toluidines),17 Gassman (from N-halo anilines),18 Leimgru-
ber-Batcho (from o-nitrotoluenes and dimethylformamide
acetals), Baccolini (reaction by P-N fission of diazaphos-
second equivalent attacks the arene core, presumably via an
electrocyclic reaction. Common side products are reduction
products such as anilines and azo and azoxy compounds.
19
2
0
21
pholes), and Bartoli, as well as, e.g., Palladium-catalyzed
In this manuscript, we disclose the first solid-phase Bartoli
reaction. A simple ester was chosen as the linker to
investigate whether a fragile anchor might be suitable in
principle. Moreover, this linker is selectively cleavable under
22,23
alkynylation reactions and many others.
synthesis of indoles and indolines, however, mainly focuses
on two different approaches, namely, the palladium-catalyzed
approaches and the Fischer indole synthesis. Some other
examples have also been reported such as the reaction of
The solid-phase
24
25
26
31
basic conditions. Other linkers might work even better.
Simple polystyrene resin (Merrifield-type) was selected as
an economical organic support.
Five different nitro benzoic acids 232 were immobilized
27
28
supported anilines, reactions using selenenyl reagents, or
the Nenitzescu reaction on solid supports.29
We were intrigued by the possibility of generating indoles
on solid supports using the seldom-used Bartoli reaction since
this reaction is particularly suitable for the synthesis of
on Merrifield resin (chloromethylated polystyrene 1, 1-2%
33
cross-linked) under standard conditions using cesium
34
carbonate as a base. The loadings were determined by
30
7
-substituted indoles. In 1989, Bartoli et al. discovered that
the reaction of 3 equiv of vinylmagnesium bromide with
-substituted nitro arenes resulted in the formation of an in-
elemental analysis and by cleavage with sodium methylate
in methanol/THF.
2
The Bartoli reactions were performed on resins 3a-e
dole moiety. With fewer equivalents of the Grignard reagent
or by reaction of o,o′-unsubstituted nitro arenes, only traces
of the indoles were isolated, if at all. The reaction mechanism
is established, however, not in all details. While 1 equiv of
the Grignard reduces the nitro group to a nitroso group, the
(
1 g scale) at -40 °C in THF with four different alkenyl
35
Grignard reagents 4-7. During the reaction, a color change
into deep red was observed. Extension to allylmagnesium
bromide failed at this point with all resins; only the reduced
aniline derivatives were isolated after the cleavage.
Subsequently, the resins were washed with different polar
and unpolar solvents (see Supporting Information).
(
17) Madelung, W. Chem. Ber. 1912, 45, 1128.
(18) Gassman, P. G.; van Bergen, T. J. J. Am. Chem. Soc. 1973, 95,
5
90-591.
(19) (a) Moyer, M. P.; Shiurba, J. F.; Rapoport, H. J. Org. Chem. 1986,
The cleavage yielding the indoles 12-15 was carried out
5
1
1, 5106-5110. (b) Clark, R. D.; Repke, D. B. Heterocycles 1984, 22,
36
with 30% sodium methylate in methanol. Most methyl
95-221.
indolecarboxylates were obtained in purities >80% without
(20) Baccolini, G.; Todesco. P. E. J. Chem. Soc., Chem. Commun. 1981,
1
5
63.
purification as judged by integration of the GC or H NMR
(21) Bartoli, G.; Palmieri, G.; Bosco, M.; Dalpozzo, R. Tetrahedron Lett.
signals. The only exceptions are the reactions of the o,o′-
unsubstituted nitroarene resin 3a with propenyl Grignard
reagents 5 and 6 (entries 2, 3). In this case, the reduced
aniline derivatives were the main products. In general,
1
989, 30, 2129-2132.
(22) (a) Dobson, D.; Todd, A.; Gilmore, J. Synth. Commun. 1991, 21,
6
4
11-617. (b) Kondo, Y.; Kojima, S.; Sakamoto, T. Heterocycles 1996,
3, 2741-2746.
(23) Recent examples: (a) Muchowski, J. M. J. Heterocycl. Chem. 2000,
3
6
7, 1293-1297. (b) Gil, G. S.; Groth, U. M. J. Am. Chem. Soc. 2000, 122,
1
-methylprop-1-enylmagnesium bromide (7) was the most
789-6790. (c) Edmondson, S. D.; Mastracchio, A.; Parmee, E. R. Org.
efficient Grignard reagent.
