Diastereoselective Synthesis of Cyclic sp 3 -Enriched cis -β-Alkoxysulfonyl Chlorides

Article abstract of DOI:10.1055/s-0037-1611277

A three-step synthesis of β-alkoxy-substituted alicyclic sulfonyl chlorides from cyclic alkenes and alcohols is reported. The scope of the method was studied for a range of the substrates with various steric and electronic properties. The title compounds were obtained on a hundred-gram scale in up to 52% overall yield scale as single cis -diastereomers.

Full text of DOI:10.1055/s-0037-1611277

SYNTHESIS
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©
Georg Thieme Verlag Stuttgart · New York
2018, 50, A–K
paper
A
en
Synthesis
A. Sokolov et al.
Paper
3
Diastereoselective Synthesis of Cyclic sp -Enriched cis-β-Alkoxy-
sulfonyl Chlorides
Andriy Sokolova,b
Sergey Golovacha
Ihor Kozlinskya,c
Krystyna Doliaa,c
Andrey A. Tolmacheva,b
Yuliya Kuchkovskaa,b
Oleksandr O. Grygorenko*a,b
0
0
0
0-0
0
0
2-
6
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3
6-5
8
5
9
a
Enamine Ltd., Chervonotkatska Street 78, Kyiv 02094,
Ukraine
www.enamine.net
National Taras Shevchenko University of Kyiv, Volodymyrska
Street 60, Kyiv 01601, Ukraine
National Technical University of Ukraine ‘Igor Sikorsky Kyiv
Polytechnic Institute’, Prospect Peremogy 37, Kyiv 03056,
Ukraine
b
c
gregor@univ.kiev.ua
Received: 07.09.2018
Accepted after revision: 01.10.2018
Published online: 22.10.2018
Cl
H2N
H2N
O
DOI: S10.1055/s-0037-1611277; Art ID: ss-2018-t0603-op
O
N
N
N
N
Abstract A three-step synthesis of β-alkoxy-substituted alicyclic sulfo-
nyl chlorides from cyclic alkenes and alcohols is reported. The scope of
the method was studied for a range of the substrates with various steric
and electronic properties. The title compounds were obtained on a
hundred-gram scale in up to 52% overall yield scale as single cis-diaste-
reomers.
H
O
O
N
MeO
O
HN
O
HN
O
S
O
O
S
O
NH2
Sulfonamidochrysoidine
Asunaprevir
antiviral drug
Key words organosulfur compounds, alicyclic compounds, heteroal-
antibiotic
iphatic compounds, sulfonyl chlorides, building blocks
MeO
O
O
N
I
S
C18H37
Since the nobel-prize-winning discovery of sulfonami-
N
O
N
H
O
H
dochrysoidine (also known as prontosil or streptocide, Fig-
OMe
1
ure 1) in 1932, dozens of new sulfonamide-based drugs
CV-3988 analogue
PAF antagonist
were discovered and brought to the market. The great ma-
jority of the sulfonamide drugs developed since then is de-
rived from aromatic frameworks. Their aliphatic counter-
parts are less common in medicinal chemistry; they are
limited mainly by simplest derivatives (e.g., methyl-, iso-
Figure 1 Some biologically active sulfonamides
related groups.14,15 One notable example is the replacement
of the carboxylic OH group by a cyclopropyl sulfonamide
fragment in a HCV NS3 protease inhibitor, which has in-
creased its potency and brought the resulting acylsulfon-
amide derivative, asunaprevir, to the Phase III clinical tri-
In another study, the sulfonamide functionality was
used to replace the phosphate moiety in the molecule of a
platelet activating factor (PAF) antagonist CV-3988;
resulting analogue showed 50-fold increase in the potency
as compared to the parent compound (Figure 1).
2
propyl-, cyclopropyl-substituted, etc.). Despite the high
3
potential of the aliphatic sulfonamides for design of sp -en-
riched lead-like compounds, this opportunity remains
largely unrealized, mainly due to the lack of well-developed
approaches to their synthesis. It should be noted that this
situation seems to be changing in recent years since a num-
16,17
als.
3
–6
18,19
ber of papers on the synthesis of aliphatic sulfonamides
and their synthetic precursors – sulfonyl halides7–13
appeared over the last decade.
the
–
One of the most intriguing applications of sulfonamides
in drug design is their use for isosteric replacement of car-
boxamides, carboxylic acids, phosphates, and some other
The aim of the current work is the development of a
simple and robust method for the synthesis of β-alkoxysul-
fonyl chlorides. These compounds are low-molecular
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–K

B
Synthesis
A. Sokolov et al.
Paper
3
SO2OR5
3
+
Cl
R O
3
+
R OH
A
C
B
D
R OH
X
X
3
R O
SO2Cl
R4
R2
3
5
R1
R3O
KSAc +
3
SO2OR5
R O
SO OR
Br
R
2
R4
O
R4
R2
Cl
+
H
R1
R2
R2
R , R , R = Alkyl, H; R3 = Alkyl, Ar, R5 = Alkyl
1
2
4
R1
R2
this work
X = Cl, Br, OMs
Scheme 1 Retrosynthetic disconnections of β-alkoxysulfonyl chlorides
3
weight, sp -enriched, relatively hydrophilic, conformation-
quence, that is, oxidative chlorination of 7d (67% vs 90–93%
for 7a–c), so that the product 8d was obtained in 34% over-
all yield. Tetrahydrofuran derivative 5e, which is less nucle-
ophilic due to electron-withdrawing effect of the oxygen at-
om, demonstrated lowered reactivity in the methoxybro-
mination step (55% yield of 6e). Formation of 3,4-
ally restricted building blocks, which are fully compatible
20
with the criteria of lead-oriented synthesis and hence
represent considerable interest for early drug discovery.
To date, only a few approaches to the preparation of β-
alkoxysulfonyl chlorides were reported in the literature.
One of them involves the reaction of S-nucleophiles and β-
alkoxyalkyl halides or sulfonates, in turn prepared from
1
dibromotetrahydrofuran side product was observed by H
NMR and LC-MS of the crude reaction mixture, presumably
due to NBS decomposition. Thus, the overall yield of the tar-
get product 8e was also diminished (28%) (Table 1).
1
A).
,2-diols, β-halohydrines or 1,2-dihaloalkanes (Scheme 1,
21–25
Another approach is based on the Michael addition
of alcohols to vinyl sulfonic acid derivatives (Scheme 1,
3-Sulfolene (5f) was even less reactive in the first step
under the standard conditions (NBS, MeOH, r.t.); increasing
the reaction temperature led to the formation of 3,4-dibro-
26,27
B).
One more retrosynthetic disconnection relies on the
alkylation of α-deprotonated sulfonic esters with α-chloro-
28
1
ethers (Scheme 1, C). All these methods have limited sub-
strate scope (in most cases, only the parent β-
alkoxyethanesufonyl chlorides were described); moreover,
none of them was designed to solve the diastereoselectivity
problem for α,β-disubstituted target compounds.
mosulfolane as the main product according to H NMR and
LC-MS. To overcome this problem, a modified protocol was
used involving the use of a catalytic amount of sulfuric acid
at 0 °C to activate the bromination agent.29 In this case, the
product 6f was obtained in 45% yield. Unfortunately, the
second step (i.e., reaction of 6f with potassium thioacetate)
appeared to be unfruitful; the elimination product 9 was
In this work, we have designed an alternative three-step
reaction sequence including alkoxybromination of an ap-
propriate alkene, nucleophilic substitution of the bromine
atom by thioacetate anion, and subsequent oxidation of the
thioester moiety with N-chlorosuccinimide (NCS) (Scheme
1
formed instead of 7f according to H NMR and LC-MS of the
crude reaction mixture (Scheme 3). This result might be ex-
plained by increased acidity of the CH groups in the mole-
2
1
, D). First of all, efficiency of this approach was validated
cule of 6f, as well as conjugation of the double bond with
the sulfone moiety in the product 9.
for styrene (1a) and α-methylstyrene (1b). It was found that
all three steps worked well for these substrates under typi-
cal conditions, and novel sulfonyl chlorides 4a and 4b were
obtained in 50% and 45% yield, respectively (Scheme 2).
MeO
Br
MeO
NBS, H2SO4
KSAc
S
MeOH
45%
DMF, Δ
S
S
O
O
Ph
Ph
Ph
O
O
O O
R
Ph NBS
MeOH
R
OMe KSAc
R
OMe NCS, HCl
R
OMe
5f
6f
9
DMF, Δ
aq MeCN
SAc
Br
SO2Cl
Scheme 3 Attempted preparation of 7f
1
1
a, R = H
b, R = Me
2a, 90%
2b, 91%
3a, 70%
3b, 66%
4a, 80%
4b, 76%
Further extension of the substrate scope included fused
benzo derivatives 5g–j, which were either commercially
available (i.e., 5g) or prepared using a slightly modified lit-
erature method30 (i.e., 5h–j). In particular, ketones 10h–j
were reduced with sodium borohydride to give alcohols
11h–j (65–84% yield), which were subjected to the thermal
dehydratation catalyzed with p-toluenesulfonic acid lead-
ing to the target substrates 5h–j (58–91% yield) (Scheme 4).
