Br?nsted-Acid-Mediated Divergent Reactions of Betti Bases with Indoles: An Approach to Chromeno[2,3-b]indoles through Intramolecular Dehydrogenative C2-Alkoxylation of Indole

Article abstract of DOI:10.1002/ejoc.201600546

Divergent reactions of various 1-(aminoalkyl)naphthols and 2-(aminoalkyl)phenols (commonly known as Betti bases) with indoles under Br?nsted acid catalysis is reported. With the reaction strategies, one can efficiently synthesize important indole derivatives such as 3-(α,α-diarylmethyl)indoles and chromeno[2,3-b]indoles. Furthermore, we disclose here a new C–C bond-cleavage reaction, in which naphthol and phenol behave as leaving groups to produce diarylmethanes. Inexpensive reagents such as p-toluenesulfonic acid monohydrate and molecular iodine are used to catalyze the reactions. No metal catalyst is required. The starting material of the reactions, Betti bases, are easily prepared from a three-component reaction of naphthol/phenol, aldehydes, and secondary amines. The mechanisms for the reactions are established through some control experiments. Quinone methide is the key intermediate for all the reactions reported herein.

Full text of DOI:10.1002/ejoc.201600546

DOI: 10.1002/ejoc.201600546
Full Paper
Synthetic Methods
Brønsted-Acid-Mediated Divergent Reactions of Betti Bases with
Indoles: An Approach to Chromeno[2,3-b]indoles through
Intramolecular Dehydrogenative C2-Alkoxylation of Indole
Mohit L. Deb,*[a] Choitanya Dev Pegu,[a] Bhaskar Deka,[a] Prantu Dutta,[a]
Amol S. Kotmale,[b] and Pranjal K. Baruah*[a]
Abstract: Divergent reactions of various 1-(aminoalkyl)naphth- Inexpensive reagents such as p-toluenesulfonic acid mono-
ols and 2-(aminoalkyl)phenols (commonly known as Betti hydrate and molecular iodine are used to catalyze the reactions.
bases) with indoles under Brønsted acid catalysis is reported. No metal catalyst is required. The starting material of the reac-
With the reaction strategies, one can efficiently synthesize im- tions, Betti bases, are easily prepared from a three-component
portant indole derivatives such as 3-(α,α-diarylmethyl)indoles reaction of naphthol/phenol, aldehydes, and secondary amines.
and chromeno[2,3-b]indoles. Furthermore, we disclose here a The mechanisms for the reactions are established through
new C–C bond-cleavage reaction, in which naphthol and some control experiments. Quinone methide is the key interme-
phenol behave as leaving groups to produce diarylmethanes. diate for all the reactions reported herein.
Introduction
phores for medicinal chemists and have a wide range of biolog-
ical applications; for example, some indole derivatives are po-
tent antifungal and antibacterial agents[9] and HIV-1 integrase
inhibitors.[10] Chromeno[2,3-b]indole is a ring-fused indole de-
rivative having medicinal importance. To date, there are very
few reports to synthesize these indole derivatives. In one in-
stance, 7-methylchromeno[2,3-b]indole was synthesized from
the decomposition of the diazonium sulfate, which itself was
prepared from 3-o-aminobenzylidene-7-methyloxindole.[11]
Some other reports reveal the synthesis of chromono[2,3-b]-
indoles from the corresponding 3-(2-hydroxybenzoyl)oxind-
oles[12] or through an aminoisoflavone–salicyloylindole ring
transformation.[13] Recently, in another report, a number of new
chromeno[2,3-b]indole derivatives were synthesized by the re-
action of 2-hydroxyacetophenones with oxindoles under harsh
reaction conditions.[14] The researchers claim that this type of
fused ring skeleton can serve as a candidate for modulating
RNA-binding proteins.[15] Therefore, the synthesis and function-
alization of indoles have been the focal point of active research
over the years.
Betti bases, 1-(aminoalkyl)naphthols and 2-(aminoalkyl)phenols,
were discovered at the beginning of the 20th century and were
synthesized by a three-component Mannich reaction of 2-
naphthol or phenol, aldehydes, and amines by Mario Betti.[1]
Betti bases have a broad range of applications; for example,
they are very good precursors for the synthesis of many nitro-
gen-containing pharmaceuticals and are key intermediates in
many multistep organic synthesis.[2] A few Betti base derivatives
have been reported as biologically active ingredients.[3] Over
the last two decades, Betti bases have been extensively used
as ligands in organometallic and asymmetric catalysis.[4] Besides
that, a few reports describe the synthesis of several worthy
heterocycles from Betti bases.[5] The amine functional group of
Betti bases is crucial in forming C–C and C–X bonds to the
benzylic carbon.[6] Therefore, the massive scope of manipulat-
ing the Betti base structure is still buried.
The indole skeleton is an important structural motif in or-
ganic and medicinal chemistry. For instance, a derivative of ind-
ole acts as a free-radical scavenger and has a broad spectrum
of antioxidant activity.[7] Many derivatives of indole are used as
antihypertensive, antineoplastic, and antimitotic agents.[8]
Moreover, C3-substituted indoles are venerable pharmaco-
Results and Discussion
There are a number of research articles regarding the C2-func-
tionalization of indole derivatives through the formation of C–
C,[16] C–N,[17] and C–S[18] bonds, but C–O bond formation is
rarely reported.[19] Most of these are intermolecular reactions.
A few reports on intramolecular C–O bond formation at the 2-
position of indole leading to indolines are available.[20a,20b] To
the best of our knowledge, there are only a couple of reports
on intramolecular dehydrogenative C–O bond formation at the
2-position of indole.[20b,20c] Therefore, we became interested in
[a] Department of Applied Sciences, GUIST, Gauhati University,
Guwahati 781014, Assam, India
E-mail: mohitdd.deb@gmail.com
baruah.pranjal@gmail.com
http://www.gauhati.ac.in/profile-faculty.php?id=304
[b] Central NMR Facility, National Chemical Laboratory,
Pune 411008, India
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/ejoc.201600546.
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developing a protocol for intramolecular C–O bond formation
at the 2-position of indole to obtain chromeno[2,3-b]indole de-
rivatives.
Table 1. Optimization of the synthesis of 3.[a]
Initially, our research plan was to synthesize 3 by three-com-
ponent reaction of 2-naphthol (or phenol), indole, and aldehyde
and then cyclization of 3 to chromeno[2,3-b]indole 5. However,
the difficulty we faced in using this strategy was the sole forma-
tion of bis(indolyl)methanes 4[21] instead of 3. Therefore, we
switched our reaction route to a two-component approach, in
which Betti bases were treated with indoles under acid-cata-
lyzed conditions (Scheme 1).
Betti bases 1 were efficiently synthesized by the reported
three-component one-pot process involving naphthol/phenol,
aromatic aldehydes, and N,N-dimethylamine.[22] We observed
during the synthesis of 3 by using the two-component ap-
proach the unanticipated formation of a minor quantity of 4 as
a side product, which rendered the purification of 3 difficult. To
minimize the formation of 4, we tried a variety of acid catalysts
and H-bond catalyst such as thiourea (Table 1). After a careful
screening of catalysts and solvents, we found p-toluenesulfonic
acid monohydrate (pTsOH·H2O, 0.1 equiv.) in toluene at 100 °C
to be the optimum conditions for the synthesis of 3a from the
reaction of Betti base 1a and indole (2a), which we considered
as our model reaction. The reaction gave 3a in 75 % yield with
no formation of bis(indolyl)methanes (Table 1).
Entry Catalyst (equiv.)
Solvent
Temp.
