Photocatalytic Difunctionalization of Vinyl Ureas by Radical Addition Polar Truce–Smiles Rearrangement Cascades

Article abstract of DOI:10.1002/anie.202003632

We report tandem alkyl-arylations and phosphonyl-arylations of vinyl ureas by way of a photocatalytic radical-polar crossover mechanism. Addition of photoredox-generated radicals to the alkene forms a new C?C or C?P bond and generates a product radical adjacent to the urea function. Reductive termination of the photocatalytic cycle generates an anion that undergoes a polar Truce–Smiles rearrangement, forming a C?C bond. The reaction is successful with a range of α-fluorinated alkyl sodium sulfinate salts and diarylphosphine oxides as radical precursors, and the conformationally accelerated Truce–Smiles rearrangement is not restricted by the electronic nature of the migrating aromatic ring. Formally the reaction constitutes an α,β-difuctionalisation of a carbon–carbon double bond, and proceeds under mild conditions with visible light and a readily available organic photocatalyst. The products are α,α-diaryl alkylureas typically functionalized with F or P substituents that may be readily converted into α,α-diaryl alkylamines.

Full text of DOI:10.1002/anie.202003632

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Accepted Article
Title: Photocatalytic Difunctionalization of Vinyl Ureas by Radical
Addition Polar Truce-Smiles Rearrangement Cascades
Authors: Roman Abrams and Jonathan Clayden
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.202003632
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10.1002/anie.202003632
Angewandte Chemie International Edition
COMMUNICATION
Photocatalytic Difunctionalization of Vinyl Ureas by Radical
Addition Polar Truce-Smiles Rearrangement Cascades
Roman Abrams and Jonathan Clayden*
Abstract: We report tandem alkyl-arylations and phosphonyl-
arylations of vinyl ureas by way of a photocatalytic radical-polar
crossover mechanism. Addition of photoredox-generated radicals to
the alkene forms a new C–C or C–P bond and generates a product
radical adjacent to the urea function. Reductive termination of the
photocatalytic cycle generates an anion that undergoes a polar Truce-
Smiles rearrangement, forming
a C–C bond. The reaction is
successful with a range of a-fluorinated alkyl sodium sulfinate salts
and diarylphosphine oxides as radical precursors, and the
conformationally accelerated Truce-Smiles rearrangement is not
restricted by the electronic nature of the migrating aromatic ring.
Formally the reaction constitutes an a,b-difuctionalisation of a carbon-
carbon double bond, and proceeds under mild conditions with visible
light and a readily available organic photocatalyst. The products are
a,a-diaryl alkylureas typically functionalised with F or P substituents
that may be readily converted into a,a-diaryl alkylamines.
Modern photoredox catalysis has provided a wide range of
methods for synthesis using radical intermediates under mild
conditions.1 Of particular value for the functionalisation of alkenes
are radical-polar crossover mechanisms,2,3 whereby the product
of a radical addition is oxidised or reduced to a cation or anion in
the redox reverse of the initial photocatalytic radical generation
step. Radical-polar crossover mechanisms terminated by
oxidation to a carbocation have been particularly successful in
enabling the 1,2-disubstitution of alkenes.2 Reductive termination
to give a carbanion is rarer, and has typically been used for
photoredox-catalysed mono-functionalisations of alkenes,
whereby the product carbanion is simply protonated.3
Nonetheless, a few examples of reductive photoredox radical-
polar crossover difunctionalisations have been recently reported
(Scheme 1a). For example, Martin and co-workers have
demonstrated that styrenes undergo alkyl-carboxylation where an
intermediate benzylic carbanion formed is intercepted by carbon
dioxide.4 Molander and co-workers5 and Aggarwal and co-
workers6,7 have independently reported methods for the alkyl-
cyclopropanation and cyclobutanation of alkenes by reductively
terminated radical-polar crossover, in which the carbanion
product of the photoredox cycle attacks a pendent alkyl halide.
These methods allow the formation of two new C–C bonds to the
alkene, but there are as yet no reports of the use of the
intermediary carbanion in carbon-aryl bond formation by, for
example, an SNAr mechanism.
