Rhodium-Catalyzed Selective C-H Trideuteromethylation of Indole at C7 Position Using Acetic- d6 Anhydride

Article abstract of DOI:10.1021/acs.joc.9b01114

Rhodium-catalyzed C7-selective decarbonylative trideuteromethylation of indoles with commercially available Ac₂O-d₆ via C-H and C-C bond activation has been developed. The key to the high reactivity and regioselectivity of this trans

Full text of DOI:10.1021/acs.joc.9b01114

Article
pubs.acs.org/joc
Cite This: J. Org. Chem. XXXX, XXX, XXX−XXX
Rhodium-Catalyzed Selective C−H Trideuteromethylation of Indole
at C7 Position Using Acetic‑d6 Anhydride
Xiaowei Han,†,‡ Yu Yuan,*,† and Zhuangzhi Shi*,†,‡
†College of Chemistry and Chemical Engineering, Yangzhou University, Yangzhou 225002, China
‡State Key Laboratory of Coordination Chemistry, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing
210093, China
S
* Supporting Information
ABSTRACT: Rhodium-catalyzed C7-selective decarbonyla-
tive trideuteromethylation of indoles with commercially
available Ac2O-d6 via C−H and C−C bond activation has
been developed. The key to the high reactivity and
regioselectivity of this transformation is the appropriate
choice of an indole N−PtBu2 chelation-assisting group. This
method has many advantages, including easy access and
removal of the directing group, the use of cheap and widely
available deuterium methylating source, no requirement of an external ligand or oxidant, a broader substrate scope, high
efficiency, and the sole regioisomer.
tracer atoms to elucidate metabolic pathways in medicinal
chemistry. Owing to the higher pyrolysis energy than the H
atom, the incorporation of deuterium can impart dramatic
improvements to drug candidates, related to absorption,
distribution, and metabolism in organisms. A significant
number of deuterium-labeled drug candidates have been
synthesized and submitted to clinical trials in the past few
decades. Austedo (deutetrabenazine), a treatment for
symptoms of Huntington’s disease, was finally approved by
the FDA in 2017 as the first deuterated drug (Figure 1a).13 In
general, the d3-methylated group has extraordinary significance,
being one of the most common fragments in biologically active
molecules. From the viewpoint of synthetic chemistry, d3-
methylation is the most ideal approach because it has the
capability to directly introduce the D-labeled methyl group
into structurally diverse molecules.
Methylated indoles are key building blocks in several
biologically active compounds. Remarkable progress has been
made in C−H trideuteromethylation of indoles during the past
five years (Figure 1b). C3-Trideuteromethylation has been
developed using methanol-d3 as a C1 building block by
transition-metal-catalyzed hydrogen-borrowing approach.14
Very recently, Yoshikai and co-worker reported a cobalt-
catalyzed directed C2 selective C−H trideuteromethylation of
indole using readily available methyl tosylate as a d3-
methylating agent.15 Inspired by our recent results on PIII-
chelation-assisted C−H functionalization of indoles, here, we
reported selective C−H trideuteromethylation of indole at C7
INTRODUCTION
■
Indoles and their derivatives belong to an important substance
class which is often found in natural products and drug
molecules.1 Considerable attention has been turned to the
synthesis and selective functionalization of these important
molecules over the years. Due to the principles of atom and
step economy, there is continuing interest in the C−H
functionalization of indoles.2 In an indole scaffold, there are six
C−H bonds, including C2−C3 and C4−C7 positions, that can
be functionalized. The usual reactivity of indoles suggested that
C−H functionalization would take place preferentially at the
C3-position.3 To override this intrinsic selectivity, the
introduction of directing groups on the N atom has been
used as a powerful strategy to ensure C2-selectivity.4 However,
general methods to access selectivity at the benzene core of
indole directly, especially the C7-position, continue to be
scarce.5 In 2010, Hartwig et al. developed the first iridium-
catalyzed C−H borylation of indoles at the C7-position, in
which the regioselectivity was controlled by a N-silyl-directing
group.6 In 2016, our group developed the first Pd(II)-catalyzed
direct C7-arylation of indoles with arylboronic acids using a
sterically hindered N−P(O)tBu2 (TBPO) directing group by
O atom chelation.7 Later, our group further developed the
rational design of a P(III) directing group (N−PtBu2) for C−
H hydroarylation of activated olefins,8 C−H arylation of aryl
halides9 and carboxylic anhydrides10 at indole C7-position.
These results led us to explore whether this C7-functionaliza-
tion strategy can be applied for other related transformations.
The installation of a methyl group to a drug lead may cause a
dramatic improvement of its biological and physical proper-
ties.11 This so-called magic methyl effect calls for the
development of efficient catalytic methods for the methylation
of organic compounds.12 Deuterium atoms can be used as
Special Issue: C-H Bond Functionalization
Received: April 23, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.joc.9b01114
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Article
Figure 1. Development of a protocol for the selective C−H trideuteromethylation of indoles at C7 position.
position by Rh-catalyzed C−H trideuteromethylation using
inexpensive and readily available acetic-d6 anhydride as the
deuterated methyl source (Figure 1c).
(CD3)2SO4 have been widely used as deuterium methylating
reagents, albeit with volatility, corrosion, toxicity, and
carcinogenicity concerns. However, these reagents did not
show any reactivity in this reaction (Table 1, entries 13−14).
Finally, with control experiments performed in the absence of a
[Rh(cod)Cl]2 catalyst, no product is observed (Table 1, entry
15).
RESULTS AND DISCUSSION
■
We studied the selective deuteration methylation process of
indole with indole 1a as the initial substrate (Table 1). The
experiments were performed with 3.0 equiv of Ac2O-d6 in the
presence of 2.5 mol % [Rh(cod)Cl]2, 3.0 equiv NaHCO3, at
150 °C under an Ar atmosphere in dry DMA. To our delight,
the desired target product 2a was observed in 10% yield after
To evaluate the utility of the PIII-chelation-assisted indole
C7-deuterated methylation by rhodium catalysis, a series of
substituents at different positions of indole were tested in
Table 2. Gratifyingly, the benzene core of the indole that
incorporates electron-donating substituents C4−C6 positions
was readily tolerated. Due to the acidity of hydrogen at the C3
position, different level H/D exchange occurs under the base
in the presence of rhodium species. Such as methyl (2b−2c),
methoxy (2d−2f), ether (2g), all the corresponding deuterated
methylation products are obtained in high deuterium ratio and
high yield. The substrates containing halogens like F (2h−2i),
Cl (2j), Br (2k−2i) were well converted into deuterated
methylation products, reflecting the potential application value
of the strategy that can be cross-coupled with other groups.
The electron-deficient substituents like cyano (3ja) group
showed that the corresponding deuterated methylation
products can also be obtained in higher yields and deuteration
rate. Surprisingly, in the presence of phenyl (2n) and some
1
18 h in GC−MS and 93% deuterated incorporation in H
NMR (Table 1, entry 1). Among various solvents (Table 1,
entry 1−5), we found that the effect of dry toluene is the most
significant, increasing the yield to 52% and deuterium ratio to
94% (Table 1, entry 5); no product was observed using HMPT
as the solvent (Table 1, entry 4). Under the conditions, we
tested different bases, such as Cs2CO3 (Table 1, entry 6),
NaOAc (Table 1, entry 7), Na2CO3 (Table 1, entry 8), NaOH
(Table 1, entry 9), NaOMe (Table 1, entry 10), Et3N (Table
1, entry 11), and KH2PO4 (Table 1, entry 12). Among these
bases, we found the best efficiency by using KH2PO4, observed
with 71% yield of 2a (78% isolated yield) and deuterium ratio
of 95%; when Cs2CO3 (Table 1, entry 6) was used as a base,
no generation of 2a was detected. Traditionally, CD3I and
B
DOI: 10.1021/acs.joc.9b01114
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a
to the coupling of a variety of indoles. These present results
represent an important discovery that is expected to be
substantially extended to other new transformations.
