Palladium-Catalyzed Heteroannulation Leading to Heterocyclic Structures with Two Heteroatoms: A Highly Convenient and Facile Method for a Totally Regio- and Stereoselective Synthesis of (Z)-2,3-Dihydro-2-(ylidene)-1,4-benzo- and -naphtho [2,3-b]dioxins

Article abstract of DOI:10.1021/jo9717595

A facile method for the synthesis of (Z)-2,3-dihydro-2-(ylidene)-1,4-benzo- and naphthodioxins (3) has been developed using palladium-copper catalysis. Aryl halides 2 were found to react with mono-prop-2-ynylated catechol (la) or 2-hydroxy-3-(prop-2-ynyloxy)naphthalene (Ib) in the presence of (PPh₃)₂PdCl₂ (3.5 mol %) and CuI (7 mol %) in triethylamine by stirring at room temperature for 20 h followed by heating at 100°C for 16 h to give products 3 in good yields. The method is regioand stereoselective and also amenable to bisheteroannulation. The Z-stereochemistry of products 3 was established firmly from ¹H NMR, ³J_CH values (between vinylic proton and methylenic carbon of the heterocyclic ring), proton NOE measurements, and finally from X-ray analysis. Based on experimental observations and known palladium chemistry, a mechanism has been proposed to explain the regio- and stereoselective product formation. Some of the products 3 were also converted , to 1,4-benzodioxan derivatives 6 using hydrogenation procedure. A uracil derivative of possible biological interest, possessing a 1,4-benzodioxinyl functionality at the C-5 position, has been synthesized.

Full text of DOI:10.1021/jo9717595

J . Org. Chem. 1998, 63, 1863-1871
1863
P a lla d iu m -Ca ta lyzed Heter oa n n u la tion Lea d in g to Heter ocyclic
Str u ctu r es w ith Tw o Heter oa tom s: A High ly Con ven ien t a n d
F a cile Meth od for a Tota lly Regio- a n d Ster eoselective Syn th esis
of (Z)-2,3-Dih yd r o-2-(ylid en e)-1,4-ben zo- a n d
-n a p h th o[2,3-b]d ioxin s†
Chinmay Chowdhury,‡ Gopeswar Chaudhuri,‡ Subhadra Guha,§ Alok k. Mukherjee,§ and
Nitya G. Kundu*,‡
Department of Organic Chemistry, Indian Association for the Cultivation of Science, J adavpur, Calcutta -
700 032, India, and Department of Physics, J adavpur University, J adavpur, Calcutta - 700 032, India
Received September 19, 1997
A facile method for the synthesis of (Z)-2,3-dihydro-2-(ylidene)-1,4-benzo- and naphthodioxins (3)
has been developed using palladium-copper catalysis. Aryl halides 2 were found to react with
mono-prop-2-ynylated catechol (1a ) or 2-hydroxy-3-(prop-2-ynyloxy)naphthalene (1b) in the presence
of (PPh3)2PdCl2 (3.5 mol %) and CuI (7 mol %) in triethylamine by stirring at room temperature for
20 h followed by heating at 100 °C for 16 h to give products 3 in good yields. The method is regio-
and stereoselective and also amenable to bisheteroannulation. The Z-stereochemistry of products
1
3 was established firmly from H NMR, 3J CH values (between vinylic proton and methylenic carbon
of the heterocyclic ring), proton NOE measurements, and finally from X-ray analysis. Based on
experimental observations and known palladium chemistry, a mechanism has been proposed to
explain the regio- and stereoselective product formation. Some of the products 3 were also converted
to 1,4-benzodioxan derivatives 6 using hydrogenation procedure. A uracil derivative of possible
biological interest, possessing a 1,4-benzodioxinyl functionality at the C-5 position, has been
synthesized.
1,4-Benzodioxins and its 2,3-dihydro analogues (1,4-
benzodioxans) are versatile organic compounds endowed
with rich and fascinating chemistry. Various 2-substi-
tuted 1,4-benzodioxans (e.g. piperoxan, pentamoxan,
idazoxan, prosympal, WB-4106 and RX 821002) have
displayed promising roles in antidepression and antihy-
pertension therapy as R-blocking agents or as â-blocking
agents.1 Some of these also exhibit antihyperglycemic
properties.2 Incorporation of 1,4-benzodioxan structural
unit in camptothecin, which has potent antitumor and
antileukemic properties,3 overcame a solubility problem
in the aqueous system and showed a better pharmaco-
logical profile.4 A recent publication5 has explored the
synthesis and biological evaluation (in vitro and in vivo)
of a series of N-hydroxyureas based on 1,4-benzodioxan
template as inhibitors of 5-lipoxygenase, which is in-
volved in the oxygenation of arachidonic acid to leuko-
trienes. Thus, compounds that contain the 1,4-benzo-
dioxan structure could form the basis for development
of drugs for future therapeutic treatment of asthma and
arthritis. Also, the 1,4-benzodioxan nucleus is prevalent
in a variety of important natural products (e.g. Silybin
and Isosilybin,6 Eusederins,7 Purpurenol,8 and others9),
some of which exhibit significant biological activity.
Moreover, in recent years 1,4-benzodioxin and its 2,3-
dihydro analogues attracted considerable interest as
intermediates for several important synthetic transfor-
mations.10
(6) (a) Merlini, L.; Zanarotti, A. J . Chem. Soc., Chem. Commun.
1979, 695. (b) Arnone, A.; Merlini, L.; Zanarotti, A. J . Chem. Soc. Chem.
Commun. 1979, 696.
(7) Merlini, L.; Zanarotti, A. Tetrahedron Lett. 1975, 42, 3621.
(8) Debenedetti, S. L.; Nadinic, E. L.; Coussio, J . D.; Kimpe, N. De.;
Dupont, J . F.; Declercq, J . P. Phytochemistry, 1991, 30, 2757.
(9) Tsukamoto, S.; Kato, H.; Hirota, H.; Fusetani, N. Tetrahedron
1994, 50, 13583. (b) Bosseray, P.; Guillaumet, G.; Coudert, G.;
Wassermann, H. Tetrahedron Lett. 1989, 30, 1387.
(10) (a) Through Grignard reactions: Lee, T. V.; Leigh, A. J .;
Chapleo, C. B. Tetrahedron 1990, 46, 921. (b) Through Diels-Alder
reactions: Lee, T. V.; Leigh, A. J .; Chapleo, C. B. Synlett 1989, 30. (c)
Through Fridel-Crafts reactions: Mata, E. G.; Suarez, A. G. Synth.
Commun. 1997, 27, 1291. (d) Other: Moreau, P.; Guillaumet, G.;
Coudert, G. Synth. Commun. 1994, 24, 1781.
(11) Lee, T. V.; Leigh, A. J .; Chapleo, C. B. Synthesis 1989, 208. (b)
Farina, G.; Zecchi, G. Synthesis 1977, 755. (c) Katrizky, A. R.; Monro,
A. M.; Potter, G. W. H.; Reavill, R. E.; Sewell, M. J . J . Chem. Soc.,
Chem. Commun. 1965, 58. (d) Katritzky, A. R.; Sewell, M. J .; Topsom,
R. D.; Monro, A. M.; Poter, G. W. H. Tetrahedron 1966, 22, 931. (e)
Guillaumet, G.; Coudert, G.; Loubinoux, B. Tetrahedron Lett. 1979,
4379. (f) Ruiz, N.; Pujol, M. D.; Guillaumet, G.; Coudert, G. Tetrahedron
Lett. 1992, 33, 2965. (g) Lee, Ho H.; Denny, W. A. J . Chem. Soc., Perkin
Trans. 1 1990, 1071. (h) Adam, W.; Schmidt, E.; Takayama, K,
Synthesis 1982, 322. (i) Chapleo, C. B.; Davis, J . A.; Myers, P. L.;
Readhead, M. J .; Stillings, M. R.; Welbourn, A. P. J . Heterocycl. Chem.
1984, 21, 77.
† This paper is dedicated to Professor J erome A. Berson.
‡ Indian Association for the Cultivation of Science.
§ J adavpur University.
(1) (a) Quaglia, W.; Pigini, M.; Tayebati, S. K.; Piergentili, A.;
Giannella, M.; Leonardi, A.; Taddei, C.; Melchiorre, C. J . Med. Chem.
1996, 39, 2253. (b) Ruffolo, R. R. J r.; Bondinell, W.; Hieble, J . P. J .
