Enantioselective, Lewis Base-Catalyzed, Intermolecular Sulfenoamination of Alkenes

Article abstract of DOI:10.1021/jacs.9b07019

A method for the catalytic, enantioselective, intermolecular, 1,2-sulfenoamination of alkenes is described. Functionalization is achieved through the intermediacy of an enantioenriched, configurationally stable thiiranium ion generated by Lewis base activation of a readily available sulfur electrophile. A diverse set of anilines and benzylamines react with different styrenes to afford products in good yield and stereoselectivity. Downstream manipulation of the products is facilitated by deprotonation of the amines to enable carbon-sulfur bond cleavage.

Full text of DOI:10.1021/jacs.9b07019

Communication
pubs.acs.org/JACS
Cite This: J. Am. Chem. Soc. XXXX, XXX, XXX−XXX
Enantioselective, Lewis Base-Catalyzed, Intermolecular
Sulfenoamination of Alkenes
Aaron Roth and Scott E. Denmark*
Roger Adams Laboratory, Department of Chemistry, University of Illinois, Urbana, Illinois 61801, United States
S
* Supporting Information
owing to the use of a strong acid (MsOH) which leads to
decomposition of starting material. We reasoned the use of
HFIP, which obviates the need for strong acids, could enable
successful intermolecular sulfenofunctionalization.
ABSTRACT: A method for the catalytic, enantioselec-
tive, intermolecular, 1,2-sulfenoamination of alkenes is
described. Functionalization is achieved through the
intermediacy of an enantioenriched, configurationally
stable thiiranium ion generated by Lewis base activation
of a readily available sulfur electrophile. A diverse set of
anilines and benzylamines react with different styrenes to
afford products in good yield and stereoselectivity.
Downstream manipulation of the products is facilitated
by deprotonation of the amines to enable carbon−sulfur
bond cleavage.
The intermolecular functionalization of thiiranium ions,
pioneered in 1982 by Trost, involves formation of a racemic
thiiranium ion (generated from dimethyl(methylthio)-
sulfonium tetrafluoroborate (DMSTF)), which then undergoes
invertive opening (Scheme 1A).16 A variety of nitrogen-based
nucleophiles afford the sulfenoamination products including
amines, azide, and nitrite nucleophiles to provide the amino,
azido, and nitro sulfides, respectively. Brownbridge subse-
quently reported the treatment of alkenes with phenyl-
sulfenamides in dichloromethane to access 1,2-aminothiols in
moderate yields and, when in the presence of acetonitrile, the
corresponding amidines were formed (Scheme 1B).17 In the
intervening years a number of methods have been disclosed to
access racemic 1,2-aminothiols including trifluoromethylthioa-
mination of alkenes catalyzed by diaryl selenides reported by
Zhao et al. and a highly efficient electrochemical oxy- and
aminosulfenylation of alkenes by Yuan et al.18,19
he transformation of simple alkenes into chiral, non-
Tracemic, vicinally functionalized building blocks serves as
an important strategy for the production of value added
chemicals. In the past 30 years, numerous approaches to alkene
difunctionalization such as epoxidation, dihydroxylation,
aminohydroxylation and halofunctionalization have been
reported.1−5 On the other hand, the sulfenofunctionalization
of alkenes proceeding through racemic thiiranium ion
intermediates has been known since the early 1960s, but
enantioselective variants are significantly less developed.
Despite their high reactivity, thiiranium ions are configura-
tionally stable at low temperature and readily intercepted
stereospecifically with various nucleophiles to afford anti-
sulfenofunctionalized products.6
Scheme 1. Intermolecular Sulfenoamination by Interception
of Thiiranium Ions
As part of an ongoing program on the enantioselective
functionalization of alkenes, we have exploited the activation of
group 16 Lewis acids by Lewis bases to access seleno- and
sulfenofunctionalized products.7 Association of a Lewis basic
selenophosphoramide catalyst 5 and group 16 Lewis acid 4
(“Sulfenylating Agent”) results in a highly electrophilic donor−
acceptor complex.8 This complex is intercepted by an
unactivated alkene to form an enantioenriched, configuration-
ally stable thiiranium ion which subsequently undergoes
stereospecific nucleophilic opening. A number of nucleophiles
including alcohols, phenols, amines, anilines, arenes and
alkenes serve effectively in intramolecular proceses.9−13 In
addition, a recent report from these laboratories demonstrated
the sulfenocyclization of polyenes enabled by the use of
hexafluoroisopropyl alcohol (HFIP) as the solvent.14 The
utility of protic solvents has since been further applied to the
carbosulfenylation of alkenylboronates.15 Although intramo-
lecular functionalization has proven successful, previous
attempts to achieve intermolecular functionalization with
similar nucleophiles have met with limited success largely
Received: July 2, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/jacs.9b07019
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
Indeed, strategies to access enantiomerically enriched 1,2-
amino thiols have largely relied on the desymmetrization of
aziridines.20 In contrast, the formation and functionalization of
enantioenriched thiiranium ions has been significantly less
explored. In 1994 Rayner reported the synthesis of
benzoxazines by the intramolecular capture of thiiranium
ions generated from enantiomerically enriched sulfenyl
sulfonium salts.21 Although the products are obtained in
acceptable yield, enantioinduction was poor, ostensibly from
substrate-mediated background reaction. In the same year,
Pasquato et al. disclosed the first enantioselective intermo-
lecular sulfenoamination achieved through an enantioenriched
thiiranium ion intermediate (Scheme 1C).22 A stoichiometric
quantity of a chiral dinaphtho[2,1-c:1′,2′-e][1,2]dithiin sulfe-
nylating agent produces enantioenriched thiiranium ions which
undergo capture with acetonitrile in a Ritter-type process to
provide the corresponding sulfeno acetamides in good yield
and enantioselectivity. Herein, we report a catalytic,
enantioselective, intermolecular sulfenoamination of alkenes
enabled by the stereospecific capture of enantioenriched
thiiranium ions.
Orienting experiments (Table 1) initially employed HFIP
(0.5 M), (E)-2-methylstyrene 1a, sulfenylating agent 48b (1.0
equiv), catalyst (S)-5 (0.1 equiv) or tetrahydrothiophene
(THT, 0.1 equiv) and p-tolulenesulfonamide (TsNH2, 1.0
equiv) as the nucleophile. Unfortunately, only the oxy-
sulfenylated product 3 corresponding to solvent incorporation
was observed (entry 1). The same result was observed when
the comparatively less nucleophilic nonafluoro-tert-butyl
alcohol (9F-t-BuOH) was employed (entry 2). The use of
mixed solvent systems (dichloromethane/HFIP, dichloro-
methane/9F-t-BuOH and toluene/9F-t-BuOH) failed to
provide the desired products, resulting in the generation of
undesired side products (entries 3−5). At this point it was
deemed prudent to survey several amines that could intercept
the thiiranium ion more readily than HFIP. Nucleophiles such
as tert-butyl carbamate and 2-aminobenzothiazole again
afforded the oxysulfenylated product (entries 6 and 7).
Gratifyingly, p-anisidine was identified as an effective
nucleophile and no solvent incorporation was observed
(entry 8).
Reaction conditions were further refined through the use of
Design of Experiment software.23 Four reaction factors were
examined in this protocol: overall concentration, equivalents of
both sulfenylating agent and p-anisidine, as well as catalyst
loading. A total of 25 experiments were conducted and the
results were analyzed by 1H NMR spectroscopy and a response
surface was generated. A slight excess of sulfenylating agent
(1.2 equiv) and p-anisidine (1.6 equiv) were required because
sulfenylation of the p-anisidine to form the corresponding
thiohydroxylamine was identified as a parasitic pathway.
Additionally, high concentration was key to minimize the
formation of any oxysulfenylated product. Lastly, reactions run
for 24 h at ambient temperature maintain high yields with
catalyst loading as low as 5 mol %.
Under the optimized conditions, a number of anilines
containing both electron rich and electron withdrawing
functional groups were evaluated (Table 2). 4-Haloanilines
were competent, affording the corresponding aminofunction-
alized products 2a−2c as single diastereomers in good yield
and 98:2 enantiomeric ratio. Absolute configuration was
confirmed by single crystal X-ray diffraction24 of 2c and
corresponds to the selectivity models previously described.8 2-
Iodoaniline was incorporated in good yield and high
enantioselectivity was maintained. Electron-rich anilines were
also incorporated giving products 2e and 2f in good yield.
Owing to the mild conditions afforded by HFIP, acid-labile
protecting groups are compatible as demonstrated by synthesis
of pivalate 2g in 84% yield and carbamate 2h in 83% yield. Of
note is the ability of electron deficient anilines to outcompete
theformation of oxysulfenylated product. 4-Aminoacetopheone
and benzocaine were cleanly incorporated to afford products 2i
and 2j respectively in good yield. 4-Aminophenylboronic acid
pinacol ester provided the desired product 2k in 82% yield and
thereby provides an additional functional group for subsequent
cross coupling reactions. 2-Aminopyridine was also competent
affording 2l in good yield and selectivity.
Table 1. Reaction Optimization
The method was extended to a number of benzylic amine
nucleophiles. Benzylamine was incorporated efficiently as was
2-methylbenzylamine to give the corresponding products 2m
and 2n in 70% and 75% yield respectively with no appreciable
loss in enantioselectivity. Benzylamines containing the
inductively withdrawing and resonance withdrawing trifluor-
omethyl and 4-cyano substituents reacted efficiently to give 2p
and 2q. 2-Furfurylmethylamine was smoothly incorporated in
75% yield and 98:2 e.r. Incorporation of aliphatic amines was
largely unsuccessful owing to their increased Brønsted basicity
(leading to protonation under these conditions) resulting in
the formation of the oxysulfenylation product exclusively.
With respect to the olefin scope (Table 3), styrene, which
had previously given poor results in the presence of strong
acid, was readily functionalized in 80% yield and 96:4 e.r.
Additionally, products 7b and 7c arising from 2-fluorostyrene
and 2-methylstyrene respectively were obtained in synthetically
a
b
Yield of isolated products. Starting material remaining and side
c
1
products were formed. Yield obtained by H NMR analysis against
an internal standard.
B
DOI: 10.1021/jacs.9b07019
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Journal of the American Chemical Society
Communication
a b c
, ,
a b c
, ,
Table 2. Aniline and Benzyl Amine Scope
Table 3. Olefin Scope
a
b
All reactions performed on a 1.00 mmol scale. Yield of isolated,
c
analytically pure product. Enantiomeric ratio determined by CSP-
HPLC or CSP SFC analysis.
reduces reactivity and complicates subsequent functionaliza-
tion. Initial attempts to affect C−S cleavage employed a variety
of reducing agents that simply returned starting material even
under forcing conditions. Treatment with lithium naphthale-
nide successfully affected C−S cleavage but resulted in
spontaneous decomposition of the anion through β-elimi-
nation. To address this limitation, we were inspired by a report
from Yus and co-workers, which describes the generation of
stable β-amido alkyllithium species through a two-step, one-
pot protocol by preforming the lithium amide, which serves to
prevent β-elimination.25 This strategy has also been employed
in the derivatization of β-oxyanionic alkyllithium reagents;26−31
however, to the best of our knowledge, no subsequent reports
using this strategy in the derivatization of β-amido
alkyllithiums have been disclosed.
By preforming the lithium amide (by deprotonation with n-
BuLi) prior to treatment with lithium 4,4′-di-tert-butylbiphe-
nylide (LiDTBB), the β-amido alkyllithium adduct i was
successfully converted into a number of functionalized
derivatives (Scheme 2). The desulfurized product 8 was
formed in 87% yield by quenching the dianion with water
whereas the 1,3-amino alcohol 9 was formed as a single
diastereomer through capture with dimethylformamide and
subsequent reduction with no loss in enantiomeric purity.
Reaction of i with acetaldehyde proceeded in good yield to
provide 10 as a mixture of C(2) diastereomers whereas
treatment with dimethyl sulfate afforded the C-methylated
product 11 in 84% yield. Aziridine 12 was accessed via the
intermediate syn-2-chlorolithophenyl amide (by reaction with
hexachloroethane) and subsequent invertive displacement.
Finally, carbon dioxide was captured to afford the syn-amino
acid 13, which was next cyclized to the β-lactam 14 after
treatment with Mukaiyama’s reagent.32 The relative config-
urations of these adducts were established by comparison to
literature values.33,34 Attempts to form the corresponding
piperidine and azepine through capture of 1,3-dibromopropane
and 1,4-dibromobutane were unsuccessful as numerous
byproducts were observed while exhaustive allylation pro-
ceeded in poor yield and afforded the bis-allylated product in
55:45 d.r. Lastly, 15, derived from 4-aminophenol, was cleanly
a
b
All reactions performed on a 1.00 mmol scale. Yield of isolated,
c
analytically pure product. Enantiomeric ratio determined by CSP-
HPLC (high performance liquid chromatography) or CSP SFC
analysis.
useful yields however, both suffered from slight degradation in
selectivity. 3-Methylbutenylbenzene reacted to afford 7d in
good yield and selectivity. Attempts to functionalize α-
methylstyrene afforded the desired sulfenofunctionalized
product, however in racemic form. This outcome likely arises
from the intermediacy of a stabilized, open carbocation rather
than by stereospecific ring opening of a thiiranium ion.
Similarly, anethole is also capable of efficient cation
stabilization which might result in a mixture of diastereomers.
Gratifyingly, anethole was competent in the reaction providing
the desired product 7e in 74% yield and 95:5 e.r.
Difunctionalized products containing extended aromatic
systems (7f), e.g., N-tosyl substituted indole (7g), heterocycles
(7h) and aliphatic alkenes (7i), were all produced in good
yield and good to excellent selectivity.
A major objective of this project was the subsequent
derivatization of the sulfenofunctionalized products. Although
the increased steric bulk of the 2,6-diisopropylsulfenylating
agent 4 affords superior enantioselectivities, this same property
C
DOI: 10.1021/jacs.9b07019
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Journal of the American Chemical Society
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employing HFIP as the solvent, both anilines and benzylic
amines were employed as competent nucleophiles. The
corresponding 1,2-sulfenoaminated products were obtained
in good yields and excellent selectivities. A number of
derivatives were accessed in high diastereoselectivity through
a β-amido organolithium intermediate.
Scheme 2. Product Manipulations
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/jacs.9b07019.
Experimental Procedures, characterization data for all
new compounds along with copies of spectra and
chromatograms (PDF)
Data for 2c (CIF)
AUTHOR INFORMATION
■
Corresponding Author
*sdenmark@illinois.edu
ORCID
Scott E. Denmark: 0000-0002-1099-9765
Notes
The authors declare no competing financial interest.
transformed to the primary amine through PIFA-mediated
oxidation and subsequent hydrolysis.
ACKNOWLEDGMENTS
■
From previous mechanistic investigations, a catalytic cycle is
proposed in Figure 1. Activation of sulfenylating agent 4 by
protonation with HFIP facilitates sulfur transfer to seleno-
phosphoramide catalyst 5 to form cationic species ii.
Subsequent transfer of the sulfenyl group to the alkene results
in enantioselective thiiranium ion formation (species iii).
Stereospecific, intermolecular nucleophilic capture and sub-
sequent deprotonation affords the vicinally functionalized
product and regenerates the catalyst.
We are grateful to the National Institutes of Health (GM R35
127010) for generous financial support. We also thank the
UIUC SCS support facilities (microanalysis, mass spectrom-
etry, X-ray and NMR spectroscopy) for their assistance. A.R.
acknowledges the NIH-NIGMS CBI Training Grant (T32-
GM070421) as well as the NSF for a Graduate Fellowship
(GRFP).
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