Flexible synthesis of diverse N-heterocycles from substrates attainable from biomass

Article abstract of DOI:10.1039/c5gc02837j

A suite of diverse N-heterocycles including dihydroindolone, indole, dihydroindolizinone, 2-pyridone, pyrido[1,2-a]indole, dihydrocarbazolone and carbazole have all been prepared from dimethyl itaconate and pyrrole, two compounds attainable from biomass.

Full text of DOI:10.1039/c5gc02837j

View Article Online
View Journal
Green
Chemistry
Accepted Manuscript
This article can be cited before page numbers have been issued, to do this please use: J. Sperry and R.
Bhusal, Green Chem., 2015, DOI: 10.1039/C5GC02837J.
This is an Accepted Manuscript, which has been through the
Royal Society of Chemistry peer review process and has been
accepted for publication.
Accepted Manuscripts are published online shortly after
acceptance, before technical editing, formatting and proof reading.
Using this free service, authors can make their results available
to the community, in citable form, before we publish the edited
article. We will replace this Accepted Manuscript with the edited
and formatted Advance Article as soon as it is available.
You can find more information about Accepted Manuscripts in the
Information for Authors.
Please note that technical editing may introduce minor changes
to the text and/or graphics, which may alter content. The journal’s
standard Terms & Conditions and the Ethical guidelines still
apply. In no event shall the Royal Society of Chemistry be held
responsible for any errors or omissions in this Accepted Manuscript
or any consequences arising from the use of any information it
contains.
www.rsc.org/greenchem

Page 1 of 20
Green Chemistry
View Article Online
DOI: 10.1039/C5GC02837J
Flexible synthesis of diverse N-heterocycles from
substrates attainable from biomass
Ram P. Bhusal and Jonathan Sperry*
Centre for Green Chemical Science, School of Chemical Sciences, The University of
Auckland, 23 Symonds Street, Auckland, New Zealand
Abstract
A suite of diverse N-heterocycles including dihydroindolone, indole, dihydroindolizinone, 2-
pyridone, pyrido[1,2-a]indole, dihydrocarbazolone and carbazole have all be prepared from
dimethyl itaconate and pyrrole, two compounds attainable from biomass.

Green Chemistry
Page 2 of 20
View Article Online
DOI: 10.1039/C5GC02837J
Introduction
Nitrogen-heterocycles (N-heterocycles) are present in many society-reliant chemicals1
including pharmaceuticals, agrochemicals, dyes, nutraceuticals, fragrances and specialty
polymers. At present, these compounds are mainly produced by synthetic chemistry using
building-blocks derived from finite resources. Flexible synthetic routes to N-heterocycles that
employ substrates attainable from biomass will ensure the supply of this important class of
compounds will continue to meet demand as fossil-fuel levels decline.
Itaconic acid (1, Figure 1) is produced by the fungal fermentation of xylose (extracted from
hardwood and agricultural residues) or glucose (typically in the form of molasses from sugar
cane or beets).2,3 Itaconic acid is classed as a fully sustainable chemical building block that
features on the U.S. DOE National Renewable Energy Laboratory's Top 12 list of renewable
chemicals attainable from biomass.4 An ongoing interest in the synthetic utility of the bio-
based molecule 15 led us to examine its potential in the sustainable synthesis of important N-
heterocycles, a strategy that requires a nitrogeneous building block also attainable from
biomass. Pyrrole was chosen as it is currently mass-produced from furan and ammonia,6 both
of which are available from biorenewable sources.7-9
Figure 1. Itaconic acid (1)
The overall plan hinges on the conjugate addition of pyrrole to dimethyl itaconate (2)10
selectively providing the mono- and di-addition products 3 and 4 (Scheme 1). With this initial
stage successful, the presence of the electron-rich heteroaromatic ring and electrophilic esters
in 3 and 4 will be used to effect distinct, selective intramolecular cyclization reactions that

Page 3 of 20
Green Chemistry
View Article Online
DOI: 10.1039/C5GC02837J
would result in a series of N-heterocycles derived from two simple substrates attainable from
biomass (Scheme 1).
Scheme 1. Proposed assembly of biomass-derived N-heterocycles
Results and Discussion
A study investigating the conjugate addition of pyrrole to dimethyl itaconate (2) was initiated
(Scheme 2). Lewis acids performed better than Brønsted acids in this reaction and
specifically, aluminium trichloride was optimal. When an excess of pyrrole was used, the
mono-addition product 3 was formed in good yield, along with a small amount of the di-
addition product 4 (Scheme 2, A). The di-addition product 4 could exclusively formed when
an excess of dimethyl itaconate was employed (Scheme 2, B).11

Green Chemistry
Page 4 of 20
View Article Online
DOI: 10.1039/C5GC02837J
CO2Me
AlCl3
MeNO2-CH2Cl2
+
4
[A]
CO2Me
N
N
H
MeO2C
(13%)
H
3
(3 eq.)
2
(60%)
CO2Me
MeO2C
CO2Me
AlCl3
MeNO2-CH2Cl2
CO2Me
[B]
N
H
CO2Me
N
H
MeO2C
2
4
(98%)
CO2Me
(2.5 eq.)
Scheme 2. Conjugate addition of pyrrole to dimethyl itaconate (2)
The intramolecular cyclization reactions of pyrrole 3 were investigated. In the presence of
polyphosphoric acid (PPA), pyrrole 3 underwent intramolecular C-acylation12 to form the
tetrahydroindolone 5, a heterocyclic motif present in the antipsychotic medication
molindole.13 Dehydrogenation of 5 delivered methyl-4-hydroxyindole-6-carboxylate 6 in
what constitutes an overall type 9 indole synthesis.14 Given the enormous importance of the
indole heterocycle,1,15,16 sustainable synthetic methodologies that provide indoles are of great
importance. The mode of cyclization could be switched upon treating pyrrole 3 with base,
effecting selective N-acylation to give the dihydroindolizinone 7, a motif present in the
alkaloids polygonatine and kinganone.18 In an interesting result, attempts to aromatize 7 to the
indolizine 8 only effected isomerization19 to the 2-pyridone 9, a heterocycle found in many
bioactive natural products and synthetic drugs.20 The synthesis outlined in Scheme 3 provides
a complementary alternative to the synthesis of 4-hydroxyindole-6-carboxylates and
indolizines from the half ester obtained from Stobbe condensation of pyrrole-2-
carboxaldehyde with a dialkyl succinate.21-24

Page 5 of 20
Green Chemistry
View Article Online
DOI: 10.1039/C5GC02837J
Scheme 3. Biomass-derived indole 6 and pyridone 9
The methodology outlined in Scheme 3 was subsequently applied to the double conjugate
addition product 4 (Scheme 4). Upon exposing 4 to PPA, a single C-acylation occurred to
give the tetrahydroindolone 10. None of tetrahydrocarbazole dione 11 was ever formed
despite extensive optimization efforts. However, dehydrogenation of 10 gave indole 12 which
did undergo C-acylation to give the dihydrocarbazolone 13, a heterocyclic motif present in
the anti-emetic drug ondansetron.25 Dehydrogenation of 13 gave carbazoles 14 and 15.26
Carbazole is a tricyclic heterocycle present in a plethora of natural products27 and functional
polymers.28 As the synthesis of carbazoles is often accomplished by the construction of the
central ring using one of the many known C–N bond forming processes, the synthesis of
14/15 from pyrrole follows a relatively uncommon strategy for the construction of this
heterocycle.29

Green Chemistry
Page 6 of 20
View Article Online
DOI: 10.1039/C5GC02837J
Treating 4 with base led to exclusive N-acylation and formation of dihydroindolizinone 16,
which underwent the same Pd/C-mediated isomerization described in Scheme 3 to give the 2-
pyridone 17. Upon subjecting 16 to PPA, C-acylation occurred to give the tricycle 18 which
resisted attempts at dehydrogenation to the desired tricycle 19. However, base-mediated
cyclization of indole 12 did provide the desired pyrido[1,2-a]indolone 19, a heterocyclic
motif present in many alkaloids including strychnine.30
Scheme 4. Biomass-derived tricyclic N-heterocycles
Conclusions
In conclusion, a series of chemically diverse N-heterocycles have been rapidly assembled
from two substrates available from biomass, demonstrating that biorenewable building blocks
can provide a sustainable alternative for the synthesis of valuable small molecules currently
acquired from finite resources.31 By only using compounds attainable from biomass in
synthetic programmes,32 interesting chemical transformations can be discovered that lead to
the production of new ‘sustainable chemical space’. Current focus is geared towards adopting

Page 7 of 20
Green Chemistry
View Article Online
DOI: 10.1039/C5GC02837J
environmentally friendly purification procedures33 and eliminating toxic solvents34 during the
exploration of new sustainable chemical space. Results from our efforts in this area will be
reported in due course.
Experimental
General. All reactions were carried out in oven-dried glassware under a nitrogen atmosphere
unless otherwise stated. Analytical thin layer chromatography was performed using 0.2 mm
silica plates and compounds were visualized under 365 nm ultraviolet irradiation followed by
staining with either alkaline permanganate or ethanolic vanillin solution. Infrared spectra
were obtained as thin films between sodium chloride plates. Absorption maxima are
expressed in wavenumbers (cm–1). Melting points were recorded on a melting point apparatus
and are uncorrected. NMR spectra were recorded as indicated on an NMR spectrometer
1
13
operating at 500, 400 and 300 MHz for H nuclei and 125, 100 and 75 MHz for C nuclei.
Chemical shifts are reported in parts per million (ppm) relative to the tetramethylsilane peak
recorded as δ 0.00 ppm in CDCl3/ TMS solvent, or the residual acetone (δ 2.05 ppm),
chloroform (δ 7.26 ppm), DMSO (δ 2.50 ppm) or methanol (δ 3.31 ppm) peaks. The 13C
NMR values were referenced to the residual acetone (δ 29.9 ppm) chloroform (δ 77.1 ppm),
DMSO (δ 39.5 ppm) or methanol (δ 49.0 ppm) peaks. 13C NMR values are reported as
1
chemical shift δ and assignment. H NMR shift values are reported as chemical shift δ,
relative integral, multiplicity (s, singlet; d, doublet; t, triplet; q, quartet; quin, quintet; m,
multiplet), coupling constant (J in Hz) and assignment. Assignments are made with the aid of
DEPT 90, DEPT 135, COSY, NOESY and HSQC experiments. High resolution mass spectra
were obtained by electrospray ionization in positive ion mode at a nominal accelerating
voltage of 70 eV on a microTOF mass spectrometer.

Green Chemistry
Page 8 of 20
View Article Online
DOI: 10.1039/C5GC02837J
General Procedure A; C-acylation
To polyphosphoric acid (PPA) at 100 ºC was added a solution of substrate in toluene and the
mixture was stirred at 100 ºC for the time stated. The reaction mixture was quenched with ice
cold water (10 mL), the aqueous suspension extracted with ethyl acetate and the organic layer
was washed with water, brine, dried (Na2SO4), filtered and concentrated in vacuo. The crude
residue was purified by flash chromatography on silica gel with eluent stated to give the
desired product.
General Procedure B; N-acylation
A solution of substrate and potassium carbonate in DMF (4 mL) was stirred at 110 ºC for the
time stated. The solvent was concentrated in vacuo and water was added to the residue. The
resulting aqueous suspension was extracted with ethyl acetate and the organic layer was
washed with water, brine, dried (Na2SO4), filtered and concentrated in vacuo. The crude
residue was purified by flash chromatography on silica gel with eluent stated to give the
desired product.
General Procedure C; Dehydrogenation
A suspension of substrate and Pd/C (10 %) in phenylether-mesitylene or n-octanol was
heated at the temperature and time stated. The reaction mixture was filtered through Celite®
and the residual catalyst washed with ethyl acetate. The filtrate was concentrated in vacuo
and the residue purified by flash chromatography on silica gel with eluent stated to give the
desired product.
Dimethyl 2-((pyrrol-2-yl)methyl)succinate (3)