[°C]
Time Yield[b] [%]
[h]
3a
4a
1
–
–
–
100
100
reflux
reflux
100
reflux
110
100
100
100
100
25
100
100
100
100
100
4
4
4
4
4
5
3
3
4
3
3
24
3
4
4
4
4
–
35
–
–
10
–
trace
–
–
15
–
12
20
–
–
15
–
2
3
4
5
6
7
8
9
10
11
12
13
14[c]
15[d]
16
17
pTsOH·H2O (0.1)
pTsOH·H2O (0.1)
pTsOH·H2O (0.1)
pTsOH·H2O (0.1)
pTsOH·H2O (0.1)
pTsOH·H2O (0.1)
pTsOH·H2O (0.1)
pTsOH·H2O (0.1)
pTsOH·H2O (0.2)
pTsOH·H2O(0.05)
pTsOH·H2O (0.1)
TFA (0.1)
EtOH
MeCN
DMF
20
15
trace
48
75
60
45
40
15
50
25
10
–
CHCl3
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
TNBA (0.2)
PNBA (0.2)
CH3CO2H (0.2)
thiourea (0.3)
–
–
–
–
[a] Unless otherwise mentioned, all reactions were performed by using 1a
(0.5 mmol, 138.5 mg) and 2a (0.5 mmol, 58.5 mg). [b] Products were purified
by column chromatography by using silica gel (100–200 mesh) and yields are
for the isolated products. [c] TNBA: 2,4,6-trinitrobenzoic acid. [d] PNBA: p-
nitrobenzoic acid.
Having identified the optimized conditions, we next investi-
gated the substrate scope for the synthesis of 3 by examining
various Betti bases and indole derivatives. To our delight, com-
pounds 3 containing a wide range of substituents were ob-
tained in moderate to good yields, as summarized in Scheme 2.
We noticed that upon increasing the temperature, time, or
Electron-donating groups on the aryl ring (Ar) of Betti bases catalyst loading in the synthesis of compound 3a, an increase
1 decreased the product yield, whereas electron-withdrawing in the formation of bis(indolyl)methane 4a was observed, which
groups increased the yield (see 3j vs. 3k, Scheme 2). Betti bases decreased the yield of 3a (Table 1, entries 7, 9, and 10). For the
having ortho-substituted aryl rings provided lower yields with generation of 4a, a molecule of naphthol must be eliminated
longer reaction times (see 3r, Scheme 2). If Ar = H, 3 was not from substrate 1a, which we isolated and characterized by NMR
formed; instead, we obtained an intractable mixture of products spectroscopy and mass spectrometry. To the best of our knowl-
(Scheme 2). N-Alkylindoles produced lower yields of 3 (see 3m– edge, there is no report of such metal-free dearylation (de-
y, Scheme 2).
naphtholation or dephenolation) in a chemical reaction. There-
Scheme 1. Divergent reactions of Betti bases with indoles.
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Scheme 2. Substrate scope for the synthesis of 3. Reaction conditions: 1 (1.0 mmol), 2 (1.0 mmol), pTsOH·H2O (19 mg, 0.1 equiv.), toluene (2.0 mL), 100 °C.
Products were purified by column chromatography by using silica gel (100–200 mesh) and yields are for the isolated products.
fore, we became interested to set the reaction conditions uct 4 of the Betti base. Hence, we screened the catalyst loading,
whereby we could obtain a maximum yield of dearylated prod- reaction time, temperature, and solvent for our model reaction
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and found that 0.25 equiv. of pTsOH·H2O in toluene at 120 °C may be due to decomposition of the bis(indolyl)methanes. We
for 3 h produced a maximum yield of 4a (68 %) along with 3a also examined polar solvents such as ethanol and acetonitrile,
(12 %) from the reaction of 1a (1.0 equiv.) with 2a (2.0 equiv., but unfortunately, we obtained a low yield of 4a in both cases.
