A Versatile Reagent and Method for Direct Aliphatic Sulfonylation

Article abstract of DOI:10.1002/adsc.201800071

An efficient methodology has been developed for the two-step synthesis of aliphatic sulfinate salts, sulfonamides, sulfonyl fluorides, and unsymmetrical sulfones on the basis of alkylation of a new versatile sulfonylating reagent. The new reagent is easily accessible in one step; the developed protocols are conducted under mild conditions and have a broad substrate scope. (Figure presented.).

Full text of DOI:10.1002/adsc.201800071

Title: A Versatile Reagent and Method for Direct Aliphatic Sulfonylation
Authors: Andre Shavnya, Kevin D. Hesp, and Andy S. Tsai
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201800071
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10.1002/adsc.201800071
Advanced Synthesis & Catalysis
COMMUNICATION
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
A Versatile Reagent and Method for Direct Aliphatic
Sulfonylation
Andre Shavnya,* Kevin D. Hesp, and Andy S. Tsai
Medicinal Sciences, Pfizer Inc., Eastern Point Road, Groton, Connecticut 06340, United States
E-mail: andre.shavnya@pfizer.com
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.
Abstract. An efficient methodology has been developed incorporated by reactions with either the molecule of
SO2 or its surrogates,[6b] e.g. DABSO[6c-g] and
for the two-step synthesis of aliphatic sulfinate salts,
2-
K2S2O5,[6h-j] or by using synthetic equivalents of SO2
sulfonamides, sulfonyl fluorides, and unsymmetrical
sulfones on the basis of alkylation of a new versatile
anion for aliphatic sulfonylation of alkyl halides
sulfonylating reagent. The new reagent is easily accessible;
(Scheme 1): sodium 3-methoxy-3-oxopropane-1-
the developed protocols are conducted under mild
sulfinate (SMOPS),[7a] sodium salt of 2-sulfinyl
conditions and have a broad substrate scope.
benzothiazole (BTS),[8a] and rongalite (not shown).[9]
Keywords: alkyl halide; potassium sulfinate; zinc
sulfinate; sulfone; sulfonamide; sulfonyl fluoride
Compounds bearing the sulfonyl structural motif
have found numerous applications in the areas of
pharmaceutical,[1a-c] agrochemical,[1d-e] and material
sciences.[1f-g] For example, in the pharmaceutical field
sulfones and sulfonamides have become established
classes of compounds that exhibit various biological
activities, desirable physico-chemical properties, and
metabolic stability due to the intrinsic three-
dimensional and electronic features of the sulfonyl
moiety.[2] Furthermore, there has been substantial
interest in sulfonyl fluorides as biological probes[3a,b]
or as stable and more selective alternatives to
sulfonyl chlorides in organic synthesis.[3c] Among
recent applications of sulfinate salts,[4a] it is
noteworthy to mention their use in carbon-carbon
bond formation via desulfinative couplings based on
Pd-catalyzed,[4b-d] oxidative,[4e-f] or photocatalytic
processes,[4g-h] for biocompatible chemoselective
ligation,[4i-j] and their emerging role as biological
probes.[4k] Consequently, the development of efficient
and versatile methodologies for the synthesis of
Scheme 1. Sulfonylating Methods Based on Synthetic
sulfonyl-containing compounds continues to be of
Equivalents of SO22- Anion.
high interest to the scientific community.[5a]
Besides the classical synthetic approaches to this
class of products, involving harsh oxidative and
chlorination conditions[5b] and recent sulfinate
syntheses via oxidation of heterocyclic sulfides,[5c-e]
in the last decade significant efforts have been made
to advance direct sulfonylation methodologies.[6a] In
this approach, sulfur in higher oxidation states is
Despite their convenience, the last three methods
also carry substantial disadvantages. In particular, the
substrate scope of the SMOPS-based method has
been rather limited and its use has not been reported
for sulfonylation of alkyl tosylates/mesylates and
unactivated chlorides or secondary halides. Its utility
1
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10.1002/adsc.201800071
Advanced Synthesis & Catalysis
Compound 1 was synthesized as shelf-stable,[10b]
safe,[10c] non-hydroscopic, free-flowing solid in one
simple step without chromatography on a 20 g scale
from 3,4,5-trimethoxybenzoyl chloride in qNMR
purity of 97%. As confirmation of molecular
connectivity, its structure was validated by single
crystal X-ray diffraction analysis (see SI).[10d] We
envisioned that after alkylation of the sulfinate group
of substance 1, the obtained sulfone intermediate
could be cleaved in mild basic conditions by
nucleophilic attack at the carbonyl group with
subsequent elimination of a benzoate byproduct and
formaldehyde, to release the desired sulfinate salt
(Scheme 1) for further transformations.
