Phosphine-Catalyzed Anti -Hydroboration of Internal Alkynes

Article abstract of DOI:10.1021/acs.orglett.8b00390

Trialkylphosphine organocatalysts have enabled regioselective anti-hydroboration of internal alkynes with pinacolborane reagents to provide (E)-disubstituted alkenylboronate compounds. The alkenylboronate can be used for derivatizations, such as protodebo

Full text of DOI:10.1021/acs.orglett.8b00390

Letter
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Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Phosphine-Catalyzed Anti-Hydroboration of Internal Alkynes
Kazunori Nagao,† Ayaka Yamazaki,† Hirohisa Ohmiya,*,‡ and Masaya Sawamura*,†
†Department of Chemistry, Faculty of Science, Hokkaido University, Sapporo 060-0810, Japan
‡Division of Pharmaceutical Sciences, Graduate School of Medical Sciences, Kanazawa University, Kakuma-machi, Kanazawa
920-1192, Japan
S
* Supporting Information
ABSTRACT: Trialkylphosphine organocatalysts have enabled
regioselective anti-hydroboration of internal alkynes with
pinacolborane reagents to provide (E)-disubstituted alkenyl-
boronate compounds. The alkenylboronate can be used for
derivatizations, such as protodeborylation, Suzuki−Miyaura
coupling, conjugate reduction, and Diels−Alder reactions.
he hydroboration of alkynes is a useful method for the
synthesis of alkenylborons, which are versatile synthetic
We report here a phosphine-catalyzed regioselective anti-
hydroboration of internal alkynes, including alkynoates,
alkynylamides, and 2-alkynylazoles, with easy-to-handle pina-
colborane, which gives 1,2-disubstituted (E)-alkenylboronates
(Scheme 1c).6 The regioselectivity of the hydroboration across
the C−C triple bond exhibited inverse electronic demand, with
the intrinsically electrophilic B atom being delivered to the
positively charged β carbon atom of the alkynes.1c,7
Accordingly, this class of alkenylboron compounds is difficult
to access through other methods. The alkenylboronates can be
used for various derivatizations, such as protodeborylation,
Suzuki−Miyaura coupling, conjugate reduction, and Diels−
Alder reactions.
T
intermediates.1,2 Typically, the H−B bond addition across the
C−C triple bond occurs with syn stereochemistry via a four-
membered transition state. Accordingly, anti-selective hydro-
boration of alkynes is an important challenge in modern
organic synthesis.3,4 More specifically, anti-hydroboration of
internal alkynes to prepare 1,2-disubstituted (E)-configured
alkenylboron compounds has been a subject of more recent
studies.5 For instance, Furstner and co-worker developed a
̈
[Cp*Ru(MeCN)3]PF6-catalyzed anti-hydroboration of internal
alkynes with pinacolborane, while the reaction of unsym-
metrical alkynes was not regioselective (Scheme 1a).5a Shi and
While phosphine-catalyzed anti-selective vicinal carbobora-
tion, silaboration, and diboration across the C−C triple bond in
alkynoates have been established in our earlier work,8 extension
of the concept toward anti-selective hydroboration faces
nontrivial challenges, such as the use of easy-to-handle
pinacolborane, the expansion of a substrate scope for alkynes,
and a diverse derivatization of 1,2-disubstituted (E)-alkenylbor-
onate products.
Scheme 1. Anti-Hydroboration of Internal Alkynes
Our screening of phosphine catalysts for the reaction
between pinacolborane (1) and 3-phenylpropiolate (2a)
identified PBu3 to be the most effective (see Table 1). Thus,
the reaction between 1 (0.3 mmol) and 2a (0.3 mmol) in the
presence of PBu3 (2.5 mol %) in THF at 60 °C over 3 h gave β-
boryl acrylate 3a in 92% isolated yield (based on 2a; 99% NMR
yield; complete conversion of 2a) (eq 1). The H−B bond
co-workers reported the intramolecular anti-hydroboration
across C−C triple bonds in propargyl amine borane-
carbonitriles with a triazole−Au complex catalyst (Scheme
1a).5b Recently, Liu and co-workers reported anti-hydro-
boration of internal 1,3-eneyne using a 1,4-azaborine−Pd
complex (Scheme 1a).5c Wang and co-workers reported the
anti-hydroboration of 2-pyridyl alkynes with 9-borabicyclo-
[3.3.1]nonane (9-BBN-H) (Scheme 1b).5d
addition was completely regioselective and anti-stereoselective
under these conditions. The B atom in 3a had no interaction
Received: February 2, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b00390
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
a
Table 1. Catalyst Effects in Reaction between 1 and 2a
Table 2. Anti-Hydroboration of β-Aryl-Substituted
Alkynoates
a
b
c
b
entry
catalyst
yield (%) of 3a
anti/syn of 3a
yield (%) of 4a
1
2
3
4
5
6
7
8
PBu3
99
93
93
56
0
>99:1
>99:1
96:4
77:23
−
0
PMe3
PPhMe2
PPh2Me
PPh3
7
7
0
−
0
PCy3
PtBu3
87
0
93:7
−
−
−
−
none
0
a
Reactions were carried out with 1 (0.3 mmol), 2a (0.3 mmol), and
b
phosphine (10 mol %) in THF (0.6 mL) at 60 °C for 4 h. 1H NMR
yield. Determined by H NMR analysis of the crude product.
