Carboxylic Acid-Promoted Single-Step Indole Construction from Simple Anilines and Ketones via Aerobic Cross-Dehydrogenative Coupling

Article abstract of DOI:10.1021/acs.joc.8b02180

The cross-dehydrogenative coupling (CDC) reaction is an efficient strategy for indole synthesis. However, most CDC methods require special substrates, and the presence of inherent groups limits the versatility for further transformation. A carboxylic acid-promoted aerobic catalytic system is developed herein for a single-step synthesis of indoles from simple anilines and ketones. This versatile system is featured by the broad substrate scope and the use of ambient oxygen as an oxidant and is convenient and economical for both laboratory and industry applications. The existence of the labile hydrogen at C-3 and the highly transformable carbonyl at C-2 makes the indoles versatile building blocks for organic synthesis in different contexts. Computational studies based on the density functional theory (DFT) suggest that the rate-determining step is carboxylic acid-assisted condensation of the substrates, rather than the functionalization of aryl C-H. Accordingly, a pathway via imine intermediates is deemed to be the preferred mechanism. In contrast to the general deduction, the in situ formed imine, instead of its enamine isomer, is believed to be involved in the first ligand exchange and later carbopalladation of the α-Me, which shed new light on this indolization mechanism.

Full text of DOI:10.1021/acs.joc.8b02180

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Article
Carboxylic Acid Promoted Single-step Indole Construction from Simple
Anilines and Ketones via Aerobic Cross-Dehydrogenative Coupling
Long Ren, Guanglei Nan, Yongcheng Wang, and Zhiyan Xiao
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b02180 • Publication Date (Web): 31 Oct 2018
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The Journal of Organic Chemistry
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Carboxylic Acid Promoted Single-step Indole Construction
from Simple Anilines and Ketones via Aerobic Cross-Dehy-
drogenative Coupling.
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Long Ren, Guanglei Nan, Yongcheng Wang, and Zhiyan Xiao*
Beijing Key Laboratory of Active Substance Discovery and Druggability Evaluation, Institute of Materia Medica, Chinese
Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.
KEYWORDS: indole synthesis, Pd-catalysis, CDC, aniline, aerobic, dioxygen, single-step
ABSTRACT: The cross dehydrogenative coupling (CDC) reaction is an efficient strategy for indole synthesis. However, most CDC
methods require special substrates, and the presence of inherent groups limits the versatility for further transformation. A carboxylic
acid promoted aerobic catalytic system is developed herein for a single-step synthesis of indoles from simple anilines and ketones.
This versatile system is featured by the broad substrate scope and the use of ambient oxygen as oxidant, and is convenient and
economical for both laboratory and industry application. The existence of the labile hydrogen at C-3 and the highly transformable
carbonyl at C-2 makes the indoles versatile building blocks for organic synthesis in different contexts. Computational studies based
on the density functional theory (DFT) suggests that the rate-determining step is carboxylic acid-assisted condensation of the sub-
strates, rather than the functionalization of aryl C-H. Accordingly, a pathway via imine intermediates is deemed to be the preferred
mechanism. In contrast to the general deduction, the in situ formed imine, instead of its enamine isomer, is believed to be involved
in the first ligand exchange and later carbopalladation of the α-Me, which shed new lights on this indolization mechanism.
Scheme 1. Indole Syntheses from Simple Anilines
1. INTRODUCTION
Indole is a ubiquitous scaffold occurring in nature products1-3
and also a commonly used heterocycle building block for a
large variety of functional molecules in different fields.4-7 Ow-
ing to the well-documented diverse biological properties asso-
ciated with indole derivatives, indole has long been regarded as
a 'privileged structure' in pharmaceutical science.1,8 Accord-
ingly, the research zeal on indole synthesis and functionaliza-
tion has never ceased over a century.9 A large collection of
methods have been developed, and many of them have been
listed as name reactions, such as Bartoli reaction, Larock reac-
tion and the most widely used Fischer reaction.10-12 These clas-
sic methods unexceptionally have their own limitations and
usually demand the preparation of special substrates through
multistep chemical operations.13-14
Along with the formidable boom of metal-catalysis chemistry,
indole synthesis has experienced a profound revolution in re-
cent decades, which aims for more accessible substrates and
more efficient protocols.15-16 Metal-catalyzed cross-dehydro-
genative coupling (CDC) has so far been one of the most fasci-
nating strategies for indole synthesis, and it enables the indole
C3-Cβ bond to be formed directly from unactivated aryl C-H
bond.17-18 In general, the CDC indole syntheses could start from
simple anilines and alkynes in a cascade reaction or by forming
various N-aryl enamines/imines. The transformation of simple
anilines with alkynes substituted by EWGs (electron-withdraw-
ing groups) was first achieved by Jiao in 2009, using the readily
available O2 as oxidant (Scheme 1a).19 While Lu, in 2012, re-
ported the transformation of simple anilines with di-aryl al-
kynes which required stoichiometric Cu(OAc)2 as oxidant.20
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According to Huang’s work, this transformation could also be to offer better results (entry 7). Notably, some carboxylic acids
accomplished by [Rh]/O2 catalytic system (Scheme 1a).21 The
indole synthesis from N-aryl enamines disclosed by Glorius in
2008 and 2011 utilized a basic Pd-catalytic system (Scheme
1b).22,23 While in 2012, Yoshikai et al. reported an indole syn-
thesis from stable N-aryl imines, which is featured by a neutral
Pd-catalytic system and the oxidant of O2 (Scheme 1b).24 In
spite of these improvements, the following two issues still hin-
der the realization of desired versatility and applicability of
CDC method.
were shown to be favorable for this transformation (cf. entries
8-10). Bases and hyamines (phase-transfer catalysts) were gen-
erally unfavorable. With the addition of 4 equiv. of AcOH, the
yield increased to 75% (entry 11). Subsequent optimization of
temperature and reaction time further increased the yield to 81%
(entry 12). Finally, when 2 equiv. of 2a was loaded, better yield
was observed (entry 13), which was applied as a standard con-
dition for later investigation.
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Firstly, EWGs or aryl (Ar) substituents are generally required
for either the alkyne substrates or the N-aryl enmanies/imine
substrates (Scheme 1a and 1b).19-28 Consequently, the indoles
produced tend to be permanently substituted with 'fixed groups'
(e.g. difficult to be removed or reluctant for further transfor-
mation), which makes the methodologies exclusive but also
limits their versatility. This limitation could be part of the rea-
son that in spite of its shortcomings, the traditional Fischer
method remains the first resort for indolization under many cir-
cumstances.
Table 1. Optimization of Reaction Conditions for CDC In-
dolization of Aniline (1a) with Ketone (2a)a
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lig. / add.
(equiv.)
temp.
(oC)
yieldb
entry
catalyst
solvent
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2
3
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
none
none
none
none
MeCN
Toluene
DMSO
DMSO
90
90
90
90
0
0
Secondly, although ketones are more accessible than alkynes,
indole synthesis by single-step reaction from simple anilines
and ketones was scarcely reported. To the best of our
knowledge, only two such examples have been reported so far
(Scheme 1b).24 In Yoshikai’s efforts to prepare indoles directly
from anilines and ketones, indole products were successfully
obtained in moderate yields via a condensation-CDC cascade.
Instead of the standard Pd/O2 condition applied to N-aryl imines,
excessive copper salt was used as oxidant for single-step indole
construction, which limits the applicability of the approach.
Such situation summons for new methods to achieve the direct
transformation more efficiently and adaptably, which needs no
preparation of N-aryl imines and therefore are applicable for
substrates generally unable to produce stable imines.
30%
11%
4c
5d
6
Pd(OAc)2
PdCl2
none
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
90
90
90
90
90
90
90
70
< 5%
< 5%
10%
41%
39%
< 5%
75%
81%
none
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Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
X-Phos (0.1)
AcOH (2)
PivOH (2)
TFAOH (2)
AcOH (4)
AcOH (4)
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9
10
11
12e
13e,f
Pd(OAc)2
AcOH (4)
DMSO
70
86%
aReaction conditions: 1a (0.4 mmol), 2a (0.48 mmol), catalyst (0.04 mmol),
O2 (1 atm), ligand or additive, solvent (2 mL), 4Å MS (80 mg), 90 oC, 12 h.
bIsolated yield (%). cAir (1 atm) was used instead of O2 (1 atm). dAr (1 atm)
was used instead of O2 (1 atm). eStirred for 18 h. f0.8 mmol of 2a (2 equiv.)
was added.
As an endeavor to cope with the two issues raised above, we
report herein a carboxylic acid promoted Pd-catalytic system
that affords indoles efficiently from simple anilines and ketones
in a single step using O2 (1 atm) as the oxidant (Scheme 1c).
The presence of a hydrogen at C-3 and a carbonyl at C-2 distin-
guishes the indoles constructed herein from those previously
prepared via CDC strategy. Instead of other intractable groups,
such as aryl, alkyl, or cyano, a sole carbonyl is installed at C-2,
which is readily transformable to a variety of functional groups
as illustrated by previous cases.29-42 The existence of a labile hy-
drogen at C-3 further extends the structural flexibility. Such fea-
tures make the current method adaptable to a range of diverse
indoles.
2.2. Investigation on Substrate Scope. We first examined
the tolerance to various substitutions on aniline. The reaction of
unsubstituted aniline delivered the simplest indole-2-carbox-
ylate in a yield of 71% (Table 2, 3fa). Generally, anilines with
EDGs (electron-donating groups) would lead to comparable or
higher yields (3aa-3ea, 3αa-3δa), while those with EWGs re-
sult in similar or lower yields (3oa-3za, 3ιa-3μa). For the same
functional group, substitution at the ortho-position would also
end with a lower yield than those at other positions (3ba, 3pa,
3sa, also cf. 3ζa & 3εa), which is probably due to the presence
of only one activatable C-H bond in the ortho-congener. To ex-
plore the effect of fused rings on reactivity, naphthalen-1-amine
was used and the desired indole-type product (3ga) was ob-
tained in high yield, while no quinoline product from C-H bond
activation (CHA) at C-8 position was detected. It could be de-
duced from this result that seven-membered cyclic Pd-interme-
diate could not be formed under this system. Such a hypothesis
was further confirmed by the reaction of 2-methylated naphtha-
len-1-amine, in which no desired product was found (Eqn S1 in
SI). Heterocyclic aromatic amines were also tested. Some gave
indole products in low yields (3na, also see Eqn S2 and S3 in
SI), while others showed no transformation, possibly because
of chelation with the catalyst (3ha). To our delight, phenolic
2. RESULTS AND DISCUSSION
2.1. Development of single-step CDC Indolization of sim-
ple aniline with ketone. Our initial efforts attempted to syn-
thesize indole-2-carboxylate from 4-methoxyaniline (1a) and
ethyl pyruvate (2a) using metal-catalyzed CDC strategy under
1 atm of O2 (Table 1, for details see the Supporting Information
(SI)). Under the catalysis of Pd(OAc)2, various solvents were
first screened and the reaction worked when DMSO was used
(entries 1-3). Changing O2 to air or argon rendered significant
decrease in the yield (entries 4-5), which suggested a role of
oxidant for O2. The reaction went worse as other palladium spe-
cies (entry 6) or other mental catalysts were loaded (data not
shown). To improve the yield, a series of phosphorus and nitro-
gen-based ligands were screened. However, these efforts failed
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hydroxyl (3ia), benzyl hydroxyl (3ja), primary benzamide with a greater ratio of C-2 CHA isomer (3οa & 3'οa). To ex-
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(3za), methanesulfonyl (e.g. 3ma), cyano (3va), nitryl (3ya),
chloride (e.g. 3ra) and even bromide (e.g. 3ta) were all well
compatible with this system.
clude the possibility of a special nature related to halides, bro-
mide (1.95 Å) with a similar size as methyl group (2.0 Å) was
investigated for its influence on regioselectivity. As expected,
the reaction with m-Br aniline was similar to meta-methyl ani-
line and only the sole regioisomer from CHA at C-6 rather than
C-2 was afforded (3μa). The significantly lower yield of 3εa as
compared with that of 3δa could also be attributed to the meta-
steric effect. However, the 3,5-dimethoxylaniline produced the
desired product in a yield comparable to that of m-methoxyani-
line with much shorter reaction time (9 h) (cf. 3αa and 3βa). It
seems that the meta-steric effect was undetected for methoxyl
group. The particular steric effect of methoxyl group (-OMe)
could come from the rotatability of the C-O bond. When the
methyl of -OMe rotates away from C-2, the steric effect at C-2
was merely derived from the oxygen atom (1.40 Å), which was
less significant than m-methyl. To validate this supposition,
methylenedioxyaniline was chosen as the substrate. In align-
ment with our expectation, two regioisomers were isolated in
comparable yields (3θa & 3'θa).
A pronounced meta-steric effect presented in the anilines with
methyl (1δ), methoxyl (1α), tert-butyl (1γ) and phenyl (1η) sub-
stituted at C-3 (Table 2). The high yields showed an obvious
preference of CHA at C-6 over that at C-2 and the regioisomers
from C-2 CHA were hardly detected. Similar regioselectivity
was also observed in reactions of anilines with relatively bulky
9
EWG at meta-position, yet in lower yields (3ιa, 3κa). However,
when m-chloroaniline was examined, the regioselectivity pro-
file differed. Products resulted from C-2 and C-6 CHA were
obtained in the ratio of 1: 3 (3λa & 3'λa). It was surmised that
the difference in regioselectivity profiles might be attributed to
steric effects of substituents at meta-position. Therefore, vari-
ous substituents differing by virtue of their van der Waals radii
(Å)29-33 were then examined for their regioselectivity profiles.
When fluorine (1.46 Å) was introduced to the meta-position of
aniline, the two products were obtained in higher total yield
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Table 2. Carboxylic Acid Promoted Pd-catalyzed CDC Indolization of Anilines (1) with Ketone (2a)a,b
aStandard conditions: 1 (0.4 mmol), 2a (0.8 mmol), Pd(OAc)2 (0.04 mmol), O2 (1 atm), AcOH (1.6 mmol), DMSO (2 mL), 4Å MS
(80 mg), 70 oC (unless noted otherwise), 18 h (unless noted otherwise). bIsolated yields. c2a (1.2 mmol). dAcOH (0.4 mmol), DMSO
(3 mL). e2a (2.0 mmol).
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Table 3. DG Directed Pd-Catalyzed CDC Indolization of
palladation. A closer examination of the results above further
Anilines (1) with Ketone (2a)a,b
supported such a hypothesis. Generally, EDGs tended to facili-
tate the formation of indole products and led to higher yield and
shorter reaction duration than substrates with EWGs. Further-
more, for EDG substituents, 4-substitution was generally fa-
vored over 3-substitution (cf. 3aa and 3αa). In contrast, for
EWG substituents, 3-substitution was preferred over 4-substi-
tution (cf. 3ya and 3ιa, 3oa and 3οa & 3'οa). Notably, the low
yields were generally owing to low transformation rates of sub-
strates (e.g. 3ad, also see Eqn S5 in SI). These observations
were again conflict with the simple SEAr mechanism. However,
a more convincing explanation for the tendency that stronger
EDGs led to higher yields could be that the N-aryl
imine/enamine intermediates from electron-rich anilines might
be more readily formed than those from electron-poor anilines,
and subsequently favored the whole transformation.
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To extend the synthetic method to indole skeletons with bulky
4-substituents, the strategy of introducing directing group (DG)
in the aniline substrate was attempted.34 In this study, some po-
tential DGs were incorporated to the C-3 of anilines (Table 3).
These DGs were assumed to coordinate with [Pd] by forming a
five- or six-membered metallacycle, thereby direct the catalytic
center to the ortho-site of the DGs to produce 4-substituted in-
doles. The effects of DGs on regioselectivity to C-2 CHA of
aniline were demonstrated by the generally increased percent-
age of 4-substituted product in the total indole yield (RDG%).
Various functional groups with carbonyl oxygen were first ex-
amined for their effects as directing groups. The total yield and
RDG% for acetamido group were both comparable to those of
carbamyl group (products of 1ρ and 1φ), while acetyl group
achieved a lower RDG% with a higher total yield (products of
1π). Although different coordinating metallacycles might be in-
volved, the RDG% generated by formic ester and acetic ester was
similarly poor (products of 1σ and 1ψ). Aliphatic hydroxyl
group was also capable of directing CHA at C-2 and affording
4-substituted indole in a similar level as corresponding esters
(products of 1υ and 1σ). However, the mesyl group showed a
poor directing effect, yet resulted in the highest yield (3χa &
3'χa), which was probably attributed to the higher catalytic rate
of CHA at C-6 of aniline and the relatively weak coordination
of the mesyl with the catalyst. Conversely, due to its relatively
strong electron-withdrawing and metal coordinating effects, the
carboxy group led to the highest RDG%, whereas, the lowest to-
tal yield (3τa & 3'τa). As shown in Chart 1, there seemed to
be a clear inverse relationship between the total yield and the
RDG%. In general, the lower the total yield is, the higher the RDG
appears, and vice versa. Such a trend might be attributed to mul-
tiple factors, including yet not limited to the electronic nature
and the chelating effect of the DGs.
aStandard conditions: 1 (0.4 mmol), 2a (0.8 mmol), Pd(OAc)2
(0.04 mmol), O2 (1 atm), AcOH (1.6 mmol), DMSO (2 mL), 4Å
MS (80 mg), 70 oC (unless noted otherwise), 18 h (unless noted
otherwise). bIsolated yields.
Chart 1. Total Yields (Yield%) and the Percentage of 3' in
Total Yields (RDG%) in the Reactions of Anilines with Dif-
ferent meta-DGs.
70%
70%
80%
60%
40%
20%
0%
67%
51%
67%
44%
38%
36%
32%
15%
36%
23%
9%
10%
2%
10%
%
Based on the van der Waals radii of selected groups (Table 2)29-
33
and the discussion above, the steric effects of the meta-sub-
The scope of ketones (2) was further investigated. The simplest
aliphatic ketone, acetone, was then tested under the standard
conditions and a satisfying yield was achieved (Table 4, 3ab).
When 4-methyl pentan-2-one and pentan-2-one were tested,
only a single isomer was identified for each ketone substrate
and only α-CH3 (3ac and 3ad) rather than α’-CH2 (Eqn S4 and
S5 in SI) of the ketone could be incorporated into the indole
skeleton as C-3. Given these results, methyl 2-oxopentanoate
(2e), a ketone without methyl group at its α-positions, was cho-
sen for further examination. As expected, the reaction failed to
give any indole product. Thus, the presence of an α-methyl
group in the ketone might be a prerequisite for successful in-
dolization. In addition, indoles substituted with amido (3af) and
ketone (3ag) at C-2 could also be directly afforded under this
stituents on aniline could be deduced. For a meta-substituent
with a van der Waals radius equivalent to or less than that of
chlorine (1.80 Å), two indole regioisomers could be produced
under this catalytic system. Otherwise, high regioselectivity
could be perceived. However, phenolic hydroxyl at the meta-
position seemed to be an exception. Despite the van der Waals
volume of hydroxyl is smaller than that of chlorine, 3-hydroxy-
aniline afforded the C-6 CHA product in a high yield (3νa). It
was thereby reasoned that the acidity of phenolic hydroxyl
might competitively disturb the dehydrogenation process of
CHA at C-2, which suggests a possible concerted metalation-
deprotonation (CMD) mechanism rather than a simple electro-
philic aromatic substitution (SEAr) mechanism for the aromatic
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catalytic system. However, the current method seemed to be in- the original yields, minor adjustments were made to the reaction
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applicable to aromatic ketone substrates, such as acetophenone.
conditions during scaling up (Table S5 in SI). For anilines with
para-substituted EDG, a low reaction concentration was gener-
ally favored, since it reduces the by-product from nucleophilic
reactions. When the model substrate 1a was reacted with 2a un-
der the concentration of 0.1 M, approximate 2 grams of product
3aa was afforded in a yield of 89% (Eqn 1). Under the same
conditions, 1a reacted with the aliphatic ketone 2b in gram-
scale, and the yield reached 76% (Eqn 2). For anilines with
meta-substituted EDG, a high concentration would be preferred.
For instance, under the concentration of 1.0 M, 20 mmol of m-
methoxyaniline 1 reacted smoothly with 2a and provided 6-
methoxyl product 3a in a yield of 81% (Eqn 3). Meanwhile,
the regioisomer 3'a was also isolated in the yield of 3%, which
further supported the unique steric effect of methoxyl group.
As compared to the previous report,24 products 3aa and 3ab
were obtained in higher yield yet without the requirement for
excessive metal salt, which makes the current method more ef-
ficient and convenient. This method is also applicable to a vari-
ety of aniline and ketone substrates, and the broad substrate
scope expands the molecular diversity of accessible indole de-
rivatives.
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Table 4. Pd-Catalyzed CDC Indolization of Aniline (1a)
with Ketones (2)a,b
Methyl
5-(methylsulfonamido)-1H-indole-2-carboxylate
(3mh), the key intermediate for the synthesis of the clinically
used anti-HIV drug Delavirdine,49-51 was also synthesized as an-
other application example, and 2.2 grams of 3mh was provided
in a yield of 80% (Eqn 4). As compared with the multiple-step
synthesis of 3mh applied in industry,51 the current method is
more convenient and efficient.
Scheme 2. H/D Kinetic Isotope Effect Experiments
aStandard conditions: 1 (0.4 mmol), 2a (0.8 mmol), Pd(OAc)2
(0.04 mmol), O2 (1 atm), AcOH (1.6 mmol), DMSO (2 mL), 4Å
MS (80 mg), 70 oC (unless noted otherwise), 18 h (unless noted
otherwise). bIsolated yields. c2 (2.0 mmol). dAcOH (0.4 mmol),
2 (2.0 mmol), DMSO (8 mL).
2.4 Mechanistic Studies.
Experimental Studies. To shed light on the underlying mech-
anism, three types of hydrogen/deuterium kinetic isotope effect
(H/D KIE) experiments were performed (Scheme 2).52,53 The
KIE between aniline (1f) and its penta-deuterated analogue (1f-
d5) was first measured in two independent parallel reactions by
real-time NMR analysis (see SI). A modest KIE of 1.7 was
2.3 Applicability in large-scale synthesis. We further ap-
plied the synthetic method to large-scale synthesis. To maintain
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given by comparing either the reaction rates during their fast enamine or the imine pathway, is actually involved in the α-
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converting stage (kH/kD, 80-180 min) or the reaction yields ar-
rested at selected time (PH/PD, 3 h) before rate degradation
(Scheme 2a). The same NMR measurement was then adopted
to examine the KIE of intermolecular competition between 1f
and 1f-d5 in the same reaction. A greater KIE of 3.0 was moni-
tored by kinetic comparison of the two reactions. Nevertheless,
the KIE measured by yields at the time point of 3h was similar
to that in parallel experiments, which was further confirmed by
the isolated yields at the endpoint of 3 h (Scheme 2b and also
see Figure S6 in SI). The modest KIE observed in both parallel
experiment and intermolecular competition suggested that aro-
matic C-H bond activation might be a turnover-limiting
step.23,24,53 Finally, mono-deuterated imine 1f-d was employed
for the intramolecular competitive reaction. The KIE was re-
flected by the ratio of final yields under standard conditions and
reached a greater value of 5.3 (Scheme 2c). This magnitude of
KIE indicates that a concerted metalation-deprotonation (CMD)
process is preferred during the aromatic C-H bond activation,
22,24,54 which is also supported by evidences accumulated in the
scope investigation.
carbopalladation and the CMD process? To provide a clearer
view and refine the mechanism, we resorted to computational
studies next.
Computational studies. Based on the mechanism outlined in
Scheme 3, computational studies were performed by applying
the density functional theory (DFT) to the model reaction.57 The
condensation of 1a and 2a was first studied. Among possible
approaches to access imine A (Figure S13 in SI), the AcOH-
assisted pathway was shown to be favored, which offered an
explanation for the important role of AcOH in the reaction. Ac-
cording to Figure 1, however, an energy barrier up to 31.7
kcal/mol is required for the completion of the transformation,
which makes the condensation a kinetically difficult process.
Moreover, the reverse process of the condensation (negative
equilibrium shift) is thermodynamically advantaged over the
forward process (positive equilibrium shift), since the free en-
ergy of starting materials is 4.2 kcal/mol lower than that of the
produced imine (A). Taking together, the imine product is nei-
ther easy to form nor stable with AcOH in the given solvent.
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To explore the valence variation of palladium during indoliza-
tion, a reaction with stoichiometric amount of Pd(OAc)2 was
next performed under argon (Eqn S6 in SI). The resultant yield
of 68% as well as the appearance of palladium black suggested
the involvement of a Pd(II)/Pd(0) redox process. Along with the
discussion above, a plausible mechanism is proposed in
Scheme 3. Firstly, aryl imine (A) or enamine (B) is formed by
the condensation of the two substrates (1 and 2). Then an α-
palladated imine C is generated in situ from A or B, which is
the first dehydrogenative carbopalladation. The intramolecular
ortho-CHA of imine C via CMD provides six-membered pal-
ladacycle D. The reductive elimination of D happens next to
give 3H-indole E and Pd(0). The aromatization of E affords the
final indole 3, while the Pd(0) is oxidized by molecular dioxy-
gen to regenerate Pd(II) catalyst.55,56
Figure 1. The energy profile of the AcOH-assisted condensa-
tion of 1a and 2a to afford imine A.
Scheme 3. The possible mechanism for aerobic Pd-catalyzed
indolization of anilines (1) with ketones (2)
Next, we investigated the tautomerization between imine A and
enamine B, as well as the first ligand exchange of Pd(OAc)2
with A or B. As presented in Figure 2, the ligand exchange of
Pd(OAc)2 with A decreases the free energy of the system by 3.0
kcal/mol, and is also an exothermic process (ΔH = -15.5
kcal/mol), which contributes to the positive shift of the conden-
sation equilibrium. In the resulted complex APd, palladium is
coordinated to A through the lone pair electrons of the nitrogen
atom and stabilized probably by the conjugative effect of π-
electrons from the imine double bond. In contrast, the ligand
exchange of Pd(OAc)2 with B demands a free energy cost of 3.6
kcal/mol. Forming the enamine-Pd species BPd from A via the
intramolecular tautomerization of APd requires an activation
energy of 18.9 kcal/mol, while the AcOH-aided tautomerization
of A to B needs to overcome a much higher free energy barrier
of 27.0 kcal/mol. Therefore, the formation of an enamine spe-
cies B through tautomerization is not necessary for the genera-
tion of BPd. The first ligand exchange is likely to happen di-
rectly with the in situ formed imine A and then offer BPd
through intramolecular tautomerization. It is worth noting that
although in the tautomerization of APd to BPd the α-methyl-H
is extracted by an oxygen atom of acetate ligand (AcO-), the
proton is bonded more tightly to amino nitrogen atom (1.05 Å)
Although the proposed mechanism is consistent with the avail-
able experimental evidences, there are still several issues to be
unraveled: 1) Is it imine A or enamine B that is metallized dur-
ing the first carbopalladation? 2) Why DMSO and AcOH are
critical for this single-step transformation and does any of them
serve as a ligand in the reaction? 3) Which pathway, the
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the early condensation (31.6 kcal/mol vs 31.7 kcal/mol relative
than to the oxygen atom of AcO- (1.68 Å, more like a hydrogen
bond) in the resting state of the produced BPd.
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to 1a + 2a), pathway b could not be locally ruled out.
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Figure 2. Comparison of the energy profiles of the pathway
from A to the enamine-Pd species BPd by tautomerization be-
fore ligand exchange (dark green) or after ligand exchange
(black). Hydrogens besides the extracted α-methyl-H (green)
are omitted for clarity in the 3D structure of BPd with key dis-
tances (Å) presented.
For the first carbopalladation (Figure 3), a η3-NCCH2-
coordinated Pd species B2C has been located in the route of
transformation from the enamine-Pd species BPd to the α-me-
thyl carbopalladation product Ca, which suggested a [1,3]-im-
migration approach for the carbopalladation of the ketone α-Me.
The formation of B2C crosses a barrier of 12.3 kcal/mol
(tsBPd), while the conversion from the η3-mode B2C to the sp3
C-bonded Pd species Ca is a facile and exergonic process (ΔH
= -3.2 kcal/mol). There is a relatively week vinyl-Pd coordina-
tion in the transition state tsBPd, which leads to the η3-mode
coordination in B2C (the lengths of two newly formed Pd-C
bonds are 2.20 Å and 2.10 Å). The single coordination of the
oxygen atom in AcOH to Pd is nearly disappeared in B2C (the
distance of Pd…O is 2.92 Å), and the oxygen atom is stabilized
by an α-methyl-H through a newly formed hydrogen bond (2.42
Å). Nonetheless, along with the formation of Ca, such a single
coordination is recovered (the distance of Pd…O is 2.13 Å).
Meanwhile, the N atom and carbonyl C atom disengage from
the coordination to Pd to reform the imine double bond (1.29 Å,
shortened from 1.44 Å in BPd).
Figure 3. Energy profile of the immigration transformation of
enamine-Pd species BPd, and the two possible pathways lead
to the final α-methyl carbopalladation products, Cd1 (dark) and
Ced1 (red). Except for those involved in hydrogen bonds, hy-
drogens are omitted for clarity in the 3D structures with key
distances (Å) presented.
According to the experimental studies above, the calculation of
CMD process was then conducted for both imine (pathway a)
and enamine pathway (pathway b) (Figure 4).58 A key interme-
diate with an agostic interaction (Cdn or Cedn) prior to the for-
mation of new aryl C-Pd bond has been located during the CMD
process.59,60 Interestingly, the agostic intermediates in the two
pathways not only originate from two individual C-Pd species
sharing the same level of free energy (Cd1 and Ced1), but also
take the same level of activation energy (ΔG‡ = 7.0 kcal/mol).
In their geometries, a new coordinative interaction between the
ortho-carbon and Pd emerges (2.37 Å in Cdn, 2.34 Å in Cedn)
and displaces one arm of the η2-AcO-. For the imine Cdn, the
distanced oxygen atom of AcO- is immobilized by the ortho-H
through hydrogen bonding (2.26 Å), setting up ideally a favor-
able six-membered cycle for the H-extraction followed.
Whereas, in enamine Cedn, it is the meta-H that is donated to
the distanced oxygen atom of the AcO- (2.32 Å), while the or-
tho-H keeps apart from the oxygen (3.17 Å). This more
stretched conformation may contribute in part to its lower free
energy (2.0 kcal/mol lower than its imine isomer), but will also
leave a higher energy barrier to conquer for the completion of
the ortho-H-transfer (4.0 kcal/mol higher than its imine isomer).
The formation of the agostic intermediates gives a strong mech-
anistic support for the meta-steric effect manifested in the scope
investigation (vide ante), as the presence of meta-substituents
will impede effective agostic interaction or at least decrease
Notably, the hydrogen bond between AcOH and N atom seems
rather essential for the stability of Ca, as its absence leads to the
formation of a U-shaped stationary conformation (C1) with a
significant increase in free energy (8.1 kcal/mol). Intriguingly,
if AcOH is replaced by DMSO to coordinate with Pd via the
intermediate Cad (ΔG = 10.4 kcal/mol), another much more
stable U-shaped stationary point Cd1 will be located (ΔΔG = -
5.7 kcal/mol). This result evidently provides an explanation for
the overwhelming superiority of DMSO in the solvent screen-
ing experiments (vide ante). By forming intermediate Cad, an-
other possibility has also been considered. It goes through
AcOH-assisted imine-enamine tautomerization (ΔG‡ = 17.1
kcal/mol) to yield an enamine-type sp2 C-Pd species Ced1
(pathway b). The U-shaped conformation of Ced1 possesses a
stationary energy comparable to its imine isomer Cd1. Given
the free energy cost of this process is extremely close to that of
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their stability. Moreover, for the double meta-substituted sub- decrease in free energy and enthalpy for the enamine process is
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strates (e.g. 1β in Table 2), only pathway a that forms ortho-
sited hydrogen bond in its agostic intermediate seems to be ac-
ceptable.
8.7 kcal/mol and 8.6 kcal/mol greater than those for the imine
process. Therefore, the enamine pathway is both kinetically and
thermodynamically favored. After the release of a zero-valent
[Pd(DMSO)2], pathway b directly gives the final indole product
(3aa). However, pathway a still needs to go through an AcOH-
assisted proton transfer of 3H-indole E, which requires 23.1
kcal/mol more free energy to complete (Figure S14 in SI). Path-
way b is thereby absolutely preferred for the stage of reductive
elimination. In addition, the regeneration of Pd(OAc)2 catalyst
by molecular dioxygen might involve the formation of multinu-
clear Pd-O intermediate and the disproportionation of hydrogen
peroxide.61 The presence of AcOH in the catalytic system may
also benefit the regeneration of Pd(OAc)2, given that the basic
effect of acetate in the amphiphilic catalyst is essential for the
dehydrogenation in CMD process.
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Figure 4. Comparison of the energy profiles of the pathway a
(dark, for imines) and pathway b (red, for enamines) for CMD
process. Nonparticipating hydrogens are partly omitted for clar-
ity in the 3D structures with key distances (Å) presented.
The single-coordinate AcOH in the newly formed six-mem-
bered cyclopalladation product is subsequently replaced by the
solvent molecule DMSO. This ligand exchange is a facile exer-
gonic process that decreases the free energy (2.2 kcal/mol for
pathway a, 3.5 kcal/mol for pathway b) of the system. Again, it
suggests a significant role of DMSO in stabilizing intermediates
during the reaction. For this reaction stage, pathway a is kinet-
ically more advantaged than pathway b (ΔΔG‡ = 2.0 kcal/mol).
On the other hand, regarding to the final 2DMSO-coordinate
palladacycle intermediates, the vinyl-Pd species Ded in pathway
b appears much more thermodynamically stable than its coun-
terpart Dd in pathway a (ΔΔG = 6.6 kcal/mol).
Figure 5. Comparison of the energy profiles of the pathway a
(dark, for imines) and pathway b (red, for enamines) for reduc-
tive elimination process. Hydrogens are partly omitted for clar-
ity in the 3D structures with key distances (Å) presented.
In respect to the whole energy profile of the two pathways (Fig-
ure S15 in SI), the rate-determining step is the starting step of
condensation, which provides the imine intermediate A and re-
quires the largest free energy increase of 31.7 kcal/mol. The
later steps decrease the free energy of the system by 29.5
kcal/mol (from A to 3aa), and thereby drive the rate-determin-
ing equilibrium shift forward constantly. These later steps of the
two pathways were compared, and the utmost free energy in-
creases for pathway a and pathway b are 28.8 kcal/mol (Figure
5) and 31.6 kcal/mol (Figure 3), respectively. Therefore, the
imine pathway is energetically favored and is expected to be the
predominant mechanism for this reaction. Nonetheless, given
that the largest free energy increase in the later steps of pathway
b is 0.1 kcal/mol smaller than that in the rate-determining step,
those enamine intermediates, though energetically unfavored,
may still be a minor mechanistic pathway for the reaction.
For the reductive elimination, a transition state demanding the
highest activation energy (tsDdEm, ΔG‡ = 24.1 kcal/mol) has
been located in pathway a (Figure 5). The product of reductive
elimination is observed to be a metal coordinate (Em or Pm).
In the imine Em, Pd(0) is tethered by the benzene ring in η2-
mode, coordinating to the functionalized ortho-carbon (2.26 Å)
and the adjacent meta-carbon (2.15 Å). In the amine Pm, con-
trastively, Pd(0) is arrested by the newly formed pyrrole ring in
η2-mode, coordinating to the two vinyl carbons (2.23 Å and 2.22
Å respectively). One of the two DMSO molecules is then de-
tached from the Pd center (the distance of O…Pd is 4.42 Å),
which is also different from the situation in Em. The energy
barrier of reductive elimination for the enamine isomer is 7.5
kcal/mol lower than that for the imine isomer. In addition, the
3. Conclusion
A carboxylic acid promoted Pd-catalytic system for indole syn-
thesis directly from anilines and ketones has been developed.
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visualized under UV and via potassium permanganate or iodine
steam staining.
For the first time, a large scope of indoles was prepared from
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8
simple anilines by a single-step aerobic reaction. Unlike previ-
ous CDC methods, the current system does not require aryl
imines/enamine substrates stable enough for isolation, which
further enriches the diversity of indoles constructed by the CDC
strategy. Such a transformation is featured by fine atom-econ-
omy, broad substrate applicability and high compatibility with
various functional groups. The presence of the labile hydrogen
at C3 and the highly transformable carbonyl group at C2 makes
the produced indoles versatile building blocks for organic syn-
thesis. Meanwhile, the relatively cheap reagents and the ambi-
ent pressure of gas oxygen make the protocol convenient and
economical for both laboratory and industry application.62
All catalysts were purchased in high quality and all commercially
obtained reactants and reagents were used as received. Anhydrous
solvents were distilled in small scale with CaH2 and stored under
Argon or purchased from J&K Chemical without further purifica-
tion. 4Å MS is received as a white powder and used after activated
under 400 oC for 4h. Reactions were carried in Schlenk tube under
given conditions with a magnetic stirrer. Unless otherwise stated,
yields were calculated based on the quantity of anilines (starting
material).
