Novel Synthesis of Hexahydrochromeno[4,3-b]pyrrolo[2,1-a]isoquinolines via C-H Functionalization

Article abstract of DOI:10.14233/ajchem.2019.21524

In present work, an efficient and direct method for the synthesis of hexahydrochromeno[4,3-b]pyrrolo[2,1-a]isoquinolines is reported. This method involves T3P mediated oxidation of alcohols to aldehydes followed by [3+2] cycloaddition to afford hexahydroc

Full text of DOI:10.14233/ajchem.2019.21524

Asian Journal of Chemistry; Vol. 31, No. 2 (2019), 261-267
A
SIAN
J
OURNAL OF HEMISTRY
C
https://doi.org/10.14233/ajchem.2019.21524
Novel Synthesis of Hexahydrochromeno[4,3-b]pyrrolo[2,1-a]isoquinolines via C-H Functionalization
*
H.E. DINESHA and K. MANTELINGU
Department of Chemistry, University of Mysore, Mysore-560 002, India
*Corresponding author: E-mail: kmlingu@gmail.com
Received: 16 June 2018;
Accepted: 14 August 2018;
Published online: 31 December 2018;
AJC-19191
In present work, an efficient and direct method for the synthesis of hexahydrochromeno[4,3-b]pyrrolo[2,1-a]isoquinolines is reported.
This method involves ®T3P mediated oxidation of alcohols to aldehydes followed by [3+2] cycloaddition to afford hexahydrochromeno[4,3-b]-
pyrrolo[2,1-a]isoquinolines with good yields.
Keywords: C-H Functionalization, ®T3P, [3+2] Cycloaddition, Chromene, Isoquinolines.
[4]. Formation of fused nitrogen-containing bicyclic systems
generally occurs with high regio and stereoselectively by intra-
molecular [3+2] cycloaddition reactions [5].Among the methods
that are available to generate non-stabilized azomethine ylides
most frequently prepared via decarboxylative condensation
of aldehydes with amino acids such as proline and sarcosine
[6]. Majority of examples described in the literature pertain to
the synthesis of chromeno[4,3-b]pyrrole fused skeletons and
only limited reports are available for the synthesis of chromeno
[3,4-b]pyrroles. Synthesis of chromeno[4,3-b]pyrrole via depro-
tonation route was first reported by Confalone and Huie [7].
Intramolecular azomethine ylide cycloaddition reaction for the
synthesis of same type of compounds extensively studied by
Grigg et al. [8]. Synthesis of 1-benzopyrano[3,4-c]pyrrolidines
by reaction of 3-substituted coumarins with N-alkyl-α-amino
acids and aldehydes by Moshkin et al. [9]. Intramolecular [3+2]
azomethine ylide cycloaddition reaction was the key step in
the synthesis of tricyclic core of martinellic acid, which are
bradykinin B1 and B2 receptor antagonists [10].
INTRODUCTION
Hexahydrochromeno[4,3-b]pyrrolo[2,1-a]isoquinolines
derivatives are structural elements of natural products of great
significance for their biological and pharmacological activity,
such as acetylcholinesterase inhibitors [1], topoisomerase I
inhibitors [2], cytotoxic effect, mitochondrial function inhib-
itors, proteinkinase inhibitors, multidrug resistance (MDR)
reversal activity, HIV I interphase inhibitors, antioxidant activity,
anticancerogenic properties [3]. Furthermore, hexahydrochro-
meno[4,3-b]pyrrolo[2,1-a]isoquinolines scaffold form the essence
structure of large marine alkaloid family Lamellarins (Fig. 1).
R
R
R
R
R
R
R
Propylphosphonic anhydride (®T3P) has received much
attention as a coupling agent and as a water scavenger [11,12],
offering several advantages such as high yields, purity, low
toxicity, broad functional group tolerance and easy work-up
when compared to traditional reagents. ®T3P was initially
employed as peptide coupling agent, dehydrating agent. Its
utility was successfully demonstrated in rearrangement reactions,
heterocyclic synthesis and C-C bond formation. In continuation
N
R
O
R
Fig. 1
O
The [3+2] cycloaddition reaction is a robust method for
the synthesis of bicyclic saturated five-membered heterocycles,
and consequently, it has been broadly studied by researchers
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262 Dinesha et al.
Asian J. Chem.
of our work on synthetic applications of ®T3P to the synthesis
of heterocyclic compounds [13]. Though, ®T3P has been
identified as a mild water scavenger, the wider scope and synt-
hetic utility of this reagent for oxidization and cycloaddition
have not been explored. With a need to develop simpler methods
for the synthesis of hexahydrochromeno[4,3-b]pyrrolo[2,1-a]-
isoquinolines annulated heterocycles and in continuation of
our work on the development of the useful synthetic methodo-
logies [6,13-20], herein we report novel, direct approach for
synthesis of hexahydrochromeno[4,3-b]pyrrolo[2,1-a]-
isoquinolines and its analogues. The tandem process involves
oxidation of alcohol to aldehyde and intramolecular 1,3-dipolar
cycloaddition reaction under mild conditions.
(dq, J = 10.7, 7.1 Hz, 1H), 3.65 (dq, J = 10.8, 7.1 Hz, 1H),
3.55 (dd, J = 9.3, 6.0 Hz, 1H), 3.50-3.45 (m, 1H), 3.30-3.25 (m,
1H), 3.04-2.96 (2H), 2.94-2.87 (m, 1H), 0.94 (t, J = 7.1 Hz, 3H).
13C NMR (125 MHz, CDCl3): δ174.2, 155.9, 135.5, 134.0, 130.5,
128.7, 128.5, 128.0, 126.6, 125.4, 123.1, 121.5, 116.9, 66.3,
62.8, 62.6, 60.7, 52.0, 46.3, 40.9, 30.0, 14.0. (ESI-MS) m/z
350.2 [M + H]+. Elemental anal. calcd. (found) % for C22H23NO3:
C, 75.62 (75.65); H, 6.62 (6.66); N, 4.01 (4.07); O, 13.75 (13.77).
(6aR,7R,7aS,14aS)-ethyl-2,4-dibromo-6a,7,7a,12,13,
14a-hexahydro-6H-chromeno[3′,4′:4,5]pyrrolo[2,1-
a]isoquinoline-7-carboxylate (3b): Colourless solid in 72 %
yield. (Rf = 0.49 in hexane/EtOAc 80:20 v/v); m.p.: 145-147
ºC; IR (KBr, νmax, cm-1): 2977, 2933, 2844, 1728, 1554, 1441,
1382, 1235, 1206, 1178, 852, 742, 647. 1H NMR (500 MHz,
CDCl3): δ 7.55-7.53 (2H), 7.12-7.05 (3H), 7.03 (d, J = 7.0 Hz,
1H), 4.46 (dd, J = 11.7, 3.5 Hz, 1H), 4.40-4.37 (2H), 4.27 (dd, J
= 11.7, 2.7 Hz, 1H), 3.78 (dq, J = 10.7, 7.1 Hz, 1H), 3.62 (dq, J
= 10.7, 7.1 Hz, 1H), 3.51 (dd, J = 9.3, 6.4 Hz, 1H), 3.45-3.38
(m, 1H), 3.33-3.29 (m, 1H), 3.03-2.94 (2H), 2.90-2.83 (m, 1H),
0.94 (t, J = 7.1 Hz, 3H). 13C NMR (125 MHz, CDCl3): δ 173.8,
151.6, 135.2, 134.5, 133.2, 132.2, 128.6, 128.1, 126.8, 126.6,
125.4, 113.5, 111.7, 67.1, 62.8, 60.8, 51.7, 46.3, 40.2, 29.0,
13.9; ESI-MS m/z 508.0 [M + H]+. Elemental anal. calcd. (found)
% for C22H21Br2NO3: C, 52.16 (52.15); H, 4.20 (4.20); N, 2.70
(2.73); O, 9.40 (9.41); Br, 31.54 (31.55).
(6aR,7R,7aS,14aS)-ethyl-2-methyl-6a,7,7a,12,13, 14a-
hexahydro-6H-chromeno[3′,4′:4,5]pyrrolo[2,1-a]iso-
quinoline-7-carboxylate (3c): Colourless solid in 66 % yield.
(Rf = 0.39 in hexane/EtOAc 80:20 v/v); m.p.: 118-120 ºC; IR
(KBr, νmax, cm-1): 2981, 2940, 2843, 1728, 1581, 1382, 1321,
1272, 1043, 912, 818, 754, 575. 1H NMR (400 MHz, CDCl3): δ
7.23 (s, 1H), 7.10-7.00 (comp, 4H), 6.95 (dd, J = 8.3, 2.2 Hz,
1H), 6.75 (app d, J = 8.3 Hz, 1H), 4.43 (d, J = 9.4 Hz, 1H),
4.39 (d, J = 7.2 Hz, 1H), 4.28 (dd, J = 11.5, 3.6 Hz, 1H), 4.17
(dd, J = 11.5, 2.6 Hz, 1H), 3.77 (dq, J = 10.8, 7.1 Hz, 1H),
3.63 (dq, J = 10.8, 7.1 Hz, 1H), 3.53 (dd, J = 9.3, 6.3 Hz, 1 H),
3.50-3.42 (m, 1H), 3.27 (tt, J = 6.4, 3.0 Hz, 1H), 3.04-2.94 (2H),
2.93-2.85 (m, 1H), 2.26 (s, 3H), 0.93 (t, J = 7.1 Hz, 3H). 13C
NMR (100 MHz, CDCl3): δ 174.3, 153.7, 135.4, 133.9, 130.7,
130.5, 129.4, 128.5, 128.1, 126.5, 125.3, 122.7, 116.6, 66.3,
62.8, 60.6, 52.0, 46.4, 41.0, 29.1, 20.9, 14.0; ESI-MS m/z 364.2
[M + H]+. Elemental anal. calcd. (found) % for C23H25NO3: C,
76.10 (76.05); H, 6.97 (6.97); N, 3.78 (3.80); O, 13.15 (13.21).
(6aR,7R,7aS,14aS)-ethyl-2-methoxy-6a,7,7a,12,13,
14a-hexahydro-6H-chromeno[3′,4′:4,5]pyrrolo[2,1-a]iso-
quinoline-7-carboxylate (3d): Colourless solid in 69 % yield.
(Rf = 0.41 in hexane/EtOAc 80:20 v/v); m.p.: 116-118 ºC. IR
(KBr, νmax, cm-1): 2982, 2935, 1719, 1498, 1461, 1249, 1259,
EXPERIMENTAL
All the chemicals were purchased from commercial sources
and used as such. Purification of reaction products was carried
out by flash column chromatography. IR spectra were recorded
by Perkin-Elmer 1000 instrument in KBr pellets. 1H and 13C NMR
were recorded in CDCl3 solvent by 400 MHz spectrometer. Mass
spectrawererecordedonaFinniganLCQ-DUOmassspectrometer.
General synthesis of products 3a-3n: To a solution of
alcohol 1 (1.0 mmol) in DMSO (2 mL), was added at 0 ºC
propylphosphonic anhydride (®T3P) (1.0 mmol, 50 % solution
in ethyl acetate) and the resulting reaction mixture was stirred
at room temperature for 1-2 h under nitrogen atmosphere. The
reaction was monitored by TLC, after the completion of reaction,
the solvent was removed under reduced pressure. The crude
product was taken in toluene, amine 2 (1.2 mmol) and acetic
acid (0.5 equiv) was added and stirred further for 1-2 h. After
completion of the reaction, the mixture was diluted with water
(20 mL) and neutralized with 10 % NaHCO3 solution. The
product was extracted with ethyl acetate (10 mL) and the combined
organic phase was washed with water (10 mL) and brine solution.
The organic phase was dried over anhydrous Na2SO4.The solvent
was dried under reduced pressure to afford a crude product,
which was purified on silica gel using ethyl acetate and petroleum
ether (Scheme-I).
Characterization data
(6aR,7R,7aS,14aS)-ethyl-6a,7,7a,12,13,14a-hexahydro-
6H-chromeno[3′,4′:4,5]pyrrolo[2,1-a]isoquinoline-7-
carboxylate (3a): Colourless solid in 89 % yield; (Rf = 0.31 in
hexane/EtOAc 80:20 v/v); m.p.: 149-151 ºC; IR (KBr, νmax
,
cm-1): 2948, 2927, 2897, 1724, 1483, 1448, 1397, 1224, 1118,
956, 757, 654. 1H NMR (500 MHz, CDCl3): δ 7.44 (d, J = 7.6
Hz, 1H), 7.16 (t, J = 7.4 Hz, 1H), 7.12-7.00 (4H), 6.94 (t, J =
7.5, Hz, 1H), 6.86 (d, J = 8.3, Hz, 1H), 4.48-4.41 (2H), 4.32
(dd, J = 11.5, 4.0 Hz, 1H), 4.22 (dd, J = 11.5, 2.8 Hz, 1H), 3.78
H
N
1. ®T3P(1.0 equiv)/DMSO
2. CH3COOH/Toluene
H
OH
+
COOEt
NH
H
Br
O
COOEt
2
Br
O
1
3
Scheme-I

Vol. 31, No. 2 (2019)
Novel Synthesis of Hexahydrochromeno[4,3-b]pyrrolo[2,1-a]isoquinolines via C-H Functionalization 263
1156, 1186, 931, 906, 817. 1H NMR (400 MHz, CDCl3): δ 7.12-
7.00 (4H), 6.97 (d, J = 3.01 Hz, 1H), 6.79 (d, J = 8.9 Hz, 1H),
6.74 (dd, J = 8.9, 3.0 Hz, 1H), 4.43-4.37 (2H), 4.27 (dd, J =
11.5, 3.5 Hz, 1H), 4.16 (dd, J = 11.5, 2.5, Hz, 1H), 3.82-3.73
(4H), 3.64 (dq, J = 10.8, 7.1, Hz, 1H), 3.53 (dd, J = 9.3, 6.3
Hz, 1H), 3.46 (tt, J = 8.3, 4.0 Hz, 1H), 3.29-3.25 (m, 1H), 3.04-
2.95 (2H), 2.93-2.85 (m, 1H), 0.94 (t, J = 7.1 Hz, 3H). 13C
NMR (125 MHz, CDCl3): δ 174.3, 154.2, 150.0, 135.5, 134.0,
128.6, 128.1, 126.6, 125.4, 123.8, 117.7, 115.3, 114.3, 66.5,
63.2, 62.9, 60.7, 56.0, 52.0, 46.5, 41.1, 29.3, 14.0. ESI-MS m/z
380.3 [M + H]+. Elemental anal. calcd. (found) % for C23H25NO4:
C, 72.82 (72.84); H, 6.63 (6.61); N, 3.63 (3.65); O, 16.82 (16.84).
(6aR,7R,7aS,14aS)-ethyl-2-chloro-6a,7,7a,12,13,14a-
hexahydro-6H-chromeno[3′,4′:4,5]pyrrolo[2,1-a]iso-
quinoline-7-carboxylate (3e): Colourless solid in 75 % yield.