The optimization of the alkylation step began with
the best conditions for alkylation of unprotected
rongalite identified in our previous work.[9] Thus,
alkyl bromide A was reacted with 1 in DMSO in the
presence of catalytic TBAB and 1.2 equiv of DIPEA
at 23 oC, which gave a mixture of the desired sulfone
intermediate 2a and the side-product of O-alkylation
(sulfinate ester) in combined 27% NMR yield (Table
1, entry 1).
for the synthesis of aliphatic secondary and tertiary
sulfonamides, sulfonyl fluorides, and dialkyl sulfones
also has not been demonstrated. In addition, to
promote release of the sulfinate salt, strongly basic
anhydrous conditions are required, which can be
detrimental for base-sensitive molecules. Other
factors that may lead towards limited application of
SMOPS could be its high cost[7b] and
environmental/safety concerns for its preparation.[7c]
The BTS-based method[8a] employs reductive or
strongly basic/nucleophilic conditions for the
intermediate cleavage and is not suitable for sensitive
molecules; four-fold excess of BTS is applied,
sulfonamides are obtained only in moderate yields,
and sulfonyl fluoride synthesis has not been
demonstrated. The reagent BTS also requires a two-
step synthesis involving chromatography and has to
o
be stored at -20 C.[8b] In the method based on
alkylation of rongalite,[9] the inherent instability of
rongalite in the reaction medium (DMSO) and lability
of the hydroxymethyl sulfone intermediate lead to a
rather narrow substrate scope and moderate yields
(and low yields for activated alkyl halides), due to a
side-reaction forming undesirable symmetrical
sulfones. Besides, the rongalite procedure requires
high dilution in DMSO, which is not practical for
scale-up syntheses. Importantly for all three described
methods, isolation of pure, free from inorganic
contaminants sulfinate salts has not been
demonstrated. With all the above considerations in
mind, a mild, convenient, high-yielding, and versatile
method to generate sulfinate salts in pure form
remains a desirable yet so far not readily attainable
goal.
Table 1. Summary of Optimization for Alkylation
of Reagent 1[a]
sulfone/sulfinate
entry
conditions
ester (%)[b]
24/3
1
2
DMSO, DIPEA, 23 oC, 44 h
DMSO, DIPEA, 50 oC
NMP, DIPEA, 50 oC
DMF, DIPEA, 50 oC
DMA, DIPEA, 50 oC
MeCN or MeOH, DIPEA, 50 oC
DMA, DIPEA, 80 oC,
DMA, 80 oC
59/13
25/8
29/7
35/11
0/0
3
4
With the strategic objective of developing a more
general, practical, readily accessible sulfonylating
5
6
2-
reagent and in the search for more effective SO2
7
55/20
anion equivalents with improved stability and
reactivity (Scheme 1), we discovered that the
hydroxyl group of rongalite can be selectively
protected by reacting with some electrophiles [see
Supporting Information (SI) for the list of explored
electrophiles]. Notably, the sulfinate group remains
available for a subsequent derivatization. After
optimizing the O-protecting group for rongalite,
reagent 1 was selected for further methodology
development based on the efficiency of its synthesis
and yields of its S-alkylation (Scheme 2).[10a]
8
40/0
9
DMA, 1 (1.5 equiv.), 80 oC
DMA, 1 (1.8 equiv.), 80 oC
68/0 (60/0)[c]
69/0
10
[a] Reaction conditions: alkyl bromide A (0.5 mmol),
reagent 1 (1.2 equiv.), TBAB (0.3 equiv.), solvent (1.2
mL), 16 h.
[b] NMR yields.
[c] Isolated yield.
o
Conducting this reaction at 50 C increased the
yields of both products (entry 2). Using other solvents
led to diminished yields (entries 3-6). Interestingly,
for DMA, increasing the reaction temperature to 80
oC improved the sulfone yield from 35% to 55%
(entry 7) and omitting DIPEA eliminated the sulfinate
ester as a detectable product (entry 8), which was an
important finding as this impurity was very difficult
to separate by chromatography. Finally, increasing
the amount of reagent 1 from 1.2 to 1.5 equiv. in the
Scheme 2. Synthesis of Sulfonylation Reagent 1.
2
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10.1002/adsc.201800071
Advanced Synthesis & Catalysis
absence of DIPEA resulted in 60% isolated yield
without formation of the sulfinate ester side-product
(entry 9) but no additional positive effect was
achieved with a larger excess of 1 (entry 10).
DIPEA/MeOH (vide infra) could also be used, in
conjunction with solvent switch from MeOH to
DMSO for reaction with the second electrophile.
With the aim of developing an expedient synthesis
of aliphatic sulfonyl fluorides, the compatibility of
the new sulfonylation with subsequent fluorination of
the released sulfinate was investigated. In line with
this goal, the sulfinic acid produced by NaOH-
induced cleavage of the sulfone intermediate 2a,
readily reacted with N-fluorobenzenesulfonimide
(NFSI), furnishing the desired sulfonyl fluoride in
good yield (Table 4, entry 1). Other functionalized
alkyl sulfonyl fluorides were synthesized in the same
manner demonstrating generality of this protocol
(Table 4).
Table 2. Representative Examples of Alkyl
Electrophiles[a]
Table 3. Representative Examples of One-Pot
Synthesis of Dialkylsulfones[a]
[a] Conditions: alkyl electrophile (0.35 mmol), 1 (1.5
equiv.), TBAB (0.3 equiv.), DMA (1.2 mL), 80 oC, 20
h.
[b] Isolated yield.
[a] Reaction conditions: 1) 2b, NaOH/DMSO/H2O, 35 °C;
2) electrophile (2 equiv.), 50 °C, 18 h.
[b] Isolated yield.
With the optimized conditions for alkylation of 1
identified, the scope of alkyl electrophiles was
explored (Table 2). Both primary (entries 1-6, 9-10,
12-13) and secondary halides (entries 7, 8, 11) were
competent substrates in this reaction. A broad range
of activated and unactivated chlorides, bromides,
iodides, tosylates gave good yields of the desired
sulfone intermediates. Carbamate (entries 1, 6) and
ester groups (entries 12, 13) were well tolerated.
Importantly, no epimerization was observed at
potentially epimerizable chiral centers (entries 12, 13).
Products 2b and 2e were also scaled-up and isolated
by crystallization (see SI).
[c] Step 2: electrophile (1.3 equiv.), 23 °C.
[d] Synthesis of primary sulfonamide. Step 2: H2NOSO3H
(4 equiv.), AcONa (7 equiv.), 23 °C.
Table 4. Representative Examples of Expedient
Synthesis of Sulfonyl Fluorides[a]
Next, we developed a one-pot procedure[11] to
cleave the sulfone intermediate 2b with NaOH and
capture the released sulfinate salt with various
electrophiles (Table 3). Primary bromides (entries 1),
primary and secondary iodides (entries 2, 4), tosylates
(entry 3), and activated chlorides (entry 5) were
found to be suitable for the second alkylation in the
synthesis of unsymmetrical dialkylsulfones. Notably,
electrophilic amination of the intermediate sulfinate
with hydroxylamine-O-sulfonic acid led to the
primary sulfonamide 3d (entry 6).[7a, 9] It should be
[a] Reaction conditions: 1) 2 NaOH/THF/H2O, 23 °C; 2)
H3PO4 (2 equiv.); 3) DIPEA (2.0 equiv.), NFSI (2
equiv.), 0 to 23 °C, 1 h.
[b] Isolated yield.
For base-sensitive substrates a milder method for
the cleavage of the sulfone intermediate was
noted that
a
milder cleavage method with
3
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10.1002/adsc.201800071
Advanced Synthesis & Catalysis
developed. For example, by treating glycoside 2h
with a methanolic solution of DIPEA, the sulfinate
protection was removed as a methyl benzoate ester to
release the desired sulfinate salt. Next, a one-pot
reaction with NFSI provided the target sulfonyl
fluoride 4e (Scheme 3). This sequence highlights the
advantages of the new methodology, which allowed
obtaining a labile product not accessible via
previously available protocols.
Finally, due to their growing importance as alkyl
radical sources[4e-h] and emerging role in biological
applications,[4i-k] the synthesis of sulfinate salts in
pure form and under mild conditions was highly
desirable. As the result of our work towards this goal,
DIPEA salts of alkylsulfinic acids were generated by
cleavage of intermediates 2 in methanolic solutions
followed by conversion to the corresponding
potassium salts by quenching with aqueous KHCO3
(Table 6). After concentration and trituration with
MTBE, the target potassium sulfinates were isolated
in pure form, free from the methyl benzoate
byproduct.
