1,3-dipolar cycloaddition in the preparation of new fused heterocyclic compounds via thermal initiation

Article abstract of DOI:10.3390/molecules21020187

This paper describes the synthesis of precursors with a benzo[b]furan skeleton for the intramolecular 1,3-dipolar cycloaddition of azomethine ylides prepared from N-substituted 3-allyl-aminobenzo[b]furan-2-aldehydes and secondary amines derived from α-amino acid esters. Reactions were initiated by heating. The products consisted of four fused rings with three stereogenic centers. Their structure and stereochemistry were determined by NMR spectra and X-ray measurements.

Full text of DOI:10.3390/molecules21020187

molecules
Article
1
,3-Dipolar Cycloaddition in the Preparation of
New Fused Heterocyclic Compounds via
Thermal Initiation
Martin Porubský, Lukáš Tenora and Milan Potá cˇ ek *
Department of Chemistry, Masaryk University, Kotlá rˇ ská 2, Brno 611-37, Czech Republic;
3
80165@mail.muni.cz (M.P.); 175258@mail.muni.cz (L.T.)
*
Correspondence: potacek@chemi.muni.cz; Tel.: +420-549-496-615; Fax: +420-549-492-688
Academic Editor: Mark Rizzacasa
Received: 3 December 2015; Accepted: 29 January 2016; Published: 4 February 2016
Abstract: This paper describes the synthesis of precursors with a benzo[b]furan skeleton for
the intramolecular 1,3-dipolar cycloaddition of azomethine ylides prepared from N-substituted
3-allyl-aminobenzo[b]furan-2-aldehydes and secondary amines derived from α-amino acid esters.
Reactions were initiated by heating. The products consisted of four fused rings with three
stereogenic centers. Their structure and stereochemistry were determined by NMR spectra and
X-ray measurements.
Keywords: 1,3-dipolar cycloaddition; fused heterocycles; thermal initiation; 3-amino-benzo[b]furan-
2
-carbaldehyde
1
. Introduction
The 1,3-dipolar cycloaddition reaction (1,3-DC) is a powerful tool for the synthesis of
five-membered heterocyclic compounds. The reactions are characterized by high regio- and
stereoselectivity. For the reaction, a dipole and a dipolarophile are required. There are several
types of dipoles which can participate in cyclization reactions. In the case of a molecule containing
both assemblies of atoms, one representing a dipole and the other a dipolarophile, it is possible to
achieve intramolecular 1,3-DC and, in this way, the formation of a new ring [1–3]. One frequently
used method for preparing azomethine ylides applies an aldehyde and an amino-substituted
ester. Such a method was used in our laboratory and, under microwave irradiation, led to
hexahydrochromeno[4,3-b]pyrroles [4–6] and hexahydropyrrolo[3,2-c]quinolines [7]. The procedure is
shown in Scheme 1.
COOR1
R
R
O
H
X
N
H
HN
COOR1
μW
X = O, NR
H
2
X
Scheme 1. Microwave-initiated 1,3-dipolar cycloadditions leading to hexahydrochromeno[4,3-b]
pyrroles and hexahydropyrrolo[3,2-c]quinolines.
In a recent paper, Cossío [8] presented a large experimental study of the formation of
chromeno-[4,3-b]pyrrolidines, which also included a computational assessment of origin of the 1,3-DC
stereocontrol. The authors prepared starting aldehydes by means of the O-alkylation of salicylaldehyde
Molecules 2016, 21, 187; doi:10.3390/molecules21020187
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with cinamyl bromide according to a standard procedure. The partners in the 1,3-DC reactions were
-aminocarboxylic acid ester hydrochlorides (Scheme 2) and the cyclizations were carried out using
α
˝
˝
both microwave irradiation (neat, 185 C) and conventional heating in polyethylene glycol (170 C).
Three diastereomers of the expected cycloaddition products were found, as determined by GC-MS
1
and H-NMR of the crude products. A significant part of the paper was devoted to computational
analysis of the intramolecular cycloaddition.
COOR3
COOR3
O
O
R1
H
2
COOR3
H
2
R
H
R
2
N
R
N
H
N
COOR3
R1
H
H
HCl . H N
+
R1
+
H
2
R1
H
+
R2
H
O
O
O
Scheme 2. Overview of 1,3-DC products prepared in [8] and their configuration.
All the fused heterocyclic compounds mentioned above demonstrated important physiological
properties. The pyrrolidino[3,2-c]tetrahydroquinoline skeleton is found in the natural alkaloid
martinelline and martinellic acid, isolated from tropical plant roots, both of which exhibit biological
activity as antagonists of the bradykinine B and B receptors and antibiotic activity [9]. Similarly,
1
2
the tetrahydrochromeno[4,3-b]pyrrolidine structure is found to be a constituent of many compounds
exibiting activity as non-competitive antagonists of the muscular nicotinic acetylcholine receptor and
the muscarinic acetylcholine receptor [10]. It is also present in various natural compounds such as
sceletium alkaloid [11], and in synthetically prepared forms, displays activity against several bacterial
pathogens [12].
Moreover, many experiments carried out on biological material have shown that the benzo[b]furan
skeleton present in both synthesized compounds as well as products isolated from natural sources
also demonstrates various biological activities. Thus, the insecticidal, fungicidal, cytotoxic and
antioxidative properties of naturally occurring benzo[b]furan derivatives isolated from plants of the
Styracaceae [13] and Moraceae [14] families have been examined. Similar activity has also been found in
synthetic materials [15–17]. Benzo[b]furan systems in combination with a chromone or cumarine
structure displayed also antimicrobial, antiviral, anticancer, anti-inflammatory, and antioxidant
properties [18]. With that knowledge and our experience with the application of intramolecular
1,3-dipolar cycloaddition, we decided to extend our synthesis to more complex systems containing
benzo[b]furan skeletons.
2
. Results and Discussion
Here, for the task to build new systems we had to prepare starting molecules. The necessary key
starting molecule was N-substituted, N-allyl-3-aminobenzo[b]furan-2-carbaldehyde (7). The procedure
applied in its preparation is depicted in Scheme 3.
