One-pot synthesis of chiral nonracemic amines

Article abstract of DOI:10.1021/jo201849j

One-pot five-component reactions of oxathiazolidine-S-oxides with mesitylmagnesium bromide, lithium bis(trimethylsilyl)amide, aldehydes and Grignard reagents afford chiral nonracemic amines or sulfinamides in good yields and high stereoselectivities.

Full text of DOI:10.1021/jo201849j

Article
pubs.acs.org/joc
One-Pot Synthesis of Chiral Nonracemic Amines
Caroline Roe,† Heather Hobbs,‡ and Robert A. Stockman*,†
†School of Chemistry, University of Nottingham, Nottingham NG7 2RD, U.K.
‡GlaxoSmithKline, Gunnels Wood Road, Stevenage SG1 2NY, U.K.
S
* Supporting Information
ABSTRACT: One-pot five-component reactions of oxathia-
zolidine-S-oxides with mesitylmagnesium bromide, lithium
bis(trimethylsilyl)amide, aldehydes and Grignard reagents
afford chiral nonracemic amines or sulfinamides in good yields
and high stereoselectivities.
Scheme 1. Four-Component Synthesis of Chiral Sulfinimines
INTRODUCTION
■
Multicomponent reactions are one of the most powerful
methods for the construction of molecules, assembling multiple
starting materials and forming numerous bonds in a one-pot
process.1 This single-pot operation involving many bond-
forming steps eliminates several purifications, reduces the use of
solvent, minimizes chemical waste, and reduces the amount of
time chemical synthesis requires.2 Thus in the ever-important
quest for more sustainable chemistry,3 the development of new
multicomponent sequences, especially those that induce
stereoselectivity, remains a high priority for synthetic chemists.4
Chiral amines are high value materials that form the basis of
many pharmaceutical ingredients (e.g., Plavix, Alna, Sifrol, and
Januvia) and serve as auxiliaries5 and as ligands for
homogeneous catalysis.6 They are also commonplace in many
natural products. This has spurred much interest in the
synthesis of α-chiral amines, and there are now a multitude of
practical methods for their formation, including catalytic
asymmetric reduction of ketimines, enamines and enamides,7
asymmetric reductive amination8 and the asymmetric addition
of organometallic reagents to imines,9 or the addition of
organometallic reagents to chiral sulfinimines.10 In many of
these cases multiple steps are required for the formation of the
enamide or imine and the chiral ligand/catalyst, or the chiral
sulfinimine, thus necessitating multiple synthetic operations,
workups, and purifications. Of these methods, organometallic
addition to imines and reductive amination combine con-
nectivity with the formation of the new stereogenic center. We
wished to investigate an approach that included a high degree
of connectivity, with a one-pot process for the simple and
convenient formation of α-chiral amines from readily available
precursors. Recently we reported the use of a chiral
oxathiazolidine oxide (readily prepared in just two steps from
simple commercially available chemicals in >90% yield) as a
template to prepare chiral sulfinimines in a four-component,
one-pot reaction in high yields and enantioselectivities (Scheme
1).11 Additionally we recently described the nucleophilic
addition of Grignard reagents to mesityl sulfinimines, which
we found to give excellent yields and high diastereoselectivities
via an open transition state, allowing a wide range of chiral
amines to be prepared.12 We describe herein the combination
of these two high-yielding and highly stereoselective reactions
into a sequential five-component, one-pot process, enabling the
facile preparation of chiral sulfinamides and chiral amines in a
connective manner, from cheap commodity chemicals in an
efficient single operation which minimizes waste and time. This
process, which forms both a C−C bond and a C−N bond, is
complementary to the asymmetric reduction of imines/
enamines and derivatives.
RESULTS AND DISCUSSION
■
Initially, we concentrated our efforts into extending our
previous four-component sulfinimine synthesis into a five-
component sulfinamide synthesis protocol, using benzaldehyde
as the fourth component (Table 1). This consisted of adding a
series of additional Grignard reagents, as the fifth component,
to the reactions after sulfinimine formation had been observed
by LC−MS or TLC. A range of mesityl sulfinamides was
produced in yields ranging from 36% to 58% (equivalent to an
average 76−87% per step over the four-step process) and
excellent diastereoselectivities. The whole process involves the
formation of four new bonds and two stereogenic centers in a
single-pot operation. It is noteworthy that diastereoselectivities
were improved over the equivalent single-step reaction from
the mesityl sulfinimine (e.g., entry 8, BnMgCl gave 70:30 dr in
the stepwise reaction).12 We found that allyl magnesium
bromide gave the opposite stereoselectivity to all other
Grignard reagents, and thus in this case we surmise that
Received: September 12, 2011
Published: October 12, 2011
© 2011 American Chemical Society
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step12 to 94:6 dr in the one-pot reaction. This may be due to
the presence of lithium counterions in the one-pot reaction or
the increased amount of metal counterions compared to the
single-step reaction. Entry 3 using mesitaldehyde required the
addition of magnesium sulfate alongside the aldehyde in step 3
to aid in the sulfinimine formation, whereas all of the other
sulfinimines formed without the need for any extra desiccant.
Also noteworthy is the tolerance of an aryl bromide in entry 9,
although it was necessary to quench the reaction quickly after
the isopropyl Grignard addition, once the reaction was judged
to be complete, or debromination was observed in increasing
yield over time.
The diastereomeric ratios of the mesityl sulfinamides were
determined from the chiral HPLC of the purified sulfinamides
and confirmed by the 1H NMR spectra. The absolute
configuration of the major diastereoisomer was deduced, as in
our previous communication,12 by the removal of the N-sulfinyl
group and comparison of the sign of the specific rotation of the
free primary amines (or hydrochloride salt) with the reported
data.
We next turned our attention to the in situ removal of the
mesitylsulfinyl auxiliary, which would give an asymmetric
synthesis of unprotected amines by formation of an imine
with a temporary chiral stereodirecting and activating group,
diastereoselective addition, and removal of the stereodirecting
group, all in a single-pot operation from simple starting
materials. The removal of the mesitylsulfinyl group was
achieved by addition of 2 M HCl in the final stage of the
workup, which allowed precipitation of the amine hydro-
chlorides and isolation by filtration without any further
purification required, rendering the whole process very
operationally simple and reducing the solvent requirement
still further. The amino-alcohol template could be recovered by
chromatography of the filtrate in >90% recovery. The
enantiomeric excess of the products was determined by
conversion to the corresponding benzamides and analysis by
chiral HPLC. Our findings are shown in Table 3.
Table 1. Five-Component Synthesis of Sulfinamides
entry
RMgX
2
yield (%)
dr
1
2
3
4
5
6
7
8
EtMgCl
2a
2b
2c
2d
2e
2f
46
46
43
44
34
39
36
58
93:7
95:5
nPrMgCl
iPrMgCl
iBuMgCl
nhexylMgBr
CyMgCl
allylMgBr
BnMgCl
>99:1
94:6
86:14
>99:1
95:5
2g
2h
84:16
reaction is proceeding via a chelated SE2′ pathway, rather than
an open transition state, which has been shown by Ellman to
induce the opposite sense of stereochemistry in the addition of
Grignard reagents to tert-butanesulfinimines.13 The reactions
were carried out in 2-methyltetrahydrofuran, and it was found
important to exclude all tetrahydrofuran from the reaction in
order to maximize stereoselectivity, as we had found in the
stepwise reaction study.12 Thus the commercial Grignard
reagents used were in solution in diethyl ether, and the lithium
hexamethyldisilazide was used as a solution in toluene. The
diastereomeric ratios were generally very high, except for
lipophilic and sterically unencumbered Grignard reagents (e.g.,
n-hexyl, n-Bn), which follows the same profile as the earlier
single-step study.12 This may be due to increased aggregation in
these reagents.14
In order to further explore the scope of the one-pot synthesis
of sulfinamides, a range of aldehydes was explored as the fourth
component, while using isopropylmagnesium chloride as the
fifth component of the one-pot reaction (Table 2). Once again,
Table 2. One-Pot Synthesis of Isopropyl-S-
mesitylsulfinamides
Table 3. Asymmetric One-Pot Synthesis of Chiral Amines
entry
R′
3
yield (%)
dr
a
yield
(%)
ee
1
Ph
3a
3b
3c
3d
3e
3f
43
48
33
45
38
40
48
44
40
36
34
>99:1
>99:1
>99:1
98:2
entry
R
R′MgX
4
(%)
2
4-MeOPh
mesityl
4-ClPh
1
Ph
EtMgCl
nPrMgCl
iPrMgCl
iBuMgCl
allylMgBr
BnMgCl
iPrMgCl
iPrMgCl
iPrMgCl
iPrMgCl
iPrMgCl
4a
4b
4c
4d
4e
4f
60
53
59
57
52
58
49
54
42
47
53
84
88
97
89
86
64
88
96
94
97
80
3
2
Ph
4
3
Ph
5
6-MeO-naphthalen-2-yl
1-Boc-1H-indol-3-yl
2-furanyl
>99:1
99:1
4
Ph
6
5
Ph
7
3g
3h
3i
97:3
6
Ph
8
1-benzofuran-2-yl
5-bromo-2-thienyl
1,3-thiazol-5-yl
Ph(CC)-
97:3
7
2-furanyl
4-MeOPh
4-ClPh
4g
4h
4i
9
98:2
8
10
11
3j
90:10
94:6
9
3k
10
11
6-MeO-naphthalen-2-yl
1-benzo-furan-2-yl
4j
4k
we were pleased to note the generality of the reaction, with
mesityl sulfinamides being produced in good yields (for a four-
step sequence) and excellent diastereoselectivities. Notably
entry 11 using the aldehyde 3-phenyl-2-propynal gave much-
improved diastereoselectivity from a 50:50 dr in the single
a
Enantiomeric excesses were determined by chiral HPLC of the
corresponding benzamides.
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filtered through a frit, and extracted a further two times with DCM.
The combined organic phase was dried using a hydrophobic frit, and
the solvent was evaporated to give the crude sulfinamide, which was
purified by flash chromatography.
The procedure was successful with a range of Grignard and
aldehyde components, giving amine hydrochlorides in very
good yields (over five steps, equivalent to 84−90% per step)
and excellent enantioselectivities, with no column chromatog-
raphy required. The yields of the one-pot reaction to the
amines were improved over the yields of the one-pot reaction
to the sulfinamides, even with the additional sulfinyl removal
step, probably due to the simplicity of the workup with no
column chromatography needed. 2-Methyltetrahydrofuran,
which is a green solvent, was used in this one-pot reaction,
and no chlorinated solvents were used in the workup, so this
protocol has a high degree of sustainability. As before we
observed that the allyl example (entry 5) gave the R
enantiome,r whereas all the others gave the opposite, S
enantiomer. It was found necessary to introduce an aqueous
ammonium chloride wash during the workup before the acidic
sulfinyl cleavage to ensure the removal of any racemic amine
that could have formed from the reaction of excess aldehyde,
LiHMDS, and Grignard reagent, which would result in the
reduction of enantiomeric excess of the final product if not
removed.
General Procedure B: Five-Step One-Pot Reaction to Amine
Hydrochlorides. Mesitylmagnesium bromide (1 M in diethyl ether)
(0.427 mL, 0.427 mmol) was added dropwise to a solution of (4S)-3-
[(4-methylphenyl)sulfonyl]-4-(phenylmethyl)-1,2,3-oxathiazolidine 2-
oxide (1) (0.15 g, 0.427 mmol) in dry MeTHF (1.5 mL) at −78 °C
and stirred for 20−40 min. Lithium hexamethyldisilazide (1 M in
toluene) (0.854 mL, 0.854 mmol) was added to the reaction mixture
at −78 °C, then the dry ice bath was removed, and the reaction
mixture was allowed to warm to room temperature (20 °C) and stirred
for 5−5.6 h. The aldehyde (0.854 mmol) was added to the reaction
mixture, and it was stirred overnight (17 h) at room temperature. The
reaction mixture was cooled to −78 °C, a Grignard solution (3.41
mmol) was added slowly, and the mixture was left to stir for 5−6.3 h
while warming to 0−5 °C. The cooled reaction mixture (0 °C) was
quenched with saturated sodium bicarbonate solution and diethyl
ether, filtered through a frit, and extracted a further two times with
diethyl ether. The combined organic phase was washed twice with
ammonium chloride solution, then with water, then 2 M HCl in
diethyl ether (0.50 mL, 1.00 mmol) was added, and the mixture was
left for 10 min. Next, 2 M HCl (aq) (6 mL) was added, the aqueous
layer was separated and extracted with diethyl ether, and then the
combined organic phase was discarded. The acidic aqueous layer was
basified (to pH 12) with solid sodium hydroxide and then extracted
twice with diethyl ether. The combined organic phase was dried using
a hydrophobic frit, then 2 M HCl in diethyl ether (0.50 mL, 1.00
mmol) was added, and after 5 min the solvent was evaporated to give
the product, which where required was further purified by trituration
with diethyl ether.
CONCLUSION
■
In conclusion, we have developed a one-pot five-component
reaction capable of producing chiral amine hydrochlorides in
high yields and high enantioselectivities from the simple
template 1 (itself available in just two steps from phenylalaninol
in >90% yield)11a and cheap commodity chemicals, under green
conditions with no column chomatography, that is applicable to
carry out in an array format.
( S ) - 2 , 4 , 6 - T r i m e t h y l - N - ( ( S ) - 1 - p h e n y l p r o p y l ) -
benzenesulfinamide (2a). General procedure A was followed using
benzaldehyde (0.087 mL, 0.854 mmol) and ethylmagnesium chloride
(2 M in diethyl ether) (1.707 mL, 3.41 mmol). Purification by flash
chromatography on silica gel (elution with 0−50% ethyl acetate/
cyclohexane) gave the title compound (59 mg, 0.195 mmol, 46%) as a
pale yellow oil. Diastereomeric ratio: 92.8:7.2, determined by HPLC
[Chiralcel OJ (heptane/ethanol 95:5, flow rate 1.0 mL/min, λ = 215
nm, retention time: 12.441 min (R,SS, minor), 14.773 min (S,SS,
EXPERIMENTAL SECTION
■
General Information. All reactions were carried out under an
environment of nitrogen. Dry solvents were purchased from
commercial suppliers. Unless otherwise noted, all reagents and
solvents were obtained commercially and used without further
purification. All reactions were stirred with a magnetic stirrer bar.
Chemical shifts are quoted with the deuterated solvent as the
reference. Data for 1H NMR are recorded as follows: chemical shift (δ,
ppm), multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, oct
= octet, m = multiplet or unresolved, coupling constant(s) in Hz,
integration). Melting points are uncorrected. The diastereomeric ratios
(dr’s) of the mesityl sulfinamides were determined by chiral HPLC
analysis in comparison with the authentic racemates (containing the
major)]; [α]20 +192 (c 1.0, CHCl3); IR (ATR) 3213, 2964, 2928,
D
1602, 1453, 1378, 1071, 1047; 1H NMR (acetone-d6, 400 MHz) major
diastereomer δ 7.16−7.34 (m, 5 H), 6.82 (s, 2 H), 5.69 (d, J = 6.5 Hz,
1 H), 4.29 (q, J = 7.1 Hz, 1 H), 2.50 (s, 6 H), 2.23 (s, 3 H), 1.92−2.03
(m, 1 H), 1.74−1.87 (m, 1 H), 0.87 ppm (t, J = 7.3 Hz, 3 H); minor
diastereoisomer δ 7.16−7.42 (m, 5 H), 6.85 (s, 2 H), 5.56 (d, J = 4.0
Hz, 1 H), 4.25−4.34 (m, 1 H), 2.42 (s, 6 H), 2.25 (s, 3 H), 1.92−2.03
(m, 1 H), 1.74−1.87 (m, 1 H), 0.83−0.90 ppm (m, 3 H); 13C NMR
(acetone-d6, 101 MHz) major diastereomer δ 144.6, 140.7, 139.5,
137.5, 131.4, 129.0, 127.8, 127.8, 62.1, 31.3, 21.0, 19.7, 11.3 ppm; m/z
(ES+) 324 ([M + Na]+, 100%), 302 ([M + H]+, 16), 237 (8), 167 (9);
HRMS found, 324.1386 C18H23NONaS 324.1398.
1
four diastereomers) and confirmed by the H NMR spectra of the
purified product in acetone-d6. The only exception to this was for the
mesityl sulfinamides prepared by hydride reduction of the mesityl
sulfinyl ketimine, for which the dr’s were determined from the crude
1H NMR spectra. The enantiomeric excesses of the amine hydro-
( S ) - 2 , 4 , 6 - T r i m e t h y l - N - ( ( S ) - 1 - p h e n y l b u t y l ) -
benzenesulfinamide (2b). General procedure A was followed using
benzaldehyde (0.087 mL, 0.854 mmol) and n-propylmagnesium
chloride (2 M in diethyl ether) (1.707 mL, 3.41 mmol). Purification
by flash chromatography on silica gel (elution with 0−50% ethyl
acetate/cyclohexane) gave the title compound (62 mg, 0.196 mmol,
46%) as a pale yellow oil. Diastereomeric ratio: 95.2:4.8, determined
by HPLC [Chiralcel OJ (heptane/ethanol 98:2, flow rate 1.0 mL/min,
λ = 215 nm, retention time: 10.839 (S,SS, major), 12.862 (R,SS,
chlorides were determined by chiral HPLC analysis of the benzoyl
protected amines in comparison with the authentic racemates
General Procedure A: Four-Step One-Pot Reaction to Sulfina-
mides. Mesitylmagnesium bromide (1 M in diethyl ether) (0.427 mL,
0.427 mmol) was added dropwise to a solution of (4S)-3-[(4-
methylphenyl)sulfonyl]-4-(phenylmethyl)-1,2,3-oxathiazolidine 2-
oxide (1) (0.15 g, 0.427 mmol) in dry 2-MeTHF (1.5 mL) at −78
°C and stirred for 20−45 min. Lithium hexamethyldisilazide (1 M in
toluene) (0.854 mL, 0.854 mmol) was added to the reaction mixture
at −78 °C, then the dry ice bath was removed, and the reaction
mixture was allowed to warm to room temperature (20 °C) and stirred
for 2.6−5.6 h. The aldehyde (0.854 mmol) was added to the reaction
mixture, and it was stirred overnight (16−18 h) at room temperature.
