Chemoselective flow hydrogenation approaches to isoindole-7-carboxylic acids and 7-oxa-bicyclio[2.2.1]heptanes

Article abstract of DOI:10.1039/c3ra47657j

Two libraries of highly decorated norcantharidin analogues were accessed via a series of sequential chemoselective flow hydrogenations and solvent-free transformations. Utilising a 10% Pd/C catalyst, modifications to reaction parameters (H₂ pressure, temperature and flow rate conditions) allowed facile access to effect selective direct reductive aminations and olefin reductions in the presence of furan, benzyl and nitrile moieties were established. The use of 20% Pd(OH)₂/C; Pd tetrakis; 5% Pt/C (sulfided) gave mixtures of furan and olefin (both reduced) and olefin reduced products. RuO₂; 0.5% Re/C and Re₂O₇ resulted in no reduction. Concurrent olefin and nitrile reduction was achieved in the presence of furan moieties by employing a RANEY nickel catalyst. In total, 31 reaction conditions were examined using less than 200 mg of reagents allowing optimised conditions to be efficiently determined. These optimised hydrogenation conditions afforded desired analogues in near quantitative yields thus removing the requirements of reaction workup and chromatography.

Full text of DOI:10.1039/c3ra47657j

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Chemoselective flow hydrogenation approaches to
isoindole-7-carboxylic acids and 7-oxa-bicyclio
[2.2.1]heptanes†
Cite this: RSC Adv., 2014, 4, 9709
*
L. Hizartzidis, M. Tarleton, C. P. Gordon and A. McCluskey
Two libraries of highly decorated norcantharidin analogues were accessed via a series of sequential
chemoselective flow hydrogenations and solvent-free transformations. Utilising a 10% Pd/C catalyst,
modifications to reaction parameters (H2 pressure, temperature and flow rate conditions) allowed facile
access to effect selective direct reductive aminations and olefin reductions in the presence of furan,
benzyl and nitrile moieties were established. The use of 20% Pd(OH)2/C; Pd tetrakis; 5% Pt/C (sulfided)
gave mixtures of furan and olefin (both reduced) and olefin reduced products. RuO2; 0.5% Re/C and
Re2O7 resulted in no reduction. Concurrent olefin and nitrile reduction was achieved in the presence of
furan moieties by employing a RANEY® nickel catalyst. In total, 31 reaction conditions were examined
using less than 200 mg of reagents allowing optimised conditions to be efficiently determined. These
optimised hydrogenation conditions afforded desired analogues in near quantitative yields thus removing
the requirements of reaction workup and chromatography.
Received 16th December 2013
Accepted 3rd January 2014
DOI: 10.1039/c3ra47657j
www.rsc.org/advances
We and others have exploited the 7-oxa-bicyclo[2.2.11]
heptane scaffold in drug development programs geared
towards developing tumor suppressing agents.9–17 We have
Introduction
Adult members of the Meloidae family of Coleoptera (beetles)
deter attacks from many predators by discharging droplets of
cantharidin-laden blood reexively from their hind leg joints.1
These cantharidin (1) rich secretions are also used as a copu-
latory gi to protect the fertilised eggs from predation.2,3
Cantharidin, in the form of the dried body of the Mylabris
beetle, has a long history of use in Chinese traditional medicine
for treatment of dermal conditions and tumours with the rst
chemotherapeutic application reported in 1264.3 Cantharidin
and norcantharidin are potent inhibitors of the serine/threo-
nine protein phosphatases, especially protein phosphatases 1
and 2A.4,5 The interplay between protein kinases, which add
phosphate to mainly serine and threonine residues, and phos-
phatases, which remove phosphate moieties, modulates the
vast majority of cellular signal transduction events including
neurotransmission, muscle contraction, glycogen synthesis, T-
cell activation, and cell proliferation.4,6 Cantharidin is nephro-
toxic, and this has prevented its widespread use in Western
medicine where current use is limited to topical applications.7,8
However, the demethylated norcantharidin (2) has no such
nephrotoxicity issues and has thus been the subject of a
considerable number of anti-tumour studies (Fig. 1).9–17
also demonstrated that the scaffold exhibits promising levels
of activity against Plasmodium falciparum,18 and Haemonchus
contortus.19 Fig. 2 shows representative examples of analogues
investigated in these studies, and include the benzoylox-
ymethyl-substituted norcantharidins (3 & 4),20 the acid amides
(5),21–23 anhydride modied ethers (6),24,25 norcantharimides
(7 & 8),36,37 the bis-norcantharimides (9 & 10),23,26 the tetracy-
clic norcantharimides (11 & 12),12 along with the tetracyclic-
bisnorcantharimides (13 & 14).26
In addition to our medicinal chemistry interest we have a
keen interest in the application of green chemistry approaches
to the development of focused compound libraries. This,
coupled with our prior report of the pivotal nature of the 7-oxa-
bicyclo[2.2.1]heptane moiety,27,28 prompted us to examine
potential expedient and green approaches to analogues such as
20 and 24 (Fig. 3). We envisaged that analogue series' based on
20 (isoindole-7-carboxylic acids) and 24 (7-oxabicyclo[2.2.1]-
heptane carboxylic acids) could be expediently accessed
Chemistry, Centre for Chemical Biology, The University of Newcastle, University Drive,
Callaghan NSW 2308, Australia. E-mail: Adam.McCluskey@newcastle.edu.au; Fax:
+61 (0)249 215472; Tel: +61 (0)249 216486
† Electronic supplementary information (ESI) available: GCMS chromatograms,
1H and 13C NMR spectra. See DOI: 10.1039/c3ra47657j
Fig. 1 Chemical structures of cantharidin (1) and the demethylated
analogue norcantharidin (2).
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Fig. 2 Illustrative examples of previously reported 7-oxa-bicyclo[2.2.1]heptane analogues.12,14,21,37
Fig. 3 Proposed sequential flow pathways Path A and Path B to provide access to analogues of compound 20 and 24, respectively. (R-groups
defined for Path A and Path B in Table 1 and Fig. 4, respectively).
through the development of sequential ow pathways i.e. Path A reagents quantities by careful manipulation of the ow hydro-
and Path B, respectively. Path A, which is adapted from a genation conditions, i.e. judicious choice of catalysts, H2 pres-
number of previously reported protocols, would allow interro- sure, temperature, and ow rate. However at the outset, we were
gation of the scaffold adjacent the 7-oxo-bridge head,29–32
a
also cognisant that furan reduction and de-benzylation were
region which is poorly described in the literature,33 whereas potential undesirable outcomes. Protocols to reduce furan
Path B would provide a means of incorporating analogues of analogues using platinum group metals have been well docu-
cyanoamide 22, which displays cytotoxicity against a range of mented,38,39 and recently a number of highly diasteroselective
carcinoma cells,34–36 into the norcantharidin scaffold.
Common to both pathways is
series of reductive furans have been reported40–43 in addition to asymmetric
protocols to access optically active tetrahydrofurans from
a
approaches including reductive amination (Path A, Step 2), hydrogenation of thiophenes and benzothiophenes.41,44,45 These
olen (Path A, Step 4 & Path B, Step 2), and nitrile reductions protocols use a range of platinum based catalysts, high pres-
(Path B, Step 2). We envisaged that each of these reductions sures, typically in the range of 30–90 bar H2 pressure, temper-
could be effected and rapidly optimised using minimum atures up to 80 ꢀC and long reaction times. We anticipated that,
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by screening milder reduction conditions and exploiting the oxisoindoline-4-carboxylic acids. This current approach allows
exquisite control of temperature, pressure, and catalyst expo- greener access to these 7-oxoisoindole analogues.29
sure provided by the ThalesNano H-cube™ (H-Cube), reaction
The nal step of reaction Path A, olen reduction, was again
conditions could be tuned to afford the desired selective carried out using the H-Cube charged with a 30 mm 10% Pd/C
reductions. Additionally the reduced contact (residence) times catcart™ (50 bar H2, 50 ꢀC, and a ow rate of 1 mL minꢁ1).
afforded by ow chemistry potentially allowed for the isolation Trituration of the eluent with diethyl ether afforded the desired
of partially reduced intermediates unlike the corresponding analogue 20a in >95% purity (Scheme 2).
batch chemistry approaches. While ow chemistry can be
With our model system, the sequential ow reaction protocol
considered inherently green as a consequence of low material of Path A afforded the desired bicyclo[2.2.1]heptane analogue
usage during process optimisation, we also sought to use easy to 20a in excellent overall yield (51%, 3 steps) with no chroma-
recycle solvents46,47 and processes that facilitated ease of tography requirement. More broadly the two 10 min ow
product access and purication.48,49
chemistry steps and one batch reaction allowed rapid access to
a diverse library of analogues with a range for functional groups
(Table 1, 20a–g) and anilines tolerated (Table 1, 20h) and afford
25–50 mg (sufficient for all preliminary biological screening) of
the desired products in >95% purity by trituration. This
protocol offers dramatic reductions in reaction times and
eliminating the requirement for catalyst preparation, reaction
work-up, and chromatography typically used to access
compounds of this nature.22,29 In keeping with previous reports
on the use of Pd-based catcarts™ we detected no Pd-leakage or
residue in the products isolated.51
Having successfully developed a small library of analogues
using Path A, our attention turned to the second proposed
sequential ow pathway, Path B (Fig. 3). Access to the desired
furan acrylamides (22a–22c) was via a solvent free condensation
of methyl cyanoacetate and small library of benzylamines. The
initial synthesis examined the use of 4-methoxybenzylamine
(16a) to afford cyanoamide 21a which was used directly in the
Knoevenagel condensation with furan-2-carbaldehyde (15) at
room temperature giving 22a in a 71% yield (2 steps) with the
product collected by ltration in >95% purity. Cyanoamides 22b
and 22c were accessed in a similar manner from 4-chlor-
obenzylamine and 4-methylbenzylamine (Scheme 3).
With 22a we next investigated the potential selective reduc-
tion of the olen and the nitrile moieties as outlined in Step 2,
Path B (Fig. 3). Excluding possible debenzylation products,
hydrogenation of 22a had the potential to give seven different
reduction products (23a, 25a–30a) arising from various combi-
nations of furan, olen and nitrile moiety reductions
(Scheme 5). Hence access to the analogues desired for subse-
quent focused library development was potentially a signicant
challenge.
A 0.05 M solution of 22a was subjected to H-Cube conditions
of 50 bar H2 pressure, 50 ꢀC, and a ow rate of 1 mL minꢁ1 for
10 minutes using a 30 mm 10% Pd/C catcart™ (Scheme 5).
Analysis showed quantitative reduction of the furan and olen
double bond moieties giving 28a (Scheme 4 and Table 2). No
nitrile reduction was observed.
Results and discussion
Our investigation commenced with a model coupling of furan-2-
carbaldehyde (15) with 4-methoxybenzylamine (16a) Step 1 of
Path A (Fig. 3 and Scheme 1), using our previously reported direct
reductive amination protocol.50 Briey, 0.05 M methanolic solu-
tion of furan-2-carbaldehyde (15) and 4-methoxybenzylamine
(16a) were passed through the H-Cube equipped with a 30 mm
10% Pd/C catcart™, under 50 bar H2 at 50 ꢀC, with a ow rate of
1 mL minꢁ1. Each optimisation step was conducted for 10 min
1
allowing collection of a 10 mL sample for H NMR and GC-MS
analysis. Analysis indicated quantitative conversion to the
desired adduct 18a (imine 17a was not isolated) with no evidence
of furan reduction or de-benzylation evident.
With 18a in hand, our attention turned to the sequential
Diels–Alder and lactam formation (Step 2, Path A, Scheme 2).
This two-step transformation proceeded smoothly and in excel-
lent overall yield (69%) with the product collected by ltration
aer trituration with diethyl ether. The diethyl ether was recov-
ered and reused in the trituration of the hydrogenated product
(below). Access to compounds such as 19a–h allow, on treatment
with protic ionic liquids, entry to N-substituted 5-hydroxy-4-
methyl-3-oxoisoindoline-1-carboxamides and N-substituted 3-
Scheme 1 Reagents and conditions: (i) H-Cube hydrogenation, 0.05
M 15 and 0.05 M 16a–h (for details of R, see Table 1) in MeOH, 10% Pd/
C, 50 ꢀC, 50 bar H2 pressure, 1 mL minꢁ1
.
Efforts to effect nitrile reduction using standard conditions
ꢀ
(70 C and 50 bar H2 pressure‡) resulted only in clean conver-
sion to 28a. A similar outcome was noted with all optimisations
ꢀ
with T $ 50 C regardless of the H2 pressure (Table 2, entries
1–6). Easing of the reduction conditions (10 ꢀC, 0 bar H2
Scheme 2 Reagents and conditions: (i) diethyl ether, rt, 24 h; (ii) H-
Cube, 0.05 M 20a in MeOH, 10% Pd/C, 50 ꢀC, 50 bar H2 pressure, 1 mL
‡ ThalesNano provide details of standard reducing conditions for a variety of
minꢁ1
.
functional groups: http://www.thalesNano.com.
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Table 1 Synthesis of a focused library of isoindole-7-carboxylic acid analogues 20a–20h by a combination of flow and batch chemistry
approaches (Path A, Fig. 3)
Compound
20a
R
Step 1 (%)
Step 2 (%)
Step 3 (%)
100
Overall (%)
89
85
69
66
51
47
20b
88
20c
20d
88
84
62
44
100
100
53
37
20e
74
33
85
24
20f
82
63
46
57
100
100
38
36
20g
20h
76
40
100
30
The production of 25a suggested that 28a resulted from over
reduction of this compound. We believed that this is most likely
related to catalyst residence time. Reducing residence time
from 4 min (1 mL minꢁ1) to 3 min resulted in an improvement
in the 25a : 28a ratio to 64 : 36 (Table 3, entry 1). Further resi-
dence time reduction to 0.5 min saw clean generation of 25a
(Table 3, entry 4).
Scheme 3 Reagents and conditions: (i) EtOH, piperidine, 0.5 h, 25 ꢀC.
pressure) did show the rst evidence of olen vs. furan
reduction selectivity with both the olen reduction product
(25a, 21%) and 28a (79%) evident (Table 2, entry 17).
To examine whether this selective reduction could be per-
formed on related heterocycles we investigated the pyrrole (31)
Scheme 4 Reagents and conditions: (i) H-Cube, 0.05 M 22a (R ¼ p-OCH3PhCH2–) in MeOH, 10% Pd/C, at 1 mL minꢁ1 and the reduction
products (23a, 25a–30a) potentially obtainable by choice of hydrogenation conditions (see Table 2 for detail).
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Table
4
Evaluation of hydrogenation catalysts for the selective
reduction of 22a to 23a, 25a, 28a and 30a at 1.0 mL minꢁ1 flow rate,
60 ꢀC, 60 bar H2, unless otherwise indicated
Entry Catalyst
23a (%) 25a (%) 28a (%) 30a (%)
Scheme 5 Reagents and conditions: (i) 0.05 M 31 or 32 (MeOH), 10%
Pd/C, 100 ꢀC, 100 bar H2, 1 mL minꢁ1, H-Cube™.
1
2
3
4
5
6
7
8
9
10% Pd/C
20% Pd(OH)2/C
Pd tetrakis
5% Pt/C (sulded)
RuO2
0.5% Ir/C
5% Re/C
Re2O7
0
0
0
0
0
0
0
0
10
4
71
65
0
0
0
0
0
90
96
29
35
0
0
0
0
0
0
0
0
0
0
0
0
0
100
0
Table
2 Optimisation of temperature and H2 pressure, for the
reduction of 22a to 25a and 28a and using a 10% Pd/C hydrogenation
catalyst at 1.0 mL minꢁ1 flow rate.a Reactions were conducted for
10 minutes and analysed using GC-MS
RaNi
RaNi
0
T (ꢀC)
H2 P (bar)
25a (%)
28a (%)
10
91a
9
0
Entry
a
Reaction conducted at 10 bar H2 pressure, 50 ꢀC and 1.0 mL minꢁ1
.
1
2
3
4
5
6
7
8
100
80
60
60
50
50
40
40
30
25
25
25
25
25
20
15
10
0
0
60
0
50
0
40
0
30
40
30
20
10
0
0
0
0
0
0
0
12
4
15
18
15
11
5
100
100
100
100
100
100
88
96
85
82
85
89
95
99
89
89
79
varying ratios of 25a and 28a, with no evidence of the desired
23a (Table 4, entries 1–4). Of the Pd-based catalysts both the
10% Pd–C and 20% Pd(OH)2 showed preference for reduction of
the furan and olen moiety (Table 4, entries 1 and 2). The Pd
tetrakis and 5% Pt/C (sulded) showed ca. 2 : 1 preference for
the formation of the olen reduced 25a over the furan and
olen reduced 28a (Table 4, entries 3 and 4). While no evidence
of the desired nitrile reduction was evident, these data suggest
that further optimisation may afford exclusive access to both
25a and 28a. We observed no reduction products at
1.0 mL minꢁ1, 60 ꢀC and 60 bar H2 pressure with the RuO2, 0.5%
Ir/C, 5% Re/C or Re2O7 (Table 4, entries 5–8). However using the
same conditions with RaNi we observed global reduction to 30a
(see Scheme 5). However repeating the RaNi reaction at 10 bar
9
10
11
12
13
14
15
16
17
1
0
0
0
11
11
21
a
1 mL minꢁ1 is equivalent to a 4 min residence time (http://
www.thalesnano.com).
ꢀ
H2 pressure and 50 C reduced the olen and nitrile moieties
giving the desired 23a (91%, Table 4 entry 10).
Table 3 Optimisation of the reduction of 22a to 25a. Reactions were
conducted at flow rates of 1.33–8 mL minꢁ1, 25 ꢀC, 0 bar, 10% H2 and
analysed using GC-MS
The RaNi reduction also proved compatible with a range of
substituted pyrrole analogues allowing access to a series of
novel amines for subsequent addition to norcantharidin (2) in
the nal step of Path B. Stirring in acetone at room temperature
for 4 hours afforded the desired product 7-oxabiclcyo[2.2.1]-
heptane 24a in a 78% yield upon ltration of the crude reaction
mixture (Scheme 6).52 Pleasingly, as with reaction Path A, reac-
tion Path B proved amenable to various functional group
alterations and was utilised to access a small library of furan
(Fig. 4, 24a–24c) and pyrrole (24d–24g), and thiophene (24h and
24i) based norcantharidin analogues.
Residence
Entry
Catalyst
time (min)
25a (%)
28a (%)
1
2
3
4
10% Pd/C
10% Pd/C
10% Pd/C
10% Pd/C
3.0
1.5
0.8
0.5
64
80
89
36
20
11
0
100
and thiophene (32) analogues of 22a (Scheme 5). Analogues 31
and 32 were synthesised as per 22a from pyrrole-2-carbaldehyde
and thiophene-2-carbaldehyde respectively. In contrast to 22a,
both 31 and 32 showed exclusive reduction of the olen moiety
affording 33 and 34, respectively. No change in this reduction
ꢀ
was evident with 31 and 32 with reaction conditions of 100 C
and 100 bar H2 pressure and once again no evidence of nitrile
reduction was evident.
As no evidence of nitrile reduction was obtained using Pd/C,
for any of the analogues examined thus far, we next conducted a
rapid catalyst scan using 22a as the model compound (Table 4).
At 60 ꢀC and 60 bar H2 pressure the Pd-based catalysts gave
Scheme 6 Reagents and conditions: (i) acetone, rt, 4 h.
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the desired furanyl amides (reduction of the olen and nitrile
moieties) (23) for subsequent synthesis of the desired 7-oxabi-
cyclo[2.2.1]heptane carboxylic acid analogues (24).
With the desired amines in hand the Diels–Alder addition of
18 with maleic anhydride followed by an intramolecular lac-
tamisation followed by a second ow reduction (of the resultant
C]C) gave a focused library of isoindole-7-carboxylic acids
(20a–h) in modest to good yields for the three steps. Importantly
these products were access in 50–100 mg quantities through two
ow chemistry (10 minute) and one batch reaction in >95%
purity requiring no purication. Similarly, with 23 in hand,
addition of norcantharidin (2) saw smooth conversion to the
desired focused library of 7-oxabicyclo[2.2.1]heptane carboxylic
acids (24a–i). In this instance analogues 24a–i were rapidly
accessed via a solvent free reaction, one 10 minute ow hydro-
genation reaction and nucleophilic addition to the anhydride
moiety of 2. These analogues were isolated by ltration and/or
trituration in 50–100 mg quantities in >95% purity.
Fig. 4 Small library of analogues access by sequential flow reaction
Path B including a number of furan (24a–24c), pyrrole (24d–24g), and
thiophene (24h and 24i) based norcantharidin analogues.
Herein we have applied the principles of green chemistry
where possible. The use of ow chemistry approaches has
allowed reagent minimisation (10 mL of a 0.05 M solution) and
rapid reaction optimisation. Careful control of residence times,
temperature and H2 pressure permitted exclusive reduction of
22 to 23a, 26a or 28a, a level of control difficult to envisage
under traditional batch hydrogenation approaches (Scheme 7).
Batch reduction approaches typically only afford the global
reduction products.43–45 The high conversion rates minimised
purication requirements typically to ltration and/or tritura-
tion. In instances were diethyl ether was the solvent of choice,
the recovered solvent was directly for product trituration in
subsequent steps. The combined use of ow an batch chemistry
provided facile access to the two series of bicycle[2.2.1]heptane
analogues, the isoindole-7-carboxylic acids (20) and the 7-oxa-
bicyclo[2.2.1]0heptane carboxylic acids (24). We are currently
developing an extended series of these analogues which will be
assessed against a panel of human cancer cell lines and the
results of these studies will be reported in due course.
Scheme 7 Reagents and conditions: (i) H-cube RANEY® Ni, 50 ꢀC,
10 bar H2, 1 mL minꢁ1; (ii) H-Cube Pd/C, 25 ꢀC, 0 bar, 10% H2,
3.0 mL minꢁ1 (iii) H-Cube Pd/C, 50 ꢀC, 50 bar H2, 1 mL minꢁ1
;
(iv) H-cube RANEY® Ni, 60 ꢀC, 60 bar H2, 1.0 mL minꢁ1
.
Conclusion
We believe that with rapid reaction optimisation, reduced
From the outset of this study we were aware that step 1 of Path work-up and chromatography requirements, sequential ow
A, reduction of the imine 17, couple potentially could yield the methodologies integrated with batch chemistry has the poten-
desired reductive amination product (18, Fig. 3) or the equiva- tial to aid sustainable practices in medicinal chemistry.
lent tetrahydrofuran; and that Path B was likely to be more
complex with the reduction of 22 potentially yielding seven
reduction products (Scheme 5, plus additional debenzylation
products). However by judicious choice of ow reduction
Experimental
General experimental
reductive amination of 15 with a range of amines was effected at All reagents were purchased from Sigma Aldrich and were used
50 ꢀC, 50 bar H2 pressure and 1.0 mL minꢁ1 to give exclusively without purication, with the exception of furfural, which was
the reductive amination product 18. Interestingly the same distilled from glass prior to use. Solvents were bulk, and
conditions with furan 22, which could give rise to seven distilled from glass prior to use.
13
1H and C NMR spectra were recorded on a Bruker
¨
reduction products (excluding debenzylation), resulted in
reduction only of the furan and olen moieties with clean Advance™ AMX 400 MHz spectrometer at 400.1 and 100.1 MHz,
generation of 28, suggesting that the amino/imine moieties of respectively. Chemical shis (d) are reported in parts per
18 drove affected the ow reduction outcomes. Reducing cata- million (ppm) measured to relative the internal standards.
lyst residence times from 4 min to 0.5 min allowed access to Coupling constants (J) are expressed in Hertz (Hz). Mass spectra
exclusively the furan olen reduced product (25). Catalyst were recorded on a Shimadzu LCMS 2010 EV using a mobile
switching from Pd/C to RaNi and manipulation of the ow phase of 1 : 1 acetonitrile : H2O with 0.1% formic acid. Gas
ꢁ1
ꢀ
conditions to 50 C, 10 bar and 1 mL min allowed access to chromatography-mass spectrometry (GC-MS) was performed on
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a Shimadzu GC-MS QF2010 EI/NCI System equipped with a 1.31 (s, 9H). 13C NMR (CDCl3, 101 MHz): d 154.0, 149.9, 141.8,
ZB-5MS capillary column of 5% phenylarylene stationary phase. 137.0, 128.0, 125.3, 125.3, 110.1, 107.0, 52.5, 45.5, 34.5, 31.4.
Melting points were recorded on a BUCHI Melting Point IR (cmꢁ1) 3330 (NH), 2961, 2904, 2868 (CH), 1597, 1508 (C]C),
M-565. IR spectra were recorded on a PerkinElmer Spectrum 1460, 1362 (CH2), 1269 (CH3), 804 (p-C Ph).
Two™ FTIR Spectrometer. Thin layer chromatography (TLC)
1-(Furan-2-yl)-N-(naphthalen-1-ylmethyl)methanamine (18e).
was performed on Merck 60 F254 pre-coated aluminium plates Synthesised as described in general procedure 1 from 1-naph-
with a thickness of 0.2 mm. Column chromatography was per- thylamine (16e) and furan-2-carbaldehyde (15).
formed under ‘ash’ conditions on Merck silica gel 60 (230–400
LRMS (ESI+) m/z 238 (M + 1). 1H NMR (CDCl3, 400 MHz):
mesh). Microwave irradiations were conducted using a CEM d 8.06 (d, J ¼ 8.2 Hz, 1H), 7.88–7.84 (m, 1H), 7.77 (d, J ¼ 8.0 Hz,
Discover® Benchmate microwave, and hydrogenations were 1H), 7.52–7.40 (m, 5H), 6.35 (dd, J ¼ 3.1, 1.9 Hz, 1H), 6.24 (d, J ¼
performed either using a ThalesNano H-Cube™ or a Tha- 3.2 Hz, 1H), 4.23 (s, 2H), 3.89 (s, 2H). 13C NMR (CDCl3,
lesNano H-CubePro™ (H-Cube™) continuous-ow hydrogena- 101 MHz): d 153.9, 141.9, 135.5, 133.9, 131.9, 128.7, 127.9, 126.3,
tion reactor. All reactions were passed through the H-Cube™ 126.2, 125.6, 125.4, 123.6, 110.2, 107.2, 50.4, 45.9. IR (cmꢁ1
)
reactor once, unless otherwise specied.
3321 (NH), 3047, 2925, 2832, (CH), 1597, 1508 (C]C), 1450,
1396 (CH2), 790 (p-C Ph).
N-(4-Fluorobenzyl)-1-(furan-2-yl)methanamine (18f). Synthe-
sised as described in general procedure 1 from 4-uorobenzyl-
amine (16f) and furan-2-carbaldehyde (15).
General procedure 1 – direct reductive amination
1-(Furan-2-yl)-N-(4-methoxybenzyl)methanamine (18a).
solution of 4-methoxybenzylamine (16a) (0.08 mL, 0.6 mmol)
A
LRMS (ESI+) m/z 206 (M + 1). 1H NMR (CDCl3, 400 MHz): d 7.37
and furan-2-carbaldehyde (15) (0.05 mL, 0.6 mmol) was diluted (d, J ¼ 1.0 Hz, 1H), 7.30–7.27 (m, 2H), 6.99 (d, J ¼ 8.7 Hz, 2H), 6.32
in MeOH (2.5 mL) to afford a 0.05 M solution which was (dd, J ¼ 3.1, 1.9 Hz, 1H), 6.18 (d, J ¼ 3.1 Hz, 1H), 3.77 (s, 2H), 3.75
subsequently hydrogenated with a H-Cube™ using a 10% Pd/C (s, 2H). 13C NMR (CDCl3, 101 MHz): d 162.0 (d, J ¼ 245.5 Hz),
catalyst at 1 mL minꢁ1 ow rate, 50 ꢀC and 50 bar H2 pressure. 152.3, 142.1, 130.5, 130.4, 115.2, 115.0, 110.1, 108.9, 56.3, 49.3. IR
The eluate was concentrated in vacuo to afford 18a as a yellow oil (cmꢁ1) 3317 (NH), 2971, 2925, 2836, (CH), 1602, 1507 (C]C),
(0.12 g, 89%).
1416, 1358 (CH2), 1009 (F–C Ph), 821 (p-C Ph).
GC-MS 4.06 r.t.; LRMS (ESI+) m/z 218 (M + 1). 1H NMR (CDCl3,
N-(4-Chlorobenzyl)-1-(furan-2-yl)methanamine (18g). Synthe-
400 MHz): d 7.45 (d, J ¼ 1.1 Hz, 1H), 7.35 (d, J ¼ 8.6 Hz, 2H), 6.92 sised as described in general procedure 1 from 4-chlorobenzyl-
(d, J ¼ 8.6 Hz, 2H), 6.38 (dd, J ¼ 2.0, 1.2 Hz, 1H), 6.27 (d, J ¼ 3.2 amine (18g) and furan-2-carbaldehyde (15).
Hz, 1H), 3.84 (s, 3H), 3.70 (s, 2H), 3.61 (m, 2H). 13C NMR (CDCl3,
LRMS (ESI+) m/z 222 (M + 1). 1H NMR (CDCl3, 400 MHz):
101 MHz): d 158.7, 152.6, 142.0, 130.9, 130.2, 113.7, 110.1, 108.8, d 7.41 (d, J ¼ 1.1 Hz, 1H), 7.36–7.25 (m, 4H), 6.34 (dd, J ¼ 3.1,
56.5, 55.3, 49.2. IR (cmꢁ1) 3330 (NH), 2960, 2763 (CH), 1615, 1513 1.9 Hz, 1H), 6.23 (d, J ¼ 3.1 Hz, 1H), 3.77 (d, J ¼ 9.2 Hz, 1H),
(C]C), 1463, 1432 (CH2), 1247 (CH3), 1218 (C–O), 830 (p-C Ph).
3.66 (s, 2H), 3.58 (s, 1H). 13C NMR (CDCl3, 101 MHz): d IR (cmꢁ1
)
N-Benzyl-1-(furan-2-yl)methanamine (18b). Synthesised as 3312 (NH), 2921, 2777, 22730 (CH), 1601, 1573 (C]C), 1452,
described in general procedure 1 from benzylamine (16b) and 1428 (CH2), 810 (p-C Ph), 599 (Cl–C Ph).
furan-2-carbaldehyde (15).
N-(Furan-2-ylmethyl)-4-morpholinoaniline (18h). Synthe-
LRMS (ESI+) m/z 188 (M + 1). 1H NMR (CDCl3, 400 MHz): d 7.30 sised as described in general procedure 1 from 4-morpholi-
(dd, J ¼ 4.2, 3.3 Hz 1H), 7.23 (d, J ¼ 4.1, Hz, 2H), 7.19–7.11 (m, noaniline (16h) and furan-2-carbaldehyde (15).
1H), 6.24–6.22 (m, 1H), 6.14 (d, J ¼ 3.1 Hz, 1H), 3.70 (s, 1H), 3.58
LRMS (ESI+) m/z 259 (M + 1). 1H NMR (CDCl3, 400 MHz):
(s, 2H), 3.53 (s, 1H). 13C NMR (CDCl3, 101 MHz): d 152.5, 142.1, d 7.36 (d, J ¼ 1.1 Hz, 1H), 6.84 (d, J ¼ 8.9 Hz, 2H), 6.66 (d, J ¼
129.0, 128.5, 128.3, 127.0, 110.1, 108.8, 57.1, 49.4. IR (cmꢁ1) 3330 8.9 Hz, 2H), 6.31 (dd, J ¼ 3.1, 1.9 Hz, 1H), 6.21 (d, J ¼ 2.8 Hz,
(NH), 2976, 2929, 2838 (CH), 1602, 1507 (C]C), 1453, 1360 (CH2). 1H), 4.28 (s, 2H), 3.85 (t, J ¼ 4.5 Hz, 4H), 3.02 (t, J ¼ 4.6 Hz, 4H).
4-((Furan-2-ylmethylamino)methyl)phenol (18c). Synthe- 13C NMR (CDCl3, 101 MHz): d 153.0, 144.1, 142.1, 141.9, 118.2,
sised as described in general procedure 1 from 4-hydroxy- 114.4, 110.3, 106.9, 67.1, 51.1, 42.2. IR (cmꢁ1) 3395 (NH), 2964,
benzylamine (16c) and furan-2-carbaldehyde (15).
2851, 2824 (CH), 1615 (C]C), 1512 (O]C–N), 1458, 1408 (CH2),
LRMS (ESI+) m/z 204 (M + 1). 1H NMR (MeOD, 400 MHz): 1220 (C–O), 1117 (C–O), 918 (C]C bend) 824 (p-C Ph).
d 7.49 (d, J ¼ 1.0 Hz, 1H), 7.19 (d, J ¼ 8.4 Hz, 1H), 6.76 (d, J ¼
8.5 Hz, 1H), 6.40–6.38 (m, 1H), 6.30 (d, J ¼ 3.0 Hz, 1H),
General procedure 2 – reaction path A
3.62 (s, 2H), 3.51 (s, 1H), 3.33 (s, 1H). 13C NMR (MeOD,
101 MHz): d 156.3, 152.0, 141.9, 130.2, 128.9, 114.6, 109.8, 108.8,
56.3, 48.4. IR (cmꢁ1) 3290 (OH), 2963, 2923, 2858 (CH), 1613, 3aH-isoindole-7-carboxylic acid (20a). 1-(Furan-2-yl)-N-(4-
1514 (C]C), 1448, 1360 (CH2), 1225 (C–O), 819 (p-C Ph). methoxybenzyl)methanamine 18a 0.12 g, 0.51 mmol and maleic
2-[(4-Dimethoxyphenyl)methyl]octahydro-1-oxo-3a,6-epoxy-
N-(4-tert-Butylbenzyl)-1-(furan-2-yl)methanamine (18d). Syn- anhydride (0.06 g, 0.61 mmol) were dissolved separately in
thesised as described in general procedure 1 from 4-tert-butyl- diethyl ether (10 mL ꢂ 2) and the solutions were added together
benzylamine (16d) and furan-2-carbaldehyde (15).
and the reaction was le to stir at room temperature overnight.
LRMS (ESI+) m/z 244 (M + 1). 1H NMR (CDCl3, 400 MHz): The solution was ltered and washed with cold diethyl ether
d 7.36–7.33 (m, 3H), 7.25 (d, J ¼ 8.3 Hz, 2H), 6.31 (dd, J ¼ 3.1, and dried under suction to afford 20a as a yellow solid. The
1.9 Hz, 1H), 6.18 (d, J ¼ 3.1 Hz, 1H), 3.79 (s, 2H), 3.76 (s, 2H), crude product was then dissolved in acetone (6 mL) to form a
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ꢃ0.05 M solution. This solution was hydrogenated using the H- 3250 (OH), 2967, 2870 (CH), 1748 (CO), 1674 (CO), 1656 (C]C),
Cube™ with a 10% Pd/C catalyst at 1 mL minꢁ1 ow rate, 50 ꢀC 1475, 1409 (CH2), 1401, 1389, 1354 (CH3), 1269 (CO), 1148 (CO),
and 50 bar H2 pressure. The eluate was concentrated in vacuo 840 (p-C Ph).
and then triturated with ether to afford 20a as a pale orange
solid; 0.1 g, overall 51%; mp 115–116 ꢀC.
2-[(Napthalen-1-yl)methyl]octahydro-1-oxo-3a,6-epoxy-3aH-
isoindole-7-carboxylic acid (20e). Synthesised as described in
1H NMR (CDCl3, 400 MHz): d 7.72 (s, 1H), 7.20 (d, J ¼ 8.6 Hz, general procedure 2 – sequential reaction Path A from 18e and
2H), 6.89 (d, J ¼ 8.6 Hz, 2H), 4.87 (d, J ¼ 5.6 Hz, 1H), 4.52 (d, J ¼ maleic anhydride to afford 20ꢀe as an off white solid, 0.1 g,
14.8 Hz, 1H), 4.42 (d, J ¼ 14.8 Hz, 1H), 3.80 (s, 3H), 3.62 (d, J ¼ overall yield 30%; mp 212–213 C.
11.8 Hz, 1H), 3.53 (d, J ¼ 11.8 Hz, 1H), 3.21–3.13 (m, 2H), 1.97
LRMS (ESI+) m/z 338 (M + 1). 1H NMR (MeOD, 400 MHz): d 8.09
(dt, J ¼ 13.3, 6.9 Hz, 1H), 1.79–1.69 (m, 2H), 1.64–1.55 (m, 1H). (d, J ¼ 8.0 Hz, 1H), 7.90 (d, J ¼ 7.5 Hz, 1H), 7.85 (d, J ¼ 8.1 Hz, 1H),
13C NMR (CDCl3, 101 MHz): d 172.9, 159.2, 129.4, 127.4, 114.3, 7.57–7.44 (m, 4H), 5.01 (d, J ¼ 15.1 Hz, 1H), 4.86 (d, J ¼ 15.1 Hz,
86.3, 79.9, 55.3, 54.4, 52.4, 48.7, 46.4, 29.5, 29.1. IR (cmꢁ1) 3592 1H), 4.67 (d, J ¼ 5.6 Hz, 1H), 3.53 (d, J ¼ 11.8 Hz, 1H), 3.44 (d, J ¼
(N), 3528 (OH), 2983, 2955, 2892, 2834 (CH), 1730 (CO), 1644 11.8 Hz, 1H), 3.16 (d, J ¼ 9.6 Hz, 1H), 3.07 (d, J ¼ 9.6 Hz, 1H),
(CO), 1612 (C]C), 1513 (O]C–N), 1473, 1422 (CH2), 1.93–1.83 (m, 1H), 1.79–1.71 (m, 1H), 1.68–1.58 (m, 2H). 13C NMR
1355 (CH3), 1173 (C–O), 842 (p-C Ph).
(MeOD, 101 MHz): d 173.5172.5, 134.0, 131.4, 131.2, 128.3, 128.3,
2-(Phenylmethyl)octahydro-1-oxo-3a,6-epoxy-3aH-isoindole-
126.5, 126.2, 125.6, 125.0, 123.2, 86.2, 79.8, 54.1, 51.6, 48.4, 44.2,
7-carboxylic acid (20b). Synthesised as described in general 28.9, 28.5. IR (cmꢁ1) 3480 (OH), 3060, 3044, 2999, 2983, 2939
procedure 2 – sequential reaction Path A from 18b and maleic (CH), 1732 (CO), 1649 (CO), 1612 (C]C), 1485, 1425 (CH2), 1264
anhydride to afford 20b as a pale orange solid; 0.07 g, overall (C–O), 1232 (C–O), 794(m-C Ph), 782 (o-C Ph).
ꢀ
yield 47%; mp 198–202 C.
2-[(4-Fluorophenyl)methyl]octahydro-1-oxo-3a,6-epoxy-3aH-
MS (ESI+) m/z 288 (M + 1). 1H NMR (MeOD, 400 MHz): d 7.37– isoindole-7-carboxylic acid (20f). Synthesised as described in
7.28 (m, 5H), 4.70 (d, J ¼ 5.6 Hz, 1H), 4.58 (d, J ¼ 15.2 Hz, 1H), general procedure 2 – sequential reaction Path A from 18f and
4.42 (d, J ¼ 15.1 Hz, 1H), 3.63 (d, J ¼ 11.7 Hz, 1H), 3.55 (d, J ¼ maleic anhydride to afford 20fꢀ as a pale yellow solid, 0.15 g,
11.7 Hz, 1H), 3.19 (d, J ¼ 9.6 Hz, 1H), 3.09 (d, J ¼ 9.6 Hz, 1H), overall yield 38%; mp 233–239 C.
1
2.00–1.90 (m, 1H), 1.84 (td, J ¼ 11.3, 7.2 Hz, 1H), 1.76–1.66 (m,
LRMS (ESI+) m/z 306 (M + 1). H NMR (MeOD, 400 MHz): d
2H). 13C NMR (MeOD, 101 MHz): d 173.6, 173.0, 135.9, 128.3, 7.34 (dd, J ¼ 8.7, 5.4 Hz, 2H), 7.07 (t, J ¼ 8.8 Hz, 2H), 4.69 (d, J ¼
127.5, 127.2, 86.3, 79.8, 54.0, 51.6, 48.3, 45.9, 29.0, 28.6. IR 5.6 Hz, 1H), 4.61 (d, J ¼ 15.2 Hz, 1H), 4.35 (d, J ¼ 15.2 Hz, 1H),
(cmꢁ1) 3378 (OH), 2972, 2935, 2878 (CH), 1713 (CO), 1685 (CO), 3.64 (d, J ¼ 11.7 Hz, 1H), 3.54 (d, J ¼ 11.7 Hz, 1H), 3.18 (d, J ¼ 9.6
1652 (C]C), 1474, 1428 (CH2), 1259 (C–O), 1163 (C–O).
Hz, 1H), 3.09 (d, J ¼ 9.6 Hz, 1H), 1.95 (dd, J ¼ 5.6, 3.6 Hz, 1H),
2-[(4-Phenol)methyl]octahydro-1-oxo-3a,6-epoxy-3aH-isoindole- 1.89–1.79 (m, 1H), 1.77–1.65 (m, 2H). 13C NMR (MeOD, 101
7-carboxylic acid (20c). Synthesised as described in general MHz): d 173.6, 173.0, 162.3 (d, J ¼ 245.1 Hz), 132.0, 129.4, 129.3,
procedure 2 – sequential reaction Path A from 18c and maleic 115.1, 114.8, 86.3, 79.8, 53.9, 51.6, 48.1, 45.1, 29.0, 28.6. IR
anhydride to afford 20c as a yellow solid, 0.1 g, overall 53%; mp (cmꢁ1) 3390 (OH), 3003, 2979, 2955, 2894 (CH), 1726 (CO), 1682
278–279 ꢀC.
LRMS (ESI+) m/z 304 (M + 1). H NMR (DMSO, 400 MHz): d 1003 (F–C Ph), 841 (p-C Ph).
(CO), 1508 (C]C), 1436, 1415 (CH2), 1262 (C–O), 1219 (C–O),
1
11.71 (s, OH), 9.33 (s, NH), 7.05 (d, J ¼ 8.4 Hz, 2H), 6.70 (d, J ¼
2-[(4-Chlorophenyl)methyl]octahydro-1-oxo-3a,6-epoxy-3aH-
8.4 Hz, 2H), 4.56 (d, J ¼ 4.8 Hz, 1H), 4.31 (d, J ¼ 14.9 Hz, 1H), isoindole-7-carboxylic acid (20g). Synthesised as described in
4.21 (d, J ¼ 14.9 Hz, 1H), 3.48 (d, J ¼ 11.5 Hz, 1H), 3.38 (d, J ¼ general procedure 2 – sequential reaction Path A from 18g and
11.5 Hz, 1H), 3.07 (d, J ¼ 9.7 Hz, 1H), 2.86 (d, J ¼ 9.7 Hz, 1H), maleic anhydride to afford 20g as a brown solid 0.1 g, overall
1.73 (dd, J ¼ 11.6, 5.3 Hz, 2H), 1.56 (t, J ¼ 10.4 Hz, 2H). 13C NMR yield 36%; mp 198–202 C.
ꢀ
(DMSO, 101 MHz): d 172.7, 171.6, 157.0, 129.3, 127.1, 115.7,
LRMS (ESI+) m/z 322 (M + 1). 1H NMR (MeOD, 400 MHz):
86.1, 79.2, 53.9, 51.7, 48.2, 45.3, 29.6, 29.0. IR (cmꢁ1) 3257 (OH), d 7.24–7.15 (m, 4H), 4.57 (d, J ¼ 5.6 Hz, 1H), 4.50 (d, J ¼ 15.4 Hz,
2979, 2955, 2950 (CH), 1713 (CO), 1650 (CO), 1620 (C]C), 1437, 1H), 4.20 (d, J ¼ 15.4 Hz, 1H), 3.52 (d, J ¼ 11.7 Hz, 1H), 3.42
1422 (CH2), 1261 (CO), 1162 (CO), 822 (p-C Ph).
(d, J ¼ 11.7 Hz, 1H), 3.06 (d, J ¼ 9.6 Hz, 1H), 2.96 (d, J ¼ 9.6 Hz,
2-[(4-tert-Butylphenyl)methyl]octahydro-1-oxo-3a,6-epoxy- 1H), 1.87–1.77 (m, 1H), 1.76–1.68 (m, 1H), 1.64–1.53 (m, 2H).
3aH-isoindole-7-carboxylic acid (20d). Synthesised as described 13C NMR (MeOD, 101 MHz): d 173.5, 173.0, 134.8, 132.9, 129.0,
in general procedure 2 – sequential reaction path A from 18d 128.4, 86.3, 79.8, 53.9, 51.6, 48.3, 45.1, 29.0, 28.6. IR (cmꢁ1) 3439
and maleic anhydride to afford 20d as a white solid, 0.2 g, (NH), 3322 (OH), 2975, 2906 (CH), 1721 (CO), 1659 (CO), 1489,
ꢀ
overall yield 37%; mp 195–197 C.
1426 (CH2), 1275 (C–O), 1215 (C–O), 841 (p-C Ph), 567 (Cl–C Ph).
2-[(4-Morpholinaniline)methyl]octahydro-1-oxo-3a,6-epoxy-
LRMS (ESI+) m/z 338 (M + 1). H NMR (MeOD, 400 MHz): d
1
7.40 (d, J ¼ 8.3 Hz, 2H), 7.24 (d, J ¼ 8.3 Hz, 2H), 4.69 (d, J ¼ 5.6 3aH-isoindole-7-carboxylic acid (20h). Synthesised as described
Hz, 1H), 4.51 (d, J ¼ 15.0 Hz, 1H), 4.41 (d, J ¼ 15.0 Hz, 1H), 3.61 in general procedure 2 – sequential reaction Path A from 18h
(d, J ¼ 11.7 Hz, 1H), 3.55 (d, J ¼ 11.7 Hz, 1H), 3.17 (d, J ¼ 9.6 Hz, and maleic anhydride to afford 20h as an off white solid, 0.1 g,
1H), 3.08 (d, J ¼ 9.6 Hz, 1H), 1.97–1.90 (m, 1H), 1.87–1.80 (m, overall 24%; mp 238–240 ꢀC.
1H), 1.70 (ddd, J ¼ 10.7, 9.1, 4.3 Hz, 2H), 1.32 (s, 9H). 13C NMR
LRMS (ESI+) m/z 359 (M + 1). 1H NMR (DMSO-d,6 400 MHz):
(MeOD, 101 MHz): d 173.8, 172.9, 150.2, 132.9, 127.3, 125.2, d 12.06 (s, OH), 7.49 (d, J ¼ 9.1 Hz, 2H), 6.93 (d, J ¼ 9.2 Hz, 2H),
86.2, 79.8, 54.0, 51.7, 48.3, 45.6, 33.9, 30.4, 29.0, 28.6. IR (cmꢁ1
)
4.59 (d, J ¼ 5.1 Hz, 1H), 4.15 (d, J ¼ 11.5 Hz, 1H), 3.90 (d, J ¼
9716 | RSC Adv., 2014, 4, 9709–9722
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11.4 Hz, 1H), 3.76–3.70 (m, 4H), 3.26 (d, J ¼ 9.7 Hz, 1H), 3.10–
Furan-2-carboxaldehyde (15) and 2-cyano-N-(4-chlorobenzyl)
3.04 (m, 4H), 2.93 (d, J ¼ 9.7 Hz, 1H), 1.88–1.73 (m, 2H), 1.74– acetamide (21b) were reacted as described in general procedure
1.55 (m, 2H). 13C NMR (MeOD, 101 MHz): d 171.8, 169.9, 147.0, 3 to afford 22b as an orange solid 67%; mp 149–151 ꢀC.
131.2, 119.8, 114.5, 84.2, 78.4, 65.5, 54.0, 51.1, 49.0, 48.1, 28.5,
LRMS (ESI+) m/z 287 (M + 1). 1H NMR (CDCl3, 400 MHz):
27.9. IR (cmꢁ1) 3300 (OH), 2999, 2955, 2922, 2882 (CH), d 8.10 (s, 1H), 7.73 (d, J ¼ 1.6 Hz, 1H), 7.35–7.31 (m, 2H), 7.27–
1740 (CO), 1689 (CO), 1606 (C]C), 1511 (O]C–N), 1455, 7.25 (m, 2H), 7.20 (d, J ¼ 3.6 Hz, 1H), 6.64 (dd, J ¼ 3.6, 1.7 Hz, 2H),
1394 (CH2), 1210 (C–O), 1170 (C–O), 824 (p-C Ph).
4.56 (d, J ¼ 5.9 Hz, 2H). 13C NMR (CDCl3, 101 MHz): d 160.4,
148.9, 147.9, 137.7, 135.8, 133.8, 129.2, 129.0, 121.4, 116.7, 113.6,
99.5, 43.8. IR (cmꢁ1) 3375 (NH), 3115, 3036, (CH), 2211 (CN), 1668
(CO), 1610 (C]C), 1540 (NH bend), 1463 (CH2), 1283 (C–O), 1253
General procedure 3 – Knoevenagel condensation
2-Cyano-3-(furan-2-yl)-N-(4-methoxybenzyl)acrylamide (22a). (C–O), 1022 (C–O–C), 826 (p-C Ph), 591 (Cl–C Ph).
2-Cyano-N-(4-methoxybenzyl)acetamide (21a) was synthesised
2-Cyno-3-(furan-2-yl)-N-(4-methylbenzyl)acrylamide (22c).
by stirring methyl cyanoacetate (1.50 g, 15.1 mmol) with 2-Cyano-N-(4-methylbenzyl)acetamide (21c) was synthesised
4-methoxybenzylamine (2.08 g, 15.1 mmol) in MeOH at room by stirring methyl cyanoacetate (0.72 g, 7.3 mmol) with
temperature for 60 min. Aer this time the solution was ltered 4-methylbenzylamine (0.88 g, 7.3 mmol) at room temperature
and washed with cold MeOH and dried under suction to afford for 60 min. Aer this time the solid was recrystallized from
21a as a white solid; 70%; mp 136–138 ꢀC. This material was EtOH to afford 21c as a white solid, 42%; mp 132–134 ꢀC. This
used directly for the synthesis of 22a.
material was used directly for the synthesis of 22c.
LRMS (ESI+) m/z 205 (M + 1). 1H NMR (CDCl3, 400 MHz):
LRMS (ESI+) m/z 287 (M + 1). 1H NMR (CDCl3, 400 MHz):
d 7.23 (d, J ¼ 8.5 Hz, 2H), 6.90 (d, J ¼ 8.6 Hz, 2H), 6.45 (s, 1H), d 7.17 (s, 4H), 6.34 (s, 1H), 4.43 (d, J ¼ 5.6 Hz, 2H), 3.38 (s, 2H),
4.41 (d, J ¼ 5.5 Hz, 2H), 3.82 (s, 3H), 3.39 (s, 2H). 13C NMR 2.35 (s, 3H). 13C NMR (CDCl3, 101 MHz): d 160.6, 137.9, 133.7,
(CDCl3, 101 MHz): d 160.7, 159.4, 129.4, 128.9, 114.7, 114.3, 129.6, 128.0, 114.6, 44.2, 25.8, 21.1. IR (cmꢁ1) 3289 (NH), 3058,
55.3, 43.9, 25.9. IR (cmꢁ1) 3284 (NH), 3073, 2939, 2841 (CH), 2928 (CH), 2261 (CN), 1644 (CO), 1545 (C]C), 1517 (NH bend),
2258 (CN), 1640 (CO), 1614, 1515 (C]C), 1515 (NH bend), 1463 (CH2), 1364 (CH3), 1229 (C–O), 1062 (C–O–C), 809 (p-C Ph).
1462 (CH2), 1368 (CH3), 1240 (CO), 1031 (C–O–C), 815 (p-C Ph).
Furan-2-carboxaldehyde (15) and 2-cyano-N-(4-methylbenzyl)
Furan-2-carboxaldehyde (15) (0.11 g, 1.2 mmol) and 2-cyano-N- acetamide (21c) were reacted as described in general procedure
(4-methoxybenzyl)acetamide (21a) (0.24 g, 1.2 mmol) were added 3 to afford 22c as a white solid, 50%; mp 130–132 ꢀC.
together in EtOH (4 mL). Piperidine (cat.) was added and the
LRMS (ESI+) m/z 267 (M + 1). 1H NMR (CDCl3, 400 MHz):
reaction was le to stir at room temperature for 30 min and then d 8.10 (s, 1H), 7.71 (d, J ¼ 1.6 Hz, 1H), 7.19 (dt, J ¼ 8.0, 3.7 Hz,
placed in the freezer for 60 min. The solution was ltered and 4H), 6.62 (dd, J ¼ 3.6, 1.7 Hz, 1H), 6.57 (s, 1H), 4.55 (d, J ¼
washed with cold EtOH and dried under suction to afford 22a as 5.7 Hz, 2H), 2.35 (s, 3H). 13C NMR (CDCl3, 101 MHz): d 160.2,
an orange solid, 71%; mp 119–121 ꢀC. GC–MS (r.t.) 15.46 min.
149.0, 147.7, 137.7, 137.5, 134.1, 129.6, 127.9, 121.1, 116.7,
LRMS (ESI+) m/z 283 (M + 1). H NMR (acetone, 400 MHz): 113.5, 99.8, 44.4, 21.1. IR (cmꢁ1) 3327 (NH), 3117, 3037 (CH),
d 8.04 (s, 1H), 7.96 (d, J ¼ 1.4 Hz, 1H), 7.92 (br s, NH), 7.38 (d, J ¼ 2225 (CN), 1655 (CO), 1604, 1531 (C]C), 1512 (NH bend), 1425
3.6 Hz, 1H), 7.31 (d, J ¼ 8.6 Hz, 2H), 6.89 (d, J ¼ 8.6 Hz, 2H), (CH2), 1392 (CH3), 1261 (C–O), 1016 (C–O–C), 810 (p-C Ph).
