1,4 -S- to O-silyl migration: Multicomponent synthesis of α-thioketones through chemoselective transformation of esters to ketones with organolithium reagents

Article abstract of DOI:10.1002/chem.201303459

A [1,4]-S- to O-silyl migration has been exploited to chemoselectively transform esters into ketones by using organolithium reagents, allowing multicomponent synthesis of α-thioketones. Mechanistic studies reveal that this migration proceeds in an intramolecular manner and is more favorable than the corresponding [1,5]-S- to O- and [1,3]-C- to O-silyl migrations. The resulting α-thioketones are valuable building blocks for the synthesis of cyclic or multifunctionalized organosulfur compounds. Productive move: A [1,4]-S- to O-silyl migration has been exploited to chemoselectively transform esters into ketones by using organolithium reagents, allowing the multicomponent synthesis of α-thioketones (see scheme, TMEDA = tetramethylethylenediamine). Mechanistic studies revealed that this migration proceeds in an intramolecular manner and is more favorable than the corresponding [1,5]-S- to O- and [1,3]-C- to O-silyl migrations. The resulting α-thioketones are valuable building blocks for the synthesis of cyclic or multifunctionalized organosulfur compounds.

Full text of DOI:10.1002/chem.201303459

FULL PAPER
DOI: 10.1002/chem.201303459
ACHTUNGTRENNUNG
Xianwei Sun,[a] Zhenlei Song,*[a, b] Hongze Li,[a] and Changzheng Sun[a]
Abstract: A [1,4]-S- to O-silyl migration has been exploited to chemoselectively
transform esters into ketones by using organolithium reagents, allowing multicom-
Keywords: multicomponent reac-
ponent synthesis of a-thioketones. Mechanistic studies reveal that this migration
tions · nucleophilic addition · orga-
proceeds in an intramolecular manner and is more favorable than the correspond-
nolithium reagents · silyl migration ·
ing [1,5]-S- to O- and [1,3]-C- to O-silyl migrations. The resulting a-thioketones
thioketones
are valuable building blocks for the synthesis of cyclic or multifunctionalized orga-
nosulfur compounds.
Introduction
that this process might be exploited to achieve otherwise
challenging selectivity in reactions, such as chemoselective
transformation of esters into ketones by using organolithium
reagents (Scheme 1).[8] Normally organolithium compounds
react with esters of typical reactivity to cause over-addition,
giving the corresponding tertiary alcohol rather than the
ketone.[9] This has been attributed to the premature release
of ketone from the initially formed tetrahedral adduct,
which is highly unstable at À788C. In fact, efforts to trap
this intermediate even at À1008C by using Me3SiCl have
met with only limited success.[10]
To avoid this problem, we used an alternative approach
based on an intramolecular trapping process in which [1,4]-
S- to O-silyl migration of 2 was expected to proceed faster
than its collapse, generating the masked ketone 3 chemose-
lectively (Scheme 1). The sulfur in ester 1 would act not
Intramolecular anionic silyl migration[1] allows the efficient,
site-specific transfer of negative charge “through-space” to
create a new anion center, which can undergo transforma-
tions in a sequential manner. Such silyl migration between
a carbon and an oxygen atom is better known as Brook rear-
rangement (from C to O) and retro-Brook rearrangement
(from O to C). Both rearrangements have been applied in
new synthetic methodologies and natural product synthesis
(Scheme 1a).[2] In sharp contrast, intramolecular anionic
silyl migration between two hetero atoms, especially the mi-
gration from a sulfur to an oxygen atom, has been studied
to a much more limited extent (Scheme 1b).[3] Because Si
À
À
O bonds are stronger than Si S bonds (ca. 110 vs. 70 kcal
molÀ1),[4] the migration from S to O should be thermody-
namically favorable and, indeed, has been observed under
some circumstances.[5] Surprisingly, the migration has not
been investigated extensively and few applications in organ-
ic synthesis have so far been reported, despite the potential
for forming organosulfur compounds.[6]
As part of our continuing investigation of silyl migra-
tion,[7] we became interested in the ease with which silyl
groups can be made to migrate from S to O. We speculated
[a] X. Sun, Prof. Dr. Z. Song, H. Li, C. Sun
Key Laboratory of Drug Targeting and
Drug Delivery Systems of the Education Ministry
Department of Medicinal Chemistry
West China School of Pharmacy, Sichuan University
Chengdu, 610041 (P.R. China)
E-mail: zhenleisong@scu.edu.cn
[b] Prof. Dr. Z. Song
State Key Laboratory of Biotherapy
West China Hospital, Sichuan University
Chengdu, 610041 (P.R. China)
Scheme 1. Top: a) General description of [1,n]-Brook and retro-Brook
rearrangement; b) general description of [1,n]-S- to O-silyl migration.
