An oxidative amidation and heterocyclization approach for the synthesis of β-carbolines and dihydroeudistomin y

Article abstract of DOI:10.3762/bjoc.10.45

A novel synthetic methodology has been developed for the synthesis of dihydro-β-carboline derivatives employing oxidative amidation-Bischler- Napieralski reaction conditions using tryptamine and 2,2-dibromo-1- phenylethanone as key starting materials. A number of dihydro-β-carboline derivatives have been synthesized in moderate to good yields using this methodology. Attempts were made towards the conversion of these dihydro-β-carbolines to naturally occurring eudistomin alkaloids.

Full text of DOI:10.3762/bjoc.10.45

An oxidative amidation and heterocyclization
approach for the synthesis of β-carbolines
and dihydroeudistomin Y
Suresh Babu Meruva*1,2, Akula Raghunadh1, Raghavendra Rao Kamaraju1,
U. K. Syam Kumar*1 and P. K. Dubey2
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2014, 10, 471–480.
1Technology Development Centre, Custom Pharmaceutical Services,
Dr. Reddy’s Laboratories Ltd., Miyapur, Hyderabad – 500049, India
and 2Department of Chemistry, College of Engineering, JNTUH,
Kukatpally, Hyderabad – 500085, India
doi:10.3762/bjoc.10.45
Received: 13 November 2013
Accepted: 29 January 2014
Published: 25 February 2014
Email:
Suresh Babu Meruva* - sureshbabum@drreddys.com;
U. K. Syam Kumar* - syam_kmr@yahoo.com
Associate Editor: J. Aubé
© 2014 Meruva et al; licensee Beilstein-Institut.
License and terms: see end of document.
* Corresponding author
Keywords:
Bischler–Napieralski reaction; dihydro-β-carboline derivatives;
dihydro-eudistomin; eudistomin; keto amide; oxidative amidation
Abstract
A novel synthetic methodology has been developed for the synthesis of dihydro-β-carboline derivatives employing oxidative
amidation–Bischler–Napieralski reaction conditions using tryptamine and 2,2-dibromo-1-phenylethanone as key starting materials.
A number of dihydro-β-carboline derivatives have been synthesized in moderate to good yields using this methodology. Attempts
were made towards the conversion of these dihydro-β-carbolines to naturally occurring eudistomin alkaloids.
Introduction
β-Carboline alkaloids [1] are widespread in plants, animals and 5-acyl group at the C-1 position and was isolated from the
some are formed naturally in the biological system. Rinehart et Okinawan marine sponge Xestopongia sp. The other β-carbo-
al. [2] reported the isolation of β-carboline alkaloids such as line alkaloids reported in the literature are fascaplysin (4) [7],
eudistomins [3] and several of its analogues from the active eudistomin A (5a) [3], harmine (5b) [8-10], harmaline (5c) [11],
Caribbean colonial tunicate Eudistoma olivaceum. β-Carboline and tetrahydroharmine (5d). Among these, methoxy substituted
alkaloids bearing a substituted phenylacetyl group at C-1 pos- β-carboline alkaloids such as 5b, 5c, and 5d are indigenously
ition such as eudistomin T (1) [4], eudistomin R (2a) and eudis- used as hallucinogenic drugs. Some β-carbolines, notably tryp-
tomin S (2b) [5] were isolated by Cardellina et al. [6], and these toline (5e) and pinoline (5f), are produced naturally in the
compounds exhibit antimicrobial activity. Xestomanzamine A human body. Recently Heonjoong et al. isolated new β-carbo-
(3) [5] is a β-carboline alkaloid with an 1-methyl-1H-imidazole- line-based metabolites, designated as eudistomins Y1−Y7
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Beilstein J. Org. Chem. 2014, 10, 471–480.
