Efficient synthesis of 3-carboxylate pyrroles using microwave irradiation

Article abstract of DOI:10.1016/j.tetlet.2004.12.102

3-Carboxylate pyrroles are prepared by microwave irradiation of 1,3-oxazolium-5-oxides and various α-acetoxy-acrylic esters in a single synthetic step, in excellent yields and with high regioselectivity.

Full text of DOI:10.1016/j.tetlet.2004.12.102

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 1061–1062
Efficient synthesis of 3-carboxylate pyrroles using
microwave irradiation
Giovanni Grassi,* Francesco Foti, Francesco Risitano and Domenico Zona
`
Dipartimento di Chimica Organica e Biologica, Universita, Vill. S. Agata, I-98166 Messina, Italy
Received 17 November 2004; revised 17 December 2004; accepted 21 December 2004
Abstract—3-Carboxylate pyrroles are prepared by microwave irradiation of 1,3-oxazolium-5-oxides and various a-acetoxy-acrylic
esters in a single synthetic step, in excellent yields and with high regioselectivity.
Ó 2004 Elsevier Ltd. All rights reserved.
3-Carboxylate pyrroles are a class of products of interest
both in applicational terms and because of the biophar-
macological properties demonstrated by some deriva-
tives of members of this family.1 A possible route of
access to this kind of molecule is through cycloaddition
Me
Me
Me
Me
N
N
i
COOR
OAc
+
CO2H
Ph
O
Ph
O
O
1
2
ii
of 1,3-oxazolium-5-oxides (munchnones)2 with acetyl-
¨
enic dipolarophiles,3 but low yields and poor regio-
chemical control makes this route unattractive.
Me
Me
N
Me
N
(Ph)Me
O
N
Me
Ph
COOR
Ph
Me
COOR
iii
+
COOR
AcO
O
In view of this, we have developed a new microwave-
assisted4 synthetic methodology, which has given excel-
lent results in terms of both yield (over 90%) and speed
and simplicity of execution; regioselectivity5 is, more-
over, high.
(Me)Ph
3
4
Scheme 1. Reagents and conditions: (i) Ac2O/dioxane; (ii) microwave,
10 min; (iii) –AcOH, –CO2.
Thus the desired pyrroles 3 and 4 were obtained by
cycloaddition between munchnone 1 and a-acetoxy-
In particular, their regiochemistry was confirmed on the
basis of intramolecular NOE effects. Dipolar interac-
tions in 3 between HC-4 and ortho-hydrogens of ArC-
5, together with the lack of any detectable contact be-
tween analogous hydrogens in 4, are vindication of the
structures assigned.
¨
acrylic esters 2 (Scheme 1).6
In a typical experiment,7 mesoionic derivative 1, pre-
pared in situ using the traditional method8 of cyclodehy-
dration from the corresponding N-substituted amino
acid with acetic anhydride in dioxane, was mixed with
olefins and the mixture was irradiated at 100 °C for
10 min. The subsequent work-up produced the results
shown in Table 1.
The efficiency of the method and its general applicability
were demonstrated by also using a b-substituted olefin
such as Z- and E-ethyl 2-acetoxy-4-oxopent-2-enoate 5
(mixture 1:2.6).
All the compounds synthesised were characterised by
their spectral and analytical data.10
Here again the expected pyrroles 6 and 7 were produced
with an overall yield of 91% as indicated in Scheme 2.
Structures 6 and 7 were assigned on the basis of
analytical and spectroscopic data11 and their relative
regiochemistry is confirmed by NOE measurements.
Thus, irradiation of H3COCC-4 in 6 resulted in NOE
Keywords: Dipolar cycloaddition; Microwave synthesis; Regioselecti-
vity; Mesoionic compounds.
*
Corresponding author. Tel.: +39 90 676 5513; fax: +39 90 393897;
e-mail: ggrassi@isengard.unime.it
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.12.102

