Synthesis of 2-Aryl-Substituted Indole-3-acetic Acid Derivatives via Intramolecular Imino-Stetter Reaction of Aldimines with Cyanide

Article abstract of DOI:10.1002/adsc.201600155

A general method to generate umpolung of aldimines with cyanide was developed via the addition of cyanide to aldimines followed by a proton transfer from the carbon atom to the nitrogen atom in the resulting cyanide adducts. This novel method was successf

Full text of DOI:10.1002/adsc.201600155

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DOI: 10.1002/adsc.201600155
Synthesis of 2-Aryl-Substituted Indole-3-acetic Acid Derivatives
via Intramolecular Imino-Stetter Reaction of Aldimines with
Cyanide
Seong Jong Lee,a Hong-Ahn Seo,a and Cheol-Hong Cheona,*
a
Department of Chemistry, Korea University, 145 Anam-ro, Seongbuk-gu, Seoul 02841, Republic of Korea
E-mail: cheon@korea.ac.kr
Received: February 4, 2016; Published online: April 15, 2016
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201600155.
Abstract: A general method to generate umpolung
of aldimines with cyanide was developed via the ad-
dition of cyanide to aldimines followed by a proton
transfer from the carbon atom to the nitrogen atom
in the resulting cyanide adducts. This novel method
was successfully applied to the first imino-Stetter
reaction of aldimines obtained from 2-aminocin-
namic acid derivatives and aromatic aldehydes with
cyanide, affording 2-aryl-substituted indole-3-acetic
acid derivatives. Furthermore, the usefulness of this
method was successfully demonstrated by the syn-
thesis of an FPTase inhibitor, one of the biologically
important 2-arylindole-3-acetic acid derivatives.
(Scheme 1a).[4] The treatment of Strecker products 2
with a strong base generated anions I that underwent
5-exo-trig cyclization affording the corresponding in-
doline products 3. The subsequent elimination of
HCN and aromatization afforded 2-arylindole-3-
acetic acid derivatives 4. Although this method pro-
vided a ready access to useful 2-arylindole-3-acetic
acid derivatives,[5] it has not been as popular as other
conventional methods in the preparation of 2-arylin-
Keywords: aldimines; 2-arylindole-3-acetic acid de-
rivatives; cyanide; imino-Stetter reaction; umpo-
lung
Since indoles are frequently found in biologically
active natural products and pharmaceuticals, the de-
velopment of new methods for the synthesis of indole
scaffolds has been a topic of great importance.[1]
Among the indole derivatives, 2-arylindole-3-acetic
acid derivatives are key subunits of several biological-
ly active natural products, and thus several protocols
to access these important scaffolds have been devel-
oped.[2,3] Conventionally, 2-arylindole-3-acetic acid de-
rivatives were prepared via either arylation of indole-
3-acetic acid derivatives carrying a pre-installed func-
tional group at the 2-position[2] or rhodium-catalyzed
À
C H functionalization of aniline derivatives with al-
kynes carrying proper substituents[3].
Alternatively, the Opatz group reported an excel-
lent example of the synthesis of 2-arylindole-3-acetic
acid derivatives 4 from Strecker products 2 of 2-ami-
nocinnamic acid derivatives 1 and aromatic aldehydes
Scheme 1. Synthesis of 2-aryl-substituted indole-3-acetic acid
derivatives 4 (a) from Strecker products 2 with a stoichio-
metric amount of a strong base (previous work) (b) from al-
with a stoichiometric amount of a strong base dimines 5 with a catalytic amount of cyanide (this work).
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Synthesis of 2-Aryl-Substituted Indole-3-acetic Acid Derivatives
dole-3-acetic acid derivatives, presumably due to its short reaction time. The usefulness of this new
drawbacks, particularly in terms of atom-economy.[6] method was further demonstrated by the syntheses of
A stoichiometric amount of HCN must be used to biologically important 2-arylindole-3-acetic acid deriv-
prepare the Strecker products, and the same amount atives, such as a farnesyl protein transferase (FPTase)
of a strong base is required to generate anions I, inhibitor.[11]
which are umpolung derivatives of aldimines. More-
over, the same amount of HCN is produced as a by- was tested using aldimine 5a, obtained from piperi-
product to regenerate the indole scaffold. dine amide 1a of 2-aminocinnamic acid and benzalde-
First, the working hypothesis shown in Scheme 1b
Very recently, we reported a protocol for the syn- hyde, as the model compound (Table 1). Cyanide was
thesis of amides from aldimines via cyanide-mediated found to play a crucial role in this transformation; the
metal-free aerobic oxidation.[7] The mechanistic stud- corresponding indole 4a was obtained in a high yield
ies indicated that amides would be formed from ald- in the presence of cyanide (entry 1), whereas no reac-
imines in the presence of cyanide through the follow- tion was observed in the absence of cyanide (entry 2).
ing sequences: (i) the addition of cyanide to aldimines Based on the working hypothesis, this transformation
to form cyanide adducts II, (ii) a proton transfer from should be possible with a catalytic amount of cyanide;
the carbon atom to the nitrogen atom in the resulting therefore, the effect of the amount of cyanide on this
cyanide adducts II generating umpolung I, and (iii) transformation was investigated (entries 1, and 3–7).
subsequent reaction of I with molecular oxygen af- To our delight, this transformation could be achieved
fording the desired amides.
with a catalytic amount of cyanide and the amount of
With this finding in hand, a literature survey was cyanide could be reduced to 5 mol% without any loss
conducted on the generation of umpolung I of aldi- of its catalytic efficiency.
mines with cyanide. Although the generation of um-
Next, the effect of reaction temperature on this
polung I of aldimines with cyanide has been recog- transformation was investigated and the reaction tem-
nized since Strainꢁs seminal report in 1928,[8] and the
chemistry of umpolung I of aldimines has been dem-
onstrated in dimerization reactions of aldimines via
Table 1. Optimization of the reaction conditions.
the addition of umpolung
I to the remaining
imines,[9,10] the chemistry of I with cyanide has been
far less investigated compared to that of aldehydes.
On the basis of our findings[7] in conjunction with
the previous reports[8–10] on the facile generation of
umpolung of aldimines with cyanide, we hypothesized
that 2-arylindole-3-acetic acid derivatives 4 could be
prepared from aldimines 5 obtained from 2-aminocin-
namic acid derivatives 1 and aromatic aldehydes in
the presence of a catalytic amount of cyanide, rather
than from the corresponding Strecker products 2 in
the presence of a stoichiometric amount of a strong
base, although the Opatz group reported that cycliza-
tion of aldimines 5 with a catalytic amount of cyanide
was unsuccessful.[4] As demonstrated in Scheme 1b,
the reaction of aldimines 5 with cyanide would afford
cyanide adducts II, and the subsequent tautomeriza-
tion of the resulting cyanide adducts generates anions
I.[7–10] The resulting anions I would follow the same
transformation as shown in Scheme 1a, leading to the
desired indole derivatives 4. Because cyanide is re-
leased from adducts 3 after the formation of an
indole ring, the entire transformation can be expected
to be performed with only a catalytic amount of cya-
nide.
Entry NaCN (x mol%) Solvent Time [min] Yield [%][a]
1
2
3
4
5
6
7
100
–
50
20
10
5
<3
10
10
10
10
10
10
10
10
10
10
10
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMSO 30
MeOH 240
EtOH
CH3CN 240
CH2Cl2 240
THF
10
240
10
10
10
10
60
60
60
82
N.R.[b]
81
85
86
64
trace
trace
trace
78
82
83
8[c]
9[d]
10[e]
11[f]
12[g]
13
14
15
16
17
18
60
<10
<10
81
45
43
240
64
N.R.[b]
trace
240
[a]
Isolated yield.
No reaction.
At room temperature.
At 408C.
At 508C.
At 708C.
Herein, we report a new protocol for the synthesis
of 2-aryl-substituted indole-3-acetic acid derivatives
from aldimines obtained from 2-aminocinnamic acid
derivatives and aromatic aldehydes with a catalytic
amount of cyanide. Various 2-arylindole-3-acetic acid
derivatives were obtained in excellent yields in a very
[b]
[c]
[d]
[e]
[f]
[g]
At 808C.
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Seong Jong Lee et al.
perature was found to significantly affect the efficien- aldehydes and piperidine amide 1a of 2-aminocinnam-
cy of this transformation (entries 5, and 8–12). The re- ic acid, could be applied to this protocol and the de-
action rate increased with reaction temperature; no sired products 4 were obtained in high yields in a very
reaction was observed below 408C, but the reaction short reaction time (generally less than 30 min) re-
was completed in less than 10 min when the reaction gardless of the electronic and steric nature of the al-
temperature was above 608C. Because the reaction at dehydes (entries 1–7). Then, the aldimines obtained
608C was sufficiently fast, 608C was selected for fur- from 2-aminocinnamic acid ethyl ester 1b and aromat-
ther investigations. The effect of the reaction media ic aldehydes were explored in this transformation. To
on this transformation was investigated (entries 5, and our delight, the aldimines from ethyl ester of 2-ami-
13–18). The choice of the solvents turned out to have nocinnamic acid could be used in this transformation;
a strong influence on the efficiency of this transforma- the desired indoles 4 were obtained in slightly better
tion. Reactions in DMF and DMSO afforded the de- yields than the corresponding amides (entries 8–
sired product 4a in a high yield and in a short reaction 16).[12] Furthermore, fused aromatic aldehydes and
time (generally <30 min) (entries 5 and 13), whereas heteroaromatic aldehydes were applicable to this pro-
those in other solvents provided 4a in moderate yields tocol to provide the desired indole products 4 in ex-
along with 2-aminocinnamic acid piperidine amide 1a cellent yields (entries 14–16). We attempted to extend
and benzaldehyde via hydrolysis of 5a under the reac- this protocol to the synthesis of 2-arylindole-3-acet-
tion conditions (entries 14–18). Because DMF provid- amides bearing a secondary amide (entry 17). When
ed the best result among the solvents tested, DMF the aldimine, obtained from benzyl amide 1c of 2-ami-
was chosen as the optimal solvent for further investi- nocinnamic acid and benzaldehyde, was subjected to
gation.
the optimized reaction conditions, the reaction did
Under these optimized reaction conditions, the sub- not go to completion, and the desired indole 4q was
strate scope of this transformation was investigated obtained in a low yield. However, when a stoichiomet-
(Table 2). Aldimines, prepared from various aromatic ric amount of cyanide was used instead, 4q was ob-
tained in an excellent yield.
To test the practicality of this protocol, the reaction
was performed on a large scale reaction even without
the isolation of the corresponding aldimines
(Scheme 2). When 2-aminocinnamic acid ethyl ester
1b and benzaldehyde were subjected to the condensa-
tion conditions with a mixture of Na2SO4 and
MgSO4,[13] and the crude mixture of the resulting aldi-
mine 5h was concentrated and subjected to the opti-
mized reaction conditions without further purifica-
tion, the desired product 4h was obtained in 88%
yield on a 20 mmol scale.[14]
Table 2. Substrate scope.
With these results in hand, we further attempted to
demonstrate the usefulness of this new protocol in the
Entry Indole 4
X
Ar
Yield [%][a]
86
1
4a
4b
4c
4d
4e
4f
4g
4h
4i
N(CH2)5
N(CH2)5
N(CH2)5
N(CH2)5
N(CH2)5
N(CH2)5
N(CH2)5
OC2H5
C6H5
4-MeOC6H4 77
2
3
4
5
4-MeC6H4
4-ClC6H4
4-FC6H4
2-FC6H4
2-naphthyl
C6H5
87
80
88
83
86
98
6
7
8
9
OC2H5
4-MeOC6H4 92
10
11
12
13
14
15
16
17[b]
4j
4k
4l
4m
4n
4o
4p
4q
OC2H5
OC2H5
OC2H5
OC2H5
OC2H5
OC2H5
OC2H5
NHCH2Ph C6H5
4-MeC6H4
4-ClC6H4
4-FC6H4
2-BrC6H4
2-naphthyl
2-furyl
96
96
81
95
93
86
86
93
2-thienyl
[a]
Isolated yield.
A stoichiometric amount of NaCN was used.
[b]
Scheme 2. A gram-scale reaction
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Synthesis of 2-Aryl-Substituted Indole-3-acetic Acid Derivatives
Experimental Section
General Procedure
To a solution of aldimine 5 (1.0 mmol) in DMF (10 mL) in
the presence of 4Š molecular sieves was added sodium cya-
nide (0.10 mmol) at room temperature. The mixture was
stirred at 608C under an argon atmosphere and monitored
by thin-layer chromatography (TLC). Upon the complete
consumption of 5, the reaction mixture was cooled to room
temperature and filtered to remove insoluble molecular
sieves. The filtrate was concentrated under vacuum to pro-
vide the crude product, indole 4. The resulting crude mix-
ture was purified by either recrystallization in diethyl ether
[when X=N(CH2)5] or by flash column chromatography on
silica (when X=OEt or NHCH2Ph) to provide the desired
indole 4.
Acknowledgements
This work was supported by National Research Foundation
of Korea (NRF) grants funded by the Korean Government
(NRF-20100020209, NRF-2013R1A1A1008434, and NRF-
2015R1D1A1A01057200). C.-H.C. also thanks for a financial
support from an NRF grant funded by the Korean Govern-
ment (NRF-2014-011165, Center for New Directions in Or-
ganic Synthesis).
Scheme 3. Synthesis of FPTase inhibitor 6
synthesis of biologically important FPTase inhibitor 6
(Scheme 3). The methylation of the free N H bond in
À
4h with methyl iodide, followed by the basic hydroly-
sis of the ester moiety in 4h-Me afforded the corre-
sponding carboxylic acid 7. Amide bond formation of
the resulting carboxylic acid 7 with a secondary
amine[11] in the presence of a coupling reagent afford-
ed FPTase inhibitor 6 in 68% yield over three steps
from readily available indole starting material.
References
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Although there have been several reports in which
the umpolung of aldimines could be generated from
aldimines with cyanide via the cyanide addition to al-
dimines, followed by a proton transfer in the cyanide
adducts,[8–10] the utility of this method has not been
fully recognized by the synthetic community for
a long time. From our recent findings[7] along with the
previous reports,[8–10] we have recognized the facile
generation of the umpolung derivatives of aldimines
with cyanide and developed a highly efficient protocol
for the synthesis of 2-aryl-substituted indole-3-acetic
acid derivatives from aldimines, obtained from 2-ami-
nocinnamic acid derivatives and aromatic aldehydes,
in the presence of a catalytic amount of cyanide via
the first imino-Stetter reaction. Various aromatic al-
dehydes and 2-aminocinnamic acid derivatives could
be used in this protocol; the desired 2-aryl-substituted
indole-3-acetic acid derivatives were obtained in ex-
cellent yields. Furthermore, the usefulness of this pro-
tocol was demonstrated in the synthesis of an FPTase
inhibitor. Studies on further applications of this um-
polung reactivity of aldimines with cyanide to other
organic transformations are currently underway in
our laboratory and will be reported in due course.
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[7] H.-A. Seo, Y.-H. Cho, Y.-S. Lee, C.-H. Cheon, J. Org.
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[12] The indole-acetic acid derivatives 4 obtained from 2-
aminocinnamic acid piperidine amide 1a exhibit much
lower solubilities than those obtained from 2-aminocin-
namic acid ethyl ester 1b, which would be one of the
reasons for the slightly lower yields of indoles bearing
an amide group.
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[14] A slightly low yield of the reaction with aldimine 4h di-
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partial hydrolysis of the aldimine during the indole for-
mation reaction via imino-Stetter reaction.
[11] For previous syntheses of the FPTase inhibitor, see:
B. W. Trotter, A. G. Quigley, W. C. Lumma, J. T. Sisko,
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