Total synthesis of indoles from Tricholoma species via Bartoli/heteroaryl radical methodologies

Full text of DOI:10.1021/jo0057396

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38
J . Org. Chem. 2001, 66, 638-641
Tota l Syn th esis of In d oles fr om Tr ich olom a
Sp ecies via Ba r toli/Heter oa r yl Ra d ica l
Meth od ologies
To test the power of this methodology, we imagined
using this approach in a short and efficient synthesis of
2
,4-dimethylindole 1, 4-(hydroxymethyl)-2-methylindole
, and 4-(methoxymethyl)-2-methylindole 3, three alka-
2
loids that have recently been isolated from two species
of European Basidomycetes (Tricholoma virgatum and
Tricholoma sciodes).9
Adrian Dobbs*
Department of Chemistry, The Open University,
Walton Hall, Milton Keynes MK7 6AA, U.K.
A.P.Dobbs@open.ac.uk
Received November 20, 2000
In tr od u ction
Resu lts a n d Discu ssion
The Bartoli indole synthesis is the treatment of an
ortho-substituted nitro-aromatic compound with 3 equiv
of vinylmagnesium bromide to give the 7-substituted
indole,1 and this method has rapidly become the shortest
and most flexible synthesis for indoles of this sub-
stitution pattern. We have recently reported an exten-
sion to this methodology, suggesting that it may not be
limited exclusively to the synthesis of 7-substituted
indoles but that modest yields of other substitution
patterns may also be obtained via this methodology.6
However, there is no doubt that the best yields are
obtained when the nitro-aromatic compound possesses
an ortho substituent, enforcing selectivity in the 3,3-
sigmatropic rearrangement and subsequent cyclization
step. This ortho substituent is, of course, undesirable in
the synthesis of many indoles when a Bartoli approach
may be advantageous.
A number of model reactions were first performed to
examine the scope of the proposed reaction sequence. The
Bartoli reaction of o-bromonitrobenzene with three simple
vinyl Grignard reagents proceeded well and in yields
comparable and consistent with previously reported
values (Table 1, entries A-C).1 The introduction of and
variation in the substituent on the vinyl Grignard
reagent seemed to have little effect on the indole syn-
thesis. This is of particular interest when employing a
cyclic vinyl Grignard reagent 1-cyclohexenylmagnesium
bromide (Table 1, entry D) where the immediate prod-
uct formed is a carbazole derivative, 8-bromo-2,3,4,9-
tetrahydro-1H-carbazole (and this is probably the short-
est synthesis to date of this class of compound). Even
more heavily substituted nitroarenes (Table 1, entries E
and F) still gave pleasing yields under the Bartoli
reaction conditions. Thus, the Bartoli reaction represents
a rapid route to a range of complex 7-bromo-substituted
indoles.
,2
1
-5
,2,6
We have also been interested in the generation and
use of heteroaryl free radicals for some time now and
have reported the radical reactions and cyclizations of
indoles bearing halogen substituents at both the 2- and
7
We envisaged a combination of these two methodolo-
The second stage in the proposed sequence was the
radical reduction of the newly synthesized 7-bromoin-
doles to give the 7-unsubstituted indoles. This reaction
was investigated using all the 7-bromoindoles prepared.
First was the reduction of 7-bromoindole with tributyltin
hydride under standard conditions (1.2 equiv of tribu-
tyltin hydride (compared to 7-bromoindole) and AIBN as
initiator in toluene at 110 °C) to give the parent com-
pound, indole. It was pleasing to find that the reaction
proceeded in near-quantitative yields (Table 1, entry A).
Therefore, these conditions were employed for all sub-
sequent reductions. No evidence of intermolecular radical
combination or addition between indoles was observed,
irrespective of dilution or concentration of the reactants,
suggesting that these reductions are proceeding very
rapidly (and in a manner consistent with our previously
-positions.3
,7,8
gies, whereby a range of o-bromonitrobenzenes are
treated under Bartoli conditions with various vinyl
Grignard reagents (using the o-bromine atom to direct
the cyclization) and then subsequently reduced using the
heteroaryl radical methodology to replace the halogen
and give a 7-unsubstituted indole, i.e., effectively using
the bromine as a labile protecting group (Scheme 1). This
method could give a significant reduction in the number
of steps required for the synthesis of many complex
indoles and also offers the advantage that many func-
tionalities are tolerant to radical-generating conditions
without the need for protection.
3
*
To whom correspondence should be addressed. Fax: +44 1908
58327.
1) Bartoli, G.; Palmieri, G.; Bosco, M.; Dalpozzo, R. Tetrahedron
Lett. 1989, 30, 2129-2132.
2) Bartoli, G.; Bosco, M.; Dalpozzo, R.; Palmieri, G.; Marcantoni,
E. J . Chem. Soc., Perkin Trans. 1 1991, 2757-2761.
3) Dobbs, A. P.; J ones, K.; Veal, K. T. Tetrahedron Lett. 1997, 38,
379-5382.
4) Dobson, D.; Todd, A.; Gilmore, J . Synth. Commun. 1991, 21,
reported results ). Almost identical results were obtained
8
with all the substrates, including a double reduction of
7-bromo-4-bromomethylindole (Table 1, entry F).
Therefore, the combination of these two methodssa
Bartoli reaction using o-bromonitrobenzenes followed by
radical reductionsrepresents a rapid and very easy route
to a range of indoles of varying substitution pattern.
Encouraged by these results, our attention was turned
to employing the method to the synthesis of various
(
(
(
5
6
(
11-617.
(
(
(
5) Dobson, D. R.; Gilmore, J .; Long, D. A. Synlett 1992, 79-80.
6) Dobbs, A. P.; Voyle, M.; Whittall, N. Synlett 1999, 1594-1596.
7) Dobbs, A. P.; J ones, K.; Veal, K. T. Tetrahedron Lett. 1995, 36,
4
2
857-4860.
8) Dobbs, A. P.; J ones, K.; Veal, K. T. Tetrahedron 1998, 54, 2149-
160.
(
(9) Garlaschelli, L.; Pang, Z. J .; Sterner, O.; Vidari, G. Tetrahedron
1994, 50, 3571-3574.
1
0.1021/jo0057396 CCC: $20.00 © 2001 American Chemical Society
Published on Web 12/22/2000

