Synthesis of remote fluoroalkylated alkenes by a palladium-catalyzed relay Heck-type reaction

Article abstract of DOI:10.1039/c9cc10048b

Herein, we report a palladium-catalyzed relay Heck-type reaction of fluoroalkyl bromide and terminal alkenes. The reaction involves fluoroalkylation of alkenes and migration of double bonds via a 1,5-hydrogen atom transfer strategy. Through this method, a

Full text of DOI:10.1039/c9cc10048b

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DOI: 10.1039/C9CC10048B
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Synthesis of Remote Fluoroalkyated Alkenes by Palladium-
Catalyzed Relay Heck-Type Reaction
Received 00th January 20xx,
Accepted 00th January 20xx
Lixin Li,*a Zhengguang Zhao,a Jing Xu,*a Haotian Luo,a Yong Li,a Xiantao Ma,a Lin Tang,a Bo Ren,a
Xinhua Caoa and Yan-Na Mab
DOI: 10.1039/x0xx00000x
Herein, we report a palladium-catalyzed relay Heck-type reaction under visible light condition were also developed. To the best
of fluoroalkyl bormide and terminalalkenes. The reaction involves of our knowledge, however, only vicinal fluoroalkyated alkenes
fluoroalkylationof alkenes and migrationof double bondsvia 1,5- can be obtained through these methods. To date, transition-
hydrogen atom transfer strategy.Through this method, a series of metal-catalyzed Heck-type reaction for the synthesis of remote
remote fluoroalkylated alkenes were obtainedunder mild fluoroalkyl alkenes remains a great challenge.
conditions.
Scheme 1 Methods for the synthesis of fluoroalkyl alkenes
a) Synthesis of vicinal fluoroalkyl alkenes
Fluoroalkyl
groups
have
profound
impact
on
physicochemical and biological properties, that exhibits to
improve the absorption, distribution, metabolism, and
excretion properties of compounds in the drugs
discovery.[1]Therefore, the introduction of fluoroalky groups
into organic molecules has attracted considerable research
attention. Fluoroalkyl alkenes are useful building blocks for the
synthesis of a wide range of fluorinated compounds.[2] Many
strategies have been developedin the past decade: in
1) Pd/Xantphos
Rf
vicinal fluoroalkyl alkenes
"Rf" Source
R
R
2) Cu/amine
3) Ir or Ru, hv
Rf source: Togni, Umemoto's regent, Rf-Br etc.
b) Remote C-H functionalization via 1,5-HAT strategy
H
X
1) Cu/Ni-catalyed
DG
DG
R
2) Ir or Ru, hv
R
particularly
transition-metal
catalyzed
direct
C-H
DG = RN-H, RN-F, double bond etc.
X = C, N, O etc.
fluoroalkylation of alkenes[3] has emerged as a powerful tool
for the synthesis of corresponding fluoroalkylated alkenes
(Scheme 1, a). For example, Buchwald[4] and Cho[5] groups
reported the synthesis of trifluoromethyl alkenes with Togni,
Umemoto’s reagent and CF3X as CF3 sources. Furthermore,
inexpensive and commerciallyavailable fluoroalkyl halides[6]
have also been exploited in the Heck-type reaction, which
appears to be an appealing and straightforward pathway for
the synthesis of fluoroalkyl alkenes. Zhang’s groups realized
c) This work
H
Pd/Xantphos
Rf-Br
Rf
Ar
Ar
remote fluoroalkyl akenes
PdLn
1) Radical addition
Rf
2) 1,5-HAT then
trapped by Pd(I)
-H elimination
Ar
Int-I
 High C-H site selective  Mild reaction condition via Pd(0)/Pd(I)/Pd(II) pathway
the
synthesis
of
fluoroalkylated
alkenes
by
Palladium/Xantphos catalyzed Heck-type reaction of
fluoroalkyl bromides. [7]Subsequently, Wang and coworkers
reported C-H difluoroalkylation and perfluoroalklation of
alkenes and hetero-arenes via Cu-PMEDA catalyst system.[8] In
addition, the Ir- or Ru-catalyzed fluoroalkylation of alkenes[9]
Over the past years, 1,5-hydrgogen atom transfer (HAT) has
been proven as
a powerful strategy for the remote
functionalization of inert C(sp3)-H bonds and construction of
structurally diverse compounds (Scheme 1, b).[10] Various
functional groups have been introduced into target molecules
efficiently to realize C-O, C-C, C-N and C-X bond formation
under mild conditions. Base on the fact, our group[11]
developed photoredox-catalyzed remote difunctionalization of
alkenes for synthesisof fluoroalkyl ketones via 1,5-HAT
strategy. Therefore, we envisioned that 1,5-HAT strategy could
be used into relay Heck-type reaction to construct the remote
fluoroalkylated alkenes (Scheme 1, c). First, the addition of
fluoroalky radical to alkenes which is initiated by [Pd(0)Ln]
a. College of Chemistry and Chemical Engineering, Xinyang Normal University,
Xinyang, Henan 464000, China.lilixin@xynu.edu.cn, xujing@xynu.edu.cn
b. College of Chemistry and Chemical Engineering, Henan Normal University,
Xinxiang, Henan 453007, China.
† Footnotes relating to the title and/or authors should appear here.
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
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produces an alkyl radical.Subsequently a key benzyl radical is supporting information), and the best yield was observed
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DOI: 10.1039/C9CC10048B
formed via 1,5-HAT, which can be trapped by [Pd(I)Ln] to when K2CO3was used. Only trace of desired product was
provide the key alkyl-palladium species Int-I. Finally, Int-I obtained when the reaction temperature was reduced to room
undergos β–hydride elimination to deliver the desired remote temperature (Table1, entry 14). Notably, It should be noticed
fluoroalky alkenes.
Table 1Optimization of the reaction conditions
that the result of this relay Heck-type reaction was messy
under 12 W blue LED and only trace amount of 3aa was
obtained (Table1, entry 15). This result revealed that Pd-
catalyzed Heck-type reaction under thermal conditions has
distinct difference compared with visible light-irradiated
condition.
[Pd] (5 mol%), ligand (10 mol%)
K2CO3 (2.0 equiv) , solvent, 80 o
CO2Et
CO2Et
C
CF2CO2Et
CO2Et
1a
CO2Et
BrCF2CO2Et (2a)
3aa
Entry
1
[Pd]/Ligand
Solvent
THF
Yield(%)[b]
37
Scheme 2 Scope of Alkenes[a]
Pd(PPh3)2Cl2/ Xantphos
Pd(PPh3)2Cl2/ Xantphos
Pd(PPh3)2Cl2/ Xantphos
Pd(PPh3)2Cl2/ Xantphos
Pd(PPh3)2Cl2/ Xantphos
Pd(PPh3)2Cl2/ Xantphos
Pd(PPh3)2Cl2/ Xantphos
Pd(CH3CN)2Cl2/Xantphos
Pd2(dba)3/ Xantphos
[Pd(allyl)Cl]2/ Xantphos
Pd(TFA)2/ Xantphos
Pd(PPh3)2Cl2 (5 mol%)
R
R
R
R
Xantphos(10 mol%)
K2CO3 (2.0 equiv), CH3CN, 80 o
2
DCE
33
Rf
C
Ar
Ar
BrCF2CO2Et (2a)
3
DCM
48
1
Rf = CF2CO2Et
CO2Et
3
4
Dioxane
CH3CN
PhCH3
MeOH
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
39
3aa, R = H, 71%;
3ba, R = 2-F, 72%
CO2Et
CO2Et
MeO
R
3ca, R = 2-Cl, 66%; 3da, R = 3-F, 70%
3ea, R = 3-Cl, 67%; 3fa, R = 3-Br, 65%
3ga, R = 4-F, 73%; 3ha, R = 4-Cl, 76%
3ia, R = 4-Me, 82%; 3ja, R = 4-MeO, 78%
Rf
CO2Et
5
72
Rf
6
33
OMe
3ka, 70%
7
NR[c]
37
CO2Et
CO2Et
CO2Et
CO2Me
CO2Me
Rf
8
CO2Et
MeO
Rf
Rf
O
9
30
O
3la, 72%
3ma, 67%
3na, 69%
10
11
12
13
14[d]
15[e]
20
O
O
CO2Et
CO2Et
25
Rf
O
Rf
Rf
Pd(PPh3)4/ Xantphos
Pd(PPh3)2Cl2/ DPEphos
Pd(PPh3)2Cl2/ Xantphos
Pd(PPh3)2Cl2/ Xantphos
42
Rf
S
Ph
3pa, 62%[b]
3qa, trace
3oa, 67%
22
trace
trace
CO2Et
CO2Et
CO2Et
Rf
O
N
CO2Et
Ph
Rf
Rf
[a] Reaction condition: 1a (0.1 mmol), 2a (0.2 mmol), [Pd] (5 mol %), ligand
(10 mol%), Base (0.2 mmol),solvent (1.0 mL), under N2, 80oC, 24h. [b] Yield
determined by 19F NMP using PhCF3 as an internal standard. [c] NR = no
reaction [d] at 25 oC. [e] Under 12 W blue LED.
3ra, NR
3sa, trace
3ta, NR
[a] Reactions were performed on a 0.2mmol scale under standard
conditons, and isolated yields are given. [b] BrCF2CO2Et (0.4 mmol).
With the optimized conditions in hand, we explored the
substrate scope of alkenes with different substituents (Scheme
2). Firstly, a series of alkenes bearing different substituents on
the remote aromatic ring were examined (Scheme 2, 3aa–3la),
which revealed that electron-withdrawing group (-F, -Cl, -Br)
and electron-donating group (-Me, -OMe) at both the ortho,
meta, and para position of aromatic ring were all suitable for
this transformation, and the reaction proceeded smoothly to
provide corresponding products in moderate to good yields. It
is noteworthy that the bromide group can also be tolerated to
avoid that oxidative addition of Pd(0) species (Scheme 2, 3fa).
The desired product 3ka was obtained in 70% yield whenthe
remote aromatic rings contains two substituents. The
heterocycle substituted alkene was also subjected to the
reaction conditions to affoard the target product 3la in 72%
yield. When a carbonyl-containing functional group was
introduced into aromatic ring, 3ma was obtained in 67% yield.
Switching gem-substituent from ethyl ester to methyl ester
groups on the aliphatic chain was well accommodated in this
transformation to furnish the corresponding product 3na in 69%
yield. Additionally, when the substituent was carbonate ester,
the product 3oa was also produced in 67% yield. To our
surprise, two fluoroalkyl groups were introduced when 1-allyl-
2-ethylbenzene was used as substrate and the desired product
To validate our hypothesis, we commenced our study by
attempting the proposed relay Heck-type reaction between
diethyl
2-allyl-2-phenethylmalonate
(1a)
and
ethyl
bromodifluoroacetate (2a) with Pd(PPh3)2Cl2 as catalyst,
o
tetrahydrofuran (THF) as solvent, K2CO3 as base under 80 C.
Studies of the reaction parameters revealed that reaction
efficiently run is highly dependent on the phosphine ligands.
No reaction occurred when other phosphine ligands except
Xantphos and DPEphos (see supporting information), which is
contributed to the large bite angle of bidentate phosphine
Xanthphos when binds with palladium.[7a] To our delight, when
Xantphos was used as ligand under the above conditions, the
desired product 3aa was obtained in 37% yield (Table1, entry
1). Encouraged by these results, a series of solvents were
examined, which revealed that CH3CN was the best choice and
3aa was gained in 72% yield, Presumably, CH3CN can be as
ligand to stabilize the palladium complex (Table1, entry 1-7). It
should be pointed out that no reaction occurred when
protonic solvent MeOH was used. The yields of 3areduced
dramatically when the pre-Pd catalyst was swtiched from
Pd(PPh3)2Cl2 to other palladium catalyst (Table 1, entry 9-12).
The species of base also influenced the reaction efficiency,
various inorganicbase and organic base were optimized (see
2 | J. Name., 2012, 00, 1-3
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3pa was obtained in 62% yield (Scheme 2). No reaction corresponding product was obtained in 67% yieVldiewuAnrtdicelerOntlhinee
DOI: 10.1039/C9CC10048B
occurred or trace product was observed when heterocycles standard conditions (Scheme 5).
such as indole-, thiophene- and1-naphthalene alkene( Scheme Scheme 5 Gram-Scale Reaction for the Synthesis of 3aa
Pd(PPh3)2Cl2 (5 mol%)
2, 3qa–3sa) were used as substrate respectively. The internal
CO2Et
CO2Et
Xantphos(10 mol%)
CF2CO2Et
K2CO3 (2.0 equiv), CH3CN, 80 o
C
alkene was also not suitable to this reaction because steric
effect (see supporting information).
CO2Et
CO2Et
BrCF2CO2Et (2a, 6 mmol)
3aa, 67%
1a, 3 mmol
Next, we studied different fluoroalkyl sources (Scheme 3). As
expected, the bromodifluoroacetamide derivatives could also
be subjected for the palladium-catalyzed relay Heck-type
reaction, particularly naked bromodifuoroacetamide, to give
corresponding products in moderate yields (3ab-3af). It is
noteworthy that monofluoroalkyl bromide was also suitable
for this transformation under the optimal reaction conditions
and generated product 3ag in 43% yield. The desired product
3ah was obtained in 76% yield when methyl
bromodifluoroacetate was used. Additionally, perfluorohexyl
and perfluorooctyl bromides could also be used into this
reaction to produce desired products in moderate yields
(Scheme 3, 3ai, 3aj) (see supporting information).
To gain insight into the reaction mechanism, some control
experiments were conducted (scheme 6). First, the radical
scavenger 2,2,6,6-tetramethyl-1-piperidinoxyl (TEMPO, 4.0
equiv) was added to the standard reaction system, which
completely inhibited the reaction. Instead of forming 3a, the
radical adduct TEMPO-CF2CO2Et 4 was detected by HRMS
(scheme 6, 1). Furthermore, ethyl 2-(4-phenyl-3,4-
dihydronaphthalen-1-yl)acetate 6 and ethyl 2,2-difluoro-4,4-
diphenylbut-3-enoate 8 were detected by HRMS when (1-(2-
phenylcyclopropyl)vinyl)benzene 5and 1,1-diphenylethene7
were explored as the radical trapping agents, respectively
(scheme 6, 2). The results suggested that •CF2CO2Et may be
existed during the reaction, and participated in relay Heck-type
reaction.
On the basis of the results mentioned above and previous
report, a plausible mechanism was proposed (Scheme 6, 3).
First, the fluoroalkyl radical generates by Pd(0)/Xantphos
complex through single electron transfer (SET) with BrCF2CO2Et
and at the same time forms a Pd(I) species. Subsequently
addition of the fluoroalkyl radical to the double bond produces
alkyl radical Int-III. Then a more stable benzyl radical Int-II is
formed via 1,5-HAT. At this point, Int-II is trapped by Pd(I)
species to afford a new Pd-alkyl species, which undergoesβ-H
elimination to give the desired product 3aa. With the
assistance of base, the Pd-H species is transformed to Pd(0) to
achieve the catalyst cycle.
Scheme 3 Scope of Fluoroalkyl Sources[a]
Pd(PPh3)2Cl2 (5 mol%)
CO2Et
CO2Et
Xantphos(10 mol%)
K2CO3 (2.0 equiv), CH3CN, 80 o
C
Rf
Ph
Ph
CO2Et
CO2Et
Rf-Br (2)
1
3
CO2Et
CO2Et
F
F
nPr
CO2Et
F
F
CO2Et
F
H
N
N
NPh
Ph
nPr
Ph
Ph
CO2Et
3ad,62%
CO2Et
F
O
O
O
3ab, 45%[b]
3ac, 55%
CO2Et
Rf
CO2Et
F
O
CO2Et
CO2Et
F
NBoc
Ph
CO2Et
N
N
Ph
Ph
3ag, Rf = CHFCO2Et, 43%
3ah, Rf = CF2CO2Me, 76%
3ai, Rf = C6F13, 45%c
CO2Et
F
F
O
O
3ae, 59%
3af 56%
3aj, Rf = C8F17, 38%c
[a] Reaction were performed on a 0.2mmol scale under standard conditions,
and isolated yields are given. [b] Rf-Br (0.3 mmol). [c] Yield determined by
19F NMP using PhCF3 as an internal standard.
Scheme 6 Control Experiments and Proposed Mechanism
1)
EtO2C CO2Et
EtO2C CO2Et
standard condition
N
O
Rf
Scheme 4 Reaction of Alkenyl Alcohol 1b
Ph
2)
Ph
TEMPO (4.0 equiv)
O
1a
3aa, No Detect
4
CF2CO2Et
280.1739 by HRMS
Pd(PPh3)2Cl2 (5 mol%)
Xantphos(10 mol%)
HO
O
O
Rf
K2CO3 (3.0 equiv), CH3CN, 80 o
C
Ph
CF2CO2Et
BrCF2CO2Et (3.0 equiv)
O
OH
Rf
standard condition
Ph
1o'
Ph
Ph
3oa, 52%
Ph
Ph
5
7
6
Ph
O
O
3) Proposal Mechanism
BrCF2CO2Et
R
2a
CF2CO2Et
Ph
Rf
1o
Ph
R
Int-III
Int-II
Pd(0)
1,5-HAT
Interestingly, when 2-allyl-2-phenethylpropane-1,3-diol (1o')
Base
R
R
was used as substrate, the remote difluoroalky alkene
containing cyclic carbonate structure was obtained in 52%
yield (Scheme 4). In this process,[12] consecutive nuclephilic
acyl substitution reaction occurred between hydroxyl groups
and ethyl bromodifluoroacetate, ethoxy group and -CF2Br act
as leaving group in the formation of 1o, then undergo relay
Heck-type reaction to give the desired product in one pot.
To examine the practicality of this method, a gram-scale
reaction was explored between 1a and 2a, and the
Pd(I)X
Rf
Ph
HPd(II)X
-H
elimination
3aa
Pd(II)X
R
Rf
Ph
R
Int-I
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J. Name., 2013, 00, 1-3 | 3
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10 For selected reviews of 1,5-HAT strategy, see (a) S. Chi, and H.
In summary, we have developed a protocol for palladium-
catalyzed relay Heck-type reaction of fluoroalkyl bromides to
synthesize remote fluoroalkyl alkenes via 1,5-HAT strategy.
This method provides a direct way for highly site selective
remote C-H activation and highly efficient access to 1,5-
fluoroalkyl alkenes in moderate to good yields. Further
investigation of remote functionalization of alkenes via 1,5-
HAT strategy with [Pd/Xantphos] complex through a SET
pathway is underway in our laboratory.
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Chen, Org. Biomol. Chem., 2014, 12, 4051; b) W. Li, W. Xu, J.
Xie, S. Yu and C. Zhu, Chem. Soc. Rev., D2O01I:81,04.1703, 96/5C49.CC10048B
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Org. Lett., 2019, 21, 9228; (b) L. Li, Y. Li, Z. Zhao, H. Luo and Y.-
N. Ma, Org. Lett., 2019, 21, 5995.
Conflicts of interest
There are no conflicts to declare.
Acknowledgements
The authors are grateful for the financial support from the
National Natural Science Foundation of China (21801065,
21602190), Foundation of Henan Province Department of
Science and Technology (192102310031, 172102210456).
Notes and references
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