Enhancement of neighbouring-group participation in Cu0-promoted cross-coupling gem-difluoromethylenation of aryl/alkenyl halides with 1,3-azolic difluoromethyl bromides

Article abstract of DOI:10.1002/chem.201402205

A copper(0)-promoted direct reductive gem-difluoromethylenation of unactivated aryl or alkenyl halides with benzo-1,3-azolic (oxa-, thia- or aza-) difluoromethyl bromides or 2-bromodifluoromethyl-1,3-oxazoline has been developed for the construction of pharmaceutically important gem-difluoromethylene-linked twin molecules. The unique π-conjugated aryl-fused 1,3-azolic moiety in difluoromethyl bromide substrates could stabilise the reaction intermediates, which promotes the reactivities, providing facile access to the cross-coupling products in good to excellent yields, and allowing significant functional group tolerance. The reaction exhibits an enhanced neighbouring-group-participation effect. This method could provide a new strategy for the construction of gem-difluoromethylene-linked identical or nonidentical twin drugs through further functionalisation of 1,3-azolic skeletons.

Full text of DOI:10.1002/chem.201402205

DOI: 10.1002/chem.201402205
Full Paper
&
Fluorinated Compounds
Enhancement of Neighbouring-Group Participation in Cu0-
Promoted Cross-Coupling gem-Difluoromethylenation of
Aryl/Alkenyl Halides with 1,3-Azolic Difluoromethyl Bromides
Haizhen Jiang,*[a, b] Wenjun Lu,[a] Kun Yang,[a] Guobin Ma,[a] Minjun Xu,[a] Jian Li,[c]
Jianhua Yao,[c] Wen Wan,[a] Hongmei Deng,[d] Shaoxiong Wu,[e] Shizheng Zhu,*[b] and
Jian Hao*[a, b]
Abstract: A copper(0)-promoted direct reductive gem-di-
fluoromethylenation of unactivated aryl or alkenyl halides
with benzo-1,3-azolic (oxa-, thia- or aza-) difluoromethyl bro-
mides or 2-bromodifluoromethyl-1,3-oxazoline has been de-
veloped for the construction of pharmaceutically important
gem-difluoromethylene-linked twin molecules. The unique
p-conjugated aryl-fused 1,3-azolic moiety in difluoromethyl
bromide substrates could stabilise the reaction intermedi-
ates, which promotes the reactivities, providing facile access
to the cross-coupling products in good to excellent yields,
and allowing significant functional group tolerance. The re-
action exhibits an enhanced neighbouring-group-participa-
tion effect. This method could provide a new strategy for
the construction of gem-difluoromethylene-linked identical
or nonidentical twin drugs through further functionalisation
of 1,3-azolic skeletons.
labile to biochemical and enzymatic degradation.[3] Based on
a wide understanding of the nature of the carbon–fluorine
bond and its specific biocompatibility, linkers containing
a gem-difluoromethylene component are proposed to be one
of the most valuable tethers for binding two pharmacophores.
