Enantioselective S?H Insertion Reactions of α-Carbonyl Sulfoxonium Ylides

Article abstract of DOI:10.1002/anie.202005563

The first example of enantioselective S?H insertion reactions of sulfoxonium ylides is reported. Under the influence of thiourea catalysis, excellent levels of enantiocontrol (up to 95 percent ee) and yields (up to 97 percent) are achieved for 31 examples

Full text of DOI:10.1002/anie.202005563

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Accepted Article
Title: Enantioselective S-H Insertion Reactions of α-Carbonyl
Sulfoxonium Ylides
Authors: Patrícia B. Momo, Alexandria N. Leveille, Elliot H. E. Farrar,
Matthew N. Grayson, Anita E. Mattson, and Antonio Carlos
Bender Burtoloso
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COMMUNICATION
Enantioselective S-H Insertion Reactions of α-Carbonyl
Sulfoxonium Ylides
[
a]
[b]
[c]
[c]
Patrícia B. Momo , Alexandria N. Leveille , Elliot H. E. Farrar , Matthew N. Grayson , Anita E.
[
b]
[a]
Mattson* , Antonio C. B. Burtoloso*
[
[
[
a]
b]
c]
Dr. P. B. Momo and Prof. Dr. A. C. B. Burtoloso
Institute of Chemistry of Sao Carlos
University of Sao Paulo
CEP 13560-970, Sao Carlos, SP (Brasil)
*
E-mail: antonio@iqsc.usp.br
M. Sc. A. N. Leveille and Prof. Dr. A. E. Mattson
Department Chemistry and Biochemistry
Worcester Polytechnic Institute
100 Institute Road, Worcester, MA 01609
*
E-mail: aemattson@wpi.edu
M. Sc. E. H. E. Farrar and Dr. M. N. Grayson
Department of Chemistry, University of Bath,
Claverton Down, Bath, BA2 7AY, U.K.
Supporting information for this article is given via a link at the end of the document.
Abstract: The first example of enantioselective S-H insertion
reactions of sulfoxonium ylides is reported. Under the influence of
thiourea catalysis, excellent levels of enantiocontrol (up to 95% ee)
and yields (up to 97%) are achieved for 31 examples in S-H insertion
reactions of aryl thiols and α-carbonyl sulfoxonium ylides.
donor catalysts, like silanediols,[16–20] squaramides,[21–25] or
(thio)ureas,[
26–30]
to effect the desired transformation with high
levels of enantiocontrol. In this communication, we describe our
successful development of the insertion reaction of sulfoxonium
carbonyl compounds into aryl thiols with high levels of
enantiocontrol under the influence of thiourea catalysis (Scheme
1B).
Sulfoxonium ylides are powerful reagents for a variety of
reactivity patterns, including insertion reactions.[1–4] Owing to their
stability, long shelf life, and ease of use, sulfoxonium ylides may
enable the safer execution of insertion chemistry when compared
to more traditionally employed α-diazocarbonyls. Industrial
applications are of particular relevance as Mangion and co-
workers from Merck noted that sulfoxonium ylides may be more
suitable for large scale work as they do not lead to the production
of gas or rapid exotherms.[5] Further adding to their allure, recent
methodologies developed separately in the Burtoloso and Aissa
laboratories enable direct access to more decorated sulfoxonium
ylides from safe commercially available starting materials in a
single step.[
6–8]
Due to their promising synthetic profile, the application of
sulfoxonium ylides in insertion chemistry has been gaining
traction in the past decade. To date, efforts have typically focused
on transition metal catalyzed insertion chemistry of sulfoxonium
ylides (Scheme 1A). Select transition metal catalyst systems (e.g.,
Scheme 1. Scheme Caption. X-H Insertion reactions from sulfoxonium ylides.
[
Ir(cod)Cl]
2
,
[Pt(cod)Cl]
2
,
[AuCl(SMe
2
)])
enable
non-
enantioselective N-H, S-H, and O-H insertion reactions of a range
of substrates in high yield.[5,9–13] To the best of our knowledge,
excluding the contributions employing diazocarbonyls,[14] no
examples of enantioselective insertion reactions of sulfoxonium
ylides have been reported.
The investigations began with the insertion of sulfoxonium
ylide 1a into the S-H bond of thiophenol 2a to generate 3a in the
presence of a variety (15 examples; see SI) of dual hydrogen
bond donor catalysts, including thioureas, ureas, squaramides,
and silanediols (Table 1, catalysts 4-8 as selected examples).
