Addition/cycloaddition of acetylenedicarboxylates to open-chain or cyclic amino carbonyl compounds

Article abstract of DOI:10.1002/ejoc.201000371

Some new, interesting, and unknown heterocyclic rings and open-chain molecules have been obtained with ease and under mild conditions by reaction of a wide range of amino carbonyl compounds with acetylenic esters. The reactivity is highly dependent on the substituents and their positions in the starting material, which can be either cyclic (pyrazolones) or open-chain compounds.

Full text of DOI:10.1002/ejoc.201000371

FULL PAPER
DOI: 10.1002/ejoc.201000371
Addition/Cycloaddition of Acetylenedicarboxylates to Open-Chain or Cyclic
Amino Carbonyl Compounds
Giacomo Guerrini[a] and Fabio Ponticelli*[a]
Keywords: Cycloaddition / Michael addition / Heterocycles / Substituent effects
Some new, interesting, and unknown heterocyclic rings and
open-chain molecules have been obtained with ease and un-
der mild conditions by reaction of a wide range of amino
carbonyl compounds with acetylenic esters. The reactivity is
highly dependent on the substituents and their positions in
the starting material, which can be either cyclic (pyrazol-
ones) or open-chain compounds.
Introduction
Results and Discussion
Dialkyl acetylenedicarboxylates (DAADs) have been in-
vestigated in the past for their high reactivity towards a
great variety of organic substrates. Diels–Alder reactions
and 1,3-dipolar and [2+2] cycloadditions have been re-
ported as key steps for access to a large class of molecules.
Good selectivity of the attack is an “added value”, which
renders these synthetic protocols of wide interest for the
preparation of natural and/or biologically active com-
pounds.[1] In addition, differently substituted pyrroles can
be prepared by a two-step reaction (Michael-like addition
and elimination) of DAADs on amino carbonyl deriva-
tives.[2]
On the other hand, the tendency of amino carbonyl de-
rivatives to dimerize limits their practical use in syntheses.
Following a similar approach, in the present work we wish
to present the reactivity of DAADs towards polyfunctional
amines A and differently substituted pyrazolones B and C
(Figure 1), whose structures contain, beside the nucleophile
amino group, two potential sites of attack, the C=O and
C=N groups, with the aim to verify the possibility to pre-
pare rare bicyclic heterocycles and to evaluate the factors
affecting the nature of the reaction processes.
Recently, the interest in amino ketones in synthetic or-
ganic chemistry was underlined.[3] To verify the potentiality
of the reaction of DAADs with these kinds of compounds,
we prepared compounds 2 and 5 according to Scheme 1.
Reaction of bromo ester 1 with ammonia gave nucleo-
philic substitution and carbonyl condensation product 2 in
good yields. On the other hand, amino keto ester 5 was
obtained from ester 1 by reduction of azide 4 with tri-
phenylphosphane. Different results were obtained when
compounds 2 or 5 were treated with DEAD (diethyl ace-
tylenedicarboxylate). In fact, only Michael-like attack of
the alkyne on the amino group of 2 occurred, followed by
hydrogen shift from nitrogen to carbon to give isomeric
imines 3a. During chromatographic separation, corre-
sponding ketone 3b was also obtained. On the other hand,
starting from amino keto ester 5, a different process was
found. In fact, in this case, attack on both the amino and
ester groups resulted in the formation of pyrrolinone 6,
whose structure was confirmed by single-crystal X-ray dif-
fraction (Figure 2). Afterwards, 1-aminopyrazole deriva-
tives were considered.
As expected, reaction of DMAD (dimethyl acetylene-
dicarboxylate) with methoxy derivative 7a (Scheme 2) oc-
curred only at the amino group, giving corresponding imine
8, whose structure was mainly assigned on the basis of sig-
1
nals at 3.92 ppm and 37.12 ppm in the H and 13C NMR
spectra, respectively, attributable to a methylene group.
On the other hand, reaction of tautomerizable com-
pound 7b gave a complex mixture of compounds, from
which by repeated chromatographic column separation
compound 9 was obtained in 30% yield. Final structure
assignment of this compound was achieved by single-crystal
X-ray analysis (Figure 3).
Figure 1. Structures of amino carbonyl compounds used.
[a] Dipartimento di Chimica, Università degli Studi di Siena,
Via A. Moro 2, 53100 Siena, Italy
Fax: +39-0577-234254
E-mail: ponticelli@unisi.it
For compounds 10a and 10b the formation of a bicyclic
molecule could be expected, and in this case, the structure
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201000371.
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G. Guerrini, F. Ponticelli
FULL PAPER
Scheme 1.
Figure 3. ORTEP drawing of compound 9.
Figure 2. ORTEP drawing of compound 6.
Scheme 3.
Finally, treatment of 4-aminopyrazolones 12a–e with
DEAD, followed by column chromatography, gave three
types of compounds in different yields according to the sub-
stituents and the reaction conditions (Scheme 4 and
Table 1).
The structures of 13a–e followed from analytical and
spectroscopic data. Maleate stereochemistry is based on
Scheme 2.
of the pyrazolone is not aromatic. However, in this case the previous reports of analogous compounds, in particular on
only observed products were the Michael-like products with the chemical shift of the olefinic proton at about 5.50 ppm
the formation of compounds 11a and 11b (Scheme 3).
in the 1H NMR spectrum.[4] In addition, Overhauser corre-
Scheme 4.
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Addition Reactions of Acetylenedicarboxylates
Table 1. Treatment of 4-aminopyrazolones 12a–e with DEAD.
was treated with triethylamine to afford the corresponding
triethylammonium salt on the acidic hydrogen atom, the re-
action occurred on the nitrogen atom (N1) of the ring,
which under these conditions is the most electron-rich site
for the Michael reaction. For reaction with DEAD, Michael
attack provided compound 16, without further cyclization
driven by the presence of the heterocyclic carbonyl group.
R1
R2
R3
Yield [%][a]
13
14
15
12a
12b
12c
12d
12e
H
H
Me
Me
Bn
Me
Ph
Ph
Me
Me
Ph
Me
Me
Ph
45
74
58
85
69
–
–
25
10
trace
13
13
–
–
Ph
trace
[a] Isolated yields after column chromatography.
lations were found between the olefinic CH proton and the
R2 substituent group, which provides further evidence for
the (E) double bond geometry. X-ray analysis of compound
14c gave the assignment reported in Figure 4, and the struc-
tures of 14d and 14e were assigned on the basis of analogy
with spectroscopic data of 14c.
Scheme 5.