Scheme 1. (a) Photoredox-catalysed alkene difunctionalisations by reductive
termination radical-polar crossover. (b) This work: N to C aryl migration of urea-
substituted anions generated by a reductive radical-polar crossover sequence.
Arylation at sp3 carbon centres typically involves transition
metal-catalyzed coupling,8 but an appealing alternative, recently
used for the stereoselective arylation of amino acid enolates,9
entails a conformationally induced Truce-Smiles rearrangement,
which transfers an aryl ring to an anionic precursor. This
transformation proceeds by a concerted SNAr mechanism,10 but
the use of a urea tether to impose a conformational preference on
the intermediate11 means that – unlike the classical Truce-Smiles
rearrangement, which typically proceeds only with electron-
deficient aromatic rings12 – the electronic nature of the migrating
aryl group is of little consequence to the reaction’s outcome.9,13
The N to C aryl migration that results has been developed into a
versatile transition metal-free route to a range of products
including
enantio-enriched
a-quaternary
amines,14a-c
hydantoins,14d,e medium-ring heterocycles,14f,g and a-quaternary
amino acids.14h-j
Anionic precursors for this C-arylation chemistry have been
made by direct lithiation of benzylic15 or allylic ureas,16 by
carbolithiation of a vinyl urea,17 or by deprotonation alpha to a
carbonyl14e,h-k or nitrile.14h,18 Generating the anion instead by
photoredox catalysis offers the opportunity to conduct C-
arylations under milder conditions, avoiding both strong base and
transition metals, while also facilitating the preparation of
previously inaccessible products. We envisaged that electrophilic
radicals generated by a reductive quenching photoredox cycle
would add to vinyl ureas 1 to form benzylic radicals 2. Single-
electron reduction would generate an anion a to the urea 3 that
would undergo rearrangement to an a,a-diaryl alkylurea 4
(Scheme 1b). This approach represents a simple way to form two
C-C bonds, one to each carbon of an alkene, and would provide
[a]
Mr. R. Abrams, Prof. Jonathan Clayden
School of Chemistry, University of Bristol
Cantock’s Close, Bristol, BS8 1TS (UK)
E-mail: j.clayden@bristol.ac.uk
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
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10.1002/anie.202003632
Angewandte Chemie International Edition
COMMUNICATION
Table 1. Optimisation studies.[a]
NaSO2CF3
(equiv.)
Cs2CO3
(equiv.)
yield
(%)[b]
Entry[a]
PC
1[c]
2[c]
3[e]
4[f]
4CzIPN
4CzIPN
4CzIPN
4CzIPN
4CzIPN
4CzIPN
3
3
0
0[d]
66
94
94
40
1.5
1.5
1.5
1
3
3
5[e]
6[e]
3
1.5
1.5
89
(87)
7[f]
8[f]
3DPAFIPN
[Ir{dF(CF3)ppy}2(dtbpy)]PF6
[Ru(bpy)3]Cl2•6H2O
-
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
Trace
70
9[f]
Trace
0
Scheme 2. Scope of migrating aryl groups for the trifluoromethyl-arylation
reaction. Reactions were carried out on a 0.20 mmol scale. The heat generated
by the LEDs resulted in reaction temperatures of ca. 30 °C. Yields of product
isolated by chromatography. R = -C(O)NHMe. [a] Acetone used as solvent. [b]
MeCN used as solvent. [c] DMF used as solvent. [d] 3 equiv. of NaSO2CF3 used.
10[e]
11[e], [g]
4CzIPN
0
[a] Reactions performed on a 0.1 mmol scale: light source 24 W blue LED strips
(see ESI); reaction time 16 h. [b] Yield determined by 19F NMR using CF3C6H5
as internal standard. Isolated yield in parentheses (0.2 mmol scale reaction). [c]
DMF used as solvent. [d] Oxidative cyclisation products formed: see ESI. [e]
MeCN used as solvent. [f] Acetone used as solvent. [g] Reaction carried out in
the dark. PC – photocatalyst.
yields of 6 formation (Entries 7-9). Control experiments were
carried out to confirm that both the light source and the
photocatalyst are required for formation of 6 from 5 (entries 10
and 11).
