Ionic liquids, microwave irradiation, and the synthesis of aryl Weinreb amides

Article abstract of DOI:10.1007/s00706-017-2089-3

Abstract: The Heck coupling of aryl halides and N-methoxy-N-methylacrylamide was investigated in the room-temperature ionic liquids [BMIM][PF₆], [BMIM][Br], [BMIM][BF₄], [BMIM][OH], [BMIM][HCOO], EAN, PAN, and ETAN. Excellent yields of the expected N-methoxy-N-methylcinnamamides (ca 90%) and purity (>?96%) were afforded on simple diethyl ether extraction from [BMIM][PF₆] and [BMIM][OH]. The described procedure was highly substrate tolerant with methyl, methoxy, fluoro, trifluoromethyl, ester, cyano, hydroxy, naphthyl, and quinolone moieties well tolerated. Poor yields or no reactions were observed with –NH₂ and –NO₂ moieties. The use of microwave irradiation reduced reaction times from 3?h (thermal) to 5–15?min with no substantive effect on reaction outcome. Graphical abstract: [Figure not available: see fulltext.].

Full text of DOI:10.1007/s00706-017-2089-3

Monatsh Chem
https://doi.org/10.1007/s00706-017-2089-3
ORIGINAL PAPER
Ionic liquids, microwave irradiation, and the synthesis of aryl
Weinreb amides
Ahmed Al Otaibi1 Adam McCluskey1
•
Received: 9 May 2017 / Accepted: 7 November 2017
Ó Springer-Verlag GmbH Austria, part of Springer Nature 2017
Abstract The Heck coupling of aryl halides and N-meth-
oxy-N-methylacrylamide was investigated in the room-
temperature ionic liquids [BMIM][PF6], [BMIM][Br],
[BMIM][BF4], [BMIM][OH], [BMIM][HCOO], EAN,
PAN, and ETAN. Excellent yields of the expected N-
methoxy-N-methylcinnamamides (ca 90%) and purity
([ 96%) were afforded on simple diethyl ether extraction
from [BMIM][PF6] and [BMIM][OH]. The described pro-
cedure was highly substrate tolerant with methyl, methoxy,
fluoro, trifluoromethyl, ester, cyano, hydroxy, naphthyl,
and quinolone moieties well tolerated. Poor yields or no
reactions were observed with –NH2 and –NO2 moieties.
The use of microwave irradiation reduced reaction times
from 3 h (thermal) to 5–15 min with no substantive effect
on reaction outcome.
Introduction
N-Methoxy-N-methyl amides, Weinreb amides, have been
widely used as flexible synthetic intermediates in organic
synthesis. They afford rapid access to ketones on treatment
with Grignard and organolithium reagents, and aldehydes
with LiAlH4 [1]. While the synthesis of aromatic a,b-un-
saturated Weinreb amides is poorly described in the litera-
ture, they have been reported from the corresponding
carboxylic acids [2–10], by Horner–Wadsworth–Emmons
and Wittig-type reactions [11–13], Julia and Julia-Kocienski
[14–17] and in the gold-catalysed reaction of vinylidenecy-
clopropanes with N,O-dimethylhydroxylamine [18]. More
recently, there have been preliminary reports of palladium-
catalysed routes to aryl a,b-unsaturated Weinreb amides in
conventional organic solvents [19, 20].
Graphical abstract
Our desire to access a wide range of aromatic ring-sub-
stituted cinnamaldehydes was as part of an ongoing medic-
inal chemistry-focused project. We believed the
corresponding Weinreb amides would provide access to a
shelf stable cinnamaldehyde surrogates, which would be
readily accessed by Heck coupling of aryl halides and N-
methoxy-N-methylacrylamide. We also viewed a Heck
coupling route as more environmentally friendly than via the
acid chloride coupling with N-methoxy-N-methylacry-
lamide. There is little doubt that the Heck reaction has
established itself as one of the most important carbon–car-
bon-forming reactions in organic and medicinal chemistry
[21–24]. However, vinyl ketone substrates are poorly rep-
resented in Heck couplings, with Baker et al. a rare example
of the Heck coupling of a limited range of aryl iodides to
afford the corresponding Weinreb amides [20], but only
under scrupulously anhydrous conditions in DMF. Given the
prior reports of the Heck coupling in a room-temperature
Keywords Microwave irradiation Á Ionic liquids Á
Heck coupling Á Protic ionic liquids
Electronic supplementary material The online version of this
article (https://doi.org/10.1007/s00706-017-2089-3) contains supple-
mentary material, which is available to authorized users.
& AdamMcCluskey
Adam.McCluskey@newcastle.edu.au
1
Department of Chemistry, School of Environmental and Life
Sciences, University Drive, Callaghan, NSW 2308, Australia
123

A. A. Otaibi, A. McCluskey
ionic liquids (RTILs) [25–31] and our desire to effect these
transformations in a green manner [32–35], herein we report
on our investigations on the Heck coupling of Weinreb
amides in traditional, basic, and protic ionic liquids [36–38].
There have been reports noting the significant acceleration of
the Heck coupling under microwave irradiation, which will
also be examined herein [39–42].
previous reports supporting a significant rate of reaction
increase for the Heck coupling of aryl iodides and bromides
through the use of microwave irradiation [39–42]. Exami-
nation of the power/temperature curves versus time showed
no evidence of a temperature overshoot on irradiation of
these ionic liquids (Supplementary Data Fig. S1) [44]. The
outcomes of these evaluations are listed in Table 1.
The Heck coupling proceeded smoothly to produce 3a with
neutral and basic ionic liquids using both batch (thermal) and
microwave methods (Table 1, entries 1–5). The highest yield
(96%) was observed with [BMIM][PF6]; however, excellent
yields were also obtained using [BMIM][Br], [BMIM][BF4],
[BMIM][OH], and [BMIM][HCOO] (Table 1, entries 2–5). No
reaction was observed with the protic ionic liquids EAN, PAN,
and ETAN (Table 1, entries 6–8). This was consistent with the
Heck reaction requiring a basic environment [45].
Results and discussion
Our optimisation studies commenced with the model
Heck coupling of iodobenzene (1a) and N-methoxy-N-
methylacrylamide (2) using Pd(OAc)2, Et3N, and PPh3 in
[BMIM][PF6] (replacing the traditionally used DMF)
(Scheme 1) [25]. While N-methoxy-N-methylacrylamide
is commercially available, it was prepared in-house from
the reaction of N,O-dimethylhydroxylamine hydrochloride
and acryloyl chloride in CH2Cl2 [9, 10].
We next expanded this study to examine the efficacy of
the coupling across a wide array of substituted aryl iodides
with [BMIM][PF6] the solvent of choice. The outcomes of
these reactions are presented in Table 2.
In [BMIM][PF6], the reaction was complete after 3 h at
100 °C, and after ether extractive workup the Heck product
3a was isolated in a 96% yield. The equivalent microwave
procedure with 5-min irradiation at 100 °C afforded 3a in a
94% yield [43]. With this positive outcome, we expanded
our investigation across a total of eight ionic liquids: the
neutral [BMIM][PF6], [BMIM][BF4], and [BMIM][Br]; the
basic [BMIM][OH] and [BMIM][HCOO]; and the protic
EAN, PAN, and ETAN. This finding was in keeping with
In almost every instance presented in Table 2, the Heck
coupling proceeded in high yield under both thermal and
microwave conditions. There was also largely concordance in
yields with both thermal and microwave approaches, with the
microwave approach providing the greener outcome through
more efficient energy transfer and a significant reduction in
reaction time. However, in instances with 2- and 3-substituted
aryl iodides, the yields were invariably lower or the reaction
failed to proceed. This was most evident, under the primary
reaction conditions of 3 h (thermal) and 5 min (microwave)
with electron-donating –OCH3 (1e and 1f), –NH2 (1h and 1i),
and also with the electron-withdrawing –NO2 (1l and 1m)
moieties. Others have observed similar outcomes with these
substituents under different conditions [46–50]. Analogues
with 4-substituted electron-withdrawing moieties were well
tolerated (Table 2, entries 13, 16, and 17), as was increasing
aromaticity (1t–1v; Table 2, entries 19–21) and the intro-
duction of potentially labile groups to the aryl moiety (1s,
Table 2, entry 18) and produced good-to-excellent yields.
