and pyrrolo[2,3-d]pyrimidine derivatives, e.g. N′-(3-cyano-
1-(4-fluorophenyl)-4-p-tolyl-1H-pyrrol-2-yl)formimidamide, pyrrolepyrim-
idine-4-amine, 3-alkylpyrrolopyrimidinium iodide salts, N-alkylpyrrolo-
[2,3-d]pyrimidin-4-amines, 7-(4-fluorophenyl)-5-p-tolyl-3H-pyrrolo[2,3-d]-
pyrimidin-4(7H)-thione, 7-(4-fluorophenyl)-4-(methylthio)-5-p-tolyl-7H-pyrrolo-
[2,3-d]pyrimidine and O-ethyl-S-7-(4-fluorophenyl)-5-p-tolyl-7H-pyrrolo-
[2,3-d]pyrimidin-4-ylcarbonothioate were synthesized and characterized.
Several examples of the synthesized compounds showed high to remarkable
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New Pyrrole and Pyrrolo[2,3-d]pyrimidine Derivatives
825
antioxidant scavenging activity, compared to ascorbic acid, as measured by
their ability to scavenge the DPPH free radical.
EXPERIMENTAL
All melting points are uncorrected. Microanalyses were carried out by the Micro analytical
Laboratory, National Research Center, Cairo, Egypt. IR spectra (KBr-disc; ν in cm–1) were re-
corded using a Jasco FT/IR-6100 spectrophotometer. UV-Vis spectra were recorded in metha-
nol on a Schimadzu UV-visible recoding spectrophotometer 240. 1H and 13C NMR spectra
(δ in ppm, J in Hz) were recorded in DMSO-d6 using a Varian mercury or a Varian Gemini
with chemical shift in δ from Me4Si. Mass spectra were recorded on a GC/MS finnigan
SSQ 7000(EIev70) spectrophotometer. Antioxidant screening was carried out using a Brucker
ELEXSYS-E500 electron paramagnetic spectrometer (Central Laboratory Services unite, Na-
tional Research Center, Cairo, Egypt) at room temperature; conditions used: microwave fre-
quency 9.77 GHz, microwave power 2 mW, modulation amplitude 4.0 G, receiver gain 60 db,
and sweep time 20.97 s. The antioxidant activity of the selected compound was assessed by
measuring the ability of each compound to scavenge the free radical of 1,1-diphenyl-
2-picrylhydrazyl (DPPH) using electron spin resonance (ESR) spectroscopy22
.
Blank probe was obtained by mixing 10–3 M of 1 mM ethanol solution of DPPH and
10–3 M/1 ml ethanol (as control solution containing no antioxidant). Standard solution was
prepared from Vitamin C (as a standard) with concentration 10–3 M/1 mM ethanol. Both the
test compounds solutions and the standard was added to 10–3 M of 1 mM ethanol solution of
DPPH (stock) to initiate the antioxidant–radical reaction. The concentration of the investi-
gated compound was 0.2 mg/ml ethanol. After that the mixture was stirred for 1 min, trans-
ferred to a quartz flat cell ER-160ft and analyzed by ESR spectroscopy. ESR signal of DPPH in
methanol usually appears at g = 2.006 characterizing the free radical. The decrease of this
signal after mixing with the solution of each compound is taken as indication of the antiox-
idant activity, measured as a double integration area (DIA).
[DIA (DPPH) – DIA (DPPH + Compound)]× 100
% Activity =
DIA (DPPH)
The scavenging activity (SA) of each investigated compound and Vitamin C was estimated
by comparing the DPPH signals in the antioxidant–radical reaction mixture and the control
reaction at the same time, and expressed percentage DPPH remaining. The DPPH-radical
scavenging activity of the investigated compound and Vitamin C was calculated using the
formula: SA = 100 × (A0 – Ax)/A0 [%], where Ax and A0 are the double-integral ESR for the
first line of samples in the presence and absence of test compounds, respectively.
2-Amino-1-(4-fluorophenyl)-4-p-tolyl-1H-pyrrole-3-carbonitrile (1)
To a solution of 2-(4-fluorophenylamino)-1-p-tolylethanone (7 g, 0.027 mol) in absolute eth-
anol (80 ml), malononitrile (2 g, 0.03 mol) was added and the mixture was heated under re-
flux while stirring, then sodium ethoxide (2.7 g) in absolute ethanol (50 ml) was added
dropwise to the reaction mixture. The whole mixture was heated under reflux for 3 h. The
solid product separated out after cooling was filtered off, washed with cold water, dried and
crystallized to give 1 as brown crystals (ethanol), yield 4.5 mg, m.p. 154–156 °C. IR: 3421,
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El-Bayouki, Basyouni, Mostafa:
3337 (NH2), 2196 (C≡N). For C18H14FN3 (291.32) calculated: 74.21% C, 4.84% H, 14.42% N;
found: 74.01% C, 4.65% H, 14.51% N.
2-Chloro-N-(3-cyano-1-(4-fluorophenyl)-4-p-tolyl-1H-pyrrol-2-yl)acetamide (2)
To a stirred solution of pyrrole 1 (0.01 mol) in dioxane (20 ml) containing few drops of
triethylamine, chloroacetylchloride was added dropwise. Stirring was continued for 5 h. The
reaction mixture was poured onto crushed ice. The obtained solid product was filtered, dried
and crystallized to give 2 as white crystals (methanol), m.p.178–180 °C, yield 86%. IR: 3180
(NH), 2229 (C≡N), 1676 (C=O). 1H NMR (200 MHz): 2.35 (s, 3 H, CH3), 4.26 (s, 2 H, CH2),
7.27–7.63 (m, 9 H, ArH), 10.54 (b, 1 H, NH, D2O-exchangeable). For C20H15ClFN3O (367.80)
calculated: 65.31% C, 4.11% H, 11.42% N; found: 65.42% C, 4.20% H, 11.60% N.
N-Acetyl-N-(3-cyano-1-(4-fluorophenyl)-4-p-tolyl-1H-pyrrol-2-yl)acetamide (3)
A solution of 1 (0.01 mol) in mixture of acetic acid (10 ml) and acetic anhydride (40 ml)
was heated under reflux for 6 h. Left to cool, the reaction mixture was poured onto crushed
ice. The obtained solid product was filtered, dried and crystallized to give 3 as white crystals
(methanol), m.p. 140–142 °C, yield 79%. IR: 2222 (C≡N), 1725 (C=O). MS, m/z (%): 375 (M,
30), 377 (3), 292 (100). 1H NMR (270 MHz): 2.27 (s, 6 H, 2 CH3), 2.37 (s, 3 H, CH3),
7.31–7.80 (m, 9 H, ArH and C5-H). For C22H18FN3O2 (375.40) calculated: 70.39% C, 4.83% H,
11.9% N; found: 69.91% C, 4.67% H, 10.98% N.
Alkyl N-3-Cyano-1-(4-fluorophenyl)-4-p-tolyl-1H-pyrrol-2-ylformimidate (4).
General Method
To a solution of 1 (0.01 mol) in methyl (or ethyl) orthoformate (30 ml), trifluoroacetic acid
(0.5 ml) was added. The reaction mixture was heated under reflux for 3 h. Left to cool,
the obtained solid product was filtered and crystallized from the proper solvent to give 4a
and 4b.
Methyl N-3-cyano-1-(4-fluorophenyl)-4-p-tolyl-1H-pyrrol-2-ylformimidate (4a): Yellowish crystals
(methanol), m.p. 152–154 °C, yield 79%. IR: 2214 (C≡N), 1635 (C=N). 1H NMR (200 MHz):
2.34 (s, 3 H, CH3), 3.77 (s, 3 H, OCH3), 7.24 (d, 2 H, J = 8.0, ArH), 7.34–7.45 (m, 5 H, ArH),
7.61 (d, 2 H, J = 7.6, ArH), 8.6 (s, 1 H, CH=N). For C20H16FN3O (333.36) calculated:
72.06% C, 4.84% H, 12.61% N; found: 72.20% C, 4.76% H, 12.54% N.
Ethyl N-3-cyano-1-(4-fluorophenyl)-4-p-tolyl-1H-pyrrol-2-ylformimidate (4b): Yellowish crystals
(methanol), m.p. 138–140 °C, yield 86%. IR: 2210 (C≡N), 1631 (C=N). MS, m/z (%): 347
(45.4), 290 (22.9), 155 (52.9), 95 (100). For C21H18FN3O (347.39) calculated: 72.61% C,
5.22% H, 12.10% N; found: 72.67% C, 5.32% H, 12.24% N.
N′-(3-Cyano-1-(4-fluorophenyl)-4-p-tolyl-1H-pyrrol-2-yl)formimidamide (5)
To a suspension of 4a or 4b (0.01 mol) in ethanol (30 ml), ammonia solution (5 ml, 33%)
was added. The reaction mixture was stirred at room temperature for 10 h. The obtained
precipitate was filtered and crystallized to give 5 as yellow crystals (ethanol), m.p.
188–190 °C, yield 85%. IR: 3396, 3331 (NH2), 2197 (C≡N), 1677 (C=N). 1H NMR (270 MHz):
2.32 (s, 3 H, CH3), 2.38 (s, 2 H, NH2, D2O-exchangeable), 7.16–7.66 (m, 9 H, ArH), 8.21 (s,
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New Pyrrole and Pyrrolo[2,3-d]pyrimidine Derivatives
827
1 H, CH=N). MS, m/z (%): 319 (M+, 41), 318 (M, 100), 94.93 (39). For C19H15FN4 (318.35)
calculated: 71.68% C, 4.75% H, 17.60% N; found: 71.66% C, 4.80% H, 17.45% N.
7-(4-Fluorophenyl)-5-p-tolyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (6)
Method A. A solution of 1 (0.01 mol) in formamide (30 ml) was heated under reflux for
3 h and left to cool. The obtained solid product was filtered and crystallized to give 6.
Method B. A mixture of 7a or 7b (0.01 mol) and formamide (20 ml) was heated under re-
flux until the color of the Schiff base 7 disappeared and a precipitate was formed. The pre-
cipitate was filtered and purified to give clean cut of 5 as an intermediate product (m.p. and
mixed m.p.). Upon heating the product 5 in ethanol for 1 h in the presence of few drops of
dilute NaOH, the reaction mixture was left to cool, the obtained solid product was filtered
and crystallized to give 6 (m.p. and mixed m.p.).
Method C. The tetrazole 21 (0.01 mol) was dissolved in glacial acetic acid (10 ml), zinc
powder (0.5 g) was added portion-wise while stirring over a period of 30 min (an exothermic
reaction was observed). After complete addition, the reaction mixture was heated under re-
flux for 4 h. Left to cool and poured onto crushed ice. The resulting mixture was neutralized
(to pH 7) with 6 M ammonia solution and extracted with chloroform (2 × 30 ml). The total
chloroform layer was dried over anhydrous magnesium sulfate, concentrated under vacuum
and cooled to give 6 as pale brown crystals (ethanol), m.p. 178–180 °C, yield 86% (method A),
80% (method B) and 67% (method C), respectively. IR: 3471, 3281 (NH2), 1630 (C=N).
1H NMR (270 MHz): 2.38 (s, 3 H, CH3), 6.23 (b, 2 H, NH2), 7.31–7.94 (m, 9 H, Ar-H and
C6-H), 8.21 (s, 1 H, C2-H). 13C NMR (270 MHz): 152.30 (C2), 157.52 (C4), 100.77 (C4a),
136.29 (C7a), 20.74 (CH3-tolyl), 115–133.79 (C5, C6, aromatics). MS, m/z (%): 319 (M+, 20),
318 (M, 100). For C19H15FN4 (318.35) calculated: 71.68% C, 4.75% H, 17.60% N; found:
71.60% C, 4.77% H, 17.55% N.
Reaction of the Pyrrolecarbonitrile 1 with Benzaldehyde and 2-Thiophenealdehyde.
General Method
To a mixture of 1 (0.01 mol) and the desired aldehyde (0.01 mol) in absolute ethanol (20 ml),
1 ml KOH solution (1%) was added. The reaction mixture was warmed for 15 min. Left to
cool, the obtained solid product was filtered to give 7a or 7b.
2-(Benzylideneamino)-1-(4-fluorophenyl)-4-p-tolyl-1H-pyrrole-3-carbonitrile (7a): Yellow crystals
(cyclohexane), m.p. 210–212 °C, yield 92.9% (1.3 g). IR: 2207 (C≡N), 1613 (C=N). For
C
25H18FN3 (379.43) calculated: 79.14% C, 4.78% H, 11.07% N; found: 79.22% C, 4.88% H,
11.23% N.
(4-Fluorophenyl)-2-(thiophen-2-ylmethyleneamino)-4-p-tolyl-1H-pyrrole-3-carbonitrile (7b): Yel-
low crystals (cyclohexane), m.p. 220–222 °C, yield 78.57% (1.1 g). IR: 2203 (C≡N), 1627
(C=N), 1590 (C=C). For C23H16FN3S (385.46) calculated: 71.67% C, 4.18% H, 10.90% N,
8.32% S; found: 71.65% C, 4.23% H, 11.00% N, 8.35% S.
Reaction of the Pyrrolopyrimidin-4-amine 6 with Alkyl Halides.
General Method
A mixture of 6 (0.01 mol) and the desired alkyl halides (methyl or ethyl iodide) (0.01 mol)
in dimethylformamide (10 ml) was heated under reflux for 8 h. Excess solvent was evapo-
rated under reduced pressure. The remaining residue was triturated with drops of methanol–
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828
El-Bayouki, Basyouni, Mostafa:
acetone mixture. The obtained solid product was filtered, dried and crystallized from metha-
nol to give 8a or 8b.
7-(4-Fluorophenyl)-3-methyl-5-p-tolyl-2,3,4,7-tetrahydro-1H-prrolo[2,3-d]primidin-4-amine,
Iodide Salt (8a): Pale brownish crystals (methanol), m.p. 242–244 °C, yield 62%. IR: 3417,
3259 (NH2), 1656 (C=N). 1H NMR (500 MHz): 2.37 (s, 3 H, CH3), 2.40 (s, 3 H, N-CH3), 7.27
(m, 7 H, ArH), 7.73–7.75 (m, 2 H, ArH), 8.00 (s, 1 H, CH-pyrimidine), 8.34 (b, 2 H, NH2).
MS, m/z (%): 335 [M+ – HI (25)], 332 (87), 331 (100), 318 (48), 317 (26), 291 (8), 127 (11).