These optimised conditions were applied to the
trifluoromethyl-arylation of a range of vinylic ureas. Firstly, we
explored the scope of aromatic rings that would undergo
migratory coupling (Scheme 2). Fluorinated and brominated
aromatics performed well under trifluoromethyl-arylation
conditions to give their respective a,a-diaryl alkylureas 9a-9d.
Notably, and consistent with related base-promoted
rearrangements, arylation with relatively electron-rich phenyl (9e)
and para-tolyl rings (9f) were successful when DMF was used as
solvent. (Use of acetone or acetonitrile inhibited the
the first example of a radical-polar crossover mechanism in which
the carbanion product of the photoredox cycle is used in C-aryl
bond formation.
The trifluoromethyl group is a desirable function in medicinal
•
chemistry,19 and CF3 is a versatile electrophilic radical, readily
generated by oxidation of sodium trifluoromethylsulfinate,
NaSO2CF3, known as the Langlois reagent.20 1,2,3,5-
Tetrakis(carbazol-9-yl)-4,6-dicyano-benzene
7 (4CzIPN) was
selected as an easily accessible photocatalyst that would render
the conversion of 5 to 6 a transition-metal free process.21 However,
initial attempts to transform 5 to 6 using 4CzIPN 7 yielded only
products arising either from cleavage of the vinyl urea or from
trifluoromethylation and oxidative cyclisation (Table 1, entry 1,
see SI for structures). Oxidative products presumably arise from
the sulfur dioxide by-product which can accept an electron (SO2
oxidation potential: –0.8 V vs SCE)22 from the radical anion of
4CzIPN (7 oxidation potential: –1.2 V vs SCE).21 Carbonate salts
may be used to sequester sulfur dioxide by adsorption or direct
reaction,23 and, gratifyingly, Cs2CO3 was found to inhibit the
formation of these unwanted products of net oxidation, giving 6 in
66% yield (entry 2). Replacing DMF with acetonitrile or acetone
improved the yield of 6 to 94% (entries 3 and 4). Reducing the
amount of Cs2CO3 to 1 equivalent lowered the yield of 6 (Table 1,
entry 5), but reducing the stoichiometry of 7 from 3.0 to 1.5 was
tolerated and gave 6 in an isolated yield of 87% (entry 6). Other
less oxidising photocatalysts were investigated but gave lower
rearrangement
step,
giving
significant
amounts
of
hydrotrifluoromethylated product). Likewise, meta-tolyl (9g) and
meta-methoxy phenyl (9h) were both tolerated, giving the
corresponding a,a-diarylalkylureas in good yield, as was the
migration of electron-deficient aromatic rings (9i-k).
With the broad scope of the migrating rings established, we
examined different aromatic rings a to the site of arylation that
could facilitate the rearrangement of vinyl ureas (Scheme 3). Both
chlorinated and iodinated aromatics were tolerated as
functionality a to the site of arylation (9l-n). Trifluoromethyl-
arylation was successful with vinyl ureas bearing both electron-
deficient trifluoromethylated and trifluoromethoxylated aromatic
rings (9o and 9p), and electron-rich p-tolyl (9q) and p-methoxy
phenyl (9r) groups. Even the thiophene-substituted substrates (9s
and 9t) participated successfully. Furthermore, a cyclic vinyl urea
– the dihydronaphthalene 8u – also underwent trifluoromethyl-
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10.1002/anie.202003632
Angewandte Chemie International Edition
COMMUNICATION
4CzIPN 7 (5 mol%)
