Copper-catalyzed highly regio- and stereoselective directed hydroboration of unsymmetrical internal alkynes: Controlling regioselectivity by choice of catalytic species

Article abstract of DOI:10.1002/chem.201103612

A highly selective synthesis of the αand β products by copper-catalyzed hydroboration utilizing two different catalytic copper species generated from pinacolborane (HBpin) and B²pin² is reported. Regioselectivity in the crude reaction mixtures is found to be high, and the corresponding a products were isolated in good yields. In the case of an alkyne containing an alkenyl moiety, the regioselectivity decreased to 72:28. In hydroboration reactions catalyzed by other transition metals, selecting between hydrometalation and boryl metalation is difficult because the oxidative addition of HB to a metal center provides an H-M-B species, containing both H-M and B-M bonds. The α and β products are valuable intermediates used in the Suzuki-Miyaura cross-coupling reaction to regioselectively prepare various trisubstituted alkenes of types 5α and 5β.

Full text of DOI:10.1002/chem.201103612

COMMUNICATION
DOI: 10.1002/chem.201103612
Copper-Catalyzed Highly Regio- and Stereoselective Directed
Hydroboration of Unsymmetrical Internal Alkynes: Controlling
Regioselectivity by Choice of Catalytic Species
Kazuhiko Semba, Tetsuaki Fujihara, Jun Terao, and Yasushi Tsuji*[a]
Hydroboration is
a robust
and practical method for the
synthesis of organoboranes.[1] In
particular, hydroboration of al-
kynes is of interest because the
products (vinylboranes) are
potent intermediates in the
Suzuki–Miyaura cross-coupling
reaction[2] and other useful
transformations.[3,4] It is known
that the hydroboration of ter-
minal alkynes proceeds regio-
and stereoselectively.[5] Howev-
er, the reaction of unsymmetrical internal alkynes often suf-
fers from low regioselectivity, even in the presence of a cata-
lyst.[6] Generally, bulky boryl moieties are added at the less
bulky site in both uncatalyzed and catalyzed hydroboration
reactions. For example, the hydroboration of alkylphenyl-
acetylenes tends to produce b-boryl styrene derivatives
(b products).[7] Bis(pinacolato)diboron (B2pin2) can also be
used as a borane source to afford the same b products.[8]
However, a general method for synthesizing the a products
(regioisomers of the b products) has not been reported. To
date, only acetylenic esters have led to the a products.[9]
Herein, we report a highly selective syntheses of the
a and b products by copper-catalyzed hydroboration utiliz-
Scheme 1.
Table 1. Copper-catalyzed hydroboration of 1a with pinacolborane
(HBpin) by using various catalysts.[a]
Entry
Ligand
Yield [%][b]
2aa/2ab
1
2
none[c]
PPh3
0
0
–
–
3
PCy3
5
–
4
5
DPPE
DPPP
trace
–
–
1
6
7
rac-BINAP
BDP
trace
–
–
1
[9,10]
À
ing two different catalytic copper species (Cu H
and
8
9
Xan
13
89
92
95:5
88:12
94:6
95:5
90:10
90:10
–
[11]
À
Cu B
)
generated from pinacolborane (HBpin) and
CF3Ar-Xan
MeAr-Xan
MeAr-Xan
IPr
B2pin2, respectively (Scheme 1). Regioselectivity was suc-
cessfully controlled through hydrocupration and borylcupra-
tion as a result of the directing effect of group G.[12,13]
10
11[d]
12
13
14
15
16
17
97 (97)[e]
89
88
0
4
9
ClIPr
AHCTUNGTRENNUNG
Firstly, the hydroboration of 1-phenyl-1-hexyne (1a) was
carried out by using HBpin at 288C with a copper catalyst
system (CuCl/tBuONa). No reaction occurred without a cat-
alyst (Table 1, entry 1). The use of monodentate phosphanes,
[f]
–
T
E
21:79
54:46
A
R
65
[14]
such as PPh3 and PCy3 (Cy=cyclohexyl; Table 1, entries 2
[a] 1a (0.50 mmol), HBpin (0.60 mmol), CuCl (0.010 mmol, 2.0 mol%),
a ligand (0.010 mmol, 2.0 mol%), tBuONa (0.060 mmol, 12 mol%), tolu-
