Visible light-mediated metal-free double bond deuteration of substituted phenylalkenes

Article abstract of DOI:10.1039/d0gc03081c

Various bromophenylalkenes were reductively photodebrominated by using 1,3-dimethyl-2-phenyl-1H-benzo-[d]imidazoline (DMBI) and 9,10-dicyanoanthracene. With deuterated DMBI analogs (the most effective was DMBI-d11), satisfactory to excellent isotopic yields were obtained. DMBI-d11 could also be regenerated from the reaction mixtures with a recovery rate of up to 50%. The combination of the photodebromination reaction with conventional methods for bromoalkene synthesis enables sequential monodeuteration of a double bond without the necessity of a metal catalyst. This journal is

Full text of DOI:10.1039/d0gc03081c

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DOI: 10.1039/D0GC03081C
ARTICLE
Visible Light-Mediated Metal-Free Double Bond Deuteration of
Substituted Phenylalkenes
Roman Iakovenko a, Jan Hlaváč *a
Received 00th January 20xx,
Accepted 00th January 20xx
Various bromophenylalkenes were reductively photodebrominated by 1,3-dimethyl-2-phenyl-1H-benzo-[d]imidazoline
(DMBI) and 9,10-dicyanoanthracene. With deuterated DMBI analogs (the most effective was DMBI-d11), satisfactory to
excellent isotopic yields were reached. DMBI-d11 could also be regenerated from reaction mixtures by up to 50%. The
combination of the photodebromination reaction with conventional methods for bromoalkenes synthesis enables
sequential monodeuteration of double bond without necessity of a metal catalyst.
DOI: 10.1039/x0xx00000x
CN
H
H
Introduction
H
O
HN
H
Deuteration of organic compounds is of considerable
significance in numerous areas of chemistry and chemical
biology. Deuterated compounds became an essential tool for
reaction mechanism studies1,2,3 or structure elucidation.4–6
Deuterium incorporation may be highly beneficial also for drug
discovery due to the inhibition of the drug metabolism. It also
enables “evergreening” of expired patents on previously
discovered drugs.7–9
O2N
HO
Me
NEt2
CN
N
N
CN
H
H
N
H
OH
Me
NMe2
Entacapone
Rilpivirine
Cyclobenzaprine
OH
OH
OH
H
HO
HO
N
O
R1
H
As deuterated synthetic building blocks are usually costly, their
implementation to an extended reaction sequence is inefficient
for preparation of the compound on a larger scale. Also,
complex natural compounds eligible for isotopic enrichment do
not allow the use of deuterated precursor. The post-synthetic
transformation is the only feasible way of deuterium
implementation in these cases.
H
NMe
H
HOOC
O
O
H
H
OH
H
N
OH
H
R2
Salvianolic acid A
R1= R2 = H Ergometrine
R1 = Me, R2 = H Methylergometrine
R1= R2 = Me Methysergide
One of the relevant groups deserving attention is the
phenylvinyl fragment, which can be found in many approved
drugs, like entacapone, rilpivirine or cyclobenzaprine, natural
compounds including flavones, chalcones, stilbenoids or more
complex compounds like semisynthetic lysergic acid derivatives,
salvianolic acid A, etc. (Figure 1). Although there are various
methods for its deuteration, the drawbacks include low
selectivity, isotopic yield, and configuration stability along with
toxicity of heavy metal catalysts or influence of too reactive
species on functional groups. These facts force chemists to
study alternative deuteration procedures.
Figure 1. Examples of approved drugs and natural compounds with phenylvinyl moiety
The use of metallocatalysts meets with problems of
contamination of the products resulting in a risk of the final
product toxicity as well as contamination of sewage water.
Formation of organolithium compounds is suitable only for
alkenes with a sufficiently acidic vinyl hydrogen atom and could
also affect other functional groups in the molecule. A metal-free
H/D exchange of hydrogen atoms at phenylvinyl double bond
using N-heterocyclic carbenes17–20 was described a few times.
The disadvantages of this method include mainly low D-
enrichment and use of strong bases. In the above papers the
phenylvinyl deuteration is usually applied for mechanistic
studies or structure confirmation. No systematic study of such
deuteration has been published.