Med. Chem. 1995, 38, 3681. (c) Marciniak, G.; Delgado, A.; Lederc, G.;
Velley, J .; Decker, N.; Schwartz, J . J . Med. Chem. 1989, 32, 1402. (d)
Fourneau, E.; Bovet, D. Arch. Int. Pharmacodyn. Ther. 1933, 46, 178.
(e) Nelson, W. L.; Wennerstrom, J . E.; Dyer, D. C.; Engel, M. J . Med.
Chem. 1977, 20, 880.
(2) Fagan, G. P.; Chapleo, C. P.; Lane, A. C.; Myers, M.; Roach, A.
G.; Roach, C. F. C.; Stillings, M. R.; Welbourn, A. P. J . Med. Chem.
1988, 31, 944.
(3) Wall, M. E.; Wani, M.; Cook, C. E.; Palmer, K. H.; McPhail, A.
T.; Sim, G. A. J . Am. Chem. Soc. 1966, 88, 3888.
(4) Luzzio, M. J .; Besterman, J . M.; Emerson, D. L.; Evans, M. G.;
Lackey, K.; Leitner, P. L.; Mcintyre, G.; Morton, B.; Myers, P. L.; Peel,
M.; Sisco, J . M.; Sternbach, D. D.; Tong, W.-Q.; Truesdala, A.; Uehling,
D. E.; Vuong, A.; Yates, J . J . Med. Chem. 1995, 38, 395.
(5) Satoh, Y.; Powers, C.; Toledo, L. M.; Kowalski, T. J .; Peters, P.
A.; Kimble, E. F. J . Med. Chem. 1995, 38, 68.
S0022-3263(97)01759-3 CCC: $15.00 © 1998 American Chemical Society
Published on Web 02/27/1998

1864 J . Org. Chem., Vol. 63, No. 6, 1998
Chowdhury et al.
While there are many synthetic routes11 toward 1,4-
benzodioxins, only a handful of synthetic methods for the
synthesis of 2,3-dihydro-2-(ylidene)-1,4-benzodioxins are
known in the literature.12 Some of these involve multi-
step procedures under harsh reaction conditions with
attendant poor overall yields, and others lack generality,
which considerably diminish their synthetic utility.
Recently, Heck reactions13 (palladium-catalyzed ary-
lation of olefins) and cross-coupling14 techniques have
emerged as powerful synthetic tools for C-C bond
formation. The general application of palladium-cata-
lyzed reactions has provided new avenues to obtain a
variety of carbocycles15 and heterocycles.16 As a part of
our ongoing research to develop heterocyclic structures
of potential biological importance,17 we reported the
palladium-catalyzed heteroannulation leading to benzo-
furans,18a phthalides,18b quinolines and quinolones18c
(heterocyclic structures with one heteroatom only). In
all these cases, we used an aryl halide which contained
a reactive nucleophilic group in the ortho-position and
alkynes or acetylenic carbinols as starting materials. Our
strategy for the development of heterocyclic ring system
relied on (i) C-C bond formation with terminal alkynes
under palladium--copper catalysis19 and (ii) subsequent
nucleophilic attack on the triple bond. With the purpose
of developing heterocyclic ring structures with two het-
eroatoms, we made a suitable modification of the above
scheme. We felt that replacing the traditional acetylenic
carbinols with mono-prop-2-ynylated catechol or 2-hy-
Sch em e 1
Sch em e 2a
a
Reaction conditions: (i) 3.5 mol % (PPh3)2PdCl2, 7 mol % CuI
in Et3N, stirring at room temperature for 20 h, followed by heating
at 100 °C for 16 h.
droxy-3-(prop-2-ynyloxy)naphthalene and its subsequent
reaction with aryl or alkenyl halides under palladium-
copper catalysis could result in the formation of 2,3-
dihydro-2-(ylidene)-1,4-benzo- or naphthodioxins as shown
in Scheme 1.
By choosing appropriate reaction conditions and cata-
lysts, the above route appeared viable. Herein, we wish
to report20 in full details the results we have obtained so
far toward this goal.
(12) Moreau, P.; Neirabeyeh, M. Al.; Guillaumet, G.; Coudert, G.
Tetrahedron Lett. 1991, 32, 5525. (b) Cabiddu, S.; Floris, C.; Melis, S.;
Sotgiu, F.; Cerioni, G. J . Heterocycl. Chem. 1986, 23, 1815. (c) Ruiz,
N.; Rollin, P. Tetrahedron Lett. 1989, 30, 1637. (d) Rosnati, V.;
Salimbeni, A. Tetrahedron 1986, 42, 4541 and see also ref 11f.
(13) (a) Heck, R. F. Palladium Reagents in Organic Syntheses;
Academic Press: London, 1985. (b) Heck, R. F. Org. React. 1982, 27,
345. (c) Davies, G. D., J r.; Hallberg, A. Chem. Rev. 1989, 89, 1433.
(14) (a) Cassar, L. J . Organomet. Chem. 1975, 93, 253. (b) Dieck,
H. A.; Heck, R. F. J . Organomet. Chem. 1975, 93, 259. (c) Suzuki, A.
Pure Appl. Chem. 1991, 63, 419. (d) Meijere, A. D.; Meyer, F. E. Angew
Chem., Int. Ed. Engl. 1994, 33, 2379. (e) Lipshutz, B. H.; Lindsley, C.
J . Am. Chem. Soc. 1997, 119 4555. (f) Takeda, A.; Ohno, A.; Kadota,
I.; Gevorgyan, V.; Yamamoto, Y. J . Am. Chem. Soc. 1997, 119, 4547.
(g) Stille, J . K.; Groh, B. L. J . Am. Chem. Soc. 1987, 109, 813. (h) Stille,
J . K. Angew. Chem., Int. Ed. Engl. 1986, 25, 508. (i) Negishi, E.-I. Acc.
Chem. Res. 1982, 15, 340. (j) Hoye, T. R.; Chen, M. J . Org. Chem. 1996,
61, 7940.
(15) (a) Dougherty, T. K.; Lau, K. S. Y.; Hedberg, F. L. J . Org. Chem.
1983, 48, 5273. (b) Larock, R. C.; Fried, C. A. J . Am. Chem. Soc. 1990,
112, 5882. (c) Trost, B. M.; Shi, Y. J . Am. Chem. Soc. 1993, 115, 12491.
(d) Balme, G.; Bouyssi, D. Tetrahedron 1994, 50, 403. (e) Besson, L.;
Bazin, J .; Gore, J .; Cazes, B. Tetrahedron Lett. 1994, 35, 2881. (f)
Negishi, E.-i.; Coperet, C.; Ma, S.; Liou, S.-Y.; Liu, F. Chem. Rev. 1996,
96, 365 and other references therein.
(16) (a) Hegedus, L. S. Angew Chem., Int. Ed. Engl. 1988, 27, 1113.
(b) Luo, F.-T.; Schreuder, I.; Wang, R.-T. J . Org. Chem. 1992, 57, 2213.
(c) Liao, H.-Y.; Cheng, C.-H. J . Org. Chem. 1995, 60, 3711. (d) Trost,
B. M.; Mcintosh, M. C. J . Am. Chem. Soc. 1995, 117, 7255. (e) Larock,
R. C.; Yum, E. K. J . Am. Chem. Soc. 1991, 113, 6689. (e) Cavicchioli,
M.; Decortiat, S.; Bouyssi, D.; Gore, J .; Balme, G. Tetrahedron 1996,
52, 11463. (f) Bouyssi, D.; Gore, J .; Balme, G. Tetrahedron Lett. 1992,
33, 2811. (g) Bouyssi, D.; Gore, J .; Balme, G.; Louis, D.; Wallach, J .
Tetrahedron Lett. 1993, 34, 3129.
Resu lts a n d Discu ssion
Mono-prop-2-ynylated catechol (1a ) or 2-hydroxy-3-
(prop-2-ynyloxy)naphthalene (1b) was found to react with
aryl, heteroaryl, or alkenyl halides 2 in the presence of
bis(triphenylphosphine)palladium(II) chloride (3.5 mol %)
and cuprous iodide (7 mol %) in triethylamine by stirring
at room temperature for 20 h followed by heating at 100
°C for 16 h to afford 2,3-dihydro-2-(ylidene)-1,4-benzo- or
naphtho[2,3-b]dioxins (3) in good yields (Scheme 2, Table
1).
