Preparation of indole containing building blocks for the regiospecific construction of indole appended pyrazoles and pyrroles

Article abstract of DOI:10.1016/j.tet.2013.05.045

The preparation of an indole appended vinamidinium salt, an indole appended vinylogous amide and an indole appended chloroenal are described. The subsequent regiospecific conversion of these indole containing building blocks to functionalized pyrazoles an

Full text of DOI:10.1016/j.tet.2013.05.045

Accepted Manuscript
Preparation of Indole Containing Building Blocks for the Regiospecific Construction of
Indole Appended Pyrazoles and Pyrroles
John T. Gupton, Nakul Telang, Dominic F. Gazzo, Peter J. Barelli, Kristin E.
Lescalleet, Jonathan W. Fagan, Brandon J. Mills, Kara L. Finzel, Rene P.F. Kanters,
Kyle R. Crocker, Sean T. Dudek, Corinne M. Lariviere, Stanton Q. Smith, Kartik M.
Keertikar
PII:
S0040-4020(13)00780-1
10.1016/j.tet.2013.05.045
TET 24383
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 15 April 2013
Revised Date: 10 May 2013
Accepted Date: 13 May 2013
Please cite this article as: Gupton JT, Telang N, Gazzo DF, Barelli PJ, Lescalleet KE, Fagan JW, Mills
BJ, Finzel KL, Kanters RPF, Crocker KR, Dudek ST, Lariviere CM, Smith SQ, Keertikar KM, Preparation
of Indole Containing Building Blocks for the Regiospecific Construction of Indole Appended Pyrazoles
and Pyrroles, Tetrahedron (2013), doi: 10.1016/j.tet.2013.05.045.
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ACCEPTED MANUSCRIPT
Preparation of Indole Containing Building Blocks for the Regiospecific Construction
of Indole Appended Pyrazoles and Pyrroles
John T. Gupton*,a, Nakul Telanga, Dominic F. Gazzoa, Peter J. Barellia, Kristin E. Lescalleeta, Jonathan W.
Fagana, Brandon J. Millsa, Kara L. Finzela, Rene P.F. Kantersa, Kyle R. Crockerb, Sean T. Dudekb, Corinne
M. Lariviereb , StantonQ. Smithb, and Kartik M. Keertikarc.
aDepartment of Chemistry, University of Richmond, Richmond, VA 23173, USA
bDepartment of Chemistry, Virginia Military Institute, Lexington, VA 24450, USA
cMerck Research Laboratories, Rahway, NJ 07065, USA
Abstract- The preparation of an indole appended vinamidinium salt, an indole appended
vinylogous amide and an indole appended chloroenal are described. The subsequent regiospecific
conversion of these indole containing building blocks to functionalized pyrazoles and pyrroles is
detailed.
1. Introduction
The indole group has long been considered a privileged structure1 as it relates to the discovery of
new medicinally active substances. The term privileged structure2 refers to the ability of “a single
molecular framework able to provide ligands for diverse receptors”. It has been suggested2 that
“indoles represent the most important of all structural classes in drug discovery” due to their
extremely wide range of pharmacological activity. Some relevant examples of bioactive indole
containing substances are presented in Figure 1.
H
N
H
N
O
Z
Z
O
N
H
MeO
H
N
H
N
H
N
N
N
H
H
H
1, Z = COOH, Lycogallic Acid
2, Z = COOMe Lycogarubin C
3, Staurosporine
aglycone
4, Novel Chalcone-like Antitumor Agent
CF3
H2N
N
N
N
OH
N
N
N
N
OMe
OMe
N
H
N
N
H
MeO
Me
SO2NH2
5, Meridianin A
7, Indolyl pyrazoline COX-2 Inhibitor
6, Microtubule inhibitor
Figure 1, Biologically Active Indole Derivatives
Keywords: Vinamidinium salt; Vinylogous amide; Chloroenal; Pyrrole; Pyrazole; Indole
*Corresponding author. Tel +1 804 287-6498: fax: +1 804 287-1897; e-mail:
jgupton@richmond.edu.
1

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The range of compounds represented in Fig. 1 include Lycogallic acid3 natural products (1 and 2),
which have been reported to be biosynthetic precursors to the antitumor agent Staurosporine4 (3),
Chalcone-like antitumor agents5 (4), Meridianin type kinase inhibitors6 (5), microtubule inhibitors7
(6) and COX-2 inhibitors8 (7). Humphrey and Kuethe1 have previously reviewed practical methods
for the synthesis of indole containing substances and a variety of useful methodologies are
available. Our research group has been interested for some time in the use of vinylogous iminium
compounds9 and their derivatives for the construction of important bioactive heterocycles and we
envisioned using such systems as building blocks for the construction of indole appended
heterocyclic motifs. Padwa10 and coworkers have recently pointed out the advantage of having
access to versatile indole containing substances, which could be used for the construction of more
highly functionalized compounds. To that end we have studied an indole appended vinamidinium
salt (8), an indole appended vinylogous amide (9) and an indole appended chloroenal (10) as
building blocks for the regio controlled synthesis of pyrazoles and pyrroles. Since pyrazole11 and
pyrrole12 ring systems are commonly found in medicinal agents as well, we believed it would be of
value to develop appropriate synthetic methodology for such a purpose.
H
O
O
Cl
NH
NMe2
H
Me
PF6
Me
Me
N
N
N
Me
N
Me
Me
8, Indole Vinamidinium Salt
9, Indole Vinylogous Amide
10, Indole Chloroenal
Figure 2, Indole Appended Building Blocks
2. Results and Discussions
The synthesis of the 2-indolyl appended vinamidinium salt (the perchlorate version of 8) was
reported in 1961 by Arnold13 but full characterization of this substance along with a detailed
experimental procedure was not provided. We now report full details on the synthesis and
characterization of the 2-indolyl appended vinamidinium hexfluorophosphate (8). Indole acetic acid
is commercially available and this material is reacted under Vilmeier-Haack-Arnold conditions
(Scheme 1) followed by quenching the reaction mixture with aqueous sodium hexfluorophosphate.
The resulting salt (8) is somewhat tacky and is usually carefully dried under vacuum prior to being
utilized in subsequent reactions.
H
N
NH
POCl3, DMF and heat
followed by NaPF6 and H2O
Me
PF6
Me
Me
N
N
Me
COOH
8
11
Greater than 80% yield
Scheme 1. Preparation of 2-Indole Apended Vinamidinium Salt
With this material (8) in hand we decided to initially look at its application to pyrazole synthesis
(Scheme 2). One of the important aspects of using such a salt (8) for synthesis lies in the ability to
control regiochemistry in the final product. Since the salt (8) is a symmetrically disposed molecule,
the indole group would be expected to be located at the central carbon of the pyrazole ring. The
2