Bottom: [1,4]-S- to O-silyl migration allowing the multicomponent syn-
thesis of a-thioketones by chemoselective transformation of esters to ke-
tones using organolithium reagents.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201303459.
Chem. Eur. J. 2013, 19, 17589 – 17594
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17589

only as carrier for the silyl migration, but also as a newly
Me2tBu group probably shields the carbonyl carbon of the
ester and prevents attack by nBuLi (entry 7). In contrast to
the results obtained with organolithium reagents, ethyl mag-
nesium bromide reacted with 1a under the optimized condi-
tions to give alcohol 5b rather than ketone 4b (entry 8).
This is consistent with the general belief that lithium is
better than magnesium as a counter ion to promote silyl mi-
gration.
The scope of electrophiles was then tested by reacting 1a
with nBuLi. The reaction was applicable to a range of alkyl,
benzyl, allyl, and propargyl halides as well as tosylate
(Table 2, entries 1–6), giving the desired a-thioketones 4c–h
in good yields. The reaction involving three epoxide deriva-
tives revealed interesting regioselectivity. Epoxide 2-(bro-
momethyl)oxirane (entry 7) underwent SN2 reaction with
bromide as the leaving group, rather than epoxide opening.
In contrast, the reaction of 2-(phenoxymethyl)oxirane
(entry 8) proceeded by ring opening at the terminal site.
The reaction with 2,3-epoxycyclohexone (entry 9) proceeded
by internal attack at the a-position, followed by E1cb elimi-
nation to give a-thiocyclohexenone 4k in 62% yield. The
process also proved suitable for thio-Michael addition to ac-
À
created anion center capable of forming a C S bond with
electrophiles in a sequential fashion. Indeed, thioethers
appear as important linkages in many bioactive natural and
pharmaceutical agents.[11] Traditional methods to synthesize
this moiety often suffer from side reactions in which thioal-
cohols undergo oxidative coupling to form disulfides, or
sulfur deactivates late transition metals.[6a] We reasoned that
our multicomponent synthesis of a-thioketones 4 by using
1 as a scaffold would also provide a valuable route to thio-
ether compounds. Herein, we report the detailed studies of
this reaction.
Results and Discussion
The model scaffold trimethylsilyl ethyl thioglycolate (1a)
was prepared in 90% yield from commercially available
ethyl thioglycolate and hexamethyldisilylamine.[12] The reac-
tion was initially examined in tetrahydrofuran (THF) at
À788C by using nBuLi as the nucleophile and allylbromide
as the electrophile. Unfortunately, severe over-addition to
the ester group occurred, giving tertiary alcohol 5a in 41%
yield after acidic hydrolysis (Table 1, entry 1). Following the
over-addition and either intra- or intermolecular S to O silyl
migration, the allylic thioether formed. Neither addition of
1.5 equiv hexamethylphosphoramide (HMPA; usually used
to promote silyl migration between C and O) nor addition
of tetramethylethylenediamine (TMEDA; to stabilize alkox-
ide lithium 2) effectively favored the formation of 3 (en-
tries 2 and 3). To our delight, replacing THF with Et2O and
adding TMEDA as a co-solvent gave rise to a-allylthioke-
tone 4a as a single adduct and in 79% yield (entry 4). This
migration proceeded reliably even when excess nBuLi
(2.0 equiv) was used, giving 4a in a comparably good yield
of 70% and without detectable levels of over-adduct 5a
(entry 5). However, use of a higher temperature (08C) gen-
erated a large amount of 5a (entry 6). Switching the SiMe3
group to SiMe2tBu led to no addition for 1b. The bulky Si-
À
tivated double C C bonds (entries 10 and 11) and triple
À
C C bonds (entry 12), with a Z/E ratio of 80:20 being ob-
tained for thioacrylate 4n. In addition, this approach can be
À
used to form an S S bond, allowing the synthesis of disul-
fide 4o in 72% yield (entry 13).