To gain more insight into the above reaction, we verified
A second useful insight into the reaction mechanism is
that in the 1H NMR spectra of the crude reaction mixtures, based on the reactivity of 1-acetyl-4-aminopyrazolone 20
the signals of compounds 13 and 15 were practically absent, toward the DAADs. Bromination of 1-acetylpyrazolone 17
whereas the presence of compounds 14 was deduced ac- afforded 18 (Scheme 6), which upon treatment with sodium
cording to a series of NMR signals. These series of NMR azide gave 19. Compound 19 then underwent reduction
signals were particularly recognizable for compounds with with molecular hydrogen to afford 20 in good yields. Treat-
R2 = methyl. In fact, molecules 12a, 12d, and 12e have a ment of 20 with DMAD or DEAD gave exclusively
C3 carbon atom of the ring that passes from sp2 to sp3 (Scheme 7) bicyclic compounds 21a or 21b, which are stable
hybridization. This NMR shift of the methyl group from and isolable by column chromatography. The structures of
about 2.0 ppm in the starting material and in the open- these products are strongly suggested by their NMR prop-
structured molecules 13 to about 1.0 ppm in the bicyclic erties; in particular, the signal for the C=O group is lacking
compounds is well detectable. On this basis, we can infer in the 13C NMR spectrum, and a signal for a nonolefinic
that compounds 13 and 15 are formed in a second time CH group at about 4.70 ppm is visible in the 1H NMR spec-
and/or during chromatographic separation. As confirm- trum and in DEPT experiments. In the case of 21b, X-ray
ation, compound 14d kept in a chloroform solution exposed analysis gave definitive support to the assignment (Fig-
to air, quantitatively decomposes to 13d and 15a in an ap- ure 5).
proximately stoichiometric ratio.
A rationale of all these results can be at this point pro-
Useful insight into the formation mechanism of com- posed. The fact that both pyrazolone 17 and 4-(dimeth-
pounds 13 follows from these considerations. The first is ylamino)-1,4-dimethyl-3-phenylpyrazolone (22; Figure 6)
that starting from aminopyrazolone 12a (Scheme 5), which are completely unaffected by these reagents suggests that
Figure 4. ORTEP drawings of compounds 14c and 15a.
Scheme 6.
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G. Guerrini, F. Ponticelli
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NMR spectra of the crude reaction mixtures: the signals at
about 4.70 ppm are attributable to the CH group at C6.
Compounds 23a–e are then transformed into alkenes 13a–
e during chromatographic separation.
Scheme 7.
Figure 5. ORTEP drawing of compound 21b.
the attack on the DAAD firstly (but not for the anion of
12a) occurs at the acetylenic carbon atom by the NH2
group. An intermediate zwitterion is formed,[5] which fol-
lows different pathways depending on the functional groups
present on the substrate. In the case of 4-aminopyrazolones
12a–e, the amino group can at this point act as a pivot
system, allowing attack at either the C=O (path i) or C=N
(path ii) group (Scheme 8). Path i is the main route followed
in every case, and in the presence of an electron-with-
drawing group (acetyl) in the 1-position, it is the only oper-
ative way. Finally, proton shift gives 14c–e, 21a,b, and 23a–
e. Whereas bicyclic compounds 14 are quite stable and usu-
ally isolable, the tetrahydropyrrolo[3,2-c]pyrazole systems
21 and 23 can be purified by column chromatography only
when an acetyl group is present in the 1-position (com-
pounds 21a,b). In the other cases (compounds 23a–e) their
presence is supposed, as confirmed by inspection of the
Scheme 8.
Similar processes are also operative for open-chain
amino esters 2 and 5, giving compounds 3a and 3b (path i)
by proton shift or pyrrolinone 6 (path ii) by exclusive attack
on the carbethoxy group followed by loss of EtOH. No at-
tack on the ketonic group was observed. Analogously, 1-
aminopyrazole derivatives 7a and 10a,b are believed to re-
act with DAADs, giving zwitterionic intermediates, which
can evolve only by proton shift and rearrangement to the
corresponding imines 8 and 11a,b. In the case of compound
7b, which can exist in three tautomeric forms, a more com-
plex behavior is observed. MS (ESI) analysis of the crude
reaction mixture evidenced species with molecular weights
m/z = 331 and m/z = 313, whereas compound 9 (m/z = 329)
was absent (Scheme 9). DMAD attack on the amino and
carbonyl group can account for the formation of bicyclic
compound 24, which then affords 25 by water elimination.
Compound 9 is finally formed by oxidation of 25 during
chromatographic separation.
Figure 6. Pyrazolone 22.
Scheme 9.
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Addition Reactions of Acetylenedicarboxylates
2 H, aryl) ppm. MS (ESI): = 248 [M + H]+, 270 [M + Na]+.
C12H13N3O3 (247.25): calcd. C 58.29, H 5.30, N 16.99; found C
58.05, H 5.39, N 17.21. A solution of 4 (420 mg, 1.70 mmol) in
THF (10.0 mL) was cooled in an ice bath. To this solution was
added triphenylphosphane (524 mg, 2.0 mmol), and the solution
was stirred for 3 h without further cooling. Water was added
(0.5 mL), and the solvent was evaporated with a nitrogen stream.
The resulting crude solution was purified by column chromatog-
raphy (petroleum ether/EtOAc, 1:1) to afford amino keto ester 5;
Conclusions
Acetylenic diesters (DAADs) are highly reactive towards
compounds containing both NH2 and C=X (X = O, NR)
moieties. Attack on the amino group and proton shift or
reaction on the C=X group give open-chain or cyclic com-
pounds. Chemoselectivity of the process is strongly depend-
ent on the structure and the position of the substituents in
the starting substrate. Reaction of DAAD with 1- and 4-
aminopyrazolones affords condensed heterocycles 9, 14, or
21 of potential biological interest. In fact, they show good
structural analogy with some pyrrolopyrazoles recently de-
scribed as enzymatic inhibitors involved in cancer therapy.[6]
1
yield 19 mg (5%); orange oil. H NMR (400 MHz): δ = 0.96–1.03
(t, J = 7.2 Hz, 3 H, CH2CH3), 1.62 (s, 3 H, CH3), 2.07 (br. s, 2 H,
NH2) 4.11–4.16 (q, J = 7.2 Hz, 2 H, CH2CH3), 7.25–7.44 (m, 3 H,
aryl), 7.84–7.88 (m, 2 H, aryl) ppm. MS (ESI): m/z = 222 [M + H]
+. C12H15NO3 (221.25): calcd. C 65.14, H 6.83, N 6.33; found C
65.04, H 6.99, N 6.54.
4-Amino-1-benzyl-3-methyl-4-phenyl-1,4-dihydropyrazol-5-one (12e):
A solution of 12a (189 mg, 1.0 mmol), benzyl chloride (0.46 mL,
2.0 mmol), and metallic sodium (43 mg, 2.0 mmol) in ethanol
(10.0 mL) was stirred and heated at reflux overnight (16 h). The
solvent from the resulting violet solution was removed in vacuo,
and the crude product was purified by column chromatography
(petroleum ether/EtOAc, 1:1) to give 12e; yield 178 mg (64%); yel-
low oil; Rf = 0.45 (petroleum ether/EtOAc, 5:3). 1H NMR
(200 MHz): δ = 1.81 (s, 3 H, CH3), 2.19 (br. s, 2 H, NH2), 4.71–
4.93 (q, J = 12.8 Hz, 2 H, CH2), 7.23–7.36 (m, 10 H, aryl) ppm.
13C NMR: δ = 12.63, 13.84, 20.60, 47.74, 59.95, 67.23, 124.93,
127.39, 127.86, 128.09, 128.32, 128.64, 136.14, 136.23, 162.59,
176.45 ppm. MS (ESI): m/z = 302 [M + Na]+. C17H17N3O (279,34):
calcd. C 73.10, H 6.13, N 15.04; found C 73.38, H 6.03, N 15.28.
Experimental Section
General: Melting points were determined with a Kofler hot stage.
1H and 13C NMR spectra were recorded at 27 °C (CDCl3), unless
otherwise stated, with a Bruker AC200 instrument operating at
200.13 and 50.33 MHz, respectively, or with a Bruker Avance 400
instrument operating at 400.13 and 100.62 MHz, respectively.
Chemical shifts are reported in ppm from internal TMS. Pyrazo-
lones 12a–e were synthesized as described in other published
works;[7] all other chemicals were of reagent grade and were used
without purification. Mass spectra were recorded in the positive or
negative ion mode with a LCQ-DECA Thermo instrument by
using electrospray ionization. GC–MS experiments were carried
out with a Saturn 2000 ion trap (EI, 70 eV) coupled with a Varian
3800 gas chromatograph (Varian, Walnut Creek, CA, USA)
equipped with a J&W DB5-MS column (30 mϫ0.25 mm ID,
0.25 µm film thickness). All solvents were previously dried accord-
ing to standard procedures. Analytical TLC was performed on sil-
ica gel 60 F254 plates. Flash column chromatography was carried
out on silica gel (0.040–0.063 mm).
1-Acetyl-4-amino-4-methyl-3-phenyl-1,4-dihydropyrazol-5-one (20):
Pyrazolone 17 (100 mg, 0.46 mmol), synthesized with excellent
yield (97%) according to a given procedure,[9] was brominated with
molecular bromine (0.04 mL, 0.78 mmol), which was added drop-
wise to a stirred solution of chloroform (1.0 mL) without stabiliz-
ing ethanol. After 1 h, the solvent was removed with a nitrogen
stream, and the oily residue was triturated with diethyl ether to get
a solid recognized as 18; yield 119 mg (88%); pale-yellow solid;
m.p. 107–112 °C; Rf = 0.62 (petroleum ether/EtOAc, 1:1). 1H NMR
(200 MHz): δ = 2.07 (s, 3 H, CH3), 2.62 (s, 3 H, COCH3), 7.41–
7.63 (m, 3 H, aryl), 7.98–8.12 (m, 2 H, aryl) ppm. C12H11BrN2O2
(295,13): calcd. C 48.84, H 3.76, N 9.49; found C 48.95, H 3.86, N
9.36. To a solution of pyrazolone 18 (87 mg, 0.29 mmol) dissolved
in DMF (2.0 mL) was added sodium azide (28 mg, 0.43 mmol).
The reaction was stirred for 2 h and monitored by TLC. When the
spot corresponding to 18 had disappeared, to the crude solution
was added water (10 mL), and the resulting solution was extracted
with diethyl ether (3ϫ10 mL). The ethereal extracts were dried
with MgSO4, and then the solvent was evaporated with a nitrogen
stream. The resulting solid corresponded to 19; yield 46 mg (62%);
light-brown solid; m.p. 135–140 °C; Rf = 0.71 (petroleum ether/
Ethyl 2-Amino-3-imino-2-methyl-3-phenylpropanoate (2): A solution
of 1 (285 mg, 1.00 mmol) in THF (5.0 mL) was cooled to –78 °C
and a stream of gaseous ammonia was insufflated until the solution
was saturated. The reaction was left to react overnight, to reach
room temperature. The crude solution was filtered to eliminate the
ammonium bromide solid residue and the solvent was removed un-
der vacuum to give 2; yield 150 mg (68%); yellow oil. 1H NMR
(200 MHz): δ = 1.04–1.11 (t, J = 7.0 Hz, 3 H, CH2CH3), 1.57 (s, 3
H, CH3), 2.59 (s, 2 H, NH2), 4.02–4.21 (q, J = 7.0 Hz, 2 H,
CH2CH3), 7.22–7.49 (m, 3 H, aryl), 7.70–7.79 (m, 2 H, aryl) ppm.
13C NMR: δ = 13.21, 23.00, 61.41, 67.21, 126.21, 127.82, 129.44,
136.23, 172.24, 178.06 ppm. MS (ESI): m/z = 219 [M – H]–.
C12H16N2O2 (220.27): calcd. C 65.43, H 7.32, N 12.72; found C
65.68, H 7.41, N 12.63.
1
Ethyl 2-Amino-2-methyl-3-oxo-3-phenylpropanoate (5): To a solu-
EtOAc, 1:1). H NMR (200 MHz): δ = 1.70 (s, 3 H, CH3), 2.53 (s,
tion of 1[8] (2.60 g, 9.12 mmol) dissolved in DMF (15 mL) was 3 H, COCH3), 7.34–7.44 (m, 3 H, aryl), 7.89–7.93 (m, 2 H,
added sodium azide (0.98 g, 15 mmol). The solution was stirred for
60 min and monitored by TLC (petroleum ether/EtOAc, 7:1). To
the resulting crude solution was then added water (10 mL) and di-
ethyl ether (10 mL). The ethereal residue was washed with water
(3ϫ10 mL) to remove DMF, and the aqueous fraction was ex-
tracted with diethyl ether (3ϫ10 mL). The organic fractions were
dried with MgSO4, and the solvent was evaporated under vacuum
aryl) ppm. C12H11N5O2 (257,25): calcd. C 56.03, H 4.31, N 27.22;
found C 55.88, H 4.12, N 26.97. Product 19 (40 mg, 0.16 mmol)
was then hydrogenated with molecular hydrogen at atmospheric
pressure by using Pd/C (10%, 5 mg) in ethanol solution. The reac-
tion was stirred overnight and monitored by TLC. Upon comple-
tion of the reaction, the solvent was removed from the crude solu-
tion, and the residue was purified by column chromatography (pe-
troleum ether/EtOAc, 1:2) to obtain 20; yield 29 mg (82%); white
to give 4 (1.67 g, 6.76 mmol, 74% yield); light orange oil; Rf = 0.68
1
(petroleum ether/EtOAc, 7:1). H NMR (200 MHz): δ = 1.00–1.07 solid; m.p. 123–127 °C; Rf = 0.44 (petroleum ether/EtOAc, 1:1). 1H
(t, J = 7.0 Hz, 3 H, CH2CH3), 1.74 (s, 3 H, CH3), 4.08–4.20 (q, J NMR (200 MHz): δ = 1.51 (s, 3 H, CH3), 2.53 (s, 3 H, COCH3),
= 7.0 Hz, 2 H, CH2CH3), 7.34–7.59 (m, 3 H, aryl), 7.88–7.93 (m, 7.34–7.44 (m, 3 H, aryl), 8.18–8.22 (m, 2 H, aryl) ppm. MS (ESI):
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G. Guerrini, F. Ponticelli
m/z = 232 [M + H]+, 254 [M + Na]+. C12H13N3O2 (231.25): calcd. 13C NMR: δ = 8.45, 35.85, 51.99, 52.20, 53.38, 100.10, 127.23,
FULL PAPER
C 62.33, H 5.67, N 18.17; found C 62.57, H 5.69, N 18.31.