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following table provides a range of N-substituted pyrazoles, which were prepared by the indicated
methodology.
NH
NH
RNHNH2HCl
Me
PF6
Me
Me
N
N
Me
Na2CO3 in EtOH and heat
N
N
R
8
12
Scheme 2. Synthesis of 4-Indole Appended Pyrazoles
Table 1. Synthesis of 4-Indolyl Appended Pyrazoles
Compound R
% Yield (purified)
12a
12b
12c
12d
12e
12f
12g
12h
12i
4-Methylphenyl
4-Methoxyphenyl
Phenyl
4-Bromophenyl
4-Chlorophenyl
4-Fluorophenyl
Methyl
H
Ethyl
t-Butyl
65
61
94
60
92
87
65
44
56
39
12j
The crude reaction products are relatively clean and mild bases, such as the carbonates, can be used
in these transformations. We envision the reaction proceeding as presented in Scheme 3.
NH
NH
RNHNH2HCl
Me
PF6
Me
Me
N
N
Me
Na2CO3 in EtOH and heat
N
N
R
8
12
NH
NH
H
Me
Me
N
NMe2
N
N
N
NH
R
R
14
13
Scheme 3. Reaction Pathway to 4-Indole Appended Pyrazoles
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Although the purified yields for the N-alkylpyrazoles were somewhat lower than for the N-
arylpyrazoles, the reaction conditions appear to have considerable generality for the efficient
preparation of 1,4-disusbtituted pyrazoles from the 2-indole appended vinamidinium salt (8).
We next turned our attention to applying the indole appended vinamidinium salt (8) to the
regioselective preparation of 2,4-disubstituted pyrroles9 (Scheme 4).
H
N
H
NH
N
R
CO2Et
Me
PF6
Me
Me
N
N
Me
NaO-t-Bu in DMF with heat
CO2Et
N
R
8
15a R = CH2Ph 68% Yield
15b R = Me 41% Yield
15c R = H 33% Yield
Scheme 4. Conversion of Indole Vinamidinium Salt to 2,4-Disubstituted Pyrroles
From a mechanistic standpoint the reaction pathway to the 2,4-disubstituted pyrroles should
resemble what is depicted in Scheme 3 with the exception that an enolate anion derived from the
alpha carbon of the glycine derivatives would be the nucleophile, which is responsible for initiating
the cyclization step. It should be noted that for the N-benzylglycine (15a) and N-methylglycine
(15b) reactions, the intermediates are in fact azomethine ylids. The yields reported for the reactions
depicted in Scheme 4 represent purified materials and may represent some physical loss during the
purification process.
The ability to prepare indole appended pyrazoles and pyrroles that would be isomeric in a
regiochemical sense to the compounds obtained from the vinamidium salt (8), could nicely
compliment the chemistry already described and we subsequently decided to look at an indole
appended vinylogous amide (9) and an indole appended chloroenal (10) for this reason. Scheme 5
represents the preparation of these materials (9 and 10).
H
O
O
O
Me
Cl
NMe2
POCl3, DCM and heat
followed by H2O/THF
DMF Acetal
DMF and heat
H
N
N
N
H
Me
Me
16
9, 85% yield
10, 75% yield
Scheme 5. Preparation of Indole Appended Vinylogous Amide and Chloroenal
Anizon6 and coworkers have previously described the preparation of the vinylogous amide (9) in
their synthesis of indole appended pyrimidines, which are similar in structure to the Meridianin
natural products. This material (9) is efficiently prepared from 3-acetylindole by reaction with DMF
acetal in which case the nitrogen of the indole undergoes methylation as well. The crude vinylogous
amide (9) is usually of very good purity and can be used in subsequent reactions without further
purification. Treatment of vinylogous amide (9) with phosphorous oxychloride in dichloromethane
with heating followed by room temperature treatment of the concentrated reaction mixture with a
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water/THF mixture produces the indole appended chloroenal (10) in good yield (75%). Our
research group, as well as others14, have established the Z stereochemistry of such chloroenals and
the indole appended chloroenal (10) exhibited spectral properties consistent with such an
assignment. It should also be noted that Buchwald15 and Pellegatti have recently reported a
continuous flow method for the preparation of the N-desmethyl analog of 10 by direct reaction of 3-
acetylindole (16) with phosphorous oxychloride/DMF.
With both vinylogous amide (9) and chloroenal (10) in hand, we initiated studies to prepare the
regioisomeric indole appended pyrazoles (17) as depicted in Scheme 6.
H
O
R
N
Cl
N
NH2NHR
H
N
N
Na2CO3, EtOH and heat
Me
Me
17
10
H
RHN
R
N
N
Cl
N
H
Cl
N
Me
N
Me
19
18
Scheme 6. Preparation of 1,5-Disubstituted Pyrazoles
Table 2. Synthesis of 1,5-Disubstituted-5-Indole Appended Pyrazoles from Chloroenal
Compound
17a
R
% Yield (purified)
4-Methylphenyl
4-Chlorophenyl
4-Bromophenyl
Phenyl
53
54
31
52
57
17b
17c
17d
17e
4-Methoxyphenyl
In order to obtain the 1,5-disubstituted regiochemistry, we propose that the hydrazone (18) of the
chloroenal (10) is formed first followed by cyclization and loss of HCl to generate the aromatized
product (17). NOESY NMR analysis of pyrazole 17a exhibited an interaction between the proton at
the C-2 position of the indole ring with the proton at the C-2 position of the phenyl ring attached to
the pyrazole nitrogen, thereby establishing the regiochemistry of the pyrazole being 1,5-disubstituted.
Interestingly, when the reaction was repeated in the absence of base, two isomeric pyrazole products
were indicated in the crude reaction mixture (Scheme 7). Our research group16 and others17 have
reported that the chemical shift differential between ortho pyrazole hydrogens is increased in polar
NMR solvents for the 1,3-isomer (chemical shift differential 1.45 Hz) relative to the 1,5-isomer
(chemical shift differential 1.13 Hz). Applying this reasoning to our crude reaction mixture suggested
an isomer ratio of 2:1 for the 1,3-isomer versus the 1,5-isomer, respectively. NOESY NMR analysis
of the purified majority isomer (20a) indicated a NOESY interaction between the proton at the C-5
5

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position of the pyrazole ring with the proton at C-2 position of the phenyl ring attached to the
pyrazole nitrogen, thereby establishing the regiochemistry of the majority pyrazole product (20a)
being 1,3-disubstituted. From a mechanistic standpoint this result suggests that, in the absence of
base, initial reaction of the hydrazine occurs preferentially at the chlorovinyl carbon followed by
cyclization at the aldehyde carbon.
H
Me
Me
O
Cl
NH2NH
Me
H
N
N
N
N
+
EtOH and heat
N
N
Me
Me
N
Me
10
20a, Major Isomer
17a, Minor isomer
Scheme 7. Preparation of Isomeric Pyrazoles
It is important to mention that most reactions conducted with the indole chloroenal (10) in the
presence of base should be stirred at room temperature for at least 30 min to initiate the early steps
in the reaction prior to providing heat to the reaction mixture. When the indole chloroenal (10) is
subjected to heat and base in the absence of other reagents, a very efficient decarbonylative
elimination takes place resulting in the clean formation of a 3-ethynylindole (21). Such a reaction
can be of some utility as Boger18 has demonstrated in his synthesis of Lycogallic acid, which
employs the use of 3-alkynylindoles.
H
H
O
Cl
NaOH, THF and heat
H
N
N
Me
Me
10
21, 89% yield
Scheme 8. Formation of 3-Ethynyl Indole
As noted in Table 2, the purified yields of the 1,5-disubstituted-5-indole appended pyrazoles (17)
were generally in the 50% range and were somewhat less than satisfying. We decided to look at the
vinylogous amide (9) as a possible alternative precursor (Scheme 9) to the 1,5-disubstituted-5-
indole appended pyrazoles (17). Using the vinylogous amide (9) would also have the advantages of
shortening the reaction sequence by one step and removing the concern about an alternate
elimination pathway (Scheme 8) in the case of the chloroenal (10). The results of this study are
presented in Table 3.
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Me
Me
Me
Solvent & heat
N
N
Solvent & heat, NH2NHR
NMe2
N
N N
NHNHR
R
O
O
17
22
Scheme 9. Conversion of Vinylogous Amide to 1,5-Disubstituted Pyrazole
9
Table 3. Synthesis of 1,5-Disubstituted-5-Indole Appended Pyrazoles from Vinylogous Amide
Entry Cpd.
R
% Yield (purified)
82
Solvent
CH3CN
Heat Source
Microwave, 85°C for
2 hrs
Microwave, 85°C for
2 hrs
Microwave, 85°C for
2 hrs
Microwave, 85°C for
2 hrs
Microwave, 85°C for
2hrs
Microwave, 85°C for
2hrs
Microwave, 85°C for
2hrs
1
2
3
4
5
6
7
17a
17b
17c
17d
17e
17c
17c
4-Methylphenyl
4-Chlorophenyl
4-Bromophenyl
Phenyl
93
97
52
CH3CN
CH3CN
CH3CN
CH3CN
HOAC
EtOH
4-Methoxyphenyl 84
4-Bromophenyl
4-Bromophenyl
82
70
8
9
17c
17a
17b
17c
17d
17e
17f
17g
4-Bromophenyl
4-Methylphenyl
4-Chlorophenyl
4-Bromophenyl
Phenyl
4-Methoxyphenyl 51
H
Me
69
60
56
82
51
CH3CN
HOAc
HOAc
HOAc
HOAc
HOAc
HOAc
HOAc
Reflux for 4 hr
Reflux for 4 hr
Reflux for 4 hr
Reflux for 4 hr
Reflux for 4 hr
Reflux for 4 hr
Reflux for 18 hr
Reflux for 18 hr
10
11
12
13
14
15
75
59 (10:1 mix of the 1,5-
to the 1,3-isomer by GC-MS)
69 (6:1 mix of the 1,5-
to the 1,3-isomer by GC-MS)
80 (32:1 mix of the 1,5-
to the 1,3-isomer by GC-MS)
96 (78:1 mix of the 1,5-
to the 1,3-isomer by GC-MS)
85 (22:1 mix of the 1,5-
to the 1,3-isomer by GC-MS)
16
17
18
19
17h
17i
17h
17i
Et
HOAc
EtOH
Reflux for 18 hr
Reflux for 18 hr
Reflux for 18 hr
Reflux for 18 hr
t-Bu
Et
CH3CN
CH3CN
t-Bu
The entries 1-7 listed in Table 3 were conducted with the vinylogous amide (9) and the appropriate
arylhydrazine in acetonitrile or acetic acid or ethanol with microwave heating. The crude reaction
products were nearly analytically pure and after flash chromatography gave very good yields of the
respective 1,5-disubstituted pyrazoles (17). When the reaction for an arylhydrazine was repeated
with traditional heating in acetonitrile (entry 8), an acceptable, purified yield of the respective 1,5-
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disubstituted pyrazole was obtained. In addition to the conditions just described, we also evaluated
arylhydrazines in acetic acid under microwave conditions (entry 6) along with arylhydrazines
(entries 9-13) and alkylhydrazines (enties 15-16) in refluxing acetic acid. Both N-aryl- and N-
alkylpyrazoles were formed in reasonable yields with acetic acid as the solvent and it was also
noted that some of the 1,3-isomer was observed as a minor product for some of the N-alkyl analogs
as determined by GC-MS analysis. The reaction with t-butyl hydrazine (entry 17) had to be
performed in EtOH, since N-dealkylation of the pyrazole product was observed in acetic acid.
When the ethylhydrazine (entry 18) and t-butylhydrazine reactions (entry 19) were repeated in
refluxing acetonitrile, very good yields of the pyrazoles were obtained and excellent regiochemical
selectivity was also observed. In an overall sense, the acetonitrile conditions appear to be superior
for producing the 1,5-isomer selectively and in high yield.
Our last set of studies involved reacting glycine ethyl ester and N-substituted derivatives with the
indole chloroenal (10) in anticipation of obtaining a 2,5-disubstituted pyrrole9 (23) as opposed to a
2,4-disubstituted pyrrole (15), which had been produced with the indole vinamidinium salt (8). The
suggested pathway for this process is given in Scheme 10.
H
R
O
N
H
CO2Et
Cl
R
N
O
H
Me
N
O
N
DMF and heat
Me
23a R = CH2Ph, 47% yield
23b R = Me, 53% yield
23c R = H, 43% yield
10
O
H
O
R
O
N
O
N
R
Me
N
O
H
OH
N
25
Me
24
Scheme 10. Preparation of 2,5-Disubstituted Pyrroles
We believe that the first step in the process involves the displacement of the chlorine of the
chloroenal (10) by the nitrogen of the amino acid ester to produce a vinylogous amide (24), which
undergoes cyclization and dehydration to the resultant 2,5-disubstituted pyrrole. The regiochemistry
of the 2,5-disubstituted pyrroles was determined by a NOESY NMR analysis of 23b, which
contains a methyl group at the pyrrole nitrogen. An NOE was seen for the hydrogen at the 2
position of the indole with both the indole methyl group and also the pyrrole methyl group. An
NOE was also seen for the methylene and methyl groups of the ester with the hydrogen at carbon 3
of the pyrrole ring.
3. Conclusions
Based on the results described herein, we believe that we have established that an indole appended
vinamidinium salt (8), an indole appended vinylogous amide (9) and an indole appended chloroenal
8

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(10) represent useful and important building blocks for the regiospecific construction of the
corresponding indole appended pyrazoles and pyrroles. Since the indole vinamidinium salt produces
different regio isomers from the vinylogous amide and chloroenal, it is now possible to select a
particular indole building block, which will furnish a predictable and selective regiochemical
outcome. The fact that the indole appended pyrazoles and pyrroles can be assembled in a minimum
number of steps from commercially available starting materials suggests that this chemistry could
be very useful for SAR guided work in the course of optimizing pharmacodynamic or
pharmacokinetic aspects of an indole containing drug candidate. Additionally, the indole appended
chloroenal (10) can be used to prepare a 3-ethynylindole (21), which presents potential applications
for Sonogashira type coupling reactions.
4. Experimental
4.1 General
All chemicals were used as received from the manufacturer (Aldrich Chemicals and Fisher
Scientific). All solvents were dried over 4 angstrom molecular sieves prior to their use. NMR
spectra were obtained on either a Bruker 300 MHz spectrometer, or a Bruker 500 MHz
spectrometer in either CDCl3, d6-DMSO or d6-acetone solutions. IR spectra were recorded on a
Nicolet Avatar 320 FT-IR spectrometer with an HATR attachment. Most high resolution mass
spectra were obtained on a Bruker Biotof Q electrospray mass spectrometer at the University of
Richmond. Some high resolution mass spectra were provided by the Merck Research Laboratories.
Low resolution GC-MS spectra were obtained on a Shimadzu QP 5050 instrument. Melting points
and boiling points are uncorrected. Chromatographic separations were carried out on a Biotage SP-1
instrument or a Biotage Isolera instrument (both equipped with a silica cartridge). Gradient elution
with ethyl acetate/hexane was accomplished in both instances. The reaction products were normally
eluted within the range of 4-8 column volumes of eluant with a gradient mixture of 60-80% ethyl
acetate in hexane. TLC analyses were conducted on silica plates with hexane/ethyl acetate as the
13
eluant. All purified reaction products gave TLC results, flash chromatograms, and C NMR
spectra consistent with a sample purity of >95%.
4.1.1 2-(1-Indolyl)-1,3-bis(dimethylamino)trimethinium hexafluorophosphate (8). To a 100 mL
round bottom flask equipped with a magnetic stirring bar, thermometer, reflux condenser and
addition funnel, was added 15 mL of dry DMF , which was immediately cooled to 0-5°C.
Phosphorous oxychloride (5.250 g) was added dropwise via the addition funnel while the reaction
temperature was controlled between 10-15 °C with an ice bath. The reaction mixture was then cooled
to 0-5°C and indole-3-acetic acid (2.000 g) was added to the reaction mixture in small portions. After
removal of the cooling bath, the reaction mixture was heated at 75-80°C for 3 hours while ensuring
that the reaction temperature never exceeded 90°C. The reaction mixture was then cooled to 30°C
and ~65g of ice was carefully added to the flask. After the ice had melted, the reaction mixture was
poured into a solution of sodium hexafluorophosphate (6.180 g in 100 mL of water) with stirring in
which case a dark solid precipitated. Due to the tacky nature of the solid, the reaction mixture was
extracted with dichloromethane (2 x 80 mL) followed by drying the organic phase with anhydrous
sodium sulfate. Removal of the drying agent via filtration and concentration of the organic phase in
vacuo produced a dark solid (3.300 g, 75% yield), which exhibited the following physical properties:
mp 196-198°C; 1H NMR (acetone-d6)
δ 2.58 (s, 6H), 3.38 (s, 6H), 7.16 (t, J=7.8 Hz, 1H), 7.23 (t,
J=7.8 Hz, 1H), 7.35 (d, J = 2.4 Hz, 1H), 7.46 (d, J = 7.8 Hz, 1H), 7.53 (d, J = 7.8 Hz, 1H) and 7.86
(s, 2H); 13C NMR (acetone-d6) 165.3, 136.2, 130.2, 127.0, 122.6, 120.5, 119.1, 112.0, 105.5, 97.3,
48.2 and 37.8; IR (neat) 1588 cm-1; HRMS (ES) m/z calcd for C15H20N3 242.1652, found 242.1582.
9

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It should be noted that the perchlorate derivative of this substance was previously prepared by
Arnold13 but was not full characterized by NMR and MS techniques.
4.1.2 3-(1-p-Tolyl-1H-pyrazol-4-yl)-1H-indole (12a). To a 100 mL round bottom flask equipped
with a magnetic stirring bar and reflux condenser was added 0.500 g (1.29 mmol) of the indole
trimethinium salt (8) along with 4-methylphenylhydrazine hydrochloride (0.307 g, 1.94 mmol) and
0.411 g (3.87 mmol) of sodium carbonate. Dry ethanol (30 mL) was then added to the flask and the
resulting mixture was refluxed overnight. After cooling the reaction mixture to room temperature, the
solvent was removed in vacuo and the residue was partitioned between chloroform (30 mL) and
water (30 mL). The aqueous phase was extracted with additional chloroform (2 x 30 mL), the
combined organic phases were dried over anhydrous magnesium sulfate, filtered and concentrated to
give a dark solid. This material was subjected to flash chromatography on a Biotage SP-1 instrument
with a silica column in which case 0.231 g (65% yield) of a red solid was obtained upon elution with
six column volumes of a hexane/ethyl acetate gradient. This solid exhibited the following properties:
mp 190-192°C; 1H NMR (acetone-d6)
7.33 (d, J = 9.0 Hz, 2H), 7.48 (d, J = 7.0 Hz, 1H),7.85 (d, J = 9.0 Hz, 2H), 7.67 (s, 1H), 7.96 (d, J =
δ 2.40 (s, 3H), 7.15 (t, J=7.0 Hz, 1H), 7.20 (t, J=7.0 Hz, 1H),
7.0 Hz, 1H), 8.06 (s, 1H) and 8.63 (s, 1H); 13C NMR (acetone-d6)
δ 138.7, 138.4, 137.0, 135.4,
129.8, 125.9, 122.4, 121.9, 121.6, 119.5, 118.7, 118.3, 111.6, 107.7, and 19.5; IR (neat) 3387 cm-1;
HRMS (ES) m/z calcd for C18H16N3 274.1339, found 274.1356.
4.1.3 3-[1-(4-Methoxyphenyl)-1H-pyrazol-4-yl]-1H-indole (12b). This material was prepared in a
manner similar to 12a with the exception that 4-methoxyphenylhydrazine hydrochloride was used in
the reaction in place of 4-methylphenylhydrazine hydrochloride in which case a maroon solid was
obtained in 61% yield after flash chromatographic purification. This solid exhibited the following
properties: mp 166-168°C; 1H NMR (acetone-d6)
δ
3.02 (s, 3H), 7.08 (d, J = 6.0 Hz, 2H), 7.17 (m,
2H), 7.49 (d, J = 7.2 Hz, 1H), 7.65 (d, J = 3.0 Hz, 1H), 7.87 (d, J = 6.0 Hz, 2H), 7.96 (d, J = 7.2 Hz,
1H), 8.06 (s, 1H) and 8.56 (s, 1H); 13C NMR (acetone-d6)
δ 158.1, 138.5, 137.0, 134.3, 125.9, 122.6,
121.8, 121.7, 119.9, 119.5, 118.5, 114.5, 111.6, 107.9 and 55.0; IR (neat) 3372 cm-1; HRMS (ES) m/z
calcd for C18H16N3O 290.1288, found 290.1285.
4.1.4 3-(1-Phenyl-1H-pyrazol-4-yl)-1H-indole (12c). This material was prepared in a manner
similar to 12a with the exception that phenylhydrazine hydrochloride was used in the reaction in
place of 4-methylphenylhydrazine hydrochloride in which case a brown solid was obtained in 94%
yield after flash chromatographic purification. This solid exhibited the following properties: mp 161-
163°C; 1H NMR (acetone-d6)
δ
7.14 (t, J=7.0 Hz, 1H), 7.20 (t, J=7.0 Hz, 1H), 7.32 (t, J=7.5 Hz, 1H),
7.48-7.55 (m, 3H), 7.69 (d, J = 2.0 Hz, 1H), 7.96-7.99 (m, 3H), 8.10 (s, 1H) and 8.69 (s, 1H); 13C
NMR (acetone-d6)
δ 140.5, 139.1, 137.1, 129.4, 125.9, 125.8, 122.6, 122.0, 121.7, 119.6, 119.5,
119.0, 118.3, 111.6 and 107.7; IR (neat) 3219 cm-1; HRMS (ES) m/z calcd for C17H14N3 260.1182,
found 260.1206.
4.1.5 3-[1-(4-Bromophenyl)-1H-pyrazol-4-yl]-1H-indole (12d). This material was prepared in a
manner similar to 12a with the exception that 4-bromophenylhydrazine hydrochloride was used in
the reaction in place of 4-methylphenylhydrazine hydrochloride in which case a dark red solid was
obtained in 60% yield after flash chromatographic purification. This solid exhibited the following
properties: mp 194-196°C; 1H NMR (acetone-d6)
δ
7.14 (t, J=8.0 Hz, 1H), 7.19 (t, J=8.0 Hz, 1H),
7.33 (d, J = 9.0 Hz, 2H), 7.47 (d, J = 8.0 Hz, 1H), 7.67 (d, J = 5.0 Hz, 1H), 7.85 (d, J = 9.0 Hz, 2H),
7.96 (d, J = 8.0 Hz, 1H), 8.06 (s, 1H) and 8.63 (s, 1H); 13C NMR (acetone-d6)
139.7, 139.6, 137.1,
δ
132.3, 125.8, 122.5, 122.2, 121.8, 120.1, 119.6, 119.5, 119.4, 118.3, 111.7 and 107.5; IR (neat) 3267
cm-1; HRMS (ES) m/z calcd for C17H13BrN3 338.0287, found 338.0271.
10

