Direct α-Monofluoroalkenylation of Heteroatomic Alkanes via a Combination of Photoredox Catalysis and Hydrogen-Atom-Transfer Catalysis

Article abstract of DOI:10.1021/acs.orglett.9b01491

In this study, a new C(sp³)-H monofluoroalkenylation reaction involving cooperative visible-light photoredox catalysis and hydrogen-atom-transfer catalysis to afford products generated by selective hydrogen abstraction and radical-radical cross-coupling was described. This mild, efficient reaction shows high regioselectivity for the α-carbon atoms of amines, ethers, and thioethers and thus allows the preparation of monofluoroalkenes bearing various substituents. The reaction was applied to two bioactive molecules, indicating its utility for late-stage monofluoroalkenylation of compounds with inert C(sp³)-H bonds.

Full text of DOI:10.1021/acs.orglett.9b01491

Letter
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
Direct α‑Monofluoroalkenylation of Heteroatomic Alkanes via a
Combination of Photoredox Catalysis and Hydrogen-Atom-Transfer
Catalysis
†
†
†
†
†
,†,‡
Hao Tian, Qing Xia, Qiang Wang, Jianyang Dong, Yuxiu Liu, and Qingmin Wang*
†State Key Laboratory of Elemento-Organic Chemistry, Research Institute of Elemento-Organic Chemistry, College of Chemistry,
Nankai University, Tianjin 300071, People’s Republic of China
‡
Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Tianjin 300071, People’s Republic of China
*
S Supporting Information
3
ABSTRACT: In this study, a new C(sp )−H monofluoroalkenylation reaction
involving cooperative visible-light photoredox catalysis and hydrogen-atom-
transfer catalysis to afford products generated by selective hydrogen abstraction
and radical−radical cross-coupling was described. This mild, efficient reaction
shows high regioselectivity for the α-carbon atoms of amines, ethers, and
thioethers and thus allows the preparation of monofluoroalkenes bearing
various substituents. The reaction was applied to two bioactive molecules,
3
indicating its utility for late-stage monofluoroalkenylation of compounds with inert C(sp )−H bonds.
rganofluorinated molecules have recently been receiving
increasing attention in various fields. For example,
only for tertiary amines, its utility for the synthesis of drugs is
severely limited. That leaves a large variety of bioactive
1
O
8
9
fluoroalkenes have found many applications in materials
molecules, such as secondary amines, ethers, and thio-
2
3
10
science and pharmaceutical chemistry, owing to their
synthetic utility and unique biological properties. Furthermore,
these compounds are resistant to enzymatic degradation and
ethers, that are difficult to monofluoroalkenylate. Therefore,
the development of methods for monofluoroalkenylation of
3
inert C(sp )−H bonds would be desirable both for synthetic
3
,4
organic chemistry and for drug-discovery research.
are thus widely used as peptidomimetics. Therefore, the
Visible-light-induced photoredox catalysis through single-
development of new methods for the synthesis of fluoroalkenes
5
electron transfer (SET) pathways has recently emerged as a
has been progressing rapidly. Recently, a series of mild,
11,12
2
powerful synthetic tool.
Moreover, several studies showed
efficient methods for C(sp )−H bond monofluoroalkenylation
that the merged of photoredox and transition-metal catalysis
can successfully deliver many selective native-group functio-
by means of a transition-metal-catalyzed C−H activation
6
3
strategy have been reported. However, C(sp )−H bond
monofluoroalkenylation remains a formidable challenge.
11f−h
nalizations.
Photoredox catalysis was recently used to
7
address the issue of native C−H functionalization by introduce
Hashmi et al. reported a catalytic visible-light-induced
12
HAT strategy. Combining HAT catalysis with photocatalysis,
not only molecules with low oxidation potentials, such as
olefins, imines, and heteroarenes, but also molecules with high
photoredox monofluoroalkenylation reaction of tertiary amines
3
at an α-C(sp ) to afford tetrasubstituted monofluoroalkenes
(
Scheme 1a). Nevertheless, because the reaction is suitable
oxidation potentials, such as secondary amines with easily
ox
3
removable protecting groups (e.g., N-Boc piperidine, E
1
/2
=
Scheme 1. Monofluoroalkenylation of C(sp )−H Bonds
13
ox
+
1.96 V vs SCE), ethers (for THF and Et O, E
> + 2.4 V
2
1/2
12a
vs SCE), and thioethers can be functionalized. Therefore,
we set out to explore a cooperative pathway involving visible-
light photoredox catalysis and HAT catalysis that would allow
hydrogen abstraction from high-oxidation-potential molecules,
3
so that compounds with inert C(sp )−H bonds could be
monofluoroalkenylated (Scheme 1b).
We began our study by carrying out reactions of diphenyl
gem-difluoroethylene (1a) and N-Boc-pyrrolidine (2b) with
the goal of optimizing the reaction conditions (Table 1). First,
we evaluated several photocatalysts: Ir[dF(CF )ppy] -
3
2
Received: April 29, 2019
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b01491
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Table 1. Optimization of the Reaction Conditions
Scheme 2. Substrate Scope with Respect to the gem-
Difluoroalkene
a
b
entry
variation from conditions shown above
none
yield (%)
1
2
3
4
5
6
7
8
9
79 (75)
NR
NR
NR
43
Ir(ppy) as photocatalyst
3
Ru(bpy) Cl ·6H O as photocatalyst
3
2
2
Acid Red 87 as photocatalyst
MeCN instead of 10:1 MeCN/H O
2
c
aceclidine instead of quinuclidine
40
3-quinuclidinol instead of quinuclidine
K CO instead of K PO
NR
60
NR
NR
NR
14
2
3
3
4
no photocatalyst
no HAT catalyst
no light
no base
under air
a
1
1
1
1
0
1
2
3
Reaction conditions, unless otherwise noted: 1 (0.2 mmol), 2b (0.3
mmol), Ir[dF(CF
)ppy]
(dtbbpy)PF
2
(0.002 mmol), quinuclidine
3
6
(
0.04 mmol), and K PO (0.2 mmol) in 10:1 MeCN/H O (2 mL,
3
4
2
volumetric ratio) were stirred in an 8 mL bottle while being irradiated
by a blue LED lamp (40 W) at rt under Ar for 24 h. Isolated yields are
given.
20
a
Reaction conditions, unless otherwise noted: 1a (0.2 mmol), 2b (0.3
mmol), Ir[dF(CF )ppy] (dtbbpy)PF (0.002 mmol), quinuclidine
3
2
6
(
0.04 mmol), and K PO (0.2 mmol) in 10:1 MeCN/H O (2 mL,
3
4
2
a hydrogen atom (3jb−3nb). It is notable that the E/Z
selectivity was low when unsymmetrical gem-difluoroalkenes
were used as substrates (3eb−3nb, up to E/Z = 2.3:1). This
result is evidence that the reaction occurred via a radical−
radical coupling. The recombination of fluoroalkenyl radicals
was fast and therefore difficult to control, so the diastereoiso-
meric ratio was low.
We next examined the generality of the reaction with respect
to amines 2 by using diphenyl gem-difluoroethylene (1a) as the
monofluoroalkenylation agent (Scheme 3). Boc-protected
volumetric ratio) were stirred in an 8 mL bottle while being irradiated
b
by a blue LED lamp (40 W) at rt under Ar for 24 h. Yields were
determined by 19F NMR with fluorobenzene as an internal standard.
c
The yield in parentheses is an isolated yield. NR = no reaction. The
solvent was MeCN.