Table 1. Reaction Development
EXPERIMENTAL SECTION
■
All new compounds were fully characterized. NMR spectra were
recorded on Bruker AV-300, ARX-400 MHz, or a ARX-600
Associated. Mass spectra were conducted at Micromass Q-ToF
instrument (ESI) and Agilent Technologies 5973N (EI). All reactions
were carried out in flame-dried reaction vessels with Teflon screw
caps under argon. Unless otherwise noted, materials obtained from
commercial suppliers were used without further purification. [Rh-
(cod)Cl]2, KH2PO4 were purchased from were purchased from Acros,
Ac2O-d6 was purchased from Sigma-Aldrich. In Table 2, 1la−1t are
known compounds.7−10
b
c
entry
cat [M]
base
solvent
[D] (%)
yield (%)
1
2
3
4
5
6
7
8
[Rh(cod)Cl]2
[Rh(cod)Cl]2
[Rh(cod)Cl]2
[Rh(cod)Cl]2
[Rh(cod)Cl]2
[Rh(cod)Cl]2
[Rh(cod)Cl]2
[Rh(cod)Cl]2
[Rh(cod)Cl]2
[Rh(cod)Cl]2
[Rh(cod)Cl]2
[Rh(cod)Cl]2
[Rh(cod)Cl]2
[Rh(cod)Cl]2
−
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
Cs2CO3
NaOAc
Na2CO3
NaOH
NaOMe
Et3N
DMA
NMP
93
92
93
−
94
−
94
95
92
92
93
95
−
10
5
24
0
52
0
31
55
57
65
60
DMSO
HMPT
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
General Procedure A: PIII-Directed Indole C7-Methylation.
To a 25 mL Schlenk tube was added indole substrates 1a (52.2 mg,
0.20 mmol), [Rh(cod)Cl]2 (4.9 mg, 0.01 mmol) and KH2PO4 (81.6
mg, 0.60 mmol). The tube was purged with Ar three times, followed
by addition of anhydrous toluene (1.0 mL) then addition of acetic
anhydride (61.2 mg, 0.60 mmol). The mixture was stirred at 150 °C
with the heating mantle for 18 h. The solution was then cooled to
room temperature, and the solvent was removed under a vacuum
directly. The crude product was purified by column chromatography
on silica gel.
9
10
11
12
13
14
d
KH2PO4
KH2PO4
KH2PO4
KH2PO4
71(78)
e
0
0
0
f
−
−
15
General Procedure B: PIII-Directed Indole C7-Deuterated
Methylation. To a 25 mL Schlenk tube was added indole substrates
1a (52.2 mg, 0.20 mmol), [Rh(cod)Cl]2 (4.9 mg, 0.01 mmol) and
KH2PO4 (81.6 mg, 0.60 mmol). The tube was purged with Ar three
times, followed by addition of anhydrous toluene (1.0 mL) and then
addition of Ac2O-d6 (64.8 mg, 0.60 mmol). The mixture was stirred at
150 °C with the heating mantle for 18 h. The solution was then
cooled to room temperature, and the solvent was removed under a
vacuum directly. The crude product was purified by column
chromatography on silica gel.
a
Reaction conditions: 1a (0.20 mmol), Ac2O-d6 (0.60 mmol), 2.5 mol
% of catalyst, 3.0 equiv of base in solvent (1.0 mL) at 150 °C, 18 h,
under Ar. Determined by H NMR. Determined by GC analysis.
b
c
1
d
e
f
Isolated yield. Using CD3I instead of Ac2O-d6. Using DMSO-d6
instead of Ac2O-d6.
chelating groups at C3 position of indole like acetyl (2o),
methyl ester (2p), cyanomethyl (2q), and amide (2r) with a
single selectivity, deuterated methylation at the C7 position
could be obtained in high deuterium ratio and yield.
Noteworthy, when the acidic hydrogen atoms are α to the
functional group, like acetyl (2o), in the presence of a base,
60% H/D exchange with these hydrogen atoms was observed.
Meanwhile, N−PtBu2 protected carbazole (2s) has also been
proven to be convertible to the desired product with excellent
deuterium incorporation and good yield. It can also install two
deuterated methyl groups in the 3,3′-dimercaptomethane
derivative (2t) by this method.
General Procedure C: Removal of the PIII Directing Group.
To the product 2d′ (30.5 mg, 0.1 mmol) or product 2d (30.8 mg, 0.1
mmol) in 25 mL Schlenk tube was added anhydrous THF (1.0 mL),
and then TBAF (0.8 mL, 0.8 mmol, 1 M in THF) was added. The
mixture was stirred under 60 °C until was consumed as determined by
TLC. The reaction was cooled to room temperature and 5 mL H2O
was added, and then the mixture was extracted by ethyl acetate and
the organic phase was combined and dried with anhydrous Na2SO4.
The solvent was evaporated under reduced pressure, and the crude
was purified by column chromatography on silica gel to provide 3d′ as
white solid (11.4 mg, 71%) or 3d as white solid (11.8 mg, 72%).
1-(Di-tert-butylphosphanyl)-7-methyl-1H-indole (2a′) and
1-(Di-tert-butylphosphanyl)-7-(methyl-d3)-1H-indole (2a). Fol-
lowing the general procedure A, 2a′ was prepared from 1a as colorless
The N−PtBu2 directing group can be easily removed by
treatment with TBAF. As shown in Scheme 1, the removal of
the N−PtBu2 directing group in products 2d and 2n formed
the desired N-free indole in good yields under mild reaction
conditions.
1
oil (43.5 mg, 79%): H NMR (400 MHz, CDCl3) δ 7.50−7.48 (m,
2H), 7.06 (t, J = 7.4 Hz, 1H), 6.99 (d, J = 7.1 Hz, 1H), 6.66 (dd, J =
3.3, 1.4 Hz, 1H), 2.90 (d, J = 4.4 Hz, 3H), 1.25 (d, J = 12.6 Hz, 18H).
13C{1H} NMR (101 MHz, CDCl3) δ 141.1 (d, J = 15.2 Hz), 132.1
(d, J = 6.1 Hz), 129.8 (d, J = 2.8 Hz), 125.9, 123.7, 120.3, 118.5,
105.6 (d, J = 2.3 Hz), 35.8 (d, J = 29.8 Hz), 29.4 (d, J = 17.3 Hz),
24.5 (d, J = 28.3 Hz). 31P NMR (162 MHz, CDCl3) δ 79.1. Following
the general procedure B, 2a was prepared from 1a as colorless oil
(43.4 mg, 78%): 1H NMR (400 MHz, CDCl3) δ 7.49−7.44 (m, 2H),
7.03 (t, J = 7.4 Hz, 1H), 6.96 (dd, J = 7.1, 1.3 Hz, 1H), 6.63 (dd, J =
3.3, 1.5 Hz, 0.65H), 2.84 (m, 0.15H), 1.22 (d, J = 12.6 Hz, 18H). IR
(film) 2941, 1698, 1684, 1653, 1558, 1541, 1473, 1364, 1136, 805,
765, 521 cm−1; HRMS m/z (ESI) calcd for C17H24D3NP (M + H)+:
Although the detailed mechanism of the reaction remains
unclear, we propose a possible catalytic cycle as shown in
Figure 2. The rhodium species A first coordinates with the
indole 1 to form a complex B. Then the deprotonation of the
C−H bond at C7 position of indole generates the rhodacycle
D16 through the assistance of the anion to transition state C.
The formed rhodacycle D can induce oxidative addition of
acetic-d6 anhydride to generate the RhIII species E.17
Subsequent decarboxylation can further yield the rhodium
species F. Finally, the reductive elimination of F produces the
final products 2 and regenerates the active catalyst A.
In summary, we have reported an efficient C7-selective
direct trideuteromethylation of indoles with the aid of the
P(III)-directed group by rhodium catalysis. The reaction
employed commercially available acetic-d6 anhydride, does not
require the addition of an exogenous ligand, and is applicable
1
279.2064, found 279.2065. According to H NMR, 35% deuterium
incorporation C3 position and 95% deuterium incorporation at C7
position was generated in product 2a.
