Synthesis of 4-acetyl-2(3H)-benzothiazolone: Sulfur bioisostere of benzoxazolone allelochemicals

Article abstract of DOI:10.1080/10426507.2017.1321645

A multi-step methodology for the synthesis of 4-acetyl-2(3H)-benzothiazolone was developed in order to prepare a new biomimetic analogue of benzoxazolone allelochemicals. The compound was prepared from commercially available o-toluidine in 23% overall yield. The structure of 4-acethyl-2(3H)-benzothiazolone was confirmed by NMR spectroscopy and X-ray crystallography.

Full text of DOI:10.1080/10426507.2017.1321645

Phosphorus, Sulfur, and Silicon and the Related Elements
ISSN: 1042-6507 (Print) 1563-5325 (Online) Journal homepage: http://www.tandfonline.com/loi/gpss20
Synthesis of 4-acetyl-2(3H)-benzothiazolone: Sulfur
bioisostere of benzoxazolone allelochemicals
Mariana S. Gerova, Filip E. Svetoslavov, Boris L. Shivachev, Rositsa P.
Nikolova & Ognyan I. Petrov
To cite this article: Mariana S. Gerova, Filip E. Svetoslavov, Boris L. Shivachev, Rositsa
P. Nikolova & Ognyan I. Petrov (2017): Synthesis of 4-acetyl-2(3H)-benzothiazolone: Sulfur
bioisostere of benzoxazolone allelochemicals, Phosphorus, Sulfur, and Silicon and the Related
Elements, DOI: 10.1080/10426507.2017.1321645
To link to this article: http://dx.doi.org/10.1080/10426507.2017.1321645
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Synthesis of 4-acetyl-2(3H)-benzothiazolone: Sulfur bioisostere of benzoxazolone
allelochemicals
Mariana S. Gerova1, Filip E. Svetoslavov2, Boris L. Shivachev3, Rositsa P. Nikolova3, Ognyan I.
Petrov1,*
1Sofia University St. Kliment Ohridski, Faculty of Chemistry and Pharmacy, Department of
Pharmaceutical and Applied Organic Chemistry, 1 James Bourchier Blvd, 1164 Sofia, Bulgaria
2Balkanpharma Dupnitsa, 3 Samokovsko shouses Str., 2600 Dupnitsa, Bulgaria
3Bulgarian Academy of Sciences, Institute of Mineralogy and Crystallography, Acad. G.
Bonchev Str., bl. 107, 1113 Sofia, Bulgaria
*Corresponding author. E-mail address: opetrov@chem.uni-sofia.bg (Prof. O. Petrov)
Abstract: A multi-step methodology for the synthesis of 4-acetyl-2(3H)-benzothiazolone was
developed in order to prepare a new biomimetic analogue of benzoxazolone allelochemicals. The
compound was prepared from commercially available o-toluidine in 23 % overall yield. The
structure of 4-acethyl-2(3H)-benzothiazolone was confirmed by NMR spectroscopy and X-ray
crystallography.
Keywords
2(3H)-benzothiazolone; allelochemicals; bioisosterism; crystal structure
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INTRODUCTION
Defined as a process of plant-plant or plant-microorganism interaction through the production of
various compounds, allelopathy suggests an alternative pathway for crop protection and weed
management.1–5 Allelochemicals are plant secondary metabolites which can be released into the
environment by roots, stems, bark, flowers or seeds in the case of microbial infections or plant
competitions for limited light, water and nutrients.4,6 A number of compounds such as
benzoxazinoids,7 coumarins,8 flavonoids9 and others1,2 have been found to possess allelopathic
activity.
Allelochemicals belonging to the benzoxazinoid group are mainly present in cereals such as
corn, rye and wheat. Three structural subgroups have been identified, including hydroxamic
acids (DIBOA, DIMBOA), lactams (HBOA, HMBOA) and benzoxazolones (BOA, MBOA,
Figure 1). Structurally related to the third subgroup is 4-acethyl-2(3H)-benzoxazolone
(4AcBOA, Figure 2), an allelochemical isolated from the kernels of the Fusarium-resistant corn
hybrid.10,11 Several studies indicated that 4AcBOA inhibits the biosynthesis of the mycotoxin
deoxynivalenol produced by certain Fusarium species, which caused gibberella ear rot in
corn.11,12 Moreover, it has been found that the presence of 4AcBOA in the kernels leads to insect
resistance against Sitophilus zeamais.11
In recent years natural allelochemicals have been increasingly used as templates for the design,
discovery and development of new useful agents in agronomy. Following the classical concept of
bioisosterism13 we planed the synthesis of 4-acethyl-2(3H)-benzothiazolone as sulfur bioisostere
of benzoxazolone allelochemical 4AcBOA (Figure 2).
