Synthesis of quaternary heterocyclic salts

Article abstract of DOI:10.3390/molecules181114306

The microwave synthesis of twenty quaternary ammonium salts is described. The syntheses feature comparable yields to conventional synthetic methods reported in the current literature with reduced reaction times and the absence of solvent or minimal solvent.

Full text of DOI:10.3390/molecules181114306

Molecules 2013, 18, 14306-14319; doi:10.3390/molecules181114306
OPEN ACCESS
molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Article
Synthesis of Quaternary Heterocyclic Salts
Angela J. Winstead *, Grace Nyambura, Rachael Matthews, Deveine Toney and Stanley Oyaghire
Department of Chemistry, Morgan State University, 1700 E Cold Spring Lane, Baltimore,
MD 21251, USA
* Author to whom correspondence should be addressed; E-Mail: angela.winstead@morgan.edu.
Received: 7 October 2013; in revised form: 28 October 2013 / Accepted: 28 October 2013 /
Published: 19 November 2013
Abstract: The microwave synthesis of twenty quaternary ammonium salts is described.
The syntheses feature comparable yields to conventional synthetic methods reported in the
current literature with reduced reaction times and the absence of solvent or minimal solvent.
Keywords: quaternary ammonium salts; microwave synthesis; heterocycles
1. Introduction
Heterocyclic chemistry has applications in diverse areas such as dyes [1], photosensitizers [2],
coordination compounds [3,4], polymeric materials [5–7] and many other fields. Of particular interest
are dyes which have widespread applications, some of which are shown in Figure 1. For example, the
bone-targeting conjugated compound monocarboxy-ICG (1) was found to bind to growing regions of
the skeleton and remain visible for two weeks [8]. The prolonged fluorescence could potentially allow
for to repeated imaging with a single injection. Optical contrast agents such as cyanine 2 have been
studied for ophthalmological surgery and exhibit good staining of tissues relevant for intraocular
microsurgery [9]. Hydroxystyryl derivatives 3a have been used for detecting endogenous and
exogenous targets in fixed cells and tissues [10], while quinoline based merocyanines 3b are being
investigated as solvatochromic indicators [11]. Finally, sulfonated water soluble cyanine dyes 4 with
reactive groups on one or both nitrogen atoms have been used extensively as fluorescence probes [12].

Molecules 2013, 18
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Figure 1. Dyes with widespread applications.
Cyanine dyes have equally as many uses and applications, but perhaps one of the most interesting is
their advantage as fluorescent probes for biomolecular labeling, as previously stated [13–15]. Cyanine
dyes are cationic molecules consisting of two terminal nitrogen heterocyclic subunits linked by a
polymethine bridge [16]. N-alkyl heterocyclic quaternary ammonium salts serve as the precursor for
styryl, squarine and other various cyanine dyes [17,18]. Traditionally, cyanine dyes are synthesized by
a condensation reaction between two heterocyclic bases containing an activated methyl group and an
unsaturated bisaldehyde in the presence of a catalyst [19].
The general procedure for symmetric cyanine dyes involves two equivalents of heterocyclic salt,
one equivalent of the bisimine reagent, two equivalents of sodium acetate and solvent, which are added
to a reaction vial, sealed and heated in a microwave system [20]. The ethyl cyanine dye, for example,
1
was synthesized in 79% yield and this was confirmed by H-NMR with the disappearance of the
singlet corresponding to the methyl protons of the salt at 2.87 ppm, and the appearance of the doublets
of the α- and β- protons of the polymethine bridge at 6.24 ppm and 8.35 ppm, respectively. These
peaks are found in the general range for all ensuing dyes.
Indolenine, benzoindolinine, quinolinium, and sulfoindolenium N-quaternary salts have been
previously synthesized using traditional organic synthetic methods, mainly via refluxing the reagents
with solvents such as chloroform, o-dichlorobenzene, acetonitrile or ethanol. Unfortunately, the
reported syntheses require longer reaction times, generally 24–48 h, and results in low yields, as the
process must often be repeated to achieve optimal yields.
Herein, an alternate synthetic route using microwave synthetic techniques that lower reaction times
significantly is described, which produces the target benozoindolenine, quinolinium and sulfo-indolenium
salts with little to no purification necessary and in comparable yield to previously reported traditional
organic synthetic techniques.

