Sulfinamide Synthesis Using Organometallic Reagents, DABSO, and Amines

Article abstract of DOI:10.1021/acs.joc.0c00334

We report the synthesis of sulfinamides using organometallic reagents, a sulfur dioxide reagent, and nitrogen based-nucleophiles. The addition of an organometallic reagent to the commercially available sulfur dioxide surrogate, DABSO, generates a metal sulfinate which is reacted with thionyl chloride to form a sulfinyl chloride intermediate. Trapping the sulfinyl chlorides in situ with a variety of nitrogen nucleophiles delivers sulfinamides in 32-83% yields. Each stage of the process is performed at room temperature, and the total reaction time is only 1.5 h.

Full text of DOI:10.1021/acs.joc.0c00334

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Sulfinamide Synthesis Using Organometallic Reagents, DABSO, and
Amines
Pui Kin Tony Lo, Gwyndaf A. Oliver, and Michael C. Willis*
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ABSTRACT: We report the synthesis of sulfinamides using
organometallic reagents, a sulfur dioxide reagent, and nitrogen
based-nucleophiles. The addition of an organometallic reagent to
the commercially available sulfur dioxide surrogate, DABSO,
generates a metal sulfinate which is reacted with thionyl chloride
to form a sulfinyl chloride intermediate. Trapping the sulfinyl
chlorides in situ with a variety of nitrogen nucleophiles delivers
sulfinamides in 32−83% yields. Each stage of the process is
performed at room temperature, and the total reaction time is only
1.5 h.
Scheme 1. Selected Methods for the Synthesis of Racemic
Sulfinamides
INTRODUCTION
■
Sulfinamides are a broadly useful class of functional groups in
organic chemistry. Chiral sulfinamides have been widely used
as chiral auxiliaries,1 as ligands in transition-metal catalysis,2
and as organocatalysts.3 They can serve as N-protecting
groups, which can be easily cleaved by acidic treatment.4
Sulfinamides are also used as intermediates to prepare
sulfonimidamides and sulfoximines, which have recently
enjoyed increased interest in the medicinal chemistry
community.5 To date, racemic sulfinamides are usually
prepared from sulfinic acids or sulfinate salts, most commonly
by reaction with oxalyl chloride6 or thionyl chloride6e,7 to give
sulfinyl chloride intermediates which then react with amines
(Scheme 1a), or by direct coupling with amines using DCC8 or
EDCI.9 Alternative methods include the oxidation of disulfides
to form sulfinate esters10 that further react with amines11 or
lithium amides (Scheme 1b).10b In 2007, the Harmata group
reported the synthesis of sulfinamides from aryl sulfonyl
chlorides and amines using PPh3 as a reductant.12 More
recently, Wei and Sun reported a synthesis based on the
activation of tert-butyl sulfoxides with NBS and acetic acid,
subsequently quenching the reactions with a selection of
nucleophiles including amines.13 Boronic acids and boronate
esters have been combined with DAST-type reagents under
aerobic conditions to prepare sulfinamides, as reported by the
Shi laboratory (Scheme 1c).14 The oxidative copper-catalyzed
synthesis of sulfinamides, starting from thiols or sulfenate
anions, has also been reported, as has the copper-catalyzed
trans-sulfinamidation.15 Despite the success of the methods
described above, there remain limitations. For example,
sulfinate salts (or their acid form),6−9 odorous thiols,15a,b
Received: February 10, 2020
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disulfides,10a,13,15a and sulfonyl chlorides12 are frequently
reacted directly (Scheme 1a) or employed as precursors to
the starting materials, and such preinstalled sulfur functional
groups can limit commercial availability, especially in complex
structural settings. Additionally, nitrogen based-nucleophiles
are generally limited to secondary and primary amines.13−15
Ammonia could only be used when sulfinyl chlorides were
employed as intermediates.1b,6a,c,e,7a Preformed amination
reagents have also been used,14,15b,c which are not
commercially available and require additional steps to prepare.
The range of sulfinamides accessible is generally limited to aryl
and alkyl variants, while the preparation of heteroaryl
sulfinamides was less common using these methods. The
exceptions to this were the reactions between sulfinyl chlorides
and amines6e and the direct reaction of heteroaryl boronic
acids and DAST-type reagents.14
sulfinyl chloride intermediates. We were pleased to find that
the in situ formed p-fluorophenylsulfinate salt, prepared from
the addition of p-fluorophenylmagnesium bromide to DABSO,
reacted smoothly with 1.1 equiv of thionyl chloride to form the
corresponding sulfinyl chloride. This was then combined with
1.5 equiv of morpholine and 1.5 equiv of triethylamine to
deliver sulfinamide 2a in 83% yield on a 0.5 mmol scale and
79% yield on a gram scale (Table 1). Each step of this one-pot,
a
Table 1. Scope of the Organometallic Reagent
Based on the limitations of the reported methods, we sought
a more general sulfinamide synthesis and in particular targeted
a method that could provide a range of sulfinyl core structures
and also tolerate a variety of nitrogen functional groups. In
2010, our laboratory reported the DABCO·(SO2)2 adduct,
DABSO, as an air-stable, and easy-to-handle sulfur dioxide
surrogate.16 DABSO now has wide commercial availability.
Addition of organometallic reagents to DABSO results in
formation of the corresponding sulfinates, which have been
converted in situ to a variety of useful sulfonyl functional
groups, such as sulfones, sulfonamides, and sulfonyl
fluorides.16b,17 We speculated that the metal sulfinates formed
in situ could be telescoped with subsequent reactions to
prepare sulfinamides, thus avoiding the use of substrates with
preinstalled sulfur functionality. Such a transformation, based
on the use of organometallic reagents, either obtained from
commercial sources or prepared from metal−halogen exchange
or direct deprotonation, should allow access to a wide range of
complex sulfinamides.
The synthesis of sulfinyl chlorides from the addition of
organometallic reagents to sulfur dioxide to form metal
sulfinate salts, which were then treated with thionyl chloride,
has been reported before;18a for example, the Ellman group
employed this method to prepare sulfinamide 1 as a single
diastereomer (Scheme 2).18b However, liquid sulfur dioxide
a
Reaction conditions: RMgX (0.5 mmol, 1 equiv), DABSO (0.25
mmol, 0.5 equiv), THF, rt, 30 min, then SOCl2 (1.1 equiv), rt, 30 min
followed by Et3N (1.5 equiv) and morpholine (1.5 equiv), rt, 30 min.
b
c
Organolithium reagent was used. A suspension of DABSO (0.6
equiv) in THF was added to the organolithium reagent at −78 °C
then warmed to rt. 5 min for step 2.
d
Scheme 2. Stepwise Synthesis of Sulfinamide from Grignard
Reagents Using Sulfur Dioxide
three-step sequence was performed at room temperature under
a nitrogen atmosphere. Oxalyl chloride could be employed in
place of thionyl chloride; however, the reactions with the metal
sulfinates were more vigorous and needed to be performed at 0
°C. More significantly, 1,2-diamides formed from oxalyl
chloride and amines often coeluted with alkyl sulfinamides in
flash column chromatography, resulting in purification
difficulties. Accordingly, thionyl chloride was selected for
further studies.