The general method for the preparation of β-alkoxysul-
fonyl chlorides described in this work gave satisfactory re-
sults with indene (5g) and 1,2-dihydronaphthalene (5h);
the corresponding products 8g and 8h were prepared in
Scheme 2 Synthesis of sulfonyl chlorides 4a and 4b
To establish the scope of the developed method, it was
applied to cyclic alkenes 5a–j with varied steric and elec-
tronic properties (Table 1). It was found that the ring size
had little impact on the outcome of the procedure, and the
target compounds 8a–c were synthesized from cy-
cloalkenes 5a–c in 45–50% overall yield. On the contrary,
the presence of heteroatoms at the β-position to the double
bond had more pronounced impact on the method efficien-
cy. In the case of Cbz-protected pyrrolidine 5d, the yield
was slightly diminished at the third step of the reaction se-
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–K

C
Synthesis
A. Sokolov et al.
Paper
Table 1 Synthesis of Sulfonyl Chlorides 8a–ja
O
X
OH
X
11h 80%
1i 84%
11j 65%
R
R
R
NaBH4
MeOH
TsOH
R1
R1
OMe
R1
OMe
R1
OMe
KSAc
DMF, Δ
NCS, HCl
toluene
reflux
NBS
X
MeOH
rt
2
H O, MeCN
SAc
R2
R2
R2
R2
8a−j
10h X = CH , R = H
2
5h 79%
5i 58%
5j 91%
Br
0−20 o
SO2Cl
1
C
10i X = O, R = H
0j X = O, R = Br
1
5a−j
6a−j
7a−j
1
R1/R2
Scheme 4 Synthesis of alkenes 5h–j
5
6 Yield (%)
6a (75)
7 Yield (%); conditions 8 Yield (%)
5
5
5
a
b
c
7a (71); 50 °C, 2 d
7b (70); 50 °C, 2 d
7c (81); 40 °C, 1 d
7d (70); 70 °C, 1 d
7e (79); 40 °C, 2 d
7f (0)
8a (92)
8b (90)
8c (93)
8d (67)
8e (65)
–
pectedly, sulfonyl chloride 12 was isolated in 24% yield (for
two steps) instead of the target product 8i (Scheme 5). This
result might be explained by electron-donating effect of the
tetrahydropyran ring in the molecule of 7i, which increased
susceptibility of the benzene ring towards electrophilic at-
tack.
6b (72)
6c (67)
6d (73)
6e (55)
6f (45)
OMe
OMe
1
2
. KSAc, DMF, Δ
Br
Cl
SO2Cl
. NCS, HCl
H2O, MeCN
CbzN
5d
5e
5f
O
O
24%
6i
12
Scheme 5 Synthesis of sulfonyl chloride 12
O
To overcome the above-mentioned effect, 6-bromo de-
rivative 5j was introduced into the corresponding reaction
sequence. As in the case of 7i, formation of 7j was also ac-
companied by partial S-deacetylation; therefore, the crude
product after the second step was used in the next step
without purification. Its oxidative chlorination proceeded
smoothly and gave the expected sulfonyl chloride 8j in 47%
yield (for two steps). The overall yield of 8j (39%) is compa-
rable to that of 8g and 8h (41% and 38%, respectively).
Finally, we have studied the scope of alkoxy substitu-
ents compatible with the developed synthetic approach. It
was found that the yield of the alkoxybromination step de-
creased in the following series: methoxy (6a, 75%); ethoxy
O
O
S
5
5
g
h
6g (73)
6h (88)
7g (64); 70 °C, 2 d
7h (59); 80 °C, 1 d
8g (88)
8h (74)
(
(
13a, 69%); isopropoxy (13b, 43%); tert-butoxy (13c, traces)
Table 2). This result is consistent with the decrease of alco-
b
5
i
j
6i (71)
6j (82)
7i; 110 °C, 3 d
8i (0)
O
hol nucleophilicity in the above-mentioned series due to
increasing steric hindrance. In the case of other primary al-
cohols, the effect of the substituent on the yield of the prod-
ucts 13d–g (60–74%) was not significant. Other steps in the
reaction sequence also were not susceptible to the variation
of the alkoxy substituent.
Br
b
8j (47)c
5
7j; 110 °C, 2 d
O
Since all the three steps in the reaction sequence stud-
ied in this work should be diastereoselective, the target
compounds 8a–j and 15a–g were expected to be obtained
as single cis-diastereomers. Indeed, the relative cis-configu-
ration was confirmed by NOE experiments with the prod-
ucts 8a, 8b, and 8d (Figure 2).
a
b
c
Relative configurations are shown.
The product was used in the next step without purification.
Yield for the two steps.
4
1% and 38% overall yield, respectively. In the case of 2H-
chromene (5i), the second step of the standard reaction se-
quence (i.e., heating of bromide 6i with potassium thioace-
tate in DMF) was accompanied by partial deacetylation of
the thioester 7i. Therefore, the crude product after this step
was subjected directly to the oxidative chlorination; unex-
In conclusion, β-alkoxy-substituted alicyclic sulfonyl
chlorides can be obtained starting from cyclic alkenes in
three steps, including alkoxybromination, nucleophilic sub-
stitution with thioacetate, and oxidative chlorination with
NCS. The developed protocol allows preparation of the tar-
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–K

D
Synthesis
A. Sokolov et al.
Paper
Table 2 Synthesis of Sulfonyl Chlorides 15a–ga
LCMSD SL instrument [chemical ionization (APCI), electrospray ion-
ization (ESI)] and Agilent 5890 Series II 5972 GCMS instrument (elec-
tron impact ionization (EI)).
3
3
3
R O
NBS
Br
R O
SAc
R O
SO2Cl
KSAc
NCS, HCl
3
MeCN, H2O
10−20 °C
R OH
DMF, Δ
β-Methoxybromides 2a, 2b, 6a–e, and 6g–j; General Procedure
To a solution of alkene 5 (1 mol) in anhyd MeOH (1 L) was added NBS
r.t.
5a
13a−g
14a−g
15a−g
(
187 g, 1.05 mol) portionwise while maintaining the temperature be-
R3
Et
13 Yield (%)
14 Yield (%); conditions 15 Yield (%)
low 30 °C. After the addition of all the NBS, the reaction mixture was
stirred at r.t. overnight. The resulting mixture was evaporated under
reduced pressure; H O (1 L) was added, and the mixture was extract-
ed with CH Cl (3 × 300 mL). The combined organic phases were
washed with H O (2 × 300 mL), 10% aq NaHSO (2 × 300 mL), H O (2 ×
13a (69)
13b (43)
13c (traces)
13d (74)
13e (62)
13f (65)
14a (70); 50 °C, 2 d
14b (66); 50 °C, 2 d
–
15a (88)
15b (88)
–
2
i-Pr
2
2
2
3
2
t-Bu
3
sure.
00 mL), dried (anhyd Na SO ), and evaporated under reduced pres-
2 4
CF
Bn
methoxyethyl
3
CH
2
14d (77); 40 °C, 1 d
14e (66); 50 °C, 2 d
14f (70); 60 °C, 2 d
14g (61); 60 °C, 2 d
15d (93)
15e (71)
15f (86)
15g (77)
(
2-Bromo-1-methoxyethyl)benzene (2a)
Yield: 279 g (90%) from 150 g of 1a; yellowish liquid.
For spectral and physical data, see refs.32,33
cyclopropylmethyl 13g (60)
a
Relative configurations are shown.
(1-Bromo-2-methoxypropan-2-yl)benzene (2b)
Yield: 529 g (91%) from 300 g of 1b; yellowish liquid.
H
H
For spectral and physical data, see refs.32,33
H
H
H
CbzN
H
SO2Cl
H
OMe
SO2Cl
OMe
SO2Cl
H
O
trans-1-Bromo-2-methoxycyclopentane (6a)34,35
H3C
8a
8b
8d
The product was purified by vacuum distillation; bp 80 °C/6 mmHg;
yield: 380.5 g (75%) from 193 g of 5a; colorless liquid.
Figure 2 Significant NOE correlations observed for 8a, 8b, and 8d
1
H NMR (400 MHz, CDCl ): δ = 4.24 (dt, J = 6.1, 2.8 Hz, 1 H), 3.96 (dt,
3
J = 6.1, 2.8 Hz, 1 H), 3.35 (s, 3 H), 2.35–2.20 (m, 1 H), 2.21–2.07 (m, 1
H), 2.06–1.94 (m, 1 H), 1.92–1.70 (m, 2 H), 1.74–1.56 (m, 1 H).
get compounds as pure cis-diastereomers in up to 52% over-
all yield and on a 100 g scale. The scope of the method in-
cludes cycloalkanes with different ring size, as well as het-
eroaliphatic compounds and benzo-fused derivatives. The
limitations of the approach are related to: (i) steric hin-
drance in the starting alcohol used for the alkoxybromina-
tion step (e.g., from the tert-butyl substituent); (ii) the pres-
13
C NMR (126 MHz, CDCl ): δ = 89.8, 57.3, 53.9, 34.9, 29.9, 21.9.
3
MS (EI): m/z = 178/180 [M]+.
Anal. Calcd for C 11BrO: C, 40.25; H, 6.19; Br, 44.62. Found: C, 40.14;
H, 5.79; Br, 44.28.
H
6
trans-1-Bromo-2-methoxycyclohexane(6b)32
The product was purified by vacuum distillation; bp 96 °C/6 mmHg;
yield: 254 g (72%) from 150 g of 5b; colorless liquid.
ence of strong electron-withdrawing groups (e.g., SO ) at
2
the β-position of the starting cyclic alkene; and (iii) side re-
actions at the benzene ring observed for electron-rich ben-
zo-fused substrates. In all other cases, the target com-
pounds of this study were prepared with high efficiency
and can be now considered as readily available for early
drug discovery programs.
1
H NMR (400 MHz, CDCl ): δ = 4.01–3.91 (m, 1 H), 3.42 (s, 3 H), 3.27–
3
3.17 (m, 1 H), 2.35–2.24 (m, 1 H), 2.22–2.11 (m, 1 H), 1.91–1.57 (m, 3
H), 1.40–1.21 (m, 3 H).
13
C NMR (126 MHz, CDCl ): δ = 83.2, 57.2, 55.4, 35.6, 30.1, 25.5, 23.3.
3
+
+
+
MS (EI): m/z = 192/194 [M] , 113 [M – Br] , 81 [M – Br – MeOH] .
Anal. Calcd for C H13BrO: C, 43.54; H, 6.79; Br, 41.38. Found: C, 43.34;
7
H, 6.49; Br, 41.58.
The solvents were purified according to the standard procedures.31 All
starting materials were purchased from commercial sources. Melting
points were measured on MPA100 OptiMelt automated melting point
system. Analytical TLC was performed using Polychrom SI F254
plates. Column chromatography was performed using silica gel Merck
trans-1-Bromo-2-methoxycycloheptane (6c)
The product was purified by vacuum distillation; bp 37 °C/0.1 mmHg;
yield: 29 g (67%) from 20 g of 5c; colorless liquid.