Notes
J . Org. Chem., Vol. 66, No. 2, 2001 639
Sch em e 1
Sch em e 2
indole alkaloids from the Tricholoma species. The Bartoli
damaged fruiting bodies of Collybia peronata and Tri-
choloma scalpturum1 ) since this has shown to be the
key intermediate in a biomimetic synthesis of peronatin
2,13
method has recently been used in two total syntheses:
1
0
by Harrowven in the synthesis of hippadine and Blech-
ert in the synthesis of (()-cis-trikentrin A.11 To test the
power and scope of our methodology, it was envisaged
as being used in the total synthesis of 2,4-dimethylindole
13
A and B.
We chose 4-bromo-3-nitrotoluene 4 as a common start-
ing material for all three alkaloids (Scheme 2). The direct
reaction of this with isopropenylmagnesium bromide
under the standard Bartoli reaction conditions yielded
2,4-dimethyl-7-bromoindole in a pleasing 67% yield. This
is in sharp contrast to a previously reported failed
attempt to synthesize these alkaloids employing a Bartoli
reaction between isopropenylmagnesium bromide and
1
, 4-(hydroxymethyl)-2-methylindole 2 and 4-(methoxy-
methyl)-2-methylindole 3, alkaloids that have recently
been isolated9 from two species of European Basido-
mycetes (Tricholoma virgatum and Tricholoma sciodes).12
The synthesis of 1 also constitutes a total synthesis of
1
3
the two biindolones peronatin A and B (isolated from
4
-methyl-2-nitroanisole.13 As with the test reactions,
(
10) Harrowven, D. C.; Lai, D.; Lucas, M. C. Synthesis 1999, 1300-
radical reduction proceeded almost quantitatively (94%)
to give the first of the alkaloids, 2,4-dimethylindole 1 in
overall 62% yield. Radical benzylic bromination of 4-bromo-
1
1
302.
(11) Wiedenau, P.; Monse, B.; Blechert, S. Tetrahedron 1995, 51,
167-1176.
(12) Soderberg, B. C.; Chisnell, A. C.; O’Neil, S. N.; Shriver, J . A. J .
3
-nitrotoluene gave 4-bromo-3-nitro-1-bromomethylben-
Org. Chem. 1999, 64, 9731-9734.
13) Stachel, S. J .; Nilges, M.; VanVranken, D. L. J . Org. Chem.
997, 62, 2.
zene 6 in excellent yields (consistently >85%). This
substrate was then subjected to the Bartoli reaction,
(
1

