Triphenylphosphine-promoted synthesis of spiroketals from phthalic anhydride with dialkyl acetylenedicarboxylates

Article abstract of DOI:10.1080/00397910903267913

Triphenylphosphine, dialkyl acetylenedicarboxylates, and phthalic anhydride react in one pot to afford novel spirocyclic compounds in fairly good yields at room temperature. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910903267913

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Triphenylphosphine-Promoted Synthesis
of Spiroketals from Phthalic Anhydride
with Dialkyl Acetylenedicarboxylates
Mohammad Bayat a , Hossein Imanieh a & Mohammad H. Farjam a
a Department of Chemistry , Imam Khomeini International
University , Qazvin, Iran
Published online: 26 Jul 2010.
To cite this article: Mohammad Bayat , Hossein Imanieh & Mohammad H. Farjam (2010)
Triphenylphosphine-Promoted Synthesis of Spiroketals from Phthalic Anhydride with Dialkyl
Acetylenedicarboxylates, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 40:16, 2475-2482, DOI: 10.1080/00397910903267913
To link to this article: http://dx.doi.org/10.1080/00397910903267913
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Synthetic Communications1, 40: 2475–2482, 2010
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910903267913
TRIPHENYLPHOSPHINE-PROMOTED SYNTHESIS OF
SPIROKETALS FROM PHTHALIC ANHYDRIDE WITH
DIALKYL ACETYLENEDICARBOXYLATES
Mohammad Bayat, Hossein Imanieh, and
Mohammad H. Farjam
Department of Chemistry, Imam Khomeini International University, Qazvin,
Iran
Triphenylphosphine, dialkyl acetylenedicarboxylates, and phthalic anhydride react in one
pot to afford novel spirocyclic compounds in fairly good yields at room temperature.
Keywords: Acetylenic ester; phthalic anhydride; spiroketal; triphenylphosphine
INTRODUCTION
Spiroketals and spirolactones are frequently occurring motifs in biologically
active molecules.[1] The lactone moiety is also present in many natural products,
especially insect pheromones, polyether antibiotics, antifungal substances, and flavor
components that occur in the essential oils of plants.[1,2] The unique structural nature
of these spirocyclic compounds has attracted the interest of many synthetic organic
chemists.[3] Recent studies demonstrate that promising pharmacological effects (such
as phosphatase inhibition, modulation of tubulin cytoskeleton of breast cancer cells,
and cytotoxity against tumor cell lines) can be achieved through construction and
screening of simple spiroketals.[4,5]
There is much interest in the development of synthetic methodologies that will
enable rapid and efficient access to spiroketal skeletons under the mildest possible
reaction conditions. The latter is important in view of the complexity of the function-
alities that may be present on the spiroketal moiety. Not surprisingly, a number of
synthetic routes to spiroketals have been reported. Most of these routes utilize
dihydroxyketones or equivalents as intermediates.[6]
The limitations of these methods are that often multistep syntheses are
involved and that purification of the mixtures can be rather complex.
Yavari and coworkers recently developed an intramolecular cyclization
method to synthesize oxygen or nitrogen heterocycles.[7] We report here a rapid
and versatile route to the construction of the new spiroketal compounds via
intramolecular cyclization.
Received July 6, 2009.
Address correspondence to Mohammad Bayat, Department of Chemistry, Imam Khomeini
International University, Qazvin, Iran. E-mail: bayat_mo@yahoo.com
2475

2476
M. BAYAT, H. IMANIEH, AND M. H. FARJAM
RESULTS AND DISCUSSION
The reaction of Ph3P and dialkyl acetylenedicarboxylates 2 in the presence of
phthalic anhydride derivatives 3 proceeded smoothly in ethyl acetate at ambient
temperature and completed after 24 h to produce spiroketals 4 and 5 in about a
4:1 ratio (Scheme 1).
The structures of compounds 4a–g and 5a–e were deduced from their elemental
1
analyses and infrared (IR), H CNMR, and 13C NMR spectra. The mass spectra
(MS) of compounds 4a–g and 5a–e displayed molecular ion peaks at appropriate
m=z values. Initial fragmentations involved partial or complete loss of the side chains
and scission of spiroketal system.
