Stereoselective halo-succinimide mediated γ-halogenations of substituted α-trialkylsilyl-β,γ-unsaturated esters

Article abstract of DOI:10.1016/j.tetlet.2019.151384

The halogenation of various α-ester allylsilanes with halo-succinimides (NXS, X = Cl, Br, and I) has been investigated. It has been shown that these reactions readily allow for good yields and excellent diastereoselectivities (up to >20:1) for a series of α-ester allylsilanes and halo-succinimide reagents, thereby providing a straightforward approach of preparing γ-halo-(E)-α,β-unsaturated esters.

Full text of DOI:10.1016/j.tetlet.2019.151384

Tetrahedron Letters xxx (xxxx) xxx
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Stereoselective halo-succinimide mediated
c-halogenations of
substituted
a
-trialkylsilyl-b,c-unsaturated esters
⇑
Lisa M. Fealy, Michael P. Jennings
Department of Chemistry and Biochemistry, 250 Hackberry Lane, The University of Alabama, Tuscaloosa, AL 35487-0336, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
The halogenation of various a-ester allylsilanes with halo-succinimides (NXS, X = Cl, Br, and I) has been
Received 27 October 2019
Accepted 10 November 2019
Available online xxxx
investigated. It has been shown that these reactions readily allow for good yields and excellent diastere-
oselectivities (up to >20:1) for a series of -ester allylsilanes and halo-succinimide reagents, thereby pro-
viding a straightforward approach of preparing
a
c
-halo-(E)-
a,b-unsaturated esters.
Ó 2019 Elsevier Ltd. All rights reserved.
Keywords:
Halogenation
Allylsilane
Olefination
Diastereoselective synthesis
The nucleophilic reaction of allylsilanes with a variety of elec-
trophilic coupling partners has afforded chemists the opportunity
to build important synthetic intermediates with high levels of
regio- and stereoselectivities in generally modest to excellent
coupling under the umpolung approach to Pd-enolates derived
from -haloesters and amides [11,12].
Based on our interest in both novel organosilane reagents and
broadening umpolung Pd-enolate chemistry to include extended
a
yields [1]. Unfortunately,
a
-ester substituted allylsilane reagents
enolates, we sought to investigate
as general nucleophilic precursors to
esters. Herein, we wish to disclose our results centered on a stere-
oselective halosuccinimide mediated -halogenation of -tri-
alkylsilyl-b, -unsaturated esters.
Unfortunately, a general stereoselective synthesis of
,b-unsaturated esters is lacking [13,14]. The approach outlined in
this paper relied on the utilization of -trialkylsilyl-b, -unsatu-
a
-ester substituted allylsilanes
have received little attention most likely due in part to the histor-
ical lack of a general synthetic pathway to said compounds coupled
with their diminished reactivity compared to that of most other
allylsilanes [2,3]. Recently, we have reported on a very general
c
-halo- ,b-unsaturated
a
c
a
c
synthesis of
oselective
b-alkyl- ,b-unsaturated esters [4,5].
Initially disclosed in 1989 by Suzuki, the Pd-catalyzed cross
coupling between an electrophilic -bromo ester and nucleophilic
aryl boronic ester afforded the -arylated ester product in 74%
a-substituted allylsilanes by means of a highly stere-
c-halo-(E)-
c-deprotonation/kinetic protonation of -trialkylsilyl-
a
a
a
a
c
rated esters coupled with N-halosuccinimides. With this in mind,
we initially employed our recently reported synthesis of a variety
a
a
of
a-ester substituted allylsilane reagents by means of a
c-depro-
yield via a proposed Pd-enolate intermediate [6]. This reaction rep-
resented an umpolung approach to nucleophilic Pd-enolate cross
coupling as developed by Hartwig and Buchwald [7,8]. Subse-
quently, Gooßen expanded the Miyaura-Suzuki reaction scope to
tonation/kinetic protonation of
rated esters.
a-trialkylsilyl-b-alkyl-a,b-unsatu-
As shown in Scheme 1, catalytic carbocupration (15 mol%
CuIÁ2LiCl) of ethyl propiolate with an assortment of Grignard
Reagents and a trialkylsilyl triflate (TMS-or TESOTf) provided vinyl
silanes 1a-1e in yields ranging from 44 to 82% post silyl group
migration with ratios of >20:1 for the E isomer in all cases. Subse-
include a variety of aryl boronic acids and
a-halo carbonyls [9].
Along this line, we reported on the syntheses of a variety of pheny-
lacetic acid lactone (PAL) natural products utilizing Pd-enolates
derived from a series of substituted
a-bromo esters coupled with
quently, a complex induced proximity effect (CIPE) mediated c-
functionalized aryl boronic acids [10]. In addition to boronic acids,
other nucleophilic coupling partners (i.e. potassium trifluo-
roboronates and alkynylstannanes) have been successful in cross-
deprotonation of esters 1a-1e all readily proceeded through the
proposed 8-membered transition state 2 to afford the transient
lithium enolate which was then transformed in situ to the TMS
silyl ketene acetal upon the addition of TMSCl [15]. Final kinetic
protonation with 1.4 M HCl furnished the
a-trialkylsilyl-b,c-unsat-
urated esters 3a-3e in 80–99% isolated yields (no purification was
⇑
Corresponding author.
E-mail address: jenningm@ua.edu (M.P. Jennings).
https://doi.org/10.1016/j.tetlet.2019.151384
040-4039/Ó 2019 Elsevier Ltd. All rights reserved.
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Please cite this article as: L. M. Fealy and M. P. Jennings, Stereoselective halo-succinimide mediated
unsaturated esters, Tetrahedron Letters, https://doi.org/10.1016/j.tetlet.2019.151384
c-halogenations of substituted a-trialkylsilyl-b,c-

2
L.M. Fealy, M.P. Jennings / Tetrahedron Letters xxx (xxxx) xxx
Table 1
NXS-mediated c
-Halogenations of Allylsilanes 3a and 3b.a,b
Scheme 1.
required) with dr values of >20:1 (where applicable) for the E alke-
1
nes as determined by H NMR.
With the requisite nucleophiles 3a-3e in hand, we commenced
our investigation by initially examining the halogenation of methyl
substituted allylsilanes 3a and 3b with NXS (X = Cl, Br, I) as
described in Table 1. Thus, treatment of 3a with NBS (1.1 equiv.)
in MeCN for 3 h at 0 °C afforded the
c-brominated ester 4a in
1
9
2% yield with a >20:1 dr for the E isomer as determined by
H
NMR (J = 15.6 Hz) [14,16]. The stereochemistry of the newly
formed alkene moiety of 4a was further assigned as the E-isomer
by 1D NOE based on the observed cross-peaks shown in Table 1.
Similar to 3a, the bromination of the TES variant (3b) with NBS
in entry 4 provided product 4a in a nearly identical yield (90 versus
9
2%) with a >20:1 dr for the newly formed alkene as well. Simi-
larly, the iodination of 3a with NIS (1.1 equiv.) readily proceeded
at 0 °C in MeCN to furnish 4c in 78% yield with an identical olefin
dr of >20:1 for the E isomer [14]. It is worth noting that iodo ester
4
c was unstable and fully decomposed at rt within 24 h post purifi-
cation, which most likely led to a lower yield of 4c versus that of
a. Surprisingly, chlorination of 3a with NCS did not proceed under
a) E/Z ratio determined by 1H NMR (500 MHz) from the crude
(
4
reaction mixture. (b) Yields are of the isolated, pure compounds. (c)
Reaction ran with 1.0 equiv of 3a/3b, and 1.1 equiv of NXS (X = Br or I)
for 3 h at 0 °C. (d) reaction ran with 1.0 equiv of 3a/3b, and 1.1 equiv
of NCS for 12 h at 50 °C.
the previous reaction conditions and only starting material was
recovered. However, heating the reaction of 3a with NCS (1.1
equiv.) to 50 °C in MeCN for 12 h afforded the chlorinated ester
4
b in 87% isolated yield with a dr of >20:1 for the newly formed
E alkene [14]. As noted above, the olefin geometries of esters 4a-
1
4
c were assigned as E by analysis of the coupling constants in
H
4d in 89% yield after purification [17]. The dr of the newly con-
NMR (J = 15.5–15.6 Hz) of the crude and subsequently isolated
and purified products.
structed olefin was >20:1 strongly favoring the E isomer
(J = 15.7 Hz) as determined by H NMR of the crude reaction mix-
ture. Similarly, the iodination of 3c proceeded with NIS under iden-
tical reaction conditions to provide the c-iodo-ester 4f with a dr of
>20:1 for the E isomer in 79% yield as noted in entry 3.
Analogous to entry 3 in Table 1, the chlorination of ester 3c with
NCS was quite sluggish at rt and furnished only the recovered
starting material. Much to our delight, heating to 50 °C and allow-
1
With the successfully regioselective
with the diastereoselective formation of
derived from -methyl-substituted allylsilanes 3a and 3b, atten-
tion was turned to investigating structurally related -disubsti-
tuted, -phenyl, and unsubstituted allyl silanes 3c-3e. Based on
c-halogenations coupled
a,b-unsaturated esters
c
c,c
c
the results from Table 1, we chose to replicate the reaction condi-
tions for esters 3c and 3d with the three NXS reagents. As shown in
ing the reaction to take place over a 12hr period afforded the
chlorinated ester 4e in 67% yield with an identical E/Z ratio of
>20:1 to that of 4d and 4f [18]. In addition to the -dimethyl
c-
Table 2, treatment of the
c,c-dimethyl allylsilane 3c with NBS (1.1
equiv.) at 0 °C in MeCN for 3 h afforded the 3°-allylic bromide ester
c,c
Please cite this article as: L. M. Fealy and M. P. Jennings, Stereoselective halo-succinimide mediated
unsaturated esters, Tetrahedron Letters, https://doi.org/10.1016/j.tetlet.2019.151384
c-halogenations of substituted a-trialkylsilyl-b,c-

