Catalytic, stereospecific syn-dichlorination of alkenes

Article abstract of DOI:10.1038/nchem.2141

As some of the oldest organic chemical reactions known, the ionic additions of elemental halogens such as bromine and chlorine to alkenes are prototypical examples of stereospecific reactions, typically delivering vicinal dihalides resulting from anti-addition. Although the invention of enantioselective variants is an ongoing challenge, the ability to overturn the intrinsic anti-diastereospecificity of these transformations is also a largely unsolved problem. Here, we describe the first catalytic, syn-stereospecific dichlorination of alkenes, employing a group transfer catalyst based on a redox-active main group element (selenium). With diphenyl diselenide (PhSeSePh) (5amol%) as the pre-catalyst, benzyltriethylammonium chloride (BnEt 3 NCl) as the chloride source and an N-fluoropyridinium salt as the oxidant, a wide variety of functionalized cyclic and acyclic 1,2-disubstituted alkenes, including simple allylic alcohols, deliver syn-dichlorides with exquisite stereocontrol. This methodology is expected to find applications in streamlining the synthesis of polychlorinated natural products such as the chlorosulfolipids.

Full text of DOI:10.1038/nchem.2141

ARTICLES
PUBLISHED ONLINE: 12 JANUARY 2015 | DOI: 10.1038/NCHEM.2141
Catalytic, stereospecific syn-dichlorination
of alkenes
Alexander J. Cresswell†, Stanley T.-C. Eey† and Scott E. Denmark
*
As some of the oldest organic chemical reactions known, the ionic additions of elemental halogens such as bromine and
chlorine to alkenes are prototypical examples of stereospecific reactions, typically delivering vicinal dihalides resulting
from anti-addition. Although the invention of enantioselective variants is an ongoing challenge, the ability to overturn the
intrinsic anti-diastereospecificity of these transformations is also a largely unsolved problem. Here, we describe the first
catalytic, syn-stereospecific dichlorination of alkenes, employing a group transfer catalyst based on a redox-active main
group element (selenium). With diphenyl diselenide (PhSeSePh) (5 mol%) as the pre-catalyst, benzyltriethylammonium
chloride (BnEt3NCl) as the chloride source and an N-fluoropyridinium salt as the oxidant, a wide variety of functionalized
cyclic and acyclic 1,2-disubstituted alkenes, including simple allylic alcohols, deliver syn-dichlorides with exquisite
stereocontrol. This methodology is expected to find applications in streamlining the synthesis of polychlorinated natural
products such as the chlorosulfolipids.
ince the seminal report of the 1,2-addition of molecular chlorine anti-addition to alkenes—an inescapable stereoelectronic conse-
to carbon–carbon double bonds in 1877 (that is, the dearomati- quence of the nucleophilic attack of chloride ion on chloriranium
S
zing addition of 2 equiv. Cl2 to 1,5-dichloronaphthalene)1, ion16 or alkene-Cl2 π-complex17 intermediates. A complementary,
the vicinal dichlorination of alkenes has continued to challenge direct syn-dichlorination is notably lacking from the synthetic che-
the ingenuity of synthetic organic chemists in providing creative sol- mist’s repertoire (Fig. 1, right). Although several examples of direct,
utions to fundamental problems of selectivity. Owing largely to the syn-stereospecific dichlorinations involving the treatment of
high reactivity of Cl2 and the difficulties associated with controlling unfunctionalized alkenes (often in excess) with stoichiometric
the stoichiometry of a gaseous reactant, the reactions of alkenes with amounts of high-valent metal chlorides based on antimony18 and
elemental chlorine are frequently plagued by side reactions (ionic molybdenum19–21 are on record, the harsh Lewis acidity, high oxi-
and/or radical)2, and the extremely toxic and corrosive nature of dation potential and toxicity of these reagents detract significantly
Cl2 gas renders it experimentally unappealing. Accordingly, some- from their utility. Consequently, the only current solution to the
what milder and more practical electrophilic chlorinating agents syn-dichlorination problem with functionalized alkene substrates
for alkene dichlorination have been developed, including SO2Cl2 is to orchestrate indirect, two-step oxidation–deoxochlorination
(ref. 3), PhICl2 (ref. 4), Et4NCl3 (ref. 5; Mioskowski’s reagent) and sequences via the intermediacy of epoxides22,23 or chlorohydrins24.
