Microwave-assisted direct thioesterification of carboxylic acids

Article abstract of DOI:10.1021/acs.joc.7b01705

A one-pot synthesis of thioesters directly from carboxylic acids, N,N′-diphenylthiourea, triethylamine, and primary alkyl halides is described. Microwave-assisted heating and a catalytic amount of 4- (dimethylamino)pyridine (DMAP) further improved the yields. Both aromatic and aliphatic carboxylic acids were converted to the corresponding thioesters, and many functional groups were compatible with this reaction. Several possible reaction intermediates were investigated, and the quaternary ammonium salts, derived from alkyl halides and tertiary amines, were the intermediates to yield thioesters. A new reaction mechanism for this thioesterification is proposed.

Full text of DOI:10.1021/acs.joc.7b01705

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Article
Microwave-assisted direct thioesterification of carboxylic acids
Yen-Lin Chou, Yi Jhong, Sharada Prasanna Swain, and Duen-Ren Hou
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b01705 • Publication Date (Web): 06 Sep 2017
Downloaded from http://pubs.acs.org on September 7, 2017
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Microwaveꢀassisted direct thioesterification of carboxylic
acids
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Yen-Lin Chou, Yi Jhong, Sharada Prasanna Swain and Duen-Ren Hou*
Department of Chemistry, National Central University, No. 300 JhongꢀDa Road, Jhongꢀli,
Taoyuan, Taiwan 32001.
drhou@ncu.edu.tw
Table of contents (TOC)
ABSTRACT. A oneꢀpot synthesis of thioesters directly from carboxylic acids, N,N’ꢀ
diphenylthiourea, triethylamine and primary alkyl halides is described. Microwaveꢀassisted
heating and a catalytic amount of 4ꢀ(dimethylamino)pyridine (DMAP) further improved the
yields. Both aromatic and aliphatic carboxylic acids were converted to the corresponding
thioesters, and many functional groups were compatible with this reaction. Several possible
reaction intermediates were investigated, and the quaternary ammonium salts, derived from
alkyl halides and tertiary amines, were the intermediates to yield thioesters. A new reaction
mechanism for this thioesterification is proposed.
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Introduction
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Thioesters (thiol esters) are useful synthetic building blocks and often considered as activated
carboxylic acids or acyl transfer agents for various nucleophiles.1,2 For example, acetylꢀCoA is
the most common thioester in cells and an acetyl donor to oxaloacetate in the citric acid cycle.3
Thioesters are also precursors to the formation of radicals and activate olefins for 1,4ꢀconjugate
addition.4,5 Recently, the synthesis of thioesters has received chemists’ attention because a Cꢀ
terminal peptide thioester is essential for native chemical ligation (NCL), an important chemical
method for synthesizing proteins.6
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Conventional methods for preparing thioesters often require the activation of carboxylic acids by
converting them to various acyl compounds amenable to subsequent acyl substitution with
thiols.7 Alternatively, the substitution reactions of alkyl halides with thiocarboxylic acids8 and
acidꢀcatalyzed condensation reaction of carboxylic acids and thiols also yield thioesters.9 Various
metalꢀcatalyzed or organocatalyzed coupling reactions such as oxidative coupling reactions
between aldehydes and thiols have also become a useful tool for preparing thioesters.10,11 These
reports indicate the interest in developing methods for synthesizing thioesters and the potential
for discovering new and interesting chemistry of thioesters.
Recently, we reported an amineꢀcatalyzed, oneꢀpot synthesis of thioesters directly from
carboxylic acids, thioureas, and Michael acceptors.12 Here, we describe a new microwaveꢀ
assisted thioesterification of carboxylic acids that features use of an activating agent and a new
source of the thiolate group, i.e., primary alkyl halides and N,N’ꢀdiphenylthiourea, thereby not
requiring use of a foulꢀsmelling thiol (Scheme 1).13 Our studies also suggest a new reaction
mechanism for this thioesterification.
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Scheme 1. Synthesis of thioesters using thiourea.
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This work
S
O
C
O
NEt3, cat. DMAP
R2
X
+
+
R'
R'
R2
C
R1
OH
N
N
S
R1
microwave, 160 °C, 30 min
H
H
R1 = aryl, R2 = benzyl, allyl, R' = Ph
alkyl primary alkyl
X = Cl, Br
28 examples
Results and Discussion
The results derived from our initial screening for the conversion of 4ꢀmethoxybenzoic acid (1a)
to Sꢀbenzyl 4ꢀmethoxybenzothioate (5aa) are summarized in Table 1. Conducting the reaction in
refluxing toluene only yielded 18% of the thioester (entry 1). Many conventional methods to
promote this reaction, such as heating in DMF (entry 2), have been attempted; however, the
formation of the desired thioester remained poor. We found that the conversion improved
significantly when the reaction mixture was heated by microwave in toluene. When the boiling
point of toluene (110 °C) was chosen as the reaction temperature, the microwaveꢀassisted
reaction (40 min) provided a yield twice of that from conventional heating (entry 3).14 Under
pressurized conditions, the reaction temperatures could be further elevated, and the yields (35–
66%) were better than those resulted from conventional heating (entries 4–11). However, the
products derived from these microwaveꢀassisted reactions were often contaminated with 3% of
dibenzyl disulfide (6) and 3% benzyl 4ꢀmethoxybenzoate (7). After screening of the reaction
conditions, the optimized reaction temperature and microwaveꢀirradiation time, 160 °C and 30
min (entry 8), were chosen for our subsequent studies.
Table 1. Reaction conditions for thioesterification.
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entrya
1
heating
oil bath
temp (°C)
110
time
16 h
yield (%)b
18
2
3
oil bath
110
110
130
150
150
160
160
160
170
170
16 h
13c
35
microwave
microwave
microwave
microwave
microwave
microwave
microwave
microwave
microwave
40 min
40 min
40 min
60 min
40 min
30 min
20 min
30 min
20 min
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35
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66
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66(61)d
47
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55
11
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aStarting materials (1aꢀ3a, 0.4 mmol each), triethylamine (0.4 mmol),
DMAP (0.04 mmol), and toluene (2 mL) were combined in a pressure tube
and heated by microwave (250 W, monitored by IR temperature sensor).
bYields determined by 1H NMR spectroscopy using 1,3,5ꢀ
c
d
trimethoxybenzene as the internal standard. DMF as the solvent. Isolated
yield.
