Pictet-Spengler cyclization in room temperature ionic liquid: A convenient access to tetrahydro β-carbolines

Article abstract of DOI:10.1002/jhet.5570430337

1,2,3,4-Tetrahydro-β-carbolines have been synthesized in moderate to good yields in short reaction time using the ionic liquid [bbim] BF₄ as reaction medium and promoter. There was no need for the use of an additional catalyst normally employed

Full text of DOI:10.1002/jhet.5570430337

May-Jun 2006
767
Pictet-Spengler Cyclization in Room Temperature Ionic Liquid:
A Convenient Access to Tetrahydro ꢀ-carbolines
M. Muthukrishnan,* Shivaji V. More, Dinesh R. Garud, C. V. Ramana,
R. R. Joshi and R. A. Joshi*
Organic Chemistry: Technology Division, National Chemical Laboratory,
Dr. Homi Bhabha Road, Pune- 411008, Maharashtra, India.
E-mail: m.muthukrishnan@ncl.res.in
Received August 4 2005
O
O
OMe
NH
OMe
NH2
+ N Bu
BF4
N
Bu
-
+
Ar-CHO
N
H
100 °C; 2-5 h
N
H
R
7
8 a-i
9 a-i
1,2,3,4-Tetrahydro-ꢀ-carbolines have been synthesized in moderate to good yields in short reaction time
using the ionic liquid [bbim] BF4 as reaction medium and promoter. There was no need for the use of an
additional catalyst normally employed in Pictet-Spengler condensation.
J. Heterocyclic Chem., 43, 767 (2006).
Introduction.
N
N
MeO
MeO
ꢀ-Carboline alkaloids are compounds that comprise the
tricyclic pyrido[3,4]indole ring system with alkyl C1-
constituents [1]. This class includes simple tricyclic
eleagnines and harmines (1, Figure 1) as well as a number
of structurally more complex examples such as
yohimbine, ajmalicine and reserpine, which are long
known as hallucinators [2]. The potential of ꢀ-carboline
and 1,2,3,4-tetrahydro-ꢀ-carboline pharmacophore was
well documented in various therapeutic areas such as
alcohol abuse, mental illness, CNS [3], CCK receptor
antagonists [4] and phosphodiesterase inhibitors [5]. The
world drugs index for instance, contains over 200 listings
of this pharmacophore [6]. HR22C16 (3, Figure 1), a
tetrahydro-ꢀ-carboline fused to a hydantoin ring, was
recently reported as a new cell-permeable small-molecule
inhibitor of cell division [7]. Similarly, hydantoins
GR30040X (4) and 5 are reported as potential candidates
for the treatment of erectile dysfunction (ED) and their
mode of action has been well established as the selective
inhibition of PDE5 vs other PDEs (type 5 phospho-
diesterase) [8]. Tadalafil (Cialis®) is a successful ꢀ-
carboline derivative that is presently in the market for the
treatment of ED related diseases [9].
N
N
H
H
Me
Harmine (1)
Harmicine (2)
O
O
N
N
N
N
N
O
N
O
N
H
H
OH
HR22C16 (3)
GR30040X (4)
O
N
CH3
O
N
N
N
O
N
H
O
N
H
O
O
Tadalafil (6)
CialisR
OMe
5
Figure 1. Medicinally Important Natural and Synthetic ꢀ-carbolines.
the synthesis of ꢀ-carboline libraries and we were
interested to explore the possibility of conducting the
Pictet-Spengler reaction in ionic liquids. Application of
ionic liquids in chemical processes has blossomed only
within the last decade. Room temperature ionic liquids
have been utilized as clean solvents and catalysts for
various organic transformations. Interest in this class of
solvent stems from the properties they exhibit. No
significant vapor pressure (thus create no volatile organic
The Pictet–Spengler reaction is a generally used
method for the synthesis of tetrahydro-ꢀ-carboline
derivatives. Normally, strong Brönsted/Lewis acids
ranging from catalytic to stoichiometric amounts are
employed to accomplish the Pictet–Spengler reaction. In
the context of our ongoing research program dealing with
drug discovery lead structure modification, we were
encountered with a need for an efficient methodology for

768
M. Muthukrishnan, S. V. More, D. R. Garud, C. V. Ramana, R. R. Joshi and R. A. Joshi
Vol 43
components), easy separation of organic molecules by
direct distillation/extraction without loss of the ionic
liquids lead to recognize them as an attractive green
alternative to conventional solvents. They are non-
volatile, recyclable, non-explosive. Comprehensive
information about this field may be found in the recent
reviews by Seddon [10] and Holbrey [11] and Welton
[12] and by Wasserscheid [13]. These provide an
excellent and essential source of the physical and
chemical properties of ionic liquids and catalog a range of
reactions that can be carried out in ionic liquids. We
herein describe an extremely facile and environmentally
friendly synthesis of 1,3–disubstituted 1,2,3,4-tetrahydro-
ꢀ-carbolines by carrying out Pictet-Spengler cyclization in
an ionic liquid [bbim]BF4.