(Rf = 0.37 in hexane/ EtOAc 80:20 v/v); m.p.: 150-152 ºC; IR
(KBr, νmax, cm-1): 2968, 2935, 1727, 1481, 1456, 1378, 1252,
1218, 1132, 912, 752. 1H NMR (500 MHz, CDCl3): δ 7.42 (d,
J = 2.6 Hz, 1H), 7.14-7.03 (4H), 7.01 (d, J = 7.4 Hz, 1H), 6.79
(d, J = 8.7 Hz, 1H), 4.42 (d, J = 9.4 Hz, 1H), 4.37 (d, J = 7.2 Hz,
1H), 4.31 (dd, J = 11.6, 3.6 Hz, 1H), 4.19 (dd, J = 11.6, 2.7
Hz, 1H), 3.77 (dq, J = 11.0, 7.2 Hz, 1H), 3.63 (dq, J = 10.9, 7.1
Hz, 1H), 3.49 (dd, J = 9.4, 6.3 Hz, 1H), 3.47-3.40 (m, 1H),
3.27 (tt, J = 6.6, 3.1 Hz, 1H), 3.04-2.96 (m, 2H), 2.91-2.83
(m, 1H), 0.93 (t, J = 7.1 Hz, 3H). 13C NMR (125 MHz, CDCl3):
δ 174.0, 154.4, 135.3, 133.6, 129.9, 128.7, 128.6, 128.0, 126.7,
126.3, 125.4, 124.8, 118.4, 66.3, 62.8, 62.6, 60.7, 51.9, 46.3,
40.5, 29.0, 13.9; ESI-MS m/z 384.3 [M + H]+. Elemental anal.
calcd. (found) % for C22H22NO3Cl: C, 68.70 (68.78); H, 5.63
(5.82); N, 3.60 (3.61); O, 12.52 (12.56); Cl, 9.25 (9.29).
(6aR,7R,7aS,14aS)-ethyl-2-bromo-6a,7,7a,12,13, 14a-
hexahydro-6H-chromeno[3′,4′:4,5]pyrrolo[2,1-a]iso-
quinoline-7-carboxylate (3f): Colourless solid in 76 % yield.
(Rf = 0.35 in hexanes/EtOAc 80:20 v/v); m.p.: 168-170 ºC; IR
(KBr, νmax, cm-1): 2975, 2920, 2845, 1719, 1486, 1469, 1412,
1338, 1311, 1232, 1164, 1112, 1032, 892, 761. 1H NMR (500
MHz, CDCl3): δ 7.83 (d, J = 2.3 Hz, 1H), 7.19 (dd, J = 8.7, 2.5
Hz, 1H), 7.09-7.04 (m, 1H), 7.02-6.95 (2H), 6.80-6.71 (2H),
4.41 (d, J = 9.5 Hz, 1H), 4.01 (dd, J = 11.7, 3.2 Hz, 1H), 3.93
(d, J = 7.2 Hz, 1H), 3.76-3.66 (2H), 3.61 (dq, J = 10.7, 7.2 Hz,
1H), 3.50 (dd, J = 9.5, 6.7 Hz, 1H), 3.47-3.40 (m, 1H), 3.08
(ddt, J = 9.9, 6.6, 2.9 Hz, 1H), 2.89 (ddd, J = 15.4, 10.6, 5.5
Hz, 1H), 2.72-2.62 (2H), 0.78 (t, J = 7.1 Hz, 3H). 13C NMR
(125 MHz, CDCl3): δ 174.0, 154.9, 135.3, 133.5, 132.9, 131.6,
128.6, 128.0, 126.7, 125.4, 125.3, 118.8, 113.6, 66.3, 62.8, 62.6,
60.7, 51.9, 46.3, 40.5, 29.0, 13.9. ESI-MS m/z 429.2 [M + H]+.
Elemental anal. calcd. (found) % for C22H22NO3Br: C, 61.70
(61.74); H, 5.18 (5.20); N, 3.22 (3.25); O, 11.21 (11.25); Br,
18.65 (18.69).
6.6, 3.7, 2.6 Hz, 1H), 3.04-2.93 (2H), 2.93-2.85 (m, 1H) 0.92
(t, J = 7.2 Hz, 3H); 13C NMR (125 MHz, CDCl3): δ 174.1, 148.3,
145.4, 135.3, 133.8, 128.6, 128.0, 126.6, 125.4, 122.1, 121.0,
110.2, 66.8, 62.8, 62.5, 60.7, 56.1, 51.8, 46.4, 40.8, 29.0, 14.0;
m/z (ESI- MS) 380.3 [M + H]+. Elemental anal. calcd. (found) %
for C23H25NO4: C, 72.82 (72.76); H, 6.60 (6.68); N, 3.60 (3.72);
O, 16.88 (16.85).
(6aR,7R,7aS,14aS)-ethyl-9,10-dimethoxy-6a,7,7a, 12,
13,14a-hexahydro-6H-chromeno[3′,4′:4,5]-pyrrolo[2,1-a]-
isoquinoline-7-carboxylate (3h): Colourless solid in 66%
yield. (Rf = 0.11 in hexane/EtOAc 80:20 v/v); m.p.: 196-198
ºC; IR (KBr, νmax, cm-1): 2940, 2908, 2841, 1724, 1522, 1464,
1380, 1257, 1244, 1228, 1118, 1017, 872, 761. 1H NMR (500
MHz, CDCl3): δ 7.43 (d, J = 7.7 Hz, 1H), 7.15 (t, J = 7.8 Hz,
1H), 6.93 (t, J = 7.5 Hz, 1H), 6.84 (d, J = 8.0, Hz, 1H), 6.57 (s,
1H), 6.53 (s, 1H), 4.42 (d, J = 7.2 Hz, 1H), 4.38-4.27 (2H),
4.21 (d, J = 11.8 Hz, 1H), 3.89-3.81 (4H), 3.78 (s, 3H), 3.68
(dq, J = 13.1, 7.2 Hz, 1H), 3.51 (dd, J = 9.4, 6.3 Hz, 1H),
3.48-3.41 (m, 1H), 3.33-3.27 (m, 1H), 2.01-2.87 (2H) 2.83-
13
2.76 (m, 1H), 0.97 (t, J = 7.2 Hz, 3H). C NMR (125 MHz,
CDCl3): δ174.3, 155.9, 147.7, 146.9, 130.5, 128.7, 127.5, 125.4,
122.9, 121.6, 116.9, 111.1, 110.9, 66.3, 62.8, 62.7, 60.7, 56.0,
55.9, 51.9, 46.4, 40.9, 28.5, 14.1. ESI-MS m/z 410.2 [M + H]+.
Elemental anal. calcd. (found) % for C24H27NO5: C, 70.40 (70.44);
H, 6.60 (6.63); N, 3.44 (3.46); O, 19.52 (19.56).
(6aR,7R,7aS,14aS)-ethyl-2,4-dibromo-9,10-dimethoxy-
6a,7,7a,12,13,14a-hexahydro-6H-chromeno[3′,4′:4,5]-
pyrrolo[2,1-a]-isoquinoline-7-carboxylate (3i): Colourless
solid in 72 % yield. (Rf = 0.11 in hexane/EtOAc 80:20 v/v);
m.p.: 136-138 ºC. IR (KBr, νmax, cm-1): 2915, 1712, 1518, 1466,
1440, 1239, 1244, 1228, 1133, 1038, 924, 855. 1H NMR (500
MHz, CDCl3): δ 7.56-7.52 (2H), 6.57 (s, 1H), 6.54 (s, 1H), 4.46
(dd, J = 11.5, 3.0 Hz, 1H), 4.37 (d, J = 7.1 Hz, 1H), 4.31 (d, J =
9.4 Hz, 1H), 4.26 (dd, J = 11.8, 2.3, 1H), 3.89-3.81 (4H), 3.79
(s, 3H), 3.67 (dq, J = 10.9, 7.2 Hz, 1H), 3.49 (dd, J = 9.4, 6.7 Hz,
1H), 3.43-3.37 (m, 1H), 3.34 (tt, J = 6.6, 3.0 Hz, 1H), 2.98-2.90
(2H), 2.81-2.72 (m, 1H), 0.97 (t, J = 7.1 Hz, 3H); 13C NMR (125
MHz, CDCl3): δ174.1, 151.7, 147.9, 146.9, 134.5, 132.3, 127.4,
126.7, 124.9, 113.6, 111.7, 111.1, 110.9, 67.2, 63.0, 62.8, 60.9,
56.0, 51.7, 46.5, 40.4, 28.7, 14.4, 14.1. ESI-MS m/z 568.2 [M
+ H]+. Elemental anal. calcd. (found) % for C24H25NO5Br2: C,
50.80 (50.87); H, 4.44 (4.48); N, 2.42 (2.44); O, 14.12 (14.15);
Br, 28.10 (28.13).
(6bS,14bS,15R,15aR)-ethyl-3,5-dibromo-1,6b,8,9,9a,
14,14a,14b,15,15a-decahydrochromeno[3′,4′:2,3]-
indolizino[8,7-b]indole-15-carboxylate (3j):Yellow solid in
58 % yield. (Rf = 0.30 in hexane/EtOAc 80:20 v/v); m.p.: 178-
180 ºC; IR (KBr, νmax, cm-1): 2975, 2920, 1719, 1486, 1442,
1
1311, 1232, 1032, 833, 760. H NMR (500 MHz, CDCl3): δ
(6aR,7R,7aS,14aS)-ethyl-4-methoxy-6a,7,7a,12,13,
14a-hexahydro-6H-chromeno[3′,4′:4,5]pyrrolo[2,1-a]iso-
quinoline-7-carboxylate (3g): Colorless solid in 67% yield
(Rf = 0.21 in hexane/EtOAc 80:20 v/v); m.p.: 128-130 ºC; IR
(KBr, νmax, cm-1): 2974, 2860, 1737, 1684, 1583, 1479, 1442,
1383, 1304, 1249, 1172, 1027, 946, 801, 758, 649; 1H NMR
(500 MHz, CDCl3): δ 7.09-7.03 (4H), 7.02-6.98 (m, 1H), 6.89
(t, J = 7.8 Hz, 1H), 6.77 (d, J = 7.7 Hz, 1H), 4.50-4.40 (3H),
4.25 (dd, J = 11.5, 2.7 Hz, 1H), 3.89 (s, 3H), 3.78 (dq, J = 10.9,
7.2 Hz, 1H), 3.68-3.56 (2H), 3.50-3.42 (m, 1H), 3.28 (tdd, J =
8.21 (s, 1H), 7.60 (d, J = 2.3 Hz, 1H), 7.52 (d, J = 7.9 Hz, 1H),
7.45 (d, J = 2.3 Hz, 1H), 7.29 (d, J = 8.2 Hz, 1H), 7.17 (t, J = 7.5
Hz, 1H), 7.11 (t, J = 7.4 Hz, 1H), 4.81 (d, J = 7.7 Hz, 1H), 4.52
(dd, J = 11.7, 2.7 Hz, 1H), 4.31 (d, J = 8.9 Hz, 1H), 4.16 (q, J
= 7.1 Hz, 2H), 4.03 (dd, J = 11.6, 3.1 Hz, 1H), 3.62 (t, J = 8.6
Hz, 1H), 3.51-3.40 (m, 1H), 3.16-3.06 (2H) 3.02-2.97 (m, 1H),
2.80-2.71 (m, 1H), 1.20 (t, J = 7.1 Hz, 3H). 13C NMR (125
MHz, CDCl3): δ 173.0, 152.4, 136.3, 134.4, 131.6, 130.8, 129.1,
126.9, 122.4, 119.7, 118.5, 114.0, 112.6, 111.1, 111.0, 68.8, 61.8,
59.4, 56.7, 48.6, 45.2, 39.7, 17.6, 14.3; ESI-MS m/z 547.0 [M

264 Dinesha et al.
Asian J. Chem.
