TCCA-mediated oxidative rearrangement of tetrahydro-β-carbolines: Facile access to spirooxindoles and the total synthesis of (±)-coerulescine and (±)-horsfiline

Article abstract of DOI:10.1039/d1ra02381k

Multi-reactive centered reagents are beneficial in chemical synthesis due to their advantage of minimal material utilization and formation of less by-products. Trichloroisocyanuric acid (TCCA), a reagent with three reactive centers, was employed in the synthesis of spirooxindoles through the oxidative rearrangement of various N-protected tetrahydro-β-carbolines. In this protocol, low equivalents of TCCA were required to access spirooxindoles (up to 99% yield) with a wide substrate scope. Furthermore, the applicability and robustness of this protocol were proven for the gram-scale total synthesis of natural alkaloids such as (±)-coerulescine (1) and (±)-horsfiline (2) in excellent yields.

Full text of DOI:10.1039/d1ra02381k

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TCCA-mediated oxidative rearrangement of
tetrahydro-b-carbolines: facile access to
spirooxindoles and the total synthesis of
(ꢀ)-coerulescine and (ꢀ)-horsfiline†
Cite this: RSC Adv., 2021, 11, 16537
d
Manda Sathish,‡ad Akash P. Sakla,‡b Fabiane M. Nachtigall,c Leonardo S. Santos
*
b
*
and Nagula Shankaraiah
Multi-reactive centered reagents are beneficial in chemical synthesis due to their advantage of minimal
material utilization and formation of less by-products. Trichloroisocyanuric acid (TCCA), a reagent with
three reactive centers, was employed in the synthesis of spirooxindoles through the oxidative
rearrangement of various N-protected tetrahydro-b-carbolines. In this protocol, low equivalents of
Received 25th March 2021
Accepted 15th April 2021
TCCA were required to access spirooxindoles (up to 99% yield) with
a wide substrate scope.
DOI: 10.1039/d1ra02381k
Furthermore, the applicability and robustness of this protocol were proven for the gram-scale total
rsc.li/rsc-advances
synthesis of natural alkaloids such as (ꢀ)-coerulescine (1) and (ꢀ)-horsfiline (2) in excellent yields.
Several approaches have been proposed in the literature to
build spirooxindoles, which mainly involve two ways: (i) multi-
step synthesis1d,8,12 and (ii) oxidative rearrangement.13 However,
Introduction
Spirooxindoles are exceptional and versatile scaffolds, and thus
have been extensively studied in the elds of synthetic and
pharmaceutical chemistry.1 The unique three-dimensional
spiro system may be the main cause for the bioactivities of
spirooxindoles.1,2 Especially, spirooxindoles have been consid-
ered to exhibit antitumor,3 antimicrobial,4 antioxidant,5 anti-
inammatory,6 antiviral1a and other bioactivities. Moreover,
many of their derivatives have been extensively used in clinical
trials,7 and some representative examples of bioactive spiroox-
indoles are depicted in Fig. 1. For example, horsline (2) is an
intoxicating snuff,8 rhynchophylline (4) is potent towards
various cancer cell lines,9 spirotryprostatin A prevents G2M
progression in mammalian tsFT210 cells,10 and corynoxine and
corynoxine B show potential for the treatment of Parkinson's
disease.11 Due to all these pharmaceutical potencies of spi-
rooxindole derivatives, chemists have been inspired to establish
various synthetic routes for this class of compounds.
oxidative rearrangement reaction is more benecial than
multistep synthesis, because it only involves a single step,
avoids the use of various toxic reagents, and ultimately time
saving. A few examples of oxidants have been reported previ-
ously to afford spirooxindoles, which involve the use of mild
organic oxidants such as oxone (Fig. 2),13f N-bromosuccinimide
(NBS),13c t-BuOCl13a,13d and transition metal oxidants such as
13f
Pb(OAc)4,13a CrO3 and OsO4.13b However, the latter oxidants
are more likely to produce highly toxic by-products. In contin-
uation of our efforts in the development of new synthetic
strategies,14 we established a simple method employing the
safer
multi-reactive
centered
reagent
(MRCR)
tri-
chloroisocyanuric acid (TCCA), a highly desirable catalyst that
requires less equivalents, thereby reducing the by-products.
a
´
´
´
Instituto de Investigacion Interdisciplinaria, Vicerrectorıa Academica, Universidad de
Talca, Campus Lircay, Talca 3460000, Chile
bDepartment of Medicinal Chemistry, National Institute of Pharmaceutical Education
and Research (NIPER), Hyderabad 500 037, India. E-mail: shankar@niperhyd.ac.in
c
´
´
Instituto de Ciencias Quımicas Aplicadas, Universidad Autonoma de Chile, Sede Talca
3467987, Chile
d
´
Laboratory of Asymmetric Synthesis, Instituto de Quımica de Recursos Naturales,
Universidad de Talca, Campus Lircay, Talca 3460000, Chile. E-mail: lssantos@
utalca.cl
† Electronic supplementary information (ESI) available. See DOI:
10.1039/d1ra02381k
Fig. 1 Representative examples of bioactive spirooxindoles (1–4).
RSC Adv., 2021, 11, 16537–16546 | 16537
‡ M. Sathish and A. P. Sakla contributed equally.
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Results and discussion
All the key substrates 5a–z were synthesized according to known
reports.21–23 Initially, we performed a model reaction with tet-
rahydro-b-carboline (5a) and TCCA (1 equiv.) in an acidic
solvent mixture of THF/water/AcOH (1 : 1 : 1) for 4 h at 0 ꢁC. The
formation of spirooxindole 6a was observed with 45% yield
(entry 1, Table 1). Next, we considered to avoid the use of acidic
solvents and executed another reaction without AcOH, which
afforded spirooxindole 6a with slightly improved yield (58%,
entry 2, Table 1). We realized that the acidic nature of AcOH and
HCl liberated from excess equivalents of TCCA may affect the
yield of 6a. Then, aer reducing the TCCA equivalents to 0.33 at
0 ꢁC for 2 h (entry 3, Table 1), we achieved 88% of 6a. However,
a slight improvement in the yield (90%) was seen aer mini-
mizing the reaction time to 30 min at room temperature (entry
4, Table 1). Considering our enthusiasm, another trial with
similar reaction conditions was performed by taking 0.35 equiv.
of TCCA, and surprisingly 6a was isolated with excellent yield
(99%, entry 5, Table 1). Hence, we established that 0.35 equiv. of
TCCA is optimal for this oxidative rearrangement reaction.
Further investigation using other immiscible solvent mixtures
such as DCE/water, DCM/water, and EtOAc/water achieved poor
isolated yields of 6a (entries 6, 7 and 8, respectively, Table 1),
thus showing the incompatibility of immiscible solvent
mixtures for this reaction. However, considerable yields of 6a
were identied in the case of miscible solvent mixtures such as
MeOH/water (82%) and MeCN/water (90%) (entries 9 and 10,
respectively, Table 1).
Fig. 2 Comparison of present work with previous methods.
Particularly, TCCA is inexpensive and produces essentially
the nontoxic cyanuric acid as a by-product, which can be easily
separated from the reaction mixture.15 TCCA is a versatile
reagent with three reactive N–Cl centers, which helps to utilize
only 0.33–0.5 equivalents in the reaction. In scaled-up reac-
tions, it is also possible to re-generate TCCA by passing chlo-
rine gas in the aqueous mixture of cyanuric acid.16 Moreover, it
is widely used in several applications such as chlorination and
mild oxidation.17 Studer and co-workers18 utilized TCCA to
obtain a-chloro aldehydes and a-chloro ketones from their
corresponding 1ꢁ and 2ꢁ alcohols. Bathini and co-workers also
reported the TCCA-mediated decarboxylative/dehydrogenative
aromatization of tetrahydro-b-carbolines (THBCs), which was
applied for the total synthesis of b-carboline alkaloids.19 Veisi
and co-workers developed a method to produce nitriles
through the direct oxidation of the corresponding amines,
alcohols, aldehydes, and benzyl halides using TCCA.20 Thus,
based on these signicant ndings such as bioactivity and
research interest on the synthesis of spirooxindoles, we
developed an efficient protocol to construct spirooxindole via
oxidative rearrangement using TCCA, which is a cost effective
and versatile reagent.
Moreover, two reactions were tested in pure THF and
distilled water as solvents, but only 40% of 6a was isolated in the
case of water (entry 11, Table 1) and no product (6a) was
Table 1 TCCA-mediated oxidative rearrangementa
Entry
TCCA (equiv.)
Solvent
Temp. (ꢁC)
Yield (%)
1
2
3
4
5
6
7
8
1
1
THF/water/AcOH (1 : 1 : 1)
THF/water (1 : 1)
THF/water (1 : 1)
THF/water (1 : 1)
THF/water (1 : 1)
DCE/water (1 : 1)
DCM/water (1 : 1)
EtOAc/water (1 : 1)
MeOH/water (1 : 1)
MeCN/water (1 : 1)
Water
0
0
0
45b
58b
88b
90
99
50
52
55
82
0.33
0.33
0.35
0.35
0.35
0.35
0.35
0.35
0.35
0.35
rt
rt
rt
rt
rt
rt
rt
rt
rt
9
10
11
12
90
40c
—
THF
a
All reactions were performed using tetrahydro-b-carboline 5a (1 equiv.) and TCCA for 30 min. b The reaction was stirred for 2 h. c The remaining
starting material was recovered.
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Table 2 Substrate scope of TCCA-mediated oxidative rearrangement
of tetrahydro-b-carbolinesa
observed in THF (entry 12, Table 1). Based on all these obser-
vations, the optimized protocol for the oxidative rearrangement
of tetrahydro-b-carbolines to spirooxindoles is 0.35 equiv. of
TCCA and THF/water (1 : 1) as the solvent at room temperature
for 30 min. During the reaction optimization, we identied that
a homogenous reaction mixture is required before adding TCCA
to achieve the complete conversion of the substrate. Accord-
ingly, it is recommended to use 2 : 1 of THF/water if precipita-
tion of tetrahydro-b-carbolines occurs in a 1 : 1 mixture of THF/
water to ensure a homogeneous reaction mixture is obtained.
Having the optimized protocol in hand, we explored
a sequential study on different substituted/protected THBCs
5a–z, which delivered the corresponding spirooxindoles 6a–x, 1
and 2 in good to excellent yields (78–99%). Totally, the protocol
was executed on ve types of THBC substrates based on their
substitution/protection pattern as follows: (i) simple THBCs
with N2-protection (5a–i); (ii) THBCs with N2-protection and
N9-protection (5j–m); (iii) THBCs with C1-substitution and N2-
protection (5n–t); (iv) THBCs with N2-protection and C3-
substitutions (5u and 5v); and (v) THBCs with C1-substitution,
N2-protection and C3-substitutions (5w–z).
The sulfonyl groups (R2 ¼ tosyl and mesyl) on N2 of THBCs
(5a and 5b) smoothly underwent oxidative rearrangement to
produce the corresponding spirooxindoles 6a and 6b with
excellent yields (99% and 94%, Table 2), respectively.
However, other electron-withdrawing groups (EWG) such as
acetyl, benzoyl, CO2Et, Boc and Cbz at N2-position of simple
THBCs (5c–g) were only slightly affected to give lower yields
(82%, 81%, 83%, 88% and 88%) of the corresponding spi-
rooxindoles (6c–g, Table 2), respectively, which may be due to
the acid sensitivity of the amide and carbamate functional-
ities. Furtheꢁrmore, the reaction of 5c with TCCA was per-
formed at 0 C, and a low yield (50%) was observed at room
temperature, affording de-protected 5c. However, an
electron-donating group (EDG) such as methyl on N2 of
THBC (5h and 5i) gave good yields of natural spirooxindoles
(ꢀ)-coerulescine (1, 93%) and (ꢀ)-horsline (2, 90%),
respectively, as depicted in Table 2.
Further, our attempts on the oxidative rearrangement of
THBCs 5k–m with indole nitrogen protection succeeded and
achieved the corresponding spirooxindoles 6h–k in high yields,
respectively. The EDGs (R4 ¼ benzyl and methyl) at the indole
nitrogen of THBCs delivered 6h and 6i with satisfactory yields
(93% and 95%), respectively. Interestingly, our protocol also
worked well on EWG (R4 ¼ tosyl and Boc)-protected THBCs (5l
and 5m) to provide spirooxindoles 6j (78%) and 6k (82%)
without affecting the protecting groups (Table 2), respectively. A
recent report13f stated that the presence of EDGs such as
hydrogen, alkyl and benzyl at the indolyl nitrogen (N–R4) is
essential to achieve oxidative rearrangement. It is noticeable
that our protocol is very advantageous given that it works well
on both EDGs and EWGs on the indole nitrogen. Next, we
explored our protocol on C1 alkyl (R1 ¼ methyl, ethyl and iso-
propyl)- and phenyl-substituted THBCs 5n–t, but only alkyl-
substituted spirooxindoles 6l–q were obtained in appreciable
yields (80–89%, Table 2). A low yield was observed for 6r (27%)
at room temperature from 1-phenyl substituted THBC (5t), and
a
All reactions were performed using tetrahydro-b-carboline 5 (1 equiv.)
and TCCA (0.35 equiv.) for 30 min at room temperature. b The reaction
was stirred at 0 ꢁC. c The diastereomeric ratio (dr) measured by 1H NMR
analysis.
interestingly another ring-opened side product (6r0, 64%) was
isolated and conrmed by comparing its NMR data (for NMR
and plausible mechanism see ESI†) with the available litera-
ture.21 However, a slight improvement in yield (45%) was
observed with good diastereoselectivity (6r, dr 1 : 7.9, Table 2)
when the reaction was carried out at 0 C and the yield of the
ring-opened side product (6r0) decreased to 50%. The diaste-
reomers of spirooxindoles 6l–q could not be separated by
ꢁ
1
column chromatography and the ratio was determined by H
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albeit with very poor yields (35% and 30%, respectively) and no
oxidative rearrangement product was observed. This can be
attributed to dehydrohalogenation (I and II, Scheme 1A) instead
of chlorohydrin formation, oxidative rearrangement, and
thereby stabilization of the dihydro-b-carbolines by conjugation
from imine, as shown in Scheme 1A.
Notably, in the reaction path of oxidative rearrangement, one
mole of TCCA is sufficient to produce three moles of spiroox-
indoles. The reaction mechanism can be explained as initial
TCCA chlorination of THBC to form Cl-THBC (III, Scheme 1B),
formation of chlorohydrin (IV, Scheme 1B) and dehy-
drohalogenation followed by semi-pinacol-type rearrangement.
The by-product cyanuric acid can be easily separated in the
work-up given that it is soluble in water.
To highlight the utility of this protocol, we accomplished the
gram-scale total synthesis of two bioactive spirooxindole
natural products, (ꢀ)-coerulescine (1) and (ꢀ)-horsline (2)
from 5h and 5i (Scheme 2), respectively. The gram-scale reac-
tion of bioactive natural products is highly desirable from
a commercial perspective. Specically, 5h (1.2 g) and 5i (1.1 g)
were reacted with TCCA to produce (ꢀ)-coerulescine (1) and
(ꢀ)-horsline (2) in high yields (1.21 g, 93% and 1.07 g, 90%,
respectively). It is important to highlight that the quantity of
TCCA used for this gram-scale synthesis is very low (0.52 g for 5h
and 0.41 g for 5i), whereas these reactions need large quantities
of other earlier reported oxidants13 when performing gram-scale
synthesis (>1 g).
Scheme 1 (A) Imine formation of N2 unprotected THBCs. (B) Plausible
reaction mechanism for the oxidative rearrangement of N2-protected
THBCs.
Conclusions
In conclusion, we developed an operationally simple and high
yield protocol for the synthesis of spirooxindoles from the cor-
responding tetrahydro-b-carbolines (THBCs) using the inex-
pensive TCCA. The reaction proceeds via oxidative
rearrangement and produced spirooxindoles in good to excel-
lent yields (up to 99%). Diversely substituted spirooxindoles
and naturally occurring (ꢀ)-coerulescine and (ꢀ)-horsline
were furnished in excellent yields using the optimized reaction
conditions. To demonstrate the commercial importance of this
protocol, we also carried out gram-scale reactions to produce
(ꢀ)-coerulescine (1) and (ꢀ)-horsline (2) with yields of 93%
and 90%, respectively. In addition, this synthetic strategy is
amenable for the generation of a library spiro-compounds and
their derivatives, which can be further utilized in the drug
discovery process.
Scheme
(ꢀ)-horsfiline (2).
2
Gram-scale synthesis of (ꢀ)-coerulescine (1) and
NMR. Nevertheless, the THBCs 5u and 5v generated from L-
tryptophan smoothly underwent oxidative rearrangement to
produce spirooxindoles 6s and 6t in excellent yields and good
diastereoselectivities (95%, dr 1.9 : 1 and 93%, dr 3 : 1 respec-
tively, Table 2). Finally, the diastereomers of 5w–z with C1 (R1 ¼
methyl or ethyl) and C3 (R3 ¼ CO2Me) substitutions were easily
separated by column chromatography and employed for
oxidative rearrangement to afford spirooxindole products 6u–x
in good yields with prominent diastereomeric ratios (95%, dr
1.7 : 1, 94%, dr 1 : 8.3, 89%, dr 4.5 : 1 and 91%, dr 1 : 6.2,
respectively) as shown in Table 2.
Experimental
General
All solvents used for the reactions and purications were of
commercial grade or were puried prior to use when necessary.
NMR spectral analyses were done on a Bruker 400 MHz or 500
1
MHz spectrometer for H and 100 MHz or 125 MHz spectrom-
eter for 13C spectra, and calibrated to either TMS (d ¼ 0 for 1H)
Further, we tested this protocol on C1-substituted (R1
¼
1
or residual DMSO (d ¼ 2.50 for H and d ¼ 39.51 for 13C) and
methyl and phenyl) and N2-unprotected (R2 ¼ hydrogen)
THBCs 7a and 7b and isolated dihydro-b-carbolines 8a and 8b,
1
residual CHCl3 (d ¼ 7.26 for H and d ¼ 77.23 for 13C). Spin
multiplicities are described as s (singlet), br s (broad singlet),
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d (doublet), t (triplet), dd (double doublet), td (triple doublet), q 5.8 Hz, 2H), 2.85 (s, 3H); 13C NMR (125 MHz, CDCl3): d 136.3,
(quartet), and m (multiplet) and the coupling constants are re- 128.6, 126.9, 122.5, 120.1, 118.3, 111.1, 108.5, 44.0, 43.4, 37.5,
ported in hertz (Hz). TLC analyses for the reactions and chro- 21.2; HRMS (ESI) calcd for C12H15N2O2S m/z 251.0849 [M + H]+,
matography purications were performed using silica gel plates found 251.0895.
(0.25 mm, E. Merck, 60 F254) with iodine and a UV lamp for
Phenyl(1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)
visualization. Mass spectral measurements were recorded via methanone (5d). Light yellow solid (375 mg, 87% yield), mp:
electrospray ionization mass spectrometry (ESI-MS). HRMS was 153–155 ꢁC; 1H NMR (500 MHz, CDCl3): d 8.37 (s, 0.76H), 7.80 (s,
performed on a Varian QFT-ESI instrument. Melting points 0.24H), 7.50–7.44 (m, 6H), 7.31 (d, J ¼ 7.3 Hz, 1H), 7.16 (t, J ¼
were measured on an electrothermal melting point apparatus 7.4 Hz, 1H), 7.11 (t, J ¼ 7.3 Hz, 1H), 4.95 (s, 1.5H), 4.60 (s, 0.5H),
and are uncorrected.
4.13 (s, 0.5H), 3.73 (s, 1.5H), 2.93 (s, 0.5H), 2.84 (s, 1.5H); 13C
All the THBCs 5a,21a,22a 5b,21b 5c,21b 5d, 5e,21b 5f,21b 5g,21c 5h,13e NMR (125 MHz, CDCl3): d 171.7, 136.4, 136.2, 130.0, 128.7,
5i,13e 5j, 5k,21a 5l, 5m, 5n, 5o,22a 5p, 5q,21b 5r, 5s,22b 5t,23 5u,23a 127.0, 127.0, 122.1, 122.0, 119.8, 118.0, 111.1, 108.1, 46.1, 41.2,
5v,23b 5w,23c 5x,23c 5y (ref. 23d and e) and 5z (ref. 23d and e) were 22.2; HRMS (ESI) calcd for C15H18NOS2 m/z 277.1335 [M + H]+,
synthesized using known procedures in the literature from their found 277.1350.
corresponding starting materials such as tryptamine (1a),
2-Methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (5h).13e
1
ꢁ
tryptophan methyl ester (1b) and 5-methoxy tryptamine (1c). For Off-white solid (298 mg, 93% yield), mp: 207–212 C; H NMR
the preparation of 5a–i and 5n–z, initially we reacted 1 with the (400 MHz, DMSO-d6 + CDCl3): d 9.70 (s, 1H), 7.42 (d, J ¼ 7.6 Hz,
respective aldehydes to achieve Pictet-Spengler cyclized prod- 1H), 7.29 (d, J ¼ 8.1 Hz, 1H), 7.12–6.96 (m, 2H), 3.59 (s, 2H),
ucts (NH-THBCs). Later, N-protection of THBCs was performed 2.87–2.75 (m, 4H), 2.50 (s, 3H); 13C NMR (100 MHz, DMSO-d6 +
with the corresponding protecting groups in the presence of CDCl3): d 135.8, 132.0, 126.6, 120.2, 118.2, 117.1, 110.5, 106.5,
bases such as triethylamine and N,N-diisopropylethylamine, as 52.6, 52.0, 45.3, 21.1; HRMS (ESI): calcd for C12H15N2 m/z
mentioned in the respective literature reports.13e,21-23
187.1230 [M + H]+, found 187.1238.
