Synthesis of oxazino[4,3-a]indoles by domino addition-cyclization reactions of (1H-indol-2-yl)methanols and vinyl selenones in the presence of 18-crown-6

Article abstract of DOI:10.1016/j.tet.2016.09.045

Herein we report the synthesis of biologically relevant oxazino[4,3-a]indoles by an environmentally friendly Michael addition-cyclization cascade using potassium hydroxide in dichloromethane employing variously substituted vinyl selenones and (1H-indol-2y

Full text of DOI:10.1016/j.tet.2016.09.045

Accepted Manuscript
Synthesis of oxazino[4,3-a]indoles by domino addition-cyclization reactions of (1H-
indol-2-yl)methanols and vinyl selenones in the presence of 18-crown-6
Martina Palomba, Elisa Vinti, Francesca Marini, Claudio Santi, Luana Bagnoli
PII:
S0040-4020(16)30961-9
10.1016/j.tet.2016.09.045
TET 28116
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 20 June 2016
Revised Date: 6 September 2016
Accepted Date: 20 September 2016
Please cite this article as: Palomba M, Vinti E, Marini F, Santi C, Bagnoli L, Synthesis of
oxazino[4,3-a]indoles by domino addition-cyclization reactions of (1H-indol-2-yl)methanols and vinyl
selenones in the presence of 18-crown-6, Tetrahedron (2016), doi: 10.1016/j.tet.2016.09.045.
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Synthesis of oxazino[4,3-a]indoles by domino addition-
cyclization reactions of (1H-indol-2-yl)methanols
and vinyl selenones in the presence of 18-crown-6
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Martina Palomba, Elisa Vinti, Francesca Marini, Claudio Santi, Luana Bagnoli*
Department of Pharmaceutical Sciences, Group of Catalysis and Organic Green Chemistry, University of Perugia, Via del Liceo
1, 06123 Perugia, Italy

1
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Tetrahedron
journal homepage: www.elsevier.com
Synthesis of oxazino[4,3-a]indoles by domino addition-cyclization reactions of (1H-
Indol-2-yl)methanols and vinyl selenones in the presence of 18-crown-6
Martina Palomba, Elisa Vinti, Francesca Marini, Claudio Santi, Luana Bagnoli
*Department of Pharmaceutical Sciences, , Group of Catalysis and Organic Green Chemistry, Università di Perugia, Via del Liceo 1, 06123 Perugia, Italy
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Herein we report the synthesis of biologically relevant oxazino[4,3-a]indoles by an
environmentally friendly Michael addition-cyclization cascade using potassium hydroxide in
dichloromethane employing variously substituted vinyl selenones and (1H-indol-2yl)methanols.
The addition of 18-crown-6, as a complexing agent, is crucial to achieve high chemo- and regio-
selectivity.
Available online
Keywords:
Vinyl selenones
Domino reactions
(1H-indol-2-yl)methanols
Oxazino[4,3-a]indoles
2009 Elsevier Ltd. All rights reserved
.
1. Introduction
oxazino[4,3-a]indoles by the domino addition-cyclization
reactions of (1H-indol-2-yl)methanols and vinyl sulfonium
salts.4c
Heterocycle-fused indoles play an important role as
biologically active compounds and pharmaceuticals.1 For
example, etodolac and pemedolac are anti-infiammatory and
analgesic agents and other pyrano[3,4-b]indoles have been
reported as potent inhibitors of hepatitis C virus (HCV) NS5B
polymerase.2 Also, oxazino[4,3-a]indoles have attracted
attention for their potential antidepressant and antitumor
properties (Figure 1).3
In recent years we have studied several domino processes
using vinyl selenones as substrates for Michael addition-
initiated ring closure reactions with carbon as well as
heteroatom-centred nucleophiles.5 Complex molecules can be
easily obtained through a domino approach that allows the
sequential formation of a number of bonds without the need
for isolation of intermediates. This increases the overall
sustainability of the protocol, minimizing the production of
waste and reducing the formation of side products. Using
vinyl selenones in domino procedures, biologically relevant
heterocycles, like enantiopure 1,4-dioxanes, morpholines and
piperazines,5b and six-membered benzo-1,4-heterocyclic
compounds5a have been successfully prepared. In continuation
of these studies we now report a novel application of vinyl
selenones in
a Michael-addition-initiated -ring closure
Figure 1 Biologically active oxazine[4,3-a]indoles
reaction (MIRC) using (1H-indol-2-yl)methanols as bis-
nucleophiles evidencing the effect of 18-crown-6 in the
control of the selectivity.
Very recently, a few examples of the preparation of
oxazino[4,3-a]indoles appeared in literature.4 Bandini4a and
Gharpure4b have reported the synthesis of densely
functionalized oxazino[4,3-a]indoles respectively through a
gold catalyzed cascade sequence and through an
intramolecular oxa-Pictet-Spengler reaction of an indole
moiety with an N-tethered vinylogous carbonate. Also, Chen,
2. Results and discussion
The (1H-indol-2yl)methanols were easily prepared by
reduction of the corresponding ester derivates according to
the procedure described in the literature.4c In the first
———
Xiao et al. have synthesized unsubstitued or mono-substituted
Corresponding author. Tel.: +39-075-585-5105; fax: +39-075-585-5116; e-mail: luana.bagnoli@unipg.it (L. Bagnoli)

2
Tetrahedron
experiments the (1H-indol-2yl)methanol 1Aa,CaCs EMPicThaEelD MANUSCRIPT
donor, and vinyl selenone 2a, as the Michael acceptor, were
used (Table 1). The phenylselenonyl group plays a dual role
in the domino reaction: it activates the olefin during the β-
addition and, subsequently, represents a good leaving group
making the cyclization possible. Firstly, we evaluated the
effect of different bases and solvents (entries 1-12, Table 1).
The choice of the base resulted to be crucial for the success of
the synthesis. The reaction did not occurred in the absence of
a base or using an excess of organic bases (entries 1-3).
