Monofluoroalkenylation of Dimethylamino Compounds through Radical–Radical Cross-Coupling

Article abstract of DOI:10.1002/anie.201602347

An unprecedented and challenging radical–radical cross-coupling of α-aminoalkyl radicals with monofluoroalkenyl radicals derived from gem-difluoroalkenes was achieved. This first example of tandem C(sp³)?H and C(sp²)?F bond functionalization through visible-light photoredox catalysis offers a facile and flexible access to privileged tetrasubstituted monofluoroalkenes under very mild reaction conditions. The striking features of this redox-neutral method in terms of scope, functional-group tolerance, and regioselectivity are illustrated by the late-stage fluoroalkenylation of complex molecular architectures such as bioactive (+)-diltiazem, rosiglitazone, dihydroartemisinin, oleanic acid, and androsterone derivatives, which represent important new α-amino C?H monofluoroalkenylations.

Full text of DOI:10.1002/anie.201602347

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International Edition: DOI: 10.1002/anie.201602347
German Edition: DOI: 10.1002/ange.201602347
Radical Coupling
Monofluoroalkenylation of Dimethylamino Compounds through
Radical–Radical Cross-Coupling
Jin Xie, Jintao Yu, Matthias Rudolph, Frank Rominger, and A. Stephen K. Hashmi*
Abstract: An unprecedented and challenging radical–radical
cross-coupling of a-aminoalkyl radicals with monofluoroal-
kenyl radicals derived from gem-difluoroalkenes was ach-
ieved. This first example of tandem C(sp )ÀH and C(sp )ÀF
H bond monofluoroalkenylation method would constitute
a novel and practical approach since it could enable access to
an array of structurally diverse monofluoroalkenes. Recently,
3
2
[6]
[7]
the groups of Hoarau and Loh reported the transition-
2
bond functionalization through visible-light photoredox catal-
ysis offers a facile and flexible access to privileged tetrasub-
stituted monofluoroalkenes under very mild reaction condi-
tions. The striking features of this redox-neutral method in
terms of scope, functional-group tolerance, and regioselectivity
are illustrated by the late-stage fluoroalkenylation of complex
molecular architectures such as bioactive (+)-diltiazem, rosi-
glitazone, dihydroartemisinin, oleanic acid, and androsterone
derivatives, which represent important new a-amino CÀH
metal-catalyzed monofluoroalkenylation of aromatic C(sp )À
H bonds, thereby streamlining access to trisubstituted alkenyl
fluorides (Scheme 1a,b). However, a general catalytic late-
3
stage monofluoroalkenylation of inert C(sp )ÀH bonds to
tetrasubstituted monofluoroalkenes has not been reported so
far and represents a new challenge (Scheme 1, lower part).
monofluoroalkenylations.
T
he monofluoroalkene substructure plays a unique role in
[
1]
various fields of current research. It shows a high potential
[
2]
as a fluorinated synthon in organic synthesis and is valuable
as a peptide bond mimic in medicinal chemistry, drug
[
3]
[4]
discovery (Figure 1), and high-performance materials.
These features have triggered the development of synthetic
[
5]
methods to complement existing strategies. Conceptually,
the development of a general, mild, and efficient catalytic CÀ
Scheme 1. Selective monofluoroalkenylation of unreactive CÀH bonds.
The tertiary amine substructure is prevalent in natural
products and pharmaceutically agents (about 20% of the 200
[
8]
top-selling pharmaceutical products contain this unit).
However, they were generally considered to be unreactive
3
coupling partners until recent efforts toward a-C(sp )ÀH
[
9]
bond functionalization changed that view. The development
Figure 1. Selected bioactive multisubstituted monofluoroalkenes.
