Straightforward entry into 5-hydroxy-1-aminopyrrolines and the corresponding pyrroles from 1,2-diaza-1,3-butadienes

Article abstract of DOI:10.1021/jo025656k

The synthesis of 5-hydroxy-1-aminopyrroline-3-carboxylic acid derivatives and 5-unsubstituted-1-aminopyrrole-3-carboxylic acid derivatives from 1,2-diaza-1,3-butadienes and aldehydes is presented. These domino reactions offer the advantage of executing multistep transformation without intermediate workup procedures. The stereoselectivity of ring closure to 5-hydroxy-1-aminopyrroline-3-carboxylic acid derivatives and phenyl transposition to 2,3-diphenyl-1-aminopyrrole-3-carboxylic acid derivatives are also studied.

Full text of DOI:10.1021/jo025656k

Str a igh tfor w a r d En tr y in to 5-Hyd r oxy-1-a m in op yr r olin es a n d th e
Cor r esp on d in g P yr r oles fr om 1,2-Dia za -1,3-bu ta d ien es
Orazio A. Attanasi, Lucia De Crescentini, Gianfranco Favi, Paolino Filippone,*
Fabio Mantellini, and Stefania Santeusanio*
Istituto di Chimica Organica, Universit a` di Urbino, Piazza della Repubblica 13, 61029 Urbino, Italy
filippone@uniurb.it
Received February 26, 2002
The synthesis of 5-hydroxy-1-aminopyrroline-3-carboxylic acid derivatives and 5-unsubstituted-1-
aminopyrrole-3-carboxylic acid derivatives from 1,2-diaza-1,3-butadienes and aldehydes is presented.
These domino reactions offer the advantage of executing multistep transformation without
intermediate workup procedures. The stereoselectivity of ring closure to 5-hydroxy-1-aminopyrroline-
3
-carboxylic acid derivatives and phenyl transposition to 2,3-diphenyl-1-aminopyrrole-3-carboxylic
acid derivatives are also studied.
7
1
,2-Diaza-1,3-butadienes have attracted increasing at-
from the relevant acetal derivatives. The reaction showed
tention because of their potential use in organic synthe-
complete stereoselectivity and allowed us to obtain only
H ,H -trans-5-hydroxy-1-aminopyrroline-3-carboxylic acid
4 5
sis.1 In previous papers, we reported the synthesis of
-5
2
-hydroxy-1-aminopyrrolines and 2-substituted-1-ami-
derivatives. By using diphenylacetaldehyde, a transposi-
tion of phenyl group to obtain 2,3-diphenyl-1-aminopyr-
role-3-carboxylic acid derivatives was also observed.
Moreover, the reaction successfully occurred also with
â-ester or â-keto aldehydes generated in situ from the
nopyrroles by reaction of 1,2-diaza-1,3-butadienes with
â-coactivated methylene or methyne carbonyl com-
pounds.3
Here, we report the first synthesis of 5-hydroxy-1-
aminopyrroline-3-carboxylic acid derivatives and 5-un-
substituted-1-aminopyrrole-3-carboxylic acid derivatives
by reaction of the same starting materials with methyl-
ene or methyne compounds bearing in the R-position only
one aldehyde carbonyl group as such or generated in situ
,6
7
relevant acetal derivatives. It is noteworthy that these
reactions were catalyzed by basic resins, making the
workup procedures of the reaction mixtures very simple
and environmentally friendly.
The synthesis of 5-hydroxy-1-aminopyrroline-3-car-
boxylic acid derivatives 5a -i starting from 1,2-diaza-1,3-
butadienes 1a -f and phenylacetaldehyde (2a ) or diphen-
ylacetaldehyde (2b) by catalysis of sodium methoxide is
illustrated in Scheme 1. The reaction took place by a
nucleophilic attack of the carbon atom in the R-position
of the aldehyde at the terminal carbon of heterodiene
system to give an adduct intermediate, not isolable, that
promptly afforded 5-hydroxy-1-aminopyrroline-3-carbox-
ylic acid derivatives by an intramolecular cyclization. The
five-membered ring closure is substantiated by several
*
To whom correspondence should be addressed. Fax: +39-0722-
2
907.
(
(
1) Attanasi, O. A.; Caglioti, L. Org. Prep. Proced. Int. 1986, 18, 299.
2) Schantl, J . G. 1-Azo-1-alchene. In Houben-Weyl, 4th ed.; Kropf,
H., Schaumann, E., Eds.; Thieme: Stuttgart, 1990; Vol. E15. Schantl,
J . G. Farmaco 1995, 50, 379 and references therein.
(
3) Attanasi, O. A.; Filippone, P. In Topics in Heterocyclic Systems,
Synthesis, Reactions and Properties; Attanasi, O. A., Spinelli, D., Eds.;
996; Vol. 1, p 157. Attanasi, O. A.; Filippone, P. Synlett 1997, 1128.
4) Attanasi, O. A.; Filippone, P.; Fiorucci, C.; Foresti, E.; Mantellini,
1
(
F. J . Org. Chem. 1998, 63, 9880. Attanasi, O. A.; De Crescentini, L.;
Filippone, P.; Perrulli, F. R.; Santeusanio, S. Synlett 1999, 339.
Attanasi, O. A.; De Crescentini, L.; Filippone, P.; Guidi, B.; Perrulli,
F. R.; Santeusanio, S. Synlett 1999, 1367. Attanasi, O. A.; Filippone,
P.; Guidi, B.; Hippe, T.; Mantellini, F.; Tietze, L. F. Tetrahedron Lett.
3
papers presented by our research group. This cyclization,
arising from the attack of hydrazone nitrogen at the
carbonyl function, showed complete stereoselectivity, and
1
999, 40, 9277. Attanasi, O. A.; De Crescentini, L.; Filippone, P.;
Foresti, E.; Mantellini, F. J . Org. Chem. 2000, 65, 2820. Arcadi, A.;
Attanasi, O. A.; Guidi, B.; Rossi, E.; Santeusanio, S. Synlett 2000, 1464.
Attanasi, O. A.; Filippone, P.; Guidi, B.; Perrulli, F. R.; Santeusanio,
S. Synlett 2001, 144. Attanasi, O. A.; De Crescentini, L.; Filippone,
P.; Fringuelli, F.; Mantellini, F.; Matteucci, M.; Piermatti, O.; Pizzo,
F. Helv. Chim. Acta 2001, 84, 513. Attanasi, O. A.; De Crescentini, L.;
Filippone, P.; Mantellini, F. Synlett 2001, 557. Attanasi, O. A.; De
Crescentini, L.; Filippone, P.; Mantellini, F. N. J . Chem. 2001, 25, 534.
Attanasi, O. A.; De Crescentini, L.; Filippone, P.; Mantellini, F.;
Santeusanio, S. Helv. Chim. Acta 2001, 84, 2379.
4 5
only H ,H -trans-5-hydroxy-1-aminopyrroline-3-carbox-
ylic acid derivatives were detected. The stereochemistry
was supported by NMR studies: in fact, in compounds
5a -c for H
4
, coupling constants J 4,5 ) 7.6 Hz were
observed, typical for two protons in the anti position in
8
5
pyrroline ring, while for H only a broad singlet was
detected probably due to the presence of hydroxy group.
By treatment with a catalytic amount of copper(II)
chloride dihydrate or Amberlyst 15 (H) or trifluoroacetic
(5) Ferguson, G.; Lough, A. J .; Mackay, D.; Weeratunga, G. J . Chem.
Soc., Perkin Trans 1 1991, 3361. Baxter, A. J . G.; Fuher, J .; Teague,
S. J . Synthesis 1994, 207. South, M. S.; J akuboski, T. L.; Westmeyer,
M. D.; Dukesherer, D. R. J . Org. Chem. 1996, 61, 8921.
(7) Coppola, G. M. Synthesis 1984, 1021.