Lett. 2000, 2, 1109-1112. (d) Brown, J. A. Tetrahedron Lett. 2000, 41,
1
623-1626. (e) Ketcha, D. M.; Wilson, L. J.; Portlock, D. E. Tetrahedron
Three features are remarkable for this overall transforma-
tion. First, in contrast to the literature precedence in liquid
phase, o,o′-unsubstituted nitro arenes proved to be good
substrates for the Bartoli reaction on solid support using
certain Grignard reagents. The reduction to the corresponding
anilines was only observed to a minor extent. The reductive
coupling of the nitro arenes to form azo or azoxy benzenes
was not detected at all. Second, the ester linker is compatible
with the Grignard reagents used. A partial cleavage of the
resin during the Bartoli reaction can be observed (10-40%
as judged by elemental analysis, see Supporting Information)
explaining the diminished yields. Only ortho-nitro benzoic
Lett. 2000, 41, 6253-6258. (f) Zhang, H.-C.; Ye, H.; Moretto, A. F.;
Brumfield, K. K.; Maryanoff, B. E. Org. Lett. 2000, 2, 89-92. (g) Takeda,
A.; Kamijo, S.; Yamamoto, Y. J. Am. Chem. Soc. 2000, 122, 5662-5663.
(
h) Tokuyama, H.; Kaburagi, Y.; Chen, X.; Fukuyama, T. Synthesis 2000,
4
6
2
1
29-434. (i) Rainier, J. D.; Kennedy, A. R. J. Org. Chem. 2000, 65, 6213-
216. (j) Toczko, M. A.; Heathcock, C. H. J. Org. Chem. 2000, 65, 2642-
645. (k) Iyengar, R.; Schildknegt, K.; Aube, J. Org. Lett. 2000, 2, 1625-
628.
(
(
24) Knepper, K.; Ziegert, R. E.; Br a¨ se, S. PharmaChem. 2003, 6, 8-11.
25) (a) Smith, A. L.; Stevenson, G. I.; Swain, C. J.; Castro, J. L.
Tetrahedron Lett. 1998, 39, 8317-8320. (b) Wu, T. Y. H.; Ding, S.; Gray,
N. S.; Schultz, P. G. Org. Lett. 2001, 3, 3827-3830. (c) Yamazki, K.;
Kondo, Y. J. Comb. Chem. 2002, 4, 191-192.
(26) (a) Hutchins, S. M.; Chapman, K. T. Tetrahedron Lett. 1996, 37,
4
1
869-4872. (b) Cheng, Y.; Chapman, K. T. Tetrahedron Lett. 1997, 38,
497-1500. (c) Cooper, L. C.; Chicchi, G. G.; Dinnell, K.; Elliott, J. M.;
Hollingworth, G. J.; Kurtz, M. M.; Locker, K. L.; Morrison, D.; Shaw, D.
E.; Tsao, K. L.; Watt, A. P.; Williams, A. R.; Swain, C. J. Bioorg. Med.
Chem. Lett. 2001, 11, 1233-1236. (d) Tanaka, H.; Ohno, H.; Kawamura,
K.; Ohtake A.; Nagase, H.; Takahashi, T. Org. Lett. 2003, 5, 1159-1162.
(31) Dahmen, S.; Br a¨ se, S. In Handbook of Combinatorial Chemistry;
Nicolaou, K. C., Hanko, R. Hartwig, W., Eds.; VCH: Weinheim, 2002;
Chapter 4.
(32) ortho-Nitro benzoic esters failed to give indoles due to premature
cleavage from the solid support.
(
27) Lee, S. H.; Clapham, B.; Koch, G.; Zimmermann, J.; Janda, K. D.
J. Comb. Chem. 2003, 5, 188-196.
28) Nicolaou, K. C.; Roecker, A. J.; Hughes, R.; van Summeren, R.;
(
Pfefferkorn, J. A.; Winssinger, N. Bioorg. Med. Chem. 2003, 11, 465-
(33) Merrifield resin (0.93 mmol/g) was obtained from Polymer Labo-
ratories (UK).
4
76.
(
29) Ketcha, D. M.; Wilson, L. J.; Portlock, D. E. Tetrahedron Lett. 2000,
(34) All new nonpolymeric compounds were characterized by NMR, IR,
MS, and HRMS. The purity was determined using GC, GC-MS, and NMR
techniques. Polymeric compounds were characterized using IR and elemental
analysis (CHN) (see Supporting Information).
(35) Grignard reagents are commercially available from Aldrich.
(36) Cleavage was quantitative as judged by elemental analysis of the
remaining resin.
4
1, 6253-6257.
(30) (a) Bo, M.; Dalpozzo, R.; Bartoli, G.; Palmieri, G.; Petrini, M. J.
Chem. Soc., Perkin Trans. 2 1991, 657-662. (b) Dobbs, A. P.; Voyle, M.;
Whittall, N. Synlett 1999, 1594-1596. (c) Pirrung, M. C.; Wedel, M.; Zhao,
Y. Synlett 2002, 143. (d) For a review: Ricci, A.; Fochi, M. Angew Chem.,
Int. Ed. 2003, 42, 1444-1446.
2830
Org. Lett., Vol. 5, No. 16, 2003