General Synthesis of Unsymmetrical 3,3′-(Aza)diindolylmethane Derivatives

Article abstract of DOI:10.1021/acs.joc.8b01349

Diindolylmethane (DIM) and its derivatives have recently been in the focus of interest due to their significant biological activities, specifically in cancer prevention and therapy. Molecular targets of DIM have been identified, e.g., the immunostimulatory G protein-coupled receptor GPR84. However, most of the reported and investigated DIM derivatives are symmetrical because general methods for obtaining unsymmetrical DIMs have been lacking. To optimize the interaction of DIM derivatives with their protein targets, unsymmetrical substitution is required. In the present study we developed a new, mild and efficient access to unsymmetrically substituted 3,3′-DIMs by reaction of (3-indolylmethyl)trimethylammonium iodides with a wide range of substituted indole derivatives. 7-Azaindole also led to the 3,3′-connected DIM analogue, while 4- and 5-azaindoles reacted at the N1-nitrogen atom as confirmed by X-ray crystallography. The reactions were performed in water without the requirement of a catalyst or other additives. Wide substrate scope, operational simplicity, environmentally benign workup, and high yields are further advantages of the new method. The synthetic protocol proved to be suitable for upscaling to yield gram amounts for pharmacological studies. This procedure will allow the preparation of a broad range of novel, unsymmetrical DIM derivatives to exploit their potential as novel drugs.

Full text of DOI:10.1021/acs.joc.8b01349

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Article
General synthesis of unsymmetrical 3,3’-(aza)diindolylmethane derivatives
Thanigaimalai Pillaiyar, Ewelina Gorska, Gregor Schnakenburg, and Christa E Müller
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b01349 • Publication Date (Web): 19 Jul 2018
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General synthesis of unsymmetrical 3,3’-(aza)diindolylmethane derivatives
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Thanigaimalai Pillaiyar,†* Ewelina Gorska,† Gregor Schnakenburg, § Christa E. Müller†,*
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† PharmaCenter Bonn, Pharmaceutical Institute, Pharmaceutical Chemistry I, University of Bonn,
An der Immenburg 4, Dꢀ53121 Bonn, Germany.
§
Institute of Inorganic Chemistry, University of Bonn, GerhardꢀDomagkꢀStr. 1, Dꢀ53121 Bonn,
Germany.
Abstract
Diindolylmethane (DIM) and its derivatives have recently been in the focus of interest due to
their significant biological activities, specifically in cancer prevention and therapy. Molecular
targets of DIM have been identified, e.g., the immunoꢀstimulatory G proteinꢀcoupled receptor
GPR84. However, most of the reported and investigated DIM derivatives are symmetrical
because general methods for obtaining unsymmetrical DIMs have been lacking. To optimize the
interaction of DIM derivatives with their protein targets, unsymmetrical substitution is required.
In the present study we developed a new, mild and efficient access to unsymmetrically
substituted 3,3’ꢀDIMs by reaction of (3ꢀindolylmethyl)trimethylammonium iodides with a wide
range of substituted indole derivatives. 7ꢀAzaindole also led to the 3,3’ꢀconnected DIM analog
while 4ꢀ and 5ꢀazaindoles reacted at the N1ꢀnitrogen atom as confirmed by Xꢀray
crystallography. The reactions were performed in water without the requirement of a catalyst or
other additives. Wide substrate scope, operational simplicity, environmentally benign workup,
and high yields are further advantages of the new method. The synthetic protocol proved to be
suitable for upscaling to yield gram amounts for pharmacological studies. This procedure will
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allow the preparation of a broad range of novel, unsymmetrical DIM derivatives to exploit their
potential as novel drugs.
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Keywords: Antiꢀcancer activity, azaindole, diindolylmethane, GPR84, environmentally benign
synthesis, indole, natural product
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Introduction
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Diindolylmethane (DIM, 1) and its derivatives and analogs constitute an important class of indole
alkaloids. They consist of two indole rings connected by a single carbon atom at the 3ꢀ and 3’ꢀ
positions (see Figure 1). DIM itself is a major metabolite of indoleꢀ3ꢀcarbinol produced from the
glycoside glucobrassicin, which is found in cruciferous vegetables such as broccoli, brussel
sprouts and cauliflower.1 DIM was reported to exhibit antiꢀoxidant,2 antiꢀinflammatory,3 antiꢀ
angiogenic,4 and antiꢀcancer activities.5,6 It is used to treat recurrent respiratory papillomatosis,7 a
rare respiratory disease with tumors in the upper respiratory tract caused by the human papilloma
virus. The compound was also evaluated in a Phase III clinical study for the treatment of cervical
dysplasia,8 and recently a Phase II clinical trial has been completed for stage I/II prostate cancer.9
DIM was found to act synergistically when combined with the antiꢀcancer drug paclitaxel, an
inhibitor of mitosis, to induce apoptosis in human breast cancer cells.10
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Several molecular targets of DIM have been identified by in vitro studies: DIM was reported to
activate the arylhydrocarbon receptor (at a concentration of 30 µM),11 a ligandꢀactivated
transcription factor that regulates cell growth and differentiation. The compound was also
reported to inhibit histone deacetylaseꢀ1 (HDACꢀ1) (at a concentration of 100 µM).12 Recently,
DIM and several fluorineꢀsubstituted derivatives were discovered to be potent agonists of the
immuneꢀstimulatory orphan G proteinꢀcoupled receptor GPR84 (at concentrations below 1
µM).13,14 Several natural derivatives of DIM were identified and reported to possess biological
activities. Bell et al. described the isolation of vibrindole A (2) from a culture of the marine
bacterium Vibrio parahemolyticus,15 and trisindoline (3) obtained from the culture of the
bacterium Vibrio sp., both of which exhibited antibiotic activity.16 Gu et al. isolated arsindoline A
(4) and B (5) from the Xiamen sea bacterium strain CB101. Arsindoline B (5) exhibited activity
against the Aꢀ549 cancer cell line (IC50 = 22.6 µM). Sterptindole (6) is a metabolite of the
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common human intestinal bacterium Streptococcus faecium IB 37, and was reported to display
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DNA damaging and genotoxic properties.17
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Figure 1 Structures of naturally occurring diindolylmethane derivatives; isolation sources are
indicated in brackets and biological activities are highlighted in red color.
