A Two-Step, One-Pot, and Multigram-Scale Synthesis of N-Difluoromethylthiophthalimide

Article abstract of DOI:10.1021/acs.oprd.7b00203

A new method for the 100 g scale synthesis of N-difluoromethylthiophthalimide 1 from cheap commodity chemical benzyl mercaptan and HCF₂Cl or other difluorocarbene precursors was described. Reagent 1 is an excellent electrophilic difluoromethylthiolating reagent as demonstrated by the gram-scale synthesis of five difluoromethylthiolated derivatives of structurally complicated drug-like molecules and natural products.

Full text of DOI:10.1021/acs.oprd.7b00203

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Full Paper
A Two-Step, One-Pot and Multigram-Scale
Synthesis of N-Difluoromethylthiophthalimide
Dianhu Zhu, Xin Hong, Dezhi Li, Long Lu, and Qilong Shen
Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.7b00203 • Publication Date (Web): 07 Jul 2017
Downloaded from http://pubs.acs.org on July 8, 2017
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A TwoꢀStep, OneꢀPot and MultigramꢀScale
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Synthesis of NꢀDifluoromethylthiophthalimide
Dianhu Zhu, Xin Hong, Dezhi Li, Long Lu* and Qilong Shen*
Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry,
University of Chinese Academy Sciences, Chinese Academy of Sciences, 345 Lingling Road,
Shanghai 200032, P. R. China
ABSTRACT.
A
new method for the 100 gramꢀscale synthesis of Nꢀ
difluoromethylthiophthalimide 1 from cheap commodity chemical benzyl mercaptan and
HCF2Cl or other difluorocarbene precursors was described. Reagent 1 is an excellent
electrophilic difluoromethylthiolating reagent as demonstrated by the gramꢀscale synthesis of
five difluoromethylthiolated derivatives of structurally complicated drugꢀlike molecules and
natural products.
Keywords: Fluorine, Difluoromethylthio, gramꢀscale, electrophilic
Introduction
Recently, the difluoromethylthio group (ꢀSCF2H) has attracted a particular attention from both
academia and industry, mainly due to its intrinsic beneficial properties that can be utilized to
improve the lead compound’s efficacy including lipophilicity and metabolic stability.1 It is also
known that the difluoromethylthio group is less electronꢀwithdrawing, less lipophilic (πR = 0.68),
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and less stable to the basic conditions than its analogꢀthe trifluoromethylthio group (ꢀSCF3).2
These characteristics of the difluoromethylthio group can be advantageous because it provides an
opportunity for the medicinal chemists to fineꢀtune the molecule’s pharmacokinetics by
judiciously decorating it with either a CF3S group or a HCF2S group. In addition, the
difluoromethylthiolated compounds are superior in the system that requires a shortꢀlived
metabolite than the trifluoromethylthiolated analogs.3 Furthermore, as a weak hydrogenꢀbonding
donor, the difluoromethylthio group may serve as a bioꢀisostere to OH or SH group, thus
enhancing the compound’s binding affinity toward the target protein.4 Thus, not surprisingly,
several drugs and agrochemicals containing the difluoromethylthio group including βꢀlactamaseꢀ
resistant oxcephalosporin antibiotic Flomoxef sodium,5 pesticide Pyriprole6 and broadꢀspectrum
paddy herbicide Pyrimisulfan7 have already been on the market (Fig. 1).
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Figure 1. Drugs and agrochemicals containing a difluoromethylthio group. Reproduced from
reference 10. Copyright 2015 American Chemical Society.