Molecules 2013, 18
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2. Results and Discussion
2.1. Benzoindolenine Salts
A total of eight benzoindolenine quaternary ammonium salts were synthesized in triplicate using a
Biotage Initiator 2.0 microwave oven and analyzed (Scheme 1). The optimized conditions for each
heterocyclic salt were determined by conducting extensive temperature and time studies. The
temperature studies for the alkyl substituted salts ranged from 120–150 °C in 10 °C increments with an
initial reaction time of 5 min. The initial temperature, 120 °C, was selected based upon previous
studies conducted on indolenine salts [21,22], while decomposition ensued at temperatures higher than
150 °C. Upon completion of the temperature studies, time studies were conducted which ranged from
5–45 min. Based on the temperature studies, reaction yields steadily increased from 5–30 min, while
reaction times greater than 30 min resulted in decomposition. The products were purified with ether
using vacuum filtration and stored in vials at room temperature under nitrogen. The structures were
confirmed using proton and carbon NMR. The optimized time and temperature studies for the salts
with various R-groups are summarized in Table 1.
Scheme 1. Benzoindolenine general reaction for salt derivatives.
Table 1. Synthesis of trimethylbenz[e]indolium deriviatives (Biotage Initiator 2.0).
Time
(min)
25
Temp Avg. Yield Lit. time
Lit. yield
(%)
Entry
R
MP (°C)
(°C)
120
135
140
140
145
120
145
145
(%)
92
65
75
69
65
64
82
51
(h)
0.25
24
1
2
3
4
5
6
7
8
CH₃
86 [23]
73 [24]
N/A
220–225
225–230
142–145
120–124
137–139
160–164
174–177
80–85
CH₂CH₃
30
(CH₂)₂CH₃
(CH₂)₃CH₃
(CH₂)₄CH₃
(CH₂)₂OH
(CH₂)₅CO₂H
(CH₂)₄SO₃
10
N/A
20
15
57 [25]
24 [9]
N/A
10
1.5
N/A
48
15
30
37 [9]
70 [8]
30
2.5
The methyl and ethyl benzoindolenine salts exhibited similar behaviors to each other. Upon
completion, both reactions resulted in solids that were isolated using vacuum filtration and cold ether
washes. The methyl salt was traditionally prepared with reflux for 15 min using acetonitrile as a
solvent with a 1.2 molar excess of iodomethane and was isolated with a yield of 86% using ether [23].
In this study the methyl salt was synthesized by a solvent free reaction with two equivalents of
iodomethane with an increased yield of 92%. The traditional synthetic pathway of the ethyl salt
consists of three lengthy steps: heating the starting material for 8 h in 1-butanol, addition of excess

Molecules 2013, 18
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iodoethane and heating for 16 h, then finally recrystallization in chloroform and ether which resulted in
a yield of 73% [24]. In this study, the salt was prepared in solvent free conditions with a significantly
lower reaction time of 30 minutes, obtaining a 65% yield.
Propyl-, butyl-, and pentylbenzoindolenine along with the butyl indolenine salts had similar
characteristics and were also synthesized in a solvent-free environment. Upon removal from the
microwave, the salts appeared as liquids, however, upon addition of acetone and ether, the salts
precipitated out and were easily filtered. The reaction time of the pentyl salt was 10 min and it was
isolated by vacuum filtration using cold ether to yield 82% of the pure product. This is a significantly
lower reaction time in comparison to traditional syntheses shown in the literature, where the time at
reflux was 1.5 h, the final product was isolated by addition of ether and stirring for 16 h, and a much
1
lower yield of 24% was achieved. Additionally, the H-NMR showed a significant amount of starting
material and the product was used without further purification [9].
The carboxyl benzoindolenine salt precipitate formed immediately despite the fact that it had an
increased number of carbons on the N-alkyl group. This behavior of the salt may be attributed to the
effect of the polarity of the carboxylic acid has on the salt’s solubility. In the microwave system, a 1:2
ratio of the starting materials produced the pure product in a yield of 82%. This is a significant
improvement in yield and reaction time compared to traditional heating, where the starting materials
were refluxed in DMPU at 120 °C for 48 h with only a 37% yield [9].
Finally, the sulfobutylbenzoindolenine salt was synthesized with the starting materials in a ratio of
1:5 for 30 min in solvent free conditions. After obtaining the grey solid, the product was dried in the
oven for 1 h at 100 °C. These conditions showed significant improvement over the literature, in terms
of both reaction time and purification procedure. Originally, the starting materials were heated to reflux
in 1,2-dichlorobenzene for 48 h and isolated by vacuum filtration with ether and later triturated in ether [8].
2.2. Quinolinium Salts
A total of five quinolinium quaternary ammonium salts were successfully synthesized in the
Biotage Initiator 2.0 microwave with optimal yields (Scheme 2). All reactions were performed in
triplicate. The initial temperature and time settings of 150 °C and 5 min were selected based upon
previous studies conducted on quinolinium salts [26]. The temperature studies for the alkyl substituted
salts ranged from 130–150 °C, as any temperature above 150 °C resulted in decomposition and
temperatures below 130 °C indicated significant amounts of unreacted starting material. As the carbon
chain increased for each heterocyclic derivative, the reactivity consistently showed a decreasing
correlation in the various reactions (Table 2).
Scheme 2. Quinolinium general reaction for salt derivatives.

Molecules 2013, 18
Table 2. Synthesis of quinolinium deriviatives (Biotage Initiator 2.0).
14310
Entry
R
Time
Temp Avg. Yield Lit. time Lit. Yield
MP
(min)
(°C)
130
130
130
130
120
(%)
98
(h)
24
(°C)
130
9
CH₃
CH₂CH₃
(CH₂)₂CH₃
5
5
98 [27]
59 [18]
80 [11]
83 [12]
N/A
10
11
12
13
70
24
126
5
96
N/A
5
130
(CH₂)₃CH₃
5
81
125
N/A*
(CH₂)5CO2CH₂CH₃
5,2
56
N/A
* denotes oil, boiling point not available.
The methyl, ethyl, propyl and butyl salts all exhibited similar behaviors, such as appearing as
viscous brown substances initially that were precipitated by using ether and acetone. The experimental
percent yield of the methyl salt was 98%, which was similar to the literature yield; however, the
reaction in the literature took 24 h, a significantly higher reaction time than in the microwave, which
was only 5 min [27]. Furthermore, the ethyl salt yield was 70% in 5 min in the microwave, compared
to the literature where the yield was only 59% after 24 h at reflux [10].
The propyl salt yielded 96% compared to the literature yield of 80%. The butyl salt resulted in an
81% yield, however, the NMR spectrum suggested significant impurities existed after the work up, so
the product was recrystallized from acetone. The pure butyl salt was a vibrant yellow color, whereas
darker shades of yellow indicated impurities. In the literature, the butyl salt reaction conditions were 5 h
by conventional heating in acetonitrile to produce an 83% yield [12]. The method by microwave
conditions reduced the reaction time sixty-fold to only 5 min. Because of the increased carbon chain
length in the 1-(6-ethoxy-6-oxohexyl)-4-methylquinolinium salt, the reaction time and temperature
differed from the previous salts. The reaction was done in cycle times. Cycle times can be described as
the exposure to microwave irradiation for a specific time followed by a cooling period. The concept of
cycle times was introduced from a previous source [14]. The cycle times pushed the reaction to
completion, after washing the product with dichloromethane and methanol, the product was
concentrated and brown oil with 56% yield was obtained.
2.3. Sulfoindolenium Salts
A total of six sulfoindolenium quaternary ammonium salts were synthesized using the CEM
Discover microwave (Scheme 3). Reactions were performed in triplicate. The optimized conditions for
each heterocyclic salt were determined by conducting extensive temperature and time studies. The
temperature studies for the alkyl substituted salts ranged from 120–160 °C in 10 °C increments with an
initial reaction time of 30 min. The reaction yields steadily increased as the temperature increased from
130–150 °C, although decomposition ensued at temperatures higher than 150 °C. Upon completion of
the temperature studies, time studies were conducted, which ranged from 30 s–90 min for the alkyl
substituted salts. Based on the temperature studies, the reaction yields steadily increased from 5–35 min;
reaction times greater than 35 min resulted in decomposition. The hydroxyethyl salt time studies ranged
from 0.5–30 min with conducted temperature studies ranging from 80–150 °C. The resulting reaction
time and temperature of 5 min and 125 °C, respectively, resulted in the highest product yield. In most
cases, the solid precipitate formed at room temperature with agitation. The purification methods of

Molecules 2013, 18
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methyl, ethyl, propyl, and butyl were similar in terms of vacuum filtration using acetone and ether
(Table 3). All salts were stored in vials at room temperature under nitrogen, and the structures were
confirmed using proton and carbon NMR.
Scheme 3. Sulfoindolenium general reaction for salt derivatives.
-O3S
-O3S
X-
N
N
R
Table 3. Synthesis of trimethyl-5-sulfo-3H-indolium derivatives (Discover SP CEM).
Time
(min)
Temp
(°C)
Avg.
Lit. time Lit. Yield
MP
Entry
R
Yield (%)
(hr)
(%)
(°C)
Sulfonate
14
CH₃
CH₂CH₃
(CH₂)₂CH₃
(CH₂)₃CH₃
(CH₂)₂OH
(CH₂)₅CO₂H
30
30
30
35
5
130
130
150
155
125
150
84
67
63
58
69
72
24
24
82 [14]
95 [14]
98 [14]
96 [14]
N/A
253
15
16
17
18
19
224–229
208–211
145–149
255–260
169–172
24
24
N/A
48
30, 15
75 [14]
Indolenine
20
(CH₂)3CH₃
15
140
71
24
82 [28]
105–110
Time and temperature studies were conducted with and without cycle times shown in the Table 4.
The cycle is repeated a second or third time as indicated. The cycle time studies included cycle 1,
which ranged from 15–90 min, and cycle 2, which ranged from 15–60 min, at a steady temperature of
150 °C. Those trials between 90–60 min resulted in a very low yield, whereas 15–30 min resulted in a
higher yield during cycles 1 and 2. There was one study with three cycle times at a constant
temperature which also resulted in low yield.
Table 4. Results from cycle vs. non cycles of 1-(5-carboxypentyl)-2,3,3-trimethyl-5-sulfo-
3H-indolium salt (Entry 19).
Non cycle Time (min)
Temp. (°C)
150
Yields (%)
30
60
37
150
51
90
150
8
75
150
-
Cycle Time (min)
60, 30
Temp. (°C)
150
Yields (%)
24
6
60, 60
150
30, 15
150, 130
150
38
5
60, 30, 15
90, 15
150
43
80
30, 15
150

