Ruthenium(II)-Catalyzed Redox-Neutral [3+2] Annulation of Indoles with Internal Alkynes via C-H Bond Activation: Accessing a Pyrroloindolone Scaffold

Article abstract of DOI:10.1021/acs.joc.7b00575

Ru(II)-catalyzed redox-neutral [3+2] annulation reactions of N-ethoxycarbamoyl indoles and internal alkynes via C-H bond activation are reported. This method features a broad internal alkyne scope, including various aryl/alkyl-, alkyl/alkyl-, and diaryl-substituted alkynes, good to excellent regioselectivity, diverse functional group tolerance, and mild reaction conditions. The N-ethoxycarbamoyl directing group, temperature, CsOAc, and ruthenium catalyst proved to be crucial for conversion and high regioselectivity. Additionally, preliminary mechanistic experiments were conducted, and a possible mechanism was proposed.

Full text of DOI:10.1021/acs.joc.7b00575

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Article
Ruthenium(II)-catalyzed redox-neutral [3+2] annulation of indoles with internal
alkynes via C-H bond activation: Accessing to a pyrroloindolone scaffold
Yanan Xie, Xiaowei Wu, Chunpu Li, Jiang Wang, Jian Li, and Hong Liu
J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 19 Apr 2017
Downloaded from http://pubs.acs.org on April 19, 2017
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Ruthenium(II)ꢀcatalyzed redoxꢀneutral [3+2] annulation of
indoles with internal alkynes via C−H bond activation: Accessing
to a pyrroloindolone scaffold
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Yanan Xie,†,& Xiaowei Wu,‡,§,& Chunpu Li,‡ Jiang Wang,‡ Jian Li,*,† and Hong Liu*,‡
†Shanghai Key Laboratory of New Drug Design School of Pharmacy, East China
University of Science and Technology, 130 Meilong Road, Shanghai 200237, China.
‡State Key Laboratory of Drug Research, Key Laboratory of Receptor Research,
Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong
Zhi Road, Shanghai, 201203, China.
§University of Chinese Academy of Sciences, No.19A Yuquan Road, Beijing 100049,
China.
* Corresponding author
Jian Li, Ph. D., Professor and Hong Liu, Ph. D., Professor
Author Contributions
&Y. Xie and X. Wu contributed equally to this work.
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Graphic Abstract
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Abstract
Ru(II)ꢀcatalyzed redoxꢀneutral [3+2] annulation reactions of Nꢀethoxycarbamoyl
indoles and internal alkynes via CꢀH bond activation are reported. This method
features broad internal alkyne scope including various aryl/alkylꢀ, alkyl/alkylꢀ, and
diarylꢀsubstituted alkynes, good to excellent regioselectivity, diverse functional group
tolerance, and mild reaction conditions. The Nꢀethoxycarbamoyl directing group,
temperature, CsOAc, and the ruthenium catalyst proved to be crucial for conversion
and high regioselectivity. Additionally, preliminary mechanistic experiments were
conducted and a possible mechanism was proposed.
Introduction
The indole ring is an important structural motif that is present in many biologically
active natural products and pharmaceuticals.1 Considering their varied activities,
tremendous effort has been devoted to develop synthetic methods to prepare and
modify indoles over the past decades.2 Arguably, transition metalꢀcatalyzed C−H
activation reactions represent a powerful approach for the synthesis and direct
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transformation of indoles.2ꢀ4 Among these processes, transition metalꢀcatalyzed
annulation reactions of indole with diverse coupling partners have received much
attention in recent years.5 These reactions allow the atomꢀeconomical and rapid
synthesis of more functionalized indoleꢀfused scaffolds from simple starting
materials.
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Figure 1. Selected examples of biologically active compounds bearing a
pyrrolo[1,2ꢀa]indole core.
Among Nꢀfused indole cores, the pyrrolo[1,2ꢀa]indole core is an integral part of
many biologically active natural molecules and pharmaceuticals (Figure 1).6ꢀ8
However, current methods to prepare pyrrolo[1,2ꢀa]indole scaffolds usually require
harsh reaction conditions or highly functionalized substrates.9 In 2012, Oestreich and
coworkers9h reported an example of aerobic palladium(II)ꢀcatalyzed intramolecular
cyclization to provide 3Hꢀ pyrrolo[1,2ꢀa]indoleꢀ3ꢀones(Scheme 1, eq 1), in which a
o
o
high reaction temperature (110 C or 150 C) was required. Recently, Kanai and
Matsunaga’s group9b pioneered the development of Cp*Co(III)ꢀcatalyzed
redoxꢀneutral C2ꢀselective C−H alkenylation/annulation cascade of Nꢀcarbamoyl
indoles with internal alkynes to produce pyrroloindolones (eq 2). In view of the
rigorous reaction conditions in the reported methods, the development of new
approaches that allow rapid construction of these scaffolds from readily available
starting materials under mild conditions remains an important challenge. To the best
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of our knowledge, Ru(II)ꢀcatalyzed C2ꢀselective C−H alkenylation and subsequent
cyclization with indoles remains underexplored. Herein, based on our interest in
developing direct C−H functionalization reactions,10 we report the first example of
Ru(II)ꢀcatalyzed redoxꢀneutral [3+2] annulation of Nꢀethoxycarbamoyl indoles which
is more reactive than Co(III)ꢀcatalyzed Nꢀcarbamoyl indoles and internal alkynes via
C−H bond activation with good regioselectivity under mild conditions (eq 3).
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Scheme 1. Transition metalꢀcatalyzed annulations of Nꢀprotected indoles for
pyrroloindolone synthesis.
Results and discussion
We initiated the coupling reaction of Nꢀmethoxycarbamoyl indole 1a and the
o
propargyl alcohol 2a catalyzed by Ru(II) in 1,2ꢀdichloroethane at 60 C. First, the
reaction did not proceed without any base (Table 1, Entry 1). Then, diverse solvents
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Table 1. Optimization of reaction conditions.a
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3a Yield
(%)b
3a/4a
NO.
R
Solvent
DCE
Base
Time(h)
T.(oC)
ratioc
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2
3
4
5
6
7
8
9
MeOꢀ
none
CsOAc
CsOAc
CsOAc
CsOAc
CsOAc
CsOAc
CsOAc
CsOAc
CsOAc
CsOAc
CsOAc
NaOAc
KOAc
Cu(OAc)2
CsOPiv
NaHCO3
CsCO3
CsOAc
CsOAc
CsOAc
CsOAc
CsOAc
12
12
12
12
12
12
12
12
12
12
12
2
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60
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60
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50
40
60
60
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0
0
0
ꢀ
ꢀ
ꢀ
MeOꢀ DMSO
MeOꢀ DMF
MeOꢀ MeCN
MeOꢀ
MeOꢀ
MeOꢀ
MeOꢀ
0
33
Trace
0
ꢀ
DCE
THF
TFE
63:37
ꢀ
ꢀ
79:21
77:23
85:15
95:5
95:5
ꢀ
PhMe
34
52
24
59
72(67)
0
MeOꢀ CH2Cl2
CH2Cl2
10d BuOꢀ
11e
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13
14
15
16
17
18
19
20
21f
EtOꢀ
EtOꢀ
EtOꢀ
EtOꢀ
EtOꢀ
EtOꢀ
EtOꢀ
EtOꢀ
EtOꢀ
EtOꢀ
EtOꢀ
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
2
2
2
0
0
ꢀ
ꢀ
2
2
67
0
93:7
ꢀ
2
2
0
ꢀ
78(71)
29
21
0
91:9
63:37
93:7
ꢀ
2
2
22g EtOꢀ
23h EtOꢀ CH2Cl2
2
2
0
ꢀ
aReaction conditions: 1a (0.2 mmol), 2a (0.26 mmol), Catalyst (5 mol %), Base (1
b
equiv.) in 4 mL Solvent at 60 °C, Ar atmosphere. NMR yields using CH2Br2 as an
internal standard, isolated yields in parentheses. cDetermined by 1HꢀNMR analysis of the
d
e
crude reaction mixtures. tꢀbutyl group instead of methyl group. ethyl group instead of
f
g
methyl group. 2.5 mol% [RuCl2(pꢀcymene)]2 was employed. using 5 mol% RuCl3
instead of [RuCl2(pꢀcymene)]2.husing
5
mol% [Cp*RhCl2]2 instead of
[RuCl2(pꢀcymene)]2.
including DMSO, DMF, MeCN, THF, TFE, DCE, PhMe and dichloromethane were
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screened, and dichloromethane provided 52% yield of product 3a, whose structure
was confirmed by Xꢀray analysis (see Supporting Information for more details and
entry 2ꢀ9 in table 1).11 Subsequently, the influence of different substituted hydroxamic
acidꢀtype substrates was investigated, and an ethyl group in the R moiety gave the
product in a moderate yield with good regioselectivity (Table 1, Entries 10ꢀ11). When
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the reaction time was reduced, the H NMR yield was improved to 72% and the ratio
of 3a/4a (95:5) was maintained. Further screening of a variety of bases such as
CsOAc, KOAc, NaOAc, NaHCO3, Cu(OAc)2, CsOPiv, NaHCO3 and CsCO3
demonstrated that CsOAc was the optimal base (Table 1, Entries 12ꢀ18). Performing
o
the reaction 50 C produced compound 3a in 78% yield, but the regioselectivity was
reduced (Table 1, Entry 19). Decreasing the reaction temperature or the amount of the
catalyst led to a significantly lower coupling efficiency (Table 1, Entries 20ꢀ21).
