Synthesis of novel 3-[(2R*)-2-[(2S*)-6-fluoro-3,4-dihydro-2H-chromen-2-yl]-2-hydroxyethyl]-urea/thiourea derivatives and evaluation of their antimicrobial activities

Article abstract of DOI:10.1080/10426507.2019.1635596

A new series of biologically active 3-[(2R*)-2-[(2S*)-6-fluoro-3,4-dihydro-2H-chromen-2-yl]-2-hydroxyethyl]-urea/thiourea derivatives (1) have been designed and synthesized in four steps from 6-fluoro-3,4-dihydro-2-(oxiran-2-yl)-2H-chromene (2). The structures of newly synthesized compounds (1a–j) were confirmed by ¹H, ¹³C NMR, and HRMS. The major advantages of the present article include the development of an efficient eluent system for good separation of diastereomers (2a and 2b) with high yields and synthesis of (R*)-2-(benzylamino)-1-((S*)-6-fluoro-3,4-dihydro-2H-chromen-2-yl)ethanol (3) in high yields (87%) from epoxide (2a) through new reaction conditions. The synthesized compounds (1a–j) exhibited moderate to excellent antimicrobial activities against both bacterial strains (gram + Ve and gram –Ve strains) and fungal strains. Among the tested compounds, promising lead compounds were identified (compounds 1a and 1d against bacterial strains and compound 1h and 1j against fungal strains) and their antimicrobial activities are comparable with the reference standard.

Full text of DOI:10.1080/10426507.2019.1635596

Phosphorus, Sulfur, and Silicon and the Related Elements
ISSN: 1042-6507 (Print) 1563-5325 (Online) Journal homepage: https://www.tandfonline.com/loi/gpss20
Synthesis of novel 3-[(2R*)-2-[(2S*)-6-fluoro-3,4-
dihydro-2H-chromen-2-yl]-2-hydroxyethyl]-urea/
thiourea derivatives and evaluation of their
antimicrobial activities
Madhava Rao Mannam, Srimurugan S., Pramod Kumar, Naga Raju
Chamarthi & Prasad K. R. S.
To cite this article: Madhava Rao Mannam, Srimurugan S., Pramod Kumar, Naga Raju Chamarthi
& Prasad K. R. S. (2019): Synthesis of novel 3-[(2R*)-2-[(2S*)-6-fluoro-3,4-dihydro-2H-chromen-2-
yl]-2-hydroxyethyl]-urea/thiourea derivatives and evaluation of their antimicrobial activities,
Phosphorus, Sulfur, and Silicon and the Related Elements, DOI: 10.1080/10426507.2019.1635596
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PHOSPHORUS, SULFUR, AND SILICON AND THE RELATED ELEMENTS
https://doi.org/10.1080/10426507.2019.1635596
ꢀ
ꢀ
Synthesis of novel 3-[(2R )-2-[(2S )-6-fluoro-3,4-dihydro-2H-chromen-2-yl]-2-
hydroxyethyl]-urea/thiourea derivatives and evaluation of their
antimicrobial activities
Madhava Rao Mannama,b, Srimurugan S.b, Pramod Kumarb, Naga Raju Chamarthic , and Prasad K. R. S.a
b
aDepartment of Chemistry, Koneru Lakshmaiah Education Foundation, Vaddeswaram, Andhra Pradesh, India; Chemical Research Division,
c
API R&D Centre, Micro Labs Ltd, Bangalore, India; Department of Chemistry, Sri Venkateswara University, Tirupathi, Andhra Pradesh, India
ABSTRACT
ARTICLE HISTORY
Received 19 February 2019
Accepted 20 June 2019
ꢀ
ꢀ
A new series of biologically active 3-[(2R )-2-[(2S )-6-fluoro-3,4-dihydro-2H-chromen-2-yl]-2-hydrox-
yethyl]-urea/thiourea derivatives (1) have been designed and synthesized in four steps from 6-flu-
oro-3,4-dihydro-2-(oxiran-2-yl)-2H-chromene (2). The structures of newly synthesized compounds
(1a–j) were confirmed by 1H, 13C NMR, and HRMS. The major advantages of the present article
include the development of an efficient eluent system for good separation of diastereomers (2a
and 2b) with high yields and synthesis of (R )-2-(benzylamino)-1-((S )-6-fluoro-3,4-dihydro-2H-chro-
men-2-yl)ethanol (3) in high yields (87%) from epoxide (2a) through new reaction conditions. The
synthesized compounds (1a–j) exhibited moderate to excellent antimicrobial activities against
both bacterial strains (gram þ Ve and gram –Ve strains) and fungal strains. Among the tested com-
pounds, promising lead compounds were identified (compounds 1a and 1d against bacterial
strains and compound 1h and 1j against fungal strains) and their antimicrobial activities are com-
parable with the reference standard.
KEYWORDS
Chromane; nebivolol
intermediate; urea and
thiourea derivatives;
antimicrobial activity
ꢀ
ꢀ
GRAPHICAL ABSTRACT
Introduction
developed resistance) are possible to achieve by alteration of
the structural feature of existing antimicrobial agents or
design of new drug candidates by combining two or more
pharmacophores.[5,6] By keeping these factors in mind, our
attention turned toward bioactive chromane, chromanone
skeleton and urea/thiourea moieties as they possess potential
biological activities. The chromane and chromanone skel-
eton was found in natural products (epigallocatechin gallate
and vitamin E), some pharmaceuticals and other biologically
active compounds as shown in Figure 1; for example,
Antibiotics usage in modern medicine has become more
abundant, after their discovery, in numerous crucial sur-
geries and treatments. The consequences of their higher util-
ity leads to antibiotic resistance, and in turn into one of the
major problems faced in public health throughout the
world.[1,2] Thus, there is an increasing and constant demand
for the discovery and development of new antimicrobial
drug candidates with a novel mechanism of action.[3,4] The
design and development of new antimicrobial agents (effect-
ive against either bacterial or fungal strains which have Nebivolol hydrochloride,[7] Repinotan[8] Fidarestat[9] and 2-
CONTACT Prasad K. R. S.
krsprasad_fed@kluniversity.in
Koneru Lakshmaiah Education Foundation, Vaddeswaram 522 502, Andhra Pradesh, India.
Color versions of one or more of the figures in the article can be found online at www.tandfonline.com/gpss.
Supplemental data for this article is available online at https://doi.org/10.1080/10426507.2019.1635596.
ß 2019 Taylor & Francis Group, LLC

2
M. R. MANNAM ET AL.
Figure 1. Biologically active chromane derivatives.
Scheme 1. Synthetic scheme for the preparation of title urea and thiourea derivatives.
Reaction conditions: (a) Column separation using 2–5% ethyl acetate in n-hexane eluent, 45%; (b) Benzylamine, IPA, 80–85 ꢁC, 87%; (c) Ammonium formate,
methanol, 10Pd/C, 20–30 ꢁC, 90%, and (d) THF, Et3N, 60–65 ꢁC, 70–85%.
