Gold-Catalyzed, SN1-Type Reaction of Alcohols to Afford Ethers and Cbz-Protected Amines

Article abstract of DOI:10.1055/s-0034-1380128

The use of a gold-catalyzed, microwave protocol to activate alcohols through an intermolecular, S_N1-type reaction to directly form unsymmetrical ethers and N-benzyloxy carbamate- (Cbz) protected amines is reported. Results have shown this reaction to be highly reproducible and tolerant of moisture, and moderate to high product yields (53-99%) were obtained. Significantly, the intermolecular catalytic amination of alcohols to directly afford Cbz-protected amines is heretofore unprecedented using gold catalysis.

Full text of DOI:10.1055/s-0034-1380128

SYNLETT
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9
3
6
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2
1
4
1
4
3
7
-
2
0
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6
© Georg Thieme Verlag Stuttgart · New York
2015, 26, 765–770
letter
765
A. R. S. Vinson et al.
Letter
Synlett
Gold-Catalyzed, SN1-Type Reaction of Alcohols to Afford Ethers
and Cbz-Protected Amines
Andrew R. S. Vinson
Victoria K. Davis
Arunamarie Arunasalam
Kate A. Jesse
AuClPPh3 (5 mol%)
AgSbF6 (5 mol%)
R1OH + HOR2
or
R1OH + H2NCbz
R1OR2
or
R1NHCbz
MW (50 °C), 90 min
dichloroethane
17 examples
53–99% yield
Rachael E. Hamilton
Morgan A. Shattuck
Allison C. Hu
Robert G. Iafe
Anna G. Wenzel*
Keck Science Department, Claremont McKenna, Pitzer and Scripps Colleges, 925 N. Mills Avenue, Claremont, CA 91711, USA
awenzel@kecksci.claremont.edu
Received: 13.12.2014
Accepted after revision: 06.01.2015
Published online: 09.02.2015
allenoate ester 1 was reacted with alcohol 2, the desired
Claisen product 3 did not form. Instead, with the applica-
tion of microwave heat (90 °C), allyl ether 4 was isolated as
the major product.
DOI: 10.1055/s-0034-1380128; Art ID: st-2014-r1025-l
Abstract The use of a gold-catalyzed, microwave protocol to activate
alcohols through an intermolecular, SN1-type reaction to directly form
unsymmetrical ethers and N-benzyloxy carbamate- (Cbz) protected
amines is reported. Results have shown this reaction to be highly repro-
ducible and tolerant of moisture, and moderate to high product yields
(53–99%) were obtained. Significantly, the intermolecular catalytic am-
ination of alcohols to directly afford Cbz-protected amines is heretofore
unprecedented using gold catalysis.
O
O
O
H
O
Ph
C
O
Ph
Ph
H
1
3
AuClPPh3 (5 mol%)
AgSbF6 (5 mol%)
(1.0 equiv)
not observed
+
Key words gold, catalysis, ethers, amination, substitution
MW (90 °C), 30 min
THF
O
OH
2
4
The first reports of gold catalysis date back to the begin-
ning of the last century.1 In comparison to other late transi-
tion metals, the use of homogeneous gold catalysis in or-
ganic chemistry is relatively new to the field, in part due to
the previously held belief that gold is a prohibitively expen-
sive, chemically inert metal. However, the past decade has
seen a dramatic re-evaluation of this assessment, with ho-
mogeneous gold compounds being shown to have high cat-
alytic activity in numerous organic transformations.2
Central to the utility of gold in most applications is its
ability to function as a carbophilic, soft Lewis acid.3 An ad-
vantageous consequence of this is that gold salts can act as
‘π acids’ to preferentially activate carbon–carbon double
and triple bonds in the presence of unprotected, Lewis
basic moieties, such as alcohols and amines.4 In particular,
cationic gold species have been shown, in some cases, to
exhibit superior Lewis acidity relative to copper and silver,
which has largely been attributed to relativistic effects.5
With this in mind, we recently embarked on a research
project to explore the possibility of using gold(I) catalysts to
activate allenes towards alcohol nucleophiles to effect alle-
noate Claisen rearrangements (Scheme 1).6 However, when
(1.5 equiv)
5% isolated yield (72% trans)
Scheme 1 Reaction of allenoate ester and allyl alcohol using AuClPPh3/
AgSbF6
The presence of 4, albeit in low yield, first required that
1 react with 2 through a gold-catalyzed transesterification
reaction7 to produce benzyl alcohol, which subsequently
underwent a gold-catalyzed substitution reaction with the
allyl alcohol8 to afford 4. This reaction was initially unex-
pected because gold has generally performed as a soft, alle-
nophilic, Lewis acid under similar conditions.2,9 In particu-
lar, ester alcoholysis is not commonly observed, even when
alcohols are used as the reaction solvent.2i
However, there is a growing body of literature associat-
ed with gold-catalyzed allylic etherification reactions.2,8,10
Most of these reports have centered on intramolecular
etherification to form six-membered rings, because direct,
intermolecular variants of this reaction must overcome
several challenges, including low reactivities, self-reaction
versus cross-reaction, and competing elimination path-
ways, among others. Despite this, recent reports by Lee,
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 765–770

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A. R. S. Vinson et al.
