1
730
N. Duhamel et al. / Tetrahedron Letters 56 (2015) 1728–1731
To form the required sulfonic acid aldehyde 4, a large excess of
sodium bicarbonate was then added to a solution of diadduct 3 in
methanol. This raised the pH of the reaction to 8, and the mixture
was stirred for 28 h resulting in the elimination of bisulfate giving
9.
2
3
aldehyde 4. Purification of aldehyde 4 again proved to be prob-
lematic. Attempts to purify the mixture through an acidic ion
exchange resin proved unsuccessful, with oxidation of the aldehy-
de to the carboxylic acid a major side-reaction. Filtration of the
excess bicarbonate and lowering to pH 6 gave aldehyde 4 in higher
purity but in yields of 5% or less. It was found that by repeated
extraction of the bicarbonate-contaminated product, using metha-
nol, the purity of aldehyde 4 could be increased. This simple proce-
1
1
1
1
dure allowed the preparation of sulfonic acid aldehydes which
have proved difficult to isolate in previous studies.1
1c,18
To elimi-
1
1
7. Synthesis and data for 2-methyl-4-oxopentane-2-sulfonic acid (1): To a stirred
nate the removal of the inorganic base, another method was also
attempted using the strong, polystyrene-bound base, tert-buty-
lamino-2-diethylamino-1,3-dimethylperhydro-1,3,2-diazaphos-
phorine (PS-BEMP). By stirring a solution of diadduct 3 in water
with 3 equivalents of PS-BEMP for 23 h, followed by release of
solution of mesityl oxide (1 mL, 8.74 mmol) in MeOH (15 mL) was added Et N
3
(3.7 mL, 26.2 mmol) and NaHSO
6.2 mmol), and the mixture was left to stir for 24 h. The resulting mixture
was then filtered and filtered again through a plug of Amberlyst-15 to give acid
(0.98 g, 62%) as a brown oil. d (400 MHz, D O): 1.43 (6H, s, C(CH ), 2.30
(3H, s, 1-CH ), 2.91 (2H, s, 3-CH ); d (100 MHz, CDCl ): 22.4 (C(CH ), 32.7 (C-
3
(40% w/v aqueous solution, 6.8 mL,
2
1
H
2
3 2
)
the sulfonic acid from the resin using 2 M HCl, aldehyde 4 was
3
2
C
3
3 2
)
obtained in a much improved 90% yield.24
In summary, the synthesis of low molecular weight sulfonic
acids 1–4 has been achieved. These methods could be applied to
the preparation of similar compounds which have previously been
reported to be difficult to obtain in pure form. Investigations into
the possibility of the compounds prepared being precursors to
wine aroma thiols have been enabled and future fermentation
experiments with a large range of yeast strains will ascertain
whether or not the sulfonic acid functionality in acids 1–4 can be
reduced to the free thiol during wine making.
19. Synthesis and data for (E)-ethyl hex-2-enoate (6): To a stirred solution of butanal
0.213 g, 2.95 mmol) in CH Cl (15 mL) under an atmosphere of nitrogen was
(
2
2
added (carbethoxymethylene)triphenylphosphorane (1.24 g, 3.50 mmol) and
the resulting mixture stirred for 47 h. The solvent was removed in vacuo,
without application of heat, and pentane (30 mL) was added to the residue,
which was then stirred for 30 min. The resulting mixture was filtered, the
solvent removed in vacuo, without application of heat, and the crude product
was purified using flash chromatography (95:5 pentane/Et
2
O) to give the ester
6 (0.30 g, 72%) as a pale yellow oil. dH (400 MHz, CDCl ): 0.93 (3H, t, J = 7.5 Hz,
3
6
-CH
m, 4-CH
1H, dt, J = 7.1, 15.2 Hz, 3-H); d
3
), 1.28 (3H, t, J = 7.0 Hz, 8-CH
), 4.18 (2H, q, J = 7.0 Hz, 7-CH
(100 MHz, CDCl
3
3
), 1.44–1.53 (2H, m, 5-CH
), 5.81 (1H, dt, J = 1.5, 15.9 Hz, 2-H), 6.96
): 13.8 (C-6), 14.4 (C-8), 21.4
2
), 2.14–2.20 (2H,
2
2
(
C
Acknowledgements
(C-5), 34.3 (C-4), 60.2 (C-7), 121.5 (C-2), 149.3 (C-3), 166.9 (C-1).
2
0. Synthesis and data for 3-sulfohexanoic acid bis triethylamine salt (7) and 1-
ethoxy-1-oxohexane-3-sulfonic acid (8): To ester 6 (1.97 g, 14.86 mmol) in 9:1
This work was funded by grants to B.F. from the New Zealand
Ministry of Business, Innovation and Employment, New Zealand
Winegrowers and Plant and Food Research and the FEM-IASMA
Fondazione Edmund Mach—Istituto Agrario di San Michele all’Adi-
ge. We also acknowledge the University of Auckland for additional
funding.
H
2
O/MeOH (100 mL), NaHSO
3
(40% w/v aqueous solution, 4.33 mL,
1
6.64 mmol) and Et (2.31 mL, 16.64 mmol) were added. The resulting
3
N
mixture was heated at reflux for 18 h. The solvent was removed in vacuo, and
the crude product was purified using flash chromatography (10:90:1 to
2
(
0:80:1, MeOH/CH
400 MHz; O): 0.94 (3H, t, J = 7.4 Hz, 6-CH
) 1.39–1.61 (3H, m, 5-CH , 4-H ), 1.83–1.92 (1H, m, 4-H
), 2.81 (1H, dd, J = 6.4, 16.1 Hz, 2-H ), 3.22 (12H, q,
), 3.26–3.33 (1H, m, 3-H); d (100 MHz; D O) 8.8
2
Cl
2
/AcOH) to give acid 7 in 31% yield as a yellow gum. d
), 1.30 (18H, t, J = 7.3 Hz,
), 2.56
H
D
2
3
(N(CH
2
CH
3
)
)
3 2
2
a
b
(
1H, dd, J = 6.9, 16.1 Hz, 2-H
a
b
J = 7.5 Hz, (N(CH CH
2
3
)
)
3 2
C
2
Supplementary data
((N(CH CH ) ) ), 13.8 (C-6), 20.2 (C-5), 32.7 (C-4), 36.7 (C-2), 47.3
2
3
3
2
À1
max cm 2987, 2704, 1716,
+
(
(N(CH
2
CH
3
)
3
2
) ), 57.6 (C-3), 178.2 (C-1); IR:
m
1
C
2
565, 1389, 1228, 1148; HRMS (ESIÀ) found [MÀHÀ2(Et
3
N)] 195.0333,
6
11 5
H O
S, required 195.0332. In a second fraction was obtained ester 8 (1.20 g,
1
5%) as a yellow oil. H (400 MHz; D
CH3, N(CH CH ), 1.38–1.46 (1H, m, 4-H
), 1.88–1.89 (1H, m, 4-H ), 2.65–2.81 (2H, m, 2-CH
J = 7.2 Hz, N(CH CH ), 3.31–3.36 (1H, m, 3-H), 4.20 (2H, q, J = 7.2 Hz,
); C (100 MHz; D O): 8.2 (N(CH CH ), 13.1 (C-6 and OCH CH ),
CH ), 56.8 (C-3), 62.1
2
O): 0.95 (3H, t, J = 7.3 Hz, 6-CH
), 1.48–1.59 (2H,
), 3.23 (6H, q,
3
), 1.28–
84. These data include MOL files and InChiKeys of the most
1.32 (12H, m, OCH
m, 5-CH
2
2
3
)
b
3
a
2
2
important compounds described in this article.
2
3 3
)
13
OCH
2
CH
3
2
2
3
)
3
2
3
References and notes
19.5 (C-5), 31.8 (C-4), 35.4 (C-2), 46.7 (N(CH
2
3 3
)
À1
(
OCH
HRMS (ESIÀ). Found [MÀHÀEt
1. Synthesis and data for 1-hydroxyhexane-3-sulfonic acid (2): To a solution of ester
(0.27 g, 1.20 mmol) in THF (10 mL) was added LiAlH (0.14 g, 3.60 mmol) and
the mixture heated at reflux for 23 h, before being cooled to room temperature.
O (10 mL) was added dropwise and the resulting mixture was stirred for
5 min, and then passed through a silica plug using MeOH/AcOH (99:1). The
2
CH
3
), 177.0 (C-1); IR:
m
max cm 2964, 2708, 1723, 1468, 1375, 1224;
N]+ 223.0652, C
H O S, required 223.0646.
8 15 5
1
.
3
2
8
4
H
1
2
2
3
4
.
.
.
solvent was removed in vacuo and the crude product was purified using flash
chromatography (99:1 MeOH/AcOH) to give alcohol 2 (0.17 g, 80%) as a
colourless solid. Mp = 135–141 °C; d
CH ), 1.41–1.64 (3H, m, 4-CH , 5-CH
.14 (1H, m, 2-CH ), 2.74–2.81 (1H, m, 3-CH), 3.72–3.83 (2H, m, 1-CH
100 MHz; D O): 13.3 (C-6), 16.5 (C-5), 31.9 (C-2), 32.1 (C-4), 56.9 (C-3), 59.5
H
(400 MHz; D
), 1.80–1.90 (2H, m, 4-CH
2
O): 0.95 (3H, t, J = 7.4 Hz, 6-
, 2-CH ), 2.05–
); d
5
6
.
.
3
a
2
b
a
2
b
2
C
(
(
1
1
2
C-1); HRMS (ESIÀ). Found (M+HÀOH): 181.0548,
6 13 4
C H O S requires
3637, 3415, 2957, 2871, 1711, 1658, 1638, 1434,
À1
81.0540; IR:
m
max cm
361, 1162, 1037, 931, 877.
2
2. Synthesis and data for 1-hydroxyhexane-1,3-disulfonic acid (3): (E)-Hex-2-enal
1 mL, 8.62 mmol) was added to a solution of NaHSO (40% w/v aqueous
solution, 4.71 g, 18.1 mmol) and Et N (0.126 mL, 1.72 mmol) in MeOH (3 mL),
(
3
3
and the resulting mixture stirred for 12 h under an atmosphere of nitrogen. The
solvent was removed in vacuo, and the crude product was purified using flash
chromatography (99:1 MeOH/AcOH) to give the disulfonic acid 3 (2.00 g, 88%)
7
.
H 2 3
as a white solid. d (400 MHz; D O): 0.96 (3H, t, J = 7.6 Hz, 6-CH ), 1.50–1.62