Copper-Catalyzed 1,6-Hydrodifluoroacetylation of para-Quinone Methides at Ambient Temperature with Bis(pinacolato)diboron as Reductant

Article abstract of DOI:10.1002/adsc.201600991

An original and efficient copper-catalyzed 1,6-hydrodifluoroacetylation of para-quinone methides with difluoroalkyl bromides has been described with bis(pinacolato)diboron (B₂pin₂) as reductant. In this reaction, a new C(sp³)–CF₂bond is constructed under smart conditions. A broad substrate scope of para-quinone methides (p-QMs) make this protocol very practical and attractive. Preliminary mechanistic studies manifested that a difluoroalkyl radical pathway was involved in this reaction. Also the presence of the diboron reagent was an essential requisite in this transformation. (Figure presented.).

Full text of DOI:10.1002/adsc.201600991

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DOI: 10.1002/adsc.201600991
Very Important Publication
Copper-Catalyzed 1,6-Hydrodifluoroacetylation of para-Quinone
Methides at Ambient Temperature with Bis(pinacolato)diboron
as Reductant
a
a,
Miaolin Ke and Qiuling Song *
a
Institute of Next Generation Matter Transformation, College of Chemical Engineering, College of Materials Science &
Engineering at Huaqiao University, Fujian, Peopleꢀs Republic of China
Fax : (+86)-592-616-2990; e-mail: qsong@hqu.edu.cn
Received: September 7, 2016; Revised: November 28, 2016; Published online: && &&, 0000
Supporting information for this article can be found under: http://dx.doi.org/10.1002/adsc.201600991.
Abstract: An original and efficient copper-catalyzed
,6-hydrodifluoroacetylation of para-quinone me-
mation, the incorporation of a difluoromethyl group
into diverse skeletons to construct a new C(sp )–CF2
3
1
thides with difluoroalkyl bromides has been de-
scribed with bis(pinacolato)diboron (B pin ) as re-
bond is underdeveloped. To the best of our knowl-
edge, there are only very few examples on this topic.
For instance, photoredox catalysts (Ir and Ru) were
reported to promote fluoroalkylation of alkenes to
2
2
3
ductant. In this reaction, a new C(sp )–CF bond is
2
constructed under smart conditions. A broad sub-
strate scope of para-quinone methides (p-QMs)
make this protocol very practical and attractive.
Preliminary mechanistic studies manifested that a di-
fluoroalkyl radical pathway was involved in this re-
action. Also the presence of the diboron reagent
was an essential requisite in this transformation.
3
[14,15]
render C(sp )–CF bond formation (Scheme 1a).
2
However, the alkenes were limited to aliphatic termi-
nal alkenes. Compared to photoredox catalysts, the
3
examples of constructing C(sp )–CF bonds via transi-
2
[
16,17]
tion metal catalysts are very scant.
In 2014, Hao
and co-workers reported a stoichiometric Ag salt-
mediated fluoroalkylation of alkenes rendering the
3
Keywords: bis(pinacolato)diboron (B pin ); hydro-
formation of new C(sp )–CF bonds, once again, only
2
2
2
difluoroacetylation; para-quinone methides (p-
QMs); radical pathway
aliphatic terminal alkenes were applicable under the
conditions with a stoichiometric oxidant required for
[
17b]
the success of the transformation.
Therefore, it is
highly attractive yet very challenging to exploit new
catalytic systems for the incorporation of di- or mono-
The introduction of fluorine atoms into organic mole-
cules has attracted great attention because of the dra-
matic improvements in biological and physicochemi-
[
1–3]
cal properties of the parent molecules.
Among
them, the difluoromethylene group (CF ) can be re-
2
garded as a bioisostere for an oxygen atom, carbonyl
group and methylene group due to its excellent stabil-
ity in metabolism, and the electron-withdrawing prop-
[4]
erty. At the same time, the CF group also affects
2
the electronic property, chemical property and reac-
tion activity of substituents on its ortho position as
[5]
well. Therefore, enormous effort has been made for
the development of new synthetic methods for the in-
[
6,7]
corporation of the CF group into molecules.
2
In the past five years, the fluoroalkyl radical addi-
tion over a p acceptor has become one of the most
[
8–11]
straightforward methods to construct C–CF bond.
2
[
12,13]
Great advances have been achieved in this field.
2
However, compared to the prevailing C(sp )–CF for- Scheme 1. Difluoroalkylation of arylalkenes.
2
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3
fluoroalkyl groups into target molecules to construct oalkyl halides for the construction of C(sp )–CF2
3
new C(sp )–CF bonds with broad substrate scope, bonds and recovery of aromatization (Scheme 1c).
2
such as to multi-substituted arylalkenes. As an earth
Initially, we investigated the difluoroalkylation of
abundant, low toxic and cost-effective transition p-QMs 1 with bromide 2 as a benchmark reaction
metal, a Cu-catalyzed difluoroalkylation of alkenes with CuBr2 as catalyst, L1 as ligand, and B pin2
2
3
for the construction of C(sp )–CF bond has not yet (30 mol%) as reductant. Only target product 3 was
2
been reported (Scheme 1b). Recently, a novel and ef- obtained with 26% isolated yield with a bit of by-
ficient Cu/B pin2 [B pin =bis(pinacolato)diboron] product 4 (Table 1, entry 1). Interestingly, it was
2
2
2
[
18]
catalytic system was developed in our group.
By found that the yield (55%) of 3 was dramatically im-
comparison to conventional Cu catalysts, higher reac- proved with one equivalent of B pin . According to
2
2
tivity and potential practical value were merged and our previous work, B pin not only acted as a reduc-
2
2
[
10c,11c,d,18]
featured in this Cu/B pin catalytic system.
tant, but served as an activator of water to provide
para-Quinone methides (p-QMs), which are struc- protons. After an extensive screening of the cata-
2
2
[18]
turally characterized by the unique assembly of car- lysts (Table 1, entries 2–5), Cu(OAc) ·H O gave the
2
2
bonyl and olefinic moieties, are known as versatile best result (83% GC yield, 78% yield on isolation;
building blocks and widely used in the synthesis of Table 1, entry 4). Next, a screening of the ligands was
[
19,20]
natural products and bioactive molecules.
Fur- carried out (Table 1, entries 6–8), and it indicated that
thermore, to expand universality in Cu/B pin -cata- ligand L1 was optimal from the price point of view by
2
2
lyzed difluoroalkylation to a p acceptor, we envi- comparison of L1 with L3, furnishing 3 in 78% isolat-
sioned the feasibility of Cu/B pin -catalyzed difluor- ed yield (Table 1, entry 4). Furthermore, a series of
2
2
oalkylation of para-quinone methides with difluor- bases was tested (Table 1, entries 9–11), obviously,
[a]
Table 1. Optimization of the reaction conditions.
Entry
Catalyst
10 mol%)
Ligand
(10 mol%)
Base
(2 equiv.)
Solvent
(1 mL)
Yield [%]
(
3
4
[
b]
1
2
3
4
5
6
7
8
9
1
1
1
1
1
CuBr2
CuBr2
CuCl2
Cu(OAc) ·H O
CuBr
Cu(OAc) ·H O
Cu(OAc) ·H O
Cu(OAc) ·H O
Cu(OAc) ·H O
Cu(OAc) ·H O
Cu(OAc) ·H O
Cu(OAc) ·H O
Cu(OAc) ·H O
L1
L1
L1
L1
L1
L2
L3
L4
L1
L1
L1
L1
L1
L1
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
Na CO
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
toluene
26
55
60
83 (78)
81
39
83
67
65
83
15
89
88
trace
trace
trace
trace
trace
trace
trace
trace
trace
trace
32
2
2
2
2
2
2
2
2
2
2
2
3
0
1
2
3
4
K CO
2
2
2
3
NaOAc
K CO
2
2
trace
trace
trace
2
2
2
3
3
3
K CO
CH CN
2
2
2
3
[
c]
Cu(OAc) ·H O
K CO
2
CH CN
95(88)
2
2
3
[
a]
Reaction conditions: 1 (0.1 mmol), BrCF COOEt (2, 0.2 mmol), B pin (1 equiv.), catalyst (10 mol%), ligand (10 mol%),
2
2
2
base (2 equiv.), solvent (1 mL), under N for 16 h at 1008C.
2
[
[
b]
B pin (30 mol%).
2
2
c]
Cu(OAc) ·H O (10 mol%), L1 (10 mol%), K CO (1 equiv.), B pin (1.2 equiv.) under N for 12 h at room temperature.
2
2
2
3
2
2
2
GC yield by using n-dodecane as an internal standard. The isolated yield is given in parenthesis.
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K CO exhibited the best catalytic activity (Table 1, corresponding products in good yields (10 and 11),
2
3
entry 10). However, the side product 4 became the which might be employed for further structural ma-
major one with 32% isolated yield on using NaOAc nipulations. Electron-withdrawing groups (R=4-NO2,
as the base (Table 1, entry 11). Further optimization 4-CF ) were competent under the standard conditions
3
on solvents demonstrated that toluene could be an al- as well and provided the desired products in good
ternative one to CH CN since it gave a similar result yields (12 and 13). Also, o- and m-substituents have
3
as the latter did in the reaction (entry 12 vs. entry 13 less impact on the reaction, albeit with slightly lower
in Table 1). But other unknown by-products were gen- yields (14–16). Gratifyingly, heteroaromatic p-QMs
erated as well, leading to separation difficulty with were proven to be good substrates in this transforma-
toluene as solvent. We also tested other parameters, tion and the desired products were obtained with
such as temperature, the loading of B pin , the load- moderate yields (17 and 18). Furthermore, it was
2
2
ing of bases etc., and eventually the optimal result found that the benzene ring could also be effectively
was achieved (Table 1, entry 14, see the Supporting replaced by a naphthalene moiety (19). 2,6-Dimethyl,
Information). Control experiments suggested that phenyl and isopropyl p-QMs were also suitable candi-
B pin , Cu(OAc) ·H O, and ligand L1 are prerequi- dates for this transformation, with the corresponding
2
2
2
2
sites for the success of the reaction (Table S6, see products obtained in decent to reasonable yields (20–
Supporting Information). Also only 10% of 3 was ob- 23).
tained in the absence of K CO .
Next, different difluoromethylated and monofluor-
2
3
With the optimized conditions in hand, the scope of omethylated bromides as reagents with p-QMs were
p-QMs was investigated (Scheme 2). A series of p- also tested (Scheme 3). Gratifyingly, the transforma-
QMS bearing electron-donating groups (R=4-Me, 4- tion was found to be compatible with a variety of bro-
OMe, 4-NMe , 4-NHAc, 3,4-dimethoxy) could be di- modifluoroacetamides with excellent yields (24–26).
2
fluoroacetylated smoothly in this transformation with To our delight, the corresponding monofluorinated p-
high efficiencies (5–9). Substrates with halo groups QM was obtained with good yield using monofluoroa-
such as Cl and Br were good candidates, giving the cetyl bromide (27).
Scheme 2. Substrate scope of p-QMs for difluoroacetylation. Reaction conditions: p-QM 1 (0.2 mmol, 1 equiv.), 2 (0.4 mmol,
2
.0 equiv.), B pin (1.2 equiv.), Cu(OAc) ·H O (10 mol%), L1 (10 mol%), K CO (0.2 mmol,1.0 equiv.), and CH CN (1 mL),
2 2 2 2 2 3 3
room temperature for 12 h. All yields are those of isolated products.
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Scheme 4. Application to the difluoroalkylation of p-QMs.
strated that a free difluoroalkyl radical pathway was
participating in the reaction [Scheme 5, Eq. (4)].
In order to determine the key intermediates of the
reaction, compound 30 was treated with difluoro re-
agent 2 under the standard condition, the desired
product was only obtained in less than 5% yield with
Scheme 3. Scope of fluoromethylated bromides. Reaction
conditions: p-QM (0.2 mmol, 1 equiv.), ethyl fluoroacetate
80% of the compound 30 remaining [Scheme 5, Eq.
reagent (0.4 mmol, 2.0 equiv.), Cu(OAc) ·H O (10 mol%), (5)], this suggested that borated alkane 30 was not
2
2
L1 (10 mol%), K CO (0.2 mmol,1.0 equiv.), CH CN (1 mL), the key intermediate. On the basis of these results,
2
3
3
room temperature for 12 h. All yields are of islolated prod- a plausible mechanism as depicted in Scheme 6 was
ucts.
proposed. Firstly, copper salt LCuX is reduced by
B pin in the presence of base to afford the copper(I)-
2
2
[
18,21]
Bpin species A.