(6a–g) [12-14] (Figure 1), from the tunicate of the genus Eudis- reported in literature for the syntheses of eudistomin T (1) and
toma and posses a benzoyl group at the C-1 position of the eudistomin S (2b). Jenkins and co-workers reported the syn-
β-carboline structural framework. Eudistomins Y1−Y7 (6a–6g) thesis of fascaplysin (4) by the reaction of tryptamine with
were evaluated for their antibacterial activity. Eudistomin Y6 phenylacetyl chloride and carried out the aromatization under
(6f) exhibits moderate antibacterial activity against the Gram- photo-oxidation conditions [15,16]. Lindsley and co-workers
positive bacteria Staphylococcus epidermis and Bacillus [17] reported the synthesis of eudistomins Y1−Y7 (6a–6g)
subtilis.
under microwave conditions [18]. Considering the complexity
involved in the synthesis of several of the starting materials
used in the preparation of carbolines, especially tricarbonyl
Results and Discussion
There are several approaches known in literature for the syn- compounds, an alternate approach for the synthesis of 3H-β-
thesis of β-carbolines. Most of the syntheses of eudistomin T carboline is sought after. Herein we described our successful
(1) are generally carried out either from indole or its suitably efforts towards the synthesis of 1-benzoyldihydro-β-carbolines
substituted derivatives. The acylation of 2-(3-indolyl)ethyl or dihydroeudistomin. The previously developed synthetic
isocyanide with phenylacetyl chloride followed by cyclization methodologies in our laboratory [19-24] were utilized for the
and aromatization is well documented in the literature for the synthesis of eudistomin Y (6) and its analogues
synthesis of 1-benzoyldihydro-β-carbolines. The cyclization of
the adduct, formed by the reaction of tryptamine with appropri- The disconnection approach employed in the synthesis of
ately substituted 1,2,3-tricarbonyl compounds or with glyoxylic 1-benzoyl-β-carboline is described in Scheme 1. Accordingly
acid derivatives under Pictet–Spengler conditions is also eudistomin Y (6) could be obtained by the aromatization of
Figure 1: Natural products containing the β-carboline skeletal.
Scheme 1: Retrosynthetic analysis of 6.
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Beilstein J. Org. Chem. 2014, 10, 471–480.
dihydro-β-carboline 12. The dihydro-β-carboline 12 in turn It was possible to limit the formation of benzamide impurity 17
could be synthesized from ketoamide 9 under Lewis acid medi- in the reaction to <15% (Table 1); however, we were unable to
ated Bischler–Napieralski reaction. The key intermediate, avoid the formation of 17 under any of the attempted reaction
ketoamide 9 required for the synthesis could easily be accessed conditions (Scheme 3).
from tryptamine (10) and appropriately substituted 2,2-
dibromo-1-phenylethanone (11) [25,26] under oxidative amida- The α-ketoamide 9 thus obtained by the oxidative amidation
tion conditions.
methodology was subjected to a Bischler–Napieralski cyclode-
hydration reaction in presence of POCl3 [27], however under
The oxidative amidation strategy employed in the current syn- these conditions 2,9-dihydro-β-carboline derivative 7 was
thesis is previously reported from our group by the reaction of a obtained as the major product (less than 10% yield) instead of
secondary amine with aryl-2,2-dibromo-1-ethanone under aerial 4-9-dihydro-β-carboline derivative 12 (Scheme 4). Our attempts
oxidation conditions [24]. Later this methodology was success- to improve the yield of 7 under Bischler–Napieralski cyclode-
fully employed in the synthesis of isoquinoline alkaloids [27]. hydration reaction conditions using POCl3 as the Lewis acid
The synthesis of eudistomin Y (6) was initiated with the conver- were proved to be futile. This prompted us to test the efficiency
sion of the respective 2,2-dibromo-1-phenylethanone to the of other Lewis acids in this cyclodehydration reaction. The
corresponding Schiff base 14 by reaction with tryptamine in Bischler–Napieralski cyclodehydration reaction was then
presence of NaI. The Schiff base on in situ oxidation with carried out with different Lewis acids such as BF3·Et2O, SnCl4,
cumene hydroperoxide afforded an unstable oxaziridine deriva- TiCl4 etc., in mutiple solvents under various reaction condi-
tive 15. Ring opening of the oxaziridine derivative 15 in pres- tions. The best conversion was obtained when the reaction was
ence of base afforded ketoiminol 16, which on iminol–amide conducted in BF3·Et2O in ether at 25–30 °C and the product
tautomerism provided the required α-ketoamide 9 (Scheme 2). dihydro-β-carboline 7 was isolated in 55% of yield.
Scheme 2: Plausible mechanism of the oxidative amidation for 9.
Table 1: Effect of solvent and additive on the ratio of 9 and 17.
Base
Solvent /Additives
Reaction time (h)
α-Ketoamide 9 (%)
Amide 17 (%)
1
2
3
TEA
TEA
TEA
DMSO/NaI
Sulfolane/NaI
DMSO
6
60
52
42
15
15
25
16
25
Scheme 3: Synthesis of α-ketoamide 9.
473

Beilstein J. Org. Chem. 2014, 10, 471–480.
Scheme 4: Synthesis of dihydroeudistomin Y analogues.
The formation of isomeric 2,9-dihydro-β-carboline derivative 7 of our knowledge, this is a novel method for the synthesis of
as the major product in Bischler–Naperalski reaction conditions 1-benzoyldihydrocarboline from α-ketoamide 9 [28].
is explained in Scheme 5. The initially formed spirocyclic com-
pound 18 undergoes intramolecular rearrangement and afforded The structure of 2,9-dihydro-β-carboline 7 and 1-hydroxytetra-
the dihydrocarboline framework 19, which on aromatization hydro-β-carboline 8 was confirmed by various NMR tech-
yielded 20. Based on the reaction conditions 8 can be obtained niques such as 2D NMR, COSY as well as HSQC (Figure 2).
from 20 after aqueous work-up or at higher temperature heating, The coupling of the H2 proton with both H1 and H3 protons is
20 undergoes a sequential prototropic migration leading to the clearly evident in the COSY for 7a, whereas the OH proton in
formation of 2,9-dihydro-β-carboline derivative 7. To the best 8a shows a high nOe (Scheme 6).
Scheme 5: Plausible mechanism for the formation of 7.
Scheme 6: Rearrangement of 8a into 7a and coupling interactions of 7a.
474

Beilstein J. Org. Chem. 2014, 10, 471–480.
Figure 2: COSY and HSQC of 8a and 7a.
Dihydro-β-carboline 7 was then subjected to an aromatization Utilizing the oxidative amidation Bischler–Napieralski reaction
reaction to obtain eudistomin Y (6). The aromatization reaction conditions we have synthesized a number of dihydro-β-carbo-
was attempted with oxidizing agents such as DDQ and MnO2 as lines (Table 2) in moderate to good yields. The structures of
per the reported conditions in literature. The formation of pro- these compounds were confirmed by spectral and analytical
duct 6 was confirmed by LCMS analysis of the crude reaction methods.
mixture. However under these conditions product 6 was
observed in less than 5% and our attempt to isolate the eudis- Conclusion
tomin Y (6) in pure form was not successful. The oxidation of In conclusion, we have developed an oxidative amidation
compound 7 with oxygen, KMnO4, MnO2 and TBHP as well as Bischler–Napieralski reaction methodology for the synthesis of
dehydrogenation with DBU in different solvents at various dihydroeudistomin Y (7a–7i). A number of 1-benzoyl dihydro-
temperatures also failed and did not yield the required product. β-carboline derivates have been synthesized as a part of these
Attempted oxidation of compound 7 under microwave irradi- studies. The oxidative amidation Bischler–Napieralski reaction
ation conditions was also not successful. Probably under all provides a simple and direct method for the synthesis of
aforementioned conditions, formation of the stable enol 21 carbolines, which are otherwise synthesized by multistage
might have retarded the aromatization during the course of reactions utilizing starting materials which are not readily avail-
dehydrogenation reaction of dihydro-β-carboline 7.
able.
