Synthesis of carbocyclic and heterocyclic fused quinolines by cascade radical annulations of unsaturated N-aryl thiocarbamates, thioamides, and thioureas.

Article abstract of DOI:10.1021/ol0344319

[reaction: see text] Tandem radical cyclizations of suitably substituted N-aryl thiocarbamates, thioamides, and thioureas are induced by exposure to tris(trimethylsilyl)silane (TTMSH) and UV light and provide furoquinolines, isofuroquinolines, cyclopentaq

Full text of DOI:10.1021/ol0344319

ORGANIC
LETTERS
2003
Vol. 5, No. 10
1765-1768
Synthesis of Carbocyclic and
Heterocyclic Fused Quinolines by
Cascade Radical Annulations of
Unsaturated N-Aryl Thiocarbamates,
Thioamides, and Thioureas
Wu Du and Dennis P. Curran*
Department of Chemistry, UniVersity of Pittsburgh, Pittsburgh, PennsylVania 15260
curran@pitt.edu
Received March 11, 2003
ABSTRACT
Tandem radical cyclizations of suitably substituted N-aryl thiocarbamates, thioamides, and thioureas are induced by exposure to tris(trimethylsilyl)-
silane (TTMSH) and UV light and provide furoquinolines, isofuroquinolines, cyclopentaquinolines, indoloquinolines, and related ring systems.
The intermediacy of an r-thioalkylamino radical, which is the synthetic equivalent of an imidoyl radical, is invoked.
Annulation reactions of imidoyl radicals 1 provide powerful
ways to make an assortment of fused quinolines 2 (Figure
1).1-3 In turn, these imidoyl radicals can be formed either
by radical additions to isonitriles or from imidoyl halides
and related radical precursors.4 R-Thioaminoalkyl radicals
4 should be readily available from thioamides 3, and they
can be considered as synthetic equivalents of imidoyl radicals
1 since elimination of the thiol may occur either during or
after cascade reactions of 4. Bachi pioneered the use of such
radicals to make assorted heterocycles in the early 1990s.5
Fukuyama’s two recent indole syntheses provide striking
examples of the power of radical cyclizations of both imidoyl
radicals and their equivalent R-thioaminoalkyl radicals.6
In this Letter, we show that cascade radical annulations
of readily available thiocarbamates 5a, thioamides 5b, and
thioureas 5c provide direct routes to carbocyclic and
heterocyclic fused quinolines 6a-c (Scheme 1). These
reactions complement existing imidoyl radical methods by
making the same products from different precursors. More
importantly, they also provide access to products that are
not readily made through imidoyl radical chemistry either
(1) Johnson, C. D. In Rodd’s Chemistry of Carbon Compounds;
Sainsbury, M., Ed.; Elsevier: Amsterdam, 1998; Vol. IV, pp 129-161.
(2) (a) Josien, H.; Ko, S. B.; Bom, D.; Curran, D. P. Chem. Eur. J. 1998,
4, 67-83. (b) de Frutos, O.; Curran, D. P. J. Comb. Chem. 2000, 2, 639-
649. (c) Curran, D. P.; Josien, H.; Bom, D.; Gabarda, A.; Du, W. In The
Camptothecins: Unfolding their Anticancer Potential; Liehr, J. G., Giov-
anella, B. C., Verschraegen, C. F., Eds.; New York Academy of Sciences:
New York, 2000; Vol. 922. (d) Gabarda, A. E.; Du, W.; Isarno, T.;
Tangirala, R. S.; Curran, D. P. Tetrahedron 2002, 58, 6329-6341. (e) Luo,
Z. Y.; Zhang, Q. S.; Oderaotoshi, Y.; Curran, D. P. Science 2001, 291,
1766-1769. (f) Curran, D. P.; Du, W. Org. Lett. 2002, 4, 3215-3218.
(3) (a) Nanni, D.; Pareschi, P.; Rizzoli, C.; Sgarabotto, P.; Tundo, A.
Tetrahedron 1995, 51, 9045-9062. (b) Nanni, D.; Pareschi, P.; Tundo, A.
Tetrahedron Lett. 1996, 37, 9337-9340. (c) Leardini, R.; Nanni, D.;
Pareschi, P.; Tundo, A.; Zanardi, G. J. Org. Chem. 1997, 62, 8394-8399.
(d) Leardini, R.; Nanni, D.; Tundo, A.; Zanardi, G. Tetrahedron Lett. 1998,
39, 2441-2442. (e) Nanni, D.; Calestani, G.; Leardini, R.; Zanardi, G. Eur.
J. Org. Chem. 2000, 707-711. (f) Leardini, R.; Nanni, D.; Zanardi, G. J.
Org. Chem. 2000, 65, 2763-2772.
(4) Reviews: (a) Ryu, I.; Sonoda, N.; Curran, D. P. Chem. ReV. 1996,
96, 177-194. (b) Nanni, D. In Radicals in Organic Synthesis, 1st ed.;
Renaud, P., Sibi, M. P., Eds.; Wiley-VCH: Weinheim, Germany, 2001;
Vol. 2, pp 44-61. (c) Zard, S. Z. In Radicals in Organic Synthesis, 1st ed.;
Renaud, P., Sibi, M. P., Eds.; Wiley-VCH: Weinheim, Germany, 2001;
Vol. 1, pp 91-108.
(5) (a) Bachi, M. D.; Bosch, E. J. Org. Chem. 1992, 57, 4696-4705.
(b) Bachi, M. D.; Balanov, A.; Barner, N.; Bosch, E.; Denenmark, D.;
Mizhiritskii, M. Pure Appl. Chem. 1993, 65, 595-601.
10.1021/ol0344319 CCC: $25.00 © 2003 American Chemical Society
Published on Web 04/15/2003

