Distal Functional Group Migration for Visible-light Induced Carbo-difluoroalkylation/monofluoroalkylation of Unactivated Alkenes

Article abstract of DOI:10.1002/adsc.201701229

A general and practical protocol for elusive carbo-difluoroalkylation/ monofluoroalkylation of unactivated alkenes based on the distal functional group migration is described. A portfolio of functional groups including heteroaryl, imino, formyl, and alkynyl groups showcase the migratory aptitude. In combination with visible-light photocatalysis, a broad range of di- and mono-fluorinated alkyl ketones are readily obtained in synthetically useful yields under mild reaction conditions. (Figure presented.).

Full text of DOI:10.1002/adsc.201701229

Title: Distal Functional Group Migration for Visible-light Induced Carbo-
difluoroalkylation/ monofluoroalkylation of Unactivated Alkenes
Authors: Chen Zhu, Jiajia Yu, Dongping Wang, Yan Xu, and Zhen Wu
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10.1002/adsc.201701229
Advanced Synthesis & Catalysis
FULL PAPER
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Distal Functional Group Migration for Visible-light Induced
Carbo-difluoroalkylation/monofluoroalkylation of Unactivated
Alkenes
Jiajia Yu,a,‡ Dongping Wang,a,‡ Yan Xu,a,‡ Zhen Wu,a and Chen Zhua,*
a
Key Laboratory of Organic Synthesis of Jiangsu Province, College of Chemistry, Chemical Engineering and Materials
Science, Soochow University, 199 Ren-Ai Road, Suzhou, Jiangsu 215123, China. E-mail: chzhu@suda.edu.cn
These authors contributed equally to this work
‡
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
Abstract. A general and practical protocol for elusive carbo-
difluoroalkylation/ monofluoroalkylation of unactivated
alkenes based on the distal functional group migration is
described. A portfolio of functional groups including
heteroaryl, imino, formyl, and alkynyl groups showcase the
migratory aptitude. In combination with visible-light
photocatalysis, a broad range of di- and mono-fluorinated
alkyl ketones are readily obtained in synthetically useful
yields under mild reaction conditions.
Keywords: difluoroalkylation; monofluoroalkylation;
photocatalysis; alkene difunctionalization; functional group
migration
Introduction
Given that the fluorine atom usually results in a
remarkable change of lipophilicity, chemical stability,
and bioactivity,[1] fluorine-containing compounds
have gained wide attention in the past decades in
many research areas across synthetic chemistry,
agrochemicals, pharmaceuticals, and material
sciences. Consequently, the development of practical
methods to incorporate the fluorine atom into organic
molecules is of high importance.[2] Recently, a
considerable progress has been made with radical
fluoroalkylation of alkenes to provide powerful and
divergent approaches for the installation of
fluoroalkyl groups. In these efforts, di- and mono-
fluoroalkylation of alkenes are relatively less
investigated than trifluoromethylation of alkenes,[3,4]
regardless of the special use of CF2 and CF units in
medicinal chemistry.[5] Moreover, the present studies
regarding di- and mono-fluoroalkylation of alkenes
are generally employing the activated alkenes as
substrates.[6] The reactions with unactivated alkenes
are mostly dependent upon the process of atom
transfer radical addition (ATRA) (Scheme 1a).[7]
Therefore, the development of a general protocol for
di- and mono-fluoroalkylation of unactivated alkenes
with simultaneous introduction of an additional
valuable functional group is still highly desirable.
Scheme 1. Di- and mono-fluoroalkylation of unactivated
olefins
Despite the great progress made in the field of
radical-mediated difunctionalization of alkenes,[8] the
manipulation of unactivated alkenes still remains
challenging. In this scenario, the strategy of
intramolecular functional group migration provides
an efficient solution for difunctionalization of
unactivated olefins.[9] A common protocol is the
radical-mediated 1,2-aryl migration.[10] In addition, a
few examples of distal aryl migration have also been
reported.[11] Recently, we achieved the first example
of application of distal cyano migration to the radical
azidocyanation of unactivated alkenes, affording the
azido-substituted alkyl nitriles.[12] Afterward, we
disclosed the distal heteroaryl and alkynyl migration
1
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10.1002/adsc.201701229
Advanced Synthesis & Catalysis
for the trifluoromethylative heteroarylation and
alkynylation of unactivated alkenes for the first time,
furnishing the trifluoroalkylated alkyl ketones.[13]
Prompted by these results, we considered to apply the
strategy of intramolecular functional group migration
to di- and mono-fluoroalkylation of unactivated
alkenes.
Heteroarenes are of high importance in both organic
and medicinal chemistry. For example, they are
present in almost half of the top 200 on-sale
pharmaceuticals.[16]
The
radical-mediated
heteroarylfluoroalkylation of alkenes provides an
efficient tool for the preparation of fluoroalkyl-
substituted heteroarenes.
Visible-light photoredox catalysis provides a
robust and eco-friendly tool for production of free
radicals.[14] Based on the analysis of catalytic
pathways, we hypothesize that the combination of
photocatalysis and functional group migration might
serve for our purpose. As depicted in Scheme 2, the
transient excited state of photocatalyst Mn* triggered
by the visible-light irradiation can be oxidatively
quenched by the bromoalkane to form a fluoroalkyl
With the benzothiazole-substituted tertiary alcohol
1 and bromodifluoroacetate 2a as substrates, the
reaction was performed under the irradiation of
visible light (Scheme 3). The substrates bearing either
electron-rich or deficient aryl substituent consistently
provided satisfactory chemical yields (3a-3k). The
yield was not appreciably affected by changing the
position (p-, m-, o-) of substituents (3c, 3j, and 3k).
The migration reaction demonstrated a unique
chemoselectivity that only the migration of
radical and Mn+1 [15]
Addition of the fluoroalkyl
.
radical to alkene gives rise to the intermediate I that
subsequently cyclizes with the radical acceptor X
group to generate the intermediate II. Ring-opening
homolysis of II results in a hydroxyl-stabilized
radical III which is then oxidized by Mn+1 to produce
the intermediate IV and regenerates Mn. The final
product is obtained after the deprotonation of IV.
Scheme 2. Combined strategies of functional group
migration and photocatalysis.
Herein, we provide concrete support for the
hypothesis. A general protocol for the carbo-
difluoroalkylation/
monofluoroalkylation
of
unactivated alkenes by merging the intramolecular
migration of functional group and photocatalysis is
described (Scheme 1b). The migratory aptitude of a
portfolio of functional groups such as heteroaryl,
imino, formyl, and alkynyl is investigated. A broad
range of synthetically useful di- and mono-
fluorinated alkyl ketones are readily furnished under
mild reaction conditions.
Scheme 3. Heteroaryldifluoroalkylation of unactivated
olefins. Reaction conditions: 1 (0.2 mmol, 1 equiv), 2a (or
2b, 4, 5) (0.4 mmol, 2.0 equiv), fac-Ir(ppy)3 (0.008 mmol,
4 mol %) in DMF (2 mL) at rt, 10 W blue LEDs irradiation.
Results and Discussion
Heteroaryl-fluoroalkylation of unactivated alkenes
2
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10.1002/adsc.201701229
Advanced Synthesis & Catalysis
benzothiazolyl group took place while the presence of
other sulfur or oxygen-containing heteroarenes (3l
and 3m). The alkyl-substituted tertiary alcohols also
proved to be apt substrates (3n and 3o). Notably, the
stereoselective migration of heteroaryl group remains
difficult as both two isomers of 1r generated the
corresponding products 3r with the similar
diastereomeric ratios. Other difluoroalkylation
reactions
(bromodifluoroacetamide),
(bromodifluoromethanesulfonylbenzene), and
(dibromodifluoromethane). A variety of synthetically
useful difluorinated alkyl ketones were readily
obtained (3s-3aa).
were
examined
with
2b
4
5
Scheme 5. Heteroarylmonofluoroalkylation of unactivated
olefins. Reaction conditions: 1 (0.2 mmol, 1 equiv), 6 (0.4
mmol, 2.0 equiv), fac-Ir(ppy)3 (0.008 mmol, 4 mol %) in
DMF (2 mL) at rt, 10 W blue LEDs irradiation. Yields of
isolated products are given, d.r. = 1 : 1.
We then assessed the migratory aptitude of
various heteroaryl groups. Under the visible-light
irradiation, a set of nitrogen-containing heteroarenes
proved to be suitable migratory functional group
(Scheme 4). The functionalized benzothiazolyls as
well as thiazolyls migrated smoothly to give the
corresponding products in good yields (3ab-3ae). The
migration of imidazolyl led to a lower yield (3af). In
addition to five-membered heteroaryl, the migration
of six-membered heteroaryl such as 2-pyridyl and 4-
pyridyl could also proceed efficiently (3ag and 3ah).
Obviously, extension of this protocol to the migration
of other functionalized five- and six-membered
nitrogen-containing heteroaryls can also be
anticipated.
This protocol was also applied to the
heteroarylmonofluoroalkylation of alkenes (Scheme
5). A variety of aryl, alkyl, and heteroaryl substituted
tertiary alcohols were readily converted into the
monofluorinated alkyl ketones in practical yields (7a-
7c).
Imino-fluoroalkylation of unactivated alkenes
Upon completion of the migration of heteroaryl group,
we were prompted to explore the migration of other
unsaturated C-N bonds such as imine. With the
imino-substituted tertiary alcohol 8 as substrate, as
expected, the reaction with either difluoroalkyl or
monofluoroalkyl reagent (2a, 2b, 4, and 6) readily
proceeded under the visible-light irradiation to afford
the corresponding imino-migrated product 9 (Scheme
6). Both electron-rich and deficient substrates were
well tolerated, furnishing a set of di- and mono-
fluorinated alkyl ketones (9a-9f). Notably, the imino
moiety of products could be conveniently
transformed into many other useful functionalities,
e.g., amine, aldehyde, and alcohol. This is the first
report of a difunctionalization of unactivated olefins
with concomitant introduction of a versatile imino
group.
Scheme 4. Scope of migratory N-containing heteroarenes.
Reaction conditions: 1 (0.2 mmol, 1 equiv), 2a (0.4 mmol,
2.0 equiv), fac-Ir(ppy)3 (0.008 mmol, 4 mol %) in DMF (2
mL) at rt, 10 W blue LEDs irradiation.
Scheme 6. Iminofluoroalkylation of unactivated olefins.
Reaction conditions: 8 (0.2 mmol, 1 equiv), 2a (2b, 4, or 6)
(0.4 mmol, 2.0 equiv), fac-Ir(ppy)3 (0.008 mmol, 4 mol %)
in DMF (4 mL) at rt, 10 W blue LEDs irradiation. Yields
of isolated products are given.
3
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10.1002/adsc.201701229
Advanced Synthesis & Catalysis
Formyl-fluoroalkylation of unactivated alkenes
With the α-formyl substituted tertiary alcohol 10 as
substrate, the migration of formyl group was induced
by addition of a fluoroalkyl radical to the olefin part,
furnishing the resultant fluorinated aliphatic aldehyde
11 (for detailed reaction conditions survey, see SI;
Scheme 7). The reaction demonstrated a broad
functional group tolerance that both electron-rich and
deficient substrates smoothly led to the desired
products. In addition to the phenyl and naphthyl
substituted tertiary alcohols (11a-11j), the thienyl and
t-butyl substrates were also compatible with the
reaction conditions to deliver good yields (11k and
11l). Other difluoroalkylating reagents including 2b,
4, and 5 were also suitable coupling partners to give
the difluoroalkylated products in synthetically useful
yields (11m-11x). Moreover, the efficient
formylmonofluoroalkylation of unactivated alkene
was exemplified as well (11y).
We envisioned that the migration of unsaturated C-O
bond such as formyl group could also be realized
under the photocatalytic reaction conditions. When
we were carrying out this project, Liu and coworkers
disclosed the radical-mediate formylation of alkenes
by means of intramolecular formyl group
migration.[17] However, only a single example of
formyldifluoroalkylation of alkene by using
bromodifluoroacetate
2a
under
visible-light
irradiation was reported in 43% yield. From the
practical point of view, the systematic studies for the
photocatalytic formyldifluoroalkylation of alkenes is
still in demand.
Alkynyl-fluoroalkylation of unactivated alkenes
As a prominent example of unsaturated C-C bonds,
alkynyl group was also studied for the migratory
aptitude. Mechanistically, there are several challenges
present in the migration of alkynyl group (Scheme 8):
(1) the addition of an extrinsic fluoroalkyl radical
should be chemoselective to the alkenyl rather than
the alkynyl part of 12a; (2) the alkynyl-substituted
tertiary alcohol 12a is prone to dehydration (path a);
and (3) the highly reactive olefinic radical b could be
terminated by other competitive pathways, e.g.,
hydrogen abstraction, intramolecular cyclization
(path b). When subjecting compound 12a to the
previous reaction conditions, indeed, the reaction was
severely suffered from the dehydration. However, the
dehydration was efficiently inhibited by the addition
of K2HPO4, affording the expected alkynyl-migrated
product 13a in 70% yield (for detailed reaction
conditions survey, see SI). Of note, the synthesis of
such distally alkynyl-substituted alkyl ketones is
useful but usually difficult.[18]
With the optimized reaction conditions in hand, we
evaluated the generality of the protocol (Scheme 9).
Both electron-rich and deficient aryl substrates
furnished the corresponding products in synthetically
useful yields (13a-13e). Substitution at different
positions (p-, m-, o-) did not significantly change the
reaction yields (13d, 13f-13h). The reaction with
aliphatic and heteroaryl substrates readily proceeded,
albeit in modest yields (13i-13k). The migratory
alkynyl group could also be variated. A set of
functionalized aryl alkynes were smoothly migrated
regardless of the electronic and steric effects (13l-
13r). However, the migration of aliphatic alkyne was
failed with the current reaction conditions. Moreover,
Scheme 7. Formylfluoroalkylation of unactivated olefins.
Reaction conditions: 10 (0.2 mmol, 1 equiv), 2a (2b, 4, 5,
or 6) (0.4 mmol, 2.0 equiv), fac-Ir(ppy)3 (0.008 mmol, 4
mol %) in DMF (4 mL) at rt, 10 W blue LEDs irradiation.
Yields of isolated products are given.
bromodifluoromethanesulfonylbenzene
4
and
dibromodifluoromethane 5 were also competent
coupling partners to generate the difluoroalkylated
products (13s and 13t).
4
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10.1002/adsc.201701229
Advanced Synthesis & Catalysis
Scheme 8. Competitive pathways in the alkynyl migration process
and visible-light photocatalysis. A series of functional
groups including heteroaryl, imino, formyl, and
alkynyl groups have showcased the migratory
aptitude. The reaction demonstrates a good tolerance
for various functionalities that a wide range of di- and
mono-fluorinated alkyl ketones are readily obtained
in synthetically useful yields under mild reaction
conditions. The combination of functional group
migration and photoredox catalysis paves a new
avenue for the radical-mediated difunctionalization of
unactivated alkenes.
Experimental Section
General Procedure for the Heteroaryl Migration
Reaction
Heteroaryl-substituted tertiary alcohol (1) (0.2 mmol,
1.0 equiv), fac-Ir(ppy)3 (0.008 mmol, 4 mol%), and
BrCF2R (2a, 2b, 4, 5)/ BrCHFR (6) (0.4 mmol, 2.0
equiv.) were loaded in a flask which was subjected to
evacuation/flushing with nitrogen for three times.
DMF (2.0 mL) was added to the mixture via syringe
and the mixture was then irradiated by 10 W blue
LEDs. The reaction was allowed for stirring at rt until
the starting material had been consumed as
determined by TLC. The mixture was extracted with
ethyl acetate (3 × 10 mL). The combined organic
extracts were washed by brine, dried over Na2SO4,
filtered, concentrated, and purified by flash column
chromatography on silica gel (eluent: ethyl acetate/
petroleum ether) to give the corresponding product 3
or 7.
Scheme 9. Alkynyldifluoroalkylation of unactivated
olefins. Reaction conditions: 12 (0.2 mmol, 1 equiv), 2a (4,
or 5) (0.4 mmol, 2 equiv), fac-Ir(ppy)3 (0.008 mmol, 4
mol %), and K2HPO4 (0.16 mmol, 0.8 equiv) in DMF (3
mL) at rt, 10 W blue LEDs irradiation. Yields of isolated
products are given.
General Procedure for the Imino Migration
Reaction
Imino-substituted tertiary alcohol (8) (0.2 mmol, 1.0
equiv), fac-Ir(ppy)3 (0.008 mmol, 4 mol%), and
BrCF2R (2a, 2b, 4)/ BrCHFR (6) (0.4 mmol, 2.0
equiv) were loaded in a flask which was subjected to
evacuation/flushing with nitrogen for three times.
DMF (4.0 mL) was added to the mixture via syringe
and the mixture was then irradiated by 10 W blue
Conclusion
In summary, we have described a general and
practical
protocol
for
elusive
carbo-
of
difluoroalkylation/
monofluoroalkylation
unactivated alkenes based on the combinational
strategy of intramolecular functional group migration
5
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10.1002/adsc.201701229
Advanced Synthesis & Catalysis
LEDs. The reaction was allowed for stirring at rt until
the starting material had been consumed as
determined by TLC. The mixture was extracted with
ethyl acetate (3 × 10 mL). The combined organic
extracts were washed by brine, dried over Na2SO4,
filtered, concentrated, and purified by flash column
chromatography on silica gel (eluent: ethyl acetate/
petroleum ether) to give the corresponding product 9.
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General Procedure for the Formyl Migration
Reaction
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Formyl-substituted tertiary alcohol (10) (0.2 mmol,
1.0 equiv), fac-Ir(ppy)3 (0.008 mmol, 4 mol%), and
BrCF2R (2a, 2b, 4, 5)/ BrCHFR (6) (0.4 mmol, 2.0
equiv) were loaded in a flask which was subjected to
evacuation/flushing with nitrogen for three times.
DMF (4.0 mL) was added to the mixture via syringe
and the mixture was then irradiated by 10 W blue
LEDs. The reaction was allowed for stirring at rt until
the starting material had been consumed as
determined by TLC. The mixture was extracted with
ethyl acetate (3 × 10 mL). The combined organic
extracts were washed by brine, dried over Na2SO4,
filtered, concentrated, and purified by flash column
chromatography on silica gel (eluent: ethyl acetate/
petroleum ether) to give the corresponding product 11.
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General Procedure for the Alkynyl Migration
Reaction
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Alkynyl-substituted tertiary alcohol (12) (0.2 mmol,
1.0 equiv), fac-Ir(ppy)3 (0.008 mmol, 4 mol%), and
BrCF2R (2a, 4, 5) (0.4 mmol, 2.0 equiv) were loaded
in a flask which was subjected to evacuation/flushing
with nitrogen for three times. DMF (3.0 mL) was
added to the mixture via syringe and the mixture was
then irradiated by 10 W blue LEDs. The reaction was
allowed for stirring at rt until the starting material had
been consumed as determined by TLC. The mixture
was extracted with ethyl acetate (3 × 10 mL). The
combined organic extracts were washed by brine,
dried over Na2SO4, filtered, concentrated, and
purified by flash column chromatography on silica
gel (eluent: ethyl acetate/ petroleum ether) to give the
corresponding product 13.
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Acknowledgements
C.Z. is grateful for the financial support from Soochow
University, the National Natural Science Foundation of China
(Grant no. 21402134, 21722205), the Natural Science
Foundation of Jiangsu Province (Grant no. BK20140306), the
Project of Scientific and Technologic Infrastructure of Suzhou
(SZS201708), and the Priority Academic Program Development
of Jiangsu Higher Education Institutions (PAPD).
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10.1002/adsc.201701229
Advanced Synthesis & Catalysis
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10.1002/adsc.201701229
Advanced Synthesis & Catalysis
FULL PAPER
Distal Functional Group Migration for Visible-light
Induced
Carbo-difluoroalkylation/
monofluoroalkylation of Unactivated Alkenes
Adv. Synth. Catal. Year, Volume, Page – Page
Jiajia Yu,a,‡ Dongping Wang,a,‡ Yan Xu,a,‡ Zhen
Wu,a and Chen Zhua,*
8
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