N-Heterocyclic Carbene Catalyzed Synthesis of δ-Sultones via α,β-Unsaturated Sulfonyl Azolium Intermediates

Article abstract of DOI:10.1002/anie.201504633

A limited array of reactive intermediates have enabled a wealth of discoveries in N-heterocyclic carbene organocatalysis. In this study, the viability of α,β-unsaturated sulfonyl azoliums as double electrophiles in new reactions is examined. Specifically,

Full text of DOI:10.1002/anie.201504633

.
Angewandte
Communications
International Edition: DOI: 10.1002/anie.201504633
German Edition: DOI: 10.1002/ange.201504633
Organocatalysis
N-Heterocyclic Carbene Catalyzed Synthesis of d-Sultones via
a,b-Unsaturated Sulfonyl Azolium Intermediates
Andrei Ungureanu, Alison Levens, Lisa Candish, and David W. Lupton*
Abstract: A limited array of reactive intermediates have
enabled a wealth of discoveries in N-heterocyclic carbene
organocatalysis. In this study, the viability of a,b-unsaturated
sulfonyl azoliums as double electrophiles in new reactions is
examined. Specifically, the (3+3) annulation of such species
with the trimethylsilyl enol ethers of various 1,3-dicarbonyl
compounds has been developed. This reaction provides access
to a range of novel unsaturated d-sultones (18 examples) in
good yields (40–88%) under mild reaction conditions. Mech-
anistic studies and the development of an enantioselective
variant (55% yield, 73:27 e.r.) support the intermediacy of an
a,b-unsaturated sulfonyl azolium species.
a-position, and finally a second nucleophile at the acyl
position. Although homoenolate (1) and a,b-unsaturated acyl
azolium (2) intermediates are now integral to NHC catalysis,
non-carbonyl analogues are yet to be reported, despite their
potential to deliver new transformations (see below). To
address this deficiency, we recently investigated nucleophilic
catalysis with a,b-unsaturated sulfonyl fluorides (3; Figure 2).
C
atalysis with a,b-unsaturated carbonyl compounds and
N-heterocyclic carbenes (NHCs) has delivered a range of
[
1]
[2]
important chemical reactions. Central to many are homo-
enolate (1) or a,b-unsaturated acyl azolium (2) intermedi-
[3]
[
4]
ates (Figure 1). These intermediates enable bond-forming
cascade processes that are characterized by reactions at
multiple electrophilic and nucleophilic sites. For example,
homoenolate intermediates (1) allow electrophiles to be
introduced at the b-carbon atom, which is then followed by
the addition of a nucleophile at the acyl carbon atom. In
contrast, a,b-unsaturated acyl azolium intermediates (2)
enable bond formation with nucleophiles at the b-carbon
atom, followed by electrophiles (often protons) at the
Figure 2. Working hypothesis and sultones of importance in medicinal
chemistry. BVDV=bovine viral diarrhea virus, PET=positron emission
tomography.
It was envisaged that with such substrates, the chemistry of
“
non-carbonyl” analogues of a,b-unsaturated acyl azoliums,
such as a,b-unsaturated sulfonyl azoliums 4, could be inves-
tigated, and that their reaction with enolates should deliver
[5]
d-sultone heterocycles. Herein, we report the NHC-cata-
lyzed synthesis of an array of d-sultones, a somewhat over-
looked heterocycle in medicinal chemistry (two bioactive
[
6]
examples are compounds 5 and 6), exploiting unsaturated
sulfonyl azoliums (4) as new doubly electrophilic intermedi-
ates for organocatalysis. Mechanistic studies in support of the
intermediacy of unsaturated sulfonyl azolium 4 and proof of
principle for an enantioselective variant (73:27 e.r.) are also
reported.