Recently published methods include direct H/D exchange or
replacement of various reactive groups. Deuterium can be
transferred from deuterated solvents under transition-metal
catalysis10–12 or by hydrolysis of organolithium compounds.13–16
a. Department of Organic Chemistry, Faculty of Science, Palacký University,
17. listopadu 12, 771 46 Olomouc, Czech Republic..
Electronic Supplementary Information (ESI) available: synthetic procedures, product
characterizations, KIE calculation, reaction optimization data. See
DOI: 10.1039/x0xx00000x
Other methods of this double bond deuteration are based on
the reduction of different groups, mainly halogen. The
systematic study for halogen/deuterium exchange including
few examples of phenylvinyl moiety was performed by
Kuriyama et al., who used the Pd/N-heterocyclic carbene
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Journal Name
complexes.21 Although this reaction affords high yields and
deuterium enrichment, the use of strong bases and possible
interaction of palladium catalyst with different functional
groups can limit the application to other substrates. Palladium
as well as many other transition metals are also known to have
numerous adverse health effects22,23 and its concentration in
e.g. medical substances is strictly regulated.24 Metal-free
dehalogenation method for haloarylalkenes was also
described,25 but it required use of hem-diiodoalkene.
Last decade significant attention was paid to reductive
dehalogenation under photoredox catalysis, however no
systematic study of deuteration has ever been published. The
published dehalogenation of vinyl iodides including phenylvinyl
derivatives26 used iridium-based photocatalysts. Although
transition-metal photocatalysts can be replaced by different
organic dyes with similar excited state reduction potential,27–29
no studies were performed for deuteration of carbon-carbon
double bond.
Table 1. Optimization of a photocatalyst and reducing agent.
DOI: 10.1039/D0GC03081C
View Article Online
Substrate
(Z/E ratio)
Reducing
agent
Conv
(NMR)
8%
#
Photocatalyst
1
2
P1a
P1a
5 eq 1
Br
Ph
2 eq 2
28%
A-Br
(1:5)
3
P2b
2 eq 2
65%
4
5
P1a
P1a
P2b
P2b
P1a
P1a
P2b
5 eq 1
2 eq 2
7%
Ph
73%
19%
96%
58%
80%
25%
Br
Br
Ph
Ph
6
2 eq Bu3N
2 eq 2
B-Br
7
8
5 eq 1
9
2 eq 2
Ph
10
2 eq Bu3N
C-Br
(1:13.3)
11
P2b
2 eq 2
>99%
Conditions - acetonitrile, 5 mol% of photocatalyst, reaction time 16 h; a Light source
380 nm LED, 13W; b Light source cool white LED, 13W.
Herein we report
a simple metal-free procedure for
The reactions led to modest results, and only conversion of
bromostilbene (C-Br) was significant. So, we switched to
another reducing agent (H-donor) – 1,3-dimethyl-2-phenyl-
benzo[d]imidazoline (2), which is widely known for its hydrogen
atom donating properties30,31 and is also capable of reductive
coupling reactions.32 The conversions with the reducing agent 2
were much higher (Table 1, entries 2, 5, 9).
deuterodebromination on phenylvinyl double bond. The
method can also be implemented in a reaction sequence
enabling the H/D exchange on the double bond. The selective
highly efficient deuterium implementation method can afford
cheap and selective isotopic enrichment of such compounds for
biological studies or improvement of pharmacological
properties thereof.
When 9,10-dicyanoanthracene (P2) as a photocatalyst in
combination with cool white LED irradiation was applied
similarly to previously described aryl halides transformation,28
the conversion has significantly increased. First, P2 was used
with tributylamine, as authors did, with modest success (Table
1, entries 6, 10). The pairing of P2 with reducing agent 2 (Table
1, entries 3, 7, 11) afforded the highest conversions of all three
substrates. Additional optimization data for reducing agent and
light source are presented in SI (Tables S2, S3). Also, (3-butyl-1-
methyl-1H-imidazol-3-ium-2-yl)borane as an alias metal-free
borohydride was tested either as an only reducer (Table S2,
entries 3, 9) or with a catalytic amount of 2 (entries 13-16) or
1,3-dimethyl-2-phenylbenzimidazolium iodide [3]I (entry 17),
but without success.
Results and discussion
Optimization of the photoreduction system
Before the necessary synthesis of the intended D-donors, we
performed the initial reactivity testing with their commercially
available non-deuterated analogs (Scheme 1).
photocatalyst
reducer
R1
R1
Br
X
Ph
Ph
MeCN, RT
cool white LED
inert atmosphere
R2
X = H,D
R1 = H, Ph;
R2
R2 = H, Me, Ph, OPh, SPh, COOMe, C(O)Ph, CN
The practical setup of the reaction is illustrated in Figure S1. The
photoreactor can be easily constructed from commercially
available laboratory washing bottle and LED strips and is
suitable for carrying out of up to six analytical-scale reactions.
Having found the suitable photocatalytic system (P2/2/cool
white LED), we tested reductions of several other bromoalkenes
(Table 2), trying to analyse effects of different substituents on
the reaction’s outcome. Optimal conditions for low-reactive
substrates, such as β-bromostyrene A-Br, 2-bromo-1-
phenylpropene D-Br, or 1-bromo-1,2,2-triphenylethylene E-Br,
include the addition of two portions of P2 in 16-hour intervals
(entries 1, 4, 5). The reactions of bromoalkenes F-Br and G-Br
(entries 7, 8) proceeded successfully in longer reaction time.
The reactions of bromophenylalkenes B-Br, C-Br, G-Br, H-Br, I-
Br, and J-Br proceeded quantitatively (entries 3, 7-10). α-
Bromostyrene was also tested as a substrate, but it did not
undergo the reduction by the P2&2 system.
Ph
N
CN
Me
N
Bu3NH+
HCOO-
Ph
N
S
Me
CN
1
P1
2
P2
reducers
photocatalysts
Scheme 1. Variety of screened substrates and reagents
First, we applied the published conditions for the bromoarene
reduction catalyzed by 10-phenylphenothiazine (P1) under 380
nm LED light.27 We subjected three bromoalkenes – β-
bromostyrene (A-Br), 2-bromo-1,1-diphenylethylene (B-Br),
and bromostilbene (C-Br) to the reaction. According to the
described conditions, we used tributylamine formate (1) as a
photoactivated H-donor (Table 1, entries 1,4, 8).
2 | J. Name., 2012, 00, 1-3
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P2
2
5 mol%
2 eq
The plausible reaction mechanism is presented at Scheme 2.
R1
R1
View Article Online
*
The excited molecule of photocatalyst PD2OIo: x10id.1i0z3e9s/Dim0GidCa0z3o0l8in1Ce
Br
H
Ph
Ph
MeCN, RT, 16 h
cool white LED 13 W
inert atmosphere
2, affording radical cation of 2(˙+) – a powerful hydrogen atom
donor. The excited radical anion of [P2(˙-)]* donates an electron
to bromoalkene yielding vinyl radical, which quickly abstracts
hydrogen from 2(˙+). It is worth mentioning that such an
interpretation might be incomplete, since an experiment
without P2 revealed that photoreduction still proceeded at
irradiation, however at a much slower rate (Table S2, entries 10,
11 in comparison to entry 5). So, the imidazoline 2, to some
extent, could work as a photoreducing agent as well. Also, by
some extent the bromoalkene after its single-electron
reduction can dissociate into alkenyl radical or anion. The
formation of the alkenyl anion can explain the stereoselectivity
in some cases or high deuterium enrichment in case of the
methanol-d4 use.
The formation of the alkenyl radical can be responsible for
abstraction of the deuterium from the aprotic solvents or not
complete deuteration, when methanol-d4 was used as the
solvent (see later).
At the beginning of the study of deuteration process according
to Scheme 1 (X=D), we tested the efficiency of deuterated
analogs of reducer 2 in various solvents. We used the 2-bromo-
1,1-diphenylethylene (B-Br) as a model substrate, and synthe-
sized deuterated derivatives 2-d and 2-d7 (see Fig. 2 and SI).
R2
R2
Table 2. Reductive debrominations of various substrates.
Conv
#
Br-alkene Z-/E- R1
R2
Z-/E-
(NMR)
77%a
96%
1
2
3
4
5
6
7
8
9
A-Br
B-Br
C-Br
D-Br
E-Br
F-Br
G-Br
H-Br
I-Br
1:5
-
1:13
1:7.3
-
H
Ph
H
H
Ph
H
H
H
H
H
H
H
Ph
-
-
>99%
85% a
70%a
88%b
>99%b
>99%
>99%
>99%
5.7:1
1:1.06
-
1:32
1:1.1
1:1.1
1:19
1.8:1
Me
Ph
Z-
OPh
SPh
COOMe
C(O)Ph
CN
1:1
1:1
Z-
10
J-Br
1.7:1
a Two 16 h intervals, two 5% portions of P2; b Reaction time 24 h.
As the system P2&2 exhibited outstanding efficiency, we tried
to compare the influence of halogen atoms on reactivity.
a series of chloro-, bromo- and
iododerivatives of the selected alkenes (Table 3).
As we expected, chloroalkenes had lower and iodoalkenes had
higher conversions into alkenes than their bromo analogs. As
the alkene iodination methods are not widely available, and
iodoalkenes suffer from low stability, the deuteration process
using bromoalkenes seems to be the best compromise.
Arylbromides were unstable towards P2/2 reducing system – in
simmilar conditions as in Table 2, e. g. p-bromoacetophenone
Therefore, we tested
X
R
2:
R = Me; X = H; Y = H
X
X
N
Y
2-d:
2-d7:
2-d11
R = Me; X = H; Y= D (96%D)
R = CD3; X = H; Y = D (98%D)
R = CD3; X = D; Y = D (96.8%D)
Ph
N
:
R
X
was debrominated by 64%, and dimethyl 2-bromoterephthalate Figure 2. Structure of reducers for Br/D exchange (see Scheme 2)
was debrominated completely (See SI, Fig. 27, 28). So the
From the reaction with reducing agent 2 in CD3CN it was shown
presence of aryl halides will not be resistant to the reaction
conditions.
that migration of deuterium from the solvent is less than 4%
(Table S4, entry 2). Additionally, the kinetic isotope effect of the
B-Br reduction by 2 in CD3CN was determined as 2.61 from the
competitive reactions experiment (See SI).
P2
2
5 mol%
2 eq
R1
R1
X
H
Ph
Ph
MeCN, RT
When monodeuterated reducer 2-d was used in non-
deuterated acetonitrile, the D-enrichment was significantly
higher and was further increased by the application of
acetonitrile-d3 (Table S4, entry 4, 5). The application of reducer
2-d7 in acetonitrile and CD3CN significantly increased the
conversion, and the isotopic enrichment was almost 90% in the
deuterated solvent (Table S4, entry 6, 8). The deutero-
debromination of B-Br by 2-d7 was also tested without addition
of P2, and despite deuterium enrichment ratio of 92.6%, the
reaction rate was much slower, and after 48 h of irradiation the
substrate was converted only by 75% (Table S2, entry 7).
Then, a comparative study of deuterodebromination of B-Br by
2-d7 in other deuterated solvents was performed (Table S3,
entries 9-12). Comparing to CD3CN, no other solvent had better
reaction conversion and D incorporation at the same time.
Some solvents as acetone-d6 or methanol-d4 afforded higher D-
enrichment (Table S4, entries 9, 12), while DMSO-d6 led to
higher conversion (Table S4, entry 10).
R2
X = Cl, Br, I
R2
cool white LED 13W
inert atmosphere
Table 3. Study of different halogen effect on photoreduction with P2&2 system
#
1
2
3
4
5
6
7
8
Structure Halogen (Z/E) Time
Conv (Z/E)
15%
65%
100%
50%
Cl (E-)
A-
B-
C-
Br (1:5)
I (E-)
Cl
16 h
4 h
Br
96%
Cl (E-)
Br (1:13.3)
I (E-)
35% (1.8:1)
56% (4.5:1)
100% (11.5:1)
9
Cl (3.5:1)
Br (1:1)
16% (1.3:1)
H-
10
100% (1.2:1)
Conditions - acetonitrile, 5 mol% P2, 2 eq 2, 13W cool white LED.
