Synthesis of chiral allylic thioesters: Enantio- and regioselective iridium-catalyzed allylations of KSAc

Article abstract of DOI:10.1002/ejoc.201201640

Chiral allylic thioesters were synthesized through a direct iridium-catalyzed asymmetric allylation of KSAc in the presence of KOAc. This strategy provided branched allylic thioesters in good yields with the high levels of enantioselectivity. Chiral allylic thioesters were prepared through a direct iridium-catalyzed asymmetric allylation of KSAc in the presence of KOAc. This synthetic strategy provided branched allylic thioesters in good yields with high levels of enantioselectivity. Copyright

Full text of DOI:10.1002/ejoc.201201640

FULL PAPER
DOI: 10.1002/ejoc.201201640
Synthesis of Chiral Allylic Thioesters: Enantio- and Regioselective Iridium-
Catalyzed Allylations of KSAc
Ning Gao[a] and Xiaoming Zhao*[a,b]
Keywords: Asymmetric catalysis / Enantioselectivity / Allylic compounds / Iridium
Chiral allylic thioesters were synthesized through a direct
iridium-catalyzed asymmetric allylation of KSAc in the pres-
ence of KOAc. This strategy provided branched allylic thio-
esters in good yields with the high levels of enantio-
selectivity.
tions appears to form an allylic thioester, but there are few
reports available,[11] perhaps, because of the high reactivity
of the resulting allylic thioesters with the metal catalyst.[12]
Nevertheless, thiol derivatives[8] such as glutathione and
(R)-thioterpineol play a crucial role not only in primary me-
tabolism[8] but also in the distinctive taste of grapefruit.[13]
Chiral thiols with the chirality at the carbon atom are of
great importance with respect to both synthetic intermedi-
ates[8,13] and biologically active compounds.[14] In 2010,
Connon described the syntheses of chiral thioesters and thi-
ols by using a kinetic resolution process as well as their
application to the synthesis of the key skeleton of (R)-mon-
telukast.[14] Herein, we report the asymmetric iridium-cata-
lyzed allylic substitution of allylic carbonates with KSAc,
which produced the branched allylic products with high
levels of enantio- and regioselectivity.
Introduction
An enantioselective iridium-catalyzed allylic substitution
reaction is a powerful method for constructing a chiral car-
bon–heteroatom bond (e.g., N[1] and O[2]). In this context,
the formation of carbon–sulfur bonds has been less investi-
gated, presumably because sulfur nucleophiles can poison
transition-metal catalysts.[3] Recently, considerable progress
in the formation of C–S bonds by using an iridium complex
as a catalyst has been made by Hartwig,[4] You,[5] Car-
reira,[6] and Zhao.[7] However, there are currently no good
strategies for the syntheses of chiral branched allylic thio-
esters.
Branched allylic thioesters are especially convenient pre-
cursors to branched allylic thiols and are also important
synthetic intermediates in their own right.[8] The direct ap-
proach to sulfur-containing compounds involves a transi-
tion-metal-catalyzed allylic substitution with a sulfur nu-
cleophile.[9] When sodium triisopropylsilanethiolate
(NaSSiiPr3) was employed as the sulfur nucleophile of an
iridium-catalyzed allylation, branched allylic products were
produced in moderate to good enantioselectivities (74–
89%ee),[7d] but the SiiPr3 protecting group was not selec-
tively removable under the conventional conditions.[10] The
drawbacks to this type of reaction prompted us to seek a
more suitable sulfur nucleophile to synthesize allylic thiols
with high enantioselectivities.
Results and Discussion
We began our study by investigating the reaction between
KSAc (3) and (E)-cinnamyl methyl carbonate (2a) with the
additive KOAc in the presence of an iridacycle[15] at room
temperature in dichloromethane (DCM). The iridacycle
was made from 2 mol-% of [Ir(COD)Cl]2 (COD = 1,5-cy-
clooctadiene) and 4 mol-% of ligand L1,[16] which con-
tained
a simplified biphenyl unit. Interestingly, the
branched allylic thioester 4a was produced in 54% yield and
with a 78%ee (see Table 1, Entry 1). Encouraged by these
results, a series of phosphoramidite ligands that included
Feringa’s ligand L2,[16,17] ligands L3,[17] L4,[18] and L5,[19]
and phosphanooxazoline (PHOX) ligand L6[20] (see Fig-
ure 1) were evaluated (see Table 1, Entries 2–6). The prelim-
inary results revealed that Feringa’s ligand L2 led to the
highest ee value of 91% (see Table 1, Entry 2), and L3,
which contained a bulky group on the phenyl ring of amine
moiety, afforded the product with 88%ee and poor regiose-
lectivity (see Table 1, Entry 3). Employing other ligands
L4–L6 resulted in a trace amount of the allylation product
Apparently, potassium ethanethioate (KSAc) is one con-
venient candidate because of its atom economy and suf-
ficient availability. The employment of KSAc in these reac-
[a] Department of Chemistry, Tongji University,
1239 Siping Lu, Shanghai 200092, P. R. China
Fax: +86-21-65981376
E-mail: xmzhao08@mail.tongji.edu.cn
Homepage: http://chemweb.tongji.edu.cn/Teachers
[b] Key Laboratory of Fluorine Chemistry, Shanghai Institute of
Organic Chemistry,
354 Fenglin Road, Shanghai 200032, P. R. China
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201201640.
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Eur. J. Org. Chem. 2013, 2708–2714

Enantio- and Regioselective Iridium-Catalyzed Allylations of KSAc
(see Table 1, Entries 4–6). (E)-Cinnamyl ethyl carbonate yield were achieved by reducing the catalyst loading to
(2m) was used as a substrate, but it produced only 48% 1 mol-% of the iridacycle {made from 1 mol-% of [Ir-
of 4a with poor regioselectivity (see Table 1, Entry 7). In (COD)Cl]2 and 2 mol-% of L2} with no loss of enantio-
addition, using (E)-cinnamyl acetate (2n) provided a trace selectivity (see Table 1, Entry 17 vs. 2). We also found that
amount of 4a (see Table 1, Entry 8). Changing the reaction these reactions are particularly moisture-sensitive, as the
temperature had a large effect on the results of this reaction addition of a very small amount of water under the optimal
(see Table 1, Entries 2, 9, and 10). Screening different sol- conditions could ruin the reaction. Controlling the ratio of
vents indicated that DCM was the best choice. Tetra- 2a/3 in the presence of the iridacycle (1 mol-%) was crucial
hydrofuran (THF) led to moderate results, and toluene led to obtain high regioselectivity. Increasing the amount of 2a
to both a poor yield and regioselectivity (see Table 1, En- led to an improvement in the regioselectivity (see Table 1,
tries 2, 11, and 12). The nature of the base also had a dra- Entry 18), and significant improvements in both the yield
matic influence on the efficiency as well as the regio- and and regioselectivity were achieved when a fourfold amount
enantioselectivity of this reaction. Therefore, a number of of 2a was utilized (see Table 1, Entry 19).
bases such as KOAc, LiCl, and CsF[7a] were examined. Sur-
prisingly, using KOAc produced 4a in good yield, with good
regioselectivity, and the highest ee value, and no allylic ester
was obtained (see Table 1, Entry 2).[21] Using either LiCl or
CsF gave 4a in poor yield with a low regioselectivity (see
Table 1, Entries 13 and 14). In contrast, conducting this re-
action in the absence of the additive resulted in somewhat
low yields and enantioselectivities (see Table 1, Entry 15 vs.
2). When a 1:1 ratio of 2a/3 was employed, poor regioselec-
tivity resulted (see Table 1, Entry 16 vs. 2). To our delight,
but unexpected, an improved regioselectivity and a good
Table 1. Optimization studies for the Ir-catalyzed asymmetric alkyl-
ation of KSAc (3).[a]
Figure 1. Chiral ligands L1–L6 that were evaluated for the allylic
substitution.
To test the feasibility of using different thiol precursors
with this synthetic strategy, NaSCOPh,[11c] potassium O,O-
Entry
L
Solvent Addi- 2a/3
T
%
4/5[d]
%
diethyl phosphorothioate [KSPO(OEt)2],[22] and potassium
ethyl xanthogenate (KSCSOEt)[23,11c] were examined under
the optimum conditions. Unfortunately, both NaSCOPh
and KSPO(OEt)2 led to poor conversion (Ͻ10%), and
KSCSOEt afforded the linear allylation product as well.
We then examined the allylation reaction of various
methyl allyl carbonates 2a–2j with KSAc (3) to explore the
generality and scope of this reaction. (E)-Cinnamyl methyl
carbonate (2a) and carbonates 2b–2h, which had various
substitution patterns on the aromatic moiety such as elec-
tron-donating (4-CH3, 4-CH3O, and 3-CH3O) or electron-
withdrawing groups (4-Cl, 4-Br, 3-Cl, and 3-CF3), afforded
the corresponding branched products 4a–4h in moderate to
good yields (57–83%) with high regioselectivities (82:18–
90:10) and excellent levels of enantioselectivity (93–95%ee,
see Table 2, Entries 1–8).
tive[b]
[°C] 4[c]
ee[e]
1
2
3
4
5
6
L1
L2
L3
L4
L5
L6
L2
L2
L2
L2
L2
L2
L2
L2
L2
L2
L2
L2
L2
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
THF
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
LiCl
2:1
2:1
2:1
2:1
2:1
2:1
2:1
2:1
2:1
2:1
2:1
2:1
2:1
2:1
2:1
1:1
2:1
3:1
4:1
25
25
25
54
65
43
79:21
77:23
62:38
78
91
88
n.d.
n.d.
n.d.
87
–
n.d.
92
77
n.d.
86
90
86
90
92
94
93
25 trace 69:31
25 trace 59:41
25 trace 16:84
7[f]
8[g]
9
25
48
60:40
25 trace 31:69
0
40
25
trace n.d.
60
46
10
11
12
13
14
15
16
17[h]
18[h]
19[h]
75:25
63:37
PhMe
DCM
DCM
DCM
DCM
DCM
DCM
DCM
25 Ͻ20 30:70
25
25
25
25
25
25
25
22
40
52
20
60
42
72
76:24
79:21
72:28
55:45
80:20
85:15
89:11
CsF
–
KOAc
KOAc
KOAc
KOAc
Remarkably, the scope of this reaction was successfully
extended to include a carbonate that contained an aliphatic
substituent as in 2i. In this case, the branched and linear
products 4i and 5i, respectively, were obtained as an insepa-
rable mixture (4i/5i, 75:25) in 76% yield with a 91%ee, (see
Table 2, Entry 9). Comparably, almost no regioselectivity
(branched/linear, 57:43) resulted for the iridium-catalyzed
[a] Reagents and conditions: [Ir(COD)Cl]2 (2 mol-%), L (4 mol-%),
2a (2.0 equiv.), and 3 (1.0 equiv.) at 25 °C. [b] Additive (3.0 equiv.)
for Entries 1–18. [c] Isolated yields. [d] Determined by 1H NMR
analysis of the crude reaction mixture. [e] Determined by chiral
HPLC analysis. [f] (E)-Cinnamyl ethyl carbonate (2m) was used in
this case. [g] (E)-Cinnamyl acetate (2n) was employed in this case.
[h] [Ir(COD)Cl]2 (1 mol-%), L2 (2 mol-%), and a range of ratios for
2a/3 were employed at 25 °C.
allylic substitution of the same substrate
2
using
Eur. J. Org. Chem. 2013, 2708–2714
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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N. Gao, X. Zhao
FULL PAPER
Table 2. Generality of the enantioselective Ir-catalyzed allylations 92%ee, and its absolute configuration was deduced to be
of KSAc (3).[a]
(S,R) on the basis of (S)-7 and (S,S,S)-10 (see compound 9
in Exp. Sect.).
Entry R1
% 4[b]
4/5[c]
% ee[d]
1
2
3
4
5
6
7
8
C6H5
4a, 72
4b, 76
4c, 71
4d, 83
4e, 69
89:11
87:13
86:14
86:14
90:10
82:18
90:10
85:15
75:25
62:38
66:34
n.d.
93
94
93
95
93
95
93
94
91
3-MeOC6H4
4-MeOC6H4
4-MeC6H4
4-ClC6H4
3-ClC6H4
4-BrC6H4
3-CF3C6H4
phenylethyl
2-thienyl
4f, 78
4g, 57
4h, 73
4i, 76[e]
4j, 56
4k, trace
4l, trace
9
10
11
12
94
cyclohexyl
(Z)-Et
n.d.[f]
n.d.
Scheme 1. ISOC reaction between (S)-7a and 8 starting from 4a.
[a] Reagents and conditions: [Ir(COD)Cl]2 (1 mol-%), L2 (2 mol-
%), 2a (4.0 equiv.), 3 (1.0 equiv.), and KOAc (3.0 equiv.) at 25 °C.
[b] Isolated yields. [c] Determined by 1H NMR analysis of the
crude reaction mixture. [d] Determined by chiral HPLC analysis.
[e] The yield of 4i and 5i. [f] n.d.: not determined.
Conclusions
We have developed a direct and atom-economic method
for the preparation of chiral branched allylic thioesters
through an enantioselective iridium-catalyzed allylic substi-
tution of KSAc. To the best of our knowledge, this is the
first protocol to synthesize chiral branched allylic thioesters
4 from KSAc in good yields and with high levels of enantio-
selectivity.
NaSSiiPr3.[7d] (E)-Methyl 3-(thiophen-2-yl)allyl carbonate
(2j) worked well, but with low regioselectivity (see Table 2,
Entry 10). With the bulkier (E)-3-cyclohexylallyl methyl
carbonate (2k), a trace amount of both 4k and 5k was ob-
tained (see Table 2, Entry 11). (Z)-Methyl pent-2-enyl carb-
onate (2l) gave a disappointing result in terms of yield (see
Table 2, Entry 12).
Experimental Section
General Methods: All air-sensitive manipulations were conducted
under argon by using standard Schlenk techniques. All glassware
was dried with an oven or flame immediately prior to use. All sol-
vents were purified and dried according to standard methods prior
to use, unless otherwise stated. All reagents were purchased from
The absolute configuration of enantioenriched 4a was
identified as (S). Compound 4a was converted into 1-phen-
ylpropane-1-thiol (6a) by a tandem reduction and deprotec-
tion process. The configuration was then determined by
comparing the data for 6a with the optical rotations of the
known (S)- or (R)-1-phenylpropane-1-thiol.[24,14]
Enantioenriched allylic thiol 7 exhibits a great synthetic
potential for organic synthesis. The preparation of tetra-
hydrothieno[3,4-c]isoxazoline derivatives from 7 is illus-
1
commercial sources and used without further purification. The H
NMR spectroscopic data were recorded at 400 MHz, and the
chemical shifts are reported relative to the tetramethylsilane signal
(δ = 0 ppm) or the residual proton in the deuterated solvent. The
13C NMR spectroscopic data were recorded at 100 MHz, and the
trated in Scheme 1.[25] According to a known synthetic se- chemical shifts were reported relative to the resonance of the sol-
vent (CDCl3, 77.0 ppm). Data for 1H NMR are recorded as chemi-
cal shift (δ, ppm), {multiplicity [s (singlet), d (doublet), t (triplet),
q (quartet), m (multiplet), unresolved, or br. s (broad singlet), cou-
pling constant(s) in Hz, and integration}. Data for the 13C NMR
are reported in terms of chemical shift (δ, ppm). HPLC analyses
were carried out with a SHIMADZU LC-15 system. IR analyses
were obtained with Nicolet FTIR spectrometers. Flash column
chromatography was performed on silica gel. The products were
visualized on TLC plates by using UV light or by staining with
KMnO4 solution or iodine vapor.
quence,[26] in one-pot (S)-1-phenylprop-2-ene-1-thiol (7a),
which was generated by the hydrolysis of enantioenriched
4a with sodium methoxide (NaOMe) in methanol at 0 °C,
was treated with (E)-1-bromo-4-(2-nitrovinyl)benzene (8) in
[27]
the presence of NEt3 followed by silylation with chloro-
trimethylsilane to produce nitronate isomers (i.e., 9 and its
diastereomer).[26e] The diastereomer of 9 subsequently
underwent an intramolecular silyl nitronate-olefin cycload-
dition (ISOC) reaction to give (S,S,S)-tetrahydrothieno[3,4-
c]isoxazoline 10 in 39% yield with a ratio of (S,S,S)-10/
(S,R,R)-10[26e] of 91:9 and with 90%ee. Its absolute config-
uration was established as (S,S,S) by using NOESY experi-
ments (see Supporting Information). The enantiopure
General Procedure for the Synthesis of Allylic Sulfane 4: [Ir-
(COD)Cl]2 (0.0020 mmol, 1.0 mol-%) and phosphoramidite ligand
L3
[O,OЈ-(S)-(1,1Ј-dinaphthyl-2,2Ј-diyl)-N,NЈ-di-(S,S)-(phenyl-
ethylphosphoramidite), 0.0040 mmol, 2.0 mol-%) were dissolved in
Michael addition product 9 was obtained in 6% yield with a mixture of THF (0.5 mL) and propylamine (0.3 mL) in a dry
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Enantio- and Regioselective Iridium-Catalyzed Allylations of KSAc
Schlenk tube filled with argon. The reaction mixture was heated at
50 °C for 30 min, and then the volatile solvents were removed under
vacuum to give a yellow solid. Allylic carbonate 2 (0.80 mmol,
400 mol-%), potassium ethanethioate (3, 0.20 mmol), potassium
acetate (0.60 mmol, 300 mol-%), and dichloromethane (2.0 mL)
were added. The reaction mixture was stirred at room temperature
overnight. Then, the crude reaction mixture was filtered through
Celite, and the solvent was removed under reduced pressure. The
crude residue was purified by flash column chromatography to give
the desired products. The ratio of the regioisomers (branched/lin-
ear) was determined by 1H NMR analysis of the crude reaction
mixture.
C12H14O2S [M]+ 222.0715; found 222.0720. IR (KBr): νmax = 3852,
3745, 3739, 3648, 3003, 2955, 2924, 2850, 2359, 2338, 1692, 1610,
1511, 1459, 1353, 1302, 1250, 1177, 1132, 1107, 1034, 956, 923,
831, 750, 629 cm–1.
˜
(S)-S-[1-p-Tolylallyl] Ethanethioate (4d): The 1H NMR spectro-
scopic data showed a branched/linear ratio of 86:14. The mixture
was purified by flash column chromatography (petroleum ether/
DCM, 20:1) to give 4d (35.9 mg, 83%) as a colorless liquid. The
enantiomeric excess value was determined by HPLC analysis
[Daicel CHIRALCEL OJ-H (0.46 cmϫ25 cm); hexane/2-prop-
anol, 90:10; 0.7 mL/min; λ = 214 nm; 25 °C]: tR = 14.85 min
(major), tR = 18.49 min (minor); 95%ee. [α]2D0 = –240.3 (c = 0.8,
CHCl3). 1H NMR (400 MHz, CDCl3): δ = 7.21–7.19 (m, 2 H),
7.14–7.12 (m, 2 H), 6.08 (ddd, J = 16.8, 10.0, 6.8 Hz, 1 H), 5.26
(d, J = 6.0 Hz, 1 H), 5.23 (d, J = 16.8 Hz, 1 H), 5.17 (d, J =
10.0 Hz, 1 H), 2.32 (s, 3 H), 2.31 (s, 3 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 194.0, 137.2, 137.0, 136.7, 129.3, 127.9,
116.6, 50.0, 30.4, 21.0 ppm. MS (EI): m/z (%) = 131 (100), 206
[M]+. HRMS (EI): calcd. for C12H14OS [M]+ 206.0765; found
(S)-S-(1-Phenylallyl) Ethanethioate (4a): The 1H NMR spectro-
scopic data showed a branched/linear ratio of 89:11. The mixture
was purified by flash column chromatography (petroleum ether/
DCM, 15:1) to give 4a (32.8 mg, 72%) as a colorless liquid. The
enantiomeric excess value was determined by HPLC analysis
[Daicel CHIRALCEL OD-H (0.46 cmϫ25 cm); hexane/2-prop-
anol, 98:2; 0.7 mL/min; λ = 214 nm; 25 °C]: tR = 5.13 min (major),
tR = 6.17 min (minor); 93%ee. [α]2D0 = –285.6 (c = 0.4, CHCl3). 1H
NMR (400 MHz, CDCl3): δ = 7.33–7.29 (m, 4 H), 7.27–7.23 (m, 1
H), 6.08 (ddd, J = 16.8, 10.4, 7.2 Hz, 1 H), 5.29 (d, J = 7.2 Hz, 1
H), 5.23 (d, J = 16.8 Hz, 1 H), 5.18 (d, J = 10.0 Hz, 1 H), 2.31 (s,
3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 193.8, 139.7, 136.8,
128.6, 128.0, 127.4, 116.8, 50.3, 30.4 ppm. MS (EI): m/z (%) = 117
(100), 192 [M]+. HRMS (EI): calcd. for C11H12OS [M]+ 192.0609;
206.0770. IR (KBr): ν
= 3853, 3747, 3649, 3022, 2922, 2855,
˜
max
2360, 2339, 1693, 1511, 1384, 1353, 1263, 1130, 1105, 986, 954,
922, 818, 750, 628 cm–1.
(S)-S-[1-(4-Chlorophenyl)allyl] Ethanethioate (4e): The 1H NMR
spectroscopic data showed a branched/linear ratio of 90:10. The
mixture was purified by flash column chromatography (petroleum
ether/DCM, 15:1) to give 4e (33.4 mg, 69%) as a colorless liquid.
The enantiomeric excess value was determined by HPLC analysis
[Daicel CHIRALCEL OJ-H (0.46 cmϫ25 cm); hexane/2-prop-
anol, 98:2; 1.0 mL/min; λ = 214 nm; 25 °C]: tR = 10.39 min (major),
tR = 11.56 min (minor); 93%ee. [α]2D0 = –215.8 (c = 0.8, CHCl3).
1H NMR (400 MHz, CDCl3): δ = 7.30–7.23 (m, 4 H), 6.04 (ddd, J
= 16.8, 10.4, 6.8 Hz, 1 H), 5.26–5.19 (m, 3 H), 2.33 (s, 3 H) ppm.
13C NMR (100 MHz, CDCl3): δ = 193.7, 138.4, 136.3, 133.3, 129.4,
128.7, 117.3, 49.6, 30.4 ppm. MS (EI): m/z (%) = 115 (100), 226
[M]+. HRMS (EI): calcd. for C11H21ClOS [M]+ 226.0219; found
found 192.0608. IR (KBr): ν
= 3734, 3674, 3649, 3629, 3029,
˜
max
2923, 2852, 2360, 2339, 1694, 1492, 1453, 1384, 1130, 1103, 957,
923, 838, 748, 697, 628 cm–1.
1
(S)-S-[1-(3-Methoxyphenyl)allyl] Ethanethioate (4b): The H NMR
spectroscopic data showed a branched/linear ratio of 87:13. The
mixture was purified by flash column chromatography (petroleum
ether/DCM, 10:1) to give 4b (32.9 mg, 76%) as a colorless liquid.
The enantiomeric excess value was determined by HPLC analysis
[Daicel CHIRALCEL OD-H (0.46 cmϫ25 cm); hexane/2-prop-
anol, 98:2; 1.0 mL/min; λ = 214 nm; 25 °C]: tR = 7.06 min (major),
tR = 9.37 min (minor); 94%ee. [α]2D0 = –222.6 (c = 0.7, CHCl3). 1H
NMR (400 MHz, CDCl3): δ = 7.26–7.22 (m, 1 H), 6.90 (d, J =
7.6 Hz, 1 H), 6.85 (m, 1 H), 6.80 (dd, J = 8.0, 2.0 Hz, 1 H), 6.08
(ddd, J = 17.2, 10.4, 6.8 Hz, 1 H), 5.27 (d, J = 16.8 Hz, 1 H), 5.26
(d, J = 7.2 Hz, 1 H), 5.18 (d, J = 10.4 Hz, 1 H), 3.8 (s, 3 H), 2.33
(s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 193.9, 159.7,
141.2, 136.7, 129.6, 120.3, 116.8, 113.7, 112.9, 55.2, 50.2, 30.4 ppm.
MS (EI): m/z (%) = 147 (100), 222 [M]+. HRMS (EI): calcd. for
226.0221. IR (KBr): ν
= 3853, 3819, 3747, 3673, 3649, 2922,
˜
max
2851, 2360, 2340, 1694, 1558, 1540, 1490, 1457, 1404, 1353, 1275,
1132, 1091, 1014, 951, 925, 823, 752, 628 cm–1.
(S)-S-[1-(3-Chlorophenyl)allyl] Ethanethioate (4f): The 1H NMR
spectroscopic data showed a branched/linear ratio of 82:18. The
mixture was purified by flash column chromatography (petroleum
ether/DCM, 15:1) to give 4f (34.9 mg, 78%) as a colorless liquid.
The enantiomeric excess value was determined by a chiral HPLC
analysis [Daicel CHIRALCEL OD-H (0.46 cmϫ25 cm); hexane/2-
propanol, 98:2; 0.7 mL/min; λ = 214 nm; 25 °C]: tR = 6.88 min
(major), tR = 7.46 min (minor); 95%ee. [α]2D0 = –230.2 (c = 0.7,
CHCl3). 1H NMR (400 MHz, CDCl3): δ = 7.30 (m, 1 H), 7.26–
7.19 (m, 4 H), 6.04 (ddd, J = 16.8, 10.4, 6.8 Hz, 1 H), 5.26–5.20
(m, 3 H), 2.34 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ =
193.6, 141.9, 136.0, 134.4, 129.8, 128.2, 127.6, 126.3, 117.4, 49.7,
30.4 ppm. MS (EI): m/z (%) = 115 (100), 226 [M]+. HRMS (EI):
calcd. for C11H11ClOS [M]+ 226.0219; found 226.0216. IR (KBr):
C12H14O2S [M]+ 222.0715; found 222.0719. IR (KBr): νmax = 3853,
˜
3601, 3747, 3673, 3649, 3083, 3003, 2957, 2921, 2835, 2360, 2339,
1694, 1599, 1489, 1457, 1435, 1263, 1132, 1105, 1047, 951, 924,
764, 695, 630 cm–1.
1
(S)-S-[1-(4-Methoxyphenyl)allyl] Ethanethioate (4c): The H NMR
spectroscopic data showed a branched/linear ratio of 86:14. The
mixture was purified by flash column chromatography (petroleum
ether/DCM, 15:1) to give 4c (37.1 mg, 71%) as a colorless liquid.
The enantiomeric excess value was determined by HPLC analysis
[Daicel CHIRALCEL OD-H (0.46 cmϫ25 cm); hexane/2-propan-
ol, 98:2; 1.0 mL/min; λ = 214 nm; 25 °C]: tR = 6.48 min (major),
tR = 7.20 min (minor); 93%ee. [α]2D0 = –212.9 (c = 0.9, CHCl3). 1H
NMR (400 MHz, CDCl3): δ = 7.25–7.21 (m, 2 H), 6.86–6.83 (m, 2
H), 6.06 (ddd, J = 17.2, 10.4, 6.8 Hz, 1 H), 5.25 (d, J = 7.2 Hz, 1
H), 5.22 (d, J = 17.2 Hz, 1 H), 5.16 (d, J = 10.4 Hz, 1 H), 3.77 (s,
3 H), 2.31 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 194.0,
158.8, 137.0, 131.6, 129.1, 116.4, 114.0, 55.2, 49.7, 30.3 ppm. MS
(EI): m/z (%) = 147 (100), 222 [M]+. HRMS (EI): calcd. for
ν
max = 3853, 3747, 3086, 2923, 2852, 2360, 2339, 1695, 1594, 1572,
˜
1475, 1428, 1384, 1353, 1131, 1103, 956, 926, 756, 715, 689,
628 cm–1.
(S)-S-[1-(4-Bromophenyl)allyl] Ethanethioate (4g): The 1H NMR
spectroscopic data showed a branched/linear ratio of 90:10. The
mixture was purified by flash column chromatography (petroleum
ether/DCM, 15:1) to give 4g (30.8 mg, 57%) as a colorless liquid.
The enantiomeric excess value was determined by HPLC analysis
[Daicel CHIRALCEL OJ-H (0.46 cmϫ25 cm); hexane/2-prop-
anol, 98:2; 1.0 mL/min; λ = 214 nm; 25 °C]: tR = 10.75 min (major),
Eur. J. Org. Chem. 2013, 2708–2714
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2711

N. Gao, X. Zhao
C9H10OS2 [M]+ 198.0173; found 198.0774. IR (KBr): ν
= 3853,
FULL PAPER
tR = 11.98 min (minor); 93%ee. [α]2D0 = –218.0 (c = 0.8, CHCl3).
˜
max
1H NMR (400 MHz, CDCl3): δ = 7.45–7.43 (m, 2 H), 7.20–7.18 3415, 2360, 2340, 1653, 1559, 1457, 1385, 668 cm–1.
