Enantioselective Conjunctive Cross-Coupling of Bis(alkenyl)borates: A General Synthesis of Chiral Allylboron Reagents

Article abstract of DOI:10.1021/jacs.7b01774

Palladium-catalyzed conjunctive cross-coupling is used for the synthesis of enantioenriched allylboron reagents. This reaction employs nonsymmetric bis(alkenyl)borates as substrates and appears to occur by a mechanism that involves selective activation of the less substituted alkene followed by migration of the more substituted alkene during the course of a Pd-induced metalate rearrangement.

Full text of DOI:10.1021/jacs.7b01774

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Communication
Enantioselective Conjunctive Cross-Coupling of Bis(alkenyl)
Borates: A General Synthesis of Chiral Allylboron Reagents
Emma K. Edelstein, Sheila Namirembe, and James P. Morken
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 24 Mar 2017
Downloaded from http://pubs.acs.org on March 25, 2017
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Enantioselective Conjunctive Cross-Coupling of Bis(alkenyl) Bo-
rates: A General Synthesis of Chiral Allylboron Reagents
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Emma K. Edelstein, Sheila Namirembe, and James P. Morken*
Department of Chemistry, Merkert Chemistry Center, Boston College, Chestnut Hill, Massachusetts 02467, United States
Supporting Information Placeholder
that this method provides an inroad to diverse allyl
boronate structures in an efficient asymmetric fashion.
ABSTRACT: Palladium catalyzed conjunctive cross-
coupling is used for the synthesis of enantioenriched
allylboron reagents.
This reaction employs non-
A
symmetric bis(alkenyl)borates as substrates and appears
to occur by a mechanism that involves selective activa-
tion of the less substituted alkene, followed by migration
of the more substituted alkene during the course of a Pd-
induced metalate rearrangement.
cat. Pd(OAc)2 / L1
RM BL2
Li
BL2
C(sp2)-OTf (1.2 equiv)
RM BL2
C(sp2)
+
(1)
RM
THF, 60 °C
16 h
Li
(1 equiv)
Me
MeO
Me
(SpSp)-L1
via:
P
Ph
NMe2
C(sp2) Pd P
P
Fe
Me
Me
2
H
Ph
BL2
P
OMe
metal-induced
metallate shift
NMe2
RM
2
Because they engage in an array of stereospecific and
1
stereoselective transformations , chiral allylboron rea-
2
B
gents hold a distinctive place in organic chemistry. Im-
BL2
BL2
BL2
BL2 R
portantly, these reactive intermediates can be readily
cat. Pd/L
E-X
E
E
E
E
Li
3
4
R
L2
B
transformed into allylic alcohols and amines , and they
can be employed in carbon-carbon bond forming reac-
R
R
A
B
C
D
R
5
terminal allyl boronates
internal allyl boronates
tions such as carbonyl and imine allylation. Moreover,
the ability to accomplish stereospecific α- and γ-
selective cross-coupling reactions with high levels of
Scheme 1. Catalytic conjunctive cross-coupling (A) and
its application to bis(alkenyl) "ate" complexes (B).
6
chirality-transfer adds to the utility of these special rea-
gents. Due to the utility of allyl boronates, a number of
catalytic asymmetric synthesis routes have been studied
for their production. Whereas construction of terminal
allylic boronates (i.e. A, Scheme 1B) can be achieved by
Recently, we reported the catalytic enantioselective
conjunctive cross-coupling reaction to furnish chiral
secondary boronic esters (Scheme 1, eq. 1).
14
This
three-component reaction employs a Pd complex in con-
junction with the diphosphine ligand, Mandyphos (L1),
to couple a boronic ester, an organolithium reagent, and
an organotriflate electrophile. During the course of the
reaction, a palladium induced 1,2-metalate shift (Scheme
1A) establishes the first C-C bond and installs the
borylated stereogenic center; subsequent reductive elim-
ination from a dialkyl Pd complex forges the second C-
C bond. Whereas previously described conjunctive cou-
pling reactions employed aryl and alkyl migrating
groups (RM in Scheme 1A), we considered that with a
migrating alkene, the reaction might provide a general
route to allyl boronate reagents (Scheme 1B). In terms
of reaction development, the demonstrated ability of
conjunctive cross-coupling reactions to accommodate
aromatic C(sp2) migrating groups was encouraging;
however, for alkene migration several critical issues re-
mained uncertain. First, it was not clear whether the Pd-
complex could selectively bind and activate one alkene
in the bis(alkenyl)borate substrate, or whether indiscri-
7
Cu-catalyzed enantioselective allylic borylation or al-
8
lylic alkylation , catalytic construction of internal allylic
boronates (i.e. C and D) by substitution reactions gener-
ally requires use of non-racemic allylic alcohol deriva-
9
tives. Other useful catalytic enantioselective routes to
internal allyl boron reagents – for example, diene dibo-
10
11
ration, cross-coupling with geminal bis(boronates) ,
12
and conjugate 1,4 or 1,6-borylation of activated dienes
– generally result in products bearing extraneous func-
tionality. While the above-described examples are pow-
erful catalytic methods, none of them provide access to
chiral allylboron reagents with a broad array of product
substitution patterns. Only Aggarwal’s stoichiometric
sparteine-mediated homologation reaction is able to ac-
cess the full complement of both terminal and internal
13
nonracemic allyl boronates structures. In this report, we
describe the application of catalytic enantioselective
conjunctive cross-coupling to
a
broad array of
alkenyl(vinyl)borate substrates (Scheme 1B) and show
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Page 2 of 5
minant activation of both alkenes would lead to product the chemoselectivity (2:3+4) and enantioselectivity with
1
2
3
4
5
6
7
8
mixtures. Second, it wasn't clear whether the allyl boro-
nate functional group in the product – a motif that can
engage in rapid transmetalation – would be consumed
by direct Suzuki reactions with the organic electrophile.
Lastly, both the chemical and configurational stability of
the "ate" complex and reaction products in the conjunc-
tive coupling process was uncertain.
other ligand classes generally doesn't measure up to that
obtained with the MandyPhos class of ligands (L1-L6).
Further optimization of reaction conditions and boronic
ester structure did not lead to additional improvements
and, accordingly, these conditions with ligand L1 were
employed in subsequent studies.
15
With the prospect for regio- and stereoselective
alkenyl migration in conjunctive coupling established,
other "ate" complexes were examined with phenyl tri-
flate as the electrophile (Table 2). Across a range of
substrates, conjunctive couplings were found to reliably
furnish stable allylboronate products in good yield and
with enantioselectivities from 77:23 to 96:4 er. Simple
E-alkyl substitution appears generally tolerated deliver-
ing substituted allylboronate products (2, 5 - 8) in good
yield and generally high enantiomeric purity. In addi-
tion, aryl E-disubstituted allyl boronates (10 - 14) as
well as a dienyl boronate (9) could be accessed with this
strategy. Of note, a terminal allylboronate (15) could
also be accessed efficiently and in good selectivity by
conjunctive coupling involving a divinylB(pin) "ate"
complex. Importantly, with Z-disubstituted alkenyl de-
rivatives (16-17), the conjunctive coupling occurred
without isomerization of the migrating alkene suggesting
that product olefin configuration can be controlled by
We began our investigation into the conjunctive cross-
coupling of bis(alkenyl) borates by treating 1-
hexenylB(pin) (1), with halide-free vinyllithium and
phenyl triflate in the presence of 1% Pd(OAc)2 and 1.2%
MandyPhos ligand L1 (Table 1, entry 1). This experi-
ment afforded the allyl boronate product (2) in good
isolated yield and high enantiomeric purity. In addition
to the conjunctive coupling product 2, the reaction mix-
ture contained detectable amounts of direct Suzuki-
9
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58
59
60
16
Miyaura cross-coupling products (3 and 4). Of note,
only a single regioisomer of conjunctive coupling prod-
uct 2 was formed and its identity was consistent with
activation of the unsubstituted vinyl ligand as opposed to
the 1-hexenyl ligand. Importantly, no evidence for al-
kene isomerization could be detected. As depicted in
Table 1, other ligand frameworks were also capable of
delivering the conjunctive cross-coupling product and,
while these provided uniformly regioselective reactions,
appropriate substrate design.
In addition, β,β-
Table
Bis(alkenyl)borates.
1.
Conjunctive
Cross-Coupling
with
disubstituted (18), α-substituted (21-23), and cyclic
Table
2.
Conjunctive
Cross-Coupling
of
Bis(alkenyl)borate Complexes.a
entry
1
ligand
L1
yield (%)a
85
2:(3+4)a
8:1
erb
92:8
89:11
89:11
na
2
L2
77
8:1
3
L3
70
5:1
4
L4
<2
na
5
L5
85
6:1
92:8
6
L6
78
7:1
72:28
77:23
59:41
70:30
69:31
53:47
7
L7
40
1:1
8
L8
30
>10:1
>20:1
1:1
9
L9
58
10
11
L10
L11
29
40
>20:1
(a) Determined by NMR versus an internal standard. (b) Deter-
mined by chiral SFC analysis.
(a) Reaction times vary from 1.5-16 h, See SI for conditions.
Isolated yield and er values represent an average of two experi-
ments. (b) With 2% Pd(OAc)2 and 2.2% L1. (c) With 3%
Pd(OAc)2 and 3.2% L1. (d) Isolated as the derived alcohol. (e)
Reaction solvent is 1:1 THF:DMSO. (f) Reaction conducted on 5
mmol scale.
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alkenyl boronic esters (19-20) are also competent sub-
strates. In terms of functional group compatibility, sub-
1
2
3
4
5
6
7
8
strates containing a silyl ether (5), furyl (11), and benzo-
dioxole (14) were compatible in the reaction as was a
Boc-protected amine (20), aryl fluoride (12), and a vinyl
silane (23). Lastly, it was demonstrated that the reaction
can be accomplished on larger scale: reaction to form 2
on 5 mmol scale gave similar yield and selectivity as
smaller scale reactions.
9
To learn about the ability of the reaction to accommo-
date different electrophilic reagents, the examples in
Table 3 were examined. It was found that various aryl
and alkenyl trifluoromethanesulfonates were processed
efficiently. In the case of electron deficient electro-
philes, a modest reduction in enantioselectivity was ob-
served (24) while electron rich electrophiles reacted with
uniformly high selectivity (25-27). The reaction em-
ploying organohalide electrophiles in place of organotri-
flates was unsuccessful in the absence of additives. At-
tributing this outcome to the inhibiting effect of halide
byproducts of the reaction the use of alkali metal triflate
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Scheme 2. Conjunctive coupling of Grignard-derived
and halide-containing borates.
triflate (for example, compound 29 was formed in 58%
yield and 78:22 er when the aryl bromide electrophile
was employed). As depicted in Table 3, a quinoline was
also accommodated in the reaction (28, 38).
The data in Tables 1-3 was obtained from reactions
that employed halide-free vinyllithium prepared from
tetravinylstannane by lithium-tin exchange. Recently,
we established that halide-containing vinyllithium (pre-
pared by Li-halogen exchange) and vinyl Grignard rea-
gents can be employed in conjunctive cross-couplings as
long as appropriate metal triflates are added to the reac-
tion.17 To determine whether these strategies could also
be employed in the reactions of bis(alkenyl)borate com-
plexes, the experiments in Scheme 2 were undertaken.
With vinylmagnesium chloride as the nucleophile (eq.
1), it was necessary to add two equivalents of sodium
triflate and to use 3:1 THF:DMSO as the reaction sol-
vent. While the reaction is markedly slower than with
halide-free vinyllithium, with these conditions, the pro-
cess occurs with the same level of enantioselectivity
(92:8 er), and with only a modestly diminished yield
(69% versus 83%). To determine whether halide-
containing vinyllithium might be employed in the reac-
17
additives was examined. Of note, the reaction in the
presence of KOTf enabled the reaction of bromide elec-
trophiles; however, in some cases the use of a bromide
electrophile gave diminished yield and, more surprising-
ly, lowered enantioselectivity when compared to the
Table
3.
Conjunctive
Cross-Coupling
of
Bis(alkenyl)borate Complexes with Various Electrophiles.a
(a) Isolated yield and er values represent an average of two ex-
periments. (b) When X=Br, 1.2 equiv. of KOTf added; see SI for
conditions. (c) This experiment conducted with 2% Pd(OAc)2
and 2.2% L1. (d) Isolated as the derived alcohol. (e) This exper-
iment conducted with 3% Pd(OAc)2 and 3.2% L1, reaction time
of 5 h.
Scheme
3.
Utility
of
a
storable,
stable
alkenyl(vinyl)borate complex.
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lytic conjunctive cross-coupling reactions.
tion, vinyl bromide was treated with t-butyllithium at -
1
2
3
4
5
6
7
8
78 °C in ether/pentane and then the alkenyl boronic ester
added to form the "ate" complex. After warming to room
temperature the solvent was removed and a conjunctive
cross-coupling conducted in THF solvent. While it was
found that KOTf (2 equiv) was indeed required, the re-
action nonetheless proceeded in similar levels of enanti-
oselectivity as the halide-free reaction.
■ ASSOCIATED CONTENT
Supporting Information. Procedures, characterization and
spectral data. This material is available free of charge via
the Internet at http://pubs.acs.org.
■ AUTHOR INFORMATION
Corresonding Author.
*morken@bc.edu
During the course of the experiments above, it was
found that the intermediate "ate" complexes are often
free-flowing crystalline solids. Thus, it was of interest to
determine the long-term stability of these materials as
potential "off-the-shelf" coupling partners. To probe
this feature, the bis(alkenyl) ate complex 39 was pre-
pared on gram scale and stored under argon atmosphere
at room temperature. As depicted in the 11B NMR spec-
trum in Scheme 3A, even after three months of storage,
the "ate" complex exhibits very little decomposition to
other boron-containing species. Importantly, this mate-
rial engages in efficient and selective conjunctive cross-
coupling with an outcome similar to that obtained with
freshly prepared reactants (eq. 3, Scheme 3B).
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Notes
The authors declare no competing financial interest.
■ ACKNOWLEDGEMENTS
This work was supported by the NIH (GM-118641). We
thank Solvias for providing MandyPhos ligand.
■ REFERENCES
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To highlight the synthetic utility of allylboron reagents
prepared by the conjunctive cross-coupling reaction, the
experiments in Scheme 4 were conducted. In the first
(eq 4), it was shown that peroxide oxidation proceeds
uneventfully and furnishes the allylic alcohol in out-
standing yield and with preservation of enantiomeric
purity. Next it was shown that direct stereospecific
amination of the boronic ester can be accomplished with
MeONH2/BuLi to furnish the derived allylic amine de-
rivative 41 (eq. 5); to our knowledge, this is the first
time that that stereospecificity in the amination of non-
racemic allyl boronates has been demonstrated. Lastly,
we examined carbonyl allylation reactions: whereas
direct allylation of benzaldehyde with allyl boronate 2
provides stereoisomeric mixtures (data not shown),
when the reaction was conducted through the intermedi-
acy of the borinic ester (eq. 6) as prescribed by Ag-
18
garwal , the allylation occurs with excellent selectivity.
In conclusion, we have described a general catalytic
enantioselective strategy for construction of both termi-
nal and internal α-chiral allyl boronate reagents by cata-
(10) (a) Pelz, N. F.; Woodward, A. R.; Burks, H. E.; Siebr, J. D.;
Morken, J. P. J. Am. Chem. Soc. 2004, 126, 16328. (b) Kliman, L. T.;
Mlynarski, S. N.; Morken, J. P. J. Am. Chem. Soc. 2012, 51, 521.
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A.; Chierchia, M. P.; Morken, J. P. Science. 2016, 351, 70.
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(16) Review: Suzuki, A. J. Organomet. Chem. 1999, 576, 147.
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Soc. 2017, 139, 3153.
Scheme 4. Functionalization of allylboron reagents.
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(18) Chen, J. L. Y.; Scott, H. K.; Hesse, M. J.; Willis, C. L.; Ag-
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garwal, V. K. J. Am. Chem. Soc. 2013, 135, 5316.
6
7
8
9
P
R
C(sp2) Pd P
10
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1% Pd(OAc)2
1.2% L1
B(pin)
R
B(pin)
C(sp2)
H
R
C(sp2)-X
R
BL2
+
R
via:
THF, 60 oC
R
R
Li
R
R
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