1-(Di-tert-butylphosphanyl)-4,7-dimethyl-1H-indole (2b′)
and 1-(Di-tert-butylphosphanyl)-4-methyl-7-(methyl-d3)-1H-
indole (2b). Following the general procedure A, 2b′ was prepared
from 1b as white solid (37.6 mg, 65%): 1H NMR (400 MHz, CDCl3)
C
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a
Table 2. Substrate Scope
a
Reaction conditions: 1a (0.20 mmol), Ac2O-d6 (0.60 mmol), 2.5 mol % of [Rh(cod)Cl]2, KH2PO4 (0.6 mmol) in 1.0 mL dry toluene at 150 °C,
18 h, under Ar.
δ 7.46 (d, J = 3.4 Hz, 1H), 6.86 (q, J = 7.3 Hz, 2H), 6.66 (dd, J = 3.4,
1.4 Hz, 1H), 2.85 (d, J = 4.5 Hz, 3H), 2.52 (s, 3H), 1.23 (d, J = 12.6
Hz, 18H). 13C{1H} NMR (101 MHz, CDCl3) δ 140.7 (d, J = 15.3
Hz), 131.6 (d, J = 6.1 Hz), 129.5 (d, J = 2.9 Hz), 127.4, 125.9, 121.2,
120.6, 103.9 (d, J = 2.3 Hz), 35.8 (d, J = 29.9 Hz), 29.4 (d, J = 17.4
Hz), 24.4 (d, J = 28.4 Hz), 18.5. 31P NMR (162 MHz, CDCl3) δ 78.7.
Following the general procedure B, 2b was prepared from 1b as white
solid (35.0 mg, 60%): 1H NMR (400 MHz, CDCl3) δ 7.47 (d, J = 3.0
Hz, 1H), 6.87 (q, J = 7.2 Hz, 2H), 6.67 (dd, J = 3.3, 1.3 Hz, 0.68H),
2.83 (s, 0.27H), 2.54 (s, 3H), 1.24 (d, J = 12.6 Hz, 18H). IR (film)
2940, 1495, 1463, 1360, 1560, 1275, 1145, 1123, 806, 764, 637, 498
cm−1; HRMS m/z (ESI) calcd for C18H26D3NP (M + H)+: 293.2220,
found 293.2226. According to 1H NMR, According to 1H NMR, 32%
D
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d3)-1H-indole (2d). Following the general procedure A, 2d′ was
Scheme 1. Removal of the Directing Group
1
prepared from 1d as white solid (48.8 mg, 80%): H NMR (400
MHz, CDCl3) δ 7.39 (d, J = 3.4 Hz, 1H), 6.89 (d, J = 7.9 Hz, 1H),
6.78 (dd, J = 3.3, 1.5 Hz, 1H), 6.49 (d, J = 7.9 Hz, 1H), 3.94 (s, 3H),
2.81 (d, J = 4.6 Hz, 3H), 1.24 (d, J = 12.6 Hz, 18H); 13C{1H} NMR
(101 MHz, CDCl3) δ 151.5 (d, J = 1.4 Hz), 142.0 (d, J = 16.2 Hz),
130.8 (d, J = 6.1 Hz), 125.8, 120.3 (d, J = 3.3 Hz), 116.7, 102.4 (d, J =
2.3 Hz), 100.0, 55.2, 35.7 (d, J = 29.7 Hz), 29.3 (d, J = 17.4 Hz), 24.0
(d, J = 28.4 Hz). 31P NMR (162 MHz, CDCl3) δ 78.5. Following the
general procedure B, 2d was prepared from 1d as white solid (49.8
1
mg, 81%): H NMR (400 MHz, CDCl3) δ 7.41−7.35 (m, 1H), 6.87
(d, J = 7.9 Hz, 1H), 6.76 (dd, J = 3.3, 1.5 Hz, 0.61H), 6.47 (d, J = 7.9
Hz, 1H), 3.93 (s, 3H), 2.76 (d, J = 2.3 Hz, 0.18 H), 1.22 (d, J = 12.6
Hz, 18H). IR (film) 2940, 2360, 1579, 1495, 1473, 1267, 1172, 1123,
1106, 806, 752, 603 cm−1; HRMS m/z (ESI) calcd for C18H26D3NOP
(M + H)+: 309.2170, found 309.2175. According to 1H NMR,
1
According to H NMR, 39% deuterium incorporation C3 position
and 94% deuterium incorporation at C7 position was generated in
product 2d.
1-(Di-tert-butylphosphanyl)-5-methoxy-7-methyl-1H-indole
(2e′) and 1-(Di-tert-butylphosphanyl)-5-methoxy-7-(methyl-
d3)-1H-indole (2e). Following the general procedure A, 2e′ was
prepared from 1e as white solid (45.7 mg, 75%): 1H NMR (400 MHz,
CDCl3) δ 7.43 (d, J = 3.3 Hz, 1H), 6.93 (s, 1H), 6.65 (d, J = 2.4 Hz,
1H), 6.57 (dd, J = 3.3, 1.4 Hz, 1H), 3.84 (s, 3H), 2.84 (d, J = 4.2 Hz,
3H), 1.23 (d, J = 12.6 Hz, 18H); 13C{1H} NMR (101 MHz, CDCl3)
δ 154.1, 136.1 (d, J = 15.5 Hz), 132.8 (d, J = 6.1 Hz), 130.3 (d, J = 3.1
Hz), 124.9, 115.6, 105.5 (d, J = 2.3 Hz), 99.8, 55.5, 35.8 (d, J = 29.6
Hz), 29.3 (d, J = 29.6 Hz), 24.3 (d, J = 28.1 Hz). 31P NMR (162
MHz, CDCl3) δ 78.6. Following the general procedure B, 2e was
prepared from 1e as white solid (44.3 mg, 72%): 1H NMR (400 MHz,
CDCl3) δ 7.44−7.42 (m, 1H), 6.93 (dd, J = 2.5, 1.5 Hz, 1 H), 6.64 (d,
J = 2.6 Hz, 1H), 6.57 (dd, J = 3.3, 1.4 Hz, 0.86 H), 3.84 (s, 3H), 2.80
(d, J = 2.1 Hz, 0.24 H), 1.22 (d, J = 12.6 Hz, 18H). IR (film) 2941,
2360, 1578, 1495, 1473, 1267, 1167, 1123, 1106, 812, 752, 512 cm−1;
HRMS m/z (ESI) calcd for C18H26D3NOP (M + H)+: 309.2170,
found 309.2175. According to 1H NMR, According to 1H NMR, 14%
deuterium incorporation C3 position and 94% deuterium incorpo-
ration at C7 position was generated in product 2e.
1-(Di-tert-butylphosphanyl)-6-methoxy-7-methyl-1H-indole
(2f′) and 1-(Di-tert-butylphosphanyl)-6-methoxy-7-(methyl-
d3)-1H-indole (2f). Following the general procedure A, 2f′ was
prepared from 1f as white solid (44.5 mg, 73%): 1H NMR (400 MHz,
CDCl3) δ 7.43−7.38 (m, 2H), 6.90 (d, J = 8.5 Hz, 1H), 6.57 (dd, J =
3.4, 1.4 Hz, 1H), 3.90 (s, 3H), 2.83 (d, J = 2.9 Hz, 3H), 1.26 (d, J =
12.6 Hz, 18H); 13C{1H} NMR (101 MHz, CDCl3) δ 154.4, 142.2 (d,
J = 13.5 Hz), 132.1 (d, J = 5.7 Hz), 124.8 (d, J = 1.7 Hz), 117.5,
112.5, 107.3, 105.2 (d, J = 1.1 Hz), 57.4, 35.9 (d, J = 30.4 Hz), 29.4
(d, J = 17.4 Hz), 14.6(d, J = 30.1 Hz). 31P NMR (162 MHz, CDCl3)
δ 79.4. Following the general procedure B, 2f was prepared from 1f as
white solid (44.9 mg, 73%): 1H NMR (400 MHz, CDCl3) δ 7.46 (d, J
= 8.4 Hz, 1H), 7.31 (d, J = 3.4 Hz, 1H), 6.87 (d, J = 8.5 Hz, 1H), 6.56
(dd, J = 3.2, 0.8 Hz, 1H), 3.83 (s, 3H), 1.19 (d, J = 12.8 Hz, 18H). IR
(film) 2940, 2360, 1580, 1495, 1473, 1267, 1167, 1223, 1106, 812,
603 cm−1; HRMS m/z (ESI) calcd for C18H26D3NOP (M + H)+:
Figure 2. Proposed catalytic cycle.
deuterium incorporation C3 position and 91% deuterium incorpo-
ration at C7 position was generated in product 2b.
