Mixed Diboration of Alkynes Catalyzed by LiOH: Regio- and Stereoselective Synthesis of cis-1,2-Diborylalkenes

Article abstract of DOI:10.1021/acs.orglett.8b02830

A diboration of terminal alkynes with an unsymmetrical diboron reagent pinBBdan has been achieved using LiOH as the catalyst in the presence of stoichiometric amounts of MeOH, affording 1,2-diborylalkenes with different boryl groups. The reaction proceeds in a highly regio- and stereoselective manner through cis-addition of pinBBdan to the C-C triple bond, with the Bdan moiety being incorporated at the internal position. By taking advantage of the different reactivities of the two boryl groups, the mixed diboration product can undergo the sequential, chemoselective cross-couplings with aryl bromides to form trisubstituted alkenes.

Full text of DOI:10.1021/acs.orglett.8b02830

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Mixed Diboration of Alkynes Catalyzed by LiOH: Regio- and
Stereoselective Synthesis of cis-1,2-Diborylalkenes
Sihan Peng, Guixia Liu,* and Zheng Huang*
State Key laboratory of Organometallic Chemistry, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic
Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, China
S
* Supporting Information
ABSTRACT: A diboration of terminal alkynes with an unsymmetrical
diboron reagent pinBBdan has been achieved using LiOH as the catalyst in
the presence of stoichiometric amounts of MeOH, affording 1,2-
diborylalkenes with different boryl groups. The reaction proceeds in a
highly regio- and stereoselective manner through cis-addition of pinBBdan
to the C−C triple bond, with the Bdan moiety being incorporated at the
internal position. By taking advantage of the different reactivities of the two
boryl groups, the mixed diboration product can undergo the sequential, chemoselective cross-couplings with aryl bromides to
form trisubstituted alkenes.
1,2-Diborylalkenes bearing two vicinal boron moieties for
elaboration are valuable building blocks for the synthesis of
multisubstituted alkenes, which are prevalent motifs present in
bioactive compounds and π-conjugated materials.1 Diboration
of alkynes with a diboron reagent2 provides a straightforward
and eco-friendly route to diborylalkenes.3 A range of transition-
metal catalysts have proven to be efficient for this trans-
formation to provide cis-1,2-diborylalkenes selectively.4−9
Recently, transition-metal-free protocols have also been
developed.10 Notable examples include photocatalyzed dibora-
tion of terminal alkynes employing organosulfide11 or
organophosphine12 catalysts under light irradiation, PBu3-
catalyzed trans-diboration of alkynoates,13 and trans-diboration
of propargylic alcohols with stoichiometric amounts of n-
BuLi.14 Although great advances have been achieved using
symmetrical diboron reagents, such as B2pin2 [bis(pinacolato)-
diborane], alkyne diboration with unsymmetrical diboron
reagents is still in its infancy.
Scheme 1. Diboration of Alkynes with Unsymmetrical
Diborons
The addition of mixed diborons across the alkynes allows
the synthesis of diborylalkenes with different protecting groups
on the boron groups. Such diborylalkenes are synthetically
valuable since the two nonequivalent C−B bonds exhibit
different reactivity and could be easily discriminated during
further transformation. However, a significant challenge exists
in mixed diboration, with the difficulty of controlling regio-
and stereoselectivity to deliver the two differentially masking
borons to specific positions.15 For example, in a direct and
base-catalyzed diboration of alkynes with pinBBMes2 (Mes =
2,4,6-Me3C6H2) developed by Lin and Yamashita et al., a
mixture of regio- or stereoisomers was obtained for some
substrates (Scheme 1a).16 The installation of a directing group
in the alkyne substrate provides an efficient strategy to control
selectivity. The Santos group developed a substrate-assisted
trans-diboration of alkynamides with pinBBdan promoted by
NaH, wherein an amide group in the alkynes acts as a directing
group to assist trans-diboration with excellent selevtivity
(Scheme 1b).17 The only example of selective mixed
diboration of alkynes without the aid of a directing group
was reported by Suginome and co-workers, who have shown
that the use of Ir and Pt catalysts was effective for cis-
diboration of alkynes with pinBBdan (dan = naphthalene-1,8-
diaminato) with Bdan being installed at the terminal carbon
(Scheme 1c).18 Therefore, it is of synthetic interest to develop
a general catalytic system that promotes the mixed diboration
of alkynes with high selectivity. In particular, a new catalytic
method that provides selectivity complementary to that of the
Received: September 5, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b02830
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
current methods without the use of a directing group is highly
desired.
To accomplish synthetically useful alkyne diboration with
unsymmetrical diboron reagents, it is essential to overcome the
in 65% yield (entry 11). Prolonging the reaction time to 24 h
further improved the yield to 76% (entry 12). No reaction
occurred in the absence of MeOH (entry 13). It is worth
noting that, under the optimized conditions, GC analysis of the
crude reaction mixture showed that 2a was the only diboration
product, which was accompanied by a structurally undefined
triborylation product. These results indicate that this base
catalysis enabled the mixed diboration with excellent regio-
and stereoselectivity.
́
regio- and steroselectivity issues. The work of Carbo and
́
Fernandez et al. demonstrated that pinBBdan could be
activated by an alkoxide, where the more Lewis-acidic Bpin
moiety could interact with the Lewis-basic alkoxide preferen-
tially over the Bdan unit.15a,19 Inspired by these findings, we
envisioned that this activation mode might be used to deliver
Bpin and Bdan moieties across the C−C triple bond in a
selective way. Given the low cost and ready accessibility, it is
surprising that simple inorganic bases have rarely been used as
catalysts in diboration of alkynes. We describe herein a LiOH-
catalyzed cis-diboration of terminal alkynes with pinBBdan to
afford cis-diborylalkenes with the Bdan group added to the
internal carbon, featuring excellent regioselectivity comple-
mentary to that obtained in Suginome’s transition-metal
catalytic system.
With the optimized catalytic conditions in hand, the scope
and limitations of the base-catalyzed mixed diborylation were
evaluated (Scheme 2). Specifically, linear aliphatic terminal
Scheme 2. LiOH-Catalyzed Diboration of Alkyl Alkynes
a
with BpinBdan
We commenced our study by identifying a suitable base
catalyst to effect mixed diboration of 1-hexyne (1a) with
pinBBdan, and the results are summarized in Table 1.
a
Table 1. Catalyst Development for Diboration of 1-Hexyne
b
entry
base
additive
solvent
THF
THF
THF
THF
THF
THF
THF
THF
THF
Et2O
Et2O/THF
Et2O/THF
Et2O/THF
yield (%)
1
2
3
4
5
6
7
8
9
LiOH
t-BuOLi
NaOH
Cs2CO3
NaOMe
CsF
LiOH
LiOH
LiOH
LiOH
LiOH
LiOH
LiOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
EtOH
i-PrOH
t-BuOH
MeOH
MeOH
MeOH
45
NR
35
14
trace
trace
37
trace
trace
36
65
76
NR
10
c
11
12
13
cd
,
a
Reaction conditions: alkynes (0.2 mmol), pinBBdan (2.0 equiv),
cd
,
LiOH (25.0 mol %), MeOH (5 equiv), in Et2O (0.8 mL) and THF
a
b
(0.2 mL) at 80 °C for 24−72 h. Isolated yields. 1H NMR yields are
Reaction conditions: 1a (0.2 mmol), pinBBdan (2 equiv), base (25
mol %), additive (5 equiv), and solvent (0.5 mL) at 80 °C for 12 h.
given in parentheses.
b
Yields are determined by GC with mesitylene as the internal
c
d
standard. Et2O/THF = 4:1 (v/v). 24 h.
alkynes underwent the reaction smoothly, affording the 1,2-
diborylated products in 65−71% isolated yields (2a−d). The
use of chloro-substituted alkynes led to moderate yields of the
corresponding products, leaving the C(sp3)−Cl bond intact
(2e and 2f). Ester-containing substrates derived from acid or
alcohol could be diborylated, albeit with low yields (2g and
2h). The reaction proceeded sluggishly for a substrate bearing
a Ph group β to the alkyne group, giving the diborylated
product (2i) in low yield. The mixed diboration could be
extended to alkynes with a branched alkyl substituent, as
demonstrated by the isolation of 2k−m in useful yields. An
alkyne with a bulky t-Bu substituent could be diborated to
form the desired product 2n in 34% isolated yield. The
reaction using 1-hexyne in the presence of an equimolar
amount of 3-hexyne or 4-methyl-1-pentene, only converted the
terminal alkyne, which indicates the current protocol is
chemoselective for terminal alkynes. It is also worth noting
Encouragingly, 1,2-diborylalkene 2a was obtained in 45% GC
yield when the reaction was performed in THF at 80 °C using
LiOH (25 mol %) as the catalyst and MeOH (5 equiv) as the
additive (entry 1). The structure of 2a was unambiguously
determined by NOE spectra,20 which implied that diboration
proceeds via cis-addition of pinB-Bdan to the C−C triple bond,
with the Bdan moiety at the internal position. The choice of
base and additive significantly influenced the reactivity. A
screen of the bases revealed that LiOH was superior to other
bases, such as LiO-t-Bu, NaOH, KOH, Cs2CO3, NaOMe, and
CsF (entries 1−6). Replacing MeOH with EtOH led to a
decline in yield (entry 7), and the use of i-PrOH or t-BuOH
gave trace amounts of 2a (entries 8 and 9). A survey of
solvents established the mixed solvents of THF and ether as
the optimal reaction medium, affording the diboration product
B
DOI: 10.1021/acs.orglett.8b02830
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
that many reactions gave moderate isolated yields of the
desired products, partly because the alkenyl boronate products
decompose relatively easily during the purification by
chromatography. Although this simple base catalytic system
is active toward alkyl acetylenes, aryl acetylenes do not react.
The application of this base catalyst in diboration of alkynes
with B2pin2 as the diboron reagent was also investigated briefly,
considering that such a transformation has rarely been effected
by a simple base.21 With NaOH as the catalyst, a range of
alkynes, including a terminal alkyne (3a), alkyl or phenyl
substituted symmetric internal alkynes (3b and 3c) and an
unsymmetric internal alkyne (3d) could be diborylated
smoothly with B2pin2, affording 1,2-diborylalkenes in moderate
to good yields (Scheme 3). In contrast, the unsymmetrical
Scheme 4. Gram-Scale Reaction and Derivatization of the
Product
Scheme 3. Base-Catalyzed Diborylation of Alkynes with
a
B2pin2
a
Reaction conditions: alkynes (0.5 mmol), B2pin2 (2 equiv), base (25
mol %), MeOH (5 equiv), and THF (0.5 mL) at 80 °C.
diboration of internal alkynes with pinBBdan was sluggish,
which resulted in low conversion and only produced a low
yield of the desired diboration product.22
Scheme 5. Proposed Catalytic Cycle
To demonstrate the synthetic utility further, a gram-scale
reaction and derivatization of the mixed diboration product
were conducted. The reaction of 1a with pinBBdan catalyzed
by LiOH could be carried out on a 5 mmol scale to produce 2a
in 61% yield (Scheme 4a). Exposure of 2a under basic
conditions in the presence of a large excess of methanol (20
equiv) led to the selective protodeboration of the Bpin moiety,
affording the Bdan-substituted alkene 4a in 80% yield.
Alternatively, 4a could be synthesized directly from alkyne
1a with BpinBdan using 25 mol % of LiOH and 40 equiv of
MeOH (Scheme 4b).23
The orthogonal reactivity of two boron moieties in the
mixed diboration product 2a was further demonstrated in a
sequential transformation. When the diboration product 2a
was submitted to the Suzuki−Miyaura coupling reaction with
phenyl bromide (Scheme 4c), the coupling occurred at the
Bpin part chemoselectively, leaving the Bdan moiety intact.
Following the deprotection of the Bdan group in 5a without
the isolation of the boronic acid, the cross-coupling with
another aryl bromide generated trisubstituted alkene 6a
stereoselectively with two newly incorporated aryl groups cis
to each other. The regioisomer of 6a, that is 6b, could be
synthesized by changing the order of the coupling partners.
A plausible catalytic cycle for the LiOH-catalyzed alkyne
mixed diboration was proposed, mainly based on the
precedents of alkene diborations under basic conditions
(Scheme 5).15a,19,24 A methoxide anion derived from the
reaction of LiOH and MeOH is expected to attack the Bpin
moiety selectively versus the less electrophilic Bdan unit.25 The
resulting [danB-Bpin(OMe)]− adduct A reacts with the alkyne
via the addition of the nucleophilic Bdan moiety to the
terminal carbon of the triple bond to form species B. This
nucleophilic addition not only increases the negative charge of
alkyne but also makes the Bpin(OMe) moiety electrophilic.
Subsequently, the terminal carbon of the alkyne attacks the
Bpin(OMe) moiety, accompanied by B−B bond cleavage and
Bdan migration to the internal carbon, furnishing the
methoxide adduct of the diborated product. Protonolysis of
intermediate D produces the desired product and regenerates
the base and MeOH.
In summary, we have developed a simple and efficient mixed
diboration of terminal alkynes with pinBBdan catalyzed by
C
DOI: 10.1021/acs.orglett.8b02830
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
11018. (b) Ishiyama, T.; Matsuda, N.; Murata, M.; Ozawa, F.; Suzuki,
A.; Miyaura, N. Organometallics 1996, 15, 713. (c) Lillo, V.; Mata, J.;
Ramírez, J.; Peris, E.; Fernandez, E. Organometallics 2006, 25, 5829.
low-cost and readily available LiOH. The most significant
aspect of this method is the excellent regio- and stereo-
selectivity, affording the cis-diboration product with the Bpin
moiety at the terminal position. Moreover, the method is
scalable, and the two differentially masked boron parts could
be sequentially transformed, which underscores its synthetic
utility. Further work on the application of this protocol to
other substrates is currently in progress in our laboratory.
́
́
(d) Prokopcova, H.; Ramírez, J.; Fernandez, E.; Kappe, C. O.