Molecules 2013, 18
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It has been stated that quaternary ammonium salts described are hygroscopic. In a previous report [29],
the structure of the indolenium carboxyl salt was confirmed using X-ray crystallography. The structure
showed that both ions in the salt form intermolecular hydrogen bonds with the water molecule. The
O-H…Br interactions form a distorted tetrahedral array about the central Br atom.
3. Experimental
3.1. General
All microwave reactions were conducted using either the single mode Biotage Initiator 2.0
(Biotage, Uppsala, Sweden); benzoindolinine and quinolinium salts) or Discover SP CEM microwave
1
13
oven (CEM Corporation, Matthews, NC, USA); sulfoindolenium salts. H and C-NMR spectra were
obtained in DMSO-d6 (obtained from Cambridge Isotope Laboratories (Cambridge Isotope Laboratories,
Tewksbury, MA, USA) using a Bruker Advance 400 MHz NMR and were recorded at 400 MHz and
100 MHz, respectively. Melting points are uncorrected. All reagents and chemicals were obtained from
Aldrich Chemical Company (St. Louis, MO, USA) and Alfa Aesar (Ward Hill, MA, USA) and were
used without further purification.
3.2. Synthesis of Trimethylbenz[e]indolium Salts
1,2,3,3-Tetramethylbenz[e]indolium iodide (1): 2,3,3-Trimethybenzolindolenine (0.30 g, 1.4 mmol)
and iodomethane (0.18 mL, 3.0 mmol) were added to a microwave reaction vial. The microwave oven
was set to 120 °C for 25 min with a ramp time of 2 min. After cooling, the green solid was filtered and
washed with cold ether and dried in vacuo, yielding a grey solid in 80% yield. MP 220–225 °C;
1H-NMR δ (ppm): 8.38 (d, J = 8.5 Hz, 1H), 8.31 (d, J = 8.9 Hz, 1H), 8.23 (d, J = 7.8 Hz, 1H), 8.12 (d,
13
J = 8.9 Hz, 1H), 7.78 (m, 2H), 4.11 (s, 3H), 2.89 (s, 3H), 1.76 (s, 6H); C-NMR δ (ppm): 195.8 (C),
139.4 (CH), 136.4 (CH), 132.9 (CH), 130.4 (CH), 129.7 (C), 129.3 (C), 127.0 (C), 123.3 (CH), 113.1
(CH), 55.2 C), 35.1(CH3), 21.2 (CH3), 14.0 (CH3).
1-Ethyl-2,3,3-trimethylbenz[e]indolium iodide (2): 2,3,3-Trimethybenzolindolenine (0.30 g, 1.4 mmol)
and iodoethane (0.52 mL, 6.5 mmol) were added to a microwave reaction vial. The microwave oven
was set to 135 °C for 30 min with a ramp time of 2 min. After cooling, the white-blue solid was
filtered and washed with cold ether and dried in vacuo, yielding 80% of pure product. MP 225–230 °C;
1H-NMR δ (ppm): 8.39 (d, J = 8.3 Hz, 1H), 8.32 (d, J = 8.9 Hz, 1H), 8.24 (d, J = 8.0 Hz, 1H), 8.18 (d,
J = 8.9 Hz, 1H), 7.78 (m, 2H), 4.64 (q, J = 7.3 Hz, 2H), 2.96 (s, 3H), 1.77 (s, 6H), 1.52 (t, J = 7.3 Hz,
3H); 13C-NMR δ (ppm): 195.9 (C), 138.1 (CH), 136.9 (CH), 132.9 (CH), 130.6 (CH), 129.6 (C), 128.3 (C),
127.23 (C), 127.20 (C), 123.3 (C), 113.1 (CH), 55.4 (C), 43.3 (CH2), 21.4 (CH3), 13.6 (CH3), 12.8 (CH3).
1-Propyl-2,3,3-trimethylbenz[e]indolium iodide (3): 2,3,3-Trimethybenzolindolenine (0.30 g, 1.4 mmol)
and iodopropane (0.54 mL, 5.5 mmol) were added to a microwave reaction vial. The microwave oven
was set to 140 °C for 10 min with a ramp time of 2 min. After cooling, the product was stirred in
acetone and ether. The yellow solid was filtered and washed with cold ether and dried in vacuo,
1
yielding 83% pure product. MP 142-145 °C; H-NMR δ (ppm): 8.40 (d, J = 8.4 Hz, 1H), 8.32 (d,
J = 8.9 Hz, 1H), 8.24 (d, J = 8.0 Hz, 1H), 8.21 (d, J = 8.9 Hz, 1H), 7.79 (m, 2H), 4.60 (t, J = 7.4 Hz,

Molecules 2013, 18
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13
2H), 2.98 (s, 3H), 1.95 (m, 2H), 1.79 (s, 6H), 1.04 (t, J = 7.4 Hz, 3H); C-NMR δ (ppm): 196.4 (C),
138.5 (CH), 136.9 (CH), 132.9 (CH), 130.6 (CH), 129.6 (C), 128.3 (C), 127.2 (C), 127.1 (C), 123.4
(C), 113.3 (CH), 55.4 (C), 49.0 (CH2), 21.6 (CH2), 21.0 (CH3), 13.9 (CH3), 10.7 (CH3).
1-Butyl-2,3,3-trimethylbenz[e]indolium iodide (4): 2,3,3-Trimethybenzolindolenine (0.30 g, 1.4 mmol)
and iodobutane (1.0 mL, 8.7 mmol) were added to a microwave reaction vial. The microwave oven
was set to 140 °C for 15 min with a ramp time of 2 min. After cooling, the product was stirred in
acetone and ether. The yellow solid was filtered and washed with cold ether and dried in vacuo,
1
yielding 82% pure product. MP 120–124 °C; H-NMR δ (ppm): 8.40 (d, J = 8.3 Hz, 1H), 8.31 (d,
J = 8.9 Hz, 1H), 8.24 (d, J = 7.9 Hz, 1H), 8.18 (d, J = 8.9 Hz, 1H), 7.77 (m, 2H), 4.61 (t, J = 7.7 Hz,
2H), 2.98 (s, 3H), 1.89 (m, 2H), 1.78 (s, 6H), 1.49 (m, 2H), 0.97 (t, J = 7.4 Hz, 3H); 13C-NMR δ (ppm):
196.2 (C), 138.4 (CH), 136.9 (CH), 133.0 (CH), 130.6 (CH), 129.6 (C), 128.3 (C), 127.2 (C), 123.4
(C), 113.3 (CH), 55.4 (C), 47.7 (CH2), 29.4 (CH2), 21.6 (CH2), 19.3 (CH3), 13.9 (CH3), 13.6 (CH3).
1-Pentyl-2,3,3-trimethylbenz[e]indolium iodide (5): 2,3,3-Trimethybenzolindolenine (0.30 g, 1.4 mmol)
and iodopentane (1.2 mL, 9.1 mmol) were added to a microwave reaction vial. The microwave oven
was set to 145 °C for 10 min with a ramp time of 2 min. After cooling, the product was stirred in
acetone and ether. The orange solid was filtered and washed with cold ether and dried in vacuo,
1
yielding 82% pure product. MP 137–139 °C; H-NMR δ (ppm): 8.40 (d, J = 8.3 Hz, 1H), 8.31 (d,
J = 8.9 Hz, 1H), 8.24 (d, J = 7.9 Hz, 1H), 8.18 (d, J = 8.9 Hz, 1H), 7.77 (m, 2H), 4.61 (t, J = 7.7 Hz,
13
2H), 2.98 (s, 3H), 1.89 (m, 2H), 1.78 (s, 6H), 1.49 (m, 2H), 0.97 (t, J = 7.4 Hz, 3H); C-NMR δ
(ppm): 196.2 (C), 138.4 (CH), 136.9 (CH), 132.9 (CH), 130.6 (CH), 129.6 (C), 128.3 (C), 127.2 (C),
127.1 (C), 127.0 (C), 123.4 (C), 113.3 (CH), 55.4 (C), 47.8 (CH2), 27.9 (CH2), 27.1 (CH2), 21.8 (CH2),
21.6 (CH3), 13.8 (CH3), 13.7 (CH3).
1-(2-Hydroxyethyl)-2,3,3-trimethylbenz[e]indolium bromide (6): 2,3,3-Trimethybenzolindolenine (0.30 g,
1.4 mmol) and 2-bromoethanol (0.2 mL, 2.8 mmol) were added to a microwave reaction vial. The
microwave oven was set to 120 °C for 15 min with a ramp time of 2 min. After cooling, the product
was stirred in acetonitrile, acetone and ether. The grey solid was filtered and washed with cold ether
and dried in vacuo, yielding 74% pure product. MP 160–164 °C; 1H-NMR δ (ppm): 8.40 (d, J = 8.4 Hz,
1H), 8.30 (d, J = 8.9 Hz, 1H), 8.23 (d, J = 7.7 Hz, 1H), 8.19 (d, J = 8.9 Hz, 1H), 7.79 (m, 2H), 4.76 (t,
13
J = 4.9 Hz, 2H), 3.95 (t, J = 4.8 Hz, 2H), 2.96 (s, 3H), 1.79 (s, 6H); C-NMR δ (ppm): 197.3 (C),
138.6 (CH), 136.7 (CH), 132.9 (CH), 130.4 (CH), 129.6 (C), 128.3 (C), 127.1 (C), 123.3 (C), 113.5
(CH), 57.9 (C), 55.5 (CH2), 50.4 (CH2), 21.5 (CH3), 14.3 (CH3).
1-(5-Carboxypentyl)-2,3,3-trimethylbenz[e]indolium iodide (7): 2,3,3-Trimethybenzolindolenine (0.30 g,
1.4 mmol), 6-bromohexanoic acid (0.60 g, 3.0 mmol) and 1,2-dichlorobenzene (1.5 mL 13.2 mmol)
were added to a microwave reaction vial. The microwave oven was set to 145 °C for 30 min with a
ramp time of 2 min. After cooling, the product was stirred in ether. The yellow solid was filtered and
1
washed with cold ether and dried in vacuo, yielding 85% pure product. MP 174–177 °C; H-NMR δ
(ppm): 8.40 (d, J = 8.2 Hz, 1H), 8.31 (d, J = 8.9 Hz, 1H), 8.24 (d, J = 8.1 Hz, 1H), 8.20 (d, J = 9.0 Hz,
1H), 7.77 (m, 2H), 4.62 (t, 7.5 Hz, 2H), 2.98 (s, 3H), 2.25 (t, J = 7.1 Hz, 2H), 1.92 (m, 2H), 1.78 (s,
13
6H), 1.60 (m, 2H), 1.49 (m, 2H); C-NMR δ (ppm): 196.3 (C), 174.3 (C), 138.4 (CH), 136.9 (CH),