ene (1.0 mL), at 288C, for 20 h. [b] Total yield of 2aa and 2ab based on
the GC internal-standard technique. [c] This reaction was performed
without CuCl, ligand, and tBuONa. [d] This reaction was performed at
208C and with 0.75 mmol of HBpin. [e] Isolated yield. [f] [{(PPh3)CuH}6]
(0.011 mmol, 2.1 mol%), PPh3 (0.010 mmol, 2.0 mol%), HBpin
(0.55 mmol), THF (0.50 mL). [g] CuCl (0.010 mmol, 2.0 mol%), BDP
(0.0050 mmol, 1.0 mol%), tBuOK (0.030 mmol, 6.0 mol%), HBpin
and 3), or bidentate phosphanes, such as 1,2-bis(diphenyl-
[a] K. Semba, Prof. Dr. T. Fujihara, Prof. Dr. J. Terao, Prof. Dr. Y. Tsuji
Department of Energy and Hydrocarbon Chemistry
Graduate School of Engineering, Kyoto University
Kyoto 615-8510 (Japan)
Fax : (+81)75-383-2514
E-mail: ytsuji@scl.kyoto-u.ac.jp
(0.55 mmol), THF (0.50 mL). [h] [RhCl
was used as the catalyst. [i] [{IrCl(COD)}2] (0.0050 mmol, 2.0 mol%) and
DPPM (P/Ir=2:1) were used as the catalyst.
ACHTUNGTREN(NNUG PPh3)3] (0.010 mmol, 2.0 mol%)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201103612.
ACHTUNGTRENNUNG
Chem. Eur. J. 2012, 18, 4179 – 4184
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4179

Table 2. Copper-catalyzed hydroboration of various alkynes to the a prod-
phosphino)ethane (DPPE), 1,3-bis(diphenylphosphino)pro-
pane (DPPP), rac-2,2’-bis(diphenylphosphino)-1,1’-binaph-
thyl (rac-BINAP), and 1,2-bis(diphenylphosphino)benzene
(BDP;[14] Table 1, entries 4–7), led to almost no product. On
the other hand, 4,5-bis(diphenylphosphino)-9,9-dimethylxan-
thene (Xantphos,[14] Xan; Figure 1) afforded the product in
ucts with HBpin.[a]
1, 2ba
2, 2ca
74% (>99:1)
3, 2da
94% (98:2)
4, 2ea
78% (100:0)
78% (93:7)[d]
Figure 1. Structures of the ligands.
5, 2 fa
6[e], 2ga
7[f,g], 2ha
8, 2ia
72% (>99:1)
90% (100:0)
94% (100:0)
88% (97:3)
13% yield with high regioselectivity: 2aa/2ab=95:5
(Table 1, entry 8). The use of the Xantphos derivative bear-
ing two 3,5-(trifluoromethyl)phenyl moieties (CF3Ar-Xan;[15]
Figure 1) led to the yield being dramatically improved to
89%, although with a somewhat lower regioselectivity was
obtained (2aa/2ab=88:12, Table 1, entry 9). Gratifyingly,
MeAr-Xan,[16] bearing 3,5-xylyl moieties, was highly effec-
tive as the ligand, giving the products in 92% total yield
with high regioselectivity (2aa/2ab=94:6, Table 1,
entry 10). Reducing the temperature to 208C improved both
the yield and the regioselectivity (Table 1, entry 11). As
ligands, N-heterocyclic carbenes (NHCs),[17] such as
1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene (IPr) and
1,3-bis(2,6-diisopropylphenyl)-4,5-dichloroimidazol-2-ylidene
(ClIPr;[10a] Figure 1), could also be used, albeit with slightly
lower efficiencies (Table 1, entries 12 and 13). The use of
the [{(PPh3)CuH}6]/PPh3 or CuCl/BDP/tBuOK systems,[9]
which are effective catalytic systems for the hydroboration
of acetylenic esters, yielded the products in only 0 and 4%
yields, respectively (Table 1, entries 14 and 15). Other transi-
9[h], 2ja
86% (97:3)
10[f,i], 2ka
92% (100:0;
Z/E=98:2)
11[j], 2la
12[l], 2ma
82% (100:0)
62%[k] (72:28)
13[h], 2na
96% (100:0)
14[m,n] (R=Bn),
2oa
16[m,o], 2qa
76% (>99:1)
17[m,p], 2ra
68%[k] (63:37)
73%[k] (92:8)
15[m,n] (R=THP),
2pa
64%[k] (93:7)
[a] Alkyne (0.50 mmol), HBpin (0.75 mmol), CuCl (0.010 mmol, 2.0 mol%),
MeAr-Xan (0.010 mmol, 2.0 mol%), tBuONa (0.060 mmol, 12 mol%), tolu-
ene (1.0 mL), at 208C, for 20 h. [b] Isolated yield. [c] Ratio of 2a/2b in the
crude reaction mixture was determined by GC. [d] After purification a/b=
98:2. [e] HBpin (0.60 mmol), at 288C. [f] CuCl (0.020 mmol, 4.0 mol%),
MeAr-Xan (0.020 mmol, 4.0 mol%). [g] HBpin (1.0 mmol), at 608C.
