Transformation of arylcarboxamides into 1,3-dioxo-1,3-dihydroisobenzofuran-4-carboxamides: Dedicated to Professor Emeritus Dr. Miha Ti?ler on the occasion of his 90th birthday

Article abstract of DOI:10.1016/j.tet.2016.12.007

In this paper, we describe a four step synthesis of 1,3-dioxo-1,3-dihydroisobenzofuran-4-carboxamides starting from (hetero)arylcarboxamides. These are first transformed to the corresponding acetamidines followed by condensation to substituted [(oxazol-4(5H)-ylidene)ethyl]benzamides, which are further derivatized to substituted [(oxazol-4(5H)-ylidene)allyl]benzamides. The latter compounds undergo a supposed [4 + 2] cycloaddition with maleic anhydride, leading to the final products.

Full text of DOI:10.1016/j.tet.2016.12.007

Accepted Manuscript
Transformation of arylcarboxamides into 1,3-dioxo-1,3-dihydroisobenzofuran-4-
carboxamides
Benjamin Prek, Jure Bezenšek, Marta Počkaj, Branko Stanovnik
PII:
S0040-4020(16)31275-3
10.1016/j.tet.2016.12.007
TET 28299
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 7 September 2016
Revised Date: 24 November 2016
Accepted Date: 6 December 2016
Please cite this article as: Prek B, Bezenšek J, Počkaj M, Stanovnik B, Transformation of
arylcarboxamides into 1,3-dioxo-1,3-dihydroisobenzofuran-4-carboxamides, Tetrahedron (2017), doi:
10.1016/j.tet.2016.12.007.
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ACCEPTED MANUSCRIPT
Transformation of arylcarboxamides into
1,3-dioxo-1,3-dihydroisobenzofuran-4-
carboxamides
Leave this area blank for abstract info.
Benjamin Prek, Jure Bezenšek, Marta Počkaj,
Branko Stanovnik*
Faculty of Chemistry and Chemical Technology,
University of Ljubljana, Večna pot 113, P.O.Box 537,
1000 Ljubljana, Slovenia
The synthesis of 1,3-dioxo-1,3-dihydroisobenzofuran-
4-carboxamides in four steps starting from (hetero)-
arylcarboxamides is described
-Graphical Abstract

2
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Transformation of arylcarboxamides into 1,3-dioxo-1,3-dihydroisobenzofuran-4-
carboxamides
Benjamin Prek, Jure Bezenšek, Marta Počkaj, Branko Stanovnik*
Faculty of Chemistry and Chemcal Technology, University of Ljubljana
Večna pot 113. P. O Box 135, 1000 Ljubljana, Slovenia
e-mail: branko.stanovnik@fkkt.uni-lj.si
Abstract
In this paper, we describe a four step synthesis of 1,3-dioxo-1,3-dihydroisobenzofuran-4-
carboxamides starting from (hetero)arylcarboxamides. These are first transformed to the
corresponding acetamidines followed by condensation to substituted [(oxazol-4(5H)-
ylidene)ethyl]benzamides, which are further derivatized to substituted [(oxazol-4(5H)-
ylidene)allyl]benzamides. The latter compounds undergo a supposed [4+2] cycloaddition with
maleic anhydride, leading to the final products.
Keywords
Enaminones, Carboxamides, Aroylacetamidines, (E)-N-(1-(dimethylamino)ethylidene)-
carboxamides, 1,3-dioxo-1,3-dihydroisobenzofuran-4-carboxamides
Dedicated to Professor Emeritus Dr. Miha Tišler on the occasion of his 90th birthday
1.Introduction
In our laboratory, much work has been done on 3-dimethylaminopropenoates and related
enaminones. These are a class of highly stable, readily available, versatile compounds with
widespread use in organic synthesis,1-3 including the preparation of natural products and their
analogues, such as aplysinopsins,4,5 meridianines,6,7 and other similar compounds.8
Recently, we described a microwave-assisted [2+2] cycloaddition of enaminones to electron-
poor acetylenes which lead to rearrangements and ring expansion reactions, as well as to
polysubstituted butadienes, which were further transformed into carbocyclic and heterocyclic
systems.9,10 The expansion of the enaminone methodology, where amide acetals are used as
reagents, was also demonstrated in the synthesis of polysubstituted benzene derivatives

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starting from methyl ketones (acetyl compounds) and compounds with an active methylene
group. In a simple, microwave-assisted reaction the formation of enaminone intermediates,
which in this case were not isolated, were key in these syntheses.11
In an analogous manner, starting from commercially affordable carboxamides, again using
N,N-dimethylacetamide dimethylacetal (DMADMA) as the building block, electron rich
pyridine derivatives were prepared.12 (Scheme 1).
Scheme 1: Transformation of carboxamides into polysusbstituted pyridines.
In this instance, similar as enaminones in the synthesis benzene derivatives, the amidine
intermediates were key intermediates in these syntheses.
From a structural point of view, formamidines and acetamidines are nitrogen containing
analogues of propenoates, and as such were interesting to us for further investigation.
Amidines are also very important building blocks in organic and heterocyclic synthesis.13,14
They also have diverse application in areas such as catalyst design,15 material science,16
medicinal chemistry17 and superbase promoted reactions.18 Starting from the general
acetamidine synthesis developed by Raczynska et al,19 we prepared various amidines, starting
from simple, commercially available (hetero)aryl carboxamides. The reaction sequence of
form/acet-amidine formation, followed by substitution of the dimethylamino group with a
heterocyclic C-nucleophile, further elongation of the conjugated system and final reaction
with maleic anhydride in a supposed [4+2] Diels-Alder reaction under microwave irradiation,
resulted in formation of 1,3-dioxo-1,3-dihydroisobenzofuran-4-carboxamides. As is described

4
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in this publication, using only elementary chemical reactions we were able to prepare a new
type of system, appropriate for an ever-interesting Diels-Alder reaction which led to the final
phthalic anhydride derivatives.
2. Results and discussion
Aryl and heteroaryl acetamidines 2a-j were prepared from aryl and
heteroarycarboxamides (1) and dimethylacetamide dimethyl acetal by heating in anhydrous
toluene. After cooling, the crystalline products were separated by filtration, washed with
diethyl ether and crystallized from the appropriate solvent. They reacted with 2-phenyloxazol-
5(4H)-one (5) prepared in situ from hippuric acid (4) by heating in acetic anhydride to afford
N-[1-(5-oxo-2-phenyloxazol-4(5H)-ylidene)ethyl](hetero)arylamides 6a-g (Scheme 2, Table
1).
Scheme 2: Synthesis of acetamidines 2 and (hetero)arylamides 6.
Yield
2a-g (%)
48
Yield
6a-g (%)
67
Compound
R
Compound
Ph
2a
2b
6a
6b
87
68
67
75
2c
6c
69
58
2d
6d
98
63
53
41
2e
2f
6e
6f

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94
61
2g
6g
Table 1: (E)-N-[(dimethylamino)ethylidene]arylamides and N-[1-(5-oxo-2-phenyloxazol-
4(5H)-ylidene)ethyl]arylamides
The methyl group in compounds 6a-f reacts with N,N-dimethyl formamide dimethyl acetal
(DMFDMA) in toluene at 90 °C to give the corresponding N-((1E,2E)-3-(dimethylamino)-1-
(5-oxo-2-phenyloxazol-4(5H)-ylidene)aryl amides 7a-f. (Scheme 3, Table 2).
Scheme 3: Synthesis of N-((1E,2E)-3-(dimethylamino)-1-(5-oxo-2-phenyloxazol-
4(5H)ylidene)arylamides 7a-f and N,N-dimethyl-7-substituted-1,2,-dioxo-1,3-dihydroiso-
benzofuran-4-carboxamides 8a-f.

