Thansandote et al.
TABLE 1. Optimization of Annulation of Haloanilines with
Norbornadiene
positions around the benzenoid ring. Among the results, some
examples deserve further comment. Substrate 7i, bearing a
potentially hindering methyl group, gives the annulated product
in 89% yield (entry 6). Whereas the aryl chloride 7o gives a
good yield of the annulated product 8o under the reaction
conditions (entry 12), chlorine functionality elsewhere in the
ring does not seem well tolerated. Thus, substrate 7g gives a
11
t
low yield with Bu3PHBF4, but using the DavePhos ligand
a
entry
R (7)
ligand
T (°C)
8
yield (%)
60
51% yield of the desired compound was obtained (entry 4). The
structure of 8h was confirmed by X-ray crystallography.12
Notably, 8e has been synthesized on a gram scale in 92% yield.
Synthesis of Benzenoid-Substituted Indoles. We next
investigated the retro Diels-Alder reactions of our annulated
products as this would give rise to a variety of benzenoid-
substituted indoles.13 Even though the present reaction is
performed at a higher temperature than our previously reported
annulation of bromoarylheterocycles leading to retro Diels-Alder
products,4 no retro Diels-Alder indole products were formed
under the reaction conditions. The annulated compounds 8 were
found to be stable up to 200 °C under microwave irradiation.
At this high temperature under the sealed conditions, we were
concerned that the retro Diels-Alder reaction may be revers-
ible.14 Therefore, substrate 8e was heated with microwave
irradiation at 190 °C in the presence of a competitive dienophile
according to a strategy used by Mander and co-workers in the
synthesis of sordaricin.15,16 Gratifyingly, indole 9e was formed,
but only in a 40% yield (eq 2).
1
2
3
4
5
6
Me (7a)
Ts (7b)
Bz (7c)
tri(2-furyl)phosphine
tri(2-furyl)phosphine
tri(2-furyl)phosphine
80
80
80
80
80
110
110
120
120
8a
8b
8c
8d
8d
8d
8d
8d
8d
Boc (7d) tri(2-furyl)phosphine
Boc (7d) tricyclohexylphosphine
Boc (7d) tricyclohexylphosphine
Boc (7d) tri(2-furyl)phosphine
Boc (7d) tricyclohexylphosphine
Boc (7d) tri-tert-butylphosphonium
tetrafluoroborate
50
40a
82
90
7
8b
9b
a Impure product. b With 6 equiv of alkene.
annulation of haloanilines with norbornadiene has not been
reported. There are considerable advantages associated with
selective monofunctionalization of this diene.
Results and Discussion
Synthesis of Annulated o-Bromoanilines. Re-examining the
reaction in eq 1, we found that it proceeded equally well in the
absence of the alkyl bromide 5. However, a simple switch from
norbornene to norbornadiene resulted in very poor yields. To
improve the yield of the annulation product, we examined the
effect of changing the nitrogen protecting group (Table 1). Alkyl,
sulfonyl, or amide protecting groups led to either recovery of
starting material or decomposition products (entries 1-3).
Pleasingly, the Boc-protected aniline gave 8 in 60% yield.
Treatment of unprotected anilines provides annulated products
in moderate yield but low purity. To promote the amination,
we increased the electron-donating properties and steric bulk
of the ligand by the use of tricyclohexylphosphine.10 Interest-
ingly, consumption of starting material was observed at both
80 and 110 °C (entries 5 and 6), while formation of product
was only observed at 110 °C. Though this suggests that a
competing process might be occurring at lower temperatures,
we were only able to recover starting material from these low
conversion reactions and were unable to identify the remainder
of the mass balance.
Noting that the indole had lost its protecting group, we
considered that the stability of the molecule at high temperatures
might be caused by the presence of the carbamate. We therefore
aimed to find conditions that would allow in situ deprotection
of the annulation products and subsequent retro Diels-Alder
reaction.
We developed two sets of conditions that enabled the
synthesis of indoles 9 from annulation products 8: treatment
with silica gel in xylenes at 170 °C or heating in ethylene glycol
at 170 °C. Removal of Boc protecting groups by reflux in
toluene in the presence of silica has previously been reported,17
but deprotection via heating in ethylene glycol is to the best of
(11) For the use of the DavePhos ligand in aminations, see: Harris, M. C.;
Geis, O.; Buchwald, S. L. J. Org. Chem. 1999, 64, 6019.
(12) For X-ray crystal data, see the Supporting Information.
(13) This would create a novel two-step approach to indole synthesis. A
related method is the Larock indole synthesis, whereby indoles can be produced
in one step from o-haloanilines and acetylenes. Larock, R. C.; Yum, E. K.; Refvik,
M. D. J. Org. Chem. 1998, 63, 7652.
However, increasing the temperature and the equivalents of
norbornadiene allowed us to generate the desired product in
82% yield (entry 8). A further increase in yield to 90% is
t
(14) [4 + 2] cycloadditions between indole and cyclopentadiene have been
reported: (a) Davies, H. M. L.; Dai, X. J. Org. Chem. 2005, 70, 6680. (b) Sato,
S.; Fujino, T.; Isobe, H.; Nakamura, E. Bull. Chem. Soc. Jpn. 2006, 79, 1288.
(15) Mander, L. N.; Thomson, R. J. J. Org. Chem. 2005, 70, 1654.
(16) For examples of retro-Diels-Alder reactions used to obtain heterocyclic
compounds, see: (a) Burgess, K. L.; Lajkiewicz, N. J.; Sanyal, A.; Yan, W.;
Snyder, J. K. Org. Lett. 2005, 7, 3795. (b) Marques, M. M. B.; Lobo, A. M.;
Prabhakar, S.; Branco, P. S. Tetrahedron Lett. 1999, 40, 3795. (c) Sha, C.-K.;
Yang, J.-F.; Chang, C.-J. Tetrahedron Lett. 1996, 37, 3487. (d) Arai, Y.; Kontani,
T.; Koizumi, T. Chem. Lett. 1991, 12, 2135. (e) Magnus, P.; Cairns, P. M. J. Am.
Chem. Soc. 1986, 108, 217.
obtained using a Bu3P ligand precursor (entry 9).
The annulation is tolerant of a variety of functionality
including electron-donating (Table 2, entries 2, 5, and 6) and
electron-withdrawing (entries 3, 4, and 7-10) groups at various
(10) Electron-rich, bulky phosphanes promote aromatic aminations: (a) Wolfe,
J. P.; Buchwald, S. L. Angew. Chem., Int. Ed. 1999, 38, 2413. (b) Kataoka, N.;
Shelby, Q.; Stambuli, J. P.; Hartwig, J. F. J. Org. Chem. 2002, 67, 5553. (c)
Zapf, A.; Beller, M. Chem. Commun. 2005, 431. (d) Watanabe, M.; Nishiyama,
M.; Yamamoto, T.; Koie, Y. Tetrahedron Lett. 2000, 41, 481.
(17) Apelqvist, T.; Wensbo, D. Tetrahedron Lett. 1996, 37, 1471.
1674 J. Org. Chem. Vol. 74, No. 4, 2009