Indoles via Knoevenagel-Hemetsberger reaction sequence

Article abstract of DOI:10.1039/c3ra42296h

A series of substituted indoles have been synthesized by the sequential reaction of aromatic aldehydes with ethyl azidoacetate in the presence of sodium ethoxide to form the corresponding ethyl α-azido-β-arylacrylates (Knoevenagel process) followed by a solvent mediated thermolysis (Hemetsberger process). The isolated yields of the ethyl α-azido-β-arylacrylates were significantly increased when employing the sacrificial electrophile ethyl trifluoroacetate. ¹H NMR and coupled ¹H-¹³C NMR analysis of the ethyl α-azido-β-arylacrylates indicate that the condensation is stereospecific - only the Z-isomer could be detected. Solvent mediated thermal treatment of the meta-substituted ethyl α-azido-β- arylacrylates resulted in the formation of both the 5- and 7- substituted indoles - the 5-regioisomer being slightly favored over the 7-regioisomer. Analogous thermal treatment of (2Z, 2Z′)-diethyl 3,3′-(1,3- phenylene)bis(2-azidoacrylate) and (2Z, 2Z′)-diethyl 3,3′-(1,4- phenylene)bis(2-azidoacrylate) exclusively produced pyrroloindoles, diethyl 1,5-dihydropyrrolo[2,3-f]indole-2,6-dicarboxylate and diethyl 1,5-dihydropyrrolo[2,3-f]indole-2,6-dicarboxylate, respectively. Results are also reported which indicate that the α-azido-β-arylacrylates can be used in the subsequent Hemetsberger indolization process without prior purification.

Full text of DOI:10.1039/c3ra42296h

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Indoles via Knoevenagel–Hemetsberger reaction
sequence3
Cite this: DOI: 10.1039/c3ra42296h
William L. Heaner IV,a Carol S. Gelbaum,a Leslie Gelbaum,a Pamela Pollet,a Kent
W. Richman,b William DuBay,b Jeffrey D. Butler,b Gregory Wellsb and Charles
L. Liotta*a
A series of substituted indoles have been synthesized by the sequential reaction of aromatic aldehydes
with ethyl azidoacetate in the presence of sodium ethoxide to form the corresponding ethyl a-azido-
b-arylacrylates (Knoevenagel process) followed by a solvent mediated thermolysis (Hemetsberger process).
The isolated yields of the ethyl a-azido-b-arylacrylates were significantly increased when employing the
sacrificial electrophile ethyl trifluoroacetate. 1H NMR and coupled 1H–13C NMR analysis of the ethyl
a-azido-b-arylacrylates indicate that the condensation is stereospecific—only the Z-isomer could be
detected. Solvent mediated thermal treatment of the meta-substituted ethyl a-azido-b-arylacrylates
resulted in the formation of both the 5- and 7- substituted indoles—the 5-regioisomer being slightly
favored over the 7-regioisomer. Analogous thermal treatment of (2Z, 2Z9)-diethyl 3,39-(1,3-phenylene)-
bis(2-azidoacrylate) and (2Z, 2Z9)-diethyl 3,39-(1,4-phenylene)bis(2-azidoacrylate) exclusively produced
pyrroloindoles, diethyl 1,5-dihydropyrrolo[2,3-f]indole-2,6-dicarboxylate and diethyl 1,5-dihydropyr-
rolo[2,3-f]indole-2,6-dicarboxylate, respectively. Results are also reported which indicate that the
a-azido-b-arylacrylates can be used in the subsequent Hemetsberger indolization process without prior
purification.
Received 16th April 2013,
Accepted 31st May 2013
DOI: 10.1039/c3ra42296h
www.rsc.org/advances
a-azido-b-arylacrylate, and finally (3) the thermolysis of the
a-azido-b-arylacrylate in an intramolecular cyclization to form
the indole skeleton (Scheme 1).
Introduction
The indole skeleton is a key structural component in many
molecules of pharmaceutical interest. In addition, it is also
common in dyes, fragrances, and flavorings.1 Indeed, the
literature contains many routes to prepare the indole
skeleton,2–16 and each of these methods is capable of
producing a wide variety of functionalized indoles. Of all the
methods cited in the literature, the Fischer and Hemetsberger
indolization methods appear to be important workhorse
processes. Of these two methods, the Hemetsberger indoliza-
tion may be the simplest since it only requires heat to promote
the cyclization of a-azido-b-arylacrylates.17 Additionally, from
an industrial point of view, the Hemetsberger indolization can
be easily conducted by a continuous flow process.14
A serious limitation in laboratory use as well as the
industrial implementation of the Hemetsberger indolization
is the low yields associated with the synthesis of the a-azido-
b-arylacrylate precursors in the Knoevenagel condensation
step. Typical yields of the a-azido-b-arylacrylates have been
reported to range from 10% to 64%.6,7,11–14,16,18 There are at
least two primary reasons for these relatively low yields. First,
alkyl azidoacetates are unstable in the presence of base; the
decomposition competes with the desired condensation
process. Second, the hydroxide by-product from the condensa-
tion can promote the hydrolysis of the ester functionality of
the alkyl azidoacetate reagent, the azido alcohol intermediate,
and the a-azido-b-arylacrylate product. Indeed, in the
Knoevenagel condensation of furfural and ethyl azidoacetate,
the undesired ester hydrolysis product of the azido alcohol
intermediate (a-azido-b-hydroxy-b-[2-furyl]propanoic acid) has
been identified as a side product in yields as high as 40%.19 In
this particular case, this acid by-product did not undergo
dehydration to afford the a-azido-b-[2-furyl]acrylic acid. In
principle, the by-product could re-esterified and subsequently
dehydrated but this would add additional steps and complex-
ity to the overall process.
The overall process to form an indole by the Hemetsberger
indolization involves three steps: (1) the synthesis of an alkyl
azidoacetate, (2) a base-promoted Knoevenagel condensation
between an azidoacetate and an aromatic aldehyde to form an
aSchool of Chemistry and Biochemistry, Georgia Institute of Technology, Atlanta,
Georgia. USA. E-mail: charles.liotta@chemistry.gatech.edu
bAmerican Pacific Corporation-Fine Chemicals (AMPAC), Rancho Cordova,
California, USA
Electronic supplementary information (ESI) available: 1H, 13C, and coupled
3
1H–13C NMRs and DSCs of azido-arylacrylates. 1-D and 2-D NMR of diethyl 1,6-
dihydropyrrolo[2,3-e]indole-2,7-dicarboxylate, 3i. See DOI: 10.1039/c3ra42296h
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Scheme 2 Synthesis of 2-(a-azido-b-phenyl)benzoxazole.
indoles via the Hemetsberger indolization. In order to avoid
hydrolysis of the ester functionality by hydroxide produced
during the condensation reaction, the first strategy explored
involved replacing the ester group of ethyl azidoacetate with
the base-stable benzoxazole group—an ester equivalent. The
2-azidomethylbenzoxazole 4 was synthesized by the condensa-
tion of 2-chloro-1,1,1-triethoxy ethane with o-aminophenol
followed by substitution of the chloro substituent for azide
with an overall yield of 86% (Scheme 2). Unfortunately, when 4
was employed in the base-promoted Knoevenagel condensa-
tion with benzaldehyde only a 25% yield of the desired product
was obtained. It was discovered that 4 undergoes a competitive
degradation in the presence of base to form products of
unknown structures. As a consequence, the oxazole protecting
group strategy was not a viable means for generating the
corresponding azido-arylacrylate for use in the Hemetsberger
indolization process.
The second strategy involved the interception of the
hydroxide ion with a highly reactive sacrificial electrophile
(SE, RCO2Et) before it could react with the ester functionality
of the product (Scheme 3).
To be successful, the sacrificial electrophile must be highly
electrophilic and react faster with hydroxide than the ester of
the desired product, and it must generate a weak base/
nucleophile upon reaction with hydroxide. Moreover, it must
not possess an enolizable hydrogen which could, in principle,
take part in the condensation reaction. Three candidates that
Scheme 1 Knoevenagel–Hemetsberger reaction sequence.
The literature cites a number of experimental procedures
used to maximize the yields. These include employing an excess
of the alkyl azidoacetate and performing the condensation
reactions at temperatures of 210 uC to 0 uC for 4–6 h. Kondo
et al. reported attempts to increase the yields in a step-wise
approach. This two-step approach involved first reacting the
aryl aldehyde with the alkyl azidoacetate at 230 uC to produce
the azidoalcohol intermediate which was then treated with
thionyl chloride and triethyl amine to promote the elimination
of water in order to produce the alkyl a-azido-b-arylacrylates.
With this two-step strategy the authors successfully increased
the yields for two specific substrates, ortho- and para-methox-
ybenzaldehyde, reporting yields of 78% and 80%, respectively.
However, the yields associated with other substituted benzal-
dehydes were low-to-moderate ranging from 9%–55%.12,13
Herein, we report (1) the results for the replacement of the
alkyl azidoacetate with the base-stable 2-azidomethyleneben-
zoxazole, (2) the use of the ‘‘sacrificial electrophile’’ ethyl
trifluoroacetate in the condensation of ethyl azidoacetate with
aromatic aldehydes, (3) the stereochemistry of the ethyl
a-azido-b-arylacrylates produced in the Knoevenagel conden-
sation, (4) the differential scanning calorimetric analyses of
the a-azido-b-arylacrylates, and (5) the yields and accompany-
ing regioselectivity associated with the thermally induced
Hemetsberger indolization reaction of meta-substituted ethyl
a-azido-b-phenylacrylates.
Results and discussion
High yields of Knoevenagel condensation products are
essential in developing a viable process for the synthesis of
Scheme 3 The role of
a sacrificial electrophile in a model Knoevenagel
condensation.
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Table 2 Stoichiometry and temperature optimization
Fig. 1 Sacrificial electrophiles.
Entry NaOEt (eq) 1 (eq) ETFA (eq) T (uC)
Time
Isolated yields
potentially possessed these properties are: ethyl formate (EF),
ethyl trichloroacetate (ETClA), and ethyl trifluoroacetate
(ETFA) (Fig. 1).
1
2
3
4
5
6
7
8
9
2
2
1.5
1.25 1.25
2
1.5
1.25 1.25
2
1.5
2
1.5
RT
RT
RT
15 min 76 ¡ 3%
15 min 71 ¡ 1%
15 min 65 ¡ 2%
1.5
1.25
2
1.5
1.25
2
2
1.5
0 uC
0 uC
0 uC
0 uC–RT 1 h
0 uC–RT 1 h
0 uC–RT 1 h
4 h
4 h
4 h
71 ¡ 2%
74%
70%
70 ¡ 4%
73%
Ethyl formate was chosen primarily on steric grounds while
ethyl trichloroacetate and ethyl trifluoroacetate were chosen
based on their highly electrophilic carbonyl carbons. Indeed,
the electron-withdrawing properties of trichloromethyl and
trifluoromethyl are reflected in their s*-values: +2.65 and
+2.60, respectively. This new strategy was first applied to the
condensation of ethyl 2-azidoacetate 1 and benzaldehyde to
yield ethyl a-azido-b-phenylacrylate 2. Table 1 summarizes the
isolated yields of product obtained when employing these
sacrificial electrophiles at various stoichiometries of base and
sacrificial electrophile at room temperature. All results are
compared to the yields when no sacrificial electrophile is
present (48%). From Table 1 it can be concluded that ethyl
formate (entries 2–4) and ethyl trichloroacetate (entries 5 and
6) had little to no effect on the yield. In contrast, the presence
of two equivalents of ethyl trifluoroacetate (Entries 7–9)
resulted in a dramatic increase in yield (74–76%) of product
2. Although the trichloromethyl group has a slightly larger s*-
value compared to the trifluoromethyl group, the latter is
smaller, giving it a kinetic advantage which is reflected in its
effectiveness as a sacrificial electrophile.
2
1.5
1.5
1.25
1.25 1.25
66 ¡ 2%
reported depending on the substituent.11 This clearly called
into question the need for reduced temperatures and
prompted us to investigate the reaction of ethyl azidoacetate
with benzaldehyde as a function of temperature, time, and
reagent stoichiometry. These results are summarized in
Table 2. At ambient temperature and with two equivalents of
ethyl trifluoroacetate, the reaction was complete within 15 min
with isolated yields after recrystallization of 76 ¡ 3% (Table 2,
entry 1). When the condensation was performed at 0 uC for 4 h,
comparable isolated yields of 71 ¡ 2% were obtained (Table 2,
entry 4).
Experimentally, it was observed that the reaction solution at
ambient temperature goes through a series of color changes—
colorless to yellow to orange (attributed to the decomposition
of ethyl azidoacetate 1). In contrast, at 0 uC the reaction
solution never gets darker than a yellow color. Moreover, the
NMR spectra of the crude reaction products showed fewer
impurities at 0 uC than at ambient temperatures. In light of
these observations the reaction protocol employed in subse-
quent experiments involved adding the reactants and the
sacrificial electrophile to the sodium ethoxide solution at 0 uC
and then allowing the reaction mixture to warm to room
temperature for a period of one hour. After recrystallization
isolated yields of 70 ¡ 4% were obtained. This protocol was
further improved by investigating the relative stoichiometries
of 1, NaOEt, and ethyl trifluoroacetate. It was found that the
optimized number of equivalents of base and ETFA could be
reduced to 1.5 while maintaining an isolated, recrystallized
yield of 73% (entry 8). A further decrease to 1.25 equivalents
resulted in a slight decrease in yield (66%) (Table 2, entry 9).
Reported
experimental
protocols
for
analogous
Knoevenagel reactions call for reaction temperatures ¡0 uC
for 4–6 h.6,7,11–13 To our knowledge only a single literature
example can be found in which the reaction was performed at
ambient temperature for 30 min. Yields from 6 to 80% were
Table 1 Effect of sacrificial electrophiles on condensation of benzaldehyde and
ethyl azidoacetate
Sacrificial electrophile (SE)
Entry 1 (eq) SE
(eq)
NaOEt (eq) Yield, isolated
This optimized procedure was applied to
a variety of
1
2
3
4
5
6
7
8
9
2
2
3
2
2
2
2
2
3
none
EF
EF
n/a
1
1
2
1
2
1
2
2
2
2
3
2
2
2
2
2
3
48%
45%
51%
50%
48%
58%
53%
74%
76%
substituted benzaldehydes, heteroaromatic aldehydes, and
alicyclic aldehydes in order to establish the scope of the
methodology. The isolated, recrystallized yields as well as the
crude yields, determined by 1H NMR analyses, are tabulated in
Table 3.