The chemistry of unsaturated sulfonyl(V) fluorides (e.g.,
3
) was first studied in 1954 by Truce and Hoerger who
Figure 1. Homoenolates and a,d-unsaturated acyl azoliums as inter-
mediates in NHC catalysis.
reported the Diels–Alder reaction of 2-para-nitrophenyl-
ethylene sulfonyl fluoride (3a, R = p-NO C H ) with cyclo-
pentadiene. Twenty-five years later, Krutak, Hyatt, and co-
workers thoroughly investigated the use of ethylene sulfonyl
fluoride (ESF, 3b, R = H) as a Michael acceptor. Although
both reports have received little attention, the application of
ESF (3b) in click chemistry has recently been studied. We
postulated that exposure of unsaturated sulfonyl(V) fluorides
3 to NHC catalysts should provide access to sulfonyl azoliums
2
6
4
[7]
[
*] A. Ungureanu, A. Levens, Dr. L. Candish, Prof. D. W. Lupton
School of Chemistry, Monash University
Clayton 3800, Victoria (Australia)
[
8]
[9]
E-mail: david.lupton@monash.edu
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201504633.
1
1780
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2015, 54, 11780 –11784

Angewandte
Chemie
4, which are potentially well-suited to cascade processes that
using other common Lewis basic catalysts, such as DMAP
involve bond formation at the b-carbon atom and the sulfonyl
(D), isothiourea E, quinine (F), or DABCO (entries 7–10). In
contrast, 10 mol% of DBU provided traces of 8a, and when
120 mol% was used, the desired product was isolated in 30%
yield (entries 11 and 12). The sensitivity of the reaction to the
nature of the Lewis base and the partial viability with DBU
group, analogous to the reactivity of unsaturated acyl
[
10–12]
azoliums.
Our investigations commenced with an examination of
the NHC-catalyzed annulation of trimethylsilyl (TMS) enol
[13]
[11]
ether 7a with 2-phenyl-substituted ESF (3c, R = Ph).
are consistent with observations by the groups of Gembus
[9b]
Pleasingly, when exposed to the Enders TPT catalyst (A;
TPT= 1,3,4-triphenyl-4,5-dihydro-1H-1,2,4-triazol-5-yli-
dene), the expected d-sultone product 8a was formed in 13%
yield (Table 1, entry 1). The yield could not be improved by
and Sharpless and Fokin
regarding organocatalysis with
aliphatic sulfonyl fluorides and sulfuryl fluorides, respectively.
Returning to IMes catalyst C1, we found that decreasing the
catalyst loading led to a decrease in yield (entry 13), whereas
its absence caused the reaction to fail (entry 14).
The generality of this reaction was examined with
a number of TMS enol ethers and a,b-unsaturated sulfonyl
fluorides. Thus, novel b-aromatic a,b-unsaturated sulfonyl
fluorides bearing electron-rich or electron-poor aromatic
Table 1: Optimization of the reaction conditions for the synthesis of
d-sultone 8a.
[13]
substituents were prepared and coupled with various TMS
enol ethers 7 (Table 2). Using the TMS enol ether derived
from dimedone (7a), we found that the reaction was
moderately sensitive to the electronic character of the
substrates; for example, electron-rich sulfonyl fluorides
afforded the corresponding sultones in modest yield (8b
and 8e), whereas electron-poor sulfonyl fluorides were
converted more efficiently (8c and 8d). 2-Furyl-substituted
sultone 8 f and ESF-derived sultone 8g were formed in
modest yield, the latter proving to be unstable during
characterization. The TMS enol ether derived from 1,3-
cyclohexadione and the acyclic TMS enol ether of acetylace-
[
a]
[b]
[c]
Entry
Cat. (mol%)
Solvent
T
[8C]
t [h]
Yield [%]
1
2
3
4
5
6
7
8
9
A (10)
A (10)
B (10)
C1 (10)
C1 (10)
C2 (10)
D (10)
E (10)
F (10)
DABCO (10)
DBU (10)
DBU (120)
C1 (5)
THF
THF
THF
THF
toluene
THF
THF
THF
THF
THF
THF
THF
THF
THF
RT
66
66
66
110
66
66
66
66
66
66
66
66
66
16
16
16
6
6
6
6
6
6
6
13
15
7
88
60
10
–
–
–
–
[
d]
[
e]
[d]
[
[
d]
d]
[a]
Table 2: d-Sultone substrate scope.
