Microwave-assisted synthesis of pyridylpyrroles from N-acylated amino acids

Article abstract of DOI:10.1016/j.tet.2009.09.094

A small library of 3- and 4-pyridyl-substituted pyrroles was prepared from N-acylated amino acids. Nicotinoyl or isonicotinoyl chloride was used for the N-acylation of benzyl esters of amino acids. Debenzylation by palladium-catalyzed hydrogenation gave N-acylated amino acids. Dehydration of the acylated amino acids gave cyclic intermediates, münchnones or azlactones, which were treated in situ with alkynes in 1,3-dipolar cycloadditions. The starting materials were prepared in a parallel fashion, and microwave irradiation was used to facilitate the cycloaddition reactions. The regiochemistry of the cycloaddition was studied.

Full text of DOI:10.1016/j.tet.2009.09.094

Tetrahedron 65 (2009) 9702–9706
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Microwave-assisted synthesis of pyridylpyrroles from N-acylated amino acids
*
Kirsi Harju, Nenad Manevski, Jari Yli-Kauhaluoma
Division of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Helsinki, P.O. Box 56, FI-00014, Finland
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 5 June 2009
Received in revised form
10 September 2009
Accepted 24 September 2009
Available online 26 September 2009
A small library of 3- and 4-pyridyl-substituted pyrroles was prepared from N-acylated amino acids. Nic-
otinoyl or isonicotinoyl chloride was used for the N-acylation of benzyl esters of amino acids. Debenzylation
by palladium-catalyzed hydrogenation gave N-acylated amino acids. Dehydration of the acylated amino
acids gave cyclic intermediates, mu¨nchnones or azlactones, which were treated in situ with alkynes in 1,3-
dipolar cycloadditions. The starting materials were prepared in a parallel fashion, and microwave irradiation
was used to facilitate the cycloaddition reactions. The regiochemistry of the cycloaddition was studied.
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
1,3-Dipolar cycloaddition
Pyrroles
Mu¨ nchnones
Azlactones
Microwave synthesis
1. Introduction
acids in the cycloaddition. The chemistry of the mu¨nchnones and
azlactones has recently been reviewed,21 and some mesoion-me-
Pyrroles are interesting aromatic heterocycles, widely present in
nature. The pyrrole ring appears in many natural compounds in-
cluding marine alkaloids,1 bacterial prodigiosins,2 and porphyrins.3
Some of these naturally occurring pyrroles have shown antitumor
activity.4 Additionally, commercial drugs such as cholesterol-re-
ducing atorvastatin5 and anti-inflammatory ketorolac6 contain the
pyrrole ring. Pyridylpyrroles, in turn, have shown antidiabetic,7
anti-inflammatory,8 antioxidant,9 antiprotozoal,10 and antiviral11
activities, and they are also found in tobacco alkaloids.12
diated syntheses of pyrroles have also been reported,22 including
one microwave-assisted synthesis.23
1,3-Dipolar cycloaddition is an efficient reaction carried out with
simple building blocks. Amino acids are readily available reagents
with a wide variety of functional groups. Another substituent is easily
added to the pyrrole ring structure through acylation of the amino
acid. Pyrroles with various substituents are then readily obtained
when the mesoionic compounds are reacted with alkynes. Micro-
waves can be used to enhance the reaction rate, and a compound li-
brary can be conveniently obtained with parallel methods. We
describe here a microwave-assisted synthesis of various pyridyl
pyrroles.
There are various methods to prepare pyrroles.13 One of the
methods involves 1,3-dipolar cycloaddition of azomethine ylides
and alkynes.14 The cycloaddition reaction of azomethine ylide-type
mesoionic dipoles, mu¨nchnones15 or azlactones,16 with alkynes
was first reported by Huisgen et al. Mu¨nchnones are obtained from
secondary amino acids and are highly reactive toward alkynes,
whereas azlactones, which are obtained from primary amino acids,
require tautomeric proton shift before cycloaddition.17 Mesoionic
azomethine ylide-type dipoles can be obtained from N-acylated
amino acids with a dehydrating agent. Typically the water-re-
moving agent has been acetic anhydride used simultaneously for
the acylation of the amino acid, but other reagents, such as N,N0-
dicyclohexylcarbodiimide (DCC),18 N-(3-dimethylaminopropyl)-N0-
ethylcarbodiimide (EDC),19 and N,N0-diisopropylcarbodiimide
(DIC),20 have been used for the dehydration of N-acylated amino
2. Results and discussion
N-Acylated amino acid benzyl esters were prepared in a parallel
fashion on a Radleys 12-place carousel reaction station from benzyl
esters of amino acids 1 and acyl chlorides (Scheme 1). Parallel
catalytic hydrogenation in Radleys reaction tubes gave pyridyl-
substituted amino acids 2. Cycloaddition with a dehydrating re-
agent and dimethyl acetylenedicarboxylate (DMAD) or methyl
propiolate led to highly functionalized pyrroles 4a–4m. Several
dehydrating agents were tested and acetic anhydride gave the
highest yields. The yields with EDC and polymer-bound N-benzyl-
N0-cyclohexylcarbodiimide were lower than those obtained with
acetic anhydride. DCC and DIC gave urea as side-product, which
was difficult to remove.