[h] HBpin (0.60 mmol). [i] HBpin (1.0 mmol), at 508C. [j] CuCl
(0.020 mmol, 4.0 mol%), MeAr-Xan (0.020 mmol, 4.0 mol%), tBuONa
(0.12 mmol, 24 mol%), toluene (0.50 mL), at 508C. [k] Yield of the a and
b product mixture. [l] HBpin (0.60 mmol), at 08C, for 1 h. [m] CF3Ar-Xan
was used instead of MeAr-Xan. [n] Toluene (0.50 mL), at 288C. [o] 288C.
[p] Toluene (0.25 mL), at 808C.
tion-metal catalysts, such as [RhCl
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
COD=1,5-cyclooctadiene),[7b,14] have been used in the hy-
droboration of terminal alkynes, but for the reaction of 1a
these catalysts showed only low catalytic activities and poor
regioselectivities (Table 1, entries 16 and 17).[19]
The hydroboration of various internal alkynes (1b–r) to
afford the a products was carried out by using HBpin with
MeAr-Xan as the ligand (Table 2). Regioselectivity in the
crude reaction mixtures (2a/2b) was high, and the corre-
sponding a products (2a) were isolated in good yields. The
reaction of 1b gave a 2ba/2bb ratio of 93:7 and 2ba was
isolated in 78% yield (Table 2, entry 1). In non-catalytic[5b]
and Ti-catalyzed[6c] hydroborations of 1b, the selectivities of
2a/2b were 15:85 (with HBpin) and 67:33 (with catechol-
borane), respectively. Electron-donating and -withdrawing
groups on the aryl ring were tolerated, maintaining high
yields and regioselectivities (Table 2, entries 2–7). Alkynes
bearing pyridine and thiophene rings on the acetylenic
carbon atoms (1i and 1j) reacted with high regioselectivities
and the a products (2ia and 2ja) were isolated in high
yields (Table 2, entries 8 and 9). An alkyne bearing a tri-
methylsilyl group was regioselectively converted into the
boryl silyl bifunctional product (2ka) in high yield (Table 2,
entry 10). In the case of an alkyne containing an alkenyl
moiety (1l), the regioselectivity decreased to 2la/2lb=72:28
(Table 2, entry 11). On the other hand, alkynes containing
ester[9] (1m) and amide (1n) functionalities instead of aro-
matic substituents afforded the corresponding a products
(2ma and 2na) in high yields and with perfect regioselectiv-
ities (Table 2, entries 12 and 13). Furthermore, alkynes bear-
ing O and N atoms in the propargylic position (Table 2, en-
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Chem. Eur. J. 2012, 18, 4179 – 4184

Directed Hydroboration of Unsymmetrical Internal Alkynes
COMMUNICATION
tries 14–16) provided the corresponding a products (2oa–
qa) in good yields with high regioselectivities when employ-
ing CF3Ar-Xan instead of MeAr-Xan as the ligand.[20] Un-
fortunately, an alkyne bearing a homopropargyl ether func-
tionality afforded the a product in only low selectivity
(Table 2, entry 17).
In contrast, when HBpin was replaced with B2pin2/MeOH
and still by using CF3Ar-Xan as the ligand, the regioselectiv-
ity was reversed to afford mostly the b products (Table 3). It
is noteworthy that even when secondary alkyl moieties were
attached to the acetylenic carbon, regioselectivities for the
b products (2gb, 2sb, and 2tb) were still high (Table 3, en-
tries 1–3).[21] An alkyne bearing an alkenyl moiety[22] also af-
forded the product regioselectively in high yield (Table 3,
entry 4). Furthermore, alkynes bearing conjugated ester[23]
and amide functionalities also afforded the respective
b
products in high yields with high regioselectivities
Scheme 2. Stoichiometric reactions relevant to the mechanism.
(Table 3, entries 5 and 6). Remarkably, alkynes bearing O
and N atoms at the propargylic (Table 3, entries 7–10) and
even homopropargylic (Table 3, entry 11) positions provided
the corresponding b products (2ob–rb and 2ub) selectively
in good to high yields.[20,24] Such high regioselectivities have
never been observed in the hydroboration of this class of
substrates (1o–r and 1u).
To gain insight into the mechanism of the a-directed hy-
droboration by using HBpin, stoichiometric reactions were
performed with the {ClIPrCu} complex (Scheme 2), since
ClIPr is an efficient ligand in the reaction (Table 1, entry 13)
and copper complexes bearing ClIPr are rather stable.
ACTHNUTRGNEUNG
[(ClIPr)Cu(OtBu)], obtained from [(ClIPr)CuCl] and
tBuONa,[25] reacted with HBpin almost instantaneously at
1
08C. A H NMR spectrum of the resulting reaction mixture
indicated that the reaction was clean and the corresponding
copper hydride, [(ClIPr)CuH] (3H), was formed quantita-
tively, judging by the presence of the diagnostic 1H reso-
Table 3. Copper-catalyzed hydroboration of various alkynes to the
1
À
nance of the Cu H bond at 2.4 ppm, as well as other H res-
b products with B2pin2/MeOH.[a]
onances in [(ClIPr)CuH][10a] (Scheme 2a).[14] Next, 3H was
reacted with an alkyne (1v; Scheme 2b). For this reaction,
3H was prepared from [(ClIPr)CuF] and (EtO)3SiH[10a] to
avoid the further reaction of excess HBpin with the result-
ing product 4vH (see Scheme 2c). As reported previous-
ly,[10a,26] [(ClIPr)CuH] reacted with the alkyne (1v) and the
corresponding alkenyl copper complex (4vH) was isolated
in 70% yield (Scheme 2b). The complex 4vH instantane-
ously reacted with HBpin at 08C to quantitatively provide
the corresponding hydroboration product (2va) and cleanly
regenerate 3H, as confirmed by 1H NMR spectroscopy
(Scheme 2c).[14] This is the first example of the stoichiomet-
ric reaction of a borane with an alkenyl copper species. As
for the b-directed hydroboration, 1a was allowed to react
with B2pin2 in the presence of CD3OD under otherwise
identical conditions to those reported in Table S1, entry 1 in
the Supporting Information. The resultant deuterated prod-
uct ([D1]-2ab), bearing D at the a position, was obtained in
90% yield with 85% deuterium content [Eq. (1)].
1[d], 2gb
88% (>99:1;
Z/E=95:5)
2[e], 2sb
3[e], 2tb
4, 2lb
94% (99:1)
70% (92:8)[f]
76% (91:9)[f]
5[g], 2mb
90% (100:0)
6[h], 2nb
78% (97:3)
7, 2ob
74% (98:2)
8, 2pb
88% (99:1)
9[i], 2ub
74% (95:5)
10, 2qb
92% (100:0; Z/E=96:4)
11[i], 2rb
86% (91:9)[j]
[a] Alkyne (0.50 mmol), B2pin2 (0.60 mmol), MeOH (1.0 mmol), CuCl
(0.010 mmol, 2.0 mol%), CF3Ar-Xan (0.010 mmol, 2.0 mol%), tBuONa
(0.060 mmol, 12 mol%), toluene (1.0 mL), at 288C, for 3 h. [b] Isolated
yield. [c] Ratio of 2b/2a in the crude reaction mixture was determined
by GC. [d] At 508C, for 20 h. [e] For 20 h. [f] After purification b/a=
>99:1. [g] B2pin2 (0.53 mmol), for 1 h. [h] B2pin2 (0.53 mmol). [i] B2pin2
(0.75 mmol). [j] After purification b/a=90:10.