1
The H NMR spectrum of 4a exhibited two singlets readily recognized as
arising from the methoxy group at d ¼ 3.76 ppm and the olefinic proton at
d ¼ 7.06 ppm. The 13C NMR spectrum of 4a showed 13 distinct resonances, in agree-
ment with the 3-methoxycarbonyl-spiro[furan-2(5H), 10(3H)-isobenzofuran]-30,5-
dione structure. The olefinic carbons resonances in the 13C NMR spectrum of 4a
appear at d ¼ 129.6 and 150.9 ppm, and the characteristic signal of the spiro carbon
appears at d ¼ 106.5 ppm. The IR spectrum of 4a showed absorption at 3090 cmꢀ1
due to the olefinic proton as a weak band. The structures of compounds 4 and 5 were
apparent from their mass spectra, which displayed in each case the molecular ion
1
peak at appropriate m=z values. The H and 13C NMR spectra of 4b–g are similar
to those of 4a, except for the signals of alkyl and ester moieties; the results are given
in the experimental section.
1
The H NMR spectrum of 5a exhibited two singlets for methoxy protons at
d ¼ 3.58 and d ¼ 4.35 ppm along with resonances at d ¼ 7.50–8.25 ppm for the aro-
matic protons. The 13C NMR spectrum of 5a showed 14 distinct resonances, in
agreement with the proposed structure. The characteristic signal due to the spiro car-
bon was discernible at d ¼ 111.5 ppm, and two signals appeared at d ¼ 126.3 and
149.7 ppm for two olefinic atoms. The spectral data of 5b, 5c, 5d, and 5e were in
agreement with the proposed structures.
Scheme 1. Synthesis of compounds 4 and 5.

TRIPHENYLPHOSPHINE-PROMOTED SYNTHESIS OF SPIROKETALS
2477
Scheme 2. Proposed mechanism for the formation of compounds 5.
A mechanistic rationalization for the reaction is provided in Scheme 2. It is
conceivable that the reaction involves the initial formation of a 1,3-dipolar inter-
mediate 6 between Ph3P and the acetylenic compound,[8–10] which reacts with the
carbonyl group of phthalic anhydride to produce 7. Cyclization of this zwitterionic
intermediate leads to the spiro intermediate 8. The intermediate 8 is then attacked by
the alkoxy anion, and subsequent loss of Ph3P leads to compound 5. The formation
of the minor product 5 is dependent on the rate of substitution, which is negligible
for bulky alkoxides such as tert-butoxide.
Another pathway may be envisaged, involving intermediate 8, followed by
attack of water on the positively charged phosphorus ion to form intermediate 9,
which is converted to the product 4 by a proton transfer and loss of Ph3PO (see
Scheme 3).
In conclusion, the three-component reaction of dialkyl acetylenedicarboxylates
with phthalic anhydride derivatives in the presence of Ph3P led to spiroketals of
Scheme 3. Proposed mechanism for the formation of compounds 4.

2478
M. BAYAT, H. IMANIEH, AND M. H. FARJAM
potential synthetic interest. The present procedure has the advantage that it is
performed under neutral conditions, and the starting material can be used without
any activation or modification.
EXPERIMENTAL
General
Dialkyl acetylenedicarboxylates, triphenylphosphine, and other reagents and
solvents used in this work were obtained from Fluka (Buchs, Switzerland) and were
used without further purification. NMR spectra were recorded with a Bruker
DRX-300 Avance instrument (299.9 MHz for 1H and 75.4 MHz. for 13C) with
CDCl3 as solvent. Chemical shifts are given in parts per million (d) relative to inter-
nal tetramethylsilane (TMS), and coupling constant (J) are reported in hertz (Hz).
Melting points were measured with an electrotherma1 9100 apparatus. Elemental
analyses for C, H, and N were performed using a Heraeus CHN-O-Rapid analyzer.
These results agreed favorably with the calculated values. Mass spectra were
recorded with a Shimadzu QP-GC Mass 1100-EX spectrometer operating at an
ionization potential of 70 eV. IR spectra were measured with Bruker Tensor
27 spectrometer.
Typical Procedure for the Preparation of Compounds 4a–g and 5a–e
Triphenylphosphine (0.262 g, 1 mmol) in 2 mL ethyl acetate was added to a
stirred solution of 0.148 g phthalic anhydride (1 mmol) and 0.142 g dimethyl acety-
lendicarboxylate (1 mmol) in 10 mL ethyl acetate at room temperature over 10 min
via a syringe. The reaction mixture was stirred at room temperature for 24 h. The
solvent was removed under reduced pressure, and the residue was separated by
silica-gel column chromatography (Merck silica gel 60, 70–230 mesh) using
n-hexane-ethyl acetate (8:2) as an eluent. The solvent was removed under reduced
pressure to afford the products.
Data
3-Methoxycarbonyl-spiro[furan-2(5H), 1’(3H)-isobenzofuran]-3’,5-dione
(4a). Colorless crystals (0.21 g, 80%), mp 220–222 ꢁC. IR (KBr) (nmax=cmꢀ1):
1
3090, 1789, 1716 and 1289. H NMR (CDCl3): d ¼ 3.76 (3H, s, OCH3), 7.06 (1H,
3
3
s, ¼CH), 7.43 (1H, d, JHH ¼ 7.5 Hz, CH), 7.75 (1H, t, JHH ¼ 7.4 Hz, CH), 7.81
(1H, t, JHH ¼ 7.5 Hz, CH), 8.05 (1H, d, JHH ¼ 7.4 Hz, CH). 13C NMR (CDCl3):
3
3
d ¼ 53.2 (OCH3), 106.5 (CSpiro), 121.9, 126.3, 126.7, 132.4, 135.3, 142.1 (aromatic
=
carbons), 129.6 (C¼CH), 150.9 (C¼CH), 159.2, 165.9 and 166.2 (3C O). MS (EI,
70 eV): m=z (%) ¼ 261 (M þ 1, 22), 230 (6), 202 (18), 185 (100), 157 (64), 149 (40),
104 (28), 53 (63). Anal. calcd. for C13H8O6 (260.20): C, 60.01; H, 3.01%. Found:
C, 60.0; H, 3.1%.
3-Methoxycarbonyl-4-methoxy-spiro[furan-2(5H),1’(3H)-isobenzofuran]-
3’,5-dione (5a). Pale yellow powder (0.06 g, 20%), mp 186–188 ꢁC. IR (KBr)
(nmax=cmꢀ1): 1780, 1734, 1711 and 1279. 1H NMR (CDCl3): d ¼ 3.60 and 4.35

TRIPHENYLPHOSPHINE-PROMOTED SYNTHESIS OF SPIROKETALS
2479
(6H, 2 s, 2OCH3), 7.50 (1H, d, 3JHH ¼ 7.6 Hz, CH), 7.80 (1H, t, 3JHH ¼ 7.5 Hz, CH),
3
3
7.82 (1H, t, JHH ¼ 7.6 Hz, CH), 8.25 (1H, d, JHH ¼ 7.5 Hz, CH). 13C NMR
=
(CDCl3): d ¼ 52.7 and 60.3 (2OCH3), 111.5 (CSpiro), 126.3 and 149.7 (C C), 121.3,
124.9, 128.7, 131.3, 134.5 and 145.9 (aromatic carbons), 159.3, 165.7 and 166.4
=
(3C O). MS (EI, 70 eV): m=z (%) ¼ (M þ 1, 3), 259 (85), 228 (40) 142 (20), 104
(100), 31 (45). Anal. calcd. for C14H10O7 (290.22): C, 57.94; H, 3.47%. Found: C,
58.0; H, 3.5.
3-Methoxycarbonyl-4,5,6,7-tetrachloro-spiro[furan-2(5H),1’(3H)-isoben-
zofuran]-3’,5-dione (4b). White powder (0.31 g, 80%), mp 180–182 ꢁC. IR (KBr)
(nmax=cmꢀ1): 3094, 1786, 1720 and 1291. 1H NMR (CDCl3): d ¼ 3.83 (3H, s,
OCH3), 7.10 (1H, s, ¼CH). 13C NMR (CDCl3): d ¼ 53.6 (OCH3), 104.4 (CSpiro),
123.9, 127.6, 132.1, 138.6, 138.9, 140.7 (aromatic carbons), 130.7 (C¼CH), 149.2
þ
=
(C¼CH), 159.2, 160.6 and 165.4 (3C O). MS (EI, 70 eV): m=z (%) ¼ (M , 12),
(M þ 2, 16), 340 (15), 323 (100), 295 (52), 287 (25), 242 (40). Anal. calcd. for
C13H4Cl4O6 (397.98): C, 39.23; H, 1.01%. Found: C, 39.2; H, 1.0%.
3-Methoxycarbonyl-4-methoxy-4,5,6,7-tetrachloro-spiro[furan-2(5H),
1’(3H)-isobenzofuran]-3’,5-dione (5b). Yellow paste (0.08 g, 20%), IR (KBr)
(nmax=cmꢀ1): 1775, 1731, 1710 and 1280. 1H NMR (CDCl3): d ¼ 3.71 and 4.44
(6H, 2 s, 2OCH3). 13C NMR (CDCl3): d ¼ 53.4 and 64.1 (2OCH3), 111.2 (CSpiro),
=
126.6 and 149.6 (C C), 121.5, 125.2, 128.9, 131.4, 134.6 and 146.1 (aromatic
=
carbons), 159.7, 165.2 and 165.4 (3C O). MS (EI, 70 eV): m=z (%) ¼ (M þ 2, 4),
397 (62), 366 (35) 280 (28), 287 (78), 242 (65), 169 (100). Anal. calcd. for C14H6Cl4O7
(428.00): C, 39.29; H, 1.41%. Found: C, 39.3; H, 1.4%.
3-Ethoxycarbonyl-spiro[furan-2(5H),1’(3H)-isobenzofuran]-3’,5-dione
(4c). Colorless crystals (0.22 g, 80%), mp 181–183 ꢁC. IR (KBr) (nmax=cmꢀ1): 3096,
1789, 1716, 1649 and 1288. 1H NMR (CDCl3): d ¼ 1.12 (3H, t, 3JHH ¼ 7.1 Hz, CH3),
3
3
4.16 (2H, q, JHH ¼ 7.1 Hz, OCH2), 7.08 (1H, s, ¼CH), 7.44 (1H, d, JHH ¼ 7.5 Hz,
3
3
CH), 7.76 (1H, t, JHH ¼ 7.5 Hz, CH), 7.81 (1H, t, JHH ¼ 7.5 Hz, CH), 8.04 (1H, d,
3JHH ¼ 7.5 Hz, CH). 13C NMR (CDCl3): d ¼ 13.6 (CH3), 62.6 (OCH2), 106.6 (CSpiro),
122.1, 126.2, 126.9, 132.0, 135.2, 142.3 (aromatic carbons), 129.5 (C¼CH),151.6
=
(C¼CH), 158.7, 166.1 and 166.3 (3C O). MS (EI, 70 eV): m=z (%) ¼ 275 (M þ 1,
26), 230 (10), 202 (15), 186 (67), 158 (45), 133 (10), 121 (14), 104 (32) 76 (40), 53
(100), 50 (35). Anal. calcd. for C14H10O6 (274.23): C, 61.32; H, 3.68%. Found: C,
61.3; H, 3.7%.
3-Ethoxycarbonyl-4-ethoxy-spiro[furan-2(5H),1’(3H)-isobenzofuran]-3’,
5-dione (5c). Brown paste (0.06 g, 20%). IR (KBr) (nmax=cmꢀ1): 1785, 1735, 1645
1
3
and 1284. H NMR (CDCl3): d ¼ 1.21 (3H, t, JHH ¼ 7.2 Hz, CH3), 1.39 (3H, t,
3JHH ¼ 7.2 Hz, CH3), 3.65 (2H, q, 3JHH ¼ 7. 2 Hz, OCH2), 4.12 (2H, q, 3JHH ¼ 7.2 Hz,
3
3
Hz, OCH2), 7.45 (1H, d, JHH ¼ 7.5 Hz, CH), 7.75 (1H, t, JHH ¼ 7.5 Hz, CH), 7.80
(1H, t, JHH ¼ 7.5 Hz, CH), 8.04 (1H, d, JHH ¼ 7.5 Hz, CH). 13C NMR (CDCl3):
d ¼ 13.0 and 13.9 (2CH3), 62.0 and 69.6 (2OCH2), 111.8 (CSpiro), 121.4, 125.6,
128.8, 131.9, 134.6, 145.9 (aromatic carbons), 124.5 (C¼CH), 150.9 (C¼CH),
3
3
=
158.9, 166.1 and 166.3 (3C O). MS (EI, 70 eV): m=z (%) ¼ 320 (M þ 2, 18), 273
(90), 228 (65), 149 (45), 104 (35), 45 (100). Anal. calcd. for C16H14O7 (318.07): C,
60.38; H, 4.43%. Found: C, 60.4; H, 4.4%.

2480
M. BAYAT, H. IMANIEH, AND M. H. FARJAM
3-Ethoxycarbonyl-4,5,6,7-tetrachloro-spiro[furan-2(5H),1’(3H)-isoben-
zofuran]-3’,5-dione (4d). White powder (0.33 g, 80%), mp 203–205 ꢁC. IR (KBr)
(nmax=cmꢀ1): 3098, 1785, 1722 and 1289. 1H NMR (CDCl3): d ¼ 1.27 (3H, t, 3JHH
¼
3
7.2 Hz, CH3), 4.23 (2H, q, JHH ¼ 7.2 Hz, OCH2), 7.11 (1H, s, ¼CH). 13C NMR
(CDCl3): d ¼ 13.9 (CH3), 63.2 (OCH2), 105.2 (CSpiro), 122.4, 128.8, 130.9, 138.7,
138.9, 140.9 (aromatic carbons), 130.6 (C¼CH), 149.5 (C¼CH), 160.1, 161.1 and
=
163.6 (3C O). MS (EI, 70 eV): m=z (%) ¼ 414 (M þ 2, 25), 368 (20), 340 (25), 324
(70), 296 (45), 242 (35), 53 (100). Anal. calcd. for C14H6Cl4O6 (412.00): C, 40.81;
H, 1.47%. Found: C, 40.8; H, 1.5%.
3-Ethoxycarbonyl-4-ethoxy-4,5,6,7-tetrachloro-spiro[furan-2(5H),1’(3H)-
isobenzofuran]-3’,5-dione (5d). Yellow paste (0.09 g, 20%), IR (KBr) (nmax
=
1
cmꢀ1): 1778, 1732, 1709 and 1278. H NMR (CDCl3): d ¼ 1.27 and 1.40 (6H, 2 t,
3JHH ¼ 7.2 Hz, 2CH3), 3.73 (2H, q, JHH ¼ 7.2 Hz, OCH2), 4.39 (2H, q,
3
3JHH ¼ 7.2 Hz, OCH2). 13C NMR (CDCl3): d ¼ 13.5 and 14.2 (2CH3), 64.1 and
=
71.7 (2OCH2), 111.3 (CSpiro), 126.6 and 149.6 (C C), 121.5, 125.1, 128.9, 131.4,
=
134.6 and 146.1 (aromatic carbons), 160.1, 162.2 and 164.0 (3C O). MS (EI,
70 eV): m=z (%) ¼ (M þ 1, 10), 411 (70), 314 (45), 366 (55), 142 (25), 45 (100). Anal.
calcd. for C16H10Cl4O7 (456.06): C, 42.14; H, 2.21%. Found: C, 42.1; H, 2.2%.
3-Methoxycarbonyl-4,5,6,7-tetrabromo-spiro[furan-2(5H),1’(3H)-isoben-
zofuran]-3’,5-dione (4e). Pale yellow solid (0.51 g, 90%), mp 214–216 ꢁC. IR (KBr)
(nmax=cmꢀ1): 3099, 1785, 1721 and 1290. 1H NMR (CDCl3): d ¼ 3.81 (3H, s, OCH3),
7.11 (1H, s, ¼CH). 13C NMR (CDCl3): d ¼ 53.4 (OCH3), 107.7 (CSpiro), 124.1, 126.7,
131.2, 137.2, 139.2, 142.3 (aromatic carbons), 133.4 (C¼CH), 149.2 (C¼CH), 159.3,
=
164.9 and 165.4 (3C O). MS (EI, 70 eV): m=z (%) ¼ 577 (M þ 2, 20), 545 (70), 517
(25), 500 (75), 465 (50), 421 (35), 31 (100). Anal. calcd. for C13H4Br4O6 (575.78):
C, 27.12; H, 0.70%. Found: C, 27.1; H, 0.8%.
3-Methoxycarbonyl-4-methoxy-4,5,6,7-tetrabromo-spiro[furan-2(5H),1’
(3H)-isobenzofuran]-3’,5-dione (5e). Yellow oil (0.06 g, 10%), IR (KBr) (nmax
=
1
cmꢀ1): 1778, 1735, 1715 and 1279. H NMR (CDCl3): d ¼ 3.82 and 4.43 (6H, 2 s,
2OCH3). 13C NMR (CDCl3): d ¼ 52.3 and 63.2 (2OCH3), 112.1 (CSpiro), 124.2 and
=
142.4 (C C), 124.2, 126.9, 132.4, 135.1, 138.5 and 141.2 (aromatic carbons),
=
159.7, 165.1 and 165.4 (3C O). MS (EI, 70 eV): m=z (%) ¼ 607 (M þ 2, 12), 575
(80), 464 (45), 574 (75), 465 (40), 421 (25), 31 (100). Anal. calcd. for C14H6Br4O7
(605.81): C, 27.76; H, 1.00%. Found: C, 27.8; H, 1.1.
3-tert-Butoxycarbonyl-4,5,6,7-tetrachloro-spiro[furan-2(5H),1’(3H)-iso-
benzofuran]-3’,5-dione (4f). Pale yellow powder (0.26 g, 60%), mp 235–237 ꢁC. IR
1
(KBr) (nmax =cmꢀ1): 3092, 1780, 1725 and 1287. H NMR (CDCl3): d ¼ 1.29 (9H, s,
CMe3), 7.06 (1H, s, ¼CH). 13C NMR (CDCl3): d ¼ 29.5 (CMe3), 63.7 (OCMe3),
106.2 (CSpiro), 124.1, 126.7, 131.2, 137.2, 139.2, 142.3 (aromatic carbons), 131.1
=
(C¼CH), 149.9 (C¼CH), 159.3, 161.9 and 164.9 (3C O). MS (EI, 70 eV): m=z
(%) ¼ 441 (M þ 1, 10), 412 (20), 287 (35), 242 (55), 367 (40), 73 (75), 57 (100). Anal.
calcd. for C16H10Cl4O6 (440.06): C, 34.67; H, 2.29%. Found: C, 34.7; H, 2.3%.

TRIPHENYLPHOSPHINE-PROMOTED SYNTHESIS OF SPIROKETALS
2481
3-tert-Butoxycarbonyl-spiro[furan-2(5H),1’(3H)-isobenzofuran]-3’,5-dione
(4g). Yellow powder (0.19 g, 65%), mp 196–198 ꢁC. IR (KBr) (nmax =cmꢀ1): 3100,
1784, 1715 and 1292. 1H NMR (CDCl3): d ¼ 1.39 (9H, s, CMe3), 7.07 (1H, s,
3
3
¼CH), 7.45 (1H, d, JHH ¼ 7.5 Hz, CH), 7.76 (1H, t, JHH ¼ 7.4 Hz, CH), 7.79
(1H, t, JHH ¼ 7.5 Hz, CH), 8.10 (1H, d, JHH ¼ 7.4 Hz, CH). 13C NMR (CDCl3):
d ¼ 29.6 (CMe3), 83.7 (CMe3), 105.7 (CSpiro), 123.4, 126.4, 126.5, 131.9, 135.1,
142.2 (aromatic carbons), 130.6 (C¼CH), 151.4 (C¼CH), 159.3, 166.4 and 168.1
3
3
=
(3C O). MS (EI, 70 eV): m=z (%) ¼ 261 (M þ 1, 22), 230 (6), 202 (18), 185 (100),
157 (64), 149 (10), 104 (28), 53 (63). Anal. calcd. for C16H14O6 (302.28): C, 63.57;
H, 4.67%. Found: C, 63.6; H, 4.7%.
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