Page 9 of 20
Green Chemistry
View Article Online
DOI: 10.1039/C5GC02837J
To a solution of dimethyl 2-methylenesuccinate (500 mg, 3.16 mmol) in dichloromethane (5
mL) and nitromethane (5 mL) was added pyrrole (0.62 mL, 9.48 mmol) and aluminium
trichloride (443 mg, 9.48 mmol) and the solution was stirred at room temperature for 45 min.
The reaction mixture was then quenched with water (20 mL). The aqueous layer was
extracted with dichloromethane and the organic layer washed with brine, dried (Na2SO4),
filtered and concentrated in vacuo. The crude residue was purified by flash chromatography
on silica gel using hexanes-ethyl acetate (3:1) as eluent to afford the title compound (427 mg,
1.90 mmol, 60%) as a light yellow liquid; νmax (neat)/cm– 1 3383, 2953, 1722, 1570, 1509,
1436, 1409, 1357, 1269, 1194, 1165, 1121, 1095, 1027, 1004, 885, 837, 789, 717; δH (400
MHz, CDCl3) 8.37 (1 H, br s, NH), 6.68 (1 H, td, J 2.7 and 1.5, ArH), 6.09 (1 H, dt, J 5.8 and
2.7, ArH), 5.93-5.92 (1 H, m, ArH), 3.71 (3 H, s, Me), 3.67 (3 H, s, Me), 3.10 (1 H, q, J 6.4,
CH), 3.00 (1 H, dd, J 14.8 and 6.4, CH of CH2), 2.90 (1 H, dd, J 14.8 and 6.4, CH of CH2),
2.68 (1 H, dd, J 16.4 and 7.2, CH of CH2), 2.50 (1 H, dd, J 16.4 and 6.4, CH of CH2); δC (100
MHz, CDCl3) 175.0 (C), 172.3 (C), 128.0 (C), 117.2 (CH), 108.3 (CH), 107.3 (CH), 52.2
(Me), 51.9 (Me), 41.9 (CH), 35.0 (CH2), 29.0 (CH2); HRMS (ESI, [M + Na]+) found
248.0893. [C11H15NO4 + Na]+ requires 248.0898. Compound 4 was also isolated (149 mg,
0.39 mmol, 13%), spectroscopic data described below.
Tetramethyl 2,2'-((pyrrole-2,5-diyl)bis(methylene))disuccinate (4)
To a solution of pyrrole (0.2 mL, 2.88 mmol) in dichloromethane (5 mL) and nitromethane (5
mL) was added dimethyl 2-methylenesuccinate (1.40 g, 7.2 mmol) and aluminium trichloride
(960 mg, 7.2 mmol) and the solution was stirred at room temperature for 45 min. The mixture
was then quenched with water (20 mL) and extracted with dichloromethane. The organic
layer was washed with brine, dried (Na2SO4), filtered and concentrated in vacuo. The crude
residue was purified by flash chromatography on silica gel using hexanes-ethyl acetate (2:1)

Green Chemistry
Page 10 of 20
View Article Online
DOI: 10.1039/C5GC02837J
as eluent to afford the title compound (1.08 g, 2.82 mmol, 98%) as a brown liquid;
νmax (neat)/cm– 1 3383, 1727, 1436, 1355, 1263, 1193, 1163, 1094, 1038, 998, 890, 839, 773;
δH (400 MHz, CDCl3) 8.33 (1 H, br s, NH), 5.76 (2 H, d, J 2.6, 2 x ArH), 3.71 (6 H, s, 2 x
Me), 3.67 (6 H, s, 2 x Me), 3.06 (2 H, quin, J 6.5, 2 x CH), 2.93 (2 H, dd, J 14.8 and 6.5, 2 x
CH of CH2), 2.83 (2 H, ddd, J 14.8 6.5 and 1.7, 2 x CH of CH2), 2.66 (2 H, dd, J 16.5 and
7.6, 2 x CH of CH2), 2.46 (2 H, dd, J 16.5 and 6.4, 2 x CH of CH2); δC (100 MHz, CDCl3)
175.04 (C), 175.00 (C), 172.5 (2 x C), 127.60 (C), 127.58 (C), 107.43 (CH), 107.42 (CH),
52.2 (2 x Me), 51.9 (2 x Me), 42.1 (CH), 42.0 (CH), 35.10 (CH2), 35.06 (CH2), 29.4 (CH2),
29.3 (CH2); HRMS (ESI, [M + Na]+) found 406.1472. [C18H25NO8 + Na]+ requires 406.1478.
Methyl 4-oxo-4,5,6,7-tetrahydroindole-6-carboxylate (5)
General procedure A was performed using PPA (2 g) and 3 (100 mg, 0.45 mmol) in toluene
(1 mL) for 3 h. Workup and column chromatography eluting with hexanes−ethyl acetate (1:1)
gave the title compound (27 mg, 0.14 mmol, 31%) as a colourless solid; M.p. 127-131 ºC;
νmax (neat)/cm–1 3289, 3130, 2952, 2922, 2851, 1725, 1632, 1569, 1505, 1474, 1435, 1377,
1350, 1293, 1271, 1244, 1234, 1193, 1152, 1116, 1077, 1003, 913, 902, 881, 866, 799, 764,
720, 692; δH (400 MHz, CDCl3) 8.80 (1 H, br s, NH), 6.70 (1 H, t, J 2.7, ArH), 6.54 (1 H, t, J
2.7, ArH), 3.72 (3 H, s, Me), 3.29-3.22 (1 H, m, CH), 3.13-3.10 (2 H, m, CH2), 2.82-2.69 (2
H, m, CH2); δC (100 MHz, CDCl3) 191.6 (C), 173.6 (C), 141.1 (C), 120.3 (C), 119.5 (CH),
106.2 (CH), 52.4 (Me), 41.3 (CH), 40.0 (CH2), 25.5 (CH2); HRMS (ESI, [M + Na]+) found
216.0631. [C10H11NO3 + Na]+ requires 216.0637.
Methyl 4-hydroxyindole-6-carboxylate (6)
General procedure C was performed using 5 (100 mg, 0.52 mmol) and Pd/C (100 mg) in
phenylether (3.6 mL) and mesitylene (0.4 mL) for 240 ºC for 36 h. Workup and column

Page 11 of 20
Green Chemistry
View Article Online
DOI: 10.1039/C5GC02837J
chromatography eluting with hexanes then hexanes-ethyl acetate (1:1) gave the title
compound (52 mg, 0.27 mmol, 54%) as a brown solid; δH (400 MHz, CD3OD) 7.68 (1 H, t, J
0.9, ArH), 7.30 (1 H, d, J 3.5, ArH), 7.06 (1 H, d, J 1.4, ArH), 6.58 (1 H, dd, J 3.5 and 0.9,
ArH), 3.88 (3 H, s, Me); δC (100 MHz, CD3OD) 170.2 (C), 151.1 (C), 138.6 (C), 127.4 (C),
124.9 (C), 123.5 (CH), 107.4 (CH), 104.5 (CH), 100.0 (CH), 52.3 (Me); spectroscopic data
consistent with the literature.21
Methyl 5-oxo-5,6,7,8-tetrahydroindolizine-7-carboxylate (7)
General procedure B was performed using 3 (375 mg, 1.7 mmol) and potassium carbonate
(470 mg, 3.4 mmol) in DMF (4 mL) for 12 h. Workup and column chromatography eluting
with hexanes−ethyl acetate (4:1) gave the title compound (198 mg, 1.02 mmol, 60%) as a
fawn solid; M.p. 83-85 ºC; νmax (neat)/cm–1 1716, 1575, 1449, 1429, 1379, 1354, 1302, 1229,
1214, 1199, 1151, 1100, 1068, 1031, 1022, 1005, 917, 870, 825, 802, 750, 621, 594; δH (400
MHz, CDCl3) 7.35 (1 H, dd, J 3.4 and 1.4, ArH), 6.22 (1 H, t, J 3.4, ArH), 6.03-6.02 (1 H, m,
ArH), 3.73 (3 H, s, Me), 3.23-3.17 (1 H, m, CH of CH2), 3.16-3.10 (1 H, m, CH), 3.03-2.97
(1 H, m, CH of CH2), 2.94-2.85 (2 H, m, CH2); δC (100 MHz, CDCl3) 172.8 (C), 166.4 (C),
130.1 (C), 116.6 (CH), 113.1 (CH), 110.0 (CH), 52.5 (Me), 39.2 (CH), 35.3 (CH2), 25.9
(CH2); HRMS (ESI, [M + Na]+) found 216.0631. [C10H11NO3 + Na]+ requires 216.0637.
Methyl 5-oxo-1,2,3,5-tetrahydroindolizine-7-carboxylate (9)
General procedure C was performed using 7 (40 mg, 0.21 mmol) and Pd/C (40 mg) in n-
octanol (2 mL) at 195 ºC for 12 h. Workup and column chromatography eluting with ethyl
acetate-methanol (9.5:0.5) gave the title compound (30 mg, 0.155 mmol, 75%) as a colourless
solid; M.p. 75-80 ºC; νmax (neat)/cm–1 1714, 1577, 1383, 1360, 1306, 1231, 1200, 1155, 1034,
1008, 827, 754; δH (400 MHz, CDCl3) 7.03 (1 H, d, J 1.3, ArH), 6.61 (1 H, d, J 1.3, ArH),

Green Chemistry
Page 12 of 20
View Article Online
DOI: 10.1039/C5GC02837J
4.16 (2 H, t, J 7.3, CH2), 3.89 (3 H, s, Me), 3.12 (2 H, t, J 7.7, CH2), 2.22 (2 H, quin, J 7.7,
CH2); δC (100 MHz, CDCl3) 165.6 (C), 161.9 (C), 151.1 (C), 141.2 (C), 119.2 (CH), 99.8
(CH), 52.7 (Me), 48.9 (CH2), 31.8 (CH2), 21.3 (CH2); HRMS (ESI, [M + Na]+) found
216.0634. [C10H11NO3 + Na]+ requires 216.0637.
Dimethyl 2-((6-(methoxycarbonyl)-4-oxo-4,5,6,7-tetrahydroindol-2-yl)methyl)succinate
(10)
General procedure A was performed using PPA (2 g) and 4 (321 mg, 0.84 mmol) in toluene
(2 mL) for 45 min. Workup and column chromatography eluting with hexanes−ethyl acetate
(1:1.5) gave the title compound (216 mg, 0.65 mmol, 73%, 1:1 mixture of diastereomers) as a
brown solid; M.p. 74-77 ºC; νmax (neat)/cm–1 3249, 2955, 1729, 1631, 1484, 1436, 1365,
1239, 1168, 1192, 1052, 1003, 915, 891, 813, 729; δH (400 MHz, CDCl3) 8.93 (2 H, br s, 2 x
NH), 6.234 (1 H, s, ArH), 6.228 (1 H, s, ArH), 3.72 (12 H, s, 4 x Me), 3.670 (3 H, s, Me),
3.668 (3 H, s Me), 3.26-3.18 (2 H, m, 2 x CH), 3.11-3.00 (6 H, m, 2 x CH + 2 x CH2), 2.96-
2.84 (4 H, m, 2 x CH2), 2.77-2.64 (6 H, m, 2 x CH of CH2 + 2 x CH2), 2.56-2.50 (2 H, m, 2 x
CH of CH2); δC (100 MHz, CDCl3) 191.2 (2 x C), 175.12 (C), 175.05 (C), 173.6 (2 x C),
172.3 (C), 172.2 (C), 141.2 (2 x C), 130.3 (2 x C), 120.3 (2 x C), 104.72 (CH), 104.69 (CH),
52.5 (2 x Me), 52.4 (2 x Me), 52.1 (2 x Me), 41.41 (CH), 41.38 (CH), 41.2 (2 x CH), 39.8 (2
x CH2), 35.1 (2 x CH2), 28.7 (2 x CH2), 25.4 (2 x CH2); HRMS (ESI, [M + Na]+) found
374.1210. [C17H21NO7 + Na]+ requires 374.1216.
Dimethyl 2-((4-hydroxy-6-(methoxycarbonyl)indol-2-yl)methyl)succinate (12)
General procedure C was performed using 10 (156 mg, 0.44 mmol) and Pd/C (237 mg) in
phenylether (2.7 mL) and mesitylene (0.3 mL) for 240 ºC for 18 h. Workup and column
chromatography eluting with hexanes-ethyl acetate (1:1) gave the title compound (100 mg,

