Unexpected behavior of the reaction between 1,2-diaza-1,3-butadienes and 3-dimethylaminopropenoates: A useful entry to new pyrrolines, pyrroles, and oxazolines

Article abstract of DOI:10.1021/jo0480343

We observed a nucleophilic attack by the ene-amino carbon of 3-dimethylaminopropenoates at the terminal carbon of the azo-ene system of 1,2-diaza-1,3-butadienes. In tetrahydrofuran at 65 °C, this attack produced 1-aminopyrrolines with a high degree of cis

Full text of DOI:10.1021/jo0480343

Unexpected Behavior of the Reaction between
1,2-Diaza-1,3-Butadienes and 3-Dimethylaminopropenoates: A
Useful Entry to New Pyrrolines, Pyrroles, and Oxazolines
Orazio A. Attanasi,† Gianfranco Favi,† Paolino Filippone,*,† Amalija Golobicˇ,‡
Branko Stanovnik,*,‡ and Jurij Svete‡
Istituto di Chimica Organica, Universita` degli Studi di Urbino “Carlo Bo”, Via Sasso 75,
61029 Urbino, Italy, and Faculty of Chemistry and Chemical Technology, University of Ljubljana,
Asˇkercˇeva 5, 1000 Ljubljana, Slovenia
filippone@uniurb.it; branko.stanovnik@uni-lj.si
Received November 4, 2004
We observed a nucleophilic attack by the ene-amino carbon of 3-dimethylaminopropenoates at the
terminal carbon of the azo-ene system of 1,2-diaza-1,3-butadienes. In tetrahydrofuran at 65 °C,
this attack produced 1-aminopyrrolines with a high degree of cis-stereoselectivity by means of an
unusual zwitterionic adduct intermediate followed by intramolecular ring closure. In toluene under
reflux, 1-aminopyrrolines produced oxazoline-fused 1-aminopyrrolines. Oxazoline-fused 1-aminopy-
rrolines were directly obtained by reaction of 1,2-diaza-1,3-butadienes with 3-dimethylaminopro-
penoates in toluene under reflux. The ring opening of oxazoline-fused 1-aminopyrrolines in acidic
or basic media provides highly substituted 1-aminopyrroles. 5-Unsubstituted 1-aminopyrrole
derivatives were obtained from 1-aminopyrrolines under basic conditions by loss of dimethylamino
and ester groups. We discuss the plausible mechanisms of the ring closure and opening.
Introduction
penoates show both electrophilic and nucleophilic apti-
tudes and 1,2-diaza-1,3-butadienes exhibit both diene and
dienophile roles in Diels-Alder reactions and act as
Michael acceptors leading to heterocycle derivatives.
The chemistry of 3-dimethylaminopropenoates1 and
1,2-diaza-1,3-butadienes2 has been studied separately in
the authors’ laboratories. These investigations demon-
strated that both these compounds are powerful tools in
organic chemistry.1-3 In particular, 3-dimethylaminopro-
(2) For the synthesis and application of this and related compounds,
see: (a) Sommer, S. Tetrahedron Lett. 1977, 18, 117. (b) Attanasi, O.
A.; Filippone, P.; Mei, A.; Santeusanio, S. Synthesis 1984, 671. (c)
Attanasi, O. A.; Filippone, P.; Mei, A.; Santeusanio, S. Synthesis 1984,
873. (d) Attanasi, O. A.; De Crescentini, L.; Filippone, P.; Mantellini,
F.; Santeusanio, S. Arkivoc 2002, xi, 274. (e) Attanasi, O. A.; De
Crescentini, L.; Favi, G.; Filippone, P.; Giorgi, G.; Mantellini, F.;
Santeusanio, S. J. Org. Chem. 2003, 68, 1947. (f) Attanasi, O. A.; De
Crescentini, L.; Favi, G.; Filippone, G.; Mantellini, F.; Santeusanio,
S. J. Org. Chem. 2004, 69, 2686.
(3) (a) Zelenin, K. N.; Nikitin, V. A.; Anodina, N. M. Khim.
Geterotsikl. Soedin. 1973, 124. (b) Sommer, S. Chem. Lett. 1977, 583.
(c) Sommer, S. Angew. Chem., Int. Ed. Engl. 1977, 16, 58. (d) Gilchrist,
T. L.; Sanchez Romero, O. A.; Wasson, R. C. J. Chem. Soc., Perkin
Trans. 1 1989, 353. (e) Boeckman, R. K. Jr.; Ge, P.; Reed, J. E. Org.
Lett. 2001, 3, 3647. (f) Boeckman, R. K., Jr.; Ge, P.; Reed, J. E. Org.
Lett. 2001, 3, 3651.
* To whom correspondence should be addressed. (P.F.) Phone: +39-
0722-303443. Fax: +39-0722-303441. (B.S.) Phone: +386-1-2419-100.
Fax: +386-1-2419-220.
† University of Urbino.
‡ University of Ljubljana.
(1) For the synthesis and application of this and related compounds,
see: (a) Hvala, A.; Simonic, I.; Stanovnik, B.; Svete, J.; Tisler, M.; Zorz,
L. Heterocycles 1988, 27, 903. (b) Cˇ adezˇ, Z.; Stanovnik, B.; Svete, J.;
Tisˇler, M. Synthesis 1990, 70. (c) Stanovnik, B. J. Heterocycl. Chem,
1999, 36, 1581. (d) Stanovnik, B.; Svete, J. Synlett 2000, 1077. (e)
Stanovnik, B.; Svete, J. In Targets in Heterocyclic Systems, Synthesis,
Reactions and Properties; Attanasi, O. A., Spinelli, D., Eds.; Italian
Society of Chemistry: Rome, 2000; Vol. 4, p 105. (f) Stanovnik, B.;
Svete, J. Chem. Rev. 2004, 104, 2433.
