Reaction of Thiocarbonyl Fluoride Generated from Difluorocarbene with Amines

Article abstract of DOI:10.1002/anie.201710186

The reaction of thiocarbonyl fluoride, generated from difluorocarbene, with various amines under mild conditions is described. Secondary amines, primary amines, and o-phenylenediamines are converted to thiocarbamoyl fluorides, isothiocyanates, and difluoromethylthiolated heterocycles, respectively. Thiocarbamoyl fluorides were further transformed into trifluoromethylated amines by using a one-pot process. Thiocarbonyl fluoride is generated in situ and is rapidly fully converted in one pot under mild conditions; therefore, no special safety precautions are needed.

Full text of DOI:10.1002/anie.201710186

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Accepted Article
Title: Reaction of thiocarbonyl fluoride formed from difluorocarbene
with amines
Authors: Ji-Chang Xiao, Jiao Yu, and Jinhong Lin
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201710186
Angew. Chem. 10.1002/ange.201710186
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COMMUNICATION
Reaction of thiocarbonyl fluoride formed from difluorocarbene
with amines
Jiao Yu,[a] Jin-Hong Lin[a]* and Ji-Chang Xiao[a]*
Abstract: The reaction of thiocarbonyl fluoride generated from
difluorocarbene with various amines under mild conditions is
described. Secondary amines, primary amines, and o-
phenylenediamines are converted to thiocarbamoyl fluorides,
fluoride 2a (Scheme 1). A brief survey of the reaction conditions
[see the Supporting Information (SI)] showed that the conversion
proceeded smoothly using 1.5 equiv of PDFA and 0.25 equiv of
S8 in 1,2-dimethoxyethane (DME) at 50 oC. After complete
consumption of amine 1a, the addition of AgF in a one-pot
process resulted in desulfurization-fluorination of 2a to afford
trifluoromethyl amine A1 in high yield (80% overall yield).[5]
Despite recent important achievements in CF3 incorporation,[6]
construction of the NCF3 moiety remains challenging. Traditional
synthetic methods such as deoxy(sulfur)-fluorination or halogen–
fluorine exchange reactions suffer from tedious procedures or
the use of hazardous agent (SF4, BrF3 or HF).[7] Although
electrophilic-, radical- and nucleophilic-trifluoromethylation
approaches are effective,[8] CF3-substituted free amines cannot
be easily obtained using these approaches because the nitrogen
atom in NCF3 must usually be attached to another heteroatom
isothiocyanates,
and
difluoromethylthiolated
heterocycles,
respectively. Thiocarbamoyl fluorides were further transformed into
trifluoromethylated amines using a one-pot process. As thiocarbonyl
fluoride is generated in situ and is rapidly fully converted in one pot
under mild conditions, no special safety precautions are needed.
Difluorocarbene is a valuable and versatile intermediate in
organic synthesis, particularly for fluorine incorporation.[1]
Recently, we described the use of difluorocarbene generated
from Ph3P+CF2CO2 (PDFA), a reagent which was developed by
-
us[2] and has also been used by other groups,[3] as a key
intermediate
in
achieving
challenging
18F-
(nitrogen,
oxygen,
or
sulfur)[8c-8f]
or
because
the
2f]
trifluoromethylthiolation.[2c,
Our mechanistic investigations of
trifluoromethylation reagent is unstable and highly reactive[8a]
.
trifluoromethylthiolation showed that the key process is the
reaction of difluorocarbene with elemental sulfur (S8) to produce
thiocarbonyl fluoride (CF2=S),[2f] a transformation which has
never been reported before. Although thiocarbonyl fluoride is an
important fluorinated material, its use in synthetic chemistry
remains largely unexplored because its preparation usually
requires the use of hazardous reagents (such as thiophosgene)
and/or harsh reaction conditions (e.g., pyrolysis at 500 oC).
Furthermore, special safety precautions must be taken during
storage and transfer of thiocarbonyl fluoride because of its high
toxicity and low boiling point (−54 oC).[4] Our protocol for the use
of thiocarbonyl fluoride is convenient and promising because
thiocarbonyl fluoride is generated in situ and rapidly fully
converted in one pot under mild conditions. Its successful use in
reaction with oxygen nucleophiles[2g] prompted us to investigate
nitrogen nucleophiles such as unprotected amines.
Scheme 1. Reaction of thiocarbonyl fluoride with secondary amine and
subsequent fluorination in one pot. Yields were determined by 19F NMR.
Our initial reaction of secondary amine 1a with thiocarbonyl
fluoride generated from the PDFA/S8 system gave thiocarbamoyl
[a] Key Laboratory of Organofluorine Chemistry, Shanghai Institute of
Organic Chemistry, University of Chinese Academy of Sciences,
Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032,
China.