2:1 NCS-PPh3 (ref. 6; Yoshimitsu’s reagent). Alternatively, Cl2 (or
In this Article, we describe the first catalytic, syn-stereospecific
its formal equivalent) may be generated in situ from the oxidation dichlorination of alkenes, employing a group transfer catalyst
of chloride sources with strong oxidants and reagent systems based on a redox-active main group element (selenium). On the
such as H2O2–HCl (ref. 7), KMnO4–Me3SiCl–BnEt3NCl (ref. 8; basis of the known ability of PhSeCl3 to chloroselenylate alkenes
Markó–Maguire reagent) and Oxone-NaCl (ref. 9) have been in an anti-stereospecific fashion25,26 and the invertive nucleophilic
tailored for this purpose.
displacement of the high-valent selenium(IV) moiety27 by chloride
However, whereas the advent of new reagents for alkene dichlor- ions in such adducts to afford syn-dichlorides28,29, we surmised
ination has largely solved the practicality and reactivity issues sur- that a direct alkene syn-dichlorination that is catalytic in selenium
rounding the use of Cl2, solutions have been less forthcoming to may be possible. However, a key challenge in formulating such a cat-
the problems of control over the relative and absolute configurations alytic cycle is the identification of a suitable stoichiometric oxidant
of the dichloride products. In recent years, state-of-the-art stereo- to regenerate Se(IV) from Se(II). Although electrophilic chlorine
selective chlorination methods have been showcased in synthetic sources may seem obvious candidates, both Sharpless30 and
efforts toward the chlorosulfolipids (for example, 1–5)10–14, a class Tunge31 have reported that the selenium-catalysed reaction of
of stereochemically complex, polychlorinated natural products iso- alkenes with N-chlorosuccinimide generates allylic chlorides as
lated from marine sources (Fig. 1, left). The daunting synthetic chal- the major products. Alternatively, a non-chlorine-based oxidant
lenge of constructing such densely functionalized arrays of could be used in the presence of an exogenous chloride source.
chlorinated stereogenic centres has provided impetus for the study Specifically, the oxidant selected must fulfil the following criteria:
of (external) diastereocontrol in the dichlorination of chiral alkene (1) it must not react (or must react only very slowly) with the
substrates12, as well as more recent efforts to effect enantioselective alkene substrate, (2) it must not oxidize chloride ions to molecular
dichlorinations of allylic alcohols15.
Cl2 or any other active ‘Cl+’ equivalent over the timescale of the reac-
However, almost invariably, all of the aforementioned reagents tion, (3) it must not contain or release nucleophiles that might out-
or reagent combinations that react via ionic reaction pathways compete chloride in the reaction, and (4) it must not lead to the
afford vicinal dichloride products resulting from stereospecific formation of selenoxide intermediates that are capable of rapid
Roger Adams Laboratory, Department of Chemistry, University of Illinois, Urbana, Illinois 61801, USA; †These authors contributed equally to this work.
e-mail: sdenmark@illinois.edu
*
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ARTICLES
a
Cl
OSO3
Cl
b
Cl Cl
OSO3
C8H17
Cl
R2
Cl
Cl
R1
Danicalipin A (1)
Cl
SO3
Cl
SO3
Cl
O
Cl
Cl
Cl
O
Cl
(known)
R1
anti-stereospecific
Cl
C8H17
Me
R2
Cl
Cl
OSO3−
Cl
Cl
Cl
Malhamensilipin A (2)
Mytilipin A (3)
syn-
stereospecific
(this
work)
C15H32
Cl
SO3
R2
O
O
Cl
O
Cl
OH
Cl
OH
R
Cl
R1
Me
OH
Cl
Cl Cl
Cl
Cl
Cl
Cl
Cl
OH
Mytilipin B (R = OH) (4)
Mytilipin C (R = H) (5)
Figure 1 | The vicinal dichloride motif in natural products. a, Selected chlorosulfolipids (with vicinal dichloride motifs highlighted). b, Most dichlorinations of
alkenes (and all of those that are catalytic) exhibit anti-stereospecificity, and no generally applicable, direct syn-stereospecific alkene dichlorination has been
reported. Such a method would complement current chlorination strategies employed in the synthesis of polychlorinated natural products such as
the chlorosulfolipids.
syn-elimination32. With these restrictions in mind, cationic N–F
reagents were considered as possible candidates, a choice that was
inspired by the use of ‘F+’ reagents as oxidants in transition
∼20 h, an encouraging 19% yield of the desired syn-dichloride 7
was observed, although 50% of starting material 6 remained
(Table 1, entry 1). It was surmised that fluoride ions generated as
a by-product from oxidant 11 may be interfering with catalytic
turnover and that the addition of a fluoride scavenger may be
advantageous. Chlorotrimethylsilane (Me3SiCl) was selected for
this purpose on the basis that silicon has a high affinity for
metal-catalysed processes33 and, more significantly, in
a
PhSeSePh-catalysed allylic amination of alkenes34.
