Water as an efficient medium for the synthesis of tetrahydro-β-carbolines via Pictet-Spengler reactions

Article abstract of DOI:10.1016/j.tetlet.2006.12.112

A mild and efficient protocol for the Pictet-Spengler reaction in water using an acid catalyst has been described. The condensation of tryptophan, tryptamine, and N_b-benzyl tryptophan with different aldehydes having both electron-withdrawing and -donating substituents in the presence of a catalytic amount of TFA in water furnished tetrahydro-β-carbolines in good isolated yields. A salient feature of the water mediated Pictet-Spengler reaction was the general trend observed during the condensation of Trp-OMe and aryl/aliphatic aldehydes furnishing diastereomeric mixtures with a preference for the cis-isomer.

Full text of DOI:10.1016/j.tetlet.2006.12.112

Tetrahedron Letters 48 (2007) 1379–1383
Water as an efficient medium for the synthesis of
tetrahydro-b-carbolines via Pictet–Spengler reactionsI
Biswajit Saha, Sunil Sharma, Devesh Sawant and Bijoy Kundu*
Medicinal and Process Chemistry Division, Central Drug Research Institute, Lucknow 226 001, India
Received 5 October 2006; revised 11 December 2006; accepted 19 December 2006
Available online 23 December 2006
Abstract—A mild and efficient protocol for the Pictet–Spengler reaction in water using an acid catalyst has been described. The con-
densation of tryptophan, tryptamine, and Nb-benzyl tryptophan with different aldehydes having both electron-withdrawing and
-donating substituents in the presence of a catalytic amount of TFA in water furnished tetrahydro-b-carbolines in good isolated
yields. A salient feature of the water mediated Pictet–Spengler reaction was the general trend observed during the condensation
of Trp-OMe and aryl/aliphatic aldehydes furnishing diastereomeric mixtures with a preference for the cis-isomer.
ꢀ 2007 Elsevier Ltd. All rights reserved.
The Pictet–Spengler reaction1 is a widely used method
for C–C bond formation.2 In general, it is a two-step
method and involves acid catalyzed condensation of
an aliphatic amine attached to a sufficiently reactive aro-
matic nucleus with aldehydes. It is now established as a
method of choice for the construction of tetrahydro-b-
carboline (THBC) and -isoquinoline frameworks; how-
ever, the current literature mostly relates to the synthesis
of THBC. The latter is found abundantly in the plant
and animal kingdom, and many exhibit potent biologi-
cal activities.3 1,2,3,4-Tetrahydro-b-carboline-3-carbox-
ylic acids, generally found in foods, arise from the
condensation of L-tryptophan and aldehydes.4 Research
in the last two decades has described the occurrence of
tetrahydro-b-carbolines and b-carbolines in biological
tissues and fluids,5 in fruit- and meat-derived products
such as juices, jams6 and sausages.7 These compounds
are readily produced, as a result of a reaction between
tryptophan and/or tryptamine and aldehydes, during
the production, processing and storage of food prod-
ucts.8 It has been argued that dietary sources provide
tetrahydro-b-carbolines that may subsequently accumu-
late in biological tissues and fluids.
Natural products with a b-carboline nucleus possess
widespread and potent biological activities. The
reported effects of this class of compounds comprise
antineoplastic (tubulin binding),9,10 anticonvulsive,
hypnotic and anxiolytic (benzodiazepine receptor
ligands),11,12 antiviral,3a antimicrobial5 as well as topoi-
somerase-II inhibition,13 inhibition of cGMP-dependent
processes,14 and antiplasmodial activity.15,16 The incre-
asing popularity of the Pictet–Spengler reaction has
been fueled by the ubiquitous nature of nitrogen-
containing compounds in drugs and natural products.17
In this context, several groups have studied the detailed
mechanistic aspects of this reaction and have developed
a number of diastereo- and enantioselective methods for
the Pictet–Spengler cyclization.18,19 However, despite
the diverse synthetic routes in both protic and aprotic
solvents reported so far for this reaction, the strategy
has not been investigated in water. The use of water as
a medium for this extensively used C–C bond forming
reaction would greatly contribute to the development
of an environmentally friendly process since it is cheap,
readily available, and nontoxic. Indeed, industry prefers
to use water as a solvent rather than toxic organic sol-
vents and in recent years, water has been demonstrated
as an ideal medium for many organic transformations
even if starting materials and products appear to be
insoluble.20 Many organic reactions such as Claisen
rearrangement, aldol condensation, benzoin condensa-
tion, and Diels–Alder cycloaddition exhibit rate
enhancement in water.21 Recently, a comprehensive
Keywords: Pictet–Spengler cyclization; b-Carboline; Stereoselective
reaction; Mannich bases.
