Intramolecular Nitrofuran Diels-Alder Reactions: Extremely Substituent-Tolerant Cycloadditions via Asynchronous Transition States

Article abstract of DOI:10.1021/acs.joc.7b00781

Nitrofurans undergo intramolecular Diels-Alder reactions with tethered electron-poor dienophiles more rapidly and in higher yield than non-nitrated furans. Computational studies indicate that increased stabilization of a partial positive charge on the nitro-substituted carbon in both transition state and product is the driving force for these reactions. Frontier molecular orbital energy differences indicate a switch from normal to inverse electron demand upon nitration. There does not appear to be a contribution from any differences in aromatic stabilization energy between furans and nitrofurans. Calculations show that the nitrofuran reactions proceed via a highly asynchronous transition state allowing easier bond formation between two sterically hindered carbons.

Full text of DOI:10.1021/acs.joc.7b00781

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Article
Intramolecular Nitrofuran Diels-Alder reactions: extremely substituent-
tolerant cycloadditions from asynchronous transition states
Thomas Y. Cowie, Marcos Veguillas Hernando, Robert L. Rae, Mathilde Rouge, Justyna
M Zurek, Andrew W. Prentice, Martin J. Paterson, and Magnus W. P. Bebbington
J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 02 Jun 2017
Downloaded from http://pubs.acs.org on June 2, 2017
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Intramolecular Nitrofuran Diels-Alder reactions: extremely
substituent-tolerant cycloadditions via asynchronous
transition states
Thomas Y. Cowie, Marcos Veguillas, Robert L. Rae, Mathilde Rougé, Justyna M. Żurek,
Andrew W. Prentice, Martin J. Paterson*a and Magnus W. P. Bebbington*a
a
School of EPSꢀChemical Sciences, Heriot Watt University, Edinburgh, EH14 4AS, UK
m.j.paterson@hw.ac.uk
m.w.p.bebbington@hw.ac.uk
Abstract: Nitrofurans undergo intramolecular DielsꢀAlder reactions with tethered
electronꢀpoor dienophiles more rapidly and in higher yield than nonꢀnitrated furans.
Computational studies indicate that increased stabilization of a partial positive
charge on the nitroꢀsubstituted carbon in both transition state and product is the
driving force for these reactions. Frontier molecular orbital energy differences
indicate a switch from normal to inverse electron demand upon nitration. There does
not appear to be a contribution from any differences in aromatic stabilization energy
between furans and nitrofurans. Calculations show that the nitrofuran reactions
proceed via a highly asynchronous transition state allowing easier bond formation
between two sterically hindered carbons.
Introduction
The DielsꢀAlder reaction remains one of the most widely–used and powerful reactions
in organic chemistry.1 The use of furan as both a diene and a dienophile has been
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studied extensively, with many applications in target synthesis.2,3 For the majority of
DielsꢀAlder reactions employing nonꢀaromatic dienes, frontier orbital energies and
coefficients are readily used to explain reactivity and selectivity.1 In contrast, a
number of experimental and computational reports4 on intramolecular DielsꢀAlder
reaction of furan (IMDAF) indicate that other factors, including tether substitution can
override frontier orbital considerations in certain cases. Padwa and Houk first
identified positive charge stabilization as being a kinetic and thermodynamic driving
force in reactions of halofurans.5 We identified a dipolar interaction term (Scheme 1)
as an additional factor in halofuran/haloalkene IMDAF reactions.6 We also discovered
a correlation between transition state structure and energy that was consistent with
the late transition state indicated in previous reports.7 We now report the results of our
investigations in intramolecular nitrofuran cycloadditions.
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Scheme 1 a) Unfavorable and b) favorable dipolar interactions
affecting IMDAF transition states in haloalkene IMDAF reactions6
There have been a number of reports of the use of nitrofurans in intramolecular Dielsꢀ
Alder reactions,8 but dienophile substitution has not been widely studied and the
reactions have not been fully analyzed by modern computational methods.
Furthermore, the relative reactivity of nitrofurans and their nonꢀnitrated counterparts is
yet to be analysed in any detail.9 The variables affecting the IMDAF reaction are
more complex than those involving nonꢀaromatic dienes, but there is much evidence
indicating that furan most often behaves as an electronꢀrich diene,2,10 reacting with
electronꢀpoor dienophiles most rapidly. Intuitively, one might therefore expect that
incorporation of a nitroꢀsubstituent would retard or prevent the reaction entirely.
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Indeed, to the best of our knowledge there are no reports of intermolecular Dielsꢀ
Alder reactions involving nitrofurans as dienes.11 Our results indicate, however, that
this intuition is incorrect for the substrates studied herein.
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Results and discussion
A series of IMDAF precursors 1a-n and 2a-n were synthesised starting from either
furfural or 5ꢀnitrofurfural to afford the required nitrated and nonꢀnitrated IMDAF
substrates (see supporting information for details). The IMDAF precursors were
heated in toluene at reflux and conversions to adducts 3a-n and 4a-n given at the
1
times indicated in Tables 1 and 2 (as measured by H NMR spectroscopy). Isolated
yields are in parentheses.12
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Ph
Ph
N
O
O
N
5
6
7
8
O
O
X
X
3a
X = H 3 h, 33% conversion;
24 h 93%,a (70% isolated yield)
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1a X = H
2a
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X = NO2
4a
X = NO2 3 h, 49%;
24 h, 100% (quant.)
Ph
Ph
N
O
O
N
O
O
X
Pr
Pr
X
3b
X = H 5 h, 9% conversion;
48 h, 28% (18)a
1b
2b
X = H
X = NO2
4b = NO2 5 h, 29% conversion;
48 h, 90% (67)a
Ph
Ph
N
O
O
N
O
O
X
X
3c X = H 2 h, 16% conversion
1c
2c
X = H
X = NO2
48 h, 60%; (54)b
4c
X = NO2 2 h, 74% conversion
24 h, 100% (78)
Ph
Ph
N
O
O
N
O
O
X
X
3d X = H 2 h, not observed;
45 h <10% (not isolated)
X = NO2 2 h, 40 % conversion;
26 h, 78% (43)a
1d
X = H
2d X = NO2
4d
Ph
N
Ph
O
O
N
O
O
X
X
3e
X = H 2 h, not observed;
27 h, not observed
1e X = H
2e
X = NO2
4e
X = NO2 2 h ~5% conversion;
27 h, 30% (27)a
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Table 1 Effect of alkyl substitution on nitrofuran and simple furan IMDAF reactions (all
reactions conducted in toluene at reflux)
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In all cases the nitroꢀsubstituted precursors reacted faster than their nonꢀnitro
analogues, as shown by the conversions at the early time points (recorded before
equilibrium was reached). We noted that it was not always possible to determine if the
reactions had reached equilibrium, because of significant decomposition (footnote a
in tables 1 and 2) concurrent with cycloaddition. However, in those cases where the
equilibrium position could be confirmed (where extended reaction time did not result
in decomposition, footnote b in tables 1 and 2), the equilibrium favored the adduct to
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a greater extent in the nitrated cases (substrates 3c/4c, 3g/4g, 3i/4i, 3j/4j, 3k/4k,
3l/4l). These effects are most striking in more substituted systems, despite the fact
that the nitrated adducts contain a fully substituted carbon adjacent to the carbon
bearing the substituents on the acrylic or cinnamic acid derivatives. Indeed, the nonꢀ
nitrated substrates do not tolerate simple alkyl substitution (Table 1) at all well, with
conversions less than 50% in most cases. By contrast, the nitro substrates are
capable of reacting to give very densely functionalized products. In the most extreme
case, nitrated substrate 2i even reacts to give partial conversion to the adduct 4i
,
which possesses four contiguous fully substituted carbons. By contrast the nonꢀnitro
substrate 1i was unreactive. Similarly, aryl substitution was tolerated far better in the
nitrated systems than the nonꢀnitro ones (Table 2), although the reactions were more
sluggish.
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Ph
3
4
5
Ph
O
N
N
O
O
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7
O
X
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X
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3j X = H 1 h, 6% conversion;
24 h, 9% (8)b
1j X = H
2j X = NO2
4j X = NO2 1 h, 17% conversion;
5 h, 28% (23)b
Ph
Ph
O
N
N
O
O
O
X
X
OMe
OMe
3k X = H 1 h, not detected;
24 h, <5% (not isolated)
4k X = NO2 1 h, 17% conversion;
24 h, 22% (17)b
1k X = H
2k X = NO2
Ph
Ph
O
N
N
O
O
O
X
X
NO2
NO2
3l X = H 3 h, not detected;
72 h, not detected
4l X = NO2, 3 h, 25% conversion;
72 h, 36% (32)b
1l X = H
2l X = NO2
Ph
Ph
O
N
N
O
O
O
X
X
1m X = H
2m X = NO2
3m X = H 120 h, not detected
4m X = NO2 ~5% conversion, 120 h
(not isolated)
b Equilibrium reached, no further conversion
nor noticeable decomposition
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Table 2 Effect of aryl substitution on nitrofuran and simple furan IMDAF reactions
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We were particularly intrigued by these results, and set out to discover why the
nitrated systems reacted more rapidly and more favorably than their nonꢀnitrated
analogues and were also more tolerant of substitution. We examined a number of
possibilities using advanced computation: 1) that positive charge stabilization is
greater for nitrated systems in the cycloadduct than the starting material, as identified
by Houk,5 providing an additional driving force for the reaction in those cases; 2) that
nitro substitution leads to an increased loss of aromatic stabilization energy, making
the nitrofuran IMDAF reaction more favourable; 3) that nitration had induced a
favourable change in frontier molecular orbital energies. Although a number of
methods are available for estimating these quantities, it would appear that, to date,
none has ever been applied to nitrofurans.
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We first calculated the energetics of the isodesmic equations5 shown in Scheme 2. It
is clear from these results that there is a significant kinetic and thermodynamic benefit
in having the nitro group attached to a fully substituted sp3 carbon (as in the
cycloadducts 4a-n) rather than an sp2 centre (as in the starting materials 2a-n). This
is consistent with analogous results in the halofuran series. Padwa and Houk
ascribed the effect as being due to hyperconjugative stabilization of partial positive
charge on the halogenꢀbearing carbon. The size of the effect for the nitro group is
intermediate in magnitude between those calculated for Br and Cl.5
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Scheme 2 Isodesmic equations allowing quantification of cation stabilization effects (∆Hr in
kcal molꢀ1)
The aromatic stabilization energy of nitrofuran was next probed using a standard
method, using the homodesmotic equations in Scheme 3, as previously outlined by
von Schleyer for 5ꢀmembered heterocycles.13 The calculations suggest that there is a
greater aromatic stabilization in 2ꢀnitrofuran than in furan itself (Equations 5 and 6).
This is therefore not likely to be a source of the increased reactivity we observe for
nitrated systems.
+
2
+
O
ꢀ 12.2 (Eq 5)
+ 2
+
O
O
+
O2N
+
O2N
+
O2N
O2N
O
O
ꢀ15.1 (Eq 6)
+
O2N
+
O2N
+
O2N
O2N
O
O
Scheme 3 Homodesmotic equations comparing aromatic stabilization for furan and 2ꢀnitrofuran (∆Hr in
kcal molꢀ1).
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Computational Details.
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All electronic structure computations were using Gaussian 09 (Revision D.01).14
Preliminary geometries were obtained by means of density based models, B3LYP15,16
functional with a splitꢀvalence doubleꢀzeta basis, 6ꢀ31G. All optimized structures were
subject to a subsequent frequency calculation, to validate the nature of the stationary
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point. The thermochemical pathway, based on the conversion of 1a, 2a, 1d, 2d, 1n
and 2n to the corresponding cycloadduct, was probed at both 298.15 K and 383.00 K
using a highly accurate complete basis set (CBS) model.17,18,19,20 The particular
extrapolation procedure utilized was CBSꢀQB3,19 a variant of the original CBSꢀQ18
model. The frontier molecular orbital (FMO) energies were obtained from the
B3LYP15,16 functional with a splitꢀvalence tripleꢀzeta basis, 6ꢀ311G(2d,d,p). The
HOMO (LUMO) orbitals relating to the dienophile were selected rationally; the highest
occupied (lowest unoccupied) orbital demonstrating significant amplitude of inꢀphase
(outꢀofꢀphase) overlap of appropriate locally outꢀofꢀplane pꢀorbitals located on the
ethylenic carbon atoms. The identification of the HOMO (LUMO) relating to the diene
segment was straightforward, although the presence of the nitro substituent gave rise
to a distinct difference in the observed LUMOs, with an extra nodal point at position
three of the nitrofuran system when compared to the nonꢀnitrated counterpart.
Electronic structure calculations were performed for substrates 1a, 2a, 1d and 2d.
Key energetic reaction parameters and FMO energies were calculated (Table 3). The
effect of nitration is substantial. Reaction of substrates 1a and 1d occurs via a normal
electronꢀdemand process, but their nitrated analogues 2a and 2d react via an inverse
electronꢀdemand process. Intuitively, 2a might be expected to be a polarityꢀ
mismatched IMDAF substrate and hence undergo slower reaction. The calculations
indicate that the switch in polarity results in a smaller FMO energy difference, which
presumably makes a contribution to increasing the reaction rate.
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Substrate
∆H‡ ∆G‡
∆rH° ∆rG°
FMO ∆E(Normal)
FMO ∆E(inverse)
4
5
6
7
8
1a
2a
1d
2d
17.0 22.2 ꢀ15.8 ꢀ9.5
15.5 21.1 ꢀ18.8 ꢀ12.5
19.9 26.4 ꢀ12.1 ꢀ4.0
15.6 22.4 ꢀ16.8 ꢀ8.1
5.3
6.0
5.3
6.0
8.1
4.9
7.1
4.9
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Table 3 Theoretically calculated reaction energetics at 383.00K and associated FMO energies
expressed in terms of kcal molꢀ1 and electron volts, respectively.21
In order to explain why the nitro systems are more tolerant of steric hindrance, the
calculated transition states for the reaction of these four representative substrates
were examined in more detail. All four pericyclic processes were found to be
asynchronous, with a significant difference in length between the partiallyꢀformed ring
fusion bond marked a (Fig. 1) than for the partiallyꢀformed bond marked b, between
the nitroꢀbearing/Hꢀbearing carbon and the alkene terminus. The difference increases
with alkene substitution and the effect is much more marked for the nitroꢀsubstituted
cases. This is consistent with a more asynchronous pericyclic process in the nitro
cases, and indicates a greater degree of charge separation in the transition state.
One might expect that transfer of electron density from dienophile to diene would lead
to a stabilization of the positive charge at the nitroꢀbearing carbon. This is then likely
to be responsible for the longer interatomic distance b in the transition state, which
would in turn suggest that the reactions of nitro substrates are likely to be less
susceptible to steric effects at the alkene terminus than the nonꢀnitro analogues.
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TS Length a/Å
Length b/Å % difference b vs a
1a
1d
2a
2d
2.04
1.99
2.04
1.92
2.22
2.30
2.24
2.46
9
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280
Figure. 1 Illustrating the asynchronicity of nitrofuran IMDA reactions
There is less reason to expect a similar electron density transfer in the nonꢀnitrated
substrates, and the interatomic distances between the atoms involved in formation of
the two new σꢀbonds are calculated to be much more equal, indicating a more
synchronous process. The activation barriers and observed rates for each of the
reactions (Table 3) are consistent with this analysis.
The only exception to the nitration effect we have observed is seen in substrates 1n
and 2n (Scheme 4 and table 4), derived from the use of monoethyl fumaryl chloride
as acylating agent, leading to the formation of 3n and 4n. These precursors contain
extremely electronꢀdeficient dienophiles. In this case, IMDA product 3n was isolated
directly upon workꢀup of the acylation reaction. Nitro substrate 4n required heating for
1 h to achieve complete conversion, but that reaction is still faster than all the others.
In this unusual case, it appears that nitration does indeed produce a polarity
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mismatched, although still favorable, IMDA reaction. We performed calculations on
the NꢀPhenyl analogues 1o and 2o of these substrates as model compounds. The
calculated activation barriers are consistent with more rapid reactions, in accord with
experiment. The calculated FMO energies indicate a switch to a normalꢀdemand
cycloaddition in these particular cases.
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Scheme 4 Fumarate cycloadditions
Substrate
∆H‡ ∆G‡ ∆rH° ∆rG°
FMO ∆E(Normal)
FMO ∆E(inverse)
1o
2o
11.9 17.9
11.7 17.9
ꢀ15.7 ꢀ9.0
4.5
5.1
8.3
5.9
ꢀ17.8 ꢀ11.0
Table 4 Theoretically calculated reaction energetics for substrates 1o and 2o at 383.00K and
associated FMO energies expressed in terms of kcal molꢀ1 and electron volts, respectively.22
Conclusion
The effect of nitroꢀsubstitution of furan on the intramolecular furan DielsꢀAlder
cycloaddition has been investigated. In all but one case the cycloaddition was faster
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and more favorable for the nitrated substrates. This was found to be due largely to an
extreme example of positive charge stabilization in the transition state and
cycloadducts, rather than any major changes to the aromaticity of the heterocycle.
Given the ready availability of nitrofuran substrates, it is likely that their use will lead
to synthetically useful yields of highly functionalized cycloadducts that are unavailable
from nonꢀnitrated cycloaddition precursors. More general consideration of
asynchronicity is likely to lead to more effective design of substrates for very sterically
demanding intramolecular cycloadditions.
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EXPERIMENTAL
General Information
1
Melting points were obtained in open capillary tubes and are uncorrected. H NMR spectra
were recorded on Bruker AV 300, DPX 400 and AV 400 spectrometers at 300 and 400 MHz
respectively and referenced to residual solvent. 13C NMR spectrum were recorded using the
same spectrometers at 75 and 100 MHz respectively. Chemical shifts (δ in ppm) were
referenced to tetramethylsilane (TMS) or to residual solvent peaks (CDCl3 at δH 7.26). J
values are given in Hz and s, d, dd, ddd, t, dt, q, m, br and app. abbreviations correspond to
singlet, doublet, doublet of doublet, doublet of doublet of doublet, triplet, triplet of doublet,
quartet, multiplet, broad and apparent respectively. Mass spectra were obtained at the
EPSRC National Mass Spectrometry Service Centre in Swansea. Infrared spectra were
obtained on PerkinꢀElmer Spectrum 100 FTꢀIR Universal ATR Sampling Accessory,
deposited neat or as a chloroform solution to a diamond/ZnSe plate.
Flash column chromatography was carried out using Matrix silica gel 60 from Fisher
Chemicals and TLC was performed using Merck silica gel 60 F254 precoated sheets and
visualised by UV (254 nm) and stained by the use of aqueous acidic KMnO4. Anhydrous
dichloromethane (DCM) was obtained from a solvent drying system (MBꢀSPSꢀ800). Eluting
solvents are indicated in the text. The apparatus for inert atmosphere experiments was
flameꢀdried under a stream of dry argon.
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N-(Furan-2-ylmethyl)aniline23:
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To a solution of furfural (1.66 mL, 20.0 mmol) in 1,2ꢀdichloroethane (70
mL) under nitrogen was added aniline (1.82 mL, 20.0 mmol) followed
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by sodiumtriacetoxy borohydride (6.0 g, 28 mmol) in one portion. The
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solution stirred at room temperature for 3 hours where the reaction was
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quenched with the addition of NaHCO3 (100 mL). The solution was extracted with chloroform
(3 x 50 mL). The combined organic layers were dried with sodium sulfate and concentrated
to yield the crude product as a red oil (4.2 g) which was chromatographed on silica gel
(EtOAc/Pet. Ether ~5%) to provide Nꢀ(furanꢀ2ꢀylmethyl)aniline as a yellow oil (3.0 g, 87%).
1H-NMR (300 MHz, CDCl3): δ = 7.43 (m, 1H), 7.20 (m, 2H), 6.87 (m, 1H), 6.79 (m, 1H), 6.39
(m, 1H), 6.30 (m, 1H), 4.37 (s, 2H), 4.07 (s, br, 1H). 13C-NMR (75 MHz, CDCl3): δ = 152.9,
147.7, 142.0, 129.3, 118.1, 113.2, 110.4, 107.1, 41.5. IR (cm-1): 3409, 3051, 1729, 1601,
1503, 1460, 1431, 1316, 1252, 1180, 1145, 1011, 883, 806.
N-((5-Nitrofuran-2-yl)methyl)aniline:24
To a solution of 5ꢀnitrofuranꢀ2ꢀcarbaldehyde (1.41 mg, 10.0 mmol) in
dichloromethane (35 mL) under nitrogen was added aniline (0.92 mL,
10.0 mmol) and the solution stirred at room temperature for 2 hours.
Following the stirring to the solution was added sodium borohydride (490 mg, 13 mmol) in
one portion followed by acetic acid (1.0 mL) to effervescence. The solution stirred at room
temperature overnight where the reaction was quenched with the addition of water (100 mL).
The solution was extracted with chloroform (3 x 50 mL). The combined organic layers were
dried with sodium sulfate and concentrated to yield the crude product as a red oil (2.4 g)
which was chromatographed on silica gel (EtOAc/Pet. Ether ~10%) to provide Nꢀ((5ꢀ
1
nitrofuranꢀ2ꢀyl)methyl)aniline as a red crystals (2.0 g, 93%). M. p.: 55ꢀ57 ºC. H-NMR (300
MHz, CDCl3): δ = 7.30 (m, 1H), 6.87 (m, 1H), 6.73 (dd, J = 8.6, 1.1 Hz, 1H), 6.54 (d, J = 3.7
Hz, 1H), 4.52 (s, 1H), 4.29 (s, br, 1H). 13C-NMR (75 MHz, CDCl3): δ = 157.4, 146.6, 129.5,
118.8, 113.2, 112.9, 110.6, 41.5. IR (cm-1): 3390, 3142, 3116, 1598, 1582, 1506, 1444,
1361, 1314, 1253, 1232, 1169, 1153, 1115, 1096, 979, 815.
N-(Furan-2-ylmethyl)-N-phenylacrylamide (1a):6
Acryloyl chloride (125 mg, 1.3 mmol) was added at ꢀ20 ºC carefully to a
solution of Nꢀ(furanꢀ2ꢀylmethyl)aniline (200 mg, 1.15 mmol),
triethylamine (0.243 mL. 1.7 mmol) and DMAP in dry dichloromethane
(5.00 mL) at 0 °C with stirring. The reaction mixture was allowed to rise
to room temperature and stirred overnight. The reaction mixture was then diluted with
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dichloromethane (10 mL) and water (10 mL) was added. The mixture was further extracted
with dichloromethane (2 × 10 mL) and the combined organic phase dried (Na2SO4).
Purification by column chromatography (1:1.5 ethyl acetate/ petroleum ether) afforded the
1
title compound: (147 mg, 52%) as an orange oil. H-NMR (300 MHz, CDCl3): δ = 7.46 –
9
7.29 (m, 4H), 7.17 – 6.98 (m, 2H), 6.44 (dd, J = 16.8, 2.0 Hz, 1H), 6.30 (dd, J = 3.2, 1.9 Hz,
1H), 6.21 (dq, J = 3.2, 0.7 Hz, 1H), 6.03 (dd, J = 16.8, 10.2 Hz, 1H), 5.56 (dd, J = 10.3, 2.0
Hz, 1H), 4.97 (s, 2H).
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N-((5-Nitrofuran-2-yl)methyl)-N-phenylacrylamide (2a):
Acryloyl chloride (415 mg, 4.60 mmol) was added carefully to a
solution of Nꢀ((5ꢀnitrofuranꢀ2ꢀyl)methyl)aniline (1.00 g, 4.60
mmol), triethylamine (0.23 mL. 9.60 mmol) and DMAP (13 mg,
0.11 mmol) in dry dichloromethane (5.00 mL) at 0 °C with stirring.
The reaction mixture was allowed to rise to room temperature and stirred overnight. The
reaction mixture was then diluted with dichloromethane (10 mL) and water (10 mL) was
added. The mixture was further extracted with dichloromethane (2 × 10 mL) and the
combined organic phase dried (Na2SO4). Purification by column chromatography (1:4 ethyl
acetate/ petroleum ether) afforded the title compound: Wt 647 mg; 52%; brown/orange oil.
1H-NMR (300 MHz, CDCl3): δ = 7.47 – 7.34 (m, 3H,), 7.24 (d, J = 3.6 Hz, 1H, Hꢀ4), 7.21 –
7.16 (m, 2H), 6.55 (d, J = 3.6 Hz, 1H), 6.42 (dd, J = 16.8, 1.9 Hz, 1H), 6.04 (dd, J = 16.8,
10.3 Hz, 1H), 5.59 (dd, J = 10.3, 1.9 Hz, 1H), 4.98 (s, 2H). 13C-NMR (75 MHz, CDCl3): δ =
165.7, 154.6, 151.5, 141.3, 123.0, 129.0, 128.6, 127.9, 127.7, 112.6, 112.1, 46.5. IR (cm-1):
3134, 3064, 3040, 2928, 1656, 1593, 1528, 1489, 1408, 1352, 1255, 1230, 1170, 1018.
HRMS (ESI-ion trap) m/z: [M + Na]+ Calcd for C14H12N2O4Na 295.0689; found: 295.0681 (δ
ppm = ꢀ1.0).
(E)-N-(Furan-2-ylmethyl)-N-phenylhex-2-enamide (1b):
(E)ꢀHexꢀ2ꢀenoyl chloride was prepared by the addition of oxalyl
chloride (1.3 mL, 15 mmol) to a solution of transꢀ2ꢀhexenoic acid
(1.0 g, 9.2 mmol). The solution was stirred at 80 ºC for 1 hour.
The crude solution was concentrated to yield pure 3ꢀmethylbutꢀ
2ꢀenoyl chloride as a yellow oil. To a solution of Nꢀ((1Hꢀfuranꢀ2ꢀyl)methyl)aniline (159 mg,
0.92 mmol) and pyridine (0.11 mL, 1.4 mmol) in dichloromethane (2 mL) under nitrogen was
added, a solution of (E)ꢀhexꢀ2ꢀenoyl chloride (145 mg, 1.1 mmol) in dichloromethane (2 mL).
The solution was stirred at room temperature for 16 hours where the reaction was quenched
with the addition of dilute HCl (20 mL). The solution was extracted with dichloromethane (3 x
30 mL). The combined organic layers were dried with sodium sulfate and concentrated to
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yield the crude product as oil (264 mg) which was chromatographed on silica gel (Pet.
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Ether/EtOAc 4:1) to afford (E)ꢀNꢀ(furanꢀ2ꢀylmethyl)ꢀNꢀphenylhexꢀ2ꢀenamide as a yellow oil
1
(177 mg, 72%). H-NMR (300 MHz, CDCl3): δ = 7.39 ~ 7.27 (m, 4H), 7.09 ~ 7.03 (m, 2H),
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6.94 (dt, J = 15.1, 7.1 Hz, 1H), 6.26 ~ 6.14 (m, 2H), 5.64 (d, J = 15.1 Hz, 1H), 4.92 (s, 2H),
2.00 (dd, J = 7.3, 1.5 Hz, 2H), 1.34 (h, J = 7.3 Hz, 2H), 0.82 (t, J = 7.4 Hz, 3H). 13C-NMR (75
MHz, CDCl3): δ = 166.0, 151.0, 146.8, 142.1, 129.4, 128.4, 127.8, 121.5, 110.4, 108.9, 45.8,
34.4, 21.6, 13.7. IR (cm-1): 2958, 2931, 2872, 1661, 1628, 1593, 1493, 1374, 1287, 1178,
1016, 975, 935, 730, 639. HRMS (ESI-ion trap) m/z: [M + H]+ Calcd for C17H20NO2
270.1489; Found 270.1487 (δ ppm = ꢀ0.6).
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(E)-N-((5-Nitrofuran-2-yl)methyl)-N-phenylhex-2-enamide (2b):
(E)ꢀHexꢀ2ꢀenoyl chloride was prepared by the addition of
oxalyl chloride (1.3 mL, 15 mmol) to a solution of transꢀ2ꢀ
hexenoic acid (1.0 g, 9.2 mmol). The solution was stirred at
room temperature for 1 hour. The crude solution was
O
Ph
NO2
N
O
concentrated to yield pure 3ꢀmethylbutꢀ2ꢀenoyl chloride as a yellow oil. To a solution of Nꢀ
((5ꢀnitrofuranꢀ2ꢀyl)methyl)aniline (200 mg, 0.92 mmol) and pyridine (0.11 mL, 1.4 mmol) in
dichloromethane (2 mL) under nitrogen was added, a solution of (E)ꢀhexꢀ2ꢀenoyl chloride
(145 mg, 1.1 mmol) in dichloromethane (2 mL). The solution was stirred at room temperature
for 16 hours where the reaction was quenched with the addition of dilute HCl (20 mL). The
solution was extracted with dichloromethane (3 x 30 mL). The combined organic layers were
dried with sodium sulfate and concentrated to yield the crude product as oil (290 mg) which
was chromatographed on silica gel (Pet. Ether/EtOAc 4:1) to afford compound 2b as an
orange oil (227 mg, 78%). 1H-NMR (300 MHz, CDCl3): δ = 7.49 ~ 7.30 (m, 3H), 7.23 (d, J =
3.7 Hz, 1H), 7.20 ~ 7.15 (m, 2H), 6.95 (dt, J = 15.1, 7.1 Hz, 1H), 6.53 (dt, J = 3.7, 0.7 Hz,
1H), 5.68 (dt, J = 15.2, 1.5 Hz, 1H), 4.96 (s, 2H), 2.02 (qd, J = 7.3, 1.5 Hz, 2H), 1.35 (h, J =
7.4 Hz, 2H), 0.83 (t, J = 7.4 Hz, 3H). 13C-NMR (75 MHz, CDCl3): δ = 166.3, 155.1, 147.9 ,
141.8, 129.9, 128.4, 128.1, 120.8, 112.7, 112.1, 46.5, 34.4, 21.5, 13.7. IR (cm-1): 2959,
2930, 2872, 1661, 1628, 1593, 1529, 1491, 1400, 1352, 1291, 1231, 1169, 1018, 970, 955.