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2. Experimental Procedures and Characterization Data of
Products.
Mechanistic studies have offered plenteous interesting insights
into the reaction. The condensation of the substrates is esti-
mated to be the rate-determining step of the reaction and the
addition of carboxylic acid (AcOH) favors the formation of
imine kinetically, which promotes the single-step construction
of indoles. Different from the initially proposed mechanism
based on literature, the first ligand exchange of the catalyst is
believed to involve the in situ formed imine, and the carbopal-
ladation of the α-Me proceeds via a [1,3]-sigmatropic rear-
rangement, rather than an electronic approach with its enamine
isomer. In addition to its role as solvent, DMSO serves as a lig-
and to replace η1-AcOH and decreases free energy of the system.
The pathway via imine-type sp3 C-Pd intermediates is observed
to be the preferred mechanism. The ortho-C-H bond activation
has been illustrated to be a CMD process both experimentally
and computationally. However, this step actually proceeds
much more facilely than the reductive elimination. Furthermore,
the located agostic intermediate in CMD process is deemed to
be responsible for the meta-steric effect.
a. Indole Syntheses for Scope Investigation
Ethyl 5-methoxy-1H-indole-2-carboxylate (3aa).63 Typical proce-
dure: 1a (49.2 mg, 0.4 mmol), Pd(OAc)2 (9.0 mg, 0.04 mmol) and
4Å MS (80 mg) were added to a 25 mL schlenk tube equipped with
a magnetic stirrer bar. After air-evacuation and refilled with O2 for
three times or more, 2a (92.8 mg, 0.8 mmol), AcOH (96.0 mg, 1.6
mmol) and DMSO (2.0 mL) were added via syringe. The mixture
was stirred at 70 °C for 18 h. Upon cooling to room temperature,
the reaction mixture was diluted with 10 mL of ethyl acetate and
filtered through a pad of celite using 5 mL of ethyl acetate as addi-
tional eluent. The filtrate was washed with NaCl aqueous solution
(3 x 10 mL), dried over Na2SO4, filtered, and evaporated under re-
duced pressure. The residue was purified through Flash Column
Chromatography on silica gel (eluent: petroleum ether/ethyl acetate
1
= 30:1) to afford 3aa (75.3 mg, 86% yield). 3aa: White solid; H
NMR (400 MHz, Chloroform-d) δ: 9.05 (brs, 1H), 7.31 (d, J = 8.9,
1H), 7.16 – 7.13 (m, 1H), 7.07 (d, J = 2.4, 1H), 6.99 (dd, J = 8.9,
2.4, 1H), 4.41 (q, J = 7.1, 2H), 3.85 (s, 3H), 1.41 (t, J = 7.1, 3H);
13C{1H} NMR (101 MHz, Chloroform-d) δ: 162.2, 154.8, 132.4,
128.0, 128.0, 117.1, 112.9, 108.3, 102.7, 61.1, 55.8, 14.5; LCMS
(ESI, positive): 220.1 [M+H]+.
In summary, the CDC single-step synthesis of indoles devel-
oped herein provides versatile prototype indole cores and sig-
nificantly expands the molecular diversity of indole derivatives
accessible by currently available methods. Computational clues
highlight a preferred mechanistic pathway via imine intermedi-
ates. The results obtained so far broaden both the applicability
of and mechanistic insights on indole synthesis via CDC strat-
egy.
Ethyl 7-methoxy-1H-indole-2-carboxylate (3ba).64 The reaction of
1b (49.2 mg, 0.4 mmol), 2a (92.8 mg, 0.8 mmol), Pd(OAc)2 (9.0
mg, 0.04 mmol), AcOH (96.0 mg, 1.6 mmol) and 4Å MS (80 mg)
in DMSO (2.0 mL), at 70 ºC, under O2 (1 atm), 18 h, afforded prod-
uct 3ba (74.0 mg, 85% yield, eluent: petroleum ether/ethyl acetate
= 30:1). 3ba: light brown solid; 1H NMR (400 MHz, Chloroform-
d) δ: 9.17 (brs, 1H), 7.26 (d, J = 8.1, 1H), 7.19 (d, J = 2.2, 1H),
7.04 (t, J = 7.9, 1H), 6.69 (d, J = 7.6, 1H), 4.39 (q, J = 7.1, 2H),
3.93 (s, 3H), 1.39 (t, J = 7.1, 3H); 13C{1H} NMR (101 MHz, Chlo-
roform-d) δ: 161.9, 146.6, 128.7, 128.2, 127.3, 121.2, 114.9, 108.9,
104.2, 61.0, 55.5, 14.5; LCMS (ESI, positive): 220.1 [M+H]+.
EXPERIMENTAL SECTION
1. General Information.
Flash Column Chromatography (FCC) was applied to obtain all re-
action yields (unless otherwise noted) and was performed on silica
gel 300-400 mesh. NMR spectra were recorded on a JEOL ECZ-
400S (400 MHz) or a Bruker AVANCEIII-400 (400 MHz) spec-
trometer. 1H-NMR Chemical shifts (δ) were reported in units parts
per million (ppm) referring to TMS (trimethyl silane) signal by as-
signing its resonance as 0.00 ppm in chloroform-d or referring to
resonance of DMSO as 2.50 ppm in DMSO-d6. All 13C{1H}-NMR
Chemical shifts were reported in units ppm by assigning resonance
of CHCl3 as 77.16 ppm in chloroform-d or that of DMSO as 39.52
ppm in DMSO-d6. Multiplicities were indicated as s (singlet), d
(doublet), t (triplet), q (quartet), p (quintet/pentet), m (multiplet),
and br (broad). All coupling constants (J) were reported in Hertz
(Hz). Molecular mass were measured on a Thermo-Exactive Plus
liquid chromatograph-mass spectrometer (LCMS) in positive ion
mode (ESI) and high-resolution mass spectra (HRMS) were rec-
orded for new compounds. Thin Layer Chromatograms (TLC) was
Ethyl 5-(tert-butyl)-1H-indole-2-carboxylate (3ca).65 The reaction
of 1c (59.7 mg, 0.4 mmol), 2a (92.8 mg, 0.8 mmol), Pd(OAc)2 (9.0
mg, 0.04 mmol), AcOH (96.0 mg, 1.6 mmol) and 4Å MS (80 mg)
in DMSO (2.0 mL), at 70 ºC, under O2 (1 atm), 18 h, afforded prod-
uct 3ca (74.2 mg, 76% yield, eluent: petroleum ether/ethyl acetate
1
= 50:1). 3ca: white solid; H NMR (400 MHz, Chloroform-d) δ:
9.22 (brs, 1H), 7.67 – 7.63 (m, 1H), 7.41 (dd, J = 8.8, 1.8, 1H), 7.35
(dt, J = 8.8, 0.8, 1H), 7.19 (dd, J = 2.1, 0.9, 1H), 4.41 (q, J = 7.1,
2H), 1.41 (t, J = 7.1, 3H), 1.37 (s, 9H); 13C{1H} NMR (101 MHz,
Chloroform-d) δ: 162.4, 143.7, 135.4, 127.6, 127.5, 124.2, 118.0,
111.6, 108.9, 61.1, 34.7, 31.8, 14.5; LCMS (ESI, positive): 246.2
[M+H]+.
Ethyl 5-methyl-1H-indole-2-carboxylate (3da).66 The reaction of
1d (42.8 mg, 0.4 mmol), 2a (92.8 mg, 0.8 mmol), Pd(OAc)2 (9.0
mg, 0.04 mmol), AcOH (96.0 mg, 1.6 mmol) and 4Å MS (80 mg)
in DMSO (2.0 mL), at 70 ºC, under O2 (1 atm), 18 h, afforded prod-
uct 3da (63.3 mg, 78% yield, eluent: petroleum ether/ethyl acetate
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1
= 40:1). 3da: white solid; H NMR (400 MHz, Chloroform-d) δ:
9.05 (brs, 1H), 7.47 – 7.43 (m, 1H), 7.31 (d, J = 8.4, 1H), 7.17 –
7.11 (m, 2H), 4.41 (q, J = 7.1, 2H), 2.43 (s, 3H), 1.41 (t, J = 7.1,
3H); 13C{1H} NMR (101 MHz, Chloroform-d) δ: 162.3, 135.5,
130.2, 127.9, 127.6, 127.4, 121.9, 111.7, 108.3, 61.1, 21.5, 14.5;
LCMS (ESI, positive): 204.1 [M+H]+.
124.5, 119.7, 112.3, 107.7, 63.5, 60.4, 14.4; LCMS (ESI, positive):
1
2
3
4
5
6
7
8
220.1 [M+H]+.
Ethyl 5-phenyl-1H-indole-2-carboxylate (3ka).66 The reaction of
1k (67.7 mg, 0.4 mmol), 2a (92.8 mg, 0.8 mmol), Pd(OAc)2 (9.0
mg, 0.04 mmol), AcOH (96.0 mg, 1.6 mmol) and 4Å MS (80 mg)
in DMSO (2.0 mL), at 70 ºC, under O2 (1 atm), 18 h, afforded prod-
uct 3ka (40.3 mg, 38% yield, eluent: petroleum ether/ethyl acetate
= 40:1). 3ka: yellow solid; 1H NMR (400 MHz, Chloroform-d) δ:
9.05 (brs, 1H), 7.90 – 7.87 (m, 1H), 7.66 – 7.61 (m, 2H), 7.58 (dd,
J = 8.6, 1.7, 1H), 7.50 – 7.42 (m, 3H), 7.35 – 7.30 (m, 1H), 7.27
(dd, J = 2.1, 0.9, 1H), 4.43 (q, J = 7.1, 2H), 1.43 (t, J = 7.1, 3H);
13C{1H} NMR (101 MHz, Chloroform-d) δ: 162.1, 142.0, 136.4,
134.5, 128.9, 128.3, 128.2, 127.5, 126.8, 125.5, 121.0, 112.3, 109.1,
61.3, 14.6; LCMS (ESI, positive): 266.1 [M+H]+.
Ethyl 5-cyclohexyl-1H-indole-2-carboxylate (3ea). The reaction of
1e (70.1 mg, 0.4 mmol), 2a (92.8 mg, 0.8 mmol), Pd(OAc)2 (9.0
mg, 0.04 mmol), AcOH (96.0 mg, 1.6 mmol) and 4Å MS (80 mg)
in DMSO (2.0 mL), at 70 ºC, under O2 (1 atm), 18 h, afforded prod-
uct 3ea (81.4 mg, 75% yield, eluent: petroleum ether/ethyl acetate
9
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13
14
15
16
17
18
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20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
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46
47
48
49
50
51
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53
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= 50:1). 3ea: white solid; mp 143-144 ºC; H NMR (400 MHz,
Chloroform-d) δ: 9.00 (brs, 1H), 7.50 – 7.47 (m, 1H), 7.33 (d, J =
8.5, 1H), 7.20 (dd, J = 8.6, 1.6, 1H), 7.17 (dd, J = 2.1, 0.9, 1H),
4.41 (q, J = 7.1, 2H), 2.57 (td, J = 11.5, 3.3, 1H), 1.89 (dd, J = 26.8,
11.9, 4H), 1.76 (d, J = 13.8, 1H), 1.52 – 1.36 (m, 7H), 1.33 – 1.21
(m, 1H); 13C{1H} NMR (101 MHz, Chloroform-d) δ: 162.3, 140.9,
135.7, 127.8, 127.6, 125.6, 119.6, 111.7, 108.6, 61.1, 44.7, 35.1,
27.2, 26.4, 14.5; HRMS (ESI, positive): m/z calculated for
C17H22NO2 ([M+H]+) 272.1645, found: 272.1646.
Ethyl 5-phenoxy-1H-indole-2-carboxylate (3la). The reaction of 1l
(74.1 mg, 0.4 mmol), 2a (92.8 mg, 0.8 mmol), Pd(OAc)2 (9.0 mg,
0.04 mmol), AcOH (96.0 mg, 1.6 mmol) and 4Å MS (80 mg) in
DMSO (2.0 mL), at 70 ºC, under O2 (1 atm), 18 h, afforded product
3la (63.0 mg, 56% yield, eluent: petroleum ether/ethyl acetate =
40:1). 3la: light yellow solid; mp 137-139 ºC; 1H NMR (400 MHz,
Chloroform-d) δ: 9.24 (brs, 1H), 7.40 (d, J = 8.9, 1H), 7.34 – 7.26
(m, 3H), 7.16 (dd, J = 2.1, 0.9, 1H), 7.09 (dd, J = 8.9, 2.3, 1H),
7.07 – 7.02 (m, 1H), 7.00 – 6.95 (m, 2H), 4.42 (q, J = 7.1, 2H),
1.42 (t, J = 7.1, 3H); 13C{1H} NMR (101 MHz, Chloroform-d) δ:
162.2, 158.9, 151.0, 134.0, 129.7, 128.7, 128.2, 122.5, 119.6, 117.8,
113.1, 112.1, 108.6, 61.3, 14.5; HRMS (ESI, positive): m/z calcu-
lated for C17H16NO3 ([M+H]+) 282.1125, found: 282.1116.
Ethyl 1H-indole-2-carboxylate (3fa).67 The reaction of 1f (37.2 mg,
0.4 mmol), 2a (92.8 mg, 0.8 mmol), Pd(OAc)2 (9.0 mg, 0.04 mmol),
AcOH (96.0 mg, 1.6 mmol) and 4Å MS (80 mg) in DMSO (2.0
mL), at 70 ºC, under O2 (1 atm), 18 h, afforded product 3fa (53.7
mg, 71% yield, eluent: petroleum ether/ethyl acetate = 30:1). 3fa:
white solid; 1H NMR (400 MHz, Chloroform-d) δ: 8.92 (brs, 1H),
7.69 (d, J = 8.2, 1H), 7.42 (d, J = 8.2, 1H), 7.32 (t, J = 7.7, 1H),
7.25 – 7.21 (m, 1H), 7.15 (t, J = 7.6, 1H), 4.42 (q, J = 7.1, 2H),
1.42 (t, J = 7.1, 3H); 13C{1H} NMR (101 MHz, Chloroform-d) δ:
162.4, 137.1, 127.6, 125.4, 122.7, 120.9, 112.1, 112.0, 108.8, 61.2,
14.5; LCMS (ESI, positive): 190.1 [M+H]+.
Ethyl 5-(methylsulfonamido)-1H-indole-2-carboxylate (3ma). The
reaction of 1m (74.5 mg, 0.4 mmol), 2a (92.8 mg, 0.8 mmol),
Pd(OAc)2 (9.0 mg, 0.04 mmol), AcOH (96.0 mg, 1.6 mmol) and
4Å MS (80 mg) in DMSO (2.0 mL), at 70 ºC, under O2 (1 atm), 18
h, afforded product 3ma (73.3 mg, 65% yield, eluent: petroleum
ether/ethyl acetate = 3:1). 3ma: light yellow solid; mp 171-172 ºC;
1H NMR (400 MHz, DMSO-d6) δ: 11.93 (s, 1H), 9.44 (s, 1H), 7.52
(d, J = 1.8, 1H), 7.42 (d, J = 8.8, 1H), 7.18 (dd, J = 8.8, 2.0, 1H),
7.14 (d, J = 1.4, 1H), 4.33 (q, J = 7.1, 2H), 2.89 (s, 3H), 1.33 (t, J
= 7.1, 3H); 13C{1H} NMR (101 MHz, DMSO-d6) δ: 161.2, 135.2,
131.0, 128.3, 127.0, 121.1, 114.7, 113.3, 107.7, 60.6, 38.5, 14.4;
HRMS (ESI, positive): m/z calculated for C12H15N2O4S ([M+H]+)
283.0747, found: 283.0741.
Ethyl 1H-benzo[g]indole-2-carboxylate (3ga).68 The reaction of 1g
(57.3 mg, 0.4 mmol), 2a (92.8 mg, 0.8 mmol), Pd(OAc)2 (9.0 mg,
0.04 mmol), AcOH (96.0 mg, 1.6 mmol) and 4Å MS (80 mg) in
DMSO (2.0 mL), at 70 ºC, under O2 (1 atm), 24 h, afforded product
3ga (78.6 mg, 82% yield, eluent: petroleum ether/ethyl acetate =
30:1). 3ga: off-white solid; 1H NMR (400 MHz, Chloroform-d) δ:
10.33 (brs, 1H), 8.29 (d, J = 7.5, 1H), 7.90 (d, J = 7.5, 1H), 7.66
(d, J = 8.7, 1H), 7.56 – 7.46 (m, 3H), 7.34 (d, J = 2.1, 1H), 4.50 (q,
J = 7.1, 2H), 1.46 (t, J = 7.1, 3H); 13C{1H} NMR (101 MHz, Chlo-
roform-d) δ: 162.5, 133.2, 132.1, 129.0, 126.0, 125.9, 125.7, 123.9,
122.2, 122.1, 121.4, 120.9, 110.4, 61.3, 14.6; LCMS (ESI, positive):
240.1 [M+H]+.
Ethyl 1,6-dihydropyrrolo[2,3-e]indole-2-carboxylate (3na). The
reaction of 1n (52.8 mg, 0.4 mmol), 2a (92.8 mg, 0.8 mmol),
Pd(OAc)2 (9.0 mg, 0.04 mmol), AcOH (96.0 mg, 1.6 mmol) and
4Å MS (80 mg) in DMSO (2.0 mL), at 70 ºC, under O2 (1 atm), 18
h, afforded product 3na (13.7 mg, 15% yield, eluent: petroleum
ether/ethyl acetate = 5:1). 3na: brown solid; mp 173-174 ºC; 1H
NMR (400 MHz, Chloroform-d) δ: 9.29 (brs, 1H), 8.46 (brs, 1H),
7.44 (d, J = 8.7, 1H), 7.33 (d, J = 2.1, 1H), 7.23 (d, J = 8.7, 1H),
7.21 – 7.18 (m, 1H), 6.77 – 6.73 (m, 1H), 4.43 (q, J = 7.1, 2H),
1.43 (t, J = 7.1, 3H); 13C{1H} NMR (101 MHz, Chloroform-d) δ:
162.4, 134.4, 131.1, 124.5, 122.3, 121.1, 117.1, 113.0, 110.6, 107.4,
99.8, 60.8, 14.7; HRMS (ESI, positive): m/z calculated for
C13H13N2O2 ([M+H]+) 229.0972, found: 229.0971.
Ethyl 5-hydroxy-1H-indole-2-carboxylate (3ia).69 The reaction of
1i (43.6 mg, 0.4 mmol), 2a (92.8 mg, 0.8 mmol), Pd(OAc)2 (9.0 mg,
0.04 mmol), AcOH (96.0 mg, 1.6 mmol) and 4Å MS (80 mg) in
DMSO (2.0 mL), at 70 ºC, under O2 (1 atm), 18 h, afforded product
3ia (28.1 mg, 34% yield, eluent: petroleum ether/ethyl acetate =
10:1). 3ia: light brown solid;1H NMR (400 MHz, Chloroform-d) δ:
8.86 (brs, 1H), 7.29 (d, J = 8.8, 1H), 7.13 – 7.08 (m, 1H), 7.06 (d,
J = 2.2, 1H), 6.93 (dd, J = 8.8, 2.4, 1H), 4.82 (brs, 1H), 4.40 (q, J
= 7.1, 2H), 1.41 (t, J = 7.1, 3H); 13C{1H} NMR (101 MHz, Chlo-
roform-d) δ: 162.2, 150.3, 132.5, 128.4, 128.3, 116.3, 112.9, 108.0,
106.1, 61.2, 14.5; LCMS (ESI, positive): 206.1 [M+H]+.
Ethyl 5-fluoro-1H-indole-2-carboxylate (3oa).64 The reaction of 1o
(44.4 mg, 0.4 mmol), 2a (92.8 mg, 0.8 mmol), Pd(OAc)2 (9.0 mg,
0.04 mmol), AcOH (96.0 mg, 1.6 mmol) and 4Å MS (80 mg) in
DMSO (2.0 mL), at 70 ºC, under O2 (1 atm), 18 h, afforded product
3oa (48.0 mg, 58% yield, eluent: petroleum ether/ethyl acetate =
40:1). 3oa: white solid; 1H NMR (400 MHz, Chloroform-d) δ: 9.24
(brs, 1H), 7.36 (dd, J = 8.9, 4.4, 1H), 7.31 (dd, J = 9.2, 2.5, 1H),
7.18 (dd, J = 2.1, 0.7, 1H), 7.08 (td, J = 9.1, 2.5, 1H), 4.43 (q, J =
7.1, 2H), 1.42 (t, J = 7.1, 3H); 13C{1H} NMR (101 MHz, Chloro-
form-d) δ: 162.1, 158.3 (d, J = 236.6), 133.7, 129.1, 127.8 (d, J =
10.4), 114.6 (d, J = 27.0), 113.0 (d, J = 9.5), 108.6 (d, J = 5.4),
Ethyl 5-(hydroxymethyl)-1H-indole-2-carboxylate (3ja).70 The re-
action of 1j (49.2 mg, 0.4 mmol), 2a (92.8 mg, 0.8 mmol),
Pd(OAc)2 (9.0 mg, 0.04 mmol), AcOH (96.0 mg, 1.6 mmol) and
4Å MS (80 mg) in DMSO (2.0 mL), at 70 ºC, under O2 (1 atm), 18
h, afforded product 3ja (55.4 mg, 63% yield, eluent: petroleum
ether/ethyl acetate = 4:1). 3ja: light yellow solid; 1H NMR (400
MHz, DMSO-d6) δ: 11.81 (brs, 1H), 7.58 (s, 1H), 7.41 (d, J = 8.5,
1H), 7.24 (d, J = 8.4, 1H), 7.12 (s, 1H), 5.10 (t, J = 5.6, 1H), 4.55
(d, J = 5.5, 2H), 4.34 (q, J = 7.0, 2H), 1.34 (t, J = 7.0, 3H); 13C{1H}
NMR (101 MHz, DMSO-d6) δ: 161.4, 136.7, 134.4, 127.5, 126.6,
ACS Paragon Plus Environment

Page 11 of 19
The Journal of Organic Chemistry
106.9 (d, J = 23.3), 61.4, 14.5; LCMS (ESI, positive): 208.1
DMSO (2.0 mL), at 70 ºC, under O2 (1 atm), 24 h, afforded product
1
2
3
4
5
6
7
8
[M+H]+.
3ua (35.4 mg, 34% yield, eluent: petroleum ether/ethyl acetate =
20:1). 3ua: light yellow solid; mp 140-142 ºC; 1H NMR (400 MHz,
Chloroform-d) δ: 9.44 (brs, 1H), 8.49 – 8.46 (m, 1H), 8.02 (dd, J =
8.7, 1.6, 1H), 7.45 (dt, J = 8.7, 0.8, 1H), 7.31 (dd, J = 2.1, 0.9, 1H),
4.44 (q, J = 7.1, 2H), 4.41 (q, J = 7.1, 2H), 1.43 (t, J = 7.1, 3H),
1.42 (t, J = 7.1, 3H); 13C{1H} NMR (101 MHz, Chloroform-d) δ:
167.3, 161.9, 139.3, 129.1, 127.1, 126.4, 125.8, 123.5, 111.8, 109.9,
61.5, 60.9, 14.6, 14.5; HRMS (ESI, positive): m/z calculated for
C14H16NO4 ([M+H]+) 262.1074, found: 262.1072.
Ethyl 7-fluoro-1H-indole-2-carboxylate (3pa). The reaction of 1p
(44.4 mg, 0.4 mmol), 2a (92.8 mg, 0.8 mmol), Pd(OAc)2 (9.0 mg,
0.04 mmol), AcOH (96.0 mg, 1.6 mmol) and 4Å MS (80 mg) in
DMSO (2.0 mL), at 70 ºC, under O2 (1 atm), 18 h, afforded product
3pa (24.0 mg, 29% yield, eluent: petroleum ether/ethyl acetate =
50:1). 3pa: white solid; mp 136-137 ºC; 1H NMR (400 MHz, Chlo-
roform-d) δ: 9.34 (brs, 1H), 7.44 (d, J = 8.0, 1H), 7.27 – 7.22 (m,
1H), 7.09 – 6.97 (m, 2H), 4.44 (q, J = 7.1, 2H), 1.43 (t, J = 7.1,
3H); 13C{1H} NMR (101 MHz, Chloroform-d) δ: 161.8, 149.8 (d,
J = 245.9), 131.0 (d, J = 4.8), 128.6 (d, J = 1.3), 125.9 (d, J = 13.8),
121.0 (d, J = 5.8), 118.4 (d, J = 4.0), 109.7 (d, J = 15.7), 109.1 (d,
J = 2.6), 61.5, 14.5; HRMS (ESI, positive): m/z calculated for
C11H11NO2F ([M+H]+) 208.0768, found: 208.0759.
9
Ethyl 5-cyano-1H-indole-2-carboxylate (3va).74 The reaction of 1v
(47.2 mg, 0.4 mmol), 2a (139.2 mg, 1.2 mmol), Pd(OAc)2 (9.0 mg,
0.04 mmol), AcOH (96.0 mg, 1.6 mmol) and 4Å MS (80 mg) in
DMSO (2.0 mL), at 70 ºC, under O2 (1 atm), 3 d, afforded product
3va (18.8 mg, 22% yield, eluent: petroleum ether/ethyl acetate =
10:1). 3va: light yellow solid; 1H NMR (400 MHz, Chloroform-d)
δ: 9.27 (brs, 1H), 8.10 – 8.05 (m, 1H), 7.56 – 7.49 (m, 2H), 7.28 (d,
J = 2.0, 1H), 4.45 (q, J = 7.1, 2H), 1.44 (t, J = 7.1, 3H); 13C{1H}
NMR (101 MHz, Chloroform-d) δ: 161.5, 138.1, 129.9, 128.7,
127.7, 127.3, 120.1, 113.1, 109.0, 104.5, 61.8, 14.5; LCMS (ESI,
positive): 215.1 [M+H]+.
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24
25
26
27
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29
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Ethyl 5-acetyl-1H-indole-2-carboxylate (3qa).71 The reaction of 1q
(54.0 mg, 0.4 mmol), 2a (92.8 mg, 0.8 mmol), Pd(OAc)2 (9.0 mg,
0.04 mmol), AcOH (96.0 mg, 1.6 mmol) and 4Å MS (80 mg) in
DMSO (2.0 mL), at 70 ºC, under O2 (1 atm), 24 h, afforded product
3qa (23.1 mg, 25% yield, eluent: petroleum ether/ethyl acetate =
10:1). 3qa: light yellow solid; 1H NMR (400 MHz, Chloroform-d)
δ: 9.48 (brs, 1H), 8.38 – 8.35 (m, 1H), 7.99 (dd, J = 8.8, 1.7, 1H),
7.47 (d, J = 8.8, 1H), 7.33 (dd, J = 2.0, 0.9, 1H), 4.45 (q, J = 7.1,
2H), 2.67 (s, 3H), 1.44 (t, J = 7.1, 3H); 13C{1H} NMR (101 MHz,
Chloroform-d) δ: 198.0, 161.8, 139.3, 131.0, 129.3, 127.1, 125.2,
125.1, 112.1, 110.2, 61.5, 26.7, 14.5; LCMS (ESI, positive): 232.1
[M+H]+.
Ethyl 5-(trifluoromethyl)-1H-indole-2-carboxylate (3wa).63 The re-
action of 1w (64.4 mg, 0.4 mmol), 2a (139.2 mg, 1.2 mmol),
Pd(OAc)2 (9.0 mg, 0.04 mmol), AcOH (96.0 mg, 1.6 mmol) and
4Å MS (80 mg) in DMSO (2.0 mL), at 70 ºC, under O2 (1 atm), 2
d, afforded product 3wa (40.1 mg, 39% yield, eluent: petroleum
ether/ethyl acetate = 40:1). 3wa: white solid; 1H NMR (400 MHz,
Chloroform-d) δ: 9.47 (brs, 1H), 8.03 – 7.98 (m, 1H), 7.56 – 7.49
(m, 2H), 7.30 (dd, J = 2.0, 0.6, 1H), 4.46 (q, J = 7.1, 2H), 1.44 (t,
J = 7.1, 3H); 13C{1H} NMR (101 MHz, Chloroform-d) δ: 161.9,
138.1, 129.3, 126.8, 125.0 (q, J = 282.0), δ: 123.5 (q, J = 42.5),
121.9 (q, J = 3.2), 120.6 (q, J = 4.4), 112.6, 109.4, 61.6, 14.5;
LCMS (ESI, positive): 258.1 [M+H]+.
Ethyl 5-chloro-1H-indole-2-carboxylate (3ra).72 The reaction of 1r
(51.0 mg, 0.4 mmol), 2a (92.8 mg, 0.8 mmol), Pd(OAc)2 (9.0 mg,
0.04 mmol), AcOH (96.0 mg, 1.6 mmol) and 4Å MS (80 mg) in
DMSO (2.0 mL), at 70 ºC, under O2 (1 atm), 18 h, afforded product
3ra (55.4 mg, 62% yield, eluent: petroleum ether/ethyl acetate =
40:1). 3ra: white solid; 1H NMR (400 MHz, Chloroform-d) δ: 9.19
(brs, 1H), 7.66 (s, 1H), 7.35 (d, J = 8.8, 1H), 7.26 (dd, J = 8.6, 2.2,
1H), 7.15 (dd, J = 2.1, 0.9, 1H), 4.43 (q, J = 7.1, 2H), 1.42 (t, J =
7.1, 3H); 13C{1H} NMR (101 MHz, Chloroform-d) δ: 162.0, 135.2,
128.9, 128.5, 126.6, 126.0, 121.9, 113.1, 108.1, 61.4, 14.5; LCMS
(ESI, positive): 224.0 [M+H]+.
Ethyl 5-(trifluoromethoxy)-1H-indole-2-carboxylate (3xa). The re-
action of 1x (70.8 mg, 0.4 mmol), 2a (92.8 mg, 0.8 mmol),
Pd(OAc)2 (9.0 mg, 0.04 mmol), AcOH (96.0 mg, 1.6 mmol) and
4Å MS (80 mg) in DMSO (2.0 mL), at 80 ºC, under O2 (1 atm), 24
h, afforded product 3xa (65.4 mg, 60% yield, eluent: petroleum
ether/ethyl acetate = 30:1). 3xa: white solid; mp 138-140 ºC; 1H
NMR (400 MHz, Chloroform-d) δ: 9.21 (brs, 1H), 7.56 – 7.52 (m,
1H), 7.42 (dt, J = 8.9, 0.7, 1H), 7.22 (dd, J = 2.1, 0.9, 1H), 7.20
(ddd, J = 8.9, 2.3, 0.8, 1H), 4.44 (q, J = 7.1, 2H), 1.43 (t, J = 7.1,
3H); 13C{1H} NMR (101 MHz, Chloroform-d) δ: 161.9, 143.7,
135.2, 129.4, 127.6, 120.9 (q, J = 256.0), 119.7, 114.8, 112.9,
108.9, 61.5, 14.5; HRMS (ESI, positive): m/z calculated for
C12H11NO3F3 ([M+H]+) 274.0686, found: 274.0690.
Ethyl 7-chloro-1H-indole-2-carboxylate (3sa).67 The reaction of 1s
(51.0 mg, 0.4 mmol), 2a (92.8 mg, 0.8 mmol), Pd(OAc)2 (9.0 mg,
0.04 mmol), AcOH (96.0 mg, 1.6 mmol) and 4Å MS (80 mg) in
DMSO (2.0 mL), at 70 ºC, under O2 (1 atm), 18 h, afforded product
3sa (15.2 mg, 17% yield, eluent: petroleum ether/ethyl acetate =
50:1). 3sa: light yellow solid; 1H NMR (400 MHz, Chloroform-d)
δ: 9.04 (brs, 1H), 7.59 (d, J = 8.1, 1H), 7.32 (dd, J = 7.6, 0.8, 1H),
7.25 (d, J = 2.2, 1H), 7.11 – 7.06 (m, 1H), 4.43 (q, J = 7.1, 2H),
1.43 (t, J = 7.1, 3H); 13C{1H} NMR (101 MHz, Chloroform-d) δ:
161.6, 134.3, 128.9, 128.4, 124.6, 121.6, 121.3, 117.4, 109.4, 61.4,
14.5; LCMS (ESI, positive): 224.0 [M+H]+.
Ethyl 5-carbamoyl-1H-indole-2-carboxylate (3za). The reaction of
1z (54.4 mg, 0.4 mmol), 2a (92.8 mg, 0.8 mmol), Pd(OAc)2 (9.0
mg, 0.04 mmol), AcOH (96.0 mg, 1.6 mmol) and 4Å MS (80 mg)
in DMSO (2.0 mL), at 70 ºC, under O2 (1 atm), 24 h, afforded prod-
uct 3za (65.9 mg, 71% yield, eluent: petroleum ether/ethyl acetate
Ethyl 5-bromo-1H-indole-2-carboxylate (3ta).73 The reaction of 1t
(68.8 mg, 0.4 mmol), 2a (92.8 mg, 0.8 mmol), Pd(OAc)2 (9.0 mg,
0.04 mmol), AcOH (96.0 mg, 1.6 mmol) and 4Å MS (80 mg) in
DMSO (2.0 mL), at 70 ºC, under O2 (1 atm), 18 h, afforded product
3ta (49.8 mg, 47% yield, eluent: petroleum ether/ethyl acetate =
25:1). 3ta: white solid; 1H NMR (400 MHz, Chloroform-d) δ: 9.14
(brs, 1H), 7.84 – 7.81 (m, 1H), 7.39 (dd, J = 8.8, 1.9, 1H), 7.30 (d,
J = 8.8, 1H), 7.15 (dd, J = 2.1, 0.9, 1H), 4.42 (q, J = 7.1, 2H), 1.42
(t, J = 7.1, 3H); 13C{1H} NMR (101 MHz, Chloroform-d) δ: 161.9,
135.5, 129.2, 128.7, 128.4, 125.1, 114.1, 113.5, 108.0, 61.5, 14.5;
LCMS (ESI, positive): 268.0 [M+H]+.
1
= 1:1). 3za: white solid; mp 208-210 ºC; H NMR (400 MHz,
DMSO-d6) δ: 12.10 (s, 1H), 8.31 – 8.25 (m, 1H), 7.91 (s, 1H), 7.81
(dd, J = 8.7, 1.7, 1H), 7.46 (d, J = 8.7, 1H), 7.23 (dd, J = 2.1, 0.8,
1H), 7.19 (brs, 1H), 4.35 (q, J = 7.1, 2H), 1.34 (t, J = 7.1, 3H);
13C{1H} NMR (101 MHz, DMSO-d6) δ: 168.5, 161.1, 138.7, 128.6,
126.7, 126.1, 124.2, 122.4, 112.0, 108.7, 60.6, 14.3; HRMS (ESI,
positive): m/z calculated for C12H13N2O3 ([M+H]+) 233.0921,
found: 233.0914.
Ethyl 6-methoxy-1H-indole-2-carboxylate (3αa).72 The reaction of
1α (49.2 mg, 0.4 mmol), 2a (92.8 mg, 0.8 mmol), Pd(OAc)2 (9.0
mg, 0.04 mmol), AcOH (96.0 mg, 1.6 mmol) and 4Å MS (80 mg)
in DMSO (2.0 mL), at 70 ºC, under O2 (1 atm), 18 h, afforded prod-
uct 3αa (65.7 mg, 75% yield, eluent: petroleum ether/ethyl acetate
Ethyl 1H-indole-2,5-dicarboxylate (3ua). The reaction of 1u
(66.1 mg, 0.4 mmol), 2a (92.8 mg, 0.8 mmol), Pd(OAc)2 (9.0 mg,
0.04 mmol), AcOH (96.0 mg, 1.6 mmol) and 4Å MS (80 mg) in
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= 30:1). 3αa: white solid; 1H NMR (400 MHz, Chloroform-d) δ:
Chloroform-d) δ: 162.3, 136.6, 129.9, 127.4, 126.8, 125.8, 121.0,
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9.18 (brs, 1H), 7.53 (d, J = 8.5, 1H), 7.17 (s, 1H), 6.84 – 6.79 (over-
lap, 2H), 4.40 (q, J = 7.1, 2H), 3.83 (s, 3H), 1.40 (t, J = 7.1, 3H);
13C{1H} NMR (101 MHz, Chloroform-d) δ: 162.3, 158.9, 138.2,
126.5, 123.5, 122.0, 112.4, 109.1, 93.9, 60.9, 55.6, 14.6; LCMS
(ESI, positive): 220.1 [M+H]+.
118.6, 107.9, 61.1, 18.5, 16.6, 14.6; LCMS (ESI, positive): 218.1
[M+H]+.
Ethyl 6-phenyl-1H-indole-2-carboxylate (3ηa).63 The reaction of
1η (67.7 mg, 0.4 mmol), 2a (92.8 mg, 0.8 mmol), Pd(OAc)2 (9.0
mg, 0.04 mmol), AcOH (96.0 mg, 1.6 mmol) and 4Å MS (80 mg)
in DMSO (2.0 mL), at 80 ºC, under O2 (1 atm), 24 h, afforded prod-
uct 3ηa (75.3 mg, 71% yield, eluent: petroleum ether/ethyl acetate
= 30:1). 3ηa: off-white solid; 1H NMR (400 MHz, Chloroform-d)
δ: 9.22 (brs, 1H), 7.73 (d, J = 8.4, 1H), 7.62 (t, J = 8.6, 3H), 7.43
(q, J = 8.3, 7.9, 3H), 7.34 (t, J = 7.3, 1H), 7.23 (d, J = 7.9, 1H),
4.43 (q, J = 7.1, 2H), 1.42 (t, J = 7.1, 3H); 13C{1H} NMR (101
MHz, Chloroform-d) δ: 162.2, 141.8, 138.9, 137.6, 128.9, 128.1,
127.5, 127.3, 126.9, 122.9, 121.0, 110.3, 108.7, 61.3, 14.5; LCMS
(ESI, positive): 266.1 [M+H]+.
Ethyl 4,6-dimethoxy-1H-indole-2-carboxylate (3βa).66 The reac-
tion of 1β (61.2 mg, 0.4 mmol), 2a (92.8 mg, 0.8 mmol), Pd(OAc)2
(9.0 mg, 0.04 mmol), AcOH (96.0 mg, 1.6 mmol) and 4Å MS (80
mg) in DMSO (2.0 mL), at 70 ºC, under O2 (1 atm), 9 h, afforded
product 3βa (76.7 mg, 77% yield, eluent: petroleum ether/ethyl ac-
etate = 15:1). 3βa: light yellow solid; 1H NMR (400 MHz, Chloro-
form-d) δ: 9.06 (brs, 1H), 7.26 (dd, J = 2.2, 0.8, 1H), 6.43 (dd, J =
1.8, 0.8, 1H), 6.18 (d, J = 1.8, 1H), 4.38 (q, J = 7.1, 2H), 3.90 (s,
3H), 3.82 (s, 3H), 1.39 (t, J = 7.1, 3H); 13C{1H} NMR (101 MHz,
Chloroform-d) δ: 162.2, 160.3, 155.2, 138.8, 125.0, 114.0, 106.9,
92.8, 86.3, 60.8, 55.7, 55.5, 14.5; LCMS (ESI, positive): 250.1
[M+H]+.
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Ethyl 5H-[1,3]dioxolo[4,5-f]indole-6-carboxylate (3θa);
ethyl
6H-[1,3]dioxolo[4,5-e]indole-7-carboxylate (3θa). The reaction
of 1θ (54.8 mg, 0.4 mmol), 2a (92.8 mg, 0.8 mmol), Pd(OAc)2 (9.0
mg, 0.04 mmol), AcOH (96.0 mg, 1.6 mmol) and 4Å MS (80 mg)
in DMSO (2.0 mL), at 70 ºC, under O2 (1 atm), 9 h, afforded prod-
uct 3θa (41.0 mg, 44% yield) and product 3θa (36.3 mg, 39% yield)
(eluent: petroleum ether/ethyl acetate = 60:1). 3θa: white solid; 1H
NMR (400 MHz, Chloroform-d) δ: 9.17 (brs, 1H), 7.10 (s, 1H),
6.98 (s, 1H), 6.83 (s, 1H), 5.96 (s, 2H), 4.39 (q, J = 7.1, 2H), 1.40
(t, J = 7.1, 3H); 13C{1H} NMR (101 MHz, Chloroform-d) δ: 162.1,
148.0, 144.3, 133.0, 126.3, 121.8, 109.2, 101.1, 99.9, 92.0, 60.9,
14.6; HRMS (ESI, positive): m/z calculated for C12H12NO4
([M+H]+) 234.0761, found: 234.0752. 3θa: light yellow solid; 1H
NMR (400 MHz, Chloroform-d) δ: 9.07 (brs, 1H), 7.13 (s, 1H),
6.97 (d, J = 8.6, 1H), 6.90 (d, J = 8.6, 1H), 6.04 (s, 2H), 4.42 (q, J
= 7.1, 2H), 1.41 (t, J = 7.1, 3H); 13C{1H} NMR (101 MHz, Chlo-
roform-d) δ: 162.0, 140.5, 139.5, 135.1, 128.9, 113.9, 108.6, 103.8,
103.6, 101.3, 61.3, 14.5; HRMS (ESI, positive): m/z calculated for
C12H12NO4 ([M+H]+) 234.0761, found: 234.0758.
Ethyl 6-(tert-butyl)-1H-indole-2-carboxylate (3γa).68 The reaction
of 1γ (59.7 mg, 0.4 mmol), 2a (92.8 mg, 0.8 mmol), Pd(OAc)2 (9.0
mg, 0.04 mmol), AcOH (96.0 mg, 1.6 mmol) and 4Å MS (80 mg)
in DMSO (2.0 mL), at 70 ºC, under O2 (1 atm), 12 h, afforded prod-
uct 3γa (80.4 mg, 82% yield, eluent: petroleum ether/ethyl acetate
= 60:1). 3γa: white solid; 1H NMR (400 MHz, Chloroform-d) δ:
9.29 (brs, 1H), 7.60 (d, J = 8.5, 1H), 7.41 (s, 1H), 7.23 (d, J = 8.6,
1H), 7.18 (s, 1H), 4.43 (q, J = 7.1, 2H), 1.42 (t, J = 7.1, 3H), 1.37
(s, 9H); 13C{1H} NMR (101 MHz, Chloroform-d) δ: 162.5, 149.1,
137.5, 127.3, 125.3, 122.1, 119.6, 108.5, 108.0, 61.1, 35.1, 31.6,
14.5; LCMS (ESI, positive): 246.2 [M+H]+.
Ethyl 6-methyl-1H-indole-2-carboxylate (3δa).75 The reaction of
1δ (42.8 mg, 0.4 mmol), 2a (92.8 mg, 0.8 mmol), Pd(OAc)2 (9.0
mg, 0.04 mmol), AcOH (96.0 mg, 1.6 mmol) and 4Å MS (80 mg)
in DMSO (2.0 mL), at 70 ºC, under O2 (1 atm), 18 h, afforded prod-
uct 3δa (64.1 mg, 79% yield, eluent: petroleum ether/ethyl acetate
= 40:1). 3δa: light yellow solid; 1H NMR (400 MHz, Chloroform-
d) δ: 9.10 (brs, 1H), 7.56 (dd, J = 8.2, 2.7, 1H), 7.22 – 7.17 (m, 2H),
6.98 (d, J = 8.2, 1H), 4.40 (q, J = 7.2, 2H), 2.46 (s, 3H), 1.41 (t, J
= 7.1, 3H); 13C{1H} NMR (101 MHz, Chloroform-d) δ: 162.4,
137.5, 135.7, 127.0, 125.5, 123.0, 122.3, 111.7, 108.8, 61.1, 22.1,
14.6; LCMS (ESI, positive): 204.1 [M+H]+.
Ethyl 6-nitro-1H-indole-2-carboxylate (3ιa).68 The reaction of 1ι
(55.2 mg, 0.4 mmol), 2a (232.0 mg, 2.0 mmol), Pd(OAc)2 (9.0 mg,
0.04 mmol), AcOH (96.0 mg, 1.6 mmol) and 4Å MS (80 mg) in
DMSO (2.0 mL), at 90 ºC, under O2 (1 atm), 48 h, afforded product
3ιa (15.0 mg, 16% yield, eluent: petroleum ether/ethyl acetate =
10:1). 3ιa: yellow solid;1H NMR (400 MHz, Chloroform-d) δ: 9.43
(brs, 1H), 8.42 (s, 1H), 8.05 (dd, J = 8.9, 2.0, 1H), 7.78 (d, J = 8.9,
1H), 7.29 (dd, J = 2.0, 1.0, 1H), 4.48 (q, J = 7.1, 2H), 1.45 (t, J =
7.1, 3H); 13C{1H} NMR (101 MHz, Chloroform-d) δ: 161.3, 145.7,
135.2, 132.6, 132.0, 123.1, 116.1, 108.9, 108.5, 62.0, 14.5; LCMS
(ESI, positive): 235.1 [M+H]+.
Ethyl 4,6-dimethyl-1H-indole-2-carboxylate (3εa).62 The reaction
of 1ε (48.4 mg, 0.4 mmol), 2a (92.8 mg, 0.8 mmol), Pd(OAc)2 (9.0
mg, 0.04 mmol), AcOH (96.0 mg, 1.6 mmol) and 4Å MS (80 mg)
in DMSO (2.0 mL), at 70 ºC, under O2 (1 atm), 9 h, afforded prod-
uct 3εa (26.0 mg, 30% yield, eluent: petroleum ether/ethyl acetate
= 50:1). The reaction of 1ε (48.4 mg, 0.4 mmol), 2a (92.8 mg, 0.8
mmol), Pd(OAc)2 (9.0 mg, 0.04 mmol), AcOH (24.0 mg, 0.4 mmol)
and 4Å MS (80 mg) in DMSO (3.0 mL), at 70 ºC, under O2 (1 atm),
36 h, afforded product 3εa (44.3 mg, 51% yield, eluent: petroleum
ether/ethyl acetate = 50:1). 3εa: white solid; 1H NMR (400 MHz,
Chloroform-d) δ = 9.00 (brs, 1H), 7.22 (s, 1H), 7.02 (s, 1H), 6.78
(s, 1H), 4.41 (q, J = 7.1, 2H), 2.51 (s, 3H), 2.42 (s, 3H), 1.41 (t, J
= 7.1, 3H); 13C{1H} NMR (101 MHz, Chloroform-d) δ = 162.4,
137.4, 135.9, 131.9, 126.4, 125.8, 123.0, 109.2, 107.5, 61.0, 22.1,
18.7, 14.6; LCMS (ESI, positive): 218.1 [M+H]+.
Ethyl 6-(trifluoromethyl)-1H-indole-2-carboxylate (3κa).77 The re-
action of 1κ (64.4 mg, 0.4 mmol), 2a (139.2 mg, 1.2 mmol),
Pd(OAc)2 (9.0 mg, 0.04 mmol), AcOH (96.0 mg, 1.6 mmol) and
4Å MS (80 mg) in DMSO (2.0 mL), at 80 ºC, under O2 (1 atm), 36
h, afforded product 3κa (20.6 mg, 20% yield, eluent: petroleum
ether/ethyl acetate = 60:1). 3κa: white solid; 1H NMR (400 MHz,
Chloroform-d) δ: 9.30 (brs, 1H), 7.79 (d, J = 8.4, 1H), 7.74 (s, 1H),
7.38 (dd, J = 8.4, 1.0, 1H), 7.28 – 7.26 (m, 1H), 4.45 (q, J = 7.1,
2H), 1.44 (t, J = 7.1, 3H); 13C{1H} NMR (101 MHz, Chloroform-
d) δ: 161.7, 135.6, 130.1, 129.7, 127.4 (q, J = 32.2), 124.8 (q, J =
272.5), 123.4, 117.5 (q, J = 3.4), 109.7 (q, J = 4.6), 108.4, 61.6,
14.5; LCMS (ESI, positive): 258.1 [M+H]+.
Ethyl 4,7-dimethyl-1H-indole-2-carboxylate (3ζa). The reaction of
1ζ (48.4 mg, 0.4 mmol), 2a (92.8 mg, 0.8 mmol), Pd(OAc)2 (9.0
mg, 0.04 mmol), AcOH (96.0 mg, 1.6 mmol) and 4Å MS (80 mg)
in DMSO (2.0 mL), at 70 ºC, under O2 (1 atm), 24 h, afforded prod-
uct 3ζa (13.9 mg, 16% yield, eluent: petroleum ether/ethyl acetate
= 100:1). 3ζa: light yellow solid; mp 114-116 ºC; 1H NMR (400
MHz, Chloroform-d) δ: 8.80 (brs, 1H), 7.27 (d, J = 2.2, 1H), 7.01
(d, J = 7.1, 1H), 6.86 (d, J = 7.1, 1H), 4.42 (q, J = 7.1, 2H), 2.53 (s,
3H), 2.48 (s, 3H), 1.43 (t, J = 7.1, 3H); 13C{1H} NMR (101 MHz,
Ethyl 6-chloro-1H-indole-2-carboxylate (3λa);72 ethyl 4-chloro-
1H-indole-2-carboxylate (3λa).58 The reaction of 1λ (51.0 mg, 0.4
mmol), 2a (92.8 mg, 0.8 mmol), Pd(OAc)2 (9.0 mg, 0.04 mmol),
AcOH (96.0 mg, 1.6 mmol) and 4Å MS (80 mg) in DMSO (2.0
mL), at 70 ºC, under O2 (1 atm), 24 h, afforded product 3λa (33.1
mg, 37% yield) and 3λa (11.6 mg, 13% yield) (eluent: petroleum
ether/ethyl acetate = 50:1). 3λa: white solid; 1H NMR (400 MHz,
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The Journal of Organic Chemistry
Chloroform-d) δ: 9.17 (brs, 1H), 7.59 (d, J = 8.6, 1H), 7.42 (s, 1H),
MHz, Chloroform-d) δ: 162.1, 161.8 (d, J = 242.1), 137.1 (d, J =
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7.19 (dd, J = 2.1, 0.9, 1H), 7.12 (dd, J = 8.6, 1.8, 1H), 4.43 (q, J =
7.1, 2H), 1.42 (t, J = 7.1, 3H); 13C{1H} NMR (101 MHz, Chloro-
form-d) δ: 162.0, 137.2, 131.4, 128.4, 126.2, 123.7, 122.0, 111.9,
108.8, 61.4, 14.5; LCMS (ESI, positive): 245.0 [M+H]+. 3λa:
white solid; 1H NMR (400 MHz, Chloroform-d) δ: 9.15 (brs, 1H),
7.35 – 7.30 (m, 2H), 7.23 (t, J = 7.9, 1H), 7.16 (dd, J = 7.5, 0.8,
1H), 4.43 (q, J = 7.1, 2H), 1.43 (t, J = 7.1, 3H); 13C{1H} NMR (101
MHz, Chloroform-d) δ: 161.9, 137.4, 128.1, 128.0, 126.8, 125.9,
120.6, 110.64, 107.14, 61.47, 14.52; LCMS (ESI, positive): 245.1
[M+H]+.
12.9), 128.2 (d, J = 3.6), 124.2, 123.9 (d, J = 10.4), 110.5 (d, J =
25.3), 108.9, 98.0 (d, J = 26.1), 61.3, 14.5; HRMS (ESI, positive):
m/z calculated for C11H11NO2F ([M+H]+) 208.0768, found:
208.0767.
Ethyl 6-acetyl-1H-indole-2-carboxylate (3πa); ethyl 4-acetyl-1H-
indole-2-carboxylate (3πa). The reaction of 1π (54.0 mg, 0.4
mmol), 2a (92.8 mg, 0.8 mmol), Pd(OAc)2 (9.0 mg, 0.04 mmol),
AcOH (96.0 mg, 1.6 mmol) and 4Å MS (80 mg) in DMSO (2.0
mL), at 80 ºC, under O2 (1 atm), 24 h, afforded product 3πa (31.4
mg, 34% yield, eluent: petroleum ether/ethyl acetate = 15:1) and
3πa (9.2 mg, 10% yield, eluent: petroleum ether/ethyl acetate =
20:1). 3πa: light yellow solid; mp 142-143 ºC; 1H NMR (400 MHz,
Chloroform-d) δ: 9.47 br(s, 1H), 8.14 – 8.11 (m, 1H), 7.77 (dd, J =
8.5, 1.4, 1H), 7.73 (d, J = 8.5, 1H), 7.24 (dd, J = 2.1, 0.9, 1H), 4.46
(q, J = 7.1, 2H), 2.68 (s, 3H), 1.44 (t, J = 7.1, 3H); 13C{1H} NMR
(101 MHz, Chloroform-d) δ: 198.3, 161.8, 136.3, 134.2, 130.8,
122.6, 120.7, 113.3, 108.4, 61.6, 27.0, 14.5; HRMS (ESI, positive):
m/z calculated for C13H14NO3 ([M+H]+) 232.0968, found:
232.0974. 3πa: white solid; mp 148-149 ºC; 1H NMR (400 MHz,
Chloroform-d) δ: 9.21 (brs, 1H), 8.00 (dd, J = 2.2, 1.0, 1H), 7.79
(dd, J = 7.4, 0.8, 1H), 7.65 (dt, J = 8.3, 0.9, 1H), 7.39 (dd, J = 8.2,
7.4, 1H), 4.44 (q, J = 7.1, 2H), 2.72 (s, 3H), 1.43 (t, J = 7.1, 3H);
13C{1H} NMR (101 MHz, Chloroform-d) δ: 199.2, 162.2, 137.6,
131.0, 129.9, 125.6, 124.5, 117.3, 110.2, 61.5, 27.8, 14.5; HRMS
(ESI, positive): m/z calculated for C13H14NO3 ([M+H]+) 232.0968,
found: 232.0975.
9
Ethyl 6-bromo-1H-indole-2-carboxylate (3μa).68 The reaction of
1μ (68.8 mg, 0.4 mmol), 2a (92.8 mg, 0.8 mmol), Pd(OAc)2 (9.0
mg, 0.04 mmol), AcOH (96.0 mg, 1.6 mmol) and 4Å MS (80 mg)
in DMSO (2.0 mL), at 70 ºC, under O2 (1 atm), 18 h, afforded prod-
uct 3μa (36.4 mg, 34% yield, eluent: petroleum ether/ethyl acetate
= 40:1). 3μa: white solid; 1H NMR (400 MHz, Chloroform-d) δ:
9.07 (brs, 1H), 7.59 (s, 1H), 7.54 (d, J = 8.6, 1H), 7.25 (dd, J = 8.2,
1.8, 1H), 7.22 – 7.16 (m, 1H), 4.42 (q, J = 7.1, 2H), 1.42 (t, J = 7.1,
3H). 13C{1H} NMR (101 MHz, Chloroform-d) δ: 162.0, 137.5,
128.2, 126.4, 124.5, 123.9, 119.2, 114.9, 108.8, 61.4, 14.5; LCMS
(ESI, positive): 268.0 [M+H]+.
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Ethyl 6-hydroxy-1H-indole-2-carboxylate (3νa). The reaction of 1ν
(43.6 mg, 0.4 mmol), 2a (92.8 mg, 0.8 mmol), Pd(OAc)2 (9.0 mg,
0.04 mmol), AcOH (96.0 mg, 1.6 mmol) and 4Å MS (80 mg) in
DMSO (2.0 mL), at 70 ºC, under O2 (1 atm), 18 h, afforded product
3νa (67.2 mg, 82% yield, eluent: petroleum ether/ethyl acetate =
6:1). 3νa: light yellow solid; mp 176-177 ºC; 1H NMR (400 MHz,
DMSO-d6) δ: 11.42 (s, 1H), 9.36 (s, 1H), 7.42 (d, J = 8.6, 1H), 7.02
(d, J = 1.3, 1H), 6.78 (d, J = 1.9, 1H), 6.61 (dd, J = 8.7, 2.1, 1H),
4.29 (q, J = 7.1, 2H), 1.31 (t, J = 7.1, 3H); 13C{1H} NMR (101
MHz, DMSO-d6) δ: 161.3, 155.8, 138.9, 125.6, 122.7, 120.3, 112.1,
108.3, 96.3, 60.0, 14.4; HRMS (ESI, positive): m/z calculated for
C11H12NO3 ([M+H]+) 206.0812, found: 206.0807.
Ethyl 6-acetamido-1H-indole-2-carboxylate (3ρa); ethyl 4-acet-
amido-1H-indole-2-carboxylate (3ρa). The reaction of 1ρ (60.0
mg, 0.4 mmol), 2a (92.8 mg, 0.8 mmol), Pd(OAc)2 (9.0 mg, 0.04
mmol), AcOH (96.0 mg, 1.6 mmol) and 4Å MS (80 mg) in DMSO
(2.0 mL), at 70 ºC, under O2 (1 atm), 18 h, afforded product 3ρa
(22.6 mg, 23% yield, eluent: petroleum ether/ethyl acetate = 2:1)
and 3ρa (12.8 mg, 13% yield, eluent: petroleum ether/ethyl acetate
= 3:1). 3ρa: light yellow solid; mp 220-221 ºC;1H NMR (400 MHz,
DMSO-d6) δ: 11.73 (s, 1H), 9.97 (s, 1H), 8.04 (s, 1H), 7.53 (d, J =
8.7, 1H), 7.11 (dd, J = 8.7, 1.8, 1H), 7.07 (dd, J = 2.1, 0.9, 1H),
4.31 (q, J = 7.1, 2H), 2.06 (s, 3H), 1.32 (t, J = 7.1, 3H); 13C{1H}
NMR (101 MHz, DMSO-d6) δ: 168.2, 161.2, 137.8, 136.6, 126.9,
122.8, 122.0, 113.9, 107.9, 101.9, 60.2, 24.1, 14.3; HRMS (ESI,
positive): m/z calculated for C13H15N2O3 ([M+H]+) 247.1077,
found: 247.1072. 3ρa: light yellow solid; mp 245-246 ºC; 1H NMR
(400 MHz, DMSO-d6) δ: 11.89 (s, 1H), 9.74 (s, 1H), 7.78 – 7.71
(m, 1H), 7.59 (d, J = 1.7, 1H), 7.20 – 7.13(m, 2H), 4.35 (q, J = 7.1,
2H), 2.15 (s, 3H), 1.35 (t, J = 7.1, 3H); 13C{1H} NMR (101 MHz,
DMSO-d6) δ: 168.6, 161.2, 138.0, 132.4, 126.0, 125.1, 119.0, 110.1,
107.9, 106.1, 60.4, 23.9, 14.3; HRMS (ESI, positive): m/z calcu-
lated for C13H15N2O3 ([M+H]+) 247.1077, found: 247.1074.
Ethyl 4,6-difluoro-1H-indole-2-carboxylate (3ξa).64 The reaction
of 1ξ (51.6 mg, 0.4 mmol), 2a (139.2 mg, 1.2 mmol), Pd(OAc)2
(9.0 mg, 0.04 mmol), AcOH (96.0 mg, 1.6 mmol) and 4Å MS (80
mg) in DMSO (2.0 mL), at 80 ºC, under O2 (1 atm), 36 h, afforded
product 3ξa (27.0 mg, 30% yield, eluent: petroleum ether/ethyl ac-
etate = 50:1). 3ξa: white solid; 1H NMR (400 MHz, Chloroform-d)
δ: 9.38 (brs, 1H), 7.27 (overlap, 1H), 6.93 (d, J = 8.8, 1H), 6.65 (td,
J = 10.0, 1.9, 1H), 4.44 (q, J = 7.1, 2H), 1.43 (t, J = 7.1, 3H);
13C{1H} NMR (101 MHz, Chloroform-d) δ: 161.7, 161.4 (dd, J =
243.4, 11.7), 157.1 (dd, J = 253.2, 15.2), 138.1 (dd, J = 14.9, 12.4),
128.1, 114.2 (d, J = 22.3), 105.0, 96.7 (dd, J = 29.3, 22.8), 94.3
(dd, J = 26.4, 4.8), 61.5, 14.5; LCMS (ESI, positive): 226.1
[M+H]+.
Ethyl 6-fluoro-1H-indole-2-carboxylate (3oa);68 ethyl 4-fluoro-
1H-indole-2-carboxylate (3oa). The reaction of 1o (44.4 mg, 0.4
mmol), 2a (92.8 mg, 0.8 mmol), Pd(OAc)2 (9.0 mg, 0.04 mmol),
AcOH (96.0 mg, 1.6 mmol) and 4Å MS (80 mg) in DMSO (2.0
mL), at 70 ºC, under O2 (1 atm), 24 h, afforded product 3oa (41.4
mg, 50% yield) and 3oa (29.0 mg, 35% yield) (eluent: petroleum
ether/ethyl acetate = 60:1). 3oa: white solid; 1H NMR (400 MHz,
Chloroform-d) δ: 9.35 (brs, 1H), 7.30 (d, J = 1.8, 1H), 7.26 – 7.19
(m, 2H), 6.80 (ddd, J = 10.2, 6.8, 1.6, 1H), 4.44 (q, J = 7.1, 2H),
1.43 (t, J = 7.1, 3H); 13C{1H} NMR (101 MHz, Chloroform-d) δ:
162.1, 157.3 (d, J = 250.4), 139.2 (d, J = 10.0), 127.7, 126.0 (d, J
= 7.9), 117.5 (d, J = 22.4), 108.1 (d, J = 4.1), 105.2 (d, J = 18.5),
104.7 (d, J = 0.7), 61.5, 14.5; LCMS (ESI, positive): 208.1 [M+H]+.
3oa: white solid; mp 137-139ºC; 1H NMR (400 MHz, Chloroform-
d) δ: 9.34 (brs, 1H), 7.61 (dd, J = 8.8, 5.4, 1H), 7.21 (dd, J = 2.0,
0.8, 1H), 7.10 (dd, J = 9.4, 2.0, 1H), 6.93 (td, J = 9.4, 2.3, 1H),
4.43 (q, J = 7.1, 2H), 1.43 (t, J = 7.1, 3H); 13C{1H} NMR (101
2-Ethyl 6-methyl 1H-indole-2,6-dicarboxylate (3σa); 2-ethyl 4-me-
thyl 1H-indole-2,4-dicarboxylate (3σa). The reaction of 1σ (60.4
mg, 0.4 mmol), 2a (92.8 mg, 0.8 mmol), Pd(OAc)2 (9.0 mg, 0.04
mmol), AcOH (96.0 mg, 1.6 mmol) and 4Å MS (80 mg) in DMSO
(2.0 mL), at 80 ºC, under O2 (1 atm), 24 h, afforded product 3σa
(45.4 mg, 46% yield) and 3σa (5.2 mg, 5% yield) (eluent: petro-
leum ether/ethyl acetate = 15:1). 3σa: light yellow solid; mp 160-
161 ºC; 1H NMR (400 MHz, DMSO-d6) δ: 12.30 (s, 1H), 8.12 (dt,
J = 1.6, 0.8, 1H), 7.77 (d, J = 8.5, 1H), 7.66 (dd, J = 8.5, 1.5, 1H),
7.22 (dd, J = 2.2, 0.9, 1H), 4.37 (q, J = 7.1, 2H), 3.87 (s, 3H), 1.35
(t, J = 7.1, 3H); 13C{1H} NMR (101 MHz, DMSO-d6) δ: 166.8,
161.0, 136.5, 130.5, 130.1, 125.4, 122.1, 120.3, 114.6, 107.5, 60.9,
52.0, 14.2; HRMS (ESI, positive): m/z calculated for C13H14NO4
([M+H]+) 248.0917, found: 248.0912. 3σa: light yellow solid; 1H
NMR (400 MHz, Chloroform-d) δ: 9.16 (brs, 1H), 7.96 (d, J = 7.4,
1H), 7.87 – 7.79 (m, 1H), 7.64 (d, J = 8.2, 1H), 7.38 (t, J = 8.0,
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1H), 4.44 (q, J = 7.1, 2H), 4.01 (s, 3H), 1.44 (t, J = 7.1, 3H);
169.0, 161.3, 137.9, 128.2, 128.0, 125.0, 123.8, 120.1, 115.5, 108.6,
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13C{1H} NMR (101 MHz, Chloroform-d) δ: 167.6, 162.1, 137.4,
129.2, 126.7, 124.7, 124.6, 123.7, 117.0, 109.7, 61.5, 52.1 14.5;
HRMS (ESI, positive): m/z calculated for C13H14NO4 ([M+H]+)
248.0917, found: 248.0915.
60.6, 14.3; HRMS (ESI, positive): m/z calculated for C12H13N2O3
([M+H]+) 233.0921, found: 233.0921.
Ethyl 6-(methylsulfonamido)-1H-indole-2-carboxylate (3χa); ethyl
4-(methylsulfonamido)-1H-indole-2-carboxylate (3χa). The reac-
tion of 1χ (74.4 mg, 0.4 mmol), 2a (92.8 mg, 0.8 mmol), Pd(OAc)2
(9.0 mg, 0.04 mmol), AcOH (96.0 mg, 1.6 mmol) and 4Å MS (80
mg) in DMSO (2.0 mL), at 70 ºC, under O2 (1 atm), 18 h, afforded
product 3χa (77.8 mg, 69% yield) and 3χa (1.1 mg, 1% yield) (el-
uent: petroleum ether/ethyl acetate = 3:1). 3χa: light yellow solid;
mp 221-222 ºC; 1H NMR (400 MHz, DMSO-d6) δ: 11.81 (s, 1H),
9.68 (s, 1H), 7.60 (d, J = 8.6, 1H), 7.40 – 7.37 (m, 1H), 7.10 (dd, J
= 2.2, 0.9, 1H), 6.99 (dd, J = 8.6, 2.0, 1H), 4.32 (q, J = 7.1, 2H),
2.95 (s, 3H), 1.33 (t, J = 7.1, 3H); 13C{1H} NMR (101 MHz,
DMSO-d6) δ: 161.1, 137.7, 135.5, 127.4, 123.7, 122.8, 115.0, 107.8,
103.2, 60.3, 38.8, 14.3; HRMS (ESI, positive): m/z calculated for
C12H15N2O4S ([M+H]+) 283.0747, found: 283.0744. 3χa: light yel-
low solid; 1H NMR (400 MHz, DMSO-d6) δ: 11.97 (s, 1H), 9.69 (s,
1H), 7.52 (d, J = 1.7, 1H), 7.26 – 7.26 (m, 2H), 7.04 (dd, J = 6.6,
1.7, 1H), 4.34 (q, J = 7.1, 2H), 2.97 (s, 3H), 1.34 (t, J = 7.1, 3H);
13C{1H} NMR (101 MHz, DMSO-d6) δ: 161.2, 138.4, 131.5, 126.8,
125.2, 121.1, 111.6, 109.2, 106.3, 60.5, 38.8, 14.3; HRMS (ESI,
positive): m/z calculated for C12H15N2O4S ([M+H]+) 283.0747,
found: 283.0743.
2-(Ethoxycarbonyl)-1H-indole-6-carboxylic acid (3τa); 2-(ethox-
ycarbonyl)-1H-indole-4-carboxylic acid (3τa). The reaction of 1τ
(54.8 mg, 0.4 mmol), 2a (92.8 mg, 0.8 mmol), Pd(OAc)2 (9.0 mg,
0.04 mmol), AcOH (96.0 mg, 1.6 mmol) and 4Å MS (80 mg) in
DMSO (2.0 mL), at 80 ºC, under O2 (1 atm), 24 h, afforded product
3τa (4.7 mg, 5% yield) and 3τa (9.3 mg, 10% yield) (eluent: pe-
troleum ether/ethyl acetate = 3:1). 3τa: white solid;mp 258-260 ºC;
1H NMR (400 MHz, DMSO-d6) δ: 12.24 (s, 1H), 8.12 – 8.10 (m,
1H), 7.74 (d, J = 8.4, 1H), 7.65 (dd, J = 8.4, 1.4, 1H), 7.21 (dd, J
= 2.1, 0.9, 1H), 4.37 (q, J = 7.1, 2H), 1.35 (t, J = 7.1, 3H); 13C{1H}
NMR (101 MHz, DMSO-d6) δ: 167.9, 161.0, 136.5, 130.2, 129.8,
126.6, 121.9, 120.6, 114.7, 107.4, 60.8, 14.3; HRMS (ESI, positive):
m/z calculated for C12H12NO4 ([M+H]+) 234.0761, found:
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234.0760. 3τa: white solid; mp 298-299 ºC; H NMR (400 MHz,
DMSO-d6) δ: 12.21 (s, 1H), 7.79 (dd, J = 7.3, 1.0, 1H), 7.71 (dt, J
= 8.3, 0.9, 1H), 7.60 (dd, J = 2.3, 0.9, 1H), 7.37 (dd, J = 8.2, 7.4,
1H), 4.36 (q, J = 7.1, 2H), 1.36 (t, J = 7.1, 3H); 13C{1H} NMR
(101 MHz, DMSO-d6) δ: 167.9, 161.2, 138.0, 128.9, 125.8, 123.9,
123.8, 123.4, 117.6, 108.4, 60.7, 14.3; HRMS (ESI, positive): m/z
calculated for C12H12NO4 ([M+H]+) 234.0761, found: 234.0769.
Ethyl 6-(2-methoxy-2-oxoethyl)-1H-indole-2-carboxylate (3ψa);
ethyl 4-(2-methoxy-2-oxoethyl)-1H-indole-2-carboxylate (3ψa).
The reaction of 1ψ (66.0 mg, 0.4 mmol), 2a (92.8 mg, 0.8 mmol),
Pd(OAc)2 (9.0 mg, 0.04 mmol), AcOH (96.0 mg, 1.6 mmol) and
4Å MS (80 mg) in DMSO (2.0 mL), at 70 ºC, under O2 (1 atm), 18
h, afforded mixture of product 3ψa and 3ψa (73.3 mg, 70% yield,
32 : 3 by NMR) (eluent: petroleum ether/ethyl acetate = 4:1). 3ψa:
off-white solid; 1H NMR (400 MHz, Chloroform-d) δ: 9.06 (brs,
1H), 7.62 (d, J = 8.3, 1H), 7.34 (s, 1H), 7.19 (d, J = 1.8, 1H), 7.07
(d, J = 8.2, 1H), 4.41 (q, J = 7.1, 2H), 3.73 (s, 2H), 3.70 (s, 3H),
1.41 (t, J = 7.1, 3H). 13C{1H} NMR (101 MHz, Chloroform-d) δ:
172.5, 162.2, 137.3, 131.5, 128.0, 126.8, 122.9, 122.7, 112.6, 108.7,
61.3, 52.3, 41.8, 14.6. 3ψa: off-white solid; 1H NMR (400 MHz,
Chloroform-d) δ: 9.18 (brs, 1H), 7.35 (overlap, 1H), 7.29 (d, J =
1.9, 1H), 7.26 (t, J = 7.5, 1H), 7.04 (overlap, 1H), 4.42 (q, J = 7.1,
2H), 3.91 (s, 2H), 3.69 (s, 3H), 1.42 (t, J = 7.1, 3H); HRMS (ESI,
positive): m/z calculated for C14H16NO4 ([M+H]+) 262.1074, found:
262.1068.
Ethyl 6-(hydroxymethyl)-1H-indole-2-carboxylate (3υa); ethyl 4-
(hydroxymethyl)-1H-indole-2-carboxylate (3υa). The reaction of
1υ (49.2 mg, 0.4 mmol), 2a (92.8 mg, 0.8 mmol), Pd(OAc)2 (9.0
mg, 0.04 mmol), AcOH (96.0 mg, 1.6 mmol) and 4Å MS (80 mg)
in DMSO (2.0 mL), at 70 ºC, under O2 (1 atm), 12 h, afforded prod-
uct 3υa (52.6 mg, 60% yield) and 3υa (6.1 mg, 7% yield) (eluent:
petroleum ether/ethyl acetate = 5:1). 3υa: light brown solid; mp
103-104 ºC; 1H NMR (400 MHz, DMSO-d6) δ: 11.81 (s, 1H), 7.58
(d, J = 8.3, 1H), 7.43 – 7.41 (m, 2H), 7.10 (dd, J = 2.1, 0.9, 1H),
7.01 (dd, J = 8.3, 1.4, 1H), 4.58 (s, 2H), 4.33 (q, J = 7.1, 2H), 3.69
(brs, 1H), 1.34 (t, J = 7.1, 3H); 13C{1H} NMR (101 MHz, DMSO-
d6) δ: 161.4, 139.5, 137.6, 127.2, 125.6, 121.6, 119.6, 110.0, 107.7,
63.4, 60.3, 14.3; HRMS (ESI, positive): m/z calculated for
C12H14NO3 ([M+H]+) 220.0968, found: 220.0972, 202.0867([M-
H2O+H]+). 3υa: light yellow solid; 1H NMR (400 MHz, DMSO-
d6) δ: 11.86 (s, 1H), 7.34 (d, J = 8.3, 1H), 7.27 – 7.18 (m, 2H), 7.05
(d, J = 7.2, 1H), 5.19 (t, J = 5.7, 1H), 4.77 (d, J = 5.7, 2H), 4.34 (q,
J = 7.1, 2H), 1.34 (t, J = 7.1, 3H); 13C{1H} NMR (101 MHz,
DMSO-d6) δ: 161.4, 137.4, 135.9, 126.8, 124.9, 124.5, 117.5, 111.3,
106.4, 61.4, 60.4, 14.3; HRMS (ESI, positive): m/z calculated for
C12H14NO3 ([M+H]+) 220.0968, found: 220.0969, 202.0860([M-
H2O+H]+).
5-Methoxy-2-methyl-1H-indole (3ab).79 The reaction of 1a (49.2
mg, 0.4 mmol), 2b (116.0 mg, 2.0 mmol), Pd(OAc)2 (9.0 mg, 0.04
mmol), AcOH (96.0 mg, 1.6 mmol) and 4Å MS (80 mg) in DMSO
(2.0 mL), at 70 ºC, under O2 (1 atm), 18 h, afforded product 3ab
(50.9 mg, 79% yield, eluent: petroleum ether/ethyl acetate = 100:1).
3ab: light yellow solid; 1H NMR (400 MHz, Chloroform-d) δ: 7.73
(brs, 1H), 7.17 (d, J = 8.8, 1H), 6.99 (d, J = 2.4, 1H), 6.76 (dd, J =
8.7, 2.4, 1H), 6.14 (brs, 1H), 3.83 (s, 3H), 2.43 (s, 3H); 13C{1H}
NMR (101 MHz, Chloroform-d) δ: 154.2, 136.1, 131.3, 129.6,
111.0, 110.8, 102.0, 100.4, 56.0, 13.9; LCMS (ESI, positive): 162.1
[M+H]+.
Ethyl 6-carbamoyl-1H-indole-2-carboxylate (3φa); ethyl 4-car-
bamoyl-1H-indole-2-carboxylate (3φa). The reaction of 1φ (54.4
mg, 0.4 mmol), 2a (92.8 mg, 0.8 mmol), Pd(OAc)2 (9.0 mg, 0.04
mmol), AcOH (96.0 mg, 1.6 mmol) and 4Å MS (80 mg) in DMSO
(2.0 mL), at 80 ºC, under O2 (1 atm), 24 h, afforded product 3φa
(18.6 mg, 20% yield) and 3φa (11.1 mg, 12% yield) (eluent: pe-
troleum ether/ethyl acetate = 2:1). 3φa: light yellow solid; 1H NMR
(400 MHz, DMSO-d6) δ: 12.21 (s, 1H), 8.07 – 7.95 (m, 2H), 7.68
(d, J = 8.5, 1H), 7.59 (dd, J = 8.5, 1.5, 1H), 7.31 (brs, 1H), 7.18
(dd, J = 2.1, 0.8, 1H), 4.36 (q, J = 7.1, 2H), 1.35 (t, J = 7.1, 3H);
13C{1H} NMR (101 MHz, DMSO-d6) δ: 168.5, 161.1, 136.8, 130.7,
129.5, 128.6, 121.5, 119.3, 112.7, 107.4, 60.7, 14.3; HRMS (ESI,
positive): m/z calculated for C12H13N2O3 ([M+H]+) 233.0921,
found: 233.0931. 3φa: light yellow solid; 1H NMR (400 MHz,
DMSO-d6) δ: 12.05 (s, 1H), 7.88 (brs, 1H), 7.63 – 7.57 (m, 2H),
7.55 (d, J = 6.9, 1H), 7.37 – 7.25 (m, 2H), 4.35 (q, J = 7.1, 2H),
1.35 (t, J = 7.1, 3H); 13C{1H} NMR (101 MHz, DMSO-d6) δ:
2-Isobutyl-5-methoxy-1H-indole (3ac).79 The reaction of 1a (49.2
mg, 0.4 mmol), 2c (80.0 mg, 0.8 mmol), Pd(OAc)2 (9.0 mg, 0.04
mmol), AcOH (96.0 mg, 1.6 mmol) and 4Å MS (80 mg) in DMSO
(2.0 mL), at 70 ºC, under O2 (1 atm), 24 h, afforded product 3ac
(22.7 mg, 28% yield, eluent: petroleum ether/ethyl acetate = 100:1).
3ac: light yellow solid; 1H NMR (400 MHz, Chloroform-d) δ: 7.73
(brs, 1H), 7.17 (d, J = 8.7, 1H), 7.01 (d, J = 2.4, 1H), 6.77 (dd, J =
8.7, 2.4, 1H), 6.15 (brs, 1H), 3.83 (s, 3H), 2.59 (d, J = 7.1, 2H),
2.03 – 1.89 (m, 1H), 0.97 (d, J = 6.6, 6H); 13C{1H} NMR (101
MHz, Chloroform-d) δ: 154.2, 139.9, 131.1, 129.5, 111.1, 110.9,
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The Journal of Organic Chemistry
102.1, 100.5, 56.0, 38.0, 29.1, 22.7; LCMS (ESI, positive): 204.1
addition of ethyl acetate (200 mL) and saline (100 mL). After
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[M+H]+.
shaken, the mixture was filtered through a pad of celite using 30
mL of ethyl acetate as additional eluent and separated. The aqueous
portion was extracted with ethyl acetate (50 mL). The organic por-
tion was combined and washed with NaCl aqueous solution (2 x
100 mL), dried over Na2SO4, filtered, and concentrated under vac-
uum. The residue was purified through Flash Column Chromatog-
raphy on silica gel (eluent: petroleum ether/ethyl acetate = 30:1) to
afford the title compound (1.23 g, 76% yield).
5-Methoxy-2-propyl-1H-indole (3ad).80 The reaction of 1a (49.2
mg, 0.4 mmol), 2d (172.2 mg, 2.0 mmol), Pd(OAc)2 (9.0 mg, 0.04
mmol), AcOH (24.0 mg, 0.4 mmol) and 4Å MS (80 mg) in DMSO
(8.0 mL), at 70 ºC, under O2 (1 atm), 18 h, afforded product 3ad
(28.0 mg, 37% yield, the recovery% of 1a is 42%, eluent: petro-
leum ether/ethyl acetate = 50:1). 3ad: white solid; 1H NMR (400
MHz, Chloroform-d) δ: 7.74 (brs, 1H), 7.16 (d, J = 8.7, 1H), 7.01
(d, J = 2.4, 1H), 6.76 (dd, J = 8.7, 2.4, 1H), 6.16 (brs, 1H), 3.83 (s,
3H), 2.69 (t, J = 7.6, 2H), 1.73 (h, J = 7.4, 2H), 0.99 (t, J = 7.3,
3H); 13C{1H} NMR (101 MHz, Chloroform-d) δ:= 154.2, 140.8,
131.1, 129.5, 111.0, 110.9, 102.1, 99.6, 56.1, 30.5, 22.7, 14.0;
LCMS (ESI, positive): 290.1 [M+H]+.
Ethyl 6-methoxy-1H-indole-2-carboxylate (3αa); ethyl 4-methoxy-
1H-indole-2-carboxylate (3αa). Procedure: 4Å MS (2.0 g) and
Pd(OAc)2 (0.44 g, 2 mmol) were added to a 100 mL round-bottom
flask equipped with a magnetic stirrer bar. After air-evacuation and
refilled with O2 for three times, 1α (2.46 g, 20 mmol), 2a (4.64 g,
40 mmol), AcOH (1.20 g, 20 mmol) and DMSO (20 mL) were
added via syringe. The mixture was stirred at 70 °C for 18 h. The
solution was then cooled to room temperature followed by the ad-
dition of ethyl acetate (60 mL) and saline (30 mL). After shaken,
the mixture was filtered through a pad of celite using 10 mL of ethyl
acetate as additional eluent and separated. The aqueous portion was
extracted with ethyl acetate (10 mL). The organic portion was com-
bined and washed with NaCl aqueous solution (2 x 40 mL), dried
over Na2SO4, filtered, and concentrated under vacuum. The residue
was purified through Flash Column Chromatography on silica gel
(eluent: petroleum ether/ethyl acetate = 30:1) to afford 3αa (0.15
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N,N-dibutyl-5-methoxy-1H-indole-2-carboxamide (3af).81 The re-
action of 1a (49.2 mg, 0.4 mmol), 2f (119.6 mg, 0.6 mmol),
Pd(OAc)2 (9.0 mg, 0.04 mmol), AcOH (96.0 mg, 1.6 mmol) and
4Å MS (80 mg) in DMSO (2.0 mL), at 80 ºC, under O2 (1 atm), 48
h, afforded product 3af (49.6 mg, 41% yield, eluent: petroleum
ether/ethyl acetate = 15:1). 3af: light yellow solid; 1H NMR (400
MHz, Chloroform-d) δ: 9.88 (brs, 1H), 7.34 (d, J = 8.9, 1H), 7.07
(d, J = 2.3, 1H), 6.94 (dd, J = 8.9, 2.3, 1H), 6.68 (d, J = 1.6, 1H),
3.85 (s, 3H), 3.62 (brs, 4H), 1.72 (brs, 4H), 1.42 (h, J = 7.3, 4H),
0.99 (t, J = 7.2, 6H); 13C{1H} NMR (101 MHz, Chloroform-d) δ:
162.7, 154.5, 131.0, 130.5, 128.3, 115.6, 112.8, 104.0, 102.3, 55.8,
48.2 (d, J = 101.7), 30.56 (d, J = 109.6), 20.37, 14.05; LCMS (ESI,
positive): 303.2 [M+H]+.
1
g, 3% yield) and 3αa (3.55 g, 81% yield). 3αa: white solid; H
NMR (400 MHz, Chloroform-d) δ: 9.26 (brs, 1H), 7.35 (s, 1H),
7.22 (t, J = 8.2, 1H), 7.01 (d, J = 8.3, 1H), 6.49 (d, J = 7.8, 1H),
4.41 (q, J = 7.1, 1H), 3.94 (s, 3H), 1.40 (t, J = 7.1, 2H); 13C{1H}
NMR (101 MHz, Chloroform-d) δ: 162.2, 154.7, 138.4, 126.5,
126.3, 119.1, 106.5, 105.0, 99.8, 61.1, 55.5, 14.5; HRMS (ESI, pos-
itive): m/z calculated for C12H14NO3 ([M+H]+) 220.0968, found:
220.0967.
(5-Methoxy-1H-indol-2-yl)(phenyl)methanone (3ag). The reaction
of 1a (49.2 mg, 0.4 mmol), 2g (118.5 mg, 0.8 mmol), Pd(OAc)2
(9.0 mg, 0.04 mmol), AcOH (96.0 mg, 1.6 mmol) and 4Å MS (80
mg) in DMSO (2.0 mL), at 70 ºC, under O2 (1 atm), 18 h, afforded
product 3ag (34.0 mg, 34% yield, eluent: petroleum ether/ethyl ac-
etate = 30:1). 3ag: yellow solid; 1H NMR (400 MHz, Chloroform-
d) δ: 9.29 (brs, 1H), 8.04 – 7.94 (m, 2H), 7.65 – 7.59 (m, 1H), 7.57
– 7.50 (m, 2H), 7.38 (d, J = 9.0, 1H), 7.13 – 7.03 (m, 3H), 3.86 (s,
3H); 13C{1H} NMR (101 MHz, Chloroform-d) δ: 187.1, 138.2,
134.9, 133.2, 132.4, 129.4, 128.6, 128.2, 118.6, 113.3, 112.4, 102.9,
55.8; HRMS (ESI, positive): m/z calculated for C16H14NO2
([M+H]+) 252.1019, found: 252.1019.
Methyl 5-(methylsulfonamido)-1H-indole-2-carboxylate (3mh).82
Procedure: 1m (1.86 g, 10 mmol), Pd(OAc)2 (0.22 g, 1 mmol) and
4Å MS (1.0 g) were added to a 250 mL round-bottom flask
equipped with a magnetic stirrer bar. After air-evacuation and re-
filled with O2 for three times, 2h (2.04 g, 20 mmol), AcOH (0.60 g,
10 mmol) and DMSO (100 mL) were added via syringe. The mix-
ture was stirred at 70 °C for 18 h. The solution was then cooled to
room temperature followed by the addition of ethyl acetate (200
mL) and saline (100 mL). After shaken, the mixture was filtered
through a pad of celite using 30 mL of ethyl acetate as additional
eluent and separated. The aqueous portion was extracted with ethyl
acetate (50 mL). The organic portion was combined and washed
with NaCl aqueous solution (2 x 100 mL), dried over Na2SO4, fil-
tered, and concentrated under vacuum. The residue was purified
through Flash Column Chromatography on silica gel (eluent: pe-
troleum ether/ethyl acetate = 3:1) to afford the title compound (2.15
g, 80% yield). 3mh: light yellow solid; 1H NMR (400 MHz,
DMSO-d6) δ: 11.95 (s, 1H), 9.41 (s, 1H), 7.51 (d, J = 1.6, 1H), 7.41
(d, J = 8.8, 1H), 7.17 (dd, J = 8.8, 2.1, 1H), 7.15 (d, J = 1.7, 1H),
3.87 (s, 3H), 2.89 (s, 3H); 13C{1H} NMR (101 MHz, DMSO-d6) δ:
161.6, 135.1, 130.9, 127.9, 126.9, 121.0, 114.6, 113.2, 107.7, 51.8,
38.5; LCMS (ESI, positive): 269.1 [M+H]+.
b. Large-Scale Indole Syntheses
Ethyl 5-methoxy-1H-indole-2-carboxylate (3aa). Procedure: 1a
(1.23 g, 10 mmol), Pd(OAc)2 (0.22 g, 1 mmol) and 4Å MS (1.0 g)
were added to a 250 mL round-bottom flask equipped with a mag-
netic stirrer bar. After air-evacuation and refilled with O2 for three
times, 2a (2.32 g, 20 mmol), AcOH (0.60 g, 10 mmol) and DMSO
(100 mL) were added via syringe. The mixture was stirred at 70 °C
for 18 h. The solution was then cooled to room temperature fol-
lowed by the addition of ethyl acetate (200 mL) and saline (100
mL). After shaken, the mixture was filtered through a pad of celite
using 30 mL of ethyl acetate as additional eluent and separated. The
aqueous portion was extracted with ethyl acetate (50 mL). The or-
ganic portion was combined and washed with NaCl aqueous solu-
tion (2 x 100 mL), dried over Na2SO4, filtered, and concentrated
under vacuum. The residue was purified through Flash Column
Chromatography on silica gel (eluent: petroleum ether/ethyl acetate
= 30:1)) to afford the title compound (1.95 g, 89% yield).
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the ACS
publications website.
All details of reaction development, supportive experiments, details
and results of DFT calculation, and copies of NMR spectra are
available within the Supplementary Information.
5-Methoxy-2-methyl-1H-indole (3ab). Procedure: 1a (1.23 g, 10
mmol), Pd(OAc)2 (0.22 g, 1 mmol) and 4Å MS (1.0 g) were added
to a 250 mL round-bottom flask equipped with a magnetic stirrer
bar. After air-evacuation and refilled with O2 for three times, 2b
(2.90 g, 50 mmol), AcOH (0.60 g, 10 mmol) and DMSO (100 mL)
were added via syringe. The mixture was stirred at 70 °C for 18 h.
The solution was then cooled to room temperature followed by the
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(20) Chen, X.; Li, X.; Wang, N.; Jin, J.; Lu, P.; Wang, Y. Palladium-
catalyzed reaction of arylamine and diarylacetylene: solvent-
controlled construction of 2,3-diarylindoles and
pentaarylpyrroles. Eur. J. Org. Chem. 2012, 2012, 4380-4386.
(21) Zhang, G.; Yu, H.; Qin, G.; Huang, H. Rh-catalyzed oxidative
C-H activation/annulation: converting anilines to indoles using
molecular oxygen as the sole oxidant. Chem. Commun. 2014, 50,
4331-4334.
(22) Wurtz, S.; Rakshit, S.; Neumann, J. J.; Droge, T.; Glorius, F. Pal-
ladium-catalyzed oxidative cyclization of N-aryl enamines: from
anilines to indoles. Angew. Chem., Int. Ed. 2008, 47, 7230-7233.
(23) Neumann, J. J.; Rakshit, S.; Droge, T.; Wurtz, S.; Glorius, F. Ex-
ploring the oxidative cyclization of substituted N-aryl enamines:
Pd-catalyzed formation of indoles from anilines. Chem-Eur. J.
2011, 17, 7298-7303.
AUTHOR INFORMATION
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Corresponding Author
* E-mail address: xiaoz@imm.ac.cn
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
We gratefully acknowledge the financial support from National
Natural Science Foundation of China (21672263) and CAMS In-
novation Fund for Medical Sciences (CIFMS, 2016-I2M-3-009).
We also thank Chuan Zhou for reproducing the results of 3ka and
3ra and Cheng Fang for his advice on DFT calculations.
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40
41
42
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45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(24) Wei, Y.; Deb, I.; Yoshikai, N. Palladium-catalyzed aerobic oxi-
dative cyclization of N-aryl imines: indole synthesis from ani-
lines and ketones. J. Am. Chem. Soc. 2012, 134, 9098-9101.
(25) Liu, W. Q.; Lei, T.; Song, Z. Q.; Yang, X. L.; Wu, C. J.; Jiang,
X.; Chen, B.; Tung, C. H.; Wu, L. Z. Visible light promoted syn-
thesis of indoles by single photosensitizer under aerobic condi-
tions. Org. Lett. 2017, 19, 3251-3254.
(26) Liu, J.; Wei, W.; Zhao, T.; Liu, X.; Wu, J.; Yu, W.; Chang, J.
Iodine/copper iodide-mediated C-H functionalization: synthesis
of imidazo[1,2-a]pyridines and indoles from N-aryl enamines. J.
Org. Chem. 2016, 81, 9326-9336.
(27) Ren, L.; Shi, Z.; Jiao, N. Pd(II)-catalyzed aerobic oxidative in-
tramolecular hydroamination and C-H functionalization of N-al-
kynyl anilines for the synthesis of indole derivatives. Tetrahe-
dron 2013, 69, 4408-4414.
(28) Bernini, R.; Fabrizi, G.; Sferrazza, A.; Cacchi, S. Copper-cata-
lyzed C-C bond formation through C-H functionalization: syn-
thesis of multisubstituted indoles from N-aryl enaminones. An-
gew. Chem., Int. Ed. 2009, 121, 8078-8081.
(29) Zhang, X.; King-Smith, E.; Renata, H. Total synthesis of tam-
bromycin by combining chemocatalytic and biocatalytic C-H
functionalization. Angew. Chem., Int. Edit. 2018, 57, 5037-5041.
(30) Al-Wabli, R.I.; Salman, A.; Shyni, V.; Ghabbour, H.A.; Joe, I.H.;
Almutairi, M.S.; Maklad, Y.A.; Attia, M.I. Synthesis, crystal
structure, vibrational profiling, DFT studies and molecular dock-
ing of N-(4-chloro-2-{[2-(1H-indol-2-ylcarbonyl)hydrazi-
nyl](oxo)acetyl}phenyl)acetamide.DMSO: A new antiprolifera-
tive agent. J. Mol. Struct. 2018, 1155, 457-468.
(31) Mistry, S.N.; Shonberg, J.; Draper-Joyce, C.J.; Klein Herenbrink,
C.; Michino, M.; Shi, L.; Christopoulos, A.; Capuano, B.; Scam-
mells, P.J.; Lane, J.R.. Discovery of a novel class of negative al-
losteric modulator of the dopamine D2 receptor through frag-
mentation of a bitopic ligand. J. Med. Chem. 2015, 58, 6819-
6843.
(32) Miao, C.B.; Sun, Y.F.; Wu, H.; Sun, X.Q.; Yang; H.T. CuI-cat-
alyzed selective 3-alkylation of indoles with N-tosylhydrazones
and the I2-mediated further cyclization to chromeno[2, 3-b]in-
doles. Adv. Synth. Catal. 2018, 360, 2440-2445.
(33) Brant, M.G.; Goodwin-Tindall, J.; Stover, K.R.; Stafford, P.M.;
Wu, F.; Meek, A.R.; Schiavini, P.; Wohnig, S.; Weaver, D.F.
Identification of potent indoleamine 2, 3-dioxygenase 1 (IDO1)
inhibitors based on a phenylimidazole scaffold. Acs. Med. Chem.
Lett. 2018, 9, 131-136.
REFERENCES AND NOTES
(1) ForZi, W.; Zuo, Z.; Ma, D. Intramolecular dearomative oxidative
coupling of indoles: a unified strategy for the total synthesis of
indoline alkaloids. Acc. Chem. Res. 2015, 48, 702-711.
(2) Ishikura, M.; Abe, T.; Choshi, T.; Hibino, S. Simple indole alka-
loids and those with a non-rearranged monoterpenoid unit. Nat.
Prod. Rep. 2013, 30, 694-752.
(3) Kochanowska-Karamyan, A. J.; Hamann, M. T. Marine indole
alkaloids: potential new drug leads for the control of depression
and anxiety. Chem. Rev. 2010, 110, 4489-4497.
(4) Patil, S. A.; Patil, S. A.; Patil, R. Medicinal applications of (Benz)
imidazole and indole-based macrocycles. Chem. Biol. Drug Des.
2017, 89, 639-649.
(5) Sravanthi, T. V.; Manju, S. L. Indoles — a promising scaffold
for drug development. Eur. J. Pharm. Sci. 2016, 91, 1-10.
(6) Singh Sidhu, J.; Singla, R.; Jaitak, V. Indole derivatives as anti-
cancer agents for breast cancer therapy: a review. Anti-Cancer
Agent. Med. Chem. 2016, 16, 160-173.
(7) Gale, P. A. Synthetic indole, carbazole, biindole and indolo-
carbazole-based receptors: applications in anion complexation
and sensing. Chem. Commun. 2008, 38, 4525-4540.
(8) Horton, D. A.; Bourne, G. T.; Smythe, M. L. The combinatorial
synthesis of bicyclic privileged structures or privileged substruc-
tures. Chem. Rev. 2003, 103, 893-930.
(9) Baeyer, A. Ueber die reduction aromatischer verbindungen mit-
telst zinkstaub. Justus. Lieb. Ann. Chem. 1866, 140, 295-296.
(10) Bartoli, G.; Dalpozzo, R.; Nardi, M. Applications of Bartoli in-
dole synthesis. Chem. Soc. Rev. 2014, 43, 4728-4750.
(11) Alonso, F.; Beletskaya, I. P.; Yus, M. Transition-metal-catalyzed
addition of heteroatom — hydrogen bonds to alkynes. Chem. Rev.
2004, 104, 3079-3160.
(12) Robinson, B. The Fischer Indole Synthesis. Chem. Rev. 1963, 63,
373-401.
(13) Gribble, G. W. Indole ring synthesis: From natural products to
drug discovery; John Wiley & Sons: West Sussex, UK, 2016.
(14) Humphrey, G. R.; Kuethe, J. T. Practical methodologies for the
synthesis of indoles. Chem. Rev. 2006, 106, 2875-2911.
(15) Agasti, S.; Dey, A.; Maiti, D. Palladium-catalyzed benzofuran
and indole synthesis by multiple C-H functionalizations. Chem.
Commun. 2017, 53, 6544-6556.
(16) Guo, T.; Huang, F.; Yu, L.; Yu, Z. Indole synthesis through tran-
sition metal-catalyzed C-H activation. Tetrahedron Lett. 2015,
56, 296-302.
(17) Li, C. J. Cross-dehydrogenative coupling (CDC): exploring C-C
bond formations beyond functional group transformations. Acc.
Chem. Res. 2008, 42, 335-344.
(18) Shi, Z.; Glorius, F. Efficient and versatile synthesis of indoles
from enamines and imines by cross-dehydrogenative coupling.
Angew. Chem., Int. Ed. 2012, 51, 9220-9222.
(34) Sun, W.; Wang, L.; Xia, C.; Liu, C. Dual functionalization of α-
monoboryl carbanions through deoxygenative enolization with
carboxylic acids. Angew. Chem., Int. Edit. 2018, 57, 5501-5505.
(35) Jose, A.; Vijaykumar, G.; Vardhanapu, P.K.; Mandal, S.K. Ab-
normal NHC supported palladacycles: Regioselective arylation
of heteroarenes via decarboxylation. J. Organomet. Chem.
2018, 865, 51-57.
(36) Chatupheeraphat, A.; Liao, H.H.; Srimontree, W.; Guo, L.;
Minenkov, Y.; Poater, A.; Cavallo, L.; Rueping, M. Ligand-con-
trolled chemoselective C(acyl)–O bond vs C(aryl)–C bond acti-
vation of aromatic esters in nickel catalyzed C(sp2)–C(sp3)
cross-couplings. J. Am. Chem. Soc. 2018, 140, 3724-3735.
(19) Shi, Z.; Zhang, C.; Li, S.; Pan, D.; Ding, S.; Cui, Y.; Jiao, N.
Indoles from simple anilines and alkynes: palladium-catalyzed
C-H activation using dioxygen as the oxidant. Angew. Chem., Int.
Ed. 2009, 48, 4642-4646.
ACS Paragon Plus Environment

Page 17 of 19
The Journal of Organic Chemistry
(37) Li, Y.; Qian, F.; Wang, M.; Lu, H.; Li, G. Cobalt-catalyzed de-
intramolecular arylation. J. Am. Chem. Soc. 2006, 128, 1066-
carboxylative C–H(hetero) arylation for the synthesis of arylhet-
eroarenes and unsymmetrical biheteroaryls. Org. Lett. 2017, 19,
5589-5592.
1067.
1
2
3
4
5
6
7
8
9
(59) Davies, D. L.; Donald, S. M. A.; Macgregor, S. A. Computa-
tional study of the mechanism of cyclometalation by palladium
acetate. J. Am. Chem. Soc. 2005, 127, 13754-13755.
(60) Gorelsky, S. I.; Lapointe, D.; Fagnou, K. Analysis of the con-
certed metalation-deprotonation mechanism in palladium-cata-
lyzed direct arylation across a broad range of aromatic substrates.
J. Am. Chem. Soc. 2008, 130, 10848-10849.
(61) Ingram, A. J.; Walker, K. L.; Zare, R, N.; Waymouth, R. M. Cat-
alytic role of multinuclear palladium-oxygen intermediates in
aerobic oxidation followed by hydrogen peroxide disproportion-
ation. J. Am. Chem. Soc. 2015, 137, 13632-13646.
(62) A Chinese patent application of this work has been filed, appli-
cation no. 201711062549.3.
(63) Clagg, K.; Hou, H.; Weinstein, A. B.; Russell, D.; Stahl, S. S.;
Koenig, S. G. Synthesis of indole-2-carboxylate derivatives via
palladium-catalyzed aerobic amination of aryl C-H bonds. Org.
let. 2016, 18, 3586-3589.
(64) Chen, H.; Yang, H.; Wang, Z.; Xie, X.; Nan, F. Discovery of 3-
substituted 1H-indole-2-carboxylic acid derivatives as a novel
class of Cyslt1 selective antagonists. ACS Med. Chem. Lett. 2016,
7, 335-339.
(65) Jansen, M.; Dannhardt, G. Variations of acidic functions at posi-
tion 2 and substituents at positions 4, 5 and 6 of the indole moiety
and their effect on NMDA-glycine site affinity. Eur. J. Med.
Chem. 2003, 38, 855.
(66) del Carmen Cruz, M.; Jimenez, F.; Delgado, F.; Tamariz, J. Re-
gioselective and versatile synthesis of indoles via intramolecular
Friedel-Crafts heteroannulation of enaminones. Synlett, 2006, 05,
0749-0755.
(67) Heaner Iv, W. L.; Gelbaum, C. S.; Gelbaum, L.; Pollet, P.; Rich-
man, K. W.; DuBay, W.; Butler, J. D.; Wells, G.; Liotta, C. L.
Indoles via Knoevenagel–Hemetsberger reaction sequence. RSC
Adv. 2013, 3, 13232-13242.
(38) Tan, E.; Konovalov, A.I.; Fernꢀndez, G.A.; Dorel, R.; Echavar-
ren, A.M. Ruthenium-catalyzed peri-and ortho-alkynylation with
bromoalkynes via insertion and elimination. Org. Lett. 2017, 19,
5561-5564.
(39) Su, F.; Lin, W.; Zhu, P.; He, D.; Lin, J.; Zhang, H.J.; Wen, T.B.
Regioselective direct C3-phosphorylation of N-sulfonylindoles
under mild oxidative conditions. Adv. Synth. Catal. 2017, 359,
947-951.
(40) Reekie, T.A.; Wilkinson, S.M.; Law, V.; Hibbs, D.E.; Ong, J.A.;
Kassiou, M. Rapid access to N-(indol-2-yl) amides and N-(indol-
3-yl) amides as unexplored pharmacophores. Org. Biomol. Chem.
2017, 15, 576-580.
(41) Chen, K.X.; Vibulbhan, B.; Yang, W.; Sannigrahi, M.; Ve-
lazquez, F.; Chan, T.Y.; Venkatraman, S.; Anilkumar, G.N.;
Zeng, Q.; Bennet, F.; Jiang, Y. Structure–activity relationship
(SAR) development and discovery of potent indole-based inhib-
itors of the hepatitis C virus (HCV) NS5B polymerase. J. Med.
Chem. 2012, 55, 754-765.
(42) Xia, Y.Q.; Li, C.; Liu, M.; Dong, L. Ruthenium-catalyzed selec-
tive C-C coupling of allylic alcohols with free indoles: Influence
of the metal catalyst. Chem.-Eur. J. 2018, 24, 5474-5478.
(43) Richards, F. M. The interpretation of protein structures: total vol-
ume, group volume distributions and packing density. J. Mol.
Biol. 1974, 82, 1-14.
(44) Willis, M.; Hicke, B.; Uhlenbeck, O.; Cech, T.; Koch, T. Photo-
crosslinking of 5-iodouracil-substituted RNA and DNA to pro-
teins. Science 1993, 262, 1255-1257.
(45) Muller, K.; Faeh, C.; Diederich, F. Fluorine in pharmaceuticals:
looking beyond intuition. Science 2007, 317, 1881-1886.
(46) Batsanov, S. S. Van der Waals radii of elements. Inorg. Mater.
2001, 37, 871-885.
(47) Mantina, M.; Chamberlin, A. C.; Valero, R.; Cramer, C. J.;
Truhlar, D. G. Consistent van der Waals radii for the whole main
group. J. Phys. Chem. A 2009, 113, 5806-5812.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(68) Tummatorn, J.; Gleeson, M. P.; Krajangsri, S.; Thongsornkleeb,
C.; Ruchirawat, S. ZrCl4-promoted facile synthesis of indole de-
rivatives. RSC Adv. 2014, 4, 20048-20052.
(48) Engle, K. M.; Mei, T. S.; Wasa, M.; Yu, J. Q. Weak coordination
as a powerful means for developing broadly useful C-H function-
alization reactions. Acc. Chem. Res. 2011, 45, 788-802.
(49) Delavirdine is one of the non-nucleoside reverse transcriptase in-
hibitors (NNRTIs) that bind into a ‘pocket’ close to the catalytic
site of reverse transcriptase of HIV-1. This drug was approved
for clinic use by the Food and Drug Administration (FDA) in
1997.
(69) Frecentese, F.; Fiorino, F.; Perissutti, E.; Severino, B.; Magli, E.;
Esposito, A.; De Angelis, F.; Massarelli, P.; Nencini, C.; Viti, B.;
Santagada, V.; Caliendo, G. Efficient microwave combinatorial
synthesis of novel indolic arylpiperazine derivatives as seroto-
ninergic ligands. Eur. J. Med. Chem. 2010, 45, 752-759.
(70) Murai, N.; Yonaga, M.; Tanaka, K. Palladium-catalyzed direct
hydroxymethylation of aryl halides and triflates with potassium
acetoxymethyltrifluoroborate. Org. Lett. 2012, 14, 1278-1281.
(71) Wang, Z.; Vince, R. Design and synthesis of dual inhibitors of
HIV reverse transcriptase and integrase: introducing a diketoacid
functionality into delavirdine. Bioorg Med Chem. 2008, 16,
3587-3595.
(72) Sanz, R.; Escribano, J.; Pedrosa, M. R.; Aguado, R.; Arnáiz, F. J.
Dioxomolybdenum(VI)-catalyzed reductive cyclization of ni-
troaromatics. Synthesis of carbazoles and indoles. Adv. Synth.
Catal. 2007, 349, 713-718.
(73) Liu, Y.; Chen, G. Q.; Tse, C. W.; Guan, X.; Xu, Z. J.; Huang, J.
S.; Che, C. M. [Fe(F20TPP)Cl]-Catalyzed Amination with Aryla-
mines and {[Fe(F20TPP)(NAr)](PhI=NAr)} Intermediate As-
sessed by High-Resolution ESI-MS and DFT Calculations.
Chem. Asian. J. 2015, 10, 100.
(74) Colombo, E.; Ratel, P.; Mounier, L.; Guillier, F. Reissert indole
synthesis using continuous-flow hydrogenation. J. Flow Chem.
2011, 1, 68-73.
(75) Zhu, Z.; Yuan, J.; Zhou, Y.; Qin, Y.; Xu, J.; Peng, Y. Ligand-
free copper-catalyzed one-pot synthesis of indole-2-carboxylic
esters. Eur. J. Org. Chem. 2014, 2014, 511-514.
(76) Wagaw, S.; Yang, B. H.; Buchwald, S. L. A palladium-catalyzed
method for the preparation of indoles via the Fischer indole syn-
thesis. J. Am. Chem. Soc. 1999, 121, 10251-10263.
(77) Stokes, B. J.; Dong, H.; Leslie, B. E.; Pumphrey, A. L.; Driver,
T. G. Intramolecular C-H amination reactions: exploitation of the
(50) De Clercq, E. Anti-HIV drugs: 25 compounds approved within
25 years after the discovery of HIV. Int. J. Antimicrob. Agents
2009, 33, 307-320.
(51) Ge, M. CN Pat., CN 102633778A, 2012.
(52) Westheimer, F. H. The magnitude of the primary kinetic isotope
effect for compounds of hydrogen and deuterium. Chem. Rev.
1961, 61, 265-273.
(53) Simmons, E. M.; Hartwig, J. F. On the interpretation of deuter-
ium kinetic isotope effects in C-H bond functionalizations by
transition-metal complexes. Angew. Chem., Int. Ed. 2012, 51,
3066-3072.
(54) Lapointe, D.; Fagnou, K. Overview of the mechanistic work on
the concerted metalation-deprotonation pathway. Chem. Lett.
2010, 39, 1118-1126.
(55) Campbell, A. N.; Stahl, S. S. Overcoming the “Oxidant Problem”:
strategies to use O2 as the oxidant in organometallic C-H oxida-
tion reactions catalyzed by Pd (and Cu). Acc. Chem. Res. 2012,
45, 851-863.
(56) Yeung, C. S.; Dong, V. M. Catalytic dehydrogenative cross-cou-
pling: forming carbon-carbon bonds by oxidizing two carbon-
hydrogen bonds. Chem. Rev. 2011, 111, 1215-1292.
(57) Hohenberg, P.; Kohn, W. Inhomogeneous electron gas. Phys.
Rev. 1964, 136, B864.
(58) García-Cuadrado, D.; Braga, A. A. C.; Maseras, F.; Echavarren,
A. M. Proton abstraction mechanism for the palladium-catalyzed
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 18 of 19
Rh(II)-catalyzed decomposition of azidoacrylates. J. Am. Chem.
(81) Mahboobi, S.; Teller, S.; Pongratz, H.; Hufsky, H.; Sellmer, A.;
Soc. 2007, 129, 7500-7501.
Botzki, A.; Uecker, A.; Beckers, T.; Baasner, S.; Schächtele, C.;
Überall, F.; Kassack, M. U.; Dove, S.; Böhmer, F.-D. Bis (1H-2-
indolyl) methanones as a novel class of inhibitors of the platelet-
derived growth factor receptor kinase. J. Med. Chem. 2002, 45,
1002-1018.
1
2
3
4
(78) Rubio-Marques, P.; Rivero-Crespo, M. A.; Leyva-Perez, A.;
Corma, A. Well-defined noble metal single sites in zeolites as an
alternative to catalysis by insoluble metal salts. J. Am. Chem. Soc.
2015, 137, 11832-11837.
5
6
7
8
(79) Bartoli, G.; Palmieri, G.; Petrini, M. A new approach to the syn-
thesis of 2-substituted indoles: reaction of dimetallated ortho-tri-
methylsilylmethylanilides with esters. Tetrahedron. 1990, 46,
1379-1384.
(80) Trabbic, C. J.; Dietsch, H. M.; Alexander, E. M.; Nagy, P. I.;
Robinson, M. W.; Overmeyer, J. H.; Maltese, W. A.; Erhardt, P.
W. Differential induction of cytoplasmic vacuolization and me-
thuosis by novel 2-indolyl-substituted pyridinylpropenones. ACS
Med. Chem. Lett. 2014, 5, 73-77.
(82) Choi, T.; Ma, E. Structural influence of indole C5-N-substi-
tutents on the cytotoxicity of seco-duocarmycin analogs. Arch.
Pharm. Res. 2011, 34, 357-367.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
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8
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12
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14
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20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
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54
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