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Herein, we report a multi-step synthetic approach for the preparation of 4-acethyl-2(3H)-
benzothiazolone in 23 % overall yield. To the best of our knowledge, there are no previous
reports on the synthesis of this compound.
RESULTS AND DISCUSSION
Chemistry
Friedel-Crafts acylation and similar electrophilic substitution reactions of benzothiazolones are
regioselective for the corresponding 6-acyl derivatives.14-16 Therefore, direct acetylation of
2(3H)-benzothiazolone cannot be applied for the synthesis of 4-substituted analogues. To address
this problem, we developed a method for the preparation of target 4-acethyl-2(3H)-
benzothiazolone, including the consecutive building of benzothiazole fragment from o-toluidine
followed by transformation of the methyl group to the acetyl moiety.
Several methods for the construction of benzothiazole moiety have been reported.17-19 The
classical protocol involves the condensation of 2-aminothiophenols with nitriles, aldehydes,
carboxylic acids or acyl chlorides leading to the corresponding 2-substituted benzothiazoles. A
second route for the formation of benzothiazole ring is based on Jacobson’s cyclization of
thiobenzanilides with potassium ferricyanide. A third general method, known as Hugerschoff
synthesis, includes the conversion of various substituted arylthiocarbamides to the corresponding
2-aminobenzothiazoles in the presence of bromine. Because a diverse set of arylthiocarbamides
are readily accessible by reaction of various anilines with thiocyanates, we chose the latter
methodology to obtain the benzothiazole scaffold.
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As depicted in Scheme 1, o-toluidine (1) was treated with ammonium thiocyanate to afford the
corresponding arylthiocarbamide 2. The cyclization of this compound to 2-amino-4-
methylbenzothiazole hydrobromide (3) was achieved with bromine in chloroform through the
Hugerschoff synthesis. The obtained compound 3 was subjected to Sandmeyer-type reaction to
provide 2-bromo-4-methylbenzothiazole (4) in 56 % overall yield.
A key step of our synthetic route was the conversion of the 4-methyl substituent to an aldehyde
group. We tried to oxidize directly compound 4 with various reagents such as CrO3, SeO2 or
KMnO4, but all attempts failed. In all cases, no product formation was observed. That is why, we
developed an alternative pathway to desired aldehyde, including a straightforward reaction
sequence: bromination of 4 with N-bromosuccinimide (NBS), followed by reaction of 5 with
potassium acetate, hydrolysis of the resulting acetate 6 and finally, oxidation of the
hydroxymethyl group in 7 with activated manganese dioxide to aldehyde 8. All these reactions
took place with high yields and purity. The obtained 2-bromobenzothiazole-4-carbaldehyde (8)
hydrolyzed in acidic medium at reflux to afford 2(3H)-benzothiazolone-4-carbaldehyde (9)
(Scheme 2).
In order to avoid the formation of byproducts in the next stage, the nitrogen atom of the
benzothiazolone moiety was protected in 10 by reaction with chloromethyl methyl ether in
dimethylformamide (DMF) in the presence of potassium carbonate. Reaction of 10 with
methylmagnesium bromide led to the corresponding secondary alcohol 11, which was treated
with Jones reagent (CrO3/aq. H2SO4) in acetone at 0 °C to give 4-acetyl-3-(methoxymethyl)-
2(3H)-benzothiazolone (12). Deprotection of methoxymethyl group was achieved with
trifluoroacetic acid (TFA) and afforded 13 in excellent yield (Scheme 3).