The multicomponent reaction was compatible with
a range of organolithium compounds, including alkyl, vinyl,
aryl, and heterocyclic lithium derivatives (Table 3, entries 1–
9). These reactions showed reliable chemoselectivity to give
a-thioketone 4p–x with no over-addition detected. Lithium
acetylide, however, did not add to the ester group
(entry 10), probably because of its weaker nucleophilicity.
The a-substituted compound trimethylsilyl ethyl thioglyco-
late (1c) worked well, giving 4z in 65% yield (entry 11).
To further demonstrate the synthetic potential of our ap-
proach, we attempted to synthesize cyclic organosulfur com-
pounds in a sequential manner. Reaction of 1a with nBuLi
and a,b-unsaturated ester led
to an intramolecular aldol reac-
tion of the initially formed
lithium enolate with ketone
(Scheme 2), giving multifunc-
tionalized tetrahydrothiophene
6a and 6b in 52 and 59% yield,
respectively, and with more
than 95:5 diastereoselectivity.
When the nucleophilic and
electrophilic centers were incor-
porated into the same species,
as in the case of a-aryl-substi-
tuted oxiranyl lithium, tetrahy-
drothiophenones 7a and 7b
were obtained in 56 and 53%
yield, respectively.
Table 1. Screening of addition/ACTHNUTRGENUG[N 1,4]-S- to O-silyl migration/S-substitution conditions.
Entry
Si
NuM
[(equiv)]
Solvent
T
[8C]
4
Yield
[%][b]
5
Yield
[%][b]
N
1
2
3
1a
1a
1a
1a
1a
1a
1b
1a
TMS
TMS
TMS
TMS
TMS
TMS
TBDMS
TMS
nBuLi (1.1)
nBuLi (1.1)
nBuLi (1.1)
nBuLi (1.1)
nBuLi (2.0)
nBuLi (1.1)
nBuLi (1.1)
EtMgBr (1.0)
THF
THF/HMPA
À78
À78
À78
À78
À78
0
4a
4a
4a
4a
4a
4a
4a
4b
–
–
–
79
70
26
–
5a
5a
5a
5a
5a
5a
5a
5a
41
39
35
–
–
21
–
THF/TMEDA=10:1
Et2O/TMEDA=10:1
Et2O/TMEDA=10:1
Et2O/TMEDA=10:1
Et2O/TMEDA=10:1
Et2O/TMEDA=10:1
4[a]
5
6
7
8
À78
À78
–
34
[a] Reaction conditions: 1a (0.26 mmol) and nBuLi (2.5m in hexanes, 0.29 mmol) in Et2O/TMEDA (10:1,
5.5 mL) at À788C; then allyl bromide (0.52 mmol), warmed to room temperature; crude products were treated
with aq. HCl (0.1n, 2.0 mL). [b] Isolated yield after purification by silica gel column chromatography.
