Organoselenium-catalyzed enantioselective syn-dichlorination of unbiased alkenes

Article abstract of DOI:10.1016/j.tet.2019.05.054

The enantioselective dichlorination of alkenes is a continuing challenge in organic synthesis owing to the limitations of selective and independent antarafacial delivery of both electrophilic chlorenium and nucleophilic chloride to an olefin. Development of a general method for the enantioselective dichlorination of isolated alkenes would allow access to a wide variety of polyhalogenated natural products. Accordingly, the enantioselective suprafacial dichlorination of alkenes catalyzed by electrophilic organoselenium reagents has been developed to address these limitations. The evaluation of twenty-three diselenides as precatalysts for enantioselective dichlorination is described, with a maximum e.r. of 76:24 Additionally, mechanistic studies suggest an unexpected Dynamic Kinetic Asymmetric Transformation (DyKAT) process may be operative.

Full text of DOI:10.1016/j.tet.2019.05.054

Accepted Manuscript
Organoselenium-catalyzed enantioselective syn-dichlorination of unbiased alkenes
Bradley B. Gilbert, Stanley T.-C. Eey, Pavel Ryabchuk, Olivia Garry, Scott E.
Denmark
PII:
S0040-4020(19)30616-7
https://doi.org/10.1016/j.tet.2019.05.054
TET 30375
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 26 April 2019
Revised Date: 22 May 2019
Accepted Date: 24 May 2019
Please cite this article as: Gilbert BB, Eey ST-C, Ryabchuk P, Garry O, Denmark SE, Organoselenium-
catalyzed enantioselective syn-dichlorination of unbiased alkenes, Tetrahedron (2019), doi: https://
doi.org/10.1016/j.tet.2019.05.054.
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ACCEPTED MANUSCRIPT
Graphical Abstract
enantio- and diastereoselective syn-dichlorination
Ar*SeSeAr* (5 mol %)
[BnNEt3 ][Cl-] (3.0 equiv.)
+
Cl
O
-
[PyrF+][BF4 ] (1.3 equiv.)
O
3
4
5
1
Me
OBn
2
Me3SiCl 16 (2.0 equiv.)
MeCN (0.2 M), rt
Me
OBn
Cl
>95:5 dr; up to 76:24 er

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Gilbert, Eey, Ryabchuk, Garry, and Denmark
page 1
Organoselenium-Catalyzed Enantioselective Syn-Dichlorination of Unbiased
Alkenes
Bradley B. Gilbert, Stanley T.-C. Eey, Pavel Ryabchuk, Olivia Garry, and Scott E. Denmark*
REVISED
Submitted to
Tetrahedron
Address Correspondence to:
Professor Scott E. Denmark
245 Roger Adams Laboratory, Box 18
Department of Chemistry
University of Illinois
600 S. Mathews Ave
Urbana, IL 61801
tel: (217) 333-0066
FAX: (217) 333-3984
e-mail: sdenmark@illinois.edu
Abstract
The enantioselective dichlorination of alkenes is a continuing challenge in organic
synthesis owing to the limitations of selective and independent antarafacial delivery of both
electrophilic chlorenium and nucleophilic chloride to an olefin. Development of a general
method for the enantioselective dichlorination of isolated alkenes would allow access to a wide
variety of polyhalogenated natural products. Accordingly, the enantioselective suprafacial
dichlorination of alkenes catalyzed by electrophilic organoselenium reagents has been developed
to address these limitations. The evaluation of twenty-three diselenides as precatalysts for
enantioselective dichlorination is described, with a maximum e.r. of 75:25. Additionally,
mechanistic studies suggest an unexpected Dynamic Kinetic Asymmetric Transformation
(DyKAT) process may be operative.
Keywords: Enantioselective Dichlorination, Electrophilic Selenium, Redox Catalysis

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1. Introduction
The vicinal dihalogenation of alkenes is familiar to every organic chemist and is taught in
every introductory organic chemistry course. This special stature is a consequence of its
generality for a wide variety of alkenes and the predictable diastereoselectivity associated with it.
The relative configuration of the dihalide products and the mechanistic explanation for the
diastereoselectivity observed were a matter of great debate in the early 20th century.1, 2 The
intermediacy of haliranium ions and the stereochemical requirement of invertive opening
eventually gained acceptance, and much later the isolation and characterization of stable
bromiranium ions established their existence with certainty.3, 4
Despite this foundational mechanistic understanding and the high diastereoselectivity
obtained with many electrophilic halogen sources, methods available for catalytic,
enantioselective vicinal halogenation of alkenes are distinctly lacking when compared to the
myriad other vicinal, difunctionalization reactions of alkenes such as epoxidation,5-7
dihydroxylation,8-10 hydrogenation,11-13 and intramolecular halofunctionalization.14-16
This deficiency is not for a lack of necessity; several classes of vicinally polyhalogenated
(usually marine) natural products could be efficiently prepared were a selective alkene
dihalogenation available (Figure 1).17 Owing in part to this limited synthetic accessibility, much
less is known about the biological activities of these natural products compared to terrestrial
bacterial, plant, and fungi isolates.

