Alkoxydienes via copper-promoted couplings: Utilizing an alkyne effect

Article abstract of DOI:10.1021/ol100707s

Simple alkenes and alkynes, with 3-hexyne in particular, are found to be important π ligands for oxidative copper-based coupling (modern Ullmann) reactions. This enabled syntheses of various alkoxydienes with removable protecting groups that are valuable substrates for Diels-Alder reactions from alcohols and vinyl boronate esters. In addition to demonstrating that 3-hexyne is a ligand for copper in both stoichiometric and catalytic reactions, the reaction atmosphere was found to play a critical role.

Full text of DOI:10.1021/ol100707s

ORGANIC
LETTERS
2010
Vol. 12, No. 11
2508-2510
Alkoxydienes via Copper-Promoted
Couplings: Utilizing an Alkyne Effect
David J. Winternheimer and Craig A. Merlic*
Department of Chemistry and Biochemistry, UniVersity of California,
Los Angeles, California 90095-1569
merlic@chem.ucla.edu
Received March 25, 2010
ABSTRACT
Simple alkenes and alkynes, with 3-hexyne in particular, are found to be important π ligands for oxidative copper-based coupling (modern
Ullmann) reactions. This enabled syntheses of various alkoxydienes with removable protecting groups that are valuable substrates for Diels-Alder
reactions from alcohols and vinyl boronate esters. In addition to demonstrating that 3-hexyne is a ligand for copper in both stoichiometric and
catalytic reactions, the reaction atmosphere was found to play a critical role.
Copper-mediated coupling reactions have emerged as
important methods for C-O and C-N bond formation in
recent years.1 Major advances have been reported in both
the classic Ullmann process employing aryl or vinyl
halides as the electrophilic coupling partners2 and the
modern Ullmann coupling (oxidative) employing aryl or
vinyl boronic acids.3 We recently reported a copper-
promoted coupling of vinyl boronate esters and alcohols
as an efficient method for the synthesis of vinyl ethers.4
One application of this chemistry is the synthesis of allyl
vinyl ether substrates for Claisen rearrangements, and
another application is the synthesis of alkoxydienes for
utilization as electron-rich dienes in Diels-Alder reac-
tions. A general direct method to synthesize alkoxydienes
would prove immensely useful. Deprotectable alkoxy-
dienes are of even greater utility, which led us to choose
2-chloroethanol and 2-(trimethylsilyl)ethanol as suitable
alcohols to couple with dienyl boronates. The resulting
activated dienes can be easily deprotected after use in
Diels-Alder reactions via addition of a metal(0)5 or
fluoride source.6 We report herein realization of a mild
alkoxydiene synthesis and the discovery of novel ligand
effects in copper-mediated cross couplings.
Coupling of dienyl boronate 1 with 2-chloroethanol at rt
in the presence of 2 equiv of cupric acetate and 4 equiv of
triethylamine gave only a 35% yield of alkoxydiene 2a. That
being unacceptable, we sought to improve upon our initial
reported copper coupling conditions by examining ligand
effects that have been so critically important for recent
improvements2 in the classic Ullmann process. Screening
phosphorus-based ligands identified tri-2-furylphosphine as
a promising ligand as it provided a significant improvement
to 60% (Table 1).
(1) For recent reviews see: (a) Monnier, F.; Taillefer, M. Angew. Chem.,
Int. Ed. 2009, 48, 6954. (b) Evano, G.; Blanchard, N.; Toumi, M. Chem.
ReV. 2008, 108, 3054. (c) Ma, D.; Cai, Q. Acc. Chem. Res. 2008, 41, 1450.
(d) Chan, D. M. T.; Lam, P. Y. S. In Boronic Acids; Hall, D. G., Ed.;
Wiley-VCH: Weinheim, 2005; Chapter 5. (e) Nelson, T. D.; Crouch, R. D.
Org. React. 2004, 63, 265. (f) Kunz, K.; Scholz, U.; Ganzer, D. Synlett
2003, 2428. (g) Ley, S. V.; Thomas, A. W. Angew. Chem., Int. Ed. 2003,
42, 5400.
(2) For recent leading references, see: (a) Kabir, M. S.; Lorenz, M.;
Namjoshi, O. A.; Cook, J. M. Org. Lett. 2010, 12, 464. (b) Monnier, F.;
Taillefer, M. Angew. Chem, Int. Ed. 2008, 47, 3096. (c) Shafir, A.; Lichtor,
P.; Buchwald, S. L. J. Am. Chem. Soc. 2007, 129, 3490.
(3) For recent leading references, see: (a) Gonzalez, I.; Mosquera, J.;
Guerrero, C.; Rodriguez, R.; Cruces, J. Org. Lett. 2009, 11, 1677. (b) Singh,
B. K; Appukkuttan, P.; Claerhout, S.; Parmar, V. S.; Van der Eycken, E.
Org. Lett. 2006, 8, 1863.
(5) Crombie, L.; Wyvill, R. D. J. Chem. Soc., Perkin Trans. 1 1985,
1983.
(6) (a) Lipshutz, B. H; Pegram, J. J. Tetrahedron Lett. 1980, 21, 3343.
(b) Paquette, L. A.; Backhaus, D.; Braun, R. J. Am. Chem. Soc. 1996, 118,
11990.
(4) Shade, R. E.; Hyde, A. M.; Olsen, J.-C.; Merlic, C. A. J. Am. Chem.
Soc. 2010, 132, 1202.
10.1021/ol100707s  2010 American Chemical Society
Published on Web 04/28/2010

Table 1. Ligand Screening Yields
Although copper-alkyne complexes have been reported,9
this is, to the best of our knowledge, the first use of an alkyne
ligand to increase the efficiency of an oxidative (modern
Ullmann) coupling method.10
Several important copper-based coupling reactions have
been discovered recently, in particular for C-N bond
formation,1 which we hypothesized may also benefit from
this alkyne effect. To test this, coupling of phenylboronic
acid with benzimidazole to yield 8 was chosen. We found
that alkyne and also reaction atmosphere have a dramatic
impact upon coupling yields (Table 2). 3-Hexyne was most
effective in the absence of a pure oxygen environment.
Our initial studies indicated that allyl alcohol was a
particularly effective alcohol partner in the coupling reaction,
resulting in yields higher than those using ethanol or
propanol. Experiments with substituted ethyl alcohols sug-
gested that this was not an inductive electronic effect, so
we postulated that the alkene might be functioning as a
π-Lewis base to copper.7 That indeed is the case as born
out by the effect of alkene additives shown in Table 1.
Interestingly, benzoquinone or dimethyl fumarate additives
gave negative results, but in striking contrast to all other
cases. Not only was no product formed, but the boronate
ester was completely consumed and only protodeboration
was detected. Electron-rich dihydropyran had no impact on
coupling yield. Ring strain increased Lewis basicity8 as
demonstrated with norbornene, which gave a 68% yield.
However, alkynes were the best ligands, with 3-hexyne
boosting the yield to 80%.
Table 2. Atmosphere and 3-Hexyne Impact on C-N Couplings
yield (%)
without 3-hexyne
with 4 equiv of 3-hexyne
argon
ambient
oxygen
17
28
90
35
42
87
Both alkyne ligand and reaction atmosphere impacted
copper-promoted couplings of 1 and 5 with 2-chloroethanol
(Table 3). In contrast to the results in Table 2, ambient
atmosphere was optimal where again 3-hexyne was critical
for the highest yields. Similar couplings of 1 and 5 with
2-bromoethanol showed drastically reduced yields, and no
coupling occurred with 2-iodoethanol. These results suggest
that a copper species is reacting with alkyl halides and the
possibility that one of the functions of 3-hexyne is to
moderate copper’s reactivity toward alkyl chlorides.
The 3-hexyne ligand effect was corroborated in coupling
3 with 2-chloroethanol, wherein the yield of 4 increased from
39% to 99% (eq 1).
One aspect of the alkyne ligand effect may involve
complexing copper(I)9 byproducts resulting from both dis-
proportionation and reductive elimination steps in the
The alkyne effect is also applicable to couplings involving
other alcohols, such as crotyl alcohol (eq 2 and 3), wherein
yields were nearly or more than doubled:
(9) (a) Baker, M. V.; Brown, D. H.; Somers, N.; White, A. H.
Organometallics 2001, 20, 2161. (b) Kovacs, A.; Frenking, G. Organome-
tallics 1999, 18, 887. (c) Lang, H.; Kohler, K.; Rheinwald, G.; Zsolnai, L.;
Buchner, M.; Driess, A.; Huttner, G.; Strahle, J. Organometallics 1999,
18, 598.
(7) For a review on alkene and alkyne ligand effects on transition-metal-
catalyzed cross-coupling reactions, see: Johnson, J. B.; Rovis, T. Angew.
Chem, Int. Ed. 2008, 47, 840.
(10) There is a primary report of alkynes promoting a copper-catalyzed
coupling of Grignard reagents and alkyl halides: Terao, J.; Todo, H.; Begum,
S. A.; Kuniyasu, H.; Kambe, N. Angew. Chem., Int. Ed. 2007, 46, 2086.
See also: Terao, J.; Kambe, N. Acc. Chem. Res. 2008, 41, 1545.
(8) Tolman, C. A. Organometallics 1983, 2, 614.
Org. Lett., Vol. 12, No. 11, 2010
2509

