Convenient Synthesis of 2-(2,2-Difluoroethoxy)-6-(trifluoromethyl)-benzenesulfonyl Chloride, A Key Building Block of Penoxsulam

Article abstract of DOI:10.1055/s-0039-1690617

A convenient and efficient three-step synthesis of 2-(2,2-difluoroethoxy)-6-(trifluoromethyl)benzenesulfonyl chloride, the key building block of penoxsulam, is described. The main features of the synthesis include a regioselective lithiation and subsequent electrophilic substitution starting from commercially available 3-bromobenzotrifluoride to provide (2-bromo-6-(trifluoromethyl)phenyl)(propyl)sulfane, then a copper-catalyzed C-O coupling to introduce the difluoroethoxy moiety and chloroxidation conditions to give the desired sulfonyl chloride.

Full text of DOI:10.1055/s-0039-1690617

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2019, 51, A–D
paper
A
en
S. S. Huang et al.
Paper
Synthesis
Convenient Synthesis of 2-(2,2-Difluoroethoxy)-6-(trifluoromethyl)-
benzenesulfonyl Chloride, A Key Building Block of Penoxsulam
CF3
Shuai Shuai Huang
Zhan Jiang Zheng*
Yu Ming Cui
CF3
S
Regioselective lithiation
Electrophilic substitution
C–O coupling
Br
Zheng Xu
Br
Ke Fang Yang
Li Wen Xu*
• Commercial reagent
• Good yields
CF3
CF3
• Eco-friendly
S
SO2Cl
chloroxidation
Key Laboratory of Organosilicon Chemistry and Material Technology
of Ministry of Education, and Key Laboratory of Organosilicon Mate-
rial Technology of Zhejiang Province, Hangzhou Normal University,
P. R. of China
O
O
CHF2
CHF2
zzjiang78@hznu.edu.cn
liwenxu@hznu.edu.cn
Received: 31.05.2019
Accepted after revision: 06.08.2019
Published online: 22.08.2019
alkylation afforded the appropriately substituted sulfide,
which was converted into the desired sulfonyl chloride 3
through the use of chlorine gas in aqueous acetic acid. After
that, Zhang and co-workers reported a method4b starting
from 4-nitro-2-(trifluoromethyl)aniline which involved
DOI: 10.1055/s-0039-1690617; Art ID: ss-2019-h0389-op
Abstract A convenient and efficient three-step synthesis of 2-(2,2-di-
fluoroethoxy)-6-(trifluoromethyl)benzenesulfonyl chloride, the key
building block of penoxsulam, is described. The main features of the
synthesis include a regioselective lithiation and subsequent electrophil-
ic substitution starting from commercially available 3-bromobenzotri-
fluoride to provide (2-bromo-6-(trifluoromethyl)phenyl)(propyl)sul-
bromination,
reduction,
acetylation,
diazotisation,
deacetylation, acid hydrolysis, and chlorination. However,
the yields of these methods were usually low owing to the
tedious processes and many reaction steps (>4). In addition,
the documented methods suffer from drawbacks such as
the high cost of starting materials,4b safety problems of the
required diazotisation reaction,5 and environmental issues
of using the heavily polluting sulfur dioxide6a and strongly
stimulating sulfuryl chloride.6b,c To overcome these draw-
backs, herein, we report a novel and convenient synthesis of
sulfonyl chloride 3 in which a C–O coupling reaction is em-
ployed.
fane, then
a copper-catalyzed C–O coupling to introduce the
difluoroethoxy moiety and chloroxidation conditions to give the desired
sulfonyl chloride.
Key words penoxsulam, regioselective lithiation, benzyne intermedi-
ate, C–O coupling, chloroxidation
Penoxsulam, a member of the triazolopyrimidine sul-
fonamide family, is the active ingredient of Granite, a prod-
uct developed by Dow AgroSciences.1 It is a highly effective,
broad spectrum, acetolactate synthase (ALS) inhibiting her-
bicide used to control a wide range of weeds in rice crops.