The reaction mixture was cooled to −78 °C, a Grignard solution (3.41
mmol) was added slowly, and the mixture was left to stir for 3.3−8 h
while warming to −10−20 °C. The cooled reaction mixture (0 °C)
was quenched with saturated sodium bicarbonate solution and DCM,
minor)]; [α]20 +188 (c 1.0, CHCl3); IR (ATR) 3213, 2958, 2929,
D
2870, 1602, 1454, 1378, 1070, 1047; 1H NMR (acetone-d6, 400 MHz)
major diastereomer δ 7.16−7.34 (m, 5 H), 6.81 (s, 2 H), 5.70 (d, J =
6.8 Hz, 1 H), 4.38 (q, J = 7.1 Hz, 1 H), 2.50 (s, 6 H), 2.23 (s, 3 H),
1.88−2.00 (m, 1 H), 1.69−1.81 (m, 1 H), 1.20−1.45 (m, 2 H), 0.90
ppm (t, J = 7.4 Hz, 3 H); minor diastereomer δ 7.16−7.43 (m, 5 H),
6.84 (s, 2 H), 5.54 (d, J = 4.3 Hz, 1 H), 4.34−4.44 (m, 1 H), 2.42 (s, 6
H), 2.25 (s, 3 H), 1.88−2.00 (m, 1 H), 1.69−1.81 (m, 1 H), 1.20−1.45
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(m, 2 H), 0.87 ppm (t, J = 7.6 Hz, 3 H); 13C NMR (acetone-d6, 101
MHz) major diastereoisomer δ 144.9, 140.7, 139.6, 137.5, 131.4,
129.0, 127.7, 127.7, 60.3, 40.7, 21.0, 20.3, 19.7, 14.2 ppm; m/z (ES+)
338 ([M + Na]+, 100%), 316 ([M + H]+, 8), 167 (10); HRMS found,
338.1544 C19H25NONaS 338.1555.
140.7, 139.5, 137.5, 131.3, 129.0, 127.7, 127.7, 60.6, 38.5, 32.6, 29.8,
27.1, 23.3, 21.0, 19.7, 14.4 ppm; m/z (ES+) 380 ([M + Na]+, 100%),
341 (12), 192 (7), 166 (6); HRMS found, 380.2024 C22H31NONaS
380.2024.
(S)-N-((S)-Cyclohexyl(phenyl)methyl)-2,4,6-trimethylbenze-
nesulfinamide (2f). General procedure A was followed using
benzaldehyde (0.087 mL, 0.854 mmol) and cyclohexylmagnesium
chloride (2 M in diethyl ether) (1.707 mL, 3.41 mmol). Purification by
flash chromatography on silica gel (elution with 0−50% ethyl acetate/
cyclohexane) gave impure product that was further purified by flash
chromatography on silica gel (elution with 0−25% ethyl acetate/
DCM) to give the title compound (59 mg, 0.166 mol, 39%) as a cream
solid. Mp 119−121 °C; diastereomeric ratio: 99.7:0.3, determined by
HPLC [Whelk-o 1 (heptane/ethanol 95:5, flow rate 1.0 mL/min, λ =
215 nm, retention time: 15.118 min (R,SS, minor), 21.620 min (S,SS,
(S)-2,4,6-Trimethyl-N-((S)-2-methyl-1-phenylpropyl)-
benzenesulfinamide (2c). General procedure A was followed using
benzaldehyde (0.087 mL, 0.854 mmol) and isopropylmagnesium
chloride (2 M in diethyl ether) (1.707 mL, 3.41 mmol). Purification by
flash chromatography on silica gel (elution with 0−50% ethyl acetate/
cyclohexane) gave impure product that was further purified by flash
chromatography on silica gel (elution with 0−25% ethyl acetate/
DCM) to give the title compound (58 mg, 0.184 mmol, 43%) as a white
solid. Mp 99−101 °C; diastereomeric ratio: 99.2:0.8, determined by
HPLC [Chiralcel OJ (heptane/ethanol 90:10, flow rate 1.0 mL/min, λ
= 215 nm, retention time: 7.475 min (S,SS, major), 10.460 min (R,SS,
major)]; [α]21 +173 (c 1.0, CHCl3); IR (ATR) 3272, 2934, 2853,
D
minor)]; [α]20 +208 (c 1.0, CHCl3); IR (ATR) 3257, 2949, 2920,
1600, 1448, 1421, 1070, 1047; 1H NMR (acetone-d6, 400 MHz) major
diastereomer δ 7.14−7.29 (m, 5 H), 6.78 (s, 2 H), 5.78 (d, J = 8.6 Hz,
1 H), 4.07 (t, J = 8.3 Hz, 1 H), 2.46 (s, 6 H), 2.22 (s, 3 H), 1.98−2.07
(m, 1 H), 1.54−1.77 (m, 4 H), 1.33−1.43 (m, 1 H), 0.81−1.24 ppm
(m, 5 H); 13C NMR (acetone-d6, 101 MHz) major diastereomer δ
144.0, 140.6, 139.7, 137.4, 131.3, 128.8, 128.1, 127.5, 66.5, 44.7, 30.9,
30.9, 27.2, 26.9, 26.8, 21.0, 19.7 ppm; m/z (ES+) 378 ([M + Na]+,
100%), 356 ([M + H]+, 9), 339 (15), 190 (7); HRMS found, 378.1857
C22H29NONaS 378.1868.
D
2865, 1602, 1456, 1383, 1064, 1045; 1H NMR (acetone-d6, 400 MHz)
major diastereomer δ 7.15−7.31 (m, 5 H), 6.79 (s, 2 H), 5.79 (d, J =
8.3 Hz, 1 H), 4.07 (t, J = 7.9 Hz, 1 H), 2.47 (s, 6 H), 2.22 (s, 3 H),
2.01−2.12 (m, 1 H), 0.99 (d, J = 6.5 Hz, 3 H), 0.77 ppm (d, J = 6.8
Hz, 3 H); 13C NMR (acetone-d6, 101 MHz) major diastereomer δ
143.9, 140.6, 139.6, 137.4, 131.3, 128.7, 128.1, 127.5, 67.2, 35.1, 21.0,
20.0, 20.0, 19.7 ppm; m/z (ES+) 338 ([M + Na]+, 100%), 316 ([M +
H]+, 11), 299 (5), 167 (9); HRMS found, 338.1546 C19H25NONaS
338.1555.
(S)-2,4,6-Trimethyl-N-((R)-1-phenylbut-3-en-1-yl)-
benzenesulfinamide (2g). General procedure A was followed using
benzaldehyde (0.087 mL, 0.854 mmol) and allylmagnesium bromide
(1 M in diethyl ether) (3.41 mL, 3.41 mmol). Purification by flash
chromatography on silica gel (elution with 0−25% ethyl acetate/
cyclohexane) gave impure product that was further purified by flash
chromatography on silica gel (elution with 0−13% ethyl acetate/
DCM) to give the title compound (48 mg, 0.153 mmol, 36%) as a
colorless oil. Diastereomeric ratio: 94.8:5.2, determined by HPLC
[Chiralcel OJ (heptane/ethanol 98:2, flow rate 1.0 mL/min, λ = 215
nm, retention time: 10.658 min (R,SS, major), 16.579 min (S,SS,
(S)-2,4,6-Trimethyl-N-((S)-3-methyl-1-phenylbutyl)-
benzenesulfinamide (2d). General procedure A was followed using
benzaldehyde (0.087 mL, 0.854 mmol) and isobutylmagnesium
chloride (2 M in diethyl ether) (1.707 mL, 3.41 mmol). Purification
by flash chromatography on silica gel (elution with 0−50% ethyl
acetate/cyclohexane) gave the title compound (62 mg, 0.189 mmol,
44%) as a pale yellow oil. Diastereomeric ratio: 93.9:6.1, determined
by HPLC [Chiralpak IA (heptane/ethanol 95:5, flow rate 1.0 mL/min,
λ = 215 nm, retention time: 7.406 min (S,SS, major), 8.744 min (R,SS,
minor)]; [α]20 +187 (c 1.0, CHCl3); IR (ATR) 3212, 2955, 2926,
D
2868, 1602, 1454, 1382, 1070, 1048; 1H NMR (acetone-d6, 400 MHz)
major diastereomer δ 7.15−7.34 (m, 5 H), 6.80 (s, 2 H), 5.73 (d, J =
7.3 Hz, 1 H), 4.46 (q, J = 7.4 Hz, 1 H), 2.50 (s, 6 H), 2.22 (s, 3 H),
1.78−1.90 (m, 1 H), 1.55−1.67 (m, 2 H), 0.95 (d, J = 6.3 Hz, 3 H),
0.90 ppm (d, J = 6.5 Hz, 3 H); minor diastereomer δ 7.15−7.44 (m, 5
H), 6.84 (s, 2 H), 5.54 (d, J = 4.8 Hz, 1 H), 4.40−4.51 (m, 1 H), 2.41
(s, 6 H), 2.25 (s, 3 H), 1.71−1.90 (m, 1 H), 1.52−1.69 (m, 2 H),
0.92−0.96 (m, 3 H), 0.87 ppm (d, J = 6.3 Hz, 3 H); 13C NMR
(acetone-d6, 101 MHz) major diastereomer δ 145.3, 140.7, 139.7,
137.5, 131.4, 129.0, 127.7, 127.6, 58.8, 48.1, 25.6, 23.0, 22.7, 21.0, 19.7
ppm; m/z (ES+) 352 ([M + Na]+, 100%), 330 ([M + H]+, 12), 313
(12), 167 (12), 164 (13); HRMS found, 352.1699 C20H27NONaS
352.1711.
minor)]; [α]20 +150 (c 1.0, CHCl3); IR (ATR) 3212, 3029, 2922,
D
1601, 1454, 1380, 1071, 1048; 1H NMR (acetone-d6, 400 MHz) major
diastereomer δ 7.43 (d, J = 7.1 Hz, 2 H), 7.36 (t, J = 7.4 Hz, 2 H),
7.24−7.31 (m, 1 H), 6.87 (s, 2 H), 5.77 (ddt, J = 17.2, 10.2, 7.0 Hz, 1
H), 5.40 (d, J = 3.6 Hz, 1 H), 5.02−5.14 (m, 2 H), 4.50 (td, J = 7.0, 3.6
Hz, 1 H), 2.59 (t, J = 7.0 Hz, 2 H), 2.43 (s, 6 H), 2.25 ppm (s, 3 H);
minor diastereomer δ 7.16−7.46 (m, 5 H), 6.82 (s, 2 H), 5.69−5.83
(m, 2 H), 4.95−5.03 (m, 2 H), 4.43−4.53 (m, 1 H), 2.56−2.63 (m, 2
H), 2.50 (s, 6 H), 2.23 ppm (s, 3 H); 13C NMR (acetone-d6, 101
MHz) major diastereomer δ 143.3, 141.1, 139.7, 137.6, 135.9, 131.5,
129.2, 128.5, 128.4, 118.5, 58.8, 43.5, 21.0, 19.4 ppm; m/z (ES+) 336
([M + Na]+, 93%), 314 (100), 287 (53), 261 (39), 217 (27); HRMS
found, 314.1569 C19H24NOS 314.1579.
( S ) - 2 , 4 , 6 - T r i m e t h y l - N - ( ( S ) - 1 - p h e n y l h e p t y l ) -
benzenesulfinamide (2e). General procedure A was followed using
benzaldehyde (0.087 mL, 0.854 mmol) and hexylmagnesium bromide
(2 M in diethyl ether) (1.707 mL, 3.41 mmol). Purification by flash
chromatography on silica gel (elution with 0−50% ethyl acetate/
cyclohexane) gave impure product which was further purified by flash
chromatography on silica gel (elution with 0−25% ethyl acetate/
DCM) to give the title compound (52 mg, 0.145 mmol, 34%) as a pale
yellow solid. Mp 45−47 °C; diastereomeric ratio: 85.6:14.4,
determined by HPLC [Chiralpak IA (heptane/ethanol 98:2, flow
rate 1.0 mL/min, λ = 215 nm, retention time: 13.222 min (S,SS,
(S)-N-((S)-1,2-Diphenylethyl)-2,4,6-trimethylbenzenesulfina-
mide (2h). General procedure A was followed using benzaldehyde
(0.087 mL, 0.854 mmol) and benzylmagnesium chloride (1 M in
diethyl ether) (3.41 mL, 3.41 mmol). Purification by flash
chromatography on silica gel (elution with 0−25% ethyl acetate/
cyclohexane) gave impure product that was further purified by flash
chromatography on silica gel (elution with 0−13% ethyl acetate/
DCM) to give the title compound (90 mg, 0.248 mmol, 58%) as a
cream solid. Mp 113−116 °C; diastereomeric ratio: 84.0:16.0,
determined by HPLC [Chiralcel OD-H (heptane/ethanol 98:2, flow
rate 1.0 mL/min, λ = 215 nm, retention time: 9.904 min (R,SS, minor),
major), 16.900 min (R,SS, minor)]; [α]20 +167 (c 1.0, CHCl3); IR
14.684 min (S,SS, major)]; [α]20 +176 (c 1.0, CHCl3); IR (ATR)
D
D
1
(ATR) 3209, 2926, 2856, 1602, 1454, 1378, 1071, 1048; H NMR
3257, 3028, 2926, 1602, 1495, 1454, 1410, 1066, 1045; 1H NMR
(acetone-d6, 400 MHz) major diastereomer δ 7.08−7.48 (m, 10 H),
6.77 (s, 2 H), 5.79 (d, J = 7.1 Hz, 1 H), 4.65 (q, J = 7.3 Hz, 1 H), 3.21
(dd, J = 13.6, 8.1 Hz, 1 H), 3.10 (dd, J = 13.6, 6.4 Hz, 1 H), 2.32 (s, 6
H), 2.22 ppm (s, 3 H); minor diastereomer δ 7.08−7.48 (m, 10 H),
6.83 (s, 2 H), 5.20−5.29 (m, 1 H), 4.69−4.75 (m, 1 H), 3.00−3.26
(m, 2 H), 2.27 (s, 6 H), 2.24 ppm (s, 3 H); 13C NMR (acetone-d6, 101
MHz) major diastereomer δ 144.3, 140.7, 139.7, 139.7, 137.5, 131.2,
130.4, 129.0, 129.0, 128.0, 127.9, 127.1, 62.8, 45.1, 21.0, 19.5 ppm; m/
(acetone-d6, 400 MHz) major diastereomer δ 7.15−7.35 (m, 5 H),
6.81 (s, 2 H), 5.76 (d, J = 7.1 Hz, 1 H), 4.37 (q, J = 7.1 Hz, 1 H), 2.50
(s, 6 H), 2.23 (s, 3 H), 1.88−2.02 (m, 1 H), 1.71−1.87 (m, 1 H),
1.14−1.44 (m, 8 H), 0.85 ppm (t, J = 6.9 Hz, 3 H); minor
diastereomer δ 7.15−7.44 (m, 5 H), 6.85 (s, 2 H), 5.61 (d, J = 3.8 Hz,
1 H), 4.32−4.43 (m, 1 H), 2.42 (s, 6 H), 2.25 (s, 3 H), 1.88−2.02 (m,
1 H), 1.71−1.87 (m, 1 H), 1.14−1.44 (m, 8 H), 0.81−0.90 ppm (m, 3
H); 13C NMR (acetone-d6, 101 MHz) major diastereomer δ 144.9,
9455
dx.doi.org/10.1021/jo201849j|J. Org. Chem. 2011, 76, 9452−9459

The Journal of Organic Chemistry
Article
z (ES+) 386 ([M + Na]+, 100%), 364 ([M + H]+, 19); HRMS found,
386.1544 C23H25NNaOS 386.1549.
19.9, 19.7 ppm; m/z (ES+) 372 ([M + Na]+, 100%), 350 ([M + H]+,
10), 151 (12); HRMS found, 372.1176 C19H24NONaSCl 372.1165.
(S)-N-((S)-1-(6-Methoxynaphthalen-2-yl)-2-methylpropyl)-
2,4,6-trimethylbenzenesulfinamide (3e). General procedure A
was followed using 6-methoxy-2-naphthalenecarbaldehyde (0.159 g,
0.854 mmol) and isopropylmagnesium chloride (2 M in diethyl ether)
(1.707 mL, 3.41 mmol). Purification by flash chromatography on silica
gel (elution with 0−50% ethyl acetate/cyclohexane) gave impure
product that was further purified by flash chromatography on silica gel
(elution with 0−25% ethyl acetate/DCM) to give the title compound
(64 mg, 0.162 mmol, 38%) as a cream solid. Mp 143−145 °C;
diastereomeric ratio: 99.3:0.7, determined by HPLC [Chiralpak IA
(heptane/ethanol 95:5, flow rate 1.0 mL/min, λ = 215 nm, retention
(S)-N-((S)-1-(4-Methoxyphenyl)-2-methylpropyl)-2,4,6-trime-
thylbenzenesulfinamide (3b). General procedure A was followed
using 4-methoxybenzaldehyde (0.104 mL, 0.854 mmol) and
isopropylmagnesium chloride (2 M in diethyl ether) (1.707 mL,
3.41 mmol). Purification by flash chromatography on silica gel (elution
with 0−50% ethyl acetate/cyclohexane) gave the title compound (71
mg, 0.205 mmol, 48%) as a cream solid. Mp 108−110 °C;
diastereomeric ratio: 99.3:0.7, determined by HPLC [Chiralpak AD
(heptane/ethanol 95:5, flow rate 1.0 mL/min, λ = 215 nm, retention
time: 9.470 min (R,SS, minor), 10.818 min (S,SS, major)]; [α]21D +197
(c 1.0, CHCl3); IR (ATR) 3236, 2949, 2917, 2866, 1614, 1517, 1460,
1383, 1252, 1181, 1064, 1024; 1H NMR (acetone-d6, 400 MHz) major
diastereomer δ 7.20 (d, J = 8.8 Hz, 2 H), 6.81 (d, J = 8.8 Hz, 2 H),
6.80 (s, 2 H), 5.67 (d, J = 7.8 Hz, 1 H), 4.02 (t, J = 7.8 Hz, 1 H), 3.76
(s, 3 H), 2.47 (s, 6 H), 2.23 (s, 3 H), 2.05 (dqq, J = 7.8, 6.8, 6.8 Hz, 1
H), 0.98 (d, J = 6.8 Hz, 3 H), 0.76 ppm (d, J = 6.8 Hz, 3 H); 13C
NMR (acetone-d6, 101 MHz) δ 159.5, 140.6, 139.7, 137.4, 135.8,
131.3, 129.2, 114.1, 66.6, 55.5, 35.0, 21.0, 20.1, 19.9, 19.7 ppm; m/z
(ES+) 368 ([M + Na]+, 100%), 346 ([M + H]+, 8), 329 (13), 163
(15); HRMS found, 368.1646 C20H27NO2NaS 368.1660.
