Photochemical O?H Functionalization Reactions of Cyclic Diazoamides

Article abstract of DOI:10.1002/adsc.202000818

Herein, we describe the photochemical O?H functionalization reaction of acidic alcohols with cyclic diazoamides. We studied the O?H functionalization reaction of different fluorinated and non-fluorinated alcohols to give the corresponding ether products in high yields (43 examples, up to 97% yield). Furthermore, we performed studies to evaluate a photoexcited proton transfer reaction pathway in comparison to classic carbene transfer reactions. (Figure presented.).

Full text of DOI:10.1002/adsc.202000818

Title: Photochemical O-H Functionalization Reactions of Cyclic
Diazoamides
Authors: Claire Empel, Dennis Verspeek, Sripati Jana, and Rene
Michael Koenigs
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10.1002/adsc.202000818
Advanced Synthesis & Catalysis
FULL PAPER
DOI: 10.1002/adsc.202((will be filled in by the editorial staff))
Photochemical O-H Functionalization Reactions of Cyclic
Diazoamides
Claire Empel,a Dennis Verspeek,a Sripati Jana,a and Rene M. Koenigsa*
a
RWTH Aachen University, Institute of Organic Chemistry, Landoltweg 1, D-52074 Aachen, Germany
[rene.koenigs@rwth-aachen.de]
Received:
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.
Abstract. Herein, we describe the photochemical O-H studies to evaluate a photoexcited proton transfer reaction
functionalization reaction of acidic alcohols with cyclic pathway in comparison to classic carbene transfer reactions.
diazoamides. We studied the O-H functionalization reaction
of different fluorinated and non-fluorinated alcohols to give
the corresponding ether products in high yields (43
examples, up to 97% yield). Furthermore, we performed
Keywords: O-H functionalization; cyclic diazoamides;
photochemistry; fluorine.
without the need to exclude air or moisture and
applicability.[6-9] More recently, our group was able to
expand the photochemical reactivity of diazoalkanes
towards photoinduced proton transfer reactions,
which now open up a new reactivity pattern of
diazoalkanes under photochemical conditions
Introduction
The reaction of diazoalkanes with O-H groups
represents an important and timely strategy for the
construction of C-O bonds.[1] In general, two different
mechanistic scenarios for this reaction can be
considered: a) proton transfer from Brønsted acidic
substrates to the diazoalkane followed by
nucleophilic substitution reaction or b) carbene
transfer of the diazoalkane to non-acidic alcohol
substrates. Acidic substrates, such as carboxylic acids,
react via the proton transfer pathway to form an ester
product.[2] More lately, the use of strong Brønsted
acids enriched this concept allowing protonation
reactions of diazoalkanes with catalytic amounts of
acid.[3] The most commonly used concept for O-H
functionalization reactions involves the use of metal-
catalysts. The latter undergo metal-carbene formation
with diazoalkanes that can subsequently react with
alcohols in ylide formation followed by 1,2-proton
shift to give the O-H functionalization product.[4a]
Due to the high reactivity of the carbene intermediate,
transition metal complexes have long been
considered a prerequisite to conduct efficient and
selective carbene transfer reactions and today, a large
variety of metal-based catalysts are employed to
control the reactivity and selectivity of carbene
transfer reactions.[5]
(Scheme 1b).[9]
a) Photochemical O-H functionalization via carbene intermediates
visible
light
N2
Nuc
OR'
Ph
EWG
R
Ph
EWG
H
1
2
3
O
R
R
purple
light
R
N
N
N
N
N
N
4
5
6
N
b) Photochemical O-H functionalization via
photoinduced proton transfer reactions
N2
N2
Nuc
hu
Nuc
OR'
Nuc-H
N2
OR'
association
OR'
H
OR'
R
R
R
excitation
R
H
H
O
O
O
O
7
8
9
3
Nuc
unreactive hydrogen
bonding complex
proton transfer
upon photoexcitation
c) This work: photoinduced proton transfer reactions of
cyclic diazoamides
N2
H
HO
11
N
R
2 O-R
O
O
R
O
O
hu
N
N
N
10
12
13
In 2018 the visible light photolysis emerged as a
new, highly attractive option in organic synthesis
methodology to conduct carbene transfer reactions
with aryldiazoacetates under mild and metal-free
reaction conditions (Scheme 1a).[6] Since then,
several groups reported on their studies to promote
visible light mediated carbene transfer reactions in
highly efficient cycloaddition, X-H insertion or
olefination reactions.[7,8] In all cases, the irradiation
with low-energy visible light enables an operationally
simple and straightforward access to conduct carbene
or proton transfer reactions of aryldiazoacetates
Scheme 1. Photochemical O-H functionalization.
