Efficient and chemoselective methods for the synthesis of some isobenzofuran and spiro[isobenzofuran-1,2′-pyrrole] derivatives

Article abstract of DOI:10.1002/hlca.201000241

An efficient and practical one-pot procedure for the direct chemoselective synthesis of isobenzofuran and spiro[isobenzofuran-1,2′-pyrrole] derivatives is developed via oxidative cleavage of 3a,8b-dihydroxyindeno[1,2-b] pyrrol-4-ones with Pb(OAc)₄

Full text of DOI:10.1002/hlca.201000241

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Efficient and Chemoselective Methods for the Synthesis of Some
Isobenzofuran and Spiro[isobenzofuran-1,2’-pyrrole] Derivatives
by Mohammad R. Mohammadizadeh*, Neda Firoozi, and R. Aradeh
Department of Chemistry, Faculty of Sciences, Persian Gulf University, Bushehr 75169, Iran
(phone/fax: þ 98-771-4541494; e-mail: mrmohamadizadeh@pgu.ac.ir)
An efficient and practical one-pot procedure for the direct chemoselective synthesis of isobenzofur-
an and spiro[isobenzofuran-1,2’-pyrrole] derivatives is developed via oxidative cleavage of 3a,8b-
dihydroxyindeno[1,2-b]pyrrol-4-ones with Pb(OAc)4 at room temperature.
Introduction. – Substituted phthalides (¼ isobenzofuran-1(3H)-ones) represent an
important class of natural products that possess significant biological properties [1]. In
particular, 3-substituted phthalides are vital heterocyclic motifs in many bioactive
compounds such as isocoumarins, anthraquinones, anthracyclines, and several alkaloids
[2]. Their notable characteristics include antibacterial, anticonvulsant, anti-HIV, anti-
asthmatic, antitumor, antiplatelet activities, anesthesia prolongation, and PGF2a
inhibitory properties [3]. Furthermore, the chemistry of isobenzofurans is of great
importance, because they are 10p electron systems with a quinoid nature, which makes
them attractive as unique building units for oligomeric and polymeric p-conjugated
compounds [4][5].
Results and Discussion. – Recently, we reported a novel and simple method for the
synthesis of spiro[isoindole-1,5’-oxazolidine] 2, as part of our research program on the
oxidative cleavage of 3a,8a-dihydroxyindeno[2,1-d]imidazole-2,8-diones 1 (Scheme 1)
[6].
Scheme 1. Our Previous Study [6] on Synthesis of Spiro[isoindole-1,5’-oxazolidine] 2 via Oxidative
Cleavage of 3a,8a-Dihydroxyindeno[2,1-d]imidazole-2,8-diones 1
In continuation, we focused on the oxidation of some similar cyclic vicinal
dihydroxy compounds, e.g., 3a,8b-dihydroxy-3a,8b-dihydroindeno[1,2-b]pyrrol-4(1H)-
ꢀ 2011 Verlag Helvetica Chimica Acta AG, Zꢁrich

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ones 8 (cf. Scheme 3), which could easily be prepared by the addition reaction of
ninhydrin 5 and enamine esters 7 [7].
When Pb(OAc)4 was added to a mixture of benzylamine 3, prop-2-ynoate 4, and
ninhydrin 5, 2-{[1-(acetyloxy)-1,3-dihydro-3-oxoisobenzofuran-1-yl]carbonyl}-3-(ben-
zylamino)prop-2-enoates 6 were achieved in excellent yields (Scheme 2). Using this
one-pot procedure, the reactions were completed after ca. 7 h as shown by TLC.
However, the same results were obtained when pure 8 were exposed to Pb(OAc)4.
Scheme 2. Synthesis of 2-{[1-(Acetyloxy)-1,3-dihydro-3-oxo-2-benzofuran-1-yl]carbonyl}-3-(benzyl-
amino)prop-2-enoate Derivatives 6a – 6c
The NMR data and elemental analysis confirmed the proposed structures of the
1
products 6a – 6c. The H-NMR spectrum of products 6a – 6c indicated two diaster-
1
eoisomeric (E)- and (Z)-compounds. For example, the H-NMR spectrum of 6a in
CDCl3 exhibited two triplets at 0.94 and 1.20 ppm both with J ¼ 7 Hz, which were
attributed to the Me groups of esters, together with two sharp singlets at 1.72 and
2.14 ppm, which were assigned to the Me groups of acetate moieties. Fig. 1 shows the
temperature-dependence of the 1H-NMR spectrum of 6a, recorded in (D6)DMSO, for
the Et resonance regions. The ester CH2 group of the two diastereoisomers resonated as
four doublets of quartets (two AB systems); two of them at 3.66 and 3.82 ppm, and two
others overlapped at 3.98 ppm. The multiplets at 3.98 ppm were separated into two d ꢀ
1
q by recording the H-NMR spectra in CDCl3; the multiplets at 1.06 and 4.13 ppm
probably arise from a 6aꢁDMSO complex, because it disappeared at elevated
temperatures, as well as by recording the spectrum in CDCl3. A 1H-decoupled
13C-NMR spectrum of 6a showed distinct signal pairs for all aliphatic, spiro and C¼O
C-atoms indicating that the product is a mixture of diastereoisomers. The C¼O groups
of the isobenzofuran ring, esters, and enaminone resonated at 189.0, 168.9, 166.5, and
160.1 ppm, respectively.
However, only single crystals of the (E)-stereoisomer were formed during
crystallization of 6a from CHCl3/hexane, which allowed determination of its structure
unambiguously by an X-ray diffraction analysis1) (Fig. 2). The crystal structure of 6a
1
)
CCDC-770133 contains the supplementary crystallographic data. These data can be obtained free of
charge from the Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.

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Fig. 1. Aliphatic region of dynamic 1H-NMR spectra of compound 6a recorded in (D6)DMSO
also shows a H2O molecule in its structure. This H2O molecule, apparently, has been
removed from the products 6 by drying at around 708, to record the NMR spectra.
Consequently, the recorded 1H-NMR spectra of compounds 6 do not contain the signal
of the H2O of hydration.
1
The H-NMR spectra of the single crystals of (E)-6a was also recorded, which
shows the same signals as its initial uncrystallized compound. This shows that (E)- and
(Z)-diastereoisomers are easily interconverted by dissolving the (E)-stereoisomer in a
solvent.
Mechanistically, it is reasonable to propose that enaminones 7, prepared from
benzylamines 3 and acetylenic ester 4, were added to ninhydrin 5 to form
dihydroxyindeno[1,2-b]pyrrol derivatives 8 [7a]. Subsequently, oxidation of 8 gave
the corresponding benz[c]azocine-1,5,6-triones 9a, which were hydrolyzed to give
benzoic acid derivative 10. Finally, products 6 were formed via intramolecular

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Fig. 2. X-Ray crystal structure of 6a
cyclization of 10 to 3-hydroxyisobenzofuran-1-one derivatives 11, followed by
esterification with AcOH (Scheme 3).
Scheme 3. Proposed Mechanism for the One-Pot Synthesis of Prop-2-enoates 6
Interestingly, when the reaction was run for 3a,8b-dihydroxy-3a,8b-dihydroinde-
no[1,2-b]pyrrol-4(1H)-ones 12, the corresponding 3H-spiro[isobenzofuran-1,2’-pyr-
role]-3,3’(1’H)-diones 13 were obtained in good yields (Scheme 4). The structures of
products 13a and 13b were unambiguously established based on their NMR, IR, and
MS data, as well as CHN analysis. Contrary to compounds 6, in the 1H-NMR spectra of

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Scheme 4. Synthesis of Spiro[isobenzofuran-1,2’-pyrrole] Derivatives 13a and 13b
products 13, no signals for acetate moieties were detected, and diastereotopic CH2 H-
atoms resonated as two distinct doublets, in the case of 13a at 4.28 and 4.35 ppm with
J ¼ 15.4 Hz.
A mechanistic proposal for the formation of spiro[isobenzofuran-1,2’-pyrrole]
derivatives 13 is presented in Scheme 5. It is reasonable to assume that benzo[c]azo-
cine-1,5,6-triones 9b could gave 13 via hydrolysis to benzoic acid derivatives 14, which
underwent cyclization by attack of the amino group on C¼O, followed by intra-
molecular esterification with the carboxylic acid.
Scheme 5. Proposed Mechanism for the Synthesis of Spiro[isobenzofuran-1,2’-pyrrole] Derivatives 13
In summary, we investigated the oxidative cleavage of dihydroxyindeno[1,2-
b]pyrroles 8 and 12 with Pb(OAc)4 in AcOH at room temperature, and developed
novel and effective chemoselective procedures for the synthesis of 2-{[1-(acetyloxy)-
1,3-dihydro-3-oxoisobenzofuran-1-yl]carbonyl}-3-(benzylamino)prop-2-enoate 6 and
spiro[isobenzofuran-1,2’-pyrrole] derivatives 13.
Experimental Part
General. Chemicals were of commercial grade and used without further purification. M.p.:
Electrothermal 9100 apparatus; uncorrected. IR Spectra: Shimadzu IR-470 spectrophotometer. 1H- and
13C-NMR spectra: in CDCl3 on a Bruker 500 DRX AVANCE at 500 and 125 MHz, resp. EI-MS:
Shimadzu QP 1100EX mass spectrometer operating at an ionization potential of 14 eV. Elemental
analyses (CHN): Heraeus CHN-O-Rapid analyzer.
General Procedure for the One-Pot Synthesis of 2-{[1-(Acetyloxy)-1,3-dihydro-3-oxoisobenzofuran-
1-yl]carbonyl}-3-(benzylamino)prop-2-enoate Derivatives 6a – 6c. A mixture of benzylamine 3 (1 mmol),
acetylenic ester 4 (1 mmol), and EtOH (1 ml) was stirred at r.t. for 0.5 h. Then, ninhydrin (5; 1 mmol)