Table 1
Pictet-spengler cyclization of 7 with various aromatic aldehydes 8 a-i
Aldehyde
Yield Diastereomeric
Product Reaction
time (h)
(%)
ratio
CHO
9a
2
90
1: 0.9
1: 0.8
1
2
CHO
O
O
70
9b
4
CHO
3
4
5
9c
2
2
85
82
1: 0.7
1: 1
F
CHO
9d
Cl
Scheme 1
CHO
O
O
OMe
NH
9e
2.5
2
84
1: 0.6
1: 0.7
1: 1
OMe
NH2
NO2
+
N
BF4
Bu
3
N
Bu
-
1
CHO
+
Ar-CHO
9f
75
80
N
H
100 °C; 2-5 h
N
6
H
R
F
7
8 a-i
The Pictet-Spengler reaction
9 a-i
CHO
CHO
9g
4
7
8
Cl
Results and Discussion.
9h
9i
2
75
82
1: 0.6
We first examined the Pictet-Spengler condensation of
D-tryptophan methyl ester 7 and benzaldehyde 8a in
different imidazolium based ionic liquids like [bbim]BF4,
[bbim]PF6 and [bbim]Br in the presence of trifluoroacetic
acid (TFA) as an acid catalyst. During the course of the
screening of a variety of reaction conditions such as
different ionic liquids, reaction temperature and reaction
time, we found that [bbim]BF4 was found to be superior in
terms of yield, reaction time and easy isolation of
products as compared with other ionic liquids. During
further optimization, surprisingly, we found that the use
of corrosive, hazardous TFA as a acid catalyst was in fact
not necessary for the efficient Pictet-Spengler cyclization
in ionic liquid [14].
O2N
CHO
5
1: 0.9
9
H3CO
a isolated and unoptimized yields.
the signals for C-1 and C-3 in the trans isomer appeared
at higher field in the carbon spectrum than the analogous
carbons of the corresponding cis isomer. For example,
trans isomer of compound 9i showed the signals of C-1
and C-3 at ꢁ 55.3 and ꢁ 54.4, while in cis isomer the
corresponding signals are at
ꢁ 58.1 and ꢁ 57.0
respectively. In addition, the NMR signals for the proton
at C-1 is more shielded in the cis isomer and appeared at ꢁ
5.19 and in the trans isomer it is at ꢁ 5.34. These values
are in full agreement with the reported NMR data for
compound 9i [8a].
After having optimized the reaction conditions for
Pictet-Spengler cyclization in [bbim]BF4, the potential of
this methodology was extended to variety of substituted
aromatic aldehydes and the results are summarized in
Table 1. In all cases moderate to good yields were
obtained. The identities of all the products were
confirmed by 1H NMR, 13C NMR and mass spectral
Thus, In a typical experiment, treatment of D-
tryptophan methyl ester 7 with benzaldehyde 8a in ionic
liquid [bbim]BF4 at 100 °C for 2 h afforded the
corresponding 1,3-disubstituted 1,2,3,4-tetrahydro-ꢀ-
carboline 9a in 90% Yield (Scheme 1). The products
were isolated as mixtures of diastereomers. The cis and
trans isomers were separated by flash chromatography.
The assignment of cis/trans stereochemistry for
tetrahydro-ꢀ-carboline 9 was based on a detailed study of
1
the H and 13C NMR spectroscopy and by comparison
with the literature data, well established by Cook [15] i.e

May-Jun 2006
Pictet-Spengler Cyclization in Room Temperature Ionic Liquid
769
analyses. For the selected example 9b, the C-1 and C-3
were unequivocally assigned by 1H-13C HSQC NMR
experiment. It has been observed that the substitution
pattern on the aromatic aldehydes seems to have little
effect on the Pictet-Spengler reaction as the aromatic
aldehydes carrying either electron-donating or electron-
withdrawing groups afford comparable results. Moreover,
in the present series of tetrahydro-ꢀ-carbolines 9, the cis
isomer is less polar than the trans, as indicated by TLC Rf
values (silica, ethyl acetate/pet ether developing solvent).
It is important to mention that, from the known literature
results [8a], the Pictet-Spengler cyclization of racemic
tryptophan methyl ester 7 with p-anisaldehyde 8i
catalyzed by TFA in molecular organic solvent, e.g.
methylenechloride gave corresponding 1,3-disubstituted
1,2,3,4-tetrahydro-ꢀ-carboline 9i in 62% yield after
stirring at room temperature for 4 days, in comparison to
the 82% yield in entry 9 of Table 1.
