Alternative Palladium-Catalyzed Vinylic C?H Difluoroalkylation of Ketene Dithioacetals Using Bromodifluoroacetate Derivatives

Article abstract of DOI:10.1002/adsc.201701554

A palladium-catalyzed cross-coupling of α-oxo ketene dithioacetals and bromodifluoroacetate derivatives has been developed for the synthesis of a class of CF₂-containing tetra-substituted olefins, which has potential to extend to drug design an

Full text of DOI:10.1002/adsc.201701554

Title: Alternative Palladium-Catalyzed Vinylic C–H Difluoroalkylation of
Ketene Dithioacetals Using Bromodifluoroacetate Derivatives
Authors: shuangquan tian, Xiaoning Song, Dongsheng Zhu, and Mang
Wang
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201701554
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10.1002/adsc.201701554
Advanced Synthesis & Catalysis
COMMUNICATION
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Alternative Palladium-Catalyzed Vinylic CH
Difluoroalkylation of Ketene Dithioacetals Using
Bromodifluoroacetate Derivatives
Shuangquan Tian,a Xiaoning Song,a Dongsheng Zhu,a,* and Mang Wanga,*
a
Jilin Province Key Laboratory of Organic Functional Molecular Design & Synthesis, College of Chemistry, Northeast
Normal University, Renmin Street 5268, Changchun 130024, P. R. China
e-mail: wangm452@nenu.edu.cn, zhuds206@nenu.edu.cn
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))
(Scheme 1, Previous work B).[7] Recently, copper-
Abstract. A palladium-catalyzed cross-coupling of -oxo
ketene dithioacetals and bromodifluoroacetate derivatives catalysed cross-coupling reactions between alkenes
has been developed for the synthesis of a class of CF2-
containing tetra-substituted olefins, which has potential to
extend to drug design and material application. The process
is proposed to involve two single electron transfer
processes accompanied by an alternative loop from
palladium(0) to palladium(I), likely due to unique structural
properties of ketene dithioacetals with ,-dialkylthiol
substituents on the olefin double bond.
and XCF2FG (FG: functional group) have
successfully been carried out (Scheme 1, Previous
work C).[8] Despite considerable progress in this field,
there are rare examples related to the
difluoroalkylation
of
tri-substituted
olefin
substrates.[6-8] In fact, the Csp2-H functionalization of
internal olefins has been an arduous problem in poly-
substituted olefin synthesis, especially in the
synthesis of fluorine-containing ones. Herein, we
wish to disclose a unique Pd-catalyzed Csp2-H
difluoroalkylation of ketene dithioacetals to provide a
facile route to CF2-containing tetra-substituted olefins.
An alternative Pd(0)/Pd(I) catalytic cycle pathway is
proposed likely due to unique structural properties of
ketene dithioacetals (Scheme 1, This work).
Keywords: cross-coupling; difluoroalkylation; ketene
dithioacetals; synthetic methods; tetra-substituted olefins
Poly-substituted
olefins
are
ubiquitous
in
pharmaceuticals, bioactive molecules, natural
products and functional materials.[1] Among them,
CF2-containing alkenes are notable examples due to
the particular value of the CF2 motif,[2] which is
considered a bioisostere of oxygen, sulfur and
carbonyl groups via increasing dipole moments or
enhancing the acidity of its adjacent groups.[3] For
instance, arginine vasopressin (AVP) shows
enormous potent affinity for recerptors,[4] and
talfuprost not only exhibits high compatibility to
receptors but also possesses potential for anti-
glaucoma drugs.[5] Consequently, many efforts have
been made to intruduce CF2-containing group onto
the olefins, among which transition-metal-catalyzed
Csp2-H difluoroalkylations of alkenes provide
efficient and direct route to these compounds. Zhang
and co-workers reported in 2015 a palladium-
catalyzed Heck-type reaction of alkenes with ethyl
bromodifluoroacetate for the construction of
difluoroalkylated olefins (Scheme 1, Previous work
A).[6a] A catalytic cycle from Pd(0) to Pd (II) via
Pd(I) was recognized as the key procedure in their
reactions. In addition, the difluoroalkylation of
alkenes has been developed through visible-light-
induced reactions using Ru, Ir or Au catalysts
Scheme
halodifluoroacetate derivatives
1.
Cross-coupling
of
alkenes
with
-Oxo ketene dithioacetals are a kind of special
internal alkenes. The push-pull electronic effects of
the two -alkylthio groups and the -carbonyl make
the carbon carbon double bond highly polarized,
which endows them unique reactivity and wide
1
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10.1002/adsc.201701554
Advanced Synthesis & Catalysis
utilizations in synthesis.[9] During our continuing
research on the synthesis of multi-substituted alkenes
from ketene dithioacetals under the catalysis of
transition metal,[10] we recently focused on their -C-
H difluoroalkylation using bromodifluoroacetate
derivatives. We started our investigation by reacting
1-(1,3-dithiolan-2-ylidene)propan-2-one (1a) with
ethyl bromodifluoroacetate (2a) under the catalysis of
Pd. Delightfully, upon treatment of 1a with 1.2 equiv
of 2a in the presence of 5 mol % Pd(PPh3)4 and 2.0
equiv of K2CO3 in 1,4-dioxane at 80 °C, the desired
cross-couplings based on the C-S bond cleavage of
ketene dithioacetals[10] usually made the reaction
complex. 3u-y were often obtained in poor yields.
Further screening of the reaction conditions could not
improve the reaction. Additionally, 1 with six
membered ring backbone also afforded 3z in good
yield.
Table 1. Optimization of the Reaction Conditions[a]
ethyl
3-(1,3-dithiolan-2-ylidene)-2,2-difluoro-4-
oxopentanoate (3a) could be obtained in 49% yield,
based on it’s NMR and MS analysis (entry 1, Table
1). Besides Pd(PPh3)4, other Pd catalysts, including
Pd2(dba)3, Pd(dba)2, PdCl2(PPh3)2, PdCl2(PhCN)2,
PdCl2(dppe), PdCl2(dppp) or a combination of PdCl2
and dppf as external ligand (entries 2-8, Table 1),
could also catalyse the reaction, among which the
yield of 3a reached 69% in the presence of 5 mol%
PdCl2(dppp) (entry 7, Table 1). A base screening
revealed that K2CO3 remained the best choice in our
case (entries 9-13, Table1). A screen of other solvents
revealed that 1,4-dioxane at 80 °C could provide
somewhat more efficiency (entry 7 versus entries 14-
18, Table 1). The yield of 3a was raised to 75% by
increasing the amounts of BrCF2CO2Et to 2.0
equivalents (entry 19, Table 1). As illustrated in table
1 (entries 20 and 21), the reaction gave higher yield at
120 °C, but led to inferior results with substrate
remaining at low temperatures. A control experiment
verified the requirement of PdCl2(dppp), K2CO3
(entries 22 and 23, Table 1).
Entry
[Pd] (x mol %)
Base
solvent
Yield
(%)[b]
1
2
3
4
5
6
7
8
Pd(PPh3)4 (5)
Pd2(dba)3 (2.5)
Pd(dba)2 (5)
K2CO3
K2CO3
K2CO3
K2CO3
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
49
36
32
35
42
40
69
60
PdCl2(PPh3)2 (5)
PdCl2(PhCN)2 (5) K2CO3
PdCl2(dppe) (5)
PdCl2(dppp) (5)
K2CO3
K2CO3
K2CO3
PdCl2 (5), ddpf
(7.5)
PdCl2(dppp) (5)
9
NEt3
dioxane
dioxane
dioxane
dioxane
dioxane
CH3CN
THF
5
10
11
12
13
14
15
16
17
18
PdCl2(dppp) (5)
PdCl2(dppp) (5)
PdCl2(dppp) (5)
PdCl2(dppp) (5)
PdCl2(dppp) (5)
PdCl2(dppp) (5)
PdCl2(dppp) (5)
PdCl2(dppp) (5)
PdCl2(dppp) (5)
PdCl2(dppp) (5)
PdCl2(dppp) (5)
PdCl2(dppp) (5)
---
K3PO4
KF
63
trace
50
With an active catalyst in hand and reliable
conditions identified for this Pd-catalyzed reaction,
we studied the scope of ketene dithioacetals. In
general, a variety of ketene dithioacetals could react
with 2a to give the corresponding cross-coupling
products. As described in Table 2, 1a-e, bearing acyl,
ester, amide, and cyano substituents at the α-position,
could afford the desired 3a-e in excellent yields. By
Cs2CO3
Na2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
---
trace
26
61
DMF
7
DMSO
toluene
dioxane
dioxane
dioxane
dioxane
dioxane
trace
27
comparison, α-benzoyl ketene dithioacetals
1
required more amount of Pd catalyst (7.5 mol%
PdCl2(dppp)) along with longer reaction time (12 h)
for good conversion. Among them, -benzoyl ketene
dithioacetals bearing electron-donating R on the
phenyl ring afforded the desire 3g, 3h, and 3l in high
yields, respectively, while those with electron-
deficient R on the phenyl ring gave 3i-k, and 3n in
lower yields. By comparison, substrates 1 with an
ortho-substituent on the phenyl ring gave 3o-q in
poor to moderate yields. Gratifyingly, the successful
formation of 3k, 3m and 3p with an intact bromide
also highlighted the advantage of the present reaction.
Furthermore, furanyl-bearing and 2-naphthyl-bearing
substrates also afforded the corresponding products
3s and 3t in acceptable yield, respectively. In the case
of piperonyl-containing substrate, 3r was isolated in
36% yield accompanied by substrate residues. When
acyclic ketene dithioacetals reacted with BrCF2CO2Et
under the identical reaction conditions, potential
19[c]
75
20[c,d]
21[c,e]
22[c,e]
95
98 (96)[f]
n.d.[g]
PdCl2(dppp) (5)
n.d.[g]
23[c,e]
[a]
Reaction Condition: 1a (0.5 mmol), base (1.0 mmol),
[Pd] (x mol %), BrCF2CO2Et (1.2 equiv), solvent (2.5
mL), 80 oC, 12 h.
[b]
Determined by 1H NMR spectroscopy using 1,3,5-
trimethoxybenzene as an internal standard.
[c] BrCF2CO2Et (2.0 equiv).
[d] 100oC.
[e] 120oC, 6 h.
[f] Isolated yield.
[g] Not detected.
2
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10.1002/adsc.201701554
Advanced Synthesis & Catalysis
Table 2. Pd-catalyzed C-H difluoroalkylation of ketene
investigated the performances of other difluoroalkyl
bromides in this catalytic system, including,
BrCF2Het (Het = 2-benzo[d]oxazole), BrCF2COPh,
and BrCF2PO(OEt)2. To our delight, BrCF2COPh and
BrCF2Het (Het = 2-benzo[d]oxazole) could couple
with 1a to afford the corresponding products in 49%
and 28% yields, respectively. However, only trace
amount of the desired product are detected in the Pd-
catalyzed reaction of BrCF2PO(OEt)2 and 1a under
the identical reaction conditions.
dithioacetals using BrCF2FG[a]
Interestingly, when we selected -carbamoyl
ketene dithioacetals 1aa-ae as the substrates to couple
with BrCF2CO2Et under the identical Pd-catalysis,
gem-difluorosuccinimides 5 were directly isolated in
59-88% yields, as shown in table 3, likely via Pd-
catalyzed cross-coupling and further cyclization.
Succinimides are a class of important natural product
skeleton and widely found in alkaloids or drug
molecules.[12] Here, we provided an efficient route to
these compounds having the CF2 motif, which would
have potential use in medicine chemistry and
biological chemistry.
Table 3. Pd-catalyzed cross-coupling-cyclization of -
carbamoyl ketene dithioacetals with BrCF2CO2Et.[a]
[a]
Reaction Condition: 1 (0.5 mmol), PdCl2(dppp) (5
mmol%), K2CO3 (1.0 mmol), BrCF2FG (1.0 mmol), 1,4-
dioxane (2.5 mL), 120 oC, 6 h, isolated yields.
[b] 12 h.
[a]
Reaction Condition: 1 (0.5 mmol), PdCl2(dppp) (7.5
mmol%), K2CO3 (1.5 mmol), BrCF2CO2Et (1.5 mmol),
1,4-dioxane (2.5 mL), 120 oC, 24 h, isolated yields.
[c]
PdCl2(dppp) 7.5 mol%, K2CO3 (1.5 mmol), BrCF2FG
(1.5 mmol), 12 h.
[d]
1H NMR yield by using 1,3,5-trimethoxybenzene as
Zhang and his co-workers[6] reported that Pd-
catalyzed cross-coupling of mono- or di-substituted
alkenes with bromodifluoroacetate likely underwent a
Pd0/PdI/PdII catalytic cycle (Scheme 1, Previous work
A), involving a single transfer process followed by a
Heck-type reaction. Tri-substituted alkene substrates
were proved to be difficult to complete the coupling
process in their work. By comparison, we realized the
cross-coupling reactions between ketene dithioacetals,
internal standard.
PdCl2(dppp) 7.5 mol%, K2CO3 (2.0 mmol), BrCF2FG
(3.0 mmol), 12 h.
Pd(PPh3)4 15 mol%, K2CO3 (1.5 mmol), BrCF2FG (1.5
[e]
[f]
mmol), 15 h.
[g]
Pd(PPh3)4 7.5 mol%, K2CO3 (1.5 mmol), BrCF2FG (1.5
mmol), 12 h.
Encouraged by the above results, we extended the
coupling partner from bromodifluoroacetate to
bromodifluoroacetamides. It was found in Table 2
that tertiary amides 2b-d could couple with 1a to
afford 4a-c in 65-73% yields, respectively, with
Pd(PPh3)4 as the catalyst. The structure of product 4c
was further identified by its X-ray.[11] Then, we
a
kind
of
tri-substituted
alkenes,
and
bromodifluoroacetate derivatives under the palladium
catalyst. The gigantic steric hindrance of the olefin
substrates resulting from the gem-dialkylthiol
substituents may lead to an alternative catalytic
pathway. On the basis of the structural features of the
3
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10.1002/adsc.201701554
Advanced Synthesis & Catalysis
ketene dithioacetals[9] and a known catalytic cycle
from Pd(I) to Pd(0),[13] two single electron transfer
(SET) process was suggested for our present
reactions. As shown in Scheme 2A, first SET from
[Pd0] to BrCF2COR generates a free difluoroacetyl
radical and [XPdI] species.[6a,14] Subsequently, the
resulting radical reacts with electron-rich olefins to
deliver radical A[15] along with the formation of a new
C-CF2CO2R bond. At this moment, the coupling of
radical A with [PdI] leading to Pd-C intermediate C
seems difficult due to the steric hindrance.[6a] Thus, a
second SET pathway may generate cation B[15]
accompanied with the reduction of [XPdl] to [Pd0] for
the next catalytic cycle. After the abstraction of a
proton with the base, the cation B delivers
difluoroalkylated product 3.[15a] In the case of the
substrates carrying an -amido group, further
To highlight the synthetic potential of our approach,
the Pd-catalyzed desulfitative cross-coupling of 3u
with phenylboronic acid was first investigated in the
presence
of
copper(I)-thiophene-2-carboxylate
(CuTC).[17] To our delight, gem-diphenyl alkene 6
was isolated from the reaction mixture in 61% yield
(Scheme 2, Eq. 1). Additionally, upon treatment of 3a
with POCl3 in DMF, the chlorovinyl-substituted
ketene dithioacetal 7 was afforded in high yield via
an enolation-chlorination sequence of the acetyl of 3a
under Vilsmeier-Haack reaction conditions (Scheme
2, Eq. 2).[18]
cycloamidations
yield
gem-difluorosuccinimide
derivatives 5 as the final products (Table 3). In fact,
the suggested intermediate B is reasonable due to its
stability resulted from the two alkylthiol groups of
ketene dithioacetals.[9] Many transformations based
on this type of cation are known.[9,10a,15,16] Thus, the
efficient formation of B is likely another key factor
which leads to a different catalytic pathway. Control
experiments using radical scavengers support the
radical process of the above conversion (Scheme 2B).
However, we can not exclude the Pd0/PdI/PdII
catalytic cycle at this stage.
Scheme 3. Further transformations of 3.
In summary, we have achieved a series of CF2-
containing tetra-substituted olefins from the cross-
coupling reaction of readily available ketene
dithioacetals with bromodifluoroacetate derivatives
under the catalysis of palladium. The reaction
proceeds with good functional group compatibility
and broad substrate scope. Different from the known
palladium-catalyzed Heck-type reaction of alkenes
with fluoroalkyl bromides, unique structural
characters of -oxo ketene dithioacetals likely
enables an alternative Pd(0)/Pd(I) catalytic cycle.
Further investigations on the reaction mechanism and
applications of the method are in progress in our
group.
Experimental Section
Typical Procedure
To a dried Schlenk flask, ketene dithioacetals 1a (0.5
mmol), PdCl2(dppp) (5% mmol), and K2CO3 (1.0 mmol)
were added under air atmosphere. After evacuated and
refilled with nitrogen 3 times, 1,4-dioxane (2.5 mL),
BrCF2CO2Et 2a (1.0 mmol) was added in one portion to
the mixture by syringe. The resulting mixture was stirred at
120 ºC for 6 h. After cooling to room temperature, the
reaction mixture was diluted with 5 mL of ethyl acetate
and filtered through a plug of celite, followed by washing
with 10-20 mL of ethyl acetate. Then, the combined filtrate
was washed by brine (20 mL), dried over anhydrous
MgSO4, and concentrated under reduced pressure to yield
the crude product, which was purified by silica gel
chromatography (petroleum ether/ethyl acetate: 30/1, v/v)
to give 3a (136.8 mg, 97%) as a yellow oil.
Scheme 2. Tentative reaction mechanism and radical
scavenger experiment.
The above cross-coupling reactions provide an
efficient route to CF2-containing tetra-substituted
alkenes. Importantly, furhter modifications of these
poly-functionalized alkene products are forseeable.
Acknowledgements
4
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10.1002/adsc.201701554
Advanced Synthesis & Catalysis
We thank National Natural Sciences Foundation of China
(NNSFC-21372040 and 21672032) for funding support of this
research.
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Min, X.-G. Zhang, Synthesis 2015, 47, 2912-2923. c) Z.
Feng, Y.-L. Xiao, X.-G. Zhang, Org. Chem. Front.
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Advanced Synthesis & Catalysis
COMMUNICATION
Alternative Palladium-Catalyzed Vinylic C
Difluoroalkylation of Ketene Dithioacetals
Using Bromodifluoroacetate Derivatives
H
Adv. Synth. Catal. Year, Volume, Page – Page
Shuangquan Tian, Xiaoning Song, Dongsheng
Zhu,* and Mang Wang*
7
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