Mild and efficient cyanuric chloride catalyzed Pictet-Spengler reaction

Article abstract of DOI:10.3762/bjoc.9.140

A practical, mild and efficient protocol for the Pictet-Spengler reaction catalyzed by cyanuric chloride (trichloro-1,3,5-triazine, TCT) is described. The 6-endo cyclization of tryptophan/tryptamine and modified Pictet-Spengler substrates with both electr

Full text of DOI:10.3762/bjoc.9.140

Mild and efficient cyanuric chloride catalyzed
Pictet–Spengler reaction
Ashish Sharma, Mrityunjay Singh, Nitya Nand Rai and Devesh Sawant*
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2013, 9, 1235–1242.
Department of Medicinal Chemistry, National Institute of
Pharmaceutical Education and Research (NIPER)-Rae Bareli, ITI
Compound, Rae Bareli-229010 (UP), India
doi:10.3762/bjoc.9.140
Received: 20 March 2013
Accepted: 07 June 2013
Published: 26 June 2013
Email:
Devesh Sawant* - devesh.sawant@niperraebareli.edu.in
NIPER-RBL communication No. 001
Associate Editor: T. J. J. Müller
* Corresponding author
Keywords:
β-carboline; cyanuric chloride; 6-endo cyclization; Pictet–Spengler;
© 2013 Sharma et al; licensee Beilstein-Institut.
License and terms: see end of document.
TCT
Abstract
A practical, mild and efficient protocol for the Pictet–Spengler reaction catalyzed by cyanuric chloride (trichloro-1,3,5-triazine,
TCT) is described. The 6-endo cyclization of tryptophan/tryptamine and modified Pictet–Spengler substrates with both electron-
withdrawing and electron-donating aldehydes was carried out by using a catalytic amount of TCT (10 mol %) in DMSO under a
nitrogen atmosphere. TCT catalyzed the Pictet–Spengler reaction involving electron-donating aldehydes in excellent yield. Thus, it
has a distinct advantage over the existing methodologies where electron-donating aldehydes failed to undergo 6-endo cyclization.
Our methodology provided broad substrate scope and diversity. This is indeed the first report of the use of TCT as a catalyst for the
Pictet–Spengler reaction.
Introduction
The Pictet–Spengler reaction is an important class of name cation of the conventional reaction led to the synthesis of a
reaction employed extensively for the synthesis of tetrahydro-β- polyheterocyclic skeleton that mimics the natural products [12-
carboline [1-9]. Typically, the Pictet–Spengler reaction is a two- 17]. The 6-endo cyclization is the rate-limiting step in the
step reaction. The first step is the condensation of aliphatic Pictet–Spengler reaction and electrophilicity of the imine is the
amine substrates such as tryptophan/tryptamine and aldehydes driving force of the reaction [1]. The Pictet–Spengler reaction is
to generate the intermediate imine in situ. The intermediate catalyzed by Brønsted acids, as they convert the intermediate
imine then undergoes a 6-endo cyclization to furnish the imine to the corresponding iminium ion, thus making it more
cyclized product, tetrahydro-β-carboline [10]. Recently, electrophilic [18-22]. Conventionally, TFA [18], HCl [20],
arylamines have been employed instead of the aliphatic amines H2SO4 [21] and p-TsOH [22] are employed as Brønsted acids.
for the Pictet–Spengler reaction. These reactions are generally However, recently several other aprotic or Lewis acids, such as
termed as modified Pictet–Spengler reaction [11]. This modifi- Yb(OTf)3 [23-25], AuCl3/AgOTf [26], Me3SiCl [27,28],
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Beilstein J. Org. Chem. 2013, 9, 1235–1242.