+ H]+. Elemental anal. calcd. (found) % for C24H24N2O3Br2: C,
52.50 (52.54); H, 4.44 (4.48); N, 5.10 (5.16); O, 8.66 (8.70);
Br, 29.10 (29.13).
(6aR,7R,7aS,13aS)-ethyl-2,4-dibromo-6,6a,7,7a,12,
13a-hexahydrochromeno[3',4':4,5]pyrrolo[2,1-a]isoindole-
7-carboxylate (3k): White solid in 68 % yield. (Rf = 0.47 in
128.6, 128.3, 127.4, 127.2, 127.0, 126.2, 125.7, 122.3, 120.2, 116.8,
79.2, 70.1, 62.7, 61.1, 58.6, 42.6, 40.1, 30.3, 14.0. ESI-MS m/z
426.2 [M + H]+. Elemental anal. calcd. (found) % for C28H27NO3:
C,79.02(79.06);H, 6.46 (6.44); N, 3.32 (3.34); O, 11.30 (11.31).
(6aR,7R,7aR,14aS)-ethyl 2,4dibromo-9,10-dimethoxy-
7a-phenyl-6a,7,7a,12,13,14a-hexahydro-6H-chromeno-
[3',4':4,5]pyrrolo[2,1-a]isoquinoline-7-carboxylate (3m):
White solid in 64 % yield. (Rf = 0.30 in hexane/EtOAc 80:20
v/v); m.p.: 222-224 ºC; IR (KBr, νmax, cm-1): 2975, 2920, 1719,
1486, 1442, 1311, 1252, 1164, 1032, 833, 760. 1H NMR (500
MHz, CDCl3): δ 7.88 (d, J = 7.5 Hz, 2H), 7.53-7.50 (m, 1H),
7.43-7.40 (m, 1H), 7.32 (t, J = 7.8 Hz, 2H), 7.20 (t, J = 7.4 Hz,
1H), 6.58 (s, 1H), 6.53 (s, 1H), 4.75 (dd, J = 10.1, 4.0 Hz, 1H),
4.12 (t, J = 10.4 Hz, 1H), 3.89 (dq, J= 11.0, 7.2 Hz, 1H), 3.82-3.78
(5H), 3.74 (dq, J = 11.1, 7.2 Hz, 1H), 3.68 (s, 3H), 3.41-3.31
(m, 1H), 3.30-3.25 (m, 1H), 3.23-3.14 (m, 1H), 3.02-2.95 (m, 1H),
2.75-2.68 (m, 1H), 1.02 (t, J = 7.1 Hz, 3H). 13C NMR (125
MHz, CDCl3): δ 173.1; 150.7, 149.6, 147.5, 146.8, 134.2, 129.4,
129.0, 128.8, 127.5, 127.2(3), 127.1(7), 125.4, 112.3, 112.2,
111.8, 110.8, 79.2, 71.0, 62.3, 61.4, 57.8, 56.0, 55.9, 41.9,
40.2, 29.7, 14.1; ESI-MS m/z 643.9 [M + H]+. Elemental anal.
calcd. (found) % for C30H29NO5Br2: C, 56.00 (56.06); H, 4.56
(4.59); N, 2.12 (2.15); O, 12.30 (12.38); Br, 24. 75 (24.79).
(6bS,14bS,15R,15aR)-ethyl-3,5-dibromo-14b-(4-
hexane/EtOAc 80:20 v/v); m.p.: 140-142 ºC. IR (KBr, νmax
,
cm-1): 2982, 2947, 2871, 1720, 1474, 1459, 1449, 1378, 1289,
1182, 1164, 1134, 1017, 941, 855, 747, 683, 630, 550, 442.
1H NMR (300 MHz, CDCl3): δ 7.63-7.53 (2H), 7.29-7.16 (3H),
7.13 (d, J = 7.3 Hz, 1H), 5.01 (d, J = 8.6 Hz, 1H), 4.64 (d, J =
13.6 Hz, 1H), 4.42-4.28 (3H), 4.23 (dd, J = 11.5, 6.5 Hz, 1H)
3.88 (dq, J = 10.6, 7.2 Hz, 1H), 3.76 (dq, J = 10.6, 7.2 Hz, 1H),
3.35 (dd, J = 8.7, 6.1 Hz, 1H), 3.19-3.07 (m, 1H), 1.06 (t, J =
7.2 Hz, 3H). 13C (NMR (75 MHz, CDCl3): δ 171.7, 150.1, 140.4,
138.1, 134.3, 132.0, 128.2, 127.0, 123.4, 122.4, 113.4, 111.7,
71.3, 66.1, 62.9, 61.0, 60.8, 50.3, 40.2, 13.9. ESI-MS m/z 494.1
[M + H]+. Elemental anal. calcd. (found) % for C21H19NO3Br2:
C, 51.10 (51.12); H, 3.90 (3.93); N, 2.80 (2.81); O, 9.72 (9.75);
Br, 32.38 (32.37).
(6aR,7R,7aR,14aR)-ethyl 7a-phenyl-6a,7,7a,12,13,14a-
hexahydro-6H-chromeno[3',4':4,5]pyrrolo[2,1-a]isoquino-
line-7-carboxylate (3l): Colourless solid in 70 % yield. (Rf =
0.62 in hexane/EtOAc 80:20 v/v); m.p.: 173-175 ºC. IR (KBr,
ν
max, cm-1): 2982, 2967, 2938, 1728, 1485, 1455, 1317, 1210,
chlorophenyl)-1,6b,8,9,14,14b,15,15a-octahydrochro-
meno[3′,4′:2,3]indolizino[8,7-b]indole-15-carboxylate (3n):
Colourless solid in 65 % yield; (Rf = 0.35 in hexane/EtOAc
80:20 v/v); m.p.: 168-170 ºC. IR (KBr, νmax, cm-1): 3060, 2975,
2845, 1719, 1469, 1486, 1338, 1240, 1220, 1164, 1073, 1061,
911, 862, 686. 1H NMR (500 MHz, CDCl3): δ 7.91 (d, J = 8.7
Hz, 2H), 7.61 (s, 1H), 7.59-7.56 (m, 1H), 7.54-7.51 (m, 1H),
7.47 (d, J = 7.6 Hz, 1H), 7.33 (d, J = 8.5 Hz, 2H), 7.17 (d, J =
1031, 746, 703, 573. 1H NMR (500 MHz, CDCl3): δ 7.96 (d,
J = 7.7 Hz, 2H), 7.38 (d, J = 7.5 Hz, 1H), 7.31 (t, J = 7.8 Hz, 2H),
7.19 (t, J = 7.3 Hz, 1H), 7.16-7.09 (2H), 7.06 (d, J = 7.3 Hz,
1H), 7.04-6.91 (3H), 6.83 (dd, J = 8.2, 1.1 Hz, 1H), 4.62 (dd,
J = 9.9, 3.9 Hz, 1H), 4.08 (dd, J = 11.4, 9.9 Hz, 1H), 3.89-3.73
(4H), 3.46-3.32 (2H), 3.31-3.21 (m, 1H), 3.07-2.98 (m, 1H),
2.81 (dt, J = 15.6, 2.5 Hz, 1H), 1.03 (t, J = 7.2 Hz, 3H). 13C NMR
(125 MHz, CDCl3): δ 173.4, 154.7, 150.1, 138.2, 135.2, 128.9,
R1
1. ®T3P(1.0 equiv)/DMSO
2. CH3COOH/Toluene
N
H
H
OH
R2
COOEt
R1
+
NH
R2
H
O
COOEt
O
1
2
3
Scheme-II
TABLE-2
SUBSTRATE SCOPE FOR [3 + 2] CYCLOADDITION REACTIONS
Entry
1
Substrate (1)
Substrate (2)
Product (3)
Yield (%)
89
OH
H
N
H
NH
O
COOEt
COOEt
3a
2a
H
1a
O
3a
Br
OH
H
COOEt
N
H
NH
2
72
Br
O
COOEt
2a
H
Br
1b
O
Br
3b

Vol. 31, No. 2 (2019)
Novel Synthesis of Hexahydrochromeno[4,3-b]pyrrolo[2,1-a]isoquinolines via C-H Functionalization 265
Me
OH
H
N
H
NH
NH
NH
3
66
69
75
Me
COOEt
O
COOEt
COOEt
COOEt
2a
2a
2a
H
1c
O
3c
MeO
OH
H
N
H
4
5
MeO
COOEt
O
H
1d
O
3d
Cl
OH
H
N
H
Cl
COOEt
O
H
1e
O
3e
Br
OH
H
N
H
NH
6
7
76
67
Br
COOEt
O
1f
COOEt
H
2a
O
3f
OH
H
N
H
NH
O
COOEt
COOEt
OMe
2a
H
1g
O
3g
OMe
OMe
OMe
MeO
MeO
OH
8
NH
66
H
N
O
COOEt
H
COOEt
1a
2b
H
O
3h
OMe
OMe
Br
MeO
MeO
OH
H
N
9
NH
72
H
O
COOEt
Br
COOEt
Br
2b
H
1b
O
Br
3i
Br
NH
OH
NH
H
10
58
N
O
COOEt
N
H
H
Br
COOEt
Br
1b
2c
H
O
3j
Br

266 Dinesha et al.
Asian J. Chem.