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Several factors for influencing this multicomponent reaction were also examined, and the results
are shown in Table 2. Compared to the standard condition (entry 1), using thiourea (2b) and
N,N’ꢀdimethylthiourea (2c) did not yield the thioester due to their limited solubility in toluene
(entries 2 and 3, respectively). Very little thioester resulted from the reaction without
triethylamine (entry 4), which suggests that the base was essential for the reaction. On the other
hand, a catalytic amount of 4ꢀ(dimethylamino)pyridine (DMAP, 4) raised the yield, but its use
also increased the formation of byꢀproducts 6 and 7 (entry 1 vs. entry 5). Raising the amount of
DMAP to 20 mol% did not further improve the yield (entry 6). Benzyl chloride yielded almost
twice amount of thioester 5aa than benzyl bromide (entry 1 vs. entry 7), and more byꢀproducts (6
and 7) were generated while using benzyl bromide.
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Table 2. Reagents for thioesterification
DMAP
(mol%)
entrya
1
reactant 2
reactant 3
BnCl
base
Et3N
Et3N
yield (%)b
2a
10
66
0
BnCl
10
10
2
3
BnCl
Et3N
0
2
4
5
6
BnCl
BnCl
BnCl
ꢀ
10
0
2a
2a
2a
Et3N
Et3N
48c,d
44
20
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BnBr
Et3N
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2a
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b
aReactions conducted in toluene, microwaveꢀassisted heating (250 W), 160 °C, 30 min. Yields
1
8
9
of 5aa determined by H NMR spectroscopy using 1,3,5ꢀtrimethoxybenzene as the internal
c
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standard. Reactions conducted in toluene, microwaveꢀassisted heating (250 W), 150 °C, 40
min. dByꢀproducts 6 and 7 were not detected.
This direct thioesterification was applied to prepare other thioesters (Table 3). As we had
observed in the previous studies,12 some thioesters were unstable and often lost during the
1
purification, so the reported yields were determined by H NMR analysis of the crude products
with an internal standard (1,3,5ꢀtrimethoxybenzene); isolated yields, shown in parentheses, were
obtained after column chromatography. Benzoic acid (1b) gave a very similar yield of the
corresponding thioester (64%, entry 1) as did 1a. Slightly lower yields were obtained with the
methylꢀsubstituted benzoic acids (1c–1f), and the difference in yields for the benzoic acids
bearing an orthoꢀ or paraꢀmethyl group was minor (within 10%, entries 2–5). SꢀBenzyl 3ꢀ
methoxyꢀ2ꢀmethylbenzothioate (5ga), derived from a diꢀsubstituted benzoic acid 1g, was isolated
in 52% yield (entry 6). Halogen substituents (1hꢀ1j, entries 7–9) did not impede the reaction, and
2ꢀiodobenzoic acid provided the best yield (74%) among the substrates screened. Both electronꢀ
donating (ꢀNMe2 in 1k) and electronꢀwithdrawing groups (ꢀCO2Me and ꢀNO2 in 1l and 1m,
respectively) were compatible with this process (entries 10–12).
The reaction is not limited to benzoic acid and its derivatives since both 2ꢀnaphthoic acid (1n)
and 4ꢀmethoxycinnamic acid (1o) were converted to the corresponding thioesters 5na and 5oa
(entries 13 and 14, respectively). However, the yield of the thioester 5pa derived from 4ꢀ
methoxyphenylacetic acid (1p) was poor (entry 15). Aliphatic carboxylic acids 1q–1t also
yielded the corresponding thioesters 5qa–5ta; however, their yields were moderate at most
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(entries 16–19). The yields of the aliphatic thioesters improved with increased steric hindrance
around the carboxyl group, i.e., the degree of substitution at the ꢀcarbon increases from 2°, to
3°, to 4° in 1r, 1s, and 1t (entries 17–19). This may be related to the relative stability of the
generated thioesters under the reaction conditions (vide infra).
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Table 3. Thioesterification with various carboxylic acids.
entrya
carboxylic acid
thioester
yield (%)b
64(60)
1
48
55
53
58
2
3
4
CO2H
1d
CO2H
1e
5
56(52)
50(49)
6
7
C(O)SBn
5ha
F
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54(51)
74(66)
38(42)
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8
CO2H
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1j
I
10
11
12
13
14
15
C(O)SBn
5la
MeO2C
O2N
51(44)
C(O)SBn
5ma
63(60)
37(32)
21(13)
19(10)
O
16
17
SBn
5qa
24
28
18
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aReactions conducted in toluene, microwaveꢀassisted heating (250 W), 160 °C,
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b
1
30 min. Yields determined by H NMR using 1,3,5ꢀtrimethoxybenzene as the
internal standard; isolated yields shown in parentheses.
In addition to benzyl halides, other alkyl bromides were also applicable in the
thioesterification (Table 4). Thioester 5ab was prepared from 1a and 2ꢀphenylethyl bromide (3b)
in 46% yield. For primary bromides (3cꢀ3f), better yields were obtained from those with a
mediumꢀlength alkyl chain, such as nꢀhexyl bromide (3c) and nꢀoctyl bromide (3d), entries 2 and
3, respectively. On the other hand, the substrate with an ethyl group (3f) or a long nꢀdecyl group
(3e) gave lower yields (entries 4 and 5, respectively). The reactivity of alkyl bromides toward to
nucleophiles is known to be reduced as the alkyl chain is lengthened.15 Similarly, the generated
thioesters bearing a long alkyl chain could be more inert to further acyl substitution reactions.
The compromise of these factors may justify the results that better yields were obtained from the
C6 and C8 alkyl halides. A much lower yield was observed for the reaction using 1ꢀchlorooctane
(entry 6 vs. entry 3), which is consistent with the results using quaternary ammonium salts (vide
infra). Unlike the substantial difference in yields observed from the thioesterifications using
benzyl bromide and benzyl chloride (Table 2), both allyl bromide and allyl chloride gave low
yields of the allyl thioester (5cg) (entries 7 and 8). In addition to the issue of stability in 5cg, the
loss of the volatile allyl halides during highꢀtemperature reactions may also account for the low
yields. Indeed, the thioesterification using cinnamyl chloride (3h) provided better yields of 5ch
(entries 9 and 10). No thioester could be isolated when secondary or tertiary alkyl bromides (3i
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and 3j, entries 11 and 12, respectively) were used. The dominance of elimination reactions for
the 2° and 3° alkyl bromides thwarted the substitution reaction to form the sulfurꢀcarbon bond
and the thioesters that would result.
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Table 4. Thioesterification with various alkyl halides.
yield
entrya
RCO2H
alkyl halide
thioester
(%)b
Ph(CH2)2Br
1
46
1a
(3b)
nꢀC6H13Br
2
3
4
44(37)
52(41)
35(29)
1a
1a
(3c)
nꢀC8H17Br
(3d)
nꢀC10H21Br
1a
(3e)
5
6
7
C2H5Br (3f)
nꢀC8H17Cl
28(8)
12
1b
1a
1c
5ad
29(27)
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63(61)c
0
10
11
3h
5ch
1c
1a
ꢀ
12
ꢀ
0
1a
aReactions conducted in toluene, microwaveꢀassisted heating (250 W), 160 °C,
30 min. bYields determined by 1H NMR spectroscopy using 1,3,5ꢀ
trimethoxybenzene as the internal standard; isolated yields shown in
parentheses. cReactions conducted in toluene, microwaveꢀassisted heating (250
W), 180 °C, 30 min.
We initially thought that the mechanism for thioesterification of carboxylic acids using alkyl
halides might resemble our previous report using Michael acceptors, in which Michael adducts
derived from thioureas and α,βꢀunsaturated ketones or esters were generated as reaction
intermediates.12 In addition, benzyl carbamimidothioate (8a) has been proposed as the reaction
intermediate and the source of benzylthiolate under basic, aqueous conditions.13, 16 However, we
found that the corresponding benzyl N,N'ꢀdiphenylcarbamimidothioate (8b), separately prepared
from benzyl bromide and diphenylthiourea (2a, eq 1),17 was a very poor reagent for this
thioesterification (eq 2). Thus, 8b is unlikely to be the key intermediate here. Other possible
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intermediates, such as benzyl benzoate (9) were also considered, but 9 also failed to yield any
thioester under our reaction conditions (eq 3). Although the benzylation of thiobenzoic acid (10)
provided thioester 5ba in excellent yield under much milder conditions (eq 4), we did not
observe thioester 5ba when we divided our oneꢀpot, oneꢀstep reaction into a twoꢀstep process, i
e., belated addition of BnCl (eq 5). Here, we assumed that thiobenzoic acid (10) could be
generated from benzoic acid and thiourea 2a and that its subsequent benzylation could generate
the desired thioester. Formation of thiobenzoic acid (10) could not be detected, however. Instead
Nꢀphenylbenzamide (11) was isolated (eq 6) and was often observed as a minor byꢀproduct in
our thioesterifications.
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thiourea 2a (1 equiv)
CO2H
Et3N (1 equiv)
microwave 160 oC
20 min
BnCl (1 equiv)
microwave 110 oC
10 min
10
(eq 5)
5ba
1b
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After excluding these potential intermediates and considering the high reaction temperature
required for this process, we suspected that the reaction may go through quaternary ammonium
salts. Indeed, the direct thioesterification of carboxylic acids was also achieved using quaternary
ammonium salts and diphenylthiourea 2a (Table 5). Both benzyltriethylammonium chloride and
bromide provided thioester 5ba, and their yields were comparable with those obtained from
using the benzyl halides and triethylamine (entries 1 and 2, Table 5 vs. entries 1 and 7, Table 2).
Tetrabutylammonium iodide, bromide, and chloride all gave butyl thioester 5bk (entries 3–5).
However, the tetrabutylammonium salts of bisulfate and tetrafluoroborate (17 and 18,
respectively) failed to form the thioester (entries 6 and 7). The difference in the yields as a
function of the counterions is consistent with their difference in nucleophilicity according to the
hardꢀsoftꢀacidꢀbase (HSAB) concept, in which a soft anion such as iodide functions more as a
nucleophile than a base that would remove a proton and yield an elimination product.18 The
addition of DMAP was not helpful for the reaction using quaternary ammonium salts (entry 8).
Table 5. Thioesterification using quaternary ammonium salts.
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entrya
ammonium salt
thioester
yield (%)b
41
(12)
1
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5ba
(13)
58 (40)
(14)
3
5bk
5bk
5bk
5bf
43 (31)
17 (8)
0
4
5
6
7
8
(15)
(16)
HSO
Bu4N
4
(17)
0
(18)
53 (33)c
5bk
(14)
a Starting materials (1b and 2a, 0.4 mmol each), quaternary ammonium salt (0.4
mmol) and toluene (2 mL) placed in a reaction tube and heated by microwave
(250 W). bYields determined by 1H NMR using 1,3,5ꢀtrimethoxybenzene as the
c
internal standard; isolated yields shown in parentheses. Addition of DMAP
(0.04 mmol).
On the basis of the above results, a plausible reaction mechanism for direct thioesterification
of carboxylic acids using thiourea 2a, benzyl chloride, and triethylamine is shown Scheme 2. At
high temperatures, the formation of the quaternary ammonium salt 12 is facilitated by DMAP
and is reversible.19 Since both compounds 8 and 9, derived from the benzylation of thiourea or
carboxylic acid, did not lead to the product and thiobenzoic acid (10) as the reaction intermediate
was unlikely, benzyl mercaptan anion (21) should come from the benzylation of the intermediate
19 to generate 20 and the following baseꢀassisted fragmentation. The acylation of 21 was
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achieved with carbamimidic anhydride 22 to give the thioester 5. The oxidation of benzyl
mercaptan to give disulfide 6 as one of the byꢀproducts was wellꢀdocumented.20 In the absence of
BnCl, the intermediate 19 will give carbamothioic anhydride 23 and aniline anion, which lead to
amide 11 as we observed in eq 6.
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Scheme 2. Proposed mechanism for the thioesterification.
cat. DMAP
NEt3
BnCl
S
+
Cl
BnNEt3
12
O
SBn
NHPh
S
O
+ Cl
20
RCO2
R
O
HN
NH
NHPh
NHPh
R
O
O
NPh
Ph Ph
19
H
NEt3
NPh
BnCl
O
RCO2Bn
S
7, R = (4-OMe)C6H4
[O]
R
O
22
NHPh
R
R
O
NHPh
BnS
(BnS)2
21
PhHN
23
6
O
O
O
+
+
HNEt3Cl
NHPh
HN
NH
R
SBn
11, R = Ph
Ph Ph
5
main pathway:
by-product formation:
Conclusions
In summary, a microwaveꢀassisted, direct thioesterification of carboxylic acids was achieved
using primary alkyl halides, amines, and N,Nꢀdiphenylthiourea. There are several advantages in
this process: a oneꢀpot procedure, short reaction time, and the absence of metals, foulꢀsmelling
reagents, or costly reagents to activate carboxylic acids. This reaction supplements our previous
method of thioesterification, which was limited to using Michael acceptors to form the thiolate
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moiety of thioesters. The formation of the thiolate group from quaternary ammonium salts and
the adducts of carboxylates and thiourea provides a new pathway for thioesterification.