1
1
1
1
1
0
1
2
3
4
6
6
6
6
trace
30
45
–
–
[
a] The free NHCs were generated using KHMDS. [b] All reaction
mixtures were prepared at 08C and then heated to the indicated
temperature. [c] Yield of isolated product after flash column chroma-
1
tography. [d] No conversion according to H NMR analysis. [e] Gener-
ated from the HCl salt with DIPEA. DABCO=1,4-diazabicyclo-
[
2.2.2]octane, DBU=1,8-diazabicycloundec-7-ene, Dip=2,6-diisopro-
pylphenyl, Mes=mesityl, M.S.=molecular sieves.
raising the reaction temperature (entry 2) nor by using the
tert-butyl-substituted triazolylidene catalyst B (entry 3). In
contrast, the use of the more nucleophilic and Lewis basic
NHC IMes (C1) gave the expected d-sultone in an improved
yield of 88% (entry 4). The reaction could be conducted in
toluene at reflux (entry 5), whereas the use of the more
hindered imidazolylidene catalyst IDip (C2; IDip = 1,3-
bis(2,6-diisopropylphenyl)imidazol-2-ylidene) resulted in sig-
nificantly decreased yield (entry 6). The reaction was sensitive
to the nature of the catalyst, as no reactions were observed
[a] Yield of isolated product after flash column chromatography.
[b] Reaction run at RT for 16 h; 8g was isolated in >90% purity as an
1
unstable material. [c] Regioisomeric ratio determined by H NMR
analysis.
Angew. Chem. Int. Ed. 2015, 54, 11780 –11784
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org 11781

.
Angewandte
Communications
tone gave the d-sultones 8h and 8i and 8j–8l, respectively, in
acceptable yields. TMS enol ethers derived from unsymmetric
diketones gave the expected d-sultones in good yield;
however, modest regioselectivities were observed, with 8m
and 8n formed as 2:1 isomeric mixtures. In contrast, TMS
enol ethers derived from b-ketoesters gave the methyl-
substituted d-sultones 8o–8q and the isopropyl sultones 8r
and 8s in good yields, without formation of the ketene acetal
isomers.
Our mechanistic studies focused on 1) clarifying the role
of the NHC catalyst and gaining evidence for the intermedi-
acy of sulfonyl azolium 4, and 2) examining the preference of
the ambident enolate nucleophile for attack through the O
versus C atom (Scheme 1). With regard to the first point,
whereas unsubstituted ESF (3b) is a potent Michael acceptor
(
for example, it reacts rapidly with methyl 2-cyanoacetate to
[
8]
form sulfonyl fluoride 9, see Scheme 1a), the ability of
b-substituted ESF derivatives such as 3c to undergo conjugate
addition is unknown. To address whether a related reaction
that potentially competes with the postulated pathway via the
sulfonyl azolium intermediate was occurring, b-phenyl-sub-
stituted ESF (3c) was exposed to dimedone (10) in the
presence of Et N or LiHMDS or under the standard reaction
3
conditions (Table 1, entry 4). In all cases, the reaction failed to
provide sulfonyl fluoride 11 (or sultone 8a), as did the
transformation of TMS enol ether 7a with 3c in the presence
of 5 mol% TBAF (Scheme 1b,c). These observations indi-
cate that phenyl-substituted ESF is a weaker Michael
acceptor than unsubstituted ESF. The impact of a b-phenyl
substituent on the electrophilicity of various Michael accept-
ors has been examined by Mayr and co-workers, who found
[14]
an approximately 1000 fold decrease in reactivity.
To
demonstrate the viability of unsaturated sulfonyl azolium 4a
as an intermediate towards d-sultones, it was independently
[
15]
synthesized. Therefore, sulfonyl azolium 4a was prepared
[
16a]
by S vinylation of imidazole 12,
thioether to sulfone 13,
oxidation of the resultant
and N methylation using modified
procedures of Mück-Lichtenfeld, Mayr, Studer, and co-work-
[16b]
[
16c]
ers.
Having prepared sulfonyl azolium 4a, it was found to
react with the dimedone anion generated from TMS enol
ether 7a with TBAF, providing 8a in 33% yield. The modest
[17]
yield may be due to the limited solubility of 4a in THF.
Further support for the intermediacy of unsaturated sulfonyl
azolium 4 in the reaction was derived from studies on an
enantioselective variant. Specifically, we found that N-iso-
[
10f]
propyl morpholinone NHC G
enantioenriched 8a’ with 73:27 e.r. and moderate yield
Scheme 1 f). This result implicates the chiral catalyst in the
catalyzed the synthesis of
(
Scheme 1. Mechanistic experiments. MCPBA=meta-chloroperbenzoic
acid, TBAF=tetrabutylammonium fluoride, Tf =trifluoromethanesul-
fonyl.
enantiodetermining step of the reaction, which is consistent
with the formation of the sulfonyl azolium. Taken together,
these studies support the mechanistically significant forma-
tion of an unsaturated sulfonyl azolium intermediate (4),
which displays enhanced electrophilicity in comparison to the
starting sulfonyl fluoride.
After formation of the a,b-unsaturated sulfonyl azolium
intermediate, it can presumably react with the nucleophile
either through the O or the C atom of the enolate. To examine
the viability of the former pathway, sulfonate ester 14 was
prepared and subjected to the reaction conditions, potentially
[18]
triggering an NHC-catalyzed Claisen-type rearrangement
(Scheme 1g). Although the expected product 8a was indeed
observed, it was isolated in reduced yield indicating that this
pathway is unlikely to be operating. To examine whether
a vinyl sulfonate ester such as 14 might be involved as an
intermediate that undergoes conjugate addition with a second
enolate molecule, a scenario not probed in Scheme 1g,
1
1782 www.angewandte.org
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2015, 54, 11780 –11784

Angewandte
Chemie
a cross-over study was performed. A mixture of dimedone
TMS enol ether 7a and sulfonyl fluoride 3d, containing also
one equivalent of sulfonate 15, was subjected to the standard
conditions. None of the cross-over products (8a, 8h, or 8i)
were observed, which would be expected to form if enolate
addition to a vinyl sulfonate intermediate 15 occurred
Bugaut, F. Glorius, Chem. Soc. Rev. 2012, 41, 3511 (acyl anion
chemistry); d) J. Izquierdo, G. E. Hutson, D. T. Cohen, K. A.
Scheidt, Angew. Chem. Int. Ed. 2012, 51, 11686; Angew. Chem.
2
012, 124, 11854 (applications in total synthesis); e) S. J. Ryan, L.
Candish, D. W. Lupton, Chem. Soc. Rev. 2013, 42, 4906 (acyl
anion free catalysis); f) S. De Sarkar, A. Biswap, R. C. Samanta,
A. Studer, Chem. Eur. J. 2013, 19, 4664 (catalysis under oxidative
conditions); g) P. Chauhan, D. Enders, Angew. Chem. Int. Ed.
2014, 53, 1485; Angew. Chem. 2014, 126, 1509 (reactions with
esters); h) M. N. Hopkinson, C. Richter, M. Schedler, F. Glorius,
Nature 2014, 510, 485 (an introduction to NHCs).
(
Scheme 1g).
Based on these mechanistic experiments (Scheme 1),
a catalytic cycle was postulated (Scheme 2). Thus, the reaction
[
2] For examples of conjugate addition reactions of NHCs and a,b-
unsaturated carbonyl compounds, see: a) C. Fischer, S. W. Smith,
D. A. Powell, G. C. Fu, J. Am. Chem. Soc. 2006, 128, 1472; b) S.
Matsuoka, Y. Ota, A. Washio, A. Katada, K. Ichioka, K. Takagi,
M. Suzuki, Org. Lett. 2011, 13, 3722; c) A. T. Biju, M. Padma-
naban, N. E. Wurz, F. Glorius, Angew. Chem. Int. Ed. 2011, 50,
8
412; Angew. Chem. 2011, 123, 8562.