1-(Di-tert-butylphosphanyl)-5,7-dimethyl-1H-indole (2c′)
and 1-(Di-tert-butylphosphanyl)-5-methyl-7-(methyl-d3)-1H-
indole (2c). Following the general procedure A, 2c′ was prepared
from 1c as white solid (39.3 mg, 68%): 1H NMR (400 MHz, CDCl3)
δ 7.44 (d, J = 3.3 Hz, 1H), 7.28 (s, 1H), 6.84 (s, 1H), 6.58 (dd, J =
3.3, 1.5 Hz, 1H), 2.86 (d, J = 4.3 Hz, 3H), 2.43 (s, 3H), 1.25 (d, J =
12.6 Hz, 18H); 13C{1H} NMR (101 MHz, CDCl3) δ 139.3 (d, J =
15.5 Hz), 132.2 (d, J = 6.1 Hz), 130.2 (d, J = 2.5 Hz), 129.5, 127.6,
123.3, 118.2, 105.2 (d, J = 1.3 Hz), 35.8 (d, J = 29.6 Hz), 29.4 (d, J =
17.3 Hz), 24.3 (d, J = 27.9 Hz), 20.9. 31P NMR (162 MHz, CDCl3) δ
78.6. Following the general procedure B, 2c was prepared from 1c as
white solid (39.7 mg, 68%): 1H NMR (400 MHz, CDCl3) δ 7.40 (d, J
= 1.9 Hz, 1H), 7.24 (d, J = 2.3 Hz, 1H), 6.80 (d, J = 0.9 Hz, 1H), 6.54
(dd, J = 3.0, 1.1 Hz, 0.68 H), 2.79 (d, J = 2.1 Hz, 0.27 H), 2.39 (s,
3H), 1.21 (d, J = 12.6 Hz, 18H). IR (film) 2941, 1494, 1472, 1363,
1558, 1275, 1145, 1120, 806, 764, 637, 498 cm−1; HRMS m/z (ESI)
calcd for C18H26D3NP (M + H)+: 293.2220, found 293.2228.
According to 1H NMR, According to 1H NMR, 32% deuterium
incorporation C3 position and 91% deuterium incorporation at C7
position was generated in product 2c.
1
1
309.2170, found 309.2174. According to H NMR, According to H
NMR, 99% deuterium incorporation at C7 position was generated in
product 2f.
4-(Benzyloxy)-1-(di-tert-butylphosphanyl)-7-methyl-1H-in-
dole (2g′) and 4-(Benzyloxy)-1-(di-tert-butylphosphanyl)-7-
(methyl-d3)-1H-indole (2g). Following the general procedure A,
1
2g′ was prepared from 1g as white solid (52.2 mg, 68%): H NMR
(400 MHz, CDCl3) δ 7.55 (d, J = 7.3 Hz, 2H), 7.47−7.39 (m, 3H),
7.38−7.32 (m, 1H), 6.92−6.81 (m, 2H), 6.56 (d, J = 7.9 Hz, 1H),
5.22 (s, 2H), 2.84 (d, J = 4.6 Hz, 3H), 1.26 (d, J = 12.6 Hz, 18H);
13C{1H} NMR (101 MHz, CDCl3) δ 150.7 (d, J = 1.4 Hz), 142.1 (d,
J = 16.1 Hz), 137.8, 130.8 (d, J = 6.2 Hz), 128.4, 127.6, 127.3, 125.8,
120.6 (d, J = 3.4 Hz), 116.9, 102.7 (d, J = 2.2 Hz), 101.5, 69.9, 35.7
(d, J = 29.8 Hz), 29.3 (d, J = 17.3 Hz), 24.0 (d, J = 28.3 Hz). 31P
NMR (162 MHz, CDCl3) δ 78.5. Following the general procedure B,
1-(Di-tert-butylphosphanyl)-4-methoxy-7-methyl-1H-indole
(2d′) and 1-(Di-tert-butylphosphanyl)-4-methoxy-7-(methyl-
E
DOI: 10.1021/acs.joc.9b01114
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
1
2g was prepared from 1g as white solid (51.4 mg, 67%): H NMR
(400 MHz, CDCl3) δ 7.52 (d, J = 7.3 Hz, 2H), 7.43−7.37 (m, 3H),
7.37−7.27 (m, 1H), 6.90−6.80 (m, 1.9H), 6.54 (d, J = 7.9 Hz, 1H),
5.19 (s, 2H), 2.83−2.72 (m, 0.14H), 1.23 (d, J = 12.6 Hz, 18H). IR
(film) 2940, 2360, 1654, 1579, 1472, 1364, 1184, 1122, 752, 696, 603
cm−1; HRMS m/z (ESI) calcd for C214H30D3NOP (M + H)+:
385.2483, found 385.2488. According to H NMR, 10% deuterium
incorporation C3 position and 95% deuterium incorporation at C7
position was generated in product 2g.
95% deuterium incorporation at C7 position was generated in product
2j.
4-Bromo-1-(di-tert-butylphosphanyl)-7-methyl-1H-indole
(2k′) and 4-Bromo-1-(di-tert-butylphosphanyl)-7-(methyl-d3)-
1H-indole (2k). Following the general procedure A, 2k′ was
1
prepared from 1k as white solid (52.2 mg, 74%): H NMR (400
MHz, CDCl3) δ 7.51 (d, J = 3.4 Hz, 1H), 7.20 (d, J = 7.7 Hz, 1H),
6.83 (d, J = 7.8 Hz, 1H), 6.72 (dd, J = 3.4, 1.5 Hz, 1H), 2.83 (d, J =
4.4 Hz, 3H), 1.23 (d, J = 12.7 Hz, 18H); 13C{1H} NMR (101 MHz,
CDCl3) δ 141.2 (d, J = 15.7 Hz), 132.7 (d, J = 5.8 Hz), 130.1 (d, J =
2.2 Hz), 126.7, 123.4. 123.2, 112.1, 105.9 (d, J = 1.8 Hz), 35.8 (d, J =
30.0 Hz), 29.3 (d, J = 17.3 Hz), 24.2 (d, J = 29.0 Hz). 31P NMR (162
MHz, CDCl3) δ 80.4. Following the general procedure B, 2k was
1-(Di-tert-butylphosphanyl)-4-fluoro-7-methyl-1H-indole
(2h′) and 1-(Di-tert-butylphosphanyl)-4-fluoro-7-(methyl-d3)-
1H-indole (2h). Following the general procedure A, 2h′ was
1
prepared from 1h as colorless oil (46.2 mg, 79%): H NMR (400
1
prepared from 1k as white solid (56.9 mg, 80%): H NMR (400
MHz, CDCl3) δ 7.43 (d, J = 3.4 Hz, 1H), 6.85 (dd, J = 7.5, 6.0 Hz,
1H), 6.76−6.52 (m, 2H), 2.81 (d, J = 4.5 Hz, 3H), 1.23 (d, J = 12.7
Hz, 18H); 13C{1H} NMR (101 MHz, CDCl3) δ 156.2 (dd, J = 244.4,
1.7 Hz), 142.9 (dd, J = 16.2, 9.4 Hz), 132.0 (d, J = 6.2 Hz), 125.6 (d,
J = 7.3 Hz), 119.5 (d, J = 3.7 Hz), 118.7 (dd, J = 22.0, 3.3 Hz), 104.7
(d, J = 18.0 Hz), 101.2 (d, J = 2.5 Hz), 35.8 (d, J = 29.9 Hz), 29.3 (d,
J = 17.3 Hz), 23.9 (d, J = 28.7 Hz). 31P NMR (162 MHz, CDCl3) δ
79.2. 19F NMR (377 MHz, CDCl3) δ −127.2. Following the general
procedure B, 2h was prepared from 1h as colorless oil (46.7 mg,
79%): 1H NMR (400 MHz, CDCl3) δ 7.43 (d, J = 3.4 Hz, 1H), 6.85
(dd, J = 8.0, 5.6 Hz, 1H), 6.75−6.66 (m, 1.92H), 2.78 (s, 0.15H),
1.23 (d, J = 12.7 Hz, 18H). IR (film) 2941, 2360, 1493, 1473, 1364,
1253, 1144, 1117, 1027, 755, 601 cm−1; HRMS m/z (ESI) calcd for
C17H23D3FNP (M + H)+: 297.1970, found 297.1973. According to
1H NMR, 8% deuterium incorporation C3 position and 95%
MHz, CDCl3) δ 7.50 (d, J = 3.4 Hz, 1H), 7.19 (d, J = 7.7 Hz, 1H),
6.82 (d, J = 7.7 Hz, 1H), 6.71 (dd, J = 3.4, 1.5 Hz, 0.91H), 2.79 (d, J =
2.1 Hz, 0.12H), 1.22 (d, J = 12.7 Hz, 18H). IR (film) 2361, 2343,
1698, 1654, 1558, 1508, 1362, 1149, 762, 669 cm−1; HRMS m/z
(ESI) calcd for C17H23D3BrNP (M + H)+: 357.1169, found 357.1170.