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Beilstein J. Org. Chem. 2014, 10, 471–480.
Table 2: Synthesis of dihydro-β-carbolinesa.
Dibromo-
ethanone 11
α-Ketoamide 9
Yield of 2,9-Dihydro-
Yield of 7 1-Hydroxy-4,9-tetra-
and 8 (%) hydroeudistomin 8
9 (%)
eudistomin 7
40 (7a)
15 (8a)
1
60
11a
9a
7a
7b
7c
8a
8b
48 (7b)
2
57
not isolated
11b
9b
8c
38 (7c)
3
52
not isolated
11c
9c
25 (7d)
12 (8d)
4
45
38
55
11d
9d
7d
7e
8d
8e
20 (7e)
5
not isolated
11e
9e
8f
38 (7f)
6
not isolated
11f
9f
7f
7g
7
50
45 (8g)
not isolated
11g
9g
8g
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Beilstein J. Org. Chem. 2014, 10, 471–480.
Table 2: Synthesis of dihydro-β-carbolinesa. (continued)
8h
46 (7h)
8
52
not isolated
11h
9h
7h
35 (7i)
20 (8i)
9
60
11i
9i
7i
8i
7j
10
42
42 (8j)
not isolated
11j
9j
8j
aAll products were characterized by 1H NMR, 13C NMR, Mass and IR.
Experimental
General procedure for the synthesis of
α-ketoamides (9a–9j)
7.15 (dd, J = 1.2, 6.8 Hz, 1H), 7.12 (dd, J = 2.0, 8.8 Hz, 1H),
7.10 (s, 1H), 3.75 (q, J = 6.8 Hz, 2H), 3.09 (t, J = 6.8 Hz, 2H);
13C NMR (100 MHz, DMSO-d6) δc 190.4, 164.8, 136.1, 134.3,
132.8, 129.6 (2C), 128.7 (2C), 127.1, 122.8, 120.8, 118.2
(2C), 111.2 (2C), 40.7, 24.7; MS m/z (%): 293 (M + 1), 315 (M
+ 23).
A mixture of 2,2-dibromo-1-phenylethanone (11a, 6.0 g,
21.6 mmol) and sodium iodide (6.48 g, 43.2 mmol) in dimethyl
sulfoxide (30.0 mL) at 25–45 °C was stirred for 40–50 minutes.
Triethylamine (6.55 g, 64.8 mmol) and tryptamine (10, 3.45 g,
21.6 mmol) were then added to the mixture under a N2 atmos-
phere and it was stirred for 1–2 h at 25–45 °C. Then cumene
hydroperoxide (88% n-hexane solution, 3.73 g, 21.6 mmol) was
added to the mixture over a period of five minutes (exothermic
reaction), and it was further stirred for another 3–6 h at the
same temperature. After completion of the reaction (TLC), ice
water was added to the mixture and extracted with DCM
(2 × 50 mL). The DCM layer was washed with aq sodium bisul-
fite solution (50 mL) followed by brine (50 mL) and H2O
(2 × 60 mL). The organic layer was dried (anhyd. Na2SO4) and
evaporated to dryness under reduced pressure. The obtained
crude product was subjected to CC purification and afforded the
desired product in moderate to good yields.
