Facile synthetic approaches to 1-thiocyclopropanecarboxylates

Article abstract of DOI:10.1080/10426507.2017.1286492

Two facile synthetic approaches to the novel biologically interesting 1-thiocyclopropanecarboxylates starting from corresponding thiols were developed. Approach A involved five steps with the key steps being the S_N2 reactions of thiols and α-br

Full text of DOI:10.1080/10426507.2017.1286492

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Facile synthetic approaches to 1-thiocyclopropanecarboxylates
Xiansheng Zhang†1,2,3, Jingwei Wu†2, Yuqiang Liu2, Yafei Xie2, Changying Liu2, Jianwu
Wang*1, Guilong Zhao*2
1School of Chemistry and Chemical Engineering, Shandong University, Jinan 250100, P. R.
China
2Tianjin Key Laboratory of Molecular Design and Drug Discovery, Tianjin Institute of
Pharmaceutical Research, Tianjin 300193, P. R. China
3Shandong Lukang Pharmaceutical Co., Ltd., Jining 272021, P. R. China
†These authors contributed equally
*Corresponding authors: Guilong Zhao, Tianjin Key Laboratory of Molecular Design and Drug
Discovery, Tianjin Institute of Pharmaceutical Research, 308 An Shan Xi Dao, Nankai District,
Tianjin 300193, P. R. China, E-mail: zhao_guilong@tjipr.com, Tel: +86-22-23006869; Jianwu
Wang, School of Chemistry and Chemical Engineering, Shandong University, 27 Shan Da Nan
Lu, Licheng District, Jinan 250100, P. R. China, E-mail: jwwang@sdu.edu.cn, Tel:
+86-531-88362708
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Abstract: Two facile synthetic approaches to the novel biologically interesting
1-thiocyclopropanecarboxylates starting from corresponding thiols were developed. Approach A
involved five steps with the key steps being the SN2 reactions of thiols and
α-bromobutyrolactone and cyclopropane formation via t-BuOK-mediated intramolecular SN2
cyclization. It had advantages such as inexpensive reagents and simplicity of operation but was
associated with limitations such as relatively more reaction steps and incompatibility with thiols
exhibiting acidic and alkaline functional groups. Approach B involved two steps with the key
step being LDA-mediated cyclopropane formation at the α-position of carboxylate groups by use
of 1,3,2-dioxathiolane-2,2-dioxide. It showed advantages such as fewer reaction steps and
simplicity of operation but was associated with limitations such as relatively expensive reagents
and incompatibility with thiols exhibiting acidic functional groups. The two approaches are
complementary in many respects, allowing for flexible choices according to specific
requirements for the characteristics of synthetic methods.
Keywords: Synthetic approach; cyclopropanecarboxylate; 1-thiocyclopropanecarboxylate;
cyclopropane formation
Running Title: Synthetic approaches to 1-thiocyclopropanecarboxylates
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Introduction
1-Substituted cyclopropanecarboxylates represent an interesting class of compounds in both
synthetic organic chemistry1 and medicinal chemistry.2 Depending on the type of substituent
located at the cyclopropane ring, the commonly encountered 1-substituted
cyclopropanecarboxylates essentially fall into four categories, i.e. 1a-1d (Figure 1). In the effort
of discovering novel uric acid transporter 1 (URAT1) inhibitors3 for the treatment of
hyperuricemia associated with gout in our laboratories, compound 2 with a moiety of
1-thiocyclopropanecarboxylate was needed.4 An initial attempt to synthesize 2 by a seemingly
straightforward approach involving the substitution reaction of thione 12k and ethyl
1-bromocyclopropanecarboxylate (3b) failed because no reaction occurred even in refluxing
DMF (see Results and Discussion for details); however, the reactions of 12k with methyl
bromoacetate, ethyl 2-bromo-2-methylpropionate and ethyl 1-bromocyclobutanecarboxylate
proceeded smoothly, at room temperature or slightly elevated temperatures.4 It should be pointed
out that 12k can exist in two tautomeric forms, thione (as in Figure 1) and thiol (as in Scheme 1),
but the thione form predominates according to earlier spectroscopic data.4 However, the thiol
form was adopted in Scheme 1 for consistency with arylthiols 12a-12j. Careful examination of
the reaction mechanism for the unusual nucleophilic substitution involving bromide 3b revealed
that either a planar trigonal carbocation (as in SN1) or pentavalent carbon species (as in SN2)
resulting from 3b was needed during the reaction. However, it is clearly impossible for 3b to
form either species with the aforementioned geometries due to the existence of a rigid
cyclopropane ring. Actually, the C-Br bond in 3b is considerably robust and can even survive
5
powerful reductants such as LiAlH4 and strong bases such as t-BuOK/KOH,6 strongly indicating
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that it is impossible for the C-Br in 3b to undergo nucleophilic substitutions. So we turned our
attention to the reported methods. Survey of the literature revealed that there are indeed a few
examples for the synthesis of a 1-thiocyclopropanecarboxylate moiety2a,2b,7. The first example
obviously lacks substrate generality because it is only applicable to the structural modification at
other positions in the cyclopropane ring instead of the position we studied in this paper and only
1-(phenylthio)cyclopropanecarboxylate 17a (in contrast to 17b-17j in Scheme 1) can be accessed
by this method. Also, this method involves rather hash reaction conditions, such as the use of
MeLi and lithium naphthalenide.7 The other three possibilities can be represented by the
synthesis of compounds 4, 6 and 9 (Figure 1). Noteworthy is that there was no description of
experimental details for the synthesis of 4, 6 and 9; instead, they were only listed as examples of
their individual general synthetic procedures2a,2b, as is often seen in patents. The synthesis of
both 42b and 92a involved nucleophilic substitutions of 3b with the corresponding thiols 5 and 12j,
exactly the same approach that failed in the initial attempt aforementioned for the synthesis of 2
from 12k and 3b; neither the reaction of 5 and 3b nor that of 12j and 3b was experimentally
reproducible in our laboratories (see Results and Discussion for details for the reaction of 12j
and 3b). On the other hand, the synthesis of 6 involved the employment of methyl
1-mercaptocyclopropanecarboxylate (8), which was neither commercially available nor
synthetically accessible.
Considering the fact that none of the reported examples for the synthesis of
1-thiocyclopropanecarboxylate were available due to the experimental irreproducibility, we
turned to the survey of synthetic approaches reported for its closest analog
1-oxycyclopropanecarboxylate. It turned out that there was only one synthetic approach reported
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for this class of structure,2c but this approach suffered from a lot of disadvantages, such as
obviously unoptimized reaction conditions, quite small reaction scale for some steps (< 0.1 g)
and quite low overall yield. More importantly, the step of MeONa-mediated ring opening of
butyrolactone was questionable, which was proved to be experimentally irreproducible in our
laboratories (see Results and Discussions for details). Another point that must be taken into
consideration is that although 1-oxycyclopropanecarboxylate is the closest analog of
1-thiocyclopropanecarboxylate based on the fact that O and S belong to the same group in
periodic table, they might be quite different from the synthetic perspective, such as the substrate
scope in addition to the aforementioned questionable MeONa-mediated ring opening of
butyrolactone. Encouraged by the great potential application in medicinal chemistry and lack of
available synthetic approaches currently, we developed a facile synthetic approach to
1-thiocyclopropanecarboxylates based on that for 1-oxycyclopropanecarboxylates after
systematic optimizations of the reaction conditions and intensive exploration of substrate scope
(approach A, Scheme 1); during the process, we devised another novel synthetic approach that is
complementary to the first one (approach B, Scheme 1).
Results and Discussion
The
two
synthetic
approaches
developed
in
the
present
study
to
1-thiocyclopropanecarboxylates 17a-17j are depicted in Scheme 1.
The synthetic approach A was initially developed using thiophenol 12a as the substrate.
