Palladium-Catalyzed C2?H Arylation of Unprotected (N?H)-Indoles “On Water” Using Primary Diamantyl Phosphine Oxides as a Class of Primary Phosphine Oxide Ligands

Article abstract of DOI:10.1002/cctc.201800187

We present the Pd-catalyzed arylation of (N?H)-indoles with functionalized haloarenes “on water” using hitherto untested primary diamantyl phosphine oxides (PPO) as ligands. Remarkable C2?H arylation selectivity was achieved by employing functionalized iodoarenes and N-unprotected indoles. We provide evidence that the in situ generated oxide of (9-hydroxydiamant-4-yl)phosphine L1 is key for the reaction efficiency by comparing a set of diamantane-based compounds structurally related to L1. Our results demonstrate the power of the new PPO ligands for the C?H functionalization of unprotected (N?H)-heterocycles.

Full text of DOI:10.1002/cctc.201800187

Accepted Article
Title: Palladium-catalyzed C2-H arylation of unprotected (N-H)-indoles
"on water" using primary diamantyl phosphine oxides as a new
class of PPO ligands
Authors: Oana Moncea, Didier Poinsot, Andrey A Fokin, Peter R
Schreiner, and Jean Cyrille Hierso
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ChemCatChem
10.1002/cctc.201800187
FULL PAPER
Palladium-catalyzed C2–H arylation of unprotected (N–H)-indoles
“
on water” using primary diamantyl phosphine oxides as a new
class of PPO ligands
[a, b]
[b]
[b, c]
[b]
Oana Moncea,
Didier Poinsot, Andrey A. Fokin,
Peter R. Schreiner,* and Jean-Cyrille
[
a, d]
Hierso*
water” after careful screening of organophosphine ligands
and bases for mastering C2- and C3-arylation selectivity.
The current state-of-the art indicates sustainable conditions
Abstract: We present the palladium-catalyzed arylation of (N–H)-
indoles with functionalized haloarenes “on water” using hitherto
untested primary diamantyl phosphine oxides (PPO) as ligands.
Remarkable C2–H arylation selectivity was achieved employing
functionalized iodoarenes and N-unprotected indoles. We provide
evidence that the in situ generated oxide of (9-hydroxydiamant-4-
yl)phosphine L1 is key for the reaction efficiency by comparison of a
set of diamantane-based compounds structurally related to L1. Our
results demonstrate the power of the new PPO ligands for the C–H
functionalization of unprotected (N–H)-heterocycles.
[
8]
[
5c, 9]
are actively being explored,
remain and concern most often (N)-protection,
need for addition of over stoichiometric amounts of metal
but limitations clearly
[
9a, 9c]
the
[
9b, 9c]
additives and/or surfactants,
and the impracticable use
of oxidation reagents such as diaryliodonium salts in
[5c, 9d]
excess.
In this context, further development of
sustainable catalytic systems available for arylating
unprotected indoles selectively among N–H, C2–H, and
C3–H bonds is clearly desirable, and may rely on a new
generation of ligand supported palladium catalysts.
Introduction
Heterocycles are building blocks in biologically active
compounds and in molecular materials with valuable
[
1]
electronic or optical properties. Because of the necessity
to provide cleaner, more convergent, and less costly
heterocycle syntheses, catalytic systems based on
[
2]
transition metals have been developed.
Palladium
catalysis has especially contributed to the straightforward
[
1, 3]
synthesis and functionalization of indoles.
Arylindoles
are recurrent motifs in biologically active molecules as well
[
2k, 4]
as pharmaceuticals
and have traditionally been
prepared using cross-coupling strategies. Development of
C–H arylation allows the direct functionalization of indoles
thus enabling the simple synthesis of aryl-substituted
indoles. An important breakthrough in the selective C2–H
functionalization of indoles (Scheme 1) was the use of (N)-
protected indoles in organic solvents at temperatures
Scheme 1. Palladium catalyzed (N–H)-indole C2-arylation.
Ackermann’s group reported palladium complexes derived
from secondary adamantyl phosphine oxide (SPO) (1-
Ad) P(O)H (A, Figure 1) as air stable catalysts for C–H arylation
2
[
5]
and benzylation of electron-deficient oxazole or oxazoline
[
5a]
higher than 120 °C.
The use of highly reactive bisaryl
[10]
heterocycles. Unfortunately, for the indole moiety this catalyst
[
5c]
[5h]
2
salts or large amounts of silver additives such as Ag O
was found ineffective although other highly hindered
heteroatom-substituted SPOs (B, Figure 1) combined with
palladium allowed C3-arylation of (N–H)-indoles with aryl
[
6]
or silver carboxylate salts enables (C–H)-arylation at
room temperature and in water. Djakovitch’s group further
developed this approach under heterogeneous conditions
[11]
bromides at fairly moderate temperature without additives.
[
7]
with a Pd/zeolite supported system in dioxane and “on
Lately, bis(diamantyl)-based SPO ligands (C, Figure 1) enabled
the C–H functionalization of electron rich oxazolines from aryl
[
12]
halides.
We have previously reported synthetic access to structurally
related primary diamantyl phosphines (4-DiAd)PH from the
facile reduction of phosphonic dichlorides with LiAlH The
[
[
a]
b]
Institut de Chimie Moléculaire de l’Université de Bourgogne
ICMUB), UMR-CNRS 6302, Université de Bourgogne Franche-
Comté, 9 avenue Alain Savary, 21078 Dijon, France
(
2
[
13]
4
.
Institute of Organic Chemistry, Justus-Liebig-University, Heinrich-
Buff-Ring 17, 35392 Giessen, Germany
reaction tolerates the presence of 9-chloro or 9-hydroxy groups
on the diamondoid scaffold, and the resulting functionalized
primary
yl)phosphine (L1) and (9-chlorodiamant-4-yl)phosphine (L6)
Figure 1) were found to be reasonably air-stable, rendering
them potentially useful as ligands for transition metal catalysis.
Herein, we present the use of such preligands in palladium
catalysis for unprotected (N–H)-indoles C–H arylation under
aqueous conditions.
diamantyl
phosphines
(9-hydroxydiamant-4-
[
c]
Department of Organic Chemistry, Igor Sikorsky Kiev Polytechnic
Institute, Prospekt. Pobedy 37, 03056 Kiev, Ukraine
(
[
d]
Institut Universitaire de France (IUF), 103 Bd. Saint Michel, 75005
Paris Cedex 5, France
Supporting information for this article is given via a link at the end of
the document.
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ChemCatChem
10.1002/cctc.201800187
FULL PAPER
confirmed by experiments in which the amount of phosphine
ligand was decreased to 5.0 mol% (entries 5–7) and 2.5 mol%
(
entries 8–10). At this lower amount, 3a formed in 80% yield
showing no efficiency decrease. We optimized the amount of L1
needed in the reaction by monitoring phosphine/palladium molar
ratio (Figure S1).
Table 1 Screening of primary diamantyl phosphine L1 for indole C–H
arylation.
[
a]
[c]
Entry
Ligand
mol%
Yield (%)
Selectivity
Figure 1. Known SPO ligands (A–C), together with diamantyl derivatives used
herein as ligands in palladium catalysis (L1–L7).
1
2
3
4
5
6
7
8
9
—
PPh
dppp
L1
PPh
dppp
L1
PPh3
dppp
L1
—
10
10
10
5
5
5
2.5
2.5
2.5
30
68
42
81
59
59
83
60
48
19:1
>20:1
9:1
3
19:1
Results and Discussion
3
>20:1
19:1
>20:1
19:1
19:1
>20:1
We investigated the selective C–H arylation reaction of
unprotected (N–H)-indole with palladium acetate and L1 under
aqueous conditions. The use of water as a solvent for C–H
arylation reactions can result in an increase in chemoselectivity
as well as rates, and may be advantageous from a sustainable
[
b]
10
80 (72)
Conditions: 1 (0.4 mmol, 50 mg), 2a (0.5 mmol, 102 mg), base (3 equiv.),
Pd] (5 mol%), H O (1 mL), 100 °C, 30 h. [a] Yield from standardized H
2
[
14]
chemistry perspective.
When reactants are water insoluble,
1
[
the “on-water” concept –often associated with the contributions
NMR; [b] Yield of isolated product; [c] 3a:3b selectivity determined by GC;
[
15]
of Sharpless– applies, and the hydrogen-bonding across the
[
16]
phase tends to increase the reaction rate. Palladium acetate
together with L1 in aqueous conditions are expected to form a
palladium phosphinous acid complex similar to the one
With these preliminary conditions in hand, we considered the
effects of the palladium source and the base (Table 2). We also
included the coupling of 1-bromo-4-iodobenzene 2b to assess
[
3c]
described with adamantyl based SPO ligands.
We initiated our screening by coupling the unprotected indole
with iodobenzene 2 in the presence of Pd(OAc) . In this case,
regioselectivity concerns N–H, C2–H, and C3–H
functionalization but the reaction conditions can be tuned in
chemoselectivity: no coupling product at the bromine function
3
was observed. Various Pd(II) sources were used: PdCl
2
, [Pd(η -
1
2
5
3
C
3
H
5
)(η -C
yields much (79–87%, Table 2 entries 1–4). The use of
Pd(OAc) is preferred owing to its availability and low cost. From
the various bases explored (CsOAc, KOH, K CO , KHCO
NaOH and LiOH, Table 2 entries 5–10, respectively) the most
effective was KHCO for which full conversion to C2-arylation
product was achieved leading to 92% yield of isolated 4a (entry
0).
Although KHCO
5 5 3 5 2
H )], and [Pd(η -C H )Cl] ). They did not affect the
[
8]
2
order to selectively obtain one of the products and for all our
2
3
3
,
1
experiments, no N–H coupling product was observed by
H
NMR or GC-MS. We used KOAc as a cheap base and water
under reflux conditions to examine the performance of L1
3
(
3
Table 1). Previously, ligands like PPh (10 mol%) and chelating
1
diphosphine bis(diphenylphosphino)methane (dppm, 5 mol%)
3
has been reported to be responsible for loss
combined with palladium gave C2–H coupling in indole
[8]
in C2-arylation/C3-arylation selectivity in other indole arylation,
this was not the case with L1. “On water” reactions usually occur
when substrates are poorly soluble in this solvent. Accordingly,
we measured palladium leakage into water by ICP-MS after the
reaction (Table S1). Using LiOH as base resulted in significant
palladium leakage but with the other bases, the amount of
palladium was less than 5 ppm.
We further examined which features of L1 play a critical role
for efficient coupling. We focused our attention on (1) whether
the primary phosphine function is essential or could be
advantageously substituted by other groups, (2) if the hydroxy
group was necessary because of strong hydrogen bonding in
[
8]
arylations with good yields; these are currently the best ligands
under biphasic catalytic conditions. Therefore, we also
compared L1 with PPh
3
and chelating diphosphine
bis(diphenylphosphino)propane (dppp). In the absence of
palladium but with L1 no reaction occurred. In the presence of
palladium without ligand, the yield was limited to 30% (Table 1,
entry 1).
Good C2–H arylation selectivity for product 3a was obtained
3
with KOAc at 5 to 10 mol% ligand loading. While PPh (Table 1
entry 2) and the chelating diphosphine dppp (Table 1 entry 3),
provided coupling with 68% and 42% yield, respectively, 10
mol% of L1 gave 81% yield (entry 4). These results were
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ChemCatChem
10.1002/cctc.201800187
FULL PAPER
water, (3) if the diamantane framework alone (or hydroxylated)
plays a role beyond the phosphine donor atom, and (4) what the
effect of oxidation of the –PH group would be. The last issue is
2
indicating that L2 does not interfere with this reaction (Table 3,
entry 3). Unsurprisingly it is neither ligand nor preligand for
palladium catalysts.
important since during our optimization studies we observed that
aerobic conditions are preferable (Tables S2 and S3) while
degassed solvent and reactions under inert atmosphere were
found much less effective. These questions could be answered
Phosphine oxide L3 is the oxidation product of L1 and can be
readily obtained by bubbling air in a dichloromethane solution of
[
17]
L1 at room temperature.
Because of the aerobic conditions
used in refluxing water, we assume that L3 forms in situ from L1.
This assumption is somewhat corroborated by the results
obtained when using L3 as a ligand (Table 3, entry 4) which are
in the same range of values as for L1. This oxide is likely to be
the efficient ligand for palladium catalysis since our experiments
have shown that using L1 under strictly anaerobic conditions
performs poorly (Table S2). A tautomeric equilibrium between
pentavalent and trivalent phosphorus species has been
by using
a specifically chosen set of diamantane-based
compounds, as shown in Table 3.
Table 2 Screening of palladium sources and bases for coupling 1 and 2b
using L1.
[
10a, 12]
described previously for diamondoid SPO ligands.
assume that this equilibrium can take place also for L3 (Scheme
) and in the presence of late transition metals that coordinate to
We
2
trivalent phosphorus.
[
a]
[c]
Entry
1
Pd source
Pd(OAc)
Base
KOAc
Yield (%)
86 (80)
Selectivity
15:1
[
b]
2
2
3
PdCl
[Pd(η -C H )(η -
3 5
2
KOAc
KOAc
87
81
>20:1
>20:1
3
5
5 5
C H )]
3
4
5
[Pd(η -C
3
H
5
)Cl]
2
KOAc
CsOAc
79
84
>20:1
>20:1
Pd(OAc)
2
6
7
8
9
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
2
2
2
2
2
KOH
K CO
2 3
NaOH
LiOH
KHCO
25
55
44
1:4
1.5:1
>20:1
1:1
34
[
b]
10
3
98 (92)
17:1
Conditions: 1 (0.4 mmol, 50 mg), 2b (0.5 mmol, 150 mg), base (3 equiv.),
Pd] (5 mol%), L1 (2.5 mol%), H O (1 mL), 100 °C, 30 h. [a] Yield from
[
2
1
standardized H NMR; [b] Yield of isolated product; [c] 4a:4b selectivity
Scheme 2. Tautomeric forms of diamantane phosphine oxide L3 and
suggested coordination to palladium.
Table 3 Influence of diamantane derivatives in the direct C2-arylation of
NMR solution studies using the reaction conditions or pure
unprotected indoles.
2
D O could not be employed to provide evidence for this
equilibrium because of solubility issues. We thus isolated the
palladium complexes that form upon reaction of L1 or L3 with
3
¼
[Pd(η -C
3
H
5
)Cl]
2
. The coordinated species were found to be
, CD Cl , CD OD, D O, (CD O,
SO supporting a polymeric nature of the
mostly insoluble in CDCl
CD CN, and (CD
3
2
2
3
2
2 4
)
[
a]
Entry
Ligand (2.5 mol%)
Yield 4a (%)
3
3 2
)
[
c]
1
2
3
4
5
6
7
8
—
L1
L2
L3
L4
L5
L6
L7
45
complex (Scheme 2). The preparation and characterization by
FT-IR and ICP-MS of these complexes is detailed in the ESI.
ICP-MS analysis indicates an expected molar ratio of 2:1 for
Pd:P in agreement with our catalytic conditions. The data
collected might be associated with an oligomeric form of the
complex which still remains to be clarified.
[
b]
b]
94 (88)
48
[
89 (82)
45
45
90
Further screening of related preligands demonstrated that the
presence of trivalent phosphorus (belonging to PH from L1 or to
2
90
PH(OH) from L3) is essential for the reaction to proceed
efficiently. This was confirmed by the poor results obtained with
diamantane L4 and hydroxydiamantane L5, which add nothing
to C2–arylation reaction (Table 3 entries 5–6, respectively).
Conversely, primary diamantyl phosphines L6 and L7 displayed
an activity comparable to that of L1. We already reported that
electron-withdrawing functions at remote positions of the
2 3
Conditions: 1 (2.0 mmol), 2b (2.4 mmol), Pd(OAc) (5 mol%), KHCO (6.0
mmol), distilled water (2 mL) in a sealed screw cap vial of 5 mL at 100 °C
1
during 30 h under air. [a] Yields determined by standardized NMR H; [b]
Yield of isolated product; [c] 48 h reaction time.