N-(2-(1H-Indol-3-yl)ethyl)-2-oxo-2-(p-tolyl)acetamide (9b):
57% yield; mp 116.8–118.1 °C; IR (cm–1): 3340, 3255, 3093,
2841, 1661, 1644, 1514, 1457, 1310, 1263, 1224, 1169, 1024,
849, 798, 742; 1H NMR (400 MHz, CDCl3) δH 8.24 (d, J = 8
Hz, 2H), 8.06 (s, 1H, NH), 7.64 (d, J = 8 Hz, 1H), 7.39 (d, J = 8
Hz, 1H), 7.21 (t, J = 7.2 Hz, 2H), 7.13 (t, J = 7.2 Hz, 2H), 7.07
(d, J = 2.4 Hz, 1H), 3.73 (d, J = 6.4 Hz, 2H), 3.07 (t, J = 6.8 Hz,
2H), 2.42 (s, 3H): 13C NMR (100 MHz, DMSO-d6) δc 190.1,
165.2, 145.2, 136.2, 132.3, 129.8, 129.4, 127.1, 125.7, 122.8,
120.9 118.3 (2C), 114.2, 111.3 (2C), 55.7, 24.8, 21.4; MS m/z
(%): 307.5 (M + 1), 329.5 (M + 23).
N-(2-(1H-Indol-3-yl)ethyl)-2-oxo-2-(4-(trifluoromethyl)phe-
nyl)acetamide (9c): 52% yield; mp 139.8–140.1 °C; IR (cm−1):
N-(2-(1H-Indol-3-yl)ethyl)-2-oxo-2-phenylacetamide (9a): 3338, 2938, 2842, 1640, 1334, 1224, 1157, 1135, 1075, 935,
60% yield; mp 135–136.7 °C; IR (cm–1): 3408, 3386, 2927, 842, 794, 747; 1H NMR (400 MHz, CDCl3) δH 8.42 (d, J = 8
2862, 1663, 1531, 1288, 1248, 1218, 1093, 1080, 1071, 838, Hz, 2H), 8.06 (s, 1H, NH), 7.73 (d, J = 8 Hz, 2H), 7.64 (d, J = 8
742; 1H NMR (400 MHz, CDCl3) δH 8.32 (d, J = 8 Hz, 2H), Hz, 1H), 7.40 (d, J = 8 Hz, 1H), 7.22 (t, J = 7.2 Hz, 1H), 7.14 (t,
8.05 (s, 1H, NH), 7.63 (dd, J = 8.4, 6.8 Hz, 2H), 7.47 (t, J = 8 J = 7.2 Hz, 2H), 3.75 (d, J = 6.8 Hz, 2H), 3.09 (t, J = 6.8 Hz,
Hz, 2H), 7.38 (d, J = 8 Hz, 1H), 7.22 (dd, J = 6.0, 7.2 Hz, 1H), 2H); 13C NMR (100 MHz, DMSO-d6) δc 189.0, 163.7, 136.1
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Beilstein J. Org. Chem. 2014, 10, 471–480.
(2C), 130.4 (2C), 127.1, 125.6 (2C), 122.8, 120.8 118.2 7.65 (d, J = 8.0 Hz, 1H), 7.42 (d, J = 7.6 Hz, 1H), 7.26 (t, J =
(2C), 111.2 (2C), 39.2, 24.7; MS m/z (%): 383 (M + 1), 405 (M 7.4 Hz, 2H), 7.22 (d, J = 7.2 Hz, 1H), 7.16 (t, J = 7.6 Hz, 1H),
+ 23).
7.08 (t, J =7.2 Hz, 1H), 7.01 (d, J = 7.2 Hz, 2H), 6.34 (d, J = 8.8
Hz, 1H), 5.77 (dd, J = 3.2 & 5.6 Hz, 1H), 5.29 (s, 1H);
N-(2-(1H-Indol-3-yl)ethyl)-2-(4-fluorophenyl)-2-oxoacet- 13C NMR (100 MHz, DMSO-d6) δc 167.1, 136.4, 136.1, 130.8,
amide (9d): 45% yield; mp 138.5–141.2 °C; IR (cm−1): 3338, 128.5 (2C), 127.2, 126.6 (2C), 125.9, 122.0, 119.6, 118.7,
3335, 2923, 2858, 1682, 1651, 1595, 1522, 1352, 1273, 1228, 118.2, 111.6, 109.9, 105.7, 53.2; MS m/z (%): 275.1 (M + 1),
1152, 850, 798, 742; 1H NMR (400 MHz, CDCl3) δH 8.41 (dd, 297.2 (M + 23); HRMS (EI) m/z: [M]+ calcd for C18H15N2O,
J = 5.2, 2 Hz, 2H), 8.09 (s, 1H, NH), 7.63 (d, J = 7.6 Hz, 1H), 275.1184; found, 275.1173.
