Stereoselective synthesis of tetrasubstituted olefins through a halogen-induced 1,2-silyl migration

Article abstract of DOI:10.1002/anie.201303007

Migrating through Si valley: The highly stereoselective formation of α-silyl-β- haloenones by way of silicon group migration is described. Electrophilic activation of the alkyne by N-halosuccinimides induced an anti-selective migration to give highly substituted enones (see scheme). These enone products can be readily converted to the all-carbon tetrasubstituted alkenes while maintaining their geometry. Copyright

Full text of DOI:10.1002/anie.201303007

Angewandte
Chemie
DOI: 10.1002/anie.201303007
Alkyne Halosilylation
Stereoselective Synthesis of Tetrasubstituted Olefins through
a Halogen-Induced 1,2-Silyl Migration**
Nicholas T. Barczak, Douglas A. Rooke, Zachary A. Menard, and Eric M. Ferreira*
All-carbon tetrasubstituted alkenes[1] have been demon-
strated to have unique structural, physical, and electronic
features.[2] Moreover, the geometry of these olefins often
provides the foundation for establishing vicinal stereogenicity
in sp3-hybridized carbon centers through face-selective addi-
tion reactions (for example, hydrogenations, cycloadditions,
dihydroxylations, among others).[3] The generation of stereo-
defined tetrasubstituted alkenes presents a particular chal-
lenge in synthetic chemistry. When endocyclic, alkene ste-
reochemistry can be rather straightforward to control using
several methods for geometrically defined olefin synthesis
(for example, Wittig-type reactions, eliminations, metathe-
sis).[4] In contrast, acyclic polysubstituted alkenes do not have
that additional element of control, and these olefination
methods are frequently problematic when extended to
tetrasubstituted systems. Consequently, the syntheses of
Figure 1. Pt-catalyzed anti-selective silicon migration to form (Z)-a-
silylenones.
these alkenes with high geometrical control is a daunting
challenge.
Nevertheless, there have been some remarkable achieve-
ments toward the syntheses of tetrasubstituted alkenes.
Arguably, the most commonly employed method for access-
ing this structural motif is the carbometalation of alkynes.[5]
Within these systems, there are still matters to address, such as
addition regiocontrol, substrate tolerance, and metal selec-
tion. Given this frame of reference, new methods to access
tetrasubstituted alkenes could prove highly useful. The
activation of alkynes by non-Brønsted acid electrophiles
toward functionalized alkenes, outlined by Koser, Gaunt, and
others,[6] offers an alternative strategic approach. Herein, we
report that halogen-based electrophiles can be used in
conjunction with a-hydroxypropargylsilanes to generate tet-
rasubstituted vinylsilane products with excellent levels of
stereoselectivity. We also demonstrate that elaboration of
these vinylsilanes offers a general modular route to tetrasub-
stituted olefins.
an anti-selective 1,2-silicon group migration to form inter-
mediate D. Protodemetalation affords the stereodefined
vinylsilane product.[8,9] We found this process attractive for
the formation of stereodefined trisubstituted alkenes because
the precursor a-hydroxypropargylsilanes were simple to
access through acetylide addition to acylsilanes.[10] Further-
more, we were intrigued by the excellent anti-selectivity in
this transformation, as the observation of related silicon
migrations has been reported somewhat sporadically.[10c,11]
From this fundamental migration process, we hypothesized
that alternative electrophilic species may be used in alkyne
activation to induce the 1,2-shift (A!E). Different electro-
philes could offer the opportunity to provide b-substitution
beyond hydrogen, incorporating an additional functional
group for further elaboration.
We have recently described our efforts in stereoselective
silicon-based additions to alkynes.[7] One such transformation
is the platinum-catalyzed synthesis of (Z)-a-silylenones from
a-hydroxypropargylsilanes (Figure 1).[7a] Mechanistically, we
proposed that the Pt catalyst coordinates the alkyne, inducing
To that end, we investigated the behavior of a-hydroxy-
propargylsilane 1 in the presence of a variety of electrophiles
(Table 1). Using a standard set of conditions (CH2Cl2, 08C to
558C), several halogenating electrophiles were investigated.
