Synthesis of new cyclazines and 4,5-diaryl-1 H -pyrrol-3(2 H)-one units in discoipyrroles from indolizinone-DMAD cycloadducts

Article abstract of DOI:10.1039/c9ob01655d

The reaction of indolizinones with dimethyl acetylenedicarboxylate gave direct access to 3′,8a-dihydrocyclopenta[hi]indolizin-8a-ol and 1H-pyrrol-3(2H)-one in good yields. The former skeleton is a precursor to cyclazines with nitrogen on the periphery, a hitherto un-accessed 10-π system. Their formation involves initial [4 + 2] or [8 + 2] modes of cycloadditions; the retro-Diels Alder reaction of the [4 + 2] cycloadduct leads to 1H-pyrrol-3(2H)-one, whereas [8 + 2] addition followed by π-reorganization leads to the azatricyle. Analysis of substituent effects on product distribution showed that electron donating groups on the C₃-aryl ring promote the formation of the azatricycle preponderantly. Treatment of one of these azatricycles (3c) with HBF₄ led to the formation of the corresponding 10e-aromatic species which was detected by NMR spectroscopy. In addition, formation of the 1H-pyrrol-3(2H)-one skeleton through the normal retro-Diels Alder pathway was employed in the total synthesis of Discoipyrrole C, which is a new lead against lung cancer.

Full text of DOI:10.1039/c9ob01655d

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Synthesis of new cyclazines and 4,5-diaryl-1H-
pyrrol-3(2H)-one units in discoipyrroles from
indolizinone-DMAD cycloadducts†
Cite this: Org. Biomol. Chem., 2019,
17, 8832
Jais Kurian and Muraleedharan Kannoth M.
*
The reaction of indolizinones with dimethyl acetylenedicarboxylate gave direct access to 3’,8a-dihydro-
cyclopenta[hi]indolizin-8a-ol and 1H-pyrrol-3(2H)-one in good yields. The former skeleton is a precursor
to cyclazines with nitrogen on the periphery, a hitherto un-accessed 10-π system. Their formation
involves initial [4 + 2] or [8 + 2] modes of cycloadditions; the retro-Diels Alder reaction of the [4 + 2]
cycloadduct leads to 1H-pyrrol-3(2H)-one, whereas [8 + 2] addition followed by π-reorganization leads to
the azatricyle. Analysis of substituent effects on product distribution showed that electron donating
groups on the C3-aryl ring promote the formation of the azatricycle preponderantly. Treatment of one of
these azatricycles (3c) with HBF4 led to the formation of the corresponding 10e-aromatic species which
was detected by NMR spectroscopy. In addition, formation of the 1H-pyrrol-3(2H)-one skeleton through
the normal retro-Diels Alder pathway was employed in the total synthesis of Discoipyrrole C, which is a
new lead against lung cancer.
Received 26th July 2019,
Accepted 18th September 2019
DOI: 10.1039/c9ob01655d
rsc.li/obc
discoipyrroles (IX) which themselves constitute an important
group of bioactive alkaloids. Here, the azatricycle VIII could
Introduction
In the realm of natural products, a large number of fused-ring act as a direct precursor to X mentioned above.
organic scaffolds with heteroatoms at one of the peripheral
Discoipyrroles A–D are produced by marine bacterium
positions, such as isodaphlongamine H and meloscine, are Bacillus hunanensis and are characterized by the presence of a
known (Fig. 1).1 Their intriguing structures and distinct bio- 1H-pyrrol-3(2H)-one core. They have interesting biological
logical activities continue to attract the attention of synthetic activities, especially against the discoidin domain receptor-2
and medicinal chemists.2 Whilst most of these compounds signaling pathway. These alkaloids are also known to exhibit
possess a saturated carbon framework,3 there exists an analo- selective cytotoxicity towards DDR2 mutant lung cancer cell
gous series, mostly of synthetic origin, which has continuous lines with IC50 values in the nano-molar range.7
conjugation along the periphery.4 Most familiar examples are
Our interest in the indolizinone class of compounds started
cyclazines, which have served as models to assess aromaticity after observing their structural resemblance to discoipyrroles.
and anti-aromaticity in extended π-systems with 4n/4n + 2 elec- Initially, the indolizinone skeleton was accessed through the
trons.5 One of the simplest ways to access this skeleton is route reported by Kim et al.,8 but we soon realized that it is
through addition of alkynes to indolizines in the presence of a not chemically stable and could undergo peroxidation and the
noble metal catalyst.6 But its analog with nitrogen on the retro-Diels Alder reaction in the presence of oxygen and light.
periphery, exemplified by X (Scheme 1), has remained elusive Analysis of the reaction mixture after exposure to UV light
thus far. During our synthetic studies involving the indolizi- (352 nm) and oxygen using methanol as the solvent resulted in
none class of compounds, we have revealed a novel reaction the isolation of 2a in 40% yield (Scheme 2) which was charac-
pathway that gives access not only to the highly functionalized terized by various spectro-analytical techniques (ESI†). We
azatricycle VIII (Scheme 1), but also to the core structure in could secure crystals of 2a suitable for X-ray analysis from
its MeOH : CHCl3 (1 : 1) solution and the diffraction data
unambiguously confirmed this structure (Fig. 2). Apart from
Department of Chemistry, Indian Institute of Technology Madras,
its striking resemblance to Discoipyrrole C, isolation of 2a
suggested involvement of 3-azacyclopentadienone as the inter-
Chennai – 600 036, Tamil Nadu, India. E-mail: mkm@iitm.ac.in
†Electronic supplementary information (ESI) available: NMR spectra. X-ray data
mediate and its interception by the nucleophilic solvent. The
of compounds 2a, 3a and 17. CCDC 1907329, 1908547 and 1908557. For ESI and
crystallographic data in CIF or other electronic format see DOI: 10.1039/
use of ethanol or isopropanol as the solvent led to the corres-
ponding adducts in supportive of this mechanism (Scheme 2).
c9ob01655d
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Fig. 1 (a) Natural products with azatricyclic units (I–III); (b) discoipyrroles A, B and C (IV–VI).
late as the major product. Though 3-azacyclopentadienone is
the expected side product in this process, this was never iso-
lated due to low stability. In another report, Hemming et al.
have discussed the generation of this species in situ from aza-
bicyclo [3.2.0] hept-2-en-4-ones and have used it for the syn-
thesis of substituted pyridines.10 However, no other systematic
study seems to have taken place to expand its application in
chemical synthesis. Since our experiments showed the feasi-
bility of trapping the 3-azacyclopentadienone intermediate
using nucleophilic solvents (Scheme 2), additional efforts were
put to expand its synthetic utility.
Results and discussion
Scheme 1 Different cycloaddition modes and products from the reac-
tion of indolizinone with DMAD.
Considering the poor solubility of indolizinone 1a in methanol
as well as its instability under UV light, the cycloaddition reac-
tion was repeated with DMAD as the dienophile (1.5 equiv.) in
a 1 : 1 benzene–methanol mixture at 80 °C (entry 2, Table 1).
Table 1 Reaction optimization
Scheme 2 Formation of 1H-pyrrol-3(2H)-one from indolizinone under
photochemical conditions.
Yield
(%)
Yield
(%)
Variation from standard
conditionsa
Reaction
time
Entry
2ab
3ab
1
2
3
4
5
6
7
8
None
12 h
24 h
24 h
12 h
48 h
20 h
12 h
12 h
12 h
18 h
48 h
4 h
40
39
38
—
10
38
20
20
10
35
5
57
56
57
25
30
57
50
56
55
57
56
48
PhH : MeOH (1 : 1)
PhMe : MeOH (1 : 1)
PhMe
MeOH
Fig. 2 X-ray structures of 2a and 3a.
PhMe : MeOH (5 : 1)
PhMe : MeOH (20 : 1)
100 °C
120 °C
70 °C
50 °C
PhMe : H2O (3 : 1)
9
Literature analysis indicated that the indolizinone diena-
mine skeleton (VII, Scheme 1) has the propensity for [4 + 2]
cycloaddition with dienophiles like maleic anhydride, methyl
acrylate, etc. to give [2.2.2] azabicycles.9 Although these
adducts are generally stable, the product from DMAD under-
goes the retro-Diels Alder reaction leading to dimethyl phtha-
10
11
12
—
a Reaction conditions: 1a (0.3 mmol), DMAD (0.45 mmol),
PhMe : MeOH (10 : 1; 3.3 mL), sealed tube, 80 °C, nitrogen atmosphere.
b Isolated yield.
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Interestingly, this condition also afforded the expected product which is evident from entries 3p–s. The outcome from 1u also
2a in 39% yield at the end of 24 h. Even more exciting was the shows that the electron withdrawing substituent at the para
isolation of another less polar product in 56% yield which position of the C3 ring leads to a reduction in the yield of 3u
showed a melting point of 150–152 °C (Rf = 0.53; 40% EtOAc/ but favours the formation of 2u.
hexane). HRMS analysis gave a peak at m/z = 442.1652, corres-
Overall, the formation of products 2 and 3 seems to involve
ponding to the molecular formula C27H24NO5 ([M + H]+). 1H two modes of cycloadditions as shown in Scheme 4. The
NMR signals corresponding to methyl esters at 3.93 and former product arises through the retro-Diels Alder reaction of
3.42 ppm, an exchangeable proton at 4.28 ppm, and three ole- the [4 + 2] cycloadduct, followed by trapping the 3-azacyclopen-
finic protons at 5.92, 6.68 and 6.84 ppm indicated that the tadienone intermediate with methanol (Path a, Scheme 4). At
product likely arises through a different pathway. This was also the same time, a [8 + 2] mode of cycloaddition between the
evident from the 13C NMR spectrum which had no carbonyl dipolar species 1′ and DMAD could lead to 1″ that on
carbon but instead had a new peak at 68.7 ppm corresponding π-reorganization and proton shift forms the azatricycle 3
to tertC–OH. These, along with COSY, HMBC and HSQC results, (Path b). The syn orientation of methyl and hydroxyl groups in
supported the presence of an azatricyclic structure 3a shown 3 suggests that cycloaddition occurs from the less hindered
in Table 1. By systematic screening of a number of solvent side as shown in Scheme 4. The fact that the electron donating
systems, we succeeded in obtaining crystals suitable for X-ray effect from the C3-aryl ring favours the formation of 3 tends to
analysis from MeOH–CH2Cl2 (1 : 1) and the diffraction data suggest better stabilization of the dipolar structure 1′ and its
unambiguously confirmed the proposed structure for 3a reaction with DMAD.
(Fig. 2).
Since π-reorganization and proton shift from C8–H are
In the literature, there are many examples of transform- essential for the formation of 3, we carried out an additional
ations involving cycloaddition products, as in bicyclo[2.2.2] experiment with the C8–methyl derivative 1v (Scheme 5).
octenones,11 2-acylfuran-diethyl azodicarboxylate cyclo- Interestingly, this resulted in the formation of only 2a in 51%
adducts,12 tetrahydropyranopyrrolone,13 2-pyrone cyclo- yield without any trace of 3a.
adducts,14 and 3H-indole styrylcyanines.15 Also, the Lewis acid-
Structurally, 3 can be considered as an immediate precursor
catalysed sequential tandem transformations of substituted for cyclazine analog X (Scheme 1) that was never synthesized
[4 + 2] cycloadducts16 and functionalized diazanorbornenes before. As mentioned in the introduction, such systems
provide easy access to diverse ring systems.17 In the present are very important to understand the ring current effects in
context, the reaction leads to a relatively strained tricyclic cyclic conjugated organic frameworks with (4n + 2)π electrons.
system with conjugation along the periphery with a central The ESI mass spectra of all tricyclic products (3a–u) prepared
quaternary carbon which is remarkable.
here had [M + H − H2O]+ as the base peak (ESI†). This indi-
Comparable yields of 2a and 3a were obtained on carrying cated that the conjugated 10e species – cyclopenta [hi]indoli-
out the reaction in the toluene–MeOH mixture (1 : 1, entry 3). zin-3-ium ion is formed under the condition of ionization. The
The use of toluene alone (entry 4) resulted in only 3a in lower ESI mass spectrum of azatricycle 3c with the characteristic
yield (25%) without any trace of 2a suggesting that the 3-azacy- [M + H − H2O]+ peak is presented in Fig. 3 as a representative
clopentadienone intermediate is intrinsically unstable. By example.
varying the relative amounts of toluene and methanol (entries
In order to detect this 10e species, we performed a NMR
1–7), a 10 : 1 proportion of these solvents turned out to be experiment after treating a solution of 3c in CDCl3 with
optimal that gave 2a and 3a in 40% and 57% respectively in HBF4·Et2O, at room temperature. Remarkably, the peak corres-
12 h (entry 1). An increase or decrease of reaction temperature ponding to the central CH3 group underwent an upfield shift
in fact did not give any improvement in yields (entries 8–11). (from 0.81 ppm to −0.20 ppm) due to the shielding effect on
Nevertheless, the overall atom economy is high considering these protons. Additionally, the olefinic ring protons, which
the total yields of both the products.
were originally at 6.0, 6.72 and 6.78 ppm, moved downfield to
The substrate scope of this method was then investigated 8.34, 8.60, and 9.46 ppm respectively as they are situated in
by varying the nature of C2 and C3-aryl rings. As evident from the deshielding zone of the 10π electron system. There was no
Scheme 3, the presence of electron donating or withdrawing significant change in these peak positions on lowering the
groups on the C2-aryl unit (1a–c: R1 = H, p-OMe, p-NO2; R2 = temperature to −50 °C. Relevant regions from the 1H NMR
H) did not affect the relative yields of 2a–c and 3a–c. Although spectra of these compounds are presented in Fig. 4 (complete
introduction of the –OMe group at the meta position of the spectra are given in ESI-Fig. 154†).
aryl ring at C3 carbon did not affect yield distribution (2d–f
An equally important outcome of the present work is the
and 3d–f), a prominent electronic effect was observed on isolation of 1H-pyrrol-3(2H)-one derivatives (2a–u) which rep-
keeping electron donating substituents at the para position resent the core structural unit in discoipyrroles A–D. A litera-
(2g–o and 3g–o). This resulted in higher yields of the tricyclic ture search showed that Yan et al. in 2017 have reported the
product 3 with a concomitant reduction in the yield of 2. total synthesis of discoipyrrole C via the MoOPH-mediated oxi-
There was a clear unfavourable effect from the ortho-substitu- dation of N-unsubstituted pyrroles with an overall yield of
ent in the C2-aryl ring irrespective of the electronic contri- ∼10% in 9 steps.18 Since we could readily access this skeleton
bution from the C3 unit in the formation of the azatricycle through the retro-Diels Alder reaction of the indolizinone
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Scheme 3 Substrate scope: product distribution as a function of substituents on 2- and 3-aryl units in indolizinones.
Scheme 4 Plausible mechanism.
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Scheme 5 Reaction of 8-methyl substituted indolizinone with DMAD.
cycloadduct, the methodology was extended for the synthesis
of Discoipyrrole C (Scheme 6). The key intermediate 11
required for the synthesis of indolizinone precursor 14 was
prepared in a straight-forward manner starting from isovaleric
acid 6 through Weinreb amide formation (7), pyridine ortho
acylation (9) and alkyne addition steps. The TBS group that
was selected to survive the n-BuLi condition was then depro-
tected and then acetylated by treatment with AcCl in the pres-
ence of triethylamine, which afforded 12 in 95% yield (over 2
steps). Subjecting this product to tandem amino-palladation,
reductive elimination and 1,2-alkyl shift gave the required
indolizinone 14 in 80% yield.8 Treatment of 14 with DMAD in
the toluene : methanol mixture (10 : 1) at 80 °C gave the tri-
cyclic compound 15 along with the expected 1H-pyrrol-3(2H)-
one derivative 16 in 55% and 40% yield, respectively. This on
deacetylation, followed by treatment with TFA in a 4 : 1
CH2Cl2 : H2O mixture, gave the target Discoipyrrole C (17) in
88% yield. In comparison with the earlier synthesis,18 the
overall yield of discoipyrrole C through this route is 13%. Its
Fig. 3 ESI MS of azatricyclic product 3c.
Fig. 4 (a) Selected region from the 1H NMR spectrum of the 10e aromatic species generated from 3c by treatment with HBF4·Et2O (solvent CDCl3
at −50 °C). (b) Corresponding peaks from 3c.
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Scheme 6 Total synthesis of discoipyrrole C.
triplet, dd = doublet of doublets, bs = broad singlet, appt =
apparent triplet. 13C NMR data are reported with the solvent
peak (CDCl3 = 77.16, CD3OD = 49.00) as the internal standard.
High-resolution mass spectra (HRMS) were recorded on a
Waters Q-TOF micro™ spectrometer with a lock spray source.
Infrared spectra were recorded using a Nicolet 6700 FT-IR
spectrometer.
Fig. 5 X-ray structure of discoipyrrole C (17).
General procedure for the synthesis of polysubstituted
indolizinone (1a–d)
structure was confirmed by various spectro analytical methods
such as NMR, HRMS, etc. and matched well with the reported
data (ESI†). Its crystals suitable for X-ray analysis were grown
from the EtOAc : acetone (1 : 1) mixture and the diffraction
data (Fig. 5) unambiguously confirmed the structure as the
same as that reported for Discoipyrrole C (17).