time: 13.404 min (S,SS, major), 14.460 min (R,SS, minor)]; [α]21
D
+167 (c 1.0, CHCl3); IR (ATR) 3266, 2949, 2920, 2864, 1606, 1487,
1
1462, 1382, 1272, 1229, 1173, 1069, 1048; H NMR (acetone-d6, 400
MHz) major diastereomer δ 7.70 (d, J = 8.5 Hz, 1 H), 7.68 (d, J = 8.9
Hz, 1 H), 7.55 (d, J = 1.6 Hz, 1 H), 7.46 (dd, J = 8.5, 1.6 Hz, 1 H),
7.24 (d, J = 2.4 Hz, 1 H), 7.11 (dd, J = 8.9, 2.4 Hz, 1 H), 6.74 (s, 2 H),
5.86 (d, J = 8.1 Hz, 1 H), 4.19 (t, J = 8.1 Hz, 1 H), 3.90 (s, 3 H), 2.46
(s, 6 H), 2.17 (s, 3 H), 2.16 (dqq, J = 8.1, 6.8, 6.8 Hz, 1 H), 1.05 (d, J
= 6.8 Hz, 3 H), 0.79 ppm (d, J = 6.8 Hz, 3 H); 13C NMR (acetone-d6,
101 MHz) major diastereomer δ 158.5, 140.6, 139.4, 139.0, 137.5,
134.8, 131.3, 130.1, 129.6, 127.4, 126.8, 126.8, 119.5, 106.5, 67.1, 55.6,
34.9, 20.9, 20.1, 19.7 ppm; m/z (ES+) 418 ([M + Na]+, 100%), 396
([M + H]+, 11), 380 (34); HRMS found, 418.1810 C24H29NO2NaS
418.1817.
(S)-N-((S)-1-Mesityl-2-methylpropyl)-2,4,6-trimethylbenze-
nesulfinamide (3c). General procedure A was followed using
mesitaldehyde (0.126 mL, 0.854 mmol) (and magnesium sulfate
(0.205 g, 1.707 mmol) was also added with the aldehyde and it was
stirred for 41 h) isopropylmagnesium chloride (2 M in diethyl ether)
(1.707 mL, 3.41 mmol). Purification by flash chromatography on silica
gel (elution with 0−50% ethyl acetate/cyclohexane) gave impure
product, which was dissolved in THF (2 mL). TBAF (1 M in THF)
(0.2 mL) was added and stirred for 20 min (to deprotect the TMS
group from the impurity) and then evaporated. Further purification by
flash chromatography on silica gel (elution with 0−50% ethyl acetate/
cyclohexane) gave the title compound (51 mg, 0.141 mmol, 33%) as a
white solid. Mp 123−125 °C; diastereomeric ratio: 99.3:0.7,
determined by HPLC [Chiralpak IA (heptane/ethanol 95:5, flow
rate 1.0 mL/min, λ = 215 nm, retention time: 4.877 min (R,SS, minor),
t e r t - B u t y l 3 - ( ( S ) - 2 - M e t h y l - 1 - ( ( S ) - 2 , 4 , 6 -
trimethylphenylsulfinamido)propyl)-1H-indole-1-carboxylate
(3f). General procedure A was followed using 1,1-dimethylethyl 3-
formyl-1H-indole-1-carboxylate (0.209 g, 0.854 mmol) and isopro-
pylmagnesium chloride (2 M in diethyl ether) (1.707 mL, 3.41 mmol).
Purification by flash chromatography on silica gel (elution with 0−25%
ethyl acetate/cyclohexane) gave impure product that was further
purified by flash chromatography on silica gel (elution with 5−15%
ethyl acetate/DCM) to give the title compound (77 mg, 0.170 mmol,
40%) as a pale yellow oil. Diastereomeric ratio: 98.8:1.2, determined
by HPLC [Chiralpak IC (heptane/ethanol 95:5, flow rate 1.0 mL/min,
λ = 215 nm, retention time: 12.231 min (R,SS, minor), 13.290 min
8.158 min (S,SS, major)]; [α]21 +251 (c 1.0, CHCl3); IR (ATR)
D
1
3252, 2959, 2865, 1605, 1464, 1378, 1071, 1050; H NMR (acetone-
d6, 400 MHz) major diastereomer δ 6.85 (s, 2 H), 6.80 (s, 1 H), 6.79
(s, 1 H), 5.24 (d, J = 7.9 Hz, 1 H), 4.40 (dd, J = 10.4, 7.9 Hz, 1 H),
2.47 (s, 6 H), 2.43 (s, 3 H), 2.34 (s, 3 H), 2.25 (s, 3 H), 2.23−2.37 (m,
1 H), 2.20 (s, 3 H), 1.17 (d, J = 6.5 Hz, 3 H), 0.67 ppm (d, J = 6.8 Hz,
3 H); 13C NMR (acetone-d6, 101 MHz) major diastereomer δ 140.9,
140.5, 137.3, 137.3, 137.2, 137.2, 137.1, 136.7, 136.0, 131.9, 131.4,
130.0, 64.2, 33.8, 21.9, 21.8, 21.6, 21.0, 20.9, 20.1, 19.6 ppm; m/z (ES
+) 380 ([M + Na]+, 100%), 358 ([M + H]+, 12), 341 (5); HRMS
found, 380.2017 C22H31NONaS 380.2024.
(S,SS, major)]; [α]21 +139 (c 1.0, CHCl3); IR (ATR) 3218, 2972,
D
1
2929, 1730, 1603, 1453, 1370, 1247, 1156, 1073; H NMR (acetone-
d6, 400 MHz) major diastereomer δ 8.11 (d, J = 7.8 Hz, 1 H), 7.72 (d,
J = 8.0 Hz, 1 H), 7.56 (s, 1 H), 7.29 (dd, J = 7.8, 7.3 Hz, 1 H), 7.20
(dd, J = 8.0, 7.3 Hz, 1 H), 6.73 (s, 2 H), 5.78 (d, J = 7.6 Hz, 1 H), 4.50
(dd, J = 7.6, 6.8 Hz, 1 H), 2.47 (s, 6 H), 2.24−2.38 (dqq, J = 6.8, 6.8,
6.5 Hz, 1 H), 2.19 (s, 3 H), 1.68 (s, 9 H), 1.02 (d, J = 6.8 Hz, 3 H),
0.96 ppm (d, J = 6.5 Hz, 3 H); 13C NMR (acetone-d6, 101 MHz) δ
150.3, 140.6, 139.2, 137.6, 136.5, 131.3, 130.3, 125.0, 124.5, 123.2,
120.7, 120.5, 115.9, 84.2, 58.6, 34.1, 28.4, 21.0, 20.2, 19.7, 19.6 ppm;
m/z (ES+) 477 ([M + Na]+, 100%), 455 ([M + H]+, 29), 421 (15);
HRMS found, 477.2184 C26H34N2O3NaS 477.2182.
(S)-N-((S)-1-(4-Chlorophenyl)-2-methylpropyl)-2,4,6-trime-
thylbenzenesulfinamide (3d). General procedure A was followed
using 4-chlorobenzaldehyde (0.120 g, 0.854 mmol) and isopropyl-
magnesium chloride (2 M in diethyl ether) (1.707 mL, 3.41 mmol).
Purification by flash chromatography on silica gel (elution with 0−50%
ethyl acetate/cyclohexane) gave impure product that was further
purified by flash chromatography on silica gel (elution with 0−25%
methanol/DCM) to give the title compound (68 mg, 0.193 mmol,
45%) as a pale yellow oil. Mp 111−113 °C; diastereomeric ratio:
97.6:2.4, determined by HPLC [Chiralpak IA (heptane/ethanol 95:5,
flow rate 1.0 mL/min, λ = 215 nm, retention time: 9.254 min (S,SS,
(S)-N-((S)-1-(Furan-2-yl)-2-methylpropyl)-2,4,6-trimethyl-
benzenesulfinamide (3g). General procedure A was followed using
furfural (0.071 mL, 0.854 mmol) and isopropylmagnesium chloride (2
M in diethyl ether) (1.707 mL, 3.41 mmol). Purification by flash
chromatography on silica gel (elution with 0−50% ethyl acetate/
cyclohexane) gave impure product that was further purified by flash
chromatography on silica gel (elution with 0−25% ethyl acetate/
DCM) to give the title compound (63 mg, 0.206 mmol, 48%) as a pale
yellow solid. Mp 70−73 °C; diastereomeric ratio: 97.3:2.7, determined
by HPLC [Chiralpak AD (heptane/isopropanol 95:5, flow rate 1.0
mL/min, λ = 215 nm, retention time: 11.686 min (R,SS, minor),
major), 11.965 min (R,SS, minor)]; [α]21 +170 (c 1.0, CHCl3); IR
D
(ATR) 3188, 2965, 2927, 2868, 1599, 1493, 1441, 1381, 1064, 1044;
1H NMR (acetone-d6, 400 MHz) major diastereomer δ 7.29 (d, J = 8.7
Hz, 2 H), 7.25 (d, J = 8.7 Hz, 2 H), 6.78 (s, 2 H), 5.88 (d, J = 8.3 Hz, 1
H), 4.10 (t, J = 7.9 Hz, 1 H), 2.46 (s, 6 H), 2.22 (s, 3 H), 1.96−2.08
(m, 1 H), 0.98 (d, J = 6.8 Hz, 3 H), 0.77 ppm (d, J = 6.8 Hz, 3 H);
minor diastereomer δ 7.33−7.42 (m, 4 H), 6.85 (s, 2 H), 5.65 (d, J =
5.3 Hz, 1 H), 4.16 (dd, J = 6.9, 5.3 Hz, 1 H), 2.41 (s, 6 H), 2.25 (s, 3
H), 1.97−2.08 (m, 1 H), 0.95−1.02 (m, 3 H), 0.74−0.80 ppm (m, 3
H); 13C NMR (acetone-d6, 101 MHz) major diastereomer δ 143.1,
140.7, 139.3, 137.5, 132.7, 131.3, 129.9, 128.7, 66.2, 35.1, 20.9, 20.0,
13.877 min (S,SS, major)]; [α]21 +197 (c 1.0, CHCl3); IR (ATR)
D
3198, 2952, 2925, 2865, 1602, 1441, 1380, 1068, 1047; 1H NMR
(acetone-d6, 400 MHz) major diastereomer δ 7.44 (d, J = 1.5 Hz, 1
H), 6.85 (s, 2 H), 6.32 (dd, J = 3.2, 1.5 Hz, 1 H), 6.24 (d, J = 3.2 Hz, 1
H), 5.66 (d, J = 8.6 Hz, 1 H), 4.19 (dd, J = 8.6, 6.8 Hz, 1 H), 2.51 (s, 6
H), 2.25 (s, 3 H), 2.19 (dqq, J = 6.8, 6.8, 6.5 Hz, 1 H), 0.93 (d, J = 6.5
Hz, 3 H), 0.88 ppm (d, J = 6.8 Hz, 3 H); 13C NMR (acetone-d6, 101
MHz) major diastereomer δ 156.6, 142.3, 140.8, 139.7, 137.4, 131.4,
9456
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Article
110.9, 107.6, 60.9, 33.7, 21.0, 19.6, 19.2 ppm; m/z (ES+) 328 ([M +
Na]+, 100%), 306 ([M + H]+, 10), 167 (16); HRMS found, 328.1335
C17H23NO2NaS 328.1347.
diastereomer δ 153.2, 142.1, 141.9, 141.0, 139.1, 137.6, 131.4, 60.0,
35.9, 21.0, 19.9, 19.7, 19.4 ppm; m/z (ES+) 345 ([M + Na]+, 100%),
323 ([M + H]+, 74); HRMS found, 345.1057 C16H22N2ONaS2
345.1066.
(S)-N-((S)-1-(Benzofuran-2-yl)-2-methylpropyl)-2,4,6-trime-
thylbenzenesulfinamide (3h). General procedure A was followed
using 1-benzofuran-2-carbaldehyde (0.103 mL, 0.854 mmol) and
isopropylmagnesium chloride (2 M in diethyl ether) (1.707 mL, 3.41
mmol). Purification by flash chromatography on silica gel (elution with
0−25% ethyl acetate/cyclohexane) gave impure product that was
further purified by flash chromatography on silica gel (elution with 0−
13% ethyl acetate/DCM) to give the title compound (67 mg, 0.188
mmol, 44%) as a pale yellow oil. Diastereomeric ratio: 97.1:2.9,
determined by HPLC [Chiralpak IA (heptane/ethanol 97:3, flow rate
1.0 mL/min, λ = 215 nm, retention time: 14.418 min (S,SS, major),
(S)-2,4,6-Trimethyl-N-((S)-4-methyl-1-phenylpent-1-yn-3-yl)-
benzenesulfinamide (3k). General procedure A was followed using
3-phenyl-2-propynal (0.104 mL, 0.854 mmol) and isopropylmagne-
sium chloride (2 M in diethyl ether) (1.707 mL, 3.41 mmol).
Purification by flash chromatography on silica gel (elution with 0−25%
ethyl acetate/cyclohexane) gave impure product that was further
purified by flash chromatography on silica gel (elution with 0−13%
ethyl acetate/DCM) to give the title compound (50 mg, 0.147 mmol,
34%) as a yellow oil. Diastereomeric ratio: 94.4:5.6, determined by
HPLC [Chiralpak AY-H (heptane/ethanol 95:5, flow rate 1.0 mL/
min, λ = 215 nm, retention time: 26.249 min (R,SS, minor), 30.222
20.705 min (R,SS, minor)]; [α]21 +159 (c 1.0, CHCl3); IR (ATR)
D
min (S,SS, major)]; [α]21 +138 (c 1.0, CHCl3); IR (ATR) 2960,
3211, 2962, 2928, 2872, 1601, 1454, 1384, 1252, 1075, 1048; 1H NMR
(acetone-d6, 400 MHz) major diastereomer δ 7.54 (dd, J = 7.2, 1.5 Hz,
1 H), 7.44 (d, J = 8.1 Hz, 1 H), 7.24 (ddd, J = 8.1, 7.5, 1.5 Hz, 1 H),
7.19 (ddd, J = 7.5, 7.2, 1.1 Hz, 1 H), 6.81 (s, 2 H), 6.67 (s, 1 H), 5.87
(d, J = 8.7 Hz, 1 H), 4.37 (dd, J = 8.7, 6.8 Hz, 1 H), 2.53 (s, 6 H), 2.31
(oct, J = 6.8 Hz, 1 H), 2.21 (s, 3 H), 1.00 (d, J = 6.8 Hz, 3 H), 0.96
ppm (d, J = 6.8 Hz, 3 H); 13C NMR (acetone-d6, 101 MHz) major
diastereomer δ 159.8, 155.6, 140.9, 139.4, 137.6, 131.4, 129.5, 124.6,
123.6, 121.7, 111.7, 104.6, 61.0, 33.6, 21.0, 19.8, 19.7, 19.2 ppm; m/z
(ES+) 378 ([M + Na]+, 100%), 356 ([M + H]+, 21); HRMS found,
378.1498 C21H25NO2NaS 378.1498.
D
1
2923, 2870, 1600, 1490, 1463, 1380, 1071, 1049; H NMR (acetone-
d6, 400 MHz) major diastereomer δ 7.32−7.42 (m, 5 H), 6.88 (s, 2
H), 5.71 (d, J = 7.1 Hz, 1 H), 4.13 (dd, J = 7.1, 6.3 Hz, 1 H), 2.58 (s, 6
H), 2.26 (s, 3 H), 2.09 (qqd, J = 6.8, 6.6, 6.3 Hz, 1 H), 1.11 (d, J = 6.6
Hz, 3 H), 1.09 ppm (d, J = 6.8 Hz, 3 H); minor diastereomer δ 7.28−
7.47 (m, 5 H), 6.85−6.91 (m, 2 H), 5.63 (d, J = 7.1 Hz, 1 H), 4.23
(dd, J = 6.7, 5.2 Hz, 1 H), 2.58 (s, 6 H), 2.26 (s, 3 H), 1.95−2.07 (m,
1 H), 1.02−1.09 ppm (m, 6 H); 13C NMR (acetone-d6, 101 MHz)
major diastereomer δ 141.0, 139.4, 137.8, 132.4, 131.5, 129.3, 129.2,
124.2, 89.5, 85.4, 54.7, 35.2, 21.0, 19.7, 19.7, 18.7 ppm; m/z (ES+)
362 ([M + Na]+, 100%), 340 ([M + H]+, 29); HRMS found, 362.1542
C21H25NONaS 362.1549.
(S)-N-((S)-1-(5-Bromothiophen-2-yl)-2-methylpropyl)-2,4,6-
trimethylbenzenesulfinamide (3i). General procedure A was
followed using 5-bromo-2-thiophenecarbaldehyde (0.101 mL, 0.854
mmol) and isopropylmagnesium chloride (2 M in diethyl ether)
(1.707 mL, 3.41 mmol), which was stirred for only 2 h while warming
to −45 °C and then immediately quenched (to prevent debromination
of the product). Purification by flash chromatography on silica gel
(elution with 0−25% ethyl acetate/cyclohexane) gave impure product
that was further purified by flash chromatography on silica gel (elution
with 0−13% ethyl acetate/DCM) to give the title compound (69 mg,
0.172 mmol, 40%) as a colorless oil. Diastereomeric ratio: 98.1:1.9,
determined by HPLC [Chiralpak AY-H (heptane/ethanol 80:20, flow
rate 1.0 mL/min, λ = 215 nm, retention time: 8.594 min (S,SS, major),
(S)-1-Phenylpropan-1-amine Hydrochloride (4a).15 General
procedure B was followed using benzaldehyde (0.087 mL, 0.854
mmol) and ethylmagnesium chloride (2 M in diethyl ether) (1.707
mL, 3.41 mmol), which gave the title compound (44 mg, 0.256 mmol,
60%) as a cream solid. Mp 226−229 °C (decomp) [lit.15 mp 192−193
°C]; [α]20 +16 (c 1.0, EtOH) [lit.15b [α]23 +17.8 (c 2.08, EtOH)
D
D
(S)]; IR (ATR) 2964, 2880, 1600, 1516, 1458, 1395; 1H NMR
(MeOH-d4, 400 MHz) δ 7.39−7.51 (m, 5 H), 4.16 (dd, J = 9.2, 5.9
Hz, 1 H), 1.89−2.11 (m, 2 H), 0.90 ppm (t, J = 7.4 Hz, 3 H); 13C
NMR (MeOH-d4, 101 MHz) δ 138.2, 130.5, 130.5, 128.5, 58.5, 28.9,
10.6 ppm; m/z (ES+) 136 ([M − Cl]+, 100%), 119 ([M − NH3Cl]+,
46); HRMS found, 136.1126 C9H14N 136.1126. All analytical data are
in accordance with the literature.15c
22.311 min (R,SS, minor)]; [α]21 +123 (c 1.0, CHCl3); IR (ATR)
D
3203, 2960, 2923, 2871, 1602, 1441, 1380, 1070, 1046; 1H NMR
(acetone-d6, 400 MHz) major diastereomer δ 6.93 (d, J = 3.8 Hz, 1
H), 6.83 (s, 2 H), 6.79 (d, J = 3.8 Hz, 1 H), 5.82 (d, J = 7.8 Hz, 1 H),
4.40 (t, J = 7.3 Hz, 1 H), 2.52 (s, 6 H), 2.24 (s, 3 H), 2.05−2.16 (m, 1
H), 0.97 (d, J = 6.8 Hz, 3 H), 0.93 ppm (d, J = 6.8 Hz, 3 H); 13C
NMR (acetone-d6, 101 MHz) major diastereomer δ 150.0, 141.0,
139.2, 137.6, 131.4, 130.4, 126.4, 110.7, 62.4, 35.5, 21.0, 19.9, 19.8,
19.2 ppm; m/z (ES+) 424 ([81Br, M + Na]+, 100%), 422 ([79Br, M +
Na]+, 92), 402 ([81Br, M + H]+, 32), 400 ([79Br, M + H]+, 30); HRMS
found, 422.0222 C17H2279BrNONaS2 422.0218.
