A Three-Component Derivatization Protocol for Determining the Enantiopurity of Sulfinamides by 1H and 19F NMR Spectroscopy

Article abstract of DOI:10.1021/acs.joc.9b02473

A practically simple three-component chiral derivatization protocol has been developed to determine the enantiopurity of eight S-chiral sulfinamides by ¹H and ¹⁹F NMR spectroscopic analysis, based on their treatment with a 2-formylphenylboronic acid template and enantiopure pinanediol to afford a mixture of diastereomeric sulfiniminoboronate esters whose diastereomeric ratio is an accurate reflection of the enantiopurity of the parent sulfinamide.

Full text of DOI:10.1021/acs.joc.9b02473

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Note
A three-component derivatization protocol for determining the
enantiopurity of sulfinamides by 1H and 19F NMR spectroscopy
Robin R. Groleau, Robert S. L. Chapman, Harry Ley-Smith, Liyuan Liu, Tony D. James, and Steven D. Bull
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b02473 • Publication Date (Web): 27 Nov 2019
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The Journal of Organic Chemistry
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A three-component derivatization protocol for determining the en-
antiopurity of sulfinamides by H and F NMR spectroscopy
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Robin R. Groleau, Robert S. L. Chapman, Harry Ley-Smith, Liyuan Liu, Tony D. James* and Steven
D. Bull*
Department of Chemistry, University of Bath, Claverton Down, Bath, BA2 7AY, U.K.
E-mail: s.d.bull@bath.ac.uk; t.d.james@bath.ac.uk
Supporting Information Placeholder
ABSTRACT: A practically simple three-component chiral derivatization protocol has been developed to determine the enan-
1
19
tiopurity of eight S-chiral sulfinamides by H and F NMR spectroscopic analysis, based on their treatment with a 2-
formylphenylboronic acid template and enantiopure pinanediol to afford a mixture of diastereomeric sulfiniminoboronate
esters whose diastereomeric ratio is an accurate reflection of the enantiopurity of the parent sulfinamide.
Enantiopure N-sulfinyl imines (sulfinimines) are widely
used for asymmetric synthesis, with Ellman’s and Davis’
sulfinamides (1a and 1b) widely used to prepare these chi-
chiral solvation methods for determining the ee’s of sulfina-
mides have been reported in the literature, using either
1
1
1a
11b
Pirkle’s alcohol, or bifunctional macrocycles. Unfortu-
nately, these methods lack simplicity and substrate scope,
and so the ee’s of S-chiral sulfinamides are normally deter-
ral sulfinimine intermediates for the stereoselective func-
2
tionalization of ketones and aldehydes. These chiral auxil-
7
b
iaries have been employed for the asymmetric synthesis of
chiral amines, alcohols, diamines, amino-alcohols, α-organ-
ometallic amines and α- and β-amino acid derivatives in
mined through chiral HPLC analysis. This approach, how-
ever, requires access to expensive HPLC equipment/chiral
columns and often requires significant development time to
identify a suitable system to resolve the enantiomers of a
target sulfinamide.
3
high enantiomeric excess (ee). They have also found appli-
cations as chiral organocatalysts, as additives/ligands in en-
4
antioselective catalytic systems, and as peptidic/transition
Scheme 1: Stereoselective syntheses of Ellman’s sulfin-
amide 1a and Davis’ sulfinamide 1b
5
state isosteres for medicinal chemistry applications. Sulfin-
amides are also produced naturally by the action of nitroxyl
HNO) on peptidic cysteine residues in cells.6
(
Several approaches have been developed to synthesise en-
antiopure sulfinamides (Scheme 1). Treatment of symmet-
ric disulfides with chiral catalysts and stoichiometric oxi-
dants (e.g. H
2
2
O ) is used to afford chiral thiosulfinate inter-
mediates, which are then reacted with nucleophilic ammo-
nia sources (with clean S
N
2 inversion), affording chiral sul-
7
finamides in high ee (Scheme 1a). Chiral auxiliaries are also
used to prepare sulfinate esters with high levels of diastere-
ocontrol, which can then be reacted with amines to afford
enantiopure sulfinamides (Scheme 1b). Classical resolu-
tion processes have also been used to separate the enantio-
2
a
Therefore, a practically simple, rapid, and inexpensive chi-
ral derivatization protocol that would enable the rapid de-
termination of the ee’s of a wide range of chiral sulfinamides
by NMR spectroscopic analysis would be of use to the wider
synthetic community. We have previously reported the
8
mers of (rac)-thiosulfinate precursors, subtilisin has been
used for enzymatic kinetic resolution of (rac)-N-acyl-aryl-
9
sulfinamides, whilst direct separation of their enantiomers
10
can be achieved by preparative chiral HPLC. To date, two
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development of three-component chiral derivatization pro-
Table 1: Chemical shift differences (Δδ
H NMR spectra of diastereomeric iminoboronate com-
plexes of Ellman's sulfinamide 1a (50% ee), 2-FPBA 2
and a range of enantiopure diols 3a-h
H
) in the 500 MHz
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
tocols for determining the ee’s of chiral primary amines, di-
1
1
amines, amino alcohols, hydroxylamines and diols by H
NMR spectroscopic analysis. These protocols involve treat-
ment of a scalemic chiral analyte with 2-formylben-
zeneboronic acid 2 (2-FPBA) and an enantiopure chiral se-
lector (amine or diol) to afford pairs of diastereomeric imi-
noboronate esters. The diastereomeric ratio (dr) of these
iminoboronate esters can then be measured by comparing
the relative intensities of the integrals of their well-resolved
1
imine proton singlets in their H NMR spectra (see Scheme
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Entry
1
Diol
Δδ
(ppm)a,b
H
2
for how this method is used to determine the ee of -
1
2
methylbenzylamine). Given its proven utility, we decided
to investigate whether this type of three-component H
1
+0.011
NMR derivatization protocol, often referred to as the Bull-
13
James assembly, could be applied to determine the ee of
(
R)-3a
scalemic samples of S-chiral sulfinamides.
