Organic Letters
Letter
abstracting reagents (Scheme 1B). Herein we report the
concrete support for the hypothesis. The reaction of
heteroarenes with simple alkanes readily proceeds in the
presence of phenyliodine(III) bis(trifluoroacetate) (PIFA)
under visible-light irradiation. The transformation is promoted
either by catalytic TsNHMe or with CF3CH2OH as cosolvent.
The reaction conditions are mild and neutral, providing a
metal-free approach for the Minisci reaction.
were screened, showing that DCM was more effective than
other solvents, e.g. CHCl3, benzene, DMSO, etc. (entries 5−
7). When using TsNH2 or PhCONHtBu in lieu of TsNHMe,
the desired product was afforded in low yields (entries 8−9).
The investigation of light sources showed that, while 30 W
blue LEDs and 34 W CFL led to moderate yields of 3a, the
reaction did not occur with 30 W green LEDs (entries 10−12).
Control experiments revealed that light and PIFA were
necessary for the reaction (entries 13 and 14). The formation
of 3a with 30% yield in the absence of TsNHMe indicated the
existence of a secondary HAT pathway, probably attributed to
the homolysis of PIFA to generate the CF3 radical10 and
iodanyl radical11 that could also abstract an H-atom (entry 15).
The reaction under air resulted in a slightly lower yield (entry
16). We next examined other alcohol-based HAT reagents,
which could deliver the alkoxy radical to promote the reaction.
While with the use of catalytic CF3CH2OH instead of
TsNHMe the desired product was obtained in 54% yields
(entry 17), the reaction resulted in almost quantitative yield by
using CF3CH2OH as solvent (entry 18). Using CCl3CH2OH
as solvent gave a 40% yield (entry 19). The reaction afforded
the best yield in a mixed solvent (1:1 CF3CH2OH/DCM)
(entry 20).
At the outset, the reaction of 2-chloroquinoline 1a with
cyclohexane 2a was investigated to optimize the reaction
a
Table 1. Reaction Conditions Survey
entry
variation from the standard conditions
yield (%)
1
2
3
none
95
0
0
PIDA instead of PIFA
IBX instead of PIFA
With the optimized reaction conditions in hand, we set
about assessing the generality of the protocol (Scheme 2).
First, we examined the tolerance of various functional groups
such as halides, cyano, and ester (3a−3i). Good to excellent
yields were given under both the TsNHCH3 and CF3CH2OH
mediated conditions, showing good functional group compat-
ibility. Notably, a cyclohexyl group was smoothly incorporated
into Quinoxyfen, a pesticide, illustrating the potential of the
protocol for the late-stage elaboration of bioactive molecules
(3j). The alkylation of isoquinoline took place regioselectively
at the 1-position (3k and 3l). Pyridines were also suitable
heteroarenes (3m−3p). While the monoalkylated pyridines
could be obtained by controlling the amount of cyclohexane
(3m and 3o), the use of excess cyclohexane led to the
dialkylated pyridine with good yield (3p). Of note, this
protocol also provided a practical entry to modify N,N-
bidentate ligands such as 4,4′-di-tert-butyl bipyridine (3q). The
reaction with electron-rich benzothiazoles also gave rise to the
desired 2-alkylated products in moderate to good yields (3r
and 3s). Site-selective alkylation of phenanthridine occurred at
the 6-position with high yield under each set of reaction
conditions (3t).
The transformation also readily proceeded with other
valuable heteroarenes containing more than one N atom,
e.g., pyrazine, benzopyrazine, pyrimidine, benzopyrimidines,
triazine, etc. (3u−3ag). The dialkylated products could be
obtained by using excess alkanes (3y, 3ab−3ad). Similarly, the
trialkylated 1,3,5-triazine was also furnished in the presence of
excess cyclohexane (3af). Surprisingly, the alkylated 4-
hydroxyquinazoline was not afforded under the TsNHMe-
catalyzed conditions, but obtained with good yield by
switching to the alcohol-based conditions (3ae). Imidazo-
[1,2-a]pyrazine could be alkylated in moderate yield with
unique regioselectivity (3ag).
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
NaIO4 instead of PIFA
CHCl3 instead of DCM
benzene instead of DCM
DMSO instead of DCM
TsNH2 instead of TsNHMe
PhCONHtBu instead of TsNHMe
30 W blue LEDs as light source
30 W green LEDs as light source
34 W CFL as light source
dark
without PIFA
without TsNHMe
under air
CF3CH2OH instead of TsNHMe
CF3CH2OH instead of DCM
CCl3CH2OH instead of DCM
CF3CH2OH/DCM (1:1)
0
73
34
0
23
trace
64
0
54
0
0
30
83
54
96
40
96
b
c
d
e
a
Reaction conditions: 1a (0.2 mmol), 2a (5.0 equiv), TsNHMe (15
mol %), and PIFA (2.3 equiv) in solvent (2 mL) under N2, irradiated
with 2 × 50 W blue LEDs at room temperature for 12 h. Isolated
yields were given. CF3CH2OH (15 mol %). CF3CH2OH as solvent
(2 mL) without TsNHMe. CCl3CH2OH as solvent (2 mL) without
TsNHMe. CF3CH2OH/DCM (1/1) as mixed solvent (2 mL)
without TsNHMe.
b
c
d
e
details). By using PIFA as oxidant, a catalytic amount of
TsNHMe as H-abstracting reagent, and dichloromethane
(DCM) as solvent, the corresponding Minisci-type product
3a was obtained in 95% yield under blue LED irradiation
(entry 1). The reaction of 1a at 1 mmol scale was also
conducted, leading to 3a with the same yield (see SI). When
replacing PIFA with other hypervalent iodine oxidants, such as
(diacetoxyiodo)benzene (PIDA), 2-iodoxybenzoic acid (IBX),
and NaIO4, no desired product was obtained (entries 2−4). It
was rationalized that the interaction between TsNHMe and
PIFA concomitantly generated the amidyl radical and strong
acid trifluoroacetic acid (TFA); the latter could efficiently
acidify N-heteroarenes to enhance the electrophilicity and thus
facilitate the alkyl radical addition. Afterward, organic solvents
Next, we investigated the scope of simple alkanes. The
reaction with linear alkanes normally gave rise to a mixture of
positional isomers and showed that the heteroarylation of
secondary C(sp3)−H bonds was superior to that of the
primary ones (3ah and 3ai). Interestingly, exclusive selectivity
on secondary C−H bonds prior to the more reactive tertiary
B
Org. Lett. XXXX, XXX, XXX−XXX
Shao, Xin