17590
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Chem. Eur. J. 2013, 19, 17589 – 17594

Synthesis of a-Thioketones
FULL PAPER
Table 2. Scope of addition/
[1,4]-S- to O-silyl migration/S-substitution of
Table 3. Scope of addition/
ACHTUNGTREN[NUNG 1,4]-S- to O-silyl migration/S-substitution of
1a and nBuLi with electrophiles.[a]
1 and allyl bromide with organolithium nucleophiles.[a]
Entry
1
R
NuLi
MeLi
Product
Yield
[%][b]
Entry
Electrophile (E)
Product
Yield
[%][b]
1a
H
H
61
70
1
2
3
4
MeI
65
70
62
67
BrCH2CO2Et
BnBr
2
3
4
1a
1a
1a
H
H
76
60
5
6
63
56
5
6
1a
1a
H
H
66
60
7
8
62
64
7
8
1a
1a
H
H
63
72
9
62
9
1a
H
71
10
11
61
65
10
11
1a
1c
H
–
Me
nBuLi
72
12
13
71
72
[a] Reaction conditions: 1 (0.26 mmol) and organolithium nucleophile
(0.29 mmol) in Et2O/TMEDA (10:1, 5.5 mL) at À788C; then allyl bro-
mide (0.52 mmol), warmed to room temperature; crude products were
treated with aq. HCl (0.1n, 2.0 mL). [b] Isolated yield after purification
by silica gel column chromatography.
PhSSPh
[a] Reaction conditions: 1a (0.26 mmol) and nBuLi (2.5m in hexanes,
0.29 mmol) in Et2O/TMEDA (10:1, 5.5 mL) at À788C; then electrophile
(0.52 mmol), warmed to room temperature; crude products were treated
with aq. HCl (0.1n, 2.0 mL). [b] Isolated yield after purification by silica
gel column chromatography. [c] The ratio was determined by 1H NMR
spectroscopy.
to O-silyl migration would afford thiolithium 10, which
could undergo S-allylation to give 11. Although 8 and 11 are
structurally different to each other, acidic hydrolysis of
either would lead to the same thioketone 4a.While path-
way b provides a logical explanation for the mechanism, we
consider that pathway a should be more reasonable based
on the following evidence: first, the key intermediate 8 was
isolated in 61% yield with partial decomposition on silica
gel and characterized by NMR spectroscopy. Second, we did
not observe the formation of either ketone 9 or silyl enol
ether 11. These results imply that the desired intramolecular
[1,4]-S- to O-silyl migration of 2a is faster, as expected, than
its collapse to ketone 9. In addition, the fact that no O-ally-
Two possible reaction pathways a and b are proposed in
Scheme 3 to account for the formation of 4a from tetrahe-
dral adduct 2a. In pathway a, a rapid [1,4]-S- to O-silyl mi-
gration of 2a may occur via pentacoordinated silicate 2a’ to
generate thiolithium 3a, which would undergo S-allylation
to give 8. Pathway b, on the other hand, provides another
possibility; the collapse of 2a may proceed first to release
ketone 9. In the presence of nBuLi and EtOLi as bases, de-
protonation could occur at the a-position of ketone 9 to
give the corresponding lithium enolate. Subsequent [1,4]-S-
Chem. Eur. J. 2013, 19, 17589 – 17594
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17591

Z. Song et al.
This result implies that, due to the longer transfer distance,
the intramolecular [1,5]-S- to O-silyl migration of 15 is less
favorable than the analogous [1,4]-migration[13] and it pro-
ceeds slower than its collapse. The fact that no formation of
14 was observed also excludes the possibility of intermolecu-
lar S to O silyl migration between two molecules of 2 in the
conversion of 1 into 4. Reaction of 1a with 1-trimethylsilyl
vinyllithium revealed further details about migration selec-
tivity (Scheme 4, bottom). Even though a [1,3]-C- to O-silyl
migration in intermediate 2-diSiMe3 offered a more favora-
ble transfer distance than [1,4]-S- to O-silyl migration, the
[1,4]-migration still appeared to be favored, giving 17 in
75% yield.
Scheme 2. Cascade transformations of 1a to functionalized tetrahydro-
thiophenes 6a, 6b and tetrahydrothiophenones 7a, 7b.