HRMS (ASAP+ - TOF) m/z: [M + H]+ Calcd for C17H19N2O4 315.1345; Found 315.1342 (δ
ppm = ꢀ1.0).
(E)-N-(Furan-2-ylmethyl)-2-methyl-N-phenylbut-2-enamide (1c):
(E)ꢀ2ꢀMethylbutꢀ2ꢀenoyl chloride was prepared by the addition of
oxalyl chloride (1.3 mL, 15 mmol) to tiglic acid (1.0 g, 10 mmol). The
solution was stirred at room temperature for 1 hour. The crude
solution was concentrated to yield pure (E)ꢀ2ꢀmethylbutꢀ2ꢀenoyl chloride as a yellow oil. To a
solution of Nꢀ((1Hꢀfuranꢀ2ꢀyl)methyl)aniline (159 mg, 0.92 mmol) and pyridine (0.11 mL, 1.4
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mmol) in dichloromethane (2 mL) under nitrogen was added, a solution of (E)ꢀ2ꢀmethylbutꢀ2ꢀ
enoyl chloride (140 mg, 1.10 mmol) in dichloromethane (2 mL). The solution was stirred at
room temperature for 16 hours where the reaction was quenched with the addition of dilute
HCl (20 mL). The solution was extracted with dichloromethane (3 x 30 mL). The combined
organic layers were dried with sodium sulfate and concentrated to yield the crude product as
oil (253 mg) which was chromatographed on silica gel (Pet. Ether/EtOAc 4:1) to afford
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1
compound 1c as a yellow oil (217 mg, 93%). H-NMR (300 MHz, CDCl3): δ = 7.33 ~ 7.13
(m, 4H), 7.07 ~ 6.96 (m, 2H), 6.25 (dd, J = 3.2, 1.9 Hz, 1H), 6.16 (dd, J = 3.3, 0.9 Hz, 1H),
5.75 (dd, J = 6.9, 1.5 Hz, 1H), 4.90 (s, 2H), 1.55 ~ 1.53 (m, 3H), 1.44 (dd, J = 6.9, 1.2 Hz,
3H). 13C-NMR (75 MHz, CDCl3): δ = 173.0, 151.2, 143.6, 142.0, 132.5, 131.0, 129.0, 127.3,
126.8, 110.4, 108.7, 46.4, 14.1, 13.4. IR (cm-1): 3038, 2920, 1736, 1658, 1635, 1594, 1584,
1493, 1454, 1365, 1294, 1196, 1164, 1014, 933, 813, 735. HRMS (ESI-ion trap) m/z: [M +
H]+ Calcd for C16H18NO2 256.1332; Found 256.1333 (δ ppm = 0.4).
(E)-2-Methyl-N-((5-nitrofuran-2-yl)methyl)-N-phenylbut-2-enamide (2c):
(E)ꢀ2ꢀMethylbutꢀ2ꢀenoyl chloride was prepared by the addition of
oxalyl chloride (1.3 mL, 15 mmol) to tiglic acid (1.0 g, 10 mmol).
The solution was stirred at room temperature for 1 hour. The
crude solution was concentrated to yield pure (E)ꢀ2ꢀmethylbutꢀ2ꢀ
enoyl chloride as a yellow oil. To a solution of Nꢀ((5ꢀnitrofuranꢀ2ꢀyl)methyl)aniline (200 mg,
0.92 mmol) and pyridine (0.11 mL, 1.4 mmol) in dichloromethane (2 mL) under nitrogen was
added,
a solution of (E)ꢀ2ꢀmethylbutꢀ2ꢀenoyl chloride (140 mg, 1.10 mmol) in
dichloromethane (2 mL). The solution was stirred at room temperature for 16 hours where
the reaction was quenched with the addition of dilute HCl (20 mL). The solution was
extracted with dichloromethane (3 x 30 mL). The combined organic layers were dried with
sodium sulfate and concentrated to yield the crude product as oil (283 mg) which was
chromatographed on silica gel (Pet. Ether/EtOAc 4:1) to afford compound 2c as an orange
1
oil (236 mg, 85%). H-NMR (300 MHz, CDCl3): δ = 7.51 ~ 7.43 (m, 2H), 7.42 ~ 7.35 (m,
2H), 7.28 ~ 7.23 (m, 2H), 6.66 (dt, J = 3.7, 0.8 Hz, 1H), 5.97 (dd, J = 6.9, 1.5 Hz, 1H), 5.11
(s, 2H), 1.70 ~ 1.67 (m, 3H), 1.62 (dd, J = 6.9, 1.2 Hz, 3H). 13C-NMR (75 MHz, CDCl3): δ =
173.1, 155.2, 143.3, 132.5, 131.9, 129.5, 127.3, 126.9, 112.8, 111.9, 47.1, 13.9, 13.6. IR
(cm-1): 2921, 2247, 1634, 1564, 1529, 1492, 1353, 1297, 1278, 1232, 1159, 1018, 909, 810,
771. HRMS (ASAP+ - TOF) m/z: [M]+ Calcd for C16H15N2O4 299.1032; Found 299.1029 (δ
ppm =ꢀ1.0).
N-(Furan-2-ylmethyl)-3-methyl-N-phenylbut-2-enamide (1d):
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3ꢀMethylbutꢀ2ꢀenoyl chloride was prepared by the addition of oxalyl
chloride (2.8 mL, 33 mmol) to a solution of 3ꢀmethyl crotonic acid
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(3.0 g, 30 mmol) in dichloromethane (25 mL). The solution was
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stirred at room temperature for 1 hour. The crude solution was concentrated to yield pure 3ꢀ
methylbutꢀ2ꢀenoyl chloride as a yellow oil. To a solution of Nꢀ((1Hꢀfuranꢀ2ꢀyl)methyl)aniline
(317 mg, 1.83 mmol) and pyridine (0.22 mL, 2.75 mmol) in dichloromethane (2 mL) under
nitrogen was added, a solution of 3ꢀmethylbutꢀ2ꢀenoyl chloride (260 mg, 2.20 mmol) in
dichloromethane (2 mL). The solution was stirred at room temperature for 16 hours where
the reaction was quenched with the addition of dilute HCl (20 mL). The solution was
extracted with dichloromethane (3 x 30 mL). The combined organic layers were dried with
sodium sulfate and concentrated to yield the crude product as oil (465 mg) which was
chromatographed on silica gel (Pet. Ether/EtOAc 4:1) to afford compound 3d as a yellow oil
(407 mg, 87%).1H-NMR (300 MHz, CDCl3): δ = 7.38 ~ 7.18 (m, 4H), 7.05 ~ 6.98 (m, 2H),
6.21 (dd, J = 3.2, 1.8 Hz, 1H), 6.11 (dd, J = 3.2, 0.9 Hz, 1H), 5.37 (s, 1H), 4.84 (s, 2H), 2.09
(d, J = 1.3 Hz, 3H), 1.61 (s, 3H). 13C-NMR (75 MHz, CDCl3): δ = 166.9, 151.5, 151.4, 142.7,
142.0, 129.3, 128.1, 127.52 117.5, 110.4, 108.7, 45.4, 27.4, 20.4. IR (cm-1): 2912, 1712,
1650, 1632, 1593, 1494, 1447, 1393, 1364, 1263, 1170, 1146, 1016, 934, 843, 747. HRMS
(ESI-ion trap) m/z: [M + H]+ Calcd for C16H18NO2 256.1332; Found 256.1330 (δ ppm =ꢀ0.8).
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3-Methyl-N-((5-nitrofuran-2-yl)methyl)-N-phenylbut-2-enamide (2d):
3ꢀmethylbutꢀ2ꢀenoyl chloride was prepared by the addition of
oxalyl chloride (2.8 mL, 33 mmol) to a solution of 3ꢀmethyl crotonic
acid (3.0 g, 30 mmol) in dichloromethane (25 mL). The solution
was stirred at room temperature for 1 hour. The crude solution was
concentrated to yield pure 3ꢀmethylbutꢀ2ꢀenoyl chloride as a yellow oil.
To a solution of Nꢀ((5ꢀnitroꢀ1Hꢀfuranꢀ2ꢀyl)methyl)aniline (400 mg, 1.83 mmol) and pyridine
(0.22 mL, 2.75 mmol) in dichloromethane (2 mL) under nitrogen was added, a solution of 3ꢀ
methylbutꢀ2ꢀenoyl chloride (260 mg, 2.20 mmol) in dichloromethane (2 mL). The solution
was stirred at room temperature for 16 hours where the reaction was quenched with the
addition of dilute HCl (20 mL). The solution was extracted with dichloromethane (3 x 30 mL).
The combined organic layers were dried with sodium sulfate and concentrated to yield the
crude product as oil (638 mg) which was chromatographed on silica gel (Pet. Ether/EtOAc
4:1) to provide 3ꢀmethylꢀNꢀ((5ꢀnitrofuranꢀ2ꢀyl)methyl)ꢀNꢀphenylbutꢀ2ꢀenamide as a yellow oil
1
(503 mg, 92%). H-NMR (300 MHz, CDCl3): δ = 7.44 ~ 7.28 (m, 3H), 7.23 (d, J = 3.6 Hz,
1H), 7.19 ~ 7.13 (m, 2H), 6.52 (dd, J = 3.7, 0.8 Hz, 1H), 5.43 (s, 1H), 4.93 (s, 2H), 2.14 (s,
3H), 1.69 (s, 3H). 13C-NMR (75 MHz, CDCl3): δ = 167.0, 155.5, 153.3, 142.4, 129.8, 128.1,
127.9, 116.7, 112.8, 111.8, 46.3, 27.5, 20.4. IR (cm-1): 2913, 1711, 1651, 1632, 1594, 1529,
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1492, 1447, 1399, 1353, 1265, 1221, 1163, 1019, 969, 955, 843, 809, 752. HRMS (ASAP+ -
TOF) m/z: [M]+ Calcd for C16H17N2O4 301.1188; Found 301.1186 (δ ppm =ꢀ0.7).
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2-Cyclopentylidene-N-(furan-2-ylmethyl)-N-phenylacetamide (1e):
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Cyclopentꢀ1ꢀeneꢀ1ꢀcarbonyl chloride was prepared by the addition of
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oxalyl chloride (66,4 ꢁL, 0.77 mmol) to 2ꢀcyclopentylideneacetic acid
(110 mg, 0.64 mmol) The solution was stirred at room temperature for 1
hour. The crude solution was concentrated to yield pure the
corresponding acyl chloride as a yellow oil. To a solution of Nꢀ(furanꢀ2ꢀ
ylmethyl)aniline (134 mg, 0.77 mmol) and pyridine (78 ꢁL, 0.97 mmol) in dichloromethane
(1.4 mL) under nitrogen was added, a solution of acyl chloride in dichloromethane (1.4 mL).
The solution stirred at room temperature for 16 hours where the reaction was quenched with
the addition of dilute HCl (10 mL). The solution was extracted with dichloromethane (3 x 10
mL). The combined organic layers were dried with sodium sulfate and concentrated to yield
the crude product which was chromatographed on silica gel (Pet. Ether/EtOAc 4:1) to
1
provide compound 1e (138 mg, 76%) as a pale yellow solid. M. p.: 72ꢀ75 ºC. H-NMR (300
MHz, CDCl3): δ = 7.31 – 7.17 (m, 4H), 7.03 – 6.96 (m, 2H), 6.17 (dd, J = 3.2, 1.9 Hz, 1H),
6.08 (dq, J = 3.2, 0.8 Hz, 1H), 5.51 (s, 1H), 4.82 (s, 2H), 3.04 – 2.61 (m, 2H), 2.31 – 2.01 (m,
3H), 1.72 – 1.56 (m, 2H), 1.55 – 1.40 (m, 2H).13C-NMR (75 MHz, CDCl3): δ = 166.5, 165.6,
151.4, 142.7, 141.9, 129.3, 128.3, 127.4, 111.8, 110.3, 108.5, 45.3, 36.0, 32.5, 26.6, 25.4.
IR (cm-1): 1655, 1626, 1594, 1493, 1393, 1384, 1257, 1247, 1230, 1218, 1178, 1154, 1142,
1130, 855, 755, 744, 732, 663, 643, 599, 566. HRMS (ESI-ion trap) m/z: [M + H]+ Calcd for
C18H20NO2 282.1489; Found 282.1488 (δ ppm ꢀ0.2).
2-Cyclopentylidene-N-((5-nitrofuran-2-yl)methyl)-N-phenylacetamide (2e):
O
Ph
N
Cyclopentꢀ1ꢀeneꢀ1ꢀcarbonyl chloride was prepared by the addition of oxalyl
chloride (78 ꢁL, 0.91 mmol) to 2ꢀcyclopentylideneacetic acid (130 mg, 0.76
mmol). The solution was stirred at room temperature for 1 hour. The crude
solution was concentrated to yield pure the corresponding acyl chloride as
O
NO2
a yellow oil. To a solution of Nꢀ((5ꢀnitrofuranꢀ2ꢀyl)methyl)aniline (200 mg, 0.91 mmol) and
pyridine (93 ꢁL, 1.14 mmol) in dichloromethane (1.7 mL) under nitrogen was added, a
solution of acyl chloride in dichloromethane (1.7 mL). The solution stirred at room
temperature for 16 hours where the reaction was quenched with the addition of dilute HCl
(10 mL). The solution was extracted with dichloromethane (3 x 10 mL). The combined
organic layers were dried with sodium sulfate and concentrated to yield the crude product
which was chromatographed on silica gel (Pet. Ether/EtOAc 5:1 to 3:1) to provide compound
2e (185 mg, 0,567 mmol, 74%) as a yellow oil. 1H-NMR (300 MHz, CDCl3): δ = 7.43 – 7.27
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(m, 3H), 7.21 (d, J = 3.7 Hz, 1H), 7.19 – 7.12 (m, 2H), 6.51 (dd, J = 3.7, 0.8 Hz, 1H), 5.61 (t,
J = 2.3 Hz, 1H), 4.92 (s, 2H), 2.92 – 2.73 (m, 2H), 2.29 – 2.16 (m, 2H), 1.77 – 1.62 (m, 2H),
1.61 – 1.45 (m, 2H). 13C-NMR (75 MHz, CDCl3): δ = 167.2, 166.7, 155.6, 142.4, 129.8,
128.0, 127.9, 112.7, 111.7, 111.1, 46.2, 36.2, 32.6, 26.5, 25.3. IR (cm-1): 1655, 1493, 1348,
1254, 1228, 1018, 809, 736, 666. HRMS (ESI-ion trap) m/z: [M + H]+ Calcd for C18H19N2O4
327.1339; Found 327.1340 (δ ppm 0.2).
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2-Cyclohexylidene-N-(furan-2-ylmethyl)-N-phenylacetamide (1f):
2ꢀCyclohexylideneacetyl chloride was prepared by the addition
of thionyl chloride (4.9 mL) to
a
solution of 2ꢀ
cyclohexylideneacetic acid (561 mg, 4.0 mmol). The solution
was stirred at room temperature for 3 hour. The crude solution was concentrated to yield 2ꢀ
cyclohexylideneacetyl chloride as a yellow oil (80% purity). To a solution of Nꢀ((1Hꢀfuranꢀ2ꢀ
yl)methyl)aniline (159 mg, 0.92 mmol) and pyridine (0.11 mL, 1.4 mmol) in dichloromethane
(2 mL) under nitrogen was added, a solution of 2ꢀCyclohexylideneacetyl chloride (221 mg,
1.4 mmol) in dichloromethane (2 mL). The solution stirred at room temperature for 16 hours
where the reaction was quenched with the addition of dilute HCl (20 mL). The solution was
extracted with dichloromethane (3 x 30 mL). The combined organic layers were dried with
sodium sulfate and concentrated to yield the crude product as oil (418 mg) which was
chromatographed on silica gel (Pet. Ether/EtOAc 4:1) to compound 1f as a yellow oil (175
1
mg, 64%). H-NMR (300 MHz, CDCl3): δ = 7.39 ~ 7.26 (m, 4H), 7.13 ~ 7.03 (m, 2H), 6.26
(dd, J = 3.2, 1.9 Hz, 1H), 6.16 (dd, J = 3.2, 0.8 Hz, 1H), 5.35 (s, 1H), 4.90 (s, 2H), 2.80 ~
2.66 (m, 2H), 1.94 (t, J = 5.7 Hz, 2H), 1.64 ~ 1.45 (m, 6H). 13C-NMR (75 MHz, CDCl3): δ =
167.7, 157.6, 151.4, 142.8, 142.0, 129.3, 128.2, 127.5, 115.1, 110.4, 108.7, 45.5, 37.9, 30.2,
28.6, 27.9, 26.5. IR (cm-1): 2927, 2852, 1650, 1594, 1494, 1446, 1420, 1398, 1355, 1228,
1255, 1173, 1042, 1006, 982, 847, 732, 666. HRMS (ESI-ion trap) m/z: [M + H]+ Calcd for
C19H22NO2 296.1656; Found 296.1649 (δ ppm ꢀ2.4).
2-Cyclohexylidene-N-((5-nitrofuran-2-yl)methyl)-N-phenylacetamide (2f):
2ꢀCyclohexylideneacetyl chloride was prepared by the
addition of thionyl chloride (4.9 mL) to a solution of 2ꢀ
cyclohexylideneacetic acid (561 mg, 4.0 mmol). The solution
was stirred at room temperature for 3 hour. The crude solution was concentrated to yield 2ꢀ
cyclohexylideneacetyl chloride as a yellow oil (80% purity).
To a solution of Nꢀ((5ꢀnitrofuranꢀ2ꢀyl)methyl)aniline (200 mg, 0.92 mmol) and pyridine (0.11
mL, 1.4 mmol) in dichloromethane (2 mL) under nitrogen was added, a solution of 2ꢀ
Cyclohexylideneacetyl chloride (221 mg, 1.4 mmol) in dichloromethane (2 mL). The solution
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stirred at room temperature for 16 hours where the reaction was quenched with the addition
of dilute HCl (20 mL). The solution was extracted with dichloromethane (3 x 30 mL). The
combined organic layers were dried with sodium sulfate and concentrated to yield the crude
product as oil (489 mg) which was chromatographed on silica gel (Pet. Ether/EtOAc 4:1) to
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provide compound 2f as a red oil (192 mg, 61%). H-NMR (300 MHz, CDCl3): δ = 7.43 ~
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7.28 (m, 3H), 7.24 (d, J = 3.6 Hz, 1H), 7.21 ~ 7.16 (m, 2H), 6.53 (d, J = 3.6 Hz, 1H), 5.38 (s,
1H), 4.94 (s, 2H), 2.81 ~ 2.65 (m, 2H), 1.97 (t, J = 5.5 Hz, 2H), 1.71 ~ 1.44 (m, 6H). 13C-
NMR (75 MHz, CDCl3): δ = 167.3, 159.5, 155.5, 142.5, 129.8, 128.1, 127.9, 114.2, 112.8,
111.9, 46.3, 31.1, 30.3, 28.7, 27.9, 26.4. IR (cm-1): 2928, 2853, 1650, 1593, 1528, 1492,
1447, 1401, 1350, 1275, 1223, 1166, 1019, 984, 969, 848, 809, 737, 668. HRMS (ASAP+ -
TOF) m/z: [M+H]+ Calcd for C19H21N2O4 341.1501; Found 341.1502 (δ ppm 0.3).
N-(Furan-2-ylmethyl)-N-phenylcyclopent-1-ene-1-carboxamide (1g):
The acyl chloride was prepared by the addition of thionyl chloride (1.2
mL, 16.07 mmol) to cyclopentꢀ1ꢀeneꢀ1ꢀcarboxylic acid (106 mg, 0.94
mmol) The solution was stirred at room temperature for 1 hour. The
crude solution was concentrated to yield pure the corresponding acyl
chloride as a yellow oil. To a solution of Nꢀ(furanꢀ2ꢀylmethyl)aniline (196 mg, 1.13 mmol) and
pyridine (115 ꢁL, 1.42 mmol) in dichloromethane (2.05 mL) under nitrogen was added, a
solution of acyl chloride in dichloromethane (2.05 mL). The solution stirred at room
temperature for 16 hours where the reaction was quenched with the addition of dilute HCl
(10 mL). The solution was extracted with dichloromethane (3 x 10 mL). The combined
organic layers were dried with sodium sulfate and concentrated to yield the crude product
which was chromatographed on silica gel (Pet. Ether/EtOAc 7:1) to provide compound 1g
(212 mg, 84% yield) as a pale yellow solid. M. p. = 48 – 50 ºC. 1H-NMR (300 MHz, CDCl3):
δ = 7.37 ~ 7.25 (m, 4H), 7.11 ~ 7.04 (m, 2H), 6.29 (ddd, J = 3.0, 1.8, 1.0 Hz, 1H), 6.20 (dt, J
= 3.2, 0.8 Hz, 1H), 5.88 ~ 5.84 (m, 1H), 4.95 (s, 2H), 2.27 ~ 2.15 (m, 4H), 1.79 ~ 1.60 (m,
2H). 13C-NMR (75 MHz, CDCl3): δ = 168.0, 151.0, 143.1, 142.1, 139.3, 139.1, 129.1, 127.9,
127.4, 110.4, 108.9, 46.4, 33.7, 33.1, 23.3. IR (cm-1): 2949, 2844, 1710, 1638, 1615, 1592,
1493, 1374, 1301, 1275, 1182, 1074, 1008, 949, 884, 735. HRMS (ASAP+ - TOF) m/z:
[M+H]+ Calcd for C17H18NO2 268.1332; Found 268.1332 (δ ppm = 0.0).
N-((5-Nitrofuran-2-yl)methyl)-N-phenylcyclopent-1-ene-1-carboxamide (2g)
The acyl chloride was prepared by the addition of thionyl chloride
(1.2 mL, 17.4 mmol) to cyclopentꢀ1ꢀeneꢀ1ꢀcarboxylic acid (115 mg,
1.0 mmol). The solution was stirred at room temperature for 1 hour.
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The crude solution was concentrated to yield pure the corresponding acyl chloride as a
yellow oil. To a solution of Nꢀ((5ꢀnitrofuranꢀ2ꢀyl)methyl)aniline (269 mg, 1.23 mmol) and
pyridine (124 ꢁL, 1.54 mmol) in dichloromethane (2.2 mL) under nitrogen was added, a
solution of acyl chloride in dichloromethane (2.2 mL). The solution stirred at room
temperature for 16 hours where the reaction was quenched with the addition of dilute HCl
(10 mL). The solution was extracted with dichloromethane (3 x 10 mL). The combined
organic layers were dried with sodium sulfate and concentrated to yield the crude product
which was chromatographed on silica gel (Pet. Ether/EtOAc 3:1) to provide compound 2g
(210 mg, 66%) as an orange oil. 1H-NMR (300 MHz, CDCl3): δ = 7.40 – 7.27 (m, 3H), 7.24
(d, J = 3.7 Hz, 1H), 7.19 – 7.12 (m, 2H), 6.54 (dt, J = 3.7, 0.7 Hz, 1H), 5.93 – 5.82 (m, 1H),
4.96 (t, J = 0.6 Hz, 2H), 2.28 – 2.13 (m, 4H), 1.77 – 1.62 (m, 2H). 13C-NMR (75 MHz,
CDCl3): δ = 167.9, 154.9, 151.4, 142.6, 140.3, 138.4, 129.4, 127.8, 127.4, 112.7, 111.9,
47.0, 33.4, 33.0, 23.1. IR (cm-1): 1641, 1593, 1529, 1491, 1451, 1398, 1303, 1276, 1233,
1173, 1075, 1019, 980, 950, 908, 810, 772, 734, 698, 682, 589, 560. HRMS (ASAP+ - TOF)
m/z: [M+H]+ Calcd for C17H17N2O4 313.1183; Found 313.1183 (δ ppm = 0.1).
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N-(Furan-2-ylmethyl)-N-phenylcyclohex-1-ene-1-carboxamide (1h):
Cyclohexꢀ1ꢀeneꢀ1ꢀcarbonyl chloride was prepared by the addition of
thionyl chloride (4.9 mL) to 1ꢀcyclohexeneꢀ1ꢀcarboxylic acid (505
mg, 4.0 mmol). The solution was stirred at room temperature for 1
hour. The crude solution was concentrated to yield pure cyclohexꢀ1ꢀ
eneꢀ1ꢀcarbonyl chloride as a yellow oil. To a solution of Nꢀ((1Hꢀfuranꢀ2ꢀyl)methyl)aniline (159
mg, 0.92 mmol) and pyridine (0.11 mL, 1.4 mmol) in dichloromethane (2 mL) under nitrogen
was added, a solution of cyclohexꢀ1ꢀeneꢀ1ꢀcarbonyl chloride (160 mg, 1.10 mmol) in
dichloromethane (2 mL). The solution stirred at room temperature for 16 hours where the
reaction was quenched with the addition of dilute HCl (20 mL). The solution was extracted
with dichloromethane (3 x 30 mL). The combined organic layers were dried with sodium
sulfate and concentrated to yield the crude product as oil (465 mg) which was
chromatographed on silica gel (Pet. Ether/EtOAc 4:1) to provide compound 1h as a yellow
1
oil (189 mg, 73%). H-NMR (300 MHz, CDCl3): δ = 7.33 ~ 7.16 (m, 4H), 7.07 ~ 7.00 (m,
2H), 6.26 (dd, J = 3.2, 1.9 Hz, 1H), 6.17 (dd, J = 3.2, 0.8 Hz, 1H), 5.85 (tt, J = 3.7, 1.7 Hz,
1H), 4.92 (s, 2H), 2.03 ~ 1.91 (m, 2H), 1.91 ~ 1.81 (m, 2H), 1.54 ~ 1.31 (m, 4H). 13C-NMR
(75 MHz, CDCl3): δ = 172.4, 151.2, 143.7, 142.0, 134.5, 133.2, 129.0, 127.3, 126.9, 110.4,
108.7, 46.3, 26.1, 25.1, 22.1, 21.5. IR (cm-1): 2929, 2857, 1633, 1594, 1493, 1376, 1292,
1260, 1186, 1112, 1044, 1009, 884, 802, 739. HRMS (ESI – ion trap) m/z: [M+H]+ Calcd for
C18H20NO2 282.1500; Found 282.1492 (δ ppm =ꢀ2.7).
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N-((5-Nitrofuran-2-yl)methyl)-N-phenylcyclohex-1-ene-1-carboxamide (2h):
Cyclohexꢀ1ꢀeneꢀ1ꢀcarbonyl chloride was prepared by the addition
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of thionyl chloride (4.9 mL) to 1ꢀcyclohexeneꢀ1ꢀcarboxylic acid (505
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mg, 4.0 mmol). The solution was stirred at room temperature for 1
hour. The crude solution was concentrated to yield pure cyclohexꢀ
1ꢀeneꢀ1ꢀcarbonyl chloride as a yellow oil. To a solution of Nꢀ((5ꢀnitrofuranꢀ2ꢀyl)methyl)aniline
(200 mg, 0.92 mmol) and pyridine (0.11 mL, 1.4 mmol) in dichloromethane (2 mL) under
nitrogen was added, a solution of cyclohexꢀ1ꢀeneꢀ1ꢀcarbonyl chloride (160 mg, 1.10 mmol)
in dichloromethane (2 mL). The solution stirred at room temperature for 16 hours where the
reaction was quenched with the addition of dilute HCl (20 mL). The solution was extracted
with dichloromethane (3 x 30 mL). The combined organic layers were dried with sodium
sulfate and concentrated to yield the crude product as oil (465 mg) which was
chromatographed on silica gel (Pet. Ether/EtOAc 4:1) to provide compound 2h as a red oil
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(275 mg, 92%). H-NMR (300 MHz, CDCl3): δ = 7.38 ~ 7.27 (m, 3H), 7.25 ~ 7.22 (m, 1H),
7.16 ~ 7.10 (m, 2H), 6.53 (dt, J = 3.7, 0.6 Hz, 1H), 5.93 (tt, J = 3.7, 1.7 Hz, 1H), 4.97 (s, 2H),
2.00 ~ 1.83 (m, 4H), 1.54 ~ 1.34 (m, 4H). 13C-NMR (75 MHz, CDCl3): δ = 172.5, 155.2,
143.4, 134.7, 133.9, 129.5, 127.5, 127.0, 112.8, 111.9, 47.1, 25.9, 25.2, 22.1, 21.5. IR (cm-
1): 2931, 1734, 1633, 1594, 1528, 1491, 1454, 1399, 1352, 1279, 1232, 1173, 1045, 1017,
968, 920, 854, 809, 697. HRMS (ASAP+ - TOF) m/z: [M+H]+ Calcd for C18H19N2O4
327.1345; Found 327.1338 (δ ppm = ꢀ2.1).
2-Cyclohexylidene-N-(furan-2-ylmethyl)-N-phenylpropanamide (1i):
The acyl chloride was prepared by the addition of oxalyl chloride
(54.5 ꢁL, 0.63 mmol) to 2ꢀcyclohexylidenepropanoic acid (86 mg,
0.56 mmol). The solution was stirred at room temperature for 1
hour. The crude solution was concentrated to yield pure the corresponding acyl chloride as a
yellow oil. To a solution of Nꢀ(furanꢀ2ꢀylmethyl)aniline (88 mg, 0.51 mmol) and pyridine (49.3
ꢁL, 0.61 mmol) in dichloromethane (0.5 mL) under nitrogen was added, a solution of acyl
chloride in dichloromethane (0.5 mL). The solution stirred at 70 ºC for 16 hours where the
reaction was quenched with the addition of dilute HCl (10 mL). The solution was extracted
with dichloromethane (3 x 10 mL). The combined organic layers were dried with sodium
sulfate and concentrated to yield the crude product which was chromatographed on silica gel
(Pet. Ether/EtOAc 6:1 to 4:1) to provide compound 1i as a colourless oil. 1H-NMR (300 MHz,
CDCl3): δ = 7.39 – 7.24 (m, 4H), 7.11 – 7.01 (m, 2H), 6.29 (dd, J = 3.2, 1.7 Hz, 1H), 6.21 (d,
J = 3.2 Hz, 1H), 4.97 (s, 2H), 2.13 (s, 2H), 1.90 (d, J = 7.8 Hz, 2H), 1.62 (s, 3H), 1.54 – 1.30
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(m, 6H). 13C-NMR (75 MHz, CDCl3): δ = 173.2, 151.0, 142.1, 141.9, 138.3, 128.6, 127.4,
127.4, 122.7, 110.4, 108.8, 45.2, 32.4, 29.1, 27.0, 26.9, 26.3, 15.9. IR (cm-1): 1634, 1594,
1494, 1372, 1012, 728, 698, 599. HRMS (ESI – ion trap) m/z: [M+H]+ Calcd for C20H24NO2
310.1800; Found 310.1802 (δ ppm = ꢀ0.5).
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2-Cyclohexylidene-N-((5-nitrofuran-2-yl)methyl)-N-phenylpropanamide (2i):
The acyl chloride was prepared by the addition of oxalyl chloride
NO2
(93 ꢁL, 1.09 mmol) to 2ꢀcyclohexylidenepropanoic acid (148 mg,
0.96 mmol). The solution was stirred at room temperature for 1
hour. The crude solution was concentrated to yield pure the
Ph
N
O
C
O
corresponding acyl chloride as a yellow oil. To a solution of Nꢀ((5ꢀnitrofuranꢀ2ꢀ
yl)methyl)aniline (190 mg, 0.87 mmol) and pyridine (85 ꢁL, 1.04 mmol) in dichloromethane
(0.9 mL) under nitrogen was added, a solution of acyl chloride in dichloromethane (0.9 mL).
The solution was stirred at 70 ºC for 16 hours where the reaction was quenched with the
addition of dilute HCl (10 mL). The solution was extracted with dichloromethane (3 x 10 mL).
The combined organic layers were dried with sodium sulfate and concentrated to yield the
crude product which was chromatographed on silica gel (Pet. Ether/EtOAc 4:1) to provide
1
compound 2i (196 mg, 63% yield) as a yellow oil. H-NMR (300 MHz, CDCl3): δ = 7.42 –
7.25 (m, 4H), 7.19 – 7.16 (m, 2H), 6.55 (d, J = 3.7 Hz, 1H), 5.03 (s, 2H), 2.14 (s, 2H), 1.93 (t,
J = 6.0 Hz, 2H), 1.62 (s, 3H), 1.55 – 1.34 (m, 6H). 13C-NMR (75 MHz, CDCl3): δ = 173.5,
155.0, 141.9, 139.7, 129.1, 127.8, 127.0, 121.9, 112.6, 111.6, 105.0, 46.0, 32.5, 29.2, 27.1,
26.8, 26.2, 15.8. IR (cm-1): 1640, 1597, 1529, 1493, 1353, 1300, 1227, 1017, 810, 738, 698.
HRMS (ASAP+ - TOF) m/z: [M+H]+ Calcd for C20H23N2O4 355.1652; Found 355.1653 (δ
ppm = 0.2).
N-(Furan-2-ylmethyl)-N-phenylcinnamamide (1j):
Cinnamoyl chloride (231 mg, 1.3 mmol) was added at ꢀ20 ºC
carefully to a solution of Nꢀ(furanꢀ2ꢀylmethyl)aniline (200 mg,
1.15 mmol), triethylamine (0.243 mL. 1.7 mmol) and DMAP in
dry dichloromethane (5.00 mL) at 0 °C with stirring. The reaction mixture was allowed
to rise to room temperature and stirred overnight. The reaction mixture was then
diluted with dichloromethane (10 mL) and water (10 mL) was added. The mixture
was further extracted with dichloromethane (2 × 10 mL) and the combined organic
phase dried (Na2SO4). Purification by column chromatography (1:1.5 Et2O/ petroleum
o
ether) afforded the title compound: (279 mg, 80%) as a white solid. M. p.: 75ꢀ76 C.
1H-NMR (300 MHz, CDCl3): δ = 7.65 (d, J = 15.5 Hz, 1H), 7.42 – 7.27 (m, 3H), 7.27 –
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7.13 (m, 6H), 7.13 – 7.00 (m, 2H), 6.30 – 6.16 (m, 2H), 6.13 (dd, J = 3.2, 0.8 Hz, 1H),
4.92 (s, 2H). 13C-NMR (75 MHz, CDCl3): δ = 165.8, 150.9, 142.4, 142.1, 141.9, 135.2,
129.6, 129.5, 128.7, 128.3, 128.0, 127.9, 118.7, 110.4, 109.0, 45.9. IR (cm-1): 3042,
1978, 1646, 1605, 706. HRMS (ESI – ion trap) m/z: [M+H]+ Calcd for C20H18NO2
304,1338; Found 304,1332 (δ ppm = ꢀ0.3).
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N-((5-Nitrofuran-2-yl)methyl)-N-phenylcinnamamide (2j):
Cinnamoyl chloride (458 mg, 2.5 mmol) was added at ꢀ20
ºC carefully to
a
solution of Nꢀ((5ꢀnitrofuranꢀ2ꢀ
yl)methyl)aniline (500 mg, 2.3 mmol), triethylamine (0.48
mL. 3.4 mmol) and DMAP in dry dichloromethane (5.00 mL)
at 0 °C with stirring. The reaction mixture was allowed to
rise to room temperature and stirred overnight. The reaction mixture was then diluted
with dichloromethane (10 mL) and water (10 mL) was added. The mixture was
further extracted with dichloromethane (2 × 10 mL) and the combined organic phase
dried (Na2SO4). Purification by column chromatography (1:1 Et2O/ petroleum ether)
afforded the title compound: (676 mg, 85%) as a dark orange oil. 1H-NMR (300 MHz,
CDCl3): δ = 7.75 (d, J = 15.6 Hz, 1H), 7.57 – 7.48 (m, 1H), 7.48 – 7.39 (m, 2H), 7.39
– 7.20 (m, 8H), 6.61 (dd, J = 3.7, 0.8 Hz, 1H), 6.35 (d, J = 15.6 Hz, 1H), 5.07 (s,
2H). 13C-NMR (75 MHz, CDCl3): δ = 166.2, 154.8, 143.3, 141.6, 134.8, 130.0, 129.9,
128.8, 128.5, 128.0, 117.8, 112.6, 112.1, 46.6. IR (cm-1): 2975, 2867, 1704, 1655,
1492, 1353, 751, 698. HRMS (ASAP+ - TOF) m/z: [M+H]+ Calcd for C20H17N2O4
349.1183; Found 349.1185 (δ ppm = 0.1).
(E)-N-(furan-2-ylmethyl)-3-(4-methoxyphenyl)-N-phenylacrylamide (1k):
(E)ꢀ3ꢀ(4ꢀmethoxyphenyl)acryloyl chloride was prepared by
the addition of thionyl chloride (5.0 mL) to (E)ꢀ3ꢀ(4ꢀ
methoxyphenyl)acrylic acid (712 mg, 4.0 mmol). The solution
was stirred at room temperature for 1 hour. The crude
solution was concentrated to yield pure (E)ꢀ3ꢀ(4ꢀ
methoxyphenyl)acryloyl chloride as a yellow oil. To a solution
of Nꢀ((furanꢀ2ꢀyl)methyl)aniline (161 mg, 0.92 mmol) and pyridine (0.11 mL, 1.4 mmol) in
dichloromethane (2 mL) under nitrogen was added,
a
solution of (E)ꢀ3ꢀ(4ꢀ
methoxyphenyl)acryloyl chloride (275 mg, 1.4 mmol) in dichloromethane (2 mL). The
solution stirred at room temperature for 16 hours where the reaction was quenched with the
addition of dilute HCl (20 mL). The solution was extracted with dichloromethane (3 x 30 mL).
The combined organic layers were dried with sodium sulfate and concentrated to yield the
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crude product as oil (462 mg) which was chromatographed on silica gel (Pet. Ether/EtOAc
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4
5
1
4:1) to yield compound 1k as a yellow oil (168 mg, 54%). H-NMR (300 MHz, CDCl3): δ =
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7
8
9
7.71 (d, J = 15.5 Hz, 1H), 7.47 – 7.35 (m, 4H), 7.29ꢀ7.26 (m, 3H), 7.20 – 7.13 (m, 2H), 6.83
(d, J = 8.8 Hz, 2H), 6.36 – 6.29 (m, 1H), 6.23 (dd, J = 3.2, 0.8 Hz, 1H), 5.02 (s, 2H), 3.81 (s,
3H). 13C-NMR (75 MHz, CDCl3): δ = 166.3, 160.9, 151.1, 142.2, 142.2, 129.6, 128.5, 128.0,
127.9, 116.4, 114.2, 110.5, 109.0, 55.4, 46.0. IR (cm-1): 2932, 1651, 1593, 1574, 1511,
1492, 1455, 1422, 1373, 1303, 1286, 1236, 1146, 1112, 1077, 1030, 1017, 980, 937, 860,
824, 750, 699, 638, 599, 584, 554. HRMS (ESI – ion trap) m/z: [M+H]+ Calcd for C21H20NO3
334.1438; Found 334.1438 (δ ppm 0.1).
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(E)-3-(4-methoxyphenyl)-N-((5-nitrofuran-2-yl)methyl)-N-phenylacrylamide (2k):
Cyclopentꢀ1ꢀeneꢀ1ꢀcarbonyl chloride was prepared by the
addition of oxalyl dichloride (75 ꢁL, 0,875 mmol) to (E)ꢀ3ꢀ
(4ꢀmethoxyphenyl)acrylic acid (130 mg, 0,730 mmol) The
solution was stirred at room temperature for 1 hour. The
crude solution was concentrated to yield pure the
corresponding acyl chloride as a yellow oil. To a solution of Nꢀ((5ꢀnitrofuranꢀ2ꢀ
yl)methyl)aniline (191 mg, 0,875 mmol) and pyridine (89 ꢁL, 1,094 mmol) in dichloromethane
(1.5 mL) under nitrogen was added, a solution of acyl chloride in dichloromethane (1.5 mL).