Scheme 2. Substrate scope for one-pot reaction of thiocarbonyl fluoride with
secondary amine and subsequent fluorination. Isolated yields. The yields in
parentheses were determined using 19F NMR spectroscopy. Reaction
conditions: 1 (0.8 mmol), PDFA (1.5 equiv), and S8 (0.25 equiv) in DME at 50
oC for 0.5 h in a N2 atmosphere. AgF (4.5 equiv) was then added and the
resulting mixture was stirred at 80 oC for 5 h.
*
*
Dr. J. -H. Lin, Tel: (+86)21-5492-5541; E-mail: jlin@sioc.ac.cn
Prof. J. -C. Xiao, Tel: (+86)21-5492-5340; E-mail: jchxiao@sioc.ac.cn
Electronic Supplementary Information (ESI) available: the
optimization of reaction conditions, experimental procedures and
characterization for products.
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COMMUNICATION
With the optimized reaction conditions in hand, we
investigated the substrate scope of the one-pot reaction of
thiocarbonyl fluoride with secondary amines and subsequent
desulfurization-fluorination (Scheme 2). Various N-aryl-N-alkyl
amines were converted to the desired products in high yields
irrespective of whether the aryl groups contained electron-rich, -
neutral, or -deficient substituents (A1–A21). N,N-Diphenyl amine
was not suitable for this reaction because of the low
nucleophilicity of the amino group (A22). The conversion of N,N-
dialkyl amines proceeded smoothly to furnish the expected
products in high yields (A23-A32). The stabilities of A23--A32
depend significantly on the electronic effects of the substituents.
The alkyl groups in the N,N-dialkyl amines must be attached to
electron-withdrawing groups such as Ph (A23 and A24), CO2Et
(A23), or CH2NR’ (A26–A30); otherwise, the products
decompose easily and therefore cannot be isolated using flash
column chromatography (A25, A31 and A32). N,N-dialkyl CF3-
amines readily undergo fluorine elimination because of n(N) →
σ*(C-F) electron donation. This decomposition process was
retarded by introducing electron-withdrawing groups into the
alkyl groups. The formation of heterocycle-containing amines
(A20-A21, A26-A30) may find utility in biochemistry.
The successful reaction of thiocarbonyl fluoride with
secondary amines prompted us to investigate its reaction with
primary amines. It was found that the PDFA/S8 system
converted primary amines to isothiocyanates instead of
thiocarbamoyl fluorides. Scheme 3 shows that all the reactions
Scheme 3. Reaction of thiocarbonyl fluoride with primary amines. Isolated
yields. Reaction conditions: 3 (0.8 mmol), PDFA (1.5 equiv), and S8 (0.375
equiv) in DME at 80 oC for 5 min in a N2 atmosphere.
o
of primary amines were fast (5 min) in DME at 80 C. Various
aryl amines were converted to the desired products in high
yields and with a high level of functional group tolerance (B1–
B19). Investigation of the electronic effects showed that neither
electron-rich nor electron-withdrawing groups suppressed the
desired conversion. Gratifyingly, heteroaryl amines were suitable
for this transformation (B20-B22). The reaction is not sensitive
to steric effects, as shown by the high yields of sterically
hindered products B4–B6 and B21. We previously reported that
an alkynyl group can undergo [2+1] cyclization with
difluorocarbene generated from PDFA,[2d] but the alkynyl group
remained intact in this reaction, confirming high functional group
compatibility (B11 and B12). The transformation of amines
containing a basic group such as a tertiary amino (B9) or
pyridinyl group (B20-B21) also proceeded smoothly. The tertiary
amine group remained intact under these conditions (B9)
although both primary and secondary amines are highly reactive
towards thiocarbonyl fluoride. The yields of the desired products
obtained from the reactions of alkyl amines (B23-B35) were
lower than the product yields from arylamines. The reactions
proceeded smoothly irrespective of whether the carbon attached
to the amino group was a primary- (B23–B26, B32 and B33),
secondary- (B27–B29 and B34), or tertiary carbon (B30, B31
and B35), further indicating that steric hindrance did not affect
the reactions of alkyl amines. Amantadine is an antiviral and
antiparkinsonian drug that has been approved by the U.S. Food
and Drug Administration. Its isothiocyanate derivative was easily
obtained by this strategy (B35). Isothiocyanates occur widely in
nature and are of interest in various areas such as food science,
medicine and synthetic chemistry,[9] and this convenient protocol
has a wide range of potential applications in their synthesis.
A convenient route to the insecticide chloromethiuron (CAS
registry number: 28217-97-2) from a commercially available
amine was developed to show the synthetic utility of this strategy
for the conversion of primary amines (Scheme 4). The formation
of isothiocyanate B36 was fast although the reaction scale was
increased to 10 mmol. A high overall yield (81%) was obtained
via a two-step procedure.
Scheme 4. Synthesis of chloromethiuron
As shown above in Scheme 4, the acyclic thiourea motif
was constructed in two steps. It is reasonable to assume that
only one step would lead to a cyclic thiourea if two amino groups
are present in the substrate. This was confirmed by the rapid
conversion of the vicinal diamine 4a to cyclic thiourea 5a
(Scheme 5). Replacing one amino group with a hydroxy group
gave oxazolidinethione 5b in 73% yield. Thioureas[10] and
oxazolidinethiones[11] are extensively used in medicinal
chemistry and catalysis, therefore, the present protocol will be of
great synthetic utility.