1
H NMR (400 MHz, CDCl ): δ = 4.18 (td, J = 7.7, 3.6 Hz, 1 H), 3.53 (td,
3
1
13
60 (230–400 mesh) as the stationary phase. H and C NMR spectra
J = 7.7, 2.8 Hz, 1 H), 3.39 (s, 3 H), 2.24–2.12 (m, 1 H), 2.10–1.97 (m, 1
H), 1.93–1.81 (m, 1 H), 1.79–1.66 (m, 3 H), 1.60–1.38 (m, 4 H).
were recorded on
a
Bruker 170 Avance 500 spectrometer (at
1
13
499.9 MHz for H and 124.9 MHz for C) and Varian Unity Plus 400
+
+
+
MS (EI): m/z = 206 [M] , 127 [M – Br] , 95 [M – Br – MeOH] .
1
13
spectrometer (at 400.4 MHz for H and 100.7 MHz for C). Chemical
shifts are reported in ppm downfield from TMS as an internal stan-
dard. Elemental analyses were performed at the Laboratory of Organ-
ic Analysis, Department of Chemistry, National Taras Shevchenko Uni-
versity of Kyiv. Mass spectra were recorded on an Agilent 1100
Anal. Calcd for C H15BrO: C, 46.39; H, 7.30; Br, 38.58. Found: C, 46.30;
8
H, 7.46; Br, 38.95.
For additional spectral and physical data, see ref.32
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–K

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Synthesis
A. Sokolov et al.
Paper
Benzyl trans-3-Bromo-4-methoxypyrrolidine-1-carboxylate (6d)
Anal. Calcd for C10H10Br O : C, 37.30; H, 3.13; Br, 49.63. Found: C,
2
2
3
7.18; H, 2.80; Br, 49.28.
The product was purified by column chromatography (gradient hex-
ane to t-BuOMe); yield: 275 g (73%) from 244 g of 5d; yellowish oil.
The compound was obtained as a ca. 1:1 mixture of rotamers.
1
trans-3-Bromo-4-methoxytetrahydrothiophene 1,1-Dioxide (6f)
H NMR (500 MHz, CDCl ): δ = 7.43–7.28 (m, 5 H), 5.19–5.13 (m, 2 H),
To a solution of 2,5-dihydrothiophene 1,1-dioxide (5f; 100 g, 0.846
3
4.33–4.28 (m, 1 H), 4.06–3.97 (m, 2 H), 3.95–3.81 (m, 2 H), 3.63–3.51
mol) in anhyd MeOH (850 mL) was added NCS (113 g, 0.846 mol).
(m, 1 H), 3.39 (s, 3 H).
The solution was cooled to 0 °C, and a catalytic amount of H SO was
2 4
1
3
added dropwise at the same temperature, and the reaction mixture
was stirred at 0 °C for 2 h. Then it was allowed to warm up to r.t. and
stirred overnight. The resulting mixture was evaporated under re-
C NMR (101 MHz, CDCl ): δ = 155.0, 136.7, 128.6, 128.2, 128.0, 86.0
3
and 85.1, 67.2, 57.41 and 57.40, 53.4 and 53.2, 49.4 and 49.3, 47.6 and
6.8.
4
duced pressure, H O (500 mL) was added, and the precipitate formed
2
+
+
MS (EI): m/z = 313/315 [M] , 234 [M – Br] .
was filtered. The crude product was dissolved in CHCl (1 L), washed
3
Anal. Calcd for C13H16BrNO : C, 49.70; H, 5.13; N, 4.46; Br, 25.43.
with 10% aq NaHSO (2 × 300 mL), dried (anhyd Na SO ), and evapo-
3
3
2
4
Found: C, 49.43; H, 5.02; N, 4.73; Br, 25.38.
rated under reduced pressure; yield: 87.3 g (45%); white crystals; mp
93–95 °C.
1
trans-3-Bromo-4-methoxytetrahydrofuran (6e)
H NMR (400 MHz, CDCl ): δ = 4.58–4.50 (m, 1 H), 4.33–4.26 (m, 1 H),
3
The product was purified by column chromatography (hexane–EtOAc
3.79 (dd, J = 14.2, 6.7 Hz, 1 H), 3.64 (dd, J = 13.8, 5.7 Hz, 1 H), 3.49–
3.38 (m, 4 H), 3.23 (dd, J = 13.8, 3.4 Hz, 1 H).
5
:1, R = 0.3); yield: 287 g (55%) from 202 g of 5e; yellowish liquid.
f
1
13C NMR (126 MHz, CDCl
H NMR (400 MHz, CDCl ): δ = 4.31–4.22 (m, 2 H), 4.19 (dd, J = 9.9, 4.8
3
): δ = 82.9, 58.23, 58.18, 54.4, 42.7.
3
Hz, 1 H), 4.15–4.09 (m, 1 H), 4.06–3.97 (m, 1 H), 3.80 (dd, J = 9.9, 1.8
Hz, 1 H), 3.39 (s, 3 H).
MS (APCI): m/z = 229/231 [M]+.
Anal. Calcd for C H BrO S: C, 26.21; H, 3.96; S, 13.99; Br, 34.88.
5
9
3
13
C NMR (126 MHz, CDCl ): δ = 88.2, 74.6, 71.7, 57.5, 48.6.
3
Found: C, 25.96; H, 3.87; S, 14.28; Br, 35.18.
+
+
MS (EI): m/z = 182 [M] , 71 [M – Br – MeO] .
β-Alkoxy Bromides 13a and 13b; General Procedure
Anal. Calcd for C H BrO : C, 33.17; H, 5.01; Br, 44.14. Found: C, 32.77;
5
9
2
H, 5.37; Br, 44.48.
To a solution of cyclopentene (5a; 50.0 g, 0.734 mol) in the corre-
sponding anhyd alcohol (700 mL), was added NBS (103 g, 0.771 mol)
portionwise while maintaining the temperature below 30 °C. After
the addition of all the NBS, the reaction mixture was stirred overnight
at r.t. The resulting mixture was evaporated under reduced pressure,
H O (700 mL) was added, and the mixture was extracted with CH Cl
trans-2-Bromo-1-methoxy-2,3-dihydro-1H-indene (6g)
The product was purified by vacuum distillation; bp 82 °C/0.1 mmHg;
yield: 143 g (73%) from 100 g of 5g; colorless liquid.
For spectral and physical data, see ref.36
2
2
2
(
3 × 200 mL). The combined organic phases were washed with H O (2
2
×
200 mL), 10% aq NaHSO (2 × 200 mL), H O (2 × 300 mL), dried (an-
3 2
trans-2-Bromo-1-methoxy-1,2,3,4-tetrahydronaphthalene (6h)
hyd Na SO ), and evaporated under reduced pressure.
2 4
Yield: 163 g (88%) from 100 g of 5h; yellowish liquid.
For spectral and physical data, see ref.36
trans-1-Bromo-2-ethoxycyclopentane (13a)
The product was purified by vacuum distillation; bp 38 °C/1 mmHg;
yield: 97.8 g (69%) from 50 g of 5a; colorless liquid.
trans-3-Bromo-4-methoxychroman (6i)
1H NMR (400 MHz, CDCl
): δ = 4.27–4.19 (m, 1 H), 4.10–4.02 (m, 1 H),
The product was purified by vacuum distillation; bp 92 °C/0.1 mmHg;
3
yield: 144 g (71%) from 110 g of 5i; colorless liquid.
3.63–3.43 (m, 2 H), 2.36–2.22 (m, 1 H), 2.21–2.07 (m, 1 H), 2.06–1.93
1
(m, 1 H), 1.92–1.70 (m, 2 H), 1.68–1.56 (m, 1 H), 1.18 (t, J = 7.0 Hz, 3
H).
H NMR (400 MHz, CDCl ): δ = 7.37–7.22 (m, 2 H), 7.02–6.89 (m, 2 H),
.56–4.47 (m, 1 H), 4.47–4.36 (m, 2 H), 4.36–4.27 (m, 1 H), 3.52 (s, 3
3
4
H).
13C NMR (126 MHz, CDCl
): δ = 88.0, 65.1, 54.7, 35.0, 30.3, 22.0, 15.6.
3
13
+
O]+.
C NMR (126 MHz, CDCl ): δ = 153.4, 131.1, 130.4, 121.1, 118.7,
MS (EI): m/z = 192/194 [M] , 67 [M – HBr – MeCH
2
3
1
17.1, 77.5, 65.7, 57.1, 43.8.
Anal. Calcd for C H13BrO: C, 43.54; H, 6.79; Br, 41.38. Found: C, 43.65;
H, 6.70; Br, 41.29.
7
+
+
+
MS (EI): m/z = 242/244 [M] , 163 [M – Br] , 131 [M – HBr – MeO] .
Anal. Calcd for C10H11BrO : C, 49.41; H, 4.56; Br, 32.87. Found: C,
2
trans-1-Bromo-2-isopropoxycyclopentane (13b)
49.38; H, 4.49; Br, 32.57.
The product was purified by column chromatography (gradient hex-
ane to t-BuOMe); yield: 65.4 g (43%) from 50 g of 5a; colorless liquid.
trans-3,6-Dibromo-4-methoxychroman (6j)
1H NMR (500 MHz, CDCl
3.69 (sept, J = 6.1 Hz, 1 H), 2.34–2.25 (m, 1 H), 2.20–2.08 (m, 1 H),
.06–1.94 (m, 1 H), 1.90–1.73 (m, 2 H), 1.63–1.55 (m, 1 H), 1.17–1.11
m, 6 H).
13C NMR (126 MHz, CDCl
2.0.
MS (EI): m/z = 206/208 [M] , 127 [M – Br] , 67 [M – HBr – Me
): δ = 4.19–4.16 (m, 1 H), 4.14–4.10 (m, 1 H),
Yield: 12.5 g (82%) from 10 g of 6j; light yellowish oil.
3
1
H NMR (400 MHz, CDCl ): δ = 7.38–7.30 (m, 2 H), 6.82 (d, J = 8.6 Hz, 1
3
2
(
H), 4.49 (d, J = 12.2 Hz, 1 H), 4.39–4.33 (m, 1 H), 4.33–4.24 (m, 2 H),
3.53 (s, 3 H).