Molecules 2013, 18
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132.9 (CH), 130.6 (CH), 129.6 (C), 128.3 (C), 127.2 (C), 127.1 (C), 123.4 (C), 113.3 (CH), 55.4 (C),
47.6 (CH2), 33.3 (CH2), 27.1 (CH2), 25.3 (CH2), 24.0 (CH2), 21.7 (CH3), 14.4 (CH3) 13.8 (CH3).
3-(4-Sulfobutyl)-1,1,2-trimethylbenz[e]indolium iodide (8): 2,3,3-Trimethybenzolindolenine (0.30 g,
1.4 mmol) and 1,4-butane sultone (0.70 mL, 6.8 mmol) were added to a microwave reaction vial. The
microwave oven was set to 145 °C for 30 min with a ramp time of 2 min. After cooling, the product
was stirred in acetone and ether. The purple solid was filtered and washed with cold ether and dried in
1
an oven at 100 °C, yielding 83% pure product. MP 80–85 °C; H-NMR δ (ppm): 8.40 (d, J = 8.3 Hz,
1H), 8.31 (d, J = 8.9 Hz, 1H), 8.24 (d, J = 7.9 Hz, 1H), 8.18 (d, J = 8.9 Hz, 1H), 7.75 (m, 2H), 4.63 (t,
J = 8.02 Hz, 2H), 2.96 (s, 3H), 2.57 (t, J = 7.19 Hz, 2H), 2.51 (m 2H), 2.04 (m, 2H), 1.75 (s, 6H);
13C-NMR δ (ppm): 196.3 (C), 138.5 (CH), 136.8 (CH), 132.9 (CH), 131 (CH), 130.6 (C), 129.6 (C),
127.1 (C), 123.3 (C), 113.4 (CH), 55.4 (C), 50.1 (CH2), 47.4 (CH2), 26.1 (CH2), 22.0 (CH2), 21.5
(CH3), 13.6 (CH3).
3.3. Synthesis of Quinolinium Salts
1,4-Dimethylquinolinium iodide (9): Lepidine (0.20 mL 1.4 mmol) and iodomethane (0.22 mL, 0.28 mmol)
were added to a microwave reaction vial. The microwave oven was set to 130 °C for 5 min with a
ramp time of 2 min. After cooling, the product was washed with cold ether and acetone and dried
in vacuo, yielding a yellow-green solid in 98% yield. MP 130 °C; 1H-NMR δ (ppm): 9.36 (q, J = 7.33 Hz,
2H), 8.52 (t, J = 8.55 Hz, 1H), 8.28 (q, J = 8.48 Hz, 2H), 8.07 (d, J = 6.05 Hz, 1H), 4.58 (s, 3H), 3.41
13
(s, 3H); C-NMR δ (ppm): 158.0 (C), 148.8 (C), 137.5 (CH), 134.8 (CH), 129.5 (CH), 128.3 (CH),
126.6 (CH), 122.3 (CH), 119.4 (CH), 44.9 (CH2), 19.5 (CH3).
1-Ethyl-4-methylquinolinium iodide (10): Lepidine (0.20 mL, 1.4 mmol) and iodoethane (0.39 mL,
0.28 mmol) were added to a microwave reaction vial. The microwave oven was set to 130 °C for 5 min
with a ramp time of 2 min. After cooling, the product was filtered and washed with cold ether and
acetone and dried in vacuo, yielding a yellow solid in 70% yield. MP 126 °C; 1H-NMR δ (ppm): 9.43
(d, J = 7.33 Hz, 1H), 8.58 (dd, J = 8.55 Hz, 2H), 8.27 (t, J = 8.48 Hz, 1H), 8.07 (d, J = 6.05 Hz, 2H),
13
5.01 (q, J = 7.22 Hz, 2H), 3.01 (s, 3H), 1.59 (t, J = 7.22 Hz, 3H); C-NMR δ (ppm): 158.2 (C), 148.0
(C), 136.4 (CH), 134.9 (CH), 129.1 (CH), 128.8 (CH), 127.0 (CH), 122.6 (CH), 119.1 (CH), 52.4
(CH2), 19.5 (CH3), 15.1 (CH3).
1-Propyl-4-methylquinolinium iodide (11): Lepidine (0.20 mL, 1.4 mmol) and iodopropane (0.27 mL,
0.28 mmol) were added to a microwave reaction vial. The microwave oven was set to 130 °C for 5 min
with a ramp time of 2 min. After cooling, the product was filtered and washed with cold ether and
1
acetone and dried in vacuo, yielding 96% pure product. MP 130 °C; H-NMR δ (ppm): 9.6 (d,
J = 6.05 Hz, 1H), 8.59 (q, J = 8.48 Hz, 2H), 8.31 (t, J = 8.55 Hz, 1H), 8.07 (q, J = 7.33 Hz, 2H), 4.98
13
(t, J = 7.39 Hz, 2H), 3.02 (s, 3H), 1.98 (m, 2H), 0.96 (t, J = 7.36 Hz 3H); C-NMR δ (ppm): 158.5
(C), 148.3 (C), 136.7 (C), 135.0 (CH), 129.5 (CH), 128.9 (CH), 127.1 (CH), 122.5 (CH), 119.3 (CH).