We also tested diamantyl dichlorophosphonate L2, which is
the precursor for L1. Only 48% yield of 4a was obtained
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diamantane cage are essential for enhancing air-stability in the
solid state of primary diamantyl phosphines.
Having established that L1 oxidizes quickly under the catalytic
conditions to L3, thereby promoting the formation of 3a and 4a,
we further explored the scope of the coupling reaction (Scheme
substitution at C3 is achieved by a cationic palladium catalyst
holding an aryl substituent (from intermediate C in Scheme 4).
Intermediate D is expected to follow two different pathways: (a)
a C3–C2 migration of the palladium center favored by weak
[
13]
3
bases such as KHCO , affording complex (E) that leads to the
3).
C2-regioisomer; (b) a re-aromatisation preferred in the presence
of strong bases such as OH affording complex (F’) that leads to
–
the C3-regioisomer. Compared to a direct carbometallation
mechanism via neutral species, this pathway justifies the
formation of both the C2 and C3 products observed (Table
[
20a]
1).
In addition, formation of cationic species are favored in
and the bulky alkyl
water. Thereby, the combination of KHCO
3
diamantyl-based PPO ligand would much favor the
deprotonation step from E vs deprotonation from D, and thus a
reductive elimination towards the C2 arylated product.
Scheme 3. C2-arylation of unprotected indole using primary diamondoid
phosphines as ligands. Conditions: indole (2.0 mmol), aryl iodide (2.4 mmol),
Pd(OAc)
2
(0.05 mmol), L1 (0.025 mmol), KHCO (6.0 mmol), H O (2 mL) at
3
2
1
100 °C during 30 h; NMR H yields and yields of isolated products in brackets.
At 2.0 mmol scale, aryl iodides incorporating various electron-
withdrawing (bromo, fluoro, cyano, and nitro), or electron-
donating (methyl, naphthyl) groups in the para-position provided
good yields of the desired C2 products. The catalytic coupling
system did not tolerate chloro acetyl group (7a does not form).
More challenging ortho-substituted aryl iodides could also be
successfully coupled, tolerating bromide (11a, 80%), methoxy
[
18]
Scheme 4. Proposed mechanism for the C2-arylation of unprotected indole
using diamantyl PPO as ligand.
(
12a, 65%), and trifluoromethyl (13a, 45%) functions.
Functionalized indole moiety with methyl group at C5 was
coupled successfully with electron deficient and electron rich
We investigated this mechanism by blocking the C2–H or C3–
H positions on the indole ring. Blocking the C2–H position first
with an electron-donating (19) and then with an electron
withdrawing (20) group shows very limited conversion (5% in the
case of electron rich indole moiety) towards the C3-regioisomer.
This also correlates with the absence of diarylation products at
both C2 and C3 under the present catalytic conditions. When
blocking the C3-position on the indole ring with an electron-
donating group, we were expecting full conversion into 21 but
only 2% conversion was achieved. This result strongly supports
the idea that a palladium-C3 to C2 migration followed by
deprotonation process has to take place but is inhibited by the
presence of methyl group in the C3 position.
aryl
iodides.
Conversely,
the
electron-withdrawing
trifluoromethyl group at C5 was found unfavorable for C2–H
indole arylation with electron deficient aryl iodides(18a).
Bromoarenes were also tested as coupling partners for this
reaction (Table S5). Using the same catalytic conditions we
achieved arylindole formation in 5–80% yields with para-
substituted bromoarenes, but we observed a loss of the C2/C3
selectivity. Notably, Manabe’s group reported recently ligand-
directed C3-arylation selectivity by tuning biphenyl phosphines
[
19]
design with a remote intervening OH group.
Detailed mechanistic studies rationalizing C2 vs C3
regioselectivity in palladium-catalyzed C–H arylation of indoles
have been reported for systems using Pd(OAc)
ligands in organic solvents.
2
and PPh
On this basis we propose a
mechanism depicted in Scheme in which electrophilic
3
[
20]
4
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Conclusions
extraction with cold dichloromethane (3 × 3 mL) and was dried over
MgSO
-yl) phosphine (L4) (0.038 g, 79%) as a white powder. H NMR (600
MHz, CDCl ): δ= 2.90 (d, 2H, JP−H = 164.4 Hz), 2.37−2.27 (m, 6H),
.89−1.73 (m, 12H); C NMR (150 MHz, CDCl
CH ), 44.6 (s, CH ), 40.3 (s, CH), 36.5 (s, CH), 26.7 (s, C); P{ H} NMR
242 MHz, CDCl
4
. The solvent was removed in vacuo, affording (9-bromodiamant-
1
4
We describe the direct C–H arylation of unprotected indoles
3
“
on water” under aerobic conditions using new primary
phosphine oxide ligands. High C2-selectivity was achieved with
bulky primary diamantyl phosphine L1 and Pd(OAc) . Excellent
13
1
3
): δ= 64.7 (s, C), 49.2 (s,
31
1
2
2
+
2
(
3
): δ= −85.9 ppm. HRMS (ESI) ([M+H]) calcd. for
functional group tolerance was observed with aryl iodides as
coupling partners. Electron-donating and electron-withdrawing
groups were tolerated at para and ortho-positions on the
iodoarenes. Control investigations of related ligands established
the superior efficiency of L1 in its in situ oxidized primary
phosphine oxide form. The trivalent phosphorus atom of L1 or
L3 and the presence of the OH group are necessary for
achieving superior performances in C2-arylation of (N–H)-
C14H21BrP 299.0558; found: 299.0552.
L6: (9-Chlorodiamant-4-yl)phosphine and L1: (9-hydroxydiamant-4-
yl)phosphine were synthesized according to the procedure described in
the literature; obtained analytical data were identical to literature data.
[
13]
General procedure for the direct C2-arylation of unprotected indole.
Indole (2.0 mmol, 0.234 g), aryl iodide (2.4 mmol), Pd(OAc)
2
(0.05 mmol),
3
indoles “on water”. KHCO as base allows the migration step to
ligand Lx (0.025 mmol), KHCO (6.0 mmol) and H O (2 mL) were
3
2
take place thus favoring C2-arylation process. The efficient use
of primary phosphines (often assumed to be pyrophoric) as
ligands in metal catalysis, under aerobic conditions in water, is
quite unusual and will be the subject of further investigations
with other branched alkyl diamondoid cages.
introduced in screw cap vial (5 mL). The resulting biphasic mixture was
heated at 100 °C for 30 h. After this time, the mixture was cooled to room
temperature and the excess of base was neutralized with HCl solution
(
1M). Ethyl acetate was added (5 mL) and the phases were separated.
The aqueous phase was further extracted with ethyl acetate (3 x 10 mL)
and the organic phases were dried over MgSO and concentrated. The
4
residue was dissolved in dichloromethane together with Celite® to form a
solid deposit for column chromatography (hexane/ethyl acetate: 95/5)
that afforded the desired product.
Experimental Section
Synthesis of functionalized diamantanes.
1
6
3
a: 2-Phenylindole. Beige solid, H NMR (500 MHz, DMSO-d ) δ=
3
3
1
1.52 (s, 1H), 7.87 (d, J = 7.4 Hz, 2H), 7.54 (d, J = 7.8 Hz, 1H), 7.47 (t,
J = 7.8 Hz, 2H), 7.41 (d, J = 8.1 Hz, 1H), 7.32 (t, J = 7.4 Hz, 1H), 7.11
ddd, J = 7.9 and 7.1 Hz, J = 0.9 Hz, 1H), 7.00 (ddd, J = 7.7 and 7.1
Hz, J = 0.6 Hz, 1H), 6.90 (d, J = 1.6 Hz, 1H); C NMR (125 MHz,
DMSO-d ) δ= 137.6 (C), 137.1 (C), 132.2 (C), 129.0 (CH), 128.6 (C),
27.4 (CH), 125.0 (CH), 121.6 (CH), 120.1 (CH), 119.4 (CH), 111.3 (CH),
8.7 (CH); HRMS (ESI) ([M+Na] ) calcd. for C14H11NNa: 216.0783;
L5: 4-Hydroxydiamantane. Obtained analytical data were identical to
3
3
3
[
21]
literature data.
3
4
3
(
4
4
13
6
L2:
(9-Hydroxydiamant-4-yl)phosphonic
dichloride.
Obtained
[
13]
analytical data were identical to literature data.
1
9
+
L7':
(9-Bromodiamant-4-yl)phosphonic
dichloride.
9-
found: 216.0780.
Hydroxydiamant-4-yl phosphonic dichloride (L2) (0.470 g, 1.47 mmol)
was placed in a 20 mL round bottom flask and cooled to a temperature
between 0 and −10 °C while 15 mL DCM were added followed by a
solution of thionyl bromide (0.5 mL, 5.88 mmol) in DCM. The solution
was stirred at r. t. for 72 h and afterwards poured on 40 mL water with 10
mL DCM. The mixture was stirred until it became colorless (30 min). The
phases were separated and the aqueous phase was extracted with DCM
1
4
a: 2-(4-Bromophenyl)-indole. Pale yellow solid, H NMR (500 MHz,
6
3
3
DMSO-d ) δ= 11.58 (s, 1H), 7.81 (d, J = 10.0 Hz, 2H), 7.65 (d, J = 10.0
Hz, 2H), 7.53 (d, J = 10.0 Hz, 1H), 7.39 (d, J = 10.0 Hz, 1H), 7.11 (ddd,
J = 10.0 and 5.0 Hz, J = 1.0 Hz, 1H), 7.00 (ddd, J = 10.0 and 5.0 Hz,
J = 1.0 Hz, 1H), 6.94 (d, J = 1.5 Hz, 1H); C NMR (125 MHz, DMSO-d )
δ= 137.2 (C), 136.4 (C), 131.8 (CH), 131.5 (C), 128.5 (C), 126.9 (CH),
21.9 (CH), 120.3 (C), 120.2 (CH), 119.5 (CH), 111.3 (CH), 99.3 (CH);
3
3
3
4
3
4
13
6
4
(3 × 10 mL) and the combined extracts were dried over MgSO . The
1
+
solvent was removed in vacuo, affording (9-bromodiamant-4-yl)
HRMS (ESI) ([M] ) calcd. for C14
H
10BrN: 270.9991; found: 270.9994.
