Catalytic, Enantioselective Syn-Oxyamination of Alkenes

Article abstract of DOI:10.1021/jacs.1c06750

The chemo-, regio-, diastereo-, and enantioselective 1,2-oxyamination of alkenes using selenium(II/IV) catalysis with a chiral diselenide catalyst is reported. This method uses N-tosylamides to generate oxazoline products that are useful both as protected

Full text of DOI:10.1021/jacs.1c06750

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Catalytic, Enantioselective Syn-Oxyamination of Alkenes
Emily M. Mumford,† Brett N. Hemric,† and Scott E. Denmark*
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ABSTRACT: The chemo-, regio-, diastereo-, and enantioselective
1,2-oxyamination of alkenes using selenium(II/IV) catalysis with a
chiral diselenide catalyst is reported. This method uses N-
tosylamides to generate oxazoline products that are useful both
as protected 1,2-amino alcohol motifs and as chiral ligands. The
reaction proceeds in good yields with excellent enantio- and
diastereoselectivity for a variety of alkenes and pendant functional
groups such as sulfonamides, alkyl halides, and glycol-protected
ketones. Furthermore, the rapid generation of oxazoline products is
demonstrated in the expeditious assembly of chiral PHOX ligands
as well as diversely protected amino alcohols.
approaches have been developed for the assembly of
enantioenriched 1,2-amino alcohols from a diverse array of
starting materials, such as alcohols, aldehydes, ketones, amino
acids, and amino esters.5 Although these multistep syntheses
provide good yields and enantioselectivities, a one-step
protocol would offer the distinct advantage of a more efficient
construction for more rapid generation of molecular complex-
ity. Alkene difunctionalization, and more specifically alkene
1,2-oxyamination, offers a potentially modular approach to the
assembly of 1,2-amino alcohols and has garnered considerable
recent interest.6 Furthermore, the broad availability of
feedstock alkenes provides an accessible platform for rapid
access to enantioenriched 1,2-amino alcohols.
INTRODUCTION
■
Enantiomerically pure 1,2-amino alcohols and their derivatives,
including oxazolines, oxazolidinones, and oxazolidines, repre-
sent a ubiquitous motif in natural products,1 bioactive
molecules,1a,b organocatalysts,2 chiral auxiliaries,3 and chiral
ligands (Figure 1).4
Given the importance of enantioenriched 1,2-amino
alcohols, versatile and modular strategies to access these
motifs are of great synthetic interest. Accordingly, a number of
BACKGROUND
■
The seminal example of alkene 1,2-difunctionalization for
accessing 1,2-amino alcohols was reported by Sharpless and co-
workers in 1996 (Scheme 1a).7 Following an initial report
using stoichiometric amounts of osmium(VIII) to furnish
racemic products,8 the authors devised a catalytic and
enantioselective method using chiral phthalazinediyl (PHAL)
ligands with osmium(VIII) and Chloramine-T. Although this
method gives respectable yields and enantioselectivities, it
necessitates the use of symmetrical and electronically biased
internal alkenes owing to deficiencies in the regioselectivity of
unsymmetrical alkenes.9 This shortcoming in regioselectivity
was partially solved by Donohoe and co-workers using
Received: June 30, 2021
Published: August 10, 2021
Figure 1. Important 1,2-amino alcohol derivatives in pharmaceuticals
and ligands.
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enantioenriched, amino-tethered alkenes to form an in situ
generated imido osmium intermediate and promote an
intramolecular 1,2-oxyamination.10 In 2008, Chemler and co-
workers disclosed an enantioselective, intramolecular 1,2-
oxyamination of alkenes, combining unsaturated sulfonamides
with copper(II) catalysts, chiral bisoxazoline (BOX) ligands,
and TEMPO (Scheme 1b).11 This method displays good to
excellent yields and enantioselectivities in which the
regioselectivity is controlled by intramolecularity. Follow-up
studies demonstrate that either enantiomer can be accessed by
this method through a judicious choice of the chiral BOX
ligand.