ACCEPTED MANUSCRIPT
4.1.6 3-[1-(4-Chlorophenyl)-1H-pyrazol-4-yl]-1H-indole (12e); This material was prepared in a
manner similar to 12a with the exception that 4-chlorophenylhydrazine hydrochloride was used in the
reaction in place of 4-methylphenylhydrazine hydrochloride in which case a brown solid was
obtained in 92% yield after flash chromatographic purification. This solid exhibited the following
properties: mp 143-145°C; 1H NMR (acetone-d6)
δ
7.12-7.23 (m, 2H), 7.50 (d, J = 9.0 Hz, 1H),
7.54 (d, J = 9 .0 Hz, 2H), 7.69 (d, J = 3.0 Hz, 1H), 7.95-8.01 (m, 3H), 8.12 (s, 1H) and 8.70 (s, 1H);
13C NMR (acetone-d6)
δ 139.5, 139.3, 137.0, 130.5, 129.3, 125.8, 122.5, 122.0, 121.7, 119.7, 119.5,
119.4, 119.3, 111.6 and 107.5; IR (neat) 3302 cm-1; HRMS (ES) m/z calcd for C17H13ClN3 294.0793,
found 294.0796.
4.1.7 3-[1-(4-Fluorophenyl)-1H-pyrazol-4-yl]-1H-indole (12f): This material was prepared in a
manner similar to 12a with the exception that 4-fluorophenylhydrazine hydrochloride was used in the
reaction in place of 4-methylphenylhydrazine hydrochloride in which case a brown solid was
obtained in 87% yield after flash chromatographic purification. This solid exhibited the following
properties: mp 148-150°C; 1H NMR (acetone-d6)
δ
7.12-7.21 (m, 2H), 7.29 (t, J= 9.0 Hz, 2H), 7.49
(d, J = 9 .0 Hz, 1H), 7.67 (d, J = 3 .0 Hz, 1H), 7.96-8.011 (m, 3H), 8.11 (s, 1H) and 8.65 (s, 1H); 13C
NMR (acetone-d6) 162.2 (d, J = 242.6 Hz), 139.1, 137.1, 125.8, 122.7, 121.8 (d, J = 19.5 Hz),
δ
120.2 (d, J = 8.6 Hz), 119.5 (d, J =4.6 Hz),119.1, 116.1, 115.8, 111.6, 111.5 and 107.6; IR (neat)
3384 cm-1; HRMS (ES) m/z calcd for C17H13FN3 278.1088, found 278.1093.
4.1.8 3-(1-Methyl-1H-pyrazol-4-yl)-1H-indole (12g). This material was prepared in a manner
similar to 12a with the exception that methylhydrazine was used in the reaction in place of 4-methyl-
phenylhydrazine hydrochloride in which case a solid was obtained in 65% yield after
chromatographic purification. This solid exhibited the following properties: mp 121-122°C (dec.); 1H
NMR (acetone-d6)
1H), 7.51 (d, J = 2.4 Hz, 1H), 7.76 (s, 1H), 7.81 (d, J = 8.0 Hz, 1H) and 7.93 (s, 1H); 13C NMR
(acetone-d6) 137.2, 135.6, 126.7, 126.2, 121.7, 121.4, 121.3, 119.5, 116.8, 111.8, 108.7 and 38.3;
δ 3.93 (s, 1H), 7.10 (t, J=7.5 Hz, 1H), 7.14 (t, J=7.5 Hz, 1H), 7.44 (d, J = 7.6 Hz,
δ
HRMS (ES) m/z calcd for C12H12N3 198.1026, found 198.1067.
4.1.9 3-(1H-Pyrazol-4-yl)-1H-indole (12h): This material was prepared in a manner similar to 12a
with the exception that hydrazine dihydrochloride was used in the reaction in place of 4-methyl-
phenylhydrazine hydrochloride in which case a solid was obtained in 44% yield after
chromatographic purification. This solid exhibited the following properties: mp 175-180°C (dec.); 1H
NMR (acetone-d6)
δ
7.10 (t, J= 7.4 Hz, 1H), 7.16 (t, J=7.4 Hz, 1H), 7.45 (d, J = 7.6 Hz, 1H), 7.54 (s,
1H), 7.84 (d, J = 7.6 Hz, 1H) and 8.00 (s, 2H); 13C NMR (acetone-d6)
δ
137.2, 126.3, 121.7, 121.6,
121.4, 119.6, 119.5, 115.9, 111.8, 111.7 and 108.8; HRMS (ES) m/z calcd for C11H10N3 184.0869,
found 184.0621.
4.1.10 3-(1-Ethyl-1H-pyrazol-4-yl)-1H-indole (12i): This material was prepared in a manner
similar to 12a with the exception that ethylhydrazine oxalate was used in the reaction in place of 4-
methylphenylhydrazine hydrochloride in which case a solid was obtained in 56% yield after
chromatographic purification. This solid exhibited the following properties: mp 87-88°C; 1H NMR
(acetone-d6)
Hz, 1H), 7.47 (d, J = 7.8 Hz, 1H), 7.53 (d, J = 2.4 Hz, 1H), 7.83 (m, 2H) and 7.98 (s, 1H); 13C NMR
(acetone-d6) 137.2, 136.5, 126.2, 125.2, 121.8, 121.4, 119.5, 119.2, 116.5, 111.8, 108.8, 46.7 and
δ 1.48 (t, J= 7.2 Hz, 3H), 4.22 (q, J= 7.1 Hz, 2H), 7.11 (t, J= 7.4 Hz, 1H), 7.18 (t, J= 7.6
δ
15.5; HRMS (ES) m/z calcd for C13H14N3 212.1182, found 212.1198.
4.1.11 3-(1-tert-Butyl-1H-pyrazol-4-yl)-1H-indole (12j): This material was prepared in a manner
similar to 12a with the exception that t-butylhydrazine oxalate was used in the reaction in place of 4-
11

ACCEPTED MANUSCRIPT
methylphenylhydrazine hydrochloride in which case a solid was obtained in 39% yield after
chromatographic purification. This solid exhibited the following properties: mp 45-47°C; 1H NMR
(acetone-d6)
7.51 (d, J = 2.4 Hz, 1H), 7.81 (s, 1H), 7.84 (d, J = 7.6 Hz, 1H) and 8.06 (s, 1H); 13C NMR
(acetone-d6) 137.2, 136.1, 126.2, 122.4, 121.7, 121.4, 119.6, 119.4, 111.7, 109.0, 58.2 and 29.0;
δ 1.64 (s, 9H), 7.08 (t, J= 7.4 Hz, 1H), 7.14 (t, J= 7.6 Hz, 1H), 7.44 (d, J = 7.6 Hz, 1H),
δ
HRMS (ES) m/z calcd for C15H18N3 240.1495, found 240.1508.
4.1.12 1-Benzyl-4-(1H-indol-3-yl)-1H-pyrrole-2-carboxylic acid ethyl ester (15a): To a 100 mL
round bottom flask equipped with a magnetic stirring bar, thermometer and reflux condenser was
added sodium hydride (0.125g, 5.16 mmol), 20 mL of dry DMF and t-butanol (0.74 mL,7.7 mmol).
Once the reaction between the sodium hydride and the t-butanol was completed, N-benzylglycine
ethyl ester (0.70 mL, 3.9 mmol) was added and the resultant mixture was stirred for several minutes.
The indoletrimethinium salt (1) (0.500 g, 1.29 mmol) was then added to the reaction mixture in one
portion and the resulting solution was heated at reflux overnight. After cooling the reaction mixture
to room temperature, it was diluted with water (100 mL) and extracted with ethyl acetate (2 x 50
mL). The combined organic phases were washed with water (2 x 50 mL), brine (2 x 50 mL) and
dried over anhydrous sodium sulfate. Removal of the drying agent by filtration and concentration of
the filtrate in vacuo, resulted in a dark solid. This solid was subjected to flash chromatography on a
Biotage SP-1 instrument with a silica column and a hexane/ethyl acetate gradient in which case a
light yellow solid (0.302 g, 68% yield) was obtained. This solid exhibited the following properties:
mp 105-107°C; 1H NMR (acetone-d6)
(m, 2H), 7.25-7.33 (m, 6H), 7.46 (d, J = 7.2 Hz, 1H), 7.55 (m, 1H), 7.57 (d, J= 2.1 Hz, 1H) and 7.88
(d, J = 7.2 Hz, 1H); 13C NMR (acetone-d6)
160.8, 139.3, 137.1, 128.4, 127.2, 126.9, 125.9, 125.8,
δ 1.31 (t, J= 7.2 Hz, 3H), 4,25 (q, 2H), 5.71 (s, 2H), 7.11-7.19
δ
122.1, 121.5, 121.4, 119.4, 119.3, 118.9, 115.7, 111.6, 110.5, 59.4, 51.5 and 13.9; IR (neat) 3382 and
1699 cm-1; HRMS (ES) m/z calcd for C22H21N2O2 345.1598, found 345.1521.
4.1.13 4-(1H-Indol-3-yl)-1-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (15b). This material
was prepared in a manner similar to compound 15a with the exception that N-methylglycine ethyl
ester hydrochloride was used in place of N-benzylglycine ethyl ester in which case a tan solid (41%
yield) was obtained after flash chromatographic purification. This material exhibited the following
properties: mp 105-107°C; 1H NMR (acetone-d6)
δ
1.36 (t, J= 7.2 Hz, 3H), 4.00 (s, 3H), 4.30 (q, J=
7.2 Hz, 2H), 7.08-7.18 (m, 2H), 7.21 (d, J = 2.1 Hz, 1H), 7.37 (d, J = 1.8 Hz, 1H),7.44 (d, J = 9.0
Hz, 1H), 7.50 (d, J = 1.8 Hz, 1H) and 7.85 (d, J = 9.0 Hz, 1H); 13C NMR (acetone-d6)
160.9,
δ
137.1, 126.3, 125.9, 122.5, 121.4, 121.2, 119.4, 119.2, 118.2, 115.0, 111.5, 110.7, 59.3, 36.0 and
13.9; IR (neat) 3391 and 1674 cm-1; HRMS (ES) m/z calcd for C16H17N2O2 269.1285, found
269.1184.
4.1.14 4-(1H-Indol-3-yl)-1H-pyrrole-2-carboxylic acid ethyl ester (15c): This material was
prepared in a manner similar to compound 15a with the exception that glycine ethyl ester
hydrochloride was used in place of N-benzylglycine ethyl ester in which case a tan solid (33% yield)
was obtained after flash chromatographic purification. This material exhibited the following
properties: mp 135-136°C; 1H NMR (acetone-d6)
δ 1.36 (t, J= 7.0 Hz, 3H), 4.32 (q, J= 7.0 Hz, 2H),
7.12 (t, J= 8.0 Hz, 1H), 7.17 (t, J= 8.0 Hz, 1H), 7.21 (m, 1H), 7.44 (m, 1H), 7.46 (d, J = 8.0 Hz, 1H),
7.55 (d, J = 2.5 Hz, 1H) and 7.86 (d, J = 8.0 Hz, 1H); 13C NMR 160.6, 137.1, 126.0, 123.0, 121.4,
121.3, 120.5, 119.7, 119.4, 119.3, 112.8, 111.5, 110.9, 59.5 and 13.9; IR (neat) 3386, 3310 and 1682
cm-1; HRMS (ES) m/z calcd for C15H15N2O2 255.1128, found 255.1127.
4.1.15 3-Dimethylamino-1-(1-methyl-1H-indol-3-yl)-propenone (9). The preparation of this
substance has been previously reported by Anizon6 and coworkers.
12

ACCEPTED MANUSCRIPT
4.1.16 3-Chloro-3-(1-methyl-1H-indol-3-yl)-propenal (10). To a 100 mL round bottom flask
equipped with a magnetic stir bar and reflux condensor was added the indole vinylogous amide (9)
(0.700 g, 3.06 mmol) followed by POCl3 (0.575 mL, 6.29 mmol) in dichloromethane (20 mL). The
mixture was refluxed for 2 hours and the dichloromethane was removed in vacuo. The residue was
dissolved in 50 mL of a 50:50 mixture of water:THF and stirred at room temperature for 24 hours.
The reaction mixture was diluted with 50 mL of water, extracted with ethyl acetate (3 x 30 mL),
washed with brine (30 mL), dried over anhydrous magnesium sulfate and concentrated in vacuo to
yield 0.500 g (74.6% yield) of a solid. This solid was suitable for use without further purification but
an analytical sample was prepared by flash chromatography on a Biotage Isolera instrument with a
hexane:ethyl acetate gradient, which produced a dark solid and this material exhibited the following
properties: mp: 103-106°C; 1H NMR (acetone-d6)
J=6.5 Hz, 1H), 7.38 (t, J= 6.5 Hz, 1H), 7.69 (d, J= 6.5 Hz, 1H), 7.97 (d, J= 6.5 Hz, 1H), 8.15 (s, 1H),
δ 3.99 (s, 3H), 6.71 (d, J=7.0 Hz, 1H), 7.34 (t,
10.20 (d, J=7.0 Hz, 1H); 13C NMR (acetone-d6)
δ 189.8, 145.9, 138.7, 135.3, 124.5, 123.3, 122.2,
120.2, 119.4, 112.2, 111.1 and 32.8; IR (neat) 1656 cm-1; HRMS (ES) m/z calculated for
C12H10NOCl 220.0524, found 220.0553. It should be noted that Buchwald15 and Pellegatti have
recently reported the N-unsubstituted analog of this material using continuous flow methodology.
4.1.17 1-Methyl-3-(2-p-tolyl-2H-pyrazol-3-yl)-1H-indole (17a) Method A. To a 100 mL round
bottom flask equipped with a magnetic stir bar and reflux condensor was added ethanol (40 mL),
sodium carbonate (0.434 g, 4.10 mmol), 4-methylphenylhydrazine hydrochloride (0.260 g, 1.64
mmol) and the indole chloroenal (10) (0.300 g, 1.37 mmol). The resulting mixture was stirred for one
hour at room temperature, heated at reflux overnight, cooled to room temperature and the solvent was
removed in vacuo. The residue was partitioned between 30 mL of a 50:50 mixture of
chloroform:water and the aqueous phase was extracted with additional chloroform (2 x 30 mL). The
combined organic phases were dried over anhydrous magnesium sulfate and concentrated in vacuo to
yield a solid, which was subjected to flash chromatographic purification on a Biotage SP-1
instrument with a silica column and hexane/ethyl acetate gradient. Elution with 5-6 column volumes
of eluant produced a dark solid (0.210 g, 53 % yield), which exhibited the following properties: mp:
122-125°C; 1H NMR (acetone-d6)
δ
2.32 (s, 3H), 3.81 (s, 3H), 6.56 (d, J= 1.8 Hz, 1H), 7.03 (t, J= 7.2
Hz, 1H), 7.05 (s, 1H), 7.16 (d, J= 6.3 Hz, 2H), 7.21 (t, J= 7.2 Hz, 1H), 7.29 (d, J= 6.3 Hz, 2H), 7.39
(d, J= 7.2 Hz, 1H), 7.41 (d, J= 7.2 Hz, 1H) and 7.69 (d, J= 1.8 Hz, 1H); 13C NMR (acetone-d6)
δ
139.7, 138.8, 137.0, 136.9, 136.8, 129.2, 128.6, 126.6, 124.7, 121.9, 119.8, 119.5, 109.7, 107.1,
104.9 , 32.1 and 20.1; HRMS (ES) m/z calcd for C19H18N3 288.1495, found 288.1689. NOESY NMR
analysis of this compound indicated a NOESY interaction between the proton at the C-2 position of
the indole ring with the proton at C-2 position of the phenyl ring, thereby establishing the
regiochemistry of the pyrazole being 2,3-disubstituted.
4.1.18 1-Methyl-3-(1-p-tolyl-1H-pyrazol-3-yl)-1H-indole (20a) Method B: The above reaction
conditions were repeated with the exception that no base was used in this trial. When the standard
workup was applied to the reaction mixture, a dark solid was obtained in 97% yield. 1H NMR
analysis of the crude product indicated a mixture of 1,2- and 1,3-isomers with regard to the location
of the phenyl and indolyl groups around the pyrazole ring system. Our research group16 as well as
others17 have reported that the chemical shift differential between ortho pyrazole hydrogens is
increased in polar NMR solvents for the 1,3-isomer versus the 2,3-isomer and applying this
reasoning to our crude reaction 1H NMR suggested an isomer ratio of 2:1 for the 1,3-isomer:2,3-
isomer, respectively. The crude reaction mixture was then subjected to flash chromatographic
purification on a Biotage SP-1 instrument with a silica column and hexane/ethyl acetate gradient.
Elution with 4-5 column volumes of eluant produced a dark solid which exhibited the following
properties: mp: 136-140°C; 1H NMR (acetone-d6)
1H), 7.21 (t, J= 7.8 Hz, 1H), 7.23 (t, J= 7.8 Hz, 1H), 7.34 (d, J= 6.6 Hz, 2H), 7.43 (d, J= 7.8 Hz, 1H),
δ 2.39 (s, 3H), 3.91 (s, 3H), 6.82 (d, J= 2.6 Hz,
13

ACCEPTED MANUSCRIPT
7.73 (s, 1H), 7.84 (d, J= 6.6 Hz, 2H), 8.27 (d, J= 2.6 Hz, 1H) and 8.42 (d, J= 7.8 Hz, 1H); 13C NMR
(acetone-d6)
δ 149.1, 138.4, 137.6, 135.0, 129.8, 127.6, 127.1, 126.0, 121.8, 121.7, 119.7, 117.9,
109.4, 109.1, 104.5, 32.1 and 19.9; HRMS (ES) m/z calcd for C19H18N3 288.1495, found 288.1504.
NOESY NMR analysis of this compound indicated a NOESY interaction between the proton at the
C-5 position of the pyrazole ring with the proton at C-2 position of the phenyl ring, thereby
establishing the regiochemistry of the pyrazole being 1,3-disubstituted.
4.1.19 3-[2-(4-Chlorophenyl)-2H-pyrazol-3-yl]-1-methyl-1H-indole (17b) Method A:This
compound was prepared in an identical fashion to compound 17a (reaction with base) with the
exception that 4-chlorophenylhydrazine hydrochloride was used in place of 4-methylphenylhydrazine
hydrochloride in which case a 54% yield of a dark solid was obtained and this material exhibited the
following properties: mp: 147-152°C; 1H NMR (acetone-d6)
δ
3.86 (s, 3H), 6.58 (d, J= 1.5 Hz, 1H),
7.04 (t, J= 7.0 Hz, 1H), 7.19 (s, 1H), 7.23 (t, J= 7.0 Hz, 1H), 7.29 (d, J= 7.0 Hz, 1H), 7.37 (d, J= 6.5
Hz, 2H), 7.43-7.47 (m, 3H) and 7.74 (d, J= 1.5 Hz, 1H); 13C NMR (acetone-d6)
140.4, 139.8,
δ
137.2, 137.1, 132.0, 128.9, 128.7, 126.4, 126.0, 122.1, 120.1, 119.4, 109.9, 107.9, 104.5 and 32.2;
HRMS (ES) m/z calcd for C18H15ClN3 308.0949, found 308.1018.
4.1.20 3-[2-(4-Bromophenyl)-2H-pyrazol-3-yl]-1-methyl-1H-indole (17c) Method A: This
compound was prepared in an identical fashion to compound 17a (reaction with base) with the
exception that 4-bromophenylhydrazine hydrochloride was used in place of 4-methylphenyl-
hydrazine hydrochloride in which case a 31% yield of a dark solid was obtained and this material
exhibited the following properties: mp: 135-138°C; 1H NMR (acetone-d6)
δ 3.86 (s, 3H), 6.58 (d, J=
1.5 Hz, 1H), 7.04 (t, J= 8.0 Hz, 1H), 7.20 (s, 1H), 7.23 (t, J= 8.0 Hz, 1H), 7.34 (d, J= 8.0 Hz, 1H),
7.38 (d, J= 6.5 Hz, 2H), 7.46 (d, J= 8.0 Hz, 1H), 7.51 (d, J= 6.5 Hz, 2H) and 7.74 (d, J= 1.5 Hz, 1H);
13C NMR (acetone-d6)
δ 140.5, 140.3, 137.1, 137.0, 131.7, 128.9, 126.4, 126.3, 122.1, 120.0, 119.9,
119.4, 109.9, 107.9, 104.5 and 32.2; HRMS (ES) m/z calcd for C18H15BrN3 352.0444, found
352.0456.
4.1.21 1-Methyl-3-(2-phenyl-2H-pyrazol-3-yl)-1H-indole (17d) Method A: This compound was
prepared in an identical fashion to compound 17a (reaction with base) with the exception that
phenylhydrazine was used in place of 4-methylphenylhydrazine in which case a 52% yield of a dark
solid was obtained and this material exhibited the following properties: mp: 135-139°C; 1H NMR
(acetone-d6)
7.5 Hz, 1H), 7.30-7.37 (m, 4H), 7.42-7.44 (m, 3H) and 7.72 (d, J= 1.5 Hz, 1H); 13C NMR (acetone-
d6) 141.2, 140.1, 137.1, 137.0, 128.7, 127.1, 126.5, 124.8, 122.0, 120.0, 119.5, 109.8, 107.4, 104.9
δ 3.81 (s, 3H), 6.59 (d, J= 1.5 Hz, 1H), 7.02 (t, J= 7.5 Hz, 1H), 7.07 (s, 1H), 7.22 (t, J=
δ
and 32.2; HRMS (ES) m/z calcd for C18H16N3 274.1339, found 274.1489.
4.1.22 3-[2-(4-Methoxyphenyl)-2H-pyrazol-3-yl]-1-methyl-1H-indole (17e) Method A: This
compound was prepared in an identical fashion to compound 17a (reaction with base) with the
exception that 4-methoxyphenylhydrazine hydrochloride was used in place of 4-methylphenyl-
hydrazine hydrochloride in which case a 57% yield of a dark solid was obtained and this material
exhibited the following properties: mp: 128-131°C; 1H NMR (acetone-d6)
δ 3.81 (s, 3H), 3.80 (s,
3H), 6.57 (d, J= 2.0 Hz, 1H), 6.91 (d, J= 7.0 Hz, 2H), 7.02 (s, 1H), 7.05 (t, J= 8.0 Hz, 1H), 7.21 (t, J=
8.0 Hz, 1H), 7.31 (d, J= 7.0 Hz, 2H), 7.42 (d, J= 8.0 Hz, 1H) and 7.67 (d, J= 2.0 Hz, 1H); 13C NMR
(acetone-d6)
δ 158.9, 139.6, 137.1, 136.9, 134.2, 128.6, 126.6, 126.4, 122.0, 119.9, 119.5, 113.9,
109.8, 106.7, 104.9, 59.7 and 32.3; HRMS (ES) m/z calcd for C19H18N3O 304.1444, found 304.1525.
4.1.23 3-Ethynyl-1-methyl-1H-indole (21): To a 100 mL round bottom flask equipped with a
magnetic stir bar and reflux condensor was added sodium hydroxide (0.920g, 22.9 mmol), THF (40
mL) and the indole chloroenal (10) (1.26g, 5.74 mmol). The resulting mixture was refluxed
14

ACCEPTED MANUSCRIPT
overnight, cooled to room temperature and diluted with water (50 mL). The reaction mixture was
extracted with ethyl acetate (3 x 20 mL) and the combined organic phases were washed with brine (2
x 25 mL), dried with anhydrous sodium sulfate, filtered and concentrated in vacuo to yield a viscous
oil (0.790g, 89% yield), which exhibited the following properties: bp: 104-105°C @ 0.67 torr; 1H
NMR (CDCl3)
δ 3.23 (s, 1H), 3.81 (s, 3H), 7.23 (t, J= 7.0 Hz, 1H), 7.32 (t, J= 7.0 Hz, 1H), 7.33 (s,
1H), 7.35 (d, J= 7.0 Hz, 1H) and 7.76 (d, J= 7.0 Hz, 1H); 13C NMR (acetone-d6)
δ 136.3, 133.5,
129.3, 122.4, 120.1, 119.3, 110.0, 79.1, 77.4 and 32.2; IR (neat) 2918 and 2362 cm-1; HRMS (ES)
m/z calcd for C11H10N 156.0808, found 156.0792.
4.1.24 3-[2-(4-Bromophenyl)-2H-pyrazol-3-yl]-1-methyl-1H-indole (17c) Method C: Into a 20
mL microwave reactor tube equipped with a magnetic stir bar was placed acetonitrile (8 mL), 4-
bromophenylhydrazine hydrochloride (0.590g, 2.63 mmol) and the indole vinylogous amide (9)
(0.400g, 1.75 mmol). The reaction tube was sealed with a crimping cap and heated in a Biotage
Initiator microwave reactor system at 85°C for two hours. After the microwave heating was
completed, the crimping cap was removed and the reaction mixture was concentrated in vacuo. The
residue was taken up in a water (40 mL) and ethyl acetate (30 mL) mixture and, after separation of
the phases, the aqueous phase was extracted with additional ethyl acetate (2 x 30 mL). The combined
organic phases were washed with brine and dried over anhydrous magnesium sulfate followed by
filtration and concentration in vacuo. The resultant solid was subjected to flash chromatographic
purification on a Biotage SP-1 instrument with a silica column and a hexane/ethyl acetate gradient.
Elution with 5-6 column volumes of eluant produced a dark solid (0.600g, 97% yield), which was
identical to compound 17c by proton NMR and tlc comparison.
4.1.25 1-Methyl-3-(1-p-tolyl-1H-pyrazol-3-yl)-1H-indole (17a) Method C: This compound was
prepared in an identical fashion to the previous example with the exception that 4-methyl-
phenylhydrazine hydrochloride was used in place of 4-bromophenylhydrazine hydrochloride in
which case an 82% yield of a dark solid was obtained and this material was identical to compound
17a by proton NMR and tlc comparison.
4.1.26 3-[2-(4-Chlorophenyl)-2H-pyrazol-3-yl]-1-methyl-1H-indole (17b) Method C: This
compound was prepared in an identical fashion to the previous example with the exception that 4-
chlorophenylhydrazine hydrochloride was used in place of 4-methylphenylhydrazine hydrochloride
in which case an 93% yield of a dark solid was obtained and this material was identical to compound
17b by proton NMR and tlc comparison.
4.1.27 1-Methyl-3-(2-phenyl-2H-pyrazol-3-yl)-1H-indole (17d) Method C: This compound was
prepared in an identical fashion to the previous example with the exception that phenylhydrazine
hydrochloride was used in place of 4-chlorophenylhydrazine hydrochloride in which case a 52%
yield of a dark solid was obtained and this material was identical to compound 17d by proton NMR
and tlc comparison.
4.1.28 3-[2-(4-Methoxyphenyl)-2H-pyrazol-3-yl]-1-methyl-1H-indole (17e) Method C: This
compound was prepared in an identical fashion to the previous example with the exception that 4-
methoxyphenylhydrazine hydrochloride was used in place of phenylhydrazine hydrochloride in
which case an 84% yield of a dark solid was obtained and this material was identical to compound
17e by proton NMR and tlc comparison.
4.1.29 3-[2-(4-Bromophenyl)-2H-pyrazol-3-yl]-1-methyl-1H-indole (17c) Method C: This
compound was prepared in an identical fashion to the previous example with the exception that
15

ACCEPTED MANUSCRIPT
glacial acetic acid was used as the solvent and 4-bromophenylhydrazine hydrochloride was used in
place of the 4-methoxyphenylhydrazine hydrochloride in which case an 82% yield of a dark solid
was obtained and this material was identical to compound 17c by proton NMR and tlc comparison.
4.1.30 3-[2-(4-Bromophenyl)-2H-pyrazol-3-yl]-1-methyl-1H-indole (17c) Method C: This
compound was prepared in an identical fashion to the previous example with the exception that
anhydrous ethanol was used as the solvent in which case a 100% crude yield of a dark solid was
obtained and this material was identical to compound 17c by proton NMR and tlc comparison.
4.1.31 3-[2-(4-Bromophenyl)-2H-pyrazol-3-yl]-1-methyl-1H-indole (17c): Method D: To a 100
mL round bottom flask equipped with a magnetic stir bar and reflux condensor was added
acetonitrile (30 mL), 4-bromophenylhydrazine hydrochloride (0.590g, 2.63 mmol) and the indole
vinylogous amide (9) (0.400g, 1.75 mmol). The mixture was stirred and heated at reflux for 4 hours
and the reaction mixture was concentrated in vacuo after cooling to room temperature. The reaction
mixture was diluted with ethyl acetate (30 mL) and water (30 mL), the phases were separated and the
aqueous phase was extracted with additional ethyl acetate (2 x 30 mL).The combined organic phases
were washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo
to yield a solid. This material was subjected to flash chromatographic purification on a Biotage SP-1
instrument with a silica column and a hexane/ethyl acetate gradient. Elution with 5-6 column
volumes of eluant produced a dark solid (0.424g, 69% yield), which was identical to compound 17c
by proton NMR and tlc comparison.
4.1.32 3-[2-(4-Bromophenyl)-2H-pyrazol-3-yl]-1-methyl-1H-indole (17c) Method D: To a 100
mL round bottom flask equipped with a magnetic stir bar and reflux condensor was added glacial
acetic acid (30 mL), 4-bromophenylhydrazine hydrochloride (0.590g, 2.63 mmol) and the indole
vinylogous amide (3) (0.400g, 1.75 mmol). The mixture was stirred and heated at reflux for 4 hours,
cooled to room temperature and diluted with 50 mL of water. The reaction mixture was carefully
neutralized with aqueous sodium bicarbonate solution and extracted with ethyl acetate (3 x 30
mL).The combined organic phases were washed with brine, dried over anhydrous magnesium sulfate,
filtered and concentrated in vacuo to yield a solid. This material was subjected to flash
chromatographic purification on a Biotage SP-1 instrument with a silica column and a hexane/ethyl
acetate gradient. Elution with 5-6 column volumes of eluant produced a dark solid (0.506g, 82%
yield), which was identical to compound17c by proton NMR and tlc comparison.
4.1.33 1-Methyl-3-(1-p-tolyl-1H-pyrazol-3-yl)-1H-indole (17a) Method D: This compound was
prepared in an identical fashion to the previous example with the exception that 4-methyl-
phenylhydrazine hydrochloride was used in place of 4-bromophenylhydrazine hydrochloride in
which case a 60% yield of a dark solid was obtained and this material was identical to compound 17a
by proton NMR and tlc comparison.
4.1.34 3-[2-(4-Chlorophenyl)-2H-pyrazol-3-yl]-1-methyl-1H-indole (17b) Method D: This
compound was prepared in an identical fashion to the previous example with the exception that 4-
chlorophenylhydrazine hydrochloride was used in place of 4-methylphenylhydrazine hydrochloride
in which case a 56% yield of a dark solid was obtained and this material was identical to compound
17b by proton NMR and tlc comparison.
4.1.35 1-Methyl-3-(2-phenyl-2H-pyrazol-3-yl)-1H-indole (17d) Method D: This compound was
prepared in an identical fashion to the previous example with the exception that phenylhydrazine
hydrochloride was used in place of 4-chlorophenylhydrazine hydrochloride in which case a 51%
16

ACCEPTED MANUSCRIPT
yield of a dark solid was obtained and this material was identical to compound 17d by proton NMR
and tlc comparison.
4.1.36 3-[2-(4-Methoxyphenyl)-2H-pyrazol-3-yl]-1-methyl-1H-indole (17e) Method D: This
compound was prepared in an identical fashion to the previous example with the exception that 4-
methoxyphenylhydrazine hydrochloride was used in place of phenylhydrazine hydrochloride in
which case a 51% yield of a dark solid was obtained and this material was identical to compound 17e
by proton NMR and tlc comparison.
4.1.37 1-Methyl-3-(2H-pyrazol-3-yl)-1H-indole (17f) Method D: This compound was prepared in
an identical fashion to the previous example with the exception that hydrazine dihydrochloride was
used in place of 4-methoxyphenylhydrazine hydrochloride in which case a 75% yield of a dark solid
was obtained and this material exhibited the following properties: mp: 119-120°C; 1H NMR
(acetone-d6)
7.41 (d, J= 8.0 Hz, 1H), 7.61 (s, 1H), 7.68 (d, J= 2.0 Hz, 1H) and 8.17 (d, J= 8.0 Hz, 1H); 13C NMR
(acetone-d6) 142.8, 137.3, 134.9, 127.4, 126.1, 122.4, 120.4, 120.3, 110.0, 107.0, 102.7 and 32.9;
δ 3.83 (s, 3H), 6.61 (d, J= 2.0 Hz, 1H), 7.15 (t, J= 7.4 Hz, 1H), 7.30 (t, J= 7.4 Hz, 1H),
δ
HRMS (ES) m/z calcd for C12H12N3 198.1026, found 198.1024.
4.1.38 1-Methyl-3-(2-methyl-2H-pyrazol-3-yl)-1H-indole (17g) Method D: This compound was
prepared in an identical fashion to the previous example with the exception that methylhydrazine was
used in place of hydrazine dihydrochloride in which case a 59% yield of a dark oil was obtained and
this material exhibited the following properties: bp: 205-215°C @ 0.75 torr; 1H NMR (acetone-d6)
δ
3.86 (s, 3H), 3,93 (s, 3H), 6.40 (d, J= 1.6 Hz, 1H), 7.16 (t, J= 7.4 Hz, 1H), 7.27 (t, J= 7.6 Hz, 1H),
7.45 (d, J= 1.6 Hz, 1H), 7.50 (d, J= 8.0 Hz, 1H), 7.54 (s, 1H) and 7.62 (d, J= 7.6 Hz, 1H); 13C NMR
(acetone-d6)
δ 138.1, 137.2, 136.9, 128.7, 127.1, 122.3, 120.2, 119.6, 110.1, 105.3, 104.9, 37.1 and
32.5; HRMS (ES) m/z calcd for C13H13N3 212.1182, found 212.1179.
4.1.39 3-(2-Ethyl-2H-pyrazol-3-yl)-1-methyl-1H-indole (17h) Method D: This compound was
prepared in an identical fashion to the previous example with the exception that ethylhydrazine
oxalate was used in place of methylhydrazine in which case a 69% yield of a dark oil was obtained
and this material exhibited the following properties: bp: 181-190°C @ 0.50 torr; 1H NMR (acetone-
d6)
J= 7.4 Hz, 1H), 7.27 (d, J= 7.6 Hz, 1H), 7.47 (s, 1H), 7.52-7.49 (m, 2H) and 7.57 (d, J= 7.6 Hz, 1H);
13C NMR (acetone-d6)
138.4, 137.3, 136.1, 128.5, 127.4, 122.3, 120.2, 119.5, 110.1, 105.7, 104.8,
δ 1.35 (t, J= 7.2 Hz, 3H), 3.91 (s, 3H), 4,22 (q, J= 7.2 Hz, 2H), 6.36 (d, J= 2.0 Hz, 1H), 7.15 (t,
δ
44.2, 32.4 and 15.4; HRMS (ES) m/z calcd for C14H16N3 226.1339, found 226.1336.
4.1.40 3-(2-Ethyl-2H-pyrazol-3-yl)-1-methyl-1H-indole (17h) Method D: This compound was
prepared in an identical fashion to the previous example with the exception that acetonitrile was used
as the solvent in which case a 96% yield of a dark oil was obtained and this material was identical to
compound 17h by proton NMR and GC-MS comparison.
4.1.41 3-(2-tert-Butyl-2H-pyrazol-3-yl)-1-methyl-1H-indole (17i) Method D: This compound was
prepared in an identical fashion to the previous example with the exception that t-butylhydrazine
hydrochloride was used in place of ethylhydrazine oxalate and ethanol was used as the solvent in
which case an 80% yield of a dark solid was obtained and this material exhibited the following
properties: mp: 118-121°C; 1H NMR (acetone-d6)
δ
1.46 (s, 9H), 3.91 (s, 3H), 6.15 (d, J= 1.6 Hz,
1H), 7.09 (t, J= 7.4 Hz, 1H), 7.20-7.27 (m, 3H), 7.34 (s, 1H) and 7.46 (d, J= 8.0 Hz, 1H); 13C NMR
(acetone-d6) 139.4, 136.2, 130.0, 129.5, 123.2, 122.5, 122.0, 120.0, 117.7, 110.8, 110.0, 60.5, 32.4
and 30.4; HRMS (ES) m/z calcd for C16H20N3 254.1652, found 254.1652.
δ
17

ACCEPTED MANUSCRIPT
4.1.41 3-(2-tert-Butyl-2H-pyrazol-3-yl)-1-methyl-1H-indole (17i) Method D: This compound was
prepared in an identical fashion to the previous example with the exception that acetonitrile was used
as the solvent in which case an 85% yield of a dark solid was obtained and this material was identical
to compound 17i by proton NMR and GC-MS comparison.
4.1.42 1-Benzyl-5-(1-methyl-1H-indol-3-yl)-1H-pyrrole-2-carboxylic acid ethyl ester (23a): Into
a 100 mL round bottom flask equipped with a magnetic stir bar and reflux condensor was placed
indole chloroenal (10) (0.250g, 1.14 mmol), 30 mL of dry DMF and benzyl glycine ethyl ester (0.53
mL, 2.9 mmol). The reaction mixture was stirred at room temperature for one hour after which it was
heated to reflux overnight. The reaction mixture was allowed to cool to room temperature, diluted
with 100 mL of water and extracted with ethyl acetate (3 x 25 mL). The combined organic layers
were washed with water (2 x 25 mL) and brine (1 x 15 mL) and dried over anhydrous sodium sulfate.
The drying agent was removed by filtration and the filtrate was concentrated in vacuo to give an
orange liquid (0.410 g). This material was subjected to flash chromatographic purification on a
Biotage SP-1 instrument with a silica column and a hexane/ethyl acetate gradient. Elution with 5-6
column volumes of eluant produced an orange liquid (0.192g, 47% yield), which exhibited the
following properties: bp: 58-59°C @ 0.13 torr; 1H NMR (acetone-d6)
δ 1.26 (t, J= 7.0 Hz, 3H), 3.83
(s, 3H), 4.18 (q, J= 7.0 Hz, 2H), 5.75 (s, 2H), 6.39 (d, J= 4.0 Hz, 1H), 6.88 (d, J= 8.5 Hz, 2H), 7.13-
7.22 (m, 6H), 7.24 (t, J= 7.0 Hz, 1H), 7.45 (d, J= 7.0 Hz, 1H) and 7.61 (d, J= 7.0 Hz, 1H); 13C NMR
(acetone-d6) δ 160.6, 140.0, 137.0, 135.6, 128.6, 128.2, 127.6, 126.6, 125.1, 122.6, 122.1, 120.0,
119.3, 118.5, 109.8, 109.7, 105.9, 59.1, 48.7, 32.1 and 13.8; IR (neat) 1690 cm-1; HRMS (ES) m/z
calcd for C23H23N2O2 359.1754, found 359.1773.
4.1.43 1-Methyl-5-(1-methyl-1H-indol-3-yl)-1H-pyrrole-2-carboxylic acid ethyl ester (23b): Into
a 100 mL round bottom flask equipped with a magnetic stir bar and reflux condensor was placed
indole chloroenal (10) (0.500g, 2.28 mmol), 30 mL of dry DMF and sarcosine ethyl ester
hydrochloride (0.700g, 4.55 mmol). The reaction mixture was stirred at room temperature for one
hour after which it was heated to reflux overnight. The reaction mixture was allowed to cool to room
temperature, diluted with 100 mL of water and extracted with ethyl acetate (3 x 25 mL). The
combined organic layers were washed with water (2 x 25 mL) and brine (1 x 15 mL) and dried over
anhydrous sodium sulfate. The drying agent was removed by filtration and the filtrate was
concentrated in vacuo to give a crude residue (0.600g). The crude residue (diluted with ethyl acetate)
was placed on the surface of a silica plug and eluted with 50 mL of hexane followed by 50 mL of
50:50 mix of hexane:ethyl acetate. The two fractiosn were combined to give 0.340g (53% yield) of a
yellow liquid, which exhibited the following properties: bp: 169-172°C @ 1.50 torr; 1H NMR
(acetone-d6)
4.0 Hz, 1H), 7.03 (d, J= 4.0 Hz, 1H), 7.16 (t, J= 7.0 Hz, 1H), 7.28 (t, J= 7.0 Hz, 1H), 7.48 (s, 1H),
7.50 (d, J= 7.0 Hz, 1H) and 7.59 (d, J= 7.0 Hz, 1H); 13C NMR (acetone-d6)
160.9, 137.0, 135.4,
δ 1.35 (t, J= 7.5 Hz, 3H), 3.92 (s, 3H), 3.95 (s, 3H), 4.28 (q, J= 7.5 Hz, 2H), 6.27 (d, J=
δ
129.0, 127.4, 122.8, 122.0, 119.9, 119.5, 117.4, 109.8, 108.7, 106.1, 59.1, 33.6, 32.2 and 13.9; IR
1702 (neat) cm-1; HRMS (ES) m/z calcd for C17H19N2O2 283.1441, found 283.1438. The
regiochemistry of the 2,5-disubstituted pyrrole was determined by a NOESY NMR analysis. An
NOE was seen for the hydrogen at the 2 position of the indole with both the indole methyl group and
also the pyrrole methyl group. An NOE was also seen for the methylene and methyl groups of the
ester with the hydrogen at carbon 3 of the pyrrole ring.
4.1.44 5-(1-Methyl-1H-indol-3-yl)-1H-pyrrole-2-carboxylic acid ethyl ester (23c): Into a 100 mL
round bottom flask equipped with a magnetic stir bar and reflux condensor was placed indole
chloroenal (10) (0.350g, 1.59 mmol), 30 mL of dry DMF and glycine ester hydrochloride (0.77 g,
5.56 mmol). The reaction mixture was stirred at room temperature for one hour after which it was
18

ACCEPTED MANUSCRIPT
heated to reflux overnight. The reaction mixture was allowed to cool, diluted with 100 mL of water
and extracted with ethyl acetate (3 x 25 mL). The combined organic layers were washed with water
(2 x 25 mL), brine (1 x 15 mL) and dried over anhydrous sodium sulfate. Removal of the drying
agent by filtration and concentration of the filtrate in vacuo gave a crude residue (0.316 g) of a dark
solid.This material was subjected to flash chromatographic purification on a Biotage SP-1 instrument
with a silica column and a hexane/ethyl acetate gradient. Elution with 5-6 column volumes of eluant
1
gave 0.137g (43% yield), which exhibited the following properties: mp: 148-150°C; H NMR
(acetone-d6)
δ 1.33 (t, J= 7.5 Hz, 3H), 3.89 (s, 3H), 4.28 (q, J= 7.5 Hz, 2H), 6.57 (d, J= 4.0 Hz, 1H),
6.95 (d, J= 4.0 Hz, 1H), 7.18 (t, J= 7.0 Hz, 1H), 7.26 (t, J= 7.0 Hz, 1H),7.46 (d, J= 7.0 Hz, 1H), 7.78
13
(s, 1H) and 7.91 (d, J= 7.0 Hz, 1H); C NMR 160.5, 137.4, 132.7, 126.9, 125.8, 121.9, 121.5,
119.9, 119.7, 116.4, 109.8, 107.5, 106.8, 59.3, 32.2 and 14.0; IR (neat) 1678 cm-1; HRMS (ES) m/z
calcd for C16H17N2O2 269.1285, found 269.1301.
Acknowledgements
We gratefully thank the National Institutes of Health (grant no. R15-CA67236) for support of this
research. Thanks also to the Floyd D. and Elisabeth S. Gottwald Endowment and to the University of
Richmond Faculty Research Grant program for support to JTG. We are exceedingly grateful to Mr.
Dave Patteson formerly of Biotage Inc. for the generous donation of an SP-1 flash chromatography
system, which was used in the majority of sample purifications. We are also very appreciative of
Advion Inc. for the generous donation of a CMS electrospray mass spectrometer. Previous grants
from the MRI program of the National Science Foundation for the purchase of a 500 MHz NMR
spectrometer (CHE-0116492) and a high resolution electrospray mass spectrometer (CHE-0320669)
are also gratefully acknowledged. We also appreciate assistance from Christopher Warme and
Wendy Zhong at the Merck Research Laboratories in obtaining HRMS data for some of our
compounds.
References and Notes
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1689.
4. Nishizawa, T.; Gruschow, S.; Jayamaha, D.; Nishizawa-Harada, C.; Sherman, D. J. Am. Chem. Soc.,
2006, 128, 724.
5. Robinson, M.; Overmeyer, J.; Young, A.; Erhardt, P.; Maltese, W. J. Med. Chem., 2012, 55, 1940.
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7. Arora, S.; Wang, X.; Keenan, S.; Andaya, C.; Zhang, Q.; Peng, Y.; Welsh, W. Cancer Res., 2009, 69,
1910.
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9. See for example; (a) Gupton, J.; Yu, R.; Krolikowski, D.; Riesinger, S.; Sikorski J. J. Org. Chem.,
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Org. Chem., 1992, 57, 5480.
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14. Prim, D.; Fuss, A.; Kirsch, G.; Silva, A. J. Chem. Soc. Perkin Trans 2, 1999, 1175.
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Hicks, F.; Wilkinson, D., Sikorski, J. Tetrahedron, 2002, 58, 5467.
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Graphical Abstract
Preparation of Indole Containing Building Blocks for the Regiospecific Construction of Indole
Appended Pyrazoles and Pyrroles. John T. Gupton*, Nakul Telang, Dominic F. Gazzo, Peter J. Barelli,
Kristin E. Lescalleet, Jonathan W. Fagan, Brandon J. Mills, Rene P.F. Kanters, Kyle R. Crocker, Sean T.
Dudek, Corinne M. Lariviere, Stanton Q. Smith, Kartik M. Keertikar.
H
O
O
Cl
NH
NMe2
H
Me
PF6
Me
Me
N
N
N
Me
N
Me
Me
Indole Chloroenal
Indole Vinamidinium Salt
Indole Vinylogous Amide
20