Journal of the American Chemical Society
Communication
unbiased nature of aliphatic terminal alkenes. Although similar
results had been seen in nickel-catalyzed Heck reactions
previously, only sterically demanding phosphine ligands had
been used successfully.12 After this initial result, we attempted
optimization of various reaction parameters,21 but quickly
discovered that catalytic turnover from Ni(II) was likely not
feasible since formation of indoline products was only observed
upon exposure of the reaction mixture to air during workup.
Csp3−N bond reductive elimination from low-valent Group 10
metals is known in rare cases,18,22 and Hillhouse and co-worker
had previously demonstrated that it could occur stoichiometri-
cally after extended reaction times at room temperature when β-
H elimination was not possible.13a However, consistent with our
results, they demonstrated that reductive elimination was made
far more facile by oxidation to Ni(III) by a number of
stoichiometric oxidants, including oxygen.
If oxidation to Ni(III) is necessary for reductive elimination,
single electron reduction of the Ni(I) species formed therein
would also be necessary to transition from a stoichiometric to a
catalytic manifold, a scenario, in theory, fulfilled by a photoredox
catalytic cycle. Spurred by the recent reports of Molander7 and
Doyle and MacMillan,8 we were excited to find that the addition
of the visible light photoredox catalyst Ru(bpy)3(PF6)2 under
conditions similar to those reported by Molander (acetone, 2,6-
lutidine) produced significantly more indoline product than the
same reaction without photoredox catalyst (Table 1, entries 4
and 5). Further optimization using triethylamine furnished, for
the first time, yields in excess of the catalyst loading (entry 6).
Use of aryl iodides rather than bromides and blue LEDs to
shorten reaction times provided the optimal conditions for
excellent yields of indoline product (entry 8). Again, we were
gratified to see that under these conditions, indoline products
were produced in high selectivities (>19:1) over Heck products.
With these optimized conditions in hand, we explored the
scope of this transformation (Scheme 3). Substitution at the 4- or
5-positions of the 2-iodoacetanilide electrophile was well-
tolerated with both electron donating (e.g., 6b) and electron
withdrawing (e.g., 6c) substituents. However, substitution at the
3- or 6- positions of the arene resulted in substantially lower
Table 1. Reaction Optimization
a
X; R
ligand
base
yield 6
0%
1
OTf; Piv (1)
phosphine, PyBOX, various
phenanthroline-
type
organic/
inorganic
2
3
1
IPr
LiOt-Bu
7%
b
Cl (2), OTf (3), IPr
Br (4), I (5);
Ac
LiOt-Bu
10−14%
c
4
5
6
7
8
9
Br; Ac (4)
IPr
2,6-lutidine
2,6-lutidine
5%
cd
,
4
IPr, Ru(bpy)3
15%
33%
90%
88%
cd
,
4
IPr, Ru(bpy)3, 66 h Et3N
IPr, Ru(bpy)3, 48 h Et3N
IPr, Ru(bpy)3, 26 h Et3N
IPr, Ru(bpy)3, 26 h Et3N
cd
,
I; Ac (5)
ce
,
5
5
cf
,
g
9%
a
Yield 6 determined by GC using dodecane as an internal standard,
selectivity 6 to sum of Heck (7), isomerized Heck (e.g., 9), and 2-alkyl
b
c
indoline (8) > 19:1 unless otherwise noted. ≥10:1. Acetone (0.22
d
M). Compact fluorescent light (CFL), Ru(bpy)3(PF6)2 (2 mol %).
e
f
Blue LEDs, Ru(bpy)3(PF6)2 (1 mol %). Ru(bpy)3(PF6)2 (1 mol %)
g
reaction run in absence of light. 9:1.
by a cyclization to form the five-membered ring. Perhaps
surprisingly, given the ubiquity of the Larock indole synthesis, a
general indoline synthesis of 2-haloaniline derivatives with
alkenes has not been reported, although a few alkene annulation
methods have been developed (Scheme 2b). This approach
presents two main challenges: C−N bond reductive elimination
must outcompete β-hydride elimination (forming Heck-type
products), and Csp3−N reductive elimination is inherently
challenging.16 These two issues were first addressed by Larock
and co-workers, who reported indoline formation using 1,3-
dienes, which cannot undergo β-H elimination.17 C−N bond
formation also presumably proceeds via external nucleophilic
attack on a π-allyl intermediate. Other intermolecular annulation
approaches involve the use of alkenes without available β-H
atoms, first reported by Catellani and co-worker,18 or forego use
of alkenes altogether.19 Perhaps the most general approach thus
far was disclosed by Glorius and co-workers earlier this year.20
They reported using an internal diazinecarboxylate oxidant and
Rh(III)-catalyzed directed C−H functionalization to couple
arenes with chiefly electron-poor alkenes, yielding 2-substituted
aminoindolines. The 1-amino group can then be removed in a
subsequent step to reveal the NH-indoline.
a
Scheme 3. Scope of Aryl Electrophile
We began our development of a complementary and general
approach to indoline synthesis by testing conditions similar to
those of Heck reactions (Table 1, entry 1) and found that for a
variety of electrophiles, aniline protecting groups, bases, and
phosphine and N-type ligands, only Heck products were
observed. Finally, upon using the N-heterocyclic carbene
(NHC) ligand IPr, we were able to detect a small amount of
indoline product (entry 2). We were gratified to see that the
indoline product was produced in high selectivity (>19:1)
compared to the sum of all other products. This suggests that not
only was β-H elimination suppressed but also that alkene
migratory insertion had been highly selective for arene insertion
at the internal position, a difficult step given the electronically
a
All yields are isolated yields. Selectivity 6 to sum of 7−9 > 19:1 unless
otherwise noted. Reaction conditions: Ni(cod)2 (15 mol %), IPr (16
mol %), Ru(bpy)3(PF6)2 (1 mol %), Et3N (2 equiv), acetone (0.22
M), blue LEDs, rt, 26 h. Ru(bpy)3(PF6)2 (2 mol %), CFL, 35 °C, 48
b
c
d
h. 7:1. GC yield.
B
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX