Use of ethyl (benzothiazol-2-ylsulfonyl)acetate for malonic ester-type syntheses of carboxylic acids and esters

Article abstract of DOI:10.1071/CH14085

A new methodology for the synthesis of substituted carboxylic acids is described. Alkylation of either ethyl (benzothiazol-2-ylsulfonyl)acetate or ethyl 2-(benzothiazol-2-ylsulfonyl)propionate was achieved with alkyl halides and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in dichloromethane solution. These products were then desulfinated and hydrolysed in one-pot under mild conditions to give substituted acetic acids in good-to-excellent yields.

Full text of DOI:10.1071/CH14085

RESEARCH FRONT
CSIRO PUBLISHING
Aust. J. Chem. 2014, 67, 1222–1227
Full Paper
http://dx.doi.org/10.1071/CH14085
Use of Ethyl (Benzothiazol-2-ylsulfonyl)acetate for Malonic
Ester-type Syntheses of Carboxylic Acids and Esters*
A
,
B
,
A C
Waleed M. Hussein
and Ross P. McGeary
A
The University of Queensland, School of Chemistry and Molecular Biosciences,
Brisbane, Qld 4072, Australia.
B
Helwan University, Pharmaceutical Organic Chemistry Department, Faculty of
Pharmacy, Ein Helwan, Helwan, Cairo, 11795, Egypt.
C
Corresponding author. Email: r.mcgeary@uq.edu.au
A new methodology for the synthesis of substituted carboxylic acids is described. Alkylation of either ethyl (benzothiazol-
-ylsulfonyl)acetate or ethyl 2-(benzothiazol-2-ylsulfonyl)propionate was achieved with alkyl halides and 1,8-
2
diazabicyclo[5.4.0]undec-7-ene (DBU) in dichloromethane solution. These products were then desulfinated and
hydrolysed in one-pot under mild conditions to give substituted acetic acids in good-to-excellent yields.
Manuscript received: 20 February 2014.
Manuscript accepted: 28 March 2014.
Published online: 12 May 2014.
Introduction
A classical method for the preparation of mono- and di-
[4,5]
Julia (Julia–Kocienski) olefination
and our recently
[6]
described epoxide deoxygenation reaction. We believe that
benzothiazol-2-sulfones, such as 5, can also undergo inter-
molecular attack of a nucleophile at C2, leading to an interme-
diate (ethoxycarbonyl)alkyl sulfinate 6. b-Carbonyl sulfinates,
[
1]
substituted carboxylic acids is the malonic ester synthesis. In
this approach, diethyl malonate 1 is alkylated with an alkyl
halide (or dialkylated with the same or a different alkyl halide),
and the resulting diester 2 or 2a is subjected to hydrolysis to
afford the substituted malonic acid 3 or 3a. The diacid 3 or 3a
can then be decarboxylated to give the carboxylic acid product
such as 6, have a fleeting existence, rapidly losing SO to give
2
[
7–9]
the carbonyl compound,
and so we expect that 6, if formed,
would rapidly desulfinate under very mild conditions, at signif-
icantly lower temperatures than those typically required for the
decarboxylation of malonic acids. This approach would be
complementary to the malonate ester synthesis of carboxylic
acids and would significantly broaden its scope. This concept
was experimentally examined and details of this new approach
are provided herein.
4
or 4a (Scheme 1).
Prolonged reaction times and high temperatures (as high as
[
80–1908C ) are required to achieve the final decarboxylation
2]
1
reaction of 3 or 3a to give 4 or 4a, accordingly, severely
restricting the scope of this methodology. Because of this
limitation, we considered a potentially milder approach,
whereby an ester of (benzothiazol-2-ylsulfonyl)acetic acid is
singly- or dialkylated to give the substituted ester 5
Results and Discussion
(
readily in intramolecular Smiles-type rearrangement reac-
Scheme 2). Benzothiazol-2-sulfones, such as 5, participate
The syntheses of b-sulfonyl esters 11a and 11b using methods
are shown in
[3]
[10]
tions with oxygen as nucleophile, as evident in the modified
modified from Blakemore and co-workers
CO Et
CO Et
CO H
2
2
2
RX, NaOEt
NaOH
Δ, ꢀCO
2
CO Et
R
CO Et
R
CO H
R
CO H
2
2
2
2
1
2
3
4
1
R X, NaOEt
R1
CO Et
CO H
2
2
NaOH
Δ, ꢀCO
2
R1
R1
CO Et
CO H
R
CO H
2
2
2
R
R
2a
3a
4a
Scheme 1. Malonic ester synthesis of carboxylic acids.
*
Dedicated to the memory of Roger F. C. Brown (1931–2013), Ph.D. supervisor of RPM.
Journal compilation Ó CSIRO 2014
www.publish.csiro.au/journals/ajc

Syntheses of Carboxylic Acids and Esters
1223
R1
O
O O
S
O
S
O
N
NaOEt
ꢀSO
2
ꢀ
OEt
O
OEt
R
CO Et
2
S
R1
R
R1
R
5
6
8
ꢁ
N
OEt
S
7
Scheme 2. Proposed formation of a-substituted acetate esters from ethyl (benzothiazol-2-ylsulfonyl)
acetates.
Br
CO Et
2
R
H O , EtOH
2
2
N
Et N, CH Cl
N
S
N
S
O O
S
3
2
2
(NH ) Mo O
4 6 7 24
SH
S
CO Et
CO Et
2
2
1
1
00 % (R ꢂ H)
00 % (R ꢂ Me)
96 % (R ꢂ H)
90 % (R ꢂ Me)
S
R
R
9
10a (R ꢂ H)
0b (R ꢂ Me)
11a (R ꢂ H)
11b (R ꢂ Me)
1
Scheme 3. Alkylation of 2-mercaptobenzothiazole (9) with a-bromo esters to yield thioethers 10, and oxidation of 10 to
produce the corresponding sulfones 11.
1
R Br, TBAI
1
. NaOEt, EtOH
R1
N
S
O
S
O
N
S
O O
S
DBU, CH Cl
2. H O
2
2
2
CO Et
CO Et
2
2
R
CO H
2
R1
R
R
1
1
1a (R ꢂ H)
1b (R ꢂ Me)
5
12
Scheme 4. Mono- and dialkylation of the sulfone esters 11, and solvolysis/desulfination of 5 followed by hydrolysis
to yield dialkyl acetic acids 12.
