Catalytic Vicinal Dichlorination of Unactivated Alkenes

Article abstract of DOI:10.1021/acscatal.9b02313

Organocatalytic strategies for the programmed, catalytic oxidation of ?-bonds through regioselective halogenation remain comparatively underdeveloped. The vicinal dichlorination of unactivated alkenes is a pertinent example, where stoichiometric reagents and prefunctionalization steps are often employed. This is surprising given the prominence of the 1,2-dichloro moiety in an array of bioactive natural products of both terrestrial and marine origin. Inspired by Willgerodt's seminal discovery in 1886 that PhICl₂ can be generated by passing Cl_2(g) through iodobenzene, a catalytic vicinal dichlorination of unactivated alkenes has been designed on the basis of an I(I)/I(III) manifold. In situ generation of p-TolICl₂ is achieved using Selectfluor and CsCl. Substrate scope, mechanistic delineation, and preliminary validation of an enantiomeric variant are established. Over a century after the initial discovery of the Willgerodt reagent (PhICl₂), an operationally simple, catalytic alternative has been validated.

Full text of DOI:10.1021/acscatal.9b02313

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Letter
Catalytic Vicinal Dichlorination of Unactivated Alkenes
Jerome Charles Sarie, Jessica Neufeld, Constantin G. Daniliuc, and Ryan Gilmour
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.9b02313 • Publication Date (Web): 08 Jul 2019
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ACS Catalysis
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Catalytic Vicinal Dichlorination of Unactivated Alkenes
Jérôme C. Sarie, Jessica Neufeld, Constantin G. Daniliuc and Ryan Gilmour*
[a]
[a]
[a]
[a]
Organisch-Chemisches Institut, Westfälische Wilhelms-Universität Münster, Corrensstraße 40, 48149 Münster,
Germany.
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ABSTRACT: Organocatalytic strategies for the programmed, catalytic oxidation of π-bonds through regioselective halo-
genation remain comparatively underdeveloped. The vicinal dichlorination of unactivated alkenes is a pertinent example,
where stoichiometric reagents and pre-functionalisation steps are often employed. This is surprising given the promi-
nence of the 1,2-dichloro moiety in an array of bioactive natural products of both terrestrial and marine origin. Inspired by
Willgerodt’s seminal discovery in 1886 that PhICl can be generated by passing Cl2(g) through iodobenzene, a catalytic
2
vicinal dichlorination of unactivated alkenes has been designed based on an I(I)/I(III) manifold. In situ generation of p-
®
TolICl is achieved using Selectfluor and CsCl. Substrate scope, mechanistic delineation and preliminary validation of an
2
enantiomeric variant are established. Over a century after the initial discovery of the Willgerodt reagent (PhICl ), an op-
erationally simple, catalytic alternative has been validated.
2
KEYWORDS. 1,2-chlorination • halogenation • iodine • organocatalysis • selectivity • stereospecificity
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Organocatalysis-based strategies to enable the vicinal
diate. It is important to highlight that there have been
rapid advances in the catalytic, diastereo- and enantiose-
lective vicinal dichlorination of allylic alcohol deriva-
dihalogenation of unactivated alkenes are conspicuously
under represented. The exigency is particularly promi-
1
1
7,18,19
nent in the 1,2-dichlorination of unactivated alkenes using
tives.
Recently, Hennecke and co-workers reported a
2
low molecular weight catalysts and simple chloride salts.
catalytic, enantioselective dichlorination of Z-configured,
alkyl substituted styrenes using 1,3-dichloro-5,5-
dimethylhydantoin (DCDMH) and TESCl as the electro-
philic and nucleophilic chlorinating reagents, respective-
ly, in the presence of a cinchona alkaloid-based catalyst.
Whilst these conditions are effective for alkyl substituted
styrenes, simple alkenes remain challenging.
This is surprising, given the diversity of marine and ter-
restrial poly-chlorinated, secondary metabolites bearing
the 1,2-dichloro motif (Figure 1), and the well-delineated
biosynthesis pathways that generate formal electrophilic
20
+
3
“
Cl ” sources from abundant salts. Prominent synthesis
campaigns directed towards the chlorosulfolipids by
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Vanderwal, Carreira, and Yoshimitsu, have been in-
strumental in triggering a renaissance in organo-chlorine
chemistry: This is a consequence of the unique conforma-
7
tional and physicochemical properties of the vicinal di-
chloro unit, and the wider biological and environmental
8
impacts of complex, polychlorinated systems. Logically,
this has led to a rapid expansion in strategies to enable
this fundamental transformation. In addition to reliable,
multi-step processes that involve alkene pre-activation,
such as epoxide functionalisation under Appel condi-
9
tions, a number of reagent-based processes remain in-
dispensable: The venerable Mioskowski reagent (Et NCl )
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3
remains popular although caution must be exercised
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0
during preparation due to the corrosive nature of Cl2(g)
.
These strategies are complemented by a series of elegant
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transition metal-mediated protocols using manganese,
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13
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molybdenum, ruthenium and vanadium. Stereospeci-
ficity is frequently observed in many scenarios due to the
involvement of transient chloronium ions; an aspect of
reagent-based chlorination that has been beautifully har-
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4
-8
nessed in the aforementioned total syntheses.
More
recently, an organo-catalytic strategy to access the elusive
vicinal syn-configured adducts has been achieved by
Denmark and co-workers via a key seleniranium interme-
Figure 1. Top: Selected examples of marine and terrestrial
natural products containing the vicinal dichloro motif. Bot-
tom: The conceptual framework of this study.
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Emulating the formal Umpolung process enabled by dichlorination of model substrate 1 in the presence of
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haloperoxidases in biology (Cl → Cl ) has proven to be a
10 mol% catalyst loading. Initially, the title reaction was
attempted with p-TolI as the catalyst and KCl in di-
chloromethane. A screen of common oxidants, including
NaOCl, NaIO , CAN, AcO H, t-BuO H, H O , K S O ,
valuable and expansive blueprint for the design of syn-
thetic chlorination processes. Inspired by this, and based
on our interest in the I(I)/I(III) manifold, we sought to
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generate Willgerodt-type reagents (ArICl2) in situ from a
simple aryl iodide organocatalyst, oxidant and chloride
source. First isolated in 1886, this reagent has a distin-
guished history in stoichiometric chlorination,
there is a conspicuous absence of catalytic variants.
Motivation stemmed from previous work on the catalytic
vicinal difluorination of alkenes, and mitigating the cur-
rent safety and sustainability shortcomings of stoichio-
metric reagent preparation.
proved ineffective. Switching to m-CPBA furnished the
corresponding epoxide in 68%, whereas reactions using
Oxone® resulted in a competing background reaction in
the absence of catalyst: This latter scenario would render
translation to an enantioselective paradigm futile. Finally,
1
7,23
yet
2
4,25
®
Selectfluor was investigated. An early study by Lal and
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co-workers disclosed its ability to oxidise iodide and bro-
mide ions but not chlorides, rendering it ideal for this
29
study. Changing solvent to TFE boosted reaction effi-
ciency, yielding the product in 51% yield (Table 1, entries
It was envisaged that inexpensive, commercially available
p-TolI would serve as an excellent small molecule organo-
catalyst upon which to base an I(I)/I(III) catalysis cy-
Inspired by the seminal studies by Cotter and co-
workers who explored the role of trifluoroacetic acid in
the stoichiometric reaction of iodobenzene dichloride
with alkenes, the effect of various additives on reaction
efficiency were also investigated (Table 1). To that end, a
1
-4). Further improvement resulted from performing the
reaction in hexafluoroisopropanol (HFIP) and utilising
CsCl as a chloride source (entries 5-10). As illustrated in
entry 11, the control reaction without p-TolI did not fur-
nish the expected product 2. Cognisant of the critical role
of HFIP in Gulder and co-workers recent study on hali-
ranium-ion cyclisation cascades, a co-solvent system was
26,27
cle.
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explored using HFIP.
process of design was initiated by exploring the vicinal
Table 1. Optimization of the I(I)/I(III)-mediated vicinal dichlorination of alkenes.
MCl
X eq.)
additive
(X eq.)
[a]
entry
solvent
CH Cl
time (h)
T (°C)
yield
(
1
KCl (5.0)
KCl (5.0)
KCl (5.0)
KCl (5.0)
KCl (5.0)
KCl (5.0)
NaCl (5.0)
CsCl (5.0)
CsCl (3.0)
CsCl (3.0)
CsCl (3.0)
CsCl (3.0)
CsCl (3.0)
CsCl (3.0)
CsCl (3.0)
CsCl (3.0)
-
15
15
15
3
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
0
<5%
<5%
<5%
2
2
2
3
4
5
MeCN
-
CF CO Et
-
3
2
TFE
-
51% (42%)
59%
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
-
3
[b]
6
7
8
9
-
3
60%
-
3
<5%
-
3
70%
-
3
76%
[c]
10
-
3
71%
[
d]
[e]
11
-
3
<5%
12
CH Cl
HFIP (9.0)
HFIP (9.0)
HFIP (9.0)
HFIP (9.0)
HFIP (9.0)
3
88% (73%)
12%
2
2
[d]
13
CH Cl
3
2
2
2
2
2
[d]
14
15
16
CH Cl
8
8
8
<5%
2
CH Cl
0
78% (65%)
84% (75%)
2
[f]
1
CH Cl
0
2
[
a] H NMR yield using DMF as internal standard (yield after column chromatography). [b] Reaction performed in the dark. [c]
1
5
mol% of p-TolI. [d] Control experiment without catalyst. [e] Complete consumption of the starting material by H NMR. [f] 20
mol% of p-TolI. N.B. A screening of common oxidants is provided in the SI.
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ACS Catalysis
which had to be suppressed with a future view to develop-
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ing an enantioselective process (entry 13). This was
achievable at 0 °C (entry 14) and so the reaction scope was
established at this temperature (entry 15, 78%). Increasing
the catalyst loading to 20 mol% further increased the
yield to 84% (entry 16). The scope of the transformation
was then explored under the standard conditions (Figure
2). Substrates containing spacers were employed to miti-
gate complications arising from anchimeric participation.
The general catalysis conditions proved to be compatible
with an array of functional groups. Esters 2, 3 and 4 were
formed in synthetically useful yields (up to 86%): Product
1
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demonstrates the chemoselectivity of the process for
electron rich alkenes in the presence of an electron defi-
cient system. Gratifyingly, unprotected alcohols were
compatible with the vicinal dichlorination conditions (5,
78%) as were free acids (6, 68%). The primary bromide
was not susceptible to Finkelstein chemistry, allowing the
desired vicinal dichloride to be formed cleanly (7, 80%),
and the corresponding sulfate and tosylate were compati-
ble with the general conditions (8, 76%; 9, 75%). In view
of the importance of phosphate groups in bioactive lipids,
compound 10 was prepared (77%). Examples with re-
duced spacer lengths proved unproblematic.
The masked amine 11 was generated in 77% yield, and the
protected C3 building blocks 12 and 13 could also be ac-
cessed via this method (up to 77%). Styrenes also proved
to be competent substrates as evidenced by dichloride 14,
15 and 16 (up to 59%). Simultaneous scope expansion and
mechanistic interrogation was achieved by moving to
internal alkenes. Consistent with Denmark’s mechanistic
1
a
description of the stoichiometric reaction, the reactions
were found to be highly stereospecific (Figure 2, lower).
The anti-configured vicinal dichlorides 17-19 were gener-
3
ated from the corresponding E-alkene ( J = 7.5 Hz for
HH
1
9). Conversely, the syn-adducts 20 and 21 derived from
3
the starting Z-alkene ( J = 3.0 Hz for 21).
HH
0
0
0
.3
.2
.1
OMe
R H
log(k /k )
Figure 2. Establishing the scope of the catalytic, vicinal
y = −1.000x
R² = 0.998
dichlorination of alkenes and a demonstration of stereospeci-
Me
1
ficity. H NMR yield using DMF as internal standard (yield
after column chromatography). [a] p-TolI (20 mol%), Select-
H
®
0.0
-0.1
-0.2
fluor (1.1 eq.), CsCl (3.0 eq.), HFIP (9.0 eq.), CH Cl , 8 h, 0 °C.
[
2
2
-0.3
-0.2
-0.1
0.0
0.1
0.2
0.3
®
σ
p
b] p-TolI (20 mol%), Selectfluor (1.1 eq.), CsCl (3.0 eq.),
HFIP (9.0 eq.), CH Cl , 8 h, r.t. [c] p-TolI (40 mol%), Select-
2
2
®
Cl
fluor (2.2 eq.), CsCl (6.0 eq.), HFIP (18.0 eq.), CH Cl , 8 h, 0
2
2
-
0.3
°
C.
The addition of 9.0 eq. of HFIP had a notable effect on
reaction efficiency, furnishing 2 in 88% yield (entry 12).
However, the control reaction without catalyst at ambient
temperature revealed a competing background reaction
Figure 3. Exploring the effects of the additive and the cata-
lyst on the dichlorination 1 → 2. Upper: Control experiments
to demonstrate the role of HFIP. Lower: Hammett plot with
para-substituted iodoarenes (ρ< 0).
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X-ray crystallographic analysis of 19 unequivocally estab-
More than a century after the discovery of the Willgerodt
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lished the relative configuration of the vicinal dichloro
motif, and revealed a dihedral angle φ = 169.5° (Figure 2,
lower, CCDC 1905463). This contrasts sharply with the
reagent, a protocol to generate p-TolICl in situ is dis-
2
closed and applied to the organocatalytic, vicinal dichlo-
rination of unactivated alkenes. The general catalysis
conditions demonstrate broad functional group tolerance
and allow single regioisomers to be generated in a highly
stereospecific manner. Importantly, preliminary valida-
tion of enantioselectivity is described on a challenging
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gauche conformation inherent to vicinal difluorides.
A
radical clock experiment also proved instructive favouring
formation of the di- (22) and tetra-chlorinated (23) prod-
ucts with 20 or 40 mol% catalyst loading respectively.
This is in contrast to the electrochemical conditions re-
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mono-substituted system, and is the subject of ongoing
research in this laboratory.
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ported by Lin and co-workers that generate the cyclic
adduct 24.
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0
The importance of HFIP as an additive in the title trans-
formation was established by unproductive control exper-
iments using the methylated and non-fluorinated ana-
logues (<5% in both scenarios) (Figure 3, top). A Ham-
mett plot of electronically distinct, para-substituted io-
doarenes (R = OMe, Me, Cl, H) established ρ< 0 indicat-
ing a build-up of positive charge in the transition state,
and a manifest rate acceleration as a result of electron-
Figure 5. Preliminary validation of an enantioselective vari-
ant.
32
donating groups (Figure 3).
ASSOCIATED CONTENT
The Supporting Information is available free of charge on the
ACS Publications website. Full experimental details and NMR
spectra (PDF).
AUTHOR INFORMATION
Corresponding Author
*
E.mail: ryan.gilmour@uni-muenster.de
Homepage: www.uni-muenster.de/chemie.oc/gilmour
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
We acknowledge financial support from the WWU Münster,
and the Deutsche Forschungsgemeinschaft (Excellence Clus-
ter EXC 1003, and SFB 858). This manuscript is dedicated to
Prof. Dr. Erick M. Carreira.
Figure 4. Top: Reference spectrum of p-TolICl in CD Cl .
2
2
2
Middle: Reaction mixture after 20 min. Standard reaction
conditions at 0.2 mmol: p-TolI (40 µmol, 20 mol%), CsCl
(0.6 mmol, 3.0 eq.), Select-
®
fluor (0.22 mmol, 1.1 eq.),
REFERENCES
HFIP (1.8 mmol, 9.0 eq.),
CD Cl (0.9 mL). Bottom:
(1) (a) Cresswell, A. J.; Eey, S. T.-C.; Denmark, S. E. Catalytic,
2
2
Stereoselective Dihalogenation of Alkenes: Challenges and Op-
portunities. Angew. Chem. Int. Ed. 2015, 54, 15642–15682; (b)
Chung, W.-J.; Vanderwal, C. D. Stereoselective Halogenation in
Natural Product Synthesis. Angew. Chem. Int. Ed. 2016, 55, 4396–
4434.
Reference spectrum of p-
TolI in CD Cl Inset: X-ray
2
2.
structure
of
p-TolICl2.
CCDC 1555066.
(2) Andries-Ulmer, A.; Gulder, T. Halogenation and Halocycliza-
tion of Alkenes. In Science of Synthesis: Catalytic Oxidation in
Organic Synthesis, 2017, 1, 389-428.
Finally, it was possible to demonstrate in situ formation of
the Willgerodt-type reagent by comparing the reaction
mixture with p-TolI and a sample of p-TolICl prepared
2
(
3) (a) Butler, A.; Walker, J. V. Marine haloperoxidases. Chem.
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C-Cl bond forming stages are mechanistically consistent
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ChemBioChem 2016, 17, 2028-2032.
1
a
with Denmark’s reaction classifications. With a view to
rendering this process enantioselective, preliminary stud-
3
3
ies with a chiral aryl iodide catalyst were conducted. The
expected dichloride 14 was generated with 64:36 e.r. thus
providing preliminary validation (Figure 5).
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9) (a) Isaacs, N. S.; Kirkpatrick, D. The chlorination of epoxides
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241; (c) Chung, W.-J.; Vanderwal, C. D. Approaches to the
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Enantiocontrolled Synthesis of Polychlorinated Hydrocarbon
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