A novel route to synthesize lavendamycin analogues through an A3 coupling reaction

Article abstract of DOI:10.1016/j.tet.2013.04.074

A convergent synthesis of lavendamycin analogues has been accomplished by using A³ coupling reaction between carboline aldehydes, anilines, and phenylacetylenes. Our approach features the use of the ionic liquids as an environmentally benign solvent medium and synthesis of lavendamycin analogues with diverse substitution pattern. Additionally, the formation of α-dihydropyrido-β-carboline was observed during the reaction of α-formyl-β-carboline, aniline, and ethylpropiolate.

Full text of DOI:10.1016/j.tet.2013.04.074

Tetrahedron 69 (2013) 4890e4898
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
A novel route to synthesize lavendamycin analogues through an A3
coupling reaction
*
Subburethinam Ramesh, Rajagopal Nagarajan
School of Chemistry, University of Hyderabad, Hyderabad 500046, India
a r t i c l e i n f o
a b s t r a c t
A convergent synthesis of lavendamycin analogues has been accomplished by using A3 coupling reaction
between carboline aldehydes, anilines, and phenylacetylenes. Our approach features the use of the ionic
liquids as an environmentally benign solvent medium and synthesis of lavendamycin analogues with
Article history:
Received 10 December 2012
Received in revised form 9 April 2013
Accepted 12 April 2013
diverse substitution pattern. Additionally, the formation of
during the reaction of -formyl- -carboline, aniline, and ethylpropiolate.
Ó 2013 Elsevier Ltd. All rights reserved.
a-dihydropyrido-b-carboline was observed
Available online 19 April 2013
a
b
Keywords:
Lavendamycin
A3 coupling
Ionic liquid
Quinoline
MCR
1. Introduction
Quinoline and tetrahydroquinoline moieties are important class
of N-containing heterocycles due to the prevalence of these struc-
tural motif in many natural products and synthetic compounds
with wide spectrum of biological activities.1 Multicomponent re-
actions have received a vast amount of attention, because of their
simple and convergent paths to synthesize structurally complex
products from simple starting materials in a one-pot fashion.2 The
three component reactions between amines, aldehydes, and ter-
minal acetylenes (A3 coupling) have been continuously witnessed
as a versatile method to construct quinoline ring systems.1i,3
Carboline alkaloids are elegant targets in organic synthesis because
of their wide range of biological activities.4 Lavendamycin, a
heteroaryl- -carboline alkaloid (Fig. 1) was isolated from the fer-
b-
Fig. 1. Some of the representative a-heteroaryl-b-carboline alkaloids.
a
-
b
mentation broth of Streptomyces lavendulae, strain C22030 as a dark
red solid in 1982 by Doyle and co-workers from Bristol laborato-
ries.5 Shortly after the isolation, Balitz and co-workers reported the
intriguing structure of lavendamycin by means of analytical and
spectroscopic studies.5 Subsequently, in 1984, Kende’s group suc-
ceeded in the first total synthesis of lavendamycin methyl ester
based on BischlereNapieralski reaction as the key step.6
been the subject of many synthesis.7 However, despite being an
antibiotic, they showed toxicity on human cells and hence the pre
clinical use of this alkaloid has been precluded. It has been partly
believed that the presence of quinolone present in the lav-
endamycin structure could perhaps cause for this toxicity.8 Lav-
endamycin analogues are associated with remarkable attributes,
such as inhibition of HIV reverse transcriptase,9a,b MKN45 gastric
carcinoma, and WiDr colon carcinoma cells9c as well as anti-
proliferative9c and cytotoxicitic9d activities. Lavendamycin exhibits
antitumor activity against topoisomerase I cell with Minimum In-
This b-carboline alkaloid is a naturally occurring antitumor an-
tibiotic, which attracted many research groups and hence it has
hibitory Concentration (MIC) of 0.1
m
g/mL.9e The important bi-
* Corresponding author. Tel.: þ91 40 23134831; fax: þ91 40 23012460; e-mail
addresses: rnsc@uohyd.ernet.in, naga_indole@yahoo.co.in (R. Nagarajan).
ological profile of these compounds and the broad scope of the A3
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.04.074

S. Ramesh, R. Nagarajan / Tetrahedron 69 (2013) 4890e4898
4891
coupling reactions promoted us to synthesize a new variety of
lavendamycin analogues with diverse substitution pattern. In
continuation of our work on A3 coupling reactions,3e we wish to
report here a methodology for the synthesize of lavendamycin
analogues. Considering the growing environmental awareness and
the negative environmental impacts of organic volatile solvents, we
decided to optimize the reaction condition with environmentally
more benign and alternatives to the traditional organic volatile
solvents, i.e., ionic liquids (so called green solvent) as a solvent
medium.10 Some of the physical properties, such as (i) nonvolatility,
(ii) greater effective surface area, (iii) potential activity of a liquid
phase and the catalytic nature make them an interesting solvent for
a synthesis.10,11
With these optimized condition in hand, next we examined the
scope of the reaction with variety of amines (2aem), acetylenes
(3aee), and aldehydes (1a,b) to generate the lavendamycin ana-
logues (4aeu).
As indicated in Scheme 1, anilines with electron donating sub-
stituents (eMe, eOMe) (entries 2, 3, 7, 16, 18, and 19) and with
electron withdrawing substituents (eF, eCl, eBr, eNO2) (entries
4e6, 9, 10, 13, 14, 20, and 21) in ortho-, para-, and meta-positions
well tolerated the reaction with good yields. Carbazole nucleus, an
important heterocyclic scaffold found in many natural products,
which possess interesting biological properties.13 In the view of
introducing a carbazole unit in the b-carboline core, we tested the
reactivity of 3-amino-9-ethylcarbazole (2h) as an amine precursor
in this reaction (entry 8). As anticipated, the reaction afforded the
pyridocarbazole derivative (4h) in good yield. The reaction with
substituted phenylacetylenes (3bee) was also efficiently proceeded
to afford the desired lavendamycin analogues (entries 11,12,15, and
2. Results and discussion
In the first attempt, the reaction between aldehyde (1a)12 ani-
line (2a), and phenylacetylene (3a) in [Bmim][Cl] at room tem-
perature without catalyst was failed to give the desired product 4a
(Table 1, entry 1). However, heating the reaction around 95e100 ꢀC
provided the compound (4a) in poor yield (Table 1, entry 2). Further
investigation with various ionic liquids (Table 1, entry 3e8) like
[Bmim][Br], [Bmim][Tfa], [Emim][Tfa], [Bmim][Tsa], [Bmim][PF6],
and [Bmim][BF4] revealed that [Bmim][BF4] was superior to other
ionic liquids and provided 4a in 34% yield (Table 1, entry 8). We
envisaged that addition of Lewis acids along with ionic liquid could
further enhance the reaction yield (Table 1, entry 9e15). To our
delight, addition of La(OTf)3 (10 mol %) to the reaction mixture
significantly increased the yield of the product 4a (Table 1, entry
14). Lowering the catalytic loading to 5 mol % resulted in the in-
complete conversion of 4a (Table 1, entry 15). On the other hand,
the yield remained unaffected on addition of 20 mol % of La(OTf)3
(Table 1, entry 16).
Scheme 1. Synthesis of lavendamycin analogues (4aeu).
Entry
Aniline
Phenylacetylene
Lavendamycin analogues
1
3a
Table 1
Optimization for the reaction conditions
2
3
4
3a
3a
3a
Entry
IL/catalyst
Yielda (%)
Time (h)
1
2
3
4
5
6
7
8
[Bmim][CI]
[Bmim][CI]
[Bmim][Br]
[Bmim][Tfa]
[Emim][Tfa]
[Bmim][Tsa]
[Bmim][PF6]
[Bmim][BF4]
[Bmim][BF4]/I2 (10 mol %)
[Bmim][BF4]/Zn(OTf)2 (10 mol %)
[Bmim][BF4]/CuI (10 mol %)
[Bmim][BF4]/Pd(OAc)2 (10 mol %)
[Bmim][BF4]/Cu(OTf)2(10 mol %)
[Bmim][BF4]/La(OTf)3 (10 mol %)
[Bmim][BF4]/Yb(OTf)3 (10 mol %)
[Bmim][BF4]/La(OTf)3 (5 mol %)
[Bmim][BF4]/La(OTf)3 (20 mol %)
d
48
24
24
24
24
48
24
24
12
10
20
20
8
14
Trace
20
22
Trace
15
34
47
Trace
d
9
10
11
12
13
14
15
16
17
d
56
78
70
72
4
3
4
4
76
General conditions. Aldehyde (1a) 0.3 mmol, aniline (2a) 0.3 mmol, and phenyl-
acetylene (3a) 0.35 mmol. Optimized reaction condition are in bold.
5
3a
a
Yield refers to column purified product. For entry 1, room temperature was
maintained. For entry 2e17, 95e100 ꢀC temperature were maintained. Tfa¼CF3COO,
Tsa¼p-toluenesulphonic acid. Emim¼1-ethyl-3-methylimidazole, Bmim¼1-butyl-
3-methylimidazole.

4892
S. Ramesh, R. Nagarajan / Tetrahedron 69 (2013) 4890e4898
(continued )
(continued)
Entry
Aniline
Phenylacetylene
Lavendamycin analogues
Entry
Aniline
Phenylacetylene
Lavendamycin analogues
6
3a
14
2f
3b
7
3a
15
16
17
2a
8
3a
3a
9
3a
2a
3a
10
3a
18
2b
11
2a
19
2c
12
2a
20
3a
13
2e
3b
21
3a

S. Ramesh, R. Nagarajan / Tetrahedron 69 (2013) 4890e4898
4893
18) in good yields. The structure of compound 4g is confirmed by
X-ray diffraction analysis (Fig. 2).14
Fig. 3. Some of the representative a-pyrido-b-carboline compounds.
and hence increasing the equivalents of 3f could perhaps enhance
the yield of the product. As expected, when we used 3 equiv of 3f
along with 1 equiv of each aldehyde (1b) and anilines (2aec), the
a-
dihydropyrido- -carbolines (5bed) were obtained in good yields
b
(Scheme 4). The observed different reactivity between phenyl-
acetylene (3a) and ethylpropiolate (3f) is explained in the proposed
mechanism (Scheme 5). First, aniline 2a undergoes Michael re-
action with ethylpropiolate instead of forming imine with aldehyde
1b as in the case of Scheme 2, followed by second Michael reaction
and reaction with aldehyde afford dihydropyrido compound 5b.
Fig. 2. The ORTEP of compound 4g.
According to the literature,3 the proposed mechanism is shown
in Scheme 2. Aldehyde (1a) and aniline (2a) are forming aldimine,
followed by Lewis acid catalyzed coupling reaction with phenyl-
acetylene (3a) to give A. Subsequent aromatization of A affords 4a.
Scheme 2. Proposed mechanism for the formation of 4a.
Scheme 4. Synthesis of a-dihydropyrido-b-carbolines (5bed).
After the successful synthesis of analogues 4aeu, this sequence
was extended from phenylacetylene (3aee) to ethylpropiolate (3f)
but, to our surprise the reaction (Scheme 3) failed to provide the
expected
ature reports15 and with the help of NMR spectroscopy, the struc-
ture of the obtained compound 5b was confirmed as a
dihydropyrido- -carboline. It is noteworthy that -pyrido- -car-
a-quinolo-b-carboline (5a). However, according to liter-
a
-
b
a
b
boline and their derivatives (Fig. 3) also have drawn attention from
synthetic chemists due to their antitumor properties and hence,
a few syntheses of these analogues have been reported.16 The
compound 5b was incorporated with two units of ethylpropiolate
Scheme 5. Proposed mechanism for the formation of 5b.
3. Conclusions
In summary, we have demonstrated a simple, novel, and effi-
cient method to generate a range of lavendamycin analogues
(4aeu) via an A3 coupling protocol in good yields. This methodol-
ogy can be exploited to construct new analogues of lavendamycin,
Scheme 3. A3 coupling reaction between aldehyde (1c), aniline (2a), and ethyl-
propiolate (3f).

4894
S. Ramesh, R. Nagarajan / Tetrahedron 69 (2013) 4890e4898
which are of great interest in the synthetic community due to their
remarkable pharmaceutical and biological properties. Moreover,
we delineated here the importance of ionic liquids and their ap-
plications. New analogues of 1,4-dihydro-3,5-pyridinedicarbo
xylate also have been efficiently synthesized.
1H NMR (400 MHz, CDCl3, TMS)
d: 11.98 (1H, s), 8.95 (1H, s), 8.88
(1H, s), 8.23 (2H, t, J¼8.0 Hz), 7.71e7.75 (2H, m), 7.55e7.68 (7H, m),
7.39 (1H, t, J¼7.2 Hz), 4.08 (3H, s), 2.53 (3H, s); 13C NMR (100 MHz,
CDCl3, TMS) d: 166.8, 156.0, 148.7, 146.2, 140.9, 138.4, 137.7, 137.2,
136.8, 136.7, 131.8, 130.6, 129.7, 129.2, 128.9, 128.5, 128.3, 126.7,
124.9, 121.9, 121.6, 120.9, 119.7, 118.5, 112.4 (aromatic C), 52.6, 21.9
(aliphatic C); HRMS (ESI-MS) calcd for C29H21N3O2; 466.1532
(MþNa), found: 466.1532. Anal. Calcd for: C, 78.54; H, 4.77; N,
9.47%; found: C, 78.47; H, 4.71; N, 9.36%.
4. Experimental section
4.1. General information
1H and 13C NMR spectra were recorded at 400 and 100 MHz,
respectively, or at 500 and 125 MHz, respectively. Chemical shifts
4.4. Methyl 1-(6-methoxy-4-phenyl-2-quinolyl)-9H-b-carbo-
line-3-carboxylate (4c)
were calculated in parts per million downfield from TMS (
d
¼0) for
1H NMR, and relative to the central CDCl3 resonance (
d
¼77.0) and
Colorless solid, 114 mg, 83%, Rf¼0.60 (20% EtOAc/Hexanes), mp:
319e321 ꢀC; IR (KBr): 3354, 2945, 1457, 1028, 705 cmꢁ1 1H NMR
(400 MHz, CDCl3, TMS) : 11.94 (1H, s), 8.95 (1H, s), 8.88 (1H, s),
DMSO-d6
(
d
¼39.51) for 13C NMR. Data presented in the
;
Experimental section are as follows: chemical shift, integration,
multiplicity (s¼singlet, d¼doublet, t¼triplet, q¼quartet,
m¼multiplet, dd¼doublet doublet), coupling constant in Hertz
(Hz), and IR spectra were recorded on a JASCO FT/IR-5300 in-
strument. HRMS (ESI) was carried out in a Bruker Maxis instrument
in the School of Chemistry, University of Hyderabad. TOF and
quadrupole mass analyzer types are used for the HRMS measure-
ments. IR spectra were recorded on a FT-IR spectrometer using KBr
pellets. X-ray diffraction measurements were carried out at 298 K
d
8.23e8.26 (2H, m), 7.73e7.75 (1H, m), 7.66e7.69 (3H, m), 7.53e7.62
(3H, m), 7.47 (1H, dd, J1¼2.8 Hz & J2¼9.2 Hz), 7.40 (1H, t, J¼7.6 Hz),
7.25 (1H, d, J¼2.4 Hz), 4.08 (3H, s), 3.84 (3H, s); 13C NMR (100 MHz,
CDCl3, TMS) d: 166.8, 158.4, 154.7, 148.1, 143.7, 140.9, 138.5, 137.9,
136.8, 136.6, 130.9, 130.5, 129.5, 128.9, 128.6, 128.4, 127.8, 122.0,
121.9, 121.6, 120.9, 119.9, 118.3, 112.3, 104.2 (aromatic C), 55.5, 52.6
(aliphatic C); HRMS (ESI-MS) calcd for C29H21N3O3; 482.1481
(MþNa), found: 482.1481. Anal. Calcd for: C, 75.80; H, 4.61; N,
9.14%; found: C, 75.91; H, 4.55; N, 9.21%.
on an automated diffractometer using graphite-monochromated
ꢀ
Mo-K
a
(l¼0.71073 A) radiation with CAD4 software or the X-ray
intensity data were measured at 298 K on an instrument equipped
with a graphite monochromator and a Mo-K fine-focus sealed
4.5. Methyl 1-(6-fluoro-4-phenyl-2-quinolyl)-9H-b-carboline-
3-carboxylate (4d)
a
ꢀ
tube (l¼0.71073 A). Melting points were measured in open capillary
tubes and are uncorrected. All the obtained products were purified
by column chromatography using silica gel (100e200 mesh). All
reaction solvents used were of GR grade and used without drying
unless mentioned. All other commercial reagents were used as
received.
Colorless solid, 103 mg, 77%, Rf¼0.52 (20% EtOAc/Hexanes), mp:
255e257 ꢀC; IR (KBr): 3353, 2969, 2843, 1720, 1342, 1019,
701 cmꢁ1; 1H NMR (400 MHz, CDCl3, TMS)
d: 11.79 (1H, s), 8.93 (2H,
s), 8.29e8.33 (1H, m), 8.23 (1H, d, J¼7.8 Hz), 7.70e7.72 (1H, m),
7.65e7.67 (1H, m), 7.54e7.63 (7H, m), 7.39 (1H, t, J¼7.4 Hz), 4.06
(3H, s); 13C NMR (100 MHz, CDCl3, TMS)
d: 166.7, 156.5, 149.0, 144.8,
4.2. A typical procedure for the preparation of methyl 1-(4-
phenyl-2-quinolyl)-9H-b-carboline-3-carboxylate (4a)
140.9, 137.7, 137.4, 136.9, 136.7, 131.9, 131.8, 130.8, 129.5, 129.1, 128.8,
127.7, 122.0, 121.6, 121.0, 120.2, 119.9, 119.7, 118.7, 112.4, 109.9, 109.7
(aromatic C), 52.7 (aliphatic C); HRMS (ESI-MS) calcd for
C28H18FN3O2 (MþNa); 470.1281, found: 470.1281. Anal. Calcd for: C,
75.16; H, 4.05; N, 9.39%; found: C, 75.26; H, 4.15; N, 9.28%.
In a round bottom flask equipped with a magnetic stirring bar,
0.3 mmol of -formyl- -carboline (1a) and 0.3 mmol of aniline (2a)
a
b
in 4 mL of [Bmim][BF4] was stirred for 12 min. Into this reaction
mixture were added 0.35 mmol of phenylacetylene (3a) and
10 mol % of La(OTf)3 and then heated around 95e100 ꢀC. After
completion of the reaction, as indicated by the TLC, water was
added and extracted with ethylacetate. The organic layer was dried
over anhydrous Na2SO4. The solvent was concentrated under the
reduced pressure. Product was purified by column chromatography
on silica gel (eluent: Hexanes/ethyl acetate) to afford 4a as a col-
orless solid (100 mg, 78%). Rf¼0.56 (20% EtOAc/Hexanes), mp:
298e300 ꢀC; IR (KBr): 3383, 2924, 1732, 1589, 1215, 1032,
4.6. Methyl 1-(6-chloro-4-phenyl-2-quinolyl)-9H-b-carbo-
line-3-carboxylate (4e)
Colorless solid, 111 mg, 80%, Rf¼0.65 (20% EtOAc/Hexanes), mp:
241e243 ꢀC; IR (KBr): 3354, 2965, 1547, 1046, 725 cmꢁ1 1H NMR
(400 MHz, CDCl3, TMS) : 11.78 (1H, s), 8.93 (2H, s), 8.24 (2H, d,
;
d
J¼8.4 Hz), 7.92 (1H, d, J¼2.4 Hz), 7.71e7.75 (2H, m), 7.60 (1H, t,
J¼7.6 Hz), 7.58e7.62 (5H, m), 7.41 (1H, t, J¼7.2 Hz), 4.07 (3H, s); 13C
NMR (100 MHz, CDCl3, TMS) d: 166.6, 157.1, 148.6, 146.1, 140.9, 137.5,
700 cmꢁ1; 1H NMR (400 MHz, CDCl3, TMS)
d: 12.01 (1H, s), 8.98 (1H,
137.1,136.9,136.7,132.9,130.9,130.8,130.5,129.6,129.1,128.8,127.4,
125.1, 121.9, 121.5, 121.0, 120.4, 118.8, 112.3 (aromatic C), 52.6 (ali-
phatic C); HRMS (ESI-MS) calcd for C28H18ClN3O2; 486.0986
(MþNa), found: 486.0986. Anal. Calcd for: C, 72.49; H, 3.91; N,
9.06%; found: C, 72.29; H, 3.86; N, 9.15%.
s), 8.95 (1H, s), 8.36 (1H, d, J¼8.4 Hz), 8.26 (1H, d, J¼8.0 Hz), 7.99
(1H, d, J¼8.4 Hz). 7.83 (1H, t, J¼7.2 Hz), 7.76 (1H, d, J¼8.4 Hz),
7.65e7.69 (3H, m), 7.56e7.62 (4H, m), 7.41 (1H, t, J¼7.4 Hz), 4.09
(3H, s); 13C NMR (100 MHz, CDCl3, TMS)
d: 166.7, 156.9, 149.5, 147.7,
140.9, 138.2, 137.6, 136.9, 136.8, 130.7, 129.7, 129.68, 129.5, 129.1,
128.5, 128.4, 127.1, 126.8, 126.2, 121.9, 121.6, 120.9, 119.6, 118.7, 112.4
(aromatic C), 52.6 (aliphatic C); HRMS (ESI-MS) calcd for
C28H19N3O2; 452.1375 (MþNa), found: 452.1375. Anal. Calcd for: C,
78.31; H, 4.46; N, 9.78%; found: C, 78.45; H, 4.41; N, 9.68%.