Scheme 2: Three-component chiral derivatization pro-
2
3
4
5
+0.006
+0.027
+0.010
+0.014
(
S)-3b
tocol for determining the enantiopurity of -
12a
methylbenzylamine
(
R,R)-3c
S)-3d
(
(
S)-3e
Treatment of a mixture of scalemic Ellman’s sulfinamide
S)-1a (50% ee) with 2-FPBA 2 and (R)-BINOL 3a in CDCl
6c
+0.037
+0.047
(
3
(
S)-3f
for 1 h led to incomplete formation of a mixture of diastere-
omeric sulfiniminoboronate ester complexes 4a and 5a
7c
(
85% conversion from 2-FPBA 2), whose imine proton res-
(R)-3g
1
onances were only partially resolved in their H NMR spec-
trum (Table 1, entry 1). The poor yield of this reaction is
presumably due to the decreased nucleophilicity of the sul-
finamide nitrogen lone pair. This is consistent with previous
reports that drying agents, Lewis-acid catalysts and forcing
conditions are often required for this type of imine conden-
sation reaction to proceed to completion. Nevertheless,
the approximate 3:1 ratio of the partially resolved imine
proton signals of the diastereomeric sulfiniminoboronate
c
8
-0.085
(1R,2R,3S,5R)-3h
a
Δδ
H
is the chemical shift difference between the imine pro-
b
tons of diastereomeric iminoboronate ester complexes 4/5. A
negative value indicates that the homochiral complex was most
1
4
c
deshielded. Full baseline resolution observed for the imine
resonances of 4/5.
1
A series of experiments were then carried out to try and
identify conditions that would result in the three-compo-
nent reaction of scalemic Ellman’s sulfinamide 1a (33% ee),
ester complexes 4a/5a in the H NMR spectrum was con-
sistent with the 50% ee of the parent sulfinamide 1a, indi-
cating that no kinetic resolution had occurred.
2
-FPBA 2 and pinanediol 3h being driven to completion. Re-
This prompted us to react Ellman’s sulfinamide 1a (50% ee)
with 2-FPBA 2 and a range of commercially available chiral
diols 3b-h to identify pairs of diastereomeric sulfinimino-
boronate esters 4/5 whose imine protons would be base-
action of these three components in CDCl for 1 h gave a
70:30 mixture of the two-component formyl boronate ester
6 and the three-component sulfiniminoboronate esters
4h/5h (Table 2, entry 1). Addition of MgSO as a drying
agent only marginally increased the amount of 4h/5h
formed to 40% (Table 2, entry 2). Two-component reaction
of 2-FPBA 2 with pinanediol 3h was found to give boronate
ester 6 in 100% conversion after 10 minutes (Table 2, entry
3
4
1
line-resolved in their H NMR spectra. This screening study
revealed that (S)-2-phenylethanediol 3f, (R)-1-phenylpro-
pane-1,3-diol 3g and (1R,2R,3S,5R)-pinanediol 3h gave
pairs of diastereomeric sulfiniminoboronate esters whose
imine proton resonances were fully resolved (Table 1, en-
tries 6-8). Derivatization with chiral pinanediol 3h gave di-
astereomeric sulfiniminoboronate esters 4h/5h that exhib-
ited sharp imine peaks with the greatest chemical shift dif-
3
1
). However, no reaction was observed when sulfinamide
a was added to a solution of preformed boronate ester 6
in CDCl , indicating that boronate ester 6 is stable towards
3
imine bond formation under these conditions (Table 2, en-
try 4). Two-component reaction of Ellman’s sulfinamide 1a
and 2-FPBA 2 proceeded more slowly, affording sulfinimi-
noboronic acid 7 in 89% yield after 1 h, increasing to 94%
ference (Δδ =-0.085 ppm), and it was therefore chosen as
H
the chiral diol for all subsequent sulfinamide derivatization
reactions.
in the presence of MgSO
premixing sulfinamide 1a, 2-FPBA 2 and MgSO
1 h, followed by addition of pinanediol 3h gave 93%
4
(Table 2, entries 5 and 6). Finally,
4
in CDCl for
3
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conversion to afford the desired three-component sulfin- Table 3: Chemical shift differences (Δδ
H
) of the imine
proton resonances of pairs of diastereomeric sulfinimi-
noboronate esters in the H NMR spectra from reaction
of sulfinamides 1a-h with 2-FPBA 2 and diol 3h
1
2
3
4
5
6
7
8
9
iminoboronate esters 4h/5h and the two-component boro-
nate ester 6 in 7% yield (Table 2, entry 7). Therefore, these
results suggest that irreversible formation of boronate ester
6 is faster than reversible formation of imine 7, with only
imine 7 competent to react further to afford the desired sul-
finiminoboronate esters 4h/5h in the three-component
1
1
5
derivatization reaction.
Table 2: Optimization study of the three-component as-
sembly reaction of Ellman's sulfinamide 1a with 2-FPBA
2
and pinanediol 3h
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Entry (rac)-Sulfinamide Conv. (%)a dra
Δδ
(ppm)b
H
1
2
99
62
50:50
49:51
0.085
0.069
3
4
5
98
97
63
50:50
51:49
50:50
0.061
0.077
0.057
Product Ratiosa
Entry
Reagents
MgSO
4
6
7
4h/5h
1
2
3
1a + 2 + 3h
1a + 2 + 3h
2 + 3h
Premix 2 + 3h
then add 1a
1a + 2
1a + 2
Premix 1a + 2
then add 3h
-
+
-
70%
60%
100%
0%
0%
--
30%
40%
--
6
7
8
69
80
55
50:50
50:50
50:50
0.070
0.062
0.061
4b
-
100%
0%
0%
c
5
6
-
+
--
--
89%
94%
--
--
c
7d
+
7%
0%
93%
a
1
Conversion and dr determined by H NMR spectroscopic
a
1
b
Determined by H NMR spectroscopic analysis. 2 and 3h
b
analysis. Δδ
H
is the chemical shift difference between the
c
premixed for 10 minutes. Remaining mass balance comprised
of unreacted 2-PFBA 2. 1a and 2 premixed for 1 h.
imine protons of diastereomeric iminoboronate ester com-
plexes 4h/5h and 8/9.
d
These results prompted us to develop a new ‘stepwise’
three-component derivatization procedure, involving reac-
tion of (rac)-Ellman’s sulfinamide 1a, 1.2 equiv. of 2-FPBA
We,17 and others,18 have previously reported the use of
fluoro-2-FPBA as an alternative template for the Bull-James
three-component protocol, which enables the dr’s of their
derived iminoboronate esters to be accurately determined
using both H and F NMR spectroscopic analysis. Conse-
quently, we decided to repeat our stepwise three-compo-
nent reaction using Ellman’s sulfinamide 1a and pinanediol
2
and MgSO
of reactive imine 7 formed. This was followed by addition of
.3 equivalents of (1R,2R,3S,5R)-pinanediol 3h which gave
4
in CDCl at rt for 1 h to maximize the amount
3
1
19
1
a 50:50 mixture of diastereomeric sulfiniminoboronate es-
ters 4h/5h in 99% conversion (Table 3, entry 1). This one-
pot stepwise protocol was then applied to the derivatization
of seven additional racemic aryl, heteroaryl, cyclic and acy-
clic sulfinamides 1b-h, affording mixtures of their corre-
sponding diastereomeric sulfiniminoboronate esters 8b-
h/9b-h in 55-99% conversions (Table 3, entries 2-8). Anal-
3
h with 3-fluoro-2-FPBA 10a, 4-fluoro-2-FPBA 10b, 3-
19
fluoro-2-FPBA 10c and 3-fluoro-2-FPBA 10d (Table 4)
These derivatization reactions gave mixtures of diastereo-
meric sulfiniminoboronate esters whose imine proton res-
onances were all well-resolved in their H NMR spectra, as
were the fluorine resonances in their F NMR spectra. 3-
fluoro-2-FPBA 10a gave the best difference for the fluorine
resonances (Δδ =-2.328 ppm), and so it was chosen as the
template to derivatize three further (rac)-sulfinamides 1b-
d, all of which gave a pair of diastereomeric sulfinimino-
boronate esters whose H NMR (imine protons) and
16
1
19
1
ysis of the H NMR spectra of these mixtures revealed that
the imine signals of all pairs of diastereomeric sulfinimino-
boronate esters were all baseline-resolved, with their 49:51
to 51:49 dr values indicating that no kinetic resolution had
occurred in each derivatization reaction.
