Enaminonitriles in heterocyclic synthesis: Novel synthesis of 3-aminopyrroles and pyrrolo[3,2-d] pyrimidine derivatives

Article abstract of DOI:10.1515/znb-2008-0514

Several new 3-aminopyrrole derivatives have been synthesized from 3-substituted amino-2-phenylacrylonitriles using Thorpe-Ziegler cyclization. These substituted pyrroles are readily converted into 5H-pyrrolo[3,2-d] pyrimidines (9-deazapurines).

Full text of DOI:10.1515/znb-2008-0514

Enaminonitriles in Heterocyclic Synthesis: Novel Synthesis of
3-Aminopyrroles and Pyrrolo[3,2-d]pyrimidine Derivatives
Abdellatif M. Salaheldin
Department of Chemistry, Faculty of Science, Cairo University, Giza, A. R. Egypt
Present address: Centro de Qu´ımica, Universidade do Minho, Campus de Gualtar, 4710-057 Braga,
Portugal
Reprint requests to Dr. A. M. Salaheldin. E-mail: amsalaheldin@yahoo.com
Z. Naturforsch. 2008, 63b, 564 – 570; received January 4, 2008
Several new 3-aminopyrrole derivatives have been synthesized from 3-substituted amino-2-phenyl-
acrylonitriles using Thorpe-Ziegler cyclization. These substituted pyrroles are readily converted into
5H-pyrrolo[3,2-d]pyrimidines (9-deazapurines).
Key words: 3-Aminopyrrole, Pyrrolo[3,2-d]pyrimidine, 9-Deazapurines, β-Enaminonitriles,
Thorpe-Ziegler Cyclization
Introduction
ditions the condensation of DMFDMA with benzyl
cyanide did not yield the enamine 3. Alternatively, a
procedure similar to that reported recently [15] was
applied. In this method the active methylene group
of benzyl cyanide was condensed with piperidinyl-1-
formamide diethylacetal (2), formed in situ from piper-
idine and triethyl orthoformate, to afford the enamino-
nitrile 3 in 70 % yield (Scheme 1).
The reaction of aniline derivatives with compound
3 in refluxing methanol afforded only the α-formyl
phenylacetonitrile (4), m. p. 157– 159 ◦C (159– 160 ◦C
[21]). On the other hand, the reaction of 3 with aro-
matic amines in toluene, in the presence of p-tolu-
enesulfonic acid, produced the enaminonitriles 5a – c
with elimination of piperidine. Compound 3 reacted
also with 2-aminopyrazole and 2-aminobenzimidazole
to yield cyclic products 6 and 7, respectively. Estab-
lishing of the structures of 5 – 7 was based on their
spectral analysis.
Enaminonitriles 5 were found to be good candidates
to obtain 3-aminopyrroles based on a Thorpe-Ziegler
cyclization [18, 19]. In this method, N-alkylation of a
β-enaminonitrile was carried out using α-haloketones
in anhydrous DMF in the presence of K2CO3 as an al-
kaline reagent. Moreover, compounds having an aryl
substitutent on the amino moiety of the enamine group
were the best for alkylation and subsequent intramolec-
Derivatives of 3-aminopyrroles have been shown
to exhibit antibacterial, antiviral, anticonvulsant, anti-
inflammatory, analgesic, and antipyretic activities
[1 – 4]. In view of the importance of pyrrole for var-
ious applications, great efforts have been made to-
wards preparation of this heterocyclic system [5 – 9].
Recently we described several efficient approaches
to heteroaromatic systems using functionally substi-
tuted enamine precursors [10– 17]. In conjunction
with our interest in the chemistry of enaminoni-
triles we report here results of our work aimed to
exploring the potential utility of 2-phenyl-3-piper-
idin-1-ylacrylonitrile in heterocyclic synthesis. The
synthesized β-enaminonitriles 5 are converted into
the corresponding 3-aminopyrrole derivatives by re-
action with α-haloketones under basic conditions
in a Thorpe-Ziegler cyclization [18, 19]. These sub-
stituted pyrroles are readily converted to 5H-pyrr-
olo[3,2-d]pyrimidines (9-deazapurines) [20]. In our
chemical reactivity studies described here, we prin-
cipally employed the intermediates 5b and 9a due
to their easy preparation and good yield of their re-
actions.
Result and Discussions
One of the main important routes to enamines is ular cyclization. The presence of this group facilitates
condensation of dimethyl-formamide dimethylacetal the formation of the N-anion required for alkylation
(DMFDMA) with activated methyl or methylene com- and subsequent carbanion formation for the cyclization
pounds [10– 12]. However, under a variety of con- involving the cyano group.
c
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A. M. Salaheldin · Novel Synthesis of 3-Aminopyrroles and Pyrrolo[3,2-d]pyrimidine Derivatives
565
Scheme 1.
The reactions of enaminonitrile 5 with chloroace- phenylisothiocyanate to yield the thiourea deriva-
tonitrile, chloroacetone, bromoacetic acid ester and α- tive 10. Trials to cyclize the latter into pyrrolopyrimid-
bromoacetophenone in DMF/K2CO3 afforded the cor- ine 11 failed (Scheme 2). The 3-amino-2-cyanopyrrole
responding 3-aminopyrrole derivatives 9 in low yield 9a is a polyfunctional compound containing an inter-
(35– 54%) via the nonisolable intermediates 8. When esting set of substituents. Although the 3-amino group
the reaction was carried out in a solution of excess has an electronegative substituent in the neighboring
of triethylamine the desired 3-aminopyrrolederivatives ortho position, it retains basic properties and is read-
9 were obtained in satisfactory yield (70 – 86 %). The ily acylated in refluxing acetic anhydride to afford the
structure of compounds 9a – d was established on the diacetyl derivative 12.
basis of elemental analysis, IR, mass, 1H and 13C NMR
The most generally used approach to pyrrolo[3,2-
spectral data (cf. Experimental Section). For example,
the H NMR spectrum of compound 9a showed the
d]pyrimidines has so far involved elaboration of the
pyrrole ring onto a preformed pyrimidine bearing re-
active functionalities at C-4 and C-5 [25]. Another
strategy has involved the formation of the pyrimi-
dine ring onto a preformed 3-aminopyrrole intermedi-
ate [26] as we describe herein. Compound 9a reacted
with triethyl orthoformate to give the corresponding
ethoxymethylene amino derivative 13 which is the key
1
absence of a signal for a methylene function and the
presence of two D2O exchangeable protons at δ =
6.14 ppm for the amino function and a singlet for the
pyrrole 5-H proton at δ = 7.84 ppm. 13C NMR and
mass spectra of compound 9a are in accordance with
the proposed structure.
In recent years, urea and thiourea derivatives compound for the preparation of pyrrolo[3,2-d]pyr-
[22– 24] have emerged as structurally novel anticon- imidine derivatives. Thus, compound 13 was stirred at
vulsant agents. Compound 9a reacted readily with r. t. in methanolic ammonia to produce 4-aminopyrr-
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A. M. Salaheldin · Novel Synthesis of 3-Aminopyrroles and Pyrrolo[3,2-d]pyrimidine Derivatives
Scheme 2.
olopyrimidine 14 (Scheme 2). The identity of pyrrol- was refluxed in boiling formic acid to produce pyrrolo-
1
opyrimidine 14 was confirmed by H NMR and ele- pyrimidinone 17. Compound 17 was refluxed in phos-
mental analysis. A similar closure of the pyrimidine phorus oxychloride to obtain the 4-chloropyrrolopyr-
ring using ammonia in the synthesis of 4-amino-pyrr- midine 18 [28]. Reacting compound 18 with p-chloro-
olopyrimidine 13 was successfully effected on heating aniline gave the pyrrolo[3,2-d]pyrimidine 16 (68 %)
compound 9a in a mixture of HCO2H/HCONH2/DMF. whose spectral characteristics were completely coinci-
dent with those of samples obtained before (Scheme 3).
Heating the ethoxymethylene amino derivative 13
with p-chloroaniline led to the formation of the Dim-
roth-rearrangement product, 4-substituted aminopyrr-
olopyrimidine 16, via the intermediate 15 (Scheme 3)
[17, 27]. The alternative structure 15 was excluded
based on NMR data. The 1D 1H NMR spectra of com-
pound 16 showed all the expected signals for aromatic
protons and four singlets at δ = 3.86 (OCH3), 6.98
(NH), 8.51 (2-H) and 8.62 (6-H), respectively, but this
was not sufficient to differentiate between structures
15 and 16. For this reason, we obtained the HMQC
and HMBC NMR spectra and made an unambiguous
assignment in the 1H and 13C NMR spectrum (see Ex-
perimental Section).
In the HMBC spectrum, we observe an intense cor-
relation peak for the NH proton at δ = 6.98 with the
carbon peak at δ = 122.52 ppm (C-b,f), which is char-
acteristic only of structure 16 but not of 15, where the
indicated proton and carbon atoms are separated by
five bonds.