A solution containing a mixture of 4-aryl-2-(pyridin-2-yl)but-3-
yn-2-ols (0.6 mmol) and iodobenzene (0.9 mmol) in aceto-
nitrile was admixed with Pd(PPh3)4 (5 mol%) and K2CO3
(1.5 mmol) under a nitrogen atmosphere. After heating this
mixture for 13 h at 90 °C under stirring, it was concentrated
under reduced pressure and the residue obtained was re-
dissolved in ethyl acetate (50 mL) and washed with water (2 ×
50 mL). The organic layer was separated and dried over anhy-
drous Na2SO4 and the solvent was evaporated under reduced
pressure. The crude product was purified by chromatography
on a silica gel column using an ethyl acetate/hexane system.
8a-Methyl-2,3-diphenylindolizin-1(8aH)-one (1a). 91% yield
Experimental section
General
Various starting materials used such as 2-acetyl pyridine, phe-
nylacetylenes and iodobenzenes were accessed through (163 mg). Orange solid, m.p. 160–162 °C. Rf = 0.53 (20%
Spectrochem or Sigma Aldrich, and were used as received EtOAc/hexane). 1H NMR (400 MHz, CDCl3): δ 7.46–7.50 (m,
unless otherwise indicated. The solvents benzene (PhH), tetra- 2H, ArH), 7.42–7.44 (m, 1H, ArH), 7.34–7.35 (m, 2H, ArH),
hydrofuran (THF) and toluene (PhMe) were dried over sodium/ 7.12–7.17 (m, 4H, ArH), 7.06–7.10 (m, 1H, ArH), 6.35 (d, J =
benzophenone and distilled before use whereas dichloro- 7.23 Hz, 1H, CH), 6.01 (d, J = 8.99 Hz, 1H, CH), 5.93–5.96 (m,
methane (DCM) and acetonitrile (MeCN) were dried over 1H, CH), 5.32–5.35 (m, 1H, CH), 1.51 (s, 3H, CH3) ppm. 13C
CaH2. Methanol was dried by refluxing over magnesium/ NMR (100 MHz, CDCl3): δ 200.9, 167.8, 131.5, 130.5, 129.3,
iodine. Column chromatography purification was carried out 129.2 (2C), 129.0 (2C), 128.8 (2C), 128.0 (2C), 126.0, 124.0,
on 100–200 mesh silica gel using an EtOAc–hexane solvent 123.2, 122.4, 110.1, 108.5, 67.6, 25.6. IR (KBr): 3051, 2958,
system in a gradient mode. Thin layer chromatography was 2922, 1673, 1607, 1542, 1414, 1372, 1322, 1169, 1076, 933, 752,
performed using 0.25 mm thick silica gel plates from Merck 894, 518 cm−1. HRMS (ESI) m/z: [M + H]+ calcd for C21H18NO
and the plates were analysed using either 254 nm UV light or 300.1388; found 300.1396.
ninhydrin staining.
2-(4-Methoxyphenyl)-8a-methyl-3-phenylindolizin-1(8aH)-one
1H NMR and 13C NMR spectra were recorded on a Bruker (1b). 80% yield (158 mg). Red-coloured gum. Rf = 0.40
1
Avance 400 MHz NMR spectrometer and the chemical shifts (20% EtOAc/hexane). H NMR (400 MHz, CDCl3): δ 7.27 (d, J =
are reported in parts per million (ppm) relative to tetramethyl- 8.61 Hz, 2H, ArH), 7.13–7.19 (m, 4H, ArH), 7.07–7.10 (m, 1H,
silane, with J values in Hertz. The splitting patterns in 1H ArH), 6.94 (d, J = 8.52 Hz, 2H, ArH), 6.42 (d, J = 7.21 Hz, 1H,
NMR are reported as follows: s = singlet, d = doublet, t = CH), 6.00 (d, J = 9.19 Hz, 1H, CH), 5.92–5.96 (m, 1H, CH),
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5.32–5.35 (m, 1H, CH), 3.84 (s, 3H, OCH3), 1.49 (s, 3H, CH3) J = 7.36 Hz, 1H, CH), 6.06 (d, J = 9.36 Hz, 1H, CH), 5.97–6.01
ppm. 13C NMR (100 MHz, CDCl3): δ 200.8, 167.9, 161.2, 131.4, (m, 1H, CH), 5.43–5.46 (m, 1H, CH), 3.78 (s, 3H, OCH3), 1.52
130.6 (2C), 129.0 (2C), 128.0 (2C), 125.9, 124.0, 123.4, 122.3, (s, 3H, CH3) ppm. 13C NMR (100 MHz, CDCl3): δ 199.9, 169.1,
121.1, 114.6 (2C), 108.4, 67.6, 55.5, 25.7 ppm. IR (KBr): 3055, 160.5, 145.2, 139.1, 131.1, 129.9, 128.3 (2C), 124.6, 123.3 (2C),
2927, 2839, 1669, 1545, 1422, 1369, 1324, 1287, 1248, 1246, 122.7, 122.4, 120.6, 116.5, 114.1, 110.3, 107.7, 68.3, 55.6,
1174, 1033, 913, 830, 766, 705, 527, 451 cm−1. HRMS (ESI) m/z: 25.7 ppm. IR (KBr): 3061, 2926, 2842, 1677, 1590, 1536, 1509,
[M + H]+ calcd for C22H20NO2 330.1494; found 330.1490.
1426, 1386, 1333, 1254, 1145, 1072, 1044, 984, 944, 903, 851,
8a-Methyl-2-(4-nitrophenyl)-3-phenylindolizin-1(8aH)-one (1c). 782, 696, 523 cm−1. HRMS (ESI) m/z: [M + H]+ calcd for
97% yield (200 mg). Orange solid, m.p. 54–56 °C. Rf = 0.36 C22H19N2O4 375.1345; found 375.1348.
1
(20% EtOAc/hexane). H NMR (400 MHz, CDCl3): δ 7.98 (d, J =
3-(4-Methoxyphenyl)-8a-methyl-2-phenylindolizin-1(8aH)-one
8.81 Hz, 2H, ArH), 7.51–7.56 (m, 3H, ArH), 7.35 (bs, 2H, ArH), (1g). 86% yield (170 mg). Orange solid, m.p. 128–130 °C. Rf =
7.30 (d, J = 8.73 Hz, 2H, ArH), 6.36 (d, J = 7.13 Hz, 1H, CH), 0.40 (20% EtOAc/hexane). 1H NMR (400 MHz, CDCl3): δ 7.27
6.06 (d, J = 9.26 Hz, 1H, CH), 5.97–6.01 (m, 1H, CH), 5.43–5.46 (d, J = 8.61 Hz, 2H, ArH), 7.13–7.19 (m, 4H, ArH), 7.07–7.10 (m,
(m, 1H, CH), 1.52 (s, 3H, CH3) ppm. 13C NMR (100 MHz, 1H, ArH), 6.94 (d, J = 8.52 Hz, 2H, ArH), 6.42 (d, J = 7.21 Hz,
CDCl3): δ 199.9, 169.2, 145.3, 139.1, 131.2, 129.8 (2C), 128.7, 1H, CH), 6.00 (d, J = 9.19 Hz, 1H, CH), 5.95 (dd, J = 5.28,
128.6 (2C), 128.4 (2C), 124.6, 123.3 (2C), 122.6, 122.4, 110.3, 9.19 Hz, 1H, CH), 5.32–5.35 (m, 1H, CH), 3.84 (s, 3H, OCH3),
107.9, 68.3, 25.6 ppm. IR (KBr): 3061, 2923, 1675, 1591, 1513, 1.49 (s, 3H, CH3) ppm. 13C NMR (100 MHz, CDCl3): δ 220.8,
1426, 1331, 1177, 1109, 1071, 942, 851, 755, 697, 521 cm−1
HRMS (ESI) m/z: [M + H]+ calcd for C21H17N2O3 345.1239; 124.0, 123.4, 122.3, 121.1, 114.6 (2C), 108.4, 67.6, 55.5,
found 345.1253. 25.66 ppm. IR (KBr): 3052, 2923, 2850, 1669, 1607, 1545, 1509,
.
167.9, 161.2, 131.4 (2C), 130.6 (2C), 129.0 (2C), 128.0, 125.9,
3-(3-Methoxyphenyl)-8a-methyl-2-phenylindolizin-1(8aH)-one 1487, 1416, 1374, 1324, 1300, 1255, 1179, 1076, 1029, 829, 739,
(1d). 90% yield (178 mg). Orange solid, m.p. 62–64 °C. Rf = 704, 594, 520 cm−1. HRMS (ESI) m/z: [M + H]+ calcd for
0.46 (20% EtOAc/hexane). 1H NMR (400 MHz, CDCl3): C22H20NO2 330.1494; found 330.1490.
δ 7.34–7.38 (m, 1H, ArH), 7.15–7.16 (m, 4H, ArH), 7.06–7.11
2,3-Bis(4-methoxyphenyl)-8a-methylindolizin-1(8aH)-one (1h).
(m, 1H, ArH), 6.99 (d, J = 8.20 Hz, 1H, ArH), 6.92 (d, J = 7.38 78% yield (168 mg). Orange solid, m.p. 62–64 °C. Rf = 0.36
1
Hz, 1H, ArH), 6.83 (s, 1H, ArH), 6.38 (d, J = 7.29 Hz, 1H, CH), (20% EtOAc/hexane). H NMR (400 MHz, CDCl3): δ 7.27 (d, J =
6.01 (d, J = 9.18 Hz, 1H, CH), 5.93–5.97 (m, 1H, CH), 5.32–5.35 8.11 Hz, 2H, ArH), 7.07 (d, J = 8.48 Hz, 2H, ArH), 6.94 (d, J =
(m, 1H, CH), 3.72 (s, 3H, OCH3), 1.50 (s, 3H, CH3) ppm. 8.14 Hz, 2H, ArH), 6.73 (d, J = 8.14 Hz, 2H, ArH), 6.40 (d, J =
13C NMR (100 MHz, CDCl3): δ 200.9, 167.6, 160.0, 131.0, 130.5, 7.16 Hz, 1H, CH), 5.98 (d, J = 9.24 Hz, 1H, CH), 5.91–5.95 (m,
130.4, 128.8 (2C), 128.0 (2C), 126.0, 123.9, 123.3, 122.4, 121.1, 1H, CH), 5.29–5.33 (m, 1H, CH), 3.84 (s, 3H, OCH3), 3.74 (s,
116.2, 114.2, 110.0, 108.5, 67.6, 55.5, 25.6 ppm. IR (KBr): 3055, 3H, OCH3), 1.48 (s, 3H, CH3) ppm. 13C NMR (100 MHz,
2922, 2862, 1675, 1578, 1543, 1457, 1423, 1373, 1323, 1282, CDCl3): δ 201.1, 167.1, 161.1, 157.9, 130.6 (2C), 130.1 (2C),
1253, 1190, 1147, 1079, 1042, 851, 779, 696, 520 cm−1. HRMS 123.9, 123.5 (2C), 122.4, 121.3, 114.6 (2C), 113.6 (2C), 109.6,
(ESI) m/z: [M + H]+ calcd for C22H20NO2 330.1494; found 108.0, 67.4, 55.5, 55.3, 25.6 ppm. IR (KBr): 2957, 2922, 2847,
330.1491.
1665, 1609, 1546, 1509, 1456, 1374, 1322, 1295, 1251, 1177,
3-(3-Methoxyphenyl)-2-(4-methoxyphenyl)-8a-methylindolizin- 1030, 827 cm−1. HRMS (ESI) m/z: [M + H]+ calcd for C23H22NO3
1(8aH)-one (1e). 84% yield (181 mg). Orange solid, 360.1600; found 360.1597.
m.p. 106–108 °C. Rf = 0.36 (20% EtOAc/hexane). 1H NMR
3-(4-Methoxyphenyl)-8a-methyl-2-(4-nitrophenyl)indolizin-
(400 MHz, CDCl3): δ 7.34–7.38 (m, 1H, ArH), 7.08 (d, J = 1(8aH)-one (1i). 93% yield (209 mg). Orange solid,
8.84 Hz, 2H, ArH), 6.99 (d, J = 7.45 Hz, 1H, ArH), 6.92 (d, J = m.p. 58–60 °C. Rf = 0.30 (20% EtOAc/hexane). 1H NMR
7.45 Hz, 1H, ArH), 6.83 (s, 1H, ArH), 6.71 (d, J = 8.38 Hz, 2H, (400 MHz, CDCl3): δ 8.00 (d, J = 8.48 Hz, 2H, ArH), 7.33 (d, J =
ArH), 6.36 (d, J = 7.45 Hz, 1H, CH), 5.98 (d, J = 9.05 Hz, 1H, 8.52 Hz, 2H, ArH), 7.27 (d, J = 8.08 Hz, 2H, ArH), 7.01 (d, J =
CH), 5.92–5.95 (m, 1H, CH), 5.30–5.33 (m, 1H, CH), 3.74 (s, 8.52 Hz, 2H, ArH), 6.44 (d, J = 7.44 Hz, 1H, CH), 6.05 (d, J =
3H, OCH3), 3.73 (s, 3H, OCH3), 1.49 (s, 3H, CH3) ppm. 9.31 Hz, 1H, CH), 5.96–6.00 (m, 1H, CH), 5.43–5.46 (m, 1H,
13C NMR (100 MHz, CDCl3): δ 201.2, 166.8, 160.1, 158.0, 130.7, CH), 3.88 (s, 3H, OCH3), 1.51 (s, 3H, CH3) ppm. 13C NMR
130.4, 129.9 (2C), 123.7, 123.4, 123.3, 122.4, 121.2, 116.1, (100 MHz, CDCl3): δ 199.8, 169.4, 161.8, 145.2, 139.4, 130.3
114.3, 113.6 (2C), 109.8, 108.1, 67.5, 55.5, 55.3, 25.6 ppm. IR (2C), 128.6 (2C), 124.7, 123.3, 122.9 (2C), 122.3, 120.3, 115.1
(KBr): 2926, 2863, 1670, 1544, 1459, 1371, 1322, 1285, 1248, (2C), 110.2, 107.6, 68.3, 55.6, 25.7 ppm. IR (KBr): 2956, 2922,
1175, 1038, 785, 524 cm−1. HRMS (ESI) m/z: [M + H]+ calcd for 1674, 1600, 1541, 1510, 1476, 1249, 1334, 1255, 1180, 1113,
C23H22NO3 360.1600; found 360.1599.
3-(3-Methoxyphenyl)-8a-methyl-2-(4-nitrophenyl)indolizin-1 calcd for C22H19N2O4 375.1345; found 375.1355.
(8aH)-one (1f). 92% yield (207 mg). Orange solid, 8a-Methyl-3-(4-(methylthio)phenyl)-2-phenylindolizin-1(8aH)-
1073, 1028, 824, 738, 701, 519 cm−1. HRMS (ESI) m/z: [M + H]+
m.p. 90–92 °C. Rf = 0.30 (20% EtOAc/hexane). 1H NMR one (1j). 85% yield (176 mg). Orange solid, m.p. 108–110 °C.
(400 MHz, CDCl3): δ 8.00 (d, J = 8.79 Hz, 2H, ArH), 7.41–7.45 Rf = 0.43 (20% EtOAc/hexane). 1H NMR (400 MHz, CDCl3):
(m, 1H, ArH), 7.34 (d, J = 9.14 Hz, 2H, ArH), 7.07 (dd, J = 2.05, δ 7.23–7.28 (m, 4H, ArH), 7.14–7.19 (m, 3H, ArH), 7.08–7.12
8.27 Hz, 1H, ArH), 6.92 (s, 1H, ArH), 6.83 (s, 1H, ArH), 6.39 (d, (m, 2H, ArH), 6.39 (d, J = 7.19 Hz, 1H, CH), 6.00 (d, J = 9.21 Hz,
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1H, CH), 5.92–5.97 (m, 1H, CH), 5.32–5.35 (m, 1H, CH), 2.50 5.91–5.95 (m, 1H, CH), 5.30–5.33 (m, 1H, CH), 3.92 (s, 3H,
(s, 3H, SCH3), 1.49 (s, 3H, CH3) ppm. 13C NMR (100 MHz, OCH3), 3.73 (s, 3H, OCH3), 3.72 (s, 3H, OCH3), 1.49 (s, 3H,
CDCl3): δ 200.8, 167.4, 142.3, 131.1, 129.4 (2C), 128.9 (2C), CH3) ppm. 13C NMR (100 MHz, CDCl3): δ 201.1, 167.0, 157.9,
128.1 (2C), 126.0 (3C), 125.1, 124.0, 123.3, 122.3, 110.0, 108.5, 150.7, 149.4, 130.1 (2C), 123.9, 123.6 (2C), 122.4, 122.0, 121.5,
67.7, 25.6, 15.0 ppm. IR (KBr): 3052, 2923, 1673, 1600, 1545, 113.6 (2C), 112.1, 111.4, 109.6, 108.1, 67.5, 56.2, 56.1, 55.3,
1486, 1416, 1372, 1325, 1191, 1084, 947, 816, 741, 703, 584, 25.6 ppm. IR (KBr): 3054, 2936, 2838, 1668, 1607, 1510, 1458,
511, 479 cm−1. HRMS (ESI) m/z: [M + H]+ calcd for C22H20NOS 1422, 1381, 1321, 1250, 1181, 1144, 1028, 936, 823, 725, 645,
346.1266; found 346.1271.
2-(4-Methoxyphenyl)-8a-methyl-3-(4-(methylthio)phenyl)indo- 390.1705; found 390.1710.
527 cm−1. HRMS (ESI) m/z: [M + H]+ calcd for C24H24NO4
lizin-1(8aH)-one (1k). 79% yield (178 mg). Orange gum. Rf =
3-(3,4-Dimethoxyphenyl)-8a-methyl-2-(4-nitrophenyl)indolizin-
0.33 (20% EtOAc/hexane). 1H NMR (400 MHz, CDCl3): δ 7.26 1(8aH)-one (1o). 90% yield (218 mg). Orange solid, m.p.