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Experimental Section
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General information: Thinꢀlayer chromatography (TLC) spots were examined under UV light
or revealed by KMnO4 solution. Dichloromethane was distilled from calcium hydride;
tetrahydrofuran and diethyl ether were distilled from sodium/benzophenone. Reagents were
purchased from commercial sources and used without further purification. Chemical shifts for
1HꢀNMR and 13C NMR spectra are reported in δ units (parts per million) with reference to
residual solvent peaks. The multiplicities are abbreviated as follows: s = singlet, d = doublet, t =
triplet, q = quartet, m = multiplet, dd = doublet of doublets, td = triplet of doublets. Assignments
1
13
of H and C resonances for complex structures were confirmed by extensive 2D experiments
(COSY, HMQC, and HMBC). TLC was conducted using preꢀcoated silica gel 60 F254 plates
containing a fluorescent indicator; purification by chromatography was conducted using silica
gel (230ꢀ400 mesh). Microwaveꢀassisted reactions were performed in a CEM Discover singleꢀ
mode microwave reactor using a sealed reaction vessel (10 mL, max. pressure: 30 bar), equipped
with a verticallyꢀfocused IR temperature sensor; controlled temperature, power and time settings
were used for all reactions. Highꢀresolution mass spectrometry (HRMS) data were recorded on a
JMSꢀ700 quadrupole mass spectrometer.
Typical Procedure for the Synthesis of Thioesters
A solution of 4ꢀmethoxybenzoic acid (1a, 60.9 mg, 0.40 mmol ), N,N’ꢀdiphenylthiourea (2a,
91.3 mg, 0.40 mmol), benzyl chloride (3a, 46.0 ꢁL, 0.40 mmol), triethylamine (56.0 ꢁL, 0.40
mmol), DMAP (4, 4.9 mg, 0.04 mmol), and toluene (2 mL) was placed in a pressure tube that
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was heated to 160 °C (250 W, monitored by IR temperature sensor) and maintained at this
temperature for 30 min. After cooling to rt, 1,3,5ꢀtrimethoxybenzene (6.7 mg, 39.8 ꢁmol) was
added to the reaction mixture which was then concentrated. The yield of thioester 5aa was
calculated according to the 1H NMR spectrum of the crude product. Thioester 5aa (63.1 mg, 0.24
mmol, 61%) was also isolated as a lightꢀyellow liquid after column chromatography (SiO2,
hexanes, Rf 0.15). 1H NMR (CDCl3, 500 MHz) δ 3.84 (s, 3H), 4.29 (s, 2H), 6.90 (d, J = 8.9 Hz,
2H), 7.23 (t, J = 7.4 Hz, 1H), 7.28–7.31 (m, 2H), 7.36 (d, J = 7.4 Hz, 2H), 7.94 (d, J = 8.7 Hz,
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13
2H); C NMR (CDCl3, 125 MHz) δ 33.2, 55.5, 113.8, 127.2, 128.6, 128.9, 129.4, 129.6, 137.7,
163.8, 189.7. The spectroscopic data are consistent with the reported values.10a
S-Benzyl benzothioate (5ba).13 The standard procedure for the thioesterification was
followed. Starting with 1b (48.8 mg, 0.40 mmol), thioester 5ba (55.0 mg, 0.24 mmol, 60%) was
1
isolated after column chromatography (SiO2, hexanes, Rf 0.18). H NMR (CDCl3, 500 MHz ) δ
4.31 (s, 2H), 7.22–7.25 (m, 1H), 7.30 (t, J = 7.8 Hz, 2H), 7.34–7.37 (m, 2H), 7.43 (t, J = 7.8 Hz,
13
2H), 7.53–7.56 (m, 1H), 7.94–7.96 (m, 2H); C NMR (CDCl3, 125 MHz) δ 33.3, 127.2, 128.6,
128.9, 133.4, 136.7, 137.4, 191.2.
S-Benzyl 2-methylbenzothioate (5ca).10a The standard procedure for the thioesterification
was followed. Starting with 1c (54.5 mg, 0.40 mmol), thioester 5ca (46.1 mg, 0.19 mmol, 48%)
1
was produced according to H NMR. Compound 5ca was purified by column chromatography
1
(SiO2, hexanes, Rf 0.15) as a lightꢀyellow liquid. H NMR (CDCl3, 300 MHz) δ 2.49 (s, 3H),
13
4.27 (s, 2H), 7.19–7.39 (m, 8H), 7.75 (d, J = 7.9 Hz, 1H); C NMR (CDCl3, 75 MHz) δ 20.6,
33.9, 125.7, 127.2, 128.5, 128.6, 128.9, 131.6, 131.7, 136.9, 137.1, 137.6, 193.6.
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S-Benzyl 4-methylbenzothioate (5da).13 The standard procedure for the thioesterification
was followed. Starting with 1d (54.5 mg, 0.40 mmol), thioester 5ea (52.9 mg, 0.22 mmol, 55%)
3
4
5
6
7
8
9
1
was produced according to H NMR analysis of the reaction mixture. Compound 5da was
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purified by column chromatography (SiO2, hexanes, Rf 0.17) as a lightꢀyellow liquid. H NMR
(CDCl3, 300 MHz ) δ 2.40 (s, 3H), 4.32 (s, 2H), 7.23–7.40 (m, 7H), 7.88 (d, J = 8.3 Hz, 2H); 13C
NMR (CDCl3, 75 MHz) δ 21.6, 33.2, 127.2, 127.3, 128.6, 128.9, 129.3, 134.3, 137.6, 144.3,
190.9.
S-Benzyl 2,4-dimethylbenzothioate (5ea). The standard procedure for the thioesterification
was followed. Starting with 1e (60.1 mg, 0.40 mmol), thioester 5ea (54.1 mg, 0.21 mmol, 53%)
1
was produced according to H NMR analysis of the reaction mixture. Compound 5ea was
1
purified by column chromatography (SiO2, hexanes, Rf 0.17) as a lightꢀyellow liquid. H NMR
(CDCl3, 300 MHz) δ 2.34 (s, 3H), 2.50 (s, 3H), 4.28 (s, 2H), 7.02–7.05 (m, 2H), 7.23–7.40 (m,
13
5H), 7.73 (d, J = 7.8 Hz, 1H); C NMR (CDCl3, 75 MHz) δ 20.7, 21.3, 33.8, 126.3, 127.1,
128.6, 128.9, 132.4, 134.2, 137.2, 137.7, 142.3, 192.9; HRMS (APCI) calcd for [M + H]+
(C16H17OS) 257.1000, found 257.0994.
S-Benzyl 2,6-dimethylbenzothioate (5fa). The standard procedure for the thioesterification
was followed. Starting with 1e (60.1 mg, 0.40 mmol), thioester 5fa (59.4 mg, 0.23 mmol, 58%)
1
was produced according to H NMR analysis of the reaction mixture. Compound 5fa was
purified by column chromatography (SiO2, hexanes, Rf 0.17) as a lightꢀyellow liquid. 1H NMR
(CDCl3, 300 MHz) δ 2.26 (s, 6H), 4.31 (s, 2H), 6.98–7.00 (m, 2H), 7.14–7.19 (m, 1H), 7.25–7.37
13
(m, 5H); C NMR (CDCl3, 75 MHz) δ 19.0, 33.8, 127.3, 127.7, 128.6, 128.9, 129.4, 133.8,
137.6, 139.8, 197.0; HRMS (APCI) calcd for [M + H]+ (C16H17OS) 257.1000, found 257.1001.
