New and efficient one-pot synthesis of functionalized γ-spirolactones mediated by vinyltriphenylphosphonium salts

Article abstract of DOI:10.1016/S0040-4020(03)00021-8

The addition of dimethyl acetylenedicarboxylate to isatin derivatives in the presence of triphenylphosphine leading to new highly functionalized γ-spirolactones is reported.

Full text of DOI:10.1016/S0040-4020(03)00021-8

Tetrahedron 59 (2003) 1169–1171
New and efficient one-pot synthesis of functionalized
g-spirolactones mediated by vinyltriphenylphosphonium salts
*
Abbas Ali Esmaili and Asghar Bodaghi
Department of Chemistry, University of Birjand, P.O. Box 79, Birjand, Iran
Received 16 September 2002; revised 5 December 2002; accepted 2 January 2003
Abstract—The addition of dimethyl acetylenedicarboxylate to isatin derivatives in the presence of triphenylphosphine leading to new highly
functionalized g-spirolactones is reported. q 2003 Elsevier Science Ltd. All rights reserved.
1. Introduction
1
We have recently described the synthesis of functionalized
dihydro-pyrroloisoindole derivatives from the reaction of
triphenylphosphine, dialkylphthalimidomalonates and
dialkyl acetylendicarboxylate using an intramolecular
2
–5
Wittig reaction. With the purpose of preparing dihydro-
pyrroloindoles, e.g. 1, dialkylisatinomalonate was treated
with dialkylacetylendicarboxylat and triphenylphosphine.
Scheme 1.
Initial fragmentations involve loss of the g-spirolactone side
chains.
1
The H NMR spectrum of 4a exhibited singlets readily
recognizable as arising from the methoxy groups (3.76,
3.84, 4.00 and 4.40) protons, along with a singlet at 5.85
from the methine proton. A fairly complex multiplet was
The dihydro-pyrroloindole derivatives 1 was not observed,
but g-spirolactones 4a and 4b were isolated in fairly high
yield. We also found that N-alkylisatins 3c and 3d reacted
with dialkylacetylendicarboxylates 2a and 2b to yield
1
3
observed for the aromatic protons at 6.9–7.8. The C NMR
spectrum of 4a displayed nineteen distinct resonances in
agreement with the g-spirolactone structure. Partial assign-
ment of these resonances are given in Section 2. The
characteristic signal due to spiro carbon was discernible at
4
c–4e in fairly high yield (Scheme 1). On the basis of the
chemistry of trivalent phosphorus nucleophiles, it is
reasonable to assume that g-spirolactone 4 result from the
initial addition of triphenylphosphine to acetylenic ester and
concomitant addition to activated carbonyl to afford
1
3
13
80.58 in the C NMR spectrum of 4a. Two C signals were
observed at about d 122 and 131 for 4a which are assigned
0
ively and are similar to those observed for spirolactones.
13
0
13
6
to C3 ( CvC–OMe) and C4 (Cv C–OMe) respect-
6
g-spirolactones. The g-spirolactone formation can be
rationalized as shown in Scheme 2. The structure of
compounds were deduced from their elemental analyses
1
13
The H and C NMR spectra of 4b–4e are similar to those
of 4a, except for ester residue, and the absence of methine
proton resonance for 4c–4e (see Section 2).
1
13
and their IR, H and C NMR spectra.
The mass spectra of compounds 4a–4e displayed molecular
ion peaks at m/z 419, 447, 303, 331 and 317 respectively.
In conclusion, we have found that the reaction of isatin
derivatives with DMAD (dimethyl acetylene dicarboxylate)
in the presence of triphenylphosphine leads to a facile
synthesis of highly functionalized g-spirolactones in fairly
high yield. The one-pot nature of the present procedure
Keywords: g-spirolactones; acetylenic esters; triphenylphosphine; isatin.
*
Corresponding author. Tel.: þ98-561-2230516; fax: þ98-561-2230515;
e-mail: aa_esmaeili@yahoo.com
0040–4020/03/$ - see front matter q 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4020(03)00021-8

1170
A. A. Esmaili, A. Bodaghi / Tetrahedron 59 (2003) 1169–1171
Scheme 2.
þ
Calcd for C H NO (305.27): C, 59.01; H, 4.95; N, 4.59%.
makes it an interesting alternative to multistep approaches.
Further investigations of the present method will be required
to establish its scope and limitations.
CO Et–EtOH, 50), 147 (M þ1–CH(CO Et) ,87); Anal.
2
2
2
1
5
15
6
1
Found: C, 59.1; H, 4.9; N, 4.6%. H NMR (90 MHz,
CDCl ): d¼1.2–1.4 (6H, 2t, J¼7.2 Hz, 2CH ), 4.2–4.5 (4
3
3
H, 2q, J¼7.2 Hz, 2OCH ), 5.9 (1H, s, N–CH), 6.85–7.8
2
1
3
2. Experimental
(4H, m, arom.); C NMR (22.6 MHz, CDCl
3
): d¼181.57,
1
64.43 and 154.83 (3CvO), 149.32 (C7a), 138.25 (C6),
25.38 (C7), 124.32 (C5), 117.93 (C4), 112.96 (C3a), 63.08
(2OCH ), 56.40 (CH–N), 13.99 and 13.95 (2CH ).
Compounds 2a and 2b were obtained from Fluka (Buchs,
Switzerland) and were used without further purification.
Melting points were measured on an Electrothermal 9100
apparatus and are uncorrected. Elemental analyses for C, H,
and N were performed using a Heraeus CHN-O-Rapid
analyzer. IR spectra were measured on a Perkin–Elmer 783
2
3
2.2. Preparation of N-alkyl isatin 3c and 3d
Compounds 3c and 3d were prepared from alkyl benzen-
7
1
13
Infrared spectrophotometer. H and C NMR spectra were
measured with BRUKER DRX-500 AVANCE spectro-
meter at 500 and 125.77 MHz, JEOL EX-90A spectrometer
at 90 and 22.6 MHz, respectively. Mass spectra were
recorded on a Finnigan-Matt 8430 mass spectrometer
operating at an ionization potential of 70 eV.
sulfonates and the potassium isatin by known methods and
identified as follows.
2.2.1. N-Methyl isatin 3c. Purple crystals, mp 129–1308C;
2
1
IR (KBr) (nmax, cm ): 1730, 1750 (CvO); m/z (%): 161
(M , 20), 147 (M þ12Me, 18); Anal. Calcd for C
þ
þ
161.16): C, 67.07; H, 4.37; N, 8.69%. Found: C, 67.2; H,
H NO
9 7 2
(
4.5; N, 8.5%. H NMR (90 MHz, CDCl
N–CH ), 6.82–7.8 (4H, m, arom.); C NMR (22.6 MHz,
3
1
2
.1. Preparation of dialkyl indolomalonate 3a, 3b
3
): d¼3.23 (3H, s,
1
3
Compounds 3a, 3b were prepared from dialkylbromomalo-
7
CDCl
138.57 (C6), 125.14 (C7), 123.87 (C5), 117.40 (C4),
110.11 (C3a), 26.22 (CH –N).
3
): d¼183.41 and 158.28 (2CvO),151.48 (C7a),
nates and the potassium isatin by known methods and
identified as follows.
3
2
crystals, mp 1558C; IR (KBr) (nmax, cm ): 1740, 1750 and
.1.1. 1-Dimethyl-2,3-dioxoindolomalonate 3a. Yellow
1
2.2.2. N-Ethyl isatin 3d. Purple crystals mp 86–878C; IR
þ
2
21
(KBr) (nmax, cm ): 1735, 1750 (CvO); m/z (%): 175 (M ,
þ
2CO Me2CO, 50), 130 [CH(CO Me) , 33], 162
þ
þ
þ
1
760 (CvO); MS, m/z (%): 277 (M ,30), 190 (M þ
87), 147 (M þ12Et, 20), 118 (M 2Et–CO, 85); Anal.
Calcd for C10 NO (175.2): C, 68.56; H, 5.18; N, 7.99%.
Found: C, 68.4; H, 5.3; N, 8.2%. H NMR (90 MHz,
1
H
9
2
2
2
2
þ
277.22): C, 56.32; H, 3.99; N, 5.05%. Found: C, 56.1; H,
1
(
(
M þ122CO Me, 87); Anal. Calcd for C H NO
2
13 11
6
CDCl
): d¼1.30 (3H, t, CH ), 6.85–
7.80 (4H, m, arom.); C NMR (22.6 MHz, CDCl ):
3
), 3.80 (2H, q, N–CH
3
3
2
1
13
4
2
.1; N, 4.9%. H NMR (90 MHz, CDCl ): d¼3.9 (6H, s,
3
1
3
OCH ), 5.9 (1H, s, NCH), 6.9–7.8 (4H, m, arom.);
3
C
d¼183.73 and 157.92 (2CvO), 150.71 (C7a), 138.37
NMR (22.6 MHz, CDCl ): d¼181.16, 164.51 and 157.46
(C6), 125.46 (C7), 123.67 (C5), 117.64 (C4), 110.07
(C3a), 34.98 (N–CH
3
(3CvO), 148.99 (C7a), 138.08 (C6), 125.01 (C7), 124.07
(C5), 117.72 (C4), 112.39 (C3a), 55.87 (CH–N), 53.26 (2
), 12.54 (CH ).
2 3
0
-alkoxy spiro[1-substituted indol-3,2 -(2 ,5 -dihydro-
OMe).
2.3. General procedure for synthesis of alkyl-5 ,2-dioxo-
4
0
furan)]-3 -carboxylate 4
0
0
0
0
2
tals, mp 95–968C; IR (KBr) (nmax, cm ): 1735, 1750 and
.1.2. 1-Diethyl-2,3-dioxoindolomalonate 3b. Red crys-
2
1
þ
þ
1
760 (CvO); MS, m/z (%): 305 (M , 25), 204 (M þ1–
To a magnetically stirred solution of N-substituted

A. A. Esmaili, A. Bodaghi / Tetrahedron 59 (2003) 1169–1171
1171
0
3,2 -(2 ,5 -dihydrofuran)]-3 -carboxylate 4d. White crys-
0
isatin (2 mmol) and triphenylphosphine (2 mmol) in
dichloromethane (3 ml) was added dropwise, dimethyl
acetylenedicarboxylate (2 mmol, 0.284 g) at room tempera-
ture over 10 min. After 3 h the solvent was removed in
vacuum. The residue was crystallized in commercial
ethanol, and purified by recrystallization from ethanol.
2.3.4. Ethyl-5 ,2-dioxo-4 -ethoxy spiro[1-methyl-indol-
0
tals, mp 115.58C, yield 80%; IR (KBr) (nmax, cm ): 1725,
0
0
0
2
1
þ
1740 and 1790 (CvO); m/z (%): 331 (M , 15), 317
þ
Anal. Calcd for C H NO (331.32): C, 61.63; H, 5.17; N,
þ
(M þ12Me, 15), 287 (M þ12OEt, 42), 73 (CO Et, 58);
2
1
7
17
6
1
4
.23%. Found: C, 61.6; H, 5.1; N, 4.1%. H NMR
0
0
acid dimethyl ester)indol-3,2 -(2 ,5 -dihydrofuran)]-3 -
2
.3.1. Methyl-5 ,2-dioxo-4 -methoxy spiro[1-(malonic
(500 MHz, CDCl ): d¼0.92 (3H, t, J¼7.1 Hz, CH of
3
3
0
carboxylate 4a. Yellow crystal, mp 1528C, yield 90%; IR
0
0
0
ester), 1.42 (3H, t, J¼7.2 Hz, CH of ether), 3.20 (3H, s, N–
3
CH ), 3.95 (2H, 2q, J¼7.1 Hz, CH of ester), 4.70 (2H, 2q,
3
2
2
1
13
(
KBr) (nmax, cm ): 1735, 1750, 1760 and 1780 (CvO);
þ
J¼7.2 Hz, CH , of ether), 6.86–7.41 (4H, m, arom.);
C
2
þ
m/z (%): 420 (M þ1, 15), 419 (M , 60), 360
NMR (125.77 MHz, CDCl ): d¼170.54, 166.17 and 160.28
3
þ
CO Me, 87); Anal. Calcd for C H NO (419.34): C,
þ
0
(C7), 123.75 (C5), 123.55 (C3 ), 119.48 (C4), 109.39 (C3a),
(
M þ12CO Me, 68), 300 (M þ122CO Me, 18), 59
(3CvO), 149.55 (C7a), 145.37 (C6), 132.15 (C4 ), 124.65
2
2
0
82.11 (C spiro), 69.94 and 61.59 (2OCH ), 27.24 (N–CH ),
15.71 and 13.91 (2CH3).
(
2
19 17
10
5
4.42; H, 4.08; N, 3.34%. Found: C, 54.7; H, 4.3; N, 3.3%.
2
3
1
H NMR (90 MHz, CDCl ): d¼3.6, 3.8, 4.0 and 4.4 (12H,
3
4
s, 4OMe), 5.85 (1H, s, NCH), 6.8–7.6 (4 H, m, arom.);
C NMR (22.6 MHz, CDCl ): d¼169.68, 164.71, 164.32,
1
3
0
0
3,2 -(2 ,5 -dihydrofuran)]-3 -carboxylate 4e. White crys-
2.3.5. Methyl-5 ,2-dioxo-4 -methoxy spiro[1-ethyl-indol-
3
0
tals, mp 163–1648C, yield 90%; IR (KBr) (nmax, cm ):
0
0
0
1
1
1
6
64.28 and 159.62 (5CvO), 149.32 (C7a), 141.83 (C6),
0
0
21
31.12 (C4 ), 123.91 (C7), 123.50 (C5), 122.10 (C3 ),
17.88 (C4), 111.04 (C3a), 80.58 (C spiro), 55.91 (CHN),
0.34, 53.10, 52.61 and 51.92 (4OMe).
þ
1730, 1740, 1780 (CvO); m/z (%): 317 (M , 14), 289
þ
Anal. Calcd for C H NO (317.3): C, 60.57; H, 4.76; N,
þ
(M þ12Et, 18), 287 (M þ12OMe, 48), 59 (CO Me, 46);
2
1
6
15
6
0
acid diethyl ester)indol-3,2 -(2 ,5 -dihydrofuran)]-3 -car-
0
1
2
.3.2. Methyl-5 , 2-dioxo-4 -methoxy spiro[1-(malonic
4.41%. Found: C, 60.6; H, 4.7; N, 4.4%. H NMR (90 MHz,
0
boxylate 4b. White crystal, mp 1258C, yield 80%; IR (KBr)
0
0
0
CDCl ): d¼1.2–1.4 (3H, t, CH of N–Et), 3.6 and 3.38 (6H,
2 s, 2OCH ), 3.5–4.1 (2H, m, CH of N–Et), 6.9–7.6 (4H,
3 2
3
3
2
1
13
(
4
nmax, cm ): 1700, 1745, 1760 and 1685 (4CvO); m/z (%):
47 (M , 75), 403 (M þ12OEt, 15), 285 (M þ12
m, arom.); C NMR (22.6 MHz, CDCl ): d¼169.56,
3
þ
CH(CO Et) 2CO Me, 53), 59 (CO Me, 62); Anal. Calcd
þ
þ
165.57 and 160.43 (3CvO), 149.48 (C7a), 144.11 (C6),
0
0
131.77 (C4 ), 124.48 (C7), 123.18 (C5), 122.90 (C3 ),
119.23 (C4), 109.21 (C3a), 81.68 (C-spiro), 60.42 and 52.12
(2OMe), 35.49 (CH of N–Et), 12.21 (CH of N–Et).
2
2
2
2
for C H NO (447.4): C, 56.38; H, 4.73; N, 3.13%.
21
2
1
10
1
Found: C, 56.3; H, 4.7; N, 3.1%. H NMR (90 MHz,
2
3
CDCl ): d¼1.1–1.5 (6H, 2t, 2CH , 3.6 and 4.4 (6H, 2 s,
3
3)
2
6
OMe), 4.2–4.4 (4H, 2q, 2OCH ), 5.85 (1H, s, N–CH),
2
Caution: acetylenic esters are lachrymator.
1
3
.9–7.6 (4H, m, arom.); C NMR (22.6 MHz, CDCl3):
d¼170.21, 165.29, 164.43, 164.40 and 160.15 (5CvO),
0
23.83 (C5), 122.61 (C3’), 118.66 (C4), 111.82 (C3a),
1
1
8
49.81 (C7a), 142.56 (C6), 131.41 (C4 ), 124.24 (C7),
Acknowledgements
1.16 (C-spiro), 62.87, 62.79 (2OCH ), 60.76 and 52.29
2
We gratefully acknowledge financial support from the
Research Council of University of Birjand.
(
2OMe), 56.81 (CH–N), 13.98 and 13.93 (2CH3).
0 0
.3.3. Methyl-5 ,2-dioxo-4 -methoxy spiro[1-methyl-
indol-3,2 -(2 ,5 -dihydrofuran)]-3 -carboxylate 4c. Pink
2
0
0
0
0
2
1
crystal, mp 1678C, yield 95%; IR (KBr) (n , cm ):
max
References
þ
1
(
705, 1740 and 1780 (CvO);); m/z (%): 303 (M , 25), 289
þ
þ
M þ12Me, 15), 273 (M þ12OMe, 53), 59 (CO Me,
1. Yavari, I.; Esmaili, A. A. J. Chem. Res. 1998, 714.
2. Ferrer, P.; Avendno, C.; Sollhurber, M. Liebigs Ann. Chem
1995, 1895.
2
6
N, 4.62%. Found: C, 59.5; H, 4.4; N, 4.6%. H NMR
2); Anal. Calcd for C H NO (303.27): C, 59.4; H, 4.32;
15 13 6
1
(
(
(
(
(
(
(
500 MHz, CDCl ): d¼3.26 (3H, s, N–CH , 3.59 and 4.36
3. Beeker, K. B. Tetrahedron 1980, 36, 1717.
4. Zbiral, E. Synthesis 1974, 775.
3
3)
1
3
6H, 2 s, 2OMe), 6.91–7.44 (4H, m, arom.); C NMR
125.77 MHz, CDCl ): d¼169.98, 165.54 and 160.59
5. Yavari, I.; Ramazani, A.; Yahya-zadeh, A. Synth. Commun.
1996, 26, 4495.
3
3CvO), 149.31 (C7a), 144.97 (C6), 131.82 (C4’), 124.23
0
C7), 123.39 (C5), 122.95 (C3 ), 119.18 (C4), 109.12
C3a), 81.64 (C-spiro), 60.36 and 52.31 (2OMe), 26.93
N–Me).
6. Nair, V.; Nair, J. S.; Vinod, A. U.; Rath, N. P. J. Chem. Soc.,
Perkin Trans. 1 1997, 3129.
7. Osterberg, A. E. Org. Synth. 1941, 1, 271.