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G. Grassi et al. / Tetrahedron Letters 46 (2005) 1061–1062
Table 1. Regioselective synthesis of 3-carboxylate pyrroles
2.53 (s, 3H), 3.43 (s, 3H), 3.73 (s, 3H), 6.49 (s, 1H), 7.18–
7.36 (m, 5H); 13C NMR (CDCl3) d 11.6, 31.8, 50.6, 109.1,
109.2, 112.4, 127.3, 128.4 (2), 129.0, 133.6, 134.8, 138.1,
166.8. Anal. Calcd for C14H15NO2: C, 73.34; H, 6.59; N,
6.11. Found: C, 73.49; H, 6.61; N, 6.05. Compound 3b: mp
85–86 °C (lit.2 mp 83–85 °C); IR (KBr): 1695, 1524, 1491,
Entry
R
3 (%)a
4 (%)a
1
a
b
c
Me
Et
100
92
—
6
29
3
n-Pr
n-Bu
88
89
4
1263, 1202 cmÀ1 1H NMR (CDCl3) d 1.13 (t, J = 7 Hz,
;
4
d
4
a Isolated yields.
3H), 2.24 (s, 3H), 3.25 (s, 3H), 4.06 (q, J = 7 Hz, 2H), 6.32
(s, 1H), 7.16–7.30 (m, 5H). Anal. Calcd for C15H17NO2: C,
74.05; H, 7.04; N, 5.76. Found: C, 74.19; H, 6.96; N, 5.85.
Compound 4b: mp 65–66 °C (lit.2 mp 64–66 °C); IR
(KBr): 1699, 1520, 1491, 1253, 1200 cmÀ1 1H NMR
;
Me
Me
N
(CDCl3) d 1.34 (t, J = 7 Hz, 3H), 2.61 (s, 3H), 3.45 (s, 3H),
4.26 (q, J = 7 Hz, 2H), 6.51 (s, 1H), 7.18–7.34 (m, 5H).
Anal. Calcd for C15H17NO2: C, 74.05; H, 7.04; N, 5.76.
Found: C, 74.21; H, 7.09; N, 5.60. Compound 3c: mp 48–
N
1
2
Me
Ph
Ph
Me
COOEt
6 (62%)
1
2
AcO
ii, iii
5
5
+
1
+
4
3
4
3
EtOOC
O
COOEt
5
O
O
1
50 °C; IR (KBr): 1694, 1529, 1409, 1242, 1208 cmÀ1; H
7 (29%)
NMR (CDCl3) d 0.95 (t, J = 7.5 Hz, 3H), 1.68 (qt, J = 7.5,
6.6 Hz, 2H), 2.51 (s, 3H), 3.36 (s, 3H), 4.13 (t, J = 6.6 Hz,
2H), 6.32 (s, 1H), 7.16–7.30 (m, 5H, Ar); 13C NMR
(CDCl3) d 10.6, 11.5, 22.3, 31.7, 64.8, 109.3, 109.4, 111.8,
127.2, 128.4 (2), 128.9, 132.6, 133.7, 136.9, 165.5. Anal.
Calcd for C16H19NO2: C, 74.68; H, 7.44; N, 5.44. Found:
C, 74.79; H, 6.36; N, 5.55. Compound 4c: oil; IR (KBr):
Scheme 2. Reagents and conditions: (ii) microwave, 10 min; (iii)
–AcOH, –CO2.
enhancement for the ortho-hydrogens of the aryl at C-5,
indicating a close spatial proximity between these
protons. Conversely, in compound 7, irradiation of
H3COCC-4 gives rise to NOE enhancement of H3C-5.
1
1697, 1529, 1414, 1245, 1210 cmÀ1; H NMR (CDCl3) d
0.76 (t, J = 7.5 Hz, 3H), 1.51 (qt, J = 7.5, 6.6 Hz, 2H), 2.24
(s, 3H), 3.26 (s, 3H), 3.98 (t, J = 6.6 Hz, 2H), 6.43 (s, 1H),
7.19–7.38 (m, 5H, Ar); 13C NMR (CDCl3) d 9.8, 10.1,
26.2, 31.7, 66.8, 109.3, 109.4, 111.8, 127.2, 128.4 (2), 128.9,
132.6, 133.7, 136.9, 164.7. Anal. Calcd for C16H19NO2: C,
74.68; H, 7.44; N, 5.44. Found: C, 74.85; H, 7.51; N, 5.32.
Compound 3d: oil; IR (KBr): 1690, 1529, 1414, 1246,
In conclusion, this microwave-assisted process provided
a simple and highly efficient method for the regioselec-
tive synthesis of various 3-carboxylate pyrroles.
1206 cmÀ1 1H NMR(CDCl3) d 0.99 (t, J = 7.2 Hz, 3H),
;
References and notes
1.46 (qt, J = 7.2, 6.5 Hz, 2H), 1.70 (tt, J = 6.4, 6.5 Hz, 2H),
2.56 (s, 3H), 3.41 (s, 3H), 4.23 (t, J = 6.4 Hz, 2H), 6.60 (s,
1H), 7.24–7.38 (m, 5H, Ar); 13C NMR (CDCl3) d 11.4,
13.7, 19.3, 31.0, 31.6, 63.0, 109.3 (2), 111.8, 127.2, 128.4
(2), 128.8, 132.6, 133.6, 136.9, 165.4. Anal. Calcd for
C17H21NO2: C, 75.25; H, 7.80; N, 5.16. Found: C, 75.36;
H, 7.91; N, 5.09. Compound 4d: oil; IR (KBr): 1695, 1529,
1. Zhang, P.; Johnson, W. T.; Klewer, D.; Paul, N.; Hoops,
G.; Davisson, V. J.; Bergstrom, D. E. Nucleic Acid Res.
1998, 26, 2208–2215.
2. Reviews on munchnones include: (a) Oxazoles: Synthesis,
¨
Reactions and Spectroscopy, Part A; Palmer, D. C., Ed.;
John Wiley & Sons: New Jersey, 2003; pp 473–576; (b)
Synthetic Applications of Dipolar Cycloaddition Chemistry
toward Heterocycles and Natural Product; Padwa, A.,
Pearson, W. H., Eds.; John Wiley & Sons: New York,
2002; pp 681–754.
1419, 1246, 1206 cmÀ1 1H NMR (CDCl3) d 0.84 (t,
;
J = 7.2 Hz, 3H), 1.18 (qt, J = 7.2, 6.5 Hz, 2H), 1.40 (tt,
J = 6.4, 6.5 Hz, 2H), 2.20 (s, 3H), 3.21 (s, 3H), 4.02 (t,
J = 6.4 Hz, 2H), 6.44 (s, 1H), 7.27–7.39 (m, 5H, Ar); 13C
NMR (CDCl3) d 10.6, 11.9, 23.2, 31.0, 31.6, 65.0, 109.3
(2), 111.8, 127.2, 128.4 (2), 128.8, 132.6, 133.6, 136.9,
164.6. Anal. Calcd for C17H21NO2: C, 75.25; H, 7.80; N,
5.16. Found: C, 75.59; H, 7.72; N, 5.28.
3. Padwa, A.; Burgess, E. M.; Gingrinch, H. L.; Roush, D.
M. J. Org. Chem. 1982, 47, 786–791.
4. Danks, T. N. Tetrahedron Lett. 1999, 40, 3957–3959.
5. Gribble, G. W.; Pelkey, E. T.; Simon, W. M.; Trujillo, H.
A. Tetrahedron 2000, 56, 10133–10140.
6. Monnin, J. Helv. Chim. Acta 1956, 39, 1721–1724.
7. General procedure: a mixture of olefin 2 (3 mmol), N-
methyl-N-benzoyl-alanine (621.6 mg, 3 mmol) and acetic
anhydride (1 mL) in dioxane (40 mL) was irradiated for
10 min in an open glass vial in a CEM microwave
synthesiser at 100 °C. After cooling the reaction to room
temperature, the solvent was removed under vacuum and
the residue was purified by silica gel flash column
chromatography using chloroform to give the regioisomer
mixture as a yellow solid or oil. Recrystallisation from
80% petroleum ether/methanol afforded 3 and 4 as
colourless crystals or a pale yellow oil.
10. In this case, the two regioisomers 3b and 4b were obtained
by the quoted means (Ref. 3) with respective yields of 13%
and 16%.
11. Selected data. Compound 6: mp 91–93 °C; IR (KBr): 1690,
1
1668, 1531, 1456, 1294, 1197 cmÀ1; H NMR (CDCl3) d
0.93 (t, J = 7.2 Hz, 3H), 2.34 (s, 3H), 2.38 (s, 3H), 3.22 (s,
3H), 3.97 (q, J = 7.2 Hz, 2H), 7.19–7.36 (m, 5H, Ar); 13C
NMR (CDCl3) d 11.3, 13.6, 31.0, 31.5, 60.0, 114.9, 124.2,
128.0 (2), 128.5 (2), 130.5, 131.2, 133.5, 138.3, 166.6, 198.2.
Anal. Calcd for C17H19NO3: C, 71.56; H, 6.71; N, 4.91.
Found: C, 71.31; H, 6.64; N, 5.04. Compound 7: mp 106–
108 °C; IR (KBr): 1684, 1660, 1528, 1456, 1258,
1
1163 cmÀ1; H NMR (CDCl3) d 1.25 (t, J = 7.2 Hz, 3H),
2.06 (s, 3H), 2.42 (s, 3H), 3.24 (s, 3H), 4.22 (q, J = 7.2 Hz,
2H), 7.21–7.38 (m, 5H, Ar); 13C NMR (CDCl3) d 11.5,
14.1, 31.4, 31.7, 60.3, 111.3, 124.8, 128.5 (2), 128.8 (2),
130.5, 130.9, 133.7, 135.1, 165.3, 189.8. Anal. Calcd for
C17H19NO3: C, 71.56; H, 6.71; N, 4.91. Found: C, 71.68;
H, 6.75; N, 5.06.
8. Huisgen, R.; Gotthard, H.; Bayer, H. O. Angew. Chem.,
Int. Ed. 1964, 3, 135–137; Bayer, H. O.; Gotthard, H.;
Huisgen, R. Chem. Ber. 1970, 103, 2356–2362.
9. Selected data. Compound 3a: mp 97–98 °C; IR (KBr):
1
1694, 1523, 1461, 1247, 1215 cmÀ1; H NMR (CDCl3) d