Due to the observed biological activities of DIM and its derivatives, a number of methods have
been reported for their synthesis, in particular those yielding symmetrically substituted DIMs.18
However, the preparation of unsymmetrically substituted DIM derivatives has remained
challenging, and there are only few reports, all of which are suffering from serious limitations
(see Figure 2). In 2000, ChalayeꢀMauger et al. developed the first synthesis of unsymmetrically
substituted DIMs by reaction of nitrones with indoles in the presence of trimethylsilyl chloride
(ClSiMe3) in dichloromethane.19 In 2007, de la Herra´n et al. reported on a rhodium or iridium
complexꢀcatalyzed benzylic substitution of 3ꢀ(dimethylaminomethyl)indoles by indoles in the
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presence of potassium phosphate as a base.20 Pathak and coꢀworkers described the reaction of
vinylindoles with a large excess of indole derivatives (10 equiv.) in the presence of paraꢀ
toluenesulfonic acid (pꢀTsOH) in N,Nꢀdimethylacetamide (DMA).21 A oneꢀpot synthesis has been
developed by performing an intermolecular Pummerer reaction using indole as a nucleophile in
the presence of trifluoroacetic anhydride (TFAA) and copper(II) acetate in dimethyl sulfoxide
(DMSO).22 Recently, Xiao et al. reported on the dehydrative23 SN1ꢀtype reaction of 3ꢀαꢀ
hydroxybenzylindoles with indoles yielding unsymmetrical phenylꢀsubstituted DIMs. Although
the described methods are useful for the synthesis of certain unsymmetrical DIMs, they have
severe limitations and drawbacks, such as the use of expensive and highly toxic catalysts
(example 2), substrate limitations (only substrates with an aromatic group at the benzylic position
of indole, example 5), low yields (example 4), formation of hazardous byꢀproducts, harsh
reaction conditions or tedious workup to isolate the products (examples 3 and 4), requirement of
stoichiometric amounts of protic acids or Lewis acids/bases (examples 1, 3 and 4) and/or large
amounts of reagents (example 3), and the use of organic solvents (examples 1ꢀ4).
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Therefore, the development of a new, general, mild and efficient procedure with broad functional
group tolerance is urgently required to provide a broad range of unsymmetrical DIMs for
biological studies. We have previously developed a new procedure for the synthesis of
symmetrical DIMs, and established their structureꢀactivity relationships (SARs) as agonists of the
immunostimulatory G proteinꢀcoupled receptor GPR84.14 Subsequently, we succeeded in
improving the synthetic procedure to access a large variety of symmetrical DIM derivatives by
reaction of indoles with various aromatic and aliphatic aldehydes in the presence of sulfuric acid
in water.24 However, we soon realized the current limitations, since unsymmetrical DIMs would
be required for optimizing the compounds’ interactions with their target.
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Figure 2 Synthetic approaches towards unsymmetrical DIMs.
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In the present study, we report on a catalystꢀfree, mild and efficient, environmental friendly
synthesis of unsymmetrical DIMs from readily accessible (3ꢀindolylmethyl)trimethylammonium
iodides as precursors. To the best of our knowledge, this is the first reported procedure for the
preparation of unsymmetrical DIMs that proceeds in water without catalyst or any other
additives. The present protocol provides an attractive and environmentally benign approach to a
diverse range of functionalized unsymmetrical DIMs in a simple oneꢀpot procedure. The new
synthetic procedure will allow optimization of DIMs and full exploitation of their potential as
novel drugs.
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Results and discussion
The reaction of 3ꢀ(dimethylaminomethyl)indoles with indoles published by de la Herra´n was
selected as a starting point with the aim to substantially modify it by omitting rhodium or iridium
complexes as catalysts in order to develop an environmentally benign procedure for the
preparation of unsymmetrically substituted DIMs. Initially, we studied the reaction of 3ꢀ
(dimethylaminomethyl)indole (7a), with 5ꢀmethoxyꢀ1Hꢀindole (8a), leading to the formation of
3ꢀ((5ꢀmethoxyꢀ1Hꢀindolꢀ3ꢀyl)methyl)ꢀ1Hꢀindole (9a), as a model for optimizing the reaction
conditions (Table 1).
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Table 1. Optimization of reaction conditions for the synthesis of 3ꢀ((1Hꢀindolꢀ3ꢀyl)methyl)ꢀ5ꢀ
methoxyꢀ1Hꢀindolea
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Yield (%)b
Time
(h)
Temp
(oC)
Entry
Solvent
7a as starting
compound
0c
10a as starting
compound
15
1
2
H2O
CH3OH
CH2Cl2
Dioxane
THF
12ꢀ48
12ꢀ48
12ꢀ48
12ꢀ48
12ꢀ48
12ꢀ48
12ꢀ48
12ꢀ48
12ꢀ48
12ꢀ48
48
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
50
0c
20
5
3
0c
4
0c
trace
0c
5
0c
6
CH3CN
DMF
0c
0c
7
0c
0c
8
DMSO
H2O
0c
0c
9
trace
0c
43
37
85
89
10
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12
CH3OH
H2O
50
80
5
H2O
48
100
20
13
14
DMF
12ꢀ48
12ꢀ48
120
120
trace
trace
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71
DMSO
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16
17
Benzene
Toluene
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48
48
100
115
130
5
0d
0d
0d
12
15
mꢀXylene
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ꢀꢀ
48
48
48
100
r.t.
ꢀꢀ
ꢀꢀ
0c
0c
CH3COOH
0c
CH3COOH/H2O
(1:1)
r.t.
0c
21
22
CH3COOH
12
48
100
100
10e
22e
0e
0e
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CH3COOH/H2O
(1:1)
aReactions were performed with 7a or 10a (0.2 mmol) and 8a (0.4 mmol) in 5 mL of solvent.
bIsolated yield after column chromatography. No reaction. Desired product was not obtained
c
d
e
although many spots appeared on TLC. Several spots appeared on TLC along with the desired
product.
Different solvent systems including water, methanol, dichloromethane, dioxane, tetrahydrofuran,
acetonitrile, dimethyl sulfoxide, N,Nꢀdimethylformamide, acetic acid, benzene, toluene, xylene as
well as neat conditions at various temperatures for different reaction times were studied. When
the reaction was performed at room temperature, no product was formed, even after 48 h (entry
o
1ꢀ8, 19 and 20). Upon gradually increasing the temperature from rt to 130 C (entry 9ꢀ17, 21 and
22), the desired product was obtained, however with a maximum yield of only 22% in acetic acid
: water (1:1) at 100 oC (entry 22). The reaction did not take place in methanol at 50 C even after
o
48 h (entry 10), while in water, at 50 oC traces of product were observed (entry 9). Increasing the
o
o
reaction temperature in water from 50 to 80 C and further to 100 C led to an increase in the
formation of product resulting in a maximum yield of only 20% (entry 11, 12). The use of
solvents such as DMF (entry 13, trace), DMSO (entry 14, trace), benzene (entry 15, yield 5%),
toluene (entry 16, yield 12%), mꢀxylene (entry 17, yield 15%) or acetic acid (entry 21, yield 10%)
did not improve the yield as compared to water, even at higher temperatures. These studies
suggested that the amine functionality of 3ꢀ(dimethylaminomethyl)indole (7a) was not a good
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leaving group, and a stabilized benzylicꢀtype cation (indolenium ion) that could be trapped by the
indole (8a) reacting as a nucleophile, was not easily formed under these conditions.