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40 J . Org. Chem., Vol. 66, No. 2, 2001
Notes
Ta ble 1. Resu lts for th e Ba r toli Rea ction a n d Su bsequ en t Ra d ica l Red u ction for a Ra n ge of Nitr oa r en es a n d Gr ign a r d
Rea gen ts
again employing isopropenylmagnesium bromide, to give
-bromo-4-(bromomethyl)-2-methylindole 7 in good yield
61%). It was at this point that the two syntheses became
divergent. Reaction of 7 with water (under acidic condi-
tions) gave 7-bromo-4-(hydroxymethyl)-2-methylindole 8
in high yields (88%) and this was then converted to the
alkaloid 2 by radical reduction (91%) without the need
for protection or manipulation of the side chain hydroxyl
function (overall yield of 2 41% from 4). Alternatively
from 7, treatment with sodium methoxide gave 7-bromo-
tributyltin hydride (94%) to give the final alkaloid 3 in
37% overall yield.
In conclusion, the total synthesis of three indole
alkaloids has been achieved employing a Bartoli synthesis/
heteroaryl radical approach. Further applications of this
synthetic sequence are currently being explored.
7
(
Exp er im en ta l Section
Rep r esen ta tive P r oced u r e for Ba r toli Rea ction . The
nitroaromatic compound (5 mmol) was placed in a two-necked
round-bottomed flask fitted with a gas inlet (argon) and rubber
septum. The flask was purged several times with argon before
4
-(methoxymethyl)-2-methylindole 9 in good yields (76%)
and this again was reduced almost quantitatively using

Notes
J . Org. Chem., Vol. 66, No. 2, 2001 641
adding dry THF (35-40 mL) and cooling to between -40 and
for 12 h. After cooling, the toluene was removed under reduced
pressure and the residue taken up in diethyl ether (200 mL),
which was then washed with 20% aqueous ammonia solution
(4 × 200 mL) and water (200 mL) and dried (magnesium sulfate)
and the solvent removed under reduced pressure. The crude
product was purified by flash column chromatography (hexane,
followed by hexane/ethyl acetate 9:1) to yield the product, either
as a white solid or a pale yellow oil, depending on the compound.
All compounds were in good agreement with literature data; new
compounds gave satisfactory spectroscopic and analytical data.
The three natural products 1, 2, and 3 were all in good
-
45 °C. The Grignard reagent (3 equiv, 15 mmol) was then
added rapidly in one portion to the THF solution and stirring
continued for a further 30 min to 1 h (exact length of time had
no effect on yield). Saturated ammonium chloride solution was
added to the reaction mixture (at ca. -40 °C) before allowing
the mixture to warm to room temperature. The mixture was
thoroughly extracted with diethyl ether (2 × 200 mL), the ether
extracts combined and thoroughly washed with further am-
monium chloride (300 mL), water (300 mL), and brine (300 mL)
before drying (MgSO
brown gum, which was purified by flash column chromatography
hexane/ethyl acetate 9:1) to give the title compound. Known
4
) and concentrating in vacuo to give a dark
9,12,13
agreement with previously reported data.
(
compounds were in good agreement with literature data; new
compounds gave satisfactory spectroscopic and analytical data.
Rep r esen ta tive P r oced u r e for Heter oa r yl Ra d ica l Re-
Ack n ow led gm en t. The author wishes to thank the
Open University for funding for this project and the
EPSRC National Mass Spectrometry Service Centre
(Swansea) for some mass spectra.
3
d u ction Rea ction . Tributyltin hydride (1.2 equiv, 3.6 mmol)
was added to a solution of the 7-bromoindole derivative (3 mmol)
in dry deoxygenated toluene (25 mL) under argon, and after the
mixture was heated to 110 °C, AIBN (a few crystals, ca. 10 mg)
was added and the mixture continued to be heated under reflux
J O0057396