The synthesis began with commercially available 2-hydroxybenzonitrile (
nucleophile for the substitution of bromine in the alkyl bromoacetate molecule and for the preparation
of alkyl-(2-cyanophenoxy) acetate . Optimal conditions for the formation of the carbanion from
and its nucleophilic attack leading to cyclic compound were sought by varying the solvent, base,
1), which was used as a
2
2
3
and temperature. The application of t-butoxide in diethyl ether at room temperature for 25 min was
identified as the optimal procedure. In the following step, it was necessary to introduce an allyl group
to the already present free amino group. However, before doing so, it was necessary to protect the
amino group from diallylation. Therefore, we introduced both tosyl or mesyl groups by the application
of the corresponding sulfonylchloride in an excess of pyridine in dichloromethane at room temperature
overnight. The following treatment with allyl bromide in the presence of potassium carbonate in DMF
at room temperature for about 20 min led from compound
allyl group.
4 to amine 5 via the introduction of the

Molecules 2016, 21, 187
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O
O
Br
R
OH
O
O
R
TsCl or MesCl
pyridine
O
O
O
O
O
O
t-BuOK
Et
K
2
CO
3
, acetone
R
DCM
O
R
N
N
2
O
NH
2
NH
9
4 %
1
65 %
88 % - 94 %
4
2
3
X
Br
O
O
X = Ts, Mes
R = Me, Et
O
O
OH
K
2
CO
3
, DMF
O
PCC
DCM
LiAlH4
Et
55 % - 59 %
82 % - 94 %
O
R
N
2
O
N
N
X
X
X
3
3 % - 55 %
7
6
5
Scheme 3.
Reaction path leading to the synthesis of the key starting molecule N-allyl-
N-(2-formyl-benzo[b]furan-3-yl)-4-methylbenzene sulfonamide (7) used for the generation of
azomethine ylides.
The procedure leading to key molecule
group included one intermediate product,
7
6
for 1,3-dipolar cycloadditions containing an aldehyde
. Instead of the direct transformation of ester to
5
aldehyde
transformation in two steps. The first reductive step was carried out by means of the ester
with LiAlH . Our best results were characterized by yields of alcohol approaching 55%. For the
7, for instance by DIBAL, which appeared to have limited success, we achieved the
5
reaction
6
4
following oxidation step, we tested pyridinium chlorochromate in dichloromethane and found it to
be successful.
Intramolecular 1,3-dipolar cycloaddition is based upon the formation of a 1,3-dipole in situ
in a molecule that contains a double bond in a position which is capable of interacting with the
dipole [4]. In our case, we generated azomethine ylides from compound 7 by its reaction with
ethyl-N-alkyl-2-amino acetates (
8
). The probable mechanism of the reaction is presented in Scheme 4.
O
O
N
R
O
H
O
N
X
O
1
0b
N
O
N
+
R
O
HO
H
R
*
2
O
H
3
1
8
O
- H
2
O
1
0
H
O
N
O
N
X
R
*
R = methyl
ethyl
a
b
c
d
O
O
9
*
H
3a
O
N
4
8
N
X
N
X
R
5
7
X = Ts
Ms
A
benzyl
isopropyl
O
6
B
7
9
N
X
Scheme 4.
Plausible mechanism of azomethine ylide formation from compound
7
and
ethyl-N-substituted 2-amino acetate (
8), and its immediate intramolecular 1,3-dipolar cycloaddition to
the already present double bond to form fused heterocycle 9.
In the reaction, the nucleophilic secondary amine attacks the electrophilic carbon atom of the
aldehyde; after water splits off, the 1,3-dipole—azomethine ylide—is formed in situ. This participates
in an intramolecular 1,3-DC and a new heterocyclic system is formed. During the addition, three
stereogenic centres are created in the new molecule (Scheme 4) at positions 2, 3a and 10b. Thus, the
existence of four possible diastereoisomers should be expected. However, even when the temperature
of the reaction was varied and the reaction mixtures were analyzed by LC/MS, LC/UV and NMR
spectra, only one major diastereoisomer was found.
˝
In all cases, reactions were carried out without any solvent in a bath preheated to 130–140 C.
Aldehyde dissolved immediately after being put into the corresponding ester . It was found that
doubling the amount of ester increased the product yield. The reaction time required for consumption
of the whole amount of compound ranged from 20 to 35 min depending upon the temperature and
7
8
8
7

Molecules 2016, 21, 187
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the steric requirements of the N-alkyl substitution. The reaction products were isolated by HPFC, with
the EtOAc/PE mobile phase ratio equal to 1:3.
The NOESY spectrum indicated that the hydrogen atoms at 10b and 3a were oriented towards one
side and to the side opposite to the hydrogen atom at 2. This finding was supported by observation of
1
the hydrogen atoms at 3 and 3 . NOESY interactions were observed only between the hydrogen atoms
1
11
at 2 and 3 and between those at 3 and 3a, which indicates the opposite orientation of the hydrogen
atoms at the 2 and 3a positions (Supplementary Materials). All these conclusions were confirmed by
X-ray structure analysis (Figure 1).
Figure 1. ORTEP diagram of molecule 9Ac.
Figure 2 attempts to depict, in perspective view, the conformation of the in situ-formed ylide
entering 1,3-dipolar cycloaddition with the configuration of the products observed.
Figure 2. Perspective view of the ylide fragment conformation affording diastereomer
9 with the
configuration (2R*, 3aR*, 10b*) and a schematic view of the product. In the scheme we neglect the
plus/minus sign of the wave function; the interactions have a stabilizing effect.
3
. Experimental Section
3
.1. General Information
All chemicals were used as purchased. If necessary, solvents were dried according to literature
procedures [19]. DCM was distilled from anhydrous CaCl , then from P O , and stored over MS (3 Å).
2
2
5
Et O was dried over Na and freshly distilled before use. Pyridine was distilled from KOH and stored
2
over MS (3 Å). 2-Hydroxybenzonitrile (1) was purchased from Sigma Aldrich (St. Louis, MO, USA).
Most reactions were carried out under a dry argon atmosphere and all reactions were monitored
by TLC (F254 silica gel, Merck, Darmstadt, Germany). Column chromatography was performed on
a Horizon HPFC system (Biotage, Uppsala, Sweden) equipped with a FLASH Si 25 + M cartridge.
Melting points were measured on an MPM HV2 instrument (Kleinfeld Labortechnik GmbH, Gehrden,

Molecules 2016, 21, 187
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Germany). FT-IR spectra were recorded on a Genesis ATI (Unicam, Cambridge, UK) apparatus.
1
13
H- and C-NMR spectra were recorded using an Avance 300 spectrometer (Bruker, Karlsruhe,
1
13
Germany) operating at frequencies of 300.13 MHz ( H) and 75.47 MHz ( C) with CDCl as the
3
solvent. Tetramethylsilane (
H-NMR spectra, and CDCl3 (
δ
= 0.00 ppm) or CHCl (
δ
= 7.27 ppm) served as internal standards for
3
13
1
δ
= 77.23 ppm) for C-NMR spectra. GC-MS data were obtained on
a GCMS-QP2010 (Shimadzu, Kyoto, Japan) in EI mode at 30 eV. MS data were obtained on a TRIO
000 spectrometer (Fisons Instruments, Hazlet, NJ, USA) at 30 eV in electron impact mode and by
1
thermal desorption. High Resolution Mass Spectra (HRMS) were recorded on a 6224 Accurate-Mass
TOF LC-MS (Agilent, DE, Wilmington, WI, USA) in APCI and ESI modes. X-ray diffraction data were
collected on a KM-4 four-circle CCD diffractometer (Kuma, Wroclaw, Poland) and corrected for Lorentz
and polarization effects. The structures were resolved by direct methods and refined by full-matrix
least-squares methods using the SHELXTL program package [20]. Hydrogen atoms were placed in
calculated idealized positions and refined as riding. The crystal structure was deposited at CCDC [21].
3
.2. Chemistry
Methyl-(2-cyanophenoxy)acetate (
bromoacetate (3.08 g, 20.2 mmol, 1.20 eq.) were added to a solution of 2-hydroxybenzonitrile (
6.8 mmol, 1.00 eq.) dissolved in dried acetone (85 mL). The reaction mixture was refluxed for 7 h.
After cooling down to room temperature, the mixture was filtered and the acetone solution evaporated.
2
). Potassium carbonate (2.78 g, 20.2 mmol, 1.20 eq.) and methyl
, 2.00 g,
1
1
˝
1
The reaction afforded light yellow crystals with a yield of 94%; mp 69 C. H-NMR:
δ
= 7.59 (dd, J = 7.7
,
1
4
.6, 1H, H1), 7.52 (td, J = 9.2, 7.7, 1.7, 1H, H4), 7.07 (td, J = 7.6, 0.7, 1H, H2), 6.86 (d, J = 8.5, 1H, H3),
13
.78 (s, 2H, CH ), 3.81 (s, 3H, COOCH3). C-NMR: δ = 168.6 (COOCH ), 159.8 (C6), 134.3 and 134.5
3
2
(
C2 and C3), 122.2 (C1), 116.3 (C5), 112.7 (C4), 103.0 (CN), 66.0 (CH ), 52.7 (COOCH ). MS (EI, 70 eV)
2 3
+
Found: 191 (M calculated for: C H NO 191.19); m/z (%) = 191 (M , 50), 162 (50), 146 (10), 132 (70),
10
9
3
1
17 (15), 102 (70), 85 (60), 83 (100), 75 (35), 45 (60).
Methyl-3-aminobenzo[b]furan-2-carboxylate ( ). Compound
3
2 (2.62 g, 13.9 mmol, 1.00 eq.) was dissolved
in dried diethyl ether and poured into a flask in which an argon atmosphere was maintained. Then,
potassium t-butoxide (0.78 g, 6.9 mmol, 0.50 eq.) was carefully added and the mixture stirred at
room temperature. After 25 min, several drops of water were added and the solvent evaporated.
The remainder was mixed with water (30 mL) and the mixture extracted three times with 30 mL of
diethyl ether. After drying by sodium sulfate, filtration, and the evaporation of ether, light yellow
˝
1
crystals were obtained with a yield of 65%; mp 94 C. H-NMR:
δ = 7.55 (d, J = 7.9, 1H, H4), 7.48–7.41
13
(
m, 2H, H7 and H6), 7.19–7.30 (m, 1H, H5), 5.00 (bs, 2H, NH ), 3.96 (s, 3H, COOCH3). C-NMR:
2
δ = 162.1 (COOCH ), 154.3 (C7a), 138.9 (C3), 129.1 (C4), 125.6 (C3a), 122.5 (C5), 121.8 (C2), 119.8
3
(
C6), 112.8 (C7), 51.7 (COOCH ). MS (EI, 70 eV) Found: 191 (calculated for C H NO : 191.19);
3 10 9 3
+
m/z (%) = 191 (M , 100), 159 (50), 133 (25), 103 (90), 83 (20), 77 (50), 51 (25).
General procedure for the preparation of compounds 4A and 4B. Either tosyl chloride (1.29 g, 6.78 mmol,
.20 eq.) or methane sulfonylchloride (1.29 g, 11.3 mmol, 2.00 eq.) were added to a stirred solution of
1.16 g, 5.65 mmol, 1.00 eq.) and pyridine (1.35 g, 16.9 mmol, 3.00 eq.) in dichloromethane (12 mL), and
1
(
3
the mixture was stirred under an argon atmosphere at room temperature overnight. The progress of
the reaction was monitored by TLC. After removal of the solvent, the crude product was dissolved in
ethyl acetate (40 mL) and subsequently extracted by 3
brine. The extract was dried by sodium sulfate, filtered, and then thickened to crystallization. It was
then subsequently recrystallized either from ethyl acetate or acetone.
ˆ
20 mL water, 1
ˆ
15 mL HCl, and 1
ˆ
15 mL
˝
1
Methyl-3-tosylaminobenzo[b]furan-2-carboxylate (4A), colourless crystals, yield 88%, mp 116 C. H-NMR:
δ
= 8.36 (bs, 1H, NH), 8.31 (d, 1H, J = 8.1, H4), 7.60 (d, J = 8.2, 2H, H ), 7.41–7.54 (m, 2H, H7 and H6),
Ts
7
.37 (t, J = 7.4, 1H, H5), 7.17 (d, J = 8.2, 2H, H ), 3.86 (s, 3H, COOCH3), 2.35 (s, 3H, SO C H CH3).
Ts
2
6
4
1
3
C-NMR:
δ = 161.0 (COOCH ), 154.3 (C7a), 144.5 (C3), 135.3 (C tosyl), 132.7 (C tosyl), 130.4 (C2), 129.8
3
(2C tosyl), 129.4 (C6), 127.6 (2C tosyl), 124.4 (C4), 124.3 (C5), 122.4 (C3a), 112.5 (C7), 52.5 (COOCH3),

Molecules 2016, 21, 187
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2
3
1.7 (NHSO C H4CH ). MS (EI, 70 eV) Found: 345 (calculated for C H NO S: 345.37); m/z (%) =
2 6 3 17 15 5
45 (M , 50), 222 (10), 190 (45), 162 (40), 134 (55), 119 (20), 103 (20), 91 (100), 76 (30), 65 (45).
+
˝
1
Methyl-3-mesylaminobenzo[b]furan-2-carboxylate (4B) ochre crystals, yield 94%, mp 173 C. H-NMR:
δ = 8.24 (bs, 1H, NH), 8.19 (d, J = 8.2, 1H, H4), 7.53 (d, J = 3.6, 2H, H7 and H6), 7.34–7.41 (m, 1H, H5),
13
4
.03 (s, 3H, COOCH3), 3.09 (s, 3H, SO CH3). C-NMR:
δ
= 161.5 (
COOCH ), 154.5 (C7a), 132.2 (C3),
3
2
1
29.6 (C6), 124.4 (C4), 124.1 (C5), 122.5 (C2), 122.0 (C3a), 112.6 (C7), 52.8 (COO
C
H ), 40.3 (NHSO2CH3).
3
+
MS (EI, 70 eV) found: 269 (calculated for C H NO S: 269.27); m/z (%) = 269 (M , 70), 237 (15), 190
11
11
5
(
85), 162 (50), 148 (15), 134 (100), 119 (30), 103 (50), 91 (35), 76 (70), 59 (20), 50 (25).
General procedure for the preparation of compounds 5A and 5B. A solution of compound 4A or 4B
3.24 mmol, 1.00 eq.) in DMF (10 mL) was mixed with anhydrous potassium carbonate (672 mg,
.86 mmol, 1.50 eq.). While the mixture was stirred, allyl bromide (590 mg, 4.86 mmol, 1.50 eq.) was
(
4
added dropwise. The stirring continued for 20 h (for compound 5A) and 6 h (for 5B). The progress
of the reaction was monitored by TLC (EtOAc/PE = 1:2). The process was finished by removing
the solvent and the remainder was mixed with water (20 mL); the final product was extracted by
dichloromethane and the extract washed with brine (15 mL). After drying by Na SO , filtration, and
2
4
removal of the solvent by distillation, the product was crystallized from methanol.
˝
Methyl-3-(N-allyl-N-tosylamino)benzo[b]furan-2-carboxylate (5A) white crystals, yield 94%, mp 86 C.
H-NMR:
1
δ = 7.64 (d, J = 8.2, 2H, H ), 7.53 (d, 1H, J = 8.3, H4), 7.43–7.50 (m, 2H, H7 and H6), 7.27–7.36
Ts
(
m, 1H, H5), 7.27 (d, J = 8.2, 2H, H ), 5.75–5.92 (m, 1H, CH CH=CH ), 5.05 (dd, J = 17.1, 1.2, 1H,
Ts 2 2
CH CH=CH2), 4.99 (dd, J = 10.1, 0.9, 1H, CH CH=CH2), 4.10–4.56 (bs, 2H, CH2CH=CH ), 3.67 (s, 3H,
2
2
2
13
COOCH3), 2.43 (s, 3H, SO C H CH3). C-NMR:
δ
= 158.8 (
COOCH ), 154.0 (C7a), 144.0 (C3), 141.3
3
2
6
4
(
(
(
C tosyl), 136.7 (C tosyl), 133.3 (CH2
C2), 127.4 (C3a), 124.6 (C4), 122.6 (C5), 119.5 (CH CH=
CH=CH ), 129.8 (2C tosyl), 128.7 (C6), 128.0 (2C tosyl), 127.7
2
C
H ), 112.7 (C7), 54.3 (CH CH=CH ), 52.5
2
2 2 2
COO
C
H ), 21.9 (SO C H4CH ). MS (EI, 70 eV) Found: 230 [M
´
Ts] (calculated for C H NO S:
20 19 5
3
2
6
3
3
85.434); m/z (%) = 230 (100), 198 (85), 170 (45), 115 (25), 91 (45), 65 (20), 45 (30).
˝
Methyl-3-(N-allyl-N-mesylamino)benzo[b]furan-2-carboxylate (5B) orange crystals, yield 82%, mp 91 C.
H-NMR:
1
δ = 7.80 (d, J = 7.8, 1H, H4), 7.44–7.56 (m, 2H, H7 and H6), 7.33–7.40 (m, 1H, H5), 5.72–5.90 (m,
1
4
H, CH C
H
=CH ), 5.11 (dd, J = 17.1, 1.3, 1H, CH CH=CH2), 5.02 (dd, J = 10.1, 1.2, 1H, CH CH=CH2),
2
2
2
2
13
.40 (bs, 2H, CH2CH=CH ), 4.02 (s, 3H, COOCH3), 3.06 (s, 3H, SO CH3).
C-NMR: δ = 159.5
2
2
(
COOCH ), 154.0 (C7a), 140.4 (C3), 133.2 (CH2CH=CH ), 129.1 (C6), 128.9 (C2), 127.7 (C3a), 124.9 (C4),
3
2
1
22.6 (C5), 119.7 (CH CH=CH ), 112.7 (C7), 54.1 (CH CH=CH ), 52.9 (COOCH ), 40.1 (SO2CH ). MS
2 2 2 2 3 3
(
1
EI 70 eV) Found: 230 [M
70 (70), 156 (15), 115 (30), 102 (15), 83 (70), 59 (15), 45 (45).
´
Ms] (calculated for C H NO S: 309.338); m/z (%) = 230 (80), 198 (100),
14
15
5
Ester group reduction—transformation of compound
5
to compound 6. A solution of compound 5A or 5B
(
1.27 mmol, 1.00 eq.) in dry diethyl ether (13 mL) was slowly added to an intensively stirred suspension
˝
of LiAlH (58 mg, 1.5 mmol, 1.2 eq.) in dry diethyl ether (2 mL) cooled down to 0 C under an argon
4
atmosphere. After addition, the temperature was raised to room temperature and the reaction mixture
was kept at this temperature for a further 30 min. Then, the reaction was stopped by the addition of
diethyl ether containing several drops of water. Subsequently, the reaction mixture was extracted by
diethyl ether (3
ˆ
10 mL). The collected extracts were dried by Na SO and filtered, and the solvent
2 4
w
as further evaporated. The liquid product was purified by column chromatography (EtOAc/PE = 1:3)
.
N-(2-Hydroxymethylbenzo[b]furan-3-yl)-N-allyl-4-methylbenzenesulfonamide (6A) light yellow oil, yield
5
2
9%. 1H-NMR:
H ), 6.87–6.98 (m, 1H, H5), 6.41 (d, J = 7.8, 1H, H7), 5.72–5.91 (m, 1H, CH C
δ = 7.54 (d, J = 8.2, 2H, H ), 7.42 (d, J = 8.3, 1H, H4), 7.12–7.24 (m, 3H, H6 and
Ts
H
=CH ), 5.03 (dd,
2
Ts
2
J = 16.9, 1.2, 1H in CH CH=CH2), 5.05 (dd, J = 1.0, J = 10.1, 1H in CH CH=CH2), 4.19–4.88 (bs, 4H,
2
2
13
2
H in CH2CH=CH and 2H in CH2OH), 2.41 (s, 3H, SO C H CH3). C-NMR:
δ
= 157.1 (C7a), 153.7
2
2
6
4
(
1
C2), 144.4 (C3), 135.9 (C tosyl), 132.6 (CH2
24.2 (C tosyl), 122.9 (C5), 119.9 (C4), 119.1 (CH CH=CH ), 117.4 (C3a), 112.5 (C7), 55.3 (CH OH),
2 2
CH=CH ), 130.0 (2C tosyl), 127.8 (2C tosyl), 125.1 (C6),
2
2

Molecules 2016, 21, 187
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+
+
52.9 (C
H CH=CH ), 21.8 (SO C H4CH ). HRMS (ESI) (m/z): [M + H] calculated for C H NO S :
2
2
2
6
3
19 20
4
3
58.1108. Found: 385.1112.
N-(2-Hydroxymethylbenzo[b]furan-3-yl)-N-allyl-methanesulfonamide (6B) light yellow oil, yield 55%.
1
H-NMR: δ = 7.54 (d, J = 7.9, 1H, H4), 7.44–7.49 (m, 1H, H7), 7.33–7.41 (m, 1H, H5), 7.31 (dd, J = 1.2,
7
4
.4, 1H, H6), 5.78–5.96 (m, 1H, CH C
H
=CH ), 5.06–5.18 (m, 2H, CH CH=CH2), 4.70 (s, 2H, CH2OH),
2
2
2
13
.37 (bs, 2H, CH2CH=CH ), 2.99 (s, 3H, NHSO CH3). C-NMR:
δ
= 157.3 (C7a), 154.0 (C2), 132.6
H ), 116.9 (C3a), 113.1
2
2
(
(
CH2
C7), 55.3 (
C
H=CH ), 125.7 (C6), 124.5 (C3), 123.9 (C5), 120.3 (C4), 118.6 (CH CH=
C
2
2
2
+
C
H OH), 53.2 (
C
H CH=CH ), 39.5 (NHSO2CH ). HRMS (ESI) (m/z): [M + H] calculated
2
2
2
3
+
for C H NO S : 282.0795. Found: 282.0795.
13
16
4
Procedure for the preparation of compound
was added to a solution of alcohol
7
. Pyridinium chlorochromate (400 mg, 1.86 mmol, 2.50 eq.)
6
(0.74 mmol, 1.00 eq.) in dry dichloromethane (5 mL). The resulting
black suspension was stirred under argon at room temperature for 26 h. Subsequently, diethyl ether (15
mL) was added and the suspension stirred again for 10 min. Then, the upper layer was decanted and
filtered through a short column (5 cm) of Florisil. The obtained light yellow solution was concentrated
to crystallization and the product recrystallized from ethanol.
˝
N-Allyl-N-(2-formylbenzo[b]furan-3-yl)-4-toluenesulfonamide (7A) yellow crystals, yield 55%, mp 107 C.
H-NMR:
1
δ = 9.72 (s, 1H, CH=O), 7.58 (d, J = 8.2, 2H, H ), 7.56 (d, J = 7.6, 1H, H4), 7.43–7.51 (m,
Ts
1
H, H6), 7.20–7.29 (m, 2H, H ), 7.18 (t, J = 7.5, 1H, H5), 7.08 (d, J = 7.8, 1H, H7), 5.73–5.89 (m, 1H,
Ts
CH C
4
H
=CH ), 5.06 (dd, J = 9.4, 0.9, 1H in CH CH=CH2), 5.04 (dd, J = 17.0, 0.9, 1H in CH CH=CH2),
2
2
2
2
.35 (bs, 2H, CH2CH=CH ), 2.43 (s, 3H, SO C H CH3). 13C-NMR: 179.0 (
C
H=O), 161.1 (C7a), 155.0
2
2
6
4
(C3), 149.4 (C-tosyl), 144.8 (C2), 135.2 (C-tosyl), 132.0 (CH2
CH=CH ), 130.1 (2C tosyl), 129.6 (C6), 127.9
2
(
2C tosyl), 124.7 (C3a), 124.8 (C5), 122.0 (C4), 120.6 (CH CH=
C
H ), 113.5 (C7), 53.8 (CH CH=CH ),
2
2 2 2
2
1.8 (SO C H4CH ). MS (EI 70 eV): Found: 200 [M
´
Ts] (calculated for C H NO S: 355.408); m/z
19 17 4
2
6
3
(%) = 200 (100), 172 (60), 158 (30), 144 (25), 115 (20), 103 (15), 91 (95), 77 (15), 65 (50).
1
N-Allyl-N-(2-formylbenzo[b]furan-3-yl)-methanesulfonamide (7B) yellow oil, yield 33%. H-NMR: δ = 10.02
(
s, 1H, CH=O), 7.80 (d, J = 8.0, 1H, H4), 7.52–7.62 (m, 2H, H7 and H6), 7.37–7.44 (m, 1H, H5), 5.72–5.89
(
m, 1H, CH C
H
=CH ), 5.11 (dd, J = 17.1, 1.2, 1H, CH CH=CH2), 5.08 (dd, J = 10.1, 0.9, 1H,
2
2
2
13
CH CH=CH2), 4.43 (d, J = 0.7, 2H, CH2CH=CH ), 3.02 (s, 3H, NSO CH3). C-NMR: 180.5 (
CH=O),
2
2
2
1
55.0 (C7a), 148.1 (C3), 133.7 (C2), 132.3 (CH2
C
H=CH ), 130.0 (C6), 125.1 (C5), 122.4 (C4), 120.4
2
+
(CH CH=CH ), 118.1 (C3a), 113.4 (C7), 53.6 (CH CH=CH ), 39.4 (NSO CH ). HRMS (APCI): m/z [M + H]
2 2 2 2 2 3
+
calculated for C H NO S : 280.0638. Found: 280.0638.
13
13
4
General procedure for the formation of azomethine ylide and its following intramolecular 1,3-dipolar
cycloaddition—preparation of compound . Compound (0.14 mmol, 1.00 eq.) and a two-fold excess of
secondary amine (0.28 mmol, 2.00 eq.) were mixed in a test tube filled with an argon atmosphere
9
7
8
˝
and stopped with a balloon. Then, the tube was immersed in a preheated oil bath (130–140 C) and
stirred for about 30 min until the mixture became darker in color. After cooling down, the mixture was
separated by HPFC (AcOEt/PE = 1:3). The products were crystallized from methanol.
(
2R,3aR,10bR) and (2S,3aS,10bS)-Ethyl-1-methyl-5-tosyl-2,3,3a,4,5,10b-hexahydro-1H-benzo[b] furo[3,2-
˝
1
b]pyrrolo[2,3-d]pyridine-2-carboxylate (9Aa). Yellow crystals, yield 80%, mp 64 C. H-NMR:
δ = 8.12–8.14 (m, 1H, H6), 7.49 (d, J = 8.3, 2H, H ), 7.44 (dd, J = 1.7, 7.1, 1H, H9), 7.28–7.35 (m, 2H, H8
Ts

Molecules 2016, 21, 187
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and H7), 7.19 (d, J = 8.0, 2H, H ), 4.10–4.18 (m, 2H, COOCH2CH ), 4.07 (dd, J = 14.1, 4.8, 1H, H4), 3.73
Ts
3
(d, J = 6.7, 1H, H10b), 3.64 (dd, J = 2.1, 8.6, 1H, H2), 3.17 (dd, J = 14.0, 12.0, 1H, H4), 2.63 (s, 3H, NCH3),
2
.39 (s, 3H, SO C H CH3), 2.03–2.09 (m, 1H, H3), 1.95–2.02 (m, 1H, H3a), 1.62–1.68 (m, 1H, H3), 1.25
2
6
4
13
(t, J = 7.1, 3H, COOCH CH3). C-NMR:
δ
= 173.3 (
COOCH CH ), 153.9 (C9a), 148.1 (C10a), 144.1
2 3
2
(
C5a), 135.3 (C-SO2C6H CH ), 129.8 (2CH SO2C6H CH ), 127.4 (2CH-SO2C6H CH ), 124.9 (C8), 123.2
4
3
4
3
4
3
(
(
(
2
C SO2C6H CH ), 123.1 (C6), 122.8 (C7), 119.1 (C5b), 111.3 (C9), 65.0 (C2), 60.3 (COO
C
H CH ), 56.0
4
3
2
3
C10b), 51.0 (C4), 36.4 (N
C
H ), 33.5 (C3a), 31.7 (C3), 21.6 (SO C H4CH ), 14.3 (COOCH2CH ). MS
3
2
6
3
3
+
EI, 70 eV) found 454 (calculated for C H N O S: 454.54); m/z (%) = 454 (M , <5), 381 (65), 299 (20),
24
26
2
5
+
25 (100), 211 (15), 196 (10), 184 (10), 170 (30), 155 (10), 91 (55), 65 (20), 57 (45). HRMS (ESI) m/z [M + H]
+
calculated for C H N O S : 455.1635). Found: 455.1636.
24
27
2
5
O
H
1
0b
H N 2
1
1
0
9
O
9a
10a
OEt
8
3
H3a
5
b 5a
N
7
4
6
5
Ts
(
2R,3aR,10bR) and (2S,3aS,10bS)-Ethyl-1-ethyl-5-tosyl-2,3,3a,4,5,10b-hexahydro-1H-benzo[b] furo[3,2-
˝
1
b]pyrrolo[2,3-d]pyridine-2-carboxylate (9Ab). Light yellow crystals, yield 94%, mp 105 C. H-NMR:
δ = 8.13–8.16 (m, 1H, H6), 7.48 (d, J = 8.3, 2H, H ), 7.44 (dd, J = 1.7, 7.1, 1H, H9), 7.28–7.34 (m, 2H, H8
Ts
and H7), 7.19 (d, J = 8.1, 2H, H ), 4.10–4.17 (m, 2H, COOCH2CH ), 4.05 (dd, J = 14.1, 4.7, 1H, H4),
Ts
3
3
.86 (d, J = 6.7, 1H, H10b), 3.81 (dd, J = 1.9, 8.7, 1H, H2), 3.30–3.38 (m, 1H, NCH CH ), 3.21 (dd, J = 14.0,
2 3
1
1
1.8, 1H, H4), 2.64–2.72 (m, 1H, NCH2CH ), 2.38 (s, 3H, SO C H CH3), 2.03–2.08 (m, 1H, H3),
3 2 6 4
.92–2.00 (m, 1H, H3a), 1.61–1.67 (m, 1H, H3), 1.25 (t, J = 7.1, 3H, COOCH CH3), 1.04 (t, J = 7.3, 3H,
2
13
NCH CH3). C-NMR:
δ
= 173.6 (
COOCH CH ), 153.9 (C9a), 148.2 (C10a), 144.1 (C5a), 135.4 (C in
2 3
2
SO2C6H CH ), 129.8 (2CH in SO2C6H CH ), 127.4 (2CH in SO2C6H CH ), 124.8 (C8), 123.2 (C in
4
3
4
3
4
3
SO2C6H CH ), 123.1 (C6), 122.8 (C7), 119.1 (C5b), 112.3 (C9), 60.7 (C2), 60.2 (COO
C
H CH ), 55.4
4
3
2
3
(
C4), 51.0 (N
C
H CH ), 43.3 (C10b), 32.9 (C3a), 31.5 (C3), 21.6 (SO C H4CH ), 14.3 (COOCH2
C
H3),
2
3
2
6
3
1
3.6 (NCH2
C
H ). MS (EI, 70 eV) Found: 395 [M
´
COOEt] (calculated for C H N O S: 468.57);
3
25 28
2
5
m/z (%) = 395 (80), 313 (20), 239 (100), 211 (25), 184 (15), 170 (20), 91 (40), 71 (25), 56 (30). HRMS (ESI)
m/z [M + H] calculated for C H N O S : 469.1792). Found: 469.1791.
+
+
25
29
2
5
(
2R,3aR,10bR) and (2S,3aS,10bS)-Ethyl-1-benzyl-5-tosyl-2,3,3a,4,5,10b-hexahydro-1H-benzo[b] furo[3,2-
˝
1
b]pyrrolo[2,3-d]pyridine-2-carboxylate (9Ac). Yellow crystals, yield 96%, mp 130 C. H-NMR:
δ = 8.17–8.21 (m, 1H, H6), 7.50 (d, J = 8.3, 2H, H ), 7.37–7.42 (m, 1H, H9), 7.30–7.33 (m, 2H, H8
Ts
and H7), 7.20 (d, J = 8.6, 2H, H ), 7.15–7.18 (m, 5H, CH C6H5), 4.58 (d, J = 13.7, 1H, H4), 4.06–4.14
Ts
2
(
m, 3H, 2H in COOCH2CH and 1H in CH2C H ), 4.05 (d, J = 3.6, 1H, H10b), 3.48–3.51 (m, 1H, H2),
3 6 5
3
.82 (d, J = 13.7, 1H, H4), 3.30 (dd, J = 14.0, 11.6, 1H, CH2C H ), 2.40 (s, 3H, SO C H CH3), 1.98–2.03
6 5 2 6 4
13
(
m, 1H, H3), 1.92–1.97 (m, 1H, H3a), 1.60–1.67 (m, 1H, H3), 1.20 (t, J = 7.1, 3H, COOCH CH3). C-NMR:
2
δ
= 173.8 (
COOCH CH ), 153.9 (C9a), 148.0 (C10a), 144.1 (C5a), 138.8 (C in CH2C6H ), 135.3 (C in
2 3 5
SO2C6H CH ), 129.8 (2CH in SO2C6H CH ), 128.4 (2CH in CH2C6H ), 128.1 (2CH in CH2C6H ), 127.4
4
3
4
3
5
5
(
2CH in SO2C6H CH ), 127.0 (CH in CH2C6H ), 123.1 (C7), 124.9 (C8), 123.1 (C in SO2C6H CH ), 122.9
4 3 5 4 3

Molecules 2016, 21, 187
9 of 11
(
3
C6), 119.2 (C5b), 111.3 (C9), 60.5 (C2), 60.2 (COO
2.9 (C3a), 31.6 (C4), 21.6 (SO C H4CH ), 14.3 (COOCH2CH ). HRMS (APCI) m/z [M + H] calculated
3
CH CH ), 55.1 (C10b), 52.8 (CH C H ), 51.0 (C3),
2 3 2 6 5
+
2
6
3
+
for C H N O S : 531.1948). Found: 531.1947.
30
31
2
5
(
2R,3aR,10bR) and (2S,3aS,10bS)-Ethyl-1-isopropyl-5-tosyl-2,3,3a,4,5,10b-hexahydro-1H-benzo [b]furo[3,2-
˝
1
b]pyrrolo[2,3-d]pyridine-2-carboxylate (9Ad). Colourless crystals, yield 44%, mp 102 C. H-NMR:
δ = 8.13–8.17 (m, 1H, H8), 7.43 (dd, J = 7.3, 1.4, 1H, H9), 7.27–7.34 (m, 2H, H8 and H7), 7.20 (d, J = 8.0,
2
3
H, H ), 4.24 (d, J = 6.6, 1H, H10b), 4.05–4.13 (m, 2H, COOCH2CH ), 3.98 (dd, J = 14.0, 4.4, 1H, H4),
Ts
3
.74 (dd, J = 8.5, 2.0, 1H, H2), 3.49–3.56 (m, 1H, C
H
(CH ) ), 3.27 (dd, J = 14.0, 11.1, 1H, H4), 2.39 (s, 3H,
3
2
SO C H CH3), 1.97–2.08 (m, 1H, H3a), 1.89–1.96 (m, 1H, H3), 1.56–1.64 (m, 1H, H3), 1.25 (t, J = 7.2,
2
6
4
1
3
3
H, COOCH CH3), 1.12 (d, J = 6.8, 3H, CH(CH ) ), 1.06 (d, J = 6.6, 3H, CH(CH ) ). C-NMR: δ = 176.6
2 3 2 3 2
(COOCH CH ), 153.8 (C9a), 147.6 (C10a), 144.0 (C5a), 135.6 (C in SO2C6H CH ), 129.8 (2CH in
2 3 4 3
SO2C6H CH ), 127.4 (2CH in SO2C6H CH ), 124.8 (C8), 123.1 (C in SO2C6H CH ), 123.0 (C6), 122.9
4
3
4
3
4
3
(
3
C7), 119.3 (C5b), 111.3 (C9), 60.5 (COO
3.0 (C3a), 31.8 (C3), 21.6 (SO C H4CH ), 21.1 (CH(CH ) ), 17.8 (CH(CH ) ), 14.3 (COOCH2CH ). MS
3 2 3 2 3
CH CH ), 58.0 (C2), 51.9 (C10b), 50.9 (C4), 47.8 (CH(CH ) ),
2 3 3 2
2
6
3
+
(EI 70 eV) found 482 (calculated for C H N O S: 482.59); m/z (%) = 482 (M , <5), 409 (95), 327 (15),
26 30 2 5
2
53 (100), 211 (75), 184 (25), 170 (25), 155 (15), 91 (65), 84 (25), 70 (55), 65 (20), 43 (30). HRMS (ESI) m/z
+
+
[M + H] calculated for C H N O S : 483.1948). Found: 483.1948.
26 31 2 5
(
2R,3aR,10bR) and (2S,3aS,10bS)-Ethyl-1-benzyl-5-mesyl-2,3,3a,4,5,10b-hexahydro-1H-benzo[b] furo[3,2-
˝
1
b]pyrrolo[2,3-d]pyridine-2-carboxylate (9Bc). Light yellow crystals, yield 29%, mp 106 C. H-NMR:
δ = 8.02 (d, J = 7.5, 1H, H6), 7.41 (d, J = 7.8, 1H, H9), 7.17–7.33 (m, 7H, 5H in C6H5, H8 and H7), 4.63
(
d, J = 13.7, 1H, CH C H ), 4.58 (d, J = 6.8, 1H, H10b), 4.11–4.21 (m, 2H, COOCH CH ), 4.07 (dd, J = 13.6,
2 6 5 2 3
4
.6, 1H, H4), 3.96 (d, J = 13.7, 1H, CH2C H ), 3.61 (dd, J = 8.9, 1H, H2), 3.41 (dd, J = 13.4, 11.2, 1H,
6 5
H4), 2.98 (s, 3H, NSO CH3), 2.79–2.88 (m, 1H, H3a), 2.21–2.29 (m, 1H, H3), 1.84–1.92 (m, 1H, H3), 1.27
2
13
(
t, J = 7.1, 3H, COOCH CH3). C-NMR:
δ
= 173.7 (
COOCH CH ), 154.0 (C9a), 147.0 (C10a), 145.1
2 3
2
(
C5a), 138.7 (C C6H ), 128.5 (2CH C6H ), 128.2 (2CH C6H ), 127.1 (CH C6H ), 125.0 (C8), 123.2 (C7),
5
5
5
5
122.2 (C6), 119.1 (C5b), 111.5 (C9), 60.8 (C2), 60.4 (CO
C
H CH ), 55.4 (C10b), 53.0 (
C
H C H ), 50.8
2
3
2
6
5
(
(
[
C4), 39.3 (SO2
C
H ), 34.9 (C3a), 31.7 (C3), 14.3 (COO H CH ). MS (EI 70 eV) Found 381[M
C
´
COOEt]
3
2
3
calculated for C H N O S: 454.539); m/z (%) = 381 (40), 301 (15), 211 (20), 91 (100). HRMS (ESI) m/z
24
26
2
5
+
+
M + H] calculated for C H N O S : 455.1641). Found: 455.1642.
24
27
2
5
4
. Conclusions
We have prepared two N-substituted 3-allylaminobenzo[b]furan-2-aldehydes with N-tosyl and
N-mesyl groups. These compounds served as precursors for the formation of azomethine ylides by

Molecules 2016, 21, 187
10 of 11
means of their reaction with four types of secondary amines derived from ethyl—
α
-amino acid esters.
Methyl, ethyl, benzyl and isopropyl groups were used as N-substituents. The ylides participated
in subsequent 1,3-dipolar cycloadditions. The azomethine ylides were generated by heating a neat
˝
mixture of components to 130–140 C. Then, they reacted intramolecularly with the already present
double bond of the build in the allyl group. We found that reaction time and temperature have an
influence upon the yield of cyclization rather than the size of the group bound at the amino group of
the α-amino acid ester. The tosyl-protected compounds 7A afforded products in a good yield.
Dipolar cycloaddition led to systems with four fused rings, and, during the reaction, three
stereogenic centers were formed. On the basis of NOESY and 2D COSY experiments, we found
compounds with (S,S,S) or (R,R,R) configurations at all centers, which was confirmed by X-ray structure
analysis. These experiments proved the theory that azomethine ylide participates in cycloadditions in
a more stable conformation and, therefore, that only the corresponding conformer is then found in
the products.
Supplementary Materials: The following are available online at http://www.mdpi.com/1420-3049/21/2/187/s1.
Table S1: Chemical shifts of hydrogen atoms at stereogenic centres in [ppm], Table S2. Reaction conditions and
1
product yields in 1,3-DC, Figure S1: NOESY spectrum of compound 9Ad
compounds 9Aa–d and 9Bc in CDCl3.
.
H-NMR and APT spectra of final
Acknowledgments: We are grateful to Masaryk University for its institutional support of our research. Our thanks
also go to Michal Babiak for help with X-ray analysis of the new compound.
Author Contributions: The listed authors contributed to this work in the following ways. Milan Potá cˇ ek
conceived the work, interpreted the results, and prepared the manuscript; Martin Porubský carried out the main
synthetic work and also interpreted the results together with Lukáš Tenora. All authors read and approved the
final manuscript.
Conflicts of Interest: The authors declare no conflicts of interest.
References and Notes
1
2
.
.
Huisgen, R. 1,3-Dipolar Cycloaddition Chemistry; Padwa, A., Ed.; Wiley: New York, NY, USA, 1984; Volume 1.
Padwa, A. Intramolecular 1,3-Dipolar Cycloaddition Reactions. Angew. Chem. Int. Ed. 1976, 15, 123–136.
[CrossRef]
3.
4.
5.
Harwood, L.; Vickers, R.J. Synthetic Applications of 1,3-Dipolar Cycloaddition Chemistry Towards Heterocycles and
Natural Products; Padwa, A., Pearson, W.H., Eds.; Wiley: New York, NY, USA, 2003.
Pospíšil, J.; Potá cˇ ek, M. Microwave-assisted solvent-free synthesis of hexahydro-chromeno[4,3-b]pyrroles.
Eur. J. Org. Chem. 2004, 3, 710–716.
Pospíšil, J.; Potá cˇ ek, M. Microwave-assisted Solvent-free Intramolecular 1,3-Dipolar Cycloaddition Reactions
Leading to Hexahydrochromeno[4,3-b] pyrroles: Scope and Limitations. Tetrahedron 2007, 63, 337–346.
[
CrossRef]
Potá cˇ ek, M.; Pospíšil, J. A Solvent-free Method for Substituted Imidazolidin-4-ones Synthesis. Heterocycles
004, 63, 1165–1174.
6
7
8
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2
Neuschl, M.; Bogdal, D.; Potá cˇ ek, M. Microwave-Assisted Synthesis of Substituted Hexahydropyrrolo[3,2-
c]quinolones. Molecules 2007, 12, 49–59. [PubMed]
Costa, P.R.R.; Sansano, J.M.; Cossío, U.; Barcellos, J.C.F.; Dias, A.G.; Nájera, C.; Arrieta, A.; Cózar, A.;
Cossío, F.P. Synthesis of Chromen[4,3-b]pyrrolidines by Intramolecular 1,3-Dipolar Cycloaddition of
Azomethine Ylides: An Experimental and Computational Assessment of the Origin of Sterecontrol.
Eur. J. Chem. 2015, 4689–4698.
9
.
Nyerges, M.; Fejes, I.; Toke, L. An intermolecular 1,3-dipolar cycloaddition approach to the tricyclic core of
martinelline and martinellic acid. Tetrahedron Lett. 2000, 41, 7951–7954.
1
0. Rosini, A.; Budriesi, R.; Bixel, M.G.; Bolognesi, M.L.; Chiarini, A.; Hucho, F.; Krogsgaard-Larsen, P.;
Mellor, A.; Minarini, I.R.; Tumiatti, V.; et al. Design, synthesis, and biological evaluation of symmetrically
and unsymmetrically substituted methoctramine-related polyamines as muscular nicotinic receptor
noncompetitive antagonists. J. Med. Chem. 1999, 42, 5212–5223. [PubMed]
1
1. Confalone, P.N.; Huie, E.M. The Stabilized Iminium Ylide-Olefin [3+2]Cycloaddition Reaction. Total
Synthesis of Sceletium Alkaloid A . J. Am. Chem. Soc. 1984, 106, 7175–7178.
4

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1
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1
2 Union Road, Cambridge CB2 1EZ, UK; Fax: +44 1223 336033; E-mail: deposit@ccdc.cam.ac.uk).
Sample Availability: Samples of the compounds 9Aa–d are available from the authors.
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