Access to Fluorazones by Intramolecular Dehydrative Cyclization of Aromatic Tertiary Amides: A Synthetic and Mechanistic Study

Article abstract of DOI:10.1021/acs.joc.7b03176

An efficient synthesis has been developed for the preparation of 9H-pyrrolo[1,2-a]indol-9-ones (fluorazones) from readily available anthranilic acid derivatives via a one-pot amide- and pyrrole-formation step, followed by an intramolecular cyclodehydratio

Full text of DOI:10.1021/acs.joc.7b03176

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Article
Access to Fluorazones by Intramolecular Dehydrative Cyclization
of Aromatic Tertiary Amides: A Synthetic and Mechanistic Study
Béla Mátravölgyi, Tamás Hergert, Erika Bálint, Péter Bagi, and Ferenc Faigl
J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 22 Jan 2018
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Access to Fluorazones by Intramolecular Dehydrative Cyclization of
Aromatic Tertiary Amides: A Synthetic and Mechanistic Study
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Béla Mátravölgyi,* Tamás Hergert, Erika Bálint, Péter Bagi and Ferenc Faigl
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Department of Organic Chemistry and Technology, Budapest University of Technology and
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Economics, H 1111 Budapest, Budafoki út 8., Hungary
*Eꢀmail: bmatravolgyi@mail.bme.hu
ABSTRACT: An efficient synthesis has been developed for the preparation of
9Hꢀpyrrolo[1,2ꢀa]indolꢀ9ꢀones (fluorazones) from readily available anthranilic acid
derivatives via a oneꢀpot amideꢀ and pyrroleꢀformation step, followed by an intramolecular
cyclodehydration. The cyclodehydration process is mediated by the activation of aromatic
tertiary amides by triflic anhydride (Tf2O). Comparison of various benzoꢀsubstituents is
shown in order to demonstrate the high functional group tolerance of this transformation. In
addition, study of the reaction mechanism is also presented to unfold the exact role of the
applied base additive. Herein, as a first example, we report our findings that Tf2Oꢀmediated
amide activation is obstructed by the easy protonation of amides by the formed triflic acid
during the activation step. Additionally, it has been also proven that the base additive is not
involved in the transformation of Oꢀtriflyliminium triflates into reactive species (e.g. nitrilium
triflates), it is only responsible to neutralize the superacid to avoid the protonation of both the
secondary or tertiary amides.
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INTRODUCTION
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In recent years, many research papers have been published describing the versatile
methodology for the synthesis of 9Hꢀpyrrolo[1,2ꢀa]indolꢀ9ꢀones (fluorazones). Fluorazones
and their analogues are still important targets for researchers due to their promising biological
and pharmaceutical activities1 as well as optical and electronic properties.2 The fused tricyclic
unit can be found in a wide range of biologically important compounds representing
psychostimulant activity1d and cytotoxic properties.3 Moreover, fluorazone serves as a
precursor for 9Hꢀpyrrolo[1,2ꢀa]indole, the basic skeleton of cytostatic mytomycin
derivatives.4 In addition, our recent progress on developing novel chromophores demonstrated
the promising application of dyes having fluorazone linker as photosensitizers for solar cells.5
Among the many methods developed for the synthesis of fluorazones, intramolecular ring
closure reaction serves as classical technique.6 Due to the growing interest, several new
synthetic ways have been published in the last few years.7 Direct cyclization strategies
represent new approaches,8 however, the scope of these methods is somewhat limited. Both
the direct double metalation of substituted 1ꢀphenylpyrroles followed by reaction with
N,Nꢀdimethylcarbamate carbonylating agent,8a and the Pdꢀcatalyzed cyclocarbonilation8c
restricted to the synthesis of specific regioisomers of substituted fluorazones, due to the
directing effects of functional groups.9 In addition, the preparation of the corresponding
bromo or iodo derivatives applicable in crossꢀcoupling reactions5 is infeasible via these
organometallic ways, as halogenꢀmetal exchange can occur during these transformations.8b,10
On the other hand, classical type ring closure requires the derivatives of 2ꢀ(pyrrolꢀ1ꢀ
yl)benzoic acid (acid,6a acid chloride,6b aldehyde,7a benzyl alcohol,7c tertiary amide11) which
could only be obtained in multiꢀstep processes from anthranilic acids. Moreover, due to the
sensitivity of the pyrrole moiety, the generally applied acidic or harsh reaction conditions for
cyclizations (e.g. polyphosphoric acid6a, chlorinating agent as PCl5,6b,11 strong Lewis acid6b or
high temperature7a) usually lead to uncontrolled polymerization and decomposition, resulting
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low overall yields. Besides these methods, the oneꢀpot sequential pyrrolationꢀcyclization of
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anthranilic acids catalyzed by 4ꢀchloropyridine hydrochloride and the intramolecular
acylation of 2ꢀ(pyrrolꢀ1ꢀyl)benzoic acids in the presence of bis(trichloromethyl) carbonate
offer simple procedures for the synthesis of fluorazones, however, we found these methods to
have poor reproducibility.12 Despite these facts, anthranilic acids have exceptional synthetic
potential as a wide range of substituted derivatives are easily accessible. Therefore, the
development of valuable alternative methods under mild reaction conditions would extend the
scope of the known synthetic routes and provide an efficient access to a diverse array of
fluorazones.
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Amides are generally considered to be one of the least reactive carboxylic acid
derivatives, thus their utilization for the synthesis of aromatic ketones by acylation13 is less
widespread compared to other FriedelꢀCraftsꢀtype reagents.14 Although, the chemoselective
activation of amides in the presence of triflic anhydride (Tf2O) has proven to be a powerful
strategy in the past few years and this approach found a broad range of applications in
synthetic organic chemistry.15 Very recently, Huang and coꢀworkers published the
chemoselective synthesis of aromatic ketimines by the intermolecular coupling of arenes with
secondary amides, where a subsequent acidic hydrolysis afforded the desired ketones
(Scheme 1/a).16 They found that Tf2Oꢀpromoted nitrilium ion generation from secondary
amides is a valuable method for the dehydrative coupling of electronꢀrich arenes such as
anisole, N,Nꢀdimethylaniline, furan, pyrrole or indole derivatives. It is worth mentioning that
during the investigation of Nꢀmethylpyrrole a phthalic acid derived diamide was also involved
to test chemoselectivtiy. Interestingly, the reaction showed preference for the secondary
amido over the tertiary amido group affording the corresponding ketimine in excellent yield.
This phenomenon is attributed to the fact that only a nitrilium intermediate formed from a
secondary amide could serve as active electrophile during Tf2Oꢀactivation.17
Our previous work with fluorazoneꢀbased conjugated systems and the recent
developments on the field of amide activation inspired us to pursue a complementary strategy
towards these heterocycles.5 We aimed to develop operationally simple conditions that can be
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used to introduce a wide variety of benzoꢀsubstituted patterns within the 9Hꢀpyrrolo[1,2ꢀ
a]indoles scaffold. In this paper, the convenient synthesis of fluorazones via a Tf2Oꢀmediated
intramolecular dehydrative cyclization is described. In addition, a simple oneꢀpot synthesis of
the key tertiary amide intermediates (3) from readily available anthranilic acids, and a study
on the determination of the exact role of the base additive as a “missing piece” of the
mechanism of Tf2Oꢀmediated amide activation are also presented.
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RESULTS AND DISCUSSION
In order, to implement a novel intramolecular cyclization for fluorazone from amide
derivatives, initially we investigated the synthesis of 3 precursors. We envisioned a simple
oneꢀpot strategy, where the amide group and the pyrrole moiety are formed in consecutive
reactions from the functional groups of anthranilic acid. CꢀC bond formation by direct CꢀH
functionalization, based on amide activation with Tf2O has never been published for aromatic
tertiary amides. However, considering the cyclization strategy of Rault and coꢀworkers, N,Nꢀ
disubstituted carboxamides are also potential functional groups for an intramolecular ring
closure reaction (Scheme 1/b).3 Additionally, the final hydrolytic step has decisive synthetic
aspects, which depends on the amide precursor. Subsequent acidic hydrolysis of fused
ketimine heterocycles requires elevated temperature, which can lead to product degradation.7a
On the other hand, the hydrolysis of iminium salts formed by the reaction of tertiary amides
can be achieved under mild basic conditions to afford ketones.3 Therefore, we opted for
merging the advantageous properties of the Tf2Oꢀactivation technique and the application of
tertiary amides as electrophilic reaction partners (Scheme 1/c).
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Scheme 1. Methods for the Synthesis of
of Amides
α-Keto-pyrroles via Dehydrative C-C Coupling
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(a) Tf2O-mediated activation of secondry amide
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(b) POCl3-mediated activation of tertiary amide
(c) This work: Tf2O-mediated activation of tertiary amide
On the basis of our previous experience with 1ꢀphenylpyrroles,10,18 we optimized the
overall transformation of the anthranilic acid derivatives (1) towards 1ꢀarylpyrrole
carboxamides (3, Scheme 2). Amide formation was promoted by 1,1'ꢀcarbonyldiimidazole
(CDI) followed by the addition of pyrrolidine. The subsequent treatment of the reaction
mixture with trifluoroacetic acid (TFA) using ClausonꢀKaas synthesis with 2,5ꢀ
dimethoxytetrahydrofurane afforded the desired 1ꢀarylpyrrole derivative 3a in excellent 85%
yield. Tetrahydrofuran (THF) was found to be suitable solvent for both transformations to
realize oneꢀpot synthesis.
To our delight, applying this oneꢀpot methodology a series of anthranilic acid derivatives
bearing either electronꢀdonating groups (Me, OMe, Scheme 2, 3b-j) or electronꢀwithdrawing
groups (Cl, Br, I and NO2, Scheme 2, 3k-q) reacted smoothly to give the corresponding
1ꢀarylpyrrole carboxamides 3b-q in good to excellent yields (63−99%).
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3ꢀAminoꢀ2ꢀnaphthoic acid (1r) reacted similarly affording the corresponding 3r in 95%
yield. Interestingly, in the cases of 6ꢀsubstituted 2ꢀaminobenzoic acids (1e, 1i, 1o) the amide
formations via CDI activation showed the presence of a significant steric hindrance. Due to
this phenomenon the activationꢀamide formation process gave satisfactory results only at high
temperature. Consequently, the overall yields were slightly lower in these cases and
compounds 3e, 3i and 3o were obtained in yields of 65%, 75% and 73%, respectively
(Scheme 2).
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Scheme 2. One-pot Synthesis of 1-Arylpyrrole Derived Tertiary Amides
Recently, we have successfully applied Rault’s method for the cyclization of 3n and 3p to
prepare haloꢀsubstituted fluorazones. However, the corresponding 7ꢀbromoꢀ (6n) and 7ꢀiodo
(6p) products were obtained in good 81% and 78% yields,5 respectively, showing that the
POCl3ꢀpromoted amideꢀactivation suffers from disadvantages. On the one hand, the activator
is used practically as the solvent of the reaction (25 equiv of POCl3), which eventuate a
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difficult workꢀup. On the other hand, the slow cyclization takes place only by means of
heating (80 °C, 8h). Moreover, due to these reaction conditions and the large excess of the
strong dehydrative agent, merely electronꢀwithdrawing group stabilized arylpyrroles give
good results (e.g. 6n and 6p), and in other cases significant acidic degradation can occur. An
example of such event is the unsubstituted 3a carboxamide, which was found to give
fluorazone (6a) only in yield of 58%. In addition, the procedure was assayed for reducing the
amount of POCl3 used. Surprisingly, a more intense degradation took place in solvents such
as CH2Cl2 or toluene (Table 1, entries 2 and 3), therefore fluorazone (6a) was isolated in only
yields of 15% and 34%, respectively.
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Table 1. Optimization of the Conditions of the Tf2O-mediated Ring Closure Reactiona
Entry Activator (equiv)
Additive (equiv)
Solvent
Yield of 6a (%)g
1b
2c
POCl3 (25)
POCl3 (2.0)
POCl3 (2.0)
Tf2O (1.1)
Tf2O (1.5)
Tf2O (2.0)
Tf2O (1.1)
Tf2O (1.1)
Tf2O (1.1)
Tf2O (1.1)
Tf2O (1.1)
Tf2O (1.1)
Tf2O (1.1)
–
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–
CH2Cl2
toluene
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
–
3b
34
–
4d
64 (29)h
62 (26)h
68 (12)h
79 (14)h
82 (7)h
91
–
5d
–
6d
–
7e
–
8d,f
9d,f
10d,f
11d,i
12d,i
13d,f
2ꢀFꢀPy (0.6)
2ꢀFꢀPy (1.2)
Py (1.2)
Py (1.2) j
2-F-Py (1.2)
TfOH (4.0)
42 (38)h
88
93
8 (83)h
aReaction conditions: 0.5 mmol 3a, 1.2 mL solvent, 5a was not isolated; in case of POCl3: EWG =
Cl, X = PO2Cl2; in case of Tf2O: EWG, X = OTf. b8h (80 °C). c8h (40 °C). d30 min (5 min, –78 °C;
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25 min –78 °C to rt). 45 h (5 min, –78 °C than rt). Protocol A: additive was added before Tf2O
at –78 °C. gIsolated yields. hRecovered starting material. iProtocol B: additive was added after Tf2O
in 5 min at –78 °C. jPyridine (Py) was added in consecutive 0.3 equiv portions.
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After these discouraging results, we turned our attention to examine the feasibility of an
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efficient Tf2Oꢀmediated cyclization. In the first attempt, 3a amide was treated with 1.1 equiv
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of Tf2O in CH2Cl2 at 78 °C and after 5 min the mixture was allowed to warm to room
temperature. We were pleased to determine that the reaction proceeded smoothly after 30 min,
and with successive workup with aqueous NaOH and purification, fluorazone (6a) was
isolated in yield of 64% (Table 1, entry 4). It is important to mention, that 29% of the starting
material 3a was also recovered. Increasing the amount of the activator to 1.5 or 2.0 equiv was
nearly ineffective to accomplish complete conversion of 3a, and fluorazone (6a) was obtained
in the same yields, along with the amide precursor (entries 5 and 6). The effect of prolonged
reaction time was also studied, however, the result was not remarkably better even after 45 h
(entry 7). The transformation afforded the desired product (6a) in an increased yield of 79%,
but residue of the starting material was still detectable (14% of 3a).
As it was exemplified in different Tf2Oꢀmediated electrophilic activations of amides, the
addition of nonꢀnucleophilic basic additives was found to be crucial to achieve a considerable
level of efficiency.17,19 Substituted pyridines, especially 2ꢀfluoropyridine (2ꢀFꢀPy) was found
to be generally eligible for this purpose.19ꢀ20 On the basis of these findings, pretreatment of the
solution of carboxamide 3a with 2ꢀFꢀPy followed by the addition of Tf2O proved to be highly
effective. Moreover, the complete activation of the amide 3a was achieved using a slight
excess of the base (1.2 equiv). Thus, this protocol resulted 6a in excellent 91% yield (Table 1,
entry 9).
Although, unsubstituted pyridine (Py) would be the choice regarding to cost efficiency,
2ꢀfluoropyridine is a more preferred base in many publications,17,19,21 as it has a decreased
nucleophilic character.22 The low efficiency of pyridine could be partially attributed to the
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formation of Nꢀ(trifluoromethylsulfonyl)ꢀpyridinium triflate, which is a side product from the
reaction of pyridine and Tf2O.19,23 Searching for a better understanding of this phenomenon,
we decided to test pyridine as a base in our cyclization aiming to compare two approaches:
namely the cases when the base is added before or after the activator. Pretreatment of the
solution of 3a with 1.2 equiv of pyridine followed by subsequent addition of 1.1 equiv of
Tf2O resulted in partial conversion only, therefore fluorazone 6a was isolated in low 42%
yield (Table 1, entry 10, Protocol A). Interestingly, in the case of the reverse order of reagent
addition, unexpected result was observed. To minimize the undesired formation of
Nꢀ(trifluoromethylsulfonyl)ꢀpyridinium triflate, pyridine was added in consecutive 0.3 equiv
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portions at 78 °C after the activation of the amide with Tf2O (Table 1, entry 11). To our
surprise, this strategy proved to be highly effective leading to the complete conversion of 3a,
thus fluorazone was obtained in respectable 88% yield. Inspired by this result, we surveyed
the ring closure of 3a using the reversal addition protocol with 2ꢀFꢀPy. In this case, the
difference was not as significant as when pyridine was used, but by means of this approach,
fluorazone was isolated in a slightly more increased yield (93%, Table 1, entry 12). Based on
these results it can be concluded, that the order of the reagent addition could have a crucial
role on the outcome of the activation process. Moreover, we were able to demonstrate, that
pyridine could also serve as efficient base additive for Tf2Oꢀmediated electrophilic activation
of amides employing ‘postꢀtreatment’ strategy.
As a proof of concept, after the efficient reaction conditions for both the amidoꢀpyrrole
derivatization and intramolecular cyclization reactions were established, the substrate scope
was studied (Scheme 3). This process was found to be effective in the presence of various
carboxamides 3, tolerating different functional groups on the benzene moiety. Thus the
corresponding products (6) were obtained uniformly in high yields (82–97%). Using this
procedure, derivatives bearing electronꢀdonating groups (6bꢀi) were also efficiently cyclized
into ketiminium salts. Moreover, the highly electron rich dimethoxyꢀsubstituted 1ꢀarylpyrrole
carboxamide (3j) also reacted smoothly, providing 6j in 90% yield after hydrolysis
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(Scheme 3). It is noteworthy, that these species (6fꢀj) may not be prepared using POCl3ꢀ
mediated amide activation, which was found to be detrimental for 6a (Table 1, entries 1ꢀ3).
Scheme 3. Synthesis of Fluorazones by Tf2O-Mediated Activation of Tertiary Amides
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The mechanism of Tf2Oꢀpromoted amide activation has been studied by several research
groups to explore the nature of the transformation.17,19,24 It has been revealed that nitrilium ion
9, formed via an Oꢀtriflyliminium triflate intermediate 8, serves as the active electrophile for
the reaction of secondary amides (7) with various substrates (Scheme 4). It is important to
note, that the studies published generally describe the fact that iminium triflates 8 can be
obtained in complete conversion by a simple Tf2Oꢀactivation. Additionally, it is also
described in various publications, that the addition of an equivalent base is necessary to
achieve a considerable level of efficiency. In spite of these findings, the exact role of the base
additive still remained unclear.
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Scheme 4. The Generally Proposed Mechanism of Tf2O-Mediated Activation of
Secondary Amides
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Earlier attempts to describe the mechanism mainly focused on studying the activation
step in the presence of pyridine. Charette and Gregon proposed that
Nꢀ(trifluoromethylsulfonyl)ꢀpyridinium triflate – formed by the reaction of triflic anhydride
and pyridine – serves as the activating reagent in the initial stage of the reaction.24 In contrast,
later findings by others suggested, that this process could inhibit the amide activation
significantly. In order to eliminate this disadvantageous effect of pyridine nonꢀnucleophilic
base additives were introduced to this field by Medley and Movassaghi.21,25 Since their
pioneering work 2ꢀFꢀPy become a generally used reagent for the accomplishment of highly
efficient electrophilic activations of amides. They observed, that optimal conditions require a
balance between the need for a base additive to promote electrophilic activation of the amide
substrate and avoidance of nucleophilic inhibition of the transformation. However, the
specific role of the base during the amide activation step was not revealed. Very recently,
Huang and coꢀwokers published an innovative study on the investigation of the exsistance of
the presumed highly electrophilic nitrilium ion intermediate (9).17 Its formation was proven by
detailed NMR experiments due to the characteristic triplet resonance and the coupling
constant of nitrilium moiety in 13C NMR spectrum. Additionally, they examined the baseꢀfree
amide activation, which showed, that the absence of base leads to partial conversion of the
first formed Oꢀtriflyliminium triflate (8) into nitrilium ion (9) in a ratio of 37:63. They found,
that the less reactive iminium triflate (8) was an unreactive species in the addition reaction to
styrene, and it hydrolysed upon workꢀup to regenerate the initial amide in a considerable yield
(31%). In addition, using an equivalent amount of 2ꢀFꢀPy a complete conversion of
Oꢀtriflyliminium triflate (8) into nitrilium ion (9) was determined by NMR.
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Reviewing the optimization of our Tf2Oꢀmediated ring closure reaction a very similar
tendency can be observed (Table 1). In the case of substrate 3a, complete transformation
could be achieved only by the addition of 2ꢀFꢀPy (entry 9), and absence of base resulted in the
recovery of a significant amount of starting material (entry 4). However, the formation of
nitrilium ion (9) from tertiary amide 3a could not take place, the results obtained suggest, that
the transformation of amide 3a into ketiminium salt 5a undergoes the same mechanistical
steps. These experimental findings and the NMR study published by Huang and coꢀworkers17
inspired us to take a closer inspection of the reaction mechanism, focusing on founding
evidence for the privileged role of the base additive.
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Although, the effects of various bases on this transformation are wellꢀstudied, the effects
of acids have never been investigated. Considering the fact, that baseꢀfree ring closures of 3a
resulted on average of 65% conversion (Table 1, entries 4–6), we envisioned that the
concentration of the TfOH formed has the determinative role in the prevention of the ongoing
reaction. To prove our assumption, the ring closure was implemented in the presence of a
large excess of TfOH (4 equiv). To our delight, TfOH significantly inhibited the
transformation, thus the initial amide was recovered in 83% yield (Table 1, entry 13). This
novel approach clearly suggested, that the Tf2Oꢀactivation of amide is inhibited by the
increasing concentration of acid during the progress of the reaction. To provide experimental
proofs for this suspicion a series of NMR experiments were carried out.
First, pyrrolidine derived benzamide (11), as a comparative model to 3a was assayed for
preliminary NMR studies.26 Both, the effects of TfOH and Tf2O were investigated
(Scheme 5). The initial experiment was carried out by addition of an excess of acid (4 equiv
TfOH) to 11 in CD2Cl2. However, decisive spectral changes were not observed, the slight
upfield shift of proton signals indicated that TfOH interacts with amide 11. In addition, the
shift of the carbonyl carbon signal to higher ppm (from 169.5 to 170.5 ppm) also suggests that
the lower electron density on the carbonyl carbon can be attributed to the protonation of
amide 11 by TfOH (12). However, superacids are known to be able to protonate amides,13 this
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phenomenon has never been investigated in the field of Tf2Oꢀmediated amide activation.
Generally, amide bonds tend to prefer Oꢀprotonation.27 In order to found further evidence for
the existence of 12, the reaction of 11 and Tf2O (1.1 equiv) in the presence of preliminary
added TfOH (0.25 equiv) was also studied. To our delight, the protonated amount of 11 (25%)
was unreactive towards Tf2O. Additionally, along with Oꢀtriflyliminium derivative 13 (63%),
the formation of a dicationic ether salt 14 from 12% of the starting amide was also observed,
which presumably arise from the attack of amide 11 on the Oꢀtriflyliminium triflate 13
(Scheme 5).24,26,28
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12
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Scheme 5. Study of the Effect of Tf2O/TfOH on the Activation of Pyrrolidine Derived
Benzamide (11) by NMR
Next, tertiary amide 3a was chosen for the mechanistic studies and baseꢀfree amide activation
with Tf2O was first investigated (Figure 1/a). After the addition of Tf2O into the solution of
amide 3a, the formation of iminium salt 5a with 65% conversion along with 35% of unreacted
arylpyrrole derivative were observed (Figure 1/a, 1H NMR). This result is in good accordance
with that obtained in bench reaction, which afforded fluorazone 6a in 64% yield (Table 1,
entry 4). The existence of 5a iminium salt was manifested by the characteristic chemical shift
of the iminium carbon which appeared at δC = 154.9 ppm (Figure 1/a, 13C NMR). Moreover,
the 13C NMR spectrum of the reaction mixture also showed the first decisive evidence for the
nature of the unreacted compound. Although, remains of the easily formed Oꢀtriflyliminium
triflate 4a would have been expected based on literature,17,24 the chemical shift of the
corresponding carbon atom of the unknown species indicated a type of carbonyl compound
(Figure 1/a, δC = 169.5 ppm). According to the preliminary NMR study of benzamide 11, it
was assumed that this unknown species is the protonated 3a.
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2
Figure 1. NMR Investigation of the Mechanism of the Tf2O-mediated cyclodehydration
3
4
of Tertiary Amide 3a
5
6
7
8
could not be
detected by NMR
e"
e
h"
e'
f"
OTf
a"
g'
OH
f'
f
Tf2O
b"
c"
N
N
N
O
N
OTf
(1.1 equiv)
a)
N
+
a'
a
CD2Cl2
d"
TfO
5a (65%)
N
N
N
b'
b
9
d
d'
c'
c
TfO
4a
10
11
12
13
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60
.
3a TfOH (35%)
3a
.
In order to prove the formation of 3a TfOH, the amide 3a was treated with 1.1 equiv
triflic acid in a separate experiment. Similarly, to the case of benzamide 11 (Scheme 5), the
spectra obtained resulted only in a slight shifts of signals in both 1H and 13C NMR (1H NMR,
Figure 1/b) compared to the spectra of starting material 3a. However, those spectral changes
were not pivotal at first sight, the individual signals of spectrum Figure 1/b were exactly the
same as the signals of the unknown species (Figure 1/a, 1H NMR signals with green letters).26
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As a consequence of these findings, we concluded that during the Tf2Oꢀmediated amide
activation the triflic acid formed can easily protonate the starting amide. Thus it loses its
nucleophilic character towards the anhydride and remains unreacted in the mixture. Therefore,
the role of the base additive (e.g. 2ꢀFꢀPy) could be attributed to its protective effect against
protonation of the amide, via the neutralization of TfOH, which is produced in an equivalent
amount during the transformation (Scheme 6). It is noteworthy, that the formation of
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Oꢀtriflyliminium triflate 4a could not be detected by NMR experiment (Figure 1/a).
Presumably, due to its high reactivity, it transformed instantaneously into iminium salt 5a.
Scheme 6. Role of the Base Additive in the Activation Process of Amide 3a
In order to provide additional evidence for the above described mechanism, finally a
secondary amide was involved in the same detailed NMR experiments as in the case of 3a
(Scheme 7). 2,6ꢀXylidene derived phenylpropanoic amide 15, a model recently investigated
by Huang and coꢀworkers17 was chosen to identify the protonation process and add a
complementary study towards this transformation. Recently, they have shown by NMR
investigations that the complete activation of 15 by Tf2O can be achieved via the addition of
equivalent amount of 2ꢀFꢀPy.17 Our results obtained from the investigation of the effects of
Tf2O/TfOH on 15 by NMR confirmed that secondary amides can also undergo protonation by
the formed superacid.26 Moreover, we have found, that – contrary to previous suspicion17 –the
formation
Oꢀtriflyliminium derivative 16 could not be observed in this case neither, similarly
to the case of tertiary amide 3a (Figure 1).26 Due to its high instability, species 16
immediately converts into nitrilium ion 17 and triflic acid. The results obtained also
confirmed that the partial conversion of amide 15 (49%) into nitrilium triflate 17 in a baseꢀ
.
free method is attributed to the protonation of the secondary amide moiety (15 TfOH, 51%,
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Scheme 7).26 Thus, according to these findings it can be conclude, that the base is not
1
2
3
4
5
6
involved in the transformation of
responsible to neutralize the acid.
Oꢀtriflyliminium derivative 16 into nitrilium triflate 17, only
7
8
9
Scheme 7. Plausible Mechanism of the Tf2O-Mediated Activation of Secondary Amides
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11
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CONCLUSION
In summary, we have successfully developed a mild intramolecular cyclodehydration process
through Tf2Oꢀmediated activation of aromatic tertiary amides. The methodology was applied
for the synthesis of a wide range of fluorazones. Comparison of a series of benzoꢀsubstituted
patterns demonstrated the high functional group tolerance of the transformation. In addition,
we have shown evidence for the exact role of the base additive as a ‘missing piece’ of the
reaction mechanism of Tf2Oꢀmediated activation of amides. Detailed NMR studies have
revealed, that the base additive is not involved to promote the transformation of
Oꢀtriflyliminium triflates into reactive species (e.g. nitrilium triflate 13), but through
neutralization its role is to avoid the easy protonation of amides by the superacid (TfOH)
formed. We expect this mechanistic finding to be useful for the application of Tf2Oꢀactivation
strategies.
EXPERIMENTAL SECTION
General Information. All starting materials were purchased from commercial source and
were used without further purification. Anhydrous solvents were typically dried and stored
over 4 Å molecular sieves. All glassware was ovenꢀdried prior to use. The reactions were
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carried out in Schlenkꢀflasks under a dry nitrogen atmosphere. Reactions were monitored by
thinꢀlayer chromatography or LCꢀMS. TLC was carried out on Kieselgel 60 F254 aluminium
sheets, visualization of the product was made by exposing the plate to UV radiation or by
staining it with the aqueous solution of (NH4)6Mo7O24, Ce(SO4)2 and sulphuric acid.
Flash column chromatography was performed using gradient elution in normal (silica column;
hexane – ethyl acetate) or reversed phase modes (C18ꢀsilica column; water (0.1% NH4OAc) –
acetonitrile (0.1% NH4OAc + 8% water)) Sample loadings were performed in case of silica
flash column by drying the sample onto silica cartridge, in case of C18ꢀsilica flash column by
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1
direct liquid injections of the concentrate solutions of the samples in DMF. Routine H and
13C spectra were obtained on 300 or 500 MHz spectrometers. The chemical shifts (
reported in parts per million (ppm) and the coupling constants ( ) in Hz. Deuterated
δ) are
J
chloroform (CDCl3) with tetramethylsilane (TMS), methylene chlorideꢀd2 (CD2Cl2) and
dimethyl sulfoxideꢀd6 (DMSOꢀd6) were used as solvents, and signal positions were measured
relative to the signals of TMS or the residual peak of solvents (δTMS = 0 ppm,
1
δCH Cl = 5.32 ppm,
δ
DMSO = 2.50 ppm for H NMR and
δ
TMS = 0 ppm, δCH Cl = 53.8 ppm,
2
2
2
2
δ
DMSO = 39.5 ppm for 13C NMR). Infrared spectra are reported in reciprocal centimetres
(cm−1). Melting points were obtained on a melting point apparatus and are uncorrected. LCꢀ
MS was performed on an HPLC system using Gemini RP C18 column (150 × 4.6 mm, 3ꢀm,
256 nm, 40°C, 0.6 mL/min, gradient elution: water (0.1% NH4HCO3) – acetonitrile
(0.1% NH4HCO3 + 8% water) in ESI mode. High resolution mass spectra were performed by
79
35
positive electrospray ionization on a TOF analyzer. The Br (
M = 78.9183371) and the Cl
(M
= 34.9688527) isotopes were used for the calculation and data interpretation of these
halogen containing compounds.
Experimental procedures and characterisation data.
General procedure for the one-pot synthesis of tertiary amides 3a-r.
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To an extensively stirred solution of 2ꢀaminobenzoic acid derivative (1, 10.0 mmol) in dry
THF (6 mL) carbonyldiimidazole (CDI, 10.5 mmol, 1.70 g) was added in small portions at
room temperature. The obtained slurry mixture was stirred for a further 15 min, than
pyrrolidine (10.5 mmol, 0.86 mL) was added, resulted in a clear solution. After stirring for
15 min, trifluoroacetic acid (30.0 mmol, 2.30 mL) and 2,5ꢀdimethoxytetrahydrofuran
(12.0 mmol, 1.55 mL) were added and the mixture was kept at 80 °C for 30 min. After
cooling, ROꢀwater (30 mL, water purified by reverse osmosis technique) was added and
extracted with ethyl acetate (3 × 30 ml). The combined organic phases were treated with a
solution of NaHCO3 (2 M in water, 10 mL) for neutralization, and after phase separation the
organic layer was dried over sodium sulphate and concentrated on a rotary evaporator. The
concentrate solution of the crude product was filtered through a pad of silica, eluted
completely with a mixture of 30% hexane in ethyl acetate and concentrated in vacuo to yield
pure products (purities >96% (HPLC)). The steps of the oneꢀpot reactions were monitored by
TLC. Analytical pure compounds 3 were prepared by flash column chromatography on silica
using gradient elution of hexane and ethyl acetate.
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Characterisation data of tertiary amides 3a-r.
(2-(1
H-Pyrrol-1-yl)phenyl)(pyrrolidin-1-yl)methanone (3a).
Following the general procedure, the known amide 3a11 was obtained as an off white solid
–
(2.04 g, 85%). Rf = 0.38 (eluent: Hexane/EtOAc = 1/2); m.p. 53 54 °C; νmax (KBr) 2975,
–
1
1
–
2964, 1698, 1624, 1507, 1474, 1419, 1338 cm ; H NMR (300 MHz, CDCl3)
δ
7.54 7.41
= 2.2, 2.1 Hz, 2H),
= 13.2, 6.4 Hz, 2H), 1.59 (dt, = 13.2, 6.4
167.5, 137.2, 132.3, 130.3, 128.5, 126.75, 124.1,
–
(m, 2H), 7.40 7.30 (m, 2H), 6.97 (dd,
J = 2.2, 2,1 Hz, 2H), 6.28 (dd, J
3.48 (t,
J
= 6.9 Hz, 2H), 2.72 (br.s, 2H), 1.75 (dt,
J
J
Hz, 2H); 13C NMR (75 MHz, CDCl3)
δ
121.1 (2C), 110.2 (2C), 47.1, 45.4, 25.6, 24.3; HRMS (ESIꢀTOF) m/z: [M+H]+ Calcd for
C15H16N2O 241.1341; Found 241.1347.
(3-Methyl-2-(1
H
-pyrrol-1-yl)phenyl)(pyrrolidin-1-yl)methanone (3b).
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Following the general procedure 3b was obtained as a slightly yellow solid (2.21 g, 87%).
3
4
5
6
–
R
f = 0.60 (eluent: Hexane/EtOAc = 1/2); m.p. 61 63 °C;
ν
max (KBr) 3097, 2980, 2876, 1734,
–
δ 7.38 7.27 (m, 2H), 7.25
–
1
1616, 1518, 1435, 1375, 1229 cm ; 1H NMR (300 MHz, CDCl3)
7
8
–
7.15 (m, 1H), 6.75 (br.s, 2H), 6.25 (t,
J
= 1.8 Hz, 2H), 3.36 (t,
J
= 6.6 Hz, 2H), 3.01 (t,
J =
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
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31
32
33
34
35
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37
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6.4 Hz, 1H), 2.17 (s, 3H), 1.75 (dt,
13C NMR (75 MHz, CDCl3)
J = 12.9, 6.3 Hz, 2H), 1.67 (dt, J = 12.9, 6.3 Hz, 2H);
δ
167.4, 136.4, 136.4, 135.5, 131.5, 128.0, 124.6, 122.1 (2C),
108.8 (2C), 48.1, 45.1, 25.6, 24.4, 17.9; HRMS (ESIꢀTOF) m/z: [M+H]+ Calcd for C16H19N2O
255.1497; Found 255.1491.
(4-Methyl-2-(1
H-pyrrol-1-yl)phenyl)(pyrrolidin-1-yl)methanone (3c).
Following the general procedure 3c was obtained as a slightly yellow solid (1.96 g, 77%).
–
R
f = 0.58 (eluent: Hexane/EtOAc = 1/2); m.p. 110 111 °C;
ν
max (KBr) 3101, 3058, 2982,
2877, 1739, 1609, 1507, 1435, 1333, 1219 cm ; H NMR (300 MHz, CDCl3) 7.35 (d,
7.7 Hz, 1H), 7.17 (s, 1H), 7.15 (d, = 7.7 Hz, 1H), 6.95 (t, = 2.1 Hz, 2H), 6.27 (t, = 2.1
= 13.9, 6.6 Hz, 2H),
167.7, 140.5, 137.2, 129.4,
–
1
1
δ
J =
J
J
J
Hz, 2H), 3.47 (t,
J = 7.0 Hz, 2H), 2.71 (br.s, 2H), 2.41 (s, 3H), 1.74 (dt, J
1.58 (dt,
J
= 13.9, 6.6 Hz, 2H); 13C NMR (75 MHz, CDCl3)
δ
128.4, 127.5, 124.6, 121.0 (2C), 110.1 (2C), 47.1, 45.4, 25.6, 24.3, 21.3; HRMS (ESIꢀTOF)
m/z: [M+H]+ Calcd for C16H19N2O 255.1497; Found 255.1499.
(5-Methyl-2-(1
H-pyrrol-1-yl)phenyl)(pyrrolidin-1-yl)methanone (3d).
Following the general procedure 3d was obtained as a yellow solid (2.31 g, 91%). Rf = 0.59
–
(eluent: Hexane/EtOAc = 1/2); m.p. 81 82 °C; νmax (KBr) 2973, 2874, 1635, 1558, 1509,
–
1
1
–
δ 7.26 7.22 (m, 3H), 6.93 (t, J = 2.1
1430, 1319, 1247 cm ; H NMR (500 MHz, CDCl3)
–
Hz, 2H), 6.26 (t,
J
= 2.1 Hz, 2H), 3.47 (br.s, 2H), 2.72 (br.s, 2H), 2.39 (s, 3H), 1.82 1.66 (m,
13
–
2H), 1.65 1.51 (m, 2H); C NMR (126 MHz, CDCl3)
δ 167.7, 136.7, 134.9, 132.1, 130.9,
128.8, 124.0, 121.1 (2C), 109.9 (2C), 47.1, 45.4, 25.5, 24.3, 20.8; HRMS (ESIꢀTOF) m/z
:
[M+H]+ Calcd for C16H19N2O 255.1497; Found 255.1495.
(6-Methyl-2-(1
H
-pyrrol-1-yl)phenyl)(pyrrolidin-1-yl)methanone (3e).
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The activation step by CDI was implemented at reflux temperature. With this exception,
3
4
following the general procedure 3e was obtained as a slightly yellow solid (1.65 g, 65%).
5
6
7
8
–
R
f = 0.62 (eluent: Hexane/EtOAc = 1/2); m.p. 76 77 °C;
ν
max (KBr) 3124, 2975, 2875, 1733,
1624, 1490, 1420, 1333, 1219 cm ; H NMR (300 MHz, CDCl3) 7.31 (t, = 7.7 Hz, 1H),
7.18 (d, = 7.7 Hz, 2H), 6.98 (t, = 2.2 Hz, 2H), 6.25 (t, = 2.2 Hz, 2H), 3.53 (dt,
6.8 Hz, 1H), 3.39 (dt, = 10.7, 6.7 Hz, 1H), 2.69 (dt,
–
1
1
δ
J
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
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32
33
34
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J
J
J
J
J
= 12.3,
= 10.7,
167.1,
J
= 12.3, 6.8 Hz, 1H), 2.88 (dt,
–
J
6.7 Hz, 1H), 2.36 (s, 3H), 1.97 1.36 (sym. m, 4H); 13C NMR (75 MHz, CDCl3)
δ
137.3, 136.1, 132.6, 129.4, 128.6, 122.1, 121.5 (2C), 109.7 (2C), 47.2, 45.0, 25.5, 24.4, 19.4;
HRMS (ESIꢀTOF) m/z: [M+H]+ Calcd for C16H19N2O 255.1497; Found 255.1506.
(3-Methoxy-2-(1
H-pyrrol-1-yl)phenyl)(pyrrolidin-1-yl)methanone (3f).
Following the general procedure 3f was obtained as a slightly yellow solid (2.54 g, 94%).
–
R
f = 0.47 (eluent: Hexane/EtOAc = 1/2); m.p. 67 68 °C;
ν
max (KBr) 3104, 2971, 2882, 1738,
1617, 1499, 1428, 1337, 1230 cm ; H NMR (300 MHz, CDCl3) 7.34 (t, = 7.9 Hz, 1H),
7.04 (d, = 7.9 Hz, 1H), 7.01 (d, = 7.9 Hz, 1H), 6.89 (s, 2H), 6.24 (s, 2H), 3.81 (s, 3H), 3.38
= 6.2 Hz, 2H), 1.74 (p, = 6.2 Hz, 2H), 1.61 (p, = 6.2 Hz, 2H);
167.1, 153.8, 136.0, 128.5, 126.5, 122.5 (2C), 119.4, 112.8,
–
1
1
δ
J
J
J
(t,
J
= 6.2 Hz, 2H), 2.88 (t,
J
J
J
13C NMR (75 MHz, CDCl3)
δ
108.7 (2C), 56.2, 47.6, 45.2, 25.6, 24.3; HRMS (ESIꢀTOF) m/z: [M+H]+ Calcd for
C16H19N2O2 271.1447; Found 271.1439.
(4-Methoxy-2-(1
H-pyrrol-1-yl)phenyl)(pyrrolidin-1-yl)methanone (3g).
Following the general procedure 3g was obtained as a slightly yellow solid (2.46 g, 91%).
–
f = 0.44 (eluent: Hexane/EtOAc = 1/2); m.p. 105 106 °C; νmax (KBr) 3116, 3095, 2971,
R
–
1
1
–
2878, 1733, 1608, 1489, 1412, 1350, 1234 cm ; H NMR (500 MHz, CDCl3)
δ
7.48 7.33
(m, 1H), 6.95 (t,
J
= 2.0 Hz, 2H), 6.88 (dd,
J
= 6.0, 2.4 Hz, 1H), 6.87 (s, 1H), 6.28 (t,
J =
2.0 Hz, 2H), 3.85 (s, 3H), 3.46 (t,
J
= 7.0 Hz, 2H), 2.69 (br.s, 2H), 1.74 (p, J = 6.8 Hz, 2H),
13
1.58 (p,
J
= 6.6 Hz, 2H); C NMR (126 MHz, CDCl3)
δ
167.6, 160.9, 138.6, 129.9, 124.7,
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121.0 (2C), 112.3, 110.3 (2C), 109.5, 55.6, 47.1, 45.5, 25.6, 24.3; HRMS (ESIꢀTOF) m/z
:
[M+H]+ Calcd for C16H19N2O2 271.1447; Found 271.1449.
5
6
(5-Methoxy-2-(1
H-pyrrol-1-yl)phenyl)(pyrrolidin-1-yl)methanone (3h).
7
8
Following the general procedure 3h was obtained as a slightly yellow solid (2.43 g, 90%).
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–
R
f = 0.47 (eluent: Hexane/EtOAc = 1/2); m.p. 96 97 °C;
ν
max (KBr) 2971, 2881, 2840, 1733,
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–
1
1634, 1488, 1434, 1294, 1231 cm ; 1H NMR (300 MHz, CDCl3)
δ
7.29 (d, J = 8.1 Hz, 1H),
–
7.05 6.93 (m, 2H), 6.90 (t,
J
= 2.0 Hz, 2H), 6.25 (t,
J
= 2.0 Hz, 2H), 3.84 (s, 3H), 3.46 (t,
J =
6.9 Hz, 2H), 2.77 (br.s, 2H), 1.74 (p,
13C NMR (75 MHz, CDCl3)
J
= 6.2 Hz, 1H), 1.59 (p, = 6.2 Hz, 1H);
J
δ
167.2, 158.2, 133.4, 130.6, 125.7, 121.2 (2C), 116.4, 112.5,
109.7 (2C), 55.7, 47.2, 45.4, 25.5, 24.3; HRMS (ESIꢀTOF) m/z: [M+H]+ Calcd for
C16H19N2O2 271.1447; Found 271.1443.
(6-Methoxy-2-(1H-pyrrol-1-yl)phenyl)(pyrrolidin-1-yl)methanone (3i).
The activation step by CDI was implemented at reflux temperature. With this exception,
following the general procedure 3i was obtained as a slightly yellow solid (2.03 g, 75%).
–
R
f = 0.56 (eluent: Hexane/EtOAc = 1/2); m.p. 131 132 °C; νmax (KBr) 3128, 2884, 2842,
–
1
1733, 1636, 1492, 1420, 1290, 1251 cm ; 1H NMR (300 MHz, CDCl3)
1H), 6.99 (t, = 2.1 Hz, 2H), 6.97 (d, = 8.4 Hz, 1H), 6.89 (d, = 8.4 Hz, 1H), 6.25 (t,
2.1 Hz, 2H), 3.88 (s, 3H), 3.59 (dt, = 12.5, 6.7 Hz, 1H), 3.38 (dt, = 12.5, 6.7 Hz, 1H), 3.02
= 10.5, 6.5 Hz, 1H), 1.96
165.0, 156.7, 138.5, 130.3, 122.2, 121.4 (2C), 116.9, 109.8
δ 7.37 (t, J = 8.2 Hz,
J
J
J
J =
J
J
–
1.41 (m, 4H);
(dt,
J
= 10.5, 6.5 Hz, 1H), 2.76 (dt,
J
13C NMR (75 MHz, CDCl3)
δ
(2C), 109.2, 56.2, 47.2, 45.1, 25.5, 24.5; HRMS (ESIꢀTOF) m/z: [M+H]+ Calcd for
C16H19N2O2 271.1447; Found 271.1445.
(4,5-Dimethoxy-2-(1
H-pyrrol-1-yl)phenyl)(pyrrolidin-1-yl)methanone (3j).
Following the general procedure 3j was obtained as a slightly yellow solid (1.70 g, 63%).
–
Rf = 0.53 (eluent: Hexane/EtOAc = 1/2); m.p. 134 135 °C; νmax (KBr) 3096, 2971, 2882,
–
1
1737, 1615, 1530, 1435, 1291, 1216 cm ; 1H NMR (300 MHz, CDCl3)
δ
6.96 (s, 1H), 6.92 (t,
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J
= 1.9 Hz, 2H), 6.85 (s, 1H), 6.27 (t,
J
= 1.9 Hz, 2H), 3.92 (s, 6H), 3.46 (t,
J
= 7.0 Hz, 2H),
= 6.4 Hz, 2H); 13C NMR (75 MHz, CDCl3)
δ
3
4
2.72 (s, 2H), 1.74 (p,
J
= 6.4 Hz, 2H), 1.59 (p,
J
5
6
167.3, 150.1, 147.8, 130.9, 124.1, 121.1 (2C), 110.7, 109.9 (2C), 107.7, 56.2, 56.2, 47.2, 45.5,
7
8
25.6, 24.3; HRMS (ESIꢀTOF) m/z: [M+H]+ Calcd for C17H21N2O3 301.1552; Found 301.1547.
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(5-Chloro-2-(1
H-pyrrol-1-yl)phenyl)(pyrrolidin-1-yl)methanone (3k).
Following the general procedure 3k was obtained as a slightly yellow solid (2.44 g, 89%).
–
Rf = 0.30 (eluent: Hexane/EtOAc = 4/1); m.p. 83 84 °C;
ν
max (KBr) 2974, 2926, 2876, 1627,
–
δ 7.49 7.38 (m, 2H), 7.31
–
1
1476, 1431, 1389, 1277, 1202 cm ; 1H NMR (300 MHz, CDCl3)
(d,
J
= 8.5 Hz, 1H), 6.93 (t,
J
= 2.1 Hz, 2H), 6.29 (t,
J = 2.1 Hz, 2H), 3.47 (t, J = 6.9 Hz, 2H),
2.73 (br.s, 2H), 1.75 (p,
J
= 6.3 Hz, 2H), 1.61 (p, J
= 6.3 Hz, 2H); 13C NMR (75 MHz, CDCl3)
δ
166.0, 135.8, 133.5, 132.4, 130.3, 128.6, 125.4, 121.0 (2C), 110.6 (2C), 47.1, 45.5, 25.5,
24.2; HRMS (ESIꢀTOF) m/z: [M+H]+ Calcd for C15H16ClN2O 275.0951; Found 275.0944.
(3-Bromo-2-(1
H-pyrrol-1-yl)phenyl)(pyrrolidin-1-yl)methanone (3l).
Following the general procedure 3l was obtained as a slightly yellow solid (3.15 g, 99%).
–
Rf = 0.38 (eluent: Hexane/EtOAc = 1/2); m.p. 120 121 °C; νmax (KBr) 3097, 2968, 2857,
–
1
1
1629, 1541, 1426, 1338, 1309, 1190 cm ; H NMR (300 MHz, CDCl3)
δ
7.72 (dd,
= 7.7 Hz, 1H), 6.83 (t, = 1.7 Hz, 2H),
= 6.4 Hz, 2H), 1.76 (dt, = 12.7,
166.6, 138.3,
J = 7.7,
1.2 Hz, 1H), 7.36 (dd,
6.28 (t, = 1.7 Hz, 2H), 3.36 (t,
5.6 Hz, 2H), 1.68 (dt,
J
= 7.7, 1.2 Hz, 1H), 7.28 (t,
J
J
J
J
= 6.2 Hz, 2H), 2.99 (t,
J
J
J
= 12.7, 5.6 Hz, 2H); 13C NMR (75 MHz, CDCl3)
δ
131.0, 130.0, 129.8, 127.0, 123.6, 120.9 (2C), 110.8 (2C), 47.1, 45.5, 25.5, 24.2; HRMS (ESIꢀ
TOF) m/z: [M+H]+ Calcd for C15H16BrN2O 319.0446; Found 319.0452.
(4-Bromo-2-(1
H-pyrrol-1-yl)phenyl)(pyrrolidin-1-yl)methanone (3m).
Following the general procedure 3m was obtained as a slightly yellow solid (3.08 g, 97%).
–
Rf = 0.23 (eluent: Hexane/EtOAc = 4/1); m.p. 82 83 °C;
ν
max (KBr) 3094, 2977, 2883, 1617,
–
1
1
1590, 1496, 1437, 1319, 1199 cm ; H NMR (300 MHz, CDCl3)
δ
7.54 (d,
J
= 1.9 Hz, 1H),
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7.48 (dd,
J
= 8.1, 1.9 Hz, 1H), 7.34 (d,
J
= 8.1 Hz, 1H), 6.94 (t,
= 6.6 Hz, 2H), 1.60 (p,
166.6, 138.3, 131.0, 130.0, 129.8, 127.0, 123.6, 120.9
J
= 2.2 Hz, 2H), 6.29 (t,
J =
2.2 Hz, 2H), 3.47 (t,
J
= 6.9 Hz, 2H), 2.70 (br.s, 2H), 1.75 (p,
J
J
= 6.6
Hz, 2H); 13C NMR (75 MHz, CDCl3)
δ
7
8
(2C), 110.8 (2C), 47.1, 45.5, 25.5, 24.2; HRMS (ESIꢀTOF) m/z: [M+H]+ Calcd for
9
C15H16BrN2O 319.0446; Found 319.0437.
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(5-Bromo-2-(1
H-pyrrol-1-yl)phenyl)(pyrrolidin-1-yl)methanone (3n).
Following the general procedure the known 3n5 was obtained as a slightly yellow solid
–
Rf = 0.31 (eluent: Hexane/EtOAc = 4/1); m.p. 92 93 °C; νmax (KBr) 3098,
(3.05 g, 96%).
–
1
1
3061, 2973, 2878, 1627, 1489, 1431, 1386, 1322, 1104 cm ; H NMR (300 MHz, CDCl3)
δ
–
7.65 7.50 (m, 2H), 7.24 (d,
J
= 8.4 Hz, 1H), 6.93 (d,
J
J
= 2.1 Hz, 2H), 6.29 (d,
= 6.6 Hz, 2H), 1.61 (p,
J
J
= 2.1 Hz,
= 6.6 Hz,
2H), 3.46 (t,
J = 6.8 Hz, 2H), 2.72 (br.s, 2H), 1.75 (p,
2H); 13C NMR (75 MHz, CDCl3)
δ
165.8, 136.3, 133.8, 133.3, 131.5, 125.7, 121.0 (2C),
120.1, 110.7 (2C), 47.1, 45.5, 25.6, 24.2; HRMS (ESIꢀTOF) m/z: [M+H]+ Calcd for
C15H16BrN2O 319.0446; Found 319.0453.
(6-Bromo-2-(1H-pyrrol-1-yl)phenyl)(pyrrolidin-1-yl)methanone (3o).
The activation step by CDI was implemented at reflux temperature. With this exception,
following the general procedure 3o was obtained as a slightly yellow solid (2.33 g, 73%).
–
Rf = 0.33 (eluent: Hexane/EtOAc = 1/2); m.p. 128 129 °C; νmax (KBr) 3098, 2968, 2857,
–
1
1
1629, 1558, 1493, 1338, 1309, 1135 cm ; H NMR (300 MHz, CDCl3)
δ 7.55 (dd, J = 6.5,
2.5 Hz, 1H), 7.31 (s, 1H) 7.30 (dd, = 12.5, 7.9 Hz, 1H), 6.98 (t, = 2.1 Hz, 2H), 6.27 (t, J =
J
J
2.1 Hz, 2H), 3.58 (dt,
6.3 Hz, 1H), 2.74 (dt,
J
J
= 12.5, 6.3 Hz, 1H), 3.40 (dt,
J
= 12.5, 6.3 Hz, 1H), 3.05 (dt, J = 10.7,
13
–
= 10.7, 6.3 Hz, 1H), 1.94 1.51 (m, 4H); C NMR (75 MHz, CDCl3)
δ
164.9, 138.9, 134.5, 131.0, 130.5, 124.0, 121.6 (2C), 120.5, 110.3 (2C), 47.3, 45.2, 25.6,
24.4; HRMS (ESIꢀTOF) m/z: [M+H]+ Calcd for C15H16BrN2O 319.0446; Found 319.0458.
(5-Iodo-2-(1
H
-pyrrol-1-yl)phenyl)(pyrrolidin-1-yl)methanone (3p).
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Following the general procedure the known 3p5 was obtained as a yellow solid (3.07 g, 84%).
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2
3
4
–
Rf = 0.52 (eluent: Hexane/EtOAc = 1/2); m.p. 132 133 °C; νmax (KBr) 3109, 3069, 2968,
5
6
–
1
1
–
δ 7.89 7.62
2883, 1612, 1470, 1381, 1340, 1227, 1105 cm ; H NMR (300 MHz, CDCl3)
7
8
(m, 2H), 7.11 (d,
J
= 8.7 Hz, 1H), 6.93 (t,
J
= 2.1 Hz, 2H), 6.29 (t,
J
= 2.1 Hz, 2H), 3.46 (t, J =
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–
–
6.7 Hz, 2H), 2.71 (br.s, 2H), 1.84 1.67 (m, 2H), 1.67 1.48 (m, 2H); C NMR (75 MHz,
CDCl3)
δ 165.7, 139.2, 137.3, 136.9, 133.9, 125.8, 120.9 (2C), 110.7 (2C), 90.9, 47.1, 45.5,
25.5, 24.2; HRMS (ESIꢀTOF) m/z: [M+H]+ Calcd for C15H16IN2O 367.0307; Found 367.0305.
(4-Nitro-2-(1
The activation step by CDI was implemented at reflux temperature. With this exception,
following the general procedure 3q was obtained as a yellow solid (2.78 g, 98%). f = 0.15
max (KBr) 3105, 3035, 2974, 2879, 1617,
1525, 1492, 1447, 1387, 1199 cm ; H NMR (300 MHz, CDCl3) 8.25 (s, 1H), 8.19 (d,
= 8.2 Hz, 1H), 7.02 (s, 2H), 6.35 (s, 2H), 3.51 (t, = 6.7 Hz, 2H), 2.72
165.5,
H-pyrrol-1-yl)phenyl)(pyrrolidin-1-yl)methanone (3q).
R
–
(eluent: Hexane/EtOAc = 4/1); m.p. 125 126 °C;
ν
–
1
1
δ
J =
8.2 Hz, 1H), 7.65 (d,
–
J
J
(br.s, 2H), 1.94 1.71 (m, 2H), 1.71 1.52 (m, 2H); 13C NMR (75 MHz, CDCl3)
δ
–
148.7, 138.2, 137.6, 130.0, 121.3, 121.0 (2C), 119.2, 111.6 (2C), 47.0, 45.7, 25.6, 24.2;
HRMS (ESIꢀTOF) m/z: [M+H]+ Calcd for C15H16N3O3 286.1113; Found 286.1107.
(3-(1
H-Pyrrol-1-yl)naphthalen-2-yl)(pyrrolidin-1-yl)methanone (3r).
Following the general procedure 3r was obtained as a yellow oil (2.76 g, 95%).
R
f = 0.38
max (KBr) 2971, 2876, 1624, 1488, 1424, 1361, 1316, 1225,
7.97 (s, 1H), 7.86 (t, = 8.5 Hz, 2H), 7.81 (s, 1H),
= 2.0 Hz, 2H), 6.32 (t, = 2.0 Hz, 2H), 3.52 (t, = 6.8
= 6.4 Hz, 2H), 1.59 (p, = 6.4 Hz, 2H);
(eluent: Hexane/EtOAc = 1/2);
ν
–
1
1192 cm ; 1H NMR (300 MHz, CDCl3)
δ
J
7.54 (qt,
J
= 6.9, 3.5 Hz, 2H), 7.07 (t,
J
J
J
Hz, 2H), 2.78 (br.s, 2H), 1.76 (p,
13C NMR (75 MHz, CDCl3)
J
J
δ
167.5, 135.2, 133.7, 131.8, 131.5, 128.3, 128.1, 127.7, 127.5,
126.6, 122.1, 121.5 (2C), 110.3 (2C), 47.4, 45.5, 25.6, 24.3; HRMS (ESIꢀTOF) m/z: [M+H]+
Calcd for C19H19N2O 291.1497; Found 291.1499.
General procedure for the synthesis of fluorazones 6aꢀr.
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To an ovenꢀdried and nitrogenꢀflushed 10 mL Schlenk tube with a magnetic stirrer was added
the amide (3, 0.5 mmol, 1.0 equiv) in anhydrous CH2Cl2 (1.2 mL). The reaction mixture was
cooled to −78 °C. Triflic anhydride (93 ꢁL, 0.55 mmol, 1.1 equiv) was added dropwise via
syringe, the reaction mixture was stirred for 5 min at −78 °C, than 2ꢀfluoropyridine (2ꢀFꢀPy)
(52 ꢁL, 0.6 mmol, 1.2 equiv) was added via syringe. The mixture was stirred for additional 5
min at −78 °C, than was allowed to warm to rt. After 20 min the reaction was quenched by the
addition of MeOH (1 mL) at 0 °C. The mixture was evaporated under reduced pressure until
the removal of CH2Cl2, then solution of NaOH (3 mL, 1 M) was added dropwise and stirred at
rt for 10 min. The product was extracted with EtOAc (3 x 5 ml). The collected organic layers
were dried over sodium sulphate and concentrated. The residue thus obtained was purified by
flash chromatography over high performance reversed phased silica gel (24 g column)
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Fractions containing 9Hꢀpyrrolo[1,2ꢀa]indolꢀ9ꢀones (6) were concentrated, the residue was
dissolved in CH2Cl2, dried over the mixture of sodium sulphate and sodium bicarbonate and
were concentrated to dryness.
Characterisation data of fluorazones 6a-r.
9
H
-Pyrrolo[1,2-a]indol-9-one (6a).
Following the general procedure the known 6a8c was obtained as a yellow solid (314 mg,
–
Rf = 0.72 (eluent: Hexane/EtOAc = 3/2); m.p. 115 116 °C; νmax (KBr) 3118, 1698,
93%).
–
1
1617, 1542, 1522, 1457, 1339 cm ; 1H NMR (300 MHz, CDCl3)
δ
7.57 (d, J = 7.5 Hz, 1H),
–
J = 7.5 Hz, 1H), 7.19 7.03 (m, 3H), 6.78 (d, J = 3.3 Hz, 1H), 6.31 (s, 1H);
7.42 (t,
13C NMR (75 MHz, CDCl3)
114.0, 110.3; HRMS (ESIꢀTOF) m/z: [M+H]+ Calcd for C11H7NO 170.0600; Found 170.0593.
δ
179.7, 143.8, 134.1, 132.0, 130.3, 125.5, 124.5, 119.5, 115.9,
5-Methyl-9
H-pyrrolo[1,2-a]indol-9-one (6b).
Following the general procedure the known 6b7d was obtained as a yellow solid (326 mg,
–
89%).
R
f = 0.70 (eluent: Hexane/EtOAc = 3/2); m.p. 119 120 °C; νmax (KBr) 3109, 1698,
–
1
1
1623, 1522, 1489, 1436, 1339 cm ; H NMR (300 MHz, CDCl3)
δ
7.26 (t,
J
= 7.8 Hz, 1H),
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J
= 1.9 Hz, 1H), 6.92 (d,
J
= 7.8 Hz, 1H), 6.87 (d,
J
= 7.8 Hz, 1H), 6.73 (d,
J
= 3.5
= 3.5, 2.7 Hz, 1H), 2.59 (s, 3H); 13C NMR (75 MHz, CDCl3)
δ
181.1,
3
4
Hz, 1H), 6.28 (dd,
J
5
6
144.1, 139.9, 133.4, 132.1, 128.1, 127.0, 118.6, 115.5, 113.0, 107.8, 17.3; HRMS (ESIꢀTOF)
7
8
m/z: [M+H]+ Calcd for C12H9NO 184.0757; Found 184.0761.
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6-Methyl-9
H-pyrrolo[1,2-a]indol-9-one (6c).
Following the general procedure the known 6c8c was obtained as a yellow solid (345 mg,
–
Rf = 0.74 (eluent: Hexane/EtOAc = 3/2); m.p. 140 141 °C; νmax (KBr) 3115, 1684,
95%).
–
1624, 1522, 1457, 1309, 1247 cm ; 1H NMR (300 MHz, CDCl3)
δ
7.44 (d,
= 3.6 Hz, 1H), 6.28 (dd,
179.7, 145.6, 144.2, 132.4, 127.8,
J
= 7.9 Hz, 1H),
1
7.03 (dd,
J
= 2.4, 0.4 Hz, 1H), 6.95 – 6.87 (m, 2H), 6.74 (d,
J
J
= 3.6,
2.8 Hz, 1H), 2.40 (s, 3H); 13C NMR (75 MHz, CDCl3)
δ
125.9, 124.4, 119.1, 115.6, 113.6, 111.2, 22.2; HRMS (ESIꢀTOF) m/z: [M+H]+ Calcd for
C12H9NO 184.0757; Found 184.0755.
7-Methyl-9
H-pyrrolo[1,2-a]indol-9-one (6d).
Following the general procedure the known 6d8c was obtained as a yellow solid (337 mg,
–
92%).
R
f = 0.61 (eluent: Hexane/EtOAc = 4/1); m.p. 99 101 °C; νmax (KBr) 3117, 2879,
–
1
1
1683, 1558, 1473, 1360, 1216, 1080 cm ; H NMR (300 MHz, CDCl3)
δ
7.32 (s, 1H), 7.16
= 3.4 Hz, 1H), 6.25 (br.s,
179.9, 141.6, 135.3, 134.3, 132.1, 130.3,
(d,
J = 7.8 Hz, 1H), 7.00 (s, 1H), 6.94 (d, J = 7.8 Hz, 1H), 6.72 (d, J
1H), 2.30 (s, 3H). 13C NMR (75 MHz, CDCl3)
δ
125.0, 119.4, 115.5, 113.6, 110.0, 21.0; HRMS (ESIꢀTOF) m/z: [M+H]+ Calcd for C12H9NO
184.0757; Found 184.0761.
8-Methyl-9
H-pyrrolo[1,2-a]indol-9-one (6e).
Following the general procedure 6e was obtained as a yellow solid (307 mg, 84%).
Rf = 0.76
–
(eluent: Hexane/EtOAc = 3/2); m.p. 129 130 °C;
ν
max (KBr) 3142, 3094, 2976, 1674, 1559,
–
1
1470, 1361, 1290, 1074 cm ; 1H NMR (500 MHz, CDCl3)
δ
7.43 (d, J = 7.4 Hz, 1H), 7.20 (d,
J
= 7.7 Hz, 1H), 7.18 (dd,
J
= 2.4, 0.6 Hz, 1H), 7.02 (t,
J
= 7.5 Hz, 1H), 6.80 (dd, J = 3.7, 0.6
13
Hz, 1H), 6.31 (dd,
J
= 3.7, 2.6 Hz, 1H), 2.48 (s, 3H). C NMR (126 MHz, CDCl3)
δ
180.0,
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2
3
4
142.3, 136.8, 132.5, 130.4, 125.4, 122.3, 122.3, 121.9, 115.8, 113.5, 17.7; HRMS (ESIꢀTOF)
m/z: [M+H]+ Calcd for C12H9NO 184.0757; Found 184.0753.
5
6
5-Methoxy-9
H-pyrrolo[1,2-a]indol-9-one (6f).
7
8
Following the general procedure 6f was obtained as a yellow solid (366 mg, 92%).
Rf = 0.67
9
–
(eluent: Hexane/EtOAc = 3/2); m.p. 153 154 °C;
νmax (KBr) 3114, 1699, 1558, 1474, 1340,
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
–
1
1272, 1051 cm ; 1H NMR (500 MHz, CDCl3)
δ
7.28 (dd,
J
J
= 2.5, 0.8 Hz, 1H), 7.19 (dd,
J
J
=
=
7.1, 1.1 Hz, 1H), 7.06 (dd,
3.7, 0.8 Hz, 1H), 6.23 (dd,
J
= 8.3, 7.1 Hz, 1H), 7.02 (dd,
= 8.3, 0.9 Hz, 1H), 6.77 (dd,
13
J
= 3.7, 2.5 Hz, 1H), 3.96 (s, 3H); C NMR (126 MHz, CDCl3)
δ
179.8, 146.2, 132.0, 131.7, 131.4, 126.3, 123.9, 117.6, 116.6, 115.1, 114.0, 56.0; HRMS
(ESIꢀTOF) m/z: [M+H]+ Calcd for C12H9NO2 200.0706; Found 200.0721.
6-Methoxy-9
H-pyrrolo[1,2-a]indol-9-one (6g).
Following the general procedure the known 6g8c was obtained as a yellow solid (346 mg,
–
Rf = 0.56 (eluent: Hexane/EtOAc = 3/2); m.p. 128 129 °C; νmax (KBr) 3122, 1684,
87%).
–
1
1625, 1525, 1308, 1182, 1077 cm ; 1H NMR (500 MHz, CDCl3)
δ
7.51 (d,
J = 8.3 Hz, 1H),
7.03 (dd,
J
= 2.6, 0.6 Hz, 1H), 6.73 (dd,
= 3.6, 2.6 Hz, 1H), 3.88 (s, 3H); C NMR (126 MHz,
J = 3.6, 0.6 Hz, 1H), 6.64 (d, J = 2.1 Hz, 1H), 6.57
13
(dd, = 8.3, 2.1 Hz, 1H), 6.29 (dd,
J
J
CDCl3)
δ 179.2, 165.3, 145.9, 133.0, 126.1, 123.1, 118.8, 115.7, 113.1, 109.0, 98.2, 56.0;
HRMS (ESIꢀTOF) m/z: [M+H]+ Calcd for C12H9NO2 200.0706; Found 200.0720.
7-Methoxy-9
H-pyrrolo[1,2-a]indol-9-one (6h).
Following the general procedure the known 6h7d was obtained as a yellow solid (362 mg,
–
Rf = 0.65 (eluent: Hexane/EtOAc = 3/2); m.p. 119 120 °C; νmax (KBr) 3109, 1696,
91%).
–
1
1608, 1492, 1352, 1289, 1224 cm ; 1H NMR (300 MHz, CDCl3)
δ
7.14 (d,
= 3.7, 0.6 Hz, 1H), 6.25 (dd,
179.5, 157.9, 137.5, 132.3,
J = 2.6 Hz, 1H),
7.06 – 6.97 (m, 2H), 6.91 (dd,
J
= 8.4, 2.5 Hz, 1H), 6.76 (dd,
J
J
= 3.7, 2.6 Hz, 1H), 3.82 (s, 3H); 13C NMR (75 MHz, CDCl3)
δ
131.6, 119.6, 119.3, 115.4, 114.2, 111.0, 109.78, 55.9; HRMS (ESIꢀTOF) m/z: [M+H]+ Calcd
for C12H9NO2 200.0706; Found 200.0716.
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2
8-Methoxy-9
H
-pyrrolo[1,2-
a
]indol-9-one (6i).
3
4
5
6
7
8
9
Following the general procedure 6h was obtained as a yellow solid (342 mg, 86%).
R
f = 0.43
max (KBr) 3110, 1685, 1593, 1508, 1465,
7.37 (dd, = 8.5, 7.9 Hz, 1H), 7.02 (dd,
= 8.5 Hz, 1H), 6.27 (dd, = 3.5, 2.6 Hz, 1H),
δ 178.5, 158.2, 145.4, 136.1, 131.9, 118.9, 116.4,
–
(eluent: Hexane/EtOAc = 3/2); m.p. 191 192 °C;
ν
–
1270, 1168 cm ; 1H NMR (500 MHz, CDCl3)
δ
J
J =
1
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
–
2.6, 0.6 Hz, 1H), 6.76 6.68 (m, 2H), 6.66 (d,
J
J
13
3.96 (s, 3H); C NMR (126 MHz, CDCl3)
115.6, 113.0, 109.4, 103.16, 56.1; HRMS (ESIꢀTOF) m/z: [M+H]+ Calcd for C12H9NO2
200.0706; Found 200.0706.
6,7-Dimethoxy-9
H-pyrrolo[1,2-a]indol-9-one (6j).
Following the general procedure the known 6j8c was obtained as a yellow solid (412 mg,
–
Rf = 0.46 (eluent: Hexane/EtOAc = 3/2); m.p. 147 148 °C; νmax (KBr) 3094, 2932,
90%).
–
1
1
1684, 1617, 1506, 1258, 1218, 1094 cm ; H NMR (500 MHz, CDCl3)
δ
7.11 (s, 1H), 6.97
= 3.7, 2.6 Hz,
179.7, 154.4, 146.9, 139.8,
(dd,
J = 2.6, 0.7 Hz, 1H), 6.70 (d, J = 3.7, 0.7 Hz, 1H), 6.69 (s, 1H), 6.22 (dd, J
1H), 3.98 (s, 3H), 3.88 (s, 3H); 13C NMR (126 MHz, CDCl3)
δ
132.5, 130.9, 121.6, 119.0, 115.0, 113.7, 107.4, 95.3, 56.6, 56.5; HRMS (ESIꢀTOF) m/z
:
[M+H]+ Calcd for C13H11NO3 230.0812; Found 230.0818.
7-Chloro-9H-pyrrolo[1,2-a]indol-9-one (6k).
Following the general procedure the known 6k8c was obtained as a yellow solid (390 mg,
–
96%).
R
f = 0.73 (eluent: Hexane/EtOAc = 3/2); m.p. 140 142 °C; νmax (KBr) 3104, 1690,
1
1617, 1542, 1508, 1391, 1267 cm–1; H NMR (300 MHz, CDCl3)
δ
7.52 (d,
J = 2.0 Hz, 1H),
–
7.39 (dd,
J
= 8.2, 2.0 Hz, 1H), 7.09 7.01 (m, 2H), 6.80 (dd,
J
= 3.7, 0.4 Hz, 1H), 6.33 (dd, J
13
= 3.7, 2.6 Hz, 1H); C NMR (75 MHz, CDCl3)
δ 178.0, 142.0, 133.5, 132.1, 131.8, 131.2,
124.9, 119.9, 116.4, 114.8, 111.3; HRMS (ESIꢀTOF) m/z: [M+H]+ Calcd for C11H7NOCl
204.0211; Found 204.0217.
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2
5-Bromo-9
H
-pyrrolo[1,2-
a
]indol-9-one (6l).
3
4
5
6
7
8
9
Following the general procedure 6l was obtained as a yellow solid (456 mg, 92%).
R
f = 0.79
max (KBr) 3122, 1698, 1609, 1558, 1489,
7.77 (d, = 2.5 Hz, 1H), 7.63 – 7.43 (m,
= 3.7 Hz, 1H), 6.35 (d, = 3.7, 2.5 Hz, 1H);
178.0, 142.0, 138.1, 132.7, 132.4, 126.5, 123.5, 123.0, 115.9,
–
(eluent: Hexane/EtOAc = 3/2); m.p. 120 121 °C;
ν
–
1
1
1339, 1274 cm ; H NMR (300 MHz, CDCl3)
δ
J
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
2H), 7.00 (t,
J
= 7.7 Hz, 1H), 6.86 (d,
J
J
13C NMR (75 MHz, CDCl3)
δ
114.8, 104.9; HRMS (ESIꢀTOF) m/z: [M+H]+ Calcd for C11H6NOBr 247.9706; Found
247.9711.
6-Bromo-9
H-pyrrolo[1,2-a]indol-9-one (6m).
Following the general procedure 6m was obtained as a yellow solid (441 mg, 89%).
Rf = 0.79
–
(eluent: Hexane/EtOAc = 3/2); m.p. 192 193 °C;
ν
max (KBr) 3115, 1698, 1609, 1558, 1508,
–
1
1
–
1419, 1290 cm ; H NMR (300 MHz, CDCl3)
δ
7.43 (d,
J
= 8.3 Hz, 1H), 7.35 7.27 (m,
= 3.2, 2.5 Hz,
178.4, 144.5, 132.2, 129.2, 128.5, 128.5, 125.6, 119.6,
2H), 7.06 (dd,
J = 2.5, 0.6 Hz, 1H), 6.81 (dd, J = 3.2, 0.6 Hz, 1H), 6.34 (dd, J
1H); 13C NMR (75 MHz, CDCl3)
δ
116.6, 114.6, 114.1; HRMS (ESIꢀTOF) m/z: [M+H]+ Calcd for C11H6NOBr 247.9706; Found
247.9701.
7-Bromo-9
H-pyrrolo[1,2-a]indol-9-one (6n).
Following the general procedure the known 6n5 was obtained as a yellow solid (481 mg,
97%).
Rf = 0.56 (eluent: Hexane/EtOAc = 4/1); m.p. 145–146 °C; νmax (KBr) 3121, 1698,
1
1616, 1558, 1508, 1457, 1339 cm–1; H NMR (300 MHz, CDCl3)
δ
7.66 (d,
J
= 1.7 Hz, 1H),
7.53 (dd,
(dd,
J
= 8.2, 1.9 Hz, 1H), 7.06 (dd,
= 3.7, 2.6 Hz, 1H); 13C NMR (75 MHz, CDCl3)
δ 177.9,
J = 2.6, 0.6 Hz, 1H), 7.00 (d, J = 8.2 Hz, 1H), 6.80
J
= 3.7, 0.6 Hz, 1H), 6.33 (dd,
J
142.4, 136.4, 132.0, 131.9, 127.7, 119.9, 118.5, 116.5, 114.7, 111.7; HRMS (ESIꢀTOF) m/z
:
[M+H]+ Calcd for C11H7NOBr 247.9706, Found 247.9704.
8-Bromo-9H-pyrrolo[1,2-a]indol-9-one (6o).
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