(
(
dtbbpy)PF , Ir(ppy) , Acid Red 87, and Ru(bpy) Cl ·6H O
6 3 3 2 2
entries 1−4). To our delight, irradiation of the substrates,
Ir[dF(CF )ppy] (dtbbpy)PF (1 mol %), quinuclidine (HAT
3
2
6
catalyst), and K PO4 in 10:1 MeCN/H O under argon
3
2
resulted in the formation of desired product 3ab (79%, entry
). When Ir[dF(CF )ppy] (dtbbpy)PF was replaced with
a
Scheme 3. Substrate Scope with Respect to the Amine
1
3
2
6
another photocatalyst, none of the desired product was
detected. The yield decreased substantially when pure
MeCN was the solvent (entry 5). We reason that water
increased the solubility of base in the reaction system (which is
barely dissolved in MeCN) and thus raised the reaction
efficiency (for details, see Table S7). The use of aceclidine or
3
(
-quinuclidinol as the HAT catalyst resulted in inferior results
entries 6 and 7). A moderate decrease in yield was observed
when K PO was changed to K CO (entry 8). Control
3
4
2
3
experiments showed that in the absence of the photocatalyst
Ir[dF(CF )ppy] (dtbbpy)PF , the HAT catalyst quinuclidine,
3
2
6
or light, the desired product was not detected (entries 9−11),
indicating that all three were essential. What is more, when the
reaction was carried out without the base or under air, the yield
of the product was low (entries 12 and 13), which indicates
that the base was necessary to neutralize hydrogen ions
produced during the reaction and that oxygen interfered with
the reaction.
a
Reaction conditions, unless otherwise noted: 1a (0.2 mmol), 2 (0.3
mmol), Ir[dF(CF )ppy] (dtbbpy)PF (0.002 mmol), quinuclidine
3
2
6
(0.04 mmol), and K PO (0.2 mmol) in 10:1 MeCN/H O (2 mL,
3
4
2
volumetric ratio) were stirred in an 8 mL bottle while being irradiated
by a blue LED lamp (40 W) at rt under Ar for 24 h. Isolated yields are
given. 30 equiv of 2e−g was used for this reaction.
Having optimized the conditions, we then examined the
generality of the monofluoroalkenylation reaction. To our
delight, a variety of gem-difluoroalkenes 1 could be converted
to the desired products (3ab−3nb) in 42−78% yields (Scheme
b
cyclic amines azetidine, piperidine, and azepane afforded
desired products 3aa, 3ac, and 3ad, respectively, in moderate
yield (39−66%). Reactions of BOC-protected acyclic amines
were somewhat sluggish, but when the amount of the amine
was increased to 30 equiv, the target products (3ae−3ag) were
obtained in satisfactory yields (71−76%). Changing the Boc
2
). Both electron-withdrawing and electron-donating sub-
stituents on the aromatic rings of 1 were compatible with
satisfactory yields of products 3ab−3ib. In addition, good
yields could still be obtained when one of the aromatic groups
on the gem-difluoroalkene was exchanged for a methyl group or
B
DOI: 10.1021/acs.orglett.9b01491
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
group (2e) to an amide group (2h) resulted in an excellent
yield of the corresponding product (3ah, 82% yield), even
when only 1.5 equiv of 2h was used, suggesting that an amide
protecting group was more suitable for acyclic amines.
Notably, when the amine contained two different types of α-
carbons, only a single product was obtained (3ai, 76% yield).
We speculated that the primary carbon radical was more active
than the secondary carbon radical attributed to the effect of the
steric component, which turned out to be an excellent regional
selectivity in 3ai. Furthermore, carbamate, urea, and amide
substrates were suitable, affording the corresponding products
Scheme 5. Mechanistic Experiments
(
3ah−3ak) in good yields (63−82%).
Next we evaluated ethers and thioethers as substrates
Scheme 4). We found that both cyclic and acyclic ethers and
(
a
Scheme 4. Reactions of Ethers, Thioethers, And Alkanes
a large extent. Therefore, we concluded that the initial step of
the reaction was reduction of the photocatalyst. Finally, we
performed a light on/off experiment involving 1a and 2b,
which showed that 3ab formed only under irradiation by the
blue LED lamp (Scheme 5d); that is, the transformation
required continuous irradiation.
a
Reaction conditions, unless otherwise noted: 1a (0.2 mmol), 2 (0.3
mmol), Ir[dF(CF )ppy] (dtbbpy)PF (0.002 mmol), quinuclidine
On the basis of these mechanistic experiments and literature
results, we propose the mechanism outlined in Scheme 6 for
3
2
6
(
0.04 mmol), and K PO (0.2 mmol) in 10:1 MeCN/H O (2 mL,
3
4
2
volumetric ratio) were stirred in an 8 mL bottle while being irradiated
by a blue LED lamp (40 W) at rt under Ar for 24 h. Isolated yields are
given. THF was used as the solvent.
b
Scheme 6. Proposed Mechanism
thioethers were acceptable substrates, affording desired
products 3al−3as in moderate to excellent yields (41−95%).
Notably, the reaction of 2n in THF rather than MeCN/H O
2
gave 3an in 95%. To our surprise, the reaction was
chemoselective: only one product (3ao, 41% yield) was
obtained from substrate 2o, which contains multiple possible
reaction sites. We also tested two alkane substrates, xylene and
trimethylbenzene, and were pleased to find that anticipated
products 3ar and 3as could be obtained, albeit in low yields
(
22% and 31%, respectively).
Next, we performed a series of mechanistic experiments.
When a radical inhibitor (TEMPO or 1,1-diphenylethylene)
was present, reaction of 1a and 2b under the standard
conditions gave only a trace of desired product 3ab (Scheme
the reaction of diphenyl gem-difluoroethylene (1a) and N-Boc-
pyrrolidine (2b). Under irradiation with blue light, the
photocatalyst is excited from ground-state Ir(III) species A
to excited-state Ir*(III) species B. SET between B (E
5
a); this result indicates that the reaction proceeds via a radical
mechanism. Then we designed and synthesized substrate 1o
and allowed it to react with amine 2b (Scheme 5b); the
formation of cyclization product 3ob (83%) confirmed that a
fluoroalkenyl radical was generated in the reaction system.
We also conducted a series of Stern−Volmer quenching
studies with Ir[dF(CF )ppy] (dtbbpy)PF and gem-difluor-
1
/2
14
[*Ir(III)/Ir(II)] = +1.21 V vs SCE) and quinuclidine (Ep
15
= +1.1 V vs SCE) forms radical cation E and reduced Ir(II)
complex D. At this stage, desired α-aminoalkyl radical G can be
formed via HAT between 2b and radical cation E.
Fluoroalkenyl radical H can be generated through SET
3
2
6
oalkene 1a or quinuclidine as a soluble additive (Scheme 5c).
The results clearly demonstrate that quinuclidine, but not the
gem-difluoroalkene, could quench the excited photocatalyst to
red
7
reduction of 1a (E1/2 = −1.04 V vs SCE) by Ir(II) complex
14
D (E1/2 [*Ir(III)/Ir(II)] = −1.37 V vs SCE) and cleavage of
C
DOI: 10.1021/acs.orglett.9b01491
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
the C−F bond. Finally, target product 3ab is generated by
selective cross-coupling of radicals G and H.
To demonstrate the synthetic utility of the target products,
we carried out a gram-scale reaction of 1a and 2b under the
standard conditions and then removed the protecting group to
obtain a monofluoroalkenylation product of a secondary amine
ORCID
Qingmin Wang: 0000-0002-6062-3766
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
(
67% yield for two steps, Scheme 7a). In addition, because
■
We are grateful to the National Key Research and Develop-
ment Program of China (2018YFD0200100) and the National
Natural Science Foundation of China (21732002, 21672117)
for generous financial support for our programs.
Scheme 7. Demonstration of Synthetic Utility
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E
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