Rea ction Con d ition s. A close look at control reac-
tions (entries 4 and 5, Table 2) indicated that in the
absence of CuI or palladium catalysts, no desired 1,4-
benzodioxan derivatives 3i could be obtained. Among
various catalysts used, (PPh3)2PdCl2 was found to be the
most effective. In addition to the palladium catalyst,
CuI21 was needed as an essential cocatalyst. The opti-
mum reaction temperature was found to be 100 °C. On
the other hand, when the reactions were carried out at
lower temperatures, an acyclic product 4i was isolated
in addition to the cyclized product 3i (entries 1 and 2,
Table 2). The reaction mixture was stirred at room
temperature for 20 h before heating.
(17) (a) Kundu, N. G.; Das, B.; Spears, C. P.; Majumder, A.; Kang,
S. I. J . Med. Chem. 1990, 33, 1975. (b) Kundu, N. G.; Dasgupta, S. K.;
Chaudhuri, L. N.; Mahanty, J . S.; Spears, C. P.; Shahinian, A. H. Eur.
J . Med. Chem. 1993, 28, 473. (c) Kundu, N. G.; Das, P. J . Chem. Soc.,
Chem. Commun. 1995, 99. (d) Mahanty, J . S.; Spears, C. P.; Kundu,
N. G. Bioorg. Med. Chem. Lett. 1996, 6, 1497.
(18) (a) Kundu, N. G.; Pal, M.; Mahanty, J . S.; Dasgupta, S. K. J .
Chem. Soc., Chem. Commun. 1992, 41. (b) Kundu, N. G.; Pal, M. J .
Chem. Soc., Chem. Commun. 1993, 86. (c) Kundu, N. G.; Mahanty, J .
S.; Das, P.; Das, B. Tetrahedron Lett. 1993, 34, 1625. (d) Mahanty, J .
S.; De, M.; Das, P.; Kundu, N. G. Tetrahedron 1997, 53, 13397.
(19) (a) Lu, X.; Huang, X.; Ma, S. Tetrahedron Lett. 1993, 34, 5993.
(b) Torii, S.; Xu, L. H.; Okumoto, H. Synlett. 1992, 515 and see also
refs 18.
(20) A part of the results appeared as a preliminary communica-
tion: Chowdhury, C.; Kundu, N. G. J . Chem. Soc., Chem. Commun.
1996, 1067.
(21) The importance of CuI in palladium-catalyzed reaction of
acetylenic compounds was first pointed out by Sonogashira and
co-workers: Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett.
1975, 4467 and see also refs 18.

Palladium-Catalyzed Heteroannulation
J . Org. Chem., Vol. 63, No. 6, 1998 1865
Ta ble 1. Resu lts of th e Rea ction of Mon o-p r op -2-yn yla ted Ca tech ol (1a ) or 2-Hyd r oxy-3-(p r op -2-yn yloxy)n a p h th a len e
(1b) w ith Ha lid es 2 in P r esen ce of P a lla d iu m Ca ta lyst, Cop p er (I) Iod id e a n d Et3Na (Sch em e 2)

1866 J . Org. Chem., Vol. 63, No. 6, 1998
Chowdhury et al.
Ta ble 1 (Con tin u ed )
a
Unless otherwise stated, reactions were carried out at room temperature for 20 h, followed by heating at 100 °C for 16 h using the
following molar ratios: 1a or 1b:2:(PPh3)2PdCl2:CuI ) 1.3:1:0.035:0.07. b Yields refer to chromatographically isolated pure products. c Entry
6 was carried out at 120 °C. Stereoselective (Z)-bis-heteroannulated products were isolated in each case.
d
Ta ble 2. Dep en d en ce of th e Yield of (Z)-2,3-Dih yd r o-2-[(3-ch lor op h en yl)m eth ylid en e]-1,4-ben zod ioxin (3i) on Ca ta lyst,
Tem p er a tu r e, a n d Ba sea
temp
condition
entry
catalyst
cocatalyst
base
product
yield, %b
1
2
3
4
5
6
7
8
9c
(PPh3)2PdCl2
(PPh3)2PdCl2
(PPh3)2PdCl2
(PPh3)2PdCl2
-
CuI
CuI
CuI
-
CuI
CuI
CuI
PPh3
CuI
i
ii
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
-
3i + 4i
69 (3i:4i ) 1:5)
3i + 4i
63 (3i:4i ) 1:3)
iii
iii
iii
iii
iii
iii
iii
3i
3i
3i
3i
3i
3i
3i
58
0
0
51
15
18
0
Pd(PPh3)4
PdCl2
Pd(OAc)2
(PPh3)2PdCl2
a
Reaction Conditions: m-Chloroiodobenzene (1 mmol), mono-prop-2-ynylated catechol (1.3 mmol), palladium complex (0.035 mmol,
except entry 5), CuI (0.07 mmol, except entries 4, 8) in Et3N (except entry 9) was used in each case employing the following conditions.
Con d ition i: Stirred at room temperature (28-30 °C) for 48 h. Con d ition ii: Stirred at room temperature for 20 h followed by heating
b
at 65 °C for 16 h. Con d ition iii: Stirred at room temperature for 20 h followed by heating at 100 °C for 16 h. Yields refer to
chromatographically isolated pure products. c Entry 9 was carried out in dry acetonitrile instead of Et3N.
An immediate heating of the reaction mixture after a
quick addition of the acetylenic component 1a or 1b
usually led to considerable amount of polymeric materials
and hence to significant reduction in yields. Omission
of base yielded no desired 1,4-benzodioxan derivatives 3i.
Among various bases (e.g. diethylamine, triethylamine,
piperidine, pyridine, sodium bicarbonate, sodium acetate,
K2CO3/Bu4NCl), triethylamine was found to be most
effective. The heteroannulation process was also carried
out using different types of solvents viz., benzene, aceto-
nitrile, acetonitrile/water (1:1), DME, DMF, and DMSO,
with Et3N (5 equiv) as base in each case. However,
cleaner products with optimum yields were obtained in
cases where Et3N was used only. Thus Et3N was found
to be the solvent as well as the base of our choice.
Mono-prop-2-ynylated catechol (1a ) required for this
investigation was obtained through selective propargy-
lation of catechol. Treatment of catechol (1 equiv) with
propargyl bromide (1 equiv) in the presence of potassium
carbonate (0.5 equiv) in acetone at 70 °C for 16 h afforded
the desired product in 87% yield. Surprisingly, attempts
to synthesize 2-hydroxy-3-(prop-2-ynyloxy)naphthalene
(1b) under similar condition led to the isolation of the
dipropargylated product of 2,3-dihydroxynaphthalene.
However, changing the base from K2CO3 to NaH under
room temperature afforded a mixture of mono- (1b) and
dipropargylated products of 2,3-dihydroxynaphthalene.
Aromatic mono- or dihalides were prepared from their
corresponding amines using known diazotization proce-
dures.22
A wide variety of aryl, heteroaryl, or alkenyl halides
possessing different functional groups have been used
successfully for the heteroannulation process. Entries
3, 5, 6, 9, 10, and 11 in Table 1 showed the compatibility
of the reaction with different functional groups (e.g.,
(22) Vogel, A. I. A Text Book of Practical Organic Chemistry, 4th
ed.; ELBS, Longman Group Limited: London, 1978, p 695.

Palladium-Catalyzed Heteroannulation
J . Org. Chem., Vol. 63, No. 6, 1998 1867
Sch em e 3
the heterocyclic rings and (δc) 96.1 to 108.05 ppm for
methine carbon (CdCH) of the exocyclic double bond of
products 3. Besides NMR spectra, mass spectral data
were also very informative. Particularly strong support
in favor of the bisheteroannulated products 3l-o which
could not be easily distinguished from mono-heteroan-
1
nulated products by H and 13C NMR (due to the same
type of regio- and stereoselective cyclization), was ob-
tained from mass spectral data. It should be pointed out
here that no E-isomers or seven-membered ring com-
pounds were isolated under our reaction conditions.
The heteroannulation process was found to be com-
pletely stereoselective since only the Z-isomers were
obtained. The Z-stereochemistry was established on the
basis of several evidences. A reasonable working hy-
pothesis26 is that the olefinic proton signal of the E-
isomers of products 3 should appear in the lower field
region (δH > 6 ppm) due to the deshielding effect of
oxygen present in 1,4-benzodioxane ring system com-
pared to the corresponding proton of Z-isomer. In our
case, olefinic proton signals generally appeared in the
range of (δH) 5-6 ppm indicating the Z-stereochemistry.
Furthermore, the stereochemistry of the exocyclic double
bond of products 3 was determined with the assistance
of 3J CH values between the vinylic proton and methylenic
carbon (OCH2) of the heterocyclic ring. From literature12a,b
vinyl, formyl, ether, chloro, nitro, and ester). As can be
seen from Table 1, electron-withdrawing groups (entries
5, 7, 9, 10, 11, and 17, Table 1) present in aryl halide
moieties facilitated the reactions compared to electron-
donating groups (entries 6 and 8, Table 1). These results
are in conformity with our earlier observations23 of
palladium catalysis. However, when 5-carbomethoxy-2-
nitroiodobenzene was used as a coupling partner in this
heteroannulation process; no corresponding 1,4-benzo-
dioxan derivative was isolated leading to the recovery of
the deiodinated starting material.24
The efficacy of this new route leading to the formation
of 2,3-dihydro-2-(ylidene)-1,4-benzodioxins (3) was also
tested by using a variety of aromatic and heteroaromatic
diiodides (see entries 12, 13, 14, and 15, Table 1) under
palladium-copper-catalyzed condition (Scheme 3).
Interestingly, a totally regio- and stereoselective (Z)-
(as shown in Scheme 3) bisheteroannulation process,
which is an active and rapidly growing area in organic
synthesis using palladium catalysis,25 took place. The
Z-stereochemistry and structural identifications were
made from spectral evidences and finally from X-ray
analysis. Thus, this method is amenable to the synthesis
of molecules containing polyheteroannulated framework
under one pot and operationally simple palladium cata-
lyzed condition.
3
the J CH values more than 7 Hz or less than 5 Hz were
attributed to E- or Z-isomers, respectively. In our case,
3
the observed J CH values of compounds 3 were always
less than 5 Hz, and hence the observed stereochemistry
was Z in nature. The assignments were also confirmed
by carrying out proton NOE experiments: when meth-
ylenic protons of the heterocyclic ring (OCH2) of com-
pound 3i were irradiated, a strong enhancement of the
vinylic proton signal of the exocyclic double bond was
observed and vice versa. This result provided a strong
support in favor of the Z-stereochemistry. Finally the
X-ray diffraction study27of 2,5-bis[(Z)-2′,3′-dihydro-2′-
methylidene-1′,4′-benzodioxinyl]thiophene (3l) was also
performed which confirmed its structure and the Z-
stereochemistry. All these observation led us to assign
the Z-stereochemistry to compound 3 unambiguously.
Mech a n ism . Based on our observations and known
palladium chemistry, the mechanism of the reaction is
suggested to proceed according to Scheme 4.
Transformation of Pd(II) to active catalytic species Pd-
(0) with the formation of dimers of the acetylenic com-
ponents is well precedented.21,28 Oxidative addition of
Pd(0) with aryl halides takes place to form σ-aryl palla-
dium(II) complex B. Complex B undergoes transmeta-
lation29 by organocopper species A to form another
intermediate C. In the next step, the latter undergoes
nucleophilic attack by phenoxide or naphthoxide ion to
form the cyclic vinyl palladium species D (through path
Id en tifica tion of Str u ctu r es. The structures of
compounds 3 could be easily assigned from spectral
1
evidences (IR, UV, H and 13C NMR, mass spectra) and
elemental analyses. In IR spectra, absorption between
1670 and 1680 cm-1 confirmed the presence of an
exocyclic double bond in products 3. In 1H NMR, the
olefinic proton of the exocyclic double bond generally
appeared in the range (δH) 5-6 ppm as a sharp singlet.
But in some cases lower field shift (δH > 6 ppm) was
observed due to the deshielding effect of the oxygen
present in proximity in electron-withdrawing groups (e.g.,
CO2Me, NO2, etc.) of the aromatic rings of 3. In addition
to it, methylenic protons (OCH2) of the heterocyclic rings
also appeared as a singlet ranging between (δH) 4.56 to
4.75 ppm. Furthermore, 13C NMR, in combination with
DEPT analysis provided support in favor of structures
3. The characteristic carbon signals appeared in the
range (δc) 64.8 to 66.3 for methylenic carbon (OCH2) of
(26) In case of (E)- and (Z)-isomers, different chemical shift values
of vinylic proton of exocyclic double bond due to the deshielding effect
of oxygen of some heterocyclic rings have been invoked to account for
the results: (a) J ager, V.; Gunther, H. J . Tetrahedron Lett. 1977, 2543.
(b) Yamamoto, M. J . Chem. Soc., Chem. Commun. 1978, 649. (c) Arcadi,
A.; Burini, A.; Cacchi, S.; Delmastro, M.; Marinelli, F.; Pietroni, B. R.
J . Org. Chem. 1992, 57, 976.
(27) X-ray data of compound 3l has been deposited at Cambridge
Cystallographic Data Centre. The coordinates can be obtained, on
request, from the Director, Cambridge Crystallographic Data Centre,
12 Union Road, Cambridge, CB2 1EZ, U.K.
(23) Pal, M.; Kundu, N. G. J . Chem. Soc., Perkin Trans. 1 1996,
449.
(24) In a parallel experiment, 2-nitro-5-carbomethoxyiodobenzene
and phenylacetylene in the presence of (PPh3)2PdCl2 (3 mol %) and
CuI (7 mol %) in Et3N, employing the reaction condition of our
heteroannulation process resulted in no coupled product. Only the
deiodinated product was obtained. This could be explained first by
oxidative coupling followed by reduction of the palladated complex by
triethylamine. We thank a referee in pointing this out.
(25) Iyoda, M.; Kuwatani, Y.; Ueno, N.; Oda, M. J . Chem. Soc.,
Chem. Commun. 1992, 158. (b) Tao, W.; Nesbitt, S.; Heck, R. F. J .
Org. Chem. 1990, 55, 63 and see also ref 14d.
(28) Kundu, N. G.; Pal, M.; Chowdhury, C. J . Chem. Res. 1993, 432.
(29) Nakamura, E.; Isaka, M.; Matsuzawa, S. J . Am. Chem. Soc.
1988, 110, 1297.

1868 J . Org. Chem., Vol. 63, No. 6, 1998
Chowdhury et al.
Sch em e 4
Sch em e 5
experiments the acyclic intermediate 4i was heated at
100 °C for 16 h in Et3N only, and with 7 mol % CuI in
Et3N, respectively. The corresponding cyclized 1,4-ben-
zodioxan derivative 3i was obtained in 30% yield in the
former case, while the latter experiment (in the presence
of CuI) afforded the product 3i in 75% yield. These
observations revealed that cooperative assistance of CuI33
and Et3N could have prompted the stereoselective cy-
clization of the acyclic intermediate E. Hence, it can be
concluded that this stereoselective heteroannulation
might be propagated either by path a or path b through
the acyclic intermediates.34,35
Scop e of th e Rea ction . To further extend the scope
of the described method, we have investigated the
feasibility of applying this method for the preparation of
the saturated analogues of compounds 3 using hydroge-
nation procedure. This will provide the 1,4-benzodioxan
derivatives 6 which display the key structural features
of many naturally occurring6-9 and biologically active
compounds.1 The hydrogenation was accomplished using
Pd/C as catalyst in excellent yields (Scheme 5, Table 3).
The saturated 1,4-benzodioxan derivatives 6 were
characterized by spectral evidence and elemental analy-
ses. Thus our method provides us with an efficient and
facile route for the construction of 1,4-benzodioxan ring
structure.
