Sulfur Assisted Tandem Electrophilic Fluorinative Deacylation: Synthesis of α-Fluoro β-Ketosulfides

Article abstract of DOI:10.1021/acs.joc.7b01547

A successful synthesis of α-fluoro-β-ketosulfides using an electrophilic fluorination method has been reported for the first time. The reaction proceeds via an electrophilic fluorination of α-sulfenyl-β-diketones followed by an unexpected tandem deacylation. The resulting products, α-fluoro-β-ketosulfides, are easily oxidized to the corresponding α-fluoro-β-ketosulfones, which can be used for further useful olefination reactions.

Full text of DOI:10.1021/acs.joc.7b01547

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Article
Sulfur Assisted Tandem Electrophilic Fluorinative
Deacylation: Synthesis of #-Fluoro #-Ketosulfides
Begur Vasanthkumar Varun, and Kandikere Ramaiah Prabhu
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b01547 • Publication Date (Web): 08 Aug 2017
Downloaded from http://pubs.acs.org on August 8, 2017
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Sulfur Assisted Tandem Electrophilic Fluorinative
Deacylation: Synthesis of α-Fluoro β-Ketosulfides
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Begur Vasanthkumar Varun and Kandikere Ramaiah Prabhu*
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Department of Organic Chemistry, Indian Institute of Science,
Bangalore 560 012, Karnataka, India.
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prabhu@orgchem.iisc.ernet.in
ABSTRACT
A successful synthesis of αꢀfluoroꢀβꢀketosulfides using electrophilic fluorination
method has been reported for the first time. The reaction proceeds via an electrophilic
fluorination of αꢀsulfenylꢀβꢀdiketones followed by an unexpected tandem deacylation. The
resulting product, αꢀfluoroꢀβꢀketosulfides, are easily oxidized to the corresponding αꢀfluoroꢀ
βꢀketosulfones, which can be used for further useful olefination reactions.
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Introduction
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Incorporation of fluorine into organic molecules is an active research area in organic
synthesis, because, fluorine containing organic compounds are found in biologically active
compounds including pharmaceuticals and agrochemicals, and material science industries,
agrochemistry and material science (Fig 1).1,2
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Fig 1: Examples of fluorine containing drug molecules
A plethora of methods are available in the literature for incorporation of fluorine into
organic molecules to obtain a variety of structurally diverse molecular scaffolds.3 However,
controlled monoꢀelectrophilic fluorination at αꢀposition of an electron withdrawing group still
remains a challenge in organic synthesis.4 This problem becomes compounded when a sulfide
group is present at αꢀposition to an electron withdrawing moiety. Several attempts towards
synthesizing αꢀfluoroꢀβꢀketosulfides via electrophilic fluorination method by various groups,
have resulted in the formation of undesired or over fluorinated products (Scheme 1).4bꢀ4d This
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is probably due to (i) the strong affinity between sulfur and fluorine to form S–F/S→F bond,
which leads to undesired side reactions; and (ii) the presence of sulfur atom at αꢀposition
increases the acidity of αꢀC–H bond, and results in the rapid uncontrolled fluorination. The
methods for the formation of αꢀfluoroꢀβꢀketosulfides are limited to a few βꢀketosulfide
derivativess that bear the substitution at αꢀposition.4b
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(i) Electrophilic fluorination by using IF5-pyridine-HF as fluorinating reagent (ref. 4b)
IF5-pyridine-HF
F F
Ar
Ar
Ar
R
R
R
DCM, rt
S
S
S
O
O
O
Ph
IF5-pyridine-HF
DCM, rt
Ph
R
F F
R=Alkoxy / Aryl / Amine
O
(ii) Electrophilic fluorination by using Selectfluor® as fluorinating reagent (ref. 4c-4d)
F F
O
Na2CO3 / CH3CN
Selectfluor®
Ar
S
degradation
Ar
Ph
S
Ar
S
S
Ar
Ph
Ph
O
detected by GCMS
Disulfide
O
O
Ar
O
O
O
Na2CO3 / CH3CN
Selectfluor®
O
S
Ar
S
Ar
S
O
+
Ph
O
Ph
O
F F
F
Major
Minor
Scheme 1: Undesired/Uncontrolled electrophilic fluorination
In contrast to electrophilic fluorination, the controlled nucleophilic fluorination of βꢀ
ketosulfides could be successfully achieved by electrochemical methods (eq 1, Scheme 2).5
The only chemical method known to obtain αꢀfluoroꢀβꢀketosulfides is the nucleophilic
fluorination of sulfoxide with DAST (diethyl amino sulfurtrifluoride) in the presence of
catalytic amount of ZnI2 (eq 2, Scheme 2).6a However, the nucleophilic substitution of αꢀ
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bromofluorocarbonyl compounds with thiols provides the expected αꢀfluoroꢀβꢀketosulfides
(eq 3, Scheme 2).6bꢀ6c
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On the other hand, several reports of deacylation of βꢀdicarbonyl compounds, such as
classical acetoacetic ester synthesis, are well documented in the literature.6dꢀ6g In recent years,
the release of trifluro acetate group from the fluorinated βꢀdicarbonyl compounds shown as
important reaction in organic synthesis.6jꢀ6k When the αꢀposition of βꢀdicarbonyl compounds
is substituted with sulfides, the deacylation is relatively facile.7 The deacylation of βꢀ
ketoesters is facile in the presence of nucleophilic base at ambient temperature.7b However,
the deacylation of βꢀdiketones, generally requires transition metal catalysts, and oxidants, and
the reaction is performed at higher temperature.7cꢀ7d A report for the electrophilic
halogenative (+Cl and +Br) deacylation of nonꢀsulfide bearing βꢀdicarbonyl compounds is
known in the literature.7e Distinct from these reports, the present work involves an
unexpected tandem deacylation of αꢀfluoro sulfenyl βꢀdiketones in mild reaction conditions to
synthesize αꢀfluoroꢀβꢀketosulfides (eq 4, Scheme 2). To the best of our knowledge, till date,
(i) a controlled fluorination leading to mono electrophilic fluorination of βꢀketosulfides, and
(ii) a successful synthesis of αꢀfluoroꢀβꢀketosulfides via electrophilic fluorination method are
unknown.
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(A) Electrochemical approach
Nucleophilic fluorination: Fuchigami et al (ref. 5)
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EWG
S
-2e- , H+
EWG
S
EWG
S
F
(eq 1)
R2
R2
R2
F
R1
R1
R1
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(B) Chemical approach
(i) Nucleophilic fluorination: McCarthy et al (ref. 6a)
O
O
S
O
O
HF
S
DAST
S
(eq 2)
(eq 3)
R3
R3
R3
R1
R1
R1
R2
R2
F
R2
(ii) Nucleophilic substitution with thiols (ref. 6b-6c)
O
O
Ar/Het
S
R
O
Br
Ar/Het
SH
+
R
F
F
(C) Present work: Electrophilic fluorination followed by deacylation
via:
O
O
R
R
O
R
R
O
NFSI, base, rt, 2-3 h
F
S
Ar/Het
Fluorination followed
by C-C bond cleavage
Ar/Het
S
Ar/Het
S F R
(eq 4)
Scheme 2: Reaction development
Results and Discussion
Optimization Studies
Initially, we performed a fluorination of αꢀsulfenylꢀβꢀdiketone (1a, 1 equiv) using NFSI (Nꢀ
fluorobenzenesulfonimide, 1.1 equiv) as a fluorinating reagent and K2CO3 (1.2 equiv) as a
base in CH3CN (2 mL). The initial reaction furnished a mixture of fluorinated product 2a and
1
the corresponding deacylated product 3a in 54 and 43%, respectively (determined by H
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NMR, Table 1, entry 1). Extending the reaction time to 1h led to the formation of 2a and 3a
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in 44 and 56%, respectively (entry 2).