Generally, the gem-difluoromethylene component has been
recognised as an isopolar isostere of the carbonyl group, and
may also enhance the stability of medicinal compounds
against biodegradation and hydrolysis, and increase the clinical
efficacy of drugs by altering their metabolism and lipophilici-
ty.[4] Moreover, the gem-difluoromethylene component has also
been shown to be a key alternative structural unit of CHOH-
linkage in cyclitol and carbohydrate systems that are under
clinical development for anticancer treatment.[5] The classical
methodology used for the incorporation of gem-difluoro-
methylene units into organic compounds has mainly been
based on the direct fluorination of carbonyl groups under
harsh reaction conditions;[6] however, mild and efficient intro-
duction of the gem-difluoromethylene component into organic
molecules remains a significant challenge because of the lack
of efficient synthetic strategies and a shortage of gem-difluoro-
methylene sources.[7]
Introduction
Identical and nonidentical twin drugs, which contain two phar-
macophores joined through a covalent linkage, have drawn
much attention in the development of drug-targeting strat-
egies in antitumor therapy.[1] As a key component in twin
drugs, the composition of the linkage, and the nature of its
binding affinity and biochemical stability etc. are priorities to
be considered in drug design and innovation.[2] In most cases,
twin drugs that are linked by ester or amide parts are generally
[a] Dr. H. Jiang, W. Lu, K. Yang, Dr. G. Ma, M. Xu, Dr. W. Wan, Dr. J. Hao
Department of Chemistry, Shanghai University
Shanghai, 200444 (P.R. China)
E-mail: hzjiang@shu.edu.cn
jhao@shu.edu.cn
[b] Dr. H. Jiang, Dr. S. Zhu, Dr. J. Hao
Key Laboratory of Organofluorine Chemistry
Shanghai Institute of Organic Chemistry
Chinese Academy of Sciences
Shanghai, 200032 (P.R. China)
E-mail: zhusz@mail.sioc.ac.cn
[c] Dr. J. Li, Dr. J. Yao
Laboratory of Computer Chemistry and Cheminformatics
Shanghai Institute of Organic Chemistry
Chinese Academy of Sciences
Herein, we describe a method for the efficient construction
of gem-difluoromethylene-linked twin molecules through Cu0-
promoted ligand-free direct reductive cross-coupling of aryl or
alkenyl halides with benzo-1,3-azolic (oxa-, thia- and aza-) di-
fluoromethyl bromides (1a–c) or 2-bromodifluoromethyl-1,3-
oxazoline (1 f) with enhanced neighbouring-group participa-
tion (Scheme 1). The unique structure with a p-conjugated
aryl-fused 1,3-azolic moiety in difluoromethyl bromide 1 could
stabilise the reaction intermediates and give the cross-coupling
Shanghai, 200032 (P.R. China)
[d] Dr. H. Deng
Laboratory for Microstructures, Shanghai University
Shanghai, 200444 (P.R. China)
[e] Dr. S. Wu
Emory NMR Research Center, Emory University
201 Dowman Drive, Atlanta, Georgia, 30322 (USA)
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201402205.
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with 2-bromomethylbenzooxazole or ethyl bromodifluoroace-
tate (Scheme S1 in the Supporting Information).
2-Bromodifluoromethylbenzo-1,3-oxazole (1a) was initially
employed to optimise the reaction conditions as shown in
Table 1. Treatment of 1a (1.0 equiv) with methyl 2-iodo-ben-
zoate (2a; 1.0 equiv) as a model substrate in the presence of
copper powder (3.0 equiv) under N2 atmosphere in dimethyl
sulfoxide (DMSO) at 558C resulted in the formation of the de-
Table 1. Optimisation of the cross-coupling of 1a and 2a or 2a’.
Scheme 1. Cu0-promoted direct reductive cross-coupling for gem-difluoro-
methylene-linked twin molecules.
products in good to excellent yields. This method could there-
fore provide a new synthetic strategy for the construction of
gem-difluoromethylene-linked identical or nonidentical twin
drugs.
