A greener and efficient access to substituted four- and six-membered sulfur-bearing heterocycles

Article abstract of DOI:10.1039/c7ob00846e

The regioselective functionalization of four- and six-membered cyclic sulfones was investigated using a lithiation/electrophile trapping strategy. The protocol features an interesting eco-compatibility profile because of the use of 2-MeTHF as a solvent (more eco-friendly than other organic solvents) and n-hexyllithium as a lithiating agent safer than other alkyllithium compounds. Several derivatives were prepared with different stereochemistry and substitution patterns. A number of selected derivatives, spanning a range of 5 logP units, were characterized for their lipophilicity through RP-HPLC. A good linear correlation, with a slope close to 1.0, was observed between the experimentally determined RP-HPLC lipophilicity parameters (logk′_w) and calculated logP (clogP) values, whereas a systematic difference in absolute values between the chromatographic parameters and in silico lipophilicity descriptors can be attributed mainly to silanophilic interactions between the H-bond acceptor SO₂ group and free silanol groups on silica-based C18 columns, which results in increased retention times.

Full text of DOI:10.1039/c7ob00846e

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Degennaro, C. Carlucci, M. de Candia, P. Mastrorilli, A. Roller, W. Holzer, C. D. Altomare, V. Pace and R.
Luisi, Org. Biomol. Chem., 2017, DOI: 10.1039/C7OB00846E.
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ISSN 1477-0520
COMMUNICATION
Takeharu Haino et al.
Solvent-induced emission of organogels based on tris(phenylisoxazolyl)
benzene
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A Greener and Efficient Access to Substituted Four- and Six-
membered Sulfur-bearing Heterocycles
Giovanna Parisi,a Leonardo Degennaro,a Claudia Carlucci,a Modesto de Candia,a Piero
Mastrorilli,b Alexander Roller,c Wolfgang Holzer,d Cosimo Damiano Altomare,*,a
Vittorio Pace,*,d Renzo Luisi*,a
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
ABSTRACT The regioselective functionalization of four- and six-membered cyclic sulfones was investigated using a
lithiation/electrophile trapping strategy. The protocol features an interesting eco-compatibility profile because of the use
of 2-MeTHF as a solvent (more eco-friendly than other organic solvents) and n-hexyllithium as a lithiating agent safer than
other alkyllithium compounds. Several derivatives were prepared with different stereochemistry and substitution
patterns. A number of selected derivatives, spanning a range of 5 log P units, were characterized for their lipophilicity
through RP-HPLC. A good linear correlation, with a slope close to 1.0, was observed between the experimentally
determined RP-HPLC lipophilicity parameters (log k’w) and calculated log P (clogP) values, whereas a systematic difference
in absolute values between the chromatrographic parameters and in silico lipophilicity descriptors can be attributed
mainly to silanophilic interactions between the H-bond acceptor SO2 group and free silanol groups on silica-based C18
columns, which results in increased retention times.
chlorination reactions.11
Introduction
In
inhibitors, Velàsquez and co-workers performed the lithiation of
four-, five-, and six-membered cyclic sulfones followed by
trapping with sulfynylimine that occurred with low
stereoselectivity.12 However, Velàsquez’s work was focused on the
a more recent work, aimed at obtaining some protease
Sulfur-bearing heterocycles have been extensively used as versatile
intermediates in organic synthesis and medicinal chemistry. In
particular, sulfone moiety is a strong H-bond acceptor considered as
carbonyl group bioisostere. Cyclic sulfones have unique synthetic
utilities and several examples of drugs and drug candidates,
including antitrypanosomal drug (Nifurtimox)®, antiglaucoma agent
(Dorzolamide)®, kinase inhibitors,1 cannabinoid receptor 2-
agonists,2 agents for the treatment of endometriosis3 and antiviral
compounds4 have been reported (Figure 1). Cyclic sulfones, such as
thietane and tetrahydro-2H-thiopyrane 1,1-dioxide, are considered
interesting analogs of oxetane and sulfonyl-oxetanes in fragment-
based drug discovery (FBDD) approaches.5 The interest towards
small cyclic compounds bearing sulfone moieties is motivated by
the paucity of efficient methodologies for metalation and
functionalization of these systems have been scarcely investigated.
In striking contrast, examples on the reactivity of five-membered
cyclic sulfones have been reported.6-10 Nevertheless, four- and six-
membered cyclic sulfones have been less explored. The few
examples on the metalation and functionalization of thietan 1,1-
dioxide at the α position, rely only on the α-bromination and α-
a
a
preparation of the pharmaceutical target rather than on
systematic study of the reactivity of cyclic sulfones.
a
Our research group recently focused the attention on the reactivity
and functionalization of four-membered heterocycles including
azetidines and thietanes, which are interesting and poorly
investigated molecular scaffolds.13
In previous works on the reactivity of thietane 1-oxide, we disclosed
that the metalation and trapping sequence with various
electrophiles occurred with
a variable degree of regio- and
stereoselectivity.14 The chemical stability of lithiated C2-substituted
thietane 1-oxides as well as the stereoselective functionalization at
the C2, C4 positions of the ring have been also reported.15 On these
grounds, we decided to investigate the regio- and stereoselectivity
of the metalation reactions of thietane 1,1-dioxide, in comparison
with six-membered homologues such as tetrahydro-2H-thiopyran
1,1-dioxide. We report herein the results of this synthetic
investigation, as well as a preliminary study on the lipophilicity (a
fundamental physicochemical property in the drug-discovery
process) of the newly synthesized cyclic sulfone derivatives.
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Thietane 1,1-dioxides-bearing bioactive molecule
O
S
O
S
O
S
O
S
O
O
O
O
N
N
N
N
N
N
O
N
N
N
N
H
O
N
F
N
N
CF3
N
N
N
O
N
S
O
NC
F
H2N
F
NC
O
Tropomyosin-Related
Kinase Inhibitor
Tyrosine Kinase Inhibitor
Cannabinoid Receptor
2-Agonist
Derivate for use in the
treatment of endometriosis
Tetrahydro-2H-thiopyran 1,1-dioxides-bearing bioactive molecule
O
N
O
S
O
N
O
O
O
O
HN
HN
N
N
S
O
S
S
HN
O
O
O
N
R
O
N
S
O
NH2
O
NH
O2N
N
O
N
Antiglaucoma
(Dorzolamide)
Antitrypanosomal
(Nifurtimox)
Antivaricella Zoster Virus
Tyrosine Kinase Inhibitor
Figure 1. Examples of biologically active molecules bearing a four- or six-membered cyclic sulfone unit.
Table 1. Optimization of the lithiation/trapping of thietane 1,1-dioxide.
1) Base
O
O
O
O
O
O
2) BnBr
S
S
Ph
S
Conditions:
solvent, time, Temp. °C
Ph
Ph
1
2a
3a
Entry
Base (equiv)
LDA (1.1)
BnBr (equiv)
Solvent
Time
Temperature (°C)
Ratio 2a/3a Yield (%)
1
THF
15 min
15 min
15 min
5 min
10 min
2 min
2 min
2 min
1 min
1 sec
-78
-78
-78
-78
-78
-50
-20
-10
-20
-20
57:43b
86:14d
75:25c
100/0
0/100
0/100
0/100
0/100
0/100
0/100
70e
77e
80e
75f
60f
22f
20f
15f
22f
14f
1
2
LDA (1.1)
1
Toluene
Toluenea
2-MeTHF
2-MeTHF
2-MeTHF
2-MeTHF
2-MeTHF
2-MeTHF
2-MeTHF
3
HexLi (1.1)
HexLi (1.1)
HexLi (2.5)
HexLi (2.5)
HexLi (2.5)
HexLi (2.5)
HexLi (2.5)
HexLi (2.5)
1
4
1
5
2.5
2.5
2.5
2.5
2.5
2.5
6
7
8
9
10
a TMEDA (1.1 equiv) was employed as co-solvent. bRatio of disubstituted thietanes 3a trans/cis (25/75) as ascertained by H NMR. cRatio of
1
1
d
disubstituted thietanes 3a trans/cis (>99:1) as ascertained by H NMR. Ratio of disubstituted thietanes 3a trans/cis (54/46) as ascertained
by 1H NMR. Stereochemistry assigned on the basis of the chemical equivalence of the ring protons. eEstablished by 1H NMR. Yield of
f
isolated product.
.
We first investigated, the lithiation of thietane 1,1-dioxide 1 under However, the use of LDA either in polar solvent such as THF or less
different reaction conditions (Table 1) using benzyl bromide (BnBr) polar one such as toluene, resulted in a mixture of C2 mono-, and
as the electrophile.
C2, C4 di-substituted derivatives 2a and 3a respectively (Table 1,
The cyclic α-sulfonyl carbanion could be generated by using either entries 1-2). The use of 1.1 equiv of HexLi in toluene also provided a
LDA (lithium diisopropylamine) or n-hexyllithium (HexLi) as bases. 75:25 mixture of 2a and 3a, with a good overall yield. However, the
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di-substituted derivative 3a was obtained exclusively as trans leading to C2-functionalized thietanes 2a-q (Scheme 1) in good
stereoisomer (Table 1, entry 3). The use of the greener solvent 2- yields. Good control of stereoselectivity was achieved in the case of
MeTHF, gave a more selective reaction leading to 2a in 75% yield prochiral electrophiles 2k-q (Scheme 1). Double functionalization at
and as single product (Table 1, entry 4). 16 Nicely, lithiation of 1 with the two α-positions (C2, C4) of the thietane was carried out by
2.5 equiv of HexLi, followed by reaction with benzylbromide, following the established conditions (Table 1, entry 5). The
furnished exclusively the C2,C4 di-substituted derivative 3a as single lithiation/trapping sequence occurred with good yields and an
trans stereoisomer (Table 1, entry 5). Performing the acceptable
trans
stereoselectivity
using
benzylbromide,
lithiation/trapping sequence at higher temperatures (in the range benzophenone and Weinreb amides as electrophiles. The structure
between –20 and -50 °C), resulted in lower yields of trapping and stereochemistry for the major stereoisomer (2R*,4R*)-3e and
product 3a, likely because of the thermal instability of the lithiated the minor one (2R*,4S*)-3e was ascertained by single crystal X-ray
intermediate (Table 1, entries 6-10).
analysis.19 The use as electrophile of Weinreb amides, which can be
The preliminary screening of the lithiation/trapping of 1, indicated subjected to a nucleophilic attack by the base, suggests that the
conditions of entries 4 and 5 as the optimal ones for the mono or double functionalization could be likely ascribed to a double
di-substitution, respectively. The inherent advantages of using 2- lithiated intermediate such as 1-2Li (Scheme 2).
MeTHF as the reaction medium – in primis the non-needing of
1) nꢀHexLi
(2.5 equiv)
classical (contaminating) organic solvents during the work-up
O
O
O
O
O
O
2) E
S
1
procedures 17– render the whole synthetic process appealing from
an eco-compatibility perspective. After optimization, the scope of
the lithiation/trapping sequence was investigated. The use of 1.1
equiv of HexLi, guaranteed the mono functionalization of thietane
1,1-dioxide 1.
S
S
Li
Li
E
E
2ꢀMeTHF
ꢀ78 °C, 10 min
3a-e
1-2Li
lithiated
intermediate
O
O
O
O
O
O
Ph
HO
Ph
Ph
OH
Ph
Ph
Ph
Ph
OH
Ph
S
S
S
HO
Ph
Ph
+
(2R*, 4R*)ꢀ3a
(2R*, 4R*)ꢀ3b
Major
(2R*, 4S*)ꢀ3b
Minor
Major, 60%
78%, dr 70:30
t-Bu
t-Bu
O
O
O
O
O
+
O
S
S
O
O
(2R*, 4R*)ꢀ3c
Major
(2R*, 4S*)ꢀ3c
Minor
t-Bu
t-Bu
72%, dr 70:30
Cl
Cl
O
O
O
O
O
O
S
+
S
O
O
(2R*, 4R*)ꢀ3d
(2R*, 4S*)ꢀ
3d
Cl
Minor
Major
Cl
67%, dr 70:30
F3C
F3C
O
O
O
O
O
O
S
+
S
O
O
(2R*, 4R*)ꢀ3e
Major
(2R*, 4S*)ꢀ3e
Minor
CF3
CF3
60%, dr 80:20
Scheme 2. Double functionalization of thietane 1,1-dioxide 1.
Scheme 1. Mono-functionalization of thietane 1,1-dioxide 1.
With the aim to demonstrate the involvement of a doubly lithiated
species such as 1-2Li, excluding
a sequential lithiation, a
Trapping of lithiated thietane 1-Li efficiently occurred with different
lithiation/deuteration experiment was run on thietane 1,1-dioxide 1
(see Supporting Information). NMR and HRMS analyses gave
support to a double lithiation at C2 and C4 carbons of 1.20,21
carbonyl-type electrophiles including aldehydes or ketones,
18
Weinreb amides, isocyanates, carbon dioxide. Analogously, silyl
and benzyl halides also proved to be suitable electrophilic partners
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Next, by using the conditions optimized for the mono functionalization are those reported in Table 2, entry 1. However, a
functionalization (Table 1, entry 4), we explored the possibility to selective C2, C4 double functionalization was hard to achieve likely
introduce a different substituent at the C4 of C2 mono-substituted for a competing double H-abstraction. Surprisingly, the solvent as
thiethanes 2. Compounds 2a,b were employed as starting well as the electrophile, seem to play a role in the regioselectivity of
materials, and subjected to a lithiation/trapping sequence with the lithiation reaction (compare entries 3 and 4 of Table 2). In this
different electrophiles, including MeI, BnBr, benzophenone and 4- regard, the four- and six-membered rings behave differently giving,
tert-butyl-N-methoxy-N-methyl-benzamide. Non symmetrically the smaller heterocycle, a more regioselective lithiation and a
substituted C2,C4 di-functionalized thietanes 4a-c were obtained in preferential trans-stereoselectivity in the double functionalization
good yields although as a mixture of diastereoisomers with modest reactions. .
stereoselectivity (Scheme 3). The stereochemistry was assigned by Under optimized conditions (Table 2, entry 1), thiopyran 5 was
Noesy experiments (see supporting information) that revealed a functionalized at the C2 with several electrophiles furnishing
trans stereochemical preference in alkylation reactions (as for products 6a-g (Scheme 4). With a prochiral aldehyde, a 1:1 mixture
(2R*,4R*)-4a and (2R*,4R*)-4b), while the cis stereoisomer was the of diastereoisomers was observed for adduct 6f. As reported for
main one in acylation reactions (as for (2R*,4R*)-4c).
thietane 1, even in this case the reaction could be conducted in a
greener solvent that does not require work-up procedures in order
to obtain the crude reaction mixture (see experimental section).