Molecules 2013, 18
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1-Butyl-4-methylquinolinium iodide (12): Lepidine (0.20 mL, 1.4 mmol) and iodobutane (0.32 mL,
0.28 mmol) were added to a microwave reaction vial. The microwave oven was set to 130 °C for 5 min
with a ramp time of 2 min. After cooling, the product was filtered and washed with cold ether and
acetone and dried in vacuo, yielding the product as yellow crystals in 81% yield. MP 125 °C; 1H-NMR
δ (ppm): 9.6 (d, J = 6.05 Hz, 1H), 8.59 (q, J = 8.48 Hz, 2H), 8.3 (t, J = 8.55 Hz, 1H), 8.08 (q, J = 7.33 Hz,
2H), 5.0 (t, J = 7.49 Hz, 2H), 3.0 (s, 3H), 1.93 (m, 2H), 1.40 (m, 2H), 0.94 (t, J = 7.32 Hz, 3H);
13C-NMR δ (ppm): 158.5 (C), 148.3 (C), 136.6 (C), 135.0 (CH), 129.5 (CH), 128.9 (CH) 127.1 (CH),
122.6 (CH), 119.3 (CH), 56.7 (CH2), 19.7 (CH2), 19.1 (CH3), 13.4 (CH3).
1-(6-ethoxy-6-oxohexyl)-4-methylquinolinium iodide (13): Lepidine (0.23 mL, 1.754 mmol) and ethyl
6-iodohexanoate (0.35 mL, 1.929 mmol) were combined in a 5 mL Biotage microwave vial equipped
with a stir bar. The vial was placed in the Biotage microwave with a ramp time of 4 min and held at
120 °C for 5 min. The vial with reaction mixture was allowed to sit for 5 min. and irradiated again
with a ramp time of 4 min and held at 120 °C for 2 min. The resulting dark brown solid was dissolved
in a mixture of ethyl acetate (5 mL) and methanol (0.5 mL). The dark brown mixture was purified by
eluting on a coarse frit packed with silica gel. Ethyl acetate (400 mL) was used to wash the product
and a mixture of dichloromethane and methanol (90:10) was used for subsequent washes. The
dichloromethane and methanol washes were concentrated and dried to obtain brown oil in 56% yield.
1H-NMR δ (ppm): 9.45 (d, J = 6.05 Hz, 2H), 8.56 (m, 2H), 8.27 (m, 1H), 8.08 (m, 2H), 5.02 (t,
J = 7.47 Hz, 2H), 4.02 (q, J = 7.11, Hz, 2H), 3.00 (s, 3H), 1.95 (m, 2H), 1.60 (m, 2H), 1.55 (m, 2H),
13
1.38 (m, 2H), 1.15 (t, J = 7.47 Hz, 3H). C-NMR δ (ppm): 172.7 (C), 158.5 (C), 148.4 (CH), 136.6
(CH), 135.0 (CH), 129.5 (CH), 128.9 (CH), 127.1 (CH), 122.6 (CH), 119.3 (CH), 59.7 (CH2), 56.6
(CH2), 33.1 (CH2), 29.0 (CH2), 25.1 (CH2), 23.8 (CH2), 19.7 (CH3), 14.1 (CH3).
3.4. Synthesis of Sulfoindolenium Salts
1,2,3,3-Tetramethyl-5-sulfo-3H-indolium (14): Iodomethane (0.11 mL, 2.2 mmol) and potassium
2,3,3-trimethyl-3H-indole-5-sulfonate (0.10 g, 0.36 mmol) in 1 mL of acetonitrile were added to a
microwave reaction vial. The CEM microwave oven was set to 130 °C for 30 min with a ramp time of
1 min. After cooling, the product was boiled in acetone for 5 min and was recrystallized upon cooling.
The solid was filtered and washed with acetone and cold ether and dried in vacuo, yielding a red solid
in 84% yield. MP 253 °C; 1H-NMR δ (ppm): 7.96 (s, 1H) 7.84 (d, J = 8.34 Hz, 2H), 7.76 (d, J = 1.5 Hz,
13
2H), 3.95 (s, 3H), 2.77 (s, 3H), 2.09 (s, 6H); C-NMR δ (ppm): 195.5 (C), 148.0 (CH), 140.7 (CH),
139.9 (CH), 124.9 (C), 119.3 (C), 113.2 (C), 52.7 (C), 33.5 (CH3), 20.3 (CH3), 13.0 (CH3).
1-Ethyl-2,3,3-Trimethyl-5-sulfo-3H-indolium (15): Iodoethane (0.11 mL, 1.4 mmol) and potassium
2,3,3-trimethyl-3H-indole-5-sulfonate (0.10 g, 0.36 mmol) in 1 mL of acetonitrile were added to a
microwave reaction vial. The CEM microwave oven was set to 130 °C for 30 min with a ramp time of
1 min. After cooling, the red solid was filtered and washed with acetone and cold ether and dried
1
in vacuo, yielding a red solid in 67% pure product. MP 224–229 °C; H-NMR δ (ppm): 8.02 (s, 1H),
7.92 (d, J = 8.35 Hz, 1H), 7.82 (d, J = 1.5 Hz, 1H), 4.49 (q, J = 7.34 Hz, 2H), 2.84 (s, 3H), 2.09 (s,
13
6H), 1.44 (t, J = 7.33 Hz, 3H); C-NMR δ (ppm): 195.6 (C), 148.1 (CH), 140.3 (CH), 139.3 (CH),
125.1 (C), 119.5 (C), 113.5 (C), 52.9 (C), 41.9 (CH2), 20.5 (CH3), 12.7 (CH3), 11.3 (CH3).