Subsequently, oxidative addition
Importantly, the cost-effectiveness and mild condi- of A into bromodifluoro reagent via SET produces
[
18,21b]
tions afforded a scale-up opportunity for the potential complex B,
elimination of X-Bpin from complex
practical application. A gram-scale experiment has B leads to R-Cu-Ln C, which further is trapped by p-
been completed using 4-OMe p-QM with difluoroace- QM to form the C-centered radical D, subsequently
tyl bromide. Noteworthily, a 4 mmol preparative-scale isomerizing into O-centered radical E. Finally, hydrol-
synthesis of the corresponding difluorinated p-QM 6 ysis of complex E with water under the basic condi-
could be acquired while sustaining a high isolated tions leads to the desired product as well as comple-
[
17a]
yield of 89% as well, thus certifying the robustness of tion of the catalytic cycle.
our method [Scheme 4, Eq. (1)]. To further expand
the application of our protocol, the alcohol 28 was ob-
tained in the presence of sodium borohydride with ex-
cellent yield [Scheme 4, Eq. (2)].
To gain insight into the mechanism, several radical
trapping experiments were conducted. It was found
that no desired product 6 was detected when the radi-
Experimental Section
Synthesis of p-QMs (1a–1s)
ical inhibitor 2,2,6,6-tetramethyl-1-piperidinyloxy Phenol (5.0 mmol) and the corresponding aldehyde
(
TEMPO) was added under our standard conditions, (6.0 mmol) in toluene (50 mL) were heated to reflux in
a round-bottomed flask. Piperidine (10 mmol, 0.8 mL) was
and the TEMPO-CF COOEt adduct was formed, sug-
gesting that a difluoroalkyl radical is indeed generat-
ed during the reaction [Scheme 5, Eq. (3)].
To further confirm that a free difluoroalkyl radical
existed in the reaction, a radical-clock experiment
was carried out. As illustrated in Eq. (4), the known
ring-expanded product 29 was observed between a-
2
dropwise added within 20 min. The reaction mixture was
further heated to reflux for 6–24 h. After cooling just below
the boiling point of the reaction mixture, acetic anhydride
(
50.0 mmol, 2.55 g) was added and stirring was continued
for 15 min. Then the reaction mixture was poured onto ice-
water (500 mL) and extracted with EtOAc (3ꢂ20 mL). The
combined organic phases were dried over anhydrous
cyclopropylstyrene and difluoroacetyl bromide under Na SO , and the solvent of the filtrate was removed under
2
4
our standard conditions. Thus, these results demon- reduced pressure. The crude products were purified by flash
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Scheme 5. Preliminary mechanistic studies.
times). Ethyl bromodifluoroacetate (0.4 mmol, 52 mL) and
CH CN (1 mL) were added subsequently. The Schlenk tube
3
was screw-capped. And the mixture was stirred at room
temperature for 12 h. The crude product mixture was dilut-
ed with ethyl ethylate and then washed with NaCl solution
(
3ꢂ5 mL). The organic layers were dried over anhydrous
Na SO , concentrated under vacuum, and purified by flash
2
4
column chromatograph to give the pure products. The struc-
tures of compounds 16 (CCDC 1482472) and 18 (CCDC
1
482210) have deen deposited. These data can be obtained
free of charge from The Cambridge Crystallographic Data
Centre via www.ccdc.cam.ac.uk/data_request/cif.
Acknowledgements
Financial support from the National Natural Science Founda-
tion of China (21202049), the Recruitment Program of
Global Experts (1000 Talents Plan), Natural Science Founda-
tion of Fujian Province (2016J01064), Fujian Hundred Tal-
ents Program, the Program of Innovative Research Team of
Huaqiao University (Z14X0047), and Graduate Innovation
Fund of Huaqiao University (for M. Ke) are gratefully ac-
knowledged. We also thank Mr. Weiqun Liu and Yuntao
Zhou for the preparation of some substrates and Instrumental
Analysis Center of Huaqiao University for analysis support.
Scheme 6. Preliminary mechanism.
column chromatography and further recrystallized from n-
hexane, affording the desired p-QMs 1a–1s.
General Procedure for the Difluoroalkylation of p-
QMs
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Adv. Synth. Catal. 0000, 000, 0 – 0
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COMMUNICATIONS
Copper-Catalyzed 1,6-Hydrodifluoroacetylation of para-
Quinone Methides at Ambient Temperature with
Bis(pinacolato)diboron as Reductant
7
Adv. Synth. Catal. 2017, 359, 1 – 7
Miaolin Ke, Qiuling Song*
Adv. Synth. Catal. 0000, 000, 0 – 0
7
ꢁ 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÞÞ
These are not the final page numbers!