Transformations of alkyl 2-(2,2-disubstituted-ethenyl)amino-3- dimethylaminoprop-2-enoates: Synthesis of alkyl 3,4-disubstituted- and alkyl 1-acyl-3,4-disubstituted pyrrole-2-carboxylates

Article abstract of DOI:10.1055/s-1999-3408

Alkyl 3,4-disubstituted pyrrole-2-carboxylates were obtained by cyclization of alkyl-2(2,2-disubstituted-ethenyl)amino-3- (dimethylamino)prop-2-enoates in acidic media, while in the presence of acyl chlorides alkyl 1-acyl-3,4-disubstituted pyrrol-2-carbox

Full text of DOI:10.1055/s-1999-3408

PAPER
479
Transformations of Alkyl 2-(2,2-Disubstituted-ethenyl)amino-
3
-dimethylaminoprop-2-enoates: Synthesis of Alkyl 3,4-Disubstituted-
and Alkyl 1-Acyl-3,4-disubstituted Pyrrole-2-carboxylates
Lovro Selic ¬, Branko Stanovnik*
Faculty of Chemistry and Chemical Technology, University of Ljubljana, Ask
ˇ
erceva 5, 1000 Ljubljana, Slovenia
Fax +386(61)1263257; E-mail: branko.stanovnik@uni-lj.si
Received 14 May 1998; revised 14 August 1998
th
Dedicated to Professor Henk van der Plas, Wageningen, on the occasion of his 75 birthday
However, when we tried to prepare 6-amino-5-oxo-5H-
thiazolo[3,2-a]pyrimidine by the reaction of 2-amino-
thiazole with 2-(2-acetyl-2-benzoyl-1-ethenyl)amino-3-
Abstract: Alkyl 3,4-disubstituted pyrrole-2-carboxylates were ob-
tained by cyclization of alkyl 2-(2,2-disubstituted-ethenyl)amino-3-
(dimethylamino)prop-2-enoates in acidic media, while in the pres-
(
dimethylamino)propenoate, ethyl 4-benzoyl-3-methyl-
ence of acyl chlorides alkyl 1-acyl-3,4-disubstituted pyrrole-2-
carboxylates were formed.
pyrrole-2-carboxylate was formed in low yield. When the
reagent itself was heated in trifluoracetic acid the pyrrole
derivative was obtained in 65% yield whose structure was
Key words: alkyl substituted pyrrole-2-carboxylates, alkyl 1-acyl
substituted pyrrole-2-carboxylates, nitogen hetrocycles
2
7
confirmed by X-ray analysis.
Since the reaction represents a new synthesis of polysub-
stituted pyrrole-2-carboxylates we investigated the reac-
tions of alkyl 2-[(2-acyl-3-oxobut-1-enyl)amino]propen-
oates 2a, 2b, 2c, 2d, and methyl 2-(2-ethoxycarbon-
yl-2-phenylethenyl)amino-3-(dimethylamino)prop-2-
enoate (2e), prepared from methyl N-(2-ethoxycarbonyl-
Recently, considerable interest has been shown in the syn-
thesis of pyrrole derivatives. This heterocycle is incorpo-
rated in many natural products which posses biological
properties and constitute the building block for por-
2
8
23
23
29
1
Ð6
phyrins, chlorophylls, corrins and bile pigments. In
view of the importance of pyrroles for various applica-
tions, a large number of papers have been published on the
2
-phenylethenyl)glycinate (1e) and N,N-dimethylform-
5
,7Ð9
amide dimethyl acetal (DMFDMA)] (Scheme 1).
preparation of this heterocyclic system.
Pyrrole-2-carboxylates have been prepared from 1,3-di-
1
0Ð12
carbonyl compounds and aminomalonate,
diethyl
13
oximinomalonate,
various
2-amino-1,3-dicarbonyl
14
compounds, 1,3-dicarbonyl compounds and a-amino
acid derivatives,1 and by addition of a-amino acids de-
5Ð18
1
9Ð20
rivatives to dimethyl acetylenedicarboxylate.