Varying degrees of success were achieved with a variety of
Inspired by the unrealized potential of enantioselective
insertion reactions of sulfoxonium ylides, we initiated
investigations to advance a metal-free approach to control the
enantioselectivity of sulfoxonium ylide insertion reactions into
polar X-H bonds (X = S, N, O). As a starting point for exploration,
we reasoned that our recently identified catalyst-free S-H bond
insertion reactions[ could be coupled with dual hydrogen bond
(thio)urea and squaramide catalysts. For instance, 10 mol% of
thioureas 4a and 4b, advanced by the Jacobsen laboratory,
delivered the desired product 3a in up to 50% enantiomeric
[31]
excess if the reaction was conducted in toluene at 23 °C. On
the other hand, thiourea 5 was able to produce only racemic
15]
[32–34]
product 3a under the same reaction conditions.
Squaramide
1
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6
provided 3a in 47% yield and 26% enantiomeric excess.[35] The
solvents, including chloroform and dichloromethane, were the
most advantageous in the reaction system producing high yields
and good enantiomeric excess (74% and 62%, entries 4 and 5).
A reduction in the reaction temperature, from 23 °C to –28 °C,
provided further improvements in enantiomeric excess (85% ee),
and extended reaction times enabled achievement of high yields
(entry 6). Further cooling of the reaction led to poor conversion
after 7 days (entry 7). Finally, the effect of catalyst loading on the
reaction platform was assessed (entries 8-10). The reduction of
the catalyst loading from 10 mol % to 5 mol % resulted in only mild
reductions in yield and stereocontrol (68% yield, 74% ee, entry 8),
but a catalyst loading of only 1 mol % proved to be rather
ineffective for this process (entry 9). Interestingly, doubling the
amount of catalyst 4b to 20 mol% did not affect yield and
enantioselectivity (entry 10). Although not depicted in the table
BINOL-based silanediols 7a and 7b were unable to control
enantioselectivity of the insertion event.[36] Quinine-derived urea
8
a and thiourea 8b furnished 3a, but with only low levels of
enantiocontrol, 4% and 12% ee, respectively.[37–39] Strong
Bronsted acids such as (S)-TRIP and (S)-VAPOL were also
evaluated (9a and 9b), providing 3a in only 2 and 20% ee,
respectively (Table 1).
Table 1. Organocatalyst screening for the enantioselective S-H insertion.
(see SI), the effect of the concentration of the reaction on yield
and stereocontrol was also tested but it was found to have a
minimal effect in chloroform with 0.05M to 0.5M reactions
providing nearly identical enantiomeric excesses (72-74% ee in
all cases, see supporting information for details). The absolute
stereochemistry of 3a (R) was assigned by the comparison of its
optical activity with literature values.[
40]
Table 2. Optimization studies employing organocatalyst 4b.
[
a] 0.1 mmol scale; See supporting information for detailed experimental
procedures. [b] 5 mol % catalyst loading. [c] 1 mol % catalyst loading. [d] 20
mol % catalyst loading.
With optimized reaction parameters identified, attention was
directed toward the study of the effect of substrate structure on
enantiocontrol and yield. First, the tolerance of the reaction toward
S-H insertion reaction partners was put to the test (Table 3).
Encouraged by the promising levels of enantiocontrol in our
initial screening, further optimization of the reaction parameters
was pursued with thiourea catalyst 4b (Table 2). The nature of the
solvent dramatically affected both the reaction rate and
enantiomeric excess observed. While the original solvent
employed, toluene, was able to give rise to 3a in 53% yield and
50% ee (entry 1), the ethereal solvents such as methyl t-butyl
ether (MTBE) produced 3a in 64% enantiomeric excess (entry 2).
Diethyl ether afforded 3a in just 24% ee (entry 3). Halogenated
2
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Table 3. Substrate scope based on aryl thiols and ylide 1a.
Table 4. Substrate scope based on both sulfoxonium ylides and aryl thiols.
The reaction was able to accommodate a diverse set of aryl
thiols. Electron withdrawing group in the para position of
thiophenol, including nitro, bromo, and chloro, gave rise to product
3
b-3d with excellent levels of enantiocontrol and good yields,
except for the nitro group. O-Chloro thiophenol gave rise to 3e in
6
7
6% yield and 71% ee while m-chlorothiophenol gave rise to 3f in
9% yield and 80% ee. Electron donating methoxy groups on the
thiophenol, such as p- and o-methoxy, gave rise to the
corresponding compounds 3g and 3h in high yield and 85% ee
and 77% ee, respectively. Methyl groups were also well tolerated
giving rise to 3i-3k with high levels of stereocontrol. Notably, the
sterically encumbered product 3k was formed in 86% ee, albeit in
low yield. The reaction occurred in the presence of an unprotected
phenol, affording 3l in 97% yield and 63% ee. 2-Naphthalenethiol
reacted to give 3m in 87% yield and 81% ee. All attempts to
conduct the reaction with an aliphatic thiol S-H insertion reaction
partner resulted in no reaction, with all starting materials
remaining. The influence of the structure of the sulfoxonium ylide
on the thiourea-catalyzed insertion reaction of a variety of aryl
thiols was probed next (Table 4).
Halogen substituents in the para-position of the aryl group
on the sulfoxonium ylides were well tolerated in the reaction,
giving rise to products 3n-p in good yields and 66-87% ee. The
introduction of a methyl group to the para position of the phenyl
sulfoxonium ylide gave rise products 3q-s in good yield and high
enantiomeric excess (84% ee, 78% ee, 82% ee, respectively).
The reaction of sulfoxonium ylide 1 (X = OCH , R’ = 2-napthyl)
3
with 4-methoxybenzenethiol gave rise to 3t in 68% yield and 80%
ee. Select heterocycles can be accommodated on the
3
sulfoxonium ylide. For example, the reaction of 1 (X = OCH , R’ =
pyridine) with 4-methoxylbenzenethiol afforded 3u in 58% yield
and 47% ee. A para-trifluormethyl group was also accommodated
well in the process, giving rise to 3v in 57% yield and 45% ee.
Next, we observed that the enantiomeric excess of the
insertion reaction could be influenced by the type of ester on the
sulfoxonium ylide 1. For instance, the methyl ester gave rise to 3g
in 94% yield and 80% ee while the improved enantiomeric excess
was observed when the ethyl ester was employed giving rise to
3
w in 90% yield and 89% ee. Benzyl ester 1 (R’ = Ph) gave rise
to 3x in 86% yield and 87% ee. An even better enantiomeric
excess resulted from insertion reactions of the t-butyl ester,
compound 3y being isolated in 66% yield and 90% ee. Additional
t-butyl sulfoxonium ylides also gave rise to products with high
3
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levels of enantiocontrol, but not in the same range. For example,
3
between the ylide and 3,5-bisfluorophenyl ring in TS-2 is made
z and 3aa were isolated in 84% and 88% ee, respectively. Finally, longer and, according to NBO analysis, 0.7 kcal·mol-1 weaker
the highest enantiomeric excess resulted from insertion reactions
of the 2,2,2-trichloroethyl esters: 3ab-3ae were isolated in 95%
ee, 92% ee, 92% ee and 93% ee, respectively.
than in TS-1. Additionally, the 3,5-bisfluorophenyl ring is twisted
slightly out of plane, inducing additional torsional strain relative to
TS-1 (see highlighted dihedral angle). Due to their greater
potential for steric interactions with the catalyst t-butyl, larger ester
groups on the ylide, such as t-butyl and trichloroethyl, enhance
both of these effects, raising the energy of TS-2 relative to TS-1
and improving selectivity. Whilst the ylide-catalyst hydrogen bond
distances do not depend significantly on the ylide orientation,
NBO analysis revealed these interactions to be 2.0 kcal·mol-1
stronger in TS-1 than in TS-2, indicating that the S=O functionality
is a better hydrogen bond acceptor than the carbonyl. The overall
preference for the binding mode in TS-1 is a major factor in
selectivity.
To understand the mechanism of this new mode of
enantioselective insertion, as well as the stereochemical outcome
of the products, we decided to perform some NMR studies and
DFT calculations. The interaction of the thiourea 4b and the
1
sulfoxonium ylide 1a was first studied by H NMR spectroscopy
(see spectra in SI). In this set of titration experiments, aliquots of
1
a were added to a 10 mM solution of the thiourea in CDCl . The
3
two N-H protons of the thiourea are visible around 9 ppm in the
1
H NMR before any sulfoxonium ylide is introduced. As aliquots
of 1a are added to 4b, there are clear shifts in the N-H protons
which may indicate that the sulfoxonium ylide is interacting with
the thiourea. On the other hand, the same titration experiments
conducted with 4b and the thiophenol resulted in no change to the
NMR spectra of 4b or the thiophenol.
