Dihalo(imidazolium)sulfuranes: A Versatile Platform for the Synthesis of New Electrophilic Group-Transfer Reagents

Article abstract of DOI:10.1021/jacs.5b05287

The syntheses of imidazolium thiocyanates and imidazolium thioalkynes from dihalo(imidazolium) sulfuranes are reported and their reactivities as CN⁺ and R-CC⁺ synthons evaluated, respectively. The easy and scalable preparation of these electrophilic reagents, their operationally simple handling, broad substrate scope, and functional group tolerance clearly illustrate the potential of these species to become a reference for the direct electrophilic cyanation and alkynylation of organic substrates.

Full text of DOI:10.1021/jacs.5b05287

Communication
pubs.acs.org/JACS
Dihalo(imidazolium)sulfuranes: A Versatile Platform for the Synthesis
of New Electrophilic Group-Transfer Reagents
Garazi Talavera, Javier Pena, and Manuel Alcarazo*
̃
Max-Planck-Institut fur Kohlenforschung, Kaiser-Wilhelm-Platz 1, 45470-Mulheim an der Ruhr, Germany
̈
̈
S
* Supporting Information
Scheme 1. Isolobal Relationship between I(III) Species and
Imidazolium-Substituted Sulfuranes; Synthesis of 2-
Thiocyanoimidazolium Salts
ABSTRACT: The syntheses of imidazolium thiocyanates
and imidazolium thioalkynes from dihalo(imidazolium)
sulfuranes are reported and their reactivities as CN+ and R-
CC+ synthons evaluated, respectively. The easy and
scalable preparation of these electrophilic reagents, their
operationally simple handling, broad substrate scope, and
functional group tolerance clearly illustrate the potential of
these species to become a reference for the direct
electrophilic cyanation and alkynylation of organic
substrates.
a
he unique ability of hypervalent iodine compounds to act as
Telectrophilic group-transfer reagents has been extensively
exploited during the last several years in a variety of synthetically
useful transformations.1 These include, among others, trifluor-
omethylation,2 alkynylation,3 arylation, amination,4 halogena-
tion, and cyanation5 of a wide variety of electron-rich substrates
under mild conditions. Considering this tremendous synthetic
utility, it is surprising that other structurally related scaffolds, yet
not based in iodine, have not been evaluated for similar purposes.
In this regard, we envisaged that imidazolium sulfuranes A, which
are isolobal to I(III) species B and also depict the key three-
center four-electron bond motive, might be considered
alternative platforms for the development of new electrophilic
group-transfer reagents (Scheme 1a). Herein, we report the
successful implementation of this working hypothesis to the
specific design of new sulfur-based direct cyanation and
alkynylation reagents. The synthetic potential as CN+ and R-
CC+ equivalents of the newly prepared species is also preliminary
assessed.
a
Reagents and conditions (yields): (a) Br2, CH2Cl2, 0 °C → RT; 3
(97%); 5 (95%); (b) SO2Cl2, CH2Cl2, RT; 4 (74%); (c) TMSCN,
CH2Cl2, RT; 6 (96%); 7 (94%); 8 (89%); (d) AgSbF6, CH3CN, RT; 9
(95%).
S1−Br2 distribution is nearly linear (177.5(2)°), and the three
center four electron bond is characterized by two identical S−Br
bond distances (2.505(3) Å) that are clearly elongated as
compared with those in sulphenyl bromides (2.169(2) Å for
Ph3CSBr).10 Formal substitution of one of the bromides by a less
polarizable cyano group causes an elongation of the S1−Br1
distance in 8. However, it is interesting to note that the measured
Br1−S1 interatomic distance (3.087(3) Å) is 15% shorter than
the sum of the van der Waals radii Br−S (3.650 Å). This speaks
for a weak interaction between these two atoms, which can be
described as the donation of electron density from the bromide
to the low lying σ*(S1−C4) orbital. Not surprisingly, the
noncoordinating nature of the hexafluoroantimonate anion in 9
cancels this interaction, and as result, the S1−C4 bond slightly
shortens (1.702(2) Å) when compared to 8 (1.734(2) Å). In
addition, the C1−S1−C4 angle slightly opens from 95.98(8)° in
8 to 98.61(9)° in 9.
As an extension of the pioneering research of Arduengo,6
Kuhn7 and Roesky8 in the area of sulfurane chemistry, we
submitted thioureas 1 and 2 to already described halogenation
conditions and obtained the corresponding hypervalent sulfur
compounds 3−5 as bright yellow to orange solids in high yields
and analytic purity (Scheme 1).9 Subsequent addition of one
equivalent of Me3SiCN caused the immediate disappearance of
the color and formation of the desired imidazolium thiocyanates
6−8. Compounds 6−8 were isolated as air stable pale yellow
solids in excellent yields and can be stored at room temperature
for months without evident decomposition. This synthetic route
toward 6−8 could be scaled to multigram quantities.
Once prepared, the ability of these species to transfer the CN
group to organic nucleophiles was evaluated. We started our
survey by studying the reaction of 8 with simple commercially
available amines and found that the employment of DIPEA as
The solid state structures of compounds 5, 8, and 9 (prepared
from 8 after anion exchange with AgSbF6) are depicted in Figure
1. As expected from a VSEPR analysis, 5 adopts the T-shape
geometry that is also characteristic for I(III) species. The Br1−
Received: May 21, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/jacs.5b05287
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
Chart 1. Substrate Scope of the Electrophilic Cyanation Using
2-Thiocyanoimidazolium Salts 6−9
Figure 1. Molecular structures of compounds 5 (up, left), 8 (up, right),
and 9 (down). Anisotropic displacement parameter shown at 50%
probability level and hydrogen atoms omitted for clarity. Selected bond
lengths [Å] and angles [deg] in 5, C1−S1, 1.736(2); S1−Br1, 2.505(3);
S1−Br2, 2.505(3); C1−S1−Br2, 88.78(1); in 8, C1−S1, 1.744(2); S1−
Br1, 3.087(3); S1−C4, 1.734(2); C1−S1−C4, 95.98(8); and in 9, C1−
S1, 1.750(2); S1−F3, 2.830(2); S1−C4, 1.702(2); C1−S1−C4,
98.61(9).11
base in dichloromethane efficiently promoted the N-cyanation to
afford the desired cyanamides 10−13 in good isolated yields and
short reaction times (Chart 1).12 The presence of alcohol
substituents, as in the case of S-diphenylprolinol, does not seem
to be detrimental for the process (13). The same protocol was
also applicable to the cyanation of other substrates such as
aromatic thiols, enolates, enamines, and activated methylenes
providing the corresponding aromatic thiocyanates 14−16, β-
amido or keto nitriles 17−22, and β-cyano sulphones 23 in good
to excellent yields.13,14 Note that for the preparation of 19 and
20, compound 6 was preferred to 8 as cyanating reagent since
thiourea byproduct 1 is easier to separate than 2 from the title
products.
The direct cyanation of C−H bonds in aromatic compounds
has a tremendous interest since (hetero)aromatic nitriles are
really valuable intermediates not only in synthetic and medicinal
chemistry but also in material science.15 Therefore, we focused
our efforts on these more challenging compounds. At the outset,
we took N-methylindole as model substrate. As shown in Chart
1, using the procedure already described (Method A), N-
methylindole was regioselectively cyanated at the C-3 position
(24), albeit with moderate conversion. Assuming that additional
activation of the cyanating reagent could be beneficial when less
nucleophilic substrates were employed, we pursued the same
transformation in the presence of catalytic amounts of Lewis
acids. In these assays the employment of 9 (with hexafluor-
oantimoniate counteranion) as cyanating reagent is mandatory
since the presence of halide anions cancels any catalyst effect.
After an extensive survey, the use of catalytic amounts of BF3·
OEt3 (20 mol %) was determined to be optimal to promote the
cyanation of N-methylindole in terms of isolated yield and
a
b
c
Method A was applied. Method B was used. Method A was applied,
d
but 6 was used as cyanating reagent. The corresponding pyrrolidine
enamine was used as starting material (see the SI). Method B was
e
applied, but the reaction was heated at 110 °C in a microwave oven.
f
g
Method A was applied, but NaH was used as base. Method A was
applied, but CH3CN was used as solvent. All yields are of isolated
products.11
reaction time, which was up to eight-fold reduced (Chart 1,
compound 24, Method B). Having found these new reaction
conditions, the scope of the transformation was further explored.
Gratifyingly, the range of additional substrates that could be also
converted into the desired nitriles could be substantially
expanded, including substituted pyrroles, electron rich benzene
B
DOI: 10.1021/jacs.5b05287
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
derivatives, and polycyclic aromatics (Chart 1, compounds 24−
33).16
To preliminarly elucidate some mechanistic aspects of this
reaction, we carried out the cyanation of N-methylindole in the
presence of typical radical inhibitors such as TEMPO or BHT
(50 mol % each), finding no drop in the yield of the cyanated
product. Moreover, the functionalization of N-methylindole is
completely selective at the C-3 position, and no oxidative
coupling products were detected. Combining these results
suggests an electrophilic substitution mechanism rather than a
radical pathway for this process.17
Our cyanation protocol distinguishes itself by operational
simplicity, safeness, and a broad reactivity profile if compared
with alternative electrophilic cyanating reagents: cyanogen
bromide has a comparable substrate scope; however, its toxicity
and low vapor pressure at room temperature warns off its use.
Cyanating reagents based on hypervalent iodine reagents show
strong exothermic decompositions on heating, and therefore,
they must be handled with appropriate knowledge and safety
measures.11 In contrast, analysis of 8 by differential scanning
calorimetry (DSC) up to 200 °C did not detect any sharp
exothermic decomposition signal (see the Supporting Informa-
tion).
Figure 2. Molecular structures of compound 35 in the solid state.
Anisotropic displacement parameter shown at 50% probability level and
hydrogen atoms omitted for clarity. Selected bond lengths [Å] and
angles [deg]: C1−S1, 1.758(8); S1−F3, 3.073(8); S1−C4, 1.684(9);
C1−S1−C4, 98.2(4).11
aromatic thiols smoothly proceeded in excellent yields (Chart 2,
36−38). Activated amides and ketoesters also afforded the
Chart 2. Substrate Scope of the Electrophilic Alkynylation
a
Using 2-Imidazolium Thioalkyne 35
In an attempt to further evaluate the utility of the imidazolium
sulfurane platform A for the design of additional electrophilic
group-transfer reagents and considering the analogue electronic
structure between cyanides and alkynes decorated with electron
withdrawing substituents, we speculated that imidazolium
thioalkynes such as 34 might also be suitable reagents for the
electrophilic alkynylation of organic substrates.18 Hence, we first
set up to prepare salt 34 by reaction of 5 with lithiated ethyl
propiolate; however, only complex reaction mixtures were
obtained. Conversely, addition of the softer silver propiolate to
solutions of 5 afforded the desired alkynylated imidazolium 34 as
dibromoargentate salt.19 This primary product slowly decom-
poses in the presence of light. Hence, 34 was directly elaborated
through anion exchange to 35, which is a slightly orange powder
insensitive to light or air (Scheme 2).
a
Scheme 2. Synthesis of 2-Imidazolium Thioalkynes
a
All yields are of isolated products.
desired alkynylated products (Chart 2, 39 and 40); however,
electron rich benzene derivatives or polycyclic aromatic
compounds did not react with 35 even in the presence of
catalytic BF3·OEt3 or stoichiometric amounts of Brønsted acids.
In summary, this work illustrates the potential of imidazolium
sulfuranes to become reference platforms for the development of
new reagents able to promote the umpolung of synthetically
useful organic groups. In this regard they might be interesting
alternatives to hypervalent I(III) reagents. Ongoing studies in
our laboratory are aimed to demonstrate the generality of the
concept, and to further evaluate the synthetic utility of the new
reagents prepared.
a
Reagents and conditions (yields): (a) AgCC−COOEt, CH2Cl2, RT;
and then (b) AgSbF6, CH2Cl2, RT; 35 (93%, two steps).
Figure 2 shows the X-ray structure of 35. It features very
similar attributes to those of 9; a S1−C4 bond length of 1.684(9)
Å and a C1−S1−C4 angle of (98.2(4)°). Of particular relevance
are the short contacts that 35 depicts between the O1 of a
molecule and the S1 and C4 atoms from an adjacent one (O1−
S1, 2.871 Å; O1−C4, 2.955 Å). This intermolecular self-
organization, which bridges the electrophilic and nucleophilic
moieties of neighboring cations, indirectly supports the
mechanistic picture already proposed (see the Supporting
Information).
ASSOCIATED CONTENT
■
S
* Supporting Information
With 35 completely characterized, its potential as ethynylation
reagent was preliminarily examined. In the presence of DIPEA,
the alkynylation of aliphatic, electron rich, and electron poor
Experimental procedures including the characterization data for
all new compounds, additional crystallographic information, and
NMR spectra. The Supporting Information is available free of
C
DOI: 10.1021/jacs.5b05287
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
(b) Akula, R.; Xiong, Y.; Ibrahim, H. RSC Adv. 2013, 3, 10731−10735.
(c) Kahne, D.; Collum, D. B. Tetrahedron Lett. 1981, 22, 5011−5014.
(15) Sundermeier, M.; Zapf, A.; Beller, M. Eur. J. Inorg. Chem. 2003,
3513−3526.
charge on the ACS Publications website at DOI: 10.1021/
jacs.5b05287.
AUTHOR INFORMATION
Corresponding Author
*alcarazo@kofo.mpg.de
■
(16) For the direct cyanation of (hetero)aromatic substrates see
(selected examples): (a) Okamoto, K.; Watanabe, M.; Murai, M.;
Hatano, R.; Ohe, K. Chem. Commun. 2012, 48, 3127−3129. (b) Yang,
Y.; Zhang, Y.; Wang, J. Org. Lett. 2011, 13, 5608−5611. (c) Buttke, K.;
Reiher, T.; Niclas, H. J. Synth. Commun. 1992, 22, 2237−2243. For
metal catalyzed/mediated processes see: (d) Li, J.; Ackermann, L.
Angew. Chem., Int. Ed. 2015, 54, 3635−3638. (e) Anbarasan, P.;
Schareina, T.; Beller, M. Chem. Soc. Rev. 2011, 40, 5049−5067.
(f) Yeung, P. Y.; So, C. M.; Lau, C. P.; Kwong, F. Y. Org. Lett. 2011, 13,
648−651. (g) Anbarasan, P.; Neumann, H.; Beller, M. Angew. Chem., Int.
Ed. 2011, 50, 519−522. (h) Anbarasan, P.; Neumann, H.; Beller, M.
Chem.Eur. J. 2010, 16, 4725−4728. (i) Torborg, C.; Beller, M. Adv.
Synth. Catal. 2009, 351, 3027−3043.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Generous financial support from the Fonds der Chemischen
Industrie (Dozentenstipendium to M.A.) and the Deutsche
Forschungsgemeinschaft (AL 1348/4-1) is gratefully acknowl-
edged. We also thank Prof. A. Furstner for constant support of
̈
our research programs, Prof. K. R. Porschke for DSC
̈
(17) (a) Shu, Z.; Ji, W.; Wang, X.; Zhou, Y.; Zhang, Y.; Wang, J. Angew.
Chem., Int. Ed. 2014, 53, 2186−2189. (b) Dohi, T.; Moromoto, K.;
Takenaga, N.; Goto, A.; Maruyama, A.; Kiyono, Y.; Tohma, H.; Kita, Y. J.
Org. Chem. 2007, 72, 109−116. (c) Dohi, T.; Morimoto, K.; Maruyama,
A.; Kita, Y. Org. Lett. 2006, 8, 2007−2010.
measurements, and our X-ray crystallography department for
assistance. G.T. thanks the regional government of the Basque
Country (Spain) for support.
REFERENCES
(1) Selected reviews: (a) Brand, J. P.; Fernan
■
(18) For selected metal-free electrophilic alkynylations see reference
́
dez-Gonzal
́
ez, D.; Nicolai,
3a and (a) Fernan
Adv. Synth. Catal. 2013, 355, 1631−1639. (b) Fernan
́
dez-Gonzal
́
ez, D.; Brand, J. P.; Mondier
̀
e, R.; Waser, J.
S.; Waser, J. Chem. Commun. 2011, 47, 102−115. (b) Merritt, E.;
Olofsson, B. Angew. Chem., Int. Ed. 2009, 48, 9052−9070. (c) Zhdankin,
V. V.; Stang, P. J. Chem. Rev. 2008, 108, 5299−5358. (d) Deprez, N. R.;
Sanford, M. S. Inorg. Chem. 2007, 46, 1924−1935.
́
dez-Gonzal
́
ez, D.;
Brand, J. P.; Waser, J. Chem.Eur. J. 2010, 16, 9457−9461. (c) Bachi,
M. D.; Bar-Ner, N.; Stang, P. J.; Williamson, B. L. J. Org. Chem. 1993, 58,
7923−7924. (d) Bachi, M. D.; Bar-Ner, N.; Critell, C. M.; Stang, P. J.;
Williamson, B. L. J. Org. Chem. 1991, 56, 3912−3915. (e) Ochiai, M.;
Kunishima, M.; Nagao, Y.; Fuji, K.; Fujita, E. J. Chem. Soc., Chem.
Commun. 1987, 1708−1709. (f) Stang, P. J.; Kitamura, T. J. Am. Chem.
Soc. 1987, 109, 7561−7563. (g) Ochiai, M.; Kunishima, M.; Nagao, Y.;
Fuji, K.; Shiro, M.; Fujita, E. J. Am. Chem. Soc. 1986, 108, 8281−8283.
(19) For the preparation of the necessary silver propiolate see:
(2) Charpentier, J.; Fruh, N.; Togni, A. Chem. Rev. 2015, 115, 650−
̈
682.
(3) (a) Frei, R.; Wodrich, M. D.; Hari, D. P.; Borin, P. A.; Chauvier, C.;
Waser, J. J. Am. Chem. Soc. 2014, 136, 16563−16573. (b) Frei, R.; Waser,
J. J. Am. Chem. Soc. 2013, 135, 9620−9623.
(4) Souto, J. A.; Martínez, C.; Velilla, I.; Muniz, K. Angew. Chem., Int.
̃
Ed. 2013, 52, 1324−1328.
́
(a) Viterisi, A.; Orsini, A.; Weibel, J. M.; Pale, P. Tetrahedron Lett. 2006,
47, 2779−2781. (b) Yerino, L. V.; Osborn, M. E.; Mariano, P. S.
Tetrahedron 1982, 38, 1579−1591.
(5) (a) Wang, Y. F.; Qiu, J.; Kong, D.; Gao, Y.; Lu, F.; Karmaker, P. G.;
Chen, F. X. Org. Biomol. Chem. 2015, 13, 365−368. (b) Frei, R.;
Courant, T.; Wodrich, M. W.; Waser, J. Chem.Eur. J. 2015, 21, 2662.
(6) Arduengo, A. J.; Burgess, E. M. J. Am. Chem. Soc. 1977, 99, 2376−
2378.
(7) Kuhn, N.; Bohnen, H.; Fahl, J.; Blaser, D.; Boese, R. Chem. Ber.
̈
1996, 129, 1579−1586.
(8) Roesky, H. W.; Nehete, U. N.; Singh, S.; Schmidt, H.;
Shermolovich, Y. G. Main Group Chem. 2005, 1, 11−21.
(9) For a previous synthesis of 1 and 2 see: Kuhn, N.; Kratz, T. Synthesis
1993, 561−562. For a large scale preparation see the Supporting
Information.
(10) (a) Goto, K.; Shimada, K.; Furukawa, S.; Miyasaka, S.; Takahashi,
Y.; Kawashima, T. Chem. Lett. 2006, 35, 862−863. (b) Minkwitz, R.;
Nass, U.; Preut, H. Z. Anorg. Allg. Chem. 1986, 538, 143−150.
(11) CCDC 1401911−1401915 contain the supplementary crystallo-
graphic data for 5, 8, 9, 30, and 35, respectively. These data can be
obtained free of charge from the Cambridge Chrystalographic Data
Centre via www.ccdc.cam.ac.uk/data_request/cif.
(12) For other N-cyanation methods see: (a) Zhu, C.; Xia, J. B.; Chen,
C. Org. Lett. 2014, 16, 247−249. (b) Kamijo, S.; Jin, T.; Yamamoto, Y.
Angew. Chem., Int. Ed. 2002, 41, 1780−1782. (c) Kaupp, G.; Schmeyers,
J.; Boy, J. Chem.Eur. J. 1998, 4, 2467−2474.
(13) Alternative methods for the cyanation of thiols (selected
examples): (a) Zhu, D.; Chang, D.; Shi, L. Chem. Commun. 2015, 51,
7180−7183. (b) Frei, R.; Courant, T.; Wodrich, M. D.; Waser, J.
Chem.Eur. J. 2015, 21, 2662−2668. (c) Kim, J. J.; Kweon, D. H.; Cho,
S. D.; Kim, H. K.; Jung, S. G.; Lee, S. G.; Falck, J. R.; Yoon, Y. J.
Tetrahedron 2005, 61, 5889−5894. (d) Wu, Y. Q.; Limburg, D. C.;
Wilkinson, D. E.; Hamilton, G. S. Org. Lett. 2000, 2, 795−797.
(e) Higashino, T.; Iwamoto, K. I.; Kawano, A.; Miyashita, A.; Nagasaki,
I.; Suzuki, Y. Heterocycles 1997, 45, 745−755.
(14) Alternative methods for the cyanation of stabilized enolates
(selected examples): (a) Wang, Y. F.; Qiu, J.; Kong, D.; Gao, Y.; Lu, F.;
Karmaker, P. G.; Chen, F. X. Org. Biomol. Chem. 2015, 13, 365−368.
D
DOI: 10.1021/jacs.5b05287
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX