Unexpected Substitution Reaction of 1,1-Dichloro-2,2,2-trifluoroethane (HCFC-123) with Phenolates

Article abstract of DOI:10.1055/s-0040-1707291

An unexpected substitution reaction of HCFC-123 with phenolates is reported. During the reaction, fluorine atoms in HCFC-123 are removed one by one in the presence of phenolates.

Full text of DOI:10.1055/s-0040-1707291

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Georg Thieme Verlag KG Rüdigerstraße 14, 70469 Stuttgart
2020, 31, A–C
letter
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X.-J. Tang, Q.-Y. Chen
Letter
Synlett
Unexpected Substitution Reaction of 1,1-Dichloro-2,2,2-trifluo-
roethane (HCFC-123) with Phenolates
Xiao-Jun Tang*
Qing-Yun Chen*
F
Cl
ArO
F
F
Cl
0.5 equiv ArOK
DMF, 90–100 °C
F
F
Cl
Cl
9 examples, 52–91% yield
Key Laboratory of Organofluorine Chemistry, Shanghai Institute of
Organic Chemistry, University of Chinese Academy of Sciences,
Chinese Academy of Sciences, Shanghai, 200032, P. R. of China
txj_seu@126.com
⇒ Synthetic use of ozone-depleting compounds
⇒ Simple conditions and valuable products
⇒ C–F cleavage by elimination–addition process
ArO
Cl
Cl
5 equiv ArOK
ArO
Corresponding Authors
DMF, 90 °C
4 examples, 82–93% yield
QXKeMeianyaogiL-lJaYuctbxuhnojne_rTnasCaeqthnouyegr@ny1mo2fa6Oi.lc.rsogimoanc.oafcl.uconrine Chemistry, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, 200032, P. R. of China
Received: 06.08.2020
Accepted after revision: 26.08.2020
Published online: 22.09.2020
afforded the phenoxylated product 2a′ [19F NMR:  = –80.8
ppm (d, J = 4.0 Hz)] through substitution of a chlorine atom
with a phenoxy group when DCE or HCFC-123 was used as
the solvent (Scheme 1; previous work).
DOI: 10.1055/s-0040-1707291; Art ID: st-2020-l0434-l
Abstract An unexpected substitution reaction of HCFC-123 with
phenolates is reported. During the reaction, fluorine atoms in HCFC-
123 are removed one by one in the presence of phenolates.
F
F
OPh
Cl
Cu-Et2NH, Et3N
DCE, 60 °C
F
Previous work
This work
OH
2a'
F
F
Cl
Cl
Key words dichlorotrifluoroethane, phenolates, elimination, substitu-
tion
F
+
PhO
F
Cl
Cl
KOH
DMF, 50–90 °C
F
1a
HCFC-123
2a
In recent decades, hydrochlorofluorocarbons (HCFCs;
for example, HCFC-21, HCFC-22 and HCFC-123) have been
produced worldwide as transitional substitutes for chloro-
fluorocarbons or as starting materials for the manufacture
of hydrofluorocarbons (e.g., HCFC-133a). As ozone-deplet-
ing compounds, HCFCs will be banned from use as refriger-
ants, aerosol propellants, and cleaning solvents by 2040 un-
der the Montreal Protocol. Nevertheless, investigations on
the reactivities of HCFCs are still attractive from the view-
point of their chemistry. On the one hand, due to the induc-
tive and stereoelectronic effect of the fluorine atoms, the C–
Cl bonds in HCFCs tend to undergo single-electron transfer
reactions1–3 rather than SN1 or SN2 reactions of other alkyl
chlorides.4 On the other hand, some HCFCs are irreplaceable
for the preparation of fluoroalkyl reagents.5,6 Therefore, re-
searches on the reactivities of HCFCs are desirable from the
points of view of both fluorine chemistry and environmen-
tal protection.
Scheme 1 The reactions of HCFC-123 with phenol (1a) under various
conditions
To our surprise, when we used DMF as the solvent and
KOH as the base, and performed the reaction at 50 °C for
three hours, a different product 2a appeared in the 19F NMR
spectrum [ = –80.2 ppm (d, J = 5.8 Hz)] (Scheme 1 and Ta-
ble 1, entry 1). The 19F NMR yield of 2a improved to 82%
when the reaction was performed at 70 °C for three hours
(entry 2). The yield decreased slightly when another aprotic
solvent (DMSO or HMPA) was used (entries 3 and 4). Note
that a byproduct with a 19F NMR peak at  = –78 ppm was
also detected; the formation of this byproduct was inhibit-
ed by increasing the amount of HCFC-123 to two equiva-
lents (entry 5). Eventually, the isolated yield 2a was in-
creased to 88% by performing the reaction at 90 °C for two
hours (entry 6).
As an HCFC with a lower ozone-depleting potential, 1,1-
dichloro-2,2,2-trifluoroethane (HCFC-123) is widely used
as the refrigerant, a cleaning solvent, or a foaming agent. In-
spired by the pioneering work of Dolbier’s group,7 we have
extensively investigated the Cu-mediated reactions of
HCFC-123 with phenols, thiophenols,8 alkynes,9,10
alkenes,11 and phosphites.12 In particular, the Cu-mediated
reaction of HCFC-123 with phenol in the presence of Et3N
With the optimized conditions in hand, we extended
this reaction to other phenols (Scheme 2). Phenols bearing
electron-donating groups gave the corresponding products
2a–f in excellent yields within three hours. In contrast, phe-
nols bearing electron-withdrawing groups afforded the de-
sired products 2g–i in moderate yields after prolonged re-
action times.
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–C
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B
X.-J. Tang, Q.-Y. Chen
Letter
Synlett
Phenols with strongly electron-withdrawing groups
shut down the reaction (2j and 2k). As mentioned above, a
small amount of a byproduct was detected at  = –78 ppm
in the 19F NMR spectrum when the molar ratio of 1m to
HCFC-123 was 1:1.2. When the molar ratio of 1m to HCFC-
123 was to 2.5:1, compound 2mm, which appeared at  =
–78 ppm in the 19F NMR spectrum, became the main prod-
uct, with a 71% isolated yield (Scheme 3).
F
Table 1 Optimization of the Conditions for the Reaction of Phenol (1a)
1) KOH, 25 to 40 °C
2) HCFC-123
OH
O
O
with HCFC-123a
DMF, 90 °C, 12 h
Cl
Cl
1) KOH, 40 °C
F
1m
2mm, 71% yield
F
2) HCFC-123, Temp
O
OH
Scheme 3 The reaction of HCFC-123 with 1m in a molar ratio of 1:2.5
Cl
Cl
1a
2a
However, with the electron-deficient phenols 1c and 1h,
although products 2cc and 2hh were detected in 19F NMR,
the defluorinated products 2ccc and 2hhh (Scheme 4),
rather than 2cc and 2hh, were isolated by column chroma-
tography on silica gel. As expected, when we increased the
molar ratio of the phenolate to HCFC-123 to 5:1, the fully
defluorinated products 2aaa–2ccc were obtained in good to
excellent yields for both electron-rich and electron-defi-
cient phenols (Scheme 4). Taking 1b as an example, prod-
ucts 2b, 2bb, and 2bbb were all detected by TLC and 19F
NMR after 30 minutes of reaction, and 2bbb was shown to
be the sole product after 12 hours.
Entry
Solvent
Temp (°C)
Yieldb (%)
1
DMF
50
70
70
70
70
90
trace
82
2
DMF
3
DMSO
HMPA
DMF
66
4
70
5c
6d
93
DMF
88e
a 1a/KOH/HCFC-123 molar ratio = 1:1.1:1.2; [HCFC-123] = 1 mol/L, 3 h.
b Determined by 19F NMR with PhCF3 as the internal standard.
c 1a/KOH/HCFC-123 molar ratio = 1:1.1:2, 3 h.
d 1a/KOH/HCFC-123 molar ratio = 1:1:2, 2 h.
e Isolated yield.