With the optimized conditions in hand, we next examined
the scope of the reaction with respect to the organometallic
reagents, using morpholine as the nucleophile, to prepare the
corresponding sulfinamides (Table 1). Generally, a wide range
of aryl, alkyl, and heteroaryl organometallic reagents could be
effectively converted into sulfinyl chlorides and on to
sulfinamides. Aryl Grignard reagents substituted at different
positions were well tolerated, delivering para- (2a, 2e), meta-
(2b), and ortho-substituted phenyl (2c) and naphthyl (2d)
sulfinamides in 70−83% isolated yields. A pharmaceutically
relevant organolithium reagent reacted smoothly under the
used at low temperature, obtained from condensing the
gaseous reagent, was employed in this transformation and as
such provides an obstacle to use in certain laboratories. We
envisioned that using DABSO as a more convenient sulfur
dioxide reagent would deliver a streamlined, user-friendly
sulfinamide synthesis.
RESULTS AND DISCUSSION
■
Prior work had shown that a range of sulfinyl chlorides,
including heteroaryl sulfinyl chlorides, had shown promising
reactivity with nitrogen-based nucleophiles,6e and as such, our
approach was based on reacting in situ formed metal sulfinates
with either thionyl chloride or oxalyl chloride to prepare
B
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optimized conditions, delivering the arene core of the COX2
inhibitor celecoxib (2e). However, alkenyl Grignard reagent
(2f) was less successful, with only 32% of the targeted
sulfinamide isolated. Primary (2g), secondary (2h), and
tertiary (2i) alkyl Grignard reagents were reacted effectively
under the optimized conditions, with 71−82% yields of the
products being isolated. It is worth noting that the primary
alkyl sulfinamide (2g) was isolated in slightly lower yield than
the corresponding secondary and tertiary alkyl systems,
possibly due to the instability of the sulfinyl chloride
intermediate. We were pleased to find that nitrogen-, oxygen-,
and sulfur-containing heteroaromatics provided effective
organometallic reagents, delivering pyridine (2j), benzofuran
(2k), and thiophene (2l) sulfinamides in 63−76% yield.
We then explored the scope of nitrogen-based nucleophiles
that could be employed, using p-fluorophenylmagnesium
bromide as the organometallic reagent (Table 2). Secondary
to find that this could be suppressed by transferring the formed
sulfinyl chloride to a solution of aniline, allowing an 82% yield
of the targeted sulfinamide to be achieved. Primary amines
were also good substrates, with both n-butylamine (3g) and
sterically demanding adamantylamine (3h) being employed.
Nucleophiles with reduced nucleophilicities, namely amide
(3i) and carbamate (3j), were also effective substrates,
providing 72% and 83% yields of the corresponding
sulfinamides, respectively. These types of amide- and
carbamate-substituted sulfinamides are typically synthesized
by derivatization of the corresponding primary sulfinamides
using strong base (e.g., n-BuLi) in combination with
anhydrides6a,19 or dicarbonates (e.g., Boc anhydride),19c,20
and their direct synthesis from sulfinyl chlorides (or sulfinic
anhydrides) is rare.21 It is worth noting that, unlike the aniline-
substituted sulfinamide, there were no significant amounts of
double-substituted sulfinamides formed when primary amines
(3g, 3h), amide (3i), and carbamate (3j) nucleophiles were
employed. Sulfinamides 3e and 3j feature an alternative arene
core, as the corresponding p-fluorophenylmagnesium bromide
derived products were difficult to purify using flash column
chromatography. Finally, we found that a biphasic mixture of
ammonium hydroxide solution and ethyl acetate proved
efficient for preparing primary sulfinamides 3k and the racemic
form of Ellman’s auxiliary 3l, in 67% and 71% yield,
respectively.6c
a
Table 2. Scope of Nitrogen-Based Nucleophiles
In conclusion, we have developed a high-yielding one-pot
synthesis of sulfinamides using organometallic reagents and
nitrogen based-nucleophiles, exploiting sulfinyl chlorides as the
reactive intermediates. The developed chemistry combines
Grignard or organolithium reagents with commercially
available DABSO as the source of sulfur dioxide to prepare
metal sulfinates which are subsequently treated with thionyl
chloride to form sulfinyl chloride intermediates. A broad range
of organometallics were compatible with the process, including
(hetero)aryl and alkyl systems. Secondary and primary amines,
aniline, amide, carbamate, and ammonia all proved suitable N-
nucleophiles, allowing access to previously difficult to
synthesize sulfinamides. The developed protocol can be
performed on a preparative gram scale. Several biologically
relevant aryl cores and amines were employed, providing a
good demonstration of the suitability of this method for the
synthesis of complex sulfinamides. Given the increasing
interest in sufinamides, we anticipate wide uptake of the
reported method.
a
Reaction conditions: RMgX (0.5 mmol, 1 equiv), DABSO (0.25
EXPERIMENTAL SECTION
mmol, 0.5 equiv), THF, rt, 30 min, then SOCl2 (1.1 equiv), rt, 30 min
■
followed by Et3N (1.5 equiv) and nucleophile (1.5 equiv), rt, 30 min.
Reactions were performed under inert nitrogen atmosphere with
anhydrous solvent unless otherwise stated. Anhydrous tetrahydrofur-
an (99.5%, Extra dry over molecular sieves, stabilized, AcroSeal) was
purchased. DABSO was prepared using a literature method and dried
under reduced pressure (<1 mbar) for at least 2 h before use.16a
Glassware was oven-dried and allowed to cool to room temperature
under nitrogen. Cooling to 0 and −78 °C was achieved using ice−
water and dry ice−acetone baths, respectively. Reactions were
monitored by HPLC analysis and/or thin-layer chromatography
(TLC) using precoated aluminum-backed silica plates (Merck
Kieselgel 60 F254). Plates were visualized under ultraviolet light
(254 nm) followed by staining with KMnO4. Flash column
chromatography was carried out using Geduran Si 60, 40−63 μm
silica gel; the compound to be purified was preabsorbed onto silica
before loading. Petrol refers to the fraction of light petroleum ether
b
Nucleophile was added as a solution in THF if it was a solid. Sulfinyl
chloride was added to a solution of aniline (3.0 equiv) in THF.
c
Sulfinyl chloride was added to a biphasic mixture of aq NH3/ethyl
acetate at 0 °C.
amines, including pyrrolidine (3a), piperidine (3b), piperazine
(3c, 3d), and indoline (3e), as well as biologically relevant
amines (3b, 3d) reacted smoothly to provide tertiary
sulfinamides in 69−83% isolated yields. Aniline (3f) was also
a suitable substrate. However, for this example, a significant
amount of the double N-substituted sulfinamide was formed as
a side product, indicating that the nitrogen in the initially
formed sulfinamide was still available for a second nucleophilic
attack on the sulfinyl chloride intermediate. We were pleased
1
boiling in the range 40−60 °C. H, 13C{1H}, and 19F NMR spectra
were recorded using 400, 101, and 376 MHz spectrometers,
C
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respectively. Chemical shifts (δ) are reported in parts per million
(ppm) from the residual solvent peak, and coupling constants (J) are
given in hertz (Hz) and rounded to the nearest 0.5 Hz. Low-
resolution electrospray ionization (ESI) mass spectra were recorded
on a Waters LCT Premier spectrometer. High-resolution mass spectra
̈
were recorded on a Bruker MicroTOF spectrometer using ESI
conditions by the internal service at the Chemistry Research
Laboratory, University of Oxford. Infrared spectra were recorded on
0.75 mmol, 1.5 equiv). Purification by flash column chromatography
(50% EtOAc in petrol) afforded the title product as a pale yellow
viscous oil (105 mg, 80%): Rf (50% EtOAc in petrol) = 0.23; H
NMR (400 MHz, CDCl3) δ 8.27 (s, 1H), 7.99−7.85 (m, 3H), 7.63−
7.52 (m, 3H), 3.78−3.63 (m, 4H), 3.20 (ddd, J = 12.0, 6.0, 3.5 Hz,
2H), 2.98 (ddd, J = 12.0, 6.0, 3.5 Hz, 2H); 13C{1H} NMR (101 MHz,
CDCl3) δ 139.5, 134.5, 132.8, 129.1, 128.9, 128.03, 127.96, 127.3,
122.0, 67.0, 46.0, 1 × ArC not observed; LRMS (ESI+) m/z 284.0
([M + Na]+). Data is consistent with the literature.15b
1
a Bruker Tensor 27 FT-IR spectrometer.
