Regiodivergent halogenation of (E)-?2-chlorovinyl ketones via soft ?±-vinyl enolization strategy

Article abstract of DOI:10.1021/ol5034354

The soft ?±-vinyl enolization of (E)-?2-chlorovinyl ketones was investigated in the presence of various halogen electrophiles. Depending on the nature of halogen electrophiles, the selective formation of three products, namely ?±,?±-dichloropropargyl keto

Full text of DOI:10.1021/ol5034354

Letter
pubs.acs.org/OrgLett
Regiodivergent Halogenation of (E)‑β-Chlorovinyl Ketones via Soft
α‑Vinyl Enolization Strategy
†
‡
‡
,†
Hun Young Kim, Seokwoo Lee, Sanghee Kim, and Kyungsoo Oh*
†
College of Pharmacy, Chung-Ang University, 84 Heukseok-ro, Dongjak, Seoul 156-756, Republic of Korea
College of Pharmacy, Seoul National University, San 56-1, Silim, Kwanak, Seoul 151-742, Republic of Korea
‡
*
S Supporting Information
ABSTRACT: The soft α-vinyl enolization of (E)-β-chlorovinyl
ketones was investigated in the presence of various halogen
electrophiles. Depending on the nature of halogen electrophiles,
the selective formation of three products, namely α,α-dichloro-
propargyl ketones, α,γ-dihaloallenyl ketones, and 3-halofurans, was
observed. The observed regiodivergent nucleophilic pathways of
(E)-β-chlorovinyl ketones demonstrate the diversity-oriented
synthesis strategy in which the nucleophilic reactivity of (E)-β-
chlorovinyl ketones can be selectively modulated by the choice of
suitable hard and soft electrophiles.
hile the enolization of carbonyl compounds with
Scheme 1. Soft α-Vinyl Enolization of β-Halovinyl Ketones
and Their Janus-like Reactivity
3
W
α-C(sp )−H bonds constitutes one of the pillars of
1
synthetic chemistry, the corresponding enolization of carbonyl
2
compounds with α-C(sp )−H bonds is virtually unknown.
Accordingly, α,β-unsaturated (i.e., conjugated) carbonyl com-
pounds are less prone to direct α-vinyl enolization except for a
few limited cases of α-vinyl deprotonation under strong basic
2
conditions using lithium amide bases. With an aim of develop-
ing a general and direct α-vinyl enolization method, we recently
disclosed a mild base-promoted dehydrohalogenation of (E)-β-
halovinyl ketones that involved a preferential α-vinyl enolization
3
3
over the α-C(sp )−H bond (Scheme 1). The fact that such
α-vinyl enolizations are readily achieved by using a mild base,
Et N, as opposed to the deprotonation conditions using hard
3
lithium amide bases prompted us to investigate the chemo- and
regioselective enol formations in a conjugated carbonyl system
that otherwise would have been difficult, if not impossible, under
4
other basic conditions. Our studies subsequently demonstrated
the synthetic utility of [3]cumulenolate intermediate species
that displayed ambivalent reactivity; the intrinsically electrophilic
5
(
E)-β-chlorovinyl ketones acted as either nucleophiles or elec-
6
trophiles under different Lewis acid conditions.
To further scrutinize the reaction pathways of (E)-β-chlorovinyl
ketones under the soft α-vinyl enolization conditions, we investi-
gated the nucleophilic character of enol intermediates using
N-halosuccinimides. Herein, we report that the regiodivergent
nucleophilic pathways of (E)-β-chlorovinyl ketones could be
realized by using different halogen sources based on their hard−
soft acid−base interactions with different nucleophilic species.
This regiodivergent approach allows halogenation at either the
α-, β-, or γ-carbon position of (E)-β-chlorovinyl ketones, leading
to a facile formation of previously unknown α,α-dichloropropargyl
ketones and α,γ-dihaloallenyl ketones as well as synthetically
useful halofuran derivatives.
First, we employed a number of halogen electrophiles to see
if selective reaction pathways between different enol species could
be achieved (Table 1). Upon employing N-chlorosuccinimde
(
NCS) in the α-vinyl enolization of 1a in CH Cl (Table 1,
2 2
entry 1), the formation of a new chemical entity, α,α-dichloro-
propargyl ketone 4a, was observed in 45% yield along with a
Received: November 27, 2014
©
XXXX American Chemical Society
A
DOI: 10.1021/ol5034354
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
Table 1. Optimization of the Regioselective Halogenation
a
b
entry
halogen (equiv)
solvent
4a/5a/6a or 7a
yield (%)
c
1
2
3
4
5
6
7
8
NCS (1.1)
NCS (2.2)
NBS (1.1)
NBS (2.1)
NIS (1.1)
CH Cl2
1:0:0
1:0:0
0:2:1
0:1:2
0:1:2
0:1:0
45
2
CH Cl2
88
2
c
CH Cl2
37
2
CH Cl2
81
2
c
CH Cl2
38
2
NIS (2.1)
CH Cl
85
2
2
d
c
Selectfluor (2.2)
TCCA (1.1)
NBS (1.1)
NBS (2.1)
NIS (1.1)
nr
d
1:0:0
0:0:1
0:0:1
0:0:1
0:0:1
<25
73
e
9
THF
THF
THF
THF
e
1
1
1
0
1
2
75
e
e
75
NIS (2.1)
75
a
1
b
c
Determined by crude H NMR. Isolated yield of products after column chromatography. The remaining molecular mass balance accounts for a
d
e
1
:2 mixture of 2a and 3a. Reactions in THF, PhCH , CH COCH , CH CN. Solvent switch from CH Cl to THF before addition of halogen
3 3 3 3 2 2
source.
3
mixture of elimination products 2a and 3a. An increased
amount of NCS (2.2 equiv) provided 4a in 88% yield (Table 1,
entry 2). The use of other N-halosuccinimides led to a mixture
of another new chemical entity, α,γ-dihaloallenyl ketones 5,
and a known chemical entity, 3-halofurans 6a/7a (Table 1,
entries 3−5). Gratifyingly, the use of 2.1 equiv of NIS provided
the exclusive formation of α,γ-diiodoallenyl ketone 5a in
excellent yields (Table 1, entry 6). While we also investigated
other electrophilic fluorine (NFSI/Selectfluor) and chlorine
sources (trichloroisocyanuric acid, TCCA), no satisfactory
results were observed, possibly due to the different counter-
cation effects (Table 1, entries 7 and 8). To optimize the forma-
tion of 3-halofurans, we screened different solvents and found
THF to be a suitable solvent for the regioselective formation
Scheme 2. Scope of α,α-Selective Chlorination
of 3-halofurans in the absence of Et N (Table 1, entries 9−12).
3
Further control experiments of the reaction also showed that
the 3-halofuran was less likely derived from the electrophilic
halogenation of furans. Thus, the formation of 3-halofurans
was not observed upon treating a nonhalogenated furan,
3
2
-butyl-5-phenylfuran, with NXS (1.2 equiv) in THF at ambient
temperature.
The scope of α,α-selective chlorination of (E)-β-chlorovinyl
ketones is summarized in Scheme 2. The reaction was readily
applicable to a range of aryl ketones with good to excellent
yields (72−94%). The electronic and steric nature of aryl
substituents of (E)-1 did not significantly affect the reaction
outcome (4a−h). However, in the case of alkyl ketones, the
chlorination did not work, resulting in the formation of
7
elimination products 2 and 3 in 50% yield. Aryl ketones
5 was greatly improved upon handling the materials in the absence
of light. Thus, the α,γ-selective iodination was achieved with a
range of aryl ketones with good to excellent yields (60−85%).
Additionally, functionalized α,γ-diiodoallenyl ketones were
produced under the optimized conditions (5i−k).
with functional groups such as a halide, 4i, an ester, 4j, and a
phthalyl group, 4k, were also tolerated under the optimized
α,α-dichlorination conditions.
The scope of α,γ-selective iodination of (E)-β-chlorovinyl
ketones is illustrated in Scheme 3. While the formation of
α,γ-dibromoallenyl ketones could be achieved in >90% yields,
the rapid decomposition of products upon isolation did not
allow the full characterization (see the Supporting Information
Scheme 4 shows the scope of β-selective halogenation of
(E)-β-chlorovinyl ketones. While the vinyl enolization of (E)-1
could be performed in THF, the reaction was sluggish and
the presence of a residual Et N resulted in the formation of
3
1
for H NMR data). The stability of α,γ-diiodoallenyl ketones
side products, α,γ-dihaloallenyl ketones 5. Thus, we adopted a
B
DOI: 10.1021/ol5034354
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Scheme 3. Scope of α,γ-Selective Iodination
Scheme 5. Regiodivergent Halogenations of Allenyl and
Propargyl Ketones
8
eliminating electrophilic halogen sources. Next, we subjected a
mixture of allenyl and propargyl ketones 2a and 3a under the
halogenation conditions in the presence and absence of Et N.
3
No reaction was observed when NCS was used in the absence
of Et N; however, the use of NBS and NIS provided the
3
exclusive formation of 3-halofurans 6a/7a. In the presence of a
catalytic amount of Et N (10 mol %), the reaction of 2a and 3a
3
with NXS led to the formation of α,α-dichloropropargyl ketone
Scheme 4. Scope of β-Selective Halogenation
4a and α,γ-dihaloallenyl ketones 5a, respectively, in high yields.
On the basis of the halogenation reaction profile of (E)-β-
chlorovinyl ketones, it is tempting to speculate that the thermo-
dynamic (Z)-alkynyl enol is responsible for the regioselective
formation of α,α-dichloropropargyl ketones 4 and α,γ-dihaloallenyl
9
ketones 5 (Scheme 6a). The formation of alkynyl enols from
allenyl ketones 2 is believed to involve the γ-enolization by
Et N, given that the pK values of γ-substituted allenyl ketones
3
a
1
0
range from 13.3−13.9. Likewise, the alkynyl enols should
have been generated from the α-enolization of propargyl
ketones 3 by Et N. While allenyl ketones can, in principle, be
11
3
directly converted to [3]cumulenolates without the intermedi-
acy of alkynyl enolates, such α-deprotonation of allenyl ketones
12
requires either hard base or Lewis acid as we recently showed
in the Ti(O-i-Pr) -promoted aldol condensation of allenyl
4
5
ketones in the absence of base. While more studies are needed
to analyze structure−reactivity relationships (i.e., using Marcus
theory by a combination of intrinsic and product stability
13
effect), on the basis of our data we propose a possible mechanism
for the regiodivergent halogenation pathways of (E)-β-chlorovinyl
ketones that involves the α-halogenation of thermodynamic enol
species followed by the interactions between hard (NCS)−soft
electrophiles (NBS/NIS) and hard (α-carbon)−soft nucleophiles
(γ-carbon of α-haloalkynyl enols).
solvent-switch strategy before adding halogen sources. In this
way, the β-selective halogenation efficiently proceeded to give
the exclusive formation of 3-halofurans in good to excellent
yields (62−91%). In general, the iodination using NIS was
slightly higher yielding than bromination using NBS. Notably,
the β-selective halogenation worked well for functionalized aryl
The formation of 3-halofurans from both allenyl and pro-
pargyl ketones can be explained by invoking the electrophilic
halogenation with assistance of the internal carbonyl oxygen
atom without involving the intermediacy of alkynyl enols
(Scheme 6b). The formation of 3-halofurans from allenyl
ketones in the absence of base strongly argues against the
possible involvement of alkynyl enol intermediates. In addition,
the fact that Selectfluor and NCS do not work in the current
3-halofuran synthesis illustrates the soft nature of NBS and
NIS toward allenyl and propargyl ketones, demonstrating the
(
6/7i-6/7k) as well as alkyl ketones (7l,m).
To delineate the reaction pathways of active enol species
under halogenation conditions, we performed control experi-
ments (Scheme 5). The use of both NXS and Et N under the
3
α-vinyl enolization conditions of (E)-1a did not produce
halogenated products. The failure of halogenation might be attrib-
14
uted to the inherent redox reactions between NXS and Et N,
subtle difference between hard and soft acid/base interactions.
3
C
DOI: 10.1021/ol5034354
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Organic Letters
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Scheme 6. Proposed Reaction Mechanisms for
Regiodivergent Halogenation Pathways
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This research was supported by CAU through a generous
startup package to K.O. as well as a Mid-Career Researcher
Program to SK (NRF-2013R1A2A1A01015998 at SNU).
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16
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6
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17
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philic modes of (E)-β-chlorovinyl ketones under the soft
α-vinyl enolization conditions. These newly observed reaction
pathways of multiple chemical species, simultaneously generated
in situ, allow complementary halogenations at respective α-, β-,
and γ-carbon of (E)-β-chlorovinyl ketones. We are currently
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using other hard/soft electrophiles. These results will be the
subject of future publications.
(
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ASSOCIATED CONTENT
Supporting Information
■
*
S
8
338.
Experimental procedures, computational studies, and character-
ization data for all new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: kyungsoooh@cau.ac.kr.
D
DOI: 10.1021/ol5034354
Org. Lett. XXXX, XXX, XXX−XXX