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Figure 1. Representative chlorosulfolipids, a
subclass of halogenated natural products.
Synthetic approaches to these natural products involve diastereo- and enantioselective
generation of oxygen-bearing stereocenters through historically well-developed asymmetric
oxidations and subsequent stereospecific replacement of oxygen with chlorine or alcohol-
directed diastereoselective dichlorination.18-22 Although several of these natural products have
been obtained in what are undoubtedly impressive feats of total synthesis, the multiple steps
required to enantioselectively transform an alkene into a vicinal dichloride highlight a major
shortcoming in the synthetic organic chemist's toolkit.
Although several attempts have been made to address this challenge in the last decade
(vide infra), all are reliant on halenium ion (or equivalent) delivery to an alkene, resulting in a
haliranium ion, which is subsequently opened by a halide anion to afford the vicinal dihalide in
an overall antarafacial fashion. Numerous hurdles must be overcome to design an alkene
dihalogenation by this approach (Scheme 1).23, 24 In a simplified system, chiral catalyst (Cat*),
coordinated by either hydrogen bonding, Lewis base association, or ion pairing to the
electrophilic halogen source (X+), delivers the halenium ion to the olefin with enantiofacial
selectivity. The possibility for enantiofacial selectivity in this transfer may be attenuated by the

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page 4
stereoelectronic requirement of interaction between the alkene π-orbital and the Cat*–X σ*
orbital, placing the most significant steric effects of the chiral catalyst far from the alkene,
axially opposite the halenium ion (Scheme 1, right). The haliranium ion thus formed is opened
by halide (X–) to afford the dihalide product. To achieve high enantioselectivity (assuming high
enantiofacial selectivity), first, halenium ion transfer to the alkene should be irreversible.25
Second, the haliranium ion thus formed should be configurationally stable. Finally, nucleophilic
trapping of the haliranium ion must be biased toward one carbon terminus of the ion, as the two
possible ring-opened products are enantiomeric. Consequently, both haliranium ion formation
and capture must be highly selective to afford highly enantioenriched vicinal dihalide product.
Scheme 1. Symmetry analysis of stereochemical
transformations in enantioselective antarafacial-
vicinal dihalogenation. Enantiodetermining steps are
highlighted with bold arrows. Cat* = chiral catalyst,
X = halogen.
In spite of the hurdles to the development of an enantioselective anti-dihalogenation,23
four methods for catalytic, enantioselective dichlorination following this process have been
developed (Figure 2).26-30

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A: Nicolaou and coworkers
(DHQ)2PHAL (20 mol %)
Cl
p-Ph-C6H4-ICl2 (1.6 equiv)
Ar
OH
Ar
OH
CH2Cl2 (0.05 M)
-78 ºC, 2.5-12 h
Cl
1
32-90% yield
72:28 - 90:10 e.r.
2
B: Borhan and coworkers
NO2
(DHQD)2PHAL (10 mol %)
DCDMH (2.0 equiv)
NO2
Cl
H
H
R2
R2
Cl
N
N
LiCl (100 equiv)
TFE (0.02 M)
-30 ºC
R1
R1
O
O
3
60-95% yield
90:10 - >99:1 e.r.
4
C: Hennecke and coworkers
R = 1-naphthyl
Ligand
DCDMH (1.2 equiv)
Et3SiCl (1.0 equiv)
Ligand 6 (10 mol%)
Et
Cl
R1
N
R1
Cl
R2
R2
O
CHCl3/hexane (1:1, 0.10 M)
-60 ºC, 48 h
H
Y
Y
MeO
N
N
O
5
40-98% yield
74:26 - 93:7 e.r.
7
N
R
R
6
D: Burns and coworkers
t-Bu
Ligand
t-BuOCl (1.1-1.5 equiv)
ClTi(Oi-Pr)3 (1.1-1.6 equiv)
Ligand 9 (10-30 mol %)
HO
R1
R1
OH
Cl
R2
R2
R
OH
OH
N
Ph
t-Bu
hexanes, -20 ºC
4-12 h
3 Cl
R3
Ph
9
8
45-83% yield
90:10 to 95:5 e.r.
10
Figure 2. State of the art for catalytic enantioselective dichlorination.
Nicolaou and coworkers first achieved moderate to good enantioselectivities for the
dichlorination of cinnamyl alcohols 1.26 This method employs Lewis base (ligand-accelerated)
catalysis to activate an iodosobenzene dichloride derivative as the chlorenium ion and chloride
source. Both the alcohol and aromatic ring on the substrate alkene are necessary to achieve good
selectivity, most likely due to the requirement for hydrogen-bonded ligand association to the
substrate a strong electronic bias for selective chloriranium ion opening.
Adaptation of these conditions by Borhan and coworkers to the dichlorination of allylic
amides 3 afforded a wide variety of E and Z-disubstituted alkenes with excellent yields and
selectivities.27 In contrast to the method of Nicolaou and coworkers, Cinnamyl and 3,3-dialkyl
(trisubstituted) alkene substrates afforded dichloride products with lower enantiomeric ratios,
suggesting that the electronic bias of chloriranium opening generally favors the carbon proximal

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Gilbert, Eey, Ryabchuk, Garry, and Denmark
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to nitrogen, and stabilization of partial positive charge at the distal carbon reduces that
selectivity.
Most recently, Hennecke and coworkers have further adapted this method, through
modification of cinchona alkaloid-derived ligand, to afford dichloride products in modest to
excellent selectivities from alkenes 5 not bearing allylic hydrogen-bonding functional groups.28
The method does nonetheless still rely on styrenyl substrates to bias chloriranium opening
toward the carbon proximal to the benzene ring. Furthermore, the substrate scope was limited to
Z-olefins and only a select few electron-poor dihydronaphthalenes gave dichloride products with
e.r. greater than 90:10.
Perhaps the most general method, developed by Burns and coworkers, requires allylic
alcohol substrates 7 but has a much broader scope. Here, a halotitanium triisopropoxide complex
and a halenium ion source (t-BuOCl or NBS) with catalytic amounts of a Salen-type ligand
provide vicinal anti-dihalide products. Exquisite selectivity is obtained in bromochlorination,
dibromination, and dichlorination across a wide variety of 1,1-di-, 1,2-E- and Z- di-, and
trisubstituted olefins. The scope and selectivity of the method rivals the Sharpless asymmetric
epoxidation (Scheme 2).29-30