4.7. Methyl 1-(6-bromo-4-phenyl-2-quinolyl)-9H-b-carbo-
line-3-carboxylate (4f)
Colorless solid, 114 mg, 75%, Rf¼0.62 (20% EtOAc/Hexanes), mp:
314e316 ꢀC; IR (KBr): 3424, 1736, 1649, 1424, 1019, 767 cmꢁ1 1H
NMR (400 MHz, CDCl3, TMS) : 11.81 (1H, s), 8.95 (1H, s), 8.93 (1H,
;
4.3. Methyl 1-(6-methyl-4-phenyl-2-quinolyl)-9H-
b
-carbo-
d
line-3-carboxylate (4b)
s), 8.25 (1H, d, J¼7.9 Hz), 8.19 (1H, d, J¼8.9 Hz), 8.09 (1H, s), 8.97
(1H, d, J¼8.7 Hz), 7.73 (1H, d, J¼8.2 Hz), 7.67 (1H, t, J¼7.3 Hz),
7.57e7.61 (5H, m), 7.40 (1H, t, J¼7.4 Hz), 4.07 (3H, s); 13C NMR
Colorless solid, 113 mg, 85%, Rf¼0.52 (20% EtOAc/Hexanes), mp:
277e279 ꢀC; IR (KBr): 3348, 2965, 1458, 1244, 1039, 758, 700 cmꢁ1
;
(100 MHz, CDCl3þDMSO-d6, TMS)
d: 166.6, 157.2, 148.6, 146.3,

S. Ramesh, R. Nagarajan / Tetrahedron 69 (2013) 4890e4898
4895
140.9, 137.4, 137.1, 136.9, 136.7, 133.1, 131.2, 130.8, 129.6, 129.2, 128.8,
4.12. Methyl 1-[4-(4-methylphenyl)-2-quinolyl]-9H-
b-carbo-
128.3, 127.9, 121.9, 121.4, 121.2, 121.1, 120.4, 118.8, 112.5 (aromatic C),
52.6 (aliphatic C); HRMS (ESI-MS) calcd for C28H18BrN4O2;
532.0460 (MþNa), found: 532.0460. Anal. Calcd for: C, 66.15; H,
3.57; N, 8.27%; found: C, 66.25; H, 3.65; N, 8.19%.
line-3-carboxylate (4k)
Colorless solid, 113 mg, 85%, Rf¼0.59 (20% EtOAc/Hexanes), mp:
248e250 ꢀC; IR (KBr): 3352, 3055, 2943, 1720, 1589, 1003,
744 cmꢁ1 1H NMR (400 MHz, CDCl3, TMS)
; d: 12.04 (1H, s), 8.99
4.8. Methyl 1-(8-methoxy-4-phenyl-2-quinolyl)-9H-
line-3-carboxylate (4g)
b
-carbo-
(1H, s), 8.94 (1H, s), 8.37 (1H, d, J¼8.3 Hz), 8.27 (1H, d, J¼7.8 Hz),
8.01 (1H, d, J¼8.4 Hz), 7.82 (1H, t, J¼7.8 Hz), 7.75e7.77 (1H, m),
7.68 (1H, t, J¼7.4 Hz), 7.54e7.58 (3H, m), 7.39e7.42 (3H, m), 4.08
Slight yellowish color solid, 109 mg, 79%, Rf¼0.56 (20% EtOAc/
Hexanes), mp: 269e271 ꢀC; IR (KBr): 3354, 1736, 1432, 1087,
(3H, s), 2.50 (3H, s); 13C NMR (100 MHz, CDCl3, TMS)
d: 166.8,
156.9, 149.6, 147.8, 141.0, 138.4, 137.7, 136.9, 135.2, 130.7, 129.7,
129.5, 129.3, 129.1, 127.0, 126.9, 126.3, 122.0, 121.6, 120.9, 119.6,
118.7, 112.4 (aromatic C), 52.7, 21.4 (aliphatic C); HRMS (ESI-MS)
calcd for C29H21N3O2; 466.1532 (MþNa), found: 466.1532. Anal.
Calcd for: C, 78.54; H, 4.77; N, 9.47%; found: C, 78.42; H, 4.71; N,
9.36%.
754 cmꢁ1; 1H NMR (400 MHz, CDCl3, TMS)
d: 12.69 (1H, s), 8.99 (1H,
s), 8.88 (1H, s), 8.27 (1H, d, J¼7.6 Hz), 7.64e7.72 (4H, m), 7.53e7.59
(4H, m), 7.48 (1H, t, J¼8.0 Hz), 7.39 (1H, t, J¼6.8 Hz), 7.17 (1H, d,
J¼7.2 Hz), 4.29 (3H, s), 4.08 (3H, s); 13C NMR (100 MHz, CDCl3, TMS)
d: 166.9, 155.4, 155.0, 149.3, 141.4, 139.4, 138.5, 138.1, 137.1, 136.6,
130.6,129.7,128.8, 128.5, 128.4, 127.6, 127.0,122.0,121.1,120.7,119.5,
118.7, 117.9, 112.4, 107.7 (aromatic C), 56.4, 52.6 (aliphatic C); HRMS
(ESI-MS) calcd for C29H21N3O3; 482.1481, found: 482.1494. Anal.
Calcd for: C, 75.80; H, 4.61; N, 9.14%; found: C, 75.86; H, 4.56; N,
9.21%.
4.13. Methyl 1-[4-(4-fluorophenyl)-2-quinolyl]-9H-b-carbo-
line-3-carboxylate (4l)
Colorless solid, 108 mg, 81%, Rf¼0.50 (20% EtOAc/Hexanes), mp:
247e248 ꢀC; IR (KBr): 3362, 2951, 1498, 1157, 1024, 767, 603 cmꢁ1
1H NMR (500 MHz, CDCl3, TMS)
: 12.01 (1H, s), 9.00 (1H, s), 8.93
;
4.9. Methyl 1-(7-ethyl-1-phenyl-7H-pyrido[2,3-c]carbazole-3-
yl)-9H-b-carboline-3-carboxylate (4h)
d
(1H, s), 8.39 (1H, d, J¼8.3 Hz), 8.28 (1H, d, J¼7.8 Hz), 7.95 (1H, d,
J¼8.3 Hz), 7.86 (1H, t, J¼7.4 Hz), 7.77e7.89 (1H, m), 7.69 (1H, t,
J¼7.4 Hz), 7.58e7.65 (3H, m), 7.43 (1H, t, J¼7.4 Hz), 7.29e7.31 (2H,
Slight yellowish solid, 118 mg, 72%, Rf¼0.35 (20% EtOAc/Hex-
anes), mp: 264e266 ꢀC; IR (KBr): 3354, 3021, 2835, 1544, 1428,
m), 4.09 (3H, s); 13C NMR (125 MHz, CDCl3, TMS)
d: 166.7, 164.0,
1378, 1054, 700, 656 cmꢁ1 1H NMR (400 MHz, DMSO-d6, TMS)
; d:
161.9, 156.9, 148.4, 147.8, 141.0, 136.8, 131.5, 131.4, 130.8, 129.8,
129.6, 129.1, 127.2, 125.9, 122.0, 121.6, 121.0, 119.7, 118.8, 115.7,
115.5, 112.4 (aromatic C), 52.8 (aliphatic C); HRMS (ESI-MS)
calcd for C28H18FN3O2; 448.1461 (MþNa), found: 448.1461. Anal.
