Double π-Bond Isomerization/Friedel–Crafts Reaction Involving γ--Amidocronates: Access to γ-Aryl/Heteroaryl GABA Scaffolds and Dihydropyrido[1,2-a]indoles

Article abstract of DOI:10.1002/ejoc.201501388

A series of pharmacologically attractive γ-indolyl/furyl/aryl-substituted γ-amino esters/γ-aminoketones were obtained in good to high combined yields by π-bond isomerization of N-protected γ-aminocrotonates/γ-aminocrotonophenones in the presence of triethylamine, followed by tandem Friedel–Crafts alkylation involving several indole/furan/arene derivatives and the resultant N-protected enamines at room temperature by using B(C₆F₅)₃(5 mol-%) as an efficient Lewis acid catalyst. Moreover, the easy synthesis of the important class of 8,9-dihydropyrido[1,2-a]indole scaffolds was realized by this unique procedure. Thus, a simple, convenient, and metal-free-based protocol may provide an alternative powerful synthetic route for heteroarylation/arylation at the γ positions of GABA derivatives in a practical manner.

Full text of DOI:10.1002/ejoc.201501388

DOI: 10.1002/ejoc.201501388
Communication
Fused-Ring Systems
Double π-Bond Isomerization/Friedel–Crafts Reaction Involving
γ-Amidocronates: Access to γ-Aryl/Heteroaryl GABA Scaffolds
and Dihydropyrido[1,2-a]indoles
Anvita Srivastava[a] and Sampak Samanta*[a]
Abstract: A series of pharmacologically attractive γ-indolyl/ ature by using B(C6F5)3 (5 mol-%) as an efficient Lewis acid cata-
furyl/aryl-substituted γ-amino esters/γ-aminoketones were ob- lyst. Moreover, the easy synthesis of the important class of 8,9-
tained in good to high combined yields by π-bond isomeriza- dihydropyrido[1,2-a]indole scaffolds was realized by this unique
tion of N-protected γ-aminocrotonates/γ-aminocrotonophen- procedure. Thus, a simple, convenient, and metal-free-based
ones in the presence of triethylamine, followed by tandem Frie- protocol may provide an alternative powerful synthetic route
del–Crafts alkylation involving several indole/furan/arene deriv- for heteroarylation/arylation at the γ positions of GABA deriva-
atives and the resultant N-protected enamines at room temper- tives in a practical manner.
Introduction
is still a need for metal-free, catalytic, high-yielding, general
methods towards the preparation of γ-aryl/heteroaryl-substi-
tuted GABA derivatives. On the other hand, the FC reaction of
electron-rich arenes/heteroarenes with N-protected imines or
enamines (surrogates of imines) catalyzed by several Lewis
acids and Brønsted acids is one of the most reliable methods
for the construction of aryl/heteroaryl-substituted methan-
amine derivatives.[5]
The development of an efficient, atom-economical, and metal-
free-based new synthetic technique for straightforward access
to the important class of γ-aminobutyric acid (GABA) analogues
is unanimously one of the most challenging research areas in
synthetic, bioorganic, and medicinal chemistry because this
nonprotein amino acid and its derivatives are largely found in
a variety of natural products and active pharmaceuticals (Fig-
ure 1).[1] Apart from its valuable applications as a reactive inter-
mediate, GABA also plays a critical role as a major inhibitory
neurotransmitter in the central nervous system of mammals,
and its critical imbalance causes several neurological and psy-
chiatric disorders including Parkinson's disease, Huntington's
disease, epilepsy, anxiety, and so on.[1,2] In view of the great
applications of GABAergic drugs, a large number of synthetic
strategies have been developed to access α- and ꢀ-substituted
GABA analogues.[3] On the contrary, access to γ-substituted
GABA derivatives has seen little attention so far.[4] For instance,
diastereoselective reduction of in situ generated 4-(sulfinyl-
imino)butanoate by using a stoichiometric amount of L-Selec-
tride was realized by Reddy et al. (Scheme 1, a).[4a] After that,
in 2013, the scandium(III) trifluoromethanesulfonate [Sc(OTf)3]-
catalyzed Friedel–Crafts (FC) alkylation of indoles with amino-
cyclopropane derivatives was reported by the Waser group
(Scheme 1, b).[4b] In 2015, Ramachandran et al. also synthesized
γ-aryl-substituted GABA derivatives in poor to good yields
through Rh-catalyzed arylboronic acid addition to optically ac-
tive 4-(sulfinylimino)butanoate.[4c] Even with this progress, there
Figure 1. Pharmacologically active GABAergic drugs.
However, the direct synthesis of alkyl-substituted aldimines/
enamines from the corresponding aldehydes and their subse-
quent isolation remain complicated issues in organic synthesis.
To overcome these difficulties, N-protected allylamine was effi-
ciently employed as an alternative imine source in a FC reaction
with several activated arenes through a one-pot tandem double
π-bond isomerization reaction by using a Ru complex/Brønsted
[a] Department of Chemistry, Indian Institute of Technology Indore,
Indore, Simrol 452020, Madhya Pradesh, India
E-mail: sampaks@iiti.ac.in
http://iiti.ac.in/people/~sampaks/
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/ejoc.201501388.
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Scheme 1. Various approaches to γ-aryl-substituted GABA derivatives (Phth = phthaloyl, cod = 1,5-cyclooctadiene, Bz = benzoyl).
acid binary system.[6] Besides the success of metal com- 4aa in 51 % yield along with a trace amount of bis-indolylmeth-
plexes,[6,7] simple bases such as NaH and KOtBu[8] have also ane 5aa (5 %) within 18 h (Table 1, entry 1). Notably, both the
been effectively used to promote the π-bond shifting process Z and E geometrical isomers of enamine 2a were isolable in
from the ꢀ,γ positions to the α,ꢀ positions of N-protected allyl
derivatives. In view of these facts, we thought that γ-aryl/
heteroaryl-substituted GABA derivatives could be obtained
from γ-amidocrotonates through π-bond isomerization by us-
ing a base, followed by FC alkylation of arenes/heteroarenes
with the generated enamines catalyzed by a Lewis acid/Brøn-
sted acid.
pure forms through column chromatography. However, the ob-
tained yield was considerably lower than expected, owing to
the instability of this acyclic enamine during silica gel column
chromatography. Very interestingly, if the isomerization step
(i.e., step I) was conducted at 50 °C for 12 h (1a was fully isomer-
ized into 2a, for details see the Supporting Information), fol-
lowed by tandem FC reaction (step II;[11] Table 1, entry 2), de-
As part of our research focused on the development of new sired product 4aa was obtained in high overall yield (76 %, two
synthetic techniques for the preparation of indole derivatives,[9] steps). Next, we focused on standardization of step II by per-
we report herein a simple protocol for the synthesis of a wide forming the FC reaction in common organic solvents (e.g., THF,
range of γ-indolyl/furyl/aryl-substituted γ-amino esters/ketones DMF, MeCN, EtOH, CH2Cl2, and CHCl3) at room temperature for
by sequential π-bond isomerization of N-protected γ-amino- 18 h in the presence of B(C6F5)3. Among the solvents studied
crotonates/aminocrotonophenones in the presence of triethyl-
amine, followed by tandem π-bond isomerization/FC reaction
of the resultant N-protected enamines with heteroarenes/
arenes by using B(C6F5)3 as a well-known Lewis acid catalyst.[10]
(Table 1, entries 3–8), toluene and halogenated solvents such
as CHCl3 (Table 1, entry 7) and CH2Cl2 (Table 1, entry 8) were
suitable media for this reaction, and they led to desired product
4aa in high yields of 76, 75, and 80 % respectively. Considering
the lower boiling point of CH2Cl2, it was chosen as the best
solvent for this tandem FC alkylation reaction (Table 1, entry 8).