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NBS (1.05 equiv.)
ClTi(Oi-Pr)3 (1.10 equiv.)
Ligand ent-9 (10-30 mol%)
R1
R1
Br
R2
R2
R
OH
OH
t-Bu
hexanes, -20 ºC
4-12 h
Ligand
3 Cl
R3
HO
8
OH
10
Br
Cl
N
Ph
t-Bu
Cl
Cl
HO
Ph
HO
Ph
Ph
HO
ent-9
Me
Me Br
Br
92% yield
95.5:4.5 e.r.
59% yield
95:5 e.r.
94% yield
10c
10a
10b
94.5:5.5 e.r.
t-BuOCl (1.1-1.5 equiv.)
ClTi(Oi-Pr)3 (1.1-1.6 equiv.)
Ligand 9 (10-30 mol%)
R1
R1
Cl
R2
R2
R
OH
OH
hexanes, -20 ºC
4-12 h
t-Bu
Ligand
3 Cl
R3
HO
8
OH
10
N
Cl
Cl
Cl
Cl
Ph
t-Bu
Et
Ph
9
Me
OH
OH
OH
Ph
10d
Cl
Cl
45% yield
92.5:7.5 e.r.
61% yield
95:5 e.r.
64% yield
90:10 e.r.
10f
10e
Scheme 2. Enantioselective dihalogenation of allylic alcohols
developed by Burns et al.
Similar to the method of Nicolaou et al., this transformation is suggested to operate
within a similar manifold of Lewis base, or ligand accelerated, catalysis. The halenium ion
source is only reactive enough to oxidize the alkene once it has been coordinated to a ligated
titanium center (coordination to chlorotriisopropoxytitanium is insufficient as little background
reaction is observed in the absence of ligand). A structural limitation to the scope of this
antarafacial dihalogenation is the requirement for an allylic alcohol to direct halenium ion and
halide addition to the double bond. Although this feature can be leveraged to their advantage as
evidenced by the presence of simple alkenes left untouched in a variety of products, the
limitation does emphasize the need to overcome unselective haliranium ion opening by tethering
the halide source, tightly bound to titanium, to the alcohol.
In contrast to these antarafacial vicinal dihalogenations, suprafacial dihalogenation
(pictured below as proceeding through a different –iranium ion intermediate but true for all
suprafacial dihalogenations)31-34 converges to a single enantiomer, or does not proceed through

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an intermediate that could diverge (Scheme 3). Here, an electrophilic complex Cat*–Y reacts
with the alkene to form non-halo –iranium ion. This intermediate is then opened at either
constitutionally heterotopic carbon to afford a mixture of isomers. This isomeric mixture
converges to a single dihalide product by displacement of Cat*–Y (now in reduced form) from
the alkane backbone of the product. Thus, the only requirements for a selective process are now
irreversible –iranium ion formation and configurational stability of that intermediate.
Scheme 3. Symmetry analysis of stereochemical
transformations in enantioselective suprafacial-vicinal
dihalogenation. Enantiodetermining step is highlighted with
a bold arrow. Cat* = chiral catalyst (or ligand), X =
halogen.
This alternative approach is distinguished by the presence of the chiral, enantioenriched
catalyst backbone Cat* in the –iranium ion and ring-opened intermediates, as Y is, unlike X, an
atom with valence greater than 1. This higher valence also allows for greater variety in the
transition state geometry of –iranium ion formation (Scheme 3, right) and the portion of the
catalyst bearing features that convey stereochemical information can be brought in closer
proximity to the olefin than in the necessarily linear Cat*–X–alkene complex (Scheme 1, right).
The mode by which two halogen atoms are incorporated into the product molecule is also
unique compared to the antarafacial dihalogenations, as both equivalents of X are introduced as
halide anions. The second halide equivalent displaces Cat*–Y from the product and results in the
formation of anionic Cat*–Y– (Scheme 4). This catalyst must be reoxidized for the cycle to turn

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over, standing in contrast to the requirement of separate halide and halenium ion sources in
conjunction for antarafacial vicinal dihalogenations. This type of transformation has been
previously categorized as a member of the larger group of "group-transfer catalysis,"35 but could
be more precisely referred to as "redox catalysis."
Scheme 2. Net transformation for suprafacial
dihalogenation and redox catalytic cycle. Y =
transition metal or main group element; oxidation
states are relative, not absolute.
The structural limitations to the scope of antarafacial enantioselective dichlorination
reactions could be overcome by employing a suprafacial dichlorination wherein the alkene need
not be electronically (or otherwise) biased. In the case of a catalytic, enantioselective syn-
dichlorination proceeding through an alternative –iranium ion, and provided that –iranium ion
formation is irreversible, then formation of that ion alone would be stereodetermining. The ring-
opening of this cationic intermediate is inconsequential to the final enantiomeric ratio,
simplifying the challenge in simultaneous installation of adjacent halogenated stereocenters.