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Overall, the target 4-acetyl-2(3H)-benzothiazolone (13) was synthesized in 12 steps from o-
toluidine in 23 % overall yield. The structures of all compounds were unambiguously confirmed
by NMR spectroscopy and some of them (8, 9 and 13) were further characterized by X-ray
crystallography. Besides the signals for the aromatic protons, two characteristic singlets were
observed in the 1H NMR spectrum of target compound 13: at 2.66 ppm for the −COCH3 protons
in position 4 and a broad singlet at 10.77 ppm for the NH proton from benzothiazolone
heterocycle. Furthermore, the 13C NMR showed a signal for the carbonyl group from
benzothiazolone moiety at 170.8 ppm, as well as a signal for the acetyl CO group at 199.5 ppm.
X-ray crystallography
Compounds 9 and 13 crystallize in the monoclinic space group P21/c while 8 crystallizes in the
orthorhombic space group P212121, all with one molecule per asymmetric unit (Figure 3, Table
1).
The majority of the bond lengths and angles in compounds 8, 9 and 13 are comparable to those
reported by others for similar structures20,21 (Figure S 1, Table S 1 Supplemental Materials). The
benzothiazole ring is nearly planar with rms of 0.016, 0.009 and 0.006 Å in 8, 9 and 13,
respectively. Interestingly, orientation of the aldehyde moiety in 8 and 9 depends on the presence
or absence of H atom on N3. In order to achieve an intramolecular hydrogen bond (N3-
H3···O12, Table S2), stabilizing the molecule, the aldehyde group rotates by 180° around C5-
C11. In 13 the intramolecular interaction is conserved and the acetyl group is slightly out of the
benzothiazole plane, the angle between the two mean planes being 3.508°.
The crystal structure of 8 reveals a halogen bonding N···Br and weak CH···O interactions (Table
S 2) as only typical hydrogen bond acceptors are available (Figure S 2). In 9 as no halogen atom
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is present the hydrogen bonding between the only available donor and acceptor produce dimers
(Figure S 3). In addition, the stabilization of the crystal structure is achieved by stacking the
dimers on top of each other through π···π interactions and by weak CH···O interactions
connecting the dimers sides. The crystal structure stabilization in 13 is similar to that observed in
9. The molecules form dimers through typical hydrogen bonding and the dimers are linked by
weak CH···O interactions (Figure S 4). However, no π···π interaction are detected in 13
probably because of the presence of the additional methyl group and in the actual case resulting
in steric hindrance effects preventing the π···π interactions.
CONCLUSION
In summary, we have developed a general and efficient method for the synthesis of 4-acetyl-
2(3H)-benzothiazolone, a sulfur bioisostere of the corresponding benzoxazolone allelochemical.
Starting from o-toluidine, 4-acetyl-2(3H)-benzothiazolone was obtained in 12 steps in 23 %
overall yield. The crystal structure and the NMR data assign unequivocally the acetyl group to
position 4 of the benzothiazolone ring.
EXPERIMENTAL
Chemistry
Melting points (m.p.) were determined on a Boetius hot-stage microscope. Infrared spectra (IR)
1
13
were recorded with a Specord 71 spectrometer in nujol. H and C NMR spectra were obtained
with a Bruker DRX 300 spectrometer in CDCl3 as a solvent. Chemical shifts were reported in
1
13
parts per million (ppm, δ) relative to the solvent peak (7.26 ppm for H; 77.16 ppm for C).
Coupling constants (J) were measured in Hertz (Hz). Thin-layer chromatography (TLC) was
carried out on silica gel plates (Kieselgel 60 F254).
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1-(2-Methylphenyl)thiocarbamide (2)
To a solution of concentrated HCl (19 mL) in water (150 mL), o-toluidine (1, 21.3 mL, 0.2 mol)
was added, followed by ammonium thiocyanate (15.20 g, 0.2 mol). The reaction mixture was
refluxed for 4 h. After cooling the obtained oil of 2 was crystallized and the crystals were
separated by filtration. An additional quantity of ammonium thiocyanate (7.60 g, 0.1 mol) was
added to the filtrate. The resulting mixture was refluxed for another 6 h, which led to the
formation of further amount of the product. Thiocarbamide 2 was obtained in 77 % yield (25.60
g) as white crystals, m.p. 161-162 °C (ethanol). Lit.22 m.p. 160 °C.