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Crowley, and Widenhoefer have found that gold(I) can func-
tion as a competent catalyst to effect the direct etherifica-
tion of allyl alcohols.8 Given that these methodologies have
generally required long reaction times (16–65 h), despite
employing mild temperatures (40–50 °C), we were in-
trigued by the potential of a microwave variant of this reac-
tion to improve reaction efficiency and expand the reaction
scope to include uninvestigated substrates.
To initially optimize this reaction, we explored the reac-
tion of 2 with benzyl alcohol 5 under a variety of condi-
tions, including modification of the solvent, silver salt, and
gold used.11 The best results were obtained by using Au-
ClPPh3 as the precatalyst and AgSbF6 as the activator
(Scheme 2). No reaction to produce 4 was observed when
control experiments were performed in the absence of ei-
ther the gold precatalyst (AuClPPh3) or the silver activator
(e.g., AgSbF6 or AgOTf), indicating that both species are
needed for catalysis to occur.
solvent from chlorobenzene to dichloroethane, decreasing
the reaction temperature to 50 °C, and increasing the reac-
tion time to 90 minutes, the yield of the corresponding
ether product was found to increase to 83%, while allowing
the amount of isopropanol used to be decreased to 5 equiv-
alents.11 Upon further inspection, it was observed that
some of the isopropanol decomposed during the course of
the reaction. Switching to the use of a primary alcohol ef-
fectively shut down this pathway, allowing for an increase
in the reaction yield to 97%. Reactions could also be scaled
to 1 mmol without any reduction in the isolated yield.
Table 1 Investigation of the Reaction of Indanol with Alcoholsa
OH
OH
OR
6
AuClPPh3 (5 mol%)
AgSbF6 (5 mol%)
(1.0 equiv)
Ph
OH
+
MW (50 °C), 90 min
dichloroethane
5
ROH
AuClPPh3 (5 mol%)
AgSbF6 (5 mol%)
(1.0 equiv)
8a–d
9
7a–e
(5 equiv)
+
O
Ph
MW (90 °C), 30 min
chlorobenzene
4
Entry
ROH
Product
Yield (%)b,c
83 (83)
OH
32% isolated yield
2
(10 equiv)
1
2
3
7a
7b
7c
8a
OH
Scheme 2 Gold-catalyzed reaction of allyl alcohol 2 with benzyl alco-
hol 5
OH
8b
8c
98
97
Chlorobenzene afforded the cleanest conversion into
product, and the use of microwave heat served to double
the yield relative to the use of conventional heat. The de-
sired ether was isolated in 32% yield after 30 minutes. Only
the trans ether was observed under these conditions, which
is consistent with the results reported for related method-
ologies.8
OH
OH
4
5
7d
7e
8d
9
96
88
OH
To our knowledge, no direct, intermolecular variant of
this reaction to substitute benzylic alcohols has been re-
ported employing a gold(I) source as the starting complex.
This stands in marked contrast to two known examples us-
ing gold(III),12 which is generally accepted to serve as a
standard Lewis acid instead of a carbophilic, π-bond pro-
moter.2f Additional examples of the generation of ethers
from alcohols frequently employ either protic acids,13 het-
erogeneous catalysis,14 iridium,15 or rhenium.16 Remaining
reports list only singular examples17 or rely upon metal-
allyl chemistry18 (e.g., Pd, Ni) to proceed. Given that the di-
rect, intermolecular generation of ethers represents a rela-
tively new avenue for gold research, we elected to study this
reaction in greater detail.
a Reactions performed on a 0.25 mmol scale.
b Determined by GC analysis, with calibration factor determination against
authentic material.
c Isolated yield given in perenthesis.
The possibility of using phenol as a nucleophile was also
investigated, because indenyl phenyl ethers are well known
to have diverse medicinal applications.19 However, instead
of the desired ether product, the reaction of 6 with phenol
(7e) afforded 9, the result of a Friedel–Crafts alkylation re-
action. Interestingly, while examples of gold(I)-catalyzed
Friedel–Crafts reactions are known,2,20 this specific trans-
formation has traditionally performed poorly with gold(I)
salts. For example, a detailed study by Rao and Chan afford-
ed only 5% yield when AuClPPh3 was employed,21 and no re-
action was observed when this gold source was employed
in Campagne and co-workers’ related investigation using
phenyl propargylic alcohols.22 The high yields (88%) we
In an effort to increase reaction yield, while reducing
the number of equivalents of the partner nucleophilic alco-
hol used, we first investigated the reaction of indanol with
isopropanol (Table 1, entry 1). By switching the reaction
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767
A. R. S. Vinson et al.
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Table 2 (continued)
Entry R1OH
have obtained for 9 and related substrates indicates that our
microwave protocol can provide enhanced substrate scope
for gold reactivity.
R2OH Time
(min)
Product Yield
(%)b
With an optimized set of reaction conditions, we next
turned towards investigating the scope of the etherification
reaction (Table 2). Similar to the trend observed with 1-in-
danol, primary alcohols afforded the best yields with
1,2,3,4-tetrahydro-1-naphthol (10; Table 2, entries 1–4).
For this reason, the primary alcohol isobutanol (7b) was se-
lected for investigating the remaining carbocation-forming
alcohols 11–19.
OH
11
17
7b
90
27
73
F
OH
12
18
19
7b
7b
90
90
28
29
–
–
NO2
Table 2 Scope of the Gold-Catalyzed Etherification Reactiona
OH
13
AuClPPh3 (5 mol%)
AgSbF6 (5 mol%)
R1OH
HOR2
R1OR2
+
MW (50 °C)
dichloroethane
a Reaction performed on a 0.25 mmol scale.
10–19
(1.0 equiv) (5 equiv)
7a–d
20–29
b Determined by GC analysis, with calibration factor determination against
authentic material.
c Reaction performed at 70 °C.
Entry R1OH
R2OH Time
(min)
Product Yield
(%)b
OH
OH
OH
Interestingly, acyclic structures, such as 11 and 12, af-
forded the ether products somewhat sluggishly, requiring
additional time (180 min) to achieve synthetically useful
reaction yields (Table 2, entries 5 and 6). However, the addi-
tion of a donor substituent allowed for high yields (up to
99%) to be obtained within a 90-minute timeframe, with
the notable example of the methoxy-substituted, alcohol
14. When the latter compound was initially reacted with 7b
at 50 °C for 90 minutes, despite 100% conversion of the lim-
iting alcohol, the desired ether 24 was not observed. Think-
ing that rapid conversion into product, followed by decom-
position, might be occurring due to the high donor capaci-
ty23 of the methoxy group, a series of experiments using
decreased reaction times was performed, which ultimately
revealed that 5 minutes afforded the best reaction time for
optimal yield (72%) in this case.
1
2
3
4
7a
7b
7c
7d
90
90
90
90
20a
20b
20c
20d
73
97
99
95
10
11
12
5
6
7b
7b
180
180
21
22
86
53
HO
7
13
7b
90
23
83
Chlorinated and fluorinated alcohols also performed
well (Table 2, entries 10 and 11), although it must be noted
that extended reaction time (180 min) and increased tem-
perature (70 °C) were required to obtain optimal yields
with the chlorinated substrate 16. In contrast, negligible
conversion of the strongly electron-deficient, nitro-substi-
tuted alcohol 18 was observed under the standard reaction
conditions used. These results are not unexpected, given
what is known of the mechanism of the SN1 reaction and
the Hammett σ+ constants23 associated with the aryl sub-
stituents on carbocation-forming alcohols. Significantly, for
all substrates investigated under the reported reaction con-
ditions, no symmetric ether formation was observed.
Alcohol 19 was investigated to explore the possibility of
extending substrate scope to include aliphatic alcohols. Un-
fortunately, when this compound was subjected to the
standard reaction conditions with 7b (Table 2, entry 13),
OH
8
9
14
15
16
7b
7b
7b
5
90
24
25
26
72
97
99
MeO
OH
Me
Cl
OH
10c
180
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 765–770

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A. R. S. Vinson et al.
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the desired ether 29 was not observed, despite 100% con-
version of the starting alcohol. Instead, a complex product
mixture of alkenes resulted.
Table 3 Gold-Catalyzed Catalytic Amination of Alcoholsa
AuClPPh3 (5 mol%)
AgSbF6 (5 mol%)
To investigate the potential for asymmetric induction in
our gold-catalyzed ether formation, the reaction of alcohol
13 with 7b in the presence of a chiral, gold(I) catalyst was
explored. Although reactions employing chiral 13 were
found to lead to racemization under our standard reaction
conditions,11 asymmetric SN1 reactions employing chiral
catalysts, while rare, have been recently reported.24 Unfor-
tunately, when the chiral precatalyst (S)-(+)-2,2′-bis[di(3,5-
di-t-butyl-4-methoxyphenyl)phosphino]-6,6′-dimethoxy-
1,1′-biphenyl gold(I) chloride was used in lieu of AuClPPh3,
chiral analysis by HPLC found that the product ether 23 was
virtually racemic. We are investigating the use of chiral
auxiliaries on the substrate to effect asymmetric induction
in this reaction in lieu of the use of a chiral catalyst.
ROH
H2NCbz
(4 equiv)
RNHCbz
+
MW (50 °C)
dichloroethane
6, 13
(1.0 equiv)
30–31
Entry
1
ROH
Time
(min)
Product
Yield
(%)b,c
NHCbz
6
60
90
30
31
92 (89)
NHCbz
2
13
88 (87)
a Reaction performed on a 0.25 mmol scale.
We have recently begun to explore the catalytic amina-
tion of alcohols to further expand the scope of our reaction
protocol. Previous reports have predominantly included the
use of hard acids25 or iron, rhenium, ruthenium, iridium, or
copper metal complexes to catalyze this reaction.26,27 A few
gold(III)-catalyzed reactions employing anilines28,29 and
tosylamides22,29 have also been reported.2c These systems,
however, are generally restricted to amine nucleophiles
bearing substituents (e.g., aryl, alkyl, or tosyl groups) that
impose several practical limitations for the deprotection of
the product amine. A notable exception to this is a 2012 re-
port by Ohshima, Mashima, and co-workers, which de-
scribes the use of aluminum triflate to catalytically activate
alcohols towards carbamate nucleophiles.30 Notably, some
examples of direct amination using ruthenium catalysts
have also been reported.27 Other methods of alcohol amina-
tion employ indirect methods utilizing azide-based nucleo-
philes.31 With this in mind, the extension of our gold-cata-
lyzed SN1 reactions to include carbamate-based nucleo-
philes would serve to expand the utility of this reaction.
Preliminary results of our ongoing study are summa-
rized in Table 3, including the successful use of N-benzyloxy
carbamate (Cbz-NH2) in the amination of alcohols 6 and 13.
Solubility considerations meant that the optimal conditions
for this reaction involved the use of four equivalents of Cbz-
NH2 relative to the starting alcohol. These reactions were
found to proceed cleanly, affording the corresponding Cbz-
protected amine products in high isolated yields. The excess
Cbz-NH2 could also be readily recovered, if desired.
b Determined by GC analysis, with calibration factor determination against
authentic material.
c Isolated yield given in parentheses.
closed a detailed study in which a series of cationic, tri-
phenylphosphine-gold(I)·SbF6 complexes were generated in
situ and these were found to readily decompose at tem-
peratures above –20 °C (e.g., t1/2 = 90 min at 0 °C).32 Indeed,
visual inspection of the microwave vials upon completion
of our etherification and amination reactions revealed a
distinctive gold mirror, indicating that decomposition of
the gold(I) salt to produce elemental gold33,34 had occurred
at some point during the reaction. This offers the intriguing
possibility that, instead of homogeneous gold catalysis,
gold nanoclusters of a few atoms generated in situ34,35 could
be the catalytically active species in our protocol. This sce-
nario could help explain the unusual behavior observed
during the application of our protocol (e.g., the failure to ac-
tivate the allene in the Claisen reaction, the divergent be-
havior of our protocol relative to other gold(I) complexes in
the Friedel–Crafts reaction, and the lack of asymmetric in-
duction using a chiral, gold(I) catalyst). Future endeavors
will attempt to probe this possibility through investigation
of the reaction media itself by using nanoanalytical chemis-
try, as well as through the preparation of gold nanoclus-
ters34–36 of various sizes and the evaluation of their perfor-
mance relative to the conditions outlined in this report.