* Corresponding author. Tel.: þ358 9 191 59170; fax: þ358 9 191 59556.
E-mail address: jari.yli-kauhaluoma@helsinki.fi (J. Yli-Kauhaluoma).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.09.094

K. Harju et al. / Tetrahedron 65 (2009) 9702–9706
9703
(Fig. 1). The yields and purities of the pyrroles are listed in Table 1.
Methyl propiolate gave two regioisomers. The regiochemistry of
the mu¨nchnone cycloaddition has been studied, and the regio-
chemical outcome depends on the substituents.24 The amino acids
behaved quite differently, and gave varying regiochemical results.
Compounds 4b and 4e, which were prepared via azlactones, were
obtained regioselectively, whereas compounds obtained via
mu¨nchnones were mixtures of regioisomers. Pyrrole 4k was an
inseparable mixture of two regioisomers, while pyrroles 4h and 4i
were a separable mixture of regioisomers. The regiochemistry of
the cycloaddition was verified with NMR experiments. The pyrrole
CH proton appeared at 6.67–6.93 ppm when the proton was closer
to the pyridyl ring and at 6.38–6.40 ppm when it was closer to the
alkyl substituent. Additionally, NOESY experiments revealed close
proximity of the aromatic pyrrole CH proton, either between the
nearest aromatic pyridyl protons and the pyrrole proton (Fig. 2,
compound 4h) or between the closest alkyl protons and the pyrrole
proton (Fig. 2, compound 4i).
R2
R1
O
N
H
O
1
a,b
R2
O
N
COOH
N
R1
2
R3
R4
c
O
R2
In summary, we have developed a fast method to prepare new
functionalized pyridylpyrroles starting from amino acids. Parallel
methods and microwave irradiation were utilized. This facile
method can be used to synthesize highly substituted pyrroles,
containing two substituents from the amino acid, one from the acyl
chloride, and two from the alkyne.
O
N+
R1
N
3
3. Experimental
3.1. General
R3
R3
R4
R4
R2
R2
Dichloromethane (DCM) was freshly distilled over calcium hy-
dride. Parallel reactions were performed on a Radleys 12-place
carousel reaction station. Microwave reactions were carried out
with the Biotage Microwave Initiator EXP EU in 2–5 mL sealed re-
action tubes with normal (PhMe) or high (Ac2O) solvent affinity,
fixed reaction time on, and pre-stirring for 30 s. 1,1,1-Tri-
fluorotoluene (TFT) was used as a polar cosolvent with toluene to
enable efficient heating. TLC plates were Merck TLC aluminum
sheets coated with silica gel 60 F254. Flash chromatography was
performed with a Biotage SP1-A2C with 12þM or 25þM silica
cartridges. Melting points were measured with an Electrothermal
IA9100 digital melting point apparatus and are uncorrected. NMR
spectra were recorded with a Varian Mercury 300 Plus spectrom-
N
R1
N
R1
or
N
N
4a–4m
Scheme 1. Synthesis of pyridylpyrroles 4. Reagents and conditions: (a) amino acid
benzyl ester 1 (1 equiv), nicotinoyl or isonicotinoyl chloride (1 equiv), prepared in situ
from nicotinic or isonicotinic acid, Et3N (3.2 equiv), DCM; 0 ꢀC, 2 h; rt, 15–20 h; (b) H2,
1 atm, 10 wt % Pd on activated carbon (catalytic amount), MeOH, rt, 5 h; (c) Ac2O, al-
kyne (1 equiv), MW irradiation, 130 ꢀC, 5 min.
A series of pyrroles was subsequently synthesized with acetic
anhydride as the dehydrating agent. Two alkynes, DMAD and
methyl propiolate, were used in microwave-assisted 1,3-dipolar
cycloaddition, and a small library of pyridylpyrroles was obtained
eter. Chemical shifts (d) are reported in ppm relative to residual
CO2Me
R
CO2Me
MeO2C
CO2Me
MeO2C
CO2Me
R
N
H
N
H
N
H
N
H
N
N
N
N
4d R = CO2Me
4e R = H
4a R = CO2Me
4b R = H
4c
4f
CO2Me
CO2Me
MeO2C
CO2Me
MeO2C
MeO2C
N
N
N
N
N
N
N
N
4i
4g
4h
4j
MeO2C
CO2Me MeO2
C
CO2Me
CO2Me
N
Me
N
Me
N
N
N
N
4l
4k
4m
Figure 1. Pyridylpyrroles 4a–4m prepared from DMAD and methyl propiolate.