use as potential redox-active catalysts is of considerable interest
(Scheme 2). Upon initial opening of the -iranium ion with a
nucleophile, a secondary nucleophile can displace the catalyst,
allowing for the 1,2-difunctionalization and regeneration of the
catalyst. However, an oxidative step is necessary to turn over
the redox process. Halogen(I/III)-based catalysts are released
in a lower oxidation state than is required for -iranium
formation and must be reoxidized to promote the -iranium
formation. Iodine has been employed as a catalyst in this
process to generate racemic oxazolines18 and enantioenriched
oxazolidinones19 using chiral iodine reagents. In contrast, some
chalcogen(II) catalysts must be oxidized to form a chalcogen-
(IV) leaving group for the second nucleophile addition.
Alternatively, some Se(II) species can serve as a competent
nucleofuge but then must be oxidized to the Se(IV) species to
reenter the catalytic cycle. By comparison to the use of iodine
as a redox catalyst to effect 1,2-oxyamination of alkenes, the
use of chalcogens for this purpose remains underexplored.
Scheme 1. Foundational Examples of Enantioselective 1,2-
Oxyamination of Alkenes
Scheme 2. General Flow for a Redox-Active Halogen/
Chalcogen Catalysis
Although chalcogens have seen prior use in the dual opening
of -iranium ions to effect 1,2-oxyamination of alkenes, this has
historically been conducted using stoichiometric amounts of
the chalcogen-based reagent. This strategy was first demon-
strated in 1988 by Ogura and co-workers using benzenetellur-
inyl trifluoroacetate to form the telluriranium ion, with opening
by the nitrile solvent in a Ritter-type process that ultimately
displaces the tellurium through an invertive process that
reduces the tellurium reagent (Scheme 3a).20 Shortly there-
after, Tiecco and co-workers demonstrated that stoichiometric
amounts of diphenyl diselenide, in the presence of an oxidant,
can react with alkenes to form a seleniranium ion that can be
opened by a variety of nucleophiles to provide 1,2-amino
alcohol scaffolds upon displacement of the selenium (Scheme
3b).21 This reaction platform generates 1,2-azido ethers,
oxazolines, and oxazolidinones. Although this reaction was
initially conducted as a two-step process with the alkyl selenide
as an intermediate, subsequent studies by these authors found
that the use of phenylselenenyl sulfate as the selenium source
allows for a one-pot protocol for the formation of oxazolines.22
The authors propose that the formation of a cationic diselenide
from the alkyl selenide intermediate promotes the second
nucleophilic attack and loss of the selenide.
Shortly thereafter, Yoon and co-workers discovered a pair of
complementary methods for the enantioselective formation of
oxazolidines from oxaziridines (Scheme 1c).12 In this strategy,
terminal olefins are functionalized enantioselectively using
chiral BOX ligands to provide access to either constitutional
isomer, depending on the choice of copper or iron as the
catalyst. Good yields and enantioselectivities are observed in
both cases, with excellent cis/trans diastereomeric selectivity in
the iron catalysis system. Additional enantioselective alkene
1,2-oxyamination methods have been developed using (1)
stoichiometric amounts of manganese,13 (2) catalytic processes
that employ copper,14 palladium,15 and iridium complexes,16
and (3) bioenzymatic catalysis.17
Another promising strategy that has been employed for
stereoselective 1,2-oxyamination of alkenes is the use of a
redox-active catalyst that can form a highly electrophilic
-iranium ion when combined with an alkene substrate.
Chalcogens and halogens in rows 3−5 are often used for
vicinal alkene difunctionalizations via -iranium ions, and their
A recent report from our laboratories demonstrated that a
chiral diselenide can be used catalytically to effect enantiose-
lective formation of oxazolidinones from alkenes and a
carbamate in the presence of a mild oxidant to promote
catalytic turnover (Scheme 3c).23,24 Drawing on knowledge
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of a chemo-, regio-, diastereo-, and enantioselective 1,2-
oxyamination of alkenes.
Scheme 3. Chalcogen−Iranium Ion Formation for the 1,2-
Amino Oxygenation of Alkenes
In addition, Michael and co-workers found that a
selenophosphoramide can generate a seleniranium ion catalyti-
cally, while also acting as a good leaving group for a secondary
nucleophilic addition (Scheme 3e).26 This method comprises
several examples using unsaturated esters and sulfonimides for
the formation of racemic 1,2-amino alcohol precursors in fair
to good yields. Interestingly, this method was disclosed as a
serendipitous discovery within the context of an alkene
diamination investigation.
Although significant progress has been made in the area of
1,2-oxyamination of alkenes, currently, few methods are
available for simultaneous control of the chemo-, regio-,
diastereo-, and enantioselectivity.18b The success of using the
chiral diselenide catalyst with bifunctional nucleophiles to
generate enantioenriched 1,2-difunctionalized alkenes (Scheme
3c) provided encouragement that a similar approach could be
formulated with other bifunctional nucleophiles. Accordingly, a
research program for the development of a general protocol for
1,2-oxyamination of alkenes that would provide useful scaffolds
to access 1,2-amino alcohols was formulated.
RESEARCH PLAN
■
The alkene 1,2-diamination report disclosed a preliminary
protocol for the use of selenium redox to accomplish 1,2-
oxyamination of alkenes to oxazolidinones using carbamate
nucleophiles.23 However, further investigation of this approach
identified a severe alkene substrate limitation, as only a narrow
range of stilbene partners were viable. Accordingly, it was
decided that a new class of bifunctional nucleophiles should be
investigated for their compatibility with a broader range of
alkenes. From the success of the N-tosyl urea nucleophiles, it
was decided that N-tosyl amides would offer a close analogy
for the nitrogen-centered nucleophile. Whereas both nucleo-
philes rely on the nucleophilicity of the carbonyl oxygen, it
should be noted that the use of N-tosyl amides would require
loss of the N-tosyl group as tosyl fluoride to create a stable
product, whereas the previous protocol necessitated the loss of
benzyl fluoride.
RESULTS
■
1. Orienting Experiments and Optimization. The
initial investigation commenced by mimicking the conditions
in the alkene 1,2-diamination report.23 Thus, N-tosyl-3-
methoxybenzamide was combined with (E)-2-methylstyrene
in the presence of a diphenyl diselenide catalyst, N-
fluorocollidinium fluoroborate,27 and sodium fluoride (Table
1). Initial evaluation with acetonitrile, the solvent from the
diamination protocol, resulted in no conversion to the desired
product (entry 1). However, upon switching to dichloro-
methane, a moderate yield of product was observed (entry 2).
In surveying a range of halogenated solvents, 1,2-dichloro-
ethane (DCE) afforded an elevated yield (entry 3), but other
solvents such as chloroform, chlorobenzene, and α,α,α-
trifluorotoluene delivered only trace amounts of the desired
product (entries 4−6). Varying the concentration of the
reaction only decreased the product yield (entries 7 and 8).
Use of the chiral diselenide catalyst (3a), afforded a 71%
isolated yield of the desired product with a 93:7 er as a single
diastereomer (entry 9).
gleaned from previous efforts in Se(II/IV) catalysis,25 this
process begins with a symmetrical diselenide Se(I) catalyst,
which is oxidized to the active Se(II) catalyst (Scheme 3d).
This species then forms a seleniranium ion, which can be
opened enantioselectively through intermolecular attack by the
carbamate. The resulting Se(II) species is oxidized to Se(IV)
to create a leaving group for intramolecular closure by the
carbamate and concomitant regeneration of the active Se(II)
catalyst. Although this was but a single example within the
context of an alkene diamination method, it nevertheless
demonstrated the viability of this approach for catalytic, chiral
selenium catalysis. Additionally, this marked the first example
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Table 1. Survey of Solvents for the 1,2-Oxyamination of
Alkenes
Table 2. Survey of N-Sulfonamide Benzamides for 1,2-
Oxyamination of (E)-2-Methylstyrene
a
a
b
entry
Se catalyst
solvent
conc (M)
yield 4 (%)
1
2
3
4
5
6
7
8
9
Ph2Se2
Ph2Se2
Ph2Se2
Ph2Se2
Ph2Se2
Ph2Se2
Ph2Se2
Ph2Se2
3a
MeCN
CH2Cl2
DCE
CHCl3
PhCl
PhCF3
DCE
DCE
0.2
0.2
0.2
0.2
0.2
0.2
0.1
0.4
0.2
0
33
43 (35)
<5
<5
<5
24
37
c
c,d
DCE
87 (71)
a
b
All reactions were performed on a 0.2 mmol scale. Yields obtained
from quantitative 1H NMR with 1,1,2,2-tetrachloroethane as an
c
internal standard. Yield in parentheses is an isolated yield.