Scarce yields of the cyclic products were obtained using
cesium carbonate or sodium hydride (entries 4-5). On the
contrary using potassium hydroxide in dichloromethane an
80% combined yield can be achieved and 3,4-dihydro-1H-
oxazino[4,3-a]indoles 3a4c and the tetrahydropyrano[3,4-
b]indoles 4a6 are formed in a ~ 2:1 ratio (entry 6). A reaction
carried out using a lower amount of base led to a lower yield
(entry 7). Moreover a survey of the solvents revealed that the
substitution of the dichloromethane with polar or apolar
solvents gave poorer results (entries 8-12). However the
addition of the complexing agent 18-crown-6 was crucial to
achieve successful selective processes (entries 13-18). In fact,
independently from the solvents, the exclusive formation of
3,4-dihydro-1H-oxazino[4,3-a]indole 3a was observed. As
shown in entry 14, Table 1, the best result was obtained using
an excess of potassium hydroxide, 18-crown-6 and starting
alcohol 1a in dicloromethane. (81% yield of 3a). With the
optimized conditions we evaluated the versatility of the
methodology using variously commercially substituted (1H-
indol-2yl)methanols bearing electron donating group and
electron withdrawing groups 1b-h. The results summarized in
Table 2 confirm that in the presence of 18-crown-6, in all
cases, 3a-h were formed as single products in good to
excellent yields and the C-3 alkylated products 4a-f were not
formed (entries 1-8, Table 2). The pyrano derivatives 4a-b
obtained in the absence of 18-crown-6 are also characterized.
(entries 1a-2a, Table 2).
Table 1. Domino Michael addition/cyclization: optimization
of the reaction conditions.
Entry
Eq.
1a
1
1
1
1
1
1
1
Base
2.5 eq.
-
DBU
Et3N
Solvent
18
Crown-6
Time
(h)
48
48
48
48
24
24
24
Yield
(%) 3a
-
-
Yield
(%) 4a
-
-
-
trace
trace
30
30
1
2
3
4
5
6
7
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
-
-
-
-
-
-
-
-
Cs2CO3
NaH
15
30
50
25
KOH
KOH
(1 eq.)
KOH
KOH
KOH
KOH
KOH
KOH
KOH
KOH
KOH
KOH
KOH
8
9
1
1
1
1
1
1
2
2
2
2
2
toluene
THF
-
-
-
-
-
24
24
24
24
24
12
12
12
12
12
12
19
15
21
45
-
71
81
66
58
55
57
28
7
-
-
-
-
-
-
-
10
11
12
13
14
15
16
17
CH3CNa
DMFa
EtOH
CH2Cl2
CH2Cl2
CH2Cl2
toluene
DMF
2.5 eq.
2.5 eq.
1 eq.
2.5 eq.
2.5 eq.
2.5 eq.
-
-
18
THF
a
Using DMF and CH3CN as solvents, 10% and 9% yields of N-addition-
elimination products were also formed respectively.
Table 2. Selective formation of oxazino[4,3-a]indoles 3a-h with 18-crown-6 from vinyl selenone 2a. Tetrahydropyrano[3,4-b]indoles
4a-b were isolated only in the absence of 18-crown-6.
Entry
1a-h
Additive
Time
3a-h
4a-b
reaction
(Yields)
(Yields)
1
1a
2
1a: R = H, R1 = H, R2 = H
18-crown-6
-
12 h
24 h
12 h
24 h
12 h
12 h
12 h
3a: 81%
3a: 50%
3b: 72%
3b: 35%
3c: 78%
3d: 91%
3e: 74%
4a: 30%
4b: 34%
1b: R = Br, R1 = H,= R2 = H
18-crown-6
-
2a
3
1c: R = Me, R1 = H, R2= H
1d: R = OMe, R1 = H, R2 = H
1e: R = Cl, R1 = H, R2 = H
18-crown-6
18-crown-6
18-crown-6
4
5

3
ACCEPTED MANUSCRIPT
6
7
8
1f: R = F, R1 = H, R2 = H
18-crown-6
18-crown-6
18-crown-6
12 h
12 h
12 h
3f: 98%
3g: 86%
3h: 61%
1g: R = H, R1 = NO2 R2 = H
1h: R = OMe, R1 = OMe R2 = H
In order to extend the applicability of the process and better
clarify the mechanism we carried out the reaction using
substituted selenones. As highlighted in Scheme 1 using (5-
bromo-1H-indol-2yl)methanol 1b and selenone 2b in the
absence of 18-crown-6 the reaction was poorly selective and
oxazino[4,3-a]indoles 3i and 3i´ and the pyrano[3,4-b]indole
4i were formed. Several typical trends in NMR and IR
spectroscopy have been considered for the structural
determination.7 The position of the alkyl substituent (C6H13)
was assigned by 13C NMR on the basis of the CHO chemical
shift at ~75ppm in 3i and 4i, and the chemical shift of the
CHN signal at 52.1 ppm in the case of 3i´. Once again we
observed that the presence of 18-crown-6 is crucial for
achieving high selectivities leading to the formation of
exclusively the oxazine derivative 3i8 (Table 3, entry 1).
Various indol-2-yl methanols 1a-f and beta and alpha
selenones 2b-e were employed in order to expand the scope
of application and in all cases we observed high selectivity.
As highlighted in Table 3 only oxazino[4,3-a]indoles 3i-r
were formed in satisfactory to good yields (entries 1-10).
Scheme 1. Results obtained using vinyl selenone 2b in the absence of 18-crown-6.
Table 3. Selective formation of the oxazino[4,3-a]indoles 3i-r
two nucleophilic sites for the initial Michael addition: the
with 18-crown-6.
indolic N-H and the hydroxyl group. The formation of
compounds such as 3i´, with the alkyl chain in the α position
of the nitrogen atom, is initiated by an aza-Michael addition.
The subsequent proton transfer forms the oxygen anion that
promotes the intramolecular displacement of the
phenylselenonyl group (route 1, Scheme 2). On the contrary
the compounds 3i and 4i, with the alkyl chain in α position of
the oxygen atom, are obtained when the oxa-Michael addition
takes place (route 2, scheme 2). The subsequent proton
transfer generates a bidentate anion which reacts by N-
cyclization or C3-cyclization affording the 3-hexyl-3,4-
dihydro-1H-[1,4]oxazino[4,3-a]indole, 3i or the 3-hexyl-
Entry
1a-f
2b-e
3i–r
(Yields)
1
2
3
4
5
6
7
1b: R = Br
1a: R = H
1d: R = OMe
1a: R = H
2b: R3 =C6H13, R4 = H
2b: R3 = C6H13,R4 = H
2b: R3 = C6H13,R4 = H
2c: R3 = C4H9,R4 = H
2c: R3 = C4H9, R4 = H
2c: R3 = C4H9, R4 = H
2da: R3 =CH3, R4= H
3i: 77%
3j: 60%
3k: 63%
3l: 61%
3m: 66%
3n: 71%
3o: 60%
1,3,4,9-tetrahydropyrano[3,4-b]indole, 4i, respectively.
A
similar competition in the presence of a bidentate nucleophile
has been observed by Aggarwal in the formation of
morpholines via Michael addition initiated cyclizations of
vinyl sulfonium salts.9 In this work a high level of oxa-
Michael selectivity was obtained trough a careful choice of
base and solvent, despite the pKa values of the nitrogen or
oxygen nucleophiles involved (TsNH, pKa 17, DMSO vs OH,
pKa 30, DMSO). In our case the presence of 18-crown-6 is
crucial for achieving the exclusive formation of the 3-
substituted oxazines 3i-r, derived by oxa-Michael attack
followed by N-cyclization. (Table 3, Scheme 2). The crown
ether, by suppressing the tight ion pairing,10 not only
accelerates the reaction of the more nucleophilic “naked”
oxygen during the formation of the Michael adduct, but also
promotes the subsequent N-cyclization, preventing the C3-
attack. Crown ethers have already been employed to promote
nucleophilic substitution exclusively at the nitrogen atom of
indoles in the presence of base in aprotic solvents.11
1f: R = F
1d: R = OMe
1a: R = H
8
9
1e: R = Cl
1c: R = CH3
1a: R = H
2da: R3 =CH3, R4 = H
2da: R3 = CH3, R4 = H
2e: R3 = H, R4 = CH3
3p: 50%
3q: 45%
3r: 40 %
10
a Selenone 2d is a mixture of E/Z (1:1) isomers.
Based on the results obtained with substituted selenones 2b-
e (Scheme 1, Table 3) we can propose a plausible mechanism.
In Scheme 2 we exemplify the process by using 1b and
β−substituted selenone 2b. The (1H-indol-2-yl)methanol has
Scheme 2. Proposed mechanism

4
Tetrahedron
ACCEPTED MANUSCRIPT
3. Conclusion
to warm to r.t.. The progress of the reactions were monitored by
TLC. After 12 h the solvent was evaporated under vacuum. The
products were purified using column chromatography on silica
gel (EtOAc/ PE 5:95 as eluant) afford the oxazine derivates 3a-r.
The physical and spectral data of the 3,4-dihydro-1H-
[1,4]oxazino[4,3-a]indoles 3a-f are identical to those reported in
the literature.4c The physical and spectral data of 3,4-dihydro-1H-
[1,4]oxazino[4,3-a]indoles 3g-r are reported below.
In summary we have carried out a new approach to synthesize
biologically relevant oxazino[4,3-a]indoles through a Michael
addition/cyclization reaction cascade of vinyl selenones with
(1H-indole-2-yl)methanols as bis-nucleophiles. An extensive
study for fine-tuning of reaction conditions has been performed,
identifying the crucial role of 18-crown-6 for achieving high
selectivity. Starting material availability, functional group
tolerance and mild reaction conditions are relevant aspects of this
simple procedure. Further applications of this strategy for the
synthesis of other important indole derivatives are currently
underway in our laboratory.
4.3.1. 3,4-Dihydro-1H-[1,4]oxazino[4,3-a]indole (3a).4c: (16.8
1
mg, 81%), H NMR (400 MHz, CDCl3, 25 °C, TMS): δ = 7.60
(d, 1H, J = 7.6 Hz, CH) 7.32 (d, 1H, J = 8.0 Hz CH), 7.21 (t, 1H,
J = 7.0 Hz, CH), 7.15 (t, 1H, J = 7.8 Hz, CH), 5.02 (s, 2H,
CH2O), 4.22-4.19 (m, 2H, CH2O), 4.14-4.11 (m, 2H, CH2N).
4.1. General
1H and 13C-NMR spectra were recorded in CDCl3 at 400 and
100.62 MHz, respectively, on a Bruker Avance-DRX 400
instrument. Chemical shifts (δ) are reported in parts per million
relative to residual solvent signals (CHCl3, 7.26 ppm for 1H
NMR, CDCl3 77.0 ppm for 13C NMR). Coupling constants are
given in Hertz (Hz). The following abbreviations are used to
indicate the multiplicity: s, singlet; d, doublet; t, triplet; m,
multiplet; br, broad signal. FT-IR spectra were recorded with a
4.3.2. 8-Bromo-3,4-dihydro-1H-[1,4]oxazino[4,3-a]indole (3b).4c
1
(21.8 mg, 72%),. H NMR (200 MHz, CDCl3, 25 °C, TMS): δ =
7.70 (d, 1H, J = 1.8 Hz, CH) 7.27 (dd, 1H, J = 1.8, 8.6 Hz CH),
7.15 (d, 1H, J = 8.6 Hz, CH), 6.17 (s, 1H, CH), 4.97 (s, 2H,
CH2O), 4.21-4.15 (m, 2H, CH2O), 4.08-4.02 (m, 2H, CH2N).
Jasco model 410 spectrometer equipped with
a diffuse
4.3.3. 8-Methyl-3,4-dihydro-1H-[1,4]oxazino[4,3-a]indole (3c).4c
(17.5 mg, 78%), H NMR (200 MHz, CDCl3, 25 °C, TMS): δ =
7.38 (s, 1H, CH) 7.24 (d, 1H, J = 8.8 Hz, CH), 7.03 (d, 1H, J =
8.4 Hz, CH), 6.16 (s, 1H, CH), 4.99 (s, 2H, CH2O), 4.20-4.14 (m,
2H, CH2O), 4.08-4.01 (m, 2H, CH2N), 2.47 (s, 3H, CH3).
reflectance accessory. High resolution mass spectra (HRMS)
were recorded on an Agilent 6540-UHD Accurate Mass Q-TOF
LC/MS instrument. The melting points are uncorrected. Thin
layer chromatography (TLC) was performed on silica gel 60 F254
(Merck) on aluminum sheets. Reaction products were purified by
column chromatography performed on Merck silica gel 60 (70-
230 mesh).
1
4.3.4.
8-Methoxy-3,4-dihydro-1H-[1,4]oxazino[4,3-a]indole
4.2. Starting material
(3d).4c (22.1 mg, 91%), 1H NMR (200 MHz, CDCl3, 25 °C,
TMS): δ = 7.18 (d, 1H, J = .8.8 Hz, CH), 7.06 (d, 1H, J = 2.4 Hz,
CH), 6.84 (dd, 1H, J = 2.4, 8.8. Hz, CH), 6.15 (s, 1H, CH), 4.97
(s, 2H, CH2O), 4.20-4.12 (m, 2H, CH2O), 4.08-4.01 (m, 2H,
CH2N), 3.83 (s, 3H, OCH3).
Starting vinyl selenones 2a-e were prepared from the
corresponding vinyl selenides by oxidation with an excess of m-
chloroperbenzoic acid.5c-d,12 The (1H-indol-2-yl)methanols 1a-h
were prepared according to literature procedures.4c,13,14
4.3. General procedure for the synthesis of 3,4-dihydro-1H-
[1,4]oxazino[4,3-a]indole 3a-r.
4.3.5. 8-Chloro-3,4-dihydro-1H-[1,4]oxazino[4,3-a]indole (3e).4c
(18.2 mg, 74%), H NMR (200 MHz, CDCl3, 25 °C, TMS): δ =
7.53 (d, 1H, J = .1.8 Hz, CH), 7.26-7.11 (m, 2H, 2CH), 6.16 (s,
1H, CH), 4.97 (s, 2H, CH2O), 4.20-4.14 (m, 2H, CH2O), 4.08-
4.02 (m, 2H, CH2N).
1
A stirred solution of (1H-indol-2-yl)methanol compounds 1a-h
(0.24 mmol) in dichloromethane (3 mL) was treated with
potassium hydroxide (16.8 mg, 0.30 mmol and 18-crown-6
(79.30 mg, 0.30 mmol) at 0 °C under argon. After 10 min a
solution of vinyl selenones 2a-e (0.12 mmol) in dichloromethane
(3 mL) was added at 0°C and the reaction mixtures were allowed

5
4.3.6. 8-Fluoro-3,4-dihydro-1H-[1,4]oxazino[4,3-a]indole (3f).4c
(22.5 mg, 98%), H NMR (200 MHz, CDCl3, 25 °C, TMS): δ =
7.27-7.15 (m, 2H, 2CH), 6.93 (dt, 1H, J = 2.5, 8.9 Hz), 6.19 (s,
1H, CH), 4.98 (s, 2H, CH2O), 4.20-4.13 (m, 2H, CH2O), 4.09-
4.02 (m, 2H, CH2N).
4.3.11. 3-Hexyl-8-methoxy-3,4-dihydro-1H-[1,4]oxazino[4,3-a]
ACCEPTED MANUSCRIPT
1
indole (3k). (21.7 mg, 63%), orange solid, mp 52-56 °C; Rf
(EtOAc/PE 20:80) 0.76. 1H NMR (400 MHz, CDCl3, 25 °C,
TMS): δ = 7.19 (d, 1H, J = 8.8 Hz), 7.07 (d, 1H, J = 2.3 Hz, CH),
6.86 (dd, 1H, J = 2.3, 8.8 Hz, CH), 6.17 (s, 1H, CH), 5.10 (d, 1H,
J = 14.8 Hz, CH2O), 4.92 (d, 1H, J = 14.8 Hz, CH2O), 4.09 (dd,
1H, J = 3.3, 11.3 Hz, CH2N), 3.94-3.87 (m, 1H, CHO), 3.88 (s,
3H, CH3O), 3.67 (t, 1H, J = 11.0 Hz, CH2N), 1.80-1.32 (m, 10H,
5CH2), 0.92 (t, 3H, J = 6.8 Hz, CH3). 13C NMR (100.62 MHz,
CDCl3, 25 °C): δ = 154.4 (Cipso), 133.6 (Cipso), 131.3 (Cipso),
128.6 (Cipso), 110.7 (CH, Ar), 109.1 (CH, Ar), 102.2 (CH, Ar),
95.0 (CH, Ar), 74.4 (CHO), 64.7 (CH2O), 55.8 (CH3O), 46.6
(CH2), 33.6 (CH2), 31.7 (CH2), 29.2 (CH2), 25.3 (CH2), 22.6
(CH2), 14.1 (CH3). HRMS (ESI): m/z calcd for C18H26NO2
(M+H)+ 288.1964 found 288.1964. FT-IR (KBr) νmax 3260, 2923,
4.3.7. 6-Nitro-3,4-dihydro-1H-[1,4]oxazino[4,3-a]indole (3g).
(24.1 mg, 86%), yellow solid. mp 91-94 °C; Rf (EtOAc/PE 20:80)
0.48. 1H NMR (400 MHz, CDCl3, 25 °C, TMS): δ = 7.83 (d, 1H,
J = 7.8 Hz, CH,) 7.80 (d, 1H, J = 8.4 Hz CH), 7.17 (t, 1H, J = 7.9
Hz, CH), 6.42 (s, 1H, CH), 5.05 (s, 2H, CH2O), 4.24-4.20 (m,
2H, CH2O), 4.14-4.09 (m, 2H, CH2N). 13C NMR (100.62 MHz,
CDCl3, 25 °C): δ = 136.4 (Cipso), 136.2 (Cipso), 132.5 (Cipso),
127.5 (Cipso), 126.4 (CH, Ar), 119.2 (CH, Ar), 119.1 (CH, Ar),
98.1 (CH, Ar), 64.9 (CH2O), 64.7 (CH2O), 45.4 (CH2N). HRMS
(ESI): m/z calcd for C11H11N2O3 (M+H)+ 219.0770, found
219.0767. FT-IR (KBr) νmax 3093, 2922, 2851, 1514, 1344, 1294,
1108, 806, 728 cm-1.
2853, 1481, 1457, 1232, 1184, 1034, 800, 739 cm-1
.
4.3.12. 3-Butyl-3,4-dihydro-1H-[1,4]oxazino[4,3-a]indole (3l).
(16.8 mg, 61%), yellow solid, mp 75-79 °C; Rf (EtOAc/PE 20:80)
0.83. 1H NMR (400 MHz, CDCl3, 25 °C, TMS): δ = 7.60 (d, 1H,
J = 7.8 Hz, CH), 7.31 (d, 1H, J = 8.0 Hz, CH), 7.20 (t, 1H, J =
7.0 Hz, CH), 7.13 (t, 1H, J = 7.1 Hz, CH), 6.24 (s, 1H, CH), 5.13
(d, 1H, J = 14.8 Hz, CH2O), 4.95 (d, 1H, J = 14.8 Hz, CH2O),
4.15 (dd, 1H, J = 3.1, 11.3 Hz, CH2N), 3.96-3.87 (m, 1H, CHO),
3.70 (t, 1H, J = 11.1 Hz, CH2N), 1.80-1.40 (m, 6H, 3CH2), 0.99
(t, 3H, J = 7.0 Hz, CH3). 13C NMR (100.62 MHz, CDCl3, 25 °C):
δ = 135.9 (Cipso), 132.9 (Cipso), 128.2 (Cipso), 120.8 (CH, Ar),
120.2 (CH, Ar), 119.9 (CH, Ar), 108.5 (CH, Ar), 95.3 (CH, Ar),
74.4 (CHO), 64.7 (CH2O), 46.5 (CH2N), 33.3 (CH2), 27.5 (CH2),
22.7 (CH2), 13.9 (CH3). HRMS (ESI): m/z calcd for C15H20NO
(M+H)+ 230.1545, found 230.1542. FT-IR (KBr) νmax 3045,
2956, 2858, 1549, 1471, 1458, 1370, 1339, 1223, 1092, 1003,
780, 741 cm-1.
4.3.8. 7,8-Dimethoxy-3,4-dihydro-1H-[1,4]oxazino[4,3-a]indole
(3h). (17.1 mg, 61%), yellow solid. mp 137-140 °C; Rf
(EtOAc/PE 20:80) 0.15. 1H NMR (400 MHz, CDCl3, 25 °C,
TMS): δ = 7.06 (s, 1H, CH), 6.08 (s, 1H, CH), 6.13 (s, 1H, CH),
4.97 (s, 2H, CH2O), 4.20-4.15 (m, 2H, CH2O), 4.06-4.02 (m, 2H,
CH2N), 3.97 (s, 3H, OCH3), 3.94 (s, 3H, OCH3). 13C NMR
(100.62 MHz, CDCl3, 25 °C): δ = 146.3 (Cipso), 145.2 (Cipso),
131.4 (Cipso), 130.5 (Cipso), 120.5 (Cipso), 102.2 (CH, Ar),
95.5 (CH, Ar), 92.3 (CH, Ar), 65.1 (CH2O), 64.6 (CH2O), 56.3
(CH3O), 56.2 (CH3O), 41.9 (CH2N). HRMS (ESI): m/z calcd for
C13H16NO3 (M+H)+ 234.1130, found 234.1125. FT-IR (KBr) νmax
2929, 1653, 1489, 1340, 1206, 1164, 1090, 912, 851, 761 cm-1
4.3.9
8-Bromo-3-hexyl-3,4-dihydro-1H-[1,4]oxazino[4,3-a]
4.3.13.
3-Butyl-8-fluoro-3,4-dihydro-1H-[1,4]oxazino[4,3-a]
indole (3i). (31.1 mg, 77%), yellow solid, mp 68-73 °C; Rf
(EtOAc/PE 20:80) 0.87. H NMR (400 MHz, CDCl3, 25 °C,
1
indole (3m). (19.6 mg, 66%), yellow solid, mp 75-79 °C; Rf
(EtOAc/PE 20:80) 0.79. 1H NMR (400 MHz, CDCl3, 25 °C,
TMS): δ = 7.23 (dd, 1H, J = 2.3 Hz, J = 9.8 Hz, CH), 7.20 (dd,
1H, J = 4.4 Hz, J = 8.8 Hz, CH), 6.94 (dt, 1H, J = 2.3 Hz, J = 9.1
Hz, CH), 6.19 (s, 1H, CH), 5.11 (d, 1H, J = 14.9 Hz, CH2O), 4.92
(d, 1H, J = 14.9 Hz, CH2O), 4.10 (dd, 1H, J = 3.2, 11.3 Hz,
CH2N), 3.95-3.86 (m, 1H, CHO), 3.69 (t, 1H, J = 11.0 Hz,
CH2N), 1.80-1.40 (m, 6H, 3CH2), 0.99 (t, 3H, J = 7.0 Hz, CH3).
13C NMR (100.62 MHz, CDCl3, 25°C): δ = 158.1 (Cipso, d, J =
232 Hz,), 134.7 (Cipso), 132.6 (Cipso), 128.4 (CH, Ar, d, J= 10.0
Hz), 109.0 (CH, Ar, d, J = 26.0 Hz), 108.9 (CH, Ar, d, J = 10.0
Hz), 105.1 (CH, Ar, d, J = 23.5 Hz), 95.4 (CH, Ar, d, J = 4.5 Hz),
74.3 (CH2O), 64.6 (CH2O), 46.6 (CH2N), 33.2 (CH2), 27.5 (CH2),
22.6 (CH2), 13.9 (CH3). HRMS (ESI): m/z calcd for C15H19FNO
(M+H)+ 248.1451, found 248.1448. FT-IR (KBr) νmax 3059,
2954, 2849, 1577, 1480, 1180, 1157, 1092, 872, 770 cm-1.
TMS): δ = 7.72 (d, 1H, J = 1.8 Hz, CH), 7.27 (dd, 1H, J = 1.8,
8.6 Hz, CH), 7.16 (d, 1H, J = 8.6 Hz, CH), 6.17 (s, 1H, CH), 5.11
(d, 1H, J = 15.0 Hz, CH2O), 4.92 (d, 1H, J = 15.0 Hz, CH2O),
4.09 (dd, 1H, J = 3.3, 11.3 Hz, CH2N), 3.94-3.87 (m, 1H, CHO),
3.68 (t, 1H, J = 11.0 Hz, CH2N), 1.80-1.29 (m, 10H, 5CH2), 0.93
(t, 3H, J = 6.8 Hz, CH3). 13C NMR (100.62 MHz, CDCl3, 25 °C):
δ = 134.6 (Cipso), 134.2 (Cipso), 129.8 (Cipso), 123.6 (CH, Ar),
122.7 (CH, Ar), 113.1 (Cipso), 109.8 (CH, Ar), 94.9 (CH, Ar),
74.3 (CHO), 64.5 (CH2O), 46.5 (CH2N), 33.5 (CH2), 31.7 (CH2),
29.2 (CH2), 25.3 (CH2), 22.6 (CH2), 14.0 (CH3). HRMS (ESI):
m/z calcd for C17H2379BrNO (M+H)+ 336.0963, found 336.0963.
FT-IR (KBr) νmax 3100, 2928, 2854, 1459, 1365, 1335, 1097,
1052, 866, 789 cm-1.
4.3.10. 3-Hexyl-3,4-dihydro-1H-[1,4]oxazino[4,3-a]indole (3j).