̈
General Procedure for the One-Pot Synthesis of Sulfina-
mides. Predried DABSO (60 mg, 0.25 mmol, 0.5 equiv) was added
to an oven-dried 10 mL reaction vial. The vial was then sealed with a
rubber septum, evacuated, and filled with N2 (×3). Anhydrous THF
(2 mL) was added. The organometallic reagent (0.50 mmol, 1.0
equiv) was added dropwise to the resulting suspension at rt, and the
reaction mixture was stirred for 30 min. SOCl2 (40 μL, 0.55 mmol, 1.1
equiv) was then added dropwise, and the mixture was stirred at rt for
30 min. After this, Et3N (110 μL, 0.75 mmol, 1.5 equiv) was added
followed by the corresponding amine (0.75 mmol, 1.5 equiv). The
mixture was stirred at rt for 30 min, quenched with brine (10 mL),
and extracted with EtOAc (3 × 10 mL). A few drops of water were
added to dissolve any solid formed during the workup. The combined
organic phases were dried (Na2SO4), filtered, and concentrated.
Purification by flash column chromatography afforded the product.
4-((4-Fluorophenyl)sulfinyl)morpholine (2a). Prepared according
to the general procedure using 4-fluorophenylmagnesium bromide
(0.55 mL, 0.91 M in THF, 0.50 mmol, 1.0 equiv) and morpholine (70
μL, 0.75 mmol, 1.5 equiv). Purification by flash column chromatog-
raphy (50% EtOAc in petrol) afforded the title product as a white
solid (95 mg, 83%). Gram scale synthesis of 2a: the same procedure
was followed using 4-fluorophenylmagnesium bromide (6.0 mL, 1.01
M in THF, 6.0 mmol, 1.0 equiv), DABSO (721 mg, 3.0 mmol, 0.5
equiv), SOCl2 (0.48 mL, 6.6 mmol, 1.1 equiv), Et3N (1.25 mL, 9.0
mmol, 1.5 equiv), morpholine (0.79 mL, 9.0 mmol, 1.5 equiv), and
THF (24 mL), affording the title product (1.08 g, 79%): Rf (50%
4-((4-(5-(p-Tolyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)-
sulfinyl)morpholine (2e). 1-(4-Bromophenyl)-5-(p-tolyl)-3-(trifluor-
omethyl)-1H-pyrazole22 (191 mg, 0.50 mmol, 1.0 equiv) and
anhydrous THF (5 mL) were added to an oven-dried 25 mL RBF
under N2 (balloon) and cooled to −78 °C. n-Butyllithium (0.21 mL,
2.37 M in THF, 0.50 mmol, 1.0 equiv) was added dropwise, and the
reaction was stirred at −78 °C for 1 h. A sonicated suspension
(prepared in an oven-dried vial under N2) of predried DABSO (72
mg, 0.30 mmol, 0.6 equiv) in anhydrous THF (5 mL) was added
slowly before warming to rt for 30 min. SOCl2 (40 μL, 0.55 mmol, 1.1
equiv) was then added dropwise, and the mixture was stirred at rt for
30 min. Et3N (110 μL, 0.75 mmol, 1.5 equiv) and morpholine (70 μL,
0.75 mmol, 1.5 equiv) were added. The mixture was stirred at rt for
30 min, quenched with brine (10 mL), and extracted with EtOAc (3
× 10 mL). A few drops of water were added to dissolve any solid
formed during the workup. The combined organic phases were dried
(MgSO4), filtered, and concentrated. Purification by flash column
chromatography (50% EtOAc in petrol) afforded the title product as a
pale yellow viscous oil (154 mg, 70%): Rf (50% EtOAc in petrol) =
0.31; 1H NMR (400 MHz, CDCl3) δ 7.69−7.63 (m, 2H), 7.50−7.44
(m, 2H), 7.16−7.11 (m, 2H), 7.11−7.06 (m, 2H), 6.73 (s, 1H),
3.77−3.62 (m, 4H), 3.20−3.11 (m, 2H), 2.99−2.89 (m, 2H), 2.35 (s,
2
3H); 13C{1H} NMR (101 MHz, CDCl3) δ 145.3, 143.9 (q, JCF
=
38.5 Hz), 142.4, 141.6, 139.7, 129.7, 128.8, 127.3, 125.9, 125.8, 121.2
1
(q, JCF = 269.5 Hz), 106.0, 66.9, 46.0, 21.4; 19F NMR (377 MHz,
CDCl3) δ −62.4; LRMS (ESI+) m/z 436.0 ([M + H]+); 458.0 ([M +
Na]+); HRMS (ESI) m/z [M + H]+ calcd for C21H21O2N3F3S
436.1301, found 436.1296; IR (thin film, νmax/cm−1) 1472, 1373,
1235, 1160, 1133, 1096, 1069, 976, 916, 807, 729.
1
EtOAc in petrol) = 0.32; H NMR (400 MHz, CDCl3) δ 7.65−7.57
(m, 2H), 7.20−7.11 (m, 2H), 3.71−3.61 (m, 4H), 3.11 (ddd, J =
12.0, 6.0, 3.5 Hz, 2H), 2.90 (ddd, J = 12.0, 6.0, 3.5 Hz, 2H); 13C{1H}
NMR (101 MHz, CDCl3) δ 164.5 (d, 1JCF = 251.5 Hz), 138.0 (d, 4JCF
4-((2-Methylprop-1-en-1-yl)sulfinyl)morpholine (2f). Prepared
according to the general procedure using 2-methyl-1-propenylmagne-
sium bromide (1.01 mL, 0.49 M in THF, 0.50 mmol, 1.0 equiv), THF
(5 mL), and morpholine (70 μL, 0.75 mmol, 1.5 equiv). Purification
by flash column chromatography (0−5% MeOH in EtOAc) afforded
the title product as a pale yellow oil (30 mg, 32%): Rf (100% EtOAc)
= 0.23; 1H NMR (400 MHz, CDCl3) δ 5.93 (app. h, J = 1.5 Hz, 1H),
3.74 (app t, J = 5.0 Hz, 4H), 3.11 (app dd, J = 5.5, 4.0 Hz, 4H), 1.91
(d, J = 1.0 Hz, 3H), 1.87 (d, J = 1.0 Hz, 3H); 13C{1H} NMR (101
MHz, CDCl3) δ 147.9, 129.1, 66.9, 45.4, 25.8, 20.1; LRMS (ESI+) m/
z 190.0 ([M + H]+); 212.0 ([M + Na]+); HRMS (ESI) m/z [M +
H]+ calcd for C8H16O2NS 190.0896, found 190.0896; IR (thin film,
νmax/cm−1) 2855, 1635, 1442, 1258, 1110, 1064, 1037, 914, 795, 695.
4-(Butylsulfinyl)morpholine (2g). Prepared according to the
general procedure using butylmagnesium chloride (0.23 mL, 2.14
M in THF, 0.50 mmol, 1.0 equiv) and morpholine (70 μL, 0.75
mmol, 1.5 equiv). The step 2 was left for 5 min instead. Purification
by flash column chromatography (100% EtOAc) afforded the title
product as a pale yellow oil (68 mg, 71%): Rf (100% EtOAc) = 0.24;
1H NMR (400 MHz, CDCl3) δ 3.82−3.69 (m, 4H), 3.21−3.06 (m,
4H), 2.83−2.67 (m, 2H), 1.58 (app dq, J = 15.0, 8.0 Hz, 2H), 1.44 (p,
J = 7.5 Hz, 2H), 0.93 (t, J = 7.5 Hz, 3H); 13C{1H} NMR (101 MHz,
CDCl3) δ 67.0, 51.9, 45.9, 25.6, 22.1, 13.8; LRMS (ESI+) m/z 192.0
([M + H]+), 214.0 ([M + Na]+); HRMS (ESI) m/z [M + H]+ calcd
for C8H18O2NS 192.1053, found 192.1054; IR (thin film, νmax/cm−1)
2980, 1653, 1455, 1382, 1259, 1111, 1068, 1038, 920.
3
2
= 3.0 Hz), 128.5 (d, JCF = 9.0 Hz), 116.2 (d, JCF = 22.5 Hz), 66.9,
45.8; 19F NMR (376 MHz, CDCl3) δ −109.0; LRMS (ESI+) m/z
481.7 ([2M + Na]+). Data is consistent with the literature.14
4-(m-Tolylsulfinyl)morpholine (2b). Prepared according to the
general procedure using m-tolylmagnesium chloride (0.65 mL, 0.77 M
in THF, 0.50 mmol, 1.0 equiv) and morpholine (70 μL, 0.75 mmol,
1.5 equiv). Purification by flash column chromatography (50% EtOAc
in petrol) afforded the title product as a colorless oil (92 mg, 82%): Rf
(50% EtOAc in petrol) = 0.27; 1H NMR (400 MHz, CDCl3) 7.48 (s,
1H), 7.43 (d, J = 8.0 Hz, 1H), 7.38 (app t, J = 7.5 Hz, 1H), 7.28 (d, J
= 7.0 Hz, 1H), 3.77−3.63 (m, 4H), 3.19−3.10 (m, 2H), 3.01−2.91
(m, 2H), 2.42 (s, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 142.1,
139.1, 131.9, 128.8, 126.5, 123.2, 66.9, 45.8, 21.4; LRMS (ESI+) m/z
226.0 ([M + H]+), 248.0 ([M + Na]+). Data is consistent with the
literature.15b
4-((2-Methoxyphenyl)sulfinyl)morpholine (2c). Prepared accord-
ing to the general procedure using 2-methoxyphenylmagnesium
bromide solution (0.49 mL, 1.02 M in THF, 0.50 mmol, 1.0 equiv)
and morpholine (70 μL, 0.75 mmol, 1.5 equiv). Purification by flash
column chromatography (60% EtOAc in petrol) afforded the title
product as a pale yellow oil which solidified on standing to an off-
white solid (95 mg, 79%): Rf (60% EtOAc in petrol) = 0.27; 1H NMR
(400 MHz, CDCl3) δ 7.81 (d, J = 7.5 Hz, 1H), 7.45 (app t, J = 8.0 Hz,
1H), 7.12 (app t, J = 7.5 Hz, 1H), 6.94 (d, J = 8.0 Hz, 1H), 3.88 (s,
3H), 3.72−3.61 (m, 4H), 3.16−3.08 (m, 2H), 2.94−2.86 (m, 2H);
13C{1H} NMR (101 MHz, CDCl3) δ 156.9, 132.9, 129.6, 127.2,
120.9, 111.4, 67.3, 56.0, 45.4; LRMS (ESI+) m/z 264.0 ([M + Na]+).
Data is consistent with the literature.14
4-(Cyclohexylsulfinyl)morpholine (2h). Prepared according to the
general procedure using cyclohexylmagnesium chloride (0.26 mL,
1.90 M in Et2O, 0.50 mmol, 1.0 equiv) and morpholine (70 μL, 0.75
mmol, 1.5 equiv). Purification by flash column chromatography (0−
5% MeOH in EtOAc) afforded the title product as a colorless oil (87
4-(Naphthalen-2-ylsulfinyl)morpholine (2d). Prepared according
to the general procedure using 2-naphthylmagnesium bromide (0.98
mL, 0.51 M in THF, 0.50 mmol, 1.0 equiv) and morpholine (70 μL,
1
mg, 80%): Rf (5% MeOH in EtOAc) = 0.50; H NMR (400 MHz,
D
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CDCl3) δ 3.82−3.68 (m, 4H), 3.21−3.04 (m, 4H), 2.75−2.63 (m,
1H), 2.15−2.05 (m, 1H), 1.93−1.60 (m, 4H), 1.46−1.14 (m, 5H);
13C{1H} NMR (101 MHz, CDCl3) δ 67.0, 58.8, 46.3, 27.2, 26.8, 25.6,
25.3; LRMS (ESI+) m/z 218.2 ([M + H]+), 240.0 ([M + Na]+);
HRMS (ESI) m/z [M + H]+ calcd for C10H20O2NS 218.1209, found
218.1211; IR (thin film, νmax/cm−1) 2925, 2853, 1450, 1257, 1111,
1066, 917.