Br
OH
H
N
NH
H
11
68
Br
COOEt
O
COOEt
2d
H
Br
1b
O
Br
H
3k
OH
Ph
COOEt
H
N
NH
12
70
O
COOEt
Ph
1a
2e
O
3l
OMe
OMe
Br
MeO
MeO
OH
Ph
COOEt
N
NH
13
64
H
O
COOEt
Br
Br
Ph
2f
1b
H
O
Br
3m
Br
NH
NH
OH
p-Cl-Ph
COOEt
H
N
14
65
O
COOEt
p-Cl-Ph
H
N
Br
H
Br
1b
2g
O
3n
Br
TABLE-1
8.2 Hz, 1H), 7.10 (t, J= 7.4 Hz, 1H), 7.05 (t, J = 7.4 Hz, 1H), 4.74
(dd, J = 10.0, 3.9 Hz, 1H), 4.08 (t, J = 10.6 Hz, 1H), 3.99-3.88
(3H), 3.59 (d, J = 10.0 Hz, 1H), 3.53 (td, J = 10.8, 3.3 Hz, 1H),
3.50-3.44 (m, 1H), 3.04-2.82 (3H), 0.95 (t, J = 7.2 Hz, 3H). 13C
NMR (125 MHz, CDCCl3): δ 172.1, 150.7, 146.2, 136.8, 134.5,
133.6, 132.3, 129.4, 129.1, 127.9, 126.1, 124.9, 122.6, 119.8,
118.9, 112.6, 112.0, 111.3, 110.9, 75.7, 70.8, 62.1, 61.9, 58.2,
41.9, 40.4, 21.4, 14.1. ESI-MS m/z 657.0 [M + H]+. Elemental
anal. calcd. (found) % for C30H26N2O3Br2: C, 56.60 (56.58); H,
4.18 (4.18); N, 4.66 (4.63); O, 8.70 (8.68); Br, 25.86 (25.84).
OPTIMIZATION OF REACTION CONDITIONS
CH3COOH
(mol %)
Time
(h)
Temp.
(°C)
Yield
(%)
No.
Solvent
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
–
10
20
30
40
50
100
150
50
50
50
50
50
50
50
50
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
THF
24
24
24
12
6
6
6
6
6
Reflux
RT
RT
RT
RT
RT
RT
RT
40
Trace
33
37
56
62
82
79
78
67
66
66
35
25
55
10
48
RESULTS AND DISCUSSION
6
6
50
60
Initially, the reaction of aldehyde (crude) was carried out
with tetrahydroisoquinoline (THIQ) in the absence of acetic
acid and toluene as a solvent, desired product 3 was obtained
in trace amount (Table-1, entry 1). Later we carried out the
reaction of aldehyde (crude) with THIQ in the presence of 10
mol % acetic acid product 3 was obtained in 33 % yield (Table
-1, entry 2). Upon increasing the amount of acetic acid 20, 30,
40 and 50 mol %, the yield of the products 3 were increased
(Table-1, entries 3 to 6). Further increase in the amount of acetic
acid to 1.0 and 1.5 equiv, no significant improvement in the
yield was observed (Table-1, entries 7 and 8). The effect of the
temperature was also tested, when the temperature was increased
24
24
24
24
24
RT
RT
RT
RT
RT
EtOAc
DMF
Ethanol
CH3CN
to 40, 50 and 60 ºC, no significant improvement in the yield
was observed (Table-1, entries 9, 10 and 11).
Later on, we screened a number of solvents viz., THF, EtOAc,
DMF, ethanol and CH3CN found that toluene was the preferred
solvent. The other molecular sieves like 4Å and 5Å were also
screened but no significant difference was observed finally, it

Vol. 31, No. 2 (2019)
Novel Synthesis of Hexahydrochromeno[4,3-b]pyrrolo[2,1-a]isoquinolines via C-H Functionalization 267
3. D. Pla, F. Albericio and M. Alvarez, Anticancer. Agents Med. Chem.,
is found that reactions with aldehyde (crude, 1.0 mmol) and
tetrahydroisoquinoline (1.0 mmol) in the presence of acetic
acid at room temperature for 6 h was ideal (Table-1, entry 6).
Under the above optimized reaction conditions, the efficiency
and versatility of this newly developed methodology, reactions
of tetrahydroisoquinolines (THIQs) with a range of alcohol
derived from differently substituted salicylalcohol were eval-
uated (Scheme-II and Table-2).
In all cases, products were obtained in good yields at room
temperature (products 3a-3n). Importantly, other benzylic amines
including 6,7-dimethoxy-THIQ, tryptoline, isoindoline, also
underwent the title reaction under equally mild conditions.
Interestingly, even sterically demanding 1-aryl THIQ′s and a
1-aryl-tryptoline readily participated in the reaction sequence
to generate polycyclic amines containing tetra substituted
carbon centers.
8, 746 (2008);
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In conclusion, a novel and direct method is developed for
the synthesis of hexahydrochromeno[4,3-b]pyrrolo[2,1-a]-
isoquinolines in good yields, starting directly from a variety
of alcohols and various tetrahydroisoquinolines. The protocol
involves ®T3P mediated oxidation of alcohols to aldehydes
followed by [3+2] cycloaddition to afford hexahydrochromeno-
[4,3-b]pyrrolo[2,1-a]isoquinolines.
https://doi.org/10.1016/j.tetlet.2006.12.098.
13. A.B. Ramesha, G.M. Raghavendra, K.N. Nandeesh, K.S. Rangappa
and K. Mantelingu, Tetrahedron Lett., 54, 95 (2013);
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ACKNOWLEDGEMENTS
The authors thank to Spectral Facility, IOE, University of
Mysore, Mysuru, India for spectral analyses.
CONFLICT OF INTEREST
The authors declare that there is no conflict of interests
regarding the publication of this article.
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