Investigation into Sonogashira reaction on 5-iodo-1-(phenyl/p-halophenyl)imidazole-4-carbonitrile compounds

Article abstract of DOI:10.1080/00397911.2017.1373298

Investigation into Sonogashira reaction on 5-iodo-1-(phenyl/p-halophenyl)imidazole-4-carbonitrile compounds had been developed by introducing an iodo atom at the C-5 position of the imidazole ring of 5-amino-1-(phenyl/p-halophenyl)imidazole-4-carbonitrile

Full text of DOI:10.1080/00397911.2017.1373298

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: http://www.tandfonline.com/loi/lsyc20
Investigation into Sonogashira reaction on
5-iodo-1-(phenyl/p-halophenyl)imidazole-4-
carbonitrile compounds
Aniruddha Das
To cite this article: Aniruddha Das (2017): Investigation into Sonogashira reaction on 5-iodo-1-
(phenyl/p-halophenyl)imidazole-4-carbonitrile compounds, Synthetic Communications, DOI:
10.1080/00397911.2017.1373298
To link to this article: http://dx.doi.org/10.1080/00397911.2017.1373298
View supplementary material
Accepted author version posted online: 11
Sep 2017.
Submit your article to this journal
Article views: 5
View related articles
View Crossmark data
Full Terms & Conditions of access and use can be found at
http://www.tandfonline.com/action/journalInformation?journalCode=lsyc20
Download by: [Australian Catholic University]
Date: 15 September 2017, At: 07:13

Investigation into Sonogashira reaction on 5-iodo-1-
(phenyl/p-halophenyl)imidazole-4-carbonitrile compounds
Aniruddha Das*
University College of Science, Technology & Agriculture, University of Calcutta, Kolkata, India
Address correspondence to Aniruddha Das, University College of Science, Technology &
Agriculture, University of Calcutta, 92, Acharya Prafulla Chandra Road, Kolkata-700009, India.
Fax: +91 033 2351 9755. E-mail: aniruddha.1086@rediffmail.com
ABSTRACT
Investigation into Sonogashira reaction on 5-iodo-1-(phenyl/p-halophenyl)imidazole-4-
carbonitrile compounds had been developed by introducing an iodo atom at the C-5 position of
the imidazole ring of 5-amino-1-(phenyl/p-halophenyl)imidazole-4-carbonitrile compounds.
Specifically, 5-iodo-1-(4-iodophenyl)imidazole-4-carbonitrile compound had shown double
Sonogashira coupling reactions with two differently substituted iodine along with the formation
of two other compounds where an unusual coupling product with self-aggregation property was
obtained. In other cases mono coupling had been observed together with another compound
where iodine atom present at C5 position of imidazole was replaced by hydrogen atom.
GRAPHICAL ABSTRACT
1

KEYWORDS: 5-iodo derivative of AICN, double scope of Sonogashira reaction, self-
aggregation property, unusual coupling
Introduction
The Sonogashira reaction of aryl halides with terminal acetylene is an important tool for
C(sp2)-C(sp) bond formation, which has been widely applied to diverse areas such as synthesis
of natural products[1], biologically active molecules[2], new organic materials for optical and
microelectronic application[3], polymeric materials[4], macro-cycles with acetylene links[5] and as
a pathway to construct new molecular architecture.[6] Catalytic cross-coupling of terminal
acetylenes with aryl halides to produce aryl-ethynyl compounds is an important step in this task.
Sonogashira coupling is envisaged as aryl donors linked to aryl or heteroaryl acceptors via a
2

triple bond. Sonogashira coupling reaction generally involves catalytic palladium with a metal
cocatalyst and a base.[7]
Substituted imidazole rings are considered to be a common structural motifs in natural
products and due to their interesting biological and medicinal properties, they have emerged as
attractive synthetic targets.[8] In present communication, the discussions will be focused on
Sonogashira coupling reactions involving 5-iodo-1-(phenyl/p-halophenyl)imidazole-4-
carbonitrile compounds (AICN)9 by direct introduction of an iodo atom at the C5 position of the
imidazole ring via the diazotisation of the 5-amino group of the starting material. It was
envisioned that iodo atom at the C5 position of imidazole ring and the halogen atom (F, Cl, Br
and I) at the para- position of phenyl moiety attached with N1 of the imidazole unit might
undergo Sonogashira coupling in a stepwise manner or in a concerted way.
Results and Discussion
The diazotization of 5-amino-4-cyano-1-substitutedimidazole compounds (AICN)[9] with
NaNO2 in dilute HCl medium led to the formation of imidazo[4,5-d][1,2,3]triazin-4-ones
(Figure 1)[10] due to in situ hydrolysis of the cyano group to amide function which underwent
condensation with the azo group.
So, the diazotization of 5-amino-4-cyano-1-(phenyl/p-halophenyl)imidazole compounds
in the acidic medium had been avoided. Sandmeyer type conversion of 5-amino group of 5-
amino-4-cyano-1-(phenyl/p-halophenyl)imidazole compounds to 5-iodo ones was attempted with
iso-amyl nitrite[11] in presence of I2 with chloroform as solvent.
3

