Efficient coupling reactions of lithium alkynyl(triisopropoxy)borates with aryl halides: Application to the antifungal terbinafine synthesis

Article abstract of DOI:10.1016/s0040-4039(00)01543-4

Thermally stable lithium alkynyl(triisopropoxy)borates were reacted with several aryl halides in the presence of palladium catalysts to give the corresponding cross-coupling products in excellent yields. The present methodology has been successfully appli

Full text of DOI:10.1016/s0040-4039(00)01543-4

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 8513–8516
Efficient coupling reactions of lithium
alkynyl(triisopropoxy)borates with aryl halides: application
to the antifungal terbinafine synthesis
Chang Ho Oh* and Seung Hyun Jung
Department of Chemistry, Hanyang University, Sungdong-Gu, Seoul 133-791, South Korea
Received 24 July 2000; revised 7 September 2000; accepted 8 September 2000
Abstract
Thermally stable lithium alkynyl(triisopropoxy)borates were reacted with several aryl halides in the
presence of palladium catalysts to give the corresponding cross-coupling products in excellent yields. The
present methodology has been successfully applied to the antifungal terbinafine synthesis. © 2000 Elsevier
Science Ltd. All rights reserved.
Keywords: palladium; alkyne; antifungal agent; terbinafine.
The palladium-catalyzed cross-coupling reaction has become a powerful tool in synthetic
organic chemistry. Tremendous development of the mechanistically related variants has drawn
1
profit from mechanistic insights into these cross-coupling reactions. In 1975, three different
research groups reported independently that disubstituted acetylenes were synthesized by
reaction of 1-alkynes with aryl halides in the presence of a palladium catalyst and an organic
2
base such as diethyl amine. The mechanism of these coupling reactions appears to involve
oxidative addition of the aryl halide to palladium(0), followed by alkynylation of the intermedi-
ate organopalladium halide and reductive elimination to the disubstituted alkyne. A major
problem with these reactions is the formation of the dimerized byproducts, 1,4-disubstituted-1,3-
3
butadiynes. In order to exclude such dimerization, modification of the alkynes to the alkynyl-
4
metallic species involving Mg, Cu, Zn, Sn, Si and B has been developed. In 1978, Negishi
reported that the 1-alkynyl group in lithium 1-hexynyl(tributyl)borate was selectively coupled
5
with iodobenzene through a palladium-catalyzed addition–elimination sequence. We thought
that replacement of the alkyl (butyl) groups in lithium 1-hexynyl(tributyl)borate by alkoxy
(
isopropoxy) groups could provide even more efficient alkynyl transfer reagents due to their
thermal stability as well as their reactivity. Here we wish to report our preliminary results on
*
Corresponding author.
0
040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01543-4

8514
cross-coupling reactions of lithium 1-alkynyl(triisopropoxy)borates with a variety of enones and
6
aryl halides.
Treatment of commercially available triisopropoxyborane with alkynyllithiums at 0°C, gener-
ated in situ from 1-alkynes plus n-butyllithium in ether, yielded lithium 1-alkynyl(triisopro-
poxy)borates as white precipitates, which were filtered and dried under reduced pressure. The
1
7
characterization of lithium 1-alkynyl(triisopropoxy)borates was confirmed by H NMR. These
compounds were quite stable in a refrigerator for several months.
Next, we investigated cross-coupling reactions of these lithium 1-alkynyl(triisopro-
poxy)borates with iodobenzene under various catalytic conditions as summarized in Table 1.
The following results could be drawn from these data. First, all three lithium 1-alkynyl(triiso-
propoxy)borates were reacted with iodobenzene in the presence of a palladium catalyst to give
the coupled products without formation of any dimerized byproducts. Second, concurrent use of
a palladium compound and copper(I) iodide as a cocatalyst dramatically improved the reaction
efficiency, although the exact role of copper iodide is not clear. These coupling reactions in
various other solvents such as dichloromethane, THF, 1,4-dioxane, toluene and acetonitrile did
occur in moderate yields. As a result, we could choose the optimal conditions for these coupling
reactions: a mixture of Pd(PPh ) and CuI as a cocatalyst and DMF as an optimal solvent. We
3
4
then applied these conditions to a wide variety of aryl halides. The results are summarized in
Table 2.
Table 1
Coupling reactions of iodobenzene with lithium 1-alkynyl(triisopropoxy)borates in DMF
Borates
Catalyst
Temp (°C)
Time (h)
Products
Yield (%)
1
2
3
4
5
6
7
8
9
0
1
2
1
No catalyst
5 mol% Pd(OAc)2
60
60
60
60
60
80
60
60
60
60
60
60
4
4
4
4
2
2
4
4
5
5a
0
59
74
79
53
88
47
93
57
75
86
94
5 mol% Pd (dba)3
2
5 mol% Pd Cl (p-C H )
2
2
3
5 2
5 mol% Pd(PPh3)4
5 mol% Pd(PPh ) , 5 mol% CuI
5 mol% PdCl (PPh )
5 mol% PdCl (PPh ) , 5 mol% CuI
5 mol% PdCl (PPh ) , 5 mol% CuI
5 mol% Pd(PPh ) , 5 mol% CuI
5 mol% PdCl (PPh ) , 5 mol% CuI
5 mol% Pd(PPh ) , 5 mol% CuI
3
4
2
3 2
2
3 2
2
3
5b
5c
2
3 2
1
1
1
5
15
15
3
4
2
3 2
3
4

8515
Table 2
Coupling reactions of lithium 1-alkynyl(triisopropoxy)borates with aryl halides in DMF
Ar-X
R
Temp (°C)
Time (h)
Yield (%)
1
2
3
4
5
6
7
8
9
0
1
2
3
4
(4-NO )C H I
n-C H ꢀ
rt
24
5
5
74
97
97
80
90
27
73
67
55
34
50
98
90
96
2
6
4
4
9
(4-NO )C H I
80
80
80
80
80
60
60
60
80
60
60
rt
2
6
4
(4-CH )C H I
3
6
4
(2-CH )C H I
20
20
48
10
24
24
5
10
15
24
15
3
6
4
(4-CH O)C H Br
3
6
4
2,4,6-(CH O) C H I
3
3
6
2
C H Br
6
5
(4-CH )C H I
Me (t-Bu)SiOCH ꢀ
3
6
4
2
2
(2-CH )C H I
3
6
4
1
1
1
1
1
(4-CH O)C H Br
3
6
4
C H Br
6
5
(4-NO )C H I
C H ꢀ
2
6
4
6
5
(4-CH )C H I
3
6
4
(2-CH )C H I
60
3
6
4
The alkynylborate 1 was reacted with electronically and sterically diverse arylhalides to give
the coupling products. Electron poor aryl halide, 1-iodo-4-nitrobenzene, was relatively labile
toward these conditions (entries 1, 2), while electron-rich aryl halide, 4-bromoanisole, required
a higher reaction temperature to complete coupling. Particularly, highly electron-rich aryl
iodide, 2,4,6-trimethoxyiodobenzene, was not completely consumed even within a prolonged
period of time (entry 6). The alkynylborates 2 and 3 were also reacted with aryl halides to yield
the corresponding coupling products without formation of any byproducts, respectively. Bro-
mobenzene was shown to be inferior to iodobenzene, since it required a longer reaction time
(
entries 7 and 11). It should be noted that these coupling reactions were slightly slowed down
with sterically congested aryl halides. For example, 2-iodotoluene was coupled with the borates
and 2 to give the corresponding coupling products in 80 and 55% yields, while 4-iodotoluene
1
gave the products in 90 and 67% yields, respectively. Again, while 4-iodotoluene was almost
completely coupled with the borate 3 even at room temperature, 2-iodotoluene required heating
for complete coupling. It is important to note from these data that the present method worked
cleanly to prepare the corresponding arylalkynes from aryl iodides without formation of any
byproducts.
This method was applied to the short preparation of an antifungal agent, terbinafine.
Terbinafine contains the (E)-1,3-enyne structural moiety and exhibits strong antimycotic activity
8
and is currently used for the treatment of skin mycoses. Several syntheses have been described
based on the Pd-catalyzed Stille coupling of an (E)-vinyl iodide with an alkynyl tin and the
9
Sonogashira coupling of an (E)-vinyl chloride with tert-butylacetylene.

8516
We have treated the vinyl bromide 6 with tert-butylethynyl(triisopropoxy)borate under the
above conditions. As expected, the desired terbinafine (7) was obtained in 98% isolated yield,
implying that this present method could provide an alternative for Stille-, Sonogashira-, and
Suzuki reactions.
A typical experimental procedure is as follows. In a 5 ml test tube were placed lithium
tert-butylethynyl(triisopropoxy)borate (116.5 mg, 0.42 mmol), Pd(PPh ) (12.8 mg, 0.011 mmol),
3
4
CuI (2.1 mg, 0.011 mmol), and then dry DMF (1.0 ml). The mixture in the test tube was purged
with a slow stream of dry argon for 5 min and then treated with a solution of the halide 6 (61.1
mg, 0.21 mmol) in DMF (1.0 ml) via cannula. The resultant mixture was stirred for 36 h at
6
0°C, and then cooled to room temperature. Extractive workup and silica gel chromatography
10
of the residue afforded the pure terbinafine (7, 60.0 mg, 98%) as a colorless liquid.
In summary, we have shown that three thermally stable lithium 1-alkynyl(triisopro-
poxy)borates 1–3 were reacted with several aryl halides in the presence of palladium–copper
catalysts to give the corresponding cross-coupling products in excellent yields. The present
methodology has been successfully applied to the antifungal terbinafine synthesis.
Acknowledgements
This work was supported by the Research Fund of Hanyang University, Korea (Project No.
HYU-99-035).
References
1
. (a) Heck, R. F. Acc. Chem. Res. 1979, 12, 146–151. (b) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457–2483.
c) Farina, V.; Krishnamurthy, V.; Scott, W. J. The Stille Reaction; Wiley & Sons, Inc.: New York, 1998. (d)
(
Heck, R. F. Palladium Reagents in Organic Syntheses; Academic Press: New York, 1985.
. (a) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett. 1975, 4467–4470. (b) Cassar, L. J. Organomet.
Chem. 1975, 93, 253–257. (c) Dieck, H. A.; Heck, R. F. J. Organomet. Chem. 1975, 93, 259–263.
. Rossi, R.; Carpita, A.; Bellina, F. Org. Prep. Proced. Int. 1995, 27, 129–160.
2
3
4
. Sonogashira, K. In Comprehensive Organic Synthesis; Trost, B. M.; Fleming, I., Eds.; Pergamon Press: Oxford,
1
991; Vol. 3, pp. 521–549.
5
6
. Negishi, E. In Aspects of Mechanism and Organometallic Chemistry; Brewster, J. H., Ed.; Plenum Press: New
York, 1978; p. 285.
. (a) Brown, H. C.; Bhat, N. G.; Srebnik, M. Tetrahedron Lett. 1988, 29, 2631–2634. (b) Negishi, E.; Lew, G.;
Yoshida, T. J. Chem. Soc., Chem. Commun. 1973, 874–875. (c) Molander, G. A.; Brown, H. C. J. Org. Chem.
1
977, 42, 3106–3108.
1
7
. 1: H NMR (200 MHz, CDCl ): l 4.02 (sept, J=6.0 Hz, 3H), 2.19 (td, J=6.6 Hz, 2.0 Hz, 2H), 1.61–1.30 (m,
3
1
4
H), 1.21 (d, J=6.1 Hz, 18H), 0.92 (t, J=7.0 Hz, 3H); 2: H NMR (400 MHz, CDCl ): l 4.29 (s, 2H), 4.00 (sept,
3
1
J=6.0 Hz, 3H), 1.20 (d, J=6.1 Hz, 18H), 0.90 (s, 9H), 0.12 (s, 6H); 3: H NMR (200 MHz, CDCl ): l 7.54–7.28
3
(m, 5H), 4.03 (sept, J=6.0 Hz, 3H), 1.21 (d, J=6.1 Hz, 18H).
8
9
. St u¨ tz, A. Angew. Chem., Int. Ed. Engl. 1987, 26, 320–328.
. (a) Rudisill, D. E.; Castonguay, L. A.; Stille, J. K. Tetrahedron Lett. 1988, 29, 1509–1512. (b) Alami, M.; Ferri,
F.; Gaslain, Y. Tetrahedron Lett. 1996, 37, 57–58. (c) Kim, G.-C.; Seo, M.-J. Bull. Kor. Chem. Soc. 1995, 16,
1
002–1003.
10. Satisfactory spectral data were obtained for all compounds.
.