Photoinduced Proton-Transfer Reactions for Mild O-H Functionalization of Unreactive Alcohols

Article abstract of DOI:10.1002/anie.201915161

Hexafluoroisopropanol is typically considered as an unreactive solvent and not as a reagent in organic synthesis. Herein, we report on a mild and efficient photochemical reaction of aryl diazoacetates with hexafluoroisopropanol that enables, under stoichiometric reaction conditions, the synthesis of fluorinated ethers in excellent yield. Mechanistic studies indicate there is a preorganization of hexafluoroisopropanol and the diazoalkane acts as an unreactive hydrogen-bonding complex. Only after photoexcitation does this complex undergo a protonation-substitution reaction to the reaction product. Investigations on the applicability of this photochemical transformation show that a broad variety of acidic alcohols can be subjected to this transformation and thus demonstrate the feasibility of this concept for O-H functionalization reactions (54 examples, up to 98 % yield).

Full text of DOI:10.1002/anie.201915161

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
Chemie
International Edition
www.angewandte.org
Accepted Article
Title: Photoinduced proton transfer reactions for mild O-H
functionalization reactions of unreactive alcohols
Authors: Sripati Jana, Zhen Yang, Fang Li, Claire Empel, Junming Ho,
and Rene M. Koenigs
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
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using the Digital Object Identifier (DOI) given below. The VoR will be
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201915161
Angew. Chem. 10.1002/ange.201915161
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10.1002/anie.201915161
Angewandte Chemie International Edition
COMMUNICATION
Photoinduced proton transfer reactions for mild O-H
functionalization reactions of unreactive alcohols
Sripati Jana,#,[a] Zhen Yang,#,[a] Fang Li,[a] Claire Empel,[a] Junming Ho,[b] and Rene M. Koenigs*[a]
Abstract: Hexafluoroisopropanol is typically considered as an
unreactive solvent and not as a reagent in organic synthesis. Herein,
we report on a mild and efficient photochemical reaction of aryl
diazoacetates with hexafluoroisopropanol that enables, under
stoichiometric reaction conditions, the synthesis of fluorinated ethers
in excellent yield. We support these findings with mechanistic
studies, which indicate a preorganization of hexafluoroisopropanol
and the diazoalkane as an unreactive hydrogen-bonding complex.
Only upon photoexcitation, this complex undergoes a protonation-
substitution reaction to the reaction product. We conclude with
investigations on the applicability of this photochemical
transformation and could show that a broad variety of acidic alcohols
can be subjected to this transformation and thus demonstrate the
feasibility of this concept in O-H functionalization reactions (54
examples, up to 98% yield).
deliver a diazonium ion and a pendant nucleophilic anion (ion
pair 8). The latter should undergo a nucleophilic substitution to
deliver the reaction product (9). This concept would now open
up a new reactivity pattern of diazoalkanes and add to known
approaches toward X-H functionalization reactions (Scheme 1b).
The latter have been described via
a carbene insertion
mechanism under metal-catalyzed and photochemical
conditions.[10,11] More lately, Jurberg and Davies reported that
acidic carboxylic acids react even in the dark via the classic
protonation mechanism with strong Brønsted acids.[11]
a) photoinduced proton transfer reactions
photobases
OR
OR
H
N
H
N
hv
proton transfer upon
photoexcitation
Excited state reactivity has developed to a fundamental reaction
principle over the past years and is today an indispensable tool
to conduct organic synthesis via facilitating elementary reactions
steps, e.g. photoinduced electron or proton transfer reactions.[1-3]
With the resurgence of photoredox catalysis over the past
decade, applications of photoinduced electron transfer reactions
found their way into the standard toolbox of organic chemistry.[2]
Contrarily, the photoinduced proton transfer (PPT) is much less
investigated,[2,3] although it is of fundamental interest in the
development of photoacids[2] and photogenerated bases (1)[3,4]
with applications to trigger e.g. protein folding,[5] pH jumps,[6] or
to regulate enzymes.[7] PPT reactions in organic synthesis are
limited and first examples of photoacids,[8,9] e.g. the UV
excitation of a bi-naphthol derived catalyst (5) can be applied in
protonation reactions of silyl enol ethers (3) albeit in low yields
(Scheme 1a).[9] Contrarily, PPT reactions for the purpose of
carbon-carbon or carbon-heteroatom bond forming reactions
and/or the activation of unreactive precursor has, to the best of
our knowledge, not been described. This approach would thus
open up a conceptually new approach in organic synthesis,
ideally in the presence of mild, low-energy visible light.
O
O
2
1
application of photoacids
OTMS
O
Ph
Ph
OH
OH
H
Ph
Ph
5, hv
proton transfer upon
photoexcitation of 5
3
4
b) reactivity of diazoalkanes
5
via metal carbene intermediates
[M]
Nuc
N2
[M]
Nuc-H
R
R
R
metal carbene
formation
R
R
R
R
H
via carbene intermediates
N2
hv
Nuc
R
Nuc-H
R
R
carbene
formation
R
R
R
R
H
reaction with strong acids
N2
H-A
A-
N2
Nuc
R
protonation
R
R
R
H
H
We hypothesized that photoexcitation of aryldiazoacetates
(6) with visible light should generate a photoexcited state that
might act as a photobase in a PPT reaction with mild acids to
c) Photoinduced proton transfer
reaction with mild acids
N2
N2
Nuc
hv
excitation
Nuc
OR'
Nuc-H
N2
OR'
association
OR'
H
OR'
R
R
[a]
Sripati Jana, Zhen Yang, Fang Li, Claire Empel, Prof. Dr. Rene M.
Koenigs
R
R
H
O
O
H
O
O
6
7
8
9
Nuc
Institute of Organic Chemistry
RWTH Aachen University
unreactive hydrogen
bonding complex
proton transfer
upon photoexcitation
Landoltweg 1, 52074 Aachen, Germany
E-mail: rene.koenigs@rwth-aachen.de
Dr. Junming Ho
School of Chemistry, University of New South Wales
Sydney, NSW 2052, Australia
[b]
Scheme 1. Photoinduced proton transfer reactions, a) concept of
photobasicity and applications of photoacids in organic synthesis, b) reactivity
of modes of diazoalkanes. c) photoinduced proton transfer reactions.
#
These authors contributed equally to this work.
Supporting information for this article is given via a link at the end of
the document.
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10.1002/anie.201915161
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COMMUNICATION
To address this challenge, we sought to study the reaction of
1,1,1,3,3,3-hexafluoroisopropanol (HFIP) with diazoalkanes
under photochemical conditions. HFIP possesses distinct
hydrogen bonding ability, low nucleophilicity, mild acidity, and is
typically considered unreactive towards functionalization and
should therefore be a suitable starting point to investigate this
concept.[12] Typically, reactions with HFIP as a reagent are
conducted in HFIP solvent[13] and the development of mild and
efficient functionalization reactions of HFIP using stoichiometric
amounts of HFIP is in high demand. Only recently Waldvogel
and co-workers reported on an electrochemical process for the
functionalization of HFIP, yet in HFIP as solvent.[14] It would
harness HFIP as a reagent in organic synthesis and allow the
direct introduction of hexafluoro isopropyl ether groups into
organic molecules. We thus commenced our studies by
investigating the reaction of HFIP with phenyl diazoacetate 6a
under photochemical conditions[15] and were delighted to
observe that the functionalization of HFIP readily occurred within
4 hours reaction time at ambient temperature in excellent yield
and without the need of further purification (Table 1, entry 1). We
could subsequently reduce the amount of HFIP to 1.0 equivalent
and obtained the desired product 10a as an analytically pure
sample after simple evaporation of solvent (Table 1, entry 2-4).
Control experiments using iPrOH revealed only a very sluggish
reaction and poor yield of the corresponding isopropoxy ether,
even with a large excess of iPrOH (10 eq.) (Table 1, entry 9). No
Control experiments with Rh(II) resulted in unproductive reaction
pathways. With a copper catalyst and a large excess of HFIP
small amounts of the hexafluoro isopropoxy ether 10a were
observed albeit substantial amounts of by-product were formed,
which is in line with observations of the Doyle group.[16] Under
comparable reaction conditions (1 eq. of HFIP) only negligible
amounts of the desired product were obtained (Table 1, entry 8).
Intrigued by this unexpected observation and the
outstanding yield even when using a 1:1 mixture of HFIP and the
diazoalkane, we questioned, if the hydrogen bond donor
properties of HFIP might play a role to promote this reaction.
Indeed, early studies on the interaction of diazoalkanes with
hydrogen bond donors indicate this potential interaction.[17,18] We
then studied the interaction of 6a with different alcohols in a 1:1
ratio by UV-vis spectroscopy, yet no significant difference (Table
2) was observed. We next carried out NMR studies in
chloroform-d1 solvent. These studies revealed a distinct pKA
related chemical shift perturbation of the alcohol O-H proton.
HFIP is the most acidic substrate and
a chemical shift
perturbation of 1.04 ppm was observed, the less acidic trifluoro
ethanol (TFE) shifted for 0.34 ppm. The least acidic iPrOH
showed only a very minor chemical shift perturbation of 0.03
ppm (Table 2). Importantly, a similar trend was observed in 13C-
NMR of the ester carbonyl and methyl group (Table 2). A similar
observation in chemical shift perturbation was made for different
mildly acidic halogenated alcohols or phenols, e.g. trichloro
ethanol, tribromo ethanol, or 3,3,3-trifluoro propanol or 2,6-
difluorophenol (for details, please see Table S1 and S2).[19] All
samples did not undergo a spontaneous O-H functionalization
reaction of the alcohol in the dark.
background
reaction
between
HFIP
and
methyl
phenyldiazoacetate 6a was observed in the dark even after 24
hours of reaction time (Table 1, entry 10).
Table 1. Realization of the photobasicity concept.
Table 2. Influence of the alcohol on the reaction yield and selected physical
CF3
properties.
N2
blue light (470 nm)
solvent
OH
CF3
O
CF3
+
CO2Me
6a
F3C
CO2Me
10a
N2
R
blue light (470 nm)
O
OH
R
+
CO2Me
CDCl3
CO2Me
10a-13a
[a]
#
conditions
solvent[b]
eq.
%yield
(1 eq.)
6a
(1 eq.)
1
2
3
4
470 nm
470 nm
470 nm
470 nm
DCM
DCM
DCM
CHCl3
DCM
DCM
10
5
>99
[a]
Δδ (O-H)
Δδ (C=O)
λEx.
#
alcohol
yield[a]
(ppm)[b]
(ppm)[c]
(nm)
>99
[d]
1
>99
1
2
3
4
5
--
--
--
--
433
430
432
433
432
1
>99
HFIP
TFE
DFE
iPrOH
>99% (10a)
96% (11a)
95% (12a)
5% (13a)
1.04
0.34
0.08
0.03
0.70
0.14
0.07
0.00
5[b]
6[b]
Rh2(OAc)4 (3 mol-%)
Rh2(esp)2 (3 mol-%)
10
10
no rct.
no rct.
7[b]
8[b]
Cu(MeCN)4PF6 (5 mol-%) +
2,2-bipyridine (7 mol-%)
DCM
DCM
10
1
28*
<5
9[c]
470 nm
DCM
DCM
9*
10
(iPrOH)
[a] 6a (0.4 mmol) and the respective alcohol (1 eq.) were dissolved in
CDCl3. Yields by 1H-NMR of the crude reaction mixtures after irradiation. [b]
By 1H-NMR before irradiation with 470 nm LED (3 W). [c] By 13C-NMR
before irradiation with 470 nm LED. [d] Absorption maximum of a 1:1
mixture of 6a and alcohol in DCM solvent (c = 0.1 mol/L). TFE = trifluoro
ethanol, DFE = difluoro ethanol.
10[d]
dark reaction
10
no rct.
[a] 6a (0.4 mmol) and the hexafluoroisopropanol were dissolved in the
solvent indicated and then irradiated with 470 nm LEDs (3 W) [b] reaction
with catalysts as indicated in the dark. [c] Reaction with iPrOH instead of
HFIP. [d] Reaction in the dark.
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When subjecting the samples to the photolysis reaction
We then set out to study competition experiments to understand,
if the reaction proceeds via a proton or carbene transfer
mechanism. We therefore probed the reaction of methyl
phenyldiazoacetate 6a with HFIP and other halogenated
alcohols in the presence of styrene as a carbene trapping
reagent and only small amounts of the cyclopropane product 14
were obtained in the case of HFIP or other halogenated alcohols
(for details see Table S3). When probing iPrOH under the same
conditions, only the cyclopropane product was observed.[19] Next,
we studied allyl and homoallyl phenyldiazoacetate 6b/c, yet no
intramolecular cyclopropanation reaction occurred and only the
reaction with HFIP took place in high yield (10b/c, Scheme 2c).
conditions, we could observe
a
clean and quantitative
conversion of HFIP and trifluoro ethanol to the O-H
functionalization product without by-product formation. Difluoro
ethanol (DFE) underwent the O-H functionalization with 95%
yield and about 5% of the diazine was observed in 1H-NMR. The
least acidic iPrOH gave only minor amounts of the O-H
functionalization product in the reaction with methyl
phenyldiazoacetate 6a, instead the formation of the diazine
byproduct was observed.
To further probe this reaction mechanism, we performed a set of
control experiments. We first studied labeling experiments using
deuterium labeled HFIP and trifluoro ethanol under
stoichiometric conditions. In both cases, we could observe a
high preservation of the deuterium label of the deuterium atom,
which is indicative of deuteron transfer or O-D insertion reaction
(Scheme 2a). When removing the weakly acidic proton under
basic conditions, the desired reaction product was not obtained
and the decomposition of diazoacetate 6a was observed, which
further corroborates the importance of the hydrogen bonding for
high reaction efficiency. Similarly, sodium salts of other
alchohols, such as trifluoroethanol or pentafluorophenol lead to
decomposition of the diazoacetate (Scheme 2b).
These observations are indicative of
a
proton transfer
mechanism is taking place in this transformation.
The above data now provides basic experimental evidence of a
reaction mechanism involving the initial formation of a hydrogen
bonded reactant complex 15. Irradiation of this complex with
visible light delivers a photoexcited complex 15*, which can then
act as a photobase and readily deprotonate mildly X-H acidic
reaction partners. This process can now result in the formation
of ion pair 16 under concomitant extrusion of nitrogen gas or in
the formation of ion pair 16’. Both ion pairs then undergo a rapid
nucleophilic substitution reaction and formation of the reaction
product 10.
a) labelling experiments
CF3
N2
H/D
CF3
N2
OD
CF3
O
hν
N2
+
OMe
CO2Me
without light
OH
R
D/H
CO2Me
+
CO2Me
CF3
D
6a
O
H
deutero-10a
1 eq.
1 eq.
OD
OR
15
HFIP-OD: 81% (H:D = 1:4)
HFIP-D2: 74% (H:D = 1:7)
6a
N2
with light
(470 nm)
hν
O
CF3
H
-N2
+
CO2Me
F3C
CO2Me
CO2Me
D
6a
1 eq.
1 eq.
N2
R
deutero-11a
O
O
R
OMe
b) experiments to probe the hydrogen bonding
69% (H:D = 1:3)
16
CO2Me
O
N2
ONa
H
hν
H
N2
10
+
-N2
decomposition of 6a
CO2Me
OR
15*
F3C
CF3
CO2Me
F
H
6a
F
F
ONa
O
R
F3C
ONa
similar observation with:
16'
F
F
c) experiments to probe the carbene vs. proton transfer
Scheme 3. Hypothesized reaction mechanism.
Protonation
Carbene
OH
CF3
CF3
CO2Me
N2
Ph
Ph
CO2Me
In subsequent investigations, we probed the generality of this
transformation. We set out to first investigate the stoichiometric
reaction of aryl diazoacetates with HFIP, trifluoro ethanol and
difluoro ethanol and were delighted to observe that in all cases
the desired O-H functionalization products were isolated in
excellent yield (Scheme 4, 10a-l, 11a-h, 12a-h). Notably, in the
majority of examples using HFIP and trifluoro ethanol no further
purification was needed, which underlines the high efficiency of
this photoinduced proton transfer process. Difluoro ethanol
reacted similarly, yet purification of the final compound by
column chromatography and a slight excess (3 eq.) of the
alcohol was required. Only in the case of ortho-substituted
aryldiazoacetate, TFE and DFE proved unreactive and only a
small amount of product (<10%) was observed by NMR
spectroscopy (Scheme 3, 11i, 12i).
F3C
CF3
(1 eq.)
hν
O
Ph
CO2Me
+
Ph
6a
Ph
(X eq.)
with
1 eq. styrene
5 eq. styrene
10a
95%
81%
14
<5%
9%
CF3
Protonation
N2
O
CF3
OH
hν
O
O
+
F3C
CF3
n
n
O
O
1 eq.
6b, n = 1
6c, n = 2
10b, n = 1, 91%
10c, n = 2, 88%
Scheme 2. Control experiments. a) Labeling studies with deuterated HFIP and
TFE. b) Experiment without the possibility of hydrogen bonding. c)
Experiments to probe a potential inter- or intramolecular carbene transfer
reaction.
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10.1002/anie.201915161
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COMMUNICATION
R
blue light
DCM
OH
CF3
- stoichiometric reaction conditions
- high yields
- reaction with mildly acidic alcohols
N2
+
O
CF3
EWG
R
Ar
EWG
Ar
reaction with hexafluoro isopropanol
CF3 CF3
CF3
CF3
CF3
CF3
CF3
CO2Me
10g, 91%
O
CF3
CO2Me
10a, 97%
O
CF3
O
CF3
O
CF3
O
CF3
O
O
CO2Et
CO2Bn
CO2tBu
n
O
F
10b, n = 1, 91%
10d, 94%
10e, 92%
10f, 93%
10c, n = 2, 88%
CF3
CF3
CO2Me
10k, 95%
CF3
CF3
CO2Me
10l, 88%
CF3
CF3
CF3
CO2Me
CF3
CF3
O
O
O
CF3
O
O
O
MeO
CO2Me
CO2Me
O
10j, 93%
Cl
Br
10h, 88%
10i, 95%
reaction with trifluoro and difluoro ethanol
O
R
O
R
O
R
O
R
O
R
CO2Me
CO2Me
CO2Me
CO2Et
CO2Bn
Cl
F
11c, R = CF3 98%
12c, R = CF2H 84%
11e, R = CF3 89%
12e, R = CF2H 94%
11d, R = CF3 80%
12d, R = CF2H 86%
11b, R = CF3 97%
12b, R = CF2H 86%
11a, R = CF3
96%
12a, R = CF2H 93%
F
O
R
O
R
O
R
O
R
MeO
CO2Me
CO2Me
CO2Me
CO2Me
Br
11f, R = CF3 69%
12f, R = CF2H 76%
11g, R = CF3 89%
12g, R = CF2H 91%
11h, R = CF3 95%
12h, R = CF2H 77%
11i, R = CF3 <10%
12i, R = CF2H <10%
reaction with halogenated alcohols
R
F3C CF3
O
R
CF3
n
CH2F
O
R
O
Ph
O
CF3
O
O
F
F
CO2Me
O
CH2F
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
94%
86%
17a, R = C2F5
17b, R = C4F9
17c, 77%
17d, R = Ph, 69%, d.r. 1:1
17e, R = Me, 91%, d.r. 1:1
17f, R = iPr, 75%, d.r. 1:2.5
17g, R = CO2Me, 60%, d.r. 1:1
n = 1, 17h, 63%
n = 2, 17i, 48%
17j, 54%
17k, 50%
18a, R = CCl3, 93%
18b, R = CBr3, 69%
18c, R = CCl2H, 79%
Ph
O
F
F
X
MeOOC
MeOOC
O
O
O
COOMe
H
F
F
F
F
O
C6F5
Ph
CO2Me
Ph
O
H
H
17n, 59%
CO2Me
MeO2C
F
F F
F
73%
55%
17l, R = -CF2-CH2OH
17m, R = -(CF2)2-CH2OH
O
O
Ph
17p, 86%
17q, 76%
d.r. 1:1
F
F
Ph
COOMe
17o, 43%
reaction with phenols
F
Br
F
F5
NO2
O
F
COOMe
Ph
O
O
O
O
COOMe
F
CO2Me
CO2Me
mixture of C and O alkylation
Ph
19d, 71%
CO2Me
O2N
19a, 81%
19b, 48%
19c, 79%
Scheme 4. Substrate scope of the photoinduced proton transfer reactions of aryldiazoacetates with alcohols.
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10.1002/anie.201915161
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COMMUNICATION
[1]
[2]
a) M. D. Kärkäs, J. A. Porco Jr., C. R. J. Stephenson, Chem. Rev. 2016,
116, 9683-9747; b) T. P. Nicholls, D. Leonori, A. C. Bissember Nat.
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We next studied different substitution patterns of fluorinated
alcohols.
Perfluorinated
alcohols
and
substituted
trifluoromethylated alcohols underwent the photoinduced proton
transfer reaction in good to high yield (Scheme 3, 17a-q).
Importantly, even a sterically highly demanding tertiary alcohol
smoothly reacted to the desired fluorinated ether 17c. Similarly,
the bis(monofluoromethyl)-substituted alcohol reacted in good
yield to give ether 17k. It is noteworthy that the trifluoromethyl
group can also be moved to the terminal position and 3,3,3-
trifluoro-propan-1-ol reacted in moderate yield to the desired
reaction product 17h. When studying diols, the product of both
mono- and difunctionalization could be obtained in moderate to
good yield, depending on the reaction stoichiometry (Scheme 3,
17l-o). The efficiency of this proton transfer is also underlined in
the reaction of one example of a tertiary fluorinated alcohol that
gave the desired ether 17c in good yield.
This reaction can further be performed using chlorinated and
brominated alcohols and the corresponding ethers were isolated
in moderate to good yield (Scheme 3, 18a-c). Phenol readily
reacted in this transformation, yet giving a complex mixture of O-
H and C-H functionalization products. When blocking ortho
and/or para position of the aromatic ring by substituents, the
desired O-H functionalization product of phenol was obtained in
moderate to high isolated yield (Scheme 3, 19a-d).
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In summary, we herein report on photoinduced proton transfer
[8]
[9]
reactions that open up
a
new reactivity window of
aryldiazoacetates. They undergo the formation of an unreactive
hydrogen bonded complex with mildly acidic fluorinated alcohols
via the ester functional group. Photoexcitation of this complex
leads to a concomitant photoinduced proton transfer reaction,
followed by nucleophilic substitution to give the ether product.
This hydrogen bond was identified by NMR spectroscopy and
further control experiments underpin the importance of this
hydrogen bond for high reaction efficiency and a carbene
transfer mechanism is unlikely. We studied the generality and
applicability of this approach in the reaction with diverse
fluorinated and other halogenated alcohols and could obtain the
desired reaction products in high yields (54 examples, up to 98%
yield).
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Acknowledgements
The authors thank the German Science Foundation, Dean’s
Seed Fund of RWTH Aachen and the Boehringer Ingelheim
Foundation for financial support. The authors thank Dr. T. Vinh
Nguyen (UNSW Sydney), Prof. Frederic W. Patureau (RWTH
Aachen), and Prof. Markus Albrecht (RWTH Aachen) for helpful
discussions.
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[19] For details, please see the supporting information.
Keywords: photochemistry • photobase • fluorine • diazoalkane
• O-H functionalization
This article is protected by copyright. All rights reserved.

10.1002/anie.201915161
Angewandte Chemie International Edition
COMMUNICATION
Entry for the Table of Contents
COMMUNICATION
Sripati Jana,# Zhen Yang,# Fang Li,
Claire Empel, Junming Ho, and Rene M.
Koenigs*
Page No. – Page No.
Photoinduced proton transfer
reactions for mild O-H
functionalization reactions of
unreactive alcohols
Photoinduced proton transfer reactions of diazoacetates enable highly efficient O-H
functionalization reactions of halogenated, unreactive alcohols under stoichiometric
reaction conditions. This concept now opens up a new reactivity pattern of
diazoacetates.
This article is protected by copyright. All rights reserved.