128.37, 131.19, 131.51, 133.37, 139.35, 152.20, 165.48, 169.03 ppm.
MS (ESI): m/z = 346 [M + H]+, 368 [M + Na]+. C17H19N3O5
(345,35): calcd. C 59.12, H 5.55, N 12.17; found C 59.20, H 5.47,
N 12.25.
General Procedure for the Reaction of DAAD with Amino Carbon-
ylic Compounds: To a stirred and warmed solution of amino car-
bonylic compound was added an excess amount (5:1) of the acety-
lenic compound. The solution was heated at reflux overnight (16 h)
until the starting material disappeared (TLC). After this the solvent
was removed in vacuo, and the residue was purified by flash col-
umn chromatography (ether petroleum/EtOAc) to give compounds
3a, 3b, 6, 8, 9, 11a, 11b, 13a–e, 14c, 14d, 15a, 15b, 16, 21a, 21b.
Dimethyl 4-Hydroxy-4-methyl-5-phenyl-4H-pyrazolo[1,5-b]pyrazole-
2,3-dicarboxylate (9): A solution of aminopyrazolone 7b (90 mg,
0.50 mmol) and DMAD (0.31 mL, 2.50 mmol) in THF (5.0 mL)
was stirred and warmed (40 °C) overnight. The solvent was then
removed under vacuum, and the crude mixture was purified by LC
by using a “Lobar LiChroprep 60” silica column and petroleum
ether/ethyl acetate (1:1) as the mobile phase. After removal of the
solvent, a yellow amorphous solid was obtained, to which was
added methanol. The solvent was allowed to evaporate slowly to
get a single crystal for X-ray diffraction analysis; yield 50 mg
(30%); colorless crystal; m.p. 127–129 °C; Rf = 0.35 (petroleum
ether/EtOAc, 1:1). 1H NMR (400 MHz): δ = 1.86 (s, 3 H, CH3),
3.87 (s, 3 H, CO2CH3), 3.88 (s, 3 H, CO2CH3), 4.40 (br. s, 1 H,
OH), 7.40–7.53 (m, 3 H, aryl), 8.21 (d, 2 H, aryl) ppm. 13C NMR: δ
= 24.16, 52.45, 52.68, 80.81, 109.82, 127.57, 128.11, 128.72, 128.93,
132.53, 161.55, 162.13, 173.94 ppm. MS (ESI): m/z = 328 [M – H]
–, 330 [M + H]+, 352 [M + Na]+. C16H15N3O5 (329,31): calcd. C
58.36, H 4.59, N 12.76; found C 58.49, H 4.37, N 12.89.
Diethyl 2-[2-(Ethoxycarbonyl)-1-imino-1-phenylpropan-2-ylimino]-
succinate (3a): A solution of 2 (200 mg, 0.90 mmol) and DEAD
(0.72 mL, 4.50 mmol) in diethyl ether was warmed at 30 °C over-
night and monitored by TLC. Then the solvent was evaporated
under vacuum, and the crude solution was purified by column
chromatography (petroleum ether/EtOAc, 4:1). The resulting prod-
uct was identified as 3a; yield 150 mg (43%); colorless oil; Rf =
0.56 (petroleum ether/EtOAc, 2:1). 1H NMR (400 MHz): δ = 1.15–
1.24 (m, 6 H, 2 CO2CH2CH3), 1.26–1.30 (t, J = 7.2 Hz, 3 H,
CO2CH2CH3), 1.83 (s, 3 H, CH3), 3.08, 3.19 (AB, J = 15.6 Hz, 2
H, CH2), 4.08–4.4.26 (m, 7 H, 3 CO2CH2CH3, NH), 7.35–7.45 (m,
3 H, aryl), 7.82–7.85 (m, 2 H, aryl) ppm. 13C NMR: δ = 13.76,
13.97, 14.02, 22.54, 43.36, 60.74, 61.92, 62.03, 91.93, 107.49,
128.50, 128.87, 129.42, 131.69, 167.88, 168.16, 169.61, 169.87 ppm.
C20H26N2O6 (390.43): calcd. C 61.53, H 6.71, N 7.18; found C
61.32, H 6.88, N 7.04.
Dimethyl 2-(1,5-Dimethyl-3-oxo-4-phenyl-1,3-dihydropyrazol-2-yl-
imino)succinate (11a): To a stirred solution of aminopyrazolone 10a
(69 mg, 0.34 mmol) in THF (4.0 mL) was added DMAD (0.21 mL,
1.70 mmol). The solution was warmed (40 °C) for 48 h and moni-
tored by TLC. The solvent was then removed by evaporation under
vacuum, and the residue was purified by column chromatography
(petroleum ether/EtOAc, 1:1); yield 67 mg (57%); yellow oil; Rf =
Diethyl 2-[2-(Ethoxycarbonyl)-1-oxo-1-phenylpropan-2-ylimino]suc-
cinate (3b): The product was obtained according to the procedure
explained for 3a; yield 50 mg (14%); colorless oil; Rf = 0.72 (petro-
1
leum ether/EtOAc, 2:1). H NMR (200 MHz): δ = 1.08–1.16 (t, J
1
0.61 (petroleum ether/EtOAc, 1:1). H NMR (400 MHz): δ = 2.29
= 7.1 Hz, 3 H, CO2CH2CH3), 1.19–1.33 (m, J = 7.0 Hz, 6 H, 2
CH2CH3), 1.70 (s, 3 H, CH3), 2.99, 3.56 (AB, J = 16.6 Hz, 2 H,
CH2), 4.13–4.31 (m, 6 H, 3 CO2CH2CH3), 4.45 (br. s, 1 H, NH),
7.38–7.55 (m, 3 H, aryl), 7.92–7.96 (m, 2 H, aryl) ppm. 13C NMR:
δ = 13.73, 13.82, 13.93, 23.43, 42.49, 62.10, 62.42, 62.94, 79.37
128.40, 128.55, 129.38, 133.63, 151.73, 168.57, 169.21, 170.21,
195.83 ppm. MS (ESI): m/z = 392 [M + H]+, 414 [M + Na]+.
C20H25NO7 (391.42): calcd. C 61.37, H 6.44, N 3.58; found C
61.69, H 6.36, N 3.84.
(s, 3 H, CH3), 3.32 (s, 3 H, NCH3), 3.67 (s, 3 H, CO2CH3), 3.87 (s,
3 H, CO2CH3), 3.92 (s, 2 H, CH2), 7.22–7.38 (m, 5 H, aryl) ppm.
13C NMR: δ = 12.09, 35.01, 37.12, 52.28, 53.26, 106.97, 126.84,
128.35, 128.46, 128.79, 152.06, 156.29, 165.00, 167.52, 168.35 ppm.
