Aromatization and chemoselective alkylation of 1-methyl-3,4-dihydro-β-carboline-3-carboxylic acid and its derivatives

Article abstract of DOI:10.1016/j.tetlet.2009.07.075

Unprecedented aromatization was observed during N-alkylation reactions of 1-methyl-3,4-dihydro-β-carboline-3-carboxylic acid methyl ester, giving rise to 9-alkyl-1-methyl-β-carboline-3-carboxylic acid methyl esters. Inverse addition of base during a simil

Full text of DOI:10.1016/j.tetlet.2009.07.075

Tetrahedron Letters 50 (2009) 5501–5504
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Aromatization and chemoselective alkylation of
1-methyl-3,4-dihydro-b-carboline-3-carboxylic acid and its derivatives
*
Keyur G. Brahmbhatt, Nafees Ahmed, Inder P. Singh, Kamlesh K. Bhutani
Department of Natural Products, National Institute of Pharmaceutical Education and Research (NIPER), Sector 67, S.A.S. Nagar, Punjab 160 062, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Unprecedented aromatization was observed during N-alkylation reactions of 1-methyl-3,4-dihydro-b-
carboline-3-carboxylic acid methyl ester, giving rise to 9-alkyl-1-methyl-b-carboline-3-carboxylic acid
methyl esters. Inverse addition of base during a similar reaction resulted in a chemoselective alkylation
to form novel 3-butyl-1-methyl-3,4-dihydro-b-carboline-3-carboxylic acid methyl ester as the major
product in good yield.
Received 1 May 2009
Revised 13 July 2009
Accepted 16 July 2009
Available online 18 July 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
1-Methyl-3,4-dihydro-b-carboline-
3-carboxylic acid
Chemoselective alkylation
Aromatization
Oxidation
N-Alkylation
1. Introduction
ther, 1-methyl homologues are known to exhibit imine–enamine
tautomerism involving C-1 methyl group, but participation of acidic
b-Carboline, constituted by fusion of indole and pyridine ring
systems with different degrees of aromaticity, is present in various
natural products and synthetic compounds.1,2 Beside various other
biological activities, these classes of compounds are also known to
possess anti-HIV activity.3 In the course of work directed towards
the development of potential anti-HIV agents,4,5 need arose for
the preparation of 9-alkyl-1-methyl-3,4-dihydro-b-carboline-3-
carboxylic acid methyl esters (5) and fully aromatic 9-alkyl-1-
methyl-b-carboline-3-carboxylic acid methyl esters (6).6 Synthesis
of 5 was attempted by alkylation of 1-methyl-3,4-dihydro-b-carb-
oline-3-carboxylic acid methyl ester (3). These attempts resulted in
the formation of 6 instead of 5, hence, completing two steps (i.e.,
oxidation and alkylation) in one-pot.
proton at C-3 or base-promoted aromatization is known to be ab-
sent in 1 N aqueous sodium hydroxide.11
With this background, we decided to study the aromatization of
1-methyl-3,4-dihydro-b-carboline-3-carboxylic acid and its deriva-
tives. These reactions were successful in anhydrous alkaline condi-
tions, however, the aromatization was not observed in oxygen-free
conditions. The aromatization resulted from carbanion formation at
C-3 and not due to involvement of indole ring nitrogen. Formation
of a carbanion was confirmed by hydrogen–deuterium exchange
study of the C-3 proton. Moreover, the carbanion formed was
alkylated at C-3 in chemoselective manner for the first time.
2. Results and discussion
The aromatization of 3 without decarboxylation during above-
mentioned alkylation was surprising, as the aromatization of this
class of compounds is generally carried out by various oxidizing
agents. Some reports are available where aromatization is observed
in the absence of oxidizing agent but not without decarboxyl-
ation.7,8 A method for the aromatization of 3,4-dihydro-b-carbo-
line-3-carboxylic acid in aqueous alkaline conditions exists,9
but no analogous methods are available for its 1-methyl homo-
logues. Previous reports indicate that 1-methyl homologues do
not undergo aromatization in aqueous alkaline conditions.10 Fur-
The synthetic strategy followed is shown in Scheme 1. N-acetyl
tryptophan (1) was obtained by Schotten–Baumann method from
the commercially available dl-tryptophan. Compound 1 was con-
verted into 1-methyl-3,4-dihydro-b-carboline-3-carboxylic acid
(2)11 which was then treated with thionyl chloride in methanol to
form methyl ester 3.12 N-(1-methyl-3,4-dihydro-b-carboline-3-car-
bonyl)morpholine (4) was synthesized by treating 2 with methane-
sulfonyl chloride in the presence of triethyl amine to form reactive
mesyl ester derivative, which was reacted in situ with morpholine
in dichloromethane.
Scheme 2 shows the results of alkylation of 3. This reaction did
not give the desired 9-alkyl-1-methyl-3,4-dihydro-b-carboline-3-
* Corresponding author. Tel./fax: +91 172 2232208.
E-mail address: kkbhutani@niper.ac.in (K.K. Bhutani).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.07.075

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K. G. Brahmbhatt et al. / Tetrahedron Letters 50 (2009) 5501–5504
Scheme 1. Synthesis of 1-methyl-3,4-dihydro-b-carboline-3-carboxylic acid and derivatives. Reagents and conditions: (i) dicyclohexylcarbodiimide (DCC), CH2Cl2, 3 h, 20 °C
then add CF3COOH, 1 h, 50 °C, 85%; (ii) SOCl2, MeOH, 30 °C, 6 h, 96%; and (iii) MeSO2Cl, Et3N, CH2Cl2, 2 h then morpholine, 20 °C, 6 h, 68%.
Scheme 2. N-alkylation of 1-methyl-3,4-dihydro-b-carboline-3-carboxylic acid methyl ester. Reagents and conditions: (i) NaH, anhydrous DMF, 0 °C, 30 min then RX (X = Br
or I), 28 °C, 60 min, (6a 85%; 6b 78%; 6c 80%; 6d 75%; 6e 85%); and (ii) inverse addition: n-BuI, anhydrous DMF, degassing by freeze-pump–thaw then NaH, 28 °C, oxygen-free
argon atmosphere, 30 min (7 76.8%; 8 12.8%).
carboxylic acid methyl ester derivatives (5a–e). Instead, it under-
went aromatization to yield 9-alkyl-1-methyl-b-carboline-3-car-
boxylic acid methyl ester derivatives (6a–e). A similar experiment,
repeated without alkyl halide, led to complete aromatization of 3
to form 1-methyl-b-carboline-3-carboxylic acid methyl ester (10)
(Scheme 3). To investigate the nature of oxidizing agent, the same
reaction was performed in oxygen-free argon atmosphere. Oxy-
gen-free condition was insured by completely degassing the reac-
tion mixture by four repetitive freeze-pump–thaw cycles. The
absence of aromatization during these conditions indicated the
involvement of oxygen. Further, compounds 2, 3 and 4 were treated
with differentbases in anhydrous and aqueousconditions in order to
study their aromatization. It is apparent from examination of the
data given in Table 1, that anhydrous condition is essential for aro-
matization of 1-methyl homologue. It is important to note that the
re-protonation at C-3 carbanion will be less in hydrogen acceptor
Scheme 3. Aromatization of 2, 3 and 4 to form 9, 10 and 11, respectively (see Table
1 for details).
solvents. This might be the reason for faster reaction rate of aroma-
tization in strong hydrogen acceptor solvent (such as DMF, Table 1,
entry 5) as compared to methanol (Table 1, entry 4) or water.13 Here,

