A Practical route to substituted 7-aminoindoles from pyrrole-3-carboxaldehydes

Article abstract of DOI:10.1021/ol503078h

Among privileged structures, indoles occupy a central place in medicinal chemistry and alkaloid research. Here we report a flexible and efficient conversion of pyrrole-3-carboxaldehydes to substituted 7-amino-5-cyanoindoles. Phosphine addition to fumaronitrile proceeds with prototropic rearrangement of the initially formed zwitterion to the thermodynamically favored phosphonium ylide, which is poised for in situ Wittig olefination. The predominantly E-alkene product positions the allylic nitrile for facile intramolecular Hoeben-Hoesch reaction in the presence of BF₃·OEt₂. Syntheses of 2,5- and 3,5-disubstituted 7-aminoindoles are illustrated. Additionally, dianion alkylation of the allylic nitrile is demonstrated to furnish, after cyclization, 5,6-disubstituted 7-aminoindoles to further exemplify this scalable and high-yielding method.

Full text of DOI:10.1021/ol503078h

Letter
pubs.acs.org/OrgLett
A Practical Route to Substituted 7‑Aminoindoles from Pyrrole-3-
carboxaldehydes
Victor K. Outlaw and Craig A. Townsend*
Department of Chemistry, Johns Hopkins University, 3400 North Charles Street, Baltimore, Maryland 21218, United States
*
S Supporting Information
ABSTRACT: Among privileged structures, indoles occupy a central place in medicinal chemistry and alkaloid research. Here we
report a flexible and efficient conversion of pyrrole-3-carboxaldehydes to substituted 7-amino-5-cyanoindoles. Phosphine addition
to fumaronitrile proceeds with prototropic rearrangement of the initially formed zwitterion to the thermodynamically favored
phosphonium ylide, which is poised for in situ Wittig olefination. The predominantly E-alkene product positions the allylic nitrile
for facile intramolecular Hoeben−Hoesch reaction in the presence of BF ·OEt . Syntheses of 2,5- and 3,5-disubstituted 7-
3
2
aminoindoles are illustrated. Additionally, dianion alkylation of the allylic nitrile is demonstrated to furnish, after cyclization, 5,6-
disubstituted 7-aminoindoles to further exemplify this scalable and high-yielding method.
ynthetic routes to indoles have long been prized owing to the
S
prevalence of the aromatic heterocycles in natural products
1
as well as synthetic medicinal agents. Classical indole syntheses,
2
3
4
5
including the work of Fischer, Bartoli, Larock, Reissert, and
6
many others, remain benchmarks in the development of
heterocyclic methodology. The majority of these approaches
utilize a functionalized benzene ring to annulate the 5-membered
pyrrolic portion of the indole. In contrast, few synthetic strategies
exist that originate from a substituted pyrrole to build up the
7
benzenoid portion of the indole. The latter strategy can benefit
from the unique chemistry of pyrroles, which react with
electrophiles preferentially at C-2 but exclusively at C-3 when
N-protected with the sterically cumbersome triisopropylsilyl
8
group. This tunable reactivity allows for ready introduction of
Figure 1. Proposed route to substituted 7-aminoindoles.
the would be C-2 and C-3 substituents of the indole prior to
annulation. Further, the intrinsic reactivity of pyrroles at C-2
introduces a disconnection optimal for the indole-forming
cyclization itself. Tactical issues of symmetry and regiochemistry
inherent to routes from substituted benzene rings are avoided.
This strategy, shown in Figure 1, utilizes a three-component
Wittig reaction of pyrrole-3-carboxaldehydes with fumaronitrile
and a trialkylphosphine to generate predominantly E-alkenes.
These allylic nitriles are positioned for intramolecular cyclization
under Houben−Hoesch conditions to furnish, after aromatiza-
tion, substituted 7-aminoindoles. An optional tailoring step to
install C-6 substituents prior to ring closure can also be
envisioned. This scheme would allow for control of the C-2,
C-3, and C-6 indole substituents on the resulting 7-amino-5-
cyanoindoles that are not readily accessible using existing
methods. The amine (e.g., by diazotization, acylation) and the
nitrile (e.g., by hydration, hydrolysis, reduction, etc.) can be
differentially modified for rapid structural diversification.