The advantage of the use of ionic liquids as novel
reaction media for this Pictet-Spengler cyclization is that
these ionic liquids can be easily recovered and reused.
Since the products were weakly soluble in the ionic phase,
they were easily separated by simple extraction with ether.
The remaining viscous ionic liquid was washed thoroughly
with ether and reused successfully for selected compounds
in Table 1 (entry 1 & 3) and obtained moderate to good
yields in second and third runs (Table 2).
1,2,3,4-tetrahydro–ꢀ-carbolines using the advantage of
ionic liquid as a solvent and promoter. There is no need to
add any acid catalyst. Shorter reaction time, easy work up,
moderate to good isolated yield and reusability of ionic
liquid makes this method simple for operation and useful
in combinatorial chemistry to prepare vast array of
tetrahydro-ꢀ-carbolines in short period.
EXPERIMENTAL
Melting points were measured using a Buchi B-540 apparatus
and are uncorrected. NMR spectra were obtained with a Bruker
AC-200 (200 MHz) spectrometer or a Bruker MSL 300 (300
MHz) or a Bruker DRX 500 (500 MHz) spectrometer in CDCl3
with TMS as an internal standard. Mass spectra were obtained
with Thermo Finnegan MSQ mass spectrometer. Column
chromatography was performed using silica-gel (60-120 mesh)
purchased from Qualigens and TLC was carried out using
aluminium sheets pre-coated with silica gel 60F254 purchased
from Merck. Ionic liquids [bbim]Br, [bbim]BF4, [bbim]PF6 were
prepared as per reported method [16].
General Procedure for the Synthesis of 1,3-Disubstituted 1,2,3,4-
tetrahydro- ꢀ –carbolines.
A mixture containing D-tryptophan methyl ester (2 mmol), an
aromatic aldehyde (2 mmol) in [bbim] BF4 (2 g) was heated at
100 °C for certain period of time (Table 1). After completion of
the reaction (indicated by TLC), the reaction mixture was
extracted with ether (3 X 5 ml). The organic layer was separated,
washed with water, brine, dried over anhydrous sodium sulphate
and the solvent evaporated under reduced pressure to afford
crude 1,3-disubstituted 1,2,3,4-tetrahydro-ꢀ-carbolines. The cis
and trans isomers were separated by flash column
chromatography over silica gel column using methylenechloride
as an eluent.
We have not made any attempt to study the mechanism
of this acid catalyst free Pictet-Spengler cyclization in
ionic liquid [bbim]BF4. But the role of the ionic liquid
may be postulated in terms of some Lewis/Brönsted
acidity of the imidazolium cation, leading to its
interaction with the carbonyl oxygen of the aldehyde
group resulting in its increased polarization and thus
promoting the reaction.
Characterization Data of 1,3ꢁDisubstituted 1, 2, 3, 4-tetrahydro-
ꢀ-carbolines.
Methyl 1,2,3,4-tetrahydro-1-phenyl-9H-pyrido [3,4-b]indole-3-
carboxylate (9a).
Table 2
1
cis Isomer: mp 184-85 °C; H NMR (300 MHz, CDCl3): ꢂ
Recyclability and reuse of [bbim]BF4 for representative PS cyclization
2.95-3.05 (m, 1H, C4-H), 3.19-3.25 (m, 1H, C4-H), 3.79 (s, 3H),
3.96 (dd, 1H, J=11.0, 4.5Hz, C3-H), 5.22 (s, 1H, C1-H), 7.11-
7.54 (m, 9H); 13C NMR (75 MHz, CDCl3): ꢂ 172.2, 140.7,
135.7, 133.9, 131.7, 128.7, 127.8, 127.7, 127.3, 125.9, 120.3,
117.9, 116.8, 110.49, 106.9, 57.6, 55.8, 51.1, 24.9; MS-ESI:
307.04 ([M+1]+, 100%), 303.04 (41%), 204.04 (92%).
Anal. Calcd. for C19H18N2O2: C, 74.49; H, 5.92; N, 9.14.
Found: C, 74.66; H, 5.52; N, 9.24.
Yield (%)a
Entry
1
Aldehyde
Product
CHO
90 (1st run)
88 (2nd run)
86 (3rd run)
9a
CHO
F
1
trans Isomer: mp 161-62 °C; H NMR (200 MHz, CDCl3): ꢂ
85 (1st run)
82 (2nd run)
75 (3rd run)
9c
2
3.09-3.22 (m, 1H, C4-H ), 3.23-3.28 (m, 1H, C4-H ) 3.72 (s, 3H),
3.97-4.03 (m, 1H, C3-H), 5.47 (s, 1H, C1-H), 7.12-7.57 (m, 9H),
7.76 (br s, 1H); 13C NMR (75 MHz, CDCl3): ꢂ 173.8, 141.7,
136.3, 132.9, 132.7, 129.8, 128.5, 128.4, 128.1, 126.9, 121.9,
119.4, 118.1, 110.9, 108.4, 54.8, 52.2, 52.0, 24.6; MS-ESI:
307.04 ([M+1]+, 100%), 204 (54%).
a isolated and unoptimized yields.
Conclusion.
In conclusion, we described here rapid and
environmentally benign synthesis of 1,3-disubstituted
Anal. Calcd. for C19H18N2O2: C, 74.49; H, 5.92; N, 9.14.
Found: C, 74.72; H, 5.62; N, 9.44.

770
M. Muthukrishnan, S. V. More, D. R. Garud, C. V. Ramana, R. R. Joshi and R. A. Joshi
Vol 43
Methyl 1,2,3,4-tetrahydro-1-(3,4-methylenedioxyphenyl)-9H-
pyrido[3,4-b]indole-3-carboxylate (9b).
Anal. Calcd. for C19H17ClN2O2: C, 66.96; H, 5.03; N, 8.22.
Found: C, 66.62; H, 5.12; N, 8.34.
trans Isomer: mp 201-02 °C; H NMR (500 MHz, CDCl3): ꢀ
1
cis Isomer: mp 92-93 °C; 1H NMR (500 MHz, CDCl3): ꢀ 3.00
(ddd, 1H, J =15.0, 11.0, 2.2 Hz, C4-H), 3.20 (ddd, 1H, J =14.9,
4.0, 1.4 Hz, C4-H), 3.81 (s, 3H), 3.95 (dd, 1H, J=11.4, 4.4 Hz,
C3-H), 5.16 (s, 1H, C1-H), 5.94 (s, 2H), 6.80-6.82 (m, 1H), 6.88
(d, 1H, J=8.1 Hz), 7.11-7.15 (m, 2H), 7.21-7.24 (m, 1H), 7.51-
7.54 (m, 2H); 13C NMR (125 MHz, CDCl3): ꢀ 173.1, 148.1,
147.7, 136.2, 136.2, 134.6, 127.1, 121.9, 121.9, 119.5, 118.1,
3.07-3.12 (m, 1H, C4-H), 3.27(dd, 1H, J=15.3, 4.8 Hz, C4-H),
3.73 (s, 3H), 3.85-3.88 (m, 1H, C3-H), 5.90 (s, 1H, C1-H), 6.94
(dd, 1H, J=7.7, 1.8 Hz), 7.10-7.16 (m, 2H), 7.18 (d, 1H, J=7.1
Hz), 7.21-7.26 (m, 2H), 7.45 (d, 1H, J=8 Hz), 7.56 (d, 1H, J =
7.7 Hz), 7.74 (br s, 1H); 13C NMR (125 MHz, CDCl3): ꢀ 171.7,
138.0, 134.8, 131.7, 130.8, 128.5, 127.9, 127.3, 125.0, 119.5,
116.9, 115.9, 109.6, 106.5, 50.0, 49.8, 23.4; MS-ESI: 341.05
([M+1]+, 100%), 339.05 (24%), 254 (39%).
1
110.9, 108.7, 108.5, 108.2, 101.1, 58.3, 56.8, 52.1, 25.6; H-13C
HSQC (CDCl3) ꢀH (ꢀC) 5.16 (58.3, C1), 3.95 (56.8, C3); MS-ESI:
:351 ([M+1]+, 72%), 349 (69%), 204.05 (100%).
Anal. Calcd. for C20H18N2O4: C, 68.56; H, 5.18; N, 8.00.
Found: C, 68.52; H, 5.09; N, 8.22.
Anal. Calcd. for C19H17ClN2O2: C, 66.96; H, 5.03; N, 8.22.
Found: C, 67.34; H, 4.88; N, 8.26.
Methyl 1,2,3,4-tetrahydro-1-(2-nitrophenyl)-9H-pyrido[3,4-b]-
indole-3-carboxylate (9e).
1
trans Isomer: mp 162-63 °C; H NMR (500 MHz, CDCl3): ꢀ
3.13-3.17 (m, 1H, C4-H), 3.27-3.31 (m, 1H, C4-H), 3.72 (s, 3H),
3.99-4.02 (m, 1H, C3-H), 5.41 (s, 1H, C1-H), 5.92 (s, 2H), 6.75-
6.76 (m, 3H), 7.12-7.20 (m, 2H), 7.23-7.25 (m, 1H), 7.53-7.54
(m, 1H), 7.66 (bs, 1H); 13C NMR (125 MHz, CDCl3): ꢀ 174.1,
148.0, 147.4, 136.2, 136.1, 133.3, 127.0, 121.9, 121.6, 119.4,
118.1, 110.9, 108.6, 108.3, 108.0, 101.1, 54.6, 52.4, 51.9, 24.6;
1H-13C HSQC (CDCl3) ꢀH (ꢀC) 5.41 (54.6, C1), 4.0 (52.4, C3);
MS-ESI: 351 ([M+1]+, 100%), 349 (25%), 275 (25%), 204.05
(100%).
1
cis Isomer: mp 177-78 °C; H NMR (500 MHz, CDCl3): ꢀ
3.11(ddd, 1H, J=14.2, 11.01, 2.4 Hz, C4-H), 3.27 (dd, 1H,
J=15.1, 4.2 Hz, C4-H), 3.82 (s, 3H), 3.98 (dd, 1H, J=11.2, 3.9
Hz, C3-H), 5.72 (s, 1H, C1-H), 7.11-7.17 (m, 2H), 7.24 (d, 1H,
J=7.7Hz), 7.45 (dd, 1H, J= 7.7, 1.5Hz), 7.52-7.62 (m, 2H), 7.71
(dd, 1H, J=7.9, 1.4Hz), 7.86 (d, 1H, J=8.2Hz); 13C NMR (125
MHz, CDCl3): ꢀ 171.6, 148.9, 135.7, 135.3, 132.4, 132.2, 130.5,
127.5, 125.41, 122.7, 120.3, 117.8, 116.7, 110.2, 107.5, 55.3,
52.0, 50.9; MS-ESI: 352.05 ([M+1]+, 55%), 341 (100%).
Anal. Calcd. for C19H17N3O4: C, 64.95; H, 4.88; N, 11.96.
Found: C, 64.81; H, 4.62; N, 12.34.
Anal. Calcd. for C20H18N2O4: C, 68.56; H, 5.18; N, 8.00.
Found: C, 68.22; H, 4.92; N, 8.32.
trans Isomer: mp 158-59 °C; 1H NMR (500 MHz, CDCl3): ꢀ
3.11-3.15 (m, 1H, C4-H), 3.26 (dd, 1H, J=15.3, 4.1Hz, C4-H),
3.68 (s, 3H), 3.90-3.93 (m, 1H, C3-H), 5.89 (s, 1H, C1-H), 7.10-
7.16 (m, 2H), 7.21-7.23 (m, 1H), 7.38-7.45 (m, 2H), 7.54 (d, 1H,
J=7.4Hz), 7.88 (d, 1H, J=7.4Hz), 8.03 (d, 1H, J=6.8Hz); 13C
NMR (125 MHz, CDCl3): ꢀ 174.4, 150.3, 137.3, 136.9, 133.6,
132.1, 131.7, 129.3, 127.3, 125.1, 122.9, 120.2, 118.9, 111.7,
110.0, 53.3, 52.8, 50.5, 25.1; MS-ESI: 352.52 ([M+1]+, 100%),
341.52 (20%).
1,2,3,4-Tetrahydro-1-(2-fluorophenyl)-9H-pyrido[3,4-b]indole-
3-carboxylate (9c).
1
cis Isomer: mp 164-65 °C; H NMR (300 MHz, CDCl3): ꢀ
3.01-3.08 (m,1H, C4-H), 3.25 (dd, 1H, J=15.6, 4.6 Hz), 3.80 (s,
3H), 3.99-4.03 (m, 1H, C3-H ) 5.97 (s, 1H, C1-H), 7.04-7.32 (m,
7H), 7.54 (d, 1H, J =7.4Hz), 7.83 (br s, 1H); 13C NMR (125
MHz, CDCl3): ꢀ 173.1, 136.1, 133.5, 129.9, 127.5, 127.3, 126.9,
124.8, 121.9, 119.5, 118.1, 115.8, 115.4, 110.9, 109.0, 56.7,
52.2, 50.8, 25.5; MS-ESI: 325.05 ([M+1]+, 54%), 238 (100%).
Anal. Calcd. for C19H17FN2O2: C, 70.36; H, 5.28; N, 8.64.
Found: C, 70.64; H, 5.02; N, 8.02.
Anal. Calcd. for C19H17N3O4: C, 64.95; H, 4.88; N, 11.96.
Found: C, 65.12; H, 4.56; N, 11.94.
1
trans Isomer: mp 194-95 °C; H NMR (300 MHz, CDCl3): ꢀ
Methyl 1,2,3,4-tetrahydro-1-(4-fluorophenyl)-9H-pyrido[3,4-b]-
indole-3-carboxylate (9f).