This reagent helped the diazotization of 5-amino-4-cyano-1-(phenyl/p-halophenyl)
imidazole compounds in absence of any added acidic reagent and the reaction took place in a
neutral condition furnishing the products in satisfactory yields (Scheme 1).[12]
Table 1 tabulates the synthesis of 5-iodo-1-(phenyl/p-halophenyl)imidazole-4-
carbonitrile compounds in terms of reaction time and corresponding yield of the each product.
ORTEP diagram of representative compound 1d of the series 1a-e is shown in Figure 2.
The mechanism of diazotization of 5-iodo-1-(phenyl/p-halophenyl)imidazole-4-
carbonitrile compounds (1a-e) in neutral medium followed radical pathway (Figure 3).
Generation of carbon centered radical of 5-amino-4-cyano-1-(phenyl/p-
halophenyl)imidazole via rapid dediazotation by homolytic cleavage followed by abstraction of
·
I from I2 molecules produced 1a-e.
Introduction of an iodo atom at C5 position of imidazole ring via Sandmeyer type
reaction of 5-amino-1-(phenyl/p-halophenyl)imidazole-4-carbonitrile compounds (1a-e) offered
a situation of dual Sonogashira coupling (Figure 4). For each of those molecules, there was
competition between halogen atoms which were attached at two different positions, namely, iodo
atom at the C5 position of imidazole ring as well as halogen atoms Cl, Br and I as para-
substituent on phenyl moiety attached to N1 of the imidazole unit.
Palladium-copper co-catalysed Sonogashira cross-coupling of terminal alkynes with aryl
halides has become a powerful tool for constructing carbon-carbon bonds leading to the
formation of arylated alkynes. Sonogashira reaction of 5-iodo-1-(4-fluorophenyl)imidazole-4-
carbonitrile (1b) obtained from Sandmeyer type conversion of 5-amino-1-(p-fluorophenyl)-
4

imidazole-4-carbonitrile and phenyl acetylene had been investigated. In order to obtain the
optimum reaction condition of Sonogashira reaction of the 5-iodo -1-(phenyl/p-
halophenyl)imidazole-4-carbonitrile compounds, I undertook the screening of a representative
reaction between 1b (1.0 mmol) and phenyl acetylene (2.0 mmol) by varying the nature of Pd(0)
or Pd(II) catalysts(5mole%) in presence of CuI (10 mol%) as co-catalyst for each set of reaction.
The reaction was carried out in presence of different bases and solvents. The reaction parameters
viz. temperatute and reaction time were also investigated and the results have been summarized
in Table 2.
Initial screening of the reaction conditions using 5-iodo-1-(4-fluorophenyl)imidazole-4-
carbonitrile (1b) and phenyl acetylene revealed that reaction did not occur in presence of Pd(0)
or Pd(II) catalysts viz. Pd(PPh3)4, PdCl2, 10% Pd-C. For this reaction, PdCl2(PPh3)2 (5mol%)
was the best catalyst keeping co-catalyst CuI (10 mol%) constant. Screening tests were carried
out varying bases, solvents and temperatures (Table 2, entries 1, 2, 3, 4, 5, 6) with no result.
Sonogashira coupling occurred successfully in presence of Et3N as base in DMF solvent
maintaining temperature ~80ºC for 16 hr.
It was evident from Table 2 that entry 7 was the optimized condition for Sonogashira
coupling of 1b and phenyl acetylene. On the basis of these data, the reaction was continued
under optimized condition for 1a and 1c-e. In all cases reaction proceeded efficiently leading to
moderate yields of the products. The reactions were summarized in Scheme 2.
It was observed that, for the compounds 1a-d, two types of products were obtained. The
major products were 2a-d where iodo atom present at the C-5 position of imidazole ring was
involved in Sonogashira coupling. In these cases halogen atom present at para-position of phenyl
moiety did not undergo the coupling reaction. Additionally, compounds 3a-d were formed where
5

iodo atom at the C-5 position of imidazole of 1a-d was replaced by a hydrogen atom. In case of
1e, the situation was little bit different where two iodo atoms were present at two different
positions in the molecular framework of 1e. Under the optimized condition of Sonogashira
coupling reaction with 1e, compounds 2e and 3e were produced alongwith the formation of a
unusual coupled product 4. It was interesting to note that iodo atom substituted at the C4′
position of the phenyl ring attached at N1 of the imidazole moiety had been replaced by phenyl
acetylene group in all three products 2e, 3e and 4. Product 2e indicated that two iodo atoms,
though differently substituted, were replaced by two phenyl acetylene groups under Sonogashira
condition. Product 3e experienced alkyne coupling only at C4′ position on aromatic ring bonded
to N1 of imidazole alongwith the substitution of iodo atom at C5 by hydrogen atom. Formation
of compound 4 followed a different pathway with the position of an iodo atom being shifted
from C-5 to C-2 of imidazole ring and survived in Sonogashira coupling reaction. Compound 4
was formed where iodo atom was found to be located at C-2 position of imidazole ring with a
hydrogen atom substitution at C-5 position and the iodo atom on aromatic ring replaced by
phenyl acetylene moiety.
The plausible mechanism for formation of Sonogashira coupling products (2a-d) from
compounds 1a-d respectively has been shown in Figure 5.
The plausible mechanism for formation of major product is presented in Figure 5
indicated three important aspects. The divalent Pd(II) catalyst, PdCl2(PPh3)2, was transformed to
Pd(0) state with the base Et3N. The palladium catalytic cycle was initiated by the oxidative
addition
with
5-iodo-1-(phenyl/p-halophenyl)imidazole-4-carbonitrile
compounds.
Simultaneously, Cu-catalytic cycle became operative involving Cu(I) and phenyl acetylene. At
this stage the nitrile group at C4 with its triple bond might participate as co-ordinating ligand.
6

Then the trans-metalation step followed by reductive elimination yielded Sonogashira coupling
products 2a-d. In respective cases of compounds 1c-d where the identity of halogen atom was
chloro and bromo present at para position of phenyl ring did not participate in Sonogashira
coupling. But 5-iodo-1-(4-iodophenyl)imidazole-4-carbonitrile compound (1e) had shown
double sonogashira coupling with differently substituted iodine. Formation of double
Sonogashira coupled product 2e could be explained from the mechanisms shown in Figure 5. In
case of 1e both iodo atoms participated in the Sonogashira coupling reaction and were
substituted by the phenyl acetylene group to product major product 2e.
The plausible mechanism for the formation of minor products where iodine atoms at C5
were substituted by hydrogen atoms is suggested in Figure 6. Figure 5 indicated that during
trans-metalation step, I- was eliminated and combined with Cu(I) to continue copper catalytic
cycle. It had been suggested in Figure 6, that I- might abstract the I+ from the nitrile group
coordinated Pd(II) complex generating anionic C5 centre which would take up a proton to form
the compounds 3a-d. Apparently Cu(I) catalytic cycle was hampered. However, Cu(I) might
stabilize the anionic C5 of imidazole ring. HX was generated in situ through reductive
elimination step in Sonogashira coupling reaction shown in Figure 5. This was the source of
proton. In case of 1e, one iodo atom at C5 position of imidazole ring was replaced by hydrogen
atom as well as second iodo atom present at para position of phenyl ring took part in
Sonogashira coupling and mono-coupled product 3e was produced as minor product. Formation
of 3e could be explained from the mechanisms shown in Figures 5 and 6.
However, the elucidation of mechanistic pathway of formation of 4 involving the
interchange in the positions of hydrogen and iodine atoms was not clear and currently underway
in the laboratory.
7

The reaction was repeated with 1a and 1e in absence of phenyl acetylene maintaining all
the parameters involving catalyst, co-catalyst, base and the reaction conditions identical with the
optimized condition. It had been observed that only iodo atom attached at C5 position of
imidazole moiety had been replaced by hydrogen atom but the iodo atom present as p-phenyl
substituent in 1e remained unchanged (Scheme 3). This observation suggested additional
reduction role of combined catalyst and co-catalyst pair of PdCl2(PPh3)2-CUI.
The structure of compound 4 was finally confirmed by single crystal XRD study. The
structure of the compound 4 is shown in Figure 7.
Compound 4 had shown the property as a candidate for fabrication of nanostructured
organic material. It possessed unique aggregation property as evident from the SEM images of
the material (Figure 8). The aggregation behaviour of compound 4 was studied in non-polar
solvent (petroleum ether). It was quickly self-organised into the right molecular orientation to
grow one dimension nano-rod. SEM image of 4 revealed construction of nano-rod of about ~
163-218 nm width.
Conclusion
Introduction of an iodo atom on 5-amino-1-(phenyl/p-halophenyl)imidazole-4-
carbonitrile compounds at the C-5 position of the imidazole ring in neutral medium had offered a
situation of Sonogashira coupling reaction with Pd(PPh3)2Cl2 as catalyst and CuI as co-catalyst.
For each case, there was competition for Sonogashira coupling reaction between halogen atoms
which were attached at two different positions, namely, iodo atom at the C5 position of
imidazole ring as well as halogen atoms Cl, Br and I as para- substituent on phenyl moiety
attached to N1 of the imidazole unit. Sonogashira cross-coupling reactions of 1a-d had been
8

