Base-promoted nucleophilic fluoroarenes substitution of C–F bonds

Article abstract of DOI:10.1016/j.tet.2017.11.067

With the use of KOH/DMSO as the superbase medium, the nucleophilic fluoroarene substitution for C–F bonds is presented. The transformation proceeds smoothly with the use of fluoroarenes bearing not only electron-withdrawing group, but also electron-donating group and a variety of nucleophiles such as alcohols, phenols, amines, amides and nitrogen-heterocyclic compounds. The double nucleophilic substitution using ortho-difluoroarenes and nucleophiles bearing ortho-dinucleophilic groups results in the formation of 2,3-dihydro-1,4-benzodioxins, dibenzo[b,e][1,4]dioxins and 10H-phenoxazines in moderate to good yields.

Full text of DOI:10.1016/j.tet.2017.11.067

Accepted Manuscript
Base-promoted nucleophilic fluoroarenes substitution of C-F bonds
Ji Su, Qian Chen, Le Lu, Yuan Ma, George Hong Lok Auyoung, Ruimao Hua
PII:
S0040-4020(17)31233-4
10.1016/j.tet.2017.11.067
TET 29147
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 16 September 2017
Revised Date: 19 November 2017
Accepted Date: 23 November 2017
Please cite this article as: Su J, Chen Q, Lu L, Ma Y, Auyoung GHL, Hua R, Base-promoted nucleophilic
fluoroarenes substitution of C-F bonds, Tetrahedron (2017), doi: 10.1016/j.tet.2017.11.067.
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ACCEPTED MANUSCRIPT
Graphical Abstract
Base-promoted nucleophilic fluoroarenes substitution for C-F bonds
1

ACCEPTED MANUSCRIPT
Base-promoted nucleophilic fluoroarenes substitution of C-F bonds
Ji Su,a,b Qian Chen,a Le Lu,a Yuan Ma,a George Hong Lok Auyoungb and Ruimao Huaa,*
a Department of Chemistry, Tsinghua University, Beijing 100084, China
b Ferguson (Wuhan) Biotechnologies Ltd. Wuhan 430014, China
E-mail: ruimao@mail.tsinghua.edu.cn
Abstract: With the use of KOH/DMSO as the superbase medium, the nucleophilic
fluoroarene substitution for C-F bonds is presented. The transformation proceeds smoothly
with the use of fluoroarenes bearing not only electron-withdrawing group, but also
electron-donating group and a variety of nucleophiles such as alcohols, phenols, amines,
amides and nitrogen-heterocyclic compounds. The double nucleophilic substitution using
ortho-difluoroarenes and nucleophiles bearing ortho-dinucleophilic groups results in the
formation of 2,3-dihydro-1,4-benzodioxins, dibenzo[b,e][1,4]dioxins and 10H-phenoxazines
in moderate to good yields.
Keywords: base-promoted; fluoroarenes; nucleophilic substitution; C-F bond
functionalization.
