Pd(0)-Catalyzed Dearomative Diarylation of Indoles

Article abstract of DOI:10.1002/chem.201600118

We have developed a protocol for a Pd(0)-catalyzed dearomative syn 1,2-diarylation of indoles using readily available boroxines (dehydrated boronic acids) as coupling partners. This reaction proceeds efficiently using PtBu₃ as the ligand to divergently access to fused indolines while minimizing the extent of direct Suzuki coupling. The scope of the reaction is remarkably broad and all products are obtained as single diastereomers in moderate to excellent yields. We have also compiled data which parallels the steric and electronic properties of both substrate and boroxine with the propensity to undergo the desired dearomative process over direct Suzuki coupling.

Full text of DOI:10.1002/chem.201600118

DOI: 10.1002/chem.201600118
Full Paper
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Arylation |Hot Paper|
Pd(0)-Catalyzed Dearomative Diarylation of Indoles
David A. Petrone,[a] Masaru Kondo,[b] Nicolas Zeidan,[a] and Mark Lautens*[a]
Abstract: We have developed a protocol for a Pd(0)-cata-
lyzed dearomative syn 1,2-diarylation of indoles using readily
available boroxines (dehydrated boronic acids) as coupling
partners. This reaction proceeds efficiently using PtBu3 as
the ligand to divergently access to fused indolines while
minimizing the extent of direct Suzuki coupling. The scope
of the reaction is remarkably broad and all products are ob-
tained as single diastereomers in moderate to excellent
yields. We have also compiled data which parallels the steric
and electronic properties of both substrate and boroxine
with the propensity to undergo the desired dearomative
process over direct Suzuki coupling.
Introduction
Easy access to alkenes and alkynes has motivated their exten-
sive use as substrates in transition-metal catalysis. Specifically,
much effort has been made to harness their synthetic potential
in various Pd-catalyzed difunctionalizations.[1] The ability of Pd
to react through multiple oxidation state manifolds has result-
ed in the development of a remarkably broad range of difunc-
tionalizations wherein most proceed via Pd0/PdII[2] or PdII/Pd0
cycles.[3] A subset of the former, referred to as Heck-type[4]
domino reactions,[5] typically proceed by a catalytic sequence
involving oxidative addition to an aryl or vinyl (pseudo)halide,
migratory insertion of an unsaturated carbon–carbon moiety,
transmetallation/ligand exchange, and reductive elimination.
These processes are important as they allow for straightfor-
ward formation and functionalization of difficult-to-access or-
ganopalladium species,[6] and their utility has been made evi-
dent by the large number of reports, which include formal hy-
droarylations,[6a,b] arylcarbonylations,[6e] aminations,[6d,7] alkeny-
lations,[8] cyanations,[6d,9] halogenations,[10] and borylations.[11]
The 1,2-diarylation involving a terminating Suzuki cou-
pling[12] of arylboronic acids[13,14] is the most widely explored
variant to date (Scheme 1a). This process is mechanistically dis-
tinct from the corresponding 1,2-diarylation arising from a ter-
minating CÀH functionalization event (Scheme 1b),[15] or the
Pd(II)-catalyzed 1,1- or 1,2-diarylation reactions using arylboron
or aryltin reagents (Scheme 1c).[16] Although numerous exam-
Scheme 1. Pd(0)-catalyzed 1,2-diarylation by: a) Heck–Suzuki process;
b) Heck/CÀH functionalization process; c) Pd(II)-catalyzed oxidative 1,1- and
1,2-diarylation of alkenes; d) diastereoselective Pd(0)-catalyzed dearomative
1,2-diarylation of indoles. DG=directing group.
ples of Pd(0)-catalyzed 1,2-diarylations[17] of alkenes,[18] al-
kynes,[19] and allenes[20] have been reported, the majority of ex-
amples concern the intramolecular 1,2-diarylation of alke-
nes[6c,21] and alkynes,[6c,22] with a strong emphasis on the latter.
Furthermore, the diarylation of carbon–carbon double bonds
has only been explored using both simple and strained bicyclic
alkenes wherein diastereoselective examples are rare.[21c,d] In-
spired by the recent application of indoles[23] in Pd(0)-catalyzed
dearomative Heck,[24a] reductive Heck,[24b] and arylcyanation re-
actions,[24c] we sought to develop a dearomative 1,2-diarylation
as a way to address the above-mentioned shortcomings
(Scheme 1d).[25] The proposed transformation would proceed
through a dearomative migratory insertion step of the indole’s
[a] D. A. Petrone, N. Zeidan, Prof. Dr. M. Lautens
Department of Chemistry, University of Toronto
80 St. George St. Toronto, M5S 3H6 (Canada)
E-mail: mlautens@chem.utoronto.ca
[b] M. Kondo
Department of Frontier Materials
Graduate School of Engineering
Nagoya Institute of Technology
Gokiso, Showa-ku, Nagoya 466-8555 (Japan)
Supporting information for this article and ORCID from one of the authors
are available on the WWW under http://dx.doi.org/10.1002/
chem.201600118.
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enamine functionality, thus fascilitating step economic and di-
vergent access to fused tetracyclic scaffolds.
and/or 2a’ by hydrolysis of the weak amide CÀN bond was oc-
curring.[27] Changing the organic component of the solvent
from PhMe to dioxane or DMF led to decreased conversion
and yields (entries 3 and 4). A switch in the reaction’s selectivi-
ty was observed when a 9:1 MeCN:H2O mixture was used,
wherein 2a was obtained in 61% yield (entry 5). Lowering the
reaction temperature to 1008C led to better overall mass re-
covery and a slight increase in the yield of 2a to 64%
(entry 6), whereas deviating from a 0.1m concentration of 1a
only led to inferior results (entries 7 and 8). Decreasing the re-
action time to 2.5 h led to an increase in yield of 2a to 71%
(entry 9), and nearly quantitative mass recovery. The use of
other potassium-containing bases, such as KOH, KOAc, or
K3PO4, all lead to marked decreases in yield and/or conversions
(entries 10–12). In the case of KOH, severe decomposition was
observed. Furthermore, although the use of Na2CO3 did not
lead to better results (entry 13), Cs2CO3 provided 2a in 75%
yield (entry 14). To further explore the effect of Cs counterions
on the reaction, CsF was tested. To our surprise, 2a was ob-
tained in 80% yield with 10% of 2a’ after only one hour
(entry 15). By lowering the catalyst loading to 2.5 mol%, 2a
could to be isolated in 88% yield with only 7% of 2a’
(entry 16). The final optimal conditions were found to be
[Pd(PtBu3)2] (2.5 mol%), CsF (2 equiv), phenyl boroxine
(0.47 equiv) in MeCN:H2O (9:1) at 1008C for one hour, and will
be referred to as the standard conditions.
Herein, we report the development and application of the
first dearomative indole 1,2-diarylation, which proceeds effi-
ciently using aryl and vinyl boroxines as coupling partners. De-
spite the challenging nature of the crucial dearomative migra-
tory insertion, the syn 1,2-diarylation products are obtained in
preference to the direct Suzuki coupling when the bulky Pd(0)
precatalyst [Pd(PtBu3)2] is used. Furthermore, key trends corre-
lating the steric and electronic properties of both the substrate
and boroxine with this observed selectivity have been outlined
for this class of reaction.
Results and Discussion
Reaction Optimization
To optimize the dearomative 1,2-diarylation reaction using aryl
boron reagents, N-benzoylated indole 1a was investigated
under various reaction conditions (Table 1). Initially, 1a was
treated with [Pd(PtBu3)2] (10 mol%), K2CO3 (2 equiv), phenyl
boroxine (0.47 equiv)[26] in PhMe at 110 8C for 18 h (entry 1).
This led to the formation of the desired 1,2-diarylation product
2a in 20% yield in >20:1 d.r., albeit with 63% of the direct
Suzuki coupling product 2a’. The use of an aqueous solvent
mixture lead to a decrease in the amount of 2a’ formed
(entry 2). However, the presence of 2-methylindole in the
crude reaction mixture suggested that decomposition of 1a
The effect of altering various reaction parameters on the effi-
cacy of the 1,2-diarylation was also investigated (Table 2).
When the dinuclear bromine-bridged complex [{Pd(PtBu3)(m-
Br)}2] was employed as the precatalyst instead, almost identical
results were obtained (entry 2). The similarity in the reaction
Table 1. Indole bisfunctionalization by Pd-catalyzed diarylation: Reaction
optimization.[a]
Table 2. Dearomative indole bisfunctionalization by Pd-catalyzed diaryla-
tion: Effect of reaction parameters.[a]
Entry Base
Solvent
T [8C] t [h] Conv [%][b] 2a [%][b] 2a’ [%][b]
1
2
3
4
5
6
7[c]
8[d]
9
10
11
12
13
14
15
K2CO3 PhMe
K2CO3 PhMe:H2O
K2CO3 Dioxane:H2O 110
K2CO3 DMF:H2O
K2CO3 MeCN:H2O
K2CO3 MeCN:H2O
K2CO3 MeCN:H2O
K2CO3 MeCN:H2O
K2CO3 MeCN:H2O
110
110
18 >95
18 >95
18 89
18 83
18 >95
20
20
34
10
61
64
64
47
71
28
29
58
67
75
80
(88)
63
43
21
9
20
29
26
44
28
8
Entry
Variation from the
standard conditions
Yield 2a [%][b–c]
Yield 2a’ [%][b]
110
110
100 18 >95
100 18 >95
100 18 >95
100 2.5 >95
100
100
100
100
100
100
1
2
3
none
88 (88)[d]
93(88)[d]
69
7
5
3
[{Pd(PtBu3)(m-Br)}2][e]
[Pd{P(o-Tol)3}2]
4
5
6
7
[Pd(PhPtBu2)4]
[Pd(PPh3)4]
42
5
79
63
67
83
45
22
17
10
17
8
KOH
MeCN:H2O
1
1
1
1
1
1
1
>95
53
KOAc MeCN:H2O
K3PO4 MeCN:H2O
Na2CO3 MeCN:H2O
Cs2CO3 MeCN:H2O
4
908C instead of 1008C
ArCl instead of ArBr
0.33 equiv of (PhBO)3
PhB(OH)2 instead of (PhBO)3
PhBF3K instead of (PhBO)3
>95
>95
>95
>95
>95
29
16
25
10
7
8
9[f,g]
10[g]
6
0
CsF
MeCN:H2O
16[e–g] CsF
MeCN:H2O 100
[a] Reactions were run on a 0.2 mmol scale. [b] Determined by 1H NMR
analysis of the crude reaction mixture using 1,3,5-trimethoxybenzene as
an internal standard. [c] Value in parentheses represents isolated yields.
[d] Average value over three experiments. [e] 1.25 mol% was used.
[f] Freshly recrystallized phenylboronic acid was used. [g] 1.4 equivalents
of the aryl boron reagent were used.
1
[a] All reactions were run on a 0.2 mmol scale. [b] Determined by H NMR
analysis of the crude reaction mixture using 1,3,5-trimethoxybenzene as
an internal standard. [c] [1a]=0.05m. [d] [1a]=0.2m. [e] Average value
over three runs. [f] Value in parentheses represents the average isolated
yield over three runs. [g] Reaction was run using [Pd(PtBu3)2] (2.5 mol%).
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outcome suggests that this PdI source may be converting to
the corresponding mononuclear Pd0 catalyst under the reac-
tion conditions.[28] In all cases, decreasing the size of the ligand
led to a decrease in yield of 2a (entries 3–5).[29] We hypothesize
that when extremely bulky ligands (such as PtBu3) are used,
only one ligand can be accommodated in the coordination
sphere of the ArPdIIBr species resulting from the oxidative ad-
dition. This translates to a vacant coordination site for easier
binding of the indole olefin moiety, and presumably a more
facile migratory insertion. Conversely, the coordination sphere
can reach saturation easier when less bulky ligands (such as
PhPtBu2) are used, therefore decreasing propensity of the PdII
species to undergo olefin insertion, which manifests itself in
the form of a higher degree of the undesired direct Suzuki
coupling process. Both decreasing the reaction temperature
below 1008C and employing the aryl chloride analog of 1a,
led to a higher amount of 2a’ being formed (entries 6 and 7).
Decreasing the amount of phenyl boroxine to 0.33 equivalents
(ꢀone equivalents of ArB) led to decreased efficiency of the
1,2-diarylation process (entry 8). The use of freshly prepared
PhB(OH)2 lead to a slight decrease in yield of 2a, whereas the
use of PhBF3K inhibited the formation of 2a’ at the expense of
overall conversion and yield of 2a (entries 9 and 10).
Substrate Scope
With the optimized conditions in hand, the generality of this
catalytic process was evaluated. We first sought to determine
the effects of various steric and electron perturbations on the
1,2-diarylation reaction using a series of substituted N-protect-
ed indoles 1a–1w (Scheme 2). Sterically hindered aryl bromide
1b was found to function exceptionally well in this reaction,
and 2b was obtained in 98% yield with only trace amounts of
the direct Suzuki coupling. Chloro- and fluoro-bromobenzoyl
analogs 1c and 1d could be converted to the corresponding
diarylated products in 70% (2c) and 82% yield (2d), respec-
tively. In the case 1c, the boroxine loading was lowered to 0.4
equivalents to inhibit the direct Suzuki coupling of the aryl
chloride in the product at higher conversions. Electron-defi-
cient and -rich aryl bromides could be converted to the corre-
sponding products in moderate to excellent yields (2e and
2 f). Various 2-alkyl (1g–1i) -carbonyl (1j) and -aryl indoles
(1k–1m) were well tolerated under the reaction conditions
and the corresponding products (2g–2m) could be obtained
in good to excellent yields. Both electron-rich (1n) and -poor
(1o and 1p) indoles led to the desired products (2n–2p),
albeit in slightly lower yield than the parent substrate. In the
case of the difluorinated 1p, a catalyst loading of 3.5 mol%
was required to reach full conversion. N-Methyindolyl (1q) and
cyclohexenyl (1r) substrates were found to undergo the de-
sired transformation, and the corresponding indolines could
be obtained in moderate yields. 3-bromothiophene derivative
1s converted cleanly under the reaction conditions, yet the de-
sired product 2s could only be obtained in 45% yield on ac-
count of a more efficient direct Suzuki coupling reaction (vide
infra).
Scheme 2. Pd(0)-catalyzed dearomative indole diarylation: Scope of N-ben-
zoyl indoles. [a] All reactions were run on a 0.2 mmol scale unless otherwise
1
stated; [b] diastereomeric ratios were determined by H NMR analysis of the
crude reaction mixture; [c] 1gram (3.20 mmol) scale using [Pd(PtBu3)2]
(1.25 mol%); [d] [Pd(PtBu3)2] (3.5 mol%); [e] (PhBO)3 (0.4 equiv); [f] reaction
was run on a 0.13 mmol scale; [g] [Pd(PtBu3)2] (5 mol%).
Some limitations with the reaction were noted. When non-
substituted indole 1t was subjected to the reaction conditions,
only 9% of the desired indoline product 2t could be isolated
in addition to 91% of the product resulting from a direct cycli-
zative CÀH functionalization at the C2-position of indole.[30]
2,3-Dialkylated indole 1u did not lead to any desired product
containing a quaternary benzylic position. Instead, the corre-
sponding dearomative Heck reaction was found to occur, and
the corresponding product containing an exomethylene could
be isolated in 92% yield.[24a] Exchanging the amide functionali-
ty of 1a for a sulfonamide (1v) negatively impacted the reac-
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tion and no dearomative cyclization was observed. Instead,
only the direct Suzuki coupled product was obtained, which
was accompanied by recovered starting material. N-benzyl
analog 1w was fully consumed when subjected to the reaction
conditions; however, no desired product was observed and
91% of the direct Suzuki was isolated instead. Finally, when
the reaction was run on a gram scale, 2a could be obtained in
76% yield and >20:1 d.r. when the catalyst loading was de-
creased to 1.25 mol%.
conversion of the starting material. Suzuki coupling of the aryl
chloride of 2ag was initially observed under the standard con-
ditions; however, decreasing the boroxine loading to 0.4 equiv-
alents eradicated this undesired process. We were able to un-
ambiguously confirm the relative stereochemistry of the diary-
lation to be syn by X-ray crystallographic analysis of 2ah
(Figure 1). 1- and 2-napthylene boroxines were well tolerated
Next, the effect of various sterically and electronically diverse
boroxines on the 1,2-diarylation reaction was explored
(Scheme 3). Overall, the reaction was quite tolerant to many
Figure 1. X-ray structure of 2ah showing relative stereochemistry.[37]
under the reaction conditions and the corresponding products
2al and 2am could be obtained in 81% and 78% yield, re-
spectively. 2-Thiophene boroxine could also be incorporated
into the indoline scaffold in 79% yield, whereas E-pentenyl
(2ao) and styrenyl (2ap) boroxines were also capable of un-
dergoing the desired tranformation in 89% and 78% yields, re-
spectively. When alkylboronic acids were used in the reaction,
none of the desired 1,2-diarylation was observed, and only
traces of the direct Suzuki coupling as the sole product were
observed.
Analysis of Selectivity
The undesired biaryl product 2’ arising from the direct Suzuki
coupling of the aryl bromide occurred to some extent in all in-
1
stances during the substrate scope determination. By H NMR
analysis of the crude reaction mixtures, trends could be ob-
served that relate steric and electronic perturbation of both
1 and the boroxine reagents to the ratio of 2:2’. Figure 2 dis-
plays the ratios of 1,2-diarylation/direct Suzuki coupling from
reactions of various N-benzoylated indoles bearing substitution
on the aryl bromide fragment, and both the indole C2- and
C5-positions, respectively.
Scheme 3. Pd(0)-catalyzed dearomative indole diarylation: Scope of borox-
ines. [a] All reactions were run on a 0.2 mmol scale; [b] diastereomeric ratios
1
were determined by H NMR analysis of the crude reaction mixture; [c] 0.4
equivalents of the corresponding boroxine; [d] reaction time=50 min;
[e] run using [Pd(PtBu3)2] (3.5 mol%); [f] reaction time=2 h.
The introduction of local steric effects (o-Me, 1b) around the
carbon–bromine bond led to the lowest amount of Suzuki
coupling (2:2’=31:1). The presence of electron donating OMe
group para to the carbon–bromine (1 f) bond also helped sup-
press the direct Suzuki coupling (2:2’=28:1), whereas p-CF3
group (2e) had the opposite effect (2:2’=3.4:1). The presence
of activating Cl or F atoms (1c and 1d) led to a similar increase
in Suzuki coupling (2:2’=ꢀ5:1). In general, heteroaryl bro-
mides exhibited the lowest ability to undergo the desired dear-
omative 1,2-diarylation reaction across all substrates. For exam-
ple, 3-bromothiophene derivative 1s led to the Suzuki cou-
pling being the major pathway (2:2’=0.8:1). Generally, both
sterically hindered and electron-rich aryl bromides led to the
largest suppression of the Suzuki pathway, whereas the oppo-
site effect was observed across all electron-deficient aryl bro-
types of aryl boroxines with varying ratios of 1,2-diarylation to
direct Suzuki coupling being observed. Aryl groups bearing
ortho-methyl, -chloro, and -formyl substituents could be incor-
porated into the tetracyclic indole scaffold in moderate to
good yields (2x–2z). No Suzuki coupling of the product aryl-
chloride was observed in the case of 2y even when using
0.47 equivalents of the boroxine. Aryl boroxines bearing meta
substituents, such as methyl, methoxy, and fluoro, were also
well tolerated (2aa–2ac). The reaction also performed well
when various electronically diverse para-substituted boroxines
were employed (2ad–2ak). In some instances (2ah–2ak), reac-
tion times had to be increased to 2 h in order to obtain full
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Figure 2. Effect of steric and electronic perturbation of 1 on the ratio of 2:2’.
mides. Varying the indole C2 substitution had similar effects on
the reaction outcome. Interestingly, 2-Et (1g) led to a decrease
in the Suzuki coupling amount with respect to 1a (2:2’=21:1),
other larger alkyl substituents (1h and 1i) also led to a similar
decrease (2:2’=10:1). A 2-Ph group (1k) decreased the ability
to undergo dearomatization (2:2’=6.4:1), whereas a further
para-CF3 (2m) and -OMe[32] substitution of this aryl group fur-
ther magnified this effect (2:2’=4.4:1 and 2.1:1). Perturbation
of the indole backbone at C5 with electron-donating (OMe,
1n) and -withdrawing (CF3, 1m) substituents led to a decrease
in the efficiency of the dearomative diarylation (2:2’=11:1 and
6:1), which echo our previous discussion concerning N-substi-
tution on the efficacy of the reaction, as it appears to be very
sensitive to the electronics of the enamine component.
substituted boroxine led to no change in the ratio of 2:2’,
which suggests that some groups at this position do not have
a significant impact. However, electron-withdrawing ortho-CHO
and -Cl substituents produce marked increases in the amount
of Suzuki coupling (2:2’=6.7:1 and 3.8:1).
Boroxines substituted with electron-donating and -with-
drawing groups at the meta-position appeared to have no
effect on the ratio of 2:2’ with respect to phenyl boroxine. Fur-
thermore, although a p-CHO group positively impact the ratio
of 2:2’ (15:1), other electron-withdrawing groups had either no
impact (p-CN and p-Cl) or a negative impact on the diarylation
reaction. Alkyl groups, such as tBu and Me, at the para-position
led to slightly more Suzuki coupling (2:2’=12:1 and 11:1),
while para electron-withdrawing groups, such as CO2Me and
CF3, produce a similar effect. Finally, the use of vinyl boroxine
derivatives, such as (E)-penten-1-ylboroxine (A1) and (E)-2-(4-
methoxyphenyl)vinylboroxine (A2), led to an increase in the
amount of observed Suzuki product (2:2’=6:1 and 5:1). De-
spite the fact that boronic acids containing electron-donating
Figure 3 displays the ratios of 1,2-diarylation/direct Suzuki
coupling from reactions of aryl and alkenyl boroxines possess-
ing various steric and electronic properties. Although differen-
ces can be seen within this data set, the trends within groups
possessing different substituents are less obvious. An o-Me-
Figure 3. Effect of steric and electronic perturbation of the boroxine reagent on the ratio of 2:2’. A1=(E)-penten-1-ylboroxine, A2=(E)-2-(4-methoxyphenyl)vi-
nylboroxine.
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groups are known to undergo faster transmetallation with PdII
species than those containing electron-withdrawing group,[26b]
this is not reflected in the ratio of 2:2’.
The amide functionality could be reduced to generate amine 5
in 98% yield by using BH3·SMe2 in refluxing THF.[36] The use of
alkenyl boroxines facilitates the introduction of benzylic al-
kenes, and 2ao could undergo oxonolysis using a reductive
workup to produce homobenzylic alcohol 6 in good yield.
