Catalytic Hydroetherification of Unactivated Alkenes Enabled by Proton-Coupled Electron Transfer

Article abstract of DOI:10.1002/anie.202003959

We report a catalytic, light-driven method for the intramolecular hydroetherification of unactivated alkenols to furnish cyclic ether products. These reactions occur under visible-light irradiation in the presence of an Ir^III-based photoredox catalyst, a Br?nsted base catalyst, and a hydrogen-atom transfer (HAT) co-catalyst. Reactive alkoxy radicals are proposed as key intermediates, generated by direct homolytic activation of alcohol O?H bonds through a proton-coupled electron-transfer mechanism. This method exhibits a broad substrate scope and high functional-group tolerance, and it accommodates a diverse range of alkene substitution patterns. Results demonstrating the extension of this catalytic system to carboetherification reactions are also presented.

Full text of DOI:10.1002/anie.202003959

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Accepted Article
Title: Catalytic Hydroetherification of Unactivated Alkenes Enabled by
Proton-Coupled Electron Transfer
Authors: Elaine Tsui, Anthony J Metrano, Yuto Tsuchiya, and Robert R
Knowles
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10.1002/anie.202003959
Angewandte Chemie International Edition
COMMUNICATION
Catalytic Hydroetherification of Unactivated Alkenes Enabled by
Proton-Coupled Electron Transfer
Elaine Tsui, Anthony J. Metrano, Yuto Tsuchiya, and Robert R. Knowles*[a]
[a]
E. Tsui, A. J. Metrano, Y. Tsuchiya, Prof. R. R. Knowles
Department of Chemistry, Princeton University
Princeton, NJ 08544
E-mail: rknowles@princeton.edu
Supporting information for this article is given via a link at the end of the document.
Abstract: We report
a catalytic, light-driven protocol for the
intramolecular hydroetherification of unactivated alkenols to furnish
cyclic ether products. These reactions occur under visible light
irradiation in the presence of an Ir(III)-based photoredox catalyst, a
Brønsted base catalyst, and a hydrogen atom transfer co-catalyst.
Reactive alkoxy radicals are proposed as key intermediates,
generated via the direct homolytic activation of alcohol O–H bonds
through a proton-coupled electron transfer mechanism. This method
exhibits a broad substrate scope and high functional group tolerance,
and it accommodates a diverse range of alkene substitution patterns.
Results demonstrating the extension of this catalytic system to
carboetherification reactions are also presented.
(a) Traditional Approach: Polar Hydroetherification Methods
[M] cat. or
Brønsted acid cat.
H
R1
HO
R1
R2
O
R2
alkene activation
(b) Goal: General Method for Alkoxylation of Structurally Diverse Alkenes
R3
R3
R1
HO
R1
HO
HO
R2
R2
R2
R3
The addition of alcohols to alkenes is a powerful approach
to C–O bond formation and the construction of oxygen-
containing heterocycles, which are common structural motifs in
natural products and medicinal agents.[1] Numerous olefin
hydroetherification methods have been developed using
Brønsted acid- or transition metal-based catalysts (Scheme 1a),
which typically operate through alkene activation mechanisms.[2–
R1
O
R2
R3
HO
R1
HO
HO
5]
Hypothesis: O–H bond activation enables hydroalkoxylation of olefins
bearing a wide range of substitution patterns
As a result, these reactions are often sensitive to C=C
substitution patterns and generally afford Markovnikov-type
addition products. More recently, an alternative mode of alkene
activation has been developed, wherein single-electron oxidation
of an olefin furnishes an electrophilic alkene radical cation that
can be intercepted by an alcohol nucleophile.[6] While this
method affords complementary anti-Markovnikov regioselectivity,
its use is largely limited to oxidizable styrenyl and trisubstituted
olefin substrates. Considering these strategies more broadly, the
(c) This Work: Catalytic Hydroetherification of Unactivated Olefins
Ir photocat.
phosphate base cat.
R1
R2
R1
HO
HAT cat.
R2
blue LEDs
O
H
R1
PCET
C–O formation
HAT
O
development
of
a
general
catalytic
protocol
for
R2
hydroetherification that accommodates electronically unbiased
alkenes with diverse substitution remains an outstanding
challenge.
BDFE (O–H)
~ 105 kcal/mol
In contrast to these alkene activation strategies, we
recently became interested in an orthogonal approach to
catalytic olefin hydroetherification that employs reactive alkoxy
radical intermediates formed through O–H bond activation
(Scheme 1b). Alkoxy radicals have been shown to undergo
addition to pendent alkenes to furnish cyclic ethers, but their
generation typically requires either prefunctionalization of the
hydroxyl group or the use of strong stoichiometric oxidants.[7–9]
While effective, these conditions can lead to poor atom economy
and incompatibility with common functional groups. As such,
Scheme 1. (a) Traditional approaches to hydroetherification typically involve
alkene activation mechanisms. (b) Development of a general strategy for
hydroalkoxylation via O–H bond activation. (c) PCET-mediated
hydroetherification of unactivated alkenes.
To this end, we envisioned that excited-state proton-
coupled electron transfer (PCET) would provide a solution to the
existing limitations of radical hydroetherification (Scheme 1c).
Our group has developed methods for the homolytic activation of
alcohol O–H bonds to access alkoxy radical intermediates,
focusing exclusively on C–C bond β-scission reactions.[10,11] As
the rates of b-scission and 1,5-hydrogen atom transfer (1,5-HAT)
are often comparable to the rate of cyclization,[12,8b,8i] we
development of
a
mild, catalytic protocol for olefin
hydroetherification utilizing alkoxy radicals generated directly
from alcohol starting materials has the potential to advance the
value of radical-based etherification in organic synthesis.
1
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10.1002/anie.202003959
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questioned whether alkoxy radicals could be leveraged instead
for productive C–O bond formation, generating cyclic ethers
directly from readily accessible alkenols while outcompeting
other pathways.[13] Within this context, we endeavored to find
catalysts and reaction conditions that could not only effectively
bias the reactivity of alkoxy radicals to favor olefin addition but to
do so with a broad scope and functional group tolerance.
providing 0% yield of 2 (Table S1). The counter-cation of the
phosphate base was found to have a marked effect on the
reaction efficiency, as the tetrabutylphosphonium ion led to a
40% boost in yield compared to the corresponding ammonium
cation (entry 2). This effect is possibly due to the enhanced
solubility of tetrabutylphosphonium diphenyl phosphate in
trifluorotoluene or to the more dissociated nature of the ion
pair.[16] After examining a series of electron-rich and electron-
deficient thiophenols (entries 3–8), we found that 2-
fluorothiophenol outperformed the other thiophenols surveyed,
providing 2 in 75% yield (entry 7)—a notable improvement over
the other fluorothiophenol regioisomers (entries 5–6). The
corresponding disulfide was equally effective in the reaction
(entry 9), and we therefore elected to use 1,2-bis(2-
fluorophenyl)disulfide as the hydrogen atom transfer (HAT) co-
catalyst due to its ease of handling.[6b] Lowering the substrate
concentration increased the yield to 80% (entry 10), and
adjusting the HAT co-catalyst loading to 30 mol% gave
tetrahydrofuran 2 in 85% yield, providing our optimal reaction
conditions (entry 11). Control experiments run in the absence of
light and photocatalyst furnished no product, and significantly
reduced yields were observed in the absence of either Brønsted
base or HAT co-catalyst (entries 12–15).
Having established the optimized reaction conditions, we
next examined the scope of this reaction with respect to various
alkene substitution patterns (Table 2). With the success of
model substrate 1, we found that a range of other 1,2-
disubstituted olefins gave excellent yields of the desired cyclic
ether products (3–9). Hydroetherification of disubstituted olefins
with secondary alcohols also proved to be viable, albeit with
moderate reactivity (10). Notably, this protocol provides direct
access to a variety of bicyclic structures from alcohol precursors,
forming fused rings (11, 12) and bridged ethers (13) with high
diastereoselectivities. Electronically diverse styrenyl alkenes
(14–16), as well as pyridine and thiophene derivatives (17, 18),
furnished tetrahydrofuran products in good yields.
Table 1. Reaction Optimization[a]
2 mol% [Ir(dF(CF3)ppy)2(5,5'-d(CF3)bpy)]PF6
Ph
20 mol% Brønsted base
20 mol% HAT co-catalyst
HO
Ph
solvent (conc.), 40 °C
blue LEDs, 24 h
O
H
1
2
Entry
Brønsted Base
HAT Co-Catalyst Solvent (Conc., M) GC Yield[b]
1
2
Bu4N+ (PhO)2P(O)O–
Bu4P+ (PhO)2P(O)O–
Bu4P+ (PhO)2P(O)O–
Bu4P+ (PhO)2P(O)O–
Bu4P+ (PhO)2P(O)O–
Bu4P+ (PhO)2P(O)O–
Bu4P+ (PhO)2P(O)O–
Bu4P+ (PhO)2P(O)O–
Bu4P+ (PhO)2P(O)O–
Bu4P+ (PhO)2P(O)O–
TRIP-SH
TRIP-SH
PhCF3 (0.1)
PhCF3 (0.1)
PhCF3 (0.1)
PhCF3 (0.1)
PhCF3 (0.1)
PhCF3 (0.1)
PhCF3 (0.1)
PhCF3 (0.1)
PhCF3 (0.1)
PhCF3 (0.05)
31%
71%
45%
41%
59%
47%
75%
45%
74%
80%
3
Ph-SH
4
4-(MeO)PhSH
4-FPhSH
5
6
3-FPhSH
7
2-FPhSH
8
4-(CF3)PhSH
(2-FPhS)2
(2-FPhS)2
9
10
Entry
Change from Entry 10
GC Yield[b]
11
12
13
14
15
30 mol% (2-FPhS)2
no light
85%
0%
no Ir(III) photocatalyst
no Brønsted base
no HAT co-catalyst
0%
11%
9%
F
F
PF6
F
F
With respect to trisubstituted alkenes, anti-Markovnikov
hydroetherification proceeded with primary, secondary, and
tertiary alcohols (19–24), providing ether products that are
generally not accessible using traditional hydroalkoxylation
strategies. Interestingly, products resulting from competing C–C
β-scission were not observed during the formation of 23 and 24,
enabling facile and efficient synthesis of spirocyclic scaffolds.
Derivatives of terpenoids were also obtained in good yields
using this protocol (25, 26), leaving the more distal olefins
unaffected and demonstrating that 5-exo-trig cyclization is
preferred. Both syn and anti diastereomers of an N-Boc-L-
prolinol derivative were transformed to their respective
tetrahydrofuran products in good yields (27, 28). Additionally, N-
Boc-indole and benzofuran derivatives proceeded through 6-
endo-trig cyclizations to favor generation of an intermediate
tertiary benzylic radical, affording tricyclic ether products in
excellent yields and diastereoselectivities (29, 30). In the case of
benzothiophene, both 6-endo and 5-exo products (2.5:1) were
formed, allowing access to both fused- and spirocyclic structures
(31a, 31b). Moreover, this hydroetherification protocol can
tolerate the presence of polar functionality, operating in systems
O
P
N
F
CF3
CF3
S
S
Ir
PhO
O
N
N
PBu4
PhO
N
CF3
F
F3C
Brønsted Base
HAT Co-Catalyst
(2-FPhS)2
Photocatalyst
[Ir(dF(CF3)ppy)2(5,5'-d(CF3)bpy)]PF6
Bu4P+ (PhO)2P(O)O–
[a] Reactions were run on a 0.05 mmol scale. [b] GC yields determined
relative to biphenyl as an internal standard.
We began our optimization studies with 1,2-disubstituted
alkenol substrate 1 (Table 1) and found that 2 mol% of
[Ir(dF(CF3)ppy)2(5,5ʹ-d(CF3)bpy)]PF6 photocatalyst, 20 mol% of
diphenyl phosphate, and 20 mol% of 2,4,6-triisopropylthiophenol
(TRIP-SH) in trifluorotoluene under blue light irradiation (~450
nm) afforded the desired ether product 2 in 31% yield (entry 1).
Notably, this highly oxidizing photocatalyst (EIII*/II = +1.30 V vs.
Fc+/Fc in MeCN)[14] is required—in combination with phosphate
bases (pKa = ~13 in MeCN)[15]—to achieve effective bond
dissociation free energies (BDFEs) approaching that of the
alcohol O–H bond (BDFE = 105 kcal/mol).[11b] Less oxidizing
Ir(III)-based photocatalysts were ineffective in the reaction,
2
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10.1002/anie.202003959
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Table 2. Substrate Scope[a]
2 mol% [Ir(dF(CF3)ppy)2(5,5'-d(CF3)bpy)]PF6
20 mol% Bu4P+ (PhO)2P(O)O–
R1
R1
30 mol% bis(2-fluorophenyl)disulfide
R2
R2
HO
O
H
PhCF3 (0.1 M), 40 °C, blue LEDs
Disubstituted Alkenes
Cl
C5H11
n-propyl
OBn
Ar
OH
n-octyl
O
H
n-octyl
O
O
O
O
O
O
H
H
H
H
H
H
7 81%
10 47%
(1.3:1 dr)
6 76%
(from cis olefin)
8 79%
5 86%
(from trans olefin)
9 81%
2 81% Ar = Ph
3 97% Ar = 4-ClPh
4 81% Ar = 4-BrPh
R3
OH
OBn
O
N
TBSO
H
H
S
O
OH
H
O
O
O
H
H
H
O
O
18 58%[b]
14 75%[b] R3 = H
15 78%[b] R3 = CF3
16 85% R3 = OMe
17 84%[b]
12 51%
(>20:1 dr)
13 98%
11 94%
(1:1 dr)
Trisubstituted Alkenes
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
H
Me
H
Me
O
H
O
O
H
O
O
H
n-octyl
O
H
O
H
N
O
Boc
19 69%[c]
21 83%[d]
25 70%[b]
20 69%[d]
22 71%[d]
23 75%
24 79%[d]
(1.2:1 dr)
(1:1 dr)
(1.2:1 dr)
(1.1:1 dr)
Me
Me
Me
Me
H
H
H
Me
H
Me
O
Me
H
H
O
O
O
H
O
O
O
H
H
S
N
O
S
H
H
H
N
N
Boc
Boc
Boc
Me
27 from syn 78%[d]
29 90%[d]
(>20:1 dr)
30 70%[d]
(>20:1 dr)
31 85%[d], 2.5:1 endo/exo (31a:31b)
(for 31a, >20:1 dr)
26 78%[d]
(1.1:1 dr)
28 from anti 78%[d]
(2:1 dr)
(1.3:1 dr)
Monosubstituted Alkenes
O
Me
Me
Me
Me
N
S
TBSO
O
S
N
O
O
H
H
N
N
O
O
H
O
H
H
H
O
O
n-octyl
N
33 46%[d]
34 73%[d]
35 71%[c]
36 52%[e]
37 53%[e]
32 95%[d]
(1.7:1 dr)
(1:1 dr)
(2:1 dr)
(1.5:1 dr)
[a] Reactions were performed on a 0.5 mmol scale. Reported yields are for isolated and purified material unless otherwise noted and represent the average of two
experiments. [b] Bu4N+ CF3C(O)O– used as the base. [c] GC yield is reported relative to an internal standard due to volatility. [d] 2-methyl-2-oxazoline used as the
base, and 4-trifluoromethylthiophenol used as the HAT co-catalyst. [e] 1,2-Bis(4-methoxyphenyl)disulfide used as the HAT co-catalyst. See Supporting
Information for details. TBS, tert-butyldimethylsilyl; Boc, tert-butyloxycarbonyl.
containing N-phenyltetrazole thioethers and sulfonamides (32,
33). Hydroetherification proceeding via 6-exo-trig ring closures is
also possible, furnishing tetrahydropyran product 34 in 73% yield
and outcompeting 1,5-HAT from the allylic C–H bonds.
Remarkably, hydroalkoxylation of unactivated monosubstituted
alkenes can also be achieved in moderate to good yields, even
with generation of a primary C-centered radical after cyclization
(35–37). Due to the high oxidation potential of monosubstituted
olefins, these substrates cannot be accommodated using current
alkene oxidation methods.
Lastly, we evaluated the synthetic versatility of our
hydroalkoxylation protocol in the context of olefin
carboetherification reactions,[17] wherein electron-deficient
olefins were used to intercept the intermediate C-centered
radical following C–O bond formation (Table 3). Tetrahydrofuran
derivatives were successfully alkylated with α-phenyl
methacrylate (38), dimethyl fumarate (39), and dehydroalanine
derivative (40), demonstrating that intermolecular C–C bond
formation can be achieved following alkoxy radical cyclization.
Moreover, acceptors containing heterocyclic scaffolds, such as
3
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COMMUNICATION
2-vinylpyridine (41) and 2-vinylpyrazine (42), provided modest
yields of alkylated product. Even in cases where a primary alkyl
radical is generated upon cyclization, addition to α-phenyl
methacrylate outcompetes other possible reaction pathways to
hv
IrIII
B
R1
O
H
R2
O–H
PCET
ET/PT
give
the
desired
difunctionalization
product
(43).
Carboetherification of
a
secondary alkenol with 1,1-
R1
R2
bis(phenylsulfonyl)ethylene also proceeded in good yield (44).
These results highlight the unique potential for alkoxy radical-
mediated C–O bond formation to be adapted for further product
derivatization, forming functionalized ethers in one step.
ArS
IrII
IrII
ArS
H
O
H
B
H
B
C–O bond
formation
HAT
Table 3. Carboetherification of Unactivated Alkenes[a]
2 mol% [Ir(dF(CF3)ppy)2(5,5'-d(CF3)bpy)]PF6
20 mol% 2-methyl-2-oxazoline
R1
R2
R1
R2
R1
R3
R1
R2
PhCF3 (0.1 M), 40 °C, blue LEDs
EWG
R4
O
R2
O
H
HO
O
EWG
IrII
H
B
R4
R3
Scheme 2. Prospective catalytic cycle.
O
CO2Me
Ph
MeO2C
O
CO2Me
N
This observation, however, does not preclude the viability
of a dominant alkoxy radical-mediated mechanism under the
optimal PCET conditions. Specifically, while investigating the
cyclizations to N-Boc-L-prolinol derivatives 27 and 28, we found
that the remaining mass balance in these reactions was
predominantly comprised of the β-scission product, N-Boc-
pyrrolidine. This observation serves as evidence that a discrete
alkoxy radical intermediate is formed under these PCET
conditions and is consistent with an alkoxy radical-mediated
mechanism for C–O bond formation. Moreover, the high yield of
cyclized product suggests that these electrophilic O-centered
radicals react more rapidly with electron-rich alkenes than they
undergo C–C cleavage, even when the C-centered radical
resulting from β-scission is stabilized by an adjacent
heteroatom.[10c] In contrast, when the monosubstituted and 1,2-
disubstituted variants of this substrate were studied under the
reaction conditions, only N-Boc-pyrrolidine was formed (Table
S7), consistent with a kinetically less favorable C–O bond-
forming event.[8i,19]
O
CO2Me
O
O
38 59%
(1:1 dr)
39 65%
(1:1 dr)
40 90%
(1.5:1 dr)
N
N
N
O
O
41 35%
42 38%
SO2Ph
SO2Ph
CO2Me
Ph
Me
O
Me
O
43 67%[b]
(1:1 dr)
44 57%[c]
(1.3:1 dr)
[a] Reactions were performed on a 0.5 mmol scale. Reported yields are for
isolated and purified material and represent the average of two experiments.