Table 2). To check the substrate scope for the formation of 4,
We assumed that bis(indolyl)methane 4 was formed via 3
we performed the reaction by using various substituted Betti and, therefore, to ensure the mechanistic pathway, we first iso-
bases and indoles and established that elimination of naphthol lated 3a and then treated it with indole in the presence of
from the Betti base was much easier than that of phenol pTsOH·H2O (0.25 equiv.) in toluene at 120 °C; this resulted in an
(Table 2). We used stronger acids, including trifluoroacetic acid excellent yield of symmetrical as well as unsymmetrical bis
(TFA) and triflic acid, believing that they might accelerate the (indolyl)methanes (see 4a, 4aa, and 4ab; Scheme 3). Therefore,
formation of 4. However, in practice we obtained lower yields we believe that compound 4 is formed from 1 through elimina-
(Table 2). Moreover, TFA and triflic acid provided a maximum tion–addition reactions via 3 under acid-catalyzed conditions
yield of 4 at 1 h, and after that time the yield decreased, which (Scheme 5, a).
Table 2. Dearylation of Betti bases.[a]
[a] All reactions were performed by using 1 (0.5 mmol) and 2 (1.0 mmol) in toluene at 120 °C. [b] Bis(indolyl)methanes and the corresponding eliminated
naphthols/phenols were purified by column chromatography by using silica gel (100–200 mesh).
Scheme 3. Reaction of 3a with indoles to furnish bis(indolyl)methanes.
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We next made an effort to synthesize 5 through C2 cycliza-
tion of the indole ring of 3 (Scheme 1). We chose the conver-
sion of 3a into 5a as a model reaction, for which the substrate
was an NH-indole derivative. We tried a variety of catalysts and
solvents, but unluckily, we did not succeed. Then, we consid-
ered the conversion of 3m into 5m as a representative example,
for which the substrate contains an N-methylindole moiety. We
found that molecular iodine (0.1 equiv.) with tert-butyl hydro-
peroxide (TBHP, 70 % in H2O, 2.0 equiv.) in toluene at room
temperature were optimal for this cyclization. The reaction took
2 h to complete, and the yield was excellent (98 %; Table 3,
entry 5). Next, we investigated the substrate scope for the syn-
thesis of 5 (Scheme 4). Chromeno[2,3-b]indoles 5, which con-
tain a wide variety of substituents, were obtained in good to
excellent yields. To our delight, functional groups on the aro-
matic ring such as –OMe, –Br, –Cl, and –NO2 were also compati-
ble. The compound containing an N-allylindole moiety gave a
comparatively lower yield (see 5w, Scheme 4). Compound 3
having a phenolic moiety did not produce the desired product
under our optimized condition (e.g., 5x, Scheme 4). We next
attempted to synthesize 5 through the two-component domino
approach from the reaction of 1 and N-substituted indole with-
out isolating intermediate 3 (Scheme 1). To achieve the goal,
compound 1a was treated with N-methylindole in the presence
of pTsOH·H2O (0.1 equiv.) under heating at 100 °C in toluene
Table 3. Optimization of the synthesis of chromeno[2,3-b]indole 5m.[a]
Entry
Catalyst
(equiv.)
Oxidant/additive Solvent
(equiv.)
Time Yield[b]
[h]
[%]
1
2
3
4
5
6
7
8
I2 (0.1)
I2 (0.1)
I2 (0.1)
I2 (0.1)
I2 (0.1)
I2 (0.1)
I2 (0.05)
I2 (0.1)
I2 (0.1)
KI (0.1)
NaI (0.1)
TBAI (0.1)
NBS (0.1)
NCS (0.1)
TBHP (2.0)
TBHP (2.0)
TBHP (2.0)
TBHP (2.0)
TBHP (2.0)
TBHP (1.5)
TBHP (2.0)
TBHP (2.0)
H2O2 (2.0)
TBHP (2.0)
TBHP (2.0)
TBHP (2.0)
TBHP (2.0)
TBHP (2.0)
CH2Cl2
CHCl3
DCE
5
5
2
5
2
2
2
1.5
2
3
65
68
88
80
98
77
85
92
MeOH
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
9
trace
80
72
10
11
12
13
14
3
3
6
6
84
n.r.[c]
n.r.[c]
[a] All reactions were performed with 3m (0.5 mmol, 181.5 mg). TBAI: tetra-
butylammonium iodide, NBS: N-bromosuccinimide, NCS: N-chlorosuccin-
imide, DCE: 1,2-dichloroethane. [b] Product 5m was purified by column chro-
matography by using silica gel (100–200 mesh) and yields are for the isolated
products. [c] n.r.: no reaction.