2-Amino-4-methylbenzothiazole hydrobromide (3)
To a cooled suspension of thiocarbamide 2 (16.60 g, 0.1 mol) in chloroform (100 mL), a solution
of bromine (5.2 mL, 0.1 mol) in chloroform (20 mL) was added dropwise during a period of 20
min. After the addition of bromine was complete, the reaction mixture was refluxed for 4 h under
vigorous stirring. The mixture was cooled and allowed to stand overnight at room temperature.
The obtained precipitate was separated by filtration, washed with chloroform and air-dried.
Yield: 81 % (19.85 g), m.p. 225-228 °C. Free base: m.p. 190 °C.22
2-Bromo-4-methylbenzothiazole (4)
To a mixture of dichloromethane (80 mL) and acetic acid (15 mL), 2-amino-4-
methylbenzothiazole hydrobromide (3, 14.70 g, 0.06 mol) was added, followed by 48 % HBr (30
mL). After cooling of the resulting suspension with ice bath, a solution of sodium nitrite (10.00
g, 0.14 mol) in water (20 mL) was added slowly keeping the temperature at 5 °C. After the
addition was complete, the reaction mixture was stirred at room temperature followed by heating
at 40 °C for 15 min (nitrogen was released). Then, the obtained dark-colored mixture was cooled
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and washed successively with water (2 × 50 mL), 5 % aqueous solution of sodium hydrogen
sulfite (2 × 50 mL) and water again (1 × 50 mL). The organic layer was separated, dried over
Na2SO4, filtered and concentrated in vacuo to afford 4 as yellow oil in 89 % yield (12.18 g). The
product was dissolved in petroleum ether (5 mL) and allowed to crystallize slowly in
1
refrigerator, m.p. 48-50 °C. H NMR (300 MHz, CDCl3): δ = 2.70 (s, 3H, CH3), 7.23-7.31 (m,
13
2H, ArH), 7.60 (dd, J = 1.3 Hz, J = 7.6 Hz, 1H, ArH). C NMR (75 MHz, CDCl3): δ = 18.4,
118.4, 125.8, 127.3, 133.0, 137.4, 137.6, 151.9.
2-Bromo-4-(bromomethyl)benzothiazole (5)
To a solution of 2-bromo-4-methylbenzothiazole23 (4, 11.40 g, 0.05 mol) in carbon tetrachloride
(200 mL), N-bromosuccinimide (9.08 g, 0.05 mol) and dibenzoyl peroxide (0.12 g, 0.00005 mol)
were added. The reaction mixture was refluxed for 5 h, allowed to stand overnight at room
temperature and filtered to remove the obtained precipitate from succinimide. The filtrate was
concentrated in vacuo to afford 5 which crystallized from cyclohexane. Yield: 68 % (10.48 g),
1
m.p. 96-97 °C. H NMR (300 MHz, CDCl3): δ = 4.99 (s, 2H, CH2Br), 7.39 (t, J = 7.8 Hz, 1H,
ArH), 7.53 (dd, J = 1.0 Hz, J = 7.5 Hz, 1H, ArH), 7.75 (dd, J = 1.1 Hz, J = 8.0 Hz, 1H, ArH). 13C
NMR (75 MHz, CDCl3): δ = 29.0, 121.2, 126.1, 127.8, 132.2, 138.0, 139.3, 150.7.
(2-Bromobenzothiazol-4-yl)methyl acetate (6)
2-Bromo-4-(bromomethyl)benzothiazole (5, 6.14 g, 0.02 mol) was added to a suspension of
anhydrous potassium acetate (2.20 g, 0.022 mol) in DMF (40 mL). The mixture was stirred for
24 h at room temperature. Then, the volume of the reaction mixture was reduced to 1/3 by
evaporation of the solvent. Water (50 mL) was added and the product was precipitated in
quantitative yield (99 %, 5.61 g). Recrystallization from isopropanol gave 6 as white powder,
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1
m.p. 57-59 °C. IR: ν = 1720 (CO) cm-1. H NMR (300 MHz, CDCl3): δ = 2.14 (s, 3H, CH3CO),
5.61 (s, 2H, CH2OCO), 7.40 (t, J = 7.7 Hz, 1H, ArH), 7.48 (dd, J = 0.6 Hz, J = 7.4 Hz, 1H, ArH),
13
7.77 (dd, J = 1.3 Hz, J = 7.9 Hz, 1H, ArH). C NMR (75 MHz, CDCl3): δ = 21.1, 62.9, 120.9,
125.9, 126.3, 130.4, 137.8, 139.1, 150.7, 170.9.