4-(Thiophene-2-ylsulfinyl)morpholine (2l). Prepared according to
the general procedure using 2-thienylmagnesium bromide solution
(0.59 mL, 0.85 M in THF, 0.50 mmol, 1.0 equiv) and morpholine (70
μL, 0.75 mmol, 1.5 equiv). Purification by flash column chromatog-
raphy (50% EtOAc in petrol) afforded the title product as an orange
1
oil (68 mg, 63%): Rf (50% EtOAc in petrol) = 0.31; H NMR (400
MHz, CDCl3) δ 7.61 (dd, J = 5.0, 1.5 Hz, 1H), 7.41 (dd, J = 3.5, 1.5
Hz, 1H), 7.14 (dd, J = 5.0, 3.5 Hz, 1H), 3.81−3.70 (m, 4H), 3.25−
3.17 (m, 2H), 3.16−3.08 (m, 2H); 13C{1H} NMR (101 MHz,
CDCl3) δ 145.3, 131.8, 130.6, 128.1, 67.1, 45.9; LRMS (ESI+) m/z
240.0 ([M + Na]+). Data is consistent with the literature.15c
4-(tert-Butylsulfinyl)morpholine (2i). Prepared according to the
general procedure using tert-butylmagnesium chloride solution (0.53
mL, 0.94 M in THF, 0.50 mmol, 1.0 equiv) and morpholine (70 μL,
0.75 mmol, 1.5 equiv). Purification by flash column chromatography
(100% EtOAc) afforded the title product as a white solid (79 mg,
1-((4-Fluorophenyl)sulfinyl)pyrrolidine (3a). Prepared according
to the general procedure using 4-fluorophenylmagnesium bromide
(0.51 mL, 0.98 M in THF, 0.50 mmol, 1.0 equiv) and pyrrolidine (63
μL, 0.75 mmol, 1.5 equiv). Purification by flash column chromatog-
raphy (30% EtOAc in petrol) afforded the title product as a pale
yellow oil (80 mg, 75%): Rf (30% EtOAc in petrol) = 0.24; 1H NMR
(400 MHz, CDCl3) δ 7.69−7.62 (m, 2H), 7.20−7.12 (m, 2H), 3.37−
3.28 (m, 2H), 3.03−2.92 (m, 2H), 1.90−1.78 (m, 4H); 13C{1H}
NMR (101 MHz, CDCl3) δ 164.2 (d, 1JCF = 250.5 Hz), 140.4 (d, 4JCF
1
82%): Rf (100% EtOAc) = 0.35; H NMR (400 MHz, CDCl3) δ
3.77−3.69 (m, 4H), 3.21−3.13 (m, 2H), 3.13−3.05 (m, 2H), 1.19 (s,
9H); 13C{1H} NMR (101 MHz, CDCl3) δ 67.3, 58.8, 47.5, 23.2;
LRMS (ESI+) m/z 192.3 ([M + H]+), 214.3 ([M + Na]+); HRMS
(ESI) m/z [M + H]+ calcd for C8H18O2NS 192.1053, found
192.1055. Data is consistent with enantiomerically pure compound.23
4-((6-Methoxypyridin-3-yl)sulfinyl)morpholine (2j). 5-Bromo-2-
methoxypyridine (65 μL, 0.50 mmol, 1.0 equiv) and anhydrous
THF (5 mL) were added to an oven-dried 25 mL RBF under N2
(balloon) and cooled to −78 °C. n-Butyllithium (0.21 mL, 2.37 M in
THF, 0.50 mmol, 1.0 equiv) was added dropwise and the reaction was
stirred at −78 °C for 40 min. A sonicated suspension (prepared in an
oven-dried vial under N2) of predried DABSO (72 mg, 0.30 mmol,
0.6 equiv) in anhydrous THF (5 mL) was added slowly before
warming to rt for 30 min. SOCl2 (40 μL, 0.55 mmol, 1.1 equiv) was
then added dropwise, and the mixture was stirred at rt for 30 min.
Et3N (110 μL, 0.75 mmol, 1.5 equiv) and morpholine (70 μL, 0.75
mmol, 1.5 equiv) were added. The mixture was stirred at rt for 30
min, quenched with brine (10 mL), and extracted with EtOAc (3 ×
10 mL). A few drops of water were added to dissolve any solid formed
during the workup. The combined organic phases were dried
(MgSO4), filtered and concentrated. Purification by flash column
chromatography (70% EtOAc in petrol) afforded the title product as a
pale yellow viscous oil (92 mg, 76%): Rf (70% EtOAc in petrol) =
0.26; 1H NMR (400 MHz, CDCl3) δ 8.35 (dd, J = 2.5, 0.5 Hz, 1H),
7.76 (dd, J = 8.5, 2.5 Hz, 1H), 6.81 (dd, J = 8.5, 0.5 Hz, 1H), 3.95 (s,
3H), 3.75−3.64 (m, 4H), 3.18−3.10 (m, 2H), 3.02−2.93 (m, 2H);
13C{1H} NMR (101 MHz, CDCl3) δ 166.1, 146.4, 136.6, 130.9,
111.5, 66.9, 54.1, 45.8; LRMS (ESI+) m/z 243.0 ([M + H]+); 265.0
([M + Na]+); HRMS (ESI) m/z [M + H]+ calcd for C10H15O3N2S
243.0798, found 243.0798; IR (thin film, νmax/cm−1) 2854, 1587,
1477, 1366, 1281, 1257, 1095, 1069, 1015, 916, 834, 694.
4-(Benzofuran-2-ylsulfinyl)morpholine (2k). Benzofuran (55 μL,
0.50 mmol, 1.0 equiv) and anhydrous THF (1.5 mL) were added to
an oven-dried 10 mL reaction vial under N2 (balloon) and cooled to 0
°C. n-Butyllithium (0.21 mL, 2.37 M in THF, 0.50 mmol, 1.0 equiv)
was added dropwise, and the reaction was stirred at 0 °C for 5 min
before reaching to rt for 1 h. The mixture was transferred via a syringe
and added dropwise to a stirred suspension of predried DABSO (60
mg, 0.25 mmol, 0.5 equiv) in THF (2.0 mL) in an oven-dried 10 mL
reaction vial at rt. The mixture was then stirred at rt for 30 min.
SOCl2 (40 μL, 0.55 mmol, 1.1 equiv) was added dropwise, and the
mixture was stirred at rt for 30 min. Et3N (110 μL, 0.75 mmol, 1.5
equiv) and morpholine (70 μL, 0.75 mmol, 1.5 equiv) were added.
The mixture was stirred at rt for 30 min, quenched with brine (10
mL) and extracted with EtOAc (3 × 10 mL). A few drops of water
were added to dissolve any solid formed during the workup. The
combined organic phases were dried (MgSO4), filtered, and
concentrated. Purification by flash column chromatography (40%
EtOAc in petrol) afforded the title product as a yellow oil (83 mg,
66%): Rf (40% EtOAc in petrol) = 0.25; 1H NMR (400 MHz,
CDCl3) δ 7.65 (app dt, J = 7.5, 1.0 Hz, 1H), 7.53 (app dq, J = 8.5, 1.0
Hz, 1H), 7.38 (ddd, J = 8.5, 7.5, 1.5 Hz, 1H), 7.34 (d, J = 1.0 Hz,
1H), 7.30 (app td, J = 7.5, 1.0 Hz, 1H), 3.83−3.65 (m, 4H), 3.31
(ddd, J = 12.5, 6.0, 4.0 Hz, 2H), 3.14 (ddd, J = 12.5, 5.5, 3.5 Hz, 2H);
13C{1H} NMR (101 MHz, CDCl3) δ 156.9, 154.4, 126.9, 126.5,
123.9, 122.3, 112.3, 112.1, 67.0, 46.1; LRMS (ESI+) m/z 274.0 ([M +
Na]+). Data is consistent with the literature.14
3
2
= 3.0 Hz), 128.2 (d, JCF = 9.0 Hz), 116.1 (d, JCF = 22.5 Hz), 46.1,
26.1; 19F NMR (377 MHz, CDCl3) δ −110.2; LRMS (ESI+) m/z
236.3 ([M + Na]+); HRMS (ESI) m/z [M + H]+ calcd for
C10H13ONFS 214.0696, found 214.0699; IR (thin film, νmax/cm−1)
2967, 2876, 1587, 1488, 1222, 1084, 1062, 969, 836, 814.