13
): δ = 85.6, 70.7, 55.7, 34.8, 30.8, 23.2, 22.4,
3
C NMR (101 MHz, CDCl ): δ = 152.4, 133.5, 133.3, 120.7, 119.0,
3
2
112.9, 77.0, 65.7, 57.3, 42.9.
+
+
CHO]+.
2
+
+
MS (EI): m/z = 320/322/324 [M] , 241/243 [M – Br] , 161 [M – Br –
HBr] .
+
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–K

F
Synthesis
A. Sokolov et al.
Paper
+
+
Anal. Calcd for C H15BrO: C, 46.39; H, 7.30; Br, 38.58. Found: C, 46.22;
H, 7.57; Br, 38.21.
MS (EI): m/z = 207 [M – Me] , 191 [M – OMe] , 163 [M –
8
+
+
MeOCH CH ] , 147/149 [M – MeOCH CH O] .
2
2
2
2
Anal. Calcd for C H BrO : C 43.07; H 6.78; Br 35.81. Found: C 43.37;
H 6.88; Br 35.85.
8
15
2
β-Alkoxy Bromides 13d–g; General Procedure
The corresponding alcohol (0.440 mol) was added to a solution of cy-
clopentene (5a; 10.0 g, 0.147 mol) in anhyd CHCl (150 mL), and NBS
trans-1-Bromo-2-(cyclopropylmethoxy)cyclopentane (13g)
3
(
20.6 g, 0.154 mol) was added portionwise while maintaining the
The product was purified by vacuum distillation; bp 65 °C/1 mmHg;
yield: 19.3 g (60%) from 10 g of 5a; colorless liquid.
temperature below 30 °C. After the addition of all the NBS, the reac-
tion mixture was stirred overnight at r.t. The resulting mixture was
washed with H O (2 × 30 mL), 10% aq NaHSO (2 × 30 mL), H O (2 × 30
mL), dried (anhyd Na SO ), and evaporated under reduced pressure.
The obtained mixture was dissolved in hexane (100 mL), the hexane
layer was washed with H O (5 × 30 mL), dried (anhyd Na SO ), and
1
H NMR (500 MHz, CDCl ): δ = 4.28–4.24 (m, 1 H), 4.12–4.08 (m, 1 H),
3
2
3
2
3
(
0
.37–3.29 (m, 2 H), 2.36–2.25 (m, 1 H), 2.22–2.11 (m, 1 H), 2.06–1.96
m, 1 H), 1.90–1.74 (m, 2 H), 1.70–1.62 (m, 1 H), 1.10–0.98 (m, 1 H),
.60–0.49 (m, 2 H), 0.27–0.16 (m, 2 H).
2
4
2
2
4
13C NMR (101 MHz, CDCl
.3, 3.2.
): δ = 87.9, 74.6, 54.7, 35.0, 30.3, 22.0, 11.0,
concentrated under vacuum.
3
3
+
+
trans-1-Bromo-2-(2,2,2-trifluoroethoxy)cyclopentane (13d)
MS (EI): m/z = 220 [M] , 147/148 [M – (CH ) CHCH O] .
2
2
2
The crude product was dissolved in hexane (100 mL), washed with
H O (5 × 30 mL), dried (anhyd Na SO ), and concentrated under vacu-
Anal. Calcd for C H15BrO: C, 49.33; H, 6.90; Br, 36.47. Found: C, 49.67;
H, 7.04; Br, 36.24.
9
2
2
4
um. The product was purified by vacuum distillation; bp 41 °C/1
mmHg; yield: 26.8 g (74%) from 10.0 g of 5a; colorless liquid.
Ethanethioates 3a,b, 7a–e, 7g,h, 14a,b, and 14d–g; General Proce-
dure
1
H NMR (500 MHz, CDCl ): δ = 4.25–4.16 (m, 2 H), 3.96–3.80 (m, 2 H),
3
2
.40–2.27 (m, 1 H), 2.25–2.14 (m, 1 H), 2.07–1.97 (m, 1 H), 1.94–1.76
KSAc (143 g, 1.25 mol) was added portionwise to a solution of the
corresponding alkoxy bromide (0.500 mol) in anhyd DMF (1 L), and
the reaction mixture was stirred at the temperature given below for
the preparation of each ethanethioate derivative until 100% conver-
sion of the starting material was observed. The resulting mixture was
(m, 2 H), 1.78–1.68 (m, 1 H).
13
C NMR (126 MHz, CDCl ): δ = 123.9 (q, J = 279.0 Hz), 90.0, 67.3 (q, J =
3
34.2 Hz), 53.3, 34.7, 29.9, 21.7.
+
+
MS (EI): m/z = 246/248 [M] , 67 [M – HBr – CF CH O] .
3
2
cooled to r.t., poured into ice-cold H O (2.5 L), and extracted with
2
Anal. Calcd for C H BrF O: C, 34.03; H, 4.08; Br, 32.34. Found: C,
7
10
3
EtOAc (3 × 1 L). The combined organic extracts were washed with H O
2
34.26; H, 4.42; Br, 32.69.
(
5 × 1 L), dried (anhyd Na SO ), and evaporated under reduced pres-
2 4
sure.
trans-{[(2-Bromocyclopentyl)oxy]methyl}benzene (13e)
Anhyd hexane (50 mL) was added to the obtained crude product. The
bottom layer containing most of benzyl alcohol was separated, and
the remaining hexane solution was concentrated under vacuum. The
product was purified by vacuum distillation (bp 80–85 °C/0.1 mmHg)
and subsequent column chromatography (gradient hexane to t-BuOMe
as eluent); yield: 23.2 g (62%) from 10 g of 5a.
S-(2-Methoxy-2-phenylethyl) Ethanethioate (3a)
The reaction mixture was stirred overnight at 70 °C. The product was
purified by vacuum distillation; bp 96 °C/0.1 mmHg; yield: 103 g
(70%) from 150 g of 2a; yellowish liquid.
1
H NMR (400 MHz, CDCl ): δ = 7.40–7.23 (m, 5 H), 4.21 (dd, J = 8.6, 4.4
3
Hz, 1 H), 3.30–3.19 (m, 4 H), 3.07 (dd, J = 13.8, 8.6 Hz, 1 H), 2.32 (s, 3
H).
1
H NMR (500 MHz, CDCl ): δ = 7.40–7.27 (m, 5 H), 4.60 (d, J = 11.8 Hz,
3
1
2
H), 4.55 (d, J = 11.8 Hz, 1 H), 4.34–4.31 (m, 1 H), 4.21–4.18 (m, 1 H),
.40–2.31 (m, 1 H), 2.22–2.13 (m, 1 H), 2.08–1.98 (m, 1 H), 1.94–1.79
13
C NMR (126 MHz, CDCl ): δ = 195.6, 140.3, 128.7, 128.3, 126.7, 82.6,
3
57.2, 36.5, 30.7.
(m, 2 H), 1.78–1.68 (m, 1 H).
MS (EI): m/z = 121 [PhCHOMe]+.
13
C NMR (126 MHz, CDCl ): δ = 138.3, 128.6, 127.8, 127.7, 87.7, 71.7,
3
54.5, 35.0, 30.2, 22.0.
Anal. Calcd for C11H O S: C, 62.83; H, 6.71; S, 15.25. Found: C, 62.74;
14 2
+
+
H, 6.75; S, 15.32.
MS (EI): m/z = 254 [M] , 175 [M – Br] .
Anal. Calcd for C12H15BrO: C, 56.49; H, 5.93; Br, 31.32. Found: C, 56.61;
H, 6.25; Br, 31.36.
S-(2-Methoxy-2-phenylpropyl) Ethanethioate (3b)
The reaction mixture was stirred overnight at 100 °C. The product
was purified by vacuum distillation; bp 107 °C/0.1 mmHg; yield: 110
g (66%) from 170 g of 2b; yellowish liquid.
1
trans-1-Bromo-2-(2-methoxyethoxy)cyclopentane (13f)
The product was purified by vacuum distillation; bp 60 °C/1 mmHg;
yield: 21.3 g (65%) from 10 g of 5a.
H NMR (400 MHz, CDCl ): δ = 7.45–7.32 (m, 4 H), 7.33–7.24 (m, 1 H),
3
3.41 (d, J = 13.5 Hz, 1 H), 3.28 (d, J = 13.5 Hz, 1 H), 3.10 (s, 3 H), 2.31 (s,
1
H NMR (400 MHz, CDCl ): δ = 4.28–4.23 (m, 1 H), 4.11–4.06 (m, 1 H),
3
3 H), 1.58 (s, 3 H).
3.69–3.57 (m, 2 H), 3.51 (t, J = 4.7 Hz, 2 H), 3.37 (s, 3 H), 2.34–2.23 (m,
1 H), 2.19–2.09 (m, 1 H), 2.02–1.94 (m, 1 H), 1.88–1.73 (m, 2 H), 1.71–
1.61 (m, 1 H).
13
C NMR (126 MHz, CDCl ): δ = 195.3, 143.5, 128.4, 127.6, 126.3, 78.5,
3
50.9, 41.1, 30.6, 22.4.
MS (EI): m/z (%) = 135 [PhC(Me)OMe]+.
13
C NMR (126 MHz, CDCl ): δ = 88.7, 72.0, 69.0, 59.1, 54.3, 34.9, 30.1,
3
21.9.
Anal. Calcd for C12H O S: C, 64.25; H, 7.19; S, 14.29. Found: C, 64.37;
16 2
H, 7.09; S, 14.06.
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–K

G
Synthesis
A. Sokolov et al.
Paper
сis-S-(2-Methoxycyclopentyl) Ethanethioate (7a)
Anal. Calcd for C15H19NO S: C, 58.23; H, 6.19; N, 4.53; S, 10.36. Found:
4
C, 58.06; H, 6.41; N, 4.48; S, 10.73.