d
Enantiomeric ratio of 93:7 determined by CSP-HPLC. See the
Supporting Information for details.
a
All reactions were performed on a 0.2 mmol scale. Yields are of
2. Identification of the Optimal Oxyamination
Reagent. With initial conditions in hand, a survey of N-
sulfonamide benzamides was conducted with (E)-2-methyl-
styrene to ascertain the optimal reagent for achieving both high
yield and enantioselectivity (Table 2). In contrast to the
original N-tosyl-3-methoxybenzamide (1a), the 4-methoxy
analog (1b) resulted in a substantial decrease in yield with a
slightly decreased enantioselectivity, whereas the 4-trifluor-
omethyl analog (1c) displayed slightly lower yield and
enantioselectivity. Both the unsubstituted phenyl- (1d) and
1-naphthylbenzamides (1e) exhibited enantioselectivities com-
parable to that of 1a, and 1e also led to a higher yield.
Appending a 2-methyl group on the benzamide (1f) resulted in
an increase in both yield and enantioselectivity, whereas
appending 2,6-dimethyl (1g) or 2-isopropyl groups on the
benzamide (1h) showed similar enantioselectivities, but with a
substantial decrease in yield. Finally, attempts to employ
aliphatic N-tosylamides were unsuccessful; either N-tosyl- (1i)
or N-nosylacetamides (1j) were unreactive. Accordingly, on
the basis of yield and enantioselectivity, the 2-methylbenza-
mide was chosen as the optimal reagent for further studies.
3. Identification of Optimal Catalyst. Several chiral
diselenide catalysts were surveyed for yield and enantiose-
lectivity that varied the ester group of the (S)-7-methoxy-
1,2,3,4-tetrahydronaphthalene-8-diselenyl scaffold (Table 3).
Upon changing the 2-naphthoate ester to a benzoate ester
(3b), comparable enantioselectivity was observed, but with
significantly reduced yield. Alkyl esters such as tert-butanoyl
(3c) or 2-adamantoyl (3d) afforded poor yields with similar
enantioselectivities. Clearly, the 2-naphthoyl catalyst offered
the best results for both product yield and enantioselectivity.
isolated, purified products. Enantiomeric ratios were determined after
chromatographic purification by CSP-HPLC. See the Supporting
Information for details.
Table 3. Survey of Chiral Diselenide Catalysts for Optimal
Yield and Enantioselectivity
a
a
All reactions were performed on a 0.2 mmol scale. Yields are of
isolated material. Enantiomeric ratios were determined after
chromatographic purification by CSP-HPLC. See the Supporting
Information for details. Performed on a 0.05 mmol scale.
b
To determine the relative and absolute configurations of the
oxazoline products, oxazoline 4a derived from (E)-2-
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methylstyrene and benzamide 1f (96:4 er) was hydrolyzed to
the corresponding 1,2-amino alcohol with strong acid. The
optical rotation recorded for 1-amino-1-phenylpropan-2-ol
hydrochloride matched the reported literature value for an
absolute configuration of 1R,2R,28 which unsurprisingly
matched the absolute configuration observed in the alkene
1,2-diamination using the same chiral diselenide catalyst (see
the Supporting Information for details).
Table 4. Alkene Substrate Scope for Functional Group
Variation
a
From these studies, it was also determined that sodium
fluoride provided no constructive advantage and only led to
increased heterogeneity. Accordingly, NaF was omitted from
the final reaction conditions (see the Supporting Information
for details).
4. Scope of Alkene Substrates. The scope of alkene
substrates began with an investigation of the compatibility of
various functional groups (Table 4). As a baseline, 2-alkyl-
substituted alkenes such as (E)-2-methylstyrene and (E)-2-
isopropylstyrene provided 4a and 4b in good yields with high
levels of enantioselectivity. Substrates bearing functional
groups on the methyl substituent such as N-tosylaniline and
phthalimide led to 4c and 4d in high yields and excellent
enantioselectivities. Furthermore, a phthalimide substrate
bearing an additional methylene group afforded 4e in modest
yield, with negligible decrease in enantioselectivity. The
presence of a primary alkyl chloride was compatible under
the reaction conditions, producing 4f in high yield and
excellent enantioselectivity. Ether or ester functionalities were
also compatible leading to 4g and 4h in high yields and high
enantioselectivities. Similarly, a glycol-protected ketone was
viable, illustrating further compatibility with protecting group
strategies (4i). Changing the 2-methylbenzamide to a 2-
bromobenzamide improved the yield slightly though the
enantioselectivity decreased slightly (4j). Finally, as was the
case for 1,2-diamination, aliphatic alkenes afforded very poor
yields but high levels of enantioselectivity were conserved (4k).
Although the poor yield for dialkyl alkenes was disappointing
(and provides a critical direction for further investigation) the
current iteration of this method displays compatibility with a
wide range of functional groups.
Next, variation of the aromatic ring on the alkene substrate
was examined (Table 5). Products bearing electron-with-
drawing groups, in the case of 4-trifluoromethyl- (4l) or 2-
bromophenyl (4n) groups, were formed in modest yields with
good enantioselectivities. A substrate bearing a 4-methoxy
group afforded 4m in a comparable yield but with a notably
lower enantioselectivity. The use of aromatic systems beyond
substituted benzene rings was also explored; e.g., a 2-thienyl
group led to a modest yield and good enantioselectivity (4o).
A 2-naphthyl-substituted alkene afforded a good yield with
good enantioselectivity (4p). A similar yield was observed for
the product bearing a 1-naphthyl group (4q), but with lower
enantioselectivity.
a
All reactions were performed on a 1.0 mmol scale. Yields are of
isolated, analytically pure material. Enantiomeric ratios were
determined after chromatographic purification by CSP-HPLC. See
the Supporting Information for details. Performed on a 0.2 mmol
scale.
b
Stilbenes were also evaluated beginning with unsubstituted
(E)-stilbene, which provided a good yield with excellent
enantioselectivity (4r). Attachment of electron-donating 3-
methoxy groups to the stilbene core afforded a noticeable drop
in yield with a slight decrease in enantioselectivity (4s). The
regioselectivity of addition was tested with an unsymmetrically
substituted 4-methoxy-4′-trifluoromethylstilbene, which af-
forded a single diastereomer in excellent yield and
enantioselectivity (4t). This connectivity was established
through heteronuclear multiple bond correlation spectroscopy
(HMBC), observing a correlation between the oxazoline
HC(5) methine and the carbons on the trifluoromethyl
aromatic ring.
Although this protocol was successfully applied to a wide
range of alkene partners, a number of substrates provided less
than satisfactory yields (Table 6). Both acetate (2u) and
propargyl ether (2v) functionalities demonstrated only
moderate compatibility with the reaction conditions. Addi-
tionally, it was known from 4n that 2-substituted styrene
derivatives gave lower yields. Accordingly, a 2-methoxyphenyl
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a
Table 5. Alkene Substrate Scope for Variation on the
Aromatic Ring
Table 6. Alkene Substrates Affording Poor or No Yields
a
a
All reactions were performed on a 0.2 mmol scale. Yields are of
isolated purified material. See the Supporting Information for details.
b
a
Run with 40 mol % of di(2,4-dimethoxyphenyl) diselenide as the
All reactions were performed on a 1.0 mmol scale. Yields are of
c
catalyst. Run with 40 mol % of diphenyl diselenide as the catalyst.
isolated, analytically pure material. Enantiomeric ratios were
determined after chromatographic purification by CSP-HPLC. See
the Supporting Information for details.
5. Manipulation of Oxazoline Products. To demon-
strate the synthetic utility of this transformation, derivatization
of the oxazoline core was examined using product 4g as a
representative substrate (Scheme 4). First, conditions were
established for partial and full hydrolysis of the imidate
functionality to the corresponding 1,2-amino alcohol deriva-
tives. Subjecting the oxazoline to acidic conditions in THF and
methanol, followed by treatment with sodium bicarbonate,
provided the N-benzoylated product (5) without compromis-
ing the enantiomeric composition. In contrast, careful
treatment of the oxazoline under aqueous acidic conditions
furnished the O-benzoylated product 6 as a stable hydro-
chloride salt in high yield. Applying the conditions used to
furnish the 1,2-amino alcohol from (E)-2-methylstyrene for
determination of the absolute configuration with oxazoline 4g
resulted in partial deprotection of the benzyl ether.
Accordingly, a milder solution was investigated that would
be applicable to the benzyl ether of 4g as well as other sensitive
functionalities. To produce the parent 1,2-amino alcohol,
treatment of the O-benzoylated hydrochloride salt (6) with
alkene (2w) or 2,2′-dichlorostilbene (2x) afforded significantly
diminished yield. Finally, a number of alkene substrates led to
no productive conversion to the desired oxazoline products as
reactions stalled quickly without alkene consumption. Styrene
(2y), 1-methylstyrene (2z), and (Z)-2-methylstyrene (2aa) all
exhibited this behavior. On the other hand, allyl cinnamyl ether
(2ab) and cinnamyl alcohol (2ac) were completely consumed
without product formation. Additionally, indole-bearing 2ad
did not display conversion, despite consumption of the alkene
and its success in the diamination protocol. Attempts to
generate product from epoxide-bearing 2ae were also
unsuccessful. Furthermore, trisubstituted alkenes were largely
unsuccessful (2af−ah) and consumed the alkene without
product generation, with the exception of 2ai, which showed a
trace (<5%) amount of product by 1H NMR. Finally, an alkene
with a pendant tertiary amine (2aj) resulted in poor
conversion (17% by 1H NMR) with a very messy crude
reaction mixture.
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a
Scheme 4. Derivatization of the Oxazoline Core
a
Yields are of isolated, analytically pure material performed on a 1.0 mmol scale from racemic starting material. Enantiomeric ratios are of
chromatographically purified material performed on ≤0.2 mmol scale from enantioenriched starting material, determined by chiral stationary phase
b
HPLC. Refer to the Supporting Information for more details. Yield and enantiomeric ratio are of chromatographically purified material performed
on a 33.0 μmol scale from enantioenriched starting material.
DIBAL provided the free 1,2-amino alcohol, which was
transformed to the hydrochloride salt (7) (for stability
purposes) in excellent yield. The enantiomeric purity of this
product was evaluated by N-acylation of the hydrochloride salt
(7).29
Scheme 5. Synthesis of PHOX and Ligands Using the
Alkene 1,2-Oxyamination Method
a
Next, experiments were conducted for the direct conversion
of the oxazoline core into functionalized 1,2-amino alcohols.
Alkylation of 4g with methyl triflate followed by reduction of
the oxazolinium moiety produced the corresponding oxazoli-
dine (8) quantitatively. From the crude oxazolidine, reduction
with DIBAL produced the N,N-dialkylated product (9) in
good yield with preservation of enantiopurity. Furthermore,
telescoping treatment of the crude oxazolidine with acidic
conditions followed by Boc protection of the amine furnished
alcohol 10 in good yield again without erosion of
enantiopurity. The diverse array of enantioenriched products
formed from the oxazoline core demonstrates the utility of the
alkene 1,2-oxyamination method.