Table 6. Synthesis of Alkylsulfinate Salts[a]
Scheme 3. One-Pot Synthesis of Sulfonyl Fluoride
Derivative of a Base- and Acid-Sensitive Glycoside.
The same mild method of the intermediate cleavage
was applied for the synthesis of aliphatic
sulfonamides. Using the optimized conditions, the
cleavage of 2b was conducted in MeOH/THF at 50
oC, followed by solvent evaporation. The crude
sulfinate was mixed with THF, the starting amine,
and DIPEA. Subsequent addition of NCS produced
desired sulfonamides in an efficient one-pot
procedure (Table 5). Both primary and secondary
amines furnished the desired sulfonamide products.
Alkene, alkyne (entries 3-4), and hydroxyl
functionalities (entry 5) were well tolerated providing
possibilities for subsequent synthetic elaboration or
bioorthogonal conjugation of the sulfonamide
products. -Aminoester (entry 6), hindered (entry 7),
and aromatic amines (entry 8) similarly produced the
target sulfonamides in useful yields.
Table 5. Representative Examples of One-Pot
Synthesis of Sulfonamides[a]
[a] Reaction conditions: 2, DIPEA, MeOH at 50 °C;
then aq. KHCO3 at 23 °C.
[b] Reaction conditions: 2e, DIPEA, Zn(OAc)2, MeOH,
THF, 50 °C.
[c] Isolated yield.
[d] qNMR purity: 96%; er > 99:1.
As depicted in Table 6, both acid- (entries 1, 4),
and base-sensitive (entry 5) groups were tolerated,
which would be difficult to achieve with the existing
methods of sulfinate synthesis. Moreover, compound
6e retained complete integrity of the chiral center (see
SI), while ibuprofen esters are known to be readily
racemized in basic media.[12] Its high qNMR purity of
96% and unaffected enantiomeric purity, relative to
the starting ibuprofen, demonstrate the capacity of the
developed method in the effective synthesis of alkyl
sulfinates in pure form. In addition, because of the
increasing use of zinc sulfinates as alkyl radical
precursors,[4f, h] the efficacy of our methodology for
accessing this class of reagents was demonstrated by
[a] Reaction conditions: 1) 2b (0.25 mmol), DIPEA, MeOH,
THF, 50 °C, 4 h; 2) amine (2 equiv.), NCS (1.0 equiv.),
DIPEA (2.0 equiv.), THF, 0 to 23 °C, 1 h.
[b] Isolated yield.
4
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10.1002/adsc.201800071
Advanced Synthesis & Catalysis
To a mixture of 2b (102 mg, 0.25 mmol) and TBAB (24
mg, 0.075 mmol) in DMSO (0.9 mL) was added aq. 10 M
NaOH (0.063 mL, 0.63 mmol) was added followed by
the synthesis of known zinc phenylmethanesulfinate
6f from sulfone intermediate 2e and zinc acetate
(entry 6).
o
stirring at 35 C for 2 h. Solid NaHCO3 (63 mg, 0.75
In summary, we have developed a versatile, stable,
and low-cost sulfonylating reagent,[10a] as well as the
corresponding methodology for the expedient
preparation of aliphatic sulfinate salts, sulfones,
sulfonamides, and sulfonyl fluorides starting from
primary and secondary alkyl halides and tosylates.
The developed protocols are performed under mild
conditions, not sensitive to air and moisture, and
exhibit high functional group tolerance. Compared to
the existing methods, alkylsulfinate salts can be
isolated in pure form after formation under very mild
reaction conditions. We anticipate that the use of the
new sulfonylating reagent will increase practical
accessibility of diverse alkylsulfonyl products and
expand their applications in various fields of science
and technology.
o
mmol) was added and the suspension was stirred at 35 C
for 15 min. At this time, the starting electrophile (1.3-2.0
equiv.) was added and the mixture was stirred for 18 h at
23 oC (for activated electrophiles) or at 50 oC (for
unactivated electrophiles). The reaction was partitioned
between water (2 mL), brine (2 mL), and EtOAc (2 mL).
The aqueous phase was re-extracted with additional EtOAc
(2 mL). The combined organic extracts were dried over
anhydrous
Na2SO4
and
loaded
on
silica
gel. Chromatography on a silica gel column, eluting with a
gradient from 0 to 50% of EtOAc in heptane gave the
target sulfone product.
