Trisubstituted Highly Activated Benzo[ d]thiazol-2-yl-sulfone-Containing Olefins as Building Blocks in Organic Synthesis

Article abstract of DOI:10.1021/acs.joc.0c00571

In this paper, we report the formation of highly electrophilic 1,1-deactivated olefins, their use as novel synthetic building blocks, and their transformation to structurally diverse molecular scaffolds. Synthesis of 1,1-deactivated olefins substituted with a BT-sulfonyl group and a carbonyl or nitrile, respectively, consists of unusual Ti(OPri)4-mediated Knoevenagel-type condensation and proceed in good to excellent yields. Generated olefins can be further transformed in a highly stereoselective manner and in good yields to various polyfunctionalized heterocycles and acyclic molecular scaffolds. Overall, the obtained structures are accessed in two to four steps starting from the (mostly) commercially available aldehydes. In addition, the presence of the BT-sulfonyl group in prepared structures allows for further chemoselective functionalization/post-synthetic transformations to provide structurally diverse final compounds.

Full text of DOI:10.1021/acs.joc.0c00571

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Article
Trisubstituted highly activated benzo[d]thiazol-2-yl-sulfone-
containing olefins as building blocks in organic synthesis
Ond#ej Ková#, František Zálešák, David J.-Y.D. Bon, Lukas
Roiser, Lubomír Vojt#ch Baar, Mario Waser, and Jiri Pospisil
J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 30 Apr 2020
Downloaded from pubs.acs.org on May 3, 2020
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The Journal of Organic Chemistry
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Trisubstituted highly activated benzo[d]thiazol-2-yl-sulfone-containing olefins as building blocks in
organic synthesis
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8
Ondřej Kováč,1 František Zálešák,1 David J.-Y. D. Bon,1 Lukas Roiser,2 Lubomír V. Baar,1 Mario Waser,2
and Jiří Pospíšil*1,3
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1 Department of Organic Chemistry, Faculty of Science, Palacky University, tř. 17. listopadu 1192/12,
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CZ-771 46 Olomouc, Czech Republic
2 Institute of Organic Chemistry, Johannes Kepler University Linz, Altenbergerstraße 69, 4040 Linz,
Austria
3 Laboratory of Growth Regulators, Palacky University & Institute of Experimental Botany AS CR,
Šlechtitelů 27, CZ-783 71 Olomouc, Czech Republic
e-mail: j.pospisil@upol.cz
O
OMe O
O
O
O
N
CH3
93%
HN
Ph
Ph
Ph
CH3
BTO2S
70%
N
OTBS
Ph
Ph
43%
85%
E/Z = >95:1
d.r. = 7:1
e.r. = 97:3
O
R
BTO2S
93%
O
EWG
R
SO2BT
EWG
BTO2S
Ti(OiPr)4 (2.0 equiv)
CH3CN, rt, 5h
O
R
= alkyl, aryl, heteroaryl
45 examples
37-95%
E/Z = >98:1
EWG
= ketone, ester, amide, nitrile
N
H3C
O
OEt
BT =
S
BTO2S
90%
Ph
Ph
O
Overall 2-4 steps,
30-80% yield,
and 13 different
OH
CH3
Ph
Ph
O
BTO2S
N
74%
molecular scaffolds
CH3
68%
S
80%
O
ABSTRACT: In this paper we report formation of highly electrophilic 1,1-diactivated olefins, their use
as novel synthetic building block, and their transformation to structurally diverse molecular scaffolds.
Synthesis of 1,1-diactivated olefins substituted with a BT-sulfonyl group and a carbonyl or nitrile,
respectively, consists of unusual Ti(OPri)4-mediated Knoveneagel-type condensation and proceed in
good to excellent yields. Generated olefins can be further transformed in highly stereoselective
manner and in good yield to various polyfunctionalized heterocycles and acyclic molecular scaffolds.
Overall, obtained structures are accessed in two to four steps starting from the (mostly) commercially
available aldehydes. In addition, the presence of the BT-sulfonyl group in prepared structures allows
for further chemoselective functionalization/post-synthetic transformations to provide structurally
diverse final compounds.
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Introduction
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Diversity-oriented synthesis (DOS) is a synthetic strategy of choice when a chemical library of small
organic molecules with a high degree of structural and functional variety have to be prepared.1–4 In
this strategy, rapid (3-5 steps) and efficient (high scaffold diversity) synthesis of structurally distinct
molecules is achieved using specially designed readily available building blocks. Such building blocks
are further transformed to structurally diverse frameworks.
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For some time, our group has been interested in the development of such building blocks.5,6 More
recently Michael-type acceptors, namely aryl vinyl sulfones, have attracted our attention. Indeed,
Michael-type additions to vinylic group of aryl vinyl sulfones have attracted, over the past two decades,
much attention of both the synthetic7–11 and medicinal12–14 community. At the same time, the use of
heteroaryl vinyl sulfones as powerful electrophilic substrates was somewhat limited. Only roughly a
dozen of seminal works (for selected examples see Scheme 1) focusing on the use of vinyl and/or 1,2-
disubstituted olefin-bearing heteroaryl sulfones were reported.15–22 Such olefins proved to be highly
superior in their reactivity in comparison to aryl vinyl sulfones and even to 1,1-diphenylvinylsulfones.16
We speculated that additional substitution with electron-withdrawing group on heteroaryl vinyl
sulfone should broader the synthetic utility of the vinyl sulfones (Figure 1). Newly generated Michael-
type adducts should not only be more reactive towards external nucleophiles and radicals but should
also react as substrates in cycloaddition reactions. In addition, the presence of heteroaryl sulfonyl
group in final adducts should allow further chemo selective transformations of obtained products.
In our group we have a long-standing experience with benzo[d]thiazol-2-yl-sulfone chemistry thus we
have designed the synthesis of sulfone 1 as a two-step protocol based on the Knoveneagel
condensation23 of aldehydes with readily available electron-withdrawing -substituted BT-sulfones
224,25,26 (Figure 2). Herewith we would like to present scope and limitations of such approach and
selected synthetic applications of prepared olefins 1.
intramolecular nucleophilic addition
- ref 19
Ph
PhCHO
OH
(3.3 equiv)
O
O
SO2PT
Ph
SO2PT
LiN(SiMe3)2
(0.3 equiv)
THF, 0°C
Ph
80%, d.r. = 90:10
intermolecular nucleophilic addition
- ref 20
O
O
cat.
(20 mol %)
SO2PT
Ph
SO2PT
+
H
H
p-NO2-C6H4CO2H
(20 mol %), CHCl3, RT
H3C Ph
CH3
76%, 94% e.e.
intermolecular radical reaction
- ref 15
PhSiH3
(1.5 equiv)
SO2Het
SO2Het
1.5 equiv
BnO
+
BnO
Fe(acac)3
(0.3 equiv)
EtOH, 60°C
Het = PT (74%), BT (72%)
OCH3
N
Ph
N
S
N
PT
=
BT
=
N
N
NH2
N
cat.
N
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Scheme 1. Selected examples of previous use of heteroaryl vinyl sulfones as substrates in
intramolecular, intermolecular and radical reactions.
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previous applications
9
or
Julia-Kocienski
olefination
R
R
R
R
R
SO2Het
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SO2Het
Michael-type
addition
further explorable as
our work
C-nucleophile in Tsuji-Trost
allylation, organocatalytic
additions etc
undergoes selective
desulfonylation
EWG
EWG
SO2BT
SO2BT
Y
intermolecular
Michael-type
addition
1
R
R
R
intramolecular
Michael-type
addition/Smiles
rearrangement
precursor to -amino acids
EWG
various heterocyclic scaffolds
N
S
O
inter and
O
OEt
BTO2S
O
O
intramolecular
cycloaddition
reactions
O
Ph
BTO2S
BTO2S
R
R
O
Het = BT, PT
EWG
Ph
S
N
= CN, COR, CO2R, CONR2
PT
=
N
BT
=
R = alkyl, aryl, heteroaryl
Z = R, OR, NR2
N
N
N
Figure 1. Comparison of previously exploited vinyl sulfones and our newly developed trisubstituted
vinyl sulfones 1.
O
BT-SO2
+
EWG
Na
Br
EWG
SO2BT
EWG
2
SO2BT
+
ref 24
R
H
ref 25,26
Knoevenagel
condensation
1
R
O
+
H3C SO2BT
S
Z
X
EWG
= CN, COR, CO2R, CONR2
R = alkyl, aryl, heteroaryl
Z = R, OR, NR2
BT
=
N
Figure 2. Retrosynthesis of trisubstituted vinyl sulfone 1.
Results and discussions
Reaction conditions optimization
Our approach to BT-sulfone 1 synthesis started with the condensation of BT-sulfone 2a and
benzaldehyde (for selected examples see Table 1). Surprisingly, the reaction proved to be more
challenging than expected and all our efforts to obtain the desired product 3a under the “classical”
Knoveneagel reaction conditions failed (Table 1, entry 1).27 In all cases, only the formation of olefin 4,
the product of Julia-Kocienski olefination,28 was observed.27 Interestingly when EDDA was used to
promote the condensation, product 3a was isolated in 26% yield (Table 1, entry 2). However further
optimization and studies demonstrated that olefin 3a is not stable under the reaction conditions and
undergoes under prolonged reaction times to retro Knoveneagel reaction.27 Observed olefin 3a
instability under basic conditions prompted us to attempt the Knoveneagel condensation under Lewis
acid catalysis (Table 1, entries 3-7). Gratifyingly it was observed that the use of Ti(OiPr)4 promotes the
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reaction yielding the desired BT-sulfone 3a not only as the only product of the reaction, but also as the
single E-izomer (Table 1, entry 3). Further reaction optimization revealed that the condensation
proceeds best when carried out in CH3CN at rt in the presence of 2.0 equiv. of Ti(OiPr)4 (Table 1, entry
6). The presence of two Ti(OiPr)4 equivalents proved to be crucial for the reaction to drive it to
completion. To shed some light on this intriguing observation we carried out some additional
experiments27 that led us to propose the dual role of Ti(OiPr)4 during the reaction; (a) it promotes
enolate formation, and (b) it works as a water molecule scavenger. The exclusive E-olefin formation
can be also attributed to the presence of bulky Lewis acid during the condensation step.27
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Table 1. Knoveneagel condensation of 1 with benzaldehyde: Reaction optimization.
O
O
SO2BT
O
Ph
O
+
SO2BT
Ph
Ph
2a
3a
4
Entry Conditions
3a/4 ratioa) Yieldb) of
3a (%)
1
Various “standard” Knoevenagel reaction
conditionsc)
<5:>95
n.d.
2
3
4
5
6
7
EDDA (10 mol%), DCE, reflux, 3h
Ti(O-iPr)4 (2.0 equiv), toluene, r.t., 5h
Ti(O-iPr)4 (1.0 equiv), CH3CN, r.t., 5h
Ti(O-iPr)4 (3.0 equiv), CH3CN, r.t., 5h
Ti(O-iPr)4 (2.0 equiv), CH3CN, r.t., 5h
Ti(O-iPr)4 (2.0 equiv), CH3CN, reflux, 5h
>95:<5
>95:<5
>95:<5
>95:<5
>95:<5
>95:<5
26%
70%
35%
52%
71%
52%
a) Based on the 1H NMR spectra of the crude reaction mixture. b) Isolated yields. c) For further details
see Supplementary Informations.
Scope and limitations of Knoveneagel condensation
Having determined the optimal reaction conditions, the reaction partners’ scope and limitations were
evaluated (Table 2). From the E/Z olefin stereochemistry viewpoint, the condensations proceed with
virtually exclusive E selectivity. The only exception was observed in case of the olefin 3s (prepared from
sulfone 2a and cinnamaldehyde) that was formed as a 7:1 E/Z mixture. From the substrate viewpoint
the influence of aldehyde coupling partner to reaction yield was first evaluated. It was observed that
aryl and heteroaryl aldehydes substituted with alkoxy and halogen substituents including sterically
crowded ortho-monosubstituted- or o,o’-disubstituted-ones are well tolerated. In contrary, strong
electron-withdrawing substituents on the aryl ring (NO2 and CF3) led to the (partial in case of CF3)
product degradation under the reaction conditions or during the reaction work up. Indeed, it seems
that the product of olefination 3f-h, 3v, 3ad, 5h, 6f-h are formed under the reaction conditions but
immediately undergo reaction with iPrOH (or another nucleophile) present in the media.29 Only in the
case of nitrile bearing condensation product 6f no degradation occurred and the product was isolated
in 93% yield.
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Table 2. Scope and limitations of the condensation reaction.
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N
S
EWG
R
R
SO2BT
O
BT =
EWG
BTO2S
Ti(OiPr)4 (2.0 equiv)
2
a)
CH3CN, rt, 5h
3,5,6
(E/Z = >98:1)
2a
2b
2c
2d
2e
2f
2g
2h
2j
, EWG = CO2tBu
, EWG = CONEt2
2l
, EWG = CN
, EWG = COCH3
, EWG = COCH2CH2CH=CH2
, EWG = COCH2CH2CH2Cl
, EWG = COtBu
, EWG = COPh
, EWG = CO2CH3
, EWG = CO2allyl
, EWG = CO2iPr
9
2k
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2i
, EWG = CO2(-)-menthyl
EWG = COCH3
O
O
O
SO2BT
SO2BT
SO2BT
Cl
3i
3j
, R2
(69%)
= iPr
, R2
, R2
R1
3lc)
(67%)
= allyl
(37%)
R2
3k
(72%)
= propargyl
Cl
3a
3b
3c
3d
3e
, R1
, R1
, R1
, R1
, R1
(71%)
(63%)
(61%)
(70%)
(71%)
= C6H5
O
O
= 4-MeO-C6H4
= 3-Me-OC6H4
= 4-Br-C6H4
= 4-Cl-C6H4
O
SO2BT
O
SO2BT
SO2BT
H3CO
H3CO
3fb)
, R1
, R1
, R1
3m
(73%)
OCH3
(<5%)
= 4-CF3-C6H4
= 4-NO2-C6H4
= 3-NO2-C6H4
Ph
3gb)
3hb)
(<5%)
(<5%)
O
(91%)
3n
3o
(81%, E/Z = 7:1)
EWG = COalkyl
O
O
O
3s
3t
3ve)
, R1
= C6H5
SO2BT
SO2BT
(90%)
, R1
SO2BT
(95%)
= 4-MeO-C6H4
, R1
R3
3qd)
3rd)
(<5%)
, R1
= 4-NO2-C6H4
= furan-2-yl
R1
3w
(87%)
, R3
(<5%)
, R3
= C6H5
= CH3
3x
, R1
(59%)
= cyclohexyl
3p
(56%)
(<5%)
O
O
EWG = COPh
SO2BT
3y
SO2BT
O
SO2BT
Cl
Ph
3zb)
(62%)
(<5%)
Ph
SO2BT
3af
Ph
R1
O
O
3aa
3ab
3ac
, R1
, R1
, R1
(58%)
(50%)
(67%)
= C6H5
Ph
SO2BT
= furan-2-yl
= 4-CF3-C6H4
Ph
(71%)
3ag
(39%, e.r. = 99:1)
3adb)
, R1
(<5%)
= 4-NO2-C6H4
= cyclohexyl
O
, R1
OTBS
3ae
(45%)
EWG = ester, amide
O
O
SO2BT
O
PriO
SO2BT
, R4
R4O
SO2BT
PriO
5j
(49%, e.r. = 99:1)
Ph
5ab,f)
5bb,f)
R1
OTBS
(<5%)
(<5%)
= CH3
, R4
O
5f
, R1
, R1
= allyl
(60%)
=furan-2-yl
= iPr
5c
, R4
, R4
(59%)
SO2BT
5g
5hb)
(36%)
= 4-CF3-C6H4
Et2N
5db,f)
5eb)
, R1
(<5%)
= (-)-menthyl
(<5%)
, R1
= 4-NO2-C6H4
= cyclohexyl
, R4
(<5%)
= t-butyl
5k
5i
(53%)
(55%)
Ph
EWG = nitrile
, R1
NC
R1
(88%)
(73%)
(71%)
SO2BT
6d
(76%)
= 4-Br-C6H4
NC
SO2BT
6e
6f
, R1
(67%)
, R1
= furan-2-yl
(93%)
= 4-CF3-C6H4
6j
(69%)
6gb)
6hb)
6i
, R1
6a
6b
6c
, R1
, R1
, R1
= C6H5
(<5%)
= 4-NO2-C6H4
= 3-NO2-C6H4
O
, R1
= 4-MeO-C6H4
= 3-MeO-C6H4
(<5%)
, R1
(88%)
= cyclohexyl
a) Based on the 1H NMR spectra of the crude reaction mixture. b) No traces of product observed. c) Reaction carried
out at 80 °C for 6h. d) Only olefin migration products 7a and 7b were isolated as the products of the reaction. e)
only the product of 1,4-addition of i-PrOH to 3v (compound 8a) were detected suggesting that trace amount of
the desired product was formed. Similar observations were made when 4-cyanobenzaldehyde and 3-
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f)
cyanobenzaldehyde were used as reaction substrates (not shown). Only product 5c was isolated in 58-61%
O
O
SO2BT
SO2BT
6
PriO
7
8
9
7a
7b
, R3
(49%, E/Z = >98:1)
, R3
= C6H5
= CH3
8a
R3
(31%, E/Z = 8:1)
NO2
yields.
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-Unbranched aldehydes represent the second limitation of the condensation reaction. In those cases
the products 7a and 7b, the products of the olefin migration, were isolated instead of expected
condensation products 3q and 3r.27 Gratifyingly, when -branched aldehydes were used, the desired
products 3p, 3x, 3ae, 3ag, 5i, 5j, and 6i were obtained in good to excellent yields. More importantly,
when -chiral aldehydes were used as the starting material, no stereo erosion was observed. When
ketones were used as the condensation partners (not showed), no product of condensation was
observed.
Next, the influence of the electron-withdrawing (EWG) group in 2 on the condensation was evaluated.
It was observed that the condensation of alkyl ketone bearing sulfone 2d is sensitive to the steric
hindrance in carbonyl proximity (sulfone 2d failed to yield adduct 3z); methyl and -unbranched
functionalized BT-sulfoketones 2a-c yielded the corresponding adducts 3a-y in good to excellent yields;
and arylketosulfone 2e yielded the products 3aa-ag in yields slightly lower to the corresponding alkyl
sulfones 2a-c. Ester, amide and nitrile bearing sulfones 2h,k, and 2l reacted under the condensation
conditions smoothly and yielded the corresponding adducts 5 and 6 in good to excellent yields and
exclusive E-selectivity. In case of esters, however, only i-propyl bearing ester adducts might be isolated
after the reaction, since rapid in situ transesterification process of ester sulfones 2f, 2g and 2i to the
sulfone 2h occurs during the condensation.27 In the case of t-butyl-bearing ester sulfone 2j, no traces
of transesterification was observed, however, no product of condensation either.
Applications of activated olefins in organic synthesis
Having desired activated olefins 3, 5 and 6 in hands, their reactivity in cycloadditions (Scheme 2),
Michael-type (Lewis acid-mediated) nucleophilic additions (Scheme 3 and 4), hydride reductions, and
radical reactions (Scheme 5) were evaluated. First, hetero-Diels-Alder cycloaddition reaction of
ketosulfones 3 with ethyl vinyl ether was investigated (Scheme 2, part A). It was observed that the
reaction proceeds well and yields the desired dihydropyran 9 in excellent yields. Similarly,
intramolecular hetero-Diels-Alder reaction of ketosulfone function to alkynes can be performed albeit
under harsher reaction conditions (W, 150°C, 200W) (Scheme 2, part B). Ketosulfones 3 can also react
with ammonium ylides to generate products of formal [4+1]-cycloaddition reaction in both racemic
(Scheme 2, part C) and enantioselective manner (Scheme 2, part D). In both cases the desired
dihydrofurans 12 are formed in very good to excellent yields and, in the case of nonracemic ammonium
ylides,30 enantioselectivity. Lastly, activated olefins 3a, 3p, 3ac and 5c were used as dipolarophiles in
1,3-cycloaddition reaction of sodium azide (Scheme 2, part E). In this case, products of [3+2]-
cycloaddition 14 undergoes to spontaneous in situ BTSO2-group elimination to provide solely
corresponding triazoles 15 in good to excellent yields. In the case of compound 15e the reaction was
chemoselective towards the activated olefin.
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Part A
: intermolecular hetero-Diels-Alder reaction
R1
O
OEt
O
OEt
(10 equiv)
BTO2S
R1
BTO2S
benzene, r.t.
12-24h
R2
R2
(R1 = CH3, R2 = Ph)
(90%, d.r.=1.1:1), R =CH3, R2 = Ph
1
9a
9b
3a
1
(70%, d.r.=1.1:1), R =CH2CH2CH=CH2
(R1 = CH2CH2CH=CH2, R2 = Ph)
(R1 = CH3, R2 = cyclohexyl)
3s
3p
R2 = Ph
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(72%, d.r.=1.1:1), R =CH3, R2 = cyclohexyl
1
9c
Part B
: intramolecular hetero-Diels-Alder reaction
O
O
N
O
S
S
N
O
S
ClCH2CH2Cl
S
O
O
150°C, 200W
O
3k
30 min, W
O
10
(93%)
Part C
: ammonium-ylide mediated formal (4+1)-cycloadition
O
O
Br
O
O
Et3N
BTO2S
R2
+
N
toluene, r.t., 4h
R2
3a
BTO2S
Ph
Ph
, R2 = CH3
, R2 = Ph
, R2 = OEt
12a
(98%, d.r. = >99:1), R2 = CH3
(70%, d.r. = 97:1), R2 = Ph
(88%, d.r. = >99:1), R2 = OEt
11a
11b
11c
12b
12c
Part D
: enantioselective ammonium-ylide mediated formal (4+1)-cycloadition
O
Cs2CO3
(2.0 equiv)
Br
O
O
O
BTO2S
3a
GrN
+
Ph
CH2Cl2, r.t.
Ph
BTO2S
13a-c
Ph
Ph
O
GrN =
12b
(70%, d.r. = >99:1, e.r. = 97:3)
O
H
13a
from
12b
from
12b
from
N
H
(71%, d.r. = >99:1, e.r. = 11:89)
13b
N
N
13b
OH
N
O
(68%, d.r. = >99:1, e.r. = 1:99)
HO
13c
13a
N
H
13c
N
OCH3
Part E
: (3+2)-cycloaddition reaction of azides
H
N
N
N
O
O
NaN3
(1.1 equiv)
N
NH
N
BTO2S
R1
R1
O
MeOH, r.t., 1h
O
R2
R2
BTO2S
R1
R2
14
15
O
O
O
O
15e
(93%)
N
N
N
Ph
H3C
N
N
CH3
CH3
OiPr
HN
HN
HN
NH
NH
N
N
N
N
N
Ph
(93%)
Ph
15b
(98%)
15d
(79%)
15c
(59%)
15a
F3C
O
Scheme 2. Cycloaddition reactions – attempted examples.
The reactivity of activated olefins towards nucleophiles under uncatalyzed (Scheme 3, part A) and
Lewis acid mediated (Scheme 3, part B, and Scheme 4) reaction conditions was also evaluated. It was
observed that simple treatment of olefins 3a and 3ag with methanol at rt under prolonged reaction
times results in the formation of 1,4-adducts 17, that can be further selectively desulfonylated31 to
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yield -methoxy ketones 16a and 16b (Scheme 3, part A). Interestingly, even under unoptimized
reaction conditions, the addition of methanol to homochiral olefin 3ag proceeds with high
diastereoselectivity.27 Similarly, olefins 3a and 6a were reacted with the Et3SiH and allylsilane in the
presence of TiCl4 (Scheme 3, part B). Rapid 1,4-addition followed by in situ desulfonylation31 then
yielded -adducts 19a-c in very good yield.
Part A
: uncatalysed addition of methanol
O
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16
17
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19
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OMe
O
OMe
O
MeO
1)
H, rt, 16h
BTO2S
CH3
Ph
CH3
SO2BT
17a
Ph
CH3
(92%)
2) Zn (5.0 equiv)
AcOH/THF = 1:2 (V/V)
rt, 12h
3a
16a
OMe
Ph
O
via
OMe
O
O
MeO
1)
H, rt, 16h
BTO2S
Ph
TBSO SO2BT
Ph
Ph
2) Zn (5.0 equiv)
AcOH/THF = 1:2 (V/V)
rt, 12h
OTBS
3ag
16b
17b
via
(43%, d.r. = 7:1)
OTBS
Part B
: Lewis acid-mediated nucleophile addition
H
1) Et3Si (3.0 equiv)
H
O
O
H
O
TiCl4 (3.0 equiv), CH2Cl2,
-78°C, 6h
2) Zn (5.0 equiv)
AcOH/THF = 1:2 (V/V)
rt, 12h
BTO2S
Ph
CH3
CH3
Ph
CH3
SO2BT
17c
16c
(87%)
3a
via
Ph
Me3Si
Ph
1)
(3.0 equiv)
TiCl4 (3.0 equiv), CH2Cl2,
-78°C, 6h
EWG
Ph
EWG
BTO2S
EWG
SO2BT
17d,e
2) Zn (5.0 equiv)
AcOH/THF = 1:2 (V/V)
rt, 12h
via
Ph
16d
16e
EWG
EWG
(74%),
(72%),
= COCH3
= CN
3a EWG
,
= COCH3
= CN
6a EWG
,
Scheme 3. Uncatalyzed and Lewis acid-mediated reactions of activated olefins 3a, 3ag and 6a.
Another interesting reaction was observed when olefin 3a was treated with TiCl4 at rt without any
additional additive (Scheme 4). In this case, an intramolecular Smiles-like rearrangement followed with
desulfonylation yielded -functionalized ketone 18.32
O
Ph
O
TiCl4 (2.1 equiv)
CH2Cl2, rt, 2h
BTO2S
N
CH3
CH3
S
3a
Ph
18
(68%)
O
proposed reaction mechanism
TiCl4
H3O
-SO2
TiCl2
TiCl3 Cl
O
O
S
O
O
S
Cl
N
S
N
O
O
S
Cl
Ph
Ph
TiCl3
TiCl3
O
S
O
O
Cl
Cl
S
O
O
S
S
O
N
N
Ph
Ph
Scheme 4. TiCl4-mediated rearrangement of 3a to ketone 18.
Since the Lewis acid-mediated Et3SiH addition proceeded with exclusive 1,4-addition, selectivity of 1,2-
vs. 1,4-hydride reduction was investigated (Scheme 5).27 It was observed that vast majority of standard
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reducing agents, to mention just a few (nBu3SnH33 or DIBAL-H in THF), favors 1,4-reduction products
17c,f (Scheme 5, part A). In contrary, the selective 1,2-hydride reduction could be performed if DIBAL-H
reduction was carried out in CH2Cl2 at -78°C under high (0.01M) dilution (Scheme 5, part B). Using such
conditions, the desired allylic alcohols 19a,c could be obtained in very good yields.27 Interestingly,
phenyl-substituted ketone 3aa do not undergo to 1,2-reduction under such conditions, and only 1,4-
adduct 17f is isolated.
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Finally, we have decided to evaluate the radicophilic behavior of activated olefins 3, 5 and 6. The
original hypothesis was that these newly generated olefins will behave similarly as vinyl BT sulfone
explored in the pioneering work of Baran et al (Fe(acac)3 promoted radical addition).15 However, quick
1,4-addition of EtOH to 3 excluded such possibility.34 Thus we have focused on classical Giese addition,
in which an electron-deficient alkene (our olefins) is attacked by a nucleophilic alkyl radical.35–38
Unfortunately, such conditions in general require a tin reagent. Since in our case nBu3SnH
spontaneously adds in a 1,4-manner to olefin 3a even at low temperature, tris(trimethylsilyl)silane
(TTMS) was used instead (Scheme 5, part C). Thus, olefins 3a, 5c, and 6a were reacted with the ethyl
radical generated in a TTMS/EtI/AIBN system. Surprisingly, only nitrile bearing olefin 6a yielded the
desired adduct 20, while carbonyl bearing olefins 3a and 5c gave unsaturated carbonyl compounds 4
and 21, respectively. Such observation suggests that in the case of carbonyl-substituted olefins, the
generated radical preferentially attacks the BT-sulfonyl group and, as suggested by the (E)-olefin 4 and
21 formation,39 generates a vinylic radical as a reaction intermediate.
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Part A
: 1,4-hydride reduction
5
6
7
8
H
nBu3Sn (1.1 equiv)
CH2Cl2, -78°C, 30 min
17c (91%), 17f (90%)
O
H
O
BTO2S
R1
Ph
R1
9
Ph
SO2BT
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1
H
DIBAL- (1.1 equiv)
3a
, R = CH3
1
17c
, R = CH3
THF, -78°C to rt, 1h
17c (85%), 17f (81%)
1
3aa
, R = Ph
1
17f
, R = Ph
Part B
: 1,2-hydride reduction
O
OH
H
H
DIBAL- (1.1 equiv)
BTO2S
BTO2S
R1
R1
CH2Cl2 (0.01M), -78°C
R2
R2
(80%), R = CH3, R = Ph
1
2
1
2
3a
19a
19b
19c
, R = CH3, R = Ph
1
2
1
2
3aa
, R = Ph, R = Ph
(<5%), R = Ph, R = Ph
1
2
1
2
3p
, R = CH3, R = cyclohexyl
(68%), R = CH3, R = cyclohexyl
Part C
: Ethyl radical addtions
TTMSS (1.5 equiv)
Et-I
BTO2S
CN
BTO2S
CN
Ph
(1.5 equiv)
6a
AIBN (20 mol%)
benzene, 80°C
Ph
O
20
(61%, d.r. = 1.2:1)
O
TTMSS (1.5 equiv)
BTO2S
R1
Et-I
(1.5 equiv)
Ph
R1
AIBN (20 mol%)
benzene, 80°C
Ph
1
4
(85%,E/Z = >95:1), R = CH3
1
3a
5c
, R = CH3
1
21
(82%,E/Z = >95:1), R = OiPr
1
, R = OiPr
Scheme 5. Selective hydride reductions and radical addition.
Conclusions
In conclusion, synthesis of highly electrophilic olefins that can be in one or two steps transformed into
valuable (enantio-enriched) heterocyclic and acyclic scaffolds has been developed. Prepared olefins
can be used as hetero-dienes, dienophiles and Michael-acceptors, respectively, and can be reacted in
various hetero-Diels-Alder, 1,3-dipolar, or formal [4+1]-cycloaddition reactions. Selective 1,2 and 1,4-
hydride addition, respectively, are possible in the case of carbonyl bearing olefins 3. Such olefins also
undergo Lewis acid-mediated 1,4-addition of allylsilanes or to unprecedented Smiles-like
rearrangement products. Finally, classical Giese 1,4-radical addition of nucleophilic ethyl radical was
observed in case of nitrile-bearing olefin 6a, but not in case of the two carbonyl-group bearing analogs
3a and 5c. The last two transformations (Smiles-like rearrangement and nucleophilic radical additions)
are currently being further investigated in our group.
Experimental section
General information. All starting materials were purchased from commercial suppliers and used
without further purification, unless otherwise stated. Chiral aldehydes,40 pyridium salts 11a-c,41 chiral
ammonium salts 13a-c,30,42 BT-sulfones 2d,43 2g,25,26 ()-2-menthyl 2-bromoacetate,44 and 2-
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(methylsulfonyl)benzo[d]thiazole25,26 were prepared using reported procedures. Progress of reactions
was monitored by thin-layer chromatography (TLC) - aluminum plates pre-coated with silica gel (silica
gel 60 F254). Column chromatography was performed on silica gel 60 (40-63 µm) or neutralized silica
gel (40-63 µm) using 5% solution of Et3N in petroleum ether. Reactions run at elevated temperatures
were carried out using the oil bath and indicated temperatures refers to the oil bath temperature.
Determination of melting points were done on a Büchi melting point apparatus and were uncorrected.
1H NMR and 13C{1H} NMR spectra were measured on Jeol ECA400II (400 and 101 MHz) or Jeol 500 ECA
(500 and 126 MHz) in CDCl3 or DMSO. Chemical shifts are reported in ppm and their calibration was
performed (a) in case of 1H NMR experiments on residual peak of non-deuterated solvent δ (CHCl3) =
7.26 ppm; δ (DMSO) = 2.50 ppm, (b) in case of C NMR experiments on the middle peak of the C
signal in deuterated solvent δ (CDCl3) = 77.2 ppm; δ (DMSO-d6) = 39.5 ppm, and (c) in case of 19F{1H}
NMR experiments on the external calibrant CFCl3 (δ (CFCl3) = 0 ppm). Proton coupling patterns are
represented as singlet (s), doublet (d), doublet of doublet (dd), triplet (t), triplet of triplet (tt) and
multiplet (m). HRMS data were obtained using quadrupole/ion trap mass analyzer. HPLC was
performed using a Dionex Summit HPLC system with a CHIRAL ART Cellulose-SB (250 x 4.6 mm, 5 μm)
or CHIRALPAK IE-3 chiral stationary phase with mobile phase 2-propanol/hexane, 2-propanol/CO2,
MeOH/CO2. HRMS analysis was performed using LC chromatograph (Dionex UltiMate 3000, Thermo
Fischer Scientific, MA, USA) + mass spectrometer Exactive Plus Orbitrap high-resolution (Thermo
Fischer Scientific, MA, USA) with electrospray ionization; Chromatographic separation: column
Phenomenex Gemini (C18, 50 x 2 mm, 3 µm particle), isocratic elution, MP: 80 % ACN and 20 % buffer
(0,01M ammonium acetate) or 95% MeOH + 5% water + 0.1% HCOOH. Microwave irradiation
experiments were carried out in a dedicated CEM-Discover mono-mode microwave apparatus. The
reactor was used in the standard configuration as delivered, including proprietary software. The
reactions were carried out in 30 mL glass vials sealed with an Silicone/PTFE Vial caps top, which can be
exposed to a maximum of 250 °C and 20 bar internal pressure. The temperature was measured with
an IR sensor on the outer surface of the process vial. After the irradiation period, the reaction vessel
was cooled to ambient temperature by gas jet cooling.
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13
Synthesis of α-electron withdrawing BT-sulfones (2). Method A.45 Synthesis of sulfide intermediate. A
mercaptobenzthiazole (10.0 g, 1.0 equiv) and α-halo compound (1.0 equiv) were dissolved in CH2Cl2
(0.2 M) and the mixture was cooled to 0°C. Triethylamine (8.6 mL, 2.0 equiv) was added dropwise and
resulting mixture was allowed warm to r.t. and stirred for 4 hours. 2 M aq. HCl (20 mL) was added and
the resulting layers were separated. The aqueous layer was extracted with CH2Cl2 (3x20mL) and the
resulting organic extracts were combined, washed with water (30 mL), brine (20 mL), dried over MgSO4
and solvents were evaporated under reduced pressure. Crude product was used in the next step
without further purification. Synthesis of targeted sulfone. Sulfide (1.1 g, 1.0 equiv) and periodic acid
(2.8 g, 3.0 equiv) were dissolved in acetonitrile (0.2 M) and mixture was cooled to 0°C. CrO3 (0.123 g,
0.3 equiv) was added portion wise and the resulting mixture stirred for 30 minutes, before it was
warmed to r.t. The reaction was stirred for another 4 hours before it was cooled to 0°C and quenched
by adding sat. aq. Na2SO3. Filtration over the Celite®, washed (5x25 mL EtOAc). Layers were separated,
and organic phase was washed with sat. Na2SO3 (2x20 mL), water (2x20mL), brine (2x20mL) and dried
over MgSO4. Solvents were removed under the reduced pressure. Method B.25 A solution of -
(methylsulfonyl)benzo[d]thiazole25,26 (0.300 g, 1.41 mmol, 1.0 equiv) in dry THF (7.0 mL, 0.2 M) was
cooled to -78°C and LiHMDS (1.0 M sol. in THF) (3.7 mL, 2.2 equiv) was added dropwise. A color of the
reaction mixture turned from colorless or slightly yellow to orange/red. Immediately after, a solution
of acyl halide (1.69 mmol, 1.2 equiv) in THF (3 mL) was added. The color of the reaction mixture faded
within few minutes. The resulting mixture was stirred at -78°C for 60 min, allowed to warm to r.t.
within 1h, and stirred at r.t. for additional 60 min before sat. aq. NH4Cl (15 mL) was added. The whole
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mixture was extracted with EtOAc (3x75 mL) and the combined organic layers were washed with brine
(50 mL), dried over MgSO4, filtered and the solvents were removed under reduced pressure. Resulting
crude product was used further without any purification, if not stated otherwise.
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8
9
1-(benzo[d]thiazol-2-ylsulfonyl)propan-2-one (2a). Crude product was prepared using the method A
and obtained with enough purity as yellow solid (4.2 g, 89%). M.p. = 125-127°C; H NMR (400 MHz,
1
Chloroform-d) δ 8.21 (dd, J = 7.6, 2.0 Hz, 1H), 8.03 – 7.99 (m, 1H), 7.67 – 7.57 (m, 2H), 4.57 (s, 2H), 2.45
(s, 3H); 13C{1H} NMR (101 MHz, Chloroform-d) δ 194.7, 164.9, 152.5, 137.0, 128.4, 127.9, 125.7, 122.5,
65.5, 31.6; MS (ESI), m/z (%) 256 [M+H]+ (100); HRMS (ESI) m/z: [M - H]- Calcd for C10H8NO3S2 253.9951;
Found 253.9950.
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22
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1-(benzo[d]thiazol-2-ylsulfonyl)hex-5-en-2-one (2b). Crude product was prepared using the method B
and purified using flash column chromatography (SiO2; EtOAc: P.E. = 1: 6), isolated as a yellow oil (1.4
g, 71%). 1H NMR (400 MHz, Chloroform-d) δ 8.24 – 8.19 (m, 1H), 8.05 – 8.00 (m, 1H), 7.67 – 7.58 (m,
2H), 5.81 – 5.70 (m, 1H), 5.08 – 4.95 (m, 2H), 4.59 (s, 2H), 2.85 (t, J = 7.2 Hz, 2H), 2.41 – 2.29 (m, 2H);
13C{1H} NMR (101 MHz, Chloroform-d) δ 196.4, 165.0, 152.5, 137.0, 136.0, 128.4, 127.9, 125.7, 122.5,
116.1, 64.7, 43.6, 27.1; MS (ESI), m/z (%) 294 [M-H]- (100); HRMS (ESI) m/z: [M + H]+ Calcd for
C13H14NO3S2 296.0410; Found 296.0407.
1-(benzo[d]thiazol-2-ylsulfonyl)-5-chloropentan-2-one (2c). Crude product was prepared using method
B and purified using flash column chromatography (SiO2; Diethylether: P.E. = 3: 1), isolated as an orange
oil (0.485 g, 82%). 1H NMR (400 MHz, Chloroform-d) δ 8.23 – 8.20 (m, 1H), 8.04 – 8.01 (m, 1H), 7.68 –
13
7.59 (m, 2H), 4.61 (s, 2H), 3.55 (t, J = 6.8 Hz, 2H), 2.96 (t, J = 6.8 Hz, 2H), 2.12 – 2.02 (m, 2H); C{1H}
NMR (101 MHz, Chloroform-d) δ 196.2, 164.9, 152.5, 137.0, 128.5, 128.0, 125.7, 122.6, 64.9, 43.8, 41.3,
26.0; MS (ESI), m/z (%) 282 [M-Cl]+ (100); HRMS (ESI) m/z: [M + H]+ Calcd for C12H13ClNO3S2 318.0020;
Found 318.0021.
2-(benzo[d]thiazol-2-ylsulfonyl)-1-phenylethan-1-one (2e). Crude product was prepared using the
1
method A and obtained with enough purity as a light brown solid (3.9 g, 92%). M.p. = 118-120°C; H
NMR (400 MHz, Chloroform-d) δ 8.21 – 8.18 (m, 1H), 8.02 – 7.99 (m, 1H), 7.95 – 7.90 (m, 2H), 7.66 –
7.57 (m, 3H), 7.50 – 7.44 (m, 2H), 5.20 (s, 2H); 13C{1H} NMR (101 MHz, Chloroform-d) δ 187.3, 165.4,
152.6, 137.2, 135.6, 134.8, 129.1, 129.1, 128.3, 127.8, 125.7, 122.5, 61.3; MS (ESI), m/z (%) 318 [M+H]+
(100); HRMS (ESI) m/z: [M + H]+ Calcd for C15H12NO3S2 318.0253; Found 318.0251.
methyl 2-(benzo[d]thiazol-2-ylsulfonyl)acetate (2f). Crude product was prepared using the method A
and obtained as a yellow solid (2.8 g, 88%). M.p. = 68-70°C; 1H NMR (400 MHz, Chloroform-d) δ 8.24 –
8.21 (m, 1H), 8.04 – 8.01 (m, 1H), 7.68 – 7.59 (m, 2H), 4.58 (s, 2H), 3.74 (s, 3H); 13C{1H} NMR (101 MHz,
Chloroform-d) δ 165.0, 162.3, 152.6, 137.1, 128.4, 127.9, 125.7, 122.5, 58.7, 53.5; MS (ESI), m/z (%)
272 [M+H]+ (27); HRMS (ESI) m/z: [M + H]+ Calcd for C10H10NO4S2 272.0046; Found 272.0043.
isopropyl 2-(benzo[d]thiazol-2-ylsulfonyl)acetate (2h). Crude product was prepared using the method
B and obtained as a light yellow solid (0.199 g, 90%). 1H NMR (400 MHz, Chloroform-d) δ 8.24 – 8.21
(m, 1H), 8.08 – 7.99 (m, 1H), 7.68 – 7.58 (m, 2H), 5.00 (hept, J = 6.4 Hz, 1H), 4.54 (s, 2H), 1.15 (d, J = 6.4
Hz, 6H); 13C{1H} NMR (101 MHz, Chloroform-d) δ 165.2, 161.2, 152.6, 137.1, 128.4, 127.9, 125.7, 122.5,
71.1, 59.1, 21.6; MS (ESI), m/z (%) 298 [M-H]- (100); HR-MS (ESI) m/z: [M]+ Calcd for C12H13NO4S2
299.0286; Found 299.0284.
(2S,5R)-2-isopropyl-5-methylcyclohexyl 2-(benzo[d]thiazol-2-ylsulfonyl)acetate (2i). Crude product was
prepared using the method A from ()-2-menthyl 2-bromoacetate44 and obtained with enough purity
as a green viscose syrup (2.24 g, 95%). 1H NMR (400 MHz, Chloroform-d) δ 8.25 – 8.17 (m, 1H), 8.07 –
7.97 (m, 1H), 7.69 – 7.54 (m, 2H), 4.65 (td, J = 10.8, 4.4 Hz, 1H), 4.62 (d, J = 15.2 Hz, 1H), 4.52 (d, J =
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15.2 Hz, 1H) 1.97 – 1.85 (m, 1H), 1.69 – 1.52 (m, 3H), 1.47 – 1.31 (m, 1H), 1.24 – 1.10 (m, 1H), 1.03 –
0.84 (m, 2H), 0.83 (d, J = 6.4 Hz, 3H), 0.84 – 0.67 (m, 1H), 0.68 (d, J = 7.2 Hz, 3H), 0.61 (d, J = 7.2 Hz, 3H);
13C{1H} NMR (101 MHz, Chloroform-d) δ 165.3, 161.3, 152.6, 137.0, 128.3, 127.9, 125.6, 122.5, 58.9,
46.7, 40.4, 34.1, 31.4, 26.0, 23.1, 22.0, 20.6, 16.0; HRMS (ESI) m/z: [M + H]+ Calcd. for C19H26NO4S2
α22
396.1298; Found 396.1300;
= - 32.5 (c 0.2, 퐶퐻퐶푙3).
퐷
2-(benzo[d]thiazol-2-ylsulfonyl)-N,N-diethylacetamide (2k). Crude product was prepared using the
method B and purified using flash column chromatography (SiO2; EtOAc: P.E. = 3:1), isolated as a yellow
solid (0.366 g, 84%). M.p. = 125-126°C; 1H NMR (400 MHz, Chloroform-d) δ 8.23 – 8.20 (m, 1H), 8.01 –
7.98 (m, 1H), 7.64 – 7.55 (m, 2H), 4.63 (s, 2H), 3.46 (q, J = 7.2 Hz, 2H), 3.35 (q, J = 7.2 Hz, 2H), 1.27 (t, J
= 7.2 Hz, 3H), 1.08 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (101 MHz, Chloroform-d) δ 165.5, 160.0, 152.6, 137.4,
128.1, 127.7, 125.7, 122.6, 58.0, 43.3, 41.1, 14.6, 12.9; MS (ESI), m/z (%) 313 [M+H]+ (100); HRMS (ESI)
m/z: [M + Na]+ Calcd for C13H16N2NaO3S2 335.0495; Found 335.0494.
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2-(benzo[d]thiazol-2-ylsulfonyl)acetonitrile (2l). Crude product was prepared using the method A and
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obtained with enough purity as a brown solid (3.4 g, 95%). M.p. = 172-174°C; H NMR (400 MHz,
Chloroform-d) δ 8.29 – 8.25 (m, 1H), 8.09 – 8.05 (m, 1H), 7.74 – 7.65 (m, 2H), 4.56 (s, 2H); 13C{1H} NMR
(101 MHz, Chloroform-d) δ 162.5, 152.4, 137.3, 129.1, 128.4, 126.0, 122.7, 109.2, 44.1; MS (ESI), m/z
(%) 237 [M-H]- (25); HRMS (ESI) m/z: [M - H]- calcd for C9H5N2O2S2: 236.9798, found 236.9798.
Ti(O-iPr)4-mediated transesterification of 2f to 2h. To solution of sulfone 2f (0.200 g, 0.73 mmol, 1.0
equiv) in CH3CN (4.0 mL, 0.2 M), Ti(O-iPr)4 (0.435 mL, 1.46 mmol, 2.0 equiv) was added dropwise at r.t.
and the resulting mixture was stirred for 2h. CH2Cl2 (15 mL) and sat. aq. NH4Cl (5 mL) were added and
the resulting mixture was filtered through Celite®. Filtrate cake was washed with CH2Cl2 (5x20mL) and
combined filtrates were washed with sat. aq. NH4Cl (2x15 mL), brine (2x15 mL), and dried over MgSO4.
Solvents were removed under reduced pressure and the crude product was isolated as a light yellow
solid (0.219 g, 95%)
General procedure for Knoveneagel condensation reaction. To a sulfone (1.0 mmol, 1.0 equiv) in
CH3CN (5.0 mL, 0.2 M) at r.t. was added Ti(O-iPr)4 (0.925 mL, 3.0 equiv) and the resulting mixture was
stirred for 30 minutes. An aldehyde (2.0 mmol, 2.0 equiv) was added dropwise and the mixture was
stirred for the indicated time. The reaction was quenched upon addition of CH2Cl2 (15 mL) and sat.
NH4Cl (5 mL) and the resulting suspension was filtered through Celite®. The filtrate cake was rinsed
with CH2Cl2 (5x20mL), and the combined filtrates were washed with sat. NH4Cl (2x15 mL), brine (2x15
mL), dried over MgSO4, filtered, and the solvents removed under reduced pressure to provide the
crude product.
(E)-3-(benzo[d]thiazol-2-ylsulfonyl)-4-phenylbut-3-en-2-one (3a). Reaction was carried out using the
described procedure with 1.5g (4.37 mmol) of sulfone 2a. Purification using flash chromatography
(SiO2; EtOAc/petroleum ether = 1:4) and concentration of the relevant fractions provided the 3a as a
light yellow solid (1.43 g, 71%). M.p. = 104-107°C; 1H NMR (400 MHz, Chloroform-d) δ 8.20 – 8.18 (m,
1H), 8.14 (s, 1H), 8.01 – 7.98 (m, 1H), 7.59 (ddd, J = 7.2, 6.4, 1.6 Hz, 2H), 7.41 (s, 5H), 2.38 (s, 3H); 13C{1H}
NMR (101 MHz, Chloroform-d) δ 198.3, 166.0, 152.9, 145.1, 139.3, 137.6, 132.2, 131.3, 130.3, 129.4,
128.1, 127.6, 125.7, 122.40, 31.92; MS (ESI), m/z (%) 344 [M+H]+ (100); HRMS (ESI) m/z: [M + H]+ Calcd
for C17H14NO3S2 344.0410; Found 344.0413.
(E)-3-(benzo[d]thiazol-2-ylsulfonyl)-4-(4-methoxyphenyl)but-3-en-2-one (3b). Reaction was carried out
using the described procedure with 0.200 g (0.79 mmol) of sulfone 2a. Purification using flash
chromatography (SiO2; EtOAc/petroleum ether = 1:3) and concentration of the relevant fractions
provided the 3b as a yellow solid (0.143 g, 63%). M.p. = 119-121°C; 1H NMR (500 MHz, Chloroform-d)
δ 8.20 – 8.18 (m, 1H), 8.07 (s, 1H), 8.00 – 7.98 (m, 1H), 7.62 – 7.55 (m, 2H), 7.39 – 7.36 (m, 2H), 6.94 –
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6.91 (m, 2H), 3.85 (s, 3H), 2.43 (s, 3H); C{1H} NMR (126 MHz, Chloroform-d) δ 198.7, 166.5, 163.0,
152.8, 145.1, 137.5, 136.2, 132.8, 128.0, 127.6, 125.7, 123.7, 122.4, 114.9, 55.7, 31.9; MS (ESI), m/z (%)
374 [M+H]+ (50); HRMS (ESI) m/z: [M]+ calcd. for C18H16NO4S2 374.0515; Found 374.0519.
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(E)-3-(benzo[d]thiazol-2-ylsulfonyl)-4-(3-methoxyphenyl)but-3-en-2-one (3c). Reaction was carried out
using the described procedure with 0.200 g (0.79 mmol) of sulfone 2a. Purification using flash
chromatography (SiO2; EtOAc/petroleum ether = 1:3) and concentration of the relevant fractions
provided the 3c as a yellow oil (0.138 g, 61%). 1H NMR (400 MHz, Chloroform-d) δ 8.20 – 8.17 (m, 1H),
8.10 (s, 1H), 8.00 – 7.97 (m, 1H), 7.62 – 7.54 (m, 2H), 7.37 – 7.28 (m, 1H), 7.06 – 6.94 (m, 3H), 3.78 (s,
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3H), 2.37 (s, 3H); C{1H} NMR (101 MHz, Chloroform-d) δ 198.3, 165.9, 160.1, 152.8, 145.0, 139.5,
137.6, 132.5, 130.4, 128.1, 127.6, 125.7, 122.6, 122.4, 118.1, 115.0, 55.5, 32.0; MS (ESI), m/z (%) 374
[M+H]+; HRMS (ESI) m/z: [M + H]+ Calcd for C18H16NO4S2: 374.0515; Found 374.0518.
(E)-3-(benzo[d]thiazol-2-ylsulfonyl)-4-(4-bromophenyl)but-3-en-2-one (3d). Reaction was carried out
using the described procedure with 0.200 g (0.79 mmol) of sulfone 2a. Purification using flash
chromatography (SiO2; EtOAc/petroleum ether = 1:4) and concentration of the relevant fractions
provided the 3d as a yellow oil (0.231 g, 70%). 1H NMR (400 MHz, Chloroform-d) δ 8.22 – 8.19 (m, 1H),
8.05 (s, 1H), 8.03 – 8.00 (m, 1H), 7.65 – 7.59 (m, 2H), 7.58 (d, J = 8.4 Hz, 2H), 7.28 (d, J = 8.4 Hz, 2H),
2.41 (s, 3H); 13C{1H} NMR (101 MHz, Chloroform-d) δ 198.0, 165.7, 152.9, 143.5, 140.1, 137.6, 132.8,
131.6, 130.2, 128.3, 127.8, 127.1, 125.8, 122.5, 32.0; MS (ESI), m/z (%) 422 [M]+ (100); HRMS (ESI) m/z:
[M + H]+ Calcd for C17H13BrNO3S2 421.9515; Found 421.9514.
(E)-3-(benzo[d]thiazol-2-ylsulfonyl)-4-(4-chlorophenyl)but-3-en-2-one (3e). Reaction was carried out
using the described procedure with 0.200 g (0.79 mmol) of sulfone 2a. Purification using flash
chromatography (SiO2; EtOAc/petroleum ether = 1:3) and concentration of the relevant fractions
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provided the 3e as a colorless oil (0.212 g, 71%). H NMR (500 MHz, Chloroform-d) δ 8.24 – 8.17 (m, 1H),
8.06 (s, 1H), 8.03 – 7.99 (m, 1H), 7.64 – 7.56 (m, 2H), 7.44 – 7.39 (m, 2H), 7.37 – 7.33 (m, 2H), 2.41 (s, 3H); 13C{1H}
NMR (126 MHz, Chloroform-d) δ 198.0, 165.8, 152.9, 143.5, 140.0, 138.6, 137.6, 131.5, 129.8, 128.3, 127.8,
125.8, 122.4, 32.0; MS (ESI), m/z (%) 378 [M+H]+ (100); HRMS (ESI) m/z: [M + Na]+ Calcd for
C17H12ClNaNO3S2 399.0939; Found 399.0940.
(E)-3-(benzo[d]thiazol-2-ylsulfonyl)-4-(2-isopropoxyphenyl)but-3-en-2-one (3i). Reaction was carried
out using the described procedure with 0.233 g (0.92 mmol) of sulfone 2a. Purification using flash
chromatography (SiO2; EtOAc/petroleum ether = 1:3) and concentration of the relevant fractions
provided the 3i as a yellow oil (0.274 g, 69%). 1H NMR (400 MHz, Chloroform-d) δ 8.51 (s, 1H), 8.18 (dd,
J = 8.0, 1.6 Hz, 1H), 8.01 (dd, J = 6.8, 2.4 Hz, 1H), 7.58 (tt, J = 7.2, 5.6 Hz, 2H), 7.43 (ddd, J = 8.8, 7.2, 1.6
Hz, 1H), 7.20 (dd, J = 8.0, 1.6 Hz, 1H), 7.02 – 6.85 (m, 2H), 4.63 (hept, J = 6.0 Hz, 1H), 2.30 (s, 3H), 1.35
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(d, J = 6.0 Hz, 6H); C{1H} NMR (101 MHz, Chloroform-d) δ 197.8, 167.0, 157.0, 142.9, 138.2, 137.5,
133.8, 131.1, 127.9, 127.4, 125.5, 122.3, 121.5, 120.7, 114.0, 71.9, 53.6, 31.3, 21.9; MS (ESI), m/z (%)
402 [M]+ (100); HRMS (ESI) m/z: [M + Na]+ Calcd for C20H19NNaO4S2 424.0653; Found 424.0648.
(E)-4-(2-(allyloxy)phenyl)-3-(benzo[d]thiazol-2-ylsulfonyl)but-3-en-2-one (3j). Reaction was carried out
using the described procedure with 0.255 g (1.0 mmol) of sulfone 2a. Purification using flash
chromatography (SiO2; EtOAc/petroleum ether = 1:3) and concentration of the relevant fractions
provided the 3j as a yellow oil (0.267 g, 67%). 1H NMR (400 MHz, Chloroform-d) δ 8.53 (s, 1H), 8.23 –
8.16 (m, 1H), 8.05 – 7.95 (m, 1H), 7.66 – 7.52 (m, 2H), 7.49 – 7.40 (m, 1H), 7.21 (dd, J = 8.0, 1.2 Hz, 1H),
7.01 – 6.90 (m, 2H), 6.02 (ddt, J = 17.2, 10.4, 5.2 Hz, 1H), 5.42 (dd, J = 17.2, 1.2 Hz, 1H), 5.30 (dd, J =
10.8, 1.2 Hz, 1H), 4.70 – 4.59 (m, 2H), 2.33 (s, 3H); 13C{1H} NMR (101 MHz, Chloroform-d) δ 197.8, 166.8,
157.4, 152.8, 142.2, 138.5, 137.5, 133.9, 132.2, 131.1, 128.0, 127.5, 125.6, 122.4, 121.1, 120.8, 118.3,
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112.8, 69.4, 31.5; MS (ESI), m/z (%) 400 [M+H]+ (100); HRMS (ESI) m/z: [M + Na]+ Calcd for
C20H17NNaO4S2 422.0497; Found 422.0490.
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(E)-3-(benzo[d]thiazol-2-ylsulfonyl)-4-(2-(prop-2-yn-1-yloxy)phenyl)but-3-en-2-one (3k). Reaction was
carried out using the described procedure with 0.200 g (0.79 mmol) of sulfone 2a. Purification using
flash chromatography (SiO2; EtOAc/petroleum ether = 1:2) and concentration of the relevant fractions
provided the 3k as a brown solid (0.224 g, 72%). 1H NMR (400 MHz, Chloroform-d) δ 8.45 (s, 1H), 8.19
(dd, J = 7.2, 2.0 Hz, 1H), 8.00 (dd, J = 7.2, 2.0 Hz, 1H), 7.63 – 7.53 (m, 2H), 7.51 – 7.45 (m, 1H), 7.24 (dd,
J = 7.2, 1.6 Hz, 1H), 7.13 (d, J = 8.4 Hz, 1H), 7.01 (t, J = 7.4 Hz, 1H), 4.78 (d, J = 2.4 Hz, 2H), 2.54 (t, J =
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2.4 Hz, 1H), 2.33 (s, 3H); C{1H} NMR (101 MHz, Chloroform-d) δ 197.8, 166.7, 156.2, 152.9, 141.7,
139.0, 137.6, 133.8, 131.4, 128.0, 127.6, 125.7, 122.4, 121.9, 121.3, 113.1, 56.2, 31.6; MS (ESI), m/z (%)
397 [M]+ (100); HRMS (ESI) m/z: [M + Na]+ Calcd for C20H15NNaO4S2 420.0340, Found 420.0335.
(E)-3-(benzo[d]thiazol-2-ylsulfonyl)-4-(2,6-dichlorophenyl)but-3-en-2-one (3l). Reaction was carried out
using the described procedure with 0.100 g (0.4 mmol) of sulfone 2a. Purification using flash
chromatography (SiO2; EtOAc/petroleum ether = 1:3) and concentration of the relevant fractions
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provided the 3l as a yellow oil (0.06 g, 37%). H NMR (500 MHz, Chloroform-d) δ 8.31 (s, 1H), 8.21 –
8.18 (m, 1H), 8.04 – 8.01 (m, 1H), 7.65 – 7.58 (m, 2H), 7.41 – 7.38 (m, 2H), 7.35 – 7.30 (m, 1H), 2.26 (s,
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3H); C{1H} NMR (126 MHz, Chloroform-d) δ 193.6, 166.2, 152.7, 143.8, 137.5, 133.9, 131.6, 130.7,
128.6, 128.3, 127.7, 126.6, 125.8, 122.5, 30.2; MS (ESI), m/z (%) 412 [M]+ (100); HRMS (ESI) m/z: [M +
Na]+ Calcd for C17H11Cl2NNaO3S2 433.9455; Found 433.9449.
(E)-3-(benzo[d]thiazol-2-ylsulfonyl)-4-(3,4,5-trimethoxyphenyl)but-3-en-2-one (3m). Reaction was
carried out using the described procedure with 0.100 g (0.4 mmol) of sulfone 2a. Purification using
flash chromatography (SiO2; EtOAc/petroleum ether = 1:4) and concentration of the relevant fractions
provided the 3m as a yellow oil (0.131 g, 73%). 1H NMR (500 MHz, Chloroform-d) δ 8.23 – 8.19 (m, 1H),
8.04 (s, 1H), 8.03 – 7.99 (m, 1H), 7.66 – 7.55 (m, 2H), 6.64 (s, 2H), 3.90 (s, 3H), 3.82 (s, 6H), 2.44 (s, 3H);
13C{1H} NMR (126 MHz, Chloroform-d) δ 198.7, 166.0, 153.6, 152.9, 145.1, 141.6, 138.1, 137.6, 128.2,
127.7, 126.4, 125.8, 122.4, 107.7, 61.2, 56.3, 32.2; MS (ESI), m/z (%) 434 [M+H]+ (100); HRMS (ESI) m/z:
[M + H]+ Calcd for C20H20NO6S2: 423.0727, found 423.0728.
(E)-3-(benzo[d]thiazol-2-ylsulfonyl)-4-(furan-2-yl)but-3-en-2-one (3n). Reaction was carried out using
the described procedure with 0.200 g (0.79 mmol) of sulfone 2a. Purification using flash
chromatography (SiO2; EtOAc/petroleum ether = 1:4) and concentration of the relevant fractions
provided the 3n as a yellow oil (0.237 g, 91%). 1H NMR (400 MHz, Chloroform-d) δ 8.20 – 8.17 (m, 1H),
7.99 – 7.96 (m, 1H), 7.74 (s, 1H), 7.62 – 7.58 (m, 3H), 7.04 (d, J = 3.6 Hz, 1H), 6.57 (dd, J = 3.6, 1.6 Hz,
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1H), 2.61 (s, 3H); C{1H} NMR (101 MHz, Chloroform-d) δ 196.8, 166.1, 152.9, 148.1, 147.6, 137.5,
134.3, 129.7, 128.1, 127.6, 125.7, 122.3, 122.0, 113.6, 32.3; MS (ESI), m/z (%) 334 [M+H]+ (49); HRMS
(ESI) m/z: [M + H]+ Calcd for C15H12NO4S2 334.0202; Found 334.0203.
(3E,5E)-3-(benzo[d]thiazol-2-ylsulfonyl)-6-phenylhexa-3,5-dien-2-one (3o). Reaction was carried out
using the described procedure with 0.740 g (2.9 mmol) of sulfone 2a. Purification using flash
chromatography (SiO2; EtOAc/petroleum ether = 1:5) and concentration of the relevant fractions
provided the 3o as a yellow solid (0.866 g, 81%, E/Z=7:1). 1H NMR (400 MHz, Chloroform-d) δ 8.20 –
8.14 (m, 1H), 8.02 – 7.97 (m, 2H), 7.69 (dd, J = 15.2, 11.6 Hz, 1H), 7.62 – 7.56 (m, 4H), 7.41 (m, 3H), 7.37
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(d, J = 15.2 Hz, 1H), 2.65 (s, 3H); C{1H} NMR (101 MHz, Chloroform-d) δ 194.1, 167.5, 152.7, 152.4,
152.3, 137.0, 135.7, 135.1, 131.4, 129.3, 128.9, 128.2, 127.7, 125.7, 123.0, 122.4, 31.9; MS (ESI), m/z
(%) 370 [M+1]+ (60); HRMS (ESI) m/z: Calcd for C19H16NO3S2 [M + H]+ 370.0566; Found 370.0568.
(E)-3-(benzo[d]thiazol-2-ylsulfonyl)-4-cyclohexylbut-3-en-2-one (3p). Reaction was carried out using
the described procedure with 1.0 g (3.9 mmol) of sulfone 2a. Purification using flash chromatography
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(SiO2; EtOAc/petroleum ether = 1:3) and concentration of the relevant fractions provided the 3p as a
colorless oil (0.764 g, 56%). H NMR (400 MHz, Chloroform-d) δ 8.20 – 8.16 (m, 1H), 8.00 – 7.97 (m,
1H), 7.64 – 7.54 (m, 2H), 7.25 (d, J = 10.8 Hz, 1H), 2.57 (s, 3H), 1.76 (bs, 5H), 1.28 (bs, 6H); 13C{1H} NMR
(101 MHz, Chloroform-d) δ 195.1, 166.5, 159.0, 152.6, 139.8, 137.1, 128.1, 127.7, 125.7, 122.4, 39.5,
32.2, 31.6, 25.5, 25.0; MS (ESI), m/z (%) 350 [M+1]+ (100); HRMS (ESI) m/z: [M + H]+ Calcd for
C17H20NO3S2 350.0879; Found 350.0877.
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(E)-2-(benzo[d]thiazol-2-ylsulfonyl)-1-phenylhepta-1,6-dien-3-one (3s). Reaction was carried out using
the described procedure with 0.200 g (0.68 mmol) of sulfone 2b. Purification using flash
chromatography (SiO2; EtOAc/petroleum ether = 1:5) and concentration of the relevant fractions
provided the 3s as a yellow oil (0.234 g, 90%). 1H NMR (400 MHz, Chloroform-d) δ 8.22 – 8.19 (m, 1H),
8.16 (s, 1H), 8.02 – 7.99 (m, 1H), 7.64 – 7.56 (m, 2H), 7.52 – 7.46 (m, 1H), 7.45 – 7.40 (m, 2H), 7.39 –
7.35 (m, 2H), 5.69 (ddt, J = 16.8, 10.0, 6.8 Hz, 1H), 5.01 – 4.92 (m, 2H), 2.74 (t, J = 7.2 Hz, 2H), 2.39 –
2.32 (m, 2H); 13C{1H} NMR (101 MHz, Chloroform-d) δ 200.1, 166.0, 153.0, 145.2, 139.2, 137.7, 136.1,
132.2, 131.4, 130.4, 129.4, 128.2, 127.7, 125.8, 122.4, 116.2, 43.5, 27.4; MS (ESI), m/z (%) 384 [M+1]+
(100); HRMS (ESI) m/z: [M + H]+ Calcd for C20H18NO3S2 384.0723; Found 384.0720.
(E)-2-(benzo[d]thiazol-2-ylsulfonyl)-1-(4-methoxyphenyl)hepta-1,6-dien-3-one (3t). Reaction was
carried out using the described procedure with 0.200 g (0.68 mmol) of sulfone 2b. Purification using
flash chromatography (SiO2; EtOAc/petroleum ether = 1:5) and concentration of the relevant fractions
provided the 3t as a yellow oil (0.266 g, 95%). 1H NMR (400 MHz, Chloroform-d) δ 8.21 – 8.17 (m, 1H),
8.07 (s, 1H), 8.01 – 7.97 (m, 1H), 7.62 – 7.54 (m, 2H), 7.35 – 7.31 (m, 2H), 6.93 – 6.89 (m, 2H), 5.73 (ddt,
J = 16.8, 10.0, 6.8 Hz, 1H), 5.04 – 4.94 (m, 2H), 3.85 (s, 3H), 2.81 (t, J = 7.2 Hz, 2H), 2.42 – 2.35 (m, 2H);
13C{1H} NMR (101 MHz, Chloroform-d) δ 200.5, 166.5, 163.0, 152.9, 145.2, 137.6, 136.3, 136.0, 132.9,
128.0, 127.6, 125.8, 123.8, 122.4, 116.1, 114.9, 55.7, 43.5, 27.5; HRMS (ESI) m/z: [M + H]+ Calcd for
C21H20NO4S2 414.0828; Found 414.0827.
(E)-2-(benzo[d]thiazol-2-ylsulfonyl)-1-(furan-2-yl)hepta-1,6-dien-3-one (3w). Reaction was carried out
using the described procedure with 0.200 g (0.68 mmol) of sulfone 2b. Purification using flash
chromatography (SiO2; EtOAc/petroleum ether = 1:6) and concentration of the relevant fractions
provided the 3w as a yellow oil (0.220 g, 87%). 1H NMR (400 MHz, Chloroform-d) δ 8.21 – 8.18 (m, 1H),
8.00 – 7.97 (m, 1H), 7.74 (s, 1H), 7.63 – 7.53 (m, 3H), 7.00 – 6.98 (m, 1H), 6.57 (dd, J = 3.6, 1.6 Hz, 1H),
5.85 (ddt, J = 16.8, 10.0, 6.4 Hz, 1H), 5.06 (dq, J = 17.2, 1.6 Hz, 1H), 4.99 (ddt, J = 10.0, 1.6, 1.2 Hz, 1H),
3.02 (t, J = 7.2 Hz, 2H), 2.50 – 2.43 (m, 2H); 13C{1H} NMR (101 MHz, Chloroform-d) δ 198.6, 166.1, 152.9,
148.0, 147.7, 137.6, 136.8, 134.5, 129.7, 128.1, 127.7, 125.8, 122.4, 121.7, 115.7, 113.6, 43.9, 27.5; MS
(ESI), m/z (%) 374 [M+1]+ (100); HRMS (ESI) m/z: [M + H]+ Calcd for C18H16NO4S2 374.0515; Found
374.0513.
(E)-2-(benzo[d]thiazol-2-ylsulfonyl)-1-cyclohexylhepta-1,6-dien-3-one (3x). Reaction was carried out
using the described procedure with 0.200 g (0.68 mmol) of sulfone 2b. Product 3x was obtained with
enough purity as a yellow oil (0.155 g, 59%). 1H NMR (400 MHz, Chloroform-d) δ 8.20 – 8.16 (m, 1H), 8.01 –
7.97 (m, 1H), 7.64 – 7.55 (m, 2H), 7.21 (d, J = 10.8 Hz, 1H), 5.79 (ddt, J = 16.8, 10.4, 6.4 Hz, 1H), 5.07 – 4.94 (m,
2H), 2.99 (t, J = 7.2 Hz, 2H), 2.54 – 2.43 (m, 1H), 2.39 (dtd, J = 7.2, 6.0, 1.6 Hz, 2H), 1.82 – 1.68 (m, 5H), 1.33 – 1.22
(m, 5H); 13C{1H} NMR (101 MHz, Chloroform-d) δ 197.4, 166.5, 158.1, 152.8, 139.9, 137.3, 136.5, 128.2, 127.7,
125.8, 122.4, 115.8, 43.7, 39.5, 31.7, 27.5, 25.6, 25.0; HRMS (ESI) m/z: [M + Na]+ Calcd for
C20H23NNaO3S2 412.1012; Found 412.1013.
(E)-2-(benzo[d]thiazol-2-ylsulfonyl)-6-chloro-1-phenylhex-1-en-3-one (3y). Reaction was carried out
using the described procedure with 0.100 g (0.68 mmol) of sulfone 2c. Purification using flash
chromatography (SiO2; EtOAc/petroleum ether = 1:3) and concentration of the relevant fractions
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provided the 3y as a yellow oil (0.079 g, 62%). 1H NMR (400 MHz, Chloroform-d) δ 8.23 – 8.18 (m, 1H),
8.17 (s, 1H), 8.03 – 7.98 (m, 1H), 7.64 – 7.55 (m, 2H), 7.52 – 7.47 (m, 1H), 7.46 – 7.41 (m, 2H), 7.39 –
7.35 (m, 2H), 3.50 (t, J = 6.4 Hz, 2H), 2.84 (t, J = 6.8 Hz, 2H), 2.13 – 2.03 (m, 2H); 13C{1H} NMR (101 MHz,
Chloroform-d) δ 199.9, 165.9, 152.9, 145.5, 139.0, 137.6, 132.3, 131.3, 130.2, 129.5, 128.2, 127.7,
125.8, 122.4, 43.7, 41.2, 26.4; MS (ESI), m/z (%) 406 [M]+ (100), 407 [M+1]+ (23); HRMS (ESI) m/z: [M +
H]+ Calcd for C19H17ClNO3S2 406.0333; Found 406.0333.
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(E)-2-(benzo[d]thiazol-2-ylsulfonyl)-1,3-diphenylprop-2-en-1-one (3aa). Reaction was carried out using
the described procedure with 0.200 g (0.68 mmol) of sulfone 2e. Purification using flash
chromatography (passive SiO2; EtOAc/petroleum ether = 1:3) and concentration of the relevant
1
fractions provided the 3aa as a yellow solid (0.367 g, 58%). M.p. = 150-153°C; H NMR (400 MHz,
Chloroform-d) δ 8.33 (s, 1H), 8.24 – 8.16 (m, 1H), 8.00 – 7.93 (m, 1H), 7.91 – 7.82 (m, 2H), 7.65 – 7.51
(m, 2H), 7.47 (tt, J = 7.2, 1.2 Hz, 1H), 7.38 – 7.27 (m, 5H), 7.24 – 7.13 (m, 2H); 13C{1H} NMR (101 MHz,
Chloroform-d) δ 191.2, 166.0, 152.9, 145.9, 137.7, 136.7, 135.3, 134.7, 131.9, 131.2, 130.9, 129.9,
129.1, 128.9, 128.1, 127.6, 125.8, 122.4; MS (ESI), m/z (%) 406 [M+1]+ (100); HRMS (ESI) m/z: [M + H]+
Calcd for C22H16NO3S2 406.0566; Found 406.0563.
(E)-2-(benzo[d]thiazol-2-ylsulfonyl)-3-(furan-2-yl)-1-phenylprop-2-en-1-one (3ab). Reaction was
carried out using the described procedure with 0.200 g (0.68 mmol) of sulfone 2e. Purification using
flash chromatography (SiO2; EtOAc/petroleum ether = 1:1) and concentration of the relevant fractions
provided the 3ab as a yellow solid (0.120 g, 50%). M.p. = 168-170°C; 1H NMR (400 MHz, Chloroform-d)
δ 8.19 (m, 1H), 8.00 (s, 1H), 7.96 – 7.93 (m, 1H), 7.92 – 7.89 (m, 2H), 7.61 – 7.54 (m, 2H), 7.53 – 7.49
(m, 1H), 7.39 – 7.33 (m, 2H), 7.24 (dq, J = 1.6, 0.8 Hz, 2H), 6.85 (d, J = 3.2 Hz, 1H), 6.41 (dd, J = 3.6, 1.6
Hz, 1H); 13C{1H} NMR (101 MHz, Chloroform-d) δ 190.1, 166.2, 152.9, 147.9, 147.5, 137.7, 136.4, 134.3,
132.3, 130.9, 129.7, 128.8, 128.0, 127.5, 125.7, 122.3, 121.4, 113.2; MS (ESI), m/z (%) 396 [M+1]+ (100);
HRMS (ESI) m/z: [M + H]+ Calcd for C20H14NO4S2 396.0359; Found 396.0359.