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Table 1: Screening studies a (Standard conditions A)
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1 H NMR yield (%) for
entry
crude reaction mixture b
solvent time (h)a
2a
54
44
10
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nd
18
22
nd
50
41
nd
nr
3a
43
56
1
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13c
14d
CH3CN
CH3CN
CH3CN
THF
0.75
1
2
1
2
2
1
2
2
2
2
2
2
90 (96) e
43
THF
100
82
acetone
EtOAc
EtOAc
DCM
toluene
MeOH
H2O
78 (92) e
100 (96)e
50
51
nd
nr
23
EtOAc
EtOAc
59
nd
2
100
a Reaction conditions A: 1a (0.1 mmol) and K2CO3 (1.2 equiv) in solvent (1 mL) were preꢀstirred for 60ꢀ90 min,
then NFSI (1.1 equiv) was added and the reaction mixture was stirred for the given time. b 1H NMR yields
e
(determined by using terephthaldehyde as internal standard). c Na2CO3 (1.2 equiv) d Cs2CO3 (1.2 equiv). Values
in the parentheses are isolated yields of 3a after passing through silica gel column (2a converts to 3a in the
column)
Further extension to 2h led to the formation of a mixture of 2a and 3a in 10 and 90%,
respectively (entry 3). On purification, we were able to isolate exclusively deacylated product
3a in 96% isolated yield (entry 3), indicating that the fluorinated product 2a underwent
deacylation under the chromatographic conditions (see the Supporting Information, SIꢀ3ꢀSIꢀ
4). Further, reaction of 1a using solvents such as THF and acetone resulted in the formation
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of a mixture of 2a and 3a (entries 4ꢀ6). The reaction of 1a with NFSI in EtOAc (1h) furnished
the products 2a and 3a in 22 and 78%, respectively (entry 7). Further, when the reaction was
carried in EtOAc for 2h, it furnished exclusively deacylated product 3a in almost quantitative
yield (entry 8). Reactions with solvents such as CH2Cl2 and toluene led to a mixture of 2a and
3a (entries 9 and 10). Furthermore, the reaction in MeOH formed a complex mixture,
whereas the reaction in H2O was not successful (entries 11 and 12). The reaction performed
using Na2CO3 gave 2a and 3a in 59 and 23%, respectively (entry 13), whereas the reaction
using Cs2CO3 proceeded smoothly to furnish only 3a in quantitative yield (entry 14).
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Substrate scope
Under the established “optimized reaction conditions A” (entry 8, Table 1), the scope and
limitations of this fluorinative deacylation reaction were explored (Scheme 3). As seen in
Scheme 3, a variety of αꢀbenzoxazoleꢀ2ꢀsulfenyl acetylacetone derivatives bearing
alkyl/aryl/halo substitution on benzoxazole ring (1a-1g) and unsubstituted αꢀbenzoxazoleꢀ2ꢀ
sulfenyl acetylactone (1h) underwent smooth electrophilic fluorination followed by
deacetylation furnishing products 3aꢀ3h in moderate to excellent yields (96, 92, 89, 80, 93,
69, 44 and 98%, respectively). Further, a facile deacylation was observed even in the case of
αꢀbenzoxazoleꢀ2ꢀsulfenylꢀ3,5ꢀheptanediones (1i and 1j) and the expected products 3i and 3j
were obtained in good yields (70 and 73%, respectively). Under the optimal conditions, the
benzothiazole derivative (1k) furnished the expected product 3k in excellent yield (96%).
However, αꢀbenzothiazoleꢀ2ꢀsulfenyl 3,5ꢀheptanediones (1l) furnished an inseparable mixture
1
of 2l and 3l in 12 and 77%, respectively (based on H NMR ratio). The fluorinative
deacylation reaction of αꢀoxazoleꢀ2ꢀsulfenylacetylacetone (1m) furnished only 30% of the
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desired product 3m after column purification. The compound 1n, which has the
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unsymmetrical diketone moiety, underwent fluorinative deacylation to give the mixture of
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Scheme 3: Substrate scope a, b, c, d
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6
7
8
OH
O
R
O
R
R
O
F
S
O
R
K2CO3 (1.2 equv)
NFSI (1.1 equiv)
N
X
N
X
N
X
S
Ar
S F R
Ar
Ar
9
EtOAc (2 mL)
rt, 2 - 3 h
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2
3
1a-1m (0.25 mmol)
F
O
F
O
F
S
O
F
S
O
N
S
O
Ph
N
S
O
N
N
O
O
(2d:3d = 5:95)c 3d (80%)
3a (96%)
3b (92%)
3c (89%)
F
S
O
F
O
F
O
F
S
O
Cl
F
N
N
N
N
O
S
O
S
O
O
(2h:3h = 7:93)c 3h (98%)
3e (93%)
3f (69%)
3g (14:86)c (44%)
O
F
O
Et
N
O
F
O
F
O
R
N
O
N
S
N
S
S
+
S
S F Et
S
Et
S
R = Me; 3i (70%)
R = Cl; 3j (73%)
3l (77%)
2l (12%)
(2l:3l = 37:63)c
(2l:3l = 16::84)d
(2k:3k = 18:82)c 3k (96%)
Reaction with a compound having unsymmetrical -diketone moity
O
F
S
O
F
O
Ph
N
O
F
S
O
N
O
N
O
N
O
+
+
S
S F
Ph
O
3m (30%)
3n (40%)
(2n:3n:3a = 40:36:24)c
3a (35%)
2n (0%)
a Reaction Conditions: 1 (0.25 mmol) and K2CO3 (1.2 equiv), were preꢀstirred for 60ꢀ90 minutes in EtOAc (2
b
mL), then NFSI (1.1 equiv) was added and reaction mixture was stirred at rt for further 2 ꢀ 3 h. Values in the
parentheses are isolated yields. 1H NMR ratio of products before column purification. 1H NMR ratio of
c
d
products after column purification.
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2n, 3n and 3a in a ratio of 40:36:24. The compounds 3n and 3a were isolated in 40 and 35%,
respectively, whereas the compound 2n underwent deacylation on silica gel column. Hence,
the increment in the isolated yields of 3n and 3a was observed.
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The compound 1o, which preferentially exists in diketone form (due to bulky carbonyl
groups) bearing relatively less acidic proton,7a did not furnish the expected product 3o and
1
starting material was intact (based on H NMR spectrum, Scheme 4). The starting materials
1p and 1q did not furnish the αꢀalkylthioꢀβꢀdiketones (Scheme 4).8a Further, when the starting
material 1a was allowed to react with NCS/NBS/NIS instead of NFSI, the reaction produced
complex inseparable mixture (Scheme 4).
Scheme 4: Unsuccessful reaction under “Optimized reaction condition A”
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Optimization for arylꢀsubstituted sulfdes.
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Under the “optimized reaction conditions A”, 3ꢀ(phenylthio)pentaneꢀ2,4ꢀdione (4a) did not
undergo complete deacylation and instead furnished a mixture of nonꢀdeacylated and
deacylated fluorine compounds. Therefore, further optimization study was under taken to
enhance the deacylation process (entries 1ꢀ5, Table 2). During this optimization study, we
found that increasing in the concentration of the reaction mixture (0.5 mmol of 4 in 2 mL of
CH3CN) in the presence of a strong base (Cs2CO3, 1.2 equiv) resulted in the complete
deacylation (entry 5, Optimized reaction condition B; Table 2).
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Table 2: Optimization for aryl substituted sulfides (6a-6i) (Standard conditions B)
Conversion
ratios in crude
reaction mixture
5a : 6a
Ratios after
subjecting to column
purification c, d
5a : 6a
solvent
(mL)
base
(equiv)
4a
(mmol)
entry
30:70
5a (19%); 6a (60%)
8: 92
5a (6%); 6a (82%)
7: 93
1
2
3
0.25
0.5
EtOAc (2.0)
EtOAc (4.0)
EtOAc (2.0)
K2CO3 (1.2)
K2CO3 (3.0)
Cs2CO3 (1.2)
68: 32
38: 62
25: 75
0.5
5a (5%); 6a (91%)
4
0.25
CH3CN (2.0)
K2CO3 (1.2)
34:66
ꢀ
0:100
5a (0%); 6a (88%)
5
0.5
CH3CN (2.0)
Cs2CO3 (1.2)
3:97
a
Reaction Conditions: 4a (1 equiv) and Base (x equiv) were preꢀstirred for 2 h, then NFSI (1.1 equiv) was
added and the reaction mixture was stirred at room temperature for 3 h. b 1H NMR ratio of products, c 1H NMR
ratio of products after silica gel column purification, Values in the parenthesis are the isolated yield of
d
inseparable mixture of products 5a and 6a. nd=not detected
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Substrate Scope
5
6
7
8
Under the reaction conditions B, αꢀthiophenyl acetyl acetone 4a and its derivatives 4b-4h
underwent smooth reaction, which upon purification on a silica gel column furnished
exclusively deacylated fluorine compounds 6a (88%), 6b (83%), 6c (62%), 6d (65%), 6e
(82%), 6f (78%), 6g (88%), 6h (87%) and 6i (82%) respectively (Scheme 5). The αꢀsulfenyl
βꢀketoester 4i furnished the mixture of 5j and 6j in 38 and 42%, respectively (1H NMR yield,
see the Supporting information, SIꢀ90 and 91). However, our attempt to isolate the 5j and 6j
was not successful as the crude compound degraded on silica gel column.
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Scheme 5: Substrate scope under the “Optimized reaction condition B” a, b, c, d
a
Reaction conditions: 4 (0.5 mmol) and Cs2CO3 (1.2 equiv), were preꢀstirred for 2 h in CH3CN (2 mL), added
b
NFSI (1.1 equiv) and reaction mixture was stirred at rt for further 3 h. Values in the parentheses are Isolated
yields. Reaction timeꢀ6 h. d 1H NMR yield (determined by using terephthaldehyde as internal standard; see SIꢀ
c
90 and 91) the compounds degraded during isolation
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αꢀFluoroꢀβꢀketosulfones are important starting materials in JuliaꢀKocienski fluoroꢀ
olefination reaction for synthesizing fluoroꢀolefins.6bꢀ6c, 10 Further, the sulfones have great
utility in organic synthesis as well as in pharmaceutical chemistry.4b, 6bꢀ6c, 9 The general
reaction sequences used for the synthesis of αꢀfluoroꢀβꢀketosulfones are cumbersome and
have multiple problems (eq 1, Scheme 6).6bꢀ6c, 10aꢀ10c Hu et al, reported an alternate strategy,
which avoids the over fluorination (eq 2, scheme 6).9b
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Scheme 6: Reaction development for the synthesis of fluorosulfones
To address these synthetic challenges, we thought that αꢀfluoroꢀβꢀketosulfides would
be suitable substrates for synthesizing αꢀfluoroꢀβꢀketosulfones (eq 3, Scheme 6). Hence, the
compound 6a was chosen as the model substrate for the oxidation, and sulfones 7a, 9a, and
9b were synthesized in good to excellent yields (96, 73 and 68%, respectively, Scheme 7)
from the starting material 6a under a mild reaction condition using mꢀCPBA as an oxidant.8b
To demonstrate further synthetic utility, both allylation and benzylation of 6a was performed,
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in which only the products 8a and 8b were obtained from 6a (see the Supporting Information,
SIꢀ95 and SIꢀ99).
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Scheme 7: Synthetic application a, b, c, d
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Reaction Conditions: a mCPBA (4 equiv), CH2Cl2 (5 mL), rt, 6 h, b 8a (0.36 mmol), c 8b (0.4 mmol), d Values in
the parentheses are isolated yields.
Control experiments
To understand the effect of sulfur on deacylation reaction, the compound 10a was fluorinated
under “optimized reaction condition B”, which furnished only the nonꢀdeacylated product 11a
in 42% yield (eq 1, Scheme 8, see SIꢀ109 and SIꢀ110). This result clearly indicates the
necessity of sulfur moiety for deacylation of αꢀfluoroꢀβꢀdiketones. Earlier, we reported a
reaction in which the active methine position of 1a is substituted (allylation and benzylation
reactions) to form the nonꢀdeacylated products (eq 2, Scheme 8).7a This result clearly suggests
the necessity of fluorine moiety for deacylation of αꢀsulfenyl βꢀdiketones. Hence, these two
results clearly indicate that the presence of both sulfur and fluorine at αꢀposition of βꢀ
dicarbonyl is essential for facile deacylation. Based on these observations, a tentative
mechanism has been proposed (Scheme 8). Fluorine being the most electronegative element,
its substitution at αꢀposition of βꢀdicarbonyl enhances the electrophilicity at of the carbonyl
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carbons and thereby facilitating a even weak nucleophiles to attack carbonyl carbons.11aꢀ11b
On the other hand, the vacant dꢀorbital of sulfur stabilizes the adjacent carbanion11bꢀ11c
(Scheme 8) thereby favouring the deacylation.
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Scheme 8: Establishment of mechanism
Therefore, the electronegativity factor as well as carbanion stabilization operate
together causing the deacylation. Further, the residue that forms after the reaction has been
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identified as the potassium/cesium salt of benzene sulfonimide and that of 4a found to be
cesium salt of benzene sulfonimide (compound 13, determined by 1H NMR in D2O, Scheme
8). This indicates that the anion of benzene sulfonimide has probably no role in deacylation.
Further, in addressing the substrate scope of the present work, the inherent instability of αꢀ
sulfenylꢀβꢀdicarbonyl to undergo deacylation 7, limits the substrate scope as synthesizing the
starting materials is cumbersome. Especially αꢀsulfenylꢀβꢀketoesters, are prone to undergo
deacylation and decompose during isolation. However, we believe that the significance of the
present fluorinative deacylation methodology and the application of αꢀfluoro βꢀketosulfides
would overcome the limitation of the substrate scope.
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Conclusion
In conclusion, we have developed an unprecedented tandem electrophilic fluorinative
deacylation method for synthesizing αꢀfluoroꢀβꢀketo sulfides under mild basic reaction
conditions at room temperature. The unexpected deacylation upon fluorination of αꢀsulfenyl
βꢀdicarbonyls is the salient feature of this method. The synthetic potential of the methodology
has been demonstrated by synthesizing a series of sulfones which can be used for
synthesizing fluro olefins.