F
1
19
F
NMR resonances were well resolved.
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19
Table 4: Chemical shift differences (ΔδH/F) in the H/ F
NMR spectra of diastereomeric sulfiniminoboronate es-
ters formed from reaction of sulfinamides 1a-d with
fluorinated FPBA derivatives 10a-d and pinanediol 3h
excess of a commercial sample of enantiopure (R)-Davis’
sulfinamide 1b (purchased from Sigma-Aldrich, Figure 1c).
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
1
19
Both H and F NMR analysis revealed that this ‘enanti-
opure’ reagent was in fact scalemic, with both NMR analyses
returning a 90% ee value for this sample, as confirmed sub-
sequently by chiral HPLC analysis (see Supporting Infor-
mation).
a)
b)
c)
9
6%
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
b
c,d
F
Δδ
(
H
/ Δδ
Entrya (rac)-Sulfinamide
2-FPBA
ppm)e
90%
Δδ
Δδ
H
= -0.064
= -2.328
1
F
(
(
R)-1a (33% ee)
R)-1a (33% ee)
7
5%
Δδ
Δδ
H
= -0.029
= -0.170
2
3
4
5
F
1
Figure 1: a) Expanded H NMR spectra of xcomplexes formed
from reaction of 10a, (1R,2R,3S,5R)-3h and (R)-1a (75%, 90%
and 96% ee). (b) Expanded F NMR spectra of diastereomeric
complexes formed from reaction of 10a, (1R,2R,3S,5R)-3h and
R)- 1a (75%, 90% and 96% ee). c) Expanded H and F{ H}
NMR spectra of diastereomeric complexes formed from reac-
tion of 10a, (1R,2R,3S,5R)-3h and a commercial ‘enantiopure’
sample of (R)-Davis’ sulfinamide 1b, revealing its ‘true’ enanti-
opurity as 90% ee.
Δδ
Δδ
H
= -0.079
= +0.197
F
(
(
R)-1a (33% ee)
R)-1a (33% ee)
19
Δδ
Δδ
H
= -0.201
= -0.578
1
19
1
(
F
Δδ
Δδ
H
= -0.063
= -1.188
F
(
rac)-1b
In conclusion, this report describes the first chiral derivati-
zation protocol for determining the enantiopurity of a range
of S-chiral sulfinamides using both H and F NMR spectro-
scopic analysis, including Ellman’s and Davis’ chiral sulfina-
mides that are widely used as chiral auxiliaries for asym-
metric synthesis.
Δδ
Δδ
H
= 0.042
= 1.457
6
7
1
19
F
(rac)-1c
Δδ
Δδ
H
= 0.070
= 1.365
F
(
rac)-1d
a
Reactions proceeded with 37-99% conversions to afford
mixtures of sulfiniminoboronate esters whose dr’s ranged from
5:35 to 69:31 (entries 1-4) and from 49:51 to 51:49 (entries
-7), indicating that no kinetic resolution had occurred. Δδ is
the chemical shift difference between the imine protons of the
diastereomeric sulfiniminoboronate esters in their H NMR
is the chemical shift difference between the fluo-
rine resonances of the diastereomeric sulfiniminoboronate es-
EXPERIMENTAL SECTION
6
5
Unless preparative details are given, reagents and solvents
were obtained from commercial suppliers. All reactions
were performed without air exclusion, at room temperature
and with magnetic stirring unless otherwise stated. Anhy-
b
H
1
c
spectra. Δδ
F
drous MgSO was used as a drying agent for organic solu-
4
d
19
1
tions. Thin layer chromatography (TLC) was carried out on
Macherey-Nagel aluminium-backed plates that were pre-
coated with silica. Compounds were visualised by either
quenching of UV fluorescence at 254 nm or by staining with
potassium permanganate dip followed by gentle heating.
Purification by flash column chromatography was per-
formed using high-purity grade silica gel (60Å pore size, 40-
ters. Quantitative F{ H} NMR experiments carried out using
a T1 relaxation time of 30 s. A negative value indicates that the
e
homochiral complex was most deshielded.
The detection limits of this new derivatization method us-
ing 3-fluoro-2-FPBA 10a and pinanediol 3h were then de-
termined using scalemic samples of Ellman’s sulfinamide 1a
of 75%, 90% and 96% ee respectively, prepared from enan-
tiopure samples of the sulfinamide (Figures 1a & 1b). Anal-
ysis of the resultant mixtures of sulfiniminoboronate esters
revealed diastereomeric excesses (de) of 75%, 91% and
7
5 μm particle size). Capillary melting points are reported
o
uncorrected to the nearest C, and were determined using a
Stuart digital SMP10 melting point apparatus. Optical rota-
tions were measured using an Optical Activity Ltd AA-10 Se-
ries Automatic Polarimeter, with a path length of 1 dm, and
with concentration (c) quoted in g/100 mL. Nuclear Mag-
netic Resonance (NMR) spectroscopy experiments were
performed in deuterated solvent at 298 K (unless stated
otherwise) on either a Brüker Avance, 300, 400 or 500 MHz
spectrometer or an Agilent ProPulse 500 MHz
1
19
9
5% ( H NMR) and 73%, 89% and 95% ( F NMR), respec-
tively, all of which were within the accepted 5% error limit
when using chiral derivatizing agents to determine ee’s val-
ues by NMR spectroscopy. Having established its applicabil-
ity, our new stepwise three-component chiral derivatiza-
tion protocol was then used to assess the enantiomeric
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spectrometer, with proton decoupling used for all 13C NMR
(rac)-Naphthalene-2-sulfinamide 1d. General procedure
1
2
3
4
5
6
7
8
9
spectra. H, C, B and F NMR chemical shifts (δ) are
quoted in parts per million (ppm) and are referenced to ei-
ther the residual solvent peak or tetramethylsilane (TMS)
when possible. Coupling constants (J) are quoted in Hz.