(E)-2-(benzo[d]thiazol-2-ylsulfonyl)-1-phenyl-3-(4-(trifluoromethyl)phenyl)prop-2-en-1-one
(3ac).
Reaction was carried out using the described procedure with 0.200 g (0.68 mmol) of sulfone 2e.
Purification using flash chromatography (SiO2; EtOAc/petroleum ether = 1:1) and concentration of the
relevant fractions provided the 3ac as a white solid (0.200 g, 67%). M.p. = 57-59°C; 1H NMR (400 MHz,
Chloroform-d) δ 8.34 (s, 1H), 8.23 – 8.20 (m, 1H), 8.00 – 7.97 (m, 1H), 7.88 – 7.85 (m, 1H), 7.65 – 7.56
(m, 2H), 7.54 – 7.44 (m, 5H), 7.36 – 7.31 (m, 2H); 13C{1H} NMR (101 MHz, Chloroform-d) δ 190.6, 165.3,
153.0, 143.5, 139.5, 137.8, 135.1, 135.0, 134.5, 133.1 (q, J = 32.9 Hz), 130.8, 129.9, 129.1, 128.3, 128.2,
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126.7 (d, J = 272.1 Hz), 126.0 (q, J = 3.7 Hz), 125.8, 122.4; F{1H} NMR (376 MHz, Chloroform-d) δ -
63.17(s, 3F); MS (ESI), m/z (%) 474 [M]+1+ (100); HRMS (ESI) m/z: [M + H]+ Calcd for C23H15F3NO3S2
474.0440; Found 474.0438.
(E)-2-(benzo[d]thiazol-2-ylsulfonyl)-3-cyclohexyl-1-phenylprop-2-en-1-one (3ae). Reaction was carried
out using the described procedure with 0.050 g (0.16 mmol) of sulfone 2e. Purification using flash
chromatography (SiO2; EtOAc/petroleum ether = 1:4) and concentration of the relevant fractions
provided the 3ae as a colorless oil (0.029 g, 45%). 1H NMR (400 MHz, Chloroform-d) δ 8.24 – 8.15 (m,
1H), 7.97 – 7.93 (m, 1H), 7.91 – 7.87 (m, 2H), 7.63 – 7.58 (m, 2H), 7.57 – 7.53 (m, 1H), 7.43 (td, J = 8.4,
7.6, 0.8 Hz, 2H), 7.37 (d, J = 10.8 Hz, 1H), 2.12 – 1.99 (m, 1H), 1.75 – 1.57 (m, 4H), 1.39 – 1.14 (m, 5H);
13C{1H} NMR (101 MHz, Chloroform-d) δ 190.0, 166.2, 155.5, 152.8, 137.7, 137.6, 136.5, 134.7, 129.9,
128.9, 128.0, 127.5, 125.7, 122.3, 39.8, 31.3, 25.3, 24.8; MS (ESI), m/z (%) 413 [M+1]+ (100); HRMS (ESI)
m/z: [M + H]+ Calcd for C22H22NO3S2 412.1036; Found 412.1038.
(E)-2-(benzo[d]thiazol-2-ylsulfonyl)-1-phenyl-3-(2-(prop-2-yn-1-yloxy)phenyl)prop-2-en-1-one
(3af).
Reaction was carried out using the described procedure with 0.100 g (0.31 mmol) of sulfone 2e.
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Purification using flash chromatography (SiO2; EtOAc/petroleum ether = 1:2) and concentration of the
relevant fractions provided the 3af as a light brown solid (0.103 g, 71%). H NMR (400 MHz,
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Chloroform-d) δ 8.72 (s, 1H), 8.22 – 8.17 (m, 1H), 7.97 (dd, J = 7.2, 1.2 Hz, 1H), 7.87 – 7.82 (m, 2H), 7.57
(pd, J = 7.2, 1.2 Hz, 2H), 7.44 (t, J = 7.2 Hz, 1H), 7.27 (td, J = 8.4, 3.2 Hz, 3H), 7.12 (dd, J = 7.6, 1.2 Hz,
1H), 6.96 (d, J = 8.4 Hz, 1H), 6.72 (t, J = 7.6 Hz, 1H), 4.72 (d, J = 2.4 Hz, 2H), 2.51 (t, J = 2.4 Hz, 1H).;
13C{1H} NMR (101 MHz, Chloroform-d) δ 191.1, 166.6, 156.3, 152.9, 142.0, 137.7, 136.2, 135.6, 134.3,
133.4, 131.4, 129.7, 128.7, 127.9, 127.5, 125.7, 122.3, 121.5, 121.1, 112.7, 77.7, 76.5, 56.0; MS (ESI)
m/z (%) 460 [M+H]+ (100); HRMS (ESI) m/z: [M + Na]+ Calcd for C25H17NNaO4S2 482.0497; Found
482.0490.
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(S,E)-2-(benzo[d]thiazol-2-ylsulfonyl)-4-((tert-butyldimethylsilyl)oxy)-1-phenylpent-2-en-1-one (3ag).
Reaction was carried out using the described procedure with 0.100 g (0.31 mmol) of sulfone 2e.
Purification using flash chromatography (SiO2; EtOAc/petroleum ether = 1:5) and concentration of the
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relevant fractions provided the 3ag as a colorless oil (0.059 g, 39%, e.r.= >99:1). H NMR (400 MHz,
Chloroform-d) δ 8.22 – 8.19 (m, 1H), 7.97 – 7.94 (m, 1H), 7.90 – 7.85 (m, 2H), 7.64 – 7.57 (m, 2H), 7.57
– 7.54 (m, 1H), 7.45 (d, J = 6.4 Hz, 1H), 7.44 – 7.39 (m, 2H), 4.49 (p, J = 6.4 Hz, 1H), 1.28 (d, J = 6.4 Hz,
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3H), 0.70 (s, 9H), -0.15 (s, 3H), -0.19 (s, 3H); C{1H} NMR (101 MHz, Chloroform-d) δ 189.3, 165.6,
153.0, 137.8, 137.6, 136.6, 134.5, 130.2, 128.8, 128.1, 127.6, 125.8, 122.4, 67.0, 25.8, 23.3, 18.2, -4.8,
α27
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-5.1; HRMS (ESI) m/z: [M + H] Calcd for C24H30NO4S2Si 488.1380; Found 488.1383;
= + 31.4 (c
퐷
0.7,퐶퐻퐶푙3); HPLC (CHIRALPAK IE-3, eluent: CO2: MeOH = 95:5, 2.2 mL/min, 38°C, retention time: t =
13.22 min).
isopropyl (E)-2-(benzo[d]thiazol-2-ylsulfonyl)-3-phenylacrylate (5c). Reaction was carried out using the
described procedure with 2.4 g (8.86 mmol) of sulfone 2f. Purification using flash chromatography
(SiO2; EtOAc/petroleum ether = 1:1) and concentration of the relevant fractions provided the 5c as a
yellow solid (2.0 g, 59%). M.p. = 76-78°C; 1H NMR (400 MHz, Chloroform-d) δ 8.22 (s, 1H), 8.21 – 8.18
(m, 1H), 8.03 – 7.99 (m, 1H), 7.64 – 7.55 (m, 4H), 7.51 – 7.39 (m, 3H), 5.15 (hept, J = 6.0 Hz, 1H), 1.16
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(d, J = 6.4 Hz, 6H); C{1H} NMR (101 MHz, Chloroform-d) δ 166.6, 161.8, 152.8, 148.2, 137.4, 132.3,
132.2, 131.4, 130.8, 129.0, 128.1, 127.6, 125.7, 122.3, 71.2, 21.4; MS (ESI), m/z (%) 328 [M-OiPr]+ (100);
HRMS (ESI) m/z: [M + H]+ Calcd for C19H18NO4S2 388.0672; Found 388.0672.
isopropyl (E)-2-(benzo[d]thiazol-2-ylsulfonyl)-3-(furan-2-yl)acrylate (5f). Reaction was carried out using
the described procedure with 0.200 g (0.74 mmol) of sulfone 2f. Purification using flash
chromatography (SiO2; EtOAc/petroleum ether = 1:3) and concentration of the relevant fractions
provided the 5f as a yellow oil (0.164 g, 60%). 1H NMR (400 MHz, Chloroform-d) δ 8.18 – 8.14 (m, 1H),
8.06 (s, 1H), 8.01 – 7.97 (m, 1H), 7.65 (d, J = 1.6 Hz, 1H), 7.61 – 7.52 (m, 2H), 7.43 (d, J = 3.6 Hz, 1H),
6.61 (dd, J = 3.6, 1.6 Hz, 1H), 5.15 (hept, J = 6.4 Hz, 1H), 1.16 (d, J = 6.4 Hz, 6H); 13C{1H} NMR (101 MHz,
Chloroform-d) δ 167.3, 161.1, 152.7, 148.4, 148.0, 137.3, 134.6, 127.9, 127.6, 126.3, 125.6, 123.6,
122.3, 114.0, 70.8, 21.6; MS (ESI): m/z (%) 318 [M]+ (100), 378 [M+1]+(21); HRMS (ESI) m/z: [M + H]+
Calcd for C17H16NO5S2 378.0464; Found 378.0461.
isopropyl (E)-2-(benzo[d]thiazol-2-ylsulfonyl)-3-(4-(trifluoromethyl)phenyl)acrylate (5g). Reaction was
carried out using the described procedure with 0.200 g (0.74 mmol) of sulfone 2f. Purification using
flash chromatography (SiO2; EtOAc/petroleum ether = 1:5) and concentration of the relevant fractions
provided the 5g as a white solid (0.120 g, 36%). M.p. = 135-137°C; 1H NMR (400 MHz, Chloroform-d) δ
8.27 (s, 1H), 8.22 – 8.19 (m, 1H), 8.05 – 8.01 (m, 1H), 7.68 (s, 4H), 7.65 – 7.57 (m, 2H), 5.12 (hept, J =
6.4 Hz, 1H), 1.13 (d, J = 6.4 Hz, 6H); 13C{1H} NMR (101 MHz, Chloroform-d) δ 166.0, 161.1, 152.7, 146.4,
137.4, 135.0, 134.8, 133.2 (q, J = 33.0 Hz), 130.6, 128.2, 127.7, 125.8 (q, J = 3.7 Hz), 125.7, 123.6 (q, J =
273.2 Hz), 122.3, 71.5, 21.3; 19F{1H} NMR (376 MHz, Chloroform-d) δ -63.04 (s, 3F); MS (ESI), m/z (%)
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414 [M]+ (100), 456 [M+1]+(32); HRMS (ESI) m/z: [M + H]+ Calcd for C20H17F3NO4S2 456.0546; found
456.0548.
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isopropyl (E)-2-(benzo[d]thiazol-2-ylsulfonyl)-3-cyclohexylacrylate (5i). Reaction was carried out using
the described procedure with 0.200 g (0.74 mmol) of sulfone 2f. Purification using flash
chromatography (SiO2; EtOAc/petroleum ether = 1:3) and concentration of the relevant fractions
provided the 5i as a yellow oil (0.160 g, 55%). 1H NMR (400 MHz, Chloroform-d) δ 8.20 – 8.12 (m, 1H),
8.03 – 7.94 (m, 1H), 7.63 (d, J = 10.4 Hz, 1H), 7.60 – 7.53 (m, 2H), 5.05 (hept, J = 6.0, 1H), 3.17 – 3.04
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(m, 1H), 1.90 – 1.68 (m, 5H), 1.37 – 1.24 (m, 5H), 1.13 (d, J = 6.0 Hz, 6H; C{1H} NMR (101 MHz,
Chloroform-d) δ 167.7, 164.5, 160.8, 152.9, 137.4, 132.3, 128.2, 127.8, 125.8, 122.6, 70.8, 39.9, 31.9,
26.0, 25.5, 21.9; MS (ESI), m/z (%) 352 [M]+ (100), 394 [M+1]+ (53); HRMS (ESI) m/z: [M + H]+ Calcd for
C19H24NO4S2 394.1141; Found 394.1141.
isopropyl (S,E)-2-(benzo[d]thiazol-2-ylsulfonyl)-4-((tert-butyldimethylsilyl)oxy)pent-2-enoate (5j).
Reaction was carried out using the described procedure with 0.100 g (0.37 mmol) of sulfone 2f.
Purification using flash chromatography (SiO2; EtOAc/petroleum ether = 1:3) and concentration of the
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relevant fractions provided the 5j as a yellow oil (0.084 g, 49%, e.r.= >99:1). H NMR (400 MHz,
Chloroform-d) δ 8.15 – 8.12 (m, 1H), 8.02 – 7.99 (m, 1H), 7.72 (d, J = 8.0 Hz, 1H), 7.63 – 7.54 (m, 2H),
5.22 (dq, J = 7.6, 6.4 Hz, 1H), 5.04 (hept, J = 6.4 Hz, 1H), 1.40 (d, J = 6.4 Hz, 3H), 1.15 (d, J = 6.4 Hz, 3H),
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1.07 (d, J = 6.4 Hz, 3H), 0.90 (s, 9H), 0.08 (d, J = 6.4 Hz, 6H); C{1H} NMR (101 MHz, Chloroform-d) δ
166.9, 162.9, 160.0, 152.6, 137.1, 131.2, 128.0, 127.6, 125.5, 122.3, 70.8, 66.6, 25.9, 23.0, 21.6, 21.5,
α27
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18.3, -4.5, -4.7; HRMS (ESI) m/z: [M + H] Calcd for C21H32NO5S2Si 470.1486; Found 470.1489;
= +
퐷
41.2 (c 1.0,퐶퐻퐶푙3) ; HPLC (CHIRALPAK IE-3, eluent: CO2: i-PrOH = 95:5, 2.2 mL/min, 38°C, retention
time: t = 5.14 min).
(E)-2-(benzo[d]thiazol-2-ylsulfonyl)-N,N-diethyl-3-phenylacrylamide (5k). Reaction was carried out
using the described procedure with 0.070 g (0.22 mmol) of sulfone 2k. Purification using flash
chromatography (SiO2; EtOAc/petroleum ether = 1:1) and concentration of the relevant fractions
provided the 5k as a white solid (0.048 g, 53%). M.p.= 158-161°C; 1H NMR (400 MHz, Chloroform-d) δ
8.22 – 8.19 (m, 1H), 8.01 (s, 1H), 7.98 – 7.95 (m, 1H), 7.60 – 7.51 (m, 4H), 7.48 – 7.41 (m, 1H), 7.41 –
7.33 (m, 2H), 3.62 (dq, J = 14.4, 7.2 Hz, 1H), 3.38 (dq, J = 14.4, 7.2 Hz, 1H), 3.27 (q, J = 7.2 Hz, 2H), 1.19
(t, J = 7.2 Hz, 3H), 0.93 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (101 MHz, Chloroform-d) δ 166.3, 162.1, 152.9,
143.0, 138.0, 134.5, 132.0, 131.7, 130.3, 129.2, 128.0, 127.5, 125.9, 122.4, 43.5, 39.7, 13.7, 12.0; MS
(ESI), m/z (%) 401 [M+1]+ (100); HRMS (ESI) m/z: [M + Na]+ Calcd for C20H20N2NaO3S2 423.0808; Found
423.0809.
(E)-2-(benzo[d]thiazol-2-ylsulfonyl)-3-phenylacrylonitrile (6a). Reaction was carried out using the
described procedure with 2.0 g (8.4 mmol) of sulfone 2l. Crude product 6a was isolated with enough
purity as a light yellow solid (2.4 g, 88%). M.p. = 158-160°C; 1H NMR (400 MHz, Chloroform-d) δ 8.45
(s, 1H), 8.26 – 8.23 (m, 1H), 8.06 – 8.03 (m,1H), 8.03 – 7.99 (m, 2H), 7.69 – 7.60 (m, 3H), 7.58 – 7.52 (m,
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2H); C{1H} NMR (101 MHz, Chloroform-d) δ 164.0, 156.0, 153.3, 138.0, 135.5, 132.2, 130.5, 130.1,
129.0, 128.5, 126.4, 122.8, 112.8, 112.2; MS (ESI), m/z (%) 327 [M+1]+ (100); HRMS (ESI) m/z: [M + H]+
Calcd for C16H11N2O2S2 327.0256; Found 327.0254.
(E)-2-(benzo[d]thiazol-2-ylsulfonyl)-3-(4-methoxyphenyl)acrylonitrile (6b). Reaction was carried out
using the described procedure with 0.100 g (0.42 mmol) of sulfone 2l. Purification using flash
chromatography (SiO2; EtOAc/petroleum ether = 1:3) and concentration of the relevant fractions
provided the 6b as a yellow oil (0.109 g, 73%). 1H NMR (400 MHz, Chloroform-d) δ 8.34 (s, 1H), 8.24 –
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8.21 (m, 1H), 8.04 – 7.99 (m, 3H), 7.66 – 7.58 (m, 2H), 7.03 – 7.00 (m, 2H), 3.91 (s, 3H); C{1H} NMR
(101 MHz, Chloroform-d) δ 165.5, 164.4, 155.0, 152.9, 137.6, 134.7, 128.5, 128.0, 125.9, 123.0, 122.5,
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115.3, 113.2, 107.7, 56.0; MS (ESI), m/z (%) 374 [M+H2O]+ (100); HRMS (ESI) m/z: [M + H]+ Calcd for
C17H13N2O3S2 357.0362; Found 357.0359.
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(E)-2-(benzo[d]thiazol-2-ylsulfonyl)-3-(3-methoxyphenyl)acrylonitrile (6c). Reaction was carried out
using the described procedure with 0.100 g (0.42 mmol) of sulfone 2l. Purification using flash
chromatography (SiO2; acetone/petroleum ether = 1:3) and concentration of the relevant fractions
provided the 6c as a yellow solid (0.106 g, 71%). 1H NMR (400 MHz, Chloroform-d) δ 8.40 (s, 1H), 8.28
– 8.19 (m, 1H), 8.08 – 7.99 (m, 1H), 7.70 – 7.57 (m, 2H), 7.61 – 7.50 (m, 2H), 7.44 (t, J = 8.0 Hz, 1H), 7.18
(ddd, J = 8.4, 2.4, 1.2 Hz, 1H), 3.85 (s, 3H).; 13C{1H} NMR (101 MHz, Chloroform-d) δ 55.7, 112.0, 112.5,
114.9, 122.1, 122.5, 125.1, 126.0, 128.1, 128.7, 130.7, 131.2, 137.7, 152.9, 155.8, 160.3, 163.7; HRMS
(ESI) m/z: [M + H]+ Calcd for C17H13N2O3S2 357.0362; Found 357.0360.
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(E)-2-(benzo[d]thiazol-2-ylsulfonyl)-3-(4-bromophenyl)acrylonitrile (6d). Reaction was carried out using
the described procedure with 0.100 g (0.42 mmol) of sulfone 2l. Purification using flash
chromatography (SiO2; acetone/petroleum ether = 1:3) and concentration of the relevant fractions
provided the 6d as a light-yellow syrup (0.129 g, 76%). 1H NMR (400 MHz, Chloroform-d) δ 8.38 (s, 1H),
8.27 – 8.22 (m, 1H), 8.06 – 8.03 (m, 1H), 7.89 – 7.85 (m, 2H), 7.71 – 7.67 (m, 2H), 7.67 – 7.61 (m, 2H);
13C{1H} NMR (101 MHz, Chloroform-d) δ(ppm): 163.5, 154.1, 153.0, 137.7, 133.3, 132.8, 130.5, 128.9,
128.8, 128.2, 126.1, 122.5, 112.6, 112.3; MS (ESI), m/z (%) 406 [M+H]+ (100); HRMS (ESI) m/z: [M + H]+
Calcd for C16H10BrN2O2S2 404.9362; Found 404.9360.
(E)-2-(benzo[d]thiazol-2-ylsulfonyl)-3-(furan-2-yl)acrylonitrile (6e). Reaction was carried out using the
described procedure with 0.100 g (0.42 mmol) of sulfone 2l. Purification using flash chromatography
(SiO2; EtOAc/petroleum ether = 1:3) and concentration of the relevant fractions provided the 6e as a
yellow oil (0.089 g, 67%). 1H NMR (400 MHz, Chloroform-d) δ 8.25 – 8.22 (m, 1H), 8.18 (s, 1H), 8.05 –
8.02 (m, 1H), 7.83 (dt, J = 1.6, 0.4 Hz, 1H), 7.67 – 7.59 (m,2H), 7.43 (d, J = 3.6 Hz, 1H), 6.72 (dd, J = 3.6,
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1.6 Hz, 1H); C{1H} NMR (101 MHz, Chloroform-d) δ 164.0, 152.9, 150.3, 147.3, 139.5, 137.6, 128.6,
128.0, 125.9, 125.3, 122.5, 114.7, 112.2, 107.2; MS (ESI), m/z (%) 334 [M+H2O]+ (100), 317 [M+1]+ (34);
HRMS (ESI) m/z: [M + H]+ Calcd for C14H9N2O3S2 317.0049; Found 317.0047.
(E)-2-(benzo[d]thiazol-2-ylsulfonyl)-3-(4-(trifluoromethyl)phenyl)acrylonitrile (6f). Reaction was carried
out using the described procedure with 0.100 g (0.42 mmol) of sulfone 2l. Crude product 6f was
isolated with enough purity as a colorless oil (0.157 g, 93%). 1H NMR (400 MHz, Chloroform-d) δ 8.48
(s, 1H), 8.26 – 8.22 (m, 1H), 8.11 (d, J = 8.4 Hz, 2H), 8.07 – 8.04 (m, 1H), 7.80 (d, J = 8.4 Hz, 2H), 7.70 –
7.62 (m, 2H); 13C{1H} NMR (101 MHz, Chloroform-d) δ 163.0, 153.5, 152.9, 137.7, 135.7 (q, J = 33.4 Hz),
133.0, 131.7, 128.9, 128.2, 126.7 (q, J = 3.7 Hz), 126.5, 126.0, 123.4 (d, J = 272.7 Hz), 114.9, 111.9;
19F{1H} NMR (376 MHz, Chloroform-d) δ -63.34 (s, 3F); MS (ESI), m/z (%) 177 [M]+ (100); HRMS (ESI)
m/z: [M + H]+ Calcd for C17H10F3N2O2S2 395.0130; Found 395.0128.
(E)-2-(benzo[d]thiazol-2-ylsulfonyl)-3-cyclohexylacrylonitrile (6i). Reaction was carried out using the
described procedure with 0.050 g (0.21 mmol) of sulfone 2l. Crude product 6i was isolated with enough
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purity as a yellow solid (0.060 g, 88%). M.p.= 112-114°C; H NMR (400 MHz, Chloroform-d) δ 8.26 –
8.23 (m, 1H), 8.05 – 8.02 (m, 1H), 7.76 (d, J = 10.4 Hz, 1H), 7.69 – 7.60 (m, 2H), 2.77 – 2.67 (m, 1H), 1.89
– 1.70 (m, 5H), 1.41 – 1.22 (m, 5H); 13C{1H} NMR (101 MHz, Chloroform-d) δ 169.0, 163.5, 152.9, 137.6,
128.7, 128.1, 126.1, 122.5, 116.5, 110.6, 42.0, 31.1, 25.3, 24.8; MS (ESI), m/z (%) 333 [M+1]+ (100); HR-
MS (ESI) m/z: [M + H]+ Calcd for C16H17N2O2S2 333.0726; Found 333.0725.
(E)-2-(benzo[d]thiazol-2-ylsulfonyl)-3-(2-(prop-2-yn-1-yloxy)phenyl)acrylonitrile (6j). Reaction was
carried out using the described procedure with 0.100 g (0.42 mmol) of sulfone 2l. Purification using
flash chromatography (SiO2; EtOAc/petroleum ether = 1:3) and concentration of the relevant fractions
provided the 6j as a brown solid (0.110 g, 69%). 1H NMR (400 MHz, Chloroform-d) δ 8.96 (s, 1H), 8.35
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– 8.20 (m, 2H), 8.05 – 8.00 (m, 1H), 7.63 (ddd, J = 9.2, 5.6, 2.0 Hz, 3H), 7.19 – 7.07 (m, 2H), 4.88 (d, J =
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2.4 Hz, 2H), 2.58 (s, 1H); C{1H} NMR (101 MHz, Chloroform-d) δ 164.0, 157.9, 152.9, 149.9, 137.6,
136.9, 129.7, 128.6, 128.0, 126.0, 122.5, 122.2, 119.8, 113.3, 112.9, 111.1, 77.3, 56.6; MS (ESI), m/z (%)
381 [M]+ (100); HRMS (ESI) m/z: [M + Na]+ Calcd for C19H12N2NaO3S2 403.0187; Found 403.0181.
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(E)-3-(benzo[d]thiazol-2-ylsulfonyl)-6-phenylhex-4-en-2-one (7a). Reaction was carried out using the
described procedure with 0.050 g (0.2 mmol) of sulfone 2a. Purification using flash chromatography
(SiO2; EtOAc/petroleum ether = 1:3) and concentration of the relevant fractions provided the 7a as a
white solid (0.036 g, 49%). 1H NMR (400 MHz, Chloroform-d) δ 8.24 – 8.16 (m, 1H), 8.01 – 7.95 (m, 1H),
7.69 – 7.56 (m, 2H), 7.13 – 7.06 (m, 3H), 6.94 – 6.86 (m, 2H), 5.92 – 5.77 (m, 2H), 5.22 (d, J = 9.2 Hz,
1H), 3.35 (d, J = 6.0 Hz, 2H), 2.51 (s, 3H); 13C{1H} NMR (101 MHz, Chloroform-d) δ 196.6, 164.2, 152.6,
142.5, 138.1, 137.1, 128.6, 128.4, 128.3, 127.8, 126.5, 125.7, 122.5, 117.5, 78.0, 39.1, 31.2; MS (ESI),
m/z (%) 372 [M+1]+ (37); HRMS (ESI) m/z: [M + H]+ Calcd for C19H18NO3S2 372.0723; Found 372.0725.
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(E)-3-(benzo[d]thiazol-2-ylsulfonyl)hept-4-en-2-one (7b). Reaction was carried out using the described
procedure with 0.050 g (0.2 mmol) of sulfone 2a. Crude product proved to be unstable on SiO2. The
yield of the crude material was 0.019 g, 31%, (keto/enol = 1.7:1). Peaks attributed to enol form marked
with *; 1H NMR (400 MHz, Chloroform-d) δ(ppm): 0.84 (t, J = 7.6 Hz, 3H*), 1.00 (t, J = 7.6 Hz, 3H), 2.04
(qd, J = 7.6, 6.8, 5.2 Hz, 2H), 2.48 (dd, J = 7.6, 3.6 Hz, 1H*), 2.50 (s, 3H*), 2.52 (dd, J = 7.6, 0.4 Hz, 1H*),
2.57 (s, 3H), 5.16 (d, J = 9.2 Hz, 1H), 5.65 – 5.85 (m, 2H), 7.50 (t, J = 7.6 Hz, 1H*), 7.55 – 7.69 (m, 2H &
2H*), 7.98 – 8.04 (m, 1H & 1H*), 8.17 – 8.20 (m, 1H), 8.24 (ddd, J = 8.4, 1.6, 0.8 Hz, 1H*); HRMS (ESI)
m/z: [M + Na]+ Calcd for C14H15NNaO3S2 332.0391, found 332.0393.
General procedure for dihydropyran 9 synthesis. A vinyl-sulfone 3 (0.100 g, 0.29 mmol) was dissolved
in benzene (1.5 mL, 0.2 M) and vinyl-ether (0.278 mL, 2.9 mmol) was added in one portion. Mixture
was stirred for 24 hours. Volatilities were evaporated under reduced pressure to yield the crude
product.
2-(((4S)-2-ethoxy-6-methyl-4-phenyl-3,4-dihydro-2H-pyran-5-yl)sulfonyl)benzo[d]thiazole
(9a).
Reaction was carried out using the described procedure with 0.100 g (0.29 mmol) of vinyl-sulfone 3a.
Purification using flash chromatography (SiO2; EtOAc/petroleum ether = 1:3) and concentration of the
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relevant fractions provided the 9a as a yellow oil (0.129 g, 90%, d.r. = 1 : 1.1). H NMR (400 MHz,
Chloroform-d) δ 8.15 – 8.08 (m, 2H), 7.85 (d, J = 8.0 Hz, 1H), 7.79 (d, J = 8.0 Hz, 1H), 7.60 – 7.54 (m,
2H), 7.53 – 7.44 (m, 2H), 7.08 (bs, 5H), 7.02 (d, J = 7.2 Hz, 2H), 6.91 (t, J = 7.2 Hz, 1H), 6.84 (t, J = 7.6 Hz,
2H), 5.11 (dd, J = 6.8, 2.4 Hz, 1H), 4.95 (t, J = 6.0 Hz, 1H), 4.31 (t, J = 4.4 Hz, 1H), 4.19 (t, J = 7.6 Hz, 1H),
3.99 – 3.88 (m, 2H), 3.62 – 3.52 (m, 2H), 2.68 (bs, 3H), 2.64 (bs, 3H), 2.35 (ddd, J = 14.0, 7.6, 2.4 Hz,
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1H), 2.12 – 2.04 (m, 3H), 1.19 (t, J = 6.0 Hz, 3H), 1.16 (t, J = 6.0 Hz, 3H); C{1H} NMR (101 MHz,
Chloroform-d) δ 170.2, 169.6, 168.1, 167.8, 152.7, 152.5, 142.7, 141.6, 137.2, 136.9, 128.9, 128.6,
128.1, 127.8, 127.4, 127.2, 127.2, 127.0, 126.8, 126.4, 125.3, 125.2, 122.1, 121.9, 113.9, 110.6, 100.2,
98.7, 65.6, 65.2, 39.1, 38.5, 37.7, 35.9, 21.2, 20.7, 15.2, 15.1; MS (ESI), m/z (%) 416 [M+H]+ (62); HRMS
(ESI) m/z: [M + H]+ Calcd for C21H22NO4S2 416.0985; Found 416.0987.
2-(((4S)-6-(but-3-en-1-yl)-2-ethoxy-4-phenyl-3,4-dihydro-2H-pyran-5-yl)sulfonyl)benzo[d]thiazole (9b).
Reaction was carried out using the described procedure with 0.100 g (0.26 mmol) of vinyl-sulfone 3s.
Purification using flash chromatography (SiO2; EtOAc/petroleum ether = 1:3) and concentration of the
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relevant fractions provided the 9b as a yellow oil (0.109 g, 70%, d.r. = 1 : 1.1). H NMR (400 MHz,
Chloroform-d) δ 8.11 (t, J = 8.4 Hz, 2H), 7.85 (d, J = 8.0 Hz, 1H), 7.78 (d, J = 8.0 Hz, 1H), 7.60 – 7.53 (m,
2H), 7.53 – 7.45 (m, 2H), 7.09 (bs, 5H), 7.01 (d, J = 7.2 Hz, 2H), 6.91 (t, J = 7.2 Hz, 1H), 6.84 (t, J = 7.2 Hz,
2H), 5.97 (dddt, J = 20.8, 16.8, 10.4, 6.8 Hz, 2H), 5.19 – 5.07 (m, 3H), 5.06 – 4.98 (m, 2H), 4.96 – 4.89
(m, 1H), 4.33 (t, J = 4.8 Hz, 1H), 4.22 (t, J = 8.0 Hz, 1H), 3.94 (dqd, J = 9.6, 7.2, 2.4 Hz, 2H), 3.56 (ddq, J =
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18.8, 9.6, 7.2 Hz, 2H), 3.33 – 3.15 (m, 3H), 3.09 – 3.01 (m, 1H), 2.60 – 2.48 (m, 4H), 2.35 (ddd, J = 14.0,
7.6, 2.4 Hz, 1H), 2.11 – 2.02 (m, 3H), 1.18 (dt, J = 14.0, 7.2 Hz, 6H); 13C{1H} NMR (101 MHz, Chloroform-d)
δ 170.4, 170.1, 170.0, 169.7, 152.6, 152.5, 142.7, 141.6, 137.6, 137.4, 137.3, 137.0, 128.9, 128.5, 128.1,
127.8, 127.5, 127.3, 127.0, 126.8, 126.4, 125.2, 125.1, 122.1, 121.9, 115.6, 115.5, 114.4, 111.1, 100.1,
98.6, 65.5, 65.2, 39.3, 38.6, 37.8, 35.8, 33.3, 32.7, 32.1, 32.1, 29.8, 15.2, 15.1; HRMS (ESI) m/z: [M + H]+
Calcd for C24H26NO4S2 456.1298; Found 456.1300.
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2-((4-cyclohexyl-2-ethoxy-6-methyl-3,4-dihydro-2H-pyran-5-yl)sulfonyl)benzo[d]thiazole (9c). Reaction
was carried out using the described procedure with 0.070 g (0.2 mmol) of vinyl-sulfone 3p. Purification
using flash chromatography (SiO2; EtOAc/petroleum ether = 1:6) and concentration of the relevant
fractions provided the 9c as a colorless oil (0.069 g, 72%, d.r. = 1.1:1). 1H NMR (400 MHz, Chloroform-
d) δ 8.13 (dddd, J = 8.0, 2.4, 1.6, 0.8 Hz, 2H), 7.96 (dddd, J = 8.0, 6.0, 1.6, 0.8 Hz, 2H), 7.61 – 7.49 (m,
4H), 5.16 (dd, J = 9.6, 3.6 Hz, 1H), 4.91 (dd, J = 7.6, 3.2 Hz, 1H), 3.95 (ddq, J = 14.0, 9.6, 7.2 Hz, 2H), 3.61
(dq, J = 9.6, 7.2 Hz, 2H), 2.05-2.97 (m,1H), 2.95-2.88 (m,1H), 2.45 (d, J = 1.2 Hz, 3H), 2.39 (d, J = 0.8 Hz,
3H), 2.18 (dt, J = 14.0, 3.6 Hz, 1H), 2.10 – 1.88 (m, 2H), 1.88 – 1.75 (m, 3H), 1.73 – 1.57 (m, 9H), 1.55 –
1.46 (m, 1H), 1.41 – 1.31 (m, 1H), 1.25 (t, J = 7.2 Hz, 3H), 1.22 (t, J = 7.2 Hz, 3H), 1.20 – 0.81 (m, 8H),
0.77 – 0.59 (m, 1H); 13C{1H} NMR (101 MHz, Chloroform-d) δ 170.0, 169.8, 168.5, 166.8, 152.7, 152.6,
136.5, 136.5, 127.6, 127.6, 127.4, 125.3, 122.2, 114.9, 112.5, 101.5, 99.7, 65.5, 65.3, 41.1, 39.6, 38.5,
37.5, 31.8, 31.6, 30.2, 30.1, 29.4, 27.1, 27.0, 26.9, 26.8, 26.6, 26.5, 26.0, 21.3, 20.9, 15.2.; HRMS (ESI)
m/z: [M + H]+ Calcd for C21H28NO4S2 422.1454; Found 422.1456.
General procedure for intramolecular Het. Diels-Alder reaction. A vinyl-sulfone (0.017 g, 0.04 mmol,
1.0 equiv) was dissolved in DCE (4.0 mL, 0.01 M) and the reaction mixture was stirred under microwave
conditions (200W, 150°C, 5 min ramp, 30 min hold). The solvent was evaporated under reduced
pressure to yield the crude product.
2-((2-methyl-5H,10bH-pyrano[3,4-c]chromen-1-yl)sulfonyl)benzo[d]thiazole (10). Reaction was carried
out using the described procedure with 0.017 g (0.04 mmol) of vinyl-sulfone 3k. Desired product 10
was isolated as a yellow oil (0.016 g, 93%) in sufficient purity. 1H NMR (400 MHz, Chloroform-d) δ 8.28
– 8.18 (m, 1H), 8.06 – 7.97 (m, 1H), 7.61 (dtd, J = 20.0, 7.6, 1.2 Hz, 2H), 7.33 (d, J = 7.6 Hz, 1H), 7.20 –
7.10 (m, 1H), 6.98 (td, J = 7.6, 1.2 Hz, 1H), 6.83 (dd, J = 8.0, 1.2 Hz, 1H), 6.44 – 6.32 (m, 1H), 4.88 – 4.81
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(m, 1H), 4.69 (s, 1H), 4.59 (d, J = 12.0 Hz, 1H), 2.45 (s, 3H); C{1H} NMR (101 MHz, Chloroform-d)
δ(ppm): 19.5, 33.7, 67.8, 110.9, 113.7, 117.3, 121.3, 122.4, 125.7, 126.3, 127.7, 128.0, 128.2, 129.6,
134.4, 136.8, 152.8, 153.8, 165.2, 168.4; MS (ESI), m/z (%) 398 [M+H]+ (30); HRMS (ESI) m/z: [M + Na]+
Calcd for C20H15NNaO4S2 420.0340; Found 420.0336.
General procedure for dihydrofurane 12 synthesis. Racemic protocol: A vinyl-sulfone 3a (0.050 g, 0.15
mmol, 1.0 equiv) and pyridinium salt 11a-c (0.217 mmol, 1.5 equiv) were dissolved in toluene (1.5 mL,
0.1 M). After 5 minutes, Et3N (0.030 mL, 1.5 equiv) was added and mixture was stirred for an additional
4 hours at r.t.. H2O (10 mL) followed by EtOAc (10 mL) were added and the resulting layers were
separated. The aqueous phase was extracted with EtOAc (4x10 mL) and the combined organic layers
were washed brine (2x10 mL), dried over MgSO4, filtered, and the solvents were removed under
reduced pressure to provide the crude product. Asymmetric protocol: A vinyl-sulfone 3a (0.030 g,
0.086 mmol, 2.0 equiv) and chiral ammonium salt 13a-c (0.043 mmol, 1.0 equiv.) were dissolved in dry
CH2Cl2 (1.0 mL, 0.043 M). After 5 minutes, Cs2CO3 (0.028 mg, 2.0 equiv.) was added in one portion and
the mixture was stirred for an additional 20 hours. H2O (10 mL) and EtOAc (10 mL) were added and the
aqueous phase was extracted with EtOAc (4x10 mL). The combined organic layers were washed with
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brine (2x10 mL), dried over MgSO4, filtered, and the solvents were removed under reduced pressure
to provide the crude product.
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1-((2S,3R)-4-(benzo[d]thiazol-2-ylsulfonyl)-5-methyl-3-phenyl-2,3-dihydrofuran-2-yl)ethan-1-one
(12a). Reaction was carried out using the described racemic procedure with 0.050 g (0.15 mmol) of
vinyl-sulfone 3a. Product 12a was isolated in good crude purity as a yellow oil (0.062 g, 98%, d.r.= 99:1).
1H NMR (400 MHz, Chloroform-d) δ 8.08 – 8.05 (m, 1H), 7.80 – 7.77 (m, 1H), 7.58 – 7.54 (m, 1H), 7.51
– 7.47 (m, 1H), 7.04 – 7.01 (m, 2H), 6.97 – 6.91 (m, 3H), 4.83 (d, J = 5.2 Hz, 1H), 4.58 (dd, J = 5.2, 1.2 Hz,
1H), 2.63 (d, J = 1.2 Hz, 3H), 2.26 (s, 3H); 13C{1H} NMR (101 MHz, Chloroform-d) δ 203.7, 171.2, 168.9,
152.6, 139.5, 137.3, 128.7, 127.9, 127.7, 127.5, 127.2, 125.4, 122.0, 112.1, 93.2, 52.0, 26.1, 14.5; MS
(ESI), m/z (%) 400 [M+1]+ (62); HRMS (ESI) m/z: [M + H]+ Calcd for C20H18NO4S2 400.0672; Found
400.0669.
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((2S,3R)-4-(benzo[d]thiazol-2-ylsulfonyl)-5-methyl-3-phenyl-2,3-dihydrofuran-2-yl)(phenyl)methanone
(12b). Reaction was carried out using the described asymmetric or racemic procedure with 0.050 g (0.2
mmol) of vinyl-sulfone 3a. Purification using flash chromatography (SiO2; EtOAc/petroleum ether = 1:2)
and concentration of the relevant fractions provided the 12b as a colorless oil (0.068 g, 98%, d.r. =
97:1). Product 12b was also prepared in enantioenriched form purified using flash column
chromatography (SiO2; CH2Cl2:heptane=6:1) and isolated as a light red oil in following manner: starting
from salt 13a: 0.013 g, 70%, e.r. = 97:3, d.r.=99:1; starting from salt 13c: 0.012 g, 68%, e.r. = 1:99,
d.r.=99:1). 1H NMR (400 MHz, Chloroform-d) δ 8.06 – 8.03 (m, 1H), 7.79 – 7.74 (m, 3H), 7.63 – 7.53 (m,
2H), 7.50 – 7.41 (m, 3H), 7.07 – 7.04 (m, 2H), 7.01 – 6.95 (m, 3H), 5.77 (d, J = 4.8 Hz, 1H), 4.64 (dd, J =
4.8, 1.2 Hz, 1H), 2.66 (d, J = 1.2 Hz, 3H); 13C{1H} NMR (101 MHz, Chloroform-d) δ 191.9, 172.0, 169.0,
152.6, 139.2, 137.3, 134.4, 133.0, 129.1, 129.0, 128.8, 128.2, 127.9, 127.4, 127.1, 125.4, 122.0, 111.9,
90.3, 52.2, 14.4; MS (ESI), m/z (%) 462 [M+1]+ (54); HRMS (ESI) m/z: [M + H]+ Calcd for C25H20NO4S2
α25
α25
=+161.4 (c 0.5,퐶퐻퐶푙3) – first enantiomer (ret. Time – 29.35 min); =-
퐷
462.0828; Found 462.0827;
퐷
148.2 (c 0.5,퐶퐻퐶푙3) – second enantiomer (ret. Time – 32.7 min); HPLC (CHIRAL ART Cellulose-SB,
eluent: n-hexane: i-PrOH = 4:1, 0.5 mL/min, 10°C, retention times: t = 29.3 and t = 32.7 min).
ethyl (2S,3R)-4-(benzo[d]thiazol-2-ylsulfonyl)-5-methyl-3-phenyl-2,3-dihydrofuran-2-carboxylate (12c).
Reaction was carried out using the described racemic procedure with 0.050 g (0.2 mmol) of vinyl-
sulfone 3a. Purification using flash chromatography (SiO2; EtOAc/petroleum ether = 1:2) and
concentration of the relevant fractions provided the 12c as a colorless oil (0.054 g, 88%, d.r. = 99:1). 1H
NMR (400 MHz, Chloroform-d) δ 8.08 – 8.05 (m, 1H), 7.80 – 7.77 (m, 1H), 7.58 – 7.53 (m, 1H), 7.51 –
7.46 (m, 1H), 7.04 – 7.01 (m, 2H), 6.97 – 6.91 (m, 3H), 4.90 (d, J = 4.8 Hz, 1H), 4.62 (dd, J = 4.8, 1.2 Hz,
13
1H), 4.30 – 4.20 (m, 2H), 2.62 (d, J = 1.2 Hz, 3H), 1.27 (t, J = 7.2 Hz, 3H); C{1H} NMR (101 MHz,
Chloroform-d) δ 171.8, 168.9, 168.7, 152.6, 139.4, 137.3, 128.6, 127.8, 127.8, 127.5, 127.2, 125.4,
122.0, 111.9, 86.7, 62.3, 53.3, 14.4, 14.2; MS (ESI), m/z (%) 430 [M+1]+ (48); HRMS (ESI) m/z: [M + H]+
Calcd for C21H20NO5S2 430.0777; Found 430.0777.
General procedure for triazole 15 synthesis. To a vinyl-sulfone (0.291 mmol, 1.0 equiv) in MeOH (1.5
mL, 0.2 M) at r.t. was added sodium azide (0.021 g, 0.32 mmol, 1.1 equiv) in one portion and the
mixture was stirred for 20 hours. H2O (10 mL) and EtOAc (10 mL) were added and aqueous phase was
extracted with EtOAc (4x10 mL). The combined organic layers were washed with brine (2x10 mL), dried
over MgSO4, filtered, and the solvents were removed under reduced pressure to provide the crude
product.
1-(5-phenyl-2H-1,2,3-triazol-4-yl)ethan-1-one (15a). Reaction was carried out using the described
procedure with 0.100 g (0.4 mmol) of vinyl-sulfone 3a. Purification using flash chromatography (SiO2;
EtOAc/petroleum ether = 1:1) and concentration of the relevant fractions provided the 15a as a pale
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yellow solid (0.032 g, 93%). M.p. = 108-110°C; 1H NMR (400 MHz, Chloroform-d) δ 7.82 – 7.77 (m, 2H),
7.51 – 7.34 (m, 3H), 2.73 (s, 3H); 13C{1H} NMR (101 MHz, Chloroform-d) δ 193.6, 141.9, 130.2, 129.2,
128.7, 127.5, 28.8; MS (ESI), m/z (%) 186 [M-H]- (100); HRMS (ESI) m/z: [M + H]+ Calcd for C10H10O
188.0818; Found 188.0819.
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1-(5-cyclohexyl-2H-1,2,3-triazol-4-yl)ethan-1-one (15b). Reaction was carried out using the described
procedure with 0.050 g (0.14 mmol) of vinyl-sulfone 3p. Purification using flash chromatography (SiO2;
EtOAc/petroleum ether = 1:4) and concentration of the relevant fractions provided the 15b as a white
solid (0.027 g, 98%). 1H NMR (500 MHz, Chloroform-d) δ 3.42 (tt, J = 11.5, 3.5 Hz, 1H), 2.71 (s, 3H), 2.04
– 1.95 (m, 2H), 1.84 (dq, J = 13.5, 3.5 Hz, 2H), 1.78 (dqd, J = 12.5, 3.0, 1.5 Hz, 1H), 1.57 – 1.39 (m, 4H),
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1.29 (qt, J = 13.0, 4.0 Hz, 1H); C{1H} NMR (126 MHz, Chloroform-d) δ 25.9, 26.3, 28.3, 31.9, 34.2,
141.9, 149.7, 194.4; MS (ESI), m/z (%) 192 [M-H]- (100); HRMS (ESI) m/z: [M + H]+ Calcd for C10H16N3O
194.1288; Found 194.1289.
isopropyl 5-phenyl-2H-1,2,3-triazole-4-carboxylate (15c). Reaction was carried out using the described
procedure with 0.100 g (0.26 mmol) of vinyl-sulfone 5c. Purification using flash chromatography (SiO2;
EtOAc/petroleum ether = 1:1) and concentration of the relevant fractions provided the 15c as a yellow
oil (0.034 g, 59%). 1H NMR (400 MHz, Chloroform-d) δ 7.81 – 7.75 (m, 2H), 7.42 – 7.38 (m, 3H), 5.23 (h,
13
J = 6.4 Hz, 1H), 1.27 (d, J = 6.4 Hz, 6H); C{1H} NMR (101 MHz, Chloroform-d) δ 160.8, 134.4, 129.7,
129.4, 128.3, 114.0, 69.8, 21.8; MS (ESI), m/z (%) 230 [M-H]- (100); HRMS (ESI) m/z: [M + H]+ Calcd for
C12H14N3O2 232.1081; Found 232.1082.
phenyl(5-(4-(trifluoromethyl)phenyl)-2H-1,2,3-triazol-4-yl)methanone (15d). Reaction was carried out
using the described procedure with 0.100 g (0.21 mmol) of vinyl-sulfone 3ac. Purification using flash
chromatography (SiO2; EtOAc/petroleum ether = 1:1) and concentration of the relevant fractions
provided the 15d as a yellow oil (0.051 g, 79%). 1H NMR (400 MHz, DMSO-d6) δ 8.04 (d, J = 6.4 Hz, 2H),
7.98 (d, J = 8.0 Hz, 2H), 7.84 (d, J = 8.0 Hz, 2H), 7.70 (t, J = 7.6 Hz, 1H), 7.56 (t, J = 7.6 Hz, 2H); 13C{1H}
NMR (101 MHz, DMSO-d6) δ 187.7, 156.0, 141.6, 136.9, 133.5, 130.1, 129.3, 128.4, 128.1, 125.4, 125.3
(q, J = 3.6 Hz), 122.7; 19F{1H} NMR (376 MHz, DMSO-d6) δ -61.15 (s, 3F); MS (ESI): m/z (%) 316 [M-H]-
(100); HRMS (ESI) m/z: [M + H]+ Calcd for C16H11F3N3O 318.0849; Found 318.0850.
1-(5-(2-(allyloxy)phenyl)-2H-1,2,3-triazol-4-yl)ethan-1-one (15e). Reaction was carried out using the
described procedure with 0.050 g (0.125 mmol) of vinyl-sulfone 3j. Purification using flash
chromatography (SiO2; EtOAc/petroleum ether = 1:3) and concentration of the relevant fractions
provided the 15e as a colorless oil (0.028 g, 93%). 1H NMR (400 MHz, Chloroform-d) δ 13.00 (bs, 1H),
8.10 (d, J = 7.6 Hz, 1H), 7.42 (ddd, J = 8.4, 7.6, 1.6 Hz, 1H), 7.09 (td, J = 7.6, 1.2 Hz, 1H), 7.04 – 6.95 (m,
1H), 6.01 (ddt, J = 17.2, 10.8, 5.6 Hz, 1H), 5.42 – 5.27 (m, 2H), 4.62 (dt, J = 5.4, 1.4 Hz, 2H), 2.76 (s, 3H);
13C{1H} NMR (101 MHz, Chloroform-d) δ 29.0, 29.8, 69.9, 112.6, 115.0, 119.1, 121.5, 132.0, 132.1,
132.3, 142.5, 155.6, 193.6; MS (ESI): m/z (%) 200 [M-allyl]- (100), 242 [M-H]- (45); HRMS (ESI) m/z: [M
+ H]+ Calcd for C13H14N3O2 244.1081; Found 244.1079.
General procedure for Michael type addition and desulfonation. A vinyl-sulfone (0.69 mmol, 1.0
equiv) was dissolved in MeOH (4.0 mL, 0.2 M) and solution was stirred for 16 hours. After consumption
of the starting material the solvent was evaporated under reduced pressure to yield the crude product,
that was used in the next step without further purification. The resulting methoxy sulfone adduct was
dissolved in THF (7.0 mL, 0.1 M) and AcOH (4.0 mL, 0.2 M). Zn (0.226 g, 5.0 equiv) was added in one
portion and the resulting mixture was stirred overnight. The reaction was quenched upon addition of
EtOAc (20 mL) and the resulting suspension filtered through Celite®, and filtrate cake was washed with
EtOAc (5x20mL). The combined filtrates were washed with sat. NaHCO3 (2x20 mL), brine (2x20 mL),
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dried over MgSO4, filtered, and the solvents were removed under reduced pressure to provide the
crude product.
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4-methoxy-4-phenylbutan-2-one (16a). Reaction was carried out using the described procedure with
0.238 g (0.69 mmol) of vinyl-sulfone 3a. Purification using flash chromatography (SiO2;
EtOAc/petroleum ether = 1:9) and concentration of the relevant fractions provided the 16a as a
colorless liquid (0.051 g, 92% over 2 steps). 1H NMR (400 MHz, Chloroform-d) δ 7.36–7.26 (m, 5H), 4.62
(dd, J = 8.8, 4.4 Hz, 1H), 3.18 (s, 3H), 2.95 (dd, J = 15.6, 8.8 Hz, 1H), 2.57 (dd, J = 15.6, 4.4 Hz, 1H), 2.14
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(s, 3H); C{1H} NMR (101 MHz, Chloroform-d) δ 206.4, 140.9, 128.5, 127.9, 126.4, 79.5, 56.6, 51.9,
31.0; HRMS (ESI) m/z: [M + Na]+ Calcd for C11H14NaO2 201.0886; Found 201.0887.
(3S,4S)-4-((tert-butyldimethylsilyl)oxy)-3-methoxy-1-phenylpentan-1-one (16b). Reaction was carried
out using the described procedure with 0.336 g (0.69 mmol) of vinyl-sulfone 3ag. Purification using
flash chromatography (SiO2; EtOAc/petroleum ether = 1:20) and concentration of the relevant
fractions provided the 16b as a colorless liquid (0.102 g, 43% over 2 steps, d.r.=7:1). 1H NMR (400 MHz,
Chloroform-d) δ 8.01 – 7.95 (m, 2H), 7.60 – 7.53 (m, 1H), 7.49 – 7.43 (m, 2H), 4.08 (qd, J = 6.4, 4.4 Hz,
1H), 3.88 (ddd, J = 8.0, 4.4, 3.6 Hz, 1H), 3.37 (s, 3H), 3.19 – 3.06 (m, 2H), 1.17 (d, J = 6.4 Hz, 3H), 0.88 (s,
9H), 0.07 (d, J = 7.2 Hz, 6H); 13C{1H} NMR (101 MHz, Chloroform-d) δ 199.4, 137.6, 133.1, 128.7, 128.4,
80.8, 68.1, 58.6, 38.5, 26.0, 18.2, 17.9, -4.5, -4.7; HRMS (ESI) m/z: [M + Na]+ Calcd for C18H30NaO3Si
훼22
345.1862; Found 345.1855;
=-7.1 (c 0.65,퐶퐻퐶푙3).
퐷
General procedure for Michael type allylation or reduction and desulfonation. A vinyl-sulfone (0.290
mmol, 1.0 equiv) was dissolved in CH2Cl2 (3.0 mL, 0.1 M) and the solution was cooled down to -78°C
(acetone/dry ice). After 30 minutes, Nu (0.290 mmol, 3.0 equiv) was added and the mixture stirred for
another 30 minutes, followed by addition of TiCl4 (0.870 mL, 3.0 equiv, 1.0M solution in CH2Cl2). The
mixture was stirred for 6 hours. NaHCO3 (10 mL) was added and the suspension warmed to r.t.. The
aqueous phase was extracted with CH2Cl2 (4x10 mL) and the combined organic layers were washed
with brine (2x10 mL), dried over MgSO4, filtered, and the solvents were removed under reduced
pressure. The crude product was used in the next step without further purification. Crude sulfone was
dissolved in THF (3.0 mL, 0.1 M) and AcOH (1.5 mL, 0.2 M) and Zn (0.019 g, 5.0 equiv) was added in
one portion. The resulting heterogenic mixture was stirred overnight before it was quenched with the
addition of EtOAc (20 mL). The resulting slurry was filtered through Celite® and the filtrate cake was
washed with EtOAc (5x15mL). The filtrates were washed with sat. NaHCO3 (2x15 mL), brine (2x15 mL),
dried over MgSO4, filtered, and the solvents removed under reduced pressure to yield the crude
product.
4-phenylbutan-2-one (16c). Reaction was carried out using the described procedure with 0.100 g (0.29
mmol) of vinyl-sulfone 3a. Purification using flash chromatography (SiO2; EtOAc/petroleum ether =
1:10) and concentration of the relevant fractions provided the 16c as a colorless liquid (0.037 g, 87%
over 2 steps). 1H NMR (400 MHz, Chloroform-d) δ 7.28-7.26 (m, 2H), 7.22–7.16 (m, 3H), 2.89 (t, J = 7.6
13
Hz, 2H), 2.76-2.72 (m, 2H), (t, J = 7.6 Hz, 2H), 2.14 (s, 3H); C{1H} NMR (101 MHz, Chloroform-d) δ
207.8, 140.9, 128.4, 128.2, 126.0, 45.1, 30.1, 29.6; HRMS (ESI) m/z: [M + H]+ Calcd for
C10H13O 149.0961; Found 149.0961.
4-phenylhept-6-en-2-one (16d). Reaction was carried out using the described procedure with 0.100 g
(0.29 mmol) of vinyl-sulfone 3a. Purification using flash chromatography (SiO2; EtOAc/petroleum ether
= 1:8) and concentration of the relevant fractions provided the 16d as a colorless oil (0.040 g, 74% over
2 steps). 1H NMR (400 MHz, Chloroform-d) δ 7.32 – 7.26 (m, 2H), 7.22 – 7.16 (m, 3H), 5.72 – 5.58 (m,
1H), 5.03 – 4.94 (m, 2H), 3.26 (p, J = 7.2 Hz, 1H), 2.82 – 2.68 (m, 2H), 2.39 – 2.33 (m, 2H), 2.02 (s, 3H);
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13C{1H} NMR (101 MHz, Chloroform-d) δ 207.8, 144.2, 136.3, 128.6, 127.6, 126.6, 116.9, 49.7, 41.0,
40.9, 30.8; HRMS (ESI) m/z: [M + H]+ Calcd for C13H17O: 189.1274, found 189.1274.
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3-phenylhex-5-enenitrile (16e). Reaction was carried out using the described procedure with 0.050 g
(0.153 mmol) of vinyl-sulfone 6a. Purification using flash chromatography (SiO2; EtOAc/petroleum
ether = 1:6) and concentration of the relevant fractions provided the 16e as a colorless oil (0.019 g,
72% over 2 steps). 1H NMR (400 MHz, Chloroform-d) δ 7.39 – 7.32 (m, 2H), 7.30 – 7.27 (m, 1H), 7.25 –
7.21 (m, 2H), 5.66 (ddt, J = 17.2, 10.0, 7.2 Hz, 1H), 5.12 (dq, J = 17.2, 1.6 Hz, 1H), 5.07 (ddt, J = 10.0, 2.0,
1.2 Hz, 1H), 3.04 (p, J = 7.2 Hz, 1H), 2.70 – 2.57 (m, 2H), 2.55 (tt, J = 7.2, 1.2 Hz, 2H); 13C{1H} NMR (101
MHz, Chloroform-d) δ 141.4, 134.7, 128.9, 127.6, 127.3, 118.5, 118.2, 41.8, 39.2, 24.0; HRMS (ESI) m/z:
[M]+ Calcd for C12H13N 171.1048; Found 171.1049.
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General procedure for Lewis acid-mediated rearrangement. A vinyl-sulfone (0.050 g, 0.145 mmol, 1.0
equiv) was dissolved in CH2Cl2 (1.5 mL, 0.1 M) at r.t., and TiCl4 (0.580 mL, 4.0 equiv, 1.0M solution in
CH2Cl2) was added. The mixture was stirred for 1 hour at r.t. prior to addition of CH2Cl2 (10 mL) and sat.
NH4Cl (5 mL). The resulting suspension was filtered through Celite® and the filter cake was washed
with CH2Cl2 (5x10mL). The combined organic layers were washed with brine (2x10 mL), dried over
MgSO4, filtered, and the solvent removed under reduced pressure to yield the crude product.
3-(3-oxo-1-phenylbutyl)benzo[d]thiazol-2(3H)-one (18). Reaction was carried out using the described
procedure with 0.050 g (0.145 mmol) of vinyl-sulfone 3a. Purification using flash chromatography
(SiO2; EtOAc/petroleum ether = 1:6) and concentration of the relevant fractions provided the 18 as a
pale-yellow oil (0.043 g, 68%). 1H NMR (400 MHz, Chloroform-d) δ 7.41 – 7.35 (m, 3H), 7.35 – 7.27 (m,
1H), 7.16 – 7.10 (m, 2H), 6.01 (dd, J = 8.0, 6.0 Hz, 1H), 3.96 (dd, J = 18.0, 8.0 Hz, 1H), 3.44 (dd, J = 18.0,
13
6.0 Hz, 1H), 2.22 (s, 3H); C{1H} NMR (101 MHz, Chloroform-d) δ 205.4, 138.2, 137.2, 129.1, 128.3,
127.0, 126.4, 122.9, 122.7, 111.9, 54.5, 45.8, 30.3.; MS (ESI), m/z (%) 297 [M+1]+ (100); HRMS (ESI) m/z:
[M]+ Calcd for C17H15NO2S 297.0823; Found 297.0825.
General procedure for 1,4 reduction of vinyl-sulfones. Procedure A: A vinyl-sulfone (0.582 mmol, 1.0
equiv) was dissolved in CH2Cl2 (6.0mL, 0.1 M) and solution was cooled down to -78°C (acetone/dry ice).
After 15 minutes, nBu3SnH (0.138 mL, 1.1 equiv) was added and the mixture was stirred for additional
30 minutes. After consumption of the starting material, CH2Cl2 (10 mL) was added and the reaction
mixture was washed with brine (2x10 mL), dried over MgSO4, filtered, and the volatiles were removed
under reduced pressure. The crude material was dissolved in CH3CN (25mL) and washed with hexane
(2x20mL) to remove any remaining organotin compounds. The resulting acetonitrile solution was
concentrated under reduced pressure to provide the crude product. Procedure B: A vinyl-sulfone
(0.582 mmol, 1.0 equiv) was dissolved in THF (0.1 M) and solution was cooled down to -78°C
(acetone/dry ice). After 15 minutes, DIBAL (0.640 mL, 1.1 equiv, 1M solution in hexane) was added
dropwise and the mixture was stirred at -78°C for 10 min and at r.t. for another 1 h (consumption of
the SM monitored by TLC). After consumption of starting material, the reaction mixture was cooled
down to -78°C, and saturated aq. solution of Rochelle salt (5 mL) was added. The resulting mixture was
allowed to warm to r.t. and stirred until the solution became clear (cca 6 hours). The whole mixture
was extracted with CH2Cl2 (3x5 mL). The combined organic layers were washed with brine (2x10 mL),
dried over MgSO4, filtered, and solvents were removed under reduced pressure to provide the crude
product.
3-(benzo[d]thiazol-2-ylsulfonyl)-4-phenylbutan-2-one (17c). Reaction was carried out using the
described procedure with 0.200 g (0.583 mmol) of vinyl-sulfone 3a. Purification using flash
chromatography (SiO2; EtOAc/petroleum ether = 1:4) and concentration of the relevant fractions
1
provided the 17c as a yellow solid Procedure A (0.181 g, 91%); Procedure B (0.170 g, 85%). H NMR
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(400 MHz, Chloroform-d) δ 8.32 – 8.23 (m, 1H), 8.09 – 7.95 (m, 1H), 7.76 – 7.55 (m, 2H), 7.25 – 7.16
(m, 3H), 7.14 – 7.08 (m, 2H), 4.91 (dd, J = 9.2, 5.6 Hz, 1H), 3.55 – 3.36 (m, 2H), 2.27 (s, 3H); 13C{1H} NMR
(101 MHz, Chloroform-d) δ 32.8, 32.9, 75.6, 122.5, 125.9, 127.5, 128.0, 128.5, 129.0, 129.1, 135.4,
137.3, 152.7, 164.1, 198.2; MS (ESI), m/z (%) 346 [M+1]+ (100); HRMS (ESI) m/z: [M + H]+ Calcd for
C17H16NO3S2 346.0566; Found 346.0563.
2-(benzo[d]thiazol-2-ylsulfonyl)-1,3-diphenylpropan-1-one (17f). Reaction was carried out using the
described procedure with 0.100 g (0.246 mmol) of vinyl-sulfone 3aa. Purification using flash
chromatography (SiO2; EtOAc/petroleum ether = 1:3) and concentration of the relevant fractions
provided the 17f as a colorless oil: Procedure A: (0.090 g, 90%); Procedure B: (0.081 g, 81%). 1H NMR
(400 MHz, Chloroform-d) δ 8.23 – 8.18 (m, 1H), 8.01 – 7.92 (m, 1H), 7.79 – 7.69 (m, 2H), 7.68 – 7.53
(m, 2H), 7.49 – 7.38 (m, 1H), 7.35 – 7.24 (m, 2H), 7.20 – 7.04 (m, 5H), 5.82 (dd, J = 10.8, 3.6 Hz, 1H),
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3.82 – 3.62 (m, 2H); C{1H} NMR (101 MHz, Chloroform-d) δ 33.7, 70.6, 122.4, 125.8, 127.3, 127.8,
128.4, 128.7, 128.9, 129.2, 134.1, 135.6, 137.0, 137.4, 152.6, 164.3, 191.0; MS (ESI), m/z (%) 408 [M+1]+
(100); HRMS (ESI) m/z: [M+ H]+ Calcd for C22H18NO3S2 408.0723; found 408.0725.
General procedure for 1,2 reduction of vinyl sulfones. A vinyl-sulfone (0.290 mmol, 1.0 equiv) was
dissolved in CH2Cl2 (30 mL, 0.01 M) and resulting solution was cooled to -78°C (acetone/dry ice). After
15 minutes, DIBAL-H (0.320 mL, 1.1 equiv, 1M solution in hexane) was added dropwise and the mixture
was stirred at -78°C for an additional 4 hours. After consumption of the starting material (checked via
TLC), a saturated aqueous solution of Rochelle salt (5 mL) was added and the reaction mixture was
allowed to warm to r.t.. The resulting mixture was stirred until the solution became clear (cca 6 hours).
The whole mixture was extracted with CH2Cl2 (3x10 mL). The combined organic layers were washed
with brine (2x10 mL), dried over MgSO4, filtered, and the solvents were removed under reduced
pressure to provide the crude product.
(E)-3-(benzo[d]thiazol-2-ylsulfonyl)-4-phenylbut-3-en-2-ol (19a). Reaction was carried out using the
described procedure with 0.100 g (0.291 mmol) of vinyl-sulfone 3a. Purification using flash
chromatography (SiO2; EtOAc/petroleum ether = 1:4) and concentration of the relevant fractions
provided the 19a as a pale-yellow oil (0.080 g, 80%). 1H NMR (400 MHz, Chloroform-d) δ 8.20 – 8.14
(m, 1H), 8.07 (s, 1H), 8.02 – 7.97 (m, 1H), 7.67 – 7.52 (m, 4H), 7.45 (dd, J = 5.2, 2.0 Hz, 3H), 5.23 (q, J =
6.8 Hz, 1H), 1.63 (d, J = 6.8 Hz, 3H); 13C{1H} NMR (101 MHz, Chloroform-d) δ 22.2, 64.8, 122.5, 125.4,
127.7, 128.1, 129.0, 130.6, 130.6, 132.7, 136.7, 142.1, 145.3, 152.3, 169.2; MS (ESI), m/z (%) 346 [M+1]+
(100); HRMS (ESI) m/z: [M + H]+ Calcd for C17H16NO3S2 346.0566; Found 346.0565.
(E)-3-(benzo[d]thiazol-2-ylsulfonyl)-4-cyclohexylbut-3-en-2-ol (19c). Reaction was carried out using the
described procedure with 0.050 g (0.143 mmol) of vinyl-sulfone 3p. Purification using flash
chromatography (SiO2; EtOAc/petroleum ether = 1:5) and concentration of the relevant fractions
provided the 19c as a colorless oil (0.034 g, 68%). 1H NMR (400 MHz, Chloroform-d) δ 8.18 – 8.12 (m,
1H), 8.02 – 7.93 (m, 1H), 7.65 – 7.51 (m, 2H), 6.98 (d, J = 10.8 Hz, 1H), 5.04 (dt, J = 13.2, 6.8 Hz, 1H),
2.94 (d, J = 6.0 Hz, 1H), 2.76 (tdt, J = 10.8, 6.8, 3.6 Hz, 1H), 1.84 – 1.64 (m, 5H), 1.54 (d, J = 6.8 Hz, 3H),
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1.34 – 1.17 (m, 5H); C{1H} NMR (101 MHz, Chloroform-d) δ 23.6, 25.2, 25.2, 25.7, 31.8, 31.9, 38.3,
65.1, 122.4, 125.4, 127.6, 128.0, 136.7, 140.7, 152.3, 154.2, 169.0; HRMS (ESI) m/z: [M + H]+ Calcd for
C17H22NO3S2 352.1036; Found 352.1034.
General procedure for radical addition. To a vinyl-sulfone (0.050 g, 0.153 mmol, 1.0 equiv) in benzene
(1.5 mL, 0.1 M) was added ethyl iodide (0.019 mL, 1.5 equiv), (Me3Si)3SiH (0.071 µL, 1.5 equiv) and
AIBN (0.005 g, 0.2 equiv) and reaction mixture was heated (oil bath) to reflux. After consumption of
starting vinyl-sulfone (8 hours), the volatilities were evaporated under reduced pressure to yield the
crude product.
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2-(benzo[d]thiazol-2-ylsulfonyl)-3-phenylpentanenitrile (20). Reaction was carried out using the
described procedure with 0.050 g (0.153 mmol) of vinyl-sulfone 6a. Purification using flash
chromatography (SiO2; EtOAc/petroleum ether = 1:5) and concentration of the relevant fractions
provided the 20 as a colorless oil (0.033 g, 61%, d.r.=1.2 : 1). 1H NMR (400 MHz, Chloroform-d) δ 8.25
– 8.18 (m,2H), 8.01 (ddd, J = 9.6, 7.6, 2.0 Hz, 2H), 7.72 – 7.57 (m, 4H), 7.45 – 7.35 (m, 2H), 7.39 – 7.23
(m, 8H), 4.96 (d, J = 5.6 Hz, 1H), 4.88 (d, J = 3.6 Hz, 1H), 3.75 – 3.62 (m, 2H), 2.36 (dqd, J = 13.6, 7.2, 3.6
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Hz, 1H), 2.21 – 1.95 (m, 3H), 0.91 (t, J = 7.2 Hz, 3H), 0.86 (t, J = 7.2 Hz, 3H); C{1H} NMR (101 MHz,
Chloroform-d) δ 163.4, 163.2, 152.4, 138.2, 137.5, 136.7, 129.3, 129.3, 128.9, 128.8, 128.7, 128.7,
128.5, 128.4, 128.2, 128.1, 128.0, 128.0, 125.9, 125.8, 122.5, 122.5, 112.3, 112.1, 62.1, 61.2, 44.6, 44.1,
27.8, 25.1, 11.8, 11.7; MS (ESI), m/z (%) 357 [M+H]+ (100); HRMS (ESI) m/z: [M + Na]+ Calcd for
C18H16N2NaO2S2 379.0551; Found 379.0546.
(E)-4-phenylbut-3-en-2-one (4). Reaction was carried out using the described procedure with 0.100 g
(0.291 mmol) of vinyl-sulfone 3a. Purification using flash chromatography (SiO2; EtOAc/petroleum
ether = 1:4) and concentration of the relevant fractions provided the 4 as a yellowish solid (0.036 g,
85%, >E/Z= 95 : 1). 1H NMR (500 MHz, Chloroform-d) δ 7.56 – 7.54 (m, 2H), 7.52 (d, J = 16.5 Hz, 1H), 7.42 – 7.38
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(m, 3H), 6.72 (d, J = 16.5 Hz, 1H), 2.39 (s, 3H); C{1H} NMR (126 MHz, Chloroform-d) 198.5, 143.5, 134.6,
130.7, 129.1, 128.4, 127.3, 27.7. HRMS (ESI) m/z: [M + H]+ Calcd for C10H11O 147.0804; Found 147.0806.
(E)-isopropyl cinnamate (21). Reaction was carried out using the described procedure with 0.100 g
(0.258 mmol) of vinyl-sulfone 5c. Purification using flash chromatography (SiO2; EtOAc/petroleum
ether = 1:5) and concentration of the relevant fractions provided the 21 as a viscose oil (0.046 g, 82%,
>E/Z= 95 : 1). 1H NMR (500 MHz, Chloroform-d) δ 7.67 (d, J = 16.0 Hz, 1H), 7.52 (dd, J = 7.0, 3.0 Hz, 2H), 7.41 –
7.35 (m, 3H), 6.42 (d, J = 16.0 Hz, 1H), 5.14 (hept, J = 6.0 Hz, 1H), 1.32 (d, J = 6.5 Hz, 6H). 13C{1H} NMR (126 MHz,
Chloroform-d) δ 166.7, 144.4, 134.6, 130.3, 129.0, 128.1, 118.9, 67.9, 22.1; MS (ESI), m/z (%) 191 [M+1]+
(10), 149 (100); HRMS (ESI) m/z: [M+ H]+ Calcd for C12H15O2 191.1067; found 191.1068.
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the ACS Publications website.
Relevant optimization tables, discussion relevant stereochemical outcomes of reactions, discussion of
the stereochemistry of obtained compounds, and a copy of 1H and 13C{1H} NMR spectra. (PDF)
AUTHOR INFORMATION
Corresponding Author
* E-mail: j.pospisil@upol.cz
Author Contributions
O.K., F.Z. and D.J.-Y.D.B. performed most of the experiments and analyzed experimental data. L.V.B.
and O.K. carried out the Smiles-like rearrangement. L.R., O.K. and M.W. performed and optimized
[4+1]-cycloaddition reaction. O.K. and D.J.-Y.D.B. partially designed the experimental plans. J.P.
initiated the project, led the project team, designed experiments, analyzed results, and wrote the
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paper with input from all authors. All authors have given approval to the final version of the
manuscript.
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ORCID
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Ondřej Kováč: 0000-0001-5721-5537
František Zálešák: 0000-0003-1469-5248
David J. -Y. D. Bon: 0000-0001-7867-6877
Lubomír V. Baar: 0000-0002-6649-0853
Mario Waser: 0000-0002-8421-8642
Jiří Pospíšil: 0000-0002-0198-8116
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
The financial support by the Ministry of Education, Youth and Sports of the Czech Republic (grant
LO1304 from the National Program of Sustainability) and (grant LO1204 from the National Program of
Sustainability I) as well as by the Internal Grant Agency of Palacky University (IGA_PrF_2019_020, and
IGA_PrF_2019_027) is gratefully acknowledged. JP is grateful for support from European Regional
Development
Fund-Project
“Centre
for
Experimental
Plant
Biology”
(no.
CZ.02.1.01/0.0/0.0/16_019/0000738), and to prof. M. Strnad, Dr. K. Doležal and prof. J. Hlaváč (Palacky
University) for their continuous support. JP is grateful to Dr. Alain De Mesmaeker (Syngenta Crop
Protection AG) for stimulating discussions. JP would like to thanks to all reviewers for their valuable
suggestions.
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