Entry Copper source Molar ratio
Time [h] Temp. [8C]
Yield
[%][a]
3aa 3aa’
(1a/2/Cu)
1
2
3
4
5
6
7
8
Cu0
Cu0
Cu0
Cu0
Cu0
Cu0
Cu0
Cu0
Cu0
Cu0
Cu0
Cu0
CuI
CuI/I2
CuBr2
Cu0
Cu0
Cu0
Cu0
1:1:3
1:1:2
1:1:1
1:1:3.5
1.2:1:2.5
1.2:1:3
1.2:1:3
3:1:6.9
4:1:12.6
3:1:6.9
3:1:6.9
1.2:1:3
1.2:1:3
1.2:1:3
1.2:1:3
1:1:6.9:2 (L1)
1:1:6.9:2 (L2)
1:1:6.9:2 (L3)
1:1:6.9:2 (L4)
4
4
55
55
55
55
55
55
25
55
55
25
25
80
55
55
55
55
55
55
55
79
68
31
75
95
96
95
96
–
97
96
95
NR
NR
NR
–
26
21
–
–
32
33
29
78
76
4
4
4
4
8
4
4
10
8
Results and Discussion
Cross-coupling reactions catalyzed or promoted by transition
metals for the formation of carbon–carbon bonds have devel-
oped tremendously in recent years.[8] Methodologies for per-
fluoroalkylation, including trifluoromethylation of arenes using
perfluoroalkyl halides via perfluoroalkylcopper (RfCu) inter-
mediates, have also been extensively studied[9] since McLough-
lin reported the first example of copper-mediated cross-cou-
pling of perfluoroalkyl iodides with aryl iodide in 1969.[10] How-
ever, compared with the successful development of copper-
mediated perfluoroalkylations,[11] examples of cross-coupling
gem-difluoromethylenation of aryl halides with gem-difluoro-
methylene-containing building blocks are rare.[7a,12] Such gem-
difluoromethylenation substrates include ethyl halodifluoroace-
tate,[12a] a-silyldifluoroacetates,[12c,g] iododifluoroacetamides,[11c]
diethyl bromodifluoromethylphosphonate[12b,f] and (benzene-
sulfonyl-difluoromethyl)trimethylsilane.[12d,e] Structure-reactivity
studies have shown that such gem-difluoromethylenation reac-
tions with aryl/alkenyl halides only occur when a CF2X group is
bonded specifically to groups such as -COOR, -CONHR,
-PO(OEt)2 or -SO2R. However, cross-coupling using some of
these gem-difluoromethylene sources can suffer from either
low yields or poor cross-coupling selectivity, or require the as-
sistance of other metals. To some extent, this might be due to
the limitation of gem-difluoromethylene sources. Our initial re-
sults showed that 2-bromodifluoromethyl-benzo-1,3-oxazole
(1a)[13] could efficiently react with aryl halides under the pro-
motion of copper(0). The high reactivity of 1a could be attrib-
uted to the superiority of the structure of 1a. First, the CF2Br
group bonds to a carbon of the C=N bond. Second, additional
heteroatoms, such as O, S and N, also bond directly to this sp2
carbon. Finally, a 1,3-oxazole ring is involved in an aromatic
system. Such structural features of 1a result in a cross-coupling
reactivity with methyl 2-iodo-benzoate that is superior to that
9
10
11
12
13
14
15
16[b]
17[b]
18[b]
19[b]
77
69
30
4
10
10
10
4
4
4
NR
NR
NR
32
–
–
–
33
trace
trace
4
[a] Isolated yield, NR=no reaction; [b] Added ligand (2 equiv):
sired product 3aa in 79% yield (entry1). Attempts to reduce
the amount of copper powder resulted in a significant de-
crease in the yield of 3aa (entries 2 and 3). Exhilaratingly, the
yield of 3aa was significantly improved from 79 to 96%
(entry 1 versus 6) when the amount of 1a was slightly in-
creased from 1 to 1.2 equiv. Further screening of the reaction
temperature revealed that this reaction could also be complet-
ed at room temperature and provide 3aa in 95% yield by
simply prolonging the reaction time (entry 7). Other copper
sources, such as CuI, CuBr2 or CuI/I2 failed to promote this
cross-coupling reaction. After scanning other reaction condi-
tions, an optimal yield of 3aa (95%) was eventually achieved
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when the reaction was conducted in anhydrous DMSO at
room temperature for 8 h under a 1a/2a/Cu0 molar ratio of
1.2:1:3 in N2 atmosphere (Table 1, entry 7).
ble coordination formed by two equivalents of 1a with difluor-
omethyl copper species II, which was generated by one equiv-
alent of 1a and Cu0 in situ, may be responsible for the high
yield of 3aa’ (Scheme 2). To investigate this idea, four ligands
were selected to substitute two equivalents of substrate 1a.
Regrettably, the reaction did not provide a better yield
(Table 1, entries 16–19). The results suggest that this Cu0-pro-
moted reductive gem-difluoromethylenation reaction does not
require ligands.
During the optimisation process, the participation of differ-
ent amounts of Cu0 was found to affect the reaction efficiency
significantly. The reaction yielded the cross-coupling product
only in 31% yield when 1.0 equivalent of copper powder was
used (Table 1, entry 3), whereas 2.1 equivalents of copper
powder (based on 1a) provided the desired product in up to
95% yield (Table 1, entry 5). However, continuously increasing
the equivalents of copper powder did not result in further im-
provement in the yield of the product (Table 1, entry 4 versus
1). These results indicated that two equivalents of Cu0 were
necessary to complete this reaction. Therefore, we deduced
a mechanism in which the initial one equivalent of Cu0 was
used to drive substrate 1 to form a radical anion, which was
then transferred into free radical I in the second step through
a CÀBr bond cleavage (Scheme 2). The free radical I obtained
an electron from the second equivalent of Cu0 and formed
“Ar’CF2Cu” species II through single electron transfer (SET).
Thus, this Cu0-promoted gem-difluoromethylenated cross-cou-
pling was suggested to proceed via a “Ar’CF2Cu” species,[9–11]
The difference in the reactivity of 1a with methyl 2-iodoben-
zoate (2a) and methyl 4-iodobenzoate (2a’) could be ascribed
to the different substitution pattern of the aromatic system.
Excellent performance of the reaction with 2a could be de-
rived from neighbouring-ester-group participation, because
the ester group could help stabilise the coordination inter-
mediate III through intramolecular chelation of the oxygen
atom of the carbonyl group in methyl 2-iodo-benzoate to the
copper ion, thus facilitating the cross-coupling gem-difluoro-
methylenation (Scheme 2). The hypothesised promotion by
neighbouring-ester-group participation was investigated ex-
perimentally, and supported by the results of DFT calculations
at the B3LYP/6-311G+ +(d)//SDD level of theory (Figure 1).
Scheme 2. Proposed mechanism of cross-coupling gem-difluoromethylena-
Figure 1. The coordination intermediate III.
tion.
although this species was not observed in our case by 19F NMR
spectroscopic analysis, possibly due to its unstable nature and
rapid decomposition in the absence of aryl halide 2. Once the
“Ar’CF2Cu” species was formed, oxidative addition with aryl
halide 2 could take place immediately, which was followed by
reductive elimination to afford the gem-difluoromethylenated
cross-coupling product 3 (Scheme 2).
When a mixture of 1a and methyl 4-iodobenzoate (2a’) was
stirred in DMSO for 8 h under the same conditions described
above, the yield of cross-coupling product 3aa’ was only 29%
(Table 1, entry 7). After further optimisation, the highest yield
of 3aa’ (77%) was obtained when the reaction was carried out
in DMSO at room temperature for 10 h with a 1a/2a’/Cu0
molar ratio of 3:1:6.9 (Table 1, entry 10). In this process, a possi-
Scheme 3. Step-by-step experiments to investigate cross-coupling gem-di-
fluoromethylenation.
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The calculated structure of intermediate III with se-
lected geometrical parameters is shown in Figure 1.
The DFT calculation results show that the bond
angles of I-Cu-C2 and O1-Cu-C1 were 160.1 and 160.58,
respectively (Table S1 in the Supporting Information),
which means that atoms O1, I, Cu, C1 and C2 in inter-
mediate III take on an approximate square-planar ge-
ometry. On the other hand, the distance between Cu
and O1 (2.034 ꢁ) is close to the normal bond length
of CuÀO (1.95–2.34 ꢁ), which indicated an oxygen
lone pair in methyl 2-iodo-benzoate could coordinate
to the copper ion centre, thus changing the Mulliken
charge of Cu from 0.438 to À0.643, as compared
with that of methyl 4-iodo-benzoate. Intermediate III
became more stable due to the dispersion of charge
because of coordination.