Scheme 4. C2 functionalization of tetrahydro-2H-thiopyran 1,1-
Scheme 3 C2,C4 double functionalization of mono substituted
dioxide.
thietane 1,1-dioxides.
From a stereochemical point of view, the results reported in
Schemes 2 and 3 show a trans stereochemical bias in the double
functionalization of thietane sulfones 1, 2a and 2b. Such
stereochemical preference could be rationalized considering the
steric effect brought about the already present C2-substituent.
However, further lithiation/deuteration experiments run on
(2R*,4R*)-3a, and on the diastereomeric mixture of keto thietane
sulfones (2R*,4R*)- and (2R*,4S*)-3d suggested that likely kinetic
products are observed under the reaction conditions (see
Supporting information for details). In the case of enolizable keto-
substituted thietane sulfones, the trans-configured stereoisomers
(Scheme 2) are likely also the thermodynamic products. However,
this kind of compounds, in protic solvent such as MeOH, undergo to
a very fast epimerization that could alter the final diastereomeric
ratio (see supporting information for details).
For sake of comparison, the lithiation trapping of six-membered
heterocycle tetrahydro-2H-thiopyran 1,1-dioxide (5) was further
investigated (Table 2).
As reported in Table 2, a mixture of mono and di substituted
derivatives 6 and 7 was obtained in all cases. The structure and
stereochemistry of the main isomer cis-7a was confirmed by single
crystal X-Ray analysis.22 The best conditions for the C2 mono
4 | J. Name., 2012, 00, 1-3
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Table 2. Optimization of the lithiation/trapping of tetrahydro-2H-thiopyran 1,1-dioxide.
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Entry
HexLi
(equiv)
1.1
Electrophile
Solvent
Time
(min)
10
Ratio
Yield
(%)a
50b
80c
6/7
1
2
3
4
BnBr (1 equiv)
2-MeTHF
THF
90/10d
87/13 d
10/90 d
2.5
BnBr (2.5 equiv)
BnBr (2.5 equiv)
Weinreb amided
10
2.5
2-MeTHF
30
60b
80c
2.5
2-MeTHF
30
85/15 e
aYield of isolated major adduct; bYield of isolated product. cAscertained by H NMR. d4-t-
Butyl-N-methoxy-N-methyl-benzamide (2.5 equiv). dThe C2,C6 disubstituted derivative
7a, was obtained as a 80:20 cis:trans mixture. eThe C2,C6 disubstituted derivative wasn’t
isolated.
1
Next, we examined the double functionalization of C2-substituted The reactivity of lithiated four- and six-membered cyclic sulfones 1
thiopyrans 6a,b disclosing an electrophile-dependent and 5 was also tested in more challenging reactions such as C2
stereoselectivity after introducing the second electrophile (Scheme arylation and fluorination (Scheme 6, a,b)
5). Derivatives 8a,b were obtained in acceptable yields but with a The direct α-arylation on both cyclic sulfones
1 and 5 was
variable degree of stereoselectivity depending on the electrophile. investigated first. Lithiation with HexLi, followed by
Interestingly, and in striking contrast to the four membered ring, transmetallation with CuCN-2LiCl, and reaction with aryliodonium
alkylation reaction with MeI furnished the cis stereoisomer (2R*, salt Ph2IPF6, as arylating agent was successful producing derivatives
6R*)-8b as the main product (dr 90:10), while acylation with a 9a,b in acceptable yields (Scheme 6, a). Surprisingly, lithiathion of
Weinreb amide gave (2R*, 6R*)-8a as the main stereoisomer (dr thietane 1,1-dioxide 1 and tetrahydro-2H-thiopyran 1,1-dioxide 5
60:40).
followed
by
subsequent
trapping
with
N-
Fluorodibenzenesulfonimide (NFSI) as the fluorinating agent, led,
almost unexpectedly, to products 10a,b (Scheme 9). It is likely that
the introduction of the fluorine at C2 renders the remaining proton
very acidic to be removed under the basic reaction conditions,
allowing a further sulfonylation.
Finally, these new transformations were also tested on five-
membered sulfolane that has been already studied in lithiation
24
trapping reactions.
We were glad to find that, under the
developed reaction conditions (Scheme 6) sulfolane 11 furnished
either the C2-arylated product 9c, or the α,α di-functionalized
fluorinated derivative 10c. In the case of 10a, the structure of this
unusual fluoro sulfonylated derivative was confirmed by single
crystal X-ray analysis.25
Scheme 5. C2, C4 di-functionalization of tetrahydro-2H-thiopyran
1,1-dioxide.
The different stereochemical preference observed in the double
(C2, C6) functionalization of thiopyrans, with respect to the four-
membered ring, could be explained considering
a different
thermodynamic stability of the C2, C6 di-substituted derivatives.
It is likely, that in thiopyrans, it is preferred the stereoisomer that
sets the two susbstituents in di-equatorial fashion as seen with 7a
(Table 2) where X-ray analysis is available, and (2R*,6R*)-8b where
higher stereoselectivity was observed.23
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1) n-HexLi, ꢀ78 °C, t
2) CuCN — 2LiCl, ꢀ78 °C
to ꢀ35 °C, 30 min
The comparison between the chromatographic parameters and in
silico lipophilicity descriptors showed that better linear
O
O
O
O
S
S
a
relationship, which holds up over a range of about 5 log P units,
exists between log k’w and clogP calculated by Bio-Loom software,
as shown by the following equation:
a)
Ph
2IPF6, ꢀ78 °C to rt
3)
n
n
9a
9b
9c
n = 1, 50%
n = 3, 60%
n = 2, 70%
1
5
11
t
t
t
n = 1, = 10 min
n = 3, = 30 min
n = 2, = 30 min
log k’w = 0.84 (±0.06) clogP + 1.51 (±0.12)
n = 24, r2 = 0.885, s = 0.411, F = 168
(1)
O
O
O
O
F
S
S
1) n-HexLi (1.1 equiv)
2ꢀMeTHF, ꢀ78 °C, 5'
b)
S
n
n
O
2) NFSI (1 equiv)
where n represents the number of data points, r2 the coefficient of
determination (squared correlation coefficient), s the standard
deviation of the regression equation, and F is the statistical
significance of fit; 95% confidence intervals of the regression
coefficients are given in parentheses.
O
10a
10b
10c
n = 1, 30%
n = 3, 50%
n = 2, 50%
1
5
11
n = 1
n = 3
n = 2
A closer look to the scatter plot relating log k’w and clogP (Figure 2)
points out that there are two groups of points lying on two almost
parallel lines. The separate regression analysis yielded the following
linear equations, one gathering all the 2-MTE derivatives (eq. 2) and
the other gathering the 2,4-DTE, 2-MTHTP and 2,6-DTHTP
derivatives (eq. 3):
10a
n = 1,
Scheme 6. a) C2-Arylation of cyclic sulfones. b) C2-Fluorination of
cyclic sulfones.
After investigating the reactivity of cyclic sulfones, the lipophilicity of
24 selected derivatives, including C2-mono- and C2,C4-
difunctionalized four-membered (2-MTE and 2,4-DTE respectively)
and C2-mono- and one C2,C6-difunctionalized six-membered (2-
MTHTP and 2,6-DTHTP respectively) cyclic sulfones, was assessed
through reversed-phase high performance liquid chromatography
(RP-HPLC). Lipophilicity is an important property affecting
absorption, distribution, metabolism, excretion and toxicity
log k’w = 1.04 (±0.15) clogP + 1.65 (±0.10)
(2)
(3)
n = 11, r2 = 0.846, s = 0.281, F = 49.3)
log k’w = 1.09 (±0.075) clogP + 0.76 (±0.19)
n = 13, r2 = 0.951, s = 0.294, F = 211.6
The slope value (sensitivity) close-to-one in both eqs. 2 and 3
suggests that the solvophobic interactions involved in the octanol-
water partitioning have similar effects on the RP-HPLC retention of
the cyclic sulfone derivatives.
(ADMET) of
a potential drug substance, and therefore its
determination has relevance in the drug discovery process.26,27
Compared to the classical ‘shake-flask’ method, the RP-HPLC
methods are less time- and sample-consuming, insensitive to
impurities and less affected by low solubility of the analyte in one or
both the liquid phases.28,29 RP-HPLC has become a practical method
for measuring drug lipophilicity at the early stages of drug
discovery.30 Two-phase titration (potentiometry),31,32 which
represents a reliable method for measuring lipophilicity of ionizable
compounds, does not apply in our case.
In contrast, the positive intercept values (+1.65 and + 0.76 in eqs. 2
and 3, respectively) can be attributed to the so-called ‘silanophilic’
interactions with free silanol groups on the silica-based C18
stationary phase, which results in increased log k’w values.
In this study, the relative lipophilicity of cyclic sulfone derivatives
was measured by previously reported RP-HPLC methods.33,34 An
alkyl modified C18 column was used as the stationary phase and
capacity factors (k’) of each compound were determined at
different MeOH/aqueous buffer (pH 5) mobile phase v/v
compositions (0.05-increments of MeOH volume fraction, ranging
between 0.7 and 0.3). For all the examined compounds the log k’
values increased linearly (r2 ≥ 0.98) with decreasing MeOH volume
fraction, and the linear relationships were extrapolated to 100%
aqueous mobile phase to yield log k’w values. Lipophilicity data
were also estimated using two well-known computational tools
(Bio-Loom software, vers. 1.7 and ACDLabs software, release 10.0)
for calculating 1-octanol-water partition coefficients (clogP).
Experimental and calculated lipophilicity parameters are listed in
Table 3 and in supplementary materials.
6 | J. Name., 2012, 00, 1-3
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ARTICLE
Table 3. Lipophilicity parameters of thietane and tetrahydro-2H-thiopyran 1,1-dioxide derivatives.
2-monofunctionalized thietane 1,1-dioxides (2-MTE)
Cmpd
clogPa
log k'w
2a
0.54
1.97
2d
-0.22
1.44
2f
1.08
2.94
2h
0.29
1.89
2i
0.85
2.50
2j
1.18
3.34
2k
0.29
2.19
2o
0.38
2.02
2p
-0.90
0.95
9a
0.21
1.47
10a
0.81
2.12
b
2,4-difunctionalized thietane 1,1-dioxides (2,4-DTE)
Cmpd
clogPa
log k'w
3a
2.48
3.71
3d
3.25
4.38
3e
3.70
5.38
4c
3.98
5.01
b
2-monofunctionalized tetrahydro 2H-thiopyran 1,1-dioxides (2-MTHTP)
Cmpd
clogPa
log k'w
6a
1.66
2.62
6b
3.01
3.90
6c
2.22
3.20
6e
1.14
2.18
6f
0.43
1.48
6g
1.40
2.19
7a
3.60
4.25
9b
1.33
1.91
10b
1.64
2.20
b
an-Octanol/water partition coefficient calculated by CLOGP software ver. 4.73 (Biobyte, Claremont, CA, USA). bRP-HPLC capacity factor
extrapolated at 100% water volume fraction in aqueous mobile phase.
Conclusions
We have investigated the reactivity of four and six-membered cyclic
sulfones in lithiation/electrophilic trapping sequences. A similar
reactivity profile has been observed with the heterocycles either in
C2-functionalization or C2,C4 (C6)-double functionalization. Several
electrophiles were tolerated resulting in a smooth synthesis of a
series of substituted cyclic sulfones. Preliminary results showed that
the developed protocol is compatible with transmetallation and Csp2
coupling reactions. Attempts of electrophilic fluorination at the C2,
resulted in an unexpected concomitant arylsulfonylation. For
representative substituted cyclic sulfones, the lipophilicity was
measured by RP-HPLC, which significantly encodes solvophobic and
silanophilic interactions of the analytes. A good linear correlation,
Figure 2. Graphical comparison between RP-HPLC lipophilicity
with a slope close to 1.0, was observed between the experimental
parameter log k’w and clog P calculated by the Bio-Loom software.
2-Monofunctionalized thiethane 1,1-dioxide derivatives (2-
MTE); ( ) 2,4-difunctionalized thiethane 1,1-dioxide (2,4-DTE), and
chromatographic parameter log k’w and in silico lipophilicity
(ꢀ)
ꢁ
descriptor clogP.
A systematic difference in absolute values
2-mono- (2-MTHTP) and 2,6-difunctionalized tetrahydro-2H-
thiopyrane 1,1-dioxide (2,6-DTHTP) derivatives.
between the two parameters can be most likely attributed to
silanophilic interactions mainly involving the H-bond acceptor SO2
group. The results obtained in this quantitative structure-property
relationship study can be useful, not only in understanding the RP-
HPLC retention of cyclic sulfones, but also in assessing lipophilicity
profiles of sulfonyl-containing bioactive substances in early drug
discovery programs.
Silanophilic interactions in RP-HPLC retention mechanisms mainly
depend upon polarity, electrostatic and H-bonding interactions of
the analytes, which are in turn negatively affected by the reduction
(due to surrounding substitution degree, steric restriction to
solvation, etc.) of the surface area available to polar groups of the
analytes to bind free silanols.35 With the cyclic sulfones examined
herein, it appeared that the degree of silanophilic interactions,
accounted by the intercept values in eqs. 2 and 3, correlate with the
cycle size (four- vs. six-membered cycles), degree of
functionalization (mono- vs. di-functionalized derivatives) and
polar/H-bonding features of the substituents in α to the H-bond
acceptor SO2 group.
Experimental section
General
THF and 2-MeTHF was freshly distilled under a nitrogen atmosphere
over Na/benzophenone. N,N,N',N'-tetramethylethylenediamine
(TMEDA) was distilled over finely powdered CaH2, hexyllithium was
purchased as hexane solution and was filtered on celite before using
and title established by titration method1. All the other chemicals
were commercially available and used without further purification.