1. Introduction
Fluoroarenes are one of the important kind of aromatic compounds not only showing
special properties in pharmaceutical compounds1 and organic material molecules,2 but also
being well used as versatile intermediates for the synthesis of functionalized aromatics via
C-F bond activation.3 Three major classification of C−F bond activation processes for its
functionalization have been developed, including transition-metal-catalyzed/mediated C−F
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bond activation,4 ortho-directing groups-driven nucleophilic aromatic substitution (SNAr)
reactions of C−F bond with organolithium or Grignard reagents,5 and base-promoted SNAr of
C−F bond with a variety of nucleophiles. Among of them, the base-promoted SNAr reactions
of fluoroarenes have been recently received particular attention due to using easily available
nucleophiles and without use of transition metal catalysts.6
The representative reported examples include the KHMDS (potassium
bis(trimethylsilyl)amide)-promoted SNAr reaction of fluroarenes with secondary nitrile anion
in toluene to form C-C bond,6a P(i-BuNCH2CH2)3N-catalyzed the reactions of fluroarenes
bearing nitro, cyano, ester, or aldehyde groups with aryl TBDMS (t-butyl dimethyl silyl) or
TMS ethers in toluene to give diaryl ethers,6b Cs2CO3/DMSO-promoted SNAr reaction
between fluoroarenes having electron-withdrawing group(s) and various secondary amines,6c
KF/CP (potassium fluoride/clinoptilolite)-mediated the coupling of nitro-activated fluroarenes
with phenols, anilines and thiophenols in DMSO,6d Cs2CO3/DMSO-promoted the synthesis of
unsymmetrical polyfluoroaryl ethers via selective C4–F bond cleavage of pentafluorobenzene
with a wide variety of phenols and benzyl alcohols,6e NaOH/DMF-mediated the synthesis of
N-tetrafluoroarylated heterocyclic compounds via selective C4–F bond cleavage of
pentafluorobenzene with N–H containing heterocycles,6f NaOtBu/DMA-promoted sequential
SNAr reactions of pentafluorobenzenes with azoles or indoles,6g and in the presence of Et3N,
pentafluoropyridine and 2,4,6-trifluoropyridine underwent SNAr reactions with a series of
primary and secondary amines for the syntheses of a library of simple and complex
fluorinated 4-aminopyridine derivatives.6h
Encouraged by our previous success in the application of KOH/DMSO as the superbasic
medium in the development of a general procedure for the synthesis of five-membered
heterocycles via the cycloaddition of 1,3-butadiynes with water, primary amines, and
Na2S.9H2O,7 and KOH/DMSO has shown the versatile diverse catalytic activity in a variety of
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organic transformation reported by Trofimov,8 Bolm,9 and other groups,10 in this paper we
investigated the application of KOH/DMSO in the nucleophilic fluoroarene substitution with
a variety of nucleophiles to provide an alternative base-promoted SNAr of C−F bonds.
2. Results and discussion
As shown in Table 1, we firstly studied the reaction of 2-fluorobenzamide (1a) with
MeOH (4 equiv) in the presence of KOH (4 equiv) in DMSO at room temperature.
Fortunately, 2-methoxybenzamide (2aa) could be isolated from the reaction mixture in 81%
yield (entry 1). 2aa could not form at all without use of KOH (entry 2). Other inorganic bases,
such as K2CO3, Cs2CO3, t-BuOK, NaOH in DMSO also promoted the SNAr reaction, but 2aa
formed in fair to mild yields (entries 3-6). When THF and dioxane were used to replace
DMSO as solvents, KOH showed fairly low ability to promote the reaction (entries 7-8). The
further studies on the effect of amounts of MeOH and KOH have disclosed that the use of 2
equivalents of MeOH and KOH is the suitable choice for the formation of 2aa in a
satisfactory yield (entries 9-13).
Table 1
Optimizing conditions for nucleophilic substitution of C-F bond with MeOH a
entry
MeOH (equiv)
base (equiv)
KOH (4)
----
solvent yield (%)b
1
2
3
4
5
6
4
4
4
4
4
4
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
81
0
K2CO3 (4)
Cs2CO3 (4)
t-BuOK (4)
NaOH (4)
15
12
47
64
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7
8
4
4
1
2
2
2
2
KOH (4)
KOH (4)
KOH (4)
KOH (4)
KOH (0.2)
KOH (1)
KOH (2)
THF
36
22
45
77
11
40
80
dioxane
DMSO
DMSO
DMSO
DMSO
DMSO
9
10
11
12
13
a 2-fluorobenzamide (0.5 mmol), solvent (2 mL), 16 h.
b Isolated yields.