BF3·Et2O [29], iodine [30], zeolite [31] and enzymes [32-34], vation, we focused our attention on optimizing the reaction
have been used for carrying out the Pictet–Spengler reaction.
conditions. First, various solvents were examined. These find-
ings are reported in Table 1. In general, the reaction proceeded
Though the Pictet–Spengler reaction has been studied exten- well in polar solvents such as EtOH, acetonitrile and DMSO. In
sively under a variety of Brønsted/Lewis acid catalyzed condi- contrast, the reaction failed to produce the desired compounds,
tions [35], most of these conditions failed to facilitate a 6-endo when nonpolar solvents such as toluene, DCM, dioxane and
cyclization where salicylaldehyde (or any electron-donating THF were used [47]. DMSO produced the best results, even
aldehyde such as 4-dimethylaminobenzaldehyde) was used as a though fully aromatized β-carboline was obtained as a side
source of aldehyde [1,22]. Even harsher reaction conditions product. This drawback can be excluded by employing an inert
such as heating at a high temperature furnished the completely atmosphere. Thus, reactions carried out in DMSO at 100 °C by
oxidized product, β-carboline [1]. The reason for this failure using 20 mol % TCT under nitrogen (Table 1, entry 8) demon-
could be attributed to the reduced electrophilicity of the corres- strated the best results. Next, we examined the amount of TCT
ponding imine generated from these aldehydes. As a result of its needed for the cyclization and 20 mol % of TCT was found to
reduced electrophilicity the imine failed to cyclize under the be optimal for the reaction. An increase of the catalytic loading
conditions reported earlier. A literature search revealed that the led to the appearance of side products on a TLC. Reaction
acyliminium strategy has been used to overcome this defect temperature was found to be optimal at 100 °C, since a lower
[25,36,37]. However, one has to cleave the N-acyl group of the temperature (50 to 80 °C) required longer reaction time (48 h)
product in order to generate the desired compound, and thus, an for the completion, and a higher temperature (beyond 120 °C)
additional deprotection step has to be introduced. Instead, a produced undesired side products [48].
mild and efficient catalyst that can effectively produce iminium
species in situ could generate the compound of interest without Once we had identified the optimized reaction conditions, we
adding any extra steps. We envisaged that the use of cyanuric scrutinized the substrate scope and limitation of the TCT-
chloride (2,4,6-trichloro-1,3,5-triazine, TCT) [38-45] as a catalyzed Pictet–Spengler reaction. We explored two different
source of HCl could trigger the 6-endo cyclization under dry
and mild conditions. TCT is used in many reactions as a source
Table 1: Method development of the TCT-catalyzed Pictet–Spengler
of anhydrous HCl in organic synthesis [46]. Moreover, it is an
attractive reagent due to its easy availability and low cost. It is
well documented in the literature that TCT reacts with the in-
cipient moisture and produces three moles of HCl and cyanuric
acid as a byproduct [46]. The latter can be removed by a simple
aqueous workup. Interestingly, this reagent has not been
explored for the Pictet–Spengler reaction yet. Here we report
the use of cyanuric chloride as a simple, inexpensive and effi-
cient catalyst for the Pictet–Spengler reaction.
reaction for the condensation of tryptamine (1) and 4-tolualdehyde
(2a).
Entry Solvent
Temp.
(°C)
TCT
(mol %)
Time
(h)
Isolated
yield (%)
1
2
3
4
5
6
7
8
EtOH
85
20
20
20
5
16
16
16
16
16
4
61a
75a
NRb
45
acetonitrile
toluene
DMSO
85
110
100
100
100
100
100
DMSO
10
20
30
20
68
DMSO
85c
78d
92
Results and Discussion
DMSO
8
We began our studies by reacting tryptamine (1) and 4-tolualde-
hyde (2a) in the presence of 20 mol % TCT in ethanol
(Scheme 1). The reaction showed the formation of the cyclized
product 3a albeit with the presence of starting materials even
after prolonged heating (16 h). Encouraged by this initial obser-
DMSO/N2
8
aStarting material recovered, ban intermediate imine observed as the
major product, cfully aromatic β-carboline observed as a side product
on TLC, dformation of multiple spots observed on TLC.
Scheme 1: The Pictet–Spengler reaction of tryptamine with 4-tolualdehyde.
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Beilstein J. Org. Chem. 2013, 9, 1235–1242.
Pictet–Spengler substrates for the TCT-catalyzed reaction as
depicted in Figure 1. Tryptamine (1) was commercially avail-
able, while substrate 4 was synthesized from the nucleophilic
substitution of indole (5) with 2-fluoronitrobenzene (6) to
generate intermediate 7, which was reduced to amine 4 by
Zn/HCl (Scheme 2).