(18.5 mg, 60%), yellow solid, mp 48-52 °C; Rf (EtOAc/PE 20:80)
0.82. 1H NMR (400 MHz, CDCl3, 25 °C, TMS): δ = 7.61 (d, 1H,
J = 7.7 Hz, CH), 7.31 (d, 1H, J = 8.1 Hz, CH), 7.23-7.13 (m, 2H,
CH), 6.25 (s, 1H, CH), 5.14 (d, 1H, J = 14.8 Hz, CH2O), 4.95 (d,
1H, J = 14.8 Hz, CH2O), 4.14 (dd, 1H, J = 3.2, 11.3 Hz, CH2N),
3.96-3.87 (m, 1H, CHO), 3.71 (t, 1H, J = 11.0 Hz, CH2N), 1.83-
1.38 (m, 10H, 5CH2), 0.94 (t, 3H, J = 6.8 Hz, CH3). 13C NMR
(100.62 MHz, CDCl3, 25 °C): δ = 135.9 (Cipso), 133.0 (Cipso),
128.2 (Cipso), 120.8 (CH, Ar), 120.2 (CH, Ar), 119.9 (CH, Ar),
108.4 (CH, Ar), 95.3 (CH, Ar), 74.4 (CHO), 64.7 (CH2O), 46.6
(CH2N), 33.6 (CH2), 31.7 (CH2), 29.2 (CH2), 25.3 (CH2), 22.6
(CH2), 14.1 (CH3). HRMS (ESI): m/z calcd for C17H24NO
(M+H)+ 258.1858, found 258.1855. FT-IR (KBr) νmax 3046,
2926, 2857, 1542, 1457, 1368, 1337, 1095, 1066, 783, 741 cm-1.
4.3.14. 3-Butyl-8-methoxy-3,4-dihydro-1H-[1,4]oxazino[4,3-a]
indole (3n). (22.1 mg, 71%), white solid, mp 86-89 °C; Rf
(EtOAc/PE 20:80) 0.73. 1H NMR (400 MHz, CDCl3, 25 °C,
TMS): δ = 7.18 (d, 1H, J = 8.8 Hz, CH), 7.05 (d, 1H, J = 2.3 Hz
CH), 6.84 (dd, 1H, J = 2.3, 8.8 Hz, CH), 6.15 (s, 1H, CH), 5.08
(d, 1H, J = 14.8 Hz, CH2O), 4.59 (d, 1H, J = 14.8 Hz, CH2O),
4.08 (dd, 1H, J = 3.2, 11.3 Hz, CH2N), 3.90-3.82 (m, 1H, CHO),
3.86 (s, 3H, CH3O), 3.66 (t, 1H, J = 11.0 Hz, CH2N), 1.84-1.35
(m, 6H, 3CH2), 0.97 (t, 3H, J = 7.1 Hz, CH3). 13C NMR (100.62
MHz, CDCl3, 25 °C): δ = 154.4 (Cipso), 133.6 (Cipso), 131.2
(Cipso), 128.5 (Cipso), 110.7 (CH, Ar), 109.2 (CH, Ar), 102.2
(CH, Ar), 94.9 (CH, Ar), 74.4 (CHO), 64.6 (CH2O), 55.8
(OCH3), 46.5 (CH2N), 33.2 (CH2), 27.4 (CH2), 22.6 (CH2), 13.9
(CH3). HRMS (ESI): m/z calcd for C16H22NO2 (M+H)+ 260.1651,

6
Tetrahedron
found 260.1646. FT-IR (KBr) νmax 3103, 2998, 2957, 2864,
2856, 1547, 1483, 1367, 1329, 1250, 1084, 1086, 978, 852, 701
ACCEPTED MANUSCRIPT
1619, 1579, 1480, 1203, 1092, 843, 781 cm-1.
cm-1.
The
formation
of
8-bromo-4-hexyl-3,4-dihydro-1H-
3i´ and the 1,3,4,9-
[1,4]oxazino[4,3-a]indole
4.3.15. 3-Methyl-3,4-dihydro-1H-[1,4]oxazino[4,3-a]indole (3o).
(13.5 mg, 60%), yellow solid, mp 113-119 °C; Rf (EtOAc/PE
20:80) 0.64. H NMR (400 MHz, CDCl3, 25 °C, TMS): δ = 7.59
tetrahydropyrano[3,4-b]indoles 4a-b, and 4i were observed when
the reactions were carried out in the absence of 18-crown-6 and
employing 1 equivalent of the compounds 1a-b. The products
were purified using column chromatography on silica gel
(EtOAc/PE from 5:95 to 20:80).The physical and spectral data of
1,3,4,9-tetrahydropyrano[3,4-b]indole 4a are identical to that
reported in the literature.6 The physical and spectral data of 3,4-
dihydro-1H-[1,4]oxazino[4,3-a]indole 3i´ and the 1,3,4,9-
tetrahydropyrano[3,4-b]indole 4b and 4i are reported below.
1
(d, 1H, J = 7.7 Hz, CH), 7.30 (d, 1H, J = 8.0 Hz, CH), 7.20 (t,
1H, J = 7.6 Hz, CH), 7.14 (t, 1H, J = 7.1 Hz, CH), 6.24 (s, 1H,
CH), 5.12 (d, 1H, J = 14.8 Hz, CH2O), 4.97 (d, 1H, J = 14.8 Hz,
CH2O), 4.13 (dd, 1H, J = 3.1, 11.2 Hz, CH2N), 4.11-4.03 (m, 1H,
CHO), 3.68 (t, 1H, J = 10.8 Hz, CH2N), 1.47 (d, 3H, J = 6.4 Hz,
CH3). 13C NMR (100.62 MHz, CDCl3, 25°C): δ = 135.9 (Cipso),
132.6 (Cipso), 128.2 (Cipso), 120.8 (CH, Ar), 120.2 (CH, Ar),
120.0 (CH, Ar), 108.5 (CH, Ar), 95.4 (CH, Ar), 70.4 (CHO),
65.0 (CH2O), 47.6 (CH2N), 19.1 (CH3). HRMS (ESI): m/z calcd
for C12H14NO2 (M+H)+ 188.1075, found 188.1071. FT-IR (KBr)
νmax 3058, 2973, 2895, 1545, 1471, 1339, 1255, 1091, 1050, 784,
740 cm-1.
4.3.19.