6-Methoxy-2-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]ı
´
General procedure for N9-protection for the synthesis of 5j–
1
m. Briey, 5j, 5k and 5m were synthesized from 5a, whereas 5l ndole (5i).13e Pale yellow oil (302 mg, 91% yield); H NMR (400
was synthesized from 5e using protecting groups (PG) such as MHz, DMSO-d6): d 10.56 (s, 1H), 7.20 (d, J ¼ 8.0 Hz, 1H), 6.90 (s,
BnBr, MeI, TsCl and Boc2O, respectively. To a stirred solution 1H), 6.69 (d, J ¼ 8.0 Hz, 1H), 3.78 (s, 3H), 3.55 (s, 2H), 2.71 (s,
of 5a (1 equiv.) in dry THF, 60% NaH (1.5 equiv.) was added at 4H), 2.44 (s, 3H); 13C NMR (100 MHz, DMSO-d6): d 152.4, 133.0,
ꢁ
0 C. Aer stirring for 15 min at room temperature, the pro- 130.3, 126.4, 110.8, 109.2, 105.4, 99.2, 54.7, 52.1, 51.6, 44.9, 20.8;
tecting group (1.1 equiv. of BnBr for 5j, MeI for 5k and TsCl HRMS (ESI): calcd for C13H17N2O m/z 217.1335 [M + H]+, found
for 5m) was added at 0 ꢁC and the reaction was stirred at room 217.1343.
temperature for 8 h. The progress of the reaction was moni-
9-Benzyl-2-tosyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole
1
ꢁ
tored by TLC analysis using EtOAc : hexane or MeOH : CH2- (5j). Pale yellow solid (210 mg, 83% yield); mp: 213–215 C; H
Cl2 solvent systems and the ninhydrin charring technique. NMR (400 MHz, DMSO-d6): d 7.65 (d, J ¼ 8.1 Hz, 2H), 7.38 (dd, J
Aer completion, the reaction was quenched with saturated ¼ 12.8, 8.2 Hz, 4H), 7.32–7.20 (m, 3H), 7.07 (t, J ¼ 7.5 Hz, 1H),
NH4Cl solution and extracted with EtOAc and the combined 7.02–6.97 (m, 3H), 5.36 (s, 2H), 4.27 (s, 2H), 3.38 (s, 2H), 2.73 (s,
organic phases were washed with water. The organic phase 2H), 2.35 (s, 3H); 13C NMR (100 MHz, DMSO-d6): d 143.5, 138.0,
was evaporated in vacuo aer drying over Na2SO4 to give the 136.5, 133.7, 130.3, 129.8, 128.6, 127.3, 127.2, 126.4, 125.9,
crude product, which was puried by silica gel column 121.3, 119.0, 117.9, 109.7, 106.8, 45.8, 43.7, 42.7, 20.9, 20.8;
chromatography using 20–50% EtOAc/hexane to afford the HRMS (ESI): calcd for C25H25N2O2S m/z 417.1631 [M + H]+,
pure products 5j, 5k and 5m. The same procedure was used found 417.1629.
for the synthesis of 5l from 5e using Boc2O as the protecting
group.
Ethyl
9-tosyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indole-2-
1
carboxylate (5l). Brown oil (286 mg, 85% yield); H NMR (400
2-Tosyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (5a).21b,22a MHz, CDCl3): d 8.13 (d, J ¼ 8.3 Hz, 1H), 7.71 (br s, 2H), 7.35 (d, J
White solid (340 mg, 90% yield), mp: 110–115 ꢁC; 1H NMR (400 ¼ 7.6 Hz, 1H), 7.33–7.27 (m, 1H), 7.24 (d, J ¼ 7.4 Hz, 1H), 7.20 (d,
MHz, DMSO-d6): d 10.75 (s, 1H), 7.71 (d, J ¼ 8.3 Hz, 2H), 7.40 (d, J ¼ 8.2 Hz, 2H), 4.95 (s, 2H), 4.20 (q, J ¼ 7.1 Hz, 2H), 3.75 (s, 2H),
J ¼ 8.1 Hz, 2H), 7.34 (d, J ¼ 7.8 Hz, 1H), 7.29 (d, J ¼ 8.0 Hz, 1H), 2.69 (s, 2H), 2.33 (s, 3H), 1.31 (t, J ¼ 7.1 Hz, 3H); 13C NMR (100
7.03 (t, J ¼ 8.0 Hz, 1H), 6.94 (t, J ¼ 8.0 Hz, 1H), 4.27 (s, 2H), 3.39 MHz, CDCl3): d 155.8, 145.0, 136.2, 136.1, 135.6, 130.0, 129.7,
(t, J ¼ 5.7 Hz, 2H), 2.73 (t, J ¼ 5.6 Hz, 2H), 2.37 (s, 3H); 13C NMR 129.6, 126.6, 124.7, 123.6, 118.4, 114.4, 61.8, 43.4, 41.1, 29.8,
(100 MHz, DMSO-d6 + CDCl3): d 143.4, 135.9, 133.5, 129.7, 129.1, 21.6, 14.8; HRMS (ESI): calcd for C21H23N2O4S m/z 399.1373 [M +
127.1, 126.1, 120.9, 118.4, 117.5, 111.0, 106.1, 43.9, 43.3, 20.9, H]+, found 399.1381.
20.9; HRMS (ESI) calcd for C18H19N2O2S m/z 327.1162 [M + H]+,
found 327.1174.
2-(Methylsulfonyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole 228 C; H NMR (400 MHz, CDCl3): d 8.12 (d, J ¼ 8.1 Hz, 1H),
(5b).21a Light yellow solid (360 mg, 98% yield), mp: 200–202 ꢁC; 7.74 (d, J ¼ 8.0 Hz, 2H), 7.34 (dd, J ¼ 19.0, 7.8 Hz, 3H), 7.28–7.18
1H NMR (500 MHz, CDCl3): d 7.88 (s, 1H), 7.49 (d, J ¼ 7.8 Hz, (m, 2H), 4.54 (s, 2H), 3.46 (t, J ¼ 5.6 Hz, 2H), 2.80 (t, J ¼ 5.3 Hz,
1H), 7.35 (d, J ¼ 8.1 Hz, 1H), 7.20 (t, J ¼ 8.1 Hz, 1H), 7.13 (t, J ¼ 2H), 2.41 (s, 3H), 1.68 (s, 9H); 13C NMR (100 MHz, CDCl3):
8.1 Hz, 1H), 4.57 (s, 2H), 3.72 (t, J ¼ 5.8 Hz, 2H), 2.93 (t, J ¼ d 149.9, 143.8, 135.8, 134.2, 130.0, 129.8, 128.6, 127.6, 124.4,
tert-Butyl 2-tosyl-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole-
9-carboxylate (5m). White solid (276 mg, 86% yield), mp: 223–
1
ꢁ
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122.9, 117.9, 115.6, 114.8, 84.3, 45.8, 43.2, 28.3, 21.6, 21.6 HRMS NMR (500 MHz, CDCl3): d 7.77 (s, 1H), 7.53 (d, J ¼ 8.2 Hz, 2H),
(ESI): calcd for C23H26N2O4S m/z 426.1613 [M + H]+, found 7.29 (d, J ¼ 8.1 Hz, 1H), 7.24 (d, J ¼ 7.9 Hz, 1H), 7.13 (t, J ¼
426.1617.
7.6 Hz, 1H), 7.02 (t, J ¼ 7.8 Hz, 1H), 6.97 (d, J ¼ 8.2 Hz, 2H), 4.79
(d, J ¼ 7.8 Hz, 1H), 4.13 (dd, J ¼ 15.0, 6.5 Hz, 1H), 3.52–3.43 (m,
1-Methyl-2-(methylsulfonyl)-2,3,4,9-tetrahydro-1H-pyrido
[3,4-b]indole (5n). White solid (333 mg, 91% yield), mp: 176– 1H), 2.44 (dd, J ¼ 15.9, 4.8 Hz, 1H), 2.32–2.23 (m, 1H), 2.19 (s,
1
ꢁ
178 C; H NMR (500 MHz, CDCl3): d 7.92 (s, 1H), 7.49 (d, J ¼ 3H), 2.17–2.08 (m, 1H), 1.17 (d, J ¼ 6.7 Hz, 3H), 1.11 (d, J ¼
7.8 Hz, 1H), 7.35 (d, J ¼ 8.1 Hz, 1H), 7.20 (t, J ¼ 7.8 Hz, 1H), 7.13 6.8 Hz, 3H); 13C NMR (125 MHz, CDCl3): d 143.2, 138.0, 135.8,
(t, J ¼ 7.8 Hz, 1H), 5.09 (q, J ¼ 6.7 Hz, 1H), 4.17 (dd, J ¼ 14.5, 132.3, 129.3, 126.8, 126.7, 122.1, 119.5, 118.1, 110.8, 108.2, 59.1,
5.7 Hz, 1H), 3.49–3.40 (m, 1H), 2.96–2.87 (m, 1H), 2.82 (s, 3H), 40.2, 34.1, 21.4, 20.2, 20.1, 19.4; HRMS (ESI) calcd for
2.79 (dd, J ¼ 16.0, 4.3 Hz, 1H), 1.60 (d, J ¼ 6.7 Hz, 3H); 13C NMR
(125 MHz, CDCl3): d 135.9, 133.7, 126.6, 122.4, 119.8, 118.2,
C
21H25N2O2S m/z 369.1631 [M + H]+, found 369.1647.
1-Phenyl-2-tosyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole
111.0, 107.4, 48.6, 40.2, 39.0, 21.4, 20.8; HRMS (ESI) calcd for (5t).22 White solid (393 mg, 93% yield), mp: 157–162 ꢁC; 1H NMR
C
13H17N2O2S m/z 265.1005 [M + H]+, found 265.0983.
(400 MHz, DMSO-d6): d 10.82 (s, 1H), 7.63 (d, J ¼ 8.1 Hz, 2H),
1-Methyl-2-tosyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole
7.38–7.13 (m, 9H), 7.05 (t, J ¼ 7.5 Hz, 1H), 6.94 (t, J ¼ 7.4 Hz, 1H),
1
(5o).22a Yellow solid (353 mg, 81% yield), mp: 206–207 ꢁC; H 6.24 (s, 1H), 3.95 (dd, J ¼ 14.5, 5.6 Hz, 1H), 3.26–3.14 (m, 1H),
NMR (400 MHz, CDCl3): d 7.94 (s, 1H), 7.67 (d, J ¼ 8.3 Hz, 2H), 2.61 (dd, J ¼ 15.7, 4.1 Hz, 1H), 2.48–2.35 (m, 1H), 2.22 (s, 3H);
7.35 (d, J ¼ 7.8 Hz, 1H), 7.28 (d, J ¼ 8.0 Hz, 1H), 7.18–7.10 (m, 13C NMR (100 MHz, DMSO-d6): d 143.0, 139.8, 137.6, 136.0,
3H), 7.06 (t, J ¼ 8.3 Hz, 1H), 5.26 (q, J ¼ 6.6 Hz, 1H), 4.16–4.09 130.6, 129.5, 128.4, 128.0, 128.0, 126.5, 126.0, 121.3, 118.5,
(dd, J ¼ 16.0, 4.0 Hz, 1H), 3.42–3.34 (m, 1H), 2.63–2.45 (m, 2H), 117.8, 111.2, 107.6, 55.3, 39.1, 20.8, 19.5; HRMS (ESI) calcd for
2.31 (s, 3H), 1.54 (d, J ¼ 6.7 Hz, 3H); 13C NMR (100 MHz, CDCl3):
d 143.3, 138.3, 136.0, 134.0, 129.7, 126.8, 126.7, 122.1, 119.6,
C
24H23N2O2S m/z 403.1475 [M + H]+, found 403.1489.
Methyl (S)-2-tosyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-
118.2, 111.0, 107.7, 48.9, 39.3, 21.5, 21.5, 20.7; HRMS (ESI) calcd 3-carboxylate (5u).23a White solid (386 mg, 94% yield), mp:
for C19H21N2O2S m/z 341.1318 [M + H]+, found 341.1326.
1-Ethyl-2-(methylsulfonyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-
138–143 ꢁC; 1H NMR (400 MHz, CDCl3): d 8.06 (br s, 1H), 7.71 (d,
J ¼ 8.3 Hz, 2H), 7.41 (d, J ¼ 7.6 Hz, 1H), 7.28–7.22 (m, 3H), 7.16–
b]indole (5p). White solid (301 mg, 78% yield), mp: 160–162 ꢁC; 7.04 (m, 2H), 5.15 (d, J ¼ 6.4 Hz, 1H), 4.82 (d, J ¼ 15.0 Hz, 1H),
1H NMR (500 MHz, CDCl3): d 7.91 (s, 1H), 7.49 (d, J ¼ 7.8 Hz, 4.64 (d, J ¼ 15.1 Hz, 1H), 3.43 (s, 3H), 3.30 (d, J ¼ 15.7 Hz, 1H),
1H), 7.35 (d, J ¼ 8.1 Hz, 1H), 7.21 (t, J ¼ 8.1 Hz, 1H), 7.13 (t, J ¼ 3.06 (dd, J ¼ 15.7, 6.6 Hz, 1H), 2.37 (s, 3H); 13C NMR (100 MHz,
7.9 Hz, 1H), 4.81 (dd, J ¼ 8.9, 5.1 Hz, 1H), 4.21 (dd, J ¼ 14.9, CDCl3): d 171.0, 143.8, 136.3, 129.7, 128.4, 127.2, 126.7, 122.2,
6.0 Hz, 1H), 3.50–3.42 (m, 1H), 2.99–2.90 (m, 1H), 2.82–2.75 (m, 119.7, 118.1, 111.1, 105.6, 54.1, 52.4, 41.0, 24.6, 21.6; HRMS
1H), 2.76 (s, 3H), 1.97–1.83 (m, 2H), 1.14 (t, J ¼ 7.4 Hz, 3H); 13
C
(ESI) calcd for C20H21N2O4S m/z 385.1217 [M + H]+, found
NMR (125 MHz, CDCl3): d 135.9, 133.1, 126.7, 122.4, 119.9, 385.1219.
118.3, 111.0, 107.4, 54.3, 40.0, 39.4, 28.6, 20.2, 10.9; HRMS (ESI)
General procedure for the synthesis of 5w, 5x, 5y and 5z. The
calcd for C14H19N2O2S m/z 279.1162 [M + H]+, found 279.1132. diastereomeric mixtures of THBC esters (5w and 5x) and (5y and
1-Ethyl-2-tosyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole
5z) were synthesized according to the procedures given in
(5q).21b Pale yellow solid (366 mg, 89% yield), mp: 68–70 ꢁC; 1H previous literature reports.23c–e These diastereomeric mixtures
NMR (500 MHz, CDCl3): d 7.81 (s, 1H), 7.63 (d, J ¼ 8.3 Hz, 2H), were separated by silica gel column chromatography using
7.30 (t, J ¼ 7.4 Hz, 2H), 7.14 (t, J ¼ 7.8 Hz, 1H), 7.09 (d, J ¼ 8.2 Hz, EtOAc/hexane (20–30%) prior to use for TCCA-mediated oxida-
2H), 7.04 (t, J ¼ 7.5 Hz, 1H), 5.06 (dd, J ¼ 8.4, 5.1 Hz, 1H), 4.13 tive rearrangement.
(dd, J ¼ 14.7, 5.7 Hz, 1H), 3.45–3.34 (m, 1H), 2.49 (dd, J ¼ 15.6,
Methyl (1R,3S)-2-benzyl-1-methyl-2,3,4,9-tetrahydro-1H-pyr-
4.1 Hz, 1H), 2.4–2.3 (m, 1H), 2.28 (s, 3H), 1.99–1.82 (m, 2H), 1.12 ido[3,4-b]indole-3-carboxylate (5x)22c. Brown oil (312 mg, 92%
(t, J ¼ 7.4 Hz, 3H); 13C NMR (125 MHz, CDCl3): d 143.1, 138.2, yield); H NMR (400 MHz, CDCl3): d 7.70 (s, 1H), 7.51 (d, J ¼
1
135.8, 133.0, 129.4, 126.7, 126.6, 121.9, 119.4, 118.1, 110.8, 7.3 Hz, 1H), 7.43 (d, J ¼ 7.4 Hz, 2H), 7.34–7.25 (m, 3H), 7.23 (t, J
107.8, 54.4, 39.7, 29.0, 21.4, 19.7, 10.8; HRMS (ESI) calcd for ¼ 7.3 Hz, 1H), 7.17–7.06 (m, 2H), 4.24 (q, J ¼ 6.8 Hz, 1H), 4.01 (d,
C
20H23N2O2S m/z 355.1475 [M + H]+, found 355.1482.
J ¼ 4.5 Hz, 2H), 3.90 (t, J ¼ 5.7 Hz, 1H), 3.62 (s, 3H), 3.26 (dd, J ¼
15.2, 6.1 Hz, 1H), 2.99 (dd, J ¼ 17.2, 5.7 Hz, 1H), 1.34 (d, J ¼
1-Isopropyl-2-(methylsulfonyl)-2,3,4,9-tetrahydro-1H-pyrido
[3,4-b]indole (5r). White solid (386 mg, 87% yield), mp: 128– 6.9 Hz, 3H); 13C NMR (100 MHz, CDCl3): d 174.2, 140.0, 136.1,
1
ꢁ
129 C; H NMR (500 MHz, CDCl3): d 7.92 (s, 1H), 7.50 (d, J ¼ 135.5, 128.6, 128.3, 127.2, 127.0, 121.7, 119.6, 118.3, 110.8,
7.8 Hz, 1H), 7.36 (d, J ¼ 8.1 Hz, 1H), 7.21 (t, J ¼ 8.1 Hz, 1H), 7.13 106.6, 60.0, 54.9, 52.9, 51.8, 22.3, 18.3; HRMS (ESI) calcd for
(t, J ¼ 7.5 Hz, 1H), 4.51 (d, J ¼ 8.3 Hz, 1H), 4.23 (dd, J ¼ 15.1,
6.5 Hz, 1H), 3.59–3.50 (m, 1H), 3.04–2.92 (m, 1H), 2.79 (dd, J ¼
C
21H23N2O2 m/z 335.1754 [M + H]+, found 335.1762.
Methyl (1R,3S)-2-benzyl-1-ethyl-2,3,4,9-tetrahydro-1H-pyrido
16.3, 5.2 Hz, 1H), 2.66 (s, 3H), 2.20–2.07 (m, 1H), 1.18 (d, J ¼ [3,4-b]indole-3-carboxylate (5z).23d,23e Brown oil (368 mg, 89%
6.7 Hz, 3H), 1.12 (d, J ¼ 6.8 Hz, 3H); 13C NMR (125 MHz, CDCl3): yield); H NMR (400 MHz, CDCl3): d 7.74 (s, 1H), 7.52 (d, J ¼
1
d 135.9, 132.4, 126.7, 122.6, 120.0, 118.4, 111.1, 107.9, 58.8, 40.1, 7.5 Hz, 1H), 7.44 (d, J ¼ 7.3 Hz, 2H), 7.34–7.29 (m, 2H), 7.29–7.22
39.9, 33.7, 20.3, 20.2, 20.1; HRMS (ESI) calcd for C15H21N2O2S m/ (m, 2H), 7.16–7.07 (m, 2H), 3.93 (d, J ¼ 1.5 Hz, 2H), 3.86–3.80
z 293.1318 [M + H]+, found 293.1288.
(m, 2H), 3.60 (s, 3H), 3.23 (dd, J ¼ 15.7, 4.5 Hz, 1H), 2.97 (dd, J ¼
1-Isopropyl-2-tosyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole 15.7, 7.0 Hz, 1H), 1.71–1.61 (m, 2H), 1.00 (t, J ¼ 7.3 Hz, 3H); 13
C
(5s).22b White solid (363 mg, 91% yield), mp: 211–215 ꢁC; 1H NMR (100 MHz, CDCl3): d 174.2, 139.6, 136.1, 134.6, 128.9,
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128.3, 127.2, 127.1, 121.6, 119.5, 118.3, 110.8, 106.5, 59.5, 59.1, 130.3, 128.8, 128.7, 128.5, 127.3, 123.2, 122.7, 110.3, 57.6, 54.2,
58.4, 51.7, 27.0, 20.4, 11.1; HRMS (ESI) calcd for C22H25N2O2 m/z 53.6, 51.9, 48.7, 45.6, 36.9, 35.0; HRMS (ESI) calcd for
349.1911 [M + H]+, found 349.1915.
C
18H17N2O2S2 m/z 293.1285 [M + H]+, found 293.1253.
General procedure for TCCA mediated oxidative rearrange-
Ethyl
2-oxospiro[indoline-3,30-pyrrolidine]-10-carboxylate
ment reaction. To a stirred homogeneous solution of THBCs (6e). Colorless oil (85 mg, 83% yield, found as 56 : 44 rotamers
1
(1.0 equiv.) in THF/H2O (1 : 1), TCCA (0.35 equiv.) was added at in CDCl3); H NMR (500 MHz, CDCl3): d 9.11 and 9.04 (s, 1H),
room temperature in one batch. The resulting reaction mixture 7.27–7.22 (m, 1H), 7.17 (t, J ¼ 5.0 Hz, 1H), 7.05 (t, J ¼ 7.4 Hz, 1H),
was stirred at room temperature for 30 min. Aer the reaction 6.97–6.90 (m, 1H), 4.23–4.12 (m, 2H), 3.95–3.87 (m, 1H), 3.85–
was completed, as monitored by TLC analysis (EtOAc : hexane 3.74 (m, 2H), 3.64 (dd, J ¼ 18.0, 9.1 Hz, 1H), 2.48–2.40 (m, 1H),
or MeOH : CH2Cl2 solvent systems), it was quenched by addi- 2.16–2.07 (m, 1H), 1.32 (t, J ¼ 7.0 Hz, 1.3H), 1.24 (t, J ¼ 7.0 Hz,
tion of saturated NaHCO3 and extracted with EtOAc three times. 1.7H); 13C NMR (125 MHz, CDCl3): d 180.2, 179.9, 155.2, 155.1,
The combined organic phases were washed with water, dried 140.3, 140.2, 132.9, 132.5, 128.6, 123.4, 123.1, 123.1, 122.8,
over Na2SO4, ltered, and evaporated under reduced pressure. 111.2, 110.2, 61.6, 61.5, 54.3, 54.1, 53.4, 52.4, 45.7, 45.3, 36.5,
The resulting crude product was puried by ash column 35.6, 14.9, 14.8; HRMS (ESI) calcd for C14H17N2O3 m/z 261.1234
chromatography (EtOAc/hexane ¼ 1 : 10 to 1 : 1) to provide the [M + H]+, found 269.1246.
pure spirooxindole. Note: This reaction was performed at 0 ꢁC in
the case of THBCs 5c and 5t.
tert-Butyl
ylate (6f).13f White solid (102 mg, 88% yield, found as 51 : 49
2-oxospiro[indoline-3,30-pyrrolidine]-10-carbox-
10-Tosylspiro[indoline-3,30-pyrrolidin]-2-one (6a).13f White rotamers in DMSO-d6), mp: 123–125 ꢁC; 1H NMR (500 MHz,
solid (98 mg, 99% yield), mp: 158–160 ꢁC; 1H NMR (400 MHz, DMSO-d6): d 10.50 (s, 1H), 7.25–7.19 (m, 2H), 6.97 (t, J ¼ 6.5 Hz,
CDCl3): d 8.63 (s, 1H), 7.77 (d, J ¼ 8.2 Hz, 2H), 7.37 (d, J ¼ 1H), 6.86 (d, J ¼ 7.6 Hz, 1H), 3.67–3.57 (m, 2H), 3.51–3.43 (m,
8.1 Hz, 2H), 7.21 (t, J ¼ 7.7 Hz, 1H), 7.03 (d, J ¼ 7.0 Hz, 1H), 6.96 2H), 2.18–2.09 (m, 2H), 1.44 and 1.39 (s, 9H); 13C NMR (125
(t, J ¼ 7.4 Hz, 1H), 6.88 (d, J ¼ 7.7 Hz, 1H), 3.74–3.68 (m, 1H), MHz, DMSO-d6): d 179.3, 153.5, 141.7, 131.8, 128.2, 122.8,
3.57 (d, J ¼ 9.6 Hz, 1H), 3.58–3.50 (m, 1H) 3.47 (d, J ¼ 9.8 Hz, 121.5, 109.4, 78.6, 53.8, 53.5, 52.2, 51.3, 45.0, 44.9, 35.5, 34.6,
1H), 2.46 (s, 3H), 2.35–2.24 (m, 1H), 2.10–2.00 (m, 1H); 13C 28.1, 28.0; HRMS (ESI) calcd for C16H20N2O3Na m/z 311.1366
NMR (100 MHz, CDCl3): d 179.3, 144.0, 139.9, 133.4, 132.8, [M + Na]+, found 311.1416.
129.9, 128.6, 127.8, 123.2, 123.2, 110.1, 56.1, 53.0, 47.4, 36.4,
Benzyl 2-oxospiro[indoline-3,30-pyrrolidine]-10-carboxylate
21.7; HRMS (ESI) calcd for C18H19N2O3S m/z 343.1111 [M + H]+, (6g). Colourless oil (75 mg, 88% yield, found as 52 : 48 rotamers
1
found 343.1123.
in CDCl3) H NMR (500 MHz, CDCl3): d 8.65 and 8.59 (s, 1H),
10-(Methylsulfonyl)spiro[indoline-3,30-pyrrolidin]-2-one (6b). 7.43–7.37 (m, 2H), 7.33–7.32 (m, 3H), 7.24 (t, J ¼ 12.8 Hz, 1H),
1
ꢁ
White solid (90 mg, 94% yield), mp: 217–219 C; H NMR (500 7.15 (dd, J ¼ 15.2, 7.4 Hz, 1H), 7.05–7.03 (m, 1H), 6.93 (d, J ¼
MHz, DMSO-d6): d 10.54 (s, 1H), 7.38 (d, J ¼ 7.4 Hz, 1H), 7.23 (t, J 7.8 Hz, 1H), 5.21 (d, J ¼ 2.8 Hz, 1H), 5.16 (s, 1H), 3.97–3.90 (m,
¼ 7.7, 1H), 7.01 (t, J ¼ 7.5 Hz, 1H), 6.88 (d, J ¼ 7.7 Hz, 1H), 3.74– 1H), 3.87–3.78 (m, 2H), 3.69 (dd, J ¼ 23.0, 11.1 Hz, 1H), 2.47–
3.65 (m, 1H), 3.63–3.59 (m, 1H), 3.56 (d, J ¼ 10.3 Hz, 1H), 3.44 (d, 2.41 (dt, J ¼ 12.7, 8.1 Hz, 1H), 2.16–2.08 (m, 1H); 13C NMR (125
J ¼ 10.3 Hz, 1H), 3.03 (s, 3H), 2.28–2.23 (m, 1H), 2.20–2.14 (m, MHz, CDCl3): d 179.7, 154.8, 140.1, 136.9, 136.7, 132.7, 132.3,
1H); 13C NMR (125 MHz, DMSO-d6): d 179.1, 141.5, 131.4, 128.4, 128.6, 128.6, 128.1, 128.1, 128.0, 127.9, 123.1, 122.9, 110.1, 67.2,
123.0, 121.87, 109.4, 54.9, 52.3, 47.0, 35.9, 34.3; HRMS (ESI) 54.5, 54.2, 53.3, 52.4, 45.8, 45.4, 36.5, 35.6; HRMS (ESI) calcd for
calcd for C12H15N2O3S m/z 267.0798 [M + H]+, found 267.0846.
10-Acetylspiro[indoline-3,30-pyrrolidin]-2-one (6c).13f This
C
19H19N2O3 m/z 323.1390 [M + H]+, found 323.1349.
(ꢀ)-Coerulescine (1).13e,13f Off-white solid (1.21 g, 93% yield),
reaction was performed at 0 ꢁC. Pale yellow solid (101 mg, 82% mp: 110–114 ꢁC; 1H NMR (400 MHz, CDCl3): d 9.24 (s, 1H), 7.42
yield, found as 50 : 50 rotamers CDCl3), mp: 75–78 ꢁC; 1H NMR (d, J ¼ 8.0 Hz, 1H), 7.22 (t, J ¼ 8.0 Hz, 1H), 7.06 (t, J ¼ 8.0 Hz,
(500 MHz, CDCl3): d 9.38 and 9.22 (s, 1H), 7.29–7.20 (m, 1H), 1H), 6.95 (d, J ¼ 8.0 Hz, 1H), 3.06–3.00 (m, 1H), 2.92 (dd, J ¼
7.19–7.10 (s, 1H), 7.09–7.00 (s, 1H), 6.95 (ddd, J ¼ 21.6, 14.1, 25.1, 9.3 Hz, 2H), 2.85 (dd, J ¼ 15.1, 6.8 Hz, 1H), 2.50 (s, 3H),
8.0 Hz, 1H), 4.05–3.95 (m, 1H), 3.93–3.80 (m, 2H), 3.68 (dd, J ¼ 2.49–2.41 (m, 1H), 2.19–2.09 (m, 1H); 13C NMR (100 MHz,
65.0, 15.0 Hz, 1H), 2.54–2.40 (m, 1H), 2.29–2.21 (m, 1H), 2.19 CDCl3): d 183.5, 140.4, 136.3, 127.8, 123.3, 122.8, 109.8, 66.4,
and 2.10 (s, 3H); 13C NMR (125 MHz, CDCl3): d 180.5, 179.4, 56.9, 53.8, 41.9, 38.0; HRMS (ESI) calcd for C12H15N2O m/z
169.7, 169.5, 140.7, 140.4, 132.5, 131.7, 128.8, 128.7, 123.1, 203.1179 [M + H]+, found 203.1175.
122.9, 122.7, 110.4, 110.3, 55.5, 53.9, 53.6, 51.9, 46.7, 45.2, 36.5,
(ꢀ)-Horsline (2).13e,13f White solid (69 mg, 90% yield), mp:
1
ꢁ
35.1, 22.6, 22.4; HRMS (ESI) calcd for C15H15N2O2 m/z 231.1128 148–152 C; H NMR (400 MHz, CDCl3): d 7.39 (s, 1H), 7.01 (s,
[M + H]+, found 231.1108.
1H), 6.75–6.66 (m, 2H), 3.77 (s, 3H), 3.05–2.95 (m, 1H), 2.88–2.80
10-Benzoylspiro[indoline-3,30-pyrrolidin]-2-one (6d). White (m, 2H), 2.71 (q, J ¼ 8.4 Hz, 1H), 2.42 (s, 3H), 2.41–2.32 (m, 1H),
solid (95 mg, 89% yield, found as 62 : 38 rotamers in CDCl3), 2.11–1.99 (m, 1H); 13C NMR (100 MHz, CDCl3): d 183.1, 156.1,
1
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mp: 83–85 C; H NMR (500 MHz, CDCl3): d 8.07 and 8.03 (s, 137.6, 133.6, 112.4, 110.2, 109.9, 66.3, 56.7, 55.8, 54.2, 41.8, 38.0;
1H), 7.63 (d, J ¼ 7.0 Hz, 1H), 7.52 (d, J ¼ 7.5 Hz, 1H), 7.47–7.43 HRMS (ESI) calcd for C13H17N2O2 m/z 233.1285 [M + H]+, found
(m, 1H), 7.41–7.32 (m, 2H), 7.27–7.20 (s, 2H), 7.17–7.01 (m, 1H), 233.1289.
6.91 (dd, J ¼ 22.2, 7.7 Hz, 1H), 4.25–4.02 (m, 2H), 3.99–3.56 (m,
1-Benzyl-10-tosylspiro[indoline-3,30-pyrrolidin]-2-one (6h).23a
2H), 2.66–2.31 (m, 1H), 2.27–2.10 (m, 1H); 13C NMR (125 MHz, Colorless gummy oil (78 mg, 93% yield); 1H NMR (400 MHz,
CDCl3): d 180.6, 178.8, 170.2, 170.1, 140.6, 140.1, 136.4, 132.4, CDCl3): d 7.78 (d, J ¼ 8.2 Hz, 2H), 7.37 (d, J ¼ 8.0 Hz, 2H), 7.33–
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7.25 (m, 3H), 7.24–7.08 (m, 4H), 6.97 (td, J ¼ 7.6, 0.8 Hz, 1H), 3.85 (m, 1H), 3.80–3.68 (m, 1H), 2.49 (s, 3H), 2.21–2.13 (m, 1H),
6.72 (d, J ¼ 7.8 Hz, 1H), 4.87 (d, J ¼ 1.3 Hz, 2H), 3.81–3.72 (m, 1.80–1.74 (m, 1H), 1.33 (d, J ¼ 6.5 Hz, 3H); minor isomer: d 8.44
1H), 3.63–3.47 (m, 3H), 2.47 (s, 3H), 2.39–2.30 (m, 1H), 2.13–2.01 (s, 1H), 7.79 (d, J ¼ 8.2 Hz, 2H), 7.40 (d, J ¼ 8.0 Hz, 2H), 7.09 (t, J
(m, 1H); 13C NMR (100 MHz, CDCl3): d 177.0, 144.0, 141.8, 135.6, ¼ 7.6 Hz, 1H), 6.95–6.85 (m, 2H), 6.57 (d, J ¼ 7.4 Hz, 1H), 4.08–
133.4, 132.5, 130.0, 128.9, 128.6, 127.8, 127.2, 123.3, 123.0, 4.00 (m, 1H), 3.93–3.85 (m, 1H), 3.80–3.68 (m, 1H), 2.46 (s, 3H),
109.3, 56.3, 52.6, 47.4, 44.0, 36.4, 21.7; HRMS (ESI) calcd for 2.21–2.13 (m, 1H), 1.80–1.74 (m, 1H), 1.14 (d, J ¼ 6.4 Hz, 3H);
C
25H25N2O3S m/z 433.1580 [M + H]+, found 433.1588.
13C NMR (100 MHz, CDCl3): d 178.9, 178.5, 143.9, 143.8, 140.6,
1-Methyl-10-tosylspiro[indoline-3,30-pyrrolidin]-2-one (6i).24a 140.2, 135.7, 133.5, 130.6, 129.9, 128.8, 127.9, 127.6, 125.2,
1
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Off-white solid (76 mg, 95% yield), 147–151 C; H NMR (400 123.0, 122.9, 122.6, 110.2, 110.0, 63.7, 62.3, 58.4, 57.8, 48.4, 48.0,
MHz, CDCl3): d 7.76 (d, J ¼ 8.2 Hz, 2H), 7.36 (d, J ¼ 8.1 Hz, 2H), 34.8, 33.8, 23.9, 21.7, 17.5, 17.3; HRMS (ESI) calcd for
7.32–7.26 (m, 1H), 7.10 (d, J ¼ 7.4 Hz, 1H), 7.01 (t, J ¼ 7.5 Hz,
1H), 6.84 (d, J ¼ 7.8 Hz, 1H), 3.78–3.70 (m, 1H), 3.57–3.47 (m,
C
19H21N2O3S m/z 357.1267 [M + H]+, found 357.1269.
20-Ethyl-10-(methylsulfonyl)spiro[indoline-3,30-pyrrolidin]-2-
1
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2H), 3.42 (d, J ¼ 9.6 Hz, 1H), 3.18 (s, 3H), 2.47 (s, 3H), 2.33–2.23 one (6n). White solid (82 mg, 85% yield), mp: 158–160 C; H
(m, 1H), 2.05–1.97 (m, 1H); 13C NMR (100 MHz, CDCl3): d 176.8, NMR (500 MHz, DMSO-d6): d 10.58 (s, 1H), 7.46 (d, J ¼ 7.4 Hz,
143.9, 142.7, 133.4, 132.6, 129.9, 128.6, 127.8, 123.3, 122.9, 1H), 7.19 (d, J ¼ 7.7 Hz, 1H), 7.00 (t, J ¼ 7.5 Hz, 1H), 6.83 (d, J ¼
108.3, 56.2, 52.6, 47.4, 36.3, 26.5, 21.7; HRMS (ESI) calcd for 7.7 Hz, 1H), 3.83–3.76 (m, 2H), 3.69–3.63 (m, 1H), 3.12 (s, 3H),
C
19H21N2O3S m/z 357.1267 [M + H]+, found 357.1273.
2.18–2.09 (m, 1H), 2.09–2.02 (m, 1H), 2.00–1.88 (m, 1H), 1.83–
Ethyl 2-oxo-1-tosylspiro[indoline-3,30-pyrrolidine]-10-carbox- 1.72 (m, 1H), 0.39 (t, J ¼ 7.6 Hz, 4H); 13C NMR (125 MHz, DMSO-
ylate (6j). Pale yellow oil (63 mg, 78% yield); 1H NMR (400 MHz, d6): d 178.1, 141.2, 131.5, 128.2, 122.9, 121.8, 109.3, 67.7, 56.6,
CDCl3 + DMSO-d6): d 7.94 (d, J ¼ 7.6 Hz, 2H), 7.44 (d, J ¼ 8.4 Hz, 47.4, 36.8, 34.8, 25.7, 10.1; HRMS (ESI) calcd for C14H19N2O3S m/
1H), 7.30 (d, J ¼ 7.4 Hz, 1H), 7.24 (d, J ¼ 7.7 Hz, 3H), 7.02 (t, J ¼ z 295.1111 [M + H]+, found 295.1099.
7.4 Hz, 1H), 4.20–4.10 (m, 3H), 3.98–3.51 (m, 2H), 3.03–2.99 (m,
20-Ethyl-10-tosylspiro[indoline-3,30-pyrrolidin]-2-one (6o).24b
1H), 2.37 (s, 3H), 2.27–1.99 (m, 2H), 1.30–1.24 (m, 3H); 13C NMR White solid (74 mg, 87% yield), mp: 208–210 C; H NMR (500
(100 MHz, CDCl3 + DMSO-d6): d 173.0, 155.5, 143.2, 137.2, 129.7, MHz, CDCl3): d 8.07 (s, 1H), 7.85 (d, J ¼ 8.2 Hz, 2H), 7.41 (d, J ¼
128.9, 127.7, 123.7, 123.0, 122.1, 113.2, 95.4, 75.7, 61.0, 60.8, 8.3 Hz, 2H), 7.17 (t, J ¼ 8.1 Hz, 1H), 6.89 (t, J ¼ 7.6 Hz, 1H), 6.83
48.4, 32.4, 21.1, 14.3; HRMS (ESI) calcd for C21H22N2O5S m/z (d, J ¼ 7.8 Hz, 1H), 6.56 (d, J ¼ 7.4 Hz, 1H), 3.97 (ddd, J ¼ 11.1,
1
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414.1249 [M]+, found 414.1255.
tert-Butyl
10.1, 5.8 Hz, 1H), 3.86 (dd, J ¼ 9.9, 4.4 Hz, 1H), 3.79–3.72 (m,
2-oxo-10-tosylspiro[indoline-3,30-pyrrolidine]-1- 1H), 2.49 (s, 3H), 2.12–2.05 (m, 2H), 2.04–1.95 (m, 1H), 1.73–1.66
carboxylate (6k). Colorless oil (84 mg, 82% yield); 1H NMR (s, 1H), 0.60 (t, J ¼ 7.5 Hz, 3H); 13C NMR (125 MHz, CDCl3):
(400 MHz, CDCl3): d 7.62 (d, J ¼ 8.2 Hz, 2H), 7.53 (d, J ¼ 8.0 Hz, d 178.8, 143.9, 139.8, 135.9, 132.4, 130.0, 128.5, 127.8, 123.0,
1H), 7.31–7.23 (m, 4H), 7.04 (t, J ¼ 7.5 Hz, 1H), 3.92 (d, J ¼ 122.6, 109.8, 69.4, 57.0, 48.1, 37.4, 26.3, 21.7, 10.8; HRMS (ESI)
13.3 Hz, 1H), 3.51–3.46 (m, 1H), 3.30 (d, J ¼ 13.3 Hz, 1H), 2.80– calcd for C15H18NOS2 m/z 371.1424 [M + H]+, found 371.1439.
2.72 (m, 1H), 2.40 (s, 3H), 2.26–2.14 (m, 2H), 1.63 (s, 9H); 13C
20-Isopropyl-10-(methylsulfonyl)spiro[indoline-3,30-
NMR (100 MHz, CDCl3): d 174.0, 152.9, 143.6, 140.3, 135.0, pyrrolidin]-2-one (6p). Colourless oil (83 mg, 80% yield); 1H
130.6, 130.3, 129.8, 127.4, 123.7, 123.3, 115.3, 91.1, 83.8, 75.7, NMR (500 MHz, CDCl3): d 7.62 and 7.60 (d, J ¼ 9.4 Hz, 1H), 7.41
50.0, 42.0, 32.2, 28.5, 21.6; HRMS (ESI) calcd for C23H27N2O5S m/ (d, J ¼ 7.5 Hz, 1H), 7.22 (t, J ¼ 7.7 Hz, 1H), 7.09 (t, J ¼ 7.6 Hz,
z 443.1635 [M + H]+, found 443.1643.
1H), 6.85 (d, J ¼ 7.7 Hz, 1H), 4.21 (d, J ¼ 9.3 Hz, 1H), 3.91–3.84
(m, 1H), 3.81–3.73 (m, 1H), 3.08 (s, 3H), 3.92–3.84 (m, 1H), 2.35–
20-Methyl-10-(methylsulfonyl)spiro[indoline-3,30-pyrrolidin]-
2-one (6l). White solid (58 mg, 87% yield, dr 1 : 1.6), mp: 140– 2.21 (m, 2H), 1.02 (d, J ¼ 6.8 Hz, 3H), 0.69 (d, J ¼ 6.6 Hz, 3H); 13
C
142 ꢁC; 1H NMR (500 MHz, DMSO-d6): major isomer: d 10.52 (s, NMR (125 MHz, CDCl3): d 179.3, 138.9, 133.7, 128.2, 123.4,
1H), 7.43 (d, J ¼ 7.4 Hz, 1H), 7.22 (t, J ¼ 8.3 Hz, 1H), 7.01 (t, J ¼ 123.1, 109.4, 73.2, 56.4, 48.4, 41.0, 40.8, 30.4, 20.9, 19.7; HRMS
7.5 Hz, 1H), 6.84 (d, J ¼ 7.7 Hz, 1H), 3.89–3.75 (m, 2H), 3.69–3.62 (ESI) calcd for C15H21N2O3S m/z 309.1267 [M + H]+, found
(m, 1H), 3.08 (s, 3H), 2.24–2.16 (m, 1H), 2.10 (dd, J ¼ 6.4, 2.1 Hz, 309.1231.
1H), 1.07 (d, J ¼ 6.4 Hz, 3H); minor isomer: d 10.58 (s, 1H), 7.33
20-Isopropyl-10-tosylspiro[indoline-3,30-pyrrolidin]-2-one
(d, J ¼ 7.4 Hz, 1H), 7.22 (t, J ¼ 8.3 Hz, 1H), 7.01 (t, J ¼ 7.5 Hz, (6q). White solid (86 mg, 85% yield), mp: 216–219 ꢁC; 1H NMR
1H), 6.88 (d, J ¼ 7.7 Hz, 1H), 3.77–3.70 (m, 2H), 3.60 (dd, J ¼ 7.0, (500 MHz, CDCl3): d 7.63 (d, J ¼ 8.3 Hz, 2H), 7.55 (d, J ¼ 7.7 Hz,
3.1 Hz, 1H), 3.01 (s, 3H), 2.14 (dd, J ¼ 12.9, 6.1 Hz, 1H), 2.07 (dd, 1H), 7.37 (t, J ¼ 7.6 Hz, 1H), 7.29 (d, J ¼ 6.8 Hz, 1H), 7.22 (t, J ¼
J ¼ 6.3, 1.9 Hz, 1H), 1.02 (d, J ¼ 6.5 Hz, 3H); 13C NMR (125 MHz, 7.4 Hz, 1H), 7.07 (d, J ¼ 8.4 Hz, 2H), 4.72 (d, J ¼ 11.3 Hz, 1H),
CDCl3): d 180.3, 178.9, 140.7, 130.0, 129.0, 128.7, 125.5, 123.2, 3.95 (dd, J ¼ 15.4, 4.2 Hz, 1H), 3.73 (ddd, J ¼ 15.1, 12.8, 2.1 Hz,
123.0, 122.8, 110.3, 110.0, 63.1, 61.4, 57.8, 57.4, 47.3, 47.2, 40.3, 1H), 2.85–2.75 (m, 1H), 2.31 (d, J ¼ 14.7 Hz, 1H), 2.20 (s, 3H),
35.1, 34.8, 34.3, 20.0, 15.8; HRMS (ESI) calcd for C13H17N2O3S m/ 1.25–1.16 (m, 1H), 1.15 (d, J ¼ 6.6 Hz, 3H), 1.02 (d, J ¼ 6.6 Hz,
z 281.0954 [M + H]+, found 281.0968.
3H); 13C NMR (125 MHz, CDCl3): d 174.6, 151.3, 143.4, 139.7,
20-Methyl-10-tosylspiro[indoline-3,30-pyrrolidin]-2-one (6m). 137.3, 130.0, 129.4, 127.3, 127.0, 122.1, 121.3, 67.6, 65.7, 39.0,
White solid (92 mg, 89% yield, dr 1 : 4), mp: 195–199 ꢁC; 1H 37.7, 28.0, 21.2, 20.2, 19.3; HRMS (ESI) calcd for C21H25N2O3S m/
NMR (400 MHz, CDCl3): major isomer: d 8.58 (s, 1H), 7.84 (d, J ¼ z 385.1580 [M + H]+, found 385.1587.
8.2 Hz, 2H), 7.40 (d, J ¼ 8.0 Hz, 2H), 7.19 (t, J ¼ 7.7 Hz, 1H), 6.95–
20-Phenyl-10-tosylspiro[indoline-3,30-pyrrolidin]-2-one (6r).
6.85 (m, 2H), 6.57 (d, J ¼ 7.4 Hz, 1H), 4.08–4.00 (m, 1H), 3.93– This reaction was performed at 0 C. White solid (52 mg, 45%
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yield, dr 1 : 7.9), mp: 169–173 ꢁC; 1H NMR (400 MHz, DMSO-d6): 13C NMR (100 MHz, CDCl3): d 180.9, 180.3, 174.3, 174.0, 140.6,
major isomer: d 10.43 (s, 1H), 7.72 (d, J ¼ 8.0 Hz, 2H), 7.47 (d, J ¼ 140.3, 139.2, 137.4, 132.8, 132.5, 129.5, 128.7, 128.4, 128.2,
7.9 Hz, 2H), 7.23–6.92 (m, 6H), 6.66 (dd, J ¼ 14.1, 7.4 Hz, 2H), 128.0, 127.9, 127.2, 126.3, 125.0, 122.8, 122.5, 109.8, 109.6, 67.0,
6.55 (d, J ¼ 7.4 Hz, 1H), 4.81 (s, 1H), 4.00–3.92 (m, 1H), 3.90–3.82 64.5, 64.2, 60.4, 57.9, 57.3, 55.8, 51.8, 51.5, 50.9, 38.6, 38.2, 14.5,
(m, 1H), 2.45 (s, 3H), 2.07–1.96 (m, 1H), 1.92–1.80 (m, 1H); 14.3; HRMS (ESI) calcd for C21H23N2O3 m/z 351.1703 [M + H]+,
minor isomer: d 10.55 (s, 1H), 7.84 (d, J ¼ 8.0 Hz, 2H), 7.57 (d, J found 351.1711.
¼ 7.9 Hz, 2H), 7.23–6.92 (m, 6H), 6.66 (dd, J ¼ 14.1, 7.4 Hz, 2H),
Methyl 10-benzyl-20-methyl-2-oxospiro[indoline-3,30-pyrroli-
6.55 (d, J ¼ 7.4 Hz, 1H), 4.83 (s, 1H), 4.28–4.00 (m, 2H), 2.45 (s, dine]-50-carboxylate (6v). Pale yellow oil (87 mg, 94% yield, dr
3H), 2.19–2.08 (m, 2H); 13C NMR (100 MHz, DMSO-d6): d 177.8, 1 : 8.3); H NMR (400 MHz, CDCl3): d 8.28 (s, 1H), 7.51 (d, J ¼
1
143.5, 141.3, 138.7, 133.7, 129.7, 128.4, 128.1, 127.7, 127.4, 7.4 Hz, 1H), 7.44 (d, J ¼ 7.3 Hz, 2H), 7.37–7.31 (m, 1H), 7.29 (d, J ¼
127.2, 126.8, 125.0, 121.0, 109.2, 69.1, 58.5, 47.9, 34.5, 21.1; 7.6 Hz, 1H), 7.25–7.16 (m, 2H), 7.06 (td, J ¼ 7.6, 0.9 Hz, 1H), 6.87 (d,
HRMS (ESI) calcd for C24H23N2O3S m/z 419.1424 [M + H]+, found J ¼ 7.7 Hz, 1H), 4.06–3.98 (m, 2H), 3.78–3.70 (m, 2H), 3.69 (s, 3H),
419.1428.
N-(2-(2-Benzoyl-1H-indol-3-yl)ethyl)-4-
2.76 (dd, J ¼ 13.7, 9.3 Hz, 1H), 2.17 (dd, J ¼ 13.7, 3.6 Hz, 1H), 1.01
(d, J ¼ 6.5 Hz, 3H); 13C NMR (100 MHz, CDCl3): d 180.8, 175.0,
methylbenzenesulfonamide (6r0).24c Yellow oil (110 mg, 50% 140.6, 139.3, 133.3, 128.5, 128.3, 128.1, 127.0, 124.2, 122.9, 109.3,
yield); 1H NMR (400 MHz, DMSO-d6): d 11.45 (s, 1H), 7.75–7.56 66.1, 62.3, 57.3, 51.8, 51.5, 38.3, 12.9; HRMS (ESI) calcd for
(m, 9H), 7.43 (d, J ¼ 8.1 Hz, 1H), 7.33–7.25 (m, 3H), 7.09 (t, J ¼ C21H23N2O3 m/z 351.1703 [M + H]+, found 351.1711.
7.2 Hz, 1H), 2.96 (s, 4H), 2.34 (s, 3H); 13C NMR (100 MHz,
Methyl
10-benzyl-20-ethyl-2-oxospiro[indoline-3,30-pyrroli-
DMSO-d6): d 188.4, 142.4, 138.7, 137.6, 136.7, 132.3, 131.4, dine]-50-carboxylate (6w). Yellow oil (96 mg, 89% yield, dr
129.5, 128.9, 128.6, 127.2, 126.4, 125.3, 120.3, 120.0, 119.9, 4.5 : 1); 1H NMR (400 MHz, CDCl3): d 8.58 and 8.41 (s, 1H), 7.48–
112.8, 43.3, 25.3, 20.9; HRMS (ESI) calcd for C24H23N2O3S m/z 7.42 (m, 3H), 7.31 (t, J ¼ 7.4 Hz, 2H), 7.26–7.15 (m, 2H), 7.05 (td,
419.1424 [M + H]+, found 419.1432.
J ¼ 7.6, 0.8 Hz, 1H), 6.86 (d, J ¼ 7.6 Hz, 1H), 4.09 (d, J ¼ 14.2 Hz,
Methyl
2-oxo-10-tosylspiro[indoline-3,30-pyrrolidine]-50- 1H), 3.99 (dd, J ¼ 9.1, 3.3 Hz, 1H), 3.88 (d, J ¼ 14.2 Hz, 1H), 3.68
carboxylate (6s). Light brown oil (87 mg, 95% yield, dr 1 : 1.9); (s, 3H), 2.75 (dd, J ¼ 13.6, 9.1 Hz, 1H), 2.16 (dd, J ¼ 13.6, 3.3 Hz,
1H NMR (400 MHz, CDCl3): d 8.62 and 8.40 (s, 1H), 7.81 (d, J ¼ 1H), 1.78–1.65 (m, 1H), 1.63–1.50 (m, 2H), 0.59 (t, J ¼ 7.5 Hz,
8.0 Hz, 2H), 7.53 (d, J ¼ 7.4 Hz, 0.5H), 7.34 (d, J ¼ 8.0 Hz, 2H), 3H); 13C NMR (100 MHz, CDCl3): d 181.3, 175.1, 140.4, 139.8,
7.26–7.18 (m, 1H), 7.06 (t, J ¼ 7.6 Hz, 0.5H), 6.92–6.85 (m, 1.5H), 134.4, 128.4, 128.3, 127.9, 126.9, 124.0, 122.9, 109.4, 73.0, 63.1,
6.77 (d, J ¼ 7.5 Hz, 0.5H), 4.79 (t, J ¼ 8.1 Hz, 0.66H), 4.57 (t, J ¼ 57.1, 52.0, 51.5, 40.0, 21.2, 11.1; HRMS (ESI) calcd for
7.9 Hz, 0.34H), 3.83 and 3.72 (s, 3H), 3.82–3.57 (m, 2H), 2.68–
2.60 (m, 1H), 2.46 and 2.43 (s, 3H), 2.42–2.34 (m, 1H); 13C NMR
C
22H25N2O3 m/z 365.1860 [M + H]+, found 365.1866.
Methyl
10-benzyl-20-ethyl-2-oxospiro[indoline-3,30-pyrroli-
(100 MHz, CDCl3): d 179.4, 177.6, 172.0, 171.5, 144.2, 144.0, dine]-50-carboxylate (6x). Pale yellow oil (98 mg, 91% yield, dr
140.2, 139.8, 136.1, 133.9, 132.3, 130.5, 129.8, 129.8, 129.0, 1 : 6.2); 1H NMR (400 MHz, CDCl3): d 8.74 (d, J ¼ 48.5 Hz, 1H),
128.8, 128.2, 127.6, 124.1, 123.4, 123.2, 123.0, 110.3, 110.1, 60.9, 7.80 (d, J ¼ 7.4 Hz, 1H), 7.39 (d, J ¼ 7.2 Hz, 2H), 7.32 (t, J ¼
60.5, 56.8, 56.5, 53.0, 52.8, 52.7, 52.1, 41.5, 40.6, 21.7, 21.7; 10.1 Hz, 2H), 7.27–7.19 (m, 2H), 7.12–7.06 (m, 1H), 6.91 (d, J ¼
HRMS (ESI) calcd for C20H21N2O5S m/z 401.1166 [M + H]+, found 7.7 Hz, 1H), 4.01 (d, J ¼ 14.3 Hz, 1H), 3.80 (d, J ¼ 14.3 Hz, 1H),
401.1172.
3.69 (dd, J ¼ 10.2, 6.3 Hz, 1H), 3.47 (s, 3H), 3.11 (dd, J ¼ 10.1,
10-(tert-Butyl) 50-methyl 2-oxospiro[indoline-3,30-pyrroli- 3.7 Hz, 1H), 2.66 (dd, J ¼ 13.3, 10.5 Hz, 1H), 2.09 (dd, J ¼ 13.3,
dine]-10,50-dicarboxylate (6t).23b Colorless oil (98 mg, 93% yield, 6.0 Hz, 1H), 1.69–1.54 (m, 2H), 0.51 (t, J ¼ 7.5 Hz, 3H); 13C NMR
1
dr 1 : 3); H NMR (400 MHz, CDCl3) Major isomer: d 8.71 (m, (100 MHz, CDCl3): d 181.6, 174.0, 140.3, 138.0, 132.3, 129.3,
1H), 7.35–7.21 (m, 1H), 7.16–7.02 (m, 2H), 6.99–6.88 (m, 1H), 128.2, 127.9, 127.1, 126.5, 122.8, 109.7, 73.0, 64.8, 56.6, 56.1,
4.88–4.71 (m, 1H), 3.94–3.68 (m, 2H), 3.79 (s, 3H), 2.74–2.48 (m, 51.8, 40.1, 23.3, 9.8; HRMS (ESI) calcd for C22H25N2O3 m/z
2H), 1.46 (s, 9H); minor isomer: d 7.63 (m, 1H), 7.35–7.21 (m, 365.1860 [M + H]+, found 365.1866.
1H), 7.16–7.02 (m, 2H), 6.99–6.88 (m, 1H), 4.66–4.59 (m, 1H),
1-Methyl-4,9-dihydro-3H-pyrido[3,4-b]indole (8a).13e Yellow
1
ꢁ
3.94–3.68 (m, 2H), 3.80 (s, 3H), 2.45–2.26 (m, 2H), 1.48 (s, 9H); solid (22 mg, 35% yield), mp: 181–184 C; H NMR (400 MHz,
13C NMR (100 MHz, CDCl3): d 178.0, 173.4, 172.5, 172.2, 154.4, CDCl3): d 9.38 (s, 1H), 7.51 (d, J ¼ 8.0 Hz, 1H), 7.37 (d, J ¼ 8.3 Hz,
153.5, 140.8, 139.8, 133.3, 133.1, 129.4, 129.0, 128.8, 123.4, 1H), 7.20 (t, J ¼ 7.5 Hz, 1H), 7.07 (t, J ¼ 7.5 Hz, 1H), 3.77 (t, J ¼
123.2, 123.1, 122.5, 110.4, 110.1, 81.0, 80.7, 59.1, 58.7, 55.4, 54.9, 8.3 Hz, 2H), 2.82 (t, J ¼ 8.4 Hz, 2H), 2.38 (s, 3H); 13C NMR (100
54.5, 52.4, 52.3, 41.0, 40.6, 40.3, 39.7, 28.4, 28.3; HRMS (ESI) MHz, CDCl3): d 159.2, 137.5, 128.6, 125.1, 125.0, 120.4, 120.1,
calcd for C18H23N2O5 m/z 347.1601 [M + H]+, found 347.1613.
117.4, 112.2, 47.0, 21.4, 19.2; HRMS (ESI) calcd for C12H13N2 m/z
Methyl 10-benzyl-20-methyl-2-oxospiro[indoline-3,30-pyrroli- 185.1073 [M + H]+, found 185.1077.
dine]-50-carboxylate (6u). Pale yellow oil (93 mg, 95% yield, dr
1-Phenyl-4,9-dihydro-3H-pyrido[3,4-b]indole (8b).13e Pale
1.7 : 1); 1H NMR (400 MHz, CDCl3): d 8.96–8.73 (m, 1H), 7.80 (d, yellow solid (28 mg, 30%), mp: 219–223 ꢁC; 1H NMR (400 MHz,
J ¼ 7.4 Hz, 1H), 7.41–7.29 (m, 4H), 7.28–7.18 (m, 2H), 7.14–7.03 CDCl3): d 8.35 (br s, 1H), 7.85–7.60 (m, 3H), 7.57–7.45 (m, 3H),
(m, 1H), 6.95–6.88 (m, 1H), 4.03–3.80 (m, 1H), 3.79–3.60 (m, 7.43–7.15 (m, 3H), 4.06 (s, 2H), 3.01 (s, 2H); 13C NMR (100 MHz,
3H), 3.50 (s, 2H), 3.17 (dd, J ¼ 12.1, 6.0 Hz, 1H), 2.76–2.66 (m, CDCl3): d 159.4, 137.7, 136.6, 130.0, 128.9, 127.9, 127.9, 125.6,
0.6H), 2.51–2.45 (m, 0.4H), 2.30 (dd, J ¼ 13.3, 9.2 Hz, 0.4H), 2.11 124.6, 120.5, 120.1, 117.9, 112.1, 48.9, 19.3; HRMS (ESI) calcd for
(dd, J ¼ 13.4, 6.0 Hz, 0.6H), 0.75 and 0.73 (d, J ¼ 10.3 Hz, 3H);
C
17H15N2 m/z 247.1230 [M + H]+, found 247.1226.
© 2021 The Author(s). Published by the Royal Society of Chemistry
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12 T. Mukaiyama, K. Ogata, I. Sato and Y. Hayashi, Chem.–Eur.
J., 2014, 20, 13583–13588.
Conflicts of interest
13 (a) H. Zinnes and J. Shavel Jr, J. Org. Chem., 1966, 1966, 1765–
1771; (b) A. C. Peterson and J. M. Cook, Tetrahedron Lett.,
There are no conicts to declare.
¨
1994, 35, 2651–2654; (c) C. Pellegrini, C. Strassler,
Acknowledgements
M. Weber and H. J. Borschberg, Tetrahedron: Asymmetry,
1994, 5, 1979–1992; (d) J. Shavel and H. Zinnes, J. Am.
Chem. Soc., 1962, 84, 1320–1321; (e) M. Sathish,
F. M. Nachtigall and L. S. Santos, RSC Adv., 2020, 10,
38672–38677; (f) J. Xu, L. Liang, H. Zheng, Y. R. Chi and
R. Tong, Nat. Commun., 2019, 10, 4754.
M. S. thank FONDECYT (Project #11200555) and Instituto de
´
´
´
Investigacion Interdisciplinaria, Vicerrectorıa Academica, Uni-
versidad de Talca, Talca, Chile for nancial support for this work. L.
S. S. and F. M. N. are grateful to FONDECYT (Project #1180084), and
A. P. S. is thankful to DoP, Ministry of Chemicals & Fertilizers, Govt.
of India, New Delhi, for the award of NIPER fellowship. NIPERH
Research Communication No. NIPER-H/2021/151.
14 (a) D. Bora, R. Tokala, S. E. John, B. Prasanth and
N. Shankaraiah, Org. Biomol. Chem., 2020, 18, 2307–2311;
(b) R. Tokala, D. Bora, S. Sana, F. M. Nachtigall,
L. S. Santos and N. Shankaraiah, J. Org. Chem., 2019, 84,
5504–5513; (c) P. Sharma, P. K. Niggula, N. H. Krishna,
D. Prasanna, B. Sridhar and N. Shankaraiah, Org. Chem.
Front., 2016, 3, 1503–1508; (d) S. Nekkanti, K. Veeramani,
P. K. Niggula and N. Shankaraiah, Green Chem., 2016, 18,
3439–3447.
References
1 (a) N. Ye, H. Chen, E. A. Wold, P. Y. Shi and J. Zhou, ACS
Infect. Dis., 2016, 2, 382–392; (b) B. Zhou, Y. Yang, J. Shi,
Z. Luo and Y. Li, J. Org. Chem., 2013, 78, 2897–2907; (c)
C. Li, C. Chan, A. C. Heimann and S. J. Danishefsky,
Angew. Chem., Int. Ed., 2007, 46, 1444–1447; (d) J. D. White, 15 K. Huthmacher and D. Most, Cyanuric Acid and Cyanuric
Y. Li and D. C. Ihle, J. Org. Chem., 2010, 75, 3569–3577.
Chloride Ullmann's Encyclopedia of Industrial Chemistry, 2000,
2 (a) G. J. Mei and F. Shi, Chem. Commun., 2018, 54, 6607–6621;
Wiley-VCH, Weinheim, DOI: 10.1002/14356007.a08191.
(b) M. Pelay-Gimeno, A. Glas, O. Koch and T. N. Grossmann, 16 A. Hu, A. Chen, B. Xie and N. Yu, Preparation of omeprazole
Angew. Chem., Int. Ed., 2015, 54, 8896–8927; (c) G. Bhaskar,
Y. Arun, C. Balachandran, C. Saikumar and P. T. Perumal,
Eur. J. Med. Chem., 2012, 51, 79–91.
intermediate 2-chloromethyl-3,5-dimethyl-4-methoxypyridine,
2019, CN 110317164.
17 S. Gaspa, M. Carraro, L. Pisano, A. Porcheddu and L. D. Luca,
Eur. J. Org. Chem., 2019, 2019, 3544–3552.
3 (a) A. Barakat, M. Shahidul Islam, H. Mansur Ghawas,
A. Mohammed Al-Majid, F. F. El-Senduny, F. A. Badria, 18 Y. Jing, C. G. Daniliuc and A. Studer, Org. Lett., 2014, 16,
Y. A. M. M. Elshaier and H. A. Ghabbour, RSC Adv., 2018, 4932–4935.
8, 14335–14346; (b) B. Yu, Y.-C. Zheng, X.-J. Shi, P.-P. Qi 19 K. L. Manasa, Y. Tangella, G. Ramu and B. N. Babu,
and H.-M. Liu, Anti-Cancer Agents Med. Chem., 2016, 16, ChemistrySelect, 2017, 2, 9162–9167.
1315–1324; (c) L. Chen, J. Xie, H. Song, Y. Liu, Y. Gu, 20 H. Veisi, Synthesis, 2010, 2631–2635.
L. Wang and Q. Wang, J. Agric. Food Chem., 2016, 64, 6508– 21 (a) J. Ye, Y. Lin, Q. Liu, D. Xu, F. Wu, B. Liu, Y. Gao and
6516; (d) K. R. Senwar, P. Sharma, T. S. Reddy,
M. K. Jeengar, V. L. Nayak, V. G. M. Naidu, A. Kamal and
N. Shankaraiah, Eur. J. Med. Chem., 2015, 102, 413–424.
4 Y.-T. Yang, J.-F. Zhu, G. C. Liao, H.-J. Xu and B. Yu, Curr. Med.
Chem., 2018, 25, 2233–2244.
H. Chen, Org. Lett., 2018, 20, 5457–5460; (b) J. Ye, J. Wu,
T. Lv, G. Wu, Y. Gao and H. Chen, Angew. Chem., Int. Ed.,
2017, 56, 14968–14972; (c) C. Yan, Y. Liu and Q. Wang,
RSC Adv., 2014, 4, 60075–60078.
22 (a) Y. Q. Huang, H. J. Song, Y. X. Liu and Q. M. Wang, Chem.–
Eur. J., 2018, 24, 2065–2069; (b) Y. Lin, J. Ye, W. Zhang, Y. Gao
and H. Chen, Adv. Synth. Catal., 2019, 361, 432–435.
5 M. A. El-Hashash and S. A. Rizk, J. Heterocycl. Chem., 2017,
54, 1776–1784.
6 R. S. Kumar, P. Antonisamy, A. I. Almansour, N. Arumugam, 23 (a) L. Shen, E. J. Park, T. P. Kondratyuk, D. Guendisch,
G. Periyasami, M. Altaf, H. R. Kim and K. B. Kwon, Eur. J.
Med. Chem., 2018, 152, 417–423.
7 L. M. Zhou, R. U. Qu and G. F. Yang, Expert Opin. Drug
Discovery, 2020, 15, 603–625.
8 M. G. Kulkarni, A. P. Dhondge, S. W. Chavhan, A. S. Borhade,
Y. B. Shaikh, D. R. Birhade, M. P. Desai and N. R. Dhatrak,
Beilstein J. Org. Chem., 2010, 6, 876–879.
9 H. Lee, S. H. Baek, J. H. Lee, C. Kim, J. H. Ko, S. G. Lee,
A. Chinnathambi, S. A. Alharbi, W. M. Yang, J. Y. Um,
G. Sethi and K. S. Ahn, Int. J. Mol. Sci., 2017, 18, 1095.
10 P. R. Sebahar, H. Osada, T. Usui and R. M. Williams,
Tetrahedron, 2002, 58, 6311–6322.
L. Marler, J. M. Pezzuto, A. D. Wright and D. Sun, Bioorg.
Med. Chem., 2011, 19, 6182–6195; (b) L. Chen, Y. Hao,
H. Song, Y. Liu, Y. Li, J. Zhang and Q. Wang, J. Agric. Food
Chem., 2020, 68, 10618–10625; (c) J. Dong, T. Z. Meng,
X. X. Shi, W. H. Zou and X. Lu, Tetrahedron: Asymmetry, 2013,
24, 883–893; (d) C. L. Hansen, J. W. Clausen, R. G. Ohm,
E. Ascic, S. T. Le Quement, D. Tanner and T. E. Nielsen, J.
Org. Chem., 2013, 78, 12545–12565; (e) P. D. Bailey and
S. P. Hollinshead, Heterocycles, 1987, 26, 389–399.
24 (a) S. Jaegli, J. Dufour, H. L. Wei, T. Piou, X. H. Duan,
J. P. Vors, L. Neuville and J. Zhu, Org. Lett., 2010, 12, 4498–
4501; (b) T. Oishi, M. Nagai, T. Onuma, H. Moriyama,
K. Tsutae, M. Ochiai and Y. Ban, Chem. Pharm. Bull., 1969,
17, 2306–2313; (c) H. Li, Z. Wang and L. Zu, RSC Adv.,
2015, 5, 60962–60965.
11 L. L. Chen, J. X. Song, J. H. Lu, Z. W. Yuan, L. F. Liu,
S. S. K. Durairajan and M. Li, J. Neuroimmune Pharmacol.,
2014, 9, 380–387.
16546 | RSC Adv., 2021, 11, 16537–16546
© 2021 The Author(s). Published by the Royal Society of Chemistry