MS (ESI): m/z = 346 [M + H]+, 368 [M + Na]+. C17H19N3O5
(345.35): calcd. C 59.12, H 5.55, N 12.17; found C 59.34, H 5.48,
N 12.30.
Dimethyl 2-(1,4-Dimethyl-3-oxo-5-phenyl-1,3-dihydropyrazol-2-yl-
imino)succinate (11b): The reaction was performed as outlined for
11a starting from 10b (101 mg, 0.5 mmol), and the product was
obtained from the crude solution by column chromatography (pe-
troleum ether/EtOAc, 2:1); yield 135 mg (78%). 1H NMR
(400 MHz): δ = 1.81 (s, 3 H, CH3), 2.96 (s, 3 H, NCH3), 3.65 (s, 3
H, CO2CH3), 3.86 (s, 3 H, CO2CH3), 3.88 (s, 2 H, CH2), 7.37–7.45
(m, 5 H, aryl) ppm. 13C NMR: δ = 7.72, 36.98, 37.90, 52.13, 53.15,
104.26, 128.37, 128.81, 129.04, 130.25, 152.37, 158.29, 163.52,
164.05, 168.51 ppm. MS (ESI): m/z = 344 [M – H]–, 346 [M + H]
+, 368 [M + Na]+. C17H19N3O5 (345.35): calcd. C 59.12, H 5.55, N
12.17; found C 59.08, H 5.81, N 12.32.
Diethyl
5-Benzoyl-4,5-dihydro-5-methyl-4-oxo-1H-pyrrole-2,3-di-
carboxylate (6): To a stirred solution of amino keto ester 5 (47 mg,
0.21 mmol) in diethyl ether (3.0 mL) was added DEAD (0.37 mL,
2.30 mmol). The reaction was warmed (30 °C) for 2 h. The presence
of a white solid was observed, which was filtered and recrystallized
1
(ethanol); yield 62 mg (85%); white crystals; m.p. 197–204 °C. H
NMR (200 MHz): δ = 1.27–1.34 (t, J = 6.9 Hz, 3 H, CH2CH3),
1.37–1.44 (t, J = 6.9 Hz, 3 H, CH2CH3), 1.82 (s, 3 H, CH3), 4.23–
4.34 (q, J = 6.9 Hz, 2 H, CH2CH3), 4.40–4.52 (q, J = 6.9 Hz, 2 H,
CH2CH3), 7.81 (br. s, 1 H, NH), 7.40–7.61 (m, 3 H, aryl), 8.05–
8.16 (m, 2 H, aryl) ppm. MS (ESI): m/z = 344 [M – H]–, 368 [M +
Na]+. C18H19NO6 (345,35): calcd. C 62.60, H 5.55, N 4.06; found
C 62.85, H 5.27, N 4.12.
Diethyl
2-(4,5-Dihydro-3-methyl-5-oxo-4-phenyl-1H-pyrazol-4-yl-
amino)maleate (13a): The product was obtained after chromato-
graphic separation (petroleum ether/EtOAc, 2:1) of the crude solu-
tion of aminopyrazolone 12a (0.5 mmol, 90 mg) and DEAD
(2.5 mmol, 0.4 mL) warmed at 30 °C in diethyl ether (5.0 mL); yield
Dimethyl 2-(5-Methoxy-4-methyl-3-phenyl-1H-pyrazol-1-ylimino)-
succinate (8): A solution of pyrazole 7a (203 mg, 1.00 mmol) and
DMAD (0.61 mL, 5.00 mmol) in diethyl ether (5.0 mL) was
warmed (30 °C) and stirred overnight and monitored by TLC. The
solvent was removed under vacuum, and the crude solution was
purified by column chromatography (petroleum ether/EtOAc, 4:1)
1
80 mg (45%); yellow oil. H NMR (200 MHz): δ = 1.13–1.20 (t, J
= 7.0 Hz, 3 H, CH2CH3), 1.25–1.30 (t, J = 7.0 Hz, 3 H, CH2CH3),
2.0 (s, 3 H, 3-Me), 3.97–4.08 (q, J = 7.0 Hz, 2 H, CH2CH3), 4.18–
to give 8 as the first eluted fraction; yield 144 mg (42%); orange 4.28 (q, J = 7.0 Hz, 2 H, CH2CH3), 4.44 (s, 1 H, NH), 5.46 (s, 1
oil. 1H NMR (400 MHz): δ = 2.15 (s, 3 H, CH3), 3.60 (s, 3 H, H, CH), 7.33 (s, 5 H, aryl), 9.45 (s, 1 H, NH) ppm. 13C NMR: δ =
OCH3), 3.90 (s, 3 H, CO2CH3), 4.08 (s, 3 H, CO2CH3), 4.34 (s, 2
13.89, 14.32, 31.85, 60.00, 62.26, 70.56, 93.59, 125.42, 129.40,
H, CH2), 7.31–7.41 (m, 3 H, aryl), 7.67–7.69 (m, 2 H, aryl) ppm. 129.67, 135.98, 148.35, 160.95, 163.51, 169.86 ppm. MS (ESI): m/z
3924
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© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 3919–3926

Addition Reactions of Acetylenedicarboxylates
= 360 [M + H]+, 382 [M + Na]+. C18H21N3O5 (359.38): calcd. C
60.16, H 5.89, N 11.69; found C 60.31, H 6.02, N 11.60.
7.3 Hz, 3 H, CH2CH3), 1.31–1.39 (t, J = 7.1 Hz, 3 H, CH2CH3),
3.14 (s, 3 H, NCH3), 3.96–4.04 (q, J = 7.3 Hz, 2 H, CH2CH3),
4.28–4.39 (q, J = 7.1 Hz, 2 H, CH2CH3), 5.96 (s, 1 H, NH), 7.24–
7.44 (m, 5 H, aryl) ppm. 13C NMR: δ = 11.81, 14.00, 14.27, 17.56,
29.18, 31.02, 60.00, 60.74, 61.01, 62.42, 71.86, 74.89, 107.31,
117.92, 126.81, 127.89, 128.20, 128.42, 129.22, 137.54, 150.13,
161.73, 163.89, 167.86 ppm. MS (ESI): m/z = 372 [M – H]–, 396
[M + H]+, 769 [2M + Na]+. C19H23N3O5 (373.40): calcd. C 61.11,
H 6.21, N 11.25; found C 61.32, H 6.06, N 11.40.
Diethyl 4-Methyl-5-phenyl-1H-pyrrole-2,3-dicarboxylate (15a): The
product was obtained after chromatographic separation (petroleum
ether/EtOAc, 3:1) of the crude solution of aminopyrazolone 12a
(0.5 mmol, 90 mg) and DEAD (2.5 mmol, 0.4 mL) in diethyl ether
(5.0 mL); yield 20 mg (13%); yellow needles; m.p. 75–78 °C; Rf =
0.94 (ethyl acetate/petroleum ether, 2:1). δ = 1.23–1.40 (t, J =
7.6 Hz, 6 H, 2 CH2CH3), 2.23 (s, 3 H, CH3), 4.23–4.38 (q, J =
7.6 Hz, 4 H, 2 CH2CH3), 7.39–7.44 (m, 5H, Ph) ppm. 13C NMR:
δ = 10.70, 14.30, 29.70, 60.86, 60.94, 118.44, 120.37, 122.56, 127.56,
128.03, 128.89, 131.11, 132.94, 160.22, 165.83 ppm. MS (ESI): m/z
= 300 [M – H]–. GC–MS: m/z = 301 [M·]+, 255 [M – 46·]+.
