Organic Letters
Letter
1a).10 However, this method requires harsh reaction
conditions, which limits the functional group compatibility.
Among the metal-catalyzed, direct difluoromethylation reac-
tions of heterocycles, only two examples have been reported to
produce CF2H-substituted furans. Vicic et al. reported a base-
metal-catalyzed transformation of aryl halides (Scheme 1b),11
whereas Mikami et al. explored a palladium-catalyzed
difluoromethylation of arylboronic acids (Scheme1c).12
Recently, an elegant direct CF2H difluoromethylation of
heterocycles via organic photoredox catalysis proved to be
efficient on a furan derivative (Scheme 1d).13
Table 1. Screening of Solvents and Catalysts
ab
,
entry
solvent
catalyst
yield (%)
1
2
3
4
5
6
7
8
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
THF
CuI
CuBr
CuCl
Cu(MeCN)4PF6
CuCl2
CuSO4
Cu(OTf)2
CuI
71
37
d
d
In view of the limited methods for introduction of the CF2H
functional group onto the furan substructure, and given our
involvement in ynamide chemistry,14 we envisioned the
addition of difluorodiazoacetone to ynamides (Scheme 1e)
traces
d
d
c
́
to provide a convenient entree to difluoromethylated furans.
9
DCE
CuI
c
Among the toolbox of reagents currently utilized to introduce a
CF2H moiety, the conveniently available CF2H diazo carbonyl
compound is conspicuously missing. Taking into account
Nikolaev’s work,15 we prepared 3-diazo-1,1-difluoropropan-2-
one 3 in a one-step procedure by reacting commercially
available 1,1,5,5-tetrafluoropentane-2,4-dione 1 in the presence
of a diazo-transfer reagent (p-acetamidobenzenesulfonyl azide
(p-ABSA)) and DBU. Spontaneous deacylation of the
difluorinated diazo diketone intermediate 2 took place in the
presence of the base, providing the desired difluorodiazoace-
tone 3 in 58% yield (Scheme 2).
10
11
12
13
14
dioxane
toluene
Et2O
DMF
MeCN
CuI
CuI
CuI
CuI
c
c
c
27
c
-
a
Reaction conditions: to a solution of 4a (0.2 mmol), catalyst (10 mol
%), and solvent (2 mL), 3 (1.5 equiv, 0.5 mol/L in Et2O) was added
dropwise at 23 °C. Isolated yields. Starting material 4a was fully
recovered. Degradation was observed.
b
c
d
cyclopentyl (5e), cyclohexyl (5f)) were perfectly accommo-
dated (Scheme 3). The reaction is not restricted to saturated
substituents; unsaturated side chains with diverse carbon linker
chains (5g−j) as well as aryl groups (5a,k,l) were tolerated as
well, although the yield of the furan 5j bearing a terminal
alkyne tether is moderate. X-ray analyses of 5l confirmed the
structure of the amido-difluorinated furan 5l obtained (CCDC
2071668 contains the supplementary crystallographic data for
the structure).17 Notably, even halogens (5m), nitriles (5n),
protected aldehydes (5o), ketones (5p), and amides (5q,r)
could be used, significantly broadening the substrate scope and
providing the corresponding difluorinated furans with good
yields.
The influence of the electron-withdrawing group on the
nitrogen atom was also explored (Scheme 4). Furans bearing
an oxazolidinone (7a,b) or amide moiety (7c) were obtained
in modest yields. Sulfonyl groups such as mesyl (7d), nosyl
(7e), and trimethyl-/triisopropyl-/trifluoromethylbenzenesul-
fonamides (7g−i) were revealed to be accommodated in this
transformation. More hindered cyclic sulfonamides were
notably effective, providing the corresponding furans (7j−l)
in good yields. A sulfamoyl derivative was also incorporated,
providing furan 7f in 70% yield.
To demonstrate the diversification potential of these
difluorinated furans, we used them as building blocks to
prepare various relevant heterocycles. Nitration18 of amido-
difluorinated furan 7l under controlled temperature led
exclusively to C-4 nitrofuran 8 (Scheme 5a). Further, we
involved the amidofurans as platforms in intramolecular
oxidative coupling reactions19 as well as in intramolecular
Diels−Alder cycloadditions (IMDAF).20 The oxidation proc-
ess on compound 5i took place in the presence of a catalytic
amount of PdCl2(MeCN)2, CuCl2, and the environmentally
sustainable reoxidant O2 to provide difluorinated furo[2,3-
b]pyrrole 9 in a yield of 83% (Scheme 5b). Whereas direct
difluorination will only provide 2-substituted indolines,13 an
intramolecular Diels−Alder reaction of the amidofuran 5h led
Scheme 2. Synthesis of Difluorodiazoacetone 3
The difluorodiazoacetone reagent was prepared on a large
scale and is perfectly stable for a few weeks at 4 °C without any
decomposition. Inspired by Fu’s work on copper-catalyzed
coupling of terminal alkynes with α-diazocarbonyl com-
pounds,16 we hypothesized that ynamides treated with
difluorodiazoacetone in the presence of a copper catalyst
would generate amido(difluoromethyl)furans.
To test our hypothesis, we subjected ynamide 4a to
difluorodiazoacetone in the presence of diverse copper
catalysts. As illustrated in Table 1, only CuI and CuBr proved
to be effective (Table 1, entries 1−4), although CuBr led to a
huge erosion of the yield (37%). Using Cu(II) catalysts, the
starting ynamide 4a underwent degradation in almost all cases
(Table 1, entries 5−7), although traces of difluoromethylated
amidofuran 5a were observed (Table 1, entry 5). The choice of
the solvent is critical: the use of tetrahydrofuran (THF),
dichloroethane (DCE), dioxane, toluene, or ether did not lead
to the target molecule (Table 1, entries 8−12), and the starting
ynamide was recovered. The use of dimethylformamide led to
a significantly lower yield of the desired product (Table 1,
entry 13, 27%). A control experiment using difluorodiazoace-
tone without any catalyst afforded none of the desired product
(Table 1, entry 14).
With the optimized reaction conditions in hand (Table 1,
entry 1), we investigated the generality of this transformation.
A diverse array of ynamides bearing a variety of functional
groups were tested. Linear alkyl groups (e.g., methyl (5b),
butyl (5c)) or cyclic alkyl groups (e.g., cyclopropyl (5d),
5529
Org. Lett. 2021, 23, 5528−5532
Zheng, Yongxiang
