Regio- And stereoselective synthesis of alkyl allylic ethers via gold(l)-catalyzed intermodular hydroalkoxylation of allenes with alcohols

Article abstract of DOI:10.1021/ol800646h

Reaction of 1-phenyl-1,2-butadiene with 2-phenyl-1-ethanol catalyzed by a 1:1 mixture of a gold(l) W-heterocyclic carbene complex and AgOTf at room temperature for 1 h led to isolation of (E)-(3-phenethoxy-1-butenyl)benzene in 96% yield as a single regio-

Full text of DOI:10.1021/ol800646h

ORGANIC
LETTERS
2008
Vol. 10, No. 10
2079-2081
Regio- and Stereoselective Synthesis of
Alkyl Allylic Ethers via Gold(I)-Catalyzed
Intermolecular Hydroalkoxylation of
Allenes with Alcohols
Zhibin Zhang and Ross A. Widenhoefer*
Duke UniVersity, French Family Science Center,
Durham, North Carolina 27708-0346
rwidenho@chem.duke.edu
Received March 20, 2008
ABSTRACT
Reaction of 1-phenyl-1,2-butadiene with 2-phenyl-1-ethanol catalyzed by a 1:1 mixture of a gold(I) N-heterocyclic carbene complex and AgOTf
at room temperature for 1 h led to isolation of (E)-(3-phenethoxy-1-butenyl)benzene in 96% yield as a single regio- and stereoisomer. Gold(I)-
catalyzed intermolecular allene hydroalkoxylation was effective for monosubsituted, 1,1- and 1,3-disubstituted, trisubstituted, and tetrasubstituted
allenes and for a range of primary and secondary alcohols, methanol, phenol, and propionic acid.
Alkyl allylic ethers are found in many naturally occurring
and biologically active molecules and are versatile substrates
and building blocks in organic synthesis. Nevertheless,
effective methods for their synthesis are limited.1 Alkylation
or allylation of a secondary or tertiary alkoxide with an allyl
or alkyl halide is generally impractical owing to the high
basicity and modest nucleophilicity of the alkoxide.1 Al-
though transition-metal-catalyzed O-allylation of a copper2
or zinc3 alkoxide or an alkyl borate4 with an allylic
electrophile circumvents the problems associated with alkox-
ide basicity, issues regarding the scope and regioselectivity
of these transformations have not been fully resolved. For
these reasons, development of complementary approaches
to the regio- and stereoselective synthesis of alkyl allylic
ethers would constitute an important advance. The intermo-
lecular hydroalkoxylation of allenes with alcohols represents
a conceptually distinct and potentially expedient route to the
synthesis of alkyl allylic ethers. A number of metals including
Ag(I),5 Au(I),6–8 Au(III),9 Pd(II),10 Cu(I),11 and Ln(III)12
catalyze the intramolecular hydroalkoxylation of allenes.
Conversely, the intermolecular hydroalkoxylation of allenes
to form alkyl allylic ethers has been realized only in the case
(5) (a) Olsson, L.-I.; Claesson, A. Synthesis 1979, 743. (b) Marshall,
J. A.; Wolf, M. A.; Wallace, E. M. J. Org. Chem. 1997, 62, 367.
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Chem. 2006, 1387. (d) Erdsak, J.; Krause, N. Synthesis 2007, 3741. (e)
Alcaide, B.; Almendros, P.; Martinez del Campo, T. Angew. Chem., Int.
(1) (a) Mitsunobu, O. In ComprehensiVe Organic Chemistry; Trost,
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(b) Feuer, H.; Hooz, J. In The Chemistry of the Ether Linkage; Patai, S.,
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R. A. J. Am. Chem. Soc. 2006, 128, 9066. (b) Zhang, Z.; Widenhoefer,
R. A. Angew. Chem. Ind. Ed. 2007, 46, 283
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Gockel, B.; Krause, N. Org. Lett. 2006, 8, 4485.
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10.1021/ol800646h CCC: $40.75
Published on Web 04/16/2008
2008 American Chemical Society

of monosubstituted aryl allenes at elevated temperatures.13–15
Here, we report a general, regio- and stereoselective gold(I)-
catalyzed protocol for the hydroalkoxylation of allenes to
form alkyl allylic ethers.
effective catalyst for intermolecular allene hydroalkoxyla-
tion (Table 1, entry 6). In a preparative-scale experiment,
reaction of 2 and 1-phenyl-1-propanol (1.1 equiv) catalyzed
by a 1:1 mixture of (5)AuCl and AgOTf led to isolation of
3 in 88% yield (Table 2, entry 1).16
Table 1. Effect of Ligand and Counterion on the
Gold(I)-Catalyzed Intermolecular Hydroalkoxylation of
3-Methyl-1,2-butadiene (2) with 1-Phenyl-1-propanol
Table 2. Intermolecular Hydroalkoxylation of Allenes Catalyzed
by a Mixture of (5)AuCl (5 mol %) and AgOTf (5 mol %) in
Toluene at 23 °C
a 3 and 4 were the only products detected by GC analysis.
We recently reported that mixtures of (1)AuCl [1 ) P(t-
Bu)2o-biphenyl] and AgOTs constituted a highly active
catalyst system for the intramolecular hydroalkoxylation of
γ- and δ-hydroxy allenes.8a Although the high activity of
(1)AuCl/AgOTs suggested potential application to intermo-
lecular allene hydroalkoxylation, reaction of 3-methyl-1,2-
butadiene (2) with 1-phenyl-1-propanol (1.1 equiv) catalyzed
by a 1:1 mixture of (1)AuCl and AgOTs at room temperature
for 27 h led to only 19% conversion to form a 67:33 mixture
of regioisomeric allylic ethers 3 and 4 (Table 1, entry 1).
However, gold(I)-catalyzed allene hydroalkoxylation was
sensitive to the nature of both the counterion and ligand,
and subsequent optimization (Table 1) identified the gold(I)
NHC complex (5)AuCl [5 ) 1,3-bis(2,6-diisopropylphe-
nyl)imidazol-2-ylidine] in combination with AgOTf as an
a Yield of isolated, regio- and stereochemically pure material of >95%
chemical purity unless noted otherwise. b Dimethyl 2-(4-phenethoxy-5-
hexenyl)malonate also isolated in 17% yield. c Employment of (R)-1-phenyl-
1-propanol (99% ee) formed 11b with 99% ee. d Formed as a 2.7:1
e
1
diastereomeric mixture. Yield determined by H NMR.
The intermolecular hydroalkoxylation of allenes with
alcohols catalyzed by (5)AuCl/AgOTf was effective for
monosubstituted, 1,1- and 1,3-disubstituted, trisubstituted,
and tetrasubstituted allenes and for a range of primary and
secondary alcohols, methanol, and phenol. The effective
employment of propionic acid as a nucleophile for allene
hydroalkoxylation suggests this approach may constitute a
useful method for the preparation of allylic acetates (Table
2, entry 14). Intermolecular hydroalkoxylation of monosub-
stituted allenes 6-8 led to selective delivery of the alcohol
(13) Patil, N. T.; Pahadi, N. K.; Yamamoto, Y. Can. J. Chem. 2005,
83, 569.
(14) A BASF patent reported the Au(I)-catalyzed sequential addition
of two molecules of methanol to the central carbon atom of allene to form
2,2-dimethoxypropane: Schulz, M.; Teles, J. H. (BASF AG), WO-A1
9721648, 1997; Chem. Abstr. 1997, 127, 121499.
(15) For some related transformations, see: (a) Utsunomiya, M.; Ka-
watsura, M.; Hartwig, J. F. Angew. Chem., Int. Ed. 2003, 42, 5865. (b)
Nishina, N.; Yamamoto, Y. Angew. Chem., Int. Ed. 2006, 45, 3314. (c)
Nishina, N.; Yamamoto, Y. Synlett 2007, 1767. (d) Kim, I. S.; Krische,
M. J. Org. Lett. 2008, 10, 513.
(16) Control experiments ruled out the presence of Ag(I) or acid-
catalyzed hydroalkoxylation pathways (see the Supporting Information).
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Org. Lett., Vol. 10, No. 10, 2008

to the less hindered terminus of the allene with exclusive
formation of (E)-allylic ethers 9-11, respectively (Table 2,
entries 2-10). Hydroalkoxylation of 1,3-disubstituted allenes
such as 12 and 13 formed the chiral (E)-allylic ethers 14
and 15 via selective delivery of the alcohol to the more
electron-rich methyl-substituted allene terminus (Table 2,
entries 11-17). Hydroalkoxylation of the differentially 1,1-
disubstituted allene 16 with 2-phenyl-1-ethanol formed (Z)-
17 without formation of detectable amounts of the (E)-
stereoisomer (Table 1, entry 18). Hydroalkoxylation of
trisubstituted allenes 18 and 19 formed chiral allylic ethers
20 and 21 via selective delivery of the alcohol to the less
substituted allene terminus (Table 2, entries 19-21).
Scheme 1
Several experiments were performed to further probe the
mechanism of gold(I)-catalyzed allene hydroalkoxylation. In
one experiment, reaction of 12 with CH3OD led to formation
of 14c-d1 (80% D) with exclusive incorporation of deuterium
at the alkene carbon atom bearing the 1-methoxyethyl group
(eq 1). In a second series of experiments, reaction of (S)-13
(97% ee) with benzyl alcohol (0.44 M) led to isolation of
(R)-15d in 83% yield with 64% ee (eq 2). The efficiency of
chirality transfer increased with increasing alcohol concentra-
tion and gold(I)-catalyzed reaction of (S)-13 (97% ee) with
1.76 M benzyl alcohol led to formation of (R)-15d with 79%
ee (eq 2), which pointed to racemization in an alcohol-
independent pathway. Indeed, treatment of (S)-13 with
(5)AuCl/AgOTf (5 mol %) in toluene at room temperature
for 30 min led to complete racemization of (S)-13.6,17
would release (R)-15d with regeneration of a cationic gold
(NHC) complex. The intermediacy of II is supported by the
stereoselective conversion of 12 and CH3OD to 14c-d1 (eq
1). We propose that racemization of (S)-13 occurs via
formation of a gold σ-allyl cation such as III, analogous to
the intermediate proposed by Krause to account for the
racemization of R-hydroxy allenes by AuCl.6,20
Acknowledgment. Acknowledgment is made to the NSF
(CHE-0555425), NIH (GM-080422), and Johnson&Johnson
for support of this research. We thank Mr. Aaron S. Fisher
for performing some preliminary experiments.
Supporting Information Available: Experimental pro-
cedures, spectroscopic data, and scans of NMR spectra and
HPLC traces. This material is available free of charge via
the Internet at http://pubs.acs.org.
OL800646H
(17) (a) Sherry, B. D.; Toste, F. D. J. Am. Chem. Soc. 2004, 126, 15978.
(b) Zhang, Z.; Bender, C. F.; Widenhoefer, R. A. J. Am. Chem. Soc. 2007,
129, 14148. (c) Morita, N.; Krause, N. Eur. J. Org. Chem. 2006, 4634
.
(18) (a) Kennedy-Smith, J. J.; Staben, S. T.; Toste, F. D. J. Am. Chem.
Soc. 2004, 126, 4526. (b) Zhang, J.; Yang, C.-G.; He, C. J. Am. Chem.
Soc. 2006, 128, 1798. (c) Hashmi, A. S. K.; Weyrauch, J. P.; Frey, W.;
Bats, J. W. Org. Lett. 2004, 6, 4391. (d) Liu, Y.; Song, F.; Song, Z.; Liu,
M.; Yan, B. Org. Lett. 2005, 7, 5409
.
Stereospecific conversion of (S)-13 to (R)-15d (eq 2) is
in accord with a mechanism involving outer-sphere attack
of the alcohol on the gold π-allene intermediate I to form
the gold(I) σ-alkenyl complex II (Scheme 1).18 Protonolysis
of the Au-C bond of II with retention of configuration19
(19) Johnson, A.; Puddephatt, R. J. J. Chem. Soc., Dalton Trans. 1978,
980
.
(20) The intermediacy of III is further supported by the rapid (e 10
min) racemization of (R)-12 (78% ee) at room temperature in the presence
of (5)AuCl/AgOTf, presumably due to enhanced stabilization of the allylic
cation by the conjugated phenyl group (see the Supporting Information)
.
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