Biradicals/zwitterions from enallene-isonitriles. Formal [4 + 1] cycloadditions leading to 11H-indeno[1,2-b]quinoline and related compounds

Article abstract of DOI:10.1021/ol035143f

1,3-Prototropic rearrangement of the benzannulated enyne-isonitriles to the corresponding enallene-isonitriles followed by cycloaromatization generated the putative quinoline biradicals/zwitterions. A subsequent intramolecular radical-radical coupling or electrophilic aromatic substitution then gave the formal [4 + 1] cycloaddition adducts leading to 11H-indeno[1,2-b]quinoline and related compounds.

Full text of DOI:10.1021/ol035143f

ORGANIC
LETTERS
2003
Vol. 5, No. 18
3277-3280
Biradicals/Zwitterions from
Enallene-Isonitriles. Formal [4 + 1]
Cycloadditions Leading to
11H-Indeno[1,2-b]quinoline and Related
Compounds
Xiaoling Lu, Jeffrey L. Petersen,† and Kung K. Wang*
Department of Chemistry, West Virginia UniVersity,
Morgantown, West Virginia 26506-6045
kung.wang@mail.wVu.edu
Received June 20, 2003
ABSTRACT
1,3-Prototropic rearrangement of the benzannulated enyne-isonitriles to the corresponding enallene-isonitriles followed by cycloaromatization
generated the putative quinoline biradicals/zwitterions. A subsequent intramolecular radical−radical coupling or electrophilic aromatic substitution
then gave the formal [4 + 1] cycloaddition adducts leading to 11H-indeno[1,2-b]quinoline and related compounds.
Thermolysis of (Z)-3-hexene-1,5-diynes (enediynes) at el-
evated temperatures provides direct access to 1,4-didehy-
drobenzene biradicals. Specifically, the parent (Z)-3-hexene-
1,5-diyne, which is stable at 25 °C, undergoes the Bergman
cyclization reaction at 200 °C with a half-life of ca. 30 s
(eq 1).1
Replacing one of the alkynyl groups of enediynes with an
allenic group causes the resulting (Z)-1,2,4-heptatrien-6-ynes
(enyne-allenes) to be thermally much more labile. The parent
(Z)-1,2,4-heptatrien-6-yne undergoes the Myers-Saito cy-
clization reaction to form the R,3-didehydrotoluene biradical
at 37 °C with a half-life of 24 h (eq 2).2 A different mode of
cyclization of enyne-allenes leading to fulvene biradicals
(Schmittel cyclization) under mild thermal conditions has
also been reported.3 Several heterocumulenes such as ketene,
(1) (a) Jones, R. R.; Bergman, R. G. J. Am. Chem. Soc. 1972, 94, 660-
661. (b) Lockhart, T. P.; Comita, P. B.; Bergman, R. G. J. Am. Chem. Soc.
1981, 103, 4082-4090. For reviews, see: (c) Nicolaou, K. C.; Dai, W.-H.
Angew. Chem., Int. Ed. Engl. 1991, 30, 1387-1416. (d) Wang, K. K. Chem.
ReV. 1996, 96, 207-222. (e) Grissom, J. W.; Gunawardena, G. U.;
Klingberg, D.; Huang. D. Tetrahedron 1996, 52, 6453-6518.
(2) (a) Myers, A. G.; Kuo, E. Y.; Finney, N. S. J. Am. Chem. Soc. 1989,
111, 8057-8059. (b) Myers, A. G.; Dragovich, P. S. J. Am. Chem. Soc.
1989, 111, 9130-9132. (c) Nagata, R.; Yamanaka, H.; Okazaki, E.; Saito,
I. Tetrahedron Lett. 1989, 30, 4995-4998. (d) Nagata, R.; Yamanaka, H.;
Murahashi, E.; Saito, I. Tetrahedron Lett. 1990, 31, 2907-2910.
† 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.
10.1021/ol035143f CCC: $25.00 © 2003 American Chemical Society
Published on Web 08/12/2003

ketenimine, and carbodiimide have also been successfully
employed to form enyne-ketenes (Moore cyclization),4
enyne-ketenimines,5 and enyne-carbodiimides6 for biradical-
forming reactions.
Scheme 1
The use of the isoelectronic nitrile group as a substitute
for the alkynyl group was less successful. (Z)-â-Alkynyl-
acrylonitriles apparently did not exhibit any propensity to
undergo aza-Bergman cyclization in 1,4-cyclohexadiene at
150 °C for 2 h.7 (Z)-2,4,5-Hexatrienenitriles and related
compounds also showed remarkable thermal stability at 150-
260 °C.8 Only in a benzannulated example where the allenic
terminus was substituted with a sulfone group was the
cycloaromatization reaction observed.9
The chemical reactivities of isonitrile in the benzannulated
enyne-isonitrile system were exploited for tin- and sulfur-
mediated intramolecular free-radical cyclization as well as
nucleophile-induced intramolecular cyclization, producing
substituted indoles and quinolines.10 However, the feasibility
of generating biradicals by thermolysis of enyne-isonitriles
did not appear to have been explored. Theoretical studies
suggest a relatively low barrier of activation enthalpy and
favorable exothermicity for the aza-Bergman cyclization
reaction of (Z)-but-1-en-3-yn-1-yl isonitrile to form 2,4-
didehydropyridine compared to other types of Bergman
cyclization reaction.11 We envisioned that by placing the
reactive isonitrile and allenic moieties on the adjacent carbon
atoms of benzene, the resulting benzannulated enallene-
isonitrile system could provide excellent opportunities for
generating biradicals under mild thermal conditions.
1,3-Prototropic rearrangement of enyne-isonitriles provided
a simple synthetic route to enallene-isonitriles as outlined
in Scheme 1. The 2-alkynylformanilide 1 was prepared by
the palladium-catalyzed cross-coupling between 2-iodofor-
manilide and 3-phenyl-1-propyne. Dehydration of 1 with
POCl3/i-Pr2NH12 then afforded in situ the enyne-isonitrile
2, which exhibited IR signals at 2121 and 2202 cm-1
attributable to the isonitrile and the alkynyl functionalities,
respectively. The enyne-isonitrile 2 did not appear to undergo
cycloaromatization even after it was kept at 0 °C for 6 h
and then at room temperature for an additional 2 h. However,
treatment of 2 with potassium t-butoxide at room temperature
then afforded 11H-indeno[1,2-b]quinoline (6) in 52% yield
from 1.
(3) (a) Schmittel, M.; Strittmatter, M.; Kiau, S. Tetrahedron Lett. 1995,
36, 4975-4978. (b) Schmittel, M.; Strittmatter, M.; Vollmann, K.; Kiau,
S. Tetrahedron Lett. 1996, 37, 999-1002. (c) Schmittel, M.; Strittmatter,
M.; Kiau, S. Angew. Chem., Int. Ed. Engl. 1996, 35, 1843-1845. (d)
Schmittel, M.; Kiau, S.; Siebert, T.; Strittmatter, M. Tetrahedron Lett. 1996,
37, 7691-7694. (e) Schmittel, M.; Keller, M.; Kiau, S.; Strittmatter, M.
Chem. Eur. J. 1997, 3, 807-816. (f) Schmittel, M.; Steffen, J.-P.; Maywald,
M.; Engels, B.; Helten, H.; Musch, P. J. Chem. Soc., Perkin Trans. 2 2001,
1331-1339.
(4) (a) Karlsson, J. O.; Nguyen, N. V.; Foland, L. D.; Moore, H. W. J.
Am. Chem. Soc. 1985, 107, 3392-3393. (b) Foland, L. D.; Karlsson, J. O.;
Perri, S. T.; Schwabe, R.; Xu, S. L.; Patil, S.; Moore, H. W. J. Am. Chem.
Soc. 1989, 111, 975-989. (c) Chow, K.; Nguyen, N. V.; Moore, H. W. J.
Org. Chem. 1990, 55, 3876-3880. (d) Tarli, A.; Wang, K. K. J. Org. Chem.
1997, 62, 8841-8847. (e) For an excellent review, see: Moore, H. W.;
Yerxa, B. R. Chemtracts 1992, 273-313.
Presumably, the reaction proceeded through an initial 1,3-
prototropic rearrangement, induced by potassium t-butoxide,
to form the desired enallene-isonitrile 3. Potassium t-butoxide
was selected because it was known to be inert to aryl
isonitriles.13 It was also reported that the 1,3-prototropic
rearrangement of 3-phenylpropyne and 1,3-diarylpropynes
could be promoted by potassium hydroxide and basic
alumina, respectively, at ambient temperature.14 The enallene-
isonitrile 3, generated in situ, then underwent cycloaroma-
tization to give the biradical 4a. It is worth noting that the
biradical 4a could also be regarded as the zwitterion 4b with
the aryl cationic center being stabilized by the lone pair
electrons on the adjacent nitrogen atom. A subsequent
intramolecular radical-radical coupling of 4a or an intramo-
(5) (a) Shi, C.; Wang, K. K. J. Org. Chem. 1998, 63, 3517-3520. (b)
Schmittel, M.; Steffen, J.-P.; Angel, M. A. W.; Engels, B.; Lennartz, C.;
Hanrath, M. Angew. Chem., Int. Ed. 1998, 37, 1562-1564.
(6) (a) Shi, C.; Zhang, Q.; Wang, K. K. J. Org. Chem. 1999, 64, 925-
932. (b) Zhang, Q.; Shi, C.; Zhang, H.-R.; Wang, K. K. J. Org. Chem.
2000, 65, 7977-7983. (c) Lu, X.; Petersen, J. L.; Wang, K. K. J. Org.
Chem. 2002, 67, 5412-5415. (d) Lu, X.; Petersen, J. L.; Wang, K. K. J.
Org. Chem. 2002, 67, 7797-7801. (e) Li, H.; Petersen, J. L.; Wang, K. K.
J. Org. Chem. 2003, 68, 5512-5518. (f) Schmittel, M.; Steffen, J.-P.; Engels,
B.; Lennartz, C.; Hanrath, M. Angew. Chem., Int. Ed. 1998, 37, 2371-
2373. (g) Schmittel, M.; Rodr´ıguez, D.; Steffen, J.-P. Angew. Chem., Int.
Ed. 2000, 39, 2152-2155. (h) Alajar´ın, M.; Molina, P.; Vidal, A. J. Nat.
Prod. 1997, 60, 747-748.
(7) (a) David, W. M.; Kerwin, S. M. J. Am. Chem. Soc. 1997, 119, 1464-
1465. (b) Feng, L.; Kumar, D.; Kerwin, S. M. J. Org. Chem. 2003, 68,
2234-2242.
(8) (a) Wang, K. K.; Wang, Z.; Sattsangi, P. D. J. Org. Chem. 1996, 61,
1516-1518. (b) Gillmann, T.; Heckhoff, S. Tetrahedron Lett. 1996, 37,
839-840.
(9) Wu, M.-J.; Lin, C.-F.; Chen, S.-H.; Lee, F.-C. J. Chem. Soc., Perkin
Trans. 1 1999, 2875-2876.
(10) (a) Rainier, J. D.; Kennedy, A. R.; Chase, E. Tetrahedron Lett. 1999,
40, 6325-6327. (b) Rainier, J. D.; Kennedy, A. R. J. Org. Chem. 2000,
65, 6213-6216. (c) Suginome, M.; Fukuda, T.; Ito, Y. Org. Lett. 1999, 1,
1977-1979.
(11) Debbert, S. L.; Cramer, C. J. Int. J. Mass Spectrom. 2000, 201,
1-15.
(12) Obrecht, R.; Herrmann, R.; Ugi, I. Synthesis 1985, 400-402.
(13) Ugi, I.; Meyr, R. Organic Syntheses; Willy: New York, 1973;
Collect. Vol. V, pp 1060-1063.
(14) (a) Landor, P. D. In The Chemistry of the Allenes; Landor, S. R.,
Ed.; Academic Press: London, 1982; Vol. 1, pp 44-47. (b) Jacobs, T. L.;
Dankner, D. J. Org. Chem. 1957, 22, 1424-1427.
3278
Org. Lett., Vol. 5, No. 18, 2003

Scheme 2
Scheme 3
tramolecular radical-radical coupling or electrophilic aro-
matic substitution, and 1,3-prototropic rearrangement as
described for 6.
Surprisingly, when 22 having a 4-methoxypyridinium
substituent was treated with POCl3, the 2-substituted indole
25 was produced in essentially quantitative yield (Scheme
4). One of the pathways that could be used to account for
lecular electrophilic aromatic substitution of 4b afforded the
formal [4 + 1] cycloaddition adduct 5, which then produced,
after a 1,3-prototropic rearrangement, the aromatized adduct
6.
The palladium-catalyzed coupling reaction between 2-io-
doformanilide and propargyl alcohol produced the alcohol
7 (96% yield), which was then converted to the mesylate 8
and the chloride 9 (Scheme 2). Interestingly, when the
chloride 9 was subjected to a similar dehydration condition,
the cycloaromatized dichloride 1415 (41%) was produced
directly along with a small amount of the trichloride 15 (6%).
The use of diisopropylamine instead of triethylamine for
dehydration under otherwise identical condition also fur-
nished 14 (38%) and 15 (12%) in a single operation.
Presumably, under the reaction conditions, the benzannulated
enallene-isonitrile 12 was formed directly. Subsequent cy-
cloaromatization led to the zwitterion 13, which was then
protonated and chlorinated to produce 14. The reaction
pathway that led to the formation of 15 is not clear at the
present time. Similarly, by starting from 10, the reaction
sequence also led to 16. A trace amount of a dichloride,
attributable to 17, was also detected by GC/MS.
Scheme 4
Treatment of 8 with 4-(dimethylamino)pyridine produced
the pyridinium mesylate 18, which upon exposure to POCl3
for dehydration afforded 2115 (Scheme 3). It is worth noting
that 21 has the core heteroaromatic ring system of the
important camptothecin family of antitumor agents.16 Pre-
sumably, dehydration followed by the 1,3-prototropic rear-
rangement of the propargylic pyridinium salt as observed
previously17 produced in situ 19, which then underwent a
sequence of reactions, including cycloaromatization, in-
the formation of 25 involves a rapid 1,3-prototropic rear-
rangement to produce the putative intermediate 23 before
dehydration to form the isonitrile could occur. A subsequent
intramolecular attack of the central carbon of the allenic
moiety17 by the nitrogen of the formanilide or of the
corresponding formimino phosphate could give 24 or a
related phosphate derivative leading to 25.
The change of the reaction pathway may be attributed to
the lower ability of the 4-methoxyl group in 22 to donate
electrons to the pyridinium ring than that of the 4-dimethy-
lamino group in 18, making the positive charge more
(15) Structure was established by X-ray structure analysis.
(16) (a) Wall, M. E.; Wani, M. C. In The Alkaloids; Cordell, G. A., Ed.;
Academic Press: San Diego, 1998; Vol. 50, pp 509-536. (b) Curran, D.
P.; Liu, H.; Josien, H.; Ko, S.-B. Tetrahedron 1996, 52, 11385-11404.
(17) Katritzky, A. R.; Schwarz, O. A.; Rubio, O. HelV. Chim. Acta 1984,
67, 939-946.
Org. Lett., Vol. 5, No. 18, 2003
3279

Scheme 5
Scheme 7
during the course of reaction. A signal at δ 206.9 attributable
to the central carbon of the allenic moiety was observed.
It also needs to be mentioned that a nucleophile-triggered
6-endo cyclization of the benzannulated enyne-isonitriles 32
was proposed to account for the formation of the 2,3-
disubstituted quinolines 35 (Scheme 7).10c While such a
mechanism may also explain the formation of 14 and 16,
although the chloride is a very poor nucleophile and is
unlikely to attack the isonitrile, it is not applicable to account
for the formation of 6 and 21.
In conclusion, a new synthetic pathway involving trans-
formation of the benzannulated enyne-isonitriles to 11H-
indeno[1,2-b]quinoline and related compounds was estab-
lished. The reaction presumably proceeded through an initial
1,3-protrotropic rearrangement to form the corresponding
benzannulated enallene-isonitriles followed by a facile cy-
cloaromatization reaction to generate the putative quinoline
biradicals/zwitterions. A subsequent intramolecular radical-
radical coupling or electrophilic aromatic substitution then
furnished the formal [4 + 1] cycloaddition adducts leading
to 11H-indeno[1,2-b]quinoline and related compounds. While
the putative quinoline biradicals/zwitterions were proposed
as key reaction intermediates by drawing on the analogy with
the Myers-Saito cyclization reaction of enyne-allenes,
additional investigations would be needed to provide concrete
evidence of their existence and to further explore the nature
of their chemical reactivities.
localized on the pyridinium nitrogen in 22.18 As a result,
the propargylic hydrogens in 22 are more acidic and thus
more prone to 1,3-prototropic rearrangement.
It was also observed that when 18 was treated only with
neutral alumina or triethylamine, the 2-substituted indole 27
was produced in quantitative yield (Scheme 5). Presumably,
the allene 26 was generated in situ as a reactive intermediate,
which then underwent cyclization to give 27. Similarly,
treatment of 1 with potassium t-butoxide at room temperature
for 2 h afforded 2-(phenylmethyl)indole (31) (Scheme 6).
Scheme 6
While the allenic derivatives 26 and 29 are proposed as the
intermediates for cyclization, it should be noted that the base-
induced formation of 2-substituted indoles from systems
similar to 1 but without the possibility of a prior 1,3-
prototropic rearrangement was also observed.19 The rate of
cyclization of 28 was considerably slower than that of 1,
allowing the formation of 30 to be detected by 13C NMR
Acknowledgment. The financial support provided by the
Chemical Instrumentation Program of the National Science
Foundation (CHE-9120098) for the acquisition of a Siemens
P4 X-ray diffractometer is gratefully acknowledged.
Supporting Information Available: Experimental pro-
1
cedures, spectroscopic data, and H and 13C NMR spectra
for 1, 6, 8-10, 14-16, 18, 21, 22, 25, 27, 28, and 31;
ORTEP drawings for 14 and 21; and tables of crystal-
lographic data for the X-ray diffraction analysis of 14. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(18) Rodima, T.; Kaljurand, I.; Pihl, A.; Ma¨emets, V.; Leito, I.; Koppel,
I. A. J. Org. Chem. 2002, 67, 1873-1881.
(19) (a) Sakamoto, T.; Kondo, Y.; Yamanaka, H. Heterocycles 1986,
24, 31-32. (b) Kondo, Y.; Kojima, S.; Sakamoto, T. J. Org. Chem. 1997,
62, 6507-6511. (c) Yasuhara, A.; Kanamori, Y.; Kaneko, M.; Numata,
A.; Kondo, Y.; Sakamoto, T. J. Chem. Soc., Perkin Trans. 1 1999, 529-
534.
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