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was added, and the mixture was stirred for 2.5 h. After addition of Pb(OAc)4 (1.1 mmol) and AcOH
(3 ml), stirring was continued for further 4 h, and then H2O was added. The mixture was filtered, and the
products 6a – 6c were purified by recrystallization from EtOH or by column chromatography (CC) with
AcOEt/hexane 1:1.
Ethyl 2-{[1-(Acetyloxy)-1,3-dihydro-3-oxo-2-benzofuran-1-yl]carbonyl}-3-[(4-methoxybenzyl)ami-
no]prop-2-enoate (6a; (E)/(Z) 62 :38). Purified by CC (AcOEt/hexane 1:1). Yield: 0.37 g (82%).
M.p. 115 – 1178. IR (KBr): 3243.7, 1770.5, 1695.4, 1656.2, 1581.4. 1H-NMR (CDCl3): 0.94 (t, J ¼ 7.0,
1.14 H, MeCH2); 1.20 (t, J ¼ 11.9, 1.86 H, MeCH2); 1.72 (s, 1.11 H, MeCO); 2.14 (s, 1.89 H, MeCO); 3.78 –
3.81 (m, 0.71 H, MeCH2); 3.85 (s, MeO); 3.9 – 4.04 (m, 1.29 H, MeCH2); 4.07 – 4.10 (m, 0.71 H, MeCH2);
4.15 – 4.21 (m, 1.29 H, MeCH2); 4.48 – 4.53 (m, NHCH2); 6.93 – 6.95 (m, 2 arom. H); 7.21 – 7.24 (m, 2
arom. H); 7.63 – 8.04 (m, 4 arom. H); 9.30 – 9.33 (m, 0.35 H, NH); 10.12 (m, 0.65 H, NH). 13C-NMR
(125 MHz, CDCl3): 14.4; 14.7; 21.2; 21.3; 53.7; 55.8; 60.3; 60.8; 98.9; 100.0; 114.9; 123.9; 124.5; 125.8;
125.9; 127.0; 127.7; 128.0; 128.5; 129.3; 129.4; 131.3; 131.4; 134.5; 135.0; 145.1; 145.4; 160.0; 160.1; 160.2;
166.6; 168.9; 169.2; 189.0; 189.5. Anal. calc. for C24H23NO8 (453.44): C 63.57, H 5.11, N 3.09; found: C
63.49, H 5.04, N 3.17.
Ethyl 2-{[1-(Acetyloxy)-1,3-dihydro-3-oxo-2-benzofuran-1-yl]carbonyl}-3-(benzylamino)prop-2-
enoate (6b; (E)/(Z) 57:43). Recrystallized from EtOH. Yield: 0.38 g (92%). M.p. 125 – 1268. IR
1
(KBr): 3048.2, 3050.1, 1751.0, 1749.1, 1695.1, 1639.2, 1592.9. H-NMR (CDCl3): 0.95 (t, J ¼ 7.1, 1.29 H,
MeCH2); 1.20 (t, J ¼ 7.1, 1.71 H, MeCH2); 2.14 (s, MeCO); 3.78 – 3.83 (m, 0.86 H, MeCH2); 3.89 – 4.02 (m,
1.14 H, MeCH2); 4.11 – 4.15 (m, 0.86 H, MeCH2); 4.15 – 4.21 (m, 1.14 H, MeCH2); 4.54 – 4.61 (m,
NHCH2); 7.29 – 7.43 (m, 4 arom. H); 7.65 – 7.80 (m, 3 arom. H); 7.96 – 7.99 (m, 2 arom. H); 9.35 – 9.39 (m,
0.37 H, NH); 10.13 – 10.20 (m, 0.63 H, NH). 13C-NMR (CDCl3): 14.4; 14.7; 21.2; 21.3; 54.2; 60.3; 60.8;
99.1; 100.3; 123.9; 124.5; 125.8; 125.9; 127.0; 127.7; 127.8; 127.9; 128.7; 128.8; 129.4; 129.5; 131.4; 131.5;
134.5; 135.0; 136.2; 136.5; 145.1; 145.2; 160.2; 160.4; 166.5; 167.7; 168.9; 169.2; 189.3; 189.5. Anal. calc. for
C23H21NO7 (423.42): C 65.24, H 5.00, N 3.31; found: C 65.14, H 5.00, N 3.39.
Methyl 2-{[1-(Acetyloxy)-1,3-dihydro-3-oxo-2-benzofuran-1-yl]carbonyl}-3-(benzylamino)prop-2-