1
13
11
19
1 was followed using naphthalene-2-thiol (500 mg,
3.12 mmol). Recrystallisation from 2:1 EtOAc/n-hexane af-
forded the title compound 1d (408 mg, 2.13 mmol) as a
o
white solid in 63% yield. m.p.: 134-138 C (decomposed); IR
13
Where C signals could not be observed by 1D NMR due to
low solubility, adjacent quadrupolar nuclei or lack of adja-
(neat): 3292, 3155, 3063, 1589, 1560, 1500, 1344, 1014,
-
1 1
822, 739 cm ; H NMR (500 MHz, CDCl
3
H
) δ 8.34 (s, 1H,ArH),
1
cent H nuclei, their chemical shift was deduced from 2D
7.99-7.89 (m, 3H, ArH), 7.71 (dd, 1H, ArH), 7.65-7.55 (m, 2H,
1
3
1
HMBC experiments, where possible. This approach was val-
idated by variable temperature (VT) 1D NMR of boronate
ester 6. Infrared (IR) spectra were recorded using a Perki-
nElmer Spectrum 100 FTIR spectrometer fitted with a Uni-
versal ATR FTIR accessory, with samples run neat and the
ArH); 4.34 (bs, 2H, -NH
2
); C{ H} NMR (126 MHz, CDCl
3
) δ
C
143.6, 134.6, 132.8, 129.2, 129.0, 128.1, 128.1, 127.3, 125.8,
+
121.9; HRMS (ESI+): Calculated for [M+Na] C10
214.0297; Found: 214.0288.
9
H NOSNa:
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(
rac)-4-Fluorobenzenesulfinamide 1e. General proce-
dure 1 was followed using 4-fluorothiophenol (332 μL,
.12 mmol). Recrystallization from 1:1 EtOAc/n-hexane af-
-
most relevant, characteristic absorbances quoted as  in cm
1
.
High resolution mass spectrometry (HRMS) results were
3
acquired on an externally calibrated Bruker Daltonics
forded the title compound 1e (268 mg, 1.68 mmol) as a
TM
maXis HD UHR-TOF mass spectrometer coupled to an
white solid in 54% yield. All characterisation data were con-
electrospray source (ESI-TOF). Molecular ions were de-
tected either in positive mode as their protonated, sodiated,
or ammonium adduct forms, or in negative mode as depro-
tonated species. Aryl boronic acids were detected as their
deprotonated methyl hydrogen boronate ions [M+13] , as
reported by Wang et al. Bruker Daltonics software DataA-
21,22
sistent with previous literature reports.
1
m.p.: 134-
39 C (lit. 128, 144.8-146.822 oC); IR (neat): 3269, 3154,
o
21
3065, 1587, 1481, 1229, 1211, 1156, 1087, 1005, 887, 834,
-1
1
667 cm ; H NMR (500 MHz, CDCl
3
) δ 7.79-7.71 (m, 2H,
H
-
13
1
ArH), 7.24-7.15 (m, 2H, ArH), 4.32 (bs, 2H,NH
2
) ; C{ H}
164.6 (d, JF-C = 251.7), 142.2,
20
1
NMR (126 MHz, CDCl
3
) δ
F-C = 9.0), 116.2 (d,
(471 MHz, CDCl ) δ -109.0 (tt, J = 8.4, 5.1).
C
TM
nalysis 4.3 was used to process NMR data.
3
2
19
1
28.0 (d,
J
JF-C = 22.4); F NMR
General procedure 1 for the synthesis of (rac)-sulfina-
mides 1c-h from thiols by the method of Di et al. N-
bromo succinimide (2.0 equiv.) was added to a stirred solu-
tion of the thiol (1.0 equiv.) in CH
3
F
1
6
(rac)-4-Methoxybenzenesulfinamide 1f. General proce-
dure 1 was followed using 4-fluorothiophenol (383 μL,
2
2
Cl /MeOH (1:1, 0.1 M) at
3
.12 mmol). Recrystallization from 1:2 EtOAc/n-hexane af-
o
0
C. The reaction was allowed to warm to room tempera-
forded the title compound 1f (262 mg, 1.53 mmol) as a
white solid in 49% yield. All characterisation data were con-
ture and reaction progress was monitored by TLC. Upon
completion (15 min - 1 h) the reaction mixture was
quenched and diluted by half through the addition of satu-
9
o
sistent with previous literature reports. m.p.: 127-131 C
9
o
(
1
lit. 129-131 C); IR (neat): 3261, 3067, 2840, 1591, 1490,
rated Na
phase extracted twice with CH
were then washed with brine, dried (MgSO
2
CO
3
. The layers were separated, and the aqueous
Cl . The combined organics
) and concen-
-1
1
450, 1245, 1025, 1001, 823, 794 cm ; H NMR (500 MHz,
) δ 7.68 (d, 2H, J = 8.8, ArH), 7.02 (d, 2H, J = 8.8, ArH),
.24 (bs, 2H, NH
126 MHz, CDCl ) δ
rac)-Hexane-1-sulfinamide 1g. General procedure 1 was
2
2
CDCl
4
3
H
4
13
1
2
), 3.87 (s, 3H, OCH
3
); C{ H} NMR
trated to dryness in vacuo to afford a methylsulfinate prod-
uct as a clear oil.
(
3
C
162.1, 138.0, 127.2, 114.4, 55.7.
(
The methylsulfinate (1.0 equiv.) was dissolved in anhy-
drous THF (0.33 M) and cooled to -78 C. LiHMDS
(1.5 equiv., 1M in THF) was then added dropwise over 5
minutes and the reaction left to stir at -78 C for 1.5 h. After
this time the reaction was quenched with saturated NH
allowed to warm to room temperature and left to stir. After
0 min, the reaction was diluted with EtOAc, the aqueous
phase extracted twice with EtOAc, and the combined organ-
ics were washed with brine, dried (MgSO ) and concen-
trated in vacuo. The crude product was purified by either
recrystallization or column chromatography to afford the
desired sulfinamide 1c-h.
followed using 1-hexanethiol (1.421 mL, 10.0 mmol). Re-
crystallization from n-hexane afforded the title compound
o
1
g (356 mg, 2.38 mmol) as an off-white solid in 24% yield.
o
o
m.p.: 41-42 C; IR (neat): 3282, 3200, 2954, 2924, 2849,
4
Cl,
-1
1
1553, 1464, 1417, 1066, 1035, 1001, 890 cm ; H NMR
(500 MHz, CDCl ) δ 3.99 (bs, 2H, NH ), 2.73 (2 x ddd, 2H,
J = 13.0, 8.5, 6.7, SCH ), 1.79-1.63 (m, 2H, SCH CH ), 1.50-
CH ), 1.36-1.29 (m, 4H,MeCH CH ),
); C{ H} NMR (126 MHz, CDCl ) δ
7.9, 31.5, 28.4, 22.9. 22. 5, 14.1; HRMS (ESI+): Calculated
3
H
2
3
2
2
2
1
0
.37 (m, 2H, SCH
.91-0.87 (m, 3H, CH
2
CH
3
2
2
13
2
2
4
1
3
C
5
+
for [M+NH
4
] C
6
H
19
2
N OSNa: 167.1213; Found: 167.1215.