Additionally, non-classical C-H···S hydrogen bonds were
also found to be essential to selectivity. While three such
interactions are formed between the ylide and thiophenol in TS-1
and TS-2, only one interaction is formed when the thiophenol
approaches the opposite face of the ylide, but keeping the same
binding modes (see TS-1’ and TS-2’ in SI). Accordingly, such TSs
are 3.8 kcal·mol-1 and 3.4 kcal·mol higher in energy than TS-1
and TS-2, respectively. NBO analysis of these C-H···S
interactions in TS-1 revealed a combined strength 3.7 kcal·mol-1
stronger than the single interaction formed by the alternative
From these studies, and mechanistic insights already
published for the non-enantioselective version (see ref. 15), our
current working hypothesis for the reaction pathway is depicted in
Scheme 2A. We propose that the thiourea catalyst 4b may
hydrogen bond to the sulfoxonium ylide to generate complex such
as complex 4b:1a. The hydrogen bond complex 4b:1a may then
-1
15
-1
deprotonate the thiophenol (rate-determining step ) to give rise
to the corresponding ion pair 10. The thiolate may then participate
in a substitution reaction to give rise to the product 3 while
simultaneously releasing the thiourea back into the catalytic cycle.
Subsequent DFT investigations (Gaussian16 (Revision A.03),[41]
see SI) allowed modelling of the selectivity-determining
protonation step from 4b:1a to 10 in order to determine the origins
of selectivity.[42] These calculations were performed on the
optimised conditions in Table 2 (entry 6, 85% ee), however the
trifluoromethyl and pyrene groups of the catalyst were truncated
to fluorines and phenyl, respectively, to reduce computational
expense. Superimposition of the lowest energy conformations of
catalyst 4b and the model catalyst (RMSD = 0.095 over core
atoms, see SI) indicates that these truncations do not significantly
impact the conformation of the catalyst, and hence allow
reasonable approximation of the full transition structures (TSs).
Overall, calculations predicted a computed ee of 82% based on a
Boltzmann weighting at 245.15 K over all structures within 3
approach TS, accounting well for the overall 3.8 kcal·mol
difference.
-
1
kcal·mol of the lowest in free energy. The lowest energy TSs
leading to the major and minor enantiomers of the product, TS-1
and TS-2, respectively, are depicted in Scheme 2B. In agreement
with the NMR results, interactions were observed between the
thiourea catalyst and the sulfoxonium ylide, but not between the
thiourea and thiophenol. In TS-1, the ylide S=O forms hydrogen
bonds with the two acidic protons of the thiourea, whilst a non-
classical C-H···O hydrogen bond is formed between the carbonyl
oxygen and the 3,5-bisfluorophenyl ring. In TS-2, the roles of the
carbonyl and the S=O groups are reversed. A weak C-H···O
interaction exists in both structures between an ylide methyl and
the carbonyl of the catalyst.
Whilst the ylide orientation is parallel to the thiourea unit of
the catalyst in TS-1, the two species are approximately
perpendicular in TS-2. This avoids unfavorable steric interactions
between the ylide ester group and the t-butyl of the catalyst and
allows the formation of the methyl C-H···O interaction with the
catalyst carbonyl. However, as a result, the C-H···O interaction
Scheme 2. a. Plausible Reaction Pathway. b. Relative free energies of TS-1
and
TS-2
(M06-2X/def2tzvpp/IEFPCM(chloroform)//B3LYP/6-31G(d)).
Distances in angstroms (Å). Highlighted atoms indicate measured dihedral
angle.
4
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The synthetic utility of the S-H insertion products was put to
the test and several of the results are depicted in Scheme 3. 3a
was oxidized from the thioether to the sulfone using 3.2 equiv. of
m-CPBA to give rise to 10 in 91% yield with 80% enantiomeric
excess. The reduction of the 3a to alcohol 11 occurred in 85%
yield with retention of enantiomeric excess upon treatment with
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3
.0 equiv. of lithium aluminum hydride in diethyl ether. The
addition of methyl magnesium bromide gave rise to alcohol 12 in
8% yield with 82% enantiomeric excess. It is also worth to
4
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Keywords: S-H insertion • enantioselective • sulfoxonium ylide •
aryl thiol • organocatalytic
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The first enantioselective S–H insertion reaction from α-carbonyl sulfoxonium ylides was developed under thiourea catalysis. Up to
5% ee and 97% isolated yields were obtained in 31 examples.
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