Fluorinated analogs 2d and 2p were found to react with
cyclic secondary amines to afford various aniline derivatives by
SNAr reactions (Scheme 5). When monofluorinated 2d was
Although reports have appeared in which boroxines are
active transmetallation species under anhydrous conditions,[33]
it is reasonable to suggest that under our standard conditions
involving an aqueous biphase (MeCN:H2O and CsF), aryl boron-
ic acid can present in the bulk organic phase as a result of aryl
boroxine hydrolysis. While we understand that the factors
behind boron reagent activation and subsequent reactivity is
nontrivial, it is likely that the ability of the dearomative diaryla-
tion to outperform the undesired Suzuki pathway is depen-
dent on a balance between hydrolytic susceptibility of the bor-
oxine in question and the transmetallation aptitude of the re-
sulting aryl boronic acid. Nevertheless, the studies depicted in
Figures 1 and 2 reveal that structural variations of the N-benzo-
yl indole generally appear to have a more pronounced effect
than those of the boroxine component on the product distri-
bution.
Derivatization of Products
The tetracyclic indoline products were subjected to various
conditions to probe their synthetic utility (Scheme 4). In an
effort to forge an all-carbon benzylic quaternary carbon by
a deprotonation/alkylation strategy, 2a was treated with tBuLi
Scheme 5. SNAr reactions of indoline products containing reactive CÀF
bonds.
treated with excess morpholine in the presence of K2CO3,
adduct 7 could be obtained in 97% yield. Furthermore, due to
the different electronic densities of the two aromatic rings in
the diarylation products, it seemed likely that a selective SNAr
reaction could occur on the more electron-deficient of the
two. When difluorinated 2p was treated with excess piperidine
under similar conditions, a highly selective substitution of the
isoindoline fluorine over the indoline fluorine could be ach-
ieved, yielding 8 in 90% yield.
Conclusion
We have developed and applied a fully syn-selective Pd(0)-cat-
alyzed dearomative indole 1,2-diarylation using boroxines as
coupling partners. This reaction employs indoles as nontradi-
tional Heck acceptors, and proceeds using relatively low cata-
lyst loadings and short reaction times. The complex indoline-
containing products generated possess a unique stereogenic
arrangement consisting of a tetrasubstituted tertiary stereo-
center vicinal to a tertiary benzylic stereocenter. The scope of
this transformation is remarkably broad, and many substrate
perturbations are well tolerated under the standard conditions
or slight variants thereof. Furthermore, the catalytic reaction
conditions were tailored to minimize the amount of undesired
(yet separable) direct Suzuki coupling product. However, due
to the challenging nature of the migratory insertion step, the
Suzuki product forms to some extent in all substrates. The di-
verse heterocyclic scaffolds generated rapidly with our method
are quite amenable to derivatization, which should encourage
their use as complex synthetic building blocks. We are current-
ly investigating the development of an enantioselective var-
Scheme 4. Product derivatization.
at À788C. Deprotonation did not result under these condi-
tions,[34] and instead hemiaminal 3 was formed in 71% as
a single diastereomer. The relative stereochemistry of 3 was
unambiguously determined by X-ray crystallographic analysis.
The unexpected reactivity of the lactam leaves it prone to nu-
cleophilic attack of the organolithium reagent at the carbonyl
from the face opposite to the flanking benzylic Ph group.[31]
Nucleophilic addition of organolithium reagents appeared to
be quite general[35] as MeLi could also be added. Subsequent
dehydration formed the enamine,[31] which could be stereose-
lectively reduced using NaBH(OAc)3 under acidic conditions to
generate amine 4 in 97% yield and >20:1 d.r. over two steps.
Chem. Eur. J. 2016, 22, 5684 – 5691
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ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

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iant, and the application of the reported transformation in nat-
ural product synthesis.
for NMR assistance. Dr. Charles C. J. Loh (University of Toronto)
is thanked for helpful discussions.
Keywords: CÀC coupling · diastereoselectivity · heterocycles ·
homogeneous catalysis · palladium
Experimental Section
Methods and Characterization: All catalytic reactions were carried
out under an inert atmosphere of dry argon utilizing glassware
that was oven (1208C) or flame dried and cooled under argon. Re-
actions were monitored using thin-layer chromatography (TLC) on
EMD Silica Gel 60 F254 plates. Visualization of the developed
plates was performed under UV light (254 nm) or using KMnO4.
MeCN was distilled over CaH2. Flash column chromatography was
performed on Silicycle 230–400 mesh silica gel. NMR characteriza-
tion data was collected at 296 K on a Varian Mercury 300, Varian
Mercury 400, Bruker Avance III, Agilent 500, or a Varian 600 operat-
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1
ing at 300, 400, 500, or 600 MHz for H NMR, and 75, 100, 125, or
1
150 MHz for 13C NMR. H NMR spectra were internally referenced to
the residual solvent signal (CDCl3 =7.26 ppm) or TMS. 13C NMR
spectra were internally referenced to the residual solvent signal
(CDCl3 =77.0 ppm). Data for 1H NMR are reported as follows: chem-
ical shift (d ppm), multiplicity (s=singlet, d=doublet, t=triplet,
q=quartet, m=multiplet, br=broad), coupling constant (Hz), inte-
gration. Coupling constants have been rounded to the nearest
0.5 Hz. All reported diastereomeric ratios in data section are those
obtained from 1H NMR analysis of the crude reaction mixtures
using a 5 second relaxation delay.
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Typical procedure for the diastereoselective Pd(0)-catalyzed
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oxines: A dry 2 dram vial containing a magnetic stir bar was
charged with anhydrous CsF (61.8 mg, 0.4 mmol, 2 equiv) using
a flame-dried spatula followed by the N-(o-bromobenzoyl)indole
derivative 1 (0.2 mmol, 1 equiv), [Pd(PtBu3)2] (2.55 mg, 0.005 mmol,
2.5 mol%), and the boroxine (0.08 mmol or 0.094 mmol, 0.4 or
0.47 equiv) and was purged with argon for 10 min. The contents of
the vial were taken up in MeCN:H2O (9:1, 2 mL), and the vial was
sealed with a Teflonꢁ lined screw-cap and then placed in an oil
bath pre-heated to 1008C where it was stirred for 1 or 2 h. The vial
was then cooled to room temperature and anhydrous Na2SO4
(50 mg) was added to remove the aqueous component of the sol-
vent. The remaining solution was passed through a short pad of
silica gel eluting with 100% EtOAc (5 mL). The diastereomeric ratio
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1
was determined by H NMR analysis of a homogeneous aliquot of
the crude reaction mixture, which was subsequently purified via
silica gel flash column chromatography using hexanes/EtOAc as
the mobile phase to afford the corresponding indolines 2. Isolated
yields were calculated based on the obtained masses and all isolat-
ed products were identified by 1HNMR, 13CNMR, IR, and HRMS
analysis.
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Acknowledgements
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We thank the Natural Sciences and Engineering Research
Council of Canada (NSERC), the University of Toronto, and Al-
phora Inc. for financial support. M.L. thanks the Canada Council
for the Arts for a Killam Fellowship. D.A.P thanks NSERC for
a
postgraduate scholarship (CGS-D). MK is thankful for
a NITech Grant for Global Initiative Projects. Dr. Alan Lough
(University of Toronto) is thanked for single-crystal X-ray analy-
sis of 2ah and 3. Darcy Burns (University of Toronto) is thanked
Chem. Eur. J. 2016, 22, 5684 – 5691
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Full Paper
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1
was analyzed by H NMR and no benzylic deuteration was observed.
[35] The addition of nBuLi led to the clean formation of an E/Z mixture of
enamines, whereas the addition of PhLi proceeded in a similar fashion
to that of tBuLi and yielded the corresponding hemiaminal as a 10:1
mixture of inseparable diastereomers.
[36] The use of LiAlH4 as the reducing agent led to lower yields and irrepro-
ducible results. See Ref. [24b].
[37] CCDC 1456617 (2ah) and 1456618 (3) contain the supplementary crys-
tallographic data for this paper. These data are provided free of charge
by The Cambridge Crystallographic Data Centre.
Received: January 11, 2016
[23] For the first known example of a Heck-type indole dearomatization
through arylcarbonylation, see Ref. [6e].
Published online on March 4, 2016
Chem. Eur. J. 2016, 22, 5684 – 5691
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5691
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim