Stereoselective synthesis and reaction of gold(I) (Z)-enethiolates

Article abstract of DOI:10.1039/c5cc02000j

Bench-top-storable (Z)-enethiol reagents: gold (Z)-1-decenylthiolates were synthesized stereoselectively in high yields. They are stable upon storage at room temperature without protection from light, and react smoothly with various alkyl halides, α,β-unsaturated ketones, and electron-deficient aryl halides with excellent stereoselectivity.

Full text of DOI:10.1039/c5cc02000j

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Stereoselective synthesis and reaction of gold(I)
(Z)-enethiolates†
Cite this:DOI: 10.1039/c5cc02000j
Kazunori Miyamoto,*ab Masaya Hirobe,c Masanobu Uchiyamaab and
Masahito Ochiaic
Received 9th March 2015,
Accepted 1st April 2015
DOI: 10.1039/c5cc02000j
www.rsc.org/chemcomm
Bench-top-storable (Z)-enethiol reagents: gold (Z)-1-decenylthiolates THF.8 In 2006, we developed a new type of configurationally stable
were synthesized stereoselectively in high yields. They are stable upon (Z)-enethiol equivalent, silver(I) (Z)-b-alkylvinylthiolate 1b, by utiliz-
storage at room temperature without protection from light, and react ing an unusual vinylic SN2 reaction of (E)-b-alkylvinyl-l3-iodane with
smoothly with various alkyl halides, a,b-unsaturated ketones, and thiobenzamide, followed by hydrolysis with silver acetate
electron-deficient aryl halides with excellent stereoselectivity.
(Scheme 2).9,10
Enethiolate 1b is stable upon storage in a refrigerator (4 1C)
The (Z)-vinylthio moiety is an important functional group in for 3 months, but it is light-sensitive, and its reactivity is only
organic synthesis and medicinal chemistry, being present in moderate. For example, (1) 50% degradation of 1b was observed at
many pharmaceutically important compounds (Scheme 1).1,2 room temperature after 5 days without light protection; (2) slow
For example, a vinylthio functionality is present as a side chain isomerization of 1b occurs in solution in the absence of a radical
in clavulanic acid derivatives, which show b-lactamase-inhibitory scavenger; (3) with less reactive substrates, addition of n-Bu4NI or LiI
activity,1a and cephem derivatives, which exhibit broad-spectrum is necessary to increase the nucleophilicity of sulfur and/or to
antibacterial activities.1b In both cases, the (Z)-isomers show activate electrophiles, and this may lead to side-reactions (vide infra).
greater activity than the (E)-isomers.
Herein, we report the first synthesis and characterization of gold(I)
The parent enethiols (RCHQCHSH) 1 are fairly tautomerically enethiolates. These are the most robust and practically convenient
stable,3 but in general, they are thermally unstable and readily enethiolates currently available, and enable straightforward
undergo dimerization to give dithiohemiacetals or divinylsulfides installation of a (Z)-enethiol unit in functional molecules. Further-
even at room temperature.4 Therefore, regio- and stereoselective more, PPh3- and N-heterocyclic carbene (NHC)-coordinated gold(I)
synthesis of functionalized vinylthio moieties remains a challenging enethiolates function as much better nucleophiles than the
issue in organic synthesis, and only limited success has been corresponding silver(I) enethiolates. Gold(I) enethiolates are
achieved by using silyl vinyl sulfides as precursors.5,6 In contrast,
some heavier-metal enethiolates are less prone to dimerization. For
example, cesium (Z)-enethiolate generated in situ at low temperature
reacts with alkyl halides to afford (Z)-vinyl sulfides with high
stereoselectivity (up to 98 : 2).7 However, the use of a harder counter
cation such as the lithium ion results in configurational lability:
enethiolate 1a (R = n-Bu, M = Li) readily isomerizes even at ꢀ40 1C in
Scheme 1 Biologically active b-lactam antibiotics containing a (Z)-vinylthio
group.
a Graduate School of Pharmaceutical Sciences, The University of Tokyo,
7-3-12 Bunkyo-ku, Hongo, Tokyo, 113-0033, Japan.
E-mail: kmiya@mol.f.u.-tokyo.ac.jp
b Advanced Elements Chemistry Research Team, RIKEN Center for Sustainable
Resource Science, and Elements Chemistry Laboratory, RIKEN, 2-1 Hirosawa,
Wako-shi, Saitama 351-0198, Japan
c Graduate School of Pharmaceutical Sciences, University of Tokushima,
1-78 Shomachi, Tokushima 770-8505, Japan
† Electronic supplementary information (ESI) available: Experimental details,
figures, and spectral data. CCDC 1026924 (10a). For ESI and crystallographic
Scheme 2 Synthesis and reaction of (Z)-silver enethiolate 1b.
data in CIF or other electronic format see DOI: 10.1039/c5cc02000j
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thermally stable, photostable, and show high reactivity towards
alkyl halides, cyclic enones, and electron-deficient aryl halides
under mild reaction conditions.
The key to success in the preparation of gold(I) enethiolates 7
was the use of AuCl–tetrahydrothiophene complex 6.11 Exposure of
S-vinylthiobenzimidonium salt 5a (1 equiv.) to gold(I) complex 6 in
the presence of sodium carbonate (2 equiv.) in THF at room
temperature under argon resulted in selective hydrolysis to afford
gold(I) enethiolate 7a stereoselectively in 90% yield, along with
N,N-dimethylbenzamide (94%) (Scheme 3). Gold(I) enethiolate 7a is
soluble in various solvents including dichloromethane, chloroform,
benzene, and THF, but exhibits poor solubility in more polar
solvents such as methanol, ethyl acetate, DMF, DMSO, and water.
Gold(I) thiolates intrinsically adopt an oligomeric structure through
intermolecular SꢁꢁꢁAu interactions.12 ESI-MS spectra indicated that
7a is prone to adopt dimer and trimer forms (Fig. S1, ESI†), which
might account for the reduced solubility in polar solvents.
It is noteworthy that 7a showed a much higher photostability
than silver enethiolate 1b, and was stable upon bench-top storage
for at least 20 days without protection from light (Fig. 1). The bond
of the Au(I) ion with the thiolate anion is much stronger than that
of the Ag(I) ion (the bond dissociation energy of Au–S is 100 kcal
molꢀ1 and that of Ag–S is 51.9 kcal molꢀ1),13 which is consistent
with the higher stability of gold(I) thiolate 7a.
The strong Au–S interaction enhances the thermal stability
and photostability of the enethiolate ion, but might cause a decrease
in the reactivity. We envisioned that addition of electron-donating
ligands such as triphenylphosphine (PPh3) and NHCs, which form
stable 1 : 1 complexes simply upon mixing with 7a at ambient
temperature, would increase the nucleophilicity via trans influence
and stereoelectronic effects (Scheme 4).14
Complexes 8a–10a showed higher solubility than parent 7a
in common organic solvents, such as ethyl acetate and metha-
nol. The increased solubility can be attributed to inhibition of
Scheme 4 Synthesis of gold(I) (Z)-enethiolate–ligand complexes.
aggregation via intermolecular AuꢁꢁꢁS interaction. The 1 : 1 complex
between 7a and PPh3 is predominant in a CDCl3 solution, as
indicated by the Job plot of the 13C NMR data (Fig. S2, ESI†). The
binding constant was measured to be Ka = 1.8 ꢂ 104 Mꢀ1 by means
of 13C NMR spectroscopic titration at room temperature (Fig. S3,
ESI†). Complexation clearly increases the configurational stability of
these compounds, and no isomerization of (Z)-enethiolate 8a was
observed even after 20 days in CDCl3 at room temperature in the
presence of TEMPO (0.1 equiv.).15 The formation of NHC adduct 10a
was unambiguously confirmed by X-ray diffraction analysis (Fig. 2).16
The structure contains one carbene ligand in the gold(I) center at the
side opposite to the sulfur atom of 10a, with a near-linear S1–Au1–
C11 triad (178.261). The thiolate ligand in 10a is tightly bound to the
gold(I) center with an Au1–S1 distance of 2.2883 Å, which is slightly
longer than the predicted sum of covalent radii (2.27 Å). The CNHC
–
Au bond length of 2.018 Å in 10a is slightly longer than that observed
in the corresponding chloride complex (1.993 Å), which probably
reflects a stronger trans influence of the thiolate anion.17 The Au–S
and Au–C bond lengths are comparable to those observed in the
thioglucoside–Au(I)–NHC complex.18 It is noteworthy that no inter-
molecular goldꢁꢁꢁgold interaction (o3.2 Å) was observed in the
crystal packing structure of 10a.19
We have reported that silver(I) enethiolate shows moderate
reactivity towards various alkyl halides. For example, silver(I)
enethiolate 1b underwent nucleophilic substitution with methyl
iodide (10 equiv.) in dichloromethane at room temperature to
Scheme 3 Synthesis of gold (Z)-enethiolate 7.
Fig. 2 ORTEP drawing of gold enethiolate-6–Mes complex 10a with
thermal ellipsoids at 50% probability. Selected bond lengths (Å) and angles
(deg): Au1–S1 2.2883(12), Au1–C11 2.018(2), S1–C1 1.774(5), C1–C2 1.354(7),
S1–Au1–C11 178.26(11), Au1–S1–C1 102.21(15), S1–C1–C2 123.5(4).
Fig. 1 Stability differences between silver(I) enethiolate 1b (open circle)
and gold(I) enethiolate 7a (filled circle).
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Table 1 Alkylation of gold (Z)-enethiolates
Entry Thiolate RI
Time (h) Yielda (%) 11 Z : Eb
1
2
3
7a
8a
9a
10a
9a
10a
8a
8a
MeI
MeI
MeI
MeI
MeI
MeI
EtI
7
3
0.5
0.5
0.5
0.5
0 11a
—
77 11a
79 11a
79 11a
95 11a
93 11a
73 11b
82 11b
33 11c
63 11c
93 11c
97 11d
77 11e
89 11f
96 : 4
99 : 1
Scheme 5 Competitive alkylation of metal thiolates between isopropyl
iodide and dichloromethane.
4
499 : 1
98 : 2
99 : 1
78 : 22
94 : 6
91 : 9
92 : 8
91 : 9
96 : 4
95 : 5
94 : 6
5c
6c
7
24
8c
9
EtI
24
48
48
48
aryl vinyl sulfide 15 in high yield with excellent stereoselectivity,
while 9a was less reactive.22
8a
i-PrI
i-PrI
i-PrI
10
11c
12
13
14
10a
10a
8a
8a
8a
In the SNAr reaction of 2,4-dinitrohalobenzene with ammonium
thiophenoxide (PhSꢀBu4N+), the reactivity of halobenzenes has
been reported to decrease monotonically in the order F 4 Cl 4
Br 4 I.23 Interestingly, the present SNAr reaction with gold(I)
enethiolate showed completely the opposite reactivity in terms of
the halogen leaving ability. The difference is due, at least in part, to
the coordination of the Au(I) ion to the halogen atom, increasing
CH2QCHCH2Br 12
PhCH2Br
PhCOCH2Br
4
4
a
b
c
Isolated yields. Determined by 1H NMR analyses. 0.1 equiv. of
TEMPO was added.
the positive charge on the ipso carbon atom of 14 (Scheme 7).24
A
give a regioisomeric mixture of methyl vinyl sulfide 11a (R = Me,
Z : E = 92: 8) in 65% yield.10 In contrast, gold(I) enethiolate 7a was
inert under similar conditions (Table 1, entry 1). However,
phosphine and NHC-treated 8a–10a reacted smoothly with alkyl
iodide to afford (Z)-vinyl sulfide 11 in high yields (entries 2–11).
The Z-selectivity was generally very high (491%), and the use of
TEMPO as an additive improved the yield and/or selectivity
(entries 5, 6, 8, and 11).20
similar mechanism has been proposed in diaryl ether synthesis by
the reaction of alkali metal phenoxide with haloarenes.25 These
observations suggest that the Au(I) ion can transform the intrinsic
reactivity of ‘‘(naked) thiolate anion’’ with electrophiles.
We have reported that silver(I) enethiolate 1b smoothly
undergoes Michael addition with 2-cyclohexen-1-one 15b, and
the reaction is accelerated by the presence of lithium iodide.10
In situ-generated gold(I) enethiolate 8a could also be used in
Michael addition with cyclic enones 15a–c in the presence of
lithium iodide. In these reactions, the lithium cation functions
as a Lewis acid; the use of n-Bu4NI or NaI instead of lithium
iodide did not afford 16b at all (Scheme 8).
Complexes 9a and 10a with stronger trans-influencing NHC
ligands showed higher reactivity toward nucleophiles than
phosphine complex 8a. For example, branched isopropyl iodide
underwent nucleophilic substitution smoothly with 10a in high
yield (entry 10), while 8a was less reactive under similar conditions
(entry 9). Allyl/benzyl bromide and 20-bromoacetophenone could be
employed in these reactions (entries 12–14), and the yields and
stereo-/regioselectivities of (Z)-vinyl sulfides 11d–f were very high.
It should be noted that gold(I) enethiolate 10a serves as a
highly selective nucleophile for alkyl iodide. In contrast, ammonium
(Z)-vinylthiolate 12 generated in situ from silver(I) enethiolate 1a
undergoes the SN2 reaction with isopropyl iodide to form the
corresponding sulfide 11c in low yield, accompanied by the for-
mation of dithioacetal 13 (22%) from solvent dichloromethane
(Scheme 5).10 However, gold(I) enethiolate 10a selectively reacted
with isopropyl iodide to afford sulfide 11c in high yield (93%), and
the formation of dithioacetal 13 was negligibly small. The superior
reactivity of gold(I) enethiolate with isopropyl iodide is probably due
to the more favorable Au(I)ꢁꢁꢁI interaction, which increases the
leaving group ability of the iodine atom in isopropyl iodide.21
Similar gold(I)–halogen interaction-assisted enhancement of
the reactivity of gold(I) enethiolate 10a was observed in arylation
with 2,4-dinitrohalobenzenes (Scheme 6). Reaction of equimolar
2,4-dinitrohalobenzenes 14a–c and enethiolate 10a at room
temperature resulted in aromatic nucleophilic substitution
(SNAr) at the halogen ipso position, affording the corresponding
In conclusion, we have developed an efficient method for the
synthesis of a bench-top-stable (Z)-enethiol equivalent, i.e.,
gold(I) (Z)-enethiolates, which serve as efficient nucleophiles
Scheme 6 SNAr reaction of 2,4-dinitrohalobenzenes with gold(I) enethiolates.
Scheme 7
A possible transition structure for the SNAr reaction of
enethiolate 10a.
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whereas without TEMPO, about 10% E-isomer was detected.
Scheme 8 Michael addition of enethiolate 8a generated in situ toward
cycloalkenone.
16 Crystal data for 10a: C32H47AuN2S, colorless prisms with dimen-
3
%
sions of 0.20 ꢂ 0.20 ꢂ 0.10 mm , monoclinic, P1 (no. 2), a =
for the SN2 reaction, the SNAr reaction, and Michael addition,
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9.6005(4), b = 11.3245(5), c = 15.2126(7) Å, a = 74.934(2), b =
82.830(2),
g = 77.842(2)1 V = Z = 2, Dcalcd =
1556.9(2) Å3,
1.469 g cmꢀ3. Data were collected on a Rigaku RAXIS-RAPID
Imaging Plate diffractometer with MoKa radiation (l = 0.71075 Å)
at T = 93 K, 2ymax = 54.91, 24 548 reflections were measured, of which
7077 were unique (Rint = 0.0321), m = 48.296 cmꢀ1. The structure was
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Fourier techniques,26b R = 0.027, Rw = 0.1063. Hydrogen atoms were
included but not refined. CCDC 1026924.
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