(
6) Attanasi, O. A.; De Crescentini, L.; Filippone, P.; Mantellini, F.
(8) Woller, P. B.; Cromwell, N. H. J . Org. Chem. 1970, 35, 888.
Padwa, A.; Ku, H. J . Org. Chem. 1979, 44, 255. Quang, L. V.; Quang,
Y. V. Tetrahedron 1981, 37, 4343. Vedejs, E.; Grissom, J . W. J . Am.
Chem. Soc. 1988, 110, 3238. Musicki, B. J . Org. Chem. 1990, 55, 910.
Gaebert, C.; Mattay, J . Tetrahedron 1997, 53, 14297.
Synlett 2000, 955. Attanasi, O. A.; Filippone, P.; Guidi, B.; Mantellini,
F.; Santeusanio, S. Synthesis 2001, 1837. Attanasi, O. A.; De Cres-
centini, L.; Filippone, P.; Mantellini, F.; Tietze, L. F. Tetrahedron 2001,
5
7, 5855.
1
0.1021/jo025656k CCC: $22.00 © 2002 American Chemical Society
Published on Web 10/23/2002
8
178
J . Org. Chem. 2002, 67, 8178-8181

Straightforward Entry into 5-Hydroxy-1-aminopyrrolines
SCHEME 1a
TABLE 1. Yield s of 5-Hyd r oxy-1-a m in op yr r olin e-3-
ca r boxylic Acid Der iva tives 5a -i, 5-Un su bstitu ted -1-
a m in op yr r ole-3-ca r boxylic Acid Der iva tives 6a -d , a n d
2
7
,3-Dip h en yla m in op yr r ole-3-ca r boxylic Acid Der iva tives
a -ea
entries
5
yield (%)
6
yield (%)
7
yield (%)
1
1
a + 2a
b + 2a
c + 2a
f + 2a
a + 2b
b + 2b
d + 2b
e + 2b
f + 2b
5a
5b
5c
5d
5e
5f
5g
5h
5i
44
39
42
57
46
67
42
61
74
6a
6b
6c
6d
89
85
91
79
1
1
1
1
1
1
1
7a
7b
7c
7d
7e
87
76
83
92
87
a
Yield of pure isolated products.
SCHEME 2 a
a
Reagents and conditions: (a) CH3ONa (cat.)/THF/rt, 0.5 h; (b)
Amberlyst 15 (H)/THF/rt, 0.5 h or CuCl2‚2H2O/THF/rt, 0.5 h or
TFA/rt, 0.5 h; (c) Cu(OTf)2/THF/rt/1 h.
4 5
acid, H ,H -trans-5-hydroxy-1-aminopyrrolines-3-carbox-
a
Reagents and conditions: (a) CuCl2‚2H2O (cat.)/THF/rt, 1 h.
ylic acid derivatives 5a -d easily afforded 5-unsubsti-
tuted-1-aminopyrrole-3-carboxylic acid derivatives 6a -d
through a water molecule elimination. This last process,
in some cases, took place in the NMR tube, and it was
tive 7e with the same 1-aminopyrrole derivative obtained
by reaction of azoalkene 1g with methyl acetoacetate (8)
in tetraydrofuran in the presence of a catalytic amount
of copper(II) chloride dihydrate10 (Scheme 2).
When 1,2-diaza-1,3-butadiene 1c was reacted with
diphenylacetaldehyde (2b) in the presence of a catalytic
amount of sodium methoxide, only product 4 was recov-
ered. This compound derives from nucleophilic attack by
oxygen of the enolic form of diphenylacetaldehyde to the
azoene system of 1,2-diaza-1,3-butadienes. The same
addition products were observed in very small yields in
all reactions of 1,2-diaza-1,3-butadienes 1a,b with diphen-
ylacetaldehyde (2b) (Scheme 1).
not possible to determine melting points of H
5
5
4
,H
-hydroxy-1-aminopyrroline-3-carboxylic acid derivatives
a -d ,j-k . In fact, the heating of these compounds 6a -f
5
-trans-
gave a partial transformation to 6a -f. When 5-hydroxy-
-aminopyrroline-3-carboxylic acid derivatives 5e-i were
1
treated with copper(II) trifluoromethanesulfonate, the
formation of 2,3-diphenylaminopyrrole-3-carboxylic acid
derivatives 7a -e was observed. These last compounds
arise from phenyl transposition and loss of a water
molecule (Scheme 1, Table 1). Presumably, the interation
of Lewis acid with the alcohol moiety facilitates the
formation of the carbocation and the subsequent 1,2-
phenyl shift to give a more stable intermediate.9
The structures of 2,3-diphenylaminopyrrole-3-carbox-
ylic acid derivatives 7a -e were supported by spectro-
scopic evidence and unequivocally confirmed by compari-
son of 2,3-diphenylaminopyrrole-3-carboxylic acid deriva-
Then, we decided to extend the investigation concern-
ing conjugate addition to 1,2-diaza-1,3-butadienes using
(
9) Manfred, R.; Elmut, E. Chem. Ber. 1980, 113, 3303. Men’shova,
N. I.; Dolginova, E. M.; Grinenko, G. S. Khim.-Farm. Zh. 1980, 14,
1. Laali, K.; Gerzina, R. J .; Geric, C. M.; Dombroski, A. M. Helv. Chim.
Acta 1987, 70, 607.
10) Attanasi, O. A.; Bonifazi, P.; Buiani, F. J . Heterocycl. Chem.
1983, 20, 1077.
6
(
J . Org. Chem, Vol. 67, No. 23, 2002 8179

Attanasi et al.
SCHEME 3 a
TABLE 2. Yield s of 5-Hyd r oxy-1-a m in op yr r olin e-3-
ca r boxylic Acid Der iva tives 5c-k a n d 5-Un su bstitu ted -
-a m in op yr r ole-3-ca r boxylic Acid Der iva tives 6a -h
1
entries
5
yield (%)
6
yield (%)
a
1
1
1
a + 9a
b + 9a
c + 9a
6a
6b
6c
39
49
5
91
7
79
8
85
6
87
89
37
a
5c
5d
5j
67a
37a
45a
35a
a
b
6
c
a
1
1
1
f + 9a
a + 9b
b + 9b
6d
b
6
d
a
6e
b
6
e
a
5k
6f
b
6
f
a
1
1
a + 9c
b + 9c
6g
6h
a
a
Yield of pure isolated products starting from 1+9. b Yield of
pure isolated products starting from 5.
access to new classes of 5-hydroxy-1-aminopyrroline-3-
carboxylic acid derivatives and 5-unsubstituted-1-ami-
nopyrrole-3-carboxylic acid derivatives from easily ac-
cessible starting materials, which are of great interest
both as products and intermediates in organic, biological,
1
1
pharmaceutical, analytical and agricultural chemistry.
The stereoselectivity of ring closure to 5-hydroxy-1-
aminopyrroline-3-carboxylic acid derivatives and phenyl
transposition to 2,3-diphenyl-1-aminopyrrole-3-carboxylic
acid derivatives is also described.
Exp er im en ta l Section
Gen er a l Meth od s. Phenylacetaldehyde, diphenylacetal-
dehyde, acetylacetaldehyde dimethyl acetal, methyl 3,3-
dimethoxypropionate, phenylacetaldehyde dimethyl acetal,
methyl acetoacetate, sodium methoxide (CH
acetic acid (TFA), Amberlyst 15 (H), Dowex 50W, Duolite A
02, copper(II) chloride dihydrate (CuCl ‚2H O), and copper-
II) trifluoromethanesulfonate (Cu(OTf) ) were commercial
3
ONa), trifluoro-
1
2
2
(
2
materials and were used without further purification. Solvents
were purchased and were used without further purification
with the exception of THF, which was distilled from sodium
hydroxide. 1,2-Diaza-1,3-butadienes 1a -g were synthesized
as standard E/ Z isomeric mixtures according to previously
a
Reagents and conditions: (a) Dowex 50W/H2O/rt, 24 h or
Amberlyst 15 (H)/CH3COCH3-H2O/rt, 12 h; (b) Duolite A 102/rt,
1
0
0 h; (c) Amberlyst 15 (H)/THF/rt, 0.5 h or CuCl2‚2H2O/THF/rt,
12,13
reported procedures.
Melting points were determined in
.5 h or TFA/rt, 0.5 h.
open capillary tubes and are uncorrected. IR-FT spectra were
obtained as Nujol mulls. Mass spectra were made at an
acetal derivatives as precursor of aldehydes not com-
mercially available. Among the methods reported in the
literature for the generation in situ of aldehydes from
the relevant acetal we used Amberlyst 15 (H) in acetone-
1
13
ionizing voltage of 70 eV. All H NMR and C NMR spectra
were recorded at 400 and 100.56 MHz, respectively. Chemical
shifts (δ
All coupling constants (J ) are given in Hz. Chemical shifts (δ
are reported relative to DMSO-d as internal standard in a
broad band decoupled mode; all the NH and OH exchanged
with D O. Precoated silica gel plates 0.25 mm were employed
for analytical thin-layer chromatography and silica gel 35-
0 µm for column chromatography. All new compounds showed
H
) are reported relative to TMS as internal standard.
C
)
7
6
water mixture in the case of 9a ,b or Dowex 50W in water
in the case of 9c. Phenylacetaldehyde, acetylacetalde-
hyde, and methyl-3-oxopropanoate generated in situ from
the relevant acetal derivatives 9a -c, after filtration of
used resins and addition of Duolite A 102, were reacted
with 1,2-diaza-1,3-butadienes 1a -c,f. Under these reac-
tion conditions, the direct formation of 5-unsubstituted-
2
7
satisfactory elemental analysis (C (0.35; H (0.30, N (0.30).
Gen er a l P r oced u r e for th e Syn th esis of 5-Hyd r oxy-1-
a m in op yr r olin e-3-ca r boxylic Acid Der iva tives 5a-i a n d
1
-aminopyrrole-3-carboxylic acid derivatives 6a -h was
observed. In the case of the reaction between 1a -c,f and
a ,b, it was possible to isolate H ,H -trans-5-hydroxy-1-
(
11) Gribble, G. W. Pyrroles and Benzo Derivatives: Applications.
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. Cirrincione, G.; Almerico, A. M.; Aiello, E.;
Dattolo, G. Pyrroles Part Two: The Synthesis, Reactivity, and Physical
Properties of Substituted Pyrroles. In The Chemistry of Heterocyclic
Compounds; J ones, R. A., Ed.; J ohn Wiley & Sons: New York, 1992;
Chapter 3, Aminopyrroles, p 299..
9
4
5
aminopyrroline-3-carboxylic acid derivatives 5c-d ,j-k .
Treatment of these substrates in tetrahydrofuran with
Amberlyst 15 (H) or copper(II) chloride dihydrate6 or
trifluoroacetic acid furnished the corresponding 5-unsub-
stituted-1-aminopyrrole-3-carboxylic acid derivatives 6c-f
(
12) Sommer, S. Tetrahedron Lett. 1977, 18, 117.
(13) Attanasi, O. A.; Filippone, P.; Mei, A.; Santeusanio, S. Synthesis
(Scheme 3, Table 2).
1
984, 873. Attanasi, O. A.; Filippone, P.; Mei, A.; Santeusanio, S.
In conclusion, this work offers a simple and convenient
Synthesis 1984, 671.
8
180 J . Org. Chem., Vol. 67, No. 23, 2002

Straightforward Entry into 5-Hydroxy-1-aminopyrrolines
2
-{3-(Dim e t h yla m in o)-1-m e t h yl-3-oxo-2-[(2,2-d ip h e n -
Meth yl 1-[(a m in oca r bon yl)a m in o]-2-m eth yl-4-p h en yl-
1
ylvin yl)oxy)]}-h ydr azin e-1-car boxam ide (4) Star tin g fr om
1
1
1H-p yr r ole-3-ca r boxyla te (6a ): mp 192-195 °C; H NMR
a -f a n d 2a ,b. To a magnetically stirred solution of 1,2-diaza-
,3-butadienes 1a -f (1 mmol) and CH ONa (0.2 mmol) in THF
(DMSO-d ) δ 2.28 (s, 3 H), 3.57 (s, 3 H), 6.28 (s, 2 H), 6.75 (s,
6
13
3
1 H), 7.16-7.32 (m, 5 H), 9.37 (s, 1 H); C NMR (DMSO-d
10.5, 50.3, 107.6, 121.5, 122.8, 125.9, 127.5, 128.6, 135.1, 137.4,
157.2, 165.0; IR 3421, 3304, 3201, 1710, 1675 cm ; MS m/z
273 (M , 100). Anal. Calcd for C14
6
) δ
(20 mL) were added aldehydes 2a ,b (1 mmol). The reaction
-
1
was allowed to stand at room temperature until the complete
disappearance of 1a -f (0.5 h, monitored by TLC). The reaction
mixture was concentrated directly under reduced pressure.
Products 4 (38%) and 5a -i (see Table 1) were isolated by
chromatography on silica gel column with cyclohexane-ethyl
acetate (10:90 v/v) and then purified by crystallization from
diethyl ether and petroleum ether (bp 40-60 °C).
Gen er a l P r oced u r e for th e Syn th esis of 5-Hyd r oxy-1-
a m in op yr r olin e-3-ca r boxylic Acid Der iva tives 5c-d ,j-k
a n d 5-Un su bstitu ted -1-a m in op yr r ole-3-ca r boxylic Acid
Der iva tives 6a -h Sta r tin g fr om 1a -c,f a n d 9a -c. To a
magnetically stirred solution of acetal 9a ,b (2 mmol) in acetone
+
15 3 3
H N O : C, 61.53; H, 5.53;
N, 15.38. Found: C, 61.59; H, 5.45; N, 15.31.
Gen er a l P r oced u r e for th e Syn th esis of 2,3-Dip h en -
ylam in opyr r ole-3-car boxylic Acid Der ivatives 7a-e Star t-
in g fr om 5e-i. To a magnetically stirred solution of 5-hy-
droxy-1-aminopyrroline-3-carboxylic acid derivatives 5e-i (1
2
mmol) in THF (10 mL) was added Cu(OTf) (0.1 mmol). The
reaction was allowed to stand at room temperature until the
complete disappearance of 5e-i (1.0 h, monitored by TLC).
After the evaporation of the solvent under reduced pressure,
the crude mixture was solved in ethyl acetate and washed with
brine, and the organic layer was dried over Na SO , filtered,
2 4
and evaporated. Compounds 7a -e (see Table 1) were purified
by crystallization from diethyl ether and petroleum ether (bp
(
8 mL) and H
g), and the mixture was stirred at rt for 12 h, while to a
solution of 9c (2 mmol) in H O (10 mL) was added Dowex 50W
0.8 g) and the mixture stirred at rt for 24 h. To this resulting
solution, after filtration of the ion-exchange resin, were added
,2-diaza-1,3-butadienes 1a -c,f (1 mmol) and Duolite A 102
0.5 mmol). The reaction was allowed to stand at room
2
O (0.12 mL) was added Amberlyst 15 (H) (0.08
7
2
4
0-60 °C).
(
Meth yl 1-[(am in ocar bon yl)am in o]-2-m eth yl-4,5-diph en -
1
yl-1H-p yr r ole-3-ca r boxyla te (7a ): mp 215-217 °C; H NMR
1
(
(
DMSO-d
6
) δ 2.37 (s, 3 H), 3.50 (s, 3 H), 6.23 (s, 2 H), 7.01-
7
1
1
1
.22 (m, 10 H), 9.20 (s, 1 H); 13C NMR (DMSO-d
6
) δ 11.7, 51.2,
temperature until the complete disappearance of 1a -c,f (10
h, monitored by TLC). The solution was filtered and concen-
trated under reduced pressure, and the mixture residue was
09.0, 121.1, 126.4, 127.7, 127.8, 128.3, 130.9, 131.0, 131.1,
31.9, 135.9, 137.6, 157.6, 165.5; IR 3405, 3263, 3197, 1719,
-
1
+
+
676 cm ; MS m/z 350 (M + 1, 23), 349 (M , 100). Anal. Calcd
2 4
dissolved in ethyl acetate, dried over Na SO , and evaporated.
for C20
19 3 3
H N O
: C, 68.75; H, 5.48; N, 12.03. Found: C, 68.89;
Products 5c-d ,j-k and 6a -h (see Table 2) were obtained by
chromatography on silica gel column with cyclohexane-ethyl
acetate (10:90 v/v) and then purified by crystallization from
diethyl ether and petroleum ether (bp 40-60 °C).
Gen er a l P r oced u r e for th e Syn th esis of 5-Un su bsti-
tu ted-1-am in opyr r ole-3-car boxylic Acid Der ivatives 6a-f
Sta r tin g fr om 5-Hyd r oxy-1-a m in op yr r olin e-3-ca r boxylic
Acid Der iva tives 5a -d ,j-k . To a magnetically stirred solu-
tion of 5-hydroxy-1-aminopyrroline-3-carboxylic acid deriva-
tives 5a -d ,j-k (1 mmol) in THF (10 mL) was added CuCl
2
The reaction was allowed to stand at room temperature until
the complete disappearance of 5a -d ,j-k (0.5 h, monitored by
TLC). After evaporation of the solvent under reduced pressure,
the crude mixture was solved in ethyl acetate and washed with
H, 5.41; N, 12.07.
P r oced u r e for th e Syn th esis of Meth yl 1-[(ter t-Bu -
toxyca r bon yl)a m in o]-2-m eth yl-4,5-d ip h en yl-1H-p yr r ole-
3
-ca r boxyla te (7e) Sta r tin g fr om 1g a n d 8.10 Copper(II)
chloride dihydrate (0.1 mmol) dissolved in THF (5 mL) was
added to a solution of azoalkene 1g (1 mmol) in methyl
acetoacetate (8) (15 mL). The mixture was magnetically stirred
at room temperature for 1 h until the reaction was completed
(
monitored by TLC). The reaction mixture was poured into
diethyl ether and washed several times with saturated aque-
ous Na CO and then with brine. The organic layer was dried
with anhydrous Na SO , and after evaporation under reduced
pressure, it provided the relevant 1-amminopyrrole derivative
2
‚
H
2
O (0.1 mmol), Amberlyst 15 (H) (0.8 g), or TFA (1.0 mmol).
2
3
2
4
7
e (35%).
Meth yl 1-[(ter t-bu toxyca r bon yl)a m in o]-2-m eth yl-4,5-
d ip h en yl-1H-p yr r ole-3-ca r boxyla te (7e): mp 180-182 °C;
2 4
brine, and the organic layer was dried over Na SO , filtered,
and evaporated. Compounds 6a -f (see Table 2) were obtained
after crystallization from diethyl ether and petroleum ether
1
H NMR (DMSO-d
6
) δ 1.34 (s, 9 H), 2.35 (s, 3 H), 3.50 (s, 3 H),
) δ
7
1
1
3
3
6
.00-7.24 (m, 10 H), 10.30 (s, 1 H); 13C NMR (DMSO-d
6
(
bp 40-60 °C).
-{3-(Dim et h yla m in o)-1-m et h yl-3-oxo-2-[(2,2-d ip h en -
ylvin yl)oxy)]}-h yd r a zin e-1-ca r boxa m id e (4): mp 150-153
C; H NMR (DMSO-d
H), 5.44 (s, 1 H), 6.31 (bs, 2 H), 6.67 (s, 1 H), 7.10-7.40 (m,
0 H), 9.40 (s, 1 H); 13C NMR (DMSO-d
) δ 12.3, 35.4, 36.5,
0.8, 27.8, 50.5, 80.7, 108.5, 120.7, 125.8, 127.0, 127.3, 127.7,
29.8, 130.1, 130.2, 130.9, 134.8, 136.0, 154.2, 164.5; IR 3325,
258, 1735, 1683 cm ; MS m/z 407 (M +1, 2), 406 (M , 24),
49 (23), 350 (100). Anal. Calcd for C24 : C, 70.92; H,
2
-1
+
+
1
°
6
) δ 1.76 (s, 3 H), 2.84 (s, 3 H), 2.95 (s,
26 2 4
H N O
3
1
8
1
1
1
1
.45; N, 6.89. Found: C, 70.99; H, 6.37; N, 6.95.
6
2.1, 119.8, 126.4, 126.5, 127.7, 127.9, 128.4, 129.6, 137.2,
39.8, 142.9, 143.8, 156.9, 166.6; IR 3431, 3284, 3235, 1685,
Ack n ow led gm en t. This work was supported by
financial assistance from the Ministero dell’Universita`
e della Ricerca Scientifica e Tecnologica-MURST, Rome
-
1
+
651 cm ; MS m/z 380 (M , 1), 362 (15), 318 (20), 196 (18),
67 (100). Anal. Calcd for C21 : C, 66.30; H, 6.36; N,
24 4 3
H N O
(
National Project “Building-blocks da e/o per sistemi
4.73. Found: C, 66.41; H, 6.32; N, 14.81.
Meth yl (4S*,5R*)-1-[(am in ocar bon yl)am in o]-5-h ydr oxy-
-m et h yl-4-p h en yl-4,5-d ih yd r o-1H -p yr r ole-3-ca r b oxy-
eterociclici. Processi innovativi e sintesi di molecole di
potenziale attivit a` biologica”), the Consiglio Nazionale
delle Ricerche-CNR, Rome, and the Universit a` degli
Studi di Urbino.
2
1
la te (5a ): H NMR (DMSO-d
6
) δ 2.14 (d, J ) 1.2 Hz, 3 H),
3
1
5
9
3
.31 (s, 3 H), 3.69 (dq, J ) 3.6 Hz, J ) 1.2 Hz 1 H), 4.65 (bs,
H), 5.98 (bs, 2 H), 6.50 (d, J ) 7.2 Hz, 1 H), 7.10-7.30 (m,
Su p p or tin g In for m a tion Ava ila ble: Product character-
1
3
H), 8.16 (bs, 1 H); C NMR (DMSO-d
6
) δ 11.8, 50.0, 54.3,
1
13
ization data, H and C NMR peak listings for 5b-k , 6b-h ,
and 7b-d . This material is available free of charge via the
Internet at http://pubs.acs.org.
3.9, 99.2, 126.2, 127.5, 128.2, 143.4, 158.2, 159.4, 165.7; IR
328, 3201, 1705, 1681 cm-1; MS m/z 291 (M , 6), 273 (100).
+
Anal. Calcd for C14
17 3 4
H N O : C, 57.72; H, 5.88; N, 14.42.
Found: C, 57.69; H, 5.81; N, 14.37.
J O025656K
J . Org. Chem, Vol. 67, No. 23, 2002 8181