9704
K. Harju et al. / Tetrahedron 65 (2009) 9702–9706
Table 1
3.3. General preparation of N-acylated amino acid benzyl
esters26,27
Yields and purities of pyridylpyrroles 4a–4m prepared with Ac2O as dehydrating
agent
Entry
Product
Yield %a
Purity %b
The reactions were performed in a parallel fashion with a Rad-
leys carousel. Nicotinic acid or isonicotinic acid (0.5 g, 4 mmol,
1 equiv) was placed in the reaction tube under argon in DCM. Oxalyl
chloride (0.4 mL, 4.5 mmol,1.1 equiv) and a catalytic amount of DMF
(2–3 drops) were added, and the reaction mixture was stirred at
room temperature for 2 h. Benzyl ester (4 mmol,1 equiv) was added
to the reaction mixture. Triethylamine (1.8 mL, 13 mmol, 3.2 equiv)
was added dropwise at 0 ꢀC, and the reaction mixture was stirred for
2 h at 0 ꢀC, and overnight (15–20 h) at room temperature. The so-
lution was washed with saturated NaHCO3 (2ꢁ) and with water
(2ꢁ), dried with Na2SO4, and evaporated. The crude products were
purified by flash chromatography.
1
2
3
4
5
6
7
8
4a
4b
4c
4d
4e
4f
49
43
32
18
48
28
78
85c
63
70d
34
21
93
93
>98
w95
>98
>98
>98
>98
>98
>98
w95
w95
4g
4hþ4i
9
4j
10
11
12
4k
4l
4m
a
Isolated yield.
b
c
Purities were evaluated on the basis of LC–MS, 1H NMR and elemental analyses.
Combined yield of regioisomers, ratio of 4h: 4i w1:2.
w1:1 mixture of regioisomers.
3.4. General preparation of N-acylated amino acids
d
The reactions were performed in a parallel fashion with a Radleys
carousel. Palladium 10 wt % on activated carbon (w100 mg) was
placed in the reaction tube. Benzyl ester of amino acid (w2–3 mmol)
was added in MeOH (20 mL), and the reaction mixture was stirred at
room temperature under a hydrogen balloon for about 5 h. The
mixture was filtered through Celite, the Celite was rinsed with
methanol, and the filtrate was evaporated and dried in vacuo. The
products were used as such in the following cycloaddition.
NOESY
H
NOESY
MeO2C
H
H
CO2Me
H
H
H
N
N
3.5. General preparation of pyridinyl-1H-pyrroles
N
N
N-Acylated amino acid (0.6 mmol, 1 equiv) and alkyne
(0.6 mmol, 1 equiv) were placed in a microwave reaction tube.
Acetic anhydride (3 mL) was added. The reaction mixture was
purged with argon, and the microwave tube was irradiated at
130 ꢀC for 5 min. Water was added and the solvent was evaporated.
The crude product was purified by flash chromatography.
4i
4h
Figure 2. Analysis of the regiochemistry of 4h and 4i with NOESY experiment.
NMR solvent peaks (DMSO-d6 2.5 and 39.51 ppm, CDCl3 7.26 and
77.16 ppm). Signals were assigned on the basis of DEPT, HSQC, and
HMBC experiments. Secondary N-acylated amino acid benzyl esters
and N-acylated amino acids were obtained as mixtures of two
rotamers. Only the NMR data of the major rotamer obtained from
the HSQC and HMBC experiments is reported. FTIR spectra were
measured with a Bruker Vertex 70 FTIR spectrometer by KBr
technique; oily samples were measured between two KBr pellets.
LC–MS analyses were carried out with an HP 1100 series in-
strument and an Esquire-LC Bruker Daltonik ion trap mass spec-
trometer with positive mode ESI ion source, UV detector
wavelength of 210 nm, column XTerra MS RP18 (4.6ꢁ30 mm,
3.5.1. 2-(2-Methylpropyl)-5-(3-pyridinyl)-1H-pyrrole-3,4-dicarboxylic
acid dimethyl ester 4a. Yield 93 mg (49%, purity 93%), white solid,
Rf¼0.1 (EtOAc–n-hexane 1:1). 1H NMR (300 MHz, CDCl3)
d (ppm):
10.14 (br s, 1H), 8.64 (dd, J¼2.1 Hz and 0.6 Hz, 1H), 8.43 (dd,
J¼4.8 Hz and 1.5 Hz,1H), 7.87 (ddd, J¼8.1 Hz, 2.1 Hz, and 1.5 Hz,1H),
7.27 (ddd, J¼8.1 Hz, 4.8 Hz, and 0.9 Hz, 1H), 3.81 (s, 3H), 3.78 (s, 3H),
2.75 (d, J¼7.2 Hz, 2H), 1.92–2.06 (m, 1H), 0.93 (d, J¼6.9 Hz, 6H). 13C
NMR (75 MHz, CDCl3)
d (ppm): 166.7, 165.2, 148.2 (ArCH), 147.9
(ArCH), 139.9, 135.9 (ArCH), 128.2, 127.9, 123.8 (ArCH), 115.5, 113.3,
52.3 (CH3), 51.5 (CH3), 35.9 (CH2), 29.5 (CH), 22.5 (2ꢁCH3). FTIR
(KBr, cmꢂ1): 1707 (C]O). LC–MS: [MþH]þ, m/z 317 (tR¼4.7 min).
HRMS [MþH]þ found 317.1494, C17H21N2O4 requires 317.1501.
2.5 mm), eluent gradient of 0.1% formic acid in water–acetonitrile
from 10% to 90%, and flow rate 0.7 mL/min. Q-TOF Micro (quadru-
pole time-of-flight) mass spectrometer (The Waters Micromass)
with electrospray ionization in positive ion mode was used for
accurate LC–MS analyses (HRMS). Elemental analyses were done at
Robertson Microlit Laboratories, Inc., Madison, NJ.
3.5.2. 2-(2-Methylpropyl)-5-(3-pyridinyl)-1H-pyrrole-3-carboxylic
acid methyl ester 4b. Yield 67 mg (43%, purity 93%), white solid,
Rf¼0.2 (EtOAc–n-hexane 1:1). 1H NMR (300 MHz, DMSO-d6)
d
(ppm): 11.68 (br s,1H), 8.90 (d, J¼1.8 Hz,1H), 8.38 (d, J¼4.5 Hz,1H),
8.02 (dt, J¼8.1 Hz and 1.8 Hz, 1H), 7.37 (dd, J¼8.1 Hz and 4.8 Hz, 1H),
6.93 (d, J¼2.7 Hz, 1H), 3.70 (s, 3H), 2.80 (d, J¼7.2 Hz, 2H), 1.95–2.06
(m, 1H), 0.88 (d, J¼6.6 Hz, 6H). 13C NMR (75 MHz, DMSO-d6)
3.2. General preparation of benzyl esters of amino acids25
The solution of
L
-leucine or DL-pipecolinic acid (30 mmol,
d (ppm): 164.7, 146.9 (ArCH), 145.0 (ArCH), 141.2, 130.6 (ArCH), 127.7,
1 equiv), benzyl alcohol (6.2 mL, 60 mmol, 2 equiv), and p-tolue-
nesulfonic acid (6.9 g, 36 mmol, 1.2 equiv) in toluene (60 mL) was
refluxed for 20 h under Dean–Stark apparatus to remove water. The
reaction mixture was cooled and stored in a freezer. The pre-
cipitated salt was filtered, washed with toluene, and dried.
The obtained products were used as such in the next reaction step.
126.6, 123.7 (ArCH), 112.1, 107.9 (ArCH), 50.4 (CH3), 35.2 (CH2), 28.9
(CH), 22.2 (2ꢁCH3). FTIR (KBr, cmꢂ1): 1698 (C]O). LC–MS: [MþH]þ,
m/z 259 (tR¼4.3 min). HRMS [MþH]þ found 259.1444, C15H19N2O2
requires 259.1447.
3.5.3. 2-(2-Methylpropyl)-5-(4-pyridinyl)-1H-pyrrole-3,4-dicarboxylic
acid dimethyl ester 4c. Yield 61 mg (32%), white solid, mp 165–
166 ꢀC, Rf¼0.1 (EtOAc–n-hexane 1:1). 1H NMR (300 MHz, CDCl3)
L-Valine benzyl ester p-toluenesulfonate [16652-76-9] and sarco-
sine benzyl ester p-toluenesulfonate [54384-06-4] were purchased
from Chem-Impex International, Inc, Wood Dale, IL.