Page 13 of 20
Green Chemistry
View Article Online
DOI: 10.1039/C5GC02837J
0.29 mmol, 66%) as a yellow oil; νmax (neat)/cm–1 3351, 2953, 1710, 1686, 1591, 1546, 1435,
1368, 1279, 1222, 1166, 1092, 1070, 1001, 867, 795, 769; δH (400 MHz, CDCl3) 8.80 (1 H,
brs, NH), 7.71 (1 H, d, J 1.0, ArH), 7.20 (1 H, d, J 1.3, ArH), 6.38 (1 H, m, ArH), 5.43 (1 H,
br s, OH), 3.91 (3 H, s, Me), 3.73 (3 H, s, Me), 3.67 (3 H, s, Me), 3.25-3.16 (2 H, m, CH +
CH of CH2), 3.13-3.07 (1 H, m, CH of CH2), 2.76-2.71 (1 H, m, CH of CH2), 2.58-2.53 (1 H,
m, CH of CH2); δC (100 MHz, CDCl3) 174.9 (C), 172.3 (C), 168.2 (C), 148.1 (C), 137.8 (C),
137.2 (C), 124.3 (C), 122.0 (C), 106.9 (CH), 105.1 (CH), 98.9 (CH), 52.6 (Me), 52.2 (2 x
Me), 41.5 (CH), 35.2 (CH2), 29.5 (CH2); HRMS (ESI, [M + Na]+) found 372.1054.
[C17H19NO7 + Na]+ requires 372.0962.
Dimethyl 5-hydroxy-4-oxo-2,3,4,9-tetrahydrocarbazole-2,7-dicarboxylate (13)
General procedure A was performed using PPA (2 g) and 12 (40 mg, 0.12 mmol) in toluene
(1 mL) for 45 min. Workup and column chromatography eluting with hexanes−ethyl acetate
(1:1.5) gave the title compound (20 mg, 0.06 mmol, 55%) as a brown solid; M.p. 255-259 ºC;
νmax (neat)/cm–1 3287, 2953, 1706, 1589, 1476, 1436, 1404, 1344, 1315, 1226, 1199, 1147,
1086, 1062, 994, 896, 875, 788, 768, 690; δH (400 MHz, DMSO-d6) 12.49 (1 H, br s, NH),
10.76 (1 H, s, OH), 7.52 (1 H, d, J 1.4, ArH) 7.03 (1 H, d, J 1.4, ArH), 3.84 (3 H, s, Me), 3.65
(3 H, s, Me), 3.56-3.49 (1 H, m, CH), 3.35-3.22 (2 H, m, CH2), 2.84-2.83 (2 H, m, CH2);
δC (100 MHz, DMSO-d6) 193.9 (C), 172.9 (C), 166.5 (C), 153.3 (C), 150.2 (C), 137.3 (C),
126.7 (C), 117.5 (C), 112.0 (C), 106.6 (CH), 105.2 (CH), 52.1 (Me), 52.0 (Me), 39.9 (CH),
37.9 (CH2), 24.8 (CH2); HRMS (ESI, [M + Na]+) found 340.0792. [C16H15NO6
Na]+ requires 340.0797.
+
Dimethyl 4,5-dihydroxycarbazole-2,7-dicarboxylate (14) and dimethyl 4-hydroxy-5-
methoxycarbazole-2,7-dicarboxylate (15)

Green Chemistry
Page 14 of 20
View Article Online
DOI: 10.1039/C5GC02837J
General procedure C was performed using 13 (100 mg, 0.31 mmol) and Pd/C (170 mg) in
phenylether (2.7 mL) and mesitylene (0.3 mL) for 240 ºC for 18 h. Workup (filtration
through silica gel instead of Celite®) and column chromatography eluting with hexanes-ethyl
acetate (1:1) gave the title compounds:
14 (25 mg, 0.08 mmol, 25%) as a brown solid; M.p. 325-330 ºC; νmax (neat)/cm–1 3313,
1692, 1590, 1518, 1456, 1436, 1427, 1360, 1334, 1313, 1226, 1190, 1089, 1074, 1010, 992,
912, 861, 848, 796, 759, 722; δH (400 MHz, DMSO-d6) 11.82 (1 H, s, NH), 11.19 (2 H, s, 2 x
OH), 7.64 (2 H, d, J 1.3, 2 x ArH), 7.18 (2 H, d, J 1.3, 2 x ArH), 3.88 (6 H, s, 2 x Me);
δC (100 MHz, DMSO-d6) 166.5 (2 x C), 150.3 (2 x C), 141.2 (2 x C), 128.7 (2 x C), 113.3 (2
x C), 104.6 (4 x CH), 52.2 (2 x Me) ; HRMS (ESI, [M + Na]+) found 338.0635. [C16H13NO6
+ Na]+ requires 338.0641.
15 (11 mg, 0.03 mmol, 10%) brown solid; M.p. 245-250 ºC; νmax (neat)/cm–13302, 1695,
1637, 1571, 1518, 1498, 1432, 1332, 1315, 1256, 1211, 1116, 1090, 1083, 1046, 1012, 964,
862, 790, 759, 729; δH (400 MHz, DMSO-d6) 11.98 (1 H, s, NH), 9.31 (1 H, s, OH), 7.82 (1
H, d, J 1.0, ArH), 7.64 (1 H, d, J 1.2, ArH), 7.33 (1 H, s, ArH), 7.12 (1 H, d, J 1.0, ArH), 4.19
(3 H, s, Me), 3.91 (3 H, s, Me), 3.88 (3 H, s, Me); δC (100 MHz, DMSO-d6) 166.5 (C), 166.3
(C), 152.1 (C), 151.1 (C), 141.4 (C), 140.8 (C), 129.1 (C), 128.4 (C), 113.4 (C), 112.6 (C),
107.2 (CH), 105.0 (CH), 104.2 (CH), 100.7 (CH), 56.8 (Me), 52.3 (Me), 52.2 (Me); HRMS
(ESI, [M + Na]+) found 352.0792. [C17H15NO6 + Na]+ requires 352.0797.
Dimethyl 2-((7-(methoxycarbonyl)-5-oxo-5,6,7,8-tetrahydroindolizin-3-
yl)methyl)succinate (16)
General procedure B was performed using 4 (420 mg, 1.09 mmol) and potassium carbonate
(757 mg, 5.47 mmol) in DMF (5 mL) for 12 h. Workup and column chromatography eluting
dichloromethane−ethyl acetate (15:1) gave the title compound (222 mg, 0.63 mmol, 58%, 1:1

Page 15 of 20
Green Chemistry
View Article Online
DOI: 10.1039/C5GC02837J
mixture of diastereomers) as a yellow oil; νmax (neat)/cm–1 1720, 1436, 1388, 1350, 1305,
1252, 1195, 1167, 1075, 1049, 1003, 920, 889, 835, 789; δH (400 MHz, CDCl3) 5.93 (1 H, s,
ArH), 5.92 (1 H, s, ArH), 5.88-5.87 (2 H, m, 2 x ArH), 3.72 (6 H, s, 2 x Me), 3.65 (3 H, s,
Me), 3.64 (3 H, s, Me), 3.62 (3 H, s, Me), 3.61 (3 H, s, Me), 3.34-2.84 (16 H, m, 4 x CH + 6
x CH2), 2.73-2.65 (2 H, m, 2 x CH of CH2), 2.53-2.47 (2 H, m, 2 x CH of CH2); δC (100
MHz, CDCl3) 175.14 (C), 175.11 (C), 172.8 (2 x C), 172.3 (2 x C), 168.1 (C), 168.0 (C),
131.0 (4 x C), 113.93 (CH), 113.88 (CH), 108.6 (2 x CH), 52.5 (2 x Me), 52.0 (2 x Me), 51.8
(2 x Me), 40.8 (2 x CH), 38.9 (2 x CH), 36.7 (2 x CH2), 35.7 (CH2), 35.6 (CH2), 31.6 (CH2),
31.5 (CH2), 26.6 (2 x CH2); HRMS (ESI, [M + Na]+) found 374.1210. [C17H21NO7 +
Na]+ requires 374.1216.
Dimethyl
2-((7-(methoxycarbonyl)-5-oxo-1,2,3,5-tetrahydroindolizin-3-
yl)methyl)succinate (17)
General procedure C was performed using 16 (32 mg, 0.09 mmol) and Pd/C (32 mg) in n-
octanol (2 mL) at 195 ºC for 12 h. Workup and column chromatography eluting with
hexanes-ethyl acetate (1:1) gave the title compound (25 mg, 0.07 mmol, 78%, 1:1 mixture of
diastereomers) as a yellow oil; νmax (neat)/cm–1 2954, 1727, 1663, 1587, 1540, 1436, 1368,
1251, 1163, 1073, 988, 878, 839, 722; δH (400 MHz, CDCl3) 6.98 (1 H, s, ArH), 6.97 (1 H, s,
ArH), 6.56 (2 H, s, ArH), 4.84-4.78 (1 H, m, CH), 4.77-4.72 (1 H, m, CH), 3.88 (6 H, s, 2 x
Me), 3.74 (3 H, s, Me), 3.69 (3 H, s, Me), 3.68 (3 H, s, Me), 3.67 (3 H, s, Me), 3.25-3.13 (2
H, m, CH2), 3.05-2.94, (4 H, m, 2 x CH + CH2), 2.89-2.78 (2 H, m, CH2), 2.70-2.57 (2 H, m,
CH2), 2.43-2.34 (1 H, m, CH of CH2), 2.32-2.22 (2 H, m, CH2), 2.11-2.02 (3 H, m, CH2 + CH
of CH2), 1.99-1.92 (1 H, m, CH of CH2), 1.72-1.65 (1 H, m, CH of CH2); δC (100
MHz, CDCl3) 174.6 (C), 174.2 (C) 172.29 (C), 172.25 (C), 165.6 (2 x C), 161.8 (C) 161.7
(C), 150.7 (2 x C), 141.4 (C), 141.3 (C), 120.0 (CH), 119.9 (CH), 99.93 (CH), 99.91 (CH),

Green Chemistry
Page 16 of 20
View Article Online
DOI: 10.1039/C5GC02837J
59.8 (CH), 59.2 (CH), 52.9 (2 x Me), 52.4 (Me), 52.3 (Me), 52.1 (Me), 52.0 (Me), 39.1 (CH),
38.9 (CH), 36.0 (CH2), 35.9 (CH2), 33.9 (CH2) 33.8 (CH2), 30.14 (CH2), 30.12 (CH2), 26.9
(CH2), 26.8 (CH2); HRMS (ESI, [M + Na]+) found 374.1210. [C17H21NO7 + Na]+ requires
374.1216.
Dimethyl 1,6-dioxo-1,2,3,4,6,7,8,9-octahydropyrido[1,2-a]indole-3,8-dicarboxylate (18)
General procedure A was performed using PPA (2 g) and 16 (170 mg, 0.48 mmol) in toluene
(2 mL) for 3 h. Workup and column chromatography eluting with hexanes−ethyl acetate (1:1)
gave the title compound (82 mg, 0.26 mmol, 53%, 1:1 mixture of diastereomers) as a
colourless solid; M.p. 82-87 ºC; νmax (neat)/cm–1 1725, 1657, 1574, 1435, 1373, 1356, 1274,
1246, 1177, 1134, 1069, 1029, 1003, 916, 756; δH (400 MHz, CDCl3) 6.34 (2 H, t, J 1.3, 2 x
ArH), 3.74 (3 H, s, Me), 3.730 (3 H, s, Me), 3.726 (3 H, s, Me), 3.721 (3 H, s, Me), 3.70-3.68
(1 H, m, CH of CH2), 3.65-3.63 (1 H, m, CH of CH2), 3.44-3.37 (2 H, m, CH2), 3.28-3.10 (6
H, m, 4 x CH + 2 x CH2), 3.08-3.01 (2 H, m, 2 x CH of CH2), 2.98-2.96 (4 H, m, 2 x CH2),
2.75 (2 H, s, CH2), 2.73 (2 H, s, CH2); δC (100 MHz, CDCl3) 192.12 (C), 192.09 (C), 173.5
(C), 173.4 (C), 172.5 (C), 172.4 (C), 168.3 (2 x C), 141.8 (2 x C), 131.8 (C), 131.7 (C), 123.5
(2 x C), 105.4 (2 x CH), 52.7 (2 x Me), 52.4 (2 x Me), 40.9 (CH), 40.7 (CH), 39.74 (CH2),
39.69 (CH2), 38.4 (CH), 38.3 (CH), 36.54 (CH2), 36.51 (CH2), 27.4 (2 x CH2), 26.3 (CH2),
26.2 (CH2); HRMS (ESI, [M + Na]+) found 342.0948. [C16H17NO6 + Na]+ requires 342.0998.
Dimethyl 1-hydroxy-6-oxo-6,7,8,9-tetrahydropyrido[1,2-a]indole-3,8-dicarboxylate (19)
General procedure B was performed using 12 (20 mg, 0.057 mmol) and potassium carbonate
(24 mg, 0.17 mmol) in DMF (1 mL) for 2 h. Workup and column chromatography eluting
with hexanes−ethyl acetate (1.5:1) gave the title compound (12 mg, 0.038 mmol, 67%) as a
colourless solid; M.p. 225-230 ºC; νmax (neat)/cm–1 1731 1695, 1578, 1432, 1326, 1313, 1233,

Page 17 of 20
Green Chemistry
View Article Online
DOI: 10.1039/C5GC02837J
1198, 1056, 1024, 996, 886, 824, 771; δH (400 MHz, DMSO-d6) 10.12 (1 H, br s, OH), 8.43
(1 H, d, J 1.1, ArH), 7.27 (1 H, d, J 1.1, ArH), 6.60 (1 H, s, ArH), 3.85 (3 H, s, Me), 3.62 (3
H, s, Me), 3.46-3.35 (2 H, m, CH + CH of CH2), 3.20-3.14 (1 H, m, CH of CH2), 3.01-3.00 (2
H, m, CH2); δC (100 MHz, DMSO-d6) 172.8 (C), 168.0 (C), 166.7 (C), 149.5 (C), 137.9 (C),
135.1 (C), 126.0 (C), 122.7 (C), 109.3 (CH), 108.8 (CH), 102.2 (CH), 52.1 (Me), 52.0 (Me),
37.4 (CH), 35.5 (CH2), 25.7 (CH2).; HRMS (ESI, [M + Na]+) found 340.0792 . [C16H15NO6 +
Na]+ requires 340.0797.
Acknowledgements
We thank the University of Auckland for financial support (FRDF grant 3704091 and
Doctoral Scholarship to R. P. B.)
References
1. (a) A. F. Pozharskii, A. Soldatenkov and A. R. Katritzky, Heterocycles in Life and Society
Wiley, New York, 2nd edn., 2011; (b) E. Vitaku, D. T. Smith and J. T. Njardarson, J. Med.
Chem., 2014, 57, 10257; (c) T. C. Barden, Top. Heterocycl. Chem., 2011, 26, 31.
2. A. Corma, S. Iborra and A. Velty, Chem. Rev., 2007, 107, 2411;
3. T. Klement and J. Büchs, Bioresource Technology, 2013, 135, 422.
4. (a) S. K. Ritter, Chem. Eng. News. 2004, 82, 31; (b) T. Werby and G. Petersen, G. (eds.) In
‘Top Value Added Chemicals from Biomass’; US Department of Energy, 2004.
www.eere.energy.gov/biomass/pdfs/35523.pdf.
5. A. M. Medway and J. Sperry, Green Chem., 2014, 16, 2084.
6. A. L. Harreus. "Pyrrole" in Ullmann's Encyclopedia of Industrial Chemistry, Wiley-VCH,
Weinheim, 2002.

