N-Substituted and N-unsubstituted 1,3-Oxazolium-5-olates cycloaddition reactions with 3-substituted coumarins

Article abstract of DOI:10.1016/j.tet.2010.02.009

The 1,3-dipolar cycloaddition reaction of unsymmetrically N-substituted and N-unsubstituted 1,3-oxazolium-5-olates with selected 3-substituted coumarins has been examined. Various types of pyrrole derivatives are isolated and their formation seems to be a function of the regio- and diastereochemistry of the initial cycloaddition step.

Full text of DOI:10.1016/j.tet.2010.02.009

Tetrahedron 66 (2010) 2713–2717
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
N-Substituted and N-unsubstituted 1,3-Oxazolium-5-olates cycloaddition
reactions with 3-substituted coumarins
*
Massimiliano Cordaro, Giovanni Grassi , Francesco Risitano, Angela Scala
`
Dipartimento di Chimica Organica e Biologica, Universita di Messina, Vill. S. Agata, I-98166 Messina, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 7 August 2009
Received in revised form 14 January 2010
Accepted 1 February 2010
Available online 10 February 2010
The 1,3-dipolar cycloaddition reaction of unsymmetrically N-substituted and N-unsubstituted 1,3-
oxazolium-5-olates with selected 3-substituted coumarins has been examined. Various types of pyrrole
derivatives are isolated and their formation seems to be a function of the regio- and diastereochemistry
of the initial cycloaddition step.
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Mesoionic compounds
Coumarins
1,3-Oxazolium-5-oxides
1,3-Cycloaddition
1. Introduction
R
a
b
c
CN
R
CO2Me COMe
N-Substituted and N-unsubstituted 1,3-oxazolium-5-olates are
a key family of building blocks employed in the construction of
a variety of highly functionalized heterocyclic compounds.1 The
importance of these mesoionic-type oxazoles1b derived from their
great reaction versatility,2 and, in particular from the role they play
in cycloaddition reactions.1c This versatility is particularly notice-
able in N-substituted derivatives 2 (mu¨nchnones), which display
more marked 1,3-dipolar reactivity than their parent N-unsub-
stituted oxazolones 1 (Fig. 1).
O
3
O
Figure 2.
2. Results and discussion
2.1. Reactions with oxazolones 1
The investigation used 4-methyl-2-phenyl-1,3-oxazol-5(4H)-
one (MPO) 4 as an unsymmetrical oxazolone template (Scheme 1)
and reactions with 3a–c were performed both in solution and un-
der solvent-free conditions (Experimental).
R2
R2
R2
H
R
N
N
N
R1
O
R1
O
R1
O
O
O
2
O
1
In solution (method A), the only product isolated in high yields
in cases a and b was carboxylic acid 5; the only reaction product
isolated in case c was the unexpected derivative 6. In the absence of
solvent (method B), product 5 was again isolated in higher yields in
cases a and b, while no product of interest was isolated in case c
(Table 1).
Derivatives 5 and 6 were identified on the basis of analytical and
spectroscopic data. Acid 5b in dioxane/THF was esterified with
ethereal diazomethane to give 7 (Scheme 2); the latter product
then underwent single-crystal X-ray analysis (Fig. 3).4
This provided structural confirmation and, importantly, stereo-
chemical assignment for 5. The structure of 6 was then further
confirmed by X-ray crystallographic analysis.4
Figure 1.
As a part of a program of investigation of the synthetic utility of
these attractive intermediates, their reactivity towards coumarin
derivatives was explored. As is known,3 these structural units dis-
play interesting dipolarophilic reactivity when activated at the
styrenic double bond. This paper reports the results of a study of
coumarins 3 bearing an electron withdrawing group at C-3 (Fig. 2)
reacting with oxazolones 1 or mu¨nchnones 2.
* Corresponding author. Tel.: þ39 090 6765513; fax: þ39 090 393897.
E-mail address: ggrassi@unime.it (G. Grassi).