c
1
with the carbonyl oxygen, as indicated by 11B NMR
spectroscopy. The hydroboration also occurred efficiently
without a solvent under catalysis of PBu3 (2.5 mol %), giving
3a in 92% yield.
The reaction was scalable: a gram-scale reaction with 1.74 g
(10 mmol) of 2a and 1.27 g (10 mmol) of 1 in the presence of
PBu3 (2.5 mol %) at 60 °C over 12 h afforded 3a in 76%
isolated yield.
a
Reactions were carried out with 1 (0.3 mmol), 2 (0.3 mmol), and
PBu3 (2.5 mol %; entries 1, 2, 4, 8, 9; 5 mol %; entry 3; 7.5 mol %;
entries 5, 6; 10 mol %; entries 10, 11, 20 mol %; entry 7) in THF (50
The effect of phosphine catalysts on the reaction between 1
and 2a are shown in Table 1. PMe3 was also effective, but a
small amount of protodeborylation product, trans ethyl
cinnamate (4a), was observed (entry 2). The use of PPhMe2
slightly decreased the anti-selectivity with 7% formation of 4a
(entry 3). PPh2Me resulted in significantly decreased product
yield and anti-selectivity (entry 4). A weaker electron-donor
PPh3 was not effective (entry 5). The effects of bulkier
trialkylphosphine PCy3 were comparable with those of PPh2Me
in terms of both product yield and anti selectivity (entry 6).
However, the sterically more demanding PtBu3 induced no
reaction (entry 7). The reaction did not occur in the absence of
a phosphine (entry 8).
The protocol with a PBu3 catalyst was applicable to various
β-aryl-substituted alkynoates (Table 2).8 Methoxy, fluoro,
bromo, 2-(dimethylamino)ethoxy, ketone, and ester groups
were tolerated at the para- or meta-positions of the β-aryl
substituent (entries 1−6). A bulky o-tolyl substituent also gave
the efficient product yield by using 20 mol % of catalyst (entry
7, 5 mol %: 37%). 2-Furyl- or 2-thienyl-substituted alkynoates
(2i, j) underwent the anti-hydroboration (entries 8 and 9). The
lower yield of 3i was due to the decomposition of 2i in the
reaction conditions. Unfortunately, this hydroboration could
not tolerate the 2-pyridyl-substituted alkynoate (data not
shown). This trend is consistent with relatively low yield of
3d (enrty 3). The reaction of 2-naphthyl-substituted alkynoate
2k gave 94% anti selectivity (entry 10). The hydroboration of
1,3-enyne 2l afforded the corresponding 2,4-dienylboronate 3l
with the alkene moiety untouched (entry 11).
b
μL; entries 2−7, 10, 11; neat; 1, 8, 9) at 60 °C for 4 h. Yield of the
c
isolated product. Determined by 1H NMR analysis of the crude
d
e
product. 4g was obtained in 19% yield. The isolated product was
f
1
contaminated with a trace of unidentified material. 76% H NMR
yield. The product was significantly decomposed during silica gel
chromatography.
yield and stereoselectivity were made by decreasing the reaction
temperature to room temperature, giving 3m in 89% yield with
an anti/syn ratio as high as 96:4 (entry 3). Thus, the reactions
of other β-alkyl-substituted alkynoates were conducted with
PMe3 (10 mol %) at room temperature (entries 4−9). The
reaction of the alkynoate (2n, o) having a Me or cyclopropyl
group at the β-position also proceeded with high anti
selectivities (entries 4 and 5). However, the alkynoate 2p
having a cyclohexyl group at the β-position reacted with poor
stereoselectivity (entry 6). Although the decomposition of
substrate 2q was observed in the reaction conditions, the
hydroboration product 3q was obtained in moderate yield
(entry 7). Alkynoates (2r, s) having THP or TBDMS ether
moieties at the terminal of the aliphatic chain were compatible
with the anti-hydroboration (entries 8 and 9). β-Silylated
alkynoates were also examined, but did not give reasonable
product yields under tested conditions (data not shown).
Applicability of the phosphine-catalyzed anti-hydroboration
was not limited to reactions with the alkynoates, but could be
extended to alkynylamides or 2-alkynylazoles (Table 4).9
Notably, the previous phosphine-catalyzed carboboration,
silaboration, and diboration were limited to the use of
alkynoates as alkynic substrates.8 The reaction of N,N-
dimethylamide (5a) or N-methyl-N-phenylamide (5b) with a
PBu3 catalyst furnished the corresponding β-borylacrylamides
with complete anti selectivity (entries 1 and 2). In this case,
MeCN was the appropriate solvent, instead of THF in terms of
Results with β-alkyl-substituted alkynoates are summarized in
Table 3. The reaction of 2-pentynoate (2m) under the
conditions optimized for 2a (eq 1: 10 mol % PBu3, THF, 60
°C) occurred with only moderate anti selectivity (anti/syn
71:29) (entry 1). The use of PMe3 instead of PBu3 improved
the anti selectivity to 89% (entry 2). Further improvement in
B
DOI: 10.1021/acs.orglett.8b00390
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Table 3. Anti-Hydroboration of β-Alkyl-Substituted
Alkynoates
Table 4. Anti-Hydroboration of Alkynylamides or 2-
Alkynylazoles
a
a
a
Reactions were carried out with 1 (0.3 mmol), 2 (0.3 mmol), and
PMe3 (10 mol %) in THF at 25 °C for 12 h unless otherwise noted.
a
b
c
1
Entries 1 and 2: Reactions were carried out with 1 (0.3 mmol), 5 (0.3
mmol), and PBu3 (2.5 mol %) in MeCN at 60 °C for 12 h. Entries 3−
6: Reactions were carried out with 1 (0.3 mmol), 7 (0.3 mmol), and
Yield of the isolated product. Determined by H NMR analysis of
d
f
g
the crude product. 60 °C, 4 h. 1 (0.45 mmol) was used. 24 h.
b
PMe3 (20 mol %) in MeCN at 60 °C for 24 h. Yield of the isolated
product. Determined by H NMR analysis of the crude product.
c
1
the product yield. The 11B NMR spectra of 6a and 6b indicated
carbonyl-to-boron coordination. However, employing the
alkynes having primary and secondary amides resulted in low
conversions (data not shown).
The reaction of 2-alkynylbenzoxazole (7a) with 1 in the
presence of PMe3 (10 mol %) in MeCN at 60 °C proceeded
efficiently over 24 h, giving the corresponding alkenylboronate
8a with the exceptional anti selectivity (entry 3). PMe3 was
better than PBu3 as a catalyst in terms of the product yield. The
boron atom of 8a has no interaction with the azole nitrogen, as
indicated by 11B NMR spectroscopy. Benzothiazole, benzoimi-
dazole, and pyrimidine were also tolerated as azole groups in
the PMe3-catalyzed reaction (entries 4−6).
A possible catalytic cycle for the hydroboration is illustrated
in Figure 1. As proposed for the phosphine-catalyzed
carboboration, silaboration, and diboration of alkynoates,8 the
catalytic cycle begins with the conjugate addition of the
phosphine to the electron-deficient alkyne with the assistance
of Lewis acidic activation of the carbonyl or azole groups by 1
through coordination with the oxygen or nitrogen atoms,
respectively, to form a zwitterionic intermediate (A). The
hydride in A migrates to the sp-hybridized central carbon of the
allene moiety to form ylide intermediates (B1/B2). Next, the
ylide carbon of B2 attacks the proximal B atom to form cyclic
borate C1. Finally, elimination of the phosphine associated with
B−X cleavage affords the hydroboration product. The B−X
interaction in C1 and the concerted nature of the final
elimination step is responsible for the anti stereochemistry of
the hydroboration.
Figure 1. A possible catalytic cycle.
The minor occurrence of syn-hydroboration with bulky
phosphines, such as PPhMe2, PPh2Me, and PCy3 suggests that
the B−X interaction in C1 becomes less favorable due to the
steric repulsion between the phosphine and the pinacol moiety
(see Table 1).10 As a result, a nonselective elimination reaction
of C2 affords anti/syn mixtures.11 Based on this consideration,
the reduced antiselectivity with the β-alkyl substituent in the
alkynoate in comparison with the β-aryl substituent may be due
to reduced Lewis acidity of the boron atom (see Table 3). This
consideration is consistent with the better anti-selectivity with
C
DOI: 10.1021/acs.orglett.8b00390
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
the less electron-donating β-cyclopropyl substituent (Table 3,
entry 5).
handle pinacolborane to produce 1,2-disubstituted (E)-
alkenylboronates. The H−B bond addition across the polar
C−C triple bond occurred with inverse electronic demand with
regard to the regioselectivity, with the intrinsically electrophilic
B atom being delivered to the positively charged β carbon
atom. The alkenylboronate derivatives underwent various
molecular transformations, such as protodeborylation, Suzu-
ki−Miyaura coupling, conjugate reduction, and intramolecular
Diels−Alder reactions. Thus, the phosphine-catalyzed protocol
allows straightforward and efficient synthesis of 1,2-disubsti-
tuted (E)-alkenylboronates, which are versatile building blocks
for organic synthesis.
The (E)-alkenylboronates obtained by the phosphine-
catalyzed anti-hydroboration was used to demonstrate their
synthetic utility (eqs 2−4). For example, protodeborylation of
β-boryl acrylate 3a with AgF gave (E)-ethyl cinnamate (4a) (eq
2).5a
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.8b00390.
Experimental details and characterization data for all new
compounds (PDF)
In contrast to the inertness of the 9-BBN-type-β-boryl
acrylate obtained by the phosphine-catalyzed anti-carbobora-
tion toward Suzuki−Miyaura coupling,8 the organoboronate 3a
underwent Pd-catalyzed coupling with 4-bromoanisole to afford
β-diaryl acrylate 9a in excellent yield and Z-selectivity.
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: ohmiya@p.kanazawa-u.ac.jp.
*E-mail: sawamura@sci.hokudai.ac.jp.
Next, conjugate reduction of 3a with poly(methylhydro-
siloxane) (PMHS) to prepare an secondary alkylboronate was
investigated (eq 4). As a result, N-heterocyclic carbene (NHC)
ligand IPr was effective for conjugate reduction of 3a, in
accordance with our earlier findings on the copper-catalyzed
conjugate reduction of β,β-diboryl acrylates with PMHS.12
The anti-hydroboration of alkynoates and subsequent
intramolecular Diels−Alder reaction allowed the stereoselective
synthesis of trans-fused bicyclic γ-lactone derivatives with a
tertiary alkylboronate moiety (eqs 5−7).13 For example, the
ORCID
Hirohisa Ohmiya: 0000-0002-1374-1137
Masaya Sawamura: 0000-0002-8770-2982
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by Grants-in-Aid for Scientific
Research (B) (No. 15H03803), JSPS, to H.O., and by CREST,
JST, to M.S. Additionally, K.N. thanks JSPS for scholarship
support.
REFERENCES
■
(1) For pioneering works on hydroboration of alkynes, see:
(a) Brown, H. C.; Zweifel, G. J. Am. Chem. Soc. 1961, 83, 3834.
(b) Brown, H. C.; Gupta, S. K. J. Am. Chem. Soc. 1972, 94, 4370.
(c) Plamondon, J.; Snow, J. T.; Zweifel, G. Organometal. Chem. Syn.
1971, 1, 249. (d) Tucker, C. E.; Davidson, J.; Knochel, P. J. Org. Chem.
1992, 57, 3482.
(2) For reviews on hydroboration of alkynes, see: (a) Beletskaya, I.;
Pelter, A. Tetrahedron 1997, 53, 4957. (b) Trost, B. M.; Ball, Z. T.
Synthesis 2005, 2005, 853. (c) Barbeyron, R.; Benedetti, E.; Cossy, J.;
Vasseur, J.; Arseniyadis, S.; Smietana, M. Tetrahedron 2014, 70, 8431.
(3) For transition-metal-catalyzed hydroboration of terminal alkynes
to prepare (Z)-alkenylboron compounds (formal anti-hydroboration),
see: (a) Ohmura, T.; Yamamoto, Y.; Miyaura, N. J. Am. Chem. Soc.