RSO2Na (2.0 equiv)
Cs2CO3 (1.5 equiv)
4CzIPN 7 (1 mol%)
HP(O)Ar2 (1.4 equiv)
Cs2CO3 (1.8 equiv)
O
O
O
NHMe
R
NHMe
P(O)Ar2
MeN
Ar1
MeN
Ar1
MeN
Ar1
NMe
Ar2
24 W blue LED
acetone (0.1 M)
30 °C
24 W blue LED
MeCN (0.1 M)
30 °C
Ar2
Ar2
10j-m
10a-i
8d or 8m
or 8n
O
O
O
NHMe
NHMe
NHMe
Me
N
Me N
Me
N
X
6X
Br
F
F
F F
F
F
Cl
Cl
Cl
Cl
Cl
Cl
10c (X = Cl) 55%[a]
10d (X = N3) 80%[b]
10e (p-Br) 71%
10f (m-Br) 48%[c]
10g (o-Br) 94%
10a (X = H) 64%
10b (X= Me) 79%
Br
Br
Br
O
N
O
NHMe
NHMe
F
Me
F F F F
F
O
Me
N
P
Ar
Cl
F
Ar
I
F
F F F F F
n
10h (n = 0) 70%[d]
10i (n = 1) 66%
Cl
10j (Ph) 64%
10k (m,m'-diCH3C6H3) 60%
10l (2-naphthyl) 80%
10m (p-ClC6H4) 48%
Br
Scheme 4. Scope of sodium sulfinate and diarylphosphine oxides radical
precursors. The heat generated by the LEDs resulted in reaction temperatures
of ca. 30 °C. Yields of product isolated by chromatography. [a] contains 15% of
X=SEt, originating from the commercial sodium sulfinate radical precursor. [b]
1.9 equiv. of sodium sulfinate radical precursor used. [c] DMF used as solvent.
[d] MeCN used as solvent.
Scheme 3. Scope of vinylic substituents in the trifluoromethyl-arylation reaction.
Reactions were carried out on a 0.20 mmol scale. The heat generated by the
LEDs resulted in reaction temperatures of ca. 30 °C. Yields of product isolated
by chromatography. R = -C(O)NHMe. [a] MeCN used as solvent. [b] Acetone
used as solvent. [c] 2.5 equiv. of CF3SO2Na used.
Diarylalkylamines are a class of compounds that are of
medicinal interest27 that also find use as starting materials in the
synthesis of nitrogen heterocycles.28 Straightforward conversion
of trifluoromethylated a,a-diarylalkylurea products 9m-p into
trifluoromethyl-containing a,a-diarylalkylamines (11m-p) was
realised by solvolysis in n-butanol (Scheme 5).14a,29 Our radical
addition Truce-Smiles arylation method thus formally delivers the
b-trifluoromethylation a-arylation of an amino group, a reaction
not possible possible using existing radical-initiated Smiles
rearrangements.30
arylation in good yield and with excellent anti-diastereoselectivity
(9u).
Other sodium sulfinate radical precursors were also used
without any alteration to our optimised conditions (Scheme 4).
Specifically, product ureas incorporating difluoromethyl (10a),
1,1-difluoroethyl (10b) and 1,1-difluoroalkyl chains bearing chloro
(10c) or azide (10d) were formed in good yields, as were those
containing
(2,2-difluoroethyl)benzene
groups
(10e-10g).
Perfluorinated sodium alkylsulfinates were also successful
precursors, giving products 10h and 10i in good yield. Sodium
alkylsulfinates that were not a-fluorinated (e.g. sodium
butanesulfinate) failed to react with the vinyl urea, presumably
because the resulting radical is too electron-rich to add to the
nucleophilic alkene.
Organophosphorus compounds have
a
range of
applications,24 and may be prepared by the addition of
phosphinoyl radicals to olefins.25 Nonetheless, examples of non-
annulative arylphosphonylations of alkenes still remain sparse.26
We found that diarylphosphine oxides functioned effectively as
radical precursors or the arylphosphonylation of vinyl urea 8n
without any appreciable alteration to conditions, yielding 1,1-
diaryl-2-phosphoryl ureas (10j-m) (Scheme 4).
Scheme 5. Solvolysis of trifluoromethyl-arylation products. Yields of product
isolated by chromatography.
The functional group tolerance of these reactions towards
halo substituents is greater than that of related reactions involving
organolithiums.17 The reactivity of these radicals also nicely
complements that of the organolithium component of related
carbolithiation reactions, which conversely work best with more
nucleophilic organometallics.17
Experiments were carried out to probe the mechanism of the
tandem alkylation-arylation reaction. None of the product urea 9d
was formed when the reaction of 8d was carried out in the
presence of TEMPO, however no TEMPO adducts could be
detected.31 Radical trap 1,1-diphenylethylene,2f,4,32 also
attenuated formation of 9d, and gave the trifluoromethyl adduct
12, confirming that trifluoromethyl radical is generated under the
reaction conditions in a redox-neutral manifold (Scheme 6a). This
was further validated by Stern-Volmer luminescence studies,
which showed that the excited state of 7 is quenched by
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10.1002/anie.202003632
Angewandte Chemie International Edition
COMMUNICATION
NaSO2CF3 (Ep/2 = 1.05 V vs SCE) to a greater degree than vinyl
urea (8b: Ep/2 = 1.33 V vs SCE). Measurement of a quantum yield
(F) of 0.18 for the reaction of 8b with NaSO2CF3, suggests that
alternative radical chain mechanisms are not operative (See ESI
for details).
resubjecting 13 to the conditions of the reaction: only trace
amounts of 9f were formed (Scheme 6b).
Several experiments were conducted to distinguish a radical
from an anionic intermediate a to N. Reaction of 8b in deuterated
solvents (Scheme 6c) led to no deuterium incorporation into the
migrating aryl ring of 8b. This result implies that a 1,5-aryl
translocation by 5-exo-trig radical cyclisation, followed by
hydrogen atom abstraction by the cyclohexadienyl radical and
elimination of the nitrogen leaving group does not occur.
(a) Radical trapping studies
O
4CzIPN 7 (5 mol%)
CF3SO2Na (1.5 equiv)
Cs2CO3 (1.5 equiv)
additive (1.5 equiv)
Me
O
Yield 9d
Additive
none
NHMe
CF3
N
MeN
MeN
84%
0%
Br
Cl
24 W blue LED
MeCN (0.1 M)
30 °C
TEMPO
Ph
Experiments with vinyl urea 14, which can undergo radical
addition but not rearrangement, showed that under the conditions
of the reaction it is possible to form an anion a to N: in the
presence of D2O, significant amounts of deuterated product 15
were formed (Scheme 6d). Direct indication of the intermediacy of
an anion was gained by performing the trifluoromethyl-arylation of
8g in the presence of deuterium oxide as an anion trap. In both
MeCN and acetone, the major product became the (mainly
deuteratred) product 16, showing that a proton source can
interrupt the migration. A similar switch in selectivity from 9f to 13
was also noted in the trifluoromethyl-arylation of 8f with solvents
of lower pKa (See ESI for details).
6%
Ph
+
8d
Cl
Br
Ph
CF3
9d
Ph
12 17%
(b) Direct aryl migration of the hydrotrifluoromethylation product
Me
O
4CzIPN 7 (5 mol%)
CF3SO2Na (2.0 equiv)
Cs2CO3 (1.5 equiv)
NHMe
CF3
O
MeN
NMe
CF3
MeN
24 W blue LED
DMF (0.1 M)
30 °C
Cl
Me
Cl
9f
Trace
13
(c) Migrating aryl isotope labelling studies
In summary, a transition-metal free difunctionalisation
(alkyl-arylation and phosphoryl-arylation) of vinyl ureas is made
possible using a readily available organic photocatalyst. The
tandem reaction sequence entails the first example of polar
Truce-Smiles arylations initiated by photoredox catalysis and first
example of a radical addition leading to Truce-Smiles arylation a
to nitrogen. The transformation is tolerant of a range of functional
groups and aromatic rings, and provides an operationally simple
method for preparing fluorinated and phosphonylated a,a-
diarylalkylureas, which may be converted into functionalised a,a-
diarylalkylamines.
Me
O
O
4CzIPN 7 (5 mol%)
CF3SO2Na (1.5 equiv)
Cs2CO3 (1.5 equiv)
N
F
Solvent
Yield 9b
NHMe
CF3
MeN
MeN
Acetone-d6 87% (0% D)
MeCN-d3 90% (0% D)
24 W blue LED
Solvent (0.1 M)
30 °C
Cl
D
DMF-d7
70% (0% D)
Cl
F
8b
9b
(d) Isotope labelling studies with D2O
4CzIPN 7 (5 mol%)
O
Me
N
Et
O
Me
Solvent
Yield 15
CF3SO2Na (2.0 equiv)
Cs2CO3 (1.5 equiv)
D2O (10.0 equiv)
N
MeN
MeN
Et
Acetone 89% (76% D)
24 W blue LED
Solvent (0.1 M)
30 °C
H/D CF3
MeCN
DMF
77% (83% D)
67% (82% D)
Cl
Cl
14
15
Acknowledgements
4CzIPN 7 (5 mol%)
CF3SO2Na (2.0 equiv)
Cs2CO3 (1.5 equiv)
Additive
Me
Me
O
O
O
NMe
MeN
N
Me
NHMe
CF3
We thank Ellie Stammers and Dr Alastair Lennox for assistance
with cyclic voltammetry experiments. The work was supported by
the EPSRC Centre for Doctoral Training in Catalysis.
MeN
MeN
+
24 W blue LED
Solvent (0.1 M)
30 °C
Cl
CF3
D/H
Cl
Me
Cl
16
8g
9g
Keywords: photochemistry • rearrangement • SNAr • urea •
Solvent
MeCN
Additive
None
Yield 9g
79%
Yield 16
trifluoromethylation
9%
MeCN D2O (10.0 equiv)
Acetone None
Acetone D2O (10.0 equiv)
20%
55% (82% D)
6%
[1]
For selected reviews, see: a) C. K. Prier, D. A. Rankic, D. W. C.
MacMillan, Chem. Rev., 2013, 113, 5322-5363; b) D. M. Schultz, T. P.
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10166; f) C.-S. Wang, P. H. Dixneuf, J.-F. Soulé, Chem. Rev., 2018, 118,
167532-167585.
70%
25%
59% (71% D)
Scheme 6. Preliminary mechanistic studies. (a) Radical probe experiments. (b)
Negligible contribution from a sequential hydrotrifluoromethylation/C-H arylation
pathway. (c) Absence of deuterium incorporation into migrating aryl ring from
solvent. (d) Inhibition of rearrangement step and deuteration by D2O.
Although we assume that the N to C aryl migration occurs
by an anionic intramolecular SNAr (Truce-Smiles) mechanism, its
electronic versatility is also characteristic of reactions mediated
by radicals.30,33 Experiments were carried out to establish the
nature of the reaction intermediates and to distinguish between
these two mechanistic possibilities. We ruled out the participation
[2]
For selected examples involving oxidative termination, see: a) Y. Yasu,
T. Koike, M. Akita, Angew. Chem. Int. Ed., 2012, 51, 9567-9571; Angew.
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Dagousset, E. Magnier, G. Masson, Synthesis, 2015, 47, 2439- 2445; e)
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2014, 50, 14197-14200; f) M. Silvi, C. Sandford, V. K. Aggarwal, J. Am.
of
a neutral hydrotrifluoromethylation intermediate 13 by
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10.1002/anie.202003632
Angewandte Chemie International Edition
COMMUNICATION
Chem. Soc., 2017, 139, 5736-5739; g) M. Silvi, V. K. Aggarwal, J. Am.
Chem. Soc., 2019, 141, 9511-9515.
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[3]
For selected examples involving reductive termination, see: a) K. Okada,
K. Okamoto, N. Morita, K. Okubo, M. Oda, J. Am. Chem. Soc., 1991, 113,
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COMMUNICATION
O
Z
O
O
Z
Roman Abrams and
Jonathan Clayden*
Cascade formation of two
C–C bonds at an
Me
Me
Me
Me
Ar2
Me
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SET
N
N
N
R
R
N
N
N
Ar2
radical
addition
Ar2
electron-rich alkene is
made possible by
R
R
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Page No. – Page No.
sequential capture of a
radical (by intermolecular
addition) and an anion
(by intramolecular
PC
intramol.
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Difunctionalization of
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aromatic substitution),
each formed in the
photoredox cycle from
the same organic
PC*
R
Ar2
Z
photochemical alkyl-arylation
photocatalyst.
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