8-Bromo-4-hexyl-3,4-dihydro-1H-[1,4]oxazino[4,3-a]
indole (3i´). (11.3 mg, 28%), brown oil; Rf (EtOAc/PE 20:80)
0.79. 1H NMR (400 MHz, CDCl3, 25 °C, TMS): δ = 7.70 (d, 1H,
J = 1.5 Hz, CH), 7.26 (dd, 1H, J = 1.5, 8.5 Hz, CH), 7.15 (d, 1H,
J = 8.5 Hz, CH), 6.14 (s, 1H, CH), 5.09 (d, 1H, J = 15.0 Hz,
CH2O), 4.91 (d, 1H, J = 15.0 Hz, CH2O), 4.18 (t, 1H, J = 11.0
Hz, CH2O), 4.18-4.07 (m, 1H, CHN), 3.95 (dd, 1H, J = 2.9, 11.8
Hz, CH2O), 2.05-1.27 (m, 10H, 5CH2), 0.89 (t, 3H, J = 6.8 Hz,
CH3). 13C NMR (100 MHz, CDCl3, 25 °C): δ = 133.8 (2Cipso),
129.9 (Cipso), 123.4 (CH, Ar), 122.8 (CH, Ar), 112.9 (Cipso),
110.4 (CH, Ar), 94.8 (CH, Ar), 66.8 (CH2O), 64.7 (CH2O), 52.1
(CHN), 31.7 (CH2), 31.6 (CH2), 29.1 (CH2), 26.0 (CH2), 22.5
(CH2), 14.0 (CH3). HRMS (ESI): m/z calcd for C17H2381BrNO
(M+H)+ 338.0943, found 338.0932. FT-IR (KBr): νmax 2928,
2855, 1456, 1359, 1337, 1263, 1099, 1051, 790 cm-1.
4.3.16. 8-Chloro-3-methyl-3,4-dihydro-1H-[1,4]oxazino[4,3-a]
indole (3p).(13.3 mg, 50%), white solid, mp 125-130 °C; Rf
(EtOAc/PE 20:80) 0.53. 1H NMR (400 MHz, CDCl3, 25 °C,
TMS): δ = 7.55 (d, 1H, J = 1.4 Hz, CH), 7.19 (d, 1H, J = 8.6 Hz,
CH), 7.14 (dd, 1H, J = 1.4, 8.6 Hz, CH), 6.18 (s, 1H, CH), 5.11
(d, 1H, J = 15.0 Hz, CH2O), 4.95 (d, 1H, J = 15.0 Hz, CH2O),
4.12-4.04 (m, 1H, CHO), 4.10 (dd, 1H, J = 3.3, 11.6 Hz, CH2N),
3.68 (t, 1H, J = 11.1 Hz, CH2N), 1.47 (d, 3H, J = 6.0 Hz, CH3).
13C NMR (100.62 MHz, CDCl3, 25 °C) δ = 134.3 (Cipso), 134.0
(Cipso), 129.2 (Cipso), 125.6 (Cipso), 121.0 (CH, Ar), 119.6
(CH, Ar), 109.3 (CH, Ar), 95.1 (CH, Ar), 70.3 (CHO), 64.4
(CH2O), 47.8 (CH2N), 18.9 (CH3). HRMS (ESI): m/z calcd for
C12H1335ClNO (M+H)+ 222.0686, found 222.0684. FT-IR (KBr)
νmax 3113, 2979, 2868, 1563, 1452, 1422, 1308, 1254, 1140,
1092, 1068, 879, 784 cm-1.
4.3.20. 1,3,4,9-Tetrahydropyrano[3,4-b]indole (4a).6 (6.2 mg,
30%), H NMR (400 MHz, CDCl3, 25 °C, TMS): δ =7.82 (brs,
1H), 7.52 (d, 1H, J = 7.6 Hz, Ar), 7.34 (d, 1H, J = 7.6 Hz, Ar),
7.22-7.08 (m, 2H, Ar), 4.84 (t, 2H, J = 1.5 Hz, CH2O), 4.05 (t,
2H, J = 5.4 Hz, CH2O), 2.87 (tt, 2H, J = 1,5, 5.4 Hz, CH2).
1
4.3.21. 6-Bromo-1,3,4,9-tetrahydropyrano[3,4-b]indole (4b).
(10.3 mg, 34%), brown solid, mp 139-142 °C; Rf (20%
EtOAc/PE) 0.25. 1H NMR (400 MHz, CDCl3, 25 °C, TMS): δ =
7.87 (brs, 1H, NH), 7.63 (d, 1H, J = 1.7 Hz, CH), 7.26 (dd, 1H, J
= 1.7, 8.5 Hz, CH), 7.20 (d, 1H, J = 8.5 Hz, CH), 4.83 (s, 2H,
CH2O), 4.04 (t, 2H, J = 5.5 Hz, CH2O), 2.81 (t, 2H, J = 5.5 Hz,
CH2). 13C NMR (100.62 MHz, CDCl3, 25 °C): δ = 134.5 (Cipso),
132.8 (Cipso), 128.9 (Cipso), 124.4 (CH, Ar), 120.7 (CH, Ar),
112.8 (Cipso), 112.2 (CH, Ar), 107.3 (Cipso), 65.6 (CH2O), 63.5
(CH2O), 21.9 (CH2). HRMS (ESI): m/z calcd for C11H1179BrNO
(M+H)+ 252.0024, found 252.0024. FT-IR (KBr) νmax 3304,
2964, 1716, 1453, 1023, 794 cm-1.
4.3.17. 3,8-Dimethyl-3,4-dihydro-1H-[1,4]oxazino[4,3-a] indole
(3q). Yield: (10.9 mg, 45%), yellow solid, mp 103-107 °C; Rf
(EtOAc/PE 20:80) 0.64. 1H NMR (400 MHz, CDCl3, 25 °C,
TMS): δ = 7.36 (s, 1H, CH), 7.17 (d, 1H, J = 8.3 Hz, CH), 7.01
(d, 1H, J = 8.2 Hz, CH), 6.14 (s, 1H, CH), 5.08 (d, 1H, J = 14.7
Hz, CH2O), 4.94 (d, 1H, J =14.7 Hz, CH2O), 4.09 (dd, 1H, J =
2.9, 12.8 Hz, CH2N), 4.07-4.00 (m, 1H, CHO), 3.63 (t, 1H, J =
11.0 Hz, CH2N), 2.45 (s, 3H, CH3), 1.45 (d, 3H, J = 5.6 Hz,
CH3). 13C NMR (100.62 MHz), CDCl3, 25 °C): δ = 134.4
(Cipso), 132.7 (Cipso), 129.2 (Cipso), 128.5 (Cipso), 122.4 (CH),
119.9 (CH), 108.1 (CH), 94.9 (CH), 70.4 (CHO), 64.6 (CH2O),
47.8 (CH2N), 21.4 (CH3), 19.1 (CH3). HRMS (ESI): m/z calcd
for C13H16NO (M+H)+ 202.1232, found 202.1227. FT-IR (KBr)
νmax 3021, 2978, 2842, 1573, 1483, 1422, 1364, 1260, 1144,
1091, 1061, 899, 761 cm-1.
4.3.22 6-Bromo-3-hexyl-1,3,4,9-tetrahydropyrano[3,4-b]indole
1
(4i). (7.3 mg, 18%), brown oil; Rf (EtOAc/PE 20:80) 0.49. H
NMR (400 MHz, CDCl3, 25 °C, TMS): δ = 7.75 (brs, 1H), 7.60
(s, 1H, CH), 7.23 (d, 1H, J = 8.6 Hz, CH), 7.18 (d, 1H, J = 8.6
Hz, CH), 4.84 (s, 2H, CH2O), 3.73-3.64 (m, 1H, CHO), 2.73 (dd,
1H, J = 2.0, 15.1 Hz, CH2), 2.57 (dd, 1H, J = 10.1, 15.1 Hz,
CH2), 1.76-1.26 (m, 10H, 5CH2), 0.89 (t, 3H, J = 6.8 Hz, CH3).
13C NMR (100.62 MHz, CDCl3, 25 °C) δ = 134.8 (Cipso), 133.1
(Cipso), 128.9 (Cipso), 124.3 (CH, Ar), 120.6 (CH, Ar), 112.7
(Cipso), 112.2 (CH, Ar), 108.0 (Cipso), 75.8 (CHO), 63.4
(CH2O), 35.8 (CH2), 31.8 (CH2), 29.3 (CH2), 27.5 (CH2), 25.7
(CH2), 22.6 (CH2), 14.1 (CH3). HRMS (ESI): m/z calcd for
C17H2379BrNO (M+H)+ 336.0963, found 336.0932. FT-IR (KBr):
νmax 3402, 2925, 2856, 1465, 1306, 1051, 792 cm-1.
4.3.18. 4-Methyl-3,4-dihydro-1H-[1,4]oxazino[4,3-a]indole (3r).
(9.0 mg, 40%), yellow solid, mp 110-114 °C; Rf (EtOAc/PE
1
20:80) 0.69. H NMR (400 MHz, CDCl3, 25 °C, TMS): δ = 7.59
(d, 1H, J = 7.6 Hz, CH), 7.34 (d, 1H, J = 7.9 Hz, CH), 7.22 (t,
1H, J = 7.2 Hz, CH), 7.13 (t, 1H, J = 7.2 Hz, CH), 6.21 (s, 1H,
CH), 5.09 (d, 1H, J = 14.7 Hz, CH2O), 4.94 (d, 1H, J = 14.7 Hz,
CH2O), 4.48-4.44 (m, 1H, CHN), 4.09 (dd, 1H, J = 3.2, 11.6 Hz,
CH2O), 4.03 (t, 1H, J = 11.6 Hz, CH2O), 1.52 (d, 3H, J = 6.5 Hz,
CH3). 13C NMR (50.31 MHz, CDCl3, 25 °C): δ = 135.1 (Cipso),
132.3 (Cipso), 128.2 (Cipso), 120.7 (CH), 120.4 (CH), 119.8
(CH), 109.1 (CH), 95.4 (CH), 70.1 (CH2O), 65.0 (CH2O), 47.6
(CHN), 18.1 (CH3). HRMS (ESI): m/z calcd for C12H14NO
(M+H)+ 188.1075, found 188.1072. FT-IR (KBr) νmax 3109,
Acknowledgments

7
10. a) Xiong, X.; Ovens, C.; Pilling, A. W.; Ward, J. W.; Dixon, D.
Financial support from Fondazione Cassa di Risparmio
Perugia Project “Nuovi catalizzatori eterogenei per lo sviluppo di
processi sintetici green in flusso” 2014.0100.021, Fondo per il
Sostegno della ricerca di base 2015 “Composti organici ed ibridi
inorgano-organici del selenio nella sintesi ecocompatibile di
molecole bioattive” Università degli Studi di Perugia and
Dipartimento di Scienze Farmaceutiche, Consorzio CINMPIS,
Bari (Consorzio Interuniversitario Nazionale di Metodologie e
Processi Innovativi di Sintesi), are gratefully acknowledged. This
work is part of the scientific activities realized under the umbrella
of the network SeS Redox and Catalysis.
ACCEPTED MANUSCRIPT
J. Org. Lett. 2008, 10, 565-567. b) Nising, C. F.; Brase, S. Chem.
Soc. Rev. 2008, 37, 1218-1228.
11. a) Santaniello, E.; Farachi, C.; Ponti, F. Synthesis, 1979, 617-618.
b) Yim, E. S.; Park, M. K.; Han, B. H. Ultrasonic Sonochemistry,
1997, 4, 95-98.
12. Buyck, T.; Wang, Q.; Zhu, J. J. Am. Chem. Soc. 2014, 136,
11524-11528.
13. Narayana, B.; Ashalatha, B. V.; Raj, K. K. V. J. Chem. Res.
2006, 309-311.
14. Bingul, M.; Kumar, N.; Black, D. StC. Tetrahedron 2016, 72,
234-239.
References and notes
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7. The oxazino[4,3-a]indoles 3i and 3i´ present a characteristic
signal in the 1H NMR spectra at ~ 6.1 ppm (H10 proton), in
analogy with other oxazino[4,3-a]indoles 3a-f.4c The pyrano[3,4-
b]indoles 4i are identified by the signal of NH in the 1HNMR
(brs, 7.75 ppm) and IR spectra (brs, 3402 cm-1).
8. The COSY and NOESY experiment confirmed the structure
indicated for compound 3i with the alkyl chain in the three
position (see supporting information). Moreover, the proton
coupling constants indicate that the alkyl chain (R2 = C6H13)
occupies an equatorial position.
9. Matlock, V. J.; Svejstrup, T. D.; Songara, P.; Overington, S.;
McGarrigle, E. M., Aggarwal, V. K. Org. Lett. 2015, 17, 5044-
5047.