A mild and efficient palladium-catalyzed homocoupling of lithium alkynyltriisopropoxyborates: A new route to synthesis of 1,3-diynes

Article abstract of DOI:10.1016/j.tetlet.2004.05.033

Lithium alkynyltriisopropoxyborates were homocoupled in the presence of palladium acetate and DPEPhos. This protocol allows a new efficient route to synthesis of 1,3-diynes under very mild conditions.

Full text of DOI:10.1016/j.tetlet.2004.05.033

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 5221–5224
A mild and efficient palladium-catalyzed homocoupling of
lithium alkynyltriisopropoxyborates: a new route to synthesis
of 1,3-diynes
Chang Ho Oh* and V. Raghava Reddy
Department of Chemistry, Hanyang University, Sungdong–Gu, Seoul 133-791, South Korea
Received 12 April 2004; revised 2 May 2004; accepted 10 May 2004
Abstract—Lithium alkynyltriisopropoxyborates were homocoupled in the presence of palladium acetate and DPEPhos. This pro-
tocol allows a new efficient route to synthesis of 1,3-diynes under very mild conditions.
Ó 2004 Elsevier Ltd. All rights reserved.
Palladium-catalyzed coupling reactions are very efficient
and reliable procedures for the construction of new
carbon–carbon bonds.1 In particular, Sonogoshira
reaction has used extensively over the past three decades
for the elaboration of arylalkynes. The reaction is a
straightforward way to achieve arylalkynyl derivatives,
although 1,3-diynes are formed as by-products.2 The
prominent occurrence of biologically active compounds
containing conjugated 1,3-diynes continues to encour-
age the devolpment of new strategies for their rapid and
efficient synthesis.3 Among the various approaches,4 the
use of organometalic reagents such as organosilanes,5
organoantimony,6 and organotin7 have attracted much
attention. However, many of these organometalic re-
agents and their by-products are highly toxic and diffi-
cult to remove.8 We imagined that the homocoupling of
alkynylborates might be an interesting alternative to-
ward the synthesis of 1,3-diynes.
carbon–carbon bond forming reactions such as Suzuki
type cross-coupling reactions,11 conjugated addition to
enones,12 allylic additions to allyliccarbonates,13 and
Mannich reaction.14 We have also reported conven-
tional Suzuki–Miyaura coupling reaction.15 On the basis
of these promising potentialities, our efforts have been
made in developing new synthetic methodologies using
alkynylborates.16
Herein we wish to report an efficient protocol for the
synthesis of 1,3-diynes from the alkynylborate salts,
which were easily prepared from the known literature
procedures.17 Our initial studies of this process focused
on developing an optimum set of reaction conditions for
the palladium-catalyzed homocoupling of alkynyl-
borates. The reaction was optimized by using phenyl-
acetyleneborate (1a) as a standard substrate as shown in
Table 1.
Comparatively, organoboron reagents are the most
intriguing since they are less toxic, stable in air, inex-
pensive, and environmentally benign. Homocoupling of
aryl-, alkenyl-, and alkylboronic acids were well stud-
ied.9 Alkynylborates have long been known to be useful
synthetic intermediates.10 More recently, significant ad-
vances have been made in the use of these reagents as
coupling partners in a number of palladium mediated
From a series of experiments, it was clear that both the
Pd(0) and Pd(II) complexes are effective. We next sur-
veyed solvents such as DMF, THF, THF/water, aceto-
nitrile/water, and 1,4-dioxane. Among the solvents we
tested, THF proved to be by far the most effective. The
presence of a small quantity of water had no adverse
effect on the reaction outcome, so that special drying of
the solvent and the reagents was not required. Even
though the reaction worked at room temperature albeit
in low yield, longer reaction times did not improve the
yield significantly (entry 7). We were gratified to learn
that the catalytic system of Pd(OAc)2 and bis[(2-diph-
enylphosphino)phenyl]ether (DPEPhos) in THF at
Keywords: Palladium; Catalyst; Homocoupling; Diyne; Borate.
* Corresponding author. Tel.: +82-2-2290-0932; fax: +82-2-2299-0762;
e-mail: changho@hanyang.ac.kr
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.05.033

5222
C. H. Oh, V. R. Reddy / Tetrahedron Letters 45 (2004) 5221–5224
Table 1. Palladium-catalyzed homocoupling of alkynyl triisopropoxy borate (1a)
Entry
Catalyst
Solvent
Temperature (°C)
Time (h)
Yield (%)
1
Pd(OAc)2/DPEPhos
Pd(OAc)2/DPEPhos
Pd(OAc)2/DPEPhos
Pd(OAc)2/DPEPhos
Pd(OAc)2/DPEPhos
Pd(OAc)2/DPEPhos
Pd(OAc)2/DPEPhos
Pd(PPh3)4
DMF
120
60
60
60
60
80
25
60
60
60
60
60
10
10
8
58
63
2
CH3CN
CH3CN/watera
THF/watera
THF
3
68
72
4
8
5
6
93
73
6
1,4-Dioxane
THF
THF
8
7
6
45
62
8
6
9
PdCl2/2PPh3
Pd(OAc)2/TFP
THF
THF
6
59
73
10
11
12b
6
Pd(OAc)2/2PPh3
Pd(OAc)2/DPEPhos
THF
THF
6
71
Trace
6
a 10:1 ratio.
b Reaction performed in absence of CuI.
60 °C afforded the corresponding 2a in 93% yield. It was
noteworthy that the present reaction did not require any
added base or any other oxidant such as molecular
oxygen,18 BrCH2CO2Et,19 allylic acetate,7 and iodine.20
We considered Cu(I) salt as a potential co-catalyst be-
cause of its ability to catalyze the Sonogoshira reaction.
To our great delight, addition of CuI to the Pd(OAc)2/
DPEPhos system resulted in exclusive formation of
homocoupled product 2a in 93% yield.21 In controlled
experiment, it was revealed that the presence of CuI is
necessary for the smooth transformation (entry 12).
When the reaction was carried out under strictly oxy-
gen-free conditions by using freeze–thaw technique, the
reaction of 1a gave the diyne 2a in 90% yield, implying
that the reaction does not require any oxidant. Although
this homocoupling reaction was smoothly occurred,
mechanistic details were not easily speculated.
respectively. Alkyl-substituted acetyleneborates such as
tert-butyl (1d) and n-butyl (1e) gave the even more
promising results. While the TMS protected alkynyl-
borate salt 1f underwent effective homocoupling to
afford the product 2f in 63% yield. Note that these
structural motifs are broadly appeared in functional
materials as well as in biologically active molecules.22
We next employed a series of terminal alkynes bearing
an oxy-functionality. The reaction of TBDMS ether 1g
of propargyl alcohol provided the corresponding 1,3-
diyne 2g in good yield. Similarly, THP ether 1h also
worked well without any deprotection. These reactions
with TBDMS ethers 1i and ij of 1-butynol and
1-pentynol afforded the corresponding 1,3-diynes 2i and
2j in 81% and 78% yields, respectively. Benzyl ether 1k
of 1-hexynol was also effective to furnish the product 2k
in 82% yield.
_
Pd cat. (5 mol%)
B(OPri)3 Li+
CuI (10 mol%)
Finally, the substrates 1l and 1m underwent smooth
homocoupling to give the products 2l and 2m in 68%
and 73% yields, respectively. Not surprisingly, two more
alkynyl substrates 1n and 1o were also effectively ho-
mocoupled under these catalytic systems to furnish the
products 2n and 2o in 62% and 60% yields, respectively.
Note that both of these products 2n and 2o were ob-
tained as a diastereomeric mixture.
1a
2a
ð1Þ
Having established the viability of the present method-
ology, we next tested the general applicability as well as
the relative reactivity of various alkynylborates. To this
end we have prepared a series of alkynylborates from
the commercially available triisopropoxyborate with
alkynyl lithium, which was in situ prepared from the
corresponding terminal alkynes with n-BuLi at ꢀ78 °C
in ether.
It is clear that the method is tolerant toward a variety of
substituents and the yields are very good irrespective of
the nature of the substituent. Disappointingly, the use of
functionalized alkynes containing an ester, cyano, and a
pyridyl substituent failed to prepare corresponding bo-
rate salts.
-
Pd(OAc)2/DPEPhos (5 mol%)
CuI (10 mol%),THF, 60 oC
R
B(OPri)3 Li+
R
2 R
1b-o
2b-o
1) n-BuLi, THF, -78 oC, 2) B(OPri)3
Ph
Ph
Ph
3) Pd(OAc)2/DPEPhos/CuI, 60oC
ð2Þ
ð3Þ
Most of the substrates were homocoupled under the
optimized conditions in good to excellent yields as
summarized in Table 2. At first, arylacetylene borates
bearing both an electron-deficient group (1b) and an
electron-rich group (1c) worked smoothly under these
conditions to afford 2b and 2c in 72% and 76% yields,
It was of interest to ascertain whether the two processes
could be combined in one pot tandem sequence by
temperature control. We treated phenylacetylene with n-
BuLi in THF at ꢀ78 °C, subsequently added triiso-

C. H. Oh, V. R. Reddy / Tetrahedron Letters 45 (2004) 5221–5224
Table 2. Palladium-catalyzed homocoupling of various alkynylborates
5223
Entry
1
Substrates
Time (h)
7
Products
Yield (%)
72
O2N
1b
2b
2
1c
6
2c
76
H3CO
tert-C4H9
n-C4H9
3
1d
10
10
4
2d
2e
2f
85
87
63
76
64
81
78
82
4
1e
Me3Si
5
1f
6
TBSOCH2
THPOCH2
TBSO(CH2)2
TBSO(CH2)3
1g
1h
1i
1j
1k
6
2g
2h
2i
7
8
8
6
9
6
2j
10
BnO(CH2)4
1-Np
7
2k
11
12
1l
10
10
2l
68
73
NCH3
1m
2m
TBSO
TBSO
13
14
1n
1o
8
2n
2o
62
60
Ph
10
pling Reactions; Diederich, F., Stang, P. J., Eds.; Wiley-
VCH: Weinheim, 1998; Chapter 5.
propoxyborate, and then treated with a catalytic mix-
ture of Pd(OAc)2, DPEPhos, and CuI in THF by can-
nula. Upon heating at 60 °C for 6 h, the reaction
afforded the corresponding homocouple product 2a in
82% yield as shown in Eq. 3.
2. (a) Sonogoshira, K.; Thoda, Y.; Hagihara, N. Tetrahedron
Lett. 1975, 6, 4467; (b) Takahashi, K.; Kuroyama, Y.;
Sonogoshira, K.; Hagihara, N. Synthesis 1980, 627; (c)
Negishi, E.; Anastasia, L. Chem. Rev. 2003, 103, 1979.
3. (a) Nicolaou, K. C.; Petasis, N. A.; Zipikin, K. E.;
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In summary, we have demonstrated a new and highly
efficient synthetic method leading to the synthesis of 1,3-
diynes under very mild neutral reaction conditions. Use
of relatively nontoxic organoborates and commercially
cheap Pd(II) catalyst makes this method useful and
attractive strategy for the synthesis of conjugated 1,3-
diynes. Further studies of this methodology for the
synthesis of unsymmetrical 1,3-diynes are currently
ongoing in our laboratory and will be published in due
course.
Acknowledgements
We wish to acknowledge the financial support of Korea
Research Foundation (2001-015-DP0334), Korea.,
V.R.R. is grateful for a graduate fellowship supported
by the BK21 project.
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21. Representative experimental procedure: To a mixture of
lithium alkynyl triisopropoxy borate 1a (1 mmol),
Pd(OAc)2 (0.05 mmol), DPEPhos (0.05 mol %), and CuI
(0.10 mmol %), THF (2.0 mL) was added under argon
atmosphere and the mixture was stirred at 60 °C. After
heating for the time specified, the reaction mixture was
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