Intermolecular Allylic C?H Etherification of Internal Olefins

Article abstract of DOI:10.1002/anie.201809863

Herein we report on the development of an oxidative allylic C?H etherification reaction, utilizing internal olefins and alcohols as simple precursors. Key advances include the use of RhCp* complexes to promote the allylic C?H functionalization of internal

Full text of DOI:10.1002/anie.201809863

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Accepted Article
Title: Intermolecular Allylic C–H Etherification of Internal Olefins
Authors: Taylor Nelson and Simon B. Blakey
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Angewandte Chemie International Edition
10.1002/anie.201809863
COMMUNICATION
Intermolecular Allylic C–H Etherification of Internal Olefins.
[
a]
Taylor A. F. Nelson and Simon B. Blakey*
Abstract: Herein we report on the development of an oxidative
allylic C–H etherification reaction, utilizing internal olefins and
alcohols as simple precursors. Key advances include the use of
RhCp* complexes to promote the allylic C–H functionalization of
internal olefins and the compatibility of the oxidative conditions with
oxidatively sensitive alcohols, enabling the direct etherification
reaction. Preliminary mechanistic studies, consistent with C–H
functionalization as the rate determining step, are presented.
A) Allylic ether and alcohol containing medicinal compounds
i-Pr
OH
OH
OH
O
N
Me
O
Me
S
O
O
OH
N
N
O
O
O
Me
N
H
F
Me
rosuvastatin (CrestorTM)
OH OMe
O
Me
2
H N
Allylic alcohols and ethers are important functional
motifs, commonly found in a variety of pharmaceutical agents
and natural products, such as rosuvastatin, zampanolide, and
H
O
O
H
O
(-)-zampanolide
O
H
1
-9
eribulin (Figure 1A).
Traditionally, these compounds are
O
synthesized using nucleophilic attack of an aldehyde with a
vinyl metal reagent or by substitution of an appropriate allylic
O
O
O
Me
1
0-12
O
leaving group.
Transition metal catalyzed allylic
substitution represents a particularly powerful tool, with the
catalyst capable of controlling both regioselectivity and
absolute stereochemistry in the etherification reaction.
eribulin (HalavenTM
)
1
3-15
B) Recent advances in allylic oxygenation (terminal olefins)
Even with the significant advances in these methods,
1
6
White (2004), Regioselective acetoxylation
H
they all rely on prefunctionalized building blocks. An attractive
alternative involves the direct oxidative coupling of an allylic C–
H bond with an alcohol, to directly forge the desired allylic
ether. Despite the intuitive nature of this disconnection
strategy, methods capable of delivering a broad array of allylic
ethers remain underdeveloped. Following pioneering work on
OAc
[
Pd] (10 mol %)
or
R
R
BQ (2 equiv.)
AcOH, 40 °C
R
OAc
White (2014), Intramolecular etherification
1
7-18
propene acetoxylation
White and co-workers developed
O
O
S
S
conditions for the regioselective allylic esterification of terminal
OH
Ph
Ph
O
1
9-30
olefins (via Pd-π-allyl complexes, 1B).
However oxidative
Pd(OAc)2 (10 mol %)
allylic etherification is considerably more challenging, with both
the starting alcohol and the allylic ether susceptible to
competitive oxidation. Only recently have intramolecular and
BQ (2 equiv.), DCE (0.3 M)
4
5 °C, 16 h
H
3
1-33
Jiang (2017), Intermolecular etherification
intermolecular allylic etherifications been disclosed (1B).
Although these palladium catalyzed methods have enabled the
H
Pd(OAc)2 (10 mol %)
3
4
development of novel synthetic strategies, they remain
limited to terminal olefins, significantly restricting their use in
synthesis.
DMSO, 80 °C
O ballooon, ROH
2
OR
C) This work: Intermolecular etherification of internal olefins
We recently discovered that Rh(III)Cp* complexes were
[
RhCp*Cl
2 2
]
capable of catalyzing intermolecular allylic C–H amination
H
AgSbF
6
OR
3
5-38
AgOAc
reactions of mono-, di-, and trisubstituted olefins.
In this
OTBDPS
OTBDPS
manuscript, we describe the evolution and development of
regioselective intermolecular allylic etherification reactions of
both terminal and internal olefins (1C) based on this Rh(III)Cp*
catalysis platform.
3
ROH
,2-DCE , 60 °C
3
1
Figure 1. Selected examples of biologically active allylic alcohols and ethers,
and reaction development advances. BQ = 1,4-benzoquinone, DCE = 1,2-
dichloroethane, Cp* = 1,2,3,4,5-pentamethylcyclopentadiene, TBDPS = tert-
Butyldiphenylsilane
[a]
T. A. F. Nelson, Prof. Dr. S. B. Blakey
Department of Chemistry
Emory University
After a short survey of potential alcohol coupling partners,
we selected benzyl alcohol as a suitable starting material for
our study. We began by testing the standard conditions
developed for our recently reported allylic C–H amination
1
515 Dickey Dr., Atlanta, GA 30322, U.S.A.
E-mail: sblakey@emory.edu
Supporting information for this article is given via a link at the end of
the document.
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Angewandte Chemie International Edition
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COMMUNICATION
Table 1. Optimization of allylic etherification
reaction but observed a surprisingly low yield of the expected
[
Rh] (4 mol %)
2
H
allylic ether
2
(27%, Table 1, entry 1). The sp C–H
Additive (10 mol %)
AgOAc (2.2 equiv.)
OR
OTBDPS
functionalization literature describes the importance of the
OTBDPS
Ph
Ph
3
BnOH
silver salt in determining reaction yields in RhCp* catalyzed
3
1,2-DCE
39-40
1
2, R = OBn
, R = OAc
reactions.
Accordingly, we investigated alternative silver
3
salts to remove the chloride ligands from the rhodium
precatalyst. The use of AgSbF resulted in a dramatic increase
time BnOH
yield yield
2 (%) 3 (%)
entry
1
[Rh]
T(ºC)
additive
6
(h)
(Eq.)
in reaction efficiency and product 2 was observed in 97% yield
(entry 2). Lowering the reaction temperature (40 ºC), even with
an extended reaction time (24 h) resulted in a reduced yield
(68%, entry 3). In an attempt to simplify the reaction conditions,
[RhCp*Cl2]
2
60
60
40
5
5
AgBF4
27
97
68
29
0
0
2
2
[RhCp*Cl2]2
[RhCp*Cl2]2
5
5
5
5
5
AgSbF6
3a
24
5
AgSbF6
-
1
we
employed the
halide
free
precatalyst
4
5
6
7
8
9
[RhCp*(MeCN) ](SbF ) 60
0
3
6 2
[
RhCp*(MeCN)
3
](SbF ) . However, this reaction resulted in
6 2
-
60
60
60
60
60
5
AgSbF6
0
only 29% yield (entry 4). In a control reaction with no RhCp*
complex present, no product is obtained, and the starting olefin
is recovered in 87% yield (entry 5). In an attempt to further
optimize the reaction, we observed that decreasing the
equivalents of nucleophile from 5 to 2.5, resulted in only 25 %
yield after five hours (entry 6),
[RhCp*Cl2]2
[RhCp*Cl2]2
[RhCp*Cl2]2
[RhCp*Cl2]2
5
2.5 AgSbF6
25
91
91
76
0
24
5
2.5 AgSbF6
2.5 AgBArF4
4
11
7
5
2.5 NaBArF
4
1
All yields were determined by H NMR assay utilizing 1, 3, 5-trimethoxybenzene
F
4
as an internal standard. Bar = Tetrakis[3,5-bis(trifluoromethyl)phenyl]borate
Table 2. Reaction scope with respect to the alcohol coupling partner for allylic C–H etherification.
[
RhCp*Cl
2
]
2
(2 mol %)
H
AgSbF
(10 mol %)
OR
6
AgOAc (2.2 equiv)
OTBDPS
OTBDPS
Ph
Ph
ROH (5-10 equiv.)
1
,2-DCE (0.2 M), 60 o C, 5 h
OMe
OEt
Oi-Pr
Ot-Bu
O
CCl
3
OTBDPS
OTBDPS
OTBDPS
OTBDPS
OTBDPS
Ph
Ph
Ph
Ph
Ph
3
3
3
3
3
, 51%[a]
5, 70%
6, 47%[b]
7, 0%
Oi-Bu
8, 44%
4
O
CF
3
O
O
Me
OTBDPS
O
t-Bu
OTBDPS
OTBDPS
OTBDPS
OTBDPS
Ph
Ph
Ph
Ph
Ph
3
3
3
3
3
, 59%[a]
10, 65%
11, 67%
d.r. 2.1:1)
12, 59%
13, 45%
9
(
CF
3
OMe
O
O
O
O
O
O
3, 51%
O
Me
OTBDPS
OTBDPS
OTBDPS
OTBDPS
OTBDPS
Ph
Ph
Ph
Ph
Ph
3
3
3
3
3
15, 42%[b]
Me
2
, 87%[c]
14, 65%
16, 49%
Me
O
Boc
N
O
O
O
O
Me
Me
NBoc
O
O
O
O
NHBoc
MeO
O
O
O
OTBDPS
OTBDPS
Ph
Ph
OTBDPS
OTBDPS
3
OTBDPS
3
3
Ph
Ph
Ph
3
3
1
7, 33%[d]
18, 56%[d]
9, 42%[d]
20, 75%[d]
21, 61%[e]
1
(d.r. 1.2:1)
(d.r. 1.0:1)
(d.r. 1.2:1)
All reactions were carried out on a 0.2 mmol scale with 5 equivalents of alcohol at 60 °C for 5 h unless otherwise stated. Yields are reported for isolated product. [a]10 equivalents
of alcohol were used. [b] Reactions were run with 3 equivalents of AgOAc. [c] Reactions were run using 5 mol % catalyst loading. [d] Reaction time was 24 h. [e] Reaction time
was 48 h. Boc = tert-Butyloxycarbonyl
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Angewandte Chemie International Edition
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COMMUNICATION
but with an increased reaction time (24 h) a 91 % yield was
appear to provide higher product yields than aliphatic alcohols
with similar steric demands. iso-Butanol and neo-pentyl alcohol
(12, 59% and 13, 45%) were both effective nucleophiles,
demonstrating that steric bulk is tolerated if it is one carbon
removed from the alcohol. The relationship between electronic
parameters and reaction yield for benzyl alcohols did not follow
any specific trend. The use of an electron deficient nucleophile
(para-trifluoromethyl benzyl alcohol) resulted in a lower yield (14,
65%) than that observed for benzyl alcohol (2, 87%). However,
the use of electron rich para-methoxy benzyl alcohol also resulted
in a low yield (15, 42%). In this case, inspection of the crude
obtained (entry 7). Additional optimization of the silver salt
F
revealed that AgBAr
4
was particularly effective, and that a 91%
yield could be obtained in just 5 h, with 2.5 equiv of benzyl alcohol.
However, under these conditions, an increased amount of the
F
undesired allylic acetate 3 was also observed (entry 8). NaBAr
4
was also moderately effective and provided the product in 76%
yield (entry 9). Despite the promising results observed with
F
AgBAr
4
this reagent must be synthesized from costly starting
materials prior to use. Thus, we proceeded to investigate the
scope of the allylic etherification reaction using the conditions
outlined in entry 2, which utilize commercially available reagents
and provide the highest yield of product.
