Concise and Additive-Free Click Reactions between Amines and CF3SO3CF3

Article abstract of DOI:10.1002/chem.201901865

Trifluoromethyl trifluoromethanesulfonate has proved to be an excellent reservoir of difluorophosgene and a promising click ligation for amines in the preparation of urea derivatives, heterocycles, and carbamoyl fluorides under metal- and additive-free conditions. The reactions are rapid, efficient, selective, and versatile, and can be performed in benign solvents, giving products in excellent yields with minimal efforts for purification. The characteristics of the reactions meet the requirements of a click reaction. The use of trifluoromethyl trifluoromethanesulfonate as a click reagent is advantageous over other “CO” sources (e.g., TsOCF₃, PhCO₂CF₃, CsOCF₃, AgOCF₃, and triphosgene) because this reagent is readily accessible; easy to scale up; and highly reactive, even under metal- and additive-free conditions. It is anticipated that CF₃SO₃CF₃ will be increasingly as important as SO₂F₂ as a click agent in future drug design and development.

Full text of DOI:10.1002/chem.201901865

DOI: 10.1002/chem.201901865
Full Paper
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Synthesis Design |Hot Paper|
Concise and Additive-Free Click Reactions between Amines and
CF3SO3CF3
Hai-Xia Song, Zhou-Zhou Han, and Cheng-Pan Zhang*[a]
Abstract: Trifluoromethyl trifluoromethanesulfonate has
proved to be an excellent reservoir of difluorophosgene and
a promising click ligation for amines in the preparation of
urea derivatives, heterocycles, and carbamoyl fluorides
under metal- and additive-free conditions. The reactions are
rapid, efficient, selective, and versatile, and can be per-
formed in benign solvents, giving products in excellent
yields with minimal efforts for purification. The characteris-
tics of the reactions meet the requirements of a click reac-
tion. The use of trifluoromethyl trifluoromethanesulfonate as
a click reagent is advantageous over other “CO” sources
(e.g., TsOCF3, PhCO2CF3, CsOCF3, AgOCF3, and triphosgene)
because this reagent is readily accessible; easy to scale up;
and highly reactive, even under metal- and additive-free
conditions. It is anticipated that CF3SO3CF3 will be increas-
ingly as important as SO2F2 as a click agent in future drug
design and development.
Introduction
cursors of hypofluorite, isocyanates, carbamate, N-fluoroalkyl-
amines, and ureas, and as the starting materials for the synthe-
sis of insecticides.[5,6] They can also be used as inhibitors of en-
zymes.[6] Carbamoyl fluorides are usually prepared from the
condensation of amines with difluorophosgene or carbonic
fluoride chloride, the halogen exchange of carbamoyl chlorides
with fluoride, the electrochemical fluorination of carbamic acid
derivatives, the hydrolysis of perfluoro(N,N-dialkylmethyl-
amines) with oleum, and the reactions of aziridines with trifluo-
romethyl hypofluorite.[7] All of these transformations involve
highly toxic reagents and/or harsh reaction conditions, which
make them difficult to handle. Thus, the development of mild
and convenient methods for the synthesis of carbamoyl fluo-
rides is highly attractive because the exploitation of environ-
mentally friendly processes has become one of the most im-
portant targets for today’s chemists.
Urea and its derivatives have played a central role in organic
synthesis, since its first preparation from ammonium cyanate
by Wçhler in 1828, which marked the beginning of classical or-
ganic chemistry and the first connection between chemistry
and biology.[1a] Although interest in these compounds fell away
in the last century because of their reputation for unreactivity
and intractability, they have experienced a remarkable reemer-
gence in the last two decades.[1] At present, urea derivatives
have been widely used as chemical reagents, ligands, catalysts,
and functional materials in numerous fields.[1–3] Their biological
applications as plant growth regulators, agrochemicals, and
pharmaceuticals have also been well documented.[2,3] The tra-
ditional synthesis of ureas mainly focused on the use of dan-
gerous reagents, such as phosgene and isocyanates.[2] In
recent years, these highly toxic reagents have been gradually
substituted for safer alternatives, such as bis(4-nitrophenyl)car-
bonate, triphosgene, di-tert-butyl dicarbonate, 1,1-carbonylbis-
imidazole, 1,1-carbonylbisbenzotriazole, S,S-dimethyldithiocar-
bonate, and trihaloacetylchlorides, which can be stored and
handled without special precautions.[2] The production of urea
derivatives from CO, CO2, and other miscellaneous carbonyla-
tion reagents has also been implemented.[3,4]
Trifluoromethyl trifluoromethanesulfonate (2a) has been
confirmed as a useful reagent in recent years, although almost
no progress was made for about 20 years after its initial and
improved syntheses from the 1960s to the 1980s.[8] Contrary to
the very reactive alkyl triflates, sulfonate 2a is fairly stable and
resistant to hydrolysis. It did not trifluoromethylate nucleo-
philes, such as pyridine, triethylamine, iodide, phenyllithium,
phenylmagnesium bromide, lithium thiophenolate, and
sodium napththalenide, but decomposed to form trifluoro-
methanesulfonyl fluoride and complex mixtures, which was
thought to limit its synthetic utility.[8g] In reality, sulfonate 2a
has the potential to be either a OCF3 or CF3SO2 transfer re-
agent.[9,10] Cleavage of the SÀO bond in 2a yields trifluoro-
methanolate salts as the most significant nucleophilic trifluoro-
methoxylation reagents.[9] The transition-metal-catalyzed or
-free reactions of organic halides, metal complexes, a-diazo
compounds, and alkenes with the ÀOCF3 anion, which is gener-
ated in situ from 2a in the presence of anhydrous fluorides,
Moreover, carbamoyl fluorides, which represent another
class of interesting compounds, have been applied as the pre-
[a] H.-X. Song, Z.-Z. Han, Prof. C.-P. Zhang
School of Chemistry, Chemical Engineering and Life Science
Wuhan University of Technology, 205 Luoshi Road
Wuhan 430070 (P.R. China)
E-mail: cpzhang@whut.edu.cn
Supporting Information and the ORCID identification number(s) for the
author(s) of this article can be found under:
https://doi.org/10.1002/chem.201901865.
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have successfully constructed a variety of trifluoromethoxylat-
ed compounds.[9] The similar employment of trifluoromethyl
arylsulfonates and trifluoromethyl benzoate as ÀOCF3 sources
has also been fully discussed.[11,12] Nonetheless, the application
of trifluoromethyl sulfonates in other reactions, rather than tri-
fluoromethoxylation and sulfonylation, has rarely been stud-
ied.[8]
Table 1. Click reactions between 1a and different “CO” sources (2).[a]
Entry
2
Yield of 3a [%]
1
2
3
4[c]
5[c,d]
6
2a
88 (90), 89[b]
4-Me-C6H4SO3CF3 (2b)
C6H5CO2CF3 (2c)
CsOCF3 (2d)
AgOCF3 (2e)
Cl3COCO2CCl3 (2 f)
CDI[f] (2g)
(24, 63[b]
(50, 56[b]
71
)
)
Furthermore, click chemistry is a chemical concept that was
first introduced by Sharpless and co-workers in 2001, and has
been extensively used in biology, medicine, and materials sci-
ences.[13] Any reaction that can produce conjugate molecules
efficiently from smaller units under simple conditions can be
considered as a click reaction.[13] The best-known click reac-
tions are the copper-catalyzed azide–alkyne cycloaddition
(CuAAC) reaction and the thiol–ene reaction. Sulfur(VI) fluoride
exchange (SuFEx), revived by Sharpless and co-workers, is an
emerging click reaction based on the high reactivity of sulfonyl
fluorides and fluorosulfates towards silyl ethers or amines.[13c,d]
It is known that trifluoromethanolates are thermally unstable
and tend to undergo a-fluorine elimination to form difluoro-
phosgene and fluoride above À308C.[9–11] Because 2a is an
easily accessible ÀOCF3 source, which can be initiated by vari-
ous nucleophiles,[8g,9] we have wondered whether it could be
used as a liquid reservoir of difluorophosgene and a click re-
agent for amines to prepare ureas and carbamoyl fluorides
under metal- and additive-free conditions.
81
13, 39[e]
73 (77)
7
[a] Reaction conditions: 1a (0.4 mmol), 2a (0.2 mmol), CH3CN (2 mL), RT,
1 h. The yield was determined by HPLC with 3a as an external standard
(tR =4.626 min, lmax =256 nm, water/methanol (v/v)=20:80). The yield of
product isolated is given in parentheses. [b] CsF (0.02 mmol) was used.
[c] Under N2. [d] À308C to RT. [e] Cl3COCO2CCl3 (0.067 mmol) was used.
[f] CDI=N,N’-carbonyldiimidazole.
24% yield, and the addition of 10 mol% CsF to the reaction
mixture could considerably improve the yield of 3a (63%).
Benzoate 2c represents another useful precursor of the ÀOCF3
anion,[9b,12] and its reaction with 1a in the absence of CsF
formed 3a in 50% yield. The choice of CsF as an additive
could only slightly increase the yield of 3a (56%). Similar treat-
ment of 1a with 2d or 2e provided 3a in 71 or 81% yield, re-
spectively, which was close to that with 2a. Nevertheless, tri-
phosgene (2 f), a commonly used CO reagent, reacted with 1a
in the absence of additives to afford 3a in 13 or 39% yield, de-
pending on the number of equivalents of 2 f employed. Fur-
thermore, the reaction of 1a with 2g under the same condi-
tions produced 3a in 73% yield (isolated in 77% yield). All of
these results suggested that 2a was the best CO source
among the tested reagents under metal- and additive-free con-
ditions.
Results and Discussion
Indeed, the reaction of 2a with aniline (1a; 2.5 equiv) as a
model substrate without any additive in CH3CN at room tem-
perature under an ambient atmosphere for 15 min provided
1,3-diphenylurea (3a) in 75% yield (Table S1 in the Supporting
Information). The molar ratios of 2a and 1a had a slight influ-
ence on the reaction. A mixture of 1a with excess 2a at room
temperature for a longer reaction time could also afford 3a in
moderate yields (Table S1 in the Supporting Information). A
screening of different solvents demonstrated that hexane,
CH2Cl2, CH3CN, and DMF gave better yields, among which
CH3CN appeared to be the best solvent (Table S2 in the Sup-
porting Information). Further investigation showed that the re-
action of 1a (2 equiv) with 2a in CH3CN at room temperature
for 1 h provided 88% yield of 3a (isolated in 90% yield) as an
optimal result (Table 1). No additional base was necessary to
trap the acid formed in the reaction. The addition of CsF to
the reaction mixture of 1a (2 equiv) and 2a led to 3a in a
yield (89%) comparable to that (88%) without CsF (Table 1).
This result proved that 1a itself could trigger the reaction.
Condensation was rapid, clean, and complete by simply mixing
the reactants under mild conditions and with the formation of
minimal or easily removable byproducts. According to the
principles of click chemistry, as mentioned above, we ambi-
tiously classify this reaction as a new type of click reaction.
To validate the efficiency of 2a as a click reagent, the reac-
tions of 1a with other CO sources were compared under the
same conditions (Table 1). It was found that the reaction of 1a
with 2b under metal- and additive-free conditions gave 3a in
With the optimized conditions in hand (1/2a/CH3CN/RT/1 h),
we next examined the substrate scope of the reaction with dif-
ferent types of amines (Table 2). To our delight, a variety of pri-
mary aniline derivatives and heteroarylamines (1b–z) with
either electron-donating or -withdrawing groups on the aryl
rings were all readily converted to form the corresponding
symmetric ureas (3b–z) in good to high yields. The ester,
ketone, amides, carboxylic acid, phenolic hydroxyl groups, allyl
and alkynyl groups, and heterocycles were well tolerated in
the reaction. It appeared that the electron-donating groups on
the aryl rings of anilines facilitated the reaction and that very
strong electron-withdrawing groups (e.g., CF3, NO2, and CN)
slowed down the transformation, which gave lower yields of
the desired products (after 1 h). The addition of CsF to the re-
action mixtures could enhance the conversion of highly elec-
tron-deficient anilines (3l–n, 3p, and 3z). Sterically hindered
2,4-dimethylaniline (1t) and 2-allylaniline (1u) reacted with 2a
under standard conditions to give 3t in 91% yield and 3u in
87% yield; thus suggesting little effect of steric hindrance of
the anilines on the reaction. In addition, click reactions of pri-
mary aliphatic amines (1aa–aj) with 2a in the absence of addi-
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Table 2. The click synthesis of urea derivatives from 1 and 2a.[a]
Table 3. The click synthesis of different types of heterocycles with 2a.[a]
[a] Reaction conditions: 4 (0.2 mmol), 2a (0.2 mmol), CH3CN (2 mL), RT,
ambient atmosphere, 1 h. Yields given are those of products isolated.
[b] 4 (1.0 mmol), 2a (1.0 mmol), CH3CN (5 mL).
tions featured intramolecular cyclization and formed five-mem-
bered rings, rather than the ureas, through the condensation
of two molecules of 4 with one molecule of 2a. 1,3-Diamine
and 1,3-aminoalcohol were also suitable substrates for the re-
action. For instance, the treatment of naphthalene-1,8-diamine
(4l) and (2-aminophenyl)methanol (4m) with 2a under stan-
dard conditions gave the six-membered ring products 5l and
5m in 77 and 99% yield, respectively. Again, Carvedilol (4p), a
nonselective beta blocker that is used for the treatment of
heart failure and hypertension, and Atenolol (4q), a cardiose-
lective beta-adrenergic blocker that is used for the treatment
of angina and hypertension, were readily condensed with 2a
to supply the oxazolidin-2-one derivatives 5p and 5q in good
yields. The aliphatic amino groups in 4p and 4q were selec-
tively transformed over the aromatic and primary amide
groups in these drugs, which hinted at a higher reactivity of
the former to 2a in these reactions. These achievements indi-
cated that 2a could be a useful cyclization “trap” for adjacent
amino, hydroxyl, and thiol groups in the target molecules
under metal- and additive-free conditions.
[a] Reaction conditions: 1 (0.4 mmol), 2a (0.2 mmol), CH3CN (2 mL), RT,
ambient atmosphere, 1 h. Yields given are those of products isolated.
[b] CsF (0.02 mmol) was added. [c] 15 min.
tives provided 3aa–aj in excellent yields. Condensation was
compatible with furanyl, thienyl, 1,3-benzodioxol-5-yl, and tet-
rahydrofuranyl groups. Shortening the reaction time of 2-(thio-
phen-2-yl)ethan-1-amine (1ad) could further improve the yield
of 3ad. If bulky aliphatic amines, such as cyclohexanamine
(1af), 2-methylpropan-2-amine (1ag), and adamantan-1-amine
(1ah), reacted with 2a under standard conditions, the desired
urea derivatives (3af–ah) were formed in relatively lower
yields; thus implying that steric hindrance of the aliphatic
amines had an impact on the transformation. It was remark-
able that Riluzole (1ak), a glutamate antagonist, and Procaine
(1al), an analgesic drug, underwent clean and smooth conden-
sation with 2a at room temperature to afford ureas 3ak and
3al in 96 and 87% yield, respectively; these may be proposed
as potential candidates for the screening of new prodrugs of
1ak and 1al. These observations showed good availability of
the reactions of 2a with primary amines.
Interestingly, the click reactions of 1,2-aminoalcohols (e.g.,
4a, 4c, 4n,o), 1,2-aminothiol (e.g. 4b), 2-aminophenols (e.g.,
4d–i), 2-aminobenzenethiol (e.g., 4j), and 1,2-diamine (e.g.,
4k) with 2a at room temperature under an ambient atmos-
phere for 1 h gave the respective oxazolidin-2-ones (5a, 5c,
5n,o), thiazolidin-2-one (5b), benzo[d]oxazol-2(3H)-ones (5d–i),
benzo[d]thiazol-2(3H)-one (5j), and 1,3-dihydro-2H-benzo[d]-
imidazol-2-one (5k) in up to >99% yield (Table 3). The reac-
In addition, the click reactions of secondary amines with 2a
were investigated (Table 4). Different from primary aromatic
and aliphatic amines, more sterically hindered secondary ali-
phatic amines (6a–i) reacted with 2a in the absence of addi-
tives to produce carbamoyl fluorides (7a–i) in high yields. The
reaction proceeded very rapidly (2–5 min) at room tempera-
ture and yielded carbamoyl fluorides as exclusive products.
Neither prolonging the reaction time nor increasing the molar
equivalents of amine could transform the carbamoyl fluoride
into the corresponding urea (Table S7 in the Supporting Infor-
mation). The reaction was also applicable to drug molecules
(6j–n) containing secondary amino groups. Ciprofloxacin (a
broad-spectrum antibiotic; 6j), Amoxapine (an antidepressant;
6k), Desioratadine (an antagonist for human histamine H1 re-
ceptor; 6l), Fluoxetine (a selective serotonin reuptake inhibitor
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Table 4. The click synthesis of carbamoyl fluorides from secondary
amines and 2a.[a]
Scheme 1. The reactions of 7a with different N-, O-, and S-nucleophiles.
[a] Reaction conditions: 6 (0.2 mmol), 2a (0.24 mmol), CH3CN (2 mL), RT,
ambient atmosphere, 2 min. Yields given are those of products isolated.
[b] 6 (1.0 mmol), 2a (1.2 mmol), CH3CN (5 mL). [c] 5 min. [d] Fluoxetine
hydrochloride was used directly as the starting material.
3ab in 89% yield and 19 in 3% yield (Table 5, entry 1). Mean-
while, the starting materials 1ab and 10 were recovered in 6
and 94% yield, respectively. Addition of CsF to the reaction
mixture did not significantly change the outcomes of the reac-
tion (Table 5, entry 2). If 2b reacted with a mixture of 1ab and
10 under the same conditions, product 3ab formed in 37%
yield and 19 was produced in 2% yield (Table 5, entry 3). The
use of 2c instead of 2b in the same reaction led to a 44%
yield of 3ab and 4% yield of 19 (Table 5, entry 4). These data
showed the predominant formation of 3ab in the reactions of
2a, 2b, and 2c, albeit the last two reagents underwent frus-
trated conversions. The production of 3ab in higher yield from
2a might be attributed to the strongly electron-withdrawing
CF3 group, which led to easier degradation of 2a by an amine
for further condensation. In contrast, the reaction of 1ab and
10 with 2d or 2e under similar conditions provided 57 or 38%
yield of 3ab and 27 or 54% of 19 (Table 5, entries 5 and 6).
antidepressant; 6m) and Troxipide (a systemic non-antisecreto-
ry gastric cytoprotective agent; 6n) reacted with 2a (1.2 equiv)
in CH3CN at room temperature for 2 or 5 min to construct the
corresponding carbamoyl fluorides (7j–n) in 92–98% yield. In
particular, the hydrochloride of fluoxetine without neutraliza-
tion could also be successfully transformed under standard
conditions to form 7m in 63% yield. Functional groups such
as ether, thioether, cyano, tertiary amino, imine, and amide in
the substrates were well tolerated and did not hamper the for-
mation and isolation of the desired carbamoyl fluorides; thus
suggesting good selectivity and compatibility of the reaction.
Additionally, it should be noted that a less nucleophilic
secondary aromatic amine, such as diphenylamine, was inert
to 2a under standard reaction conditions; thus offering an op-
portunity to selectively functionalize the secondary aliphatic
amines over the aromatic analogues.
Table 5. Competitive click reactions of 2 with amines and alcohols.[a]
The carbamoyl fluoride of a secondary amine (e.g., 7a) was
an unreactive reagent for secondary aliphatic amines (e.g., 6a),
aromatic amines (e.g., 1a), alcohols (e.g., 10), phenols (e.g.,
12), benzenethiols (e.g., 14), and thiols (e.g., 16) at either
room temperature or 608C (conditions A, Scheme 1). The addi-
tion of NEt3 to the reaction mixtures at room temperature
overnight could not form the condensed products (8, 9, 11,
13, 15, and 17) either (conditions B, Scheme 1). However, the
carbamoyl fluoride was reactive to primary aliphatic amines
because the reaction of 7a with 1ab at room temperature for
1 h gave 18 in 92% yield (Scheme 1). The results implied that
the carbamoyl fluoride was substantially inactive to N-, O-, and
S-nucleophiles, except the primary aliphatic amine; thus
boding well for the compatibility of this type of compound
with ordinary nucleophilic agents.
