Synthesis of 3,3′-Disubstituted Indolenines Utilizing the Lewis Acid Catalyzed Alkylation of 2,3-Disubstituted Indoles with Trichloroacetimidates

Article abstract of DOI:10.1055/s-0036-1588491

Trichloroacetimidates function as effective electrophiles for the selective C3-alkylation of 2,3-disubstituted indoles to provide 3,3′-disubstituted indolenines. These indolenines are common synthetic intermediates that are often utilized in the synthesis of complex molecules. Effective reaction conditions utilizing Lewis acid catalysts have been determined, and the scope of the reaction with respect to indole and imidate reaction partner has been investigated. This chemistry provides an alternative to base promoted and transition-metal-catalyzed methods that are more commonly utilized to access similar indolenines.

Full text of DOI:10.1055/s-0036-1588491

SYNLETT
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
© Georg Thieme Verlag Stuttgart · New York
2017, 28, A–E
letter
A
en
A. A. Adhikari et al.
Letter
Synlett
Synthesis of 3,3′-Disubstituted Indolenines Utilizing the Lewis
Acid Catalyzed Alkylation of 2,3-Disubstituted Indoles with
Trichloroacetimidates
Arijit A. Adhikari
Léa Radal
NH
R
O
CCl3
R
John D. Chisholm*
0
0
0
0
0-
0
0
1
9-
5
1
8
2-
3
9
3
20 mol% TMSOTf
R = allyl, benzyl
propargyl
DCE, r.t., 3 h
N
N
H
Department of Chemistry, Syracuse University, 1-014 Center
for Science and Technology, Syracuse, NY 13244-4100, USA
jdchisho@syr.edu
20 examples
36–92% yield
Received: 09.05.2017
Accepted after revision: 13.06.2017
Published online: 11.07.2017
Imidates typically function as alkylating agents under mild
acidic conditions, and the use of imidates in the alkylation
of indoles would facilitate the introduction of a wide vari-
ety of allyl, benzyl, and propargyl groups from the corre-
sponding imidate, which are readily available from the re-
spective alcohol.
DOI: 10.1055/s-0036-1588491; Art ID: st-2017-r0343-l
Abstract Trichloroacetimidates function as effective electrophiles for
the selective C3-alkylation of 2,3-disubstituted indoles to provide 3,3′-
disubstituted indolenines. These indolenines are common synthetic in-
termediates that are often utilized in the synthesis of complex mole-
cules. Effective reaction conditions utilizing Lewis acid catalysts have
been determined, and the scope of the reaction with respect to indole
and imidate reaction partner has been investigated. This chemistry pro-
vides an alternative to base promoted and transition-metal-catalyzed
methods that are more commonly utilized to access similar indolenines.
MeN
H
H
H
MeO2C
N
Et
H
H
H
N
O
N
N
N
strictamine (1)
koumine (2)
tubifoline (3)
Key words indole, trichloroacetimidate, alkylation, indolenine, Lewis
acid, catalysis
O
N
H
H
O
N
MeO2C
The dearomatization of indoles is a powerful strategy
for the synthesis of 3,3′-disubstituted indolenine interme-
diates.1 Similar indolenine substructures are present in
many complex molecules, like strictamine,2 koumine,3 and
tubifoline4 (Figure 1). In addition, many indoline-contain-
ing structures (like aspidophylline A5 and communesin B6)
appear readily accessible from similar indolenine substruc-
tures. Given their prevalence in alkaloids, it is not surpris-
ing that a number of techniques have been reported for the
intermolecular C3-alkylation of 3-substituted indoles with
benzyl, allyl, and propargyl electrophiles to form C3-qua-
ternary indolenines. Typically these methods rely on the
use of strong base to activate the indole by deprotonation7
or on the use of a transition-metal catalyst to activate the
electrophile.8 More recently work has turned to utilizing
acid catalysts to perform similar transformations.9 Our re-
cent studies on substitution reactions with trichloroace-
timidate electrophiles10 led us to investigate the propensity
of electron-rich aromatic systems like indoles to undergo
dearomatization/alkylation reactions with trichloroacetim-
idate electrophiles to access 3,3′-disubstituted indolenines.
H
N
NH
H
O
N
H
N
CHO
aspidophylline A (4)
Me
communesin B (5)
Figure 1 Selected 3,3′-disubstituted indolenine and indoline natural
products
Trichloroacetimidates have been shown to be effective
electrophiles in Friedel–Crafts-type alkylation reactions
with substituted benzene rings as nucleophiles.11 Indoles
provide an interesting heterocyclic regime to explore, as
they may undergo alkylation at different sites depending on
their substitution pattern. A number of Friedel–Crafts al-
kylation reactions between imidates and indoles have been
previously reported,11g,h,12 but there have been no reports
on the use of imidates to form 3,3′-indolenine structures.
Indole itself provides C3-alkylation products with a variety
of imidates.11g,h In cases where the indole C3-position is
substituted C2-alkylation usually predominates,12d al-
though in some cases N-alkylation is observed.12c
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–E

B
A. A. Adhikari et al.
Letter
Synlett
In order to evaluate the potential of trichloroacetimi-
dates as electrophiles in the formation of 3,3′-disubstituted
indolenines, the Friedel–Crafts reaction of 2,3-dimethylin-
dole with allyl trichloroacetimidate was investigated (Table
1). A number of Brønsted and Lewis acid catalysts were
evaluated to facilitate the transformation. TMSOTf was
found to be the most effective catalyst, with nonpolar halo-
genated solvents like CH2Cl2 and DCE being found to be the
optimal reaction medium. Performing the transformation
with lower loadings of TMSOTf led to significantly slower
reactions and lower conversions, so 20 mol% was used in
subsequent experiments. Shorter reaction times also led to
incomplete conversion (Table 1, entry 12). In order to rule
out triflic acid as a catalyst in the alkylation with TMSOTf,
the reaction was performed in the presence of 2,6-di-tert-
butyl-4-methylpyridine, which is known to bind Brønsted
acids but not Lewis acids.13 A 67% yield was obtained in this
case, implicating TMSOTf as the operative catalyst in the re-
action.
of a second aliquot of 20 mol% of TMSOTf after 24 hours,
and then another 24 hours of reaction time at reflux for the
consumption of starting material (Table 2, entry 2). Using
Table 2 Alkylation of 2,3-Dimethylindole with Trichloroacetimidates
NH
R
O
CCl3
R
20 mol% TMSOTf
DCE, r.t., 3 h
N
N
H
6
Entry
1
Imidate
Product
Yield (%)a
NH
NH
74
O
CCl3
N
N
7
8
2
67b
O
CCl3
Table 1 Optimization of Reaction Conditions
9
10
NH
X
7
X
O
CCl3
conditions
N
NH
N
H
6
8
O
CCl3
N
Entry Conditions
NMR yield (%)a Yield (%)b
3
4
5
6
7
8
9
11 X = NO2
13 X = CN
15 X = CF3
17 X = Cl
12 X = NO2
14 X = CN
16 X = CF3
18 X = Cl
92c
71d
69
1
2
20 mol% PPTS, DCE, rt, 21 h
20 mol% CSA, DCE, rt, 21 h
20 mol% TfOH, DCE, rt, 21 h
5c
10c
–
–
–
3
50
14
–
58
4
20 mol% Cu(OTf)2, DCE, rt, 21 h
20 mol% ZnBr2, DCE, rt, 21 h
20 mol% BF3·OEt2, DCE, rt, 21 h
20 mol% TMSOTf, DCE, rt, 21 h
20 mol% TMSOTf, CH2Cl2, rt, 21 h
20 mol% TMSOTf, PhCF3, rt, 21 h
20 mol% TMSOTf, THF, rt, 21 h
20 mol% TMSOTf, DCE, rt, 3 h
20 mol% TMSOTf, DCE, rt, 1 h
20 mol% TMSOTf, DCE, rt, 3 h
–
19 X = H
20 X = H
50c
47
5
28c
–
21 X = Me
23 X = OMe
22 X = Me
24 X = OMe
6
5
45
7
–
70
69
9
8
–
Y
9
–
Y
NH
10
11
12
13
–
21
74
–
O
CCl3
–
N
76c
–
10
11
25 Y = NO2
27 Y = Cl
26 Y = NO2
28 Y = Cl
43d
52e
67d
a Yield as estimated by crude 1H NMR analysis against an external standard
(mesitylene).
Ph
b Isolated yield.
Ph
NH
c Some starting material still remained.
d 20 mol% 2,6-di-tert-butyl-4-methylpyridine was added.
Ph
12
71
Ph
O
CCl3
N
29
30
With conditions in hand that provide good yield of the
desired indolenine product, the transformation was evalu-
ated with regard to trichloroacetimidate alkylation partner
(Table 2). The propargyl imidate 9 appeared to be a less re-
active substrate under these reaction conditions, and re-
quired both heating the reaction to reflux and the addition
a Isolated yield.
b Reaction was heated to reflux for 24 h, then another 20 mol% of TMSOTf
were added, and the reaction was refluxed for another 24 h prior to work-
up.
c Reaction was stirred at rt for 48 h.
d Reaction was heated to reflux for 24 h.
e Reaction was heated to reflux for 6 h.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–E

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A. A. Adhikari et al.
Letter
Synlett
Table 3 (continued)
these modified conditions a 67% yield of the propargyl
product 10 could be isolated. Attention was then turned to
benzylic trichloroacetimidates. Benzylic imidates with elec-
tron-withdrawing groups on the aromatic ring gave signifi-
cantly higher isolated yields of product than more electron-
rich systems (Table 2, entries 3–6). This is unusual as typi-
cally imidates with electron-releasing groups are more re-
active alkylating agents in esterification and etherification
reactions.14 The alkylations with the more electron-rich
benzylic trichloroacetimidates were also more difficult to
purify and seemed to provide more side products than al-
kylations with electron-poor benzylic trichloroacetimidates
Entry
Indole
Product
Yield (%)a
Br
Br
3
81c
N
H
N
Br
Br
33
35
34
36
38
4
5
42
N
1
H
(Table 2, entries 8 and 9). Careful examination of the H
N
NMR analysis of the crude reaction mixture showed that
mixtures of the undesired Friedel–Crafts alkylation at the
indole 5- and 7-positions made up the bulk of these side
products. The formation of these unwanted products and
complications with purifying them away from the desired
3,3′-indolenine product led to the lower isolated yields.
Substitution at the ortho position of the benzylic trichloro-
acetimidates also provided lower isolated yields, perhaps
for steric reasons (Table 2, entries 10 and 11). Adding sub-
stitution at the benzylic carbon of the imidate was well tol-
erated as shown by the use of imidate 29, which provided
the 3,3′-indolenine product 30 in 71% yield (Table 2, entry 12).
The effect of the structure of the indole nucleophile on
the alkylation was then explored, with a number of differ-
ent indoles being used in the alkylation reaction with allyl
trichloroacetimidate 7 (Table 3). Addition of a chlorine atom
at the 5-position of the indole slowed the reaction signifi-
cantly, with the reaction mixture needing to be heated to
reflux to access a reasonable reaction rate. Still, a 60% yield
of the indolenine 32 could be isolated. The slower reaction
was attributed to the reduced nucleophilicity of the indole
due to the electron-withdrawing chlorine atom.
47d
N
H
N
37
39
41
43
CO2Et
CO2Et
N
N
6
7
8
54
N
H
N
40
42
NPhth
Me
NPhth
52
Me
N
N
H
NPhth
Ph
NPhth
36e
Ph
N
N
H
44
Table 3 Alkylation of Allyl Trichloroacetimidate with Differentially
Substituted Indoles
a Isolated yield.
b Reaction was heated to reflux for 3 h.
c Reaction was heated to reflux for 2 h.
d Reaction was heated to reflux for 8 h.
e Reaction was heated to reflux for 18 h.
indole
20 mol%
TMSOTf
R
NH
X
R’
O
CCl3
DCE, r.t., 3 h
N
7
Dibromoindole 33 also required heating (Table 3, entry
3), but provided the desired product 34 in 81% isolated
yield. This increase in yield is rationalized by the bromine
atoms protecting the indole benzene ring from competing
alkylation reactions. Indoles with carbocyclic rings tethered
between the indole 2- and 3-positions were also evaluated
(Table 3, entries 4–6). These systems gave more moderate
conversions, likely due to steric factors. The protected γ-
carboline derivative 39 underwent selective alkylation at
the indole 3-position in 54% yield. A phthalimide protected
2-methyltryptamine was also utilized as a substrate, pro-
Entry
1
Indole
Product
Yield (%)a
74
N
N
H
8
6
Cl
Cl
2
60b
N
H
N
31
32
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–E

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A. A. Adhikari et al.
Letter
Synlett
viding the alkylated product in 52% yield (Table 3, entry 7).
Increasing the size of the substituent at the indole 2-posi-
tion resulted in a decrease in yield, as shown with the 2-
phenyl indole 43 (Table 3, entry 8).
Funding Information
Acknowledgement is made to the Donors of the American Chemical
Society Petroleum Research Fund for a New Directions award in sup-
port of this research (54823-ND1). The National Institute of General
Medical Sciences (R15-GM116054) also provided financial support.
NMR spectra were obtained at Syracuse University using instrumen-
tation acquired with the assistance of the National Science Founda-
tion (CHE-1229345). L. R. thanks the Laboratoire d’Excellence
Multiscale Integrative Chemistry (LabEx MiChem) for a travel grant to
The application of this method in the synthesis of the
core system of the communesin natural products15 was also
undertaken (Scheme 1).16 This route takes advantage of im-
idate 45, which was synthesized from the commercially
available 2-aminobenzyl alcohol in two steps (see Support-
ing Information for details). Subjecting imidate 45 and 2,3-
dimethylindole to the alkylation reaction conditions result-
ed in the formation of indolenine 46, but no cyclization of
the pendant acetamide on the imine was observed. This
may be due to the enhanced stability of the indolenine of
46 due to the presence of a methyl group at the 2-position.
Switching to 3-methylindole 47 as a nucleophile to avoid
this issue gave indoline 48, where the pendant acetamide
group cyclized into the imine to provide the core tetracyclic
ring system of communesin. While currently the yield of
this transformation is moderate (23%), with further optimi-
zation similar reactions may find use in accessing commu-
nesin analogues or similar structures.
facilitate study in the USA.
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Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0036-1588491.
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References and Notes
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AcHN
Cl3C
NH
2,3-dimethylindole 6
O
20 mol% TMSOTf
DCE, r.t., 18 h
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46 30%
N
45
AcHN
Cl3C
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NH
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3-methylindole 47
20 mol% TMSOTf
O
NAc
DCE, r.t., 3 h
N
H
H
48 23%
45
AcHN
Scheme 1 Synthesis of the communesin core ring system
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In closing, reported herein are conditions where trichlo-
roacetimidates function as electrophiles for the selective
C3-alkylation of 2,3-disubstituted indoles in the presence of
a Lewis acid catalyst.17 Allyl trichloroacetimidate served as
an excellent electrophile to provide the C3-allyl indolenine
product in good yields with a number of substituted in-
doles. The scope of the reaction with electron-poor and
electron-rich primary benzylic trichloroacetimidates has
also been investigated. In the future chiral Lewis acid cata-
lysts may be explored to access enantioenriched indolenine
products. This protocol may be useful in accessing complex
3,3′-indolenine-containing structures. Further studies on
the reactivity of differentially substituted indoles with tri-
chloroacetimidates are under way and will be reported in
due course.
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(17) Representative Procedure for C3-Alkylation of 2,3-Disubsti-
tuted Indoles with Trichloroacetimidates
In a flame-dried flask allyl trichloroacetimidate 7 (121 mg, 0.60
mmol) was dissolved in 4 mL of anhydrous DCE. 2,3-Dime-
thylindole (6, 130 mg, 0.90 mmol) was then added followed by
freshly distilled TMSOTf (20 mol%, 27 μL, 0.12 mmol). After 3 h
at rt the reaction mixture was quenched with the addition of 10
mL of 1 M NaOH. The organic layer was separated, and the
aqueous layer was extracted with CH2Cl2 (2 × 5 mL). The com-
bined organic extracts were dried over Na2SO4, filtered, and
concentrated. The residue was purified by silica gel chromatog-
raphy (30% EtOAc/70% hexanes) to provide 2,3-dimethyl-3-
(prop-2-en-1-yl)-3H-indole (8) as a yellow oil (82.0 mg, 74%).
TLC Rf = 0.11 (10% EtOAc/90% hexanes). IR (neat): 3079, 3009,
2966, 2827, 2869, 1579 cm–1 1H NMR (400 MHz, CDCl3): δ =
.
(13) (a) Anderson, A. G.; Stang, P. J. J. Org. Chem. 1976, 41, 3034.
(b) Brown, H. C.; Kanner, B. J. Am. Chem. Soc. 1966, 88, 986.
(14) (a) Schmidt, R. R.; Michel, J. J. Carbohydr. Chem. 1985, 4, 141.
(b) Thierry, J.; Yue, C.; Potier, P. Tetrahedron Lett. 1998, 39, 1557.
(c) Respondek, T.; Cueny, E.; Kodanko, J. J. Org. Lett. 2012, 14,
150. (d) Adhikari, A. A.; Shah, J. P.; Howard, K. T.; Russo, C. M.;
7.52 (d, J = 8.0 Hz, 1 H), 7.33–7.21 (m, 2 H), 7.19 (td, J = 7.2, 0.8
Hz, 1 H), 5.21–5.11 (m, 1 H), 4.98–4.85 (m, 2 H), 2.66–2.60 (m, 1
H), 2.42 (dd, J = 14.0, 8.0 Hz, 1 H), 2.26 (s, 3 H), 1.31 (s, 3 H). 13
C
NMR (100 MHz, CDCl3): δ = 186.6, 154.2, 143.4, 132.5, 127.7,
125.0, 121.8, 119.8, 118.0, 57.5, 41.2, 21.8, 15.9. This compound
has been reported previously.8f
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–E