10.1021/jo0480343 CCC: $30.25 © 2005 American Chemical Society
Published on Web 04/19/2005
J. Org. Chem. 2005, 70, 4307-4313
4307

Attanasi et al.
SCHEME 1
Based on these facts and our continuing investigations,
we decided to explore a possible nucleophilic attack of
3-dimethylaminopropenoates at the azo-ene system of
1,2-diaza-1,3-butadienes in an attempt to obtain pyrro-
lines and pyrroles by subsequent intramolecular cycliza-
tion of the preliminary 1,4-adduct intermediates. Sur-
prisingly, we first isolated new highly substituted
oxazolines. The mechanisms of formation of pyrrolines,
pyrroles, and oxazolines, as well as the behaviors of ring
closure and opening, have been elucidated and are
reported in this paper.
The synthesis of pyrroles is an attractive area of
heterocyclic chemistry,4 primarily because many pyrroles
are subunits of natural products5 and some are the
building blocks for porphyrin synthesis.6 In particular,
1-aminopyrroles are used as precursors in the synthesis
of biologically active compounds such as analgesics7 and
NMDA-receptor antagonists.8 Despite these applications,
the limited number of papers on 1-aminopyrroles in the
literature can be ascribed to the few procedures available
for their preparation.9 Direct synthetic routes to 1-ami-
nopyrroles are relatively few, and these derivatives seem
to be quite difficult to prepare by both classic10 and recent
methods,11 especially because of the severe reaction
conditions, formation of byproducts, reiterate reaction
steps, and workup manipulations.
(4) (a) Patterson, J. M. Synthesis 1976, 281. (b) Jones, R. A.; Bean,
G. P. The Chemistry of Pyrroles; Academic Press: London, 1977. (c)
Jones, G. B.; Chapman, B. J. In Comprehensive Heterocyclic Chemistry;
Bird, C. W., Ed.; Pergamon Press: Oxford, 1996; Vol. 2, p 1. (d) Black,
D. St. C. In Comprehensive Heterocyclic Chemistry; Bird, C. W., Ed.;
Pergamon Press: Oxford, 1996; Vol. 2, p 39. (e) Sundberg, R. J. In
Comprehensive Heterocyclic Chemistry; Bird, C. W., Ed.; Pergamon
Press: Oxford, 1996; Vol. 2, p 119. (f) Gribble, G. W. In Comprehensive
Heterocyclic Chemistry; Bird, C. W., Ed.; Pergamon Press: Oxford,
1996; Vol. 2, p 207.
(5) Inter alia, see: (a) Herbert, R. B. In The Alkaloids; Grundon,
M. F., Ed.; Chemical Society: London, 1982; Vol. 12. (b) Falk, H. The
Chemistry of Linear Oligopyrroles and Bile Pigments; Springer-
Verlag: Berlin, 1989. (c) Biosynthesis of Tetrapyrroles; Jordan, P. M.,
Ed.; Elsevier: London, 1991.
(6) (a) Porphyrins and Metalloporphyrins; Smith, K. M., Ed.;
Elsevier: Amsterdam, 1975. (b) Franck, B.; Nonn, A. Angew. Chem.,
Int. Ed. Engl. 1995, 34, 1795. (c) Sessler, J. L:; Weghorn, S. J.
Expanded, Contracted and Isomeric Porphyrins; Pergamon Press:
Oxford, 1997.
(7) Effland, R. C.; Klein, J. T. U.S. Patent 4,546,105, 1985; Chem.
Abstr. 1986, 104, 186307.
(8) Kulagowski, J.; Janusz, J.; Leeson, P. D. UK. Patent 2,265,372,
1993; Chem. Abstr. 1993, 120, 134504.
(9) (a) Sommer, S. Angew. Chem., Int. Ed. Engl. 1979, 18, 695. (b)
Bean, G. P. Pyrroles Part One. In The Chemistry of Heterocyclic
Compounds; Jones, R. A., Ed.; John Wiley & Sons: New York, 1990;
Vol. 48, Chapter 2. (c) Cirrincione, G.; Almerico, A. M.; Aiello, E.;
Dattolo, G. Pyrroles Part Two. In The Chemistry of Heterocyclic
Compounds; Jones, R. A., Ed.; John Wiley & Sons: New York, 1992;
Vol. 48, Chapter 3. (d) Seino, H.; Ishii, Y.; Sasagawa, T.; Hidai, M. J.
Am. Chem. Soc. 1995, 117, 12181. (e) McLeod, M.; Boudreault, N.;
Leblanc, Y. J. Org. Chem. 1996, 61, 1180. (f) Arcadi, A.; Anacardio,
R.; D’Anniballe, G.; Gentile, M. Synlett 1997, 1315. (g) Jolivet Fouchet,
S.; Hamelin, J.; Texier Boullet, F.; Toupet, L.; Jacquault, P. Tetrahe-
dron 1998, 54, 4561. (h) Palacios, F.; Aparicio, D.; De los Santos, J. M.
Tetrahedron 1999, 55, 13767. (i) Attanasi, O. A.; De Crescentini, L.;
Favi, G.; Filippone, P.; Mantellini, F.; Santeusanio, S. J. Org. Chem.
2002, 67, 8178 and references therein.
(10) (a) Beelen van, D. C.; Wolters, J.; Gen van der, A. Recl. Trav.
Chim. Pays-Bas 1979, 98, 437. (b) Kleinspehn, G. G. J. Am. Chem.
Soc. 1955, 77, 1546. (c) Huisgen, R.; Stangl, H.; Sturm, H. J.;
Wagenhofer, H. Angew. Chem., Int. Ed. Engl. 1962, 1, 50.
(11) (a) Padwa, A.; Deen, D. C.; Hertzog, D. C.; Wadler, W. R.; Zhi,
L. Tetrahedron 1992, 48, 7565. (b) Danks, T. N.; Velo-Rego, D.
Tetrahedron Lett. 1994, 35, 9443. (c) Furstner, A.; Bogdanovic, B.;
Angew. Chem., Int. Ed. Engl. 1996, 35, 2443. (d) South, M. S.;
Jakuboski, T. L.; Westmeyer, M. D.; Dukesherer, D. R. J. Org. Chem.
1996, 61, 8921. (e) Gilchrist, T. L. J. Chem. Soc., Perkin Trans. 1 1998,
615.
This paper reports a simple one-pot protocol for the
synthesis of variously functionalized 1-aminopyrrolines
and oxazoline-fused 1-aminopyrrolines from which can
be readily obtained substituted and (4 or 5)-unsubstituted
1-aminopyrroles.
The presence of different functional groups in many
positions of these systems merits particular emphasis.
In fact, such compounds may be, in turn, useful for
further interesting structural modifications producing
more complex compounds.
Results and Discussion
1,2-Diaza-1,3-butadienes 1a,c,i,j easily reacted with
methyl 2-substituted-3-dimethylaminopropenoates 2a,b
under various conditions (Scheme 1, Table 1). When the
reactions between 1,2-diaza-1,3-butadienes 1a,c and
methyl 2-benzoylamino-3-dimethylaminopropenoate 2a
were carried out in tetrahydrofuran at 65 °C (10-30 h),
the cis-1-aminopyrroline intermediates 4a,b were ob-
tained almost exclusively and in excellent yields (75-
92%). Trace amounts of trans diastereomeric products
5a,b were also isolated from the crude reaction mixture
(Scheme 1, Table 1). Moreover, when 1,2-diaza-1,3-
butadienes 1i,j reacted with methyl 2-benzyloxycarbo-
nylamino-3-dimethylaminopropenoate 2b in toluene un-
der reflux, only cis-1-aminopyrrolines 4c,d were recovered.
The exact stereochemistry of 1-aminopyrroline deriva-
tives 4a-d was assigned by X-ray analysis of compound
1
4b. H NMR spectra of the compounds 4a, 5a and 4b,
5b did not allow the exhaustive identification of these
two diastereomers. The high yield of these products may
be ascribed to the favorable intramolecular hydrogen
bond between O(1) and N(3) of substituted carbonylamino
and dimethylamino residues, respectively, in cis isomers
4308 J. Org. Chem., Vol. 70, No. 11, 2005

Useful Entry to New Pyrrolines, Pyrroles, and Oxazolines
TABLE 1. Reaction Times and Yields of 1-Aminopyrrolines 4a-d and 5a,b
1
R1
R2
2
R3
4
yielda (%)
5
yielda (%)
solvent, T (°C)
time (h)
1a
1c
1i
CO2Me
CO2t-Bu
CONH2
CONH2
Me
Me
Me
Et
2a
2a
2b
2b
Ph
4a
4b
4c
4d
92
75
44
38
5a
5b
2
9
THF, 65
10
30
6
Ph
THF, 65
OBn
OBn
toluene, reflux
toluene, reflux
1j
6
a Yield of pure isolated products.
SCHEME 2
SCHEME 3
TABLE 2. Reaction Times and Yields of Oxazolines
6a-h
1
R1
R2
6
yielda (%)
timeb (h)
1a
1b
1c
1d
1e
1f
CO2Me
Me
Et
Me
Bn
Me
Et
6a
6b
6c
6d
6e
6f
70
56
65
51
56
54
61
66
20
26
30
30
27
20
30
25
CO2Et
CO2t-Bu
CO2t-Bu
CO2Bn
CO2Bn
1g
1h
CO2p-MeO-Bn
CO2p-MeO-Bn
Me
Et
6g
6h
a Yield of pure isolated products. b Time of reflux.
state. Alternatively, intermolecular protonation could
precede the elimination, allowing loss of Me2NH instead
of Me2N-.
The treatment of 4a,b and/or 5a,b in toluene under
reflux for 20 h yielded unexpected oxazoline-fused 1-ami-
nopyrrolines 6a,c (Scheme 2). It is likely that, once the
1-aminopyrroline stereoisomers are formed, they undergo
isomerization affording the oxazoline-fused 1-aminopy-
rroline via five-membered ring closure by internal nu-
cleophilic attack of oxygen of the benzoylamino residue
with dimethylamine elimination or by attack of the same
oxygen atom at the iminium moiety of an azomethine
imine intermediate (Scheme 2).
Oxazoline-fused 1-aminopyrrolines 6a-h were directly
synthesized in one pot and produced good yields by
reaction of 1,2-diaza-1,3-butadienes 1a-h with 3-dim-
ethylaminopropenoate 2a in toluene under reflux (20-
30 h; Scheme 3, Table 2). Contrary to what has been
reported in a previous paper,12 we observed the formation
of oxazoline-fused 1-aminopyrrolines instead of aziridine-
fused 1-aminopyrrolines. Unfortunately, the coupling
constant value for the carbon at approximately 98.1 ppm
(JCH ) 179.5 Hz) that allowed us to attribute the aziridine
system falls in a range that does not unequivocally assign
the real structure. Indeed, the X-ray structure of com-
pound 6a has confirmed the exact oxazoline structure.
To the best of our knowledge, this is the first time that
these oxazoline-fused 1-aminopyrrolines have been syn-
thesized. The only structure that has an oxazoline ring
4a-d. Furthermore, an equimolar mixture of the iso-
meric couples 4a, 5a and 4b, 5b was achieved when the
single diastereomers 4a,b or 5a,b were treated for 0.5 h
in toluene under reflux (Scheme 2).
An analogous equimolar mixture was also obtained
when diastereomers 4a,b or 5a,b were treated in chlo-
roform or methanol under reflux. Different reaction times
and temperatures considerably influenced the behavior
of the reaction. Higher temperatures led to an increase
in the percentage of the minor isomeric (trans) interme-
diate. On the basis of these results, it seems reasonable
to conclude that the reaction takes place by means of a
preliminary 1,4-addition of methyl 2-benzoylamino-3-
dimethylaminopropenoate to 1,2-diaza-1,3-butadienes as
a consequence of the nucleophilic attack of the ene-amino
carbon in the heterodiene system. This attack produces
the zwitterionic hydrazone adduct intermediate and then
a mixture of cis/trans pyrroline derivatives by subsequent
intramolecular cyclization (Scheme 1).
The trans diastereomer is in thermal equilibrium with
the cis form via the opened zwitterionic hydrazone
intermediate 3 (Scheme 1) or via the formation of an
azomethine imine by Me2N- elimination (Scheme 2). A
more reasonable could be a mechanism in which the
dimethylamino group picks up a proton as it leaves.
Either the hydrazine N-H or the amide N-H can do this
intramolecularly through a five-membered transition
(12) Attanasi, O. A.; Favi, G.; Filippone, P.; Stanovnik, B.; Svete, J.
Synlett 2003, 995.
J. Org. Chem, Vol. 70, No. 11, 2005 4309

Attanasi et al.
SCHEME 4a
nopyrroline 6a by treatment with trifluoroacetic acid
under reflux for 2 h (Scheme 5). In this case, selective
hydrolysis, decarboxylation, and transposition of the ester
group with a final aromatization process took place. The
exact structures of 4-unsubstituted-1-aminopyrrole-2-
carboxylic acid derivatives 8a-c were established by
X-ray crystallography of compound 8b. Presumably, the
protonation of nitrogen atom of oxazoline ring facilitates
the formation of the azomethine imine intermediate and
the subsequent 1,2-carboxyl shift to give a more stable
intermediate. In the case of the reaction with 6b, the
1-aminopyrrole derivative 8b was isolated. The conver-
sion of compound 8b into the corresponding 4-unsubsti-
tuted-1-aminopyrrole-2-carboxylic acid derivative 10b
was achieved after a longer reaction time (an additional
10 h). The presence of different alkyl groups on the
carbamoyl moiety remarkably influenced this acidic
process. In fact, under the same reaction conditions, the
oxazoline-fused 1-aminopyrroline 6c, containing a tert-
butyl group instead of methyl or ethyl, was converted into
1-trifluoroacetylaminopyrrole derivative 11 (Scheme 5).
No hydrolysis of the ester group in position 4 was
observed, even after several additional hours.
5-Unsubstituted 1-aminopyrroles 7a,c-e and 13 were
also obtained from 1-aminopyrrolines 4a-d and 5a,b
under basic conditions (Scheme 6, Table 3).
Treatment of these substrates in methanol at room
temperature with an aqueous 1 M NaOH solution yielded
exclusively H4-H5-trans-5-(dimethylamino)-4-substituted-
1-aminopyrroline-3-carboxylic acid derivatives 12a-d.
The stereochemical results were supported by the results
of 1H NMR analysis. In compound 12b for H5, a coupling
constant of J4,5 ) 6.0 Hz was observed, which is typical
for two protons in the anti-position in the pyrroline ring,15
whereas for H4 only a broad singlet was detected,
probably due to the presence of the benzoylamino group.
In toluene under reflux, 1-aminopyrroline derivatives
12a-d provided 5-unsubstituted-1-aminopyrrole-3-car-
boxylic acid derivatives 7a,c-e as the main products.
These latter compounds arise from the loss of a dimethy-
lamine molecule, with consequent aromatization. Analo-
gous compound 13 was also obtained from 1-aminopyr-
rolines 4a,b and 5a,b by the same basic treatment under
reflux (Scheme 6).
a Reagents and conditions: (a) NaOH(aq) 0.2 M, MeOH, rt,16
h; (b) Montmorillonite KSF, toluene, reflux, 6 h; (c) Amberlyst 15
(H), MeOH, reflux, 15 h.
fused with a five-membered heterocycle reported in the
literature is a hydrogenated furan fused with oxazoline.13
The substituted oxazolines fused with pyrroline rings
are both interesting products and useful intermediates
for the preparation of various functionalized 1-aminopy-
rroles. It was observed that the reactivity of this hetero-
cyclic ring system14 is strongly dependent on the reaction
medium. Two possible pathways to pyrrole derivatives
from the relevant oxazolines that result in exclusive
opening of the oxazoline ring at the C(1)-O(1) bond were
detected. The behavior of these bicyclic oxazolines under
basic and acidic conditions is illustrated in Schemes 4
and 5. Oxazoline-fused 1-aminopyrrolines 6a-c were
converted into 5-unsubstituted-1-aminopyrrole-3-carbox-
ylic acid derivatives 7a-c in methanol in the presence
of an aqueous NaOH (0.2 M) solution at room tempera-
ture for 16 h. These products result from the base-
induced hydrolysis and decarboxylation of the ester group
on the oxazoline ring with consequent aromatization. In
the presence of Montmorillonite KSF in toluene under
reflux for 6 h, the same compounds 6a-c yielded 1-ami-
nopyrrole derivatives 8a-c. The treatment of the 1-ami-
nopyrrole derivative 8c with Amberlyst 15 (H) in metha-
nol under reflux for 15 h led to the corresponding
1-aminopyrrole 9 by the hydrolytic cleavage of the tert-
butoxycarbonyl group (Scheme 4).
Conclusion
Our detailed investigation of the reaction between 1,2-
diaza-1,3-butadienes and 3-dimethylaminopropenoates
demonstrated that a final [3 + 2] cycloaddition reaction
takes places by a stepwise pathway via zwitterionic
intermediates to produce 1-aminopyrrolines with a high
degree of cis-stereoselectivity. In toluene under reflux,
1-aminopyrrolines were easily converted into unexpected
oxazoline-fused 1-aminopyrrolines. Oxazoline-fused 1-ami-
nopyrrolines were directly obtained by reaction of 1,2-
diaza-1,3-butadienes with 3-dimethylaminopropenoates
in toluene under reflux. We also developed an efficient
protocol for the preparation of variously functionalized
The 4-unsubstituted-1-aminopyrrole-2-carboxylic acid
derivative 10a was obtained from oxazoline-fused 1-ami-
(13) (a) Meyer zu Reckendorf, W.; Feldkamp, J. Chem. Ber. 1968,
101, 2289. (b) Meyer zu Reckendorf, W.; Jochims, J. C. Chem. Ber.
1969, 102, 4199.
(14) For an excellent review see: Gant, T.; Meyers, A. J. Tetrahedron
1994, 50, 2297.
(15) (a) Woller, P. B.; Cromwell, N. H. J. Org. Chem. 1970, 35, 888.
(b) Padwa, A.; Ku, H. J. Org. Chem. 1979, 44, 255. (c) Quang, L. V.;
Quang, Y: V. Tetrahedron 1981, 37, 4343. (d) Vedejs, E.; Grissom, J.
W. J. Am. Chem. Soc. 1988, 110, 3238. (e) Musicki, B. J. Org. Chem.
1990, 55, 910. (f) Gaebert, C.; Mattay, J. Tetrahedron 1997, 53, 14297.
4310 J. Org. Chem., Vol. 70, No. 11, 2005

Useful Entry to New Pyrrolines, Pyrroles, and Oxazolines
SCHEME 5a
a Reagents and conditions: TFA, reflux.
SCHEME 6a
methyl 2-substituted-3-dimethylaminopropenoates 2a,b (6-
30 h, monitored by TLC). The reaction mixture was concen-
trated under reduced pressure. Products 4a-d and 5a,b were
isolated by chromatography on silica gel column with cyclo-
hexane-ethyl acetate (70:30 v/v).
Dimethyl (2R*,3S*)-3-benzoylamino-2-(dimethylamino)-
1-[(methoxycarbonyl)amino]-5-methyl-2,3-dihydro-1H-
pyrrole-3,4-dicarboxylate (4a): mp 95-98 °C; 1H NMR
(DMSO-d6) δ 2.15 (s, 3H), 2.30 (s, 6H), 3.52 (s, 3H), 3.57 (s,
3H), 3.67 (s, 3H), 5.22 (brs, 1H), 7.40-7.55 (m, 3H), 7.80-
7.85 (m, 2H), 8.46 (brs, 1H), 9.64 (brs, 1H); 13C NMR (DMSO-
d6) δ 11.9, 40.0, 50.1, 52.0, 52.1, 65.4, 86.2, 90.5, 127.0, 128.2,
131.1, 133.8, 155.5, 160.6, 164.8, 169.5, 170.3; IR 3277, 1739,
1673 cm-1; EIMS m/z 389 (M+ - 45, 10), 360 (8), 343 (12), 330
(10), 313 (100). Anal. Calcd for C20H26N4O7: C, 55.29; H, 6.03;
N, 12.90. Found: 55.41; H, 6.22; N, 13.04.
Dimethyl (2R*,3R*)-3-benzoylamino-2-(dimethylamino)-
1-[(methoxycarbonyl)amino]-5-methyl-2,3-dihydro-1H-
pyrrole-3,4-dicarboxylate (5a): mp 55-59 °C; 1H NMR
(DMSO-d6) δ 2.13 (s, 3H), 2.38 (s, 3H), 2.47 (s, 3H), 3.49 (s,
3H), 3.59 (s, 6H), 5.24 (brs, 1H), 7.40-7.55 (m, 3H), 7.70-
7.80 (m, 2H), 7.77 (brs, 1H), 9.56 (brs, 1H); 13C NMR (DMSO-
d6) δ 11.8, 40.9, 50.3, 52.1, 52.3, 69.4, 87.3, 98.2, 127.0, 128.1,
131.1, 134.9, 155.6, 161.6, 164.3, 164.9, 169.8; IR 3419, 3231,
1749, 1695 cm-1; EIMS m/z 389 (M+ - 45, 35), 360 (15), 347
(3), 320 (22), 313 (100). Anal. Calcd for C20H26N4O7: C, 55.29;
H, 6.03; N, 12.90. Found: 55.11; H, 6.15; N, 13.02.
General Procedure for the Synthesis of Oxazolines
6a-h from 1a-h and 2a. 1,2-Diaza-1,3-butadienes 1a-h (1
mmol) and methyl 2-benzoylamino-3-dimethylaminoprope-
noate 2a (1 mmol) were dissolved in 30 mL of toluene and
refluxed until the disappearance of the reagents (20-30 h,
monitored by TLC). The reaction mixture was concentrated
under reduced pressure. Products 6a-h were isolated by
chromatography on silica gel column with cyclohexane-ethyl
acetate (70:30 v/v) and then purified by crystallization from
diethyl ether.
a Reagents and conditions: (a) NaOH(aq) 1 M, MeOH, rt; (b)
toluene, reflux; (c) NaOH(aq) 1 M, MeOH, reflux.
1-aminopyrroles either through the regioselective ring
opening of these bicyclic oxazolines or through treatment
of 1-aminopyrrolines under basic conditions. Thus, the
present work offers a simple and convenient entry to new
classes of 1-aminopyrrolines, 1-aminopyrroles, and ox-
azolines fused with pyrroline rings from easily accessible
starting materials. These compounds are of great interest
as both products and intermediates in organic, biological,
pharmaceutical, analytical, and agricultural chemistry.16
Experimental Section
General Procedure for the Synthesis of 1-Aminopyr-
rolines 4a-d and 5a,b from 1a,c,i,j and 2a,b. 1,2-Diaza-
1,3-butadienes 1a,c,i,j (1.5 mmol) and methyl 2-substituted-
3-dimethylaminopropenoates 2a,b (1 mmol) were dissolved in
toluene (30 mL) or THF (30 mL) and were stirred under the
conditions shown in Table 1 until the disappearance of the
Dimethyl 4-[(methoxycarbonyl)amino]-5-methyl-2-
phenyl-4,6a-dihydro-3aH-pyrrolo[3,2-d][1,3]oxazole-6,6a-
1
dicarboxylate (6a): mp 106-110 °C; H NMR (DMSO-d6) δ
2.07 (s, 3H), 3.60 (s, 3H), 3.66 (s, 6H), 6.17 (s, 1H), 7.45-7.91
(m, 5H), 9.94 (brs, 1H); 13C NMR (DMSO-d6) δ 11.3, 50.6, 52.5,
83.8, 98.2, 100.7, 126.0, 128.1, 128.5, 132.1, 156.0, 161.5, 163.3,
163.8, 169.4; IR 3287, 2765, 1704, 1658 cm-1; EIMS m/z 389
(M+, 76), 360 (32), 330 (88), 254 (32), 222 (35), 167 (100).
(16) (a) Sundberg, R. J. In Comprehensive Heterocyclic Chemistry;
Katritzky, A. R., Rees, C. W., Eds.; Pergamon Press: Oxford, 1984;
Vol. 4, p 314. (b) Gribble, G. W. In Comprehensive Heterocyclic
Chemistry II; Katritzky, A. R., Rees, C. W., Scriven E. F. V., Eds.;
Pergamon-Elsevier Science: Amsterdam, 1996; Vol. 2, Chapter 4.
J. Org. Chem, Vol. 70, No. 11, 2005 4311

Attanasi et al.
TABLE 3. Reaction Times and Yields of 1-Aminopyrrolines 12a-d and 1-Aminopyrroles 7a,c-e and 13
4 (5)
R1
R2
R3
12
yielda (%)
time (h)
7
yielda (%)
time (h)
13
yielda (%)
time (h)
4a
5a
4b
5b
4c
4d
CO2Me
CO2Me
CO2t-Bu
CO2t-Bu
CONH2
CONH2
Me
Me
Me
Me
Me
Et
Ph
12a
12a
12b
12b
12c
12d
61
65
53
69
58
52
12
12
12
12
12
18
7a
7a
7c
7c
7d
7e
93
93
95
95
83
79
2
13
13
13
13
63
59
47
56
9
10
6
Ph
2.5
4
Ph
Ph
OBn
OBn
4
7
4
4
a Yield of pure isolated products.
Anal.Calcd for C18H19N3O7: C, 55.53; H, 4.92; N, 10.79.
Found: C, 55.69; H, 5.04; N, 10.94.
General Procedure for the Synthesis of 1-Aminopyr-
roles 8b, 10a,b, and 11 from 6a-c. The appropriate oxazo-
lines 6a-c (1 mmol) in TFA (3 mL) was refluxed until the
disappearance of the reagents (1.5-10 h). The reaction mixture
was neutralized with saturated aqueous NaHCO3 solution and
concentrated under reduced pressure. Products 8b, 10a,b, and
11 were isolated by chromatography on silica gel column with
cyclohexane-ethyl acetate (50:50 v/v).
Methyl 3-benzoylamino-1-[(methoxycarbonyl)amino]-
5-methyl-1H-pyrrole-2-carboxylate (10a): mp 170-174 °C;
1H NMR (CDCl3) δ 2.21 (s, 3H), 3.74 (s, 3H), 3.79 (s, 3H), 6.89
(s, 1H), 7.45-7.55 (m, 3H), 7.62 (brs, 1H), 7.89-7.94 (m, 2H),
10.22 (brs, 1H); 13C NMR (CDCl3) δ 11.5, 51.2, 53.5, 99.7, 106.7,
127.0, 128.7, 131.8, 133.3, 133.8, 138.4, 156.5, 161.1, 164.7;
IR 3333, 3226, 1754, 1663 cm-1; EIMS m/z 331 (M+, 100). Anal.
Calcd for C16H17N3O5: C, 58.00; H, 5.17; N, 12.68. Found:
58.13; H, 5.28; N, 12.53.
General Procedure for the Synthesis of 1-Aminopyr-
roles 7a-c from 6a-c. To appropriate oxazolines 6a-c (1
mmol) in MeOH (5 mL) was added aqueous 0.2 M NaOH (10
mL). The reaction mixture was magnetically stirred at room
temperature for 16 h. The crude mixture was neutralized with
aqueous 1 M HCl solution and concentrated under reduced
pressure. Products 7a-c were isolated by chromatography on
silica gel column with cyclohexane-ethyl acetate (50:50 v/v).
General Procedure for the Synthesis of 1-Aminopyr-
roles 7a,c-e from 12a-d. 1-Aminopyrrolines 12a-d (1
mmol) in toluene (15 mL) were allowed under reflux until the
disappearance of the starting material (2-4 h, monitored by
TLC). The reaction mixture was concentrated under reduced
pressure. Products 7a,c-e were isolated by chromatography
on silica gel column with cyclohexane-ethyl acetate (50:50 v/v).
Methyl 4-benzoylamino-1-[(methoxycarbonyl)amino]-
2-methyl-1H-pyrrole-3-carboxylate (7a): mp 162-167 °C;
1H NMR (CDCl3) δ 2.36 (s, 3H), 3.74 (s, 3H), 3.87 (s, 3H), 7.45-
7.55 (m, 4H), 7.91-7.95 (m, 2H), 8.68 (brs, 1H), 10.53 (s, 1H);
13C NMR (CDCl3) δ 10.8, 51.3, 53.4, 100.5, 111.6, 122.8, 126.9,
128.6, 131.6, 133.7, 135.0, 155.6, 164.2, 167.0; IR 3358, 3149,
1751, 1677 cm-1; EIMS m/z 331 (M+, 100). Anal. Calcd for
C16H17N3O5: C, 58.04; H, 5.17; N, 12.68. Found: 57.91; H, 5.09;
N, 12.63.
Dimethyl 3-benzoylamino-5-methyl-1-[(2,2,2-trifluoro-
acetyl)amino]-1H-pyrrole-2,4-dicarboxylate (11): mp 193-
1
196 °C; H NMR (CDCl3) δ 2.36 (s, 3H), 3.36 (s, 3H), 3.77 (s,
3H), 7.50-7.67 (m, 3H), 7.90-8.05 (m, 2H), 9.62 (brs, 1H),
11.18 (s, 1H); 13C NMR (CDCl3) δ 10.0, 51.6, 51.7, 107.4, 110.5,
115.4 (1JCF ) 285.6 Hz), 127.5, 128.3, 128.9, 132.5, 132.9, 140.2,
156.8 (2JCF ) 38.6 Hz), 159.7, 164.5, 165.9; IR 3361, 3195, 3140,
1761, 1727, 1655 cm-1; EIMS m/z 427 (M+, 27), 105 (100). Anal.
gCalcd for C18H16N3O6F3: C, 50.59; H, 3.77; N, 9.83. Found:
50.47; H, 3.88; N, 9.72.
General Procedure for the Synthesis of 1-Aminopyr-
roles 8a-c from 6a-c. To oxazolines 6a-c (1 mmol) in
toluene (30 mL) was added Montmorillonite KSF (0.53 g), and
the mixture was refluxed until the reaction was complete (6
h, monitored by TLC). The reaction mixture was filtered and
the solution was concentrated under reduced pressure. Prod-
ucts 8a-c were isolated by chromatography on silica gel
column with cyclohexane-ethyl acetate (50:50 v/v).
General Procedure for the Synthesis of 1-Aminopyr-
rolines 12a-d from 4a-d or 5a,b. To 1-aminopyrrolines
4a-d or 5a,b (1 mmol) in MeOH (5 mL) was added aqueous
1 M NaOH (10 mL). The reaction mixture was stirred at room
temperature (12-18 h), neutralized with aqueous 1 M HCl,
and concentrated under reduced pressure. Products 12a-d
were isolated by chromatography on silica gel column with
ethyl acetate-methanol (95:5 v/v).
Methyl (4R*,5R*)-4-benzoylamino-5-(dimethylamino)-
1-[(methoxycarbonyl)amino]-2-methyl-4,5-dihydro-1H-
pyrrole-3-carboxylate (12a): mp 61-65 °C; 1H NMR (CDCl3)
δ 2.26 (s, 3H), 2.38 (s, 6H), 3.63 (s, 3H), 3.70 (s, 3H), 4.25 (brs,
1H), 5.35 (brs, 1H), 6.57 (brs, 1H), 7.38-7.50 (m, 3H), 7.76-
7.80 (m 2H), 8.77 (brs, 1H); 13C NMR (CDCl3) δ 12.1, 38.5,
48.2, 50.8, 53.0, 90.3, 98.8, 126.9, 128.3, 131.4, 134.1, 156.7,
162.6, 165.5, 166.6; IR 3547, 3267, 1745, 1660 cm-1; EIMS m/z
376 (M+, 1), 331 (80), 302 (78), 270 (61), 255 (100). Anal. Calcd
for C18H24N4O5: C, 57.44; H, 6.43; N, 14.88. Found: 57.53; H,
6.29; N, 14.70.
General Procedure for the Synthesis of 1-Aminopyr-
roles 13 from 4a,b or 5a,b. To 1-aminopyrrolines 4a,b or
5a,b (1 mmol) in MeOH (5 mL) was added aqueous 1 M NaOH
(10 mL), and the mixture was allowed to stir under reflux (2-4
h). The reaction mixture was neutralized with aqueous 1 M
HCl and concentrated under reduced pressure. Product 13 was
isolated by chromatography on silica gel column with cyclo-
hexane-ethyl acetate (50:50 v/v).
1-Amino-4-benzoylamino-2-methyl-1H-pyrrole-3-car-
boxylic acid (13): mp 195-198 °C; 1H NMR (DMSO-d6) δ 2.40
(s, 3H), 5.88 (brs, 2H), 7.32 (s, 1H), 7.50-7.60 (m, 3H), 7.78-
7.90 (m, 2H), 10.59 (s, 1H), 12.39 (brs, 1H); 13C NMR (DMSO-
d6) δ 10.6, 98.3, 111.6, 121.6, 126.3, 128.7, 131.4, 132.7, 133.7,
161.9, 167.7; IR 3422, 3314, 3233, 1659 cm-1; EIMS m/z 259
Dimethyl 3-benzoylamino-1-[(methoxycarbonyl)amino]-
5-methyl-1H-pyrrole-2,4-dicarboxylate (8a): mp 169-172
1
°C; H NMR (CDCl3) δ 2.42 (s, 3H), 3.64 (s, 3H), 3.80 (s, 6H),
7.45-7.58 (m, 3H), 7.92-7.96 (m, 2H), 8.36 (brs, 1H), 9.48 (s,
1H); 13C NMR (CDCl3) δ 10.8, 51.4, 51.6, 53.6, 105.0, 112.3,
127.3, 127.5, 128.6, 132.0, 133.7, 140.8, 156.1, 160.7, 165.0,
165.2; IR 3374, 3175, 1754, 1724, 1670 cm-1; EIMS m/z 389
(M+, 100). Anal. Calcd for C18H19N3O7: C, 55.53; H, 4.92; N,
10.79. Found: 55.38; H, 4.81; N, 10.61.
General Procedure for the Synthesis of 1-Aminopyr-
role 9 from 8c. To 1-aminopyrrole 8c (1 mmol) in MeOH (30
mL) was added Amberlyst 15(H) (1.55 g), and the mixture was
allowed under reflux (15 h). The reaction mixture was filtered
off and the solution was concentrated under reduced pressure.
Product 9 was isolated by chromatography on silica gel column
with cyclohexane-ethyl acetate (50:50 v/v).
Dimethyl 1-amino-3-benzoylamino-5-methyl-1H-pyr-
role-2,4-dicarboxylate (9): mp 151-154 °C; 1H NMR (CDCl3)
δ 2.54 (s, 3H), 3.80 (s, 6H), 5.28 (brs, 2H), 7.42-7.56 (m, 3H),
7.91-7.96 (m, 2H), 9.35 (s, 1H); 13C NMR (CDCl3) δ 11.2, 51.3,
51.5, 103.1, 113.5, 127.0, 127.3, 128.6, 131.7, 134.3, 139.6,
162.0, 165.0, 165.4; IR 3343, 3262, 1709, 1668 cm-1; EIMS m/z
331 (M+, 57), 229 (19), 267 (46), 226 (26), 210 (72), 194 (33),
105 (100). Anal. Calcd for C16H17N3O5: C, 58.00; H, 5.17; N,
12.68. Found: 57.87; H, 5.03; N, 12.81.
4312 J. Org. Chem., Vol. 70, No. 11, 2005

Useful Entry to New Pyrrolines, Pyrroles, and Oxazolines
(M+, 100). Anal. Calcd for C13H13N3O3: C, 60.22; H, 5.05; N,
16.21. Found: 60.08; H, 4.89; N, 16.12.
Supporting Information Available: General experimen-
tal information, product characterization data, and 1H and 13
C
NMR peak listings for 4b-d, 5b, 6b-h, 7b-e, 8b,c, 10b, and
12b-d. X-ray crystallographic data (CIF) and ORTEP draw-
ings of compounds 4b, 6a, and 8b. The authors have deposited
atomic coordinates for these structures with the Cambridge
Crystallographic Data Centre. This material is available free
of charge via the Internet at http://pubs.acs.org.
Acknowledgment. This work was supported by
financial assistance from the Ministero dell’Universita`
e della Ricerca Scientifica e Tecnologica, MURST, Rome,
the Universita` degli Studi di Urbino, and Ministry of
Education, Science and Sport, Slovenia (Grant No. PS-
502-0103).
JO0480343
J. Org. Chem, Vol. 70, No. 11, 2005 4313