5-((4-Fluorophenyl)sulfinyl)-4,5,6,7-tetrahydrothieno[3,2-c]-
pyridine (3b). Prepared according to the general procedure using 4-
fluorophenylmagnesium bromide (0.51 mL, 0.98 M in THF, 0.50
mmol, 1.0 equiv) and 4,5,6,7-tetrahydrothieno[3,2-c]pyridine (90 μL,
0.75 mmol, 1.5 equiv). Purification by flash column chromatography
(20% EtOAc in petrol) afforded the title product as a pale yellow
1
viscous oil (116 mg, 83%): Rf (20% EtOAc in petrol) = 0.22; H
NMR (400 MHz, CDCl3) δ 7.72−7.65 (m, 2H), 7.23−7.16 (m, 2H),
7.10 (d, J = 5.0 Hz, 1H), 6.68 (d, J = 5.0 Hz, 1H), 4.26 (d, J = 15.0
Hz, 1H), 3.90 (d, J = 15.0 Hz, 1H), 3.61−3.52 (m, 1H), 3.48−3.39
(m, 1H), 3.04−2.93 (m, 1H), 2.92−2.83 (m, 1H); 13C{1H} NMR
(101 MHz, CDCl3) δ 164.5 (d, 1JCF = 252.0 Hz), 138.7 (d, 4JCF = 2.9
3
Hz), 133.0, 131.8, 128.7 (d, JCF = 9.5 Hz), 125.1, 123.5, 116.3 (d,
2JCF = 22.5 Hz), 45.7, 43.9, 26.2; 19F NMR (377 MHz, CDCl3) δ
−109.2; LRMS (ESI+) m/z 282.4 ([M + H]+), 304.4 ([M + Na]+);
HRMS (ESI) m/z [M + Na]+ calcd for C13H12ONFNaS2 304.0237,
found 304.0237; IR (thin film, νmax/cm−1) 2848, 1587, 1488, 1223,
1086, 1064, 906, 836, 704.
Benzyl 4-((4-Fluorophenyl)sulfinyl)piperazine-1-carboxylate
(3c). Prepared according to the general procedure using 4-
fluorophenylmagnesium bromide (0.51 mL, 0.98 M in THF, 0.50
mmol, 1.0 equiv) and benzyl piperazine-1-carboxylate (0.15 mL, 0.75
mmol, 1.5 equiv). Purification by flash column chromatography (40%
EtOAc in petrol) afforded the title product as a pale yellow viscous oil
1
(145 mg, 80%): Rf (40% EtOAc in petrol) = 0.23; H NMR (400
MHz, CDCl3) δ 7.68−7.61 (m, 2H), 7.37−7.27 (m, 5H), 7.23−7.16
(m, 2H), 5.12 (s, 2H), 3.65−3.45 (m, 4H), 3.18−3.08 (m, 2H),
3.02−2.90 (m, 2H); 13C{1H} NMR (101 MHz, CDCl3) δ 164.6 (d,
1JCF = 252.0 Hz), 155.1, 138.2 (d, 4JCF = 3.0 Hz), 136.5, 128.6, 128.5
(d, 3JCF = 9.0 Hz), 128.3, 128.0, 116.3 (d, 2JCF = 22.5 Hz), 67.5, 45.8,
44.2; 19F NMR (377 MHz, CDCl3) δ −108.7; LRMS (ESI+) m/z
385.0 ([M + Na]+); HRMS (ESI) m/z [M + Na]+ calcd for
C18H19O3N2FNaS 385.0993, found 385.1000; IR (thin film, νmax
/
cm−1) 1698, 1587, 1489, 1427, 1240, 1124, 1086, 1067, 914, 837,
697.
2-Chloro-11-(4-((4-fluorophenyl)sulfinyl)piperazin-1-yl)dibenzo-
[b,f ][1,4]oxazepine (3d). Prepared according to the general
procedure using 4-fluorophenylmagnesium bromide (0.51 mL, 0.98
M in THF, 0.50 mmol, 1.0 equiv) and amoxapine (235 mg, 0.75
mmol, 1.5 equiv). Purification by flash column chromatography (20%
EtOAc in petrol) afforded the title product as a pale yellow foam (158
1
mg, 69%): Rf (20% EtOAc in petrol) = 0.23; H NMR (400 MHz,
CDCl3) δ 7.70−7.63 (m, 2H), 7.34 (dd, J = 8.5, 2.5 Hz, 1H), 7.25 (d,
J = 2.5 Hz, 1H), 7.22−7.15 (m, 2H), 7.15−7.09 (m, 2H), 7.09−7.03
(m, 2H), 7.01−6.95 (m, 1H), 3.53 (s, 4H), 3.37−3.20 (m, 2H),
E
https://dx.doi.org/10.1021/acs.joc.0c00334
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
pubs.acs.org/joc
Featured Article
3.20−2.99 (m, 2H); 13C{1H} NMR (101 MHz, CDCl3) δ 164.4 (d,
mmol, 1.0 equiv) and an emulsion of 1-adamantylamine (114 mg,
0.75 mmol, 1.5 equiv) in THF (3 mL). During aqueous workup, the
combined organic phases were dried over MgSO4 instead. Purification
by flash column chromatography (25% EtOAc in petrol) afforded the
title product as a white solid (91 mg, 62%): Rf (25% EtOAc in petrol)
1JCF = 251.5 Hz), 159.3, 158.6, 151.7, 139.8, 138.2 (d, 4JCF = 3.0 Hz),
3
132.7, 130.4, 128.8, 128.5 (d, JCF = 9.0 Hz), 127.1, 125.8, 124.9,
2
124.7, 122.7, 120.1, 116.2 (d, JCF = 22.5 Hz), 47.7, 45.5; 19F NMR
(377 MHz, CDCl3) δ −108.8; LRMS (ESI+) m/z 478.1 ([M + Na]+);
HRMS (ESI) m/z [M + H]+ calcd for C23H20O2N335ClFS 456.0943,
found 456.0939; IR (thin film, νmax/cm−1) 1561, 1471, 1399, 1238,
1086, 905, 836, 725; mp (CH2Cl2) 108−109 °C.
1
= 0.29; H NMR (400 MHz, CDCl3) δ 7.73−7.63 (m, 2H), 7.20−
7.11 (m, 2H), 3.83 (s, 1H), 2.19−2.10 (m, 3H), 2.04−1.94 (m, 3H),
1.94−1.86 (m, 3H), 1.75−1.63 (m, 6H); 13C{1H} NMR (101 MHz,
CDCl3) δ 164.3 (d, 1JCF = 251.0 Hz), 142.4 (d, 4JCF = 3.0 Hz), 128.2
1-((2-Methoxyphenyl)sulfinyl)indoline (3e). Prepared according to
the general procedure using 2-methoxyphenylmagnesium bromide
solution (0.49 mL, 1.02 M in THF, 0.50 mmol, 1.0 equiv) and
indoline (85 μL, 0.75 mmol, 1.5 equiv). Purification by flash column
chromatography (15−25% EtOAc in petrol) afforded the title product
as a brown solid (113 mg, 82%): Rf (15% EtOAc in petrol) = 0.21; 1H
NMR (400 MHz, CDCl3) δ 7.94 (dd, J = 7.5, 1.5 Hz, 1H), 7.47 (ddd,
J = 8.0, 7.5, 1.5 Hz, 1H), 7.23−7.13 (m, 3H), 7.11 (d, J = 7.5 Hz,
1H), 6.95−6.85 (m, 2H), 4.06−3.93 (m, 1H), 3.76 (s, 3H), 3.13−
2.88 (m, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 156.6, 146.6,
132.8, 130.7, 130.2, 127.5, 126.5, 125.1, 121.9, 120.8, 111.5, 111.2,
56.0, 42.1, 28.4; LRMS (ESI+) m/z 296.0 ([M + Na]+), 569.2 ([2M +
Na]+); HRMS (ESI) m/z [M + H]+ calcd for C15H16O2NS 274.0896,
found 274.0895; IR (thin film, νmax/cm−1) 1590, 1477, 1274, 1240,
1088, 1050, 1016, 931, 749; mp (CH2Cl2) 116−118 °C.