ꢀ
ꢀ
ꢀ
ꢀ
f6-[(3,4-dihydro-2H-chromen-2-yl-methyl)amino]hexylg tet-
rahydro-1H-pyrrolo[1,2-c] imidazole-1,3(2H)-dione.[10]
Nebivolol hydrochloride (S , R , R , R ) is a well-known
antihypertensive drug and it is a racemic compound, formed
ꢀ
ꢀ
ꢀ
ꢀ
Molecules with a chromane moiety and fluorine atom by the reaction of both (S , R ) and (R , R ) 2-amino-6-flu-
substitution can attain various chemical and biological prop-
orochroman-2-yl)ethanol (4) where compound 4 was syn-
thesized from 6-fluoro-3,4-dihydro-2-(oxiran-2-yl)-2H-
erties.[11] For example, it is well known that the presence of
a fluorine atom in the chemical structure of a drug can chromene (2).[13]
enhance the distribution of the drug, drug clearance, and
An extensive literature search revealed that the molecules
extent of drug metabolism.[12] We anticipate that the com- with chromane moiety[14–16] and urea/thiourea[17–19] func-
bination of fluorine-substituted chromanes with urea/thio- tionalities exhibit excellent antimicrobial and anti cancer[20]
urea would enhance the biological activity of presently activities. Recently, it was reported that the combination of
designed molecules (1a–j).
chromane with urea and thiourea derivatives displayed good

PHOSPHORUS, SULFUR, AND SILICON AND THE RELATED ELEMENTS
3
Scheme 2. Synthetic scheme for the preparation of compound 3.
Table 1. Separation of (2a) from the diastereomeric compound (2) by column
Table 2. Screening of various solvents for preparation of compound (3).
chromatographya.
Entry
Solvent
Temp’(ꢁC)
Time (h)
Yieldb(%)
Entry
Eluent
Yieldb (%)
1
2
3
4
5
6
7
8
Methanol
Methanol
Ethanol
IPA
ACN
DMF
25–30
60–65
60–65
80–85
80–85
80–85
80–85
80–85
24
4
4
5
4
3
3
24
10
30
40
45
28
20
24
5
1
2
3
4
5
6
7c
Toluene (100%)
EtOAc (100%)
DCM (100%)
25
20
15
26
40
35
45
n-Hexane (100%)
2 % EtOAc in hexane
5% EtOAc in hexane
2% to 5% EtOAc in hexane
DMSO
Toluene
aColumn separation conditions: eluent, stationary phase: silica gel-100-200
Reaction conditions: Compound 2a (10.0 mmol), benzylamine (12.0 mmol) in
mesh at 20–30 ꢁC.
solvent (5 vol.) at 80–85 ꢁC.
bIsolated yield.
bIsolated yield.
cConcentration of EtOAc increase from 2% to 5% gradually.
robust and cost-effective process. Along this line, we found
there are reports for resolving a diastereomeric mixture
using column chromatography.[13] The reported method was
adopted to separate a diastereomeric mixture (2) using tolu-
ene alone. However, low yield (25%) of single diastereomer
was obtained (entry 1, Table 1). Hence, our attention turned
toward the utilization of other solvents or mixture of sol-
vents for efficient separation.
antimicrobial activities.[21,22] Hence, we have planned to
design and synthesize a new series of molecules comprised
of both the chromane skeleton and urea/thiourea moieties.
Results and discussion
Chemistry
In place of toluene, other single solvents, both polar and
non-polar, were screened such as ethyl acetate, dichlorome-
thane, and n-hexane. Compound (2a) was obtained in the
yields of 20%, 15%, and 32%, respectively (entries 2, 3, and
4). Therefore, we attempted to use a mixture of solvents of
n-hexane and ethyl acetate. The isocratic elution with ethyl
acetate (2%) in hexane was applied and obtained a 40% yield
of compound 2a (entry 5). With ethyl acetate (5%) in hex-
ane, the desired diastereomer was obtained in 35% yield
(entry 6). Alternatively, when gradient elution was applied
using ethyl acetate (2–5%) in hexane and desired diaster-
eomer in good yield 45% was obtained.
ꢀ
ꢀ
Herein, we report the synthesis of 3-[(2R )-2-[(2S )-6-flu-
oro-3,4-dihydro-2H-chromen-2-yl)-2-hydroxyethyl]-urea/
thiourea derivatives (1a–j) starting from a commercially
available diastereomeric mixture (2a and 2b in 1:0.8 ratio,
respectively) of 6-fluoro-3,4-dihydro-2-(oxiran-2-yl)-2H-
chromene (2) as shown in Scheme 1. The in-vitro antimicro-
bial activity studies of synthesized compounds (1a–j) were
also reported.
At the outset, the diastereomeric mixture of compound
(2) 6-fluoro-3,4-dihydro-2-(oxiran-2-yl)-2H-chromene was
resolved by column chromatography.[13] The resulting
desired racemic compound (2a) of epoxide was treated with
benzylamine to obtain (R )-2-(benzylamino)-1-((S )-6-flu-
oro-3,4-dihydro-2H-chromen-2-yl)ethanol (3). The resulting
compound 3 was debenzylated using 10% palladium on car-
bon with ammonium formate as a hydrogen source to afford
ꢀ
ꢀ
Epoxide ring opening with benzylamine
The ring opening of epoxide compound 2a was carried out
by the reaction of compound 2a with benzylamine (1.2
equiv.) in methanol at room temperature to prepare com-
pound 3 as shown in Scheme 2. The desired compound 3
was obtained in low yield (10%) (entry 1, Table 2) as sub-
strate 2a was found unreacted at room temperature. The
same reaction was carried out at reflux temperature and the
yield of desired compound 3 was improved slightly (30%)
(entry 2, Table 2). In this condition, the compound 3 was
obtained in low yield even though, the substrate 2a was con-
sumed completely due to formation of undesired dimer
compound 3a (Scheme 2). To suppress the formation of
undesired compound 3a, the same reaction was screened in
various solvents and the obtained results were presented in
Table 2. The study revealed that the reaction proceeded well
ꢀ
ꢀ
(S )-2-amino-1-((R )-6-fluorochroman-2-yl)ethanol
(4).
Further, compound 4 was treated with various isocyanates
(5a–e) and isothiocyanate (5f–j) in the presence of triethyl-
amine in THF to afford the target molecules (1a–j) in good
to moderate yields.
Separation of diastereomer by column chromatography
Several asymmetric methods were reported for the synthesis
of amino alcohol (4) as a racemic and enantiomerically
[23,24]
enriched compound in the literature.
But, the major
disadvantages associated with these methods include the
number of chemical steps, low conversion and low reported
yields. Hence, our attention turned toward finding a more and provide moderate yields of compounds in the presence

4
M. R. MANNAM ET AL.
Table 3. Screening of benzylamine equivalents for the synthesis of com-
pound 3a.