Table 1. Yields of alkylated sulfone esters 5 from 11 and yields of carboxylic acids 12 following alkaline hydrolysis of 5
A
1
Entry
Starting sulfone
R
R
Yield of sulfone
Yield of carboxylic
ester 5 [%]
acid 12 [%]
B
a
11a
11a
11a
11a
11a
5a
H
Hexyl
38
53
67
68
55
24
84
82
85
81
83
18
80
81
63
42
84
–
C
b
Hexyl
Dodecyl
Benzyl
Allyl
Hexyl
Hexyl
Me
Hexyl
D,E
c
Dodecyl
Benzyl
Allyl
E
d
E
e
E
f
Dodecyl
Benzyl
Hexyl
E
g
5a
82
84
95
34
83
100
F
h
11b
11b
11b
11b
11b
i
Me
Benzyl
Dodecyl
Allyl
j
Me
k
l
Me
Me
Isopropyl
A
Five equivalents of DBU was used in all cases; 4 equiv. of alkyl bromide and 0.05 equiv. of TBAI were used in most cases.
One equivalent of iodohexane was used.
B
C
Eight equivalents of iodohexane was used.
D
E
Eight equivalents of KI was used instead of TBAI.
Eight equivalents of alkyl bromide was used.
Four equivalents of iodohexane was used.
F
Scheme 3. Alkylation of 2-mercaptobenzothiazole (9) with
either ethyl bromoacetate or ethyl 2-bromopropanoate gave the
corresponding thioethers 10a and 10b in quantitative yields.
Oxidation of 10a and 10b to the corresponding sulfones 11a and
iodide was performed in dichloromethane solution at room
temperature, using 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU)
as base (Scheme 4, Table 1). In the examples using alkyl
bromides, a catalytic amount of tetrabutylammonium iodide
[11]
1
1b was accomplished in high yields using aqueous hydrogen
was also added. As reported by other groups,
selective
peroxide in ethanol solution in the presence of a catalytic
amount of ammonium molybdate.
monoalkylation of a-sulfonylacetates is difficult to achieve in
acceptable yields. This was confirmed in our case for the
alkylation of 11a using one molar equivalent of iodohexane
(Table 1, entry a); the adduct was obtained in only 38 % yield. In
Alkylation of sulfonyl esters 11a, 11b, and 5a (5: R ¼ H,
1
R ¼ Hexyl) with an excess of either alkyl bromide or alkyl

1
224
W. M. Hussein and R. P. McGeary
other cases, the use of excess alkyl halide gave the disubstituted
products 5 in good-to-excellent yields (Table 1, entries b–e).
Similarly, alkylation of 5a and 11b with an excess of alkyl
halides gave the disubstituted products 5 in very good yields
(1H, ddd, J 6.2, 1.3, 0.6, ArH), 7.72 (1H, ddd, J 6.0, 1.3, 0.6,
ArH), 7.41–7.36 (1H, m, ArH), 7.30–7.25 (1H, m, ArH), 4.22
(2H, q, J 7.1, CH CH ), 4.15 (2H, s, SCH ), 1.27 (3H, t, J 7.1,
2
3
2
1
CH CH ) ( H NMR spectrum is in agreement with that
2
3
[10]
described by Blakemore et al. ).
(
Table 1, entries f–k). However, alkylation with the secondary
halide, isopropyl bromide, gave a very poor yield (18 %) of the
product (Table 1, entry l).
Ethyl 2-(Benzo[d]thiazol-2-ylthio)propanoate (10b)
Treatment of the sulfone esters 5 with sodium ethoxide in
ethanol gave the expected ethyl esters 8 (Scheme 2). These could
be isolated if desired. However, performing the subsequent
hydrolysis step without isolation of the intermediate esters
was more efficient, by simply adding water to the sodium
ethoxide solution. Extraction of the carboxylic acid product
from the reaction mixture then facilitated purification of the
final product 12. Yields for this step were generally very good,
except for these cases (Table 1, entries f and j) in which
pronounced emulsion formation during extraction with base
led to product loss.
Ethyl bromopropanoate (9.4 mL, 13.0 g, 72.0 mmol) and tri-
ethylamine (30.0 mL, 21.2 g, 210 mmol) were added to a
solution of 2-mercaptobenzothiazole (9) (10.0 g, 60.0 mmol) in
dichloromethane (250 mL). The reaction mixture was stirred for
1
4 h at room temperature under argon. The reaction mixture was
evaporated under vacuum and the residue was extracted in
diethyl ether (100 mL) and filtered off. The mixture was evap-
orated under vacuum to afford 10b as an orange oil, which
slowly solidified upon storage in the fridge (16.0 g, 100 %). RF
0
.55 (10 % EtOAc in LP). d (CDCl , 300 MHz) 7.86 (1H, ddd,
H 3
J 6.2, 1.3, 0.6, ArH), 7.73 (1H, ddd, J 6.0, 1.3, 0.6, ArH), 7.43–
.37 (1H, m, ArH), 7.31–7.26 (1H, m, ArH), 4.68 (1H, q, J 7.3,
SCH), 4.27–4.16 (2H, m, CH CH ), 1.70 (3H, d, J 7.3, CHCH ),
7
Conclusions
2
3
3
We have developed a new route to synthesising substituted
carboxylic acids and esters. Mono- or dialkylation of ethyl
1.25 (3H, t, J 7.1, CH CH ). d (CDCl , 75 MHz) 171.5, 164.2,
152.9, 135.4, 126.0, 124.4, 121.7, 120.9, 61.7, 45.0, 17.9, 14.0
(NMR spectra are in agreement with those described by
2
3
C
3
(benzothiazol-2-ylsulfonyl)acetate or ethyl 2-(benzothiazol-2-
[12]
Kuroda et al. ).
ylsulfonyl)propionate occurs readily, and these products can
undergo solvolysis with sodium ethoxide, followed by hydro-
lysis within a single reaction process to give substituted
carboxylic acids. Unlike the classical malonate ester synthesis
of carboxylic acids, our method does not employ the elevated
temperatures required for decarboxylation of malonic acid
intermediates.