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Reaction time Yield
Product
7a
R
(h)
(%)
Ph-
2
85
2
1
37
90
93
87b
7c
0.5
7d
2
97
94
7e
7f
Ph-CH2O-
0.5
Table 2: N-((1E,2E)-3-(dimethylamino)-1-(5-oxo-2-phenyloxazol-4(5H)-ylidene)aryl amides
7a-f.
Reaction time Yield
Product
8a
R
(min)
(%)
Ph-
40
48
25
50
25
52
42
41
8b
8c
8d
15
20
50
34
8e
8f
Ph-CH2O-
Table 3: N,N-dimethyl-7-substituted-1,2,-dioxo-1,3-dihydroisobenzofuran-4-carboxamides
8a-f.

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Compounds 7a-f exist in s-cis orientation and as electron-rich compounds, they are
suitable for [4+2] cycloadditions with electron-poor maleic anhydride. In this connection, the
reaction of compound 7a with maleic anhydride was carried out in dry toluene under
microwave irradiation for 20–40 minutes at 160–180 °C. On the basis of analytical data for
C, H, and N, as well as spectroscopic data it became clear that major rearrangement was
taking place during this reaction. On the basis of this evidence and on the mass spectrum, m/e
= 338 (M+), it was immediately evident that one of the benzamide groups had been
eliminated. The starting compound 7a contained two benzamide groups, one is the
carboxamide group and the other one which originates from N-benzoyl glycine and is
incorporated in the oxazole ring. In order to solve this problem the reaction was repeated with
compounds 7b-f, where the substituent on the starting carboxamide would help answer the
question of which group is eliminated during the reaction. It turned out that benzoyl group
originating from hippuric acid was eliminated during the reaction. The structure of 8a was
also confirmed by X-ray analysis.
The following reaction path was proposed for this transformation:
Scheme 4. Proposed reaction path for the formation of 1,2-dioxo-1,3-dihydroisobenzofuran-
4-carboxamides 8a-f.

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3. Structure determination
1
The structures of new compounds were determined by H and 13C NMR, IR and
HRMS spectral characteristics, and by elemental analyses for C, H, and N. The structure of
compounds 2c,h, 6b,d,f, 7a,d,f, and 8a were supported also by X–ray analysis.
1
The H NMR spectra of substituted acetamidines 2a-h show a singlet integrating for three
protons for a methyl group in the range of δ =2.24–2.44 ppm and a singlet integrating for six
protons for the dimethylamino group at δ = 3.04–3.24 ppm. Since the orientation around the
double bond was not possible to determine on the basis of NMR spectra, the X–ray analyses
for 2c,g were carried out to show that this type of compounds exist in (E)–form.
1
Compound 6f shows in H NMR spectrum two singlets at δ = 2.84 and 2.88 ppm and two
singlets for NH proton of the carbamate group at δ = 8.42 and 9.96 ppm indicating that it
exists in solution in the (E)– and (Z)– forms. However, it crystallizes only in the (E)– form.
All other compounds, 6a-e,g exist in solution only in (E)– form concluded on the basis of
chemical shift for the amide proton at δ = 11.33–11.50 ppm. The structures for 6b,d,f were
supported by X–ray analyses.
Compounds 7a-f show two doublets in the range of δ = 7.01–7.08 and δ = 9.34–9.40 ppm
3
with a coupling constant J = 12.5–12.6 Hz characteristic for protons attached to the C=C
double bond indicating that the orientation around the newly formed double bond is (E), two
singlets for two methyl groups of NMe2 group in the range of δ = 3.08–3.11 ppm and δ =
3.33–3.39 ppm, and a singlet in the range of δ = 11.89–12.09 ppm for the NH group which
show no correlation in 2D NMR spectra. The structures of 7a,d, f were confirmed by X–ray
analyses (Figure 1).
Compounds 8a-f show two singlets in the range of δ = 2.79–2.83 ppm and δ = 3.03–3.06 ppm
corresponding to two methyl groups of the N,N-dimethylamino group, two doublets in the
range of δ = 7.83–7.96 ppm and δ = 8.39–8.55 ppm with a coupning constant 3J = 7.8–8.4 Hz,
characteristic for aromatic ortho protons, a multiplet for benzoyl group, and a singlet at δ =
10.14 ppm for an amide proton.
The NMR apectral data are also in agreement with the proposed structures. (Table 4).

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δ C=O (NMe2)
δ 5-CH δ 6-CH J5H-6H
δ NMe2
δ NH
Solvent
Product
(ppm)
7.91
(ppm) (Hz)
(ppm)
(ppm)
165.0
165.0
165.0
165.0
165.0
165.0
(ppm)
8.55
8.39
8.40
8.36
8.48
8.50
8.4 2.82 in 3.05
7.8 2.83 in 3.06
8.3 2.83 in 3.06
8.2 2.83 in 3.06
8.4 2.82 in 3.05
8.5 2.79 in 3.03
10.43 DMSO-d6
10.77 DMSO-d6
10.81 DMSO-d6
10.90 DMSO-d6
10.47 DMSO-d6
9.39 DMSO-d6
8a
8b
8c
8d
8e
8f
7.92
7.93
7.91-7.96
7.90
7.83
4. Conclusion
A four step synthesis of 1,3-dioxo-1,3-dihydroisobenzofuran-4-carboxamides starting from
(hetero)arylcarboxamides is described. Carboxamides are first transformed to the
corresponding acetamidines followed by condensation to substituted [(oxazol-4(5H)-
ylidene)ethyl]benzamides, which are further transformed into substituted [(oxazol-4(5H)-
ylidene)allyl]benzamides. The latter compounds undergo a [4+2] cycloaddition with maleic
anhydride leading to the final products.
O3
C9
C5
C6
C7
N3
C10
C8
C4
N2
O2
C1
N1
C11
C3
C2
O1

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O2
C7
O1
C4
C1
C5
C8
N2
C6
N1
C3
C2
C9
C9
O3
O2
C18
N3
N2
C10
C17
C5
C6
C7
C13
C8
C4
N1
C12
C16
O1
C3
C1
C11
O5
C14
O4
C15
C2

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C11
C2
O3
C1
N1
C3
C18
C19
C9
C7
N2
C10
C17
C6
C13
C12
C4
C14
C5
C8
O4
O1
C16
C15
O2
C20
C21
C19
C18
O3
C15
C16
N2
C17
C13
C10
C11
C12
O2
N3
C9
C8
O1
C14
N1
C7
C6
C5
C1
C2
C4
C3
C11
N3
C12
O2
O3
C10
C9
N1
C2
C7
N2
C3
N4
C13
C8
C17
C1
O1
C18
C15
C14
C6
C19
C4
C16
C5
O4
O5
C20
C21

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C22
N3
C21
C20
O2
C19
C9
C18
N2
C17
C16
N1
C13
C10
C8
C12
C7
C6
C1
O1
C15
C11
C14
O4
C2
O3
C5
C4
C3
C18
O4
N2
C14
C12
C17
C13
C15
C7
C11
C5
N1
C16
C6
C3
O5
C4
C8
C10
O3
C2
C1
C9
O1
O2
Figure 1: ORTEP view of compounds 2c, 2g, 6b, 6d, 6f, 7a, 7d, 7f, 8a
5. Experimental
5.1 General
Melting points were determined on a Stanford Research Systems MPA100 OptiMelt
automated melting point system. The NMR spectra were obtained on a Bruker Avance DPX
1
13
300 at 300 MHz for H and 75.5 MHz for C and on a Bruker Avance III UltraShield 500
plus at 500 MHz for 1H and 126 MHz for 13C, using CDCl3 and DMSO-d6 with Me4Si as the
internal standard, as solvents. Mass spectra were recorded on an Agilent 6224 Accurate Mass
TOF LC/MS spectrometer, IR spectra on a Perkin Elmer Spectrum BX FTIR
spectrophotometer. Microanalyses were performed on a Perkin-Elmer CHN Analyzer 2400 II.
Column chromatography (CC) was performed on silica gel (Fluka, Silica gel 60, particle size
35-70 ꢀm).