enoate (6c; (E)/(Z) 56 :44). Purified by CC (AcOEt/hexane). Yield: 0.37 g (90%). M.p. 135 – 1378. IR
(KBr): 3309.2, 3286.1, 1766.5, 1760.7, 1683.3, 1600.6, 1592.9. 1H-NMR (CDCl3): 2.13 (s, OCOMe); 3.4 (s,
1.32 H, MeO); 3.6 (s, 1.68 H, MeO); 4.57 – 4.63 (m, CH2); 7.29 – 7.30 (m, 2 arom. H); 7.34 – 7.43 (m, 3
arom. H); 7.60 – 7.81 (m, 3 arom. H); 7.96 – 8.06 (m, 1 arom. H); 9.38 – 9.43 (m, 0.45 H, NH); 10.11 – 10.19
(m, 0.55 H, NH). 13C-NMR (CDCl3): 21.2; 21.3; 41.3; 51.3; 52.0; 54.2; 98.8; 99.8; 123.8; 124.5; 125.6;
125.8; 127.0; 127.7; 127.8; 127.9; 128.7; 128.8; 129.5; 129.6; 131.4; 131.5; 134.6; 135.0; 136.1; 136.4; 145.0;
145.2; 160.5; 160.7; 166.9; 168.3; 168.9; 169.2; 189.2; 189.8. Anal. calc. for C22H19NO7 (409.39): C 64.54, H
4.68, N 3.42; found: C 64.62, H 4.61, N 3.32.
General Procedure for the One-Pot Preparation of 3H-Spiro[2-benzofuran-1,2’-pyrrole] Derivatives
13a and 13b. A mixture of indeno[1,2-b]pyrrole-2,3-diol 12 (1 mmol) and Pb(OAc)4 (1.1 mmol) in AcOH
(3 ml) was stirred at r.t. for 4 h. Then, H2O was added, and the precipitated products 13 were separated
from the mixture by filtration and further purified by recrystallization from EtOH.
Dimethyl 1’-Benzyl-1’,3’-dihydro-3,3’-dioxo-3H-spiro[2-benzofuran-1,2’-pyrrole]-4’,5’-dicarboxylate
1
(13a). Yield: 0.32 g (80%). M.p. 190 – 1918. IR (KBr): 1787.7, 1737.5, 1689.3, 1548.6, 1540.8. H-NMR
(CDCl3): 3.77 (s, MeO); 3.86 (s, MeO); 4.28 (d, J ¼ 15.4, 1 H of CH2); 4.35 (d, J ¼ 15.4, 1 H of CH2);
7.01 – 7.03 (m, 2 arom. H); 7.15 – 7.21 (m, 4 arom. H.); 7.55 – 7.57 (m, 2 arom. H); 7.87 – 7.88 (m, 1 arom.
H). 13C-NMR (CDCl3): 49.4; 52.2; 54.3; 94.8; 101.4; 122.7; 126.7; 127.0; 129.0; 129.1; 129.2; 131.9; 133.5;
135.5; 141.9; 161.4; 162.5; 167.4; 173.4; 187.5. Anal. calc. for C22H17NO7 (407.37): C 64.86, H 4.21, N 3.44;
found: C 64.77, H 4.31, N 3.40.
4’-Benzoyl-1’-benzyl-5’-phenyl-3H-spiro[2-benzofuran-1,2’-pyrrole]-3,3’(1’H)-dione (13b). Yield:
1
0.39 g (84%). M.p. 207 – 2088. IR (KBr): 1788.5, 1690.8, 1655.2, 1590.6, 1553.4. H-NMR (CDCl3): 4.37
(d, J ¼ 15.6, 1 H of CH2); 4.42 (d, J ¼ 15.6, 1 H of CH2); 6.85 (d, J ¼ 7.1, 2 arom. H); 7.06 – 7.12 (m, 3
arom. H); 7.33 – 7.36 (m, 3 arom. H); 7.44 – 7.60 (m, 8 arom. H); 7.74 (dd, J ¼ 7.7, 0.9, 2 arom. H); 7.84 (d,
J ¼ 7.6, 1 arom. H). 13C-NMR (CDCl3): 48.6; 95.1; 111.8; 122.5; 126.6; 127.2; 128.0; 128.3; 128.4; 128.5;
129.0; 129.4; 129.7; 129.9; 131.6; 131.7; 133.0; 134.7; 135.3; 138.5; 143.1; 167.8; 185.0; 188.9; 189.0. Anal.
calc. for C31H21NO4 (471.50): C 78.97, H 4.49, N 2.97; found: C 78.90, H 4.41, N 3.06.

