The regio- and stereospecific intermolecular dehydrative alkoxylation of allylic alcohols catalyzed by a gold(I) N-heterocyclic carbene complex

Article abstract of DOI:10.1002/chem.201203987

A 1:1 mixture of [AuCl(IPr)] (IPr=1,3-bis(2,6-diisopropylphenyl)imidazol-2- ylidine) and AgClO₄ catalyzes the intermolecular dehydrative alkoxylation of primary and secondary allylic alcohols with aliphatic primary and secondary alcohols to for

Full text of DOI:10.1002/chem.201203987

FULL PAPER
DOI: 10.1002/chem.201203987
The Regio- and Stereospecific Intermolecular Dehydrative Alkoxylation of
Allylic Alcohols Catalyzed by a Gold(I) N-Heterocyclic Carbene Complex
Paramita Mukherjee and Ross A. Widenhoefer*[a]
Abstract: A 1:1 mixture of [AuCl
(IPr=1,3-bis(2,6-diisopropylphenyl)im-
idazol-2-ylidine) and AgClO4 catalyzes
the intermolecular dehydrative alkoxyl-
ation of primary and secondary allylic
alcohols with aliphatic primary and sec-
ondary alcohols to form allylic ethers.
These transformations are regio- and
G
stereospecific with preferential addi-
tion of the alcohol nucleophile at the
g-position of the allylic alcohol syn to
the departing hydroxyl group and with
predominant formation of the
E
stereoisomer. The minor a regioisomer
AHCTUNGTRENNUNG
G
is formed predominantly through a sec-
ondary reaction manifold involving re-
gioselective g-alkoxylation of the ini-
tially formed allylic ether rather than
by the direct a-alkoxylation of the al-
lylic alcohol.
ACHTUNGTRENNUNG
Keywords: alcohols
· allylation ·
gold · stereoselective catalysis
Introduction
alcohols to form secondary alkyl allylic ethers.[18–20] Howev-
er, given the ready access to regio- and stereochemically
pure allylic alcohols,[21] an effective method for the regio-
and stereospecific conversion of substituted allylic alcohols
to allylic ethers would also be significant, particularly if
these transformations occurred with concomitant 1,3-allylic
transposition.[22]
Alkyl allylic ethers are found in a number of naturally oc-
curring and biologically active compounds and are versatile
building blocks for further synthetic manipulation.[1] As a
result, considerable effort has been directed toward the de-
velopment of efficient and selective methods for the synthe-
sis of allylic ethers.[2,3] The transition-metal-catalyzed alkox-
ylation of allylic alcohol derivatives represents an attractive
We have recently reported the intermolecular dehydrative
amination of allylic alcohols with imidazolidin-2-ones cata-
ꢀ
route to allylic ethers with the potential to form C O bonds
lyzed by a mixture of [AuCl(1)] (1=PACTHNGUTRENU(NG tBu)2-o-biphenyl)
under mild conditions with high levels of regio- and stereo-
control.[3,4] Indeed, Pd0,[5] RhII,[6] Ru,[7] and IrI[8] complexes
catalyze the alkoxylation of allylic carboxylates, carbonates,
and related substrates with metal alkoxides, silanoates, alco-
hols, and phenols, and a number of these transformations
occur with high enantioselectivity.
and AgSbF6.[23,24] The g regiospecificity and syn stereospeci-
ficity displayed by this transformation distinguished it from
extant methods for the amination of allylic alcohols. In this
context, we considered that a similar catalyst system might
also effect the regiospecific and stereospecific intermolecu-
lar dehydrative alkoxylation of allylic alcohols with O-
With the goal of condensing synthetic sequences and min-
imizing byproduct formation, there has been an ongoing in-
terest in the utilization of underivatized allylic alcohols as
electrophiles for the transition-metal-catalyzed allylation of
heteroatom nucleophiles.[9] Regarding the formation of
carbon–oxygen bonds, PdII,[10] AuI,[11–16] and RuII[17] com-
plexes catalyze the intramolecular dehydrative alkoxylation
of allylic alcohols with simple alcohol nucleophiles. Con-
versely, the intermolecular alkoxylation of underivatized al-
lylic alcohols remains an unsolved challenge in homogene-
ous catalysis. The most notable example of such a transfor-
mation is the iridium(I)-catalyzed, regio- and enantioselec-
tive alkoxylation of secondary allylic alcohols with aliphatic
nucleo
and syn stereospecific intermolecular alkoxylation of unde-
rivatized allylic alcohols with primary and secondary ali-
ACHTUNGTRENpNGNU hiles. Indeed, here we report the g regioselective
G
ACHTUNGTRENNUNG
phatic alcohols catalyzed by a gold N-heterocyclic carbene
complex.[20]
Results and Discussion
Development of the protocol: An initial experiment direct-
ed toward the gold(I)-catalyzed intermolecular dehydrative
alkoxylation of allylic alcohols was encouraging. Treatment
of a 1:4 mixture of trans-2-buten-1-ol and 4-methylbenzyl al-
cohol with a catalytic 1:1 mixture of [AuCl(1)] and AgSbF6
in dioxane at room temperature for 48 h led to 53% conver-
sion to form a 96:4 mixture of the g-addition product 2a
and the a-addition product 3a (Scheme 1).[25] Substitution of
AgSbF6 with AgClO4 led to 98% conversion after 25 h at
room temperature to generate a 92:8 mixture of 2a and 3a
(Scheme 1).
[a] Dr. P. Mukherjee, Prof. R. A. Widenhoefer
Department of Chemistry, Duke University
French Family Science Center, Durham, NC 27708 (USA)
Fax : (+1)919-660-1605
E-mail: rwidenho@chem.duke.edu
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201203987.
Chem. Eur. J. 2013, 19, 3437 – 3444
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3437

entry 1). To improve upon this result, the gold-catalyzed re-
action of 4-methylbenzyl alcohol and trans-4-hexen-3-ol was
screened as a function of supporting ligand, silver salt, and
solvent (Table 1). Among the supporting ligands tested, the
N-heterocyclic carbene ligand IPr (IPr=1,3-bis(2,6-diiso-
ACHUTNGRENpNUG ropylCAHTUNGTRENNpUGN henyl)imidazol-2-ylidine) gave the best combination
of conversion (99%) and selectivity (75:25) after 24 h at
room temperature (Table 1, entries 2–4). Among the differ-
ent solvents screened utilizing the [AuClACTHNUTRGNEG(NU IPr)]/AgClO4 cata-
lyst mixture, methylene chloride and chloroform showed re-
activity and selectivity comparable to that realized in diox-
ane (Table 1, entries 5–10). Among the silver salts tested,
AgOTf, AgOTs, and AgPF6 proved less effective than
Scheme 1. Gold-catalyzed alkoxylation of trans-2-buten-1-ol with 4-meth-
ylbenzyl alcohol.
Unfortunately, continued experimentation revealed the
shortcomings of the [AuCl(1)]/AgClO4 catalyst system. For
example, reaction of a 1:4 mixture of trans-4-hexen-3-ol and
AgClO4 (Table 1, entries 10–14; OTf=triflate, OTs=tos
ate). However, two experiments utilizing AgOTs pointed to
a potential relationship between conversion and regioselec-
tivity. Specifically, the reaction of 4-methylbenzyl alcohol
ACHTUNGTRENNUNGyl-
AHCTUNGTRENNUNG
4-methylbenzyl alcohol catalyzed by
a 1:1 mixture of
[AuCl(1)] and AgClO4 in dioxane at room temperature for
24 h led to 85% conversion to form a 64:36 mixture of the
g-addition product 4 and the a-addition product 5 (Table 1,
with trans-4-hexen-3-ol catalyzed by [AuClACTHNGUTER(NNUG IPr)]/AgOTs
gave 47% conversion with 92% selectivity for 4 after 24 h.
In comparison, performing the reaction for 4 h led to only
10% conversion, but with>99% selectivity for 4 (Table 1,
entries 12 and 13).
Table 1. Effect of ligand, counterion and reaction conditions on the
gold(I)-catalyzed intermolecular allylic alkoxylation of trans-4-hexen-3-ol
with 4-methylbenzyl alcohol
Origin of the a and g regioisomers in gold-catalyzed allylic
alkoxylation: The conversion dependent regioselectivity of
the reaction of 4-methylbenzyl alcohol with trans-4-hexen-3-
ol catalyzed by [AuClACTHNUTRGNE(NUG IPr)]/AgOTs suggested that a-substi-
tution product 5 was formed through a secondary process in-
volving gold-catalyzed alkoxylation of g-substitution product
4. Supporting this contention, Aponick has shown that allyl-
ic ethers are competent electrophiles for the gold(I)-cata-
lyzed intramolecular allylation of alcohols.[12] To more thor-
oughly probe for the presence of primary and secondary re-
action pathways in the gold-catalyzed formation of 4 and 5,
a solution of a 1:4 mixture of trans-4-hexen-3-ol and 4-meth-
ylbenzyl alcohol and a catalytic 1:1 mixture of [AuClACHTUNGTRENNUNG(IPr)]
and AgClO4 in CD2Cl2 was analyzed periodically by
1H NMR spectroscopy at room temperature. In accord with
our expectations, the corresponding concentration versus
time plot revealed rapid formation of 4 early in the reaction
superimposed on slower formation of 5, which led to degra-
dation of the 4:5 ratio with increasing conversion (Figure 1).
For example, 4 constituted 97% of the product mixture at
50% conversion, 91% of the product mixture at 85% con-
version, and 82% of the product mixture at 100% conver-
sion. Following complete consumption of trans-4-hexen-3-ol,
the isomerization of 4 to 5 was apparent to ultimately gener-
ate an equilibrium of roughly 1:1 of the two regioisomers
(Figure 1).
Periodic analysis of the gold-catalyzed reaction of trans-2-
butene-1-ol and 4-methylbenzyl alcohol also revealed the
rapid formation of g-alkoxylation product 2a superimposed
on the slower, secondary formation of a-alkoxylation prod-
uct 3a (2a:3aꢁ95:5 at 63% conversion; 2a:3a=92:8 at
85% conversion; see Figure S9 in the Supporting Informa-
tion). One additional experiment further established the re-
L
Solvent
Xꢀ
t [h] Conv [%]
(yield [%])[a]
4/5[b]
AHCTUNGTRENNUNG
ꢀ
1
2
3
4
5
6
7
8
9
1
dioxane
dioxane
dioxane
ClO4ꢀ 24
ClO4ꢀ 24
ClO4ꢀ 24
ClO4ꢀ 24
ClO4ꢀ 24
85 (81)
99 (90)
100 (89)
90
100
99
<5
99
99
64:36 (67:33)
75:25 (75:25)
55:45 (55:45)
62:38
69:31
73:27
IPr
PPh3
PACHTUNGTRENNUNG(tBu)3 dioxane
IPr
IPr
IPr
IPr
IPr
toluene
m-xylene ClO4ꢀ 24
CH3CN
C2H4Cl2
CH2Cl2
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
ClO4ꢀ 24
ClO4ꢀ 24
ClO4ꢀ 24
–
71:29
75:25
85:15
86:14
99:1
92:8
79:21
10 IPr
11 IPr
12 IPr
13 IPr
14 IPr
ClO4
OTfꢀ
OTsꢀ
OTsꢀ
5
4
91
85
4
10
24
4
47
76
ꢀ
PF6
[a] Conversion determined by GC analysis of the crude reaction mixture;
value in parenthesis refers to isolated yield of a mixture of 4 and 5.
[b] Isomer ratio determined by GC analysis of the crude reaction mixture
at the indicated time; value in parenthesis refers to isomer ratio of the
purified mixture as determined by GC analysis; for both 4 and 5, E/Z ap-
proximately 9:1.
activity of alkyl allylic ethers toward gold-catalyzed alkACHTUNGTRENNUNGoxACHTUNGTRENNUNGyl-
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Chem. Eur. J. 2013, 19, 3437 – 3444

Dehydrative Alkoxylation of Allylic Alcohols
FULL PAPER
Scheme 3. Minor regioisomer 5 is formed primarily by secondary g-alkox-
ylation of 4 and not through direct a-alkoxylation of trans-4-hexen-3-ol.
primary g-addition product whilst minimizing the formation
of the a-addition byproduct generated in the secondary re-
action manifold. In all cases, the minor a regioisomer was
removed by a single-column chromatographic separation to
provide the regiochemically pure g-addition product in good
to excellent yield.
Figure 1. Concentration versus time plot for the reaction of a 1:4 mixture
^
of trans-4-hexen-3-ol ( ) with 4-methylbenzyl alcohol catalyzed by a 1:1
mixture of [AuCl
ACHTUNGTRENNUNG(IPr)] and AgClO4 (5 mol%) in CD2Cl2 at room tem-
~
perature to form 4 (&) and 5 ( ).
A
The scope of the gold-catalyzed intermolecular alkoxyla-
tion of allylic alcohols was evaluated as a function of both
the allylic and nucleophilic alcohol component (Table 2). In-
termolecular alkoxylation of primary (E)-allylic alcohols
that contained a single methyl, ethyl, or n-propyl substituent
at the g-position with primary or secondary alcohol nucleo-
philes led to isolation of the corresponding secondary allylic
ethers 2, 6, and 8 in 79–95% yield as single regioisomers
(Table 2, entries 1–7). Similarly, both (E)-9 and (Z)-9 that
possessed a more electron deficient g-benzyloxymethyl sub-
stitutent underwent gold-catalyzed alkoxylation with n-buta-
nol with complete regioselectivity, albeit in modest yield
(Table 2, entries 8 and 9). This pair of transformations re-
vealed no significant impact of the C=C bond geometry on
the rate or regioselectivity of allylic alkoxylation. Further
establishing the g-regiospecificity of the transformation,
gold-catalyzed alkoxylation of 3-buten-2-ol with 4-methyl-
benzyl alcohol formed the primary allylic ether 3a in 98%
yield with 89% regioselectivity, from which regiochemically
pure 3a was isolated in 85% yield as an 84:16 mixture of E/
Z isomers (Table 2, entry 10).
ACHTUNGTRENNUNG
conversion to the corresponding allylic ether 7b (Scheme 2).
Scheme 2. Gold-catalyzed alkoxylation of allylic ether 7a with benzyl al-
cohol.
Taken together, these experiments established that the gold-
catalyzed reaction of 4-methylbenzyl alcohol with either
trans-2-buten-1-ol or trans-4-hexen-3-ol occurs with high g
selectivity (>95%) and that the minor a regioisomers are
formed predominantly through secondary-reaction pathways
involving gold-catalyzed g-alkoxylation of the initially
formed allylic ether (Scheme 3).
We likewise explored the gold-catalyzed dehydrative alk-
AHCTUNGTREGoNNUN xylation of secondary allylic alcohols substituted at the g-
position. In addition to the gold-catalyzed formation of 4
from reaction of trans-4-hexen-3-ol and 4-methylbenzyl alco-
hol (Table 2, entry 11), gold-catalyzed alkoxylation of the
monobenzyl-protected trans-2-pentene-1,4-diol 11 with
either n-butanol or methanol led to isolation of 1,2-diethers
12 as single regioisomers in >75% yield (Table 2, entries 12
and 13). The analogous reaction of n-butanol with the
Scope of dehydrative alkoxylation: The procedure used for
the preparatory scale, gold-catalyzed dehydrative alkoxyla-
tion of allylic alcohols draws from our observations regard-
ing the intermolecular alkoxylation of trans-2-buten-1-ol and
trans-3-penten-2-ol. Preparative-scale reactions were typical-
ly run with a fourfold excess of the nucleophilic alcohol to
enhance the reaction rate and minimize self-condensation
mono
benzyloxy-protected
trans-2-pentene-1,4-diol
13
formed allylic ether 14 with 94% regioselectivity, but with
diminished yield (Table 2, entry 14). 1,2-Dioxygenated com-
pounds such as 12 and 14 are potentially important synthetic
building blocks.[26] Both the symmetrically disposed allylic
alcohol (E)-pent-3-en-2-ol and the tertiary allylic alcohol 2-
methyl-3-penten-2-ol also underwent efficient gold-catalyzed
and utilized the [AuClACHTNUTRGNEU(GN IPr)]/AgClO4 catalyst system in
methylene chloride at room temperature.[25] Reactions were
run to 80–95% conversion to maximize the formation of the
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3439

R. A. Widenhoefer and P. Mukherjee
Table 2. Intermolecular alkoxylation of allylic alcohols with alcohol nucleophiles (ROH, 4 equiv) catalyzed by
lecular dehydrative alkoxyla-
tion of allylic alcohols. These
experiments were conducted so
that sufficient quantities of
both the g- and a-regioisomeric
allylic ethers were isolated so
that the stereoselectivity of
both the primary and secondary
reaction pathways could be
evaluated. In one experiment,
the gold(I)-catalyzed reaction
of (R,E)-11 (98% ee) with n-
butanol (4 equiv) at 408C for
24 h led to isolation of two
chromatographic fractions. The
first fraction consisted of an 8:1
mixture of (R,E)-12a (97% ee)
and (S,Z)-12a (87% ee) in 81%
combined yield and the second
a mixture of [AuCl
ACHTUNGTRENNUNG(IPr)] (5 mol%) and AgClO4 (5 mol%) in methylene chloride (0.6m) at 238C.
R of ROH
Allylic
alcohol
Allylic
ether
t
Conv [%]
ACHTUNGTRENNUNG
(yield [%])[a]
g/a[b]
E/Z[c]
[h]
1
2
3
4
CH2-4-C6H4Me R’=Me
CH2-Ph R’=Me
CH2-4-C6H4Me R’=Et
2a
2b
6a
6b
6c
6d
8
4
5
9
96 (76)
98 (95)
95 (83)
94:6
>99:1
92:8
>99:1
93:7
90:10
92:8
–
–
–
–
–
–
–
CH2-Ph
CH2CH2Ph
Cy
R’=Et
R’=Et
R’=Et
14 83 (81)
11 88 (87)
21 87 (76)
18 82 (79)
5
6[d]
7
CH2-4-C6H4Me R’=nPr
8[e]
nBu
24 ND (52)
>99:1
>99:1
–
–
9[e]
10
11
nBu
10
24 ND (57)
12 98 (85)
fraction consisted of
a 7.2:1
mixture of (R,E)-16 (97% ee)
and (S,Z)-16 (87% ee) in 15%
combined yield (Scheme 4).[28]
A second experiment involving
the gold-catalyzed reaction of
(R,Z)-11 (98% ee) with n-buta-
nol likewise led to isolation of
two chromatographic fractions.
The first fraction consisted of a
>50:1 mixture of (S,E)-12a
(95% ee) and (R,Z)-12a (ꢁ
85% ee) in 81% combined
yield and the second fraction
consisted of a 6.2:1 mixture of
(S,E)-16 (94% ee) and (R,Z)-16
(ꢁ85% ee) in 19% combined
yield (Scheme 5).[28]
CH2-4-C6H4Me
CH2-4-C6H4Me
89:11 84:16
4
82 (76)
92:8
90:10
12[d] nBu
13[d] Me
14[f] nBu
R’=Bn (11)
R’=Bn (11)
R’=Bz (13)
12a
12b
14
24 ND (80)
ND (77)
24 ND (53)
84:16 89:11
84:16 91:9
7
94:6
93:7
15
16
CH2-4-C6H4Me
7a
7b
7
100 (96)
–
–
90:10
91:9
CH2-Ph
14 100 (99)
Several conclusions can be
drawn from the gold-catalyzed
alkoxylation of enantiomerical-
ly enriched (R,E)-11 and (R,Z)-
11. Firstly, high levels of chirali-
ty transfer were observed in the
primary reaction pathway (11!
12a) for both (R,E)-11 and
(R,Z)-11, particularly in the
pathways leading to major dia-
17
CH2-4-C6H4Me
1
100 (88)
>99:1
–
[a] Conversion determined by GC analysis of the crude reaction mixture at the indicated time; ND=not deter-
mined. Value in parenthesis refers to isolated yield of the g-regioisomer in >95% regioisomeric and chemical
purity. [b] g/a ratio determined by GC analysis of the crude reaction mixture at the indicated time point. [c] E/
Z ratio determined by 1H NMR analysis of the purified reaction mixture. [d] Reaction temperature=408C.
[e] Catalyst system=[AuCl(1)] (5 mol%) and AgClO4 (5 mol%) in dioxane at 608C. [f] Reaction performed
in neat nBuOH (0.5m) at 508C.
dehydrative alkoxylation to form allylic ethers 7 and 15, re-
spectively (Table 2, entries 15–17).
stereomer (E)-12a, which occurred with ꢁ97% transfer of
chirality; the pathways leading to the minor diastereomer
(Z)-12a occurred with approximately 88% chirality transfer.
Also worth noting is the high E selectivity of the alkoxyla-
tion of (R,Z)-11, which was not revealed by the alkoxylation
of primary allylic alcohol (Z)-9 (Table 2, entry 9). Secondly,
the stereochemical outcome of these primary alkoxylation
pathways, specifically the conversion of (R,E)-11 to (R,E)-
12a and (S,Z)-12a and the conversion of (R,Z)-11 to (S,E)-
12a and (R,Z)-12a, establish the net syn displacement of
1,3-Chirality transfer in gold-catalyzed dehydrative alkoxyla-
tion: Efficient 1,3-chirality transfer from chiral, non-racemic
secondary allylic alcohols has been previously observed in
the gold(I)-catalyzed inter-[23] and intramolecular[27] dehydra-
tive amination and intramolecular dehydrative alkoxylation
of allylic alcohols.[13,14] We therefore sought to evaluate the
extent of 1,3-chirality transfer in the gold-catalyzed intermo-
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Dehydrative Alkoxylation of Allylic Alcohols
FULL PAPER
to acidify the hydroxyl group of an alcohol.[31] For this
reason, we investigated the efficiency and regio- and stereo-
selectivity of Brønsted and Lewis acid catalyzed pathways
for intermolecular alkoxylation of allylic alcohols. In one ex-
periment, a 1:4 mixture of (R,E)-11 (98% ee) and n-butanol
was treated with a catalytic amount of triflic acid (5 mol%)
in methylene chloride at 408C and analyzed periodically by
GC. After 5 h, 30% of (R,E)-11 was consumed to form a
40:60 mixture of regioisomeric allylic ethers 12a and 16, in-
dicating that both regioisomers were formed directly from
11 (Scheme 6).[32] After 24 h, the regioisomeric ratio had not
Scheme 4. Stereochemical analysis of the gold-catalyzed reaction of
(R,E)-11 with n-butanol.
Scheme 6. Regio- and stereochemical outcomes of the triflic acid cata-
lyzed intermolecular alkoxylation of (R,E)-11.
changed significantly (12a:16=36:64) and purification of
the reaction mixture at this time led to isolation of two chro-
matographic fractions. One fraction consisted of a 5.8:1 mix-
ture of (E)-12a (ꢂ10 ee) and (Z)-12a (<5% ee) in 22%
combined yield while the second fraction consisted of (E)-
16 (8% ee) in 40% yield (Scheme 6). In a second experi-
ment, treatment of a 1:4 mixture of (R,E)-11 and n-butanol
with a catalytic amount of BF3·OEt2 (5 mol%) in methylene
chloride at 408C for 24 h generated an approximate 30:70
mixture of 12a and 16 (Scheme 7). Purification of the reac-
tion mixture led to isolation of two chromatographic frac-
tions. One fraction consisted of a >50:1 mixture of (E)-12a
(14% ee) and (Z)-12a (ꢂ5% ee) in 22% combined yield,
while the second fraction consisted of (E)-16 (ꢂ5% ee) in
26% yield (Scheme 7).
Scheme 5. Stereochemical analysis of the gold-catalyzed reaction of
(R,Z)-11 with n-butanol.
the hydroxyl group by n-butanol. Thirdly, high levels of chi-
ACHTUNGTRENNUNG
A
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
ACHTUNGTRENNUNG
to (E)-16, approximately 88% chirality transfer leading to
(Z)-16). Fourthly, this stereochemical outcome likewise es-
tablishes the net syn displacement of the butoxy group of
(E)-12a or (Z)-12a by n-butanol.[29] Together these observa-
tions indicate that the mechanism and origin of stereocon-
trol in the secondary alkoxylation pathway is similar to that
of the primary alkoxylation pathway.
Although triflic acid catalyzed the intermolecular dehy-
drative alkoxylation of (R,E)-11 with n-butanol, this trans-
formation occurred with neither the regioselectivity nor
stereoACTHUNRTGNEUNGselectivity displayed by the gold(I)-catalyzed alkoxyla-
Brønsted and Lewis acid catalyzed pathways for dehydrative
alkoxylation: The syn stereoselectivity observed for the
gold(I)-catalyzed alkoxylation of both (R,E)-11 and (R,Z)-
11 with n-butanol is characteristic of a concerted SN2’ substi-
tution reaction[30] involving the s activation of the hydroxyl
group by gold(I) or a Brønsted acid generated under reac-
tion conditions. Importantly, Toste has demonstrated that
tion of (R,E)-11. It is worth noting that triflic acid failed to
catalyze the intermolecular alkoxylation of trans-2-buten-1-
ol with 4-methylbenzyl alcohol.[32] Therefore, triflic acid is
neither a selective nor general catalyst for the intermolecu-
lar dehydrative alkoxylation of allylic alcohols. Furthermore,
there is no indication that the acidity of a gold-complexed
hydroxyl group approaches that of triflic acid.[31] Taken to-
gether, we can confidently rule out a mechanism for gold-
bisACHTUNGTRENNUNG(gold) phosphine complexes are sufficiently Lewis acidic
Chem. Eur. J. 2013, 19, 3437 – 3444
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3441

R. A. Widenhoefer and P. Mukherjee
spired by the computational analyses of Maseras.[33] This
mechanism invoked initial p complexation of the C=C bond
of the allylic alcohol to gold followed by outer-sphere, anti
addition of the nucleophile facilitated by an intramolecular
ꢀ
N H···O hydrogen bond, anti elimination of water, and de-
complexation of gold.[23] Aponick later invoked an analo-
gous mechanism to account for the gold(I)-catalyzed intra-
molecular dehydrative alkoxylation of allylic alcohols[13] and
provided further support for this mechanism through a com-
bined experimental/computational study.[14] Therefore, it ap-
pears likely that a similar p-activation mechanism is respon-
sible for the gold(I)-catalyzed intermolecular dehydrative
alkACTHNUGRTENUNGoxylation of allylic alcohols. Complexation of gold to
either of the diastereotopic C=C p faces of (R,E)-11 or
(R,Z)-11 followed by outer-sphere, anti addition of n-buta-
Scheme 7. Regio- and stereochemical outcomes of the BF3·OEt2 cata-
lyzed intermolecular alkoxylation of (R,E)-11.
ꢀ
nol facilitated by an O H···O hydrogen bond would form
the gold s-alkyl intermediates I (Scheme 8). Subsequent anti
elimination of water and displacement of gold would form
allylic ethers 12a with g regioselectivity and net syn stereo-
selectivity (Scheme 8).
catalyzed intermolecular alkoxylation involving s activation
of the hydroxyl group by a Brønsted acid. Similarly, because
gold(I) is a much weaker and less oxophilic Lewis acid than
BF3·OEt2, the sluggish dehydrative alkoxylation of (R,E)-11
catalyzed by BF3·OEt2 argues strongly against a mechanism
for gold-catalyzed dehydrative alkoxylation involving s acti-
vation of the hydroxyl group by gold(I).
In addition to accounting for the regio- and stereospecific-
ity of gold-catalyzed intermolecular alkoxylation of (R,E)-11
and (R,Z)-11, the proposed mechanism provides a rationale
for the predominant formation of the (E)-12a stereoisomers
in these transformations (Scheme 8). For example, in the
gold(I)-catalyzed alkoxylation of (R,E)-11, intermediate Ia,
Mechanism of dehydrative alkoxylation: In 2010, we pro-
posed a mechanism to account for the g regiospecificity and
syn stereospecificity of the gold(I)-catalyzed intermolecular
dehydrative amination of allylic alcohols,[23] which was in-
which leads to major product (R,E)-12a, possesses
a
trans,trans arrangement of the benzyloxymethyl, gold phos-
phine, and methyl groups, whereas in intermediate Ib, which
Scheme 8. Proposed mechanism for the gold-catalyzed g-regioselective and syn-stereoselective alkoxylation of (R,E)-11 and (R,Z)-11.
3442
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Chem. Eur. J. 2013, 19, 3437 – 3444

Dehydrative Alkoxylation of Allylic Alcohols
FULL PAPER
leads to minor product (S,Z)-12a, the methyl group and
gold phosphine moiety are arranged in a less favorable cis
orientation (Scheme 8). Likewise, in the gold(I)-catalyzed
alkoxylation of (R,Z)-11, intermediate Ic, which leads to
major product (S,E)-12a, possesses a cis,trans arrangement
of the benzyloxymethyl, gold phosphine, and methyl groups,
whereas intermediate Id, which leads to minor product
(R,Z)-12a, possesses a cis,cis arrangement of these groups
and what appears to be a particularly destabilizing 1,3-di-
Acknowledgements
We thank the NIH (GM-080422) for support of this research. P.M. thanks
Duke University for support through the Burroughs Welcome and C.R.
Hauser Fellowships.
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ACHTUNGTRENNUNGaxial interaction that may help explain the high E/Z selectiv-
ity (>50:1) observed in this transformation (Scheme 8).
Conclusion
In summary, we have developed a gold(I)-catalyzed method
for the intermolecular dehydrative alkoxylation of primary
and secondary allylic alcohols with primary and secondary
aliphatic alcohols to form allylic ethers in good yield under
mild conditions. These transformations occur through regio-
and stereospecific addition of the alcohol nucleophile to the
g-position of the allylic alcohol on the C=C p face syn to
the departing hydroxyl group. Analysis of concentration
versus time plots for the gold(I)-catalyzed alkoxylation of
trans-4-hexen-3-ol and stereochemical analysis of the gold-
catalyzed alkoxylation of (R,E)-11 and (R,Z)-11 revealed
that the minor a-substitution products are formed predomi-
nantly through secondary reaction pathways involving g re-
giospecific and syn stereospecific alkoxylation of the allylic
ethers formed in the primary reaction pathway.
Experimental Section
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1-{(Hex-3-en-2-yloxy)methyl}-4-methylbenzene (4): A mixture of [AuCl-
ACHTUNGTRENNUNG
(IPr)] (9.3 mg, 1.5ꢁ10ꢀ2 mmol] and AgClO4 (3.1 mg, 1.5ꢁ10ꢀ2 mmol) in
CH2Cl2 (0.3 mL) was stirred at room temperature for 5 min. To this was
added a solution of 4-methylbenzyl alcohol (147 mg, 1.20 mmol) and
trans-4-hexen-3-ol (36 mL, 0.30 mmol) in CH2Cl2 (0.2 mL), and the result-
ing mixture was stirred at 238C for 4 h. Flash column chromatography of
the crude reaction mixture (pentane/CH2Cl2 =4:1!1:1) gave 4 (47 mg,
76%, E/Z=9.1:1) as a colorless oil. The E configuration of the major
stereoisomer of 4 was established by the vicinal olefinic sp2–sp2 coupling
constant of 3JHH =15.6 Hz in the 1H NMR spectrum. TLC (hexanes/
CH2Cl2 =1:1): Rf =0.47; 1H NMR (400 MHz, CDCl3): d=7.23 (d, J=
8 Hz, 2H), 7.14 (d, J=7.6 Hz, 2H), [5.66 (td, J=6, 15.6 Hz), 5.55 (td, J=
7.6, 10.8 Hz), 9.1:1, 1H], 5.38 (tdd, J=1.6, 8, 15.6 Hz, 1H), 4.51 (d, J=
12 Hz, 1H), [4.33 (d, J=12 Hz), 4.31 (d, J=11.6 Hz), 9.1:1, 1H], 3.87
(qd, J=6.4, 7 Hz, 1H), 2.34 (s, 3H), 2.08 (qd, J=7.6, 6.2 Hz, 2H), [1.26
(d, J=6.8 Hz), 1.24 (d, J=6.8 Hz), 9.1:1, 3H], [1.02 (t, J=7.6 Hz),
0.98 ppm (t, J=7.6 Hz), 9.1:1, 3H]; 13C{1H} NMR (100 MHz, CDCl3): d=
136.9, 135.9, 134.7, 130.9, 129.0, 127.8, 75.5, 69.4, 25.2, 21.7, 21.1,
13.6 ppm; IR (neat): n˜ =2967, 2928, 2863, 1454, 1369, 1074, 969, 910, 799,
732, 475 cmꢀ1
[M+HꢀH2O]+; found 187.1178.
;
HRMS (EI): m/z calcd for C14H19
:
187.1481
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[28] The absolute configurations of (E)-12a, (Z)-12a, (E)-16, and (Z)-16
were determined by HPLC correlation with authentic samples ob-
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(R,Z)-16 are described in the Supporting Information.
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[29] Note the stereoconvergence of the secondary reaction manifold.
Syn-selective alkoxylation of both (R,E)-12a and (S,Z)-12a form a
mixture of (R,E)-16 and (R,Z)-16. Likewise, syn-selective alkoxyla-
tion of both (S,E)-12a and (R,Z)-12a form a mixture of (S,E)-16
and (R,Z)-16.
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[32] See Supporting Information for additional details regarding control
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Received: November 7, 2012
Published online: January 24, 2013
3444
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Chem. Eur. J. 2013, 19, 3437 – 3444