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Microwave irradiations were performed on CEM Corporation Discover microwave unit.
Column chromatography was performed on silica gel (Fluka, silica gel 60, 0.04–0.06 mm).
5.2 General procedure for the preparation of (E)-N-(1-(dimethylamino)ethylidene)-
carboxamides
The starting amides (30.0 mmol) were suspended in toluene (40 mL) and 1.5
equivalents of N,N-dimethylacetamide dimethyl acetal (45.0 mmol) were added. The reaction
mixture was refluxed for 2-10 h. The reaction mixture was then cooled. Generally, the
corresponding products deposited upon cooling and were thus collected via vacuum filtration
and washed with diethyl ether to remove any impurities. In other cases, the volatile
components were removed under reduced pressure and the products were obtained and
purified with column chromatography, using various mixtures of ethyl acetate/petroleum ether
as the eluent.
5.2.1 (E)-N-(1-(Dimethylamino)ethylidene)-3-nitrobenzamide (2d)
Prepared from 3-nitrobenzamide (1d; 4.980 g, 30.0 mmol), reflux for 8 h. The product was
isolated from the reaction mixture via vacuum filtration, which was followed by washing with
diethyl ether. Yield: 69% (4.871 g), off-white solid; mp = 92.7-96.4 °C. 1H NMR (CDCl3, 500
MHz): δ 2.40 (3H, s, CH3); 3.19 (3H, s, N(CH3)2); 3.27 (3H, s, N(CH3)2); 7.57 (1H, t, J = 7.9
Hz, 5-CH); 8.30 (1H, dd, J1 = 8.1 Hz, J2 = 1.2 Hz, 4-CH); 8.46-8.49 (1H, m, 6-CH); 8.96 (1H,
13
br. s, 2-CH). C NMR (CDCl3, 125 MHz): δ 17.8, 38.7, 124.5, 125.6, 128.9, 135.1, 139,7,
148.1, 167.6, 172.8. EA C11H13N3O3 requires: C 56.16; H 5.57; N 17.86. Found: C 55.90; H
5.49; N 17.81. EI-HRMS: m/z = 236.1030 (MH+) found; C11H14N3O3 calculated: m/z =
236.1030 (MH+). νmax 3365, 3162, 3084, 1711, 1616, 1565, 1521, 1398, 1367, 1343, 1308,
1238, 1191, 1070, 1017, 951, 822, 702.
5.2.2 (E)-N-(1-(Dimethylamino)ethylidene)-4-fluorobenzamide (2e)

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Prepared from 4-fluorobenzamide (1e; 330 mg, 2.37 mmol), reflux for 8 h. The product was
isolated and purified with column chromatography, using a 2:1 mixture of ethyl acetate and
petroleum ether as the mobile phase. Yield: 98% (493 mg), yellow oil. 1H NMR (CDCl3, 500
MHz): δ 2.30 (3H, s, CH3); 3.08 (3H, br. s, N(CH3)2); 3.16 (3H, br. s, N(CH3)2); 7.02-7.08
(2H, m, 3-CH and 4-CH); 8.12-8.18 (2H, m, 2-CH and 6-CH). 13C NMR (CDCl3, 125 MHz):
δ 17.4, 38.2, 38.3, 114.6 (d, J = 21.5 Hz), 131.7 (d, J = 8.9 Hz), 133.9 (br. s), 164.8 (d, J =
250 Hz), 174.6. EI-HRMS: m/z = 209.1086 (MH+) found; C11H14FN2O calculated: m/z =
209.1085 (MH+). νmax 3065, 2929, 2894, 1621, 1555, 1497, 1421, 1395, 1305, 1293, 1237,
1212, 1143, 1085, 1021, 936, 847, 806, 768, 685.

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5.2.3 Benzyl (E)-(1-(dimethylamino)ethylidene)carbamate (2f)
Prepared from benzyl carbamate (1f; 3.078 g, 20.40 mmol), reflux for 4 h. The product was
isolated from the reaction mixture with column chromatography, using a 4:1 mixture of ethyl
1
acetate and petroleum ether as the mobile phase. Yield: 63% (2.816 g), yellow oil. H NMR
(CDCl3, 500 MHz): δ 2.24 (3H, s, CH3); 3.04 (3H, br. s, N(CH3)2); 3.06 (3H, br. s, N(CH3)2);
5.14 (2H, s, CH2); 7.25-7.30 (1H, m, 4H-Ph); 7.30-7.37 (2H, m, 3H-Ph and 5H-Ph); 7.39-7.43
(2H, m, 2H-Ph and 6H-Ph). 13C NMR (CDCl3, 125 MHz): δ 17.3, 38.3, 38.6, 67.2, 127.8,
128.2, 128.3, 137.1, 162.5, 166.3. EI-HRMS: m/z = 221.1284 (MH+) found; C12H17N2O2
calculated: m/z = 221.1285 (MH+). νmax 3031, 2932, 2894, 2819,1665, 1571, 1497, 1453,
1422, 1399, 1372, 1283, 1210, 1184, 1049, 1020, 809, 740, 698.
5.2.4 (E)-N-(1-(Dimethylamino)ethylidene)furan-2-carboxamide (2g).
Prepared from furan-2-carboxamide (1f; 164 mg, 1.48 mmol), reflux for 2 h. Volatile
components were removed under vacuo, the residue was dissolved in H2O (20 mL) and
extracted with dichloromethane (3 x 5 mL). The organic phases were collected, dried over
anhydrous Na2SO4 and concentrated under reduced pressure to afford the final product. Yield:
1
94% (250 mg), brown oil. H NMR (CDCl3, 500 MHz): δ 2.35 (3H, s, CH3); 3.12 (3H, s,
N(CH3)2); 3.19 (3H, s, N(CH3)2); 6.46 (1H, dd, J1 = 3.4 Hz, J2 = 1.7 Hz, 4-CH); 7.07 (1H, dd,
13
J1 = 3.4 Hz, J2 = 0.9 Hz, 3-CH); 7.52 (1H, dd, J1 = 1.7 Hz, J2 = 0.9 Hz, 5-CH). C NMR
(CDCl3, 125 MHz): δ 17.9, 38.5, 111.6, 115.6, 144.9, 152.3, 166.7, 167.5. EA C9H12N2O2
requires: C 59.99; H 6.71; N 15.55. Found: C 59.85; H 6.83; N 15.35. EI-HRMS: m/z =
181.0970 (MH+) found; C9H13N2O2 calculated: m/z = 181.0972 (MH+). νmax 2927, 2878, 1611,
1574, 1551, 1501, 1470, 1421, 1387, 1310, 1259, 1196, 1166, 1113, 1024, 1008, 946, 823,
763.

16
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5.3. General procedure for the preparation of substituted-N-(1-(5-oxo-2-phenyloxazol-
4(5H)-ylidene)ethyl)benzamides:
Hippuric acid (1.200 g, 6.70 mmol) was added to acetic anhydride (8 mL). The
reaction mixture was heated to 85 °C and stirred vigorously until the reaction mixture became
yellow in appearance, meaning that the 2-phenyloxazol-5(4H)-one had formed in situ.
Immediate addition of N-(1-(dimethylamino)ethylidene)-carboxamides (4.44 mmol) followed.
The reaction mixture was than stirred at 85 °C for 0.5-4 h. The reaction mixture was then
cooled to room temperature, upon which the products participated from the reaction mixture.
The products were filtered off and washed with cold ethanol.
5.3.1. N-(1-(5-Oxo-2-phenyloxazol-4(5H)-ylidene)ethyl)benzamide (6a).
Prepared from N-(1-(dimethylamino)ethylidene)benzamide (2a; 293 mg, 1.50 mmol) and
hippuric acid (415 mg, 2.30 mmol) in acetic anhydride (3 mL). Stirred at 85 °C for 1 h, then
cooled to room temperature. The product was filtered and washed with cold ethanol. Yield:
1
67% (310 mg), white-yellowish solid; mp = 154.0-155.8 °C. H NMR (CDCl3, 500 MHz): δ
3.01 (3H, s, CH3); 7.46-7.50 (3H, m, Ph); 7.52-7.56 (2H, m, Ph); 7.60-7.64 (1H, m, Ph); 8.02-
13
8.06 (4H, m, Ph); 11.40 (1H, br. s, NH). C NMR (CDCl3, 125 MHz): δ 17.0, 188.8, 126.1,
127.2, 127.5, 127.8, 128.9, 129.1, 132.0, 133.2, 152.3, 156.8, 165.5, 168.0. EA C18H14N2O3
requires: C 70.58; H 4.61; N 9.15. Found: C 70.28; H 4.73; N 9.15. EI-HRMS: m/z =
307.1073 (MH+) found; C18H15N2O3 calculated: m/z = 307.1077 (MH+). νmax 3373, 3065,
3005, 1781, 1727, 1696, 1639, 1597, 1587, 1525, 1488, 1447, 1423, 1388, 1343, 1320, 1291,
1242, 1217, 1168, 1065, 1007, 871, 775.

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5.3.2.
(6b).
(E)-N-(1-(5-Oxo-2-phenyloxazol-4(5H)-ylidene)ethyl)-3-(trifluoromethyl)benzamide
Prepared from N-(1-(dimethylamino)ethylidene)-3-(trifluoromethyl)benzamide (2b; 612 mg,
2.37 mmol) and hippuric acid (636 mg, 3.56 mmol) in acetic anhydride (4 mL). Stirred at 85
°C for 4 h, then cooled to room temperature. Volatile components were removed under
reduced pressure and the product was obtained from the residue with flash chromatography,
using ethyl acetate : petroleum ether = 1:5 as the mobile phase. Yield: 67% (593 mg), yellow
solid; mp = 116.0-120.7 °C. 1H NMR (CDCl3, 500 MHz): δ 3.02 (3H, s, CH3); 7.47-7.51 (2H,
m, Ph); 7.51-7.55 (1H, m, Ph); 7.67-7.73 (1H, m, 5-CH); 7.86-7.90 (1H, m, 4-CH); 8.03-8.07
(2H, m, Ph); 8.18-8.21 (1H, m, 6-CH); 8.33 (1H, deg. t, J = 1.8 Hz, 2-CH); 11.46 (1H, br. s,
13
NH). C NMR (CDCl3, 125 MHz): δ 17.1, 119.6, 123.6 (q, J = 273 Hz), 125.5 (q, J = 3.8
Hz), 126.0, 127.5, 129.0, 129.8 (q, J = 3.6 Hz), 129.9, 130.5, 132.0 (q, J = 33 Hz), 132.3,
134.0, 151.8, 157.4, 164.2, 168.3. EA C19H13F3N2O3 requires: C 60.97; H 3.50; N 7.48.
Found: C 61.28; H 3.31; N 7.24. EI-HRMS: m/z = 375.0947 (MH+) found; C19H14F3N2O3
calculated: m/z = 375.0951 (MH+). νmax 3063, 3023, 2936, 1786, 1728, 1697, 1639, 1599,
1522, 1490, 1443, 1331, 1320, 1232, 1212, 1150, 1111, 1071, 1062, 997, 953, 884, 805, 771,
738, 682.
5.3.3.
4-Nitro-N-(1-(5-oxo-2-phenyloxazol-4(5H)-ylidene)ethyl)benzamide
(6c).
Prepared from N-(1-(dimethylamino)ethylidene)-4-nitrobenzamide (2c; 1.040 g, 4.44 mmol)
and hippuric acid (1.200 g, 6.70 mmol) in acetic anhydride (8 mL). Stirred at 85 °C for 1 h,
then cooled to room temperature. The product was filtered and washed with cold ethanol.
1
Yield: 75% (1.174 g), yellow solid; mp = 250.0-253.4 °C. H NMR (CDCl3, 500 MHz): δ
3.02 (3H, s, CH3); 7.48-7.53 (2H, m, Ph); 7.54-7.59 (1H, m, Ph); 8.04-8.08 (2H, m, Ph); 8.19-
8.23 (2H, m, 2-CH and 6-CH); 8.38-8.42 (2H, m, 3-CH and 5-CH) 11.49 (1H, br. s, NH). 13C
NMR (CDCl3, 125 MHz): δ 17.1, 120.0, 124.4, 125.9, 127.5, 129.1, 129.2, 132.5, 138.5,

18
Tetrahedron
ACCEPTED MANUSCRIPT
149.8, 150.6, 157.7, 166.4, 168.3. EA C18H13N3O5 requires: C 61.54; H 3.73; N 11.96. Found:
C 61.45; H 3.52; N 11.97. EI-HRMS: m/z = 352.0923 (MH+) found; C18H14N3O5 calculated:
m/z = 352.0928 (MH+). νmax 3073, 1737, 1700, 1642, 1599, 1518, 1482, 1446, 1382, 1339,
1322, 1240, 1214, 1086, 1064, 1004, 871, 847, 727, 695, 670, 660.
5.3.4. (E)-3-Nitro-N-(1-(5-oxo-2-phenyloxazol-4(5H)-ylidene)ethyl)benzamide (6d).
Prepared from N-(1-(dimethylamino)ethylidene)-3-nitrobenzamide (2d; 1.040 g, 4.44 mmol)
and hippuric acid (1.200 g, 6.70 mmol) in acetic anhydride (8 mL). Stirred at 85 °C for 1 h,
then cooled to room temperature. The product was filtered and washed with cold ethanol.
1
Yield: 58% (898 mg), yellow solid; mp = 181.5-185.8 °C. H NMR (CDCl3, 500 MHz): δ
3.02 (3H, s, CH3); 7.47-7.52 (2H, m, Ph); 7.53-7.58 (1H, m, Ph); 7.77 (1H, t, J = 8.0 Hz, 5-
CH); 8.03-8.07 (2H, m, Ph); 8.32 (1H, dt, J1 = 7.7 Hz, J2 = 1.3 Hz, 4-CH); 8.47 (1H, ddd, J1 =
8.4 Hz, J2 = 2.2 Hz, J3 = 1.0 Hz, 6-CH); 8.91 (1H, t, J = 2.0 Hz, 2-CH); 11.50 (1H, br. s, NH).
13C NMR (CDCl3, 125 MHz): δ 16.9, 119.8, 123.4, 125.8, 127.3, 127.4, 128.9, 130.4, 132.3,
132.8, 134.8, 148.8, 151.2, 157.5, 163.2, 168.2. EA C18H13N3O5 requires: C 61.54; H 3.73; N
11.96. Found: C 61.77; H 3.69; N 11.91. EI-HRMS: m/z = 352.0923 (MH+) found;
C18H14N3O5 calculated: m/z = 352.0928 (MH+). νmax 3033, 1787, 1734, 1698, 1644, 1597,
1518, 1448, 1381, 1322, 1292, 1236, 1224, 1179, 1113, 1077, 1064, 1004, 883, 777, 709, 697.
5.3.5. 4-Fluoro-N-(1-(5-oxo-2-phenyloxazol-4(5H)-ylidene)ethyl)benzamide (6e).
Prepared from N-(1-(dimethylamino)ethylidene)-4-fluorobenzamide (2e; 480 mg, 2.30 mmol)
and hippuric acid (620 mg, 3.46 mmol) in acetic anhydride (3.5 mL). Stirred at 85 °C for 30
min, then cooled to room temperature. The product was filtered and washed with a small
1
amount of cold ethanol. Yield: 53% (397 mg), yellow solid; mp = 167.2-168.9 °C. H NMR
(CDCl3, 500 MHz): δ 3.00 (3H, s, CH3); 7.19-7.24 (2H, m, 3-CH and 5-CH); 7.46-7.50 (2H,