The reaction mixture was stirred for 2 days at 50 °C. The product was
purified by vacuum distillation; bp 61 °C/0.1 mmHg; yield: 69.1 g
(71%) from 100 g of 6a; yellowish liquid.
cis-S-(4-Methoxytetrahydrofuran-3-yl) Ethanethioate (7e)
1
H NMR (400 MHz, CDCl ): δ = 3.84–3.74 (m, 2 H), 3.30 (s, 3 H), 2.33
The reaction mixture was stirred for 2 days at 40 °C. The product was
purified by vacuum distillation; bp 73 °C/0.1 mmHg; yield: 76.9 g
(79%) obtained from 100 g of 6e; yellowish liquid.
3
(s, 3 H), 2.17–2.00 (m, 1 H), 1.91–1.53 (m, 5 H).
13
C NMR (101 MHz, CDCl ): δ = 196.6, 83.2, 57.1, 47.1, 30.8, 30.7, 29.7,
3
1H NMR (500 MHz, CDCl
4.00–3.85 (m, 3 H), 3.70–3.61 (m, 1 H), 3.35 (s, 3 H), 2.35 (s, 3 H).
): δ = 4.21–4.12 (m, 1 H), 4.09–4.01 (m, 1 H),
3
2
1.5.
+
+
+
MS (EI): m/z = 174 [M] , 131 [M – MeCO] , 98 [M – MeCOSH] .
13
C NMR (126 MHz, CDCl ): δ = 195.7, 81.0, 71.7, 71.6, 57.9, 45.5, 30.7.
3
Anal. Calcd for C H O S: C, 55.14; H, 8.10; S, 18.40. Found: C, 55.24;
H, 7.97; S, 18.61.
8
14
2
+
+
MS (EI): m/z = 176 [M] , 133 [M – MeO] .
Anal. Calcd for C H O S: C, 47.71; H, 6.86; S, 18.19. Found: C, 47.38;
7
12
3
cis-S-(2-Methoxycyclohexyl) Ethanethioate (7b)
H, 7.21; S, 17.98.
The reaction mixture was stirred for 2 days at 50 °C. The product was
purified by vacuum distillation; bp 73 °C/0.1 mmHg; yield: 68.3 g
cis-S-(1-Methoxy-2,3-dihydro-1H-inden-2-yl) Ethanethioate (7g)
(
1
70%) from 100 g of 6b; yellowish liquid.
The reaction mixture was stirred for 2 days at 70 °C. The product was
purified by vacuum distillation; bp 120 °C/0.1 mmHg; yield: 35.7 g
(64%) from 57 g of 6g; yellowish liquid.
H NMR (400 MHz, CDCl ): δ = 3.92–3.83 (m, 1 H), 3.43–3.35 (m, 1 H),
3
3
1
.31 (s, 3 H), 2.32 (s, 3 H), 1.89–1.63 (m, 3 H), 1.62–1.52 (m, 3 H),
.51–1.28 (m, 2 H).
1
H NMR (400 MHz, CDCl ): δ = 7.35 (d, J = 7.3 Hz, 1 H), 7.32–7.17 (m, 3
3
1
3
C NMR (101 MHz, CDCl ): δ = 196.0, 78.8, 56.5, 46.2, 31.0, 29.5, 28.9,
H), 4.67 (d, J = 5.5 Hz, 1 H), 4.38 (td, J = 7.5, 5.5 Hz, 1 H), 3.36 (s, 3 H),
3
24.5, 21.2.
3.26 (dd, J = 15.8, 7.5 Hz, 1 H), 3.06 (dd, J = 15.8, 7.5 Hz, 1 H), 2.35 (s, 3
+
+
+
H).
MS (EI): m/z = 188 [M] , 145 [M – MeO] , 112 [M – MeCOSH] , 81 [M –
MeCOSH – MeO] .
+
13C NMR (101 MHz, CDCl
25.2, 125.0, 84.0, 56.9, 47.7, 38.0, 30.8.
): δ = 196.4, 142.1, 140.9, 129.1, 126.7,
3
1
Anal. Calcd for C H16O S: C, 57.41; H, 8.57; S, 17.03. Found: C, 57.34;
H, 8.68; S, 17.42.
9
2
+
+
MS (EI): m/z = 146 [M – MeCOSH] , 115 [M – MeCOSH – MeO] .
Anal. Calcd for C12H14O S: C, 64.84; H, 6.35; S, 14.42. Found: C, 64.5;
2
cis-S-(2-Methoxycycloheptyl) Ethanethioate (7c)
H, 6.30; S, 14.37.
The reaction mixture was stirred overnight at 40 °C. The product was
purified by vacuum distillation; bp 97 °C/0.1 mmHg; yield: 15.8 g
cis-S-(1-Methoxy-1,2,3,4-tetrahydronaphthalen-2-yl) Ethanethio-
(81%) from 20.0 g of 6c; yellowish liquid.
ate (7h)
1
H NMR (400 MHz, CDCl ): δ = 3.91 (dt, J = 9.6, 3.0 Hz, 1 H), 3.49 (td,
The reaction mixture was stirred overnight at 80 °C. The product was
purified by vacuum distillation; bp 125 °C/0.1 mmHg; yield: 11.6 g
(59%) from 20 g of 6h; yellowish liquid.
3
J = 5.6, 2.9 Hz, 1 H), 3.32 (s, 3 H), 2.32 (s, 3 H), 1.98–1.84 (m, 1 H),
1
.82–1.36 (m, 9 H).
13
1H NMR (400 MHz, CDCl
C NMR (126 MHz, CDCl ): δ = 196.1, 82.5, 57.0, 48.6, 31.0, 30.8, 30.4,
3
): δ = 7.54–6.81 (m, 4 H), 4.23 (d, J = 3.3 Hz, 1
3
2
7.0, 25.9, 21.8.
H), 4.10–4.00 (m, 1 H), 3.37 (s, 3 H), 3.07–2.73 (m, 2 H), 2.49–2.10 (m,
4 H), 2.02–1.93 (m, 1 H).
+
+
+
MS (EI): m/z = 202 [M] , 159 [M – MeO] , 126 [M – MeCOSH] , 95 [M –
MeCOSH – MeO] .
+
13C NMR (126 MHz, CDCl
28.3, 125.5, 79.0, 57.2, 44.3, 30.8, 28.0, 24.9.
): δ = 195.9, 135.7, 134.8, 129.2, 129.1,
3
1
Anal. Calcd for C10H18O S: C, 59.37; H, 8.97; S, 15.85. Found: C, 59.69;
H, 8.64; S, 15.57.
2
+
+
MS (EI): m/z = 193 [M – MeCO] , 160 [M – MeCOSH] , 128 [M –
MeCOSH – MeOH] .
+
Benzyl cis-3-(Acetylthio)-4-methoxypyrrolidine-1-carboxylate
Anal. Calcd for C13H16O S: C, 66.07; H, 6.82; S, 13.57. Found: C, 65.95;
2
(7d)
H, 6.96; S, 13.66.
The reaction mixture was stirred overnight at 70 °C. The product was
purified by column chromatography (gradient hexane to t-BuOMe as
eluent); yield: 186 g (70%) from 270 g of 6d; yellowish oil.The product
was obtained as a ca. 2:3 mixture of rotamers.
cis-S-(2-Ethoxycyclopentyl) Ethanethioate (14a)
The reaction mixture was stirred for 2 days at 50 °C. The product was
purified by vacuum distillation; bp 70 °C/0.1 mmHg; yield: 61.4 g
(70%) from 90.0 g of 13a; yellowish liquid.
1
1
H NMR (400 MHz, CDCl ): δ = 7.39–7.27 (m, 5 H), 5.20–5.06 (m, 2 H),
3
4
(
2
.10–4.01 (m, 1 H), 3.94–3.81 (m, 2 H), 3.72 (d, J = 11.7 Hz, 0.6 H), 3.60
d, J = 11.8 Hz, 0.4 H) 3.55–3.45 (m, 1 H), 3.49–3.28 (m, 4 H), 2.38–
.32 (m, 3 H).
H NMR (400 MHz, CDCl ): δ = 3.78–3.73 (m, 1 H), 3.72–3.65 (m, 1 H),
3
3.46–3.24 (m, 2 H), 2.21 (s, 3 H), 2.04–1.92 (m, 1 H), 1.76–1.47 (m, 5
H), 1.05 (t, J = 7.0 Hz, 3 H).
13
C NMR (101 MHz, CDCl ): δ = 195.3 and 195.1, 154.8 and 154.6,
13
3
C NMR (101 MHz, CDCl ): δ = 196.3, 81.1, 64.8, 47.2, 30.7, 30.5, 30.4,
3
1
5
3
36.7 and 136.6, 128.6, 128.1, 128.0, 80.5 and 79.9, 67.12 and 67.08,
7.6 and 57.4, 49.73 and 49.68, 49.5 and 49.4, 44.9 and 44.3, 30.7 and
0.6.
21.3, 15.2.
+
+
+
MS (EI): m/z = 188 [M] , 145 [M – MeCO] , 112 [M – MeCOSH] .
Anal. Calcd for C H O S: C, 57.41; H, 8.57; S, 17.03. Found: C, 57.65;
MS (APCI): m/z = 267 [M – MeCO + H]+.
9
16
2
H, 8.67; S, 16.66.
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–K

H
Synthesis
A. Sokolov et al.
Paper
cis-S-(2-Isopropoxycyclopentyl) Ethanethioate (14b)
cis-S-[2-(Cyclopropylmethoxy)cyclopentyl] Ethanethioate (14g)
The reaction mixture was stirred for 2 days at 50 °C. The product was
purified by vacuum distillation; bp 79 °C/0.1 mmHg; yield: 48.4 g
The reaction mixture was stirred for 2 days at 60 °C. The product was
purified by vacuum distillation; bp 99 °C/0.1 mmHg; yield: 8.94 g
(61%) from 15.0 g of 13g; yellowish liquid.
1
(66%) from 75.0 g of 13b; yellowish liquid.
1
H NMR (400 MHz, CDCl ): δ = 3.91–3.83 (m, 1 H), 3.74–3.61 (m, 1 H),
H NMR (400 MHz, CDCl ): δ = 3.93–3.84 (m, 1 H), 3.84–3.73 (m, 1 H),
3
3
3
.51 (sept, J = 6.1 Hz, 1 H), 2.24 (s, 3 H), 2.06–1.93 (m, 1 H), 1.83–1.59
3.33–3.16 (m, 2 H), 2.33 (s, 3 H), 2.12–2.00 (m, 1 H), 1.85–1.66 (m, 4
H), 1.63–1.54 (m, 1 H), 1.05–0.94 (m, 1 H), 0.53–0.42 (m, 2 H), 0.24–
0.13 (m, 2 H).
(m, 4 H), 1.58–1.44 (m, 1 H), 1.08–1.00 (m, 6 H).
13
C NMR (101 MHz, CDCl ): δ = 196.7, 78.9, 70.6, 47.5, 31.8, 30.8, 30.6,
3
13
22.7, 22.2, 21.5.
C NMR (101 MHz, CDCl ): δ = 196.8, 81.1, 74.3, 47.5, 31.0, 30.8, 30.7,
3
+
+
+
21.5, 10.8, 3.1, 3.0.
MS (EI): m/z = 202 [M] , 159 [M – MeCO] , 126 [M – MeCOSH] , 67 [M
+
+
+
–
MeCOSH – Me CHO] .
MS (EI): m/z = 171 [M – MeCO] , 138 [M – MeCOSH] .
2
Anal. Calcd for C10H18O S: C, 59.37; H, 8.97; S, 15.85. Found: C, 58.97;
Anal. Calcd for C11H18O S: C, 61.65; H, 8.47; S, 14.96. Found: C, 61.46;
2
2
H, 8.69; S, 15.70.
H, 8.31; S, 14.71.
cis-S-[2-(2,2,2-Trifluoroethoxy)cyclopentyl] Ethanethioate (14d)
Sulfonyl Chlorides 8a–e, 8g, 8h, 15a, 15b, and 15d–g; General Pro-
cedure
The reaction mixture was stirred overnight at 40 °C; yield: 3.78 g
(77%) from 5 g of 13d; yellowish liquid.
To a mixture of NCS (267 g, 2 mol), concd HCl (28 mL), H O (100 mL),
2
1
and MeCN (1 L) was added a solution of the corresponding ethaneth-
ioates 3, 7, or 14 (0.500 mol) in MeCN (600 mL) dropwise at 10 °C.
When the addition was finished and no more exothermic reaction
was observed, the solution was stirred at 10–20 °C for an additional
H NMR (400 MHz, CDCl ): δ = 4.07–3.99 (m, 1 H), 3.91–3.71 (m, 3 H),
.34 (s, 3 H), 2.14–2.02 (m, 1 H), 1.97–1.48 (m, 5 H).
3
2
13
C NMR (126 MHz, CDCl ): δ = 196.5, 123.9 (q, J = 279.4 Hz), 84.0,
3
6
7.4 (q, J = 34.1 Hz), 47.0, 30.7, 30.6, 30.0, 21.4.
4
0 min. The reaction mixture was poured into H O (2 L) and extracted
2
+
+
MS (EI): m/z = 199 [M – MeCO] , 166 [M – MeCOSH] .
with t-BuOMe (3 × 1 L). The combined organic phases were washed
with brine (5 × 1 L), dried (anhyd Na SO ), and evaporated under re-
Anal. Calcd for C H F O S: C, 44.62; H, 5.41; S, 13.23. Found: C, 44.56;
H, 5.24; S, 13.54.
2
4
9
13
3
2
duced pressure.
2-Methoxy-2-phenylethanesulfonyl Chloride (4a)
cis-S-[2-(Benzyloxy)cyclopentyl] Ethanethioate (14e)
Yield: 107 g (80%) from 120 g of 3a; yellowish oil.
The reaction mixture was stirred for 2 days at 50 °C. The product was
purified by vacuum distillation; bp 135 °C/0.1 mmHg; yield: 6.48 g
1
H NMR (400 MHz, CDCl ): δ = 7.47–7.33 (m, 5 H), 4.91 (dd, J = 9.5, 2.9
3
(66%) from 10.0 g of 13e; yellowish oil.
Hz, 1 H), 4.19 (dd, J = 14.3, 9.5 Hz, 1 H), 3.87 (dd, J = 14.3, 2.9 Hz, 1 H),
1
3.32 (s, 3 H).
H NMR (500 MHz, CDCl ): δ = 7.37–7.25 (m, 5 H), 4.50 (d, J = 12.0 Hz,
H), 4.40 (d, J = 12.0 Hz, 1 H), 4.01–3.97 (m, 1 H), 3.85–3.80 (m, 1 H),
.26 (s, 3 H), 2.16–2.06 (m, 1 H), 1.92–1.73 (m, 4 H), 1.71–1.59 (m, 1
3
13
1
2
H).
C NMR (126 MHz, CDCl ): δ = 137.3, 129.4, 126.7, 78.5, 72.3, 57.3.
3
–
MS (APCI): m/z = 215 [M – H] (for the corresponding sulfonic acid).
Anal. Calcd for C H ClO S: C, 46.06; H, 4.72; S, 13.66; Cl, 15.11.
Found: C, 45.75; H, 4.39; S, 13.52; Cl, 15.40.
9
11
3
13
C NMR (126 MHz, CDCl ): δ = 196.6, 138.6, 128.4, 127.52, 127.50,
3
8
1.0, 71.2, 47.4, 30.9, 30.8, 30.4, 21.5.
+
+
+
MS (EI): m/z = 250 [M] , 207 [M – MeCHO] , 174 [M – MeCOSH] , 67
2
-Methoxy-2-phenylpropane-1-sulfonyl Chloride (4b)
+
[
M – MeCOSH – PhCH OH] .
2
Yield: 85.1 g (76%) from 101 g of 3b; yellowish liquid.
Anal. Calcd for C14H18O S: C, 67.16; H, 7.25; S, 12.81. Found: C, 67.55;
2
1
H NMR (400 MHz, CDCl ): δ = 7.47–7.30 (m, 5 H), 4.26 (d, J = 14.0 Hz,
3
H, 7.47; S, 13.11.
1
H), 4.04 (d, J = 14.0 Hz, 1 H), 3.16 (s, 3 H), 1.97 (s, 3 H).
13
C NMR (126 MHz, CDCl ): δ = 141.0, 129.1, 128.7, 126.3, 78.5, 77.8,
3
cis-S-[2-(2-Methoxyethoxy)cyclopentyl] Ethanethioate (14f)
5
1.0, 21.5.
The reaction mixture was stirred for 2 days at 60 °C. The product was
purified by vacuum distillation; bp 96 °C/0.1 mmHg; yield: 13.7 g
–
MS (APCI): m/z = 229 [M – H] (for the corresponding sulfonic acid).
(70%) from 20.0 g of 13f; yellowish liquid.
Anal. Calcd for C10H13ClO S: C, 48.29; H, 5.27; S, 12.89; Cl, 14.25.
3
1
Found: C, 48.36; H, 5.49; S, 13.04; Cl, 14.05.
H NMR (500 MHz, CDCl ): δ = 3.95–3.88 (m, 1 H), 3.79 (td, J = 8.1, 4.9
3
Hz, 1 H), 3.64–3.46 (m, 4 H), 3.37 (s, 3 H), 2.31 (s, 3 H), 2.13–2.02 (m, 1
H), 1.89–1.78 (m, 3 H), 1.78–1.70 (m, 1 H), 1.67–1.56 (m, 1 H).
cis-2-Methoxycyclopentane-1-sulfonyl Chloride (8a)
1
3
Yield: 84.9 g (92%) from 81 g of 7a; yellowish liquid.
C NMR (126 MHz, CDCl ): δ = 196.6, 82.1, 72.0, 69.1, 59.2, 47.3, 30.8,
3
1
3
0.7, 30.5, 21.4.
H NMR (400 MHz, CDCl ): δ = 4.25–4.12 (m, 2 H), 3.38 (s, 3 H), 2.59–
3
+
+
2.45 (m, 1 H), 2.33–2.23 (m, 1 H), 2.14–1.96 (m, 2 H), 1.86–1.66 (m, 2
H).
MS (EI): m/z = 175 [M – MeCO] , 142 [M – MeCOSH] .
Anal. Calcd for C10H18O S: C, 55.02; H, 8.31; S, 14.69. Found: C, 54.65;
3
13
C NMR (126 MHz, CDCl ): δ = 82.8, 79.5, 57.8, 30.5, 26.8, 21.2.
H, 7.97; S, 14.38.
3
–
MS (APCI): m/z = 179 [M – H] (for the corresponding sulfonic acid).
Anal. Calcd for C H ClO S: C, 36.28; H, 5.58; S, 16.14; Cl, 17.84.
6
11
3
Found: C, 36.56; H, 5.71; S, 16.22; Cl, 17.65.
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–K

I
Synthesis
A. Sokolov et al.
Paper
cis-2-Methoxycyclohexane-1-sulfonyl Chloride (8b)
Anal. Calcd for C10H11ClO S: C, 48.68; H, 4.49; S, 13.00; Cl, 14.37.
3
Found: C, 48.81; H, 4.40; S, 13.29; Cl, 14.02.
Yield: 102 g (90%) from 100 g of 7b; yellowish liquid.
1
H NMR (500 MHz, CDCl ): δ = 4.11–4.05 (m, 1 H), 3.73–3.64 (m, 1 H),
3
cis-1-Methoxy-1,2,3,4-tetrahydronaphthalene-2-sulfonylChloride
3
.26 (s, 3 H), 2.20–2.04 (m, 3 H), 1.94–1.83 (m, 1 H), 1.58–1.37 (m, 2
(
8h)
Yield: 8.16 g (74%) from 10 g of 7h; yellowish oil.
1H NMR (400 MHz, CDCl
): δ = 7.39–7.28 (m, 1 H), 7.29–7.13 (m, 3 H),
.87 (d, J = 2.8 Hz, 1 H), 4.07–3.98 (m, 1 H), 3.39 (s, 3 H), 3.23 (ddd, J =
17.4, 7.0, 2.7 Hz, 1 H), 2.97 (ddd, J = 17.4, 10.9, 7.0 Hz, 1 H), 2.85–2.69
H), 1.37–1.16 (m, 2 H).