performed with phenyl acetylene compound and simple cross-coupled products (2a-d) had been
produced in each case. Additionally, compounds 3a-d had been produced where iodo atom at the
C5 position of imidazole of 1a-e was replaced by hydrogen atom. But Sonogashira coupling
reaction on 1e produced 2e and 3e along with the formation of an unusual coupled product 4.
Product 2e experienced double replacement of two iodo atoms, though differently substituted, by
two phenyl acetylene groups under Sonogashira condition. In case of 3e, substitution of iodo
atom at C-5 of imidazole ring by hydrogen atom was observed along with alkyne coupling only
at C-4′ position on aromatic ring bonded to N1 of imidazole. Product 4 was an interesting
product with aryl-alkyne coupling at C-4′ and an interchange of positioning of hydrogen atom
with iodo atom. Self-aggregation property had been studied of compound 4 which revealed nano-
rod formation in non-polar medium.
Experimental section
The reagents were purchased from commercial sources. Organic solvents were dried by
standard methods. Progress of all reactions were monitored by TLC by using precoated silica gel
aluminum plates. Visualization of TLC plates was monitored with an UV lamp. Melting points
were recorded on an electrically heated Köfler Block apparatus and are uncorrected. The solid-
state FT-IR measurements were done with a Perkin-Elmer-782 model spectrometer in the form
of KBr discs of the compounds. All products were characterized by IR, NMR and HRMS
1
13
spectra. H NMR and C NMR spectra were run with CDCl3 solutions at ambient temperature
on a Bruker Avance 300 spectrometer at 300 MHz for 1H and at 75 MHz for 13C. Chemical shifts
are reported in δ and coupling constants in Hz. The multiplicity of the carbon atoms was
determined by the DEPT 135º experiment. Chemical shifts were reported in parts per million
(ppm, δ) downfield from tetramethylsilane. Proton coupling patterns are assigned as singlet (s),
9

doublet (d), triplet (t), quartet (q), multiplet (m), and broad (br). In general, for Scanning
Electron Mictroscopic study (SEM), freshly prepared solutions (5mM) of compounds in different
solvents were sonicated with a UC 250WINECO ultrasonicator for 2 hour. Then one drop of
each these solutions were taken on (SEM) glass cover slips and allowed to dry slowly for 48 h. A
gold coating was applied to the top of the samples to make it conductive for analysis. Then, SEM
measurements were performed on a S3400N, Hitachi, Japan instrument with 10.0 to 15 kV
operating voltage and 1.5 k to 45.0 k magnification. HRMS data were acquired by electron spray
ionization technique on a Q-tof-micro quadrupole mass spectrometer (Bruker). All solvents were
distilled before use of single crystal X-ray diffraction studies of the compounds 1d and 4.
Diffraction data for 1d and 4 were collected with MoKα radiation at 296 K using the Bruker
APEX-II CCD System by generation of single crystal obtained by slow evaporation of aqueous
ethanol .The crystals were positioned 50 mm from the CCD. Frames were measured with a
counting time of 10 s. Data analyses were carried out with the Bruker APEX2 and Bruker
SAINT program. The structures were solved using direct methods with the Shelxs97 program
(Sheldrick, 2008).
General procedure for the preparation of 5-iodo-1-(phenyl/p-
halophenyl)imidazole-4-carbonitrile compounds (1)
Iodine (0.012 mol) and iso-amyl nitrite (0.012 mol) were added to chloroform (25 ml)
taken in a round bottomed flask. 5-Amino-1-(phenyl/p-halophenyl)imidazole-4-carbonitrile
(0.01mol) was taken in 100 ml of chloroform in a another conical flask. Then the suspended
chloroform solution of 5-amino-1-(phenyl/p-halophenyl)imidazole-4- carbonitrile was added
dropwise to chloroform solution of iodine and iso-amyl nitrite over 30 minutes . The reaction
was exothermic in nature. The rate of nitrogen evolution was dependent on the amine present and
10