Yield [%]
Entry
2
3ab[b]
19[c]
Recovery of 1ab/10 [%][d]
1
2a
2a
2b
2c
2d
2e
89
86
37
44
57
38
3
4
2
4
27
54
6/94
2[e]
3
10/89
55/91
50/86
26/74
33/64
4
5[f]
6[f,g]
[a] Reaction conditions: 1ab (0.4 mmol), 10 (0.4 mmol), 2 (0.2 mmol),
CH3CN (2 mL), RT, ambient atmosphere, 1 h. [b] Yield of product isolated.
[c] The yields were determined by HPLC with 19 as an external standard
(tR =4.930 min, lmax =212 nm, water/methanol (v/v)=20:80). [d] Starting
material 1ab was recovered by column chromatography. The recovery of
10 was determined by HPLC with 10 as an external standard (tR =
water/methanol
(0.02 mmol) was added. [f] Under N2. [g] À308C to RT.
15.575 min,
l=212 nm,
(v/v)=20:80).
[e] CsF
Furthermore, the competitive reaction of 1ab (2 equiv) and
2-phenylethan-1-ol (10, 2 equiv) with 2a in one pot provided
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The comparable yields of 3ab and 19 in both cases indicated
the poor selectivity of AgOCF3 and CsOCF3 to the primary
amine and alcohol, which was likely, in part, to be caused by
the countercation of the ÀOCF3 salts.
with another equivalent of amine to produce the correspond-
ing urea derivative (3). If the amine possesses an adjacent hy-
droxyl, amino, or thiol group, intramolecular cyclization of 7
and/or 26 occurs to supply five- or six-membered heterocycles.
In the case of secondary amines without neighboring hydroxyl,
amino, or thiol groups, the reaction stops at the carbamoyl
fluoride intermediate, yielding various drug-like molecules. The
fluorides generated in situ from decomposition of the ÀOCF3
anion and condensation of the amine with COF2 are other im-
portant initiators for the degradation of 2a (path b, Scheme 2).
Because only a trace amount of TfNHC6H5 was formed (<1%)
in the standard reaction of 1a and 2a, as determined by
19F NMR spectroscopy analysis of the reaction mixture (see the
Supporting Information), the catalytic cycle of the reaction
should be largely sustained by in situ formed fluorides. Addi-
tionally, the relative inertness of the O- and S-nucleophiles to
2a, in comparison with the amines, might be attributed to the
inability of these substrates to trigger the decomposition of 2a
to the key CO2F intermediate under standard reaction condi-
tions.
For further comparison, the reactions of 2a with O- or S-nu-
cleophiles under standard or modified conditions were investi-
gated (see the Supporting Information). If a mixture of 2a and
10 (2 equiv), phenol (12, 2 equiv), benzenethiol (14, 2 equiv),
or octane-1-thiol (16; 2 equiv) was kept without an additive at
room temperature for 1–72 h, no desired product was formed
(see the Supporting Information). Nevertheless, the same reac-
tion of 2a and 10 with CsF (0.1 equiv) or NEt3 (1 equiv) as an
additive provided diphenethyl carbonate (20) in 37 or 53%
yield, respectively (see the Supporting Information). The addi-
tion of CsF or NEt3 to reaction mixtures of 2a/12 and 2a/14,
respectively, gave diphenyl carbonate (21) in 20–88% yield
and S,S-diphenyl carbonodithioate (22) in 49–87% yield after
12–72 h (see the Supporting Information). Different from 10,
12, and 14, octane-1-thiol (16) reacted with 2a at room tem-
perature in the presence of CsF or NEt3 to produce 1,2-dioctyl-
disulfane instead of S,S-dioctyl carbonodithioate (23; see the
Supporting Information). If 1-phenylethane-1,2-diol (24) was
mixed with 2a at room temperature for 1–12 h, no product
was formed (see the Supporting Information). The use of CsF
or NEt3 in the same reaction could greatly improve the produc-
tion of 4-phenyl-1,3-dioxolan-2-one (25), which was obtained
in up to 94% yield after 1 h. These findings, combined with
the above discussions for amines, indicated that the N-, O- and
S-nucleophiles might have distinct reaction profiles for 2a, and
that the N-nucleophiles might have priority for condensation
with 2a under additive-free conditions, compared with homol-
ogous O- and S-nucleophiles.
Conclusion
We have developed an efficient and convenient method for
the synthesis of ureas, heterocycles, and carbamoyl fluorides
from amines and 2a. The reaction proceeded very rapidly and
supplied a large number of useful, potentially bioactive mole-
cules under mild conditions. Sulfonate 2a has proved to be a
safe and stable replacement for difluorophosgene and a won-
derful click reagent for amines without additional additives at
room temperature. It was revealed that the click reactions of
2a with primary amines at room temperature formed ureas in
good to high yields, while the same reactions with secondary
aliphatic amines provided selectively carbamoyl fluorides in ex-
cellent yields. If 2a reacted with amines containing adjacent
hydroxyl, amino, or thiol groups under standard conditions, a
variety of five- and six-membered heterocycles were eventually
produced. The reactions featured simplicity, high efficiency, a
wide range of substrates, good functional group tolerance, ex-
cellent selectivity, no additives, and effortless purification of
the products because of the formation of gaseous or easily re-
movable byproducts. It was significant that even the hydro-
chloride of fluoxetine, without neutralization, could be trans-
formed under the standard conditions; thus suggesting good
applicability and compatibility of this method. Further applica-
tion of 2a as a promising precursor of difluorophosgene and
anhydrous fluoride in organic synthesis is currently underway
in our laboratory.
Based on the results above, a plausible reaction mechanism
is suggested in Scheme 2. The synthesis of urea derivatives
and carbamoyl fluoride from 2a and amines might start from
the nucleophilic substitution of 2a by an amine at the sulfur
center, which first forms the ÀOCF3 anion and trifluorometh-
À
anesulfonamide (path a, Scheme 2). Then, the OCF3 anion rap-
idly fragments into COF2 and fluoride through a-F elimination.
Carbonylation of amine with COF2 yields a carbamoyl fluoride
(7) and releases an equal equivalent of HF. In the case of pri-
mary amines, fluoride 7 possibly undergoes elimination of HF
to form a highly reactive isocyanate (26). This process could be
reversed in the presence of HF. Both 7 and 26 react further
Experimental Section
A sealed tube was charged with amine 1 (0.4 mmol), CH3CN
(1.5 mL), and a solution of 2a (43.6 mg, 0.2 mmol) in CH3CN
(0.5 mL) with stirring. The mixture was reacted at room tempera-
ture under ambient atmosphere for 1 h, quenched with water (2–
3 drops), and concentrated to dryness under reduced pressure. The
residue was purified by means of column chromatography on
Scheme 2. A plausible reaction mechanism for the production of ureas, het-
erocycles, and carbamoyl fluorides from 2a and amines.
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Acknowledgements
We thank the Wuhan University of Technology, the National
Natural Science Foundation of China (21602165), the “Chutian
Scholar” Program from the Department of Education of Hubei
Province, the “Hundred Talent” Program of Hubei Province, the
Wuhan Youth Chen-Guang Project (2016070204010113), and
the Excellent Dissertation Cultivation Funds of Wuhan Universi-
ty of Technology (2018-YS-082) for financial support.
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Conflict of interest
The authors declare no conflict of interest.
Keywords: amines · click chemistry · fluorides · sulfur ·
synthesis design
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Manuscript received: April 24, 2019
Revised manuscript received: June 4, 2019
Version of record online: && &&, 0000
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FULL PAPER
&
Synthesis Design
H.-X. Song, Z.-Z. Han, C.-P. Zhang*
&& – &&
Concise and Additive-Free Click
Reactions between Amines and
CF3SO3CF3
Back to basics: Trifluoromethyl
scheme). The click reactions are rapid,
efficient, and selective, and simply car-
ried out in benign solvents to afford
products with minimal efforts for purifi-
cation.
trifluoromethanesulfonate is a promis-
ing click reagent for amines in the prep-
aration of urea derivatives, heterocycles,
and carbamoyl fluorides under metal-
and additive-free conditions (see
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ꢀ 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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These are not the final page numbers! ÞÞ