Both substrates reacted with benzaldehyde derivatives and
results are summarized in Table 2. Tryptamine (1) reacted well
with aldehydes with both electron-donating and electron-with-
drawing substituents to furnish 1,2,3,4-tetrahydro-β-carboline 3.
It is interesting to note that salicylaldehyde (2g) and 4-dimethy-
Figure 1: The two Pictet–Spengler substrates employed in the TCT
catalyzed cyclization.
laminobenzaldehyde (2h) produced the desired cyclized prod- such as salicylaldehyde with tryptophan methyl ester or trypta-
ucts 3g and 3h, respectively, when condensed with tryptamine mine in acidic media, provided the 6-endo cyclized product in
(1) in the presence of cyanuric chloride. It is reported in the poor yield along with impurities [1,22]. In contrast, our method-
literature that the condensation of electron-donating aldehydes, ology proved effective in catalyzing the condensation of trypta-
Scheme 2: Synthesis of the Pictet–Spengler substrate 4. Reaction conditions: (a) K2CO3, DMF, 80 °C, 3 h; (b) Zn, AcOH-EtOH, 60 °C, 4 h.
Table 2: Condensation of the Pictet–Spengler substrates 1 and 4 (1 equiv) with aldehyde (1 equiv) in the presence of TCT (20 mol %) in DMSO under
a nitrogen atmosphere.
Entry Substrate
Aldehyde
Product
Time
(h)
Yield
(%)
mp
(°C)
Lit. mp
(°C)
ESI: m/z
(%)
1
2
3
1
1
1
3
4
2
92
83
95
138–139 135–137 [19] 263 [M + H+, 100]
2a
2b
3a
3b
327 [M + H+, 100];
329 [M + H+, 97]
155–157
—a [49]
169–171 170–171 [50] 294 [M + H+, 100]
2c
3c
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Beilstein J. Org. Chem. 2013, 9, 1235–1242.
Table 2: Condensation of the Pictet–Spengler substrates 1 and 4 (1 equiv) with aldehyde (1 equiv) in the presence of TCT (20 mol %) in DMSO under
a nitrogen atmosphere. (continued)
4
1
5
92
205–206 207–208 [50] 283 [M + H+, 100]
2d
3d
5
1
6
85
191–193
—b [51]
279 [M + H+, 100]
2e
3e
6
7
1
1
3
4
88
84
151–152
—c [52]
294 [M + H+, 100]
2f
3f
190–191 189–191 [19] 265 [M + H+, 100]
2g
3g
8
1
6
79
231–233 235–237 [53] 292 [M + H+, 100]
2h
2a
2c
3h
9
4
2
91
160–162
—
309 [M + H+, 100]
8a
10
4
1
88
214–215 213–214 [12] 340 [M + H+, 100]
8b
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Beilstein J. Org. Chem. 2013, 9, 1235–1242.
Table 2: Condensation of the Pictet–Spengler substrates 1 and 4 (1 equiv) with aldehyde (1 equiv) in the presence of TCT (20 mol %) in DMSO under
a nitrogen atmosphere. (continued)
11
4
2
95
205–207
—
329 [M + H+, 100]
2d
8c
12
4
3
85
146–147 145–147 [12] 338 [M + H+, 100]
2h
8d
aNo melting point reported, spectral data of 3b is consistent with the reported spectra. bNo melting point reported. Spectral data of 3e are consistent
with the reported spectra. cNo physical and spectral data are reported.
mine and electron-donating aldehydes. Interestingly, the ortho- the aromatic amine side chain originates from the N-1 of indole.
substitution on benzaldehyde is also well tolerated. For It was subjected to the TCT catalyzed Pictet–Spengler reaction
instance, the condensation of 2-bromobenzaldehyde (2b) or with benzaldehyde derivatives. The results are summarized in
2-nitrobenzaldehyde (2f) with tryptamine in the presence of Table 2.
TCT furnished the title compounds 3b or 3f, respectively, in
excellent yield.