(m, 2 H), 6.04 (ddd, J = 16.8, 10.4, 7.2 Hz, 1 H), 5.24–5.19 (m, 3
(E)-S-[3-(Thiophen-2-yl)allyl] Ethanethioate (5j): 1H NMR
(400 MHz, CDCl3): δ = 7.13 (d, J = 5.2 Hz, 2 H), 6.95–6.92 (m, 2
H), 6.69 (d, J = 15.6 Hz, 1 H), 5.99 (dt, J = 15.2, 7.6 Hz, 1 H),
3.66 (d, J = 7.6 Hz, 1 H), 2.35 (s, 3 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 195.0, 141.5, 127.3, 126.2, 125.7, 124.7, 123.9, 31.5,
30.4 ppm. MS (EI): m/z (%) = 123 (100), 198 [M]+. HRMS (EI):
calcd. for C9H10OS2 [M]+ 198.0173; found 198.0176. IR (KBr):
H), 2.32 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 193.6,
138.9, 136.2, 131.7, 129.8, 121.4, 117.3 49.6, 30.4 ppm. MS (EI):
m/z (%) = 116 (100), 270 [M]+. HRMS (EI): calcd. for C11H11BrOS
[M]+ 269.9714; found 269.9713. IR (KBr): νmax = 3747, 3673, 3648,
˜
3628, 3366, 3085, 2921, 2851, 2359, 1693, 1485, 1401, 1352, 1131,
1103, 1072, 1010, 951, 925, 818, 754, 627 cm–1.
ν
= 3551, 3476, 3414, 1685, 1636, 1617, 1558, 1540, 1133, 954,
˜
(S)-S-{1-[3-(Trifluoromethyl)phenyl]allyl} Ethanethioate (4h): The
1H NMR spectroscopic data showed a branched/linear ratio of
85:15. The mixture was purified by flash column chromatography
(petroleum ether/DCM, 15:1) to give 4a (37.5 mg, 73%) as a color-
less liquid. The enantiomeric excess value was determined by
HPLC analysis [Daicel CHIRALCEL OJ-H (0.46 cmϫ25 cm);
max
697, 626 cm–1.
(S)-1-Phenylpropane-1-thiol (6a):[14] To a solution of the (S)-S-1-
phenylallyl ethanethioate (4a, 48.0 mg, 0.25 mmol) in THF (2 mL)
and iPrOH (2 mL) were added o-nitrobenzenesulfonylhydrazide
(142.8 mg, 0.65 mmol) and triethylamine (169.9 mg, 1.6 mmol)
slowly at 30 °C. The reaction was carried out overnight and moni-
tored by TLC.[7d] The crude reaction mixture was filtered through
Celite, and the solvent was removed under reduced pressure. The
mixture was purified by flash column chromatography (petroleum
ether/ethyl acetate (EA), 100:1) to give 6a (29.6 mg, 61%) as a col-
orless, volatile liquid. [α]2D0 = –60.2 (c = 0.7, CHCl3). 1H NMR
(400 MHz, CDCl3): δ = 7.32–7.30 (m, 4 H), 7.25–7.22 (m, 1 H),
3.91–3.86 (m, 1 H), 1.98–1.90 (m, 3 H), 0.93 (t, J = 7.6 Hz, 3
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 144.6, 128.6, 127.0,
126.9, 45.9, 32.9, 12.5 ppm.
hexane/2-propanol, 98:2; 1.0 mL/min; λ = 214 nm; 25 °C]: tR
=
6.44 min (minor), tR = 8.84 min (major); 94%ee. [α]2D0 = –210.0 (c
= 0.7, CHCl3). 1H NMR (400 MHz, CDCl3): δ = 7.57 (m, 1 H),
7.53–7.51 (m, 2 H), 7.46–7.43 (m, 1 H), 6.07 (ddd, J = 17.2, 10.0,
6.8 Hz, 1 H), 5.33 (d, J = 6.8 Hz, 1 H), 5.24 (d, J = 10.8 Hz, 1 H),
5.23 (d, J = 16.0 Hz, 1 H), 2.34 (s, 3 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 193.5, 141.0, 135.9, 131.6 (q, J = 1.5 Hz), 131.0 (q, J
= 32.8 Hz), 129.1, 123.9 (q, J = 270.7 Hz), 124.8 (q, J = 3.7 Hz),
124.3 (q, J = 3.7 Hz), 117.7, 49.8, 30.4 ppm. 19F NMR (376 MHz,
CDCl3): δ = –181.0 ppm. MS (EI): m/z (%) = 185 (100), 260 [M]+.
HRMS (EI): calcd. for C12H11F3OS [M]+ 260.0483; found
General Procedure for the Synthesis of 9 and 10: Sodium methoxide
(NaOMe, 141 mg, 2.6 mmol) and anhydrous methanol (5 mL) were
added to a dry Schlenk tube equipped with a stir bar. The reaction
mixture was cooled to 0 °C, and (S)-S-1-phenylallyl ethanethioate
(4a, 194.9 mg, 1.01 mmol) was slowly added. After 1 h of stirring
at 0 °C, TLC (petroleum ether (PE)/EA, 15:1) indicated that allyl-
thioester 4a had been consumed. The reaction was quenched with
dilute hydrochloric acid solution (5%). The water layer was ex-
tracted with Et2O (3ϫ). The combined organic layers were washed
with a saturated aqueous solution of NaCl and then dried with
MgSO4.[28] The solvent was removed under reduced pressure to give
(S)-1-phenylprop-2-ene-1-thiol (7a) as colorless volatile liquid and
as the major product. Without further purification, 7a was directly
used in next step. (E)-1-Bromo-4-(2-nitrovinyl)benzene (8,
203.3 mg, 0.90 mmol) was dissolved in anhydrous THF (5 mL). A
solution of (S)-1-phenylprop-2-ene-1-thiol (7a), THF (3 mL), and
NEt3 (0.25 mL) was added dropwise to the reaction mixture under
argon. After the addition was complete, the reaction mixture was
stirred at room temperature and monitored by TLC (PE/EA, 15:1).
Trimethylchlorosilane (TMSCl, 0.25 mL) was added when the (E)-
1-bromo-4-(2-nitrovinyl)benzene (8) was completely consumed.
The mixture was then stirred at room temperature overnight under
argon. The reaction was quenched with dilute hydrochloric acid
solution (5%), and the organic and aqueous layers were separated.
The aqueous layer was extracted with Et2O (3ϫ). The combined
organic layers were washed with an aqueous solution of NaCl,
dried with MgSO4, filtered, and concentrated in vacuo.[26e] The res-
idue was purified by flash column chromatography (PE/EA, 35:1)
to give the desired products 10 along with byproduct 9.
260.0480. IR (KBr): ν
= 3852, 3746, 3672, 3648, 2924, 2853,
˜
max
2359, 2338, 1696, 1157, 1447, 1331, 1262, 1165, 1127, 1073, 927,
805, 749, 701, 629 cm–1.
(R)-S-(5-Phenylpent-1-en-3-yl) Ethanethioate (4i): The 1H NMR
spectroscopic data showed a branched/linear ratio of 75:25. The
mixture was purified by flash column chromatography (petroleum
ether/DCM, 15:1) to give 4i and linear product 5i (33.7 mg, 76%)
as a colorless liquid. The enantiomeric excess value was determined
by HPLC analysis [Daicel CHIRALCEL OJ-H (0.46 cmϫ25 cm);
hexane/2-propanol, 98:2; 1.0 mL/min; λ = 214 nm; 25 °C]: tR
=
13.25 min (major), tR = 17.37 min (minor); 91%ee. [α]2D0 = –110.9
1
(c = 0.6, CHCl3). H NMR (400 MHz, CDCl3): δ = 7.29–7.24 (m,
2 H), 7.20–7.14 (m, 3 H), 5.80 (ddd, J = 17.6, 10.0, 8.0 Hz, 1 H),
5.26 (d, J = 17.2 Hz, 1 H), 5.12 (d, J = 10.4 Hz, 1 H), 4.08 (dt, J
= 11.2, 7.2 Hz, 1 H), 2.70–2.64 (m, 2 H), 2.32 (s, 3 H), 2.00–1.94
(m, 2 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 194.6, 141.2,
137.4, 128.4, 128.3, 125.9, 116.4, 46.1, 35.7, 33.2, 30.6 ppm. MS
(EI): m/z (%) = 91 (100), 220 [M]+. HRMS (EI): calcd. for
C13H16OS [M]+ 220.0922; found 220.0924. IR (KBr): ν
3747, 3649, 3629, 3084, 3062, 3026, 2923, 2853, 2360, 2339, 1692,
1558, 1540, 1495, 1454, 1353, 1263, 1133, 1108, 954, 921, 748, 699,
629 cm–1.
= 3853,
˜
max
(S)-S-[1-(Thiophen-2-yl)allyl] Ethanethioate (4j): The 1H NMR
spectroscopy showed a branched/linear ratio of 62:38. The mixture
was purified by flash column chromatography (petroleum ether/
DCM, 15:1) to give 4j (21.8 mg, 56%) as a colorless oil. The enan-
tiomeric excess value was determined by HPLC analysis [Daicel
CHIRALCEL OJ-H (0.46 cmϫ25 cm); hexane/2-propanol, 98:2;
1.0 mL/min; λ = 214 nm; 25 °C]: tR = 14.11 min (major), tR
=
(R)-1-(4-Bromophenyl)-2-nitroethyl[(S)-1-phenylallyl]sulfane
(9):
18.33 min (minor); 94%ee. [α]2D0 = –72.9 (c = 1.0, CHCl3). 1H NMR
(400 MHz, CDCl3): δ = 7.22 (d, J = 5.2 Hz, 1 H), 6.99–6.97 (m, 1
H), 6.95–6.92 (m, 1 H), 6.09 (ddd, J = 16.8, 10.0, 8.0 Hz, 1 H),
The mixture was purified by flash column chromatography (petro-
leum ether/EA, 35:1) to give 9 (21.1 mg, 6%) as a thick, yellow
substance. The enantiomeric excess value was determined by HPLC
5.54 (d, J = 8.0 Hz, 1 H), 5.36 (d, J = 16.8 Hz, 1 H), 5.22 (d, J = analysis [Daicel CHIRALPAK AD-H (0.46 cmϫ25 cm); hexane/
10.4 Hz, 1 H), 2.35 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ 2-propanol, 98:2; 1.0 mL/min; λ = 214 nm; 25 °C]: tR = 7.06 min
= 193.6, 143.0, 136.3, 126.8, 125.7, 125.1, 117.2, 45.5, 30.3 ppm.
(major), tR = 9.37 min (minor); 92%ee. [α]2D0 = –186.7 (c = 1.1,
CHCl3). (S)-1-Phenylprop-2-ene-1-thiol (7a) was treated with (E)-
MS (EI): m/z (%) = 123 (100), 198 [M]+. HRMS (EI): calcd. for
2712
www.eurjoc.org
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 2708–2714

Enantio- and Regioselective Iridium-Catalyzed Allylations of KSAc
[2]
For recent leading references, see: a) F. Lopez, T. Ohmura, J. F.
Hartwig, J. Am. Chem. Soc. 2003, 125, 3426–3427; b) C. T.
Shu, J. F. Hartwig, Angew. Chem. Int. Ed. 2004, 43, 4794–4797;
c) C. Fischer, C. Defieber, T. Suzuki, E. M. Carreira, J. Am.
Chem. Soc. 2004, 126, 1628–1629; d) I. Lyothier, C. Defieber,
E. M. Carreira, Angew. Chem. Int. Ed. 2006, 45, 6204–6027; e)
S. Ueno, J. F. Hartwig, Angew. Chem. Int. Ed. 2008, 47, 1928–
1931; f) L. M. Stanley, C. Bai, M. Ueda, J. F. Hartwig, J. Am.
Chem. Soc. 2010, 132, 8918–8920; g) M. Gärtner, S. Mader, K.
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2075.
For representative references, see: a) L. L. Hegedus, R. W.
McCabe, in Catalyst Poisoning, Marcel Dekker, New York,
1984; b) A. T. Hutton in Comprehensive Coordination Chemis-
try (Ed.: G. Wilkinson), Pergamon, New York, 1987, vol. 5,
pp. 1131–1155.
1-bromo-4-(2-nitrovinyl)benzene (8) to give 9 and its diastereomer,
and the diastereomer underwent an ISOC reaction[26e] to produce
(S,S,S)-10. The configuration of the diastereomer of 9 was deduced
to be (S,S). Consequently, the absolute configuration of 9 was de-
duced to be (S,R). 1H NMR (400 MHz, CDCl3): δ = 7.48–7.46 (m,
2 H), 7.37–7.25 (m, 5 H), 7.14–7.11 (m, 2 H), 6.00 (ddd, J = 16.8,
10.0, 8.0 Hz, 1 H), 5.20 (d, J = 10.0 Hz, 1 H), 5.18 (d, J = 16.8 Hz,
1 H), 4.69–4.59 (m, 2 H), 4.35 (d, J = 8.0 Hz, 1 H), 4.32–4.28 (m,
1 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 138.8, 136.9, 136.3,
132.2, 129.4, 128.9, 128.0, 127.9, 122.4, 117.4, 53.2, 45.7 ppm. MS
(EI): m/z (%) = 117 (100), 377 [M]+. HRMS (ESI): calcd. for
C17H16BrNO2SNa [M + Na]+ 399.9983; found 399.9977. IR (KBr):
[3]
ν
max
= 3853, 3648, 3446, 1653, 1558, 1541, 1384, 1010, 698,
˜
517 cm–1.
(S,S,S)-Tetrahydrothieno[3,4-c]isoxazoline (10): The 1H NMR spec-
troscopic data showed a cis/trans ratio of 91:9. The mixture was
purified by a flash column chromatography (petroleum ether/EA,
35:1) to give 10 (125.3 mg, 39%) as a colorless, thick oil. The enan-
tiomeric excess of the product was determined by a chiral HPLC
analysis [Daicel CHIRALPAK AD-H (0.46 cmϫ25 cm); hexane/
2-propanol, 90:10; 1.0 mL/min; λ = 214 nm; 25 °C]: tR = 15.57 min
(major), tR = 17.22 min (minor); 90%ee. The NOESY spectra of
compound 10 demonstrated that the three hydrogen atoms on the
tetrahydrothiophene ring extended in the same direction. As
known, the configuration of enantioenriched thiol 7a is (S). As a
result, the absolute configuration of compound 10 was identified
as (S,S,S). [α]2D0 = –81.2 (c = 1.1, CHCl3). 1H NMR (400 MHz,
CDCl3): δ = 7.54–7.50 (m, 2 H), 7.44–7.31 (m, 7 H), 5.35 (s, 1 H),
4.45–4.41 (m, 2 H), 4.34–4.26 (m, 1 H), 4.22–4.18 (m, 1 H) ppm.
13C NMR (100 MHz, CDCl3): δ = 166.0, 138.0, 137.1, 132.0, 129.1,
129.0, 128.5, 127.6, 122.0, 62.0, 53.3, 44.8 ppm. MS (EI): m/z (%)
= 361 (100), 361 [M]+. HRMS (EI): calcd. for C17H14BrNOS
[4]
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M. Ueda, J. F. Hartwig, Org. Lett. 2010, 12, 92–94.
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M. Roggen, E. M. Carreira, Angew. Chem. Int. Ed. 2012, 51,
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[6]
[7]
[8]
[9]
For an excellent review, see: J. Clayden, P. MacLellan, Beilstein
J. Org. Chem. 2011, 7, 582–595.
For studies of transition-metal-catalyzed allylic substitutions of
thiols and sulfinates to give racemic sulfides, see: a) B. M.
Trost, T. S. Scanlan, Tetrahedron Lett. 1986, 27, 4141–4144; b)
T. Kondo, Y. Morisaki, S. Y. Uenoyama, K. Wada, T. A. Mit-
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M. Frank, H. J. Gais, Tetrahedron: Asymmetry 1998, 9, 3353–
3357; h) H. J. Gais, N. Spalthoff, T. Jagusch, M. Frank, G.
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The deprotection of the branched 1-substituted (allylthio)tri-
isopropylsilanes under tetra-n-butylammonium fluoride
(TBAF)/THF, LiAlH4, or NaOH/MeOH gave complex prod-
ucts.
a) S. Divekar, M. Safi, M. Soufiaoui, D. Sinor, Tetrahedron
1999, 55, 4369–4376; b) G. Ilyashenko, A. Whiting, A. Wright,
Adv. Synth. Catal. 2010, 352, 1818–1825; c) X. Duan, B. Maji,
H. Mayr, Org. Biomol. Chem. 2011, 9, 8046–8050.
The branched allylic thioester, S-(1-phenylallyl) ethanethioate
(0.2 mmol), in the presence of the iridacycle made from
[Ir(COD)Cl]2 (2 mol-%) and Feringa ligand L3 (4 mol-%) in
DCM (2 mL) at room temperature overnight formed a mixture
of (S)-1-phenylallyl ethanethioate and (S)-cinnamyl ethane-
thioate in a ratio of 4:1.
For excellent reviews, see: a) D. J. Procter, J. Chem. Soc. Perkin
Trans. 1 2001, 335–354; b) A. Roland, R. Schneider, A. Ra-
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B. Peschiulli, A. Procuranti, C. J. O’Connor, S. J. Connon, Nat.
Chem. 2010, 2, 380–384.
[M]+ 360.2682; found 360.0052. IR (KBr): νmax = 3902, 3853, 3837,
˜
3820, 3675, 3648, 3628, 3566, 3029, 2923, 2851, 1771, 1733, 1683,
1652, 1558, 1487, 1455, 1397, 1301, 1172, 1072, 1009, 878, 847,
828, 746, 697 cm–1.
Supporting Information (see footnote on the first page of this arti-
cle): Copies of the 1H and 13C NMR spectra, HPLC chromato-
grams of products 4a–4i, 6a, 9, and 10, and NOESY experimental
spectra of 10.
Acknowledgments
[10]
[11]
[12]
We gratefully acknowledge Pu Jiang Program of Shanghai (2010–
2013) and the National Natural Science Foundation of China
(NSFC) (grant number 21272175) for the generous financial sup-
port.
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[13]
[14]
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Received: December 5, 2012
Published Online: March 13, 2013
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