7.38 (d, J = 8 Hz, 1H), 7.21 (t, J = 7.2 Hz, 1H), 7.14 (t, J = 2
Hz, 1H), 7.13 to 7.11 (m, 1H), 7.10 (t, J = 2 Hz, 1H), 7.06 (d, J (1-Hydroxy-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-
= 1.6 Hz, 1H), 3.73 (d, J = 6.4 Hz, 2H), 3.07 (t, J = 6.8 Hz, 2H); yl)(phenyl)methanone (8a): 15% yield; mp 138.5–141.2 °C;
13C NMR (100 MHz, CDCl3) δc 188.6, 164.3, 163.0, 136.1, 1H NMR (400 MHz, DMSO-d6) δH 10.93 (s, 1H), 8.52 (t, J =
132.9, 132.7, 129.6, 127.1, 122.8, 120.9, 116.1, 115.7, 118.2 5.2 Hz, 1H, NH), 7.44 (d, J = 6.8 Hz, 2H), 7.33 to 7.26 (m, 3H,
(2C), 111.2 (2C), 39.2, 24.7; MS m/z (%): 311.5 (M + 1), 333.4 ArH), 7.11 (t, J = 6.0 Hz, 1H), 7.06 (d, J = 5.6 Hz, 2H), 7.00 (t,
(M + 23).
J = 6.0 Hz, 1H), 6.13 (s, 1H, D2O exchangable proton),
3.10–3.02 (m, 2H), 2.88–2.49 (m, 2H); 13C NMR (100 MHz,
N-(2-(1H-Indol-3-yl)ethyl)-2-(3-nitrophenyl)-2-oxoacet- DMSO–d6) δc 173.9, 143.9, 135.0, 131.0, 128.3 (2C), 127.8,
amide (9e): 38% yield; mp 138.1–139.5 °C; IR (cm−1): 3364, 127.8, 126.0 (2C), 121.3, 118.5, 117.9, 111.5, 108.4, 75.6
3331, 3121, 2860, 1662, 1523, 1346, 1263, 1212, 1098, 815, (alkoxy carbon), 38.3, 25.2. HRMS (EI) m/z: [M]+ calcd for
752, 725; 1H NMR (400 MHz, CDCl3) δH 9.13 (s, 1H), 8.68 (d, C18H17N2O2, 293.1290; found, 293.1333; HRMS of dehy-
J = 7.2 Hz, 1H), 8.46 (d, J = 7.2 Hz, 2H), 8.09 (s, 1H, NH), 7.67 drated 8a (EI) m/z: [M]+ calcd for C18H15N2O, 275.1184;
(dd, J = 8 Hz, 1H), 7.40 (d, J = 8 Hz, 1H), 7.25 to 7.10 (m, 3H, found, 275.1220.
ArH), 3.77 (d, J = 6.6 Hz, 2H), 3.10 (t, J = 7 Hz, 2H);
13C NMR (100 MHz, DMSO-d6) δc 187.3, 162.8, 147.7, (2,9-Dihydro-1H-pyrido[3,4-b]indol-1-yl)(p-tolyl)methanone
136.1, 135.8, 134.1, 130.4, 128.2, 127.2, 124.2, 122.7, 120.8, (7b): 48% yield; mp 213.2–215.7 °C; IR (cm−1): 3222, 3179,
118.2, 111.2, 39.2, 24.7; MS m/z (%): 338.5 (M+), 360.5 (M+, 3043, 2940, 1656, 1625, 1558, 1479, 1335, 1246, 1065, 802,
23).
768, 739; 1H NMR (400 MHz, DMSO-d6) δH 11.36 (br s, 1H,
NH), 9.64 (d, J = 4.8 Hz, 1H), 7.64 (d, J = 7.6 Hz, 1H), 7.41 (d,
J = 8.0 Hz, 1H), 7.15 (t, J = 7.6 Hz, 1H), 7.10 (d, J = 7.6 Hz,
1H), 7.06 (d, J = 7.6 Hz, 2H), 6.89 (d, J = 8.0 Hz, 2H), 6.32 (d,
General procedure for the synthesis of dihy-
droeudistomin (7a–7j)
To a stirred solution of N-(2-(1H-indol-3-yl)ethyl)-2-oxo-2- J = 8.4 Hz, 1H), 5.76 (dd, J = 3.6 & 5.6 Hz, 1H), 5.23 (s, 1H),
phenylacetamide (9a, 2.0 g, 6.8 mmol) in diethyl ether (20 mL) 2.20 (s, 3H); 13C NMR (100 MHz, CDCl3 + DMSO-d6) δc
was added 48% boron trifluoride etherate (10.1 g, 34.2 mmol) 166.3, 135.1, 134.9, 131.5, 129.7, 127.5 (2H), 125.4 (2C),
in a round-bottom flask under a N2 atmosphere, and the mix- 124.6, 120.3, 118.1, 117.1, 116.5, 110.1, 108.5, 104.5, 51.6,
ture was stirred at 25–30 °C for 2 h. After TLC indication for 19.5; MS m/z (%): 289.5 (M + 1), 311.5 (M + 23); HRMS
absence of starting material toluene (20 mL) was added. Then (EI) m/z: [M]+ calcd for C19H17N2O, 289.1341; found,
mixture was heated to 55–70 °C and it was maintained under 289.1329.
stirring at that temperature for 4–8 h (TLC). The mixture was
cooled to 25–30 °C and it was poured into a pre-cooled sat. (2,9-Dihydro-1H-pyrido[3,4-b]indol-1-yl)(4-(trifluoro-
NaHCO3 solution (160 mL) at 10 °C. The product was then methyl)phenyl)methanone (7c): 38% yield. mp 162–164 °C;
extracted with ethyl acetate (2 × 25 mL) and the organic layer IR (cm−1): 3222, 3185, 3042, 2937, 2835, 1657, 1624, 1509,
was washed with 10% NaHCO3 solution (25 mL) and dried 1456, 1249, 1177, 1055, 1032, 848, 810, 770, 742; 1H NMR
(anhyd. Na2SO4). The solvent was distilled off under reduced (400 MHz, CDCl3) δH 8.10 (s, 1H), 7.69 (d, J = 7.6 Hz, 1H),
pressure and the crude residue was subjected to column chro- 7.58 (d, J = 8.0 Hz, 2H), 7.38 (t, J = 8.0 Hz, 2H), 7.29–7.21 (m,
matography purification. The product was obtained in good to 4H), 6.48 (d, J = 8.8 Hz, 1H), 5.94 (dd, J = 3.6 & 5.6 Hz, 1H),
moderate yields.
5.19 (s, 1H); 13C NMR (100 MHz, DMSO-d6) δc 166.0, 140.5,
136.3, 129.9, 127.9, 127.6, 127.4 (2C), 125.6 (doublet), 125.3
(2,9-Dihydro-1H-pyrido[3,4-b]indol-1-yl)(phenyl)methanone (2C), 121.9, 119.5, 118.7, 118.1, 111.6, 109.9, 105.7, 52.7; MS
(7a): 40% yield; mp 228.5–230.6 °C; 1H NMR (400 MHz, m/z (%): 343 (M + 1); HRMS (EI) m/z: [M]+ calcd for
DMSO-d6) δH 11.37 (br s, 1H, NH), 9.68 (d, J = 5.2 Hz, 1H), C19H14N2OF3, 343.1058; found, 343.1038.
478

Beilstein J. Org. Chem. 2014, 10, 471–480.
4. Rocca, P.; Marsais, F.; Godard, A.; Quéguiner, G.; Adams, L.; Alo, B.
Synth. Commun. 1995, 25, 3373–3379.
(2,9-dihydro-1H-pyrido[3,4-b]indol-1-yl)(4-fluoro-
phenyl)methanone (7d): 25% yield; mp 230.6–232.2 °C; IR
(cm−1): 3351, 3279, 3083, 2895, 2839, 1659, 1605, 1508, 1459,
1304, 1234, 1161, 1072, 956, 837, 747; 1H NMR (400 MHz,
CDCl3) δH 8.12 (s, 1H), 7.68 (d, J = 7.6 Hz, 1H), 7.37 (d, J =
7.6 Hz, 1H), 7.27–7.19 (m, 4H, ArH), 7.00 (t, J = 8.8 Hz, 2H),
6.51 (d, J = 8.4 Hz, 1H), 5.94 (dd, J = 3.6 & 4.8 Hz, 1H), 5.08
(s, 1H); 13C NMR (100 MHz, DMSO-d6) δc 166.7, 162.4,
136.3, 132.1, 132.1, 130.6 (doublet), 128.6 (2C), 128.6, 125.7,
121.9, 119.5, 118.7, 118.1, 115.3, 115.1, 111.6, 109.8, 105.6,
52.3; MS m/z (%): 293 (M + 1); HRMS (EI) m/z: [M]+ calcd for
C18H14N2OF, 293.1090; found, 293.1073.
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1506, 1471, 1335, 1239, 1225, 1156, 1014, 976, 840, 816, 738;
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(t, J = 6.8 Hz, 1H), 7.47 (t, J = 9.4 Hz, 3H), 7.22–7.08 (m, H,
ArH), 6.96 (t, J = 8.8 Hz, 2H), 5.92 (s, 1H), 3.24–3.19 (m, 2H),
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293.1090; found, 293.1070.
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Supporting Information
doi:10.1039/B613861F
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Supporting Information File 1
2009, 50, 7067–7069. doi:10.1016/j.tetlet.2009.09.180
Experimental and analytical data.
18.Jin, H.; Zhang, P.; Bijian, K.; Ren, S.; Wan, S.; Alaoui-Jamali, M. A.;
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-10-45-S1.pdf]
Jiang, T. Mar. Drugs 2013, 11, 1427–1439. doi:10.3390/md11051427
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48, 540–548. doi:10.1002/jhet.590
20.Wagh, M. B.; Shankar, R.; Kumar, U. K. S. Synlett 2011, 84–88.
doi:10.1055/s-0030-1259098
Acknowledgements
The authors would like to thank Dr. Vilas H. Dahanukar,
Dr.Reddy’s Laboratories for useful discussions and constant
encouragement. We also thank Gajanan S. Botre from the
analytical department, Dr. Reddy’s Laboratories, for providing
the HRMS data.
21.Shankar, R.; Wagh, M. B.; Madhubabu, M. V.; Vembu, N.;
Kumar, U. K. S. Synlett 2011, 844–848. doi:10.1055/s-0030-1259921
22.Wagh, M. B.; Shankar, R.; Mini, K.; Krishnamohan, T.;
Madhubabu, M. V.; Pal, K. A.; Jayaprakash, S.; Krishna, T.;
Dahanukar, V.; Kumar, U. K. S.; Gill, C. H. J. Heterocycl. Chem. 2013,
50, 49–55. doi:10.1002/jhet.991
23.Raghunadh, A.; Meruva, S. B.; Kumar, N. K.; Kumar, G. S.; Rao, L. V.;
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