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S-Benzyl 3-methoxy-2-methylbenzothioate (5ga). The standard procedure for the
thioesterification was followed. Starting with 1g (66.5 mg, 0.40 mmol), thioester 5ga (59.4 mg,
0.23 mmol, 58%) was produced according to 1H NMR analysis of the reaction mixture. Thioester
5ga (56.3 mg, 0.21 mmol, 52%) was isolated after column chromatography (SiO2, hexanes, Rf
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0.10) as a lightꢀyellow liquid. H NMR (CDCl3, 500 MHz) δ 2.30 (s, 3H), 3.83 (s, 3H), 4.28 (s,
2H), 6.94 (d, J = 8.1 Hz, 1H), 7.18 (t, J = 7.9 Hz, 1H), 7.23–7.26 (m, 2H), 7.29–7.32 (m, 2H),
13
7.36–7.38 (m, 2H); C NMR (CDCl3, 125 MHz) δ 12.3, 34.1, 55.7, 113.0, 119.9, 125.1, 126.3,
127.2, 128.6, 128.9, 137.5, 139.2, 158.0, 194.2; HRMS (APCI) calcd for [M + H]+ (C16H17O2S )
273.0949, found 273.0951.
S-Benzyl 4-fluorobenzothioate (5ha). The standard procedure for the thioesterification was
followed. Starting with 1h (56.0 mg, 0.40 mmol), thioester 5ha (49.3 mg, 0.20 mmol, 50%) was
1
produced according to H NMR analysis of the reaction mixture. Thioester 5ha (48.2 mg, 0.19
mmol, 50%) was isolated as a lightꢀyellow liquid after column chromatography (SiO2, hexanes,
Rf 0.21). 1H NMR (CDCl3, 500 MHz) δ 4.31 (s, 2H), 7.08–7.12 (m, 2H), 7.23–7.26 (m, 1H), 7.31
(t, J = 7.7 Hz, 2H), 7.35–7.37 (m, 2H), 7.96–8.00 (m, 2H); 13C NMR (CDCl3, 125 MHz) δ 33.4,
115.7 (JC-F = 22.1 Hz), 127.4, 128.7, 128.9, 129.8 (JC-F = 9.3 Hz), 133.1, 137.3, 165.9 (JC-F
=
253.5 Hz), 189.8; HRMS (APCI) calcd for [M + H]+ (C14H12FOS) 247.0593, found 247.0591.
S-Benzyl 4-bromobenzothioate (5ia).21 The standard procedure for the thioesterification
was followed. Starting with 1i (80.4 mg, 0.40 mmol), thioester 5ia (66.3 mg, 0.22 mmol, 54%)
1
was produced according to H NMR analysis of the reaction mixture. Thioester 5ia (62.5 mg,
0.20 mmol, 51%) was isolated as a lightꢀyellow liquid after column chromatography (SiO2,
hexanes, Rf 0.20). 1H NMR (CDCl3, 500 MHz) δ 4.30 (s, 2H), 7.23–7.26 (m, 1H), 7.29–7.32 (m,
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2H), 7.35–7.36 (m, 2H), 7.56 (d, J = 8.5 Hz, 2H), 7.81 (d, J = 8.6 Hz, 2H); C NMR (CDCl3,
5
6
125 MHz) δ 33.4, 127.4, 128.5, 128.7, 128.7, 128.9, 131.9, 135.5, 137.1, 190.3.
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S-Benzyl 2-iodobenzothioate (5ja). The standard procedure for the thioesterification was
followed. Starting with 1j (99.2 mg, 0.40 mmol), thioester 5ja (105.5 mg, 0.30 mmol, 74%) was
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produced according to H NMR analysis of the reaction mixture. Thioester 5ja (95.8 mg, 0.27
mmol, 66%) was isolated as a lightꢀyellow liquid after column chromatography (SiO2, hexanes,
Rf 0.15). 1H NMR (CDCl3, 300 MHz) δ 4.32 (s, 2H), 7.13 (dt, J = 7.7 Hz, J = 1.6 Hz, 1H), 7.24–
13
7.40 (m, 6H), 7.57 (dd, J = 7.7 Hz, J = 1.6 Hz, 1H), 7.92 (dd, J = 7.9 Hz, J = 1.0 Hz, 1H); C
NMR (CDCl3, 75 MHz) δ 34.4, 91.3, 127.4, 127.9, 128.7, 128.8, 129.0, 132.4, 137.0, 140.8,
142.3, 193.4; HRMS (ESI) calcd for [M + Na]+ ( C14H11ONaSI ) 376.9473, found 376.9465.
S-Benzyl 4-(dimethylamino)benzothioate (5ka).22 The standard procedure for the
thioesterification was followed. Starting with 1k (66.1 mg, 0.40 mmol), thioester 5ka (40.8 mg,
0.15 mmol, 38%) was produced according to 1H NMR analysis of the reaction mixture.Thioester
5ka (46.0 mg, 0.17 mmol, 42%) was isolated as a lightꢀyellow solid after column
1
chromatography (SiO2, hexanes, Rf 0.10). Mp 103.0–104.0 °C; H NMR (CDCl3, 500 MHz) δ
3.02 (s, 6H), 4.28 (s, 2H), 6.61 (d, J = 9.2 Hz, 2H), 7.20–7.23 (m, 1H), 7.27–7.30 (m, 2H), 7.36–
13
7.37 (m, 2H), 7.87 (dd, J = 9.1 Hz, J = 1.4 Hz, 2H); C NMR (CDCl3, 125 MHz) δ 32.9, 40.0,
110.6, 124.3, 127.0, 128.5, 128.9, 129.4, 138.3, 153.7, 188.9.
Methyl 4-(benzylthiocarbonyl)benzoate (5la).23 The standard procedure for the
thioesterification was followed. Starting with 1l (72.1 mg, 0.40 mmol), thioester 5la (68.5 mg,
1
0.24 mmol, 60%) was produced according to H NMR analysis of the reaction mixture.
Compound 5la was purified by column chromatography (SiO2, hexanes, Rf 0.13) as a lightꢀ
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yellow liquid. 1H NMR (CDCl3, 300 MHz) δ 3.92 (s, 3H), 4.32 (s, 2H), 7.24–7.37 (m, 5H), 7.99
3
4
5
6
13
(d, J = 8.4 Hz, 2H), 8.08 (d, J = 8.5 Hz, 2H); C NMR (CDCl3, 75 MHz) δ 33.5, 52.5, 127.2,
7
8
9
127.5, 128.7, 129.0, 129.8, 134.2, 137.0, 140.0, 166.1, 190.7.