K. G. Brahmbhatt et al. / Tetrahedron Letters 50 (2009) 5501–5504
5503
Table 1
Aromatization of 1-methyl-3,4-dihydro-b-carboline-3-carboxylic acid and its derivatives in various alkaline conditions
Entry
1
Reaction conditions
Reactant
Time (h)
% Isolated yielda,b
% Yieldc (using water as solvent)
NaH, anhydrous DMF, 28 °C
2
3
4
2
3
4
2
3
4
2
3
4
2
3
4
4
0.5
0.5
20
8
62
80
78
60
74
77
62
69
71
69
76
80
59
65
70
—
—
—
2
3
4
5
K2CO3, anhydrous DMF, 50 °C
NaOH, anhydrous DMF, 50 °C
NaOMe, anhydrous MeOH, 65 °C
NaOMe, anhydrous DMF, 50 °C
No reaction
—
No reaction
No reaction
6
20
3.5
4
18
3
3
8
0.5
1
—
No reaction
—
—
—
—
—
—
a
Dihydro derivatives completely disappeared (monitored by TLC).
Identity was confirmed by 1H NMR, MS and 13C NMR.
Starting material was recovered.
b
c
we hypothesized that aromatization under investigation might in-
volve abstraction of acidic proton at C-3 by base in anhydrous med-
ium. The resulting carbanion can undergo oxidative pathway in a
manner similar to that reported for 3,4-dihydro-b-carboline-3-car-
boxylic acid.9
To substantiate our hypothesis, we performed hydrogen–deute-
rium exchange experiment under conditions similar to that used
for aromatization. The experiment was performed on 2 in deuter-
ated sodium methoxide (NaOCD3)/deuterated methanol (CD3OD)
mixture and the 1H NMR spectra were recorded. Deuterated so-
dium methoxide (NaOCD3) was prepared by addition of sodium
to the deuterated methanol in nitrogen atmosphere. Figure 1
shows the upfield part of the 1H NMR spectra of 2. Here, the peak
at d 3.41 corresponds to the acidic proton at C-3. Figure 2 shows 1H
NMR spectra recorded after heating the mixture at 65 °C for 2 h.
The decrease in intensity after 2 h indicated the formation of carb-
anion at C-3.
argon atmosphere. This resulted in alkylation of 3 at C-3 before
oxidation. In fact, we were able to isolate 3-butyl-1-methyl-3,4-
dihydro-b-carboline-3-carboxylic acid methyl ester (7) as the
major product in 76.7% isolated yield, along with 3,9-dibutyl-1-
methyl-3,4-dihydro-b-carboline-3-carboxylic acid methyl ester
(8) in 12.8% isolated yield.14 The method is suitable for the synthe-
sis of new C-3 alkylated derivatives in preparative scales.
Chemoselectivity in this reaction can be explained by hard and soft
acid-base concept (HSAB).15 The soft electrophile, n-butyl iodide,
can be attacked by either of the two nucleophiles, N9 anion or
C-3 carbanion. Here, the attack was preferred by a soft nucleophile,
that is, C-3 carbanion over N9 anion. The chemoselective alkylation
presents the evidence for formation of carbanion at C-3. To the best
of our knowledge, no method is reported in the literature to pre-
pare C-3 substituted derivatives of 3,4-dihydro-b-carboline class
of compounds.
In conclusion, we report a method for aromatization of 1-
methyl-3,4-dihydro-b-carboline-3-carboxylic acid and derivatives
accompanied by alkylation in one-pot with excellent yields. Upon
inverse addition, alkylation is preferred at C-3, and thus, a new
Formation of the carbanion was further confirmed by quench-
ing it with alkylating agent. This was performed by changing the
order of addition of base during alkylation reaction in oxygen-free
Figure 1. Aliphatic region of the 1H NMR (300 MHz, NaOCD3/CD3OD, Me4Si) of 2.

5504
K. G. Brahmbhatt et al. / Tetrahedron Letters 50 (2009) 5501–5504
Figure 2. Aliphatic region of the 1H NMR (300 MHz, NaOCD3/CD3OD, Me4Si) of 2 showing hydrogen–deuterium exchange of C-3 proton after heating at 65 °C for 2 h.
13. Reichardt, C. Solvents and Solvent Effects in Organic Chemistry, 3rd ed.; Wiley-
VCH: Weinheim, 2002.
14. General procedure for alkylation of 1-methyl-3,4-dihydro-b-carboline-3-carboxylic
direct synthesis of 3-substituted derivatives is presented. These
methods can find applications in synthetic strategies to obtain bio-
logically important b-carboline-3-carboxylic acid derivatives.
acid methyl ester (3) (inverse addition): Compound 3 (242 mg, 1.0 mmol), n-
butyl iodide (0.34 ml, 3 mmol) and anhydrous DMF (10 ml) were mixed
together in a 50 ml Schlenk flask. The mixture was degassed by four freeze-
pump–thaw cycles to remove oxygen. This was followed by addition of sodium
hydride (60%) (48 mg, 1.2 mmol) under argon atmosphere. The mixture was
stirred at 28 °C for 30 min. The resulting mixture was poured into cold water,
and extracted with ethyl acetate. The organic phase was washed with water
and brine, then dried over anhydrous sodium sulfate and evaporated. The oil
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2009.07.075.
obtained was purified on Silica Gel 60 (15–40
lm) by dry column vacuum
chromatography (DCVC) by using hexane–ethyl acetate as mobile phase in
gradient manner to obtain compounds 7 (228.8 mg, 76.7%) and 8 (45.3 mg,
12.8%) as racemic mixture. 3-Butyl-1-methyl-3,4-dihydro-b-carboline-3-
carboxylic acid methyl ester (7): IR (KBr, cmÀ1):3435, 2954, 2854, 1732, 1649,
References and notes
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;
s, 1H); 7.60 (d, 1H, J = 7.9 Hz); 7.38 (d, 1H, J = 8.2 Hz); 7.26 (m, 1H); 7.14 (m,
1H); 3.69 (s, 3H, –CO2CH3); 3.44 (d, 1H, J = 16.8 Hz, H-4a); 3.03 (d, 1H,
J = 16.8 Hz, H-4b); 2.40 (s, 3H, 1-CH3); 1.93 (m, 2H); 1.26 (m, 4H); 0.87 (t, 3H,,
J = 6.9 Hz); 13C NMR (75.5 MHz, CDCl3, ppm): d 176.21, 158.07, 137.64, 128.99,
126.21, 125.32, 121.00, 120.66, 115.47, 112.70, 67.78, 53.04, 39.12, 27.54,
27.33, 23.56, 22.60, 14.51; MS APCI: m/z 299 (M+1)+, Anal Calcd. for
C18H22N2O2: C, 72.46; H, 7.43; N, 9.39. Found: C, 72.26; H, 7.52; N, 9.35. 3,9-
Dibutyl-1-methyl-3,4-dihydro-b-carboline-3-carboxylic acid methyl ester (8): IR
(KBr, cmÀ1): 2955, 2871, 1736, 1533, 1457, 1350, 1204; 1H NMR (300 MHz,
CDCl3, ppm): d 7.59 (d, 1H, J = 7.9 Hz); 7.30 (m, 2H); 7.13 (m, 1H); 4.31 (t, 2H,
J = 7.2 Hz); 3.63 (s, 3H, –CO2CH3); 3.38 (d, 1H, J = 16.6 Hz, H-4a); 2.91 (d, 1H,
J = 16.6 Hz, H-4b); 2.57 (s, 3H, 1-CH3); 1.91 (m, 2H); 1.68 (m, 2H); 1.23 (m, 6H);
0.89 (m, 6H); 13C NMR (75.5 MHz, CDCl3, ppm): d 176.09, 158.42, 139.19,
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(M+1)+, Anal Calcd. for C22H30N2O2: C, 74.54; H, 8.53; N, 7.90. Found: C, 74.32;
H, 8.58; N, 7.88.
a grant entitled ‘Identification of anti-viral
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