C17H19NO4 (301.34): calcd. C 67.76, H 6.36, N 4.65; found C
67.59, H 6.16, N 4.80.
Diethyl 2-(4,5-Dihydro-1,3-dimethyl-5-oxo-4-phenyl-1H-pyrazol-4-
ylamino)maleate (13d): The purified product was obtained after
chromatographic separation (petroleum ether/ethyl acetate, 3:1) of
the crude solution of aminopyrazole 12d (100 mg, 0.49 mmol) and
DEAD (0.39 mL, 2.46 mmol) warmed at 30 °C in diethyl ether
(10.0 mL); yield 158 mg (85%); yellow solid; m.p. 145–151 °C; Rf
= 0.64 (petroleum ether/EtOAc, 2:1). 1H NMR (200 MHz) δ =
1.23–1.35 (m, J = 6.8 Hz, 6 H, 2 CH2CH3), 2.12 (s, 3 H, CH3),
3.19 (s, 3 H, NCH3), 4.11–4.19 (m, J = 6.8 Hz, 4 H, 2 CH2CH3),
5.49 (s, 1 H, CH), 7.32–7.46 (m, 5 H, aryl), 8.86 (s, 1 H, NH) ppm.
13C NMR: δ = 13.89, 14.20, 14.32, 31.85, 60.00, 62.26, 70.56, 93.59,
125.42, 129.40, 129.67, 135.98, 148.35, 160.95, 163.51, 169.86 ppm.
MS (ESI): m/z = 374 [M + H]+, 396 [M + H]+, 412 [M + K]+.
C19H23N3O5 (373.40): calcd. C 61.11, H 6.21, N 11.25; found C
60.97, H 6.40, N 11.48.
Diethyl
2-(4,5-Dihydro-4-methyl-5-oxo-3-phenyl-1H-pyrazol-4-yl-
amino)maleate (13b): The product was obtained after chromato-
graphic separation (petroleum ether/EtOAc, 1:1) of the crude solu-
tion of aminopyrazolone 12b (0.26 mmol, 50 mg) and DEAD
(1.3 mmol, 0.21 mL) warmed at 45 °C in THF (5.0 mL); yield
1
69 mg (74%); yellow oil. H NMR (200 MHz): δ = 1.14–1.21 (t, J
= 6.7 Hz, 3 H, CH2CH3), 1.27–1.32 (t, J = 6.7 Hz, 3 H, CH2CH3),
1.62 (s, 3 H, 4-Me), 3.85–4.38 (m, J = 6.7 Hz, 2 H, CH2CH3), 5.86
(s, 1 H, CH), 7.30–7.48 (m, 3 H, aryl), 7.72–7.92 (m, 2 H, aryl),
8.71 (s, 1 H, NH), 9.28 (s, 1 H, NH) ppm. 13C NMR: δ = 13.66,
14.29, 26.29, 32.07, 59.98, 62.02, 93.24, 125.89, 128.82, 130.13,
147.47, 157.79, 162.00, 170.13, 176.23 ppm. MS (ESI): m/z = 360
[M + H]+, 382 [M + Na]+, 358 [M – H]–. C18H21N3O5 (359.38):
calcd. C 60.16, H 5.89, N 11.69; found C 60.03, H 5.75, N 11.82.
Diethyl 1,2,3,3a,4,6a-Hexahydro-2,6a-dimethyl-3-oxo-3a-phenylpyr-
rolo[3,2-c]pyrazole-5,6-dicarboxylate (14d): The purified product
was obtained after chromatographic separation (petroleum ether/
ethyl acetate, 3:1) of the crude solution of aminopyrazole 12d
(100 mg, 0.49 mmol) and DEAD (0.39 mL, 2.46 mmol) warmed at
30 °C in diethyl ether (10.0 mL); yield 18 mg (10%); brown oil; Rf
= 0.57 (petroleum ether/EtOAc, 2:1). 1H NMR (200 MHz): δ =
1.04 (s, 3 H, CH3), 1.19–1.26 (t, J = 7.0 Hz, 3 H, CH2CH3), 1.28–
1.37 (t, J = 7.3 Hz, 3 H, CH2CH3), 3.19 (s, 3 H, NCH3), 4.12–4.23
(q, J = 7.0 Hz, 2 H, CH2CH3), 4.26–4.36 (q, J = 7.3 Hz, 2 H,
CH2CH3), 5.33 (s, 1 H, NH), 7.25–7.37 (m, 5 H, aryl) ppm. 13C
NMR: δ = 2.78, 8.64, 10.70, 14.02, 14.15, 19.01, 19.51, 31.86, 40.96,
53.43, 60.27, 60.87, 62.36, 63.45, 73.35, 126.60, 127.57, 128.06,
128.92, 133.92, 147.85, 161.60, 163.81, 170.9 ppm. MS (ESI): m/z
= 374 [M + H]+, 396 [M + Na]+, 372 [M – H]–. C19H23N3O5
(373.40): calcd. C 61.11, H 6.21, N 11.25; found C 61.22, H 6.07,
N 11.09.
Diethyl 5-Methyl-4-phenyl-1H-pyrrole-2,3-dicarboxylate (15b): The
product was obtained after chromatographic separation (petroleum
ether/EtOAc, 1:1) of the crude solution of aminopyrazolone 12b
(0.26 mmol, 50 mg) and DEAD (1.3 mmol, 0.21 mL) warmed at
45 °C in THF (5.0 mL); yield 10 mg (13%). Melting point and
NMR spectra were identical to those obtained with authentic sam-
ple.[2g]
Diethyl 2-(4,5-Dihydro-1,4-dimethyl-5-oxo-3-phenyl-1H-pyrazol-4-
ylamino)maleate (13c): The purified product was obtained after
chromatographic separation (petroleum ether/ethyl acetate, 3:1) of
the crude solution of aminopyrazole 12c (230 mg, 1.13 mmol) and
DEAD (0.91 mL, 5.66 mmol) warmed at 30 °C in diethyl ether
(20.0 mL); yield 244 mg (58%); light-brown oil; Rf = 0.72 (petro-
leum ether/EtOAc, 1:1). 1H NMR (200 MHz) δ = 1.04–1.11 (t, J =
6.9 Hz, 3 H, CH2CH3), 1.23–1.31 (t, J = 6.9 Hz, 3 H, CH2CH3),
1.68 (s, 3 H, CH3), 3.14 (s, 3 H, NCH3), 3.95–4.12 (q, J = 6.9 Hz,
2 H, CH2CH3), 4.16–4.30 (q, J = 6.9 Hz, 2 H, CH2CH3), 5.40 (s,
1 H, CH), 7.31–7.34 (m, 3 H, aryl), 7.76–7.81 (m, 2 H, Ph), 8.70
(s, 1 H, NH) ppm. 13C NMR: δ = 13.66, 13.86, 14.29, 26.29, 32.07,
59.98, 62.02, 62.97, 63.31, 93.23, 125.89, 126.14, 126.65, 128.82,
129.47, 130.13, 147.47, 157.79, 170.13, 176.23 ppm. MS (ESI): m/z
= 374 [M + H]+, 396 [M + Na]+, 412 [M + K]+. C19H23N3O5
(373.40): calcd. C 61.11, H 6.21, N 11.25; found C 61.23, H 6.06,
N 11.47.