Table 4. Optimization of reaction conditions for the synthesis of com-
pound 1a.
Entry
Reagent
equiv.
Temp (ꢁC)
Yieldb(%)
Entry
Solvent
Time (h)
Temp (ꢁC)
Product
Yieldb(%)
1
2
3
4
5
Benzylamine
Benzylamine
Benzylamine
Benzylamine
BenzylamineC
2.0
5.0
8.0
10.0
8.0
80–85
80–85
80–85
80–85
80–85
47
55
65
64
87
1
2
3
4
5
6
7
Toluene
THF
ACN
EtOH
DMF
DMSO
24
5
10
24
3
60–65
60–65
60–65
60–65
60–65
60–65
60–65
1a
1a
1a
1a
1a
1a
1a
17
80
61
44
52
61
49
aReaction conditions: Compound 2a (10.0 mmol), in IPA (5 vol) at 80–85 ꢁC.
3
2.5
bIsolated yield.
DMAc
cAddition of compound 2a to Benzylamine.
aReaction conditions: Compound 4 (10.0 mmol), compound 5a (12.0 mmol),
Et3N (12.0 mmol) in solvent (6 vol.) at 60–65 ꢁC.
bIsolated yields.
of polar protic solvents such as ethanol and isopropyl alco-
hol (entries 3 and 4, Table 2). The same reaction provided
low yields in presence of polar aprotic solvents, for example,
acetonitrile, DMF and DMSO afforded 28%, 20%, and 24%
yields of compound 3, respectively (entries 5–7). The same
reaction was unsuccessful in toluene because of poor solubil-
ity of reactants (entry 8). The study disclosed that isopropyl
alcohol afforded good yield of desired compound 3 as well
as control the formation of undesired compound 3a.
Table 4) at 60–65 ꢁC. The study disclosed that THF is the
best solvent for maximum conversion and formation of
compound 1a (entry 2, Table 4). The same reaction in THF
at room temperature offered low yield 38% even on pro-
longed reaction time. With the help of the above-optimized
reaction conditions, the other desired compounds (1b–j)
were synthesized by the reaction of compound 4 with sub-
strates (5b–j) as shown in Table 5.
To further improve the yield, the effect of mole equiva-
lents of benzylamine was studied on the course of the reac-
tion. Accordingly, the reaction was carried out in isopropyl
alcohol using different equivalents of benzylamine at
80–85 ꢁC, for example at 2.0, 5.0, 8.0, and 10.0 equiv. of
benzylamine to obtained 47%, 55%, 65%, and 64% of com-
pound 3 respectively (entries 1–4, Table 3). The study
revealed that 8.0 equiv of benzylamine offered 65% yield
(entry 3). To improve the yield further, the mode of add-
ition of benzylamine was studied. The compound 2a was
added dropwise to benzylamine at 80–85 ꢁC and observed
minimum formation of the dimer (4–5%) and the yield was
dramatically increased to 87% (entry 5). The study disclosed
that the addition of 2a to benzylamine at 80–85 ꢁC offered
an excellent yield.
Spectroscopic data
The structures of the synthesized compounds (1a–j) were
characterized and confirmed their structures using by FT-IR,
1H, 13C-NMR and HRMS data. For structure elucidation, 1-
(4-bromophenyl)-3-[(2R )-2-[(2S )-6-fluoro-3,4-dihydro-2H-
1-benzopyran-2-yl]-2-hydroxyethyl]urea (1b) was selected
and discussed.
ꢀ
ꢀ
The characteristic absorption bands in the region of 3406,
3312, 1675, 1535, and 1017 cmꢂ1 of IR spectra are mainly
attributed due to the presence of –OH, –NH, C ¼ O, C ¼ C,
and C–O functionalities respectively. In 1H NMR spectra,
the chemical shift value in the region of dH 8.77 as singlet
indicated the presence of –NH proton attached to urea func-
tionality. The chemical shift value at dH 5.35 as a broad
singlet indicated the presence of –OH proton, Moreover, the
aromatic protons based on the structural orientation, reson-
ated in the range of dH 6.75–7.39. Chemical shift value dH
1.67, 2.10, 2.74, 3.06, 3.51 and 3.80 multiplets confirmed
presence the eight aliphatic protons. The signal dC 155.16 in
13C NMR spectra has attributed the carbon attached to a
urea carbonyl group. The doublet peaks at dC 157.04 and
154.70 with a coupling constant 234 Hz confirmed the pres-
ence of the –CF group. Chemical shifts in the region of dC
22.33–77.06 are correlated with five aliphatic carbons and
other aromatic carbons are observed in the range of dC
112.12–150.53. The mass value found in HRMS m/z
409.0540 in positive mode was evident to in the structural
characterization of compound 1b.
ꢀ
ꢀ
Synthesis of (S )-2-amino-1-((R )-6-fluorochroman-2-
yl)ethanol (4)
The debenzylation of compound (3) to prepare amino alcohol 4
was carried out using the literature process and the results were
reproduced.[25] The yield of compound 4 was good (90%).
ꢀ
ꢀ
Synthesis of 3-[(2R )-2-[(2S )-6-fluoro-3,4-dihydro-2H-1-
chromen-2-yl]-2-hydroxy ethyl]-urea/thiourea
derivatives (1a–j)
ꢀ
Initially, the synthesis of target compound 3-[(2R )-2-
[(2S )-6-fluoro-3,4-dihydro-2H-1-chromen-2-yl]-2-hydroxy
ꢀ
ethyl]-1-(4-fluorophenyl) urea (1a) was carried out by the
reaction of compound 4 with substrate 5a in toluene at
room temperature and the desired compound 1a was
obtained in low yield 6%. The same reaction at 60–65 ꢁC
temperature provided 17% of compound 1a (entry 1, Table
4). It may be due to the insolubility of compound 4 in tolu-
ene. To increase the yield further, various solvents were
studied, for example, THF, ACN, EtOH, DMF, DMSO,
DMAc and obtained 80%, 61%, 44%, 52%, 61%, and 49%,
Antibacterial activity
The newly synthesized urea/thiourea derivatives (1a–j) were
screened for their antibacterial activity against both
Gram þ Ve bacterial strains, Staphylococcus aureus (ATCC-
19433), Bacillus cereus (ATCC-11778) and Gram –Ve bacter-
isolated yields of compound 1a respectively (entries 2–7, ial strains, Acinetobacter baumannii (ATCC-19606),

PHOSPHORUS, SULFUR, AND SILICON AND THE RELATED ELEMENTS
5
a
ꢀ
ꢀ
Table 5. Synthesis of 3-[(2R )-2-[(2S )-6-fluoro-3,4-dihydro-2H-chromen-2-yl]-2-hydroxyethyl]-urea/thiourea derivatives (1a–j).