L.M. Fealy, M.P. Jennings / Tetrahedron Letters xxx (xxxx) xxx
3
Table 2
NXS-mediated c
-Halogenations of Allylsilanes 3c-3e.a,b.
Fig. 1. Stereochemical rationale for selective E-olefin formation.
trophilic halogenating reagent to afford a subsequent secondary
carbocation [19a]. The intermediate cation was stabilized via
hyperconjugation as the adjacent C-Si bond was either anti-or
syn-periplanar to the empty p-orbital. While elimination of either
rotamer A or B was possible, the one that minimized A1 -strain
should have been favored (i.e. rotamer A) and ultimately
provided the E-olefin product. The other possible conformation,
,3
1
,3
rotamer B, would maximize
A
-strain and would have
consequently led to the Z-alkene [19b]. Based on examination of
1
the crude reaction mixture by H NMR, no Z-olefins were observed
and we concluded that rotamer A was favored en route to the
highly selective formation of the E isomer of the newly created
alkenes in esters 4a-4g.
In conclusion, we have described a general reaction sequence
that highlights regio-and stereoselective additions of a series of
a-ester allylsilanes to halosuccinimides resulting in the formation
of -halo-(E)- ,b-unsaturated ester products in modest to high
c
a
yields with dr values of >20:1. The straightforward nature and
enhanced scope of the described synthetic process should enable
for the broadening of umpolung Pd-enolate chemistry to include
extended enolates. Results from these studies will be reported in
due course.
Declaration of Competing Interest
The authors declare that they have no known competing finan-
cial interests or personal relationships that could have appeared
to influence the work reported in this paper.
a) E/Z ratio determined by 1H NMR (500 MHz) from the crude
(
reaction mixture. (b) yields are of the isolated, pure compounds. (c)
reaction ran with 1.0 equiv of 3c/3d, and 1.1 equiv of NXS (X = Br or I)
for 3 h at 0 °C. (d) reaction ran with 1.0 equiv of 3c and 1.1 equiv of
NCS for 12 h at 50 °C.
Acknowledgment
Support for this project was provided by the University of
Alabama.
silane reagent 3c, the bromination of the unsubstituted allylsilane
3
d was accomplished upon addition of 1.1 equiv. of NBS in MeCN
at 0 °C to afford -bromo ester 4g in 73% isolated yield. Unfortu-
nately, the attempted NBS mediated bromination of the -phenyl
c
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unsaturated esters, Tetrahedron Letters, https://doi.org/10.1016/j.tetlet.2019.151384
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Please cite this article as: L. M. Fealy and M. P. Jennings, Stereoselective halo-succinimide mediated
unsaturated esters, Tetrahedron Letters, https://doi.org/10.1016/j.tetlet.2019.151384
c-halogenations of substituted a-trialkylsilyl-b,c-