Chlorine- and fluorine-based species (N-chlorosuccinimide
(NCS), trichloroisocyanuric acid (TCCA), Selectfluor) were
generally unreactive. However, other N-halosuccinimides
were remarkably effective at promoting the 1,2-silicon
group shift. Both N-bromosuccinimide (NBS) and N-iodo-
succinimide (NIS) accomplished the desired transformation,
[*] Dr. N. T. Barczak, D. A. Rooke, Z. A. Menard, Prof. E. M. Ferreira
Department of Chemistry, Colorado State University
1872 Campus Delivery, Fort Collins, CO 80523 (USA)
E-mail: emferr@mail.colostate.edu
introducing
a halogen atom at the b-position of the
[**] Colorado State University is acknowledged for the support of our
program. Eli Lilly is gratefully acknowledged for a graduate research
fellowship to D.A.R.
enone.[12,13] Importantly, the reaction proceeded with high
stereoselectivity, forming the (E)-silylenone in greater than
19:1 geometrical purity. The transformation proceeded at
room temperature with NBS, whereas the more reactive NIS
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201303007.
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Communications
all cases).[15] The reaction was quite effective for several
silicon species (Me3Si-, PhMe2Si-, and BnMe2Si-). A partic-
ularly hindered alkyne substrate (entry 6) reacted to afford
the desired enone, albeit requiring a longer reaction time and
with diminished yield. Only in the case of the tert-butyl
substituted alkyne did we not see the formation of the (E)-
silylenone (entry 3).[16]
Table 1: Electron-withdrawing group analysis.
Entry
Oxidant
T [8C]
Yield [%][a,b]
E:Z[c]
A similar evaluation of scope was conducted using NBS
(Table 3). Without exception, the preparation of a-silyl-b-
bromoenones occurred with high yields and excellent stereo-
selectivities. Even the notably hindered alkyne substrates
were competent reactants (entries 3,6).[17] We consider this
process a net trans-selective halosilylation, because the
1
2
3
4
5
6
7
mCPBA[d]
NCS
50
55
50
23
23
23
0
NR
NR
NR
NR
91
–
–
–
–
TCCA[e]
Selectfluor
NBS
>19:1
15:1
>19:1
NIS
NIS
90
90
[a] Yield of the isolated product. [b] NR=no reaction. [c] Selectivity
determined by H NMR analysis of the crude reaction mixture.
1
Table 3: NBS-induced 1,2-silicon migration.
[d] mCPBA: meta-chloroperbenzoic acid. [e] TCCA: trichloroisocyanuric
acid.
Entry Product
T [8C]
t
Yield [%][a]
required lower temperatures to achieve a high degree of
stereoselectivity.[14]
ꢀ15
0
1
2
3
R2 =H
R2 =nBu
R2 =tBu
15 min 89[b]
15 min 91
2.5 h
With a standard migration method in hand, we evaluated
the scope of the iodination reaction (Table 2). Substrates with
terminal, unbranched, or even branched propargylic substitu-
ents reacted smoothly, affording the (E)-silylenones with
uniformly excellent geometrical selectivity (more than 19:1 in
ꢀ78!
75
ꢀ10
4
5
6
0
15 min 92
30 min 89
ꢀ15
Table 2: NIS-induced 1,2-silicon migration.
ꢀ78!
ꢀ10
5 h
85
Entry Product
T [8C]
t
Yield [%][a]
0
7
8
R2 =CH2OTHP
R2 =Ph
20 min 92
1
2
3
R2 =H
R2 =nBu
R2 =tBu
ꢀ10
0
ꢀ10
15 min 90
15 min 94
3 h
ꢀ78!
4 h
94
0
0[b]
0
0
9
10
11
R2 =nBu
R2 =CH2OTHP
R2 =Ph
45 min 92
45 min 88
ꢀ78!
4
5
6
7
0
30 min 95
30 min 93
4 h
80
0
[a] Yield of the isolated product. [b] Yield of allylic alcohol after in situ
reduction (DIBAL, ꢀ788C).
ꢀ15
halogen atom and silicon group are added to the alkyne
functional group in a trans fashion.
