Synthesis of stereodefined 1,1-diborylalkenes via copper-catalyzed diboration of terminal alkynes

Article abstract of DOI:10.1021/acs.orglett.0c01901

A copper-catalyzed method for the E-selective 1,1-diboration of terminal alkynes is described. The tandem process involves sequential dehydrogenative borylation of the alkyne substrate with HBdan (1,8-diaminonaphthalatoborane), followed by hydroboration w

Full text of DOI:10.1021/acs.orglett.0c01901

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Letter
Synthesis of Stereodefined 1,1-Diborylalkenes via Copper-Catalyzed
Diboration of Terminal Alkynes
Yang Gao, Zhong-Qian Wu, and Keary M. Engle*
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sı Supporting Information
ABSTRACT: A copper-catalyzed method for the E-selective 1,1-
diboration of terminal alkynes is described. The tandem process
involves sequential dehydrogenative borylation of the alkyne
substrate with HBdan (1,8-diaminonaphthalatoborane), followed
by hydroboration with HBpin (pinacolborane). This method
proceeds efficiently under mild conditions, furnishing 1,1-
diborylalkenes with excellent stereoselectivity and broad functional
group tolerance. Taking advantage of the different reactivities of the two boryl moieties, the products can then be employed in
stepwise cross-couplings with aryl halides for the stereocontrolled construction of trisubstituted alkenes.
lkenyl boronic acids and their derivatives are nontoxic,
shelf-stable organometallic compounds that react with high
Scheme 1. (A) Synthesis and Reactivity of 1,1-
Diborylalkenes, (B and C) Prior Steps to Access Z-
Configured 1,1-Diborylalkenes, and (D) This Work
A
fidelity in a range of C−C and C−heteroatom couplings, making
1
them useful reagents in organic synthesis. 1,1-Diborylalkenes
make up an emerging subclass that offers exciting potential for
accessing multisubstituted olefins in a stereocontrolled manner
2
through sequential reaction at each of the two C−B bonds. To
this end, many approaches to synthesize 1,1-diboryl alkenes
bearing two −Bpin (pinacolatoboryl) groups have been
2
c,3
4
developed from alkene
and alkyne starting materials.
When such compounds are then employed in cross-coupling,
the inherently similar reactivity of the two C−Bpin bonds makes
it challenging to achieve high selectivity for a monofunctional-
ized product. Indeed, successful monoselectivity at the less
hindered position has been demonstrated only when the 1,1-
diborylalkene contains an aryl group at the C2 position and
when an aryl iodide is employed as the electrophile (Scheme
2
c,4b
1
A).
We reasoned that the scope of substrates and coupling
partners could be expanded if the two boron centers were
differentially protected with one −(pin) (pin = pinacolate)
group and one −(dan) (dan = naphthalene-1,8-diaminato)
group (Scheme 1A). The Bdan group is well-known to possess
diminished Lewis acidity and to be generally inactive toward
5
transmetalation, a key step of cross-coupling. This so-called
protected boron moiety can be reactivated by either
5
deprotection under acidic conditions or interaction with
6
KOtBu or Ba(OH)2. The sequential masking/unmasking
strategy enabled by the Bdan group has been successfully
applied to iterative cross-coupling, providing efficient and
concise approaches to functional organic molecules including
Received: June 5, 2020
5a,c,6c
5d
complex oligoarenes
and optoelectronic materials. More-
over, these isomerically pure 1,1-diborylalkenes represent a
promising class of prochiral substrates to generate enantioen-
7
riched 1,1-diborylalkanes, which are valuable and versatile
©
XXXX American Chemical Society
https://dx.doi.org/10.1021/acs.orglett.0c01901
Org. Lett. XXXX, XXX, XXX−XXX
A