Ethyl 2-(Benzo[d]thiazol-2-ylsulfonyl)acetate (11a)
Ammonium molybdate (3.5 g, 2.8 mmol) and aqueous hydrogen
peroxide 30 % (21.5 mL, 25.4 g, 0.22 mol) were added to a
solution of 10a (14.2 g, 56.0 mmol) in ethanol (50 mL) at 08C.
The reaction mixture was stirred for 48 h at room temperature
then evaporated under vacuum. The residue was extracted in
ethyl acetate (250 mL) and washed with water (2 ꢀ 50 mL) and
Experimental
˚
brine (50 mL), then dried over anhydrous Na SO , filtered, and
2 4
Ethanol was dried over 3-A molecular sieves. Light petroleum
LP, bp 40–608C) was distilled before use. NMR spectra were
evaporated under vacuum to afford 11a as a green solid (15.3 g,
(
[10]
9
d (CDCl , 300 MHz) 8.18 (1H, ddd, J 5.2, 2.2, 0.8, ArH), 7.98
6 %), mp 588C (lit. 58–598C ). R 0.45 (35 % EtOAc in LP).
F
recorded on 300, 400, and 500 MHz Bruker spectrometers.
Chemical shifts are reported in parts per million (ppm) on a d
scale, relative to the solvent peak (CDCl : d 7.24, d 77.0).
H
3
(
1H, ddd, J 5.0, 1.5, 0.9, ArH), 7.64–7.54 (2H, m, ArH), 4.54
2H, s, SO CH ), 4.14 (2H, q, J 7.1, CH CH ), 1.27 (3H, t, J 7.2,
3
H
C
(
CH CH ) ( H NMR spectrum is in agreement with that
[10]
described by Blakemore et al. ).
Coupling constants (J) are reported in hertz and peak multi-
plicities described as singlet (s), doublet (d), triplet (t), quartet
2
2
2
3
1
2
3
(q), quintet (quin), and multiplet (m). High-resolution (HR)
electrospray ionisation (ESI) accurate mass spectrometry (MS)
measurements were recorded in positive and negative modes on
a quadrupole time-of-flight instrument (Bruker) equipped with
an ESI source. Accurate mass measurements were carried out
with external calibration using sodium formate as reference
calibrant and/or Agilent tune mix (MW .500). Low- and high-
resolution electron impact ionisation mass measurements were
recorded using perfluorokerosene-H as reference calibrant. TLC
plates were visualised under UV illumination and KMnO4
solution.
Ethyl 2-(Benzo[d]thiazol-2-ylsulfonyl)propanoate (11b)
Ammonium molybdate (3.7 g, 3.0 mmol) and aqueous hydrogen
peroxide 30 % (23.0 mL, 27.2 g, 0.22 mol) were added to a
solution of 10b (16.0 g, 59.9 mmol) in ethanol (50 mL) at 08C.
The reaction mixture was stirred for 48 h at room temperature
then evaporated under vacuum. The residue was extracted in
ethyl acetate (250 mL) and washed with water (2 ꢀ 50 mL) and
brine (50 mL), then dried over anhydrous Na SO , filtered, and
2
4
evaporated under vacuum to afford 11b as a green solid (15.1 g,
0 %), mp 51–538C. R 0.56 (35 % EtOAc in LP). d (CDCl ,
500 MHz) 8.20 (1H, dt, J 6.1, 0.6, ArH), 7.99 (1H, dt, J 6.3,
9
F
H
3
Ethyl 2-(Benzo[d]thiazol-2-ylthio)acetate (10a)
0
4
.7, ArH), 7.68–7.55 (2H, m, ArH), 4.58 (1H, q, J 7.3, SCH),
.16–4.07 (2H, m, CH CH ), 1.75 (3H, d, J 7.4, CHCH ), 1.07
Ethyl bromoacetate (8.0 mL, 12.0 g, 72.0 mmol) and triethyla-
mine (30.0 mL, 21.2 g, 210 mmol) were added to a solution of
2
3
3
(3H, t, J 7.2, CH CH ). d (CDCl , 125 MHz) 165.1, 164.4,
2 3 C 3
2
-mercaptobenzothiazole (9) (10.0 g, 60.0 mmol) in dichloro-
1
1
52.5, 137.0, 128.2, 127.7, 125.5, 122.2, 64.3, 62.6, 13.6,
þ
methane (250 mL). The reaction mixture was stirred for 14 h at
room temperature under argon. The reaction mixture was
evaporated under vacuum and the residue was extracted in
diethyl ether (100 mL) and filtered off. The mixture was evap-
orated under vacuum to afford 10a as a yellow oil, which slowly
0.8. m/z (ESI–MS) 322 [M þ Na] . HRMS Anal. Calc. for
þ
C H NNaO S 322.0184. Found: 322.0176.
12 13
4
2
General Alkylation Procedure for the Preparation of 5
solidified upon storage in the fridge (15.0 g, 100 %). R 0.21
F
DBU (5 equiv.) was added to a solution of either 11a or 11b
(1 equiv.) in dichloromethane (5–10 mL). After stirring the
(
5 % ethyl acetate (EtOAc) in LP). d (CDCl , 300 MHz) 7.82
H
3

Syntheses of Carboxylic Acids and Esters
1225
þ
yellow solution for 10 min at room temperature under argon, the
alkyl iodide was added (when alkyl bromide was used,
13.5. m/z (ESI–MS) 488 [M þ Na] . HRMS Anal. Calc. for
þ
C H NNaO S 488.0966. Found: 476.0956.
2
5
23
4
2
0
.05 equiv. Tetrabutylammonium iodide (TBAI) was added).
The reaction mixture was stirred for 14–48 h then dichloro-
methane (150 mL) was added and the solution was washed
with 5 % HCl (3 ꢀ 50 mL), then dried over anhydrous Na SO ,
Ethyl 2-Allyl-2-(benzo[d]thiazol-2-ylsulfonyl)pent-
4-enoate (5e)
2
4
The product was purified by silica flash column chromato-
graphy (20 % EtOAc/LP) to afford 5e as a colourless oil (55 %
yield). R 0.24 (10 % EtOAc in LP). d (CDCl , 300 MHz) 8.19
filtered, and evaporated under vacuum to give the crude
product 5.