[
3] For a review, see: a) V. Nair, R. S. Menon, A. T. Biju, C. R. Sinu,
R. R. Paul, A. Jose, V. Sreekumar, Chem. Soc. Rev. 2011, 40,
5
336; for early contributions, see: b) K. Y.-K. Chow, J. W. Bode,
J. Am. Chem. Soc. 2004, 126, 8126; c) C. Burstein, F. Glorius,
Angew. Chem. Int. Ed. 2004, 43, 6205; Angew. Chem. 2004, 116,
6
331; d) A. Chan, K. A. Scheidt, Org. Lett. 2005, 7, 905.
[
4] For a review on NHC-catalyzed reactions with acyl azolium and
azolium enolate intermediates, see: J. Mahatthananchai, J. W.
Bode, Acc. Chem. Res. 2014, 47, 696.
[
[
5] For a review on the synthesis and applications of sultones, see: S.
Mondal, Chem. Rev. 2012, 112, 5339.
6] For examples of sultones in medicinal chemistry, see: a) S.
Schmitt, C. Bouteiller, L. BarrØ, C. Perrio, Chem. Commun.
2
011, 47, 11465; b) T. Priem, C. Bouteiller, D. Camporese, X.
Scheme 2. Proposed reaction mechanism.
Brune, J. Hardouin, A. Romieu, P. -Y. Renard, Org. Biomol.
Chem. 2013, 11, 469; c) H.-W. Xu, L.-J. Zhao, H.-F. Liu, D. Zhao,
J. Luo, X.-P. Xie, W.-S. Liu, J.-X. Zheng, G.-F. Dai, H.-M. Liu, L.-
H. Liu, Y.-B. Liang, Bioorg. Med. Chem. Lett. 2014, 24, 2388;
d) S. De Castro, C. García-Aparicio, G. Andrei, R. Snoeck, J.
Balzarini, M.-J. Camarasa, S. Velµzquez, J. Med. Chem. 2009, 52,
1582.
commences with addition of the NHC to unsaturated sulfonyl
fluoride 3c with concomitant loss of fluoride and desilylation
of TMS enol ether 7a, which provides dimedone anion 16 and
sulfonyl azolium 4. Intermediate 4 then undergoes conjugate
addition with the dimedone anion to provide sulfonyl azolium
enolate 17, which, after proton transfer and loss of the NHC,
affords d-sultone 8a.
In conclusion, we have introduced a new double electro-
phile for nucleophilic catalysis, namely a,b-unsaturated
sulfonyl azoliums. In this study, they were combined with
enolates for the synthesis of unsaturated d-sultones. Prelimi-
nary studies on an enantioselective variant of this reaction
demonstrate its viability (55% yield, 73:27 e.r.), while
providing mechanistic insight. The studies reported herein
raise questions related to the chemistry of sulfonyl Lewis base
intermediates, some of which we continue to investigate.
[
7] 2-Phenyl-ESF was reported in 1954 as a useful dienophile, but
has received no attention since; see: W. E. Truce, F. D. Hoerger,
J. Am. Chem. Soc. 1954, 76, 3230.
8] J. J. Krutak, R. D. Burpitt, W. H. Moore, J. A. Hyatt, J. Org.
Chem. 1979, 44, 3847.
9] For a recent review on the “click” chemistry of sulfonyl fluorides,
see: a) J. Dong, L. Krasnova, M. G. Finn, K. B. Sharpless, Angew.
Chem. Int. Ed. 2014, 53, 9430; Angew. Chem. 2014, 126, 9584; for
applications in polymerization catalysis, see: b) J. Dong, K. B.
Sharpless, L. Kwisnek, J. S. Oakdale, V. V. Fokin, Angew. Chem.
Int. Ed. 2014, 53, 9466; Angew. Chem. 2014, 126, 9620.
[
[
[
10] Our group has studied related reactions with acyl fluorides; see:
a) S. J. Ryan, L. Candish, D. W. Lupton, J. Am. Chem. Soc. 2009,
1
31, 14176; b) S. J. Ryan, L. Candish, D. W. Lupton, J. Am.
Chem. Soc. 2011, 133, 4694; c) S. J. Ryan, A. Stasch, M. N.
Paddon-Row, D. W. Lupton, J. Org. Chem. 2012, 77, 1113; d) S.
Pandiancherri, S. J. Ryan, D. W. Lupton, Org. Biomol. Chem.
2012, 10, 7903; e) L. Candish, D. W. Lupton, J. Am. Chem. Soc.
Keywords: N-heterocyclic carbenes · nucleophilic catalysis ·
organocatalysis · sulfonyl azolium intermediates ·
sulfonyl fluorides
2
013, 135, 58; f) L. Candish, C. M. Forsyth, D. W. Lupton,
How to cite: Angew. Chem. Int. Ed. 2015, 54, 11780–11784
Angew. Chem. 2015, 127, 11946–11950
Angew. Chem. Int. Ed. 2013, 52, 9149; Angew. Chem. 2013, 125,
9319.
[
11] For the DBU-catalyzed formation of sulfonate esters from
aliphatic sulfonyl fluorides, see: a) V. Gembus, F. Marsais, V.
Levacher, Synlett 2008, 1463; for a review comparing the
reactivity of different nucleophilic catalysts in common reac-
tions, see: b) L. Candish, Y. Nakano, D. W. Lupton, Synthesis
2014, 1823.
[
1] For a selection of recent reviews on NHC catalysis, see: a) D.
Enders, O. Niemeier, A. Henseler, Chem. Rev. 2007, 107, 5606;
b) A. Grossmann, D. Enders, Angew. Chem. Int. Ed. 2012, 51,
3
14; Angew. Chem. 2012, 124, 320 (cascade catalysis); c) X.
Angew. Chem. Int. Ed. 2015, 54, 11780 –11784
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org 11783

.
Angewandte
Communications
[
12] a,b-Unsaturated sulfones are good Michael acceptors; see: a) M.
Nielsen, C. B. Jacobsen, N. Holub, M. W. Paix¼o, K. A. Jørgen-
sen, Angew. Chem. Int. Ed. 2010, 49, 2668; Angew. Chem. 2010,
[16] a) M. S. Kabir, M. Lorenz, M. L. Van Linn, O. A. Namjoshi, S.
Ara, J. M. Cook, J. Org. Chem. 2010, 75, 3626; b) C. Bakhtiar,
E. H. Smith, J. Chem. Soc. Perkin Trans. 1 1994, 239; c) R. C.
Samanta, B. Maji, S. De Sarkar, K. Bergander, R. Frçhlich, C.
Mück-Lichtenfeld, H. Mayr, A. Studer, Angew. Chem. Int. Ed.
2012, 51, 5234; Angew. Chem. 2012, 124, 5325.
[17] In THF, a colloid formed over the course of the transformation.
Changing the solvent to acetonitrile allowed the reaction
(Scheme 1e) to occur, providing 8a in 75% yield.
1
22, 2726; b) A.-N. R. Alba, X. Companyó, R. Rios, Chem. Soc.
Rev. 2010, 39, 2018; for an NHC-catalyzed sulfone rearrange-
ment, see: c) R. L. Atienza, H. S. Roth, K. A. Scheidt, Chem.
Sci. 2011, 2, 1772.
[
13] All sulfonyl fluorides were prepared using a modified procedure
of the Liskamp group; see: A. J. Brouwer, T. Ceylan, A. M.
Jonker, T. van der Linden, R. M. J. Liskamp, Bioorg. Med.
Chem. 2011, 19, 2397.
[18] For related reactions of unsaturated esters, see Refs. [4] and
[10a].
[
[
14] D. Allgauer, H. Mayr, unpublished results.
15] The direct synthesis of the sulfonyl azolium from the sulfonyl
fluoride was not succussful. This is consistent with our previous
observations in acyl fluoride reactions, which have indicated that
the direct substitution of fluoride is not possible, with silicon
additives required to facilitate the reaction.
Received: May 21, 2015
Revised: June 30, 2015
Published online: August 10, 2015
1
1784 www.angewandte.org
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2015, 54, 11780 –11784