2000, 122, 4990. (b) Gunanathan, C.; Holscher, M. M.; Pan, F.;
̈
Leitner, W. J. Am. Chem. Soc. 2012, 134, 14349. (c) Cid, J.; Carbo,
́
J. J.;
alkynoate 3t bearing a diene moiety underwent anti-hydro-
boration. The succeeding intramolecular Diels−Alder reaction
produced bicyclic lactone 11t with excellent exo-selectivity (eq
5). The protocol was also applicable to the stereoselective
synthesis of the 2,3-fused furan or indole derivatives (11u, v)
(eqs 6 and 7).
In summary, we have developed phosphine-catalyzed
regioselective anti-hydroboration of internal alkynes, including
alkynoates, alkynylamides, and 2-alkynylazoles with easy-to-
Fernandez, E. Chem. - Eur. J. 2012, 18, 1512. (d) Obligacion, J. V.;
Neely, J. M.; Yazdani, A. N.; Pappas, I.; Chirik, P. J. J. Am. Chem. Soc.
2015, 137, 5855.
́
(4) For catalytic anti-hydroboration of terminal alkynes, see: (a) Jang,
W. J.; Lee, W. L.; Moon, J. H.; Lee, J. Y.; Yun, J. Org. Lett. 2016, 18,
1390. (b) McGough, J. S.; Butler, S. M.; Cade, I. A.; Ingleson, M. J.
Chem. Sci. 2016, 7, 3384.
(5) (a) Sundararaju, B.; Furstner, A. Angew. Chem., Int. Ed. 2013, 52,
̈
14050. (b) Wang, Q.; Motika, S. E.; Akhmedov, N. G.; Petersen, J. L.;
D
DOI: 10.1021/acs.orglett.8b00390
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
Shi, X. Angew. Chem., Int. Ed. 2014, 53, 5418. (c) Xu, S.; Zhang, Y.; Li,
Bo.; Liu, S.-Y. J. Am. Chem. Soc. 2016, 138, 14566. (d) Yuan, K.;
Suzuki, N.; Mellerup, S. K.; Wang, X.; Yamaguchi, S.; Wang, S. Org.
Lett. 2016, 18, 720.
(6) For organocatalytic syn-hydroboration of alkynes, see: (a) Wen,
K.; Chen, J.; Gao, F.; Bhadury, P. S.; Fan, E.; Sun, Z. Org. Biomol.
Chem. 2013, 11, 6350. (b) Ho, H. E.; Asao, N.; Yamamoto, Y.; Jin, T.
Org. Lett. 2014, 16, 4670.
(7) For Cu-catalyzed syn-hydroboration of alkynoates, see:
̌
̌
(a) Lipshutz, B. H.; Boskovic, Z. V.; Aue, D. H. Angew. Chem., Int.
Ed. 2008, 47, 10183. (b) Semba, K.; Fujihara, T.; Terao, J.; Tsuji, Y.
Chem. - Eur. J. 2012, 18, 4179. (c) Lee, J.-E.; Kwon, J.; Yun, J. Chem.
Commun. 2008, 733.
(8) (a) Nagao, K.; Ohmiya, H.; Sawamura, M. J. Am. Chem. Soc.
2014, 136, 10605. (b) Nagao, K.; Ohmiya, H.; Sawamura, M. Org. Lett.
2015, 17, 1304. (c) Yamazaki, A.; Nagao, K.; Ohmiya, H.; Sawamura,
M. Angew. Chem., Int. Ed. 2018, DOI: 10.1002/anie.201712351.
(9) As alkynic substrates, the corresponding conjugated aldehydes
and ketones showed no reactivity under similar conditions. The
reaction of propiolate afforded a complex mixture with no hydro-
boration product.
(10) The subjection of isomerically pure anti-3m or syn-3m to the
standard reaction conditions resulted in no reaction.
(11) Ohmura, T.; Morimasa, Y.; Suginome, M. Chem. Lett. 2017, 46,
1793.
(12) Morinaga, A.; Nagao, K.; Ohmiya, H.; Sawamura, M. Angew.
Chem., Int. Ed. 2015, 54, 15859.
(13) (a) Lorvelec, G.; Vaultier, M. Tetrahedron Lett. 1998, 39, 5185.
(b) Hilt, G.; Bolze, P. Synthesis 2005, 2005, 2091.
E
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