(
rac)-Pyridine-2-sulfinamide 1h. General procedure 1
was followed using 2-mercapto pyridine (1.998 g,
8.0 mmol). Recrystallization from CH Cl afforded the title
(
rac)-Cyclopentanesulfinamide 1c. General procedure 1
was followed using cyclopentanethiol (334 μL, 3.12 mmol).
Recrystallisation from 1:10 EtOAc/n-hexane afforded the ti-
tle compound 1c (299 mg, 2.24 mmol) as a white solid in
1
2
2
compound 1h (128 mg, 0.972 mmol) as a white solid in 5%
yield. All characterisation data were consistent with previ-
7
2% yield. All characterisation data were consistent with
23
o
23
o
ous literature reports. m.p.: 102-104 C (lit. 98-100 C);
16
o
16
o
previous literature reports. m.p.: 86-88 C (lit. 82-83 C);
IR (neat): 3189, 3089, 2957, 2868, 1450, 1166, 1001, 908,
1
H NMR (500 MHz, CDCl
3
) δ 8.71 (ddd, 1H, J = 4.7, 4.7, 1.5,
H
ArH), 7.99-7.89 (m, 2H, ArH), 7.44 (ddd, 1H, J = 7.4, 4.7, 1.4,
-
1
1
697 cm ; H NMR (500 MHz, CDCl
3
) δ
H
3.91 (bs, 2H, -NH
2
),
),
13
1
ArH), 4.66 (bs, 2H, NH
2
); C{ H} NMR (126 MHz, CDCl
3
) δ
C
3.05 (p, 1H, J = 7.5, SCH), 2.04 (dt, 2H, J = 13.9, 6.9, CH
.98-1.88 (m, 2H, CH
126 MHz, CDCl ) δ 65.2, 27.7, 26.1, 25.9, 25.6.
2
1
64.5, 150.0, 138.1, 125.6, 120.6.
1
3
1
1
2
), 1.83-1.59 (m, 4H, CH ); C{ H} NMR
2
General procedure 2 for the synthesis of 1-bromo-2-(di-
methoxymethyl)-fluorobenzenes 11a-d by the method
(
3
C
19
of Kowalska et al.
H
2
SO (0.093 equiv., 0.47 mmol, 25 μL)
4
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 9
and trimethyl orthoformate (1.3 equiv., 6.50 mmol, 711 μL)
were added to a stirred solution of a 2-bromo-fluorobenzal-
dehyde (1.0 equiv., 5.00 mmol, 1.02 g) in MeOH (2.0 mL).
The reaction was heated at reflux for 1.5 h, before cooling to
room temperature and quenching with triethylamine
δ
H
7.43-7.39 (m, 1H, ArH), 7.34-7.28 (m, 1H, ArH), 7.14-7.09
(m, 1H, ArH), 5.57 (s, 1H, MeOCH), 3.39 (s, 6H, 2 x OCH );
159.2 (d, JF-C = 246.5),
139.4, 128.3 (d, JF-C = 7.9), 123.7 (d, JF-C = 3.3), 116.5 (d,
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
3
1
3
1
1
C{ H} NMR (126 MHz, CDCl
3
) δ
C
1
9
J
F-C = 22.6), 110.2 (d, JF-C = 21.3), 102.6 (d, JF-C = 3.6), 54.1; F
(
1.00 mL, 7.17 mmol). The volatiles were removed in vacuo,
and the resulting mixture dissolved in water (30 mL) and
extracted with Et O (30 mL). The organics were washed
with water (3 x 30 mL) and brine (30 mL), dried (MgSO
NMR (470 MHz, CDCl
(ESI+): Calculated for [M+Na] C
Found: 270.9741.
3
) δ
F
-105.5 (dd, J = 8.3, 5.1); HRMS
+
9
H
10
2
O BrFNa: 270.9740;
2
4
)
General procedure 3 for the synthesis of fluoro-2-
formylphenyl boronic acids 10a-d by the method of
Kowalska et al. n-Butyllithium (2.5 M in THF, 1.15 equiv.)
was added dropwise (15 min) to a stirred solution of a
fluoro-1-bromo-2-(dimethoxymethyl)-fluorobenzene 11a-
and concentrated in vacuo to afford the desired dimethyl ac-
etals 11a-d as clear oils.
19
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
-Bromo-2-(dimethoxymethyl)-3-fluorobenzene 11a.
General procedure 2 was followed using 2-bromo-6-fluoro-
benzaldehyde (5.00 mmol, 1.02 g), affording the title com-
pound 11a (1.09 g, 4.41 mmol) as a colourless oil in 88%
yield. IR (neat): 2930, 2830, 1602, 1572, 1455, 1376, 1249,
d (1.0 equiv.) in anhydrous Et O/THF (5:1 mixture, 0.33 M)
under an inert N
2
2
atmosphere. The resultant solution was
o
then cooled to -78 C, and stirred for 1 h, before addition of
trimethyl borate (1.15 equiv.). The reaction was warmed to
room temperature and allowed to stir for 15 min, before
acidifying to pH 3 using HCl (3M, aq.). The reaction was di-
luted with Et
The combined organics were washed with brine, dried over
MgSO , and concentrated to dryness, with the resultant
crude product recrystallised from EtOAc/hexane to afford
the desired formyl boronic acid 10a-d (observed by NMR in
tautomeric equilibrium with the related benzoxaborole mi-
nor product, see Supporting Information).
1
(
1
201, 1102, 1062, 168, 893, 781, 730 cm-1
500 MHz, CDCl ) δ
H, J = 8.2, 5.6, ArH), 7.05 (dd, 1H, J = 10.4, 8.3, 1.2, ArH),
;
1
H NMR
3
H
7.73 (dt, 1H, J = 8.0, 1.1, ArH), 7.17 (td,
1
3
1
5.71 (d, 1H, J = 1.2, MeOCH), 3.49 (s, 6H, 2xOCH
NMR (126 MHz, CDCl
3
); C{ H}
161.5 (d, JF-C = 256.3), 131.0 (d,
2
O, and the aqueous phase extracted 3 times.