1
reaction mixture by H NMR revealed competing oxidation of
alcohol to para-anisaldehyde had occurred, highlighting the
delicate balance between productive allylic etherification and the
known oxidative side reaction. Naphthyl-2-methanol resulted in
Methanol (51%), ethanol (70%) and iso-propanol (47% table
2
, 4-6) were all effective nucleophiles, although no specific steric
4
9 % yield (16). As acetate addition had been observed as a side
trend was observed. However, no product was obtained when
tert-butanol was used, presumably due to the particularly
hindered nature of this alcohol. The use of less nucleophilic
alcohols such as trichloroethanol (TCE) and trifluoroethanol (TFE)
resulted in lower yields (8, 44% and 9, 39% respectively). The
reaction could be improved by increasing the equivalents of TFE
reaction during the optimization process, we conducted a reaction
with acetic acid replacing the alcohol. In this case the acetate
addition product was isolated in moderate yield (3, 51%). To
demonstrate the potential utility of this reaction for medicinal
chemistry purposes, we investigated a series of relevant alcohols
with more complex functionality. Small ring heterocycles, such as
(
10 equiv resulted in 59% yield 9). To further evaluate the impact
3
-oxetanemethanol (17, 33%), and N-Boc-3-azetidinemethanol
of steric factors on the reaction outcome two other secondary
alcohols were tested. The reaction of 2-indanol under the
standard conditions resulted in 65% yield (10) and 1-
phenylethanol provided product in 67% yield (11). However, only
modest stereoinduction was observed (2.1:1 d.r.). These
observations follow a general trend that benzylic alcohols
(
18, 56%) were competent in the reaction. Reaction with a
representative carbohydrate (acetonide protected galactose)
gave the product in 42 % yield (19, 1.2:1 d.r.). An N-Boc-
morpholine containing alcohol gave 75% yield (20, 1:1 d.r.) and
the use of N-Boc-Ser-OMe provided product in 61% yield (21,
1
.2:1 d.r.). In all cases the chiral nucleophile did not provide
significant stereoinduction. These substrates highlight that the
reaction is capable of tolerating significant functional group
complexity in the alcohol coupling partner.
Table 1. Optimization of allylic etherification
[
RhCp*Cl2]2 (2 mol %)
AgSbF6 (10 mol %)
AgOAc (2.2 equiv)
H
OBn
Ar
R
Ar
R
To further investigate the efficiency of the allylic
etherification, a range of aryl-alkyl disubstituted olefin substrates
were investigated. Ortho substituents on the aryl ring were
tolerated, albeit with lower yield than parent compound (table 2,
o-Me (22) 43%, o-i-Pr (23) 57%). Electronic variation of the aryl
ring impacted both the rate and yield of the reaction although no
correlation between Hammett parameters and reaction yields was
BnOH (5 equiv)
1
,2-DCE (0.2 M), 60 o
C
OBn
OTBDPS
OBn
3
OTBDPS
R
3
R
2, R = Me 43%[
3, R = i-Pr 57%[
a]
3
observed (p-CF (24) 45%, p-Br (25) 60%, p-F (26) 61%, p-OMe
(27) 58%). We note that the electron deficient substrates required
2
2
a]
longer reaction times.
OBn
4, R = CF3 45%[b,c]
2
2
2
2
5, R = Br
6, R = F
60%[c]
61%[d]
R
We also note that the reaction is effective for the terminal
olefin of allyl benzene, producing the allyl ether 28 in 60% yield.
1,3-Diphenylpropene provided allyl ether 29 in 70% yield. More
complex substrates derived from estrone (30, 75%),
phenylalanine (31,41%), and tocopherol (32, 33%) were all
effectively converted to their corresponding allyl ethers,
illustrating the potential for late stage modification of complex
biologically relevant molecules.