Experimental Section
Melting points were determined on a Gallenkamp melting
point apparatus and are uncorrected. IR spectra were regis-
tered on a Perkin Elmer FTIR-1600 instrument using KBr
discs or Nujol emulsions between NaCl plates. 1H NMR
(300 MHz) and 13C NMR (75.4 MHz) spectra were recorded
in deuterated dimethylsulfoxide [D6]DMSO on a Varian
Unity Plus Spectrometer using tetramethylsilane (TMS) as
an internal reference, and results are expressed as δ values.
Double resonance, HMQC and HMBC experiments were
carried out for complete assignment of proton and carbon
signals in the NMR spectra, whenever possible. Mass spec-
tra were obtained on a Shimadzu GCMS-QP 1000 Ex mass
spectrometer at 70 eV. Elemental analyses were obtained on
a Leco CHNS-932 instrument.
2-Phenyl-3-piperidin-1-yl-acrylonitrile (3)
To a mixture of benzyl cyanide 1 (0.3 mol), triethyl ortho-
formate (0.32 mol) and piperidine (0.3 mol) DMF (40 mL)
pendent synthetic route was followed. Compound 9a was added, and the solution was refluxed for 72 h. The re-
To confirm the structure of compound 16 an inde-
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A. M. Salaheldin · Novel Synthesis of 3-Aminopyrroles and Pyrrolo[3,2-d]pyrimidine Derivatives
567
Scheme 3.
action mixture was then cooled and poured onto water. The 70 eV): m/z (%) = 220 (78) [M]+. – C15H12N2 (220.28):
solid product formed was collected by filtration and crys- calcd. C 81.79, H 5.49, N 12.72; found C 81.97, H 5.61,
◦
tallized from ethanol. M. p. 115 – 116 C. – Yield: 70 %. – N 12.89.
IR (KBr): ν = 2190 (CN), 1616 (C=C) cm−1. – 1H NMR
(300 MHz, [D6]DMSO, 25 ◦C, TMS): δ = 1.60 (s, 6H,
3CH2), 3.63 (s, 4H, 2CH2), 7.16 (s, 1H, olefinic-H), 7.26 –
7.45 (m, 5 H, Ar-H). – 13C NMR (75.4 MHz, [D6]DMSO):
δ = 24.36, 26.41, 51.96, 75.41 (C=CH), 121.59 (CN),
124.48, 125.51, 129.14, 137.27, 149.29 (C=CH). – MS (EI,
70 eV): m/z (%) = 212 (42) [M]+. – C14H16N2 (212.29):
calcd. C 79.21, H 7.60, N 13.20; found C 79.29, H 7.67,
N 13.17.
3-(4-Methoxyphenylamino)-2-phenylacrylonitrile (5b)
M. p. 128 – 130 ◦C (EtOH). Yield: 89 %. – IR (KBr):
1
ν = 2198 (CN), 1614 (C=C) cm−1. – H NMR (300 MHz,
[D6]DMSO, 25 ◦C, TMS): δ = 3.71 (s, 3H, OCH3), 6.87 (d,
2H, J = 9 Hz, Ar-H), 7.15 (t, 1H, J = 7.9 Hz, Ar-H), 7.29 –
7.35 (m, 4H, Ar-H), 7.48 (d, 2H, J = 9 Hz, Ar-H), 8.01 (d,
1H, J = 13.5 Hz, olefinic-H), 9.59 (d, 1H, J = 13.5 Hz, NH). –
MS (EI, 70 eV): m/z (%) = 250 (91) [M]+. – C16H14N2O
(250.30): calcd. C 76.78, H 5.64, N 11.19; found C 76.51,
H 5.80, N 11.05.
General procedure for the preparation of 3-arylamino-2-
phenylacrylonitrile derivatives 5a – c, triazolopyrimidine (6)
and pyrimidobenzimidazole (7)
3-(4-Chlorophenylamino)-2-phenylacrylonitrile (5c)
An aromatic or heteroaromatic amine (0.01 mol) and p-
toluenesulfonic acid (0.15 g) were added to a solution of an
enaminonitrile 3 (0.01 mol) in toluene (40 mL). The reac-
tion mixture was refluxed for 7 h, and the precipitated solid
was collected by filtration, then crystallized from the proper
solvent, to afford 5a – c, 6 and 7, respectively.
M. p. 145 – 146 ◦C (EtOH). Yield: 74 %. – IR (KBr):
1
ν = 2204 (CN), 1618 (C=C) cm−1. – H NMR (300 MHz,
[D6]DMSO, 25 ◦C, TMS): δ = 7.18 (d, 2H, J = 9 Hz, Ar-H),
7.21 – 7.33 (m, 5H, Ar-H), 7.42 (d, 2H, J = 9 Hz, Ar-H), 8.15
(d, 1H, J = 13.4 Hz, olefinic-H), 9.65 (d, J = 13.4 Hz, 1H,
NH). – MS (EI, 70 eV): m/z (%) = 254 (100) [M, 35Cl]+, 256
(26) [M, 37Cl]+. – C15H11ClN2 (254.71): calcd. C 70.73,
H 4.35, N 11.00; found C 70.47, H 4.58, N 11.22.
2-Phenyl-3-(phenylamino)acrylonitrile (5a)
M. p. 165 – 166 ◦C (EtOH). Yield: 70 %. – IR (KBr):
1
ν = 2202 (CN), 1617 (C=C) cm−1. – H NMR (300 MHz,
6-Phenyl-[1,2,4]triazolo[4,3-a]pyrimidin-5-amine (6)
[D6]DMSO, 25 ◦C, TMS): δ = 7.02 (t, 1H, J = 7 Hz, Ar-H),
7.16 (t, 1H, J = 7 Hz, Ar-H), 7.30 – 7.52 (m, 8H, Ar-H),
◦
M. p. 262 – 264 C (EtOH-DMF, 2 : 1). Yield: 64 %. – IR
8.08 (brs, 1H, olefinic-H), 9.68 (brs, 1H, NH). – MS (EI, (KBr): ν = 3420, 3238 (NH2) cm−1. – 1H NMR (300 MHz,
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A. M. Salaheldin · Novel Synthesis of 3-Aminopyrroles and Pyrrolo[3,2-d]pyrimidine Derivatives
◦
[D6]DMSO, 25 C, TMS): δ = 7.23 – 7.31 (m, 1H, Ar-H), (m, 4H, Ar-H), 7.84 (s, 1H, 5-H). – 13C NMR (75.4 MHz,
7.38 – 7.44 (m, 4H, Ar-H), 7.90 (s, 2H, NH2), 8.27 (s, [D6]DMSO): δ = 55.65 (OCH3), 98.98 (C-2), 113.23 (CN),
1H, 7-H), 8.49 (s, 1H, 4-H). – 13C NMR (75.4 MHz, 114.71 (C-3ꢀ,5ꢀ), 120.72 (C-2ꢀꢀ,6ꢀꢀ), 123.42 (C-4ꢀꢀ), 125.44
[D6]DMSO): δ = 104.95 (C-1a), 124.32 (C-4ꢀ), 127.71 (C-2ꢀ,6ꢀ), 128.86 (C-3ꢀꢀ,5ꢀꢀ), 130.12 (C-1ꢀ), 132.52 (C-5),
(C-3ꢀ,5ꢀ), 129.17 (C-2ꢀ,6ꢀ), 133.22 (C-1ꢀ), 146.50 (C-6), 136.84 (C-1ꢀꢀ), 142.23 (C-4), 144.32 (C-3), 159.21 (C-4ꢀ). –
154.04 (C-7), 154.83 (C-4), 155.12 (C-5). – MS (EI, 70 eV): MS (EI, 70 eV): m/z ( %) = 289 (66) [M]+. – C18H15N3O
m/z (%) = 211 (77) [M]+. – C11H9N5 (211.22): calcd. (289.33): calcd. C 74.72, H 5.23, N 14.52; found C 74.58,
C 62.55, H 4.29, N 33.16; found C 62.91, H 4.37, N 33.31.
H 5.57, N 14.79.
1-(3-Amino-1-(4-methoxyphenyl)-4-phenyl-1H-pyrrol-2-
yl)ethanone (9b)
3-Phenylpyrimido[1,2-a]benzimidazol-4-amine (7)
◦
M. p. 220 – 222 C (EtOH-DMF, 2 : 1). Yield: 51 %. – IR
◦
M. p. 192 – 193 C. Yield: 77 %. – IR (KBr): ν = 3440 –
(KBr): ν = 3405,◦3251 (NH2) cm−1. – 1H NMR (300 MHz,
[D6]DMSO, 25 C, TMS): δ = 6.85 (s, 2H, NH2), 7.01 –
7.14 (m, 2H, Ar-H), 7.26 – 7.30 (m, 1H, Ar-H), 7.42 – 7.50
(m, 4H, Ar-H), 7.52 (d, 1H, J = 8.5 Hz, Ar-H), 7.98 (d, 1H,
J = 8.5 Hz, Ar-H), 8.42 (s, 1H, 2-H). – MS (EI, 70 eV): m/z
(%) = 260 (40) [M]+. – C16H12N4 (260.29): calcd. C 73.83,
H 4.65, N 21.52; found C 73.52, H 4.47, N 21.28.
