Base-mediated direct fluoroalkenylation of 2-phenyl-1,3,4-oxadiazole, benzothiazole and benzoxazole with gem-difluoroalkenes

Article abstract of DOI:10.1039/c4ra13761b

Direct α-fluorovinylation of 2-phenyl-1,3,4-oxadiazole, benzothiazole and benzoxazole with gem-difluoroalkenes via nucleophilic vinylic substitution reaction (S_NV) under the assistance of KHMDS or NaH at room temperature is described.

Full text of DOI:10.1039/c4ra13761b

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Base-mediated direct fluoroalkenylation of
2-phenyl-1,3,4-oxadiazole, benzothiazole and
Cite this: RSC Adv., 2015, 5, 7905
benzoxazole with gem-difluoroalkenes†
Received 4th November 2014
Accepted 22nd December 2014
*
Xuxue Zhang, Yingyin Lin, Juan Zhang and Song Cao
DOI: 10.1039/c4ra13761b
www.rsc.org/advances
Direct a-fluorovinylation of 2-phenyl-1,3,4-oxadiazole, benzothiazole direct C–H alkenylation of various 1,3,4-diazoles using gem-bro-
and benzoxazole with gem-difluoroalkenes via nucleophilic vinylic mouoroalkenes as electrophiles (Scheme 1a).9
substitution reaction (SNV) under the assistance of KHMDS or NaH at
Generally, alkenyl chlorides, bromides or iodides could be
served as alkenylating agents in the coupling with heteroarenes.10
However, unreactive alkenyl uorides are rarely used as coupling
partners or substrates in alkenylation reaction due to the unique
nature of the carbon–uorine bond.11 Up to now, there are only
three examples of direct C–H alkenylation of heterocycles with
uoroalkenes (Scheme 1b–d).12 The drawbacks of these methods
are the lithiation of heterocycles with the moisture sensitive n-
butyllithium in the rst step, very low reaction temperature,
relatively low yield, the mixture of E/Z isomers and the need for
highly electron-decient polyuoroalkenes. Furthermore, n-
butyllithium is prone to nucleophilic attack of uorine atom in
uoroalkene, followed by uorine elimination to produce unde-
sired product.12a Thus, a simple method for the direct C–H
alkenylation of heterocycles with uoroalkenes under mild
conditions is highly desirable. In continuation of our research on
the functionalization of gem-diuoroalkenes,13 in this commu-
room temperature is described.
The alkenylated heteroarenes have gained much attention over
the past decades due to their widespread applications as
versatile building blocks for the synthesis of pharmaceuticals,
agrochemicals and functional materials.1 As a consequence,
considerable efforts have been made to develop efficient
methods for the synthesis of alkenyl-substituted heteroarenes.2
The traditional method to prepare the alkenyl-substituted het-
eroarene is the Knoevenagel-type condensation of 2-methyl
heteroarene with the appropriate aldehyde.3
Nowadays, the direct conversion of C–H bonds into
C–C bonds is a very useful methodology for the construction of
complex molecules.4 At the same time, direct C–H alkenylation
through C–H bond cleavage has been developed into a powerful
tool for the synthesis of alkenylated arenes and particularly
alkenylated heteroaromatics.5 Among the protocols for the direct
C–H alkenylation of (hetero)arenes, the alkenylation of (hetero)
arenes with alkenyl halides by using palladium or copper as
catalyst is becoming more popular.6
nication, we report
a straightforward protocol for direct
C–H bond monouoroalkenylation of 2-phenyl-1,3,4-oxadiazole,
Monouoroalkenes are useful uorinated synthons in
synthetic organic chemistry and precursors of biologically
active compounds.7 In medicinal chemistry and peptide chem-
istry, they are oen considered as peptide bond isosteres.8
However, very few reports are available on the synthesis of uo-
roalkenyl-substituted heterocycles. In 2013, Schneider et al.
reported a novel and facile approach to heteroarylated mono-
uoroalkenes through the base-assisted Pd- and Cu-catalyzed
Shanghai Key Laboratory of Chemical Biology, School of Pharmacy, East China
University of Science and Technology (ECUST), Shanghai 200237, China. E-mail:
scao@ecust.edu.cn; Fax: +86-21-64252603; Tel: +86-21-64253452
† Electronic supplementary information (ESI) available: General procedure for
synthesis, characterization data, and 1H, 13C, 19F NMR and HRMS spectra of
compounds 3. See DOI: 10.1039/c4ra13761b
Scheme 1 C–H alkenylation of heterocycle with alkenyl bromide or
alkenyl fluoride.
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Table 2 Reactions of gem-difluoroalkenes 1a–g with 2-phenyl-1,3,4-
oxadiazole 2a and benzothiazole 2ba,b
Scheme 2 Synthesis of fluoroalkenyl substituted heterocycles.
benzothiazole and benzoxazole with gem-diuoroalkenes under
the assistance of base (KHMDS or NaH) at room temperature
(Scheme 2).
We began our investigation by using (2,2-diuoroethene-
1,1-diyl)dibenzene 1a and 2-phenyl-1,3,4-oxadiazole 2a as the
model substrates to optimize the reaction conditions and the
results are summarized in Table 1. Initially, the effect of base on
the reaction was examined. In the absence of the base, the
Table 1 Optimization of reaction conditionsa
a
Reaction conditions: gem-diuoroalkenes 1a–g (1.0 mmol), 2a
(4.0 mmol) or 2b (2.0 mmol), KHMDS (4.0 mmol or 2.0 mmol), DMSO
(5 mL). b Isolated yields. c GC-MS yield.
2a
Entry (equiv.) Base (equiv.) Temp (ꢀC) Solvent Yield of 3aab (%)
reaction hardly proceeded and no expected product 3aa was
observed (entry 1). Among the various bases evaluated, KHMDS
was better than the other bases such as t-BuOLi, n-BuLi, KOH,
NaOH, LiHMDS and NaHMDS, and could provide the highest
yield (entries 2–10). Although KOH and NaOH are cheaper and
commercially more readily available than KHMDS, the lower
yields of the valuable desired products render them less
economically attractive. Too much or too little KHMDS led to a
remarkable decrease in the yield (entries 11–12). Decreasing the
amount of 2a resulted in low yield of 3aa (entries 13–14). The
results also indicated that the solvent has a dramatic effect on
the reaction. Only DMSO could afford the expected product 3aa
in good yield (entries 10, 15–19). Moreover, increasing reaction
temperature obviously diminished the yield (entries 20–21).
Finally, we also used the reaction system of literatures (n-
BuLi/Et2O, entry 22), however, no desired product was detected.
With the optimized reaction conditions established (Table 1,
entry 10), we proceeded to investigate the direct C–H alkenylation
of 2-phenyl-1,3,4-oxadiazole 2a with several gem-diuoroalkenes
(Table 2, 3aa–ga). The results indicated that gem-diuoroalkenes
bearing electron-withdrawing groups on the benzene ring
were somewhat more reactive and provided the alkenylated
1
2
3
4
5
6
7
8
4
4
4
4
4
4
4
4
4
4
4
4
3
2
4
4
4
4
4
4
4
4
—
25
25
25
25
25
25
25
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMF
DMA
THF
Dioxane Trace
Et2O
DMSO
DMSO
Et2O
0
20
27
64
68
70
71
55
50
81
26
17
23
16
17
8
LiOH (4)
t-BuOK (4)
t-BuOLi (4)
n-BuLi (4)
KOH (4)
NaOH (4)
LiHMDS (4) 25
NaHMDS (4) 25
9
10
11
12
13
14
15
16
17
18
19
20
21
22
KHMDS (4)
KHMDS (5)
KHMDS (3)
KHMDS (4)
KHMDS (4)
KHMDS (4)
KHMDS (4)
KHMDS (4)
KHMDS (4)
KHMDS (4)
KHMDS (4)
KHMDS (4)
n-BuLi (4)
25
25
25
25
25
25
25
25
25
25
70
40
25
0
0
22
21
0
a
Reagents and conditions: 1a (1.0 mmol), KHMDS (4.0 mmol, 1.0 mol LÀ1
b
in THF), DMSO (5 mL), 12 h. Yields were determined by GC-MS
analysis and based on 1a.
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Table 3 Reactions of gem-difluoroalkenes 1a–c, 1g with benzoxazole
breaking was expanded to benzoxazole 2c (Table 3). However,
KHMDS as well as other bases such as t-BuOLi, t-BuOK, KOH and
LiHMDS failed to furnish the desired products. Gratifyingly, we
found that the alkenylation of benzoxazole 2c with gem-diuor-
oalkenes 1a–c, 1g could occur in presence of NaH and give the
expected alkenylated products in moderate yield at room temper-
ature (3ac–cc, 3gc). Unfortunately, both compound 1f having
electron-donating group and compound 1e bearing strong
electron-withdrawing group on benzene ring were not suitable
substrates for the transformation and only trace amounts of
alkenylated products were detected.
2ca,b
Based on the above observations, we suggest that the
mechanism is analogous to those proposed in the literatures.14
gem-Diuoroalkenes undergo nucleophilic vinylic substitution
(SNV) with heteroarenes in the presence of base via addition–
elimination processes to afford uoroalkenylated hetero-
aromatics. The abstraction of the C–H proton of hetero-
aromatics with assistance of base to generate the corresponding
sp2 carbanion on the heterocycles is essential for efficient
transformation. The presence of benzene group in 2-phenyl-
a
Reaction conditions: gem-diuoroalkenes 1a–c, 1g (1.0 mmol), 2c (4.0
b
mmol), NaH (4.0 mmol), DMSO (5 mL). Isolated yields.
1,3,4-oxadiazoles in good yields (3ba–da). However, the gem- 1,3,4-oxadiazole, benzothiazole and benzoxazole is favorable
diuoroalkenes bearing strong electron-withdrawing group such for the activation of the C–H bond.
as CF3 was unfavorable for the reaction (3ea). gem-Diuoroalkene
In conclusion, we have developed a mild and efficient
having electron-donating group such as CH3 was not a suitable method for the KHMDS or NaH-mediated alkenylation of three
substrate for this transformation and furnished only small amount azole heterocycles, including 2-phenyl-1,3,4-oxadiazole, benzo-
of alkenylated product (3fa). Unsymmetrical gem-diuoroalkene thiazole and benzoxazole with various gem-diuoroalkenes.
could also furnish high yield of desired product (3ga), but with Although, at present stage, the substrate scope of this new
poor E/Z selectivity (4 : 3, the ratio of E/Z isomers in the crude approach was relatively limited due to the fact that the cleavage
reaction mixture was determined by 19F NMR). When 1-(2,2- of heteroaromatic C–H bonds is much more difficult in absence
diuorovinyl)-4-methoxybenzene was used as substrate, no reac- of metal catalyst, it will pave the way for realizing direct
tion was observed. It appears that two diaryl groups attached at the C–H alkenylation of heterocycles without prefunctionalization
C–C double bond of gem-diuoroalkenes is necessary, which could of Csp2–H of heterocycles such as halogenation. Further studies
stabilize carbanion transition state. Furthermore, the replacement to expand the substrates and increase yields are in progress in
of phenyl group in 2-phenyl-1,3,4-oxadiazole with hydrogen or our laboratory.
alkyl group can not make the reaction proceed smoothly.
To explore the scope of the novel alkenylation reaction, we
next evaluated the reaction of benzothiazole 2b with different
Acknowledgements
gem-diuoroalkenes (Table 2, 3ab–gb). Much to our delight, We are grateful for nancial supports from the National Natural
2.0 equiv. KHMDS and 2.0 equiv. benzothiazole 2b were enough Science Foundation of China (Grant nos 21472043, 21272070),
to make the reaction proceed smoothly. Furthermore, gem- and the Key Project in the National Science & Technology Pillar
diuoroalkenes were almost completely consumed within Program of China in the twelh ve-year plan period
2 hours, affording the desired products in high yield (3ab, 3bb, (2011BAE06B01-15).
3db, 3). This might be in part due to the ease of dissociation of
the C–H bond in benzothiazole 2b in the presence of base.
Contrary to the reactions of 2-phenyl-1,3,4-oxadiazole 2a, the
Notes and references
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diuoroalkene could react with benzothiazole 2b smoothly and
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gem-diuoroalkenes with 2-phenyl-1,3,4-oxadiazole 2a, the
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