Given the poor outcomes noted above with the 2- and
3-substituted aryl iodides 1e and 1f (–OCH3), 1h and 1i (–
NH2), and 1l and 1m (–NO2) we sought to optimise these
reactions further. In all instances, increasing microwave
irradiation to 30 min with the 2-substituted aryl iodides
afforded only an intractable black residue with no evidence
Scheme 1
Table 1 Investigation of the effects of thermal and microwave
approaches on the reaction between iodobenzene (1a) and N-meth-
oxy-N-methylacrylamide (2) to produce 3a in selected ionic liquids
Entry
Aryl halide
Thermal (3 h)
Yield/%a
Microwave (5 min)
Yield/%a
1
2
3
4
5
6
7
8
[BMIM][PF6]
[BMIM][BF4]
[BMIM][Br]
[BMIM][OH]
[BMIM][HCOO]
EAN
96
90
92
95
91
94
91
88
82
88
1
by TLC or H NMR (data not shown) of the desired Heck
product. The 3-substituted aryl iodides on 30-min micro-
wave irradiation and the addition of an additional 4 mol%
Pd(OAc)2 gave good yields of 3f (79%), 3i (53%), and 3m
(75%). Application of these conditions with 1j resulted in an
increased yield from 13% (5-min microwave irradiation) to
66% of 3j. In general, the 3-substituted aryl iodides required
longer reaction times than the 4-substituted aryl iodides [51].
b
b
–
–
b
b
–
PAN
–
b
b
–
ETAN
–
Reagents and conditions: Pd(OAc)2, Et3N, PPh3, 100 °C
aIsolated yield
bNo reaction, starting materials recovered
123

Ionic liquids, microwave irradiation, and the synthesis of aryl Weinreb amides
Table 2 Isolated yields of the Heck reaction of aryl halides 1b–1v and N-methoxy-N-methylacrylamide (2) to produce 3b–3v under thermal and
microwave reaction conditions
Entry
Aryl halide
R1
Product
Thermal (3 h)
Yield/%
Microwave (5 min)
Yield/%
1
1b
1c
1d
1e
1f
2-CH3C6H4
3-CH3C6H4
4-CH3C6H4
2-CH3OC6H4
3-CH3OC6H4
4-CH3OC6H4
2-NH2C6H4
3-NH2C6H4
4-NH2C6H4
4-OHC6H4
3b
3c
3d
3e
3f
96
95
94
95
90
91
73c
2
3
a
–
4
a
–
a
–
5
6
1g
1h
1i
3g
3h
3i
93
a
–
89
a,b
–
7
a
–
8
53c
66c
51
9
1j
3j
23
61
10
11
12
13
14
15
16
17
18
19
20
1k
1l
3k
3l
a
–
a
–
2-NO2C6H4
3-NO2C6H4
4-NO2C6H4
2-BrC6H4
a
–
1m
1n
1o
1p
1q
1r
1s
3m
3n
3o
3p
3q
3r
3s
75c
61
72
77
83
70
71
53
71
75
96
75
78
75
63
61
65
4-BrC6H4
4-CF3C6H4
4-CNC6H4
4-(EtOOC)C6H4
Quinolin-7-yl
1t
3t
1u
3u
O
O
21
1v
Naphthalen-2-yl
3v
94
78
aNo reaction, starting materials recovered
1
bTrace amounts detected by H NMR (\ 5%) after 30-min microwave irradiation at 100 °C
cAfter 5 min an additional aliquot of Pd(OAc)2 (0.04 mmol), Et3N (2 mmol), PPh3 (0.08 mmol), added and microwave irradiation continued for
25 min at 100 °C (30-min total irradiation at 100 °C)
The high efficacy of the aryl iodide coupling encouraged
us to explore the possible coupling of 2 with a range of aryl
bromides and aryl chlorides (Table 3). As anticipated, and
in keeping with literature precedents, the coupling with
aryl chlorides failed (data not shown) [52]. Despite the
known lower reactivity of aryl bromides (versus aryl
iodides) in the Heck coupling, the yields observed with aryl
bromides in [BMIM][PF6] were excellent and comparable
to the outcomes noted with aryl iodides in yield with both
thermal and microwave reactions, albeit requiring longer
reaction times (12-h thermal and 15-min microwave)
[20, 32, 52]. The Heck coupling of bromobenzene with N-
methoxy-N-methylcinnamamide under microwave irradia-
tion in [BMIM][PF6] afforded a 91% yield, while 1,4-di-
bromobenzene afforded a 76% yield (Table 3, entries 1 and
2). Simple electron-donating groups –CH3 and –OCH3
(Table 3, entries 3 and 4) also produced excellent yields.
Conclusion
Herein, we have demonstrated an efficient aryl halide (io-
dides and bromides) Heck coupling with N-methoxy-N-
methylacrylamide in [BMIM][PF6]. Eight ionic liquids
123

A. A. Otaibi, A. McCluskey
Table 3 Isolated yields of the Heck reaction of aryl bromides 4a–4d and N-methoxy-N-methylacrylamide (2) under thermal and microwave
reaction conditions
Entry
Aryl halide
R1
Product
Thermal (12 h)
Yield/%
Microwave (15 min)
Yield/%
1
2
3
4
4a
4b
4c
4d
C6H5
3a
3p
3d
3g
84
75
89
92
91
76
90
88
4-BrC6H4
4-CH3C6H4
4-CH3OC6H4
were examined: the neutral [BMIM][PF6], [BMIM][Br],
[BMIM][BF4]; basic [BMIM][OH], [BMIM][HCOO]; and
protic EAN, PAN, and ETAN. Excepting the protic ionic
liquids, excellent yields of the desired Weinreb amides
were observed on isolation by simple ether extraction from
the ionic liquid, with [BMIM][PF6] used as the main ionic
liquid within this study. Largely, the ether isolated products
were [ 95% pure, but in those cases where the reaction
yield was \ 90% traces of unreacted aryl halide and N-
and, although not specifically studied here, the recycling of
the ionic liquid [20].
Experimental
All reagents were purchased from Sigma-Aldrich, Matrix
Scientific or Lancaster Synthesis, and were used without
purification.
1
methoxy-N-methylacrylamide were evident in the H and
1H and 13C NMR spectra were recorded on a Bruker
AvanceTM AMX 400 MHz spectrometer at 400.13 and
100.62 MHz, respectively. Chemical shifts (d) are reported
in parts per million (ppm) measured to relative the internal
standards. Coupling constants (J) are expressed in hertz
(Hz). Mass spectra were recorded on a Shimadzu LCMS
2010 EV or Agilent 6100 series single quadrupole LCMS
using a mobile phase of 1:1 acetonitrile:H2O with 0.1%
formic acid.
13C NMR spectra (Supporting Information). The described
procedure was widely applicable with methyl, methoxy,
fluoro, trifluoromethyl, ester, cyano, hydroxy, naphthyl,
and quinolone substituted aryl iodides (and bromides)
moieties well tolerated.
In all instances, lower isolated yields of the 2- and
3-substituted aryl Heck products were observed with 5-min
microwave irradiation at 100 °C. However, increasing the
reaction to 30-min duration and increased Pd(OAc)2
loading afforded excellent reaction outcomes. Using the
same methodology, the 4-amino analogue 3j was isolated
in a 66% yield (up from 13% after 5-min microwave
irradiation). We were unable to determine reaction condi-
tions that facilitated access to the 2-/3-substituted 3e/3f (–
OCH3), or the 2-substituted 3h (–NH2) and 3l (–NO2). As
anticipated, no reaction was observed on the use of aryl
chloride, but with a moderate extension of microwave
irradiation to 15 min (up from 5 min) afforded excellent
yields (76–91%) of the Heck products on use of aryl bro-
mides. Across all analogues examined herein, the use of
microwave irradiation typically resulted in much shorter
reaction times and increased product yields. These findings
are in keeping with similar reports [39–42].
Analytical HPLC traces were obtained using a Shi-
madzu system possessing a SIL-20A auto-sampler, dual
LC-20AP pumps, CBM-20A bus module, CTO-20A col-
umn heater, and a SPD-20A UV/Vis detector. This system
was
fitted
with
an
AlltimaTM
C18
5 lm
150 mm 9 4.6 mm column with solvent A: 0.06% triflu-
oroacetic acid (TFA) in water and solvent B: 0.06% TFA in
CH3CN–H2O (90:10). In each case, HPLC traces were
acquired at a flow rate of 2.0 cm3 min-1, gradient 10–100
(%B), over 15.0 min, with detection at 220 and 254 nm.
Melting points were recorded on a Bu¨chi Melting Point
M-565 instrument. IR spectra were recorded on an UTAR-
equipped PerkinElmer Spectrum TwoTM FTIR Spectrom-
eter. Thin-layer chromatography (TLC) was performed on
Merck 60 F254 pre-coated aluminium plates with a thick-
ness of 0.2 mm. Column chromatography was performed
under ‘flash’ conditions on Merck silica gel 60
(230–400 mesh).
The use of ionic liquids and microwave irradiation
facilitated a significant reduction in reaction time, while
allowing simple extractive workup of the Heck product
123

Ionic liquids, microwave irradiation, and the synthesis of aryl Weinreb amides
Microwave synthesis was conducted using a Biotage
Initiator Plus with the system set to the specified temper-
ature and operated under automatic mode. A typical time
versus temperature plot for these microwave irradiation
conditions using the ionic liquid, [BMIM][Br], is provided
in supplementary material (Fig. S1).
reaction mixture was cooled to room temperature, and the
product was extracted by using diethyl ether (5 cm3 and
2 9 10 cm3). The organic layers were combined, dried
over magnesium sulphate, and evaporated in vacuo to
afford N-methoxy-N-methylcinnamamide (3a), yield 94%
as an orange oil.
(E)-N-Methoxy-N-methyl-3-(2-tolyl)acrylamide
(3b) [55, 56]
Yield: 96% (method A), 95% (method B).
Synthesis of N-methoxy-N-methylacrylamide (2) [53]
Sodium hydrogen carbonate (8.40 g, 0.1 mol) was added to
4.87 g N,O-dimethylhydroxylamine hydrochloride (0.05 mol)
in 200 cm3 dichloromethane, and the mixture was stirred for
30 min at room temperature. Acryloyl chloride (4.04 cm3,
0.05 mol) in 10 cm3 dichloromethane was added dropwise to
the solution under ice cooling and stirred for 1 h at room tem-
perature. The solution was dried over magnesium sulphate,
filtered and the solvent removed in vacuo to yield the titled
compound, 5.12 g (89% yield).
(E)-N-Methoxy-N-methyl-3-(3-tolyl)acrylamide
(3c) [57]
Yield: 95% (method A), 90% (method B).
(E)-N-Methoxy-N-methyl-3-(4-tolyl)acrylamide
(3d) [20, 56, 57]
Yield: 94% (method A), 91% (method B).
(E)-N-Methoxy-3-(2-methoxyphenyl)-N-methylacrylamide
(3e) [58]
Synthesis of a,b-unsaturated Weinreb amides:
general methods for synthesis of N-methoxy-N-
methylcinnamamide (3a) [54]
Synthesised using a modification of general procedure
(method A and method B) as described for 3a from N-
methoxy-N-methylacrylamide (2) and 2-iodoanisole (1e).
After 5-min microwave irradiation, an additional 4 mol%
Pd(OAc)2, Et3N (2.15 mmol), PPh3 (0.08 mmol) was
added and microwave irradiation continued for 25 min at
100 °C, to afford the titled compound 3e as a brown oil.
Yield 79%.
Method A (batch reaction): To a reaction vessel (Rad-
leys carousel tube) equipped with a magnetic stirrer were
added 3.00 cm3 of the ionic liquid, 0.05 g palladium (II)
acetate (0.20 mmol), and 0.11 g triphenylphosphine
(0.40 mmol), and the reaction mixture was heated to
100 °C for 5 min with stirring. A second mixture con-
taining 0.52 cm3 triethylamine (3.75 mmol), 0.12 cm3
iodobenzene (1a, 1 mmol), and 0.21 cm3 N-methoxy-N-
methylacrylamide (2, 1 mmol) was prepared, and this
mixture was added dropwise to the reaction mixture
while stirring. Once the addition was complete, the
reaction mixture was heated to 100 °C for 3 h. After this
time, the reaction mixture was allowed to cool to room
temperature. Diethyl ether (5 cm3) was added and the
mixture gently agitated, and the layers were then sepa-
rated. The ionic liquid was extracted further with diethyl
ether (2 9 10 cm3). The organic extracts were com-
bined, dried over MgSO4, and solvent removed in vacuo
to afford pure N-methoxy-N-methylcinnamamide (3a),
yield 96% as an orange oil.
(E)-N-Methoxy-3-(4-methoxyphenyl)-N-methylacrylamide
(3g) [20, 56, 58]
Yield: 93% (method A), 89% (method B).
(E)-3-(2-Aminophenyl)-N-methoxy-N-methylacrylamide
(3h, C11H14N2O)
Yield: 96% (method A), 95% (method B); 1H NMR
(400 MHz, CDCl3): d = 7.80 (d, J = 15.6 Hz, 1H), 7.43
(dd, J = 7.8, 1.5 Hz, 1H), 7.15 (ddd, J = 8.4, 7.3, 1.5 Hz,
1H), 6.94 (d, J = 15.6 Hz, 1H), 6.79–6.73 (m, 1H), 6.74–
6.67 (m, 1H), 3.76 (s, 3H), 3.31 (s, 3H), 3.19 (br, 2H) ppm;
13C NMR (101 MHz, CDCl3): d = 167.2, 145.7, 138.9,
131.0, 128.1, 120.8, 118.9, 116.7, 116.1, 62.0, 31.1 ppm;
ꢀ
IR: m = 3354, 2943, 2833,1706, 1645, 1607, 1425, 1280,
1020, 836, 757, 672 cm-1; MS (ESI?): m/z = 207
([M ? H]?); HRMS (ESI?): calc. for C11H15N2O
(M ? H) 207.1134.
Method B (microwave reaction): To a microwave tube
were added 2.00 cm3 of the ionic liquid, 0.009 g palladium
(II) acetate (0.04 mmol), and 0.021 g triphenylphosphine
(0.08 mmol) with a magnetic stirrer, and the reaction was
stirred at room temperature for 5 min. Then, 0.3 cm3 tri-
ethylamine (2.15 mmol), 0.12 cm3 iodobenzene (1a,
1 mmol), and 0.20 cm3 N-methoxy-N-methylacrylamide
(2, 0.95 mmol) were added. The mixture was stirred at
room temperature for 5 min and then subjected to micro-
wave irradiation for 5 min at 100 °C. After this time, the
(E)-3-(2-Aminophenyl)-N-methoxy-N-methylacrylamide
(3i, C11H14N2O)
Yield: 0% (method A), 53% (method B); yellow oil; H
1
NMR (400 MHz, CDCl3): d = 7.64 (d, J = 15.8 Hz, 1H),
7.17 (t, J = 7.8 Hz, 1H), 7.01–6.94 (m, 2H), 6.88–6.86 (m,
1H), 6.69 (dd, J = 7.9, 1.6 Hz, 1H), 3.76 (s, 3H), 3.30 (s,
3H), 1.60 (s, 2H) ppm; 13C NMR (101 MHz, CDCl3):
d = 167.2, 146.8, 143.9, 136.3, 129.8, 118.7, 116.8, 115.7,
123

A. A. Otaibi, A. McCluskey
114.4, 62.0, 32.7 ppm; IR (ATR): mꢀ = 3328, 2940, 2833,
1734,1695, 1645, 1634, 1598, 1021, 781, 716, 699 cm-1
(E)-3-(4-Bromophenyl)-N-methoxy-N-methylacrylamide
;
(3p, C11H12BrNO2)
Yield: 75% (method A), 77% (method B); brown oil; H
1
MS (ESI?): m/z = 207 ([M ? H]?); HRMS (ESI?): calc.
for C11H15N2O (M ? H) 207.1134.
NMR (400 MHz, CDCl3): d = 7.57 (d, J = 15.8 Hz, 1H),
7.42 (d, J = 8.5 Hz, 2H), 7.33 (d, J = 8.5 Hz, 2H), 6.92
(d, J = 15.8 Hz, 1H), 3.67 (s, 3H), 3.21 (s, 3H) ppm; 13C
NMR (101 MHz, CDCl3): d = 166.8, 142.3, 133.3, 132.1,
(E)-3-(4-Aminophenyl)-N-methoxy-N-methylacrylamide
(3j, C11H14N2O)
Yield: 23% (method A), 66% (method B); brown oil; H
1
ꢀ
129.6, 124.1, 116.6, 62.1, 32.7 ppm; IR (ATR): m = 3392,
2966, 2937, 1651, 1615, 1381, 1178, 1025, 999, 855, 754,
NMR (400 MHz, CDCl3): d = 7.64 (d, J = 15.7 Hz, 1H),
7.39 (d, J = 8.1 Hz, 2H), 6.83 (d, J = 15.7 Hz, 1H), 6.65
(d, J = 8.2 Hz, 2H), 3.90 (br, 2H), 3.50 (s, 3H), 3.29 (s,
3H) ppm; 13C NMR (101 MHz, CDCl3): d = 167.9, 148.4,
143.8, 129.9, 125.7, 114.9, 111.6, 61.9, 32.7 ppm; IR
665, 542 cm-1; MS (ESI?): m/z = 271 ([M ? H]?).
(E)-N-Methoxy-N-methyl-3-(4-(trifluo-
romethyl)phenyl)acrylamide (3q) [61]
Yield: 78% (method A), 83% (method B); brown oil.
ꢀ
(ATR): m = 3347, 3231, 2938, 2832, 1739, 1634, 1606,
1175, 1098, 1001, 824, 770, 513 cm-1; MS (ESI?): m/
z = 207 ([M ? H]?); HRMS (ESI?): calc. for C11H15N2O
(M ? H) 207.1134.
(E)-3-(4-Cyanophenyl)-N-methoxy-N-methylacrylamide
(3r) [20]
Yield: 75% (method A), 70% (method B); brown oil.
(E)-3-(4-Hydroxyphenyl)-N-methoxy-N-methylacrylamide
(3k) [59]
Yield: 61% (method A), 51% (method B); brown oil.
Ethyl (E)-4-[3-(methoxy(methyl)amino]-3-oxoprop-1-en-1-
yl)benzoate (3s, C14H17NO4)
Yield: 63% (method A), 71% (method B); brown oil; H
1
(E)-N-Methoxy-N-methyl-3-(3-nitrophenyl)acrylamide
NMR (400 MHz, CDCl3): d = 8.01 (d, J = 8.3 Hz, 2H),
7.71 (d, J = 15.8 Hz, 1H), 7.59 (d, J = 8.3 Hz, 2H), 7.08
(d, J = 15.8 Hz, 1H), 4.38–4.33 (q, J = 7.1 Hz, 2H), 3.75
(s, 3H), 3.29 (s, 3H), 1.38–1.35 (t, J = 7.1 Hz, 3H) ppm;
13C NMR (101 MHz, CDCl3): d = 166.5, 166.1, 142.2,
139.4, 131.4, 130.0, 127.9, 118.1, 62.1, 61.2, 32.6,
14.4 ppm; IR (ATR): mꢀ = 3367, 2979, 2939, 1712, 1655,
1608, 1277, 1178, 1104, 1019, 844, 770, 543 cm-1; MS
(ESI?): m/z = 264 ([M ? H]?); HRMS (ESI?): calc. for
C14H18NO4 (M ? H) 264.1236.
