A R T I C L E S
Penoni et al.
Scheme 1
Scheme 2
yields (Scheme 1).5 Subsequently, Ragaini and co-workers
reported a similar palladium-catalyzed reaction.6 The directness
of this indole construction from commercial reactants and its
high regioselectivity, producing 3-substituted indoles from
terminal alkynes, has prompted us to explore the synthetic
potential of the reaction and its mechanistic pathway. A follow-
up investigation in our group established that nitrosoarenes react
with conjugated alkynes without a catalyst to produce N-
hydroxyindoles (Scheme 1) in moderate to good yields and
comparable regioselectivity.7 Curiously, early reports of 1:1 and
1:2 alkyne/nitrosoarene reactions identified acyclic nitrones
and diimines8 and the polycyclic kabutanes9 as products
(Scheme 2). The efficiency of the ArNO/alkyne cycloaddition
can be improved significantly by alkylative trapping of the labile
N-hydroxyindoles with K2CO3Me2SO4,10 providing access to a
variety of N-methoxyindoles from substituted nitrosoarenes and
arylacetylenes.11 The comparable regioselectivity of these
reactions to the metal-catalyzed nitroarene reactions and the
ready reductive conversion of the hydroxyindoles to indoles
(Scheme 1) suggests that the Cp2M-catalyzed reaction of the
nitroarenes could proceed via metal-promoted nitroarene deoxy-
genation,12 followed by an uncatalyzed nitrosoarene/alkyne
cycloaddition, and conclude with a second Cp2M-promoted
deoxygenation of the N-hydroxyindole. The unprecedented
nature of the nitrosoarene/alkyne cycloaddition itself has led to
the present study that seeks to elucidate the mechanism of this
transformation.
(2) (a) Humphrey, G. R.; Kuethe, J. T. Chem. ReV. 2006, 106, 2875–
2911. (b) Robinson, B. The Fischer Indole Synthesis; John Wiley and
Sons: New York, 1982; ref. 1a, pp 54-70. (c) Gassman, P. G.; Van
Bergen, T. J.; Gilbert, D. P.; Cue, B. W. J. Am. Chem. Soc. 1974, 96,
5495. (d) Sugasawa, T.; Adachi, M.; Sasakura, K.; Kitagawa, A. J. J.
Org. Chem. 1979, 44, 578. (e) Bartoli, G.; Bosco, M.; Dalpozzo, R.;
Palmeri, G.; Marcantoni, E. J. J. Chem. Soc., Perkin Trans. 1 1991,
2757. (f) Hwu, J. R.; Patel, H. V.; Lin, R. J.; Gray, M. O. J. Org.
Chem. 1994, 59, 1577. (g) Gribble, G. W. Contemp. Org. Synth. 1994,
1, 145. (h) Gribble, G. W. J. Chem. Soc., Perkin Trans. 1 2000, 1045.
(i) Cacchi, S. J. Organomet. Chem. 1999, 576, 42. (j) Cacchi, S.;
Fabrizi, G. Chem. ReV. 2005, 105, 2873. (k) Ackermann, L. Org. Lett.
2005, 7, 439. (l) Zeni, G.; Larock, R. C. Chem. ReV. 2004, 104, 2285.
(m) Zeni, G.; Larock, R. C. Chem. ReV. 2006, 106, 4644.
The nitrosoarene (NA)-alkyne to N-hydroxyindole (NHI)
conversion involves the net scission of N-O, C-C, and C-H
bonds and the formation of C-N, C-C, and O-H bonds. The
fundamental mechanistic issues of interest include the timing
of these steps, i.e., the stepwise or concerted timing of bond-
breaking/making, and the possible involvement of discrete
intermediates, be they neutral, polar, or radical. In our initial
survey of the reaction’s scope and selectivity three mechanisti-
cally relevant observations were noted.7 First, the yields are
relatively insensitive to the electronic character of the ni-
trosoarene, being comparatively efficient with both electron-
rich and -poor NA. Second, representative terminal alkynes with
conjugating substituents (R ) -Ar, -CO2R) react most
efficiently and regioselectively, placing the alkyne substituent
at the 3-position. Third, the reaction solvent polarity/proticity
(e.g., benzene, toluene, dioxane, isopropanol) has little effect
on the course or efficiency of the reaction. Together, these
(3) (a) Wong, A.; Kuethe, J. T.; Davies, I. W. J. Org. Chem. 2003, 68,
9865. (b) Leach, A. G.; Houk, K. N.; Davies, I. W.; Kuethe, J. T.
Synthesis 2005, 3463. (c) Fang, Y.-Q.; Lautens, M. J. Org. Chem.
2008, 73, 538. (d) Davies, I. W.; Guner, V. A.; Houk, K. N. Org.
Lett. 2004, 6, 743.
(4) (a) Srivastava, R. S.; Nicholas, K. M. Chem. Commun. 1998, 2705.
