Organic Letters
Letter
Our method does not require an external oxidant because the
diazonium salt plays a dual role as a diazene source and oxidant.
It is worth noting that diazenes are used as dyes,39
pharmaceuticals,40−42 and photoswitches.43,44 The catalytic
synthesis of diazenes by diazonium salt trapping of alkyl radicals
is underexplored.45−48 Our mild protocol offers the first metal-
free azotrifluoromethylation of olefins without the use of
stoichiometric oxidants, with broad functional group compat-
ibility.
Table 1. Reaction Conditions for the Optimization of the
Azotrifluoromethylation of Alkenes
a
Several reports have indicated that diazonium salt could
generate aryl or diazene radicals with a base.49−52 Because this
process involves an electron absorption by a diazonium salt, we
speculated that the Langlois’ reagent could serve as an electron
donor that can be oxidized to a trifluoromethyl radical, which
may further react with an alkene and produce an azotrifluor-
omethylated product. To prove our hypothesis, we chose
allylbenzene 1a, 4-bromophenyldiazonium tetrafluoroborate 2a,
and CF3SO2Na (Langlois’ reagent) to test a base-catalyzed
three-component azotrifluoromethylation. The results are
summarized in Table 1. We screened different organic and
inorganic bases and found that the reaction indeed generated the
azotrifluoromethylation product, that tetrabutylammonium
acetate (TBAOAc) gave the highest yield (entries 1−9), and
that acetonitrile and DMF were superior solvents. The addition
of water was conducive to the reaction (entries 9−17). The
amount of TBAOAc was also crucial because the reaction gave
lower yields with either higher or lower molar equivalent of
TBAOAc (entries 11−13).
The temperature during the diazonium salt addition also
impacted the reaction efficiency. At room temperature, the
reaction produced fierce bubbling and lower yields. In contrast,
if the reaction mixture was kept at −10 °C during the diazonium
addition, the reaction was smoother and the yield higher (entry
18 vs entry 9). Further, two equivalents of both diazonium salt
and Langlois’ reagent were required (entry 9 vs entries 19, 20).
Remarkably, increasing the reaction concentration to 0.5 M
increased the reaction yield to 78% (entry 22).
a
Unless otherwise noted, reactions were conducted with a solution of
With optimized reaction conditions in hand, we explored the
reaction scope. As shown in Scheme 2, all the monosubstituted,
disubstituted, and trisubstituted alkenes showed good to
excellent yields of the corresponding products. Linear (4d and
4t) and cyclic (4u and 4v) internal alkenes also displayed good
yields of the corresponding azo compounds, albeit with varying
degrees of diastereoselectivity. A wide range of functional groups
such as esters (4b, 4g−4i, 4q, 4r, and 4z), ethers (4f, 4j−4n, 4p,
4s, and 4y), nitro (4g and 4k), nitriles (4c and 4j), aldehydes (4f
and 4m), ketones (4n and 4x), alcohol (4w), and sulfonate (4e,
4o, and 4z) were tolerated in this protocol. Acceptable to good
yields were also obtained with heterocyclic substrates like
thiophene (4q) and furan (4h). We then explored late-stage
azotrifluoromethylation of natural products (4w and 4x) and
biologically active molecule derivatives (4y, 4z). We found that
the natural products (−)-ß-citronellol (4w) and nootkatone
gave excellent yields. Methyl eugenol (4y), an active natural
ingredient pollinator attractant, furnished the azotrifluorome-
thylation product in an acceptable yield. Our protocol provides
an easy-to-use synthetic tool for the modification of drug
molecules. For example, we obtained a derivative of Probenecid
(4z) in 85% yield. Probenecid is a prototypical uricosuric agent
used to treat patients with renal impairment. These examples
further demonstrate that our azotrifluoromethylation protocol is
suitable for the late-stage, protecting-group-free modification of
biologically interesting molecules.
2a (2 equiv) in 200 μL of mixed solvent (DMF/H2O = 3/1) added
dropwise to the mixture 1a (0.2 mmol), base (0.5 equiv), and 3 (2
equiv) in 800 μL mixed solvent (DMF/H2O = 3/1) at −10 °C; the
b
reaction was then stirred at rt for 1 h. Yields were determined by 19
F
c
NMR using 4-fluoroanisole as an internal standard. 0.1 equiv of
TBAOAc. 1 equiv of TBAOAc. Room temperature. 3 (1.5 equiv)
and 2a (1.5 equiv) were used. 3 (2 equiv) and 2a (1.5 equiv) were
d
e
f
g
used.
Encouraged by these results, we explored the scope of
diazonium salts under the standard conditions (Scheme 3). It
was found that aryldiazonium salts 2b−2k bearing electron-
withdrawing or -donating groups at the para-, meta-, or ortho-
positions were well tolerated, affording the corresponding
products 5b−5k in moderate to good yields. However, electron-
rich diazonium salt gave a lower yield than the electron-deficient
diazonium salts (5g vs 5d−5f). The reason for this result could
be attributed to electron-rich diazonium salts being less stable
under basic conditions.
In contrast to various methods for the synthesis of
trifluoromethylated organic substrates, direct difluoromethyla-
tion is still underdeveloped,53−63 albeit the difluoromethyl
group (CF2H) is an intriguing structural motif in drug
design.64,65 We are glad to find that our protocol can also be
applied to the azodifluoromethylation of alkenes by just
switching the Langlois’ reagent with the commercially available
B
Org. Lett. XXXX, XXX, XXX−XXX
Lu, Zhichao