–
For C20H18FIN4 (463.31) calculated: 51.85% C, 4.57% H, 12.09% N; found: 51.44% C,
4.33% H, 12.20% N.
3-Ethyl-7-(4-fluorophenyl)-5-p-tolyl-2,3,4,7-terahydro-1H-pyrrolo[2,3-d]pyrimidin-4-amine,
Iodide Salt (8b): Pale brownish crystals (methanol), m.p. 247–249 °C, yield 50%. IR: 3345
(NH2), 2951, 2920 (CH-aliphatic), 1626 (C=N). 1H NMR (500 MHz): 1.33 (t, 3 H, CH3), 2.33
(s, 3 H, CH3), 4.27 (q, 2 H, CH2), 7.31–7.78 (m, ArH, NH2), 7.33 (s, 1 H, CH-pyrrole), 8.52 (s,
1 H, C-2). 13C NMR (500 MHz): 160.82 (C2), 162.77 (C4), 100.54 (C4a), 146.24 (C5), 151.21
(C7a), 14.03 (CH3-ethyl), 21.24 (CH3-tolyl), 39.50 (CH2-ethyl), 116.73–138.52 (C6, aromatics).
MS, m/z (%): 349 [M+ – HI (13)], 348 (15), 347 (62), 350 (24), 318 (base peak, 100). For
–
C
21H20FIN4 (477.34) calculated: 52.84% C, 4.86% H, 11.74% N; found: 53.16% C, 4.68% H,
11.7 4% N.
7-(4-Fluorophenyl)-5-p-tolyl-3H-pyrrolo[2,3-d]pyrimidin-4(7H)-one (10)
A solution of 1 (0.01 mol) in formic acid (20 ml) was heated under reflux for 3 h and then
allowed to cool. The reaction mixture was poured onto crushed ice. The obtained solid prod-
uct was filtered, dried and crystallized to give 10 as buff crystals (ethanol–DMF 2:1 v/v),
m.p. > 250 °C, yield 86%. IR: 3232 (NH), 1651 (C=O). 1H NMR (200 MHz): 2.32 (s, 3 H,
CH3), 7.15 (d, 2 H, J = 8.0, ArH), 7.38 (m, 2 H, ArH), 7.71 (s, 1 H, CH-pyrrole), 7.79 (m, 2 H,
ArH), 7.91 (d, 2 H, J = 7.6, ArH), 7.98 (s, 1 H, H-2), 12.16 (b, 2 H, NH, D2O-exchangeable).
MS, m/z (%): 320 (22), 319 (M+, 100), 318 (75). For C19H14FN3O (319.33) calculated:
71.46% C, 4.42% H, 13.16% N; found: 71.37% C, 4.51% H, 13.22% N.
4-Chloro-7-(4-fluorophenyl)-5-p-tolyl-7H-pyrrolo[2,3-d]pyrimidine (11)
A solution of 10 (0.01 mol) in POCl3 (20 ml) was heated under reflux for 3 h and then al-
lowed to cool. The reaction mixture was poured onto crushed ice. The obtained solid
product was filtered, dried and crystallized to give 11 as colorless crystals (methanol), m.p.
162–164 °C, yield 81%. IR: 1587 (C=N), 1535 (C=C). MS, m/z (%): 340 (6), 339 (M•+, 29),
337 (29), 336 (100). For C19H13ClFN3 (337.78) calculated: 67.56% C, 3.88% H, 12.44% N;
found: 67.40% C, 3.76% H, 12.51% N.
Reaction of the 4-Chloro Product 11 with Primary Aliphatic Amines
Method A. To a mixture of 11 (0.01 mol) and methyl- or ethylamine (0.01 mol) in ethanol
(25 ml), few drops of triethylamine were added. The reaction mixture was heated under re-
flux for 6 h, concentrated and left to cool. The obtained solid product was filtered and crys-
tallized to give 12a or 12b.
Method B. To a solution of 8a or 8b (0.82 g, 0.0025 mol) in aqueous ethanol (100 ml,
50%), sodium hydroxide solution (2 ml, 4%) was added. The reaction mixture was heated
(water-bath temperature) for 3 h and left to cool. The obtained solid product was filtered
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New Pyrrole and Pyrrolo[2,3-d]pyrimidine Derivatives
829
off, washed with water and crystallized from ethanol to give product 12a or 12b (m.p. and
mixed m.p. with the products obtained from method A gave no depression).
7-(4-Fluorophenyl)-N-methyl-5-p-tolyl-7H-pyrrolo[2,3-d]pyimidin-4-amine (12a): Colorless
crystals (ethanol), m.p. 126–128 °C, yield 49% (0.7 g). IR: 3403 (NH), 1592 (C=N). 1H NMR
(270 MHz): 2.38 (s, 3 H, CH3), 2.94 (s, 3 H, N-CH3), 5.6 (b, 1 H, NH), 7.31–7.46 (m, 6 H,
ArH), 7.63 (s, 1 H, CH-pyrrole), 7.88–7.91 (m, 2 H, ArH), 8.29 (s, 1 H, H-2). For C20H17FN4
(332.37) calculated: 72.27% C, 5.16% H, 16.86% N; found: 72.31% C, 5.20% H, 16, 90% N.