d
(ppm): 10.29 (br s, 1H), 8.44 (d, J¼6.3 Hz, 2H), 7.39 (dd, J¼4.8 Hz

K. Harju et al. / Tetrahedron 65 (2009) 9702–9706
9705
and 2.1 Hz, 2H), 3.86 (s, 3H), 3.81 (s, 3H), 2.79 (d, J¼7.2 Hz, 2H),
1.93–2.07 (m, 1H), 0.93 (d, J¼6.9 Hz, 6H). 13C NMR (75 MHz, CDCl3)
(EtOAc–n-hexane 1:1). 1H NMR (300 MHz, CDCl3)
d
(ppm): 8.65
(s, 1H), 8.54 (d, J¼3.9 Hz, 1H), 7.68 (dt, J¼7.5 Hz and 1.8 Hz, 1H), 7.32
(dd, J¼7.5 and 4.5 Hz, 1H), 6.67 (s, 1H), 3.91 (t, J¼6.0 Hz, 2H), 3.80 (s,
3H), 3.18 (t, J¼6.0 Hz, 2H) 1.88–1.96 (m, 4H). 13C NMR (75 MHz,
d
(ppm): 167.2, 164.7, 149.6 (ArCH), 141.1, 139.0, 127.3, 121.4 (ArCH),
117.3, 113.4, 52.6 (CH3), 51.6 (CH3), 36.1 (CH2), 29.5 (CH), 22.6
(2ꢁCH3). FTIR (KBr, cmꢂ1): 1735, 1709 (C]O). LC–MS: [MþH]þ, m/z
317 (tR¼4.2 min). Calcd for C17H20N2O4: C, 64.54%; H, 6.37%; N,
8.85%, found C, 64.28%; H, 6.13%; N, 8.84%.
CDCl3)
d (ppm): 165.6, 149.5 (ArCH), 148.3 (ArCH), 138.6, 136.0
(ArCH), 129.3, 128.6, 123.4 (ArCH), 111.1, 110.7 (ArCH), 50.9 (CH3),
45.2 (CH2), 24.2 (CH2), 23.4 (CH2), 19.9 (CH2). FTIR (KBr, cmꢂ1): 1695
(C]O). LC–MS: [MþH]þ, m/z 257 (tR¼3.8 min). Calcd for
C15H16N2O2: C, 70.29%; H, 6.29%; N, 10.93%, found C, 69.95%; H,
6.37%; N, 10.90%.
3.5.4. 2-(1-Methylethyl)-5-(3-pyridinyl)-1H-pyrrole-3,4-dicarboxylic
acid dimethyl ester 4d. Yield 33 mg (18%, purity w95%), white solid,
mp 207–209 ꢀC, Rf¼0.1 (EtOAc–n-hexane 1:1). 1H NMR (300 MHz,
DMSO-d6)
d
(ppm): 11.73 (br s, 1H), 8.68 (d, J¼1.8 Hz, 1H), 8.54 (dd,
3.5.10. 3-(3-Pyridinyl)-5,6,7,8-tetrahydroindolizine-2-carboxylic acid
methyl ester 4i. Analytical sample (61 mg) separated from the
mixture of regioisomers, white solid, mp 85–87 ꢀC, Rf¼0.1 (EtOAc–
J¼4.8 Hz and 1.2 Hz, 1H), 7.87 (ddd, J¼7.8 Hz, 2.4 Hz, and 1.2 Hz,
1H), 7.46 (ddd, J¼7.8 Hz, 4.8 Hz, and 0.9 Hz, 1H), 3.71 (s, 3H), 3.66 (s,
3H), 3.55 (sept, J¼6.9 Hz, 1H), 1.27 (d, J¼7.2 Hz, 6H). 13C NMR
n-hexane 1:1). 1H NMR (300 MHz, CDCl3)
d (ppm): 8.59–8.61
(75 MHz, DMSO-d6)
d
(ppm): 165.8, 164.6, 148.6 (ArCH), 148.4
(m, overlapping 2H), 7.72 (dt, J¼7.8 Hz and 1.8 Hz, 1H), 7.36
(dd, J¼7.5 Hz and 4.8 Hz, 1H), 6.40 (t, J¼0.9 Hz, 1H), 3.68
(t, J¼6.3 Hz, 2H), 3.64 (s, 3H), 2.84 (t, J¼6.3 Hz, 2H), 1.82–1.91
(ArCH), 144.8, 135.4 (ArCH), 128.6, 126.9, 123.3 (ArCH), 114.0, 110.7,
51.6 (CH3), 51.2 (CH3), 25.5 (CH), 21.8 (2ꢁCH3). FTIR (KBr, cmꢂ1):
1710 (C]O). LC–MS: [MþH]þ, m/z 303 (tR¼4.1 min). HRMS [MþH]þ
found 303.1331, C16H19N2O4 requires 303.1345.
(m, 4H). 13C NMR (75 MHz, CDCl3)
d (ppm): 165.3, 151.1 (ArCH),
149.0 (ArCH), 138.6 (ArCH), 132.8, 130.5, 128.3, 122.9 (ArCH), 113.6,
107.0 (ArCH), 51.0 (CH3), 44.8 (CH2), 23.6 (CH2), 23.5 (CH2), 20.8
(CH2). FTIR (KBr, cmꢂ1): 1699 (C]O). LC–MS: [MþH]þ, m/z 257
(tR¼4.0 min). Calcd for C15H16N2O2: C, 70.29%; H, 6.29%; N, 10.93%,
found C, 70.05%; H, 6.23%; N, 10.75%.