The substrate 4 reacted equally well with both electron-donating
as well as electron-withdrawing aldehydes to yield the 6-endo
The Pictet–Spengler reaction is a two-step process, where an product indolo[1,2-a]quinoxalines 8 (Table 2). It is interesting
aldehyde and an amine first react to give an imine as an inter- to note that the cyclized products of the modified Pictet–Spen-
mediate. This is followed by a 6-endo intramolecular cycliza- gler substrate 4 are fully aromatized. This is probably because
tion of the imine to produce the cyclized product. The second the cyclized dihydro derivatives formed in situ are prone to oxi-
step is the rate-limiting step and the electrophilicity of the imine dation. Substrate 4 furnished the cyclized product faster
is the driving force of the cyclization. HCl generated in situ compared to tryptamine (1). This might be attributed to the
from TCT protonated the imine intermediate to an iminium ion, enhanced electrophilicity of the imine derived from the
which undergoes a cyclization. The presence of an inert arylamine compared to the aliphatic amine as reported earlier
nitrogen atmosphere abated formation of the oxidized product [16].
(β-carboline), thus allowing for a clean reaction. In a nutshell,
the Pictet–Spengler reaction of tryptamine can be elegantly The TCT catalyzed condensation of the Pictet–Spengler
catalyzed by TCT with a high substrate scope and diversity, substrates 1 and 4 with aldehydes furnished tetrahydro-β-carbo-
hence TCT proved to be a robust catalyst in the 6-endo cycliza- line 3 and indolo[1,2-a]quinoxaline 8, respectively. The
tion.
β-carboline skeleton is widely distributed in marine organisms
[54-56]. Eudistomine and manzamine isolated from marine
Recently, the Pictet–Spengler reaction has been successfully invertebrates exhibited promising anticancer activity [57,58].
extended to arylamine substrates [11-17]. These substrates are Tedalafil, a drug based on the tetrahydro-β-carboline skeleton,
designed by replacing the aliphatic amine side chain attached to is widely used to treat erectile dysfunction [59]. Hence, these
activated heterocycles, for example tryptamine (1), by aromatic nuclei constitute an important class of heterocyclic compounds,
amines [11]. Moreover, the aromatic amines can be originated which posses a wide range of pharmacological properties.
from either carbon or nitrogen of the activated heterocycle.
Hence, these substrates are referred to as “modified Conclusion
Pictet–Spengler substrates”. We employed one of the arylamine Here we disclosed the first report of the Pictet–Spengler reac-
substrates for our studies (Figure 1). In substrate 4 (Figure 1), tion catalyzed by cyanuric acid. Both conventional and modi-
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Beilstein J. Org. Chem. 2013, 9, 1235–1242.
fied Pictet–Spengler substrates reacted equally well with elec-
tron-donating and electron-withdrawing aldehydes. TCT proved
effective in catalyzing the 6-endo cyclization of aldehydes such
as salicylaldehyde and 4-dimethylaminobenzaldehyde. These
aldehydes failed to produce the cyclized product in desired
yield under conventional Brønsted acid catalysis and often
produced the oxidized products under harsher reaction condi-
tions. TCT under an inert atmosphere allowed for a clean reac-
tion with a broad substrate scope and application. We demon-
strated application of this methodology for the synthesis of
tetrahydro-β-carbolines 3 and indolo[1,2-a]quinoxalines 8.
These scaffolds are present in numerous biologically active
compounds. Nevertheless, TCT is inexpensive and readily
available. Therefore, this methodology can be easily employed
in the synthesis of a spectrum of pharmacologically active com-
pounds on multigram to industrial scales.
Supporting Information
Supporting Information File 1
Analytical data and copies of 1H and 13C NMR of 3a, 3c,
3h and 8d.
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-9-140-S1.pdf]
Acknowledgements
The authors thank the Open Source Drug Discovery (OSDD)
program of CSIR, New Delhi for funding as well as the Depart-
ment of Pharmaceuticals, Ministry of Chemicals and Fertilizers,
Government of India for granting a fellowship to A.S. and M.S.
We are grateful to Dr. P. K. Shukla, Project Director NIPER-
RaeBareli, and Dr. B. Kundu, Dean, NIPER-RaeBareli for their
support and motivation.
Experimental
References
A typical experimental procedure: Cyanuric chloride
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was poured on the bed of crushed ice to obtain the crude. The
solid so obtained was filtered and washed with chilled water
and 10% EtOAc/hexane solution to remove water-soluble side
products and excess aldehydes. Wherever needed the crude was
further purified either by recrystallization in EtOH or by flash
chromatography.
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