Results
Reaction development. To probe the feasibility of a syn- fluoride35 and that the by-products of such scavenging would
dichlorination process that is catalytic in selenium, orienting simply
be
additional
chloride
ion
and
unreactive
experiments were carried out with cyclohexene 6 (1.0 equiv.) as fluorotrimethylsilane (Me3SiF). Gratifyingly, the addition of
the substrate, 5 mol% of PhSeSePh as the pre-catalyst, n-Bu4NCl 1.0 equiv. Me3SiCl gave a substantial improvement in catalytic
as the chloride source (3.0 equiv.) and N-fluoropyridinium turnover (61% yield of 7 by 1H NMR spectroscopic analysis;
tetrafluoroborate 11 (CAS# 107264-09-5) as the oxidant, with entry 2) and complete consumption of alkene 6 occurred when
MeCN-d3 as the solvent (Table 1). 1,1,2,2-Tetrachloroethane 2.0 equiv. Me3SiCl was added, affording 7 in 81% yield (entry 3).
(1.0 equiv.) was added as an internal standard, and 1H NMR However, increasing the amount of Me3SiCl to 3.0 equiv. led to
peaks for species 6–10 were compared against authentic samples no further enhancement (entry 4). The reaction also proved
in MeCN-d3. Under these conditions at ambient temperature for sensitive to the quantity of n-Bu4NCl; an attempt to lower the
Table 1 | Reaction development with cyclohexene.
PhSeSePh (5 mol%)
Cl– source (x equiv.)
11 or 12 (1.3 equiv.)
Me3SiCl (y equiv.)
Cl
Cl
Cl
SePh
Cl
SeCl2Ph
Cl
N
+
+
+
N
N
F
Solvent (0.2 M)
rt, ~20 h
Cl
BF4
F
2BF4
6
7
8
9
10
11
12
Entry
Cl– source (equiv.)
Oxidant
Me3SiCl (equiv.)
Solvent
NMR yield (%)*
8
6
7
9
10
1
2
3
n-Bu4NCl (3.0)
n-Bu4NCl (3.0)
n-Bu4NCl (3.0)
n-Bu4NCl (3.0)
n-Bu4NCl (2.5)
n-Bu4NCl (0.0)
n-Bu4NCl (3.0)
n-Bu4NCl (3.0)
n-Bu4NCl (3.0)
BnEt3NCl (3.0)
11
11
11
11
11
11
11
11
12
11
0.0
1.0
MeCN-d3
MeCN-d3
MeCN-d3
MeCN-d3
MeCN-d3
MeCN-d3
CD2Cl2
THF-d8
MeCN-d3
MeCN-d3
50
12
0
0
0
54
0
55
0
19
3
9
0
0
0
0
0
8
0
0
0
0
61
81
81
74
0
73
17
71
83
10
10
8
10
2
12
2
10
10
10
0
0
0
0
4
0
0
0
2.0
3.0
2.0
2.0
2.0
2.0
2.0
2.0
4
5
6†
7
8
9
10
0
*Measured by 1H NMR spectroscopy with 1,1,2,2-tetrachloroethane (1.0 equiv.) as an internal standard; †11% of an unidentified species was also observed by 1H NMR spectroscopy.
2
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NATURE CHEMISTRY DOI: 10.1038/NCHEM.2141
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amount to 2.5 equiv. led to an erosion in the yield of 7 (entry 5) and
no 7 was produced when the n-Bu4NCl was omitted altogether
(entry 6). The effect of solvent was also briefly investigated, with
both CD2Cl2 and THF-d8 giving inferior results (entries 7 and 8).
Pleasingly, the reaction could also be carried out with Selectfluor
12 as an alternative stoichiometric oxidant, albeit with a slightly
diminished yield of 7 (71%) (entry 9). Finally, n-Bu4NCl was
replaced with BnEt3NCl, which is far less expensive, and the results
were essentially identical (entry 10). Notably, in no case was any
of the diastereomeric anti-dichloride product detected; an
observation that is particularly surprising given that Selectfluor 12
is known to oxidize chloride ions to a ‘Cl+’ equivalent (possibly
Cl2) in MeCN36. In fact, a control experiment with cyclohexene 6
in which PhSeSePh was omitted from the reaction gave ∼35%
yield of the anti-dichloride after 20 h, implying that a background
anti-dichlorination process is possibly operative but is
significantly slower than the catalysed reaction.
OTBDPS
Cl
a
PhSeSePh (5 mol%)
BnEt3NCl (3.0 equiv.)
11 (1.3 equiv.)
Me
Cl
14, 63%, >99:1 d.r.
OTBDPS
Me3SiCl (2.0 equiv.)