Table 3. Atmosphere and 3-Hexyne Impact on C-O Couplings
Table 4. Synthesis of Alkoxydienes
yield (%)
yield (%)
with
4 equiv
product 3-hexyne 3-hexyne product 3- hexyne 3-hexyne
with
without
4 equiv
without
postulated mechanism.4,11 Calculations indicate copper(I) to
be a better π-Lewis acid than copper(II),12 and very recently
a monomeric Cu(I) 3-hexyne complex was isolated and
characterized.13 This might address the haloethanol results
but may not be the only function of 3-hexyne. In analogy to
calculations for gold(I) and gold(III) π-Lewis acidity,12
copper(III), a key postulated intermediate resulting from
disproportionation,11 may also coordinate alkynes facilitating
its formation and subsequent reductive elimination to cop-
per(I).
With the reaction conditions optimized for copper-
promoted coupling of pinacol vinyl boronates and function-
alized alcohols, seven different alkoxydienes and two
alkoxytrienes were prepared (Table 4). The 3-hexyne ligand
was beneficial in every instance, although the magnitude of
change was not always the same.
2a
35
43
46
60
80
69
56
68
2b
57
0
61
46
34
80
57
81
54
37
10a
11a
13
10b
11b
12
14
yield jumped to 95%, thus providing significant promise for
development of a catalytic process. These catalytic reaction
conditions did not uniformly produce yields superior to the
stoichiometric conditions, thus the latter were employed for
the current studies delineating the ligand effects.
Further refinements in the coupling are necessary for an
ideal process as alcohol partners are utilized as solvent and
2 equiv of Cu(OAc)2 are used. Attempts to couple 5 with
only 3 equiv of allyl alcohol in CH2Cl2 failed, but adding
3-hexyne ligand promoted the reaction, albeit in only 33%
yield (eq 4).
In conclusion, we found that simple alkenes and alkynes,
with 3-hexyne in particular, can be important π ligands for
oxidative copper-based coupling reactions. These results
enabled syntheses of various alkoxydienes with removable
protecting groups that are valuable substrates for Diels-Alder
reactions. We also found that the 3-hexyne ligand was critical
for improved modifications, such as catalytic reactions, of
the copper-promoted coupling of alcohols and vinyl boronate
esters. Finally, even in the presence of excess Cu(OAc)2,
the reaction atmosphere plays a critical role.
An even more dramatic 3-hexyne effect was seen in a test
catalytic reaction. Coupling of 5 with 2-chloroethanol using
50 mol % of Cu(OAc)2 and pyridine N-oxide under an
oxygen atmosphere resulted in only a 29% yield of vinyl
ether 9 (eq 5). In the presence of 4 equiv of 3-hexyne, the
Acknowledgment. We are grateful to the National Science
Foundation and the Research Corporation for Science
Advancement for financial support of this research.
Supporting Information Available: Experimental pro-
cedures and spectral data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(11) (a) Lam, P. Y. S.; Vincent, G.; Bonne, D.; Clark, C. G. Tetrahedron
Lett. 2003, 44, 4927. (b) Collman, J. P.; Zhong, M. Org. Lett. 2000, 2,
1233
.
(12) Yamamoto, Y. J. Org. Chem. 2007, 72, 7817.
(13) Dias, H. V. R.; Flores, J. A.; Wu, J.; Kroll, P. J. Am. Chem. Soc.
2009, 131, 11249.
OL100707S
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Org. Lett., Vol. 12, No. 11, 2010