3348 (NH2), 16◦78 (C=O) cm−1. – 1H NMR (300 MHz,
[D6]DMSO, 25 C, TMS): δ = 2.23 (s, 3H, CH3), 3.80 (s,
3H, OCH3), 6.67 (s, 2H, NH2), 7.03 (d, 2H, J = 9 Hz, Ar-H),
7.09 (t, 1H, J = 9 Hz, Ar-H), 7.36 (d, 2H, J = 9 Hz, Ar-H),
7.42 – 7.55 (m, 4H, Ar-H), 7.65 (s, 1H, 5-H). – 13C NMR
(75.4 MHz, [D6]DMSO): δ = 28.52 (CH3), 55.53 (OCH3),
114.28 (C-3ꢀ,5ꢀ), 118.20 (C-2), 122.12 (C-2ꢀꢀ,6ꢀꢀ), 127.93
(C-2ꢀ,6ꢀ), 128.51 (C-4ꢀꢀ), 132.21 (C-1ꢀ), 133.62 (C-3ꢀꢀ,5ꢀꢀ),
135.21 (C-5), 138.64 (C-1ꢀꢀ), 143.31 (C-4), 147.45 (C-3),
159.38 (C-4ꢀ), 186.21 (C=O). – MS (EI, 70 eV): m/z (%) =
306 (80) [M]+. – C19H18N2O2 (306.36): calcd. C 74.49,
H 5.92, N 9.14; found C 74.79, H 6.18, N 9.42.
General procedure for preparation of 3-aminopyrrole
derivatives 9a – d
Method A: A mixture of 5b (0.01 mol), an α-halo com-
pound (chloroacetonitrile, chloroacetone, bromoacetic acid
ester and α-bromoacetophenone) (0.011 mol), and potassium
carbonate (2.0 g) in dimethylformamide (20 mL) was stirred
for 1 h at an oil bath temperature of 90 ◦C. The reaction mix-
ture was cooled and poured into water (60 mL). The precipi-
tated solid products formed were filtered off, washed several
times with cold water and recrystallized from EtOH to afford
the corresponding cyclized products 9a – d (35 – 54 %).
Method B: To the intermediate 5b (0.01 mol), an α-halo
compound (chloroacetonitrile, chloroacetone, bromoacetic
acid ester and α-bromoacetophenone) (0.011 mol) and tri-
ethylamine (4 mL) were added with external cooling. The
reaction mixture was refluxed for 10 – 15 min, after cool-
ing water (50 mL) was added, the solid product was filtered
off, washed several times with cold water and crystallized
from ethanol (in case of 9a, 86 %). For the other cases 9b – c,
brown sticky oils separated, the water was decanted and the
oil washed several times with cold water, then dissolved in
ethanol and boiled for 3 min, filtered and left to cool over
night. The solid products so formed were filtered off and
were found pure enough for analyses.
(3-Amino-1-(4-methoxyphenyl)-4-phenyl-1H-pyrrol-2-
yl)(phenyl)methanone (9c)
◦
M. p. 224 – 226 C. Yield: 72 %. – IR (KBr): ν = 3452 –
3367 (NH2), 1690 (C=O) cm−1. – 1H NMR (300 MHz,
[D6]DMSO, 25 ◦C, TMS): δ = 3.61 (s, 3H, OCH3), 6.58 (s,
2H, NH2), 6.84 (d, 2H, J = 9 Hz, Ar-H), 7.14 (d, 2H, J =
9 Hz, Ar-H), 7.20 – 7.26 (m, 4H, Ar-H), 7.30 – 7.38 (m, 6H,
Ar-H), 7.83 (s, 1H, 5-H). – MS (EI, 70 eV): m/z (%) = 368
(42) [M]+. – C24H20N2O2 (368.43): calcd. C 78.24, H 5.47,
N 7.60; found C 78.54, H 5.19, N 7.96.