N-Ethyl-7-(4-fluorophenyl)-5-p-tolyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (12b): Colorless crys-
tals (ethanol), m.p. 138–140 °C, yield 79.5% (0.65 g). IR: 3437 (NH), 1590 (C=N), 1543
(C=C). 1H NMR (500 MHz): 1.09 (t, 3 H, CH3), 2.34 (s, 3 H, CH3), 3.45 (q, 2 H, CH2), 5.51
(b, 1 H, NH), 7.42 (s, 1 H, CH-pyrrole), 7.30–7.62 (m, ArH), 8.23 (s, 1 H, C-2). MS, m/z (%):
346 (M, 96), 276 (29), 122 (43), 95 (100). For C21H19FN4 (346.40) calculated: 72.81% C,
5.53% H, 216.17% N; found: 72.75% C, 5.62% H, 16.21% N.
7-(4-Fluorophenyl)-5-p-tolyl-3H-pyrrolo[2,3-d]pyrimidin-4(7H)-thione (13)
A mixture of 11 (0.01 mol) and thiourea (0.01 mol) in absolute ethanol (30 ml) was heated
under reflux for 2 h and then left to cool. The obtained solid product was filtered and crys-
tallized to give the thione 13 as yellowish crystals (ethyl acetate), m.p. 272–274 °C, yield
71%. IR: 3127 (NH), 1577 (C=N), 1550 (C=C), 1442, 1353, 1207 (C=S). MS, m/z (%): 336
(16.30), 335 (M, 51), 334 (100). For C19H14FN3S (335.40) calculated: 68.04% C, 4.21% H,
12.53% N, 9.56% S; found: 68.10% C, 4.23% H, 12.58% N, 9.63% S.
7-(4-Fluorophenyl)-4-(methylthio)-5-p-tolyl-7H-pyrrolo[2,3-d]pyrimidine (14a)
To a suspension of 13 (0.83 g, 0.0025 mol) in ethanol (10 ml) and KOH solution (2 ml water
containing 0.0125 mol KOH), dimethyl sulfate (0.0025 mol) was added. The reaction mix-
ture was stirred at room temperature (~25 °C) for 4 h. The obtained precipitate was filtered
off, washed with water and crystallized to give 14a as colorless crystals (ethanol), m.p.
136–138 °C, yield 72.3% (0.6 g). IR: 1579 (C=N), 1540 (C=C). MS, m/z (%): 349 (M, 100),
350 (22). 1H NMR (270 MHz): 2.36 (s, 3 H, CH3), 2.56 (s, 3 H, CH3), 7.0–7.91 (m, 9 H, ArH
and CH-pyrrole), 8.67 (s, 1 H, C2-H). For C20H16FN3S (349.42) calculated: 68.75% C, 4.62% H,
12.03% N, 9.18% S; found: 68.70% C, 4.58% H, 12.20% N, 9.22% S.
O-Ethyl S-7-(4-Fluorophenyl)-5-p-tolyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylcarbonothioate (14b)
To a suspension of 13 (0.83 g, 0.0025 mol) in benzene (10 ml) and KOH solution (2 ml wa-
ter containing 0.0125 mol KOH), ethyl chloroformate (0.0025 mol) was added. The reaction
mixture was stirred at room temperature (~25 °C) for 4 h. The obtained precipitate was fil-
tered off, washed with water and crystallized to give 14b as colorless crystals (ethanol), m.p.
132–134 °C, yield 79.5% (0.66 g). IR: 1718 (C=O), 1578 (C=N), 1515 (C=C). 1H NMR (500 MHz):
1.33 (t, 3 H, CH3), 3.87 (q, 2 H, CH2), 7.13–7.92 (m, ArH), 7.93 (s, CH-pyrrole), 8.85 (s, 1 H,
C-2). MS, m/z (%): 408 (M+, 17), 407 (7), 334 (24), 171 (15), 122 (16). For C22H18FN3O2S
(407.46) calculated: 64.85% C, 4.45% H, 10.31% N, 7.87% S; found: 64.90% C, 4.51% H,
10.38% N, 7.90% S.
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El-Bayouki, Basyouni, Mostafa:
7-(4-Fluorophenyl)-4-imino-5-p-tolyl-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-3-amine (15)
To a suspension of the formimidate 4a or 4b (0.01 mol) in ethanol (50 ml), hydrazine hy-
drate (0.012 mol) was added. The reaction mixture was stirred at room temperature for 5 h.
The obtained precipitate was filtered and crystallized to give 15 as colorless crystals (ben-
zene), m.p. 156–160 °C, yield 84%. IR: 3324, 3290, 3140 (NH, NH2), 1629 (C=N). 1H NMR
(300 MHz): 2.3 (s, 3 H, CH3), 5.6 (s, 2 H, N-NH2, D2O-exchangeable), 6.8 (b, 1 H, NH,
D2O-exchangeable), 7.2–7.8 (m, 9 H, ArH and CH-pyrrole), 8.2 (s, 1 H, C2-H). For C19H16FN5
(333.36) calculated: 68.46% C, 4.84% H, 21.015% N; found: 68.50% C, 4.73% H, 21.22% N.
7-(4-Fluorophenyl)-3-methyl-5-p-tolyl-3H-pyrrolo[2,3-d]pyrimidin-4(7H)-imine (16a)
To a stirred suspension of 4a or 4b (0.01 mol) in ethanol (50 ml), methylamine (0.01 mol)
was added. The stirring was continued at room temperature for 15 h. The obtained precipi-
tate was filtered and crystallized to give 16a as colorless crystals (methanol–few drops of wa-
ter), m.p. 162–164 °C, yield 80% (0.8 g). IR: 3326 (NH), 1628 (C=N). 1H NMR (270 MHz):
2.37 (s, 3 H, CH3), 3.4 (s, 3 H, CH3), 6.5 (1 H, s, NH), 7.27–7.75 (m, 9 H, ArH and
CH-pyrrole), 8.0 (s, 1 H, C2-H). MS, m/z (%): 333 (M+1, 27), 332 (M, 82), 331 (100). For
C
20H17FN4 (332.37) calculated: 72.27% C, 5.16% H, 16.86% N; found: 72.34% C, 5.10% H,
16.72% N.
Synthesis of 16b and 16c
To a suspension of 4a or 4b (0.01 mol) in ethanol (50 ml), ethylamine (0.01 mol) was added
and the reaction mixture was stirred at room temperature (~25 °C) for 15 h. The obtained
precipitate was filtered and purified by chromatographic TLC plate (eluent: petroleum
ether–ethyl acetate 2:1) and crystallized to give 16b (major) and 16c (minor).
3-Ethyl-7-(4-fluorophenyl)-5-p-tolyl-3H-pyrrolo[2,3-d]pyrimidin-4(7H)-imine (16b): Colorless
crystals (ethanol), m.p. 160–162 °C, yield 60.3% (0.55 g). IR: 3345 (NH), 1626 (C=N), 1514
(C=C). MS, m/z (%): 347 (M+, 11), 346 (M, 100), 318 (83). For C21H19FN4 (346.40) calculated:
72.81% C, 5.53% H, 16.17% N; found: 72.77% C, 5.49% H, 16.33% N.
N′-(3-Cyano-1-(4-fluorophenyl)-4-p-tolyl-1H-pyrrol-2-yl)-N-ethylformimidamide (16c): Colorless
crystals (ethanol), m.p. 138–140 °C, yield 40% (0.35 g). IR: 3346 (NH), 2199 (C≡N), 1617
(C=N). 1H NMR (500 MHz): 1.16 (t, 3 H, CH3), 2.28 (s, 3 H, CH3), 3.15 (q, 2 H, CH2), 2.05
(s, 1 H, NH), 7.19 (s, 1 H, pyrrole), 7.15–7.54 (ArH and N=CH). MS, m/z (%): 346 (M, 73), 94
(100). For C21H19FN4 (346.40) calculated: 72.81% C, 5.53% H, 16.17% N; found: 72.83% C,
5.55% H, 16.21% N.
Cyclization of 16c to 16b
To a solution of 16c (0.01 mol) in absolute ethanol (20 ml), sodium ethoxide solution (0.5 g
Na metal dissolved in 7 ml of absolute ethanol) was added. The reaction mixture was heated
under reflux for 5 h and left to cool. The obtained solid product was filtered and crystallized
from benzene–methanol (1:2) to give 16b (m.p. and mixed m.p. no depression).
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New Pyrrole and Pyrrolo[2,3-d]pyrimidine Derivatives
831
2-(4-Aryl)-7-(4-fluorophenyl)-9-p-tolyl-7H-pyrrolo[3,2-e][1,2,4]triazolo[1,5-c]pyrimidines
17a–17e
A mixture of 15 (0.01 mol) and the desired aldehyde (0.01 mol) in absolute ethanol (30 ml)
was heated under reflux for 12 h and then left to cool. The obtained solid product was fil-
tered to give 17a–17e.
7-(4-Fluorophenyl)-2-phenyl-9-p-tolyl-7H-pyrrolo[3,2-e][1,2,4]triazolo[1,5-c]pyrimidine (17a):
White powder (benzene), m.p. 252–254 °C, yield 68% (1.1 g). IR: 1625 (C=N), 1514 (C=C).
MS, m/z (%): 419 (M, 100), 420 (19), 95 (4), 77 (2.65). UV-Vis: 267 nm (ε 37 453). For
C
26H18FN5 (419.45) calculated: 74.45% C, 4.33% H, 16.70% N; found: 74.39% C, 4.45% H,
17.00% N.
7-(4-Fluorophenyl)-2-(4-methoxyphenyl)-9-p-tolyl-7H-pyrrolo[3,2-e][1,2,4]triazolo[1,5-c]pyrimi-
dine (17b): White powder (benzene), m.p. 230–232 °C, yield 81%. IR: 1639 (C=N), 1612
(C=C). MS, m/z (%): 450 (35), 449 (M+, 100), 318 (23), 317 (12.9), 224 (17). For C27H20FN5O
(449.48) calculated: 72.15% C, 4.48% H, 15.58% N; found: 72.34% C, 5.51% H, 15.66% N.
2-(4-Chlorophenyl)-7-(4-fluorophenyl)-9-p-tolyl-7H-pyrrolo[3,2-e][1,2,4]triazolo[1,5-c]pyrimidine
(17c): Colorless crystals (benzene), m.p. 258–260 °C, yield 75% (1.2 g). IR: 1626 (C=N), 1513
(C=C). 1H NMR (200 MHz): 2.4 (s, 3 H, CH3), 7.35–8.42 (m, 13 H, ArH and CH-pyrrole), 9.53
(s, 1 H, C2-H). UV-Vis: 267 nm (ε 37 037). For C26H17ClFN5 (453.90) calculated: 68.80% C,
3.78% H, 15.43% N; found: 69.00% C, 3.82% H, 15.29% N.
7-(4-Fluorophenyl)-2-(furan-2-yl)-9-p-tolyl-7H-pyrrolo[3,2-e][1,2,4]triazolo[1,5-c]pyrimidine
(17d): Brownish white crystals (benzene), m.p. 220–222 °C, yield 62%. IR: 1630 (C=N), 1555
(C=C). 1H NMR (200 MHz): 2.4 (s, 3 H, CH3), 6.76 (s, 1 H, C4-H furyl), 7.3–8.3 (m, 11 H,
ArH, C6-H and C3-H, C5-H furyl), 9.5 (s, 1 H, C2-H). For C24H16FN5O (409.42) calculated:
70.41% C, 3.94% H, 17.11% N; found: 70.54% C, 4.00% H, 17.35% N.
7-(4-Fluorophenyl)-2-(thiophen-2-yl)-9-p-tolyl-7H-pyrrolo[3,2-e][1,2,4]triazolo[1,5-c]pyrimidine
17e: Pale brown crystals (benzene), m.p. 222–224 °C, yield 81%. IR: 1623 (C=N), 1559
(C=C). 1H NMR (200 MHz): 2.32 (s, 3 H, CH3), 7.2 (s, 1 H, CH-pyrrole), 7.25–7.9 (m, Ar-H),
9.45 (s, 1 H, C-2). MS, m/z (%): 425 (M, 16), 343.94 (28%), 318 (75), 308 (100). For
C
24H16FN5S (425.48) calculated: 67.75% C, 3.79% H, 16.46% N, 7.54% S; found: 67.80% C,
3.83% H, 16.60% N, 7.66% S.
N-Benzylidene-7-(4-fluorophenyl)-4-imino-5-p-tolyl-4,7-dihydro-
3H-pyrrolo[2,3-d]pyrimidin-3-amine (18)
A mixture of 15 (1.64 g, 0.005 mol) and benzaldehyde (0.005 mol) in absolute ethanol
(20ml) was heated under reflux for 10 h and left to cool. The obtained solid product was fil-
tered off to give 17a (as a major product) and 18 (as a minor product). The two products
were separated by dissolving in methanol and then filtered off to give the soluble product
18 and the insoluble product 17a.
18: Yellow crystals (methanol), m.p. 218–220 °C, yield 24.4% (0.4 g). IR: 3321 (NH), 1587
(C=N). MS, m/z (%): 421 (M, 33), 422 (26), 344.2 (32), 318 (100). UV-Vis: 270 nm (ε 37 037),
320 nm (ε 31 250). For C26H20FN5 (421.47) calculated: 74.09% C, 4.78% H, 16.62% N;
found: 74.12% C, 4.76% H, 16.66% N.
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832
El-Bayouki, Basyouni, Mostafa:
N-(3-Amino-7-(4-fluorophenyl)-5-p-tolyl-3H-pyrrolo[2,3-d]pyrimidin-4(7H)-ylidene)-
4-arylsulfonamide 19a and 19b. General Method
A mixture of 15 (0.01 mol) and benzene sulfonylchloride or toluene sulfonylchloride
(0.012 mol) in benzene was stirred at room temperature for 1 h then left overnight at room
temperature. The reaction mixture was extracted with chloroform. The chloroform extract
was dried over anhydrous sodium sulfate and evaporated under vacuum. The obtained solid
product was crystallized to give 19a and 19b.
N-(3-Amino-7-(4-fluorophenyl)-5-p-tolyl-3H-pyrrolo[2,3-d]pyrimidin-4(7H)-ylidene)benzene-
sulfonamide (19a): Colorless crystals (methanol), m.p. 208–210 °C, yield 73%. IR: 3455, 3314,
3224 (NH2), 1657 (C=N). 1H NMR (270 MHz): 2.3 (s, 3 H, CH3), 6.62 (s, 2 H, 2 NH), 7.3–7.98
(m, 13 H, ArH and C6-H), 8.58 (s, 1 H, C2-H). MS, m/z (%): 473 (M, 0.2), 334 (23), 333 (100).
For C25H20FN5O2S (473.52) calculated: 63.41% C, 4.26% H, 14.79% N, 6.77% S; found:
63.46% C, 4.32% H, 14.65% N, 6.82% S.
N-(3-Amino-7-(4-fluorophenyl)-5-p-tolyl-3H-pyrrolo[2,3-d]pyrimidin-4(7H)-ylidene-4-methyl-
benzenesulfonamide (19b): Colorless crystals (methanol), m.p. 236–238 °C, yield 79.8%.
IR: 3445, 3303, 3204 (NH2), 1658 (C=N). 1H NMR (270 MHz): 2.28 (s, 3 H, CH3), 2.40 (s,
3 H, CH3), 6.61 (b, 2 H, NH2, D2O-exchangeable), 7.09–7.98 (m, 13 H, ArH and CH-pyrrole),
8.58 (s, 1 H, C2-H). MS, m/z (%): 487 (M+, 0.40), 333 (100). For C26H22FN5O2S (487.15) cal-
culated: 64.05% C, 4.55% H, 14.36% N, 6.58% S; found: 64.12% C, 4.56% H, 14.42% N;
6.64% S.
7-(4-Fluorophenyl)-4-hydrazinyl-5-p-tolyl-7H-pyrrolo[2,3-d]pyrimidine (20)
A mixture of 11 (0.01 mol) and hydrazine hydrate (0.012 mol) in absolute ethanol (20 ml)
was heated under reflux for 4h and then left to cool. The obtained solid product was filtered
and crystallized to give 20 as colorless crystals (aqueous ethanol), m.p. 144–146 °C, yield
93.75% (1.5 g). IR: 3432, 3322 (NH, NH2), 1579 (C=N), 1540 (C=C). MS, m/z (%): 333 (M,
100), 334 (23), 303 (56), 57 (42). 1H NMR (270 MHz): 2.4 (s, 3 H, CH3), 4.55 (s, 2 H,
N-NH2), 6.56 (b, 1 H, NH, D2O-exchangeable), 7.36–7.93 (m, 9 H, ArH and CH-pyrrole), 8.37
(s, 1 H, C2-H). For C19H16FN5 (333.36) calculated: 68.46% C, 4.84% H, 21.01% N; found:
68.50% C, 4.90% H, 20.97% N.
7-(4-Fluorophenyl)-9-p-tolyl-7H-pyrrolo[3,2-e]tetrazolo[1,5-c]pyrimidine (21)
Method A. A mixture of sodium azide (0.072 g, 0.011 mol) and ammonium chloride (0.059 g,
0.011 mol) in DMSO (20 ml) was stirred for at 90 °C 5 min and the 4-chloro 11 (3.4 g,
0.01 mol) was added portion-wise while stirring. After complete addition, the reaction mix-
ture was stirred for further 2.0–2.5 h at the same temperature and for 1 h at room tempera-
ture, then poured on crushed ice while stirring. The obtained solid product was filtered,
washed with water, dried and crystallized from benzene–ethanol (2:1 v/v) to give the
tetrazole 21.
Method B. An aqueous solution of sodium nitrite (4.2 ml, 20% w/v) was slowly added
portion-wise at ~0–5 °C to a stirred mixture of the hydrazine 20 (3.3 g, 0.01 mol) dissolved
in acetic acid (40 ml). The reaction mixture was stirred for 2 h at the same temperature and
then diluted with cold water. The obtained solid product was filtered, washed with aqueous
sodium bicarbonate solution (20% w/v), followed by another water washing, dried and crys-
tallized to give the tetrazole 21 (m.p. and mixed m.p. no depression with the sample ob-
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New Pyrrole and Pyrrolo[2,3-d]pyrimidine Derivatives
833
tained from method A) as colorless crystals (benzene–ethanol 2:1 v/v), m.p. 224–226 °C,
yield 90.63% (0.75 g) (method A) and 66% (0.64 g) (method B), respectively. IR: 1615 (C=N),
1512 (C=C). MS, m/z (%): 345 (7), 344 (M+, 35), 316 (100). 1H NMR (270 MHz): 2.3 (s, 3 H,
CH3), 7.24–8.39 (m, 9 H, ArH and CH-pyrrole), 9.88 (s, 1 H, C2-H). For C19H13FN6 (344.35)
calculated: 66.27% C, 3.81% H, 24.41% N; found: 66.25% C, 3.83% H, 24.47% N.
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