q CDRI Communication No. 7124.
*
Corresponding author. Tel.: +91 522 2612411–18x4383; fax: +91 522
2623405; e-mail: bijoy_kundu@yahoo.com
0040-4039/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.12.112

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B. Saha et al. / Tetrahedron Letters 48 (2007) 1379–1383
review on C–C bond formation in aqueous conditions
has been published.22 The significant enhancement in
the rate of the reaction in water has been attributed to
hydrophobic packing,23 solvent polarity,24 hydration,25
and hydrogen bonding.26
carry out the reaction at elevated temperatures as
racemization has been reported under heating.29
For characterization of the crude cyclized product 2a,
we initially isolated the Pictet–Spengler product as a
mixture of diastereomers to determine the yields and
cis:trans ratios. This was followed by the separation of
the cis and trans diastereomers by column chromatogra-
phy and characterization using HPLC, MS, and NMR.
The assignments of the stereochemistry were based on
In this Letter we describe a mild, convenient, and simple
procedure for the condensation of an amine and an alde-
hyde to give tetrahydro-b-carbolines in water in the
presence of an acid catalyst. The studies are part of
our ongoing program27 for the development of new vari-
ants/applications of Pictet–Spengler reactions.
13
NOESY, HMBC, and by C NMR30 experiments
developed by Cox and Cook.2c
Initially, the two-component Pictet–Spengler reaction of
freshly distilled benzaldehyde (0.45 mmol) and trypto-
phan methyl ester (0.45 mmol) was examined in water
(7.5 mL) at room temperature in the presence of a series
of acid catalysts, traditionally used under Pictet–Spen-
gler protocols. We were pleased to see that the Pictet–
Spengler reactions in 10% TFA–water, proceeded
smoothly and afforded the desired compound in 82%
isolated yield (HPLC revealed a mixture of two diaste-
reomers) at room temperature (Table 1).28 Reduction
in the concentration of TFA from 10 to 5 or 2% pro-
duced cyclized products in diminished yields. endo Cycli-
zation in the presence of 10% AcOH at rt furnished the
desired compound in only 23% yield. The use of other
acid/Lewis acid catalysts traditionally used under Pic-
tet–Spengler protocols such as p-TsOH and Yb(OTf)3
at rt or complete absence of acid catalyst failed to pro-
duce endo cyclized products. No attempt was made to
After successfully optimizing the reaction conditions in
water, we conducted a broader investigation of this reac-
tion utilizing various amine substrates and aldehydes.
The results of the Pictet–Spengler reaction of trypto-
phan methyl ester (1a; L-Trp-OMe), tryptamine (1b)
and Nb-benzyl-L-tryptophan methyl ester (1c) with
different aldehydes are summarized in Table 1.
In 10% TFA–water, aryl aldehydes having either
electron-withdrawing or -donating groups underwent
Pictet–Spengler reaction with Trp-OMe to furnish 2a–g
in good yields. This is unlike the traditional Pictet–Spen-
gler protocol involving aprotic solvents wherein alde-
hydes bearing electron-donating substituents failed to
undergo cyclization and furnished imines as the only
product. This was attributed to the decrease in the reac-
tivity of the iminium ion intermediate derived from alde-
hydes bearing the electron-donating group,31 which in
Table 1.