Chem. Eur. J. 2012, 18, 4179 – 4184
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4181

Y. Tsuji et al.
Based on these experimental results, possible catalytic
cycles for the Cu-catalyzed hydroboration by using HBpin
(catalytic cycle A) and B2pin2 (catalytic cycle B) are shown
lytic species in step B-1 (Y=B, Scheme 3). Indeed, Sadighi
et al. have reported that [(IPr)CuACHTUNTRGNEUNG(OtBu)] reacted readily
with B2pin2 at room temperature, forming [(IPr)CuACHTUNGTRENNUNG(Bpin)],
in Scheme 3. Firstly, [LCu
A
the X-ray structure of which has been determined.[29] The
addition of the [LCuB] species (3B) to the alkyne (boryl-
cupration;[30] step B-2) provides a (b-boryl)
ACTHNUTRGNE(NUG alkenyl)copper
intermediate (4B) with high regioselectivity owing to the
same directing effect of substituent G as was observed in
step H-2. Next, protonation of 4B with MeOH provides the
b products (2b) efficiently (step B-3). If CD3OD was used,
an a-deuterated product ([D1]-2ab) was obtained, as shown
in Equation (1). Finally, the reaction between the resulting
[LCuOMe] species and B2pin2 regenerates [LCuB] (3B),
and the catalytic cycle is closed (step B-4). Through these
mechanisms, the regioselectivity can be successfully con-
trolled in the hydrocupration or borylcupration steps
(steps H-2 or B-2, respectively) with the different catalytic
species ([LCuH], 3H, or [LCuB], 3B) in their respective
catalytic cycles. In hydroboration reactions catalyzed by
other transition metals (such as Rh and Ir), selecting be-
tween hydrometalation (Scheme 3, cycle A) and boryl met-
alation (Scheme 3, cycle B) is difficult because the oxidative
addition of HB to a metal center provides an H-M-B spe-
[1b,c,31,32]
À
À
cies, containing both H M and B M bonds.
The utility of these transformations is shown in Schemes 4
and 5. The copper-catalyzed hydroboration reactions are
amenable to gram-scale procedures with much lower cata-
Scheme 3. A possible catalytic cycle.
[LCuCl] and tBuONa.[25] As indicated by the clean stoichio-
metric reaction of [(ClIPr)Cu
(OtBu)] with HBpin
AHCTUNGTRENNUNG
(Scheme 2a), the active catalytic species in the hydrobora-
tion with HBpin must be a copper hydride ([LCuH]; 3H,
Y=H, step H-1, Scheme 3). Syn addition of 3H to al-
kynes[10a,26] (hydrocupration: step H-2) affords alkenyl
copper species (4H) with high regioselectivity owing to the
directing effect of substituent G. Finally, reaction of 4H
with HBpin affords the corresponding a product (2a) and
closes the catalytic cycle by regenerating the active catalytic
species [LCuH] (3H; step H-3). The process in step H-2 is
supported by the stoichiometric reaction depicted in
Scheme 2b and that in step H-3 was confirmed by the reac-
tion shown in Scheme 2c.
Xan derivatives were so effective as ligands for the a-bor-
ylation reactions because the bulky Xan derivatives would
suppress the aggregation of the {CuH} species. It is known
that {CuH} species are liable to aggregate, which considera-
bly decreases their reactivity.[10b,27] Furthermore, the bulky
Scheme 4.
lyst loadings. For example, with only 0.10 mol% of either
catalyst, 1.5 g of 1m was selectively converted into the cor-
responding hydroboration products 2ma and 2mb in high
yields, depending on which reagent was used (HBpin and
B2pin2; Scheme 4). The a and b products (2a and 2b) are
valuable intermediates used in the Suzuki–Miyaura cross-
coupling reaction[2] to regioselectively prepare various tri-
substituted alkenes of types 5a and 5b (Scheme 5).[33]
À
Xan ligand derivatives may accelerate the insertion of Cu
H into an alkyne; a recent paper reported that the bulky bi-
À
dentate phosphane ligand accelerates the insertion of Cu H
In conclusion, we have developed a highly regio- and ste-
reoselective, copper-catalyzed hydroboration of unsymmetri-
cal internal alkynes. The regioselectivity is controlled by
using one of two different catalytic species ([LCuH] and
into a styrene.[28]
In contrast, for the hydroboration by using B2pin2, a boryl
copper species ([LCuB]; 3B) must be generated as the cata-
4182
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ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2012, 18, 4179 – 4184

Directed Hydroboration of Unsymmetrical Internal Alkynes
COMMUNICATION
“molecular activation directed toward
straightforward
synthesis”)
from
MEXT, Japan, and in part by the Mit-
subishi Foundation. K.S. is grateful for
a Research Fellowship from JSPS for
young scientists. T.F. acknowledges
a Naito Foundation Natural Science
Scholarship.
Keywords: alkynes · copper ·
homogeneous
catalysis
·
hydroboration · internal alkynes
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Experimental Section
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General procedure for Table 2: CuCl (0.99 mg, 0.010 mmol, 2.0 mol%),
MeAr-Xan (6.91 mg, 0.010 mmol, 2.0 mol%), and tBuONa (5.77 mg,
0.060 mmol, 12 mol%) were placed in an oven dried Schlenk flask
(20 mL). The flask was evacuated and backfilled with argon three times.
Toluene (1.0 mL) was added, and the mixture was stirred for 15 min at
room temperature, under an argon atmosphere. Pinacolborane (HBpin;
109 mL, 0.75 mmol) was added to the resulting solution at 08C, and the
mixture was stirred at 08C for 5 min. An alkyne (0.50 mmol) was then
added at 08C, and the mixture was stirred at 208C for 20 h. After the re-
action, the mixture was filtered through a pad of silica gel and all of the
volatiles were removed in vacuo. The products were isolated by silica gel
column chromatography.
[7] To obtain the b products very selectively by hydroboration, bulky
boranes and methyl acetylene (R=Me in Scheme 1a) must be used;
see refs. [5a,7] and N. Iwadate, M. Suginome, Org. Lett. 2009, 11,
1899–1902.
General procedure for Table 3: CuCl (0.99 mg, 0.010 mmol, 2.0 mol%),
CF3Ar-Xan (11.2 mg, 0.010 mmol, 2.0 mol%), and tBuONa (5.77 mg,
0.060 mmol, 12 mol%) were placed in an oven dried Schlenk flask
(20 mL). The flask was evacuated and backfilled with argon three times.
Toluene (1.0 mL) was added, and the mixture was stirred for 15 min at
room temperature under an argon atmosphere. Bis(pinacolato)diboron
(B2pin2; 152 mg, 0.60 mmol) was added to the resulting solution, and the
mixture was stirred at room temperature for 5 min. An alkyne
(0.50 mmol) and MeOH (42 mL, 1.0 mmol) were then added and the mix-
ture was stirred at 288C for 3 h. After the reaction, the mixture was fil-
tered through a pad of silica gel and all of the volatiles were removed in
vacuo. The products were isolated by silica gel column chromatography.
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Acknowledgements
This work was supported by a Grant-in-Aid for Scientific Research on
Innovative Areas (“organic synthesis based on reaction integration” and
Chem. Eur. J. 2012, 18, 4179 – 4184
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
4183

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ACHTUNGTRENNUNG
C
CHTUNGTRENNUNG
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[21] Previously, the regioselectivity has mostly been governed by the
steric effects. Therefore, to provide the b products, the limitations
on the size of the alkyl moiety on the acetylenic carbon are very
severe: the alkyl moiety must be methyl (even Et lowered the regio-
selectivity considerably, see ref. [8a]) or primary (secondary alkyl
lowered the regioselectivity, see ref. [8b]). For these substrates, our
catalyst system afforded the b products: (2ab–jb) in 72–98% yields
and with high regioselectivities (2b/2a=96:4 to >99:1; see Table S1
in the Supporting Information).
Received: November 17, 2011
Revised: January 11, 2012
Published online: March 2, 2012
4184
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