Tetrahedron
19
ACCEPTED MANUSCRIPT
m, Ph); 7.51-7.54 (1H, m, Ph); 8.02-8.07 (4H, m, 2-CH and 6-CH and Ph); 11.37 (1H, br. s,
13
NH). C NMR (CDCl3, 125 MHz): δ 17.1, 116.4 (d, J = 22 Hz), 119.0, 126.1, 127.3, 129.0,
129.3 (d, J = 3.1 Hz), 130.5 (d, J = 9.4 Hz), 132.2, 152.3, 157.0, 164.5, 165.9 (d, J = 255 Hz),
168.2. EA C18H13FN2O3 requires: C 66.66; H 4.04; N 8.64. Found: C 66.70; H 3.79; N 8.65.
EI-HRMS: m/z = 325.0979 (MH+) found; C18H14FN2O3 calculated: m/z = 325.0983 (MH+).
νmax 3363, 3076, 3000, 1781, 1740, 1698, 1643, 1598, 1590, 1517, 1481, 1387, 1342, 1320,
1301, 1232, 1223, 1167, 1084, 1069, 989, 947, 877, 773, 752, 693, 680, 664, 643.
5.3.6. Benzyl (E)-(1-(5-oxo-2-phenyloxazol-4(5H)-ylidene)ethyl)carbamate and benzyl (Z)-(1-
(5-oxo-2-phenyloxazol-4(5H)-ylidene)ethyl)carbamate (6f).
Prepared from benzyl (E)-(1-(dimethylamino)ethylidene)carbamate (2f; 268 mg, 1.22 mmol)
and hippuric acid (328 mg, 1.83 mmol) in acetic anhydride (2 mL). Stirred at 85 °C for 2 h,
then cooled to room temperature. The product was filtered and washed with cold ethanol. The
product was found to be a mixture of stereoisomers in a 1:1.5 ratio, based on NMR evidence,
where the (E)-isomer was the major isomer. Yield: 41% (170 mg), white solid; mp = 122.3-
124.7 °C (mixture).
EA C19H16N2O4 requires: C 67.85; H 4.80; N 8.33. Found: C 67.77; H 4.81; N 8.38. EI-
HRMS: m/z = 337.1181 (MH+) found; C19H17N2O4 calculated: m/z = 337.1183 (MH+). νmax
3363, 3304, 3037, 2973, 1778, 1747, 1729, 1651, 1597, 1490, 1426, 1394, 1320, 1295, 1257,
1193, 1158, 1058, 1043, 1031, 977, 873, 753, 689.
(E)-isomer:
1H NMR (CDCl3, 500 MHz): δ 2.84 (3H, s, CH3); 5.22 (2H, s, CH2); 7.36-7.44 (5H, m, Ph);
7.45-7.48 (2H, m, Ph); 7.49-7.53 (1H, m, Ph); 7.99-8.03 (2H, m, Ph); 9.96 (1H, br. s, NH).
13C NMR (CDCl3, 125 MHz): δ 16.3, 68.2, 117.5, 126.3, 127.2, 128.7, 128.8, 128.9, 129.0,
132.0, 135.1, 151.9, 152.4, 156.6, 167.5.
(Z)-isomer:

20
Tetrahedron
ACCEPTED MANUSCRIPT
1H NMR (CDCl3, 500 MHz): δ 2.88 (3H, s, CH3); 5.23 (2H, s, CH2); 7.36-7.44 (5H, m, Ph);
7.45-7.48 (2H, m, Ph); 7.49-7.53 (1H, m, Ph); 7.98-8.02 (2H, m, Ph); 8.42 (1H, br. s, NH).
13C NMR (CDCl3, 125 MHz): δ 13.9, 68.3, 116.4, 126.0, 127.5, 128.8, 128.9, 129.0, 129.1,
132.3, 135.1, 148.6, 151.8, 156.7, 166.0.
5.3.7. N-(1-(5-Oxo-2-phenyloxazol-4(5H)-ylidene)ethyl)furan-2-carboxamide (6g).
Prepared from N-(1-(dimethylamino)ethylidene)furan-2-carboxamide (2g; 180 mg, 1.00
mmol) and hippuric acid (268 mg, 1.50 mmol) in acetic anhydride (2.5 mL). Stirred at 85 °C
for 2 h, then cooled to room temperature. The product was filtered and washed with a small
1
amount of cold ethanol. Yield: 61% (182 mg), yellowish solid; mp = 136.2-143.5 °C. H
NMR (CDCl3, 500 MHz): δ 2.97 (3H, s, CH3); 6.60 (1H, dd, J1 = 3.4 Hz, J2 = 1.7 Hz, 3-CH);
7.33 (1H, dt, J1 = 3.4 Hz, J2 = 0.7 Hz, 4-CH); 7.45-7.55 (3H, m, Ph); 7.65 (1H, dd, J1 = 1.7
Hz, J2 = 0.7 Hz, 5-CH); 8.01-8.05 (2H, m, Ph); 11.33 (1H, br. s, NH). 13C NMR (CDCl3, 125
MHz): δ 17.1, 113.0, 117.6, 118.9, 126.2, 127.4, 129.0, 132.1, 146.2, 147.0, 151.3, 156.4,
157.1, 167.6. EA C16H12N2O4 requires: C 64.86; H 4.08; N 9.46. Found: C 64.19; H 3.98; N
9.24. EI-HRMS: m/z = 297.0869 (MH+) found; C16H13N2O4 calculated: m/z = 297.0870
(MH+). νmax 3061, 1735, 1696, 1643, 1582, 1504, 1492, 1468, 1446, 1381, 1337, 1277, 1264,
1213, 1156, 1088, 1065, 1004, 953, 882, 845, 765, 736, 693.
5.4. General procedure for the preparation of N-(3-(dimethylamino)-1-(5-oxo-2-
phenyloxazol-4(5H)-ylidene)allyl)-(substituted)benzamides
and
benzyl
(3-
(dimethylamino)-1-(5-oxo-2-phenyloxazol-4(5H)-ylidene)allyl)carbamate:
The starting compounds (1.00 mmol) were dissolved in anhydrous toluene (4 mL) and
N,N-dimethylformamide dimethyl acetal (2.00 mmol) were added. The reaction mixture was
heated to 90 °C and vigorously stirred for 30 min–2 h. The reaction mixture was then cooled
to room temperature, upon which the products deposited from the reaction mixture as solids.
The products were collected by vacuum filtration and thoroughly washed with diethyl ether,
to remove any present impurities.

Tetrahedron
21
ACCEPTED MANUSCRIPT
5.4.1.
N-((1E,2E)-3-(Dimethylamino)-1-(5-oxo-2-phenyloxazol-4(5H)-
ylidene)allyl)benzamide (7a).
Prepared from N-(1-(5-oxo-2-phenyloxazol-4(5H)-ylidene)ethyl)benzamide (6a; 2.035 g, 6.65
mmol) and N,N-dimethylformamide dimethyl acetal (1.76 mL, 13.30 mmol) in anhydrous
toluene (25 mL). Heated to 90 °C for 2 h, then cooled to room temperature. The product was
filtered and washed with diethyl ether to remove any present impurities. Yield: 85% (2.040 g),
1
crimson solid; mp = 180.4-184.2 °C. H NMR (CDCl3, 500 MHz): δ 3.11 (3H, s, N(CH3)2);
3.35 (3H, s, N(CH3)2); 7.08 (1H, d, J = 12.6 Hz, 2'-CH); 7.40-7.45 (3H, m, Ph); 7.49-7.54
(2H, m, Ph); 7.55-7.60 (1H, m, Ph); 7.93-7.98 (2H, m, Ph); 8.10-8.14 (2H, m, Ph); 9.35 (1H,
13
d, J = 12.6 Hz, 3'-CH); 11.91 (1H, s, NH). C NMR (CDCl3, 125 MHz): δ 37.2, 46.5, 90.0,
100.1, 108.5, 126.2, 128.0, 128.8, 129.0, 130.3, 132.6, 134.4, 151.7, 152.0, 159.9, 167.0,
168.6. EA C21H19N3O3 requires: C 69.79; H 5.30; N 11.63. Found: C 69.63; H 5.19; N 11.62.
EI-HRMS: m/z = 362.1495 (MH+) found; C21H20N3O3 calculated: m/z = 362.1499 (MH+). νmax
3322, 3060, 1696, 1663, 1604, 1591, 1546, 1499, 1464, 1443, 1405, 1383, 1323, 1272, 1258,
1244, 1116, 1095, 1058, 1023, 982, 899, 854, 761, 689.
5.4.2. N-3-(Dimethylamino)-1-(5-oxo-2-phenyloxazol-4(5H)-ylidene)allyl)-3-(trifluoromethyl)
benzamide (7b).
Prepared
from
N-(1-(5-oxo-2-phenyloxazol-4(5H)-ylidene)ethyl)-3-
(trifluoromethyl)benzamide (6b; 300 mg, 0.80 mmol) and N,N-dimethylformamide dimethyl
acetal (212 µL, 1.60 mmol) in anhydrous toluene (4 mL). Heated to 90 °C for 2 h, then cooled
to room temperature. The product was filtered and washed with diethyl ether to remove any

22
Tetrahedron
ACCEPTED MANUSCRIPT
1
present impurities. Yield: 37% (127 mg), red solid; mp = 205.8-207.4 °C. H NMR (CDCl3,
500 MHz): δ 3.14 (3H, s, N(CH3)2); 3.39 (3H, s, N(CH3)2); 7.07 (1H, d, J = 12.6 Hz, 2'-CH);
7.44-7.49 (3H, m, Ph); 7.69 (1H, t, J = 7.8 Hz, 5-CH); 7.83-7.87 (1H, m, 4-CH); 7.96-8.01
(2H, m, Ph); 8.33-8.37 (1H, m, 6-CH); 8.43 (1H, br. s, 2-CH); 9.40 (1H, d, J = 12.6 Hz, 3'-
CH); 12.05 (1H, s, NH). 13C NMR (CDCl3, 125 MHz): δ 37.1, 46.5, 89.8, 108.5, 123.7 (q, J =
271 Hz), 125.4 (q, J = 3.8 Hz), 126.1, 127.2, 128.7, 128.9 (q, J = 3.2 Hz), 129.6, 130.3, 131.5
(q, J = 33 Hz), 135.1, 151.1, 152.1, 159.9, 165.3, 168.6. EA C22H18F3N3O3 requires: C 61.54;
H 4.23; N 9.79. Found: C 61.59; H 4.19; N 9.74. EI-HRMS: m/z = 430.1370 (MH+) found;
C22H19F3N3O3 calculated: m/z = 430.1373 (MH+). νmax 3134, 3060, 1665, 1631, 1606, 1592,
1471, 1441, 1406, 1382, 1328, 1276, 1252, 1218, 1187, 1166, 1119, 1100, 1063, 982, 925,
854, 806, 761, 714, 693.
5.4.3. N-3-(Dimethylamino)-1-(5-oxo-2-phenyloxazol-4(5H)-ylidene)allyl)-4-nitrobenzamide
(7c).
Prepared from 4-nitro-N-(1-(5-oxo-2-phenyloxazol-4(5H)-ylidene)ethyl)benzamide (6c; 689
mg, 1.96 mmol) and N,N-dimethylformamide dimethyl acetal (520 µL, 3.92 mmol) in
anhydrous toluene (4 mL). Heated to 90 °C for 1 h, then cooled to room temperature. The
product was filtered and washed with diethyl ether to remove any present impurities. Yield:
1
90% (717 mg), gray-greenish solid; mp = 245.4-246.7 °C. H NMR (CDCl3, 500 MHz): δ
3.13 (3H, s, N(CH3)2); 3.38 (3H, s, N(CH3)2); 7.01 (1H, d, J = 12.5 Hz, 2'-CH); 7.42-7.46
(3H, m, Ph); 7.94-7.98 (2H, m, Ph); 8.26-8.30 (2H, m, 2-CH and 6-CH); 8.34-8.37 (2H, m, 3-
13
CH and 5-CH); 9.38 (1H, d, J = 12.5 Hz, 3'-CH); 12.07 (1H, s, NH). C NMR (CDCl3, 125
MHz): δ 37.3, 46.7, 89.9, 108.8, 124.2, 126.3, 127.2, 128.9, 129.2, 130.5, 139.8, 150.2, 150.9,
ͥ
152.4, 160.2, 164.8, 168.7. EA C21H18N4O5* H2O requires: C 61.88; H 4.48; N 13.75.
ͥͩ
Found: C 61.59; H 4.18; N 13.59. EI-HRMS: m/z = 407.1341 (MH+) found; C21H19N4O5
calculated: m/z = 407.1350 (MH+). νmax 3118, 3055, 2894, 2855, 1680, 1606, 1585, 1493,
1469, 1442, 1407, 1378, 1335, 1286, 1255, 1236, 1174, 1094, 1069, 1056, 978, 896, 859, 850,
763, 692.

Tetrahedron
23
ACCEPTED MANUSCRIPT

24
Tetrahedron
ACCEPTED MANUSCRIPT
5.4.4.
N-((1E,2E)-3-(Dimethylamino)-1-(5-oxo-2-phenyloxazol-4(5H)-ylidene)allyl)-3-
nitrobenzamide (7d).
Prepared from (E)-3-nitro-N-(1-(5-oxo-2-phenyloxazol-4(5H)-ylidene)ethyl)benzamide (6d;
90 mg, 0.26 mmol) and N,N-dimethylformamide dimethyl acetal (70 µL, 0.52 mmol) in
anhydrous toluene (2 mL). Heated to 90 °C for 30 min, then cooled to room temperature. The
product was filtered and washed with diethyl ether to remove any present impurities. Yield:
1
93% (106 mg), red solid; mp = 224.1-227.3 °C. H NMR (CDCl3, 500 MHz): δ 3.13 (3H, s,
N(CH3)2); 3.38 (3H, s, N(CH3)2); 7.01 (1H, d, J = 12.5 Hz, 2'-CH); 7.42-7.46 (3H, m, Ph);
7.72 (1H, t, J = 8.0 Hz, 5-CH); 7.92-7.96 (2H, m, Ph); 8.41 (1H, ddd, J1 = 8.2 Hz, J2 = 2.2 Hz,
J3 = 1.0 Hz, 6-CH); 8.46 (1H, dt, J1 = 7.8 Hz, J2 = 1.3 Hz, 4-CH); 8.98 (1H, t, J = 2.0 Hz, 2-
13
CH); 9.37 (1H, d, J = 12.5 Hz, 3'-CH); 12.09 (1H, s, NH). C NMR (CDCl3, 125 MHz): δ
37.3, 46.7, 89.9, 108.8, 123.7 126.3, 126.9, 127.3, 128.8, 130.3, 130.5, 133.0, 136.2, 148.8,
151.0, 152.4, 160.2, 164.4, 168.8. EA C21H18N4O5 requires: C 62.06; H 4.46; N 13.79. Found:
C 62.00; H 4.27; N 13.76. EI-HRMS: m/z = 407.1345 (MH+) found; C21H19N4O5 calculated:
m/z = 407.1350 (MH+). νmax 3135, 2915, 1665, 1625, 1590, 1527, 1487, 1467, 1445, 1400,
1383, 1346, 1329, 1297, 1258, 1216, 1171, 1124, 1108, 1085, 1064, 977, 903, 850, 813, 759,
711.
5.4.5. N-3-(Dimethylamino)-1-(5-oxo-2-phenyloxazol-4(5H)-ylidene)allyl)-4-fluorobenzamide
(7e).
Prepared from 4-fluoro-N-(1-(5-oxo-2-phenyloxazol-4(5H)-ylidene)ethyl)benzamide (6e; 324
mg, 1.00 mmol) and N,N-dimethylformamide dimethyl acetal (265 µL, 2.00 mmol) in
anhydrous toluene (4 mL). Heated to 90 °C for 2 h, then cooled to room temperature. The
product was filtered and washed with diethyl ether to remove any present impurities. Yield:

Tetrahedron
25
ACCEPTED MANUSCRIPT
97% (370 mg), orange solid; mp = 218.1-220.0 °C. 1H NMR (CDCl3, 500 MHz): δ 3.08 (3H,
s, N(CH3)2); 3.33 (3H, s, N(CH3)2); 7.04 (1H, d, J = 12.6 Hz, 2'-CH); 7.15-7.21 (2H, m, 3-CH
and 5-CH); 7.40-7.45 (3H, m, Ph); 7.92-7.96 (2H, m Ph); 8.12-8.16 (2H, m, 2-CH and 6-CH);
13
9.34 (1H, d, J = 12.6 Hz, 3'-CH); 11.89 (1H, s, NH). C NMR (CDCl3, 125 MHz): δ 37.2,
46.5, 89.9, 108.4, 116.1 (d, J = 22 Hz), 126.2, 127.4, 128.8, 130.3, 130.5 (d, J = 9.0 Hz),
130.6, 151.6, 151.9, 160.0, 165.6 (d, J = 229 Hz), 165.8, 168.6. EA C21H18FN3O3 requires: C
66.48; H 4.78; N 11.08. Found: C 66.41; H 4.88; N 11.06. EI-HRMS: m/z = 380.1396 (MH+)
found; C21H19FN3O3 calculated: m/z = 380.1405 (MH+). νmax 3123, 3072, 2922, 1659, 1622,
1590, 1508, 1459, 1448, 1375, 1259, 1228, 1164, 1117, 1095, 1055, 981, 897, 851, 844, 761,
742, 693, 672.
5.4.6. Benzyl ((1E,2E)-3-(dimethylamino)-1-(5-oxo-2-phenyloxazol-4(5H)-
ylidene)allyl)carbamate (7f).
Prepared from benzyl (1-(5-oxo-2-phenyloxazol-4(5H)-ylidene)ethyl)carbamate (6f; 131 mg,
0.39 mmol) and N,N-dimethylformamide dimethyl acetal (104 µL, 0.78 mmol) in anhydrous
toluene (1 mL). Heated to 90 °C for 30 min, then cooled to room temperature. The product
was filtered and washed with diethyl ether to remove any present impurities. Yield: 94% (144
1
mg), orange solid; mp = 206.7-210.5 °C. H NMR (CDCl3, 500 MHz): δ 3.04 (3H, s,
N(CH3)2); 3.31 (3H, s, N(CH3)2); 5.20 (2H, s, CH2); 6.55 (1H, d, J = 12.6 Hz, 2'-CH); 7.33-
7.45 (8H, m, Ph); 7.91-7.95 (2H, m, Ph); 9.25 (1H, d, J = 12.6 Hz, 3'-CH); 10.58 (1H, s, NH).
13C NMR (CDCl3, 125 MHz): δ 37.1, 46.4, 67.4, 88.6, 107.4, 126.1, 127.5, 128.4, 128.5,
128.7, 128.8, 130.2, 135.8, 151.6, 151.8, 153.5, 159.3, 168.1. EA C22H21N3O4 requires: C
67.51; H 5.41; N 10.74. Found: C 67.73; H 5.21; N 10.74. EI-HRMS: m/z = 392.1602 (MH+)
found; C22H22N3O4 calculated: m/z = 392.1605 (MH+). νmax 3087, 2915, 1736, 1668, 1612,
1592, 1493, 1461, 1402, 1378, 1276, 1245, 1227, 1195, 1180, 1114, 1087, 1069, 1018, 978,
905, 850, 783, 746, 667.

26
Tetrahedron
ACCEPTED MANUSCRIPT
5.5. General procedure for the preparation of N,N-dimethyl-7-(substituted)-1,3-dioxo-
1,3-dihydroisobenzofuran-4-carboxamides and benzyl (7-(dimethylcarbamoyl)-1,3-
dioxo-1,3-dihydroisobenzofuran-4-yl)carbamate:
The starting compounds (0.30 mmol) were placed in a microwave tube and were
dissolved in 1 mL of anhydrous toluene. Next, 1.2 equvialents of maleic anhydride was added
(0.33 mmol) and the reaction mixture was placed in a CEM Microwave unit. The reaction
temperature varied from 160-180 °C, Power max option was set to OFF, maximum allowed
pressure was set to 16 bar, irradiation power 300 W, reaction times were between 15-50 min.
The microwave tube, along with its contents was left to cool to room temperature. Deposition
of the product from the reaction mixture was assisted by scratching the walls of the cooled
microwave tube with a glass stick. If the product did not participate from the reaction mixture
at room temperature, additional cooling of the microwave tube and its contents was applied by
immersing it in to an ice bath. The participated products were filtered and thoroughly washed
with diethyl ether to remove any present impurities.
5.5.1. 7-Benzamido-N,N-dimethyl-1,3-dioxo-1,3-dihydroisobenzofuran-4-carboxamide (8a)
Prepared
from
N-((1E,2E)-3-(dimethylamino)-1-(5-oxo-2-phenyloxazol-4(5H)-
ylidene)allyl)benzamide (7a; 100 mg, 0.28 mmol) and maleic anhydride (33 mg, 0.33 mmol)
in anhydrous toluene (1 mL). The reaction mixture was heated under microwave irradiation at
180 °C for 40 min, cooled in an ice bath. The participated product was filtered and washed
with diethyl ether. Yield: 48% (46 mg), brown solid; mp = 247.8-251.5 °C. 1H NMR (CDCl3,
500 MHz): δ 2.93 (3H, s, N(CH3)2); 3.21 (3H, s, N(CH3)2); 7.56-7.61 (2H, m, Ph); 7.64-7.70
(1H, m, Ph); 7.85 (1H, d, J= 8.6 Hz, 6-CH); 8.00-8.04 (2H, m, Ph); 9.18 (1H, d, J = 8.6 Hz, 5-
CH); 10.14 (1H, s, NH). 13C NMR (CDCl3, 125 MHz): δ 35.3, 38.5, 115.6, 126.5, 126.7,
ͥ
127.6, 129.4, 130.5, 132.8, 133.4, 137.3, 139.6, 160.4, 164.7, 165.4, 165.8. EA C18H14N2O5*
ͪ
H2O requires: C 63.34; H 4.23; N 8.21. Found: C 63.37; H 3.89; N 7.99. EI-HRMS: m/z =