1
phosphonic dichloride (L3') (0.510 g, 90%) as a white powder. H NMR
(
(
300 MHz, CDCl
3
): δ= 2.28−2.23 (m, 6H), 1.99−1.92 (m, 9H), 1.86−1.80
m, 3H); C NMR (75 MHz, CDCl ): δ = 62.2 (s, C), 48.6 (d, J = 2.5 Hz,
), 44.4 (d, J = 92.5 Hz, C), 39.8 (d, J = 2.5 Hz, CH), 34.9 (d, J = 16.0
1
5
a: 2-(4-Benzonitrile)-indole. Pale yellow solid, H NMR (500 MHz,
13
3
6
3
3
DMSO-d ) δ= 11.84 (s, 1H), 8.31 (td, J = 10.0 Hz, 2H), 8.11 (td, J =
CH
Hz, CH), 34.9 (d, J = 3.5 Hz, CH
6
2
3
3
4
1
1
0.0 Hz, 2H), 7.60 (d, J = 5.0 Hz, 1H), 7.45 (dd, J = 5.0 and J = 1.0 Hz,
31
1
2
); P{ H} NMR (121 MHz, CDCl
3
): δ=
3
4
13
H), 7.18 (m, 2H), 7.04 (ddd, J = 10.0 and 5.0 Hz, J = 1.0 Hz, 1H);
C
+
4.63 ppm. HRMS (ESI) ([M+Na]) calcd. for
04.9547; found: 404.9552.
14
C H18BrCl
2
NaOP
6
NMR (125 MHz, DMSO-d ) δ= 142.6 (C), 137.7 (C), 136.5 (C), 135.6 (C)
32.8 (CH), 128.3 (d, J = 34.0 Hz, C), 125.3 (CH), 122.7 (CH), 120.6
CH), 119.8 (CH), 118.9 (C), 111.6 (CH), 109.1 (C), 101.5 (CH); HRMS
4
1
(
(
+
L3: (9-Hydroxydiamant-4-yl)phosphine oxide. Obtained analytical
data were identical to literature data.
ESI) ([M] ) calcd. for C15
H N
10 2
: 218.0838; found: 218.0836.
[17]
1
6
a: 2-(4-Nitrophenyl)-indole. Yellow solid, H NMR (500 MHz, DMSO-
6
3
3
L7: (9-Bromodiamant-4-yl)phosphine.
9-Bromodiamant-4-yl
d ) δ= 11.84 (s, 1H), 8.31 (td, J = 10.0 Hz, 2H), 8.11 (td, J = 10.0 Hz,
H), 7.60 (d, J = 5.0 Hz, 1H), 7.45 (dd, J = 5.0 and J = 1.0 Hz, 1H),
.18 (m, 2H), 7.04 (ddd, J = 10.0 and 5.0 Hz, J = 1.0 Hz, 1H); C NMR
125 MHz, DMSO-d ) δ= 145.8 (C), 138.6 (C), 137.9 (C), 135.2 (C),
28.7 (d, J = 41.0 Hz, C), 125.5 (CH), 124.3 (CH), 124.2 (CH), 123.1
CH), 120.8 (CH) 119.9 (CH), 111.7 (CH), 102.4 (CH); HRMS (ESI)
3
3
4
phosphonic dichloride (L7') (0.054 g, 0.14 mmol) was placed in a 5 mL
two-neck flask under argon and cooled to a temperature between −78
and −60 °C while 1 mL dry THF was added. To the colorless solution, a
LiAlH solution (0.18 mL, 1 M in THF, 0.18 mmol, 1.3 equiv) was added
4
dropwise over the course of 10 min. The mixture was stirred at −10 °C
2
7
(
1
(
(
3
4
13
6
+
for 5 h. The reaction was quenched with HCl (5%, 0.1 mL) followed by
10 2 2
[M] ) calcd. for C14H N O : 238.0736; found: 238.0735.
This article is protected by copyright. All rights reserved.

ChemCatChem
10.1002/cctc.201800187
FULL PAPER
1
8
a: 2-(4-Fluorophenyl)-indole. Pale yellow solid, H NMR (500 MHz,
(C), 132.3 (C), 128.9 (CH), 128.8 (C), 127.7 (CH), 127.2 (CH), 124.6
6
3
DMSO-d ) δ= 11.52 (s, 1H), 7.90 (m, 2H), 7.52 (d, J = 5.0 Hz, 1H), 7.39
dd, J = 10.0 and 5.0 Hz, 1H), 7.31 (t, J = 5.0 Hz, 2H), 7.09 (ddd, J =
0.0 and 5.0 Hz, J =1.0 Hz, 1H), 7.00 (ddd, J = 10.0 and 5.0 Hz, J =
.0 Hz, 1H), 6.87 (d, J = 5.0 Hz, 1H); C NMR (125 MHz, DMSO-d ) δ=
62.5 (C), 160.6 (C), 137.1 (C), 136.7 (C), 128.9 (C), 128.6 (CH), 126.9
d, J = 9 Hz, CH), 121.5 (CH), 120.0 (CH), 119.4 (CH), 115.9 (CH),
15.73 (CH), 111.3 (CH), 98.7 (CH); HRMS (ESI) ([M+H] ) calcd. for
3
(CH), 123.1 (CH), 119.5 (CH), 110.9 (CH), 98.8 (CH), 21.2 (CH ); HRMS
3
3
3
+
(
(ESI) ([M-H] ) calcd. for C15
H12N: 206.0975; found:206.0976.
4
3
4
1
1
1
(
1
13
6
1
1
(
(
5a: 2-(4-Methylphenyl)-5-methylindole. Pale yellow solid, H NMR
6
3
400 MHz, DMSO-d ) δ = 11.30 (s, 1H), 7.72 (d, J = 8.0 Hz, 2H), 7.26
m, 4H), 6.89 (dd, J = 8.0 Hz, J = 4.0 Hz, 1H), 6.73 (m, 1H), 2.34 (d,
H); C NMR (100 MHz, DMSO-d ) δ = 137.7 (C), 136.5 (C), 135.3 (C),
29.5 (C), 129.3 (CH), 128.9 (C), 127.6 (C), 124.8 (CH), 122.9 (CH),
3
4
+
13
6
6
1
1
14
C H
11FN: 212.0870; found: 212.0869.
19.4 (CH), 110.8 (CH), 97.5 (CH), 21.1 (CH
3
), 20.1 (CH
14N: 220.1131; found: 220.1132.
3
) ; HRMS (ESI)
1
+
9
a: 2-(4-Methylphenyl)-indole. Pale yellow solid, H NMR (500 MHz,
([M-H] ) calcd. for C16
H
6
3
3
DMSO-d ) δ= 11.45 (s, 1H), 7.75 (d, J = 5.0 Hz, 2H), 7.49 (d, J = 10.0
Hz, 2H), 7.38 (d, J = 10.0 Hz, 1H), 7.26 (d, J = 10.0 Hz, 1H), 7.06 (t, J
7.4 Hz, 1H), 6.97 (t, J = 7.9 Hz, 1H), 6.80 (s, 1H), 2.34 (s, 3H);
NMR (125 MHz, DMSO-d ) δ= 137.8 (C), 136.9 (C), 136.7 (C), 129.4
3
3
3
1
1
(
2
8
3
1
6a: 2-(4-Bromophenyl)-5-methylindole. Pale yellow solid, H NMR
3
13
=
C
6
3
4
400 MHz, DMSO-d ) δ = 11.42 (s, 1H), 7.79 (dt, J = 8.0 Hz, J = 4.0 Hz,
H), 7.63 (dt, J = 8.0 Hz, J = 4.0 Hz, 2H), 7.31 (br s, 1H), 7.28 (d, J =
.0 Hz, 1H), 6.94 (dd, J = 8.0 Hz, J = 4.0 Hz, 1H), 6.84 (m, 1H), 2.36 (s,
H); C NMR (100 MHz, DMSO-d ) δ = 136.3 (C), 135.6 (C), 131.7 (CH),
6
3
4
3
3
4
(
CH), 128.7 (C), 124.9 (CH), 121.3 (CH), 119.8 (CH), 119.3 (CH), 119.4
+
(
CH), 111.2 (CH), 98.0 (CH), 20.8 (CH
14N: 208.1169; found: 208.1121.
3
); HRMS (ESI) ([M+H] ) calcd. for
13
6
15
C H
28.7 (C), 127.9 (C), 126.7 (CH), 123.5 (CH), 120.0 (C), 119.7 (C), 111.2
+
(CH), 111.0 (CH), 98.8 (CH), 21.2 (CH
3
); HRMS (ESI) ([M-H] ) calcd. for
1
10a:2-(1-Naphthyl)-indole. Pale yellow solid,
H
NMR (400 MHz,
15
C H11BrN: 284.0075; found:284.0080.
6
DMSO-d ) δ= 11.57 (s, 1H), 8.31-8.35 (m, 1H), 7.97-8.04 (m, 2H), 7.72
d, J = 8.0 Hz, 1H), 7.45-7.64 (m, 4H), 7.46 (d, J = 8.0 Hz, 1H), 7.16 (t,
J = 8.0 Hz, 1H), 7.07 (t, J = 8.0 Hz, 1H), 6.74 (s, 1H); C NMR (100
MHz, DMSO-d ) δ= 136.7 (C), 136.4 (C), 133.5(C), 130.9 (C), 130.8 (C),
28.4 (CH), 128.3 (C), 128.1 (CH), 127.2 (CH), 126.7 (CH), 126.1 (CH),
25.5 (CH), 125.4 (CH), 121.4 (CH), 119.9 (CH), 119.2 (CH), 111.3 (CH),
3
3
(
1
1
(
7a: 2-(4-Fluorophenyl)-5-methylindole. Pale yellow solid, H NMR
3
3
13
6
3
4
400 MHz, DMSO-d ) δ = 11.37 (s, 1H), 7.87 (dd, J = 8.0 Hz, J = 4.0
6
3
Hz, 2H), 7.28 (m, 4H), 6.92 (d, J = 8.0 Hz, 1H), 6.77 (m, 1H), 2.36 (s,
H); C NMR (100 MHz, DMSO-d ) δ = 162.6 (C), 160.2 (C), 136.6 (C),
35.5 (C), 128.9 (C), 127.8 (C), 126.8 (d, J = 8.0 Hz, 2 CH), 123.1 (CH),
3
19.5 (CH), 115.8 (CH), 115.5 (CH), 110.9 (CH), 98.1 (CH), 21.1 (CH );
1
1
1
13
6
3
1
1
3
+
02.4 (CH); HRMS (ESI) ([M+Na] ) calcd. for C18
H
13NNa: 266.0940;
found: 266.0940.
+
HRMS (ESI) ([M-H] ) calcd. for C15H11FN: 224.0881; found: 224.0885.
1
1
1a: 2-(2-Bromophenyl)-indole. Pale yellow solid, H NMR (500 MHz,
6
3
4
DMSO-d ) δ= 11.40 (s, 1H), 7.77 (dd, J = 8.0 Hz, J = 1.0 Hz, 1H), 7.65
3
4
3
Acknowledgments
(
1
dd, J = 7.5 Hz, J = 1.5 Hz, 1H), 7.58 (d, J = 7.5 Hz, 1H), 7.52-7.48 (m,
3
4
3
4
H), 7.41 (dd, J = 8.0 Hz, J = 1.0 Hz, 1H), 7.32 (td, J = 7.5 Hz, J = 1.5
3
Hz, 1H), 7.15- 7.10 (m, 1H), 7.04- 7.00 (m, 1H), 6.80 (d, J = 2.5 Hz, 1H);
C NMR (125 MHz, DMSO-d ) δ= 136.4 (C), 135.8 (C), 133.7 (C), 133.6
This work was supported by the ANR–DFG program
(Hybridiams ANR-16-CE92-0037-01 and Schr 597/31-1),
Conseil Rꢀgional de Bourgogne through the plan d’actions
rꢀgional pour l’innovation (PARI: projects CDEA for OM and
13
6
(
(
(
C), 131.3 (CH), 129.4 (CH), 127.9 (CH), 127.8 (C), 121.7 (CH), 121.5
CH), 120.2 (CH), 119.3 (CH), 111.4 (CH), 102.7 (CH); HRMS (ESI)
+
[M+H] ) calcd. for C14
H11BrN: 272.0069; found: 272.0069.
3MIM-P4) and the fonds europꢀen de dꢀveloppement regional
1
(FEDER). The work in Giessen was supported in part (for OM
and PRS) by the US Department of Energy, Office of Science,
Basic Energy Sciences, Materials Sciences and Engineering
Division, under contract DE-AC02-76SF00515.
1
2a: 2-(2-Methoxyphenyl)-indole. Pale yellow solid, H NMR (500 MHz,
6
3
4
DMSO-d ) δ= 11.17 (s, 1H), 7.80 (dd, J = 8.0 Hz, J = 2.0 Hz, 1H), 7.52
d, J = 8.0 Hz, 1H), 7.44 (dd, J = 8.0 Hz, J = 0.5 Hz, 1H), 7.34-7.29 (m,
H), 7.15 (m, 1H), 7.09-7.04 (m, 2H), 6.99-6.96 (m, 1H), 6.94 (br s,1H),
.94 (s, 3H); C NMR (125 MHz, DMSO-d ) δ= 156.0 (C), 136.3 (C),
34.5 (C), 128.6 (CH), 128.1 (C), 127.7 (CH), 121.2 (CH), 120.7 (CH),
20.6 (C), 119.8 (CH), 119.0 (CH), 112.0 (CH), 111.3 (CH), 101.5 (CH),
3
3
4
(
1
3
1
1
5
2
13
6
Keywords: C–H arylation • diamondoid • indole • primary
phosphine ligand • water catalysis
+
5.5 (CH
24.1067.
3
); HRMS (ESI) ([M+H] ) calcd. for C15
H
14NO: 224.1069; found:
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1
3a: 2-(2-Trifluoromethylphenyl)-indole. Pale yellow solid, H NMR
6
3
(
500 MHz, DMSO-d ) δ= 11.43 (s, 1H), 7.88 (d, J = 5.0 Hz, 1H), 7.78 (t,
J = 5.0 Hz, 1H), 7.69 (d, J = 5.0 Hz, 1H), 7.64 (t, J = 5.0 Hz, 1H), 7.57
d, J = 5.0 Hz, 1H), 7.41 (d, J = 10.0 Hz, 1H), 7.14 (t, J = 5 Hz, 1H),
.03 (t, J = 10.0 Hz, 1H), 6.56 (s, 1H); C NMR (125 MHz, DMSO-d )
3
3
3
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3
3
3
(
7
3
13
6
δ= 136.5 (C), 134.4 (C), 132.4 (CH), 132.3 (CH), 128.5 (CH), 127.9 (C),
127.2 (d, J = 30 Hz, C), 126.3 (d, J = 5Hz, CH), 125.2 (C), 123.0 (C),
1
21.6 (CH), 120.2 (CH), 119.3 (CH), 111.3 (CH), 102.6 (CH); HRMS
3
2
4
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(ESI) ([M+H] ) calcd. for C15
11 3
H F N: 262.0838; found: 262.0834.
1
14a: 2-(4-phenyl)-5-methylindole. Pale yellow solid, H NMR (400 MHz,
6
3
3
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DMSO-d ) δ = 11.37 (s, 1H), 7.83 (d, J = 8.0 Hz, 2H), 7.44 (t, J = 8.0
Hz, 2H), 7.29 (m, 3H), 6.93 (dd, J = 8.0 Hz, J = 4.0 Hz, 1H), 6.80 (m,
3
4
13
6
1H), 2.36 (s, 3H); C NMR (100 MHz, DMSO-d ) δ = 137.6 (C), 135.5
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ChemCatChem
10.1002/cctc.201800187
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ChemCatChem
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FULL PAPER
FULL PAPER
(
9-Hydroxydiamant-4-yl) phosphine is
Oana Moncea, Didier Poinsot, Andrey A.
Fokin, Peter R. Schreiner,* and Jean-
Cyrille Hierso*
key for the aerobic Pd-catalyzed C2-
arylation of unprotected (N–H)-indoles
with functionalized haloarenes “on
water”. Our results demonstrate the
power of the new primary phosphine
oxide (PPO) ligands for the C–H
functionalization of unprotected (N–
H)-heterocycles.
Page No. – Page No.
Palladium-catalyzed C2–H arylation of
unprotected (N–H)-indoles “on water”
using primary diamantyl phosphine
oxides as a new class of PPO ligands
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