Organic Letters
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Letter
Table 1. Optimization of Reaction Conditions for Cu-
Catalyzed 1,1-Diboration of Phenylacetylene
mol % (R )-DTBM-SEGPHOS in THF for 15 min. After this
a
period, HBpin is added, and the reaction mixture is allowed to
stir for an additional 16 h at room temperature, at which point
the desired product 2a is isolated in 69% yield (Table 1, entry 1).
The timing of HBpin addition was found to be important. The
yield of 2a decreased when HBpin was added earlier, with a
larger amount of side products observed (Table 1, entries 2 and
3
).
Another key finding from these studies was that the acetate
counteranion and the (R )-DTBM-SEGPHOS ligand were both
a
b
required (Table 1, entries 4−12). CuOAc was slightly less
yield (%)
effective than Cu(OAc) (Table 1, entry 4), while other copper
a
2
entry
variation from standard conditions
2a
2aa + 2ab
sources such as CuBr and CuCl, together with NaOtBu, showed
1
2
3
4
5
6
7
8
9
none
69
52
31
55
0
0
23
0
4
9
23
64
0
17
23
20
20
0
0
5
0
0
no catalytic activity. In terms of other ligands tested, (R )-DM-
a
HBpin added after 8 min
HBpin added together with 1a
SEGPHOS gave a yield of 2a that was slightly lower than that of
c
(
Ra)-DTBM-SEGPHOS (Table 1, entry 12). Unfortunately,
CuOAc in place of Cu(OAc)
2
other phosphine ligands led to either a low yield or no reaction.
There was no reaction in the absence of a ligand (Table 1, entry
13). The structure and (E)-stereochemical configuration of 2a
were unambiguously assigned by X-ray crystallography (Table 1,
top left).
d
CuBr in place of Cu(OAc)2
d
CuCl in place of Cu(OAc)2
PPh as the ligand
3
PCy as the ligand
3
dppp as the ligand
dppf as the ligand
Next, we evaluated the scope and functional group
compatibility of this stereoselective process (Scheme 2). The
10
11
12
13
14
4
5
e
(R )-SEGPHOS as the ligand
a
e
(R )-DM-SEGPHOS as the ligand
10
0
46
a
Scheme 2. Copper-Catalyzed Stereoselective 1,1-Diboration
no ligand
toluene as the solvent
a
of Terminal Alkynes
48
a
Standard reaction conditions: 1a (0.10 mmol), HBdan (0.11 mmol),
HBpin (0.12 mmol), Cu(OAc)2 (5 mol %), and (R )-DTBM-
a
b
1
SEGPHOS (5 mol %) in THF (0.25 mL). H NMR yield using
CH Br as the internal standard. Also observed was 10% PhCHCH-
c
2
2
d
e
(Bpin). Together with NaOtBu (10%). Also observed was 9%
PhCHC(Bpin)2.
building blocks for accessing enantioenriched functionalized
8
alkanes.
In view of the unique synthetic value of differentially
protected 1,1-diborylalkenes, practical synthetic methods for
accessing such compounds in a stereodefined manner are
desirable. However, few methods are currently available. In
2
017, Chirik and colleagues described a Co-catalyzed 1,1-
diboration of aliphatic alkynes to synthesize (Z)-1,1-dibor-
ylakenes with use of the mixed diboron reagent pinB−Bdan
4
b
(
Scheme 1B). Later, Marder reported a base-catalyzed
stereoselective diboration of alkynyl esters and amides with
9
pinB−Bdan (Scheme 1C). Both methods, though highly
enabling in their own right, have limited substrate scope and
provide access to only the Z-configured products.
Driven by our interest in developing new metal-catalyzed
10
alkyne functionalization methods, we recently reported a
CuH-catalyzed cascade process to access enantioenriched α-
aminoboron compounds via sequential hydroboration and
11,12
a
hydroamination of terminal alkynes.
Here we report an
Conditions: 0.10 mmol scale, THF (0.25 mL). Percentages
exclusively E-selective Cu-catalyzed three-component reaction
to produce 1,1-diborylalkenes through a tandem sequence
comprised of dehydrogenative C(sp)−H borylation with
HBdan and hydroboration of the resulting alkynylBdan
correspond to isolated yields.
reactions with aryl-substituted alkynes were found to be
sensitive to both electronic and steric effects. Aryl acetylenes
with electron-donating groups normally performed better than
those with electron-withdrawing groups. For example, p-MeO-
substituted phenylacetylene gave product 2c in70% yield, while
p-CF -substituted phenylacetylene gave product 2f in 47% yield.
Diboration of para-substituted phenylacetylenes generally
occurred smoothly, while meta- and ortho-substituted phenyl-
13
intermediate with HBpin (Scheme 1D).
Our investigation commenced by examining reaction
conditions using phenylacetylene (1a) as a pilot substrate,
with HBdan and HBpin as coupling partners. After extensive
optimization, we identified an effective protocol in which HBdan
3
is first mixed with 1a in the presence of 5 mol % Cu(OAc) and 5
2
B
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Letter
acetylenes gave relatively low yields. A range of functional
which furnished 1,1-diborylalkene 2h with no deuterium label at
the internal alkenyl carbon atom, as judged by H NMR
1
groups, such as halides (2e and 2k−2m), an ester (2g), ethers
(
2c and 2i), and amines (2d and 2j), were well tolerated. 2-
spectroscopy (eq 3). This result is consistent with an initial
dehydrogenative borylation event. Next, subjecting sterically
bulky mesitylacetylene to the standard reaction conditions did
not lead to formation of the typical 1,1-diborylated product;
instead, alkynylBdan 3u was isolated in 55% yield (eq 4). This
result suggests that alkynylBdan is the product from the first step
of the tandem process and that the second hydroboration step is
sensitive to steric hindrance. Consistent with this notion, the
reaction between 1a and HBdan before addition of HBpin was
Ethynyl-naphthalene and 3-ethynylthiophene underwent dibo-
ration as well to give corresponding 1,1-diborylalkenes (2h and
2
n).
1
,1-Diboration was similarly effective with aliphatic alkynes,
furnishing the corresponding E-configured products. The
structure of 1,1-diborylalkene 2o was confirmed by X-ray
crystallography (Table 1, bottom left). Remarkably, 1-
ethynylcyclohexene underwent 1,1-diboration to furnish prod-
uct 2s with the CC bond intact. Functional groups like
carbonate (2p), ether (2q), and silyl ether (2t) were tolerated,
with products isolated in useful yields.
Interestingly, when terminal alkynes 1 were reacted with 2.2
equiv of HBdan in the absence of HBpin, 1,1-homodiboration
proceeded smoothly, furnishing 1,1-diborylalkenes 4 bearing
two −Bdan groups in excellent yields (eq 1).
1
monitored by H NMR spectroscopy (eq 5), and alkynylBdan
14
3a (16%) and H
To further support our hypothesis, the proposed intermediate
a was independently synthesized and submitted to the reaction
were both observed after 30 min (Figure S2).
2
3
with HBpin under the standard conditions. Hydroboration of 3a
proceeded smoothly to furnish 2a in 60% yield (eq 6). Control
experiments revealed that hydroboration of 3a with HBpin
15
requires copper as a catalyst and that the presence of HBdan
improves the hydroboration efficiency of 3a (60% compared to
3
5% yield). An explanation for this latter result is that HBdan
could be involved in regeneration of the active [LCuH]
catalyst. On the basis of our experimental observations and
11
To illustrate the practical utility of this procedure, we
performed stepwise Suzuki−Miyaura cross-couplings of the
1
,1-diborylalkenes (Scheme 3). The selective monoarylation of
Scheme 3. Stepwise Suzuki−Miyaura Coupling Reactions of
2a
2
a worked well using 4-iodotoluene as a coupling partner under
standard cross-coupling conditions, giving 92% 5a after 12 h at
0 °C. Notably, the reaction with 4-bromotoluene also
3
proceeded, albeit at a higher temperature of 80 °C, giving
product 5a in 85% yield with no diarylation product detected.
Next, the Bdan group of 5a was deprotected, and the resulting
boronic acid was carried forward without purification in a
second cross-coupling reaction with 4-iodoanisole to produce
triarylated alkene 6a as a single stereoisomer.
1
1−13,16,17
previous reports,
a Cu-catalyzed tandem process
comprised of dehydrogenative borylation of the terminal alkyne
and subsequent hydroboration is proposed (Scheme 4).
LCuOAc] a1, generated by reduction of Cu(OAc) in the
[
2
Selective Suzuki−Miyaura cross-coupling of the Bpin group of
o also proceeded smoothly, furnishing 5o in 94% yield (eq 2).
Scheme 4. Proposed Mechanism
2
The olefin geometry in 5o was confirmed by NOESY (see the
4b,9
Supporting Information).
Having established the scope and utility of the (E)-selective
alkyne 1,1-diboration method, we shifted our attention to
investigating the reaction mechanism. First, we performed
copper-catalyzed 1,1-diboration of 2-(ethynyl-d)naphthalene
(
98% isotopic purity) under the standard reaction conditions,
C
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presence of phosphine and HBdan, 8−20 reacts with the terminal
1
Notes
18b
alkyne to give the alkynylcopper intermediate a2 and HOAc.
Following σ-bond metathesis between a2 and HBdan,
alkynylBdan 3 and [LCuH] a3 are formed.
The authors declare no competing financial interest.
16,21
Next, syn-
ACKNOWLEDGMENTS
■
insertion of intermediate 3 into the Cu−H bond of a3 generates
1
5,17,18,22
This work was financially supported by the National Institutes of
Health (5R35GM125052-03) and an ACS PRF Doctoral New
Investigator Grant. Additionally, the authors gratefully acknowl-
edge Tsinghua University Department of Chemistry for a
Xuetang Program Scholarship (Z.-Q.W.). Dr. Jason Chen and
Brittany Sanchez (Scripps Research Automated Synthesis
Facility) are acknowledged for HRMS analysis. The authors
further thank Drs. Milan Gembicky and Jake B. Bailey
alkenyl copper species a4,
which then undergoes σ-
bond metathesis with HBpin to furnish the (E)-1,1-dibor-
ylalkene with concomitant regeneration of [LCuH] a3.
Under the optimal conditions, prior to the addition of HBpin,
the dehydrogenative borylation cycle (right, Scheme 4) alone
proceeds through several turnovers to build up 3a, and upon
addition of HBpin, the hydroboration cycle (left, Scheme 4)
turns on. This strategy limits the formation of side products
caused by the high reactivity of HBpin. In the 1,1-
homodiboration system with HBdan only, both cycles
2
3
(
University of California, San Diego, La Jolla, CA) for X-ray
crystallographic analysis.
24
presumably proceed in parallel.
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25) A previous version of this paper was deposited on a preprint
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Diborylalkenes via Copper-Catalyzed Diboration of Terminal Alkynes.
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0233−10241.
14) Neither of the potential reduced byproducts, alkenylBdan nor
alkylBdan, could be detected by LC-MS.
(
E
https://dx.doi.org/10.1021/acs.orglett.0c01901
Org. Lett. XXXX, XXX, XXX−XXX