To evaluate the best catalyst for this FC reaction, several well-
known Brønsted acids (Table 1, entries 9–13) and Lewis acids
(Table 1, entries 14–16) catalysts were tested in CH2Cl2 at room
temperature. Among them, trifluoroacetic acid (TFA), trichloro-
acetic acid (TCA), 10-camphorsulfonic acid (CSA), 4-toluene-
sulfonic acid (PTSA), and In(OTf)3 were able to promote this
Results and Discussion
To optimize the reaction conditions, we began an isomerization
reaction of N-Bz-γ-aminocrotonate 1a in toluene at room tem-
perature for 24 h by using Et3N (2.0 equiv.) as a Lewis base,
followed by removal of the base [N-Bz protected enamine 2a,
Z/E = 3:2, 63 % conversion by 1H NMR spectroscopy] and subse-
quent addition of indole (3a) and B(C6F3)3 (5 mol-%) in toluene reaction effectively; they gave moderate to good yields (55–
at room temperature to provide γ-indol-3-yl-GABA derivative 71 %; Table 1, entries 9–14) of GABA analogue 4aa along with
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Table 1. Optimization of the reaction conditions.[a]
Entry
Conditions (Step II)[c]
Yield[d] [%]
4aa
5aa
1[b]
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
B(C6F5)3, toluene, r.t., 18 h
B(C6F5)3, toluene, r.t., 18 h
B(C6F5)3, THF, r.t., 18 h
B(C6F5)3, DMF, r.t., 18 h
B(C6F5)3, EtOH, r.t., 18 h
B(C6F5)3, MeCN, r.t., 18 h
B(C6F5)3, CHCl3, r.t., 18 h
B(C6F5)3, CH2Cl2, r.t., 18 h
PhCO2H, CH2Cl2, r.t., 18 h
TFA, CH2Cl2, r.t., 18 h
51
76
17
19
13
57
75
80
<5
64
67
70
71
55
5
<5
9
8
7
<5
11
14
9
–
15
10
14
15
17
–
TCA, CH2Cl2, r.t., 18 h
( )-CSA, CH2Cl2, r.t., 18 h
PTSA, CH2Cl2, r.t., 18 h
In(OTf)3, CH2Cl2, r.t., 18 h
Yb(OTf)3, CH2Cl2, r.t., 18 h
Gd(OTf)3, CH2Cl2, r.t., 18 h
7
–
[a] Unless otherwise noted, step I was performed with compound 1a (0.2 mmol) and Et3N (2.0 equiv.) in dry toluene (0.2 mL) at 50 °C for 12 h under an
argon atmosphere. [b] Step I was performed with compound 1a (0.2 mmol) and Et3N (2.0 equiv.) in dry toluene (0.2 mL) at room temperature for 24 h under
an argon atmosphere. [c] After removal of Et3N, a mixture of crude enamine 2a, indole (3a, 0.24 mmol), and catalyst (5.0 mol-%) was stirred in the specified
dry solvent (0.2 mL) at room temperature under an atmosphere of argon. [d] Combined yield (two steps) of isolated product after column chromatography.
10–17 % yields of 5aa. Thus, B(C6F5)3 was chosen as the best amine to produce enamine 2a. The latter isomerizes to iminium
catalyst for further experiments (Table 1, entry 8).
ion 2a′ under 3the influence of B(C6F5)3 as a Lewis acid [LA].
Subsequently, indole (3a) attacks 2a′ to give FC adduct 4aa. On
the other hand, B(C6F5)3 may further coordinate to the amide
N atom of 4aa to form Lewis acid complex 6, which undergoes
Considering the above experimental results collectively, a
possible mechanism for the formation of both FC adducts 4aa
and 5aa is shown in Scheme 2. In the first step, the π bond of
N-Bz-protected 1a is shifted from the α,ꢀ positions to the ꢀ,γ elimination of PhCONH2 by pushing a lone pair of electrons
positions through an isomerization process by using triethyl- from the ring N atom to generate vinyl iminium ion 7. Finally,
Scheme 2. Possible mechanism for the formation of 4aa and 5aa.
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Table 2. Two-step synthesis of γ-indolyl-substituted γ-amino esters/ketones 4aa–ei.
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Table 3. Synthesis of γ-aryl-substituted amino ester/ketones 4as–4eu.
bis-indolyl adduct 5aa is formed through FC alkylation of indole the chemoselective Friedel–Crafts alkylation reaction was inves-
with intermediate 7.
tigated by combining indoles 3a and 3i with N-Bz-protected
enamine 2e possessing two reactive groups such as C=O and
enamine (CH=CH–NH–, tautomeric form of imine C=N). Gratify-
ingly, the indoles attacked exclusively at the imine bond instead
of the C=O group in the present catalytic system, which re-
sulted in FC adducts 4ea and 4ei in yields of 85 and 83 %,
respectively. Notably, several chemically sensitive functional
groups, namely, CO2Et, CO2tBu, NHBz, 4-NO2BzNH, Cbz, N-OMe,
OMe, O-benzyl (Bn), NBn, OH, F, Cl, Br, allyl, and furyl were un-
affected under our present conditions, and this provides addi-
tional scope for further modification of the above functional
groups.
Next, we applied the above optimal reaction conditions to
examine the general trends of this sequence process by per-
forming the FC alkylation reaction of a variety of structurally
and electronically diverse indoles with N-protected enamines
2a–e (generated in situ from corresponding N-protected γ-
aminocrotonates/γ-aminocrotonophenones 1a–e) by using a
catalytic amount of B(C6F5)3 as a Lewis acid catalyst. Typical
results are systematically organized in Table 2. The results
clearly demonstrate that reactions of N-unprotected indoles
having a variety of substituents, including Me, OMe, F, Cl, and
Br, at the C2, C5, and C7 positions ran easily with several
N-Bz/4-nitrobenzoyl (4-NO2Bz)/benzyloxycarbonyl (Cbz)-pro-
Towards expanding the substrate scope, 2-methylfuran (3r)
tected enamines 2a–d derived from corresponding N-protected was employed as a nucleophile in Friedel–Crafts reactions with
γ-aminocrotonates 1a–d under the present conditions, which N-Bz enamines 2a and 2d under this sequence process. Satisfac-
led to new functionalized γ-indol-3-yl-substituted GABA ana- torily, after 20 h, corresponding 2-furyl-functionalized GABA de-
logues 4aa–da in good to high combined yields (69–84 %, two rivatives 4ar and 4br were obtained in good yields (70–73 %,
steps). During the course of the reactions, we observed that Scheme 3).
reactions of indoles with electron-rich substituents ran slightly
faster than those performed with indoles with electron-poor
substituents (18–20 h vs. 26–28 h). Next, several N-protected
indoles were used as FC donors in the present catalytic system.
The results show that Me, OMe, and allyl protecting groups did
not hamper the reactivity of the indoles towards enamines 2a
and 2b, which afforded corresponding GABA derivatives 4ai–
ak in high overall chemical yields (78–84 %) within 16–20 h.
Scheme 3. γ-(2-Furyl)-substituted GABA analogues 4ar and 4br.
However, indoles with benzyl/4-trifluoromethylbenzyl/tert-butyl
acetate protecting groups also reacted with enamine 2a by this
After successfully employing several heteroarenes as suitable
procedure but delivered the targeted products in slightly lower FC donors, we decided to use several simple electron-rich
yields over reaction times that were longer than those with arenes, namely, 3-cresol (3r), 2,5-dimethoxyphenol (3s), and
other protecting groups. To our satisfaction, 3-methylindole was 1,3,5-trimethoxybenzene (3t) as nucleophiles. By this proce-
employed as a challenging nucleophile in the tandem FC reac- dure, the FC reactions between phenolic derivatives 3r–s and
tion with enamines 2a and 2d in our present catalytic system, N-Bz-protected enamine 2a (in situ generated from 1a) took
and it furnished 3-methyl-2-indolyl-substituted GABA deriva- place exclusively at the ortho position (i.e., C2) of the phenolic
tives 4aq and 4dq in high yields (76–77 %). Very interestingly, OH group. As a consequence, corresponding products 4ar and
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coated silica gel plates (0.25 mm thickness); the products were visu-
alized by UV detection. Flash chromatography was performed with
silica gel (200–300 mesh). 1H NMR and 13C NMR spectra were re-
corded with a Bruker Avance (III) 400 MHz spectrometer. High-reso-
lution mass spectrometry (HRMS) was performed by using a ESI-TOF
mass spectrometer. All catalysts were procured from commercial
sources.
4as were obtained in a regioselective manner in high yields
(84–86 %). Similarly, 1,3,5-trimethoxybenzene (3t) also reacted
smoothly with enamines 2a and 2e, which resulted in high
yields (81–83 %, Table 3) of corresponding products 4au and
4eu.
Next, we turned our efforts towards the development of a
convenient method for the preparation of hydropyrido[1,2-a]-
indole frameworks from simple raw materials. This angular tri-
cyclic building block is a common precursor of a variety of bio-
logically active natural alkaloids and pharmacophores.[12] There-
fore, research directed towards the efficient synthesis of this
core moiety is a longstanding goal for synthetic organic and
medicinal chemists.[8,12,13] In our synthetic exercise, 3-methyl-
indole was employed as a binucleophile in a tandem π-bond
isomerization/FC/cyclization reaction with N-Bz-protected en-
amines 2e–h, derived in situ from γ-aminocrotonophenones
1e–h under our conditions, catalyzed by B(C6F5)3. All the reac-
tions furnished satisfactory yields (60–68 %) of corresponding
Representative Procedure for the Synthesis of Ethyl 4-Benz-
amido-4-(1H-indol-3-yl)butanoate (4aa): A mixture of compound
1a (0.0466 g, 0.2 mmol) and Et3N (0.4 mmol, 56.0 μL) in dry toluene
(0.2 mL) under an argon atmosphere was heated at 50 °C for 12 h
(monitored by TLC). Upon complete consumption of 1a, triethyl-
amine was evaporated under reduced pressure to give protected
enamine 2a, to which a mixture of indole (3a, 0.24 mmol) and
B(C6F5)3 (0.01 mmol, 5.0 mol-%) in dry CH2Cl2 (0.2 mL) was added
at room temperature. After 18 h, the mixture was directly purified
by column chromatography (silica gel, EtOAc/hexane 1:9) to afford
chemically pure 4aa (0.056 g, 80 %). IR (KBr): ν = 3317, 2981, 2955,
˜
1719, 1630, 1602, 1578, 1519, 1488, 1459, 1413, 1382, 1323 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 8.23 (br. s, 1 H), 7.75 (d, J = 7.52 Hz,
2 H), 7.72 (d, J = 8.04 Hz, 1 H), 7.45–7.48 (m, 1 H), 7.37–7.41 (m, 3
H), 7.19–7.23 (m, 2 H), 7.10–7.14 (m, 1 H), 6.57 (d, J = 8.0 Hz, 1 H),
5.58–5.62 (m, 1 H), 4.02–4.13 (m, 2 H), 2.37–2.51 (m, 4 H), 1.19 (t,
J = 7.28 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 174.0, 166.8,
136.6, 134.4, 131.5, 128.5, 126.9, 125.9, 122.5, 121.8, 120.0, 119.3,
116.4, 111.4, 60.6, 46.7, 31.5, 29.7, 14.1 ppm. HRMS (ESI): calcd. for
8,9-dihydropyrido[1,2-a]indole building
blocks
4eq–hq
(Scheme 4).
C
21H22N2O3[M + Na]+ 373.1523; found 373.1514.
Supporting Information (see footnote on the first page of this
1
article): All copies of the H NMR and 13C NMR spectra.
Acknowledgments
Scheme 4. One-pot, two-step method for the construction of hydropy-
rido[1,2-a]indole scaffolds possessing an amino group at C9.
The authors thank the Department of Science and Technology
(DST), Government of India, New Delhi for generous financial
support (project number SB/S1/OC-19/2013). A. S. is also thank-
ful to the University Grants Commission (UGC), New Delhi for
her fellowship.
Conclusions
We developed a one-pot, two-step sequential approach to ac-
cess biologically attractive, functionalized γ-heteroaryl/aryl-sub-
stituted γ-amino ester/γ-aminoketone derivatives in good to
high overall yields. The two-step method proceeds by π-bond
isomerization of N-benzoyl-protected γ-aminocrotonates/γ-
aminocrotonophenones by using Et3N, followed by tandem π-
bond isomerization/Friedel–Crafts reaction of the resultant en-
amines with a variety of heteroarenes/arenes in the presence
of B(C6F5)3 as a powerful Lewis acid catalyst. Interestingly, this
unprecedented method also constituted easy entry to the phar-
macologically important class of 8,9-dihydropyrido[1,2-a]ind-
oles in a practical manner. Furthermore, this two-step synthetic
process has several advantageous points: it is simple, mild
(room temperature), tolerant to functional groups, has a wide
substrate scope, provides good to high overall yields, and re-
quires a low catalyst loading (5 mol-%). Enantioselective synthe-
sis as well as application of γ-heteroaryl/aryl-substituted GABA
derivatives in medical science is in a preliminary stage, which
will be published in due course.
Keywords: Synthetic methods · Isomerization · Alkylation ·
Drug design · Nitrogen heterocycles · Lewis acids
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Received: November 3, 2015
Published Online: January 15, 2016
Eur. J. Org. Chem. 2016, 647–653
www.eurjoc.org
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