Green Chemistry
Page 18 of 20
View Article Online
DOI: 10.1039/C5GC02837J
7. For the decarbonylation of furfural, see: (a) C. M. Cai, T. Zhang, R. Kumar and C. E.
Wyman, J. Chem. Technol. Biotechnol., 2014, 89, 2; (b) P. Lejemble, A. Gaset and P. Kalck.
Biomass, 1984, 4, 263.
8. For a discussion on the production of ammonia from biomass, see (a) J. Andersson and J.
Lundgren, Applied Energy, 2014, 130, 484; (b) P. Gilbert, S. Alexander, P. Thornley and J.
Brammer, J. Clean. Prod., 2014, 64, 581.
9. For a recent publication on the direct synthesis of N-heterocycles (including pyrroles) from
biomass, see: L.j. Xu, Q. Yao, J. Deng, Z. Han, Y. Zhang, Y. Fu, G. H. Huber and Q. Guo,
ACS Sustainable Chem. Eng., 2015, 3, 2890.
10. Dimethyl itaconate is obtained by the acid-catalysed diesterification of itaconic acid with
methanol (wood alcohol), see: M. Enoki, Y. Honda, M. Kuwahara and T. Watanabe, Chem.
Phys. Lipids, 2002, 120, 9.
11. Despite screening several different catalysts and solvents, AlCl3 in CH2Cl2-MeNO2 was
the only combination that gave acceptable yields.
12. For a similar cyclization using a carboxylic acid, see: M. Julia and Y. R. Pascal, Chimica
Therapeutica, 1970, 5, 279.
13. A. A. Sugennan and J. Herman, Clin. Pharmacol. Therap., 1967, 8, 261.
14. D. F. Taber and P. K. Tirunahari, Tetrahedron, 2011, 67, 7195.
15. R. J. Sundberg, The Chemistry of Indoles, Academic Press, New York, 1970.
16. J. A. Joule, Science of Synthesis, ed. E. J. Thomas, Thieme, Stuttgart, 2000, vol. 10, ch.
10.13.
17. (a) N. K. Kaushik, N. Kaushik, P. Attri, N. Kumar, C. H. Kim, A. K. Verma and E. H.
Choi, Molecules, 2013, 18, 6620.
18. (a) Y.-F.Wang, C.-H. Lu, G.-F. Lai, J.-X. Cao and S.-D. Luo, PlantaMed., 2003, 69,
1063; (b) A. Dinsmore, K. Mandy and J. P. Michael, Org. Biomol. Chem., 2006, 4, 1032.

Page 19 of 20
Green Chemistry
View Article Online
DOI: 10.1039/C5GC02837J
19. The isomerization does not occur in the absence of Pd/C. For related examples, see:
(a) N. J. Leonard and D. M. Locke, J. Am. Chem. Soc., 1955, 77, 1852; (b) Y. Shimoji, T.
Hashimoto, Y. Furukawa and Y. Yanagisawa, Heterocycles, 1993, 36, 123.
20. (a) Q. Li, L. A. Mitscher and L. L. Shen, Med. Res. Rev., 2000, 20, 231; (b) H. J. Jessen
and K. Gademann, Nat. Prod. Rep., 2010, 27, 1168; (c) M. A. Ciufolini and B. K. Chan,
Heterocycles, 2007, 74, 101; (d) M. Torres, S. Gil and M. Parra, Curr. Org.
Chem., 2005, 9, 1757.
21. M. Kim and E. Vedejs, J. Org. Chem., 2004, 69, 6945.
22. (a) N. R. El-Rayyes, J. Prakt. Chem., 1973, 315, 295; (b) C. Fuganti and S. Serra, J.
Chem. Res., Miniprint, 1998, 2726.
23. J. G. Kodet, and D. F. Wiemer, J. Org. Chem., 2013, 78, 9291.
24. For applications of 4-hydroxyindole-6-carboxylic acid derivatives, see: (a) M. Kim and E.
Vedejs, J. Org. Chem., 2004, 69, 7262; (b) J. G. Kodet, J. A. Beutler and D. F. Wiemer,
Bioorg. Med. Chem., 2014, 22, 2542; (c) Z. Shi, M. Boultadakis-Arapinis, D. C. Koester and
F. Glorius, Chem. Commun., 2014, 50, 2650.
25. C. R. Culy, N. Bhana and G. L. Plosker, Paediatric Drugs, 2001, 3, 441.
26. The formation of O-methylated carbazole 15 requires comment. It is possible water
contained in the Pd/C hydrolyses the ester(s) during the reaction. At the high temperatures,
the liberated methanol then attacks the carbonyl in compound 13 or directly methylates 14,
both of which would result in compound 15.
27. A. W. Schmidt, K. R. Reddy and H.-J. Knölker, Chem. Rev., 2012, 112, 3193.
28. J. V. Grazulevicius, P. Strohriegl, J. Pielichowski and K. Pielichowski, Prog. Polym. Sci.,
2003, 28, 1297.
29. For the synthesis of carbazoles from pyrroles, see: (a) C. Kashima, S. Hibi, T. Maruyama
and Y. Omote, Tetrahedron Lett., 1986, 27, 2131; (b) K. S. Rathore, M. Harode and S.

Green Chemistry
Page 20 of 20
View Article Online
DOI: 10.1039/C5GC02837J
Katukojvala, Org. Biomol. Chem., 2014, 12, 8641; (c) B. Y. Chung, D. J. Bae, J. I. Jin and S.
D. Lee, J. Kor. Chem. Soc., 1992, 36, 603; (d) M. L. Baron, L. L. Martin, I. D. Rae, P. M.
Simmonds and M. L. Woolcock, Aust. J. Chem., 1990, 43, 741; (e) M. Yamashita, H.
Horiguchi, K. Hirano, T. Satoh and M. Miura, J. Org. Chem., 2009, 74, 7481.
30. I. Karthikeyan, D. Arunprasath and G. Sekar, Chem. Commun., 2015, 51, 1701 and
references therein.
31. For a review on sustainable approaches to heterocycle synthesis, see: N. R. Candeias, L.
C. Branco, P. M. P. Gois, C. A. M. Afonso and A. F. Trindade, Chem. Rev., 2009, 109, 2703.
32. (a) P.-F. Koh and T.-P. Loh, Green Chem., 2015, 17, 3746 (b) D. Stubba, G. Lahm, M.
;
Geffe, J. W. Runyon, A. J. Arduengo III and T. Opatz, Angew. Chem., Int Ed., 2015, 54,
14187.
33. D. Prat, J. Hayler and A. Wells, Green Chem., 2014, 16, 4546.
34. E. A. Peterson, B. Dillon, I. Raheem, P. Richardson, D. Richter, R. Schmidt and H. F.
Sneddon, Green Chem., 2014, 16, 4060.