Scheme 4. Substrate scope for the synthesis of chromeno[2,3-b]indoles 5. [a] Reaction conditions for 3→5: 3 (0.5 mmol), I2 (13 mg, 0.1 equiv.), TBHP (70 % in
H2O, 128.5 mg, 2.0 equiv.), toluene (1.0 mL), r.t. [b] Reaction conditions for 1→5: 1 (0.5 mmol), 2 (0.5 mmol), pTsOH·H2O (0.1 equiv.), toluene (1.0 mL), 100 °C;
then, I2 (0.1 equiv.), TBHP (70 % in H2O, 2.0 equiv.), r.t. The first fraction of the time is under heating and the last one is at r.t, yields are for the isolated
products. [c] Yield of 5r was determined by analysis of the crude product by 1H NMR spectroscopy, as we could not isolate the pure compound.
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for 3 h and then I2 (0.1 equiv.) and TBHP (2.0 equiv.) were
added, and the mixture was stirred for 2.5 h at room tempera-
ture. The reaction afforded desired product 5m but in a low
yield (Scheme 4).
A tentative mechanism for the formation of 3, bis(indolyl)-
methanes 4, and chromeno[2,3-b]indoles
5 is proposed
(Scheme 5, a). pTsOH·H2O helps to eliminate the tert-amine of
the Betti base by protonation, which generates o-quinone
methide (A).[23] A molecule of indole thereafter attacks A to
produce 3-(α,α-diarylmethyl)indole 3. On further heating with
an acid catalyst, the naphthol moiety of 3 is protonated and
eliminated through the formation of alkylideneindoleninium
ion B. Subsequently, another molecule of indole attacks B to
furnish bis(indolyl)methane 4. The mechanism for the formation
of 5 is proposed on the basis of some control experiments
(Scheme 6) and relevant reports on the C2-functionalization of
indole.[16–19] Given that many reactions involving the use of iod-
ine as a catalyst involve a free-radical pathway,[24] we per-
Scheme 6. Control experiments to explore the mechanism.
formed the reaction in the presence of a couple of radical scav- the reaction by using an equivalent amount of iodine in the
engers, such as butylated hydroxytoluene (BHT) and 2,2,6,6- absence of TBHP and found that there was no reaction at all
tetramethylpiperidin-1-oxyl (TEMPO), under the optimized reac- (Scheme 6). This result implies that iodine is probably not the
tion conditions. However, we did not observe any significant active catalytic species. Therefore, we assume that the purpose
reaction inhibition (Scheme 6). Therefore, we conclude that the of TBHP is not only to reoxidize the resulting HI to I2 but also
dehydrogenative coupling reaction of 3 to 5 is not a free-radi- to generate the electrophilic iodine species (“I+”) from the reac-
cal-mediated process. To ensure the role of TBHP, we performed tion of iodine and TBHP.[25]
Scheme 5. (a) Proposed mechanism for the formation of 3, 4, and 5. (b) Proposed mechanism for the prevention of 5 by HI.
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uct was purified by column chromatography (silica gel, 100–
200 mesh; ethyl acetate/hexane).