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
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DOI: 10.1039/D0GC03081C
h2
CN
Me
N
Ered = -1.6...-2 V
Ph
H
P2(
R1
Br
Me
[
)]*
N
Ph
H
N
Me
N
Ph
+ e
R2
2(
)
Eox = -3.2 V
Me
CN
2(
)
)
P2(
- e
R1
Ph
R1
Ph
Br-
Br
- e
+ e
+
R2
CN
Br
R2
Me
N
R1
Ph
R1
Ph
H
Ered = +2 V
Ph
P2*
N
H
R2
Me
-
h1
+
R2
2
Me
N
CN
Eox = +0.64 V
Ph
Br-
P2
Ered = -0.91 V
N
Me
[3]Br
Scheme 2. Plausible phenylbromoalkene photoreduction mechanism. Electrode potentials of bromoalkenes,33,34 reducer 2 35 and photocatalyst P2 36 are recalculated vs. SCE.
Results of preparative deuterodebromination experiments
However, the higher deuteration of 2 also decreased the
reaction rate, so we had to take longer reaction times for
reactions with 2-d11. The reactions were monitored every 24
hours for maximum of three days.
The preparative yields vary between 45-94%. In some cases, it
was not possible to fully separate the product from the starting
compound (Table 4, entries 1, 4, 5). E/Z-preference was
conserved in most cases during the reaction except derivatives
A-Br, G-Br, and J-Br.
After that, 2-d11 was synthesized, starting from aniline-d5 (see
SI) and used in preparative deuterodebrominations of ten
bromophenylalkenes (Table 4). Comparing reductions of six
substrates with 2-d7 and 2-d11 (Table S5), the more highly
deuterated reducing agent provided comparable or higher D-
enrichment, the conversion and yield were similar or higher. In
cases when the bromine atom was sterically hindered (E-Br, I-
Br), the use of 2-d11 proved to be more advantageous.
A scale-up experiment was also performed. The results – yield,
reagent and solvent regeneration ratios, are exemplified at
Scheme 3.
Table 4. Preparative-scale deuterations.
substrate Conva
(Z-/E-) (NMR)
Yielda
(Z-/E-)
[3-d10]Br
recovery
#
D content Time
D
CD3
P2
5 mol%
1.7 eq
Br-
Ph
D
D
N
2-d
COOMe
COOMe
11
Ph
Ph
+
N
A-Br
66%
(1:5)
58%
Br
D
CD3CN, RT, 16 h
cool white LED
inert atmosphere
1
2
3
90%
93%
96%
72 hb
48 h
48 h
37%
49%
52%
(2.85:1)c
CD3
H-Br
1 mmol
H-d
, 76%
125 mg
90%D (E-)
96%D (Z-)
D
[3-d10]Br
, 55%
B-Br
99%
51%
LiBD4
CD3OD
recovery of CD3CN - 77%
2-d
THF
recovery of
11 - 44%
C-Br
(1:13)
64%
(49:1)
>99%
2-d11
80%
D-Br
(1:7.3)
77% (E)
86% (Z)
56%
4
60%
72 hb
72 hb
32%
(1.7:1)c
Scheme 3. High-loading deuterodebromination experiment
5
6
E-Br
53%
95%
77%
89%
45%c
40%
41%
The precipitate of benzimidazolium bromide [3-d10]Br formed
during the reduction could be collected and reduced allowing
for partial regeneration of the reducer. Thus, up to half of the
used amount of 2-d11 can be regenerated.
F-Br (Z-)
48 hd 94% (E-)
67% (E)
77% (Z)
84%
48 hd
7
G-Br (Z-) >99%
55%
(1:1)
In order to analyse the influence of substituents in the phenyl
H-Br
>99%
(1:1)
89% (E)
96% (Z)
86%
24 h
ring on the reaction outcome,
debrominations of substituted α-bromochalcones was also
performed (Table 5).
a series of deutero-
8
9
41%
55%
41%
(1.3:1)
I-Br (Z-) >99%
78%
24 h
24 h
81% (E-)
This experiment results in several implications about
substituent influence. Firstly, electron-deficient substrates
(K-Br, L-Br) reacted significantly slower and the reaction had to
be stopped before completion, because holding it until full
conversion led to partial decomposition of the reaction product.
Although both substrates were used as Z-isomers, the products
were formed as a mixture of E- and Z-chalcones, which could be
caused by photoisomerisation of the substrate before the
reduction due to lower reactivity.