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S-Benzyl 4-nitrobenzothioate (5ma).23 The standard procedure for the thioesterification was
followed. Starting with 1m (66.8 mg, 0.40 mmol), thioester 5ma (56.0 mg, 0.21 mmol, 51%)
1
was produced according to H NMR analysis of the reaction mixture. Thioester 5ma (48.1 mg,
0.18 mmol, 44%) was isolated as a lightꢀyellow solid after column chromatography (SiO2,
1
hexanes, Rf 0.23). Mp 80.5–82.5 °C; H NMR (CDCl3, 500 MHz) δ 4.35 (s, 2H), 7.24–7.37 (m,
13
5H), 8.09 (d, J = 8.7 Hz, 2H), 8.28 (d, J = 8.7 Hz, 2H); C NMR (CDCl3, 125 MHz) δ 33.8,
123.9, 127.6, 128.3, 128.8, 129.0, 136.6, 141.3, 150.5, 189.7.
S-Benzyl naphthalene-2-carbothioate (5na).22 The standard procedure for the
thioesterification was followed. Starting with 1n (68.9 mg, 0.40 mmol), thioester 5na (70.5 mg,
0.25 mmol, 63%) was produced according to 1H NMR analysis of the reaction mixture. Thioester
5na (67.1 mg, 0.24 mmol, 60%) was isolated as a lightꢀyellow liquid after column
chromatography (SiO2, hexanes, Rf 0.18). 1H NMR (CDCl3, 500 MHz) δ 4.38 (s, 2H), 7.25–7.27
(m, 1H), 7.31–7.34 (m, 2H), 7.41–7.42 (m, 2H), 7.52–7.55 (m, 1H), 7.57–7.60 (m, 1H), 7.84–
13
7.88 (m, 2H), 7.93 (d, J = 7.8 Hz, 1H), 7.98–8.00 (m, 1H), 8.53 (s, 1H); C NMR (CDCl3, 125
MHz) δ 33.5, 123.1, 126.9, 127.3, 127.5, 127.8, 128.5, 128.7, 128.7, 129.0, 129.5, 132.4, 134.1,
135.8, 137.5, 191.2.
(E)-S-Benzyl 3-(4-methoxyphenyl)prop-2-enethioate (5oa). The standard procedure for the
thioesterification was followed. Starting with 1o (71.3 mg, 0.40 mmol), thioester 5oa (41.8 mg,
1
0.15 mmol, 37%) was produced according to H NMR analysis of the reaction mixture..
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Thioester 5oa (36.6 mg, 0.13 mmol, 32%) was isolated as a lightꢀyellow liquid after column
5
6
1
chromatography (SiO2, hexanes, Rf 0.21). H NMR (CDCl3, 500 MHz) δ 3.82 (s, 3H), 4.24 (s,
7
8
9
2H), 6.58 (d, J = 15.7 Hz, 1H), 6.88 (d, J = 8.8 Hz, 2H), 7.21–7.22 (m, 1H), 7.27–7.33 (m, 4H),
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7.47 (d, J = 8.8 Hz, 2H), 7.59 (d, J = 15.7 Hz, 1H); C NMR (CDCl3, 125 MHz) δ 33.1, 55.4,
114.4, 122.3, 126.7, 127.2, 128.6, 128.9, 130.1, 137.8, 140.7, 161.7, 189.0; HRMS (APCI) calcd
for [M + H]+ ( C17H17O2S ) 285.0949, found 285.0946.
S-Benzyl 2-(4-methoxyphenyl)ethanethioate (5pa).24 The standard procedure for the
thioesterification was followed. Starting with 1p (66.5 mg, 0.40 mmol), thioester 5pa (23.1 mg,
0.08 mmol, 21%) was produced according to 1H NMR analysis of the reaction mixture. Thioester
5pa (14.1 mg, 0.05 mmol, 13%) was isolated as a lightꢀyellow liquid after column
1
chromatography (SiO2, hexanes, Rf 0.10). H NMR (CDCl3, 500 MHz) δ 3.76 (s, 2H), 3.78 (s,
13
3H), 4.07 (s, 2H), 6.85 (d, J = 8.7 Hz, 2H), 7.18 (d, J = 8.7 Hz, 2H), 7.21–7.27 (m, 5H); C
NMR (CDCl3, 125 MHz) δ 33.6, 49.4, 55.2, 114.1, 125.4, 127.2, 128.6, 128.8, 130.7, 137.3,
159.0, 197.3.
S-Benzyl propanethioate (5qa). The standard procedure for the thioesterification was
followed. Starting with 1q (29.6 mg, 0.40 mmol), thioester 5qa (13.7 mg, 0.076 mmol, 19%) was
1
produced according to H NMR analysis of the reaction mixture. Thioester 5qa (7.5 mg, 0.042
mmol, 10%) was isolated as a lightꢀyellow liquid after column chromatography (SiO2, hexanes,
Rf 0.14). 1H NMR (CDCl3, 500 MHz) δ 1.13 (t, J = 7.5 Hz, 3H), 2.53 (q, J = 7.5 Hz, 2H), 4.06 (s,
13
2H), 7.17–7.24 (m, 5H); C NMR (CDCl3, 125 MHz) δ 9.6, 33.0, 37.1, 127.2, 128.6, 128.8,
137.7, 199.5; HRMS (EI) calcd for M+ (C10H12OS) 180.0609, found 180.0602.
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S-Benzyl 3-methylbutanethioate (5ra). The standard procedure for the thioesterification
was followed. Starting with 1r (40.9 mg, 0.40 mmol), thioester 5ra (19.8 mg, 0.095 mmol, 24%)
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was produced according to H NMR analysis of the reaction mixture. Compound 5ra was
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purified by column chromatography (SiO2, hexanes, Rf 0.12) as a lightꢀyellow liquid. 1H NMR
(CDCl3, 300 MHz) δ 0.94 (d, J = 6.7 Hz, 6H), 2.17 (m, J = 6.7 Hz, 1H), 2.43 (d, J = 7.1 Hz, 2H),
13
4.11 (s, 2H), 7.20–7.33 (m, 5H); C NMR (CDCl3, 75 MHz) δ 22.3, 26.5, 33.1, 52.6, 127.1,
128.6, 128.7, 137.8, 198.2; HRMS (EI) calcd for M+ (C12H16OS) 208.0922, found 208.0922.
S-Benzyl cyclohexanecarbothioate (5sa).25 The standard procedure for the thioesterification
was followed. Starting with 1s (51.3 mg, 0.40 mmol), thioester 5sa (26.1 mg, 0.11 mmol, 28%)
1
was produced according to H NMR analysis of the reaction mixture. Compound 5sa was
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purified by column chromatography (SiO2, hexanes, Rf 0.15) as a lightꢀyellow liquid. H NMR
(CDCl3, 300 MHz) δ 1.15–1.33 (m, 3H), 1.40–1.53 (m, 2H), 1.60–1.67 (m, 1H), 1.73–1.80 (m,
2H), 1.88–1.93 (m, 2H), 2.48 (tt, J = 11.4, J = 3.5 Hz, 1H), 4.08 (s, 2H), 7.15–7.30 (m, 5H); 13C
NMR (CDCl3, 75 MHz) δ 25.5, 25.6, 29.5, 32.8, 52.4, 127.1, 128.6, 128.8, 137.8, 202.4.
S-Benzyl 2,2-dimethylpropanethioate (5ta).26 The standard procedure for the
thioesterification was followed. Starting with 1t (40.9 mg, 0.40 mmol), thioester 5ta (29.3 mg,
1
0.14 mmol, 35%) was produced according to H NMR analysis of the reaction mixture.
Compound 5ta was purified by column chromatography (SiO2, hexanes, Rf 0.22) as a lightꢀ
1
13
yellow liquid. H NMR (CDCl3, 300 MHz) δ 1.23 (s, 9H), 4.07 (s, 2H), 7.20–7.31 (m, 5H); C
NMR (CDCl3, 75 MHz) δ 27.4, 33.0, 46.4, 127.1, 128.5, 128.8, 137.7, 206.1.
S-Phenethyl 4-methoxybenzothioate (5ab).27 The standard procedure for the
thioesterification was followed. Starting with 1a (60.9 mg, 0.40 mmol) and (2ꢀ
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bromoethyl)benzene (3b, 74.0 mg, 0.40 mmol), thioester 5ab (49.6 mg, 0.18 mmol, 46%) was
produced according to 1H NMR analysis of the reaction mixture. Compound 5ab was purified by
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column chromatography (SiO2, hexanes, Rf 0.12) as a lightꢀyellow liquid. H NMR (CDCl3, 300
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MHz) δ 2.93–2.98 (m, 2H), 3.26–3.31 (m, 2H), 3.85 (s, 3H), 6.91 (d, J = 8.9 Hz, 2H), 7.19–7.33
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(m, 5H), 7.94 (d, J = 8.9 Hz, 2H); C NMR (CDCl3, 75 MHz) δ 30.3, 36.1, 55.5, 113.7, 126.5,
128.5, 128.6, 129.4, 130.0, 140.2, 163.7, 190.3.
S-Hexyl 4-methoxybenzothioate (5ac). The standard procedure for the thioesterification
was followed. Starting with 1a (60.9 mg, 0.40 mmol) and 1ꢀbromohexane (3c, 56.1 ꢁL, 0.40
1
mmol), thioester 5ac (44.0 mg, 0.17 mmol, 44%) was produced according to H NMR analysis
of the reaction mixture. Thioester 5ac (37.0 mg, 0.15 mmol, 37%) was isolated as a light yellowꢀ
liquid after column chromatography (SiO2, hexanes, Rf 0.20). 1H NMR (CDCl3, 500 MHz) δ 0.87
(t, J = 6.9 Hz, 3H), 1.27–1.30 (m, 4H), 1.39–1.43 (m, 2H), 1.61–1.67 (m, 2H), 3.02 (t, J = 7.4
Hz, 2H), 3.83 (s, 3H), 6.89 (d, J = 9.0 Hz, 2H), 7.93 (d, J = 9.0 Hz, 2H); 13C NMR (CDCl3, 125
MHz) δ 14.0, 22.5, 28.6, 28.9, 29.6, 31.3, 55.4, 113.7, 129.3, 130.2, 163.6, 190.7; HRMS (APCI)
calcd for [M + H]+ ( C14H21O2S ) 253.1262, found 253.1255.
S-Octyl 4-methoxybenzothioate (5ad).28 The standard procedure for the thioesterification
was followed. Starting with 1a (60.9 mg, 0.40 mmol) and 1ꢀbromooctane (3d, 69.0 ꢁL, 0.40
1
mmol), thioester 5ad (58.5 mg, 0.21 mmol, 52%) was produced according to H NMR analysis
of the reaction mixture. Thioester 5ad (46.0 mg, 0.16 mmol, 41%) was isolated as a lightꢀyellow
liquid after column chromatography (SiO2, hexanes, Rf 0.20). 1H NMR (CDCl3, 500 MHz) δ 0.86
(t, J = 6.8 Hz, 3H), 1.25–1.31 (m, 8H), 1.37–1.42 (m, 2H), 1.61–1.67 (m, 2H), 3.02 (t, J = 7.5
Hz, 2H), 3.84 (s, 3H), 6.89 (d, J = 8.9 Hz, 2H), 7.93 (d, J = 8.9 Hz, 2H); 13C NMR (CDCl3, 125
MHz) δ 14.1, 22.6, 28.9, 28.9, 29.1, 29.2, 29.7, 31.8, 55.5, 113.7, 129.3, 130.2, 163.6, 190.7.
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S-Decyl 4-methoxybenzothioate (5ae).29 The standard procedure for the thioesterification
was followed. Starting with 1a (60.9 mg, 0.40 mmol) and 1ꢀbromodecane (3e, 83.0 ꢁL, 0.40
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9
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mmol), thioester 5ae (43.3 mg, 0.14 mmol, 35%) was produced according to H NMR analysis
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of the reaction mixture. Thioester 5ae (36.4 mg, 0.12 mmol, 29%) was isolated as a lightꢀyellow
liquid after column chromatography (SiO2, hexanes, Rf 0.20). 1H NMR (CDCl3, 500 MHz) δ0.86
(t, J = 6.8 Hz, 3H), 1.24–1.31 (m, 12H), 1.37–1.43 (m, 2H), 1.61–1.67 (m, 2H), 3.02 (t, J = 7.4
Hz, 2H), 3.84 (s, 3H), 6.89 (d, J = 8.9 Hz, 2H), 7.93 (d, J = 9.1 Hz, 2H); 13C NMR (CDCl3, 125
MHz) δ 14.1, 22.7, 28.9, 28.9, 29.2, 29.3, 29.5, 29.5, 29.7, 31.9, 55.4, 113.7, 129.3, 130.2, 163.6,
190.6.