Ethyl 3-amino-1-(4-methoxyphenyl)-4-phenyl-1H-pyrrole-2-
carboxylate (9d)
◦
M. p. 153 – 155 C. Yield: 62 %. – IR (KBr): ν = 3492 –
3380 (NH2), 1715 (C=O) cm−1. – 1H NMR (300 MHz,
[D6]DMSO, 25 ◦C, TMS): δ = 0.98 (t, 3H, J = 7.5 Hz, CH3),
3.78 (s, 3H, OCH3), 4.04 (q, 2H, J = 7.5 Hz, CH2), 5.94
(s, 2H, NH2), 6.93 (d, 2H, J = 9 Hz, Ar-H), 7.21 (d, 2H,
J = 9 Hz, Ar-H), 7.28 (t, 1H, J = 8 Hz, Ar-H), 7.31 – 7.39
(m, 4H, Ar-H), 7.66 (s, 1H, 5-H). – 13C NMR (75.4 MHz,
[D6]DMSO): δ = 14.12 (CH3), 55.44 (OCH3), 59.10 (CH2),
108.72 (C-2), 113.53 (C-3ꢀ,5ꢀ), 121.23 (C-2ꢀꢀ,6ꢀꢀ), 127.21
3-Amino-1-(4-methoxyphenyl)-4-phenyl-1H-pyrrole-2-
carbonitrile (9a)
M. p. 202 – 204 C. Yield: 86 %. – IR (KBr): ν = 3450 – (C-2ꢀ,6ꢀ), 127.94 (C-4ꢀꢀ), 132.14 (C-1ꢀ), 132.92 (C-3ꢀꢀ,5ꢀꢀ),
3358 (NH2), 2217 (CN) cm−1. – 1H NMR (300 MHz, 134.54 (C-5), 137.31 (C-1ꢀꢀ), 141.96 (C-4), 146.41 (C-3),
[D6]DMSO, 25 ◦C, TMS): δ = 3.79 (s, 3H, OCH3), 6.14 (s, 158.86 (C-4ꢀ), 160.32 (C=O). – MS (EI, 70 eV): m/z (%) =
2H, NH2), 7.06 (d, 2H, J = 9.5 Hz, Ar-H), 7.12 (t, 1H, J = 336 (27) [M]+. – C20H20N2O3 (336.38): calcd. C 71.41,
8.5 Hz, Ar-H), 7.41 (d, 2H, J = 9.5 Hz, Ar-H), 7.45 – 7.53 H 5.99, N 8.33; found C 71.58, H 6.16, N 8.59.
◦
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A. M. Salaheldin · Novel Synthesis of 3-Aminopyrroles and Pyrrolo[3,2-d]pyrimidine Derivatives
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1-(2-Cyano-1-(4-methoxyphenyl)-4-phenyl-1H-pyrrol-3-yl)-
3-phenylthiourea (10)
(15 mL). The reaction mixture was stirred for 3 h, cooled,
and the precipitated solid filtered off and crystallized from
EtOH-DMF, 2 : 1.
To a solution of (0.01 mol) 9a in dry acetone (20 mL)
was added phenyl isothiocyanate (0.01 mol), and the reac-
tion mixture was refluxed for 3 h. The reaction mixture was
allowed to cool to r. t., and the solid formed was collected by
filtration and crystallized from ethanol/DMF (2 : 1) to afford
(10). M. p. 242 – 244 ◦C. Yield: 64 %. – IR (Nujol): ν = 2195
(CN), 3260 (NH)◦, 1668 (C=S) cm−1. – 1H NMR (300 MHz,
[D6]DMSO, 25 C, TMS): δ = 3.61 (s, 3H, OCH3), 6.86
(d, 2H, J = 9 Hz, Ar-H), 7.03 (d, 2H, J = 9 Hz, Ar-H),
7.32 – 7.53 (m, 10H, Ar-H), 7.88 (s, 1H, NH), 7.93 (s, 1H,
5-H), 8.20 (s, 1H, NH). – MS (EI, 70 eV): m/z (%) = 424
(36) [M]+. – C25H20N4OS (424.52): calcd. C 70.73, H 4.75,
N 13.20, S 7.55; found C 70.41, H 4.70, N 13.54, S 7.96.
Method B: A mixture of 3-amino-2-cyanopyrrole 9a
(0.01 mol), formamide (15 mL), N,N-dimethylformamide
(5 mL), and formic acid (2 mL) was heated under reflux for
6 – 8 h. The reaction mixture was allowed to stand overnight
at r. t. The solid obtained was filtered, washed with cold
methanol, dried, and crystallized from EtOH-DMF, 2 : 1.
M. p. 268 – 270 ◦C. Yield: 71 %. – IR (Nujol): ν = 3458 –
3344 (NH2) cm−1. – 1H NMR (300 MHz, [D6]DMSO,
◦
25 C, TMS): δ = 3.84 (s, 3H, OCH3), 6.04 (bs, 2H, NH2),
7.14 (d, 2H, J = 9 Hz, Ar-H), 7.21 (t, 1H, J = 8 Hz,
Ar-H), 7.29 – 7.35 (m, 4H, Ar-H), 7.54 (d, 2H, J = 9 Hz,
Ar-H), 8.29 (s, 1H, 2-H), 8.47 (s, 1H, 6-H). – 13C NMR
(75.4 MHz, [D6]DMSO): δ = 55.61 (OCH3), 114.43 (C-7a),
114.97 (C-3ꢀ,5ꢀ), 122.51 (C-2ꢀꢀ,6ꢀꢀ), 126.42 (C-4ꢀꢀ), 127.80
(C-2ꢀ,6ꢀ), 129.94 (C-1ꢀ), 131.76 (C-3ꢀꢀ,5ꢀꢀ), 137.76 (C-1ꢀꢀ),
139.64 (C-6), 142.43 (C-7), 148.43 (C-4a), 150.86 (C-4),
152.63 (C-2), 159.91 (C-4ꢀ). – MS (EI, 70 eV): m/z (%) = 316
(48) [M]+. – C19H16N4O (316.36): calcd. C 72.13, H 5.10,
N 17.71; found C 72.34, H 5.45, N 17.98.
N-Acetyl-N-(2-cyano-1-(4-methoxyphenyl)-4-phenyl-1H-
pyrrol-3-yl)acetamide (12)
To compound 9a (0.01 mol) was added acetic anhy-
dride (10 mL), the reaction mixture was heated under reflux
for 3 h, cooled and the precipitate filtered off. M. p. 131 –
◦
132 C. Yield: 67 %. – IR (Nujol): ν = 2206 (CN), 1678
◦
(C=O) cm−1. – 1H NMR (300 MHz, [D6]DMSO, 25 C,
N-(4-Chlorophenyl)-5-(4-methoxyphenyl)-7-phenyl-5H-
pyrrolo[3,2-d]pyrimidin-4-amine (16)
TMS): δ = 2.27 (s, 6H, 2CH3), 3.80 (s, 3H, OCH3), 7.10
(d, 2H, J = 9 Hz, Ar-H), 7.30 – 7.35 (m, 2H, Ar-H), 7.36 –
7.51 (m, 3H, Ar-H), 7.56 (d, 2H, J = 9 Hz, Ar-H), 8.06 (s,
1H, 5-H). – MS (EI, 70 eV): m/z (%) = 373 (54) [M]+. –
C22H19N3O3 (373.40): calcd. C 70.76, H 5.13, N 11.25;
found C 70.94, H 5.55, N 11.58.
Method A: To a solution of amidine 13 (3.0 mmol) in
methanol (20 mL) was added p-chloroaniline (3.0 mmol).
The reaction mixture was heated under reflux for 7 h. The
precipitate formed after cooling overnight was filtered off
and dried and recrystallized from ethanol (74 %).
Ethyl N-2-cyano-1-(4-methoxyphenyl)-4-phenyl-1H-pyrrol-
Method B: To a solution of 4-chloropyrrolopyrmidines 18
(2.0 mmol) in methanol (20 mL) was added p-chloroaniline
(2.0 mmol). The reaction mixture was refluxed for 5 h. The
precipitate formed during reflux was filtered off and found
identical in all respect with that obtained from method A
(68 %).
3-ylformimidate (13)
A
mixture of 3-aminopyrrole-2-carbonitrile 9a
(0.015 mol), triethyl orthoformate (20 mL) and acetic
anhydride (20 mL) was heated under reflux for 7 h and then
evaporated under reduced pressure. The residue was treated
with ethanol, and the solid product formed was collected by
filtration, washed with ethanol and crystallized from EtOH.
◦
M. p. 235 – 237 C. Yield: 74 %. – IR (Nujol): ν = 3410
(NH) cm−1. – 1H NMR (300 MHz, [D6]DMSO, 25 ◦C,
TMS): δ = 3.86 (s, 3H, OCH3), 6.98 (s, H, NH), 7.01 –
7.08 (m, 1H, Ar-H), 7.16 (d, 2H, J = 9 Hz, Ar-H), 7.25 –
7.33 (m, 4H, Ar-H), 7.46 (d, 2H, J = 9 Hz, Ar-H), 7.61 (d,
2H, J = 9 Hz, Ar-H), 8.21 (d, 2H, J = 9 Hz, Ar-H), 8.51
(s, 1H, 2-H), 8.62 (s, 1H, 6-H). – 13C NMR (75.4 MHz,
[D6]DMSO): δ = 55.71 (OCH3), 114.11 (C-7a), 114.89
(C-3ꢀ,5ꢀ), 120.76 (C-2ꢀꢀ,6ꢀꢀ), 122.52 (C-b,f), 123.42 (C-4ꢀꢀ),
128.10 (C-2ꢀ,6ꢀ), 128.81 (C-3ꢀꢀ,5ꢀꢀ), 129.21 (C-c,e), 129.84
(C-1ꢀ), 130.35 (C-d), 137.65 (C-a), 138.21 (C-1ꢀꢀ), 140.10
(C-7), 140.62 (C-6), 147.43 (C-4), 148.87 (C-4a), 152.11
(C-2), 160.21 (C-4ꢀ). – MS (EI, 70 eV): m/z (%) = 426 (90)
[M, 35Cl]+, 428 (23) [M, 37Cl]+. – C25H19ClN4O (426.90):
◦
M. p. 150 – 152 C (EtOH). Yield: 74 %. – IR (Nujol): ν =
2208 (CN), 1620 (C=N) cm−1. – 1H NMR (300 MHz,
[D6]DMSO, 25 ◦C, TMS): δ = 1.32 (t, 3H, J = 7.5 Hz, CH3),
3.82 (s, 3H, OCH3), 4.33 (q, 2H, J = 7.5 Hz, CH2), 7.15 (d,
2H, J = 9 Hz, Ar-H), 7.21 – 7.40 (m, 5H, Ar-H), 7.53 (d, 2H,
J = 9 Hz, Ar-H), 8.19 (s, 1H, N=CH), 8.34 (s, 1H, 5-H). –
MS (EI, 70 eV): m/z (%) = 345 (80) [M]+. – C21H19N3O2
(345.39): calcd. C 73.03, H 5.54, N 12.17; found C 73.31,
H 5.78, N 12.42.