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Therefore, we improved the leaving group ability of the tertiary amine of 3ꢀ
(dimethylaminomethyl)indole (7a) by reacting it with methyl iodide yielding the quaternary
ammonium salt 10a, which would easily allow expulsion of the leaving group. Subsequently, the
test reaction was studied using (3ꢀindolylmethyl)trimethylammonium iodide (10a) instead of 3ꢀ
(dimethylaminomethyl)indole (7a), with 5ꢀmethoxyindole (8a) under the same conditions as
previously applied to the indole 7a to yield product 9a. Even at room temperature, this reaction
led to the following yields: 15% in water, 20% in methanol, and 5% in CH2Cl2, while only traces
were observed in dioxane (entries 1ꢀ4, 7 and 8). No product was obtained in THF, CH3CN, DMF,
DMSO, acetic acid or acetic acid/water (1:1) as solvents (entries 5ꢀ8, 19 and 20). Bingul et al.
reported the synthesis of 4,6’ꢀ and 4,7’ꢀunsymmetrical DIMs from hydroxymethyl indoles in
acetic acid.25 Using the same solvent for the reaction of 10a did not yield any product. Elevating
the reaction temperature led to a significant increase in the formation of the product (entry 9ꢀ12).
To our delight, the desired product 9a could be obtained in a high yield of 89% by reaction at 100
oC in water (entry 12). Screening of solvents demonstrated that water was a highly suitable
solvent, while in apolar organic solvents like benzene, toluene or mꢀxylene (entries 15ꢀ17) the
desired product was not formed. The reaction in polar aprotic solvents such as DMF or DMSO
also led to very good results with 71% and 77% yield, respectively (entry 13 and 14), but water
was the best solvent. The reaction in acetic acid or acetic acid/water (1:1) did not lead to the
product. In the absence of solvent, no product was obtained either (entry 18).
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The isolation of product 9a and its analogs was straightforward when compared to other methods.
After completion of the reaction, water was decanted from the mixture and the product that
settled on the wall of the flask was dissolved in ethyl acetate. The resulting solution was dried
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over anhydrous sodium sulfate and, after filtration, evaporated under reduced pressure yielding
the desired crude product, which was purified by recrystallization, or column chromatography,
using nonꢀchlorinated solvents.
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Figure S3 shows the H NMR spectrum of product 9a (DMSOꢀd6, 303K). The two NH protons
for the indole moieties appeared at δ 10.70 and 10.53 ppm, respectively. The bridging methylene
protons appeared as a singlet at δ 4.08 ppm. The nine aromatic protons were observed from δ
6.66ꢀ7.52 ppm. The two C2 protons of the indole moieties appeared at δ 7.12 and 7.05 ppm.
These data confirmed that the indole residues were connected in the 3,3’ꢀpositions.
The optimized conditions were subsequently employed for synthesizing a wide range of both,
symmetrical and unsymmetrical DIMs to examine the scope of the reaction. In general, the
reactions of 10aꢀ10e with various indoles proceeded smoothly producing the desired DIM
derivatives in good to excellent yields (9bꢀ9z, and 9aa). The electronic properties of the
substituents at the indole that reacted as a nucleophile had a significant effect on the yields of the
product, electronꢀdonating substituents resulting in higher yields. For example, the reaction of (3ꢀ
indolylmethyl)trimethylammonium iodides 10aꢀ10e with 5ꢀmethoxyindole (8a), 4ꢀ
methoxylindole (8b), 6ꢀmethylindole (8c), and 5ꢀmethylindole (8k), respectively, afforded the
corresponding DIMs in yields of 76 ꢀ 93% (Table 2, products 9bꢀ9c, 9k, 9n, 9r, 9t, 9u, and 9y).
Electronꢀwithdrawing substituents mostly led to a moderate decrease in yields. For example,
halogen (F, Cl or Br), carboxylic acid ester, or trifluoromethyl substitution at the indole (8d, 8e,
8fꢀ8h, 8j and 8p) resulted in yields of 64 ꢀ 79% (Table 2, compounds 9dꢀ9h, 9j, 9l, 9m, 9o, 9s,
9v-9x). In case of two fluorine substituents, yields were significantly reduced to 53ꢀ57% (Table
2, compounds 9p, and 9q). The reaction proceeded well with N1ꢀsubstituted indole 8i, which
provided 9i in 78% yield, significantly higher as compared to the previously reported yield (40%)
obtained by the Pummerer reaction.14
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Table 2. Reaction of (3-indolylmethyl)trimethylammonium iodides with indoles
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Indole (8)
Producta (9)
Yieldb
(published yield)
Purityc
Ammonium
derivative (10)
Unsymmetrically substituted DIMs
89%
98%
99%
(64%)22
8a
10a
9a22
85%
10a
9b
8b
76%
74%
98%
99%
8c
9c
10a
10a
9d
8d
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79%
(48%)14
96%
95%
95%
98%
96%
8e
8f
8
9
10a
10a
10a
10a
10a
9e14
9f22
9g20
9h14
9i14
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73%
(55%)22
71%
(81%)20
8g
72%
(35%)14
8h
78%
(40%)14
8i
75%
93%
95%
96%
10b
10b
8e
9j
8b
9k
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71%
64%
>99%
10b
10b
8d
8j
9l
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96%
9m
80%
73%
96%
98%
8k
8l
10b
10b
9n
9o
57%
53%
96%
97%
8m
8n
10b
10b
9p
9q
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86%
98%
9
9r
10c
8b
8f
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70%
72%
95%
98%
10c
10c
9s
9t
8k
87%
95%
8a
10d
9u
73%
64%
68%
95%
>99%
95%
8e
8j
10d
10d
10d
9v
9w
9x
8p
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89%
96%
8
9
9y
10e
8q
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Symmetrically substituted DIMs
92%
(Gram scale,
94%)
98%
98%
(80%)22
8r
10a
122
86%
(37)26
8e
10c
9z 26
87%
97%
(68)27
8a
10b
9aa27
aAll isolated products were characterized by H and C NMR spectra and their structures were
confirmed. In addition, HPLC analysis coupled to electrospray ionization mass spectrometry
(LC/ESIꢀMS) was performed. bIsolated yields. cPurity was determined by HPLC coupled to a UV
diode array detector (DAD) at 220ꢀ400 nm.
1
13
Next, this method was applied to the preparation of symmetrical diindolylmethane derivatives.
As reported in Table 2, products 1, 9z and 9aa were obtained in high yields of 86 ꢀ 92%, and
these were in all cases higher than those reported for previously published methods (37 – 80%).
In order to investigate whether the new method could be used on a larger scale, we performed
gramꢀscale reactions of (3ꢀindolylmethyl)trimethylammonium iodide (10a, 2.3 g, 7.3 mmol) with
indole (8r, 1.74 g, 14.6 mmol), and with 5ꢀfluoroindole (8e, 2.00 g, 14.8 mmol), respectively.
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The reactions proceeded without any significant loss in efficiency affording 1.69 g of 1 (94%
yield) and 1.65 g of 9e (80% yield). Compounds 9z and 9aa had previously been identified as
potent agonists of the immunostimulatory orphan G proteinꢀcoupled receptor GPR84,14 which
was proposed as a drug target for acute myeloid leukemia,28 and might have potential for the
treatment of other cancers as well.
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We further studied whether the reaction could be employed for the preparation of DIM
derivatives substituted at the bridging methylene group. For that purpose the sterically demanding
αꢀisopropylꢀsubstituted (3ꢀindolylmethyl)trimethylammonium iodide 10f was reacted with
various substituted indole derivatives (8e, 8k or 8m, Scheme 1). All reactions proceeded
smoothly yielding the desired DIM derivatives in good yields of 68 ꢀ 79% (see 11aꢀ11c, Scheme
1); an electronꢀwithdrawing substituent at the indole only slightly reduced the yields (product
11c; 68%). The products (11a-c) are chiral representing mixtures of enantiomers, which have not
been separated.
N
R2
R1
I
H2O
R2
R1
N
N
H
H
NH
HN
(R,S) 11a-11c
10f
8e, 8k or 8m
CH3
F
F
F
NH
11a: 79%
NH
11b: 73%
NH
HN
HN
HN
11c: 68%
Scheme 1. Synthesis of unsymmetrical DIM derivatives substituted at the methylene bridge 11aꢀ
11c (racemates).
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N
I
R1
R1
X
Z
H2O
Y
6
7
8
9
N
or
N
N
N
H
H
N
H
HN
NH
; 89%
X
10a: R1 = H
Y
8s: X = N, Y = H, Z = H
8t
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12d
: X = H, Y = N, Z = H
8u
1
12a-12c
10b
: R = OCH3
: X = H, Y = H, Z = N
1
12a
12b
; R = H, X = N, Y = CH; 79%
1
; R = H, X = H, Y = N; 68%
12c; R1 = OCH3, X = H, Y = N; 84%
Scheme 2. Synthesis of azaindole derivatives 12aꢀ12d and Xꢀray structures of products 12a, 12c
and 12d.
Next, we investigated the reaction of (3ꢀindolylmethyl) trimethylammonium iodides 10a and 10b
with 4ꢀazaindole (8s) and 5ꢀazaindole (8t), respectively. Interestingly, we noticed that in these
cases, the N1 rather than the 3ꢀposition of 4ꢀazaindole (8s) and 5ꢀazaindole (8t) was alkylated
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yielding products 12a (79%), 12b (68%) and 12c (84%) in high yields (Scheme 2). The reason
for this regioselectivity may be due to the different electronic properties of the azaindoles. The
1HꢀNMR spectra indicated N1ꢀalkylation: the shift of the bridging methylene protons appeared at
5.54 ppm compared to 4.08ꢀ4.15 ppm for DIM derivatives. Xꢀray crystallography unambiguously
confirmed the structures of 12a and 12c (see Scheme 2).29 In contrast, the reaction of 10a with 7ꢀ
azaindole (8u) yielded the desired product 12d, in which the 3ꢀposition of 8u is connected via the
3ꢀposition to the indole like in the DIM derivatives. Compound 12d had previously been prepared
by reaction of 7ꢀazaindole with 3ꢀhydroxymethylindole in the presence of metallic sodium at 100
oC for 9 h. The yield of 12d obtained in that reaction was significantly lower (44%) when
compared to the present method (89%).30 We confirmed the structure of 12d by Xꢀray
crystallography (see Scheme 2).29 Compound 12d had previously been reported to exhibit
anticancer activity against prostate cancer and leukemia in DU145 and HL60 cells.30
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Next we studied reactions of benzofuran, and benzothiophene, respectively, with 10a using the
same conditions. However, no products were formed even after an extended reaction time of 72
h. This can be explained by the significantly lower nucleophilic character of benzofuran and
benzothiophene as compared to indole.
The proposed reaction mechanism is outlined in Scheme 3 for 9a as an example. The
trimethylammonium iodide 10a, formed by Mannich reaction of indole (8r), formaldehyde and
dimethylamine, undergoes nucleophilic attack by indole derivative 8a, forming the 3,3’ꢀDIM
derivative 9a along with trimethylammonium iodide. As an intermediate, the elimination product
A can be formed upon heating, which represents a strong electrophile (Scheme 3).
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Scheme 3. Plausible mechanism for the developed synthesis of DIMs.
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Taken together, the described environmentally benign synthetic protocol provides a convenient
access to a wide range of unsymmetrical diindolylmethanes and some of their azaꢀanalogs. The
reaction tolerates a broad range of substrates and proceeds with notable regioselectivity. It is
clean and performed under mild conditions in water and no catalyst or any other additive is
required. The described reaction provides an economic, simple handling, alternative to copperꢀ,
iridiumꢀ or rhodiumꢀcatalyzed reactions for the synthesis of unsymmetrical DIMs. The protocol is
suitable for upscaling to obtain gram amount of the target molecules, which represent an
important new class of immunostimulatory antiꢀcancer drug molecules.
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EXPERIMENTAL SECTION
General Experimental Methods. All materials were purchased from commercial suppliers and
used without further purification. Thinꢀlayer chromatography was performed using TLC
aluminum silica gel 60 F254 sheets, or TLC aluminum RP silica gel 18 F254 sheets. An LCMS
instrument coupled to electrospray ionization mass spectrometry (LC/ESIꢀMS) determined the
purities of isolated products using the following procedure: the compounds were dissolved at a
concentration of 1.0 mg/mL in acetonitrile, containing 2 mM NH4CH3COO. Then, 10 µL of the
sample was injected into an HPLC column (Phenomenex Luna 3µ C18, 50 × 2.00 mm). Elution
was performed with a gradient of water : methanol (containing 2 mM NH4CH3COO) from 90:10
to 0:100 starting the gradient immediately at a flow rate of 250 µL/min for 15 min followed by
washing with 100 % methanol for another 15 min. UV absorption was detected from 200 to 600
nm using a diode array detector. The purity of the compounds was determined at 220ꢀ400 nm and
1
13
13
was ≥ 95% for all products. Hꢀ and CꢀNMR or CꢀNMR Attached proton test (13CaptꢀNMR)
data were measured in CDCl3 or DMSOꢀd6 as a solvent. Chemical shifts are reported in parts per
1
million (ppm) relative to the deuterated solvents (DMSOꢀd6), H: 2.49 ppm, 13C: 39.70 ppm;
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(CDCl3) 1H: 7.25 ppm, 13C: 77.17 ppm; coupling constants J are given in Hertz and spin
multiplicities are given as s (singlet), d (doublet), t (triplet), q (quartet), sext (sextet), m
(multiplet), br (broad). Melting points were measured on a melting point apparatus (BÜCHI
melting point Bꢀ545) and are uncorrected.
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Compounds 1,22 9a,22 9e,14 9f,22 9g,20 9h,14 9z,26 9aa,27 and 12d,30 have previously been reported
but were now obtained by new methods.
General Procedure for the Synthesis of Indole Derivatives 7. To a solution of 17.0 ml of
o
dimethylamine (2 M in THF, 34.1 mmol) in a 100 mL round bottom flask at 0 C, 2.6 ml (34.1
mmol) of formaldehyde (37 % w/v in H2O) and glacial acetic acid (3.0 ml, 78.5 mmol, 2.3
equiv.) were added and the solution was stirred for 10 min. To this mixture, 34.1 mmol of the
appropriate indole dissolved in glacial acetic acid (4 ml) was added dropwise. After the addition
was completed, the reaction mixture was slowly brought to room temperature and stirred
overnight. Completion of the reaction was monitored by TLC. The reaction mixture was poured
into water and brought to an alkaline pH by the addition of 2 N aq. NaOH solution. The resulting
precipitate was filtered off, washed with water and dried under vacuum.
1
3ꢀ(Dimethylaminomethyl)indole (7a).31 Yield 70% (4.20 g); Colorless solid. H NMR (500 MHz,
DMSOꢀd6) δ (ppm) 10.86 (s, 1H, NH), 7.58 (d, J = 8.0 Hz, 1H), 7.36 – 7.29 (m, 1H), 7.18 (d, J =
2.2 Hz, 1H), 7.05 (dd, J = 8.2, 7.0 Hz, 1H), 6.95 (dd, J = 8.1, 7.0, 1.1 Hz, 1H), 3.51 (s, 2H), 2.13
(s, 6H). 13C NMR (126 MHz, DMSOꢀd6) δ (ppm) 136.5, 127.7, 124.4, 121.0, 119.2, 118.4, 111.8,
111.2, 54.6, 45.0.
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5ꢀMethoxyꢀ3ꢀ(dimethylaminomethyl)indole (7b).32 Yield 56% (3.89 g); Colorless solid. H NMR
(500 MHz, DMSOꢀd6) δ (ppm) 10.69 (s, 1H, NH), 7.22 (d, J = 8.7 Hz, 1H), 7.13 (d, J = 2.4 Hz,
1H), 7.04 (d, J = 2.4 Hz, 1H), 6.70 (dd, J = 8.7, 2.5 Hz, 1H), 3.73 (s, 3H), 3.47 (s, 2H), 2.13 (s,
9
13
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6H). C NMR (126 MHz, DMSOꢀd6) δ (ppm) 153.1, 131.6, 128.0, 125.2, 112.0, 111.6, 111.1,
101.1, 55.5, 54.6, 45.7.
5ꢀFluoroꢀ3ꢀ(dimethylaminomethyl)indole (7c).33 Yield 59% (3.86 g); Yellow solid. 1H NMR (500
MHz, DMSOꢀd6) δ (ppm) 10.85 (s, 1H, NH), 7.32 (dd, J = 8.2, 1.0 Hz, 1H), 7.17 (s, 1H), 7.02 (d,
13
J = 2.1 Hz, 1H), 6.92 (dd, J = 8.1, 7.0, Hz, 1H), 3.44 (s, 2H), 2.17 (s, 6H). C NMR (126 MHz,
DMSOꢀd6) δ (ppm) 157.7, 132.5, 128.2, 123.5, 118.6, 115.5, 114.6, 111.1, 54.5, 45.0.
1
5ꢀBenzyloxyꢀ3ꢀ(dimethylaminomethyl)indole (7d).31 Yield 60% (5.7 g); Colorless solid. H NMR
(500 MHz, DMSOꢀd6) δ (ppm) 10.71 (s, 1H, NH), 7.55 – 7.42 (m, 2H), 7.42 – 7.33 (m, 2H), 7.33
– 7.26 (m, 1H, 7.23 (d, J = 8.6 Hz, 1H), 7.15 (dd, J = 6.2, 2.5 Hz, 2H), 6.79 (dd, J = 8.8, 2.5 Hz,
1H), 5.06 (s, 2H), 3.46 (s, 2H), 2.12 (s, 6H). 13C NMR (126 MHz, DMSOꢀd6) δ (ppm) 152.1,
138.0, 131.8, 128.4, 128.1, 127.7, 127.7, 125.3, 112.0, 111.6, 111.5, 102.9, 70.1, 54.5, 45.0.
1
6ꢀFluoroꢀ3ꢀ(dimethylaminomethyl)indole (7e):34 Yield 53% (3.55 g), Colorless solid. H NMR
(600 MHz, DMSOꢀd6) δ (ppm) 10.92 (s, 1H), 7.56 (dd, J = 8.7, 5.6 Hz, 1H), 7.18 (d, J = 2.2 Hz,
1H), 7.09 (dd, J = 10.1, 2.4 Hz, 1H), 6.81 (ddd, J = 9.8, 8.6, 2.4 Hz, 1H), 3.48 (s, 2H), 2.11 (s,
13
6H). C (500 MHz, DMSOꢀd6) δ (ppm) 159.7, 158.2, 136.4, 136.3, 125.0, 125.0, 124.5, 120.3,
120.2, 112.2, 107.0, 106.8, 97.5, 97.3, 54.6, 45.0.
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(R,S)ꢀ3ꢀ((1ꢀN,NꢀDimethylaminoꢀ2ꢀmethyl)propyl)ꢀ1Hꢀindole (7f). Compound 7f was synthesized
from 8r (34.1 mmol) and isobutyraldehyde (34.1 mmol) using the same procedure as for the
synthesis of 7aꢀ7d. After completion of the reaction, the mixture was poured into water and
brought to an alkaline pH value by the addition of 2 N aq. NaOH solution. The product was
extracted using 10% methanol in ethylacetate (2 x 100 mL), and the combined organic layers
were washed with brine, dried over magnesium sulfate and evaporated under reduced pressure.
Red solid, yield; 45% (3.32 g); 1H NMR (500 MHz, DMSOꢀd6) δ (ppm) 10.92 (s, 1H, NH), 7.60
(dd, J = 7.9, 1.0 Hz, 1H), 7.32 (dt, J = 8.2, 0.9 Hz, 1H), 7.09 (d, J = 2.4 Hz, 1H), 7.02 (dd, J =
8.1, 6.9, Hz, 1H), 6.93 (d, J = 8.0, 6.9, 1.0 Hz, 1H), 3.39 (d, J = 9.2 Hz, 1H), 2.25 (dp, J = 9.4, 6.5
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Hz, 1H), 2.02 (s, 6H), 0.98 (d, J = 6.4 Hz, 3H, CH3), 0.68 (d, J = 6.5 Hz, 3H, CH3). C NMR
(126 MHz, DMSOꢀd6) δ (ppm) 136.1, 128.9, 123.9, 120.5, 119.2, 118.4, 111.4, 110.4, 67.7, 41.9,
29.7, 21.3, 20.3. LCꢀMS (m/z): positive mode 217 [M+H]1+. Purity by HPLCꢀUV (254 nm)ꢀESIꢀ
MS: 96%. HRMS (ESIꢀTOF) m/z: for (C14H20N2 [M+H]+) calcd: 217.1705. Found 217.1699.
General Procedure for the Synthesis of Ammonium Iodide Derivatives 10. To a solution of 7
(40 mmol) in benzene (20 ml), methyl iodide (80 mmol) was added. After 24 h of stirring at room
temperature, diethylether (50 ml) was added. The resulting precipitate was filtered off and
washed with diethyl ether to yield 10, which was used without further purification and
characterizations.
General Procedures for the Synthesis of (Un)symmetrical Di(aza)indolylmethanes (1, 9a-9z,
and 9aa). A 50 mL sealed tube was charged with (3ꢀindolylmethyl)trimethylammonium iodide
(10, 1.6 mmol) and indole derivative or azaindole (8, 3.2 mmol) in H2O (5 mL). The slurry
reaction mixture was stirred at 80 °C. TLC monitoring indicated the progress of the reaction; a
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small amount of the mixture was taken from the reaction mixture, dissolved in ethyl acetate and
checked. The elution was carried out with the suitable solvent system for each case, and the spots
on the chromatograms were visualized under UV light. Once the reaction was completed, the
mixture was allowed to cool to room temperature. Water was decanted from the mixture, and the
product that settled on the wall of the tube was dissolved in ethyl acetate (10 mL). The resulting
solution was dried over Na2SO4 and the product was purified by recrystallization or column
chromatography as described below.
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Diꢀ(1Hꢀindoleꢀ3ꢀyl)methane (1).22 (3ꢀIndolylmethyl)trimethylammonium iodide (10a, 1.6 mmol)
1
and an indole (8r, 3.2 mmol) were used for this reaction. Yield 92% (362 mg). White solid; H
NMR (600 MHz, CDCl3ꢀd) δ (ppm) 7.90 (s, 2H, 2 x NH), 7.61 (d, J = 7.9 Hz, 2H), 7.35 (d, J =
8.1 Hz, 2H), 7.19 – 7.12 (m, 2H, 6ꢀH), 7.07 (t, J = 7.5 Hz, 2H), 6.94 (d, J = 1.2 Hz, 2H), 4.23 (s,
2H). 13C NMR (151 MHz, CDCl3ꢀd) δ (ppm) 136.4, 127.5, 122.1, 121.9, 119.1, 115.7, 111.0,
21.2. LCꢀMS (m/z): positive mode 247 [M+H]1+. Purity by HPLCꢀUV (254 nm)ꢀESIꢀMS: 98%.
3ꢀ((5ꢀMethoxyꢀ1Hꢀindolꢀ3ꢀyl)methyl)ꢀ1Hꢀindole (9a).22 (3ꢀIndolylmethyl)trimethylammonium
iodide (10a, 1.6 mmol) and 5ꢀmethoxyindole (8a, 3.2 mmol) were used for this reaction. Yield
89% (393 mg). Brown solid; m.p. 103−105 °C. 1H NMR (600 MHz, DMSOꢀd6) δ (ppm) 10.69 (s,
1H, NH), 10.53 (d, J = 2.4 Hz, 1H, NH), 7.51 (d, J = 8.0 Hz, 1H), 7.30 (d, J = 8.1 Hz, 1H), 7.19
(d, J = 8.7 Hz, 1H), 7.12 (d, J = 2.1 Hz, 1H), 7.05 (d, J = 2.3 Hz, 1H), 7.04 – 6.99 (m, 1H), 6.99
(d, J = 2.4 Hz, 1H), 6.94 – 6.83 (m, 1H), 6.67 (dd, J = 8.7, 2.4 Hz, 1H), 4.08 (s, 2H), 3.69 (s, 3H).
13C NMR (151 MHz, DMSOꢀd6) δ 152.9, 136.5, 131.7, 127.6, 127.4, 123.6, 122.9, 120.9, 118.8,
118.1, 112.0, 100.9, 55.5, 21.0. LCꢀMS (m/z): positive mode 277 [M+H]1+. Purity by HPLCꢀUV
(254 nm)ꢀESIꢀMS: 98%.
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3ꢀ((4ꢀMethoxyꢀ1Hꢀindolꢀ3ꢀyl)methyl)ꢀ1Hꢀindole (9b). (3ꢀIndolylmethyl)trimethylammonium
iodide (10a, 1.6 mmol) and 4ꢀmethoxyindole (8b, 3.2 mmol) were used for this reaction. Yield
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85% (375 mg); Pale orange oil; H NMR (600 MHz, DMSOꢀd6) δ (ppm) 10.70 (s, 1H, NH),
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10.61 (s, 1H, NH), 7.51 (dd, J = 7.9, 1.1 Hz, 1H), 7.31 (dd, J = 8.3, 1.0 Hz, 1H), 7.08 (d, J = 2.3
Hz, 1H), 7.02 (dd, J = 8.1, 7.0 Hz, 1H), 6.98 – 6.85 (m, 3H, 2ꢀH), 6.76 (d, J = 2.3 Hz, 1H), 6.45 –
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6.37 (m, 1H), 4.25 (d, J = 1.1 Hz, 2H), 3.84 (s, 3H, OCH3). C NMR (151 MHz, DMSOꢀd6) δ
(ppm) 154.6, 138.0, 136.4, 127.4, 122.9, 121.8, 121.6, 120.7, 118.1 115.3, 111.4, 105.0, 98.8,
55.1, 22.4. LCꢀMS (m/z): positive mode 277 [M+H]1+. Purity by HPLCꢀUV (254 nm)ꢀESIꢀMS:
99%. HRMS (ESIꢀTOF) m/z: for (C18H17N2O [M+H]+) calcd: 277.1341. Found 277.1331.
3ꢀ((6ꢀMethylꢀ1Hꢀindolꢀ3ꢀyl)methyl)ꢀ1Hꢀindole (9c). (3ꢀIndolylmethyl)trimethylammonium iodide
(10a, 1.6 mmol) and 6ꢀmethylindole (8c, 3.2 mmol) were used for this reaction. Yield 76% (316
mg); Brown solid; m.p. 121−123 °C. 1H NMR (500 MHz, DMSOꢀd6) δ (ppm) 10.87 (s, 1H, NH),
10.51 (s, 1H, NH), 7.49 (dd, J = 7.8, 1.1 Hz, 1H), 7.37 (d, J = 8.1 Hz, 1H), 7.30 (dd, J = 8.1, 1.0
Hz, 1H), 7.09 (d, J = 1.9 Hz, 2H, 2ꢀH), 7.04 – 6.99 (m, 2H), 6.90 (dd, J = 8.0, 6.9 Hz, 1H), 6.77 –
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6.65 (m, 1H), 4.08 (d, J = 0.9 Hz, 2H), 2.34 (s, 3H). C NMR (126 MHz, DMSOꢀd6) δ (ppm)
137.0, 136.5, 129.8, 127.3, 125.3, 122.8, 122.1, 120.8, 119.9, 118.8, 118.5, 118.1, 114.4, 114.1,
111.4, 111.2, 21.5, 21.1. LCꢀMS (m/z): positive mode 261[M+H]1+. Purity by HPLCꢀUV (254
nm)ꢀESIꢀMS: 98%. HRMS (ESIꢀTOF) m/z: for (C18H17N2 [M+H]+) calcd: 261.1392. Found
261.1374.
3ꢀ((4ꢀFluoroꢀ1Hꢀindolꢀ3ꢀyl)methyl)ꢀ1Hꢀindole
(9d).
(3ꢀIndolylmethyl)trimethylammonium
iodide (10a, 1.6 mmol) and 4ꢀfluoroindole (8d, 3.2 mmol) were used for this reaction. Yield 74%
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(312 mg); Pale orange solid; m.p. 137−139 °C. 1H NMR (500 MHz, DMSOꢀd6) δ (ppm) 10.99 (s,
1H, NH), 10.78 (s, 1H, NH), 7.55 – 7.48 (m, 1H), 7.32 (dd, J = 8.2, 1.0 Hz, 1H), 7.17 – 7.11 (m,
1H), 7.08 – 7.02 (m, 2H), 7.02 – 6.94 (m, 2H), 6.92 (dd, J = 8.1, 7.0, Hz, 1H), 6.70 – 6.59 (m,
1H), 4.20 (s, 2H). 13C NMR (126 MHz, DMSOꢀd6) δ (ppm) 157.7, 139.5, 139.4, 136.5, 127.2,
123.5, 123.3, 122.7, 121.5, 121.4, 120.9, 118.6, 115.5, 114.6, 113.1, 108.1, 103.4, 22.0. LCꢀMS
(m/z): positive mode 265[M+H]1+. Purity by HPLCꢀUV (254 nm)ꢀESIꢀMS: 99%. HRMS (ESIꢀ
TOF) m/z: for (C17H14ClN2 [M+H]+) calcd: 281.0846. Found 281.0838.
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3ꢀ((5ꢀFluoroꢀ1Hꢀindolꢀ3ꢀyl)methyl)ꢀ1Hꢀindole (9e).14 (3ꢀIndolylmethyl)trimethylammonium
iodide (10a, 1.6 mmol) and 5ꢀfluoroindole (8e, 3.2 mmol) were used for this reaction. Yield 79%
(333 mg); Brown solid; 1H NMR (500 MHz, DMSOꢀd6) δ (ppm) 10.96 (s, 1H, NH), 0.63 (s, 1H,
NH), 7.50 (d, J = 7.8 Hz, 1H), 7.33 – 7.25 (m, 2H), 7.21 (td, J = 5.2, 2.6 Hz, 2H), 7.16 (d, J = 2.3
Hz, 1H), 7.02 (dd, J = 8.1, 6.9, Hz, 1H), 6.91 (dd, J = 7.9, 6.9, Hz, 1H), 6.85 (td, J = 9.2, 2.6 Hz,
1H), 4.09 (s, 2H). 13Capt NMR (126 MHz, DMSOꢀd6) δ (ppm) 157.5, 136.5, 133.2, 127.3, 125.0,
122.9, 122.8, 120.9, 120.8, 118.1, 114.7, 114.0, 112.2, 111.4, 108.1, 103.4, 20.9. LCꢀMS (m/z):
positive mode 263 [MꢀH]1−. Purity by HPLC UV (254 nm) ESIꢀMS: 96%.
3ꢀ((5ꢀChloroꢀ1Hꢀindolꢀ3ꢀyl)methyl)ꢀ1Hꢀindole (9f).22 (3ꢀIndolylmethyl)trimethylammonium
iodide (10a, 1.6 mmol) and 5ꢀchloroindole (8f, 3.2 mmol) were used for this reaction. Yield 73%
1
(327 mg); Brown solid; H NMR (500 MHz, DMSOꢀd6) δ (ppm)10.91 (s, 1H), 10.70 (s, 1H),
7.55 – 7.39 (m, 2H), 7.38 – 7.27 (m, 2H), 7.22 (d, J = 2.3 Hz, 1H), 7.14 (d, J = 2.3 Hz, 1H), 7.06
– 6.96 (m, 2H), 6.96 – 6.83 (m, 1H), 4.10 (d, J = 1.1 Hz, 2H). 13C NMR (126 MHz, DMSOꢀd6) δ
(ppm) 136.5, 135.0, 128.4, 127.2, 124.8, 122.9, 122.8, 120.9, 120.8, 118.7, 118.2, 118.0, 114.3,
113.9, 113.0, 111.4, 20.9. LCꢀMS (m/z): positive mode 281 [M+H]1+. Purity by HPLCꢀUV (254
nm)ꢀESIꢀMS: 95%.
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3ꢀ((5ꢀBromoꢀ1Hꢀindolꢀ3ꢀyl)methyl)ꢀ1Hꢀindole (9g).20 (3ꢀIndolylmethyl)trimethylammonium
iodide (10a, 1.6 mmol) and 5ꢀbromoindole (8g, 3.2 mmol) were used for this reaction. Yield 71%
(370 mg); Slightly red powder; 1H NMR (600 MHz, DMSOꢀd6) δ (ppm) 11.13 (s, 1H, NH), 10.62
(s, 1H, NH), 7.64 (d, J = 2.0 Hz, 1H), 7.49 (dd, J = 7.9, 1.1 Hz, 1H), 7.35 – 7.24 (m, 2H), 7.21 (d,
J = 2.3 Hz, 1H), 7.18 – 7.08 (m, 2H), 7.02 (dd, J = 8.2, 6.9, Hz, 1H, 6.91 (dd, J = 7.9, 6.9 Hz,
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1H), 4.10 (s, 2H). C NMR (151 MHz, DMSOꢀd6) δ (ppm) 135.2, 129.2, 127.2, 124.7, 123.3,
123.0, 121.0, 120.9, 118.8, 118.2, 114.2, 113.9, 113.5, 111.5, 20.9. LCꢀMS (m/z): positive mode
326 [M+H]1+. Purity by HPLCꢀUV (254 nm)ꢀESIꢀMS: 95%.