S-Ethyl benzothioate (5bf).27 The standard procedure for the thioesterification was
followed. Starting with 1b (48.8 mg, 0.40 mmol) and 1ꢀbromoethane (3f, 30.0 ꢁL, 0.40 mmol),
1
thioester 5bf (18.8 mg, 0.11 mmol, 28%) was produced according to H NMR analysis of the
reaction mixture. Thioester 5bf (5.3 mg, 0.03 mmol, 8%) was isolated as a lightꢀyellow liquid
after column chromatography (SiO2, hexanes, Rf 0.15). 1H NMR (CDCl3, 500 MHz) δ 1.33 (t, J =
7.4 Hz, 3H), 3.06 (q, J = 7.4 Hz, 2H), 7.42 (t, J = 8.2 Hz, 2H), 7.54 (t, J = 7.4 Hz, 1H), 7.93–7.95
(m, 2H); 13C NMR (CDCl3, 125 MHz) δ 14.7, 23.4, 127.1, 128.5, 133.2, 137.2, 192.1.
S-Allyl 2-methylbenzothioate (5cg). The standard procedure for the thioesterification was
followed. Starting with 1c (54.5 mg, 0.40 mmol) and allyl bromide (3f, 34.6 ꢁL, 0.40 mmol),
1
thioester 5cg (22.3 mg, 0.12 mmol, 29%) was produced according to H NMR analysis of the
reaction mixture. Thioester 5cg (20.7 mg, 0.11 mmol, 27%) was isolated as a lightꢀyellow liquid
1
after column chromatography (SiO2, hexanes, Rf 0.17). H NMR (CDCl3, 500 MHz) δ 2.47 (s,
3H), 3.68 (d, J = 6.9 Hz, 2H), 5.13 (dd, J = 9.9 Hz, J = 0.9 Hz, 1H ), 5.30 (dq, J = 17.0 Hz, J =
1.4 Hz, 1H), 5.89 (qt, J = 10.0 Hz, J = 7.0 Hz, 1H), 7.21–7.24 (m, 2H), 7.35–7.38 (m, 1H), 7.74–
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7.76 (m, 1H); 13C NMR (CDCl3, 75 MHz) δ 20.5, 32.5, 117.9, 125.7, 128.4, 131.5, 131.6, 133.1,
136.8, 137.4, 193.6; HRMS (APCI) calcd for [M + H]+ (C11H13OS) 193.0687, found 193.0690.
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S-Cinnamyl 2-methylbenzothioate (5ch). The standard procedure for the thioesterification
was followed except the reaction temperature (180 °C). Starting with 1c (54.5 mg, 0.40 mmol)
and cinnamyl chloride (3h, 55.7 ꢁL, 0.40 mmol), thioester 5ch (67.6 mg, 0.24 mmol, 63%) was
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produced according to H NMR analysis of the reaction mixture. Thioester 5ch (65.5 mg, 0.24
mmol, 61%) was isolated as a lightꢀyellow liquid after column chromatography (SiO2, hexanes,
Rf 0.14). 1H NMR (CDCl3, 300 MHz) δ 2.50 (s, 3H), 3.87 (dd, J = 7.2 Hz, J = 1.2 Hz, 2H), 6.27
(dt, J = 15.6 Hz, J = 7.2 Hz 1H), 6.65 (dd, J = 15.6 Hz, J = 1.2 Hz, 1H), 7.20–7.41 (m, 8H),
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7.77–7.80 (m, 1H); C NMR (CDCl3, 75 MHz) δ 20.6, 32.2, 117.6, 124.5, 125.7, 126.4, 127.1,
127.6, 128.5, 129.1, 131.6, 131.7, 133.2, 136.7, 193.6; HRMS (FAB) calcd for [M]+ (C17H16OS)
268.0922, found 268.0914.
S-Butyl benzothioate (5bk).30 A solution of benzoic acid (1b, 60.9 mg, 0.40 mmol ), N,N’ꢀ
diphenylthiourea (2a, 91.3 mg, 0.40 mmol), tetrabutylammonium iodide (147.7 mg, 0.40 mmol)
and toluene (2 mL) was placed in a pressure tube that was heated to 160 °C and maintained at
this temperature for 30 min. After cooling to rt, the reaction mixture was added with 1,3,5ꢀ
trimethoxybenzene (10.1 mg, 60.1 ꢁmol) and concentrated. Thioester 5bk (44.3 mg, 0.23 mmol,
1
40%) was produced according to H NMR analysis of the reaction mixture. Thioester 5bk (30.6
mg, 0.16 mmol, 40%) was isolated as a lightꢀyellow liquid after column chromatography (SiO2,
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hexanes, Rf 0.15). H NMR (CDCl3, 500 MHz) δ 0.93 (t, J = 7.4 Hz, 3H), 1.40–1.48 (m, 2H),
1.61–1.67 (m, 2H), 3.06 (t, J = 7.4 Hz, 2H), 7.42 (t, J = 7.7 Hz, 2H), 7.52–7.55 (m, 1H), 7.94–
13
7.96 (m, 2H); C NMR (CDCl3, 125 MHz) δ 13.6, 22.0, 28.7, 31.6, 127.1, 128.5, 133.1, 137.3,
192.1.
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Benzyl N,N'-diphenylcarbamimidothioate (8b). Benzyl bromide (57.3 ꢁL. 0.48 mmol) was
added to a solution of N,N’ꢀdiphenylthioura (100.0 mg, 0.44 mmol) and methanol (2 mL) at 0 °C.
The reaction mixture was stirred at rt for 3 h, quenched with sat NaHCO3(aq) (0.5 mL) and
extracted with ethyl acetate (4 mL × 3). The combined organic layers were dried over sodium
sulfate, filtered and concentrated to give 8b (138.5 mg, 0.43 mmol, 99%) as a lightꢀyellow liquid.
1H NMR (CDCl3, 300 MHz) δ 4.03 (s, 2H), 7.05–7.10 (m, 2H), 7.14–77.17 (m, 4H), 7.28–77.35
(m, 10H); 13C NMR (CDCl3, 75 MHz) δ 36.1, 121.5, 123.6, 127.6, 128.7, 128.9, 129.0, 137.1; IR
(neat) 3400, 3059, 3028, 1623, 1285, 1490, 1434, 1309, 1220, 1128, 912, 758, 694 cmꢀ1; HRMS
(ESI) calcd for [M + H]+ (C20H19N2S) 319.1269, found 319.1264.
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Supporting Information. NMR spectra for the synthesized thioesters.
Acknowledgements. Financial support from the Ministry of Science and Technology
(MOST 104ꢀ2113ꢀMꢀ008ꢀ003 and MOST 105ꢀ2113ꢀMꢀ008ꢀ001), Taiwan, is gratefully
acknowledged. We thank Prof. John C. Gilbert, Santa Clara University, for helpful comments.
Thanks are also due to the Institute of Chemistry, Academia Sinica and the Valuable Instrument
Center at National Central University, Taiwan, for mass analysis.
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