Organic Letters
Letter
methyl, methoxy, benzyloxy, chloro, and carboxylate, at
different positions (1o−u) reacted smoothly, generating the
corresponding 3-(2,2,2-trifluoro-1-hydroxyethyl)indoles
(3oa−3ua) in moderate to good yields (49−72%). Captivat-
ingly, N-substituted indoles with methyl, ethyl, and benzyl
groups (1v−z′) also afforded corresponding products 3va−
3z′a in good yields (60−79%). Notably, the tolerance of
halogen substituents provided handles for late-stage function-
alization. The structures of the products were confirmed by
NMR (1H, 19F, and 13C{1H}) and HMRS data. The structures
unambiguously confirmed by single-crystal X-ray analysis.
After evaluating the substrate scope with respect to indoles,
we explored the possibility of using different alcohols under
optimal conditions. 2,2,3,3,3-Pentafluoropropan-1-ol (2b) and
2,2,3,3,4,4,4-heptafluorobutan-1-ol (2c) reacted with indole
(1o) under optimized reaction conditions to afford the
corresponding hydroxyfluoroalkylated products 3ob and 3oc
in 63 and 69% yield, respectively. Similarly, 2-tolylindole (1d)
upon reaction with 2b produced hydroxyfluoroalkylated
product 3db in 74% yield. Unfortunately, hydroxyalkylated
product could not be isolated from the reaction of 1a with
ethanol, butanol, and 2-hexafluoropropanol under these
conditions.
good yields (63−81%). 2-(Thiophen-3-yl)imidazo[1,2-a]-
pyridine (1m) also successfully afforded the desired product
5ma in 81% yield. Reaction of imidazo[1,2-a]pyrimidines (1o
and 1p) with 2a provided the corresponding 2,2,2-trifluoro-1-
hydroxyethyl derivatives 5oa and 5pa in 54 and 47%,
respectively. Interestingly, reaction of 4a, 4c, and 4g with 2b
afforded the corresponding products 5ab, 5cb, and 5mb in
good yields (65−73%). Reaction of 4a with 2c also gave the
corresponding 2,2,2-trifluoro-1-hydroxyethyl derivative 5ac in
56% yield. The NMR (1H, 19F, and 13C{1H}) and HRMS data
of 5 were in good agreement with the structures, and the
structures of 5aa (CCDC 2033967) and 5ba (CCDC
2033968) were unambiguously confirmed by single-crystal X-
ray analysis.
The robustness of this protocol was demonstrated by
generating gram quantities of 3aa and 5ia. The gram-scale
reaction of 1a and 4i with 2a produced corresponding
products 3aa and 5ia in 83% (1.25 g) and 74% (1.06 g)
yield, respectively (Scheme 4).
Scheme 4. Gram-Scale Synthesis of 3aa and 5ia
To further extend the scope of this reaction, imidazo[1,2-
a]pyridine (4a) was allowed to react with 2a. A small change in
the reaction conditions (increase in reaction time to 36 h and
decreasing reaction temperature to 120 °C; see Table S1,
phenylimidazo[1,2-a]pyridin-3-yl)ethanol 5aa in good yield
(81%). We then evaluated the substrate scope for imidazo[1,2-
a]pyridines (Scheme 3). Reaction of imidazo[1,2-a]pyridines
having electron-donating as well electron-withdrawing sub-
stituents on the C2-phenyl ring and imidazo[1,2-a]pyridine
nucleus (4b−p) with 2a afforded the corresponding 2,2,2-
trifluoro-1-hydroxyethyl derivatives 5ba−pa in moderate to
To demonstrate the synthetic utility of the developed
protocol, late-stage functionalization of Zolimidine (4q), a
gastroprotective drug, was performed. Delightfully, reaction of
4q with TFE under standard conditions produced the
hydroxyfluoroalkylated product 5qa in 63% yield (Scheme 5).
Scheme 5. Late-Stage Functionalization of Zolimidine
Scheme 3. Hydroxyfluoroalkylation of Imidazo[1,2-
a b
,
a]pyridines
Furthermore, the synthetic application of the synthesized
products was demonstrated by converting 3aa to trifluorinated
3-indolyl(heteroaryl)methanols via the Yb(OTf)3-catalyzed
Friedel−Crafts reaction (Scheme 6). Reaction of 3aa with 1a
Scheme 6. Yb(OTf)3-Catalyzed Friedel−Crafts Reaction of
3aa
and pyrrole (6) in the presence of Yb(OTf)3 (10 mol %) in
toluene at 90 °C for 12 h gave 3,3′-(2,2,2-trifluoroethane-1,1-
diyl)bis(2-phenyl-1H-indole) (7) and 2-phenyl-3-(2,2,2-tri-
fluoro-1-(1H-pyrrol-3-yl)ethyl)-1H-indole (8) in 60 and 59%
yields, respectively.
Some control experiments were performed to gain insights
into the reaction mechanism of this CDC reaction (Scheme 7).
First, the effect of a radical scavenger was studied by
performing the reaction of 1a with 2a in the presence of
butylated hydroxytoluene (BHT) (Scheme 7a). Formation of
3aa was completely suppressed with concomitant formation of
a
Reaction conditions: 1 (1 equiv, 0.5 mmol), 2 (2.0 mL), TEMPO
b
(3.0 equiv), sealed tube, 120 °C in an oil bath, 36 h. Isolated yields.
1375
Org. Lett. 2021, 23, 1373−1377