3.5.5. 2-(1-Methylethyl)-5-(3-pyridinyl)-1H-pyrrole-3-carboxylic
acid methyl ester 4e. Yield 70 mg (48%), white solid, Rf¼0.2 (EtOAc–
n-hexane 1:1). 1H NMR (300 MHz, CDCl3)
d (ppm): 8.85 (br s, 1H),
8.77 (d, J¼1.8 Hz, 1H), 8.44 (dd, J¼4.8 Hz and 1.5 Hz, 1H), 7.75 (ddd,
J¼8.1 Hz, 2.1 Hz, and 1.8 Hz, 1H), 7.29 (dd, J¼7.8 Hz and 4.8 Hz, 1H),
6.88 (d, J¼2.7 Hz, 1H), 3.87 (sept, J¼6.9 Hz, 1H), 3.83 (s, 3H), 1.34 (d,
3.5.11. 3-(4-Pyridinyl)-5,6,7,8-tetrahydroindolizine-1,2-dicarboxylic
acid dimethyl ester 4j. Yield 119 mg (63%), white solid, mp
139 ꢀC, Rf¼0.1 (EtOAc–n-hexane 1:1). 1H NMR (300 MHz, DMSO-d6)
J¼6.9 Hz, 6H). 13C NMR (75 MHz, CDCl3)
d (ppm): 165.5, 147.54
(ArCH), 147.48, 145.3 (ArCH), 131.4 (ArCH), 128.2, 126.6, 123.9
(ArCH), 112.1, 109.2 (ArCH), 51.1 (CH3), 26.3 (CH), 22.1 (2ꢁCH3). FTIR
(KBr, cmꢂ1): 1699 (C]O). LC–MS: [MþH]þ, m/z 245 (tR¼3.8 min).
Calcd for C14H16N2O2: C, 68.83%; H, 6.60%; N, 11.47%, found
C, 68.57%; H, 6.64%; N, 11.32%.
d
(ppm): 8.64 (d, J¼4.8 Hz, 2H), 7.38 (dd, J¼4.8 Hz and 1.8 Hz, 2H),
3.82 (t, J¼6.0 Hz, 2H), 3.70 (s, 3H), 3.60 (s, 3H), 2.98 (t, J¼5.7 Hz, 2H),
1.78–1.84 (m, 4H). 13C NMR (75 MHz, DMSO-d6)
d
(ppm): 165.6,
163.8, 149.6 (ArCH), 137.5, 137.1, 129.9, 124.3 (ArCH), 116.2, 109.5,
51.7 (CH3), 51.0 (CH3), 44.6 (CH2), 23.3 (CH2), 22.3 (CH2), 18.9 (CH2).
FTIR (KBr, cmꢂ1): 1703 (C]O). LC–MS: [MþH]þ, m/z 315
(tR¼3.7 min). Calcd for C17H18N2O4: C, 64.96%; H, 5.77%; N, 8.91%,
found C, 64.64%; H, 5.54%; N, 8.79%.
3.5.6. 2-(1-Methylethyl)-5-(4-pyridinyl)-1H-pyrrole-3,4-dicarboxylic
acid dimethyl ester 4f. Yield 50 mg (28%), mp 177–178 ꢀC, white
solid, Rf¼0.1 (EtOAc–n-hexane 1:1). 1H NMR (300 MHz, CDCl3)
d
(ppm): 9.86 (br s, 1H), 8.44 (br s, 2H), 7.37 (br s, 2H), 3.84 (s, 3H),
3.5.12. 3-(4-Pyridinyl)-5,6,7,8-tetrahydroindolizine-1-carboxylic acid
methyl ester and 3-(4-pyridinyl)-5,6,7,8-tetrahydroindolizine-2-car-
boxylic acid methyl ester 4k. Yield 108 mg (70%, w1:1 mixture of
regioisomers), white solid, Rf¼0.1 (EtOAc–n-hexane 1:1). 1H NMR
3.82 (s, 3H), 3.73 (sept, J¼6.9 Hz, 1H), 1.31 (d, J¼6.9 Hz, 6H). 13C NMR
(75 MHz, CDCl3)
d (ppm): 167.0, 164.7, 149.7 (ArCH), 146.7, 138.8,
127.4, 121.5, 117.1, 111.9, 52.6 (CH3), 51.7 (CH3), 26.2 (CH), 22.2
(2ꢁCH3). FTIR (KBr, cmꢂ1): 1733, 1700 (C]O). LC–MS: [MþH]þ, m/z
303 (tR¼3.7 min). Calcd for C16H18N2O4: C, 63.57%; H, 6.00%; N, 9.27%,
found C, 63.47%; H, 5.89%; N, 8.99%.