Scheme 5. Reaction of thiocarbonyl fluoride with vicinal diamine and vicinal
hydroxyl amine
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COMMUNICATION
Thiocarbonyl fluoride generated from the PDFA/S8 system the same reaction conditions as for the reaction of a vicinal
is the key intermediate in the conversion of both primary and diamine in Scheme 5. This unexpected product was formed via
secondary amines. Simply heating a mixture of PDFA/S8 in DME
a tandem cyclization/difluoromethylation process (For the
produces CF2=S, as confirmed using HRMS-EI spectroscopy proposed mechanism and the experimental evidences, please
(Scheme 6, eq 1). The reaction of conjugated diene 6 with the see SI). After identifying the optimum conditions (See SI), we
PDFA/S8 system generates
a
CF2S-containing bridged explored the substrate scope for the reaction of thiocarbonyl
compound (7, eq 2). This bridged compound is formed via a fluoride with o-phenylenediamines or vicinal hydroxy (or amino)
Diels–Alder reaction of diene 6 with CF2=S produced in situ. arylamines. As shown in Scheme 8, all the reactions occurred
Furthermore, addition of substrate 1a after complete rapidly (5 min) to furnish the desired HCF2S heterocycles in
o
consumption of PDFA by heating the PDFA/S8 mixture at 80 C good yields. The electronic effects of the substituents in various
still gave the desired thiocarbamoyl fluoride 2a in 15% yield (eq o-phenylenediamines (C1–C19) were investigated. Although
3). This low yield can be explained by side reactions of CF2=S in electron-withdrawing groups decrease the nucleophilicity of the
the absence of a substrate because of its high reactivity.
amino group, substrates containing electron-withdrawing groups
were converted smoothly to the desired HCF2S-substituted
benzimidazoles (C11–C19). Replacing one of the amino groups
with a hydroxy or thiol group afforded the HCF2S-substituted-
benzoxazole (C20) and -benzothiazole (C21), respectively, but
the yields were lower because of the lower nucleophilicities of
hydroxy and thiol groups. Besides five-membered heterocycles
(C1–C21), six-membered heterocycles were formed using this
strategy (C22–C25). When the ortho substituent of the amino
group was an amide or carboxylic acid group, HCF2S-substituted
4-quinazolinone (C22 and C23) and 3,1-benzoxazin-4-one (C24),
respectively, were obtained. The imidazole N-H was able to act
as a nucleophilic site to form a bridged ring (C25). Increasing the
reaction scale to 10 mmol still afforded the desired product C25
in good yield (70%), showing the synthetic utility of this tandem
strategy. Although the heterocyclic N-H group is a potential
reactive site for difluoromethylation with difluorocarbene,[2d] the
N-H moieties in the above products remained intact, enabling
further transformations. The structures of products C6[14] and
C23[15] were confirmed using X-ray diffraction (see the SI).
Scheme 6. Generation and detection of CF2=S. a The yield was determined
using 19F NMR spectroscopy.
Recently, Schoenebeck reported an excellent procedure for
the synthesis of trifluoromethyl amines and isothiocyanates via
the reaction of [Me4N+ CF3S−] with secondary amines (Scheme 7,
eq 1)[5b] and primary amines (eq 2).[12] Thioureas could also be
obtained if two amino groups are present in the substrates.[12]
Their strategy for the synthesis of trifluoromethyl amines,
pioneering work involving a one-pot-two-step transformation, is
quite attractive due to a rapid reaction process, a wide substrate
scope, and a simple purification procedure.[5b] Thiocarbonyl
fluoride is not the intermediate for Schoenebeck’s reaction [5b,12]
.
During the preparation of this manuscript, Zheng et al. reported
that Langlois reagent (CF3SO2Na) can also participate in
isothiocyanation of primary amines in the presence of
CuI/HPO(OEt)2 (eq 2).[13] Although they propose that
thiocarbonyl fluoride is one of the key intermediates, no direct
evidence was observed. This approach suffers from a narrow
substrate scope (limited suitability of alkyl amines), low
functional group tolerance (e.g., pyridinyl and terminal alkynyl
groups are not tolerated), and the need for long reaction time
(16 h).
Scheme 8. Reaction of thiocarbonyl fluoride with o-phenylenediamines or
vicinal hydroxyl (or amino) arylamines and isolated yields. Reaction conditions:
8 (0.8 mmol), PDFA (3 equiv), and S8 (0.375 equiv) in DME at 80 oC for 5 min
in a N2 atmosphere. aThe reaction was performed on a 10-mmol scale. A
reaction time of 10 min was required.
Scheme 7. Recently reported methods for CF3 incorporation and
isothiocyanation.
The HCF2S-substituted benzimidazole C1 (18% yield) was
obtained from conversion of vicinal phenylenediamine 8a under
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