Organocatalytic, Enantioselective Dichlorination of Unfunctionalized Alkenes

Article abstract of DOI:10.1002/anie.201901777

The use of a new class of unsymmetrical cinchona-alkaloid-based, phthalazine-bridged organocatalysts enabled the highly enantioselective dichlorination of unfunctionalized alkenes. In combination with the electrophilic chlorinating agent 1,3-dichloro-5,5-dimethylhydantoin (DCDMH) and triethylsilyl chloride (TES-Cl) as the source of nucleophilic chloride, 1-aryl-2-alkyl alkenes were dichlorinated with enantioselectivities of up to 94:6 er. Initial mechanistic investigations suggest that no free chlorine is formed, and by replacement of the chloride by fluoride, enantioselective chlorofluorinations of alkenes are possible.

Full text of DOI:10.1002/anie.201901777

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Accepted Article
Title: Organocatalytic, Enantioselective Dichlorination of
Unfunctionalized Alkenes
Authors: Volker Wedek, Ruben Van Lommel, Constantin G Daniliuc,
Frank De Proft, and Ulrich Hennecke
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201901777
Angew. Chem. 10.1002/ange.201901777
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Organocatalytic, Enantioselective Dichlorination of
Unfunctionalized Alkenes
Volker Wedek,[a] Ruben Van Lommel,[b] Constantin G. Daniliuc,[a] Frank De Proft,[b] and Ulrich
Hennecke*[a,c]
Abstract: The use of a new class of unsymmetrical cinchona
alkaloid-based, phthalazine-bridged organocatalysts enabled the
highly enantioselective dichlorination of unfunctionalized alkenes. In
combination with the electrophilic chlorinating agent 1,3-dichloro-5,5-
dimethylhydantoin (DCDMH) and triethylsilyl chloride TES-Cl as
source of nucleophilic chloride, 1-aryl-2-alkyl alkenes were
dichlorinated with enantioselectivities up to 94:6 er. Initial
mechanistic investigations suggest that no free chlorine is formed
and, by replacement of the chloride by fluoride, enantioselective
chlorofluorinations of alkenes are possible.
by Burns using stoichiometric or substoichiometric quantities of
chiral titanium complexes in combination with electrophilic
halogenating agents.[11] Enantioselective dichlorination is also
possible on allylic amines as shown by Borhan who used
(DHQD)2PHAL as catalyst in combination with 1,3-dichloro-5,5-
dimethylhydantoin (DCDMH) and a large excess of LiCl.[12]
These reports show that remarkable progress in asymmetric
dihalogenation of substrates with a functional group in allyl
position as been made, however, for unfunctionalized alkenes
enantioselective dihalogenation methods are still highly
problematic.
The dihalogenation of alkenes is a prime example of an
electrophilic addition reaction and is of fundamental importance
to organic chemistry.[1,2] The often observed anti-selectivity of
this reaction is usually explained by the formation of a halonium
ion (more precisely
a
haliranium ion) as
a
reaction
intermediate.[3] In organic synthesis, alkene dihalogenation is an
important method, especially in the synthesis of halogenated
natural
products.[4]
However,
while
diastereoselective
dihalogenation is well established,[1,4,5] reagent-controlled
enantioselective alkene dihalogenation is still very challenging
and has only been demonstrated for selected cases.[6-13]
A
unique example for this challenge can be found in the
enantioselective synthesis of Napyradiomycin A1 by Snyder,
who had to precomplex a synthetic intermediate with four
equivalents of a chiral Lewis acid to achieve enantioselective
dichlorination with chlorine as reagent.[7] A first catalytic, highly
enantioselective dihalogenation, in this case a dibromination,
was reported by Henry, however, according to Denmark
reproduction of the results was not possible.[8] Snyder developed
chiral sulfonium salts as stoichiometric dihalogenating agents,
which provided dihalogenides with up to 57:43 er.[9] High
enantioselectivities have been reported by Nicolaou for the
dichlorination of cinnamyl alcohols using (DHQD)2PHAL as
catalyst.[10] Enantioselective dichlorination, dibromination and
chlorobromination of allylic alcohols have also been described
Figure
1. Structure of unsymmetrical, cinchona alkaloid-based
organocatalysts for enantioselective halogenation.
In contrast to dihalogenations, a range of new catalytic
methods for enantioselective halocyclisations have been
reported.[14] (DHQD)2PHAL has also been applied as
organocatalysts in intermolecular haloetherification and
haloesterification.[15] Recently, we have developed new
unsymmetrical derivatives of this important catalyst for
enantioselective halocyclizations of alkenoic and alkynoic acids
(Figure 1).[16] With these novel catalysts in hand, we set out to
investigate the challenging enantioselective dihalogenation of
unfunctionalized alkenes. For 1-aryl-2-alkyl-substituted alkenes
reaction conditions were found leading to highly enantioselective
dichlorination. Initial mechanistic studies showed that most likely
no free dichlorine is formed and that substitution of the chloride
nucleophile by fluoride leads to an enantioselective
chlorofluorination.
[a]
[b]
V. Wedek, Dr. C. G. Daniliuc, Prof. Dr. U. Hennecke
Organisch-Chemisches Institut
Westfälische Wilhelms-Universität Münster
Corrensstr. 40, 48149 Münster, Germany
R. Van Lommel, Prof. Dr. F. De Proft
General Chemistry Research Group
Department of Chemistry
Vrije Universiteit Brussel (VUB)
Pleinlaan 2, 1050 Brussels, Belgium
Prof. Dr. U. Hennecke
[c]
Organic Chemistry Research Group
Departments of Chemistry and Bioengineering Sciences
Vrije Universiteit Brussel (VUB)
As a model substrate for the investigation of enantioselective
dihalogenation
we
chose
1,2-dihydronaphthalene
3a.
Dichlorination without
a
catalyst using 1,3-dichloro-5,5-
Pleinlaan 2, 1050 Brussels, Belgium
E-mail: ulrich.hennecke@vub.be
dimethylhydantoin (DCDMH) and triethylsilyl chloride (TES-Cl)
provided trans-1,2-dichloro-1,2,3,4-tetrahydronaphthalene 4a in
good yield and essentially as a single diastereoisomer. When
(DHQD)2PHAL was added as a typical catalyst for asymmetric
Supporting information for this article is given via a link at the end
of the document.
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10.1002/anie.201901777
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halogenation[15a] and the reaction was run at low temperature
(-40 °C), the product was obtained with only low
enantioselectivity (35:65 er; table 1, entry 1). A significantly
higher selectivity of 21:79 er was obtained, when catalyst 1a
was employed under these conditions (entry 2). A strong
influence of the electrophilic chlorinating agent on reactivity and
enantioselectivity was observed. While the highly reactive
trichloroisocyanuric acid (TCCA) provided enough reactivity, the
product was only formed in moderate yield with reduced
enantioselectivitiy (29:71 er) and was accompanied by several
byproducts (entry 3). N-Chlorosuccinimide (NCS) on the other
hand was not reactive enough and only low conversion to
racemic product was observed (entry 4).
in 11:89 er (entry 7). Attempts to improve the catalyst structure
by replacement of the di(1-naphthyl)methoxy-group in 1a led to
interesting results. The 1-napthyl groups could be replaced by
phenyl- or cyclohexyl groups without a significant change in
enantioselectivity (entries 8, 9), however, replacement by
2-napthyl groups led to a reduced enantioselectivity (25:75 er,
entry 10). Improved selectivity was observed for the
pseudoenantiomeric catalyst 2a based on dihydroquinine. Under
the optimized reaction conditions, 4a was formed with a very
good enantioselectivity of 90:10 er using of this catalyst
(entry 11).
With the optimized reaction conditions in hand, the scope of
the enantioselective dihalogenation was investigated. 1,2-
dihydronaphthalene derivatives 3 with electron-withdrawing or
electron neutral substituents on the aromatic ring were in
general dichlorinated in acceptable to excellent isolated yields
(43-87%) and with very good enantioselectivities from 89:11 er
to 93:7 er (Scheme 1). These enantioselectivities could be
achieved with either catalyst 2a or its pseudoenantiomer 1a. The
very electron-deficient alkene 3e required a slightly increased
reaction temperature (-40 °C) to achieve good conversion, but
the enantioselectivity even at this higher temperature remained
very good (11:89 er).
Table 1. Enantioselective dichlorination of 1,2-dihydronaphthalene 3a.[a]
Entry
catalyst
“Cl+”-
“Cl-“-source
Yield[b]
er[c]
source
1
(DHQD)2PHAL
DCDMH
DCDMH
TCCA
TES-Cl
TES-Cl
TES-Cl
TES-Cl
NBu4Cl
KCl, 18-C-6
TES-Cl
TES-Cl
TES-Cl
TES-Cl
TES-Cl
79%
99%
46%
22%
76%
97%
99%
99%
99%
99%
70%[d]
35:65
20:80
29:71
50:50
23:77
20:80
11:89
13:87
13:87
25:75
90:10
2
1a
1a
1a
1a
1a
1a
1b
1c
1d
2a
3
4
NCS
5
DCDMH
DCDMH
DCDMH
DCDMH
DCDMH
DCDMH
DCDMH
6
7[e]
8[e]
9[e]
10[e]
11[e]
[a] Reaction conditions: alkene (0.10 mmol), catalyst (10 mol%), electrophilic
halogenating agent (0.12 mmol) and chloride source (0.10 mmol) in
CHCl3/hexane (1/1, 1 mL) at -40 °C or -60 °C. [b] Determined by GC using an
internal standard. [c] Determined by GC on a chiral stationary phase. [d]
Isolated yield. [e] Reaction conducted at -60 °C.
The source of the nucleophilic chloride had significantly less
influence on the reaction outcome and not only silyl chlorides,
but also simple chloride salts such as NBu4Cl or KCl (in
combination with a crown ether) could be used (entries 5, 6). For
its ease of use and its high solubility, TES-Cl was chosen as
chloride source for subsequent experiments.
A
further
improvement of the enantioselectivity was achieved by
conducting the reaction at -60 °C, leading to the formation of 4a
Scheme 1. Substrate scope of the enantioselective dichlorination using
catalysts 1a and 2a. [a] Reaction at -40 °C. [b] Yield and enantioselectivity
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10.1002/anie.201901777
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given for the trans-diastereomer. The cis-diastereomer is formed in 17% yield
(70:30 dr; trans:cis; no method for determination of the enantiomeric ratio was
found).
well as 2a (59 and 53% yield, respectively), but the product was
obtained in both cases only as a mixture of two racemic
diastereomers. For (Z)-1-phenylpropene (Z)-5a, catalyst 1a
provided the product 6a as an almost 1:1 mixture of
diastereomers (54:46 dr), and only the syn-diastereomer syn-6a
resulting from anti-addition was obtained with an appreciable
enantioselectivity (29:71 er). Catalyst 2a induced a significant
diastereoselectivity (79:21 dr) favouring the syn-addition product,
but only low enantioselectivity for both isomers. Catalyst 1a was
also applied to the dichlorination of alkene 5b, which provided
product 6b as an inseparable mixture of diastereomers (61%,
66:34 dr). The major diastereomer, presumably resulting from
anti-addition, was formed with a good enantioselectivity of
79:21 er. These experiments suggest, that the (Z)-geometry of
the alkene is important for good enantioinduction and that only
the diastereomer resulting from anti-addition is formed with good
enantioselectivity. The observation that indene and open chain
alkenes react to give a mixture of syn- and anti-addition products
is at first instance rather surprising, because dihalogenations are
accepted to be stereospecific reactions.[1,3] However, non-
stereospecific chlorination of these alkenes has been reported
previously and seems to be a feature of this specific alkenes.[18]
The catalysts 1a/2a influence this diastereoselectivity, with
catalyst 2a inducing a shift towards syn-addition, however, the
effects on diastereoselectivity are small.
2-Methyl-1,2-dihydronaphthalene
3f
containing
a
trisubstituted alkene was also dichlorinated under the current
reaction conditions with a good enantioselectivity (83:17 er using
2a; 20:80 er using 1a). While indene 3g was indeed
dichlorinated,
the
reaction
was
only
moderately
diastereoselective (70:30 dr) and the major trans-diastereomer
was formed with appreciable enantioselectivity (26:74 er). No
method was found to determine the enantioselectivity for the
minor diastereomer. Interestingly, 2-substituted indenes such as
2-methyl and 2-ethylindene were again dichlorinated with very
high diastereoselectivity (>95:5 dr) and good enantioselectivity
(87:13 and 79:21 er, respectively) to provide trans-1,2-
dichloroindanes 4h and 4i in good yields. Cycloheptene 3j could
be transformed into the trans-dichlorocycloheptane 4j in
acceptable yield and high enantioselectivity (11:89 er and 88:12
er, respectively). Enantioselective dichlorination was not limited
to carbocyclic rings and dihydroquinoline 3k and 2H-chromene
3l underwent enantioselective dichlorination as well when
conducted at -40 °C. The dichlorotetrahydroquinoline 4k was
obtained under these conditions with very good yield and
excellent enantioselectivity (6:94 er), while dichlorochromane 4l
was produced in excellent yield, but with slightly reduced
enantioselectivity (22:78 er).
To establish the absolute configuration of the major
enantiomer obtained with the different catalysts, crystals of 4a
and 4j were studied by X-ray crystallography.[17] The crystal of
4a obtained using 2a as catalyst was determined to have the
R,R-configuration (Figure 2, A). GC analysis of the crystal used
for X-ray crystallography confirmed that the major enantiomer
obtained with 2a as catalyst has indeed the R,R-configuration.
This assignment is in agreement with the S,S-configuration
found in the crystal of 4j obtained with catalyst 1a (Figure 2, B)
and the S,S-configuration found in a crystal of 4e also obtained
with catalyst 1a (see SI for details).
Scheme 2. Dichlorination of open-chain alkenes.
Figure 2. Solid state structure of 4a (A) and 4j (B) as determined by X-ray
crystallography (thermal ellipsoids are shown with 50% probability).
While the catalysts 1a and 2a proved to be capable of
inducing high enantioselectivity in organocatalytic dichlorination,
the mode of action of these catalysts is not clear. Borhan has
Open chain 1-aryl-2-alkyl alkenes were investigated next.
Styrene derivatives without an alkyl substituent at the alkene
showed poor reactivity and conversion. (E)-1-phenylpropene
(E)-5a was dichlorinated in acceptable yield using catalyst 1a as
observed
(DHQD)2PHAL proceeds via syn-addition[19] and has suggested
mechanistic scenario via nucleophile-assisted alkene
activation.[20] However, the current dichlorination is on most
that
the
related
chlorolactonization
using
a
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10.1002/anie.201901777
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alkenes highly anti-selective and initial NMR experiments do
provide evidence for the interaction of these catalysts with
In conclusion, unsymmetrical cinchona alkaloid-based
phthalazines have been shown to be excellent organocatalysts
DCDMH, but not with the chloride nucleophile (see SI for details). for enantioselective dihalogenation of unfunctionalized alkenes.
Interesting observations were made when the chloride source
was replaced by other halides. When NBu4Br was used as the
only halide source, almost no reaction was observed except the
formation of a small amounts of dichloride 4a (Scheme 3). When
a commercial mixture of NBu4Cl and NBu4Br (85:15) was used,
the main product was again the dichloride 4a in 85:15 er.
However, under these conditions a small amount of the mixed 1-
bromo-2-chloro product 7 was formed as a racemic mixture. The
formation of this product argues against the formation of ClBr in
situ, which should provide the other regioisomer.[21] The use of
NBu4Cl3,[22] which is supposed to release Cl2 in situ, led only to
racemic dichlorination supporting the idea that no elemental
halogens are formed (see SI). While the replacement of chloride
by bromide was not successful, chloride could be replaced by
fluoride. When KHF2 and a crown ether (18-K-6) were used, the
In dichlorinations enantioselectivities of up to 94:6 er can be
obtained under practical reaction conditions. The current
generation of catalyst is best suited for 1,2-disubstituted or
trisubstituted alkenes with one aryl substitutent. Symmetrical
1,2-dialkylalkenes such as cyclohexene remain challenging,
however, the simple modular synthesis of the catalysts suggests
that further optimization should be possible. This will also enable
not only dichlorinations, but also other highly enantioselective
(mixed)
dihalogenations
and
intermolecular
halofunctionalisations of alkenes in general.
Acknowledgements
Financial support by the DFG (HE 6020/2-2, HE 6020/3-1 and
HE 6020/4-1 to U.H.) is gratefully acknowledged. Tier2
computational resources and services were provided by the
Shared ICT Services Centre Funded by the Vrije Universiteit
Brussel, the Flemish Supercomputer Center (VSC) and the
Research Foundation-Flanders (FWO). F.D.P wishes to
acknowledge the VUB for financial support throught a Strategic
Research Program. F. D. P. also acknowledges the Francqui
foundation for a position as “Francqui research professor”. R. V.
L. acknowledges the FWO for the PhD fellowship received
(1185219N).
2-chloro-1-fluoro-tetrahydronaphthalene
8
was formed in
excellent yield (99%).[23] At -40 °C, the product was obtained
with an enantioselectivity of 81:19 er, very similar to the
dichlorination product 4a under these conditions. On alkene 3j,
this
chlorofluorination
proceeds
even
with
higher
enantioselectivity providing the product 9 in 67% yield and 93:7
er (Scheme 3). Overall, these experiments suggest that the
combination of catalyst 1a/2a and DCDMH enables the stereo-
determining, enantioselective addition of the chlorine
electrophile to the alkene to provide a chiral intermediate, which
can then add a nucleophile such as chloride or fluoride, usually
with high diastereoselectivity. To get more insight into this
intermediate, DFT calculations were performed on likely cationic
structures (see SI for details). These calculations do not support
the formation of a typical chloriranium ion, but result in highly
asymmetric, benzylcarbocation-type structures with only a weak
interaction of the cationic center with the chloro substituent. This
could be the reason, why only 1-aryl-substituted alkene provide
good enantioselectivity.
Keywords: alkenes • dichlorination • enantioselectivity •
halogenation • organocatalysis
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10.1002/anie.201901777
Angewandte Chemie International Edition
COMMUNICATION
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COMMUNICATION
The enantioselective
dichlorination of
unfunctionalized alkenes is
enabled by the use of
unsymmetrical cinchona
alkaloid-based
Volker Wedek, Constantin
G. Daniliuc, Ulrich
Hennecke*
Page No. – Page No.
Organocatalytic,
Enantioselective
Dichlorination of
Unfunctionalized Alkenes
organocatalysts. In
combination with the
electrophilic chlorinating
agent 1,3-dichloro-5,5-
dimethylhydantoin
(DCDMH) and TES-Cl as
source of nucleophilic
chloride, 1-aryl-2-alkyl
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