(3m, C11H12N2O4)
Yield: 0% (method A), 75% (method B); brown oil; H
1
NMR (400 MHz, CDCl3): d = 8.42 (s, 1H), 8.20 (d,
J = 8.2 Hz, 1H), 7.83 (d, J = 7.7 Hz, 1H), 7.75 (d,
J = 15.8 Hz, 1H), 7.57 (t, J = 8.0 Hz, 1H), 7.15 (d,
J = 15.8 Hz, 1H), 3.79 (s, 3H), 3.32 (s, 3H) ppm; 13C
NMR (101 MHz, CDCl3): d = 166.0, 148.8, 140.8, 137.0,
134.3, 130.0, 124.2, 122.1, 119.0, 62.2, 32.6 ppm; IR
(ATR): mꢀ = 3464, 2983, 2938, 1734, 1656, 1622, 1530,
1373, 1236, 1043, 848, 740 cm-1; MS (ESI?): m/z = 237
([M ? H]?); HRMS (ESI?): calc. for C11H13N2O4
(M ? H) 237.0875.
(E)-N-Methoxy-N-methyl-3-(quinolin-7-yl)acrylamide
(3t) [62]
Yield: 61% (method A), 53% (method B); brown oil.
(E)-N-Methoxy-N-methyl-3-(4-nitrophenyl)acrylamide
(3n) [60]
Yield: 75% (method A), 61% (method B); brown oil.
(E)-3-(2,3-Dihydrobenzo[b] [1,4] dioxin-6-yl)-N-methoxy-
N-methylacrylamide (3u, C13H15NO4)
Yield: 65% (method A), 71% (method B); brown oil; H
1
(E)-3-(2-Bromophenyl)-N-methoxy-N-methylacrylamide
NMR (400 MHz, CDCl3): d = 7.60 (d, J = 15.7 Hz, 1H),
7.10–7.04 (m, 2H), 6.89–6.83 (m, 2H), 4.26 (s, 4H), 3.73
(s, 3H), 3.28 (s, 3H) ppm; 13C NMR (101 MHz, CDCl3):
d = 167.3, 145.4, 143.7, 143.1, 129.0, 122.1, 117.7, 116.6,
(3o, C11H12BrNO2)
Yield: 96% (method A), 72% (method B); brown oil; H
1
NMR (400 MHz, CDCl3): d = 8.0 (d, J = 15.7 Hz, 1H),
7.62–7.59 (m, 2H), 7.31 (t, J = 7.5 Hz, 1H), 7.20 (td,
J = 7.7, 1.7 Hz, 1H), 6.98 (d, J = 15.7 Hz, 1H), 3.76 (s,
3H), 3.31 (s, 3H) ppm; 13C NMR (101 MHz, CDCl3):
d = 166.4, 142.1, 135.5, 133.5, 130.8, 128.0, 127.7, 125.4,
ꢀ
114.1, 64.6, 64.3, 61.9, 32.6 ppm; IR (ATR): m = 3391,
2935, 1739, 1651, 1580, 1506, 1434, 1378, 1291, 1249,
1067, 1024, 889, 850, 740 cm-1; LRMS (ESI?): m/
z = 250 ([M ? H]?).
ꢀ
119.0, 62.1, 32.6 ppm; IR (ATR): m = 2966, 2829, 1737,
(E)-N-Methoxy-N-methyl-3-(naphthalen-2-yl)acrylamide
(3v) [20]
Yield: 94% (method A), 78% (method B); brown oil.
1651, 1615, 1467, 1381, 1201, 1178, 1025, 754, 665,
542 cm-1; LRMS (ESI?): m/z = 271 (79Br, [M ? H]?);
HRMS (ESI?): calc. for C11H13BrNO2 (79Br, M ? H)
270.0130.
123

Ionic liquids, microwave irradiation, and the synthesis of aryl Weinreb amides
Acknowledgements AAO thanks the Saudi Arabian government for
the provision of a PhD scholarship. AM acknowledges project
funding from the Australian Research Council.
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