Methyl
3ꢀ((1HꢀIndolꢀ3ꢀyl)methyl)ꢀ1Hꢀindoleꢀ5ꢀcarboxylate
(9h).14
(3ꢀ
Indolylmethyl)trimethylammonium iodide (10a, 1.6 mmol) and methyl 4ꢀ1Hꢀindoleꢀ5ꢀ
1
carboxylate (8h, 3.2 mmol) were used for this reaction. Yield 72% (350 mg); Brown solid; H
NMR (600 MHz, DMSOꢀd6) δ (ppm) 11.32 (s, 1H), 10.72 (s, 1H), 8.20 (s, 1H), 7.68 (dd, J = 8.6,
1.7 Hz, 1H), 7.50 (dd, J = 7.9, 1.1 Hz, 1H), 7.39 (d, J = 8.4 Hz, 1H), 7.31 (dt, J = 8.1, 0.9 Hz,
1H), 7.26 (d, J = 2.2 Hz, 1H), 7.07 (d, J = 2.3 Hz, 1H), 7.03 (ddd, J = 8.1, 6.9, 1.2 Hz, 1H), 6.91
(ddd, J = 8.0, 7.0, 1.0 Hz, 1H), 4.17 (d, J = 1.1 Hz, 2H), 3.79 (s, 3H). 13C NMR (151 MHz,
DMSOꢀd6) δ (ppm) 167.4, 139.2, 136.6, 127.2, 126.9, 124.9, 122.9, 122.0, 121.4, 121.0, 119.8,
118.7, 118.2, 115.9, 113.9, 111.5, 51.7, 20.9. LCꢀMS (m/z): positive mode 305 [MꢀH]1+. Purity
by HPLC UV (254 nm) ESIꢀMS: 98%.
3ꢀ(1HꢀIndolꢀ3ꢀylmethyl)ꢀ1ꢀmethylꢀ1Hꢀindole (9i).14 (3ꢀIndolylmethyl)trimethylammonium iodide
(10a, 1.6 mmol) and 1ꢀmethylꢀ1Hꢀindole (8i, 3.2 mmol) were used for this reaction. Yield 78%
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(324 mg); Brown solid;. H NMR (500 MHz, DMSOꢀd6) δ (ppm) 10.71 (s, 1H), 7.52 (dd, J =
18.0, 7.9 Hz, 2H), 7.32 (dd, J = 11.6, 8.2 Hz, 2H), 7.13 (d, J = 2.3 Hz, 1H), 7.12 – 7.05 (m, 2H),
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7.05 – 6.98 (m, 1H), 6.93 (dt, J = 20.4, 7.4 Hz, 2H), 4.11 (s, 2H), 3.69 (s, 3H). C NMR (126
MHz, DMSOꢀd6) δ (ppm) 136.9, 136.5, 127.6, 127.2, 122.9, 121.0, 120.9, 118.9, 118.7, 118.22,
118.16, 114.1, 113.8, 111.4, 109.5, 33.0, 20.8. LCꢀMS (m/z): positive mode 261 [MꢀH]1+. Purity
by HPLC UV (254 nm) ESIꢀMS: 96%.
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5ꢀMethoxyꢀ3ꢀ((5ꢀfluoroꢀ1Hꢀindolꢀ3ꢀyl)methyl)ꢀ1Hꢀindole
(9j).
(5ꢀMethoxyꢀ3ꢀ
indolylmethyl)trimethylammonium iodide (10b, 1.6 mmol) and 5ꢀfluoroindole (8e, 3.2 mmol)
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were used for this reaction. Yield 75% (353 mg); Brown solid; m.p. 112−114 °C. H NMR (500
MHz, DMSOꢀd6) δ (ppm) 10.80 (s, 1H, NH), 10.53 (s, 1H, NH), 7.29 (dd, J = 8.8, 4.6 Hz, 1H),
7.24 – 7.16 (m, 3H), 7.09 (d, J = 2.3 Hz, 1H), 6.98 (d, J = 2.5 Hz, 1H), 6.85 (td, J = 9.2, 2.6 Hz,
1H), 6.68 (dd, J = 8.7, 2.4 Hz, 1H), 4.05 (s, 2H), 3.69 (s, 3H). 13C NMR (126 MHz, DMSOꢀ d6) δ
(ppm) 157.5, 155.7, 133.2, 131.7, 127.6, 125.0, 123.6, 113.8, 112.33, 112.25, 112.0, 110.8,
109.0, 108.8, 103.5, 103.3, 55.5, 20.9. LCꢀMS (m/z): positive mode 295 [M+H]1+. Purity by
HPLCꢀUV (254 nm)ꢀESIꢀMS: 95%. HRMS (ESIꢀTOF) m/z: for (C18H16FN2O [M+H]+) calcd:
295.1247. Found 295.1240.
5ꢀMethoxyꢀ3ꢀ((4ꢀmethoxyꢀ1Hꢀindolꢀ3ꢀyl)methyl)ꢀ1Hꢀindole
(9k).
(5ꢀMethoxyꢀ3ꢀ
indolylmethyl)trimethylammonium iodide (10b, 1.6 mmol) and 4ꢀmethoxyindole (8b, 3.2 mmol)
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were used for this reaction. Yield 76% (372 mg); Orange viscous oil. H NMR (500 MHz,
DMSOꢀd6) δ (ppm) 10.62 (s, 1H, NH), 10.49 (s, 1H, NH), 7.20 (dd, J = 8.8, 2.1 Hz, 1H), 7.04 (d,
J = 2.2 Hz, 1H), 6.98 (d, J = 2.4 Hz, 1H), 6.97 – 6.85 (m, 2H), 6.77 (d, J = 2.3 Hz, 1H), 6.67 (dt,
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J = 8.7, 2.5 Hz, 1H), 6.45 – 6.40 (m, 1H), 4.22 (s, 2H), 3.84 (s, 3H), 3.69 (s, 3H). C NMR (126
MHz, DMSOꢀd6) δ (ppm) 154.6, 152.9, 138.0, 131.6, 127.7, 123.6, 121.7, 121.6, 117.0, 115.14,
115.06, 111.9, 110.7, 105.0, 100.1, 98.8, 55.4, 55.0, 22.4. LCꢀMS (m/z): positive mode 307
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