Finally, in view of the ubiquitous presence of oxazolines in
many ligand classes, the utility of this 1,2-oxyamination
protocol was further demonstrated by synthesis of phosphi-
nooxazoline (PHOX) ligands. For the assembly of the PHOX
ligand (Scheme 5), 2-(bromophenyl) and 2-(fluorophenyl)-
oxazoline derivatives were produced through the oxyamination
protocol using (E)-stilbene as the substrate in good yields and
enantioselectivities (4u−v). From 4u, a copper-coupling
method using diphenylphosphine, described by Stoltz and
co-workers,30 produced the targeted PHOX ligand (11) in
69% yield. Additionally, the canonical SNAr attack on 4v with
potassium diphenylphosphide also produced the targeted
PHOX ligand in 44% yield.
a
All reactions were performed on a 1.0 mmol scale. Enantiomeric
ratios were determined after chromatographic purification by CSP-
HPLC. Yields are of isolated, analytically pure materials. See the
b
Supporting Information for details. Performed on 0.6 mmol scale.
c
d
Performed on 0.45 mmol scale. Enantiomeric ratios were
determined after chromatographic purification by CSP-SFC.
DISCUSSION
■
the nucleophilic addition was degenerate, whereas the
oxyamination results in two possible constitutional isomers.
Foremost, the regioselectivity of this addition is largely dictated
by the electronic character of the seleniranium ion
intermediate (Figure 2a). In alkenes that contain an aryl and
One of the distinguishing aspects of this alkene 1,2-
oxyamination method when compared to the alkene 1,2-
diamination method is the regioselectivity of the addition of
the oxygen and nitrogen nucleophile. In the diamination case,
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of the nitrogen nonbonding electron pair to the carbonyl
group. Second, the pKa of the N−H bond is predicted to be
∼5, which would allow for it to be easily deprotonated by the
2,4,6-collidine, increasing its nucleophilicity. Accordingly, it
follows that the nitrogen on the N-tosyl benzamide should act
as the first nucleophile to attack the seleniranium ion at the site
more capable of supporting positive charge. Finally, because
the seleniranium ion formation is syn selective, the nucleophilic
attack on the seleniranium ion takes place in an anti fashion,
and the subsequent displacement of the Se(IV) intermediate
by the carbonyl oxygen is invertive (see Scheme 3d), the
overall stereochemical outcome can be predicted from the
alkene geometry. Thus, an E alkene will result in a trans
relationship for the 4,5-substitutents on the oxazoline, whereas
a Z alkene would result in a cis relationship.
Although this alkene 1,2-oxyamination method provided
high yields and enantioselectivities for a wide range of
substrates, still many limitations provide opportunities for
improvement. One notable aspect of the current protocol is the
reduction in yield for styrenyl substrates bearing ortho
substitutions. In the cases of a 2-methoxyphenyl alkene (2w)
or 2,2-dichlorostilbene (2x), the yield was significantly
diminished, potentially owing to the steric encumbrance of
the alkene affecting either the seleniranium ion formation or
the nucleophilic opening of the seleniranium ion, if formed.
Furthermore, when a 1-naphthyl alkene was used (2q), the
product conversion was good, but the enantioselectivity was
attenuated compared to the 2-naphthyl substrate (2p). In this
case, it appears that the increased steric bulk of the 1-naphthyl
group interferes with the enantioinduction provided by the
chiral selenium catalyst.
Figure 2. Regioselectivity of attack on the electrophilic sites in the
seleniranium ion.
an alkyl substituent, the stabilization of the partial positive
charge (pink) by the aryl substituent renders this site more
electrophilic than the alkyl site (green). In the case of the
unsymmetrical stilbene (2t), the electron donating nature of
the 4-methoxy group enhances that stabilization more so than
the 4-trifluoromethyl group and accordingly leads to product
4t in which the nitrogen atom resides next to that substituent.
Furthermore, when comparing the relative nucleophilicities of
the oxygen and nitrogen nucleophiles on the N-tosyl
benzamides (Figure 2b), the electron-withdrawing nature of
the tosyl group would lower the propensity for delocalization
Figure 3. Kinetic plots for the alkene 1,2-oxyamination reaction. All reactions were performed on a 0.2 mmol scale with 0.2 mmol of 1,1,2,2-
tetrachloroethane as an internal standard. Yields were determined through quantitative comparison of integrations. For (E)-4-octene, 25 mol % of
catalyst was used.