(bs, 4H, ArH), 7.06 (d, J = 8.82 Hz, 2H, ArH), 6.73 (d, J = 8.82 68–70 °C. Rf = 0.13 (20% EtOAc/hexane). 1H NMR (400 MHz,
Hz, 2H, ArH), 6.38 (d, J = 7.24 Hz, 1H, CH), 5.98 (d, J = 9.25 Hz, CDCl3): δ 8.01 (d, J = 8.63 Hz, 2H, ArH), 7.35 (d, J = 9.24 Hz,
1H, CH), 5.92–5.95 (m, 1H, CH), 5.30–5.33 (m, 1H, CH), 3.74 2H, ArH), 6.92–6.98 (m, 2H, ArH), 6.76 (s, 1H, ArH), 6.47 (d, J =
(s, 3H, OCH3), 2.51 (s, 3H, SCH3), 1.48 (s, 3H, CH3) ppm. 7.39 Hz, 1H, CH), 6.06 (d, J = 9.24 Hz, 1H, CH), 5.97–6.00 (m,
13C NMR (100 MHz, CDCl3): δ 201.1, 166.6, 157.9, 142.1, 130.1 1H, CH), 5.43–5.47 (m, 1H, CH), 3.95 (s, 3H, OCH3), 3.77 (s,
(2C), 129.4 (2C), 126.0 (2C), 125.3, 123.8, 123.33, 123.25, 122.4, 3H, OCH3), 1.52 (s, 3H, CH3) ppm. 13C NMR (100 MHz,
113.7 (2C), 109.8, 108.2, 67.5, 55.3, 25.6, 15.6 ppm. IR (KBr): CDCl3): δ 199.8, 169.3, 151.3, 149.9, 145.1, 139.4, 128.5 (2C),
3049, 2924, 2844, 1670, 1601, 1545, 1425, 1370, 1323, 1293, 124.6, 123.3 (2C), 122.9, 122.3, 121.8, 120.5, 111.8, 111.2,
1246, 1177, 1084, 1031, 1031, 946, 812, 775, 716, 674, 110.2, 107.5, 68.3, 56.3, 56.2, 25.7 ppm. IR (KBr): 3061, 2929,
529 cm−1. HRMS (ESI) m/z: [M + H]+ calcd for C23H22NO2S 2839, 1673, 1594, 1537, 1511, 1479, 1426, 1385, 1332, 1259,
376.1371; found 376.1379.
8a-Methyl-3-(4-(methylthio)phenyl)-2-(4-nitrophenyl)indolizin- m/z: [M + H]+ calcd for C23H21N2O5 405.1450; found 405.1444.
1(8aH)-one (1l). 87% yield (204 mg). Orange solid, (2,4-Dimethoxyphenyl)-8a-methyl-3-phenylindolizin-1(8aH)-
1189, 1143, 1071, 1026, 853, 815, 696, 517 cm−1. HRMS (ESI)
m.p. 122–124 °C. Rf = 0.30 (20% EtOAc/hexane). 1H NMR one (1p). 70% yield (150 mg). Orange gum. Rf = 0.20 (20%
(400 MHz, CDCl3): δ 8.01 (d, J = 8.66 Hz, 2H, ArH), 7.31–7.34 EtOAc/hexane). 1H NMR (400 MHz, CDCl3): δ 7.35 (d, J =
(m, 4H, ArH), 7.24 (d, J = 7.80 Hz, 2H, ArH), 6.41 (d, J = 4.88 Hz, 3H, ArH), 7.28–7.29 (m, 2H, ArH), 7.08 (d, J = 8.25 Hz,
7.48 Hz, 1H, CH), 6.06 (d, J = 9.14 Hz, 1H, CH), 5.97–6.00 (m, 1H, 1H, ArH), 6.47 (d, J = 7.57 Hz, 1H, ArH), 6.43 (dd, J = 1.97, 8.52
CH), 5.43–5.46 (m, 1H, CH), 2.53 (s, 3H, SCH3), 1.51 (s, 3H, CH3) Hz, 1H, CH), 6.25 (s, 1H, ArH), 5.98 (d, J = 8.96 Hz, 1H, CH),
ppm. 13C NMR (100 MHz, CDCl3): δ 199.8, 168.9, 145.3, 143.6, 5.92–5.95 (m, 1H, CH), 5.29–5.32 (m, 1H, CH), 3.75 (s, 3H,
139.1, 129.0 (2C), 128.6 (2C), 126.3 (2C), 124.6, 124.3, 123.4 (2C), OCH3), 3.26 (s, 3H, OCH3), 1.51 (s, 3H, CH3) ppm. 13C NMR
122.7, 122.3, 110.3, 107.8, 68.3, 25.7, 15.0 ppm. IR (KBr): 2930, (100 MHz, CDCl3): δ 201.2, 168.2, 160.2, 158.0, 132.2, 130.9,
2852, 1672, 1603, 1544, 1432, 1376, 1324, 1298, 1252, 1171, 1086, 129.9, 129.4, 128.5, 128.3, 127.2, 123.7, 123.6, 122.3, 120.4,
1040, 1039, 814, 740, 588 cm−1. HRMS (ESI) m/z: [M + H]+ calcd 112.5, 107.7, 104.4, 99.0, 67.4, 55.4, 54.8, 25.5 ppm. IR (KBr):
for C22H19N2O3S 391.1116; found 391.1109.
2929, 2838, 1672, 1618, 1550, 1489, 1458, 1423, 1384, 1316,
3-(3,4-Dimethoxyphenyl)-8a-methyl-2-phenylindolizin-1(8aH)- 1260, 1202, 1154, 1038, 785, 706, 530 cm−1. HRMS (ESI) m/z:
one (1m). 83% yield (179 mg). Orange solid, m.p. 56–58 °C. [M + H]+ calcd for C23H22NO3 360.1600; found 360.1596.
Rf = 0.30 (20% EtOAc/hexane). 1H NMR (400 MHz, CDCl3):
2-(2,4-Dimethoxyphenyl)-3-(3-methoxyphenyl)-8a-methyl-
δ 7.13–7.19 (m, 4H, ArH), 7.07–7.10 (m, 1H, ArH), 6.96 (d, J = indolizin-1(8aH)-one (1q). 77% yield (180 mg). Orange solid,
8.57 Hz, 1H, ArH), 6.92 (d, J = 8.27 Hz, 1H, ArH), 6.73 (s, 1H, m.p. 98–100 °C. Rf = 0.16 (20% EtOAc/hexane). 1H NMR
ArH), 6.47 (d, J = 7.12 Hz, 1H, CH), 6.00 (d, J = 9.23 Hz, 1H, (400 MHz, CDCl3): δ 7.25–7.29 (m, 1H, ArH), 7.05 (d, J =
CH), 5.93–5.96 (m, 1H, CH), 5.33–5.36 (m, 1H, CH), 3.92 (s, 8.70 Hz, 1H, ArH), 6.88–6.91 (m, 2H, ArH), 6.78 (s, 1H, ArH), 6.50
3H, OCH3), 3.69 (s, 3H, OCH3), 1.50 (s, 3H, CH3) ppm. 13C (d, J = 7.07 Hz, 1H, ArH), 6.43 (dd, J = 8.38, 1.99 Hz, 1H, CH),
NMR (100 MHz, CDCl3): δ 200.8, 167.8, 150.7, 149.4, 131.3, 6.28 (bs, 1H, ArH), 5.98 (d, J = 9.16 Hz, 1H, CH), 5.91–5.95 (m,
129.0 (2C), 128.0, (2C), 126.0, 124.0, 123.5, 122.3, 122.0, 121.3, 1H, CH), 5.30–5.33 (m, 1H, CH), 3.75 (s, 3H, OCH3), 3.67 (s, 3H,
112.1, 111.4, 109.9, 108.4, 67.7, 56.0, 25.7 ppm. IR (KBr): 3056, OCH3), 3.33 (s, 3H, OCH3), 1.51 (s, 3H, CH3) ppm. 13C NMR
2930, 2839, 1669, 1602, 1543, 1512, 1489, 1421, 1384, 1322, (100 MHz, CDCl3): δ 201.3, 168.1, 160.2, 159.5, 158.2, 132.2,
1256, 1188, 1143, 1076, 1026, 814, 737, 695, 616, 519 cm−1
HRMS (ESI) m/z: [M + H]+ calcd for C23H22NO3 360.1600; 104.5, 99.1, 67.4, 55.5, 55.4, 55.0, 25.5 ppm. IR (KBr): 2927, 2841,
.
131.5, 129.6, 123.7, 123.7, 122.3, 120.6, 115.9, 113.5, 112.6, 107.7,
found 360.1608.
1669, 1612, 1551, 1499, 1460, 1426, 1379, 1314, 1256, 1207, 1154,
3-(3,4-Dimethoxyphenyl)-2-(4-methoxyphenyl)-8a-methyl- 1038, 779, 706, 521 cm−1. HRMS (ESI) m/z: [M + H]+ calcd for
indolizin-1(8aH)-one (1n). 76% yield (178 mg). Orange solid, C24H24NO4 390.1705; found 390.1701.
m.p. 52–54 °C. Rf = 0.16 (20% EtOAc/hexane). 1H NMR
2-(2,4-Dimethoxyphenyl)-3-(4-methoxyphenyl)-8a-methyl-
(400 MHz, CDCl3): δ 7.07 (d, J = 7.85 Hz, 2H, ArH), 6.90–6.96 indolizin-1(8aH)-one (1r). 67% yield (157 mg). Brown gum. Rf =
(m, 2H, ArH), 6.74 (d, J = 6.06 Hz, 2H, ArH), 6.71 (s, 1H, ArH), 0.13 (20% EtOAc/hexane). 1H NMR (400 MHz, CDCl3): δ 7.21
6.44 (d, J = 7.13 Hz, 1H, CH), 5.98 (d, J = 9.12 Hz, 1H, CH), (d, J = 8.60 Hz, 2H, ArH), 7.04 (d, J = 8.34 Hz, 1H, ArH), 6.85 (d,
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J = 8.60 Hz, 2H, ArH), 6.50 (d, J = 7.21 Hz, 1H, ArH), 6.43 (dd, J = 5.63 Hz, 1H, CH), 5.27–5.30 (m, 1H, CH), 2.13 (s, 3H, CH3),
J = 8.44, 1.76 Hz, 1H, CH), 6.29 (bs, 1H, ArH), 5.97 (d, J = 9.22 1.61 (s, 3H, CH3) ppm. 13C NMR (100 MHz, CDCl3): δ 199.1,
Hz, 1H, CH), 5.91–5.94 (m, 1H, CH), 5.29–5.32 (m, 1H, CH), 166.8, 135.2, 131.2, 130.3, 129.5, 129.1 (2C), 129.0 (2C), 128.9
3.79 (s, 3H, OCH3), 3.76 (s, 3H, OCH3), 3.34 (s, 3H, OCH3), (2C), 128.0 (2C), 125.9, 120.8, 119.1, 110.5, 109.0, 69.5, 24.2,
1.49 (s, 3H, CH3) ppm. 13C NMR (100 MHz, CDCl3): δ 201.1, 18.1 ppm. IR (KBr): 3057, 2972, 2922, 1668, 1603, 1551, 1416,
168.2, 160.8, 160.1, 158.2, 132.3, 130.5, 129.9 (2C), 123.79, 1338, 1178, 1103, 1069, 1026, 939, 740, 694, 548 cm−1. HRMS
123.75, 122.2, 113.9 (2C), 112.8, 112.7, 107.6, 104.5, 99.1, 67.3, (ESI) m/z: [M + H]+ calcd for C22H20NO 314.1545; found
55.4 (2C), 55.1, 25.5 ppm. IR (KBr): 2932, 2840, 1663, 1608, 314.1539.
1552, 1500, 1549, 1417, 1297, 1254, 1206, 1165, 1120, 1033,
General procedure for the synthesis of 2a–u and 3a–u
937, 813, 729, 586, 524 cm−1. HRMS (ESI) m/z: [M + H]+ calcd
for C24H24NO4 390.1705; found 390.1697.
A solution containing a mixture of indolizinone 1 (0.3 mmol)
2-(2,4-Dimethoxyphenyl)-3-(3,4-dimethoxyphenyl)-8a-methyl- and dimethyl acetylene dicarboxylate (0.45 mmol) in
a
indolizin-1(8aH)-one (1s). 60% yield (151 mg). Brown gum. toluene–methanol mixture (10 : 1; 3.0 mL : 0.3 mL) was taken
Rf = 0.06 (20% EtOAc/hexane). 1H NMR (400 MHz, CDCl3): in a sealed tube under a nitrogen atmosphere and was heated
δ 7.01 (d, J = 8.17 Hz, 1H, ArH), 6.92 (d, J = 8.17 Hz, 1H, ArH), at 80 °C for 12 h under stirring. After cooling to room tempera-
6.84 (d, J = 8.17 Hz, 1H, ArH), 6.73 (s, 1H, ArH), 6.57 (d, J = ture, the mixture was concentrated under reduced pressure
6.91 Hz, 1H, ArH), 6.43 (dd, J = 1.89, 8.44 Hz, 1H, CH), 6.30 and the crude residue was purified by silica gel chromato-
(bs, 1H, ArH), 5.98 (d, J = 9.28 Hz, 1H, CH), 5.91–5.95 (m, 1H, graphy using the EtOAc–hexane solvent system to obtain the
CH), 5.31–5.34 (m, 1H, CH), 3.88 (s, 3H, OCH3), 3.75 (s, 3H, products 2 and 3. The yields and spectral data of these com-
OCH3), 3.66 (s, 3H, OCH3), 3.38 (s, 3H, OCH3), 1.51 (s, 3H, pounds are presented below.
CH3) ppm. 13C NMR (100 MHz, CDCl3): δ 201.1, 168.1, 160.3,
2-Methoxy-2-methyl-4,5-diphenyl-1H-pyrrol-3(2H)-one (2a).
158.4, 150.3, 148.8, 132.4, 123.9, 123.8, 122.5, 122.2, 121.4, 40% yield (34 mg). Yellow solid, m.p. 138–140 °C. Rf = 0.50
1
113.0, 111.7, 110.8, 107.7, 107.6, 104.6, 99.1, 67.4, 56.0 (2C), (60% EtOAc/hexane). H NMR (400 MHz, CDCl3): δ 7.53 (d, J =
55.5, 55.2, 25.5 ppm. IR (KBr): 2931, 2838, 1655, 1605, 1605, 7.53 Hz, 2H, ArH), 7.48 (d, J = 6.93 Hz, 1H, ArH), 7.36–7.40 (m,
1548, 1520, 1464, 1304, 1262, 1240, 1208, 1141, 1025, 823, 764, 2H, ArH), 7.23–7.25 (m, 4H, ArH), 7.17–7.20 (m, 1H, ArH), 5.16
734, 698, 616, 525 cm−1. HRMS (ESI) m/z: [M + H]+ calcd for (s, 1H, NH), 3.26 (s, 3H, OCH3), 1.60 (s, 3H, CH3) ppm.
C25H26NO5 420.1811; found 420.1818.
13C NMR (100 MHz, CDCl3): δ 199.1, 171.1, 131.9, 131.4, 131.0,
3-(4-Fluorophenyl)-8a-methyl-2-(4-nitrophenyl)indolizin-1(8aH)- 129.3 (2C), 129.0 (2C), 128.4 (2C), 128.3 (2C), 126.6, 112.3,
one (1t). 94% yield (204 mg). Orange solid, m.p. 90–92 °C. Rf = 89.8, 51.7, 23.3 ppm. IR (KBr): 3255, 2926, 2850, 1778, 1658,
0.33 (20% EtOAc/hexane). 1H NMR (400 MHz, CDCl3): δ 8.00 1598, 1546, 1449, 1147, 1054, 910, 697, 598 cm−1. HRMS (ESI)
(d, J = 8.74 Hz, 2H, ArH), 7.34–7.37 (m, 2H, ArH), 7.29 (d, J = m/z: [M + H]+ calcd for C18H18NO2 280.1338; found 280.1349.
8.86 Hz, 2H, ArH), 7.20–7.24 (m, 2H, ArH), 6.35 (d, J = 7.29 Hz,
Dimethyl
8a-hydroxy-3′-methyl-1,2-diphenyl-3′,8a-dihydro-
1H, CH), 6.06 (d, J = 9.32 Hz, 1H, CH), 5.97–6.01 (m, 1H, CH), cyclopenta[hi]indolizine-7,8-dicarboxylate (3a). 57% yield
5.45–5.48 (m, 1H, CH), 1.51 (s, 3H, CH3) ppm. 13C NMR (75 mg). Orange solid, m.p. 150–152 °C. Rf = 0.53 (40% EtOAc/
1
(100 MHz, CDCl3): δ 199.8, 168.1, 165.4, 162.9, 145.4, 138.8, hexane). H NMR (400 MHz, CDCl3): δ 7.23–7.24 (m, 3H, ArH),
131.0, 130.9, 128.6 (2C), 124.7, 123.4 (2C), 122.4 (2C), 117.3, 7.17–7.18 (m, 5H, ArH), 7.08–7.09 (m, 2H, ArH), 6.84 (d, J =
117.1, 110.6, 108.1, 68.4, 25.6 ppm. IR (KBr): 2922, 2922, 6.55 Hz, 1H, CH), 6.68 (d, J = 5.76 Hz, 1H, CH), 5.91 (appt, J =
1674, 1599, 1509, 1430, 1332, 827, 702 cm−1. HRMS (ESI) m/z: 5.96 Hz, 1H, CH), 4.28 (s, 1H, OH), 3.93 (s, 3H, OCH3), 3.42 (s,
[M + H]+ calcd for C21H16FN2O3 363.1145; found 363.1139.
3H, OCH3), 0.80 (s, 3H, CH3) ppm. 13C NMR (100 MHz,
8a-Methyl-2,3-bis(4-nitrophenyl)indolizin-1(8aH)-one (1u). CDCl3): δ 165.4, 165.3, 144.9, 143.8, 133.7, 132.1 (2C), 129.9,
95% yield (222 mg). Red gum. Rf = 0.20 (20% EtOAc/hexane). 129.4 (2C), 129.0, 128.9, 128.4 (3C), 127.6 (2C), 127.0, 126.3,
1H NMR (400 MHz, CDCl3): δ 8.38 (d, J = 8.29 Hz, 2H, ArH), 124.5, 119.8, 109.7, 91.9, 68.7, 52.7, 51.8, 13.3 ppm. IR (KBr):
8.01 (d, J = 8.88 Hz, 2H, ArH), 7.59 (d, J = 7.10 Hz, 2H, ArH), 3473, 2955, 2923, 1723, 1568, 1443, 1292, 1232, 737, 704 cm−1
.
7.25 (d, J = 8.29 Hz, 2H, ArH), 6.25 (d, J = 9.05 Hz, 1H, CH), HRMS (ESI) m/z: [M + H]+ calcd for C27H24NO5 442.1654;
6.08 (d, J = 9.36 Hz, 1H, CH), 5.99–6.03 (m, 1H, CH), 5.48–5.51 found 442.1652.
(m, 1H, CH), 1.54 (s, 3H, CH3) ppm. 13C NMR (100 MHz,
2-Methoxy-4-(4-methoxyphenyl)-2-methyl-5-phenyl-1H-pyrrol-
CDCl3): δ 199.6, 166.1, 149.4, 145.8, 137.9, 135.1, 130.1 (2C), 3(2H)-one (2b). 37% yield (34 mg). Yellow solid, m.p.
128.7 (2C), 125.0 (2C), 124.7, 123.6 (2C), 122.4, 121.9, 111.2, 150–152 °C. Rf = 0.50 (60% EtOAc/hexane). 1H NMR (400 MHz,
108.9, 68.6, 25.6 ppm. IR (KBr): 2924, 1673, 1605, 1507, 1459, CDCl3): δ 7.54 (d, J = 7.68 Hz, 2H, ArH), 7.46–7.50 (m, 1H,
1366, 1286, 1239, 1190, 1030, 840, 737 cm−1. HRMS (ESI) m/z: ArH), 7.37–7.40 (m, 2H, ArH), 7.17 (d, J = 8.41 Hz, 2H, ArH),
[M + H]+ calcd for C21H16N3O5 390.1090; found 390.1088.
6.80 (d, J = 8.41 Hz, 2H, ArH), 4.96 (s, 1H, NH), 3.78 (s, 3H,
8,8a-Dimethyl-2,3-diphenylindolizin-1(8aH)-one (1v). 88% OCH3), 3.26 (s, 3H, OCH3), 1.60 (s, 3H, CH3) ppm. 13C NMR
yield (165 mg). Orange solid, m.p. 134–136 °C. Rf = 0.63 (20% (100 MHz, CDCl3): δ 199.5, 170.3, 158.5, 131.8, 131.6, 130.5
EtOAc/hexane). 1H NMR (400 MHz, CDCl3): δ 7.42–7.47 (m, (2C), 129.0 (2C), 128.4 (2C), 123.3, 114.0 (2C), 112.3, 89.6, 55.4,
3H, ArH), 7.33–7.35 (m, 2H, ArH), 7.10–7.16 (m, 4H, ArH), 51.7, 23.4 ppm. IR (KBr): 3441, 2954, 2922, 2860, 1776, 1649,
7.05–7.08 (m, 1H, ArH), 6.23 (d, J = 7.04 Hz, 1H, CH), 5.61 (d, 1514, 1459, 1372, 1298, 1251, 1154, 1035, 818, 695, 524 cm−1
.
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HRMS (ESI) m/z: [M + H]+ calcd for C19H20NO3 310.1443; 608 cm−1. HRMS (ESI) m/z: [M + H]+ calcd for C19H20NO3
found 310.1450.
310.1443; found 310.1446.
Dimethyl 8a-hydroxy-1-(4-methoxyphenyl)-3′-methyl-2-phenyl-
Dimethyl-8a-hydroxy-2-(3-methoxyphenyl)-3′-methyl-1-phenyl-
3′,8a-dihydrocyclopenta[hi]indolizine-7,8-dicarboxylate
(3b). 3′,8a-dihydrocyclopenta[hi]indolizine-7,8-dicarboxylate
(3d).
58% yield (82 mg). Yellow solid, m.p. 152–154 °C. Rf = 0.45 56% yield (79 mg). Yellow solid, m.p. 134–136 °C. Rf = 0.45
(40% EtOAc/hexane). 1H NMR (400 MHz, CDCl3): δ 7.24–7.26 (40% EtOAc/hexane). 1H NMR (400 MHz, CDCl3): δ 7.14–7.17
(m, 3H, ArH), 7.16–7.18 (m, 2H, ArH), 6.99 (d, J = 8.63 Hz, 2H, (m, 4H, ArH), 7.09–7.10 (m, 2H, ArH), 6.89 (d, J = 6.14 Hz, 1H,
ArH), 6.83 (d, J = 6.41 Hz, 1H, CH), 6.70 (d, J = 8.63 Hz, 2H, ArH), 6.77–6.82 (m, 2H, ArH), 6.67 (d, J = 5.59 Hz, 1H, CH),
ArH), 6.67 (d, J = 5.77 Hz, 1H, CH), 5.90 (appt, J = 6.14 Hz, 1H, 6.65 (s, 1H, CH), 5.92 (appt, J = 5.97 Hz, 1H, CH), 4.27 (s, 1H,
CH), 4.28 (s, 1H, OH), 3.92 (s, 3H, OCH3), 3.73 (s, 3H, OCH3), OH), 3.93 (s, 3H, OCH3), 3.60 (s, 3H, OCH3), 3.42 (s, 3H,
3.47 (s, 3H, OCH3), 0.79 (s, 3H, CH3) ppm. 13C NMR OCH3), 0.80 (s, 3H, CH3) ppm. 13C NMR (100 MHz, CDCl3):
(100 MHz, CDCl3): δ 165.43, 165.39, 158.7, 144.9, 143.6, δ 165.4, 165.3, 159.4, 144.8, 143.8, 133.8, 132.1 (2C), 131.1,
133.2 (2C), 130.0, 129.5 (2C), 129.0, 128.8, 128.4 (2C), 126.2, 129.5, 129.1, 127.7 (2C), 127.0, 126.3, 124.4, 121.6, 119.8,
125.6, 124.5, 119.8, 113.2 (2C), 109.6, 109.2, 91.9, 68.6, 55.2, 115.1, 114.6, 109.7 (2C), 91.9, 68.8, 55.3, 52.7, 51.8, 13.3 ppm.
52.7, 51.9, 13.2 ppm. IR (KBr): 3482, 2924, 1729, 1605, 1507, IR (KBr): 3486, 3050, 2995, 2948, 2843, 1726, 1577, 1478, 1437,
1567, 1459, 1366, 1286, 1239, 1190, 1030, 737 cm−1. HRMS 1356, 1290, 1235, 1051, 1002, 906, 851, 734, 454 cm−1. HRMS
(ESI) m/z: [M + H]+ calcd for C28H26NO6 472.1760; found (ESI) m/z: [M + H]+ calcd for C28H26NO6 472.1760; found
472.1764.
472.1764.
2-Methoxy-2-methyl-4-(4-nitrophenyl)-5-phenyl-1H-pyrrol-3(2H)-
2-Methoxy-5-(3-methoxyphenyl)-4-(4-methoxyphenyl)-2-methyl-
one (2c). 41% yield (40 mg). Orange solid, m.p. 132–134 °C. 1H-pyrrol-3(2H)-one (2e). 35% yield (35 mg). Yellow solid,
Rf = 0.42 (60% EtOAc/hexane). 1H NMR (400 MHz, CDCl3): m.p. 94–96 °C. Rf = 0.50 (60% EtOAc/hexane). 1H NMR
δ 8.07 (d, J = 8.68 Hz, 2H, ArH), 7.57–7.60 (m, 1H, ArH), 7.52 (400 MHz, CDCl3): δ 7.28–7.32 (m, 1H, ArH), 7.18 (d, J =
(d, J = 7.47 Hz, 2H, ArH), 7.48 (d, J = 7.32 Hz, 2H, ArH), 7.43 (d, 8.56 Hz, 2H, ArH), 7.12 (d, J = 7.69 Hz, 1H, ArH), 7.00–7.03 (m,
J = 8.85 Hz, 2H, ArH), 5.42 (s, 1H, NH), 3.28 (s, 3H, OCH3), 2H, ArH), 6.81 (d, J = 8.78 Hz, 2H, ArH), 4.93 (s, 1H, NH), 3.78 (s,
1.63 (s, 3H, CH3) ppm. 13C NMR (100 MHz, CDCl3): δ197.8, 3H, OCH3), 3.69 (s, 3H, OCH3), 3.26 (s, 3H, OCH3), 1.60 (s, 3H,
172.7, 145.8, 138.4, 132.7, 130.7, 129.6 (2C), 129.0 (2C), 128.3 CH3) ppm. 13C NMR (100 MHz, CDCl3): δ 199.5, 170.1, 159.8,
(2C), 123.6 (2C), 109.5, 90.4, 52.0, 23.2 ppm. IR (KBr): 3448, 158.5, 132.8, 130.5 (2C), 130.2, 123.2, 120.6, 117.8, 113.9 (2C),
2964, 2925, 2859, 1776, 1659, 1518, 1440, 1374, 1280, 1248, 113.5, 112.5, 89.6, 55.4 (2C), 51.7, 23.5 ppm. IR (KBr): 3337, 2924,
1160, 1025, 816, 698, 540 cm−1. HRMS (ESI) m/z: [M + H]+ 2851, 1776, 1735, 1595, 1509, 1458, 1370, 1297, 1250, 1158, 1039,
calcd for C18H17N2O4 325.1188; found 325.1171.
918, 872, 787, 577, 527, 459 cm−1. HRMS (ESI) m/z: [M + H]+
Dimethyl
8a-hydroxy-3′-methyl-1-(4-nitrophenyl)-2-phenyl- calcd for C20H22NO4 340.1549; found 340.1553.
3′,8a-dihydrocyclopenta[hi]indolizine-7,8-dicarboxylate
(3c).
Dimethyl,8a-hydroxy-2-(3-methoxyphenyl)-1-(4-methoxyphenyl)-
57% yield (83 mg). Orange solid, m.p. 124–126 °C. Rf = 0.43 3′-methyl-3′,8a-dihydrocyclopenta[hi]indolizine-7,8-dicarboxylate
1
(40% EtOAc/hexane). H NMR (400 MHz, CDCl3): δ 7.99 (d, J = (3e). 59% yield (88 mg). Yellow solid, m.p. 102–104 °C. Rf =
8.59 Hz, 2H, ArH), 7.28–7.32 (m, 3H, ArH), 7.25–7.27 (m, 2H, 0.42 (40% EtOAc/hexane). 1H NMR (400 MHz, CDCl3): δ 7.16 (t,
ArH), 7.12 (d, J = 6.97 Hz, 2H, ArH), 6.78 (d, J = 6.50 Hz, 1H, J = 7.87 Hz, 1H, ArH), 7.00 (d, J = 8.60 Hz, 2H, ArH), 6.87 (d, J =
CH), 6.72 (d, J = 5.75 Hz, 1H, CH), 5.99 (appt, J = 6.15 Hz, 1H, 6.39 Hz, 1H), 6.77–6.80 (m, 2H, ArH), 6.71 (d, J = 8.60 Hz, 2H,
CH), 4.32 (s, 1H, OH), 3.93 (s, 3H, OCH3), 3.54 (s, 3H, OCH3), ArH), 6.66–6.68 (m, 2H, CH), 5.90 (appt, J = 6.13 Hz, 1H, CH),
0.80 (s, 3H, CH3) ppm. 13C NMR (100 MHz, CDCl3): δ 165.7, 4.27 (s, 1H, OH), 3.93 (s, 3H, OCH3), 3.73 (s, 3H, OCH3), 3.63
164.9, 146.6, 143.2, 142.0, 132.5, (2C), 129.5, 129.4 (2C), 129.3, (s, 3H, OCH3), 3.47 (s, 3H, OCH3), 0.79 (s, 3H, CH3) ppm. 13C
128.9 (2C), 128.8, 127.3, 125.6, 123.7, 122.8 (2C), 120.0, 110.8, NMR (100 MHz, CDCl3): δ 165.4 (2C) 159.4, 158.7, 144.8, 143.7,
107.3, 92.3, 69.0, 52.8, 52.2, 13.2 ppm. IR (KBr): 3468, 2940, 133.1 (2C), 131.2, 129.5, 129.1, 126.2, 125.6, 124.4, 121.7,
2851, 1725, 1591, 1511, 1439, 1341, 1236, 1107, 1060, 1004, 119.8, 115.0, 114.6, 113.2 (2C), 109.6, 109.2, 91.9, 68.7, 55.3,
852, 702, 530 cm−1. HRMS (ESI) m/z: [M + H]+ calcd for 55.2, 52.7, 51.9, 13.3 ppm. IR (KBr): 3483, 2945, 2841, 1727,
C27H23N2O7 487.1505; found 487.1476.
1579, 1469, 1437, 1286, 1239, 1184, 1104, 907, 836, 763, 724,
2-Methoxy-5-(3-methoxyphenyl)-2-methyl-4-phenyl-1H-pyrrol- 659, 620 cm−1. HRMS (ESI) m/z: [M + H]+ calcd for C29H28NO7
3(2H)-one (2d). 40% yield (37 mg). Yellow solid, 502.1866; found 502.1871.
m.p. 108–110 °C. Rf = 0.50 (60% EtOAc/hexane). 1H NMR
2-Methoxy-5-(3-methoxyphenyl)-2-methyl-4-(4-nitrophenyl)-
(400 MHz, CDCl3): δ 7.29–7.33 (m, 1H, ArH), 7.26 (d, J = 4.58 1H-pyrrol-3(2H)-one (2f). 40% yield (43 mg). Yellow solid,
Hz, 4H, ArH), 7.17–7.21 (m, 1H, ArH), 7.13 (d, J = 7.41 Hz, 1H, m.p. 140–142 °C. Rf = 0.50 (60% EtOAc/hexane). 1H NMR
ArH), 7.01–7.03 (m, 2H, ArH), 5.08 (s, 1H, NH), 3.66 (s, 3H, (400 MHz, CDCl3): δ 8.08 (d, J = 8.72 Hz, 2H, ArH), 7.45 (d, J =
OCH3), 3.28 (s, 3H, OCH3), 1.61 (s, 3H, CH3) ppm. 13C NMR 8.71 Hz, 2H, ArH), 7.35–7.39 (m, 1H, ArH), 7.06–7.10 (m, 2H,
(100 MHz, CDCl3): δ 199.1, 170.8, 159.8, 132.6, 131.0, 130.2, ArH), 7.00 (s, 1H, ArH), 5.37 (s, 1H, NH), 3.75 (s, 3H, OCH3),
129.4 (2C), 128.3 (2C), 126.7, 120.5, 118.0, 113.5, 112.6, 89.8, 3.28 (s, 3H, OCH3), 1.62 (s, 3H, CH3) ppm. 13C NMR (100 MHz,
55.4, 51.7, 23.4 ppm. IR (KBr): 3265, 2925, 1779, 1657, 1579, CDCl3): δ 197.8, 172.6, 160.2, 145.8, 138.4, 132.0, 130.8, 129.1
1464, 1372, 1309, 1248, 1149, 1046, 985, 916, 866, 734, (2C), 123.6 (2C), 120.4, 118.1, 113.7, 109.6, 90.3, 55.6, 52.0,
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23.2 ppm. IR (KBr): 3241, 2922, 1661, 1591, 1591, 1506, 1604, 1508, 1460, 1373, 1300, 1255, 1174, 1030, 910, 833, 733,
1463, 1336, 1257, 1146, 1044, 849, 793 cm−1. HRMS (ESI) m/z: 580, 523, cm−1. HRMS (ESI) m/z: [M + H]+ calcd for C20H22NO4
[M + H]+ calcd for C19H19N2O5 355.1294; found 355.1290.
340.1549; found 340.1555.
Dimethyl 8a-hydroxy-1,2-bis(4-methoxyphenyl)-3′-methyl-
nitrophenyl)-3′,8a-dihydrocyclopenta[hi]indolizine-7,8-dicarboxy- 3′,8a-dihydrocyclopenta[hi]indolizine-7,8-dicarboxylate (3h).
Dimethyl
8a-hydroxy-2-(3-methoxyphenyl)-3′-methyl-1-(4-
late (3f). 54% yield (84 mg). Orange solid, m.p. 74–76 °C. Rf = 69% yield (104 mg). Brown solid, m.p. 132–134 °C. Rf = 0.43
1
0.44 (40% EtOAc/hexane). 1H NMR (400 MHz, CDCl3): δ 1H (40% EtOAc/hexane). H NMR (400 MHz, CDCl3): δ 7.10 (d, J =
NMR (CDCl3, 400 MHz): δ 8.00 (d, J = 8.31 Hz, 2H, ArH), 7.27 8.53 Hz, 2H, ArH), 6.99 (d, J = 8.53 Hz, 2H, ArH), 6.87 (d, J =
(d, J = 8.59 Hz, 2H, ArH), 7.20 (t, J = 7.87 Hz, 1H, ArH), 6.84 (m, 6.30 Hz, 1H, CH), 6.77 (d, J = 8.53 Hz, 2H, ArH), 6.71 (d, J =
1H, ArH), 6.81 (d, J = 6.44 Hz, 1H, CH), 6.70–6.72 (m, 2H, 8.90 Hz, 2H, ArH), 6.66 (d, J = 5.93 Hz, 1H, CH), 5.89 (appt, J =
ArH), 6.64 (s, 1H, CH), 6.00 (appt, J = 6.08 Hz, 1H, CH), 4.33 (s, 6.31 Hz, 1H, CH), 4.26 (s, 1H, OH), 3.92 (s, 3H, OCH3), 3.75 (s,
1H, OH), 3.93 (s, 3H, OCH3), 3.67 (s, 3H, OCH3), 3.54 (s, 3H, 3H, OCH3), 3.74 (s, 3H, OCH3), 3.47 (s, 3H, OCH3), 0.77 (s, 3H,
OCH3), 0.80 (s, 3H, CH3) ppm. 13C NMR (100 MHz, CDCl3): CH3) ppm. 13C NMR (100 MHz, CDCl3): δ 165.5, 165.4, 159.8,
δ 165.7, 164.9, 159.7, 146.6, 146.5, 143.2, 142.0, 132.5 (2C), 158.7, 144.7, 143.5, 133.2 (2C), 130.8 (2C), 129.0, 126.1, 125.8,
130.5, 130.0, 128.8, 127.3, 125.5, 122.7 (2C), 121.7, 120.0, 124.4, 122.2, 119.8, 113.9 (2C), 113.2 (2C), 109.4, 108.5, 91.9,
115.2, 114.8, 110.8, 107.2, 92.3, 69.0, 55.4, 52.8, 52.2, 68.6, 55.3, 55.2, 52.7, 51.9, 13.2 ppm. IR (KBr): 3473, 2947,
13.2 ppm. IR (KBr): 3458, 2925, 1723, 1588, 1509, 1509, 1455, 2845, 1731, 1605, 1568, 1510, 1442, 1359, 1285, 1245,
1339, 1239, 1095, 847, 752 cm−1. HRMS (ESI) m/z: [M + H]+ 1177, 1103, 1062, 1030, 837, 732, 460 cm−1. HRMS (ESI) m/z:
calcd for C28H25N2O8 517.1611; found 517.1605.
[M + H]+ calcd for C29H28NO7 502.1866; found 502.1860.
2-Methoxy-5-(4-methoxyphenyl)-2-methyl-4-phenyl-1H-pyrrol-
2-Methoxy-5-(4-methoxyphenyl)-2-methyl-4-(4-nitrophenyl)-
3(2H)-one (2g). 24% yield (22 mg). Yellow solid, m.p. 1H-pyrrol-3(2H)-one (2i). 32% yield (34 mg). Yellow solid,
172–174 °C. Rf = 0.45 (60% EtOAc/hexane). 1H NMR (400 MHz, m.p. 130–132 °C. Rf = 0.43 (60% EtOAc/hexane). 1H NMR
CDCl3): δ 7.49 (d, J = 8.62 Hz, 2H, ArH), 7.27 (d, J = 4.08 Hz, (400 MHz, CDCl3): δ 8.09 (d, J = 8.86 Hz, 2H, ArH), 7.47 (d, J =
4H, ArH), 7.17–7.20 (m, 1H, ArH), 6.87 (d, J = 8.62 Hz, 2H, 5.31 Hz, 2H, ArH), 7.45 (d, J = 5.31 Hz, 2H, ArH), 6.94 (d, J =
ArH), 5.00 (s, 1H, NH), 3.84 (s, 3H, OCH3), 3.25 (s, 3H, OCH3), 8.75 Hz, 2H, ArH), 5.30 (s, 1H, NH), 3.87 (s, 3H, OCH3), 3.26 (s,
1.60 (s, 3H, CH3) ppm. 13C NMR (100 MHz, CDCl3): δ 198.7, 3H, OCH3), 1.61 (s, 3H, CH3) ppm. 13C NMR (100 MHz,
170.6, 162.5, 131.3, 130.2 (2C), 129.4 (2C), 128.4 (2C), 126.5, CDCl3): δ 197.5, 172.4, 163.2, 145.7, 139.0, 130.2 (2C), 129.2
123.4, 114.4 (2C), 111.8, 89.8, 55.6, 51.7, 23.4 ppm. IR (KBr): (2C), 123.6 (2C), 122.5, 114.8 (2C), 108.8, 90.3, 55.7, 51.8,
3256, 2953, 2925, 2846, 1658, 1604, 1488, 1375, 1312, 1174, 23.2 ppm. IR (KBr): 3241, 2922, 2857, 2357, 1658, 1596, 1503,
1128, 1028, 839, 705, 597 cm−1. HRMS (ESI) m/z: [M + H]+ 1257, 1175, 1126, 1052, 1126, 1099, 838, 737, 689, 522 cm−1
calcd for C19H20NO3 310.1443; found 310.1455.
Dimethyl 8a-hydroxy-2-(4-methoxyphenyl)-3′-methyl-1-phenyl- found 355.1288.
3′,8a-dihydrocyclopenta[hi]indolizine-7,8-dicarboxylate (3g). Dimethyl
.
HRMS (ESI) m/z: [M + H]+ calcd for C19H19N2O5 355.1294;
8a-hydroxy-2-(4-methoxyphenyl)-3′-methyl-1-(4-
66% yield (93 mg). Orange solid, m.p. 92–94 °C. Rf = 0.50 (40% nitrophenyl)-3′,8a-dihydrocyclopenta[hi]indolizine-7,8-dicarboxy-
EtOAc/hexane). 1H NMR (400 MHz, CDCl3): δ 7.17–7.18 (m, late (3i). 55% yield (85 mg). Orange solid, m.p. 58–60 °C. Rf =
3H, ArH), 7.07–7.12 (m, 4H, ArH), 6.88 (d, J = 6.57 Hz, 1H, 0.43 (40% EtOAc/hexane). 1H NMR (400 MHz, CDCl3): δ 8.00
CH), 6.76 (d, J = 8.59 Hz, 2H, ArH), 6.67 (d, J = 5.81 Hz, 1H, (d, J = 8.88 Hz, 2H, ArH), 7.26 (d, J = 8.88 Hz, 2H, ArH), 7.04 (d,
CH), 5.91 (appt, J = 6.21 Hz, 1H, CH), 4.25 (s, 1H, OH), 3.93 (s, J = 8.88 Hz, 2H, ArH), 6.79–6.82 (m, 3H, ArH, CH), 6.71 (d, J =
3H, OCH3), 3.74 (s, 3H, OCH3), 3.42 (s, 3H, OCH3), 0.79 (s, 3H, 5.46 Hz, 1H, CH), 5.89 (appt, J = 6.17 Hz, 1H, CH), 4.30 (s, 1H,
CH3) ppm. 13C NMR (100 MHz, CDCl3): 165.4, 165.3, 159.9, OH), 3.92 (s, 3H, OCH3), 3.76 (s, 3H, OCH3), 3.53 (s, 3H,
144.7, 143.6, 133.9, 132.2 (2C), 130.7 (2C), 129.0, 127.6 (2C), OCH3), 0.78 (s, 3H, CH3) ppm. 13C NMR (100 MHz, CDCl3):
126.9, 126.2, 124.4, 122.0, 119.8, 113.9 (2C), 109.5, 109.0, 91.9, δ 165.7, 165.0, 160.4, 146.54, 146.48, 143.1, 142.3, 132.6 (2C),
68.6, 55.3, 52.7, 51.8, 13.2 ppm. IR (KBr): 3482, 2948, 2846, 130.8 (2C), 128.8, 127.2, 125.6, 122.7 (2C), 121.3, 120.0, 114.3
1731, 1605, 1507, 1440, 1359, 1286, 1246, 1181, 1027, 840, 704, (2C), 110.7, 106.7, 92.2, 68.9, 55.4, 52.8, 52.2, 13.2 ppm. IR
643, 544, cm−1. HRMS (ESI) m/z: [M + H]+ calcd for C28H26NO6 (KBr): 3456, 2926, 2849, 2361, 2333, 1727, 1599, 1511,
472.1760; found 472.1755.
2-Methoxy-4,5-bis(4-methoxyphenyl)-2-methyl-1H-pyrrol-3(2H)- [M + H]+ calcd for C28H25N2O8 517.1611; found 517.1607.
one (2h). 22% yield (22 mg). Yellow solid, m.p. 140–142 °C. 2-Methoxy-2-methyl-5-(4-(methylthio)phenyl)-4-phenyl-1H-
1440, 1342, 1243, 1024, 847, 703, 527 cm−1. HRMS (ESI) m/z:
Rf = 0.40 (60% EtOAc/hexane). 1H NMR (400 MHz, CDCl3,): pyrrol-3(2H)-one (2j). 26% yield (25 mg). Yellow solid, m.p.
δ 7.49 (d, J = 8.74 Hz, 2H, ArH), 7.17 (d, J = 8.74 Hz, 2H, ArH), 150–152 °C. Rf = 0.50 (60% EtOAc/hexane). 1H NMR (400 MHz,
6.87 (d, J = 8.74 Hz, 2H, ArH), 6.81 (d, J = 8.40 Hz, 2H, ArH), CDCl3): δ 7.43–7.45 (m, 2H, ArH), 7.24–7.29 (m, 4H, ArH),
5.02 (s, 1H, NH), 3.83 (s, 3H, OCH3), 3.77 (s, 3H, OCH3), 3.23 7.18–7.20 (m, 3H, ArH), 5.12 (s, 1H, NH), 3.26 (s, 3H, OCH3),
(s, 3H, OCH3), 1.58 (s, 3H, CH3) ppm. 13C NMR (100 MHz, 2.50 (s, 3H, SCH3), 1.60 (s, 3H, CH3) ppm. 13C NMR (100 MHz,
CDCl3): δ 199.1, 170.1, 162.4, 158.3, 130.5 (2C), 130.2 (2C), CDCl3): δ 198.9, 170.4, 144.4, 131.1, 129.3 (2C), 128.7 (2C),
123.7, 123.5, 114.3 (2C), 114.0 (2C), 111.5, 89.6, 55.6, 55.3, 128.4 (2C), 127.2, 126.7, 125.5 (2C), 112.1, 89.8, 51.7, 23.4,
51.6, 23.4 ppm. IR (KBr): 3354, 2940, 2838, 1775, 1718, 1658, 14.9 ppm. IR (KBr): 3248, 2925, 2858, 1740, 1657, 1596, 1569,
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1472, 1374, 1303, 1142, 1066, 1024, 828, 742, 705, 596 cm−1
.
520 cm−1. HRMS (ESI) m/z: [M + H]+ calcd for C19H19N2O4S
HRMS (ESI) m/z: [M + H]+ calcd for C19H20NO2S 326.1215; 371.1066; found 371.1078.
found 326.1221.
Dimethyl 8a-hydroxy-3′-methyl-2-(4-(methylthio)phenyl)-1-(4-
Dimethyl 8a-hydroxy-3′-methyl-2-(4-(methylthio)phenyl)-1- nitrophenyl)-3′,8a-dihydrocyclopenta[hi]indolizine-7,8-dicarboxy-
phenyl-3′,8a-dihydrocyclopenta[hi]indolizine-7,8-dicarboxylate (3j). late (3l). 61% yield (98 mg). Orange solid, m.p. 74–76 °C. Rf =
65% yield (95 mg). Orange solid, m.p. 48–50 °C. Rf = 0.53 (40% 0.44 (40% EtOAc/hexane). 1H NMR (400 MHz, CDCl3): δ 8.00
EtOAc/hexane). 1H NMR (400 MHz, CDCl3): δ 7.17–7.19 (m, (d, J = 8.84 Hz, 2H, ArH), 7.26 (d, J = 8.21 Hz, 2H, ArH), 7.12 (d,
3H, ArH), 7.06–7.09 (m, 6H, ArH), 6.85 (d, J = 6.45 Hz, 1H, J = 8.21 Hz, 2H, ArH), 7.02 (d, J = 7.58 Hz, 2H, ArH), 6.80 (d, J =
CH), 6.67 (d, J = 5.73 Hz, 1H, CH), 5.91 (appt, J = 6.00 Hz, 1H, 6.94 Hz, 1H, CH), 6.71 (d, J = 5.68 Hz, 1H, CH), 5.99 (appt, J =
CH), 4.26 (s, 1H, OH), 3.93 (s, 3H, OCH3), 3.42 (s, 3H, OCH3), 6.07 Hz, 1H, CH), 4.34 (s, 1H, OH), 3.93 (s, 3H, OCH3), 3.54 (s,
2.42 (s, 3H, SCH3), 0.79 (s, 3H, CH3) ppm. 13C NMR (100 MHz, 3H, OCH3), 2.44 (s, 3H, SCH3), 0.80 (s, 3H, CH3) ppm.
CDCl3): δ 165.4, 165.3, 144.4, 143.8, 139.8, 133.7, 132.1 (2C), 13C NMR (100 MHz, CDCl3): δ 165.7, 165.0, 146.6, 146.2, 143.2,
129.7 (2C), 129.0, 127.7 (2C), 127.1, 126.3, 126.2, 125.7 (2C), 142.0, 140.9, 132.6 (2C), 129.7 (2C), 128.7, 127.3, 125.9 (2C),
124.4, 119.8, 109.7, 109.5, 91.9, 68.7, 52.7, 51.8, 15.2, 125.5, 125.4, 122.8 (2C), 120.0, 110.8, 107.2, 92.2, 67.0, 52.8,
13.29 ppm. IR (KBr): 3348, 2955, 2922, 2860, 1638, 1461, 1371, 52.2, 15.1, 13.2 ppm. IR (KBr): 3472, 2953, 2859, 1730, 1593,
1288, 1233, 1200, 707, 648, 564, 515 cm−1. HRMS (ESI) m/z: 1513, 1465, 1441, 1343, 1314, 1234, 1104, 1061, 1010, 854, 739,
[M + H]+ calcd C28H26NO5S 488.1532; found 488.1524.
705 cm−1. HRMS (ESI) m/z: [M + H]+ calcd for C28H25N2O7S
2-Methoxy-4-(4-methoxyphenyl)-2-methyl-5-(4-(methylthio) 533.1382; found 533.1368.
phenyl)-1H-pyrrol-3(2H)-one (2k). 21% yield (22 mg). Yellow
5-(3,4-Dimethoxyphenyl)-2-methoxy-2-methyl-4-phenyl-1H-
solid, m.p. 148–150 °C. Rf = 0.45 (60% EtOAc/hexane). 1H NMR pyrrol-3(2H)-one (2m). 30% yield (31 mg). Yellow solid,
(400 MHz, CDCl3): δ 7.44 (d, J = 8.26 Hz, 2H, ArH), 7.17–7.20 m.p. 158–160 °C. Rf = 0.30 (60% EtOAc/hexane). 11H NMR
(m, 4H, ArH), 6.82 (d, J = 8.90 Hz, 2H, ArH), 4.83 (s, 1H, NH), (400 MHz, CDCl3): δ 7.26–7.30 (m, 4H, ArH), 7.22–7.25 (m, 1H,
3.79 (s, 3H, OCH3), 3.25 (s, 3H, OCH3), 2.50 (s, 3H, SCH3), 1.59 ArH), 7.17–7.21 (m, 1H, ArH), 6.91 (s, 1H, ArH), 6.87 (d, J =
(s, 3H, CH3) ppm. 13C NMR (100 MHz, CDCl3): δ 199.3, 169.7, 8.44 Hz, 1H, ArH), 4.97 (s, 1H, NH), 3.92 (s, 3H, OCH3), 3.58 (s,
158.5, 144.2, 130.5 (2C), 128.7 (2C), 127.4, 125.6 (2C), 3H, OCH3), 3.28 (s, 3H, OCH3), 1.61 (s, 3H, CH3) ppm.
123.4, 114.0 (2C), 112.2, 89.6, 55.4, 51.7, 23.5, 15.0 ppm. 13C NMR (100 MHz, CDCl3): δ 198.7, 170.5, 152.2, 148.9, 131.4,
IR (KBr): 3257, 2924, 2844, 1768, 1659, 1591, 1516, 1454, 129.7 (2C), 128.4 (2C), 126.7, 123.5, 121.3, 112.2, 111.8, 111.0,
1371, 1295, 1249, 1169, 1029, 960, 824, 732, 580 cm−1. HRMS 89.8, 56.2, 55.8, 51.7, 23.5 ppm. IR (KBr): 3413, 2927, 2847,
(ESI) m/z: [M + H]+ calcd for C20H22NO3S 356.1320; found 1652, 1598, 1552, 1491, 1447, 1372, 1262, 1139, 1069, 1023,
356.1327.
865, 740, 704, 613, 584, 465 cm−1. HRMS (ESI) m/z: [M + H]+
Dimethyl
8a-hydroxy-1-(4-methoxyphenyl)-3′-methyl-2-(4- calcd for C20H22NO4 340.1549; found 340.1556.
(methylthio)phenyl)-3′,8a-dihydro cyclopenta[hi]indolizine-7,8-
Dimethyl-2-(3,4-dimethoxyphenyl)-8a-hydroxy-3′-methyl-1-
dicarboxylate (3k). 68% yield (106 mg). Yellow solid, phenyl-3′,8a-dihydrocyclopenta[hi]indolizine-7,8-dicarboxylate
m.p. 84–86 °C. Rf = 0.43 (40% EtOAc/hexane). 1H NMR (3m). 63% yield (96 mg). Brown solid, m.p. 58–60 °C. Rf = 0.40
(400 MHz, CDCl3): δ 7.09 (s, 4H, ArH), 6.98 (d, J = 7.99 Hz, 2H, (40% EtOAc/hexane). 1H NMR (400 MHz, CDCl3): δ 7.17–7.18
ArH), 6.84 (d, J = 6.22 Hz, 1H, CH), 6.71 (d, J = 7.99 Hz, 2H, (m, 3H, ArH), 7.09–7.10 (m, 2H, ArH), 6.95 (d, J = 6.53 Hz, 1H,
ArH), 6.66 (d, J = 5.33 Hz, 1H, CH), 5.90 (appt, J = 5.77 Hz, 1H, ArH), 6.85 (d, J = 8.34 Hz, 1H, ArH), 6.75 (d, J = 8.34 Hz, 1H,
CH), 4.27 (s, 1H, OH), 3.92 (s, 3H, OCH3), 3.74 (s, 3H, OCH3), CH), 6.67 (d, J = 5.80 Hz, 1H, CH), 6.56 (s, 1H, ArH), 5.92
3.47 (s, 3H, OCH3), 2.42 (s, 3H, SCH3), 0.78 (s, 3H, CH3) ppm. (appt, J = 5.99 Hz, 1H, CH), 4.26 (s, 1H, OH), 3.93 (s, 3H,
13C NMR (100 MHz, CDCl3): δ 165.4 (2C), 158.7, 144.4, 143.6, OCH3), 3.82 (s, 3H, OCH3), 3.58 (s, 3H, OCH3), 3.43 (s, 3H,
139.6, 133.2 (2C), 129.7 (2C), 129.0, 126.3, 126.2, 125.7 (2C), OCH3), 0.80 (s, 3H, CH3) ppm. 13C NMR (100 MHz, CDCl3):
125.5, 124.4, 119.8, 113.2 (2C), 109.6, 109.1, 91.8, 68.6, 55.2, δ 165.5, 165.3, 149.3, 148.6, 144.8, 143.8, 134.1, 132.2 (2C),
52.7, 51.9, 15.2, 13.3 ppm. IR (KBr): 3470, 2954, 2922, 2862, 129.1, 127.7 (2C), 127.0, 126.3, 124.3, 122.1, 121.9, 119.9,
1731, 1601, 1501, 1461, 1371, 1287, 1238, 1190, 1092, 968, 112.7, 110.8, 109.6, 109.0, 91.8, 68.8, 55.9, 55.8, 52.7, 51.8,
812, 775, 746, 702, 664, 590, 575, 544 cm−1. HRMS (ESI) m/z: 13.3 ppm. IR (KBr): 3493, 2945, 1730, 1605, 1570, 1512, 1442,
[M + H]+ calcd for C29H28NO6S 518.1637; found 518.1626.
2-Methoxy-2-methyl-5-(4-(methylthio)phenyl)-4-(4-nitrophenyl)- [M + H]+ calcd for C29H28NO7 502.1866; found 502.1850.
1H-pyrrol-3(2H)-one (2l). 30% yield (33 mg). Yellow solid, 5-(3,4-Dimethoxyphenyl)-2-methoxy-4-(4-methoxyphenyl)-2-
1232, 1140, 1062, 1024, 765, 737, 705 cm−1. HRMS (ESI) m/z:
m.p. 118–120 °C. Rf = 0.45 (60% EtOAc/hexane). 1H NMR methyl-1H-pyrrol-3(2H)-one (2n). 26% yield (29 mg). Yellow
(400 MHz, CDCl3): δ 8.08 (d, J = 8.54 Hz, 2H, ArH), 7.40–7.45 solid, m.p. 142–144 °C. Rf = 0.23 (60% EtOAc/hexane). 1H NMR
(m, 4H, ArH), 7.24 (d, J = 8.15 Hz, 2H, ArH), 5.50 (s, 1H, NH), (400 MHz, CDCl3): δ 7.19–7.24 (m, 3H, ArH), 6.97 (s, 1H, ArH),
3.25 (s, 3H, OCH3), 2.51 (s, 3H, SCH3), 1.60 (s, 3H, CH3) ppm. 6.87 (d, J = 8.49 Hz, 1H, ArH), 6.83 (d, J = 8.49 Hz, 2H, ArH),
13C NMR (100 MHz, CDCl3): δ 197.6, 172.1, 145.8, 145.7, 138.7, 4.94 (s, 1H, NH), 3.92 (s, 3H, OCH3), 3.78 (s, 3H, OCH3), 3.62
129.1 (2C), 128.6 (2C), 126.2, 125.8 (2C), 123.7 (2C), 109.2, (s, 3H, OCH3), 3.26 (s, 3H, OCH3), 1.60 (s, 3H, CH3) ppm. 13C
90.3, 51.9, 23.2, 14.9 ppm. IR (KBr): 3318, 2954, 2922, 2845, NMR (100 MHz, CDCl3): δ 199.1, 170.0, 158.5, 152.1, 148.9,
1737, 1652, 1584, 1507, 1470, 1341, 1250, 1130, 1014, 840, 130.8 (2C), 123.7 (2C), 121.4, 114.0 (2C), 111.9, 111.7, 111.0,
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89.7, 56.1, 55.8, 55.4, 51.7, 23.5 ppm. IR (KBr): 3331, 2928, NH), 3.80 (s, 3H, OCH3), 3.36 (s, 3H, OCH3), 3.28 (s, 3H,
2848, 1778, 1654, 1601, 1569, 1509, 1460, 1370, 1257, 1147, OCH3), 1.60 (s, 3H, CH3) ppm; 13C NMR (100 MHz, CDCl3):
1028, 915, 731 cm−1. HRMS (ESI-TOF) m/z: [M + H]+ calcd for δ 199.7, 171.4, 160.5, 158.0, 132.7, 132.3, 131.4, 128.7 (2C),
C21H24NO5 exact mass: 370.1654; found 370.1662.
127.2 (2C), 113.1, 109.2, 104.8, 99.4, 89.5, 55.5, 55.2, 51.7,
Dimethyl 2-(3,4-dimethoxyphenyl)-8a-hydroxy-1-(4-methoxy- 23.3 ppm. IR (KBr): 3252, 2926, 2857, 1659, 1600, 1553, 1576,
phenyl)-3′-methyl-3′,8a-dihydro
cyclopenta[hi]indolizine-7,8- 1461, 1375, 1299, 1208, 1152, 1039, 917, 830, 781, 731, 697,
dicarboxylate (3n). 65% yield (104 mg). Brown solid, 573, 481 cm−1. HRMS (ESI) m/z: [M + H]+ calcd for C20H22NO4
m.p. 50–52 °C. Rf = 0.30 (40% EtOAc/hexane). 1H NMR 340.1549; found 340.1559.
(400 MHz, CDCl3): δ 7.00 (d, J = 8.51 Hz, 2H, ArH), 6.93 (d, J =
Dimethyl
1-(2,4-dimethoxyphenyl)-8a-hydroxy-3′-methyl-2-
6.44 Hz, 1H, ArH), 6.82 (d, J = 8.28 Hz, 1H, ArH), 6.75 (d, J = phenyl-3′,8a-dihydrocyclopenta[hi]indolizine-7,8-dicarboxylate
8.28 Hz, 1H, CH), 6.71 (d, J = 8.51 Hz, 2H, ArH), 6.66 (d, J = (3p). 40% yield (60 mg). Orange solid, m.p. 54–56 °C. Rf = 0.42
5.61 Hz, 1H, CH), 6.58 (s, 1H, ArH), 5.90 (appt, J = 6.16 Hz, 1H, (40% EtOAc/hexane). 1H NMR (400 MHz, CDCl3): δ 7.22 (bs,
CH), 4.27 (s, 1H, OH), 3.93 (s, 3H, OCH3), 3.83 (s, 3H, OCH3), 3H, ArH), 7.17 (bs, 2H, ArH), 6.82 (d, J = 5.35 Hz, 2H, ArH),
3.73 (s, 3H, OCH3), 3.62 (s, 3H, OCH3), 3.48 (s, 3H, OCH3), 0.79 6.55 (d, J = 5.74 Hz, 1H, CH), 6.33 (s, 1H, ArH), 6.27 (d, J = 8.03
(s, 3H, CH3) ppm. 13C NMR (100 MHz, CDCl3): δ 165.5, 165.4, Hz, 1H, CH), 5.84 (bs, 1H, CH), 3.92 (s, 3H, OCH3), 3.72 (s, 3H,
158.7, 149.2, 148.6, 144.8, 143.6, 133.2 (2C), 129.1, 126.2, OCH3), 3.61 (bs, 3H, OCH3), 3.46 (s, 3H, OCH3), 0.82 (s, 3H,
125.9, 124.4, 122.3, 122.0, 119.8, 113.2 (2C), 112.7, 110.8, CH3) ppm; one exchangeable proton did not appear. 13C NMR
109.5, 108.6, 91.8, 68.7, 55.9, 55.3, 52.7, 51.9, 13.3 ppm. IR (100 MHz, CDCl3): δ 166.0, 164.8, 160.4, 159.7, 143.1, 134.8
(KBr): 3545, 2923, 2863, 1726, 1602, 1507, 1459, 1237, 1183, (2C), 130.3, 129.1 (3C), 128.9, 128.67 (2C), 128.3 (4C),
1139, 1024, 728, 423 cm−1. HRMS (ESI) m/z: [M + H]+ calcd for 126.6, 118.8, 109.9, 104.0, 98.1, 68.9, 55.3 (2C), 52.6, 51.5,
C30H30NO8 532.1971; found 532.1966.
13.4 ppm. IR (KBr): 3461, 2923, 1730, 1607, 1459, 1371, 1294,
5-(3,4-Dimethoxyphenyl)-2-methoxy-2-methyl-4-(4-nitrophenyl)- 1210, 1371, 1294, 1210, 1160, 1105, 1035, 839, 736, 651 cm−1
.
1H-pyrrol-3(2H)-one (2o). 31% yield (36 mg). Yellow solid, HRMS (ESI) m/z: [M + H]+ calcd for C29H28NO7 502.1866;
m.p. 104–106 °C. Rf = 0.30 (60% EtOAc/hexane). 1H NMR found 502.1894.
(400 MHz, CDCl3): δ 8.09 (d, J = 8.37 Hz, 2H, ArH), 7.48 (d, J =
4-(2,4-Dimethoxyphenyl)-2-methoxy-5-(3-methoxyphenyl)-2-
8.37 Hz, 2H, ArH), 7.17 (d, J = 8.37 Hz, 1H, ArH), 6.93 (s, 1H, methyl-1H-pyrrol-3(2H)-one (2q). 39% yield (52 mg). Yellow
ArH), 6.90 (d, J = 8.35 Hz, 1H, ArH), 5.39 (s, 1H, NH), 3.94 (s, solid, m.p. 110–112 °C. Rf = 0.50 (80% EtOAc/hexane). 1H NMR
3H, OCH3), 3.70 (s, 3H, OCH3), 3.26 (s, 3H, OCH3), 1.62 (s, 3H, (400 MHz, CDCl3): δ 7.23 (d, J = 7.87 Hz, 1H, ArH), 7.12 (d, J =
CH3) ppm. 13C NMR (100 MHz, CDCl3): δ 197.5, 172.3, 152.9, 8.32 Hz, 1H, ArH), 7.08 (d, J = 7.65 Hz, 1H, ArH), 6.98 (s, 1H,
149.4, 145.7, 138.9, 129.3 (2C), 123.6 (2C), 122.6, 122.0, 111.4, ArH), 6.95 (d, J = 8.10 Hz, 1H, ArH), 6.48 (dd, J = 1.97, 8.33 Hz,
111.0, 109.0, 90.4, 56.3, 56.1, 51.9, 23.3 ppm. IR (KBr): 3310, 1H, ArH), 6.38 (d, J = 1.84 Hz, 1H, ArH), 5.05 (s, 1H, NH), 3.78
2953, 2920, 2858, 1733, 1659, 1592, 1500, 1461, 1334, 1262, (s, 3H, OCH3), 3.63 (s, 3H, OCH3), 3.40 (s, 3H, OCH3), 3.27 (s,
1138, 1019, 851, 582 cm−1. HRMS (ESI) m/z: [M + H]+ calcd for 3H, OCH3), 1.58 (s, 3H, CH3) ppm. 13C NMR (100 MHz,
C20H21N2O6 385.1400; found 385.1405.
CDCl3): δ 199.8, 171.1, 160.5, 159.6, 158.1, 133.7, 132.3, 129.8,
Dimethyl 2-(3,4-dimethoxyphenyl)-8a-hydroxy-3′-methyl-1-(4- 119.5, 117.6, 113.2, 112.3, 109.4, 104.8, 99.4, 89.5, 55.5, 55.3
nitrophenyl)-3′,8a-dihydrocyclopenta[hi]indolizine-7,8-dicarboxy- (2C), 51.7, 23.3 ppm. IR (KBr): 3255, 2948, 2841, 1738, 1660,
late (3o). 60% yield (98 mg). Orange solid, m.p. 90–92 °C. Rf = 1554, 1513, 1462, 1372, 1294, 1255, 1210, 1151, 1039, 937, 839,
1
0.33 (40% EtOAc/hexane). H NMR (400 MHz, CD3OD): δ 7.98 785, 729, 572 cm−1. HRMS (ESI) m/z: [M + H]+ calcd for
(d, J = 8.89 Hz, 2H, ArH), 7.43 (d, J = 8.89 Hz, 2H, ArH), 6.92 (d, C21H24NO5 370.1654; found 370.1661.
J = 8.33 Hz, 1H, ArH), 6.80 (d, J = 6.66 Hz, 1H, CH), 6.75 (d, J =
8.30 Hz, 1H, CH), 6.67–6.69 (m, 2H, ArH), 6.08 (appt, J = 6.05 phenyl)-3′-methyl-3′,8a-dihydro
Dimethyl 1-(2,4-dimethoxyphenyl)-8a-hydroxy-2-(3-methoxy-
cyclopenta[hi]indolizine-7,8-
Hz, 1H, CH), 3.86 (s, 3H, OCH3), 3.79 (s, 3H, OCH3), 3.64 (s, dicarboxylate (3q). 41% yield (65 mg). Orange solid,
3H, OCH3), 3.35 (s, 3H, OCH3), 0.73 (s, 3H, CH3) ppm; one m.p. 74–76 °C. Rf = 0.30 (40% EtOAc/hexane). 1H NMR
1
exchangeable proton did not appear. 13C NMR (100 MHz, (400 MHz, CDCl3): δ H NMR (CDCl3, 400 MHz): δ 7.15 (t, J =
CD3OD): δ 166.6, 166.5, 151.4, 150.6, 148.8, 147.4, 144.3, 143.1, 7.92 Hz, 1H, ArH), 6.87 (bs, 2H, ArH), 6.81 (d, J = 7.40 Hz, 1H,
133.3 (2C), 131.2, 129.2, 129.0, 123.6, 123.4, 123.1 (2C), 119.3, CH), 6.75–6.78 (m, 1H, ArH), 6.67 (s, 1H, ArH), 6.55 (d, J =
114.0, 112.8, 111.8, 106.7, 94.0, 69.8, 56.4, 56.3, 53.0, 51.9, 5.71 Hz, 1H, CH), 6.28–6.33 (m, 2H, ArH), 5.85 (bs, 1H, CH),
13.6 ppm. IR (KBr): 3392, 2930, 2840, 2364, 2342, 1724, 1589, 3.92 (s, 3H, OCH3), 3.73 (s, 3H, OCH3), 3.62 (bs, 3H, OCH3),
1510, 1459, 1342, 1213, 1027, 868, 713, 545 cm−1. HRMS (ESI) 3.45 (s, 3H, OCH3), 0.82 (s, 3H, CH3) ppm; one exchangeable
m/z: [M + H]+ calcd for C29H27N2O9 547.1717; found 547.1707.
proton did not appear. 13C NMR (100 MHz, CDCl3): δ 166.0,
4-(2,4-Dimethoxyphenyl)-2-methoxy-2-methyl-5-phenyl-1H- 164.8, 160.5, 159.7, 159.3, 143.3, 134.7 (2C), 131.5, 129.3 (2C),
pyrrol-3(2H)-one (2p). 38% yield (39 mg). Yellow solid, m.p. 129.0, 126.5, 121.3 (2C), 118.9, 115.0 (2C), 114.1 (2C), 109.0,
62–64 °C. Rf = 0.33 (60% EtOAc/hexane). 1H NMR (400 MHz, 104.0, 98.2, 68.9, 55.3 (2C), 55.2, 52.6, 51.5, 13.4 ppm. IR (KBr):
CDCl3): δ 7.48 (d, J = 7.85 Hz, 2H, ArH), 7.41–7.45 (m, 1H, 3485, 2953, 2922, 2861, 1735, 1705, 1602, 1460, 1368, 1294,
ArH), 7.32–7.35 (m, 2H, ArH), 7.15 (d, J = 8.32 Hz, 1H, ArH), 1232, 1162, 1036, 730, 620 cm−1. HRMS (ESI) m/z: [M + H]+
6.50 (d, J = 8.30 Hz, 1H, ArH), 6.37 (s, 1H, ArH), 4.97 (s, 1H, calcd for C30H30NO8 532.1971; found 532.1975.
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4-(2,4-Dimethoxyphenyl)-2-methoxy-5-(4-methoxyphenyl)-2- 98.0, 68.8, 55.8 (2C), 55.7, 55.4, 52.6, 51.5, 13.4 ppm. IR (KBr):
methyl-1H-pyrrol-3(2H)-one (2r). 37% yield (41 mg). Yellow 3500, 2953, 2848, 1734, 1704, 1604, 1509, 1460, 1460, 1360,
solid, m.p. 144–146 °C. Rf = 0.33 (60% EtOAc/hexane). 1H NMR 1360, 1295, 1228, 1031, 915, 731, 639, 598 cm−1. HRMS (ESI)
(400 MHz, CD3OD): δ 7.47 (d, J = 8.75 Hz, 2H, ArH), 6.99 (d, J = m/z: [M + H]+ calcd for C31H32NO9 562.2077; found 562.2081.
7.77 Hz, 1H, ArH), 6.98 (d, J = 8.75 Hz, 2H, ArH), 6.50–6.52 (m,
5-(4-Fluorophenyl)-2-methoxy-2-methyl-4-(4-nitrophenyl)-1H-
1H, ArH), 6.49 (s, 1H, ArH), 3.80 (s, 3H, OCH3), 3.79 (s, 3H, pyrrol-3(2H)-one (2t). 30% yield (31 mg). Yellow solid,
OCH3), 3.47 (s, 3H, OCH3), 3.22 (s, 3H, OCH3), 1.51 (s, 3H, m.p. 174–176 °C. Rf = 0.50 (60% EtOAc/hexane). 1H NMR
CH3) ppm; one exchangeable proton did not appear. 13C NMR (400 MHz, CDCl3): δ 8.09 (d, J = 8.88 Hz, 2H, ArH), 7.54 (dd, J =
(100 MHz, CD3OD): δ 201.4, 175.6, 164.0, 162.0, 159.8, 133.6, 7.24, 5.25 Hz, 2H, ArH), 7.41 (d, J = 8.74 Hz, 2H, ArH),
130.9 (2C), 125.0, 114.8 (3C), 107.4, 106.0, 99.9, 90.9, 55.9, 7.13–7.18 (m, 2H, ArH), 5.35 (s, 1H, NH), 3.28 (s, 3H, OCH3),
55.8, 55.7, 51.7, 22.8 ppm. IR (KBr): 3210, 2964, 2840, 1732, 1.63 (s, 3H, CH3) ppm. 13C NMR (100 MHz, CDCl3): δ 197.7,
1671, 1550, 1504, 1480, 1344, 1284, 1245, 1218, 1158, 1035, 171.3, 146.0, 138.2, 130.7, 130.6, 129.2 (2C), 126.8, 123.7 (2C),
845, 723, 568 cm−1. HRMS (ESI) m/z: [M + H]+ calcd for 117.1, 116.9, 109.8, 90.4, 52.0, 23.2 ppm. IR (KBr): 3255, 2954,
C21H24NO5 370.1654; found 370.1666.
2922, 2860, 1653, 1594, 1551, 1508, 1479, 1322, 1229, 1189,
Dimethyl 1-(2,4-dimethoxyphenyl)-8a-hydroxy-2-(4-methoxy- 1149, 1059, 970, 904, 835, 732, 581 cm−1. HRMS (ESI) m/z:
phenyl)-3′-methyl-3′,8a-dihydro cyclopenta[hi]indolizines-7,8- [M + H]+ calcd for C18H16FN2O4 343.1094; found 343.1100.
dicarboxylate (3r). 44% yield (70 mg). Brown solid,
Dimethyl 2-(4-fluorophenyl)-8a-hydroxy-3′-methyl-1-(4-nitro-
m.p. 64–66 °C. Rf = 0.30 (40% EtOAc/hexane). 1H NMR phenyl)-3′,8a-dihydrocyclopenta[hi]indolizine-7,8-dicarboxylate
(400 MHz, CDCl3): δ 7.08 (d, J = 8.71 Hz, 2H, ArH), 6.84 (bs, (3t). 61% yield (92 mg). Orange solid, m.p. 140–142 °C. Rf =
2H, ArH), 6.74 (d, J = 8.51 Hz, 2H, ArH), 6.54 (d, J = 5.49 Hz, 0.45 (40% EtOAc/hexane). 1H NMR (400 MHz, CDCl3): δ 8.00 (d,
1H, CH), 6.33 (s, 1H, ArH), 6.28 (d, J = 7.69 Hz, 1H, CH), 5.83 J = 8.40 Hz, 2H, ArH), 7.24 (d, J = 8.40 Hz, 2H, ArH), 7.10–7.13
(bs, 1H, CH), 3.91 (s, 3H, OCH3), 3.73 (s, 6H, OCH3), 3.60 (bs, (m, 2H, ArH), 6.96–7.00 (m, 2H, ArH), 6.73 (d, J = 6.40 Hz, 1H,
3H, OCH3), 3.45 (s, 3H, OCH3), 0.80 (s, 3H, CH3) ppm; one CH), 6.71 (d, J = 5.60 Hz, 1H, CH), 6.01 (appt, J = 5.96 Hz, 1H,
exchangeable proton did not appear. 13C NMR (100 MHz, CH), 4.35 (s, 1H, OH), 3.93 (s, 3H, OCH3), 3.53 (s, 3H, OCH3),
CDCl3): δ 166.0, 164.8, 160.4, 159.8, 159.7, 142.9, 134.8 (2C), 0.80 (s, 3H, CH3) ppm. 13C NMR (100 MHz, CDCl3): δ 165.6,
130.4 (3C), 129.0, 126.4, 122.4, 118.8, 113.7 (4C), 108.9, 103.9, 164.8, 146.7, 145.6, 143.3, 141.7, 132.5 (2C), 131.4, 131.3, 128.5,
98.0, 92.0, 68.8, 55.3, 55.2, 52.5, 51.5, 13.4 ppm. IR (KBr): 127.5, 125.7, 125.3 (2C), 122.8 (2C), 120.0, 116.3, 116.0, 111.08,
3487, 2925, 2856, 1733, 1604, 1503, 1458, 1361, 1295, 1244, 107.5, 92.2, 69.0, 52.8, 52.2, 13.2 ppm. IR (KBr): 3471, 2955,
1167, 1034, 838, 736 cm−1. HRMS (ESI) m/z: [M + H]+ calcd for 2923, 2862, 1728, 1596, 1512, 1462, 1345, 1314, 1232, 1201,
C30H30NO8 532.1971; found 532.1973.
4-(2,4-Dimethoxyphenyl)-5-(3,4-dimethoxyphenyl)-2-methoxy- [M + H]+ calcd for C27H22FN2O7 505.1411; found 505.1407.
2-methyl-1H-pyrrol-3(2H)-one (2s). 34% yield (41 mg). Yellow 2-Methoxy-2-methyl-4,5-bis(4-nitrophenyl)-1H-pyrrol-3(2H)-
1163, 1102, 1061, 1008, 850, 737, 707 cm−1. HRMS (ESI) m/z:
solid, m.p. 136–138 °C. Rf = 0.45 (80% EtOAc/hexane). 1H NMR one (2u). 55% yield (61 mg). Orange solid, m.p. 136–138 °C.
(400 MHz, CDCl3): δ 7.18 (d, J = 8.21 Hz, 1H, ArH), 7.10 (d, J = Rf = 0.45 (80% EtOAc/hexane). 1H NMR (400 MHz, CDCl3,
8.21 Hz, 1H, ArH), 6.94 (s, 1H, ArH), 6.82 (d, J = 8.57 Hz, 1H, CD3OD): δ 8.25 (d, J = 8.29 Hz, 2H, ArH), 8.04 (d, J = 8.29 Hz,
ArH), 6.49 (d, J = 8.57 Hz, 1H, ArH), 6.41 (s, 1H, ArH), 5.01 (s, 2H, ArH), 7.69 (d, J = 8.29 Hz, 2H, ArH), 7.31 (d, J = 8.29 Hz,
1H, NH), 3.88 (s, 3H, OCH3), 3.78 (s, 3H, OCH3), 3.58 (s, 3H, 2H, ArH), 3.24 (s, 3H, OCH3), 1.56 (s, 3H, CH3) ppm; one
OCH3), 3.47 (br, 3H, OCH3), 3.27 (s, 3H, OCH3), 1.59 (s, 3H, exchangeable proton did not appear. 13C NMR (100 MHz,
CH3) ppm. 13C NMR (100 MHz, CDCl3): δ 199.4, 170.7, 160.6, CDCl3, CD3OD): δ 198.4, 170.5, 149.7, 145.9, 137.7, 136.7,
158.4, 151.8, 148.7, 132.5, 124.6, 120.4, 113.7, 110.8 (2C), 129.6 (2C), 129.0 (2C), 124.4 (2C), 123.8 (2C), 109.8, 90.4, 51.9,
108.8, 104.9, 99.4, 89.5, 56.1, 55.7, 55.5, 51.6, 23.3 ppm. IR 22.6 ppm. IR (KBr): 3223, 2955, 2923, 2861, 2359, 2335, 1664,
(KBr): 3257, 2933, 2841, 1728, 1658, 1604, 1523, 1463, 1374, 1593, 1514, 1465, 1340, 1121, 1051, 968, 905, 855, 751,
1293, 1212, 1149, 1030, 939, 824, 732, 571 cm−1. HRMS (ESI) 606 cm−1. HRMS (ESI) m/z: [M + H]+ calcd for C18H16N3O6
m/z: [M + H]+ calcd for C22H26NO6 400.1760; found 400.1764.
370.1039; found 370.1035.
Dimethyl 1-(2,4-dimethoxyphenyl)-2-(3,4-dimethoxyphenyl)-
Dimethyl 8a-hydroxy-3′-methyl-1,2-bis(4-nitrophenyl)-3′,8a-
8a-hydroxy-3′-methyl-3′,8a-dihydro
cyclopenta[hi]indolizine- dihydrocyclopenta[hi]indolizine-7,8-dicarboxylate (3u). 40%
7,8-dicarboxylate (3s). 43% yield (72 mg). Orange gum. Rf = yield (64 mg). Orange solid, m.p. 98–100 °C. Rf = 0.42 (40%
0.23 (40% EtOAc/hexane). 1H NMR (400 MHz, CDCl3): δ 6.93 EtOAc/hexane). 1H NMR (400 MHz, CDCl3): δ 8.15 (d, J =
(bs, 2H, ArH), 6.84 (d, J = 7.84 Hz, 1H, ArH), 6.74 (d, J = 8.27 8.63 Hz, 2H, ArH), 8.03 (d, J = 8.63 Hz, 2H, ArH), 7.34 (d, J =
Hz, 1H, CH), 6.59 (s, 1H, ArH), 6.55 (d, J = 5.53 Hz, 1H, CH), 8.63 Hz, 2H, ArH), 7.24 (d, J = 8.63 Hz, 2H, ArH), 6.71 (d, J =
6.29–6.32 (m, 2H, ArH), 5.84 (bs, 1H, CH), 3.92 (s, 3H, OCH3), 5.61 Hz, 1H, CH), 6.69 (d, J = 6.54 Hz, 1H, CH), 6.04 (appt, J =
3.81 (s, 3H, OCH3), 3.73 (s, 3H, OCH3), 3.61 (bs, 6H, OCH3), 6.29 Hz, 1H, CH), 4.46 (s, 1H, OH), 3.94 (s, 3H, OCH3), 3.56 (s,
3.45 (s, 3H, OCH3), 0.82 (s, 3H, CH3) ppm; one exchangeable 3H, OCH3), 0.84 (s, 3H, CH3) ppm. 13C NMR (100 MHz,
proton did not appear. 13C NMR (100 MHz, CDCl3): δ 166.0, CDCl3): δ 165.5, 164.7, 148.3, 147.1, 144.2, 143.8, 140.8, 136.0,
164.8, 160.5, 159.7, 149.1, 148.4, 143.0, 134.8 (3C), 129.0, 132.5 (2C), 130.5 (2C), 128.3, 128.1, 125.8, 124.1 (2C), 123.0
126.6, 122.6, 121.4, 119.0, 112.3 (2C), 110.7 (3C), 109.0, 104.0, (2C), 120.1, 111.9, 109.6, 92.3, 69.2, 52.9, 52.4, 13.4 ppm. IR
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(KBr): 3479, 2953, 2921, 2860, 1728, 1593, 1519, 1346, n-BuLi (6.79 mL, 7.35 mmol, 1.6 M solution in hexane) was
1314, 1234, 1199, 1104, 1062, 1010, 855, 743, 514 cm−1. HRMS added drop-wise under stirring. After 15 min, a solution of
(ESI) m/z: [M + H]+ calcd for C27H22N3O9 532.1356; found 3-methyl-1-(pyridin-2-yl) butan-1-one 9 (1 g, 6.12 mmol) in
532.1340.
THF was added drop-wise to this mixture at the same tempera-
ture. The reaction was continued for 30 minutes, allowed to
warm to room temperature and left stirring for an additional
Total synthesis of discoipyrrole C
Synthesis of N-methoxy-N,3-dimethylbutanamide (7). N-(3- 1 h. It was then quenched with saturated NH4Cl (100 ml) at
Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride 0 °C and extracted with EtOAc (3 × 50 mL). The combined
(EDC·HCl) (4.5 g, 23.4 mmol) was added to a stirred solution organic layers were dried over anhydrous Na2SO4 and concen-
containing a mixture of isovaleric acid 6 (2 g, 19.5 mmol), Et3N trated under reduced pressure and the resulting residue was
(8.19 mL, 58.7 mmol) and N,O-dimethylhydroxylamine hydro- purified by column chromatography on silica gel using the
chloride (2.47 g, 21.5 mmol) in dry CH2Cl2 (30 mL) under a EtOAc–hexane solvent system to obtain the tertiary propargylic
nitrogen atmosphere. It was continued to stir at room tempera- alcohol 11. Yield 82% (1.98 g); colourless liquid; Rf = 0.66
1
ture for 24 h and quenched with water. After separating the (40% EtOAc/hexane). H NMR (400 MHz, CDCl3): δ 8.52 (d, J =
organic layer, the aqueous phase was extracted with EtOAc (3 × 4.67 Hz, 1H, ArH), 7.72–7.76 (m, 1H, ArH), 7.67–7.69 (m, 1H,
30 mL) and the combined organic layers were washed with ArH), δ 7.32 (d, J = 8.82 Hz, 2H, ArH), δ 7.23–7.24 (m, 1H, ArH),
saturated aqueous NaHCO3 (2 × 50 mL) and dil. HCl (1 M, 2 × δ 6.75 (d, J = 8.82 Hz, 2H, ArH), 5.48 (s, 1H, OH), 2.00–2.07 (m,
40 mL) followed by brine (20 mL). It was dried over anhydrous 2H, CH2), 1.81–1.85 (m, 1H, CH), 1.01 (d, J = 6.37 Hz, 3H,
Na2SO4, and concentrated under reduced pressure and the CH3), 0.96 (s, 9H, CH3), 0.89 (d, J = 6.42 Hz, 3H, SiCH3), 0.18
resulting residue was purified by column chromatography on (s, 6H, SiCH3) ppm. 13C NMR (100 MHz, CDCl3): δ 162.1,
silica gel using the EtOAc–hexane solvent system to obtain the 156.1, 147.3, 137.3, 133.3 (2C), 122.8, 120.9, 120.2 (2C), 115.7,
corresponding Weinreb amide 7. Yield 75% (2.13 g). 90.8, 84.7, 72.2, 53.4, 25.8 (3C), 25.0, 24.4, 24.2, 18.3, −4.3 (2C)
Colourless liquid. Rf = 0.43 (40% EtOAc/hexane). 1H NMR ppm. IR (KBr): 3368, 2952, 2864, 1597, 1506, 1468, 1394, 1263,
(400 MHz, CDCl3): δ 3.60 (s, 3H, NCH3), 3.10 (s, 3H, OCH3), 1158, 1033, 911, 840, 784, 680, 626 cm−1. HRMS (ESI) m/z:
2.23 (d, J = 7.0 Hz, 2H, CH2), 2.04–2.14 (m, 1H, CH), 0.89 (d, [M + H]+ calcd for C24H34NO2Si 396.2359; found 396.2361.
J = 6.60 Hz, 6H, CH3) ppm. 13C NMR (100 MHz, CDCl3):
Synthesis of 4-(3-hydroxy-5-methyl-3-(pyridin-2-yl)hex-1-yn-1-
δ 174.1, 61.1, 40.6, 32.0, 25.1, 22.7 (2C) ppm. IR (KBr): yl)phenyl acetate (12). DBU (0.60 ml, 4.04 mmol) was added to
1640, 719, 707, 680, 396, 602, 487, 450 cm−1. HRMS (ESI) m/z: a stirred solution of 1-(4-((tert-butyldimethylsilyl)oxy)phenyl)-5-
[M + H]+ calcd for C7H16NO2 146.1181; found 146.1179.
methyl-3-(pyridin-2-yl)hex-1-yn-3-ol 11 (1.6 g, 4.04 mmol) in the
Synthesis of 3-methyl-1-(pyridin-2-yl) butan-1-one (9). To a CH3CN : H2O mixture (95 : 5) at room temperature. The reaction
stirred solution of 2-bromopyridine 8 (1.16 mL, 12.3 mmol) in was continued for 15 min at the end of which TLC indicated
dry THF at −78 °C under a nitrogen atmosphere was added complete consumption of the starting material. The reaction
n-BuLi (7.75 mL, 12.3 mmol, 1.6 M solution in hexane). After mixture was then quenched with sat. aq. NH4Cl (50 mL), and
15 min, a solution of 7 (1.5 g, 10.3 mmol) in THF was added extracted with CH2Cl2 (2 × 50 mL). The organic portion was dried
drop-wise to this mixture at −78 °C and the reaction was con- over anhydrous Na2SO4 and concentrated under reduced pressure
tinued at the same temperature for 30 min and then at room to obtain the crude de-silylated product. This was directly taken
temperature for 1 h. It was then quenched with saturated NH4Cl for acetylation without further purification as discussed below.
at 0 °C and extracted with EtOAc (2 × 50 mL); the combined
The de-silylated product was dissolved in dry CH2Cl2
organic layers were dried over anhydrous Na2SO4 and concen- (15 mL), cooled to 0 °C and was admixed with Et3N (0.85 mL,
trated under reduced pressure to obtain the crude residue. It was 6.06 mmol) and AcCl (0.721 mL, 10.1 mmol). After stirring at
purified by column chromatography on silica gel using the the same temperature for 0.5 h, the reaction mixture was
EtOAc–hexane solvent system to obtain the pure product. Yield quenched with H2O (100 mL) and extracted with CH2Cl2 (3 ×
80% (1.34 g). Colourless liquid. Rf = 0.60 (40% EtOAc/hexane). 1H 50 mL). The combined organic layers were dried (Na2SO4) and
NMR (400 MHz, CDCl3): δ 8.66 (d, J = 4.60 Hz, 1H, ArH), 8.02 (d, concentrated under reduced pressure. The residue thus obtained
J = 7.78 Hz, 1H, ArH), 7.79–7.83 (m, 1H, ArH), 7.42–7.45 (m, 1H, was purified by column chromatography on silica gel using the
ArH), 3.09 (d, J = 6.71 Hz, 2H, CH2), 2.25–2.35 (m, 1H, CH), 0.98 EtOAc–hexane solvent system. Yield 95% (1.30 g); colourless
(d, J = 6.60 Hz, 6H, CH3) ppm. 13C NMR (100 MHz, CDCl3): δ liquid; Rf = 0.50 (40% EtOAc/hexane). 1H NMR (400 MHz, CDCl3):
201.9, 153.9, 149.0, 137.0, 127.1, 121.9, 46.5, 24.8, 22.8 (2C) ppm. δ 8.52 (d, J = 4.70 Hz, 1H, ArH), 7.73–7.77 (m, 1H, ArH), 7.66 (d,
IR (KBr): 3059, 2958, 2926, 2867, 1695, 1579, 1462, 1392, 1363, J = 7.56 Hz, 1H, ArH), 7.44 (d, J = 8.54 Hz, 2H, ArH), 7.24–7.27
1301, 1217, 1006, 913, 768, 735, 686, 592 cm−1. HRMS (ESI) m/z: (m, 1H, ArH), 7.03 (d, J = 8.54 Hz, 2H, ArH), 5.54 (s, 1H, OH),
[M + H]+ calcd for C10H14NO 164.1075; found 164.1074.
2.28 (s, 3H, CH3), 1.98–2.07 (m, 2H, CH2), 1.80–1.86 (m, 1H, CH),
Synthesis of 1-(4-((tert-butyldimethylsilyl)oxy)phenyl)-5- 1.01 (d, J = 6.36 Hz, 3H, CH3), 0.89 (d, J = 6.36 Hz, 3H, CH3) ppm.
methyl-3-(pyridin-2-yl)hex-1-yn-3-ol (11). A solution of tert- 13C NMR (100 MHz, CDCl3): δ 169.2, 161.7, 150.6, 147.4, 137.4,
butyl(4-ethynylphenoxy)dimethylsilane 10 (1.70 g, 7.35 mmol) 133.0 (2C), 122.9, 121.7 (2C), 120.9, 120.6, 92.2, 83.8, 72.1, 53.3,
in dry THF was taken in a 100 mL two neck round bottom 25.0, 24.3, 24.1, 21.2 ppm. IR (KBr): 3367, 2953, 2873, 1764, 1592,
flask, and cooled to −78 °C under a nitrogen atmosphere and 1502, 1465, 1430, 1375, 1198, 1020, 911, 846, 784, 753, 627,
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530 cm−1. HRMS (ESI) m/z: [M + H]+ calcd for C20H22NO3 (KBr): 3484, 2954, 1745, 1710, 1639, 1570, 1502, 1436, 1366,
324.1600; found 324.1604.
1288, 1199, 1199, 1018, 912, 734, 666 cm−1. HRMS (ESI) m/z:
Synthesis of (8a-isobutyl-1-oxo-1,8a-dihydroindolizine-2,3- [M + H]+ calcd for C34H34NO9 600.2234; found 600.2221.
diyl)bis(4,1-phenylene) diacetate (14). A solution containing a (5-Isobutyl-5-methoxy-4-oxo-4,5-dihydro-1H-pyrrole-2,3-diyl)
mixture of 12 (1.2 g, 3.71 mmol) and aryl halide 13 (1.45 g, bis(4,1-phenylene) diacetate (16). 40% yield (382 mg). Yellow
1
5.56 mmol) in dry acetonitrile was admixed with Pd(PPh3)4 solid, m.p. 78–80 °C. Rf = 0.46 (60% EtOAc/hexane). H NMR
(214 mg, 5 mol%) and Et3N (1.26 mL, 9.2 mmol) under a nitro- (400 MHz, CDCl3): δ 7.57 (d, J = 8.32 Hz, 2H, ArH), 7.25 (d, J =
gen atmosphere. After heating this mixture for 2 h at 90 °C 8.92 Hz, 2H, ArH), 7.15 (d, J = 8.62 Hz, 2H, ArH), 6.98 (d, J =
under stirring, it was concentrated under reduced pressure 8.62 Hz, 2H, ArH), 5.13 (s, 1H, NH), 3.24 (s, 3H, OCH3), 2.33 (s,
and the residue obtained was re-dissolved in ethyl acetate 3H, OCH3), 2.27 (s, 3H, OCH3), 1.83–1.93 (m, 2H, CH2),
(100 mL) and washed with water (2 × 100 mL). The organic 1.76–1.79 (m, 1H, CH), 0.98 (d, J = 4.07 Hz, 3H, CH3), 0.96 (d,
layer was separated and dried over anhydrous Na2SO4 and the J = 4.07 Hz, 3H, CH3) ppm. 13C NMR (100 MHz, CDCl3):
solvent was evaporated under reduced pressure. The crude δ 199.2, 170.3, 169.6, 169.1, 153.3, 149.3, 130.0 (2C), 129.7
product was purified by chromatography on a silica gel (2C), 128.8, 128.4, 122.6 (2C), 121.5 (2C), 112.2, 92.2, 53.6,
column using the ethyl acetate/hexane system. Yield 80% 51.3, 45.4, 24.4, 24.2, 24.0, 21.30 ppm. IR (KBr): 3275, 2955,
(1.35 g); orange solid; m.p. 152–154 °C. Rf = 0.46 (40% EtOAc/ 2923, 2866, 1751, 1663, 1601, 1553, 1487, 1460, 1372, 1199,
hexane). 1H NMR (400 MHz, CDCl3): δ 7.36 (d, J = 8.15 Hz, 2H, 1078, 1013, 912, 851, 735, 670, 521 cm−1. HRMS (ESI) m/z:
ArH), 7.21 (d, J = 8.47 Hz, 2H, ArH), 7.12 (d, J = 8.44 Hz, 2H, [M + H]+ calcd for C25H28NO6 438.1917; found 438.1924.
ArH), δ 6.89 (d, J = 8.80 Hz, 2H, ArH), 6.35 (d, J = 7.17 Hz, 1H,
Synthesis of 4,5-bis(4-hydroxyphenyl)-2-isobutyl-2-methoxy-
CH), 5.94 (d, J = 3.20 Hz, 2H, CH), 5.34–5.38 (m, 1H, CH), 2.32 1H-pyrrol-3(2H)-one (16a). Potassium carbonate (113 mg,
(s, 3H, OCH3), 2.24 (s, 3H, OCH3), 1.84 (d, J = 4.99 Hz, 2H, CH2), 0.82 mmol) was added to a stirred solution of (5-isobutyl-5-
1.74–1.80 (m, 1H, CH), 0.96 (d, J = 6.65 Hz, 3H, CH3), 0.88 (d, methoxy-4-oxo-4,5-dihydro-1H-pyrrole-2,3-diyl)bis(4,1-pheny-
J = 6.23 Hz, 3H, CH3) ppm. 13C NMR (100 MHz, CDCl3): δ 200.7, lene) diacetate 16 (300 mg, 0.68 mmol) in MeOH (20 mL) at
169.5, 169.0, 168.3, 152.3, 148.9, 130.2 (2C), 129.7 (2C), 128.5, 0 °C and the mixture was stirred at the same temperature for
126.6, 125.1, 123.8, 122.7 (2C), 122.3, 121.2 (2C), 111.3, 109.8, 1 h. After admixing with H2O (30 mL), the mixture was concen-
70.9, 48.4, 24.8, 24.5, 23.5, 21.3 ppm. IR (KBr): 2956, 2873, 1762, trated under reduced pressure and the residue obtained was
1674, 1611, 1547, 1503, 1425, 1371, 1324, 1200, 1054, 1011, 911, extracted with EtOAc (3 × 50 mL). The combined organic layers
841, 716, 668, 524 cm−1. HRMS (ESI) m/z: [M + H]+ calcd for were dried (Na2SO4) and concentrated under reduced pressure
C28H28NO5 458.1967; found 458.1965.
and the yellow solid obtained was further purified by chrom-
Synthesis of (5-isobutyl-5-methoxy-4-oxo-4,5-dihydro-1H- atography on silica gel using the EtOAc–hexane solvent system.
pyrrole-2,3-diyl)bis(4,1-phenylene) diacetate (16). A solution Yield 96% (232 mg); yellow solid; m.p. 126–128 °C. Rf = 0.23
containing a mixture of (8a-isobutyl-1-oxo-1,8a-dihydroindoli- (60% EtOAc/hexane). 1H NMR (400 MHz, CD3OD,): δ 7.41 (d,
zine-2,3-diyl)bis(4,1-phenylene) diacetate 14 (1 g, 2.1 mmol) J = 8.70 Hz, 2H, ArH), 6.95 (d, J = 8.52 Hz, 2H, ArH), 6.77 (d, J =
and dimethyl acetylene dicarboxylate (DMAD) (0.398 mL, 8.64 Hz, 2H, ArH), 6.71 (d, J = 8.50 Hz, 2H, ArH), 3.19 (s, 3H,
3.2 mmol) in a dry toluene–methanol mixture (10 mL : 1 mL) OCH3), 1.83–1.85 (m, 2H, CH2), 1.67–1.74 (m, 1H, CH), 0.95 (d,
was taken in a sealed tube under a nitrogen atmosphere. The J = 2.74 Hz, 3H, CH3), 0.93 (d, J = 2.83 Hz, 3H, CH3) ppm; three
reaction mixture was heated at 80 °C for 12 h, cooled to room exchangeable protons did not appear. 13C NMR (100 MHz,
temperature and was concentrated under reduced pressure to CD3OD): δ 200.7, 175.7, 162.5, 157.1, 131.9 (4C), 124.4, 122.6,
obtain a crude residue. It was then purified by silica gel chrom- 116.4 (2C), 116.2 (2C), 111.6, 93.6, 51.0, 46.3, 24.8, 24.7 (2C)
atography using the EtOAc–hexane solvent system to obtain ppm. IR (KBr): 3290, 2926, 1643, 1600, 1537, 1455, 1368, 1239,
products 15 and 16.
Dimethyl
1,2-bis(4-acetoxyphenyl)-8a-hydroxy-3′-isobutyl- H]+ calcd for C21H24NO4 354.1705; found 354.1709.
3′,8a-dihydrocyclopenta[hi]indolizine-7,8-dicarboxylate (15). Synthesis of 2-hydroxy-4,5-bis(4-hydroxyphenyl)-2-isobutyl-
1176, 1176, 1070, 831, 569, 518 cm−1. HRMS (ESI) m/z: [M +
55% yield (720 mg). Orange solid, m.p. 120–122 °C. Rf = 0.40 1H-pyrrol-3(2H)-one (17). To a stirred suspension of 4,5-bis(4-
1
(40% EtOAc/hexane). H NMR (400 MHz, CDCl3): δ 7.18 (d, J = hydroxyphenyl)-2-isobutyl-2-methoxy-1H-pyrrol-3(2H)-one 16a
8.31 Hz, 2H, ArH), 7.10 (d, J = 8.31 Hz, 2H, ArH), δ 7.01 (d, J = (200 mg, 0.56 mmol) in a mixture of CH2Cl2 (20 mL) and H2O
8.49 Hz, 2H, ArH), 6.90 (d, J = 8.31 Hz, 2H, ArH), 6.83 (d, J = (5 mL) at 0 °C under a nitrogen atmosphere was added trifluor-
6.50 Hz, 1H, CH), 6.68 (d, J = 5.89 Hz, 1H, CH), 5.91–5.94 (m, oacetic acid (2.04 mL, 29.0 mmol) drop-wise, over a period of
1H, CH), 4.23 (s, 1H, OH), 3.92 (s, 3H, OCH3), 3.41 (s, 3H, 5 min. After stirring for 25 min, this mixture was admixed with
OCH3), 2.26 (s, 3H, OCH3), 2.24 (s, 3H, OCH3), 1.65–1.74 (m, H2O (50 mL) followed by EtOAc (50 mL) at the same tempera-
1H, CH), 1.21 (dd, J = 13.86 Hz, 4.62 Hz, 1H, CH), 1.00 (dd, J = ture. The organic phase was separated and washed with H2O
13.86 Hz, 5.46 Hz, 1H, CH), 0.88 (d, J = 6.72 Hz, 6H, CH3) (1 × 50 mL), followed by a saturated aqueous solution of
ppm. 13C NMR (100 MHz, CDCl3): δ 169.4, 169.2, 165.4, 165.0, NaHCO3 (2 × 50 mL) at 0 °C until the pH of the aqueous wash-
151.0, 150.0, 144.6, 144.5, 133.0 (2C), 131.2, 130.5 (2C), 129.0, ings was between 5 and 7. The organic layer was then separ-
127.3, 125.8, 124.1, 121.8 (2C), 120.8 (2C), 120.3, 109.9, 109.8, ated, dried (Na2SO4), and concentrated under reduced
92.6, 71.4, 52.7, 51.8, 35.8, 24.8, 24.3, 23.9, 21.5 (2C) ppm. IR pressure, and the resulting residue was purified by column
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chromatography using the EtOAc–hexane solvent system. Yield
88% (173 mg); yellow solid; m.p. (decomposed above 140 °C).
Rf = 0.20 (60% EtOAc/hexane). 1H NMR (400 MHz, CD3OD):
δ 7.38 (d, J = 8.73 Hz, 2H, ArH), 6.96 (d, J = 8.69 Hz, 2H, ArH),
6.75 (d, J = 8.86 Hz, 2H, ArH), 6.70 (d, J = 8.69 Hz, 2H, ArH),
1.87 (d, J = 6.07 Hz, 2H, CH2), 1.63–1.75 (m, 1H, CH), 0.95 (d,
J = 2.74 Hz, 3H, CH3), 0.93 (d, J = 2.83 Hz, 3H, CH3) ppm; four
exchangeable protons did not appear. 13C NMR (100 MHz,
CD3OD): δ 202.1, 174.4, 162.1, 156.9, 131.9 (2C), 131.8 (2C),
124.9, 123.0, 116.3 (2C), 116.0 (2C), 108.9, 88.8, 46.7, 25.1,
24.7, 24.6 ppm. IR (KBr): 3278, 2926, 1596, 1533, 1440, 1361,
1235, 1173, 1102, 831, 569 cm−1. HRMS (ESI) m/z: [M + H]+
calcd for C20H22NO4 340.1549; found 340.1552.
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Conclusions
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V. Boekelheide, J. Am. Chem. Soc., 1959, 81, 1459–1465;
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In summary, indolizinones and DMAD exhibited two different
cycloaddition modes and subsequent bond reorganization pos-
sibilities, leading to 1H-pyrrol-3(2H)-one (2) and 3′,8a-dihydro-
cyclopenta[hi]indolizin-8a-ol (3) in
a combined yield of
77–98%. The former group of compounds (2) arises through
the retro-Diels Alder reaction of [4 + 2] cycloadducts whereas
the latter (3) requires [8 + 2] cycloaddition followed by
π-reorganization. Electron donating substituents on the C3-aryl
ring were found to promote the formation of an azatricycle,
which indicates better stabilization and reactivity of the 8π
cycloaddition partner involved in the reaction. Formation of
10e aromatic species from this azatricycle was demonstrated
through an NMR experiment by treating 3c with HBF4·Et2O,
which resulted in characteristic shifts of CH3 and olefinic
proton signals. The retro-Diels Alder product 3-azacyclopenta-
dienone is intrinsically unstable but can be trapped using a
nucleophilic solvent like methanol. Remarkably, the resulting
methanol adducts represent the core of discoipyrroles, which
are promising leads against cancer. This was advantageously
used for the total synthesis of discoipyrrole C.
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Conflicts of interest
13 D. Kalaitzakis, M. Triantafyllakis, G. I. Ioannou and
G. Vassilikogiannakis, Angew. Chem., Int. Ed., 2017, 56,
4020–4023.
The authors declare no competing financial interests.
14 K. Afarinkia, V. Vinader, T. D. Nelson and G. H. Posner,
Tetrahedron, 1992, 48, 9111–9171.
Acknowledgements
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Thottiparambil,
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Financial support to this work by SERB, DST (EMR/2016/
003973) is gratefully acknowledged. We thank the Dept. of
Chemistry, IIT Madras and DST-FIST facility for instrumenta-
tion support. We also thank Mr V. Ramkumar, IITM for X-ray
analysis. JK thanks IIT Madras for his research fellowship.
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8848 | Org. Biomol. Chem., 2019, 17, 8832–8848
This journal is © The Royal Society of Chemistry 2019