Table 2. Cross-coupling of 1a with aryl halides.
Entry Ar-X (2)
Compound 3
Yield of 3 [%][a]
1
96 (A)
2
3
29 (A), 71 (B)
40 (A), 71 (B)
This cross-coupling gem-difluoromethylenation of
1a with 2a or 2a’ involved coupling of two halides
under the promotion of Cu0. The following step-by-
step experiments were executed to determine which
of the carbon–halogen bonds reacts with Cu0 first.
After the reaction of 1a with copper powder was car-
ried out for 4 h with a 1a/Cu0 molar ratio of 1:2.3 in
DMSO at room temperature, no clear signal could be
detected in the reaction mixture by 19F NMR spectro-
scopic analysis, which clearly showed that 1a was
consumed completely during the process. Strangely,
no new products could be observed by TLC or
19F NMR analysis. When 2a’ was added to the above
reaction mixture, neither cross-coupling gem-difluoro-
methylenated product nor other byproducts could
be traced. However, addition of 2a to this mixture
led to the formation of only homocoupling product
6, arising from 2a (Scheme 3). On the other hand,
when 2a’ was treated with copper powder at first, no
reaction could be observed according to TLC analysis.
However, further addition of 1a (3 equiv) to this reac-
tion mixture gave the cross-coupling product 3aa’ in
56% yield after 10 h. Although 2a provided homo-
coupling product biphenyl-2,2’-dicarboxylic acid di-
methyl ester in 60% yield after stirring the mixture of
Cu0 and 2a in DMSO (Scheme 3), the reaction only
gave the cross-coupling product when 1a reacted
with 2a and Cu0 in a one-pot process (Table 2,
entry 1). These experimental results indicated that
Cu0 tended to react selectively with 1 rather than
with aryl halide 2 first. Therefore, the “Ar’CF2Cu” spe-
cies II was suggested to be involved in this Cu0-pro-
moted gem-difluoromethylenated cross-coupling re-
action.
4
5
86 (A)
65 (B)
6
7
8
9
49 (A)
21 (B)
65 (A)
36 (B)
10
11
37 (A)
35 (B)
12
13
75 (A)
68 (B)
14
52 (A), 84 (B)
The optimised reaction conditions
A (Table 1,
15
16
82 (B)
entry 7) for the cross-coupling gem-difluoromethyl-
enation of 1a and methyl 2-iodobenzoate 2a with
a 1a/2a/Cu0 molar ratio of 1.2:1:3, and optimised
conditions B (Table 1, entry 10) for cross-coupling of
1a and 2a’ with a 1a/2a’/Cu0 molar ratio of 3:1:6.9
were found to be suitable for the conversion of
20 (B)[b]
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2 versus 7). In particular, the substitution pattern of
the aromatic system was found to have a great influ-
ence on the reaction efficiency. ortho-Substituted
aryl halides (such as -COOCH3, -NO2, -OCH3, and
-CH2OCH3) provided the cross-coupling products in
higher yields than those substituted at other posi-
tions, revealing an extraordinarily significant neigh-
bouring-group effect (e.g., entries 1 versus 2 and 4
versus 5). Furthermore, ortho-substituted ester aryl
iodide displayed a more efficient neighbouring-
group effect than the corresponding substrates sub-
stituted with -NO2 or -CH2OCH3. No clear neighbour-
ing-group effect was observed when aryl iodides
bearing -CH3, -CN or -Ph groups at the ortho position
were used (Table 2, entries 10, 14 and 23). Therefore,
the neighbouring-group effect was reasoned to stem
mainly from interactions between the copper ion
centre and a lone pair of electrons in the O atom (in
-COOCH3, -NO2, -OCH3, -CH2OCH3; Scheme 2). The
weak interaction of the copper ion centre with the
electrons present in a sigma bond (-CH3) or pi bond
(Ph-, CN) resulted in poor stability of the intermedi-
ates and the low yields in the process of Cu0-pro-
moted gem-difluoromethylenated cross-coupling
(entries 10, 14 and 23). The steric effect exerted by
the ortho-substituent in aryl halides was unclear.
Nevertheless, the Cu0-promoted cross-coupling pro-
cess was tolerant of a variety of functional groups at-
tached to the aryl halides, including ester, cyano,
nitro, ether and halide groups. Additionally, aromatic
heterocyclic halides could also react by using this
method, providing the desired products in good
yields (entries 12, 13 and 22). Clearly, this reaction
provides gem-difluoromethylene-linked cross-cou-
pling compounds more efficiently than using ethyl
bromodifluoroacetate.[12a] It is noteworthy that the
use of 1a as substrate gave the cross-coupling prod-
uct as the only detectable compound, and no by-
product formed by dehalogenation or homocoupling
was observed under these reaction conditions.[14]
Furthermore, only 1.2 equivalents of 1a were re-
quired to make the cross-coupling reaction with
ortho-substituted aryl iodides reach completion.[12a]
These remarkable reaction characteristics could be
attributed to the role of the fluorine atom in the 2-
bromodifluoromethylbenzo-1,3-oxazole molecule, in
addition to the unique structure with an p-conjugat-
ed aryl-fused 1,3-azolic moiety in difluoromethyl bro-
mide substrates. When 2-bromomethylbenzooxazole
was used as substrate, the reaction with methyl 2-io-
dobenzoate merely provided homocoupling byprod-
ucts and no cross-coupling product was observed by
Table 2. (Continued)
Entry Ar-X (2)
Compound 3
Yield of 3 [%][a]
17
–
0 (A), 0 (B)
18
19
26 (B)
10 (B)
20
21
22
47 (B)
52 (B)
58 (B)
23
24
25
29 (A), 41 (B)
42 (B)
0 (B),[c] 63 (A)[d]
26
27
95 (A)
94 (A)
28
0 (B)[e]
29
CH3I (2t)
–
0 (A), 0 (B)
[a] Isolated yield obtained under optimum conditions A or B. [b] Obtained together
with 40% homocoupling compound. [c] Formation of double cross-coupling of 2,5-
position product 4 in 88% yield under reaction conditions B. [d] Formed together
with 11% double cross-coupling of 2,5-position product. [e] Homocoupling product 5
(96%) from iodoalkyne formed.
a range of 2-substituted aryl halides and other substituted aryl
halides 2 into gem-difluoromethylene-linked compounds 3, re-
spectively (Table 2). The reactions with aryl halides bearing an
electron-withdrawing group gave much higher yields than
those with an electron-donating group (entries 1 versus 6, and
LC-MS analysis (Scheme S1 in the Supporting Information). Aryl
iodides presented higher reactivity than aryl bromides (en-
tries 1 versus 16 or 18 versus 19). When methyl 2-bromometh-
ylbenzoate (2h) was used in the cross-coupling reaction with
1a, in addition to the cross-coupling product 3aa (20%), an
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unexpected homocoupling product of 2h was ob-
tained in 40% yield (Table 2, entry 16). However, the
aryl chloride, even with an ester group installed at
the ortho-position, did not give the desired product
(entry 17). Aliphatic iodine alkanes, such as methyl
iodide, proved to be inert in this cross-coupling reac-
tion (entry 29). In the case of iodoalkyne, homo-cou-
pling product 5 was obtained in 96% yield as the
only isolated product (entry 28).
This Cu0-promoted reaction was also suitable for
the cross-coupling of 1a with alkenyl halides 2u–z
under the above standard reaction conditions
(Table 3). The use of (Z)-3-halogenated (I or Br) acrylic
acid ethyl ester as substrates provided the cross-cou-
pling products in high yields with retention of con-
figuration of the alkene functionality, and showed ex-
cellent neighbouring-group-enhancement effect
when an ester group was present in the Z-configura-
tion (entries 1 versus 2 and 3 versus 4). The multisub-
stituted alkenyl halide could be also used in this re-
action to give the desired cross-coupling product
(Table 3, entry 5).
Table 3. Cross-coupling of 1a with alkenyl halides 2.
Entry
1
Alkenyl halide 2
Compound 3
Yield of 3 [%][a]
97
51
92
49
2
3
4
5
6
58
78
Other 1,3-azolic difluoromethyl bromides, such as
2-bromodifluoromethylbenzothiazole[13] (1b) and N-
alkyl-2-bromodifluoromethylbenzoimidazole[15] (1c)
also reacted with aryl (or alkenyl) halides in this pro-
tocol to form cross-coupling products with enhanced
neighbouring-group effect (Table 4). We observed
[a] Isolated yield obtained under optimum reaction conditions B.
that the choice of heteroatom in 1,3-azolic difluoromethyl bro-
mides significantly affected the cross-coupling efficiency. The
reaction of O- and N-containing benzo-1,3-oxazolic difluoro-
methyl bromide (1a) gave the products in the highest yields
among the 1,3-azolic difluoromethyl bromides (Table 2, entry 1
versus Table 4, entries 1 and 6), and the reaction of S- and N-
containing 1,3-thiazolic difluoromethyl bromide (1b) could
provide the corresponding products in higher yields than that
of N- and N-containing 1,3-imidazolic difluoromethyl bromide
(1c) (Table 4, entry 1 versus 6). However, what stood out for us
was that the reaction of bromodifluoromethylbenzene (1e)
with 2-iodo-benzoic acid methyl ester (2a) under the cross-
coupling conditions was difficult to promote by Cu0, and gave
benzoic acid in 42% yield together with homocoupling prod-
uct 6. Benzoic acid was demonstrated to form from 1e,[16] be-
cause when the reaction of 1e and 2a was independently car-
ried out under the cross-coupling conditions, benzoic acid was
obtained in 56% yield and homocoupling product 6 was gen-
erated in 60% yield (Scheme 4). Similar results were obtained
in the reaction of (Z)-3-iodo-acrylic acid ethyl ester (2u). These
observations stimulated us to explore the reaction with one
heteroatom N-containing 2-bromodifluoromethylquinoline[17]
(1d). In this case, the cross-coupling occurred, but gave the
desired cross-coupling product only in low yields (Table 4, en-
tries 10 and 11).
providing the desired gem-difluoromethylenated cross-cou-
pling twin molecules in moderate to good yields. However, the
reaction required a temperature of 608C with a 1 f/2/Cu0 molar
ratio of 3:1:6.9. Compound 1 f not only coupled with aryl hal-
ides but also with alkenyl halides (Table 5). The neighbouring-
group-enhancement effect was also observed (Table 5, en-
tries 1 versus 2 or 4 versus 6). The results further revealed that
the two heteroatoms in the 1,3-azolic difluoromethyl bromides
play important roles in the cross-coupling reaction.
Heterocycles of 1,3-azoles are important synthetic intermedi-
ates, and undergo extensive chemical transformations involv-
ing nucleophilic addition of the C=N bond or nucleophilic
ring-opening,[19] sodium-alcohol reduction then acid hydrolysis
to aldehyde,[20] base hydrolysis to organic acid,[21] and thermal
rearrangement to 2-bromodifluoromethylisocyanates.[22] There-
fore, functionalisation of the 1,3-azolic moiety could provide
possibilities for construction of a new generation of gem-di-
fluoromethylene-linked identical or nonidentical twin drugs.
Conclusion
A copper(0)-promoted reductive approach to the construction
of gem-difluoromethylene-linked twin molecules has been in-
vestigated through the use of gem-difluoromethylenated
cross-coupling of aryl/alkenyl halides with partially fluorinated
benzo-1,3-azolic (oxa-, thia- or aza-) difluoromethyl bromides
(1a–e) or 2-bromodifluoromethyl-1,3-oxazoline (1 f). The neigh-
bouring groups were shown to promote this reaction efficient-
ly. The unique structures of 1,3-azolic difluoromethyl bromides
To confirm the main contribution to intermediate stability
from heteroatoms, we attempted to use 4-benzyl-2-bromodi-
fluoromethyl-1,3-oxazoline[18] (1 f) as the substrate, and found
that it was also effective under this cross-coupling method,
Chem. Eur. J. 2014, 20, 10084 – 10092
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experimental results reveal that Cu0 first se-
lectively reacted with 1,3-azolic difluorometh-
yl bromides to provide the Ar’CF2Cu species,
which is followed by oxidative addition with
aryl (or alkenyl) halides then reductive elimi-
nation to yield the desired gem-difluorome-
thylenated cross-coupling products. This
copper(0)-promoted gem-difluoromethylenat-
ed cross-coupling method could provide
a new synthetic strategy for the construction
of gem-difluoromethylene-linked identical or
nonidentical twin drugs by the functionalisa-
tion of 1,3-azolic skeletons of the cross-cou-
pling products.
Table 4. Effect of heteroatom in substrate 1 on the cross-coupling reaction.
Entry Reactant 1
Reactant 2
Compound 3
Yield [%][a]
86 (A)
1
2
3
51 (B)
88
Experimental Section
4
5
92
78
Method A (for aryl/alkenyl halides with
neighbouring group)
A 10 mL round-bottom flask was charged with
1,3-azolic difluoromethyl bromide (0.6 mmol),
aryl/alkenyl halide (0.5 mmol), Cu powder
(79 mg, 1.25 mmol), and DMSO (2 mL) under a ni-
trogen atmosphere. The reaction mixture was
stirred at RT for 8 h. When the reaction was com-
plete, the crude product was directly purified by
silica gel chromatography (petroleum ether/ethyl
acetate, 20:1 v/v), to give cross-coupling product
3.
6
7
78 (A)
16 (B)
8
42
Method B (for aryl/alkenyl halides without
neighbouring group)
A 10 mL round-bottom flask charged with 1,3-
azolic difluoromethyl bromide (1.5 mmol), aryl/al-
kenyl halide (0.5 mmol), Cu powder (219 mg,
3.45 mmol), and DMSO (2 mL). The reaction mix-
ture was stirred at RT for 10 h. When the reaction
was complete, the crude product was directly
purified by silica gel chromatography (petroleum
ether/ethyl acetate, 20:1 v/v), to give cross-cou-
pling product 3.
9
88
10
12 (A)
11
32 (A)
Acknowledgements
This work was financially supported by the
National Natural Science Foundation of China
(21072127, 21032006, 21172141, 21302121),
the Science Foundation of Shanghai Munici-
pal Commission of Sciences and Technology
(10JC1405600), and the Ministry of Science
and Technology of the People’s Republic of
China (2010CB126103). We are grateful to Pro-
fessor Min Shi at Shanghai Institute of Organic
12
13
–
–
0 (A), 0 (B)[b]
0 (A), 0 (B)[b]
[a] Isolated yield. [b] Reaction of the substrate itself.
1 allow significant functional group tolerance and specifically
provide the gem-difluoromethylene-linked twin compounds in
good to excellent yields under mild reaction conditions. The
Chemistry for discussion, and the High-Performance Comput-
ing and Data Center, Shanghai Advanced Research Institute,
Chinese Academy of Sciences for computational resources.
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Keywords: copper · cross-coupling · drug design · fluorine ·
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Received: February 15, 2014
Published online on July 2, 2014
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