3
of a mild and general method for the selective C(sp )ÀH
monofluoroalkenylation of complex tertiary amine skeletons
would thus be highly attractive and meaningful for both
[
*] Dr. J. Xie, Dr. J. Yu, Dr. M. Rudolph, Dr. F. Rominger,
Prof. Dr. A. S. K. Hashmi
[
10a]
organic and medicinal chemistry. Recently, we
and
[11]
Organisch-Chemisches Institut, Universität Heidelberg
Im Neuenheimer Feld 270, 69120 Heidelberg (Germany)
E-mail: hashmi@hashmi.de
others have described a new radical–radical recombination
of a-aminoalkyl radicals for CÀC coupling reactions under
[12]
photoredox catalysis. We now report the recombination of
Homepage: http://www.hashmi.de
a-aminoalkyl radicals with monofluoroalkenyl radicals, which
readily enables the late-stage modification of complex
bioactive molecules by photoredox catalysis.
Prof. Dr. A. S. K. Hashmi
Chemistry Department, Faculty of Science, King Abdulaziz University
(
2
KAU)
1589 Jeddah (Saudi Arabia)
Transition-metal-catalyzed CÀF bond functionalization
[13]
has become an important strategy for coupling reactions.
Supporting information for this article can be found under:
http://dx.doi.org/10.1002/anie.201602347.
Still, mechanistically distinct, visible-light-induced CÀF bond
9
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[
14]
3
[a]
functionalization is still underdeveloped.
With readily
Table 1: Initial studies towards a C(sp )ÀH monofluoroalkenylation.
[
15]
formed a-aminoalkyl radicals in our mind, we wondered
whether we could achieve a visible-light-promoted CÀF bond
[7,13a]
functionalization of tetrasubstituted gem-difluoroalkenes
to produce monofluoroalkenyl radicals for radical–radical
heterocoupling. A preliminary mechanistic sketch of our
proposal is shown in Scheme 2. Upon irradiation, the excited-
1
9
[b]
Entry
Photocatalyst (PC)
F NMR yield
[
c]
1
2
3
4
5
6
7
8
9
1
1
1
3a
3b
3c
3d
10%
96% (85%)
>99% (88%)
62%
43%
9%
12%
0
3e
Ru(bpy) Cl 3 f
Ir(ppy) 3g
–
3c
3c
3c
3c
3
2
3
[
d]
0
[
e]
f]
0
1
2
16%
85% (71%)
60%
[
[
g]
[
a] 0.1 mmol scale with 1.5 equiv 1a. [b] With 2-bromo-4-fluorobenz-
aldehyde as an internal standard. The isolated yield is given in brackets.
[
[
c] UVA light. [d] In the dark. [e] Without Na CO . [f] 1.2 equiv amine.
2 3
g] 0.1 mmol 1a with 1.5 equiv 2a.
Scheme 2. Proposed a-amino monofluoroalkenylation. The SOMO
energies were obtained at the DFT/UM06-2X/6-311+ +g(d,p) level.
II
state photocatalyst 5 is formed and it then undergoes single
electron transfer (SET) by accepting one electron from
tertiary amine 1a to generate radical cation 6, which would
strong reducing ability of the corresponding Ir complex (E
1/
III
II
[19]
[Ir /Ir ] = À1.37 V vs. SCE). Regarding these values, both
2
ox
[16]
SET oxidation of 1a (E
= 0.96 V vs. SCE)
and SET
1/2
red
[16]
form a-aminoalkyl radical 7 by deprotonation. Subsequent
reduction of 2a (E1/2 = À1.04 V vs. SCE) are thermody-
red
SETreduction of gem-difluoroalkene 2a (E
= À1.04 V vs.
namically feasible. In accordance with previous
1/2
[16]
[10a,11,15]
SCE) would generate radical anion 9, which might be prone
to undergo CÀF bond fragmentation to generate a fluoride
reports,
a slight excess of amine favored the coupling
process (Table 1, entry 3 vs. entries 11 and 12). Control
experiments revealed that the photocatalyst, light, and base
were essential for a successful transformation (Table 1,
entries 8–10).
and fluoroalkenyl radical 10 (similar fragmentations have
[14b,c]
already been reported for perfluoroaryl radical anions).
DFT calculations indicate that a-aminoalkyl radical 7 has
a higher SOMO energy than monofluoroalkenyl radical 10.
[16]
Under these optimized reaction conditions (Table 1,
entry 3), we examined the substrate scope with respect to
the applied tertiary amines (Table 2). In general, the mono-
fluoroalkenylation method has a very broad scope. Both
acyclic and cyclic N-Ar and aliphatic tertiary amines selec-
tively underwent monofluoroalkenylation to give the corre-
sponding products 4aa–ax in 50%–97% yield. The result of
the X-ray single-crystal structure analysis of 4ap is shown in
Figure 2. The reaction showed excellent functional-group
compatibility; esters, aldehydes, nitriles, halides, amides,
alcohols, ethers, acetals, and heteroaromatic rings were
tolerated. Selective monofluoroalkenylation of the strong
Then, selective cross-recombination of the less reactive a-
aminoalkyl radical 7 with the more reactive monofluoroal-
kenyl radical 10 could afford product 4aa according to the
[17]
“
persistent-radical effect”.
Alternatively, chemoselective
radical CÀC heterocoupling of a-aminoalkyl radical 7 with
radical anion 9 and subsequent extrusion of fluoride could
also efficiently deliver 4aa. Radical addition of the a-amino-
alkyl radicals to the electron-deficient gem-difluoroalkenes
[
18]
were not observed in any of our examples.
3
As shown in Table 1, the proposed a-C(sp )ÀH mono-
fluoroalkenylation was indeed feasible during an initial test
[10]
3
with [Au (m-dppm) ] OTf. A further screening of various
primary a-C(sp )ÀH bonds was preferred even in the
2
2 2
photocatalysts revealed that Ir[dF(CF )ppy] (dtbbpy)PF 3c
presence of weaker secondary and tertiary CÀH bonds
(4aq–ax). Notably, the prevalence of the 1,1-diaryl-2-fluo-
roethenyl motif in pharmaceuticals lead structures underlines
the potential of products 4aa–ax in the context of drug
3
2
6
was the optimal choice (88% yield; Table 1, entry 3). This can
be rationalized by the strong oxidation potential of its long-
III
II
lived excited state (E [*Ir /Ir ] =+ 1.21 V vs. SCE) and the
1/2
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Scheme 3. Exploration of other coupling partners. Reaction conditions:
3
c (1 mol%), 2a (0.2 mmol), A-E (1.5 equiv), Na CO (1.5 equiv),
2 3
DMF (0.6 mL), blue LEDs, RT.
[a]
Table 3: Substrate scope with regard to the gem-difluoroalkenes.
[20]
Figure 2. Solid-state molecular structure of 4ap.
[
a]
Table 2: Scope with regard to the applied tertiary amines.
[
a] Yields of isolated product and the major product are shown. The E/Z
1
9
ratio was determined by F NMR analysis of reaction mixture.
gem-Difluoroalkenes are readily available building
[24]
blocks. A variety of gem-difluoroalkenes were converted
Table 3). Both electron-donating and electron-withdrawing
(
groups in the ortho, meta, and para positions of the attached
aromatic rings were compatible, affording the corresponding
tetrasubstituted alkenyl fluorides 4aa–ja in satisfactory yields
[25]
(up to 99%).
With an electron-rich thiophene moiety,
[
a] Yields of isolated product. [b] 1 mmol scale. [c] 3 equiv tertiary amines
besides the desired product 4ha, an interesting double CÀF
were used due to lower reactivity.
bond functionalization delivered the C -symmetrically tetra-
2
substituted alkene 4ha’ in significant amounts. In the case of
unsymmetrical gem-difluoroalkenes as starting materials,
moderate E/Z selectivity was obtained (4ja–pa, ratio up to
82:18). The observed stereoselectivity is consistent with our
initial hypothesis of a radical–radical coupling model as
depicted in Scheme 2. The diastereoisomeric ratio is kineti-
cally controlled through trapping of the transient fluroalkenyl
radical and, owing to the extremely fast radical recombination
process, it is poorly controllable. Trisubstituted gem-difluoro-
[
21]
[22a]
discovery. However, with a-oxo acids,
acid,
alkyl carboxylic
[
22b]
[22c]
and alkyl trifluoroborates or boronic acids
of tertiary amines, only small amounts or traces of the desired
products were observed under the same conditions
Scheme 3). We speculate that replacement of the a-amino-
alkyl radicals by more short-lived acyl or alkyl radicals is
instead
(
[23]
unfavorable for the radical recombination process.