R
R
R1CHO, 10% TFA in H O, rt,
2
HN
X
N
X
N
H
N
H
1a/1c = 24 h.
1b = 36 h.
R1
2: X = H; R = COOCH3
3: X = H; R = H
1a = R = COOCH3; X = H
1b = R = H; X = H
4: X = CH2C6H5; R = COOCH3
1c = R = COOCH3; X = CH2C6H5
Entry
Amine
R1
Producta
Yieldb (%)
Cis:transc
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
1a
1a
1a
1a
1a
1a
1a
1a
1a
1b
1b
1b
1b
1b
1c
1c
1c
4-NO2–C6H4
C6H5
2a
2b
2c
2d
2e
2f
83
82
75
68
72
77
79
65
68
72
75
64
61
45
73
77
61
75:25
70:30
83:17
90:10
60:40d
80:20
55:45
70:30d
75:25d
—
—
—
—
—
(0:100)
(0:100)
(0:100)
4-CH3–C6H4
2-HO–C6H4
4-(CH3)2N–C6H4
4-Br–C6H4
4-CH3O–C6H4
CH3–CH2–
C6H5CH2
2g
2h
2i
4-NO2–C6H4
C6H5
3a
3b
3c
3d
3e
4a
4b
4g
4-CH3–C6H4
2-HO–C6H4
4-(CH3)2N–C6H4
4-NO2–C6H4
C6H5
4-CH3O–C6H4
a Compound 2 = diastereomeric mixture, 3 = enantiomeric mixture, 4 = trans-isomer.
b Yields are quoted for the pure isolated cis/trans mixture of diastereoisomers.
c As determined by integration of the 1H NMR spectrum ( 3%). The stereochemistry of the diastereomers was determined by 13C NMR
spectroscopy using the method of Cox and Cook2c and Bailey et al.29
d Diastereomers not separated.

B. Saha et al. / Tetrahedron Letters 48 (2007) 1379–1383
1381
Table 2. Comparative profile of the Pictet–Spengler reaction of aldehydes having electron-donating groups with amines under three different
protocols (A, B, and C)
Amine
Aldehydes
Product
Yield (%) under different protocolsa
B
A
C
1a
1a
1b
1b
4-Dimethylaminobenzaldehyde
Salicylaldehyde
4-Dimethylaminobenzaldehyde
Salicylaldehyde
2e
2d
3e
3d
72
68
45
61
38
42
22
19
NR
NR
NR
NR
a Protocol A: 10% TFA in water, rt; protocol B: 10% TFA in DCM, rt; protocol C: 10 mol % p-TsOH in toluene, reflux.; NR = no reaction.
turn prevented the formation of tetrahydro-b-carbo-
lines. We further established this fact experimentally
by examining the Pictet–Spengler reaction of the aryl
aldehydes having electron-donating groups (salicylalde-
hyde and 4-dimethylaminobenzaldehyde) with 1a in
10% TFA–water, 10% TFA–dichloromethane and
10 mol % p-TsOH in toluene at reflux (Table 2).
and 61%, respectively (Table 2). It is thus apparent that
in 10% TFA–water, the electrophilicity (a driving force
for endo cyclization) of the aldiminium ions derived
from aryl aldehydes, irrespective of their electronic envi-
ronment, appears to be enhanced, a phenomenon, which
is neither observed in 10% TFA–dichloromethane nor in
p-TsOH–toluene.
Condensation of Trp-OMe with salicylaldehyde in apro-
tic medium and in dichloromethane furnished cyclized
products in 0% and 42% yields, respectively, while the
same reaction in water furnished the Pictet–Spengler
product in 68% isolated yield. Similarly, condensation
of 4-dimethylaminobenzaldehyde with 1a in toluene
again failed to produce the cyclized product, whereas
dichloromethane and water furnished endo cyclized
products in 22% (Table 2) and 72% yields, respectively.
Thus, water, probably due to its unique abilities such as
hydrogen bonding and high dielectric constant appears
to be a more efficient medium than toluene or dichloro-
methane in promoting endo cyclization of aldimines
derived from Trp-OMe and aldehydes with different
electronic environments. Further, it is interesting to note
that using our protocol at room temperature, condensa-
tion of 1a with different aldehydes furnished the cis 1,
3-disubstituted tetrahydro-b-carboline as the major
isomer, whereas reports in the literature for the same
set of reactions in aprotic and protic media depict
no general trend in the diastereoselectivity.2c,32 The
Pictet–Spengler product 2d derived from 1a and salicyl-
aldehyde exhibited the best cis selectivity (9:1).
To enhance further the scope of our strategy, we exam-
ined the reaction of Nb-benzyl-L-Trp-OMe (1c) with
three different aryl aldehydes: 4-nitrobenzaldehyde, 4-
anisidine, and benzaldehyde in water. The utility of
the substrate 1c has been demonstrated, (1) in enhancing
the electrophilicity of the iminium ion derived from
aldehydes having an electron-donating substitutent (sal-
icylaldehyde), which in turn favors cyclization and, (2)
in the diastereoselective synthesis of the trans-isomer
of the 1,2,3-trisubstituted tetrahydro-b-carbolines.2c,28
In 10% TFA–water, the Pictet–Spengler products (4a,
4b, and 4g) derived from 1c were obtained in good
isolated yields (Table 1, entries 15, 16, and 17) and, as
expected, were obtained as a single trans-isomer. Their
structural identity was established using the 13C chemi-
cal shift of the N-benzylic carbon as described earlier
by Bailey et al.29 and accordingly, the d value for the
benzylic carbon for compound 4b matched with the re-
ported value for the trans-isomer. Aliphatic aldehydes:
propanaldehyde (Table 1, entry 8) and phenylacetalde-
hyde dimethylacetal (Table 1, entry 9) underwent endo
cyclization with 1a in good yields and high cis selectivity;
however, the ketones completely failed to undergo endo
cyclization in water.
Encouraged by our results with Trp-OMe, we extended
our protocol to tryptamine (1b), which is known to be a
less reactive substrate than Trp-OMe, toward Pictet–
Spengler reaction. Interestingly, using our protocol,
tryptamine successfully underwent endo cyclization in
water in good yields, when condensed with 4-nitrobenz-
aldehyde, benzaldehyde, 4-methylbenzaldehyde, salicyl-
aldehyde, and 4-dimethylamino benzaldehyde (Table 1,
entries 10–14). Our findings are in contrast to the reac-
tion in aprotic solvents where tryptamine furnished only
Schiff’s bases when condensed with benzaldehyde/sali-
cylaldehdye/4-dimethylaminobenzaldehyde and failed
to undergo endo cyclization due to the poor electro-
philicity of the resulting imines.2c Similarly, in 10%
TFA–dichloromethane, reaction of 4-dimethyl amino-
benzaldehyde and salicylaldehyde with tryptamine fur-
nished the endo cyclized product in only 22% and 19%
yields, respectively (Table 2). However, in 10% TFA–
water, the yield for the same set of reactions was 45%
In conclusion, we have developed a mild and efficient
protocol for the synthesis of tetrahydro-b-carbolines
via Pictet–Spengler reaction in water. With judicious
choice of tryptophan derivative (1a or 1c) good yields
and high cis or trans selectivity for the Pictet–Spengler
products can be obtained in water. Another interesting
feature of our studies was that aryl aldehydes bearing
either electron-withdrawing or -donating groups suc-
cessfully underwent the Pictet–Spengler reaction with
equal ease. Finally, our Pictet–Spengler strategy in water
might be an attractive starting point for the synthesis of
indole alkaloids by avoiding the use of toxic solvents.
Acknowledgment
S.S., B.S. and D.S. are grateful to CSIR, New Delhi,
India, for fellowships.