(300 MHz, CDCl3)
d
(ppm): 1-carboxylic acid 8.59 (d, J¼4.2 Hz, 2H),
7.27–7.30 (m, overlapping 2H), 6.80 (s, 1H), 4.02 (t, J¼5.7 Hz, 2H),
3.81 (s, 3H), 3.18 (t, J¼5.7 Hz, 2H), 1.83–1.93 (m, overlapping 4H);
2-carboxylic acid 8.66 (d, J¼5.7 Hz, 2H), 7.27–7.30 (m, overlapping
2H), 6.38 (t, J¼0.9 Hz, 1H), 3.68 (t, J¼5.7 Hz, 2H), 3.64 (s, 3H), 2.83 (t,
J¼5.7 Hz, 2H), 1.83–1.93 (m, overlapping 4H). 13C NMR (75 MHz,
3.5.7. 3-(3-Pyridinyl)-5,6,7,8-tetrahydroindolizine-1,2-dicarboxylic
acid dimethyl ester 4g. Yield 147 mg (78%), white solid, mp
123–124 ꢀC, Rf¼0.2 (EtOAc–n-hexane 7:3). 1H NMR (300 MHz,
CDCl3)
d (ppm): 1-carboxylic acid 165.5, 150.0 (ArCH), 139.9, 139.6,
DMSO-d6)
d
(ppm): 8.60 (d, J¼4.5 Hz, 1H), 8.56 (s, 1H), 7.83 (ddd,
130.2, 122.4 (ArCH), 111.9 (ArCH), 111.5, 51.0 (CH3), 45.8 (CH2), 24.3
(CH2), 23.4 (CH2), 19.8 (CH2); 2-carboxylic acid 165.2, 149.5 (ArCH),
140.2,133.3,130.8,125.6 (ArCH), 113.4,107.2 (ArCH), 51.0 (CH3), 44.9
(CH2), 23.6 (CH2), 23.4 (CH2), 20.8 (CH2). FTIR (KBr, cmꢂ1): 1684
(C]O). LC–MS: [MþH]þ, m/z 257 (tR¼3.6 min). Calcd for
C15H16N2O2: C, 70.29%; H, 6.29%; N, 10.93%, found C, 70.11%; H,
6.17%; N, 11.04%.
J¼8.1 Hz, 2.1 Hz, and 1.8 Hz, 1H), 7.48 (dd, J¼8.1 Hz and 5.1 Hz, 1H),
3.73 (t, J¼6.0 Hz, 2H), 3.70 (s, 3H), 3.56 (s, 3H), 2.96 (t, J¼5.7 Hz, 2H),
1.78–1.84 (m, 4H). 13C NMR (75 MHz, DMSO-d6)
d (ppm): 165.4,
164.0, 150.2 (ArCH), 149.2 (ArCH), 137.6 (ArCH), 136.5, 130.0, 126.0,
123.2 (ArCH), 115.5, 109.6, 51.5 (CH3), 51.0 (CH3), 44.3 (CH2), 23.2
(CH2), 22.3 (CH2), 19.0 (CH2). FTIR (KBr, cmꢂ1): 1733, 1697 (C]O).
LC–MS: [MþH]þ, m/z 315 (tR¼4.3 min). Calcd for C17H18N2O4:
C, 64.96%; H, 5.77%; N, 8.91%, found C, 64.89%; H, 5.57%; N, 9.01%.
3.5.13. 1-Methyl-2-(3-pyridinyl)-1H-pyrrole-3,4-dicarboxylic acid
dimethyl ester 4l. Yield 56 mg (34%, purity w95%), off-white solid,
mp 113–114 ꢀC, Rf¼0.1 (EtOAc–n-hexane 7:3). 1H NMR (300 MHz,
3.5.8. 3-(3-Pyridinyl)-5,6,7,8-tetrahydroindolizine-1-carboxylic acid
methyl ester 4h and 3-(3-pyridinyl)-5,6,7,8-tetrahydroindolizine-2-
carboxylic acid methyl ester 4i. Yield 131 mg (85%, w1:2 ratio of
regioisomers 4h and 4i).