(b) Tollari, S.; Penoni, A.; Cenini, S. J. Mol. Catal. A: Chem. 2000,
152, 47. (c) Kolel-Veetil, M. K.; Nicholas, K. M. Organometallics
2000, 19, 3754. (d) Srivastava, R. S.; Kolel-Veetil, M. K.; Nicholas,
K. M. Tetrahedron Lett. 2002, 43, 931. (e) Cenini, S.; Gallo, E.;
Penoni, A.; Ragaini, F.; Tollari, S. Chem. Commun. 2000, 2265. (f)
Ragaini, F.; Penoni, A.; Gallo, E.; Tollari, S.; Lapadula, M.; Li Gotti,
C.; Mangioni, E.; Cenini, S. Chem. Eur. J. 2003, 9, 249. (g) O’Dell,
D. K.; Nicholas, K. M. Tetrahedron 2003, 59, 747. (h) O’Dell, D. K.;
Nicholas, K. M. J. Org. Chem. 2003, 68, 6427. (i) O’Dell, D. K.;
Nicholas, K. M. Heterocycles 2004, 63, 373. (j) Beccalli, E. M.;
Broggini, G.; Paladino, G.; Penoni, A.; Zoni, C. J. Org. Chem. 2004,
69, 5627. (k) Maldotti, A.; Amadelli, R.; Samiolo, L.; Molinari, A.;
Penoni, A.; Tollari, S.; Cenini, S. Chem. Commun. 2005, 1749. (l)
Bhuyan, R.; Nicholas, K. M. Org. Lett. 2007, 9, 3957.
(10) Penoni, A.; Palmisano, G.; Broggini, G.; Kadowaki, A.; Nicholas,
K. M. J. Org. Chem. 2006, 71, 823.
(11) Mondelli, A.; Tibiletti, F.; Palmisano, G.; Galli, S.; Penoni, A.;
Nicholas, K. M. manuscript in preparation.
(5) Penoni, A.; Nicholas, K. M. Chem. Commun. 2002, 484.
(6) Ragaini, F.; Rapetti, A.; Visentin, E.; Monzani, M.; Caselli, A.; Cenini,
S. J. Org. Chem. 2006, 71, 3748.
(12) (a) Cenini, S.; Ragaini, F. Catalytic ReductiVe Carbonylation of
Organic Nitro Compounds; Kluwer Academic Publishers: Dordrecht,
The Netherlands, 1996. (b) Ragaini, F.; Cenini, S.; Gallo, E.; Caselli,
A.; Fantauzzi, S. Curr. Org. Chem. 2006, 10, 1479. (c) Tsoungas,
P. G.; Diplas, A. I. Curr. Org. Chem. 2004, 8, 1579. (d) Tsoungas,
P. G.; Diplas, A. I. Curr. Org. Chem. 2004, 8, 1607. (e) Ono, N. The
Nitro Group in Organic Synthesis; Wiley-VCH: Weinheim, 2001. (f)
Soderberg, B. C.; Shriver, J. A. J. Org. Chem. 1997, 62, 5838. (g)
Preston, P. N.; Tennant, G. Chem. ReV. 1972, 72, 627. (h) Sundberg,
R. J. J. Org. Chem. 1968, 33, 487. (i) Cadogan, J. I. G.; Cameron-
Wood, M.; Mackie, R. K.; Searle, R. J. G. J. Chem. Soc. 1965, 4831.
(j) Tollari, S.; Cenini, S.; Rossi, A.; Palmisano, G. J. Mol. Catal. A:
Chem. 1998, 135, 241. (k) Annunziata, R.; Cenini, S.; Palmisano, G.;
Tollari, S. Synth. Commun. 1996, 26, 495.
(7) Penoni, A.; Volkman, J.; Nicholas, K. M. Org. Lett. 2002, 4, 699.
(8) (a) Alessandri, L. Gazz. Chim. Ital. 1922, 52, 193. (b) Alessandri, L.
Gazz. Chim. Ital. 1924, 54, 426. (c) Alessandri, L. Gazz. Chim. Ital.
1925, 55, 729. (d) Alessandri, L. Gazz. Chim. Ital. 1926, 56, 398. (e)
Devi, P.; Sandhu, J. S. Indian J. Chem. 1984, 23B, 81.
(9) (a) Iball, J.; Motherwell, W. D. S.; Pollock, J. J. S.; Tedder, J. M.
J. Chem. Soc. Chem. Commun. 1968, 365. (b) Iball, J.; Motherwell,
W. D. S.; Barnes, J. C.; Golnazarians, W. Acta Crystallogr. 1986,
C42, 239. (c) Hasegawa, M.; Tabata, M.; Satoh, K.; Yamada, F.;
Somei, M. Heterocycles 1996, 43, 2333. (d) Somei, M. Heterocycles
1999, 50, 1157.
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