Gold Sulfinyl Mesoionic Carbenes: Synthesis, Structure, and Catalytic Activity

Article abstract of DOI:10.1021/acs.orglett.6b01555

Gold mesoionic carbenes having a chiral sulfoxide group attached to the C4 position of the five membered ring have been prepared and tested as catalysts in the cycloisomerization of enynes. These new catalysts are very efficient, with the sulfoxide moiety

Full text of DOI:10.1021/acs.orglett.6b01555

Letter
pubs.acs.org/OrgLett
Gold Sulfinyl Mesoionic Carbenes: Synthesis, Structure, and Catalytic
Activity
María Frutos, Marta G. Avello, Alma Viso, Roberto Fernan
́
dez de la Pradilla,†,§
†
,§
†,§
†,§
,‡,§
,
†,§
∥,⊥
∥,⊥
María C. de la Torre,* Miguel A. Sierra,* Heinz Gornitzka, and Catherine Hemmert
†
́
Instituto de Química Organica General, Consejo Superior de Investigaciones Científicas (CSIC), Juan de la Cierva 3, 28006 Madrid,
Spain
‡
Departmento de Química Organ
́
ica I, Facultad de Química, Universidad Complutense, 28040 Madrid, Spain
en Química Avanzada (ORFEO−CINQA)
CNRS, LCC (Laboratoire de Chimie de Coordination), 205 route de Narbonne, BP 44099, F-31077 Cedex 4 Toulouse, France
de Toulouse, UPS, INPT, F-31077 Cedex 4 Toulouse, France
S Supporting Information
§
Centro de Innovacion
́
∥
⊥Universite
́
*
ABSTRACT: Gold mesoionic carbenes having a chiral sulfoxide
group attached to the C4 position of the five membered ring have
been prepared and tested as catalysts in the cycloisomerization of
enynes. These new catalysts are very efficient, with the sulfoxide
moiety playing a key role in their activity and the N1-substituent in
control of the regioselectivity of these processes.
n 2008, 1,2,3-triazole carbene complexes were unveiled by
another conceivable problem in the achievement of the metal
complexes.
1
I
Albrecht, initiating a lightning race in the preparation of
2
new structural types and their use as catalysts. The synthesis of
this type of heterocycle is performed through the highly
efficient and regioselective Cu(I)-catalyzed Huisgen cyclo-
Sulfur based ligands can be present in hybrid N-heterocyclic
8
carbenes (NHC). Nevertheless, there are few examples of
sulfoxide containing Arduengo type carbenes in the literature
and, to the best of our knowledge, none in which the sulfoxide
3
addition between a terminal alkyne and an azide (CuAAC). A
large number of functional groups with different electronic and
steric properties are compatible providing a high tunability of
the electronic properties of the carbenes. These new features
could be transferred to the coordinating metal center with the
group is directly attached to one of the carbons of the
9
heterocycle. Tato and Car
́
denas reported the synthesis of an
imidazolylidene by alkylating a racemic sulfinyl bromide with
different 1-substituted imidazoles to prepare mono- and
4
10
aim of seeking novel applications. New groups can be
binuclear Pd-complexes. Previously, Huynh et al. had
introduced in the core of the heterocycle through the terminal
alkyne, the azide, or both, which could also be accompanied by
chirality, should the functional group of the alkyne be chiral or
the azide contain a chiral center.
reported a bridged Pd-bis(imidazolylidene) complex containing
a racemic sulfoxide ligand building the sulfoxide moiety by
oxidation of a bis(imidazolesulfide). These Pd-derivatives
were active as catalysts in the C−H activation of arenes and in
the Heck reaction, respectively.
11
Sulfoxides have emerged as a paramount alternative among
Herein we describe the first examples of the synthesis of a
new class of mesoionic triazolylidene ligands containing
enantiopure (S)-sulfoxides, the preparation of the correspond-
ing gold complexes, the determination of their structures, and
their catalytic activity in the cycloisomerization reaction of
enynes.
Alkynyl sulfoxides 1a−c were reacted with azides 2a−e under
the usual conditions (1.20 equiv of organic azide, 1.00 equiv of
alkyne, 0.50 equiv of sodium L-ascorbate and 0.25 equiv of
the scarce chiral functional groups based on elements different
from chiral-carbon groups. In fact, enantiopure ethynyl
5
sulfoxides are, in general, easy to make through the Andersen
method, which involves the reaction between acetylenic
6
Grignard reagents and enantiopure menthyl sulfinate. The
incorporation of an enantiomerically pure sulfoxide moiety in a
1,2,3-triazolylidene carbene could present some uncertainties.
First, the chirality of the sulfoxide center introduced through
the alkyne must be preserved along the synthetic pathway. The
second challenge would arise in the alkylation of the triazole to
yield the corresponding triazolium salts since the compatibility
CuSO ·5H O in DMF) yielding enantiomerically pure triazoles
4
2
3
in good to excellent yields. Moreover, to confirm that the
CuAAC reaction proceeds without racemization of the
sulfoxide, a secondary chiral group was introduced through
of the sulfoxide group with strong alkylating agents is not
7
obvious. Deprotonation of the salt using Ag O followed by
2
transmetalation with a metal source could yield the enantiopure
(S)-sulfoxide carbene complexes. The coordinating nature of
Received: May 30, 2016
the sulfoxide would compete with the emerging carbene in
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b01555
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
−
+
the enantiopure α-phenylethyl azides 2b and 2c. The formation
of only one diastereoisomer (3ab and 3ac) proved the
selectivity of the cycloaddition (Scheme 1). (R)-1-Bromo-4-
The HRMS spectra show a peak at m/z [M − Cl ] , which is
consistent with the gold carbene structures proposed. The
structures of some gold complexes (5aa, 5ab, 5ac, and 5ca)
were unambiguously confirmed by X-ray diffraction analysis
(Figure 1).
Scheme 1. Synthesis of 1,2,3-Triazoles 3
Figure 1. Molecular structures of 5ab and 5ac in the solid state
depicted at a 50% thermal ellipsoid level.
The gold-cations in 5ab and 5ac show typical nearly perfect
linear geometries for gold(I) with C−Au−Cl angles between
1
75° and 177°. All Au−C distances (1.980 to 1.991 Å) and
(
ethynylsulfinyl)benzene 1b was reacted with benzyl azide 2a
to form triazole 3ba in excellent yield. The bulkier (R)-1-
ethynylsulfinyl)-8-methoxynaphthalene derivative 1c reacted
Au−Cl distances (2.272 to 2.282 Å) lie in normal ranges for
NHC−Au−Cl complexes. A gold(I)−gold(I) distance of 3.223
Å in the case of 5ac reflects unsupported strong aurophilic
interactions in the solid state. The two involved C−Au−Cl
units show a crossed arrangement with a C−Au−Au−C torsion
angle of 66.5°.
With the synthesis of structurally diverse enantiopure
mesoionic gold carbene complexes 5 confirmed, their catalytic
activity was next tested. Mesoionic gold carbenes have been
applied as effective catalysts in a limited number of processes
and that prompted us to explore the cycloisomerization of
enynes. Complex 5aa was chosen, as well as the more
sterically hindered at N1 5ab and its diastereoisomer 5ac. Thus,
enyne 6 was reacted with complexes 5aa, 5ab, and 5ac using 3
mol % complex in the presence of 3 mol % NaBArF (Table 1,
entries 1−3). The reaction carried out using complex 5aa
afforded a mixture of 7 and 8 (1:1.4) along with unreacted
material after 24 h (22% conversion) (Table 1, entry 1).
Interestingly, complex 5ab reacted with 6 in only 5 min
producing exclusively cyclopentene 7 (Table 1, entry 2). An
(
with benzyl azide 2a, 4-methoxyphenyl azide 2d, and 1-
naphthyl azide 2e uneventfully rendering triazoles 3ca, 3cd, and
3
compatible with alkyl and aryl azides as well as with differently
substituted sulfoxides.
ce in good yields. Therefore, the synthesis of triazoles 3 is
To our delight, triazoles 3 were methylated (Me OBF )
3
4
yielding the N-3-methyltriazolium salts 4 in essentially
quantitative yields. Finally, the triazolium salts (1.00 equiv)
were reacted with 0.75 equiv of Ag O in the presence of 1.50
equiv of NMe Cl. The complete formation of the intermediate
silver carbene complexes was ensured by H NMR analysis.
Transmetalation with [AuCl(SMe )] gave the corresponding
1
2
15
2
4
1
2
(
S)-sulfinyl gold carbenes 5 that were isolated and fully
characterized (Scheme 2).
Scheme 2. Synthesis of Gold Carbenes 5
Table 1. Optimization of Catalytic Conditions for the
Reaction of Enyne 6
complex load
(mol %)
conversion
(%)
entry complex
product
time
24 h
The structures proposed above were confirmed by NMR
analysis. A remarkable deshielding of the triazole proton signal
1
2
3
4
5
6
7
8
5aa
5ab
5ac
5ab
5ac
9b
3
3
3
1
1
3
3
7/8 (1:1.4)
22
100
100
100
91
c
7
5 min
1 min
60 min
24 h
(
Δδ = 0.66 and 0.86 ppm) upon formation of the triazolium
7
13
salts is observed. This signal disappears as a consequence of
formation of the silver and the subsequent gold carbenes. For
7
7/8 (1:1)
1
3
C NMR spectra, signals corresponding to the CH of
24 h
triazolium salts appear at lower field (δc 130.2−132.3 ppm)
compared with those of the corresponding triazoles (δc 122.7−
9c
24 h
c
24 h
c
1
27.3 ppm). The new C−Au bonds formed appear between δc
a
b
1
57.5−162.3 ppm, which is in agreement with other gold
NaBArF load was used in a 1:1 proportion to complex. Conversion
c
2c,d,14
1
carbenes previously reported.
was calculated measuring H NMR spectra of the crude. No reaction.
B
DOI: 10.1021/acs.orglett.6b01555
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Organic Letters
Letter
analogous result was obtained with complex 5ac (Table 1, entry
Table 2. Gold Carbene 5ab Catalyzed Cycloisomerization of
Enyne 6
3).
Apparently, complex 5aa having a sulfoxide and a benzyl
group attached to N1 is not as efficient as complexes 5ab or 5ac
in either conversion or controlling the reaction regioselectivity.
To determine the origin of this effect, complexes 9b and 9c
lacking the sulfoxide group were prepared from benzylacetylene
and enantiomerically pure azides 2b and 2c, as described above
(Scheme 3).
Scheme 3. Synthesis of Gold Carbenes 9a and 9b
Complexes 9b and 9c were then used as complexes in the
cycloisomerization of 6 (Table 1, entries 6−7). No reaction was
observed after 24 h under identical conditions to those used for
5
ab and 5ac. Clearly, the sulfoxide moiety is required for the
reaction, while the presence of both the sulfoxide and the α-
phenylethyl groups in the gold carbene complex is required to
achieve good conversions and complete regioselectivities.
Lower catalyst loads were tested for 5ab and 5ac (Table 1,
entries 4−5). The use of 1 mol % of 5ab promotes the
complete conversion of 6 to form 7 in 1 h, while 1 mol % of
5
ac produces a partial transformation of the starting material to
a mixture of 7 and 8.
Since the ability of silver catalysts to promote cyclo-
1
6
isomerization reactions is known, enyne 6 was reacted
using the silver carbene obtained from triazolium salt 4ac under
a
b
Isolated products. E/Z, 5:1.
17
conditions already described. No reaction was observed after
2
4 h, recovering unaltered enyne 6 (Table 1, entry 8).
After determining the optimum catalyst, the effect of the
a mere spectator. However, the inability of complexes 9b and
9c to promote the cyclization questions this assertion.
structure of the enyne in the outcome of the reaction was next
addresed. Enynes 6, 13, and 16 having a terminal alkyne and a
monosubstituted or disubstituted alkene nicely cyclized to the
five-membered derivatives in high yields (Table 2, entries 1−3).
It is worth noting that compound 18 lacking the Thorpe−
Ingold effect imposed by the methoxycarbonyl groups in 6, 13,
and 16 formed the five membered derivative 19 together with
diol 20 arising from the opening of the dihydrofuran ring in a
quantitative combined yield (3:1 mixture, Table 2, entry 4).
Meldrum’s acid derivative 21 formed spirane 22 in a
respectable 50% yield (Table 2, entry 5). In contrast,
substitution of the terminal acetylenic hydrogen (compounds
Results above pointed to the involvement of the sulfoxide
oxygen to stabilize gold carbene intermediates I and II probably
by interaction either of the oxygen or the sulfur lone pair with
the carbene carbon or the gold center. This stabilization
should allow the reaction to proceed, thence the inertia of
complexes lacking the sulfoxide moiety. Intermediates I and II
18
Scheme 4. Mechanistic Hypothesis
2
3 and 25) inhibits the reaction.
Despite of the efforts devoted to this cycloisomerization,
issues such as the 5-exo/6-endo selectivity still deserve
1
5c
attention. Remarkably, our results point to a crucial effect
of the sulfoxide moiety in determining the activity of the
complex, while the bulkiness of the N-substituent (contributed
by the azide) is involved in the 5-exo vs 6-endo selectivity. The
lack of reactivity of substituted alkyne derivatives 23 and 25
proves that at least in the first reaction step, formation of gold
carbene complexes I (5-exo cyclization) and II (6-endo
cyclization) should occur through the standard triple-bond
coordination by the gold complex followed by cyclization
(Scheme 4). The role of the sulfoxide at this point seems to be
C
DOI: 10.1021/acs.orglett.6b01555
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
will evolve to the cyclized products through the well-established
pathways (Scheme 4). Formation of intermediate I over II is
related to the bulkiness of the carbon linked to N1 position
(i) Bidal, Y. D.; Lesieur, M.; Melaimi, M.; Nahra, F.; Cordes, D. B.;
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19
(
compare 5aa with 5ab or 5ac in Table 1). Although much
experimental and computational work remains to be done, this
working hypothesis is congruent with the results obtained and
confers to the apparently ancillary moiety (the sulfoxide group)
a key role unprecedented in the literature.
(
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To conclude, the synthesis of new homochiral C-4-sulfinyl
triazole derivatives using the CuAAC is reported. These
functionalized triazoles are transformed uneventfully into gold
mesoionic carbenes, fully characterized spectroscopically and by
X-ray analysis, by standard methods. Their ability as cyclo-
isomerization catalysts has been studied finding that their
catalytic activity is due to the presence of the sulfoxide group
acting in a previously unreported fashion. Moreover, the high
degree of 5-exo-dig selectivity in these processes is attributed to
the bulkiness of the substituent at the N-1-triazole ring.
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Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b01555.
2
2
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Experimental procedures and H and 13C spectra for all
the compounds and experimental data for the catalytic
tests (PDF)
Crystallographic information for compound 5aa (CIF)
Crystallographic information for compound 5ab (CIF)
Crystallographic information for compound 5ac (CIF)
Crystallographic information for compound 5ca (CIF)
1
(
(
Commun. 2001, 2340. (c) Mata, J. A.; Chianese, A. R.; Miecznikowski,
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(12) Occasionally, a minor byproduct was detected by H NMR
1
(
<10%) tentatively assigned as the O-methylated sulfonium salt that
disappeared upon work up.
AUTHOR INFORMATION
Corresponding Authors
■
*
*
(13) In the case of 4ce, the triazolium proton is not significantly
deshielded probably due to the opposite effect of the naphthyl group
at N1.
E-mail: mc.delatorre@csic.es.
E-mail: sierraor@ucm.es.
Notes
(
14) (a) Frutos, M.; de la Torre, M. C.; Sierra, M. A. Inorg. Chem.
015, 54, 11174. (b) Mendoza-Espinosa, D.; Gonzalez-Olvera, R.;
Negron-Silva, G. E.; Angeles-Beltran, D.; Suarez-Castillo, O. R.;
Alvarez-Hernandez, A.; Santillan, R. Organometallics 2015, 34, 4529.
15) (a) Nieto-Oberhuber, C.; Lopez, S.; Echavarren, A. M. J. Am.
Chem. Soc. 2005, 127, 6178. (b) Lopez, S.; Herrero-Gomez, E.; Perez-
Galan, P.; Nieto-Oberhuber, C.; Echavarren, A. M. Angew. Chem., Int.
Ed. 2006, 45, 6029. (c) Marion, N.; Lemiere, G.; Correa, A.; Costabile,
C.; Ramon, R. S.; Moreau, X.; de Fremont, P.; Dahmane, R.; Hours,
2
́
́
́
́
́
The authors declare no competing financial interest.
́
(
́
́
́
́
ACKNOWLEDGMENTS
■
́
Support for this work under Grants CTQ2013-46459-C2-01-P
to M.A.S., CTQ2013-46459-C2-02-P to M.C.T., and
CTQ2014-51912-REDC from the MINECO (Spain) is
gratefully acknowledged. M.F.P. and M.G.A. thank the
MINECO for FPI fellowships. Ms. M. Velado (IQOG-CSIC)
is acknowledged for helping in the preparation of some starting
materials.
̀
́
́
A.; Lesage, D.; Tabet, J.-C.; Goddard, J.-P.; Gandon, V.; Cavallo, L.;
Fensterbank, L.; Malacria, M.; Nolan, S. P. Chem. - Eur. J. 2009, 15,
3243.
(16) (a) Fang, G.; Bi, X. Chem. Soc. Rev. 2015, 44, 8124. (b) Peshkov,
A. A.; Nechaev, A. A.; Pereshivko, O. P.; Goeman, J. L.; Van der
Eycken, J.; Peshkov, V. A.; Van der Eycken, E. V. Eur. J. Org. Chem.
2
(
015, 2015, 4190.
17) Synthesis and characterization details of this silver carbene will
be discussed in future studies.
18) (a) Dorel, R.; Echavarren, A. M. J. Org. Chem. 2015, 80, 7321.
For intermolecular reaction of sulfoxides with Au carbene
intermediates, see: (b) Witham, C. A.; Mauleon, P.; Shapiro, N. D.;
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