3.27-3.35 (m, 1H, C4-H), 3.60 (dd, 1H, J = 15.6, 4.8 Hz, C4-H),
3.75 (s, 3H), 4.21-4.25 (m, 1H, C3-H), 6.32 (s, 1H, C1-H), 7.05-
7.21 (m, 6H), 7.34-7.38 (m, 1H), 7.52 (d, 1H, J=7.5Hz), 8.47 (br
s,1H); 13C NMR (75 MHz, CDCl3): ꢀ 172.3, 135.2, 131.0, 128.8,
128.4, 128.0, 125.3, 122.5, 120.0, 117.4, 116.4, 114.4, 113.9,
110.01, 106.9, 50.4, 50.0, 46.9, 23.8; MS-ESI: 325.05 ([M+1]+,
60%), 238 (100%).
1
cis Isomer: mp 151-52 °C; H NMR (500 MHz, CDCl3): ꢀ
3.0 (ddd, 1H, J=14.6, 11.0, 2.4 Hz, C4-H), 3.22 (dd, 1H, J=15.1,
4.1Hz, C4-H), 3.81 (s, 3H), 3.97 (dd, 1H, J=11.2, 4.2 Hz, C3-H),
5.24 (s, 1H, C1-H), 7.03-7.07 (m, 2H), 7.10-7.17 (m, 2H), 7.20
(d, 1H, J=7.7Hz), 7.34-7.37 (m, 2H), 7.42 (s,1H) 7.55 (d, 1H
J=7.7Hz); 13C NMR (125 MHz, CDCl3): ꢀ 171.7, 136.6, 135.5,
133.6, 129.2, 125.5, 120.0, 117.6, 116.4, 114.1, 113.8, 110.1,
106.4, 55.4, 55.4, 50.6, 24.5; MS-ESI: 325.03 ([M+1]+, 71%),
323.03 (31%), 238.04 (100%).
Anal. Calcd. for C19H17FN2O2: C, 70.36; H, 5.28; N, 8.64.
Found: C, 70.14; H, 5.56; N, 8.82.
Methyl 1,2,3,4-tetrahydro-1-(2-chlorophenyl)-9H-pyrido[3,4-b]-
indole-3-carboxylate (9d).
Anal. Calcd. for C19H17FN2O2: C, 70.36; H, 5.28; N, 8.64.
Found: C, 70.42; H, 5.31; N, 8.22.
1
cis Isomer: mp 170-01 °C; H NMR (500 MHz, CDCl3): ꢀ
1
trans Isomer: mp 161-62 °C; H NMR (300 MHz, CDCl3): ꢀ
3.03 (ddd, 1H, J=14.2, 11.2, 2.5 Hz, C4-H), 3.24 (ddd, 1H,
J=15.0, 4.0, 1.7 Hz, C4-H), 3.81 (s, 3H), 4.01 (dd, 1H, J=11.4,
4.1 Hz, C3-H), 5.84 (s, 1H, C1-H), 7.10-7.16 (m, 2H), 7.21-7.29
(m, 3H), 7.42 (d, 1H, J=7.7Hz), 7.45 (d, 1H, J=7.7Hz), 7.54
(d,1H, J=7.7Hz), 7.59 (br s, 1H); 13C NMR (125 MHz, CDCl3):
ꢀ 173.1, 138.6, 136.2, 133.7, 130.4, 129.7, 129.5, 127.6, 127.0,
122.0, 119.6, 118.2, 110.9, 109.2, 56.7, 54.5, 52.1, 25.5; MS-
ESI: 341.05 ([M+1]+, 100%), 339.05 (31%), 254 (37%).
3.11-3.18 (m, 1H, C4-H), 3.25-3.31 (m, 1H, C4-H), 3.73 (s, 3H),
3.96 (dd, 1H, J=11.4, 4.0 Hz, C3-H), 5.41(s, 1H, C1-H), 6.99-
7.05 (m, 2H), 7.14-7.18 (m, 2H), 7.23-7.28 (m, 2H), 7.56 (dd,
1H, J=9Hz), 7.64 (br s, 1H); 13C NMR (75 MHz, CDCl3): ꢀ
174.0, 137.9, 136.3, 133.0, 130.0, 127.0, 122.1, 119.6, 118.2,
115.6, 115.3, 110.9, 108.4, 54.2, 52.5, 52.0, 24.6; MS-ESI:
325.04 ([M+1]+, 89%), 323.05 (21%), 238.04 (100%).

May-Jun 2006
Pictet-Spengler Cyclization in Room Temperature Ionic Liquid
771
Anal. Calcd. for C19H17FN2O2: C, 70.36; H, 5.28; N, 8.64.
Found: C, 70.18; H, 5.35; N, 8.44.
Anal. Calcd. for C20H20N2O3: C, 71.41; H, 5.99; N, 8.33.
Found: C, 71.01; H, 6.15; N, 8.36.
trans Isomer: mp 193-94 °C; H NMR (500 MHz, CDCl3): ꢀ
1
Methyl 1,2,3,4-tetrahydro-1-(4-chlorophenyl)-9H-pyrido[3,4-b]-
indole-3-carboxylate (9g).
3.12 (dd, 1H, J=14.60, 6.0 Hz, C4-H), 3.24 (dd, 1H, J=15.42, 4.5
Hz, C4-H), 3.77 (s, 3H), 3.85 (s, 3H), 3.92-3.97 (m, 1H, C3-H),
5.34 (s, 1H, C1-H), 6.84 (d, 2H, J=8.5 Hz), 7.09-7.22 (m, 5H),
7.54 (d, 1H, J=7.2Hz), 7.29 (d, 2H, J=8.5 Hz), 7.53 (d, 1H,
J=7.2 Hz), 7.68 (br s, 1H) ; 13C NMR (125 MHz, CDCl3): ꢀ
174.1, 159.6, 136.3, 134.1, 133.6, 129.6, 127.1, 121.9, 119.5,
118.2, 114.1, 110.9, 108.3, 55.3, 54.4, 52.6, 52.0, 24.6; MS-ESI:
337.04 ([M+1]+, 100%), 204.05 (34%), 181.05 (75%).
1
cis Isomer: mp 136-37 °C; H NMR (500 MHz, CDCl3): ꢀ
3.00 (m, 1H, C4-H), 3.23 (br d, 1H, J=14.8 Hz, C4-H), 3.81 (s,
3H), 3.94 (ddd, 1H, , J=11.4, 4.1, 1.4 Hz, C3-H), 5.22 (s, 1H, C1-
H), 7.10-7.16 ( m, 2H), 7.21(d, 1H, J=7.5Hz), 7.30-7.35 (m,
4H), 7.53 (d, 1H, J=7.5 Hz); 13C NMR (125 MHz, CDCl3): ꢀ
172.8, 140.2, 136.5, 134.3, 133.3, 130.0, 128.4, 126.5, 121.1,
118.7, 117.5, 111.1, 107.7, 57.6, 56.5, 51.8, 25.5; MS-ESI:
341.04 ([M+1]+, 100%), 339 (95%), 204.05 (78%).
Anal. Calcd. for C20H20N2O3: C, 71.41; H, 5.99; N, 8.33.
Found: C, 71.73; H, 5.62; N, 8.12.
Anal. Calcd. for C19H17ClN2O2: C, 66.96; H, 5.03; N, 8.22.
Found: C, 66.59; H, 4.82; N, 8.12.
trans Isomer: mp 205-06 °C; H NMR (500 MHz, CDCl3): ꢀ
Acknowledgements.
1
We would like to express our sincere thanks to Dr. M. K.
Gurjar, Head, Organic Chemistry: Technology division for his
constant encouragement and support. We also thank Mr. V. T.
Sathe for spectral analysis.
3.10-3.15 (m, 1H, C4-H), 3.26 (dd, 1H, J=15.4, 5.1Hz, C4-H),
3.71 (s, 3H), 3.92-3.94 (m, 1H, C3-H), 5.38 (s, 1H, C1-H), 7.11-
7.18 (m, 2H), 7.20-7.24 (m, 3H), 7.30 (d, 1H, J=8.2Hz), 7.55 (d,
1H, J=7.5 Hz); 13C NMR (125 MHz, CDCl3): ꢀ 172.7, 140.5,
135.4, 132.2, 131.92, 128.8, 127.2, 125.6, 120.2, 117.7, 116.7,
110.2, 106.3, 53.0, 51.0, 50.7, 23.8; MS-ESI: 341.04 ([M+1]+,
43%), 339 (20%), 204.05 (100%).
REFERENCES AND NOTES
[1] W. M. Whaley and T. R. Govindhachari, Organic Reactions,
Wiley, New York, 1951, Vol 6, pp. 151.
[2] R. H. F. Manske, The Alkaloids, Chemistry and Physiology,
Academic Press, New York, 1981, vol XX.
Anal. Calcd. for C19H17ClN2O2: C, 66.96; H, 5.03; N, 8.22.
Found: C, 67.14; H, 4.84; N, 8.43.
Methyl 1,2,3,4-tetrahydro-1-(4-nitrophenyl)-9H-pyrido[3,4-b]-
indole-3-carboxylate (9h).
[3a] M. F. Brana, M. Garrido, M. L. L. Lopez Rodriguez, P.
Miguel, M. J. Morcillo and A. Riano, J. Heterocyclic Chem., 27, 703
(1990); [b] M. F. Brana, M. Garrido, M. L. Lopez, P de Miguel and A.
Riano, Synth. Commun., 20, 1793 (1990); [c] M. Cain, R. W. Weber, F.
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124, 55977 (1996); [b] A. C. M. Daugan, US Patent 6140329, 2000;
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Renduchintala, T. U. Mayer and T. M. Kapoor, Angew. Chem., Int. Ed.
Engl., 42, 2379 (2003).
1
cis Isomer: mp 171-72 °C; H NMR (500 MHz, CDCl3): ꢀ
3.00 (m, 1H, C4-H), 3.23 (br d, 1H, J=14.8 Hz, C4-H), 3.81 (s,
3H), 3.94 (ddd, 1H, J=11.4, 4.1, 1.4 Hz, C3-H), 5.36 (s, 1H, C1-
H), 7.05-7.11 (m, 2H), 7.24 (d, 1H, J=7.8 Hz), 7.51 (d, 1H,
J=7.8 Hz), 7.59 (dd, 2H, J=8.8, 1.7 Hz), 8.16 (dd, 2H, J=8.8,
1.7 Hz); 13C NMR (125 MHz, CDCl3): ꢀ 172.3, 149.0, 147.0,
136.4, 133.4, 129.5, 126.1, 123.0, 120.9, 118.5, 117.4, 110.9,
107.3, 57.2, 55.9, 51.6, 25.0; MS-ESI: 352.03 ([M+1]+, 100%),
348.03 (25%), 265.04 (34%).
Anal. Calcd. for C19H17N3O4: C, 64.95; H, 4.88; N, 11.96.
Found: C, 64.86; H, 4.82; N, 12.33.
trans Isomer: mp 202-03 °C; 1H NMR (500 MHz, CDCl3): ꢀ
3.00 (m, 1H, C4-H), 3.23-3.29 (dd, 1H, J=11.32, 4.14 Hz, C4-H),
3.73 (s, 3H), 3.85-3.90 (m, 1H, C3-H) 5.52 (s, 1H, C1-H) 7.09-
7.20 (m, 2H), 7.31 (dd, 1H, J=7.8, 2.2 Hz), 7.50-7.57 (m, 3H),
8.17 (dd, 2H, J=8.6, 2.3 Hz); 13C NMR (125 MHz, CDCl3): ꢀ
172.6, 149.2, 146.0, 135.4, 131.4, 128.2, 125.5, 122.1, 120.3,
117.73, 116.7, 110.2, 106.3, 52.8, 51.0, 50.7, 23.7; MS-ESI:
352.04 ([M+1]+, 60%), 265.04 (76%). 246.05 (100%).
Anal. Calcd. for C19H17N3O4: C, 64.95; H, 4.88; N, 11.96.
Found: C, 65.12; H, 4.95; N, 12.05.
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Coste, J. Kirilovsky, F. Hyafil and R. Labaudiniere, J. Med. Chem., 46,
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Fiordeliso, J. C. Lanter, J. Guan, Y. Qiu, P. Kraft, S. Bhattacharjee, E.
Craig, D. H. Johnson, T. M. John and J. Clancy, J. Med. Chem., 46, 441
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H. Coste, J. M. Linget, J. Kirilovsky, F. Hyafil and R. Labaudiniere, J.
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39, 3772 (2000).
Methyl 1,2,3,4-tetrahydro-1-(4-methoxyphenyl)-9H-pyrido [3,4-
b]indole-3-carboxylate (9i).
1
cis Isomer: mp 138-39 °C; H NMR (500 MHz, CDCl3): ꢀ
3.00 (ddd, 1H, J=14.42, 11.1, 2.5 Hz, C4-H), 3.20 (dd, 1H,
J=15.2, 4.3 Hz, C4-H), 3.81 (s, 6H), 3.97 (dd, 1H, J=11.2,
4.1Hz, C3-H), 5.19 (s, 1H, C1-H), 6.89 (d, 2H, J=8.5 Hz), 7.09-
7.15 (m, 2H), 7.21 (d, 1H, J=7.2Hz), 7.29 (d, 2H, J=8.5 Hz),
7.46 (br s, 1H), 7.53 (d, 1H, J=7.2 Hz); 13C NMR (125 MHz,
CDCl3): ꢀ 173.1, 159.8, 136.2, 135.1, 132.9, 129.7, 127.2, 121.9,
119.6, 118.1, 114.3, 110.9, 108.8, 58.1, 57.0, 55.3, 52.1, 25.8;
MS-ESI: 337.04 ([M+1]+, 100%), 204.05 (19%).

772
M. Muthukrishnan, S. V. More, D. R. Garud, C. V. Ramana, R. R. Joshi and R. A. Joshi
Vol 43
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