J-Br
97%
(E and Z)
92%
(1.78:1)
10
>99%
(1.7:1)
For structures of the bromoderivatives see Table 1. Conditions - CD3CN, 5 mol% P2,
1.7 eq 2-d11, 13W cool white LED; a Conversion is calculated from NMR spectra of
crude reaction mixtures. The yield is calculated after isolation and purification;
Three 24 h intervals, three 5 mol% portions of P2; c D-alkene was isolated as a
mixture with starting bromoalkene (see SI for details); d Two 24 h intervals, two 5
mol% portions of P2. (Compound A-Br was purchased from Sigma-Aldrich, Inc; for
syntheses of other compounds see SI).
b
4 | J. Name., 2012, 00, 1-3
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P2
5 mol%
1.7 eq
O
O
View Article Online
DOI: 10.1039/D0GC03081C
2
2-d
11
D
CD3
3
Ph
Ph
1
D
N
CD3CN, RT
cool white LED
inert atmosphere
D
D
Br
R
R
Ph
N
D
CD3
1
D
2-d11
3
2
Table 5. Preparative-scale deuterations of substituted α-bromochalcones.
0.030
0.061
0.037
substrate
(pure Z-)
conv
(NMR)
yield
(Z-/E-)
[3-d10]Br
recovery
#
1
2
R
D content
0.007
0.008
0.024
65% (E)
89% (Z)
85%a
K-Br
L-Br
NO2
CN
87%
75%
55%
40%
6.8 6.6 6.4 6.2 6.0 5.8 5.6 5.4 5.2 5.0 4.8
(1.7:1)b
Figure 3. Compared fragments of 1H NMR spectra of the new and recovered 2-d11 (the
integrals are normalised to phenyl protons).
71% (E)
59% (Z)
89% a
(9:1)
That fact could, in turn, explain the dramatic decrease of
enrichment and isolated yield in the reactions of E-Br and I-Br
with both 2-d7 and recovered 2-d11. Also, in the cases when two
stereoisomeric D-alkenes were formed, the deuterium content
in Z-deuteroalkene was usually higher, and this can also be
explained by steric hindrance, because the hydrogen atom at
position 2 in the molecule of reducing agent, being the most
electropositive, is not the most sterically accessible one.
3
4
M-Br MeO >99%
N-Br Me2N >99%
87%
85%
68% (E-)
24% (E-)
53%
60%
a
Conditions - CD3CN, 5 mol% P2, 1.7 eq 2-d11, 13W cool white LED, 24 h; Yield
considering partial regeneration of the starting compound; b Time of reaction 18 h.
Secondly, substrate N-Br despite excellent conversion to
product was isolated only with the yield as low as 24%, which
could be caused by partial decomposition of the reaction
product as well as by interaction with silica gel during
chromatography.
Economical aspects of 2-d7/2-d11 selection
We also made some calculations to compare the costs of
preparation and implementation of deuterated imidazolines
(see SI, p. 19). The major part of the cost being the deuterated
reagents, and considering the lowest prices found by us for
multigram-scale quantities, we estimated the cost of
preparation as 29.5$/g for 2-d7 and as 67.5$/g for 2-d11. The
regeneration procedure lowers these prices by 20-30%,
although it requires additional amounts of NaBD4 and CD3OD.
Unfortunately, for 2-d11 the recovered reagent cannot be used
in the reactions with sterically hindered substrates with the
same efficiency as a new one (see Table 6, entries 3,5), so in
these cases after regeneration 2-d11 should be used with more
reactive bromoalkenes. The reagent 2-d7 can be recovered
without loss of its properties.
Considering the deuterodebromination of E-Br, the cost of 2-d7
and CD3CN used is 29.3$/1 mmol of obtained D-alkene, and for
2-d11 it is 59.2$/1 mmol of D-alkene. So, the first 56% of
deuteration in 1 mmol of E-d is worth 0.52$ per one percent
point of deuteration, and if it’s needed to achieve higher
enrichment, the last 21%D will come at a price of 1.42$ per one
percent point. So, the average cost of deuteration of 1 mmol of
E-Br up to 77%D will be 0.77$ per percent point of D.
For more reactive substrates, it is possible to greatly cut the
costs using 2-d7. Thus, the deuterodebromination of H-Br would
consume 20.45$/(mmol of H-d) worth of deuterated reagents
and solvents, or 0.22$ per percent point of D-enrichment (for
details, see SI, p. 19). The cost could be further lowered by
increase of regeneration ratio of acetonitrile-d3, which is easier
to achieve at higher scales.
So, for non-complicated and non-sterically hindered substrates
the reagent of choice is in the most cases 2-d7, since the
additional 1-5 percent points of enrichment, which the use of 2-
d11 could afford, would be exceptionally costly.
Regenerated 2-d11 was also tested with the same six substrates
that were used for comparison of 2-d7 and 2-d11 (Table 6). The
screening revealed that, as in the case of 2-d7, only with
sterically hindered substrates (E-Br, I-Br) there was a great
difference in D-enrichment, so in those cases the use of
recovered reducing agent may be less justified.
Additionally, NMR spectra of recovered 2-d11 revealed that it
had decreased deuterium enrichment in benzimidazoline
aromatic positions – by 5.3 and 2.3 percent points for positions
4 and 5, respectively (see Figure 3). This could serve as an
evidence that the reactive species, which are formed after
debromination of E-Br or I-Br, can sometimes abstract
hydrogen/deuterium competitively from aromatic positions of
reducing agent 2 due to steric hindrance.
Table 6. Deuterations with regenerated 2-d11 compared to the ones with new 2-d11
.
substrate
(Z-/E-)
conv
(NMR)
[3-d10]Br
recovery
#
time
48 h
D content differenceb
1
2
3
B-Br
C-Br
E-Br
98%
87%
89%
60%
6
7
37%
41%
49%
48 h >99%
72 ha >99%
17
87% (E)
95% (Z)
2 (E)
1 (Z)
4
5
6
H-Br
I-Br
J-Br
24 h >99%
24 h >99%
24 h >99%
52%
49%
60%
58%
20
93% (E)
97% (Z)
4 (E)
≈1 (Z)
Conditions - CD3CN, 5 mol% P2, 1.7 eq 2-d11, 13W cool white LED; a Three 24 h
b
intervals, three 5 mol% portions of P2; Decrease in %D with recovered 2-d11
compared to the reaction with a new one.
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Green Chemistry
Page 6 of 7
ARTICLE
Journal Name
Environmental aspects of the reaction
5
A. Adejare and P. W. Brown, Anal. Chem., 1997, 69, 1525–
1529.
View Article Online
DOI: 10.1039/D0GC03081C
The deuterodebromination reaction can be considered
environmentally benign. The solvent, acetonitrile-d3, can be
easily regenerated and corresponds green chemistry principles.
There is a limited amount of data about toxicity of photocatalyst
P2, but a functionalized dicyanoantracene compound exhibited
very low in vitro cytotoxicity.37 The reducing agent 2 is reported
to have quite high LD50 of 97 mg/kg in mice,38 but it becomes
converted into salt [3]Br with around 50% recovery ability.
By implementation of recovery procedures, the toxic waste of
the reaction can be limited to minimum amounts.
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Synthesis of bromoalkenes
The starting bromoalkenes can be prepared by conventional
methods from appropriate alkenes. We demonstrated this
possibility on all derivatives with use of methods published in
literature.39–44 Only the derivatives F-Br and G-Br were not
possible to get in sufficient yield or purity and were synthesized
via substitution reactions (see SI for details).
Conclusions
A
new metal-free method for light-mediated reductive
debromination of phenylvinyl derivatives with the use of
(poly)deuterated benzimidazoline derivatives has been
developed. The reaction is possible to perform efficiently with
the simple and cheap equipment. It allows the synthesis of
deuterated derivatives of various substitution patterns, usually
with excellent conversion and very high isotopic yield. The
reducing agent can be regenerated with its recovery up to 50%.
For some substrate types, it is possible to implement a
sequential bromination-deuterodebromination process. The
developed methodology thus offers a new environmentally
benign possibility of Br/D or H/D exchange on a double bond
without any special instrumental equipment.
22
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24
Conflicts of interest
There are no conflicts to declare.
25
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Acknowledgements
This work was supported by the Czech Ministry of Education,
Youth, and Sports (project IGA_PrF_2020_012).
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