Moreover, the structure-activity relationship and
pharmacological profile of 2-methylene-1,4-benzodioxan
and 3-substituted-2-methylene-1,4-benzodioxans is well
established in the literature.36 Thus a facile and efficient
method for the synthesis of 2-methylene-1,4-benzodioxan
(7) and its analogues was highly desirable. In the
past,11d,36 2-methylene-1,4-benzodioxan has been synthe-
sized through multistep procedures with poor overall
yield starting from catechol. We have accomplished the
synthesis of compound 7 in two steps with an overall
yield of 65% as shown in Scheme 6.
a) where Pd(II) is stabilized by coordination with oxy-
gen.30 Finally, elimination of Pd(0) from D furnishes the
1,4-benzodioxan derivative 3 ensuring the Z-stereochem-
istry. On the other hand, intermediate C undergoes
(path b) reductive elimination to afford the acyclic
intermediate E. The acyclic intermediate E would be
cyclized in a stereoselective way with the assistance of
CuI and Et3N leading to the products 3. Our stereo-
chemical outcome (Z) rules out the possibility of mecha-
nistic pathway proposed by Luo et al.,16b and also addition
of RPdX on the triple bond is less probable due to the
requirement of CuI as a cocatalyst. Furthermore, cy-
clization of the acyclic intermediate E driven by Pd(0) is
less likely due to the involvement of a negative pal-
ladium(0) species 5 which is an unfavorable process from
energy consideration.16c The feasibility of Pd(0) and
Pd(II)31 catalyzed cyclization was also discarded on the
Recently, we have also synthesized a number of uracil
derivatives substituted at the C-5 position leading to
5-acylethynyl uracils17a (5-AEUs), 5-acylvinyl uracils (5-
AVUs),17b or at the C-6 position leading to 6-acylvinyl
uracils17c (6-AVUs) and other 6-substituted uracil com-
pounds.17d Some of these compounds were found to act
(32) In two separate experiments, the acylic intermediate 4i (240
mg, 1 mmol) was heated at 100 °C for 16 h in Et3N in the presence of
(PPh3)2PdCl2 (20 mg, 0.035 mmol) or Pd(PPh3)4 (40 mg, 0.035 mmol),
no cyclized product 3i was obtained.
(33) See other CuI-catalyzed heteroannulation: Ezquerra, J .; Pe-
dregal, C.; Lamas, C. J . Org. Chem. 1996, 61, 5804.
basis of control experiments.32 To understand the role
of CuI and base toward cyclization, in two separate
(34) Although a referee suggested that path b is the most probable
path for the formation of the products 3, we, however, do not preclude
path a in the stereoselective formation of the products 3.
(35) To shed some light on the mechanistic rationale in favor of
Z-stereochemistry, we also performed molecular mechanics calculations
(MMX) on two representative molecules (3a , 3p ) which show that
Z-isomers are slightly more stable than E-isomers from energy
considerations [3a (Z): MMX energy ꢀ(Z)-3a )24.84 kcal mol-1; 3a (E):
ꢀ(E)-3a ) 25.27 kcal mol-1 and 3p (Z): ꢀ(Z)-3p ) 32.35 kcal mol-1; ꢀ(E)-3p
) 32.79 kcal mol-1].
(30) The coordination between palladium and oxygen or other
heteroatom is well precedented in the literature: (a) J effery, T.
Tetrahedron Lett. 1993, 34, 1133. (b) Kang, S.-K.; J ung, K.-Y.; Park,
C.-H.; Namkoong, E.-Y.; Kim, T.-H. Tetrahedron Lett. 1995, 36, 6287.
(c) Bernocchi, E.; Cacchi, S.; Ciattini, P. G.; Morera, E.; Ortar, G.
Tetrahedron Lett. 1992, 33, 3073. (d) Chiusoli, G. P.; Costa, M.;
Pergreffi, P.; Reverberi, S.; Salerno, G. Giazz. Chim. Ital. 1985, 115,
691.
(31) Lambert, C.; Utimoto, K.; Nozaki, H. Tetrahedron Lett. 1984,
25, 5323.
(36) Augstein, J .; Green, S. M.; Monro, A. M.; Potter, G. W. H.;
Worthing, C. R.; Wrigley, T. I. J . Med. Chem. 1965, 8, 446.

Palladium-Catalyzed Heteroannulation
J . Org. Chem., Vol. 63, No. 6, 1998 1869
Ta ble 3. Hyd r ogen a tion of 2-Ar ylid en e-1,4-ben zod ioxa n
Der iva tives 3a ,b,f,i,k ,oa (Sch em e 5)
Con clu sion
We have described for the first time, a successful
palladium-catalyzed procedure for the synthesis of 2,3-
dihydro-2-(ylidene)-1,4-benzo- and naphtho[2,3-b]dioxins.
The most attractive features of the synthesis are that
readily available, inexpensive reagents are used under
easily attainable experimental conditions. The excellent
regio- and stereoselectivity exhibited by this procedure
makes it all the more attractive. A variety of functional
groups can be accommodated in the structures without
affecting the main heteroannulation process. The method
is also amenable for the (Z)-stereoselective bisheteroan-
nulation process. The possible biological significance of
the compounds, which can be synthesized through this
procedure, makes it all the more attractive to both
organic and medicinal chemists.
Exp er im en ta l Section
Melting points are uncorrected. Reactions were performed
under argon atmosphere. All catalysts and cocatalyst used
were commercially available. Solvents and reagents were
purified by conventional methods. The petroleum ether used
is the fraction boiling at 60-80 °C. Ether refers to diethyl
ether. Silica gel TLC was performed on 60F-254 precoated
sheets. Aryl iodides (2b, 2g, 2i, 2j, 2m , 2n , and 20) were
prepared according to the procedure given in ref 22 for the
synthesis of iodobenzene (2a ) and are also commercially
avialable. â-Bromostyrene,39 2-iodothiophene,40 2,5-diiodo-
thiophene,40 5-iodo-2,4-dimethoxypyrimidine,41 and methyl-2-
iodobenzoate42 were synthesized according to known proce-
dures. 2-Bromo-5-formylthiophene (2e) and 2-iodoanisole (2h )
were purchased from a commercial source.
a
Hydrogenation was carried out by treatment of compound 3
(0.05 mmol) in dry ethanol (8 mL) with hydrogen at room
temperature under atmospheric pressure with Pd/C (10%) as
catalyst. Yields refer to chromatographically isolated pure prod-
b
ucts.
Sch em e 6
1H NMR in CDCl3 solutions were recorded at 100, 200, or
300 MHz and that of CCl4 solutions at 60 MHz. 13C NMR
3
spectra were recorded at 50 or 75 MHz. J CH values were
Sch em e 7
obtained performing 13C NMR experiments under proton-
coupled mode.
Mon o-p r op -2-yn yla ted Ca tech ol (1a ). A mixture of
pyrocatechol (20 g, 181.63 mmol) and anhydrous K2CO3 (12.54
g, 90.81 mmol) in dry acetone was stirred for 1 h at room
temparature. Propargyl bromide (21.6 g, 181.63 mmol) in 15
mL of dry acetone was then added very carefully during 1 h.
The whole mixture was then heated under reflux for 16 h with
constant stirring. Acetone was removed from the mixture, and
the residue was poured in 500 mL of water and extracted with
chloroform (3 × 150 mL). The combined organic layer was
washed with water and dried over anhydrous Na2SO4. After
removal of solvent, the residue was purified through sublima-
tion (120 °C, at 0.25 mmHg press). A colorless white solid (23.4
g, 87%) was obtained; mp 46-47 °C; IR 3510 (br), 3300, 1600
as inhibitors of thymidylate synthase (TS), a crucial
enzyme required for cellular multiplication processes.
They were also active against CCRF-CEM human lym-
phoblastoid cells, HT-29 colon carcinoma cells, and
L1210/0 mouse leukemia cells. In view of these promis-
ing results, we have synthesized the novel 5-substituted
uracil derivative 8 with a 1,4-benzodioxinyl functional
group at the C-5 position of the uracil ring (Scheme 7).
Compound 3f was synthesized using our synthetic
protocol. Demethylation of compound 3f under neutral
condition37 afforded the uracil derivative 8. The structure
of product 8 was assigned from spectral evidences. Thus
we have enlarged the scope of our synthetic protocol by
the synthesis of novel uracil derivatives of possible
biological significance.38
1
cm-1. UV (EtOH) λmax/nm 204.4 (log ꢀ 4.10), 276.8 (3.39); H
NMR (60 MHz, CCl4) δ 2.49 (t, J ) 2 Hz, 1H), 4.59 (d, J ) 2
Hz, 2H), 5.89 (br, 1H), 6.59-7.06 (m, 4H). Anal. Calcd for
C9H8O2: C, 72.95; H, 5.44. Found: C, 72.81; H, 5.86.
2-Hyd r oxy-3-(p r op -2-yn yloxy)n a p h th a len e (1b). A 1.09
g (27.5 mmol) amount of sodium hydride (60% suspension in
mineral oil) was placed in a 500 mL round-bottom flask fitted
with an anhydrous calcium chloride guard tube. After washing
the sodium hydride with dry benzene (3 × 10 mL) and flushing
with argon, dry THF (100 mL) was added. To this mixture,
2,3-dihydroxynaphthalene (4.22 g, 26.4 mmol) in dry THF (50
mL) dropwise during 90 min. After stirring for 6 h at room
temperature, propargyl bromide (2.4 g, 20 mmol) was added
to the mixture, and it was stirred again for another 20 h. The
reaction mixture was then poured into ice-water, acidified
with dilute HCl, and extracted with ether. The ether layer
was washed with brine, dried over anhydrous Na2SO4, and
(37) Morita, T.; Okamoto, Y.; Sakurai, H. J . Chem. Soc., Chem.
Commun. 1978, 874.
(38) The biological activity of compound 12 is under study and will
be reported elsewhere.
(39) A. I. Vogel, A Text Book of Practical Organic Chemistry; 4th
ed.; ELBS, Longman Group Limited: London, 1978; p 349.
(40) Barker, J . M.; Huddleston, P. R.; Wood, M. L. Synth. Commun.
1975, 5, 59.
(41) Das, B.; Kundu, N. G. Synth. Commun. 1988, 855.
(42) Larock, R. C.; Harrison, L. W. J . Am. Chem. Soc. 1984, 106,
4218.

1870 J . Org. Chem., Vol. 63, No. 6, 1998
Chowdhury et al.
concentrated. The residue showed two spots on TLC plate,
and they were separated by column chromatography over
neutral alumina. 2,3-Bis(prop-2-ynyloxy)naphthalene (970
mg, 20%) was collected first with benzene as eluent. 2-Hy-
droxy-3-(prop-2-ynyloxy)naphthalene (1b) (2.08 g, 40%) was
eluted later with ethyl acetate/benzene (5/95, v/v); mp 94-96
°C; IR 3515 (br), 3300, 1600 cm-1; UV (EtOH) λmax/nm 210.5
(log ꢀ 3.12), 280.4 (4.1); 1H NMR (60 MHz, CCl4) δ 2.49 (t, J )
2 Hz, 1H), 4.83 (d, J ) 2 Hz, 2H), 5.73 (br, 1H), 7.09-7.76 (m,
6H). Anal. Calcd for C13H10O2: C, 78.76; H, 5.08. Found: C,
78.52; H, 5.21.
Typ ica l P r oced u r e for th e Syn th esis of (Z)-2,3-Dih y-
d r o-2-ben zylid en e-1,4-ben zod ioxin s (3a ). A mixture of
iodobenzene 2a (410 mg, 2 mmol), (PPh3)2PdCl2 (50 mg, 0.07
mmol), and CuI (26 mg, 0.14 mmol) in triethylamine (8 mL)
was stirred under argon atmosphere for 15 min. Then mono-
prop-2-ynylated catechol 4 (390 mg, 2.63 mmol) was added very
slowly with great care. The resulting solution was further
stirred at room temperature for 20 h and then heated at 100
°C for 16 h. After removal of triethylamine, the reaction
mixture was poured in 150 mL of water and extracted with
ether (3 × 75 mL). The ether extracts were washed with
water, dried over anhydrous Na2SO4, and concentrated. The
residue was chromatographed over neutral alumina eluting
with petroleum ether/chloroform (70/30, v/v), affording com-
pound 3a (200 mg, 44%) as a colorless oil: IR (liquid film) 1680,
1600, 1580 cm-1; UV (EtOH) λmax/nm 339.2 (log ꢀ 3.51), 262.2
(4.16); 1H NMR (200 MHz, CDCl3) δ 4.60 (s, 2H), 5.56 (s, 1H),
6.92-6.99 (m, 2H), 7.10-7.38 (m, 5H), 7.67 (d, J ) 8 Hz, 2H);
13C NMR (75 MHz, CDCl3) δ 65.94 (3J CH ) 4.83 Hz), 106.91,
116.67, 117.35, 122.16, 122.50, 126.81, 128.28, 128.80, 134.19,
142.42, 143.38, 144.08. Anal. Calcd for C15H12O2: C, 80.33;
H, 5.39. Found: C, 80.67; H, 5.41.
Similar reaction conditions were employed for 3b-q. The
only difference was that in case of 3f a temp of 120 °C was
used instead of 100 °C. The yields of the products from the
reactions are listed in Table 1. The important spectral data
of some of the compounds 3 are listed below and others (3b,
3c, 3d , 3g, 3h , 3j, 3q) have been incorporated in Supporting
Information.
(Z)-2,3-Dih yd r o-2-[(5-for m ylth ien yl)m eth ylid en e]-1,4-
ben zod ioxin (3e): mp 107-109 °C; IR 1675, 1650, 1600, 1500
cm-1; UV (EtOH) λmax/nm 207.2 (log ꢀ 4.4), 278.8 (3.85), 356.6
(4.42); 1H NMR (200 MHz, CDCl3) δ 4.60 (s, 2H), 5.92 (s, 1H),
6.92-7.01 (m, 3H), 7.11 (d, J ) 4 Hz, 1H), 7.18-7.25 (m, 1H),
7.62 (d, J ) 4 Hz, 1H), 9.86 (s, 1H); 13C NMR (50 MHz, CDCl3)
δ 64.81 (3J CH ) 4.4 Hz), 100.66, 116.89, 117.39, 122.59, 123.34,
127.18, 136.14, 141.88, 142.56, 143.57, 145.51, 146.39, 182.93.
Anal. Calcd for C14H10O3S: C, 65.11; H, 3.90. Found: C,
65.04; H, 3.98.
J ) 8 Hz, 1H); 13C NMR (50 MHz, CDCl3) δ 51.78, 65.95 (3J CH
) 4.95 Hz), 104.46, 116.55, 117.24, 122.06, 122.47, 126.41,
128.72, 130.26, 130.69, 131.46, 134.50, 142.23, 143.84, 144.06,
167.77. Anal. Calcd for C17H14O4: C, 72.32; H, 4.99. Found:
C, 72.24; H, 5.11.
2,5-Bis[(Z)-2′,3′-dih ydr o-2′-m eth yliden e-1′,4′-ben zodiox-
in yl]th iop h en e (3l): mp 146-148 °C; IR 1680, 1600, 1500
cm-1; UV (EtOH) λmax/nm 361.4 (log ꢀ 4.37), 344.2 (4.46), 288.2
(3.85), 205.4 (4.44); 1H NMR (300 MHz, CDCl3) δ 4.63 (s, 4H),
5.91 (s, 2H), 6.95-7.03 (m, 6H), 7.04 (s, 2H), 7.23 (t, J ) 6 Hz,
2H); 13C NMR (50 MHz, CDCl3) δ 65.21 (3J CH ) 4.36 Hz),
101.97, 116.72, 117.50, 122.28, 122.68, 126.45, 136.97, 141.38,
142.54, 143.90; MS m/e (rel inten) 376 (M+, 100), 268 (21), 256
(21), 160 (30), 148 (21), 115 (16). Anal. Calcd for C22H16O4S:
C, 70.19; H, 4.28. Found: C, 70.42; H, 4.50.
1,4-Bis[(Z)-2′,3′-dih ydr o-2′-m eth yliden e-1′,4′-ben zodiox-
in yl]ben zen e (3m ): mp 210-212 °C; IR 1680, 1600, 1495
cm-1; UV (CHCl3) λmax/nm 241.8 (log ꢀ 4.08), 321.4 (4.64), 336
(4.54); 1H NMR (300 MHz, CDCl3) δ 4.63 (s, 4H), 5.60 (s, 2H),
6.95-7.01 (m, 6H), 7.17-7.20 (m, 2H), 7.71 (s, 4H); 13C NMR
(75 MHz, CDCl3) δ 66.06 (3J CH ) 4.48 Hz), 106.80, 116.72,
117.38, 122.20, 122.53, 128.81, 132.82, 142.46, 143.47, 144.09;
MS m/e (rel intensity) 370 (M+, 100), 261 (25), 152 (88), 147
(20), 141 (24), 115 (48). Anal. Calcd for C24H18O4: C, 77.82;
H, 4.89. Found: C, 77.94; H, 4.97.