Magnetic Resonance spectra were recorded using Varian 500 MHz,
This journal is © The Royal Society of Chemistry 20xx
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ARTICLE
Journal Name
and Bruker 400 and 600 MHz spectrometers. For the 1H, 13C NMR (1,1-dioxido-2-thietanyl)-(diphenyl)methanol-2b.
Column
spectra (1H NMR 400, 500, 600 MHz, 13C NMR 100, 125, 150 MHz), chromatography on silica gel (Hexane/AcOEt 70:30), white solid, mp
CDCl3, methanol-d4 and toluene-d8 were used as the solvents. MS- 143-146 °C, 70% (160 mg). 1H NMR (400 MHz, CDCl3) δ 1.80-1.89
ESI analyses were performed on LC/MSD trap system VL. Melting (m, 1H, CH2CHSO2), 2.36-2.46 (m, 1H, CH2CHSO2), 3.91-3.96 (m, 2H,
points were uncorrected. GC-MS spectrometry analyses were CH2SO2), 4.03 (s, 1H, OH), 5.36 (t, J = 9.3 Hz, 1H, CHSO2), 7.12-7.32
carried out on a gas chromatograph (dimethylsilicon capillary (m, 8H, ArH), 7.46-7.48 (m, 2H, ArH). 13C NMR (101 MHz, CDCl3) δ
column, 30 m, 0.25 mm i.d.) equipped with a mass selective 8.8 (CH2CHSO2), 62.5 (CH2SO2), 72.8 ((Ar)2CCHOH), 84.4 (CHSO2),
detector operating at 70 eV (EI). Analytical thin layer 125.4 (ArCH), 126.0 (ArCH), 127.4 (ArCH), 128.2 (ArCH), 128.8
chromatography (TLC) was carried out on precoated 0.25 mm thick (ArCH), 142.8 (ArC), 144.8 (ArC). FT-IR (KBr, cm-1) υ 511, 546, 698,
plates of Kieselgel 60 F254; visualization was accomplished by UV 800, 1123, 1152, 1250, 1449, 1490, 2965, 3011, 3029, 3063, 3090,
light (254 nm) or by spraying a solution of 5 % (w/v) ammonium 3489. HRMS (ESI-TOF) m/z [M+Na]+ calcd for C16H16O3SNa 311.0712;
molybdate and 0.2 % (w/v) cerium(III) sulfate in 100 ml 17.6 % (w/v) found 311.0717.
aq. sulphuric acid and heating to 200 °C for some time until blue 1,1-dioxido-2-thietanyl-carboxylic acid-2c. White solid, mp 143-146
spots appear. Infra-red spectra of the compounds were recorded °C, 55% (85 mg). 1H NMR (600 MHz, CD3OD) δ 2.28-2.32 (m, 1H,
neat, as film, as KBr disc as indicated, by a Perkin-Elmer 283 CH2-CHSO2), 2.39-2.44 (m, 1H, CH2CHSO2), 4.05-4.13 (m, 1H,
spectrometer. For flash chromathography silica Gel 60, 0.04-0.063 CH2SO2), 4.16-4.21 (m, 1H, CH2SO2), 5.23 (m, 1H, CHSO2). 13C NMR
mm particle size was used. CHN analyses were performed on a (150 MHz, CD3OD) δ 9.5 (CH2-CHSO2), 63.8 (CH2SO2), 79.5 (CHSO2),
EuroEA 3000 analyzer. The high resolution mass spectrometry 165.8 (C=O). FT-IR (KBr, cm-1) υ 584, 607, 804, 1136, 1180, 1303,
(HRMS) analyses were performed using a Bruker microTOF QII mass 1387, 1449, 1633, 1732, 2974. HRMS (ESI-TOF) m/z [M+Na]+ calcd
spectrometer equipped with an electrospray ion source (ESI) for C4H6O4SNa 172.9879; found 172.9888.
operated in positive ion mode. The sample solutions (CH3OH or N-phenyl-2-thietanecarboxamide
1,1-dioxide-2d.
Column
CH3OH + 0.1%v/v HCOOH) were introduced by continuous infusion chromatography on silica gel (Hexane/AcOEt 70:30), white solid, mp
at a flow rate of 180 mL min-1with the aid of a syringe pump. The 150-152 °C, 66% (150 mg). 1H NMR (400 MHz, CDCl3) δ 2.32-2.42
instrument was operated with end-plate offset and capillary (m, 1H, CH2-CHSO2), 2.68-2.77 (m, 1H, CH2CHSO2), 4.12-4.31 (m, 2H,
voltages set to -500 V and -4500 V respectively. The nebulizer CH2SO2), 5.12-5.16 (m, 1H, CHSO2), 7.12-7.16 (m, 1H, ArH), 7.29-
pressure was 0.4 bar (N2), and the drying gas (N2) flow rate was 4.0 L 7.33 (m, 2H, ArH), 7.53-7.55 (m, 2H, ArH), 8.33 (bs, 1H, NH). 13C
min-1. The capillary exit and skimmer 1 voltages were 90 V and 30 V, NMR (101 MHz, CDCl3) δ 10.1 (CH2CHSO2), 65.0 (CH2SO2), 80.6
respectively. The drying gas temperature was set at 180 °C. The (CHSO2), 120.3 (ArCH), 125.2 (ArCH), 129.1 (ArCH), 137.0 (ArC),
calibration was carried out with sodium formate: a solution made up 160.6 (C=O). 15N δ -248.0. FT-IR (KBr, cm-1) υ 604, 620, 689, 753,
of 10 µl of 98% formic acid, 10 µl of sodium hydroxide (1.0 M), 490 1136, 1302, 1315, 1539, 1599, 1688, 3368. HRMS (ESI-TOF) m/z
µl of i-propanol and 490 µl of deionized water. The software used [M+Na]+ calcd for C10H11NO3SNa 248.0532; found 248.0533.
for the simulations was Bruker Daltonics DataAnalysis (version 4.0). (1,1-dioxido-2-thietanyl)(trimethyl)silane-2e.
Column
All reactions involving air-sensitive reagents were performed under chromatography on silica gel (Hexane/AcOEt 70:30), yellow oil, 50%
1
argon in oven-dried glassware using syringe septum cap technique.
(90 mg). H NMR (400 MHz, CDCl3) δ 0.22 (s, 9H, CH3Si), 1.88-1.97
(m, 1H, CH2CHSO2), 2.15-2.24 (m, 1H, CH2CHSO2), 3.98-4.06 (m, 2H,
General procedure for lithiation/electrophile trapping sequence on CH2SO2), 4.12-4.21 (m, 1H, CHSO2). 13C NMR (101 MHz, CDCl3) δ -2.9
C2-substituted thietane-1,1-dioxide. To
a stirred solution of (CH3Si), 7.7 (CH2-CHSO2), 65.8 (CH2SO2), 69.9 (CHSO2). FT-IR (NaCl,
thietane 1,1-dioxide commercially available (1.0 mmol, 1.0 equiv) in cm-1) υ 608, 840, 1126, 1304, 2957. HRMS (ESI-TOF) m/z [M+Na]+
dry 2-MeTHF (10 mL) cooled at -78°C, a solution of n-HexLi (2.5M in calcd for C6H14O2SSiNa 201.0376; found 201.0376.
hexane, 1.1 equiv) was added dropwise. After stirring for 5 min. at - (1,1-dioxido-2-thietanyl)[4-(trifluoromethyl)phenyl]methanone-2f.
78°C, the electrophile (1 equiv) was added neat if liquid and in 1.0 Column chromatography on silica gel (Hexane/AcOEt 60:40), white
mL of solvent if solid. After the reaction was complete, as solid, mp 108-110 °C, 62% (173 mg). 1H NMR (400 MHz, CDCl3) δ
ascertained by GC or TLC, the reaction mixture was quenched at -78 2.30-2.39 (m, 1H, CH2CHSO2), 2.94-3.04 (m, 1H, CH2CHSO2), 4.15-
°C with saturated aqueous NH4Cl (0.1mL) and directly filtered over 4.34 (m, 2H, CH2SO2), 5.91-5.96 (m, 1H, CHSO2), 7.80-7.82 (m, 2H,
Na2SO4 and concentrated in vacuo. Flash chromatography on silica ArH), 8.15-8.17 (m, 2H, ArH). 13C NMR (101 MHz, CDCl3) δ 7.6
gel (Hexane/AcOEt) afforded the substituted thietane 1,1-dioxide.
(CH2CHSO2), 64.4 (CH2SO2), 82.4 (CHSO2), 123.3 (d, J = 272.9 Hz,
2-benzylthietane 1,1-dioxide-2a. Column chromatography on silica CF3), 126.3 (q, J = 3.7 Hz, ArCH), 129.0 (ArCH), 135.6 (q, J = 33.0 Hz,
gel (Hexane/AcOEt 70:30), white solid, mp 67-70 °C, 70% (142 mg). ArC), 137.9 (ArC), 186.5 (C=O). 19F NMR (377 MHz, CDCl3) δ -63.3 (s).
1H NMR (600 MHz, CDCl3) δ 1.84-1.90 (m, 1H, CH2CHSO2), 2.23-2.29 FT-IR (KBr, cm-1) υ 587, 864, 1065, 1122, 1171, 1314, 1688. HRMS
(m, 1H, CH2CHSO2), 3.03 (dd, J = 14.6, 7.8 Hz, 1H, ArCH2CH), 3.43 (ESI-TOF) m/z [M+Na]+ calcd for C11H9F3O3SNa 301.0117; found
(dd, J = 14.6, 7.8 Hz, 1H, ArCH2CH), 3.92-4.04 (m, 2H, CH2SO2), 4.59 301.0119.
(m, 1H, CHSO2), 7.23-7.26 (m, 3H, ArH), 7.31-7.34 (m, 2H, ArH). 13C (1,1-dioxido-2-thietanyl)[4-(2-methyl-2-propanyl)phenyl]
NMR (150 MHz, CDCl3) δ 14.0 (CH2CHSO2), 35.2 (ArCH2CH), 61.8 methanone-2g. Column chromatography on silica gel
(CH2SO2), 79.0 (CHSO2), 127.0 (ArCH), 128.7 (ArCH), 128.9 (ArCH), (Hexane/AcOEt 60:40), white solid, mp 98-101 °C, 61% (161 mg). 1H
136.4 (ArC). FT-IR (KBr, cm-1) υ 613, 700, 757, 1121, 1161, 1294, NMR (400 MHz, CDCl3) δ 1.35 (s, 9H, C(CH3)3), 2.23-2.33 (m, 1H,
2922. HRMS (ESI-TOF) m/z [M+Na]+ calcd for C10H12O2SNa 219.0450; CH2CHSO2), 2.94-3.03 (m, 1H, CH2CHSO2), 4.12-4.29 (m, 2H,
found 219.0456.
CH2SO2), 5.91-5.95 (m, 1H, CHSO2), 7.54-7.57 (m, 2H, ArH), 7.97-
8 | J. Name., 2012, 00, 1-3
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8.00 (m, 2H, ArH). 13C NMR (101 MHz, CDCl3) δ 7.6 (CH2CHSO2), 31.0 1-(1,1-dioxido-2-thietanyl)-2-cyclopenten-1-ol-2l.
View Article Online
DOI: 10.1039/C7OB00846E
ARTICLE
Column
(C(CH3)3), 35.3 (C(CH3)3), 64.1 (CH2SO2), 82.2 (CHSO2), 126.2 (ArCH), chromatography on silica gel (Hexane/AcOEt 75:25), colorless oil,
1
128.7 (ArCH), 132.8 (ArC), 158.7 (ArC), 186.6 (C=O). FT-IR (KBr, cm-1) 62% (120 mg), dr 75:25. H NMR (400 MHz, CDCl3) δ 1.81-1.88 (m,
υ 593, 722, 753, 805, 1133, 1313, 1686. HRMS (ESI-TOF) m/z 1H, minor, CCH2CH2), 1.93-2.02 (m, 1H, minor, CCH2CH2), 2.09-2.40
[M+Na]+ calcd for C14H18O3SNa 289.0869; found 289.0869.
(m, 5H, major, CCH2CH2, CCH2CH2, CH2CHSO2), 2.17-2.45 (m, 3H,
(1,1-dioxido-2-thietanyl)(4-methoxyphenyl)methanone-2h. Column minor, CH2CHSO2, CH2CH=), 2.51-2.60 (m, 1H, minor, CH2CH=), 2.54-
chromatography on silica gel (Hexane/AcOEt 60:40), white solid, mp 2.63 (m, 1H, major, CH2CH=), 3.10 (s, 1H, OH, minor), 3.11 (s, 1H,
137-140 °C, 68% (153 mg). 1H NMR (400 MHz, CDCl3) δ 2.23-2.32 (m, OH, major), 3.97-4.07 (m, 2H, minor, CH2SO2), 3.97-4.01 (m, 2H,
1H, CH2CHSO2), 2.95-3.01 (m, 1H, CH2CHSO2), 3.89 (s, 3H, OCH3), major, CH2SO2), 4.37-4.41 (m, 1H, minor, CHSO2), 4.42-4.46 (dd, J =
4.11-4.26 (m, 2H, CH2SO2), 5.87-5.91 (m, 1H, CHSO2), 6.99-7.02 (m, 10.0, 7.6 Hz, 1H, major, CHSO2), 5.68-5.70 (dt, d = J = 5.7 Hz, t = J =
2H, ArH), 8.01-8.04 (m, 2H, ArH). 13C NMR (101 MHz, CDCl3) δ 7.7 2.2 Hz, 1H, major, CH=CH), 5.92 (dt, d = J = 5.6 Hz, t = J = 2.2 Hz, 1H,
(CH2CHSO2), 55.6 (OCH3), 64.1 (CH2SO2), 82.1 (CHSO2), 114.4 (ArCH), minor, CH=CH), 6.03 (dt, d = J = 5.6 Hz, t = J = 2.4 Hz, 1H, minor,
128.5 (ArC), 131.1 (ArCH), 164.9 (ArC), 185.3 (C=O). FT-IR (KBr, cm-1) CH=CH), 6.02-6.04 (m, 1H, major, CH=CH). 13C NMR (101 MHz,
υ 577, 788, 843, 1016, 1132, 1175, 1313, 1594, 1662, 2923. HRMS CDCl3) δ 9.0 (minor, CH2CHSO2), 9.6 (major, CH2CHSO2), 30.5 (minor,
(ESI-TOF) m/z [M+Na]+ calcd for C11H12O4SNa 263.0349; found CH2CH=), 31.4 (major, CH2CH=), 36.1 (minor, CCH2CH2), 37.7 (major,
263.0349.
CCH2CH2), 63.4 (minor, CH2SO2), 63.5 (major CH2SO2), 84.0 (minor,
(3-chlorophenyl)(1,1-dioxido-2-thietanyl)methanone-2i.
Column COH), 84.4 (major COH), 85.6 (major, CHSO2), 85.6 (minor, CHSO2),
chromatography on silica gel (Hexane/AcOEt 60:40), white solid, mp 131.4 (major, CH=CH), 133.4 (minor, CH=CH), 135.9 (minor, CH=CH),
1
93-95 °C, 57% (140 mg). H NMR (400 MHz, CDCl3) δ 2.27-2.37 (m, 136.9 (major, CH=CH). FT-IR (NaCl, cm-1) υ 518, 727, 1119, 1264,
1H, CH2CHSO2), 2.93-3.02 (m, 1H, CH2CHSO2), 4.15-4.22 (m, 1H, 1408, 2851, 2919. HRMS (ESI-TOF) m/z [M+Na]+ calcd for
CH2SO2), 4.26-4.32 (m, 1H, CH2SO2), 5.87-5.91 (m, 1H, CHSO2), 7.48- C8H12NaO3S 211.0399; found 211.0398.
7.52 (m, 1H, ArH), 7.62-7.65 (m, 1H, ArH), 7.90-7.93 (m, 1H, ArH), 1-(1,1-dioxido-2-thietanyl)-2-cyclohepten-1-ol-2m.
Column
8.02-8.03 (m, 1H, ArH). 13C NMR (101 MHz, CDCl3) δ 7.7 (CH2- chromatography on silica gel (Hexane/AcOEt 70:30), white solid, mp
1
CHSO2), 64.4 (CH2SO2), 82.2 (CHSO2), 126.7 (ArCH), 128.6 (ArCH), 61-64 °C, 65% (140 mg) dr 70:30. H NMR (400 MHz, CDCl3) δ 1.50-
130.5 (ArCH), 134.6 (ArCH), 135.7 (ArC), 136.8 (ArC), 186.2 (C=O). FT- 1.72 (m, 5H, minor, CCH2CH2, CH2CH2C, CH2CH2CH=), 1.47-1.57 (m,
IR (KBr, cm-1) υ 593, 722, 753, 805, 1133, 1313, 1686. HRMS (ESI- 1H, major, CH2CH2CH=), 1.64-1.77 (m, 2H, major, CH2CH2C,
TOF) m/z [M+Na]+ calcd for C10H9ClO3SNa 266.9853; found CH2CH2CH=), 1.89-1.97 (m, 1H, minor, CH2CH2CH=), 1.91-2.03 (m,
266.9855.
2H, major, CH2C, CH2CH2C), 2.06-2.15 (m, 3H, major, CH2C, CH2CH=,
adamantan-1-yl(1,1-dioxido-2-thietanyl)methanone-2j.
Column CH2-CHSO2), 2.08-2.16 (m, 2H, minor, CH2CH=, CH2CHSO2), 2.18-
chromatography on silica gel (Hexane/AcOEt 60:40), white solid, mp 2.27 (m, 1H, major, CH2CH=), 2.26-2.42 (m, 2H, minor, CH2CHSO2,
1
95-97 °C, 47% (127 mg). H NMR (400 MHz, CDCl3) δ 1.69-1.78 (m, CH2CH=), 2.39-2.49 (m, 1H, major, CH2-CHSO2), 3.10 (bs, 1H, OH,
6H, CH2CHCH), 1.80-1.93 (m, 6H, CH2CHC), 2.01-2.10 (m, 4H, major), 3.33 (bs, 1H, OH, minor), 3.90-4.03 (m, 2H, major, CH2SO2),
CH2CHSO2, CHCH2CH2), 2.64-2.73 (m, 1H, CH2CHSO2), 4.06-4.16 (m, 3.92-4.06 (m, 2H, minor, CH2SO2), 4.64-4.69 (m, 1H, minor, CHSO2),
2H, CH2SO2), 5.54-5.58 (m, 1H, CHSO2). 13C NMR (101 MHz, CDCl3) δ 4.69-4.73 (m, 1H, major, CHSO2), 5.43 (td, t = J = 1.7 Hz, d = Jcis
=
7.6 (CH2CHSO2), 27.6 (CHCH2CH2), 36.3 (CH2CHCH), 37.3 (CH2CHC), 11.9 Hz, 1H, major, CH=CH), 5.77 (ddd = J = 11.9, 7.4, 5.0 Hz, 1H,
46.0 (CCH2CH2), 64.4 (CH2SO2), 80.1 (CHSO2), 202.5 (C=O). FT-IR major, CH=CH), 5.82 (d = J = 11.9 Hz, 1H, minor, CH=CH), 5.91 (ddd =
(KBr, cm-1) υ 589, 1130, 1167, 1308, 1698, 2903. HRMS (ESI-TOF) J = 11.9, 6.6, 5.6 Hz, 1H, minor, CH=CH). 13C NMR (101 MHz, CDCl3)
m/z [M+Na]+ calcd for C14H20O3SNa 291.1025; found 291.1025.
δ 8.3 (minor, CH2CHSO2), 8.6 (major, CH2CHSO2), 23.9 (minor,
1-(1,1-dioxido-2-thietanyl)-2-cyclohexen-1-ol-2k.
Column CH2CH2C), 24.6 (major, CH2CH2C), 27.0 (major, CH2CH2CH=), 27.0
chromatography on silica gel (Hexane/AcOEt 60:40), white solid, mp (minor, CH2CH2CH=), 27.7 (major, CH2CH=), 27.8 (minor, CH2CH=),
1
57-62 °C, 55% (112 mg) dr 80:20. H NMR (400 MHz, CDCl3) δ 1.38- 35.8 (minor, CH2C), 39.1 (major, CH2C), 62.8 (minor, CH2SO2), 62.9
1.43 (m, 1H minor, CCH2CH2) 1.54-1.88 (m, 3H major + 3H minor, (major, CH2SO2), 74.8 (minor, COH), 75.9 (major, COH), 82.5 (major,
CCH2CH2, CCH2CH2), 1.94-2.21 (m, 4H major + 3H minor, CH2CH=, CHSO2), 85.3 (minor, CHSO2), 132.1 (major, CH=CH), 133.3 (minor,
CCH2CH2, CH2CHSO2), 2.34-2.48 (m, 1H minor
+ 1H major, CH=CH), 134.2 (major, CH=CH), 135.8 (minor, CH=CH). FT-IR (KBr,
CH2CHSO2), 3.13 (s, 1H major + 1H, minor, OH), 3.96-4.05 (m, 2H cm-1) υ 800, 1128, 1292, 1307, 1650, 2941, 3514. HRMS (ESI-TOF)
major + 2H minor, CH2SO2), 4.39-4.45 (m, 1H minor + 1H major, m/z [M+Na]+ calcd for C10H16O3SNa 239.0712; found 239.0713.
CHSO2), 5.48 (d, J = 10.0 Hz, 1H, major, CH=CH), 5.89-5.93 (m, 2H (3E)-2-(1,1-dioxido-2-thietanyl)-3-hepten-2-ol-2n.
Column
minor + 1H minor, CH=CH, CH=CH). 13C NMR (101 MHz, CDCl3) δ 8.2 chromatography on silica gel (Hexane/AcOEt 60:40), colorless oil,
1
(minor, CH2CHSO2), 8.6 (major, CH2-CHSO2), 18.1 (minor, 65% (145 mg), dr 70:30. H NMR (400 MHz, CDCl3) δ 0.88 (t, J = 7.4
CH2CH2CH2), 18.3 (major, CH2CH2CH2), 24.9 (minor, CH2CH=), 24.9 Hz, 3H, major, CH3CH2), 0.90 (t, J = 7.4 Hz, 3H, minor, CH3CH2), 1.19
(major, CH2CH=), 33.1 (minor, CCH2CH2), 35.7 (major, CCH2CH2), (s, 3H, minor, CH3C), 1.35-1.42 (m, 2H, major, CH3CH2CH2), 1.39-
63.2 (major, CH2SO2), 63.2 (minor, CH2SO2), 69.3 (minor, COH), 69.6 1.45 (m, 2H, minor, CH3CH2CH2), 1.56 (s, 3H, major, CH3C), 1.98-2.09
(major, COH), 85.6 (major, CHSO2), 86.1 (minor, CHSO2), 126.6 (m, 3H, major, CH2CH=, CH2CHSO2), 2.02-2.08 (m, 2H, minor,
(major, CH=CH), 129.2 (minor, CH=CH), 131.7 (minor, CH=CH), 132.6 CH2CH=), 2.12-2.19 (m, 1H, minor, CH2CHSO2), 2.24-2.33 (m, 1H,
(major, CH=CH). FT-IR (KBr, cm-1) υ 506, 729, 1104, 1123, 1307, major, CH2CHSO2), 2.39-2.49 (m, 1H, minor, CH2CHSO2), 3.20 (bs,
1408, 2927, 3517. HRMS (ESI-TOF) m/z [M+Na]+ calcd for 1H, OH, major), 3.36 (bs, 1H, OH, minor), 3.88-4.04 (m, 2H, minor,
C9H14O3SNa 225.0556; found 225.0556.
CH2SO2), 3.93-3.97 (m, 2H, major, CH2SO2), 4.34 (dd, J = 10.0, 8.2 Hz,
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1H, major, CHSO2), 4.49 (t, J = 9.4 Hz, 1H, minor, CHSO2), 5.24 (dt, d CHSO2), 4.47-4.60 (m, 1H, minor, CHSO2), 4.70-4.76 (m, 1H, minor,
= J = 15.7 Hz, t = J = 1.3 Hz, 1H, major, CH=CH), 5.67 (dt, d = J = 15.7 CHOH), 5.03-5.05 (m, 1H, major, CHOH), 6.07 (dd, J = 15.9, 5.5 Hz,
Hz, t = J = 1.3 Hz, 1H, minor, CH=CH), 5.74 (dt, d = J = 15.7 Hz, t = J = 1H, major, CH=CH), 6.21 (dd, J = 15.9, 5.5 Hz, 1H, minor, CH=CH),
6.7 Hz, 1H, major, CH=CH), 5.81 (dt, d = J = 15.7 Hz, t = J = 6.7 Hz, 6.74 (d, J = 15.9 Hz, 1H, minor, CH=CH), 6.76 (dd, J = 15.9, 1.5 Hz,
1H, minor, CH=CH). 13C NMR (101 MHz, CDCl3) δ 8.8 (minor, 1H, major, CH=CH), 7.27-7.40 (m, 5H, major, ArH), 7.29-7.44 (m, 5H,
CH2CHSO2), 8.9 (major, CH2CHSO2), 13.5 (major, CH3CH2), 13.5 minor, ArH). 13C NMR (101 MHz, CDCl3) δ 7.8 (major, CH2-CHSO2),
(minor, CH3CH2), 22.2 (minor, CH3CH2CH2), 22.2 (major, CH3CH2CH2), 10.4 (minor, CH2CHSO2), 62.7 (minor, CH2SO2), 64.0 (major, CH2SO2),
26.0 (minor, CH3C), 28.1 (major, CH3C), 34.2 (major, CH2CH=), 34.2 68.2 (major, CHOH), 71.9 (minor, CHOH), 81.5 (major, CHSO2), 82.2
(minor, CH2CH=), 62.6 (minor, CH2SO2), 62.7 (major, CH2SO2), 71.8 (minor, CHSO2), 125.7 (major, CH=CH), 126.1 (minor, CH=CH), 126.6
(major, C=CH), 72.0 (minor, C=CH), 85.6 (minor, CHSO2), 85.7 (major, ArCH), 126.7 (minor, ArCH), 128.2 (major, ArCH), 128.4
(major, CHSO2), 130.7 (minor, CH=CH), 131.3 (major, CH=CH), 131.6 (minor, ArCH), 128.7 (minor, ArCH), 128.7 (major, ArCH), 132.3
(major, CH=CH), 133.7 (minor, CH=CH). FT-IR (NaCl, cm-1) υ 730, (major, CH=CH), 133.5 (minor, CH=CH), 135.7 (minor, ArC), 135.9
974, 1122, 1309, 1458, 2960, 3522. HRMS (ESI-TOF) m/z [M+Na]+ (major, ArC). FT-IR (KBr, cm-1) υ 749, 1129, 1302, 1640, 1722, 3457.
calcd for C10H18O3SNa 241.0869; found 241.0873.
HRMS (ESI-TOF) m/z [M+Na]+ calcd for C12H14O3SNa 261.0556;
Column found 261.0560.
(4-chlorophenyl)(1,1-dioxido-2-thietanyl)methanol-2o.
chromatography on silica gel (Hexane/AcOEt 60:40), white solid, mp General procedure for lithiation-electrophile trapping sequence
123-125 °C, 60% (149 mg) dr 80:20. 1H NMR (400 MHz, CDCl3) δ on C2,C2'-substituted thietane-1,1-dioxide. To a stirred solution of
1.80-1.90 (m, 1H, minor, CH2CHSO2), 1.97-2.08 (m, 1H, minor, thietane 1,1-dioxide (1.0 mmol, 1.0 equiv) in dry 2-MeTHF (10 mL)
CH2CHSO2), 1.97-2.07 (m, 1H, major, CH2CHSO2), 2.36-2.45 (m, 1H, cooled at -78°C, a solution of n-HexLi (2.5M in hexane, 2.5 equiv)
major, CH2CHSO2), 3.10 (bs, 1H, OH, minor), 3.32 (bs, 1H, OH, was added dropwise. After stirring for 10 min. at -78°C, the
major), 3.96-4.02 (m, 2H, minor, CH2SO2), 4.02-4.07 (m, 2H, major, electrophile (2.5 equiv) was added neat if liquid and in 1.0 mL of
CH2SO2), 4.52-4.57 (m, 1H, major, CHSO2), 4.60-4.66 (m, 1H, minor, solvent if solid. After the reaction was complete, as ascertained by
CHSO2), 5.08 (d, J = 9.0 Hz, 1H, minor, CHOH), 5.44 (d, J = 3.0 Hz, 1H, GC or TLC, the reaction mixture was quenched at -78 °C with
major, CHOH), 7.30-7.37 (m, 4H, major, ArH), 7.32-7.36 (m, 4H, saturated aqueous NH4Cl (0.1 mL) and directly filtered over Na2SO4
minor, ArH). 13C NMR (101 MHz, CDCl3) δ 7.5 (major, CH2CHSO2), and concentrated in vacuo. Flash chromatography on silica gel
10.8 (minor, CH2-CHSO2), 62.1 (minor, CH2SO2), 63.6 (major, (Hexane/AcOEt) afforded the disubstituted thietane 1,1-dioxide.
CH2SO2), 68.6 (major, CHOH), 72.4 (minor, CHOH), 82.8 (major, 2,4-dibenzylthietane 1,1-dioxide-3a. Column chromatography on
CHSO2), 83.1 (minor, CHSO2), 126.9 (major, ArCH), 127.9 (minor, silica gel (Hexane/AcOEt 80:20), white solid, mp 78-81 °C, 60% (174
ArCH), 129.0 (major, ArCH), 129.2 (minor, ArCH), 134.1 (major, ArC), mg). 1H NMR (400 MHz, CDCl3) δ 1.97 (t, J = 8.1 Hz, 2H, CH2CHSO2),
134.7 (minor, ArC), 137.5 (major, ArC), 137.5 (minor, ArC). FT-IR 2.97 (dd, J = 14.6, 9.6 Hz, 1H, ArCH2CH), 3.44 (dd, J = 14.6, 6.9 Hz,
(KBr, cm-1) υ 585, 782, 802, 1125, 1190, 1305, 1490, 3506. HRMS 1H, ArCH2CH), 4.44-4.52 (m, 2H, CHSO2), 7.19-7.31 (m, 10H, ArH).
(ESI-TOF) m/z [M+Na]+ calcd for C10H11ClO3SNa 269.0010; found 13C NMR (101 MHz, CDCl3) δ 20.9 (CH2CHSO2), 35.4 (ArCH2CH), 75.7
269.0009.
(CHSO2), 127.1 (ArCH), 128.7 (ArCH), 128.9 (ArCH), 136.3 (ArC). FT-
IR (KBr cm-1) υ 699, 744, 1163, 1303, 1454, 1495, 2925. HRMS (ESI-
4-[(1,1-dioxido-2-thietanyl)(hydroxyl)methyl]benzonitrile-2p.
Column chromatography on silica gel (Hexane/AcOEt 60:40), white TOF) m/z [M+Na]+ calcd for C17H18O2SNa 309.0922; found 309.0920.
solid mp 104-106 °C, 69% (164 mg), dr 80:20. 1H NMR (400 MHz, (1,1-dioxido-2,4-thietanediyl)bis(diphenyl)methanol-3b. Column
CDCl3) δ 1.96-2.06 (m, 2H minor + 1H major, CH2CHSO2), 2.32-2.42 chromatography on silica gel (Hexane/AcOEt 80:20), white solid, mp
(m, 1H, major, CH2CHSO2), 3.49 (bs, OH, 1H), 4.03-4.11 (m, 2H major 218-223 °C, 78% (370 mg), dr 70:30. 1H NMR (500 MHz, CDCl3) δ
+ 2H minor, CH2SO2), 4.53-4.59 (m, 1H, major, CHSO2), 4.62-4.66 (m, 1.60-1.64 (m, 1H, minor, CH2CHSO2), 2.19 (t, J = 9.0 Hz, 2H, major,
1H, minor, CHSO2), 5.15 (d, J = 9.0 Hz, 1H, minor, CHOH), 5.49 (m, CH2CHSO2), 3.09-3.13 (m, 1H, minor, CH2CHSO2), 3.90 (s, 2H, minor,
1H, major, CHOH), 7.50-7.53 (m, 2H major + 2H minor, ArH), 7.66- OH), 3.96 (s, 2H, major, OH), 5.20 (t, J = 9.9 Hz, 2H, minor, CHSO2),
7.68 (m, 2H major + 2H minor, ArH). 13C NMR (101 MHz, CDCl3) δ 5.36 (t, J = 8.9 Hz, 2H, major, CHSO2), 7.17-7.20 (m, 2H major + 2H
7.5 (major, CH2-CHSO2), 10.7 (minor, CH2CHSO2), 62.4 (minor, minor, ArH), 7.24-7.38 (m, 16H major + 16H minor, ArH), 7.49-7.51
CH2SO2), 63.8 (major, CH2SO2), 68.6 (major, CHOH), 72.3 (minor, (m, 2H, major, ArH), 7.57-7.58 (m, 2H, minor, ArH). 13C NMR (125
CHOH), 82.3 (major, CHSO2), 82.7 (minor, CHSO2), 112.1 (major, MHz, CDCl3) δ 12.5 (major, CH2CHSO2), 12.8 (minor, CH2CHSO2),
ArCCN), 112.7 (minor, ArCCN), 118.2 (minor, CN), 118.4 (major, CN), 79.7 (minor, CHSO2), 82.6 (major, CHSO2), 125.3 (minor, ArCH),
126.4 (major, ArCH), 127.2 (minor, ArCH), 132.6 (major, ArCH), 125.4 (major, ArCH), 125.8 (major, ArCH), 126.0 (minor, ArCH),
132.8 (minor, ArCH), 144.2 (minor, ArC), 144.3 (major, ArC). FT-IR 127.3 (major, ArCH), 127.4 (minor, ArCH), 128.1 (major, ArCH),
(KBr, cm-1) υ 563, 590, 784, 1124, 1292, 1605, 3449. HRMS (ESI-TOF) 128.2 (minor, ArCH), 128.4 (minor, ArCH), 128.5 (major, ArCH),
m/z [M+Na]+ calcd for C11H11NO3SNa 260.0352; found 260.0354.
128.7 (minor, ArCH), 128.8 (major, ArCH), 142.7 (major, ArC), 143.0
(minor, ArC), 144.8 (minor, ArC), 145.0 (major, ArC). FT-IR (KBr, cm-
(2E)-1-(1,1-dioxide-2-thietanyl)-3-phenyl-2-propen-1-ol-2q.
Column chromatography on silica gel (Hexane/AcOEt 50:50), white 1) υ 528, 698, 1101, 1265, 1449, 2853, 2965, 3027, 3495. HRMS (ESI-
solid, mp 114-118 °C, 89% (238 mg), dr 80:20. 1H NMR (400 MHz, TOF) m/z [M+Na]+ calcd for for C29H26O4SNa 493.1444; found
CDCl3) δ 1.96-2.34 (m, 2H, minor, CH2CHSO2), 2.12-2.22 (m, 1H, 493.1446.
major, CH2CHSO2), 2.33-2.42 (m, 1H, major, CH2CHSO2), 2.95 (bs, (1,1-dioxido-2,4-thietanediyl)bis[4-(2-methyl-2-propanyl)phenyl]
1H, OH, minor), 3.08 (bs, 1H, OH, major), 3.97-4.12 (m, 2H, minor, methanone-3c. Column chromatography on silica gel
CH2SO2), 4.04-4.08 (m, 2H, major, CH2SO2), 4.46-4.51 (m, 1H, major, (Hexane/AcOEt 80:20), colorless oil, 72% (310 mg), dr 70:30. 1H
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NMR (400 MHz, CDCl3) δ 1.34 (s, 18H, minor, C(CH3)3), 1.35 (s, 18H, mL of solvent if solid. After the reaction was complete, as
major, C(CH3)3), 2.39 (dt, d = J = 12.7 Hz, t = J = 9.7 Hz, 1H, minor, ascertained by GC or TLC, the reaction mixture was quenched at -78
CH2CHSO2), 3.06 (t, J = 8.2 Hz, 2H, major, CH2CHSO2), 3.81 (dt, d = J °C with saturated aqueous NH4Cl (0.1mL) and directly filtered over
= 12.7 Hz, t = J = 9.7 Hz, 1H, minor, CH2CHSO2), 5.94 (t, J = 9.7 Hz, Na2SO4 and concentrated in vacuo. Flash chromatography on silica
2H, minor, CHSO2), 5.98 (t, J = 8.2 Hz, 2H, major, CHSO2), 7.48-7.56 gel (Hexane/AcOEt) afforded the 2,4-disubstituted thietane 1,1-
(m, 4H minor + 4H major, ArH), 7.92-8.02 (m, 4H major + 4H minor, dioxide.
ArH). 13C NMR (101 MHz, CDCl3) δ 10.0 (major, CH2CHSO2), 10.1 2-benzyl-4-methylthietane
1,1-dioxide-4a.
Column
(minor, CH2CHSO2), 31.0 (major, C(CH3)3), 31.0 (minor, C(CH3)3), chromatography on silica gel (Hexane/AcOEt 70:30), yellow oil,
35.3 (minor, C(CH3)3), 35.4 (major, C(CH3)3), 79.3 (minor, CHSO2), >99%, dr 60:40. 1H NMR (500 MHz, CDCl3) δ 1.33-1.41 (m, 1H,
81.0 (major, CHSO2), 126.2 (minor, ArCH), 126.2 (major, ArCH), minor, CH2CHSO2), 1.43 (d, J = 7.0 Hz, 3H, minor, CH3CHSO2), 1.46
128.6 (minor, ArCH), 128.8 (major, ArCH), 132.8 (minor, ArC), 158.7 (d, J = 7.2 Hz, 3H, major, CH2CHSO2), 1.83 (ddd, J = 12.0, 9.9, 5.5 Hz,
(minor, ArC), 158.9 (major, ArC), 185.4 (minor, C=O), 186.7 (major, 1H, major, CH2CHSO2), 2.03 (ddd, J = 12.0, 9.9, 7.1 Hz, 1H, major,
C=O). FT-IR (NaCl, cm-1) υ 545, 991, 1125, 1325, 1603, 1677, 2961. CH2CHSO2), 2.34-2.41 (m, 1H, minor, CH2CHSO2), 2.91-2.98 (m, 1H
HRMS (ESI-TOF) m/z [M+Na]+ calcd for C25H30O4SNa 449.1757; major + 1H minor, ArCH2CH), 3.36 (ddd, J = 14.6, 7.9 Hz, 1H, minor,
found 449.1756.
ArCH2CH), 3.42 (dd, J = 14.6, 7.4 Hz, 1H, major, ArCH2CH), 4.13-4.26
(m, 1H major + 1H minor, CHSO2), 4.33-4.41 (m, 1H, minor, CHSO2),
(1,1-dioxido-2,4-thietanediyl)bis[(3-chlorophenyl)methanone]-3d.
Column chromatography on silica gel (Hexane/AcOEt 80:20), yellow 4.42-4.50 (m, 1H, major, CHSO2), 7.18-7.23 (m, 6H, ArH), 7.27-7.29
solid, mp 122-125 °C, 67% (254 mg), dr 80:20. 1H NMR (400 MHz, (m, 4H, ArH). 13C NMR (125 MHz, CDCl3) δ 13.2 (minor, CH2CHSO2),
CDCl3) δ 2.45 (dt, d = J = 12.8 Hz, t = J = 9.7 Hz, 1H, minor, 14.8 (major, CH2CHSO2), 22.9 (major, CH3CHSO2), 23.9 (minor,
CH2CHSO2), 3.08 (t, J = 8.1 Hz, 2H, major, CH2CHSO2), 3.76-3.80 (dt, CH3CHSO2), 34.8 (minor, ArCH2CH), 35.3 (major, ArCH2CH), 69.2
d = J = 12.8 Hz, t = J = 9.5 Hz, 1H, minor, CH2CHSO2), 5.93 (t, J = 9.6 (minor, CHSO2), 70.0 (major, CHSO2), 75.7 (minor, CHSO2), 76.1
Hz, 2H, minor, CHSO2), 5.95 (t, J = 8.1 Hz, 2H, major, CHSO2), 7.51 (t, (major, CHSO2), 127.0 (minor, ArCH), 127.0 (major, ArCH), 128.6
J = 7.9 Hz, 2H minor + 2H major, ArH), 7.62-7.65 (m, 2H minor + 2H (minor, ArCH), 128.7 (minor, ArCH), 128.7 (major, ArCH), 128.9
major, ArH), 7.85-7.87 (dt, J = 7.8, 1.7, 1.0 Hz, 2H, major, ArH), 7.90- (major, ArC), 136.5 (minor, ArC). FT-IR (KBr, cm-1) υ 511, 546, 698,
7.93 (dt, J = 7.8, 1.7, 1.0 Hz, 2H, minor, ArH), 8.02 (t, J = 1.9 Hz, 2H, 800, 1123, 1152, 1250, 1449, 1490, 2965, 3011, 3029, 3063, 3090,
major, ArH), 8.04 (t, J = 1.9 Hz, 2H, minor, ArH). 13C NMR (125 MHz, 3489. HRMS (ESI-TOF) m/z [M+Na]+ calcd for C17H18O3SNa 325.0869;
CDCl3) δ 10.1 (minor, CH2CHSO2), 10.2 (major, CH2CHSO2), 79.5 found 325.0872.
(minor, CHSO2), 81.1 (major, CHSO2), 126.6 (minor, ArCH), 126.8 (4-methyl-1,1-dioxido-2-thietanyl)(diphenyl)methanol-4b. Column
(major, ArCH), 128.6 (minor, ArCH), 128.7 (major, ArCH), 130.6 chromatography on silica gel (Hexane/AcOEt 70:30), white solid, mp
(major, ArCH), 134.8 (minor, ArCH), 134.8 (major, ArCH), 135.8 143-146 °C, 60%. 1H NMR (600 MHz, CDCl3) δ 1.51 (d, J = 7.0 Hz, 3H,
(minor, ArC), 135.8 (major, ArC), 136.7 (minor, ArC), 136.7 (major, CH3CHSO2), 1.51-1.57 (m, overlapping d at 1.51, 1H, CH2CHSO2),
ArC), 184.9 (minor, C=O), 186.1 (major, C=O). FT-IR (KBr, cm-1) υ 2.56-2.61 (m, 1H, CH2CHSO2), 4.27-4.33 (m, 1H, CHSO2), 5.33-5.36
767, 777, 1162, 1320, 1425, 1687, 3068. HRMS (ESI-TOF) m/z (m, 1H CHSO2), 7.20-7.22 (m, 1H, ArH), 7.28-7.39 (m, 7H, ArH), 7.53-
[M+Na]+ calcd for C17H12Cl2O4SNa 404.9726; found 404.9724.