(S)-1-Phenylbutan-1-amine Hydrochloride (4b).16 General
procedure B was followed using benzaldehyde (0.087 mL, 0.854
mmol) and n-propylmagnesium chloride (2 M in diethyl ether) (1.707
mL, 3.41 mmol), which gave the title compound (42 mg, 0.226 mmol,
53%) as a cream solid. Mp 277−280 °C (decomp) [lit.16a mp 299 °C
(decomp)]; [α]21 +20 (c 1.0, EtOH); IR (ATR) 2961, 2876, 1601,
D
1515, 1458, 1392; 1H NMR (MeOH-d4, 400 MHz) δ 7.37−7.51 (m, 5
H), 4.24 (dd, J = 8.5, 6.7 Hz, 1 H), 1.88−2.02 (m, 2 H), 1.15−1.39
(m, 2 H), 0.95 ppm (t, J = 7.3 Hz, 3 H); 13C NMR (MeOH-d4, 101
MHz) δ 138.4, 130.5, 130.4, 128.5, 56.9, 37.7, 20.2, 14.0 ppm; m/z
(ES+) 150 ([M − Cl]+, 29%), 133 ([M − NH3Cl]+, 100); HRMS
found, 150.1272 C10H16N 150.1277. All analytical data are in
accordance with the literature.16b The amine hydrochloride was
converted to the free amine by treatment with sodium hydroxide.
[α]22 −4 (c 0.9, EtOH) [lit.17 [α]25 −2.8 (c 1.0, EtOH) (S)].
(S)-2,4,6-Trimethyl-N-((S)-2-methyl-1-(thiazol-5-yl)propyl)-
benzenesulfinamide (3j). General procedure A was followed using
1,3-thiazole-5-carbaldehyde (0.074 mL, 0.854 mmol) and isopropyl-
magnesium chloride (2 M in diethyl ether) (1.707 mL, 3.41 mmol).
Purification by flash chromatography on silica gel (elution with 0−50%
ethyl acetate/cyclohexane) gave impure product that was further
purified by flash chromatography on silica gel (elution with 0−100%
ethyl acetate/DCM) to give the title compound (50 mg, 0.155 mmol,
36%) as a pale yellow oil. Diastereomeric ratio: 89.7:10.3, determined
by HPLC [Chiralpak IA (heptane/ethanol 95:5, flow rate 1.0 mL/min,
λ = 215 nm, retention time: 22.571 min (R,SS, minor), 24.335 min
D
D
(S)-2-Methyl-1-phenylpropan-1-amine Hydrochloride
(4c).15a,c General procedure B was followed using benzaldehyde
(0.087 mL, 0.854 mmol) and isopropylmagnesium chloride (2 M in
diethyl ether) (1.707 mL, 3.41 mmol), which gave the title compound
(47 mg, 0.253 mmol, 59%) as a cream solid. Mp 266−269 °C
(S,SS, major)]; [α]21 +183 (c 1.0, CHCl3); IR (ATR) 3194, 2960,
(decomp) [lit.15a mp 265−267 °C (decomp)]; [α]22 +12 (c 0.4,
D
D
1
2926, 2873, 1603, 1459, 1382, 1066, 1034; H NMR (acetone-d6, 400
EtOH); IR (ATR) 2963, 2893, 1600, 1515, 1460, 1395; 1H NMR
(MeOH-d4, 400 MHz) δ 7.36−7.51 (m, 5 H), 3.93 (d, J = 9.1 Hz, 1
H), 2.12−2.27 (m, 1 H), 1.15 (d, J = 6.6 Hz, 3 H), 0.81 ppm (d, J =
6.8 Hz, 3 H); 13C NMR (MeOH-d4, 101 MHz) δ 138.2, 130.4, 130.3,
128.7, 63.3, 34.0, 19.8, 19.6 ppm; m/z (ES+) 150 ([M − Cl]+, 15%),
133 ([M − NH3Cl]+, 100); HRMS found, 150.1273 C10H16N
150.1277. All analytical data are in accordance with the literature.15a,c
The amine hydrochloride was converted to the free amine by
MHz) major diastereomer δ 8.80 (s, 1 H), 7.70 (s, 1 H), 6.82 (s, 2 H),
5.91 (d, J = 8.1 Hz, 1 H), 4.57 (t, J = 7.6 Hz, 1 H), 2.51 (s, 6 H), 2.23
(s, 3 H), 2.07−2.20 (m, 1 H), 1.00 (d, J = 6.8 Hz, 3 H), 0.92 ppm (d, J
= 6.8 Hz, 3 H); minor diastereomer δ 8.92 (s, 1 H), 7.86 (s, 1 H), 6.87
(s, 2 H), 5.73 (d, J = 5.2 Hz, 1 H), 4.61 (dd, J = 6.0, 5.2 Hz, 1 H), 2.45
(s, 6 H), 2.26 (s, 3 H), 2.08−2.20 (m, 1 H), 1.00−1.04 (m, 3 H), 0.87
ppm (d, J = 6.5 Hz, 3 H); 13C NMR (acetone-d6, 101 MHz) major
9457
dx.doi.org/10.1021/jo201849j|J. Org. Chem. 2011, 76, 9452−9459

The Journal of Organic Chemistry
Article
treatment with sodium hydroxide. [α]22 −12 (c 1.1, CHCl3) [lit.18
130.0, 130.0, 115.6, 62.9, 56.0, 34.0, 19.9, 19.7 ppm; m/z (ES+) 180
([M − Cl]+, 13%), 179 ([M − HCl]+, 43), 163 ([M − NH3Cl]+, 100);
HRMS found, 163.1120 C11H15O 163.1123. All analytical data are in
accordance with the literature.15a
D
[α]23 −12.4 (c 0.97, CHCl3) (S)].
(S)D-3-Methyl-1-phenylbutan-1-amine Hydrochloride (4d).16
General procedure B was followed using benzaldehyde (0.087 mL,
0.854 mmol) and isobutylmagnesium chloride (2 M in diethyl ether)
(1.707 mL, 3.41 mmol), which gave the title compound (49 mg, 0.245
mmol, 57%) as a white solid. Mp 272−275 °C (decomp) [lit.16a mp
(S)-1-(4-Chlorophenyl)-2-methylpropan-1-amine Hydro-
chloride (4i).22 General procedure B was followed using 4-
chlorobenzaldehyde (0.120 g, 0.854 mmol) and isopropylmagnesium
chloride (2 M in diethyl ether) (1.707 mL, 3.41 mmol), which gave
the title compound (39 mg, 0.177 mmol, 42%) as a cream solid. Mp
>310 °C]; [α]21 +22 (c 1.0, EtOH); IR (ATR) 2887, 1600, 1514,
D
1
1459, 1393; H NMR (MeOH-d4, 400 MHz) δ 7.38−7.51 (m, 5 H),
276−279 °C (decomp) [lit.22 mp 256−259 °C]; [α]21 +11 (c 1.0,
4.31 (dd, J = 10.0, 5.6 Hz, 1 H), 1.94 (ddd, J = 14.8, 10.0, 5.3 Hz, 1 H),
1.80 (ddd, J = 14.8, 8.6, 5.6 Hz, 1 H), 1.33−1.48 (m, 1 H), 0.96 (d, J =
6.5 Hz, 3 H), 0.92 ppm (d, J = 6.8 Hz, 3 H); 13C NMR (MeOH-d4,
101 MHz) δ 138.3, 130.5, 130.5, 128.6, 55.4, 44.4, 25.9, 23.5, 22.0
ppm; m/z (ES+) 164 ([M − Cl]+, 70%), 147 ([M − NH3Cl]+, 100);
HRMS found, 164.1444 C11H18N 164.1439. All analytical data are in
accordance with the literature.16b
D
EtOH); IR (ATR) 2962, 2878, 1609, 1512, 1469, 1394, 1090; 1H
NMR (MeOH-d4, 400 MHz) δ 7.48 (d, J = 8.4 Hz, 2 H), 7.39 (d, J =
8.4 Hz, 2 H), 3.96 (d, J = 9.3 Hz, 1 H), 2.11−2.25 (dqq, J = 9.3, 6.8,
6.8 Hz, 1 H), 1.14 (d, J = 6.8 Hz, 3 H), 0.81 ppm (d, J = 6.8 Hz, 3 H);
13C NMR (MeOH-d4, 101 MHz) δ 136.9, 136.2, 130.5, 130.4, 62.5,
33.9, 19.8, 19.5 ppm; m/z (ES+) 184 ([M − Cl]+, 8%), 169 (33), 167
([M − NH3Cl]+, 100), 127 (23); HRMS found, 184.0887 C10H15ClN
184.0888.
(R)-1-Phenylbut-3-en-1-amine Hydrochloride (4e).15a,19
General procedure B was followed using benzaldehyde (0.087 mL,
0.854 mmol) and allylmagnesium bromide (1 M in diethyl ether)
(3.41 mL, 3.41 mmol), which gave the title compound (41 mg, 0.223
mmol, 52%) as a pale brown solid. Mp 208−211 °C (decomp) [lit.15a
mp 223−225 °C (decomp)]; [α]21 +13 (c 1.1, CHCl3) [lit.17 [α]25
(S)-1-(6-Methoxynaphthalen-2-yl)-2-methylpropan-1-amine
Hydrochloride (4j). General procedure B was followed using 6-
methoxy-2-naphthaldehyde (0.159 g, 0.854 mmol) and isopropylmag-
nesium chloride (2 M in diethyl ether) (1.707 mL, 3.41 mmol), which
gave the title compound (53 mg, 0.199 mmol, 47%) as a cream solid.
D
D
+36.2 (c 1.4, CHCl3) (R)]; IR (ATR) 2885, 1597, 1511, 1459, 1438,
Mp 256−259 °C (decomp); [α]22 +13 (c 0.9, EtOH); IR (ATR)
1
D
1395; H NMR (MeOH-d4, 400 MHz) δ 7.38−7.51 (m, 5 H), 5.63−
1
2963, 2845, 1606, 1509, 1488, 1200, 1024; H NMR (MeOH-d4, 400
5.77 (ddt, J = 17.1, 10.1, 7.1 Hz, 1 H), 5.11−5.25 (m, 2 H), 4.34 (t, J =
7.4 Hz, 1 H), 2.74 ppm (dd, J = 7.4, 7.1 Hz, 2 H); 13C NMR (MeOH-
d4, 101 MHz) δ 138.1, 133.4, 130.4, 130.4, 128.4, 120.5, 56.4, 40.3
ppm; m/z (ES+) 148 ([M − Cl]+, 8%), 131 ([M − NH3Cl]+, 100);
HRMS found, 148.1125 C10H14N 148.1121. All analytical data are in
accordance with the literature.15a
MHz) δ 7.88 (d, J = 8.5 Hz, 1 H), 7.80 (d, J = 8.5 Hz, 1 H), 7.79 (s, 1
H), 7.44 (dd, J = 8.5, 1.8 Hz, 1 H), 7.29 (d, J = 2.4 Hz, 1 H), 7.20 (dd,
J = 8.5, 2.4 Hz, 1 H), 4.06 (d, J = 9.3 Hz, 1 H), 3.93 (s, 3 H), 2.24−
2.36 (dqq, J = 9.3, 6.5, 6.5 Hz, 1 H), 1.19 (d, J = 6.5 Hz, 3 H), 0.84
ppm (d, J = 6.5 Hz, 3 H); 13C NMR (MeOH-d4, 101 MHz) δ 160.0,
136.4, 133.0, 130.7, 130.2, 129.2, 128.3, 126.0, 120.8, 106.9, 63.5, 56.0,
34.0, 19.9, 19.8 ppm; m/z (ES+) 213 ([M − NH3Cl]+, 100%), 178
(18); HRMS found, 213.1273 C15H17O 213.1279.
(S)-1,2-Diphenylethanamine Hydrochloride (4f).15c,20 Gener-
al procedure B was followed using benzaldehyde (0.087 mL, 0.854
mmol) and benzylmagnesium chloride (1 M in diethyl ether) (3.41
mL, 3.41 mmol), which gave the title compound (58 mg, 0.248 mmol,
58%) as a cream solid. Mp 238−240 °C (decomp) [lit.19 mp 259−260
°C]; [α]21 +83 (c 1.0, EtOH) [lit.19 [α]20 +128.0 (c 0.99, EtOH)
(S)-1-(Benzofuran-2-yl)-2-methylpropan-1-amine Hydro-
chloride (4k). General procedure B was followed using benzofur-
an-2-carbaldehyde (0.100 mL, 0.854 mmol) and isopropylmagnesium
chloride (2 M in diethyl ether) (1.707 mL, 3.41 mmol), which gave
the title compound (51 mg, 0.226 mmol, 53%) as a brown solid. Mp
D
D
1
(S)]; IR (ATR) 3027, 2883, 1598, 1514, 1498, 1455, 1394; H NMR
(MeOH-d4, 400 MHz) δ 7.32−7.46 (m, 5 H), 7.18−7.28 (m, 3 H),
7.07−7.13 (m, 2 H), 4.51 (dd, J = 9.0, 6.5 Hz, 1 H), 3.31 (dd, J = 13.6,
6.5 Hz, 1 H), 3.21 ppm (dd, J = 13.6, 9.0 Hz, 1 H); 13C NMR
(MeOH-d4, 101 MHz) δ 137.8, 136.9, 130.6, 130.4, 130.3, 129.8,
128.6, 128.4, 58.5, 42.1 ppm; m/z (ES+) 198 ([M − Cl]+, 43%), 181
([M − NH3Cl]+, 100), 166 (11); HRMS found, 198.1279 C14H16N
198.1283. All analytical data are in accordance with the literature.15c
(S)-1-(Furan-2-yl)-2-methylpropan-1-amine Hydrochloride
(4g). General procedure B was followed using furfural (0.070 mL,
0.854 mmol) and isopropylmagnesium chloride (2 M in diethyl ether)
(1.707 mL, 3.41 mmol), which gave the title compound (37 mg, 0.211
mmol, 49%) as a brown solid. Mp 194−197 °C (decomp); IR (ATR)
2966, 2878, 1588, 1495, 1158; 1H NMR (MeOH-d4, 400 MHz) δ 7.60
(d, J = 1.7 Hz, 1 H), 6.51 (d, J = 3.2 Hz, 1 H), 6.48 (dd, J = 3.2, 1.7
Hz, 1 H), 4.17 (d, J = 8.0 Hz, 1 H), 2.28 (dqq, J = 8.0, 6.8, 6.8 Hz, 1
H), 1.09 (d, J = 6.8 Hz, 3 H), 0.92 ppm (d, J = 6.8 Hz, 3 H); 13C
NMR (MeOH-d4, 101 MHz) δ 150.4, 144.9, 111.9, 111.3, 56.0, 32.4,
19.5, 19.0 ppm; m/z (ES+) 140 ([M − Cl]+, 6%), 138 (27), 123 ([M
− NH3Cl]+, 100); HRMS found, 123.0803 C8H11O 123.0810. The
amine hydrochloride was converted to the free amine by treatment
with sodium hydroxide. [α]22D +16 (c 0.5, EtOH) [lit.21 [α]20D +9.6 (c
1.0, EtOH) (S)].
220−223 °C (decomp); [α]22 +21 (c 0.3, EtOH); IR (ATR) 2963,
D
2871, 1598, 1510, 1453, 1394, 1257, 1175, 1098; 1H NMR (MeOH-d4,
400 MHz) δ 7.63 (d, J = 7.5 Hz, 1 H), 7.53 (d, J = 8.3 Hz, 1 H), 7.35
(t, J = 7.4 Hz, 1 H), 7.27 (t, J = 7.3 Hz, 1 H), 6.95 (s, 1 H), 4.34 (d, J =
8.0 Hz, 1 H), 2.33−2.46 (dqq, J = 8.0, 6.5, 6.5 Hz, 1 H), 1.16 (d, J =
6.5 Hz, 3 H), 0.97 ppm (d, J = 6.5 Hz, 3 H); 13C NMR (MeOH-d4,
101 MHz) δ 156.6, 152.8, 129.0, 126.5, 124.7, 122.8, 112.3, 108.2,
56.4, 32.3, 19.5, 19.2 ppm; m/z (ES+) 188 (23%), 173 ([M −
NH3Cl]+, 100), 145 (10); HRMS found, 173.0962 C12H13O 173.0966.
ASSOCIATED CONTENT
■
S
* Supporting Information
Experimental details for synthesis of benzamides, NMR spectra,
and HPLC analyses. This material is available free of charge via
the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: robert.stockman@nottingham.ac.uk.
■
(S)-1-(4-Methoxyphenyl)-2-methylpropan-1-amine Hydro-
chloride (4h).15a General procedure B was followed using 4-
methoxybenzaldehyde (0.010 mL, 0.854 mmol) and isopropylmagne-
sium chloride (2 M in diethyl ether) (1.707 mL, 3.41 mmol), which
gave the title compound (50 mg, 0.232 mmol, 54%) as a pale brown
solid. Mp 218−220 °C (decomp) [lit.15a mp 217−219 °C (decomp)];
ACKNOWLEDGMENTS
■
This research was supported by EPSRC/GSK (EP/F068352/
1). Eric Hortense (GSK) is thanked for carrying out chiral
HPLC analyses and Bill Leavens (GSK) for accurate mass
analyses.
[α]22 +8 (c 1.0, EtOH); IR (ATR) 2966, 2914, 1612, 1574, 1511,
D
1
1261, 1183, 1027; H NMR (MeOH-d4, 400 MHz) δ 7.31 (d, J = 8.8
REFERENCES
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ppm (d, J = 6.5 Hz, 3 H); 13C NMR (MeOH-d4, 101 MHz) δ 161.8,
■
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Article
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