0040-4020/$ – see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.02.009

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M. Cordaro et al. / Tetrahedron 66 (2010) 2713–2717
The products isolated show that the cycloaddition reaction of
COOH
N
Me
H
the mesoionic heterocycle proceeds differently from the standard
decarboxylative cycloreversion of the initial 1:1 cycloadduct.1 In-
deed, either (path i) retention of carboxylic function with formation
of 5, or (path ii) an unprecedented transformation into 6 are
observed.
Ph
R
O
H
Me
O
O
i
N
3
+
5
This unusual behaviour may be explained by the high levels of
regiochemical control observed and by the exo/endo preference in
the cycloaddition step. Indeed, as described in Scheme 3, the exo
cycloadduct 8 fully accounts for the formation of the stable
Ph
O
ii
Ph
NC
H
4
NH
Me
O
a
-aminoacid 5,5 while only the endo diastereomer 9 can be
O
expected to evolve to derivative 6 via translactonization and sub-
sequent facile decarboxylation.
6
Scheme 1. (i) In solution or solvent free; (ii) only in solution when R¼CN.
COO
Me
O
H
O
R
NH
Me
NH
H
Ph
Table 1
5
O
R
Reactions of coumarins 3a–c with MPO
O
O
O
Ph
Entry
Starting material
Products (yield %)a
Method A
3
+
4
8
Method B
COO
1
2
3
3a
3b
3c
5a (77)
5b (69)
6 (40)
5a (89)
5b (80)
d
O
NC
O
O
Ph
Me
-CO2
NH
O
6
Me
O
NC
a
H
NH
O
Yield of pure isolated product.
Ph
9
Scheme 3. Proposed mechanism of oxazolone reactions.
COOMe
Me
N
H
Ph
CH2N2
5b
Reactions with MPO were performed with a variety of other
COMe
O
O
7
coumarins, but with consistently negative results, and the starting
coumarin was recovered along with the products of azlactone
degradation. It thus appears that cycloaddition occurs without
evolving towards stable products.
Scheme 2.
Figure 3. Ortep drawing of 6, 7, 12 and 17.

M. Cordaro et al. / Tetrahedron 66 (2010) 2713–2717
2715
¨
2.2. Reaction with munchnones 2
The structures of derivatives 11 and 12 were assigned on the
basis of analytical and spectroscopic data, and confirmed by X-ray
crystallographic analysis (Fig. 3).4
These results appear to confirm the reaction mechanism pre-
viously hypothesized with azlactone.
This investigation used 4,5-dimethyl-2-phenyl-1,3-oxazolium-
5-olate (DMPO) 10 as an unsymmetrical mu¨nchnone template, and
its behaviour was observed with the previously selected coumarins.
Of the reactions studied only case c (R¼CN) produced results of any
interest, namely isolation of the fused pyrrole derivative 11 (15%)
and fully substituted pyrrole 12 (35%) (Scheme 4).
With the more reactive mu¨nchnone a lower level of regio-
chemical control is observed in the initial cycloaddition step, and
when R¼CN endo selective attack is confirmed.
As illustrated in Scheme 5, the two non-isolated regioiso-
meric endo cycloadducts 13 and 14 evolve, respectively, into 11
Ph
NC
H
via transesterification/decarboxylation, in
a similar way as
NMe
Me
O
described with MPO, or into 12 through decarboxylative
degradation.
O
11
Our proposed mechanism of fragmentation of the cycloadduct
13 to cyanopyrrole 11 is perfectly in line with a similar result
obtained in the reaction between 3-cyanochromone 156 and DMPO
10. A cyanopyrrole derivative was isolated together with salicylic
acid as summarized in Scheme 6.
This result is consistent with the initial formation of the endo
cycloadduct 16 and its subsequent decarboxylative degradation to
pyrrole 17. X-ray crystallographic analysis confirmed the structure
(Fig. 3).4
Me
Ph
Me
O
N
3c
+
Me
N
O
Ph
Me
CN
10
OH
12
Scheme 4.