ꢀ78!
ꢀ10
6 h
63
Not only were tertiary a-hydroxypropargylsilanes com-
petent for the preparation of enones, but the corresponding
secondary a-hydroxypropargylsilanes were also proficient
reactants. Secondary a-hydroxypropargylsilane 4 was sub-
jected to both NIS and NBS (Scheme 1). Each reaction
proceeded effectively to afford only one isomer. Iodoenal 5
was isolated in excellent yield, whereas the related bromide
was unstable and therefore subjected to in situ DIBAL
reduction. The resulting allylic alcohol (6) was isolated in
91% yield with high E-selectivity.
0
20 min 92
8
9
R2 =nBu
R2 =CH2OTHP
0
0
15 min 94
15 min 92
10
ꢀ10
20 min 90
With the trans-selective halosilylation of alkynes in hand,
we hypothesized whether this transformation would provide
[a] Yield of the isolated product. [b] See Ref. [16].
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Scheme 1. Reactivity of secondary a-hydroxypropargylsilanes.
a method for the synthesis of all-carbon tetrasubstituted
alkenes. We predicted that both the halogen atom and the
silicon group would serve as convenient handles for cross
ꢀ
couplings to form C C bonds (Figure 2). Ultimately, this
strategy would represent a straightforward and general
Figure 2. Modularity of the all-carbon tetrasubstituted alkene synthe-
sis.
approach to synthesizing polysubstituted stereodefined ole-
fins, wherein an acylsilane, terminal alkyne, and two coupling
reagents can be introduced in a modular fashion. Further-
more, the stereochemistry generated in the silyl migration
event should transfer directly to the final alkene products.
To demonstrate this approach, a-hydroxypropargylsilanes
7 and 8 were subjected to the reaction sequences shown in
Scheme 2. For each silane, an NBS-mediated migration was
followed by Suzuki–Miyaura cross coupling, stereoretentive
iododesilylation,[18] and a second Suzuki–Miyaura cross
coupling.[19,20] Using this migration as the key step for
establishing geometrical control, complementary (Z)- and
(E)-alkenes of 12 can be readily made in good yields and with
very high maintenance of the stereochemistry throughout.
Importantly, these types of complementary pairs of alkenes
would otherwise be difficult to access selectively using
standard olefination methods (Wittig-type reactions, among
others).
In summary, we have described a trans-selective metal-
free halosilylation of alkynes by way of a silicon group
migration. A range of a-hydroxypropargylsilanes can be
converted to the corresponding a-silyl-b-haloenones through
treatment with an N-halosuccinimide under mild conditions.
The transformations generally proceed in high yields and with
remarkable E/Z selectivities. The enone products provide
several functional groups for further synthetic manipulations,
most aptly demonstrated by the direct conversion to geo-
metrically defined all-carbon tetrasubstituted alkenes. This
modular approach to tetrasubstituted olefins represents
Scheme 2. Selective formation of (Z)- and (E)-isomers of alkene 12.
Step A: NBS (1.1 equiv), CH2Cl2, ꢀ78!08C (for 7) or 08C (for 8). E/Z
ratios: 9: >19:1; 10: >19:1. Step B: ArB(OH)2 (2.0 equiv),
(Ph3P)2PdCl2 (0.05 equiv), Cs2CO3 (10 equiv), 1,4-dioxane/H2O, 508C.
Step C: 1) ICl (1.1 equiv), CH2Cl2, ꢀ788C; 2) ArB(OH)2 (2.0 equiv),
(Ph3P)2PdCl2 (0.05 equiv), Cs2CO3 (10 equiv), 1,4-dioxane/H2O, 508C.
E/Z ratios: (Z)-12: 1:10.4; (E)-12: 11.3:1.
a notable departure from the carbometalation strategies
that have been commonly employed toward these alkene
products. Currently, efforts are directed toward further
exploring the reactivity of these a-hydroxypropargylsilanes
in other synthetically useful contexts.
Received: April 11, 2013
Published online: June 10, 2013
Keywords: alkene geometry · alkynes · stereoselectivity ·
.
halosilylation · migration
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