Despite this progress, currently available methods
for photochemical, metal-free applications of
diazoalkanes are mainly limited to the application of
aryldiazoacetates, and there is only a limited number
of reports on the reaction of other diazoalkanes.
Gevorgyan and co-workers recently made
significant progress with regards to the diversity of
different carbene precursors. In their report, they
a
1
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10.1002/adsc.202000818
Advanced Synthesis & Catalysis
studied pyridotriazoles that can undergo a Dimroth-
like rearrangement to give an intermediate pyridyl-
substituted diazoalkane, which in turn can be
photolyzed with near-UV light (385 nm) to give a
carbene intermediate (Scheme 1a).[10]
Cyclic diazoamides are another important class of
diazoalkanes that have been studied in different
metal-catalyzed carbene transfer reactions to give
cyclopropanes or spirocycles.[11] Given the
importance of photochemical carbene transfer
reactions, we planned to study photochemical
reactions of cyclic diazoamides, which in a next step
could react in metal-free proton or carbene transfer
reactions (Scheme 1c).
absorption of cyclic diazoamides and thus less
efficient photolysis. In further optimization
experiments we studied the influence of solvents and
reaction stoichiometry to give the optimized reaction
conditions (Table 1, entry 5-7 and Table S1 in the
ESI).[12] It is important to note that the reaction
mixture needs to be cooled to room temperature with
an additional fan, to avoid warming caused by the
LED irradiation (Table 1, entry 8). While a
substantial decrease in reaction yield was observed
with 1 eq. of water, no additional drop in yield was
observed with 5 eq. of water (Table 1, entry 9,10).
Finally, we studied, if this O-H functionalization
reaction can be performed by heating a mixture of
10a and 11a in the dark in a sealed tube, however,
only the decomposition of the diazoamide 10a was
observed (Table 1, entry 11).[13]
Results and Discussion
Table 1. Reaction Optimization.
Photochemical properties and O-H functionalization reactions
of halogenated alcohols.
CF3
N2
O
CF3
DCM
OH
CF3
11a
We first studied the photochemical properties of
cyclic diazoamide (10a) and compared these
properties with the most widespread used methyl
phenyldiazoacetate (1a) (Figure 1). While the latter
possesses a distinct absorption band in the visible
light region (λmax = 432 nm), cyclic diazoamides
exhibit a rather strong absorption in the purple light
region (<400 nm) and a very weak shoulder in the
blue light region between 430 and 470 nm (for details
please see ESI, Table S1).[12]
O
O
24 h, rt
F3C
N
N
10a
13a
entrya) wavelength
10a : 11a
Yield (%)
1
2
3
4
5
6
7
385 nm
470 nm
530 nm
in the dark
470 nm
470 nm
470 nm
470 nm
470 nm
470 nm
In the dark
1 : 1
1 : 1
1 : 1
1 : 1
2 : 1
1 : 2
1 : 5
1 : 5
1 : 5
1 : 5
1 : 5
38
77
8
no rct.
23
81
97
77
1,2
N2
N2
8b)
9c)
10d)
CO2Me
1
0,8
0,6
0,4
0,2
0
O
1a
72
70
dec.
N
10a
1a
10a
11e)
0,05
a)
Reaction conditions: 10a and 11a were dissolved in
2.0 mL DCM. The mixture was irradiated with the light
source indicated for 24 h from 5 cm distance at rt (25 °C).
b) reaction without additional cooling at 40 °C. c) with 1 eq.
0,04
0,03
0,02
0,01
0
d)
e)
of water. with 5 eq. of water. reaction without light,
reaction temperature 70 °C.
350
400
450
500
550
wavelength [nm]
220
270
320
370
420
470
520
570
wavelength [nm]
With the optimized conditions in hand, we next
embarked on studies using different halogenated
alcohols to investigate the applicability of this
photochemical O-H functionalization reaction
(Scheme 2). Different fluorinated alcohols bearing a
perfluoroalkyl, difluoromethyl or pentafluorophenyl
group reacted in high yield to the desired O-H
functionalization product (Scheme 2, 13a -13o).
When studying 1,1,1-trifluoro-propan-2-ol the
desired O-H functionalization product was obtained
with low diastereoselectivity (d.r. 1:1.5). Further
investigations involved the reaction of different
chlorinated alcohols, which reacted in similar yield to
the desired O-H functionalization products (13l-13n).
In a next step, we evaluated different cyclic
diazoamides in the reaction with HFIP 11a. Different
alkylated and arylated protecting groups were well
tolerated (13p-t), while Boc- and Ts-protection
Figure 1. Photochemical properties of diazo compounds.
To probe the viability of photochemical
applications of cyclic diazoamides, we thus set out to
study the O-H functionalization reaction of 10a with
hexafluoroisopropanol (HFIP) 11a. At first, we
studied the influence of different light sources in this
reaction, which revealed a significant influence of the
light source. While low to moderate yields were
obtained under UV-A or green light irradiation, a
high yield of the O-H functionalization product was
obtained when using blue LEDs (470 nm) (Table 1,
entry 1-3). In comparison to our previous study on
the reaction of aryldiazoacetates, longer reaction
times were required, which is in line with the weaker
2
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10.1002/adsc.202000818
Advanced Synthesis & Catalysis
groups did not provide the desired reaction product,
which might be reasoned by a weaker hydrogen
bonding complex and changed electronic properties
of the cyclic diazoamide (for details, please see table
S2 and S3 in ESI). Furthermore, we investigated
different substitution pattern of the annellated phenyl
well tolerated and the corresponding products were
isolated in high to excellent yields (13v-13aa).
Moreover, unprotected cyclic diazoamides can be
used in this O-H functionalization reaction; the
desired product was isolated in slightly reduced yield
(13u, 52%).
ring; to our delight substituents in all poitions were
R''
O
N2
blue LEDs
DCM (0.1 M), 24 h
OH
R
O
R
O
R''
rt
N
N
10
11
13
R'
1.0 eq., 0.2 mmol
R'
5.0 eq., 1 mmol
R
different fluorinated alcoholes
CF3
O
O
O
O
O
O
O
CF3
CF3
CF3
O
CF2H
C2F5
C2F4H
C3F7
O
N
O
O
O
O
O
N
N
N
N
N
N
13a, 97%
13b, 75%
13c, R = Me, 72%, d.r. 1:1.5
13d, R = Ph, 70%, d.r. 1:1.5
13e, R = CO2Me, 88%, d.r. 1:1.2
13f, 84%
13g, 61%
13h,, 97%
13i, 73%
F5
O
O
O
O
O
O
CF3
CF2Cl
CCl3
CCl2H
CF3
O
N
O
O
O
O
O
N
N
N
N
N
13j, 71%
13k, 81%
13l, 76%
13m, 81%
13n, 75%
13o, 79%
different N-protections
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
O
O
O
O
O
N2
N2
CF3
CF3
O
O
N
O
O
O
O
O
N
N
N
N
N
N
H
R
Boc
Ts
CO2Et
10b
10c
R = nPr, 13p, 77%
R = Bn, 13q, 59%
13r, 95%
13s, 97%
13t, 81%
13u, 52%
no product formation
different cyclic diazoamides
CF3
CF3
CF3
CF3
CF3
CF3
CF3
Cl
O
O
O
O
O
CF3
CF3
O
CF3
Cl
R
O
O
O
O
N
N
N
N
N
Cl
F
13v, 79%
13w, 97%
13x, R = OMe, 97%
13y, R = OCF3, 92%
13z, 76%
13aa,71%
Scheme 2. Studies on O-H functionalization reaction with different halogenated alcohols, N-protections and diazoamides.
products were obtained in moderate to good yield
Studies on O-H functionalization of non-fluorinated alcohols
and phenols.
(16a-b).
R
blue LEDs
DCM (0.1 M)
N2
O
R
EWG/R'
+
O
24 h, rt
O
HO
EWG/R'
11
In further studies, we embarked on investigations
of non-halogenated alcohols (Scheme 3). For this
purpose, we first probed alcohols with electron-
withdrawing substituents e.g. ester- and nitrile-
substituted alcohols. When investigating ester-
substituted alcohols the desired products were
obtained in moderate to good yield with low
N
N
10a
14-16
1.0 eq., 0.2 mmol 5.0 eq., 1 mmol
EWG = CN, CO2R
Ph
O
O
O
CO2nBu
CO2Me
CO2Me
O
N
O
O
N
N
diastereoselectivity
(14a-c).
Nitrile-substituted
14a, 56%
14b, 68%, d.r. 1:3
Ph
CN
14c, 40%, d.r. 1:1.4
alcohols proved more efficient in the O-H
functionalization reaction and the corresponding
products were isolated in good to excellent yield with
low d.r. values (15a-b). Moreover, weakly acidic
alcohols like methanol and iso-propanol were studied.
When using five equivalents of the alcohol the
products were obtained in low yield. When
performing the reaction in methanol or iso-propanol
as solvent, the corresponding O-H functionalization
O
O
O
O
CN
O
O
O
O
N
N
N
N
15a, 96%
15b, 83%, d.r. 1:1.5 16a, (29%), 59%* 16b, (21%), 44%*
* alcohols as reaction solvent
Scheme 3. Studies on O-H functionalization reaction with
non-fluorinated alcohols.
3
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10.1002/adsc.202000818
Advanced Synthesis & Catalysis
Additionally, we studied different fluorinated and
corresponding ester products in moderate yield of
33-43% (18a-c). The dropped yields may be reasoned
by the lower nucleophilicity of the carboxylate anion
compared to an alkoxide. No reaction was observed
in the absence of light.
non-fluorinated phenols under the optimized reaction
conditions (Scheme 4). Phenol gave only a moderate
yield of the O-H functionalization product and the
para-C-H functionalization of phenol was identified
as the major side reaction product by 1H-NMR of the
crude reaction mixture (17a).[14] Similarly, para-
cyano or para-trifluoromethyl phenol or the sterically
demanding 2,6-difluoro phenol gave the product only
in moderate yield (17b,c,e), yet no major by-products
could be identified. Pentafluorophenol provided the
O-H functionalization product in 82% yield (17f). In
an additional step, we investigated benzoic acids
under the optimized reaction conditions to give the
Mechanistic experiments on the O-H functionalization.
To probe the reaction mechanism of this O-H
functionalization reaction with cyclic diazoamides,
we carried out a set of control experiments to
evaluate carbene and photoinduced proton transfer
reaction pathways.
For this purpose, we probed a potential hydrogen
bond interaction between cyclic diazoamide 10a and
with one and five equivalents of HFIP 11a by NMR
spectroscopy in a first set of experiments. We
observed a significant chemical shift perturbation for
blue LEDs
DCM (0.1 M)
N2
O
R
OH
+
R
O
24 h, rt
O
N
N
10a
11
17
1.0 eq., 0.2 mmol
5.0 eq., 1.0 mmol
1
the alcohol proton and the carbonyl carbon in H and
CN
CF3
13C NMR, respectively. The observation of this
chemical shift perturbation points at the formation of
a hydrogen-bonding complex of 10a and 11a in the
dark (Scheme 5a).
O
O
O
O
N
O
O
N
N
17a, 40%
17b, 47%
17c, 37%
Further experiments involved studies on the role of
the O-H group of the fluorinated alcohol 11. For this
purpose we studied the reaction of deuterated HFIP
11a-D/11a-D2, deuterated trifluoroethanol 11b-D and
sodium hexafluoro isopropoxide salt 20. Deuterated
alcohols 11a-D/11a-D2 or 11b-D gave a high
incorporation of deuterium in the reaction product,
which is in line with the formation of a hydrogen-
bonding complex and a proton transfer reaction from
the fluorinated alcohol upon photoexcitation (Scheme
5b). When using the sodium salt 20, we only
observed the decomposition of diazoamide 10a and
the O-H functionalization product was not observed
(Scheme 5c), which highlights the importance and
necessity of the hydrogen bond for high reaction
efficiency.
F
F
O
O
F
O
F5
O
N
O
O
N
N
17d, 84%
17e, 24%
17f, 82%
F
Cl
O
O
O
O
O
O
O
N
O
O
N
N
18a, 43%
18b, 33%
18c, 33%
Scheme 4. Studies on O-H functionalization reaction with
phenols and benzoic acids.
a.) NMR studies
N2
N2
OH
1 eq. HFIP
Dd (O-H) = 2.02 ppm
Dd (C=O) = 0.47 ppm
5 eq. HFIP
Dd (O-H) = 0.96 ppm
Dd (C=O) = 1.14 ppm
in the dark
C
O
H
O
N
O
F3C
CF3
N
CF3
F3C
10a
11a
1 eq. or 5 eq.
19
hydrogen bonding complex
b.) labeling experiments
F3C
c.) experiments to probe the hydrogen bonding
H/D
F3C
blue LEDs
DCM, rt,
24 h
N2
N2
D
O
OD
Na
O
O
no product formation
diazoamide decomposed
O
H/D
CF3
CF3
O
N
N
N
F3C
CF3
10a
20
10a
11a-D
11a-D2
13a-D, 96% (D:H = 83:17)
13a-D2: 93% (D:H = 94:6)
d.) performed control experiments with metal catalysts
OH
11a
N2
F3C
CF3
Rh2esp2 (1 mol%)
or CuI (5 mol%)
N2
blue LEDs
DCM, rt,
24 h
and
CF3
D
O
no product formation
diazoamide decomposed
O
OD
OH
N
O
O
11b
N
F3C
10a
CF3
N
1 eq. or 5 eq.
10a
11b-D
13b-D, 72% (D:H = 88:12)
Scheme 5. Control and labeling experiments.
4
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10.1002/adsc.202000818
Advanced Synthesis & Catalysis
Next, we studied the O-H functionalization
strong influence of the acidity of the alcohol on the
hydrogen-bonding complex and the final reaction
outcome.
reaction under typical metal-catalyzed carbene
transfer reaction conditions using Rh(II)- or Cu(I)-
catalysts. However, no product formation was
observed even with five equivalents of HFIP 11a, and
diazoamide 10a decomposed under the present
reaction conditions (Scheme 5d). This now shows
that undergo O-H functionalization of HFIP via a
metal carbene intermediate is rather challenging.[15]
To further probe the reaction mechanism and a
potential carbene transfer pathway, we performed
competition experiments using a mixture of HFIP 11a
and TFE 11b. We proposed a stronger hydrogen-
bonding complex with HFIP 11a compared to the less
acidic TFE 11b. Indeed, we observed the O-H
functionalization product of HFIP 11a as the major
Moreover, we examined styrene 21 as a carbene
trap and added either five or ten equivalents of
styrene 21. We studied styrene 21 in competition
reactions with HFIP 11a and TFE 11b, and we could
observe O-H functionalization as the major reaction
pathway in all cases. While only little amounts of
cyclopropane 22 were observed using HFIP 11a as
reaction partner, a significantly higher amount of
cyclopropane 22 was observed using TFE 11b
(Scheme 6b), which might be related to weaker
hydrogen-bonding of TFE.[16] This data is now
indicative of a photoexcited proton transfer reaction
pathway instead of a classic carbene transfer reaction.
product 13a (Scheme 6a). This observation points at a
a) competition experiments to probe the effect of acidity of fluorinated alcohols
CF3
blue LEDs
DCM, rt,
24 h
13a :13b
N2
O
O
OH
OH
CF3
CF3
1.0 eq.: 30% + 21%
2.5 eq.: 40% + 23%
5.0 eq.: 60% + 21%
and
O
O
O
F3C
CF3
11a
CF3
11b
N
N
N
10a
13a
13b
1 eq., 2.5 eq., or 5 eq.
b) experiments to probe proton vs. carbene transfer
CF3
CF3
blue LEDs
DCM, rt,
24 h
O
Ph
N2
OH
13a : 22
5 eq.: 94% + 6%
10 eq.: 90% + 10%
O
O
O
F3C
CF3
N
N
N
N
10a
10a
11a
5 eq.
21
5 eq.
10 eq.
13a
22
22
blue LEDs
DCM, rt,
24 h
O
Ph
N2
CF3
OH
O
O
13b : 22
5 eq.: 65% + 21%
10 eq: 68% + 22%
O
N
CF3
N
11b
5 eq.
21
5 eq.
10 eq.
13b
Scheme 6. Competition experiments.
5 cm distance. The reaction temperature was
controlled by external cooling with a fan. The solvent
was evaporated under reduced pressure and the
Conclusion
In summary, we studied the photochemical O-H
functionalization reaction of cyclic diazoamides in
detail. Under optimized reaction conditions a broad
scope of different fluorinated and non-fluorinated
alcohols was performed. Moreover, phenols were
residue
was
purified
by
silica
column
chromatography.
compatible with the present reaction conditions (43 Acknowledgements
examples, up to 97%). Control, labeling and
competition experiments were performed to prove the
photoexcited proton transfer reaction pathway.
RMK thanks the German Science Foundation and Dean’s Seed
Fund of RWTH Aachen Foundation for financial support. CE
thanks RWTH Aachen University for a doctoral scholarship.
Experimental Section
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10.1002/adsc.202000818
Advanced Synthesis & Catalysis
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1
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6
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10.1002/adsc.202000818
Advanced Synthesis & Catalysis
FULL PAPER
Photochemical O-H functionalization reactions of
cyclic diazoamides
R''
EWG
O-H functionalization via photoexcited proton transfer reaction
N2
O
blue LEDs
Adv. Synth. Catal. Year, Volume, Page – Page
DCM (0.1 M), 24 h
R''
OH
R
O
R
O
N
R'
N
R'
EWG
Claire Empel, Dennis Verspeek, Sripati Jana and
Rene M. Koenigs*
7
This article is protected by copyright. All rights reserved.