F
H
3
(
1H, ddd, J 5.1, 2.2, 1.4, ArH), 7.96 (1H, ddd, J 4.9, 1.6, 0.7,
Ethyl 2-(Benzo[d]thiazol-2-ylsulfonyl)octanoate (5a)
ArH), 7.61–7.51 (2H, m, ArH), 5.92–5.78 (2H, m, 2 ꢀ
The product was purified by silica flash column chromato-
graphy (10 % EtOAc/LP) to afford 5a as a colourless oil (38 %
yield). R 0.22 (10 % EtOAc in LP). d (CDCl , 500 MHz) 8.22
CH CH¼CH ), 5.21–5.12 (4H, m, 2 ꢀ CH CH¼CH ), 4.08
2
2
2
2
(2H, q, J 7.1, OCH CH ), 3.13–2.98 (4H, m, 2 ꢀ CH CH¼CH ),
2
3
2
2
F
H
3
1.04 (3H, t, J 7.1, OCH CH ). d (CDCl , 75 MHz) 166.2,
3
2
3
C
(
1H, dt, J 6.6, 0.7, ArH), 8.00 (1H, dt, J 6.6, 0.6, ArH), 7.65–7.57
2H, m, ArH), 4.40 (1H, dd, J 10.0, 5.2, SCH), 4.15 (2H, q, J 7.1,
163.8, 152.5, 137.2, 130.6, 128.1, 127.5, 125.6, 122.0, 120.5,
þ
(
OCH CH ), 2.25–2.19 (2H, m, CH (CH ) CH ), 1.42–1.20
76.4, 62.6, 34.8, 13.5. m/z (ESI–MS) 388 [M þ Na] . HRMS
þ
2
3
2
2 4
3
Anal. Calc. for C H NNaO S 388.0653. Found: 388.0651.
2
17 19
4
(8H, m, (CH ) CH ), 1.10 (3H, t, J 7.2, OCH CH ), 0.84 (3H,
t, J 7.0, (CH ) CH ). d (CDCl , 125 MHz) 164.9, 164.4, 152.6,
2 4 3 2 3
Ethyl 2-(Benzo[d]thiazol-2-ylsulfonyl)-2-
2
5
3
C
3
1
2
37.1, 128.2, 127.7, 125.7, 122.3, 69.8, 62.6, 31.3, 28.6, 26.8,
þ
hexyltetradecanoate (5f)
6.0, 22.4, 13.9, 13.8. m/z (ESI–MS) 392 [M þ Na] . HRMS
The product was purified by silica flash column chromato-
graphy (3–10 % EtOAc/LP) to afford 5f as a colourless oil (24 %
yield). R 0.49 (10 % EtOAc in LP). d (CDCl , 500 MHz) 8.22
þ
Anal. Calc. for C H NNaO S 392.0966. Found: 392.0950.
1
7
23
4
2
F
H
3
Ethyl 2-(Benzo[d]thiazol-2-ylsulfonyl)-2-
hexyloctanoate (5b)
(
7
1H, dd, J 6.7, 0.8, ArH), 7.98 (1H, dd, J 6.2, 1.2, ArH), 7.62–
.55 (2H, m, ArH), 4.10 (2H, q, J 7.1, OCH CH ), 2.32–2.27
2
3
The product was purified by silica flash column chromato-
graphy (10 % EtOAc/LP) to afford 5b as a yellow oil (53 %
yield). R 0.36 (10 % EtOAc in LP). d (CDCl , 300 MHz) 8.22
(2H, m, CH (CH ) CH ), 2.21–2.15 (2H, m, CH (CH ) CH ),
2 2 4 3 2 2 10 3
1.39–1.18 (28H, m, (CH ) CH and (CH ) CH ), 1.10 (3H,
2
4
3
2 10
3
t, J 7.1, OCH CH ), 0.86 (6H, t, J 6.4, (CH ) CH and
3
F
H
3
2
3
2 5
(1H, dt, J 5.3, 0.6, ArH), 7.98 (1H, dt, J 5.0, 1.5, ArH), 7.64–7.54
(CH ) CH ). d (CDCl , 125 MHz) 167.4, 164.3, 152.6,
2 11 3 C 3
(
2
2H, m, ArH), 4.10 (2H, q, J 7.1, OCH CH ), 2.35–2.13 (4H, m,
2
137.5, 128.0, 127.5, 125.7, 122.0, 78.1, 62.4, 31.9, 31.4, 30.3,
29.9, 29.62 (2 ꢀ C), 29.56, 29.49, 29.3, 29.2, 24.00, 23.97, 22.7,
3
ꢀ CH (CH ) CH ), 1.33–1.28 (16H, m, 2 ꢀ (CH ) CH ), 1.10
2
2 4
3
2 4
3
þ
(
(
3H, t, J 7.1, OCH CH ), 0.86 (6H, t, J 6.7, 2 ꢀ (CH ) CH ). d
22.5, 14.1, 14.0, 13.7. m/z (ESI–MS) 560 [M þ Na] . HRMS
2
3
2 5
3
C
þ
CDCl , 75 MHz) 167.4, 164.3, 152.6, 137.5, 128.0, 127.5,
3
Anal. Calc. for C H NNaO S 560.2844. Found: 560.2825.
2
29 47
4
1
1
25.8, 122.1, 78.1, 62.4, 31.4, 30.3, 29.6, 24.0, 22.5, 14.0,
þ
3.7. m/z (ESI–MS) 476 [M þ Na] . HRMS Anal. Calc. for
Ethyl 2-(Benzo[d]thiazol-2-ylsulfonyl)-2-
benzyloctanoate (5g)
þ
C H NNaO S 476.1905. Found: 476.1908.
2
3
35
4
2
The product was purified by silica flash column chromato-
graphy (5–10 % EtOAc/LP) to afford 5g as a colourless oil
Ethyl 2-(Benzo[d]thiazol-2-ylsulfonyl)-2-
dodecyltetradecanoate (5c)
(84 % yield). RF 0.34 (10 % EtOAc in LP). dH (CDCl3,
The product was purified by silica flash column chromato-
graphy (3–10 % EtOAc/LP) to afford 5c as a yellow oil (67 %
yield). R 0.44 (10 % EtOAc in LP). d (CDCl , 300 MHz)
500 MHz) 8.23 (1H, dd, J 6.1, 1.3, ArH), 8.00 (1H, dd, J 6.2,
1.4, ArH), 7.64–7.57 (2H, m, ArH), 7.24–7.14 (5H, m, BzH),
4.17–4.06 (2H, m, OCH CH ), 3.82 (1H, d, J 13.8, CH Ph), 3.57
F
H
3
2
3
a
8
7
2
2
.21 (1H, dd, J 5.2, 1.4, ArH), 7.97 (1H, dd, J 5.1, 1.3, ArH),
.62–7.53 (2H, m, ArH), 4.10 (2H, q, J 7.1, OCH CH ),
(1H, d, J 13.8, CH Ph), 2.20–2.14 (1H, m, CH H (CH ) CH ),
b A B 2 4 3
2.11–2.05 (1H, m, CH H (CH ) CH ), 1.62–1.57 (2H, m,
A
2
3
B
2 4
3
.29–2.14 (4H, m, 2 ꢀ CH (CH ) CH ), 1.38–1.18 (40H, m,
CH CH (CH ) CH ), 1.25–1.20 (6H, m, (CH ) CH ), 1.07
2 2 2 3 3 2 3 3
2
2 10
3
ꢀ (CH ) CH ), 1.10 (3H, t, J 7.1, OCH CH ), 0.85 (6H, t,
(3H, t, J 7.2, OCH CH ), 0.83 (3H, t, J 7.0, (CH ) CH ). d
2 3 2 5 3 C
(CDCl , 125 MHz) 167.1, 164.9, 152.6, 137.5, 134.1, 130.4,
3
2
10
3
2
3
J 6.4, 2 ꢀ (CH ) CH ). d (CDCl , 75 MHz) 167.4, 164.3,
2
11
3
C
3
1
3
1
52.6, 137.5, 128.0, 127.4, 125.7, 122.0, 78.1, 62.4, 31.9,
0.3, 29.9, 29.60, 29.55, 29.5, 29.3, 29.2, 24.0, 22.6, 14.1,
3.7. m/z (ESI–MS) 644 [M þ Na] . HRMS Anal. Calc. for
128.4, 128.1, 127.7, 127.4, 125.8, 122.1, 79.0, 62.5, 38.0, 31.3,
þ
30.9, 29.9, 24.3, 22.5, 14.0, 13.6. m/z (ESI–MS) 482 [M þ Na] .
þ
þ
HRMS Anal. Calc. for C H NNaO S 482.1436. Found:
2
4
29
4
2
þ
C H NNaO S 644.3783. Found: 644.3764.
4
482.1422.
3
5
59
2
Ethyl 2-(Benzo[d]thiazol-2-ylsulfonyl)-2-benzyl-3-
Ethyl 2-(Benzo[d]thiazol-2-ylsulfonyl)-2-
phenylpropanoate (5d)
methyloctanoate (5h)
The product was purified by silica flash column chromato-
graphy (5–20 % EtOAc/LP) to afford 5d as a colourless
semisolid (68 % yield). R 0.27 (10 % EtOAc in LP). d (CDCl ,
500 MHz) 8.19 (1H, dt, J 6.6, 0.7, ArH), 7.94 (1H, dt, J 7.3, 0.9,
ArH), 7.63–7.55 (2H, m, ArH), 7.27–7.20 (10H, m, BzH), 4.20
The product was purified by silica flash column chromato-
graphy (5–10 % EtOAc/LP) to afford 5h as a colourless oil
(82 % yield). RF 0.28 (10 % EtOAc in LP). dH (CDCl3,
300 MHz) 8.21 (1H, dt, J 5.3, 1.5, ArH), 7.97 (1H, dt, J 4.9,
0.9, ArH), 7.63–7.53 (2H, m, ArH), 4.26–4.02 (2H, m,
OCH CH ), 2.46 (1H, dt, J 12.1, 7.5, SO CCH ), 2.05 (1H, dt,
F
H
3
(
(
(
2H, q, J 7.1, OCH CH ), 3.82 (2H, d, J 14.4, 2 ꢀ CH Ph), 3.68
2
3
a
2
3
2
a
2H, d, J 14.4, 2 ꢀ CH Ph), 1.13 (3H, t, J 7.2, OCH CH ). d
b 2 3 C
J 12.2, 7.6, SO CCH ), 1.73 (3H, s, SO CCH ), 1.48–1.19 (8H,
2 b 2 3
CDCl , 125 MHz) 166.9, 166.0, 152.2, 137.3, 134.0, 131.0,
3
m, (CH ) CH ), 1.12 (3H, t, J 7.1, OCH CH ), 0.84 (3H, t, J 6.8,
2 4 3 2 3
1
28.0, 127.8, 127.3, 127.2, 125.5, 121.9, 79.4, 62.6, 38.6,
(CH ) CH ). d (CDCl , 75 MHz) 167.3, 163.6, 152.7, 137.3,
2 5 3 C 3

1
226
W. M. Hussein and R. P. McGeary
1
2
28.0, 127.5, 125.7, 122.0, 74.5, 62.6, 32.6, 31.3, 29.2, 24.1,
þ
General Desulfination/Hydrolysis Procedure
for the Preparation of 12
2.4, 16.4, 13.9, 13.7. m/z (ESI–MS) 406 [M þ Na] . HRMS
þ
Anal. Calc. for C H NNaO S 406.1123. Found: 406.1128.
1
8
25
4
2
Sodium metal (20 equiv.) was added to a solution of the ester 5
(1 equiv.) in ethanol (5 mL). The solution was stirred for 14 h at
Ethyl 2-(Benzo[d]thiazol-2-ylsulfonyl)-2-methyl-3-
phenylpropanoate (5i)
room temperature under argon atmosphere. Water (5 mL) was
added and the reaction mixture was heated at 30–408C for 14 h.
The solution was evaporated under vacuum and the residue was
taken up in 2 M sodium hydroxide solution (100 mL) and
washed with dichloromethane (3 ꢀ 50 mL). The aqueous layer
was acidified with concentrated HCl and extracted with
dichloromethane (3 ꢀ 50 mL). The organic layer was dried over
anhydrous Na SO , filtered, and evaporated under vacuum to
The product was purified by silica flash column chromato-
graphy (5–20 % EtOAc/LP) to afford 5i as a colourless semi-
solid (85 % yield). R 0.17 (10 % EtOAc in LP). d (CDCl3,
3
ArH), 7.66–7.57 (2H, m, ArH), 7.26–7.24 (3H, m, BzH), 7.12–
F
H
00 MHz) 8.25 (1H, dd, J 5.1, 1.6, ArH), 8.00 (1H, dt, J 3.3, 1.4,
7
.10 (2H, m, BzH) 4.13 (2H, q, J 7.2, OCH CH ), 3.98 (1H, d, J
2 3
2
4
1
SO CCH ), 1.09 (3H, t, J 7.1, OCH CH ). d (CDCl3,
3.2, CH Ph), 3.35 (1H, d, J 13.3, CH Ph), 1.64 (3H, s,
give the carboxylic acid products 12.
a
b
2
3
2
3
C
7
1
5 MHz) 166.8, 163.4, 152.7, 137.4, 133.6, 131.3, 128.5,
28.2, 127.6, 127.5, 125.8, 122.1, 75.1, 62.7, 38.6, 15.9, 13.7.
Octanoic Acid (12a)
Colourless oil (70 mg, 80 %). dH (CDCl , 300 MHz) 2.31
3
þ
m/z (ESI–MS) 412 [M þ Na] . HRMS Anal. Calc. for
(
2H, t, J 7.5, CH COOH), 1.67–1.55 (2H, m, CH CH COOH),
2 2 2
þ
C H NNaO S 412.0653. Found: 412.0654.
1
9
19
4
2
1
d (CDCl , 75 MHz) 180.7, 34.1, 31.6, 29.0, 28.9, 24.6, 22.6,
.35–1.21 (8H, m, (CH ) CH ), 0.85 (3H, t, J 6.8, CH ).
2 4 3 3
C
3
Ethyl 2-(Benzo[d]thiazol-2-ylsulfonyl)-2-
methyltetradecanoate (5j)
14.0 (NMR spectra are in agreement with those described by
[13]
Zweifel et al. ).
The product was purified by silica flash column chromato-
graphy (3–20 % EtOAc/LP) to afford 5j as a colourless oil (81%
yield). R 0.47 (10 % EtOAc in LP). d (CDCl , 500 MHz) 8.18
2-Hexyloctanoic Acid (12b)
F
H
3
Colourless oil (90mg, 81 %). d (CDCl , 300MHz) 2.35–2.27
H
3
(1H, dt, J 6.5, 0.6, ArH), 7.95 (1H, dt, J 6.2, 0.7, ArH), 7.60–7.52
(
1H, m, CHCOOH), 1.64–1.57 (2H, m, 2 ꢀ CH CHCOOH),
a
(
2H, m, ArH), 4.17–4.07 (2H, m, OCH CH ), 2.46 (1H, dt, J 8.3,
3
2
1
2
7
.48–1.42 (2H, m, 2 ꢀ CH CHCOOH), 1.28–1.23 (16H, m,
b
4
SO CCH ), 1.45–1.12 (20H, m, (CH ) CH ), 1.09 (3H, t, J 7.1,
.4, SO CCH ), 2.04 (1H, dt, J 8.5, 4.7, SO CCH ), 1.71 (3H, s,
2 a 2 b
ꢀ (CH ) CH ), 0.86 (6H, t, J 13.5, 2 ꢀ CH ). d (CDCl ,
2
4
3
3
C
3
2
3
2 10
3
5MHz) 182.7, 45.5, 32.2, 31.7, 29.2, 27.3, 22.6, 14.0 (NMR
OCH CH ), 0.82 (3H, t, J 7.0, (CH ) CH ). d (CDCl3,
2
[14]
3
2 11
3
C
spectra are in agreement with those described by Cohen et al. ).
1
1
2
25 MHz) 167.2, 163.5, 152.6, 137.2, 128.0, 127.4, 125.6,
22.0, 74.4, 62.4, 32.5, 31.7, 29.44, 29.39, 29.3, 29.2, 29.1,
2-Dodecyltetradecanoic Acid (12c)
þ
4.1, 22.5, 16.3, 14.0,13.6. m/z(ESI–MS)490[Mþ Na] . HRMS
þ
Colourless solid (117 mg, 63 %). dH (CDCl , 400 MHz)
3
Anal. Calc. for C H NNaO S 490.2062. Found: 490.2063.
37
24
4
2
2
.34–2.32 (1H, m, CHCOOH), 1.58–1.55 (2H, m, 2 ꢀ CH CH-
a
COOH), 1.47–1.43 (2H, m, 2 ꢀ CH CHCOOH), 1.38–1.15
Ethyl 2-(Benzo[d]thiazol-2-ylsulfonyl)-2-
methylpent-4-enoate (5k)
b
(
(
40H, m, 2 ꢀ (CH ) CH ), 0.86 (6H, t, J 6.8, 2 ꢀ CH ). d
3
2 10
3
3
C
CDCl , 100 MHz) 183.2, 45.6, 32.2, 31.9, 29.7, 29.65, 29.61,
The product was purified by silica flash column chromato-
graphy (20 % EtOAc/LP) to afford 5k as a colourless oil (83 %
yield). R 0.25 (10 % EtOAc in LP). d (CDCl , 300 MHz) 8.22
2
ment with those described by Nishizawa et al. ). m/z (ESI–
9.57, 29.5, 29.4, 27.4, 22.7, 14.1 (NMR spectra are in agree-
[15]
F
H
3
ꢁ
ꢁ
MS) 395 [M ꢁ H] . HRMS Anal. Calc. for C H O 395.3889.
2
6
51
2
(1H, ddd, J 5.1, 2.2, 0.8, ArH), 7.98 (1H, ddd, J 5.0, 2.2, 1.6,
Found: 395.3899.
ArH), 7.64–7.57 (2H, m, ArH), 5.69–5.56 (1H, m, CH¼CH ),
2
5
3
.23–5.16 (2H, m, CH¼CH ), 4.21–4.02 (2H, m, OCH CH ),
a 2
2
2
3
2-Benzyl-3-phenylpropanoic Acid (12d)
.29 (1H, dd, J 13.5, 6.6, CH CH¼CH ), 2.79 (1H, dd, J 9.7, 7.9,
Colourlesssolid(116 mg, 42 %). d (CDCl , 300 MHz)7.32–
H
CH CH¼CH ), 1.72 (3H, s, SO CCH ), 1.11 (3H, t, J 7.1,
3
b
2
2
3
7
.16 (10H, m, BzH), 3.03–2.96 (3H, m, CHCOOH and 2 ꢀ
OCH CH ). d (CDCl , 75 MHz) 166.8, 163.3, 152.7, 137.4,
2
3
C
3
CH Ph), 2.86–2.80 (2H, m, 2 ꢀ CH Ph). d (CDCl , 75 MHz)
1
1
30.1, 128.1, 127.6, 125.8, 122.1, 121.2, 73.7, 62.7, 37.3, 16.3,
þ
a
b
C
3
180.4, 138.7, 128.9, 128.5, 126.5, 49.2, 37.7 (NMR spectra are in
3.7. m/z (ESI–MS) 362 [M þ Na] . HRMS Anal. Calc. for
[16]
agreement with those described by Koder et al. ).
þ
C H NNaO S 362.0497. Found: 362.0498.
1
5
17
4
2
2-Allylpent-4-enoic Acid (12e)
Ethyl 2-(Benzo[d]thiazol-2-ylsulfonyl)-2,3-
dimethylbutanoate (5l)
Colourless oil (138 mg, 84 %). d (CDCl , 300 MHz) 5.82–
H
3
5
2
.68 (2H, m, 2 ꢀ CH¼CH ), 5.11–5.02 (4H, m, 2 ꢀ CH¼CH ),
The product was purified by silica flash column chromatog-
raphy (5–10 % EtOAc/LP) to afford 5l as a colourless oil (18 %
yield). R 0.27 (10 % EtOAc in LP). d (CDCl , 300 MHz) 8.20
2
2
.53 (1H, quin, J 6.9, CHCOOH), 2.43–2.22 (4H, m, 2 ꢀ
CH CH¼CH ). d (CDCl , 75 MHz) 180.6, 134.9, 117.3,
2
2
C
3
F
H
3
1
4.8, 35.4 ( H NMR spectrum is in agreement with that
4
described by Hyun et al. ).
(
1H, dt, J 5.1, 0.7, ArH), 7.97 (1H, dt, J 5.0, 1.6, ArH), 7.63–7.53
2H, m, ArH), 4.27–4.01 (2H, m, OCH CH ), 3.02 (1H, septet,
[
17]
(
J 6.8, CH(CH ) ), 1.71 (3H, s, SO CCH ), 1.29 (3H, d, J 6.7,
2
3
3
2
2
3
2-Benzyloctanoic Acid (12g)
CHCH ), 1.14 (3H, t, J 7.1, OCH CH ), 0.89 (3H, d, J 6.8,
3
a
2
3
CHCH ). d (CDCl , 75 MHz) 168.0, 164.4, 152.5, 137.2,
3
Colourless semisolid (70 mg, 82 %). d (CDCl , 300 MHz)
3
3
b
C
H
1
1
28.0, 127.5, 125.7, 122.0, 78.9, 62.5, 31.2, 18.8, 17.7, 13.7,
þ
7.30–7.18 (5H, m, BzH), 3.00(1H, dd, J 13.4, 7.8, CH Ph), 2.81–
a
1.1. m/z (ESI–MS) 364 [M þ Na] . HRMS Anal. Calc. for
2.66 (2H, m, CH Ph and CHCOOH), 1.76–1.59 (1H, m, CH CH-
b
a
þ
C H NNaO S 364.0653. Found: 364.0658.
19
COOH), 1.59–1.42 (1H, m, CH CHCOOH), 1.42–1.22 (8H, m,
b
1
5
4
2

Syntheses of Carboxylic Acids and Esters
1227
(
CH ) CH ), 0.89(3H, t, J 6.6, CH ). d (CDCl , 75 MHz)182.0,
3
Supplementary Material
2
4
3
3
C
1
2
39.1, 128.9, 128.4, 126.4, 47.4, 38.1, 31.7, 31.6, 29.1, 27.1,
þ
The NMR spectra of all new compounds are available on the
Journal’s website.
2.6, 14.0. m/z (ESI–MS) 257 [M þ Na] . HRMS Anal. Calc. for
þ
C H NaO 257.1517. Found 257.1506.
22
1
5
2
References
2-Methyloctanoic Acid (12h)
[
1] M. B. Smith, J. March, March’s Advanced Organic Chemistry:
Reactions, Mechanisms, and Structure, 6th ed. 2007 (John Wiley &
Sons, Inc.: New Jersey).
Colourless oil (130 mg, 84 %). dH (CDCl , 400 MHz) 2.43
3
(1H, sextet, J 7.0, CHCOOH), 1.72–1.62 (1H, m, CH CH-
COOH), 1.44–1.37 (1H, m, CH CHCOOH), 1.35–1.22 (8H,
a
[2] J. Cason, Org. Synth. 1958, 38, 52. doi:10.15227/ORGSYN.038.0052
[3] K. Plesniak, A. Zarecki, J. Wicha, Top. Curr. Chem. 2007, 275, 163.
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[4] C. A ¨ı ssa, Eur. J. Org. Chem. 2009, 1831. doi:10.1002/EJOC.
200801117
b
m, (CH ) CH ), 1.15 (3H, d, J 7.0, CHCH ), 0.86 (3H, t, J 7.2,
2
4
3
3
(
CH ) CH ). d (CDCl , 75 MHz) 183.3, 39.4, 33.5, 31.7, 29.2,
2 5 3 C 3
1
7.1, 22.6, 16.8, 14.0 ( H NMR spectrum is in agreement with
2
that described by Kumagai et al. ).
[
18]
[
5] P. R. Blakemore, J. Chem. Soc. Perkin Trans. 1 2002, 2563.
doi:10.1039/B208078H
2-Methyl-3-phenylpropanoic Acid (12i)
[
6] F.L. Wu, B.P. Ross, R.P. McGeary, Eur. J. Org. Chem. 2010, 2010,
1989. doi:10.1002/EJOC.200901264
[7] M. Baltas, L. Cazaux, L. Gorrichon-Guigon, P. Maroni, P. Tisnes,
Colourless oil (80 mg, 95 %). dH (CDCl , 300 MHz) 7.35–
3
.22 (5H, m, BzH), 3.13 (1H, dd, J 13.1, 6.1, CH Ph), 2.85–2.68
a
7
Tetrahedron Lett. 1985, 26, 4447. doi:10.1016/S0040-4039(00)
(2H, m, CH Ph and CHCOOH), 1.22 (3H, d, J 6.8, CH ).
d (CDCl , 75 MHz) 182.5, 139.0, 129.0, 128.4, 126.4, 41.2,
b
3
8
8926-1
C
3
[
[
8] W. F. Jarvis, M. D. Hoey, A. L. Finocchio, D. C. Dittmer, J. Org.
Chem. 1988, 53, 5750. doi:10.1021/JO00259A026
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doi:10.1002/PRAC.19301270119
10] P. R. Blakemore, D. K. H. Ho, W. M. Nap, Org. Biomol. Chem. 2005,
3
9.3, 16.4 (NMR spectra is in agreement with those described by
ꢁ
[
19]
Ueberbacher et al. ). m/z (ESI–MS) 163 [M ꢁ H] . HRMS
ꢁ
Anal. Calc. for C H O 163.0759. Found: 163.0763.
1
0
11
2
[
[
[
[
[
2-Methyltetradecanoic Acid (12j)
3, 1365. doi:10.1039/B500713E
11] D. A. Alonso, C. Najera, M. Varea, Helv. Chim. Acta 2002, 85, 4287.
doi:10.1002/HLCA.200290013
12] K. Kuroda, Y. Maruyama, Y. Hayashi, T. Mukaiyama, Bull. Chem.
Soc. Jpn. 2009, 82, 381. doi:10.1246/BCSJ.82.381
13] T. Zweifel, J.-V. Naubron, H. Gruetzmacher, Angew. Chem. Int. Ed.
Colourless solid (110 mg, 34 %). d (CDCl , 300 MHz) 2.43
H
3
(1H, sextet, J 7.0, CHCOOH), 1.52–1.51 (1H, m, CH CH-
COOH), 1.50–1.37 (1H, m, CH CHCOOH), 1.36–1.19 (20H,
a
b
m, (CH ) CH ), 1.15 (3H, d, J 7.0, CHCH ), 0.86 (3H, t, J 6.7,
2
10
3
3
(CH ) CH ). d (CDCl , 75 MHz) 183.5, 39.4, 33.5, 31.9, 29.7,
2 11 3 C 3
2
009, 48, 559. doi:10.1002/ANIE.200804757
14] Y. Cohen, E. Bodner, M. Richman, M. Afri, A. A. Frimer, Chem. Phys.
2
9.63, 29.59, 29.50, 29.46, 29.3, 27.1, 22.7, 16.8, 14.1. m/z
ꢁ
ꢁ
(ESI–MS) 241 [M ꢁ H] . HRMS Anal. Calc. for C H O
1
5
29
2
Lipids 2008, 155, 98. doi:10.1016/J.CHEMPHYSLIP.2008.07.004
2
41.2168. Found: 241.2179.
[15] M. Nishizawa, H. Imagawa, H. Yamamoto, J. Sakurai, M. Oda,
Preparation of trehalose compound, process for production of the
compound, and immuno-stimulative agent comprising the compound,
WO 2008093700 2008.
2-Methylpent-4-enoic Acid (12k)
Colourless oil (90 mg, 83 %). dH (CDCl , 300 MHz) 5.82–
3
[
16] R. L. Koder, B. R. Lichtenstein, J. F. Cerda, A.-F. Miller, P. L. Dutton,
5
2
.69 (1H, m, CH CH¼CH ), 5.11–5.01 (2H, m, CH CH¼CH ),
2
2
2
2
Tetrahedron Lett. 2007, 48, 5517. doi:10.1016/J.TETLET.2007.
.54 (1H, sextet, J 6.9, CHCOOH), 2.47–2.38 (1H, m,
0
5.165
CH CH¼CH ), 2.24–2.14 (1H, m, CH CH¼CH ), 1.17 (3H,
a
2
b
2
[17] M. H. Hyun, Y. Song, Y. J. Cho, D. H. Kim, J. Chromatogr. A 2006,
1108, 208. doi:10.1016/J.CHROMA.2006.01.012
[18] A. Kumagai, Y. Nagaoka, T. Obayashi, Y. Terashima, H. Tokuda,
Y. Hara, T. Mukainaka, H. Nishino, H. Kuwajima, S. Uesato, Bioorg.
Med. Chem. 2003, 11, 5143. doi:10.1016/J.BMC.2003.08.016
1
d, J 6.6, CH ) ( H NMR spectrum is in agreement with that
3
[
19]
described by Ueberbacher et al. ).
2,3-Dimethylbutanoic Acid (12l)
[
19] B. J. Ueberbacher, H. Griengl, H. Weber, Tetrahedron Asymmetry
008, 19, 838. doi:10.1016/J.TETASY.2008.03.009
Colourless oil (50 mg, 100 %). dH (CDCl , 300 MHz) 2.26
3
2
(1H, quin, J 7.0, CHCOOH), 1.93 (1H, sextet, J 6.8, CH(CH ) ),
3 2
[20] Y. C. Kuo, T. Aoyama, T. Shioiri, Chem. Pharm. Bull. (Tokyo) 1982,
30, 2787. doi:10.1248/CPB.30.2787
1
CH CHCHCOOH), 0.91 (3H, d, J 6.8, CH CHCHCOOH)
.11 (3H, d, J 7.0, CH CHCOOH), 0.95 (3H, d, J 6.8,
3
3
3
1
( H NMR spectrum is in agreement with that described by
20]
Kuo et al. ).
[