it was accelerated in the presence of iodine. After that, the reaction was allowed to reflux for
additional 2 hr. The mixture was then washed with 5% sodium bisulfite solution. The organic
layer was separated. Then column chromatography separation was performed. Then the desired
compound was obtained by using 10% EtOAc- petroleum solvent mixture using as eluent. Then
it was crystallized from chloroform and petroleum ether solvent mixture. After that, it was
filtered and dried. The melting point has been noted.
General procedure for the Sonogashira reaction of preparation of 5-iodo-1-
(phenyl/p-halophenyl)imidazole-4-carbonitrile compounds (1)
A mixture of 5-iodo-1-(phenyl/p-halophenyl)imidazole-4-carbonitrile compounds (1),
PdCl2(PPh3)2 (5 mol%), CuI (10 mol %) and triethylamine (10 eq. of 1) were taken in DMF
(5mL) and the mixture was stirred at 25-30ºC for 30 min under nitrogen atmosphere. The
acetylenic compound (2 eq.) was then added and the mixture was initially stirred at room
temperature for 1 hr. and then the temperature was maintained at 85-90ºC for 15-17hr. The
completion of reaction was monitored by TLC. After completion of the reaction (the colour of
the reaction mixture turned in darkened colour), the mixture was cooled to room temperature and
dilute with EtOAc (50 mL). The organic layer was washed with water (3x30 mL). Then organic
layer was dried over anhydrous Na2SO4 and concentrated. The crude residue was purified by
column chromatography on silica gel using petroleum ether and ethyl acetate to afford the
desired product. Compounds 2a-d, 3a-d, 2e, 3e, 4 and 7 were obtained by using EtOAc-
petroleum solvent mixture as eluent in ~ 7%, 10%, 5%, 7.5%, 3% and 10% ratio respectively.
(a) Characterization data of 5-iodo-1-(4-fluorophenyl)imidazole-4-carbonitrile
(1b)
11

Yield: 55.74%; Characteristic: Colourless crystal (CHCl3 and pet. ether solvent mixtre);
Melting point: 120°C; 1H-NMR (300 MHz, CDCl3): δ 7.78(1H, s), 7.31-7.35 (2H, m), 7.22-7.28
C-F
(2H, m); 13C-NMR (75MHz, CDCl3): δ 163.31 (J1C-F= 250.5 Hz), 141.34, 131.66, 128.69 (J3
=
9 Hz), 123.81, 117.02 (J2C-F= 23.25 Hz), 114.16, 84.23; IR υmax(KBr), cm¯1: 3143, 3073, 2232,
1897, 1513, 1480, 1293, 1213, 1157, 969, 825; HRMS(m/z) for C10H6F1I1N3 (M+H)+: found
313.8468, calc. 313.9567.
(b) Characterization data of 1-(4-bromophenyl)-5-(phenylethynyl)imidazole-4-
carbonitrile (2d)
Yield: 47.98%; Characteristic: Colourless crystal (CHCl3 and pet. ether solvent mixture);
1
Melting point: 120-122°C; H-NMR (300 MHz, CDCl3): δ 7.58-7.68 (3H, m), 7.23-7.36
(7H, m);13C-NMR (75MHz, CDCl3): δ 138.02, 133.75, 133.05, 131.71, 130.01, 128.61, 126.13,
123.70, 120.68, 119.45, 113.73, 102.20, 73.90; IR υmax(KBr), cm¯1: 3829, 3636, 3458, 3578,
79
3118, 2268, 2236, 1500, 1451, 1269, 1112, 981, 849, 754; HRMS(m/z) for C18H11Br1 N3
81
(M+H)+ and C18H11Br1 N3 (M+H)+ respectively: found 348.4735 and 350.4734 (in intensity
ratio~1:1); calc. 348.4756, 350.4747.
(c) 5-(phenylethynyl)-1-(4-(phenylethynyl)phenyl)imidazole-4-carbonitrile (2e)
Yield: 43.4%; Characteristic: Colourless crystal (CHCl3 and pet. ether solvent mixture);
1
Melting point: 142°C; H-NMR (300 MHz, CDCl3): δ 7.71-7.75 (3H, m), 7.46-7.55 (5H, m),
7.36-7.44 (7H, m); 13C-NMR (75MHz, CDCl3): δ 137.78, 133.18, 132.25, 131.60, 131.47,
131.40, 131.34, 129.69, 128.66, 124.80, 124.25, 122.24, 120.55, 119.17, 113.55, 101.87, 91.65,
87.42, 78.15, 73.85; IR υmax(KBr), cm¯1: 3745, 3672, 3432, 3274, 2247, 2236, 1511, 1411, 1253,
1121, 967, 811.52, 736; HRMS(m/z) for C26H16N3 (M+H)+: found 370.1337, calc. 370.1356.
12

(d) Characterization data of 1-(4-chlorophenyl)imidazole-4-carbonitrile (3c)
Yield: 32.68%; Characteristic: Colourless crystal (CHCl3 and pet. ether solvent mixture);
Melting point: 160-162°C; 1H-NMR (300 MHz, CDCl3): δ 7.78(1H, s), 7.73(1H, s), 7.46
(2H, d, J=8.4Hz), 7.29 (2H, d, J=8.4Hz); 13C-NMR (75MHz, CDCl3): δ 137.03, 135.05, 134.20,
130.46, 126.54, 123.30, 115.94, 114.11; IR υmax(KBr), cm¯1: 3155, 3123, 2979, 2247, 1775,
35
37
1555, 1506, 1070, 1000; HRMS(m/z) for C10H7Cl1 N3 (M+H)+ and C10H7Cl1 N3 (M+H)+
respectively: found 204.0760 and 206.0707 (in intensity ratio~3:1); calc. 204.0785, 206.0798
Please view the supplementary material, available online, for complete spectral data
analysis.
Acknowledgements
The author, Aniruddha Das thanks the University of Calcutta for providing laboratory
experiment and spectroscopic facilities. I thank Prof. (retd.) Sibdas Ray, Dr. Kaliprasanna Dhara
of Chemistry Dept., University of Calcutta for their valuable suggestions and support. Single X-
ray Crystallographic studies had been performed with Single Crystal Diffractometer Facilities
sponsored by DST-FIST programme of department of Chemistry of University of Calcutta. The
author expresses deep gratitude to Centre for Research in Nanoscience & Nanotechnology
(CRNN) of University of Calcutta for scanning electron microscopic study. The author thanks
the Council of Scientific and Industrial Research (CSIR), New Delhi, India for financial
assistance.
References
13

[1] (a) Yoshimura, F.; Kawata, S.; Hirama, M. Synthetic Study of Kedarcidin Chromophore:
Atropselective Construction of the Ansamacrolide. Tetrahedron Lett. 1999, 40, 8281–
8285. DOI: 10.1016/S0040-4039(99)01744-X; (b) Toyota, M.; Komori, C.; Ihara, M. A
Concise Formal Total Synthesis of Mappicine and Nothapodytine B via an
Intramolecular Hetero Diels–Alder Reaction. J. Org. Chem. 2000, 65, 7110–7113. DOI:
10.1021/jo000816i; (c) Paterson, I.; Davies, R. D. M.; Marquez, R. Total Synthesis of the
Callipeltoside Aglycon. Angew. Chem. Int. Ed. 2001, 40, 603–607. DOI: 10.1002/1521-
3773(20010202)40:3<603::AID-ANIE603>3.0.CO;2-O.
[2] (a) Taylor, E. C.; Dowling, J. E. Replacement of the 1,4-Phenylene Region in 5,10-Dideaza-
5,6,7,8-Tetrahydrofolic Acid (DDATHF) by 4,5,6,7-Tetrahydrobenzo[c]Thiophene and
4,5,6,7-Tetrahydroisobenzofuran Nuclei. J. Org. Chem. 1997, 62, 1599–1603. DOI:
10.1021/jo9619903; (b) Liu, T.-Z.; Isobe, M. Synthesis of the H-I-J Tricyclic Fragment
of Ciguatoxin, a Marine Polyether Toxin. Synlett 2000, 266–268. DOI: 10.1055/s-2000-
6507; (c) Nakamura, H.; Aizawa, M.; Takeuchi, D.; Murai, A.; Shimoura, O. Convergent
and Short-Step Syntheses of dl-Cypridina Luciferin and Its Analogues Based on Pd-
Mediated Cross Couplings. Tetrahedron Lett. 2000, 41, 2185–2188. DOI:
10.1016/S0040-4039(00)00131-3; (d) Amiet, G.; Hügel, H. M.; Nurlawis, F. The
Synthesis of the Kynurenamines K1 and K2, Metabolites of Melatonin. Synlett 2002,
495–497. DOI: 10.1055/s-2002-20476; (e) Cosford, N. D. P.; Tehrani, L.; Roppe, J.;
Schweiger, E.; Smith, N. D.; Anderson, J.; Bristow, L.; Brodkin, J.; Jiang, X.; McDonald,
I.; et al. 3-[(2-Methyl-1,3-thiazol-4-yl)ethynyl]-pyridine:ꢀ A Potent and Highly Selective
Metabotropic Glutamate Subtype 5 Receptor Antagonist with Anxiolytic Activity. J.
Med. Chem. 2003, 46, 204–206. DOI: 10.1021/jm025570j.
[3] (a) Wong, K.-T.; Hsu, C. C. Control of the Arrangement of Dipolar Orientation of Pyrimidine
Inside the Conjugated Backbone. Org. Lett. 2001, 3, 173–175. DOI: 10.1021/ol006877k;
(b) Sonoda, M.; Inaba, A.; Itahashi, K.; Tobe, Y. Synthesis of Differentially Substituted
Hexaethynylbenzenes Based on Tandem Sonogashira and Negishi Cross-Coupling
Reactions. Org. Lett. 2001, 3, 2419–2421. DOI: 10.1021/ol016274o; (c) Perez-Balderas,
F.; Santoyo-González, F. Synthesis of Deeper Calix-sugar-Based on the Sonogashira
Reaction. Synlett 2001, 1699–1702. DOI: 10.1055/s-2001-18076; (d) Brunsveld, L.;
Meijer, E. W.; Prince, R. B.; Moore, J. S. Self-Assembly of Folded m-Phenylene
Ethynylene Oligomers into Helical Columns. J. Am. Chem. Soc. 2001, 123, 7978–7984.
DOI: 10.1021/ja010751g; (e) Mongin, O.; Porrés, L.; Moreaux, L.; Mertz, J.; Blanchard-
Desce, M. Synthesis and Photophysical Properties of New Conjugated Fluorophores
Designed for Two-Photon-Excited Fluorescence. Org. Lett. 2002, 4, 719–722. DOI:
10.1021/ol017150e.
[4] (a) Strachan, J.-P.; Gentemann, S.; Seth, J.; Kalsbeck, W. A.; Lindsey, J. S.; Holten, D.;
Bocian, D. F. Synthesis and Characterization of Tetrachlorodiarylethyne-Linked
Porphyrin Dimers. Effects of Linker Architecture on Intradimer Electronic
Communication. Inorg. Chem. 1998, 37, 1191–1201. DOI: 10.1021/ic970967c; (b)
Wagner, R. W.; Seth, J.; Yang, S. I.; Kim, D.; Bocian, D. F.; Holten, D.; Lindsey, J. S.
Synthesis and Excited-State Photodynamics of a Molecular Square Containing Four
Mutually Coplanar Porphyrins. J. Org. Chem. 1998, 63, 5042–5049. DOI:
10.1021/jo9803683; (c) Li, J.; Ambroise, A.; Yang, S. I.; Diers, J. R.; Seth, J.; Wack, C.
R.; Bocian, D. F.; Holten, D.; Lindsey, J. S. Template-Directed Synthesis, Excited-State
14

Photodynamics, and Electronic Communication in a Hexameric Wheel of Porphyrins. J.
Am. Chem. Soc. 1999, 121, 8927–8940. DOI: 10.1021/ja991730d.
[5] (a) Li, C.-J.; Slaven IV, W. T.; John, V. T.; Banerjee, S. Palladium Catalysed Polymerization
of Aryl Diodides with Acetylenegas in Aqueous Medium: A Novel Synthesis of
Areneethynylene Polymers and Oligomers. Chem. Commun. 1997, 1569–1570. DOI:
10.1039/A703723F; (b) Höger, S.; Rosselli, S.; Ramminger, A.-D.; Enkelmann, V. A
Facile Synthesis of Large Extraannular-Functionalized Phenyl-Ethynyl Macrocycles
Containing m-Terphenyl Units. Org. Lett. 2002, 4, 4269–4272. DOI: 10.1021/ol026870y.
[6] (a) Mongin, O.; Papamicael, C.; Hoyler, N.; Gossauer, A. Modular Synthesis of Benzene-
Centered Porphyrin Trimers and a Dendritic Porphyrin Hexamer. J. Org. Chem. 1998, 63,
5568–5580; DOI: 10.1021/jo980846+; (b) Onitsuka, K.; Fujimoto, M.; Ohshiro, N.;
Takahashi, S. Convergent Route to Organometallic Dendrimers Composed of Platinum–
Acetylide Units. Angew. Chem. Int. Ed. 1999, 38, 689–692. DOI: 10.1002/(SICI)1521-
3773(19990301)38:5<689::AID-ANIE689>3.0.CO;2-D.
[7] (a) Burnagin, N. A.; Sukhomlinova, L. I.; Luzikova, E. V.; Tolstaya, T. P.; Beletskaya, I. P.
Catalytic Coupling of Terminal Acetylenes with Iodoarenes and Diaryliodonium Salts in
Water. Tetrahedron Lett. 1996, 37, 897–900. DOI: 10.1016/0040-4039(95)02255-4; (b)
Hundertmark, T.; Littke, A. F.; Buchwald, S. L.; Fu, G. C. Pd(PhCN)2Cl2/P(t-Bu)3:ꢀ A
Versatile Catalyst for Sonogashira Reactions of Aryl Bromides at Room Temperature.
Org. Lett. 2000, 2, 1729–1731. DOI: 10.1021/ol0058947; (c) Erdélyi, M.; Gogoll, A.
Rapid Homogeneous-Phase Sonogashira Coupling Reactions Using Controlled
Microwave Heating. J. Org. Chem. 2001, 66, 4165–4169. DOI: 10.1021/jo0057250; (d)
Negishi, E.-I.; Anastasia, L. Palladium-Catalyzed Alkynylation. Chem. Rev. 2003, 103,
1979–2018. DOI: 10.1021/cr020377i.
[8] (a) Alkaloid, M.; Kawasaki, I.; Taguchi, N.; Yamamoto, T.; Yamashita, M.; Ohta, S. Total
Synthesis of Kealiiquinone, an Imidazole. Tetrahedron Lett. 1995, 36, 8251–8254. DOI:
10.1016/0040-4039(95)01770-1; (b) Kawasaki, I.; Taguchi, N.; Youko, Y.; Yamashita,
M.; Ohta, S. Highly Effective Procedure for Introduction of Amino Group into the 2-
Position of Imidazole Ring. Heterocycles 1996, 43, 1375–1379. DOI: 10.3987/COM-96-
7475; (c) Lindel, T.; Hochgurtel, M. Synthesis of the Marine Natural Product Oroidin and
Its Z-Isomer. J. Org. Chem. 2000, 65, 2806–2809. DOI: 10.1021/jo991395b.
[9] Das, A. Studies on Complex π-π and T-Stacking Features of Imidazole and Phenyl/p-
Halophenyl Units in Series of 5-Amino-1-(phenyl/p-Halophenyl)Imidazole-4-
Carboxamides and Their Carbonitrile Derivatives: Role of Halogens in Tuning of
Conformation.
DOI:10.1016/j.molstruc.2017.06.124.
[10] Colomer, J. P.; Moyano, E. L. New Application of Heterocyclic Diazonium Salts. Synthesis
of Pyrazolo[3,4-d][1,2,3]triazin-4-ones and Imidazo[4,5-d][1,2,3]triazin-4-ones.
J.
Mol.
Struct.
2017,
1147,
520–540.
Tetrahedron Lett. 2011, 52, 1561–1565. DOI: 10.1016/j.tetlet.2011.01.040.
[11] Furniss, B. S.; Hannaford, A. J.; Smith, P. W. G., Tatchell, A. R. Vogel’s Textbook of
Practical Organic Chemistry, PUB, 5th ed., 4th Indian Reprint, Longman Group UK
Limited, 2005; p 413.
[12] Friedman, L.; Chlebowski, J. Aprotic Diazotization of Aniline in the Presence of Iodine. J.
Org. Chem. 1968, 33, 1636–1638. DOI: 10.1021/jo01268a070.
15

Table 1. Synthesis of 5-iodo-1(phenyl/p-halophenyl)imidazole-4-carbonitrile compounds.
Entry
1
Reactantsa
Time (hr.)
2:30
Product
Yield(%)b
52.5
2
3
2:30
2:30
55.74
58.9
4
5
2:30
2:30
60.06
50.16
aReaction condition: Iodine (0.012 mol), iso-amyl nitrite (0.012 mol), 5-Amino-1-(phenyl/p-halophenyl)imidazole-4-carbonitrile
(0.01mol), chloroform (25 ml), reflux.
16

bIsolated yields after column chromatography was noted.
17

Table 2. Optimization study using 1b and phenyl acetylenea.
Entry Catalyst (5
mol%)
Solvent
Base
Time
(hr)
16
Temp
(º)
Yieldb
1.
2.
3.
4.
5.
6.
7.
Pd(PPh3)4
Pd(PPh3)4
PdCl2
Acetonitrile
DMF
DBU
70
-
Et3N
15
80
-
Acetonitrile
Methanol
Acetonitrile
DMF
Et3N
15
70
-
PdCl2
pyrrolidine
DBU
12
50
-
10% Pd-C
Pd(OAc)2
PdCl2(PPh3)2
16
70
-
Et3N
15
80
-
DMF
Et3N
16
80
2b:
51.6%,
3b:
38.45%
aOptimized protocol: Catalyst: 5 mol% PdCl2(PPh3)2, 10 mol% CuI, Solvent: DMF, Base: Et3N (4eq.), Phenyl acetylene: 2 eq.
bIsolated yields after column chromatography.
18

Figure 1. Diazotization of 5-amino-4-cyano-1-substitutedimidazole in acidic medium produces
imidazo[4,5-d][1,2,3]triazin-4-ones.
19

Figure 2. ORTEP diagram of 1d (CCDC no. 1543200).
20

Figure 3. Mechanism of diazotization of 5-amino-1-(phenyl/p-halophenyl)imidazole-4-
carbonitrile compounds in neutral medium.
21

Figure 4. Scope of dual Sonogashira coupling of 5-iodo-1-(phenyl/p- halophenyl)imidazole-4-
carbonitrile compounds.
22

Figure 5. The plausible mechanism for formation of Sonogashira coupling product (2a-d) of
compounds 1a-d.
23

Figure 6. The plausible mechanism for formation of 3a-d.
24

Figure 7. ORTEP diagram of 4 (CCDC no. 1543202).
25

Figure 8. SEM image of compound 4 in petroleum ether.
26

Scheme 1. Preparation of 5-iodo-1(phenyl/p-halophenyl)imidazole-4-carbonitrile compounds by
using iodine and iso-amyl nitrite in neutral condition.
27

Scheme 2. Sonogashira coupling of the series of 5-iodo-1(phenyl/p-halophenyl)imidazole-4-
carbonitrile (1a-e).
28

Scheme 3. Reactions of 1a and 1e in absence of phenyl acetylene.
29