1
6.78 (dd, J ¼ 3.5, 1.7 Hz, 1H), 4.50 (d, J ¼ 6.0 Hz, 1H), 3.78
2-Cyano-3-(pyrrole-2-yl)-N-(4-methoxybenzyl)acrylamide (31).
(s, 3H), 13C NMR (acetone, 101 MHz): d 160.3, 159.1, 149.2, Pyrrole-2-carboxaldehyde (0.10 g, 1.0 mmol) and 2-cyano-N-
148.0, 136.2, 131.0, 129.1, 120.7, 115.9, 113.7, 113.6, 101.1, 54.6, (4-methoxybenzyl)acetamide (21a) (0.21 g, 1.0 mmol) were
43.1. IR (cmꢁ1) 3323 (NH), 3128, 3038, 3006, 2833 (CH), 2226 added together in EtOH (4 mL). Piperidine (cat.) was added
(CN), 1657 (CO), 1605 (C]C), 1532 (NH bend), 1436 (CH2), and the reaction was irradiated with microwaves (120 ꢀC, 200
1351 (CH3), 1298 (C–O), 1244 (C–O), 1029 (C–O–C), 826 (p-C Ph). W) for 45 min and then placed in the freezer for 60 min. The
2-Cyano-3-(furan-2-yl)-N-(4-chlorobenzyl)acrylamide (22b). 2- solution was ltered and washed with cold EtOH and dried
Cyano-N-(4-chlorobenzyl)acetamide (21b) was synthesised by under suction to afford 31 as an orange solid; 93%; mp 204–
ꢀ
adding together methyl cyanoacetate (0.5 g, 5.1 mmol) with 208 C.
4-chlorobenzylamine (0.71 g, 5.1 mmol) in EtOH (4 mL).
GC-MS (r.t.) 19.08 min. LRMS (ESI+) m/z 282 (M + 1). 1H NMR
Piperidine (cat.) was added and the reaction was irradiated with (acetone, 400 MHz): d 8.07 (s, 1H), 7.38 (d, J ¼ 3.5 Hz, 1H), 7.27
ꢀ
microwaves (120 C, 200 W) for 15 min and then placed in the (d, J ¼ 8.5 Hz, 2H), 7.22 (s, 1H), 6.90 (d, J ¼ 8.6 Hz, 2H), 6.49–
freezer for 60 min. The solution was ltered and washed with 6.38 (m, 1H), 4.45 (s, 2H), 3.79 (s, 3H) 13C NMR (Acetone, 101
cold EtOH and dried under suction to afford to afford 21b as a MHz): d 163.2, 159.0, 140.3, 130.6, 128.5, 126.7, 126.3, 117.2,
pale yellow solid, 50%; mp 131–133 ꢀC. This material was used 117.2, 113.5, 112.29, 93.9, 54.3, 42.8. IR (cmꢁ1) 3360 (NH), 3089,
directly for the synthesis of 22b.
3008, 2936 (CH), 2202 (CN), 1647 (CO), 1611, 1550 (C]C), 1510
LRMS (ESI+) m/z 209 (M + 1). 1H NMR (CDCl3, 400 MHz): (NH bend), 1426 (CH2), 1395 (CH3), 1254 (C–O), 1050 (C–O–C),
d 7.39–7.27 (m, 2H), 7.22 (d, J ¼ 8.5 Hz, 2H), 6.47 (s, 1H), 4.44 821 (p-C Ph).
(d, J ¼ 5.8 Hz, 2H), 3.41 (s, 2H). 13C NMR (CDCl3, 101 MHz):
2-Cyano-3-(pyrrole-2-yl)-N-(4-chlorobenzyl)acrylamide (22d).
Pyrrole-2-carboxaldehyde and 2-cyano-N-(4-chlorobenzyl)acet-
d 160.8, 135.3, 134.0, 129.3, 129.1, 114.6, 43.7, 25.9. IR (cmꢁ1
)
3281 (NH), 3083, 2965, 2919 (CH), 1648 (CO), 1565 (C]C), amide (21b) were reacted as described in general procedure 3 to
1456 (CH2), 1220 (C–O), 1204 (C–O), 804 (p-C Ph), 533 (Cl–C Ph). afford 22d as a white solid; 78%; mp 230–232 ꢀC.
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LRMS (ESI+) m/z 286 (M + 1). 1H NMR (DMSO, 400 MHz): white solid; 67%; mp 164–166 ꢀC. This material was used
d 11.90 (s, NH), 8.68 (t, J ¼ 5.9 Hz, 1H), 8.07 (s, 1H), 7.45– directly for the synthesis of 22g.
1
7.33 (m, 2H), 7.33–7.29 (m, 3H), 6.42 (dd, J ¼ 3.5, 2.6 Hz, 1H),
LRMS (ESI+) m/z 251 (M + 1). H NMR (CDCl3, 400 MHz): d
4.37 (d, J ¼ 6.0 Hz, 2H). 13C NMR (DMSO, 101 MHz): d 162.4, 7.60–7.56 (m, 5H), 7.46–7.43 (m, 2H), 7.40–7.34 (m, 2H), 6.41 (s,
140.8, 138.8, 131.8, 129.7, 128.7, 127.0, 126.8, 118.2, 116.1, 1H), 4.53 (d, J ¼ 5.7 Hz, 2H), 3.43 (s, 2H). 13C NMR (CDCl3, 101
113.1, 94.9, 42.9. IR (cmꢁ1) 3349 (NH), 3097, 3025, 2971 (CH), MHz): d 160.7, 141.1, 140.5, 135.7, 128.9, 128.4, 127.7, 127.5,
2205 (CN), 1645 (CO), 1574, 1524 (C]C), 1490 (NH bend), 1421 127.1, 114.6, 44.1, 25.9. IR (cmꢁ1) 3312 (NH), 3098, 3055, 3034,
(CH2), 1231 (C–O), 1012 (C–O–C), 810 (p-C Ph), 557 (Cl–C Ph).
2960, 2921 (CH), 2259 (CN), 1656 (CO), 1557 (C]C), 1450 (CH2),
2-(3-Fluorophenyl)-3-(1H-pyrrol-2-yl)acrylonitrile (22e). Pyrrole- 816 (p-C Ph).
2-carboxaldehyde (0.2 g, 2.1 mmol) and 3-uorophenylacetonitrile
Thiophene-2-carboxaldehyde (0.2 g, 1.8 mmol) and 3-uo-
(0.24 g, 2.1 mmol) were added together in EtOH (4 mL). Piperidine rophenylacetonitrile (0.45 g, 1.8 mmol) were added together in
(cat.) was added and the reaction was irradiated with microwaves EtOH (4 mL). Piperidine (cat.) was added and the reaction was
(120 ꢀC, 200 W) for 20 min and then placed in the freezer for irradiated with microwaves (120 ꢀC, 200 W) for 20 min and then
60 min. The solution was ltered and washed with cold EtOH placed in the freezer for 60 min. The solution was ltered and
and dried under suction to afford 22e as a yellow solid; 70%; mp washed with cold EtOH and dried under suction to afford 22g as
ꢀ
99–100 ꢀC.
LRMS (ESI+) m/z 213 (M + 1). 1H NMR (CDCl3, 400 MHz):
an orange solid; 57%; mp 183–185 C.
LRMS (ESI+) m/z 345 (M + 1). 1H NMR (DMSO-d6, 400 MHz): d
d 9.72 (br s, NH), 7.33–7.28 (m, 2H), 7.22–7.18 (m, 2H), 7.02 8.98 (s, 1H), 8.47 (s, 1H), 8.11 (d, J ¼ 5.0 Hz, 1H), 7.91 (d, J ¼ 3.2
(d, J ¼ 1.2 Hz, 1H), 6.99–6.90 (m, 1H), 6.65 (t, J ¼ 3.7 Hz, 1H), Hz, 1H), 7.64 (dd, J ¼ 7.6, 6.1 Hz, 4H), 7.49–7.40 (m, 4H), 7.39–
6.32–6.26 (m, 1H). 13C NMR (CDCl3, 101 MHz): d 164.5, 136.3, 7.29 (m, 2H), 4.46 (d, J ¼ 5.7 Hz, 2H). 13C NMR (DMSO-d6, 101
131.9, 127.5, 124.6, 120.8, 119.9, 115.1, 114.9, 111.9, 111.7, MHz): d 161.5, 144.2, 140.4, 139.4, 138.7, 138.5, 136.3, 135.5,
111.1, 100.1. IR (cmꢁ1) 3330 (NH), 3028, 2972 (CH), 2220 (CN), 129.4, 129.1, 128.5, 127.8, 127.1, 127.1, 117.0, 102.0, 43.4. IR
1608, 1542 (C]C), 1512 (NH bend), 1050 (F–C Ph), 759 (m-C Ph). (cmꢁ1) 3323 (NH), 3104, 3086, 3025, 2971 (CH), 2221 (CN), 1655
2-Cyano-3-(thiophene-2-yl)-N-(4-methoxybenzyl)acrylamide (32). (CO), 1583, 1537 (C]C), 1414 (CH2), 810 (p-C Ph).
Thiophene-2-carboxaldehyde (0.12 g, 1.0 mmol) and 2-cyano-N-
(4-methoxybenzyl)acetamide (21a) (0.21 g, 1.0 mmol) were added
General procedure 4 – concurrent olen and furan reduction
together in EtOH (4 mL). Piperidine (cat.) was added and the
reaction was irradiated with microwaves (120 C, 200 W) for 45
min and then placed in the freezer for 60 min. The solution was
ltered and washed with cold EtOH and dried under suction to
afford 32 as an orange solid; 93%; mp 137–138 ꢀC.
2-Cyano-N-(4-methoxybenzyl)-3-(tetrahydrofuran-2-yl)prop-
anamide (28a). (E)-2-Cyano-3-(furan-2-yl)-N-(4-methoxybenzyl)
acrylamide 22a (0.1 g, 0.35 mmol) was dissolved in sufficient
MeOH (7 mL) to form a 0.05 M solution. This solution was
hydrogenated using the H-Cube™ with a 10% Pd/C catalyst at 1
mL minꢁ1 ow rate, 50 ꢀC and 0 bar H2 pressure. The MeOH was
removed in vacuo to afford 28a as a clear oil; 0.1 g, 97%. GC-MS
(r.t.) 13.28 min.
ꢀ
GC-MS (r.t.) 8.19 min. LRMS (ESI+) m/z 299 (M + 1). 1H NMR
(CDCl3, 400 MHz): d 8.44 (s, 1H), 8.01 (d, J ¼ 5.0 Hz, 1H), 7.91
(d, J ¼ 3.5 Hz, 1H), 7.31 (dd, J ¼ 8.6, 3.7 Hz, 3H), 6.89 (d, J ¼
8.7 Hz, 2H), 4.51 (d, J ¼ 5.8 Hz, 2H), 3.78 (s, 3H). 13C NMR
(CDCl3, 101 MHz): d 160.3, 159.1, 143.8, 137.2, 136.4, 134.1,
MS (ESI+) m/z 285 (M + 1). 1H NMR (CDCl3, 400 MHz): d 7.21–
7.16 (m, 2H), 6.85–6.83 (m, 2H), 6.77 (br s, 1H), 4.43–4.30 (m,
2H), 4.05–3.86 (m, 1H), 3.83–3.78 (m, 1H), 3.77 (s, 3H), 3.75–3.66
(m, 1H), 3.55–3.53 (m, 1H), 2.24–2.17 (m, 1H), 2.09–1.95 (m,
2H), 1.92–1.81 (m, 2H), 1.55–1.54 (m, 1H). 13C NMR (CDCl3, 101
MHz): d 164.7, 159.3, 129.4, 129.3, 118.2, 114.2, 75.8, 67.9, 55.4,
43.8, 36.3, 35.9, 31.4, 25.7. IR (cmꢁ1) 3303, 3251 (NH), 3077,
2955, 2930, 2830 (CH), 2253 (CN), 1644 (CO), 1611 (C]C), 1552
(NH bend), 1461, 1436 (CH2), 1351 (CH3), 1298 (C–O), 1244 (C–
O), 1029 (C–O–C), 826 (p-C Ph).
131.0, 129.1, 128.4, 116.3, 113.7, 101.8, 54.6, 43.1. IR (cmꢁ1
)
3333 (NH), 3106, 3074, 2836 (CH), 2220 (CN), 1655 (CO), 1615,
1534 (C]C), 1512 (NH bend), 1415 (CH2), 1320 (CH3), 1249 (C–
O), 1031 (C–O–C), 797 (p-C Ph).
2-Cyano-3-(thiophene-2-yl)-N-(4-methylbenzyl)acrylamide (22f).
Pyrrole-2-carboxaldehyde and 2-cyano-N-(4-methylbenzyl)acet-
amide (21c) were reacted as described in general procedure 3 to
ꢀ
afford 22f as an orange solid; 78%; mp 149–151 C.
LRMS (ESI+) m/z 283 (M + 1). 1H NMR CDCl3, 400 MHz:
d 8.46 (s, 1H), 7.74 (dd, J ¼ 12.2, 4.4 Hz, 2H), 7.22–7.15 (m, 4H),
6.51 (s, 1H), 4.55 (d, J ¼ 5.7 Hz, 2H), 2.35 (s, 2H), 1.56 (s, 3H).
13C NMR (CDCl3, 101 MHz): d 160.4, 145.0, 137.7, 136.5, 136.4,
General procedure 5 – selective olen reduction
2-Cyano-3-(furan-2-yl)-N-(4-methoxybenzyl)propanamide (25a).
134.2, 134.1, 129.5, 128.5, 127.9, 117.0, 100.4, 44.3, 21.1. IR (E)-2-Cyano-3-(furan-2-yl)-N-(4-methoxybenzyl)acrylamide 22a (0.1
(cmꢁ1) 3338 (NH), 3073, 3020 (CH), 2217 (CN), 1655 (CO), 1583, g, 0.35 mmol) was dissolved in MeOH (7 mL) to form a 0.05 M
1532 (C]C), 1436 (CH2), 1360 (CH3), 808 (p-C Ph).
solution. This solution was hydrogenated using the H-Cube Pro™
2-Cyano-3-(thiophene-2-yl)-N-(4-biphenyl)acrylamide (22g). with a 10% Pd/C catalyst at 3 mL minꢁ1 ow rate, 25 ꢀC and 0 bar
2-Cyano-N-(4-biphenyl)acetamide (21d) was synthesised by 10% H2 pressure. The MeOH was removed in vacuo to afford 25a
stirring methyl cyanoacetate (0.20 g, 2.0 mmol) with 4-phenyl- as a white solid; 100%; mp 121–123 ꢀC. GC-MS (r.t.) 10.09 min.
benzylamine (0.37 g, 2.0 mmol) in MeOH at room temperature
1
LRMS (ESI+) m/z 285 (M + 1). H NMR (CDCl3, 400 MHz): d
for 60 min. Aer this time the solution was ltered and washed 7.32 (d, J ¼ 1.1 Hz, 1H), 7.15 (d, J ¼ 8.6 Hz, 2H), 6.88–6.83 (m,
with cold MeOH and dried under suction to afford 21d as a 2H), 6.34 (br s, NH), 6.31 (dd, J ¼ 3.1, 1.9 Hz, 1H), 6.22 (d, J ¼ 3.2
9718 | RSC Adv., 2014, 4, 9709–9722
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Hz 1H), 4.47–4.32 (m, 2H), 3.80 (s, 3H), 3.70 (dd, J ¼ 7.8, 5.6 Hz, (CH), 2251 (CN), 1642 (CO), 1615 (C]C), 1555 (C]C), 1461
1H), 3.32 (m, 2H). 13C NMR (CDCl3, 101 MHz): d 163.4, 159.5, (CH2), 1434 (CH2), 1247 (CH3), 1223 (C–O), 813 (p-C Ph) 550 (Cl–
149.4, 142.6, 129.4, 129.0, 117.6, 114.4, 110.7, 108.6, 55.5, 44.1, C Ph).
38.2, 28.8. IR (cmꢁ1) 3305 (NH), 3121, 3020, 2931, 2834 (CH),
3-Amino-2-(pyrrole-2-ylmethyl)-N-(4-methoxybenzyl)prop-
2251 (CN), 1642 (CO), 1615 (C]C), 1555 (C]C), 1461 (CH2), anamide (23d). (E)-2-Cyano-3-(pyrrole-2-yl)-N-(4-methoxybenzyl)
1434 (CH2), 1247 (CH3), 1223 (C–O), 813 (p-C Ph).
acrylamide 31 was hydrogenated using the H-Cube Pro™ with a
RaNi catalyst at 1 mL minꢁ1 ow rate, 50 ꢀC and 10 bar H2
pressure. The MeOH was removed in vacuo to afford 23d as a
yellow oil; 77%.
General procedure 6 – selective nitrile and olen reduction
3-Amino-2-(furan-2-ylmethyl)-N-(4-methoxybenzyl)-prop-
1
LRMS (ESI+) m/z 288 (M + 1). H NMR (CDCl3, 400 MHz): d
anamide (23a). (E)-2-Cyano-3-(furan-2-yl)-N-(4-methoxybenzyl)- 9.05 (s, NH), 7.76 (s, NH), 7.11 (d, J ¼ 8.7 Hz, 2H), 6.86–6.80 (m,
acrylamide 22a (0.1 g, 0.35 mmol) was dissolved in sufficient 2H), 6.61 (dd, J ¼ 4.1, 2.6 Hz, 1H), 6.07–6.05 (m, 1H), 5.88 (s,
MeOH (7 mL) to form a 0.05 M solution. This solution was 1H), 4.40–4.29 (m, 2H), 3.78 (s, 3H), 2.98–2.83 (m, 3H), 2.82–
hydrogenated using the H-Cube Pro™ with a RaNi catalyst at 1 2.77 (m, 1H), 2.46–2.40 (m, 1H), 1.40 (s, 2H). 13C NMR (CDCl3,
mL minꢁ1 ow rate, 50 C and 10 bar H2 pressure. The MeOH 101 MHz): d 175.2, 158.9, 130.5, 129.5, 128.8, 116.9, 114.0,
ꢀ
was removed in vacuo to afford 23a as a clear oil; 100%. GC-MS 107.6, 106.3, 55.3, 48.7, 43.9, 42.81, 27.9. IR (cmꢁ1) 3310 (NH),
(r.t.) 13.19 min.
3101, 3025, 2899, 2835 (CH), 1642 (CO), 1618 (C]C), 1532 (C]
1
LRMS (ESI+) m/z 289 (M + 1). H NMR (CDCl3, 400 MHz): d C), 1463 (CH2), 1434 (CH2), 1249 (CH3), 1223 (C–O), 813 (p-C
7.27 (dd, J ¼ 1.9, 0.8 Hz, 1H), 7.12 (d, J ¼ 8.7 Hz, 2H), 6.82 (dd, J Ph).
¼ 8.6, 1.9 Hz, 2H), 6.26 (dd, J ¼ 3.1, 1.9 Hz, 1H), 6.09–5.96 (m,
3-Amino-2-(pyrrole-2-ylmethyl)-N-(4-chlorobenzyl)propanamide
1H), 4.38 (dd, J ¼ 14.6, 5.9 Hz, 1H), 4.29 (dd, J ¼ 14.6, 5.4 Hz, (23e). (E)-2-Cyano-3-(pyrrole-2-yl)-N-(4-chlorobenzyl)acrylamide
1H), 3.78 (s, 3H), 3.02 (dd, J ¼ 15.1, 7.5 Hz, 1H), 2.92 (dd, J ¼ 22d was hydrogenated using the H-Cube Pro™ with a RaNi
12.7, 8.3 Hz, 1H), 2.88–2.80 (m, 1H), 2.76 (d, J ¼ 15.0 Hz, 1H), catalyst at 1 mL minꢁ1 ow rate, 50 ꢀC and 10 bar H2 pressure.
2.56 (dd, J ¼ 17.4, 9.9 Hz, 1H), 1.46 (s, 2H). 13C NMR (CDCl3, 101 The MeOH was removed in vacuo to afford 23e as a clear oil;
MHz): d 173.8, 158.9, 153.3, 141.3, 130.6, 129.0, 114.0, 110.3, 84%.
1
106.6, 55.3, 48.4, 43.3, 42.8, 28.6. IR (cmꢁ1) 3285 (NH2), 3065,
LRMS (ESI+) m/z 292 (M + 1). H NMR (CDCl3, 400 MHz): d
2933, 2836 (CH), 1643 (CO), 1612 (C]C), 1548, 1511 (NH bend), 8.97 (s, NH), 8.03 (s, NH), 7.26 (t, J ¼ 3.2 Hz, 2H), 7.10 (d, J ¼ 8.4
1463, 1440 (CH2), 1301 (CH3), 1243 (C–O), 1175 (C–O), 1030 (C– Hz, 2H), 6.62 (dd, J ¼ 4.1, 2.6 Hz, 1H), 6.07 (dd, J ¼ 5.6, 2.8 Hz,
O–C), 808 (p-C Ph).
1H), 5.89 (s, 1H), 4.38 (qd, J ¼ 15.1, 5.9 Hz, 2H), 3.12–2.64 (m,
3-Amino-2-(furan-2-ylmethyl)-N-(4-chlorobenzyl)propanamide 4H), 2.47 (td, J ¼ 9.1, 4.5 Hz, 1H), 1.57 (s, 2H). 13C NMR (CDCl3,
(23b). 2-Cyano-3-(furan-2-yl)-N-(4-chlorobenzyl)acrylamide 22b 101 MHz): d 175.4, 137.0, 133.0, 128.8, 128.8, 117.0, 107.7, 106.4,
was hydrogenated using the H-Cube Pro™ with a RaNi catalyst at 48.4, 43.9, 42.6, 27.9. IR (cmꢁ1) 3287 (NH), 3084, 3035 2923,
1 mL minꢁ1 ow rate, 50 ꢀC and 10 bar H2 pressure. The MeOH 2860 (CH), 1644 (CO), 1540, 1514 (C]C), 1434 (CH2), 808 (p-C
was removed in vacuo to afford 23b as a clear oil; 83%.
Ph), 519 (Cl–C Ph).
1
LRMS (ESI+) m/z 293 (M + 1). H NMR (CDCl3, 400 MHz): d
2-(3-Fluorophenyl)-3-(1H-pyrrol-2-yl)propan-1-amine (23f).
7.33–7.27 (m, 2H), 7.24 (d, J ¼ 1.8 Hz, 1H), 7.11 (d, J ¼ 8.4 Hz, (E)-2-Cyano-3-(furan-2-yl)-N-(4-methoxybenzyl)acrylamide 22e
2H), 6.26 (dd, J ¼ 3.0, 2.0 Hz, 1H), 6.04 (d, J ¼ 2.9 Hz, 1H), 4.45 was hydrogenated using the H-Cube Pro™ with a RaNi catalyst
(dd, J ¼ 9.6, 5.7 Hz, 1H), 4.29 (dd, J ¼ 15.1, 5.4 Hz, 1H), 3.06–3.01 at 1 mL minꢁ1 ow rate, 50 ꢀC and 10 bar H2 pressure. The
(m, 1H), 2.94 (dt, J ¼ 21.5, 8.4 Hz, 2H), 2.80 (dd, J ¼ 15.0, 7.2 Hz, MeOH was removed in vacuo to afford 23f as a yellow oil; 100%.
1H), 2.67 (dd, J ¼ 7.8, 4.3 Hz, 1H), 2.39 (br s, 2H). 13C NMR
LRMS (ESI+) m/z 219 (M + 1). 1H NMR (Acetone, 400 MHz): d
(CDCl3, 101 MHz): d 173.9, 152.9, 141.4, 137.0, 129.0, 128.7, 8.60 (s, 1H), 7.39–7.22 (m, 1H), 7.05–6.87 (m, 3H), 6.61 (dd, J ¼
127.6, 110.4, 106.8, 47.5, 42.9, 42.6, 28.6. IR (cmꢁ1) 3330 (NH), 3.9, 2.4 Hz, 1H), 6.10 (dd, J ¼ 5.5, 2.8 Hz, 1H), 5.88 (s, 1H), 3.06–
3121, 3014, 2931, 2834 (CH), 16412 (CO), 1615 (C]C), 1552 (C] 2.82 (m, 5H). 13C NMR (acetone, 101 MHz): d 164.3, 146.0, 130.2,
C), 1462, 1430 (CH2), 1223 (C–O), 813 (p-C Ph), 547 (Cl–C Ph).
129.7, 123.6, 116.6, 114.5, 113.6, 108.1, 106.4, 49.5, 46.9, 32.3. IR
3-Amino-2-(furan-2-ylmethyl)-N-(4-methylbenzyl)propanamide (cmꢁ1) 3288 (NH), 3029, 2965 (CH), 1612, 1515 (C]C), 1049 (F–
(23c). 2-Cyno-3-(furan-2-yl)-N-(4-methylbenzyl)acrylamide (22c) C Ph), 759 (m-C Ph).
was hydrogenated using the H-Cube Pro™ with a RaNi catalyst at 1
3-Amino-2-(thiophene-2-ylmethyl)-N-(4-methoxybenzyl)prop-
mL minꢁ1 ow rate, 50 ꢀC and 10 bar H2 pressure. The MeOH was anamide (23g). (E)-2-Cyano-3-(thiophene-2-yl)-N-(4-methoxy-
removed in vacuo to afford 23c as a clear oil, 85%.
benzyl)acrylamide 32 was hydrogenated using the H-Cube
LRMS (ESI+) m/z 273 (M + 1). H NMR (CDCl3, 400 MHz): d Pro™ with a RaNi catalyst at 1 mL minꢁ1 ow rate, 50 ꢀC and 10
7.28–7.26 (m, 1H), 7.19–7.09 (m, 4H), 6.27 (t, J ¼ 2.2 Hz, 1H), bar H2 pressure. The MeOH was removed in vacuo to afford 23g
6.02 (d, J ¼ 3.1 Hz, 1H), 4.43–4.31 (m, 2H), 3.04 (dd, J ¼ 15.1, 7.4 as a clear oil, 88%.
1
Hz, 1H), 2.92 (dd, J ¼ 12.7, 8.4 Hz, 1H), 2.85 (dd, J ¼ 7.8, 4.8 Hz,
LRMS (ESI+) m/z 305 (M + 1). 1H NMR (acetone, 400 MHz): d
1H), 2.77 (dd, J ¼ 15.1, 7.4 Hz, 1H), 2.56 (qd, J ¼ 7.6, 4.1 Hz, 1H), 7.59 (s, 1H), 7.23 (dd, J ¼ 5.1, 1.0 Hz, 2H), 7.13 (d, J ¼ 8.7 Hz,
2.32 (s, 3H), 1.35 (br s, NH). 13C NMR (CDCl3, 101 MHz): d 173.9, 2H), 6.91 (dd, J ¼ 5.1, 3.4 Hz, 1H), 6.83–6.81 (m, 2H), 4.29 (dd, J
153.3, 141.3, 136.9, 135.4, 129.26, 127.6, 110.3, 106.6, 48.4, 43.3, ¼ 25.4, 5.9 Hz, 2H), 3.76 (d, J ¼ 1.2 Hz, 3H), 3.74 (d, J ¼ 0.9 Hz,
43.1, 28.6, 21.1. IR (cmꢁ1) 3305 (NH), 3121, 3020, 2931, 2834 1H), 3.41 (dd, J ¼ 14.0, 7.9 Hz, 1H), 3.30 (d, J ¼ 7.5 Hz, 1H), 3.21–
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3.16 (m, 1H), 3.04 (dd, J ¼ 14.6, 6.2 Hz, 1H), 1.28 (s, 2H). 13C 28.6. IR (cmꢁ1) 3295 (NH), 3091 (OH), 2985, 2937 (CH), 1692
NMR (Acetone, 101 MHz): d 173.2, 158.7, 142.6, 131.6, 128.6, (CO), 1651 (C]C), 1562, 1514 (NH bend), 1302 (CH3), 1247 (C–
128.5, 126.6, 125.4, 123.43, 113.5, 54.6, 53.0, 50.1, 41.9, 30.3. IR O), 1032 (CH3), 818 (p-C Ph), 731 (CH2 bend).
(cmꢁ1) 3285 (NH), 3106, 3056, 2834 (CH), 1645 (CO), 1612, 1534
3-(2-(Furan-2-ylmethyl)-3-(4-chlorobenzylamino)-3-oxopro-
(C]C), 1415 (CH2), 1319 (CH3), 1250 (C–O), 1030 (C–O–C), 812 pylcarbamoyl)-7-oxabicyclo[2.2.1]heptane-2-carboxylic acid
(p-C Ph). (24b). Synthesised as described in general procedure 7 – sequen-
3-Amino-2-(thiophene-2-ylmethyl)-N-(4-methylbenzyl)prop- tial reaction Path B to afford 16b as a white solid (diastereomers
anamide (23h). (E)-2-Cyano-3-(thiophene-2-yl)-N-(4-methyl- collected in a 1 : 1 ratio); 0.3 g, overall yield 56%; mp 166 ꢀC.
benzyl)acrylamide 22f was hydrogenated using the H-Cube
MS (ESIꢁ) m/z 459 (M ꢁ 1). 1H NMR (DMSO-d6, 400 MHz): d
Pro™ with a RaNi catalyst at 1 mL minꢁ1 ow rate, 50 ꢀC and 10 11.91 (br s, OH), 8.45 (t, J ¼ 6.0 Hz, NH), 7.66 (t, J ¼ 5.8 Hz, NH),
bar H2 pressure. The MeOH was removed in vacuo to afford 23h 7.50 (d, J ¼ 1.1 Hz, 1H), 7.32 (dd, J ¼ 8.3, 1.5 Hz, 1H), 7.16 (t, J ¼
as a yellow oil; 100%.
8.6 Hz, 2H), 6.35 (t, J ¼ 11.7, 2.9 Hz, 1H), 6.09 (dd, J ¼ 11.7, 2.9
1
LRMS (ESI+) m/z 289 (M + 1). H NMR (CDCl3, 400 MHz): d Hz, 1H), 4.72 (dd, J ¼ 3.5, 2.4 Hz, 1H), 4.40 (d, J ¼ 3.4 Hz, 1H),
7.12 (dd, J ¼ 5.1, 1.0 Hz, 1H), 7.08 (d, J ¼ 7.8 Hz, 2H), 7.02 (d, J ¼ 4.30–4.14 (m, 2H), 3.27–3.18 (m, 2H), 3.06–3.01 (m, 1H), 2.85–
7.9 Hz, 2H), 6.90 (dd, J ¼ 5.1, 3.5 Hz, 1H), 6.79 (d, J ¼ 3.0 Hz, 2.67 (m, 5H), 1.56–1.47 (m, 4H). 13C NMR (DMSO-d6, 101 MHz):
1H), 4.39–4.31 (m, 2H), 3.28–3.13 (m, 1H), 3.04–2.88 (m, 2H), d 173.1, 173.0*, 171.3, 171.2*, 153.6, 153.6*, 142.0, 139.0,
2.53–2.42 (m, 1H), 2.31 (s, 3H), 2.28 (dd, J ¼ 11.7, 5.2 Hz, 1H), 138.9*, 131.6, 129.5, 129.4*, 128.5, 127.6, 110.8, 106.7, 106.6*,
1.38–1.17 (m, 2H). 13C NMR (CDCl3, 101 MHz): d 173.7, 141.9, 79.3, 79.2*, 77.2, 77.2*, 53.6, 53.3*, 51.9, 51.6*, 45.3, 45.0*, 41.8,
135.3, 129.3, 127.6, 126.9, 125.8, 123.8, 114.1, 51.7, 43.3, 43.2, 41.3*, 29.4, 29.2*, 28.9, 28.8, 28.6*. IR (cmꢁ1) 3309 (NH), 3063
30.3, 21.1. IR (cmꢁ1) 3238 (NH), 3054, 3020 (CH), 1650 (CO), (OH), 2984, 2967, 2920, 2879 (CH), 1729 (CO), 1692 (CO), 1647
1580, 1512 (C]C), 1426 (CH2), 1360 (CH3), 808 (p-C Ph).
3-Amino-2-(thiophene-2-ylmethyl)-N-(4-biphenyl)propanamide 737 (CH2 bend), 696 (C–Cl). *Diastereomers peaks.
(23i). (E)-2-Cyano-3-(furan-2-yl)-N-(4-methoxybenzyl)acrylamide 22i 3-(2-(Furan-2-ylmethyl)-3-(4-methylbenzylamino)-3-oxopro-
(C]C), 1537 (NH bend), 1247 (C–O), 1183 (C–O), 819 (p-C Ph),
was hydrogenated using the H-Cube Pro™ with a RaNi catalyst at 1 pylcarbamoyl)-7-oxabicyclo[2.2.1]heptane-2-carboxylic acid (24c).
mL minꢁ1 ow rate, 50 ꢀC and 10 bar H2 pressure. The MeOH was Synthesised as described in general procedure 7 – sequential
removed in vacuo to afford 23g as a clear oil; 83%.
reaction path B to afford 24c as a white solid (diastereomers
1
LRMS (ESI+) m/z 340 (M + 1). H NMR (CDCl3, 400 MHz): d collected in a 1 : 1 ratio); 0.42 g, overall yield 60%; mp 166–
ꢀ
7.56–7.48 (m, 3H), 7.45–7.32 (m, 5H), 7.21 (d, J ¼ 8.1 Hz, 1H), 167 C.
7.13 (dd, J ¼ 3.8, 1.3 Hz, 1H), 6.98–6.86 (m, 1H), 6.82 (d, J ¼ 3.0
MS (ESIꢁ) m/z 439 (M ꢁ 1). 1H NMR (DMSO-d6, 400 MHz): d
Hz, 1H), 4.51–4.38 (m, 2H), 3.26 (dd, J ¼ 9.3, 5.2 Hz, 1H), 3.02– 11.92 (br s, OH), 8.37 (t, J ¼ 5.6 Hz, NH), 8.22 (t, J ¼ 5.5 Hz, NH)*,
2.91 (m, 2H), 2.83 (d, J ¼ 12.0 Hz, 1H), 2.51 (dd, J ¼ 7.4, 4.3 Hz, 7.62 (t, J ¼ 5.6 Hz, NH), 7.42 (t, J ¼ 5.4 Hz, NH)*, 7.12–7.01 (m,
1H). 13C NMR (CDCl3, 101 MHz): d 173.8, 140.8, 140.3, 137.8, 4H), 6.34 (s, 1H), 6.10 (dd, J ¼ 12.0, 2.7 Hz, 1H), 4.72 (d, J ¼ 10.0
137.4, 128.8, 128.1, 128.0, 127.4, 127.1, 123.8, 31.9, 30.2, 22.5, Hz, 1H), 4.41 (s, 1H), 4.27–4.13 (m, 2H), 3.25–3.21 (m, 2H), 3.06–
14.0. IR (cmꢁ1) 3287 (NH), 3060, 2930, 2858 (CH), 1643 (CO), 3.03 (m, 2H), 2.85–2.68 (m, 5H), 2.26 (s, 3H), 1.56–1.40 (m, 4H).
1612, 1511 (C]C), 1462 (CH2), 1440 (CH2), 818 (p-C Ph).
13C NMR (DMSO-d6, 101 MHz) d 173.0, 172.9*, 172.9, 172.8*,
171.3, 171.2*, 153.7, 153.7*, 141.9, 141.9*, 136.8, 136.7*, 136.1,
136.0*, 129.2, 127.6*, 110.8, 106.5, 106.6*, 79.3, 79.2*, 77.2,
77.2*, 53.6, 53.3*, 52.0, 51.7*, 45.2, 45.0*, 42.3, 41.3, 31.2, 29.4,
General procedure 7 – reaction path B
3-(2-(Furan-2-ylmethyl)-3-(4-methoxybenzylamino)-3-oxopro- 29.2*, 28.9, 28.8*, 28.8, 28.6*, 21.1. IR (cmꢁ1) 3306 (NH), 3001
pylcarbamoyl)-7-oxabicyclo[2.2.1]heptane-2-carboxylic acid (24a). (OH), 2984, 2947, 2919, 2871 (CH), 1729 (CO), 1692 (CO), 1644
3-Amino-2-(furan-2-ylmethyl)-N-(4-methoxybenzyl)propanamide (C]C), 1537 (NH bend), 1381 (CH3), 1251 (C–O), 1180 (C–O),
(23a) (0.35 g, 1.2 mmol) and norcantharidin (2) (0.20 g, 1.8 835 (p-Ar), 738 (CH2 bend). *Diastereomers peaks.
mmol) were dissolved separately in acetone (10 mL ꢂ 2) and the
solutions were added together and the reaction was le to stir at
room temperature for 4 hours. The solution was ltered and
General procedure 8 – reaction path B, with selective nitrile
and olen reduction of thiophene and pyrrole based
analogues
washed with cold acetone and dried under suction to afford 24a
ꢀ
as a white solid; 0.30 g, 55%; mp 168–170 C.
MS (ESIꢁ) m/z 455 (M ꢁ 1). 1H NMR (DMSO-d6, 400 MHz): d
3-(2-(Pyrrole-2-ylmethyl)-3-(4-methoxybenzylamino)-3-oxo-
11.91 (br s, OH), 8.21 (t, J ¼ 5.4 Hz, NH), 7.49 (d, J ¼ 1.0 Hz, NH), propylcarbamoyl)-7-oxabicyclo[2.2.1]heptane-2-carboxylic acid
7.40 (t, J ¼ 5.9 Hz, NH), 7.07 (d, J ¼ 8.6 Hz, 2H), 6.83 (d, J ¼ 8.6 (24d).
3-Amino-2-(pyrrole-2-ylmethyl)-N-(4-methoxybenzyl)
Hz, 2H), 6.34 (dd, J ¼ 3.0, 1.9 Hz, 1H), 6.08 (d, J ¼ 2.9 Hz, 1H), propanamide 22d (0.14 g, 0.50 mmol) was dissolved in sufficient
4.73 (d, J ¼ 3.7 Hz, 1H), 4.40 (d, J ¼ 3.8 Hz, 1H), 4.22 (dd, J ¼ EtOH : EtoAc (1 : 1) (10 mL) to form a 0.05 M solution. This
14.9, 6.0 Hz, 1H), 4.11 (dd, J ¼ 14.9, 5.6 Hz, 1H), 3.72 (s, 3H), solution was hydrogenated using the H-Cube Pro™ with a RaNi
3.24–3.18 (m, 1H), 3.07–2.99 (m, 1H), 2.83 (s, 2H), 2.77–2.68 (m, catalyst at 1 mL minꢁ1 ow rate, 70 ꢀC and 70 bar H2 pressure.
3H), 1.57–1.40 (m, 4H). 13C NMR (DMSO-d6, 101 MHz) d 173.0, The solvent was removed in vacuo and to afford 2-((1H-pyrrol-
172.7, 171.3, 158.6, 153.7, 141.9, 131.7, 128.9, 114.0, 110.8, 2-yl)methyl)-3-amino-N-(4-methoxybenzyl)propanamide as
a
106.6, 79.3, 77.2, 55.5, 53.6, 52.0, 45.2, 42.0, 41.3, 29.2, 28.8, yellow oil, 0.11 g, 77%. The crude product and norcantharidin
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(2) (0.20 g, 1.8 mmol) were dissolved separately in acetone sequential reaction Path B to afford 24g as a white solid; 0.1 g,
ꢀ
(10 mL ꢂ 2) and the solutions were added together and the overall yield 41%; mp 158–159 C.
reaction was le to stir at room temperature for 4 hours. The
MS (ESIꢁ) m/z 471 (M ꢁ 1).1 H NMR (DMSO-d6, 400 MHz): d
solution was ltered and washed with cold acetone and dried 11.89 (br s, 1H), 8.33 (t, J ¼ 4.7 Hz, NH), 8.20 (t, J ¼ 5.6 Hz, NH)*,
under suction to afford 24d as a white solid; 0.18 g, overall yield 7.58 (t, J ¼ 5.9 Hz, NH), 7.40 (t, J ¼ 6.2 Hz, NH)*, 7.30 (d, J ¼ 5.2
26%; mp 166 ꢀC.
Hz, 1H), 7.25 (t, J ¼ 6.0 Hz, 1H)*, 7.17 (d, J ¼ 8.5 Hz, 2H), 7.03 (t,
MS (ESIꢁ) m/z 517 (M ꢁ 1). 1H NMR (DMSO-d6, 400 MHz): d J ¼ 8.2 Hz, 2H), 6.98–6.87 (m, 1H), 6.90–6.74 (m, 3H), 4.72 (d, J ¼
11.89 (br s, OH), 10.39 (s, NH), 8.20 (t, J ¼ 5.5 Hz, NH), 8.07 (t, J 9.9 Hz, 1H), 4.41 (d, J ¼ 2.8 Hz, 1H)*, 4.37 (d, J ¼ 4.0 Hz, 1H)*,
¼ 5.3 Hz, NH)*, 7.50 (t, J ¼ 5.4 Hz, NH), 7.29 (t, J ¼ 5.3 Hz, NH)*, 4.23–4.09 (m, 2H), 3.71 (s, 3H), 3.26–3.17 (m, 1H), 3.05 (dd, J ¼
7.07 (d, J ¼ 8.4 Hz, 2H), 6.82 (d, J ¼ 8.5 Hz, 2H), 6.55 (s, 2H), 12.8, 7.5 Hz, 1H), 3.01–2.93 (m, 1H), 2.93–2.66 (m, 4H), 1.55–
5.90–5.75 (m, 2H), 4.71 (s, 1H), 4.39 (s, 1H), 4.23–4.13 (m, 2H), 1.38 (m, 4H). 13C NMR (DMSO-d6, 101 MHz): 172.9, 172.8, 171.2,
3.71 (s, 3H), 3.21–3.15 (m, 1H), 3.07 (dd, J ¼ 12.0, 5.7 Hz, 1H), 158.5, 142.1, 142.0*, 131.8, 129.0*, 128.9, 127.2, 126.0, 124.4,
2.86–2.61 (m, 5H), 1.55–1.39 (m, 4H). 13C NMR (DMSO-d6, 101 114.0, 79.2, 77.3, 55.5, 53.4, 48.0, 42.0, 41.3, 30.4, 29.4, 28.9,
MHz): d 174.0, 173.0, 172.8, 171.2, 142.1, 142.02, 140.5, 139.4, 22.5. IR (cmꢁ1) 3308 (NH), 3078 (OH), 2984, 2964, 2921, 2874
139.1, 139.0, 129.4, 128.4, 128.3, 128.2, 127.8, 127.2, 127.0, (CH), 1694 (CO), 1646 (C]C), 1545, (NH bend), 1382 (CH3),
126.9, 126.0, 124.5, 79.3, 79.2, 77.2, 53.7, 53.3, 51.8, 48.4, 48.1, 1242 (C–O), 817 (p-C Ph). * Diastereomers peaks.
42.2, 41.4, 31.7, 30.4, 29.4, 29.2, 28.9, 26.8, 22.5, 14.3. IR (cmꢁ1
)
3-(2-(Thiophene-2-ylmethyl)-3-(4-methylbenzylamino)-3-oxo-
3432 (NH), 3306 (NH), 3074 (OH), 2992, 2937, 2882, 2834 (CH), propylcarbamoyl)-7-oxabicyclo[2.2.1]heptane-2-carboxylic acid
1685 (CO), 1653 (CO), 1635 (C]C), 1538, 1513 (NH bend), 1302 (24h). Synthesised as described in general procedure 8 –
(CH3), 1245, 1223 (C–O), 806 (p-C Ph). *Diasteromer peaks.
sequential reaction Path B to afford 24h as a white solid (dia-
3-(2-(Pyrrole-2-ylmethyl)-3-(4-chlorobenzylamino)-3-oxopro- stereomers collected in a 1 : 1 ratio); 0.13 g, overall yield 38%;
pylcarbamoyl)-7-oxabicyclo[2.2.1]heptane-2-carboxylic acid (24e). mp 161–163 ꢀC.
Synthesised as described in general procedure 8 – sequential
MS (ESIꢁ) m/z 455 (M ꢁ 1). 1H NMR (DMSO-d6, 400 MHz): d
reaction Path B to afford 24e as a pale brown solid (diastereo- 11.91 (br s, OH), 8.33 (t, J ¼ 5.8 Hz, NH)*, 8.2 (t, J ¼ 5.8 Hz, NH),
mers collected in a 1 : 0.7 ratio); 0.1 g, overall yield 27%; mp 7.61 (t, J ¼ 5.7 Hz, NH)*, 7.41 (t, J ¼ 5.8 Hz, NH), 7.32 (dd, J ¼
129–131 ꢀC.
5.1, 0.8 Hz, 1H), 7.05 (d, J ¼ 7.9 Hz, 2H), 6.98 (t, J ¼ 8.5 Hz, 2H),
MS (ESIꢁ) m/z 459 (M ꢁ 1). 1H NMR (DMSO-d6, 400 MHz): d 6.94–6.90 (m, 1H), 6.83 (dd, J ¼ 8.9, 2.9 Hz, 1H), 4.75–4.69 (m,
11.94 (br s, OH), 8.45 (t, J ¼ 6.1 Hz, NH), 8.30 (t, J ¼ 5.8 Hz, NH), 1H)*, 4.42 (d, J ¼ 3.3 Hz, 1H), 4.27–4.11 (m, 2H), 3.27–3.19 (m,
7.67 (t, J ¼ 5.6 Hz, NH), 7.43 (t, J ¼ 5.7 Hz, NH), 7.32 (d, J ¼ 8.3 1H), 3.09–2.95 (m, 2H), 2.89 (dd, J ¼ 12.3, 6.9 Hz, 1H), 2.84–2.67
Hz, 2H), 7.17 (t, J ¼ 8.5 Hz, 2H), 6.14 (d, J ¼ 2.9 Hz, 1H), 6.01 (dd, (m, 2H), 2.51–2.49 (m, 2H), 2.25 (s, 3H), 1.57–1.40 (m, 4H). 13
C
J ¼ 12.6, 2.9 Hz, 1H), 5.11 (t, J ¼ 5.5 Hz, 1H), 4.74 (d, J ¼ 3.1 Hz, NMR (DMSO-d6, 101 MHz): d 172.9, 172.8*, 172.7, 171.2*, 171.1,
1H), 4.71 (s, 1H), 4.41 (d, J ¼ 12.9 Hz, 1H), 4.31 (d, J ¼ 5.2 Hz, 142.1, 142.0*, 136.8, 136.6*, 136.1, 136.0*, 129.1, 127.6, 127.2*,
2H), 4.29–4.14 (m, 2H), 3.26–3.20 (m, 1H), 3.06 (d, J ¼ 5.4 Hz, 126.0, 124.4, 80.1, 79.3, 79.2*, 77.2, 77.2*, 53.6, 53.3*, 51.9,
1H), 2.87–2.67 (m, 5H), 1.57–1.41 (m, 4H). 13C NMR (DMSO-d6, 51.7*, 51.2, 48.3, 48.0*, 42.3, 41.3*, 30.4, 30.2*, 29.4, 29.2*, 28.9,
101 MHz): d 173.5, 173.1*, 173.0, 172.9*, 171.3, 171.2*, 154.4, 28.8*, 21.1. IR (cmꢁ1) 3310 (NH), 3062 (OH), 2986, 2963, 2920,
152.9, 152.8*, 139.0, 138.9*, 131.6, 129.5, 129.4*, 128.6, 128.5*, 2874 (CH), 1695 (CO), 1646 (C]C), 1545, (NH bend), 1382
127.6, 108.0, 107.1*, 80.1, 79.3, 79.2*, 77.2, 56.1, 53.6, 53.2*, (CH3), 1244 (C–O), 816 (p-C Ph). *Diastereomers peaks.
51.9, 51.6*, 51.2, 45.1, 44.9*, 41.9, 41.3*, 31.2, 29.2*, 28.9, 28.8*,
3-(2-(Thiophene-2-ylmethyl)-3-(4-biphenylamino)-3-oxopro-
28.8, 27.9*. IR (cmꢁ1) 3292 (NH), 3087 (OH), 2987, 2984, 2920, pylcarbamoyl)-7-oxabicyclo[2.2.1]heptane-2-carboxylic acid (24i).
2875 (CH), 1702 (CO), 1646 (C]C), 1545, 1494 (NH bend), 1240, Synthesised as described in general procedure 8 – sequential
1200 (C–O), 1170 (C–O), 799 (p-C Ph). *Diastereomers peaks.
reaction Path B to afford 24i as a white solid (diastereomers
3-(2-(pyrrole-2-ylmethyl)-3-(3-uorophenyl))-7-oxabicyclo- collected in a 1 : 1 ratio); 0.23 g, overall yield 46%; mp 171–174 ꢀC.
[2.2.1]heptane-2-carboxylic acid (24f). Synthesised as described
1H NMR (DMSO-d6, 400 MHz): d 11.89 (br s, OH), 8.44 (t, J ¼
in general procedure 8 – sequential reaction Path B to afford 24f 5.3 Hz, NH), 8.31 (t, J ¼ 5.6 Hz, NH)*, 7.63 (d, J ¼ 7.9 Hz, 2H),
as a yellow oil, 0.08 g, overall yield 15%.
7.61 (d, J ¼ 2.1 Hz, 1H)*, 7.59 (d, J ¼ 2.3 Hz, 1H), 7.54 (d, J ¼ 8.2
MS (ESIꢁ) m/z 385 (M ꢁ 1). 1H NMR (CDCl3, 400 MHz): d 8.35 Hz, 2H), 7.46 (d, J ¼ 7.6 Hz, 2H), 7.35 (dd, J ¼ 8.8, 6.2 Hz, 2H),
(br s, NH), 7.27–7.24 (m, 1H), 6.94 (td, J ¼ 8.1, 2.2 Hz, 2H), 6.90– 7.18 (t, J ¼ 8.6 Hz, 2H), 6.97–6.91 (m, 1H), 6.85 (dd, J ¼ 8.7, 3.2
6.85 (m, 1H), 6.63 (dd, J ¼ 4.0, 2.8 Hz, 1H), 6.06 (dd, J ¼ 6.0, 2.8 Hz, Hz, 1H), 4.73 (d, J ¼ 11.1 Hz, 1H), 4.50–4.40 (m, 1H), 4.37–4.09
1H), 5.77 (s, 1H), 4.83 (dt, J ¼ 5.2, 2.8 Hz, 2H), 3.77 (dd, J ¼ 13.4, 8.4 (m, 2H). 3.25 (d, J ¼ 7.0 Hz, 1H), 3.08 (dd, J ¼ 8.0, 5.2 Hz, 1H),
Hz, 1H), 3.66 (dd, J ¼ 13.4, 6.4 Hz, 1H), 3.42–3.33 (m, 1H), 2.91 (d, J 2.96–2.71 (m, 5H), 1.46–1.37 (m, 2H), 1.27–1.17 (m, 2H). 13C
¼ 6.9 Hz, 2H), 2.76 (d, J ¼ 7.3 Hz, 2H), 1.90–1.83 (m, 2H), 1.60 (q, J NMR (DMSO-d6, 101 MHz): d 174.0, 173.0, 172.8, 171.2, 142.1,
¼ 6.4 Hz, 2H). 13C NMR (CDCl3, 101 MHz): d 177.4, 177.4, 162.8 (d, 142.02, 140.5, 139.4, 139.1, 139.0, 129.4, 128.4, 128.3, 128.2,
J ¼ 246 Hz), 143.9, 130.0, 128.8, 123.5, 116.7, 114.7, 114.1, 108.3, 127.8, 127.2, 127.0, 126.9, 126.0, 124.5, 79.3, 79.2, 77.2, 53.7,
106.9, 79.1, 77.2, 49.8, 49.8, 43.6, 31.4, 28.6, 28.5.
53.3, 51.8, 48.4, 48.1, 42.2, 41.4, 31.7, 30.4, 29.4, 29.2, 28.9, 26.8,
3-(2-(Thiophene-2-ylmethyl)-3-(4-methoxybenzylamino)-3-oxo- 22.5, 14.3. IR (cmꢁ1) 3316 (NH), 3070 (OH), 3033, 2985, 2923,
propylcarbamoyl)-7-oxabicyclo[2.2.1]heptane-2-carboxylic acid 2876 (CH), 1691 (CO), 1646 (C]C), 1534, 1487 (NH bend), 1242,
(24g). Synthesised as described in general procedure 8 – (C–O), 819 (p-C Ph). *Diastereomers peaks.
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23 S. G. Stewart, T. A. Hill, J. Gilbert, S. P. Ackland, J. A. Sakoff
and A. McCluskey, Bioorg. Med. Chem., 2007, 15, 7301.
24 M. Tarleton, J. Gilbert, J. A. Sakoff and A. McCluskey, Eur. J.
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25 B. Sauer, J. Gilbert, J. A. Sakoff and A. McCluskey, Lett. Drug
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Acknowledgements
This project as supported by the Australian Cancer Research
Foundation, Ramaciotti Foundation and the Australian
Research Council. CPG is the recipient of an ARC DECRA
fellowship. LH acknowledges the receipt of a Postgraduate
Scholarship from the University of Newcastle.
26 L. Deng, Z. Yong, W. Tao, J. Shen and W. Wang, J. Heterocycl.
Chem., 2010, 48, 158.
27 A. Thaqi, J. L. Scott, J. Gilbert, J. A. Sakoff and A. McCluskey,
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9722 | RSC Adv., 2014, 4, 9709–9722
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