Additionally, the reaction did not proceed in the absence of the catalyst
[RuCl2(pꢀcymene)]2 (Table 1, Entries 22ꢀ23). Briefly, the optimum results could be
obtained when Nꢀethoxycarbamoyl indole 1a (0.2 mmol) and 2a (0.26 mmol, 1.3
equiv) in CH2Cl2 were treated with 5 mol % Ru(II) catalyst and CsOAc (0.2 mmol, 1
equiv) at 60 oC for 2 h.
With the optimized reaction conditions in hand, we first examined the scope of
differentially substituted Nꢀethoxycarbamoyl indoles in cyclization with propargyl
alcohol 2a (Table 2). In general, the introduction of various electronꢀdonating or
electronꢀwithdrawing groups at the Cꢀ3, 4, 5, or 6 positions of the indoles all
underwent smooth coupling with propargyl alcohol 2a, and the desired cyclization
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products were obtained in acceptable to good yields, with good regioselectivity.
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Table 2. Scope of Indolesa,b,c
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Me
Me
Me
OH
OH
N
N
O
O
NO2
3b, 62%, >99:1d
NO2
X-Ray of 3a
3a, 67%, 95:5
aReaction conditions: 1 (0.2 mmol), 2a (0.26 mmol), Catalyst (5 mol %), base (1 equiv)
b
c
in DCM (4 mL) at 60 °C, Ar atmosphere. Isolated yields of product 3 was reported. The
ratio of 3/4 was determined by 1HꢀNMR analysis of the crude reaction mixtures. dReaction
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was run for 6 h. eReaction was run for 24 h. fReaction was run for 36 h.
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Introduction of a methyl group at the Cꢀ3 position of indole gave a single isomer 3b in
62% yield. Substrates bearing electronꢀwithdrawing or electronꢀdonating substituents,
such as chlorine (3c), methyl (3d), and benzyloxy (3e) at the Cꢀ4 position of the
indoles, also provided the desired products in good yields and with high
regioselectivity. In addition, similar results were observed when halogen groups
(3fꢀ3h), methyl (3i), and methoxy (3j) were introduced at the Cꢀ5 position of the
indoles. However, the yield of product 3k decreased when an ester group was placed
at the Cꢀ5 position of the indoles. We further investigated the influence of Cꢀ6
substituents at the benzene ring of the indoles on the reaction. The results showed that
it provided the corresponding product (3l) in good yield and regioselectivity when
fluorine was introduced at the Cꢀ6 position of the indoles. By contrast, the
electronꢀrich substrate bearing a methoxy group provided the desired product (3m) in
decreased yield. In general, regardless of electronꢀwithdrawing groups,
electronꢀdonating groups at the Cꢀ4 and Cꢀ5 position of indoles; it provided the
desired products with good regioselectivity. Besides, it also afforded the
corresponding product with good regioselectivity when electronꢀwithdrawing group
was introduced at the Cꢀ6 position of indoles. However, the electronꢀrich substrate
bearing a methoxy group at the Cꢀ6 position gave the desired product with poor
regioselectivity.
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We also examined the scope of the reaction with respect to the internal alkynes as
coupling partners (Table 3). In general, the coupling reaction of the indoles proceeded
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well with various aryl/alkylꢀ, alkyl/alkylꢀ, and diarylꢀsubstituted alkynes (3nꢀ3zj).
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Table 3. The Scope of Internal Alkynesa,b,c,d,e
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aReaction conditions: 1 (0.2 mmol), 2 (0.26 mmol), Catalyst (5 mol %), CsOAc
b
(1 equiv) in CH2Cl2 (4 mL) at 60 °C, Ar atmosphere. Isolated yields of 3 was
c
1
reported. The ratio of 3/4 was determined by HꢀNMR analysis of the crude
d
e
reaction mixtures. Reaction of 3nꢀ3x was run for 2h. Reaction of 3yꢀ3zj was
run for 24 h. fusing 2a (0.4 mmol) and Catalyst (10 mol %).
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With unsymmetrical aryl/alkylꢀalkynes, each cyclization product was obtained as a
single isomer in moderate to good yield (3n, 3o, 3q, 3v, 3w, and 3x). However, it did
not provide the desired product when using a terminal alkyne as the coupling partner
(3p). In addition, annulation adducts were obtained from diarylꢀsubstituted alkynes in
good yields, regardless of the use of electronꢀrich or electronꢀpoor alkynes (3r, 3t, and
3u). Notably, diethylꢀsubstituted alkynes was compatible in this method (3s); in
contrast, it did not work in the Cp*Co(III)ꢀcatalyzed annulation reaction.
Furthermore, we investigated the scope of propargyl alcohols. Generally, the coupling
of Nꢀethoxycarbamoyl indole 1a and various substituted propargyl alcohols 2
provided the annulation adducts in moderate to good yields (3yꢀ3zk). Substrates
bearing electronꢀwithdrawing groups, such as halides, trifluoromethyl, and an eater, at
the benzene ring of propargyl alcohols were well tolerated under the reaction
conditions (3zaꢀ3zf). However, some electronꢀrich substrates did not provide the
desired products (3z and 3zg). In addition, diverse heteroaryl groups were compatible
in this method (3zhꢀ3zj).
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To evaluate the efficiency and potential for the synthetic utility of the method, we
carried out some transformations of pyrroloindolones (Scheme 2). Reduction of 3y
with Pd/C under H2 atmosphere gave pyrroloindolone 5a in 84% yield. Interestingly,
ringꢀopening by cleavage of the amide linkage would provide a Cꢀ2 alkenylated
indole 5b in 94% yield, which is hardly accessible through direct CꢀH coupling with
trisubstituted α,βꢀunsaturated acceptors.
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To shed more light on the reaction mechanism, H/D exchange and
deuteriumꢀlabeling experiments were conducted. We performed the reaction in the
presence of methanolꢀd4 to determine the reversibility of C−H activation by removing
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Scheme 2. Transformation of Pyrroloindolones
Scheme 3. Deuteration Experiments
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1
the other coupling partner (Scheme 3a). H NMR analysis showed that about 20%
deuteration was observed both at the Cꢀ2 and Cꢀ3 positions of indoles. In contrast, no
deuteration was observed when removing the base CsOAc (Scheme 3b). Carrying out
the same reaction in the presence of 2a also led to no deuterium incorporated into
indole 1a (Scheme 3c). These results suggest that the C2ꢀselective C−H activation
might be reversible and that cycloruthenation occurs under Ru catalysis with the aid
of acetate.12 To explore the C−H activation process further, kinetic isotope effect (KIE)
experiments were performed. An intermolecular competitive coupling reaction of an
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equimolar mixture of 1a and 1aꢀD with propargyl alcohol 2a was carried out, and a
kH/kD value of 0.82 was obtained based on recovered substrates 1a and 1aꢀD (Scheme
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3d). Besides, two independent reactions using 1a and 1aꢀD gave a KIE value of
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0.94. The results suggested that C−H bond cleavage is unlikely involved in the
rateꢀlimiting step9a.
Scheme 4. Proposed catalytic cycle.
Based on these experiments and previous literatures,5e,9b a possible mechanism is
proposed (Scheme 4). As the initial step, an active catalyst is generated through ligand
exchange to cesium acetate. Coordination of Nꢀcarboxamides of indoles 1a to the
Ru(II) catalyst and subsequent Cꢀ2 selective CꢀH bond activation with the aid of
CsOAc forms a fiveꢀmembered ruthenacycle A. Then, the regioselective coordination
and migratory insertion of internal alkynes into the RuꢀC bond of ruthenacycle A
produces intermediate B. Intramolecular nucleophilic addition of intermediate II
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would give the intermediate C, which was followed by release of ethoxyamine to give
product 3, with the regeneration of the Ru(II) catalyst.
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Conclusions
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In summary, we have developed novel Ru(II)ꢀcatalyzed redoxꢀneutral [3+2]
annulation reactions of Nꢀethoxycarbamoyl indoles and internal alkynes. Moderate to
excellent yields of pyrroloindolone derivatives were obtained, with broad internal
alkynes scope, good to excellent regioselectivities, and mild reaction conditions.
Preliminary mechanistic experiments were conducted, and a plausible mechanism was
proposed. Additionally, the easy transformations of the products might further
underscore its synthetic utility and versatile applicability.
Experimental Section
General Information. Analytical thin layer chromatography (TLC) was HSGF 254
(0.15ꢀ0.2 mm thickness). Preparative thin layer chromatography (PTLC) was HSGF
254 (0.4ꢀ0.5 mm thickness). All products were characterized by their NMR and MS
1
spectra. H and 13C NMR spectra were recorded on a 400 MHz, 500 MHz or 600
MHz instrument. Chemical shifts were reported in parts per million (ppm, δ)
downfield from tetramethylsilane. Proton coupling patterns are described as singlet (s),
doublet (d), triplet (t), quartet (q), multiplet (m), doublet of doublets (dd) and broad
(br). Highꢀresolution mass spectra (HRMS) were measured on Micromass Ultra
QꢀTOF spectrometer. All Nꢀcarbamoylindoles were prepared by following the same
procedure as described in the literature12. Alkynes (2e,13 2j,14 2k,15 2m,15 2n,16 2o,14
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2p,17 2r,15) were prepared by following the same procedure as described in the
literature. 2a, 2l, 2q, 2s, 2t, 2u were prepared using modified literature procedures.14
Other reagents (chemicals) were purchased and used without further purification.
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Typical Synthesis Procedure of 1aꢀ1m and [D]ꢀ1a.
In a 250 mL threeꢀnecked flask a solution of nꢀBuLi (19.2 mL, 2.5 M in hexane)
was added dropwise to a solution of indole I (4.7g, 40.0 mmol) in THF (120 mL) over
30 min at 0 oC under Ar atmosphere. The reaction mixture was stirred for another 30
o
o
min at 0 C. CO2 was bubbled to the solution for 1 h at 0 C, then H2O (20 mL) was
dropped to quench the reaction. The solution was concentrated to about 30 mL under
vacuum. Aqueous HCl (6 M) was added dropwise to adjust the pH value of the
solution to 3. After the solution was extracted with ethyl acetate (60 mL × 3), the
combined organic layer was dried over anhydrous Na2SO4, evaporated to afford crude
Nꢀ carboxyl indole II. (COCl)2 (1.72 mL, 20.0 mmol) was dropped to a solution of
crude product II (10.0 mmol) in anhydrous DCM (20 mL) and DMF (0.1 mL) over 30
min at 0 oC. The solution was kept at room temperature for 2 h. Then the solution was
concentrated to afford crude acyl chloride III for next step without further
purification.
The crude acyl chloride III in EA (5ml) was dropped to a solution of ethoxylamine
hydrhloride (1.67 g, 20.0 mmol) and NaHCO3 (3.36 g, 40.0 mmol) in EA (50 mL) and
H2O (10 mL) over 30 min at 0 oC. The solution was kept at room temperature for 3 h.
Then the solution was filtered and the filtrate was concentrated to give a residue. The
residue was subject to flash column chromatography [silica gel, ethyl
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acetate/petroleum ether (v/v, 1/5) as eluent] to afford Nꢀcarbamoyl indoles 1a.
2ꢀDeuterium indole was prepared according to the literature and NMR spectral
data matched the data18. According to the general procedures [D]ꢀ1a was synthesized
with 94% Dꢀincorporation.
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Typical Synthesis Procedure of 2a, 2l, 2q, 2s, 2t, 2u
In a dry 100ml threeꢀnecked flask was dissolved the corresponding aldehyde (10 m
o
mol) in dry THF under nitrogen atmosphere and then cooled to 0 C. The Grignard
reagent (12 mmol, 0.5 M in THF) was added to the mixture and then was kept at 0 oC
for one hour and then 1 hour at room temperature. The completion of the reactions
was confirmed by TLC, and then the saturated solution of ammonium chloride was
added. The organic mixture was extracted by EA, dried with Na2SO4 and the solvent
removed under vacuum. The crude product was purified by column chromatography
using silica gel [silica gel, ethyl acetate/petroleum ether (v/v, 1/8) as eluent].
Typical Synthesis Procedure and Characterization of 3aꢀ3o, 3qꢀ3y, 3zaꢀ3zf and
3zhꢀ3zj.
To a reaction tube was added Nꢀethoxyꢀ1Hꢀindoleꢀ1ꢀcarboxamide 1a (41 mg, 0.2
mmol), alkyne 2a (50mg, 0.26mmol), CsOAc (39 mg, 0.2 mmol),
[Ru(pꢀcymene)Cl2]2 (6mg, 5% mmol) and dichloromethane (4.0 mL), then was
evacuated and purged with Ar three times. The solution was kept at 60 oC for 2 h – 24
h. After the solution was cooled to room temperature, it was diluted with CHCl3 and
then transferred to a round bottom flask. The crude mixture was purified by silica gel
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column chromatography [ethyl acetate/petroleum ether (v/v, 1:6) as eluent] to give a
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corresponding product 3a.
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Transformation of Pyrroloindolones
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(a) Hydrogenation of 3y
To a solution of 3y (29 mg, 0.1 mmol) in AcOEt (2 mL) was added Pd/C (5 wt%,
11mg, 5%mmol) .The solution was stirred under H2 atmosphere for 4h at room
temperature. Then the solution was Filtrated and evaporated, The residue was subject
to flash column chromatography [silica gel, ethyl acetate/petroleum ether (v/v, 1/6) as
eluent] to afford colorless oil 5a (24.5 mg, 84% yield).
(b) Transformation of pyrroloindolone 3y to α,βꢀunsaturated amide 5b
To a solution of 3y (29 mg, 0.1 mmol) in THF (2 mL) were added DBU (45 µL, 0.3
mmol), and pyrrolidine (25 µL, 0.3 mmol) at room temperature. After the mixture was
o
stirred at 60 C for 6 h, saturated aq. NH4Cl was added. Then the mixture was
extracted with AcOEt (x 3), and dried over Na2SO4. The residue was subject to flash
column chromatography [silica gel, ethyl acetate/petroleum ether (v/v, 1/6) as eluent]
to afford colorless oil 5b (24.0 mg, 94% yield).
Analytical Characterization Data of Substrates and Products.
Nꢀethoxyꢀ1Hꢀindoleꢀ1ꢀcarboxamide 1a. Yellow solid (5.9 g, 72% yield). m.p. 73–74
oC. 1H NMR (400 MHz, CDCl3) δ 8.22 (s, 1H), 8.14 – 8.09 (dd, J = 8.3, 0.7 Hz, 1H),
7.61 – 7.56 (d, J = 7.8 Hz, 1H), 7.44 – 7.40 (d, J = 3.7 Hz, 1H), 7.37 – 7.30 (m, 1H),
7.26 – 7.22 (m, 1H), 6.65 – 6.61 (dd, J = 3.7, 0.6 Hz, 1H), 4.13 – 4.06 (q, J = 7.0 Hz,
13
1H), 1.37 – 1.32 (t, J = 7.0 Hz, 1H). C NMR (126 MHz, CDCl3) δ 153.4, 135.2,
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130.2, 124.8, 123.7, 123.0, 121.4, 114.7, 108.3, 72.8, 13.6. HRMS (ESI) m/z:
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ꢀ
calculated for C11H11N2O2 [M ꢀ H]ꢀ: 203.0826, found: 203.0820.
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Nꢀethoxyꢀ3ꢀmethylꢀ1Hꢀindoleꢀ1ꢀcarboxamide 1b. Yellow solid (4.4 g, 50% yield).
m.p. 72–73 oC. 1H NMR (400 MHz, CDCl3) δ 8.48 (br, 1H), 8.15 – 8.10 (m, 1H), 7.52
– 7.47 (d, J = 7.6 Hz, 1H), 7.35 – 7.28 (m, 1H), 7.26 – 7.21 (m, 1H), 7.17 (s, 1H),
4.10 – 4.02 (m, 2H), 2.24 (m, 3H), 1.34 – 1.28 (m, 3H). 13C NMR (151 MHz, CDCl3)
δ 153.5, 135.6, 131.0, 124.9, 122.7, 120.4, 119.3, 117.8, 114.8, 72.8, 13.7, 13.7, 9.8,
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ꢀ
9.8. HRMS (ESI) m/z: calculated for C12H13N2O2 [M ꢀ H]ꢀ: 217.0983, found:
217.0978.
4ꢀchloroꢀNꢀethoxyꢀ1Hꢀindoleꢀ1ꢀcarboxamide 1c. Yellow solid (6.4 g, 67% yield).
o
1
m.p. 103–104 C. H NMR (400 MHz, CDCl3) δ 8.27 (s, 1H), 8.07 – 8.00 (m, 1H),
7.46 – 7.42 (d, J = 3.7 Hz, 1H), 7.25 (d, J = 2.1 Hz, 1H), 7.24 (s, 1H), 6.77 – 6.74 (dd,
J = 3.7, 0.7 Hz, 1H), 4.14 – 4.06 (q, J = 7.0 Hz, 2H), 1.37 – 1.31 (t, J = 7.0 Hz, 3H).
13C NMR (151 MHz, CDCl3) δ 153.1, 136.0, 128.9, 126.5, 125.5, 124.1, 122.8, 113.3,
ꢀ
106.6, 72.9, 13.7, 13.6. HRMS (ESI) m/z: calculated for C11H10ClN2O2 [M ꢀ H]ꢀ:
2370436, found: 237.0430.
Nꢀethoxyꢀ4ꢀmethylꢀ1Hꢀindoleꢀ1ꢀcarboxamide 1d. Yellow solid (4.8 g, 55% yield).
o
m.p. 69–70 C. 1H NMR (400 MHz, CDCl3) δ 8.22 (br, 1H), 7.93 – 7.89 (dd, J = 8.4,
0.5 Hz, 1H), 7.44 – 7.41 (d, J = 3.7 Hz, 1H), 7.26 – 7.20 (t, J = 7.8 Hz, 1H), 7.07 –
7.02 (m, 1H), 6.68 – 6.63 (m, 1H), 4.14 – 4.06 (m, 2H), 2.52 (s, 3H), 1.38 – 1.33 (m,
3H). 13C NMR (151 MHz, CDCl3) δ 153.5, 134.9, 130.9, 129.9, 124.8, 123.4, 123.2,
112.0, 106.7, 72.8, 18.7, 18.66, 13.7, 13.6. HRMS (ESI) m/z: calculated for
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C12H13N2O2 [M ꢀ H]ꢀ: 217.0983, found: 217.0978.
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4ꢀ(benzyloxy)ꢀNꢀethoxyꢀ1Hꢀindoleꢀ1ꢀcarboxamide 1e. Yellow solid (5.2 g, 42%
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yield). m.p. 107–108 C. 1H NMR (400 MHz, CDCl3) δ 8.11 (br, 1H), 7.72 – 7.67 (d,
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J = 8.4 Hz, 1H), 7.50 – 7.46 (m, 2H), 7.43 – 7.47 (m, 2H), 7.37 – 7.31 (m, 2H), 7.26 –
7.20 (m, 1H), 6.83 – 6.80 (m, 1H), 6.76 – 6.71 (d, J = 8.0 Hz, 1H), 5.21 (s, 2H), 4.14
– 4.07 (m, 2H), 1.39 – 1.32 (m, 3H). 13C NMR (151 MHz, CDCl3) δ 153.4, 152.5,
137.2, 136.5, 128.7, 128.1, 127.5, 125.7, 122.2, 120.9, 107.8, 105.6, 104.7, 72.9, 70.2,
+
13.7, 13.6. HRMS (ESI) m/z: calculated for C18H19N2O3 [M + H]+: 311.1390, found:
311.1392.
Nꢀethoxyꢀ5ꢀfluoroꢀ1Hꢀindoleꢀ1ꢀcarboxamide 1f. Yellow solid (6.9 g, 78% yield).
o
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m.p. 105–106 C. H NMR (400 MHz, CDCl3) δ 8.28 (s, 1H), 8.12 – 8.07 (m, 1H),
7.45 – 7.41 (d, J = 3.7 Hz, 1H), 7.25 – 7.19 (dd, J = 8.8, 2.5 Hz, 1H), 7.09 – 7.01 (td,
J = 9.1, 2.6 Hz, 1H), 6.60 – 6.56 (dd, J = 3.7, 0.7 Hz, 1H), 4.12 – 4.04 (q, J = 7.0 Hz,
2H), 1.36 – 1.30 (t, J = 7.0 Hz, 3H). 13C NMR (126 MHz, CDCl3) δ 159.39 (d, J =
239.3 Hz) 153.2, 131.9, 130.9 (d, J = 10.1 Hz), 124.9, 115.8 (d, J = 9.2 Hz), 112.7 (d,
J = 25.3 Hz), 108.1 (d, J = 4.0 Hz), 106.6 (d, J = 23.8 Hz), 72.9, 13.6. 19F NMR (471
ꢀ
MHz, CDCl3) δ ꢀ120.9 ppm. HRMS (ESI) m/z: calculated for C11H10FN2O2 [M ꢀ H]ꢀ:
221.0732, found: 221.0725.
5ꢀchloroꢀNꢀethoxyꢀ1Hꢀindoleꢀ1ꢀcarboxamide 1g. Yellow solid (6.4 g, 67% yield).
1
m.p. 124–125 oC. H NMR (400 MHz, CDCl3) δ 8.40 (s, 1H), 8.08 – 8.04 (d, J = 8.9
Hz, 1H), 7.54 – 7.51 (d, J = 2.1 Hz, 1H), 7.44 – 7.40 (d, J = 3.7 Hz, 1H), 7.28 – 7.24
(dd, J = 8.8, 2.1 Hz, 1H), 6.56 – 6.53 (d, J = 3.7 Hz, 1H), 4.11 – 4.03 (q, J = 7.0 Hz,
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2H), 1.35 – 1.29 (t, J = 7.0 Hz, 3H). C NMR (126 MHz, CDCl3) δ 153.1, 133.8,
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131.2, 128.7, 124.9, 124.7, 120.8, 115.9, 107.7, 72.9, 13.6. HRMS (ESI) m/z:
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calculated for C11H10ClN2O2 [M ꢀ H]ꢀ: 237.0436, found: 237.0430.
ꢀ
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5ꢀbromoꢀNꢀethoxyꢀ1Hꢀindoleꢀ1ꢀcarboxamide 1h. Yellow solid (9.9 g, 88% yield).
m.p. 120–121 oC. 1H NMR (400 MHz, CDCl3) δ 8.36 (br, 1H), 8.04 – 7.99 (d, J = 8.8
Hz, 1H), 7.70 (d, J = 1.7 Hz, 1H), 7.43 – 7.37 (m, 2.8 Hz, 1H), 6.57 – 6.53 (d, J = 3.5
13
Hz, 1H), 4.12 – 4.03 (q, J = 7.0 Hz, 2H), 1.29 – 1.36 (t, J = 7.0 Hz, 3H). C NMR
(126 MHz, CDCl3) δ 153.1, 134.2, 131.7, 127.6, 124.6, 123.9, 116.3, 116.3, 107.6,
ꢀ
72.9, 13.6. HRMS (ESI) m/z: calculated for C11H10BrN2O2 [M ꢀ H]ꢀ: 280.9931, found:
280.9930.
Nꢀethoxyꢀ5ꢀmethylꢀ1Hꢀindoleꢀ1ꢀcarboxamide 1i. Yellow solid (5.8 g, 66% yield).
o
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m.p. 74–76 C. H NMR (400 MHz, CDCl3) δ 8.14 (br, 1H), 7.99 – 7.94 (d, J = 8.5
Hz, 1H), 7.39 (d, J = 3.7 Hz, 1H), 7.37 (d, J = 0.7 Hz, 1H), 7.17 – 7.12 (d, J = 8.5 Hz,
1H), 6.57 – 6.53 (m, 1H), 4.13 – 4.05 (m, 2H), 2.44 (m, 3H), 1.37 – 1.31 (m, 3H). 13C
NMR (151 MHz, CDCl3) δ 153.5, 133.4, 132.5, 130.4, 126.1, 123.7, 121.2, 114.2,
ꢀ
108.0, 72.8, 21.4, 21.4, 13.7, 13.6. HRMS (ESI) m/z: calculated for C12H13N2O2 [M ꢀ
H]ꢀ: 217.0983, found: 217.0978.
Nꢀethoxyꢀ5ꢀmethoxyꢀ1Hꢀindoleꢀ1ꢀcarboxamide 1j. Yellow solid (4.1 g, 44% yield).
o
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m.p. 76–78 C. H NMR (400 MHz, CDCl3) δ 8.18 (br, 1H), 8.02 – 7.97 (d, J = 9.0
Hz, 1H), 7.41 – 7.37 (d, J = 3.6 Hz, 1H), 7.03 (d, J = 2.0 Hz, 1H), 6.97 – 6.91 (m, 1H),
13
6.55 (m, 1H), 4.14 – 4.04 (m, 2H), 3.84 (s, 3H), 1.38 – 1.30 (m, 3H). C NMR (126
MHz, CDCl3) δ 156.1, 153.4, 131.0, 130.0, 124.2, 115.5, 113.7, 108.2, 103.7, 72.8,
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55.8, 13.6. HRMS (ESI) m/z: calculated for C12H14N2NaO3 [M + Na]+: 257.0897,
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found: 257.0902.
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methyl 1ꢀ(ethoxycarbamoyl)ꢀ1Hꢀindoleꢀ5ꢀcarboxylate 1k. Yellow solid (7.6 g, 72%
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o
yield). m.p. 104–105 C. 1H NMR (400 MHz, CDCl3) δ 8.62 (s, 1H), 8.28 – 8.25 (m,
1H), 8.18 – 8.13 (m, 1H), 8.00 – 7.95 (dd, J = 8.8, 1.7 Hz, 1H), 7.59 – 7.45 (d, J = 3.7
Hz, 1H), 6.67 – 6.64 (dd, J = 3.7, 0.6 Hz, 1H), 4.13 – 4.06 (q, J = 7.0 Hz, 2H), 3.93 (s,
13
3H), 1.36 – 1.30 (t, J = 7.0 Hz, 3H). C NMR (126 MHz, CDCl3) δ 167.7, 153.0,
138.0, 129.8, 125.9, 124.9, 124.9, 123.6, 114.5, 108.7, 72.9, 52.3, 13.6. HRMS (ESI)
m/z: calculated for C13H13N2O4 [M ꢀ H]ꢀ: 261.0881, found: 261.0874.
ꢀ
Nꢀethoxyꢀ6ꢀfluoroꢀ1Hꢀindoleꢀ1ꢀcarboxamide 1l. Yellow solid (6.2 g, 70% yield).
m.p. 74–76 oC 1H NMR (400 MHz, CDCl3) δ 8.17 (br, 1H), 7.87 – 7.94 (dd, J = 10.2,
1.7 Hz, 1H), 7.53 – 7.44 (m, 1H), 7.37 – 7.31 (d, J = 3.6 Hz, 1H), 7.04 – 6.96 (m, 1H),
6.62 – 6.59 (m, 1H), 4.14 – 4.04 (q, J = 7.0 Hz, 2H), 1.39 – 1.29 (t, J = 7.0 Hz, 3H).
13C NMR (126 MHz, CDCl3) δ 161.17 (d, J = 240.9 Hz), 153.2, 135.7 (d, J = 12.9
Hz), 126.2, 123.6 (d, J = 3.9 Hz), 121.9 (d, J = 10.0 Hz), 111.5 (d, J = 24.4 Hz), 108.3,
102.3 (d, J = 28.6 Hz), 72.9, 13.6. 19F NMR (471 MHz, CDCl3) δ ꢀ116.7 ppm. HRMS
(ESI) m/z: calculated for C11H10FN2O2 [M ꢀ H]ꢀ: 221.0732, found: 221.0725.
ꢀ
Nꢀethoxyꢀ6ꢀmethoxyꢀ1Hꢀindoleꢀ1ꢀcarboxamide 1m. Yellow solid. (3.0 g, 32%
o
1
yield). m.p. 75–76 C. H NMR (400 MHz, CDCl3) δ 8.11 (br, 1H), 7.78 (d, J = 2.3
Hz, 1H), 7.45 – 7.41 (d, J = 8.6 Hz, 1H), 7.23 – 7.20 (d, J = 3.7 Hz, 1H), 6.91 – 6.85
(m, 1H), 6.57 – 6.54 (m, 1H), 4.13– 4.06 (m, 2H), 3.87 (d, J = 0.8 Hz, 3H), 1.38 –
1.32 (m, 3H) 13C NMR (126 MHz, CDCl3) δ 158.2, 153.6, 136.6, 123.6, 121.7, 121.6,
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ꢀ
112.6, 108.5, 98.9, 72.8, 55.8, 13.7. HRMS (ESI) m/z: calculated for C12H14N2NaO3
[M + Na]+: 257.0897, found: 257.0902.
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Nꢀethoxyꢀ1Hꢀindoleꢀ2ꢀdꢀ1ꢀcarboxamide. Brown solid. (5.5 g, 67% yield). m.p.
69–70 oC. 1H NMR (500 MHz, CDCl3) δ 8.28 (s, 1H), 8.12 (dd, J = 8.3, 0.7 Hz, 1H),
7.58 (m, 1H), 7.43 (d, J = 3.7 Hz, 0.06H), 7.33 (m, 1H), 7.26 – 7.22 (m, 1H), 6.62 (d,
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J = 0.5 Hz, 1H), 4.09 (q, J = 7.0 Hz, 2H), 1.34 (t, J = 7.0 Hz, 3H). C NMR (151
MHz, CDCl3) δ 153.5, 135.2, 130.2, 124.7, 123.0, 121.3, 114.7, 108.1, 72.8, 13.6.
+
HRMS (ESI) m/z: calculated for C11H10DN2O2 [M – H]ꢀ: 204.0889, found: 204.0884.
1ꢀ(4ꢀnitrophenyl)butꢀ2ꢀynꢀ1ꢀol 2a. pale yellow solid. (1.6 g, 85% yield). m.p.
o
1
171–173 C. H NMR (400 MHz, CDCl3) δ 8.26 – 8.19(m, 2H), 7.70 (d, J = 8.4 Hz,
2H), 5.52 (d, J = 2.1 Hz, 1H), 2.21 (br, 1H), 1.91 (d, J = 2.1 Hz, 3H). 13C NMR (151
MHz, CDCl3) δ 148.1, 147.8, 127.4, 123.9, 84.6, 78.2, 63.9, 3.8. HRMS (ESI) m/z:
–
calculated for C10H8NO3 [M–H]– : 190.0510, found: 190.0512.
1
1ꢀ(4ꢀfluorophenyl)butꢀ2ꢀynꢀ1ꢀol 2l. colorless oil. (1.3 g, 78% yield). H NMR (500
MHz, CDCl3) δ 7.45 – 7.65 (m, 2H), 7.07 – 7.02 (m, 2H), 5.40 (d, J = 2.2 Hz, 1H),
13
2.25 (br, 1H), 1.91 (d, J = 2.2 Hz, 3H). C NMR (126 MHz, CDCl3) δ 162.7 (d, J =
246.5 Hz), 137.2 (d, J = 3.0 Hz), 128.5 (d, J = 8.3 Hz), 115.5 (d, J = 21.6 Hz), 83.5,
79.1, 64.2, 3.8. 19F NMR (471 MHz, CDCl3) δ ꢀ114.1 ppm. HRMS (EI) m/z:
calculated for C10H9FO [M]+: 164.0637, found: 164.0636.
methyl 4ꢀ(1ꢀhydroxybutꢀ2ꢀynꢀ1ꢀyl)benzoate 2q. colorless oil. (1.7 g, 83% yield). 1H
NMR (600 MHz, CDCl3) δ 8.05 ꢀ 8.02 (d, J = 8.4 Hz, 2H), 7.61 ꢀ 7.58 (d, J = 8.1 Hz,
2H), 5.49 ꢀ 5.46 (d, J = 2.1 Hz, 1H), 3.91 (s, 3H), 2.24 (s, 1H), 1.91 (d, J = 2.2 Hz,
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3H). 13C NMR (151 MHz, CDCl3) δ 167.0, 146.1, 130.0, 126.6, 83.9, 78.8, 64.4, 52.3,
3.9. HRMS (EI) m/z: calculated for C12H12O3 [M]+: 204.0788, found: 204.0786.
1ꢀ(thiophenꢀ3ꢀyl)butꢀ2ꢀynꢀ1ꢀol 2s. colorless oil. (1.0 g, 63% yield). 1H NMR (400
MHz, CDCl3) δ 7.40 ꢀ 7.35 (m, 1H), 7.33 ꢀ 7.28 (m, 1H), 7.22 ꢀ 7.17 (m, 1H), 5.46 (s,
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1H), 2.19 (br, 1H), 1.91 (d, J = 1.9 Hz, 3H). C NMR (151 MHz, CDCl3) δ 142.9,
126.5, 126.5, 122.5, 82.4, 79.1, 60.9, 3.8. HRMS (EI) m/z: calculated for C8H8OS
[M]+ : 152.0296, found: 152.0298.
1ꢀ(benzofuranꢀ2ꢀyl)butꢀ2ꢀynꢀ1ꢀol 2t. colorless oil. (1.0 g, 55% yield). 1H NMR (600
MHz, CDCl3) δ 7.58 ꢀ 7.54 (m, 1H), 7.50 ꢀ 7.48 (dd, J = 8.2, 0.7 Hz, 1H), 7.31 –
7.28(m, 1H), 7.25 ꢀ 7.21 (td, J = 7.7, 0.9 Hz, 1H), 6.81 (s, 1H), 5.56 ꢀ 5.58 (m, 1H),
13
2.43 (s, 1H), 1.94 (d, J = 2.2 Hz, 3H). C NMR (151 MHz, CDCl3) δ 155.9, 155.3,
127.9, 124.8, 123.1, 121.5, 111.6, 104.2, 83.4, 76.3, 59.0, 3.9. HRMS (EI) m/z:
calculated for C12H10O2 [M]+: 186.0682, found:186.0681.
1ꢀ(naphthalenꢀ2ꢀyl)butꢀ2ꢀynꢀ1ꢀol 2u. colorless oil. (1.3 g, 65% yield). 1H NMR
(400 MHz, CDCl3) δ 7.97 (s, 1H), 7.89 ꢀ 7.80 (m, 3H), 7.65 (dd, J = 8.5, 1.5 Hz, 1H),
7.56 – 7.44 (m, 2H), 5.59 (d, J = 2.2 Hz, 1H), 2.36 (br, 1H), 1.94 (d, J = 2.2 Hz, 3H).
13C NMR (151 MHz, CDCl3) δ 138.7, 133.3, 133.3, 128.6, 128.3, 127.8, 126.3, 126.3,
125.3, 124.7, 83.5, 79.3, 65.0, 3.9. HRMS (EI) m/z: calculated for C14H12O [M]+ :
196.0888, found: 196.0891.
2ꢀ(hydroxy(4ꢀnitrophenyl)methyl)ꢀ1ꢀmethylꢀ3Hꢀpyrrolo[1,2ꢀa]indolꢀ3ꢀone
3a.
Yellow solid (44.8 mg, 67% yield). m.p. 179–181 oC. 1H NMR (400 MHz, DMSOꢀd6)
δ 8.23 – 8.19 (d, J = 8.8 Hz, 2H), 7.73 – 7.69 (d, J = 8.9 Hz, 2H), 7.51 – 7.45 (m, 2H),
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7.29 – 7.22 (m, 1H), 7.11 – 7.05 (m, 1H), 6.80 – 6.76 (d, J = 2.7 Hz, 1H), 6.25 – 6.21
(m, 1H), 5.76 – 5.72 (d, J = 4.0 Hz, 1H), 2.19 (s, 3H). 13C NMR (126 MHz, DMSOꢀd6)
δ 163.7, 150.6, 146.5, 143.2, 142.3, 134.8, 133.7, 133.5, 127.3, 127.1, 123.4, 123.2,
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ꢀ
111.4, 107.1, 65.5, 11.2. HRMS (ESI) m/z: calculated for C19H13N2O4 [M ꢀ H]ꢀ:
333.0881, found: 333.0878.
1ꢀ(hydroxy(4ꢀnitrophenyl)methyl)ꢀ2ꢀmethylꢀ3Hꢀpyrrolo[1,2ꢀa]indolꢀ3ꢀone
4a.
Yellow solid. (2.4 mg, 3.5% yield) m.p. 199–201 oC. 1H NMR (500 MHz, DMSOꢀd6)
δ 8.25 – 8.22 (d, J = 8.9 Hz, 2H), 7.82 – 7.78 (d, J = 8.6 Hz, 2H), 7.50 – 7.47 (dd, J =
7.9, 0.6 Hz, 1H), 7.45 – 7.42 (d, J = 7.7 Hz, 1H), 7.24 – 7.20 (td, J = 7.9, 1.0 Hz, 1H),
7.08 – 7.04 (td, J = 7.6, 0.9 Hz, 1H), 6.54 – 6.51 (d, J = 3.8 Hz, 1H), 6.50 (s, 1H),
6.00 – 5.98 (d, J = 3.7 Hz, 1H), 1.99 (s, 3H).. 13C NMR (126 MHz, DMSOꢀd6) δ
164.8, 149.7, 146.9, 145.2, 139.5, 133.8, 133.5, 130.9, 127.3, 126.8, 123.6, 123.2,
123.0, 111.3, 107.5, 66.8, 9.1. HRMS (ESI) m/z: calculated for C19H13N2O4 [M ꢀ H]ꢀ:
ꢀ
333.0881, found: 333.0878.
2ꢀ(hydroxy(4ꢀnitrophenyl)methyl)ꢀ1,9ꢀdimethylꢀ3Hꢀpyrrolo[1,2ꢀa]indolꢀ3ꢀone
o
1
3b. Yellow solid (43.2 mg, 62% yield). m.p. 205–207 C. H NMR (500 MHz,
DMSOꢀd6) δ 8.23 – 8.19 (d, J = 8.9 Hz, 2H), 7.67 – 7.69 (d, J = 8.4 Hz, 2H), 7.45 –
7.43 (t, J = 7.8 Hz, 2H), 7.24 – 7.26 (td, J = 7.8, 1.0 Hz, 1H), 7.13 – 7.09 (td, J = 7.6,
1.0 Hz, 1H), 6.19 – 6.15 (d, J = 4.2 Hz, 1H), 5.76 – 5.72 (d, J = 4.1 Hz, 1H), 2.30 (s,
3H), 2.28 (s, 3H). 13C NMR (126 MHz, DMSOꢀd6) δ 163.2, 151.0, 146.4, 143.7,
137.1, 134.7, 134.2, 133.1, 127.7, 126.9, 123.4, 122.9, 121.2, 119.1, 111.1, 65.2, 11.9,
8.9. HRMS (ESI) m/z: calculated for C20H15N2O4 [M ꢀ H]ꢀ: 347.1037, found:
ꢀ
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347.1041.
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8ꢀchloroꢀ2ꢀ(hydroxy(4ꢀnitrophenyl)methyl)ꢀ1ꢀmethylꢀ3H-pyrrolo[1,2ꢀa]indolꢀ3ꢀo
ne 3c.
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Yellow solid (44.3 mg, 60% yield). m.p. 223–225 oC. 1H NMR (500 MHz, DMSOꢀd6)
δ 8.23 – 8.19 (d, J = 8.7 Hz, 2H), 7.74 – 7.70 (d, J = 8.6 Hz, 2H), 7.47 – 7.43 (d, J =
7.9 Hz, 1H), 7.30 – 7.26 (t, J = 8.0 Hz, 1H), 7.19 – 7.15 (d, J = 7.9 Hz, 1H), 6.87 (s,
13
1H), 6.25 (d, J = 4.1 Hz, 1H), 5.75 (d, J = 4.0 Hz, 1H), 2.23 (s, 3H). C NMR (126
MHz, DMSOꢀd6) δ 163.6, 150.3, 146.5, 143.5, 142.9, 135.1, 134.2, 131.7, 128.5,
127.1, 126.6, 123.4, 122.9, 110.3, 104.2, 65.4, 11.2. HRMS (ESI) m/z: calculated for
ꢀ
C19H12ClN2O4 [M ꢀ H]ꢀ: 367.0491, found: 367.0490
2ꢀ(hydroxy(4ꢀnitrophenyl)methyl)ꢀ1,8ꢀdimethylꢀ3Hꢀpyrrolo[1,2ꢀa]indolꢀ3ꢀone 3d.
Yellow solid (46.7 mg, 67% yield). m.p. 198–201 oC. 1H NMR (500 MHz, DMSOꢀd6)
δ 8.22 – 8.18 (d, J = 8.8 Hz, 2H), 7.72 – 7.68 (d, J = 8.7 Hz, 2H), 7.27 – 7.21 (d, J =
7.9 Hz, 1H), 7.12 – 7.09 (t, J = 7.7 Hz, 1H), 6.91 – 6.87 (m, 2H), 6.18 (d, J = 4.1 Hz,
1H), 5.72 (d, J = 4.1 Hz, 1H), 2.38 (s, 3H), 2.18 (s, 3H). 13C NMR (126 MHz,
DMSOꢀd6) δ 163.8, 150.7, 146.5, 143.1, 141.7, 134.5, 133.5, 133.0, 132.6, 127.4,
127.0, 123.8, 123.4, 108.9, 105.9, 65.4, 18.0, 11.2. HRMS (ESI) m/z: calculated for
ꢀ
C20H15N2O4 [M ꢀ H]ꢀ: 347.1037, found: 347.1041.
8ꢀ(benzyloxy)ꢀ2ꢀ(hydroxy(4ꢀnitrophenyl)methyl)ꢀ1ꢀmethylꢀ3Hꢀpyrrolo[1,2ꢀa]indo
lꢀ3ꢀone 3e. Yellow solid (61.7 mg, 70% yield). m.p. 164–165 oC.1H NMR (500 MHz,
DMSOꢀd6) δ 8.23 – 8.19 (d, J = 8.8 Hz, 2H), 7.73 – 7.69 (d, J = 8.5 Hz, 2H), 7.51 –
7.47 (d, J = 7.3 Hz, 2H), 7.42 – 7.38 (m, 2H), 7.36 – 7.32 (m, 2H), 7.24 – 7.20 (t, J =
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8.1 Hz, 1H), 7.10 (d, J = 7.9 Hz, 1H), 6.87 (s, 1H), 6.80 (d, J = 8.2 Hz, 1H), 6.18 (d, J
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7
13
= 4.1 Hz, 1H), 5.73 (d, J = 4.1 Hz, 1H), 5.22 (s, 1H), 2.18 (s, 3H). C NMR (126
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9
MHz, DMSOꢀd6) δ 163.9, 152.9, 150.7, 146.4, 143.4, 140.8, 136.8, 134.7, 134.2,
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128.9, 128.5, 127.9, 127.6, 127.0, 123.4, 122.8, 106.4, 104.8, 104.4, 69.4, 65.4, 11.13.
HRMS (ESI) m/z: calculated for C26H19N2O5 [M ꢀ H]ꢀ: 439.1299, found: 439.1295.
ꢀ
7ꢀfluoroꢀ2ꢀ(hydroxy(4ꢀnitrophenyl)methyl)ꢀ1ꢀmethylꢀ3Hꢀpyrrolo[1,2ꢀa]indolꢀ3ꢀo
o
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ne 3f. Yellow solid (50.7 mg, 72% yield). m.p. 113–115 C. H NMR (500 MHz,
DMSO-d6) δ 8.23 – 8.19 (d, J = 8.8 Hz, 2H), 7.74 – 7.70 (d, J = 8.8 Hz, 2H), 7.46 –
7.42 (dd, J = 8.7, 4.5 Hz, 1H), 7.38 – 7.34 (dd, J = 9.2, 2.5 Hz, 1H), 7.13 – 7.09 (td, J
= 9.2, 2.5 Hz, 1H), 6.78 (s, 1H), 6.22 (d, J = 4.1 Hz, 1H), 5.74 (d, J = 4.1 Hz, 1H),
2.19 (s, 3H). 13C NMR (126 MHz, DMSOꢀd6) δ 163.4, 158.5 (d, J = 236.9 Hz), 150.5,
146.5, 143.9, 143.2, 135.0, 134.6 (d, J = 10.2 Hz), 130.1, 127.1, 123.4, 114.3 (d, J =
25.3 Hz), 112.1 (d, J = 9.5 Hz), 109.3 (d, J = 24.7 Hz), 106.5 (d, J = 3.8 Hz), 65.4,
11.2. 19F NMR (471 MHz, DMSO-d6) δ ꢀ119.9 ppm. HRMS (ESI) m/z: calculated for
ꢀ
C19H12FN2O4 [M ꢀ H]ꢀ: 351.0787, found: 351.0787.
7ꢀchloroꢀ2ꢀ(hydroxy(4ꢀnitrophenyl)methyl)ꢀ1ꢀmethylꢀ3Hꢀpyrrolo[1,2ꢀa]indolꢀ3ꢀo
o
1
ne 3g. Yellow solid (49.4 mg, 67% yield). m.p. 150–152 C. H NMR (500 MHz,
DMSOꢀd6) δ 8.22 – 8.18 (d, J = 8.9 Hz, 2H), 7.73 – 7.69 (d, J = 8.5 Hz, 2H), 7.59 –
7.56 (d, J = 2.0 Hz, 1H), 7.47 – 7.43 (d, J = 8.5 Hz, 1H), 7.30 – 7.26 (dd, J = 8.5, 2.1
Hz, 1H), 6.76 (s, 1H), 6.23 (d, J = 4.1 Hz, 1H), 5.73 (d, J = 4.0 Hz, 1H), 2.19 (s, 3H).
13C NMR (126 MHz, DMSOꢀd6) δ 163.4, 150.4, 146.5, 143.6, 143.3, 135.2, 135.0,
132.0, 127.3, 127.1, 126.9, 123.4, 122.7, 112.5, 106.1, 65.4, 11.2. HRMS (ESI) m/z:
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ꢀ
calculated for C19H12ClN2O4 [M ꢀ H]ꢀ: 367.0491, found: 367.0489.
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7ꢀbromoꢀ2ꢀ(hydroxy(4ꢀnitrophenyl)methyl)ꢀ1ꢀmethylꢀ3Hꢀpyrrolo[1,2ꢀa]indolꢀ3ꢀo
8
9
o
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ne 3h. Yellow solid (62.8 mg, 76% yield). m.p. 182–184 C. H NMR (500 MHz,
DMSOꢀd6) δ 8.23 – 8.19 (d, J = 8.9 Hz, 2H), 7.74 – 7.69 (m, 3H), 7.43 – 7.41(m, 2H),
6.77 (s, 1H), 6.23 (d, J = 3.5 Hz, 1H), 5.74 (d, 1H), 2.20 (s,3H). 13C NMR (126 MHz,
DMSOꢀd6) δ 163.5, 150.4, 146.5, 143.4, 143.3, 135.5, 135.2, 132.3, 129.6, 127.1,
125.6, 123.4, 115.2, 113.0, 106.0, 65.4, 11.3. HRMS (ESI) m/z: calculated for
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ꢀ
C19H12BrN2O4 [M ꢀ H]ꢀ: 410.9986, found: 410.9977.
2ꢀ(hydroxy(4ꢀnitrophenyl)methyl)ꢀ1,7ꢀdimethylꢀ3Hꢀpyrrolo[1,2ꢀa]indolꢀ3ꢀone 3i
Yellow solid (49.5 mg, 71% yield). m.p. 165–166 oC. 1H NMR (500 MHz, DMSO-d6)
δ 8.23 – 8.19 (d, J = 8.6 Hz, 2H), 7.73 – 7.69 (d, J = 8.8 Hz, 2H), 7.38 – 7.34 (d, J =
8.1 Hz, 1H), 7.29 (s, 1H), 7.10 – 7.06 (d, J = 8.3 Hz, 1H), 6.72 (s, 1H), 6.18 (d, J =
4.1 Hz, 1H), 5.73 (d, J = 4.1 Hz, 1H), 2.30 (s, 3H), 2.17 (s, 3H). 13C NMR (126 MHz,
DMSOꢀd6) δ 163.6, 150.7, 146.4, 142.9, 142.5, 134.7, 133.7, 132.2, 131.8, 128.2,
127.0, 123.4, 123.2, 111.0, 106.9, 65.4, 20.8, 11.2. HRMS (ESI) m/z: calculated for
C20H15N2O4 [M ꢀ H]ꢀ: 347.1037, found: 347.1041.
ꢀ
2ꢀ(hydroxy(4ꢀnitrophenyl)methyl)ꢀ7ꢀmethoxyꢀ1ꢀmethylꢀ3Hꢀpyrrolo[1,2ꢀa]indolꢀ3
o
1
ꢀone 3j. Yellow solid (47.4 mg, 65% yield). m.p. 166–167 C. H NMR (500 MHz,
DMSO-d6) δ 8.23 – 8.19 (d, J = 8.6 Hz, 2H), 7.73 – 7.69 (d, J = 8.7 Hz, 2H), 7.38ꢀ
7.34 (d, J = 8.7 Hz, 1H), 7.09 – 7.05 (d, J = 2.3 Hz, 1H), 6.86 – 6.84 (dd, J = 8.7, 2.3
Hz, 1H), 6.71 (s, 1H), 6.18 (d, J = 4.1 Hz, 1H), 5.72 (d, J = 4.0 Hz, 1H), 3.74 (s, 3H),
2.17 (s, 3H). 13C NMR (126 MHz, DMSOꢀd6) δ 163.4, 155.7, 150.7, 146.5 143.1,
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ꢀ
11.2. HRMS (ESI) m/z: calculated for C20H15N2O5 [M ꢀ H]ꢀ: 363.0986, found:
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363.0981.
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methyl 2ꢀ(hydroxy(4ꢀnitrophenyl)methyl)ꢀ1ꢀmethylꢀ3ꢀoxoꢀ3Hꢀpyrrolo[1,2ꢀa]ind
o
oleꢀ7ꢀcarboxylate 3k. Yellow solid (32.3 mg, 41% yield). m.p. 204–206 C. 1H NMR
(500 MHz, DMSO-d6) δ 8.23 – 8.19 (d, J = 8.8 Hz, 2H), 8.15 – 8.11 (d, J = 1.7 Hz,
1H), 7.90 – 7.86 (d, J = 8.4 Hz, 1H), 7.75 – 7.71 (d, J = 8.5 Hz, 2H), 7.59 – 7.55 (dd,
J = 8.3, 2.1 Hz, 1H), 6.91 (d, J = 3.2 Hz, 1H), 6.25 (d, J = 4.2 Hz, 1H), 5.76 (d, J =
4.1 Hz, 1H), 3.84 (s, 3H), 2.22 (s, 3H). 13C NMR (125 MHz, DMSOꢀd6) δ 166.1,
163.5, 150.4, 146.5, 143.8, 143.3, 136.1, 135.3, 133.6, 128.5, 127.1, 124.5, 124.4,
ꢀ
123.4, 111.2, 107.0, 65.4, 52.1, 11.3. HRMS (ESI) m/z: calculated for C21H15N2O6
[M ꢀ H]ꢀ: 391.0936, found: 391.0932.
6ꢀfluoroꢀ2ꢀ(hydroxy(4ꢀnitrophenyl)methyl)ꢀ1ꢀmethylꢀ3Hꢀpyrrolo[1,2ꢀa]indolꢀ3ꢀo
o
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ne 3l. Yellow solid (50.0 mg, 71% yield). m.p. 178–181 C. H NMR (500 MHz,
DMSO-d6) δ 8.23 – 8.19 (d, J = 8.8 Hz, 2H), 7.74 – 7.70 (d, J = 8.7 Hz, 2H), 7.54 –
7.50 (m, 1H), 7.26 – 7.22 (d, J = 8.8 Hz, 1H), 6.97 – 6.93 (t, J = 9.2 Hz, 1H), 6.80 (s,
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1H), 6.21 (d, J = 4.1 Hz, 1H), 5.74 (d, J = 3.7 Hz, 1H), 2.19 (s, 3H). C NMR (126
MHz, DMSOꢀd6) δ 163.47, 161.90 (d, J = 243.3 Hz), 150.5, 146.5, 143.7, 142.7 (d, J
= 4.0 Hz), 134.6, 133.9 (d, J = 13.0 Hz), 130.0, 127.0, 124.4 (d, J = 10.1 Hz), 123.4,
110.6 (d, J = 23.8 Hz), 106.7, 99.0 (d, J = 27.7 Hz), 65.4. 19F NMR (471 MHz,
ꢀ
DMSO-d6) δ ꢀ113.3 ppm. HRMS (ESI) m/z: calculated for C19H12FN2O4 [M ꢀ H]ꢀ:
351.0787, found: 351.0779.
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The Journal of Organic Chemistry
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2ꢀ(hydroxy(4ꢀnitrophenyl)methyl)ꢀ6ꢀmethoxyꢀ1ꢀmethylꢀ3Hꢀpyrrolo[1,2ꢀa]indolꢀ3
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o
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ꢀone 3m. Yellow solid (19.7 mg, 27% yield). m.p. 208–210 C. H NMR (500 MHz,
DMSO-d6) δ 8.23 – 8.19 (d, J = 8.8 Hz, 2H), 7.73 – 7.69 (d, J = 8.5 Hz, 2H), 7.41 –
7.37 (d, J = 8.6 Hz, 1H), 7.04 – 7.00 (d, J = 2.3 Hz, 1H), 6.72 (s, 1H), 6.71 – 6.68 (dd,
J = 8.6, 2.4 Hz, 1H), 6.17 – 6.15 (d, J = 4.1 Hz, 1H), 5.72 (d, J = 4.0 Hz, 1H), 3.78 (s,
3H), 2.17 (s, 3H). 13C NMR (126 MHz, DMSOꢀd6) δ 163.7, 159.8, 150.8, 146.4,
143.5, 140.9, 135.0, 133.7, 127.0, 126.8, 123.9, 123.4, 110.8, 107.5, 96.6, 65.4, 55.49,
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ꢀ
11.2. HRMS (ESI) m/z: calculated for C20H15N2O5 [M ꢀ H]ꢀ: 363.0986, found:
363.0981.
1ꢀ(hydroxy(4ꢀnitrophenyl)methyl)ꢀ6ꢀmethoxyꢀ2ꢀmethylꢀ3Hꢀpyrrolo[1,2ꢀa]indolꢀ3
o
ꢀone 4m. Yellow solid (19.7 mg, 27% yield). m.p. 201–202 C.1H NMR (600 MHz,
DMSO-d6) δ 8.25 – 8.22 (d, J = 8.8 Hz, 2H), 7.80 – 7.76 (d, J = 8.8 Hz, 2H), 7.34 –
7.31 (m, 1H), 7.03 (m, 1H), 6.68 – 7.65 (m, 1H), 6.49 (d, J = 3.8 Hz, 1H), 6.42 (s, 1H),
5.96 (d, J = 3.7 Hz, 1H), 3.77 (s, 3H), 1.96 (s, 3H). 13C NMR (151 MHz, DMSO-d6) δ
164.9, 159.4, 149.8, 146.8, 145.5, 138.1, 134.8, 129.6, 127.3, 127.1, 123.7, 123.6,
ꢀ
110.5, 107.9, 96.8, 66.9, 55.5, 9.1. HRMS (ESI) m/z: calculated for C20H15N2O5 [M ꢀ
H]ꢀ: 363.0986, found: 363.0984.
1ꢀmethylꢀ2ꢀphenylꢀ3Hꢀpyrrolo[1,2ꢀa]indolꢀ3ꢀone 3n. Yellow solid (47.2 mg, 91%
yield). m.p. 108–111 oC. 1H NMR (400 MHz, DMSO-d6) δ 7.60 – 7.51 (m, 4H), 7.51
– 7.45 (t, J = 7.6 Hz, 2H), 7.43 – 7.37 (m, 1H), 7.33 – 7.27 (t, J = 7.6 Hz, 1H), 7.15 –
7.09 (t, J = 7.6 Hz, 1H), 6.86 (s, 1H), 2.29 (s, 3H). 13C NMR (126 MHz, DMSOꢀd6) δ
164.0, 142.5, 141.1, 133.8, 132.1, 130.5, 128.9, 128.4, 128.2, 127.3, 123.3, 123.1,
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