Synthesis of indeno-fused derivatives of quinolizinium salts, imidazo[1,2-a]pyridine, pyrido[1,2-a]indole, and 4H-quinolizin-4-one via benzannulated enyne-allenes

Article abstract of DOI:10.1021/jo0505730

The benzannulated enediynyl propargylic alcohol 8 was prepared from 1-bromo-2-iodobenzene by two consecutive Sonogashira cross-coupling reactions. The subsequent transformation to mesylate 9 followed by treatment with 4-substituted pyridines 10 then furni

Full text of DOI:10.1021/jo0505730

Synthesis of Indeno-Fused Derivatives of Quinolizinium Salts,
Imidazo[1,2-a]pyridine, Pyrido[1,2-a]indole, and
4H-Quinolizin-4-one via Benzannulated Enyne-Allenes
Weixiang Dai, Jeffrey L. Petersen,† and Kung K. Wang*
C. Eugene Bennett Department of Chemistry, West Virginia University,
Morgantown, West Virginia 26506-6045
kung.wang@mail.wvu.edu
Received March 21, 2005
The benzannulated enediynyl propargylic alcohol 8 was prepared from 1-bromo-2-iodobenzene by
two consecutive Sonogashira cross-coupling reactions. The subsequent transformation to mesylate
9 followed by treatment with 4-substituted pyridines 10 then furnished the benzannulated enediynes
11. On exposure of 11 to triethylamine, the indeno-fused quinolizinium salts 15 were produced in
quantitative yield. Presumably the reaction proceeded through a 1,3-prototropic rearrangement to
form the benzannulated enyne-allenes 12, which then underwent either a concerted Diels-Alder
reaction or a two-step process involving a Schmittel cyclization reaction to form biradical 13 followed
by an intramolecular radical-radical coupling to afford 14. A subsequent prototropic rearrangement
then produced 15. Similarly, 21a and 21b were produced from 19a and 19b, respectively. The use
of the Sonogashira reaction for cross-coupling between 1-iodo-2-(phenylethynyl)benzene (7) and
1-(2-propynyl)-1H-imidazole (25) followed by treatment of the resulting adduct with potassium tert-
butoxide gave the indeno-fused imidazo[1,2-a]pyridine 24 in 98% yield. Similarly, the indeno-fused
pyrido[1,2-a]indole 32 and 4H-quinolizin-4-one 35 were obtained by starting from 7 for cross-coupling
with 1-(2-propynyl)-1H-indole (30) and 1-(2-propynyl)-2(1H)-pyridinone (33), respectively, followed
by treatment with potassium tert-butoxide.
SCHEME 1
Introduction
Benzannulated enyne-allenes bearing an aryl sub-
stituent at the alkynyl terminus have been shown to
undergo the Schmittel cyclization reaction to produce the
corresponding benzofulvene biradicals under mild ther-
mal conditions.1 One such example involves a potassium
tert-butoxide-promoted 1,3-prototropic rearrangement of
the benzannulated enediyne 1 to produce in situ enyne-
allene 2 for the subsequent Schmittel cyclization reaction
to generate biradical 3 (Scheme 1).2 The presence of a
second phenyl substituent at the allenic terminus of 2
* To whom correspondence should be addressed. Phone: (304) 293-
3068, ext 6441. Fax: (304) 293-4904.
† To whom correspondence concerning the X-ray structures should
be addressed. Phone: (304) 293-3435, ext 6423. Fax: (304) 293-4904.
E-mail: jeffrey.petersen@mail.wvu.edu.
(1) (a) Schmittel, M.; Strittmatter, M.; Vollmann, K.; Kiau, S.
Tetrahedron Lett. 1996, 37, 999-1002. (b) Schmittel, M.; Strittmatter,
M.; Kiau, S. Angew. Chem., Int. Ed. Engl. 1996, 35, 1843-1845. (c)
Schmittel, M.; Kiau, S.; Siebert, T.; Strittmatter, M. Tetrahedron Lett.
1996, 37, 7691-7694. (d) Schmittel, M.; Keller, M.; Kiau, S.; Stritt-
matter, M. Chem. Eur. J. 1997, 3, 807-816.
permits an intramolecular radical-radical coupling to
furnish the formal Diels-Alder adduct 4, which in turn
undergoes a prototropic rearrangement to afford 5 as a
benzo[b]fluorene derivative. Several other synthetic meth-
(2) Li, H.; Zhang, H.-R.; Petersen, J. L.; Wang, K. K. J. Org. Chem.
2001, 66, 6662-6668.
10.1021/jo0505730 CCC: $30.25 © 2005 American Chemical Society
Published on Web 07/28/2005
J. Org. Chem. 2005, 70, 6647-6652
6647

Dai et al.
SCHEME 2
ods have also been reported to furnish enyne-allenes for
similar cascade transformations to a variety of benzo[b]-
fluorenes and related polycyclic aromatic compounds.3
By placing a heteroaromatic substituent at the allenic
terminus of the enyne-allene system, the cascade reac-
tion sequence has been reported to lead to the derivatives
of 10H-indeno[1,2-g]quinoline, 9H-fluoreno[2,3-b]furan,
9H-fluoreno[2,3-b]thiophene, and 5H- and 6H-indeno[2,1-
f]indolizines.1a,4 A similar strategy also finds success in
the enyne-carbodiimide5 and enallene-isonitrile sys-
tems,6 producing a variety of novel heteroaromatic com-
pounds. We have further applied this synthetic strategy
to the preparation of the indeno-fused derivatives of
quinolizinium salts, imidazo[1,2-a]pyridine, pyrido[1,2-
a]indole, and 4H-quinolizin-4-one, taking advantage of
the facile 1,3-prototropic rearrangements of the corre-
sponding benzannulated enediynes to furnish the requi-
site enyne-allenes for subsequent cascade transforma-
tions to heteroaromatic ring systems.
1-bromo-2-iodobenzene and phenylacetylene produced 6
as reported previously.3c Treatment of 6 with butyl-
lithium followed by iodine then afforded 7, which was
used for a second palladium-catalyzed coupling with
propargyl alcohol to give 8 and subsequently, after
treatment with methanesulfonyl chloride and triethy-
lamine, mesylate 9. Upon exposure of 9 to 4-aminopyri-
dine, 4-(dimethylamino)pyridine, and 4-methoxypyridine,
the benzannulated enediynes 11a-c were obtained in
essentially quantitative yield.7 Efficient transformations
of 11a-c to the indeno-fused quinolizinium methane-
sulfonates 15a-c were achieved also in essentially
quantitative yield with triethylamine in ethanol. The
products 15a-c appeared to be free of other byproducts
as judged by 1H NMR spectra without the need for
purification by column chromatography. The structures
of 15a-c were established by X-ray structure analyses.
Presumably, a 1,3-prototropic rearrangement of 11 oc-
curred to give the corresponding benzannulated enyne-
allenes 12, which then underwent either a concerted
Diels-Alder reaction or a two-step process involving a
Schmittel cyclization reaction to form biradical 13 fol-
lowed by an intramolecular radical-radical coupling to
afford 14. A subsequent prototropic rearrangement then
produced the indeno-fused quinolizinium methane-
sulfonates 15. It is worth noting that several 2-amino-
substituted quinolizinium salts and related compounds
were reported to exhibit interesting biological activities
and pronounced DNA-binding properties.8
Results and Discussion
The synthetic sequence outlined in Scheme 2 provides
an efficient route to benzannulated enediynes 11a-c.
The palladium-catalyzed Sonogashira reaction between
(3) (a) Wang, K. K.; Zhang, H.-R.; Petersen, J. L. J. Org. Chem. 1999,
64, 1650-1656. (b) Zhang, H.-R.; Wang, K. K. J. Org. Chem. 1999, 64,
7996-7999. (c) Li, H.; Petersen, J. L.; Wang, K. K. J. Org. Chem. 2001,
66, 7804-7810. (d) Yang, Y.; Petersen, J. L.; Wang, K. K. J. Org. Chem.
2003, 68, 5832-5837. (e) Yang, Y.; Petersen, J. L.; Wang, K. K. J. Org.
Chem. 2003, 68, 8545-8549. (f) Dai, W.; Petersen, J. L.; Wang, K. K.
Org. Lett. 2004, 6, 4355-4357. (g) Han, X.; Zhang, Y.; Wang, K. K. J.
Org. Chem. 2005, 70, 2406-2408. (h) Wang, K. K. In Modern Allene
Chemistry; Krause, N., Hashmi, A. S. K., Eds.; Wiley-VCH: Weinheim,
Germany, 2004; Vol. 2, pp 1091-1126.
It was reported earlier that placing a sterically de-
manding substituent, such as tert-butyl or trimethylsilyl,
at the alkynyl terminus of the enyne-allene system also
(4) Schmittel, M.; Steffen, J.-P.; Bohn, I. Heterocycl. Commun. 1997,
3, 443-447.
(7) Katritzky, A. R.; Schwarz, O. A.; Rubio, O.; Markees, D. G. Helv.
Chim. Acta 1984, 67, 939-946.
(5) (a) Zhang, Q.; Shi, C.; Zhang, H.-R.; Wang, K. K. J. Org. Chem.
2000, 65, 7977-7983. (b) Lu, X.; Petersen, J. L.; Wang, K. K. J. Org.
Chem. 2002, 67, 5412-5415. (c) Lu, X.; Petersen, J. L.; Wang, K. K. J.
Org. Chem. 2002, 67, 7797-7801.
(6) Lu, X.; Petersen, J. L.; Wang, K. K. Org. Lett. 2003, 5, 3277-
3280.
(8) (a) Alaimo, R. J.; Hatton, C. J.; Eckman, M. K. J. Med. Chem.
1970, 13, 554-556. (b) Alaimo, R. J.; Goldenberg, M. M. J. Med. Chem.
