Iridium-catalyzed, intermolecular hydroetherification of unactivated aliphatic alkenes with phenols

Article abstract of DOI:10.1021/ja4052153

Metal-catalyzed addition of an O-H bond to an alkene is a desirable process because it allows for rapid access to ethers from abundant starting materials without the formation of waste, without rearrangements, and with the possibility to control the stereoselectivity. We report the intermolecular, metal-catalyzed addition of phenols to unactivated α-olefins. Mechanistic studies of this rare catalytic reaction revealed a dynamic mixture of resting states that undergo O-H bond oxidative addition and subsequent olefin insertion to form ether products.

Full text of DOI:10.1021/ja4052153

Subscriber access provided by University of South Florida
Communication
Iridium-Catalyzed, Intermolecular Hydroetherification
of Unactivated Aliphatic Alkenes with Phenols
Christo S. Sevov, and John F. Hartwig
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/ja4052153 • Publication Date (Web): 04 Jun 2013
Downloaded from http://pubs.acs.org on June 5, 2013
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a free service to the research community to expedite the
dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts
appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been
fully peer reviewed, but should not be considered the official version of record. They are accessible to all
readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered
to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published
in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just
Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor
changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers
and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors
or consequences arising from the use of information contained in these “Just Accepted” manuscripts.
Journal of the American Chemical Society is published by the American Chemical
Society. 1155 Sixteenth Street N.W., Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 5
Journal of the American Chemical Society
1
2
3
4
5
6
7
8
9
Iridium-Catalyzed, Intermolecular Hydroetherification of
Unactivated Aliphatic Alkenes with Phenols
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Christo S. Sevov and John F. Hartwig*
Division of Chemical Sciences, Lawrence Berkeley National Laboratory, and the Department of Chemistry, University of
California, Berkeley, California 94720.
Supporting Information Placeholder
lent ee, but the reactions do not occur intermolecularly or with
ABSTRACT: Metal-catalyzed addition of an O–H bond to an
mono-enes.6 Likewise, Ir, Pd, Pt, and lanthanide complexes
alkene is a desirable process because it allows for rapid access
catalyze intramolecular additions of alcohols to alkenes and
to ethers from abundant starting materials without formation
alkynes, but the intermolecular additions to alkenes catalyzed
of waste, without rearrangements, and with the possibility to
by such complexes are unknown.7 Intermolecular hydroetheri-
fication of allenes with both carboxylic acids and phenols to
control stereoselectivity. We report the intermolecular, metal-
catalyzed addition of phenols to unactivated α-olefins. Mech-
form allylic ethers has been reported to occur in high yield and
anistic studies on this rare catalytic reaction reveal a dynamic
ee in the presence of a Rh catalyst, but the reactions do not
mixture of resting states that undergo O–H bond oxidative
occur with mono-enes.8 Finally, the intermolecular additions
addition and subsequent olefin insertion to form ether prod-
of alcohols to unstrained, isolated alkenes have been reported
ucts.
to occur in the presence of triflates of coinage metals.9 In these
cases, the reactions form side products that are characteristic
of carbocation intermediates.10
Metal-catalyzed hydrofunctionalization of alkenes offers the
potential to control regioselectivity, diastereoselectivity and
Here, we report intermolecular, metal-catalyzed additions of
phenols to unactivated α-olefins in good yields. The measura-
enantioselectivity of the addition process and to form products
ble enantioselectivity and lack of reaction in the presence of
from readily accessible starting materials without formation of
acid, but absence of the metal, show that the iridium complex,
waste. Metal-catalyzed hydrofunctionalizations also could be
not a proton, catalyzes the addition reaction. Mechanistic stud-
more tolerant of auxiliary functionality than acid-catalyzed
ies imply that the reaction proceeds by reversible oxidative
additions and could occur without the rearrangements that are
addition of the O–H bond of the phenol, followed by turnover-
characteristic of acid-catalyzed additions to alkenes. Hy-
limiting insertion of the alkene.
droamination, the addition of an N–H bond across an unsatu-
Table 1. Reaction Development for the Ir-
Catalyzed Addition of 3-OMe-Phenol to 1-Octenea
rated C–C bond, remains one of the most studied transfor-
mations in hydrofunctionalization chemistry,1 but hydroetheri-
fication, the addition of an O–H bond across an unsaturated
C–C bond, is much less developed.
OAr
OAr
+
4 mol % metal precursor
4.2 mol % (S)-DTBM-Segphos
n-Hex
n-Hex
1-ox
n-Hex
MeO
OH
The ether products of hydroetherification are more often
formed by substitution reactions than addition reactions.2 The
electrophiles in substitution reactions are typically prepared by
a multistep sequence that often includes oxidation or reduction
and functional group interconversion or activation of an alco-
hol. Moreover, these substitution reactions generate salt by-
products. Alternatively, ethers are formed by acid-catalyzed
additions of alcohols to alkenes.3 However, these additions
often require strong acids and high temperatures, form side
products from isomerization of carbocationic intermediates,
and occur without control of the stereochemistry of the prod-
uct. Moreover, acid-catalyzed additions of phenols to alkenes
occur with competitive reaction of the alkene at the O–H bond
and at an ortho or para C–H bond.4 Thus, metal-catalyzed
hydroetherification would exploit the abundance and stability
of alkene starting materials, and could overcome many of the
limitations of the classical syntheses of ethers.
+
1
n
equiv
18 h, 140 °C
+
n-Hex
metal
precursor
additive
(4 mol %)
n equiv % 1-octeneb
% 1b % 1-oxb
entry
1-octene
remaining
30
46c
0
35
68d
0
18
24
60e
51f
38
1
2
3
4
5
6
7
8
9
10
10
10
10
10
10
10
5
11
26
88
48
2
2
5
3
4
10
0
6
0
0
2
5
[Ir(coe)2Cl]2
[Ir(cod)Cl]2
--
[Ir(cod)Cl]2
[Ir(cod)Cl]2
[Ir(cod)2][BF4]
--
--
4% HOTf
17 % Et3N
AgBF4
--
[Ir(cod)2][BF4] KHMDS
[Ir(cod)Cl]2
[Ir(cod)Cl]2
[Ir(cod)Cl]2
[Ir(cod)Cl]2
--
--
--
--
20
40
80
48
64
70
16
17
20
10
11
b
aReactions were performed with 0.2 mmol phenol. Determined
c
d
by GC analysis. 19% ee. 1:1:1 racemic mixture of 2-, 3-, 4-
aryloxy octane. e25% ee. f36% ee.
We previously showed that the combination of iridium and
DTBM-Segphos catalyzes the additions of amides to alkenes.11
On the basis of these studies we tested the combination of
[Ir(coe)2Cl]2 and a series of phosphine, bisphosphine, and che-
lating nitrogen ligands as catalyst for the addition of 3-OMe-
phenol to 1-octene (see Supporting Information for studies
with various ligands). Only Ir complexes of (S)-DTBM-
However, current hydroetherification reactions are limited
in scope. Most reported metal-catalyzed hydroetherifications
of unsaturated C–C bonds are intramolecular and occur with
carbon-carbon multiple bonds that are more reactive than
those of unactivated alkenes.5 Cationic gold complexes cata-
lyze the cyclization of allenyl-alcohols in high yield and excel-
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 2 of 5
Segphos (DTBM = 3,5-di-tert-butyl-4-methoxy) led to sub- with olefins containing activated allylic C–H bonds, such as
1
2
3
4
5
6
7
8
stantial amounts of ether and enol-ether products. Further ex-
periments conducted with (S)-DTBM-Segphos as ligand are
summarized in Table 1. Isomerization of the terminal alkene to
unreactive internal olefin isomers was observed over the
course of the reaction; because internal alkenes are less reac-
tive than terminal alkenes, this isomerization limited conver-
sion of the alkene to the ether. Reactions conducted with
[Ir(cod)Cl]2 as a precursor with a slight excess of bisphos-
phine, relative to Ir, occurred with less alkene isomerization
and concomitantly greater yield of products, compared to reac-
tions conducted with [Ir(coe)2Cl]2 as the iridium precursor
(entry 2 vs. 1).
