Chemo-, regio-, and stereoselective hydroboration of conjugated enyne alcohol/amine: Facile synthesis of Z,Z-/Z,E-1,3-dien-1/2-ylboronic ester bearing hydroxyl/amino group

Article abstract of DOI:10.1016/j.tetlet.2016.05.075

Hydroboration of conjugated enyne alcohol/amine is studied by using copper salts and bis(pinacolato)diboron as pre-catalysts and boron source respectively. It is suggested that the chemo-selectivity is derived from a combined electronic influence of the heteroatoms on the substrate and the ligand on the transition metal. The regioselectivity is probably dominated mainly by electronic effect of the alkyne substituent. This study resulted in a highly selective protocol to access Z,Z-/Z,E-1,3-dien-1/2-ylboronic ester bearing hydroxyl/amino group.

Full text of DOI:10.1016/j.tetlet.2016.05.075

Tetrahedron Letters 57 (2016) 2915–2918
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Chemo-, regio-, and stereoselective hydroboration of conjugated
enyne alcohol/amine: facile synthesis of Z,Z-/Z,E-1,3-dien-1/2-
ylboronic ester bearing hydroxyl/amino group
⇑
⇑
Hua-Dong Xu , Hao Wu, Chun Jiang, Peng Chen, Mei-Hua Shen
School of Pharmaceutical Engineering and Life Science, Changzhou University, Changzhou, Jiangsu Province 213164, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Hydroboration of conjugated enyne alcohol/amine is studied by using copper salts and bis(pinacolato)di-
boron as pre-catalysts and boron source respectively. It is suggested that the chemo-selectivity is derived
from a combined electronic influence of the heteroatoms on the substrate and the ligand on the transition
metal. The regioselectivity is probably dominated mainly by electronic effect of the alkyne substituent.
This study resulted in a highly selective protocol to access Z,Z-/Z,E-1,3-dien-1/2-ylboronic ester bearing
hydroxyl/amino group.
Received 22 March 2016
Revised 19 May 2016
Accepted 20 May 2016
Available online 20 May 2016
Keywords:
1,3-Enyne
Ó 2016 Elsevier Ltd. All rights reserved.
Hydroboration
Dienyl boronic ester
Borylcopper
Bis(pinacolato)diboron
H
H
In early 2001, Miyaura group reported the synthesis of pinB-Cu
species via the reaction of bis(pinacolato)diboron [B2(pin)2] with
CuCl in the presence of a base, and its C–B bond forming ability
during the course of addition to enones and alkynes C–C bonds.1,2
Following this seminal discovery, various pinBCu catalyzed
hydroboration of unsaturated systems (alkene, alkyne, 1,3-diene
etc.) have been developed using B2(pin)2 as boron source, giving
rise to highly desired organoboron compounds.3–11 One appealing
aspect of these reactions is that the good to excellent chemo-,
regio-, and stereoselectivity could be achieved through steric and
electronic adjustment of substrate substitution and metal
ligand.12–28 Hydroboration of 1,3-enyne is a relatively less studied
case in comparison with hydroboration of alkene and alkyne, and
could theoretically deliver six hydroboration isomers of three addi-
tion models (Fig. 1). Ito group achieved a ligand controlled diver-
gent hydroboration of dialkyl enyne 1 (R2–R4: 2 H, 1 alkyl group)
providing vinyl boronic ester 2 and homopropargyl boronic ester
3 (Scheme 1, top).29 Hoveyda group coupled aromatic enyne 4,
bearing the terminal alkene moiety, with aldehyde 5 to give homo-
propargyl alcohol 6 which was formed through chemo- and site-
selective 1,2-borocuperation followed by addition to aldehyde 5
(Scheme 1, bottom).30
H
Bpin
H
•
Bpin
H
Bpin
C
2
B
D
3
(pin)2B2
Cu*
1
4
Bpin
Bpin
A
Bpin
•
H
B'
D'
C'
3,4-addition
1,2-addition
1,4-addition
Figure 1. Six possible hydroboration products of 1,3-enyne.
R1 R2
CuOtBu
PPh3
CuOtBu
xantphos
R2
R2
R3
R3
R3
Bpin
R4
Bpin
B2(pin)2
MeOH
B2(pin)2
MeOH
H
R4
R1
R4
R1
1
2
3
R
OH
OH
R
OH
Bpin
CuCl, ligand
NaOtBu
NaBO3
Ar
4
Ar
+
B2(pin)2
RCHO
7
Ar
6
5
Scheme 1. Selective hydroboration of simple 1,3-enynes.
We set out to study the hydroboration of internal enynes carry-
ing proximal hydroxyl and amino groups (1) to probe the effect of
their coordination feature on hydroboration selectivity; and (2) to
⇑
Corresponding authors.
E-mail addresses: hdxu@cczu.edu.cn (H.-D. Xu), shenmh@cczu.edu.cn
(M.-H. Shen).
http://dx.doi.org/10.1016/j.tetlet.2016.05.075
0040-4039/Ó 2016 Elsevier Ltd. All rights reserved.

2916
H.-D. Xu et al. / Tetrahedron Letters 57 (2016) 2915–2918
Table 1
Ligand and copper source exploration for enyne alcohol hydroborationa
Me
Cu* (10 mol%)
ligand (20 mol%)
NaOtBu (15 mol%)
OH
Bpin
Me
OH
9a
H
B2(pin)2
+
Me
toluene
8a
H
OH
Bpin 9a'
c
Entry
Ligand
Cu⁄
Yieldb (%)
9/90
1
2
3
4
5
6
7
8
PPh3
XantPhos
dppf
—
CuCl
CuCl
CuCl
CuSIMesCl
CuIMesCl
CuCl
CuCl
CuBr
61
Complex
37
92
80
2.1:1
nd
nd
1.8:1
3.2:1
2/1
>98:2
>98:2
nd
—
SPhos
PCy3
PCy3
PCy3
PCy3
—
85
90
85
9
10
11
CuI
Cu(acac)2
CuCl
40d
88
2.3/1
nd
44
PPh2
PPh2
PCy2
OMe
N
N
Fe
MeO
O
PPh2
PPh2
IMes: imidazole NHC
SIMes: imidazoline NHC
Xantphos
DPPF
Sphos
a
b
c
Conditions: 0.2 mmol 8a, 0.24 mmol, B2(pin)2, CuXn (0.02 mmol), ligand (0.02 mmol), NaOtBu (0.03 mmol), toluene (2 mL), rt, 14 h.
isolated yield.
Determined by 1H NMR.
50% conversion.
d
Table 2
Substrate scope for hydroboration of enyne alcohola
CuCl
PCy3
R
OH
( )n
OH
( )n
+
R
OH
( )n
H
Bpin
+
NaOtBu
toluene
B2(pin)2
9'
Bpin
R
H
8
9
Entry
1
Substrate
Product yieldb
Entry
Substrate
Product yieldb (ratio of 9/90)c
OH
H
OMOM
OMOM
BnO
Bpin
OH
8i
Me
( )4
OH
8
( )4
OBn
8b
8c
8d
9b, 89%
9c, 75%
Me
Bpin
9i, 70%
OH
OH
OH
H
H
Bpin
Bpin
OH
OH
OH
OH
OH
Bpin
8j
9j/9j'
, 62%
(5/1)
2
3
9
OH
Bpin
8k
10
9k/9k', 51%
(3/1)
9d
, 93%
OH
H
H
OH
OH
OH
Bpin
H
Bpin
Me
( )5
OH
8l
4
5
11
12
( )5
8e
9e, 85%
9l, 84%
OH
Bpin
OH
( )3
H
OH
Bpin
( )3
9m, 96%
( )5
( )5
8m
8f
9f', 80%
Me
OH
OH
Bpin
OH
H
Bn
8g
Bpin
Bn
OH
6
7
13
14
9n/9n'd
(1/5)
, 87%
9g
, 87%
OH
8n
OH
MeO
O
OMe
Bpin
OH
H
BnO
8h
Bpin
BnO
OH
9o/9o'
(1/ 8)
, 91%
O
8o
9h
, 68%
a
b
c
Conditions: 0.2 mmol 8, B2(pin)2 (0.24 mmol), CuCl (0.02 mmol), PCy3 (0.02 mmol), NaOtBu (0.03 mmol), toluene (2 mL), rt, 14 h.
Isolated yield.
Determined by 1H NMR.
d
Structures were determined by the product of Suzuki coupling reaction with PhI (see SI Scheme 8).

H.-D. Xu et al. / Tetrahedron Letters 57 (2016) 2915–2918
2917
Table 3
Substrate scope for hydroboration of amino enynea
CuCl
NR1R2
R
NR1R2
NR1R2
B2(pin)2
R
PCy3
NaOtBu
toluene
Bpin
H
+
+
H
Bpin
11'
R
10
11
Entry
1
Substrate
Product yieldb (ratio)
Entry
7
Substrate
Product yieldb (ratio)c
NHTs
NHTs
H
NHBn
H
Bpin
Bpin
Me
NHBn
11g, 53%d
Bn
NHTs
( )5
( )5
10g
10h
10a
10b
Bn
11a, 92%
H
NBn2
H
Bpin
NBn2
d
Bpin
2
3
4
8
Ph
NHTs
( )5
( )5
3
Me
11h
Ph
, 90%
11b, 93%
1
NHTs
H
NHTs
10i
Bpin
NHTs
Bpin
9
Ph
11i/11i'
, 70%
(1/1.2)
( )5
11c, 79%
NHTs
Ph
( )5
10c
Me
NHTs
H
NHTs
Bpin
NHTs
, 70%
Bpin
BnO
10
p-ClPh
BnO
11j/11j'
(1/2.3)
10j
10d
NHTs
p-ClPh
11d, 81%
NHTs
H
NHTs
Bpin
p-MeOPh
NHTs
OMOM
OPiv
Bpin
5
6
11
11k/11k', 68%
NHTs
11e, 90%
NHTs
p-MeOPh
10k
10e
PivO
(1/4.3)
MOMO
NHTs
H
Bpin
11f/11f', 60%
(3.3/1)
10f
a
b
c
Conditions: 0.2 mmol 10, B2(pin)2 (0.24 mmol), CuCl (0.02 mmol), PCy3 (0.02 mmol), NaOtBu (0.03 mmol), toluene (2 mL), rt, 14 h.
Isolated yield.
Determined by 1H NMR.
MeOH (0.3 mmol) was needed.
d
Table 4
Reducing catalyst loading for hydroborationa
much lower yield of 37% was obtained when another phosphine
based bidentate ligand dppf was used (entry 3). NHC ligated pre-
catalysts CuSIMesCl and CuIMesCl could promote the yields of 9a
up to 92%, whereas only modest regioselectivity was observed
for these reactions (entries 4 and 5). Then we came back to mon-
odentate phosphine ligands. With bulky Sphos, a 2/1 mixture (via
NMR) of 9a and 9a0 was isolated in 85% yield (entry 6). To our
delight, both high yield (90%) and excellent selectivity (>98/2)
were achieved by using electron rich PCy3 as ligand (entry 7). With
this optimal ligand, different copper sources were examined as
well. While CuBr provided comparable results, CuI showed signif-
icantly decreased catalytic efficiency since only 50% conversion
of the starting enyne was accomplished in the same time scale
(entries 7, 8 vs 9). Interestingly, when Cu(acac)2 was used as cop-
per source, a high yield accompanied with a low regioselectivity
was observed, indicating that the acac anion ligand might involve
in the copper promoted B–C coupling event (entry 10).
Noteworthy, without an external ligand, CuCl catalyzed the reac-
tion to give only 44% yield (entry 11). Data shown above make it
clear that not only the ligand plays a pivotal role on the yield
and regioselectivity, but also the copper source is important to
achieve good outcome.
OH
Me
standard conditions
toluene
Bpin
OH
(pin)2B2
+
9a
H
Me
8a
Entry
CuCl (mol %)
Cy3P (mol %)
NaOtBu (mol %)
Yieldb (%)
1
2
3
5
2
1
5
4
2
10
4
2
90
92
89
a
Conditions: 0.2 mmol scale.
Isolated yield.
b
develop methods accessing multi-functionalized boronic esters
which, formed with any addition model, would be valuable build-
ing blocks in synthesis. First, enyne 8a was chosen as the substrate
for initial studies. Thus, a mixture of 8a and B2(pin)2 in toluene was
treated with 15 mol % NaOtBu and 10 mol % ligand chelated CuX at
room temperature for 12 h. Selected examples are listed in Table 1.
With PPh3 as ligand and CuCl2 as precatalyst, a 2/1 inseparable
mixture (by 1H NMR) of (E,E)-1,3-dien-1-ylboronic ester 9a and
(E,E)-1,3-dien-2-ylboronic ester 9a0 was collected in 61% combined
yield without the detection of products derived from alkene
hydroboration (entry 1). With bidentate ligand XantPhos, a ligand
that rendered 1,2-hydroboration of enyne 1 at alkene group in Ito’s
study (Scheme 1), the related reaction of 8a with B2(pin)2 gave rise
to a complex mixture in the current system (entry 2). This diver-
gence at chemoselectivity (alkyne hydroboration vs alkene
hydroboration) between enyne 8a and simple aliphatic enyne did
evidence the crucial effect of a hydroxyl group on the reaction. A
At this stage we set the conditions used for entry 7 in Table 1 as
the standard condition to explore substrate scope for this hydrob-
oration of conjugated enyne carrying hydroxyl group (Table 2).
Alkyl substituted enynes 8b–8e all underwent hydroboration to
give corresponding 1,3-dienylboronic esters 9b–9e solely in high
yields, excellent chemo- and regioselectivities (entries 1–4).
Complete inversion in regioselectivity occurred to the reaction of
enyne 8f which has a steric demanding tert-butyl group substi-

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H.-D. Xu et al. / Tetrahedron Letters 57 (2016) 2915–2918
tuted at the alkyne terminus (entry 5). When it was subjected to
the identical reaction conditions, 1,3-dien-2-yl boronic ester 9f0
was collected free from its regioisomer 1,3-dienylboronic ester in
80% isolated yield. Z-Enyne alcohol with benzyl, ether, or acetal
group at the alkyne termini such as 8g, 8h, and 8i were also excel-
lent substrates for this reaction, and therefore, E,Z-1,3-dienyl-
boronic esters were prepared conveniently (entries 6–8). Even
though the latter two afforded a slight drop-off in yields, the
regioselectivities remained very high. These examples also implied
that the oxygen coordination, if exists, unlikely has any effect on
the C–B bond formation event. Interestingly, the parent enyne 8j
(without substituent at alkyne terminus) gave modest yield and
selectivity (entry 9). Hydroboration of analogous terminal enyne
8k bearing a homoallylic hydroxyl group gave similar results
(entry 10: 51% yield, 3/1 selectivity). Both high levels of yield
and selectivity regained when alkyl substituents were incorpo-
rated on the alkynyl terminus as demonstrated by exclusive isola-
tion of 9l and 9m in 84% and 96% yield respectively (entries 11 and
12). Aryl substituted enynes 8n and 8o reacted smoothly at the
alkyne moiety as well under these conditions, while opposite regio
preference for the hydroboration was obtained (entries 13 and 14).
This contrast in regio-selectivity presumably reflects the different
electronic properties between alkyl and aryl substituents, namely
with an aryl group on the alkyne end, the formation of an extended
conjugate system in the cis-borylcuperation intermediate is
believed to be the origin for selectivity switch.
hetero atoms on the reaction is not strongly supported. The
chemo-selectivity is derived presumably from a combined elec-
tronic influence of the heteroatoms on the substrate and the ligand
on the transition metal. The regioselectivity is probably dominated
mainly by electronic effect of the alkyne substituent, except in an
extreme case like 8f, where it is determined by steric effect solely.
Acknowledgments
The authors wish to thank the Natural Science Foundation of
China (21402014 and 21272077), the Natural Science Foundation
of Jiangsu Province (BK20131143), the Priority Academic Program
Development of Jiangsu Higher Education Institutions (PADA),
and Jiangsu Key Laboratory of Advanced Catalytic Materials and
Technology (BM2012110).
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2016.05.
075.
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