7.54 (m, 2H, ArH). 13C NMR (125 MHz, CDCl3) δ 15.1 (CH2CHSO2),
18.5 (CH3CHSO2), 70.9 (COH), 82.0 (CHSO2), 125.4 (ArCH), 126.0
(1,1-dioxido-2,4-thietanediyl)bis{[4-
(trifluoromethyl)phenyl]}methanone-3e. Column chromatography (ArCH), 127.3 (ArCH), 128.1 (ArCH), 128.4 (ArCH), 128.8 (ArCH),
on silica gel (Hexane/AcOEt 80:20), yellow solid, mp 180-183 °C, 143.2 (ArC), 145.0 (ArC). FT-IR (KBr, cm-1) υ 511, 546, 698, 800,
60% (277 mg), dr 80:20. 1H NMR (400 MHz, CDCl3) δ 2.45-2.53 (dt, d 1123, 1152, 1250, 1449, 1490, 2965, 3011, 3029, 3063, 3090, 3489.
= J = 12.8 Hz, t = J = 9.7 Hz, 1H, minor, CH2CHSO2), 3.13 (t, J = 8.1Hz, HRMS (ESI-TOF) m/z [M+Na]+ calcd for C17H18O3SNa 325.0869;
2H, major, CH2CHSO2), 3.80-3.85 (dt, d = J = 12.8 Hz, t = J = 9.4 Hz, found 325.0872.
1H, minor, CH2CHSO2), 5.99 (t, J = 9.5 Hz, 2H, minor CHSO2), 6.01 (t, (4-benzyl-1,1-dioxido-2-thietanyl)[4-(2-methyl-2-
J = 8.1Hz, 2H, major, CHSO2), 7.81-7.84 (m, 4H minor + 4H major, propanyl)phenyl]methanone-4c. Column chromatography on silica
ArH), 8.12-8.18 (m, 4H major + 4H, minor, ArH). 13C NMR (101 MHz, gel (Hexane/AcOEt 80:20), white solid, mp 96-99 °C, 75% (270 mg),
1
CDCl3) δ 9.9 (minor, CH2CHSO2), 10.0 (major, CH2CHSO2), 79.7 dr 60:40. H NMR (400 MHz, CDCl3) δ 1.34 (s, 9H, minor, C(CH3)3),
1
(minor, CHSO2), 81.3 (major, CHSO2), 123.2 (d, JC,F = 273.1 Hz, 1.35 (s, 9H, major, C(CH3)3) 1.96-2.03 (m, 1H, minor, CH2CHSO2),
3
major, CF3), 126.4 (q, JC,F = 3.7 Hz, major, ArCH), 128.9 (minor, 2.30-2.37 (m, 1H, major, CH2CHSO2), 2.68-2.75 (m, 1H, major,
2
ArCH), 129.1 (major, ArCH), 136.1 (q, JC,F = 33.0 Hz, major, ArC), CH2CHSO2), 2.97-3.05 (m, 1H, minor, CH2CHSO2), 3.079 (m, 1H,
137.7 (major, ArC), 185.0 (minor, C=O), 186.3 (major, C=O). 19F (377 major, ArCH2CH), 3.127 (m, 1H, minor, ArCH2CH), 3.41 (dd, J = 14.5,
MHz, CDCl3) δ -63.4(s). FT-IR (KBr, cm-1) υ 809, 859, 1070, 1128, 7.7 Hz, 1H, major, ArCH2CH), 3.51 (dd, J = 14.5, 7.5Hz, 1H, minor,
1169, 1333, 1692, 2957. HRMS (ESI-TOF) m/z [M+Na]+ calcd for ArCH2CH), 4.62-4.75 (m, 1H major + 1H minor, CHSO2), 5.74 (t, J =
C19H12F6O4SNa 473.0253; found 473.0255.
9.2 Hz, 1H, major, CHSO2), 5.81 (ddd, J = 9.8, 4.7, 1.3Hz, 1H, minor,
General procedure for lithiation/electrophile trapping sequence CHSO2), 7.25-7.28 (m, 3H minor + 3H major, ArH), 7.32-7.35 (m, 2H
on C2'-substituted thietane-1,1-dioxide. To a stirred solution of minor + 2H major, ArH), 7.53-7.57 (m, 2H minor + 2H major, ArH),
thietane 1,1-dioxide 2-substituted (1.0 mmol, 1.0 equiv) in dry 2- 7.94-7.96 (m, 2H, minor, ArH), 8.01-8.03 (m, 2H, major, ArH). 13C
MeTHF (10 mL) cooled at -78°C, a solution of n-HexLi (2.5M in NMR (101 MHz, CDCl3) δ 15.5 (major, CH2CHSO2), 15.8 (minor,
hexane, 1.1 equiv) was added dropwise. After stirring for 5 min. at - CH2CHSO2), 31.0 (major, C(CH3)3), 35.1 (major, ArCH2CH), 35.3
78°C, the electrophile (1 equiv) was added neat if liquid and in 1.0 (major, C(CH3)3), 35.4 (minor, ArCH2CH), 77.5 (major, CHSO2), 78.6
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(major, CHSO2), 79.0 (minor, CHSO2), 79.3 (minor, CHSO2), 126.1 (CH2CHSO2), 55.2 (CH2SO2), 67.3 (CHSO2), 79.1 (COH), 124.9 (ArCH),
(minor, ArCH), 126.2 (major, ArCH), 127.2 (major, ArCH), 127.2 125.6 (ArCH), 127.0 (ArCH), 127.3 (ArCH), 127.9 (ArCH), 128.5
(minor, ArCH), 128.6 (major, ArCH), 128.7 (minor, ArCH), 128.7 (ArCH), 143.9 (ArC), 144.5 (ArC). FT-IR (KBr, cm-1) υ 693, 747, 1130,
(minor, ArCH), 128.8 (major, ArCH), 128.9 (major, ArCH), 132.9 1265, 1318, 1448, 2927, 3454. HRMS (ESI-TOF) m/z [M+Na]+ calcd
(major, ArC), 133.0 (minor, ArC), 135.8 (minor, ArC), 136.1 (major, for C18H20O3SNa 339.1025; found 339.1028.
ArC), 158.5 (minor, ArC), 158.6 (major, ArC), 186.4 (major, C=O), cyclopropyl(1,1-dioxidotetrahydro-2H-thiopyran-2-yl)methanone-
187.1 (minor, C=O). FT-IR (KBr, cm-1) υ 545, 700, 1129, 1312, 1685, 6d. Column chromatography on silica gel (Hexane/AcOEt 60:40),
2959. HRMS (ESI-TOF) m/z [M+Na]+ calcd for C21H24O3SNa 379.1338; white solid, mp 110-113 °C, 75% (155 mg). 1H NMR (400 MHz,
found 379.1345.
General procedure for lithiation/electrophile trapping sequence CH2CH2CHSO2), 1.85-1.92 (m, 1H, CH2CH2CHSO2), 2.08-2.11 (m, 2H,
on C2-substituted tetrahydro-2H-thiopyran 1,1-dioxide. To CH2CH2SO2), 2.26-2.32 (m, 3H, CH2CHSO2, CH2CH2CH), 2.96-3.03 (m,
CDCl3) δ 1.03-1.24 (m, 4H, CH2CH2CH, CH2CH2CH), 1.51-1.56 (m, 1H,
a
stirred solution of tetrahydro-2H-thiopyran 1,1-dioxide (1.0 mmol, 1H, CH2SO2), 3.24-3.30 (m, 1H, CH2SO2), 4.13 (ddd, J = 8.2, 4.5, 1.5
1.0 equiv) in dry 2-MeTHF (10 mL) cooled at -78°C, a solution of n- Hz, 1H, CHSO2). 13C NMR (125 MHz, CDCl3) δ 12.9 (CH2CH2CH,
HexLi (2.5M in hexane, 1.1 equiv) was added dropwise. After CH2CH2CH), 21.6 (CH2CH2CHSO2), 22.1 (CH2CH2CH), 24.2
stirring for 10 min. at -78°C, the electrophile (1 equiv) was added (CH2CH2SO2), 27.1(CH2CHSO2), 52.4 (CH2SO2), 71.3 (CHSO2), 201.5
neat if liquid and in 1.0 mL of solvent if solid. After the reaction was (C=O). FT-IR (KBr, cm-1) υ. 550, 1120, 1677, 2788, 2967. HRMS (ESI-
complete, as ascertained by GC or TLC, the reaction mixture was TOF) m/z [M+Na]+ calcd for C9H14O3SNa 225.0556; found 225.0559.
quenched with saturated aqueous NH4Cl (0.1mL) and directly N-(2-phenylethyl)tetrahydro-2H-thiopyran-2-carboxamide
1,1-
filtered over Na2SO4 and concentrated in vacuo. Flash dioxide-6e. Column chromatography on silica gel (Hexane/AcOEt
chromatography on silica gel (Hexane/AcOEt) afforded the 70:30), white solid, mp 50-53 °C, 70% (200 mg). 1H NMR (400 MHz,
substituted tetrahydro-2H-thiopyran 1,1-dioxide.
2-benzyltetrahydro-2H-thiopyran 1,1-dioxide-6a.
CDCl3) δ 1.46-1.53 (m, 1H, CH2CH2CHSO2), 1.90-1.96 (m, 1H,
Column CH2CH2CHSO2), 2.04-2.10 (m, 2H, CH2CH2SO2), 2.15-2.24 (m, 1H,
chromatography on silica gel (Hexane/AcOEt 70:30), white solid, mp CH2CHSO2), 2.31-2.39 (m, 1H, CH2CHSO2), 2.86 (t, J = 7.1 Hz, 2H,
111-114 °C, 50% (114 mg). 1H NMR (400 MHz, CDCl3) δ 1.27-1.35 (m, CH2CH2NH), 2.89-3.01 (m, 1H, CH2SO2), 3.08-3.14 (m, 1H, CH2SO2),
1H, CH2CH2CHSO2), 1.67-1.83 (m, 2H, CH2CH2CHSO2, CH2CHSO2), 3.50-3.67 (m, 3H, CH2CH2NH, CHSO2), 6.74 (bs, NH, 1H), 7.21-7-25
1.88-1.93 (m, 1H, CH2CHSO2), 2.04-2.09 (m, 2H, CH2CH2SO2), 2.65 (m, 3H, ArH), 7.29-7.33 (m, 2H, ArH). 13C NMR (101 MHz, CDCl3) δ
(dd, J = 13.5, 11.1 Hz, 1H, ArCH2CH), 2.88-3.05 (m, 2H, CH2SO2, 22.7 (CH2CH2CHSO2), 24.1 (CH2CH2SO2), 27.9 (CH2CHSO2), 35.4
CHSO2), 3.10-3.16 (m, 1H, CHSO2), 3.52 (dd, J = 13.5, 2.7 Hz, 1H, (CH2CH2NH), 41.2 (CH2CH2NH), 52.1 (CH2SO2), 65.6 (CHSO2), 126.5
ArCH2CH), 7.17-7.19 (m, 2H, ArH), 7.23-7.26 (m, 1H, ArH), 7.30-7.33 (ArCH), 128.6 (ArCH), 128.8 (ArCH), 138.5 (ArC), 163.0 (C=O). 15N δ -
(m, 2H, ArH). 13C NMR (101 MHz, CDCl3) δ 23.8 (CH2CH2CHSO2), 24.3 263.3. FT-IR (KBr, cm-1) υ 702, 746, 917, 1129, 1192, 1290, 1318,
(CH2CH2SO2), 28.6 (CH2CHSO2), 30.8 (ArCH2CH), 51.9 (CH2SO2), 63.0 1557, 1651, 3314. HRMS (ESI-TOF) m/z [M+Na]+ calcd for
(CHSO2), 126.9 (ArCH), 128.7 (ArCH), 129.3 (ArCH), 136.5 (ArC). FT- C14H19NO3SNa 304.0978; found 304.0973.
IR (KBr, cm-1) υ 473, 707, 760, 1127, 1282, 2927. HRMS (ESI-TOF) (1,1-dioxidotetrahydro-2H-thiopyran-2yl)(3-thienyl)methanol-6f.
m/z [M+Na]+ calcd for C12H16O2SNa 247.0763; found 247.0762.
Column chromatography on silica gel (Hexane/AcOEt 70:30), white
solid, mp 105-108 °C, 73% (183 mg), diastereoisomeric mixture, dr
(1,1-dioxidotetrahydro-2H-thiopyran-2-yl)[4-(2-methyl-2-
propanyl)phenyl]methanone-6b. Column chromatography on silica 50:50. 1H NMR (400 MHz, CDCl3) δ 1.50-2.30 (m, 12H, 3 x CH2 ring),
gel (Hexane/AcOEt 80:20), white solid, mp 151-154 °C, 68% (200 2.97-3.00 (m, 3H, CH2SO2, CHSO2), 3.15-3.30 (m, 3H, CH2SO2,
mg). 1H NMR (400 MHz, CDCl3) δ 1.35 (s, 9H, C(CH3)3), 1.59-1.67 (m, CHSO2), 5.36 (d, J = 9.1 Hz, 1H, CHOH), 5.89 (s, 1H, CHOH), 6.99 (dd,
1H, CH2CH2CHSO2), 1.86-1.95 (m, 1H, CH2CH2CHSO2), 2.15-2.20 (m, J = 4.9, 1.3 Hz, 1H, ArH), 7.10 (dd, J = 5.0, 1.3 Hz, 1H, ArH), 7.28 (dd,
2H, CH2CH2SO2), 2.32-2.46 (m, 2H, CH2CHSO2), 3.03-3.10 (m, 1H, J = 3.0, 1.3 Hz, 1H, ArH), 7.30 (dd, J = 3.0, 1.3 Hz, 1H, ArH), 7.33 (dd,
CH2SO2), 3.59-3.65 (m, 1H, CH2SO2), 4.87-4.90 (m, 1H, CHSO2), 7.51- J = 4.9, 3.0 Hz, 1H, ArH), 7.35 (dd, J = 5.0, 3.0 Hz, 1H, ArH). 13C NMR
7.53 (m, 2H, ArH), 7.91-7.93 (m, 2H, ArH). 13C NMR (101 MHz, (125 MHz, CDCl3) δ 22.4 (CH2CHSO2), 23.5 (CH2CH2CHSO2), 23.8
CDCl3) δ 20.3 (CH2CH2CHSO2), 24.2 (CH2-CH2SO2), 28.3 (CH2CHSO2), (CH2CH2SO2), 24.0 (CH2CH2CHSO2), 24.2 (CH2CH2SO2), 27.5
31.1 (C(CH3)3), 35.3 (C(CH3)3), 51.4 (CH2SO2), 64.9 (CHSO2), 125.9 (CH2CHSO2), 52.3 (CH2SO2), 53.0 (CH2SO2), 65.4 (CHOH), 66.4
(ArCH), 128.9 (ArCH), 133.2 (ArC), 158.4 (ArC), 192.0 (C=O). FT-IR (CHSO2), 67.3 (CHSO2), 68.1 (CHOH), 121.8 (ArCH), 123.3 (ArCH),
(KBr, cm-1) υ. 548, 926, 1118, 1270, 1324, 1677, 2866, 2967. HRMS 124.9 (ArCH), 125.6 (ArCH), 126.4 (ArCH), 126.8 (ArCH), 140.0 (ArC),
(ESI-TOF) m/z [M+Na]+ calcd for C16H22O3SNa 317.1182; found 140.8 (ArC). FT-IR (KBr, cm-1) υ 616, 790, 1129, 1281, 1637, 2925,
317.1183.
3418. HRMS (ESI-TOF) m/z [M+Na]+ calcd for C10H14O3S2Na
269.0277; found 269.0281.
(1,1-dioxidotetrahydro-2H-thiopyran-2-yl)(diphenyl)methanol-6c.
Column chromatography on silica gel (Hexane/AcOEt 80:20), white (1,1-dioxidotetrahydro-2H-thiopyran-2yl)(4-
solid, mp 98-102 °C, 60% (195 mg). 1H NMR (400 MHz, CDCl3) δ methoxyphenyl)methanone-6g. Column chromatography on silica
1.39-1.51 (m, 1H, CH2CH2CHSO2), 1.87-1.98 (m, 2H, CH2CH2CHSO2, gel (Hexane/AcOEt 70:30), white solid, mp 161-163 °C 65% (179
CH2CHSO2), 2.02-2.09 (m, 2H, CH2CH2SO2), 2.20-2.30 (m, 1H, mg). 1H NMR (500 MHz, CDCl3) δ 1.60-1.65 (m, 1H, CH2CH2CHSO2),
CH2CHSO2), 2.98-3.06 (m, 2H, CH2SO2), 4.09 (dd, J = 12.2, 3.2 Hz, 1H, 1.90-1.97 (m, 1H, CH2CH2CHSO2), 2.14-2.18 (m, 2H, CH2CH2SO2),
CHSO2), 4.65 (bs, 1H, OH), 7.18-7.23 (m, 2H, ArH), 7.30-7.34 (m, 4H, 2.36-2.40 (m, 2H, CH2CHSO2), 3.03-3.08 (m, 1H, CH2SO2), 3.57-3.63
ArH), 7.50-7.53 (m, 2H, ArH), 7.63-7.66 (m, 2H, ArH). 13C NMR (101 (m, 1H, CH2SO2), 3.89 (s, 3H, OCH3), 4.84 (td, J = 5.3, 2.0 Hz, 1H,
MHz, CDCl3)
δ
24.0 (CH2CH2SO2), 24.2 (CH2CH2CHSO2), 26.7 CHSO2), 6.95-6.98 (m, 2H, ArH), 7.95-7.98 (m, 2H, ArH). 13C NMR
12 | J. Name., 2012, 00, 1-3
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(125 MHz, CDCl3) δ 20.4 (CH2CH2CHSO2), 24.1 (CH2CH2SO2), 28.3 + minor), 2.07-2.12 (m, 1H, CH2CHSO2, minor), 2.24-2.27 (m, 1H,
(CH2CHSO2), 51.5 (CH2SO2), 55.6 (OCH3), 64.8 (CHSO2), 114.1 (ArCH), CH2CHSO2, major), 2.49-2.56 (m, 1H, CH2CHSO2, major), 2.60-2.65
128.8 (ArCH), 131.5 (ArC), 164.5 (C=O). FT-IR (KBr, cm-1) υ 713, 827, (m, 1H, CH2CHSO2, minor), 2.67-2.72 (dt, J = 9.3, 8.4 Hz, 2H,
934, 1132, 1174, 1270, 1316, 1663, 2933. HRMS (ESI-TOF) m/z CHCH2Ar, major + minor), 3.15-3.21 (m, 1H, CHCH2Ar, minor), 3.54-
[M+Na]+ calcd for C13H16O4SNa 291.0662; found 291.0669.
3.56 (dd, J = 13.5, 3.1 Hz, 2H, CHCH2Ar, minor + major), 3.88-3.94
General procedure for lithiation-electrophile trapping sequence (ddd, J = 11.4, 7.3, 3.4 Hz, 1H, CHCH2Ar, major), 4.87-4.90 (dd, J =
on C2,C2'-substituted tetrahydro-2H-thiopyran 1,1-dioxide. To a 12.6, 2.9 Hz, 1H, CHCOAr, minor), 4.98-5.00 (dd, J = 5.3, 2.7 Hz, 1H,
stirred solution of tetrahydro-2H-thiopyran 1,1-dioxide (1.0 mmol, CHCOAr, major), 7.20-7.35 (m, 10H), 7.51-7.53 (m, 4H), 7.89 (d, J =
1.0 equiv) in dry 2-MeTHF (10 mL) cooled at -78°C, a solution of n- 8.5 Hz, 2H), 8.02 (d, J = 8.5 Hz, 2H). 13C NMR (125 MHz, CDCl3) δ 19.5
HexLi (2.5M in hexane, 2.5 equiv) was added dropwise. After (CH2CH2CHSO2, major), 23.8 (CH2CH2CHSO2, minor), 28.2
stirring for 30 min at -78°C, the electrophile (2.5 equiv) was added (CH2CHSO2, minor), 28.6 (CH2CHSO2, major), 28.75 (CH2CHSO2,
neat if liquid and in 1.0 mL of solvent if solid. After the reaction was major), 28.8 (CH2CHSO2, minor), 30.7 (CHCH2Ar, major), 30.9
complete, as ascertained by GC or TLC, the reaction mixture was (CHCH2Ar, minor), 31.0 (C(CH3)3, major), 31.0 (C(CH3)3, minor), 35.2
quenched with saturated aqueous NH4Cl (0.1mL) and directly (C(CH3)3, minor), 35.3 (C(CH3)3, major), 61.1 (CHCH2Ar, major), 64.6
filtered over Na2SO4 and concentrated in vacuo. Flash (CHCOAr, major), 65.5 (CHCH2Ar, minor), 67.0 (CHCOAr, minor),
chromatography on silica gel (Hexane/AcOEt) afforded the 125.7 (ArCH, major), 126.0 (ArCH, major), 126.9 (ArCH, minor),
disubstituted tetrahydro-2H-thiopyran 1,1-dioxide.
2,6-dibenzyltetrahydro-2H-thiopyran 1,1-dioxide-7a.
127.0 (ArCH, minor), 128.7 (ArCH, major), 128.8 (ArCH, major),
Column 128.8 (ArCH, minor), 129.4 (ArCH, minor), 129.5 (ArCH, major),
chromatography on silica gel (Hexane/AcOEt 80:20), white solid, mp 129.5 (ArCH, minor), 132.8 (ArC, major), 134.0 (ArC, minor), 136.4
179-181 °C 60% (190 mg), dr 80:20. 1H NMR (400 MHz, CDCl3) δ (ArC, major), 136.4 (ArC, minor), 158.1 (ArC, minor), 158.4 (ArC,
1.13-1.26 (m, 1H, major, CH2CH2CHSO2), 1.57-1.63 (m, 2H, minor, major), 189.0 (C=O, minor), 192.9 (C=O, major). FT-IR (KBr, cm-1) υ
CH2CH2CHSO2), 1.70-1.80 (m, 3H major + 2H minor, CH2CH2CHSO2, 511, 701, 1119, 1269, 1301, 1602, 1674, 2952, 3453. HRMS (ESI-
CH2CHSO2), 1.85-1.90 (m, 2H, major, CH2CHSO2), 1.98-2.06 (m, 2H, TOF) m/z [M+Na]+ calcd for C23H28O3SNa 407.1651; found 407.1653.
minor, CH2CHSO2), 2.71 (dd, J = 13.6, 11.0 Hz, 2H, major, ArCH2CH), 2-(hydroxydiphenylmethyl)-6-methyltetrahydro-2H-thiopyran 1,1-
2.79 (dd, J = 13.5, 12.0 Hz, 2H, minor, ArCH2CH), 2.97-3.05 (m, 2H, dioxide-8b. Column chromatography on silica gel (Hexane/AcOEt
major, CHSO2), 3.16-3.22 (m, 2H, minor, CHSO2), 3.53 (dd, J = 13.5, 80:20), white solid, mp 159-164 °C, 71% (235 mg), dr 90:10. 1H NMR
3.2 Hz, 2H, minor, ArCH2CH) 3.58 (dd, J = 13.6, 3.2 Hz, 2H, major, (500 MHz, CDCl3) δ 1.27 (d, J = 6.8 Hz, 3H, major, CH3CHSO2), 1.42
ArCH2CH), 7.20-7.22 (m, 4H major + 4H minor, ArH), 7.23-7.29 (m, (d, J = 7.1 Hz, 3H, minor, CH3CHSO2), 1.50-1.54 (m, 1H, major,
2H major + 2H minor, ArH), 7.30-7.36 (m, 4H major + 4H minor, CH2CH2CHSO2), 1.59-1.67 (m, 1H, minor, CH2CH2CHSO2), 1.73-1.79
ArH). 13C NMR (101 MHz, CDCl3) δ 18.6 (minor, CH2CH2CHSO2), 24.4 (m, 1H, minor, CH2CH2CHSO2), 1.77-1.90 (m, 2H, major,
(major, CH2CH2CHSO2), 27.1 (minor, CH2CHSO2), 29.0 (major, CH2CH2CHSO2, CH2CHSO2), 1.83-1.91 (m, 2H, minor, CH2CHSO2),
CH2CHSO2), 30.9 (major, ArCH2CH), 31.7 (minor, ArCH2CH), 60.4 1.93-2.01 (m, 2H, major, CH2CHSO2), 2.11-2.21 (m, 2H, minor,
(minor, CHSO2), 63.6 (major, CHSO2), 126.9 (major, ArCH), 127.0 CH2CHSO2), 2.24-2.33 (m, 1H, major, CH2CHSO2), 3.00-3.06 (m, 1H,
(minor, ArCH), 128.7 (major, ArCH), 128.8 (minor, ArCH), 129.2 major, CHSO2), 3.16-3.22 (m, 1H, minor, CHSO2), 4.05 (dd, J = 12.6,
(minor, ArCH), 129.4 (major, ArCH), 136.8 (minor, ArC), 136.8 3.1 Hz, 1H, major, CHSO2), 4.19 (dd, J = 10.9, 3.8 Hz, 1H, minor,
(major, ArC). FT-IR (KBr, cm-1) υ 491, 700, 756, 1114, 1307, 1455, CHSO2), 4.50 (bs, 1H, OH, minor), 4.79 (s, 1H, OH, major), 7.18-7.23
1722, 2934 HRMS (ESI-TOF) m/z [M+Na]+ calcd for C19H22O2SNa (m, 2H, minor, ArH), 7.18-7.24 (m, 2H, major, ArH), 7.29-7.33 (m,
337.1233; found 337.1230.
General procedure for lithiation/electrophile trapping sequence minor, ArH), 7.53-7.54 (m, 2H, major, ArH), 7.60-7.62 (m, 2H, minor,
on C2'-substituted tetrahydro-2H-thiopyran 1,1-dioxide. To
ArH), 7.63-7.65 (m, 2H, major, ArH). 13C NMR (125 MHz, CDCl3) δ
4H, minor, ArH), 7.30-7.34 (m, 4H, major, ArH), 7.46-7.48 (m, 2H,
a
stirred solution of tetrahydro-2H-thiopyran 1,1-dioxide 2- 10.3 (major, CH3CHSO2), 12.7 (minor, CH3CHSO2), 19.0 (minor,
substituted (1.0 mmol, 1.0 equiv) in dry 2-MeTHF (10 mL) cooled at CH2CH2CHSO2), 24.6 (major, CH2CH2CHSO2), 25.8 (minor,
-78 °C, a solution of n-HexLi (2.5M in hexane, 1.1 equiv) was added CH2CHSO2), 27.1 (major, CH2CHSO2), 29.4 (minor, CH2CHSO2), 32.2
dropwise. After stirring for 10 min at -78 °C, the electrophile (1 (major, CH2CHSO2), 57.7 (minor, CHSO2), 60.3 (major, CHSO2), 64.6
equiv) was added neat if liquid and in 1.0 mL of solvent if solid. (minor, CHSO2), 67.4 (major, CHSO2), 79.2 (minor, COH), 79.2
After the reaction was complete, as ascertained by GC or TLC, the (major, COH), 124.9 (major, ArCH), 125.0 (minor, ArCH), 125.6
reaction mixture was quenched at -78 °C with saturated aqueous (minor, ArCH), 125.6 (major, ArCH), 126.9 (minor, ArCH), 127.0
NH4Cl (0.1mL) and directly filtered over Na2SO4 and concentrated in (major, ArCH), 127.3 (minor, ArCH), 127.3 (major, ArCH), 127.9
vacuo. Flash chromatography on silica gel (Hexane/AcOEt) afforded (major, ArCH), 128.0 (minor, ArCH), 128.4 (minor, ArCH), 128.5
the 2,4-disubstituted tetrahydro-2H-thiopyran 1,1-dioxide.
(6-benzyl-1,1-dioxidotetrahydro-2H-thiopyran-2-yl)[4-(tert-
(major, ArCH), 144.0 (major, ArC), 144.2 (minor, ArC), 144.6 (major,
ArC), 145.1 (minor, ArC). FT-IR (KBr, cm-1) υ 571, 695, 964, 1132,
butyl)phenyl]methanone-8a. Column chromatography on silica gel 1273, 1449, 1637, 2863, 2972, 3492. HRMS (ESI-TOF) m/z [M+Na]+
(Hexane/AcOEt 80:20), white solid, mp 149-152 °C, 72% (235 mg), calcd for C19H22O3SNa 353.1182; found 353.1183.
dr 60:40. 1H NMR (500 MHz, CDCl3) δ 1.35 (s, 18H, C(CH3)3), 1.40- General procedure for direct α-arylation of cyclic sulfones 1, 5 and
1.48 (m, 2H, CH2CH2CHSO2, minor), 1.61-1.66 (m, 1H, CH2CH2CHSO2, 11. To a stirred solution of thietane 1,1-dioxide (1.0 mmol, 1.0
major), 1.75-1.81 (m, 2H, CH2CH2CHSO2, CH2CHSO2, major), 1.83- equiv) in dry THF (10 mL) cooled at -78°C, a solution of n-HexLi
1.91 (m, 1H, CH2CHSO2,minor ), 1.94-1.97 (m, 2H, CH2CHSO2, major (2.5M in hexane, 1.1 equiv) was added dropwise. After stirring for
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the time indicated in Scheme6, at -78°C, anhydrous Copper(I) was quenched with saturated aqueous NH4Cl (0.1mL), directly
cyanide di(lithium chloride) complex solution (CuCN 2LiCl, 1 equiv) filtered over Na2SO4 and concentrated in vacuo. Flash
was added in one portion. The mixture was allowed to warm to -35 chromatography on silica gel (Hexane/AcOEt) afforded the 2-phenyl
°C, stirred for 15 min at this temperature. Diphenyliodonium substituted cyclic sulfones.
hexafluorophoshate (1 equiv) was added, in one portion, resulting 2-fluoro-2-(phenylsulfonyl)thietane
1,1-dioxide-10a
Column
in the immediate formation of a bright yellow mixture. The reaction chromatography on silica gel (Hexane/AcOEt 60:40), yellowish solid,
was maintained at -35 °C for 15 min then allowed to slowly to warm mp 130-132 °C, 30% (85 mg). 1H NMR (400 MHz, CDCl3) δ 2.50-2.65
to room temperature. After stirring for 4 hour to rt, the reaction (m, 1H, CH2CFSO2), 3.23-3.32 (m, 1H, CH2CFSO2), 4.06-4.27 (m, 2H,
mixture was quenched with saturated aqueous NH4Cl (0.1mL) and CH2SO2), 7.62-7.66 (m, 2H, ArH), 7.78-7.80 (m, 1H, ArH), 8.07-8.10
the organic layer was separated, and the acqueous layer was (m, 2H, ArH). 13C NMR (101 MHz, CDCl3) δ 20.9 (d, J = 20.6 Hz,
extracted with Et2O (3 x 20 mL). The combined organic extracts CH2CFSO2), 61.2 (d, J = 5.0 Hz, CH2SO2), 125.6 (d, J = 298 Hz, CF),
were dried over Na2SO4, filtered and the solvent evaporated under 129.5 (ArCH), 130.8 (ArCH), 133.1 (ArCH), 136.0 (ArC). 19F NMR (377
vacuum and the product purified on silica gel.
MHz, CDCl3) δ -128.99 (ddd, J = 21.6, 8.0, 1.8 Hz). FT-IR (KBr, cm-1) υ
2-phenylthietane 1,1-dioxide-9a. Flash chromatography on silica 557, 720, 1153, 1328, 1448, 2854, 2926, 3049. HRMS (ESI-TOF) m/z
gel (Hexane/AcOEt 70:30) afforded 2-phenylthietane 1,1-dioxide, [M+Na]+ calcd for C9H9FO4S2Na 286.9818; found 286.9822.
yellow solid, mp 81-84°C, 50% (111 mg). 1H NMR (400 MHz, CDCl3) δ 2-fluoro-2-(phenylsulfonyl)tetrahydro-2H-thiopyran 1,1-dioxide-
2.36-2.47 (m, 1H, CH2CHSO2), 2.54-2.62 (m, 1H, CH2CHSO2), 3.98- 10b. Column chromatography on silica gel (Hexane/AcOEt 60:40),
4.20 (m, 2H, CH2SO2), 5.45-5.49 (m, 1H, CHSO2), 7.38-7.44 (m, 5H, yellowish solid, mp 114-117, 50% (146 mg). 1H NMR (500 MHz,
ArH). 13C NMR (101 MHz, CDCl3) δ 15.0 (CH2CHSO2), 62.1 (CH2SO2), CDCl3)
δ 1.77-1.85 (m, 1H, CH2CH2CFSO2), 1.99-2.23 (m, 3H,
82.3 (CHSO2), 128.5 (ArCH), 128.9 (ArCH), 129.2 (ArCH), 130.8 (ArC). CH2CH2CFSO2, CH2CH2SO2), 2.65-2.72 (m, 1H, CH2CFSO2), 2.80-2.92
FT-IR (KBr, cm-1) υ 583, 704, 734, 769, 1125, 1189, 1301, 1455, (m, 1H, CH2CFSO2), 3.18-3.31 (m, 2H, CH2SO2), 7.58-7.61 (m, 2H,
1492, 2360, 2920. HRMS (ESI-TOF) m/z [M+Na]+ calcd for ArH), 7.74-7.77 (m, 1H, ArH), 8.02-8.04 (m, 2H, ArH). 13C NMR (125
C9H10O2SNa 205.0294; found 205.0296.
MHz, CDCl3) δ 19.5 (d, J = 4.1 Hz, CH2CH2CFSO2), 23.6 (CH2CH2SO2),
2-phenyltetrahydro-2H-thiopyran 1,1-dioxide-9b. The solid was 29.3 (d, J = 18.2 Hz, CH2CFSO2), 51.9 (CH2SO2), 111.8 (d, J = 251 Hz,
washed two times with diethyl ether and one time with distilled CF), 129.0 (ArCH), 131.1 (d, J = 1.2 Hz, ArCH), 134.8 (ArC), 135.5
hexane afforded 2-phenyltetrahydro-2H-thiopyran 1,1-dioxide as (ArCH). 19F NMR (470 MHz, CDCl3) δ -150.4 (m). FT-IR (KBr, cm-1) υ
white solid, mp 84-87°C, 60% (126 mg). 1H NMR (500 MHz, CDCl3) δ 582, 867, 1160, 1328, 1451, 2862, 2926, 3444. HRMS (ESI-TOF) m/z
1.55-1.65 (m, 1H, CH2CH2CHSO2), 2.04-2.09 (m, 2H, CH2CH2CHSO2), [M+Na]+ calcd for C11H13FO4S2Na 315.0131; found 315.0148.
2.17-2.24 (m, 2H, CH2CH2SO2), 2.46-2.54 (m, 1H, CH2CHSO2), 3.02- 2-fluoro-2-(phenylsulfonyl)tetrahydrothiphene 1,1-dioxide-10c
3.08 (m, 1H, CH2SO2), 3.23 (dtd, J = 14.1, 3.5, 1.4 Hz, 1H, CH2SO2), Column chromatography on silica gel (Hexane/AcOEt 60:40), yellow
4.02 (dd, J = 13.0, 3.0 Hz, 1H, CHSO2), 7.38-7.44 (m, 5H, ArH). 13C oil, 50%. 1H NMR (500 MHz, CDCl3) δ 2.23-2.39 (m, 2H, CH2CH2SO2),
NMR (125 MHz, CDCl3) δ 24.6 (CH2CH2CHSO2), 25.2 (CH2CH2SO2), 2.52-2.61 (m, 1H, CH2CF), 3.04-3.17 (m, 1H, CH2CF), 3.23-3.32 (m,
31.0 (CH2CHSO2), 52.7 (CH2SO2), 67.6 (CHSO2), 128.6 (ArCH), 129.0 2H, CH2SO2 ), 7.61-7.64 (t, J = 7.6 Hz, 2H, ArH), 7.7-7.78 (t, J = 7.4
(ArCH), 129.9 (ArCH), 130.4 (ArC). FT-IR (KBr, cm-1) υ 697, 727, 1124, Hz, 1H, ArH), 8.06-8.07 (d, J = 7.7 Hz, 2H, ArH). 13C NMR (126 MHz,
2
1281, 1446, 1493, 2862, 2935. HRMS (ESI-TOF) m/z [M+Na]+ calcd CDCl3) δ 16.3 (CH2CH2SO2), 28.8 (d, JCF = 19.5 Hz, CH2CF), 50.9
for C11H14O2SNa 233.0607; found 233.0609.
(CH2SO2), 111.4 (d, J = 267.8 Hz, CF), 129.2 (ArCH), 130.9 (ArCH),
113.8 (ArC), 135.7 (ArCH); 19F NMR (470 MHz, CDCl3) δ -142.53 (dd,
2-phenyltetrahydrothiophene 1,1-dioxide-9c
Column chromatography on silica gel (Hexane/AcOEt 60:40), JHF = 28.4, 21.2 Hz); FT-IR (NaCl, cm-1) υ 572, 887, 1156, 1328,1450,
colorless oil, 70%. 1H NMR (500 MHz, CDCl3) δ 2.19-2.27 (m, 1H, 2860, 2926, 3060; HRMS (ESI-TOF) m/z [M+Na]+ calcd for
CH2CH2SO2), 2.34-2.39 (m, 1H, CH2CH2SO2), 2.45-2.49 (m, 1H, C10H11FNaO4S2 300.9975; found 300.9980.
CH2CHAr), 2.51-2.58 (m, 1H, CH2CHAr), 3.14-3.20 (m, 1H, CH2SO2),
3.28-3.32 (m, 1H, CH2SO2), 4.15-4.19 (dd, J = 12.2, 7.2 Hz, 1H, CHAr), Determination of lipophilicity by RP-HPLC
7.39-7.41 (m, 5H, ArH); 13C NMR (126 MHz, CDCl3)
δ 19.8 Lipophilicity parameters of the cyclic sulfone derivatives were
(CH2CH2SO2), 28.7 (CH2CHAr), 50.6 (CH2SO2), 66.7 (CHAr), 128.8 measured by an RP-HPLC technique.28,29 Methanol solutions of the
(ArCH), 129.0 (ArCH), 129.1 (ArCH), 130.3 (ArC); FT-IR (NaCl, cm-1) υ investigated compounds (0.25 mg/mL) were injected into a HPLC
594, 724, 1132, 1189, 1301, 1449, 1493, 2359, 2921;HRMS (ESI- equipped with a Kinetex C18 column (150 × 4.6 mm, 5ꢀ) from
TOF) m/z [M+Na]+ calcd for C10H12NaO2S 219.0450; found 219.0459. Phenomenex (Phenomenex Italy s.r.l., Castel Maggiore, BO, Italy).
General procedure for C2-fluorination cyclic sulfones 1, 5 and 11. The cyclic sulfones were eluted at different mobile phase
To a stirred solution of thietane-1,1- dioxide or tetrahydro-2H- composition (0.05 increments of MeOH volume fraction in 10 mM
thiopyran 1,1-dioxide (1.0 mmol, 1.0 equiv) in dry 2-MeTHF (10 mL) ammonium formate buffer at pH 5, ranging between 0.70 and
cooled at -78°C, a solution of n-HexLi (2.5M in hexane, 1.1 equiv) 0.30). All RP-HPLC measurements were carried out at 25 ± 1 °C, flow
was added dropwise. After stirring for the time indicated in rate of 1.0 mL/min, at 254 nm wavelength on an Agilent 1260
Scheme6, at -78°C, the electrophilic fluorinated reagent N- infinity HPLC system (Agilent Technologies Italia, Milan), equipped
Fluorobenzenesulfonimide (NFSI, 1 equiv) was added in 2.0 mL of with a diode array detector (DAD).
solvent. The reaction was maintained at -78°C for 15 min then The logarithm of capacity factors (log k’ = log (tR-t0)/t0) of each
allowed to slowly to warm to room temperature. After the reaction compound at different mobile phase compositions have been
was complete, as ascertained by GC or TLC, the reaction mixture calculated; tR represents the retention time of the solute and t0 is
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11 a) J. P. Marino, J. Chem. Soc., Chem. Commun. 1973, 861a. b)
H.-J. Gais, Asymmetric Reactions of α-Sulfonyl Carbanions in
Organosulfur Chemistry. In Asymmetric Synthesis; T. Toru, C.
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375−398.
the column dead time, measured as the elution time of a KNO3
solution in MeOH. For each compound, the log k’ values increased
linearly with decreasing MeOH volume fraction. The logarithm of
capacity factors extrapolated to 100% aqueous mobile phase (log
k’w) were calculated from the linear regressions on at least five data
points.
12 F. Velàzquez, M. Sannigrahi, F. Bennett, R. G. Lovey, A.
Arasappan, S. Bogen, L. Nair, S. Venkatraman, M. Blackman,
S. Hendrata, Y. Huang, R. Huelgas, P. Pinto, K.-C. Cheng, X.
Lipophilicity was also computationally assessed with the BioLoom
software vers. 1.7 (BioByte Corp. Claremont, CA, USA) and ACDLabs
software, release 10.0 (Advanced Chemistry Development, Inc.,
Toronto, Canada).
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Luisi, Chem. - Eur. J. 2014, 20, 12190-12200. b) L. Degennaro,
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Acknowledgements
We thank the University of Bari “A. Moro”, the Polytechnic
University of Bari, the Interuniversities Consortium CINMPIS and the
project Laboratorio SISTEMA, (Code PONa300369) financed by
Italian Miur. We are also grateful to Laura Carroccia, and Nicola Loi
for their contribution. We thank Prof. Gerhard Ecker for support.
Romanazzi, A. Falcicchio, R. Luisi, Chem. Commun. 2014, 50
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1698-1700. c) G. Parisi, E. Capitanelli, A. Pierro, G.
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19 The structure of (2R*,4R*)-3e holds the CCDC 1541515
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TOC
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