allylbenzene, under the conditions we developed. Rapid isom-
erization of these terminal alkenes occurred. Alkenes with
steric bulk in close proximity to the reactive alkene reacted
more slowly than alkenes lacking this property. For example,
the reaction of tert-butyl ethylene formed addition product 14
in low yield. However, reaction of 4,4-dimethyl-1-pentene and
4-methyl-1-pentene did form products 13, 17, and 18 in sub-
stantial yields. Reactions of phenols with ethylene and pro-
pene occurred with only 2.5 atm of alkene to form ether and
enol ether products. Catalyst decomposition was observed
upon accumulation of the enol ether during the reactions with
ethylene. Nonetheless, the yields of reactions with these al-
kenes were higher than those with longer chain olefins be-
cause alkene isomers cannot form during reactions of these
two alkenes.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Several experiments provide strong evidence that the reac-
tion is catalyzed by iridium, not a proton. Measurable, albeit
modest, ee values for this reaction (19-40%) rule out alkene
hydroetherification catalyzed by a proton alone. Products were
not detected from reactions conducted in the presence of lig-
and HOTf (entry 3), excluding an addition catalyzed by a
phosphonium salt. Reactions conducted with excess tributyla-
mine relative to iridium, which would quench trace acid, oc-
curred with comparable yields (entry 4) to the reaction in the
absence of this additive. Reactions conducted by initial halide
abstraction from iridium with AgBF4 led to the formation of a
mixture of racemic ether products, consistent with an acid-
catalyzed process. Reactions conducted with a cationic Ir pre-
cursor and ligand did not yield product (entry 6), but those
conducted with a cationic Ir precursor, ligand, and base
formed product (entry 7), presumably after generating a neu-
tral Ir complex. A greater fraction of 1-octene vs. other iso-
mers was observed for reactions conducted with 20 equiva-
lents of olefin than reactions conducted with 5 or 10 equiva-
lents of alkene and resulted in a 60% yield of 1 (entry 9).
The scope of the Ir-catalyzed addition of phenols to α-
olefins by the procedure we developed is summarized in Chart
1. Products containing the phenoxy group at the 2-position of
the alkyl chain were formed exclusively with ee’s ranging
from 8% to 60%, the highest value being observed for reaction
of an alkene containing steric bulk proximal to the alkene (13).
Upon completion of the reaction, the enol-ether products that
result from oxidative etherification of the alkene were hydro-
lyzed with acid to facilitate isolation of the alkyl aryl ether
products. A broad range of functional groups located meta and
para to the OH-group were compatible with the addition pro-
cess; the reaction between olefins and phenols containing hal-
ides, ethers, and tertiary amines occurred in good yields. Alt-
hough reactions of 1-naphthol formed product 19 in good
yield, other phenols containing substituents ortho to the OH-
group did not add to the α-olefins under similar conditions.
The electronic properties of the substituents on the phenol
influenced the reaction conversion and yield. Reactions of
electron-poor phenols typically occurred in lower yields than
reactions of electron-rich phenols because there was a greater
amount of alkene isomerization during the reaction of the elec-
tron-poor phenol. Complete isomerization of the terminal al-
kene was observed after 24 h for reactions of 4-CF3-phenol
while only half of the terminal alkene isomerized during reac-
tions of 4-OMe-phenol. Consequently, reactions of electron-
rich phenols conducted with 10 equivalents of olefin, rather
than the 20 equivalents used for a majority of the reactions,
formed the addition products in good yield.
Chart 1. Ir-Catalyzed Additions of Phenols to
Olefinsa
ꢀ
-
2.5 mol % [Ir(cod)Cl]2
OH
R
5.2 mol % (S)-DTBM-Segphos
+
R
R
O
*
30 h, 140 °C
then HCl(aq)/THF, 80°C, 4 h
1 equiv
20 equiv
R
OPh
O
OMe
CF3
O
O
O
O
NMe2
n-Hex
64%, 1
n-Hex
67%c, 2
n-Hex
73%, 3
n-Hex
60%c, 4
OMe
O
O
CF3
O
Br
n-Hex
49%b, 5
n-Hex
66%c, 6
n-Hex
59%b, 7
n-Hex
54%, 8
Br
Cl
Br
O
O
O
Me
O
O
O
Me
n-Hex
72%, 9
n-Hex
70%, 10
n-Hex
57%, 11
n-Bu
80%, 12
F
O
OMe
O
O
OMe
OMe
O
O
n-Hex
n-Hex
79%b, 16
OMe
53%b, 60% ee, 13
Br
16%, 14
60%, 15
OMe
O
Me
O
O
OMe
n-Hex
65%, 19
n-Hex
56%, 20
56%, 17
67%, 18
F
PhO
OEt
OiPr
71%, 23d
OEt
73%, 21d
69%, 22d
b
aIsolated yields. Reaction was performed with: 40 equivalents or
d
c10 equivalents of alkene relative to ArOH. Reactions were con-
ducted in mesitylene solvent.
Mechanistic studies were conducted to gain insight into the
elementary steps of this unusual process. Kinetic analysis of
the additions of 4-F-phenol to propene was conducted. Initial
rates (to 15% conversion) were measured by 19F NMR spec-
troscopy (see Supporting Information). The reaction was
found to be first-order in catalyst, zero-order in the concentra-
The scope of the reaction in alkene also was examined. Ad-
dition products were not detected from reactions of phenols
ACS Paragon Plus Environment

Page 3 of 5
Journal of the American Chemical Society
plexes are known to be hydrogen-bond acceptors. NOE corre-
tion of alkene and partial positive order (0.6) in the concentra-
1
2
3
4
5
6
7
8
tion of 4-F-phenol.
lations between metal-hydrides and alcoholic protons, as well
as a reduced metal-hydride IR stretching frequency in the
presence of an alcohol, are commonly observed for systems
containing these hydrogen-bonding interactions.13 In contrast
to these characteristics of a M-H•HX interaction, no NOE was
observed between the Ir–H resonance of 24 and the OH reso-
nance of 4-F-phenol. In addition, the IR stretching frequency
of the Ir–H bond of 24 increased by 20 cm-1 to 2226 cm-1 in
the presence of 1 M 4-F-phenol (vs. 24 in the absence of alco-
hol), while the O-H stretching frequency of the phenol de-
creased by 115 cm-1 to 3323 cm-1 (vs. 1 M 4-F-phenol in the
absence of 24). These data suggest that the hydrogen-bond
acceptor in complex [24•HOAr] is a ligand other than the
hydride. The remaining likely hydrogen-bond acceptor in the
coordination sphere of 1 is the chloride ligand (Figure 1b). We
suggest that the reduced electron donation by a hydrogen-
bound Ir–Cl ligand strengthens the Ir–H bond trans to the
chloride and accounts for the increased Ir–H stretching fre-
quency observed by IR spectroscopy.
Monitoring the reactions by 31P NMR spectroscopy indicat-
ed that an unsymmetrical bisphosphine complex persisted
throughout the course of the reaction (Figure 1a, spectrum V).
This observed species was characterized to allow interpreta-
tion of the kinetic data. The oxidative addition of O–H bonds
to Ir(I) is well established.12 However, addition of 4-F-phenol
to a solution of [Ir(cod)Cl]2 and DTBM-Segphos in benzene
did not form any new species. In contrast, the combination of
Ir, ligand, and olefin in the absence of alcohol did react; the
original orange solution turned light yellow in 1 h at 294 K. A
similar color change was observed at the start of the catalytic
reaction. The product of this reaction was shown by NMR
spectroscopy to be the Ir(allyl)hydride complex 24 shown in
Figure 1.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
a.
I.
[ArOH] = 0 M
II.
III.
IV.
V.
[ArOH] = 0.11 M
[ArOH] = 0.26 M
[ArOH] = 0.52 M
1
The fraction of 24 and 24•HOAr was determined by H
NMR spectroscopy, and this ratio was consistent with the or-
der of the reaction in phenol. The resonance in the Ir–H region
1
of the H NMR spectrum results from the average of the frac-
[ArOH] = 0.98 M
tional contributions of the absolute Ir–H chemical shifts of 24
and [24•HOAr] (Eq 1). The equilibrium concentrations of the
two complexes were determined by measuring the observed
chemical shift of the Ir–H resonance as a function of the con-
centration of 4-F-phenol (Figure 2). The value of Keq from
fitting the data to eq 2 is 4.4 M-1, and the chemical shift of the
Ir–H of [24•HOAr] is -24.1 ppm at 294 K. Van’t Hoff analy-
sis of the equilibrium constants determined by conducting this
experiment at temperatures from 294 to 335 K (see supporting
information) revealed the following thermodynamic parame-
ters for the equilibrium: ∆Heq = -1.9 kcal/mol and ∆Seq = -3.5
eu.14 From these thermodynamic parameters, an equilibrium
constant of 1.6 M-1 at the 140 °C temperature of the reaction
was calculated; this equilibrium constant corresponds to a
40:60 ratio of 24:[24•HOAr]. A significant concentration of
both complexes is consistent with the measured partial-order
(0.6) of the catalytic addition reaction in [4-F-phenol].
A comparison of the initial rates for the addition of O-
deuterated 4-F-phenol and proteo 4-F-phenol to propene in
separate vessels revealed a kinetic isotope effect (KIE) of 1.6.
Although greater than unity, this KIE is likely too small to be
consistent with a turnover-limiting protonolysis or oxidative
addition of the O–H bond,6d but it would be consistent with
reversible oxidative addition of the alcohol O–H bond to the Ir
center prior to a turnover-limiting step. In this case, the prod-
uct of oxidative addition would be less stable than the catalyst
resting state. This conclusion is consistent with the lack of O-
H addition product from the reaction of DTBM-Segphos,
[Ir(coe)2Cl]2 and 4-F-phenol.
ꢂꢀ
ꢁ
ꢀ
ꢀꢁꢁꢃꢆ
ꢀꢁꢅꢃꢄ
ꢀꢁꢅꢃꢆ
ꢀꢁꢂꢃ
31P NMR (ppm)
1H NMR (ppm)
iPr
~
ν
b.
H
H
Ir
(Ir–H) = 2226 cm-1
~
iPr
P
(∆ν = +20 cm-1
)
Ir
P
*
P
*
+
ArO
H
P
C6H6
Cl
24
Cl
~
ν
(O–H) = 3323 cm-1
(∆ν = -115 cm-1
(Ar = 4-F)
ν(O–H)
~
~
~
H
OAr
ν(Ir–H)
2206 cm-1
)
3438 cm-1
[24•HOAr]
Figure 1. a. 31P (left) and 1H (right, Ir–H region only) NMR spec-
tra i.-v. of 24 in the presence of varying concentrations of 4-F-
phenol at 294 K. b. IR stretching frequencies of the Ir–H and O–H
bonds of 24, free 4-F-phenol, and [24•HOAr].
δobs = δ24µ24 + δ[24•HOAr]µ[24•HOAr]
δ24 + δ[24•HOAr]Keq[ArOHo]
(1)
(2)
(1)
δobs
=
1 + Keq[ArOHo]
Keq = 4.35 ± 0.07 M-1
δ[24•HOAr] = -24.09 ± 0.06 ppm
Figure 2. Plot of the Ir–H chemical shift as a function of 4-
F-phenol concentration in C6D6 at 294 K, fit to Eq 2.
The hydride resonance and phosphorus resonances observed
by NMR spectroscopy of isolated 24 in C6D6 (spectrum I) did
not match those of the species in the catalytic reaction (spec-
These mechanistic data are consistent with the proposed
catalytic cycle in Scheme 1. In this mechanism, the (al-
lyl)iridium hydride resting state 24, which equilibrates with
hydrogen bonded 24•HAr, undergoes C–H bond-forming re-
ductive elimination to release olefin and form an Ir(I) complex
that can undergo reversible, endergonic oxidative addition of
the O–H bond of the phenol to form 25. Subsequent olefin
coordination and turnover-limiting insertion into the Ir–O
bond forms an alkyl-Ir complex 26. C–H bond-forming reduc-
tive elimination would then release the ether product, whereas
1
trum V). However, the hydride chemical shift in the H NMR
spectrum of solutions of 24 containing varying concentrations
of 4-F-phenol depended on the concentration of the phenol,
and the 1H and 31P NMR spectra of the solution containing a 1
M concentration of alcohol matched those of the complex
observed in the catalytic reactions (Figure 1a, spectra I-V).
The interaction of the phenol with 24 was investigated by
NOESY and IR spectroscopy (Figure 1b). Metal-hydride com-
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 4 of 5
Corresponding Author
β-H elimination from the same intermediate would form the
enol-ether side product. This mechanism is consistent with the
observed zero-order dependence of the rate on the concentra-
tion of alkene because the alkene is released and added prior
to the turnover-limiting transition state. This mechanism is
also consistent with the partial positive order dependence of
the rate on the concentration of alcohol because a significant
fraction of the resting state exists as the alcohol adduct
[24•HOAr]. The alcohol dissociates and adds prior to the
turnover-limiting step of a reaction initiated from [24•HOAr].
Scheme 1. Proposed Catalytic Cycle for the Ir-
1
2
3
4
5
6
7
8
*jhartwig@berkeley.edu
ACKNOWLEDGMENT
This work was supported by the Director, Office of Science, of
the U.S. Department of Energy under Contract No. DE-AC02-
05CH11231. We thank Johnson-Matthey for a gift of [Ir(cod)Cl]2,
and Takasago for a gift of (S)-DTBM-Segphos. C.S.S. thanks the
NSF for a graduate research fellowship.
9
REFERENCES
(1) (a) Müller, T. E.; Hultzsch, K. C.; Yus, M.; Foubelo, F.; Tada, M.
Chem. Rev. 2008, 108, 3795. (b) Hannedouche, J.; Schulz, E. Chem. Eur.
J. 2013, 19, 4972.
(2) (a) Trost, B. M.; Toste, F. D. J. Am. Chem. Soc. 1999, 121, 4545. (b)
Muci, A. R.; Buchwald, S. L. Cross-Coupling Reactions 2002, 219, 131.
(c) López, F.; Ohmura, T.; Hartwig, J. F. J. Am. Chem. Soc. 2003, 125,
3426. (d) Beletskaya, I. P.; Cheprakov, A. V. Coord. Chem. Rev. 2004,
248, 2337. (e) Onitsuka, K.; Okuda, H.; Sasai, H. Angew. Chem. Int. Ed.
2008, 47, 1454.
(3) Smith, M. B.; March, J. In March's Advanced Organic Chemistry; 5
ed.; John Wiley and Sons: New York, NY, 2001, p 996.
(4) (a) Ronchin, L.; Quartarone, G.; Vavasori, A. J. Mol. Catal. A-Chem.
2012, 353, 192. (b) Ronchin, L.; Vavasori, A.; Toniolo, L. J. Mol. Catal.
A-Chem. 2012, 355, 134.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Catalyzed Hydroetherification of
ꢀ
-Olefins
H
Ir
H
R
R
+ HOAr
- HOAr
P
P
P
P
resting state
Ir
Cl HOAr
[24•HOAr]
*
*
24
Cl
OAr
R
R
-
1 - 23
P
Ir
*
+ ArOH
P
Cl
OAr
H
P
H
P
R
β-H
Ir
R
Ir OAr
*
*
+
P2IrH2Cl
elim.
P
P
OAr
Cl
Cl
26
25
R
(5) Hintermann, L.; Vigalok, A., Ed.; Springer Berlin / Heidelberg: 2010;
Vol. 31, p 123.
H
Ir
P
P
R
*
TLS
(6) (a) Hamilton, G. L.; Kang, E. J.; Mba, M.; Toste, F. D. Science 2007,
317, 496. (b) Zhang, Z. B.; Widenhoefer, R. A. Angew. Chem. Int. Ed.
2007, 46, 283. (c) Wang, Z. J.; Brown, C. J.; Bergman, R. G.; Raymond,
K. N.; Toste, F. D. J. Am. Chem. Soc. 2011, 133, 7358. (d) Brown, T. J.;
Weber, D.; Gagné, M. R.; Widenhoefer, R. A. J. Am. Chem. Soc. 2012,
134, 9134. (e) Butler, K. L.; Tragni, M.; Widenhoefer, R. A. Angew.
Chem. Int. Ed. 2012, 51, 5175.
(7) (a) Qian, H.; Han, X.; Widenhoefer, R. A. J. Am. Chem. Soc. 2004,
126, 9536. (b) Li, X.; Chianese, A. R.; Vogel, T.; Crabtree, R. H. Org.
Lett. 2005, 7, 5437. (c) Patil, N. T.; Lutete, L. M.; Wu, H.; Pahadi, N. K.;
Gridnev, I. D.; Yamamoto, Y. J. Org. Chem. 2006, 71, 4270. (d) Messerle,
B. A.; Vuong, K. Q. Organometallics 2007, 26, 3031. (e) Yu, X.; Seo, S.;
Marks, T. J. J. Am. Chem. Soc. 2007, 129, 7244. (f) Seo, S. Y.; Yu, X. H.;
Marks, T. J. J. Am. Chem. Soc. 2009, 131, 263. (g) Weiss, C. J.; Marks,
T. J. Dalton Trans. 2010, 39, 6576. (h) Atesin, A. C.; Ray, N. A.; Stair, P.
C.; Marks, T. J. J. Am. Chem. Soc. 2012, 134, 14682.
OAr
Cl
Several aspects of this mechanism are distinct from those
for addition of the N-H bonds of amides to alkenes catalyzed
by the combination of [Ir(coe)2Cl]2 and Segphos.11 The product
from oxidative addition of the amide was the resting state of
the catalyst in the hydroamidations of alkenes; the open coor-
dination site of the L2IrCl(H)(amide) complex formed by oxi-
dative addition was occupied by a second amide. The system
for the catalytic additions of phenols lacks a basic component,
making the stable 18-electrin Ir(III) complex in the system the
allyl hydride complex 24 and its phenol adduct 24•HOAr.
Consequently, isomerization of the alkene occurs faster during
the Ir-catalyzed additions of phenols to alkenes than during the
additions of amides to alkenes.
In summary, we report a rare example of a metal-catalyzed
intermolecular addition of an alcohol to an unactivated alkene.
The lack of products from rearrangements and addition of the
ortho C–H bond, the measurable enantiomeric excess, the
absence of product from phosphonium salts, the lack of an
effect of added tertiary alkylamine, and kinetic data that are
consistent with the observed species show that the reaction is
not purely acid-catalyzed. Instead, it likely occurs by genera-
tion of an Ir(I) intermediate by reductive elimination of the
observed allyliridium hydride species, followed by reversible
O–H bond oxidative addition, turnover-limiting olefin inser-
tion, and product-releasing reductive elimination. Efforts to
mitigate olefin isomerization and increase the enantioselectivi-
ty of the reaction are in progress.
(8) (a) Kim, I. S.; Krische, M. J. Org. Lett. 2008, 10, 513. (b)
Kawamoto, T.; Hirabayashi, S.; Guo, X.-X.; Nishimura, T.; Hayashi, T.
Chem. Commun. 2009, 3528. (c) Koschker, P.; Lumbroso, A.; Breit, B. J.
Am. Chem. Soc. 2011, 133, 20746.
(9) (a) Yang, C.-G.; He, C. J. Am. Chem. Soc. 2005, 127, 6966. (b) Yang,
C.-G.; Reich, N. W.; Shi, Z.; He, C. Org. Lett. 2005, 7, 4553. (c) Hirai, T.;
Hamasaki, A.; Nakamura, A.; Tokunaga, M. Org. Lett. 2009, 11, 5510.
(10) For a discussion of the parallels between intermolecular O–H bond
additions to unactivated alkenes catalyzed by metal triflates and Brønsted
acids see: (a) Li, Z.; Zhang, J.; Brouwer, C.; Yang, C.-G.; Reich, N. W.;
He, C. Org. Lett. 2006, 8, 4175. (b) Rosenfeld, D. C.; Shekhar, S.;
Takemiya, A.; Utsunomiya, M.; Hartwig, J. F. Org. Lett. 2006, 8, 4179.
(11) Sevov, C. S.; Zhou, J.; Hartwig, J. F. J. Am. Chem. Soc. 2012, 134,
11960.
(12) (a) Ladipo, F. T.; Kooti, M.; Merola, J. S. Inorg. Chem. 1993, 32,
1681. (b) Blum, O.; Milstein, D. J. Organomet. Chem. 2000, 593–594,
479. (c) Dorta, R.; Rozenberg, H.; Shimon, L. J. W.; Milstein, D. J. Am.
Chem. Soc. 2001, 124, 188. (d) Blum, O.; Milstein, D. J. Am. Chem. Soc.
2002, 124, 11456. (e) Schaub, T.; Diskin-Posner, Y.; Radius, U.;
Milstein, D. Inorg. Chem. 2008, 47, 6502.
(13) (a) Stevens, R. C.; Bau, R.; Milstein, D.; Blum, O.; Koetzle, T. F. J.
Chem. Soc., Dalton Trans. 1990, 0, 1429. (b) Lee, J. C.; Peris, E.;
Rheingold, A. L.; Crabtree, R. H. J. Am. Chem. Soc. 1994, 116, 11014.
(c) Siegbahn, P. E. M.; Eisenstein, O.; Rheingold, A. L.; Koetzle, T. F.
Acc. Chem. Res. 1996, 29, 348.
(14) The small negative value of ∆Seq is consistent with an equilibrium
between a self associated phenol and [24•HOAr], as would be expected in
the nonpolar organic solvent benzene.
ASSOCIATED CONTENT
Experimental procedures and characterization of all new com-
pounds including NMR spectroscopy data, conditions for
HPLC separations on a chiral stationary phase, kinetic studies,
and optimization data are supplied. This material is available
free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
ACS Paragon Plus Environment

Page 5 of 5
Journal of the American Chemical Society
1
2
3
4
5
6
TOC Graphic
OH
R
2.5 mol % [Ir(cod)Cl]2
R
O
5.2 mol % DTBM-Segphos
7
22 examples
49-80% yield
H
Ralkyl
140 °C
8
9
+
Ralkyl
exclusive O-H addition
no carbocation rearrangements
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
5
ACS Paragon Plus Environment