Total Syntheses of the Amaryllidaceae Alkaloids Zephycandidine III and Lycosinine A and Their Evaluation as Inhibitors of Acetylcholinesterase

Article abstract of DOI:10.1002/ejoc.201700705

The title alkaloids, 1 and 2, have been prepared using cross-coupling chemistries and together with various analogues they have been evaluated for their capacity to inhibit acetylcholinesterase. Contrary to an earlier report, it was found that biaryl 1 is not a significant inhibitor of this enzyme, and neither are any of its congeners, including alkaloid 2.

Full text of DOI:10.1002/ejoc.201700705

A Journal of
Accepted Article
Title: Total Syntheses of the Amaryllidaceae Alkaloids Zephycandidine
III and Lycosinine A and Their Evaluation as Inhibitors of
Acetylcholinesterase
Authors: Martin Banwell, Xingjun Xu, Hye-Sun Kim, Wei-Min Chen,
Xiang Ma, Galen J Correy, Colin J Jackson, Anthony C Willis,
and Paul D Carr
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201700705
Link to VoR: http://dx.doi.org/10.1002/ejoc.201700705
Supported by

European Journal of Organic Chemistry
10.1002/ejoc.201700705
Total Syntheses of the Amaryllidaceae Alkaloids Zephycandidine III and Lycosinine
A and Their Evaluation as Inhibitors of Acetylcholinesterase
a,b
b
a
b
b
Xingjun Xu, Hye-Sun Kim, Wei-Min Chen, Xiang Ma, Galen J. Correy,
b
b
b
b
Martin G. Banwell*, Colin J. Jackson, Anthony C. Willis and Paul D. Carr
Keywords: AChE inhibition, alkaloids, biaryls, cross-coupling, lycosinine A,
zephycandidine III
–
–––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––
The title alkaloids, 1 and 2 respectively, have been prepared using cross-coupling
chemistries and together with various analogues they have been evaluated for their
capacity to inhibit acetylcholinesterase. Contrary to an earlier report, we have found that
biaryl 1 is not a significant inhibitor of this enzyme and nor are any of its congeners,
including alkaloid 2.
Introduction
[
1]
Very recently Yao and co-workers reported the isolation of three new Amaryllidaceae
alkaloids through extraction of the dried whole plant Zephyranhes candida collected at
Shiyan, Hubei in China. Their structures were established by conventional spectroscopic
methods and each was evaluated as a possible inhibitor of acetylcholinesterase (AChE).
The most active of these [with an IC of 8.82 M] was reported to be the novel biaryl
5
0
zephycandidine III (1) (Figure 1). This compound bears a strong structural resemblance
to the Amaryllidaceae alkaloid lycosinine A (2) that was isolated by Zhao and co-
[
2]
workers from the ornamental plant Lycoris aurea collected in Kunming, Yunnan
Province, China. The corresponding aldehyde, viz. lycosinine B (3), was also obtained
from the same source. Lycosinine B (3) has since been isolated from the bulbs of Lycoris
[
3]
sprengeri collected from Taizhou City, Zhejiang Province, China and from the bulbs of
Hippeastrum breviflorum Herb. Amaryllidaceae (flowering sage) collected in São
[
4]
Francisco de Paula in the Brazilian state of Rio Grande do Sul. No biological activities
have been ascribed to the lycosinines thus far but given the structural resemblance of
compound 2 to zephycandidine III it might also be expected to display AChE-inhibiting
activities.
–
–––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––
College of Pharmacy, Jinan University, Guangzhou, 510632,
[
a]
People’s Republic of China
[
b]
Research School of Chemistry, Institute of Advanced Studies,
The Australian National University, Canberra, ACT 2601, Australia
Email: Martin.Banwell@anu.edu.au
URL: http://chemistry.anu.edu.au/research/groups/synthesis-mechanism
Supporting information for this article is available on the WWW under http://dx.doi.org...
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European Journal of Organic Chemistry
10.1002/ejoc.201700705
Figure 1: Structures of the Amaryllidaceae Alkaloids Zephycandidine III (1), Lycosinine
A (2) and Lycosinine B (3)
To date there have been no reports concerned with synthesis of zephycandidine III (1)
and just one dealing with the preparation of the lycosinines. Specifically, Hsieh and co-
[
5]
workers reported generating compounds 2 and 3 using, as the key step, the Suzuki-
Miyuara cross-coupling of a borylated derivative of 3,4-dimethoxybenzaldehyde with 7-
bromo-1-methylindoline. It is against this background that we now report our own studies
in the area that have culminated in syntheses of the title alkaloids (viz. 1 and 2) and thus
allowed for their evaluation as inhibitors of AChE derived from Electrophorus electricus.
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European Journal of Organic Chemistry
10.1002/ejoc.201700705
Results and Discussion
1
.
Total Synthesis of Zephycandidine III (1)
Our initial approach to biaryl core of zephycandidine III (1) is shown in Scheme 1 and
sought to exploit Suzuki-Miyuara cross-coupling chemistry. Thus, the known nitroarene
[
6]
[7]
4
was reduced to the corresponding and previously reported aniline 5 (67%) using
iron filings in mildly acidic aqueous ethanol and the later compound subjected to
electrophilic aromatic iodination with molecular iodine.
Scheme 1: Initial Attempts to Assemble the Biaryl Core of Zephycandidine III (1) Using
Suzuki-Miyaura Cross-coupling Protocols. Reagents and conditions (a) Fe, NH4Cl,
ethanol/water, reflux, 3 h, 67%; (b) I , NaHCO , DCM, 22 °C, 18 h, 75%; (c) p-TsCl,
2
3
pyridine, 22 °C, 1 h, 92%.
Product 6 (75%) was then converted into the corresponding p-toluenesulfonamide 7
92%) under standard conditions. Disappointingly, and despite extensive experimentation
(
involving a range of reaction conditions, attempts to engage aniline 6 in a Suzuki-
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European Journal of Organic Chemistry
10.1002/ejoc.201700705
[
8]
Miyaura cross-coupling reaction with the known and readily accessible arylboronate 8
failed to deliver the biaryl 9. Related attempts to cross-couple sulfonamide 7 with ester 8
and thereby generate compound 10 were equally unsuccessful.
In a second approach (Scheme 2) to the biaryl core of target 1 that sought to exploit the
often-beneficial effects of electron-withdrawing groups in Suzuki-Miyaura cross-
[
9]
coupling reactions, attempts were made to link the boronate ester 8 and 3-bromo-4-
[
10]
nitrobenzaldehyde (11)
under a range of seemingly relevant reaction conditions.
Unfortunately, none of these led to the formation of the hoped-for biaryl 12.
Scheme 2: An Alternate Attempt to Effect a Relevant Suzuki-Miyaura Cross-coupling
Reaction
The palladium-catalyzed Ullmann cross-coupling reaction has proven to be a useful but
under-utilized method for cross-coupling various aryl halides with other species, most
[
11]
notably -iodoenones. Given our familiarity with this process we sought to apply it in
the present context. To such ends (Scheme 3) the commercially available alcohol 13 was
treated with a combination of molecular iodine and silver trifluoroacetate and thereby
[
12]
12
affording compound 14
(
(93%) that was oxidized to corresponding aldehyde 15
[13]
95%) using Attenborrow manganese dioxide
under sonication conditions. Pinnick
oxidation of compound 15 to the corresponding acid and esterification of this using
[
12]
methyl iodide in the presence of potassium carbonate then gave ester 16
in 85%
overall yield. Gratifyingly, when a DMSO solution of this last compound was reacted
with bromoarene 11 in the presence of copper metal as well as small amounts of CuI and
PdCl (dppf) at 50 °C for 5 h then the biaryl 17 was obtained in 60% yield. Treatment of
2
compound 17 with sodium borohydride in methanol gave the benzyl alcohol 18 and O-
methylation of this using methyl iodide in DMSO containing potassium hydroxide then
afforded the methyl ether 19 (63%). The structure of compound 18 was confirmed by
single-crystal X-ray analysis [see Experimental Section and Supporting Information (SI)
for details]. Unfortunately, all attempts to effect the reduction of the nitro- and ester-
groups associated with this last compound, and thereby generate zephycandidine III (1)
directly, were unsuccessful. In every instance complex product mixtures were obtained.
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European Journal of Organic Chemistry
10.1002/ejoc.201700705
Scheme 3: Successful Synthesis of the Biaryl Core of Target 1. Reagents and conditions
a) I , AgOCOCF , MeOH, –5 °C, 0.5 h, 93%; (b) MnO , DCM, 22 °C, 18 h, 95%; (c)
(
2
3
2
Pinnick oxidation then MeI, K CO , acetone, 22 °C, 18 h, 90%; (d) Cu, CuI, PdCl (dppf),
2
3
2
DMSO, 50 °C, 5 h, 60%; (e) NaBH , MeOH, 0 to 22 °C, 0.5 h; (f) MeI, KOH, DMSO, 22
4
°
C, 2 h, 63% (from 17).
The ultimately successful route to zephycandidine III (1) is displayed in Scheme 4 and
exploited various of the chemistries defined in Scheme 3. Thus, the reaction sequence
started with the conversion of aldehyde 11, through a reduction/O-methylation sequence,
into the methyl ether 20 (63%). Like its precursor 11, compound 20 could be engaged in
a palladium-catalyzed Ullmann cross-coupling, this time with aldehyde 15, and thereby
affording the biaryl 21, the structure of which was confirmed by single-crystal X-ray
analysis. The aldehydic residue within compound 21 was reduced with sodium
borohydride and the nitro-group associated with product 22 (90%) subjected to
hydrogenolysis using dihydrogen in the presence of 10% palladium on carbon. By such
means aniline 22 was obtained in 95% yield. Reductive mono-methylation of compound
2
2 using one molar equivalent of formaldehyde in the presence of sodium
cyanoborohydride then gave compound 1 as a clear, colourless oil in 95% yield. All of
the spectral data acquired on this product were in complete according with the assigned
structure. Furthermore, relevant comparisons with the analogous data reported by Yao
[
1]
and co-workers for zephycandidine III revealed a good match (tabular comparisons of
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European Journal of Organic Chemistry
10.1002/ejoc.201700705
1
3
the C NMR data sets are provided in the SI) and thus leaving no doubt about the
structure of the natural product.
Scheme 4: Successful Total Synthesis of Zephycandidine III (1). Reagents and conditions
(
a) NaBH , MeOH, 0 to 22 °C, 0.5 h then MeI, KOH, DMSO, 22 °C, 2 h, 63%; (b) Cu,
4
CuI, PdCl (dppf), DMSO, 50 °C, 5 h, 70%; (c) NaBH , MeOH, 0 to 22 °C, 0.5 h, 90%;
2
4
(
d) H , 10% Pd on C, MeOH, 22 °C, 16 h, 95%; (e) HCHO (1.0 equiv.), NaBH CN,
2
3
MeOH, 22 °C, 16 h, 95%.
The two-fold reductive N-methylation of aniline 23 was readily effected (Scheme 5)
using 9 molar equivalents of formaldehyde in the presence of sodium cyanaoborohydride
and compound 24 was thereby obtained in 95% yield. This product is the N-methyl
derivative of zephycandidine III (1) and arguably, therefore, more closely resembles
lycosinine A (2).
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European Journal of Organic Chemistry
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Scheme 5: Reductive Methylation of Aniline 23 Leading to the N-Methyl Derivative, 24,
of Zephycandidine III (1). Reagents and conditions (a) (f) HCHO (9.0 equiv.),
NaBH CN, AcOH, MeCN, 0 to 22 °C, 16 h, 95%.
3
2
.
Total Synthesis of Lycosinine A (2) and an Examination of Its Behavior
Under Oxidative Conditions
The two-step synthesis of lycosinine A (2) from known materials is shown in Scheme 6.
This simply involved Suzuki-Miyaura cross-coupling of the known C7-borylated indole
2
5 (prepared in a one-pot process and 86% yield from indole itself using a procedure
[
14]
[15]
reported by Hartwig ) with the readily available aryl iodide 26
under relatively
standard conditions and so affording the 7-arylindole 27 (91%), the structure of which
was confirmed by single-crystal X-ray analysis. Reductive N-methylation of the last
compound using paraformaldehyde in the presence of sodium cyanoborohydride was
accompanied by conversion of the indole residue into the corresponding indoline and so
affording lycosinine A (2) directly and in 91% yield. All of the of spectral data acquired
on this compound were in accord with the assigned structure and matched those
[
2]
13
reported for the natural product (tabular comparisons of the C NMR data sets are
provided in the SI). In addition, a single-crystal X-ray analysis of the synthetically
derived material was carried out and served to confirm the illustrated structure.
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European Journal of Organic Chemistry
10.1002/ejoc.201700705
Scheme 6: Two-step Synthesis of Lycosinine A (2). Reagents and conditions (a)
PdCl (dppf), Et N, THF/water, 85 °C, 19 h, 91%; (b) (CH O)n, NaBH CN, 0 to 22 °C, 24
2
3
2
3
h, quant.
With compound 2 in hand various efforts were made to convert it into lycosinine B (3).
However, despite numerous efforts this conversion failed due to the oxidative sensitivity
of the indoline unit associated with the substrate. For example, on treating lycosinine A
[
13]
(2) (Scheme 7) with Attenborrow manganese dioxide
in dichloromethane indole 28
(76%) was obtained. On the other hand, when the same substrate (viz. 2) was treated with
pyridinium chlorochromate (PCC) in the presence of sodium acetate then indole 28 (5%)
was again obtained but the two-fold oxidation product 29 (35%) was now the
[
5]
predominant one. It is interesting to note that in Hsieh’s synthesis of lycosinine B (3)
the associated aldehyde residue was installed directly through a cross-coupling reaction
involving a C2-borylated benzaldehyde and this natural product was then reduced to
lycosinine A (2).
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European Journal of Organic Chemistry
10.1002/ejoc.201700705
Scheme 7: Outcomes of the Oxidation of Lycosinine A (2). Reagents and conditions (a)
MnO , DCM, 22 °C, 72 h; (b) PCC, NaOAc, DCM, 22 °C, 17 h.
2
3
.
Evaluation of Compounds 1, 2, 17-19, 21-24 and 27 as Inhibitors of AChE
Alkaloids 1 and 2, as well as congeners 17-19, 21-24 and 27 were each evaluated for their
[
16]
ability to inhibit AChE derived from Electrophorus electricus.
A summary of the
inhibition data thus obtained is shown in Table 1.
Table 1: Inhibition of AChE by compounds 1, 2, 17-19, 21-24 and 27
a
Entry
Compound
IC (M)
50
b
1
2
3
4
5
6
7
8
9
1
2
17
18
19
21
22
23
>500
>500
120 [110-150]
210 [180-260]
270 [190-430]
280 [250-330]
>500
>200
24
27
140 [130-160]
>500
1.1 [0.9-1.2]
1
1
0
4
Galanthamine (+ve control)
a
Values in brackets represent the 95% confidence interval in the IC50. The IC50 was calculated from a
dose-response curve with three repeat measurements of enzyme activity at each concentration of
b
compound. A lower limit is given for compounds where the IC50 was greater than the maximum
soluble concentration of the compound.
Compounds 17 and 24 (viz. the N-methyl derivative of zephycandidine III) were the most
effective inhibitors exhibiting IC values of 120 and 140 μM respectively, however this
5
0
is two orders of magnitude weaker than the alkaloid galanthamine, an established AChE
inhibitor used to treat Alzheimer’s disease. The assay results are also at odds with those
[
1]
of Yao and co-workers who have suggested that zephycandidine III (compound 1) is a
notable inhibitor of the enzyme. When assayed against AChE, 1 reduced activity by only
2
5% at the maximum concentration tested (500 μM). The origins of the discrepancies
between the work of Yao and co-workers and our own reported herein are unclear but
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European Journal of Organic Chemistry
10.1002/ejoc.201700705
could be the result of the natural product being contaminated with a potent but as yet
unidentified inhibitor of AChE.
Conclusions
The studies reported herein serve to confirm the structures assigned to the title natural
products but cast serious doubt on the merits of trying to develop related
polyfunctionalized biaryls as new, effective inhibitors of AChE.
Experimental Section
General Experimental Procedures
1
13
Unless otherwise specified, proton ( H) and carbon ( C) NMR spectra were recorded at
room temperature in base-filtered CDCl on a Varian spectrometer operating at 400 MHz
3
for proton and 100 MHz for carbon nuclei. The signal due to residual CHCl appearing at
3
H 7.26 and the central resonance of the CDCl triplet appearing at  77.0 were used to
3
C
1
13
1
reference H and C NMR spectra, respectively. H NMR data are recorded as follows:
chemical shift () [multiplicity, coupling constant(s) J (Hz), relative integral] where
multiplicity is defined as: s = singlet; d = doublet; t = triplet; q = quartet; m = multiplet or
combinations of the above. Infrared spectra (max) were recorded on a Perkin–Elmer 1800
Series FTIR Spectrometer. Samples were analyzed as thin films on KBr plates. Low-
resolution ESI mass spectra were recorded on a single quadrupole liquid chromatograph-
mass spectrometer, while high-resolution measurements were conducted on a time-of-
flight instrument. Low- and high-resolution EI mass spectra were recorded on a
magnetic-sector machine. Melting points were measured on an Optimelt automated
melting point system and are uncorrected. Analytical thin layer chromatography (TLC)
was performed on aluminum-backed 0.2 mm thick silica gel 60 F254 plates as supplied by
Merck. Eluted plates were visualized using a 254 nm UV lamp and/or by treatment with a
suitable dip followed by heating. These dips included phosphomolybdic acid : ceric
sulfate : sulfuric acid (conc.) : water (37.5 g : 7.5 g : 37.5 g : 720 mL) or potassium
permanganate : potassium carbonate : 5% sodium hydroxide aqueous solution : water (3
g : 20 g: 5 mL : 300 mL). Flash chromatographic separations were carried out following
[
17]
protocols defined by Still et al. with silica gel 60 (40–
and using the AR- or HPLC-grade solvents indicated. The melting points of solids
purified by such means were recorded directly (i.e. after they had crystallized from the
concentrated chromatographic fractions). Starting materials and reagents were generally
available from the Sigma–Aldrich, Merck, TCI, Strem or Lancaster Chemical Companies
and were used as supplied. Drying agents and other inorganic salts were purchased from
the AJAX, BDH or Unilab Chemical Companies. Tetrahydrofuran (THF), methanol and
dichloromethane were dried using a Glass Contour solvent purification system that is
[
18]
based upon a technology originally described by Grubbs et al.
reactions were performed under an nitrogen atmosphere.
Where necessary,
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European Journal of Organic Chemistry
10.1002/ejoc.201700705
Specific Chemical Transformations
4
9
-(Methoxymethyl)aniline (5). A magnetically stirred suspension of iron filings (5.41 g,
7.0 g.atom) in ethanol (30 mL) containing in NH Cl (12 ml of a 22% w/v aqueous
4
[
6]
solution) was treated with nitroarene 4 (1.67 g, 10 mmol) and the ensuing mixture
heated under reflux for 2 h then cooled and filtered. The filtrate was extracted with ethyl
acetate (3 × 30 mL) and the combined organic phases washed with brine (1  50 mL)
before being dried (Na SO ), filtered and concentrated under reduced pressure. The
2
4
resulting light-yellow oil was subjected to flash chromatography (silica gel, 5:1 v/v
0−60 petroleum spirit/ethyl acetate elution) and concentration of the relevant fractions
4
[
7]
(R = 0.3 in 5:1 v/v hexane/ethyl acetate) afforded compound 5 (920 mg, 67%) as clear,
f
1
light-brown oil. H NMR (400 MHz, CDCl ): δ 7.13 (d, J = 8.4 Hz, 2H), 6.67 (d, J = 8.4
Hz, 2H), 4.33 (s, 2H), 3.66 (broad s, 2H), 3.34 (s, 3H) ppm. C NMR (100 MHz,
3
1
3
CDCl ): δ 146.2, 129.6, 128.2, 115.1, 74.8, 57.8 ppm.
3
2
-Iodo-4-(methoxymethyl)aniline (6). A magnetically stirred solution of compound 5
(
686 mg, 5.0 mmol) in CH Cl (20 mL) maintained at 22 °C was treated with water (10
2
2
mL), NaHCO (1.26 g, 15 mmol) and molecular iodine (1.27 g, 5.0 mmol). The ensuing
3
mixture was stirred at 22 °C for a further 16 h then quenched with Na S O (10 mL of a
2
2
3
saturated aqueous solution) and separated aqueous layer extracted with CH Cl (3  30
2
2
mL). The combined organic layers were washed with brine (1 25 mL) then dried
(
Na SO ), filtered and concentrated under reduced pressure. The ensuing light-brown oil
2
4
was subjected flash chromatography (silica gel, 10:1 v/v 40−60 petroleum spirit/ethyl
acetate elution) and concentration of the relevant fractions (R = 0.4 in 5:1 v/v
f
1
hexane/ethyl acetate) gave compound 6 (980 mg, 75%) as a clear, brown oil. H NMR
(
400 MHz, CDCl ): δ 7.62 (d, J = 1.9 Hz, 1H), 7.11 (dd, J = 8.1 and 1.9 Hz, 1H), 6.72 (d,
3
1
3
J = 8.1 Hz, 1H), 4.29 (s, 2H), 4.09 (s, 2H), 3.34 (s, 3H) ppm. C NMR (100 MHz,
CDCl ): δ 146.5, 138.9, 129.9, 129.5, 114.6, 84.0, 73.8, 57.9 ppm. IR: ν = 3455, 3348,
2
3
max
−
1
817, 1614, 1500, 1352, 1305, 1352, 1201, 1088, 1031, 885, 820, 666 cm . MS (ESI,
+
+
127
+
ve): m/z 286 [(M+Na) , 100%]. HRMS: (M+Na) calcd for C H
INNaO 285.9705;
8
10
found 285.9705.
N-(2-Iodo-4-(methoxymethyl)phenyl)-4-methylbenzenesulfonamide (7). A solution of
compound 6 (522 mg, 2.1 mmol) and p-toluenesulfonyl chloride (477 mg, 2.5 mmol) in
pyridine (10 mL) was stirred at 22 °C for 4 h then water (30 mL) was added and the
separated aqueous phase extracted with ethyl acetate (3  30 mL). The combined organic
fractions were washed with CuSO (1 50 mL of a 10% w/v aqueous solution) and water
4
(
1 50 mL) before being dried (Na SO ), filtered and concentrated under reduced
2
4
pressure. The filtrate was concentrated under reduced pressure and the ensuing light-
yellow oil subjected to flash chromatography (silica gel, 5:1 v/v 40−60 petroleum
spirit/ethyl acetate elution). Concentration of the relevant fractions (R = 0.3 in 3:1 v/v
f
hexane/ethyl acetate) then gave compound 7 (806 mg, 92%) as white, crystalline solid,
1
mp = 121.5-123 °C. H NMR (400 MHz, DMSO-d ): δ 9.65 (s, 1H), 7.75 (d, J = 1.8 Hz,
6
1
6
H), 7.59 (d, J = 8.1 Hz, 2H), 7.36 (d, J = 8.1 Hz, 2H), 7.22 (dd, J = 8.2 and 1.8 Hz, 1H),
.96 (d, J = 8.2 Hz, 1H), 4.32 (s, 2H), 3.26 (s, 3H), 2.37 (s, 3H) ppm. C NMR (100
1
3
MHz, DMSO-d ): δ 143.1, 138.7, 138.3, 137.8, 137.3, 129.6, 127.9, 126.8, 98.6, 71.9,
6
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European Journal of Organic Chemistry
10.1002/ejoc.201700705
5
1
1
7.7, 21.0 (one signal obscured or overlapping) ppm. IR: ν = 3289,1598, 1489, 1386,
max
−1
+
335, 1164, 1091, 1037,916, 814, 667, 545 cm . MS (ESI, +ve): m/z 440 [(M+Na) ,
+
127
16
00%]. HRMS: (M+Na) calcd for C H
INNaO S 439.9793; found 439.9794.
1
5
3
3
-Bromo-4-nitrobenzaldehyde (11). Compound 11 was prepared according to the
[
10]
[10]
method of Katritzky and obtained as crystalline yellow solid, mp = 99-101 °C (lit.
mp. = 101-102 °C). H NMR (400 MHz, CDCl ): δ 10.05 (s, 1H), 8.23 (d, J = 1.6 Hz,
1
1
3
13
H), 7.97 (dd, J = 8.2 and 1.6 Hz, 1H), 7.93 (d, J = 8.2 Hz, 1H) ppm. C NMR (100
MHz, CDCl ): δ 188.9, 153.2, 139.0, 136.0, 129.1, 126.1, 115.4 ppm. IR: ν = 3094,
3
max
−
1
1
(
694, 1584, 1529, 1373, 1360, 1300, 1191, 1037, 900, 841, 831, 748, 699, 682 cm . MS
EI, 70 eV): m/z 231 and 229 (M , 88 and 90%), 75 (100). HRMS: M calcd for
+
•
+•
79
4
C H BrNO 228.9375; found 228.9376.
7
3
(6-Iodobenzo[d][1,3]dioxol-5-yl)methanol (14). A flame-dried 200 mL round-bottom
flask was covered with aluminium foil then charged with piperonyl alcohol (3.00 g, 19.7
mmol), AgOCOCF (4.80 g, 22.0 mmol), a magnetic stirring bar and CHCl (20 mL).
3
3
The ensuing mixture was cooled to −5 °C (ice-salt bath) then treated, dropwise over ca.
.10 h, with a solution of molecular iodine (5.50 g, 18.0 mmol) in CHCl (25 mL).
0
3
Additional quantities of solid molecular iodine were added to the reaction mixture until
TLC analysis revealed that all of the starting alcohol had been consumed. The reaction
mixture was then filtered through a pad of tightly packed diatomaceous earth and the
solids thus retained rinsed with CHCl (150 mL). The combined filtrates were washed
3
with Na S O (2  200 mL of a 2 M aqueous solution) before being dried (Na SO ),
2
2
3
2
4
filtered, and concentrated under reduced pressure. The resulting solid was subjected to
flash chromatography (silica gel, 5:1 v/v 40−60 petroleum spirit/ethyl acetate elution) and
concentration of the relevant fractions (R = 0.2 in 4:1 v/v 40−60 petroleum spirit/ethyl
f
[
12]
acetate) afforded compound 14 (5.10 g, 93%) as a white, crystalline solid, mp = 109-
[
12a]
1
1
(
11 °C (lit.
mp. = 109.3-109.8 °C). H NMR (400 MHz, CDCl ): δ 7.24 (s, 1H), 6.99
3
1
3
s, 1H), 5.98 (s, 2H), 4.59 (s, 2H), 1.88 (s, 1H) ppm. C NMR (100 MHz, CDCl ): δ
3
1
48.8, 148.1, 136.4, 118.7, 109.2, 101.8, 85.5, 69.4 ppm.
6
-Iodobenzo[d][1,3]dioxole-5-carbaldehyde (15). A magnetically stirred solution of
compound 14 (4.00 g, 14.4 mmol) in CH Cl (75 mL) was treated, in one portion, with
2
2
MnO (12.5 g, 143.9 mmol) and the resulting dark suspension was stirred at 22 °C for 18
2
h then filtered through pad of diatomaceous earth. The solids thus retained were washed
with CH Cl (2  80 mL) and the combined filtrates were concentrated under reduced
2
2
pressure. The resulting brown oil was subjected to flash chromatography (silica, 4:1 v/v
4
0−60 petroleum spirit/ethyl acetate elution) and concentration of the relevant fractions
1
2
(R = 0.4 in 4:1 v/v 40−60 petroleum spirit/ethyl acetate) then gave aldehyde 15 (3.85 g,
f
[12a]
1
9
7%) as a white, crystalline solid, mp = 112-113 °C (lit.
mp. = 112-113 °C). H NMR
13
(400 MHz, CDCl ): δ 9.89 (s, 1H), 7.37 (s, 1H), 7.34 (s, 1H), 6.08 (s, 2H) ppm. C NMR
3
(
=
[
100 MHz, CDCl ): δ 194.6, 153.7, 149.3, 129.8, 119.6, 109.0, 102.8, 93.5 ppm. IR: ν
3
max
−
1
1664, 1610, 1505, 1386, 1268, 1113, 925 cm . MS (ESI, +ve): m/z 331 (100%), 299
+
+
127
(M+Na) , 45]. HRMS: (M+Na) calcd for C H INaO 298.9181; found 298.9188.
8 5 3
Methyl 6-Iodobenzo[d][1,3]dioxole-5-carboxylate (16). Step i: A magnetically stirred
solution of aldehyde 15 (3.60 g, 13.0 mmol) and 2-methyl-2-butene (7.6 mL, 65.0 mmol)
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European Journal of Organic Chemistry
10.1002/ejoc.201700705
in acetone (50 mL) maintained at 0 °C (ice bath) was treated, dropwise, with a solution of
sodium chlorite (4.40 g of 80% technical grade material, 39.0 mmol) and sodium
dihydrogen phosphate dihydrate (6.10 g, 39.0 mmol) in water (20 mL). The ensuing
mixture was allowed to warm to 22 °C, stirred at this temperature for 3 h then treated
with NH Cl (60 mL of a saturated aqueous solution). The resulting mixture was extracted
4
with ethyl acetate (3  100 mL) and the combined organic phases were washed with brine
(
1 × 150 mL) before being dried (Na SO ), filtered and concentrated under reduced
2 4
pressure to give the anticipated acid (3.42 g, 90%) as white, crystalline solid. The
material was used without purification in next step of the reaction.
Step ii: A magnetically stirred solution of the acid (3.42 g, 11.7 mmol) from step i in
acetone (60 mL) was treated with potassium carbonate (4.85 g, 35.1 mmol). The ensuing
mixture was stirred at 22 °C for 0.25 h before treated with iodomethane (2.5 mL, 58.5
mmol) then stirred at 22 °C for 18 h before being passed through a pad of TLC-grade
silica gel. The filtrate thus obtained was concentrated under reduced pressure to give ester
[
12]
[12a]
1
°
6
(3.22 g, 90%) as a white, crystalline solid, mp = 83-85 °C (lit.
mp = 84.6-86.1
1
C). H NMR (400 MHz, CDCl ): δ 7.41 (s, 1H), 7.37 (s, 1H), 6.04 (s, 2H), 3.89 (s, 3H)
ppm. C NMR (100 MHz, CDCl ): δ 166.0, 151.2, 148.3, 127.7, 121.1, 111.2, 102.5,
3
1
3
3
8
1
5.0, 52.5 ppm. IR: νmax = 2951, 2905, 1727, 1614, 1502, 1480, 1435, 1378, 1348, 1243,
−
1
+•
133, 1088, 1037, 934, 776 cm . MS (EI, 70 eV): m/z 306 (M , 100%), 275 (72).
+
•
127
HRMS: M calcd for C H IO 305.9389; found 305.9390.
9
7
4
Methyl 6-(5-Formyl-2-nitrophenyl)benzo[d][1,3]dioxole-5-carboxylate (17).
A
magnetically stirred mixture of compound 11 (510 mg, 2.2 mmol), ester 16 (814 mg, 2.6
mmol), copper powder (699 mg, 11 g.atom), CuI (628 mg, 3.3 mmol) and Pd(dppf)Cl2
(161 mg, 0.22 mmol) in degassed DMSO (25 mL) was heated at 50 C under a nitrogen
atmosphere for 12 h. The cooled reaction mixture was treated with water (30 mL) then
diluted with ethyl acetate (40 mL) before being filtered through a pad of diatomaceous
earth. The pad and the solids thus retained were washed with ethyl acetate (2  40 mL)
and the separated organic phase associated with the filtrate was washed with water (2 
5
0 mL) and brine (2  40 mL) before being dried (Na SO ), filtered and concentrated
2
4
under reduced pressure to give a brown oil. Subjection of this material to flash
chromatography (silica gel, 20:1 → 5:1 40−60 petroleum spirit/ethyl acetate elution)
afforded, after concentration of the appropriate fractions (R = 0.2 in 5:1 v/v 40−60
f
petroleum spirit/ethyl acetate), compound 17 (427 mg, 59%) as a yellow crystalline solid,
1
mp = 150.5–152.9 °C. H NMR (400 MHz, CDCl ): δ 10.10 (s, 1H), 8.18 (d, J = 8.3 Hz,
3
1
1
1
1
1
H), 8.01 (dd, J = 8.3 and 1.8 Hz, 1H), 7.78 (d, J = 1.8 Hz, 1H), 7.54 (s, 1H), 6.69 (s,
1
3
H), 6.13 (ABq, J = 1.3 Hz, 2H), 3.64 (s, 3H) ppm. C NMR (100 MHz, CDCl ): δ
3
90.3, 165.7, 151.7, 151.2, 148.0, 138.4, 138.1, 134.4, 132.6, 129.2, 124.7, 122.0, 110.6,
10.2, 102.6, 52.2 ppm. IR: νmax = 2981, 2890, 1710, 1615, 1585, 1530, 1505, 1490,
−
1
436, 1382, 1350, 1256, 1168, 1134, 1037, 930, 841 cm . MS (ESI, +ve): m/z 384
+
+
+
[
(M+CH OH+Na) , 100%], 352, [(M+Na) , 5], 330 (<1). HRMS: (M+Na) calcd for
3
C H NNaO 352.0433; found 352.0437.
16
11
7
Methyl
6-(5-(Hydroxymethyl)-2-nitrophenyl)benzo[d][1,3]dioxole-5-carboxylate
(
18). A suspension of NaBH (23 mg, 0.61 mmol) in methanol (3.0 mL) was added to a
4
magnetically stirred solution of compound 17 (200 mg, 0.61 mmol) in methanol (5 mL)
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European Journal of Organic Chemistry
10.1002/ejoc.201700705
maintained at 0 C. The ensuing mixture was allowed to warm to 22 °C then stirred at
this temperature for 0.5 h before being quenched with NaOH (5 mL of a 15% w/v
aqueous solution). The ensuing mixture was stirred until it became homogeneous and
then it was concentrated under reduced pressure and the residue extracted with CH Cl (3
2
2

10 mL). The combined organic phases were washed with NaHCO (2  10 mL of a
3
saturated aqueous solution) then H O (2  10 mL) before being dried (Na SO ), filtered
2
2
4
and concentrated under reduced pressure to give a light-yellow oil. Subjection of this
material to flash chromatography (silica gel, 5:1 → 1:1 v/v 40-60 petroleum ether/ ethyl
acetate elution) gave, after concentration of the appropriate fractions (R = 0.25 in 2:1 v/v
f
petroleum ether/ethyl acetate) a yellow solid. Recrystallization (CHCl /hexane) of this
3
1
solid then gave compound 18 (182 mg, 90%) as yellow crystals, mp = 114.5-116.2 °C. H
NMR (400 MHz, CDCl ): δ 8.08 (d, J = 8.4 Hz, 1H), 7.51 (s, 1H), 7.47 (dd, J = 8.4 and
3
1
2
.8 Hz, 1H), 7.24 (d, J = 1.8 Hz, 1H), 6.66 (s, 1H), 6.10 (s, 1H), 6.09 (s, 1H), 4.78 (s,
H), 3.62 (s, 3H) (signal due to hydroxyl group proton not observed) ppm. C NMR
13
(
100 MHz, CDCl ): δ 166.0, 151.0, 147.5, 147.4, 146.3, 137.5, 136.1, 129.2, 126.0,
3
1
1
24.5, 122.0, 110.4, 110.3, 102.4, 64.1, 52.1 ppm. IR: νma x− = 3425, 2953, 2908, 1716,
1
615, 1520, 1505, 1343, 1249, 1132, 1035, 928, 819 cm . MS (ESI, +ve): m/z 354
+
+
[
(M+Na) , 100%]. HRMS: (M+Na) calcd for C H NNaO 354.0590; found 354.0588.
16 13 7
Methyl
6-(5-(Methoxymethyl)-2-nitrophenyl)benzo[d][1,3]dioxole-5-carboxylate
(19). A solution of compound 18 (100 mg, 0.30 mmol) and methyl iodide (75 µL, 1.2
mmol) in DMSO (2 mL) was added, in portions over 1.5 h, to a magnetically stirred
suspension of potassium hydroxide (68 mg, 1.2 mmol) in DMSO (3 mL) maintained at 22
°
C under an atmosphere of nitrogen. The ensuing mixture was stirred for a further 1.0 h
then poured into water (25 mL) and extracted with CH Cl (3  20 mL). The combined
2
2
organic phases were washed with water (1  50 mL) and brine (1  50 mL) before being
dried (Na SO ), filtered and then concentrated under reduced pressure. The oily residue
2
4
thus obtained was subjected to flash chromatography (silica gel, 4:1 v/v 40−60 petroleum
spirit/ethyl acetate elution) and concentration of the relevant fractions (R = 0.4 in 4:1 v/v
f
hexane/ethyl acetate) afforded compound 19 (80 mg, 77%) as yellow, crystalline solid,
1
mp = 150.7-153.4 °C. H NMR (400 MHz, CDCl ): δ 8.07 (d, J = 8.4 Hz, 1H), 7.51 (s,
3
1
1
H), 7.44 (dd, J = 8.4 and 1.8 Hz, 1H), 7.21 (d, J = 1.8 Hz, 1H), 6.67 (s, 1H), 6.09 (s,
H), 6.07 (s, 1H), 4.53 (s, 2H), 3.61 (s, 3H), 3.43 (s, 3H) ppm. C NMR (100 MHz,
1
3
CDCl ): δ 166.0, 151.0, 147.5, 143.9, 137.5, 136.1, 129.9, 126.7, 124.3, 122.1, 110.4,
3
1
10.3, 102.4, 73.4, 58.8, 52.1 (signal due to one carbon obscured or overlapping) ppm.
IR: νmax = 2903, 1720, 1615, 1522, 1505, 1490, 1480, 1436, 1374, 1346, 1249, 1132,
−
1
+
+
1
096, 1037, 842, 766 cm . MS (ESI, +ve): m/z 368 [(M+Na) , 100%]. HRMS: (M+Na)
calcd for C H NNaO 368.0746; found 368.0741.
1
7
15
7
2
-Bromo-4-(methoxymethyl)-1-nitrobenzene (20). Step i: A suspension of NaBH (165
4
mg, 4.36 mmol) in methanol (15 mL) was added in portions over 0.17 h to a magnetically
stirred solution of compound 11 (1.50 g, 6.50 mmol) in methanol (30 mL) maintained at
2
2 °C. The ensuing mixture was stirred for a further 0.5 h then quenched with NaOH (40
mL of a 10% w/v aqueous solution). Stirring was continued until a clear solution was
obtained and this was then concentrated under reduced pressure and the aqueous residue
extracted with CH Cl (3  50 mL). The combined organic phases were washed with
2
2
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European Journal of Organic Chemistry
10.1002/ejoc.201700705
NaHCO (2  50 mL of saturated aqueous solution) and water (2  30 mL) before being
3
dried (Na SO ), filtered and concentrated under reduced pressure to give a yellow solid
2
4
presumed to be (3-bromo-4-nitrophenyl)methanol. This material was used without
purification in Step ii as detailed immediately below.
Step ii: A solution of the product from step i and methyl iodide (1.60 mL, 26 mmol) in
DMSO (10 mL) was added over 1.5 h to a magnetically stirred suspension of potassium
hydroxide (1.46 g, 26 mmol) in DMSO maintained at 22 °C. The resulting mixture was
stirred for a further 1 h then poured into water (150 mL) and extracted with CH Cl (3 
2
2
1
00 mL). The combined organic phases were washed with water (1  150 mL) and brine
(
1  50 mL) before being dried (Na SO ), filtered and concentrated under reduced
2
4
pressure. The residue thus obtained was subjected to flash chromatography (silica gel, 4:1
v/v 40−60 petroleum spirit/ethyl acetate elution) and concentration of the relevant
fractions (R = 0.5 in 4:1 v/v 40−60 petroleum spirit/ethyl acetate) afforded compound 20
f
1
(
1.15 g, 72%) as a clear, light-brown oil. H NMR (400 MHz, CDCl ): δ 7.84 (d, J = 8.3
3
Hz, 1H), 7.72 (d, J = 0.8 Hz, 1H), 7.40 (dd, J = 8.3 and 0.8 Hz, 1H), 4.50 (s, 2H), 3.44 (s,
1
3
3
5
H) ppm. C NMR (100 MHz, CDCl ): δ 144.9, 133.3, 126.5, 125.7, 114.7, 100.0, 72.6,
3
8.7 ppm. IR ν
= 2932, 2823, 1584, 1528, 1469, 1347, 1197, 1109, 1039, 825, 747
max
−
1
+
cm . MS (ESI, +ve): m/z 270 and 268 [(M+Na) , both 10%], 248 and 246 (17 and 20),
7 (100). HRMS: (M+Na) calcd for C H BrNNaO 267.9585; found 267.9581.
+
79
8
8 8 3
6
-(5-(Methoxymethyl)-2-nitrophenyl)benzo[d][1,3]dioxole-5-carbaldehyde (21). A
magnetically stirred mixture of compound 20 (246 mg, 1 mmol), aryl iodide 15 (359 mg,
.3 mmol), copper powder (318 mg, 5 mmol), CuI (286 mg, 1.5 mmol) and Pd(dppf)Cl2
73 mg, 0.1 mmol) in degassed DMSO (10 mL) was heated at 50 C under a nitrogen
1
(
atmosphere for 12 h. The cooled reaction mixture was quenched with water (20 mL) then
diluted with ethyl acetate (30 mL) before being filtered through a pad of diatomaceous
earth. The pad and the solids thus retained were washed with ethyl acetate (2  30 mL)
and the combined organic phases were washed with water (2  40 mL) and brine (2  40
mL) before being dried (Na SO ), filtrated and concentrated under reduced pressure to
2
4
give a light-brown oil. Subjection of this material to flash chromatography (silica gel,
5:1 → 3:1 v/v 40-60 petroleum ether/ ethyl acetate gradient elution) gave, after
1
concentration of the appropriate fractions (R = 0.2 in 5:1 v/v 40-60 petroleum ether/ ethyl
f
1
acetate elution), compound 21 (190 mg, 70%) as a light-yellow oil. H NMR (400 MHz,
CDCl ): δ 9.57 (s, 1H), 8.06 (d, J = 8.4 Hz, 1H), 7.53 (dd, J = 8.4 and 1.8 Hz, 1H), 7.44
3
(
s, 1H), 7.33 (d, J = 1.8 Hz, 1H), 6.67 (s, 1H), 6.11 (ABq, J = 1.1 Hz, 2H), 4.55 (s, 2H),
13
3
1
2
7
.45 (s, 3H) ppm. C NMR (100 MHz, CDCl ): δ 189.0, 152.3, 148.6, 148.2, 144.2,
3
38.1, 133.3, 131.2, 129.0, 127.7, 124.8, 109.7, 107.5, 102.6, 73.2, 58.9 ppm. IR: νmax
=
922, 1681, 1611, 1522, 1477, 1412, 1345, 1261, 1238, 1136, 1107, 1036, 931, 880, 844,
−
1
+
+
92, 764 cm . MS (ESI, +ve): m/z 338 [(M+Na) , 100%]. HRMS: (M+Na) calcd for
C H NNaO 338.0641; found 338.0638.
16
13
6
(6-(5-(Methoxymethyl)-2-nitrophenyl)benzo[d][1,3]dioxol-5-yl)methanol (22).
A
suspension of NaBH (18 mg, 0.48 mmol) in methanol (2 mL) was added, in portions
4
over 0.17 h, to a magnetically stirred solution of compound 21 (150 mg, 0.48 mmol) in
methanol (3 mL) maintained at 0 C. The ensuing mixture was allowed to warm to 22 °C,
stirred at this temperature for 0.5 h then quenched with a sodium hydroxide (5 mL of a
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European Journal of Organic Chemistry
10.1002/ejoc.201700705
1
0% w/v aqueous solution). Stirring was continued until a clear solution had been
obtained and this was then concentrated under reduced pressure. The resulting aqueous
residue was extracted with CH Cl (3  6 mL) and the combined organic phases washed
2
2
with NaHCO (2  10 mL of a saturated aqueous solution) then water (2  10 mL) before
3
being dried (Na SO , filtered and concentrated under reduced pressure to give a light-
2
4
yellow oil. Subjection of this material to flash chromatography (silica gel, 6:1 → 2:1
0−60 petroleum spirit/ethyl acetate gradient elution) gave, after concentration of the
appropriate fractions (R = 0.4 in 2:1 v/v 40−60 petroleum spirit/ethyl acetate), compound
4
f
1
2
2 (137 mg, 90%) as a light-yellow oil. H NMR (400 MHz, CDCl ): δ 7.95 (d, J = 8.4
3
Hz, 1H), 7.47 (dd, J = 8.4 and 1.8 Hz, 1H), 7.31 (d, J = 1.8 Hz, 1H), 7.01 (s, 1H), 6.58 (s,
H), 6.01 (ABq, J = 1.4 Hz, 2H), 4.53 (s, 2H), 4.30 (ABq, J = 12.3 Hz, 2H), 3.44 (s, 3H)
1
13
(signal due to hydroxyl group proton not observed) ppm. C NMR (100 MHz, CDCl ): δ
3
1
6
2
48.6, 148.1, 147.2, 143.8, 135.2, 132.3, 131.0, 130.1, 127.2, 124.5, 109.1, 101.6, 73.4,
3.1, 58.9 (signal due to one carbon obscured or overlapping) ppm. IR: ν = 3405,
max
−
1
892, 1523, 1502, 1476, 1347, 1227, 1105, 1038, 931, 841 cm . MS (ESI, +ve): m/z 340
+
+
[
(M+Na) , 100%]. HRMS: (M+Na) calcd for C H NNaO 340.0797; found 340.0796.
16 15 6
(6-(2-Amino-5-(methoxymethyl)phenyl)benzo[d][1,3]dioxol-5-yl)methanol (23). A
magnetically stirred solution of compound 22 (125 mg, 0.40 mmol) in methanol (8 mL)
containing 10% Pd on carbon (20 mg) was placed under a hydrogen atmosphere at 22 °C
for 12 h then filtered through a short pad of diatomaceous earth that was washed with
ethyl acetate (20 mL). The combined filtrates were concentrated under reduced pressure
to afford a light-yellow oil and this was subjected to flash chromatography (silica gel, 9:1
v/v CH Cl /diethyl ether). Concentration of the appropriate fractions (R = 0.3 in 9:1 v/v
2
2
f
CH Cl /diethyl ether) then provided the title compound 23 (108 mg, 95%) as a clear,
2
2
1
colourless oil. H NMR (400 MHz, CDCl ): δ 7.17 (dd, J = 8.1 and 2.0 Hz, 1H), 7.01 (d,
3
J = 2.0 Hz, 1H), 7.01 (s, 1H), 6.83 (d, J = 8.1 Hz, 1H), 6.69 (s, 1H), 5.99 (ABq, J = 1.4
Hz, 2H), 4.36 (s, 2H), 4.28 (ABq, J = 12.0 Hz, 2H), 3.45 (broad s, 3H), 3.37 (s, 3H) ppm.
1
3
C NMR (100 MHz, CDCl ): δ 147.8, 147.6, 142.2, 133.7, 131.0, 130.5, 130.1, 128.9,
3
1
1
28.2, 116.7, 110.2, 110.1, 101.4, 74.6, 63.8, 58.1 ppm. IR: ν = 3360, 2889, 1621,
max
−
1
502, 1482, 1365, 1224, 1086, 1038, 931, 872, 826 cm . MS (ESI, +ve): m/z 310
+
+
[
(M+Na) , 100%]. HRMS: (M+Na) calcd for C H NNaO 310.1055; found 310.1055.
16 17 4
(
(
6-(5-(Methoxymethyl)-2-(methylamino)phenyl)benzo[d][1,3]dioxol-5-yl)methanol
Zephcandidine III, 1). A magnetically stirred solution of compound 23 (30 mg, 0.11
mmol) in methanol (10 mL) maintained at 0 °C was treated with formaldehyde (8 µL of a
7% aqueous solution, 0.11 mmol). The ensuing mixture stirred for 0.5 h at 0 °C then
3
treated with NaBH CN (7 mg, 0.11 mmol) before being warmed to 22 °C and stirred at
3
this temperature for 6 h then concentrated under reduced pressure to afford a light-yellow
oil. This was partitioned between ethyl acetate (10 mL) and NaOH (12 mL of a 1 M
aqueous solution) and the separated aqueous phase was extracted with ethyl acetate (1 
1
0 mL). The combined organic extracts were washed with brine (1  20 mL) then dried
(Na SO ), filtered and concentrated under reduced pressure. The light-yellow oil thus
2
4
obtained was subjected to flash chromatography (silica gel, 20:1 → 5:1 v/v
CH Cl /diethyl ether gradient elution) and concentration of the relevant fractions (R =
2
2
f
0
.3 in 9:1 v/v CH Cl /diethyl ether) afforded compound 1 (25 mg, 80%) as a clear,
2 2
This article is protected by copyright. All rights reserved.

European Journal of Organic Chemistry
10.1002/ejoc.201700705
1
colourless oil. H NMR (400 MHz, CD OD): δ 7.21 (dd, J = 8.3 and 2.0 Hz, 1H), 7.06 (s,
3
1
2
H), 6.90 (d, J = 2.0 Hz, 1H), 6.67 (d, J = 8.3 Hz, 1H), 6.59 (s, 1H), 5.97 (s, 2H), 4.34 (s,
H), 4.23 (ABq, J = 12.7 Hz, 2H), 3.33 (s, 2H), 2.73 (s, 3H) (signals due to hydroxyl and
1
3
amino group protons not observed) ppm. C NMR (100 MHz, CD OD): δ 149.1, 148.6,
3
1
6
1
48.4, 135.2, 131.9(0), 131.8(6), 130.5, 127.4, 127.1, 111.3, 110.9, 109.3, 102.6, 76.0,
2.7, 57.9, 31.0 ppm. IR: νmax = 3420, 2919, 2889, 2817, 1611, 1519, 1503, 1484, 1246,
−
1
+
223, 1085, 1038, 933, 871, 814 cm . MS (ESI, +ve): m/z 324 [(M+Na) , 100%].
+
HRMS: (M+Na) calcd for C H NNaO 324.1212; found 324.1210.
1
7
19
4
(6-(2-(Dimethylamino)-5-(methoxymethyl)phenyl)benzo[d][1,3]dioxol-5-yl)methanol
(24). A magnetically stirred solution of compound 23 (40 mg, 0.14 mmol) in acetonitrile
(2.0 mL) maintained at 22 °C was treated with formaldehyde (110 µL of a 37% aqueous
solution, 1.32 mmol), acetic acid (40 µL, 0.70 mmol) and NaBH CN (46 mg,
3
0
.73 mmol). The ensuing mixture was stirred for 1 h then quenched with NaHCO (5 mL
3
of a saturated aqueous solution) and extracted with ethyl acetate (3  15 mL). The
combined organic phases were washed with brine (1  20 mL) before being dried
(
Na SO ), filtered, and concentrated under reduced pressure. The ensuing light-yellow oil
2 4
was subjected to flash column chromatography (silica gel, 15:1 → 5:1 v/v CH Cl /diethyl
2
2
ether gradient elution) and concentration of the appropriate fractions (R = 0.4 in 9:1 v/v
f
1
CH Cl /diethyl ether) afforded compound 24 (42 mg, 95%) as a clear, colourless oil. H
2
2
NMR (400 MHz, CD OD): δ 7.28 (dd, J = 8.3 and 2.2 Hz, 1H), 7.10 (d, J = 8.3 Hz, 1H),
3
7
1
.05 (d, J = 2.2 Hz, 1H), 7.01 (s, 1H), 6.71 (s, 1H), 5.98 (s, 2H), 4.41 (s, 2H), 4.29 (d, J =
2.5 Hz, 1H), 4.18 (d, J = 12.5 Hz, 1H), 3.36 (s, 3H), 2.51 (s, 6H) (signal due to hydroxyl
1
3
group proton not observed) ppm. C NMR (100 MHz, CD OD): δ 152.3, 148.6, 148.5,
3
1
35.3, 134.7, 133.8, 133.1, 133.0, 129.4, 118.8, 111.1, 109.6, 102.5, 75.3, 63.7, 58.1, 43.7
ppm. IR: νmax = 3399, 2981, 2883, 2835, 1502, 1484, 1411, 1222, 1129, 1094, 1039, 933,
−
1
+
+
8
69, 822 cm . MS (ESI, +ve): m/z 338 [(M+Na) , 100%], 298 (54). HRMS: (M+Na)
calcd for C H NNaO 338.1368; found 338.1372.
1
8
21
4
7
-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (25).
A
magnetically
stirred solution of indole (502 mg, 4.29 mmol), [Ru(p-cymene)Cl ] (52 mg, 0.09 mmol,
2
2
2
9
mol%) and diethylsilane (1.7 mL, 13.1 mmol) in degassed toluene (2 mL) was stirred at
0 °C for 13 h then cooled to 22 °C and concentrated under reduced pressure to give a
brown oil. [Ir(OMe)COD] (43 mg, 0.065 mmol, 3 mol%), di-tert-butylbipyridine (35
2
mg, 0.13 mmol, 3 mol %), bis(pinacolato)diboron (1.09 g, 4.29 mmol), pinacolborane
(0.09 mL, 0.62 mmol) and degassed THF (4 mL) were then added to this oil and the
ensuing mixture stirred at 80 °C for 16 h. After cooling to 22 °C the volatile components
of the reaction mixture were removed under reduced pressure at 40 °C and the resulting
brown oil was dissolved in THF (4 mL). The solution thus obtained was treated with
sodium acetate (2.1 mL of a 3 M aqueous solution) and the ensuing mixture stirred at 22
°
C for 2 h before being diluted with diethyl ether (40 mL) and water (40 mL). The
separated aqueous phase was extracted with diethyl ether (2  40 mL) and the combined
organic phases were washed with brine (1  40 mL) before being dried (MgSO ), filtered,
4
and concentrated under reduced pressure to afford a brown oil. Subjection of this material
to flash chromatography (silica, 5:95 v/v diethyl ether/pentane elution) and concentration
[13]
of the appropriate fractions (R = 0.2) gave compound 25
(893 mg, 86%) as a white,
f
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European Journal of Organic Chemistry
10.1002/ejoc.201700705
[
13]
1
crystalline solid, mp = 89-90 °C (lit. mp = 83-85 °C). H NMR (CDCl , 400 MHz): 
3
9
.25 (broad s, 1H), 7.79 (d, J = 7.9 Hz, 1H), 7.67 (d, J = 7.0 Hz, 1H), 7.28 (m, 1H), 7.15
m, 1H), 6.56 (m, 1H), 1.41 (s, 12H) ppm. C NMR (CDCl , 100 MHz):  140.9, 129.2,
26.8, 124.2, 124.0, 119.3, 101.9, 83.8, 25.0 (signal due to one carbon obscured or
13
(
3
1
overlapping) ppm. IR: νmax = 3454, 3398, 3055, 2977, 2930, 1595, 1511, 1429, 1369,
–
1
1
2
1
330, 1296, 1272, 1192, 1145, 1130, 973, 857, 842, 798, 733 cm . MS (EI, 70 eV): m/z
+
•
43 and 242 (M , 39 and 100%), 228 (15), 187 (21), 186 and 185 (93 and 38), 170 (28),
61 (16), 158 (17), 144 (33), 143 and 142 (78 and 33), 117 (16), 116 (23). HRMS: M
+
•
1
18
1
calcd for C H BNO 243.1429; found 243.1431.
1
4
2
(
2-(1H-Indol-7-yl)-4,5-dimethoxyphenyl)methanol (27). A magnetically stirred
[
14]
solution of indole 25 (406 mg, 1.67 mmol), aryl iodide 26
(327 mg, 1.11 mmol),
PdCl (dppf)•CH Cl (90 mg, 0.11 mmol) and triethylamine (0.78 mL, 5.59 mmol) in
2
2
2
degassed THF/water (3 mL of a 4:1 v/v mixture) was stirred in a sealed vessel at 85 °C
for 19 h then cooled to 22 °C before being diluted with ethyl acetate (40 mL) and water
(40 mL). The separated aqueous phase was extracted with ethyl acetate (2  40 mL) and
the combined organic phases were passed through a pad of TLC-grade silica gel and
diatomaceous earth. The filtrate thus obtained was concentrated under reduced pressure
to give a brown oil and subjection of this material to flash chromatography (silica, 7:3 v/v
ethyl acetate/hexane elution) followed by concentration of the appropriate fractions (R =
f
0
.4) gave a brown solid. Recrystallization (methanol) of this material afforded the title
1
compound 27 (285 mg, 91%) as a white, crystalline solid, mp = 173-174 °C. H NMR
(
7
4
CD OD, 800 MHz):  7.54 (d, J = 7.5 Hz, 1H), 7.25 (s, 1H), 7.17 (d, J = 2.9 Hz, 1H),
3
.06 (t, J = 7.5 Hz, 1H), 6.97 (d, J = 7.5 Hz, 1H), 6.90 (s, 1H), 6.49 (d, J = 2.9 Hz, 1H),
.37 (m, 2H), 3.91 (s, 3H), 3.80 (s, 3H) (signals due to hydroxyl and indole N-H group
13
protons not observed) ppm. C NMR (CD OD, 200 MHz): 150.0, 149.5, 136.1, 133.3,
3
1
5
1
4
31.6, 129.7, 126.0, 125.4, 123.5, 120.5, 120.1, 114.8, 113.1, 102.7, 62.5, 56.5(2),
6.4(6) ppm. IR: νmax = 3363, 3053, 3000, 2935, 2846, 1607, 1519, 1507, 1463, 1427,
–
1
+•
346, 1335, 1244, 1208, 1142, 1077, 995, 803, 734 cm . MS (EI, 70 eV): m/z 283 (M ,
+
•
6%), 265 (54), 264 (100). HRMS: M calcd for C H NO 283.1208; found 283.1208.
17
17
3
(4,5-Dimethoxy-2-(1-methylindolin-7-yl)phenyl)methanol (Lycosinine A, 2). A
magnetically stirred solution of compound 27 (283 mg, 1.00 mmol) and
paraformaldehyde (300 mg, 9.99 mmol) in glacial acetic acid (3 mL) was cooled to 0 °C
then treated, in one portion, with sodium cyanoborohydride (314 mg, 5.00 mmol). The
ensuing mixture was warmed to 18 °C, stirred at this temperature for 24 h then diluted
with water (10 mL) before being cooled to 0 °C then treated, dropwise, with NaOH (5 M
aqueous solution) until pH 13 was attained. The resulting mixture was extracted with
CH Cl (3  40 mL) and the combined organic phases were washed with brine (1  40
2
2
mL) before being dried (MgSO ), filtered and concentrated under reduced pressure to
4
give a clear, colourless oil. Subjection of this material to flash chromatography (silica,
7
0
:3 v/v ethyl acetate/hexane elution) and concentration of the appropriate fractions (R =
f
.4) gave a clear, colourless oil. Trituration (hexane) of this material at 10 °C afforded the
[2]
title compound 2 (298 mg, quantitative) as a white, crystalline solid, mp = 104-107 °C.
1
H NMR (CDCl , 600 MHz):  7.15 (dm, J = 7.2 Hz, 1H), 7.00 (s, 1H), 6.94 (dm, J = 7.2
3
Hz, 1H), 6.90 (t, J = 7.2 Hz, 1H), 6.84 (s, 1H), 4.93, (broad s, 1H), 4.22 (s, 2H), 3.95 (s,
This article is protected by copyright. All rights reserved.

European Journal of Organic Chemistry
10.1002/ejoc.201700705
3
2
1
H), 3.88 (s, 3H), 3.60 (m, 1H), 3.12-3.06 (complex m, 1H), 3.01-2.91 (complex m, 2H),
13
.20 (s, 3H) ppm. C NMR (CDCl , 150 MHz): 151.0, 148.5, 148.4, 132.1, 132.0,
3
31.7, 129.7, 126.2, 123.8, 120.9, 112.9, 112.5, 64.6, 56.6, 56.0, 55.9, 40.9, 28.9 ppm.
IR: νmax = 3303, 2964, 2939, 2874, 2828, 1605, 1515, 1464, 1438, 1345, 1245, 1219,
–
1
+
1
1
144, 1060, 1010, 990, 862, 791, 766, 610 cm . MS (ESI, +ve): m/z 322 [(M+Na) ,
+
00%], 282 (46). HRMS: (M+Na) calcd for C H NNaO 322.1419; found 322.1420.
1
8
21
3
(4,5-Dimethoxy-2-(1-methyl-1H-indol-7-yl)phenyl)methanol (28). A magnetically
stirred solution of compound 2 (20 mg, 0.07 mmol) in CH Cl (1 mL) was treated with
2
2
manganese(IV) oxide (32 mg, 0.368 mmol) at 22 °C. The ensuing mixture was stirred at
2 °C for 72 h then filtered through a pad of diatomaceous earth. The filtrate thus
2
obtained was concentrated under reduced pressure to give a brown oil and subjection of
this to flash chromatography (silica, diethyl ether elution) followed by concentration of
the appropriate fractions (R = 0.3) gave compound 28 (15 mg, 76%) as a clear, colourless
f
1
oil. H NMR (CDCl , 400 MHz):  7.63 (d, J = 7.5 Hz, 1H), 7.13-7.09 (complex m, 2H),
.98-6.95 (complex m, 2H), 6.86 (s, 1H), 6.53 (d, J = 3.1 Hz, 1H), 4.38 (s, 2H), 3.98 (s,
H), 3.85 (s, 3H), 3.24 (s, 3H) (signal due to hydroxyl group proton obscured/not
observed) ppm. C NMR (CDCl , 100 MHz):  148.6, 147.4, 134.1, 132.1, 130.8, 129.6,
23.8(1), 123.7(6), 120.5, 119.1, 113.9, 110.6, 101.1, 63.1, 56.0, 55.9, 35.7 (one signal
3
6
3
1
3
3
1
obscured or overlapping) ppm. IR: νmax = 3493, 2999, 2936, 2847, 1606, 1523, 1509,
-
1
1
464, 1443, 1342, 1318, 1243, 1212, 1142, 1118, 1074, 998, 729 cm . MS (EI, 70 eV):
+
•
+•
m/z 297 (M , 100%). HRMS: M calcd for C H NO 297.1365; found 297.1369.
1
8
19
3
4
,5-Dimethoxy-2-(1-methyl-1H-indol-7-yl)benzaldehyde (29). A mixture of molecular
sieves (20 mg of powdered, 4 Å material), diatomaceous earth (20 mg), activated
magnesium silicate (20 mg of 60-100 mesh material), sodium acetate (14 mg, 0.171
mmol) and pyridinium chlorochromate (25 mg, 0.12 mmol) in CH Cl (2 mL) was stirred
2
2
at 22 °C for 0.5 h then treated with a solution of compound 2 (20 mg, 0.067 mmol) in
CH Cl (1 mL). The ensuing mixture was stirred at 22 °C for 17 h then diluted with
2
2
diethyl ether (20 mL) and the resulting mixture filtered through a pad of diatomaceous
earth. The filtrate thus obtained was concentrated under reduced pressure to give a clear,
colourless oil that was subjected to flash chromatography (silica, 3:7 v/v diethyl
ether/pentane elution) and thereby affording two fractions, A and B.
Concentration of fraction A (R = 0.4 in 3:7 v/v diethyl ether/pentane) afforded the
f
1
title compound 29 (7 mg, 35%) as a clear, colourless oil. H NMR (CDCl , 400 MHz): 
.62 (s, 1H), 7.69 (dd, J = 7.5 and 1.0 Hz, 1H), 7.55 (s, 1H), 7.14 (t, J = 7.5 Hz, 1H), 7.03
3
9
(
dd, J = 7.5 and 1.0 Hz, 1H), 6.98 (d, J = 3.1 Hz, 1H), 6.93 (s, 1H), 6.57 (d, J = 3.1 Hz,
1
3
1
1
1
1
1
H), 4.02 (s, 3H), 3.94 (s, 3H), 3.25 (s, 3H) ppm. C NMR (CDCl , 100 MHz):  191.1,
3
53.0, 149.1, 139.1, 134.8, 131.1, 129.6, 128.6, 125.0, 121.2, 120.9, 118.9, 113.8, 107.7,
01.4, 56.3, 56.1, 36.1 ppm. IR: νmax = 2937, 2848, 1676, 1596, 1508, 1463, 1395, 1349,
–
1
+•
284, 1256, 1243, 1217, 1141, 1118, 1072, 911, 730 cm . MS (EI, 70 eV): m/z 295 (M ,
+
•
00%), 280 (15), 266 (22), 252 (15), 236 (17), 86 (12), 84 (19). HRMS: M calcd for
C H NO 295.1208; found 295.1208.
18
17
3
Concentration of fraction B (R = 0.1 in 3:7 v/v diethyl ether/pentane) afforded
f
compound 28 (1 mg, 5%) as a clear, colourless oil. This material was identical, in all
respects, with that obtained as described above.
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European Journal of Organic Chemistry
10.1002/ejoc.201700705
X-ray Crystallographic Studies
Crystallographic Data
Compound 2. C H NO , M = 299.37, T = 150 K, triclinic, space group P , Z = 2, a =
18
21
3
8
6
1
.0070(4) Å, b = 8.6147(3) Å, c = 12.8193(6) Å;  = 84.737(4)°,  = 79.243(4)°,  =
3
–3
3.307 (4)°; V = 776.10(7) Å , D = 1.281 g cm , 3055 unique reflections (2
=
x
max
44.6), R = 0.034 [for 2898 reflections with I > 2.0(I)]; Rw = 0.091 (all data), S = 1.00.
Compound 18. C H NO , M = 331.27, T = 150 K, monoclinic, space group P2 /c, Z =
16
13
7
1
4
1
, a = 8.92045(5) Å, b = 11.34780(6) Å, c = 14.26284(8) Å;  = 102.5075(6); V =
3
–3
409.53(1) Å , D = 1.561 g cm , 2837 unique reflections (2 = 145.4), R = 0.038
x
max
[
for 2815 reflections with I > 2.0(I)]; Rw = 0.100 (all data), S = 1.08.
Compound 21. C H NO , M = 315.27, T = 150 K, triclinic, space group P , Z = 2, a =
1
6
13
6
6
8
5
.6160(3) Å, b = 9.3462(3) Å, c = 11.3791(5) Å;  = 86.286(3)°,  = 89.459(4)°,  =
3
–3
5.502(3)°; V = 699.97(5) Å , D = 1.496 g cm , 3536 unique reflections (2
=
x
max
9.8), R = 0.043 [for 2887 reflections with I > 2.0(I)]; Rw = 0.123 (all data), S = 1.02.
Compound 27. C H NO , M = 283.33, T = 150 K, monoclinic, space group P2 /n, Z =
17
17
3
1
8
, a = 17.4725(2) Å, b = 8.6511(1) Å, c = 18.9278(2) Å;  = 96.8003(8)°; V = 2840.93(6)
3
–3
Å , D = 1.325 g cm , 5617 unique reflections (2
= 144.8), R = 0.038 [for 5080
x
max
reflections with I > 2.0(I)]; Rw = 0.107 (all data), S = 1.00.
Structure Determinations
The images for compound 21 were measured on a diffractometer (Mo K, graphite
monochromator,  = 0.71073 Å) fitted with an area detector and the data extracted using
[
19]
CrysAlis PRO. Images for compounds 2, 18 and 27 were measured on a diffractometer
Cu K, mirror monochromator,  = 1.54184 Å) fitted with an area detector and the data
(
[
19]
extracted using the CrysAlis PRO. The structure solutions for all four compounds were
solved by direct methods (SIR92)
package. Atomic coordinates, bond lengths and angles, and displacement parameters
have been deposited at the Cambridge Crystallographic Data Centre (CCDC nos.
[
20]
then refined using the CRYSTALS program
[
21]
1
543361, 1543362, 1543363 and 1543364). These data can be obtained free-of-charge
via www.ccdc.cam.ac.uk/data_request/cif, by emailing data_request@ccdc.cam.ac.uk, or
by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge
CB2 1EZ, UK; fax: +44 1223 336033.
AChE Inhibition Assay
[
22]
AChE activity was assayed according to the method of Ellman and co-workers.
Compounds 1, 2, 17-19, 21-24, 27 and galanthamine were prepared in DMSO to 50 mM,
then serially diluted one-in-three in DMSO to give concentrations ranging from 50 mM
to 30 nM. 2 μL of compound at each concentration was added to 98 μL of 5-5’-dithiobis-
(
2-nitrobenzoic acid) (510 μM in phosphate buffer (100 mM Na HPO pH 7.4)) and 60
2 4
μL of Electrophorus electricus AChE (Type V-S, 1 nM in phosphate buffer
supplemented with 1 mg/ml bovine serum albumin). The enzymatic reaction was initiated
by addition of 40 μl of acetylthiocholine iodide (1.15 mM in phosphate buffer) and
progress monitored by measuring absorbance at 412 nm for six minutes. Measurements
were conducted in triplicate. Velocities were determined by linear regression, and were
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European Journal of Organic Chemistry
10.1002/ejoc.201700705
corrected for non-enzymatic substrate hydrolysis. The concentration of compound
required to reduce AChE activity to 50% of a neat DMSO control (IC ) was calculated
5
0
by fitting a sigmoidal dose-response curve to percentage activity using GraphPad Prism.
Acknowledgements
We thank Jinan University, the Australian Research Council and the Institute of
Advanced Studies for financial support. HSK and GJC are the grateful recipients of
Scholarships provided by the Australian Government.
References
1
2
3
4
.
.
.
.
Zhan, G.; Liu, J.; Zhou, J.; Sun, B.; Aisa, H. A.; Yao, G. Eur. J. Med. Chem.
017, 127, 771.
Yang, Y.; Huang, S.-X.; Zhao, Y.-M.; Zhao, Q.-S.; Sun, H.-S. Helv. Chim. Acta
005, 88, 2550.
Wu, W.-M.; Zhu, Y.-Y.; Li, H.-R.; Yu, H.-Y.; Zhang, P.; Pi, H.-F.; Ruan, H.-L.
J. Asian Nat. Prod. Res. 2014, 16, 192.
Sebben, C.; Giordani, R. B.; de Andrade, J. P.; Berkov, S.; Osorio, E. J.; Sobral,
M.; de Almeida, M. V.; Henriques, A. T.; Bastida, J.; Zuanazzi, J. A. S. Revista
Brasil. Farmacog. 2015, 25, 353.
2
2
5
6
7
.
.
.
Fan-Chiang, T.-T.; Wang, H.-K.; Hsieh, J.-C. Tetrahedron 2016, 72, 5640.
Joshi, G.; Adimurthy, S. Synth. Commun. 2011, 41, 720.
Pitts, M. R.; Harrison, J. R.; Moody, C. J. J. Chem. Soc., Perkin Trans. 1, 2001,
955.
8
9
.
.
Gao, N. (Y.); Banwell, M. G.; Willis, A. C. Org. Lett. 2017, 19, 162.
Khaddour, Z.; Eleya, N.; Akrawi, O. A.; Hamdy, A. M.; Patonay, T.; Villinger,
A.; Langer, P. Synlett. 2013, 24, 2114.
1
1
0.
1.
Katritzky, A. R.; Xie, L. Tetrahedron Lett. 1996, 37, 347.
For some recent examples see (a) Yan, Q.; Gin, E.; Wasinska-Kalwa, M.;
Banwell, M. G.; Carr, P. D. J. Org. Chem. 2017, 82, 4148; (b) Yan, Q.; Gin, E.;
Banwell, M. G.; Willis, A. C.; Carr, P. D. J. Org. Chem. 2017, 82, 4328; For a
relevant review on earlier work see (c) for Banwell, M. G. Chemistry in New
Zealand 2011, 75, 122.
1
1
2.
3.
(a) Matveenko, M.; Kokas, O. J.; Banwell, M. G.; Willis, A. C. Org. Lett. 2007, 9,
3683. (b) Yalcouye, B.; Choppin, S.; Panossian, A.; Leroux, F. R.; Colobert, F.
Eur. J. Org. Chem. 2014, 6285.
Attenburrow, J.; Cameron, A. F. B.; Chapman, J. H.; Evans, R. M.; Hems, B. A.;
Jansen, A. B. A.; Walker, T. J. Chem. Soc. 1952, 1094.
1
1
1
1
1
4.
5.
6.
7.
8.
Robbins, D. W.; Boebel, T. A.; Hartwig, J. F. J. Am. Chem. Soc. 2010, 132, 4068.
Press, D. J.; Back, T. G. Can. J. Chem. 2016, 94, 305.
Massoulie, J.; Rieger, F. Eur. J. Biochem. 1969, 11, 441.
Still, W. C.; Kahn, M.; Mitra, A. J. Org. Chem. 1978, 43, 2923.
Pangborn, A. B.; Giardello, M. A.; Grubbs, R. H.; Rosen, R. K.; Timmers, F. J.
Organometallics 1996, 15, 1518
1
9.
CrysAlis PRO Version 1.171.37.35h (released 09-02-2015 CrysAlis171.NET)
This article is protected by copyright. All rights reserved.

European Journal of Organic Chemistry
10.1002/ejoc.201700705
(compiled Feb 9 2015,16:26:32) Agilent Technologies: Oxfordshire, UK.
2
2
2
0.
1.
2.
SIR92. Altomare, A.; Cascarano, G.; Giacovazzo, C.; Guagliardi, A.; Burla, M.
C.; Polidori, G.; Camalli, M. J. Appl. Crystallogr., 1994, 27, 435.
Betteridge, P. W.; Carruthers, J. R.; Cooper, R. I.; Prout, K.; Watkin, D. J. J.
Appl. Crystallogr., 2003, 36, 1487.
Ellman, G. L.; Courtney, K. D.; Andres, V.; Featherstone, R. M. Biochem.
Pharmacol. 1961, 7, 88.
Table of Contents Material
Alkaloid Synthesis
The structurally related alkaloids 1 and 2 have each been prepared using Pd[0]-catalysed
cross-coupling reactions and the derived spectral data match those reported for the natural
products. In contrast to the earlier suggestion that zephycandidine III is a potent inhibitor
of acetylcholinesterase, the synthetically derived sample of compound 1 did not inhibit
this enzyme and nor did various congeners, including 2.
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