The popularity of this herbicide is probably due to its high
weed vs crop selectivity and low toxicity in animals.2
Therefore, a number of synthetic pathways have been es-
tablished in the past decade for the preparation of penoxsu-
lam.3
OCH3
OCH3
N
CF3
N
N
N
N
NH
S
O
SO2Cl
O
H2N
N
CF3
+
N
N
O
OCH3
F2HC
CHF2
O
OCH3
2
3
1
Scheme 1 Synthesis of penoxsulam
Typically, penoxsulam (1) has been prepared from the
reaction between the corresponding amine 2 and sulfonyl
chloride 3 (Scheme 1), which forms the sulfonamide unit.4
It is obvious that one of the key intermediates of penoxsu-
lam is sulfonyl chloride 3. Consequently, many efforts have
been devoted to the synthesis of sulfonyl chloride 3. In the
original method,3a 3-(trifluoromethyl)phenol was protect-
ed with chloromethyl methyl ether (MOMCl) first, then the
protected phenol was metalated with n-BuLi. and quenched
with dipropyl disulfide to introduce a thiopropyl moiety.
Standard MOM deprotection conditions followed by phenol
Our retrosynthetic analysis of sulfonyl chloride 3 is out-
lined in Scheme 2. Inspired by the renaissance of copper ca-
talysis,7 we envisioned that the difluoroethyl aryl ether 9
could be constructed by C–O coupling between 2,2-difluo-
roethanol and aryl bromide 7, which in turn could be gen-
erated from a regioselective lithiation and subsequent elec-
trophilic substitution of the commercially available 3-bro-
mobenzotrifluoride (4).
© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–D
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
S. S. Huang et al.
Paper
Synthesis
CF3
S
CF3
CF3
C–O Coupling
CF3
CF3
SO2Cl
LDA (1.1 eq)
Dipropyl disulfide (1.1 eq)
O
Br
O
CHF2
CHF2
THF, Temp (> –60 °C)
CF3
Br
Li
4
3
5
9
CF3
CF3
Regioselective lithiation
S
6a
–60 °C, 6a/6b = 55:22
–40 °C, 6a/6b = 67:33
–20 °C, 6a/6b = 70:30
N
Br
Br
Electrophilic substitution
4
7
CF3
Scheme 2 Retrosynthetic analysis of the sulfonyl chloride building
block 3
6b
N
Initially, we used 3-bromobenzotrifluoride (4) as start-
ing material to carry out the lithiation step. Generally, if two
lithiation-directing groups are placed meta to one another,
lithiation nearly always occurs between them.8 However,
when the lithiation reaction was performed at a tempera-
ture of –40 °C, the main products we obtained were two
aniline derivatives, 6a and 6b (Scheme 3), probably due to
lithiation occurring at the uncongested ortho position to Br
to form the lithium salt of the 1,2,5-trisubstituted benzene
5, which then forms a benzyne intermediate by elimination
of LiBr at >–60 °C,9 followed by in situ reaction with diiso-
propylamine to provide the aniline derivatives 6a and 6b.
Given that the temperature can dramatically affect the
regioselectivity of the lithiation step, compound 4 was then
sequentially treated with LDA and dipropyl disulfide at –78 °C
(Scheme 4). To our delight, the reaction proceeded smooth-
ly, with lithiation occurring mainly between CF3 and Br, and
the desired sulfide 7 was obtained in good yield (71% isolat-
ed yield).
Scheme 3 Side reaction of the lithiation step and aniline formation
through a benzyne intermediate
CF3
CF3
CF3
LDA (1.1 eq)
Dipropyl disulfide (1.1 eq)
S
+
Br
THF, –78 °C
Br
Br
S
4
7
8
major
minor
Scheme 4 Synthesis of compound 7
With
(2-bromo-6-(trifluoromethyl)phenyl)(propyl)-
sulfane (7) in hand, we set out to explore the reaction be-
tween aryl bromide 7 and 2,2-difluoroethanol. As shown in
Table 1, we first checked the documented palladium-cata-
lyzed C–O coupling conditions and found no target prod-
uct.10 Then, we turned to a copper-mediated C–O coupling
reaction in the presence of different ligands, for example
Table 1 Copper (or Palladium)-Catalyzed C–O Couplinga
CF3
L (20 mol%)
Base
Cu or Pd salt (10 mol%)
CF3
S
S
CHF2CH2OH (3 eq), 100 °C
O
CHF2
Br
9
7
Entry
Ligand (L)
Base
Catalyst
Yieldb (%)
1
PPh3
Cs2CO3 (2 eq)
NaH (3 eq)
Pd(OAc)2
–
NR
NR
NR
NR
NR
68
2c
3
–
1,10-phenanthroline
N,N′-diphenethyloxalamide
8-hydroxyquinoline
–
Cs2CO3 (2 eq)
t-BuONa (1.5 eq)
K3PO4 (1.5 eq)
CHF2CH2ONa (3 eq)
CuI
4d
5
CuI
CuI
6e
CuBr
a Reaction conditions: CHF2CH2OH (3 eq), ligand (20 mol%), catalyst (10 mol%), 100 °C, 24 h.
b NR = no reaction.
c At 70 °C in THF.
d At 80 °C in the presence of 4 Å molecular sieves in 1,4-dioxane.
e In the presence of ethyl formate (2 eq) and LiCl (1 eq).
© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–D

C
S. S. Huang et al.
Paper
Synthesis
1,10-phenanthroline,11 8-hydroxyquinoline12 or N,N′-di-
phenethyloxalamide.13 Unfortunately, allreactionsproceed-
ed sluggishly and showed almost no activity, probably due
to the sterically bulky mercaptopropyl substituent at the
ortho position. Finally, we performed the reaction with so-
dium 2,2-difluoroethoxide as nucleophile, CuBr/ethyl for-
mate as catalyst system and lithium chloride as additive in
the presence of neat 2,2-difluoroethanol.14 In this case, the
reaction proceeded well to give the desired difluoroethyl
aryl ether 9 in good yield (68% isolated yield).
After the successful introduction of the difluoroethoxy
group, we aimed to convert the propyl sulfide group of 9
into the corresponding sulfonyl chloride (Scheme 5).
Following the method developed by Nishiguchi and co-
workers,15 which involves the combination of N-chloro-
succinimide and dilute hydrochloric acid, the desired sulfo-
nyl chloride 3 was obtained in good yield (76% isolated
yield). The 1H and 13C NMR spectra were in good agreement
with the reported data of compound 3. This method is more
eco-friendly than using sulfuryl chloride6c or chlorine.16,17
phase was dried over Na2SO4, concentrated in vacuo and purified by
flash column chromatography on silica gel to give 7 as a colorless oil;
yield: 4.3 g (71%).
IR: 2968, 2924, 1403, 1307, 1194, 1169, 1133, 794, 685 cm–1
.
1H NMR (400 MHz, CDCl3):  = 7.78 (d, J = 7.9 Hz, 1 H), 7.60 (d, J = 7.8
Hz, 1 H), 7.19 (t, J = 8.0 Hz, 1 H), 2.80 (t, J = 7.4 Hz, 2 H), 1.56 (m, 2 H),
0.93 (t, J = 7.3 Hz, 3 H).
13C NMR (100 MHz, CDCl3):  = 136.92, 136.52 (q, J = 29 Hz), 134.72,
129.43, 126.04 (q, J = 6 Hz), 124.49, 121.77, 38.76, 22.73, 13.50.
HRMS (APCI): m/z [M + H]+ calcd for C10H10BrF3S: 298.9711; found:
298.9726.
(2-(2,2-Difluoroethoxy)-6-(trifluoromethyl)phenyl)(propyl)sul-
fane (9)
To a freshly prepared solution of CHF2CH2ONa (from 0.69 g metallic
Na) in CHF2CH2OH (30 mL) was added CuBr (0.14 g, 1 mmol), LiCl
(0.43 g, 10 mmol), 7 (3.0 g, 10 mmol) and HCOOEt (1.48 g, 20 mmol).
The mixture was stirred at 100 °C for 48 h. Then, H2O (10 mL) was
added and the mixture was diluted with MTBE (50 mL), filtered, dried
over Na2SO4 and concentrated in vacuo. The residue was purified by
flash column chromatography to give 9 as a yellow oil; yield: 2.0 g
(68%).
IR: 2967, 2924, 1436, 1307, 1132, 1050, 800 cm–1
.
CF3
CF3
SO2Cl
O
S
1H NMR (400 MHz, CDCl3):  = 7.41 (m, 2 H), 7.08 (m, 1 H), 6.23 (tt,
J = 55.0, 4.0 Hz, 1 H), 4.30 (td, J = 12.9, 4.0 Hz, 2 H), 2.87 (t, J = 7.4 Hz, 2
H), 1.62–1.53 (m, 2 H), 0.98 (t, J = 7.3 Hz, 3 H).
NCS/2 M HCl (5 eq)
O
CHF2
CHF2
13C NMR (100 MHz, CDCl3):  = 159.44, 135.31 (q, J = 29 Hz), 129.13,
124.43, 122.03, 120.23 (q, J = 7 Hz), 115.98, 113.37 (t, J = 240 Hz),
68.38 (t, J = 30 Hz), 36.85, 23.00, 13.32.
3
9
Scheme 5 Synthesis of compound 3
HRMS (APCI): m/z [M + H]+ calcd for C12H13F5OS: 301.0680; found:
301.0695.
In conclusion, the convenient and efficient synthesis of
2-(2,2-difluoroethoxy)-6-(trifluoromethyl)benzenesulfonyl
chloride (3) has been achieved by using regioselective lithi-
ation, electrophilic substitution and a copper-catalyzed
C–O coupling as key steps, followed by a chloroxidation re-
action. The synthetic method provides a facile, eco-friendly,
and economical approach to the preparation of the sulfonyl
chloride building block of penoxsulam.
2-(2,2-Difluoroethoxy)-6-(trifluoromethyl)benzenesulfonyl Chlo-
ride (3)
To a solution of NCS (3.45 g, 26 mmol, 5 eq) in CH3CN (20 mL) was
added 9 (1.55 g, 5.2 mmol). Then, aq 2 M HCl (13 mL, 5 eq) was slowly
added. The reaction mixture was stirred at rt overnight, quenched
with aq saturated Na2CO3, then extracted with EtOAc (3 × 20 mL). The
combined organic phase was dried over Na2SO4, concentrated in vac-
uo and purified by flash column chromatography on silica gel to give
3 as a white powder; yield: 1.3 g (76%); mp 70 °C.
IR: 2924, 1480, 1440, 1307, 1050, 898, 800 cm–1
.
All reagents were used as purchased. Flash column chromatography
was performed over silica gel (100–200 mesh). 1H NMR and 13C NMR
spectra were recorded at 400 and 100 MHz, respectively, on an
Avance (Bruker) 400 MHz Nuclear Magnetic Resonance Sspectrome-
ter, and were referenced to the internal solvent signals. High-resolu-
tion mass spectra (ESI-HRMS) were obtained on a micrOTOF-Q II
(Bruker) spectrometer. IR spectra were recorded using a Nicolet 5700
FTIR apparatus. TLC was performed using silica gel.
1H NMR (400 MHz, CDCl3):  = 7.74 (t, J = 8.2 Hz, 1 H), 7.55 (d, J = 7.9
Hz, 1 H), 7.35 (d, J = 8.5 Hz, 1 H), 6.22 (tt, J = 54.8, 4.1 Hz, 1 H), 4.39
(td, J = 12.4, 4.1 Hz, 2 H).
13C NMR (100 MHz, CDCl3):  = 157.89, 136.25, 132.07, 130.00 (q,
J = 34 Hz), 123.09, 121.41 (q, J = 7 Hz), 120.36, 119.65, 112.76 (t,
J = 240 Hz), 69.63 (t, J = 30 Hz).
HRMS (APCI, sulfonyl chloride 3 derivatised with NH3/H2O before de-
tection): m/z [M + H]+ calcd for C9H8F5NO3S: 306.0218; found:
306.0227.
(2-Bromo-6-(trifluoromethyl)phenyl)(propyl)sulfane (7)
To a solution of 3-bromobenzotrifluoride (4; 4.5 g, 20 mmol) in THF
(50 mL) was added LDA (11 mL, 22 mmol, 2 M in THF/heptane) over a
period of 10 min at –78 °C. After stirring for 45 min at this tempera-
ture, dipropyl disulfide (3.3 g, 22 mmol) was added. The mixture was
stirred for 2 h at rt, then saturated NH4Cl solution (30 mL) was added,
followed by extraction with EtOAc (3 × 30 mL). The combined organic
N,N-Diisopropyl-4-(trifluoromethyl) aniline (6a) and N,N-Diiso-
propyl-3-(trifluoromethyl) aniline (6b)
To a solution of 3-bromobenzotrifluoride (4; 4.5 g, 20 mmol) in THF
(50 mL) was added LDA (11 mL, 22 mmol, 2 M in THF/heptane) over a
period of 10 min at –20 °C. After stirring for 45 min at this tempera-
ture, dipropyl disulfide (3.3 g, 22 mmol) was added. The mixture was
© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–D

D
S. S. Huang et al.
Paper
Synthesis
stirred for 2 h at rt, then saturated NH4Cl solution (30 mL) was added,
followed by extraction with EtOAc (3 × 30 mL). The combined organic
phase was dried over Na2SO4, concentrated in vacuo and purified by
flash column chromatography on silica gel to give 6a and 6b as color-
less oils.
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6a
Yield: 3.1 g (63%).
IR: 2973, 2930, 1607, 1582, 1497, 1403, 1307, 865, 777, 698 cm–1
.
1H NMR (400 MHz, CDCl3):  = 7.38 (d, J = 8.0 Hz, 2 H), 6.82 (d, J = 8.0
Hz, 2 H), 3.89 (m, 2 H), 1.29 (d, J = 8.0 Hz, 12 H).
13C NMR (100 MHz, CDCl3):  = 150.37, 125.85 (q, J = 4 Hz), 125.18 (q,
J = 261 Hz), 117.52, 117.12, 114.77, 47.36, 20.98.
HRMS (APCI): m/z [M + H]+ calcd for C13H18F3N: 246.1464; found:
246.1472.
(3) (a) Johnson, T. C.; Martin, T. P.; Mann, R. K.; Pobanz, M. A.
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Yield: 1.3 g (27%).
IR: 2973, 2930, 1607, 1583, 1498, 1403, 1307, 865, 777, 699 cm–1
.
1H NMR (400 MHz, CDCl3):  = 7.25 (t, J = 8.0 Hz, 1 H), 7.03 (s, 1 H),
6.98 (d, J = 8.0 Hz, 1 H), 6.92 (d, J = 8.0 Hz, 1 H), 3.83 (m, 2 H), 1.25 (d,
J = 8.0 Hz, 12 H).
13C NMR (100 MHz, CDCl3):  = 148.35, 130.87 (q, J = 31 Hz), 128.85,
125.99, 123.28, 120.27, 113.51 (q, J = 4 Hz), 113.39 (q, J = 4 Hz), 47.56,
21.15.
HRMS (APCI): m/z [M + H]+ calcd for C13H18F3N: 246.1464; found:
246.1470.
Funding Information
This work was supported by the Natural Science Foundation of Zheji-
ang Province (LY17E030003) and the Hangzhou Science and Technol-
ogy Bureau of China (20160432B08 and 20170533B08).
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Supporting Information
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Dev. 2007, 11, 52.
Supporting information for this article is available online at
https://doi.org/10.1055/s-0039-1690617.
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(17) Sun, Z.; Xu, J.; Wang, H.; Li, Ya.; Wen, K.; Fan, E. CN 102001979,
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© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–D