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The authors thank the Research Council of the Persian Gulf University of Bushehr for financial
support for this work. We would like also to thank Dr. M. Helliwell at the University of Manchester, UK,
for X-ray data.
REFERENCES
[1] S. M. Landge, M. Berryman, B. Tçrçk, Tetrahedron Lett. 2008, 49, 4505; R. Pedrosa, S. Sayalero, M.
Vicente, Tetrahedron 2006, 62, 10400; X. Z. Zhu, X.-Y. Li, J. Liu, Eur. J. Pharmacol. 2004, 500, 221;
G. Lin, S. S.-K. Chan, H.-S. Chung, S.-L. Li, ꢂChemistry and Biological Action of Naturally
Occurring Phthalidesꢃ, in ꢂStudies in Natural Products Chemistryꢃ, Ed. Atta-ur-Rahman, Elsevier,
Amsterdam, 2005, Vol. 32, p. 611.
[2] N. S. Narasimhan, R. S. Mali, Synthesis 1975, 796; J. E. Baldwin, K. W. Bair, Tetrahedron Lett. 1978,
19, 2559; K. S. Kim, M. W. Spatz, F. Johnson, Tetrahedron Lett. 1979, 20, 331; P. Pahari, B. Senapati,
D. Mal, Tetrahedron Lett. 2004, 45, 5109; D. Mal, P. Pahari, S. R. De, Tetrahedron 2007, 63, 11781.
[3] J. Safari, H. Naeimi, A. A. Khakpour, R. S. Jondani, S. D. Khalili, J. Mol. Catal. A: Chem. 2007, 270,
236; S. F. Brady, M. M. Wagenaar, M. P. Sing, J. E. Janso, J. Clardy, Org. Lett. 2000, 2, 4043; K.
Yoganathan, C. Rossant, S. Ng, Y. Huang, M. S. Butler, A. D. Buss, J. Nat. Prod. 2003, 66, 1116; P. V.
Ramachandran, G.-M. Chen, H. C. Brown, Tetrahedron Lett. 1996, 37, 2205; H. Yang, G.-Y. Hu, J.
Chen, Y. Wang, Z.-H. Wang, Bioorg. Med. Chem. Lett. 2007, 17, 5210; S. Mor, S. N. Dhawan, M.
Kapoor, D. Kumar, Tetrahedron 2007, 63, 594; E. W. Bousquet, M. D. Moran, J. Harmon, A. L.
Johnson, J. C. Summers, J. Org. Chem. 1975, 40, 2208.
[4] A. O. Patil, A. J. Heeger, F. Wudl, Chem. Rev. 1988, 88, 183; J. Roncali, Chem. Rev. 1997, 97, 173.
[5] H. Zhang, A. Wakamiya, S.Yamaguchi, Org. Lett. 2008, 10, 3591, and refs. cit. therein.
[6] M. R. Mohammadizadeh, N. Firoozi, Tetrahedron Lett. 2010, 51, 2467.
[7] a) J. Azizian, F. Hatamjafari, A. R. Karimi, M. Shaabanzadeh, Synthesis 2006, 765; b) A. Ziyaei-
Halimehjani, M. R. Saidi, Tetrahedron Lett. 2008, 49, 1244.
Received June 26, 2010