The a-thioketones produced by using this method are
useful building blocks for the synthesis of organosulfur com-
pounds. For example, reaction of 1a with chiral epoxide 18
generated a-thioketone 19 in 58% yield, which underwent
reductive cyclization to give (R,S)-cis-1,4-oxathiane 20 in
74% yield (Scheme 5a). Recently, 1,4-oxathianes have been
reported to be potential muscarinic agonists, with some se-
lectively activating the ileal M3 receptor subtype.[14] Our ap-
proach also allowed the transformation of 21, a substrate for
Gassman indolization,[15] into multifunctionalized 2-aryl-3-
thioindoles 22a and 22b in 75 and 72% yield, respectively
(Scheme 5b).
Scheme 3. Two possible reaction pathways a and b for the formation of
4a from tetrahedral adduct 2a.
lation of 2a was observed also implies that the [1,4]-S- to O-
silyl migration is irreversible.
To gain further mechanistic insights into this reaction, we
submitted 12 to the optimal reaction conditions. This com-
pound contains one more methylene than 1a between the
ester and thio groups, so we expected it to undergo a long-
range [1,5]-S- to O-silyl migration. However, only tertiary
alcohol 13 was obtained in 38% yield by over-addition, and
no desired b-thioketone 14 was produced (Scheme 4, top).
Scheme 5. a) Synthesis of 19 and its reductive cyclization to form cis-1,4-
oxathiane 20. b) Synthesis of 21 and its Gassman indolization to form 2-
aryl-3-thioindoles 22a and 22b.
Conclusion
We have exploited a [1,4]-S- to O-silyl migration to chemo-
selectively transform esters into ketones by using organo-
lithium reagents. This approach allows efficient multicompo-
nent synthesis of a-thioketones. Mechanistic studies indicate
that this migration proceeds in an intramolecular manner
and is favored over the corresponding [1,5]-S- to O- and
[1,3]-C- to O-silyl migrations. The a-thioketones synthesized
in this way are valuable building blocks for the synthesis of
cyclic or multifunctionalized organosulfur compounds. Fur-
ther applications of this methodology are underway.
Scheme 4. Attempts to achieve [1,5]-S- to O-silyl migration of 12 (top)
and [1,4]-S- to O-silyl migration/addition of 1a and allyl bromide with
1-trimethylsilyl vinyllithium (bottom).
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Synthesis of a-Thioketones
FULL PAPER
The combined organic phases were dried over Na2SO4 and concentrated
under reduced pressure. Purification of the crude residue by silica gel
flash column chromatography (gradient EtOAc/petroleum ether, 5%) af-
forded 7a (23.0 mg, 56%) as a light-yellow oil. 1H NMR (400 MHz,
CDCl3): d=3.26 (d, J=12.0 Hz, 1H; CH2), 3.38 (d, J=17.6 Hz, 1H;
CH2), 3.42 (d, J=12.0 Hz, 1H; CH2), 3.45 (d, J=17.6 Hz, 1H; CH2), 3.69
(s, 1H; OH), 7.35–7.41 (m, 3H; CH), 7.52 ppm (d, J=7.2 Hz, 2H; CH);
13C NMR (100 MHz, CDCl3): d=33.6 (CH2), 37.1 (CH2), 79.5 (Cq), 125.6
(CH), 128.7 (CH), 138.6 (Cq), 210.1 ppm (CO); IR (neat): n˜ =3445 (br
m), 3060 (w), 2924 (w), 2875 (w), 1740 (s), 1494 (m), 1448 (m), 1395 (m),
1350 (m), 1200 (m), 1159 (m), 1066 (s), 1031 (m), 951 (w), 918 (w), 878
(w), 820 cmÀ1 (w); HRMS (MALDI): m/z calcd for C10H10O2SK:
233.0033 [M+K]+; found: 233.0032.