Me
MeCN (0.2 M)
rt, 18 h
OTBDPS
Me
OTBDPS
Me
13
+
+
Cl
Cl
15
16
14% combined (59:41 15:16)
b
SeCl2Ph
SeCl2Ph
OTBDPS
Me
Cl
R
R
Me
H
Me
Cl
Cl
H
15
Before further optimization efforts aimed at minimizing the for-
mation of allylic chloride 8, it was first necessary to establish the
mechanistic provenance of this particular species. Although 8 is a
known by-product in the reaction of 6 with Cl2 under both ionic
and radical reaction manifolds2, the absence of any anti-dichloride
under our conditions argues against the involvement of molecular
Cl2. Another possibility is synperiplanar elimination of a selenoxide
intermediate32 derived from the hydrolysis of 10 with adventitious
water, although both rigorously dry conditions and the addition
of trace water had no effect on the 7/8 ratio. Lastly, antiperiplanar
E2 elimination of the Se(IV) moiety in intermediate 10 could also
furnish 8. To unambiguously determine which elimination
pathway is in operation, an acyclic alkene substrate capable of gen-
erating (E)- or (Z)-configured vinylic chloride by-products was con-
sidered (note, for cyclohexene 6, antiperiplanar elimination to give a
vinylic chloride is geometrically impossible from 10).
Dichlorination of (E)-tert-butyl(hex-4-en-1-yloxy)diphenylsilane
13 under the optimized conditions gave a 68:23:9 mixture of syn-
dichloride 14, vinylic chlorides 15 + 16, and two (tentatively
assigned) allylic chlorides, respectively, with 14 being isolated in
63% yield (>99:1 d.r.) and 15 + 16 in 14% combined yield (Fig. 2).
Crucially, the configurations within 15 and 16, as deduced via 1D
nuclear Overhauser enhancement spectroscopy (NOESY) experi-
ments (reciprocal enhancements indicated with double-headed
arrows), were found to be consistent with their formation via an
antiperiplanar E2 elimination process (Fig. 2b). Similar
conclusions were drawn from an analogous experiment with
the (Z)-isomer of alkene 13, which also gave vinylic chloride
by-products consistent with antiperiplanar E2 elimination
(Supplementary Information, p. 117).
With this information in hand, additional optimization
experiments to minimize the competitive elimination process were
conducted on (E)-1-benzyloxy-4-hexene 17 as the substrate
(Table 2). Interestingly, a threefold rate acceleration was noted when
sulfolane was used as a co-solvent (1:3 vol/vol) with MeCN-d3,
although the extent of E2 elimination was unperturbed (compare
entries 1 and 2). Based on this observation, we elected to screen a
variety of Lewis basic additives (1.0 equiv.) to search for similar
acceleration effects (entries 3–8). Although the amount of elimin-
ation consistently proved insensitive to the presence of these addi-
tives, the rate enhancement effect appeared to be general and 2,6-
lutidine N-oxide 23 was identified as the optimal additive in this
respect (entry 8).
Cl–
SeCl2Ph
Me
Cl
OTBDPS
Me
Cl
H
R
Me
Cl
R
H
SeCl2Ph
16
Cl–
Figure 2 | Identification of E2 elimination by-products. a, Formation of
vinylic chloride by-products 15 and 16 from the dichlorination of alkene
13 and determination of their configurations via 1D NOESY experiments
(reciprocal enhancements indicated with double-headed arrows).
b, Mechanistic rationale for the formation of vinyl chlorides 15 and 16
from constitutionally isomeric anti-chloroselenylated intermediates via
antiperiplanar elimination. TBDPS, tert-butyldiphenylsilyl.
pre-catalyst 26 behaved in precisely the opposite sense, giving
reduced reaction times, less E2 elimination and near complete
syn-diastereoselectivity (entry 11). In contrast, the 2-methoxyphenyl
pre-catalyst 27 behaved similarly to PhSeSePh, albeit with a slightly
extended reaction time (entry 12).
Reaction generality. The generality of the catalytic syn-
dichlorination with a range of alkene substrates was next surveyed
(Table 3). Despite the fact that our optimization studies had
identified 26 as the optimal pre-catalyst, its ability to reduce
elimination by-products (relative to PhSeSePh) did not prove to
be general with other substrates (see Supplementary Information,
page 48). Consequently, PhSeSePh was used in all preparative-scale
reactions. To take advantage of the rate enhancement imparted by
23, this additive was included in all preparative reactions, with the
exception of allylic alcohols 28t–x, for which reduced conversions
and the formation of unidentified by-products were observed in the
presence of 23. However, the inclusion of 23 is not mandatory for
the success of the reactions and it can generally be omitted without
detriment to yields or diastereoselectivities, albeit at the expense of
reaction rates (for comparison, the yields and diastereoselectivities
for reactions conducted for 18 h without 23 are given in square
brackets for several substrates).
As representative cyclic alkenes, both cyclohexene 6 and
cycloheptene 28a underwent efficient syn-dichlorination with
>99:1 and 99:1 d.r., respectively, with the disparity between the
isolated yields and those calculated by 1H NMR spectroscopy
being attributed to difficulties in product isolation. Cyclopentene
derivatives 28b and 28c also participated and the sense of diastereo-
facial selectivity in both cases was consistent with preferential
attack of the selenium electrophile on the sterically more
accessible alkene faces, culminating in net, contrasteric syn-
The effect of tuning the electronic nature of the aryl group on the
selenium pre-catalyst was also examined (entries 9–12).
Interestingly, electron-deficient pre-catalysts 24 and 25 gave
longer reaction times, favoured E2 elimination processes,
and significantly eroded the syn:anti dichlorination ratio (entries 9
and 10). On the other hand, the electron-rich 4-methoxyphenyl
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Table 2 | Reaction development with (E)-1-benzyloxy-4-hexene.
(ArylSe)2 (5 mol%)
BnEt3NCl (3.0 equiv.)
11 (1.3 equiv.)
Cl
Me
Me
Cl
R
+
+
+
+
Me
R
Me
R
R
Cl
Cl
R
Me
R
Me3SiCl (2.0 equiv.)
additive (1.0 equiv.)
MeCN-d3 (0.2 M), rt
Cl
18
Cl
19
17
20
21
22
(R = CH2CH2OBn)
Entry
(ArylSe)2
Additive
Time (h)
18:(19 + 20 + 21 + 22)*
18 d.r.*
1
PhSeSePh
PhSeSePh
PhSeSePh
PhSeSePh
PhSeSePh
PhSeSePh
PhSeSePh
PhSeSePh
–
6
2
3
3.5
2.5
3.5
2.5
2
80:20
80:20
82:18
80:20
80:20
80:20
80:20
80:20
99:1
99:1
98:2
98:2
99:1
98:2
98:2
99:1
2
3
4
5
6
7
8
Sulfolane†
HMPA
DMPU
DMI
Ph3P=O
Pyridine N-oxide
2,6-Lutidine N-oxide 23
CF3
9
–
10
58:42
88:18
Se
CF3
F3C
Se
24
CF3
NO2
Se
10
11
–
–
–
18
3.5
8
59:41
90:10
83:17
55:45
99:1
Se
25
O2N
MeO
Se
Se
26
OMe
OMe
12
98:2
Se
Se
OMe
27
*Measured by 1H NMR spectroscopy; †sulfolane was used as a co-solvent with MeCN-d3 in 1:3 vol/vol. HMPA, hexamethylphosphoramide; DMPU, N,N′-dimethylpropyleneurea; DMI,
N,N′-dimethyl-2-imidazolidinone.
3
dichlorinations. The relative configurations within both 29b and which the syn-configured isomer (29q) gave a JHH value of 2.2 Hz,
29c were secured by chemical correlation to an epoxy alcohol of whereas the anti-configured isomer (29r) gave a value of 6.3 Hz.
known configuration.
In terms of functional group compatibility, the reaction is toler-
For acyclic alkenes, the reaction proved generally applicable to ant of free hydroxyl groups (28t–x), benzyl ethers (17, 28h,w,x),
both terminal and 1,2-disubstituted olefins, although 1,1-disubsti- tert-butyldiphenylsilyl (TBDPS) ethers (13, 28c,d,i,q,r), esters
tuted, trisubstituted and aryl-conjugated alkenes afforded complex (28b,k,l,n), acetals (28e,m), simple or electron-rich arenes (for
mixtures of products. Similarly, alkenes bearing pendant example, 28f,j,s,u,v), cyclopropanes (28l), electron-poor alkenes
nucleophiles able to engage in cyclizations also formed complex (28n), tert-butoxy carbamates (28o) and imides (28p). However,
mixtures (see Supplementary Information, p. 122, for a table of pro- silicon-based protecting groups other than TBDPS, including triiso-
blematic substrates). Crucially, the stereospecific nature of the syn- propylsilyl (TIPS, 28j) and tert-butyldimethylsilyl (TBS, 28s), are
dichlorination reaction was confirmed by reaction of various pairs partially cleaved under the reaction conditions. Although this meth-
of (E)- and (Z)-configured alkenes, in which both isomers could odology can accommodate silyl ether functionality at the allylic pos-
be dichlorinated with exceptional syn-diastereoselectivity (that is, ition (for example, 28q–s), free allylic (primary) alcohols are also
17/28h, 13/28i, 28q/r, 28u/v). The relative configurations in each perfectly competent substrates (28t–x), providing a convenient
case were typically assigned by comparison to known (or analogous) functional handle for further elaboration. However, allylic second-
dichlorides, or to authentic samples of the diastereomeric dichlor- ary alcohols, as well as their silyl ether or O-acyl derivatives, afforded
ides prepared by an anti-selective dichlorination method. For complex mixtures of products for reasons that are currently unclear
acyclic vicinal dichlorides, the 3JHH coupling constant was diagnos- (see Supplementary Information, page 122). Curiously, subjection of
tic, with syn-configured dichlorides 14, 18, 29j–n and anti-config- the (E)-configured 1,4-dioxygenated alkene 28w to the dichlorination
3
ured dichlorides 29h,i,o,p giving JHH values of 3.0–3.3 and conditions returned a 56:44 diastereomeric mixture of syn- and anti-
6.5–6.6 Hz, respectively. A similar trend was noted for dichlorides dichlorides 29w, respectively, whereas the analogous (Z)-configured
such as 29q and 29r derived from allylic alcohol derivatives, for alkene 28x underwent syn-dichlorination with 93:7 diastereoselectivity.