1
3
) δ
C
J
J
(
F-C = 9.9), 129.2 (d, JF-C = 3.4), 125.4 (d, JF-C = 14.4), 123.5 (d,
F-C = 5.3), 116.2 (d, JF-C = 23.0), 104.9, 55.7; F NMR
4
1
9
470 MHz, CDCl
3
) δ
F
-111.1 (dd, J = 10.6, 5.6); HRMS (ESI+):
+
Calculated for [M+Na] C
9
H
10
2
O BrFNa: 270.9740; Found:
2
70.9749.
1
-Bromo-2-(dimethoxymethyl)-4-fluorobenzene 11b.
(3-Fluoro-2-formylphenyl)boronic acid 10a. General
procedure 3 was followed using 1-bromo-2-(dimethoxyme-
thyl)-3-fluorobenzene 11a (1.09 g, 4.41 mmol), affording
the title compound 10a (444 mg, 2.64 mmol) as a white
solid in 60% yield. All characterisation data were consistent
with previous literature reports. m.p.: 125-128 C (lit.
127-129 C); IR (neat): 3309, 3071, 2943, 1675, 1561, 1427,
1294, 1235, 1184, 1083, 908, 825, 793, 732 cm ; H NMR
(500 MHz, acetone–d ) δ 10.38 (s, 1H, OCH, major), 8.42
(bs, 1H, BOH, minor), 7.77-7.61 (m, 1H, ArH, major), 7.54-
7.41 (m, 2H major + 1H minor, ArH), 7.32 (bs, 2H, BOH, ma-
jor), 7.26 (ddd, 1H, J = 11.2, 8.3, 1.1, ArH, major), 7.21 (ddd,
1H, J = 9.8, 7.9, 1.1, ArH, minor), 6.45 (s, 1H, HCO, minor),
General procedure 2 was followed using 2-bromo-5-fluoro-
benzaldehyde (5.00 mmol, 1.02 g), affording the title com-
pound 11b (1.16 g, 4.65 mmol) as a colourless oil in 95%
yield. IR (neat): 2935, 2832, 1581, 1464, 1365, 1264,1154,
-
1
1
24
o
24
1
(
095, 1055, 972, 880 cm ; H NMR (300 MHz, CDCl
dd, 1H, J = 8.8, 5.1, ArH), 7.35 (dd, 1H, J = 9.4, 3.1, ArH), 6.93,
ddd, J = 8.8, 7.7, 3.1, ArH), 5.50 (d, 1H, J = 1.2, MeCOCH), 3.38
3
) δ
H
7.51
o
-1
1
13
1
(
J
s, 6H, 2x OCH
3
); C{ H} NMR (126 MHz, CDCl
F-C = 247.2), 139.3 (d, JF-C = 7.0), 134.2(d, JF-C = 7.7), 117.4
(d, JF-C = 22.7), 116.9 (d, JF-C = 3.2), 115.9 (d, JF-C = 24.3),
102.4, 54.0; F NMR (470 MHz, CDCl
(ESI+): Calculated for [M+Na] C
Found: 270.9748.
3
) δ
C
162.1 (d,
6
H
1
1
9
3
) δ
F
-114.3; HRMS
+
9
H
10
O
2
BrFNa: 270.9740;
1
1
6.13 (bs, 1H, COH, minor); B NMR (375.5 MHz, acetone–
1
9
d
6
) δ
tone–d
J = 121.1, 5.3, major). HRMS (ESI-): Calculated for
B
31.2 (minor), 29.5 (major); F NMR (470 MHz, ace-
1-Bromo-2-(dimethoxymethyl)-5-fluorobenzene 11c.
General procedure 2 was followed using 2-bromo-4-fluoro-
benzaldehyde (5.00 mmol, 1.02 g), affording the title com-
pound 11c (1.16 g, 4.65 mmol) as a colourless oil in 93%
yield. IR (neat): 2937, 2826, 1599, 1484, 1361, 1226, 1193,
6
) δ -120.8 (dd, J = 9.9, 4.2, minor), -122.4 (dd,
F
-
13
[
M-H
2
O+OMe] C
8
H
7
FBO
3
: 181.0478; Found: 181.0475.
C
NMR spectrum is not reported, as the signal intensity was
too weak due to the combined effect of tautomerization, F
splitting and the adjacent B.
1
9
103, 1054, 982, 857, 812 cm-1 2826,1735, 1694, 1585,
475, 1253, 1221, 1111, 1033, 880, 864; H NMR (500 MHz,
1
1
1
1
1
CDCl
3
) δ
H
7.60 (dd, 1H, J = 8.7, 6.2, ArH), 7.31 (dd, 1H, J = 8.2,
(4-Fluoro-2-formylphenyl)boronic acid 10b. General
procedure 3 was followed using 1-bromo-2-(dimethoxyme-
thyl)-4-fluorobenzene 11b (1.18 g, 4.75 mmol), affording
the title compound 10b (410 mg, 2.44 mmol) as a white
solid in 55% yield. All characterisation data were consistent
with previous literature reports. m.p.: 123-126 C (lit.
123-125 C); IR (neat): 3217, 1670, 1601, 1578, 1428, 1366,
1339, 1273, 1221, 1156, 1088, 1039, 886, 829, 768,
2
.6, ArH), 7.05(td, 8.3, 2.6, ArH), 5.52 (s, 1H, MeOCH), 3.37
1
3
1
(
s, 6H, 2 x OCH
3
); C{ H} NMR (126 MHz, CDCl
3
) δ 162.5 (d,
C
J
F-C = 251.8), 133.2 (d, JF-C = 3.6), 129.7 (d, JF-C = 8.5), 123.2
(
1
d, JF-C = 9.4), 120.2 (d, JF-C = 24.8), 114.5 (d, JF-C = 20.9),
19
17
o
17
02.6, 54.0; F NMR (470 MHz, CDCl
3
) δ
F
-111.4; HRMS
+
o
(
ESI+): Calculated for [M+Na] C
Found: 270.9747.
-Bromo-2-(dimethoxymethyl)-6-fluorobenzene 11d.
9
H
10
O
2
BrFNa: 270.9740;
-
1 1
727 cm ; H NMR (500 MHz, acetone-d
OCH, major), 8.28 (bs, 1H, BOH, minor), 7.93 (dd, 1H, J = 8.3,
.9, ArH, major), 7.74 (bs, 2H, BOH, major), 7.74 (dd, 1H,
6
) δ
H
10.33 (s, 1H,
1
General procedure 2 was followed using 2-bromo-3-fluoro-
benzaldehyde (5.00 mmol, 1.02 g), affording the title com-
pound 11d (1.18 g, 4.75 mmol) as a colourless oil in 95%
yield. IR (neat): 2959, 2835, 1577, 1464, 1436, 1357, 1261,
5
J = 8.0, 5.7, ArH, minor), 7.66 (dd, 1H, J = 9.6, 7.2, ArH, ma-
jor), 7.44 (td, J = 8.4, 2.7, ArH, major), 7.21-7.13 (m, 2H, ArH,
minor); B NMR (375.5 MHz, acetone–d
1
1
-
1
1
6
) δ 31.3 (minor),
B
1115, 1035, 1004, 825, 776 cm ; H NMR (500 MHz, CDCl )
3
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Page 7 of 9
The Journal of Organic Chemistry
-1 1
2
8.9 (major); 19F NMR (470 MHz, acetone–d
nor), -111.7 (major); HRMS (ESI-): Calculated for
6
) δ -111.2 (mi-
F
1593, 1488, 1370, 1337, 1236, 1076, 754, 666 cm ; H NMR
(500 MHz, CDCl ) δ 10.55 (s, 1H, OCH), 7.98-7.95 (m, 1H,
1
2
3
4
5
6
7
8
9
3
-
13
[M-H
2
O+OMe] C
8
H
7
FBO
3
: 181.0478; Found: 181.0471.
C
ArH), 7.90-7.86 (m, 1H,ArH), 7.62-7.53 (m, 2H, ArH), 4.52
(dd, 1H, J = 8.8, 1.9 H-7a), 2.48-2.39 (m, 1H, H-7), 2.32-2.23
(m, 1H, H-8), 2.16 (dd, 1H, J = 6.0, 4.9, H-4), 2.04-1.94 (m,
2H, H-6 + H-7), 1.53 (s, 3H, H-9), 1.33 (d, 1H, J = 10.8, H-8),
NMR spectrum is not reported, as the signal intensity was
too weak due to the combined effect of tautomerization,
splitting and the adjacent B.
1
9
F
1
1
1
3
1
1
.32 (s, 3H, H-10/11), 0.90 (s, 3H, H-10/11); C{ H} NMR
(5-Fluoro-2-formylphenyl)boronic acid 10c. General
procedure 3 was followed using 1-bromo-2-(dimethoxyme-
thyl)-5-fluorobenzene 11c (1.16 g, 4.65 mmol), affording
the title compound 10c (388 mg, 2.31 mmol) as a white
solid in 50% yield. m.p.: 126-131 C; IR (neat): 3309, 3069,
1
7
(
126 MHz, CDCl
3
) δ
C
194.7, 141.4, 135.7, 133.1, 131.9 (de-
duced from HMBC, confirmed by -15 C VT NMR), 130.8,
28.0, 86.9, 78.6, 51.5, 39.7, 38.4, 35.5, 28.7, 27.2, 26.6, 24.2;
o
1
1
1
o
B NMR (375.5 MHz, CDCl
3
) δ
21BO
B
30.7; HRMS (ESI+): Calcu-
Na: 307.1479; Found:
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
+
lated for [M+Na]
307.1493.
C
17
H
3
669, 1596, 1571, 1419, 1344, 1226, 1167, 1103, 1044, 905,
-
1 1
97, 737, 692 cm ; H NMR (500 MHz, acetone-d
6
) δ 10.17
H
(
7
s, 1H, OCH, major), 8.06 (m, 1H major + 1H minor, ArH),
.84 (s, 2H, BOH, major), 7.56 (dd, 1H, J = 9.5, 2.7, ArH, ma-
2-fluoro-6-((3aS,4S,6S,7aR)-3a,5,5-Trimethylhexahy-
dro-4,6-methanobenzo[d][1,3,2]dioxaborol-2-yl)ben-
zaldehyde 3-F-6. General procedure 4 was followed using
3-fluoro-2-FPBA 10a (47 mg, 0.28 mmol) and (1S,2S,3R,5S)-
pinanediol 3h (96 mg, 0.25 mmol), affording the title com-
jor), 7.50 (dd, 1H, J = 8.3, 4.7, ArH, minor), 7.37 (td, 1H,
J = 8.4, 2.7, ArH, major), 7.31-7.22 (m, 1H, ArH, minor), 6.27
(
bs, 1H, OCH, minor) (some signals not observed due to low
19 11
concentration of minor tautomer) ; B NMR (375.5 MHz,
pound (3aS,4S,6S,7aR)-3-F-6 (73 mg, 0.39 mmol) as a clear
1
9
23
acetone–d
(470 MHz, acetone-d
jor), -116.1 (minor); HRMS (ESI-): Calculated for
6
) δ
B
28.9 (major), 20.2 (minor); F NMR
oil in 96% yield. [α]
D
= +20 (c 1.0, CHCl ); IR (neat): 2918,
3
6
) δ -106.7 (dd, J = 8.1, 8.1, ma-
F
2869, 1695, 1568, 1480, 1439, 1339, 1238, 1029, 794,
-
1 1
666 cm ; H NMR (500 MHz, CDCl ) δ 10.43 (d, 1H, J = 1.0,
3
-
13
[
M-H
2
O+OMe] C
8
H
7
FBO
3
: 181.0478; Found: 181.0473.
C
OCHC), 7.58 (ddd, 1H, J = 8.3, 7.2, 5.2, ArH), 7.40 (d, 1H,
J = 7.2, ArH), 7.17 (ddd, 1H, J = 10.6, 8.3, 1.0, ArH), 4.55 (dd,
1H, J = 8.8, 2.0, H-7a), 2.48-2.38 (m, 1H, H-7), 2.37-2.27 (m,
1H, H-8), 2.17-2.11 (m, 1H, H-4), 2.06-1.96 (m, 2H, H-6 and
H-7), 1.58 (s, 3H, H-9), 1.55 (d, 1H, J = 10.8, H-8), 1.34 (s, 3H,
NMR spectrum is not reported, as the signal intensity was
1
9
too weak due to the combined effect of tautomerization,
splitting and the adjacent B.
F
1
1
(
6-Fluoro-2-formylphenyl)boronic acid 10d. General
1
3
1
H-10/11), 0.91 (s, 3H, H-10/11); C{ H} NMR (126 MHz,
CDCl ) δ 189.0 (d, JF-C = 6.2), 164.3 (d, JF-C =259.8), 135.7 (d,
F-C = 8.7), 129.1 (d, JF-C = 3.8), 127.8 (d, JF-C = 6.9), 121.6 (de-
duced from HMBC), 117.5 (d, JF-C = 20.9), 86.6, 78.8, 51.7,
procedure 3 was followed using 1-bromo-2-(dimethoxyme-
thyl)-6-fluorobenzene 11d (1.18 g, 4.75 mmol), affording
the title compound 10d (223 mg, 1.33 mmol) as a white
3
C
J
o
solid in 28% yield. m.p.: 153-156 C; IR (neat): 3255, 2848,
11
3
CDCl
9.7, 38.5, 35.5, 28.4, 27.3, 26.5, 24.2; B NMR (375.5 MHz,
1
1
1
674, 1601, 1567, 1451, 1324, 1301, 1231, 1213, 1160,
19
-
1
1
3
) δ
B
30.9; F NMR (470 MHz, CDCl
J = 10.5, 5.3); HRMS (ESI+): Calculated for [M+Na]
FNa: 325.1385; Found: 325.1381.
3
) δ
F
-121.0 (dd,
040, 786, 730, 681 cm ; H NMR (500 MHz, acetone-d
6
) δ
H
+
0.04 (d, 1H, J = 2.3, OCH, major), 7.75 (d, 1H, J = 7.4, ArH,
C
17
H20BO
3
major), 7.64-7.54 (m, 1H major + 1H minor, ArH), 7.38-7.24
m, 1H major + 1H minor, ArH), 7.06 (t, 1H, J = 8.1, ArH, ma-
jor), 6.26 (bs, 1H, OCH, minor) (some signals not observed
(
General procedure 5 for the synthesis of tert-butyl sul-
finiminoboronates 4h and 5h. tert-Butyl sulfinamide 1a
(61 mg, 0.50mmol, 1.0 equiv.) was added to a stirred sus-
pension of 2-formylbenzene boronic acid 2 (90 mg,
19
11
due to low concentration of minor tautomer ); B NMR
(375.5 MHz, acetone–d
1
9
6
) δ
B
29.3 (major), 20.2 (minor);
F
NMR (470 MHz, acetone-d
6
) δ
F
-105.6 (minor), -106.1 (t, J =
0.60 mmol, 1.2 equiv.) and MgSO
4
(1.00 g) in CHCl and the
3
-
6
C
.7, major); HRMS (ESI-): Calculated for [M-H
2
O+OMe]
reaction stirred for 2 h, before (1R,2R,3S,5R)-pinanediol 3h
(111 mg, 0.65 mmol, 1.3 equiv.) was added. After 10 min,
the reaction was filtered and concentrated to dryness in
vacuo and the residue purified by chromatography (0.5%
MeOH in 1:1 DCM/n-hexane) afforded the desired sulfinimi-
noboronate ester as a clear oil. The low stability of these
complexes to the purification conditions employed meant
that small amounts of 2-formyl boronate ester 6 remained.
: 181.0478; Found: 181.0473. 1 C NMR spectrum
3
8
H
7
FBO
3
is not reported, as the signal intensity was too weak due to
1
9
the combined effect of tautomerization, F splitting and the
1
1
adjacent B.
General procedure 4 for the synthesis of 2-formyl boro-
nate esters 6 and 3-F-6. (1S,2S,3R,5S)-pinanediol 3h
(
1.0 equiv) was added to a stirred suspension of a 2-
formylbenzene boronic acid 2 (1.1 equiv) in CHCl (0.10 M).
After 15 min, the reaction was diluted with an equivalent
amount of CH Cl and passed through a silica plug. The plug
was washed with CH Cl until no more product eluted and
3
(R)-2-methyl-N-((E)-2-((3aR,4R,6R,7aS)-3a,5,5-trime-
thylhexahydro-4,6-methanobenzo[d][1,3,2]dioxabo-
rol-2-yl)benzylidene)propane-2-sulfinamide 4h. Gen-
eral procedure 5 was followed using (R)-Ellman’s sulfina-
mide 1a (61 mg, 0.50 mmol), affording the title compound
2
2
2
2
the solvent removed in vacuo to afford the desired boronate
ester as a clear oil.
S
(R ,3aR,4R,6R,7aS)-4h (24 mg, 0.062 mmol) as a clear oil in
2
-((3aS,4S,6S,7aR)-3a,5,5-Trimethylhexahydro-4,6-
methanobenzo[d][1,3,2]dioxaborol-2-yl)benzaldehyde
. General procedure 4 was followed using 2-FPBA 2
1
6
(83 mg, 0.55 mmol) and (1S, 2S, 3R, 5S)-pinanediol 3h
(85 mg, 0.5 mmol), affording the title compound
(3aS,4S,6S,7aR)-6 (110 mg, 0.39 mmol) as a clear oil in 70%
2
3
yield. [α]
D
= +18 (c 1.0, CHCl ); IR (neat): 2921, 2870, 1693,
3
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The Journal of Organic Chemistry
Page 8 of 9
1
.26 (s, 9H, tert-butyl), 1.23 (d, 1H, J = 10.9, H-8), 0.88 (s, 3H,
AUTHOR INFORMATION
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
H-10/11); B NMR (375.5 MHz, CDCl
(ESI+): Calculated for [M+H]
Found 388.2118; Calculated for [M+Na] C21
410.1936; Found: 410.1940. IR and specific rotation data
were not acquired due to the presence of significant resid-
ual (3aR,4R,6R,7aS)-6. C NMR spectra are not reported, as
this impurity and the adjacent B nucleus led to unassigna-
ble spectra.
11
) δ
30.5; HRMS
S: 388.2116,
3
B
+
Corresponding Author
C
21
H
31BNO
3
+
H30BNO
3
SNa:
*E-mail: s.d.bull@bath.ac.uk; t.d.james@bath.ac.uk
ACKNOWLEDGMENT
This work was supported by the EPSRC Centre for Doctoral
Training in Catalysis (EP/L016443/1).
1
3
1
1
REFERENCES
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mide 1a, affording the title compound (S
5
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(
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) δ
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+
(
ESI+): Calculated for [M+H]
C
21
H
31BNO
+
Found 388.2112; Calculated for [M+Na]
4
were not acquired due to the presence of significant resid-
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C
21
H
30BNO S:
3
10.1936; Found: 410.1937; IR and specific rotation data
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3
1
1
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4
(
1
3
standard). The reaction was stirred at room temperature
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tered and the 500 MHz H NMR spectrum and/or 470 MHz
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9
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19
1
quired. The acquired H and F{ H} NMR spectra can be
found in the associated Supporting Information.
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were prepared from commercially available enantiopure
samples of (R)- and (S)-tert-butyl sulfinamide 1a. 0.1 M so-
lutions of enantiopure 1a in CDCl were prepared, and then
3
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and H. Duan, Highly Enantioselective Nitro-Mannich Reaction of
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13) (a) H. Y. Su, D. Gorelik and M. S. Taylor, Chiral phosphine
(24) S. L. Lulinski, I. Madura, J. Serwatowski, H. Szatyƚowicz and
ligand libraries based on the Bull-James three-component supra-
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́cile, S. Le Duff, T. D. James, G. Lees,
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