Molecules 2013, 18
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1-Propyl-2,3,3-trimethyl-5-sulfo-3H-indolium (16): Iodopropane (0.20 mL, 2.1 mmol) and potassium
2,3,3-trimethyl-3H-indole-5-sulfonate (0.10 g, 0.36 mmol) in 1 mL of acetonitrile were added to a
microwave reaction vial. The CEM microwave oven was set to 150 °C for 30 min with a ramp time of
1 min. After cooling, the product was concentrated under reduced pressure. The resulting red solid was
stirred in acetone then filtered and washed with acetone and cold ether. The light pink solid was dried
1
in vacuo, yielding 63% pure product. MP 208–211 °C; H-NMR δ (ppm): 8.03 (s, 1H), 7.95 (d,
J = 8.38 Hz, 2H), 7.81 (d, J = 1.49 Hz, 2H), 4.44 (t, J = 7.69 Hz, 2H), 2.86 (s, 3H), 1.86 (m, 2H), 1.55
(s, 6H), 0.99 (t, J = 7.40 Hz, 3H); 13C-NMR δ (ppm): 195.7 (C), 149.3 (CH), 141.5 (CH), 140.9 (CH),
126.3 (C), 120.7 (C), 114.9 (C), 54.2 (C), 48.9 (CH2), 21.9 (CH2), 20.7 (CH3), 14.1 (CH3), 10.7 (CH3).
1-Butyl-2,3,3-trimethyl-5-sulfo-3H-indolium (17): Iodobutane (0.20 mL, 1.8 mmol) and potassium
2,3,3-trimethyl-3H-indole-5-sulfonate (0.10 g, 0.36 mmol) in 1 mL of acetonitrile were added to a
microwave reaction vial. The CEM microwave oven was set to 155 °C for 35 min with a ramp time of
1 min. After cooling, the product was concentrated under reduced pressure then stirred in acetone until
residue formed. The solution was decanted and the residue was suspended in acetone until solid
product had further formed. The solid was filtered and washed with acetone and cold ether and dried
in vacuo, yielding a red solid in 58% yield. MP 145–149 °C; 1H-NMR δ (ppm): 8.02 (s, 1H), 7.95 (d,
J = 8.38 Hz, 1H), 7.81 (d, J = 1.34 Hz, 1H), 4.46 (t, J = 7.63 Hz, 2H), 2.87 (s, 3H), 1.82 (q, J = 7.08 Hz,
2H), 1.55 (s, 6H), 1.42 (q, J = 7.78 Hz, 2H), 0.93 (t, J = 7.36 Hz, 3H); 13C-NMR δ (ppm): 197.1 (C),
149.1 (CH), 141.4 (CH), 140.8 (CH), 126.2 (C), 120.5 (C), 114.9 (C), 54.1 (C), 47.5 (CH2), 30.6
(CH2), 29.0 (CH2), 21.8 (CH2), 19.2 (CH3), 14.0 (CH3), 13.4 (CH3).
1-(2-Hydroxyethyl)-2,3,3-trimethyl-5-sulfo-3H-indolium (18): 2-bromoethanol (0.20 mL, 2.8 mmol)
and potassium 2,3,3-trimethyl-3H-indole-5-sulfonate (0.10 g, 0.36 mmol) were added to a microwave
reaction vial. The CEM microwave oven was set to 125 °C for 5 min with a ramp time of 1 min. After
cooling, the product was stirred in 1:1:3 of chloroform/acetone/ether. The light grey solid was filtered
and washed with cold ether and dried in vacuo, yielding 69% pure product. MP 255–260 °C; 1H-NMR
δ (ppm): 8.03 (s, 1H), 7.94 (d, J = 8.38 Hz, 2H), 7.80 (d, J = 1.40 Hz, 2H), 4.61 (t, J = 4.84 Hz, 2H),
3.87 (t, J = 4.86 Hz, 2H), 2.85 (s, 3H), 1.56 (s, 6H); 13C-NMR δ (ppm): 198.1 (C), 149.1 (CH), 141.4
(CH), 141.0 (CH), 126.1 (C), 115.0 (C), 57.7 (C), 54.4 (C), 50.4 (CH2), 21.9 (CH2), 14.6 (CH3).
1-(5-Carboxypentyl)-2,3,3-trimethyl-5-sulfo-3H-indolium (19): 6-Bromohexanioc acid (0.23 g, 1.2 mmol)
and potassium 2,3,3-trimethyl-3H-indole-5-sulfonate (0.10 g, 0.36 mmol) in 1 mL of acetonitrile were
added to a microwave reaction vial. The CEM microwave oven was set to 150 °C for 30 min with a
ramp time of 1 min. After cooling for one hour, the vial was reintroduced to the microwave oven
which was set to 150 °C for 15 min. After sitting and cooling for one hour, the precipitate was induced
by agitation. The light pink solid was filtered and washed with 1:1 2-propanol/ether and dried
1
in vacuo, yielding 72% pure product. MP 169–172 °C; H-NMR δ (ppm): 8.02 (s, 1H), 7.94 (d,
J = 8.37 Hz, 1H), 7.81 (d, J = 1.31 Hz,1H), 4.46 (t, J = 7.41 Hz, 2H), 2.87 (s, 3H), 2.53 (q, J = 1.75 Hz,
2H), 2.22 (t, J = 7.20 Hz, 2H), 1.84 (q, J = 7.02 Hz, 2H), 1.55 (s, 6H), 1.41 (q, J = 7.03 Hz, 2H);
13C-NMR δ (ppm): 196.1 (C), 173.1 (C), 148.1 (CH), 140.3 (CH), 139.7 (CH), 125.1 (C), 119.5 (C), 113.7
(C), 53.0 (C), 46.3 (CH2), 32.1 (CH2), 25.6 (CH2), 24.1 (CH2), 22.8 (CH2), 20.6 (CH3), 12.9 (CH3).

Molecules 2013, 18
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1-Butyl-2,3,3-trimethylindolium iodide (20): 2,3,3-Trimethylindolenine (0.52 mL, 3.2 mmol) and
iodobutane (0.76 mL, 6.6 mmol) were added to a microwave reaction vial. The microwave oven was
set to 130 °C for 20 min with a ramp time of 2 min. After cooling, the product was stirred in acetone
and ether. The yellow solid was filtered, washed with cold ether and dried in vacuo, yielding 70% pure
product. MP 105-110 °C; 1H-NMR δ (ppm): 0.95 (t, J = 7.29 Hz, 3H), 1.44 (m, 2H), 1.55 (s, 6H), 1.83
13
(m, 2H), 2.87 (s, 3H), 4.47 (t, J = 7.72 Hz, 2H), 7.64 (m, 1H), 7.8 (m, 1H), 8 (m, 1H); C-NMR δ
(ppm): 196.3 (C), 141.8 (CH), 141.0 (CH), 129.3 (C), 128.9 (C), 123.5 (C), 115.4 (CH), 54.1 (C), 47.4
(CH2), 29.2 (CH2), 22.0 (CH2), 19.3 (CH3), 14.1 (CH3), 13.6 (CH3).
4. Conclusions
The single mode microwave system has provided substantially decreased reaction times, simplicity
of reaction procedure, and comparable or increased reaction yields observed for 20 heterocyclic salts.
Acknowledgements
This study was supported by the following grants: Department of Defense W911NF-11-1-0157,
NIH-RISE 5R25GMO58904 and MARC U*STAR 5T34GM007977-27.
Conflicts of Interest
The authors declare no conflict of interest.
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Sample Availability: Samples of compounds 1–20 are available from authors.
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