Tetrahedron
27
ACCEPTED MANUSCRIPT
339.0976 (MH+) found; C18H15N2O5 calculated: m/z = 339.0975 (MH+). νmax 3365, 3056,
2930, 1842, 1767, 1689, 1628, 1594, 1516, 1489, 1415, 1295, 1255, 1239, 1201, 1149, 1112,
1090, 1068, 1030, 933, 859, 701, 685.
5.5.2. N,N-Dimethyl-1,3-dioxo-7-(3-(trifluoromethyl)benzamido)-1,3-dihydroisobenzofuran-4-
carboxamide (8b).
Prepared
from
N-3-(dimethylamino)-1-(5-oxo-2-phenyloxazol-4(5H)-ylidene)allyl)-3-
(trifluoromethyl)benzamide (7b; 55 mg, 0.13 mmol) and maleic anhydride (19 mg, 0.20
mmol) in anhydrous toluene (0.7 mL). The reaction mixture was heated under microwave
irradiation at 160 °C for 25 min, then cooled in an ice bath. The participated product was
filtered and washed with diethyl ether. Yield: 52% (27 mg), brown solid; mp = 195.3-199.4
1
°C. H NMR (d6-DMSO, 500 MHz): δ 2.83 (3H, s, N(CH3)2); 3.06 (3H, s, N(CH3)2); 7.89
(1H, deg. t, J = 7.8 Hz, 5'-CH); 7.92 (1H, d, J = 8.3 Hz, 5-CH); 8.07-8.10 (1H, m, 4'-CH);
8.29-8.32 (1H, m, 6'-CH); 8.32-8.34 (1H, m, 2'-CH); 8.39 (1H, d, J = 8.3 Hz, 6-CH); 10.77
(1H, s, NH). 13C NMR (d6-DMSO, 125 MHz): δ 34.4, 37.9, 121.1, 123.7 (q, J = 270 Hz),
124.4 (q, J = 4.1 Hz), 127.4, 129.2 (q, J = 3.7 Hz), 129.6 (q, J = 32 Hz), 129.8, 130.4, 131.4,
131.8, 134.2, 135.3, 136.7, 161.3, 161.9, 164.1, 165.0. EA C19H13F3N2O5 requires: C 56.17; H
3.23; N 6.89. Found: C 55.89; H 3.10; N 6.76. EI-HRMS: m/z = 407.0852 (MH+) found;
C19H14F3N2O5 calculated: m/z = 407.0849 (MH+). νmax 2937, 1850, 1773, 1690, 1638, 1601,
1524, 1489, 1457, 1404, 1361, 1329, 1294, 1252, 1234, 1205, 1166, 1119, 1071, 902, 855,
841, 749, 736, 690, 643.
5.5.3.
N,N-Dimethyl-7-(4-nitrobenzamido)-1,3-dioxo-1,3-dihydroisobenzofuran-4-
carboxamide (8c).

28
Tetrahedron
ACCEPTED MANUSCRIPT
Prepared
from
N-3-(dimethylamino)-1-(5-oxo-2-phenyloxazol-4(5H)-ylidene)allyl)-4-
nitrobenzamide (7c; 59 mg, 0.15 mmol) and maleic anhydride (19 mg, 0.19 mmol) in
anhydrous toluene (2 mL). The reaction mixture was heated under microwave irradiation at
160 °C for 50 min, then cooled to room temperature. The participated product was filtered
and washed with diethyl ether. Yield: 42% (45 mg), brown-red solid; mp = 253.1-257.6 °C.
1H NMR (d6-DMSO, 500 MHz): δ 2.83 (3H, s, N(CH3)2); 3.06 (3H, s, N(CH3)2); 7.93 (1H, d,
J = 8.3 Hz, 5-CH); 8.22-8.26 (2H, m, 2'-CH and 6-CH); 8.40 (1H, d, J = 8.3 Hz, 6-CH); 8.45-
8.49 (2H, m, 3'-CH and 5'-CH); 10.81 (1H, s, NH). 13C NMR (d6-DMSO, 125 MHz): δ 34.4,
37.9, 121.2, 124.1, 127.5, 129.3, 129.8, 131.5, 135.4, 136.5, 138.7, 149.8, 161.3, 161.9, 163.9,
165.0. EA C18H13N3O7 requires: C 56.40; H 3.42; N 10.96. Found: C 56.95; H 3.16; N 10.65.
EI-HRMS: m/z = 384.0825 (MH+) found; C18H14N3O7 calculated: m/z = 384.0826 (MH+). νmax
3367, 3106, 2940, 1846, 1771, 1691, 1633, 1600, 1520, 1488, 1409, 1345, 1309, 1295, 1259,
1240, 1201, 1150, 1112, 1092, 1012, 901, 850, 757, 745, 678.
5.5.4.
N,N-Dimethyl-7-(3-nitrobenzamido)-1,3-dioxo-1,3-dihydroisobenzofuran-4-
carboxamide (8d).
Prepared from N-((1E,2E)-3-(dimethylamino)-1-(5-oxo-2-phenyloxazol-4(5H)-ylidene)allyl)-
3-nitrobenzamide (7d; 50 mg, 0.12 mmol) and maleic anhydride (18 mg, 0.19 mmol) in
anhydrous toluene (1 mL). The reaction mixture was heated under microwave irradiation at
160 °C for 25 min, then cooled to room temperature. The participated product was filtered
1
and washed with diethyl ether. Yield: 41% (19 mg), brown solid; mp = 200.0-203.5 °C. H
NMR (d6-DMSO, 500 MHz): δ 2.83 (3H, s, N(CH3)2); 3.06 (3H, s, N(CH3)2); 7.91-7.96 (2H,
m, 5'-CH and 5-CH); 8.36 (1H, d, J = 8.2 Hz, 6-CH); 8.42-8.45 (1H, m, 6'-CH); 8.52-8.55
(1H, m, 4'-CH); 8.82 (1H, t, J = 1.9 Hz, 2'-CH); 10.90 (1H, s, NH). 13C NMR (d6-DMSO, 125

Tetrahedron
29
ACCEPTED MANUSCRIPT
MHz): δ 34.4, 37.9, 121.4, 122.6, 127.2, 127.5, 130.1, 130.8, 131.6, 134.1, 134.6, 135.3,
ͥ
136.5, 148.0, 161.3, 161.7, 163.5, 165.0. EA C18H13N3O7* toluene requires: C 57.74; H 3.62;
ͪ
N 10.54. Found: C 57.45; H 3.23; N 10.82. EI-HRMS: m/z = 384.0823 (MH+) found;
C18H14N3O7 calculated: m/z = 384.0826 (MH+). νmax 3102, 3091, 2936, 1986, 1844, 1769,
1701, 1629, 1602, 1523, 1487, 1412, 1305, 1268, 1252, 1241, 1202, 1152, 1080, 1002, 943,
905, 870, 768, 671.
5.5.5.
7-(4-Fluorobenzamido)-N,N-dimethyl-1,3-dioxo-1,3-dihydroisobenzofuran-4-
carboxamide (8e).
Prepared
from
N-3-(dimethylamino)-1-(5-oxo-2-phenyloxazol-4(5H)-ylidene)allyl)-4-
fluorobenzamide (7e; 53 mg, 0.14 mmol) and maleic anhydride (21 mg, 0.21 mmol) in
anhydrous toluene (0.7 mL). The reaction mixture was heated under microwave irradiation at
150 °C for 15 min, then cooled to room temperature. The participated product was filtered
1
and washed with diethyl ether. Yield: 50% (25 mg), brown solid; mp = 287.3-291.8 °C. H
NMR (d6-DMSO, 500 MHz): δ 2.82 (3H, s, N(CH3)2); 3.05 (3H, s, N(CH3)2); 7.46-7.51 (2H,
m, 2'-CH and 6'-CH); 7.90 (1H, d, J = 8.4 Hz, 5-CH); 8.06-8.11 (2H, m, 3'-CH and 5'-CH);
8.48 (1H, d, J = 8.4 Hz, 6-CH); 10.47 (1H, s, NH). 13C NMR (d6-DMSO, 125 MHz): δ 34.4,
37.9, 116.1 (d, J = 22 Hz), 120.2, 128.8, 130.5 (d, J = 9.4 Hz), 130.6, 130.9, 135.5, 137.2,
161.3, 162.3, 164.2, 164.7 (d, J = 249 Hz), 165.0. EA C18H13FN2O5 requires: C 60.68; H 3.68;
N 7.86. Found: C 60.52; H 3.67; N 7.64. EI-HRMS: m/z = 357.0878 (MH+) found;
C18H14FN2O5 calculated: m/z = 357.0881 (MH+). νmax 3368, 3054, 1847, 1768, 1689, 1631,
1603, 1527, 1498, 1402, 1364, 1319, 1296, 1254, 1234, 1200, 1166, 1088, 902, 850, 755, 734,
684.
5.5.6.Benzyl
(7-(dimethylcarbamoyl)-1,3-dioxo-1,3-dihydroisobenzofuran-4-yl)carbamate
(8f).