Several methods have been reported for the preparation of difluoromethylthiolated
compounds that typically involves nucleophilic attack of an in situ formed difluoromethyl
carbene intermediate or an electrophilic difluoromethyl reagent by an appropriate thiolate.8ꢀ9 Yet,
these classic methods require the preformation of thiols, which might constitute a challenging
task for more complicated molecules. To overcome this shortcoming, in 2015, we invented the
first shelfꢀstable electrophilic difluoromethylthiolating reagentꢀNꢀdifluoromethylthiophthalimide
1,10 which reacted with a wide range of nucleophiles including aryl/vinyl boronic acids, alkynes,
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βꢀketoesters, oxindoles and electronꢀrich heteroarenes such as indole, pyrrole, 1Hꢀpyrrolo[2,3ꢀ
b]pyridine, imidazo[1,2ꢀa]pyridine, aminothiazole, isoxazole and pyrazole, and
heteronucleophiles such as amines and thiols under mild conditions. The excellent functional
group tolerance in these reactions makes reagent 1 the choice for the preparation of more
complicated, densely functional drugꢀlike molecules. However, there is one limitation of reagent
1 that hampered its further widespread applications. Its preparation required a stoichiometric
amount of [(SIPr)Ag(CF2H)]11 (SIPr = 1,3ꢀbis(2,6ꢀdiisopropylphenyl)imidazolinꢀ2ꢀylidene),
which make reagent 1 rather expensive since silver is one of the precious metals. Herein, we
report an alternative twoꢀstep, oneꢀpot route for the 100 gꢀscale preparation of reagent 1 from
easily available benzyl difluoromethylthioether 1a. This synthetic method for the preparation of
reagent 1 circumvents the use of silver complex, making it easy for scaleꢀup and warranting its
widespread applications in the preparation of structurally complicated molecules in the future.
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Figure 2. The synthesis of Nꢀdifluoromethylthiophthalimide.
Results and Discussion
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Synthesis of N-difluoromethylthiophthalimide 1. The starting material benzyl
difluoromethylthioether 1a was prepared by reaction of benzyl mercaptan with HCF2Cl (R22)12
or bromodifluoromethanephosphonate13 under basic conditions, according to the reported
procedures. As shown in Figure 2, treatment of benzyl difluoromethylthioether 1a with a
solution of Cl2 in CHCl3 at room temperature for 2 h, followed by the addition of potassium
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phthalimide
gave
desired
N-difluoromethylthiophthalimide
1.
Presumably,
difluoromethylthioether 1a reacted with chlorine to generate a highly reactive intermediate
19
HCF2SCl, which was observed by F NMR spectroscopy with a chemical shift at ꢀ97.2 ppm.
The in situ formed HCF2SCl then reacted with potassium phthalimide gave the Nꢀ
difluoromethylthiophthalimide 1 in high yield. Even though the toxicity of HCF2SCl has not
been reported, its analog CF3SCl was known to be highly toxic.14 Thus, the oneꢀpot procedure
that avoiding the isolation of HCF2SCl is highly desirable.
During the development of the procedure for the preparation of Nꢀ
difluoromethylthiophthalimide 1, we noticed that the way how chlorine was added to the solution
of benzyl difluoromethylthioether 1a was crucial for the high yielding formation of reagent 1.
When chlorine gas was bubbled into the solution of difluoromethylthioether 1a in a reaction
vessel which was connected to an oil bubbler, the reaction was messy and the yield for the
19
formation of reagent 1 was low, as determined by F NMR spectroscopy. It was reasoned that
o
the chlorine bubbles blow away the volatile HCF2SCl (b.p. 25ꢀ35 C).15 Consequently, the yield
of the desired reagent 1 decreased significantly. Secondary, we also found that the yield of
reagent 1 decreased when excess chlorine gas was used. It is likely that excess chlorine would
react with reagent 1 to from intermediate HCF2SCl and a byproduct Nꢀchlorophthalimide, which
was difficult to be separated from reagent 1. Thus, to maximize the yield for the formation of
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reagent 1, an aliquot was withdrawn from the reaction vessel from time to time. An internal
standard (trifluorotoluene) was added and the conversion of the starting material benzyl
difluoromethylthioether 1a was then determined by 19F NMR spectroscopy. Accordingly, a
stoichiometric amount of chlorine solution in CHCl3 was added and the mixture was allowed to
react at room temperature for 2 h before an excess amount of potassium phthalimide (1.2 equiv.)
was added to ensure the full conversion of the intermediate to generate the desired product.
We also found that the solvent has a great influence on the yield of reagent 1, as shown in
Table 1. When the reaction was conducted in CHCl3, a high yield of 78% was observed, while
the yield decreased to 63% when chlorobenzene was used as the solvent. More strikingly,
formation of the reagent was observed in less than 10% yields when the same reaction was
conducted in toluene or acetonitrile. Under the optimized reaction conditions, 113 g of Nꢀ
difluoromethylthiophthalimide 1 was isolated after a simple recrystallization when 120 g of
difluoromethylthioether 1a was reacted with 650 mL of chlorine solution in CHCl3 (1.0 M) and
then further treated with 145 g of potassium phthalimide.
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Table 1．The effects of the Cl2/solvent solution of the reaction.a
aYields were determined by 19F NMR analysis of the crude reaction mixture with PhCF3 as an internal standard.
Reactions of N-difluoromethylthiophthalimide 1. With the new method for the 100 gꢀscale
synthesis of reagent 1 in hand, we next explored its applications by synthesizing
difluoromethylthiolated derivatives of a few drug, agrochemical molecules or natural products on
gramꢀscale, as summarized in Scheme 1.
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Pyriprole,16 a classic insecticide with a comparable efficacy with other modern insecticidal active
ingredients such as fipronil, imidacloprid, spinetoram or spinosad, is highly effective against
fleas and several tick species. It was found that in the presence of 10 mol% NaCl, pyriprole
precursor reacted efficiently with reagent 1 to give pyriprole in 63% yield on gramꢀscale
(Scheme 1, Eq. 1).17 Likewise, its furylꢀsubstituted analog was also synthesized in 62% yield
(Scheme 1, Eq. 1). Furthermore, Melatonine,18 a hormone from the pineal gland that regulates
sleep and wakefulness, reacted with reagent 1 in the presence of 10 mol% NaCl to give the
corresponding difluoromethylthiolated malatonine derivative in 86% yield (Scheme 1, Eq. 2).
We also found that in the presence of a copper catalyst, boronic acid derivative of natural
product estrone was able to be difluoromethylthiolated in 70% yield (Scheme 1, Eq. 3). Finally,
it was found that tryptamine could react smoothly with reagent 1 in toluene in the absence of any
transitionꢀmetal catalyst to afford the corresponding difluoromethylthiolated tryptamine in high
yields (Scheme 1, Eq. 4).
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O
Me
O
Me
H
O
5.0 mol % CuI
5.0 mol % bpy
H
H
H
H
(3)
(4)
N
SCF2H
+
+
H
Li2CO3
diglyme
60 oC, 15 h
(HO)2B
O
HF2CS
1 (1.2 equiv)
4, 70%, 1.18 g
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O
NH2
NHSCF2H
toluene
N
SCF2H
N
80 oC, 16 h
N
H
H
O
1 (1.5 equiv)
5, 88%, 1.07 g
Scheme 1. Preparation of difluoromethylthiolated derivatives of a few drug, agrochemical
molecules or natural products on gramꢀscale.
Conclusion
In summary, a new and simple synthetic method of Nꢀdifluoromethylthiophthalimide 1 on a
hundred gramꢀscale has been developed. Reagent 1 can be efficiently synthesized in three steps
from cheap commodity chemical benzyl mercaptan and HCF2Cl or other difluorocarbene
precursors.
Nꢀdifluoromethylthiophthalimide
1
is
an
excellent
electrophilic
difluoromethylthiolating reagent as demonstrated by the gramꢀscale synthesis of five
difluoromethylthiolated derivatives of structurally complicated drugꢀlike molecules and natural
products. Thus, the method developed for 100 gramꢀscale synthesis of Nꢀ
difluoromethylthiophthalimide 1 open a door for its further applications and should contribute to
the development of drug or agrochemicals bearing the difluoromethylthio group in the future.
Experimental Section
General procedure for the synthesis of difluorobenzyl thioether. nꢀHexane (3.0 L) was
placed into threeꢀneck round bottom flask equipped with a stirring bar under the cold bath (ꢀ78
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oC) and chlorodifluoromethane (Rꢀ22, 1.5 mol) was bubbled slowly. Sodium hydroxide (100 g,
2.50 mol), tris(2ꢀ(2ꢀmethoxyethoxy)ethyl)amine (TDAꢀ1, 16.2 g, 50.0 mmol) and benzyl
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mercaptan (124 g, 1.00 mol) were added. The reaction was stirred at 60 C for 2ꢀ4 h under the
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dry iceꢀacetone condensation. The resulting precipitate was filtered and the filtrate was
evaporated in vacuo. The residue was purified by flash chromatography on silica gel to give
difluorobenzyl thioether as light pink oil (106 g, 61%).
Alternatively, potassium hydroxide (168 g, 3.00 mol), acetonitrile/H2O (1400 mL，1:1）and
benzyl mercaptan (18.6 g, 150 mmol) were placed into three round bottom flask equipped with a
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stirring bar. The mixture was cooled to ꢀ78 C and diethyl bromodifluoromethanephosphonate19
(80.1 g, 300 mmol) were added. The reaction was stirred at room temperature for 4ꢀ6 h. Et2O
(2.0 L) was added and the organic phase was separated. The aqueous phase was extracted with
Et2O (400 mL × 3). The combined organic extracts were dried over anhydrous Na2SO4, filtered
and concentrated in vacuo. The residue was purified by flash chromatography on silica gel to
give difluorobenzyl thioether as light pink oil (22.5 g, 86%). 1H NMR (400 MHz, CDCl3, 293 K,
TMS) δ 7.35 (s, 2 H), 7.34 (t, J = 1.2 Hz, 2 H), 7.27ꢀ7.30 (m, 1 H), 6.73 (t, J = 56.0 Hz, 1 H);
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4.02 (s, 2 H); F NMR (375 MHz, CDCl3) δ ꢀ94.4 (d, J = 56.2 Hz, 2 F); C NMR (125 MHz,
CDCl3, 293 K, TMS) δ 136.2, 128.9, 128.8, 127.6, 120.2 (t, J = 271.2 Hz), 31.8 ppm.
General procedure for the synthesis of N-difluoromethylthiophthalimide 1. Into a 2.0 L
Shlenk tube was added dry CHCl3 (1.5 L) and get weighed. Chlorine gas was bubbled slowly for
15 min. The Shlenk tube was weighed again to get the amount of chlorine gas in CHCl3. The
concentration of Cl2 in CHCl3 was then calculated. An aliquot of Cl2 in CHCl3 (650 mL, 1.0 M)
was added with 850 mL of CHCl3 in a 2.0 L threeꢀneck round bottom flask. The mixture was
cooled to ꢀ30 °C in the dark and BnSCF2H (120.4 g, 650 mmol) was added slowly over a period
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of 30 min. The mixture was warmed to 23 °C and the mixture was further stirred for 2 hours. The
mixture was then cooled to ꢀ30 °C and potassium phthalimide (144.5 g, 1.2 equiv, 780 mmol)
was added in three times. The temperature was then warmed to 23 °C and the reaction was
further stirred at room temperature for 8 hours. The mixture was filtered through a layer of Celite
and washed with CH2Cl2 (200 mL × 3). The solvent was evaporated in vacuo and the residue was
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purified
(difluoromethylthio)phthalimide as a white solid (113.2 g, 76%).
General procedure for difluoromethylthiolation of heteroarenes with N-
(difluoromethylthio)phthalimide 1. Heteroarene (4.0 mmol), Nꢀ
by
recrystallization
from
CH2Cl2/petroleum
ether
to
give
Nꢀ
(difluoromethylthio)phthalimide 1 (5.2 mmol) and NaCl (0.4 mmol) were placed into an ovenꢀ
dried Schlenk tube that was equipped with a stirring bar under argon. Freshly distilled DMF
(20.0 mL) was added. The reaction was stirred at 80 oC for 16 h. Distilled water (100.0 mL) and
diethyl ether (400.0 mL) was added and the organic phase was separated. The aqueous phase was
extracted with diethyl ether (80.0 mL×3). The combined organic extracts were dried over
anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by flash chromatography
on silica gel to give the difluoromethylthiolated heteroarene. 1-(2,6-Dichloro-4-
(trifluoromethyl)phenyl)-4-((difluoro-methyl)thio)-5-((pyridin-2-ylmethyl)amino)-1H-
pyrazole-3-carbonitrile 2a. 1.24 g, 63%. 1H NMR (400 MHz, CDCl3, 293 K, TMS) δ 8.38 (d, J
= 8.0 Hz, 1 H), 7.73 (s, 2 H), 7.64 (t, J = 8.0 Hz, 1 H), 7.17 (t, J = 8.0 Hz, 2 H), 6.70 (t, J = 56.0
19
Hz, 1 H), 5.92 (t, J = 8.0 Hz, 1 H), 4.55 (d, J = 4.0 Hz, 2 H); F NMR (375 MHz, CDCl3) δ ꢀ
13
63.27 (s, 3 F), ꢀ93.3 (d, J = 56.2 Hz, 2 F); C NMR (125 MHz, CDCl3, 293 K, TMS) δ 154.8,
152.0, 148.8, 136.9, 136.7, 135.8, 134.5 (q, J = 33.6 Hz), 134.2, 126.2 (q, J = 3.75 Hz), 123.4,
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122.7, 121.9 (q, J = 272.5 Hz), 121.5, 121.4, 119.2 (t, J = 277.4 Hz), 112.0, 85.4 (t, J = 3.75 Hz),
48.0 ppm.
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1-(2,6-Dichloro-4-(trifluoromethyl)phenyl)-4-((difluoromethyl)thio)-5-((furan-2-yl-methyl)
amino)-1H-pyrazole-3-carbonitrile 2b. 1.20 g, 62%. 1H NMR (400 MHz, CDCl3, 293 K, TMS)
δ 7.75 (s, 2 H), 7.27 (d, J = 4.0 Hz, 1 H), 6.65 (t, J = 56.0 Hz, 1 H), 6.26ꢀ6.27 (q, J = 4.0 Hz, 1
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H), 6.13 (d, J = 4.0 Hz, 1 H), 4.37 (s, 1 H), 4.37 (s, 2 H); F NMR (375 MHz, CDCl3) δ ꢀ63.32
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(s, 3 F), ꢀ92.8 (d, J = 56.2 Hz, 2 F); C NMR (125 MHz, CDCl3, 293 K, TMS) δ 151.6, 150.2,
142.7, 136.7, 136.5, 135.7, 134.7 (q, J = 33.6 Hz), 134.1, 126.3 (q, J = 3.75 Hz), 121.9 (t, J =
272.5 Hz), 119.1 (t, J = 276.2 Hz), 111.8, 110.5, 108.2, 108.0, 87.2 (t, J = 3.75 Hz), 41.8 ppm.
1
N-(2-(2-((Difluoromethyl)thio)-5-methoxy-1H-indol-3-yl)ethyl)acetamide 3. 1.08 g, 86%. H
NMR (400 MHz, CDCl3, 293 K, TMS) δ 8.69 (s, 1 H), 7.24 (d, J = 8.0 Hz, 1 H), 7.04 (d, J = 4.0
Hz, 1 H), 6.91 (dd, J = 8.0, 4.0 Hz, 1 H), 6.71 (t, J = 56.0 Hz, 1 H), 5.70 (s, 1 H), 3.82 (s, 3 H),
3.54 (q, J = 8.0 Hz, 2 H), 3.06 (t, J = 8.0 Hz, 2 H), 1.90 (s, 3 H); 19F NMR (375 MHz, CDCl3) δ ꢀ
13
91.0 (d, J = 56.2 Hz, 2 F); C NMR (125 MHz, CDCl3, 293 K, TMS) δ 170.4, 154.4, 132.7,
127.7, 122.1, 119.8 (t, J = 277.5 Hz), 115.6 (t, J = 2.50 Hz), 115.2, 112.2, 100.4, 55.8, 39.9, 24.8,
23.3 ppm.
General procedure for difluoromethylthiolation of aryl boronic acids with N-
(difluoromethylthio)phthalimide 1. Boronic acid derivative of estrone (1.49 g, 5.00 mmol), Nꢀ
(difluoromethylthio)phthalimide 1 (1.4 g, 6.0 mmol), Li2CO3 (128 mg, 2.50 mmol), CuI (0.25
mmol, 0.05 equiv), 2,2'ꢀbipyridine (39 mg, 0.25 mmol) were placed into an ovenꢀdried Schlenk
tube that was equipped with a stirring bar under argon. Freshly distilled diglyme (30.0 mL) was
o
added and the mixture was stirred at 60 C for 15 h. Distilled water (100.0 mL) and Et2O (400.0
mL) was added and the organic phase was separated. The aqueous phase was extracted with Et2O
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(3×80.0 mL). The combined organic extracts were washed with 80 mL of distilled water, dried
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over anhydrous Na2SO4 and concentrated in vacuo. The product was purified by flash
chromatography on silica gel to give the difluoromethylthiolated estrone (1.18 g, 70%).
(8R,9S,13S,14S)-3-((Difluoromethyl)thio)-13-methyl-7,8,9,11,12,13,15,16-octahydro-6H-
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1
cyclopenta[a]phenanthren-17(14H)-one 4. H NMR (400 MHz, CDCl3, 293 K, TMS) δ 7.24ꢀ
7.34 (m, 3 H), 6.78 (t, J = 56.0 Hz, 1 H), 2.91 (t, J = 4.0, 2 H), 2.50 (q, J = 8.0, 1 H), 2.40 (m, 1
19
H), 2.29 (m, 1 H), 1.93ꢀ2.18 (m, 4 H), 1.38ꢀ1.67 (m, 6 H), 0.89 (s, 3 H); F NMR (375 MHz,
13
CDCl3) δ ꢀ91.4 (d, J = 56.2 Hz, 2 F); C NMR (125 MHz, CDCl3, 293 K, TMS) δ 220.47,
141.86, 137.98, 135.85, 132.62, 126.46, 122.89 (t, J = 2.5 Hz), 121.15 (t, J = 273.7 Hz), 50.48,
47.89, 44.32, 37.84, 35.80, 31.53, 29.15, 26.23, 25.57, 21.57, 13.81 ppm.
General
procedure
for
difluoromethylthiolation
of
tryptamine
with
N-
(difluoromethylthio)phthalimide 1. A Shlenk tube charged with tryptamine (0.80 g, 5.0 mmol)
and Nꢀ(difluoromethylthio) phthalimide 1 (1.7 g, 7.5 mmol) was added toluene (30.0 mL). The
o
mixture was stirred at 80 C for 16 h. The solvent was removed under vacuum and the residue
was purified by flask column chromatography to give difluoromethylthiolated tryptamine (1.07,
1
88%). N-(2-(1H-Indol-3-yl)ethyl)-S-(difluoromethyl)thiohydroxylamine 5. H NMR (400
MHz, CDCl3, 293 K, TMS) δ 8.01 (s, 1 H), 7.61 (d, J = 8.0 Hz, 1 H), 7.36 (d, J = 8.0 Hz, 1 H),
7.22 (td, J = 8.0, 0.8 Hz, 1 H), 7.14 (td, J = 8.0, 0.8 Hz, 1 H), 7.01 (d, J = 2.0 Hz, 1 H), 6.61 (t, J
= 56.0 Hz, 1 H), 3.35 (q, J = 8.0, 2 H), 2.99 (t, J = 8.0, 2 H), 2.73 (s, 1 H); 19F NMR (375 MHz,
13
CDCl3) δ ꢀ100.3 (d, J = 56.2 Hz, 2 F); C NMR (100.7 MHz, CDCl3, 293 K, TMS) δ 136.3,
127.3, 123.2 (t, J = 275.9 Hz), 122.2 (d, J = 1.0 Hz), 120.4, 119.5, 118.7, 112.7, 111.3, 54.0, 26.4
ppm.
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Supporting Information. NMR data of compound 1-5. This material is available free of charge
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via the Internet at http://pubs.acs.org.
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AUTHOR INFORMATION
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Corresponding Author
*Email: lulong@sioc.ac.cn; shenql@sioc.ac.cn
Notes
A provisional patent (application No. CN201610469651.4) about the preparation of Nꢀ
difluoromethylthiophthalimide 1 was filed by Shanghai Institute of Organic Chemistry.
ACKNOWLEDGMENT
The authors gratefully acknowledge the financial support from National Natural Science
Foundation of China (21625206, 21632009, 21372247, 21572258, 21421002) and the Strategic
Priority Research Program of the Chinese Academy of Sciences (XDB20000000) for financial
support.
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