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2. Background
As a prelude to the development of an enantioselective vicinal dihalogenation, these
laboratories recently disclosed the stereospecific syn-dichlorination of alkenes using redox
catalysis (Scheme 5).24 The reaction employs diphenyl diselenide (PhSeSePh 13) as the
precatalyst, with benzyltriethylammonium chloride ([BnNEt3]+[Cl]– 14) as the chloride source
and N-fluoropyridinium tetrafluoroborate ([PyF]+[BF4]– 15) as the oxidant. Trimethylsilyl
chloride (Me3SiCl 16) was also employed in stoichiometric amounts to serve as a trap for the
fluoride generated as a byproduct of oxidation. The reaction shows good functional group
tolerance, proceeding smoothly in the presence of neighboring nucleophilic groups that would
often be expected to participate in anchimeric assistance (12b, d), and leaving electron-poor
olefins untouched (12c). Diastereoselectivity was excellent with respect to stereocenters already
present on the alkene substrate (12f).
Scheme 5. Stereospecific syn-dichlorination of
olefins: representative scope.
The mechanistic hypothesis for the catalytic cycle is based on previous knowledge of the
elementary steps.36-40 Namely, that diphenyl diselenide is oxidized to phenylselenyl trichloride

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page 11
with three equivalents of chlorine (or other electrophilic chlorine source), that areneselenenyl
trichlorides react with olefins to give chloroselenylated adducts, and that chloroalkyl
areneseleninium(IV) dichlorides can be displaced by chloride to afford syn-vicinal dichlorides
(Scheme 6).
Scheme 6. Stereospecific syn-dichlorination of olefins:
mechanistic hypothesis. Ox = [BnNEt3]+[Cl]– (14) + [PyF]+[BF4]–
(15) + Me3SiCl (16).
At reaction onset, diphenyl diselenide is oxidized to two equivalents of
phenylselenium(II) chloride 17 with one equivalent each of chloride source 14, oxidant 15, and
fluoride scavenger 16. Typically, alkene is not added until the other reaction components have
been stirred for 10 minutes at room temperature, so this oxidation presumably occurs once more
to afford phenylselenium(IV) trichloride 18. Subsequent ionization is assumed necessary to
afford the charge-separated complex 19, which has the requisite open valence available for
alkene coordination. Reaction with alkene produces the Se(IV) seleniranium ion 20, which can
be opened antarafacially by chloride at either of the constitutionally heterotopic carbons,

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affording a mixture of isomers 21a and 21b. Ionization to 22 followed by stereospecific, SN2
displacement of the cationic phenylselenium(IV) chloride by chloride anion results in a
convergence of these constitutional isomers to a single vicinal syn-dichloride product 12 and
regenerates phenylselenium(II) chloride 17.
The β-chloroalkyl phenylselenium(IV) dichlorides 21 are postulated to be the catalytic
1
resting state based on their presence in the H NMR spectra of incomplete reaction mixtures.
Thus, the turnover-limiting step is likely the ionization of 21 to 22 and nucleophilic displacement
by chloride to afford the product syn-dichloride 12.
Further catalytic turnover need not, however, proceed again through oxidation to 18, but
could instead result from reaction of 17 with alkene to form Se(II) seleniranium ion 23.
Antarafacial nucleophilic ring opening at the constitutionally heterotopic carbons by chloride
affords β-chloroalkyl phenyl selenides 24a and 24b. This mixture of aryl-alkyl selenides is then
further oxidized by 14/15/16 to return to the previous cycle at 21a and 21b. These two paths are
indistinguishable by NMR analysis of an incomplete reaction mixture, as the resting state of
either pathway could be at their point of convergence, i.e. 21. Indeed, the relative rates of
oxidation of 17 versus its reaction with alkene may vary with the concentration of alkene or
oxidant, both of which decrease as the reaction progresses.
Nevertheless, phenylselenyl chloride 17 was demonstrated to be an effective catalyst for
the stereospecific vicinal syn-dichlorination of alkenes, allowing for the opportunity to develop
an enantioselective method using a chiral, enantioenriched arylselenium catalyst.
Diastereoselective selenofunctionalizations have been performed with a variety of chiral,
enantioenriched electrophilic selenium reagents in the last several decades.41 It was thus
hypothesized that application of one of these reagents to syn-dichlorination could potentially

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page 13
result in good enantioselectivity, provided that the initial seleniranium ion formation proceeded
with high enantiotopic face selectivity. Moreover, the structural features that lead to high
selectivity in diastereoselective selenofunctionalizations have been identified, allowing for the
formulation of selectivity models that can be used to improve the performance of these
reagents.41, 42 Such chiral, enantioenriched organoselenium reagents typically feature an aryl
selenide substituted at the 2-position by a stereogenic substituent bearing a coordinating
heteroatom (O, N, S) (Figure 3).
Figure 3. General structure for a chiral,
enantioenriched organoselenium reagent. Y
= O, N, S; R1 = R2 = alkyl, aryl; X = Cl, Br,
OTf, HSO4, PF6, etc.
The coordination of the heteroatom to the electrophilic selenium atom (i.e. chalcogen
bonding, Lewis base activation of Lewis acid),43, 44 rigidifies the structure and enhances
electrophilicity. In addition to the use of these chiral, enantioenriched organoselenium reagents
to stoichiometric, diastereoselective processes, several applications to catalytic enantioselective
transformations have also been reported, namely in inter- and intramolecular
selenofunctionalization-eliminations (Scheme 7).45-50