Thus, α-bromobutyrolactone (10) underwent SN2 reaction with 12a to produce 13a in the
presence of K2CO3 in DMF at room temperature. Butyrolactone 13a was hydrolyzed with NaOH
in MeOH at room temperature to furnish sodium carboxylate 14a, which in turn was smoothly
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esterified by MeI to give methyl ester 15a in the presence of NaHCO3 in DMF/CHCl3 at 0°C to
room temperature.8 Attempted one-step conversion of 13a into 15a according to the method
reported2c for the synthesis of 1-oxocyclopropanecarboxylates involving the use of
MeONa/MeOH mixture at room temperature was in vain. As shown in Scheme 2, the ring
opening of 13a to produce 15a proceeded very slowly in anhydrous MeOH even in the presence
of more than 10 equ. of MeONa with a conversion of only about 20% being achieved within 5 h
and, more unfortunately, almost all the 15a generated in the reaction underwent re-lactonization
back to 13a during the workup. If the reaction time was prolonged beyond 24 h, the byproduct
sodium carboxylate 14a would dominate the reaction mixture. Alcohol 15a was treated with
methanesulfonyl chloride in the presence of Et3N in CH2Cl2 at 0°C to room temperature to
furnish mesylate 16a. Treatment of mesylate 16a with t-BuOK in dried THF at 0°C to room
temperature triggered the intramolecular SN2 reaction, leading to the desired 17a. The leaving
group employed in 16a in this approach was explored with anticipation of finding the optimal
one (Table 1). As clearly shown in Table 1, among the four commonly employed leaving groups
(LG), MsO was the best one with the highest overall yield resulting from the excellent yield 1
and yield 2 (entry 1). Both tosylate and iodide were also acceptable since their overall yields
were moderate (entries 2 and 4), whereas bromider was obviously unacceptable with a markedly
low overall yield arising from the quite low first step yield 1 (entry 3).
Like in approach A, the development of synthetic approach B was also based on 12a as the
substrate. Thus, methyl bromoacetate 11 smoothly underwent SN2 reaction with 12a to afford
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18a under reaction conditions analogous to those applied for the synthesis of 13a. The isolated
product was then deprotonated with 2.2 equ. of lithium diisopropylamide (LDA) at -78°C in
dried THF and subsequently alkylated with 1.5 equ. of 1,3,2-dioxathiolane-2,2-dioxide (19a) in
the presence of 1.1 equ. of 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU) at
-78°C to room temperature to successfully produce the desired 17a. Given 19a was a rarely used
bidentate electrophile that was relatively expensive, we initially explored other commonly
encountered bidentate electrophiles that could be used for its potential surrogates (Table 2).
However, as shown in Table 2, the yield corresponding to 19a was overwhelmingly higher than
those of other counterparts 19b-19f, strongly suggesting that the relatively expensive 19a was the
only available bidentate electrophile among the commonly encountered ones.
With the two fully optimized synthetic approaches in hand, we evaluated the substrate scope to
study the generality of both approaches (Table 3). This study demonstrated that both synthetic
approach A and synthetic approach B were applicable to a variety of thiols with varying
substituents, i.e. aryl groups such as benzene ring with substituents ranging from
electron-donating to electron-withdrawing (entries 1-3) and naphthalene ring (entry 7), alkyl
groups such as linear (entry 4), bulky (entry 5) and cycloalkyl groups (entry 6), and heteroaryl
groups (entries 8-9). However, approach A was applicable to neither thiol 12j (entry 10) nor 12k
(entry 11); approach B was only applicable to thiol 12j (entry 10) but not to 12k (entry 11). After
careful examination of the mechanisms for each synthetic step in both approaches and the
structural characteristics of 12j and 12k, we proposed tentative explanations for the failures
observed in entries 10 and 11, which are discussed at the end of the Results and Discussion. As
shown in Table 3, the overall yields for the synthesis of 17a-17i by approach A were uniformly
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higher than those by approach B although the former involved much more reaction steps.
Apparently, moderate yield (35-41%) of the cyclopropanation step limits applications of the
latter approach B from the overall yield perspective.
Finally, we went on to try to complete the synthesis of compounds 9 (Scheme 3) and 2 (Scheme
4) by the aforementioned approaches
A
and B. As shown in Scheme 3,
6-bromo-4-chloroquinoline (20) was treated with Na2S·9H2O in DMF at 100°C in N2
atmosphere to give rise to thiol 12j,2a which in turn was converted to 17j according to synthetic
approach B (entry 10 in Table 3). Alkaline hydrolysis of ester 17j with aqueous LiOH in MeOH
1
at room temperature finally produced the desired 9. The H NMR data of 9 synthesized by
synthetic approach B in the present study seemed different to some extent from those reported in
the literature.2a Considering the reported synthetic procedure for 92a to be experimentally
irreproducible in our laboratories and almost theoretically impossible as discussed above, we
tentatively conclude that the reported 1H NMR data might be questionable due to some unknown
reasons. It is noted that since there were no data on other physical properties reported for 9 for
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further comparison such as melting point and C NMR, we can’t draw a definitive conclusion
1
concerning the authenticity of the reported H NMR data for 9.2a We carefully repeated the
reported seemingly straightforward approach involving the reaction of 12j and ethyl
1-bromocyclopropanecarboxylate (3b).2a Thus, heating of a mixture of thiol 12j and methyl or
ethyl 1-bromocyclopropanecarboxylate (3a, 3b) in the presence of Cs2CO3 in DMF in nitrogen
atmosphere, starting from room temperature, at intervals of 10°C, showed that reactions indeed
occurred at about 90°C for 3a and 120°C for 3b, respectively. However, the isolated products
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were identified to be 21a and 21b, respectively, instead of the expected 17j and 17j', which
presumably resulted from alkylation of the mercapto group in 12j by the methyl and ethyl ester
functionality in 3a and 3b in the presence of base at high temperatures. An initial attempt to
synthesize 9 by the synthetic approach A failed due to the unsuccessful preparation of the
intermediate 15j. Thus, SN2 reaction of 12j and 10 under the identical conditions for the
synthesis of 13a afforded 13j. Ring opening of butyrolactone 13j with NaOH in MeOH at room
temperature gave 14j. When 14j was subjected to the same esterification conditions described
above for the synthesis of 15a, it re-lactonized back to 13j instead of yielding the expected 15j.
In another attempt, treatment of 13j with MeONa in MeOH produced 14j as the single product
instead of 15j, a phenomenon similar to that observed when 13a was treated with MeONa in
MeOH as discussed above (Scheme 2).
As shown in Scheme 4, compound 2 was inaccessible by the synthetic route involving the
direct reaction of 12k and 3b (approach A or approach B). Thus, no reaction occurred when
thione 12k was treated with 3b in the presence of K2CO3 in DMF at temperatures ranging from
room temperature to reflux in N2 atmosphere. SN2-Reaction of 12k and 11 following the reaction
conditions discussed above smoothly afforded 18k. However, treatment of 18k with 19a
following the procedure used for the synthesis of 17a failed, and a complex mixture of
unidentified products was obtained. On the other hand, compound 16k was successfully prepared
from 12k following the procedure used for the synthesis of 16a from 12a. Unfortunately,
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treatments of 16k with various bases led in all cases to a complex mixture of unidentified
products instead of the desired 17k.
The failures of synthetic approach A in the synthesis of 17j and 17k and of synthetic
approach B in the synthesis of 17k as well as their success in the synthesis of other
1-thiocyclopropanecarboxylates prompted us to figure out the reasons underlying the failure to
prepare certain 1-thiocyclopropanecarboxylates by these two approaches and, more importantly,
to better understand the substrate scope and the strengths and weaknesses of these two
approaches. After careful examination of the mechanisms for each synthetic steps in both
approaches and the structural characteristics of 12j and 12k, we proposed tentative explanations
for the failures observed in entries 10 and 11: the failure of approach A in the synthesis of 9
actually arose from the unsuccessful synthesis of 15j from 14j due to the re-lactonization of 15j
to 13j (Scheme 3) which was probably mediated by the basical N atom in the quinoline ring,
while its failure in the synthesis of 2 arose from the unsuccessful synthesis of 17k from 16k
(Scheme 4) which likely resulted from the competitive intramolecular SN2 reaction owing to the
concomitant deprotonation of reactive methylene group connecting naphthalene and triazole
rings in 16k under the alkaline reaction conditions. The failure of approach B in the synthesis of
17k, on the other hand, arose from the unsuccessful synthesis of 17k from 18k, which could also
be attributable to the presence of the same reactive methylene group in 16k. Thus, a tentative
conclusion can be drawn that the synthetic approach A cannot be compatible with those starting
thiols with acidic and alkaline functional groups, and synthetic approach B cannot be compatible
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with thiols with acidic functional groups, because these reactive groups can interfere with some
reaction steps in two approaches.
Conclusion
We have developed two synthetic approaches to 1-thiocyclopropanecarboxylates starting
from corresponding thiols, a class of versatile structures that has great potential to be used in
synthetic organic chemistry and medicinal chemistry. The synthetic approach A was mainly
characterized by inexpensive reagents but was associated with relatively more reaction steps and
incompatibility with those starting thiols with acidic and alkaline functional groups; in contrast,
the synthetic approach B was characterized by fewer reaction steps but had limitations such as
relatively expensive reagents and incompatibility with those starting thiols with acidic functional
groups. The two approaches are complementary in many respects, allowing for flexible choices
according to specific requirements for the characteristics of synthetic methods. For example,
approach A can find application in cases where low cost is required, whereas approach B can be
applied in cases where fewer synthetic steps are required.
Experimental
Melting points were measured with an RY-2 microscopic melting point apparatus and are
1
13
uncorrected. H NMR (400 MHz) and C NMR spectra (100MHz) were recorded on a Bruker
AV400 NMR spectrometer with DMSO-d6 as solvent and TMS (δ = 0.00) as internal standard.
High-resolution mass spectra (HRMS) were obtained with an Agilent Q-TOF 6510 mass
spectrometer with electrospray ionization technique (in ESI+ mode) using the direct injection
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1
13
method. The Supplemental Materials contains sample H and C NMR spectra for products 17
(Figures S 1 – S 26)
Thiols 12a-12i, α-bromoesters 3a, 3b, 10 and 11, bidentate electrophiles 19a-19f and
6-bromo-4-chloroquinoline 20 were commercially available. Thione 12k was prepared according
to a known procedure.9 Solvents were dried by standard methods. Column chromatography was
performed on silica gel (SiO2) eluting with EtOAc/n-hexane in suitable ratios.
General procedure for the synthesis of 13a-13k
To a stirred mixture of thiols 12a-12k (100 mmol) and K2CO3 (27.64 g, 200 mmol) in DMF
(120 mL) at room temperature was added α-bromobutyrolactone (10, 14.85 g, 90 mmol), and the
resulting mixture was stirred at room temperature until the completion of reaction as indicated by
TLC analysis (typically within 12 h).
The reaction mixture was poured into ice-water (400 mL), and the mixture thus obtained
was extracted with CH2Cl2 (3 × 100 mL). The combined extracts were washed successively with
10% aqueous Na2CO3 (2 × 100 mL) and 5% brine (3 × 100 mL), dried over anhydrous Na2SO4
and evaporated on a rotary evaporator to afford a residue, which was purified by column
chromatography to yield 13a-13k after trituration with EtOAc/n-hexane if the product was a
solid.
1
α-(Phenylthio)-γ-butyrolactone (13a). 16.61 g (95%). Colorless oil. H NMR, δ 7.47-7.49
(m, 2H), 7.30-7.38 (m, 3H), 4.35 (t, J = 8.2 Hz, 1H), 4.19-4.27 (m, 2H), 2.62-2.71 (m, 1H),
2.08-2.17 (m, 1H). The 1H NMR data were in good agreement with those reported.10
α-[(4-Methoxyphenyl)thio]-γ-butyrolactone (13b). 18.77 g (93%). Colorless oil. 1H NMR, δ
7.44-7.47 (m, 2H), 6.94-6.96 (m, 2H), 4.15-4.21 (m, 1H), 4.05-4.12 (m, 2H), 3.76 (s, 3H),
12
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2.54-2.63 (m, 1H), 2.04-2.13 (m, 1H). 13C NMR, δ 174.98, 159.85, 135.65, 121.70, 114.80,
66.25, 55.21, 44.28, 29.12. ESI-HR-MS, calcd. for C11H13O3S ([M+H]+) 225.0585, found
225.0587.
α-[(4-Nitrophenyl)thio]-γ-butyrolactone (13c). 19.38 g (90%). Pale yellow solid, m.p.
103-105°C. 1H NMR, δ 8.16-8.19 (m, 2H), 7.64-7.67 (m, 2H), 4.76 (t, J = 8.8 Hz, 1H), 4.37-4.42
13
(m, 1H), 4.29-4.35 (m, 1H), 2.76-2.84 (m, 1H), 2.18-2.28 (m, 1H). C NMR, δ 174.65, 145.38,
144.26, 128.04, 123.91, 66.81, 41.58, 29.30. ESI-HR-MS, calcd. for C10H10NO4S ([M+H]+)
240.0331, found 240.0318.
1
α-(n-Hexylthio)-γ-butyrolactone (13d). 17.12 g (94%). Colorless oil. H NMR, δ 4.22-4.32
(m, 2H), 3.74-3.77 (m, 1H), 2.58-2.74 (m, 3H), 1.99-2.07 (m, 1H), 1.48-1.60 (m, 2H), 1.21-1.37
13
(m, 6H), 0.85 (t, J = 6.8 Hz, 3H). C NMR, δ 175.52, 66.47, 39.13, 30.76, 30.29, 29.56, 28.52,
27.82, 21.96, 13.75. ESI-HR-MS, calcd. for C10H19O2S ([M+H]+) 203.1106, found 203.1098.
1
α-(t-Butylthio)-γ-butyrolactone (13e). 14.90 g (95%). Colorless oil. H NMR, δ 4.19-4.28
1
(m, 2H), 3.87 (t, J = 8.2 Hz, 1H), 2.64-2.72 (m, 1H), 2.01-2.10 (m, 1H), 1.33 (s, 9H). The H
NMR data were in good agreement with those reported.11
1
α-(Cyclohexylthio)-γ-butyrolactone (13f). 16.40 g (91%). White solid, m.p. 35-37°C. H
NMR, δ 4.22-4.32 (m, 2H), 3.82-3.85 (1H), 2.94-3.01 (m, 1H), 2.59-2.68 (m, 1H), 1.97-2.05 (m,
13
2H), 1.86-1.88 (m, 1H), 1.67-1.69 (m, 2H), 1.53-1.56 (m, 1H), 1.19-1.39 (m, 5H). C NMR, δ
175.78, 66.45, 42.44, 38.01, 32.97, 32.65, 30.07, 25.31, 25.19, 25.16. ESI-HR-MS, calcd. for
C10H16NaO2S ([M+Na]+) 223.0769, found 223.0779.
1
α-[(Naphth-2-yl)thio]-γ-butyrolactone (13g). 19.35 g (88%). Colorless oil. H NMR, δ 8.04
(s, 1H), 7.87-7.92 (m, 3H), 7.50-7.58 (m, 3H), 4.49 (dd, J = 8.0 Hz and 8.4 Hz, 1H), 4.27 (m,
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2H), 2.68-2.76 (m, 1H), 2.14-2.23 (m, 1H). 13C NMR, δ 174.96, 133.15, 131.93, 130.24, 129.84,
128.58, 128.48, 127.57, 127.27, 126.75, 126.42, 66.51, 43.08, 29.54. ESI-HR-MS, calcd. for
C14H13O2S ([M+H]+) 245.0636, found 245.0640.
α-[(3-Methylfuran-2-yl)thio]-γ-butyrolactone (13h). 17.13 g (96%). Colorless oil. 1H NMR,
δ 7.58 (d, J = 2.0 Hz, 1H), 6.47 (d, J = 1.6 Hz, 1H), 4.10-4.20 (m, 2H), 3.91-3.95 (m, 1H),
2.52-2.61 (m, 1H), 2.31 (s, 3H), 2.04-2.13 (m, 1H). 13C NMR, δ 175.00, 156.75, 141.60, 115.44,
106.46, 66.19, 43.67, 28.94, 11.50. ESI-HR-MS, calcd. for C9H11O3S ([M+H]+) 199.0429, found
199.0437.
1
α-[(Thiophen-2-yl)thio]-γ-butyrolactone (13i). 16.94 g (94%). Colorless oil. H NMR, δ
7.75 (dd, J = 1.2 Hz and 5.2 Hz, 1H), 7.31 (dd, J = 1.2 Hz and 3.6 Hz, 1H), 7.11 (dd, J = 3.8 Hz
13
and 5.4 Hz, 1H), 4.02-4.19 (m, 3H), 2.56-2.65 (m, 1H), 2.11-2.20 (m, 1H). C NMR, δ 174.43,
136.96, 132.47, 128.19, 128.11, 66.10, 45.98, 28.68. ESI-HR-MS, calcd. for C8H9O2S2 ([M+H]+)
201.0044, found 201.0040.
α-[(6-Bromoquinolin-4-yl)thio]-γ-butyrolactone (13j). 25.38 g (87%). White solid, m.p.
1
143-145°C. H NMR, δ 8.81 (d, J = 4.8 Hz, 1H), 8.22 (d, J = 2.0 Hz, 1H), 7.98 (d, J = 8.8 Hz,
1H), 7.93 (dd, J = 2.0 Hz and 8.8 Hz, 1H), 7.71 (d, J = 4.8 Hz, 1H), 4.88 (t, J = 8.8 Hz, 1H),
4.43-4.48 (m, 1H), 4.34-4.40 (m, 1H), 2.84-2.92 (m, 1H), 2.28-2.38 (m, 1H). 13C NMR, δ 174.38,
150.10, 145.72, 142.70, 133.05, 131.98, 127.07, 125.33, 120.19, 119.93, 66.94, 41.31, 29.42.
