Rhodium-catalyzed cycloisomerization: Formation of indoles, benzofurans, and enol lactones

Article abstract of DOI:10.1002/anie.200604183

(Chemical Equation Presented) Internal affairs: Indoles, benzofurans, and enol lactones are formed chemoselectively from the rhodium-catalyzed cyclo-isomerization reaction of easily prepared alkynyl aniline substrates (see scheme, cod = cycloocta-1,5-diene, DMF = N,N-dimethylformamide). The reaction may proceed by nucleophilic capture of a vinylidene intermediate. Indoles are formed under mild conditions using low catalyst loadings.

Full text of DOI:10.1002/anie.200604183

Communications
DOI: 10.1002/anie.200604183
Vinylidenes
Rhodium-Catalyzed Cycloisomerization: Formation of Indoles,
Benzofurans, and Enol Lactones**
Barry M. Trost* and Andrew McClory
The development of atom-economical reactions is one of the
primary challenges for synthetic chemists.[1] Accordingly, our
research group has developed addition and isomerization
reactions in which all of the reactant atoms are expressed in
the product.[2] The involvement of vinylidenes in catalytic
cycles represents a relatively new and attractive approach
towards such reactions.[3] The precursor alkynes are readily
available, and the unique reactivity of these intermediates
opens the door to the discovery and invention of new
reactions. Herein we present our results on one such reaction:
the rhodium-catalyzed cycloisomerization of alkynyl anilines,
phenols, and carboxylic acids to give indoles, benzofurans, and
enol lactones, respectively.
Scheme 1. Representative synthesis of the substrates. TMS=trimethyl-
silyl.
ꢀ
The first use of vinylidenes to form C C bonds in a
catalytic reaction was reported by our research group some
Table 1: Optimization of the internal cycloisomerization of alkynyl
aniline 4.
years ago.[4] Subsequently, we extended the use of vinylidene
ꢀ
intermediates to the formation of C O bonds in the cyclo-
isomerization of homopropargyl and bis-homopropargyl
alcohols to give dihydrofurans and dihydropyrans, respec-
tively.[5] Earlier studies by MacDonald et al. investigated
similar transformations.[6] We then hypothesized that nitrogen
and less-nucleophilic oxygen (for example, phenol and
carboxylic acid) substrates could be used. Herein we report
the results of our studies.
The synthesis of the substrates for cycloisomerization was
straightforward (Scheme 1). For example, 4-chloroaniline (1)
was iodinated in high yield,[7] and a Sonogashira cross-
coupling of 2 with trimethylsilylacetylene, followed by pro-
todesilylation, provided the desired substrate 4 in an overall
yield of 88% for the three steps.
The rhodium-catalyzed cycloisomerization reaction was
optimized by systematically changing the reaction parameters
(Table 1). The initial conditions, derived from the cyclo-
isomerization of homopropargyl and bis-homopropargyl
alcohols,[5b] provided the product indole 5 in good yield
(entry 1, Table 1). Lowering the ligand to metal ratio
Entry Conc. of [{Rh(cod)Cl}2]
Ligand
t
Yield
4 [m]
[mol%]
[mol%] [min] [%]
1
2
3
4
5
6
7
0.20
0.20
0.20
0.20
0.20
0.20
0.20
5.0
5.0
5.0
2.5
2.5
–
(4-FC6H4)3P
60
45
30
15
–
120 84
120 89
120 87
120 89
120 11
120 n.r.
120 53
(4-FC6H4)3P
(4-FC6H4)3P
(4-FC6H4)3P
–
(4-FC6H4)3P
(4-
15
15
2.5
MeOC6H4)3P
Ph3P
8
9
0.20
0.20
0.20
0.50
1.0
2.5
2.5
1.0
1.0
1.0
1.0
1.0
15
10
4
4
4
120 80
120 80
120 77
120 69
120 59
Ph3P
Ph3P
Ph3P
Ph3P
Ph3P
Ph3P
10
11
12
13
14
0.20
0.20
4
4
30
60
49[a]
61[b]
[a] 29% of substrate 4 was recovered. [b] 16% of substrate 4 was
recovered. DMF=N,N-dimethylformamide, cod=cycloocta-l,5-diene,
n.r.=no reaction.
[*] Prof. B. M. Trost, A. McClory
Department of Chemistry
Stanford University
Stanford, CA 94305–5080 (USA)
Fax: (+1)650-725-0259
E-mail: bmtrost@stanford.edu
(entries 2 and 3), as well as the overall loading (entry 4),
provided the product in similar yields. Control experiments
showed that both ligand and metal were essential (entries 5
and 6). The use of a more electron rich ligand was detrimental
to the reaction (entry 7), while use of the less expensive
triphenylphosphine gave a similar yield of product (entry 8).