Table 2 summarizes the SNAr reactions of 1a with O-nucleophiles (2 equivalents) in the
presence of 2 equivalents of KOH. In the case of without using additional nucleophile, KOH
can act as a nucleophile to generate 2ab in 55% yield, and the addition of H2O improved the
yield to 83%. It is worth that the direct Pd-catalyzed synthesis of phenols by the reactions of
aryl bromides or chlorides with KOH has been developed by Buchwald’s group.11 The use of
EtOH and i-PrOH afforded the corresponding alkylaryl ethers 2ac and 2ad in 63% and 74%
yields, respectively. Although it is commonly acknowledged that the alcohols having more
alkyl substituents engage higher nucleophilicity, on the basis of the obtained results, methanol
shows higher nucleophilicity (the yield of 2aa in Table 1 of entry 13 vs the yields of 2ac and
2ad in Table 2). We assume that methanol has less steric hindrance to benefit the SNAr
reactions. Benzyl alcohol also undergoes the substitution to give 2ae in 55% yield. However,
trifluoroethanol shows sluggishly at room temperature, and when the reaction performed at
o
100 C, the corresponding ether 2af could form in 98% yield. In addition, phenols show low
reactivity for the SNAr reactions at room temperature, and at 100 oC, a variety of diaryl ethers
could be obtained in 42 ~ 86% yield. As expected, the phenols bearing electron-withdrawing
group such as 4-chlorophenol and 4-nitrophenol show very low reactivity to afford trace
o
amount of the expected products at 100 C. Moreover, the substituent position effect on the
nucleophilicity of phenols can be also obviously observed (2ai vs 2aj). Under the similar
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reaction conditions, the reaction of 1a with 1,3,5-trimethylphenol afforded 2ak in a moderate
yield (42%) due possible to the steric hindrance of methyl groups.
Table 2
C-F bond nucleophilic substitution by ROH nucleophiles a
O
NH2
F
O
NH2
OR
KOH (2 equiv), DMSO
rt or 100 oC for 16 h
+
R-OH
2.0 equiv
1a
NH2
OH
2
O
O
NH2
OiPr
O
NH2
O
O
NH2
OEt
Ph
2ab
2ad 74%
2ae 55%
2ac 63%
without ROH: 55%
H2O: 83%
O
NH2
O
NH2
O
O
NH2
O
O
Ph
CF3
2ah 73% (100 oC)
2ag 68% (100 oC)
2af 98% (100 oC)
O
NH2
O
NH2
O
O
NH2
O
OMe
O
OMe
OMe
2aj 42% (100 oC)
2ak 42% (100 oC)
2ai 86% (100 oC)
a The reactions were carried out using 0.5 mmol of 1a, 1.0 mmol of
O-nucleophiles and 1.0 mmol of KOH in DMSO (2 mL).
Table 3 concludes the SNAr reactions of 4-nitrofluoroarene (1b) with amines and amides.
Although all the reactions at room temperature are very sluggish, the formation of C-N bonds
o
at 80 C is smoothly. 2bl could be isolated from the reaction mixture in a fair yield by the
reaction of 1b with 2 equiv of dimethylamine hydrochloride in the presence of 4 equiv. of
KOH. The use of piperidine led to the formation of 2bm in 54% yield. When 4-methylaniline
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and 2-aminopyridine were used, 4-methyl-N,N-bis(4-nitrophenyl)aniline (2bn) and
2-amino-N,N-bis(4-nitrophenyl)pyridine (2bo) were obtained in 48% and 63% yields,
respectively, resulting from the subsequent SNAr reactions of one molecule of primary amines
with two molecules of 1b, and only small amount of diaryl amines could be detected by
GC-MS. Pyrrole and its derivatives, such as indole and 5-methoxyindole could be also used as
the N-nucleophiles to afford the expected products (2bp, 2bq and 2br) in fair yields. In
addition, benzamide shows good reactivity in the SNAr reaction giving
N-(4-nitrophenyl)benzamide (2bs) in 68% yield. More interestingly, urea could be employed
as an efficient precursor of ammonia as N-nucleophile to give 4-nitroaniline (2bt) in 61%
yield.
Table 3
Amines and amides as nucleophile a
KOH (2 equiv), DMSO
F
O2N
O2N
+ N-H
2 equiv
O2N
N
80 oC for 16 h
2
1b
NO2
NMe2
O2N
NO2
O2N
N
2bl 32%b
2bm 54%
O2N
O2N
N
N
2bn 48%
N
O2N
O2N
N
N
2bp 38%
2bo 63%
2bq 34%
N
O2N
NH
O2N
NH2
O
Ph
2bt 61%(urea)
O
2bs 68%
2br 32%
a Unless otherwise noted, the reactions were carried out using 0.5 mmol
of 1b, 1.0 mmol of N-nucleophiles and 1.0 mmol of KOH in DMSO (2 mL)
at 80 oC.
b 4 equiv. of KOH.
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Table 4 concludes the SNAr reactions of a variety of fluoroarenes having different
substituents with methanol in KOH/DMSO. The reactions of N-methyl-2-fluobenzamide (1c)
and 4-fluorobenzamide (1d) at room temperature produced the expected products 2ca and 2da
in 64% and 56% yields, respectively. Both 4-fluobenzonitrile (1e) and 3-fluobenzaldehyde (1f)
were also able to afford corresponded products 2ea and 2fa albeit in relatively low yields with
cyano and aldehyde groups untouched. At room temperature, although the reaction of
3,4-difluoronitrobenzene (1g) with 2 equiv. of methanol resulted in the formation of a mixture
of mono- and di-SNAr products, and the mono-SNAr product of 2-fluoro-1-methoxy-4-
nitrobenzene (2ga) formed as the predominant one. However, when the reaction was
performed using 1 equiv. of methanol, 2ga was obtained in high yield (85%), indicating that
the reaction occurred with excellent regioselectivity resulted from the position-effect of two
fluoro atoms related to nitro group in benzene ring, and fluoro at para-position exhibits
significantly high reactivity. Under the similar reaction conditions, the reaction of
2-bromo-4-fluoroacetophenone (1h) at room temperature afforded the expected product (2ha)
in 17% yield, and the reaction of 4-bromofluoroarene (1i) at 100 oC produced
1-bromo-4-methoxybenzene (2ia) in 45% yield. These results imply that fluorine was exactly
a better SNAr leaving group rather than bromo group.
In addition, although the base-promoted SNAr reactions of fluoroarenes have been
well-documented, the fluoroarenes are limited to bearing electron-withdrawing group(s).6 To
date, it has not reported an efficient reaction conditions for the SNAr reactions of
fluorobenzene, and fluoroarenes having electron-donating group. Therefore, it is very
interesting and significant to examine the SNAr reactions of fluorobenzene (1j) and
fluoroarenes bearing electron-donating group under the similar reaction conditions. As shown
Table 4, it is surprising that 1j, 2-methoxyfluorobenzene (1k) and 4-methoxyfluorobenzene
(1l) underwent the SNAr reactions smoothly with methanol to give the corresponding aryl
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methyl ethers 2ja ~ 2la in good yields, when the reactions were carried out at 100 oC.
Table 4
Scope of fluoroarenes a
F
O
KOH (2 equiv), DMSO
16 h
R
R
+
MeOH
2.0 equiv
1
2
O
O
O
NHMe
O
O
OHC
O
F
H2N
NC
O
2ca 64%
2da 56%
2ea 47%
2fa 26%
NO2
2ga 85%b
O
Br
O
O
O
O
OMe
MeO
O
Br
2ha 17%
2ia 45%c
2ja 53%c 2ka 79%d
2la 72%d
a Unless otherwise noted, the reactions were carried out using 0.5 mmol of 1,
1.0 mmol of MeOH and 1.0 mmol of KOH in DMSO (2 mL) at room temperature
for 16 h.
b 1 equiv of MeOH.
c 100 oC.
d 130 oC.
We also tried to develop a synthetic strategy for construction of 1,4-diheteroatom ring via
a double SNAr reaction of 1g with double nucleophiles. As shown in Table 5, the reactions of
o
1g with 1 equiv. of glycol, ortho-dihydroxybenzene and 2-aminophenol at 100 C for 16 h
afforded the corresponding 1,4-diheteroatom ring in moderate yields, with the formation of
by-product resulted from the mono-SNAr reaction.