According to 1H NMR, 9% deuterium incorporation C3 position and
96% deuterium incorporation at C7 position was generated in product
2k.
6-Bromo-1-(di-tert-butylphosphanyl)-7-methyl-1H-indole
(2l′) and 6-Bromo-1-(di-tert-butylphosphanyl)-7-(methyl-d3)-
1H-indole (2l). Following the general procedure A, 2l′ was prepared
from 1l as white solid (49.4 mg, 70%): 1H NMR (400 MHz, CDCl3)
δ 7.45 (d, J = 3.4 Hz, 1H), 7.36 (d, J = 8.3 Hz, 1H), 7.29 (d, J = 8.3
Hz, 1H), 6.58 (dd, J = 3.3, 1.4 Hz, 1H), 3.05 (d, J = 1.6 Hz, 3H), 1.22
(d, J = 12.7 Hz, 18H); 13C{1H} NMR (101 MHz, CDCl3) δ 141.8
(d, J = 13.0 Hz), 133.2 (d, J = 5.5 Hz), 129.2 (d, J = 1.8 Hz), 125.2,
123.5 (d, J = 0.6 Hz), 121.2, 119.1, 105.6 (d, J = 2.4 Hz), 36.0 (d, J =
30.9 Hz), 29.3 (d, J = 17.4 Hz), 22.8 (d, J = 32.0 Hz). 31P NMR (162
MHz, CDCl3) δ 81.2. Following the general procedure B, 2l was
prepared from 1l as white solid (52.7 mg, 74%): 1H NMR (400 MHz,
CDCl3) δ 7.44 (d, J = 3.4 Hz, 1H), 7.35 (d, J = 8.3 Hz, 1H), 7.29 (dd,
J = 8.3, 1.2 Hz, 1H), 6.58 (dd, J = 3.3, 1.3 Hz, 1H), 2.99 (d, J = 2.1
Hz, 0.09H), 1.22 (d, J = 12.7 Hz, 18H). IR (film) 2940, 2360, 2213,
1673, 1654, 1553, 1508, 1364, 1184, 762, 669, 601 cm−1; HRMS m/z
(ESI) calcd for C17H23D3BrNP (M + H)+: 357.1169, found 357.1163.
deuterium incorporation at C7 position was generated in product 2h.
1-(Di-tert-butylphosphanyl)-6-fluoro-7-methyl-1H-indole
(2i′) and 1-(Di-tert-butylphosphanyl)-6-fluoro-7-(methyl-d3)-
1H-indole (2i). Following the general procedure A, 2i′ was prepared
from 1i as colorless oil (38.0 mg, 65%): 1H NMR (400 MHz, CDCl3)
δ 7.42 (d, J = 3.4 Hz, 1H), 7.35 (dd, J = 8.2, 5.6 Hz, 1H), 6.90 (dd, J
= 10.2, 8.5 Hz, 1H), 6.58 (dd, J = 3.4, 1.5 Hz, 1H), 2.79 (t, J = 2.8 Hz,
3H), 1.23 (d, J = 12.7 Hz, 18H); 13C{1H} NMR (101 MHz, CDCl3)
δ 159.7 (d, J = 234.0 Hz), 141.4 (dd, J = 14.1, 7.7 Hz), 132.6 (dd, J =
5.8, 3.3 Hz), 126.0 (d, J = 2.7 Hz), 117.9 (d, J = 11.1 Hz), 110.5 (d, J
= 20.5 Hz), 109.1 (d, J = 27.8 Hz), 105.5 (d, J = 1.3 Hz), 36.0 (d, J =
29.9 Hz), 29.3 (d, J = 17.3 Hz), 13.8 (dd, J = 29.9, 7.5 Hz). 31P NMR
(162 MHz, CDCl3) δ 79.8. 19F NMR (377 MHz, CDCl3) δ −120.8.
Following the general procedure B, 2i was prepared from 1i as
1
According to H NMR, 32% deuterium incorporation C3 position
and 97% deuterium incorporation at C7 position was generated in
product 2l.
1-(Di-tert-butylphosphanyl)-7-methyl-1H-indole-4-carboni-
trile (2m′) and 1-(Di-tert-butylphosphanyl)-7-(methyl-d3)-1H-
indole-4-carbonitrile (2m). Following the general procedure A,
1
colorless oil (37.3 mg, 63%): H NMR (400 MHz, CDCl3) δ 7.43−
7.40 (m, 1H), 7.34 (ddd, J = 8.5, 5.5, 1.2 Hz, 1H), 6.90 (dd, J = 10.3,
8.5 Hz, 1H), 6.58 (dd, J = 3.4, 1.5 Hz, 0.85H), 2.75 (dd, J = 11.6, 9.2
Hz, 0.15H), 1.23 (d, J = 12.7 Hz, 18H). IR (film) 2940, 2360, 1487,
1473, 1364, 1253, 1134, 1121, 1077, 755, 601 cm−1; HRMS m/z
(ESI) calcd for C17H23D3FNP (M + H)+: 297.1970, found 297.1975.
1
2m′ was prepared from 1m as light yellow solid (37.8 mg, 63%): H
NMR (400 MHz, CDCl3) δ 7.62 (d, J = 3.4 Hz, 1H), 7.37 (d, J = 7.5
Hz, 1H), 6.99 (d, J = 7.6 Hz, 1H), 6.86 (dd, J = 3.4, 1.5 Hz, 1H), 2.92
(d, J = 4.1 Hz, 3H), 1.22 (d, J = 12.8 Hz, 18H); 13C{1H} NMR (101
MHz, CDCl3) δ 140.6 (d, J = 15.4 Hz), 134.8 (d, J = 5.9 Hz), 131.3
(d, J = 2.6 Hz), 129.8, 125.9, 125.5, 119.0, 104.4 (d, J = 2.5 Hz),
100.9, 35.8 (d, J = 30.0 Hz), 29.2 (d, J = 17.3 Hz), 24.7 (d, J = 29.1
Hz). 31P NMR (162 MHz, CDCl3) δ 81.9. Following the general
procedure B, 2m was prepared from 1m as light yellow solid (38.2
1
According to H NMR, 15% deuterium incorporation C3 position
and 95% deuterium incorporation at C7 position was generated in
product 2i.
4-Chloro-1-(di-tert-butylphosphanyl)-7-methyl-1H-indole
(2j′) and 4-Chloro-1-(di-tert-butylphosphanyl)-7-(methyl-d3)-
1H-indole (2j). Following the general procedure A, 2j′ was prepared
from 1j as white solid (50.6 mg, 82%): 1H NMR (400 MHz, CDCl3)
δ 7.50 (d, J = 3.4 Hz, 1H), 7.04 (d, J = 7.7 Hz, 1H), 6.88 (d, J = 7.8
Hz, 1H), 6.77 (dd, J = 3.4, 1.5 Hz, 1H), 2.84 (d, J = 4.4 Hz, 3H), 1.23
(d, J = 12.7 Hz, 18H); 13C{1H} NMR (101 MHz, CDCl3) δ 141.6
(d, J = 15.8 Hz), 132.8 (d, J = 6.0 Hz), 128.4 (d, J = 2.9 Hz), 126.3,
123.5 (d, J = 1.4 Hz), 122.6, 120.0, 104.1 (d, J = 2.4 Hz), 35.9 (d, J =
30.0 Hz), 29.3 (d, J = 17.3 Hz), 24.2 (d, J = 28.9 Hz). 31P NMR (162
MHz, CDCl3) δ 80.1. Following the general procedure B, 2j was
prepared from 1j as white solid (52.4 mg, 84%): 1H NMR (400 MHz,
CDCl3) δ 7.5 (d, J = 3.4 Hz, 1H), 7.0 (d, J = 7.7 Hz, 1H), 6.9 (d, J =
7.7 Hz, 1H), 6.8 (dd, J = 3.4, 1.5 Hz, 0.94H), 2.85−2.77 (m, 0.14H),
1.22 (d, J = 12.7 Hz, 18H). IR (film) 2941, 2360, 1684, 1560, 1480,
1363, 1253, 1144, 1117, 1027, 755, 601 cm−1; HRMS m/z (ESI)
calcd for C17H22D3ClNNaP (M + Na)+: 335.1494, found 335.1497.
According to 1H NMR, 6% deuterium incorporation C3 position and
1
mg, 63%): H NMR (400 MHz, CDCl3) δ 7.62 (d, J = 3.4 Hz, 1H),
7.37 (d, J = 7.5 Hz, 1H), 6.99 (d, J = 7.5 Hz, 1H), 6.86 (dd, J = 3.4,
1.5 Hz, 0.94H), 2.89 (dd, J = 5.3, 3.2 Hz, 0.24H), 1.22 (d, J = 12.8
Hz, 18H). IR (film) 2941, 2360, 2219, 1698, 1653, 1541, 1474, 1364,
1274, 1143, 766, 632, 421 cm−1; HRMS m/z (ESI) calcd for
C18H23D3N2P (M + H)+: 304.2016, found 304.2022. According to 1H
NMR, 6% deuterium incorporation C3 position and 92% deuterium
incorporation at C7 position was generated in product 2m.
1-(Di-tert-butylphosphanyl)-7-methyl-3-phenyl-1H-indole
(2n′) and 1-(Di-tert-butylphosphanyl)-7-(methyl-d3)-3-phenyl-
1H-indole (2n). Following the general procedure A, 2n′ was
1
prepared from 1n as white solid (52.6 mg, 75%): H NMR (400
MHz, CDCl3) δ 7.77 (d, J = 7.8 Hz, 1H), 7.67 (dd, J = 8.2, 1.2 Hz,
2H), 7.59 (s, 1H), 7.48 (t, J = 7.7 Hz, 2H), 7.36−7.29 (m, 1H), 7.13
(t, J = 7.5 Hz, 1H), 7.05 (d, J = 7.1 Hz, 1H), 2.93 (d, J = 4.5 Hz, 3H),
1.29 (d, J = 12.6 Hz, 18H); 13C{1H} NMR (101 MHz, CDCl3) δ
141.9 (d, J = 14.9 Hz), 135.4, 129.9 (d, J = 6.2 Hz), 128.7, 128.0,
F
DOI: 10.1021/acs.joc.9b01114
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
127.9, 126.4, 126.2, 124.1, 120.7, 120.6 (d, J = 2.0 Hz), 117.3, 35.9 (d,
J = 30.1 Hz), 29.4 (d, J = 17.3 Hz), 24.6 (d, J = 28.7 Hz). 31P NMR
(162 MHz, CDCl3) δ 79.8. Following the general procedure B, 2n
was prepared from 1n as white solid (53.8 mg, 76%): 1H NMR (400
MHz, CDCl3) δ 7.76 (dt, J = 7.9, 1.4 Hz, 1H), 7.72−7.61 (m, 2H),
7.58 (s, 1H), 7.52−7.42 (m, 2H), 7.38−7.29 (m, 1H), 7.18−7.09 (m,
1H), 7.04 (dd, J = 7.1, 1.2 Hz, 1H), 2.89 (s, 0.27H), 1.28 (d, J = 12.6
Hz, 19H); IR (film) 2941, 2360, 1678, 1653, 1636, 1540, 1478, 1360,
1243, 1151, 765, 630, 421 cm−1; HRMS m/z (ESI) calcd for
C23H28D3NP (M + H)+: 355.2377, found 355.2377. According to 1H
NMR, 91% deuterium incorporation at C7 position was generated in
product 2n.
1-(1-(Di-tert-butylphosphanyl)-7-methyl-1H-indol-3-yl)-
ethan-1-one (2o′) and 1-(1-(Di-tert-butylphosphanyl)-7-
(methyl-d3)-1H-indol-3-yl)ethan-1-one (2o). Following the gen-
eral procedure A, 2o′ was prepared from 1o as white solid (45.6 mg,
72%): 1H NMR (400 MHz, CDCl3) δ 8.29 (d, J = 7.9 Hz, 1H), 8.11
(s, 1H), 7.18 (t, J = 7.6 Hz, 1H), 7.05 (d, J = 7.2 Hz, 1H), 2.86 (d, J =
4.5 Hz, 3H), 2.56 (s, 3H), 1.26 (d, J = 12.8 Hz, 18H); 13C{1H} NMR
(101 MHz, CDCl3) δ 193.1, 141.8 (d, J = 13.9 Hz), 139.8 (d, J = 6.0
Hz), 127.6, 127.0 (d, J = 2.2 Hz), 123.9, 122.8, 120.1 (d, J = 2.7 Hz),
120.0, 35.9 (d, J = 31.4 Hz), 29.2 (d, J = 17.3 Hz), 27.7, 24.4 (d, J =
28.3 Hz). 31P NMR (162 MHz, CDCl3) δ 84.6. Following the general
procedure B, 2o was prepared from 1o as white solid (47.3 mg, 74%):
1H NMR (400 MHz, CDCl3) δ 8.33−8.24 (m, 1H), 8.11 (s, 1H),
3-(1-(Di-tert-butylphosphanyl)-7-methyl-1H-indol-3-yl)-1-
morpholinopropan-1-one (2r′) and 3-(1-(Di-tert-butylphos-
phanyl)-7-(methyl-d3)-1H-indol-3-yl)-1-morpholinopropan-1-
one (2r). Following the general procedure A, 2r′ was prepared from
1
1r as white solid (52.4 mg, 63%): H NMR (400 MHz, CDCl3) δ
7.40 (d, J = 7.7 Hz, 1H), 7.28 (s, 1H), 7.04 (t, J = 7.4 Hz, 1H), 6.97
(d, J = 7.1 Hz, 1H), 3.61 (s, 4H), 3.49−3.44 (m, 2H), 3.36−3.30 (m,
2H), 3.13 (t, J = 7.5 Hz, 2H), 2.85 (d, J = 4.3 Hz, 3H), 2.71−2.64 (m,
2H), 1.21 (d, J = 12.6 Hz, 18H); 13C{1H} NMR (101 MHz, CDCl3)
δ 171.3, 141.5 (d, J = 15.4 Hz), 129.6 (d, J = 6.3 Hz), 129.1 (d, J = 2.6
Hz), 126.0, 124.0, 119.9, 117.5 (d, J = 1.7 Hz), 116.1, 66.7, 66.4, 45.9,
41.8, 35.8 (d, J = 29.7 Hz), 33.5, 29.3 (d, J = 17.3 Hz), 24.6 (d, J =
28.3 Hz), 21.0. 31P NMR (162 MHz, CDCl3) δ 78.1. Following the
general procedure B, 2r was prepared from 1r as white solid (50.3 mg,
60%): 1H NMR (400 MHz, CDCl3) δ 7.40 (dt, J = 7.7, 1.4 Hz, 1H),
7.27 (s, 1H), 7.04 (t, J = 7.4 Hz, 1H), 6.96 (dd, J = 7.1, 1.1 Hz, 1H),
3.61 (s, 4H), 3.48−3.44 (m, 2H), 3.35−3.30 (m, 2H), 3.12 (t, J = 7.5
Hz, 2H), 2.82 (s, 0.3H), 2.72−2.65 (m, 2H), 1.20 (d, J = 12.6 Hz,
18H). IR (film) 2939, 2360, 1698, 1652, 1558, 1541, 1508, 1457,
1117, 747, 669 cm−1; HRMS m/z (ESI) calcd for C24H35D3N2O2P
1
(M + H)+: 420.2854, found 420.2858. According to H NMR, 90%
deuterium incorporation at C7 position was generated in product 2r.
9-(Di-tert-butylphosphanyl)-1-methyl-9H-carbazole (2s′)
and Methyl 9-(Di-tert-butylphosphanyl)-1-(methyl-d3)-9H-car-
bazole (2s). Following the general procedure A, 2s′ was prepared
from 1s as white solid (52.0 mg, 80%): 1H NMR (400 MHz, CDCl3)
δ 8.07 (d, J = 7.7 Hz, 1H), 7.95 (d, J = 8.4 Hz, 2H), 7.43−7.37 (m,
1H), 7.24 (ddd, J = 24.6, 10.9, 6.1 Hz, 3H), 3.05 (d, J = 6.1 Hz, 3H),
1.36 (d, J = 13.4 Hz, 18H); 13C{1H} NMR (101 MHz, CDCl3) δ
145.8 (d, J = 21.6 Hz), 143.6 (d, J = 10.3 Hz), 130.6, 126.8 (d, J = 2.1
Hz), 125.7 (d, J = 3.6 Hz), 120.3, 119.5, 117.4, 116.0, 36.8 (d, J =
37.2 Hz), 30.8 (d, J = 19.4 Hz), 26.5 (d, J = 35.3 Hz). 31P NMR (162
MHz, CDCl3) δ 81.7. Following the general procedure B, 2s was
prepared from 1s as white solid (53.7 mg, 82%): 1H NMR (400 MHz,
CDCl3) δ 8.15−8.00 (m, 1H), 8.00−7.87 (m, 2H), 7.39 (ddd, J = 8.4,
7.1, 1.4 Hz, 1H), 7.34−7.12 (m, 3H), 3.02 (d, J = 6.9 Hz, 0.21H),
1.35 (d, J = 13.4 Hz, 18H). IR (film) 2941, 2360, 1653, 1558, 1473,
1450, 1397, 1364, 1196, 1079, 960, 751, 476 cm−1; HRMS m/z (ESI)
calcd for C211H26D3NP (M + H)+: 329.2220, found 329.2224.
According to H NMR, 93% deuterium incorporation at C7 position
was generated in product 2s.
Bis(1-(di-tert-butylphosphanyl)-7-methyl-1H-indol-3-yl)-
methane (2t′) and Bis(1-(di-tert-butylphosphanyl)-7-(methyl-
d3)-1H-indol-3-yl)methane (2t). Following the general procedure
A, 2t′ was prepared from 1t as white solid (58.4 mg, 52%): 1H NMR
(400 MHz, CDCl3) δ 7.43 (d, J = 7.6 Hz, 2H), 7.08 (s, 2H), 6.99 (dt,
J = 14.3, 7.0 Hz, 4H), 4.19 (s, 2H), 2.87 (d, J = 4.3 Hz, 6H), 1.11 (d, J
= 12.5 Hz, 36H); 13C{1H} NMR (101 MHz, CDCl3) δ 141.7 (d, J =
15.6 Hz), 130.1 (d, J = 6.2 Hz), 129.5 (d, J = 2.9 Hz), 125.9, 123.7,
119.8, 117.7 (d, J = 1.8 Hz), 117.0, 35.6 (d, J = 29.4 Hz), 29.3 (d, J =
17.3 Hz), 24.5 (d, J = 28.2 Hz), 21.5. 31P NMR (162 MHz, CDCl3) δ
77.8. Following the general procedure B, 2t was prepared from 1t as
white solid (56.8 mg, 50%): 1H NMR (400 MHz, CDCl3) δ 7.43 (d, J
= 7.6 Hz, 2H), 7.08 (s, 2H), 7.03−6.93 (m, 4H), 4.20 (s, 2H), 2.84
(s, 0.6 H), 1.12 (d, J = 12.5 Hz, 36H). IR (film) 2941, 2360, 1698,
1684, 1653, 1558, 1508, 1457, 749, 669, 421 cm−1; HRMS m/z (ESI)
calcd for C351H47D6N2P2 (M + H)+: 569.4055, found 569.4059.
According to H NMR, 90% deuterium incorporation at C7 position
was generated in product 2t.
7.19 (dd, J = 7.8, 7.3 Hz, 1H), 7.05 (dd, J = 7.2, 1.3 Hz, 1H), 2.82 (s,
0.09H), 2.68−2.32 (m, 1.2H), 1.26 (d, J = 12.8 Hz, 18H). IR (film)
2941, 2360, 1698, 1652, 1558, 1488, 1473, 1398, 1225, 1168, 1147,
765, 669, 421 cm−1; HRMS m/z (ESI) calcd for C19H23D6NOP (M +
H)+: 324.2358, found 324.2359. According to 1H NMR, 97%
deuterium incorporation at C7 position was generated in product 2o.
Methyl 1-(di-tert-butylphosphanyl)-7-methyl-1H-indole-3-
carboxylate (2p′) and Methyl 1-(di-tert-butylphosphanyl)-7-
(methyl-d3)-1H-indole-3-carboxylate (2p). Following the general
procedure A, 2p′ was prepared from 1p as white solid (48.6 mg,
1
73%): H NMR (400 MHz, CDCl3) δ 8.16 (s, 1H), 8.09 (d, J = 7.9
Hz, 1H), 7.17 (t, J = 7.6 Hz, 1H), 7.04 (d, J = 7.2 Hz, 1H), 3.92 (s,
3H), 2.87 (d, J = 4.6 Hz, 3H), 1.24 (d, J = 12.8 Hz, 18H); 13C{1H}
NMR (101 MHz, CDCl3) δ 165.3, 141.6 (d, J = 14.3 Hz), 139.1 (d, J
= 6.0 Hz), 127.4 (d, J = 1.5 Hz), 127.1, 124.1, 122.2, 119.2, 110.8 (d,
J = 2.3 Hz), 51.1, 35.8 (d, J = 31.0 Hz), 29.2 (d, J = 17.4 Hz), 24.5 (d,
J = 28.6 Hz). 31P NMR (162 MHz, CDCl3) δ 84.4. Following the
general procedure B, 2p was prepared from 1p as white solid (50.4
1
mg, 75%): H NMR (400 MHz, CDCl3) δ 8.16 (s, 1H), 8.09 (d, J =
7.9 Hz, 1H), 7.17 (t, J = 7.6 Hz, 1H), 7.06−6.99 (m, 1H), 3.92 (s,
3H), 2.83 (s, 0.18H), 1.24 (d, J = 12.8 Hz, 18H). IR (film) 2947,
2360, 1714, 1542, 1399, 1303, 1211, 1139, 1058, 913, 882, 748, 669
cm−1; HRMS m/z (ESI) calcd for C19H26D3NO2P (M + H)+:
1
337.2119, found 337.2125. According to H NMR, 94% deuterium
incorporation at C7 position was generated in product 2p.
2-(1-(Di-tert-butylphosphanyl)-7-methyl-1H-indol-3-yl)-
acetonitrile (2q′) and 2-(1-(Di-tert-butylphosphanyl)-7-(meth-
yl-d3)-1H-indol-3-yl)acetonitrile (2q). Following the general
procedure A, 2q′ was prepared from 1q as light yellow solid (50.2
1
mg, 80%): H NMR (400 MHz, CDCl3) δ 7.50 (s, 1H), 7.38 (d, J =
7.7 Hz, 1H), 7.11 (t, J = 7.5 Hz, 1H), 7.04 (d, J = 7.1 Hz, 1H), 3.83
(d, J = 1.0 Hz, 2H), 2.88 (d, J = 4.4 Hz, 3H), 1.24 (d, J = 12.7 Hz,
18H); 13C{1H} NMR (101 MHz, CDCl3) δ 141.6 (d, J = 15.2 Hz),
130.3 (d, J = 6.4 Hz), 127.8 (d, J = 2.8 Hz), 126.9, 124.4, 120.7,
118.0, 115.6, 107.2 (d, J = 3.0 Hz), 35.8 (d, J = 30.0 Hz), 29.3 (d, J =
17.3 Hz), 24.4 (d, J = 28.3 Hz), 14.49. 31P NMR (162 MHz, CDCl3)
δ 80.4. Following the general procedure B, 2q was prepared from 1q
as light yellow solid (52.6 mg, 83%): 1H NMR (400 MHz, CDCl3) δ
7.49 (s, 1H), 7.37 (d, J = 7.8 Hz, 1H), 7.11 (t, J = 7.5 Hz, 1H), 7.06−
7.01 (m, 1H), 3.83 (s, 2H), 2.84 (d, J = 1.9 Hz, 0.21H), 1.23 (d, J =
12.7 Hz, 18H). IR (film) 2939, 2360, 2221, 1472, 1400, 1365, 1282,
1170, 1135, 1077, 806, 757, 671, 513 cm−1; HRMS m/z (ESI) calcd
for C19H24D3N2NaP (M + Na)+: 340.1992, found 340.1996.
4-Methoxy-7-methyl-1H-indole (3d′) and 4-Methoxy-7-
(methyl-d3)-1H-indole (3d). Following the general procedure C,
1
3d′ was prepared from 2d′ as white solid (11.4 mg, 71%): H NMR
(400 MHz, CDCl3) δ 8.07 (s, 1H), 7.14−7.09 (m, 1H), 6.91 (d, J =
7.7 Hz, 1H), 6.69 (dd, J = 3.1, 2.2 Hz, 1H), 6.47 (d, J = 7.8 Hz, 1H),
3.96 (s, 3H), 2.44 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ
151.8, 136.6, 122.6, 122.4, 118.0, 113.2, 100.4, 99.6, 55.4, 16.0. 3d was
1
prepared from 2d as white solid (11.8 mg, 72%): H NMR (400
MHz, CDCl3) δ 8.08 (s, 1H), 7.19−7.11 (m, 1H), 6.90 (d, J = 7.8 Hz,
1H), 6.67 (dd, J = 3.1, 2.2 Hz, 1H), 6.45 (d, J = 7.8 Hz, 1H), 3.94 (s,
3H), 2.41 (m, 0.21 H). IR (film) 3395, 3110, 2962, 2941, 1684, 1653,
1524, 1508, 1262 cm−1; HRMS m/z (ESI) calcd for C10H9D3NO (M
1
According to H NMR, 93% deuterium incorporation at C7 position
was generated in product 2q.
G
DOI: 10.1021/acs.joc.9b01114
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
+ H)+: 165.1102, found 165.1105. According to 1H NMR, 93%
deuterium incorporation at C7 position was generated in product 3d.
7-Methyl-3-phenyl-1H-indole (3n′) and 7-(Methyl-d3)-3-
phenyl-1H-indole (3n). Following the general procedure C, 3n′
was prepared from 2n′ as white solid (16.6 mg, 80%): 1H NMR (400
MHz, CDCl3) δ 8.11 (s, 1H), 7.88 (d, J = 8.0 Hz, 1H), 7.73 (d, J =
7.8 Hz, 2H), 7.51 (t, J = 7.7 Hz, 2H), 7.35 (q, J = 6.2 Hz, 2H), 7.19
(t, J = 7.5 Hz, 1H), 7.12 (d, J = 7.0 Hz, 1H), 2.54 (s, 3H). 13C{1H}
NMR (101 MHz, CDCl3) δ 136.1, 135.7, 128.7, 127.4, 125.9, 125.2,
122.9, 121.5, 120.5, 120.5, 118.7, 117.5, 16.6. 3n was prepared from
Functionalization of β-Keto Esters with Indoles at Room Temper-
ature. J. Am. Chem. Soc. 2012, 134, 5750−5753. (d) Wu, J.-C.; Song,
R.-J.; Wang, Z.i-Q.; Huang, X.-C.; Xie, Y.-X.; Li, J.-H. Copper-
Catalyzed CH Oxidation/Cross-Coupling of a-Amino Carbonyl
Compounds. Angew. Chem., Int. Ed. 2012, 51, 3453−3457. (e) Zhu,
Y.; Rawal, V. H. Palladium-Catalyzed C3-Benzylation of Indoles. J.
Am. Chem. Soc. 2012, 134, 111−114. (f) Li, Y.; Yan, T.; Junge, K.;
Beller, M. Catalytic Methylation of CH Bonds Using CO2 and H2.
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(d) Moselage, M.; Sauermann, N.; Richter, S. C.; Ackermann, L. C-H
Alkenylations with Alkenyl Acetates, Phosphates, Carbonates, and
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1
2n as white solid (16.8 mg, 80%): H NMR (400 MHz, CDCl3) δ
8.17 (s, 1H), 7.81 (d, J = 7.9 Hz, 1H), 7.73−7.64 (m, 2H), 7.50−7.42
(m, 2H), 7.39 (d, J = 2.5 Hz, 1H), 7.33−7.26 (m, 1H), 7.17−7.10 (m,
1H), 7.10−7.04 (m, 1H), 2.52 (m, 0.3H). IR (film) 3394, 3110, 2965,
2941, 1678, 1653, 1636, 1474, 1364, 1243, 1151 cm−1; HRMS m/z
(ESI) calcd for C15H11D3N (M + H)+: 211.1309, found 211.1315.
1
According to H NMR, 90% deuterium incorporation at C7 position
was generated in product 3n.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.9b01114.
■
S
Experimental procedures and full spectroscopic data for
all new compounds (PDF)
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metal-catalyzed site- and regio-divergent C−H bond functionalization.
Chem. Soc. Rev. 2017, 46, 4299−4328. (b) Leitch, J. A.; Bhonoah, Y.;
Frost, C. G. Beyond C2 and C3: Transition-Metal-Catalyzed C−H
Functionalization of Indole. ACS Catal. 2017, 7, 5618−5627.
(c) Hartung, C. G.; Fecher, A.; Chapell, B.; Snieckus, V. Directed
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15552−15553. (e) Loach, R. P.; Fenton, O. S.; Amaike, K.; Siegel, D.
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Regiocontrolled Direct C-H Arylation of Indoles at the C4 and C5
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AUTHOR INFORMATION
■
Corresponding Authors
*E-mail: yyuan@yzu.edu.cn.
*E-mail: shiz@nju.edu.cn.
ORCID
Zhuangzhi Shi: 0000-0003-4571-4413
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the National Science Foundation of China (Grants
21672097) and Jiangsu Provincial Nature Science Foundation
(SBK2016021885) for their financial support.
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