Selective C?C Coupling of Vinyl Epoxides with Diborylmethide Lithium Salts

Article abstract of DOI:10.1002/chem.201901406

Vinyl epoxides and styrene oxide can react with diborylmethide lithium salts through an exclusive S_N2 borylmethylation/ring opening in a regio- and diastereoselective way, depending on the nature of the substrate. The ring-opening protocol prov

Full text of DOI:10.1002/chem.201901406

A Journal of
Accepted Article
Title: Selective SN2 ring opening / C-C coupling of vinyl epoxides and
styrene oxide with diborylmethide lithium salts
Authors: Elena Fernández and Riccardo Gava
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Selective C-C coupling of vinyl epoxides with diborylmethide
lithium salts
Riccardo Gava[a] and Elena Fernández*[a]
Dedication ((optional))
Abstract: Vinyl epoxides and styrene oxide can react with
diborylmethide lithium salts throughout an exclusive SN2
borylmethylation / ring opening in a regio- and diastereoselctive way,
depending on the nature of the substrate. The ring opening protocol
provides homoallylboronates that can be transformed into challenging
diastereomeric bishomoallylic alicyclic 1,3-diols. Eventually,
unprecedented 3-borylated 1,2-oxaborolan-2-ol products are
Copper(I) catalysts seem to be essential for the borylmethylation
/ ring opening of epoxides (Scheme 2a)[6] as well as for the
borylmethylation / ring opening of vinyl cyclic carbonates through
SN2’ mechanism.[7] However, the reaction of vinyl epoxides with
geminal-diborylalkanes has been elusive to our days. Only the
borylative ring opening reaction of vinyl epoxides has been
postulated to proceed with B2pin2 in the presence of Cu[8], Ni[9] or
in the absence of transition metal complexes[10] through a SN2’
mechanism (Scheme 2b). Now, we face here the challenge to
perform the borylmethylation of vinyl epoxides with
diborylmethide lithium salts that undergo direct ring opening of the
epoxide keeping the conjugated double bond unreacted (Scheme
2c). Total regiocontrol on the epoxide ring opening is achieved
depending on the cyclic or non-cyclic type of the vinyl epoxide
substrates. Diastereoselective control in the C-C coupling is also
possible when substituted diborylmethide lithium salts are
involved.
prepared by borylmethylation
/ ring opening of 2-methyl-2-
vinyloxirane followed by intramolecular cyclization.
Geminal-diborylalkanes have risen as valuable building blocks for
C–C bond formation, due to the easy access to nucleophilic  -
boryl carbanions via deprotonation or deborylation processes.[1]
The use of lithium bases, such as lithium 2,2,6,6-
tetramethylpiperidide (LiTMP), allows efficient deprotonation of
geminal-diborylalkanes[2]
generating
partially
stable
diborylmethide lithium salts that undergo straightforward reactivity
with electrophiles under mild reaction conditions. The reactivity
explored with diborylmethide lithium salts for C–C bond formation
involves alkylation reactions with aryl- or alkyl halides (Scheme
1a)[3] as well as boron-Witting reactions with carbonyl
compounds[4] (Scheme 1b). Reactivity of diborylmethide lithium
salts with electrophiles other than aldehydes/ketones or RX has
not been explored, except for an attempt to contribute to the
copper-catalyzed one-pot three-component stereoselective
a)
Previous work: borylmethylation / ring opening
Bpin
OH
Bpin
R
O
R
R'
Bpin
[Cu][6]
R'
b)
Previous work: SN2' borylation / ring opening
OH
O
B2pin2
B2pin2
rt
HO
coupling
of
epoxides
with
allyl
electrophiles
and
Bpin
bis[(pinacolato)boryl]methane (Scheme 1c)[5a] or palladium-
catalyzed coupling/dehydroboration (Scheme 1c)[5b]
rt
Bpin
[Cu],[8] [Ni][9] or
transition-metal-free protocol[10]
c) This work: SN2 borylmethylation / ring opening
Bpin
Bpin
Bpin
Li+
Bpin
Bpin
Li
Bpin
OH
O
+
-
-
Bpin
OH
Bpin
rt
with regioselective control
rt
Scheme 2. Reactions of epoxides and vinyl epoxides with geminal-
diborylalkanes and B2pin2
We selected the commercially available vinyl epoxide 3,4-epoxy-
1-cyclohexene (1) as model substrate to search the reaction
Scheme 1. Synthetic strategies for C-C coupling reactions with diborylmethide
lithium salts trough alkylation, boron-Wittig reaction and ring opening.
conditions
for
an
efficient
reactivity
with
bis[(pinacolato)boryl]methane (2) in the presence of LiTMP.
Scheme 3 shows that a slight excess of diborylmethane reagent
and LiTMP favors the formation of 2-(bis(4,4,5,5-tetramethyl-
1,3,2-dioxaborolan-2-yl)methyl)cyclohex-3-en-1-ol (3), at room
temperature. Higher temperature reaction around 50ºC or other
bases, such as KHDMS, did not improve the yields. The
nucleophilic ring opening takes place exclusively on the allylic
[a]
Dr. Riccardo Gava, Dr. Elena Fernández
Department Química Física i Inorgànica
University Rovira i Virgili
Tarragona, Spain
E-mail: mariaelena.fernandez@urv.cat
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position as a matter of a SN2 attack of the diborylmethide lithium
salt, suggesting that is acting as a hard nucleophile, generating a
trans disposition of the OH and CH(Bpin)2 groups (Scheme 3).
The reactivity observed by the C-C coupling of 1 with the
diborylmethide lithium salt might be influenced by the conjugated
nature of the strained oxirane,[11] since the ring opening of the
related cyclohexene oxide did not occur under the same reaction
conditions. Interestingly, by applying the optimized reaction
conditions to the reactivity of 2 with the unsubstituted non cyclic
vinyl epoxide 3,4-epoxy-1-butene (4), the nucleophilic attack of
the diborylmethide lithium salt occurred exclusively at the
homoallylic position (Scheme 3). The more activated substrate
styrene oxide (6) also conducted the SN2 attack of the
diborylmethide lithium salt at the less hindered position (Scheme
3).
cases both diastereoisomers could be isolated in pure form and
the structural configuration was confirmed by X-Ray Diffraction of
the crystalline product 17 (Figure 1).
Table 1. Regioselective ring opening / C-C cross coupling of 3,4-epoxy-1-
cyclohexene with ArCH(Bpin)2 via LiTMP assistance.[a]
Products [Isolated Yield%]
Entry
OH Bpin
1
10 [48%]
2
3
4
OH Bpin
19 [47%]
Scheme 3. Regioselective ring opening / cross coupling of vinyl epoxides and
styrene oxide with diborylmethide lithium salts via SN2 attack.
F
[a]Reaction conditions: substrate (0.4 mmol, 0.8 equiv), geminal-diborylalkane (1
equiv), LiTMP (1.2 equiv), THF (1 mL), rt, 16h. [Isolated yields %].
Having demonstrated the opposite regioselective SN2 ring
opening / cross coupling of 3,4-epoxy-1-cyclohexene (1) versus
the non-cyclic vinyl epoxides 4 and styrene oxide 6 with
diborylmethide lithium salts, we proceeded to investigate the
scope of the reaction using a variety of geminal-diborylalkanes
(Table 1). Towards this end, a series of reagents with molecular
formula ArCH(Bpin)2 were prepared,[12a] being for 11, 17 its first
synthesis, and reacted with 1 to prove the general trend in the
regioselective SN2 ring opening / C-C coupling. We observed that
the reaction of (phenylmethylene)bis(pinacolborane) (8) with 1 in
the presence of LiTMP resulted in a quantitative SN2 attack at the
allylic position of the cyclic vinyl epoxide although two
diastereoisomeric products 9 and 10 were generated in almost
1/1 ratio. The characterization of the products determined that
only one Bpin moiety remained in the final product, probably as a
consequence of a H-deborylative process favoured by the
sterically hindered multisubstituted carbon (Table 1, entry 1).
When alternative ArCH(Bpin)2 reagents were used introducing
electron withdrawing or electron donating substituents in the aryl
group, similar reactivity was observed (Table 1, entries 2-4). In all
Figure 1. X-Ray Diffraction of product 15.
Remarkably, when the geminal-diborylalkane reagents contained
an alkyl group instead of an aryl group, their reaction with 1
showed the regioselective SN2 ring opening / C-C coupling but
only one exclusive diastereoiosmer was formed along the H-
deborylative process (Table 2). Reagents such as (2-
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phenylethane-1,1-diyl)bis(pinacolborane)
(20)
and
(3-
We also conducted the nucleophilic ring opening / cross coupling
of 2-methyl-2-vinyloxirane (28), with diborylmethide lithium salt,
and we proved not only that the nucleophilic attack occurred
exclusively at the homoallylic position, but also that the new
product suffered an intramolecular cyclization to give the
substituted 3-borylated 1,2-oxaborolan-2-ol product 29 (Table3,
entry 1). 1,2-Oxaborolanes are important synthons[14] but their
synthesis has mainly been explored through carboboration
protocols.[15-18] Compound 29 represents an unprecedented cyclic
organoborane involving a simple C-B-O five-membered ring with
a geminal C-B moiety, where the vinyl and methyl substituents
keep unaltered from the 2-methyl-2-vinyloxirane (28) starting
material. The reaction has been extended to prepare
polysubstituted 3-borylated 1,2-oxaborolan-2-ol products by
reaction of 28 with alkyldiborylmethide lithium salts 20, 22 and 26.
Despite the fact that bulky substituents were introduced in the
substituted 3-borylated 1,2-oxaborolan-2-ol products the yield
was quantitative and the isolated yields were moderate to high,
with a diastereoisomeric ratio 4/6 in all the cases (Table 3).
phenylpropane-1,1-diyl)bis(pinacolborane) (22) generated the
products 21 and 23 in moderate yield as a sole diastereoisomer
(Table 2, entries 1-2), while reagents octane-1,1-
diylbis(dimethylborane)
(24)
and
(bis(pinacolboranyl)methyl)trimethylsilane (26)[12b] contributed to
higher isolated yields of the single diastereoisomers 25 and 27,
(Table 2, entries 3-4) being the last one full characterised by X-
Ray Diffraction (Figure 2). Interestingly, the fact that
protodeboronation reaction can be stereoselective when an alkyl
group is attached to the diborylmethide lithium salt, is in
agreement with a recent observation in diastereoselective
protodeboronation between 1,1-diborylalkanes and N-tert-
butanesulfinyl aldimines.[13]
Table 2. Regio- and diastereoselective ring opening / C-C cross coupling of 3,4-
epoxy-1-cyclohexene with RCH(Bpin)2 via LiTMP assistance.[a]
Table 3. Regioselective ring opening/cross coupling of 2-methyl-2-vinyloxirane
with alkyldiborylmethide lithium salts followed by intramolecular cyclization.[a]
Entry
Product [Isolated Yield%]
1
Entry
Product [Isolated Yield%]
2
1
2
3
4
3
4
[a]Reaction conditions: substrate (0.4 mmol, 0.8 equiv), geminal-diborylalkane (1
equiv), LiTMP (1.2 equiv), THF (1 mL), rt, 16h. [Isolated yields %].
[a]Reaction conditions: substrate (0.4 mmol, 0.8 equiv), geminal-diborylalkane (1
equiv), LiTMP (1.2 equiv), THF (1 mL), rt, 16h. [Isolated yields %].
The in situ oxidation of the homoallylboronates prepared in Table
1 allows the isolation of challenging bishomoallylic alicyclic 1,3-
diols (Scheme 4) in a straightforward manner. Interestingly
compounds 33, 35 and 37 have a complementary conformation
to the previously reported method via Ni or transition-metal-free
catalysed SN2’ borylation/ring opening of vinyl epoxides with
B2pin2.[9a,10]
Figure 2. X-Ray Diffraction of product 27.
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The added value of the regio- and diastereoselective ring opening
subsequently coupled with 4-bromoanisole in the presence of
Pd(PtBu3)2, at room temperature, giving the coupled product 42
(Scheme 5), in d.r =6/4. The oxidative work up of 42, generated
1-(4-methoxyphenyl)-3-methylpent-4-ene-1,3-diol (43) in good
yield. This method represents a new access to polyfunctional 1,3-
diols which are considered interesting skeleton for bioactive
trisubstituted tetrahydropyrans[20] which have been mostly
prepared via condensation of an allylic alcohols with aldehydes in
the presence of Lewis acids.
/
C-C cross coupling of 3,4-epoxy-1-cyclohexene with Li
[RC(Bpin)2] (R= trimethylsilyl)methyl group) allowed the in situ
oxidative work up towards 2-
(hydroxy(trimethylsilyl)methyl)cyclohex-3-en-1-ol (39) as a single
diastereosiomer with full retention of the configuration (Scheme
4). The consecutive ring-opening / ring-closing of substrate 2-
methyl-2-vinyloxirane when reacts with diborylmethide lithium
salts 22, generates the 3-borylated 1,2-oxaborolan-2-ol product
31, that under oxidative work up conditions ends up in the
formation of polyfunctional allylic alcohol 5-hydroxy-5-methyl-1-
phenylhept-6-en-3-one (40), containing a tertiary -hydroxyl
group,[19] characteristic of high therapeutic value (Scheme 4).
We conclude that diborylmethide lithium salts react with vinyl
epoxides and styrene oxide along borylmethylation / ring opening
via exclusive SN2 mechanism. Regioselection is achieved by
substrate
influence
and
diastereoselection
on
the
homoallylboronate products depends on the geminal-
diborylalkane used. Unprecedented ring opening followed by ring
closing provides access to unexpected cyclic geminal diboronates.
Further functionalization opens a new methodology to generate
diastereomeric secondary and tertiary alcohols of high added
value.
Experimental Section
Experimental Details can be found at the Supporting Information
Document.
Acknowledgements
The present research was supported by the Spanish Ministerio de
Economia y competitividad (MINECO) through project FEDER-
CTQ2016-80328-P.
Scheme 4. Ring opening/cross coupling followed by in situ oxidation with
NaOH/H2O2
Keywords: • Geminal-diborylalkanes • diborylmethide lithium
salts • cyclic germinal diboronates • homoallylboronates • SN2
mechanism
The single diastereosiomer 27 formed from rection of epoxide 3,4-
epoxy-1-cyclohexene
(1)
and
(bis(pinacolboranyl)methyl)trimethylsilane (26), in the presence of
LiTMP, was further functionalized by cross coupling reaction with
pCH3-C6H4I in the presence of Pd(OAc)2/RuPhos (Scheme 5).
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product
2-(p-
tolyl(trimethylsilyl)methyl)cyclohex-3-en-1-ol (41) preserved the
configuration along the Pd catalyzed reaction.
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1)
LiTMP
0ºC to rt, 16h
THF
OH SiMe3
41 [58%]
O
Bpin
Bpin
+
Me3Si
2)
Pd(OAc)2
RuPhos
p-Me-C6H5I
[4]
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THF/H2O
90ºC, 12h
1)
LiTMP
0ºC to rt, 16h
THF
OH OH
MeO
OH
B
O
Bpin
Bpin
+
O
[5]
[6]
[7]
MeO
Pd(tBu3)2
NaOH,
H2O2
2)
43 [84%]
dr=1/1
42 [71%]
dr=6/4
p-OMe-C6H5I
dioxane/KOH
rt, 12h
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Scheme 5. Functionalization by cross coupling with ArI.
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bis[(pinacolato)boryl]methane (2), in the presence of LiTMP, was
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Riccardo Gava and Elena Fernández*
Page No. – Page No.
Selective C-C coupling of vinyl
epoxides with diborylmethide lithium
salts
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