5-(4-Methoxyphenyl)-7-phenyl-5H-pyrrolo[3,2-d]
pyrimidin-4-amine (14)
Method A: Amidine 13 (2.0 mmol) was added to a mixture calcd. C 70.34, H 4.49, N 13.12; found C 69.98, H 4.71,
of methanol (15 mL) and 25 % aqueous ammonia solution N 13.25.
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570
A. M. Salaheldin · Novel Synthesis of 3-Aminopyrroles and Pyrrolo[3,2-d]pyrimidine Derivatives
5-(4-Methoxyphenyl)-7-phenyl-3H-pyrrolo[3,2-d]
pyrimidin-4(5H)-one (17)
completion of the reaction, the excess of phosphorus oxy-
chloride was removed under vacuum. The cooled reaction
mixture was then added to crushed ice (25 g). The resulting
solid was filtered, washed with sodium bicarbonate (5 % w/v)
followed by cold water, dried, and crystallized from ethanol
and chloroform (8 : 2 v/v). M. p. 136 – 138 ◦C. Yield: 56 %. –
A mixture of 3-amino-2-cyanopyrrole 9a (0.01 mol) and
formic acid (25 mL) was stirred at reflux temperature for
8 h. The reaction mixture was then allowed to cool, poured
onto crushed ice (50 g), neutralized with sodium hydrox-
ide solution (2 N), filtered, dried, and crystallized from a
mixture of (EtOH-DMF, 2 : 1). M. p. 301 – 304 ◦C. Yield:
66 %. – IR (Nujol): ν = 3340 (NH), 1690 (C=O) cm−1. –
1H NMR (300 MHz, [D6]DMSO, 25 ◦C, TMS): δ = 3.80 (s,
3H, OCH3), 6.99 (d, 2H, J = 9 Hz, Ar-H), 7.15 – 7.35 (m,
5H, Ar-H), 7.64 (d, 2H, J = 9 Hz, Ar-H), 8.09 (s, 1H, 2-H),
8.14 (s, 1H, 6-H), 11.85 (s, 1H, NH). – MS (EI, 70 eV):
m/z (%) = 317 (55) [M]+. – C19H15N3O2 (317.34): calcd.
C 71.91, H 4.76, N 13.24; found C 72.14, H 4.95, N 13.48.
◦
1H NMR (300 MHz, [D6]DMSO, 25 C, TMS): δ = 3.81
(s, 3H, OCH3), 7.21 (d, 2H, J = 9 Hz, Ar-H), 7.35 – 7.38
(m, 2H, Ar-H), 7.50 – 7.54 (m, 3H, Ar-H), 7.56 (d, 2H, J =
9 Hz, Ar-H), 8.19 (s, 1H, 6-H), 8.35 (s, 1H, 2-H). – MS
(EI, 70 eV): m/z (%) = 335 (46) [M, 35Cl]+, 337 (12) [M,
37Cl]+. – C19H14ClN3O (335.79): calcd. C 67.96, H 4.20,
N 12.51; found C 67.66, H 4.35, N 12.19.
Acknowledgements
We thank Fundac¸a˜o para
a Cieˆncia e Tecnologia
4-Chloro-5-(4-methoxyphenyl)-7-phenyl-5H-pyrrolo[3,2-d]
pyrimidine (18)
(FCT-Portugal) for a fellowship grant, Prof. A. M. Cam-
pos for hospitality, continuous help and Miss Elisa
Pinto for obtaining the NMR and elemental analyses
data.
A mixture of pyrrolopyrimidin-4-one 17 (0.01 mol) and
phosphorus oxychloride (25 mL) was refluxed for 9 h. After
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