COO
Ph
NC
O
O
O
H
O
Me
Ph
NMe
Me
O
11
-CO2
NC
O
NMe
3c
10
+
13
Ph
Ph
O
O
NMe
Me
CN
O
NMe
Ph
O
COOH
O
Me
CN
12
NC
-CO2
-CO2
NMe
O
O
O
H
Me
14
Scheme 5. Proposed mechanism of mu¨nchnone reactions.
O
O
O
O
O
CN
+ 10
Ph
O
CN
Me
O
NMe
O
O
15
NMe
NC
Me
O
H
H
Ph
16
O
O
O
COOH
Me
CN
NC
NMe
Ph
+
-CO2
OH
Ph
O
Me
N
Me
17
Scheme 6. Cycloaddition of mu¨nchnone to 3-cyanochromone.
In the other cases, cycloaddition with DMPO probably always
occurs but the primary 1:1 cycloadduct quickly degrades to form
the starting coumarin and the products of mu¨nchnone
fragmentation.1
3. Conclusions
In conclusion, our results show that the reaction of selected
coumarins with N-substituted or N-unsubstituted unsymmetrical

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M. Cordaro et al. / Tetrahedron 66 (2010) 2713–2717
1,3-oxazolium-5-olates is an intriguing process and that the regio-
and diastereochemistry of the initial 1:1 cycloadduct determine the
competitive routes that lead to the diverse types of isolated pyrrole
derivatives.
152.2, 134.8, 133.2, 128.8, 128.2, 127.9, 127.4, 126.3, 125.9, 121.5,
117.2, 81.5, 66.8, 48.5, 22.5; ESI-MS (m/z)¼303.3 [Mþ1]þ. Anal.
Calcd for C19H14N2O2: C, 75.48; H, 4.67, N, 9.27. Found: C, 75.29; H,
4.50; N, 9.41.
4. Experimental section
4.1. General method
4.3. Esterification of 5b
N-Methyl-N-nitrosotoluene-p-sulfonamide (2.14 g, 10 mmol)
was dissolved in ether (30 ml) and cooled in an ice bath, KOH (0.4 g,
70 mmol) in ethanol 96% (10 ml) was added. If a precipitate formed,
more ethanol was added until it just dissolved. After 5 min, ethereal
diazomethane solution was distilled from a water bath.
3-Acetyl-[3,4-c]pyrrole-coumarin acid 5b (1.3 g, 3.58 mmol)
was dissolved in a solution of dioxane/THF 7:3 (30 ml) and fresh
ethereal diazomethane solution (30 ml) was added dropwise. The
mixture was stirred for an hour at room temperature then the
solvent was removed by rotavapor and hot methanol (10 ml) was
added. After cooling a white solid 7 was obtained.
Melting points were determined on a Kofler melting apparatus
and are uncorrected. IR spectra were recorded in Nujol with
a Nicolet Impact 410D spectrometer. 1H and 13C NMR spectra were
obtained with a Bruker AMX R300. Mass spectrometry analyses and
Microanalyses were carried out on a 3200 QTRAP (Applied Bio-
systems SCIEX) and on a Carlo Erba EA 1102, respectively. All sol-
vents and reagents were obtained from commercial sources and
purified before use if necessary. 3-Substituted coumarins,7 MPO8
and DMPO9 were prepared according to literature method. Merck
Kieselgel 60F254 plates were used for TLC, and Merck Silica gel 60
(0.063–0.100 mm) for column chromatography.
Mp 178–179 ꢀC; IR (cmꢁ1): 1766, 1738, 1709 (CO); 1H NMR
(CDCl3, ppm): 8.08–7.13 (9H, m, CHarom), 3.73 (1H, s, CH), 3.35 (3H, s,
COOMe), 2.18 (3H, s, COMe), 1.96 (3H, s, Me); 13C NMR (CDCl3, ppm):
201.5,170.6,168.1,161.9,150.5,132.0,131.2,129.8,128.6,128.4,128.1,
127.5, 124.6, 116.5, 74.4, 53.8, 52.3, 40.1, 26.5, 22.9; ESI-MS (m/
z)¼378.4 [Mþ1]þ. Anal. Calcd for C22H19NO5: C, 70.02; H, 5.07, N,
3.71. Found: C, 69.84; H, 4.89; N, 3.58.
4.2. Reactions of MPO 4 with coumarins 3
Method A. 3-Substituted coumarin 3 and MPO 4 were dissolved
in anhydrous toluene and heated at reflux under a N2 atmosphere
for 2–3 h. After evaporation the product was purified by chro-
matographic column (10% ethyl acetate/chloroform).
4.4. Reaction of DMPO 10 with 3c
Method B. 3-Substituted coumarin 3 and MPO 4 were triturated
together in a mortar rapidly and then reacted in a sealed vial in
a bath set at 100 ꢀC for 15–20 min. The product was washed with
ether and purified in good yields by crystallization in methanol.
DMPO 10, generated in situ from N-benzoyl-N-methylalanine
(0.62 g, 3 mmol) and acetic anhydride (0.61 g, 6 mmol), was heated
with coumarin 3c (0.5 g, 2.9 mmol) in anhydrous toluene (30 ml) at
reflux under a N2 atmosphere for 3 h. The solvent was removed by
vacuum evaporation and the residue was purified in column
chromatography (3%AcOEt/CHCl3).
The first eluted component was a light yellow solid 12 (0.29 g,
yield 35%). Mp 128 ꢀC; IR (cmꢁ1): 3300 (OH), 2216 (CN); 1H NMR
(CDCl3, ppm): 7.33–6.78 (9H, m, CHarom), 3.50 (3H, s, NMe), 2.50
(3H, s, Me); 13C NMR (CDCl3, ppm): 155.6, 150.4, 138.5, 131.5, 129.3,
130.1,129.2,128.8,128.7,128.5,120.6,120.0,118.3,118.0,116.0,115.5,
32.5, 12.0; ESI-MS (m/z)¼289.4 [Mþ1]þ. Anal. Calcd for C19H16N2O:
C, 79.14; H, 5.59, N, 9.72. Found: C, 78.92; H, 5.68, N, 9.87.
The second eluted component was a white solid 11 (0.14 g, yield
15%). Mp 155–158 ꢀC; IR (cmꢁ1): 2177 (CN), 1744 (CO); 1H NMR
(CDCl3, ppm): 7.35–7.07 (9H, m, CHarom), 4.40 (1H, s, CH), 2.97 (3H, s,
NMe), 2.14 (1H, s, Me); 13C NMR (CDCl3, ppm): 172.4, 162.3, 152.0,
134.8, 133.2, 128.8, 128.0, 127.3, 127.0, 126.1, 125.8, 121.3, 117.3, 79.0,
75.9, 48.8, 33.0, 19.7; ESI-MS (m/z)¼317.4 [Mþ1]þ. Anal. Calcd for
C20H16N2O2:C, 75.93;H, 5.10, N, 8.86. Found:C, 75.53;H, 5.02, N, 8.69.
4.2.1. Compound 5a. Method A. From 3-acetyl-coumarin 3a (0.5 g,
2.6 mmol) and MPO 4 (1.0 g, 5.7 mmol) in toluene (10 ml) was
obtained after purification a light orange solid (0.72 g, yield 77%).
Method B. From 3-acetyl-coumarin 3a (0.3 g, 1.6 mmol) and MPO 4
(0.5 g, 2.9 mmol) was obtained after crystallization in MeOH
a white solid (0.51 g, yield 89%). Mp 134–137 ꢀC; IR (cmꢁ1): 2800–
2500 (br, COOH), 1749, 1722, 1712 (CO); 1H NMR (DMSO-d6, ppm):
10.90 (1H, s, COOH), 7.98–7.14 (9H, m, CHarom), 4.15 (1H, s, CH), 2.16
(3H, s, COMe), 1.87 (3H, s, Me); 13C NMR (DMSO-d6, ppm): 203.0,
171.2, 168.6, 161.6, 149.9, 131.9, 129.6, 128.6, 128.2, 127.4, 124.5,
116.5, 116.3, 83.3, 74.6, 53.6, 26.1, 23.6; ESI-MS (m/z)¼380.3
[Mþ1]þ. Anal. Calcd for C21H17NO6: C, 66.49; H, 4.52, N, 3.69.
Found: C, 66.13; H, 4.69; N, 3.31.
4.2.2. Compound 5b. Method A. From 3-carbomethoxy-coumarin
3b (0.5 g, 2.45 mmol) and MPO 4 (1.0 g, 5.7 mmol) in toluene
(10 ml) was obtained after purification a white solid (0.64 g, yield
69%). Method B. From 3-carbomethoxy-coumarin 3b (0.3 g,
1.47 mmol) and MPO 4 (0.5 g, 2.9 mmol) was obtained after crys-
tallization in MeOH a white solid (0.45 g, yield 80%). Mp 160–
161 ꢀC; IR (cmꢁ1): 2800–2400 (br, COOH), 1767, 1740, 1713 (CO); 1H
NMR (DMSO-d6, ppm): 7.92–7.16 (9H, m, CHarom), 4.02 (1H, s, CH),
3.66 (3H, s, COOMe), 1.78 (3H, s, Me); 13C NMR (DMSO-d6, ppm):
171.2, 169.2, 167.9, 160.3, 149.9, 131.7, 131.4, 129.6, 129.3, 128.4,
124.8, 116.4, 83.2, 66.6, 56.3, 54.2, 23.6; ESI-MS (m/z)¼364.4
[Mþ1]þ. Anal. Calcd for C21H17NO5: C, 69.41; H, 4.72, N, 3.85. Found:
C, 69.94; H, 4.62; N, 4.07.
4.5. Reaction of DMPO 10 with 3-cyanochromone 15
3-CN-Chromone 15 (1 g, 5.8 mmol) and N-methyl-N-benzoyl-
alanine (1.6 g, 7.7 mmol) were dissolved in anhydrous dioxane
(30 ml) and acetic anhydride (1.6 g, 15.7 mmol) and the solution
heated at reflux for 0.5 h. After the usual workup process and col-
umn chromatographic purification (CHCl3) light brown solid 17
(0.45 g, yield 40%) and salicylic acid were isolated.
4.5.1. Compound 17. Mp 112–114 ꢀC; IR (cmꢁ1): 2216 (CN); 1H NMR
(CDCl3, ppm): 7.43–7.33 (5H, m, Ph), 6.33 (1H, s, CHpyrr), 3.50 (3H, s,
NMe), 2.43 (3H, s, Me); 13C NMR (CDCl3, ppm): 138.7, 134.9, 131.6,
129.0, 128.6, 127.9, 117.3, 109.5, 91.0, 32.2, 11.8; ESI-MS (m/z)¼197.5
[Mþ1]þ. Anal. Calcd for C13H12N2: C, 79.56; H, 6.16, N, 14.27. Found:
C, 79.77; H, 6.04, N, 14.48.
4.2.3. Compound 6. Method A. From 3-cyano-coumarin 3c (0.5 g,
2.9 mmol) and MPO 4 (1.0 g, 5.7 mmol) in toluene (10 ml) was
obtained after purification a light yellow solid (0.35 g, yield 40%).
Mp 175–180 ꢀC; IR (cmꢁ1): 3373 (NH), 2199 (CN), 1766 (CO); 1H
NMR (CDCl3, ppm): 7.70–7.09 (9H, m, CHarom), 5.48 (1H, s, NH), 4.24
(1H, s, CH), 1.66 (3H, s, Me); 13C NMR (CDCl3, ppm): 173.6, 161.6,
Salicylic acid was identified by comparison with an authentic
sample.

M. Cordaro et al. / Tetrahedron 66 (2010) 2713–2717
2717
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4. X-ray data to be submitted to Acta Crystallogr.
Supplementary data
Supplementary data associated with this article can be found in
the online version, at doi:10.1016/j.tet.2010.02.009.
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