Synthesis, characterization and computational studies of 2-cyano-6-methoxybenzothiazole as a firefly-luciferin precursor

Article abstract of DOI:10.1515/hc-2018-0047

A novel approach to the synthesis of 2-cyano-6-methoxybenzothiazole via the Cu-catalyzed cyanation of 2-iodo-6-methoxybenzothiazole was developed. K₄[Fe(CN)₆] was used as a source of cyanide, and a Cu/N,N,N′,N′-tetramethylethylenediamine (TMEDA) system was utilized as a catalyst. This approach is scalable and can be practiced with operational benign. The most stable conformation of 2-cyano-6-methoxybenzothiazole was delineated using the density functional theory (DFT)/B3LYP method with 6-311++G(d, p) basis set.

Full text of DOI:10.1515/hc-2018-0047

Heterocycl. Commun. 2018; 24(5): 255–258
GShyasnemthSheahsmiosra,dicahndaSareaidcAtmeanrii*zation and computational
studies of 2-cyano-6-methoxybenzothiazole
as a firefly-luciferin precursor
https://doi.org/10.1515/hc-2018-0047
Received March 21, 2018; accepted July 10, 2018; previously
published online August 27, 2018
developed. In 2004, Beller and co-workers introduced
K4[Fe(CN)6] as a low-cost and eco-friendly source of
cyanide [19]. Due to its strong CN bond, the catalyst deacti-
vation was prevented through a slow release of cyanide ion
[24]. Herein, a Cu-catalyzed cyanation of 2-iodo-6-meth-
oxybenzothiazole for the synthesis of 2-cyano-6-methoxy-
benzothiazole was introduced. K4[Fe(CN)6] was applied as
a source of cyanide, and CuI in the presence of N,N N′,N′-
tetramethylethylenediamine (TMEDA) [25] was used as
part of the catalyst system. Density functional theory (DFT)
calculations were made with the structural parameters cal-
culated using the B3LYP/6-311++G(d, p) method [26–29].
Abstract: A novel approach to the synthesis of 2-cyano-
6-methoxybenzothiazole via the Cu-catalyzed cyana-
tion of 2-iodo-6-methoxybenzothiazole was developed.
K4[Fe(CN)6] was used as a source of cyanide, and a
Cu/N,N,N′,N′-tetramethylethylenediamine (TMEDA) sys-
tem was utilized as a catalyst. This approach is scalable
and can be practiced with operational benign. The most
stable conformation of 2-cyano-6-methoxybenzothiazole
was delineated using the density functional theory (DFT)/
B3LYP method with 6-311++G(d, p) basis set.
Keywords: 2-cyano-6-methoxybenzothiazole; 2-iodo-
6-methoxyenzothiazole; Cu catalyst; cyanation; DFT; Results and discussion
firefly luciferin; K4[Fe(CN)6].
2-Amino-6-methoxybenzothiazole as a starting material
was synthesized from p-anisidine as shown in Scheme
2 [30] and subsequently converted into 2-iodo-6-meth-
oxybenzothiazole using a simple and efficient one-pot
Introduction
Firefly luciferin is a common substrate in biological sequential diazotization-iodination method.
imaging [1] that originates from some insects [2]. It is
Reagents and conditions: (a) –CH3COOH, Br2, KSCN,
widely applied in life sciences [3–5]. The chemical prepa- 20 h, temperature <35°C, yield 85%; (b) –H2SO4, NaNO2,
ration of firefly luciferin has been described previously KI, 0°C, 30 min, yield 80%.
[6–9]. In particular, 2-cyano-6-methoxybenzothiazole has
The one-pot cyanation of 2-iodo-6-methoxybenzothi-
been converted to 2-cyano-6-hydroxybenzothiazole fol- azole to 2-cyano-6-methoxybenzothiazole was achieved
lowed by the reaction with cysteine [6] (Scheme 1). Typical using 0.25 mmol of K4[Fe(CN)6], 0.25 mmol of CuI and
routes to 2-cyano-6-methoxybenzothiazole include the 3 mmol of TMEDA in acetonitrile at 160°C (Scheme 3). In
classical Rosenmund-von Braun [10] and Sandmeyer [11] addition, 1 mmol of mystril trimethyl bromide (MTMAB)
reactions. These methods proceed with low atom economy was used as a phase transfer agent. The presence of a
and require toxic reagents such as KCN [12], NaCN [13], phase-transfer catalyst is essential for a successful cya-
Zn(CN)2 or TMSCN [14] that are also difficult to handle in a nation reaction. Under these conditions, 2-cyano-6-meth-
large-scale synthesis [15, 16].
oxybenzothiazole was produced in a 90% yield. In the
The Cu-catalyzed cyanation of aryl halides to benzo- presence of 0.18 mmol of K4[Fe(CN)6], the cyanation still
nitrile derivatives has been reported [13]. Various copper proceeded in a 90% yield, indicating that all six cyanide
catalyst systems with bidentate ligands [17–23] have been ions in the molecule are utilized in the reaction. On the
other hand, increasing the amount of K4[Fe(CN)6] to more
than 0.25 mmol resulted in a moderate yield of 60%, pre-
*Corresponding author: Saeid Amani, Department of Chemistry,
sumably due to the catalyst deactivation. In addition, a
Faculty of Science, Arak University, P.O. Box: 38156-88349, Arak,
decrease in the CuI loading to 0.1 mmol from 0.25 mmol,
resulted in a poor yield of 40%, even after an increase of
the reaction time to 40 h.
Iran, e-mail: s-amani@araku.ac.ir, amani1331@yahoo.com
Ghasem Shahmoradi: Department of Chemistry, Faculty of Science,
Arak University, P.O. Box: 38156-88349, Arak, Iran
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ꢀG. Shahmoradi and S. Amani: 2-Cyano-6-methoxybenzothiazole as a firefly-luciferin precursor
H2N
COOH
SH
N
S
N
S
COOH
N
S
N
S
CN
CN
+
H3CO
HO
HO
2-Cyano-6-methoxybenzothiazole
2-Cyano-6-hydroxybenzothiazole
D-cysteine
Firefly luciferin
Scheme 1ꢀSynthesis of firefly luciferin.
N
N
S
NH2
a
NH
b
I
2
S
H3CO
H3CO
H3CO
Scheme 2ꢀSynthesis of 2-iodo-6-methoxybenzothiazole from p-anisidine.
N
CuI/ L
N
S
I
+
K4[Fe(CN)6]
C
N
S
CH3CN, 160°C,16 h
H3CO
H3CO
Scheme 3ꢀCyanation reaction of 2-iodo-6-methoxybenzothiazole.
an Agilent 575 mass spectrometer equipped with a quadruple ana-
lyzer. 2-Amino-6-methoxybenzothiazole was synthesized according
to the method described by Stuckwisch [30].
The optimized geometric structures of 2-cyano-
6-methoxyoxybenzothiazole were calculated using the
B3LYP 6-311++G(d, p) method. This molecule has C1 full
point group and 51 fundamental modes of vibrations. It
exists in two stable conformers, I and II. Conformer III is
the transition state structure (Figure 1). Conformer I with
the dihedral angle (C7-C6-O15-C16) of 1.4° is 0.17 kcal/mol
more stable than conformer II and 2.02 kcal/mol more
stable than conformer III. The dihedral angle (C7-C6-O15-
C16) of the second stable structure is 179.98°.
Synthesis of 2-iodo-6-methoxybenzothiazole
A solution of 2-amino-6-methoxybenzothiazole (1.81 g, 0.01 mol) in
water (3 mL) was stirred at 0°C and treated with acetic acid (3 mL) and
sulfuric acid (6 m, 4.5 mL). The mixture was stirred for 1 h. The result-
ant clear solution was treated dropwise for 15 min at 0°C with an aque-
ous solution (3 mL) of NaNO2 (0.70 g, 0.01 mol). After stirring for 1 h,
an aqueous solution (3 mL) of KI (1.65 mg, 0.01 mol) was added slowly
for 30 min, until the evolution of nitrogen gas ceased. The product
was extracted with EtOAc (3ꢀ×ꢀ12 mL), and the combined organic lay-
ers were washed with a 10% aqueous solution of Na2SO4, dried and
concentrated. The residue of 2-iodo-6-methoxybenzothiazole was
Conclusions
2-Cyano-6-methoxybenzothiazole, a synthetic interme-
diate of firefly luciferin, was prepared by a high-yield
Cu-catalyzed cyanation of 2-iodo-6-methoxybenzothia-
zole. K4[Fe(CN)6] was applied as an eco-friendly cyanide
source. The cyanation reaction was performed efficiently
by applying the catalytic system of CuI/TMEDA that is
non-toxic and environmentally friendly. The structure
of 2-cyano-6-methoxybenzothiazole was characterized
using computational studies.
Experimental
All chemicals and solvents were supplied by Merck (Germany) and
used without purification. The Fourier transform infrared (FT-IR)
spectra were recorded on an Alpha Centauri FT-IR (Bruker, Germany)
1
spectrophotometer using KBr pellets. The H NMR (300 MHz) and
13C NMR (75 MHz) spectra were determined on a Mercury-300 MHz
(Bruker, Germany) instrument. The mass spectra were obtained on Figure 1ꢀConformers of 2-cyano-6-methoxybenzothiazole.
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1
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(C-N), 1053, 875 cm−1; MS: m/z 291.0 (M ). Anal. Calcd for C8H6INOS: C,
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Synthesis of 2-cyano-6-methoxybenzothiazole from
2-iodo-6-methoxybenzothiazole
A solution of CuI (47.6 mg, 0.25 mmol), K4[Fe(CN)6] (90 mg,
0.18 mmol) and TMEDA (348 mg, 3 mmol) in dry acetonitrile (5 mL)
was stirred for 30 min and then treated with MTMAB (34 mg,
1 mmol) and 2-iodo-6-methoxybenzothiazole (290 mg, 1 mmol). The
mixture was stirred under argon atmosphere at room temperature
for 30 min and then under reflux at 160°C for 16 h. After cooling
to room temperature, the mixture was extracted with diethyl ether
(3ꢀ×ꢀ5 mL). The extract was dried with anhydrous MgSO4, filtered
and concentrated. The red-brown solid residue was purified by col-
umn chromatography on silica gel eluting with hexane/CH2Cl2, 1:10,
to give 2-cyano-6-methoxybenzothiazole in the form of pale yellow
1
needles; yield 90%; mp 128–130°C; H NMR (300 MHz, CDCl3): δ
3.87 (s, 3H), 7.11 (m, 1H), 7.23 (m, 1H), 7.52 (m, 1H); 13C NMR (75 MHz,
DMSO-d6): δ 160.6, 147.3, 141.3, 135.6, 125.6, 118.6, 113.1, 103.5, 55.6;
IR: 3030, 2932, 2240, 1651, 1280, 1207, 1034, 872 cm−1; MS: m/z 190.1
+
(M ). Anal. Calcd for C9H6N2OS: C, 56.83; H, 3.18; N, 14.73. Found: C,
56.68; H, 3.01; N, 14.42.
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