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page 14
Scheme 7. Catalytic, enantioselective
allylic etherification with chiral,
enantioenriched electrophilic selenium
catalysts.
Previous studies in organoselenium catalyzed suprafacial dichlorination show that anti-
dichlorination can be observed, likely owing to chloride oxidation to chlorine, when catalyst
turnover becomes sluggish. Thus, the catalyst design was guided by the optimization of two key
parameters: sufficient room-temperature turnover to avoid anti-dichloride formation, and
excellent enantiotopic face selectivity.
3. Results and Discussion
3.1. Synthesis and Evaluation of Chiral, Enantioenriched Diselenides
3.1.1. Diselenides Bearing Ether Coordinating Groups
Orienting experiments for enantioselective dichlorination began with the most
synthetically accessible chiral diselenides that also displayed optimal diastereoselectivity in
selenofunctionalization reactions. Thus, diether 34 was selected as the first target as it was
accessible by well-described synthetic transformations in six steps from 2-bromoisophthalic
acid.51, 52 These syn-dichlorination reactions were performed with conditions identical to those
used in the racemic reaction catalyzed by diphenyl diselenide (Scheme 5). E-4-Hexen-1-yl
benzyl ether 30 and benzyl E-4-hexenoate 31 were selected as substrates for their synthetic

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page 15
accessibility and lack of any strong electronic bias. Although the diselenide precatalyst effected
dichlorination much more slowly than diphenyl diselenide, and a significant portion of anti-
dichloride was obtained from background oxidation of chloride, the enantiomeric ratio of 61:39
for the syn-dichloride was an encouraging first result suggesting that enantioselection was
achievable with chiral diselenides (Table 1, entry 1).
Table 1. Syn-Dichlorination Selectivities of Catalysts Bearing Ether Coordinating Groups.
entry
1
catalyst
product; d.r. (syn/anti)a
32; 30:70
e.r.c
configurationb
61:39
R,R
34
32; >95:5
33; >95:5
54:46
54:46
S,S
S,S
2
3
4
5
35
36
37
38
32; 90:10
32; 70:30
32; 90:10
55:45
58:42
50:50
S,S
R,R
--
a
The d.r. was determined by 1H NMR integration of diagnostic signals at HC(4) and HC(5) (see
b
Experimental).
The absolute configuration of the major enantiomer was determined by elution order
compared to dichloride of known configuration (for Y = O) or by analogy to the ester (for Y = H2) (see
c
Supporting Information). The e.r. was determined by chiral stationary phase HPLC (see Supporting
Information).
This initial result suggested that the steric crowding about the selenium atom was
contributing to the significant attenuation of the rate of the catalytic process and motivated the
investigation of singly 2-substituted catalyst structures. Thus, the methyl ether 3553, 54, (entry 2)
gave substantially improved reactivity, but with a decrease in enantioselectivity. Exchanging the

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page 16
methyl ether for the benzyl ether in 36 (entry 3) resulted in similar selectivity, while the acetate
3755 (entry 4) improved enantioselectivity with concomitant decrease in diastereoselectivity.
Exchange for a methoxymethyl acetal in 3856 (entry 5) gave nearly racemic product.
3.1.2. Diselenides Bearing Carbonyl Coordinating Groups
It was readily apparent that the oxygen substituent imparted relatively little influence on
enantioselectivity. Finding a more selective catalyst would require examining different
coordinating groups and catalyst geometries. Urea 3957 was therefore selected for its alternative
binding mode in which the carbonyl oxygen serves as an alternative coordinating group, forming
what is expected to be a 7-membered ring. The dichloride products obtained with urea 39 and
with the novel pivalamide 40 (Table 2, entries 1 and 2) had enantiomeric ratios exceeding any
previously obtained with absolute configuration matching what was obtained with acetate 37.
Further examination involved structural modifications to the pivalamide catalyst 40.
Exchange of the methyl group adjacent to the stereocenter for an isopropyl group on 41 resulted
in a decrease in both enantioselectivity and diastereoselectivity (entry 3). Substitution of the
aromatic ring at the 6-position with a methoxy group or a benzene ring fusion (42 and 43) also
resulted in a decrease in enantioselectivity (entries 4 and 5). Only placement of a methyl group at
the 6-position in 44 resulted in an increase in enantioselectivity, albeit with an attendant decrease
in diastereoselectivity (entry 6), likely due to increased steric crowding about the reactive center,
thus attenuating the catalytic rate.

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page 17
Table 2. Syn-Dichlorination Selectivities of Catalysts Bearing Carbonyl Coordinating Groups.
entry
1
catalyst
33 d.r. (syn/anti)a
e.r.c
e.s.
configurationb
70:30
65:35
65:35
R,R
39
40
41
90:10
83:17
65:35 65:35
R,R
S,S
2
3
62:38
58:42
62:38
59:41
4
5
6
42d
43e
95:5
80:20
80:20
R,R
R,R
R,R
61:39
73:27
64:36
74:26
44f, g
a
1
b
The d.r. was determined by H NMR integration of diagnostic signals at HC(4) and HC(5) (see Experimental).
The absolute configuration of the major enantiomer was determined by elution order compared to dichloride of
known configuration (see Supporting Information). c The e.r. was determined by chiral stationary phase HPLC (see
d
e
f
Supporting Information). The e.r. of the catalyst was 95:5. The e.r. of the catalyst was 90:10. The e.r. of the
catalyst was 97:3. g Reaction with (Z)-31 afforded predominately the anti-dichloride with a d.r. of 70:30 and an e.r.
of 55:45.
3.1.3. Diselenides Bearing Oxazoline Coordinating Groups
A reasonable hypothesis posited that the relatively weak binding of the ether and
carbonyl coordinating groups were contributing to the low selectivities. Under this premise
stronger Lewis basic donors beginning with readily accessible oxazolines were tested. Although
oxazoline coordinating groups had previously been employed in diastereoselective
selenofunctionalizations,58 diselenide 45 did not impart any appreciable selectivity in
dichlorination (Table 3, entry 1). Catalysts 46-49 were prepared to examine the effect of 6-
membered ring coordination structures. Systematic variation of the substituent adjacent to the

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coordinating nitrogen atom had very little effect on enantioselectivity (entries 2-5). The most
significant effect of the stronger coordinating group can be observed in the decreased
diastereoselectivity across all oxazoline catalysts, that is, the stronger coordinating group
resulted in slower catalytic dichlorination and greater predominance of the background anti-
dichlorination. Introduction of an adjacent, bulky group led to further deterioration of the
diastereomeric ratio.
Table 3. Syn-Dichlorination Selectivities of Catalysts Bearing Oxazoline Coordinating Groups.
entry
1
catalyst
33 d.r. (syn/anti)a
e.r.c
configurationb
60:40
50:50
--
45
46
47
48
49
90:10
90:10
83:17
70:30
54:46
53:47
52:48
50:50
R,R
S,S
S,S
--
2
3
4
5
a
1
The d.r. was determined by H NMR integration of diagnostic signals at HC(4) and HC(5) (see
b
Experimental).
The absolute configuration of the major enantiomer was determined by elution
c
order compared to dichloride of known configuration (see Supporting Information). The e.r. was
determined by chiral stationary phase HPLC (see Supporting Information).
3.1.4. Bicyclic Diselenides
At this stage greater variation in catalyst backbone was sought, with a return to more
weakly coordinating neighboring heteroatoms to improve diastereoselectivity. Rigid tetralin-
derived organoselenium reagents had been previously described and appeared to be suitable
candidates.54, 56 Additionally, related electrophilic selenium reagents had recently been employed

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catalytically to afford excellent enantioselectivities in oxidative lactonization.59 Silyl ether 50
provided the dichloride in a d.r. of >95:5 and an e.r. of 74:26 (Table 4, entry 1). Exchanging the
silyl ether for a benzoate, pivalate, or methoxymethyl acetal (51-53) resulted in a decrease in
enantioselectivity (entries 2-4), whereas replacing the tert-butyldimethylsilyl ether with a
triisopropylsilyl ether 54 resulted in only a slight improvement in enantioselectivity (entry 5).
The ring-contracted indane catalyst 55 gave poorer selectivity, as did the ring-expanded
benzosuberan catalyst 56 (entries 6 and 7). Notably, all of the catalysts derived from tetralin 50
Table 4. Syn-Dichlorination Selectivities of Rigid Bicyclic Catalysts.
entry
1
catalyst
33 d.r. (syn/anti)a
e.r.c
configurationb
>95:5
74:26
R,R
50
51
52
53
>95:5
>95:5
>95:5
65:35
66:34
70:30
R,R
R,R
R,R
2
3
4
>95:5
>95:5
>95:5
76:24
63:37
55:45
R,R
R,R
R,R
5
6
7
54
55
56
a
1
The d.r. was determined by H NMR integration of diagnostic signals at HC(4) and HC(5) (see
b
Experimental). The absolute configuration of the major enantiomer was determined by elution order
compared to dichloride of known configuration (see Supporting Information).
determined by chiral stationary phase HPLC (see Supporting Information).
c
The e.r. was

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led to substantially faster reactions than the more flexible enantioenriched diselenides employed
above. For example, the dichlorination catalyzed by 50 was complete in 5 h – faster even than
diphenyl diselenide.
3.2. Mechanistic Investigations
Despite a wide variety of diselenide structures surveyed, many of which afforded
excellent enantioselectivities in other transformations, the enantioselectivity had plateaued at
75:25. To better understand the mechanistic features that could be leading to reduced
enantioselectivity, three potential sources were identified for consideration and evaluation: (1)
low intrinsic selectivity in formation of the seleniranium ion; (2) competing pathways of Se(II)
and Se(IV) addition to the olefin, each pathway imparting different selectivity; and (3)
epimerization of catalytic intermediates owing to reversible addition prior to catalyst turnover.
3.2.1. Determination of Selenium Oxidation State at Seleniranium Formation
Before intrinsic selectivity could be considered, it was necessary to establish whether the
transformation was proceeding through Se(II) or Se(IV) addition to the alkene. On the basis of
X-ray crystal structural data60 for intramolecularly coordinated arylselenium(II) and (IV)
chlorides, the two have very different geometries. Coordinated arylselenium(II) chlorides assume
a T-shape geometry, with chlorine atom opposite the coordinating group, whereas
arylselenium(IV) trichlorides are pseudo-pyramidal. It follows that alkene approach to the
electrophilic selenium atom at either oxidation state could be subject to entirely different steric
environments. Furthermore, both pathways could potentially be operative over the course of the
reaction, as relative rates of oxidation and seleniranium ion formation could be differentially
dependent on oxidant and olefin concentrations, respectively.