O
O
1) KOH, 25 to 40 °C
2) HCFC-123
OH
R
R
R
Cl
Cl
DMF, 90 °C, 12 h
F
Cl
Cl
R
R
F
1) 1 equiv KOH, 25 to 40 °C
2) 2 equiv HCFC-123
O
O
O
O
O
OH
R = H, 2aaa, 93%
R = Me, 2bbb, 82%
R = Cl, 2ccc, 92%
DMF
N
Cl
Cl
N
R
Cl
Cl
R
1a–k
2a–k
2hhh, 83%
F
F
F
Cl
Cl
Cl
Cl
Cl
F
F
F
Scheme 4 Reactions of HCFC-123 with selected phenols at a molar ra-
O
Cl
O
O
Cl
tio of 1:5
2a, 90 °C, 2 h, 88%
2b, 90 °C, 3 h, 91%
2c, 90 °C, 8 h,72%
F
F
F
Cl
Cl
In addition, the reaction of purified 2e with four equiva-
lents of potassium 4-methylphenoxide gave the defluori-
nated product 2ebb in 86% yield (Scheme 5).
Cl
Cl
2f, 90 °C,8 h, 79%
F
O
Cl
Cl
F
F
MeO
O
O
HN
O
2d, 90 °C, 2 h, 84%
2e, 90 °C, 3.5 h, 88%
Finally, an acid-base pathway was proposed for the re-
action mechanism (Scheme 6). The key intermediate, 1,1-
dichloro-2,2-difluoroethene, generated by an acid–base re-
action, reacts further with the phenolate and affords the
product 2a.13 However, a halophilic mechanism, similar to
the reaction of the phenolate with CF3CCl3 cannot be ex-
cluded.14,15 In this pathway, the phenolate attacks the chlo-
rine atom in HCFC-123 and produces 1-chloro-2,2-difluoro-
ethene, which reacts with a second phenolate ion16 to af-
ford the product through a chain–anion mechanism.
F
Cl
Cl
F
F
Cl
F
Cl
Cl
Cl
F
F
MeO
O
N
O
O
Cl
O
2g, 90 °C, 9 h, 76%
2h, 100 °C, 12 h, 61%
2i, 90 °C, 12 h, 52%
F
F
Cl
Cl
F
F
N
H
O
O
Cl
O
Cl
2j, 110 °C, 24 h, 0%
2k, 110 °C, 24 h, 0%
Scheme 2 Reactions of HCFC-123 with various phenols in a molar ratio
of 2:1
O
O
(4 equiv)
OK
OCF2CHCl2
O
O
Cl
Cl
N
N
H
DMF, 90 °C, 12 h
H
2e
2ebb, 86% yield
Scheme 5 The reaction of 2e with potassium 4-methylphenolate at a molar ratio of 1:4
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–C

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X.-J. Tang, Q.-Y. Chen
Letter
Synlett
(5) Tang, X.-J.; Thomoson, C. S.; Dolbier, W. R. Jr. Org. Lett. 2014, 16,
4594.
(6) Stahly, G. P. J. Fluorine Chem. 1989, 43, 53.
(7) Xu, Y.; Dolbier, W. R.; Rong, X. X. J. Org. Chem. 1997, 62, 1576.
(8) Tang, X.-J.; Chen, Q.-Y. Org. Lett. 2012, 14, 6214.
(9) Han, E.-J.; Sun, Y.; Shen, Q.; Chen, Q.-Y.; Guo, Y.; Huang, Y. G.
Org. Chem. Front. 2015, 2, 1379.
Cl
F
F
–
+ Cl
Cl
F
OPh
F
Cl
Cl
F
F
H
F
PhO K
–
Cl
+
PhO K
– KF
proton transfer
(10) Zheng, J.; Chen, Q.-Y.; Sun, K.; Huang, Y.; Guo, Y. Tetrahedron
Lett. 2016, 57, 5757.
(11) Han, E.-J.; Guo, Y.; Chen, Q.-Y. Youji Huaxue 2017, 37, 1714.
(12) Luo, J.; Han, E.-J.; Shen, Q.; Huang, M.; Huang, Y.; Liu, H.-M.;
Wang, W.; Chen, Q.-Y.; Guo, Y. Org. Process Res. Dev. 2016, 20,
1988.
Cl
Cl
F
OPh
F
PhOH
2a
Scheme 6 Proposed plausible reaction mechanisms
(13) Subramanian, R.; Johnson, F. J. Org. Chem. 1985, 50, 5430.
(14) Li, X.-y.; Pan, H.-q.; Jiang, X.-k.; Zhan, Z.-y. Angew. Chem. Int. Ed.
1985, 24, 871.
(15) Li, X.-y.; Jiang, X.-k.; Pan, H.-q.; Hu, J.-s.; Fu, W.-m. Pure Appl.
Chem. 1987, 59, 1015.
(16) Tarrant, P.; Brown, H. C. J. Am. Chem. Soc. 1951, 73, 5831.
(17) Fukui, H.; Sanechika, K.-i.; Watanabe, M.; Ikeda, M. J. Fluorine
Chem. 2000, 101, 91.
(18) Fukui, H.; Muruta, H.; Sanechika, K.-i.; Ikeda, M. J. Fluorine
Chem. 2000, 103, 129.
In summary, we have reported unexpected substitution
reaction of fluorine in HCFC-123 by phenolates. By increas-
ing the amount of the phenolate, the fluorine atoms in
HCFC-123 could be removed one by one. This reaction can
produce valuable fluorinated alkyl aryl ethers17,18 and un-
usual tetrasubstituted alkenes from readily available HCFC-
123 under simple conditions.19
(19) (2,2-Dichloro-1,1-difluoroethoxy)benzene (2a): Typical Pro-
cedure
Funding Information
A 20 mL Schlenk tube was charged with DMF (10 mL) and 1a (5
mmol, 470 mg). KOH (5 mmol, 280 mg) was added, and the
mixture was stirred at 40 °C until the KOH disappeared. The
mixture was then cooled to r.t. Precooled HCFC-123 (10 mmol,
1.52 g) was added to the solution, and the mixture was stirred
at 90 °C for 2 h, then cooled to r.t. The mixture was then poured
into Et2O (100 mL), washed with H2O, dried (Na2SO4), and con-
centrated by rotary evaporation under vacuum. The residue was
purified by flash column chromatography [silica gel, PE–CH2Cl2
(20:1)] to give a colorless oil; yield: 994 mg (88%).
1H NMR (300 MHz, CDCl3):  = 7.35–7.40 (m, 2 H), 7.21–7.29 (m,
3 H), 5.91 (t, J = 4.4 Hz, 1 H). 13C NMR (100 MHz, CDCl3):  =
149.5, 129.6, 126.4, 121.7, 119.7 (t, J = 270 Hz), 67.8 (t, J = 42
Hz). 19F NMR (282 MHz, CDCl3):  = –80.2 (d, J = 5.8 Hz). MS (EI):
m/z (%) = 226 (M+, 21.51), 77 (100), 143 (50.87), 65 (38.96), 94
(30.34), 226 (21.51).
We thank the Chinese Academy of Science, the National Natural Sci-
ence Foundation of China (21032006), and the 973 Program of China
(2012CBA01200) for the financial support.Natio
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Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0040-1707291. Su
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References and Notes
(1) Tang, X.-J.; Chen, Q.-Y. Chem. Sci. 2012, 3, 1694.
(2) Tang, X.-J.; Chen, Q.-Y. J. Fluorine Chem. 2015, 169, 1.
(3) Long, Z.-Y.; Chen, Q.-Y. J. Fluorine Chem. 1998, 91, 95.
(4) Lee, H.; Kim, K. H.; Kim, H.; Lee, S. D.; Kim, H. S. J. Fluorine Chem.
2004, 125, 95.
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–C