DMSO-d6)
d
(ppm): 8.63 (dd, J¼4.8 Hz and 1.2 Hz, 1H), 8.58
(d, J¼2.4 Hz, 1H), 7.86 (ddd, J¼8.4 Hz, 2.1 Hz, and 0.6 Hz, 1H), 7.64
(s, 1H), 7.50 (dd, J¼7.5 Hz and 4.8 Hz, 1H), 3.72 (s, 3H), 3.57 (s, 3H),
3.53 (s, 3H).13C NMR (75 MHz, DMSO-d6)
d (ppm): 164.8,163.2,150.2
3.5.9. 3-(3-Pyridinyl)-5,6,7,8-tetrahydroindolizine-1-carboxylic acid
methyl ester 4h. Analytical sample (38 mg) separated from the
mixture of regioisomers, white solid, mp 125–126 ꢀC, Rf¼0.2
(ArCH), 149.5 (ArCH), 137.6 (ArCH), 132.9, 129.1 (ArCH), 125.9, 123.3
(ArCH), 115.5, 113.5, 51.5 (CH3), 51.2 (CH3), 35.0 (CH3). FTIR
(KBr, cmꢂ1): 1717, 1698 (C]O). LC–MS: [MþH]þ, m/z 275

9706
K. Harju et al. / Tetrahedron 65 (2009) 9702–9706
(tR¼3.0 min). HRMS [MþH]þ found 275.1019, C14H15N2O4 requires
7. De Laszlo, S. E.; Hacker, C.; Li, B.; Kim, D.; MacCoss, M.; Mantlo, N.; Pivnichny,
J. V.; Colwell, L.; Koch, G. E.; Cascieri, M. A.; Hagmann, W. K. Bioorg. Med. Chem.
Lett. 1999, 9, 641–646.
275.1032.
8. De Laszlo, S. E.; Visco, D.; Agarwal, L.; Chang, L.; Chin, J.; Croft, G.; Forsyth, A.;
Fletcher, D.; Frantz, B.; Hacker, C.; Hanlon, W.; Harper, C.; Kostura, M.; Li, B.;
Luell, S.; MacCoss, M.; Mantlo, N.; O’Neill, E. A.; Orevillo, C.; Pang, M.; Parsons,
J.; Rolando, A.; Sahly, Y.; Sidler, K.; Widmer, W. R.; O’Keefe, S. J. Bioorg. Med.
Chem. Lett. 1998, 8, 2689–2694.
3.5.14. 1-Methyl-2-(4-pyridinyl)-1H-pyrrole-3,4-dicarboxylic acid
dimethyl ester 4m. Yield 35 mg (21%, purity w95%), off-white solid,
mp 158 ꢀC, Rf¼0.05 (EtOAc–n-hexane 1:1). 1H NMR (300 MHz,
´
´
CDCl3)
d
(ppm): 8.69 (d, J¼5.7 Hz, 2H), 7.28–7.30 (m, overlapping
9. Lehuede, J.; Fauconneau, B.; Barrier, L.; Ourakow, M.; Piriou, A.; Vierfond, J.-M.
Eur. J. Med. Chem. 1999, 34, 991–996.
3H), 3.82 (s, 3H), 3.70 (s, 3H), 3.54 (s, 3H). 13C NMR (75 MHz, CDCl3)
(ppm): 165.2, 163.8, 150.0 (ArCH), 138.4, 133.7, 128.9 (ArCH), 124.8
10. Allocco, J. J.; Donald, R.; Zhong, T.; Lee, A.; Tang, Y. S.; Hendrickson, R. C.; Lib-
erator, P.; Nare, B. Int. J. Parasitol. 2006, 36, 1249–1259.
d
(ArCH), 116.8, 115.3, 52.1 (CH3), 51.7 (CH3), 35.6 (CH3). FTIR
(KBr, cmꢂ1): 1713 (C]O). LC–MS: [MþH]þ, m/z 275 (tR¼2.4 min).
HRMS [MþH]þ found 275.1025, C14H15N2O4 requires 275.1032.
11. Snoeck, R.; Andrei, G.; Bodaghi, B.; Lagneaux, L.; Daelemans, D.; de Clercq, E.;
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7213–7256; (c) Balme, G. Angew. Chem., Int. Ed. 2004, 43, 6238–6241.
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Acknowledgements
Ms. Pa¨ivi Uutela (Faculty of Pharmacy, University of Helsinki)
and Dr. Velimatti Ollilainen (Faculty of Agriculture and Forestry,
University of Helsinki) are thanked for LC–MS support, and
Mr. Teemu Nissila¨ (Faculty of Pharmacy, University of Helsinki) for
HRMS analyses.
17. Gotthardt, H.; Huisgen, R.; Bayer, H. O. J. Am. Chem. Soc. 1970, 92, 4340–4344.
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Supplementary data
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Characterization data of the intermediates, and 1H and 13C NMR
spectra of the products. The supplementary data associated with
this article can be found in the on-line version at doi:10.1016/
j.tet.2009.09.094.
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