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It was hypothesized that with a low concentration of oxidant relative to olefin,
seleniranium ion formation would proceed (at least predominately) at the Se(II) oxidation state.
To maintain low oxidant concentration for the duration of the dichlorination, a solution of
oxidant 15 was added by syringe pump over 8 hours (the typical time to full conversion) to a
solution of precatalyst 53, chloride source 14, fluoride scavenger 16, and alkene 31 (Scheme 8).
The dichloride product obtained had the same e.r. (70:30) as when all reagents were combined at
the start of the reaction. Likewise, it was hypothesized that with a low concentration of alkene
relative to the oxidant, seleniranium ion formation would proceed at the Se(IV) oxidation state.
Thus, slow addition of a solution 31 to a solution of 14, 15, 16 and 53 also afforded the same e.r.
(70:30). Therefore, either the same pathway was operative in all three circumstances, or the
Se(II) and Se(IV) seleniranium ion formation pathways impart nearly identical selectivities on
the overall transformation.
Scheme 8. Syringe pump addition experiments limiting selenium
oxidation state.
A more informative experiment was then performed by measurement of the enantiomeric
ratio of aliquots at 10% and 100% conversion. In a typical dichlorination reaction, all of the
reagents save for the alkene substrate were combined for 10 min24 to allow for oxidation of the

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diselenide precatalyst to the arylselenium trichloride species. Therefore, at 10% conversion (i.e.
one catalytic turnover), the vast majority of dichloride product should arise from Se(IV)
seleniranium ion formation. At a 1 mmol scale, the amount of syn-dichloride product obtained at
10% conversion was insufficient to achieve UV detection on HPLC. Thus, new olefin substrates
were prepared to allow for detection at lower concentrations, while the reaction with alkene 31
was run on 5 mmol scale. For all three ester substrates there appeared to be no significant change
(Table 5). Thus, the reaction most likely proceeds through Se(IV) seleniranium ion formation
from initiation through to full conversion or both oxidations states afford similar selectivity.
Table 5. Measurement of Dichloride e.r. at 10% and 100% Conversion.
entry
Alkene
31
57
e.r. at 10% conversiona e.r. at 100% conversion
76:24
79:21
77:23
75:25
76:24
75:25
1
2
3
58
a e.r. was determined by chiral stationary phase HPLC (see experimental)
Unfortunately little is known about the enantiotopic face selectivity of Se(IV) addition to
olefins, as the vast majority of stoichiometric reactions have been performed using reagents at
the Se(II) oxidation state. Attempts to measure diastereomeric ratio of the Se(IV) chloroalkyl
adduct by combination of stoichiometric amounts of precatalyst 50 with either sulfuryl chloride
or N-F oxidant/chloride and olefin led to 1H NMR spectra too complex to make any conclusions
about the d.r. It was therefore difficult to rule out low facial selectivity as a contributor to the
overall low selectivity. There was, however, one especially compelling piece of evidence that
pointed to a mechanistic origin for low enantioselectivity.

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Gilbert, Eey, Ryabchuk, Garry, and Denmark
page 23
+
3.2.2. Reversibility of ArSe(IV)Cl2 Addition to Alkene
1
Early H NMR studies wherein the combination of the β-chloroalkylarylselenium(IV)
dichloride prepared from E-octene 60 (formed in situ by treatment of a trifluoroacetate precursor
59 with ethereal HCl)61 and E-1,4-diphenyl-2-butene 61 led to exchange between the olefins to
afford mixture of alkenes and chloroselenylated adducts (Figure 4). At t = 0 before the addition
of hydrochloric acid, trifluoroacetate 59 and diphenylbutene are visible. However, 20 hours after
the addition of hydrochloric acid, there was a clear increase in spectral complexity as multiple
chloroselenylated species began to appear. These new signals changed over the subsequent 45
hours until equilibrium was reached. Comparison of the new component, 63, to an independently
prepared chloroselenylated 1,4-diphenylbutene adduct confirmed its identity. The reverse
reaction in which E-octene 62 was introduced to the β-chloroalkylarylselenium(IV) dichloride
prepared from E-1,4-diphenyl-2-butene 63 likewise led to a similar mixture in the same amount
of time, ruling out any thermodynamic bias.

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Gilbert, Eey, Ryabchuk, Garry, and Denmark
page 24
t = 0
61
HC(2)
Before addition of HCl
only 59 and 61
59
59
HC(4)
HC(5)
t = 20 h
59 and 61 reduce in intensity
60, 62, and 63 appear
61
HC(2)
62
HC(4)
59
HC(4)
60
HC(5)
59
HC(5)
63
HC(2)
60
HC(4)
63
HC(3)
t = 40 h
61
62
HC(4)
HC(2)
60
59
HC(5)
63
60
HC(4)
59
HC(4)
HC(5)
HC(2)
63
HC(3)
t = 65 h
59 is completely consumed
equilibrium is reached
62
HC(4)
61
HC(2)
60
HC(5)
63
HC(2)
60
HC(4)
63
HC(3)
Figure 4. Scrambling of arylselenium(IV) chloride adduct with external olefin.
The reversibility of seleniranium ion formation and opening indicated that, although the
initial seleniranium ion formation may have been selective, it was not likely to be the
enantiodetermining step. The mechanism of the transformation may be far more complicated, as
diastereomeric ring-opened chloroalkylarylselenium(IV) dichloride adducts could now

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Gilbert, Eey, Ryabchuk, Garry, and Denmark
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equilibrate prior to irreversible chloride displacement. Furthermore, the diastereomeric and
constitutionally isomeric chloroselenylated adducts comprising this mixture have the potential to
undergo SN2 displacement by chloride at different rates, funneling the equilibrium to the
intermediate that undergoes fastest displacement by chloride, leading to a dynamic kinetic
asymmetric transformation (DyKAT) (Scheme 9).62
Scheme 9. Dynamic kinetic asymmetric
transformation
of
equilibrating
chloroselenylated adducts.
3.2.3. Intramolecular Trapping of the Seleniranium Intermediate
To provide support for this new mechanistic hypothesis and to make seleniranium ion
formation the enantiodetermining step, we sought to preclude reversibility by rapid capture using
a tethered nucleophile. Adapting the method to chlorolactonization indeed proved simple.
Exchanging benzyl E-hexenoate for 7-phenyl-4-heptenoic acid 64 under identical reaction
conditions afforded a mixture of syn-γ-lactone 66, syn-δ-lactone 67, syn-dichlorinated carboxylic
acid 68,63 and various elimination products (Scheme 10). When catalyst 50 was employed with
similar conditions, substituting 15 for 1-fluoro-2,4,6-trimethylpyridinium tetrafluoroborate 65 to
improve reaction homogeneity, γ-lactone 66 was formed in a 78:9:13 ratio with 67 and 68,
respectively, and with an e.r. of 81:19, marginally higher than the e.r. of syn-dichloride obtained