Table 5
Intermolecular Cyclo-nucleophilic Substitution of 1g
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It has been commonly known that most SNAr reactions occur by addition-elimination
reactions involving the formation of a carbanion intermediate.12 The computational study for
the reaction of fluorobenzene with KOMe, generated in situ by the reaction of KOH with
MeOH,13 in DMSO solution or under vacuum state has disclosed that the addition of MeO-
anion to carbon (C-F bond) in DMSO requires lower activation energy than that under
vacuum state, indicating the considerable DMSO solvent effect on the present SNAr
reactions.14
3. Conclusion
In summary, we have developed the SNAr reactions of fluoroarenes with a variety of
nucleophiles such as alcohols, phenols, amines, amides and nitrogen-heterocyclic compounds
using KOH/DMSO as medium under mild conditions, providing an alternative base-promoted
C−F bond activation process. Fluoroarenes having either electron-withdrawing groups or
electron-donating group undergo the SNAr reactions smoothly. Therefore, this work addresses
the limitations of the previous reports on the SNAr reactions of fluoroarenes bearing
electron-withdrawing group(s), and realizes the C−F bond activation of fluoroarenes bearing
electron-donating group. In addition, the present process is tolerant of amide, bromo, cyano,
aldehyde, and acetyl functional groups.
4. Experimental section
4.1 General methods
All commercial reagents are analytically pure and used without further purification. All
reactions were carried out without any particular precautions to moisture or oxygen. Nuclear
magnetic resonance (NMR) spectra were recorded on a JEOL ECA-400 using CDCl3 or
1
DMSO-d6 as solvent at 298 K. H NMR (400 MHz) chemical shifts (δ) were referenced to
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internal standard TMS (δ = 0.00 ppm). 13C NMR (100 MHz) chemical shifts were referenced
to internal solvent (δ = 77.16 ppm in CDCl3; 39.52 ppm in DMSO-d6). GC-MS were obtained
on a Shimadzu GCMS-QP2010S, and high-resolution mass spectra (ESI) were obtained with
a microTOF-Q 10142 spectrometer. The melting points are uncorrected.
4.2 Typical procedure for the synthesis of 2aa. A mixture of 2-fluorobenzamide (1a, 69.5
mg, 0.5 mmol), MeOH (ca. 32.0 mg, 1.0 mmol), KOH (56.0 mg, 1.0 mmol) and DMSO (2.0
mL) in a 25 mL screw-capped thick-walled Pyrex tube was stirred at room temperature for 16
h, and then water (10 mL) was added to the reaction mixture with stirring, and the mixture
was extracted with ethyl acetate three times (3 x 10 mL). The combined organic phases were
dried over Na2SO4 overnight. The filtered solution was concentrated under reduced pressure,
and the crude residue was purified by column chromatography on silica gel with the use of
petroleum ether/ethyl acetate/trimethylamine (gradient mixture ratio from 6:1:0.05 to 2:1:0.05
in volume) to afford 2aa as a white solid in 80% yield (60.7 mg).
4.3 Characterization data of product
The characterization data for known products are reported in the Supporting Information.
2af, 2ah, 2ai, 2aj and 2ak are new compounds, their spectroscopic data are reported below.
2-(2,2,2-Ttrifluoroethoxy)benzamide (2af). White solid (107.3 mg, 98%), mp 127~129 oC. 1H
NMR (400 MHz, DMSO-d6): δ 7.68 (dd, J = 6.3, 1.5 Hz, 1H), 7.60 (s, 1H), 7.49–7.45 (m,
1H), 7.38 (s, 1H), 7.21 (d, J = 6.6 Hz, 1H), 7.13–7.09 (m, 1H), 4.86 (q, J = 6.3 Hz, 2H). 13C
NMR (100 MHz, CDCl3): δ 166.4, 155.2, 133.6, 133.2, 123.3, 123.1 (q, J = 280.7 Hz), 122.1,
112.6, 66.5 (q, J = 28.7 Hz). GC-MS m/z (% rel. inten.) 219 (M+, 29), 203 (87), 182 (75), 150
(65), 133 (78), 105 (100), 92 (52), 72 (53). HRMS (ESI) calcd for C9H8F3NO2 ([M + H]+):
220.0580. Found: 220.0579.
o
1
2-(m-Tolyloxy)benzamide (2ah). Pale yellow solid (82.7 mg, 73%), mp 89~91 C. H NMR
(400 MHz, CDCl3): δ 8.27–8.24 (m, 1H), 7.62 (s, 1H), 7.41–7.37 (m, 1H), 7.29–7.25 (m, 1H),
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7.21–7.16 (m, 1H), 7.02 (d, J = 6.2 Hz, 1H), 6.88–6.82 (m, 3H), 6.23 (s, 1H), 2.35 (s, 3H). 13C
NMR (100 MHz, CDCl3): δ 149.0, 140.4, 139.7, 127.9, 122.0, 121.3, 119.4, 115.9, 114.1,
113.9, 111.8, 110.0, 108.9, 32.5. GC-MS m/z (% rel. inten.) 227 (M+, 23), 120 (18), 108 (100),
65 (13). HRMS (ESI) calcd for C14H13NO2 ([M + H]+): 228.1019. Found: 228.1018.
o
2-(4-Methoxyphenoxy)benzamide (2ai). White solid (104.3 mg, 86%), mp 156~158 C.1H
NMR (400 MHz, CDCl3): δ 8.24 (dd, J = 6.3, 1.3 Hz, 1H), 7.71 (s, 1H), 7.37–7.32 (m, 1H),
7.16–7.11 (m, 1H), 7.03–7.00 (m, 2H), 6.94–6.91 (m, 2H), 6.75 (d, J = 8.4Hz, 1H), 6.54 (s,
1H), 3.82 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 149.0, 141.2, 141.0, 134.0, 122.0, 121.4,
113.7, 113.2, 112.7, 108.9, 107.6, 60.0. HRMS (ESI) calcd for C11H11NO3 ([M + H]+):
244.0968. Found: 244.0967.
o
2-(3,5-Dimethoxyphenoxy)benzamide (2aj). Pale yellow solid (57.5 mg, 42%), mp 84~86 C.
1H NMR (400 MHz, CDCl3): δ 8.24 (dd, J = 6.3, 1.4 Hz, 1H), 7.52 (s, 1H), 7.43 – 7.38 (m,
1H), 7.23 – 7.18 (m, 1H), 6.91 (dd, J = 6.6, 0.5 Hz, 1H), 6.33 (s, 1H), 6.31 (t, J = 1.7 Hz, 1H),
13
6.21 (d, J = 1.7 Hz, 2H), 3.76 (s, 6H). C NMR (100 MHz, CDCl3): δ 148.8, 145.0, 141.2,
139.9, 122.1, 121.3, 114.4, 114.0, 110.4, 94.0, 92.9, 59.9. HRMS(ESI) calcd for C15H15NO4
([M + H]+): 274.1074. Found: 274.1071.
2-(Mesityloxy)benzamide (2ak). White solid (103.3 mg, 42%), mp 192~194 oC. 1H NMR (400
MHz, CDCl3): δ 8.30 (dd, J = 6.3, 1.4 Hz, 1H), 7.94 (s, 1H), 7.31 – 7.26 (m, 1H), 7.09 (t, J =
6.0 Hz, 1H), 6.95 (s, 2H), 6.45 (d, J = 6.6 Hz, 1H), 6.28 (s, 1H), 2.32 (s, 3H), 2.09 (s, 7H). 13C
NMR (100 MHz, CDCl3): δ 149.0, 140.6, 133.6, 124.0, 122.2, 121.8, 120.2, 119.5, 113.0,
111.7, 106.0, 32.2, 28.5.HRMS (ESI) calcd for C16H17NO2 ([M + H]+): 255.1312. Found:
255.1310.
Acknowledgements
This project was supported by National Natural Science Foundation of China (21473097).
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Supplementary data
1
The characterization data for known products, copies of H and 13C NMR charts of all
products associated with this article can be found in the online version, at
http://dx.doi.org/10.1016/j.tet.xxxx.
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14. The detailed data have been reported in Supporting Information.
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