ESI-HR-MS, calcd. for C13H11BrNO2S ([M(79Br)+H]+) 323.9694, found 323.9691; calcd. for
C13H11BrNO2S ([M(81Br)+H]+) 325.9673, found 325.9672.
α-{4-[(4-Bromonaphth-1-yl)methyl]-4H-1,2,4-triazol-3-yl}thio-γ-butyrolactone (13k). 32.02 g
1
(88%). White solid, m.p. 148-150°C. H NMR, δ 8.71 (s, 1H), 8.22-8.25 (m, 1H), 8.15-8.17 (m,
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1H), 7.88 (d, J = 7.6 Hz, 1H), 7.72-7.79 (m, 2H), 6.91 (d, J = 7.6 Hz, 1H), 5.76 (s, 2H), 4.58 (t, J
13
= 9.4 Hz, 1H), 4.32-4.37 (m, 1H), 4.22-4.28 (m, 1H), 2.66-2.74 (m, 1H), 2.41-2.51 (m, 1H). C
NMR, δ 173.94, 146.97, 146.13, 131.60, 131.24, 131.15, 129.64, 128.11, 127.88, 127.26, 125.81,
123.67, 122.49, 66.50, 45.35, 43.37, 29.18. ESI-HR-MS, calcd. for C17H15BrN3O2S
([M(79Br)+H]+) 404.0068, found 404.0071; calcd. for C17H15BrN3O2S ([M(81Br)+H]+) 406.0048,
found 406.0054.
General procedure for the synthesis of 14a-14k
To stirred methanol (200 mL) at room temperature was added NaOH (4.20 g, 105 mmol),
and the mixture was stirred at reflux in N2 atmosphere until the NaOH dissolved completely. The
reaction mixture was cooled to room temperature followed by addition of 13a-13k (75 mmol)
dissolved in methanol (30 mL), and the stirring was continued at room temperature until the
completion of reaction as indicated by TLC analysis (typically within 12 h).
The reaction mixture was evaporated on a rotary evaporator to dryness, and the residue thus
obtained was further dried in vacuo at room temperature to give rise to 14a-14k typically as a
powder, which was used directly in the next step without further purification.
General procedure for the synthesis of 15a-15i and 15k
To a stirred mixture of 14a-14k as prepared above (deemed to be 75 mmol) in DMF (300
mL) and CHCl3 (30 mL) cooled on an ice-water bath were added MeI (12.77 g, 90 mmol) and
NaHCO3 (18.90 g, 225 mmol), and the resulting mixture was stirred at room temperature until
completion of the reaction as indicated by TLC analysis (typically within 12 h).
The reaction mixture was poured into ice-water (900 mL), and the mixture thus obtained
was extracted with CH2Cl2 (3 × 200 mL). The combined extracts were washed with 5% brine (3
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× 100 mL), dried over anhydrous Na2SO4 and evaporated on a rotary evaporator to afford a
residue, which was purified by column chromatography to yield 15a-13i or 15k after trituration
with EtOAc/n-hexane if the product was a solid.
Methyl 4-hydroxy-2-(phenylthio)butanoate (15a). 13.75 g (overall 81% for 13a→15a).
1
Colorless oil. H NMR, δ 7.39-7.42 (m, 2H), 7.29-7.37 (m, 3H), 4.64 (t, J = 5.0 Hz, 1H), 3.91
(dd, J = 7.0 Hz and 7.4 Hz, 1H), 3.58 (s, 3H), 3.49-3.55 (m, 1H), 3.40-3.47 (m, 1H), 1.90-1.98
13
(m, 1H), 1.74-1.82 (m, 1H). C NMR, δ 171.95, 132.90, 131.95, 129.09, 127.79, 57.75, 51.96,
46.35, 34.36. ESI-HR-MS, calcd. for C11H15O3S ([M+H]+) 227.0742, found 227.0740.
Methyl 4-hydroxy-2-[(4-methoxyphenyl)thio]butanoate (15b). 15.76 g (overall 82% for
13b→15b). Colorless oil. 1H NMR, δ 7.34-7.37 (m, 2H), 6.91-6.94 (m, 2H), 4.59 (brs, 1H), 3.75
(s, 3H), 3.70 (t, J = 7.4 Hz, 1H), 3.57 (s, 3H), 3.50-3.52 (m, 1H), 3.40-3.41 (m, 1H), 1.82-1.90
13
(m, 1H), 1.67-1.75 (m, 1H). C NMR, δ 171.96, 159.85, 135.99, 122.27, 114.62, 57.88, 55.18,
51.77, 47.35, 34.12. ESI-HR-MS, calcd. for C12H17O4S ([M+H]+) 257.0848, found 257.0845.
Methyl 4-hydroxy-2-[(4-nitrophenyl)thio]butanoate (15c). 16.28 g (overall 80% for
13c→15c). Pale yellow oil. 1H NMR, δ 8.15-8.19 (m, 2H), 7.58-7.62 (m, 2H), 4.74 (t, J = 5.0 Hz,
1H), 4.31 (t, J = 7.2 Hz, 1H), 3.63 (s, 3H), 3.47-3.57 (m, 2H), 2.03-2.12 (m, 1H), 1.84-1.92 (m,
1H). ESI-HR-MS, calcd. for C11H14NO5S ([M+H]+) 272.0593, found 272.0597. Despite repeated
13
column chromatography, the sample of 15c was not pure enough for the collection of C NMR
data.
Methyl 2-(n-hexylthio)-4-hydroxybutanoate (15d). 14.59 g (overall 83% for 13d→15d).
Colorless oil. 1H NMR, δ 4.56 (t, J = 5.2 Hz, 1H), 3.63 (s, 3H), 3.35-3.51 (m, 3H), 2.52-2.58 (m,
2H), 1.88-1.97 (m, 1H), 1.63-1.72 (m, 1H), 1.45-1.53 (m, 2H), 1.21-1.35 (m, 6H), 0.85 (t, J = 6.8
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Hz, 3H). 13C NMR, δ 172.66, 57.88, 51.80, 42.40, 34.34, 30.72, 30.57, 28.75, 27.74, 21.93,
13.81. ESI-HR-MS, calcd. for C11H23O3S ([M+H]+) 235.1368, found 235.1376.
Methyl 4-hydroxy-2-(t-butylthio)butanoate (15e). 12.53 g (overall 81% for 13e→15e).
Colorless oil. 1H NMR, δ 4.60 (t, J = 5.0 Hz, 1H), 3.62 (s, 3H), 3.43-3.51 (m, 2H), 3.34-3.39 (m,
1H), 1.87-1.92 (m, 1H), 1.63-1.68 (m, 1H), 1.28 (s, 9H). 13C NMR, δ 173.86, 57.86, 51.83, 43.93,
40.54, 36.47, 30.67. ESI-HR-MS, calcd. for C9H18NaO3S ([M+Na]+) 229.0874, found 229.0876.
Methyl 2-(cyclohexylthio)-4-hydroxybutanoate (15f). 14.64 g (overall 84% for 13f→15f).
Colorless oil. 1H NMR, δ 4.56 (t, J = 5.2 Hz, 1H), 3.63 (s, 3H), 3.44-3.53 (m, 2H), 3.35-3.41 (m,
1H), 2.75-2.80 (m, 1H), 1.87-1.96 (m, 2H), 1.81-1.84 (m, 1H), 1.62-1.70 (m, 3H), 1.51-1.54 (m,
1H), 1.17-1.31 (m, 5H). 13C NMR, δ 173.05, 57.96, 51.71, 43.40, 41.51, 35.03, 33.32, 33.28,
25.43, 25.33, 25.27. ESI-HR-MS, calcd. for C11H21O3S ([M+H]+) 233.1211, found 233.1208.
Methyl 4-hydroxy-2-[(naphth-2-yl)thio]butanoate (15g). 14.92 g (overall 72% for
1
13g→15g). Colorless oil. H NMR, δ 7.99 (s, 1H), 7.88-7.92 (m, 3H), 7.49-7.56 (m, 3H), 4.67
(brs, 1H), 4.05 (t, J = 7.4 Hz, 1H), 3.54-3.58 (m, 4H), 3.44-3.49 (m, 1H), 1.95-2.04 (m, 1H),
1.80-1.88 (m, 1H). 13C NMR, δ 171.94, 133.11, 132.00, 130.59, 130.46, 129.15, 128.50, 127.56,
127.36, 126.73, 126.53, 57.79, 52.02, 46.38, 34.43. ESI-HR-MS, calcd. for C15H17O3S ([M+H]+)
277.0898, found 277.0892.