[b] Bu4P+ (PhO)2P(O)O– used as the base. [c] Reactions were performed on a
0.25 mmol scale in PhCF3 (0.05 M).
In summary, we have developed a catalytic protocol for the
intramolecular hydroetherification of unactivated alkenes with a
wide range of substitution patterns. This work leverages light-
driven PCET for the homolysis of strong alcohol O–H bonds,
thereby enabling the activation of common hydroxyl groups, for
productive C–O bond formation. Taken together, this strategy
further illustrates the potential of excited-state PCET to access
alkoxy radicals from simple alcohol starting materials under mild,
catalytic conditions.
A prospective mechanism for the transformation is detailed
in Scheme 2. Based on prior work, we envisioned that PCET
activation of the alcohol O–H bond of the substrate would form
an alkoxy radical intermediate through the concerted action of
an Ir(III)-based visible-light photooxidant and a weak Brønsted
base catalyst.[10,11] The resulting O-centered radical would
undergo addition to a pendent olefin, forming a new C–O bond
and an adjacent alkyl radical. Hydrogen-atom transfer from a
thiol-derived co-catalyst to the C-centered radical would furnish
the desired cyclic ether.[18] Subsequent reduction of the thiyl
radical by the Ir(II) state of the photocatalyst and protonation of
the resulting thiolate by the conjugate acid of the Brønsted base
would close the catalytic cycle. Notably, for more oxidizable
trisubstituted and styrenyl olefins, we observed diminished
conversion to the desired ether products in the absence of base,
suggesting that an alternative but much less efficient alkene
oxidation pathway could also be operative.[6]
Acknowledgements
Financial support was provided by the NIH (R35 GM134893).
A.J.M. is grateful to the National Institute of General Medical
Sciences of the NIH for
a postdoctoral fellowship (F32
GM128245). Y.T. thanks the Institute of Transformative Bio-
Molecules (WPI-ITbM), Nagoya University for support. The
authors would like to thank Alec Mendelsohn for the synthesis of
4
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10.1002/anie.202003959
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COMMUNICATION
Zhao, K. Yamashita, J. E. Carpenter, T. C. Sherwood, W. R. Ewing, P.
T. W. Cheng, R. R. Knowles, J. Am. Chem. Soc. 2019, 141, 8752–
8757; d) S. T. Nguyen, P. R. D. Murray, R. R. Knowles, ACS Catal.
2020, 10, 800–805.
materials and helpful discussions. We also acknowledge Nick
Chiappini and Hunter Ripberger for the preparation of materials.
[11] a) S. Y. Reece, D. G. Nocera, Annu. Rev. Biochem. 2009, 78, 673–699;
b) J. J. Warren, T. A. Tronic, J. M. Mayer, Chem. Rev. 2010, 110,
6961–7001; c) D. R. Weinberg, C. J. Gagliardi, J. F. Hull, C. F. Murphy,
C. A. Kent, B. C. Westlake, A. Paul, D. H. Ess, D. G. McCafferty, T. J.
Meyer, Chem. Rev. 2012, 112, 4016–4093; d) E. C. Gentry, R. R.
Knowles, Acc. Chem. Res. 2016, 49, 1546–1556.
Keywords: alcohols • ethers • hydroetherification •
photocatalysis • radicals
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5
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10.1002/anie.202003959
Angewandte Chemie International Edition
COMMUNICATION
Entry for the Table of Contents
via
OTBS
O
O
OBn
O
OBn
TBSO
TBSO
C–O formation
HAT
O–H PCET
H
OBn
O
O
OH
>35 examples
>20:1 dr
Alkoxy radicals generated directly from the activation of alcohol O–H bonds under catalytic, light-driven conditions are leveraged for
the intramolecular hydroetherification of a diverse range of unactivated olefins. This strategy allows for productive C–O bond
formation from highly reactive alkoxy radical intermediates and accommodates a broad substrate scope with high functional group
tolerance.
6
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