Scheme 2
and reactive ketene imine (7b) or carbodiimide (7c) inter-
mediates.
We initially focused on identifying reaction conditions to
convert phenylcarbamic acid pent-3-ynyl ester 8a into known
4-methyl-2,3-dihydrofuro[2,3-b]quinoline 9a.10 Thiocarbam-
ate 8a was readily prepared by reaction of 4-pentyn-1-ol with
phenyl isothiocyanate promoted by NaH.11 Heating or
irradiating 8a in the presence of tributyltin hydride or
hexamethylditin (typical conditions for cascade isonitrile
annulations2) provided little or no furoquinoline 9a. Substi-
tuting with tristrimethylsilyl silane12 (TTMSH) gave better
results, and standard conditions involved UV irradiation of
a 0.05 M solution of 8a, AIBN (1 equiv), and TTMSH
(4 equiv) in benzene in a Pyrex test tube. After 20 h, the
Figure 1. Imidoyl radical and R-thioaminoalkyl radical routes to
fused quinolines.
because the needed imidoyl radical precursors are not
available or not stable or because the requisite radicals do
not add cleanly to isonitriles. Fused quinolines 6b and 6c
Table 1. Cyclizations of Thiocarbamatesa
Scheme 1
can also be made by thermal cyclizations of ketene imines7
7b or carbodiimides 7c.8 These reactions were originally
formulated as intramolecular Diels-Alder reactions and more
recently as diradical electrocyclizations.9 The direct route
to 6b,c reported herein bypasses the formation of the sensitive
(6) (a) Fukuyama, T.; Chen, X. Q.; Peng, G. J. Am. Chem. Soc. 1994,
116, 3127-3128. (b) Kobayashi, Y.; Fukuyama, T. J. Heterocycl. Chem.
1998, 35, 1043-1055. (c) Tokuyama, H.; Yamashita, T.; Reding, M. T.;
Kaburagi, Y.; Fukuyama, T. J. Am. Chem. Soc. 1999, 121, 3791-3792.
(d) Reding, M. T.; Kaburagi, Y.; Tokuyama, H.; Fukuyama, T. Heterocycles
2002, 56, 313-330. (e) Rainier, J. D.; Kennedy, A. R.; Chase, E.
Tetrahedron Lett. 1999, 40, 6325-6327. (f) Rhee, J. U.; Bliss, B. I.;
RajanBabu, T. V. J. Am. Chem. Soc. 2003, 125, 1492-1493.
(7) Differding, E.; Ghosez, L. Tetrahedron Lett. 1985, 26, 1647-1650.
(8) Molina, P.; Alajarin, M.; Vidal, A.; Sanchez-Andrada, P. J. Org.
Chem. 1992, 57, 929-939.
(9) (a) Schmittel, M.; Steffen, J.-P.; Engels, B.; Lennartz, C.; Hanrath,
M. Angew. Chem., Int. Ed. 1998, 37, 2371-2373. (b) Schmittel, M.; Steffen,
J.-P.; Angel, M. A. W.; Engels, B.; Lennartz, C.; Hanrath, M. Angew. Chem.,
Int. Ed. 1998, 37, 1562-1564. (c) Shi, C.; Zhang, Q.; Wang, K. K. J. Org.
Chem. 1999, 64, 925-932.
a Reaction conditions: C6H6, 4 equiv of TTMSH, 20 h, irradiation.
b Isolated yield.
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Org. Lett., Vol. 5, No. 10, 2003

reaction mixture was concentrated and the crude product was
purified by flash chromatography to provide 9a in 48% yield.
Five other N-aryl thiocarbamates were prepared and
cyclized in a similar fashion, and the results of this series of
experiments are summarized in Table 1. Isolated yields of
furoquinolines 9b-f ranged from 44 to 88%. The N-aryl
thiocarbamates 8d and 8e with substituents in the ortho and
para positions, respectively, provided a single regioisomeric
product 9d or 9e (entries 3 and 4), while the thiocarbamate
8f with a meta-substituent provided two regioisomers 9f/
9f ′′ in a ratio of 1.3/1. This lack of regioselectivity for meta-
substituted systems is typical for related cascade radical
annulations of isonitriles.2,3
clization of benzylthioamide 10b gave 6H-indeno[2,1-b]-
quinoline 11b in 52% yield (entry 2). Cyclizations of four
R-propargyloxy thioamides 10c-f gave the unusual 1,3-
dihydrofuro[3,4-b]quinolines 11c-f, respectively, in moder-
ate yields (50-62%, entries 3-6).
Finally, cyclizations of three thioureas were tried with
mixed results, as summarized in Table 3. Attempts to cyclize
Table 3. Cyclizations of Thioureasa
Thioamides also undergo cyclizations under the standard
conditions as shown by the six examples in Table 2.
Table 2. Cyclizations of Thioamidesa
a Reaction conditions: C6H6, 4 equiv of TTMSH, 20 h, irradiation.
b Isolated yield. c nd ) not detected.
N-homopropargyl thiourea 12a under the standard conditions
or other variants were not successful (entry 1); however,
N-(o-propargylaryl) thioamides 12b and 12c both underwent
clean cyclizations to give indoloquinoline derivatives 13b9c,14
and 13c in 64 and 47% yields, respectively (entries 2, 3).
Indoloquinolines exhibit a diverse assortment of biological
activities,15 and this new approach opens the door to
preparation of new members of this family.
a Reaction conditions: C6H6, 4 equiv of TTMSH, 20 h, irradiation.
b Isolated yield.
Cyclization of standard thioamide 10a provided 2,3-dihydro-
1H-cyclopenta[b]quinoline 11a in 87% yield (entry 1). This
can also be prepared by reaction of p-methoxyphenylisonitrile
with the appropriate pentynyl radical precursor.13 The cy-
(10) Shanmugam, P.; Lakshminarayana, P.; Palaniappan, R. Monatsh.
Chem. 1973, 104, 633-639.
(11) Preparations of this precursor and all the others in Tables 1-3 are
described in Supporting Information.
(12) Chatgilialoglu, C.; Ferreri, C.; Gimisis, T. In Chemistry of Organic
Silicon; Rappoport, Z., Apeloig, Y., Eds.; Wiley: Chichester, UK, 1998;
Vol. 2, pp 1539-1579.
Figure 2. Suggested mechanism for thiocarbamate (Y ) O),
thioamide (Y ) CR2), and thiourea (Y ) NR) cyclizations.
Org. Lett., Vol. 5, No. 10, 2003
1767

We posit the mechanistic framework in Figure 2 to
interpret the results of these reactions. Reversible addition
of the TTMS radical to the thiocarbonyl group of 14 gives
stabilized radical 15, which undergoes cyclization to vinyl
radical 16. Now 1,6-cyclization to one of the vacant ortho
sites provides delocalized radical 17. From here, oxidative
rearomatization16 is followed by ionic loss of the thiol.17 The
failure of the N-homopropargyl analogue 12a to participate
in this annulation may be because radical 15 with Y )
N-alkyl is too stable.5 The mixture of regioisomers formed
from meta-substituted precursors such as 8f arises because
there are two vacant ortho sites on radical 16. Ipso cyclization
of 16 is also possible and sometimes occurs in related imidoyl
radical cascades.2,3 But the results to date suggest that it does
not occur in thiocarbonyl cascades because ipso cyclization
is postulated to lead to rearranged products,2,3 and we have
not yet isolated any such products.
These radical annulations of thiocarbamates, amides, and
ureas supplement the related reactions of imidoyl radicals
generated either from standard radical precursor or by
additions to isonitriles. Likewise, they shortcut pericyclic and
electrocyclic routes to these compounds since the formation
of high energy cumulenes is not needed. Accordingly, radical
annulations of thiocarbamates, amides and ureas show
excellent potential for making a wide assortment of fused
quinolines both rapidly and efficiently.
Acknowledgment. We thank the National Institutes of
Health for funding this work. Wu Du thanks the University
of Pittsburgh for a Mellon Predoctoral Fellowship.
(13) Curran, D. P.; Liu, H. J. Am. Chem. Soc. 1991, 113, 2127-2132.
(14) Marsili, A. Tetrahedron 1968, 24, 4981-4991.
(15) (a) Peczynska-Czoch, W.; Pognan, F.; Kaczmarek, L.; Boratynski,
J. J. Med. Chem. 1994, 37, 3503. (b) Kaczmarek, L.; Peczynska-Czoch,
W.; Osiadacz, J.; Mordarski, M.; Sokalski, W. A.; Boratynski, J.; Marcinkows-
ka, E.; Glazman-Kusnierczyk, H.; Radzikowski, C. Bioorg. Med. Chem.
1999, 7, 2457.
(16) Bowman, W. R.; Heaney, H.; Jordan, B. M. Tetrahedron 1991, 47,
10119-10128.
(17) Resulting thiol is a precursor of a thio radical, which in turn may
add to the starting CdS bond to initiate a cyclization. Chatgilialoglu, H.;
Crich, D.; Komatsu, M.; Ryu, I. Chem. ReV. 1999, 99, 1991-2069.
Supporting Information Available: Typical procedure
and characterization data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
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