The solution stirred at room temperature for 16 hours where the reaction was quenched with
the addition of dilute HCl (10 mL). The solution was extracted with dichloromethane (3 x 10
mL). The combined organic layers were dried with sodium sulfate and concentrated to yield
the crude product which was chromatographed on silica gel (Pet. Ether/EtOAc 4:1) to
1
provide compound 2k (239 mg, 87%) as a yellow oil. H-NMR (300 MHz, CDCl3): δ = 7.67
(d, J = 15.5 Hz, 1H), 7.55 – 7.36 (m, 3H), 7.32 – 7.22 (m, 5H), 6.81 (d, J = 8.8 Hz, 2H), 6.58
(d, J = 3.7 Hz, 1H), 6.18 (d, J = 15.5 Hz, 1H), 5.13 – 4.94 (m, 2H), 3.79 (s, 3H). 13C-NMR (75
MHz, CDCl3): δ = 166.6, 161.2, 155.1, 143.1, 141.8, 130.1, 130.0, 129.7, 128.5, 128.1,
127.6, 115.3, 114.3, 112.8, 112.1, 55.4, 46.7. IR (cm-1): 2912, 1712, 1650, 1632, 1593,
1494, 1447, 1393, 1364, 1263, 1170, 1146, 1016, 934, 843, 747. HRMS (ESI – ion trap)
m/z: [M+H]+ Calcd for C21H19N2O5 379.1288; Found 379.1283 (δ ppm ꢀ1.4).
(E)-N-(furan-2-ylmethyl)-3-(4-nitrophenyl)-N-phenylacrylamide (1l):
(E)ꢀ3ꢀ(4ꢀnitrophenyl)acryloyl chloride was prepared by the
O
Ph
addition of thionyl chloride (5.0 mL) to (E)ꢀ3ꢀ(4ꢀ
nitrophenyl)acrylic acid (773 mg, 4.0 mmol). The solution was
stirred at room temperature for 1 hour. The crude solution
was concentrated to yield pure (E)ꢀ3ꢀ(4ꢀnitrophenyl)acryloyl
H
N
O
O2N
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chloride as a yellow oil. To a solution of Nꢀ((furanꢀ2ꢀyl)methyl)aniline (159 mg, 0.9 mmol) and
pyridine (0.11 mL, 1.4 mmol) in dichloromethane (2 mL) under nitrogen was added, a
solution of (E)ꢀ3ꢀ(4ꢀnitrophenyl)acryloyl chloride (296 mg, 1.4 mmol) in dichloromethane (2
mL). The solution stirred at room temperature for 16 hours where the reaction was quenched
with the addition of dilute HCl (20 mL). The solution was extracted with dichloromethane (3 x
30 mL). The combined organic layers were dried with sodium sulfate and concentrated to
yield the crude product as oil (462 mg) which was chromatographed on silica gel (Pet.
Ether/EtOAc 4:1) to yield compound 1l as a white crystals (141 mg, 44%). M. p.: 136ꢀ138
oC. 1H-NMR (300 MHz, CDCl3): δ = 8.12 (d, J = 8.8 Hz, 2H), 7.74 (d, J = 15.6 Hz, 1H), 7.47
~ 7.38 (m, 5H), 7.34 (dd, J = 1.8, 0.8 Hz, 1H), 7.19 ~ 7.09 (m, 2H), 6.40 (d, J = 15.6 Hz, 1H),
6.29 (dd, J = 3.2, 1.9 Hz, 1H), 6.21 (dd, J = 3.2, 0.8 Hz, 1H), 5.00 (s, 2H). 13C-NMR (75 MHz,
CDCl3): δ = 164.9, 150.5, 148.1, 142.3, 141.5, 141.4, 139.6, 129.8, 128.5, 128.4, 128.3,
124.1, 122.9, 110.5, 109.3, 46.1. IR (cm-1): 3075, 2936, 1651, 1614, 1592, 1511, 1503,
1413, 1392, 1338, 1281, 1191, 1077, 1033, 980, 884.
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HRMS (ESI – ion trap) m/z: [M+H]+ Calcd for C20H17N2O4 349.1183; Found 349.1186 (δ
ppm =0.9).
(E)-N-((5-nitrofuran-2-yl)methyl)-3-(4-nitrophenyl)-N-phenylacrylamide (2l):
(E)ꢀ3ꢀ(4ꢀnitrophenyl)acryloyl chloride was prepared by the
addition of thionyl chloride (5.0 mL) to (E)ꢀ3ꢀ(4ꢀ
nitrophenyl)acrylic acid (773 mg, 4.0 mmol). The solution
was stirred at room temperature for 1 hour. The crude
solution was concentrated to yield pure (E)ꢀ3ꢀ(4ꢀ
nitrophenyl)acryloyl chloride as a yellow oil. To a solution
of Nꢀ((5ꢀnitrofuranꢀ2ꢀyl)methyl)aniline (119 mg, 0.55 mmol) and pyridine (0.11 mL, 1.4 mmol)
in dichloromethane (2 mL) under nitrogen was added, a solution of (E)ꢀ3ꢀ(4ꢀ
nitrophenyl)acryloyl chloride (296 mg, 1.4 mmol) in dichloromethane (2 mL). The solution
stirred at room temperature for 16 hours where the reaction was quenched with the addition
of dilute HCl (20 mL). The solution was extracted with dichloromethane (3 x 30 mL). The
combined organic layers were dried with sodium sulfate and concentrated to yield the crude
product as oil (462 mg) which was chromatographed on silica gel (Pet. Ether/EtOAc 4:1) to
1
yield compound 2l as beige crystals (195 mg, 90%). M. p.: 152ꢀ154 oC. H-NMR (300 MHz,
CDCl3): δ = 8.15 (d, J = 8.8 Hz, 2H), 7.74 (d, J = 15.6 Hz, 1H), 7.54 ~ 7.39 (m, 5H), 7.27 (d,
J = 2.1 Hz, 1H), 7.26 (d, J = 3.7 Hz, 2H), 6.58 (d, J = 3.7 Hz, 1H), 6.43 (d, J = 15.5 Hz, 1H),
5.05 (s, 2H). 13C-NMR (75 MHz, CDCl3): δ = 165.3, 154.3, 148.4, 141.3, 141.0, 140.5, 130.3,
129.0, 128.7, 128.1, 124.2, 122.0, 112.6, 112.4, 46.8. IR (cm-1): 3140, 1657, 1620, 1530,
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1504, 1374, 1339, 1240, 1169, 1109, 1017, 979, 867, 735. HRMS (ESI – ion trap) m/z:
[M+H]+ Calcd for C20H16N3O6 394.1039; Found 394.1040 (δ ppm 0.3).
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(E)-N-(furan-2-ylmethyl)-N,3-diphenylbut-2-enamide (1m):
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(E)ꢀ3ꢀphenylbutꢀ2ꢀenoyl chloride was prepared by the addition of
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thionyl chloride (5.7 mL) to (E)ꢀ3ꢀphenylbutꢀ2ꢀenoic acid (650
mg, 4.0 mmol). The solution was stirred at room temperature for
1 hour. The crude solution was concentrated to yield pure (E)ꢀ3ꢀ
phenylbutꢀ2ꢀenoic acid as a yellow oil. To a solution of Nꢀ((1Hꢀfuranꢀ2ꢀyl)methyl)aniline (159
mg, 0.92 mmol) and pyridine (0.11 mL, 1.4 mmol) in dichloromethane (2 mL) under nitrogen
was added, a solution of (E)ꢀ3ꢀphenylbutꢀ2ꢀenoyl chloride (253 mg, 1.4 mmol) in
dichloromethane (2 mL). The solution stirred at room temperature for 16 hours where the
reaction was quenched with the addition of dilute HCl (20 mL). The solution was extracted
with dichloromethane (3 x 30 mL). The combined organic layers were dried with sodium
sulfate and concentrated to yield the crude product as oil (398 mg) which was
chromatographed on silica gel (Pet. Ether/EtOAc 4:1) to yield compound 1m as a yellow oil
1
(255 mg, 87%). H-NMR (300 MHz, CDCl3): δ = 7.42 ~ 7.28 (m, 4H), 7.23 (d, J = 3.3 Hz,
2H), 7.16ꢀ7.12 (m, 4H), 6.29 (dd, J = 3.2, 1.9 Hz, 1H), 6.22 (dd, J = 3.3, 0.9 Hz, 1H), 5.89 (s,
1H), 4.97 (s, 2H), 2.52 (s, 3H). 13C-NMR (75 MHz, CDCl3): δ = 167.0, 151.2, 150.0, 142.9,
142.6, 142.1, 129.5, 128.4, 128.3, 128.1, 127.8, 126.2, 119.6, 110.5, 108.9, 45.5, 18.2. IR
(cm-1): 3058, 1654, 1615, 1593, 1493, 1446, 1366, 1277, 1176, 114, 1075, 1016, 927, 883,
755. HRMS (ESI – ion trap) m/z: [M+H]+ Calcd for C21H20NO2 318.1489; Found 318.1492 (δ
ppm 1.1).
(E)-N-((5-nitrofuran-2-yl)methyl)-N,3-diphenylbut-2-enamide (2m):
(E)ꢀ3ꢀphenylbutꢀ2ꢀenoyl chloride was prepared by the addition
of thionyl chloride (5.7 mL) to (E)ꢀ3ꢀphenylbutꢀ2ꢀenoic acid
(650 mg, 4.0 mmol). The solution was stirred at room
temperature for 1 hour. The crude solution was concentrated
to yield pure (E)ꢀ3ꢀphenylbutꢀ2ꢀenoic acid as a yellow oil. To a
solution of Nꢀ((5ꢀnitrofuranꢀ2ꢀyl)methyl)aniline (200 mg, 0.92 mmol) and pyridine (0.11 mL,
1.4 mmol) in dichloromethane (2 mL) under nitrogen was added, a solution of (E)ꢀ3ꢀ
phenylbutꢀ2ꢀenoyl chloride (253 mg, 1.4 mmol) in dichloromethane (2 mL). The solution
stirred at room temperature for 16 hours where the reaction was quenched with the addition
of dilute HCl (20 mL). The solution was extracted with dichloromethane (3 x 30 mL). The
combined organic layers were dried with sodium sulfate and concentrated to yield the crude
product as oil (462 mg) which was chromatographed on silica gel (Pet. Ether/EtOAc 4:1) to
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