Methyl 4-hydroxy-2-[(3-methylfuran-2-yl)thio]butanoate (15h). 13.99 g (overall 81% for
13h→15h). Colorless oil. 1H NMR, δ 7.56 (d, J = 2.0 Hz, 1H), 6.38 (d, J = 2.0 Hz, 1H), 4.59 (t,
J = 5.0 Hz, 1H), 3.59 (s, 3H), 3.49-3.56 (m, 2H), 3.37-3.42 (m, 1H), 2.25 (s, 3H), 1.81-1.90 (m,
1H), 1.65-1.73 (m, 1H). 13C NMR, δ 171.76, 156.43, 141.36, 115.63, 106.85, 57.75, 51.88, 46.06,
33.87, 11.37. ESI-HR-MS, calcd. for C10H15O4S ([M+H]+) 231.0691, found 231.0689.
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Methyl 4-hydroxy-2-[(thiophen-2-yl)thio]butanoate (15i). 14.64 g (overall 84% for
1
13i→15i). Colorless oil. H NMR, δ 7.72 (dd, J = 0.8 Hz and 5.2 Hz, 1H), 7.20-7.21 (m, 1H),
7.08 (dd, J = 3.6 Hz and 5.2 Hz, 1H), 4.62 (t, J = 5.2 Hz, 1H), 3.69 (t, 1H, J = 7.4 Hz), 3.60 (s,
13
3H), 3.49-3.56 (m, 1H), 3.38-3.45 (m, 1H), 1.85-1.93 (m, 1H), 1.70-1.78 (m, 1H). C NMR, δ
171.25, 136.79, 132.39, 128.81, 128.06, 57.65, 51.96, 48.73, 33.68. ESI-HR-MS, calcd. for
C9H13O3S2 ([M+H]+) 233.0306, found 233.0303.
Methyl 2-[(6-bromoquinolin-4-yl)thio]-4-hydroxybutanoate (15j). Synthesis of 15j failed.
See Results and Discussion for details.
Methyl
2-({4-[(4-bromonaphth-1-yl)methyl]-4H-1,2,4-triazol-3-yl}thio)-4-
1
hydroxybutanoate (15k). 23.23 g (overall 71% for 13k→15k). White solid, m.p. 90-92°C. H
NMR, δ 8.70 (s, 1H), 8.22-8.25 (m, 1H), 8.13-8.16 (m, 1H), 7.87 (d, J = 8.0 Hz, 1H), 7.72-7.79
(m, 2H), 6.84 (d, J = 7.6 Hz, 1H), 5.72 (s, 2H), 4.66 (t, J = 5.0 Hz, 1H), 4.21 (t, J = 7.0 Hz, 1H),
3.59 (s, 3H), 3.42-3.52 (m, 2H), 1.98-2.05 (m, 1H), 1.88-1.95 (m, 1H). 13C NMR, δ 171.00,
147.23, 146.19, 131.80, 131.19, 131.14, 129.66, 128.13, 127.89, 127.28, 125.57, 123.63, 122.43,
57.60, 52.42, 46.78, 45.28, 34.45. ESI-HR-MS, calcd. for C18H19BrN3O3S ([M(79Br)+H]+)
436.0330, found 436.0323; calcd. for C18H19BrN3O3S ([M(81Br)+H]+) 438.0310, found
438.0316.
General procedure for the synthesis of 16a-16i, 16k and 16aa-16ac
Procedure for the synthesis of 16a-16i, 16k and 16aa: To a stirred solution of 15a-15i or
15k (12 mmol) and Et3N (3.64 g, 36 mmol) in dried CH2Cl2 (50 mL) cooled on an ice-water bath
was added MsCl (2.06 g, 18 mmol) or TsCl (3.43 g, 18 mmol) dissolved in dried CH2Cl2 (10 mL)
dropwise, and the resulting mixture was stirred at room temperature until the completion of the
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reaction as indicated by TLC analysis (typically within 3 h). The reaction mixture was diluted
with CH2Cl2 (100 mL), washed successively with ice-water (100 mL), 1 M HCl (2 × 50 mL) and
5% brine (100 mL), dried over anhydrous Na2SO4 and evaporated on a rotary evaporator to
afford a residue, which was purified by column chromatography to furnish 16a-16i, 16k or 16aa.
Procedure for the synthesis of 16ab: To a stirred solution of 15a (2.72 g, 12 mmol) in dried
CH2Cl2 (20 mL) cooled on an ice-water bath was added dropwise PBr3 (4.87 g, 18 mmol)
dissolved in dried CH2Cl2 (10 mL), and the resulting mixture was stirred at room temperature
until the completion of the reaction as indicated by TLC analysis (typically within 3 h). The
reaction mixture was diluted with CH2Cl2 (100 mL), washed successively with ice-water (100
mL), saturated aqueous NaHCO3 (2× 100 mL) and 5% brine (100 mL), dried over anhydrous
Na2SO4 and evaporated on a rotary evaporator to afford a residue, which was purified by column
chromatography to furnish 16ab.
Procedure for the synthesis of 16ac: To a stirred solution of I2 (3.65 g, 14.4 mmol) in dried
CH2Cl2 (100 mL) cooled on an ice-water bath was portionwise added PPh3 (3.93 g, 15 mmol),
and after addition the mixture thus obtained was stirred at this temperature for 1 h followed by
portionwise addition of imidazole (2.94 g, 43.2 mmol). The resulting mixture was stirred at this
temperature for 1 h followed by dropwise addition of 15a (2.72 g, 12 mmol) dissolved in dried
CH2Cl2 (10 mL). The reaction mixture was stirred at room temperature until the completion of
the reaction as indicated by TLC analysis (typically within 5 h). The reaction mixture was diluted
with CH2Cl2 (100 mL), washed with 5% brine (3 × 100 mL), dried over anhydrous Na2SO4 and
evaporated on a rotary evaporator to afford a residue, which was in turn triturated with
EtOAc/n-hexane (1/3 by v/v, 30 mL in total) and filtered off to remove the byproduct Ph3P=O.
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The filtrate was evaporated on a rotary evaporator to afford a residue, which was purified by
column chromatography to furnish 16ac.
Compounds 16a, 16aa-16ac and 16k were subjected to structural characterization, while
16b-16i were directly used in the next step without collection of spectroscopic data.
Methyl 4-[(methylsulfonyl)oxy]-2-(phenylthio)butanoate (16a). 3.21 g (88%). Colorless oil.
1H NMR, δ 7.43-7.46 (m, 2H), 7.33-7.40 (m, 3H), 4.26-4.38 (m, 2H), 3.92 (t, J = 7.2 Hz, 1H),
13
3.61 (s, 3H), 3.15 (s, 3H), 2.15-2.24 (m, 1H), 1.99-2.07 (m, 1H). C NMR, δ 171.18, 132.82,
131.71, 129.20, 128.36, 67.37, 52.19, 45.94, 36.55, 30.45. ESI-HR-MS, calcd. for C12H16NaO5S2
([M+Na]+) 327.0335, found 327.0345.
Methyl 4-[(4-methylbenzenesulfonyl)oxy]-2-(phenylthio)butanoate (16aa). 2.97 g (65%).
Colorless oil. 1H NMR, δ 7.76 (d, J = 8.4 Hz, 2H), 7.47 (d, J = 8.0 Hz, 2H), 7.32-7.36 (m, 5H),
4.15-4.21 (m, 1H), 4.08-4.12 (m, 1H), 3.79 (t, J = 7.2 Hz, 1H), 3.55 (s, 3H), 2.41 (s, 3H),
2.07-2.12 (m, 1H), 1.90-1.95 (m, 1H). 13C NMR, δ 170.97, 144.97, 132.73, 132.06, 131.54,
130.11, 129.13, 128.31, 127.54, 67.81, 52.10, 45.68, 30.05, 21.02. ESI-HR-MS, calcd. for
C18H20NaO5S2 ([M+Na]+) 403.0650, found 403.0665.
1
Methyl 4-bromo-2-(phenylthio)butanoate (16ab). 0.62 g (18%). Colorless oil. H NMR, δ
7.43-7.46 (m, 2H), 7.35-7.40 (m, 3H), 3.92 (t, J = 7.2 Hz, 1H), 3.56-3.66 (m, 5H), 2.25-2.34 (m,
1H), 2.10-2.18 (m, 1H). 13C NMR, δ 171.03, 132.83, 131.73, 129.22, 128.38, 52.25, 48.09, 33.74,
31.00. ESI-HR-MS, calcd. for C11H14BrO2S ([M(79Br)+H]+) 288.9898, found 288.9887; calcd.
for C11H14BrO2S ([M(81Br)+H]+) 290.9877, found 290.9877.
