Dialkylation of indoles with trichloroacetimidates to access 3,3-disubstituted indolenines

Article abstract of DOI:10.3390/molecules24224143

2-Substituted indoles may be directly transformed to 3,3-dialkyl indolenines with trichloroacetimidate electrophiles and the Lewis acid TMSOTf. These reactions provide rapid access to complex indolenines which are present in a variety of complex natural products and medicinally relevant small molecule structures. This method provides an alternative to the use of transition metal catalysis. The indolenines are readily transformed into spiroindoline systems which are privileged scaffolds in medicinal chemistry.

Full text of DOI:10.3390/molecules24224143

molecules
Article
Dialkylation of Indoles with Trichloroacetimidates to
Access 3,3-Disubstituted Indolenines
Tamie Suzuki , Nilamber A. Mate , Arijit A. Adhikari and John D. Chisholm *
Department of Chemistry, Syracuse University, 1-014 Center for Science and Technology, Syracuse,
NY 13244-4100, USA; tsuzuki@southern.edu (T.S.); namate@syr.edu (N.A.M.);
Arijit_Adhikari@hms.harvard.edu (A.A.A.)
* Correspondence: jdchisho@syr.edu; Tel.: +315-443-6894
Academic Editor: Paula Sério Branco
Received: 30 October 2019; Accepted: 13 November 2019; Published: 15 November 2019
ꢀꢁꢂꢀꢃꢄꢅꢆꢇ
ꢀꢁꢂꢃꢄꢅꢆ
Abstract: 2-Substituted indoles may be directly transformed to 3,3-dialkyl indolenines with
trichloroacetimidate electrophiles and the Lewis acid TMSOTf. These reactions provide rapid
access to complex indolenines which are present in a variety of complex natural products and
medicinally relevant small molecule structures. This method provides an alternative to the use of
transition metal catalysis. The indolenines are readily transformed into spiroindoline systems which
are privileged scaffolds in medicinal chemistry.
Keywords: indole; dialkylation; indolenine; trichloroacetimidate; spiroindoline
1. Introduction
3,3-Dialkyl indolenines are common substructures found in many complex alkaloids like
strictamine
intramolecular addition of heteroatom nucleophiles to the indolenine. This includes complex alkaloids
such as echiboline ], aspidophylline A ], and perophoramidine ] (Figure 1). 3,3-Dialkyl
], as a means to
1 [1] and tubifoline 2 [2] (Figure 1). A number of other alkaloids appear to derive from the
3
[
3
4
[
4
5 [5
indolenines have also been utilized as platforms in medicinal chemistry studies [6,7
move towards more three-dimensional structures with a greater proportion of sp3 hybridized carbons,
which is desirable in order to create molecules which interact with more complex pharmaceutical target
receptors [
scaffolds” [12
agonists MK-0677
8
–
11]. Structurally related spiropiperidine-indanes have also been referred to as “privileged
14] for the design of medicinally relevant small molecules, including the ghrelin receptor
15] and 16], the Akt inhibitor 17] and the P2Y1 antagonist 18]. Besides their
–
6
[
7
[
8
[
9 [
presence in natural products, similar indolines are also utilized as precursors to indolenine dyes [19],
which have applications in biological imaging [20–23], sensors [24,25], and in solar cells [26,27].
Given the common nature of 3,3-dialkyl indolenines and related structures, researchers have
been active in investigating efficient methods to access similar architectures [28
intramolecular condensation of an aniline [32 34], the interrupted Fischer indole synthesis [35
and the addition of organometallic reagents to benzylic nitriles [38 40]. One popular method is the
dearomatization of indoles [41 44] with an electrophilic alkylating agent. Many of these reactions
are complicated by competing N-alkylation of the indole. In spite of this issue, a number of acid
promoted [45 47], base promoted [48 54], and transition metal catalyzed [55 64] transformations have
–31]. These include
–
–
37],
–
–
–
–
–
been described to access indolenines from 3-substituted indoles.
Molecules 2019, 24, 4143; doi:10.3390/molecules24224143
www.mdpi.com/journal/molecules

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Figure 1. Natural products containing the 3,3-dialkyl indolenine motif and related spiroindoline
structures.
In a recent study on the alkylation of indoles utilizing trichloroacetimidate electrophiles [65],
we observed a small amount of the dialkylated indolenine 13 as a side product from the TMSOTf
catalyzed C3-alkylation of 2-methyl-5-nitroindole 10 with allyl imidate 11 in dichloromethane (DCM)
(Scheme 1). While the formation of indolenines from 2,3-disubstituted indoles with imidates has been
reported [66], the direct dialkylation of indoles could provide a rapid entry to 3,3-dialkyl indolenine
intermediates from less substituted (and therefore less expensive) indole starting materials. This would
provide an efficient alternative approach for the direct C3-dialkylation of indoles that does not rely on
costly transition metal catalysts. The use of trichloroacetimidate electrophiles as the alkylating agent is
attractive because they can be easily formed from readily available alcohols under mild conditions [67].
Intrigued by the potential of this dialkylation reaction, we began optimization studies to explore the
scope of this Lewis acid promoted dearomatization reaction.
Scheme 1. Detection of the dialkylation product 13 during alkylation of 5-nitro-2-methyl-indole 10.
2. Results & Discussion
Our recent studies on promoter free substitution reactions with trichloroacetimidate
electrophiles [68–74] led us to speculate that imidates may be reactive enough to participate in
indole dialkylation without the need for a Lewis acid catalyst. Heating 2-methyl indole 14 and allyl
trichloroacetimidate 11 in refluxing 1,2-dichloroethane (DCE) for 24 h showed no trace of alkylation
product, however, so the use of TMSOTf as the Lewis acid was then investigated (Table 1). Previous
investigations with indoles and trichloroacetimidates have demonstrated that TMSOTf is especially
effective in these systems [65,66], and encouraging results were immediately obtained. Use of 20 mol%
TMSOTf led to the formation of indolenine 15 with a 27% yield (Table 1, Entry 2). Increasing reaction
time, temperature and using excess imidate were then evaluated, but these changes only led to modest
increases in yield (Entries 3–5). Given that a more basic reaction media is being formed after the second
alkylation (the imine on 15 is a functional base), it was considered that perhaps product inhibition
was occurring, with the imine scavenging the Lewis acid and halting the reaction. An increase in the
TMSOTf loading would therefore be necessary to obtain higher conversions. Increasing the amount of

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TMSOTf provided a 61% yield of 15 when a stoichiometric amount of the Lewis acid was employed
(Entry 7). Further increasing the amount of TMSOTf did not significantly improve the yield, nor did
heating the reaction. Little indole starting material 14 was isolated from the reaction, with the rest of
the mass balance being a mixture of overalkylation products (alkylation can also occur at C5 and C7 of
the indole ring).
Table 1. Optimization of the diallylation reaction.
Entry
Temp. (◦C)
Yield (%)
Equiv
Imidate 11
Equiv
TMSOTf
Reaction
Time
1
2
3
4
5
6
7
8
9
2.2
2.2
2.2
2.2
3.0
2.5
2.5
2.5
2.5
0
84
rt
rt
84
rt
rt
rt
rt
84
24 h
3 h
6 h
3 h
3 h
3 h
3 h
3 h
3 h
0
0.2
0.2
0.2
0.2
0.5
1.0
1.5
1.0
27
20
41
31
39
61
59
59
Conditions: 1,2-Dichloroethane (DCE), TMSOTf, rt or reflux.
The indole dialkylation was then evaluated with regard to the indole nucleophile. The addition of
either electron donating or electron withdrawing groups to the 5-position of the indole was tolerated,
with yields in the 40%–70% range being observed (Table 2). Interestingly, the 5-nitro-2-methyl indole 10
provided the diallylation product 13, which is not accessible using palladium catalysis, as N-alkylation
is favored when this indole is employed [6]. Changing the alkyl group at the 2-position of the indole
was also explored. Use of indole (Entry 7) provided only a complex mixture of products, and this
substrate was not pursued further. A more moderate yield was obtained with 2-phenylindole, likely
due to steric effects from the larger group at the indole 2-position. Indole 2-carboxylic acid methyl ester
14h was not reactive under these conditions, returning the starting indole and decomposed imidate
from the reaction mixture. While many of these yields are moderate, it is important to realize that two
reactions are actually occurring in sequence during the dialkylation, so the yield may perhaps be best
thought of in terms of a sequence of two separate steps proceeding a ~75% yield where isolation and
purification of the intermediate 3-alkylindole is avoided.
The efficacy of these conditions was then evaluated using a number of allylic and benzylic
imidates (Table 3). More highly substituted allylic imidates gave lower yields, this may be due to
the electrophile being more highly stabilized and therefore less reactive. Improved yields could be
achieved by performing many of the reactions in refluxing DCE. Similar results were obtained with
propargyl imidate 18, which was less reactive (only providing trace product at room temperature)
but would participate when the reaction was heated to reflux, albeit in a moderate yield. Benzylic
trichloroacetimidates were also evaluated. The highly reactive 4-methoxybenzyl imidate 19 gave
a complex mixture of products due to polyalkylation. Better results were obtained with the less
reactive benzyl imidate 20, which gave a 30% yield of the dialkylation product 15m (38% when the
reaction was performed under reflux). Benzylic imidates decorated with electron withdrawing groups
(21–23) were also less reactive and provided only trace amounts of the dialkylation products at rt, with
C3-monoalkylation being the major product [65]. Heating the reaction to reflux provided the desired
dialkylation products in much improved overall yields, however.

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Table 2. C3-Dialkylation of functionalized indoles with allyl imidate.
Entry
Indole
Product
Yield (%)
Me
1
2
3
4
5
6
61
N
H
1
14a
1
15a
MeO
Me
Cl
Me
61
41
45
68
70
N
H
1
14b
15b
Me
Me
Me
N
H
114c
15c
N
H
1
14d
15d
F
N
H
14e
15e
1
O2N
Me
N
H
10
13
7
8
9
0 a
34
N
H
1
14f
1
15f
Ph
N
H
1
14g
15g
1
CO2Me
0 b
N
H
114h
1
15h
a
b
A complex mixture resulted. Starting material was recovered.

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Table 3. Direct C3-dialkylation of 2-methyl indole 14a with trichloroacetimidates.
R
R
2.5 equiv ROC(NH)CCl3
1 equiv TMSOTf
Me
14a
Me
N
H
DCE, rt, 3 h
N
Entry
Imidate
Product
Yield (%)
1
61 (59 a)
11
15a
15i
2
40 (46 a)
116
3
4
12 (20 a)
17
115j
trace (24 a)
1
18
1
15k
0 b
5
6
7
19
15l
30 (38 a)
trace (52 a)
2
20
1
15m
21
1
15n
8
9
trace (45 a)
trace (63 a)
2
22
15o
223
15p
a
b
Yield when the reaction was performed at reflux. A complex mixture resulted.
With ready access to 3,3-diallyl indolenines via imidate alkylation, we turned our attention to the
functionalization of these systems to three-dimensional scaffolds like those used in medicinal chemistry
studies. Initially a spirocycle formation was explored utilizing the Grubbs metathesis catalyst. This
led to the formation of spirocycle 24 (Scheme 2). The indolenine 15a was also transformed into a
spiropiperidine-indane that is similar to that found in the ghrelin receptor agonists MK-0677
6 and
7
. This involved initial reduction of the indolenine 15a to the indoline 25 with lithium aluminum
hydride. The sulfonamide 26 was then formed with TsCl and triethylamine. Oxidative cleavage
of the alkenes to the corresponding aldehyde was executed via ozonolysis. Purification of this
dialdehyde proved difficult when triphenylphosphine was used to reduce the ozonide, but the use
of 1,3-bis(diphenylphosphino)propane (dppp) as the reductant made the purification easier as the

Molecules 2019, 24, 4143
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bisphosphine oxide was more polar and easier to separate from the product. The dialdehyde proved
to be unstable and readily self-condensed, so it was immediately subjected to a reductive amination
with benzylamine and NaBH(OAc)3, which provided the desired spiropiperidine-indane 27 with a
35% yield over two steps.
Scheme 2. Elaboration of the 3,3-Diallyl indolenine 15a to spiro-polycyclic systems.
Oddly, the spiropiperidine 27 showed a multiplet in the 1H NMR at 0.28 ppm that integrated
for a single hydrogen resonance. A proton with this chemical shift was not congruent with the
proposed structure, so some additional studies were performed. A COSY experiment verified that the
upfield proton was part of the piperidine ring. Some molecular modeling studies indicated that this
unusual chemical shift is likely to be attributed to diamagnetic anisotropy from the aromatic ring of the
toluenesulfonamide, which prefers to reside on the opposite face of the pyrroline ring as the methyl
group due to steric effects. This holds the -system of the sulfonamide in a position to shield one of
the protons on the piperidine ring (Ha, Figure 2). The molecular modeling predicts that in the lowest
energy conformation Ha is only ~2.8 Å from the center of the aromatic ring. This upfield chemical
shift is consistent with literature reports of similar spiropiperidine-indanes [75]. In further support of
this rationale, in structures where the C2 position of the pyrroline is unsubstituted [76], or there is no
aromatic sulfonamide [77], no similar upfield shifts are observed in the 1H NMR.
Figure 2. Upfield Shift of Ha in the 1H NMR of Spiropiperidine 27 due to Diamagnetic Anisotropy
from the Sulfonamide -System.

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3. Materials and Methods
3.1. General Experimental Information
All anhydrous reactions were run under a positive pressure of argon. Dichloromethane (DCM)
was dried by passage through an alumina column. 1,2-Dichloroethane (DCE) was freshly distilled
from calcium hydride before use. Silica gel column chromatography was performed using 60 Å silica
gel (230 400 mesh). Melting points are uncorrected. The indoles used in this study were purchased
−
from commercial sources.
3.2. Preparation of Trichloroacetimidates
Allyl-2,2,2-trichloroacetimidate 11
79], propargyl-2,2,2-trichloroacetimidate 18 [
[
78], 1-(1-imino-2,2,2-trichloroethoxy)-3-phenyl-2(E)-propene 17
70], (4-methoxyphenyl)methyl-2,2,2-trichloroacetimidate
69], benzyl-2,2,2-trichloroacetimidate 20 78], (4-chloro)methyl-2,2,2-trichloroacetimidate
[
19
[
[
21 [80], (4-trifluoromethyl)methyl-2,2,2-trichloroacetimidate 22 [66], and (4-nitrophenyl)methyl-2,2,2-
trichloroacetimidate 23 [81] were synthesized as previously reported.
2-Methyl-2-propenyl trichloroacetimidate (16). A flame dried flask was charged with 2-methyl-
2-propen-1-ol (7.0 mmol, 0.589 mL) and placed under argon. Dry DCM (35 mL) was then added, and
the flask was cooled to 0 ◦C. 1,8-Diazabicyclo [5.4.0]undec-7-ene (0.7 mmol, 0.108 mL) was added to
the solution, followed by trichloroacetonitrile (8.4 mmol, 0.843 mL). After ~22 h the reaction mixture
was concentrated and the residue purified by silica gel column chromatography (10% EA/3% Et3N/87%
hexanes). Clear oil (1.502 g, 99%). TLC Rf = 0.42 (60% DCM/40% hexanes); IR (thin film) 3365, 3072,
2975, 2904, 1637, 1607, 1482, 912 cm−1; 1H NMR (400 MHz, CDCl3)
δ 162.6, 139.4, 113.3, 91.5, 72.3, 19.4.;
HRMS (ESI+) calcd for C6H8Cl3NONa+ [M + Na]+: 237.9563. Found: 237.9564.
δ
8.31 (bs, 1H), 5.11 (s, 1H), 4.99
(s, 1H), 4.71 (s, 2H), 1.83 (s, 3H); 13C NMR (100 MHz, CDCl3)
3.3. Synthesis of 3,30-Disubstituted Indolenines
General procedure for C3-dialkylation of indoles. In a flame dried flask, the imidate (2.5 equiv)
was dissolved in anhydrous DCE (0.3 M) followed by the addition of the indole (1.0 equiv). To this
solution freshly distilled TMSOTf (1.0 equiv) was added and the resulting mixture was stirred at
room temp. or heated to reflux for 3 h. After cooling to room temperature, the reaction mixture was
quenched with 10 mL 1 M NaOH. The organic layer was separated and the aqueous layer was extracted
with DCM (3
×
5 mL). The combined organic layers were dried over sodium sulfate, filtered and
concentrated. The residue was purified by silica gel chromatography using the listed solvent system.
3,3-Diallyl-2-methyl-3H-indole (15a). Synthesized by the general procedure from 2-methylindole
14a and imidate 11
has been previously reported [58]. Orange oil (0.14 g, 59%); TLC Rf = 0.35 (5% EA/95% DCM); 1H NMR
(300 MHz, CDCl3) 7.52 (d, J = 7.6 Hz, 1H), 7.34–7.28 (m, 2H), 7.22–1.17 (m, 1H), 5.18–5.05 (m, 2H),
[78], purified using silica gel chromatography (3% EA/97% DCM). This compound
δ
4.95 (d, J = 17.0 Hz, 2H), 4.85 (d, J = 10.9 Hz, 2H), 2.69 (dd, J = 13.9, 6.1 Hz, 2H), 2.45 (dd, J = 13.9, 7.7
Hz, 2H), 2.25 (s, 3H); 13C NMR (100 MHz, CDCl3)
118.1, 61.8, 40.3, 16.5.
δ 185.2, 154.8, 141.2, 132.1, 127.9, 125.0, 122.2, 119.8,
3,3-Diallyl-5-methoxy-2-methyl-3H-indole (15b). Synthesized by general procedure from 5-methoxy-
2-methyl-1H-indole 14b and imidate 11 78], purified using silica gel chromatography (5% EA/95%
DCM). This compound has been previously reported [
]. Brown solid (0.18 g, 61%); mp = 45–46 ◦C;
TLC Rf = 0.33 (10% EA/90% DCM); IR (ATR) 3077, 3000, 1640, 1591, 1576, 908 cm−1; 1H NMR (300 MHz,
CDCl3) 7.44 (d, J = 9.0 Hz, 1H), 6.85–6.83 (m, 2H), 5.20–5.06 (m, 2H), 4.96 (d, J = 16.2 Hz, 2H), 4.87 (d, J
= 9.8 Hz, 2H), 3.83 (s, 3H), 2.66 (dd, J = 13.8, 5.8 Hz, 2H), 2.45 (dd, J = 13.9, 7.7 Hz, 2H), 2.25 (s, 3H); 13
NMR (100 MHz, CDCl3) 182.9, 157.8, 142.9, 132.1, 119.9, 118.1, 117.5, 112.2, 109.2, 61.9, 55.7, 40.4, 16.4.
3,3-Diallyl-2,5-dimethyl-3H-indole (15c). Synthesized by general procedure from 2,5-dimethyl-
1H-indole 14c and imidate 11 78], purified using silica gel chromatography (20% EA/80% hexanes).
Brown solid (0.13 g, 41%); mp = 38–40 ◦C; TLC Rf = 0.38 (40% EA/60% hexanes); IR (ATR) 3081, 3002,
[
6
δ
C
δ
[

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1638, 1574, 820 cm−1; 1H NMR (400 MHz, CDCl3)
δ
7.38 (d, J = 7.8 Hz, 1H), 7.11 (d, J = 7.8 Hz, 1H),
7.07 (s, 1H), 5.16–5.06 (m, 2H), 4.95 (d, J = 17.0 Hz, 2H), 4.85 (d, J = 9.9 Hz, 2H), 2.66 (dd, J = 13.9, 6.0
Hz, 2H), 2.43 (dd, J = 13.9, 7.8 Hz, 2H), 2.39 (s, 3H), 2.22 (s, 3H); 13C NMR (100 MHz, CDCl3)
δ
184.0,
152.7, 141.3, 134.7, 132.3, 128.5, 122.9, 119.3, 118.0, 61.5, 40.4, 21.5, 16.5; HRMS (ESI+) m/z calcd for
C16H19NNa+ [M + Na]+: 248.1409, found: 248.1409.
3,3-Diallyl-5-chloro-2-methyl-3H-indole (15d). Synthesized by general procedure from 5-chloro-
2-methyl-1H-indole 14d and imidate 11
hexanes). Yellow oil (0.10 g, 45%); TLC Rf = 0.42 (30% EA/70% hexanes); IR (ATR) 3076, 1728, 1577,
1451, 920, 825 cm−1; 1H NMR (400 MHz, CDCl3)
7.44 (d, J = 8.4 Hz, 1H), 7.31–7.26 (m, 2H), 5.18–5.08
(m, 2H), 4.99 (d, J = 16.8 Hz, 2H), 4.91 (d, J = 10.4 Hz, 2H), 2.68 (dd, J = 13.6, 6.0 Hz, 2H), 2.47 (dd, J
[78], purified using silica gel chromatography (10% EA/90%
δ
= 14.0, 7.6 Hz, 2H), 2.26 (s, 3H); 13C NMR (100 MHz, CDCl3)
δ 185.7, 153.4, 143.1, 131.5, 130.9, 128.1,
122.7, 120.6, 118.6, 62.3, 40.1, 16.5; HRMS (ESI+) m/z calcd for C15H16ClNNa+ [M + Na]+: 268.0863,
found: 268.0864.
3,3-Diallyl-5-fluoro-2-methyl-3H-indole (15e). Synthesized by general procedure from 5-chloro-
2-methyl-1H-indole 14e and imidate 11
hexanes). Purple oil (0.16 g, 68%); TLC Rf = 0.37 (30% EA/70% hexanes); IR (ATR) 3077, 1727, 1581,
1462, 918, 821 cm−1; 1H NMR (400 MHz, CDCl3)
7.41 (dd, J = 8.2, 4.7 Hz, 1H), 7.00–6.94 (m, 2H),
5.15–5.04 (m, 2H), 4.94 (d, J = 16.8 Hz, 2H), 4.85 (d, J = 10.0 Hz, 2H), 2.63 (dd, J = 13.9, 6.3 Hz, 2H), 2.43
(dd, J = 13.6, 7.7 Hz, 2H), 2.21 (s, 3H); 13C NMR (100 MHz, CDCl3)
184.8 (d, J = 3.5 Hz), 161.0 (d, J =
[78], purified using silica gel chromatography (10% EA/90%
δ
δ
242.1 Hz), 150.8 (d, J = 1.8 Hz), 143.2 (d, J = 8.5 Hz), 131.6, 120.3 (d, J = 8.8 Hz), 118.5, 114.6 (d, J =
23.4 Hz), 109.9 (d, J = 23.3 Hz), 62.3 (d, J = 2.0 Hz), 40.2, 16.4; HRMS (ESI+) m/z calcd for C15H16FNNa+
[M + Na]+: 252.1159, found: 252.1158.
3,3-Diallyl-5-nitro-2-methyl-3H-indole (13). Synthesized by the general procedure from 2-methyl-
5-nitro-1H-indole 10 and imidate 11
Brown oil (0.21 g, 71%); TLC Rf = 0.47 (10% EA/90% DCM); IR (ATR) 3007, 1703, 1571, 1518, 1338 cm−1
1H NMR (300 MHz, CDCl3)
8.28 (dd, J = 8.5, 2.3 Hz, 1H), 8.16 (d, J = 2.0 Hz, 1H), 7.62 (d, J = 8.5 Hz,
1H), 5.17–5.04 (m, 2H), 5.03–4.88 (m, 4H), 2.77 (dd, J = 14.0, 6.1 Hz, 2H), 2.53 (dd, J = 14.0, 7.1 Hz, 2H),
[78], purified using silica gel chromatography (5% EA/95% DCM).
;
δ
2.35 (s, 3H); 13C NMR (100 MHz, CDCl3)
δ 191.6, 159.6, 145.6, 142.4, 130.7, 124.9, 119.9, 119.4, 117.9,
62.9, 40.0, 17.0; HRMS (ESI+) m/z calcd for C15H16N2O2Na+ [M + Na]+: 279.1104, found: 279.1103.
3,3-Diallyl-2-phenyl-3H-indole (15g). Synthesized by general procedure from the known indole
14g and imidate 11
has been previously reported [
[
78], purified using silica gel chromatography (5% EA/95% hexanes). This compound
6
]. Yellow oil (0.09 g, 34%); TLC Rf = 0.52 (5% EA/95% DCM); 1H NMR
(300 MHz, CDCl3) δ 8.14–8.10 (m, 2H), 7.67 (d, J = 7.5 Hz, 1H), 7.49–7.47 (m, 3H), 7.40–7.26 (m, 3H),
5.18–5.05 (m, 2H), 4.79–4.71 (m, 4H), 2.90 (d, J = 6.9 Hz, 4H); 13C NMR (100 MHz, CDCl3)
δ 180.3, 154.4,
142.9, 133.9, 131.8, 130.6, 128.6, 128.1, 128.0, 125.7, 121.7, 120.7, 118.3, 62.4, 41.8.
2-Methyl-3,3-bis(2-methyl-2-propenyl)-3H-indole (15i). Synthesized by general procedure from
2-methylindole 14a and imidate 16, purified using silica gel chromatography (10% EA/90% hexanes).
Yellow oil (0.13 g, 46%); TLC Rf = 0.52 (5% EA/95% DCM); IR (ATR) 3074, 2967, 2918, 1642, 1575,1447,
765 cm−1; 1H NMR (400 MHz, CDCl3)
δ
7.42 (d, J = 8.0 Hz, 1H), 7.25–7.21 (m, 2H), 7.12–7.09 (m, 1H),
4.48–4.47 (m, 2H), 4.40 (s, 2H), 2.63 (d, J = 13.6 Hz, 2H), 2.53 (d, J = 14.0 Hz, 2H), 2.26 (s, 3H), 1.06 (s,
6H); 13C NMR (100 MHz, CDCl3)
δ 185.8, 155.2, 141.7, 140.9, 127.8, 124.6, 122.9, 120.0, 114.2, 62.3, 45.5,
23.4, 17.2; HRMS (ESI+) m/z calcd for C17H21NNa+ [M + Na]+: 262.1566, found: 262.1566.
3,3-Bis[(E)-3-phenyl-2-propenyl]-2-methyl-3H-indole (15j). Synthesized by the general procedure
from 2-methylindole 14a and imidate 17
Yellow oil (0.055 g, 20%); TLC Rf = 0.26 (100% DCM); IR (ATR) 3024, 2919, 1576, 1447, 906, 730 cm−1
1H NMR (400 MHz, CDCl3)
7.53 (d, J = 7.6 Hz, 1H), 7.35–7.31 (m, 3H), 7.26–7.12 (m, 10H), 6.35 (d, J
= 15.7 Hz, 2H), 5.60–5.52 (m, 2H), 2.89 (dd, J = 14.0, 6.7 Hz, 2H), 2.63 (dd, J = 13.9, 8.0 Hz, 2H), 2.33
[79], purified using silica gel chromatography (100% DCM).
;
δ
(s, 3H); 13C NMR (100 MHz, CDCl3)
δ 185.0, 154.8, 141.2, 136.9, 133.3, 128.5, 128.4, 128.1, 127.3, 126.1,
125.1, 123.7, 122.3, 120, 62.1, 39.4, 16.7; HRMS (ESI+) m/z calcd for C27H25NNa+ [M + Na]+: 386.1879,
found: 386.1878.

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2-Methyl-3,3-di(prop-2-yn-1-yl)-3H-indole (15k). Synthesized by the general procedure from
2-methylindole 14a and imidate 18 70], purified using silica gel chromatography (3% EA/97% DCM).
Yellow oil (0.06 g, 24%); TLC Rf = 0.55 (10% EA/90% DCM); IR (ATR) 3285, 2924, 2119, 1579, 1468, 770,
624 cm−1; 1H NMR (400 MHz, CDCl3)
7.53 (t, J = 7.7 Hz, 2H), 7.36 (dt, J = 7.6, 1.2 Hz, 1H), 7.22 (t, J =
7.4 Hz, 1H), 2.76 (dd, J = 16.7, 2.6 Hz, 2H), 2.60 (dd, J = 16.8, 2.6 Hz, 2H), 2.37 (s, 3H), 1.98 (t, J = 2.6 Hz,
[
δ
2H); 13C NMR (100 MHz, CDCl3)
δ 183.1, 154.4, 140.0, 128.7, 125.4, 122.4, 120.0, 78.6, 71.5, 57.6, 24.4,
16.7; HRMS (ESI+) m/z calcd for C15H13NNa+ [M + Na]+: 230.0940, found: 230.0939.
3,3-Dibenzyl-2-methyl-3H-indole (15m). Synthesized by the general procedure from 2-methylindole
14a the imidate 20
[78], purified using silica gel chromatography (1% EA/99% DCM). This compound
has been previously reported [58]. Brown oil (0.10 g, 30%); TLC Rf = 0.49 (5% EA/95% DCM); 1H NMR
(400 MHz, CDCl3)
δ 7.18–7.14 (m, 2H), 7.06 (td, J = 7.2, 1.6 Hz, 1H), 7.02–6.95 (m, 7H), 6.68 (dd, J = 7.2,
1.2 Hz, 4H), 3.28 (d, J = 13.6 Hz, 2H), 2.99 (d, J = 13.6 Hz, 2H), 2.32 (s, 3H); 13C NMR (100 MHz, CDCl3)
δ 184.1, 155.1, 140.5, 135.7, 129.4, 127.9, 127.8, 126.7, 124.4, 23.7, 119.8, 64.0, 42.3, 17.3.
3,3-Bis[(p-chlorophenyl)methyl]-2-methyl-3H-indole (15n). Synthesized by the general procedure
from 2-methylindole 14a and imidate 21
DCM). Yellow oil (0.08 g, 18%); TLC Rf = 0.24 (30% EA/70% hexanes); IR (ATR) 3046, 2918, 2848, 1595,
1491, 1013, 837 cm−1; 1H NMR (300 MHz, CDCl3)
7.32–7.17 (m, 3H), 7.11 (d, J = 6.9 Hz, 1H), 7.02 (d, J
= 8.4 Hz, 4H), 6.66 (d, J = 8.4 Hz, 4H), 3.32 (d, J = 13.7 Hz, 2H), 3.04 (d, J = 13.6 Hz, 2H), 2.42 (s, 3H);
[80], purified using silica gel chromatography (3% EA/97%
δ
13C NMR (100 MHz, CDCl3)
δ 183.3, 155.1, 139.8, 133.9, 132.7, 130.5, 128.3, 128.0, 124.6, 123.3, 120.2,
63.8, 41.5, 17.3; HRMS (ESI+) m/z calcd for C23H19Cl2NNa+ [M + Na]+: 402.0787, found: 402.0785.
2-Methyl-3,3-bis{[p-(trifluoromethyl)phenyl]methyl}-3H-indole (15o). Synthesized by the general
procedure from the known indole 14a and imidate 22
(2% EA/98% DCM). Yellow oil (0.23 g, 45%); TLC Rf = 0.51 (5% EA/95% DCM); IR (ATR) 3049, 2924,
1919, 1726, 1616, 1319, 1100 cm−1; 1H NMR (400 MHz, CDCl3)
7.30 (d, J = 8.4 Hz, 4H), 7.26–7.19 (m,
3H), 7.15 (d, J = 7.2 Hz, 1H), 6.84 (d, J = 8.0 Hz, 4H), 3.42 (d, J = 13.6 Hz, 2H), 3.15 (d, J = 13.6 Hz,
2H), 2.40 (s, 3H); 13C NMR (100 MHz, CDCl3)
182.8, 154.9, 139.4, 129.5, 129.4 (q, J = 32.3 Hz), 128.6,
[66], purified using silica gel chromatography
δ
δ
124.8 (q, J = 3.7 Hz), 124.0 (q, J = 270.3 Hz), 123.2, 120.3, 63.6, 42.0, 17.2; HRMS (ESI+) m/z calcd for
C25H19F6NNa+ [M + Na]+: 470.1314, found: 470.1311.
2-Methyl-3,3-bis[(p-nitrophenyl)methyl]-3H-indole (15p). Synthesized by general procedure
from 2-methylindole 14a and imidate 23
hexanes). Yellow oil (0.29 g, 63%); TLC Rf = 0.50 (10% EA/90% DCM); IR (ATR) 3076, 1728, 1577, 1451,
920, 825 cm−1; 1H NMR (400 MHz, CDCl3)
7.90 (d, J = 8.8 Hz, 4H), 7.31–7.20 (m, 4H), 6.88 (d, J =
8.4 Hz, 4H), 3.48 (d, J = 13.6 Hz, 2H), 3.26 (d, J = 13.6 Hz, 2H), 2.44 (s, 3H); 13C NMR (100 MHz, CDCl3)
[81], purified using silica gel chromatography (50% EA/50%
δ
δ
182.0, 154.9, 147.0, 142.6, 138.7, 129.9, 129.0, 125.3, 123.1, 123.0, 120.6, 63.6, 41.9, 17.2; HRMS (ESI+)
m/z calcd for C23H19N3O4 [M + H]+: 402.1448, found: 402.1451.
3.4. Elaboration of the 3,30-Disubstituted Indolenines
2’-Methylspiro[3-cyclopentene-1,3’-indole] (24). The diallyl indoline 15a (0.236 mmol, 50 mg) was
dissolved in 2 mL of DCM. In a round bottom flask, Grubbs II catalyst (0.024 mmol, 21 mg) was taken
in DCM (4 mL) and flushed with argon. The indoline in DCM was then added dropwise to the flask
and stirred for 6 h at rt. Evaporated the solvent, purified using silica gel chromatography (5% EA/95%
DCM). This compound has been previously prepared [
7
]. Yellow oil (21 mg, 46%); TLC Rf = 0.43
(10% EA/90% DCM); 1H NMR (400 MHz, CDCl3)
δ
7.52 (d, J = 7.6 Hz, 1H), 7.34 (d, J = 7.6 Hz, 1H),
7.29 (dt, J = 7.6, 0.8 Hz, 1H), 7.18 (t, J = 7.6 Hz, 1H), 5.92 (s, 2H), 2.68 (s, 4H), 2.27 (s, 3H); 13C NMR
(100 MHz, CDCl3) δ 186.9, 153.7, 146.4, 129.8, 127.6, 125.5. 121.0, 119.5, 61.4, 41.4, 15.6.
3,3-Diallyl-2-methylindoline (25). The diallyl indoline 15a (2.37 mmol, 0.50 g) was dissolved in
10 mL THF and cooled to 0 ◦C using an ice bath. LiAlH4 solution (1 M in THF, 8.3 mmol, 8.3 mL)
was then slowly added. After 5 min the reaction mixture was allowed to warm to room temperature.
After 30 min the reaction mixture was recooled to 0 ◦C and quenched by dropwise addition of 15 mL
solution of saturated aqueous Rochelle’s salt (potassium sodium tartrate). The reaction was poured

Molecules 2019, 24, 4143
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into another 15 mL solution of saturated aqueous Rochelle’s salt and extracted to with EA (3
×
20 mL).
The organic layers were combined and washed with saturated aqueous sodium chloride (50 mL), dried
over sodium sulfate, filtered and concentrated. Purification using silica gel chromatography (60%
DCM/40% hexanes) provided indoline 25. Colorless oil (0.35 g, 70%); TLC Rf = 0.42 (60% DCM/40%
hexanes); IR (ATR) 3365, 3072, 2975, 2904, 1637, 1607, 1482, 912 cm−1; 1H NMR (400 MHz, CDCl3)
δ
7.04 (dt, J = 7.6, 1.2 Hz, 1H), 6.99 (d, J = 7.4 Hz, 1H), 6.74 (dt, J = 7.4, 0.8 Hz, 1H), 6.65 (d, J = 7.8 Hz,
1H), 5.80–5.68 (m, 2H), 5.06–4.97 (m, 4H), 3.78 (q, J = 6.6 Hz, 1H), 2.53 (dd, J = 14.2, 6.6 Hz, 1H), 2.39
(dd, J = 14.0, 7.9 Hz, 2H), 2.16 (dd, J = 13.8, 7.8 Hz, 1H), 1.24 (d, J = 6.6 Hz, 3H); 13C NMR (100 MHz,
CDCl3) δ 149.5, 134.92, 134.91, 134.6, 127.5, 124.4, 118.6, 117.7, 117.5, 109.7, 62.5, 49.3, 40.5, 37.5, 15.3.
HRMS (ESI+) calcd for C15H19NH+ [M + H]+: 214.1590, found: 214.1594.
3,3-Diallyl-2-methyl-1-(p-tolylsulfonyl)indoline (26). The diallyl indole 25 (5.02 mmol, 1.07 g) was
dissolved in 20 mL of DCM and p-toluene sulfonyl chloride (8.78 mmol, 1.67 g) was added followed by
triethylamine (10.97 mmol, 1.52 mL). After 16 h the reaction was quenched with 1M aq. HCl (50 mL)
and extracted with DCM (3
×
50 mL). The combined organic extracts were washed with sat. aq. NaCl
(50 mL), dried over Na2SO4, filtered and concentrated. Purification using silica gel chromatography
(70% DCM/30% hexanes) provided sulfonamide 26. Colorless oil (1.49 g, 81%); TLC Rf = 0.48 (80%
DCM/20% hexanes); IR (ATR) 3073, 2979, 1637, 1457,1351, 1163, 915 cm−1; 1H NMR (300 MHz, CDCl3)
δ
7.70–7.67 (m, 3H), 7.25–7.19 (m, 3H), 6.98–6.96 (m, 2H), 5.80–5.66 (m, 1H), 5.41–5.27 (m, 1H), 5.11
(s, 1H), 5.07 (d, J = 7.6 Hz, 1H), 4.83 (d, J = 13.6 Hz, 1H), 4.59 (d, J = 16.8 Hz, 1H), 3.99 (q, J = 6.6
Hz, 1H), 2.49 (dd, J = 14.9, 7.7 Hz, 1H), 2.35 (s, 3H), 2.30 (dd, J = 14.8, 6.3 Hz, 1H), 1.92 (dd, J = 13.9,
7.2 Hz, 1H) 1.46–1.39 (m, 4H); 13C NMR (100 MHz, CDCl3)
δ 143.9, 140.2, 136.5, 135.6, 133.9, 132.7,
129.5, 128.2, 127.0, 124.6, 123.2, 118.7, 118.6, 115.5, 67.4, 49.6, 42.8, 36.3, 21.5, 17.5. HRMS (ESI+) calcd
for C22H25NO2SNa+ [M + Na]+: 390.1498, found: 390.1495.
1’-Benzyl-2-methyl-1-(p-tolylsulfonyl)spiro[indoline-3,4’-piperidine] (27). The diallyl indole 26
(0.517 mmol, 0.190 g) was dissolved in 5 mL DCM and cooled to
100 ◦C (dry ice/ethyl ether bath). Ozone
−
was then bubbled through the solution for about 2 min until the color changed to blue. The reaction
mixture was then purged with argon until the blur color dissipated. 1,3-Bis(diphenylphosphino)propane
(0.517 mmol, 0.213 g) was then added and reaction mixture was allowed to warm to room temp.
The reaction mixture was then stirred for 1.5 h and then the solvent was evaporated. The resulting
residue was purified by silica gel chromatography (75%EA/25%DCM) to provide the corresponding
crude dialdehyde. The dialdehyde was dissolved in DCE (5.3 mL) and benzylamine (0.269 mmol, 0.029
mL) was added. After 5 min, sodium triacetoxyborohydride (1.07 mmol, 0.227 g) was added. After
16 h, the reaction was quenched with addition of water (5 mL) and extracted with DCM (3
×
10 mL).
The combined organic extracts were washed with sat. aq. NaCl (20 mL), dried over sodium sulfate
and concentrated. Purification of the residue using silica gel chromatography (20% EA/80% DCM)
provided piperidine 27. Off-white powder (0.08 g, 35% over 2 steps); TLC Rf = 0.47 (80% DCM/20%EA);
IR (ATR) 2927, 2802, 2757, 2359, 2341, 1598, 1493, 1348, 1132 cm−1; 1H NMR (400 MHz, CDCl3)
δ 7.67
(d, J = 8.2 Hz, 2H), 7.64 (d, J = 8.0 Hz, 1H), 7.33–7.28 (m, 5H), 7.23–7.17 (m, 3H), 7.06–6.99 (m, 2H), 4.30
(q, J = 6.6 Hz, 1H), 3.51–3.43 (m, 2H), 2.88 (d, J = 9.1 Hz, 1H), 2.44 (d, J = 11.7 Hz, 1H), 2.32 (s, 3H),
2.07–1.94 (m, 3H), 1.76 (d, J = 11.8 Hz, 1H), 1.34 (d, J = 6.6 Hz, 3H), 1.14 (t, J = 11.1 Hz, 1H), 0.28 (d, J =
13.2 Hz, 1H); 13C NMR (100 MHz, CDCl3)
δ 143.8, 139.3, 136.3, 129.6, 129.1, 128.3, 128.2, 127.1, 126.6,
124.0, 123.0, 115.7, 64.5, 63.4, 51.4, 50.1, 45.7, 38.6, 28.9, 21.5, 17.6; HRMS (ESI+) calcd for C27H31N2O2S+
[M + H]+: 447.2101. Found: 447.2108.
4. Conclusions
A new method for the synthesis of 3,3-dialkyl indolenines has been developed utilizing the Lewis
acid promoted alkylation of indoles with trichloroacetimidates. This method is differentiated from past
methods in that it does not depend on transition metal mediated alkylation or the use of strong base,
instead a Lewis acid and a trichloroacetimidate leaving group are utilized to perform the alkylation.
Notably even electron poor indoles undergo the dialkylation, which are difficult substrates for other

Molecules 2019, 24, 4143
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alkylation reactions. The indolenines generated from this reaction provide ready access to spirocyclic
structures which are useful platforms for the development of three dimensional architectures that may
interact with more complex biological receptors of interest to the medicinal chemistry community.
Supplementary Materials: Copies of 1H and 13C spectra are available at http://www.mdpi.com/1420-3049/24/22/
4143/s1.
Author Contributions: Conceptualization, J.D.C., T.S., N.A.M. and A.A.A.; investigation, T.S., N.A.M., and
A.A.A.; formal analysis, J.D.C., T.S. and N.A.M.; writing—original draft preparation, J.D.C., T.S. and N.A.M.;
writing—review and editing, J.D.C., T.S. and N.A.M.; supervision, J.D.C.
Funding: Acknowledgement is also made to the Donors of the American Chemical Society Petroleum Research
Fund for a New Directions award in support of this research (54823-ND1). The National Institute of General
Medical Sciences (R15-GM116054) also provided partial financial support.
Conflicts of Interest: The authors declare no conflict of interest. The funders had no role in the design of the
study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to
publish the results.
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