Asymmetric synthesis of trisubstituted allenes: Copper-catalyzed alkylation and arylation of propargylic phosphates

Article abstract of DOI:10.1021/ol2031119

Asymmetric synthesis of trisubstituted allenes is accomplished by copper-catalyzed alkylation and arylation of propargylic phosphates using organoboron nucleophiles. Excellent chirality transfer and regioselectivity, together with good functional group co

Full text of DOI:10.1021/ol2031119

ORGANIC
LETTERS
2012
Vol. 14, No. 1
362–365
Asymmetric Synthesis of Trisubstituted
Allenes: Copper-Catalyzed Alkylation and
Arylation of Propargylic Phosphates
Mycah R. Uehling, Samuel T. Marionni, and Gojko Lalic*
Department of Chemistry, University of Washington, Seattle, Washington 98195,
United States
lalic@chem.washington.edu
Received November 20, 2011
ABSTRACT
Asymmetric synthesis of trisubstituted allenes is accomplished by copper-catalyzed alkylation and arylation of propargylic phosphates using
organoboron nucleophiles. Excellent chirality transfer and regioselectivity, together with good functional group compatibility, were observed in
reactions with both alkyl boranes and arylboronic esters.
Allenes play an important role in organic chemistry as
synthetic targets1 and intermediates.2 While numerous
methods for their synthesis exist,3 asymmetric synthesis
of chiral allenes is still a considerable challenge. Most
methods mandate the presence of a specific functional
group in the allene product,4 and have a limited substrate
scope. Reactionsdevelopedby Myers5 and Ready6 have no
such requirements and can be applied to the synthesis of a
wide variety of chiral allenes. Unfortunately, neither meth-
od can be used to prepare trisubstituted allenes. In view of
the limitations of existing methodology and the utility of
chiral trisubstituted allenes as synthetic intermediates,7 we
pursued the development of a practical method for their
synthesis.
We used copper-catalyzed substitution of propargylic
electrophiles as a starting point for the development of
such a method.8,3a This transformation has a broad scope
and relies on readily available substrates. However, its
applications in asymmetric synthesis have been limited
(1) (a) Cleasson, A. In The Chemistry of the Allenes; Landor, S. R., Ed.;
€
Academic Press: London, 1982. (b) Hoffmann-Roder, A.; Krause, N. Angew.
Chem., Int. Ed. 2004, 43, 1196.
(2) (a) Ma, S. Acc. Chem. Res. 2003, 36, 701. (b) Ma, S. Chem. Rev.
ꢀ
~
2005, 105, 2829. (c) Alvarez-Corral, M.; Munoz-Dorado, M.; Rodrıguez-
Garcıa, I. Chem. Rev. 2008, 108, 3174. (d) Bongers, N.; Krause, N. Angew.
Chem., Int. Ed. 2008, 47, 2178. (e) Widenhoefer, R. A. Chem.;Eur. J.
2008, 14, 5382. (f) Ma, S. Acc. Chem. Res. 2009, 42, 1679. (g) Aubert, C.;
Fensterbank, L.; Garcia, P.; Malacria, M.; Simonneau, A. Chem. Rev.
ꢀ
2011, 111, 1954. (h) Corma, A.; Leyva-Perez, A.; Sabater, M. J. Chem.
Rev. 2011, 111, 1657.
(3) Selected reviews on allene synthesis: (a) Krause, N.; Hoffmann-Roder,
€
A. Tetrahedron 2004, 60, 11671. (b) Brummond, K. M.; DeForrest
J. E. Synthesis 2007, 795. (c) Yu, S.; Ma, S. Chem. Commun. 2011, 47
5384.
(5) Myers, A. G.; Zheng, B. J. Am. Chem. Soc. 1996, 118, 4492.
(6) Pu, X.; Ready, J. M. J. Am. Chem. Soc. 2008, 130, 10874.
(7) (a) Wan, Z.; Nelson, S. G. J. Am. Chem. Soc. 2000, 122, 10470. (b)
Liu, Z.; Wasmuth, A. S.; Nelson, S. G. J. Am. Chem. Soc. 2006, 128,
10352. (c) Volz, F.; Krause, N. Org. Biomol. Chem. 2007, 5, 1519. (d)
Volz, F.; Wadman, S. H.; Hoffmann-Roder, A.; Krause, N. Tetrahedron
2009, 65, 1902.
(8) Rona, P.; Crabbe, P. J. Am. Chem. Soc. 1968, 90, 4733.
(9) Selected examples: (a) Oehlschlager, A. C.; Czyzewska, E. Tetra-
hedron Lett. 1983, 24, 5587. (b) Alexakis, A.; Marek, I.; Mangeney, P.;
Normant, J. F. J. Am. Chem. Soc. 1990, 112, 8042. (c) Gooding, O. W.;
Beard, C. C.; Jackson, D. Y.; Wren, D. L.; Cooper, G. F. J. Org. Chem.
1991, 56, 1083. (d) Myers, A. G.; Condroski, K. R. J. Am. Chem. Soc.
1995, 117, 3057. (e) Brummond, K. M.; Kerekes, A. D.; Wan, H. J. Org.
Chem. 2002, 67, 5156.
(4) (a) Han, J. W.; Tokunaga, N.; Hayashi, T. J. Am. Chem. Soc.
2001, 123, 12915. (b) Ogasawara, M.; Ikeda, H.; Nagano, T.; Hayashi, T.
J. Am. Chem. Soc. 2001, 123, 2089. (c) Schultz-Fademrecht, C.; WibbelingB.;
€
€
Frohlich, R.; Hoppe, D. Org. Lett. 2001, 3, 1221. (d) Sherry, B. D.;
Toste, F. D. J. Am. Chem. Soc. 2004, 126, 15978. (e) Trost, B. M.;
Fandrick, D. R.; Dinh, D. C. J. Am. Chem. Soc. 2005, 127, 14186. (f)
Ogasawara, M.; Fan, L.; Ge, Y.; Takahashi, T. Org. Lett. 2006, 8, 5409.
(g) Kolakowski, R. V.; Manpadi, M.; Zhang, Y.; Emge, T. J.; Williams,
L. J. J. Am. Chem. Soc. 2009, 131, 12910. (h) Liu, H.; Leow, D.; Huang,
K.-W.; Tan, C.-H. J. Am. Chem. Soc. 2009, 131, 7212. (i) Cerat, P.;
Gritsch, P. J.; Goudreau, S. R.; Charette, A. B. Org. Lett. 2010, 12, 564.
(j) Nishimura, T.; Makino, H.; Nagaosa, M.; Hayashi, T. J. Am. Chem.
Soc. 2010, 132, 12865.
r
10.1021/ol2031119
Published on Web 12/16/2011
2011 American Chemical Society

mainly to reactions of substrates featuring terminal
alkynes9 or benefiting from the “alkoxy effect”7a,10 dis-
covered by Marshall.11
Table 1. Reaction Optimization
Several problems prevent a more general application of
Cu-catalyzed propargylic substitution in asymmetric
synthesis. For example, racemization of allene products
caused by organocuprates,12 Grignard reagents,12 or Cu
metal13 is often encountered in these reactions. In addi-
tion, regio- and stereoselectivity of the reaction can vary
significantly with subtle changes of the electrophile,
nucleophile, and leaving group.9b,14 These problems can
be attributed to the presence of organocuprate inter-
mediates,12,15 which form in the presence of hard organo-
metallic nucleophiles commonly used in these reactions.
We speculated that cuprate formation could be avoided
with less reactive nucleophiles and decided to explore the
use of organoboron compounds in Cu-catalyzed pro-
pargylic substitutions. During the preparation of this
manuscript, a similar alkylation of propargylic phosphates
was published by Sawamura et al. focusing on the regios-
electivity of the alkylation reaction.15 Sawamura reported
three reactions with high chirality transfer, two of which
rely on the “alkoxy effect” previously used in reactions of
Grignard reagents.7a,10
entrya,b
cat.
M
t (°C)
solvent
yieldc eed
1
2
3
4
5
6e
7
IMesCuOt-Bu Na
60
60
60
60
60
60
35
1,4-dioxane 45% 30%
1,4-dioxane 35% 26%
1,4-dioxane 33% 29%
1,4-dioxane 16% 37%
1,4-dioxane 79% 30%
IPrCuCl
IMeCuCl
It-BuCuCl
ICyCuCl
ICyCuCl
ICyCuCl
Na
Na
Na
Na
Na
Li
pentane
pentane
47% 81%
95% 96%
a 2 was prepared in situ from 4-phenyl-1-butene (1.5 equiv) and
9-BBN (1.5 equiv). b 1 (1.0 equiv), t-BuOM (1.0 equiv). c Determined by
GC. d Determined by chiral HPLC. e Reaction performed in a sealed
vessel.
In initial experiments, we explored the reaction of alkyl
borane 2 with enantioenriched phosphate 1 using condi-
tions originally developed for arylation of allylic elec-
trophiles.16 The desired allene product 3 was formed
in modest yield and with low chirality transfer (Table 1,
entry 1). Encouragingly, only the product of the SN20
substitution was detected in the crude reaction mixture.
Catalyst optimization (Table 1, entries 2ꢀ5) resulted in a
significant improvement of the yield, but not the enantio-
meric excess of the allene. The low chirality transfer is a
result of the inherent selectivity of the substitution step, as
we found that neither the phosphate nor the allene product
racemize under the reaction conditions.
explore other base additives. The use of lithium tert-
butoxide allowed the reaction to be performed at lower
temperature, resulting in a complete suppression of the
byproduct formation (Table 1, entry 7). The allene product
was obtained in excellent yield and with high chirality
transfer (98%).
In Table 2, we show that under optimized reaction
conditions the transformation can be accomplished in
the presence of silyl ethers, phenyl ethers, alkyl chlorides,
thioacetals, aryl bromides, and esters. In addition, 1,1-di-
substituted alkenes are viable substrates and provide the
desired allene in good yield (Table 2, entry 5). It is worth
noting that excellent chirality transfer and regioselectivity
were observed in all reactions.18
Significantlyhigherchirality transferwasobservedwhen
1,4-dioxane was replaced by pentane (Table 1, entry 6).
Unfortunately, the allene product was obtained in lower
yield and was accompanied by a significant amount of
allenyl phosphate 4.
Even with substrates biased against SN20 substitution, such
as tert-butyl substituted phosphate 6, the reaction proceeded
with excellent regioselectivity (Table 2, entry 8). Similarly,
excellent regio- and stereoselectivity were obtained with
trimethylsilyl-substituted phosphate 7 (Table 2, entries 9
and 10). These results stand in contrast to previous reports
in which the presence of a bulky substituent at the γ-
position of the propargylic electrophile diminishes the
regioselectivity or completely prevents the reaction.15
Encouraged by the broad scope and consistently high
regio- and stereoselectivity in the alkylation reaction, we
also explored the reactivity of arylboronic esters. Using
conditions similar to those developed for the alkylation
reaction, we accomplished highly regio- and stereoselective
arylation of propargylic phosphates (Table 3). Good yields
We suspected that this byproduct was formed by depro-
tonation of the propargylic phosphate17 and decided to
(10) Tang, X.; Woodward, S.; Krause, N. Eur. J. Org. Chem. 2009,
2836.
(11) Marshall, J. A.; Pinney, K. G. J. Org. Chem. 1993, 58, 7180.
(12) Claesson, A.; Olsson, L. I. J. Chem. Soc., Chem. Commun. 1979,
524.
(13) Chenier, J. H. B.; Howard, J. A.; Mile, B. J. Am. Chem. Soc.
1985, 107, 4190.
(14) Alexakis, A.; Marek, I.; Mangeney, P.; Normant, J. F. Tetra-
hedron 1991, 47, 1677.
(15) For example, better regioselectivities are usually observed in
stoichiometric vs catalytic reactions. For an example of a direct com-
parison of a catalytic and a stoichiometric reaction with a Grigranrd
reagent, see: Ohmiya, H.; Yokobori, U.; Makida, Y.; Sawamura, M.
Org. Lett. 2011, 13, 6312.
(16) Whittaker, A. M.; Rucker, R. P.; Lalic, G. Org. Lett. 2010, 12,
3216.
(17) Hammerschmidt, F.; Schneyder, E.; Zbiral, E. Chem. Ber. 1980,
113, 3891.
(18) Only one regioisomer of the product could be identified by GC/
MS analysis of crude products obtained from alkylation reactions.
Org. Lett., Vol. 14, No. 1, 2012
363

observed even with 6, a substrate sterically biased against
the SN20 substitution (Table 3, entry 4).
Table 2. Alkylation of Propargylic Phosphatesa
Table 3. Arylation of Propargylic Phosphates
a ArB(OR)2 (1.25 equiv), propargylic phosphate (1.00 equiv), NaOt-
Pent (1.00 equiv), ICyCuCl (0.10 equiv), isooctane, 60 °C, 24 h. All
reactions performed on 0.5 mmol scale. Isolated yields of pure products
are reported.
To the best of our knowledge, this is the first example of
an SN20-selective Cu-catalyzed arylation of propargylic
electrophiles. More importantly, aside from a single ex-
ample reported by Ihara in a Pd-catalyzed reaction,20 this
is the only instance of high chirality transfer (>95%) in
arylations of propargylic electrophiles.21
Based on previous explorations of copper-catalyzed
reactions of organoboron compounds,16,22 we propose
that the allene formation proceeds according to the
mechanism outlined in Scheme 1. The first step of the
proposed catalytic cycle involves transmetalation from
boron to copper, followed by the antiselective substitution
involving the putative alkyl copper intermediate and the
propargylic electrophile. Finally, the alkoxide form of the
a Alkyl borane (1.5 equiv), phosphate (1.0 equiv), t-BuOLi (1.0 equiv),
ICyCuCl (0.1 equiv), pentane, 35 °C, 6 h. All reactions performed on
0.5 mmol scale. Isolated yields of pure products are reported. b Product
isolated as a 1:1 mixture of diastereoisomers. c Complete conversion of the
phosphate required 18 h.
(19) See Supporting Information for the assignment of the absolute
stereochemistry of the allene products.
(20) (a) Yoshida, M.; Gotou, T.; Ihara, M. Tetrahedron Lett. 2004,
45, 5573. (b) Yoshida, M.; Ueda, H.; Ihara, M. Tetrahedron Lett. 2005,
46, 6705.
(21) For a discussion of propargylic arylation reactions, see:
Molander, G. A.; Sommers, E. M.; Baker, S. R. J. Org. Chem. 2006,
71, 1563.
(22) Ohmiya, H.; Yokobori, U.; Makida, Y.; Sawamura, M. J. Am.
Chem. Soc. 2010, 132, 2895.
and antiselectivity19 were obtained in the presence of both
electron-donating and -withdrawing substituents (Table 3,
entries 2 and 3). Finally, excellent regioselectivity was
364
Org. Lett., Vol. 14, No. 1, 2012

catalyst is regenerated by the reaction with lithium tert-
butoxide.
Scheme 2. Reactivity of Potassium Boratea
Scheme 1. Proposed Catalytic Cycle
a 2 (1.5 equiv), 1 (1.0 equiv), ICyCuCl (0.1 equiv), t-BuOK (1.0 equiv),
pentane, 35 °C, 24 h. b11 (1.0 equiv), 1 (1.0 equiv), ICyCuCl (0.1 or 1.0
equiv), pentane, 35 °C, 24 h.
In the context of the catalytic cycle outlined in Scheme 1,
we were interested in exploring the mechanism of the trans-
metalation reaction, which has been previously invoked as a
key step in several Cu-catalyzed transformations of organo-
boron compounds. Most reports propose that the reaction
proceeds through a borate intermediate,15,23 while a sole
theoretical study of the transmetalation reaction favors the
mechanism involving borane and copper alkoxide.24 We
sought to provide data that would help us distinguish
between the two mechanisms.
In a preliminary experiment, we examined the reaction
between alkyl borane 2 and lithium tert-butoxide in both
toluene and 1,4-dioxane using 11B NMR. The borate
formation was not observed in either solvent, even at
60 °C. While this result suggests that under the standard
reaction conditions transmetalation proceeds through the
alkyl borane, it is still possible that a small amount of
boratepresent inequilibrium with borane isresponsible for
the reaction.
In an effort to provide evidence for the role of copper(I)
alkyl complexes in the proposed catalytic cycle (Scheme 1), we
explored the reactivity of ICyCuMe27 (12) with phosphate 13.
In a stoichiometric reaction shown in Scheme 3, the expected
allene product 14 was obtained in 80% yield and 97% ee.
Furthermore, when 12 was used as a catalyst in a reaction
between 1 and 2, the desired allene was obtained in 85% yield
and 98% ee.28 The results of both experiments support the
proposed role of copper(I) alkyl complexes as intermediates in
the catalytic alkylation of propargylic phosphates.
Scheme 3. Stoichiometric Reactivity of Copper(I) Alkyl Complexa
To rule out this possibility, we compared the reactiv-
ities of preformed potassium borate 1125 and the cor-
responding alkyl borane 2. While the alkyl borane
yielded the allene product together with a small amount
of substituted alkyne 9 (Scheme 2, eq 1), borate 11
yielded 9 as the major product (Scheme 2, eq 2). Inter-
estingly, only the allene product was formed in the
presence of a stoichiometric amount of the copper
catalyst, suggesting a possible involvement of an orga-
nocuprate intermediate in a catalytic reaction with
borate 11. These experiments suggest not only that
the transmetalation occurs with both boranes and
borates but also that the outcome of the reaction can
be different depending on the form of the organoboron
compound participating in the reaction.26
a 10:1 mixture of pentane and 1,4-dioxane, 35 °C.
In conclusion, we developed a new method for asym-
metric synthesis of chiral allenes based on copper-cata-
lyzed alkylation and arylation of propargylic phosphates.
In addition to good functional group compatibility, the
new method offers consistently high chirality transfer and
regioselectivity. Overall, the unique effectiveness and the
scope of this reaction will make it a valuable addition to the
existing methods for the synthesis of chiral allenes.
(23) (a) Wada, R.; Shibuguchi, T.; Makino, S.; Oisaki, K.; Kanai, M.;
Shibasaki, M. J. Am. Chem. Soc. 2006, 128, 7687. (b) Ohishi, T.;
Nishiura, M.; Hou, Z. Angew. Chem., Int. Ed. 2008, 47, 5792.
(24) Dang, L.; Lin, Z.; Marder, T. B. Organometallics 2010, 29, 917.
(25) 11B NMR indicated no presence of free alkyl borane in a solution
of 11 in toluene-d8. See Supporting Information for details.
(26) It is important to note that neither 2 nor 11 reacts with the
phosphate in the absence of the copper catalyst.
Acknowledgment. This work was supported by the
University of Washington.
Supporting Information Available. Experimental pro-
cedures and characterization data for new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(27) For synthesis of 12, see Supporting Information.
(28) See Supporting Information for details.
Org. Lett., Vol. 14, No. 1, 2012
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