EF
ETClA
ETClA
ETFA
ETFA
ETFA
The crude yields ranged from 84–95% with purities of
y90% by 1H NMR, indicating that the crude a-azido-
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Table 3 Products from condensations of aromatic aldehydes and ethyl azidoacetate20
Crude yield
Isolated yield
Crude yield
Isolated yield
2a
2b
2c
94 ¡ 5%
76 ¡ 3%
2f
92 ¡ 8%
60 ¡ 5%
88 ¡ 4%
88 ¡ 5%
70 ¡ 3%
78 ¡ 3%
2g
2h
89 ¡ 2%
77 ¡ 2%
77 ¡ 2%
n/a
2d
94 ¡ 5%
72 ¡ 4%
2i
2j
n/a
72 ¡ 1%
2e
84 ¡ 2%
70 ¡ 2%
90 ¡ 2%
83 ¡ 1%
b-arylacrylates could, in principle, be used in the subsequent
Hemetsberger indolization process. The efficacy of this
strategy will be discussed later in this article. The isolated,
recrystallized yields from the substituted benzaldehydes were
good to excellent (>70%) with the exception of m-nitrobenzal-
dehyde (2f, Table 3) which afforded 60 ¡ 5% yield.21 Iso- and
terephthalaldehydes not only gave high yields (2h, 77 ¡ 2%;
2i, 72 ¡ 1%) but the products precipitated during reaction—
allowing for simple isolation via filtration; the products were
analytically pure. The heteroaromatic, furfural, also produced
configurations of ethyl a-azido-b-arylacrylates can be obtained.
Quite surprisingly, only one vinyl hydrogen was observed in
1
the H NMR spectra for all of the products listed in Table 3
indicating the formation of only one stereoisomer. The
question remained as to which stereoisomer was present. It
has been reported in the literature that the coupling constant
between the cis and trans b-vinyl hydrogens and the carbonyl
carbon in a,b-unsaturated esters have substantially different
coupling constants. A 3JCLO,H value y5 Hz is associated with a
3
cis relationship whereas a JCLO,H value greater than 10 Hz is
associated with the trans relationship (Fig. 2).22 It was found
high yields (2j, 83
¡
1%). In contrast, however,
N-methylpyrrole-2-carboxaldehyde (not shown in Table 3) gave
very poor yields, y10%. Pyrrole-2-carboxaldehyde, cyclopenta-
necarboxaldehyde, and cyclohexanecarboxaldehyde failed to
yield any products using the above protocol.
In the process of optimizing the yields of indole products, it
was of interest to understand the stereochemistry of the
a-azido-b-arylacrylates products and the relationship of the
stereochemistry to the yields and regioselectivity associated
with the Hemetsberger process. In principle, both the Z and E
3
Fig. 2 JCLO,H coupling.
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that 3JCLO,H , 5 Hz for all of products reported in Table 3 (the
NMR spectra can be found in the ESI ). These results strongly
3
suggest that the products formed in the Knoevenagel reaction
are of the Z configuration. Density functional theory calcula-
tions (B3LYP-6-31G*) on molecule 2a indicated that the
Z-isomer is thermodynamically more stable than the
E-isomer by 6.86 kcal/mole. In fact, the calculations indicate
that the equilibrium geometry for the Z-isomer showed that all
the atoms in the molecule were essentially in one plane. In
contrast, the equilibrium geometry of the E-isomer clearly
showed that the interaction of the bulky carboethoxy group
with the phenyl group resulted in a distorted, non-planar
structure. Based on these calculations it was concluded that
the energy of the transition state leading to the Z-isomer is
substantially lower than that leading to the E-isomer, the
origin of the difference being steric in nature.
Fig. 3 DSC: (Z)-Ethyl a-azido-b-(m-chlorophenyl)acrylate (2d).
attributed to the formation of the azirene intermediate (134
uC) followed by cyclization to the indole (166 uC). Two distinct
exothermic events were observed for most molecules listed in
Table 3 except for the 2f, 2h, 2i, and 2j (Table 4). Since in each
of these cases the indole products were also formed upon
thermally induced cyclization, both DSC exothermic events
were assumed to take place at temperatures too close to
resolve.
The a-azido-b-arylacrylates listed in Table 3 (2a–2j) were
subjected to the Hemetsberger indolization in o-dichloroben-
zene at 150 uC for 30 min. The isolated yields of the indoles
(3a-3j) were consistently in the 75% range suggesting that
neither electronic nor steric effects influence the efficacy of the
cyclization (Table 5). When a meta-substituent is present on
the aromatic ring both 5- and 7-substituted regioisomeric
indoles are possible (Fig. 4).
Table 5 summarizes (1) the isolated, recrystallized yields
from the Hemetsberger indolization process, with and without
purification of the ethyl a-azido-b-arylacrylates and (2) the
regiochemical ratio (5-substituted/7-substituted) associated
with each of the indole products. It is obvious that there is
no overwhelming preference for either the 5- or the 7-sub-
stituted indole products. Although no significant electronic
effects were observed, steric effects appeared to more strongly
influence the regiochemistry of the reaction. Specifically, it
was found that, in the thermolysis of ethyl a-azido-b-
Hemetsberger indolization reaction
The thermally induced Hemetsberger indolization is typically
carried out in refluxing p-xylene or mesitylene (bp 138 uC and
165 uC, respectively), with yields ranging from 50%–
100%.4,7,11–13,23 The mechanism is believed to proceed in a
stepwise fashion through an azirene intermediate
5
(Scheme 4).7 While the literature contains several reports
regarding the yields associated with the thermally induced
Hemetsberger indolization, there have been no reports
discussing the regiochemical outcome in the cyclization of
meta-substituted ethyl a-azido-b-phenylacrylates. It was of
interest, therefore, to explore the regiochemistry associated
with indole formation and to determine the potential role of
electronic and/or steric factors in controlling the outcome.
In order to provide guidance for optimal reaction conditions
for the thermal cyclization process, as well as for safety
purposes, differential scanning calorimetric (DSC) analyses
were conducted on all of the a-azido-b-arylacrylates reported in
this study (all DSC plots can be found in the ESI ). As an
3
example, the DSC for (Z)-ethyl a-azido-b-(m-chlorophenyl)acry-
late 2d is presented in Fig. 3. The first is an endothermic
transformation at 47.65 uC which corresponds to the melting
point of 2d. The two subsequent exothermic events are
Table 4 Exothermic events of a-azido-b-arylacrylates measured by DSC
Exothermic events (uC)
a-azido-b-arylacrylate
First
Second
2a
2b
2c
2d
2e
2f
2g
2h
2i
136.8
136.2
137.2
134.4
136.3
136.2a
134.6
139.4a
129.7a
129.0a
159.5
160.7
158.9
166.3
160.8
154.6
2j
a
Only one exothermic event observed.
Scheme 4 Hemetsberger indolization mechanism.
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Table 5 Comparison Knoevenagel–Hemetsberger processes with and without purification of the ethyl a-azido-b-arylacrylates
Yield (%) w/o
intermediate purification
Yield (%) w/
intermediate purification
Regioisomer ratio
(5- vs. 7- substitution)
a-azido-b-arylacrylate
2a
2b
2c
2d
2e
2f
2g
2h
2i
81
76
78
72
74
56
—
64
70
80
78
60
71
68
63
62
80
n/a
n/a
76
n/a
1.1 : 1a
1 : 1a
1.2 : 1b
2 : 1b
1.1 : 1a
n/a
3h only
3i only
n/a
2j
a
b
determined by 1H NMR. 5- and 7- isomers separated by column chromatography.
(m-phenylphenyl)acrylate, ethyl 5-phenyl-indole-2-carboxylate
was favored by a 2 : 1 ratio over the ethyl 7-phenyl-indole-2-
carboxylate implying that steric factors may play a small role.
In contrast to the meta-substituted ethyl a-azido-b-phenyla-
crylates, the thermal cyclization of m-phenylene-bis(a-azidoa-
crylate) and p-phenylene-bis(a-azidoacrylate) (2h and 2i,
respectively) showed exclusive preferences; only one regioi-
somer was detected in each case. Fig. 5 shows the two possible
regioisomers which can be formed from 2h and 2i.
Thermolysis of m-phenylene-bis(a-azidoacrylate) (2h) could
result in the formation of 3h and/or 3h9. These isomers can be
easily distinguished from each other using 13C NMR. 3h9 has a
mirror plane of symmetry; whereas, 3h possesses no symme-
try. Experimentally, ten aromatic/vinyl carbons were observed
which is consistent with the regioisomer 3h. In contrast, the
thermolysis of 2i could result in regioisomers, 3i and 3i9,
which cannot be distinguished by one-dimensional NMR as
both possess symmetry elements, a C2-axis and sv elements,
respectively. Therefore, two-dimensional 1H–13C-HMBC NMR
experiments were used to determine the identity of the
To proceed from the a-azido-b-arylacrylates directly to the
indoles without prior purification of the vinylazide precursors
would simplify the synthetic process and potentially have great
industrial appeal. The high purity of the crude a-azido-
b-arylacrylates obtained from our methodology (y90%) would
enable the realization of
a Knoevenagel–Hemetsberger
sequence without intermediary purification. Operationally,
the a-azido-b-arylacrylates were extracted from the condensa-
tion reaction mixture with o-dichlorobenzene, and the result-
ing o-dichlorobenzene solution was heated to 150 uC in order
to perform the Hemetsberger process. The results, employing
this protocol, are tabulated in Table 5.
In all examples, the isolated yields are very good (>70%) with
the exception of the nitro-substituted indoles. In this case, the
major impurity was determined to be an amide, (Z)-ethyl 2-(3-
nitrobenzamido)-3-(3-nitrophenyl)acrylate, a by-product from
the reaction of m-nitrobenzaldehyde and the (Z)-ethyl m-nitro-
a-azido-b-phenylacrylate (Scheme 5). Analysis of the starting
reaction mixture revealed the presence of approximately 10%
m-nitrobenzaldehyde. Thus, it is postulated that when the
‘‘crude’’ azide was used directly in the Hemetsberger indoliza-
tion process the intermediate azirene or nitrene reacted with
the aldehyde impurity in the reaction mixture to form an
product (see ESI ). The relationships of interest were the
3
correlations between the protons on the nitrogens and the
carbons possessing hydrogens within a distance of three
bonds. Regioisomer 3i would exhibit two three-bond correla-
tions while only one such correlation would be expected in 3i9.
Two three-bond correlations were observed in the 1H-13C-
HMBC experiment. It was concluded that regioisomer 3i had
been formed. Thus, the pyrroloindoles24–27 formed in the
thermolysis of 2h and 2i were specific towards those
regioisomers in which the nitrogens are anti to each other
(3h and 3i respectively).28
Fig. 4 Regioisomeric indoles R = Me, OMe, Cl, NO2, Ph.
Fig. 5 Stereoisomers of pyrroloindoles.
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Experimental
All solvents and reagents were purchased from commercial
sources in ‘‘reagent’’ grade form and were used without
further purification. Nuclear magnetic resonance spectra were
measured on a 400 MHz Varian (1-D measurements) and a
Bruker AVIII HD 500 MHz (2-D measurements). Mass spectro-
metry measurements were performed by electron impact (EI)
on a Micromass (Waters) Autospec M. Differential scanning
calorimetry experiments were performed on a TA Instruments
Q20; samples were heated at a rate of 10 uC min21. Infrared
spectroscopy measurements were performed with neat sam-
ples on a Shimadzu FTIR Prestige-21 equipped with a Specac
Golden Gate ATR cell. Elemental analyses were performed by
Atlantic MicroLab, Inc.
2-(chloromethyl)benzo[d]oxazole29
2-chloro-1,1,1-triethoxy ethane (10.31 g, 0.5242 mol) was added
to a solution of o-aminophenol (5.454 g, 0.4998 mol) in 70 mL
of anhydrous ethanol under an inert atmosphere. The reaction
mixture was heated, with stirring to 60 uC for four hours and
subsequently cooled and concentrated in vacuo. The crude
organic product was purified by distillation, 68 uC at 11
Scheme 5 Formation of side product in thermolysis of crude (Z)-ethyl meta-
nitro-a-azido-b-phenylacrylate.
1
mmHg, yielding a colorless oil, 79% yield (6.615 g). H NMR
oxaziridine which ring-opens to form the amide shown in
Scheme 5.
Thus, with the exception of the nitro-substituted azido-
arylacrylate, it can be concluded that it is not necessary to have
(CDCl3, d (ppm)): 4.66 (2 H, s), 7.17 (2 H, m), 7.34 (1 H, m), 7.58
(1 H, m). 13C NMR: 36.37, 110.53, 120.22, 124.45, 125.58,
140.69, 150.80, 160.57.
2-(azidomethyl)benzo[d]oxazole (4)
a
purification step between the condensation and the
thermolysis; the yields of the products are essentially the
same.
NaN3 (1.42 g, 0.0218 mol) was added to a solution of 2-
(chloromethyl)benzo[d]oxazole (2.09 g, 0.0125 mol) in 80 mL
anhydrous ethanol under an inert atmosphere. The reaction
mixture was heated at reflux overnight. Approximately 20 mL
of water and 40 mL of EtOAc were added to the heterogeneous
reaction mixture. The organic layer was separated and the
aqueous layer was extracted with EtOAc (2 6 20 mL). The
combined organic fractions were dried over MgSO4 and
concentrated in vacuo to give a dark green oil. The crude
organic product was purified by distillation, 95 uC 11 mmHg,
Conclusions
In conclusion, the utility of the Knoevenagel–Hemetsberger
sequence for the formation of substituted indoles has been
significantly improved. The use of the sacrificial electrophile,
ethyl trifluoroacetate, in the Knoevenagel condensation
1
to give a colorless oil, 97% yield (2.10 g). H NMR (CDCl3, d
increases
the
yield
of
a-azido-b-arylacrylates,
the
(ppm)): 4.55 (2 H, s), 7.33 (2 H, m), 7.52 (1 H, m), 7.71 (1 H, m).
13C NMR: 47.19, 110.83, 120.46, 124.78, 125.72, 140.75, 151.00,
160.54. MS (m/z): 174.0 [M+], 146 [M+–N2], 132 [M+–N3].
Hemetsberger precursors, from an average of approximately
45% to 72%. The subsequent indolization step, conducted in
o-dichlorobenzene at 150 uC, also resulted in relatively high
yields (75%). In most cases, the crude a-azido-b-arylacrylates
were successfully taken through the indolization step without
prior isolation and purification. This observation has positive
implications for both laboratory and industrial scale pro-
cesses. Finally, it was observed that (1) the stereochemistry
associated with the Knoevenagel process produces only one
stereoisomer—the Z ethyl a-azido-b-arylacrylates and (2) the
regioselectivity associated with the Hemetsberger process from
meta-substituted ethyl a-azido-b-arylacrylates is not strongly
influenced by either electronic or steric effects—the exceptions
being the cyclization of the ethyl esters of m- and p-phenylene-
bis(a-azidoacrylate).