Experimental Section
General experimental
All the reactions were carried out using commercially available AR grade solvents without
further distillation. Unless otherwise noted, starting materials and solvents obtained from
commercial suppliers were used without further purification. Reactions were monitored by
using precoated silica TLC plates. Column chromatography was performed on Silica gel 100ꢀ
200 mesh. Distilled petroleum ether was used for column chromatography. The starting
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materials αꢀsulfenyl βꢀdiketones (1aꢀ1n) were prepared as described in the our earlier
reports7a, 12 and αꢀsulfenyl βꢀdiketones (3aꢀ3h) were prepared as described in the literature13
with necessary modifications (see the given procedure and note 1). NMR spectra were
recorded at 400 MHz, using either CDCl3. For the spectra recorded in CDCl3, TMS
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(tetramethylsilane) or residual CHCl3 served as internal standard for H NMR (0.00 ppm or
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7.26) and solvent signal was used as reference signal for C NMR (77.00 ppm). IR spectra
were measured using a FTꢀIR spectrometer. Mass spectra were measured using QꢀTof (ESIꢀ
HRMS).
(A) Experimental procedures for the synthesis of the starting materials
(i) Typical experimental procedure for the synthesis of (E)-3-(ethylthio)-4-hydroxypent-
3-en-2-one (1p) 13
To a wellꢀstirred, ice cold mixture of ethyl thiol (10 mmol) and αꢀchloro acetylacetone (10
mmol) was added pyridine slowly (11 mmol) for the period of 1 minute. The reaction mixture
was stirred vigorously at room temperature for 12 h. Then the diethyl ether (15 mL) was
added to the reaction mixture and crude compound was filtered through sintered funnel, and
the filtrate containing crude compound was adsorbed on silica gel (100ꢀ200 mesh size) and
purified on a silica gel column using EtOAc/Petroleum ether (2:98 – 5:95) as eluent to obtain
the expected αꢀsulfenyl βꢀdiketone 1p.
(ii) Typical experimental procedure for the synthesis of (E)-4-hydroxy-3-
(isopropylthio)pent-3-en-2-one (1q) 13
To a wellꢀstirred, ice cold mixture of isopropyl thiol (10 mmol) and αꢀchloro acetylacetone
(10 mmol) was added pyridine slowly (11 mmol) for the period of 1 minute. The reaction
mixture was stirred vigorously at room temperature for 12 h. After, the reaction mixture was
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diluted with 3ꢀ4 mL of diethyl ether and directly transferred on silica gel column and purified
using EtOAc/Petroleum ether (2:98 – 5:95) as eluent to obtain the expected αꢀsulfenyl βꢀ
diketone 1q.
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* We observed, the starting materials 1p and 1q are low boiling point liquids
(iii) General experimental procedure for the synthesis of starting materials (4a-4i) 13
To a wellꢀstirred, ice cold mixture of thiol (10 mmol) and αꢀchloro acetylacetone (10 mmol)
was added pyridine slowly (11 mmol) for the period of 1 minute (please see the note 1). The
reaction mixture was stirred vigorously at room temperature for 12 h. Then the diethyl ether
(15 mL) was added to the reaction mixture and crude compound was filtered through sintered
funnel, and the filtrate containing crude compound was adsorbed on silica gel (100ꢀ200 mesh
size) and purified on a silica gel column using EtOAc/Petroleum ether (0:100 – 4:96) as
eluent to obtain the expected αꢀsulfenyl βꢀdiketone.
Note 1: When thiols are liquid no solvent used in the reaction. When thiols are solid, the
reaction was performed in diethyl ether (15 mL) i.e., pyridine was added to the ice cold
solution of thiol and αꢀchloro acetylacetone in diethyl ether.
(iv) Typical experimental procedure for the synthesis of starting material 4j 13
To a wellꢀstirred, ice cold mixture of thiophenol (10 mmol) and αꢀchloro methyl acetoacetate
(10 mmol) was added pyridine slowly (11 mmol) for the period of 1 minute. The reaction
mixture was stirred vigorously at room temperature for 12 h. Then the diethyl ether (15 mL)
was added to the reaction mixture and crude compound was filtered through sintered funnel,
and the filtrate containing crude compound was adsorbed on silica gel (100ꢀ200 mesh size)
and purified on a silica gel column using EtOAc/Petroleum ether (0:100 – 5:95) as eluent to
obtain the expected product 4j.
(B) Experimental procedures for the synthesis of the products
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(i) General experimental procedure for the synthesis of α-fluoro β-ketosulfides (3a-3n)
To a wellꢀstirred, solution of αꢀsulfenyl βꢀdiketone (1, 0.25 mmol) in EtOAc (2 mL) was
added anhydrous K2CO3 (1.2 equiv). The reaction mixture was stirred at room temperature,
till it turned into a white turbid heterogeneous reaction mixture (generally 60ꢀ90 min). The
round bottom flask was then placed under the ice bath and NFSI (1.1 equiv) was added
slowly to the cold reaction mixture. After 5 minutes of complete addition of NFSI, the ice
bath was removed and stirring was continued at room temperature for 3 h. Then, the crude
compound was filtered through sintered funnel and the residue was washed with EtoAc (5 mL
x 2). The filtrate was adsorbed on silica gel (100ꢀ200 mesh size) and purified on silica gel
(100ꢀ200 mesh size) column by using EtOAc/Petroleum ether (0:100 – 5:95) as the eluent to
obtain the expected αꢀfluoro βꢀketosulfides (3aꢀ3n).
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(ii) General experimental procedure for the synthesis of α-fluoro β-ketosulfides (6a-6i)
To a wellꢀstirred, solution of αꢀsulfenyl βꢀdiketone (4, 0.5 mmol) in CH3CN (2.0 mL) was
added anhydrous Cs2CO3 (1.2 equiv). The reaction mixture was stirred at room temperature
until it turned into a white turbid heterogeneous reaction mixture (generally 2 h). The round
bottom flask was then placed under the ice bath and NFSI (1.1 equiv) was added slowly to the
cold reaction mixture. After 5 minutes of complete addition of NFSI, the ice bath was
removed and stirring was continued at room temperature for 3 h. Then, the crude compound
was filtered through sintered funnel and the residue was washed with EtOAc (5 mL x 2). The
filtrate was adsorbed on silica gel (100ꢀ200 mesh size) and purified on silica gel (100ꢀ200
mesh size) column by using EtOAc/Petroleum ether (0:100 – 5:95) as the eluent to obtain the
expected αꢀfluoro βꢀketosulfides (6aꢀ6i).
Note 2: For optimization studies, the following workup procedure was followed
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The crude compound in EtOAc (10 mL) was taken in separating funnel, and then water (10
mL) was added and shaken well to form white turbid mixture. To this white turbid mixture,
the brine solution was added (3ꢀ5 mL) to obtain a clear bilayer of organic and aqueous
mixture. The organic layer was separated and the aqueous layer was washed with EtOAc (5
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mL x 2). The combined organic fraction was dried over anhydrous Na2SO4 and H NMR
yield was determined by using terephthaldehyde as internal standard.
Note 3: Other than in the reaction medium, we observed the deacylation process on silica gel
column also. Under the standard reaction condition, in some cases the complete mono
deacyalation of fluorinated compound was not occurred. Therefore, retaining of small amount
of non deacylated compounds i.e., α,αꢀfluoro sulfenyl βꢀdiketones was observed after the
work up (found by 1H and F NMR). However, such non deacylated fluorinated compounds
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(2 or 5) underwent deacylation on silica gel column during purification to give additional
amount of expected product. As we observed, the α,αꢀfluoro sulfenyl βꢀdiketones containing
hetero aryl sulfenyl moity showed the high propensity to undergo deacylation. In these cases,
irrespective of ratio of deacylated and non deacylated products obtained from the reaction
media, the complete mono deacylated compounds were obtained after silica gel column
chromatography. However, α,αꢀfluoro sulfenyl βꢀdiketones containing aryl sulfenyl moity
showed less propensity to undergo deacylation on silica gel column.
Note 4: As silica gel also influenced the deacylation process, 100ꢀ200 mesh sized silica gel
columns with fixed size of 5 x 20 cm2 was preferred for purification of all the crude
compounds.
(iii) Typical experimental procedure for the synthesis of 1-fluoro-1-
(phenylsulfonyl)propan-2-one (7a) 4d, 9c
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To a wellꢀstirred, solution of 1ꢀfluoroꢀ1ꢀ(phenylthio)propanꢀ2ꢀone (6a, 0.5 mmol) in CH2Cl2
(5 mL) was added mꢀCPBA (55ꢀ70%, 4 equiv) at room temperature and the reaction mixture
was stirred at room temperature for 6 h. Then, the saturated aqueous sodium sulfite solution
was added to the reaction mixture and stirring was continued at room temperature for further
2 h. The crude compound was extracted into CH2Cl2 (10 mL x 3) and dried over anhydrous
Na2SO4. The crude compound in CH2Cl2 was then adsorbed on silica gel (100ꢀ200 mesh size)
and purified on silica gel (100ꢀ200 mesh size) column by using EtOAc/Petroleum ether
(20:80ꢀ40:60) as eluent to obtain the 1ꢀfluoroꢀ1ꢀ(phenylsulfonyl)propanꢀ2ꢀone (7a) in 96%
(104 mg) yield.
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(iv) Typical experimental procedure for the synthesis of 3-fluoro-3-(phenylthio)hex-5-
en-2-one (8a)
To a wellꢀstirred, heterogeneous mixture of 1ꢀfluoroꢀ1ꢀ(phenylthio)propanꢀ2ꢀone (6a, 0.5
mmol) and anhydrous K2CO3 (4.0 equiv) in CH3CN (4 mL) was added allyl bromide (6
equiv) at room temperature and the reaction mixture was refluxed for 24 h. Then, the crude
compound was filtered through sintered funnel and the residue was washed with EtoAc (5
mL). The filtrate was then adsorbed on silica gel (100ꢀ200 mesh size) and purified on silica
gel (100ꢀ200 mesh size) column by using EtOAc/Petroleum ether (0:100 – 2:98) as the eluent
to obtain the allylated product 8a in 72% (81 mg) yield.
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Note 5: The H NMR of the crude compound showed the presence of only allylated product
8a.
(v) Typical experimental procedure for the synthesis of 3-fluoro-4-phenyl-3-
(phenylthio)butan-2-one (8b)
To a wellꢀstirred, heterogeneous mixture of 1ꢀfluoroꢀ1ꢀ(phenylthio)propanꢀ2ꢀone (6a, 0.5
mmol) and anhydrous K2CO3 (4.0 equiv) in CH3CN (4 mL) was added benzyl bromide (2
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equiv) at room temperature and the reaction mixture was refluxed for 24 h. Then, the crude
compound was filtered through sintered funnel and the residue was washed with EtOAc (5
mL). The filtrate was then adsorbed on silica gel (100ꢀ200 mesh size) and purified on silica
gel (100ꢀ200 mesh size) column by using EtOAc/Petroleum ether (0:100 – 2:98) as the eluent
to obtain the benzylated product 8b in 81% (112mg) yield.
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Note 6: The H NMR of the crude compound showed the presence of only the benzylated
product 8b.
(vi) Typical experimental procedure for the synthesis of 3-fluoro-3-(phenylsulfonyl)hex-
5-en-2-one (9a) 4d, 9c
To a wellꢀstirred, solution of 1ꢀfluoroꢀ1ꢀ(phenylthio)propanꢀ2ꢀone (8a, 0.36 mmol) in CH2Cl2
(5 mL) was added mCPBA (55ꢀ70%, 4 equiv) at room temperature and the reaction mixture
was stirred at room temperature for 6 h. Then, the saturated aqueous sodium sulfite solution
was added to the reaction mixture and stirring was continued at room temperature for further
2 h. The crude compound was extracted into CH2Cl2 (10 mL x 3) and dried over anhydrous
Na2SO4. The crude compound in CH2Cl2 was then adsorbed on silica gel (100ꢀ200 mesh size)
and purified on silica gel (100ꢀ200 mesh size) column flash chromatography by using
EtOAc/Petroleum ether (20:80ꢀ40:60) as eluent to obtain the αꢀfluoroꢀβꢀketosulfone 9a in
73% yield.
(vii) Typical experimental procedure for the synthesis of 3-fluoro-4-phenyl-3-
(phenylsulfonyl)butan-2-one (9b) 4d, 9c
To a wellꢀstirred, solution of 1ꢀfluoroꢀ1ꢀ(phenylthio)propanꢀ2ꢀone (8b, 0.4 mmol) in CH2Cl2
(5 mL) was added mCPBA (55ꢀ70%, 4 equiv) at room temperature and the reaction mixture
was stirred at room temperature for 6 h. Then, the saturated aqueous sodium sulfite solution
was added to the reaction mixture and stirring was continued at room temperature for further
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2 h. The crude compound was extracted into CH2Cl2 (10 mL x 3) and dried over anhydrous
Na2SO4. The crude compound in CH2Cl2 was then adsorbed on silica gel (100ꢀ200 mesh size)
and purified on silica gel (100ꢀ200 mesh size) column flash chromatography by using
EtOAc/Petroleum ether (20:80ꢀ40:60) as eluent to obtain the αꢀfluoroꢀβꢀketosulfone 9b in
68% yield.
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Note 7: For synthesis of sulfones mCPBA was dried under reduced pressure (4ꢀ5 h) before
using in the reaction
(viii) Typical experimental procedure for the synthesis of 3-benzyl-3-fluoropentane-2,4-
dione (11a)
To a wellꢀstirred, solution of 3ꢀbenzylpentaneꢀ2,4ꢀdione (7a, 0.25 mmol) in CH3CN (1.5 mL)
was added anhydrous Cs2CO3 (1.2 equiv). The reaction mixture was stirred at room
temperature, until it turned into a white turbid heterogeneous reaction mixture (4ꢀ5 h). The
round bottom flask was then placed under the ice bath and NFSI (1.1 equiv) was added
slowly to the cold reaction mixture. After 5 minutes of complete addition of NFSI, the ice
bath was removed and stirring was continued at room temperature for 8 h. Then, the crude
compound was filtered through sintered funnel and the residue was washed with EtOAc (5
mL x 2). The filtrate was then adsorbed on silica gel (100ꢀ200 mesh size) and purified on
silica gel (100ꢀ200 mesh size) column by using EtOAc/Petroleum ether (2:98ꢀ5:95) as the
eluent to obtain only the non deacylated product 11a in 42%.