1
Methyl 4-iodo-2-(phenylthio)butanoate (16ac). 2.74 g (68%). Colorless oil. H NMR, δ
7.42-7.45 (m, 2H), 7.35-7.40 (m, 3H), 3.85 (t, J = 7.4 Hz, 1H), 3.62 (s, 3H), 3.31 (d, J = 7.2 Hz,
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2H), 2.21-2.29 (m, 1H), 2.07-2.14 (m, 1H). 13C NMR, δ 170.83, 132.77, 131.70, 129.09, 128.26,
52.17, 50.16, 34.50, 3.18. ESI-HR-MS, calcd. for C11H13INaO2S ([M+Na]+) 358.9579, found
358.9576.
Methyl
4-[(methylsulfonyl)oxy]-2-{4-[(4-bromonaphth-1-yl)methyl]-4H-1,2,4-
1
triazol-3-yl}thiobutanoate (16k). 3.77 g (61%). White foam. H NMR, δ 9.28 (s, 1H), 8.26-8.28
(m, 1H), 8.13-8.15 (m, 1H), 7.95 (d, J = 8.0 Hz, 1H), 7.75-7.82 (m, 2H), 7.44 (d, J = 7.6 Hz, 1H),
5.93 (d, J = 16.0 Hz, 1H), 5.88 (d, J = 16.0 Hz, 1H), 4.94-4.97 (m, 1H), 4.38-.4.49 (m, 2H), 3.75
13
(s, 3H), 2.61-2.69 (m, 2H), 2.28 (s, 3H). C NMR, δ 168.27, 148.64, 144.13, 131.47, 131.33,
129.54, 128.35, 128.24, 128.21, 128.02, 127.40, 123.88, 123.78, 53.58, 47.42, 46.75, 43.09,
39.70, 24.24. ESI-HR-MS, calcd. for C18H17BrN3O2S ([M(79Br)-MsOH+H]+) 418.0225, found
418.0222; calcd. for C18H17BrN3O2S ([M(81Br)-MsOH+H]+) 420.0204, found 420.0202.
General procedure for the synthesis of 17a-17i by synthetic approach A
To a stirred solution of 16a-16i, 16k or 16aa-16ac (for 16b-16k, deemed to be 12 mmol; for
16a, 16aa and 16ac, 7 mmol; for 16ab, 2 mmol) in dried THF (for 16b-16k, 80 mL; for 16a,
16aa and 16ac, 50 mL; for 16ab, 20 mL) cooled on an ice-water bath was added t-BuOK (for
16b-16k, 1.62 g, 14.4 mmol; for 16a, 16aa and 16ac, 0.94 g, 8.4 mmol; for 16ab, 0.22 g, 2
mmol) in a portionwise manner, and the mixture thus obtained was stirred at room temperature
until the completion of reaction as indicated by TLC analysis (typically within 3 h).
The reaction mixture was concentrated on a rotary evaporator at 30°C to half its original
volume and poured into ice-water (100 mL), and the resulting mixture was extracted with
CH2Cl2 (3 × 50 mL). The combined extracts were washed with 5% brine (2 × 100 Ml), dried
over anhydrous Na2SO4 and evaporated on a rotary evaporator to afford a residue, which was
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purified by column chromatography to furnish 17a-17i after trituration with EtOAc/n-hexane if
the product was a solid.
Methyl 1-(phenylthio)cyclopropanecarboxylate (17a). Yields are shown in Table 1.
Colorless oil. 1H NMR, δ 7.31-7.34 (m, 2H), 7.25-7.28 (m, 2H), 7.17-7.21 (m, 1H), 3.61 (s, 3H),
1.73-1.76 (m, 2H), 1.31-1.34 (m, 2H). 13C NMR, δ 171.93, 136.20, 128.93, 127.00, 125.68,
52.75, 25.70, 19.90. ESI-HR-MS, calcd. for C11H13O2S ([M+H]+) 209.0636, found 209.0629.
Methyl 1-[(4-methoxyphenyl)thio]cyclopropanecarboxylate (17b). 1.94 g (overall 68% for
15b→17b). Colorless oil. 1H NMR, δ 7.31-7.34 (m, 2H), 6.90-6.93 (m, 2H), 3.74 (s, 3H), 3.61 (s,
3H), 1.58-1.61 (m, 2H), 1.29-1.32 (m, 2H). 13C NMR, δ 172.20, 158.74, 131.99, 125.54, 114.65,
55.12, 52.63, 28.02, 19.64. ESI-HR-MS, calcd. for C12H15O3S ([M+H]+) 239.0742, found
239.0749.
Methyl 1-[(4-nitrophenyl)thio]cyclopropanecarboxylate (17c). 2.19 g (overall 72% for
1
15c→17c). Pale yellow solid, m.p. 78-80°C. H NMR, δ 8.14-8.17 (m, 2H), 7.45-7.48 (m, 2H),
3.63 (s, 3H), 1.86-1.89 (m, 2H), 1.40-1.43 (m, 2H). 13C NMR, δ 171.14, 147.07, 144.66, 125.61,
123.88, 53.04, 24.55, 20.05. ESI-HR-MS, calcd. for C11H12NO4S ([M+H]+) 254.0487, found
254.0487.
Methyl 1-(n-hexylthio)cyclopropanecarboxylate (17d). 1.84 g (overall 71% for 15d→17d).
Colorless oil. 1H NMR, δ 3.61 (s, 3H), 2.65 (t, J = 7.2 Hz, 2H), 1.46-1.53 (m, 4H), 1.22-1.36 (m,
6H), 1.15-1.18 (m, 2H), 0.85 (t, J = 6.8 Hz, 3H). 13C NMR, δ 172.56, 52.30, 32.53, 30.84, 28.47,
27.95, 25.46, 21.97, 19.16, 13.70. ESI-HR-MS, calcd. for C11H21O2S ([M+H]+) 217.1262, found
217.1267.
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Methyl 1-(t-butylthio)cyclopropanecarboxylate (17e). 1.58 g (overall 70% for 15e→17e).
1
13
Colorless oil. H NMR, δ 3.61 (s, 3H), 1.49-1.52 (m, 2H), 1.27 (s, 9H), 1.16-1.19 (m, 2H). C
NMR, δ 173.05, 52.27, 45.30, 31.17, 23.91, 18.25. ESI-HR-MS, calcd. for C9H16NaO2S
([M+Na]+) 211.0769, found 211.0768.
Methyl 1-(cyclohexylthio)cyclopropanecarboxylate (17f). 1.75 g (overall 68% for 15f→17f).
Colorless oil. 1H NMR, δ 3.61 (s, 3H), 2.93-2.98 (m, 1H), 1.84-1.88 (m, 2H), 1.66-1.67 (m, 2H),
1.52-1.55 (m, 1H), 1.48-1.51 (m, 2H), 1.19-1.32 (m, 5H), 1.15-1.18 (m, 2H). 13C NMR, δ 172.91,
52.42, 44.46, 32.89, 25.32, 25.26, 24.38, 19.07. ESI-HR-MS, calcd. for C11H19O2S ([M+H]+)
215.1106, found 215.1105.
Methyl 1-[(naphth-2-yl)thio]cyclopropanecarboxylate (17g). 1.98 g (overall 64% for
15g→17g). White solid, m.p. 64-66°C. 1H NMR, δ 7.84-7.87 (m, 3H), 7.77 (d, J = 1.2 Hz, 1H),
7.44-7.52 (m, 2H), 7.40 (dd, J = 1.6 Hz and 8.8 Hz, 1H), 3.62 (s, 3H), 1.79-1.82 (m, 2H),
1.39-1.42 (m, 2H). 13C NMR, δ 171.96, 133.88, 133.29, 131.15, 128.38, 127.54, 126.99, 126.61,
125.62, 125.47, 124.84, 52.84, 25.82, 20.00. ESI-HR-MS, calcd. for C15H15O2S ([M+H]+)
259.0793, found 259.0798.
Methyl 1-[(3-methylfuran-2-yl)thio]cyclopropanecarboxylate (17h). 1.86 g (overall 73% for
15h→17h). Colorless oil. 1H NMR, δ 7.54 (d, J = 1.2 Hz, 1H), 6.53 (d, J = 0.9 Hz, 1H), 3.62 (s,
13
3H), 2.33 (s, 3H), 1.45-1.48 (m, 2H), 1.29-1.32 (m, 2H). C NMR, δ 172.18, 154.99, 141.29,
114.90, 109.44, 52.53, 28.88, 19.02, 11.52. ESI-HR-MS, calcd. for C10H13O3S ([M+H]+)
213.0585, found 213.0580.