(2-Bromobenzothiazol-4-yl)methanol (7)
Compound 6 (4.30 g, 0.015 mol) was added to a suspension of anhydrous potassium carbonate
(2.20 g, 0.022 mol) in methanol (30 mL). The mixture was stirred for 2.5 h at room temperature
to obtain a clear solution. Then, the solvent was evaporated in vacuo and water was added to the
residue. The resulting crystals were filtered off, washed with water and air-dried. Yield: 98 %
1
(3.59 g), m.p. 87-88 °C (tetrachloromethane). IR: ν = 3400-3200 (OH) cm-1. H NMR (300
MHz, CDCl3): δ = 3.31 (br s, 1H, OH), 5.09 (s, 2H, CH2), 7.35-7.43 (m, 2H, ArH), 7.72 (dd, J =
1.5 Hz, J = 7.6 Hz, 1H, ArH). 13C NMR (75 MHz, CDCl3): δ = 63.1, 120.1, 125.0, 126.0, 135.1,
137.6, 139.0, 150.3.
2-Bromobenzothiazole-4-carbaldehyde (8)
To a solution of compound 7 (2.44 g, 0.01 mol) in dichloromethane (50 mL), activated
manganese dioxide (5.00 g, 0.058 mol) and anhydrous magnesium sulfate (4.00 g, 0.04 mol)
were added. The mixture was stirred at room temperature until the alcohol 7 was no longer
detectable by TLC (cyclohexane/ethyl acetate, 4:1). The reaction time was depended on the
quality and the activity of manganese dioxide. The mixture was filtered through a Celite and
washed with dichloromethane. The filtrate was concentrated in vacuo to afford 8. Yield: 84 %
1
(2.03 g), m.p. 123-125 °C (benzene). IR: ν = 1680 (CO) cm-1. H NMR (300 MHz, CDCl3): δ =
7.54 (t, J = 7.8 Hz, 1H, ArH), 8.01 (dd, J = 1.2 Hz, J = 7.7 Hz, 1H, ArH), 8.05 (dd, J = 1.2 Hz, J
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13
= 8.0 Hz, 1H, ArH), 10.90 (s, 1H, CHO). C NMR (75 MHz, CDCl3): δ = 125.3, 125.9, 126.6,
128.8, 138.9, 142.0, 153.0, 190.4.
2(3H)-Benzothiazolone-4-carbaldehyde (9)
A mixture of compound 8 (1.80 g, 0.0075 mol), 2-methoxyethanol (10 mL) and concentrated
HCl (10 mL) was refluxed for 8 h (TLC, cyclohexane/ethyl acetate, 4:1). After cooling, the
resulting solution was allowed to stand overnight in refrigerator to afford pure crystals of 9.
1
Yield: 88 % (1.18 g), m.p. 154-155 °C (ethanol). IR: ν = 3260 (NH), 1700, 1680 (CO) cm-1. H
NMR (300 MHz, CDCl3): δ = 7.32 (t, J = 7.8 Hz, 1H, ArH), 7.64 (d, J = 7.8 Hz, 1H, ArH), 7.70
13
(dd, J = 1.1 Hz, J = 7.8 Hz, 1H, ArH), 9.98 (s, 1H, CHO), 10.35 (br s, 1H, NH). C NMR (75
MHz, CDCl3): δ = 119.6, 122.7, 126.0, 128.4, 130.7, 135.2, 170.3, 192.3.
3-(Methoxymethyl)-2(3H)-benzothiazolone-4-carbaldehyde (10)
To a solution of compound 9 (0.90 g, 0.005 mol) in DMF (10 mL), powdered potassium
carbonate (1.38 g, 0.01 mol) was added followed by chloromethyl methyl ether (0.57 g, 0.0075
mol). The mixture was stirred for 2 h at room temperature and poured into water (50 mL). The
obtained precipitate was filtered off, washed with water to neutral pH and air-dried. Yield: 95 %
1
(1.06 g), m.p. 105-107 °C (ethanol) IR: ν = 1650 (CO) cm-1. H NMR (300 MHz, CDCl3): δ =
3.40 (s, 3H, CH3), 5.48 (s, 2H, CH2), 7.30 (t, J = 7.8 Hz, 1H, ArH), 7.63 (dd, J = 1.3 Hz, J = 7.7
13
Hz, 1H, ArH), 7.84 (dd, J = 1.3 Hz, J = 7.9 Hz, 1H, ArH), 10.43 (s, 1H, CHO). C NMR (75
MHz, CDCl3): δ = 56.8, 75.2, 123.4, 123.8, 124.1, 127.6, 128.1, 136.4, 171.1, 190.1.
4-(1-Hydroxyethyl)-3-(methoxymethyl)-2(3H)-benzothiazolone (11)
To a cooled solution of compound 10 (0.78 g, 0.0035 mol) in THF (15 mL), methyl magnesium
bromide (3 M solution in ether, 1.27 mL, 0.0038 mol) was added dropwise with stirring. The
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mixture was stirred for 15 min at 0 °C and for 30 min at room temperature (TLC, heptane/ethyl
acetate, 7:3). A saturated solution of ammonium chloride (20 mL) was added. Then, the organic
phase was separated and the aqueous one was extracted with ethyl acetate (2 × 15 mL). The
combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated
in vacuo to afford 11. Yield: 97 % (0.81 g), m.p. 70-71 °C (cyclohexane/diethyl ether). 1H NMR
(300 MHz, CDCl3): δ = 1.58 (d, J = 6.4 Hz, 3H, CH3), 2.54 (br s, 1H, OH), 3.37 (s, 3H, CH3),
5.36 (d, J = 11.5 Hz, 1H, CH2), 5.52 (q, J = 6.4 Hz, 1H, CH), 5.68 (d, J = 11.5 Hz, 1H, CH2),
7.19 (t, J = 7.8 Hz, 1H, ArH), 7.34 (dd, J = 1.3 Hz, J = 7.7 Hz, 1H, ArH), 7.56 (dd, J = 1.1 Hz, J
= 7.9 Hz, 1H, ArH). 13C NMR (75 MHz, CDCl3): δ = 24.2, 56.8, 63.8, 74.7, 122.1, 123.1, 123.8,
124.7, 130.9, 133.8, 172.1.
4-Acetyl-3-(methoxymethyl)-2(3H)-benzothiazolone (12)
To a cooled solution of compound 11 (0.63 g, 0.0026 mol) in acetone (15 mL), Jones reagent
(0.8 mL) was added dropwise. The mixture was stirred for 45 min at 0 °C, and then isopropanol
was added to remove the excess of the oxidizing reagent. Magnesium oxide (0.50 g) was added,
the reaction mixture was stirred for 15 min and filtered through a Celite. The filtrate was
evaporated in vacuo to afford compound 12. Yield: 96 % (0.59 g), m.p. 76-77 °C
1
(cyclohexane/diethyl ether). H NMR (300 MHz, CDCl3): δ = 2.60 (s, 3H, CH3CO), 3.13 (s, 3H,
CH3), 5.32 (s, 2H, CH2), 7.22 (t, J = 7.8 Hz, 1H, ArH), 7.39 (dd, J = 1.1 Hz, J = 7.8 Hz, 1H,
13
ArH), 7.52 (dd, J = 1.2 Hz, J = 7.7 Hz, 1H, ArH). C NMR (75 MHz, CDCl3): δ = 29.5, 55.6,
74.2, 122.6, 124.4, 124.5, 125.0, 128.4, 131.2, 170.5, 200.3.
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4-Acetyl-2(3H)-benzothiazolone (13)
The mixture of compound 12 (0.59 g, 0.0025 mol) in trifluoroacetic acid (4 mL), THF (1 mL)
and water (1 mL) was refluxed for 2 h (TLC, cyclohexane/ethyl acetate, 4:1). After cooling, the
reaction mixture was poured into water (50 mL). The obtained precipitate was separated by
filtration, washed with water and air-dried. Yield: 98 % (0.47 g), m.p. 181-182 °C (ethanol). IR:
1
ν = 3280 (NH), 1690, 1650 (CO) cm-1. H NMR (300 MHz, CDCl3): δ = 2.66 (s, 3H, CH3CO),
7.22 (t, J = 7.9 Hz, 1H, ArH), 7.58 (d, J = 7.6 Hz, 1H, ArH), 7.80 (dd, J = 1.1 Hz, J = 8.0 Hz,
13
1H, ArH), 10.77 (br s 1H, NH). C NMR (75 MHz, CDCl3): δ = 26.9, 119.7, 122.3, 126.5,
127.8, 128.0, 136.2, 170.8, 199.5.
X-ray crystallography
Single crystals of 8, 9 and 13 were obtained by slow evaporation from ethanol. In all cases a
transparent and visually crack free crystal was carefully selected and mounted on a glass
capillary. Diffraction data were collected at room temperature by ω-scan technique, on an
Agilent Diffraction SuperNova Dual four-circle diffractometer equipped with Atlas CCD
detector using mirror-monochromatized Mo-Kα radiation from micro-focus source (λ = 0.7107
Å) for 8 and 9 and Cu Kα (1.54184 Å) for 13. The determination of cell parameters, data
integration, scaling and absorption correction were carried out using the CrysAlis Pro program
package24. The structures were solved by direct methods (SHELXS-201425) and refined by full-
matrix least-square procedures on F2 (SHELXL-201425). The heavy atoms (C, N, O, S and Br)
and the N hydrogen atom (H3) were positioned from difference Fourier map while all other
hydrogen atoms were placed at idealized positions. The non-hydrogen atoms were refined
anisotropically while hydrogen atoms were constrained to ride on their parent atom with Uiso(H)
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values of 1.2Ueq (C or N). A summary of the fundamental crystal and refinement data is provided
in Table 1. Crystallographic data (excluding structure factors) for the structural analysis has been
deposited with the Cambridge Crystallographic Data Centre, Nos. CCDC – 1487520, 1487521,
1487522 for compounds 8, 9 and 13, respectively. Copies of this information may be obtained
free of charge from: The Director, CCDC, 12 Union Road, Cambridge, CB2 1EZ, UK. Fax:
+44(1223)336-033, e-mail:deposit@ccdc.cam.ac.uk, or www.ccdc.cam.ac.uk.
ACKNOWLEDGMENTS
The financial support by Bulgarian Science Fund (DRNF-02/01) and by Sofia University
Scientific Research Fund (grant 117/2016) is gratefully acknowledged.
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Table 1 Crystal data and most important structure refinement indicators for compounds 8, 9 and
13
Compound
Chemical formula
Formula mass
Crystal system
Space group
a/Å
b/Å
c/Å
8
C8H4BrNOS
242.09
9
C8H5NO2S
179.19
13
C9H7NO2S
193.22
monoclinic
P21/c
8.9208(11)
13.4545(15)
7.0335(9)
90
orthorhombic monoclinic
P212121
5.3071(3)
6.2899(3)
24.8242(9)
90
P21/c
9.2227(4)
5.01333(17)
16.4345(6)
90
α/°
β/°
γ/°
90
90
101.558(4)
90
102.139(12)
90
Z
4
4
4
Cell volume/Å3
Temperature/K
μ/mm-1
828.66(6)
290
5.155
3371
744.46(5)
290
0.382
9365
1882
0.0295
0.0388
0.0964
0.0549
0.1058
1.054
825.33(18)
140
3.182
5332
1664
0.0396
0.0937
0.2957
0.0994
0.3012
1.182
Reflections measured
Independent reflections
Rint
Final R1 values (I > 2σ(I))
Final wR(F2) values (I > 2σ(I))
Final R1 values (all data)
Final wR(F2) values (all data)
Goodness of fit on F2
Δρmax, Δρmin / e Å−3
CCDC number
2309
0.0330
0.0445
0.0830
0.0808
0.0968
0.933
0.441, -0.588 0.323, -0.218 1.452, -0.556
1487520 1487521 1487522
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Figure 1 Allelochemicals from benzoxazinoid group
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Figure 2 The natural allelochemical 4-AcBOA and its synthetic sulfur bioisostere
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Figure 3 Molecular structures of compounds a) 8, b) 9 and c) 13 in the crystal
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Scheme 1 Synthesis of 2-bromo-4-methylbenzothiazole (4)
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Scheme 2 Synthesis of 2(3H)-benzothiazolone-4-carbaldehyde (9)
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Scheme 3 Synthesis of 4-acetyl-2(3H)-benzothiazolone (13)
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