Preparation of Primary Sulfonamide 3d (Table 3)
To a mixture of 2b (102 mg, 0.25 mmol) and THF (1.4
mL) was added 10 M aq. NaOH (0.055 mL, 0.55 mmol).
o
The mixture was stirred at 35 C for 2 h. The resulting
clear solution was added dropwise to a stirred solution of
hydroxylamine-O-sulfonic acid (85 mg, 0.75 mmol) and
sodium acetate (92 mg, 1.12 mmol) in water (4 mL) at +5
oC. The mixture was warmed to room temperature and
stirred for 18 h. Saturated aq. NaHCO3 (3 ml) was added
and the mixture was stirred for 15 min, then diluted with
brine (5 mL) and extracted with EtOAc (2 x 6 mL). The
combined extracts were washed with brine, dried over
MgSO4, and concentrated. Chromatography on a silica gel
column, eluting with a gradient from 20 to 80% of EtOAc
in heptane gave compound 3d (59 mg, 74%) as white solid.
Experimental Section
Synthesis of Sulfonylating Reagent 1
Sodium hydroxymethylsulfinate dihydrate (rongalite)
(18.50 g, 120 mmol) was dissolved in a solution of NaOH
(4.16 g, 104 mmol) in 104 mL of water and the clear
solution was kept without stirring at room temperature for
90 min. A 40% solution of NaBr (50 mL) was added and
o
the resulting solution was cooled to +3 C under stirring.
Solid 3,4,5-trimethoxybenzoyl chloride (20.0 g, 86.7
mmol) was added in one portion. The heavy slurry was
warmed under stirring to room temperature in 1 h and
stirred for 3 more hours (thin slurry formed). Solid NaBr
(65 g) was added and the mixture was stirred for 1 h. The
solid was filtered off and washed with 40% NaBr (2 x 80
mL) and ethyl acetate (2 x 80 mL), then dried on filter
General Procedure for the Preparation of Alkylsulfonyl
Fluorides (Table 4)
A mixture of sulfone intermediate 2 (0.25 mmol) in THF
(0.8 mL) was treated with 10 M aq. NaOH (0.10 mL, 1.0
o
o
mmol), followed by stirring at 35 C for 2 h (gradually
under vacuum suction and then in a vacuum oven at 45 C
went from a homogeneous solution to a heterogeneous
suspension). At this time 2 M aq. H3PO4 (3 mL) and brine
(1 mL) were added to the mixture followed by extraction
with EtOAc (2 x 3 mL). The combined organic extracts
were transferred to a 25 mL round-bottom flask. DIPEA
(0.13 mL, 0.75 mmol) was added, the mixture was cooled
for 18 h to obtain the target product as white solid (17.07 g,
63%).
General Procedure for the Alkylation of Reagent 1 -
Synthesis of Sulfone Intermediates 2 (Table 2)
to
0 a solution of N-
oC under nitrogen, and
In a reaction flask were combined alkyl halide (or tosylate)
(1 equiv.), reagent 1 (1.5 equiv.), tetrabutylammonium
bromide (0.3 equiv.), and DMA (0.4 M). The solution was
fluorobenzenesulfonimide (79 mg, 0.25 mmol) in dry THF
(1 mL) was added dropwise. Upon complete addition, the
mixture was warmed to ambient temperature and the
reaction was stirred for an additional 1 h. Without workup,
silica gel (~1g) was added to the reaction mixture and all
solvent was evaporated. The dried material was then
purified on a silica gel column to give the expected
sulfonyl fluoride product.
o
stirred at 80 C for 20 h. The reaction was cooled to room
temperature, quenched with half-saturated NaHCO3 (5 mL)
and extracted with ethyl acetate (3 x 3 mL). The combined
organic extracts were dried over magnesium sulfate,
concentrated and the residue was purified by
chromatography on a silica gel column, eluting with a
gradient of EtOAc in heptane or acetone in heptane.
Preparation of Sulfonyl Fluoride 4e (Scheme 3)
General Procedure for One-Pot Preparation of Dialkyl
Sulfones (Table 3)
To a solution of intermediate 2h (90 mg, 0.13 mmol) in
MeOH (1.6 mL) DIPEA (0.14 mL, 0.80 mmol) was added
and the clear solution was kept at room temperature for 18
h. The starting material was consumed (TLC). The reaction
5
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10.1002/adsc.201800071
Advanced Synthesis & Catalysis
was concentrated in vacuo, then MeCN (5 mL) was added
to the residue and the solution was concentrated (repeated
2 times). The residue was dissolved in dry MeCN (2 mL),
mmol, 6 equiv.) was stirred at 50°C for 4 h. The reaction
was cooled to room temperature and concentrated in vacuo
to dryness. The crude residue was combined with DCM (1
mL) and then MTBE (5 mL) was slowly added under
stirring. The suspension was stirred at room temperature
for 2 h, then the solid was filtered off and dried in vacuo at
45°C to yield the pure title compound as white solid (72
mg, 81%). Known compound, analytical results are
consistent with the literature data (see Tetrahedron 2006,
62, 4540).
o
the solution was cooled to 0 C, and a solution of N-
fluorobenzenesulfonimide (46 mg, 0.146 mmol) in dry
THF (0.3 mL) was added dropwise. Upon complete
addition, the mixture was warmed to room temperature and
stirred for an additional 1 h. Without workup, silica gel
(~1g) was added to the reaction mixture and all solvent
was evaporated. The dried material was then purified on a
silica gel column, eluting with a gradient from 10 to 70%
of EtOAc in heptane, to give the target compound as
colorless gum (38 mg, 61%).
Acknowledgements
We thank Benjamin N. Rocke (Pfizer) and Stuart C. Ross
(Syracuse University) for extensive technical assistance and
useful discussions, Ivan J. Samardjiev (Pfizer) and Brian Samas
(Pfizer) for help in crystallographic studies, and Matthew Teague
(Pfizer) for HRMS analysis. We would also like to thank Pfizer
External Research Solutions (ERS) and Procurement group for
their support in the strategy and implementation of the
General Procedure for One-Pot Preparation of Alkyl
Sulfonamides (Table 5)
A mixture of sulfone intermediate 2b (102 mg, 0.25 mmol),
MeOH (1 mL), and THF (0.25 mL) was treated with
DIPEA (0.180 mL, 1.0 mmol), followed by stirring at 50
oC for 4 h. At this time, the reaction was concentrated and
the residue was azeotroped with toluene twice. The flask
with the crude residue was flushed with nitrogen, followed
by addition of THF (4.5 mL), DIPEA (0.090 mL, 0.50
mmol), and the amine (0.50 mmol). The reaction was
commercialization
of
reagent
1
(sodium
((3,4,5-
trimethoxybenzoyl)oxy)methanesulfinate) with key partner.
References
cooled to
0
oC and under nitrogen solid N-
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portion. The mixture was warmed to room temperature and
then stirred for 1 h. The byproduct ester was hydrolyzed in
the same pot by addition of MeOH (2 mL) and 1 M aq.
NaOH (1.5 mL) followed by stirring at ambient
temperature for 18 h. The reaction was partitioned between
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and the aqueous phase was re-extracted with MTBE. The
combined organic extracts were dried over MgSO4,
filtered, evaporated, and loaded on silica gel (~1g).
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gradient from 0 to 40% of EtOAc in heptane gave desired
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The corresponding starting sulfone intermediate 2 (1
equiv.), MeOH (0.2 M), and DIPEA (3 equiv.) were
combined in a reaction flask. The initial suspension was
stirred at 50 °C for 0.5 to 2 h until starting material is
consumed as monitored by TLC; the reaction mixture
turned clear solution. The reaction was cooled to room
temperature, treated with 1 M aq. KHCO3 (1 equiv.),
concentrated, and the residue was azetoroped with toluene
to dryness. The crude residue was slurried repeatedly in
portions of MTBE to extract methyl 3,4,5-
trimethoxybenzoate byproduct. The final residue was dried
in vacuo at 35 °C to yield the purified alkyl sulfinate as
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Synthesis of Zinc Phenylmethanesulfinate 6f (Table 6)
A mixture of sulfone intermediate 2e (180 mg, 0.47 mmol,
2 equiv.), zinc acetate (43 mg, 0.24 mmol, 1 equiv.),
MeOH (4 mL), THF (1 mL), and DIPEA (0.25 mL, 1.42
6
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10.1002/adsc.201800071
Advanced Synthesis & Catalysis
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7
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10.1002/adsc.201800071
Advanced Synthesis & Catalysis
COMMUNICATION
A Versatile Reagent and Method for Direct
Aliphatic Sulfonylation
Adv. Synth. Catal. 2018, Volume, Page – Page
Andre Shavnya,* Kevin D. Hesp, and Andy S. Tsai
8
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