Methyl 1-[(thiophen-2-yl)thio]cyclopropanecarboxylate (17i). 1.83 g (overall 71% for
15i→17i). Colorless oil. 1H NMR, δ 7.66-7.67 (m, 1H), 7.25-7.26 (m, 1H), 7.06 (dd, J = 3.6 Hz
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and 5.2 Hz, 1H), 3.65 (s, 3H), 1.53-1.56 (m, 2H), 1.35-1.38 (m, 2H). 13C NMR, δ 171.71, 134.31,
132.09, 130.93, 127.62, 52.62, 30.84, 19.65. ESI-HR-MS, calcd. for C9H11O2S2 ([M+H]+)
215.0200, found 215.0200.
Methyl
1-({4-[(4-bromonaphth-1-yl)methyl]-4H-1,2,4-triazol-3-yl}thio)cyclo
propanecarboxylate (17k). Synthesis of 17k failed. See Results and Discussion for details.
General procedure for the synthesis of 18a-18k
To a stirred mixture of thiols 12a-12k (10 mmol) and K2CO3 (2.76 g, 20 mmol) in DMF (20
mL) at room temperature was added methyl bromoacetate (11, 1.84 g, 12 mmol), and the
resulting mixture was stirred at room temperature until the completion of reaction as indicated by
TLC analysis (typically within 12 h).
The reaction mixture was poured into ice-water (100 mL), and the mixture thus obtained
was extracted with CH2Cl2 (3 × 50 mL). The combined extracts were washed with 5% brine (5 ×
100 mL), dried over anhydrous Na2SO4 and evaporated on a rotary evaporator to afford a residue,
which was purified by column chromatography to yield 18a-18k after trituration with
EtOAc/n-hexane if the product was a solid.
1
Methyl 2-(phenylthio)acetate (18a). 1.69 g (93%). Colorless oil. H NMR, δ 7.30-7.35 (m,
1
4H), 7.19-7.23 (m, 1H), 3.89 (s, 2H), 3.61 (s, 3H). The H NMR data were in good agreement
with those reported12.
1
Methyl 2-[(4-methoxyphenyl)thio]acetate (18b). 2.00 g (94%). Colorless oil. H NMR, δ
7.33-7.37 (m, 2H), 6.89-6.93 (m, 2H), 3.74 (s, 3H), 3.70 (s, 2H), 3.58 (s, 3H). 13C NMR, δ
169.84, 158.90, 132.71, 124.73, 114.68, 55.10, 51.93, 36.90. ESI-HR-MS, calcd. for C10H13O3S
([M+H]+) 213.0585, found 213.0592.
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Methyl 2-[(4-nitrophenyl)thio]acetate (18c). 2.09 g (92%). Pale yellow solid, m.p. 63-65°C
(lit.13 51-52°C). 1H NMR, δ 8.14 (d, J = 9.2 Hz, 2H), 7.52 (d, J = 9.2 Hz, 2H), 4.16 (s, 2H), 3.66
(s, 3H).
1
Methyl 2-(n-hexylthio)acetate (18d). 1.81 g (95%). Colorless oil. H NMR, δ 3.62 (s, 3H),
3.31 (s, 2H), 2.56 (t, J = 7.4 Hz, 2H), 1.46-1.54 (m, 2H), 1.22-1.35 (m, 6H), 0.85 (t, J = 6.8 Hz,
3H). The 1H NMR data were in good agreement with those reported.14
1
Methyl 2-(t-butylthio)acetate (18e). 1.54 g (95%). Colorless oil. H NMR, δ 3.62 (s, 3H),
13
3.36 (s, 2H), 1.26 (s, 9H). C NMR, δ 171.00, 51.80, 42.49, 30.32, 30.23. ESI-HR-MS, calcd.
for C7H14NaO2S ([M+Na]+) 185.0612, found 185.0609.
1
Methyl 2-(cyclohexylthio)acetate (18f). 1.73 g (92%). Colorless oil. H NMR, δ 3.68 (s,
3H), 3.34 (s, 2H), 2.74-2.79 (m, 1H), 1.88-1.90 (m, 2H), 1.66-1.69 (m, 2H), 1.52-1.55 (m, 1H),
13
1.18-1.28 (m, 5H). C NMR, δ 170.71, 51.77, 43.19, 32.62, 31.10, 25.27, 25.24. ESI-HR-MS,
calcd. for C9H17O2S ([M+H]+) 189.0949, found 189.0942.
1
Methyl 2-[(naphth-2-yl)thio]acetate (18g). 2.02 g (87%). White solid, m.p. 47-49°C. H
13
NMR, δ 7.82-7.88 (m, 4H), 7.45-7.53 (m, 3H), 4.02 (s, 2H), 3.62 (s, 3H). C NMR, δ 169.67,
133.25, 132.68, 131.29, 128.41, 127.56, 126.95, 126.69, 126.38, 125.94, 125.83, 52.20, 34.55.
ESI-HR-MS, calcd. for C13H12NaO2S ([M+Na]+) 255.0456, found 255.0453.
1
Methyl 2-[(3-methylfuran-2-yl)thio]acetate (18h). 1.75 g (94%). Colorless oil. H NMR, δ
13
7.53 (d, J = 1.6 Hz, 1H), 6.46 (d, J = 1.2 Hz, 1H), 3.59 (s, 3H), 3.47 (s, 2H), 2.27 (s, 3H). C
NMR, δ 169.81, 154.83, 141.23, 114.57, 109.08, 51.82, 36.97, 11.21. ESI-HR-MS, calcd. for
C8H11O3S ([M+H]+) 187.0429, found 187.0424.
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Methyl 2-[(thiophen-2-yl)thio]acetate (18i). 1.73 g (92%). Colorless oil. H NMR, δ
7.64-7.65 (m, 1H), 7.21-7.23 (m, 1H), 7.05 (dd, J = 3.6 Hz and 5.2 Hz, 1H), 3.68 (s, 2H), 3.61 (s,
13
3H). C NMR, δ 169.29, 134.45, 131.86, 130.82, 127.82, 52.01, 39.90. ESI-HR-MS, calcd. for
C7H9O2S2 ([M+H]+) 189.0044, found 189.0045.
Methyl 2-[(6-bromoquinolin-4-yl)thio]acetate (18j). 2.68 g (86%). White solid, m.p.
1
111-113°C. H NMR, δ 8.76 (d, J = 4.8 Hz, 1H), 8.20 (d, J = 1.6 Hz, 1H), 7.91-7.97 (m, 2H),
7.44 (d, J = 4.8 Hz, 1H), 4.29 (s, 2H), 3.68 (s, 3H). 13C NMR, δ 168.73, 150.04, 145.50, 144.24,
132.96, 131.93, 126.68, 125.03, 119.94, 117.79, 52.58, 32.56. ESI-HR-MS, calcd. for
C12H11BrNO2S ([M(79Br)+H]+) 311.9694, found 311.9682; C12H11BrNO2S ([M(81Br)+H]+)
313.9673, found 313.9673.
Methyl 2-({4-[(4-bromonaphth-1-yl)methyl]-4H-1,2,4-triazol-3-yl}thio)acetate (18k). 3.65
g (93%). White solid, m.p. 113-114°C (lit.4 112.5-114°C). 1H NMR, δ 8.67 (s, 1H), 8.22-8.25 (m,
1H), 8.15-8.17 (m, 1H), 7.88 (d, J = 7.6 Hz, 1H), 7.72-7.79 (m, 2H), 6.92 (d, J = 7.6 Hz, 1H),
5.72 (s, 2H), 4.07 (s, 2H), 3.62 (s, 3H).
General procedure for the synthesis of 17a-17j by synthetic approach B
To a stirred solution of diisopropylamine (1.86 g, 18.4 mmol) in dried THF (50 mL) cooled
at -78°C in N2 atmosphere was dropwise added via syringe a 1.6 M solution of n-BuLi in
n-hexane (11 mL, 17.6 mmol), and after addition the resulting solution was stirred for another
0.5 h followed by dropwise addition via syringe of 18a-18k (8 mmol) dissolved in dried THF (5
mL). The mixture thus obtained was stirred for another 1 h, and 1,3,2-dioxathiolane-2,2-dioxide
(19a, 1.49 g, 12 mmol) or 19b-19f dissolved in dried THF (10 mL) and DMPU (1.13 g, 8.8
mmol) dissolved in dried THF (5 mL) were dropwise added successively via syringe. The
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reaction mixture was stirred at room temperature for 10 h. The reaction mixture was poured into
ice-water (200 mL), and the mixture thus obtained was extracted with CH2Cl2 (3 × 100 mL). The
combined extracts were washed with 5% brine (5 × 100 mL), dried over anhydrous Na2SO4 and
evaporated on a rotary evaporator to afford a residue, which was purified by column
chromatography to yield 17a-18j after trituration with EtOAc/n-hexane if the product was a
solid.
Methyl 1-(phenylthio)cyclopropanecarboxylate (17a). Yields are shown in Table 2.