Lowering the metal and ligand loadings further did not
diminish the yield (entries 9 and 10); however, an increase in
the concentration proved detrimental (entries 11 and 12), and
[**] We thank the National Science Foundation and the National
Institutes of Health, General Medical Sciences Institute (GM 33049)
for their generous support of our programs. Mass spectra were
provided by the Mass Spectrometry Regional Center of the
University of California, San Francisco, which is supported by the
NIH Division of Research Resources.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
2074
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Chemie
Table 2: Cycloisomerization of alkynyl anilines into indoles.
shortening the reaction time led to
incomplete conversion (entries 13
and 14). Thus the initial optimal
conditions for indole formation
were seen to be those used in
entry 10, because the least expen-
sive phosphine was used.
Entry
Substrate
Product
Conditions
B
A
C
yield [%][a]
yield [%][b]
yield [%][c]
1
2
3
4
52[d]
77
79
84
98
98
72
88
92
89
A variety of alkynyl anilines
were converted into the corre-
sponding indole products in syn-
thetically useful yields using the
initial optimized conditions (col-
umn A, Table 2). The chemoselec-
tivity of the process was excellent,
with a wide range of functional
groups (for example, chloro, ester,
nitrile, ketone, nitro, and ether)
being compatible. The higher
yields obtained with tris(4-fluoro-
phenyl)phosphine (Table 1) led us
to return to this ligand, and as a
result, the yields increased invaria-
bly (column B, Table 2). When the
catalyst loading was lowered to that
of the conditions in column A, but
with this ligand, we achieved results
that were comparable to those with
the higher catalyst loading (col-
umn C, Table 2). Benzyl- and para-
methoxybenzyl-protected anilines
could serve as substrates (entries 7
and 8), although the use of a more
84
90
5
6
77
81
93
79
85
80
7
8
61
88
94
73
74
52[e]
strongly
electron-withdrawing
ligand was required to provide sim-
ilar yields as those achieved with
the parent system (entry 2). The
failure of an allyl-protected aniline
may be explained by the proclivity
of such groups to undergo isomer-
ization to the enamine,[8] which then
9
decomp
59
decomp
83
decomp
73
10
[a] 1% [{Rh(cod)Cl}2], 4% Ph3P, DMF, 858C, 2 h. [b] 5% [{Rh(cod)Cl}2], 60% (4-FC6H4)3P, DMF, 858C,
2 h. [c] 1% [{Rh(cod)Cl}2], 4% (4-FC6H4)3P, DMF, 858C, 2 h. [d] 15% of the substrate was recovered. could lead to various undesired
[e] 5% of the substrate was recovered. decomp=decomposed.
products.
As we had established that ani-
lines were viable nucleophiles, we
Table 3: Cycloisomerization of alkynyl phenols and carboxylic acids.
Entry
Substrate
Product
Conditions
B
reasoned that the formation of
benzofurans and enol lactones
from alkynyl phenols and carbox-
ylic acids, respectively, would be
feasible. As shown in Table 3, this
proved to be the case. Use of
triphenylphosphine as a ligand in
this reaction failed; however,
higher loadings of the metal and
use of the more strongly electron-
withdrawing ligand were sufficient
to promote the reaction. This may
be because of the reduced nucleo-
philicity of the oxygen atom com-
pared to nitrogen atom.
A
C
yield [%][a]
yield [%][b]
yield [%][c]
1
n.r.[d]
77
12
2
3
n.r.[d]
n.r.[d]
75
81
52
n.r.[d]
[a] 1% [{Rh(cod)Cl}2], 4% Ph3P, DMF, 858C, 2 h. [b] 5% [{Rh(cod)Cl}2], 60% (4-FC6H4)3P, DMF, 858C,
2 h. [c] 1% [{Rh(cod)Cl}2], 4% (4-FC6H4)3P, DMF, 858C, 2 h. [d] Partial decomposition.
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Communications
Substrates 30 and 31 were subjected to the reaction
reactions suggest that either nucleophilic attack or reductive
elimination may be the rate-determining steps of the catalytic
cycle, as these processes would be facilitated by such ligands.
One alternative mechanism involves coordination of the
catalyst to the alkyne to induce nucleophilic attack (VII,
Scheme 3), followed by proton transfer from the nitrogen
atom to the rhodium center, and subsequent reductive
elimination. Complexes of palladium(II),[11] gold(III),[11a,12]
and indium(III)[13] catalyze the reaction of internal alkynes
and free amines in this manner, while complexes of palladiu-
m(II),[11a,14] gold(III),[11a] and copper(II)[15] catalyze the reac-
tion of internal alkynes and amines that contain electron-
withdrawing groups. There are limited examples that involve
terminal alkynes and free amines.[12,15a,b] This mechanism is
consistent with the observation that anilines were superior to
phenols in the reaction, as the former are better nucleophiles.
Another possible mechanism involves insertion of the metal
conditions to probe the reaction mechanism (Scheme 2). We
reasoned that if a vinylidene mechanism were operational,
then only terminal alkynes could serve as substrates for indole
formation. Thus, substrate 30 bearing an internal alkyne
should not react, whereas 31 should react exclusively through
the terminal alkyne to give indole 33. In the event, these
predictions were borne out experimentally.
ꢀ
into the N H bond (VIII, Scheme 3), followed by coordina-
tion/insertion into the pendant alkyne and reductive elimi-
nation. Ruthenium catalyzes hydroamination reactions of
alkynyl amines in this manner.[16] The fact that anilines
reacted more readily than phenols, despite the similar
[17]
ꢀ
ꢀ
strength of N H and O H bonds, is inconsistent with a
mechanism involving oxidative addition of the metal into
these bonds. Neither of these alternative mechanisms explains
the lack of reactivity of internal alkynes.
Scheme 2. Studies into the mechanism.
These results may be interpreted according to the
proposed mechanism shown in Scheme 3. The dimeric
rhodium precursor [{Rh(cod)Cl}2] may react with the phos-
phine ligand to form the coordinatively unsaturated mono-
meric species I.[9] Coordination of the alkyne substrate II,
followed by rearrangement, leads to vinylidene intermediate
III.[10] This process has good precedent for terminal alkynes
but is unknown for internal alkynes, and is also consistent with
the results in Scheme 2. This key intermediate may undergo
nucleophilic capture by the pendant amine to give IV. Finally,
proton transfer from the nitrogen atom to the rhodium center,
followed by reductive elimination, could provide indole
product VI, and regenerate the active catalyst. The fact that
electron-withdrawing phosphine ligands perform best in the
In summary, a chemoselective cycloisomerization reaction
has been reported for the formation of indoles, benzofurans,
and enol lactones. Substrates are readily available and
functional-group tolerance is high for this atom-economical
reaction. In the case of alkynyl aniline substrates, low loadings
of metal and triphenylphosphine make for a very practical
method of forming indoles.[18] The synthesis of parent indoles
from the cyclization of unprotected anilines and terminal
alkynes distinguishes this process from other metal-catalyzed
cyclization methods. Collectively, these reactions further
increase the scope of known nucleophiles that react with
metal vinylidene intermediates in catalytic processes.[5,6,19]
Experimental Section
Typical experimental procedure (Method A):
N,N-dimethylformamide (2.50 mL) was degassed
(Ar balloon) for 20 min and then added through
a cannula to a mixture of 4 (76 mg, 0.500 mmol),
[{Rh(cod)Cl}2] (2.5 mg, 0.005 mmol), and triphe-
nylphosphine (5.2 mg, 0.020 mmol). The solution
was stirred for 2 h at 858C under Ar. The reaction
mixture was then cooled to 258C and extracted
from saturated aq NaHCO3 (50 mL) with diethyl
ether (3” 10 mL). The combined organic extracts
were washed with saturated aq NaHCO3
(10 mL), dried with anhydrous MgSO4, filtered,
and evaporated in vacuo. Purification by flash
column chromatography through silica gel
(petroleum ether/diethyl ether/triethylamine
90:10:3!50:50:3!25:75:3) gave the product 5
(58 mg, 77%) as pale tan crystals; mp: 71.5–
72.08C; IR (CHCl3): n˜ = 3476, 2252, 1721, 1569,
1458, 1447, 1413, 1338, 1315, 1265, 1242, 1196,
Scheme 3. Proposed mechanism of the cycloisomerization.
1094, 1068 cmꢀ1 1H NMR (400 MHz, CDCl3):
;
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Angewandte
Chemie
d = 8.06 (br s, 1H), 7.60 (d, J = 2.0 Hz, 1H), 7.24 (d, J = 8.6 Hz, 1H),
7.17 (t, J = 2.9 Hz, 1H), 7.13(dd, J = 2.0, 8.6 Hz, 1H), 6.48–6.47 ppm
(m, 1H); 13C NMR (100 MHz, CDCl3): 134.0, 128.8, 125.5, 125.3,
122.2, 120.0, 112.0, 102.3ppm; HRMS (EI) m/z calcd for C8H6ClN
[M+]: 151.0189, found: 151.0183.
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Received: October 13, 2006
Published online: February 7, 2007
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Keywords: alkynes · atom economy · cyclization ·
homogeneous catalysis · rhodium
.
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