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radical–radical coupling is possible
at this stage, an alternative radical
addition and a subsequent base-
mediated elimination pathway has
to be considered as well. To evaluate
the possibility of this alternative
mechanistic scenario, several gem-
difluoro-phenylethane derivatives
(
20–22) bearing acidic benzylic CÀ
H bonds were prepared as mimics
for the possible intermediates that
would be formed if a radical addi-
tion were to initiate the reaction.
However, under the standard reac-
tion conditions, none of the mono-
fluoroalkene products were formed
(Scheme 5c). Therefore, an addi-
tion/elimination process is less
likely, and indeed a radical–radical
coupling pathway dominated by the
persistent-radical effect could oper-
ate.
Scheme 4. Late-stage a-amino CÀH monofluoroalkenylation of top-selling drugs and complex
molecules. [a] 3 equiv tertiary amine. [b] 1.5 equiv tertiary amine. [c] 2 equiv tertiary amine.
[
d] 1.2 equiv tertiary amine.
alkenes prepared from aldehydes were also suitable coupling
partners (4qa and 4ra).
The challenging late-stage application of complex molec-
ular architectures is indispensable for the development of
innovative methods. As depicted in Scheme 4, a variety of
top-selling drugs such as (+)-diltiazem (a potent vasodilator),
citalopram (an antidepressant), rosiglitazone (an antidia-
betic), and venlafaxine (an antidepressant) tolerated the
monofluoroalkenylation conditions well, even in the presence
of functional groups that are sensitive to oxidants or acidic/
basic conditions. Products 11–15 were obtained in 52–84%
3
yields with primary a-C(sp )ÀH bond selectivity. The deriv-
atives of complex biologically important compounds such as
dihydroartemisinin, oleanic acid, and androsterone can also
3
be a-C(sp )ÀH monofluoroalkenylated while keeping other
versatile functional groups (ester, aldehyde, alkene, acetal,
peroxide, ketone) intact. The successful incorporation of the
monofluoroalkenyl motif into such bioactive compounds
could help to improve their bioactivity and other properties.
These examples demonstrate that the applied method repre-
sents a powerful late-stage monofluoroalkenylation. The
small drawback that an excess of tertiary amine is needed
becomes tolerable if one considers that all of the mono-
fluoroalkenylation reactions run cleanly, which significantly
simplifies the recovery of unreacted amine.
With regard to the mechanism, we first performed radical
inhibition experiments with various radical inhibitors. The
observed inhibition is in all cases indicative of a SET-
mediated radical pathway (Scheme 5a). Adding Michael
acceptor but-3-en-2-one into the model reaction led to the
formation of byproduct 19 in 35% yield, which strongly
implies the involvement of a-aminoalkyl radical 7 (Scheme
Scheme 5. Control experiments and mechanistic studies.
[
15]
3
5
b). In addition, the monofluoroalkenyl radical or gem-
In summary, we describe an unprecedented a-C(sp )ÀH
difluoroalkenyl radical anion can be trapped by different acyl
or alkyl radicals as listed in Scheme 3. Although the proposed
monofluoroalkenylation of unactivated tertiary amines
through a mild, efficient, and redox-neutral route to priv-
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ileged tetrasubstituted monofluoroalkenes by photoredox
catalysis. Mechanistic studies indicate a radical–radical
cross-coupling reaction of a-aminoalkyl radicals with mono-
fluoroalkenyl radicals. The mild reaction conditions, a broad
scope, excellent functional-group tolerance, and exclusive
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Keywords: late-stage functionalization ·
monofluoroalkenylation · photoredox catalysis ·
radical coupling · CÀH activation
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Angewandte
Communications
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luminescence quenching experiments, and quantum yields.
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[
[
Received: March 7, 2016
Published online: June 28, 2016
Angew. Chem. Int. Ed. 2016, 55, 9416 –9421
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
9421