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Note 8: The H NMR and F NMR (single peak) of the crude compound showed only the
presence of 11a.
(ix) Potassium or Cesium salt of Benzene sulfonamide (13a or 13b): The residue obtained
after filtration of the crude reaction mixture of the fluorinative deacylation reaction of 1 or 4
under the respective optimized reaction conditions.
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(C) Experimental data for starting materials
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(E)-3-(Ethylthio)-4-hydroxypent-3-en-2-one (1p):13 colourless liquid; Yield–66% (1.06 g);
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Rf (5% EtoAc/Pet ether) 0.6; IR (Neat, cmꢀ1): 1587, 1407, 1259, 1014; H NMR (400 MHz,
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CDCl3): δ (ppm) 15.40 (brs, 1H), 2.54 (q, J = 7.2 Hz, 2H), 2.43 (s, 6H), 1.22 (t, J = 7.4 Hz,
3H); 13C NMR (100 MHz, CDCl3): δ (ppm) 197.5, 104.0, 30.4, 24.5, 14.1; ESI-HRMS
(m/z): Calculated for C7H12O2SNa (M + Na): 183.0456, found (M + Na): 183.0453.
(E)-4-Hydroxy-3-(isopropylthio)pent-3-en-2-one (1q):13 Yellow liquid; Yield–24% (417
mg); Rf (5% EtoAc/Pet ether) 0.6; IR (Neat, cmꢀ1): 2360, 2335, 1628, 1446, 1180, 1128,
1
1
1020; H NMR (400 MHz, CDCl3): δ (ppm) H NMR (400 MHz, CDCl3): δ (ppm) 2.86
(septet, J = 6.8 Hz, 1H), 2.42 (s, 6H), 1.22 (d, J = 2.8 Hz, 6H); 13C NMR (100 MHz, CDCl3):
δ (ppm) 197.9, 104.2, 39.6, 24.7, 24.6; ESI-HRMS (m/z): Calculated for C8H14O2SNa (M +
Na): 197.0612, found (M + Na): 197.0614.
13,14,15
(E)-4-Hydroxy-3-(phenylthio)pent-3-en-2-one (4a):
Yellow liquid; Yield–82% (1.7
1
g); Rf (Pet ether) 0.2; IR (Neat, cmꢀ1): 1582, 1477, 1404, 1255, 1081, 1018, 909; H NMR
(400 MHz, CDCl3): δ (ppm) 17.26 (brs, 1H), 7.29ꢀ7.25 (m, 2H), 7.13ꢀ7.08 (m, 3H), 2.35 (s,
13
6H); C NMR (100 MHz, CDCl3): δ (ppm) 198.3, 137.7, 129.2, 125.2, 124.6, 101.5, 24.3.
ESI-HRMS (m/z): Calculated for C11H12O2SNa (M + Na): 231.0456, found (M + Na):
231.0459.
(E)-4-Hydroxy-3-(o-tolylthio)pent-3-en-2-one (4b): White solid; Yield–80% (1.78 g); mp –
ᵒ
67ꢀ69 C Rf (Pet ether) 0.25; IR (KBr, cmꢀ1): 1573, 1458, 1386, 1255, 1044, 1003, 748; 1H
NMR (400 MHz, CDCl3): δ (ppm) 7.15ꢀ7.10 (m, 2H), 7.06ꢀ7.02 (m, 1H), 6.83 (d, J = 7.6 Hz,
13
1 H), 2.38 (s, 3H), 2.30 (s, 6H); C NMR (100 MHz, CDCl3): δ (ppm) 198.3, 136.5, 134.3,
130.3, 126.7, 124.7, 122.7, 100.7, 24.2, 19.6; ESI-HRMS (m/z): Calculated for C12H14O2SNa
(M + Na): 245.0612, found (M + Na): 245.0611.
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(E)-4-Hydroxy-3-(p-tolylthio)pent-3-en-2-one (4c):14,15 Low melting Yellow crystalline
solid; Yield–82% (1.82 g); Rf (Pet ether) 0.25; IR (Neat, cmꢀ1): 1729, 1674, 1589, 1492,
1413, 1376, 1252, 1014; 1H NMR (400 MHz, CDCl3): δ (ppm) 7.09 (d, J = 7.2 Hz, 2H), 6.99
(dd, J1 = 7.2 Hz, J2 = 1.6 Hz, 2H), 2.34 (s, 6 H), 2.30 (s, 3H); 13C NMR (100 MHz, CDCl3):
δ (ppm) 198.2, 135.1, 134.2, 129.9, 124.9, 102.1, 24.4, 20.8; ESI-HRMS (m/z): Calculated
for C12H14O2SNa (M + Na): 245.0612, found (M + Na): 245.0609.
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(E)-4-Hydroxy-3-((4-methoxyphenyl)thio)pent-3-en-2-one (4d):14,15 White crystalline
ᵒ
solid; mp – 87ꢀ89 C; Yield–72% (1.71 g); Rf (Pet ether) 0.3; IR (Neat, cmꢀ1): 1576, 1490,
1
1403, 1290, 1241, 1173, 1024; H NMR (400 MHz, CDCl3): δ (ppm) 7.04 (d, J = 9.2 Hz, 2
13
H), 6.84 (d, J = 8.8 Hz, 2 H), 3.78 (s, 3 H), 2.36 (S, 6H); C NMR (100 MHz, CDCl3): δ
(ppm) 198.0, 157.9, 128.4, 126.9, 114.9, 103.0, 55.4, 24.4; ESI-HRMS (m/z): Calculated for
C12H14O3SNa (M + Na): 261.0561, found (M + Na): 261.0562.
(E)-3-((2-Fluorophenyl)thio)-4-hydroxypent-3-en-2-one (4e): Pale Yellow crystalline
ᵒ
solid; mp – 54ꢀ56 C; Yield–70% (1.58 g); Rf (Pet ether) 0.2; IR (KBr, cmꢀ1): 1585, 1544,
1
1394, 1343, 1265, 1194, 1133, 1057, 1012, 909, 850, 811; H NMR (400 MHz, CDCl3): δ
(ppm) 7.16ꢀ7.11 (m, 1 H), 7.09ꢀ7.03 (m, 2 H), 6.93 (t, J = 8.0 Hz, 1H), 6.96 (d, J = 7.6 Hz,
1H), 2.34 (s, 6 H); 13C NMR (100 MHz, CDCl3): δ (ppm) 198.4, 159.3 (d, 1J (CF) = 242 Hz),
3
4
2
126.82 (d, J (CF) = 8 Hz), 126.13 (d, J (CF) = 1 Hz), 124.91 (d, J (CF) = 16 Hz), 124.75
(d, 3J (CF) = 4 Hz), 115.69 (d, 2J (CF) = 21 Hz), 99.7, 24.3; 19F NMR (377 MHz, CDCl3): δ
(ppm) ꢀ113.5; ESI-HRMS (m/z): Calculated for C11H11O2FSNa (M + Na): 249.0361, found
(M + Na): 249.0364.
(E)-3-((3-Chlorophenyl)thio)-4-hydroxypent-3-en-2-one (4f): Yellow liquid; Yield–78%
(1.89 g); Rf (Pet ether) 0.2; IR (Neat, cmꢀ1): 1573, 1460, 1403, 1256, 1113, 1073, 1016, 910;
1H NMR (400 MHz, CDCl3): δ (ppm) 7.20 (t, J = 8.0 Hz, 1H), 7.10 (d, J = 8.0 Hz, 1H), 7.04
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(s, 1 H), 6.96 (d, J = 8.0 Hz, 1H), 2.33 (s, 6 H); 13C NMR (100 MHz, CDCl3): δ (ppm) 198.3,
140.0, 135.3, 130.2, 125.4, 124.3, 122.6, 101.8, 24.3; ESI-HRMS (m/z): Calculated for
C11H11O2SClNa (M + Na): 265.0066, found (M + Na): 265.0064.
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(E)-3-((4-Chlorophenyl)thio)-4-hydroxypent-3-en-2-one (4g):15 White solid; Yield–83%
1
(2.0 g); Rf (Pet ether) 0.25; IR (KBr, cmꢀ1): 1554, 1466, 1385, 1087, 1001, 907; H NMR
(400 MHz, CDCl3): δ (ppm) 17.27 (brs, 1H), 7.47 (d, J = 8.8 Hz, 2H), 7.17 (d, J = 8.8 Hz,
13
2H), 2.32 (s, 6H); C NMR (100 MHz, CDCl3): δ (ppm) 198.3, 136.4, 131.1, 129.3, 125.9,
101.3, 24.3; ESI-HRMS (m/z): Calculated for C11H11O2SClNa (M + Na): 265.0066, found
(M + Na): 265.0065.
(E)-3-((4-Bromophenyl)thio)-4-hydroxypent-3-en-2-one (4h):14,15 White crystalline solid;
Yield–87% (2.5 g); Rf (Pet ether) 0.25; IR (KBr, cmꢀ1): 1548, 1465, 1379, 1244, 1079, 997,
1
905, 803; H NMR (400 MHz, CDCl3): δ (ppm) 7.39 (d, J = 8.4 Hz, 2H), 6.96 (dd, J1 = 8.8
13
Hz, J2 = 2.0 Hz, 2H), 2.32 (s, 6 H); C NMR (100 MHz, CDCl3): δ (ppm) 198.2, 137.0,
132.1, 126.1, 118.7, 101.1, 24.3; ESI-HRMS (m/z): Calculated for C11H11O2SBrNa (M +
Na): 308.9561, found (M + Na): 308.9562, (M +2 + Na): 310.9602.
(E)-4-Hydroxy-3-(naphthalen-1-ylthio)pent-3-en-2-one (4i): White solid; Yield–75% (1.93
ᵒ
g); mp – 92ꢀ94 C; Rf (Pet ether) 0.25; IR (KBr, cmꢀ1): 1538, 1496, 1393, 1265, 1058, 1012,
905, 850, 810, 744; 1H NMR (400 MHz, CDCl3): δ (ppm) 7.75 (m, 2H), 7.70 (d, J = 8.0 Hz,
13
1H), 7.48ꢀ7.39 (m, 3 H) 7.26ꢀ7.24 (m, 1H), 2.37 (s, 3H); C NMR (100 MHz, CDCl3): δ
(ppm) 198.4, 135.3, 133.9, 131.5, 128.9, 127.8, 126.8, 125.4, 123.6, 121.8, 101.5, 24.4; ESI-
HRMS (m/z): Calculated for C15H14O2SNa (M + Na): 281.0612, found (M + Na): 281.0612.
(E)-4-Hydroxy-3-(phenylthio)pent-3-en-2-one (4j):13 Brown liquid; Yield–40% (896 mg);
Rf (5% EtOAc/Pet ether) 0.5; IR (Neat, cmꢀ1): 1633, 1589, 1441, 1338, 1254, 1070; 1H NMR
(400 MHz, CDCl3): δ (ppm) 13.80 (brs, 1H), 7.27ꢀ7.24 (m, 2H), 7.13ꢀ7.09 (m, 3H), 3.76 (s,
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3H), 2.34 (s, 3H); C NMR (100 MHz, CDCl3): δ (ppm) 185.2, 173.4, 137.8, 132.5, 128.9,
125.1, 125.0, 91.5, 52.7, 20.9; ESI-HRMS (m/z): Calculated for C11H12O3SNa (M + Na):
247.0405, found (M + Na): 247.0403.
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(D)Experimental data for the products (3a-3n)
1-Fluoro-1-((5-methylbenzo[d]oxazol-2-yl)thio)propan-2-one (3a): Colorless liquid;
Yield–96% (57 mg); Rf (5% EtOAc/hexane) 0.25; IR (Neat, cmꢀ1): 1738, 1508, 1479, 1423,
1
1359, 1256, 1220, 1151, 1104, 1030; H NMR (400 MHz, CDCl3): δ (ppm) 7.45 (s, 1H),
7.35 (d, J = 8.4 Hz, 1H), 7.11 (d, J = 8.0 Hz, 1H), 6.78 (d, 2J (CHꢀF) = 50.4 Hz, 1H), 2.49 (d,
13
2
4J (CH3ꢀF) = 3.2 Hz, 3H), 2.45 (s, 3H); C NMR (100 MHz, CDCl3): δ (ppm) 198.9 (d, J
1
(CF) = 25.0 Hz), 158.9, 150.4, 141.4, 134.7, 126.0, 119.2, 109.6, 97.1 (d, J (CF) = 238.0
Hz), 26.3, 21.4; 19F NMR (377 MHz, CDCl3): δ (ppm) ꢀ162.3; Calculated for
C11H10NO2SFNa (M + Na): 262.0310, found (M + Na): 262.0315.
1-Fluoro-1-((6-methylbenzo[d]oxazol-2-yl)thio)propan-2-one (3b): White Solid; Yield–
92% (55 mg); Rf (5% EtOAc/hexane) 0.25; IR (KBr, cmꢀ1): 1698, 1627, 1527, 1422, 1332,
1214; 1H NMR (400 MHz, CDCl3): δ (ppm) 7.51 (d, J = 8.1 Hz, 1H), 7.29 (s, 1H), 7.14 (d, J
2
4
= 8.2 Hz, 1H), 6.77 (d, J (CHꢀF) = 50.5 Hz, 1H), 2.484 (d, J (CH3ꢀF) = 3.2 Hz, 3H), 2.47
13
2
(s, 3H); C NMR (100 MHz, CDCl3): δ (ppm) 199.4 (d, J (CF) = 25.4 Hz), 158.2, 152.5,
1
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139.2, 135.5, 126.0, 118.6, 110.5, 97.1 (d, J (CF) = 238.3 Hz), 26.3, 21.7; F NMR (377
MHz, CDCl3): δ (ppm) ꢀ162.2; HRESI-MS (m/z): Calculated for C11H10NO2SFNa (M +
Na): 262.0314, found (M + Na): 262.0312.
1-((5,7-Dimethylbenzo[d]oxazol-2-yl)thio)-1-fluoropropan-2-one (3c): white solid paste;
Yield–89% (56 mg); Rf (5% EtOAc/hexane) 0.1; IR (KBr, cmꢀ1): 2924, 1732, 1633, 1511,
1
1151, 1116, 1018; H NMR (400 MHz, CDCl3): δ (ppm) 7.25 (s, 1H), 6.92 (s, 1H), 6.78 (d,
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2J (CHꢀF) = 50.4 Hz, 1H), 2.486 (d, 4J (CH3ꢀF) = 3.2 Hz, 3H), 2.44 (s, 3H), 2.41 (s, 3H); 13C
5
6
2
NMR (100 MHz, CDCl3): δ (ppm) 198.9 (d, J (CF) = 26.0 Hz), 158.5, 149.8, 141.1, 134.6,
7
8
9
1
127.2, 120.2, 116.5, 97.1 (d, J (CF) = 238 Hz), 26.3, 21.3, 14.9; 19F NMR (377 MHz,
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CDCl3): δ (ppm) ꢀ162.3; HRESI-MS (m/z): Calculated for C12H12NO2SFNa (M + Na):
276.0470, found (M + Na): 276.0468.
1-Fluoro-1-((5-phenylbenzo[d]oxazol-2-yl)thio)propan-2-one (3d): pale yellow gummy
solid; Yield–80% (60 mg); Rf (5% EtOAc/hexane) 0.2; IR (Neat, cmꢀ1): 1737, 1507, 1466,
1
1419, 1359, 1258, 1141, 1105, 1023; H NMR (400 MHz, CDCl3): δ (ppm) 7.83 (s, 1H),
2
7.58 (d, J= 7.6 Hz, 2H), 7.52 (s, 2H), 7.45 (t, J = 7.4 Hz, 2H), 7.38ꢀ7.34 (m, 1H), 6.81 (d, J
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13
(CHꢀF) = 50 Hz, 1H), 2.503 (d, J (CH3ꢀF) = 3.2 Hz, 3H); C NMR (100 MHz, CDCl3): δ
(ppm) 198.8 (d, 2J (CF) = 25.0 Hz), 159.8, 151.6, 141.9, 140.6, 138.7, 128.8, 127.4 (2 peaks),
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124.4, 117.6, 110.2, 97.1 (d, J (CF) = 238.0 Hz), 26.3; F NMR (377 MHz, CDCl3): δ
(ppm) ꢀ162.3; HRESI-MS (m/z): Calculated for C16H12NO2FSNa (M + Na): 324.0471, found
(M + Na): 324.0481.
1-Fluoro-1-(naphtho[1,2-d]oxazol-2-ylthio)propan-2-one (3e) : Yellow liquid; Yield–93%
(60 mg); Rf (5% EtOAc/hexane) 0.2; IR (Neat, cmꢀ1): 1737, 1499, 1374, 1190, 1139, 1028;
1H NMR (400 MHz, CDCl3): δ (ppm) 8.42 (d, J = 8.2 Hz, 1H), 7. 94 (d, J = 8.2 Hz, 1H),
7.76 (d, J = 8.9 Hz, 1H), 7.67ꢀ7.62 (m, 2H), 7.54 (dd, J1 = J2 = 8.0 Hz, 1H), 6.77 (d, 2J (CHꢀ
4
13
F) = 52.0 Hz, 1H), 2.544 (d, J (CH3ꢀF) = 3.4 Hz, 3H); C NMR (100 MHz, CDCl3): δ
(ppm) 199.0 (d, 2J (CF) = 25.0 Hz), 156.94 (d, 3J (CF) = 2.0 Hz), 149.8, 137.0, 131.1, 128.5,
127.2, 126.0, 125.71, 125.69, 122.1, 110.3, 97.3 (d, 1J (CF) = 239.0 Hz), 26.3; 19F NMR (377
MHz, CDCl3): δ (ppm) ꢀ162.1; HRESI-MS (m/z): Calculated for C14H10NO2FSNa (M + Na):
298.0316, found (M + Na): 298.0318.
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1-Fluoro-1-((5-fluorobenzo[d]oxazol-2-yl)thio)propan-2-one (3f): white gummy solid;
Yield–69% (42 mg); Rf (5% EtOAc/hexane) 0.1; IR (KBr, cmꢀ1): 1726, 1471, 1433, 1362,
1330, 1238, 1127, 1045, 951; 1H NMR (400 MHz, CDCl3): δ (ppm) 7. 42 (dd, J1 = 9.0 Hz, J2
= 4.4 Hz, 1H), 7.33 (d, J = 8.0 Hz, 1H), 7.04 (ddd, J1 = J2 = 9.0 Hz, J3 = 2.0 Hz, 1H), 6.79 (d,
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4
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2J (CHꢀF) = 50.0 Hz, 1H), 2.505 (d, J (CH3ꢀF) = 3.2 Hz, 3H), 2.45 (s, 3H); C NMR (100
2
1
MHz, CDCl3): δ (ppm) 198.8 (d, J (CF) = 25.0 Hz), 161.3 160.1 (d, J (CF) = 233.0 Hz),
148.5, 142.1 (d, J (CF) = 14.0 Hz), 112.46 (d, J (CF) = 26.0 Hz), 110.57 (d, 3J (CF) = 11.0
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2
Hz), 105.87 (d, J (CF) = 26.0 Hz), 97.0 (1J (CF) = 239.0 Hz), 26.3; F NMR (377 MHz,
CDCl3): δ (ppm) ꢀ117.0, ꢀ162.5; HRESI-MS (m/z): Calculated for C10H7NO2F2SNa (M +
Na): 266.0063, found (M + Na): 266.0063.
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1-((5-Chloro-7-methylbenzo[d]oxazol-2-yl)thio)-1-fluoropropan-2-one (3g): pale yellow
liqid; Yield – 44% (30 mg); Rf (20% EtOAc/hexane) 0.2; IR (Neat, cmꢀ1): 1737, 1503, 1464,
1
1220, 1130, 1020; H NMR (400 MHz, CDCl3): δ (ppm) 7.45 (s, 1H), 7.11 (s, 1H), 6.77 (d,
2J (CHꢀF) = 50.4 Hz, 1H), 2.509 (d, 4J (CH3ꢀF) = 3.6 Hz, 3H), 2.47 (s, 3H), 2.41 (s, 3H); 13C
2
NMR (100 MHz, CDCl3): δ (ppm) 198.9 (d, J (CF) = 26.0 Hz), 160.5, 150.1, 141.7, 130.1,
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126.1, 122.0, 116.5, 97.0 (d, J (CF) = 239 Hz), 26.4, 14.9; F NMR (377 MHz, CDCl3): δ
(ppm) ꢀ162.9; HRESI-MS (m/z): Calculated for C11H9NO2FSClNa (M + Na): 295.9924,
found (M + Na): 295.9925.
1-(Benzo[d]oxazol-2-ylthio)-1-fluoropropan-2-one (3h); Colorless liquid; Yield–98% (56
mg); Rf (5% EtOAc/hexane) 0.2; IR (Neat, cmꢀ1): 1778, 1735, 1509, 1481, 1452, 1359, 1135;
1H NMR (400 MHz, CDCl3): δ (ppm) 7.66 (dd, J1 = 6.0 Hz, J2 = 2.4 Hz, 1H), 7.49 (dd, J1 =
2
5.8 Hz, J2 = 2.0 Hz, 1H), 7.34 (m, 2H), 7.11 (d, J = 8.0 Hz, 1H), 6.80 (d, J (CHꢀF) = 50.4
Hz, 1H), 2.504 (d, 4J (CH3ꢀF) = 3.2 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ (ppm) 198.9 (d,
2J (CF) = 26.0 Hz), 159.2, 152.1, 141.3, 124.9, 124.8, 119.2, 110.3, 97.1 (d, J (CF) = 238.0
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