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B. Saha et al. / Tetrahedron Letters 48 (2007) 1379–1383
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28. Representative Procedure: To a 10% solution of TFA in
water (7.5 mL), tryptophan methyl ester (2.0 mmol) and
aldehyde (2.0 mmol) were added at rt. The mixture was

B. Saha et al. / Tetrahedron Letters 48 (2007) 1379–1383
1383
further stirred at ambient temperature and the progress of
the reaction was monitored by TLC. Upon completion
of the reaction, 5% aqueous NaHCO3 was added to
quench the acid in the reaction mixture. The product was
extracted using ethyl acetate (50 mL) and the organic layer
was washed with water (2 · 10 mL), brine solution
(1 · 10 mL) and finally dried over anhydrous Na2SO4. It
was then evaporated in vacuo to afford a residue and
purified by column chromatography to give 2. Purification
of the crude reaction mixture was carried out by flash
column chromatography to afford a cis/trans mixture of
diastereoisomers. Care was taken to avoid separation of
the isomers, to ensure that NMR would give accurate
values for the cis:trans ratios. Finally, the mixture was
again subjected to column chromatography on silica gel
(200–400 mesh) using hexane/EtOAc (5:1) as eluent to
separate both the isomers and their stereochemistry was
assigned using the methods of Cox and Cook2c and Bailey
et al.29
Compound 2d: cis-isomer, white solid; yield 59%; mp:
162–164 ꢁC; 1H NMR (CDCl3, 300 MHz) d 7.54–7.51
(2H, m), 7.31–7.26 (2H, m), 7.21–7.12 (3H, m), 6.98–6.93
(1H, m), 6.86 (1H, d, J = 7.7 Hz), 5.37 (1H, s), 3.98–3.96
(1H, m), 3.89 (3H, s), 3.54–3.30 (1H, m), 3.14–2.98 (1H,
m); 13C NMR (CDCl3, 75.5 MHz) d 172.14, 157.69,
136.50, 132.39, 130.27, 128.50, 127.14, 123.45, 122.32,
119.93, 119.61, 118.45, 118.01, 111.24, 107.92, 58.92,
56.63, 52.76, 24.94, IR (KBr) 3397, 3334, 2941, 2849,
1741, 1594 cmÀ1; MS (ES+) m/z: 323.1 (M+H)+. Anal.
Calcd for C19H18N2O3 C, 70.79; H, 5.63; N, 8.69%.
Found: C, 70.59; H, 5.53; N, 8.89%.
(CDCl3, 300 MHz) d 7.77 (1H, br s), 7.59–7.56 (1H, m),
7.26–7.24 (2H, m), 7.20–7.11 (5H, m), 5.34 (1H, s), 4.00
(1H, t, J = 6.1 Hz), 3.74 (3H, s), 3.33–3.26 (1H, m), 3.18–
3.11 (1H, m), 2.36 (3H, s); 13C NMR (CDCl3, 75 MHz) d
174.28, 139.14, 138.03, 136.30, 133.56, 129.52, 128.48,
127.12, 122.01, 119.59, 118.34, 111.07, 108.80, 54.79,
52.55, 52.25, 24.85, 21.25; IR (KBr) 3287, 2949, 2843,
1744, 1595 cmÀ1; MS (ES+) m/z 321.1 (M+H).
1
Compound 3b: grey solid; yield 75%; mp: 160–161 ꢁC; H
NMR (CDCl3, 300 MHz) d 7.64 (1H, br s), 7.57 (1H, dd,
J = 5.5, 2.9 Hz), 7.38–7.32 (5H, m), 7.25–7.22 (1H, m),
7.19–7.11 (2H, m), 5.18 (1H, s), 3.43–3.36 (1H, m), 3.20–
3.11 (1H, m), 3.00–2.82 (2H, m); 13C NMR (CDCl3,
75.5 MHz) d 141.86, 136.03, 134.48, 128.90, 128.68,
128.30, 127.43, 121.78, 119.43, 118.30, 110.99, 110.23,
58.09, 42.77, 22.57, IR (KBr) 3406, 2925, 2846, 1594 cmÀ1
;
MS (ES+) m/z: 271.1 (M+Na)+.
Compound 4b: yellow solid; yield 77%; mp: 218–220 ꢁC
[Bailey et al. Heterocycles 1987, 26, 389; mp: 221–
223 ꢁC]; 1H NMR (CDCl3, 300 MHz) d 7.51–7.47 (3H,
m, J = 8.6, 2.2 Hz), 7.36 (1H, s), 7.33–7.16 (8H, m), 7.22–
7.10 (1H, m), 7.10–7.07 (2H, m), 5.46 (1H, s), 3.94 (1H, t,
J = 4.59 Hz), 3.87 (2H, d, J = 5.58 Hz), 3.62 (3H, s), 3.21
(2H, d, J = 1.17 Hz); 13C NMR (CDCl3, 75 MHz) d
173.76, 142.34, 139.59, 136.65, 135.10, 129.08, 128.90,
128.72, 128.51, 128.23, 127.26, 127.17, 121.76, 119.45,
118.38, 111.00, 106.49, 61.01, 56.21, 54.51, 51.55, 24.60;
IR (KBr) 3338, 2925, 2843, 1721 cmÀ1; MS (ES+) m/z: 397
(M+H). Anal. Calcd for C26H24N2O2: C, 78.76; H, 6.10;
N, 7.07%. Found: C, 78.66; H, 6.34; N, 6.88%.
29. Bailey, P. D.; Hollinshead, S. P.; McLay, N. R.; Morgan,
K.; Palmer, S. J.; Prince, S. N.; Reynolds, C. D.; Wood, S.
D. J. Chem. Soc., Perkin. Trans 1 1993, 431–436.
30. See Supplementary data for details.
31. Jiang, W.; Sui, Z.; Chen, X. Tetrahedron Lett. 2002, 43,
8941–8945.
32. (a) Mayer, J. P.; Davis, D. B.; Zhang, J.; Beaton, G.;
Bjergarde, K.; Andersen, C. M.; Goodman, B. A.;
Herrera, C. J. Tetrahedron Lett. 1996, 37, 5633; (b) Yang,
L.; Guo, L. Tetrahedron Lett. 1996, 37, 5041; (c) Yen, Y.
H.; Chu, Y. H. Tetrahedron Lett. 2004, 45, 8137; (d)
Cheng, C. C.; Chu, Y. H. J. Comb. Chem. 1999, 1, 461; (e)
Yen, Y. H.; Chu, Y. H. Tetrahedron Lett. 2004, 45, 8137.
Compound 2c: cis-isomer: white solid; yield 61%; mp:
1
142–144 ꢁC; H NMR (CDCl3, 300 MHz) d 7.55 (1H, dd,
J = 5.5, 3.0 Hz), 7.46 (1H, br s), 7.30–7.28 (2H, m), 7.21–
7.11 (5H, m), 5.23 (1H, s), 4.00 (1H, dd, J = 11.1, 4.2 Hz),
3.83 (3H, s), 3.28–3.21 (1H, m), 3.07–2.98 (1H, m), 2.39
(3H, s); 13C NMR (CDCl3, 75.5 MHz) d 173.39, 138.52,
137.83, 136.25, 135.04, 129.74, 128.67, 127.26, 122.01,
119.71, 118.32, 111.07, 108.90, 58.47, 57.05, 52.38, 25.87,
21.33; IR (KBr) 3344, 2941, 2845, 1717, 1593 cmÀ1; MS
(ES+) m/z: 321.1 (M+H)+, HRMS (EI+) C20H20N2O2 m/z
calcd 320.1525 for [M]+ found 320.1527; trans-isomer:
Yield 11%; white solid; mp: 174–176 ꢁC; 1H NMR