In summary, a protocol involving the use of gold cataly-
sis has been developed to directly prepare unsymmetrical
benzylic ethers and Cbz-protected amines in moderate to
excellent yields under mild conditions.37 No symmetric
ether formation was observed under the reported reaction
conditions. The etherification reaction was found to toler-
ate a wide range of alcohols. Of particular note, the inter-
molecular catalytic amination of alcohols to directly pro-
duce carbamate-protected amines is heretofore unprece-
dented using gold catalysis. Efforts are ongoing to extend
In addition to expanding the substrate scope, a future
direction of this project will involve an attempt to ascertain
the precise identity of the active catalytic species in these
reactions. Although cationic gold(I) methodologies abound
in the literature,2 of late, reports have begun to question
whether some of these homogeneous gold species are truly
the active catalysts, particularly when heat is employed in
the reaction. Widenhoefer and co-workers recently dis-
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A. R. S. Vinson et al.
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this methodology to include additional alcohols and carba-
mates, as well as to explore chiral applications through the
use of substrate auxiliaries. Mechanistic studies will be em-
ployed to investigate whether gold nanoclusters generated
in situ could play an active role in the catalysis of these re-
actions.
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Acknowledgment
Acknowledgment is made to the National Science Foundation (CHE
#1151933) for support of this research. A.R.V. was supported by a
summer research grant from the Jean Dreyfus Boissevain Lectureship
for Undergraduate Institutions. S.A. and R.E.H. were funded through a
Keck Foundation Summer Research Grant. A.C.H. was supported by a
grant from the Rose Hills Foundation. Dr. Scott Virgil of 3CS Caltech is
gratefully acknowledged for chiral separation analysis; Professor Hal
Van Ryswyk of Harvey Mudd College is thanked for ESMS and NMR
spectrometer use. Dr. Mona Shahgholi and Naseem Torian of the
Caltech Mass Spectrometry Facility are acknowledged for performing
HR mass spectral analyses.
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Supporting Information
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(37) SN1 Reaction; Typical Procedure for 20b: A stock solution was
prepared in an oven-dried, 4-mL vial equipped with a septum
cap; the stock contained the carbocation-forming alcohol 10
(0.375 mmol, 1.0 equiv), the nucleophilic alcohol 7b (1.88
mmol, 5.0 equiv), and undecane (internal standard for GC;
0.075 mmol, 0.2 equiv), which were dissolved in dichloroethane
(2.4 mL) until homogeneous. In a glove box, a second solution
was prepared in an oven-dried, foil-covered, 0.5–2.0 mL micro-
wave vial by first measuring out AuClPPh3 (6.2 mg, 0.0125
mmol, 5 mol%) and AgSbF6 (4.3 mg, 0.0125 mmol, 5 mol%). The
vial was sealed with a crimp-top cap equipped with a septum,
then it was removed from the glovebox and attached to a needle
connected to a nitrogen line. Dichloroethane (0.2 mL) was
added into the microwave vial by using a syringe, and the
resulting mixture was stirred for 10 min to initiate the catalyst.
Two-thirds of the stock solution was then added to the micro-
wave vial. The nitrogen line was removed, and the reaction vial
was placed in a microwave reactor and heated to 50 °C for
90 min. The reaction was directly purified by flash chromatog-
raphy on silica gel. After purification of the product, its GC
response factor was determined and retroactively used to calcu-
late the reaction yields from the corresponding GC data; GC
yields (97%) were correlated with the isolated yield (48 mg,
94%) obtained from duplicate reactions. IR (Na plate): 2949,
2869, 1119, 1080 cm–1 1H NMR (500 MHz, CDCl3, 20 °C): δ =
;
7.43–7.41 (m, 1 H), 7.21–7.17 (m, 2 H), 7.12–7.09 (m, 1 H), 4.41
(t, J = 5.1 Hz, 1 H), 3.45 (dd, J = 8.7, 8.8 Hz, 1 H), 3.29 (dd, J = 8.7,
8.7 Hz, 1 H), 2.89–2.82 (m, 1 H), 2.77–2.70 (m, 1 H), 2.07–1.89
(m, 4 H), 1.79–1.72 (m, 1 H), 0.99 (d, J = 6.8 Hz, 3 H), 0.98 (d, J =
6.8 Hz, 3 H). 13C NMR (125 MHz, CDCl3, 20 °C): δ = 137.4, 137.3,
129.1, 128.8, 127.2, 125.7, 75.8, 75.6, 29.2, 28.9, 28.1, 19.6, 19.1.
HRMS (EI+): m/z [M + H – H2] calcd for C14H19O: 203.1436;
found: 203.1447.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 765–770

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