13
C NMR (126 MHz, CDCl ): δ = 79.6, 73.9, 56.3, 27.4, 24.4, 22.5, 18.4.
3
–
3
MS (APCI): m/z = 193 [M–H] (for the corresponding sulfonic acid).
4
Anal. Calcd for C H ClO S: C, 39.53; H, 6.16; S, 15.07; Cl, 16.67.
Found: C, 39.67; H, 5.93; S, 14.81; Cl, 16.51.
7
13
3
(m, 1 H), 2.56–2.45 (m, 1 H).
13
C NMR (126 MHz, CDCl ): δ = 135.5, 132.1, 130.1, 129.7, 129.5,
3
cis-2-Methoxycycloheptane-1-sulfonyl Chloride (8c)
1
26.2, 77.9, 75.7, 56.9, 27.8, 19.5.
Yield: 14.6 g (93%) from 14 g of 7c; colorless liquid.
–
MS (APCI): m/z = 241 [M – H] (for the corresponding sulfonic acid).
1
H NMR (400 MHz, CDCl ): δ = 4.37–4.30 (m, 1 H), 3.69–3.58 (m, 1 H),
3
Anal. Calcd for C11H13ClO S: C, 50.67; H, 5.03; S, 12.30; Cl, 13.60.
Found: C, 50.82; H, 5.28; S, 12.02; Cl, 13.29.
3
3.37 (s, 3 H), 2.39–2.23 (m, 2 H), 2.18–2.05 (m, 1 H), 2.00–1.87 (m, 1
H), 1.79–1.64 (m, 2 H), 1.64–1.41 (m, 4 H).
13
C NMR (126 MHz, CDCl ): δ = 82.1, 76.4, 57.1, 30.2, 26.8, 25.4, 23.5,
3
cis-2-Ethoxycyclopentane-1-sulfonyl Chloride (15a)
2
1.1.
Yield: 32.8 g (88%) from 33 g of 14a; yellowish liquid.
+
+
MS (EI): m/z = 127 [M – SO Cl] , 95 [M – SO Cl – MeOH] .
2
2
1
H NMR (400 MHz, CDCl ): δ = 4.33–4.24 (m, 1 H), 4.24–4.12 (m, 1 H),
3
Anal. Calcd for C H ClO S: C, 42.38; H, 6.67; S, 14.14; Cl, 15.64.
Found: C, 41.98; H, 6.35; S, 14.18; Cl, 15.48.
8
15
3
3.64–3.48 (m, 2 H), 2.62–2.46 (m, 1 H), 2.35–2.20 (m, 1 H), 2.13–1.93
(m, 2 H), 1.88–1.68 (m, 2 H), 1.18 (t, J = 7.0 Hz, 3 H).
13
C NMR (126 MHz, CDCl ): δ = 81.1, 79.6, 66.2, 31.5, 27.0, 21.3, 15.1.
3
cis-Benzyl 3-(Chlorosulfonyl)-4-methoxypyrrolidine-1-carboxyl-
ate (8d)
–
MS (APCI): m/z = 193 [M – H] (for the corresponding sulfonic acid).
Anal. Calcd for C H ClO S: C, 39.53; H, 6.16; S, 15.07; Cl, 16.67.
Found: C, 39.81; H, 5.76; S, 14.68; Cl, 17.07.
Yield: 62.2 g (67%) from 86 g of 7d; brown oil. The product was ob-
tained as a ca. 45:55 mixture of rotamers.
7
13
3
1
H NMR (400 MHz, CDCl ): δ = 7.41–7.27 (m, 4 H), 5.19–5.08 (m, 2 H),
3
cis-2-Isopropoxycyclopentane-1-sulfonyl Chloride (15b)
4
3
3
.44–4.33 (m, 2 H), 4.29–3.98 (m, 2 H), 3.89–3.81 (m, 0.55 H), 3.78–
.70 (m, 0.45 H), 3.65–3.57 (m, 0.45 H), 3.57–3.49 (m, 0.55 H), 3.45 (s,
H).
Yield: 44.4 g (88%) from 45 g of 14b; yellowish liquid.
1
H NMR (400 MHz, CDCl ): δ = 4.41–4.32 (m, 1 H), 4.20–4.09 (m, 1 H),
3
13
C NMR (126 MHz, CDCl ): δ = 154.5, 136.24 and 136.16, 128.7,
3.70 (sept, J = 6.3 Hz, 1 H), 2.59–2.44 (m, 1 H), 2.32–2.18 (m, 1 H),
2.12–1.98 (m, 1 H), 1.98–1.85 (m, 1 H), 1.86–1.60 (m, 2 H), 1.13 (t, J =
6.3 Hz, 6 H).
3
128.45 and 128.41, 128.31 and 128.20, 80.1 and 79.1, 75.8 and 74.9,
67.7 and 67.6, 58.5 and 58.2, 50.1 and 49.7, 46.4 and 45.6.
–
13C NMR (101 MHz, CDCl
MS (APCI): m/z = 314 [M – H] (for the corresponding sulfonic acid).
3
): δ = 80.2, 78.8, 72.5, 32.9, 27.1, 22.6, 22.0,
21.5.
Anal. Calcd for C13H16ClNO S: C, 46.78; H, 4.83; N, 4.20; S, 9.61; Cl,
5
–
10.62. Found: C, 47.03; H, 5.09; N, 4.04; S, 9.36; Cl, 10.81.
MS (APCI): m/z = 207 [M – H] (for the corresponding sulfonic acid).
Anal. Calcd for C H ClO S: C, 42.38; H, 6.67; S, 14.14; Cl, 15.64.
8
15
3
cis-4-Methoxytetrahydrofuran-3-sulfonyl Chloride (8e)
Found: C, 42.11; H, 6.44; S, 14.34; Cl, 15.84.
The product was purified by vacuum distillation; bp 101 °C/0.1
mmHg; yield: 37.0 g (65%) obtained from 50 g of 7e; yellowish liquid.
cis-2-(2,2,2-Trifluoroethoxy)cyclopentane-1-sulfonyl Chloride
1
(15d)
H NMR (400 MHz, CDCl ): δ = 4.59–4.45 (m, 2 H), 4.42–4.33 (m, 1 H),
3
4.37–4.25 (m, 1 H), 4.01 (dd, J = 9.8, 4.0 Hz, 1 H), 3.94 (dd, J = 9.8 Hz,
Yield: 4.09 g (93%) from 4 g of 14d; yellowish liquid.
4
.7, 1 H), 3.48 (s, 3 H).
1
H NMR (500 MHz, CDCl ): δ = 4.52–4.45 (m, 1 H), 4.19–4.09 (m, 1 H),
3
13
C NMR (126 MHz, CDCl ): δ = 81.3, 76.7, 72.0, 68.3, 59.3.
4.10–3.94 (m, 1 H), 3.94–3.81 (m, 1 H), 2.63–2.50 (m, 1 H), 2.40–2.28
(m, 1 H), 2.21–2.03 (m, 2 H), 1.97–1.85 (m, 1 H), 1.87–1.74 (m, 1 H).
3
–
MS (APCI): m/z = 181 [M – H] (for the corresponding sulfonic acid).
13
C NMR (101 MHz, CDCl ): δ = 123.7 (q, J = 279.5 Hz), 83.5, 78.8, 68.3
3
Anal. Calcd for C H ClO S: C, 29.93; H, 4.52; S, 15.98; Cl, 17.67. Found:
C, 29.69; H, 4.16; S, 16.29; Cl, 18.00.
5
9
4
(q, J = 34.6 Hz), 32.0, 26.6, 21.3.
–
MS (APCI): m/z = 247 [M – H] (for the corresponding sulfonic acid).
cis-1-Methoxy-2,3-dihydro-1H-indene-2-sulfonyl Chloride (8g)
Anal. Calcd for C H ClF O S: C, 31.53; H, 3.78; S, 12.02; Cl, 13.29.
7
10
3
3
Found: C, 31.26; H, 3.4; S, 11.76; Cl, 13.53.
Yield: 54.7 g (88%) from 56 g of 7g; yellowish crystals; mp 63–65 °C.
1
H NMR (400 MHz, CDCl ): δ = 7.43–7.27 (m, 4 H), 5.11 (d, J = 5.7 Hz, 1
3
cis-2-(Benzyloxy)cyclopentane-1-sulfonyl Chloride (15e)
H), 4.63 (td, J = 8.5, 5.7 Hz, 1 H), 3.91 (dd, J = 15.9, 8.5 Hz, 1 H), 3.52–
3.41 (m, 4 H).
Yield: 3.89 g (71%) from 5 g of 14e; yellowish crystals, mp 47–49 °C.
13
1H NMR (400 MHz, CDCl
C NMR (101 MHz, CDCl ): δ = 139.3, 138.2, 130.3, 127.8, 125.5,
3
): δ = 7.45–7.15 (m, 5 H), 4.64 (d, J = 12.0 Hz,
3
125.4, 83.4, 78.4, 57.6, 33.8.
1 H), 4.58 (d, J = 12.0 Hz, 1 H), 4.45–4.37 (m, 1 H), 4.19 (td, J = 8.8, 5.3
+
+
Hz, 1 H), 2.65–2.52 (m, 1 H), 2.37–2.25 (m, 1 H), 2.15–2.01 (m, 2 H),
MS (EI): m/z = 147 [M – SO Cl] , 115 [M – SO Cl – MeOH] .
2
2
1.83–1.66 (m, 2 H).
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–K

J
Synthesis
A. Sokolov et al.
Paper
13
13
C NMR (101 MHz, CDCl ): δ = 137.4, 128.5, 127.9, 127.8, 80.5, 79.4,
C NMR (101 MHz, CDCl ): δ = 151.9, 131.4, 130.0, 126.0, 119.6,
3
3
72.2, 31.2, 27.0, 21.3.
119.1, 73.1, 71.9, 60.1, 57.1.
–
–
MS (APCI): m/z = 255 [M – H] (for the corresponding sulfonic acid).
MS (APCI): m/z = 277 [M – H] (for the corresponding sulfonic acid).
Anal. Calcd for C12H15ClO S: C, 52.46; H, 5.50; S, 11.67; Cl, 12.90.