Physical properties were in agreement with those for the sample from synthetic approach A.
Methyl 1-[(4-methoxyphenyl)thio]cyclopropanecarboxylate (17b). 0.78 g (41%). Physical
properties were in agreement with those for the sample from synthetic approach A.
Methyl 1-[(4-nitrophenyl)thio]cyclopropanecarboxylate (17c). 0.75 g (37%). Physical
properties were in agreement with those for the sample from synthetic approach A.
Methyl 1-(n-hexylthio)cyclopropanecarboxylate (17d). 0.62 g (36%). Physical properties
were in agreement with those for the sample from synthetic approach A.
Methyl 1-(t-butylthio)cyclopropanecarboxylate (17e). 0.59 g (39%). Physical properties
were in agreement with those for the sample from synthetic approach A.
Methyl 1-(cyclohexylthio)cyclopropanecarboxylate (17f). 0.69 g (40%). Physical properties
were in agreement with those for the sample from synthetic approach A.
Methyl 1-[(naphth-2-yl)thio]cyclopropanecarboxylate (17g). 0.89 g (43%). Physical
properties were in agreement with those for the sample from synthetic approach A.
Methyl 1-[(3-methylfuran-2-yl)thio]cyclopropanecarboxylate (17h). 0.65 g (38%). Physical
properties were in agreement with those for the sample from synthetic approach A.
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Methyl 1-[(thiophen-2-yl)thio]cyclopropanecarboxylate (17i). 0.60 g (35%). Physical
properties were in agreement with those for the sample from synthetic approach A.
Methyl 1-[(6-bromoquinolin-4-yl)thio]cyclopropanecarboxylate (17j). 2.68 g (40%). White
solid, m.p. 97-98.5°C. 1H NMR, δ 8.77 (d, J = 4.8 Hz, 1H), 8.07 (d, J = 2.0 Hz, 1H), 7.90-7.97
(m, 2H), 7.42 (d, J = 4.8 Hz, 1H), 3.63 (s, 3H), 1.94-1.97 (m, 2H), 1.49-1.52 (m, 2H). 13C NMR,
δ 170.92, 150.15, 145.50, 145.29, 132.97, 131.95, 126.18, 124.66, 119.80, 117.55, 53.16, 23.62,
20.03. ESI-HR-MS, calcd. for C14H13BrNO2S ([M(79Br)+H]+) 337.9850, found 337.9851; calcd.
for C14H13BrNO2S ([M(81Br)+H]+) 339.9830, found 339.9839.
Methyl
1-({4-[(4-bromonaphth-1-yl)methyl]-4H-1,2,4-triazol-3-yl}thio)cyclo
propanecarboxylate (17k). Synthesis of 17k failed. See Results and Discussion for details.
Direct reactions of 12j-12k with 3a-3b
A mixture of 6-bromo-4-chloroquinoline (20, 7.28 g, 30 mmol) and Na2S·9H2O (14.41 g,
60 mmol) in DMF (100 mL) was stirred at 100°C in N2 atmosphere until the completion of
reaction as indicated by TLC (typically within 5 h). On cooling to room temperature, the reaction
mixture was poured into ice-water (300 mL) and the resulting mixture was acidified (pH = 5-6)
with 1M hydrochloric acid to give a yellow slurry. The precipitates were collected by vacuum
filtration, washed with water (50 mL), dried in vacuo at 50°C and triturated with
1
EtOAc/n-hexane to afford 12j as a yellow solid. M.p. 198°C (dec). 6.41 g (89%). H NMR, δ
13.05 (brs, 1H), 8.79 (d, J = 2.0 Hz, 1H), 7.86-7.89 (m, 2H), 7.63 (d, J = 8.8 Hz, 1H), 7.32 (d, J
= 6.8 Hz, 1H). 13C NMR, δ 191.11, 134.77, 134.70, 133.96, 133.52, 130.42, 124.59, 122.01,
118.63. ESI-HR-MS, calcd. for C9H7BrNS ([M(79Br)+H]+) 239.9483, found 239.9474; calcd. for
C9H7BrNS ([M(81Br)+H]+) 241.9462, found 241.9454.
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A mixture of 12j (2.40 g, 10 mmol), 3a-3b (15 mmol) and Cs2CO3 (9.77 g, 30 mmol) in
DMF (50 mL) was stirred at 90°C (for 3a) or 120°C (for 3b) in N2 atmosphere until the
completion of reaction as indicated by TLC (typically within 12 h). On cooling to room
temperature, the reaction mixture was poured into ice-water (200 mL), and the mixture thus
obtained was extracted with CH2Cl2 (3 × 100 mL). The combined extracts were washed with 5%
brine (5 × 100 mL), dried over anhydrous Na2SO4 and evaporated on a rotary evaporator to
afford a residue, which was purified by column chromatography to yield 21a-21b after trituration
with EtOAc/n-hexane.
1
6-Bromo-4-methylthioquinoline (21a). 1.07 g (42%). White solid, m.p. 88-90°C. H NMR,
δ 8.75 (d, J = 4.8 Hz, 1H), 8.14 (d, J = 1.6 Hz, 1H), 7.94 (d, J = 8.8 Hz, 1H), 7.90 (dd, J = 2.0 Hz
13
and 9.2 Hz, 1H), 7.40 (d, J = 4.8 Hz, 1H), 2.66 (s, 3H). C NMR, δ 149.97, 146.97, 145.21,
132.71, 131.85, 126.63, 124.88, 119.56, 116.27, 13.37. ESI-HR-MS, calcd. for C10H9BrNS
([M(79Br)+H]+) 253.9639, found 253.9641; calcd. for C10H9BrNS ([M(81Br)+H]+) 255.9619,
found 255.9628.
1
6-Bromo-4-(ethylthio)quinoline (21b). 0.27 g (10%). White solid, m.p. 49-51°C. H NMR,
δ 8.74 (d, J = 4.8 Hz, 1H), 8.16 (d, J = 1.6 Hz, 1H), 7.88-7.95 (m, 2H), 7.47 (d, J = 4.8 Hz, 1H),
13
3.23 (q, J = 7.3 Hz, 2H), 1.37 (t, J = 7.4 Hz, 3H). C NMR, δ 150.06, 145.68, 145.58, 132.82,
131.97, 126.95, 125.11, 119.64, 117.15, 24.41, 13.21. ESI-HR-MS, calcd. for C11H11BrNS
([M(79Br)+H]+) 267.9796, found 267.9787; calcd. for C11H11BrNS ([M(81Br)+H]+) 269.9775,
found 269.9771.
Synthesis of 1-[(6-bromoquinolin-4-yl)thio]cyclopropanecarboxylic acid (9)
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To a stirred solution of 17j (0.68 g, 2 mmol) in MeOH (10 mL) at room temperature was
added LiOH·H2O (0.25 g, 6 mmol) dissolved in water (1 mL). The resulting mixture was stirred
at room temperature until the completion of reaction as indicated by TLC analysis (typically
within 3 h). The reaction mixture was poured into ice-water (50 mL), and the mixture thus
obtained was acidified (pH = 5-6) with 1 M HCl and extracted with CH2Cl2 (3 × 50 mL). The
combined extracts were washed with water (50 mL), dried over anhydrous Na2SO4 and
evaporated on a rotary evaporator to afford a residue, which was triturated with EtOAc/n-hexane
to afford compound 9. 0.53 g (82%). White solid, m.p. 210°C (dec). 1H NMR, δ 13.07 (brs, 1H),
8.78 (d, J = 4.8 Hz, 1H), 8.07 (d, J = 1.6 Hz, 1H), 7.96 (d, J = 9.2 Hz, 1H), 7.91 (dd, J = 1.6 Hz
13
and 8.8 Hz, 1H), 7.44 (d, J = 4.8 Hz, 1H), 1.89-1.92 (m, 2H), 1.42-1.45 (m, 2H). C NMR, δ
172.00, 150.12, 145.87, 145.52, 132.99, 131.99, 126.27, 124.72, 119.75, 117.55, 23.75, 19.41.
ESI-HR-MS, calcd. for C13H11BrNO2S ([M(79Br)+H]+) 323.9694, found 323.9692; calcd. for
C13H11BrNO2S ([M(81Br)+H]+) 325.9673, found 325.9681.
Acknowledgment
The authors are very grateful to the financial support from Key Projects of Tianjin Science
and Technology Support Plan (16YFZCSY00910), Tianjin Natural Science Foundation
(12JCYBJC18800 and 13JCQNJC13700) and Shandong Natural Science Foundation
(ZR2015BM028).
Supplemental Materials
1
Copies of H NMR and 13C NMR spectra for compounds 17a-17j, 21a-21b and 9 are
available online in the supplemental materials.
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