4,4′-Bis[(Z)-2′,3′-dih ydr o-2′-m eth yliden e-1′,4′-ben zodiox-
in yl]bip h en yl (3n ): mp 204-206 °C, IR 1680, 1600, 1500
1
cm-1; UV (EtOH) λmax/nm 270.4 (log ꢀ 4.02), 314.4 (4.33); H
NMR (300 MHz, CDCl3) δ 4.64 (s, 4H), 5.63 (s, 2H), 6.95-
7.01 (m, 6H), 7.15-7.19 (m, 2H), 7.63 (d, J ) 8 Hz, 4H), 7.75
(d, J ) 8 Hz, 4H); 13C NMR (75 MHz, CDCl3) δ 66.10 (3J CH
)
4.34 Hz), 106.62, 116.76, 117.44, 122.28, 122.61, 126.77,
129.28, 133.33, 139.01, 142.49, 143.65, 144.13; MS m/e (rel
inten) 446 (M+, 46), 328 (10), 230 (15), 216 (100), 160 (62), 154
(30). Anal. Calcd for C30H22O4: C, 80.71; H, 4.96. Found: C,
80.62; H, 4.78.
1,2-Bis[(Z)-2′,3′-dih ydr o-2′-m eth yliden e-1′,4′-ben zodiox-
in yl]ben zen e (3o): mp 116-118 °C; IR 1680, 1600, 1500
cm-1; UV (EtOH) λmax/nm 209 (log ꢀ 4.66), 289.4 (4.46); 1H
NMR (200 MHz, CDCl3) δ 4.58 (s, 4H), 5.72 (s, 2H), 6.86-
6.93 (m, 6H), 6.97-7.04 (m, 2H), 7.18-7.28 (m, 2H), 7.81-
7.86 (m, 2H); 13C NMR (50 MHz, CDCl3) δ 65.93 (3J CH ) 4.81
Hz), 104.78, 116.80, 117.28, 122.22, 122.44, 126.85, 129.68,
131.96, 142.40, 143.55, 144.04; MS m/e (rel inten) 370 (M+,
7), 261 (100), 153 (30), 141 (10), 128 (31). Anal. Calcd for
C
24H18O4: C, 77.82; H, 4.89. Found: C, 77.60; H, 4.94.
(Z)-2,3-Dih yd r o-2-ben zylid en e-1,4-n a p h th o[2,3-b]d iox-
in (3p ): mp 131-133 °C; IR 1680, 1600, 1510 cm-1; UV
(EtOH) λmax/nm 331.4 (log ꢀ 3.72), 274.8 (4.58), 224.2 (4.66);
1H NMR (300 MHz, CDCl3) δ 4.71 (s, 2H), 5.66 (s, 1H), 7.25-
7.43 (m, 6H), 7.57 (s, 1H), 7.70-7.77 (m, 4H); 13C NMR (75
MHz, CDCl3) δ 66.26, 107.03, 112.42, 112.99, 124.67, 124.81,
126.62, 126.69, 126.94, 128.37, 128.85, 129.78, 129.86, 134.07,
142.41, 143.50, 144.20. Anal. Calcd for C19H14O2: C, 83.18;
H, 5.14. Found: C, 83.41; H, 5.19.
(Z)-2,3-Dih yd r o-2-[(2,4-d im eth oxyp yr im id in -5-yl)m eth -
ylid en e]-1,4-ben zod ioxin (3f): mp 100-103 °C; IR 1685,
1600, 1570, 1500 cm-1; UV (EtOH) λmax/nm 206.4 (log ꢀ 4.27),
270.4 (4.30); 1H NMR (200 MHz, CDCl3) δ 4.0 (s, 6H), 4.65 (s,
2H), 5.7 (s, 1H), 6.85-7.0 (m, 3H), 7.05-7.20 (m, 1H), 9.05 (s,
1H); 13C NMR (50 MHz, CDCl3) δ 54.07, 54.76, 65.76, 96.12,
116.70, 117.45, 122.37, 122.78, 127.63, 129.21, 142.27, 144.0,
144.13, 157.69; MS m/e (rel inten) 286 (M+, 100), 177 (37), 163
(51), 148 (20), 133 (33). Anal. Calcd for C15H14N2O4: C, 62.92;
H, 4.92; N, 9.78. Found: C, 62.52; H, 5.04; N, 9.64.
Syn th esis of Mon o-3-(3-ch lor op h en yl)p r op -2-yn yla ted
Ca tech ol (4i) a n d (Z)-2,3-Dih yd r o-2-[(3-ch lor op h en yl)-
m eth ylid en e]1,4-ben zod ioxin (3i) u n d er Con d ition i. To
a magnetically stirred solution of 3-chlorophenyl iodide 2i (715
mg, 3 mmol) in triethylamine was added a mixture of (PPh3)2-
PdCl2 (73 mg, 0.10 mmol) and CuI (40 mg, 0.21 mmol) under
oxygen free argon atmosphere, and the resulting solution was
further stirred for another 30 min. Mono-prop-2-ynylated
catechol 1a (580 mg, 3.91 mmol) was added carefully, and the
whole mixture was further stirred at room temperature for
another 48 h. After usual workup, the crude product obtained
was purified by column chromatography over neutral alumina.
The cyclized product 3i (95 mg, 12%) was obtained in earlier
fractions by elution with CHCl3/petroleum ether (30/70, v/v).
On the other hand, the acyclic product 4i (450 mg, 57%) was
isolated with CHCl3 as eluent. The spectral data for compound
3i has been reported earlier. Compound 4i: colorless oil; IR
(Z)-2,3-Dih yd r o-2-[(3-ch lor op h en yl)m eth ylid en e)]-1,4-
ben zod ioxin (3i): mp 65-67 °C; IR 1680, 1590, 1495 cm-1
;
1
UV (EtOH) λmax/nm 209.8 (log ꢀ 4.47), 280.0 (4.30); H NMR
(200 MHz, CDCl3) δ 4.60 (s, 2H), 5.52 (s, 1H), 6.96-6.98 (m,
3H), 7.13-7.32 (m, 3H), 7.51-7.55 (m, 1H), 7.72-7.74 (m, 1H);
13C NMR (75 MHz, CDCl3) δ 65.85, 105.52, 116.70, 117.39,
122.31, 122.78, 126.76, 126.83, 128.61, 129.44, 134.13, 135.95,
142.20, 144.01, 144.51. Anal. Calcd for C15H11O2Cl: C, 69.65;
H, 4.28. Found: C, 69.62; H, 4.36.
(Z)-2,3-Dih yd r o-2-[(2-ca r b om e t h oxyp h e n yl)m e t h yl-
id en e]-1,4-ben zod ioxin (3k ): colorless oil; IR (liquid film)
1720, 1675, 1600 cm-1; UV (EtOH) λmax/nm 279.8 (log ꢀ 4.04),
1
235.8 (4.11); H NMR (200 MHz, CDCl3) δ 3.86 (s, 3H), 4.65
(s, 2H), 6.48 (s, 1H), 6.74-7.07 (m, 4H), 7.29 (t, J ) 8 Hz, 1H),
7.51 (t, J ) 8 Hz, 1H), 7.93 (dd, J ) 7.8, 1.4 Hz, 1H), 8.03 (d,
(liquid film) 2240, 3450 (br), 1600 cm-1
;
1H NMR (60 MHz,
CDCl3) δ 4.93 (s, 2H), 7.04-7.49 (m, 9H, OH, and aromatic).

Palladium-Catalyzed Heteroannulation
J . Org. Chem., Vol. 63, No. 6, 1998 1871
1H NMR (200 MHz, CDCl3) δ 3.26 (dd, J AB ) 13.3 Hz, J AX
Anal. Calcd for C15H11O2Cl: C, 69.63; H, 4.28. Found: C,
69.78; H, 4.16.
)
7.5 Hz, 1HA), 3.41 (dd, J AB ) 13.3 Hz, J BX ) 5.2 Hz, 1HB), 3.89
(s, 3H), 3.98 (dd, J A′B′ ) 11.2 Hz, J A′X ) 6.5 Hz, 1HA′), 4.24
(dd, J A′B′ ) 11.2 Hz, J B′X ) 2 Hz, 1HB′), 4.43-4.46 (m, 1H),
6.75-6.87 (m, 4H, aromatic), 7.32 (t, J ) 6.9 Hz, 2H, aromatic),
7.45 (t, J ) 8 Hz, 1H, aromatic), 7.96 (d, J ) 8 Hz, 1H,
aromatic); 13C NMR (50 MHz, CDCl3) δ 35.95, 51.94, 67.23,
73.51, 96.24, 116.65, 117.49, 121.46, 122.01, 126.89, 129.62,
130.92, 131.93, 132.64, 139.15, 143.15, 167.43. Anal. Calcd
for C17H16O4: C, 71.81; H, 5.67. Found: C, 71.61; H, 5.84.
2,3-Dih yd r o-2-m eth ylen e-1,4-ben zod ioxin (7). To a well
stirred solution of mono-prop-2-ynylated catechol 1a (444 mg,
3 mmol) in Et3N was added CuI (40 mg, 0.21 mmol), and the
whole mixture was allowed to stir at room temperature for 30
min. Then it was heated at 100 °C for 16 h. After removal of
solvent, it was diluted with water and extracted with Et2O.
The ether extracts were washed with water, dried (anhydrous
Na2SO4), and concentrated. The residue was chromatographed
over neutral alumina, eluting with chloroform in petroleum
ether (10/90, v/v) to afford 330 mg (74%) of 7 as colorless oil:
Syn th esis of Mon o-3-(3-ch lor op h en yl)p r op -2-yn yla ted
Ca tech ol (4i) a n d (Z)-2,3-Dih yd r o-2-[(3-ch lor op h en yl)-
m eth ylid en e]-1,4-ben zod ioxin (3i) u n d er Con d ition ii. To
a magnetically stirred solution of 3-chlorophenyl iodide 2i (715
mg, 3 mmol) in trimethylamine (8 mL) was added a mixture
of (PPh3)2PdCl2 (73 mg, 0.10 mmol) and CuI (40 mg, 0.21
mmol) under oxygen free argon atmosphere, and the whole
mixture was stirred for 30 min at room temperature. Then
mono-prop-2-ynylated catechol 1a (580 mg, 3.91 mmol) was
added carefully, and the stirring was continued for another
20 h. It was then heated at 65 °C for 16 h. After removal of
triethylamine, workup and chromatography over neutral
alumina as usual, the mixture of products 3i and 4i were
separated as described in the previous experiment. Yields of
compounds 3i and 4i were 120 mg (16%) and 370 mg (47%),
respectively. The spectral data of compound 3i and 4i were
given earlier.
Typ ica l P r oced u r e for th e Syn th esis of 2,3-Dih yd r o-
2-ben zyl-1,4-ben zod ioxin (6a ) via Hyd r ogen a tion P r o-
ced u r e. Compound 3a (110 mg, 0.5 mmol) was hydrogenated
in the presence of 10% Pd/C catalyst (20 mg) in dry ethanol (8
mL) under atmospheric pressure. After 16 h, the catalyst was
removed by filtration and washed with ethanol (5 mL). The
combined filtrate was evaporated to dryness to give a gummy
material which was purified by column chromatography over
neutral alumina with chloroform as eluent. This afforded 6a
as a colorless oil (100 mg, 88%): IR (liquid film) 1600, 1490,
1450 cm-1; UV (EtOH) λmax/nm 279.2 (log ꢀ 3.46), 308.2 (4.31);
11d
IR 1670, 1600, 1500 cm-1; UV (EtOH) λmax/nm 212 (log ꢀ
4.29), 234.8 (3.0), 278 (3.32); 1H NMR (60 MHz, CCl4) δ 4.4 (s,
2H), 4.26 (d, J AB ) 2 Hz, 1HA), 4.66 (d, J AB ) 2 Hz, 1HB), 6.86-
7.03 (m, 4H).
(Z)-2,3-Dih yd r o-2-[(2′,4′-d ioxo-1′,2′,3′,4′-tetr a h yd r op y-
r im id in -5-yl)m eth ylid en e]-1,4-ben zod ioxin (8). To a mag-
netically stirred solution of compound 3f (143 mg, 0.5 mmol)
in dry acetonitrile (8 mL) under argon atmosphere were added
anhydrous sodium iodide (250 mg, 1.67 mmol) and chlorotri-
methylsilane (0.2 mL, 1.58 mmol). The resulting mixture was
stirred at room temperature for 24 h. The solvent was
removed under reduced pressure, and the residue was treated
with a few drops of sodium metabisulfite solution and then
water, filtered and dried to yield compound 8 as pale yellow
1H NMR (200 MHz, CDCl3) δ 2.89 (dd, J AB ) 13.8 Hz, J AX
)
7.4 Hz, 1HA), 3.12 (dd, J AB ) 13.8 Hz, J BX ) 6.2 Hz, 1HB), 3.89
(dd, J A′B′ ) 11.2 Hz, J A′X ) 6.9 Hz, 1HA′), 4.16 (dd, J A′B′ ) 11.2
Hz, J B′X ) 2.2 Hz, 1HB′), 4.29-4.40 (m, 1H), 6.76-6.88 (m, 4H,
aromatic), 7.18-7.36 (m, 5H, aromatic); 13C NMR (75 MHz,
CDCl3) δ 37.47, 66.89, 73.60, 116.97, 117.32, 121.18, 121.48,
126.76, 128.54, 129.29, 136.38, 143.20. Anal. Calcd for
solid (93 mg, 72%): mp >275 °C; IR 1710, 1680, 1600 cm-1
;
UV (EtOH) λmax/nm 205.2 (log ꢀ 4.11), 253 (4.32), 312.2 (3.21);
1H NMR (100 MHz, DMSO d6) δ 4.64 (s, 2H), 5.68 (s, 1H),
6.96-7.2 (m, 4H), 8.0 (s, 1H), 10.48 (br, 1H), 11.36 (br, 1H).
Anal. Calcd for C13H10O4N2: C, 60.48; H, 3.90; N, 10.85.
Found: C, 60.34; H, 4.10; N, 10.98.
C
15H14O2: C, 79.62; H, 6.23. Found: C, 79.30; H, 6.29.
Similarly, compounds 6b,f,i,k ,o) were synthesized through
hydrogenation of the corresponding unsaturated analogues
3b,f,i,k ,o. Yields have been reported under Table 3. The
important spectral data of some of the compounds (6i,k ) are
listed below and others (6b,f,o) have been incorporated in
Supporting Information.
Ackn owledgm en t. We gratefully acknowledge CSIR
(Project no. 01(1385)/95/EMR-II) for financial support.
We are indebted to Professor A. Chakravorty, National
Single Crystal Diffractometer Facilities, IACS, Calcutta,
for providing X-ray diffraction data of compound 3l and
to Dr. D. Datta, IACS, Calcutta, for MMX calculations.
2,3-Dih ydr o-2-[(3-ch lor op h en yl)m eth yl]-1,4-ben zod iox-
in (6i): colorless oil; IR (liquid film) 1600, 1490 cm-1; UV
1
(EtOH) λmax/nm 207.4 (log ꢀ 4.41), 279.4 (3.52); H NMR (200
MHz, CDCl3) δ 2.89 (dd, J AB ) 13.8 Hz, J AX ) 7.5 Hz, 1HA),
3.12 (dd, J AB ) 13.8 Hz, J BX ) 6.3 Hz, 1HB), 3.90 (dd, J A′B′
11.4 Hz, J A′X ) 7.2 Hz, 1HA′), 4.17 (dd, J A′B′ ) 11.4 Hz, J B′X
)
)
Su p p or tin g In for m a tion Ava ila ble: Spectroscopic data
for compounds 3b-d ,g,h ,j,q, 6b,f,o and experimental details
of the X-ray diffraction study for compound 3l with ORTEP
diagram (4 pages). This material is contained in libraries
on microfiche, immediately follows this article in the microfilm
version of the journal, and can be ordered from the ACS; see
any current masthead page for ordering information.
2 Hz, 1HB′), 4.34-4.41 (m, 1H), 6.79-6.91 (m, 3H, aromatic),
7.22-7.38 (m, 5H, aromatic); 13C NMR (50 MHz, CDCl3) δ
37.69, 66.90, 73.70, 96.25, 117.11, 117.45, 121.29, 121.57,
126.90, 128.68, 129.41, 136.49, 143.23, 143.33. Anal. Calcd
for C15H13O2Cl: C, 69.10; H, 5.02. Found: C, 69.18; H, 5.11.
2,3-Dih yd r o-2-[(2-ca r b om et h oxyp h en yl)m et h yl]-1,4-
ben zod ioxin (6k ): mp 72-74 °C; IR 1715, 1600, 1490 cm-1
UV (EtOH) λmax/nm 207.8 (log ꢀ 4.43), 224.4 (4.18), 279.8 (3.69);
;
J O9717595