3
2
(d, JCF = 9.0 Hz), 115.9 (d, JCF = 22.0 Hz), 54.7, 44.8, 36.1, 29.8;
19F NMR (376 MHz, CDCl3) δ −110.2; LRMS (ESI+) m/z 294.1
([M + H]+); HRMS (ESI) m/z [M + H]+ calcd for C16H21ONFS
294.1322, found 294.1326; IR (thin film, νmax/cm−1) 3090, 2981,
2903, 2849, 1588, 1490, 1452, 1396, 1224, 1159, 1086, 1040, 948,
835, 744; mp (CH2Cl2) 264−266 °C.
N-((4-Fluorophenyl)sulfinyl)-4-methylbenzamide (3i). Prepared
according to the general procedure using 4-fluorophenylmagnesium
bromide (0.50 mL, 1.01 M in THF, 0.50 mmol, 1.0 equiv) and a
solution of p-toluamide (101 mg, 0.75 mmol, 1.5 equiv) in THF (4.0
mL). During aqueous workup, the combined organic phases were
dried over MgSO4 instead. Purification by flash column chromatog-
raphy (40% EtOAc in petrol) afforded the title product as a white
1
solid (100 mg, 72%): Rf (40% EtOAc in petrol) = 0.38; H NMR
4-Fluoro-N-phenylbenzenesulfinamide13 (3f). Predried DABSO
(60 mg, 0.25 mmol, 0.5 equiv) was added to an oven-dried 10 mL
reaction vial. The vial was then sealed with a rubber septum,
evacuated, and filled with N2 (×3). Anhydrous THF (2 mL) was
added. 4-Fluorophenylmagnesium bromide (0.50 mL, 1.01 M in
THF, 0.50 mmol, 1.0 equiv) was added dropwise to the resulting
suspension at rt, and the reaction mixture was stirred for 30 min.
SOCl2 (40 μL, 0.55 mmol, 1.1 equiv) was then added dropwise, and
the mixture was stirred at rt for 30 min. The reaction mixture was
transferred via a syringe and added dropwise to a solution of Et3N
(110 μL, 0.75 mmol, 1.5 equiv) and aniline (140 μL, 1.5 mmol, 3
equiv) in THF (2 mL) in a 25 mL oven-dried RBF under N2 at rt.
Anhydrous THF (2 mL × 2) was then added to the reaction vial and
transferred to the 25 mL RBF to ensure a quantitative transfer of the
sulfinyl chloride. After addition, the mixture was stirred at rt for 30
min, quenched with brine (10 mL), and extracted with EtOAc (3 ×
10 mL). A few drops of water were added to dissolve any solid formed
during the workup. The combined organic phases were dried
(MgSO4), filtered, and concentrated. Purification by flash column
chromatography (20−25% EtOAc in petrol) afforded the title product
as a pale yellow solid (97 mg, 82%): Rf (20% EtOAc in petrol) = 0.21;
1H NMR (400 MHz, CDCl3) δ 7.81−7.71 (m, 2H), 7.31−7.24 (m,
2H), 7.23−7.17 (m, 2H), 7.11−7.04 (m, 3H), 6.30 (s, 1H); 13C{1H}
NMR (101 MHz, CDCl3) δ 164.7 (d, 1JCF = 252.0 Hz), 140.4, 140.2
(d, 4JCF = 3.0 Hz), 129.6, 128.1 (d, 3JCF = 9.0 Hz), 124.0, 119.4, 116.4
(400 MHz, CDCl3) δ 8.95 (s, 1H), 7.75−7.66 (m, 4H), 7.21 (d, J =
8.0 Hz, 2H), 7.19−7.13 (m, 2H), 2.38 (s, 3H); 13C{1H} NMR (101
MHz, CDCl3) δ 167.5, 164.9 (d, J = 252.5 Hz), 144.3, 139.5 (d, J =
3.0 Hz), 129.6, 128.7, 128.3, 127.5 (d, J = 9.0 Hz), 116.8 (d, J = 23.0
Hz), 21.7; 19F NMR (377 MHz, CDCl3) δ −107.1; LRMS (ESI+) m/
z 300.0 ([M + Na]+); HRMS (ESI) m/z [M + H]+ calcd for
C14H13O2NFS 278.0646, found 278.0646; IR (thin film, νmax/cm−1)
3181, 1670, 1587, 1491, 1420, 1395, 1231, 1090, 1060, 888, 833, 750;
mp (CH2Cl2) 135−136 °C.
tert-Butyl ((2-Methoxyphenyl)sulfinyl)carbamate (3j). Prepared
according to the general procedure using 2-methoxyphenylmagnesium
bromide solution (0.49 mL, 1.02 M in THF, 0.50 mmol, 1.0 equiv)
and a solution of tert-butyl carbamate (88 mg, 0.75 mmol, 1.5 equiv)
in THF (2.0 mL). Purification by flash column chromatography (30−
40% EtOAc in petrol) afforded the title product as a colorless viscous
oil (113 mg, 83%): Rf (30% EtOAc in petrol) = 0.15; 1H NMR (400
MHz, CDCl3) δ 7.84 (dd, J = 7.5, 1.5 Hz, 1H), 7.48 (ddd, J = 8.0, 7.5,
1.5 Hz, 1H), 7.11 (app td, J = 7.5, 1.0 Hz, 1H), 6.99 (s, 1H), 6.95
(dd, J = 8.5, 1.0 Hz, 1H), 3.89 (s, 3H), 1.48 (s, 9H); 13C{1H} NMR
(101 MHz, CDCl3) δ 156.3, 152.7, 133.6, 131.3, 126.0, 121.2, 111.5,
83.1, 56.1, 28.2.; LRMS (ESI+) m/z 294.0 ([M + Na]+); HRMS
(ESI) m/z [M + H]+ calcd for C12H17O4NNaS 294.0771, found
294.0770; IR (thin film, νmax/cm−1) 3156, 2979, 1707, 1590, 1478,
1369, 1276, 1241, 1154, 1087, 1051, 1019, 904, 820, 755, 727.
4-Fluorobenzenesulfinamide (3k). Predried DABSO (60 mg, 0.25
mmol, 0.5 equiv) was added to an oven-dried 10 mL reaction vial.
The vial was then sealed with a rubber septum, evacuated and filled
with N2 (×3). Anhydrous THF (2.0 mL) was added. 4-
Fluorophenylmagnesium bromide (0.50 mL, 1.01 M in THF, 0.50
mmol, 1.0 equiv) was added dropwise to the resulting suspension at
rt, and the reaction mixture was stirred for 30 min. SOCl2 (40 μL,
0.55 mmol, 1.1 equiv) was then added dropwise, and the mixture was
stirred at rt for 30 min. The reaction mixture was transferred via a
syringe and added dropwise to a stirred solution of 35% aq NH3 (0.5
mL) and EtOAc (1.0 mL) in a 25 mL RBF at 0 °C. Anhydrous THF
(2.0 mL × 2) was added to the reaction vial and transferred to the 25
mL RBF to ensure a quantitative transfer of the sulfinyl chloride. After
addition, the mixture was stirred at rt for 30 min, quenched with brine
(10 mL), and extracted with EtOAc (3 × 10 mL). A few drops of
water were added to dissolve any solid formed during the workup.
The combined organic phases were dried (MgSO4), filtered, and
concentrated. Purification by flash column chromatography (100%
EtOAc) afforded the title product as a white solid (53 mg, 67%): Rf
(100% EtOAc) = 0.50; 1H NMR (400 MHz, DMSO-d6) δ 7.75−7.64
(m, 2H), 7.41−7.30 (m, 2H), 6.29 (s, 2H); 13C{1H} NMR (101
2
(d, JCF = 23.0 Hz); 19F NMR (377 MHz, CDCl3) δ −108.4; LRMS
(ESI+) m/z 258.0 ([M + Na]+); HRMS (ESI) m/z [M + Na]+ calcd
for C12H10ONFNaS 258.0359, found 258.0361; IR (thin film, νmax
/
cm−1) 3174, 1586, 1487, 1224, 1154, 1085, 1055, 882, 816, 745, 688;
mp (CH2Cl2): 115−117 °C.
N-Butyl-4-fluorobenzenesulfinamide (3g). Prepared according to
the general procedure using 4-fluorophenylmagnesium bromide (0.51
mL, 0.98 M in THF, 0.50 mmol, 1.0 equiv) and n-butylamine (74 μL,
0.75 mmol, 1.5 equiv). Purification by flash column chromatography
(30% EtOAc in petrol) afforded the title product as a pale yellow oil
1
(77 mg, 71%): Rf (30% EtOAc in petrol) = 0.26; H NMR (400
MHz, CDCl3) δ 7.68−7.62 (m, 2H), 7.17−7.10 (m, 2H), 4.28 (t, J =
6.0 Hz, 1H), 3.11−3.01 (m, 1H), 2.80−2.69 (m, 1H), 1.49−1.40 (m,
2H), 1.33−1.23 (m, 2H), 0.83 (t, J = 7.3 Hz, 3H); 13C{1H} NMR
(101 MHz, CDCl3) δ 164.4 (d, 1JCF = 250.5 Hz), 140.1 (d, 4JCF = 3.0
3
2
Hz), 128.4 (d, JCF = 9.0 Hz), 116.0 (d, JCF = 22.5 Hz), 40.8, 32.6,
20.0, 13.7; 19F NMR (377 MHz, CDCl3) δ −109.8; LRMS (ESI+) m/
z 216.0 ([M + H]+), 238.1 ([M + Na]+). Data is consistent with the
literature.24
3N-((3s,5s,7s)-Adamantan-1-yl)-4-fluorobenzenesulfinamide
(3h). Prepared according to the general procedure using 4-
fluorophenylmagnesium bromide (0.50 mL, 1.01 M in THF, 0.50
1
4
MHz, DMSO-d6) δ 163.2 (d, JCF = 247.0 Hz), 144.2 (d, JCF = 2.5
Hz), 127.9 (d, JCF = 9.0 Hz), 115.6 (d, JCF = 22.0 Hz); 19F NMR
3
2
F
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(377 MHz, DMSO) δ −111.4; LRMS (ESI+) m/z 341.4 ([2M +
Atom: Applications in Asymmetric Synthesis. Chem. Rev. 2017, 117,
4147−4181.
Na]+). Data is consistent with the literature.19b
2-Methylpropane-2-sulfinamide (3l). Predried DABSO (60 mg,
0.25 mmol, 0.5 equiv) was added to an oven-dried 10 mL reaction
vial. The vial was then sealed with a rubber septum, evacuated, and
filled with N2 (× 3). Anhydrous THF (2.0 mL) was added. tert-
Butylmagnesium chloride (0.53 mL, 0.94 M in THF, 0.50 mmol, 1.0
equiv) was added dropwise to the resulting suspension at rt, and the
reaction mixture was stirred for 30 min. SOCl2 (40 μL, 0.55 mmol, 1.1
equiv) was then added dropwise, and the mixture was stirred at rt for
30 min. The reaction mixture was transferred via a syringe and added
dropwise to a stirred solution of 35% aq NH3 (0.5 mL) and EtOAc
(0.5 mL) in a 25 mL RBF at 0 °C. Anhydrous THF (2.0 mL × 2) was
added to the reaction vial and transferred to the 25 mL RBF to ensure
a quantitative transfer of the sulfinyl chloride. After addition, the
mixture was stirred at rt for 30 min, quenched with brine (10 mL),
and extracted with EtOAc (3 × 10 mL). A few drops of water were
added to dissolve any solid formed during the workup. The combined
organic phases were dried (MgSO4), filtered, and concentrated.
Purification by flash column chromatography (0−5% MeOH in
EtOAc) afforded the title product as a pale yellow viscous oil (43 mg,
71%): Rf (100% EtOAc) = 0.17; 1H NMR (400 MHz, CDCl3) δ 3.72
(s, 2H), 1.22 (s, 9H); 13C{1H} NMR (101 MHz, CDCl3) δ 55.5,
22.3; LRMS (ESI+) m/z 122.0 ([M + H]+); 144.0 ([M + Na]+). Data
is consistent with the literature.25
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ASSOCIATED CONTENT
* Supporting Information
hThe Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.0c00334.
■
sı
1H, 13C, and 19F NMR spectra of synthesized
compounds (PDF)
AUTHOR INFORMATION
Corresponding Author
Michael C. Willis − Department of Chemistry, Chemistry
Research Laboratory, University of Oxford, Oxford OX1 3TA,
United Kingdom; orcid.org/0000-0002-0636-6471;
Email: michael.willis@chem.ox.ac.uk
■
Authors
Pui Kin Tony Lo − Department of Chemistry, Chemistry
Research Laboratory, University of Oxford, Oxford OX1 3TA,
United Kingdom
Gwyndaf A. Oliver − Department of Chemistry, Chemistry
Research Laboratory, University of Oxford, Oxford OX1 3TA,
United Kingdom
(8) Furukawa, M.; Okawara, T. Convenient Syntheses of
Sulfinamide Derivatives. Synthesis 1976, 1976, 339−340.
(9) Gafur, S. H.; Waggoner, S. L.; Jacobsen, E.; Hamaker, C. G.;
Hitchcock, S. R. Efficient Synthesis of Sulfinate Esters and
Sulfinamides via Activated Esters of p-Toluenesulfinic Acid. Synthesis
2018, 50, 4855−4866.
(10) (a) Brownbridge, P.; Jowett, I. C. ’One-Pot’ Synthesis of
Sulphinic Esters from Disulphides. Synthesis 1988, 1988, 252−254.
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.0c00334
́
́
(b) García Ruano, J. L.; Aleman, J.; Belen Cid, M.; Parra, A. A
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Notes
(11) (a) García Ruano, J. L.; Parra, A.; Yuste, F.; Mastranzo, V. M.
Mild and General Method for the Synthesis of Sulfonamides. Synthesis
2008, 2008, 311−319. (b) García Ruano, J. L.; Parra, A.; Marzo, L.;
Yuste, F.; Mastranzo, V. M. One-Pot Synthesis of Sulfonamides from
Methyl Sulfinates using Ultrasound. Tetrahedron 2011, 67, 2905−
2910.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We thank the EPSRC (EP/K024205/1) for support of this
study.
■
(12) Harmata, M.; Zheng, P.; Huang, C.; Gomes, M. G.; Ying, W.;
Ranyanil, K.-O.; Balan, G.; Calkins, N. L. Expedient Synthesis of
Sulfinamides from Sulfonyl Chlorides. J. Org. Chem. 2007, 72, 683−
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Arylboronic Acids and Derivatives with DAST-Type Reagents for
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