Recent-
ly, substituted 2-acylamino-3-dimethylaminopropen-
2
1
oates, masked a-formyl-a-amino acid derivatives, and
alkyl 2-(2,2-disubstituted-ethenyl)amino-3-(dimethyl-
amino)prop-2-enoates and related compounds as reagents
for the preparation of several heterocyclic systems, in-
cluding 2H-pyran-2-one and fused pyran-2-ones, fused
Scheme 1
Compounds 2aÐe were cyclized under various conditions:
by heating in anhydrous acetic acid (Method A), in tri-
2
2Ð26
pyridinones and pyrimidinones,
have been described.
Scheme 2
Synthesis 1999, No. 3, 479Ð482 ISSN 0039-7881 © Thieme Stuttgart á New York

4
80
L. Selic
¬
, B. Stanovnik
PAPER
fluoroacetic anhydride at room temperature or heating at The following compounds were prepared according to the proce-
2
8
23
23
29
dures described in literature: 2a, 2b, 2c, 2d.
4
0¡C (Method B), or in acetone in the presence of an acyl
chloride at reflux or room temperature (Method C) to give
,4-disubstituted 3aÐd and 1-acyl-3,4-trisubstituted pyr-
role-2-carboxylates 4aÐc, respectively (Scheme 2, Tables
and 2).
Methyl N-(2-Ethoxycarbonyl-2-phenylethenyl)glycinate (1e)
A mixture of ethyl phenylacetate (63 mmol, 10 mL) and tert-bu-
tyloxy-bis(dimethylamino)methane (65 mmol, 13 mL) in toluene
20 mL) was refluxed for 3.5 h. Volatile components were evap-
orated in vacuo and methyl glycinate hydrochloride (63 mmol,
.91 g) in glacial AcOH (15 mL) was added and the mixture was
heated under reflux for another 2 h. Then volatile components were
evaporated and propan-2-ol (5 mL) was added for initiating the
crystallization. The precipitate was collected by filtration and re-
crystallized from EtOH to give 1e in 45% yield [100% (E)-config-
uration]; mp 74Ð76¡C.
3
1
(
The formation of the pyrrole derivatives can be explained
by the mechanism shown on Scheme 3 which is also sup-
ported experimentally. Namely, when the reaction of 3a
was followed by H NMR spectroscopy, the formation of
dimethylformamide as the side product was observed.
7
1
Anal. Found: C, 63.45; H, 6.62; N, 5.29. C H NO requires: C,
14
17
4
6
3.87; H, 6.51; N, 5.32.
1
H NMR (DMSO-d /TMS): d = 1.18 (t, 3 H, J = 7.1 Hz,
6
CO CH CH ), 3.67 (s, 3 H, CO CH ), 4.11 (q, 2 H, J = 7.1 Hz,
2
2
3
2
3
CO CH CH ), 4.15 (d, 2 H, J = 6.0 Hz, CH ), 7.05 (d, 1 H, J = 13.3
2
2
3
2
Hz, CHNH), 7.21Ð7.27 (m, 5 H, C H ), 8.32 (td, 1 H, J = 13.3, 6.0
6
5
Hz, NH).
Methyl 2-[2-Ethoxycarbonyl-2-phenylethenyl]amino-3-(di-
methylamino)prop-2-enoate (2e)
A mixture of 1e (15 mmol, 3.95 g) and DMFDMA (45 mmol, 7 mL)
in DMF (15 mL) was heated at 80¡C for 5 h. Volatile components
were evaporated in vacuo to yield 4.20 g (88%) of 2e [100%
(2Z,1'E)-configuration]. This compound was used in further exper-
iments without purification.
MS: m/z = 318 (M+).
1
H NMR (CDCl /TMS): d = 1.27 (t, 3 H, J = 7.1 Hz, CO CH CH ),
3
2
2
3
3
.05 [s, 6 H, N(CH ) ], 3.68 (s, 3 H, CO CH ), 4.21 (q, 2 H, J = 7.1
3 2 2 3
Hz, CO CH CH ), 6.78 (d, 1 H, J = 12.7 Hz, CHNH), 7.21 (s, 1 H,
2
2
3
H-3), 7.18Ð7.42 (m, 5 H, C H ), 8.82 (d, 1 H, J = 12.7 Hz, NH).
6
5
Pyrroles 3, 4; General Procedure
Method A: Propenoate 2 (1 mmol) was heated in glacial AcOH (3Ð
4
mL) under reflux for several hours. Volatile components were
Scheme 3
evaporated in vacuo, the oily residue was triturated with an appro-
priate solvent to form a precipitate, which was collected by filtra-
tion and purified by recrystallization. (Tables 1 and 2).
This reaction failed with 2e and the expected methyl 3-hy-
Method B: Propenoate 2 (1 mmol) was suspended in trifluoracetic
anhydride (TFAA) (1Ð1.5 mL) and stirred at r.t., until a clear solu-
tion was obtained. After that, the mixture was cooled in an ice bath
and MeOH (2Ð3 mL) was added dropwise, until all TFAA was de-
stroyed. The mixture was then cooled to Ð20¡C to form a precipi-
tate, or evaporated in vacuo and then triturated with an appropriate
solvent. The precipitate was collected by filtration and purified by
recrystallization (Tables 1 and 2).
droxy-4-phenylpyrrole-2-carboxylate was not formed.
1
Melting points were taken on a Kofler micro hot stage. The H
NMR spectra were obtained on Bruker Avance DPX 300 spec-
trometer with TMS as the internal standard, IR spectra on a Perkin-
Elmer 1600 spectrometer (KBr pellets), mass spectra on
AutoSpecQ spectrometer and elemental analyses for C, H and N on
a Perkin-Elmer CHN Analyser 2400.
Table 1 Compounds 3 and 4 Prepared
Reactant(s)
Reaction Conditions
Method
A; (B)
Prod-
uct
R1
R2
R3
Yield
(%)
mp (ûC)
(solvent)
2
2
2
2
2
2
2
a; (2a)
b; (2b)
c
d
reflux, 5 h; (r.t., 10 min)
reflux, 3.5 h; (r.t., 10 min) A; (B)
r.t., 10 min
r.t., 10 min
3a
3b
3c
3d
4a
4b
4c
Me
Me
Me
Et
Me
Me
Me
Ð
Ð
Ð
Ð
Me
Ph
Me
COMe
CO Bn
CO Me
CO Et
COMe
COMe
CO Bn
45; (54)
51; (61) >300 (CF CO Me)
3 2
128Ð131 (toluene)
2
B
B
C
C
C
49
60
41
23
34
124Ð127 (CF CO Me)
79Ð80 (EtOH)
77 (EtOH)
125Ð126 (toluene)
69Ð70 (EtOH)
2
3
2
2
a + MeCOCl reflux, 2 h
a + PhCOCl r.t., 2 h
b + MeCOCl reflux, 2.5 h
2
Synthesis 1999, No. 3, 479–482 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Synthesis of Alkyl 3,4-Disubstituted- and Alkyl 1-Acyl-3,4-disubstituted Pyrrole-2-carboxylates
481
Table 2 Spectroscopic Data of Compounds 3 and 4
13
1
Prod-
ucta
IR (KBr)
n (cm )
MS (M+)
m/z
C NMR (75 MHz, DMSO-d /TMS)
H NMR (300 MHz, DMSO-d /TMS)
6
6
Ð1
d
d, J (Hz)
3
a
3241, 1722, 181
645, 1561
12.25 (3-CH3), 28.97 (COCH3), 51.93 2.34 (s, 3 H, COCH ), 2.44 (s, 3 H, 3-CH ), 3.79
3
3
1
(OCH ), 121.18, 125.05, 128.78 and 130.31 (s, 3 H, CO CH ), 7.74 (d, 1 H, J = 3.5, HÐ5),
3
2
3
(
Pyrrole), 162.07 (CO Me), 194.61 (COMe)
12.05 (d, 1 H, J = 3.5, NH)
2
3
b
3350, 1715, 273
684, 1593
11.93 (3-CH ), 51.98 (OCH ), 65.48 (PhCH ), 2.51 (s, 3 H, 3-CH ), 3.79 (s, 3 H, CO CH ),
3 3 2 3 2 3
1
115.75, 121.06, 128.56, 128.68, 128.80, 5.24 (s, 2 H, CH Ph), 7.29Ð7.45 (m, 5 H, C H ),
2
6
5
1
1
29.29, 129.68 and 137.59 (Pyrrole, Ph), 7.51 (d, 1 H, J = 3.4, HÐ5), 12.21 (d, 1 H, J = 3.4,
61.84 and 164.44 (C=O) NH)
3
3
c
3252, 1704
197
11.85 (3-CH ), 51.54 and 51.98 (OCH ), 2.49 (s, 3 H, 3-CH ), 3.71 and 3.79 (s, 6 H,
3 3 3
1
1
15.81, 120.92, 128.61 and 129.60 (Pyrrole), CO CH ), 7.45 (d, 1 H, J = 3.4, H), 12.16 (d, 1
2 3
61.87 and 165.14 (C=O)
H, J = 3.4, NH)
d
3292, 1716, 225
668
11.87 (3-CH ), 15.12 (2×OCH CH ), 50.91 1.26 and 1.30 (t, 6 H, J = 7.1, CO CH CH ), 2.49
3 2 3 2 2 3
1
and 60.58 (OCH CH ), 116.11, 121.12, 128.45 (s, 3 H, 3-CH ), 4.18 and 4.25 (q, 4 H, J = 7.1,
2
3
3
and 129.37 (Pyrrole), 161.49 and 164.71 CO CH CH ), 7.43 (d, 1 H, J = 3.4, HÐ5), 12.09
2
2
3
(C=O)
(d, 1 H, J = 3.4, NH)
4
a
3244, 1716, 224b
681, 1645
11.62 (3-CH ), 23.71 and 29.03 (COCH ), 2.25 (s, 3 H, 4-COCH ), 2.43 (s, 3 H, 3-CH ),
3
3
3
3
1
51.97 (OCH ), 121.20, 125.67, 128.48 and 2.65 (s, 3 H, NCOCH ), 3.75 (s, 3 H, CO CH ),
3
3
2
3
1
31.56 (Pyrrole), 162.10 and 162.78 (CO Me, 8.35 (s, 1 H, HÐ5)
2
NCOMe), 194.61 (COMe)
4
b
3110, 1715
285
12.18 (3-CH3), 29.19 (COCH3), 52.49 2.34 (s, 3 H, COCH ), 2.41 (s, 3 H, 3-CH ), 3.48
3
3
(
OCH ), 125.36, 129.06, 130.07, 130.61, (s, 3 H, CO CH ), 7.58Ð7.64 and 7.72Ð7.80 (m,
3
2
3
1
31.60, 132.76, 133.52 and 135.32 (Pyrrole, 5 H, C H ), 8.23 (s, 1 H, HÐ5)
6 5
C H ), 161.37 and 168.68 (CO Me, NCOPh),
6
5
2
1
94.93 (COMe)
4
c
3350, 3126, 274b
11.33 (3-CH3), 23.77 (COCH3), 52.98 2.27 (s, 3 H, 3-CH ), 2.63 (s, 3 H, NCOCH ),
3
3
1
1
742, 1712,
580
(OCH ), 66.21 (PhCH ), 117.32, 123.50, 3.75 (s, 3 H, CO CH ), 5.29 (s, 2 H, CH Ph),
3 2 2 3 2
128.56, 128.76, 129.30, 129.35, 130.29, and 7.34Ð7.47 (m, 5 H, C H ) 8.11 (s, 1 H, H-5)
6
5
1
37.11 (Pyrrole, C H ), 162.61, 163.70 and
6 5
1
69.52 (C=O)
a
Satisfactory microanalyses obtained for all compounds: C ± 0.40, H ± 0.40, N ± 0.25.
MH .
b
+
Method C: Propenoate 2 (1 mmol) was suspended in acetone (3Ð
mL), then the appropriate acyl chloride (0.5Ð1 mL) was added and
(6) Scott, A. J. Pure and Appl. Chem. 1981, 53, 1215.
(7) Sundberg, R. J. Pyrroles and Their Benzo Derivatives: Syn-
thesis and Applications, In Comprehensive Heterocyclic Che-
mistry; Katritzky, A. R.; Rees, C. W.; Eds.; Vol 4, Bird, C. W.;
Cheeseman, G. W. H.; Eds.; Pergamon: Oxford, 1984, pp
313Ð376.
(8) Sundberg, R. J. Pyrroles and Their Benzo Derivatives: Syn-
thesis, In Comprehensive Heterocyclic Chemistry II; Katritz-
ky, A. R. ; Rees, C. W.; Scriven, E. F. V.; Eds.; Vol. 2, Bird,
C. W.; Ed.; Pergamon: Oxford, 1996, pp 119Ð206.
4
the reaction mixture was heated under reflux, for several hours (Ta-
ble 1) or stirred at r.t. The mixture was then cooled to Ð20¡C and
left until a precipitate was formed, or evaporated in vacuo and then
tritutated with an appropriate solvent. Precipitate was collected by
filtration and purified by recrystallization. (Tables 1 and 2).
Acknowledgement
(
9) Jones, A. R. In The Chemistry of Heterocyclic Compounds;
The authors wish to express their gratitude to the Ministry of Sci-
ence and Technology, Slovenia, for the Þnancial support.
Vol. 48, Pyrroles, Part I; Taylor, E. C.; Ed.; Wiley: New York,
1
990, p 105.
(
10) Paine III, J. B.; Dolphin, D. J. Org. Chem. 1985, 50, 5598.
Paine III, J. B.; Brough, J. R.; Buller, K. K.; Erikson, E. E. J.
Org. Chem. 1987, 52, 3986.
References
(
1) Battersby, A. R. Angew. Chem. 1995, 107, 421; Angew. Chem.
Int. Ed. Engl. 1995, 34, 383.
(12) Plieninger, H.; Husseini, H. Synthesis 1970, 587.
(13) Kleinspehn, G. G. J. Am. Chem. Soc. 1955, 77, 1546.
(14) Cohnen, E.; Dewald, R. Synthesis 1987, 566.
(15) Treibs, A.; Ohorodnik, A. Liebigs Ann. Chem. 1958, 611, 139.
(16) Gupta, S. K. Synthesis 1975, 726.
(2) Sessler, J. L.; Weghorn, J. S.; Hiseada, Y. L. Chem. Eur.
J. 1995, 1, 56.
(
(
3) Leeper, F. J. Nat. Prod. Rep. 1989, 171.
4) Kitamura, C.; Yamashita, Y. J. Chem. Soc., Perkin Trans 1
(17) Mataka, S.; Takahashi, K.; Tsuda, Y.; Tashiro, M. Synthesis
1
997, 1443.
1982, 157.
(5) Patterson, J. M. Synthesis 1976, 281.
(18) Hombrecher, H. K.; Horter, G. Synthesis 1990, 389.
Synthesis 1999, No. 3, 479–482 ISSN 0039-7881 © Thieme Stuttgart · New York

4
82
L. Selic
¬
, B. Stanovnik
PAPER
(
(
(
19) Winterfeldt, E.; Dillinger, H. J. Chem. Ber. 1966, 99, 1558.
(25) Pizzioli, L.; Ornik, B.; Svete, J.; Stanovnik, B. Helv. Chim.
Acta 1998, 81, 231.
20) Kolar, P.; Tisler, M. Synth. Commun. 1994, 24, 1887.
ˇ
21) For a review, see:
(26) Smodis
(27) Malesic
B. J. Heterocycl. Chem.1997, 34, 1757.
(28) Selic, L.; Stanovnik, B. J. Heterocycl. Chem. 1997, 34, 813.
(29) Toplak, R.; Zucchiati, M.; Golic Grdadolnik, S.; Stanovnik, B.
Heterocycles, in press.
ˇ
Stanovnik, B. Prog. Heterocycl. Chem. 1993, 5, 34.
22) Stanovnik, B. Molecules 1996, 1, 123.
23) Selic, L.; Golic
997, 80, 2418.
24) Toplak, R.; Selic
997, 45, 555.
ˇ
¬
¬
¬
¬
(
(
¬
Grdadolnik S.; Stanovnik, B. Helv. Chim. Acta
¬
1
¬
(
¬, L.; Sors ˇa k, G.; Stanovnik, B. Heterocycles
1
Synthesis 1999, No. 3, 479–482 ISSN 0039-7881 © Thieme Stuttgart · New York