Visible-Light-Mediated Reactions of Electrophilic Radicals with Vinyl and Allyl Trifluoroborates

Article abstract of DOI:10.1021/acscatal.7b01120

Visible-light photoredox catalysis enables the vinylation and allylation of electrophilic radicals with readily available potassium trifluoroborate reagents. The processes show good functional group compatibility, and mechanistic and computational studies

Full text of DOI:10.1021/acscatal.7b01120

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Letter
Visible-Light-Mediated Reactions of Electrophilic
Radicals with Vinyl and Allyl Trifluoroborates.
Daniel Fernandez Reina, Alessandro Ruffoni, Yasair S.S. Al-
Faiyz, James J. Douglas, Nadeem S. Sheikh, and Daniele Leonori
ACS Catal., Just Accepted Manuscript • Publication Date (Web): 15 May 2017
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ACS Catalysis
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Visible-Light-Mediated Reactions of Electrophilic Radicals with Vi-
nyl and Allyl Trifluoroborates
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Daniel Fernandez Reina,a‡ Alessandro Ruffoni,a‡ Yasair S. S. Al-Faiyz,b James J. Douglas,c
Nadeem S. Sheikh,b* and Daniele Leonoria*
a School of Chemistry, University of Manchester, Oxford Road, Manchester, M13 9PL, UK. b Department of Chemis-
try, Faculty of Science, King Faisal University, Al-Ahsa 31982, Saudi Arabia. c AstraZeneca, Silk Road Business Park,
Macclesfield SK10 2NA, UK.
ABSTRACT: Visible-light photoredox catalysis enables the vinylation and allylation of electrophilic radicals with readily
available potassium trifluoroborate reagents. The processes show good functional group compatibility and mechanistic
and computational studies have elucidated some of the aspects associated with the key radical addition step. Photoredox,
vinylation, allylation, trifluoroborate, electrochemistry.
The addition of carbon-centered radicals to olefins is
one of the most used reactions for the construction of C–
C bonds.1-2 Despite its apparent simplicity, this process is
mechanistically intriguing as it relies on a complex inter-
play between enthalpic, steric and polar effects.3-5 State
correlation diagrams that describe these transformations
involve three components: the reactants in (i) the ground,
(ii) the excited state and (iii) the polar charge transfer
configuration (CTC).5-6 As a result, the identification of
polarity-matched systems might result in more facile re-
actions owing to the stabilization of the CTC in the transi-
tion state.7 A classical example is the addition of electro-
philic radicals (e.g. malonyl radical) to electron rich ole-
fins like enol ethers and enamines (Scheme 1A).8-9
with, to the best of our knowledge, only two examples
reported in the literature by Koike and Akita11-12 and, very
recently, by Studer13 and Aggarwal.14 In this paper we de-
scribe our work on understanding and exploiting the re-
activity of vinyl- and allyl-BF3K reagents with electrophilic
radicals under photoredox catalysis (Scheme 1B).15-19 This
has resulted in the development of novel transition metal-
free vinylation and allylation processes.
At the outset, we were concerned about the possibility of
employing vinyl-BF3K reagents in photoredox processes
owing to the potential SET oxidation of the C–B bond as
pioneered by Molander in the chemistry of benzylic-BF3K
reagents.20-21 However, cyclic voltammetry analysis on
several vinyl-BF3K revealed high potentials for oxidation
ox
(E1/2 > 2.0 V vs SCE)22 which could make them suitable
A) Addition of electrophilic radicals to enol ethers: known
OR1
OR1
coupling partners in visible-light-mediated transfor-
δ+
R
–
mations. A selection of vinyl/allyl-BF3 22reagents (A–E)
R
were then studied by DFT and characterized in terms of
electron donor properties by calculating their adiabatic
ionization potential (IP) and absolute electronegativity
(χDB) (Scheme 2A).22 When compared to known IP and
B) This work: radical addition to vinyl-BF3K: unexplored
BF3K
BF3K
BF3K
a
b
a
b
δ+
R
R
a
R
b
χ
DB for other electron rich olefins (e.g. methyl vinyl ether,
Key questions:
F),23 A–E displayed remarkably lower values, which indi-
cate a highly electron rich character. We then decided to
assess their preferred site of radical attack by determining
the carbon spin density in the triplet state (ππ*) as well as
the enthalpy of reaction (–ꢀHr) with the electrophilic
malonyl radical24-25 (electrophilicity index ω–rc = 1.15 eV)22
(Scheme 2B).9, 26 This study revealed a potential difference
in the site-reactivity profile of vinyl-BF3K reagents with
respect to other electron rich olefins like enol ethers. Ac-
cording to our calculations reagents A–D should preferen-
ꢀ polarity match? ꢀ a vs b selectivity? ꢀ compatible under photoredox conditions?
SCHEME 1. Polarised radical addition to olefins: (A)
enol ethers and (B) vinyl-BF3K.
Vinyl potassium trifluoroborates (vinyl-BF3K) are exten-
sively used in contemporary organic synthesis owing to (i)
their versatility in transition metal-catalyzed reactions,
(ii) their chemical stability, (iii) ease of preparation and
(iv) their availability from commercial suppliers.10 Surpris-
ingly however, their use as olefinic partners in radical
addition reactions has been comparatively overlooked,
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tially react at the ipso-C (Ca) owing to the higher spin in MeOH under green LEDs irradiation (530 nm), the
1
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3
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density and the more favorable reaction enthalpy.
ipso-vinylated product 3a was obtained in 81% yield (en-
try 1). Such a reactivity is intriguing, because its exploita-
tion would represent an umpolung strategy for a formal
radical alternative to sp3–sp2 Suzuki-type processes. Con-
trol experiments (entries 2–4) and light ON-OFF reaction
analysis22 confirmed the requirement for light, photocata-
lyst and base. We then evaluated the possibility of using
(i-Pr)2NEt in sub-stoichiometric amounts but this result-
ed in a lower yield (entry 5). Other bases, solvents and
photoredox catalysts were evaluated but they generally
provided 3a with lower efficiency.28 Iodo-malonate 2b
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A) Olefin electron donor properties [UB3LYP/6-31+G(d)]
red
(E1/2 = –0.74 V vs SCE) was also a competent coupling
OMe
BF3
BF3
BF3 Me
Me
BF3
BF3
red
partner (entry 7) while chloro-malonate 2c (E1/2 = –0.52
Me
Ph
A
B
C
D
E
F
V vs SCE) gave 3a in very low yield (entry 8). This was
surprising as its redox profile is well in the range for SET
reduction from the excited state of EY (*EY). We attribut-
ed this lack of reactivity to the fact that 2c does not serve
as competent quencher of *EY as determined by Stern-
Volmer studies (see below).
IP (eV)
DB (eV)
4.15
–0.14
4.53
0.22
4.27
0.49
4.24
0.16
5.14
0.56
8.69
3.6
χ
B) Spin density and enthalpies of reaction with malonyl radical [UB3LYP/6-31+G(d)]
EtO2C
EtO2C
EtO2C
EtO2C
EtO2C
EtO2C
a
b
a
b
δ+
EtO2C
CO2Et
Me
BF3K
Me
BF3
EY (1 mol%), base
CO2Et
EtO2C
BF3
BF3 Me
Me
BF3
BF3
OMe
+
b
a
B
b
a
A
b
a
C
b
a
D
b
a
b a
Me
X
MeOH (0.1 M), rt
Ph
Me
1a
(1.0 equiv.)
E
F
visible light
Me
2a–c
3a
Mulliken atomic spin density (ππ* triplet state)
(1.0 equiv.)
a
b
1.00
0.99
0.98
0.90
0.83
0.32
0.99
0.86
0.86
1.01
0.821
1.01
Entry
X
Base (equiv.)
Light Source
Yield (%)
–ꢀHr (KJ mol–1
)
1
2
3
4
5
6
7
8
Br
Br
Br
Br
Br
Br
I
EtN(i-Pr)2 (1.0)
–
green LEDs
green LEDs
green LEDs
–
green LEDs
green LEDs
green LEDs
green LEDs
81
traces
–
a
b
89.5
85.6
86.1
72.2
113.6
44.8
80.3
59.7
47.8
78.3
18.7
57.3
EtN(i-Pr)2 (1.0)
EtN(i-Pr)2 (1.0)
EtN(i-Pr)2 (0.2)
K2CO3 (1.0)
EtN(i-Pr)2 (1.0)
EtN(i-Pr)2 (1.0)
–
24
37
67
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SCHEME 2. Computational studies on the electron
donor properties of vinyl-BF3 reagents and their reac-
tion with malonyl radical.
Cl
To assess this hypothesis, we started by investigating the
reaction of vinyl-BF3K reagent 1a and malonates 2a–c. As
illustrated in Scheme 3, we were pleased to find that with
SCHEME 3. Optimization of the visible-light-
mediated vinylation of malonates 2a–c.
red
bromomalonate 2a (E1/2 = –0.62 V vs SCE)27 using eosin
Y (EY) as the photoredox catalyst, EtN(i-Pr)2 as the base
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R
EY (2 mol%)
i-Pr2NEt (2.0 equiv.)
EWG
R2
BF3K
R1
R4
R
EWG
R4
+
1
2
R1
R2
MeOH (0.1 M), rt
green LEDs
Photoredox Vinylations
Br
2a,d–o
R3
1a–h
R3
3a–t
3
4
5
6
7
8
9
O
EtO2C
Me
CO2Et EtO2C
CO2Et
Me
Me
O
EtO2C
R2
CO2Et
R4
N
N
Me
Me
Me
Me
Me
O
Me
Me
3b
41%
Me
3c
74%
[1 gram]
Br
NC
Ph
3f
70%
PMP
p-FPh
3h
90%
Me
3i
35%
Ph
3j
36%
R3
3a
81%
3d
40%
E:Z = 1.5:1 E:Z = 1.5:1
3e
3g
71%
3k
90%
Ph
Ph
67%
E:Z = 1.5:1
NO2
NO2
NO2
F
Ar
O2N
CN
F
F
F
EWG
3l : EWG = CO2Et ; Ar = Ph
3m : EWG = CN
3n : EWG = CN
: 31%
; Ar = PMP : 47%
; Ar = p-FPh : 42%
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NO2
CN
F
Ph
Me
Me
3o : EWG = SO2Ph ; Ar = Ph
: 21%
BF3K
4
Ar
3q
3r
75%
3s
47%
3t
16%
3p
72%
57%
R
R1
EY (2 mol%)
i-Pr2NEt (2.0 equiv.)
EWG
R
R1
EWG
+
MeOH (0.1 M), rt
green LEDs
Photoredox Allylations
Br
2–c,g–i,m
5a–i
O
NO2
NO2
NO2
O
Ar
EtO2C
CO2Et
Ph(O)C
C(O)Ph
Ph(O)C
Ts
Me
Me
O
EtO2C
Me
CO2Et
N
N
O
NO2
CN
F3C
Ph
5a
57%
5b
45%
5c
47%
5d
67%
5e
62%
5f
5g
53%
5h
65%
5i
60%
68%
Modification of bioactive molecules
Ph
Ph
O
Ph
Ph
O
O
O
O
O
N
N
N
N
Me
Me
Me
O
O
R
Ph
Me
R
MeO
t-Bu
MeO
t-Bu
Me
Me
phenylbutazone (6)
[veterinary NSAID]
8a
66%
8b
74%
8c
70%
avobenzone (7)
[sunscreen]
9a
57%
9b
42%
SCHEME 4. Scope of the visible-light-mediated vinylation and allylation of electrophilic radicals.
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With these optimized conditions in hand, we evaluated
the scope of this photoredox vinylation reaction (Scheme
4). Pleasingly, our protocol enabled the reaction of vari-
ous vinyl-BF3K partners as shown by the formation of
products containing di-, tri- and tetra-substituted olefins
(3a–c) and could be run on a gram-scale. Several func-
tional groups were tolerated such as a terminal alkyl bro-
mide (3d) and a nitrile (3e). Styrenyl-BF3K reagents were
also successful with both electron donating and electron
withdrawing substituents (3f–h). We then looked at the
alkyl bromide unit and extended the scope to methyl-Br-
malonate and a barbituric acid derivative which gave ac-
cess to products with fully substituted C-centres (3i–k).
We then evaluated the use of radical precursors with a
single electron-withdrawing group. In this case 4-MeO-
pyridine29 was used as an additive (40 mol%) to facilitate
the SET reduction en route to the carbon-radical.22 As
these radicals are not as electrophilic as those previously
employed,8 they provided the desired products 3l–o in
somewhat diminished yields. Finally, we extended this
methodology to electron poor benzyl bromides that pro-
vided 3p–t in good to moderate yields. The successful
formation of 3p–t offers a transition metal-free alternative
to current methods for the vinylation of benzylic bro-
agent. Our DFT studies supported its ability to serve as
highly electron rich system (Scheme 2) and we were
please to see that both benzyl and malonyl-type bromides
could be engaged under identical reaction conditions to
provide the corresponding allylated products (5a–i).
As many biologically active compounds contain 1,3-
dicarbonyl motifs, we showcased the applicability of this
methodology with the late-stage vinylation and allylation
of the veterinary anti-inflammatory drug phenylbutazone
(6) and the sunscreen agent avobenzone (7), which, after
bromination,22 gave 8a–c and 9a–b in good yields.
Having evaluated the scope of these photoredox trans-
formations we decided to perform mechanistic and com-
putational studies to gain more information about the
reaction mechanism. As illustrated in Scheme 5A, fluores-
cence quenching studies were conducted on all reaction
partners and the quencher rate coefficients were obtained
using the Stern-Volmer relationship. We also determined
all the redox potentials by cyclic voltammetry analysis. A
salient conclusion of this study is that all the carbon-
radical precursors (with the exception of Cl-malonate)
quench *EY at a significantly higher rate than (i-Pr)2NEt.
As a result, we propose that upon visible-light irradiation,
*EY preferentially undergoes oxidative quench with the
alkyl bromides I providing access to the corresponding
carbon-radicals II by SET reduction and fragmentation
(Scheme 5B).32-33 Radical ipso-addition to the vinyl-BF3K
reagent III, where the highest spin density is located,
mides that normally requires Pd- or Cu-based catalysts.30-
31
Having developed a photoredox transition metal-free vi-
nylation of electrophilic radicals, we decided to evaluate if
allyl-BF3K (4) could serve as competent radical allylating
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Page 4 of 6
ought to be highly electron rich in nature, it can directly
would deliver a β-boron radical IV. As the BF3 group can-
not be expelled as a borato radical (endothermic pro-
cess),34 we propose that a SET oxidation is necessary to
trigger the olefination and give V. At the moment we
cannot exclude that other productive pathways might be
operative from the β-boryl radical IV. As this species is
1
2
3
4
5
6
close the photoredox cycle or regenerate the malonyl rad-
ical II by oxidative SET with I. However, when the reac-
tion was run in the absence of EtN(i-Pr)2 but with Na2CO3
as the base, the reaction product was obtained in a con-
siderably lower yield (see Scheme 3, entry 6).
7
A) Stern-Volmer quenching rates [kq (M–1 s–1)] and redox potentials (V vs SCE)
8
9
KF3B
Me
Et
N
EtO2C
EtO2C
CO2Et
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12
13
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Me
i-Pr
i-Pr
Br
I
E1/2ox = 2.29
2.9 104
E1/2ox = 0.50
5.3 105
E1/2red = –1.08
1.8 106
E1/2red = –0.74
2.9 106
104
105
106
107
kq (M–1 s–1
)
EtO2C
CO2Et
EtO2C
CO2Et
MeO2C
Br
Cl
Br
N
O2N
1.2 105
1.4 106
E1/2red = –0.61
2.3 106
E1/2red = –0.62
3.0 106
E1/2red =–0.06
E1/2red = –0.52
OMe
B) Proposed mechanism
C) Enthalpic vs polar effects [UB3LYP/6-31G(d)]
R
EWG
NR3
R1
– e–
EY
BF3
BF3
Me
Me
BF3
BF3
EtO2C
EtO2C
a
b
– BF3
δ+
R
SET
R2
b
a
b
a
C
b
a
b a
Me
Ph
V
B
D
E
R
NR3
EWG
R1
R2
EY•+
*EY
a
b
a
b
a
b
a
b
KF3B
IV
SET
–ꢀHr (KJ mol–1
)
86.1
2.28
72.2
2.14
113.6
2.45
44.8
2.07
80.3
2.29
59.7
2.20
78.3
2.22
47.8
2.13
d(C–C) (Å)
BF3K
δ+
δTS
–0.08 –0.09
–0.06 –0.08
–0.08 –0.13
–0.07 –0.12
R
EWG
EWG
R
EWG
R
R1
R2
Br
I
R1
R1
II
III
SCHEME 5. A) Luminescence quenching studies and cyclic voltammetry studies. B) Proposed mechanism for
photoredox vinylations. C) DFT studies on enthalpic and polar effects.
ly available potassium trifluoroborate reagents. We are
currently evaluating the possibility to render these trans-
formations asymmetric.
As the radical ipso-addition is a key aspect of this reaction
pathway, we performed further DFT studies aimed at
evaluating enthalpic and polar contributions in the transi-
tion state. As illustrated in Scheme 5C, we calculated the
ASSOCIATED CONTENT
reaction enthalpy (–ꢀHr) as well as the bond formation
Supporting Information
distance [d(C–C)] and the δTS of the charge transfer com-
The Supporting Information is available free of charge on the
ACS Publications website.
35
plex8,
from the vinyl/allyl-BF3 reagents (B–E) to the
malonyl radical for both reactions at Ca and Cb. According
to our studies, radical ipso-additions (Ca), while energeti-
cally more favourable, have low |δTS| values and therefore
are less influenced by polar effects compared to the addi-
tions at Cb. We also observed a good correlation between
–ꢀHr and d(C–C)22 which is in agreement with the Ham-
mond postulate: the reaction exothermicity is directly
related to the earliness of the corresponding transition
state. Hence, our results suggest that even if highly elec-
tron rich, the behavior of vinyl/allyl-BF3K in the reaction
with electrophilic radicals is predominantly controlled by
enthalpic effects.
Details of all synthetic, electrochemical, spectroscopic and
computational experiments (PDF).
AUTHOR INFORMATION
Corresponding Author
* Email: daniele.leonori@manchester.ac.uk.
ORCID: 0000-0002-7692-4504
Website: http://leonoriresearchgroup.weebly.com.
* Email: nsheikh@kfu.edu.sa
Author Contributions
D. L. designed the project and wrote the manuscript with the
contribution of all the authors. D. F. R. and A.R. performed
the experimental work. N. S. S. and D. L. envisaged the com-
In conclusion, we have developed an easy and simple
method to perform transition metal-free vinylation and
allylation reactions of electrophilic C-radicals using readi-
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putational investigation and Y. S. S. A-F. assisted with this.
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1
All authors analyzed the results.
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3
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7
8
9
‡These authors contributed equally.
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abstraction.
ACKNOWLEDGMENT
D. L. thanks the European Union for a Career Integration
Grant (PCIG13-GA-2013-631556), EPSRC for a research grant
(4500284613). D. F. R. thanks AstraZeneca for a PhD CASE
Award. A. R. thanks the Marie Curie Actions for a Fellowship
(703238). Y. S. S. A-F. and N. S. S. gratefully acknowledge the
support offered by the Department of Chemistry, King Faisal
University, Saudi Arabia.
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ꢀ sp3-sp2 radical coupling
ꢀ also applied to allyl-BF3
ꢀ 34 examples
ꢀ modification of biomolecules
ꢀ DFT studies
R
EWG
BF3K
R3
R1
R4
R
eosin Y
visible light
EWG
R1
+
R4
R2
R2
Br
R3
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via polarised radical addition
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OR
OR
BF3K
BF3K
δ+
R
δ+
R
R
vs
R
known reactivity
this work
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