Diborylalkyllithium Salts Trigger Regioselective Ring Opening of Vinyl Aziridines

Article abstract of DOI:10.1021/acs.orglett.9b03672

gem-Diborylalkanes treated with LiTMP produce α-diborylalkane lithium bases that perform nucleophilic attack on vinyl aziridines with controlled regioselectivity. Preferred S_N2 diborylalkylation ring opening reaction on the less sterically hind

Full text of DOI:10.1021/acs.orglett.9b03672

Letter
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Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Diborylalkyllithium Salts Trigger Regioselective Ring Opening of
Vinyl Aziridines
́
Oriol Salvado, Riccardo Gava,* and Elena Fernandez*
̀
Dept. Química Física i Inorganica, Universitat Rovira i Virgili, Tarragona, Spain
S
* Supporting Information
ABSTRACT: gem-Diborylalkanes treated with LiTMP pro-
duce α-diborylalkane lithium bases that perform nucleophilic
attack on vinyl aziridines with controlled regioselectivity.
Preferred SN2 diborylalkylation ring opening reaction on the
less sterically hindered position is observed with 1-tosyl-2-
vinylaziridine, whereas exclusive SN2′ nucleophilic attack
occurs on 2-methyl-1-tosyl-2-vinylaziridine. Cyclic vinyl
aziridines interact through a third venue, via SN2 dibor-
ylalkylation ring opening reaction on the allylic position. Homoallylic diboronates are formed with complete stereochemical
control.
ucleophilic ring opening reactions involving the
construction of useful organoboron molecular structures
carbanion stabilization allows that both boryl moieties remain
in the final product.9
N
combine the selective control of the ring cleavage together with
total atom economy parameters.1 Versatile allylic amines are
efficiently formed from Pd,2 Ni,3 or transition metal-free4
catalyzed borylative SN2′ ring opening of vinyl aziridines with
bis(pinacolato)diboron (B2pin2), along the concomitant
formation of the allylic boronate functionality (Scheme 1a).
To study the viability of our work hypothesis we selected 1-
tosyl-2-vinylaziridine (1) as model substrate, to react with
HC(CH3)(Bpin)2 (2) in the presence of 1.2 equiv of LiTMP.
When the reaction took place initially at 0 °C (10 min),
followed by 16 h at rt, the substrate was quantitatively
transformed into two products. The major product was 4
(isolated yield 64%) formed via SN2 diborylalkylation ring
opening reaction on the less sterically hindered position
(Scheme 2). However, the SN2′ ring opening reaction became
competitive forming the E-homoallylboronate product 3
(Scheme 2). Similar reaction outcome was observed using
the gem-diborylalkanes HC(tBu)(Bpin)2 (5) and HC(Si-
Scheme 1. C−B and C−C Bond Formation through Ring
Opening of Alkyl-, Aryl-, and Vinyl Aziridines
Scheme 2. Diborylalkylation/Ring Opening Reaction of 1-
Tosyl-2-vinylaziridine (1)
Alternatively, SN2 borylative ring opening reaction of aryl
aziridines through a palladium-catalyzed protocol allows the
formation of difunctional β-aminoboronate compounds
(Scheme 1b).5 The use of gem-diborylmethane instead of
B2pin2 resulted in the formation of γ-aminoboronic esters
through copper-catalyzed ring opening/C−C bond formation
of alkyl aziridines in the presence of LiOtBu (Scheme 1c).6
However, to the best of our knowledge, the activation of gem-
diborylalkanes with lithium bases to promote diborylalkylation
ring opening of vinyl aziridines is unknown (Scheme 1d),
despite the fact that the analogue reaction with epoxides7 and
vinyl epoxides8 has recently been explored. The activation of
gem-diborylalkanes with LiTMP via deprotonation and
Received: October 17, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b03672
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(CH3)3)(Bpin)2 (8) being the SN2 ring opening/C−C
coupling throughout the less sterically hindered position, the
most favored reactivity (Scheme 2).
Table 1. Regioselective SN2′ Diborylalkylation/Ring
a
Opening of 2-Methyl-1-tosyl-2-vinylaziridine (20)
Interestingly, when (tetrahydro-2H-pyran-4-yl)methylene-
bispinacolboronate (11) was employed as the gem-diborylal-
kane reagent, the SN2′ ring opening reaction was weakened,
and only products formed via SN2 pathway were isolated (63%
due to the nucleophilic attack on the less sterically hindered
position and 36% on the most congested position, Scheme 2).
A similar trend was detected when (E)-2-styryl-1-tosylaziridine
(14) was treated with HC(Si(CH3)3)(Bpin)2 (8) since SN2′
ring opening reaction was suppressed in favor of the
nucleophilic attack on the more congested position (Scheme
3). The analogue vinyl aziridine (E)-2-(1-phenylprop-1-en-1-
Scheme 3. Diborylalkylation/Ring Opening Reaction of
Substituted Vinyl Aziridines 14 and 17
yl)-1-tosylaziridine (17) also performed a favored diborylalky-
lation ring opening reaction through SN2 ring opening, despite
the fact that isolated yields on the products diminished
significantly, probably due to the instability of the electroni-
cally conjugated allylic products (Scheme 3).
To our delight, when 2-methyl-1-tosyl-2-vinylaziridine (20)
was explored for diborylalkylation ring opening reaction with
reagent HC(Si(CH3)3)(Bpin)2 (8) and LiTMP, we observed
the exclusive formation of the allylic amine/homoallylic
boronate 21 as a result of the regioselective nucleophilic
attack via SN2′ mechanism (Table 1, entry 1). To the best of
our knowledge, this is the first example of a lithium stabilized
α-diboryl carbanion reacting along conjugate addition since it
has only been reported that diborylmethide lithium salts
transmetallate with zinc(II) halide to form the corresponding
diborylmethyl zinc(II) species that interact with π-allyliridium
intermediates to promote a SN2 allylic substitution.10 On the
contrary, SN2′ allylic substitution of primary and secondary
allylic chlorides with diborylmethane has been reported to
proceed in the presence of Cu/NHC catalyst and LiOtBu (3
equiv), where the NHC ligand (IMes = 1,3-bis(2,4,6-
trimethylphenyl)imidazole-2-ylidene]) played an important
role in the conjugated mechanism.11 Even with substoichio-
metric amounts of base (Cs2CO3, 0.5 equiv) in combination
with MeOH as solvent and Cu(I) as catalyst without any
ligand, the deborylative allyl−alkyl coupling between diboryl-
methane and vinyl cyclic carbonates has been reported,
throughout copper-catalyzed SN2′ ring opening pathway with
extrusion of CO2.12 Diborylmethane can be also activated with
Ag(I) to further transmetalation to π-allylpalladium inter-
mediates in order to conduct the corresponding allyl−alkyl
coupling, with the aid of an oxidant to regenerate the Pd(II)
species.13 All these Cu- and Pd- methods have in common that
a
Reaction conditions: substrate (0.4 mmol, 0.8 equiv), gem-
diborylalkanes (0.5 mmol, 1 equiv), LiTMP (0.6 mmol, 1.2 equiv),
THF (3 mL), rt, 16 h.
homoallylboronates are selectively formed through allylic
reactions while deborylation is undertaken, and consequently,
the final product contains only one boryl unit. Here, we report
an exclusive SN2′ ring opening of vinylaziridines through
diborylalkyllithium salts keeping the two boryl moieties
unaltered in the final product. The reaction occurs with
complete stereocontrol toward the formation of the (E)-isomer
as it can be seen in Table 1. This fact was proved doing a NOE
experiment of product 21 (see Supporting Information).
When the gem-diborylalkanes involved in the reaction were
2, 5, or 11, containing primary, secondary, and tertiary Cβ
substituents, the isolated yields on the desired product were
quantitative (Table 1, entries 2−4). However, the gem-
diborylalkanes 25 and 27, containing 1-phenyl-ethyl and
benzyl substituents, respectively, proceed toward the ring
B
DOI: 10.1021/acs.orglett.9b03672
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opening C−C cross coupling in moderate isolated yield (Table
1, entries 5−6). No other byproducts were observed, and the
lack of the product’s stability during the purification process
justifies the moderate values of isolated yields. Interestingly,
the reaction with HC(p-MeC6H4)(Bpin)2 (29) allowed the
reaction to take place efficiently, although protodeboronation
occurred toward the formation of product 30 containing only
one boryl moiety (Table 1, entry 7). We suggest that the inner
reactivity of the benzylic boron group in the α-diborylbenzyl
carbanion might justify the favored protodeboronation under
basic conditions.14
Table 2. Regioselective SN2 Diborylalkylation/Ring
Opening of 7-Tosyl-7-azabicyclo[4.1.0]hept-2-ene (35)
a
Remarkably, the observed regioselective diborylmethylation
of vinyl aziridine 1 and 20 is significantly different to the one
observed in the analogue vinyl epoxides 31 and 32, under the
same reaction conditions (Scheme 4). Nucleophilic attack of
Scheme 4. Diborylalkylation Ring Opening Reaction of
Substituted Vinyl Epoxides 31 and 32
diborylalkyllithium salts occurred exclusively at the homoallylic
position of 31, with concomitant intramolecular cyclization to
give the substituted 3-borylated 1,2-oxaborolan-2-ol product
(Scheme 4).8 The substrate 2-vinyloxirane (32) also provides
the SN2 ring opening with H2CB2pin2,8 whereas the use of
substituted diboryllkyllithium salts favors the exclusive SN2′
ring opening/C−C coupling as we demonstrated in this work
(Scheme 4).
Next, we explored the diborylalkylation/ring opening of
cyclic vinyl aziridines such as 7-tosyl-7-azabicyclo[4.1.0]hept-
2-ene (35),15 and in contrast to the observed SN2′ ring
opening of noncyclic vinylaziridine 20, we found that 35
suffered a SN2 nucleophilic attack at the allylic position, instead
(Table 2). The reaction is stereocontrolled forming exclusively
homoallyldiboronate species with trans disposition of the
NHTs and CR(Bpin)2 groups, keeping the two boryl moieties
unaltered in the final product. With substituted gem-
diborylalkanes 2, 5, 8, and 11, containing primary, secondary,
and tertiary Cβ substituents, the regioselective SN2 ring
opening was efficiently performed isolating quantitative
percentages of the desired homoallyldiboronate products
36−39 (Table 2, entries 1−4). Reagent 27 containing the
benzyl group also allowed the formation of the desired
homoallyldiboronate species 40 in moderate isolated yield
(Table 2, entry 5). However, when the phenyl substituted gem-
diborylalkane 29 is involved in the reaction, we observed that
a
Reaction conditions: substrate (0.4 mmol, 0.8 equiv), gem-
diborylalkanes (0.5 mmol, 1 equiv), LiTMP (0.6 mmol, 1.2 equiv),
THF (3 mL), rt, 16h.
the coupled product 41 retained only one boryl moiety,
suggesting the protodeboronation pathway as a consequence of
the α-diborylbenzyl carbanion’s reactivity (Table 2, entry 6).
Both entries 5 and 6 provided quantitative conversion on the
desired products without any observation of byproduct
formation, although isolated yields were moderate due to the
instability of products during purification.
A similar protodeboronation sequence was involved in the
diborylalkylation of the analogue cyclic vinyl epoxide 3,4-
epoxy-1-cyclohexene (42), providing the homoallylboronate
products with only one boryl moiety at the final product,
independently of R = aryl or alkyl group (Scheme 5).6 It
suggests that the OH functionality might favor the intra-
molecular deborylation in a sterically hindered quaternary C
C
DOI: 10.1021/acs.orglett.9b03672
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
́
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Scheme 5. Comparative Diborylalkylation Ring-Opening
Reaction of Cyclic Vinyl Epoxide and Vinyl Aziridine
́
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It can be concluded that α-diboryl carbanions formed from
gem-diborylalkanes and LiTMP perform regioselective nucle-
ophilic attack on vinyl aziridines. Preferred SN2 ring opening/
C−C bond forming on the less sterically hindered 1-tosyl-2-
vinylaziridine in contrast to the favored SN2′ diborylalkylation
on 2-methyl-1-tosyl-2-vinylaziridine. In contrast to the two
previous examples, the allylic position of cyclic vinyl aziridines
traps the α-diboryl carbanions along the diborylalkylation/ring
opening to form exclusively homoallyldiboronate species with
trans disposition of the amine and diborylalkyl groups. Despite
the fact that regioselectivity depends on the nature of vinyl
aziridine substrate, the resulting product maintains the two
boryl moieties unaltered, except for those reactions where
HCArB2pin2 are involved since protodeboronation seems to
proceed, under the basic reaction conditions, in order to
diminish the steric hindrance around the quaternary C centers.
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ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b03672.
Experimental Procedures and spectra data, as well as 1H,
13C, and 11B spectra (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*mariaelena.fernandez@urv.cat.
ORCID
́
Elena Fernandez: 0000-0001-9025-1791
Author Contributions
All authors have given approval to the final version of the
manuscript
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We thank the Spanish Ministerio de Ciencia, Innovacion y
Universidades (MCIU) through project FEDER-CTQ2016-
80328-P.
■
́
REFERENCES
■
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D
DOI: 10.1021/acs.orglett.9b03672
Org. Lett. XXXX, XXX, XXX−XXX