Diethyl 2-(1-Benzyl-4,5-dihydro-3-methyl-5-oxo-4-phenyl-1H-pyr-
azol-4-ylamino)maleate (13e): The purified product was obtained
after chromatographic separation (petroleum ether/ethyl acetate,
1:1) of the crude solution of aminopyrazole 12e (178 mg,
0.64 mmol), and DEAD (0.51 mL, 3.2 mmol) warmed at 30 °C in
diethyl ether (5.0 mL); yield 198 mg (69%); orange oil; Rf = 0.49
1
(petroleum ether/EtOAc, 1:1). H NMR (200 MHz): δ = 1.07–1.10
(t, J = 7.0 Hz, 3 H, CH2CH3), 1.28–1.31 (t, J = 7.0 Hz, 3 H,
CH2CH3), 2.02 (s, 3 H, CH3), 4.07–4.10 (q, J = 7.0 Hz, 2 H,
CH2CH3), 4.11–4.13 (t, J = 7.0 Hz, 2 H, CH2CH3), 4.48–4.52 (d,
J = 15.1 Hz, 1 H, NCH2Ph), 4.85–4.88 (d, J = 15.1 Hz, 1 H,
NCH2Ph), 7.15–7.35 (m, 5 H, aryl), 8.88 (s, 1 H, NH) ppm. 13C
NMR: δ = 13.89, 14.07, 14.19, 48.32, 59.87, 62.01, 70.70, 93.57,
125.28, 127.33, 127.91, 128.28, 128.63, 129.06, 135.88, 136.28,
148.24, 160.97, 163.20, 169.72, 173.91 ppm. MS (ESI): m/z = 450
[M + H]+, 472 [M + Na]+. C25H27N3O5 (449.50): calcd. C 66.80,
H 6.05, N 9.35; found C 67.01, H 6.11, N 9.28.
Diethyl 1,2,3,3a,4,6a-Hexahydro-2,3a-dimethyl-3-oxo-6a-phenylpyr-
rolo[3,2-c]pyrazole-5,6-dicarboxylate (14c): The purified product
was obtained after chromatographic separation (petroleum ether/
ethyl acetate, 3:1) of the crude solution of aminopyrazole 12c
(230 mg, 1.13 mmol) and DEAD (0.91 mL, 5.66 mmol) warmed at
30 °C in diethyl ether (20.0 mL). Further purification was achieved
through crystallization (chloroform); yield 105 mg (25%); white
crystals; m.p. 204–206 °C; Rf = 0.49 (petroleum ether/EtOAc, 1:1).
1H NMR (200 MHz): δ = 0.91 (s, 3 H, CH3), 1.00–1.08 (t, J =
Diethyl 2-(4-Amino-4,5-dihydro-3-methyl-5-oxo-4-phenylpyrazol-1-
yl)but-2-enedioate (16): To a stirred solution of aminopyrazolone
12a (90 mg, 0.50 mmol) in THF (2.0 mL), was added triethylamine
(0.14 mL, 1.0 mmol). After 15 min, DEAD (0.40 mL, 2.50 mmol)
Eur. J. Org. Chem. 2010, 3919–3926
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3925

G. Guerrini, F. Ponticelli
FULL PAPER
was added to the solution. A sudden change in the color of the
solution was observed. The solution was stirred overnight and
monitored by TLC. The solvent from the crude solution was re-
moved in vacuo, and the residue was purified by chromatography
(petroleum ether/EtOAc, 1:1) to give 16; yield 101 mg (56%); yel-
low oil; Rf = 0.70 (petroleum ether/EtOAc, 1:1). 1H NMR
(200 MHz): δ = 1.19–1.26 (t, J = 7.2 Hz, 3 H, CH2CH3), 1.27–1.34
(t, J = 7.2 Hz, 3 H, CH2CH3), 1.89 (s, 3 H, CH3), 4.12–4.22 (q, J
= 7.2 Hz, 2 H, CH2CH3), 4.25–4.35 (q, J = 7.2 Hz, 2 H, CH2CH3),
6.83 (s, 1 H, CH), 7.24–7.52 (m, 5 H, aryl) ppm. 13C NMR: δ =
12.81, 13.85, 13.90, 61.18, 62.44, 67.07, 124.27, 125.38, 128.49,
128.81, 134.47, 135.54, 162.20, 163.03, 163.17, 175.56 ppm. MS
(ESI): m/z = 360 [M + H]+, 382 [M + Na]+. C18H21N3O5 (359.38):
calcd. C 60.16, H 5.89, N 11.69; found C 60.42, H 5.68, N 11.87.
CCDC-752424 (for 14c), -752425 (for 6), -752426 (for 15a), -752427
(for 9), -752428 (for 21b) contain the supplementary crystallo-
graphic data for this paper. These data can be obtained free of
charge from the Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk.
Supporting Information (see also the footnote on the first page of
this article): Experimental characterization data for compounds 2–
21.
Acknowledgments
The work was financially supported by the University of Siena as
a PAR Project 2007. The authors wish to thank the “Centro di
Analisi e Determinazioni Strutturali” of the University of Siena for
MS spectra and X-ray data collection and Dr. Serena Ferrini for
helpful collaborations.
Diethyl
1-Acetyl-1,3a,6,6a-tetrahydro-6a-hydroxy-3a-methyl-3-
phenylpyrrolo[3,2-c]pyrazole-5,6-dicarboxylate (21a): A solution of
aminopyrazolone 20 (100 mg, 0.43 mmol) and DEAD (0.35 mL,
2.2 mmol) in dichloromethane (5.0 mL) was stirred and warmed up
to 40 °C for 72 h. After that the solvent was removed under vac-
uum, and the crude solution was purified by column chromatog-
raphy (petroleum ether/EtOAc, 1:1) to give 21a; yield 106 mg
(62%); colorless needles; m.p. 123–127 °C; Rf = 0.63 (petroleum
[1] a) Q. Ding, Z. Wang, J. Wu, J. Org. Chem. 2009, 74, 921–924;
b) I. Iqbal, M. Imran, P. Langer, Synthesis 2009, 2430–2434; c)
K. Kawashima, M. Hiromoto, K. Hayashi, A. Kakehi, M.
Shiro, M. Noguchi, Tetrahedron Lett. 2007, 48, 941–944; d)
A. R. Katritzky, Y. Zhang, S. K. Singh, Heterocycles 2003, 60,
1225–1239; e) Z. Riedl, G. Hajòs, P. Kovér, G. Kollenz, Arkivoc
2003, 62–68; f) D. Ramaiah, M. Muneer, K. R. Gopidas, P. K.
Das, N. P. Rath, M. V. George, J. Org. Chem. 1996, 61, 4240–
4246; g) A. Padwa, A. D. Woolhouse, J. J. Blount, J. Org. Chem.
1983, 48, 1069–1074.
[2] a) M. Anary-Abbasinejad, K. Charkhati, H. Anaraki-Ardak-
ani, Synlett 2009, 1115–1117; b) I. Erden, G. Olzer, C. Hoarau,
W. Cao, J. Song, C. Gartner, I. Baumgardt, H. Butenschon, J.
Org. Chem. 2008, 73, 6943–6945; c) M. L. Crawley, I. Goljer,
D. J. Jenkins, J. F. Mehlmann, L. Nogle, R. Dooley, P. H. Mah-
aney, Org. Lett. 2006, 8, 5837–5840; d) H. Mastalerz, A. V.
Gavai, B. Fink, C. Struzynski, J. Tarrant, G. D. Vite, T. W.
Wong, G. Zhang, D. M. Vyas, Can. J. Chem. 2006, 84, 528–533;
e) L. A. Evans, K. E. Griffiths, H. Guthmann, P. J. Murphy,
Tetrahedron Lett. 2002, 43, 299–301; f) P. Kolar, M. Tisler,
Synth. Commun. 1994, 24, 1887–1893; g) J. Barluenga, F. Pala-
cios, V. Gotor, Synthesis 1975, 642–643; h) J. B. Hendrickson,
R. Rees, J. F. Templeton, J. Am. Chem. Soc. 1964, 86, 107–111.
[3] S. Baktharaman, R. Hili, A. K. Yudin, Aldrichimica Acta 2008,
41, 109–119.
1
ether/EtOAc, 1:1). H NMR (200 MHz): δ = 1.21–1.34 (m, 6 H, 2
CH2CH3), 1.60 (s, 3 H, CH3), 2.38 (s, 3 H, COCH3), 4.23–4.34 (m,
4 H, 2 CH2CH3), 4.68 (s, 1 H, CH), 5.16 (br. s, 1 H, OH), 7.40–
7.44 (m, 3 H, aryl), 8.02–8.11 (m, 2 H, aryl) ppm. 13C NMR: δ =
13.97, 14.10, 16.76, 21.88, 62.14, 62.50, 62.96, 63.34, 68.16, 96.42,
128.25, 128.61, 129.32, 130.50, 155.83, 160.79, 162.36, 165.94,
170.97 ppm. MS (ESI): m/z = 400 [M – H]–, 402 [M + H]+, 424 [M
+ Na]+. C20H23N3O6 (401.41): calcd. C 59.84, H 5.78, N 10.47;
found C 59.71, H 5.93, N 10.34.
Dimethyl
1-Acetyl-1,3a,6,6a-tetrahydro-6a-hydroxy-3a-methyl-3-
phenylpyrrolo[3,2-c] pyrazole-5,6-dicarboxylate (21b): The reaction
was performed as outlined for 21a by using 20 (300 mg. 1.30 mmol)
and DMAD (0.80 mL, 6.50 mmol) in dichloromethane (8.0 mL).
After 72 h the solvent was removed in vacuo, and the presence of
a white solid was noticed. A small quantity of diethyl ether was
then added, and the white solid (21b) was filtered through a Buch-
ner filter and characterized without further purification; yield
292 mg (60%); white powder; m.p. 190–193 °C; Rf = 0.61 (petro-
leum ether/EtOAc, 1:1). 1H NMR (200 MHz): δ = 1.61 (s, 3 H,
CH3), 2.38 (s, 3 H, COCH3), 3.82 (s, 3 H, CO2CH3), 3.88 (s, 3 H,
CO2CH3), 4.73 (s, 1 H, CH), 5.00 (br. s, 1 H, OH), 7.40–7.48 (m,
3 H, aryl), 7.97–8.08 (m, 2 H, aryl) ppm. 13C NMR: δ = 16.76,
21.93, 53.15, 53.29, 63.14, 93.32, 96.35, 128.14, 128.25, 128.69,
129.24, 130.60, 161.38, 161.99, 166.58, 171.08 ppm. MS (ESI): m/z
= 372 [M – H]–, 396 [M + Na]+. C18H19N3O6 (373.76): calcd. C
57.90, H 5.13, N 11.25; found C 58.06, H 5.01, N 11.53.
[4] a) Q. Zhu, H. Jiang, J. Li, M. Zhang, X. Wang, C. Qi, Tetrahe-
dron 2009, 65, 4604–4613; b) D. Zewge, C. Chen, C. Deer, P. G.
Dormer, D. L. Hughes, J. Org. Chem. 2007, 72, 4276–4279; c)
D. Ramaiah, H. Ashok, R. Barik, D. Venugopal, N. P. Rath,
K. Bhattacharyya, P. K. Das, M. V. George, J. Org. Chem.
1992, 57, 6032–6037; d) W. E. Truce, D. G. Brady, J. Org.
Chem. 1966, 31, 3543–3550.
[5] J. B. Hendrickson, R. Rees, J. F. Templeton, J. Am. Chem. Soc.
1964, 86, 107–111.
X-ray Crystallography: Single crystals were obtained by dissolving
a few milligrams of powder in the solvents mentioned and allowing
the solution to evaporate at room temperature. A “Siemens P4”
four-circle diffractometer and a “OXFORD Xcalibur S” with
graphite-monochromated Mo-Kα radiation (λ = 0.71073 Å) and the
ω scan technique were used for data collections. The structure was
solved by direct methods implemented in the SHELXS-97 pro-
gram. The refinement was carried out by full-matrix anisotropic
least-squares methods on F2 for all reflections for non-hydrogen
atoms by using the SHELXL-97 program. The crystallographic
views reported above were elaborated with ORTEP (50% prob-
ability thermal ellipsoids).
[6] a) D. Fancelli, J. Moll, M. Varrasi, R. Bravo, R. Artico, D.
Berta, S. Bindi, A. Cameron, I. Candiani, P. Cappella, P. Carpi-
nelli, W. Croci, B. Forte, M. L. Giorgini, P. Storici, R. Tonani,
P. Zugnoni, P. Vianello, J. Med. Chem. 2006, 49, 7247–7251; b)
Y. Wang, A. Benn, N. Flinn, T. Monk, M. Ramjee, J. Watts,
M. Quibell, Bioorg. Med. Chem. Lett. 2005, 15, 1327–1331.
[7] A. M. Celli, S. Ferrini, F. Ponticelli, Eur. J. Org. Chem. 2006,
3021–3025 and references cited therein.
[8] D. Yang, Y. L. Yan, B. Lui, J. Org. Chem. 2002, 67, 7429–7431.
[9] L. A. Carpino, J. Am. Chem. Soc. 1958, 80, 599–601.
Received: March 17, 2010
Published Online: May 26, 2010
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Eur. J. Org. Chem. 2010, 3919–3926