Experimental Section
Synthesis of trimethylsilyl ethyl thioglycolate (1a): Ethyl 2-mercaptoace-
tate (3.2 mL, 29.2 mmol) and imidazole (73.4 mg, 1.1 mmol) in hexame-
thyldisilazane (15.7 mL, 75.0 mmol) were heated at 1308C for 18 h under
an argon atmosphere. After cooling to RT, the excess hexamethyldisila-
zane was removed by distillation at atmospheric pressure. Compound 1a
(5.04 g, 90%) was collected by further distillation of the resultant liquid
under vacuum (b.p. 52–548C; 8 Torr); 1H NMR (400 MHz, CDCl3): d=
0.35 (s, 9H; CH3), 1.28 (t, J=7.2 Hz, 3H; CH3), 3.20 (s, 2H; CH2),
4.17 ppm (q, J=7.2 Hz, 2H; CH2); 13C NMR (100 MHz, CDCl3): d=0.6
(CH3), 14.0 (CH3), 28.0 (CH2), 61.3ACHTNUGTRENUNG(CH3), 171.1 ppm (CO); IR (neat):
n˜ =2955 (s), 2930 (s), 2854 (s), 1740 (s), 1468 (m), 1399 (w), 1245 (s),
1126 (m), 1095 (m), 939 (w), 805 cm–1 (s); HRMS (MALDI): m/z calcd
for C7H17O2SSi: 193.0713 [M+H]+; found: 193.0717.
Synthesis of cis-1,4-oxathiane 20: TMSOTf (26 mL, 0.13 mmol) was
added to a solution of 19 (32 mg, 0.1 mmol) in anhyd CH2Cl2 (3 mL) at
08C under an argon atmosphere. After stirring for 20 min, Et3SiH (36 mL,
0.2 mmol) was added and the resulting solution was warmed to RT with
stirring for another 1 h. The reaction was quenched by the addition of
NaHCO3 (0.5 mL) and extracted with Et2O (2ꢁ4 mL). The combined or-
ganic phases were dried over Na2SO4 and concentrated under reduced
pressure. Purification of the crude residue by silica gel flash column chro-
matography (gradient EtOAc/petroleum ether, 10%) afforded 20
(15.1 mg, 74%) as a light-yellow oil. [a]2D5 =À13.40 (c 0.5 in EtOH);
1H NMR (400 MHz, CDCl3): d=0.89 (t, J=6.4 Hz, 3H; CH3), 1.29–1.32
(m, 3H; CH2), 1.42–1.46 (m, 2H; CH2), 1.52–1.54 (m, 1H; CH2), 1.64 (s,
1H; OH), 1.69–1.83 (m, 2H; CH2), 2.27 (t, J=14.4 Hz, 2H; CH2), 2.52
(dd, J1 =10.8 Hz, J2 =13.2 Hz, 1H; CH2), 2.61 (dd, J1 =10.8 Hz, J2 =
13.2 Hz, 1H; CH2), 3.60–3.65 (m, 1H; CH), 3.78–3.79 (m, 2H; CH2),
3.83–3.88 ppm (m, 1H; CH); 13C NMR (100 MHz, CDCl3): d=13.9
(CH3), 22.5 (CH2), 27.5 (CH2), 30.7 (CH2), 30.8 (CH2), 36.0 (CH2), 38.1
(CH2), 61.0 (CH2), 79.0 (CH), 79.1 ppm (CH); IR (neat): n˜ =3419 (br m),
2957 (s), 2925 (s), 2858 (m), 1738 (w), 1511 (w), 1461 (m), 1415 (m), 1380
(m), 1332 (m), 1260 (m), 1053 ppm (m); HRMS (MALDI): m/z calcd for
C10H21O2S: 205.1257 [M+H]+; found: 205.1248.
Synthesis of a-allylthioketone 4a: nBuLi (2.5m in hexanes, 0.11 mL,
0.29 mmol) was added to a solution of 1a (50 mg, 0.26 mmol) in anhyd
Et2O (5 mL) and anhyd TMEDA (0.5 mL) at À788C under an argon at-
mosphere. After stirring for 10 min, allyl bromide (44 mL, 0.52 mmol) was
added and the resulting solution was warmed to RT with stirring for an-
other 1 h. The reaction was quenched by the addition of H2O (3 mL) and
extracted with Et2O (2ꢁ4 mL). The combined organic phases were
stirred with aq. HCl (0.1n, 2 mL) for 30 min followed by dilution with
H2O (3 mL) and extraction with Et2O (2ꢁ4 mL). The combined organic
phases were dried over Na2SO4 and concentrated under reduced pres-
sure. Purification of the crude residue by silica gel flash column chroma-
tography (gradient EtOAc/petroleum ether, 0.2%) afforded 4a (35.3 mg,
79%) as a light-yellow oil. 1H NMR (400 MHz, CDCl3): d=0.90 (t, J=
7.2 Hz, 3H; CH3), 1.29–1.35 (m, 2H; CH2), 1.53–1.59 (m, 2H; CH2), 2.57
(t, J=7.2 Hz, 2H; CH2), 3.10 (d, J=6.8 Hz, 2H; CH2), 3.17 (s, 2H; CH2),
5.13 (d, J=11.2 Hz, 1H; CH2), 5.14 (d, J=16.0 Hz, 1H; CH2), 5.71 ppm
(dddd, J1 =J2 =6.8 Hz, J3 =11.2 Hz, J4 =16.0 Hz, 1H; CH); 13C NMR
(100 MHz, CDCl3): d=13.8 (CH3), 22.2 (CH2), 25.9 (CH2), 34.5 (CH2),
39.2 (CH2), 40.4 (CH2), 118.3 (CH2), 132.9 (CH), 205.9 ppm (CO); IR
(neat): n˜ =2959 (s), 2953 (s), 2870 (m), 1708 (s), 1634 (m), 1580 (s), 1463
(w), 1404 (m), 1372 (m), 1333 (m), 1248 (s), 1152 (w), 1030 (m), 990 (m),
921 cm–1 (m); HRMS (MALDI): m/z calcd for C9H16OSNa: 195.0814
[M+Na]+; found: 195.0819.
Synthesis of 2-aryl-3-thioindole 22a: A solution of tBuOCl (28.8 mg,
0.22 mmol) in CH2Cl2 (0.2 mL) was added dropwise to a vigorously
stirred solution of aniline (20.5 mg, 0.22 mmol) in CH2Cl2 (1.5 mL) at
À658C under an argon atmosphere. After stirring for 10 min, a solution
of 21 (43 mg, 0.22 mmol) in CH2Cl2 (0.2 mL) was added and the reaction
was kept at the same temperature for 5 h. A solution of Et3N (22.2 mg,
0.22 mmol) in CH2Cl2 (0.2 mL) was then added and the resulting mixture
was warmed to RT with stirring for 30 min. The reaction was quenched
by the addition of H2O (1 mL) and the mixture was extracted with
CH2Cl2 (3ꢁ2 mL). The combined organic phases were dried over Na2SO4
and concentrated under reduced pressure. Purification of the crude resi-
due by silica gel flash column chromatography (gradient EtOAc/petrole-
um ether, 2%) afforded 22a (44.3 mg, 75%) as a white solid. M.p. 141.2–
Synthesis of tetrahydrothiophene 6a: nBuLi (2.5m in hexanes, 0.11 mL,
0.29 mmol) was added to a solution of 1a (50 mg, 0.26 mmol) in anhyd
Et2O (5 mL) and anhyd TMEDA (0.5 mL) at À788C under argon atmo-
ACHTUNGTRENNUNGsphere. After stirring for 10 min, methyl crotonate (33 mL, 0.31 mmol)
was added and the resulting solution was warmed to RT with stirring for
another 24 h. The reaction was quenched by the addition of H2O (3 mL)
and extracted with Et2O (2ꢁ4 mL). The combined organic phases were
dried over Na2SO4 and concentrated under reduced pressure. Purification
of the crude residue by silica gel flash column chromatography (gradient
EtOAc/petroleum ether, 5%) afforded 6a (31.4 mg, 52%) as a light-
1
143.08C; H NMR (400 MHz, CDCl3): d=2.31 (s, 3H; CH3), 3.91 (s, 3H;
CH3), 7.04 (d, J=8.0 Hz, 1H; CH), 7.13 (dt, J1 =0.8 Hz, J2 =8.4 Hz, 1H;
CH), 7.19–7.25 (m, 2H; CH), 7.37 (d, J=8.8 Hz, 1H; CH), 7.40 (d, J=
8.0 Hz, 1H; CH), 7.82 (d, J=7.6 Hz, 1H; CH), 8.16 (dd, J1 =1.6 Hz, J2 =
8.0 Hz, 1H; CH), 9.19 ppm (s, 1H; NH); 13C NMR (100 MHz, CDCl3):
d=19.7 (CH3), 55.8 (CH3), 105.0 (Cq), 111.0 (CH), 111.4 (CH), 119.3
(CH), 120.1 (CH), 120.2 (Cq), 120.9 (CH), 122.6 (CH), 129.6 (CH), 130.1
(Cq), 131.9 (CH), 135.1 (Cq), 136.9 (Cq), 156.5 ppm (Cq); IR (neat): n˜ =
3551 (m), 3474 (m), 3412 (s), 2918 (m), 2838 (w), 1899 (w), 1780 (w),
1723 (m), 1638 (m), 1617 (m), 1598 (m), 1578 (m), 1530 (m), 1501 (w),
1473 (m), 1461 (m), 1450 (s), 1433 (s), 1400 (m), 1350 (m), 1324 (m),
1296 (m), 1272 (m), 1244 (s), 1224 (m), 1179 (m), 1163 (m), 1133 (m),
1118 (m), 1048 cmÀ1 (m); HRMS (MALDI): m/z calcd for C16H16NOS:
270.0947 [M+H]+; found: 270.0952.
1
yellow oil. H NMR (400 MHz, CDCl3): d=0.90 (t, J=7.2 Hz, 3H; CH3),
1.28–1.34 (m, 2H; CH2), 1.34 (d, J=6.8 Hz, 3H; CH3), 1.44–1.50 (m, 1H;
CH2), 1.56–1.67 (m, 3H; CH2), 2.50 (d, J=10.8 Hz, 1H; CH), 2.89 (d, J=
11.6 Hz, 1H; CH2), 3.04 (d, J=11.6 Hz, 1H; CH2), 3.45 (s, 1H; OH), 3.77
(s, 3H; CH3), 3.82–3.89 ppm (m, 1H; CH); 13C NMR (100 MHz, CDCl3):
d=13.9 (CH3), 19.9 (CH3), 23.1 (CH2), 26.4 (CH2), 39.1 (CH2), 42.3
(CH2), 43.7 (CH), 52.2 (CH), 62.9 (CH3), 84.9 (Cq), 173.6 ppm (CO); IR
(neat): n˜ =3500 (br. m), 2957 (s), 2930 (s), 2865 (m), 1737 (s), 1457 (m),
1438 (m), 1358 (m), 1258 (m), 1211 (m), 1166 (m), 1076 (m), 1022 (m),
924 (w), 837 cm–1 (w); HRMS (MALDI): m/z calcd for C11H20O3SNa:
255.1025 [M+Na]+; found: 255.1034.
Synthesis of tetrahydrothiophenone 7a: tBuLi (1.3m in pentane, 0.21 mL,
0.27 mmol) was added to
a solution of styrene oxide (32.8 mg,
0.27 mmol) in anhyd Et2O (5 mL) and anhyd TMEDA (0.5 mL) at
À988C under an argon atmosphere. After stirring for 5 min, 1a (40 mg,
0.21 mmol) was added and the mixture was stirred for 10 min before
warming to RT for another 30 min. The reaction was quenched by the ad-
dition of H2O (3 mL) and extracted with Et2O (2ꢁ4 mL). The combined
organic phases were stirred with aq. HCl (0.1n, 2 mL) for 30 min fol-
lowed by dilution with H2O (3 mL) and extraction with Et2O (2ꢁ4 mL).
Acknowledgements
We are grateful for financial support from the National Natural Science
Foundation of China (21172150, 21021001, 21290180), the National Basic
Chem. Eur. J. 2013, 19, 17589 – 17594
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
17593

Z. Song et al.
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Received: September 3, 2013
Published online: November 14, 2013
17594
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ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2013, 19, 17589 – 17594