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With regard to the substrates in Table 6 that provided poor/
no product yield, the reaction profile for styrenes (2y/2z), as
well as (Z)-2-methylstyrene (2aa), displayed stalling with only
partial consumption of the alkene and no product conversion.
Additionally, sensitive functionalities such as allyl (2ab) or
epoxide groups (2ae) likely interfere with other reactive groups
(including the possibility of intramolecular reactivity with the
alkene) in the system before the alkene is able to affect the
productive reaction. Trisubstituted alkenes (2af−ai), which
were also a challenge for the 1,2-diamination chemistry, are
likely too sterically encumbered for either seleniranium ion
formation or the nucleophilic attack thereon. However, the
observation of observable reactivity for 2ai shows promise that
tuning of the selenium catalyst and/or nucleophilic reagent
could provide reactivity for this substrate class in the future.
Finally, the diminished reactivity in the presence of a tertiary
amine (2aj) likely arises from the coordinative effect of the
nonconjugated electron lone pair on the nitrogen interfering
with electrophilic species within the reaction system.
Experimental procedures and characterization data for
all new compounds (PDF)
AUTHOR INFORMATION
■
Corresponding Author
Scott E. Denmark − Roger Adams Laboratory, Department of
Chemistry, University of Illinois, Urbana, Illinois 61801,
United States; orcid.org/0000-0002-1099-9765;
Phone: (217) 333-0066; Email: sdenmark@illinois.edu;
Fax: (217) 333-3984
Authors
Emily M. Mumford − Roger Adams Laboratory, Department
of Chemistry, University of Illinois, Urbana, Illinois 61801,
United States
Brett N. Hemric − Roger Adams Laboratory, Department of
Chemistry, University of Illinois, Urbana, Illinois 61801,
United States
In addition to these problematic alkene classes, the most
serious deficiency is the poor performance with aliphatic
alkenes, such as (E)-4-octene, suggesting the need for an
improved catalyst system. An initial hypothesis suggested that
the aliphatic alkene sources were particularly unreactive.
However, time course monitoring found them to be consumed
extremely rapidly compared to a selection of different alkene
types that led to productive reaction (Figure 3a). Correspond-
ingly, although the productive conversion of other alkene
partners was well-behaved, the reaction of (E)-4-octene
showed no productive conversion early in the reaction and
minimal productive conversion by 5 h, by which time the other
alkene sources had achieved a productivity plateau (Figure 3b).
This rapid consumption of the alkene, coupled with the
sluggish conversion to product suggests the presence of a
deleterious pathway, such as alkene polymerization, that
outcompetes the productive oxyamination reaction. A number
of remediations were attempted to overcome this deleterious
pathway, such as slow addition of the alkene, use of a large
excess of (E)-4-octene, and increasing/decreasing the dis-
elenide catalyst loading; however, none of these efforts
improved the reaction outcome. Moving forward, it is clear
that a more tailored diselenide catalyst (potentially in concert
with a more nucleophilic bifunctional nucleophile) will be
needed to access this alkene class by outcompeting the off-
cycle reactivity.
Complete contact information is available at:
https://pubs.acs.org/10.1021/jacs.1c06750
Author Contributions
†E.M.M. and B.N.H. contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors are grateful to the National Science Foundation
(NSF CHE 1664376 and CHE 2102232) for generous
financial support. The authors are indebted to Dr. Zhonglin
Tao and Dr. Bradley B. Gilbert for synthesis of several
substrates. The authors also thank the UIUC SCS support
facilities (microanalysis, mass spectrometry, and NMR) for
their assistance.
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CONCLUSIONS AND FUTURE DIRECTIONS
■
In conclusion, a mild chemo-, regio-, diastereo-, and
enantioselective alkene 1,2-oxyamination has been developed
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ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/jacs.1c06750.
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