Tetrahedron Lett. 2008, 49, 4831. (e) Hyodo, K.; Suetsugu, M.;
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́
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Cuenca, A. B.; Carbo, J. J.; Fernandez, E. Chem. Commun. 2015, 51,
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Radacki, K.; Seeler, F.; Sigritz, R. Angew. Chem., Int. Ed. 2006, 45,
8048. For Rh catalyzed trans-diboration, see: (b) Curto, S. G.;
ASSOCIATED CONTENT
* Supporting Information
■
́
́
Esteruelas, M. A.; Olivan, M.; Onate, E.; Velez, A. Organometallics
2018, 37, 1970.
̃
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b02830.
(6) For Au-catalyzed diborations, see: (a) Chen, Q.; Zhao, J.;
Ishikawa, Y.; Asao, N.; Yamamoto, Y.; Jin, T. Org. Lett. 2013, 15,
5766. (b) Kidonakis, M.; Stratakis, M. Eur. J. Org. Chem. 2017, 2017,
4265.
(7) For Cu-catalyzed diboration, see: (a) Yoshida, H.; Kawashima,
S.; Takemoto, Y.; Okada, K.; Ohshita, J. Angew. Chem., Int. Ed. 2012,
Experimental procedures and product characterization
(PDF)
́
51, 235. (b) Zhao, T. S. N.; Yang, Y.; Lessing, T.; Szabo, K. J. J. Am.
Chem. Soc. 2014, 136, 7563.
AUTHOR INFORMATION
Corresponding Authors
■
(8) For Fe-catalyzed diboration, see: Nakagawa, N.; Hatakeyama, T.;
Nakamura, M. Chem. - Eur. J. 2015, 21, 4257.
(9) For Co catalysis, see: Adams, C. J.; Baber, R. A.; Batsanov, A. S.;
Bramham, G.; Charmant, J. P. H.; Haddow, M. F.; Howard, J. A. K.;
Lam, W. H.; Lin, Z.; Marder, T. B.; Norman, N. C.; Orpen, A. G.
Dalton Trans 2006, 1370.
*E-mail: guixia@sioc.ac.cn.
*E-mail: huangzh@sioc.ac.cn.
ORCID
Guixia Liu: 0000-0001-7565-2183
Zheng Huang: 0000-0001-7524-098X
Notes
(10) For a review, see: Cuenca, A. B.; Shishido, R.; Ito, H.;
́
Fernandez, E. Chem. Soc. Rev. 2017, 46, 415.
(11) Yoshimura, A.; Takamachi, Y.; Han, L. B.; Ogawa, A. Chem. -
Eur. J. 2015, 21, 13930.
(12) Yoshimura, A.; Takamachi, Y.; Mihara, K.; Saeki, T.;
Kawaguchi, S.-i.; Han, L.-B.; Nomoto, A.; Ogawa, A. Tetrahedron
2016, 72, 7832.
(13) Nagao, K.; Ohmiya, H.; Sawamura, M. Org. Lett. 2015, 17,
1304.
(14) Nagashima, Y.; Hirano, K.; Takita, R.; Uchiyama, M. J. Am.
Chem. Soc. 2014, 136, 8532.
(15) (a) Miralles, N.; Cid, J.; Cuenca, A. B.; Carbo, J. J.; Fernandez,
E. Chem. Commun. 2015, 51, 1693. (b) Guo, X.; Nelson, A. K.;
Slebodnick, C.; Santos, W. L. ACS Catal. 2015, 5, 2172.
(16) Kojima, C.; Lee, K.-H.; Lin, Z.; Yamashita, M. J. Am. Chem. Soc.
2016, 138, 6662.
(17) Verma, A.; Snead, R. F.; Dai, Y.; Slebodnick, C.; Yang, Y.; Yu,
H.; Yao, F.; Santos, W. L. Angew. Chem., Int. Ed. 2017, 56, 5111.
(18) Iwadate, N.; Suginome, M. J. Am. Chem. Soc. 2010, 132, 2548.
(19) Cid, J.; Carbo, J. J.; Fernandez, E. Chem. - Eur. J. 2014, 20,
3616.
(20) Please see the NOSY spectra in the Supporting Information.
(21) During the preparation of this manuscript, a base-catalyzed
diboration of alkynes with B2pin2 was reported by the Song group:
Kuang, Z.; Gao, G.; Song, Q. Sci. China: Chem. 2018, DOI: 10.1007/
s11426-018-9344-4.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We gratefully acknowledge financial support from the National
Key R&D Program of the MOST of China (2016YFA0202900,
2015CB856600), the NSFC (21432011, 21572255,
21732006), the CAS (XDB20000000, QYZDB-SSW-
SLH016), and the STCSM (17JC1401200).
́
́
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DOI: 10.1021/acs.orglett.8b02830
Org. Lett. XXXX, XXX, XXX−XXX