Anal. Calcd for C10H10Cl O S: C, 40.42; H, 3.39; S, 10.79; Cl, 23.86.
3
2
4
Found: C, 52.14; H, 5.55; S, 11.71; Cl, 12.85.
Found: C, 40.56; H, 3.32; S, 11.19; Cl, 23.88.
cis-2-(2-Methoxyethoxy)cyclopentane-1-sulfonyl Chloride (15f)
Cis-6-Bromo-4-methoxychroman-3-sulfonyl Chloride (8j)
Yield: 10.5 g (86%) from 11 g of 14f; yellowish liquid.
The reaction mixture was stirred at 110 °C for 2 d. The product was
purified by column chromatography (gradient hexane to t-BuOMe as
eluent); yield: 4.99 g (47%) from 10 g of 6j; yellowish oil.
1
1
H NMR (500 MHz, CDCl ): δ = 4.44–4.37 (m, 1 H), 4.22–4.13 (m, 1 H),
3
3.74–3.66 (m, 2 H), 3.61–3.50 (m, 2 H), 3.38 (s, 3 H), 2.62–2.53 (m, 1
H), 2.35–2.24 (m, 1 H), 2.16–2.01 (m, 2 H), 1.90–1.79 (m, 1 H), 1.79–
H NMR (400 MHz, CDCl ): δ = 7.40 (dd, J = 8.8, 2.6 Hz, 1 H), 7.33 (d, J =
3
1.69 (m, 1 H).
2.7 Hz, 1 H), 6.83 (d, J = 8.8 Hz, 1 H), 4.86 – 4.61 (m, 3 H), 4.26–4.17
1
3
(m, 1 H), 3.49 (s, 3 H).
C NMR (101 MHz, CDCl ): δ = 82.0, 79.5, 72.1, 70.1, 59.3, 31.5, 27.0,
3
13
2
1.2.
C NMR (126 MHz, CDCl ): δ = 152.5, 134.3, 132.9, 120.2, 119.5,
3
–
113.1, 73.1, 71.8, 60.1, 57.1.
MS (APCI): m/z = 223 [M – H] (for the corresponding sulfonic acid).
–
MS (APCI): m/z = 321/323 [M – H] (for the corresponding sulfonic ac-
id).
Anal. Calcd for C H ClO S: C, 39.59; H, 6.23; S, 13.21; Cl, 14.61.
Found: C, 39.74; H, 5.96; S, 13.18; Cl, 14.99.
8
15
4
Anal. Calcd for C10H10BrClO S: C, 35.16; H, 2.95; S, 9.39; Cl, 10.38; Br,
4
23.39. Found: C, 34.93; H, 3.03; S, 9.13; Cl, 10.03; Br, 23.17.
cis-2-(cyclopropylmethoxy)cyclopentane-1-sulfonyl Chloride
(15g)
Compounds 11h–j; General Procedure
Yield: 4.71 g (77%) from 5.5 g of 14g; yellowish liquid.
1
To a solution of ketone 10 (1.00 mol) in anhyd MeOH (2 L) was added
H NMR (400 MHz, CDCl ): δ = 4.36–4.28 (m, 1 H), 4.14 (td, J = 8.7, 5.5
3
NaBH (75.7 g, 2.00 mol) portionwise at r.t. The reaction mixture was
Hz, 1 H), 3.45–3.29 (m, 2 H), 2.62–2.47 (m, 1 H), 2.33–2.19 (m, 1 H),
2
4
stirred overnight and evaporated under reduced pressure. The residue
was dissolved in H O (1.5 L) and extracted with CHCl (3 × 500 mL).
.13–1.95 (m, 2 H), 1.85–1.64 (m, 2 H), 1.10–0.95 (m, 1 H), 0.53–0.45
(m, 2 H), 0.28–0.14 (m, 2 H).
2
3
The combined organic phases were washed with H O (3 × 500 mL),
2
13
C NMR (126 MHz, CDCl ): δ = 80.8, 79.7, 75.0, 31.6, 27.0, 21.4, 10.5,
3
dried (anhyd Na SO ), and evaporated under reduced pressure.
2
4
3
.2, 3.0.
MS (APCI): m/z = 219 [M – H] (for the corresponding sulfonic acid).
Anal. Calcd for C H ClO S: C, 45.28; H, 6.33; S, 13.43; Cl, 14.85.
–
1,2,3,4-Tetrahydronaphthalen-1-ol (11h)
9
15
3
Yield: 36.5 g (80%) from 45.0 g of 10h; colorless oil.
For spectral and physical data, see ref.37
Found: C, 45.11; H, 6.06; S, 13.64; Cl, 15.04.
Sulfonyl Chlorides 12 and 8j; General Procedure
Chroman-4-ol (11i)
KSAc (28.5 g, 0.250 mol) was added portionwise to a solution of 6i or j
Yield: 128 g (84%) from 150 g of 10i; colorless oil.
For spectral and physical data, see ref.38
(0.100 mol) in anhyd DMF (200 mL), and the reaction mixture was
stirred at 110 °C for the time given below for the preparation of 12
and 8j. The resulting mixture was cooled to r.t., poured into ice-cold
H O (500 mL), and extracted with EtOAc (3 × 200 mL). The combined
6-Bromochroman-4-ol (11j)
2
organic extracts were washed with H O (5 × 200 mL), dried (anhyd
2
Yield: 5.04 g (65%) from 7.7 g of 10j; yellowish crystals.
For spectral and physical data, see ref.39
Na SO ), and evaporated under reduced pressure. The crude product
2
4
was used in the next step without further purification. To a mixture
of NCS (53.4 g, 0.400 mol), concd HCl (5.7 mL), H O (20 mL), and
2
Compounds 5h–j; General Procedure
MeCN (200 mL) was added a solution of the crude product from the
previous step in MeCN (120 mL) dropwise at 10 °C. When the addi-
tion was finished and no more exothermic reaction was observed, the
solution was stirred at 10–20 °C for 40 min. The reaction mixture was
p-TsOH·H O (0.25 mol) was added to a solution of alcohol 11 (0.1 mol)
2
in anhyd toluene (4 L), and the solution was refluxed until the com-
plete conversion of the starting material. Then, the reaction mixture
poured into H O (400 mL) and extracted with t-BuOMe (3 × 200 mL).
was cooled to r.t., washed with H
2
O (2 × 1 L), 10% aq NaHCO
3
(3 × 1 L),
2
The combined organic phases were washed with brine (5 × 200 mL),
dried (anhyd Na SO ), and evaporated under reduced pressure.
and H O (2 × 1 L), dried (anhyd Na
duced pressure.
2
2
SO ), and evaporated under re-
4
2
4
cis-6-Chloro-4-methoxychroman-3-sulfonyl Chloride (12)
1,2-Dihydronaphthalene (5h)
The reaction mixture was stirred at 110 °C for 3 d. The product was
purified by column chromatography (gradient CHCl3 to t-BuOMe as
eluent); yield: 8.8 g (24%) from 30 g of 6i; yellowish oil;
1
Yield: 25.3 g (79%) from 36.5 g of 11h; colorless oil.
For spectral and physical data, see refs.40,41
H NMR (500 MHz, CDCl ): δ = 7.29 (dd, J = 8.8, 2.6 Hz, 1 H), 7.21 (d, J =
2H-Chromene (5i)
3
2
2
.6 Hz, 1 H), 6.91 (d, J = 8.8 Hz, 1 H), 4.82–4.78 (m, 1 H), 4.79–4.67 (m,
H), 4.28–4.21 (m, 1 H), 3.50 (s, 3 H).
The product was purified by vacuum distillation; bp 45 °C/0.1 mmHg;
yield: 41.3 g (58%) from 81 g of 11i; colorless liquid.
For spectral and physical data, see ref.41
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–K

K
Synthesis
A. Sokolov et al.
Paper
6
-Bromo-2H-chromene (5j)
(17) Scola, P. M.; Wang, A. X.; Good, A. C.; Sun, L.-Q.; Combrink, K. D.;
Campbell, J. A.; Chen, J.; Tu, Y.; Sin, N.; Venables, B. L.; Sit, S.-Y.;
Chen, Y.; Cocuzza, A.; Bilder, D. M.; D’Andrea, S.; Zheng, B.;
Hewawasam, P.; Ding, M.; Thuring, J.; Li, J.; Hernandez, D.; Yu,
F.; Falk, P.; Zhai, G.; Sheaffer, A. K.; Chen, C.; Lee, M. S.; Barry, D.;
Knipe, J. O.; Li, W.; Han, Y.-H.; Jenkins, S.; Gesenberg, C.; Gao, Q.;
Sinz, M. W.; Santone, K. S.; Zvyaga, T.; Rajamani, R.; Klei, H. E.;
Colonno, R. J.; Grasela, D. M.; Hughes, E.; Chien, C.; Adams, S.;
Levesque, P. C.; Li, D.; Zhu, J.; Meanwell, N. A.; McPhee, F. J. Med.
Chem. 2014, 57, 1708.
Yield: 11.7 g (91%) from 14.0 g of 11j; yellowish oil.
For spectral and physical data, see ref.42
Funding Information
This work was funded by Enamine Ltd.()
(18) Tsuri, T.; Haga, N.; Matsui, T.; Kamata, S.; Kakushi, H.; Uchida, K.
Chem. Pharm. Bull. 1992, 40, 75.
Acknowledgment
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19) Tsuri, T.; Matsui, T.; Haga, N.; Kamata, S.; Hagishita, S.;
Takahashi, K.; Kakushi, H.; Uchida, K.; Hatakeyama, H.;
Kurosawa, A. Chem. Pharm. Bull. 1992, 40, 85.
The authors thank Mr. Vitaliy Polovinko for 2D NMR and NOE experi-
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Supporting Information
(
21) Yang, Z.; Zhou, B.; Xu, J. Synthesis 2013, 46, 225.
Supporting information for this article is available online at
(22) Yang, Z.; Zheng, Y.; Xu, J. Synlett 2013, 24, 2165.
(23) Yang, Z.; Xu, J. Synthesis 2013, 45, 1675.
https://doi.org/10.1055/s-0037-1611277.
S
u
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p
orti
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©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–K