4
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Table 3 | Reaction generality.
PhSeSePh (5 mol%)
BnEt3NCl (3.0 equiv.)
[PyF+][BF4−] 11 (1.3 equiv.)
R1
R4
R2
R3
Cl
R1
R4
Cl
R2
R3
Me
N
O
Me
N
F
Me3SiCl (2.0 equiv.)
23 (1.0 equiv.)
BF4
28
MeCN (0.2 M), rt
29
11
23
Cl
Cl
Cl
Cl
Cl
Cl
AcO
TBDPSO
OTBDPS
1
1
Cl
Cl
Cl
Cl
29b, 73%, >99:1 d.r.,
89:11 d.r. at C(1)†
29c, 71%, >99:1 d.r.,
91:9 d.r. at C(1)
(16 h)
29d, 91% (6 h)
7, 51% (80%* ),
>99:1 d.r. (10 h)
[83%* , >99:1 d.r.]
29a, 77% (96%* ) d.r.
[91%]
99:1 d.r. (4 h)
(24 h), [76%, >99:1 d.r.,
90:10 d.r. at C(1)†]
Me
Me
Cl
Cl
Me
O
O
O
Cl
Me
O
Me
Me
OBn
Cl
OBn
Cl
Cl
Cl
Cl
Cl
Cl
29e, 85% (4.5 h)
29f, 77% (3.5 h)
29h, 67%, >99:1 d.r.
(4 h) [67%, >99:1 d.r.]
18, 71%, 99:1 d.r.
(3.5 h) [64%, >99:1 d.r.]
29g, 40% (66%*) d.r.
99:1 d.r. (4 h)
Cl
Me
Cl
Cl
CO2Et
Me
OTBDPS
Cl
OTBDPS
Ph
OTIPS
Me
Cl
Cl
Cl
Cl
14, 64%, >99:1 d.r.
29i, 67%, >99:1 d.r.
29j, 37%‡, 97:3 d.r.
29k, 70%, >99:1 d.r.
(4 h) [63%, >99:1 d.r.]
(3.5 h)
(6 h) [63%, >99:1 d.r.]
(5 h)
Cl
O
Cl
Me
Cl
O
O
CO2Me
Boc
Ph
Me
O
Me
Cl
N
Me
Cl
Cl
Cl
Bn
Cl
29l, 69%, >99:1 d.r.
29m, 73%, >99:1 d.r.
29n, 70%, 99:1 d.r.
29o, 72%, 99:1 d.r.
(3.5 h)
(3.5 h)
(4.5 h)
(5 h)
Me
O
Cl
OTBDPS
Cl
OTBS
Me
OTBDPS
Cl
N
Me
Ph
Cl
Cl
Cl
Cl
Cl
O
29s, 47%§, >98:2 d.r.||
29p, 72%, 97:3 d.r.
29q, 71%, >99:1 d.r.
29r, 67%, 99:1 d.r.
(3.5 h)
(7 h)
(9 h)
(6 h)
BnO
OH
Cl
OH
Cl
OH
Cl
OH
Ph
OH
BnO
Me
Ph
Cl
Cl
Cl
Cl
Cl
Cl
Cl
29t, 66%¶, 99:1 d.r.
29u, 76%¶ , 98:2 d.r.
29v, 71%¶, 98:2 d.r.
29w, 67%¶, 56:44 d.r.
29x, 73%¶, 93:7 d.r.#
(14 h)
(9 h)
(9 h)
(47 h)
(15 h)
For comparison, yields and diastereoselectivities for selected reactions conducted for 18 h without additive 23 are given in square brackets. Each diastereomeric ratio (d.r.) was determined on the crude mixture
after passing through a short plug of silica gel.
*Yield was determined by 1H NMR spectroscopy with 1,1,2,2-tetrachloroethane (1.0 equiv.) as an internal standard; †91:9 d.r. at C(1) after isolation; ‡24% of the free alcohol syn-dichloride was also isolated and
tentatively assigned cyclized products were also observed in the crude product mixture; §21% of the free alcohol syn-dichloride was also isolated; ||the d.r. corresponds to the sum of the dichlorides; ¶additive 23
was omitted; #97:3 d.r. after isolation.
Certain alkene substates unexpectedly returned dichloride pro- Discussion
ducts resulting from anti-addition upon exposure to the standard A proposed catalytic cycle for the selenium-catalysed syn-dichlori-
reaction conditions. Similarly, the presence of branching at the nation process is outlined in Fig. 3, albeit with omission of the
allylic position of acyclic (E)-alkenes led to incomplete conversion 2,6-lutidine N-oxide additive 23. Initial oxidation of the PhSeSePh
and ≥80:20 selectivity in favour of anti-addition (Supplementary pre-catalyst with oxidant 11 in the presence of chloride ion could
Information, p. 122). The preference for anti-dichlorination in generate PhSeCl3 as the active catalyst, with Me3SiCl presumably
these cases is difficult to rationalize at present, and may be sub- serving to trap the 0.3 equiv. (w.r.t. alkene) of fluoride ion by-
strate-dependent. A better understanding of this phenomenon will product as Me3SiF. Addition of PhSeCl3 to the alkene may then
+
form part of a broader mechanistic investigation of the catalytic ensue, possibly via loss of chloride to generate PhSeCl2 30 as the
syn-dichlorination, to be reported in due course.
active electrophile, which can then intercept the alkene to form
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NATURE CHEMISTRY DOI: 10.1038/NCHEM.2141
ARTICLES
PhSeSePh
this process cannot be excluded (pKa of pyridinium ion = 12.3 in
MeCN40) although its concentration (particularly early in the
reaction) will be much lower than chloride ion.
3
+ 3 Me3SiCl
BF4
N
F
Initiation
The role of the 2,6-lutidine N-oxide additive 23 is not clear, but a
control experiment with alkene 17 in which the N-fluoropyridinium
salt 11 was omitted (leaving 23 as the only potential oxidant for sel-
enium) gave no reaction, indicating that 23 is not functioning as an
oxidant. Similarly, omission of the PhSeSePh pre-catalyst gave no
syn-dichloride and only a slow background anti-dichlorination
was observed (40% conversion after 20 h), verifying that the combi-
nation of BnEt3NCl, 11 and 23 alone is not capable of effecting syn-
dichlorination via some other mechanistic pathway. As the turn-
over-limiting step of the catalytic cycle is yet to be elucidated, it
would be premature to speculate on the origin of the rate enhance-
ment imparted by 23.
In summary, we have developed the first catalytic, syn-stereospe-
cific dichlorination of alkenes, employing a group transfer catalyst
based on a redox-active main group element (selenium). The
method is applicable to a wide variety of functionalized cyclic and
acyclic 1,2-disubstituted alkenes, including simple (primary)
allylic alcohols, and is operationally simple to perform. As well as
providing a convenient solution to the problem of direct alkene
syn-dichlorination, this process could also form the basis of a con-
ceptually new strategy for catalytic, enantioselective alkene dichlor-
ination. Importantly, the absence of chloriranium ion intermediates
can circumvent the site selectivity issue inherent in the nucleophilic
trapping of such species with chloride ion—a recognized, and as yet
unsolved, problem in controlling the enantioselectivity of dichlori-
nations of electronically unbiased, (E)- or (Z)-configured alkenes15.
Py + Me3SiF
+ Me3SiCl
BF4
3 Py + 3 Me3SiF
– Cl–
PhSeCl3
Reoxidation
Cl–
N
F
+ Cl–
PhSeCl2
+
PhSeCl
Cl
R2
30
R2
R1
R1
Chlorodeselenylation
Alkene addition
Cl
Cl
Cl
Ph
R2
Cl
Cl
Cl
Se
Ph
R2
Se
R1
Cl
R1
31
Cl
Allylic/vinylic
chloride
Cl
Ph
Cl
Se
–Cl
Nucleophilic
ring-opening
by-product(s)
E2 elimination
R2
Cl–
R1
32
Figure 3 | Proposed catalytic cycle for the selenium-catalysed syn-
dichlorination of alkenes. Following oxidation of the PhSeSePh pre-catalyst,
the catalytic cycle commences with anti-chloroselenylation of the alkene to
give 32. Invertive displacement of the selenium moiety with chloride ion
furnishes the syn-dichloride product. Finally, reoxidation of Se(II) to Se(IV)
closes the cycle. Py, pyridine.
Methods
seleniranium ion intermediate 31. Nucleophilic ring-opening of 31 Full experimental details and characterization of compounds can be found in the
Supplementary Information.
with chloride ion would then furnish the (β-chloroalkyl)phenylsele-
nium dichloride species 3225,26 and subsequent invertive displace-
ment of the Se(IV) nucleofuge with chloride ion28,29 would deliver
the syn-dichloride product, releasing the selenium as PhSeCl. The
dissociation of a chloride ligand from the selenium atom within
General procedure for catalytic syn-dichlorination of alkenes. The general
procedure for the catalytic, syn-dichlorination of alkenes with 2,6-lutidine N-oxide
as additive is as follows. In a typical experiment, an oven-dried, 10 ml Schlenk flask
equipped with a magnetic stirrer bar was taken into the glovebox and charged
32 before nucleophilic displacement is a possibility, as this would sequentially with diphenyl diselenide (15.8 mg, 0.05 mmol, 5 mol%),
benzyltriethylammonium chloride (690 mg, 3.03 mmol, 3.0 equiv.) and
N-fluoropyridinium tetrafluoroborate (240 mg, 1.30 mmol, 1.3 equiv.) and was then
sealed with a rubber septum, removed from the box and placed under argon. MeCN
(5.0 ml), 2,6-lutidine N-oxide (126 mg, 115 μl, 1.02 mmol, 1.0 equiv.) and
enhance the nucleofugality of the selenium by rendering it cationic.
The stereochemical outcome in the chlorodeselenylation step hinges
on the fact that neighbouring chloro substituents are comparatively
reluctant to engage in anchimeric assistance37.
chlorotrimethylsilane (218 mg, 255 μl, 2.01 mmol, 2.0 equiv.) were then added
sequentially and stirring was commenced. After ∼10 min, an off-white suspension
was observed. At this point, the requisite alkene (1.00 mmol, 1.0 equiv.) was
transferred via syringe to the reaction mixture (for alkenes of unknown density, only
3.0 ml MeCN was added initially and the remaining 2.0 ml (in two 1.0 ml portions)
was used to transfer the alkene across from an oven-dried, 4 ml dram vial under
argon, via syringe). The resultant suspension was stirred at room temperature and
was monitored by thin layer chromatography (TLC) until no alkene substrate was
detected. Once the reaction had reached completion, sat. aq. NaHCO3 (1.0 ml) was
added to quench any unreacted chlorotrimethylsilane and stirred for ∼10 min. The
mixture was then transferred to a separatory funnel and diluted with H2O (15 ml).
The aqueous layer was extracted with Et2O (3 × 15 ml) and the combined organic
extracts were washed with brine (15 ml), then dried (MgSO4), filtered and
concentrated in vacuo (20–23 °C at ∼20 mmHg for non-volatile products or 5–8 °C,
∼20 mmHg for volatile products). The resultant residue was re-dissolved in Et2O
(5.0 ml) and eluted through a short plug of silica gel (∼0.55 g SiO2 packed into a
Pasteur pipet to a height of ∼40 mm) to partially remove 2,6-lutidine N-oxide and
any ammonium salts, and the plug was then rinsed through with further portions of
Et2O (3 × 5 ml). The solvent was removed in vacuo (20–23 °C, ∼20 mmHg for non-
volatile products or 5–8 °C, ∼20 mmHg for volatile products) and an aliquot of the
crude mixture was dissolved in CDCl3 to measure the syn/anti diastereoisomeric
ratio (d.r.) by 1H NMR spectroscopy. The syn-dichloride product was then isolated
by flash column chromatography on silica gel and/or Kugelrohr distillation at
reduced pressure. The procedure for the catalytic, syn-dichlorination of allylic
alcohols and the preparations of the alkene substrates are presented in the
Supplementary Information.
To complete the cycle, oxidation of PhSeCl by 11 in the presence
of chloride ions could regenerate the PhSeCl3 catalyst, although it is
possible that addition of PhSeCl to the alkene could precede the oxi-
dation of Se(II) to Se(IV). In any case, the mechanism of the reoxida-
tion process requires further scrutiny and the possibility that trace
amounts of Cl2 (generated from the oxidation of Cl– by 11) may
serve as the active oxidant cannot be ruled out at this stage.
The crucial role of Me3SiCl in the reaction also requires further
investigation, but an initial hypothesis is that it may serve to trap fluo-
ride ions (from the reduction of oxidant 11) that would otherwise
interfere with catalytic turnover (note that Me3SiF was observed
in reaction mixtures by 1H and 19F NMR spectroscopy).
Specifically, it may be that halide dissociation (Cl– or F–) from
+
PhSeX3 to generate the active PhSeX2 electrophile (where X = Cl
or F) is slower when the selenium centre carries one or more
fluoride ligands. In support of this assertion, it is known that the
stoichiometric reaction of cyclohexene with PhSeF3 is slow,
requiring 2–3 h to reach completion38, whereas the analogous
addition of PhSeCl3 requires only a few minutes26.
The observation of allylic or vinylic chloride by-products can be
accounted for by a competitive E2 elimination between 32 and
chloride ion, which is a weak but competent base in acetonitrile
(pKa of HCl = 10.3 in MeCN39). The possibility that pyridine (gen-
Received 18 September 2014; accepted 18 November 2014;
erated from the reduction of oxidant 11) may serve as the base in published online 12 January 2015
6
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NATURE CHEMISTRY DOI: 10.1038/NCHEM.2141
ARTICLES
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The authors acknowledge the National Institutes of Health (GM R01-085235) for financial
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A.J.C. planned and carried out the experimental work and initial optimization. S.T-C.E.
completed the experimental work and final characterizations. S.E.D. directed and
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Additional information
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to S.E.D.
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Competing financial interests
The authors declare no competing financial interests.
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