7, R = MeO 58%[e]
[
f]
2
2
8, R = H 60%
9, R = Ph 70%
[g]
OBn
OTBDPS
H
H
3
OBn
OTBDPS
H
NHBoc
3
MeO
Me
O
To probe the reaction mechanism, we investigated
deuterium exchange under the reaction conditions, as well as
kinetic isotope effects. Deuterated 1,3-diphenylpropene ([D] 33)
was submitted to the reaction conditions. The reaction was run to
partial completion yielding a (0.85:1) mixture of deutero products
O
31, 41%[i]
3
0, 75%[h]
OBn
OTBDPS
Me
Me
Me
3
[
D]29 and [D’]29 in 30% combined yield as well as a 50% yield of
Me
O
Me
recovered deutero starting material. No deuterium to proton
exchange was observed in either product or recovered starting
material. An inverse secondary isotope was measured as 0.85,
Me
3
2, 33%[j]
2
3
consistent with a change from sp to sp hybridization during the
C–O bond forming step. A primary kinetic isotope effect was
measured using a 1:1 mixture of proteo and deutero 1,3-
diphenylpropene. The reaction was run to 11% conversion and a
KIE of 3.3 was observed (Scheme 1, eq. 2). These results suggest
an irreversible C–H bond cleavage to give a symmetric π-allyl
[
a] Reaction time was 24 h. [b] Reactions were run using 5 mol % catalyst loading.
[
[
c] Reaction time was 48 h. [d] Reaction time was 31 h. [e] Reaction time was 4 h.
f] Reaction time was 20.5 h. [g] Reaction time was 6 h. [h] AgBAr
F
4
was utilized as
the halide scavenger in place of AgSbF
was 26 h.
6
. [i] Reaction time was 27 h. [j] Reaction time
4
1
complex. Subsequent C–O bond formation delivers the ether
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Angewandte Chemie International Edition
10.1002/anie.201809863
COMMUNICATION
product. A detailed mechanistic study to further elucidate the full
mechanistic details of this transformation is ongoing in our
laboratory.
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H
OBn
Ph
H
8.
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Dactylolide and Formal Synthesis of (−)-Zampanolide. Org. Lett.
D
OBn
Ph
+
Ph
Ph
[
RhCp*Cl2]2 (2 mol %)
AgSbF6 (10 mol %)
AgOAc (2.2 equiv)
D
D
Ph
[D]29
[D’]29
9.
(1)
Ph
30% ([D]29, [D’]29,0.85:1)
2
005, 7, 2321-2324.
BnOH (5 equiv)
1
,2-DCE (0.2 M),
+
10.
11.
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[
D]33
6
0 C, 24 h
o
H
D
D
100% D
Ph
Ph
[
D]33
5
0%
1
2.
D
D
1
4% D 12% D
Ph
Ph
[RhCp*Cl2]2 (2 mol %)
AgSbF6 (10 mol %)
AgOAc (2.2 equiv)
+
H
H
H
OBn
Ph
13.
14.
H
(
2)
BnOH (5 equiv)
Ph
1
,2-DCE (0.2 M),
Ph
(
Ph
o
6
0 C, 0.3 h
1
1%
[D]33,33, 1:1)
KIE = [H/D] = 3.3
1
1
1
5.
6.
7.
Scheme 1. Deuterium exchange and kinetic isotope effect experiments.
In conclusion, we have developed the first allylic C–H
etherification of internal olefins with a wide variety of alcohols and
olefin substrates. The reaction is tolerant of oxidatively sensitive
alcohols and compatible with several biologically relevant olefin
coupling partners. Mechanistic studies provide evidence for
irreversible formation of a π-allyl complex. The ability to convert
simple internal olefins to complex allylic ethers represents a
significant advance in C–H functionalization methodology.
1
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This research was supported by the National Science Foundation
under the Center for Chemical Innovation in Selective C–H
Functionalization (CHE-1700982) and in part by the University
Research Committee, Emory University. NMR studies were
performed on instrumentation funded by the NSF (CHE-
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and the Emory University Mass Spectrometry Center. We
gratefully acknowledge Caitlin M. B. Farr (Department of
Chemistry, Emory University) and Karthikeyan Jaganathan for
preliminary investigations and helpful discussions.
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Keywords: C-H functionalization • π-allyl • rhodium •etherification
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Another piece of the π-allyl puzzle: Rhodium Cp* complexes promote the
activation of a broad range of allylic C–H bonds, and catalyze oxidative coupling with
complex alcohols, overcoming competing alcohol oxidation reactions to provide
direct access to allylic ethers.
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