Potential targets (Figure 2) include a class of potent β-secretase
9
1 (BACE1) inhibitors, a class of nicotinic acetylcholine receptor
10
(nAChR) allosteric modulators, and analogues of recently
reported inhibitors of glycerol-3-phosphate acyltransferase
11
(GPAT).
Of fundamental importance to the planned synthesis was the
acquisition of E-alkenes such as 2 (Figure 1). The E-selective
olefination of aldehydes with esters of fumarate and maleate,
maleic anhydride, or maleimide and tributyl- or triphenylphos-
phine has been previously described. We envisioned a similar
,4-addition of a phosphine to fumaronitrile proceeded by rapid
prototropic rearrangement of the initially formed zwitterion A to
the thermodynamically favored phosphonium ylide B, which is
poised for in situ Wittig olefination with pyrrole-3-carboxalde-
hydes such as 1. Trimethyl-, triethyl-, tributyl-, and triphenyl-
12
1
Received: October 21, 2014
©
XXXX American Chemical Society
A
dx.doi.org/10.1021/ol503078h | Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
To demonstrate scope, the optimized conditions using PEt at
3
6
5 °C were applied to various 4- and 5-substituted pyrrole-3-
carboxaldehydes 1a−g. Alkenes 2a−g were obtained in generally
good to excellent yield and moderate diastereoselectivity (Table
2
). The reaction conditions were tolerant of a wide range of
Table 2. Scope of Wittig Reaction
a
entry
1
R2
−H
−Br
−CO Et
−Ph
−H
−H
−H
R3
time (h) product yield (%) E/Z
Figure 2. Representative medicinal chemistry targets.
1
2
3
4
5
6
7
1a
1b
1c
1d
1e
1f
−H
−H
−H
−H
−Me
−Et
−Br
8
10
10
8
2a
2b
2c
2d
2e
2f
97
97
96
88
85
85
93
3:1
3:1
5:1
3:1
4:1
4:1
5:3
phosphine, as well as trimethyl phosphite, were evaluated for the
efficiency of their reactions with fumaronitrile and aldehyde 1a as
shown in Table 1. PPh and P(OMe) were unreactive under the
2
8
3
3
8
Table 1. Optimization of Wittig Reaction with Aldehyde 1a
1g
8
2g
a
E/Z values were calculated from the ratio of the integrals of the allylic
1
methylenes in the H NMR spectra.
substituents including alkyl, aryl, halogen, and ester moieties.
Electron-withdrawing substituents at the pyrrolic α-position led
to slower conversion. Additionally, minor substituent effects
were observed for the diastereoselectivity of the reactions.
To further diversify the library of E-alkenes, we next sought to
functionalize the allylic nitrile. To accomplish this task without
the use of protecting groups, we elected to exploit the relatively
more acidic pyrrole N−H and developed a dianion approach to
alkylate the allylic position chemoselectively (Table 3). Addition
a
b
entry
PR3
X
temp (°C) time (h) yield of 2a (%) E/Z
1
2
3
4
5
6
7
8
9
PMe3
1.4
1.4
1.4
1.4
1.4
1.2
1.2
1.2
1.2
23
23
23
23
23
23
23
23
65
48
48
48
48
48
48
48
48
8
76
80
72
0
4:3
PEt3
PBu3
PPh3
4:3
4:3
P(OMe)3
0
PMe3
95
99
91
97
3:1
3:1
3:1
3:1
PEt3
PBu3
PEt3
Table 3. Alkylation of Allylic Nitrile 2a
a
b
Isolated yield. E/Z values were calculated from the ratio of the
1
integrals of the allylic methylenes in the H NMR spectra.
reaction conditions. PMe , PEt , and PBu , when used in excess,
3
3
3
exhibited understandably similar reactivity, converting aldehyde
a to alkene 2a in moderate yield (72−80%) but with only slight
1
entry
electrophile
product
R6
yield (%)
E-selectivity (4:3) after extended reaction time (48 h).
Concerned that the excess phosphine was adding into the
product, itself an α,β-unsaturated nitrile, and causing isomer-
ization of the alkene, we next attempted the reaction with
limiting phosphine. At room temperature, these reactions gave
the desired alkene 2a in high yield (91−99%) and good E/Z ratio
1
2
3
4
5
6
MeI
4a
4b
4c
4d
4e
4f
−CH3
77
80
75
67
72
80
EtI
−CH CH3
2
BnBr
−CH Ph
2
allyl-Br
propargyl-Br
BrCH CO Et
−CH CHCH
2
2
−CH CCH
2
−CH CO Et
2
2
2
2
(
3:1), suggesting that the excess phosphine was indeed causing
alkene isomerization. To ameliorate the sluggish reaction rate, we
heated the reaction with PEt to 65 °C. These improved
of 2.1 equiv of LDA followed by the addition of various
electrophiles effected selective α-alkylation of nitrile 2a to afford
4a−f without detection of N-alkylated pyrrole side products
10a−f. Analogous attempts with the electrophiles ethyl
3
conditions cut the reaction time 6-fold while maintaining the
favorable yield (97%) and E/Z ratio (3:1) of the room
temperature reaction. There are distinct advantages to each of
the phosphines tested. The volatility of PMe (bp 38 °C) allows
chloroformate, methyl acrylate, Br , and NBS showed no desired
3
2
for easy removal upon workup but prohibits heating of the
reaction.
reaction without a sealed vessel. PBu (bp 240 °C) requires an
With reaction conditions established to E-olefinic precursors
2a−g and 4a−f, we next sought to optimize indole cyclization
conditions as shown in Table 4. Of the Lewis acids tested, only
BF ·OEt successfully effected cyclization. Initial attempts to use
3
additional oxidative workup step but is the most economical
choice. Finally, PEt (bp 126 °C) afforded the highest yield and
3
allows for heating to reflux while maintaining the option of low-
3
2
pressure removal.
a catalytic amount of BF ·OEt gave only stoichiometric yield.
3 2
B
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Organic Letters
Letter
Table 4. Optimization of Cyclization to indole 3a
In addition, a functionally one-pot reaction was run to indole
a, shown in Scheme 1, in which pyrrole-3-carboxaldehyde and
3
Scheme 1. One-Pot Synthesis of indole 3a
entry
Lewis acid
X
solvent
CH Cl
temp (°C)
yield (%)
1
2
3
4
5
6
7
8
none
45
45
45
45
45
70
85
90
0
0
2
2
AlCl3
0.2
0.2
0.2
0.2
1.1
1.1
2.5
CH Cl
2
2
2
2
2
Sc(OTf)3
TiCl4
CH Cl
0
2
CH Cl
0
2
BF ·OEt
CH Cl
19
0
3
2
2
2
2
2
BF ·OEt
THF
3
fumaronitrile were reacted in dry THF with PMe as before
3
BF ·OEt
PhCH3
DCE
61
91
3
(
Table 1). Taking advantage of the relatively low boiling point of
BF ·OEt
3
PMe , the solvent and any unreacted phosphine were removed
3
by rotary evaporation and the residue taken up in 1,2-DCE.
Presumably, this is due to chelation of the Lewis acid by the 7-
aminoindole product thereby preventing catalytic turnover.
Similarly, using THF as the solvent afforded no reaction, likely
owing to association of the Lewis acid with the ethereal solvent.
The optimized conditions used 2.5 equiv of BF ·OEt in 1,2-
Treatment of this mixture as above with BF ·OEt gave the
3
2
desired indole in 77% yield, approximately the theoretical limit
from the E-isomer, after crystallization of the product from the
crude mixture containing unreacted Z-isomer.
Encouraged by the success of this approach, we next tested
whether the corresponding furan- and thiophene-3-carboxalde-
hydes could undergo a similar two-step sequence to the
corresponding 7-amino-5-cyanobenzofurans and benzothio-
phenes, respectively (Scheme 2). We hypothesized that, with
decreased C-2 nucleophilicity and increased heteroatomic
interaction with the BF ·OEt , the annulation of these hetero-
3
2
dichloroethane at 90 °C for 12 h, which gave efficient annulation
of alkene 2a to indole 3a.
Application of the annulation conditions to the E-alkenes 2a−
g and 4a−f gave indoles 3a−g and 5a−f in good to excellent
yields (Table 5). The reaction conditions were amenable to a
wide scope of substituents. Of particular interest to us, the
bromo- and propargyl-substituted indoles can be further
functionalized through coupling reactions or click chemistry,
respectively, to rapidly generate large libraries of compounds.
The more electron-deficient pyrroles (e.g., 2c, 2g) demonstrated
lower yields, typical of electrophilic aromatic substitution with an
electron-deficient arene. The reaction times for the 6-substituted
alkenes were slightly shorter than for cyclization of the 2- and 3-
substituted examples. This behavior points to a possible
Thorpe−Ingold effect, whereby the C-6 substituent increases
the population of the reactive rotamer resulting in an increased
reaction rate. It is likely that this tactic can also be applied to
pyrroles additionally substituted at the 2- and 3-positions.
3
2
cycles would be less facile. First, Wittig reaction using the
optimized conditions afforded the olefins 12a,b in excellent yield
and better stereoselectivity than for the pyrrolic reactions.
Treatment with BF ·OEt effected annulation to benzofuran 13a
3
2
and benzothiophene 13b in low to moderate yield. As expected,
the reaction rates were much slower with conversion stalling
around 24 h. Neither additional equivalents of Lewis acid nor
longer reaction times improved the yields. It is possible that use
of a less oxophilic Lewis acid could improve the yields for these
classes of heterocycles.
Finally, to illustrate practical applications of this method we
chose to demonstrate functional group conversions from the 7-
Table 5. Scope of Indole Annulation
entry
pyrrole
R2
−H
R3
R6
indole
time (h)
yield (%)
1
2
3
4
5
6
7
8
9
2a
2b
2c
2d
2e
2f
−H
−H
−H
−H
−H
−H
−H
−H
−H
−H
−H
−CH3
3a
3b
3c
3d
3e
3f
12
12
12
12
12
12
12
8
91
67
62
87
94
92
75
88
95
96
93
92
72
−Br
−CO Et
2
−Ph
−H
−H
−H
−H
−H
−H
−H
−H
−H
−CH3
−CH CH3
2
2g
4a
4b
4c
4d
4e
4f
−Br
−H
−H
−H
−H
−H
−H
3g
5a
5b
5c
5d
5e
5f
−CH CH3
−CH Ph
8
2
10
11
12
13
8
2
−CH CHCH
8
2
2
−CH CCH
8
2
−CH CO Et
8
2
2
C
dx.doi.org/10.1021/ol503078h | Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 2. Application to the Synthesis of Benzofuran and
Benzothiophene Derivatives
will aim to expand the scope of this method and to demonstrate
its potential for the synthesis of bioactive targets of interest.
ASSOCIATED CONTENT
Supporting Information
■
*
S
Detailed synthetic procedures and characterization data. This
material is available free of charge via the Internet at http://pubs.
acs.org.
AUTHOR INFORMATION
Corresponding Author
■
*
E-mail: ctownsend@jhu.edu.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
amino-5-cyanoindole intermediates to readily identifiable
precursors of the medicinal chemistry targets noted above
We thank Dr. I. P. Mortimer for mass spectral analysis and Dr. C.
Moore for NMR assistance. This work was supported by the
National Institutes of Health research grant ES001670.
(
Figure 2). First, we utilized Sandmeyer chemistry to substitute
the amino group of indole 3a with chloro or bromo as shown in
Scheme 3. These aryl halides allow access to a variety of C-7
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Scheme 3. Functional Group Conversion of 3a to Precursors
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(
(
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(
(
(
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́
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dx.doi.org/10.1021/ol503078h | Org. Lett. XXXX, XXX, XXX−XXX