Compound 5
Entry
1
R
X
Time (h)
Product
OH
Yieldb (%)
O
O
NH
NH
(R*)
O
5
87
(S*)
O
F
F
F
1a
5a
OH
NH
NH
(R*)
2
O
4
82
(S*)
O
F
Br
Br
1b
5b
OH
O
O
NH
NH
NH
NH
Cl
(R*)
3
4
O
O
6
6
75
79
(S*)
O
O
Cl
F
F
F
5c
1c
OH
F
(R*)
(S*)
F
F
1d
5d
5e
OH
O
NH
NH
(R*)
(S*)
5
6
O
5
5
70
81
O
F
CH3
1e
OH
O
NH
NH
(R*)
S
(S*)
S
F
F
F
1f
F
5f
OH
O
NH
NH
NH
NH
(R*)
7
S
4
79
(S*)
S
Br
1g
Br
5g
OH
O
Cl
(R*)
(S*)
8
S
5
82
S
Cl
F
5h
1h
(continued)

6
M. R. MANNAM ET AL.
Table 5. Continued.
Compound 5
R
Entry
X
S
Time (h)
Product
OH
Yieldb (%)
O
NH
NH
Cl
Cl
(R*)
(S*)
9
7
75
S
Cl
F
1i
Cl
5i
OH
O
NH
NH
CF3
(R*)
(S*)
10
S
6
72
S
CF
F
3
1j
5j
aReaction conditions: Compound 4 (10.0 mmol), isocyanate (5a–e)/isothiocyanate (5f–j) (12.0 mmol), Et3N (12.0 mmol) in THF (6 vol) at 60–65 ꢁC.
Escherichia coli (ATCC-25922), and Pseudomonas aerugi- displayed inferior activity as shown in Table S3 (Supplemental
nosa (ATCC-27853) using agar disc diffusion method[26,27] Materials) and Figure S2 (Supplemental Materials).
The structure-activity relationship (SAR) studies of the
synthesized compounds revealed that the presence of elec-
tron withdrawing group, for example, fluoro substitution on
phenyl ring (1a, 1d) of urea-based (S )-2-amino-1-((R )-6-
fluorochroman-2-yl)ethanol derivatives exhibited excellent
antibacterial activity. Interestingly, the compounds with –Cl
at two different concentrations 50 lg/mL and 100 lg/mL.
The antibacterial activity of DMSO against the test microor-
ganisms was investigated and was found to be nil. Most of
the tested compounds (1a–j) exhibited promising activity
against S. aureus, P. aeruginosa, K. pneumonia, A. bauman-
nii, and E. coli.
ꢀ
ꢀ
It was found that the urea-based compounds with 4-fluo- (1h) and trifluoromethyl (1j) substitution on phenyl ring at
rophenyl (1a) and 2,4-difluorophenyl (1d) substitution meta position displayed good antifungal activity.
The minimum inhibitory concentration of lead compounds
(1a, 1d, 1h, and 1j) was reported in Table S4 (Supplemental
Materials) and Figure S3 (Supplemental Materials).
exhibited excellent antibacterial activity against all the tested
bacterial strains. The same other urea-based compounds, for
example, compound 1b, 1c, and 1e showed low activity as
shown in Tables S1 and S2 (Supplemental Materials).
Interestingly, the thiourea-based compound with 4-fluo-
rophenyl (1f) substitution exhibited moderate antibacterial
activity against all the tested bacterial strains. Interestingly,
the other thiourea based compounds 1g, 1h, 1i, and 1j with
–Cl, –Br, and –CF3 substitution exhibited very low activity
against all the tested bacterial strains.
Experimental
Materials and methods
The solvents and reagents were obtained from commercial
sources and were used without any purification. Nuclear
magnetic resonance (NMR) spectra of the synthesized com-
pounds were recorded on Ascend Bruker 400 (Bruker,
Fallanden, Switzerland) instrument and operated at
The antibacterial activity studies revealed that the urea-based
ꢀ
ꢀ
fluoro substituted (S )-2-amino-1-((R )-6-fluoro chroman-2-
yl)ethanol derivatives (1a and 1d) showed excellent antibacterial
activity which is comparable with standard ciprofloxacin drug as
presented in Figure S1 (Supplemental Materials).
1
400 MHz for H NMR and 100 MHz for 13C NMR using
CDCl3, DMSO–d6 solvents and tetramethylsilane (TMS) as
an internal standard. Spin multiplicities are given as s (sing-
let), d (doublet), dd (doublet of doublets), qd (quartet of
doublets), t (triplet), and m (multiplet) as well as brs (broad
Antifungal activity
1
singlet). The H chemical shift values were reported on d
The synthesized compounds (1a–j) were tested to evaluate scale in ppm relative to TMS (d ¼ 0.00 ppm) and the 13C
their antifungal activity against various fungal strains, chemical shift values were reported relative to DMSO–d6
Aspergillus niger (MTCC-1881), Fusarium oxysporum (MTCC- (d ¼ 39.5 ppm). The ESI/MS experiments were performed on
1755) and Aspergillus foetidus (NCIM-505) using two-fold dilu- a Velos Pro Ion Trap mass spectrometer from Thermo
tion method[28] at two different concentrations of 50 mg/mL Scientific San Jose, CA, USA) and HRMS spectra were
and 100 mg/mL. Among the tested compounds, the thiourea recorded on Q-Exactive benchtop Orbitrap mass spectrometer
based compound (1h) with chloro substitution and the com- (Thermo Scientific). The Supplemental Materials contains char-
pound (1j) with trifluoromethyl substitution on phenyl ring at acterization data for the previously reported compounds, in
1
meta position exhibited excellent antifungal activity against A. addition to selected H and 13C NMR and High Resolution
niger, F. oxysporum, and A. foetidus. All other compounds Mass spectra for products 1 (Figures S4–S58).

PHOSPHORUS, SULFUR, AND SILICON AND THE RELATED ELEMENTS
7
Disc diffusion method for antimicrobial activity
50–60 min. and stirred for 4 h. The reaction progress was
monitored by TLC, upon completion of the reaction, the
mass was cooled to 20–30 ꢁC and stirred at the same tem-
perature for 3 h. The solid was filtered, washed with IPA
(10 mL), and vacuum-pump dried for 30 min. The com-
pound was dried in a hot air oven at 50 ꢁC for 6 h, dry
weight: 13.5 g, yield: 87.0%.
The bacteria were cultured with 0.5 mL containing 1 ꢃ 107
CFU/mL in nutrient broth spread on nutrient agar medium
in agar plates. The nutrient agar medium was prepared and
sterilized in an autoclave at 120 ꢁC for 15–20 min and then
stored at room temperature, 20 mL of agar medium was
added to each agar plates and allowed for solidification. The
bacterial lawn culture was made using a sterile cotton swab
for uniform growth. Ciprofloxacin was used as standard and
soluble in DMSO, whereas, DMSO was used as a solvent for
test compounds at a concentration of 1.0 mg/mL. The
DMSO was used as a negative control. To test the activity of
compounds, wells were made in the media with the help of
a metallic border with centers at least 6.0 mm. The tested
solutions were introduced aseptically through micropipette
into the wells in the agar plates and incubated at 37 ꢁC for
24 h, and the process was repeated thrice. The inhibition
zone of microbial growth was appeared at around the wells
in each agar plate. The bacterial growth of the tested com-
pounds was determined by measuring the diameter of zone
inhibition (mm) around the wells. The activity of each com-
pound was compared with standard antibiotic ciprofloxacin.