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Gilbert, Eey, Ryabchuk, Garry, and Denmark
page 26
from benzyl hexenoate with the same catalyst (vide supra). The constitutional isomer 67 was
obtained with a lower e.r. of 60:40.
Scheme 10. Chlorolactonization of E-7-phenylhept-4-
enoic acid 64.
Modifying oxidant stoichiometry, chloride stoichiometry, and solvent all resulted in small
changes to both the product ratio and, to a lesser degree, enantioselectivity. Unfortunately, the
presence of the syn-dichloride regardless of the modified conditions indicated that reversibility
was still operative owing to the unexpected intermolecular chloride capture outcompeting an
intramolecular capture by carboxylate. It is possible that the equivalent of acid produced as a
reaction byproduct was capable of activating the lactone towards displacement by the adjacent
selenium to reform the seleniranium ion (Scheme 11).
racemization
SeCl2Ar*
Cl
Ar*
Se+
Ar*SeCl3
slow?
Cl
CO2H
R
R
CO2H
reversible?
O
R
Cl–
O
Cl–
Cl
SeCl2Ar*
Cl
Cl
CO2H
CO2H
R
+
R
R
O
Cl
O
Scheme 11. Chlorolactonization of E-7-phenylhept-4-enoic acid:
mechanistic hypothesis for reversibility.

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4. Conclusions
In this study we have demonstrated that chiral, enantioenriched arylselenium(IV)
chlorides can be employed as redox catalysts for the suprafacial dichlorination of alkenes to
provide vicinal, syn-dichloride products with modest enantioselectivity. Twenty-three diaryl
diselenides across four general classes were evaluated for their selectivity in the dichlorination,
with a maximum e.r. of 75:25 obtained with triisopropylsilyl ether 54.
Higher product enantioenrichment may not be attainable through improvement of catalyst
enantiofacial selectivity toward the alkene alone, as the free alkene and the catalytic resting state
β-chloroalkylarylselenium(IV) dichloride appear to be in equilibrium. Furthermore, it does not
appear that acceleration of the seleniranium ion opening by a tethered carboxylate results in any
appreciable reduction in the reversibility of the overall transformation. There is, however,
potential to improve selectivity by accelerating the second displacement to outcompete any
reversibility by change of substrate to allow for intramolecular capture of the resting state
intermediate. Likewise, there is potential to leverage the equilibrium for a DyKAT process with a
second chiral catalyst to deliver chloride selectively to one isomer of the resting state
intermediate.
Research employing chiral, enantioenriched diselenides as redox catalysts for suprafacial
alkene difunctionalization, wherein the second displacement is accelerated, is ongoing.
5. Experimental
5.1. General Experimental
All reactions were performed in 120 ºC oven- or flame-dried glassware equipped with a
Teflon-coated magnetic stir bar under inert nitrogen atmosphere unless otherwise noted.

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page 28
Catalytic chlorination reactions were performed in flame-dried dram vials equipped with
magnetic stir bars and septa under nitrogen atmosphere.
Benzyltriethylammonium chloride was purchased from Oakwood Chemical and moved
into the glove box without purification. N-fluoropyridinium tetrafluoroborate and N-fluoro-2,4,6-
trimethylpyridinium tetrafluoroborate were purchased from TCI America and moved into the
glove box without purification. Trimethylsilyl chloride (Aldrich, 97+%) was distilled from
calcium hydride at atmospheric pressure. Reaction solvent acetonitrile (Fisher, HPLC grade) was
distilled from calcium hydride. Reaction solvents hexane, tetrahydrofuran, diethyl ether, toluene,
N,N-dimethylformamide and dichloromethane were dried by percolation through two columns
packed with neutral alumina under a positive pressure of argon. Reaction solvent ethyl acetate
was degassed by sparging with argon for 2 h and stored over molecular sieves. Reaction solvent
pentane was distilled from sodium. Sodium hydride suspension in mineral oil was washed
several times with hexanes and stored in the glove box. Solvents for chromatography were:
hexanes (Fisher, ACS Grade), ethyl acetate (Fisher, ACS Grade), diethyl ether (Fisher, ACS
Grade), pentane (J. T. Baker, reagent grade), petroleum ether (J. T. Baker, reagent grade),
dichloromethane (Aldrich, ACS Grade), and tert-butyl methyl ether (Acros, reagent grade). Brine
refers to a saturated solution of sodium chloride in water.
13
1
1H NMR, and C NMR were recorded on Varian Unity-400 (400 MHz, H; 100 MHz,
1
13C) and Varian Inova-500 (500 MHz, H; 126 MHz, 13C) spectrometers. Spectra were
1
13
referenced to residual chloroform (7.26 ppm, H; 77.00 ppm, C). Chemical shifts are reported
in parts per million (ppm), multiplicities are indicated by s (singlet), d (doublet), t (triplet), q
(quartet), quint (quintet), m (multiplet) and br (broad). Coupling constants, J, are reported in
Hertz with integration provided and assignments indicated. Electron Impact (EI) mass spectra