(Z)-2-(1-azido-2-phenylvinyl)benzo[d]oxazole (5)
A freshly prepared solution of sodium ethoxide (50 mL, 0.35
M) was transferred to a round bottom flask under an
atmosphere of argon or nitrogen and cooled to 210 uC. In a
separate flask, under an inert atmosphere, were added 2-
(azidomethyl)benzo[d]oxazole (1.00 g, 0.00574 mol) and
benzaldehyde (0.203 g, 0.00191 mol). The resulting solution
was added drop-wise to the stirring solution of sodium
ethoxide over the period of one hour. The reaction mixture
was allowed to warm to 0 uC, and after four hours, the reaction
was quenched with 3 mL of NH4Cl(sat.). The ethanol was
removed in vacuo. Approximately 20 mL of EtOAc and 20 mL of
H2O were added to the slurry. The organic phase was
separated, and the aqueous phase was extracted with
additional EtOAc (2 6 25 mL). The combined organic layers
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were washed with brine (25 mL), dried with MgSO4, and
concentrated in vacuo. The crude organic product was purified
by short column silica, 60 Å, 60–200 mm, chromatography,
hexanes : ethyl acetate, 85 : 15, and recrystallization in etha-
nol : water yielding yellow-white crystals, 25% yield (0.125 g).
1H NMR (CDCl3, d (ppm)): 7.02 (1 H, s), 7.38 (5 H, m), 7.57 (1
H, m), 7.79 (1 H, m), 7.89 (2 H, d, J = 7.4 Hz). 13C NMR: 110.49,
120.57, 122.90, 122.92, 124.87, 128.55, 129.05, 130.27, 133.66,
141.56, 150.22, 158.57. MS: 263 [M + 1], 235 [M + 1, –N2]. IR:
2122 cm21(N3, str).
layers were washed with brine (25 mL), dried with MgSO4, and
concentrated in vacuo.
(Z)-ethyl a-azido-b-phenylacrylate (2a)
Crude product appears as wet orange crystals, 90% yield.
Recrystallization (3x) with ethanol : water yields pale yellow
crystals, 79% yield (1.253 g). 1H NMR (CDCl3, d (ppm)): 1.41 (3
H, t, J = 8.0 Hz), 4.38 (2 H, q, J = 8.0 Hz), 6.92 (1 H, s), 7.37 (3 H,
m), 7.81 (2H, m). 13C NMR: 14.04, 62.08, 125.18, 125.51,
3
128.30, 129.20, 130.43, 133.14, 163.32; JC,H: 4.2 Hz. MS: 217.1
[M+]. IR: 1713 cm21 (CLOstr), 2110 cm21(N3, str). EA (calc.): C,
60.82; H, 5.10; N, 19.34. (found): C, 61.08; H, 5.14; N, 18.68. mp
37–41 uC.
Ethyl azidoacetate (1)30
Ethyl bromoacetate (15.0 mL, 0.135 mol) was added to a
solution of sodium azide (17.91 g, 0.276 mol) in 50 : 50
acetone : water (100 mL). The biphasic reaction mixture was
allowed to stir at room temperature overnight. The organic
layer was separated and the aqueous layer was extracted with
EtOAc (2 6 25 mL). The combined organic layers were washed
with brine (25 mL), dried over MgSO4, and concentrated in
vacuo to give a colorless oil, 89% yield (15.52 g) yield. The
compound was stored in brown glass and in the refrigerator to
prevent discoloration. 1H NMR (CDCl3, d (ppm)): 1.06 (3 H, t, J
= 8.0 Hz), 3.65 (2 H, s), 4.00 (2 H, q, J = 8.0 Hz). 13C NMR: 13.58,
49.81, 61.37, 168.11. HRMS: (calc) 129.0538, (found) 129.0539.
IR: 1740 cm21 (CLOstr), 2102 cm21(N3, str).
(Z)-ethyl a-azido-b-(m-methylphenyl)acrylate (2b)
Crude product appears as red-orange oil, 92% yield. Silica
chromatography ethyl acetate : hexanes (10 : 90), 73% yield
1
yellow oil (1.235 g). H NMR (CDCl3, d (ppm)): 1.41 (3 H, t, J =
8.0 Hz), 2.39 (3H, s), 4.37 (2 H, q, J = 8.0 Hz), 6.91 (1 H, s), 7.37
(3 H, m), 7.20 (2H, d, J = 8.0 Hz), 7.72 (2H, d, J = 8.0 Hz). 13C
NMR: 14.04, 21.24, 62.05, 125.13, 125.36, 127.60, 128.18,
3
130.09, 131.04, 132.99, 137.85, 163.38; JC,H: 4.9 Hz. HRMS:
(calc) 231.1008, (found) 231.0998. IR: 1707 cm21 (CLOstr), 2110
cm21(N3, str).
(Z)-ethyl a-azido-b-(m-methoxyphenyl)acrylate (2c)
Meta-phenylbenzaldehyde31
Crude product appears as wet orange crystals, 93% yield.
Recrystallization with ethanol : water (36) yields pale yellow-
white crystals 78% yield (1.410 g). H NMR (CDCl3, d (ppm)):
Pd(OAc)2 (0.313 g, 1.7 mol%), triphenylphosphine (0.885 g, 4.1
mol%), phenyl boronic acid (11.127 g, 0.0913 mol, 1.12 eq),
K2CO3 (25.002 g, 0.18090 mol, 2.2 eq) and meta-bromobenzal-
dehyde (15.046 g, 0.0813 mol, 1 eq) were added to a flask
containing 100 mL THF and 50 mL H2O. The reaction mixture
was heated at 65 uC, and then cooled after 24 h. The organic
layer was separated, and the aqueous layer was extracted with
EtOAc (2 6 40 mL). The combined organic layers were washed
with brine (25 mL), dried over MgSO4, and concentrated in
vacuo. The resulting crude organic product was purified by
distillation, 150 uC at 3 mmHg, yielding a colorless oil, 95%
yield (14.08 g). 1H NMR (CDCl3, d (ppm)): 7.42 (1 H, m) 7.47 (2
H, m), 7.60 (3 H, m), 7.85 (2 H, t, J = 7.49 Hz), 8.09 (1 H, s),
10.06 (1 H, s). 13C NMR: 126.94, 127.85, 127.96, 128.45, 128.84,
129.32, 132.84, 136.71, 139.44, 141.88, 192.14. MS: 182.0 [M+].
1
1.40 (3 H, t, J = 8.0 Hz), 3.84 (3H, s), 4.37 (2 H, q, J = 8.0 Hz),
6.88 (2 H, m), 7.31 (2 H, m), 7.44 (1H, s). 13C NMR: 14.21,
55.29, 62.30, 115.26, 115.43, 123.38, 125.11, 125.74, 129.36,
3
134.40, 159.42, 163.47; JC,H: 4.9 Hz. MS: M+, 247.1. IR: 1707
cm21 (CLOstr), 2102 cm21(N3, str). EA (calc.): C, 58.29; H, 5.30;
N, 17.00. (found): C, 58.35; H, 5.30; N, 17.02. mp 49.6 uC.
(Z)-ethyl a-azido-b-(m-chlorophenyl)acrylate (2d)
Crude product appears as wet yellow-orange crystals, 99%
yield. Recrystallization with ethanol : water (36) yields pale
yellow-white crystals 76% yield (1.408 g). 1H NMR (CDCl3, d
(ppm)): 1.40 (3 H, t, J = 8.0 Hz), 4.37 (2 H, q, J = 8.0 Hz), 6.80 (2
H, m), 7.28 (2 H, m), 7.63 (1H, s), 7.85 (1 H, s). 13C NMR: 14.12,
62.41, 123.17, 126.69, 128.63, 129.11, 129.54, 130.00, 134.28,
3
134.83, 163.10; JC,H: 4.9 Hz. MS [M+]: 262.0. IR: 1708 cm21
Knoevenagel condensations
(CLOstr), 2119 cm21(N3, str). EA (calc.): C, 52.49; H, 4.01; Cl,
14.08; N, 16.70. (found): C, 52.81; H, 4.09; Cl, 14.08; N 16.52.
mp 47.7 uC.
A freshly prepared solution of sodium ethoxide (50 mL, 0.35
M) was transferred to a round bottom flask under an
atmosphere of argon or nitrogen and cooled to 0 uC. In a
separate flask under an inert atmosphere was added ethyl
azidoacetate (1.4119 g, 0.0109 mol), ethyl trifluoroacetate
(1.5533 g, 0.0109 mol), and the appropriate amount of
aldehyde (0.00727 mol). The resulting solution was added
with stirring to the solution of sodium ethoxide in a single
portion. The ice bath was then removed, and after one hour,
the reaction was quenched with 3 mL of NH4Cl(sat.). The
ethanol-water was removed in vacuo. Approximately 20 mL of
EtOAc and 20 mL of H2O were added to the slurry. The organic
phase was separated, and the aqueous phase was extracted
with additional EtOAc (2 6 25 mL). The combined organic
(Z)-ethyl a-azido-b-(m-phenylphenyl)acrylate (2e)
Crude product appears as wet orange crystals, 86% yield (1.546
g). Recrystallization with ethanol : water (36) yields pale
yellow-white crystals 72% yield. 1H NMR (CDCl3, d (ppm)):
1.42 (3 H, t, J = 8.0 Hz), 4.39 (2 H, q, J = 8.0 Hz), 6.99 (1 H, s),
7.31 (2 H, m), 7.44 (1H, s), 7.38 (1 H, m) 7.47 (3 H, m) 7.61 (3 H,
m) 7.83 (1 H, d, J = 8.0 Hz) 8.03 (1 H, s). 13C NMR: 14.21, 62.32,
125.09, 125.81, 127.16, 127.52, 128.15, 128.81, 128.87, 129.29,
3
133.63, 140.62, 141.45, 163.49; JC,H: 4.9 Hz. MS, exact mass:
293.1164. IR: 1707 cm21 (CLOstr), 2118 cm21(N3, str). EA (calc):
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C, 69.61; H, 5.15; N, 14.33. (found): C, 69.74; H, 5.09; N, 13.96.
Hemetsberger indolization
mp 88.1 uC.
A flask containing 1 g of crude or pure a-azido-b-arylacrylate in
50 mL of ortho-dichlorobenzene was heated to 150 uC. The
reaction is cooled after 30 min, and the solvent is removed in
vacuo. The regioisomeric indoles are purified by silica column
chromatography. The 60 Å, 60–200 mm silica particles were
stirred in hexanes:triethylamine 98 : 2 overnight, and the
mobile phase used was hexanes:ethyl acetate, 85 : 15.
(Z)-ethyl a-azido-b-(m-nitrophenyl)acrylate (2f)
2 equivalents of ethyl azidoacetate, sodium ethoxide, and ethyl
trifluoroacetate were used in this condensation. Crude product
appears as a wet, red solid, 89% yield (1.239 g). Flash column
chromatography with ethyl acetate: hexanes (15 : 85) yields
white solid, 65% yield (0.91 g). 1H NMR (CDCl3, d (ppm)): 1.40
(3 H, t, J = 7.14 Hz), 4.38 (2 H, q, J = 7.15 Hz), 6.88 (1H, s), 7.54
(1H, t, J = 7.89 Hz), 8.09 (1H, d, J = 7.86), 8.16 (1 H, dd, J =
8.23.), 8.66 (1H, m). 13C NMR: 14.10, 62.70, 121.52, 123.43,
124.80, 128.20, 129.33, 134.71, 135.91, 148.18, 162.81; 3JC,H: 4.9
Hz. HRMS: (calc) 262.0702 (found) 262.0713. IR: 1711 cm21
(CLOstr), 2112 cm21(N3, str). mp 58.6 uC.
Ethyl 1H-indole-2-carboxylate (3a)
White-beige crystals, 81% yield (0.706 g). 1H NMR (CDCl3, d
(ppm)): 1.43 (3H, t, J = 8.0 Hz), 4.42 (2H, q, J = 8.0 Hz), 7.16 (1H,
dt, J = 8.0 Hz), 7.25 (1H, dd), 7.33 (1H, dt, J = 8.0 Hz), 7.44 (2H,
dd, J = 8.0 Hz), 7.70 (1H, dd, J = 8.0 Hz), 9.27 (1H, s). 13C NMR:
14.34, 61.01, 108.57, 111.88, 120.68, 122.51, 125.24, 127.41,
127.84, 136.86, 162.14. HRMS: (calc) 189.0790, (found)
189.0795. EA: (calc.) C, 69.83; H, 5.86; N, 7.40; (found) C,
69.81; H, 5.85; N, 7.40.
(Z)-ethyl a-azido-b-(p-methylphenyl)acrylate (2g)
Crude product appears as wet orange crystals, 89% yield.
Recrystallization with ethanol : water (36) yields pale yellow-
white crystals 77% yield (1.307 g). H NMR (CDCl3, d (ppm)):
1.40 (3 H, t, J = 8.0 Hz), 2.37 (3H, s), 4.36 (2 H, q, J = 8.0 Hz),
6.90 (1 H, s), 7.37 (3 H, m), 7.20 (2H, d, J = 8 Hz), 7.72 (2H, d, J =
8.0 Hz). 13C NMR: 14.21, 21.47, 62.14, 124.63, 125.52, 129.20,
130.58, 139.75, 163.62. MS: 231.1 [M+]. IR: 1707 cm21 (CLOstr),
2112 cm21(N3, str). EA (calc.): C, 60.82; H, 5.10; N, 19.34.
(found): C, 61.08; H, 5.14; N, 18.68. mp 47–53u.
1
Ethyl 5-methyl-1H-indole-2-carboxylate and ethyl 7-methyl-
1H-indole-2-carboxylate (3b)32
White crystals, mixture of regioisomers 1.1 : 1 respectively by
1H NMR of the –Me signals, 76% yield (0.668 g). 1H NMR
(CDCl3, d (ppm)): 1.40 (3H, t, J = 7.12 Hz), 1.41 (3H, t, J = 7.12
Hz), 2.42 (3H, s), 2.51 (3H, s), 4.41 (4H, p, J = 7.19 Hz), 7.04–
7.14 (4H, m), 7.23 (1H, d, J = 2.04 Hz), 7.30 (1H, d, J = 8.44 Hz),
7.44 (1H, s), 7.53 (1H, d, J = 7.68), 9.12 (1H, s), 9.25 (1H, s). 13
C
(2Z,29Z)-diethyl 3,39-(1,3-phenylene)bis(2-azidoacrylate) (2h)
NMR: 14.40, 16.71, 21.41, 60.95, 61.04, 108.07, 109.19, 111.59,
120.16, 120.98, 121.29, 121.77, 125.52, 125.56, 127.06, 127.20,
127.24, 127.45, 127.71, 129.97, 135.37, 136.79, 162.25, 162.34.
MS: 203 [M+]. EA: (calc.) C, 70.92; H, 6.45; N, 6.89; (found) C,
71.00; H, 6.50; N, 6.86.
Product precipitates as a white solid, 77% yield (1.995 g). No
purification. 1H NMR (CDCl3, d (ppm)): 1.41 (6 H, t, J = 8.0 Hz),
4.38 (4 H, q, J = 8.0 Hz), 6.90 (2 H, s), 7.38 (2 H, 2), 7.40 (1H, t, J
= 8.0 Hz), 7.81 (2 H, d, J = 8.0 Hz), 8.18 (1 H, s). 13C NMR: 14.19,
62.36, 124.51, 126.14, 128.58, 131.07, 132.65, 133.41, 163.34;
3JC,H: 5.0 Hz. HRMS: (calc) 356.1233, (found) 356.1240. IR:
1707 cm21 (CLOstr), 2108 cm21(N3, str). mp 106.0 uC.
Ethyl 5-methoxy-1H-indole-2-carboxylate and ethyl 7-methoxy-
1H-indole-2-carboxylate (3c)
1
Mixture of regioisomers 1 : 1 respectively, by H NMR of the –
(2Z,29Z)-diethyl 3,39-(1,4-phenylene)bis(2-azidoacrylate) (2i)
OMe signals. White crystals, 78% yield (0.692 g). 1H NMR
(CDCl3, d (ppm)): 1.42 (3H, 7.13 Hz), 3.86 (3H, s), 3.96 (3H, s),
4.42 (4H, q, J = 7.13 Hz), 7.00 (1H, dd, J = 8.94 Hz, J = 1.56 Hz),
7.06 (2H, m), 7.14 (1H, dd, J = 2.14 Hz), 7.20 (1H, d, J = 2.29),
7.27 (1H, d, J = 8.17 Hz), 7.31 (1H, d, J = 8.92 Hz), 9.08, (1H, s),
9.19 (1H, s). 13C NMR: 14.34 (2C), 55.31, 55.59, 60.90 (2C),
102.42, 104.01, 108.10, 108.78, 112.75, 114.71, 116.87, 121.08,
127.16, 127.74, 127.80, 128.02, 128.57, 132.23, 146.40, 154.59,
161.79, 162.00. MS [M+]: 219.0. IR: 1684 cm21 (CLOstr), 3226
cm21(N–H, str). EA: (calc.) C, 65.74, H, 5.98, N, 6.39; (found) C,
65.97, H, 5.99, N. 6.26.
Product precipitates as a pale yellow solid, 72% yield (1.865 g).
No purification. The product should be stored under N2
because it turns brown in air within 2 h. The decomposition is
limited to the exposed surfaces. 1H NMR (CDCl3, d (ppm)): 1.42
(6 H, t, J = 8.0 Hz), 4.38 (4 H, q, J = 8.0 Hz), 6.90 (2 H, s), 7.83 (4
H, s). 13C NMR: 14.21, 62.39, 124.13, 126.35, 130.53, 133.99,
163.36. 3JC,H: 4.9 Hz. HRMS: (calc.) 356.1233, (found) 356.1240.
IR: 1703 cm21 (CLOstr), 2102 cm21(N3, str). mp decomposes at
129.7 uC.
(Z)-ethyl 2-azido-3-(furan-2-yl)acrylate (2j)
Ethyl 5-chloro-1H-indole-2-carboxylate (3d–5)32
Crude product is a dark brown oil, 90% yield. Purified by silica
plug (ethyl acetate : hexanes, 10 : 90) and recrystallization in
ethanol : water, 83% yield (1.254 g). 1H NMR (CDCl3, d (ppm)):
1.35 (3 H, t, J = 8.0 Hz), 4.31 (2 H, q, J = 8.0 Hz), 6.50 (1 H, m),
6.84 (1 H, m), 7.08 (1 H, d, J = 4.0 Hz), 7.46 (1 H, m). 13C NMR:
14.02, 62.01, 112.44, 113.23, 115.02, 122.73, 143.71, 149.39,
162.96. 3JC,H: 4.6 Hz. HRMS: (calc) 207.0644, (found) 207.0643.
IR: 1703 cm21 (CLOstr), 2104 cm21(N3, str) mp 30.5 uC.
1
White crystals, 39% yield (0.347 g). H NMR (CDCl3, d (ppm)):
1.42 (3H, t, J = 7.12 Hz), 4.41 (2H, q, J = 7.13 Hz), 7.15 (1H, d, J =
2.09), 7.28 (1H, dd, J = 8.75), 7.35 (1H, m, J = 8.79), 7.66 (1H, d,
J = 1.92) 9.18 (1H, s). 13C NMR: 14.35, 61.27, 107.92, 112.97,
121.71, 125.79, 126.40, 128.35, 128.70, 135.06, 161.78. HRMS:
(calc) 223.0400, (found) 223.0393. EA: (calc.) C, 59.07; H, 4.51;
N, 6.26; Cl, 15.85 (found) C, 58.99; H, 4.67; N, 6.18; Cl, 15.58.
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(2H, s), 7.31 (2H, s), 11.58 (2H, s). 13C NMR: 14.33, 60.40,
109.64, 115.65, 124.12, 124.14, 124.81, 161.09. HRMS: (calc.)
300.1110, (found) 300.1101.
Ethyl 7-chloro-1H-indole-2-carboxylate (3d–7)
1
White crystals, 33% yield (0.293 g). H NMR (CDCl3, d (ppm)):
1.43 (3H, t, J = 7.13 Hz), 4.44 (2H, q, J = 7.13 Hz), 7.07 (1H, t, J =
8.03 Hz), 7.25 (1H, d, J = 2.22 Hz), 7.31 (1H, d, J = 7.59 Hz), 7.58
(1H, d, J = 8.05 Hz) 9.23 (1H, s). 13C NMR: 14.31, 61.23, 109.22,
117.15, 121.05, 121.35, 124.32, 128.21, 128.64, 134.18, 161.49.
HRMS: (calc) 223.0400, (found) 223.0400.
Ethyl 4H-furo[3,2-b]pyrrole-5-carboxylate (3j)
Brown needle-like crystals, 80% yield (0.692 g). 1H NMR
(CDCl3, d (ppm)): 1.37 (3H, t, J = 7.12 Hz), 4.35 (2H, q, J = 7.13
Hz), 6.45 (1H, dd, J = 2.21 Hz), 6.80 (1H, m, J = 1.69), 7.51 (1H,
d, J = 2.22 Hz), 8.84 (1H, s). 13C NMR: 14.45, 60.48, 96.81,
98.88, 124.20, 128.66, 147.97, 148.56, 162.16. HRMS: (calc)
179.0582, (found) 179.0580. EA: (calc.) C, 60.33; H, 5.06; N,
7.82; (found) C, 60.31; H, 5.07; N, 7.81.
Ethyl 5-phenyl-1H-indole-2-carboxylate (3e–5)33
1
White crystals, 49% yield (0.443 g). H NMR (CDCl3, d (ppm)):
1.45 (3H, t, J = 7.14), 4.46 (2H, q, J = 7.14), 7.30 (1H, dd, J =
2.09), 7.35 (1H, dt, J = 7.37), 7.45 (4H, m), 7.60 (2H, dd, J =
8.61), 7.66 (2H, dd, J = 8.40), 7.91 (1H, s), 9.22 (1H, s). 13C NMR:
14.34, 61.01, 108.96, 121.27, 121.73, 124.95, 126.40, 127.71,
127.75, 127.93, 128.12, 129.23, 134.82, 138.32, 161.87. HRMS:
(calc) 265.1103, (found) 265.1009.
Notes and references
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3 A. V. Butin, S. K. Smirnov, T. A. Stroganova, W. Bender and
G. D. Krapivin, Tetrahedron, 2007, 63, 474–491.
4 C. E. Castro, E. J. Gaughan and D. C. Owsley, J. Org. Chem.,
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5 P. G. Gassman, T. J. Van Bergen, D. P. Gilbert and B.
W. Cue, J. Am. Chem. Soc., 1974, 96, 5495–5508.
6 H. K. Hemetsberger and D. Weidmann, Monatsh. Chem.,
1969, 100, 1599–1603.
7 H. K. Hemetsberger and D. und Weidmann, Monatsh.
Chem., 1970, 101, 161–165.
8 U. Hengartner, A. D. Batcho, J. F. Blount, W. Leimgruber,
M. E. Larscheid and J. W. Scott, J. Org. Chem., 1979, 44,
3748–3752.
9 W. J. Houlihan, Y. Uike and V. A. Parrino, J. Org. Chem.,
1981, 46, 4515–4517.
10 G. R. Humphrey and J. T. Kuethe, Chem. Rev., 2006, 106,
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11 D. Knittel, Synthesis, 1985, 186.
Ethyl 7-phenyl-1H-indole-2-carboxylate (3e–7)
1
White crystals, 25% yield (0.226 g). H NMR (CDCl3, d (ppm)):
1.42 (3H, t, J = 7.12), 4.40 (2H, q, J = 7.13), 7.27 (1H, m), 7.32
(1H, d, J = 2.15), 7.36 (1H, dd, J = 7.21, 1.13), 7.43 (1H, dt, J =
7.41), 7.55 (2H, t, J = 7.31), 7.65 (2H, m), 7.71 (1H, d, J = 8.00
Hz), 9.08 (1H, s). 13C NMR: 14.37, 61.10, 108.90, 112.13, 120.76,
125.33, 126.62, 127.27, 128.69, 134.27, 136.31, 141.80, 162.03.
MS (EI): 265 [M+]. EA: (calc.) C, 76.96; H, 5.70; N, 5.28; (found)
C, 77.03 H, 5.78; N, 5.19.
Ethyl 5-nitro-1H-indole-2-carboxylate and ethyl 7-nitro-
1H-indole-2-carboxylate (3f)34
Mixture of regioisomers 1.1 : 1, by 1H NMR of the N–H signals.
Yellow-white crystals, 62% yield (0.553 g). 1H NMR (acetone-d6,
d (ppm)): 1.37–1.42 (6H, 2-t), 4.38–4.44 (4H, 2-q), 7.39 (1H, t, J =
7.97 Hz), 7.44–7.46 (2H, m), 7.71 (1H, d, J = 9.13 Hz), 8.17 (1H,
dd, J = 9.13 Hz, J = 2.27 Hz), 8.23 (1H, d, J = 7.88 Hz), 8.32 (1H,
d, J = 8.03 Hz), 8.73 (1H, d, J = 2.23 Hz), 10.74 (1H, s), 11.58
(1H, s). 13C NMR: 13.43, 13.65, 60.96, 61.14, 109.17, 109.84,
112.89, 119.40, 119.47, 120.24, 121.92, 128.71, 130.55, 130.86,
131.10, 131.17, 160.32. MS: 234 [M+].
12 K. Kondo, S. Morohoshi, M. Mitsuhashi and Y. Murakami,
Chem. Pharm. Bull., 1999, 47, 1227–1231.
13 Y. W. Murakami, et al., Chem. Pharm. Bull., 1997, 45,
1739–1744.
Ethyl 6-methyl-1H-indole-2-carboxylate (3g)
1
White crystals, 80% yield (0.703 g). H NMR (CDCl3, d (ppm)):
1.42 (3H, t, J = 7.14 Hz), 2.47 (3H, s), 4.41 (2H, q, J = 7.15 Hz),
6.99 (1H, d, J = 8.22 Hz), 7.20 (2H, m, J = 6.69 Hz), 7.57 (1H, d, J
= 8.21 Hz), 8.88 (1H, s). 13C NMR: 14.30, 21.88, 60.84, 108.55,
111.54, 122.01, 122.74, 125.24, 126.76, 135.33, 137.47, 162.23.
MS: 203.1 [M+].
14 A. G. O’Brien, F. Levesque and P. H. Seeberger, Chem.
Commun., 2011, 47, 2688–2690.
15 V. S. Velezheva, A. I. Sokolov, A. G. Kornienko, K.
A. Lyssenko, Y. V. Nelyubina, I. A. Godovikov, A.
S. Peregudov and A. F. Mironov, Tetrahedron Lett., 2008,
49, 7106–7109.
Diethyl 1,5-dihydropyrrolo[2,3-f]indole-2,6-dicarboxylate (3h)26
16 F. Lehmann, M. Holm and S. Laufer, Tetrahedron Lett.,
2009, 50, 1708–1709.
White/beige crystals, 64% yield (0.590 g). 1H NMR (DMSO, d
(ppm)): 1.32–1.36 (6H, 2-q), 4.30–4.36 (4H, 2-t), 7.19–7.21 (2H,
m), 7.47 (1H, d, J = 8.84 Hz), 7.60 (1H, d, J = 1.27 Hz), 12.09
(1H, s), 12.29 (1H, s). 13C NMR: 14.34, 14.40, 59.99, 60.18,
106.48, 107.88, 110.00, 113.29, 119.88, 120.00, 123.98, 124.87,
131.35, 136.20, 161.16, 161.30. HRMS: (calc.) 300.1110, (found)
300.1118.
17 The Hemetsberger indolization can be performed at room
temperature with a rhodium catalyst (also see ref. 18).
18 B. J. Stokes, H. Dong, B. E. Leslie, A. L. Pumphrey and T.
G. Driver, J. Am. Chem. Soc., 2007, 129, 7500–7501.
19 Unpublished results, American Pacific Fine Chemicals Co.
20 Alicyclic aldehydes, cyclohexanecarboxaldehyde and cyclo-
pentanecarboxaldehyde did not react under these condi-
tions.
Diethyl 1,6-dihydropyrrolo[2,3-e]indole-2,7-dicarboxylate (3i)
1
Yellow/beige crystals, 70% yield (0.645 g). H NMR (DMSO, d
21 The lower yields observed for this substrate are in
agreement with Knittel’s comment that the meta-nitroben-
(ppm)): 1.34 (6H, t, J = 6.98 Hz), 4.34 (4H, q, J = 6.93 Hz), 7.23
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zaldehyde reacts poorly with ethoxide/ethanol and t-but-
oxide/t-butanol solutions.
synthesized a pyrrolindole similar to 3i9 via the
Hemetsberger indolization by having two methoxy sub-
stituents between the para-azidoacrylates in 2i.
29 J. Hou, Z. Li, Q. Fang, C. Feng, H. Zhang, W. Guo, H. Wang,
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rhodium catalyst. In these reactions quantitative yields are
obtained at temperatures ranging from 25 uC to 60 uC (also
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24 D. Curiel, A. Espinosa, M. Mas-Montoya, G. Sanchez,
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28 Pyrroloindoles with these core structures have been
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