The sabouraud dextrose agar (Himedia) was used as a
medium for the test of fungal activity, and the fungi strains
were incubated for three days at 30 ꢁC. The culture was
spread on Sabouraud dextrose agar using sterile glass
spreader for the uniform distribution of inoculums. The
incubated Fungi spore suspension contain approximately
1–2 ꢃ 106 CFU/mL population. After solidification of media,
respective fungal spore suspensions were transferred to well
plates. The 1 mg of the test compounds were dissolved in
1 mL of DMSO. The DMSO was used as a negative control.
The wells were made in the media with the help of a sterile
metallic borer with centers at least 6.0 mm. Prepared tested
solutions were introduced into the wells and immediately
incubated at 30 ꢁC for 72 h. After the incubation time, anti-
fungal activity was evaluated by measuring the diameter of
zone inhibition (mm) around the wells. The activity of each
compound was compared with fluconazole as a standard.
ꢀ
ꢀ
Synthesis of 3-[(2R )-2-[(2S )-6-fluoro-3,4-dihydro-2H-1-
benzopyran-2-yl]-2-hydroxy ethyl]-urea/thiourea
(general method)
ꢀ
ꢀ
A mixture of (S )-2-Amino-1-((R )-6-fluorochroman-2-yl)e-
thanol 4 and TEA in THF (20 mL) was taken in a three-
neck round bottom flask at 20–30 ꢁC. The isocyanate 5a–j
was added to the reaction mixture at 20–30 ꢁC and stirred
for 10 min. The temperature of the reaction mass was raised
to 50–60 ꢁC and stirred at the same temperature for 4–7 h.
After completion of the reaction on TLC, the reaction mass
was cooled to 20–30 ꢁC. The solvent was evaporated under
vacuum at below 50 ꢁC, to the crude residue, diisopropyl
ether (36 mL) was added and kept under stirring for
30 minutes. The solid was filtered and washed with diiso-
propyl ether (12 mL) The obtained solid was dried under
vacuum 50–55 ꢁC for 4 h.
ꢀ
ꢀ
3-[(2R )-2-[(2S )-6-Fluoro-3,4-dihydro-2H-1-benzopyran-2-
yl]-2-hydroxyethyl]-1-(4-fluorophenyl)urea (1a)
Yield: 86.5%, White crystalline solid, m.p.: 187.9–188.3 ꢁC.
IR (KBr, t, cmꢂ1): 3360, 3253, 1674, 1614, 1573, 1508, 1263,
1
1222, 1056, 835. H NMR (400 MHz; DMSO-d6), d, ppm (J,
Hz):1.64–1.74 (1H, m, H-3a); 2.09–2.13 (1H, m, H-3b);
2.74–2.78 (2H, m, H-4a, 4b); 3.04–3.1 (1H, m, H-13a);
3.51–3.62 (2H, m, H-13b, H-2); 3.80–3.84 (1H, m, H-11);
5.34 (1H, d, J ¼ 5.6, ꢂOH); 6.18 (1H, t, J ¼ 4.8, H-14,
ꢂNH); 6.75 (1H, dd, J ¼ 4.8, 4.8H-7); 6.87–6.93 (2H, m, H-
8, 10); 7.04 (2H, t, J ¼ 8.0, H-19, 21); 7.35–7.39 (2H, m, H-
18, 22); 8.65 (1H, s, H-16, -NH). 13C NMR (100 MHz,
DMSO-d6), d, ppm (J, Hz): 22.33 (C-4); 23.85 (C-3); 42.22
(C-13); 70.93 (C-11); 77.09 (C-2); 113.75–113.52 (d, J ¼ 22.0,
C-8); 115.10 (d, J ¼ 17.0, C-19, 21); 115.32, (d, J ¼ 17.0, C-
21); 117.39 (d, J ¼ 8.0, C-10); 119.0 (d, J ¼ 7.0, C-22); 123.83
(d, J ¼ 7.0, C-5); 136.90 (d, J ¼ 2.0, C-17); 150.55 (d, J ¼ 2.0,
C-6); 155.66 (C-15),157.06,154.72 (d, J ¼ 234.0, C-9), 158.01,
155.44 (d, J ¼ 257.0, C-20); 155.66 (C-9). HRMS (FAB) Calc:
C18H18F2N2O3: 348.1285; Found m/z 349.1354 [M þ H]þ
and 371.1171 [M þ Na]þ.
Separation of 2a from compound 2 by column
chromatography
ꢀ
ꢀ
ꢀ
ꢀ
The diastereomeric mixture (R , S and R , R ) of com-
pound 2 was separated by using column chromatography
with silica gel (eluent: n-hexane followed by 2–5% ethyl
ꢀ
acetate in n-hexane) to obtained enantiomeric mixture (R ,
ꢀ
ꢀ
ꢀ
S ) of compound 2a. The enantiomeric mixture (R , S ) of
compound 2a was eluted first. The fraction was collected
and the solvent was evaporated to get compound 2a.
ꢀ
ꢀ
1-(4-Bromophenyl)-3-[(2R )-2-[(2S )-6-fluoro-3,4-dihydro-
2H-1-benzopyran-2-yl]-2-hydroxyethyl]urea (1b)
*
*
Synthesis
(R )-2-(benzylamino)-1-((S )-6-fluoro-3,4-
dihydro-2H-chromen-2-yl)ethanol (3). In a three–neck
round bottom flask, a solution of benzylamine (44.17 g,
0.412 mol) in isopropyl alcohol (40 mL) was taken at
20–30 ꢁC. The temperature of the reaction mixture was
Yield: 82%, White crystalline solid, m.p.: 192.6–194.1 ꢁC. IR
(KBr, t, cmꢂ1): 3406, 3312, 1675, 1594, 1535, 1492, 1212,
1
1017, 835. H NMR (400 MHz; DMSO-d6), d, ppm (J, Hz):
ꢁ
ꢀ
heated to 80–85 C. At this temperature, A solution of (S )- 1.67–1.72 (1H, m, H-3a); 2.10–2.13 (1H, m, H-3b); 2.74-2.78
6-fluoro-2-((R )-oxiran-2-yl)chroman 2a (10 g, 0.0514 mol) (2H, m, H-4a, 4b); 3.06–3.11 (1H, m, H-13a); 3.51–3.62
in isopropyl alcohol 10 mL was added dropwise over (2H, m, H-13b, 2; 3.80–3.85 (1H, m, H-11); 5.35 (1H, d,
ꢀ

8
M. R. MANNAM ET AL.
ꢀ
ꢀ
J ¼ 5.6, OH); 6.23–6.26 (1H, t, J ¼ 4.8, H-14, ꢂNH); 6.75 3-[(2R )-2-[(2S )-6-Fluoro-3,4-dihydro-2H-1-benzopyran-2-
(1H, dd, H-7); 6.86 ꢂ 6.93 (2H, m, H-8,10); 7.34 ꢂ 7.39 (4H,
yl]-2-hydroxyethyl]-1-(4-methylcyclohexyl) urea (1e)
m, H-18, 19, 21, 22); 8.77 (1H, s, H-16, ꢂNH). 13C NMR
Yield: 70%, White crystalline solid, m.p.: 170.4–171.1 ꢁC. IR
(100 MHz, DMSO-d6), d, ppm (J, Hz): 22.33 (C-4); 23.82
(KBr, t, cmꢂ1): 3354, 2926, 1614, 1577, 1492, 1215. 1H
(C-3); 42.17 (C-13); 70.84 (C-11); 77.06 (C-2); 112.12 (C-
20); 113.61 (d, J ¼ 23.0, C-8); 115.28 (d, J ¼ 22.0, C-10);
NMR (400 MHz; DMSO-d6), d, ppm (J, Hz): 0.84 (3H d,
J ¼ 6.0, H-23); 0.91–1.04 (4H, m, H-19, 21); 1.26 (1H, m, H-
117.38 (d, J ¼ 8.0, C-7); 119.40, (C-18,22); 123.81 (d, J ¼ 7.0,
20); 1.60–1.67 (3H, m, 18, 3a); 1.75–1.78 (2H, m, H-22);
C-5); 131.37, (C-19,21); 139.94 (C-17); 150.53 (C-6);
2.06 (1H, m, H-3b); 2.72–2.73 (2H, m, H-4a, 4b); 2.96–2.98
157.04,154.70 (d, J ¼ 234.0, C-9); 155.16 (C-15). HRMS
(1H, m, H-13a); 3.22–3.24 (1H, m, H-17); 3.40–3.41 (1H, m,
(FAB) Calc: C18H18BrFN2O3: 408.0485; Found m/z
409.0540 [M þ H]þ.
13b); 3.50–3.51 (1H, m, H-2); 3.75–3.78 (1H, m, H-11); 5.33
(1H, d, J ¼ 5.2, OH); 5.79–5.82 (1H, m, H-14, ꢂNH),
5.89–5.91(1H, d, J ¼ 8.0, H-16) 6.71–6.75 (1H, m, H-7),
6.86–6.92 (2H, m, H-8,10). 13C NMR (100 MHz, DMSO-d6),
d, ppm (J, Hz): 22.16 (C-23), 23.81(C-4), 31.49 (C-3), 33.28
(C-19,21), 33.69 (C-18, 22), 42.50 (C-13), 48.25 (C-17),
71.50 (C-11), 77.01 (C-2), 113.55 (d, J ¼ 23.0, C-8), 115.24
(d, J ¼ 22.0, C-10), 117.32 (d, J ¼ 8.0, C-7), 123.80 (d,
J ¼ 8.0, C-5), 150.57 (C-6), 156.98,154.64 (d, J ¼ 234.0, C-9),
157.91 (C-15). HRMS (FAB) Calc: C19H27FN2O3: 350.2006;
Found m/z 351.20725 [M þ H]þ and 373.18885 [M þ Na]þ.
ꢀ
ꢀ
1-(3-Chlorophenyl)-3-[(2R )-2-[(2S )-6-fluoro-3,4-dihydro-
2H-1-benzopyran-2-yl]-2-hydroxyethyl] urea (1c)
Yield: 75%, White crystalline solid, m.p.: 175.5–175.2 ꢁC. IR
(KBr, t, cmꢂ1): 3358, 3290, 1678, 1595, 1562, 1213, 1082,
1
856, 684. H NMR (400 MHz; DMSO-d6), d, ppm (J, Hz):
1.67–1.72 (1H, m, H-3a); 2.10–2.14 (1H, m, H-3b);
2.75–2.78 (2H, m, H-4a, 4b); 3.06–3.12 (1H, m, H-13a);
3.34–3.62 (2H, m, H-2,13b); 3.81–3.85 (1H, m, H-11); 5.35
(1H, d, J ¼ 5.6, ꢂOH); 6.27–6.30 (1H, t, J ¼ 5.2, H-14,
ꢂNH); 6.74–6.76 (1H, m, H-20); 6.78–6.93 (3H, m, H-7, 10,
21); 7.15 (1H, d, J ¼ 8.0, H-8); 7.22 (1H, t, J ¼ 8.0 Hz, H-22);
7.67 (1H, s, H-18); 8.85 (1H, s, H-16, ꢂNH). 13C NMR
(100 MHz, DMSO-d6), d, ppm (J, Hz): 22.32 (C-4); 23.81(C-
3); 42.15 (C-13); 70.79 (C-11); 77.04 (C-2); 113.60 (d,
J ¼ 23.0, C-8); 115.26 (d, J ¼ 22.0, C-10); 115.83 (C-22);
116.82 (C-18); 117.36 (d, J ¼ 8.0, C-7); 120.54 (C-20); 123.79
(d, J ¼ 8.0, C-5); 130.24 (C-21); 133.12 (C-19); 142.05 (C-
17); 150.40 (d, J ¼ 2.0, C-6); 155.07 (C-15); 157.03,154.70 (d,
J ¼ 233.0, C-9). HRMS (FAB) Calc: C18H18ClF2N2O3:
ꢀ
ꢀ
3-[(2R )-2-[(2S )-6-Fluoro-3,4-dihydro-2H-1-benzopyran-2-
yl]-2-hydroxyethyl]-1-(4-fluorophenyl)thiourea (1f)
Yield: 81%, White crystalline solid, m.p.: 139.5–139.8 ꢁC. IR
(KBr, t, cmꢂ1): 3323, 3226, 3055, 1546, 1510, 1492, 1219,
1143, 1058, 835, 677. 1H NMR (400 MHz; DMSO-d6), d,
ppm (J, Hz): 1.66–1.76 (1H, m, H-3a); 2.09–2.12 (1H, m, H-
3b); 2.76-2.83 (2H, m, H-4a, 4b); 3.33–3.45 (1H, m, H-2);
3.77–3.88 (2H, m, H-13a, 13b); 3.95 (1H, broad s, H-11);
5.39 (1H, s, OH); 6.71–6.74 (1H, m, H-7); 6.85–6,93 (2H, m,
H-8, 10); 7.15 (2H, t, J ¼ 8.8, H-19, 21); 7.43-7.46 (2H, m,
H-18, 22); 7.66 (1H, brs s, H-14, NH), 9.65 (1H, s, H-16,
NH). 13C NMR (100 MHz, DMSO-d6), d, ppm (J, Hz): 22.18
(C-4); 23.82 (C-3); 46.93 (C-13); 70.02 (C-11); 77.31 (C-2);
113.60 (d, J ¼ 23.0, C-8); 115.28 (d, J ¼ 22.0, C-10); 115.14
(d, J ¼ 22.0, C-19,21); 117.39 (d, J ¼ 8.0, C-7); 123.82 (C-5);
125.36 (C-18, 22); 135.65 (C-17); 150.53 (C-6); 157.05,
154.72 (d, J ¼ 233.0, C-9); 160.07, 157.67 (d, J ¼ 240.0, C-
364.0990;
Found
m/z
365.10567[M þ H]þ
and
387.08740 [M þ Na]þ.
ꢀ
ꢀ
1-(2,4-Difluorophenyl)-3-[(2R )-2-[(2S )-6-fluoro-3,4-dihydro-
2H-1-benzopyran-2-yl]-2-hydroxyethyl]urea (1d)
Yield: 79%, White crystalline solid, m.p.: 184.2–185.9 ꢁC. IR
(KBr, t, cmꢂ1): 3356, 1658, 1573, 1494, 1219, 962, 854. H
1
20);
180.93
(C-15).
HRMS
(FAB)
Calc:
NMR (400 MHz; DMSO-d6), d, ppm (J, Hz): 1.69–1.70 (1H,
m, H-3a); 2.11-2.14 (1H, m, H-3b); 2.75–2.78 (2H, m, H-4a,
4b); 3.07–3.10 (1H, m, H-13a); 3.55–3.60 (2H, m, H-2,13b);
3.81–3.84 (1H, m, H-11); 5.35 (d, J ¼ 5.6, 1H,-OH);
6.71–6,77 (2H, m, H-14, -NH, 19); 6.86–6.93 (2H, m, H-
7,21); 6.95–6.99 (1H, m, H-10); 7.19–7.25 (1H, m, H-8);
8.05–8.11 (1H, m, H-22); 8.44 (1H, s, H-16, -NH). 13C
NMR (100 MHz, DMSO-d6), d, ppm (J, Hz): 22.35 (C-4);
23.80(C-3); 42.20 (C-13); 70.83 (C-11); 76.98 (C-2); 103.48
(dd, J ¼ 24.0, 24.0, C-19); 110.76 (dd, J ¼ 18.0, 3.0, C-21);
113.60 (d, J ¼ 22.0, C-8); 115.26 (d, J ¼ 22.0, C-10); 117.36
(d, J ¼ 8.0, C-7); 121.20 (d, J ¼ 6.0, C-22); 123.79 (d, J ¼ 7.0,
C-5); 124.94 (dd, J ¼ 8.0, 3.0, C-17); 150.51 (C-6); 155.11
(C-15); 157.03,154.69 (d, J ¼ 234.0, C-9); 152.74, 150.31,
152.61, 150.19 (dd, J ¼ 243.0, 12, C-18); 157.32, 154.93,
157.20, 154.82 (dd, J ¼ 239.0, 12.0, C-20). HRMS
C18H18F2N2O2S:364.1057; Found m/z 365.1076 [M þ H]þ.
ꢀ
ꢀ
1-(4-Bromophenyl)-3-[(2R )-2-[(2S )-6-fluoro-3,4-dihydro-
2H-1-benzopyran-2-yl]-2-hydroxyethyl]thiourea (1g)
Yield: 79%, White crystalline solid, m.p.: 140.1–141.7 ꢁC. IR
(KBr, t, cmꢂ1): 3223, 3012, 1629, 1591, 1562, 1492, 1211,
777. 1H NMR (400 MHz; DMSO-d6), d, ppm (J,
Hz):1.67–1.77 (1H, m, H-3a); 2.10–2.13 (1H, m, H-3b);
2.76–2.83 (2H, brs, H-4a, 4b); 3.42–3.45 (1H, m, H-2);
3.81–3.88 (2H, m, H-13a,13b); 4.036 (1H, brs, H-11); 5.43
(1H,-s, OH); 6.72–6.75 (1H, m, H-7); 6.86–6,93 (2H, m, H-
8,10); 7.25–7.26 (2H, s, H-19, 21); 7.38 (1H, brs, H-14,
-NH); 7.87(brs, 1H, H-18); 7.93 (brs, 1H, H-22); 9.83 (1H, s,
H-16, ꢂNH). 13C NMR (100 MHz, DMSO-d6), d, ppm (J,
(FAB) Calc: C18H18F3N2O3: 366.1191; Found m/z Hz): 22.21 (C-4); 23.82 (C-3); 46.83 (C-13); 69.86 (C-11);
367.1221 [M þ H]þ.
77.26 (C-2); 113.61 (d, J ¼ 23.0, C-8); 115.27 (d, J ¼ 23.0, C-

PHOSPHORUS, SULFUR, AND SILICON AND THE RELATED ELEMENTS
9
10); 117.40 (d, J ¼ 8.0, C-7); 121.03 (C-20); 123.80 (d, (1H, m, H-13a); 3.87 ꢂ 3.91 (1H, m, H-13b); 3.97 (1H, brs,
J ¼ 7.0, C-5); 124.60 (C-18); 126.28 (C-22); 130.38 (C-19,21); H-11); 5.45 (1H, s, ꢂOH), 6.73 ꢂ 6.76 (1H, m, H-7);
141.28 (C-17); 150.50 (C-6); 154.72; 157.06,154.72 (d,
6.86 ꢂ 6,94 (2H, m, H-8,10); 7.41 (d, J ¼ 8.0, 1H, H-20);
J ¼ 234.0, C-9); 180.44 (C-15). HRMS (FAB) Calc:
77.53 (1H, t, J ¼ 7.6, H-21); 7.70 (1H, d, J ¼ 8.0, H-18); 7.94
(1H, brs, H-18); 8.10 (1H, brs, H-14, -NH); 9.65 (1H, s, H-
16, -NH). 13C NMR (100 MHz, DMSO-d6), d, ppm (J, Hz):
22.24 (C-4); 23.83 (C-3); 46.81 (C-13); 69.87 (C-11); 77.24
(C-2); 113.75–113.52 (d, J ¼ 23.0, C-8); 115.30 (d, J ¼ 22.0,
C-10); 117.42 (d, J ¼ 8.0, C-7); 118.37 (C-20); 119.93 (C-18);
125.46, 122.75, (d, J ¼ 271.0, C-9); 123.81 (d, J ¼ 7.0, C-5);
125.86 (C-21); 129.15,128.17 (q, J ¼ 38.0, 36.0, C-23); 129.61
(22); 140.57 (C-17); 150.52-150.51 (d, J ¼ 1.2, C-6); 157.08,
154.74 (d, J ¼ 234.0, C-9); 180.64 (C-15). HRMS (FAB) Calc:
C18H18BrFN2O2S:424.0256; Found m/z 425.03248 [M þ H]þ.
ꢀ
ꢀ
1-(3-Chlorophenyl)-3-[(2R )-2-[(2S )-6-fluoro-3,4-dihydro-
2H-1-benzopyran-2-yl]-2-hydroxyethyl] thiourea (1h)
Yield: 82%, White crystalline solid, m.p.: 156.6–157.0 ꢁC. IR
(KBr, t, cmꢂ1): 3327, 3282, 1552, 1496, 1317, 1170, 1058,
1
933, 813, 700. H NMR (400 MHz; DMSO-d6), d, ppm (J,
Hz): 1.67–1.77 (1H, m, H-3a); 2.10–2.13 (1H, m, H-3b);
2.73–2.84 (2H, m, H-4a, 4b); 3.41–3.47 (1H, m, H-2); C19H18F4N2O2S: 414.1025; Found m/z 415.10931 [M þ H]þ
3.78–3.81 (1H, m, H-13a); 3.82–3.9 (1H, m, H-113b); 3.95 and 437.09115 [M þ Na]þ.
(1H, brs, H-11); 5.43 (1H, s, OH); 6.72–6.86 (1H, m, H-20);
6.86–6,94 (2H, m, H-7,10); 7.11–7.14 (1H, d, 21); 7.30–7.37
Conclusion
(2H, m, H-8, 18); 7.81(1H, brs, H-22); 7.87 (1H, brs, ꢂNH);
9.83 (1H, s, H-16, ꢂNH). 13C NMR (100 MHz, DMSO-d6),
d, ppm (J, Hz): 22.22 (C-4); 23.81 (C-3); 46.83 (C-13); 69.87
(C-11); 77.25 (C-2); 1113.61 (d, J ¼ 22.0, C-8); 115.27 (d,
J ¼ 22.0, C-10); 117.40 (d, J ¼ 8.0, C-7); 120.71 (C-21);
121.73 (C-18); 123.39 (C-20); 123.80 (d, J ¼ 7.0, C-5); 130.09
(C-22); 132.59 (C-19); 141.14 (C-17); 150.50 (C-6); 157.06,
154.72 (d, J ¼ 234.0, C-9); 180.45 (C-15). HRMS (FAB) Calc:
C18H18ClFN2O2S: 380.0762; Found m/z 381.08315 [M þ H]þ
and 403.06486 [M þ Na]þ.
ꢀ
ꢀ
We have synthesized a new series of 3-[(2R )-2-[(2S )-6-flu-
oro-3,4-dihydro-2H-1-chromen-2-yl]-2-hydroxyethyl]-urea/
thiourea derivatives (1a–j) starting from 6-fluoro-2-(oxiran-
2-yl)chroman (2) in high yields (80–90%). The structures of
the synthesized compounds were confirmed by FT-IR, NMR
(1H, 13C) and HRMS data. Among the synthesized mole-
cules, the urea-based fluoro substituted compounds (1a, 1d)
showed outstanding antibacterial activity against both
Gram þ Ve, Gram –Ve bacterial strains and the thiourea
based –Cl, –CF3 substituted compounds 1h and 1j showed
excellent antifungal activity against fungal strains. The pre-
sent work helped in addition to a new library of biologically
active molecules to the heterocyclic chemistry domain. The
identified promising lead compounds (1a, 1d, and 1h) are
useful for further studies in the development of new anti-
microbial agents in drug discovery and development pro-
grams. The screening of anticancer activities of the present
molecules is under progress.
ꢀ
ꢀ
1-(3,4-Dichlorophenyl)-3-[(2R )-2-[(2S )-6-fluoro-3,4-dihydro-
2H-1-benzopyran-2-yl]-2-hydroxyethyl]thiourea (1i)
Yield: 75%, White crystalline solid, m.p.: 114.9–115.4 ꢁC. IR
(KBr, t, cmꢂ1): 3271, 1593, 1492, 1215, 1138, 1029, 929,
810. 1H NMR (400 MHz; DMSO-d6), d, ppm (J, Hz):
1.60–1.77 (1H, m, H-3a); 2.10–2.18 (1H, m, H-3b); 2.77
(2H, brs, H-4a, 4b); 3.42–3.45 (1H, m, H-2); 3.81-3.86 (1H,
m, H-13a); 3.88-3.89 (1H, m, H-113b); 3.95 (1H, brs, H-11);
5.43 (1H, s, OH); 6.73-6.76 (1H, m, H-7); 6.87–6,93 (2H, m,
H-10, 22); 7.42 (1H, d, J ¼ 8.0, H-8); 7.54 (1H, d, J ¼ 8.0, H-
21); 7.95 (1H, brs, H-18); 8.03 (1H, brs, ꢂNH); 9.83 (1H, s,
H-16, ꢂNH). 13C NMR (100 MHz, DMSO-d6), d, ppm (J,
Hz): 22.22 (C-4); 23.82 (C-3); 46.84 (C-13); 69.83 (C-11);
77.23 (C-2); 113.62 (d, J ¼ 23.0, C-8); 115.29 (d, J ¼ 22.0, C-
10); 117.41 (d, J ¼ 8.0, C-7); 122.25 (C-22); 123.39 (C-18);
123.80 (d, J ¼ 7.0, C-5); 125.16 (C-21), 130.21, (C-20);
130.47 (C-19), 139.86 (C-17), 150.50 (C-6); 157.07,154.73 (d,
J ¼ 234.0, C-9); 180.43 (C-15). HRMS (FAB) Calc:
C18H18Cl2FN2O2S: 414.0372; Found m/z 415.0399 [M þ H]þ.
Acknowledgments
The authors are thankful to the management of Micro Labs Limited,
API R&D Centre, Bangalore and Dr. Mohan Reddy Bodireddy,
Chemical Research Division, API R&D Centre, Bangalore, for valu-
able support.
Disclosure statement
The author declared no conflict of interest.
ORCID
ꢀ
ꢀ
3-[(2R )-2-[(2S )-6-Fluoro-3,4-dihydro-2H-1-benzopyran-2-
yl]-2-hydroxyethyl]-1-[3-(trifluoromethyl)
phenyl]thiourea (1j)
Naga Raju Chamarthi
Prasad K. R. S. http://orcid.org/0000-0002-8087-954X
http://orcid.org/0000-0001-6566-2118
Yield: 72%, White crystalline solid, m.p.: 134.8–135.3 ꢁC. References
IR(KBr, t, cmꢂ1): 3223 1631, 1593, 1568, 1492, 1211, 779.
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1H NMR spectrum, (400 MHz, DMSO-d6) d, ppm (J, Hz):
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(2H, m, H-4a, 4b); 3.43 ꢂ 3.49 (1H, m, H-2); 3.73 ꢂ 3.82
Strategy for the 21st Century; US Department of Health and
Human Services, Centers for Disease Control and Prevention:
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