Calcd for: C, 75.16; H, 4.05; N, 9.39%; found: C, 74.98; H, 4.12; N,
9.26%.
12.39 (1H, s), 9.06 (1H, s), 8.99 (1H, d, J¼9.1 Hz), 8.81 (1H, s), 8.49
(1H, d, J¼7.9 Hz), 8.44 (1H, d, J¼9.0 Hz), 8.12 (1H, d, J¼7.9 Hz),
7.59e7.71 (7H, m), 7.39 (1H, t, J¼6.6 Hz), 7.28 (1H, t, J¼7.3 Hz), 6.62
(1H, t, J¼7.4 Hz), 5.98 (1H, d, J¼7.9 Hz), 4.69 (2H, q, J¼6.1 Hz), 3.97
(3H, s), 1.42 (3H, t, J¼6.6 Hz); Due to limited solubility of compound
4h in both CDCl3 as well as in DMSO-d6, we were unable to record
the 13C NMR spectra; HRMS (ESI-MS) calcd for C36H26N4O2;
547.2134 (MþNa), found: 547.2134. Anal. Calcd for: C, 79.10; H,
4.79; N, 10.25%; found: C, 79.25; H, 4.71; N, 1018%.
4.14. Methyl 1-[6-chloro-4-(4-methylphenyl)-2-quinolyl]-9H-
b-carboline-3-carboxylate (4m)
Colorless solid, 120 mg, 84%, Rf¼0.62 (20% EtOAc/Hexanes), mp:
4.10. Methyl 1-(6-nitro-4-phenyl-2-quinolyl)-9H-b-carboline-
3-carboxylate (4i)
297e299 ꢀC; IR (KBr): 3362, 2932, 1493, 1020, 744, 561 cmꢁ1 1H
;
NMR (400 MHz, CDCl3, TMS) d: 11.83 (1H, s), 8.97 (1H, s), 8.95 (1H,
s), 8.25e8.28 (2H, m), 7.97 (1H, d, J¼2.0 Hz), 7.73e7.75 (2H, m),
Yellowish solid, 96 mg, 68%, Rf¼0.40 (20% EtOAc/Hexanes), mp:
283e285 ꢀC; IR (KBr): 3364, 3071, 1544, 1467, 1027, 705 cmꢁ1 1H
NMR (400 MHz, CDCl3, TMS) : 11.76 (1H, s), 9.12 (1H, s), 9.03 (1H,
7.68 (1H, t, J¼7.4 Hz), 7.52e7.54 (2H, m), 7.41e7.43 (3H, m), 4.08
;
(3H, s), 2.54 (3H, s); 13C NMR (100 MHz, CDCl3, TMS)
d: 166.7,
d
157.2, 148.8, 146.1, 140.9, 138.7, 137.2, 136.9, 136.7, 134.6, 132.9,
130.9, 130.8, 130.5, 129.5, 129.4, 129.1, 127.6, 125.2, 121.9, 121.0,
120.4, 118.7, 112.3 (aromatic C), 52.6, 21.4 (aliphatic C); HRMS (ESI-
MS) calcd for C29H20ClN3O2; 500.1142 (MþNa), found: 500.1142.
Anal. Calcd for: C, 72.88; H, 4.22; N, 8.79%; found: C, 72.96; H,
4.32; N, 8.61%.
s), 8.93 (1H, d, J¼2.3 Hz), 8.58e8.61 (1H, m), 8.48e8.50 (1H, m),
8.29 (1H, d, J¼7.9 Hz), 7.79 (1H, d, J¼8.0 Hz), 7.62e7.75 (6H, m), 7.44
(1H, t, J¼7.6 Hz), 4.09 (3H, s); Due to limited solubility of compound
4i in CDCl3 as well as in DMSO-d6, we were unable to record the 13
C
NMR spectra; LCMS calcd for C28H18N4O4; 474.13 (m/z), found:
475.25 (Mþ1) (positive mode). Anal. Calcd for: C, 70.88; H, 3.82; N,
11.81%; found: C, 70.72; H, 3.93; N, 11.68%.
4.15. Methyl 1-[6-bromo-4-(4-methylphenyl)-2-quinolyl]-9H-
4.11. Methyl 1-(5,7-dichloro-4-phenyl-2-quinolyl)-9H-
b-car-
b-carboline-3-carboxylate (4n)
boline-3-carboxylate (4j)
Colorless solid, 125 mg, 80%, Rf¼0.55 (20% EtOAc/Hexanes), mp:
Colorless solid, 112 mg, 75%, Rf¼0.54 (20% EtOAc/Hexanes), mp:
255e257 ꢀC; IR (KBr): 3369, 1738, 1054, 709, 654 cmꢁ1 1H NMR
(400 MHz, CDCl3, TMS) : 11.64 (1H, s), 8.98 (1H, s), 8.84 (1H, s),
319e321 ꢀC; IR (KBr): 3350, 3055, 1732, 1215, 1145, 603 cmꢁ1 1H
;
;
NMR (400 MHz, CDCl3, TMS) d: 11.81 (1H, s), 8.96 (1H, s), 8.93 (1H,
d
s), 8.25 (1H, d, J¼7.8 Hz), 8.18 (1H, d, J¼8.9 Hz), 8.13 (1H, s), 8.86 (1H,
d, J¼8.4 Hz), 7.72e7.74 (1H, m), 7.67 (1H, t, J¼7.1 Hz), 7.51e7.53 (2H,
m), 7.39e7.43 (3H, m), 4.08 (3H, s), 2.54 (3H, s); 13C NMR (100 MHz,
8.26e8.29 (2H, m), 7.78e7.80 (1H, m), 7.71 (1H, t, J¼8.0 Hz), 7.61
(1H, d, J¼2.0 Hz), 7.42e7.49 (6H, m), 4.07 (3H, s); 13C NMR
(100 MHz, CDCl3, TMS)
d: 166.5, 157.5, 149.4, 149.3, 140.9, 140.3,
CDCl3, TMS) d: 166.6, 157.3, 148.7, 146.3, 140.9, 138.7, 137.1, 136.9,
137.1, 136.9, 136.3, 134.7, 132.5, 131.1, 130.3, 129.4, 129.1, 128.1, 128.0,
127.8, 123.2, 123.0, 122.1, 121.5, 121.3, 119.1, 112.4 (aromatic C), 52.7
(aliphatic C); HRMS (ESI-MS) calcd for C28H17Cl2N3O2; 520.0596
(MþNa), found: 520.0596. Anal. Calcd for: C, 67.48; H, 3.44; N,
8.43%; found: C, 67.38; H, 4.41; N, 8.56%.
136.7, 134.5, 133.1, 131.1, 130.8, 129.5, 129.4, 129.1, 128.4, 128.1, 121.9,
121.5, 121.1, 121.0, 120.4, 118.8, 112.3 (aromatic C), 52.6, 21.4 (ali-
phatic C); HRMS (ESI-MS) calcd for C29H20BrN3O2; 544.0637
(MþNa), found: 544.0637. Anal. Calcd for: C, 66.68; H, 3.86; N,
8.04%; found: C, 66.52; H, 3.75; N, 8.16%.

4896
S. Ramesh, R. Nagarajan / Tetrahedron 69 (2013) 4890e4898
4.16. Methyl 1-[4-(3,5-dimethylphenyl)-2-quinolyl]-9H-
boline-3-carboxylate (4o)
b
-car-
4.20. Methyl 1-[4-(4-chlorophenyl)-6-methoxy-2-quinolyl]-
9H- -carboline-3-carboxylate (4s)
b
Colorless solid, 108 mg, 79%, Rf¼0.55 (20% EtOAc/Hexanes), mp:
309e311 ꢀC; IR (KBr): 3369, 1724, 1358, 1107, 761 cmꢁ1 1H NMR
(400 MHz, CDCl3, TMS) : 12.06 (1H, s), 8.99 (1H, s), 8.93 (1H, s),
Colorless solid, 122 mg, 82%, Rf¼0.52 (20% EtOAc/Hexanes),
mp: 265e267 ꢀC; IR (KBr): 3402, 2924, 1728, 1358, 746 cmꢁ1 1H
NMR (500 MHz, CDCl3, TMS) : 11.88 (1H, s), 8.94 (1H, s), 8.80
(1H, s), 8.21e8.26 (2H, m), 7.73e7.74 (1H, m), 7.67 (1H, t,
J¼7.4 Hz), 7.56e7.61 (4H, m), 7.47 (1H, dd, J1¼2.2 Hz
J2¼9.1 Hz), 7.41 (1H, t, J¼7.4 Hz), 7.16 (1H, d, J¼2.4 Hz), 4.08 (3H,
s), 3.85 (3H, s); 13C NMR (125 MHz, CDCl3, TMS)
: 166.7, 158.6,
;
;
d
d
8.36 (1H, d, J¼8.3 Hz), 8.28 (1H, d, J¼7.5 Hz), 8.00 (1H, d, J¼8.0 Hz),
7.83 (1H, t, J¼7.3 Hz), 7.76e7.78 (1H, m), 7.68 (1H, t, J¼7.6 Hz), 7.57
(1H, t, J¼7.7 Hz), 7.41 (1H, t, J¼7.4 Hz), 7.26e7.27 (2H, m), 7.18 (1H,
&
s), 4.08 (3H, s), 2.46 (6H, s); 13C NMR (100 MHz, CDCl3, TMS)
d:
d
166.8, 156.9, 149.9, 147.7, 141.0, 138.1, 137.7, 136.9, 130.7, 130.0,
129.6, 129.4, 129.1, 127.5, 126.9, 126.5, 122.0, 121.6, 120.9, 119.5,
118.7, 112.4 (aromatic C), 52.6, 21.4 (aliphatic C); HRMS (ESI-MS)
calcd for C30H23N3O2; 480.1688 (MþNa), found: 480.1688. Anal.
Calcd for: C, 78.75; H, 5.07; N, 9.18%; found: C, 78.62; H, 5.15; N,
9.07%.
154.6, 146.7, 143.7, 140.9, 137.7, 136.9, 136.8, 136.5, 134.6, 131.1,
130.8, 130.5, 128.98, 128.9, 127.5, 122.2, 121.9, 121.6, 120.9, 119.9,
118.4, 112.3, 103.8 (aromatic C), 55.6, 52.6 (aliphatic C); HRMS
(ESI-MS) calcd for C29H20ClN3O3; 516.1091, found: 516.1091. Anal.
Calcd for: C, 70.52; H, 4.08; N, 8.51%; found: C, 70.65; H, 4.12; N,
8.71%.
4.17. Methyl 1-(7-bromo-5,8-dimethoxy-4-phenyl-2-
4.21. Methyl 1-(8-bromo-4-phenyl-2-quinolyl)-9H-b-carbo-
quinolyl)-9H-
b-carboline-3-carboxylate (4p)
line-3-carboxylate (4t)
Colorless solid, 126 mg, 74%, Rf¼0.52 (20% EtOAc/Hexanes), mp:
277e279 ꢀC; IR (KBr): 3356, 2939, 2841, 1259, 1107, 744, 545 cmꢁ1
1H NMR (400 MHz, CDCl3, TMS)
: 12.51 (1H, s), 9.01 (1H, s), 8.77
Colorless solid, 111 mg, 73%, Rf¼0.52 (20% EtOAc/Hexanes), mp:
245e247 ꢀC; IR (KBr): 3354, 2781, 1547, 1327, 782 cmꢁ1 1H NMR
(500 MHz, CDCl3, TMS) : 12.57 (1H, s), 9.01 (1H, s), 9.00 (1H, s),
;
;
d
d
(1H, s), 8.28 (1H, d, J¼7.7 Hz), 7.76e7.78 (1H, m), 7.69 (1H, t,
8.27 (1H, d, J¼7.9 Hz), 8.16 (1H, dd, J1¼0.9 Hz & J2¼7.5 Hz), 7.96
(1H, dd, J1¼0.8 Hz & J2¼8.3 Hz), 7.74e7.76 (1H, m), 7.56e7.69 (6H,
m), 7.39e7.44 (2H, m), 4.09 (3H, s); 13C NMR (125 MHz, CDCl3,
J¼7.4 Hz), 7.40e7.45 (6H, m), 6.99 (1H, s), 4.31 (3H, s), 4.08 (3H, s),
3.56 (3H, s); 13C NMR (100 MHz, CDCl3, TMS)
d: 166.7, 156.3, 153.2,
149.7, 147.2, 143.3, 141.9, 141.3, 137.3, 137.2, 136.9, 130.8, 129.2,
128.3, 127.2, 127.1, 122.1, 121.6, 121.3, 120.9, 119.0, 118.9, 116.7, 112.3,
110.3 (aromatic C), 61.6, 55.7, 52.6 (aliphatic C); HRMS (ESI-MS)
calcd for C30H22BrN3O4; 590.0692 (MþNa), found: 590.0692. Anal.
Calcd for: C, 63.39; H, 3.90; N, 7.39%; found: C, 63.25; H, 3.98; N,
7.21%.
TMS) d: 166.7, 157.1, 150.2, 144.6, 141.5, 137.8, 137.0, 136.8, 136.7,
133.1, 130.9, 129.7, 129.1, 128.7, 128.6, 128.3, 127.2, 126.2, 125.3,
121.9, 121.5, 120.9, 120.2, 119.1, 112.4 (aromatic C), 52.6 (aliphatic C);
HRMS (ESI-MS) calcd for C28H18BrN3O2; 532.0460 (MþNa), found:
532.0480. Anal. Calcd for: C, 66.15; H, 3.57; N, 8.27%; found: C,
66.38; H, 3.51; N, 8.35%.
4.18. Ethyl 4-methyl-1-(4-phenyl-2-quinolyl)-9H-
b
-carboline-
4.22. Methyl 1-(8-chloro-4-phenyl-2-quinolyl)-9H-b-carbo-
3-carboxylate (4q)
line-3-carboxylate (4u)
Colorless solid, 100 mg, 73%, Rf¼0.45 (20% EtOAc/Hexanes),
mp: 238e240 ꢀC; IR (KBr): 3350, 2962, 1728, 1493, 1261, 700,
Colorless solid, 107 mg, 77%, Rf¼0.52 (20% EtOAc/Hexanes),
mp: 267e269 ꢀC; IR (KBr): 3329, 2922, 1711, 1356, 1016,
403 cmꢁ1
;
1H NMR (400 MHz, CDCl3, TMS)
d
: 12.08 (1H, s), 8.89
671 cmꢁ1 1H NMR (500 MHz, CDCl3, TMS)
; d: 12.49 (1H, s), 9.00
(1H, s), 8.36e8.40 (2H, m), 7.98 (1H, d, J¼8.3 Hz), 7.77e7.84
(2H, m), 7.63e7.68 (3H, m), 7.53e7.59 (4H, m), 7.40 (1H, t,
J¼7.6 Hz), 4.53 (2H, q, J¼7.1 Hz), 3.20 (3H, s), 1.49 (3H, t,
(1H, s), 8.99 (1H, s), 8.27 (1H, d, J¼7.8 Hz), 7.96 (1H, d, J¼7.4 Hz),
7.91 (1H, dd, J1¼0.7 Hz & J2¼8.3 Hz), 7.74e7.75 (1H, m),
7.56e7.69 (6H, m), 7.48 (1H, t, J¼8.1 Hz), 7.41 (1H, t, J¼7.3 Hz),
J¼7.1 Hz); 13C NMR (100 MHz, CDCl3, TMS)
d
: 167.8, 157.2, 149.2,
4.09 (3H, s); 13C NMR (125 MHz, CDCl3, TMS)
d: 166.7, 156.8,
147.8, 140.8, 138.3, 135.7, 135.1, 131.4, 129.9, 129.7, 129.6, 129.5,
128.5, 128.4, 128.1, 126.8, 126.6, 126.2, 124.0, 122.3, 120.7, 119.6,
112.3 (aromatic C), 61.4, 16.8, 14.5 (aliphatic C); HRMS (ESI-MS)
calcd for C30H23N3O2; 480.1688 (MþNa), found: 480.1688. Anal.
Calcd for: C, 78.75; H, 5.07; N, 9.18%; found: C, 78.62; H, 5.13;
N, 9.25%.
150.1, 143.8, 141.4, 137.8, 137.1, 136.9, 136.8, 133.5, 130.9, 129.7,
129.5, 129.1, 128.7, 128.6, 128.1, 126.6, 125.4, 121.9, 121.5, 120.9,
120.1, 119.0, 112.5 (aromatic C), 52.6 (aliphatic C); HRMS (ESI-MS)
calcd for C28H18ClN3O2; 486.0986 (MþNa), found: 486.0986.
Anal. Calcd for: C, 72.49; H, 3.91; N, 9.06%; found: C, 72.31; H,
3.85; N, 9.18%.
4.19. Methyl 1-[4-(4-chlorophenyl)-6-methyl-2-quinolyl]-9H-
4.23. Diethyl 4-(3-ethyloxycarbonyl-9H-b-carbolin-1-yl)-1-
b-carboline-3-carboxylate (4r)
phenyl-1,4-dihydro-3,5-pyridinedicarboxylate (5b)
Colorless solid, 115 mg, 80%, Rf¼0.64 (20% EtOAc/Hexanes),
Colorless solid, 116 mg, 72%, Rf¼0.32 (20% EtOAc/Hexanes), mp:
mp: 288e290 ꢀC; IR (KBr): 3337, 2945, 1562, 1265, 1003,
166e168 ꢀC; IR (KBr): 3344, 2955, 1597, 1211, 1012, 896, 742 cmꢁ1
;
605 cmꢁ1
;
1H NMR (500 MHz, CDCl3, TMS)
d
: 11.97 (1H, s), 8.98
1H NMR (400 MHz, CDCl3, TMS)
d: 9.84 (1H, s), 8.72 (1H, s), 8.14 (1H,
(1H, s), 8.86 (1H, s), 8.26 (2H, t, J¼8.3 Hz), 7.75e7.77 (1H, m),
d, J¼7.4 Hz), 7.81 (2H, s), 7.59e7.62 (1H, m), 7.53e7.57 (1H, m),
7.46e7.52 (4H, m), 7.27e7.34 (2H, m), 5.58 (1H, s), 4.40 (2H, q,
J¼6.9 Hz), 3.99e4.13 (4H, m), 1.38 (3H, q, J¼7.0 Hz), 1.11 (6H, t,
7.66e7.70 (3H, m), 7.57e7.59 (4H, m), 7.42 (1H, t, J¼7.2 Hz), 4.09
(3H, s), 2.54 (3H, s); 13C NMR (125 MHz, CDCl3, TMS)
d: 166.7,
156.1, 147.4, 146.3, 141.0, 137.6, 137.5, 136.9, 136.8, 136.7, 134.6,
132.0, 131.0, 130.7, 129.4, 129.0, 128.8, 126.5, 124.7, 121.9, 121.6,
120.9, 119.6, 118.6, 112.4 (aromatic C), 52.6, 21.9 (aliphatic C);
HRMS (ESI-MS) calcd for C29H20ClN3O2; 500.1142, found:
500.1142. Anal. Calcd for: C, 72.88; H, 4.22; N, 8.79%; found: C,
72.96; H, 4.12; N, 8.91%.
J¼7.0 Hz); 13C NMR (100 MHz, CDCl3, TMS)
d: 167.3, 166.5, 146.9,
143.5,141.1,138.1,137.9,134.9, 129.8,128.0,128.3,126.8,122.3, 121.9,
121.7, 120.4, 116.7, 112.4, 107.8 (aromatic C), 60.9, 60.4, 35.1, 14.4,
14.2 (aliphatic C); LCMS calcd for C31H29N3O6; 540.21 (Mþ1),
found: 540.15. Anal. Calcd for: C, 69.00; H, 5.42; N, 7.79%; found: C,
69.21; H, 5.53; N, 7.65%.

S. Ramesh, R. Nagarajan / Tetrahedron 69 (2013) 4890e4898
4897
3. (a) Zhang, X.; Liu, B.; Shu, X.; Gao, Y.; Lv, H.; Zhu, J. J. Org. Chem. 2012, 77,
501; (b) Peshkov, V. A.; Pereshivko, O. P.; Eycken, E. V. V. Chem. Soc. Rev.
2012, 41, 3790; (c) Tang, J.; Wang, S.; Mao, D.; Wang, W.; Zhang, L.; Wu, S.;
Xie, Y. Tetrahedron 2011, 67, 8465; (d) Kulkarni, A.; Torok, B. Green Chem.
2010, 12, 875; (e) Gaddam, V.; Ramesh, S.; Nagarajan, R. Tetrahedron 2010,
66, 4218; (f) Huang, H.; Jiang, H.; Chen, K.; Liu, H. J. Org. Chem. 2009, 74,
5476; (g) Cao, K.; Zhang, F. M.; Tu, Y. Q.; Zhuo, X. T.; Fan, C. A. Chem.dEur.
J. 2009, 15, 6332; (h) Xiao, F.; Chen, Y.; Liu, Y.; Wang, J. Tetrahedron 2008,
64, 2755; (i) Zhang, J.; Yang, W.; Song, L.; Caib, X.; Zhub, S. Tetrahedron Lett.
2004, 45, 5771.
4.24. Diethyl 4-(3-ethyloxycarbonyl-9H-b-carbolin-1-yl)-1-(4-
methylphenyl)-1,4-dihydro-3,5-pyridinedicarboxylate (5c)
Colorless solid, 126 mg, 76%, Rf¼0.35 (20% EtOAc/Hexanes), mp:
175e177 ꢀC; IR (KBr): 3365, 2903, 1398, 1025, 700 cmꢁ1 1H NMR
;
(500 MHz, CDCl3, TMS) d: 9.88 (1H, s), 8.73 (1H, s), 8.14 (1H, d,
J¼7.8 Hz), 7.78 (2H, s), 7.58e7.61 (1H, m), 7.54e7.57 (1H, m),
7.38e7.39 (2H, m), 7.29e7.32 (3H, m), 5.59 (1H, s), 4.43 (2H, q,
J¼7.2 Hz), 4.08e4.15 (2H, m), 3.99e4.06 (2H, m), 2.43 (3H, s), 1.41
(3H, t, J¼7.1 Hz), 1.12 (6H, t, J¼7.2 Hz); 13C NMR (125 MHz, CDCl3,
4. For some of the b-carboline alkaloids, see: (a) Hibino, S.; Sugino, E.; Yamochi, T.;
Kuwata, M.; Hashimoto, H.; Sato, K.; Amanuma, F.; Karasawa, Y. Chem. Pharm.
Bull. 1987, 35, 2261; (b) Panarese, J. D.; Waters, S. P. Org. Lett. 2009, 11, 5086; (c)
Nissen, F.; Richard, V.; Alayracab, C.; Witulski, B. Chem. Commun. 2011, 6656; (d)
Davis, R. A.; Carroll, A. R.; Quinn, R. J. J. Nat. Prod. 1998, 61, 959; (e) Yamashita, T.;
Kawai, N.; Tokuyama, H.; Fukuyama, T. J. Am. Chem. Soc. 2005, 127, 15038.
5. (a) Doyle, T. W.; Balitz, D. M.; Grulich, R. E.; Nettleton, D. E.; Gould, S. J.; Tann,
C.-H.; Moews, A. E. Tetrahedron Lett. 1981, 22, 4595; (b) Balitz, D. M.; Bush, J. A.;
Bradner, W. T.; Doyle, T. W.; O’Herron, F. A.; Nettleton, D. E. J. Antibiot. 1982, 35,
259.
TMS) d: 167.4, 166.5, 147.1, 141.2, 141.1, 138.2, 138.1, 136.7, 134.9,
130.3, 128.9, 128.3, 122.3, 122.1, 121.6, 120.4, 116.6, 112.3, 107.4 (ar-
omatic C), 60.8, 60.4, 35.1, 20.9, 14.4, 14.2 (aliphatic C); HRMS (ESI-
MS) calcd for C32H31N3O6; 576.2111 (MþNa), found: 576.2111. Anal.
Calcd for: C, 69.43; H, 5.64; N, 7.59%; found: C, 69.28; H, 5.58; N,
7.71%.
6. Kende, A. S.; Ebetino, F. H. Tetrahedron Lett. 1984, 25, 923.
7. (a) Boger, D. L.; Panek, J. S. Tetrahedron Lett. 1984, 25, 3175; (b) Boger, D. L.; Duff,
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S. P.; Sivadasan, L. Tetrahedron 1986, 42, 5065; (e) Boger, D. L.; Yasuda, M.;
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4.25. Diethyl 4-(3-ethyloxycarbonyl-9H-b-carbolin-1-yl)-1-(4-
methoxyphenyl)-1,4-dihydro-3,5-pyridinedicarboxylate (5d)
Colorless solid, 128 mg, 75%, Rf¼0.30 (20% EtOAc/Hexanes), mp:
165e167 ꢀC; IR (KBr): 3387, 2980, 1672, 1197, 798 cmꢁ1 1H NMR
;
(400 MHz, CDCl3, TMS) d: 9.86 (1H, s), 8.71 (1H, s), 8.13 (1H, d,
J¼7.6 Hz), 7.69 (2H, s), 7.52e7.59 (2H, m), 7.43 (2H, d, J¼8.3 Hz),
7.27e7.31 (1H, m), 6.99e7.01 (2H, m), 5.57 (1H, s), 4.42 (2H, q,
J¼7.1 Hz), 3.99e4.12 (4H, m), 3.86 (3H, s), 1.42 (3H, t, J¼6.9 Hz), 1.10
ꢁ
Rocca, P.; Marsais, F.; Godard, A.; Queguiner, G. Tetrahedron Lett. 1993, 34, 2937;
(l) Molina, P.; Murcia, F.; Fresneda, P. M. Tetrahedron Lett. 1994, 35, 1453; (m)
Behforouz, M.; Haddad, J.; Cai, W.; Arnold, M. B.; Mohammadi, F.; Sousa, A. C.;
Horn, M. A. J. Org. Chem. 1996, 61, 6552; (n) Godard, A.; Rocca, P.; Pomel, V.;
(6H, t, J¼6.8 Hz); 13C NMR (100 MHz, CDCl3, TMS)
d: 167.4, 166.5,
ꢁ
Thomas-dit-Dumont, L.; Rovera, J. C.; Thaburet, J. F.; Marsais, F.; Queguiner, G. J.
158.6, 147.1, 141.1, 138.6, 138.1, 137.0, 134.9, 128.9, 128.3, 124.2, 122.3,
121.6, 120.4, 116.6, 114.9, 112.3, 107.1 (aromatic C), 60.8, 60.3, 55.6,
34.9, 14.5, 14.2 (aliphatic C); HRMS (ESI-MS) calcd for C32H31N3O7;
592.2060 (MþNa), found: 592.2060 (MþNa). Anal. Calcd for: C,
67.48; H, 5.49; N, 7.38%; found: C, 67.59; H, 5.42; N, 7.51%.
Organomet. Chem. 1996, 517, 25; (o) McElroy, W. T.; Deshong, P. Org. Lett. 2003,
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Bioorg. Med. Chem. 2007, 15, 495; (r) Hassani, M.; Cai, W.; Koelsch, K. H.; Holley,
D. C.; Rose, A. S.; Olang, F.; Lineswala, J. P.; Holloway, W. G.; Gerdes, J. M.;
Behforouz, M.; Beall, H. D. J. Med. Chem. 2008, 51, 3104; (s) Nourry, A.; Legoupy,
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E. D.; Koelsch, K. H.; Seradj, H.; Lineswala, J. P.; Mirzaei, H.; York, J. S.; Olang, F.;
Sedighi, M.; Lucas, J. S.; Eads, T. J.; Rose, A. S.; Charkhzarrin, S.; Hermann, N. G.;
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Acknowledgements
We gratefully acknowledge DST for financial assistance (Project)
number: (SR/S1/OC-70/2008) and for providing a single crystal X-
ray diffractometer facility to our school. S.R. thanks CSIR for a Senior
Research Fellowship.
8. (a) England, D. B.; Padwa, A. Org. Lett. 2008, 10, 3631; (b) Nourry, A.; Legoupy,
S.; Huet, F. Tetrahedron Lett. 2007, 48, 6014.
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Kuno, A. J. Antibiot. 1988, 41, 1471; (b) Behforouz, M.; Cai, W.; Stocksdale, M. G.;
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Supplementary data
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.tet.2013.04.074.
References and notes
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S. Ramesh, R. Nagarajan / Tetrahedron 69 (2013) 4890e4898
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