1975, 18, 1145-1147. (c) Marivingt-Mounir, C.; Norez, C.; De´rand, R.;
Bulteau-Pignoux, L.; Nguyen-Huy, D.; Viossat, B.; Morgant, G.; Becq,
F.; Vierfond, J.-M.; Mettey, Y. J. Med. Chem. 2004, 47, 962-972. (d)
Ihmels, H.; Faulhaber, K.; Wissel, K.; Bringmann, G.; Messer, K.; Viola,
6648 J. Org. Chem., Vol. 70, No. 17, 2005

Indeno-Fused Quinolizinium Salts via Benzannulated Enyne-Allenes
SCHEME 3
SCHEME 4
SCHEME 5
SCHEME 6
directed the biradical-forming reaction toward the Schmit-
tel cyclization pathway.1c We have thus synthesized the
benzannulated enediynes 19a and 19b bearing a tert-
butyl group and a trimethylsilyl group at the alkynyl
terminus, respectively, as outlined in Scheme 3. The
starting iodide 16 was prepared by the palladium-
catalyzed Sonogashira reaction between 1,2-diiodoben-
zene and propargyl alcohol as described previously.9
Unlike 11b, which underwent cyclization on exposure to
triethylamine at room temperature to form 15b, it was
necessary to heat the reaction mixtures of 19a and 19b
under refluxing ethanol to produce 20a and 20b. It was
also necessary to purify the resulting products by column
chromatography because significant amounts of uniden-
1
tified byproducts were present as indicated by H NMR
spectra. Purification by column chromatography on neu-
tral alumina resulted in an exchange of the mesylate
anion by chloride to produce quinolizinium chlorides 21a
and 21b in relatively low yields. The structure of 21a
was established by X-ray structure analysis.
cyclized adduct 24 (22:24 ) 1:4) was produced in 98%
combined yield (Scheme 5). Upon treatment of the
mixture with potassium tert-butoxide, 22 was converted
to 24 in essentially quantitative yield. The structure of
24 was established by X-ray structure analysis. A variety
of imidazo[1,2-a]pyridine derivatives were also reported
to exhibit useful pharmacological activities.11
Unlike biradicals 13, a direct intramolecular radical-
radical coupling involving a π bond of the imidazole
substituent of biradical 26 could not be achieved (Scheme
6). Instead, a 6-exo-trig radical cyclization reaction
involving the carbon-nitrogen double bond to form
biradical 27 occurred and, after a prototropic rearrange-
ment, produced 24. This is reminiscent of what had been
An attempt to alkylate imidazole with 9 in a mixture
containing sodium hydroxide and tetrabutylammonium
iodide to produce 22 resulted in the formation of the
indeno-fused imidazo[1,2-a]pyridine 24 directly albeit in
relatively low yield (Scheme 4). Presumably 22 was
formed initially, which then underwent a sodium hy-
droxide-promoted 1,3-prototropic rearrangement to the
corresponding benzannulated enyne-allene 23 for the
subsequent cascade reaction sequence to yield 24. Alter-
natively, the palladium-catalyzed Sonogashira reaction
between 7 and 1-(2-propynyl)-1H-imidazole (25)10 was
employed to produce 22. Under the reaction condition, a
mixture of the benzannulated enediyne 22 and the
(11) (a) Kno¨lker, H.-J.; Boese, R.; Hitzemann, R. Chem. Ber. 1990,
123, 327-339. (b) Gueiffier, A.; Mavel, S.; Lhassani, M.; Elhakmaoui,
A.; Snoeck, R.; Andrei, G.; Chavignon, O.; Teulade, J.-C.; Witvrouw,
M.; Balzarini, J.; De Clercq, E.; Chapat, J.-P. J. Med. Chem. 1998, 41,
5108-5112. (c) Kaminski, J. J.; Doweyko, A. M. J. Med. Chem. 1997,
40, 427-436. (d) Sanfilippo, P. J.; Urbanski, M.; Press, J. B.; Dubinsky,
B.; Moore, J. B., Jr. J. Med. Chem. 1988, 31, 2221-2227. (e) Gueiffier,
A.; Lhassani, M.; Elhakmaoui, A.; Snoeck, R.; Andrei, G.; Chavignon,
O.; Teulade, J.-C.; Kerbal, A.; Essassi, E. M.; Debouzy, J.-C.; Witvrouw,
M.; Blache, Y.; Balzarini, J.; De Clercq, E.; Chapat, J.-P. J. Med. Chem.
1996, 39, 2856-2859.
G.; Vedaldi, D. Eur. J. Org. Chem. 2001, 1157-1161. (e) Pastor, J.;
Siro, J. G.; Garc´ıa-Nav´ıo, J. L.; Vaquero, J. J.; Alvarez-Builla, J.; Gago,
F.; de Pascual-Teresa, B.; Pastor, M.; Rodrigo, M. M. J. Org. Chem.
1997, 62, 5476-5483.
(9) Grissom, J. W.; Klingberg, D.; Huang, D.; Slattery, B. J. J. Org.
Chem. 1997, 62, 603-626.
(10) Casaschi, A.; Grigg, R.; Sansano, J. M. Tetrahedron 2001, 57,
607-615.
J. Org. Chem, Vol. 70, No. 17, 2005 6649

Dai et al.
SCHEME 7
Conclusions
Benzannulated enyne-allenes bearing a heteroaro-
matic substituent at the allenic terminus are excellent
precursors of a variety of indeno-fused heteroaromatic
ring systems. The use of the 1,3-prototropic rearrange-
ment of the corresponding benzannulated enediynes to
furnish enyne-allenes is especially attractive because of
the simplicity of the procedure and ready availability of
enediynes with diverse structural features. The resulting
heteroaromatic compounds are of interest as potential
candidates for pharmacological applications.
SCHEME 8
Experimental Section
Propargylic Alcohol 8. To a solution of 6 (480 mg, 1.87
mmol) in 20 mL of anhydrous diethyl ether at -78 °C was
added dropwise 0.9 mL of a 2.5 M solution of n-butyllithium
(2.25 mmol) in hexanes. After 1 h of stirring at -78 °C, a
solution of 640 mg of iodine (2.52 mmol) in 30 mL of anhydrous
diethyl ether was added dropwise via cannula. The reaction
mixture was allowed to warm to room temperature before 15
mL of a 5% sodium thiosulfate solution was introduced. The
organic layer was separated, washed with water, dried over
sodium sulfate, and concentrated to give 477 mg of 7. To a
mixture of 477 mg of the crude iodide 7, 55 mg (0.078 mmol)
of Pd(PPh3)2Cl2, and 29 mg (0.15 mmol) of copper(I) iodide in
25 mL of triethylamine under a nitrogen atmosphere was
added dropwise via cannula a solution of 240 mg of propargyl
alcohol (4.29 mmol) in 5 mL of triethylamine. The reaction
mixture was stirred vigorously at 75 °C for 12 h before it was
allowed to cool to room temperature. Then 50 mL of a
saturated NH4Cl solution and 50 mL of diethyl ether were
introduced. The organic layer was separated, and the aqueous
layer was back extracted with diethyl ether. The combined
organic layers were washed with water, dried over MgSO4, and
concentrated. The residue was purified by column chromatog-
raphy (silica gel/diethyl ether:hexanes ) 3:7) to give 286 mg
(1.23 mmol, 66% overall yield) of 8 as a colorless liquid: IR
observed previously in a benzannulated enyne-allene
system bearing a 1-pyrrolyl substituent at the allenic
terminus.4 It is also worth noting that because 29 was
not observed the radical cyclization reaction did not
appear to occur with the carbon-carbon double bond of
the imidazole ring to give biradical 28.
The palladium-catalyzed Sonogashira reaction between
7 and 1-(2-propynyl)-1H-indole (30)12 was successful in
producing 31 in excellent yield (Scheme 7). Treatment
of 31 with potassium tert-butoxide at room temperature
for 48 h produced the indeno-fused pyrido[1,2-a]indole
32 in 98% yield. It was reported that some pyrido[1,2-
a]indole derivatives were unstable on exposure to air and
decomposed to tarry materials in chloroform and meth-
3334, 2217, 755, 690 cm-1 1H δ 7.45-7.60 (4 H, m), 7.23-
;
7.40 (5 H, m), 4.57 (2 H, d, J ) 5.9 Hz), 1.75 (1 H, t, J ) 6.2
Hz); 13C δ 131.9, 131.7, 128.5, 128.4, 128.2, 127.9, 125.8, 125.0,
123.1, 93.5, 91.3, 88.0, 84.5, 51.8; MS m/z 232 (M+), 231, 202,
101.
Propargyl Methanesulfonate 9. To a solution of 8 (322
mg, 1.39 mmol) and triethylamine (211 mg, 2.01 mmol) in 10
mL of methylene chloride at -50 °C under a nitrogen atmo-
sphere was added dropwise methanesulfonyl chloride (207 mg,
1.81 mmol). The reaction mixture was allowed to warm to room
temperature and stirred for 1 h before 5 mL of water was
introduced. The organic layer was separated, and the aqueous
layer was back extracted with methylene chloride. The com-
bined organic layers were washed with water, dried over
MgSO4, and concentrated. The residue was purified by column
chromatography (silica gel/diethyl ether:hexanes ) 3:7) to give
353 mg (1.14 mmol, 82%) of 9 as a colorless liquid: IR 2217,
1360 cm-1; 1H δ 7.48-7.61 (4 H, m), 7.28-7.42 (5 H, m), 5.18
(2 H, s), 3.12 (3 H, s); 13C δ 132.3, 132.0, 131.7, 129.2, 128.8,
128.5, 128.1, 126.2, 123.5, 122.7, 93.9, 88.1, 87.5, 84.6, 58.5,
39.2.
1
ylene chloride solutions.13 The H NMR spectrum of 32
in CDCl3, taken immediately after the solution was
prepared, was found to be relatively clean. However, the
solution gradually turned dark on standing at room
temperature. Attempts to purify 32 by silica gel column
chromatography also appeared to cause some decomposi-
tion.
Similarly, 34 was produced from coupling between 7
and 1-(2-propynyl)-2(1H)-pyridinone (33)10 (Scheme 8).
Treatment of 34 with potassium tert-butoxide under
refluxing toluene for 12 h produced the indeno-fused 4H-
quinolizin-4-one 35 in 56% yield. The structure of 35 was
established by X-ray structure analysis. Development of
new synthetic pathways to 4H-quinolizin-4-ones is an
area of interest because these heteroaromatic compounds
could serve as precursors to naturally occurring alkaloids
possessing interesting biological activities.14
Pyridinium Methanesulfonate 11a. To a solution of 9
(186 mg, 0.600 mmol) in 5 mL of methylene chloride was added
dropwise a solution of 4-aminopyridine (56 mg, 0.60 mmol) in
5 mL of methylene chloride. The reaction mixture was stirred
at room temperature for 24 h and concentrated. The residue
was washed with diethyl ether to give 242 mg (0.599 mmol,
(12) Galons, H.; Bergerat, I.; Combet-Farnoux, C.; Miocque, M.;
Decodts, G.; Bram, G. J. Chem. Soc., Chem. Commun. 1985, 23, 1730-
(14) (a) Eberbach, W.; Maier, W. Tetrahedron Lett. 1989, 30, 5591-
5594. (b) Forti, L.; Gelmi, M. L.; Pocar, D.; Varallo, M. Heterocycles
1986, 24, 1401-1410. (c) Goldberg, S. I.; Lipkin, A. H. J. Org. Chem.
1970, 35, 242-244.
1731.
(13) Ohsawa, A.; Kawaguchi, T.; Igeta, H. J. Org. Chem. 1982, 47,
3497-3503.
6650 J. Org. Chem., Vol. 70, No. 17, 2005

Indeno-Fused Quinolizinium Salts via Benzannulated Enyne-Allenes
100%) of 11a as a colorless solid: mp 189-190 °C; IR 3330,
3120, 1197 cm-1; 1H δ 8.11 (2 H, s), 7.97 (2 H, d, J ) 6.9 Hz),
7.22-7.52 (9 H, m), 6.96 (2 H, d, J ) 6.9 Hz), 5.23 (2 H, s),
2.79 (3 H, s); 13C δ 159.7, 140.9, 132.2, 132.0, 131.5, 129.2,
129.0, 128.6, 128.2, 126.0, 123.3, 122.4, 93.7, 88.0, 87.4, 83.6,
47.6, 39.7.
was removed in vacuo, and the residue was purified by column
chromatography (neutral alumina/ethanol:methylene chloride
) 1:10) to give 7 mg (0.020 mmol, 32%) of 21a as a yellow
solid: mp >360 °C; IR 1646, 1236, cm-1; 1H δ 10.14 (1 H, d, J
) 7.6 Hz), 9.52 (1 H, s), 8.03 (1 H, dd, J ) 6.9, 2.1 Hz), 7.60 (1
H, d, J ) 6.6 Hz), 7.41-7.51 (2 H, m), 7.24 (1 H, dd, J ) 7.6,
2.9 Hz), 7.11 (1 H, d, J ) 2.6 Hz), 4.17 (2 H, s), 3.27 (6 H, s),
1.77 (9 H, s); 13C δ 150.4, 148.1, 146.3, 143.5, 139.1, 138.6,
136.2, 133.7, 130.4, 129.7, 127.1, 126.7, 125.7, 109.1, 101.8,
40.1, 37.1, 34.7, 31.8. Recrystallization of 21a from a mixture
of dichloromethane and hexanes produced a crystal suitable
for X-ray structure analysis.
2-Amino-12-phenyl-7H-indeno[1,2-b]quinolizin-5-ium
Methanesulfonate (15a). A solution of 11a (45 mg, 0.11
mmol) and triethylamine (11 mg, 0.11 mmol) in 10 mL of
ethanol was heated under reflux for 12 h. The solvent was
removed and the residue was washed with diethyl ether to
give 45 mg (0.11 mmol, 100%) of 15a as a yellow solid:
compound becomes black at 270 °C without melting; IR 3361,
1652, 1194 cm-1; 1H δ 8.67 (1 H, d, J ) 7.4 Hz), 8.63 (1 H, s),
7.60-7.62 (3 H, m), 7.52 (1 H, d, J ) 7.6 Hz), 7.28-7.39 (4 H,
m), 7.05 (1 H, t, J ) 7.6 Hz), 6.33-6.43 (2 H, m), 4.13 (2 H, s),
2.99 (2 H, s), 2.75 (3 H, s); 13C (10% CD3OD in CDCl3) δ 153.9,
145.5, 145.1, 144.4, 136.9, 136.6, 133.4, 131.9, 131.0, 130.0,
129.4, 129.1, 128.5, 127.5, 126.7, 125.4, 125.2, 112.9, 101.6,
38.9, 33.8. Recrystallization of 15a from a mixture of chloro-
form and methanol produced a crystal suitable for X-ray
structure analysis.
11-Phenyl-6H-indeno[1,2-d]imidazo[1,2-a]pyridine (24).
To a stirred mixture of imidazole (10 mg, 0.15 mmol), tetrabu-
tylammonium iodide (27 mg, 0.073 mmol), and sodium hy-
droxide (50% aqueous solution, 0.52 mL) in toluene (0.41 mL)
was added 9 (47 mg, 0.15 mmol). After 15 min at room
temperature, toluene (0.5 mL) and water (0.5 mL) were added.
The organic layer was separated, washed with water, dried
over MgSO4, and concentrated. The residue was purified by
column chromatography (silica gel/diethyl ether:methanol )
100:3) to give 11 mg (0.039 mmol, 26%) of 24 as a pale yellow
solid.
Alternatively, 24 was synthesized by treatment of a mixture
of 15 mg (0.021 mmol) of Pd(PPh3)2Cl2, 7.5 mg (0.039 mmol)
of copper(I) iodide, and 200 mg (0.658 mmol) of 7 under a
nitrogen atmosphere with 5 mL of DMF, 2 mL of triethy-
lamine, and a solution of 85 mg (0.80 mmol) of 25 in 5 mL of
DMF. The reaction mixture was heated at 100 °C for 48 h
before it was allowed to cool to room temperature. The reaction
mixture was then poured into a flask containing 40 mL of ethyl
acetate and 5 mL of a saturated NH4Cl solution. The organic
layer was separated, washed with water, dried over MgSO4,
and concentrated. The residue was purified by column chro-
matography (silica gel/diethyl ether:methanol ) 100:3) to give
181 mg (0.642 mmol, 98%) of a mixture of 22 and 24 (1:4) as
a pale yellow solid. The 1H NMR spectrum of the mixture
exhibited a singlet at δ 5.02, attributable to the methylene
hydrogens of 22.
Propargylic Alcohol 17a. To a mixture of 269 mg (1.04
mmol) of 16, 22 mg (0.030 mmol) of Pd(PPh3)2Cl2, and 11 mg
(0.060 mmol) of copper(I) iodide in 20 mL of triethylamine
under a nitrogen atmosphere was added dropwise via cannula
a solution of 103 mg of 3,3-dimethyl-1-butyne (1.25 mmol) in
5 mL of triethylamine. The reaction mixture was stirred at
room temperature for 12 h before 20 mL of a saturated NH4-
Cl solution and 50 mL of diethyl ether were introduced. The
organic layer was separated, and the aqueous layer was back
extracted with diethyl ether. The combined organic layers were
washed with water, dried over MgSO4, and concentrated. The
residue was purified by column chromatography (silica gel/
diethyl ether:hexanes ) 1:2) to give 203 mg (0.96 mmol, 92%)
of 17a as a colorless liquid: IR 3331, 1025, 755 cm-1 1H δ
;
7.33-7.42 (2 H, m), 7.14-7.25 (2 H, m), 4.52 (2 H, s), 1.97 (1
H, br), 1.33 (9 H, s); 13C δ 131.6, 131.5, 128.1, 127.1, 126.6,
124.9, 103.0, 90.6, 84.6, 77.7, 51.6, 30.9, 28.1; MS m/z 212 (M+),
197, 178, 165.
To a solution of 181 mg (0.642 mmol) of a mixture of 22
and 24 (1:4) in 5 mL of tert-butyl alcohol under a nitrogen
atmosphere was added 0.64 mL of a 1.0 M solution of
potassium tert-butoxide in tert-butyl alcohol. The reaction
mixture was stirred at room temperature for 12 h before 5 mL
of water and 20 mL of ethyl acetate were introduced. The
organic layer was separated, washed with water, dried over
MgSO4, and concentrated. The residue was purified by column
chromatography (silica gel/diethyl ether:methanol ) 100:3) to
give 181 mg (0.642 mmol, 100%) of 24 as a pale yellow solid:
mp 217-218 °C; IR 1301, 1234, 727, 699 cm-1; 1H δ 8.34 (1 H,
s), 7.68 (1 H, d, J ) 1.2 Hz), 7.47-7.64 (7 H, m), 7.29 (1 H, td,
J ) 7.4, 1.0 Hz), 7.08 (1 H, t, J ) 7.9 Hz), 6.87 (1 H, d, J ) 7.9
Hz), 4.07 (2 H, s); 13C δ 145.7, 144.0, 139.3, 137.2, 134.9, 133.8,
129.6, 129.1, 128.6, 128.4, 128.1, 126.9, 125.1, 123.9, 120.0,
112.3, 33.6. Recrystallization of 24 from a mixture of dichlo-
romethane and hexanes produced a crystal suitable for X-ray
structure analysis.
Indole 31. To a mixture of 7 mg (0.010 mmol) of Pd(PPh3)2-
Cl2, 4 mg (0.020 mmol) of copper(I) iodide, and 104 mg (0.34
mmol) of 7 under a nitrogen atmosphere was added in
sequence 5 mL of DMF, 2 mL of triethylamine, and a solution
of 58 mg (0.38 mmol) of 30 in 5 mL of DMF. After 4 h of stirring
at room temperature, the reaction mixture was poured into a
flask containing 40 mL of ethyl acetate and 5 mL of a saturated
NH4Cl solution. The organic layer was separated, washed with
water, dried over MgSO4, and concentrated. The residue was
purified by column chromatography (silica gel/hexanes:meth-
ylene chloride ) 95:5) to give 111 mg (0.335 mmol, 99%) of 31
as a white solid: mp 123-124 °C; IR 2216, 1494, 755, 742,
690 cm-1; 1H δ 7.67-7.71 (1 H, m), 7.48-7.58 (3 H, m), 7.39-
7.46 (3 H, m), 7.28-7.38 (5 H, m), 7.14-7.26 (2 H, m), 6.52 (1
H, dd, J ) 3.2, 0.8 Hz), 5.19 (2 H, s); 13C δ 135.8, 132.1, 131.9,
Propargyl Methanesulfonate 18a. To a solution of 17a
(68 mg, 0.32 mmol) and triethylamine (49 mg, 0.48 mmol) in
10 mL of methylene chloride at -50 °C under a nitrogen
atmosphere was added dropwise methanesulfonyl chloride (48
mg, 0.42 mmol). The reaction mixture was allowed to warm
to room temperature and stirred for 1 h before 5 mL of water
was introduced. The organic layer was separated, and the
aqueous layer was back extracted with methylene chloride.
The combined organic layers were washed with water, dried
over MgSO4, and concentrated. The residue was purified by
column chromatography (silica gel/ethyl acetate:hexanes ) 1:2)
to give 76 mg (0.26 mmol, 81%) of 18a as a colorless liquid:
IR 2239, 1362, 1179 cm-1; 1H δ 7.35-7.44 (2 H, m), 7.28 (1 H,
td, J ) 7.6, 1.6 Hz), 7.21 (1 H, td, J ) 7.4, 1.6 Hz), 5.11 (2 H,
s), 3.16 (3 H, s), 1.34 (9 H, s); 13C δ 132.0, 131.8, 129.0, 127.2,
127.1, 103.6, 88.3, 83.8, 77.3, 58.4, 39.2, 30.9, 28.1.
Pyridinium Methanesulfonate 19a. To a solution of 18a
(26 mg, 0.090 mmol) in 5 mL of methylene chloride was added
dropwise a solution of 4-(dimethylamino)pyridine (11 mg, 0.090
mmol) in 5 mL of methylene chloride. The reaction mixture
was stirred at room temperature for 24 h and concentrated.
The residue was washed with diethyl ether to give 36 mg
(0.087 mmol, 97%) of 19a as a colorless solid: mp 127-128
1
°C; IR 2238, 1652, 1192 cm-1; H δ 8.56 (2 H, d, J ) 7.4 Hz),
7.35-7.41 (2 H, m), 7.16-7.28 (2 H, m), 6.96 (2 H, d, J ) 7.6
Hz), 5.44 (2 H, s), 3.22 (6 H, s), 2.75 (3 H, s), 1.25 (9 H, s); 13
C
δ 156.5, 141.9, 132.3, 131.9, 129.0, 127.3, 126.8, 123.1, 108.1,
103.2, 88.6, 82.7, 47.7, 40.3, 39.5, 30.9, 28.1.
2-(Dimethylamino)-12-(1,1-dimethylethyl)-7H-indeno-
[1,2-b]quinolizin-5-ium Chloride (21a). A solution of 19a
(26 mg, 0.063 mmol) and triethylamine (6 mg, 0.06 mmol) in
10 mL of ethanol was heated under reflux for 48 h. The solvent
J. Org. Chem, Vol. 70, No. 17, 2005 6651

Dai et al.
131.7, 128.8, 128.4, 128.33, 128.28, 127.9, 127.3, 125.9, 124.7,
122.9, 121.8, 121.0, 119.7, 109.4, 101.8, 93.4, 87.9, 86.9, 84.0,
36.7.
anhydrous toluene under a nitrogen atmosphere was added
0.5 mL of a 1.0 M solution of potassium tert-butoxide in tert-
butyl alcohol. The reaction mixture was heated under reflux
for 12 h. After the reaction mixture was allowed to cool to room
temperature, 20 mL of water and 50 mL of ethyl acetate were
introduced. The organic layer was separated, washed with
water, dried over MgSO4, and concentrated. The residue was
purified by column chromatography (silica gel/methanol:me-
thylene chloride ) 1:100) to give 87 mg (0.28 mmol, 56%) of
12-Phenyl-7H-indeno[1′,2′:4,5]pyrido[1,2-a]indole (32).
To a solution of 41 mg (0.12 mmol) of 31 in 5 mL of anhydrous
toluene under a nitrogen atmosphere was added 0.1 mL of a
1.0 M solution of potassium tert-butoxide in tert-butyl alcohol.
After 48 h of stirring at room temperature, 5 mL of water and
20 mL of ethyl acetate were introduced. The organic layer was
separated, washed with water, dried over MgSO4, and con-
centrated. The residue was purified by column chromatogra-
phy (silica gel/hexanes:methylene chloride ) 95:5) to give 40
mg (0.12 mmol, 98%) of 32 as a pale yellow solid: mp 170-
35 as a pale yellow solid: mp 205-207 °C; IR 1659, 1482 cm-1
;
1H δ 9.44 (1 H, s), 7.59-7.72 (3 H, m), 7.50-7.59 (2 H, m),
7.32-7.43 (3 H, m), 7.08 (1 H, t, J ) 7.9 Hz), 6.69 (1 H, d, J )
8.6 Hz), 6.46 (1 H, d, J ) 7.9 Hz), 6.36 (1 H, d, J ) 7.9 Hz),
4.18 (2 H, s); 13C δ 145.5, 143.4, 141.9, 138.1, 137.0, 135.6,
130.5, 129.8, 129.7, 129.5, 129.0, 128.9, 127.3, 125.4, 124.8,
121.7, 107.4, 103.3, 34.4. Recrystallization of 35 from a mixture
of dichloromethane and hexanes under a nitrogen atmosphere
produced a crystal suitable for X-ray structure analysis.
1
173 °C; IR 1459, 1323, 762, 724, 700 cm-1; H δ 8.44 (1 H, s),
7.90 (1 H, d, J ) 7.6 Hz), 7.70 (1 H, d, J ) 7.6 Hz),7.50-7.65
(5 H, m), 7.48 (1 H, d, J ) 7.6 Hz), 7.22-7.35 (3 H, m), 7.05 (1
H, t, J ) 7.5 Hz), 6.79 (1 H, d, J ) 7.9 Hz), 6.31 (1 H, s), 4.09
(2 H, s); 13C δ 144.4, 139.5, 138.5, 137.0, 134.5, 129.5, 129.1,
128.2, 127.8, 126.7, 125.2, 123.9, 123.7, 122.4, 120.3, 119.4,
118.1, 110.0, 91.9, 33.6.
Acknowledgment. K.K.W. thanks the Petroleum
Research Fund (38169-AC1), administered by the Ameri-
can Chemical Society, and the National Science Foun-
dation (CHE-0414063) for financial support. J.L.P.
acknowledges the support (CHE-9120098) provided by
the National Science Foundation for the acquisition of
a Siemens P4 X-ray diffractometer.
2(1H)-Pyridinone 34. To a mixture of 12 mg (0.017 mmol)
of Pd(PPh3)2Cl2, 6.5 mg (0.034 mmol) of copper(I) iodide, and
171 mg (0.56 mmol) of 7 under a nitrogen atmosphere was
added in sequence 5 mL of DMF, 2 mL of triethylamine, and
a solution of 82 mg (0.62 mmol) of 33 in 5 mL of DMF. After
1 h of stirring at room temperature, the reaction mixture was
poured into a flask containing 40 mL of ethyl acetate and 10
mL of a saturated NH4Cl solution. The organic layer was
separated, washed with water, dried over MgSO4, and con-
centrated. The residue was purified by column chromatogra-
phy (silica gel/hexanes:ethyl acetate ) 1:1) to give 171 mg
(0.553 mmol, 99%) of 34 as a colorless solid: mp 76-78 °C; IR
Supporting Information Available: Experimental pro-
cedures and spectroscopic data for 11b,c, 15b,c, 18b, 19b, and
21b; 1H and 13C NMR spectra of compounds 8, 9, 11a-c, 15a-
c, 17a, 18a,b, 19a,b, 21a,b, 24, 31, 32, 34, and 35; and ORTEP
drawings of the crystal structures of 15a-c, 21a, 24, and 35
in PDF format; and X-ray crystallographic data of 15a-c, 21a,
24, and 35 as CIF. This material is available free of charge
via the Internet at http://pubs.acs.org.
1
1660, 1588, 1538, 757 cm-1; H δ 7.91 (1 H, dt, J ) 6.9, 0.9
Hz), 7.45-7.57 (4 H, m), 7.24-7.39 (6 H, m), 6.58 (1 H, dd, J
) 9.2, 0.5 Hz), 5.93 (1 H, dt, J ) 6.7, 0.8 Hz), 5.07 (2 H, s); 13
C
δ 162.1, 139.7, 135.7, 132.0, 131.9, 131.7, 128.6, 128.4, 128.1,
125.9, 124.3, 122.8, 120.2, 106.4, 93.4, 87.8, 86.6, 85.6, 38.5.
4,7-Dihydro-12-phenylindeno[2,1-g]quinolizin-4-one
(35). To a solution of 155 mg (0.502 mmol) of 34 in 30 mL of
JO0505730
6652 J. Org. Chem., Vol. 70, No. 17, 2005