To gain more insight into the mechanism, we next per-
formed the reaction by using a stoichiometric amount of both
iodine and the base, including NaHCO3, Cs2CO3, and Et3N, in
the absence of TBHP. We obtained a good yield of 5m, although
a longer time was needed relative to that required for the
I2/TBHP method. These results suggest that in situ generation
of “I+” is not indispensable to the reaction. Iodination of 3 may
take place by direct attack either to iodine (path a, Scheme 5,
a) or to “I+” (path b, Scheme 5, a). Therefore, we strongly believe
that the expulsion of HI from the reaction medium is necessary
for a successful reaction either by means of neutralization (us-
ing base) or reoxidation to I2 (using oxidant). To reinforce this
thought, whether HI could prevent product formation, we per-
formed a dehydrogenative coupling in the presence of an
General Procedure for the Synthesis of 5 (from 1 and 2): Com-
pound 2 (0.5 mmol) was added to a solution of 1 (0.5 mmol) in
toluene (1 mL). Then, pTsOH·H2O (9.5 mg, 0.1 equiv.) was added,
and the mixture was heated at 100 °C for 3–5 h and brought to
room temperature. I2 (13 mg, 0.1 equiv.) and TBHP (70 % in H2O,
128.5 mg, 2.0 equiv.) were added, and the mixture was stirred at
room temperature for 2–3 h (monitored by TLC). The solvent was
removed under reduced pressure, and the crude product was puri-
fied by column chromatography (silica gel, 100–200 mesh; ethyl
acetate/hexane).
Acknowledgments
equivalent amount of HI under the optimized conditions. We M. L. D. is thankful to the Science and Engineering Research
observed a remarkable decrease in the yield, and we were able Board (SERB), India for financial support (grant number SB/FT/
to isolate 5m in only 20 % yield even after 4 h (Scheme 6). The CS-073/2014) under the Fast Track Scheme. P. K. B. is thankful
presence of HI seems to prevent the formation of 5 most likely to Department of Biotechnology (DBT), New Delhi, India (grant
through the pathway shown in Scheme 5 (b).
number BCIL/NER-BPMC/2015-230) and the Department of Sci-
ence and Technology (DST), New Delhi (grant number SB/FT/
CS-100/2012) for financial support. C. D. P. is thankful to DST for
a research fellowship.
Conclusions
In summary, we successfully developed reactions of Betti base
with indoles by which we can efficiently synthesize 3-(α,α-di-
arylmethyl)indoles and chromeno[2,3-b]indoles. In addition, we
revealed a new reaction strategy for which naphthol/phenol
behaves as a leaving group to generate bis(indolyl)methane de-
rivatives. The reactions do not use any expensive metal catalyst
or solvent. Neither dry solvents nor precautions for an inert
atmosphere are required. This method for the synthesis of 3-
(α,α-diarylmethyl)indoles and chromeno[2,3-b]indoles should
be of great utility in medicinal chemistry. Further studies re-
garding applications of these reactions and screening of biolog-
ical activities of the synthesized compounds are underway and
will be disclosed in due course.
Keywords: Nitrogen heterocycles · Fused-ring systems · C–O
bond formation · Dearylation · Betti bases
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General Procedure for the Synthesis of 4: Compound
2
(1.0 mmol) was added to a solution of 1 (0.5 mmol) in toluene
(2 mL). Then, pTsOH·H2O (24 mg, 0.25 equiv.) was added, and the
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0.1 equiv.) and TBHP (70 % in H2O, 128.5 mg, 2.0 equiv.) were added
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Received: May 2, 2016
Published Online: ■
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Synthetic Methods
M. L. Deb,* C. D. Pegu, B. Deka,
P. Dutta, A. S. Kotmale,
P. K. Baruah* ....................................... 1–9
Brønsted-Acid-Mediated Divergent
Reactions of Betti Bases with Ind-
oles: An Approach to Chromeno[2,3-
b]indoles through Intramolecular
Dehydrogenative C2-Alkoxylation of
Indole
Parents of three siblings: Three differ- the reaction of indole with Betti bases.
ent kinds of indole derivatives, namely, o-Quinone methide is the key interme-
3-(α,α-diarylmethyl)indoles,
chrom- diate in the reactions. A metal-free
eno[2,3-b]indoles, and bis(indolyl)- dearylation is also reported here for
methanes, can be synthesized from the first time.
DOI: 10.1002/ejoc.201600546
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© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim