Vinylation of a secondary amine core with calcium carbide for efficient post-modification and access to polymeric materials

Article abstract of DOI:10.3390/molecules23030648

We developed a simple and efficient strategy to access N-vinyl secondary amines of various naturally occurring materials using readily available solid acetylene reagents (calcium carbide, KF, and KOH). Pyrrole, pyrazole, indoles, carbazoles, and diarylamines were successfully vinylated in good yields. Cross-linked and linear polymers were synthesized from N-vinyl carbazoles through free radical and cationic polymerization. Post-modification of olanzapine (an antipsychotic drug substance) was successfully performed.

Full text of DOI:10.3390/molecules23030648

molecules
Article
Vinylation of a Secondary Amine Core with Calcium
Carbide for Efficient Post-Modification and Access to
Polymeric Materials
Konstantin S. Rodygin , Alexander S. Bogachenkov 1 and Valentine P. Ananikov 1,2,* ID
1
1
Saint Petersburg State University, Universitetsky Prospect, 26, St. Petersburg 198504, Russia;
konstantinrs@rambler.ru (K.S.R.); alexterve@gmail.com (A.S.B.)
Zelinsky Institute of Organic Chemistry, Russian Academy of Science, Leninsky Prospect, 47,
2
Moscow 119991, Russia
*
Correspondence: val@ioc.ac.ru
Received: 16 February 2018; Accepted: 9 March 2018; Published: 13 March 2018
Abstract: We developed a simple and efficient strategy to access N-vinyl secondary amines of various
naturally occurring materials using readily available solid acetylene reagents (calcium carbide, KF,
and KOH). Pyrrole, pyrazole, indoles, carbazoles, and diarylamines were successfully vinylated in
good yields. Cross-linked and linear polymers were synthesized from N-vinyl carbazoles through
free radical and cationic polymerization. Post-modification of olanzapine (an antipsychotic drug
substance) was successfully performed.
Keywords: acetylene; calcium carbide; vinylation; olanzapine; functionalization
1
. Introduction
Nitrogen-containing compounds are one of the most important functional molecules in
modern chemistry, biology, and drug development. Nucleic acids, N-heterocyclic compounds,
amines, amino-acids, and their biopolymers are pivotal to a vast majority of biochemical processes.
Effective modification of secondary amines by the insertion of a vinyl group leads to demanded
N-vinyl derivatives with a variety of new applications. Vinylated products are interesting both as
biologically active cores [
carbazole-based compounds are considered promising as photoconductors and charge-transporting
materials [ ] in the aftermath of the discovery of photoconductivity in poly(N-vinylcarbazole) [ ].
The unique properties of vinyl amines are exemplified by their ability to polymerize under both
cationic [ ] and free radical conditions [ ]. Polymer synthesis with N-heterocyclic moieties like
1] and as versatile building blocks for polymerization [2]. At the same time,
3
4
5
6
diazepine has great potential for application. The biologically active core can be converted into a
polymeric form, which is capable of gradual depolymerization and release under specific conditions.
Current methods for preparing N-vinyl derivatives of secondary amines involve the vinyl
exchange reaction (Scheme 1, route a), which requires a source of vinyl group (in most cases represented
by vinyl acetate) and a metal catalyst. Enamines from nitrogenous bases [7], imidazole [8], triazoles [9],
carbazole [10], and pyrrolidone [11] can be successfully obtained by this approach.
Molecules 2018, 23, 648; doi:10.3390/molecules23030648
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Scheme 1. Synthetic procedures to access N-vinyl derivatives.
Cross-coupling reactions, catalyzed by copper [12] and iron [13], or palladium complexes [14],
require a partner: trimethyloxyvinylsilane [15], potassium vinyltrifluoroborate [16], or vinyl halide [17
Scheme 1, route b). Another non-atom economic strategy, elimination, is based on a two-step sequence,
]
(
which is carried out under basic conditions (Scheme 1, route c). The Clemo-Perkin method [18] and
dehydrohalogenation in the presence of phase transfer catalyst [19] lead to N-vinyl derivatives of
indoles [20], carbazoles [21], imidazoles [22], pyrazoles, triazoles, or tetrazoles [23] and nitrogenous
bases [24]. Several other transformations leading to N-vinyl derivatives, such as dehydrogenation [25],
ethylene insertion [26], and amine/aldehyde condensation could be also mentioned [27].
An excellent atom-economic opportunity is provided by the addition reaction of acetylene,
proceeding without by-product formation, which is to say that all atoms of starting materials become
incorporated into products. This reaction (Scheme 1, route d) was originally implemented by
Reppe [28], and it is still used with several optimizations [29]. Arylamines can be successfully
vinylated according to this procedure [30]. However, using and handling pressured acetylene is
technically difficult and requires dedicated hardware [31,32]. Not surprisingly, this atom-economic
approach, despite being efficient in terms of chemistry, has not found widespread application in
synthetic practice.
As an alternative to high pressure acetylene, calcium carbide has demonstrated a very impressive
potential in organic transformations [32–40]. Calcium carbide is inexpensive and readily available at
the large-scale commercial production level. Currently, a carbide-based synthesis is underestimated in
its potential to provide not only useful intermediates for lab chemistry, but also materials and polymers
for fine technology [32
,40]. As representative examples, the vinylation of O-H and S-H groups has
been reported [36 40]. However, the vinylation of the N-H group is challenging, and only indole
–
derivatives have been studied [41]. Recently, we developed a concept involving a solid acetylene
reagent, where the reactivity of calcium carbide and in situ generated acetylene was tuned by the
addition of KF [38].
In this work, we developed a synthetic methodology for preparing N-vinyl derivatives of
secondary amines by utilizing a solid acetylene reagent (Scheme 1, route e). Fluoride-mediated

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vinylation is a powerful and new approach not addressed previously for the functionalization of
amines. The vinylation of pyrrole, pyrazole, carbazoles, and diarylamines is reported here for the first
time. This method has a number of key advantages from the standpoint of green chemistry (Scheme 1,
route e) and a very simple practical procedure was developed using a combination of CaC /KOH/KF.
2
2
. Results and Discussion
Optimization of the proposed system was carried out to find the optimal conditions, particularly
the solvent and the temperature. First, a dedicated experiment was performed to choose a solvent:
pieces of calcium carbide were exposed to a solvent/water mixture under stirring. In cases of
hydrophobic solvents (e.g., hexane or toluene), two phases appeared, and calcium carbide reacted
much faster when the water was heavier than the solvent. In both cases, the release of acetylene did
not match the rate of nucleophilic addition to the triple bond, and the product yields were low (Table 1,
entries 1 and 2). In cases of dimethyl sulfoxide (DMSO) and dimethyl formamide (DMF), a sufficiently
slow release of gaseous acetylene allowed us to obtain and utilize its constant flow. To minimize losses,
we finally chose to employ DMSO, avoiding DMF for its partial decomposition during the reaction.
Furthermore, acetylene has good solubility in DMSO, and inorganic salts are also soluble in DMSO.
Reaction in DMSO gave the product in 38% yield (Table 1, entry 3), which was further improved
to 80% (Table 1, entry 4). Increasing loads of CaC and water did not improve the yields (Table 1,
2
entries 5, 6). Different bases were probed (NaOH, TEA, K CO , Na CO , pyridine), and potassium
2
3
2
3
hydroxide turned out to be the most suitable. It was also important to use both components—KOH and
KF—simultaneously, since using them separately significantly decreased the yields (Table 1, cf. entries
7
, 8, and 4). Interesting to note, the usage of KF provided a higher yield as compared to KOH (Table 1,
entries 7, 8).
Table 1. Optimization of the reaction conditions. 1
CaC2, base
H O, additive
2
N
o
Solvent, T C, h
N
H
◦
Yield, % 2
Entry Solvent Base + Additive, equiv.
CaC2, equiv.
Water, equiv.
T,
C
Time, h
1
2
3
Hexane
Toluene
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
KOH (1.1), KF (1)
KOH (1.1), KF (1)
KOH (1.1), KF (1)
KOH (1.1), KF (1)
KOH (1.1), KF (1)
KOH (1.1), KF (1)
KF (1)
2
2
2
2
2
4
2
2
2
2
2
2
2
4
4
4
4
8
8
4
4
4
4
4
4
-
130
130
130
130
130
130
130
130
130
110
150
130
130
4
4
8
4
4
4
4
4
4
4
4
4
4
trace
trace
38
80
62
57
54
25
88
66
50
52
trace
3
4
5
6
7
8
KOH (1.1)
4
9
1
1
1
KOH (1.1), KF (1)
KOH (1.1), KF (1)
KOH (1.1), KF (1)
KOH (1.5), KF (1.5)
KOH, KF
0
1
2
5
1
3
1
2 2
Reaction conditions: substrate (1 equiv.), CaC (2 equiv.), KOH (1.1 equiv.), KF (1 equiv.), H O (4 equiv.),
2
3
4
DMSO (1 mL), 4 h; NMR yields; DMSO 3 mL; the yield after double vinylation, the yield after single
vinylation was 84%; dry DMSO.
5
Performing sequential vinylation by splitting the amount of calcium carbide into two parts
provided an excellent product yield of 88% (Table 1, entry 9). The optimum temperature was estimated:
lower temperatures led to incomplete conversion (Table 1, entry 10), while higher temperatures resulted
in the decomposition and polymerization of the product (Table 1, entry 11). The optimal amount of
base was also established; further increasing its amount led to a decrease in the product yields (Table 1,

Molecules 2018, 23, 648
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entry 12). The presence of water was necessary, as indicated by the control experiment, in which the
reaction did not start without water in dry DMSO (Table 1, entry 13).
The role of potassium fluoride in the studied system represents an interesting question.
Microscopic examination of the solid inorganic postreaction waste, obtained in the absence of KF,
indicated the formation of Ca(OH) , as could be expected due to reaction of calcium carbide with water.
2
The presence of KF promoted the formation of CaF as a predominant component of the inorganic
2
postreaction residue. The observed difference is explained by the lower solubility and higher stability
of CaF2 [38]. The presence of potassium fluoride in the developed system importantly contributes to
the reactivity of calcium carbide and allows the controlled release of acetylene (Scheme 2). Another
important role may include the fluoride-mediated functionalization of acetylene (Scheme 2). A similar
effect was reported for the concept of a solid acetylene reagent in the OH bond vinylation process [38].
Scheme 2. Plausible mechanism of vinylation of secondary amines.
To assess the substrate scope of the developed vinylation protocol, it was applied to arylamines
(
2b
and diazepine (2n) (Schemes 3–5). The vinylation of aryl amines was flawless and produced excellent
yields (2b 2c). Pyrrole (2d) and pyrazole (2e) were also successfully vinylated. The vinylation of
indoles delivered moderate to good product yields (2f ). Surprisingly, despite N-vinylindole being
, 2c), pyrrole (2d), pyrazole (2e), indoles (2f–k), tetrahydrocarbazole (2l), bicarbazole (2m),
,
–k
a well-known compound [42], its X-ray structure is considered obscure due to its low melting point
◦
(
about 30 C) [43]. Extraction with hexane applied in this study allowed the isolation of pure vinylated
derivatives, which included N-vinylindole, and the determination their structures by means of X-ray
crystallography (Scheme 3).
The yield of vinyl indoles depended on the nature of a substituent in the aromatic ring.
Substituents with an electron-withdrawing effect, especially in the 2-position, substantially decreased
the yield (2j). This effect was probably due to the delocalization of negative charge throughout the
molecule after the proton elimination and corresponding decrease in reactivity of the nucleophile.
Isolated vinylindoles were air- and moisture-sensitive, especially in presence of trace amounts of acids.
Devinylation occurred as hydrolysis to an initial indole and acetic aldehyde. Simplicity of the synthetic
procedure is noteworthy; the products can be thoroughly purified through extraction with hexane
(other postreaction components are insoluble inorganic molecules).

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Scheme 3. Structures of vinylated secondary amine products and yields (in %). Reaction conditions:
amine (1 mmol), CaC (2 mmol), KOH (1.1 mmol), KF (1 mmol), H O (4 mmol), DMSO (1 mL).
NMR yields are given without parentheses, isolated yields are given in parentheses.
1
2
2
Upon the extraction of the vinylated carbazoles (2a, 2l), their low solubility in nonpolar solvents
became evident, and hexane was replaced by ether for more efficient separation.
N
H
1l
CaC , H O
2
2
KOH, KF
o
DMSO, 130 C
Toluene
BF · O(C H )
2 5 2
N
AIBN (2 mol%)
N
N
Toluene
3
o
48 h, 70 C
2 mol%
4 h, - 40 C
n
n
o
2
3l, 35 %
2l, 79 %
4l, 82 %
Mn, SEC = 6600 [g/mol]
Mn, SEC = 50000 [g/mol]
Scheme 4. N-vinyl-1,2,3,4-tetrahydrocarbazole synthesis and polymerization.

Molecules 2018, 23, 648
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It was very interesting to probe the vinylated tetrahydrocarbazole (2l) in polymerization reactions
Scheme 4). To try the possibility of polymerization, we used N-vinyl-1,2,3,4-tetrahydrocarbazole (1l)
(
as a monomer in either free radical or cationic conditions (Scheme 4). The 3l oligomer was isolated
in low yield and moderate average mass after free radical polymerization in the presence of AIBN
(
2 mol %) in toluene medium. The electron-donating and steric effects of methylene groups led to a
decreased molecular mass of the 3l polymer as compared with polymers derived from completely
aromatic carbazole. The presence of such substituents in carbazoles also led to decreasing molecular
weight. Cationic polymerization worked better, leading to a polymer of a greater mass (4l). Note that
a simple protocol was utilized and reaction conditions were not optimized. Both polymers were
reprecipitated from methanol and characterized by NMR and size exclusion chromatography (SEC).
Comparing monomers 2a and 2l, one may note that both N-vinyl derivatives easily undergo
cationic polymerization and produce polymers of similar molecular mass range. However,
different behavior was observed in the case of free radical polymerization, where the vinylated
tetrahydrocarbazole (2l) gave shorter polymer chains. Thus, access to both monomers provides good
potential for material science applications as an extension of well-known carbazole-containing systems.
0
3
,3 -bicarbazole (1m) was chosen as a model substrate for further polymerization experiments
in connection with the promising potential of polyvinyl carbazole (PVC) in optoelectronics. One-pot
insertion of two vinyl groups is challenging, since spontaneous oligomerization may readily occur
0
during the synthetic procedure. Nevertheless, the individual double vinylated 3,3 -bicarbazole (2m
)
was isolated in 32% yield using the developed procedure with calcium carbide (Scheme 5). The presence
of two vinyl groups in the monomer was clearly confirmed by X-ray analysis (Scheme 5).
0
Scheme 5. Double vinylation followed by the polymerization of bis(N-vinyl-3,3 -carbazole) and the
X-ray structure of 2m.
Polymerization of the bis-vinyl derivative in the presence of radical initiator (AIBN) resulted in
high yields (85%) of the insoluble cross-linked polymer 3m. Comparison of the registered solid-state
NMR-spectra with literature-derived NMR data on PVC [44] indicated the polymeric nature of the
obtained material (see Supplementary Materials for details).
The developed vinylation procedure was successfully utilized for post-modification of a drug
substance. Olanzapine (Zyprexa) is thienobenzodiazepine used for the treatment of schizophrenia
and bipolar disorder [45]; it acts by suppressing dopamine and serotonin receptor activities. Currently
available antipsychotic drugs have certain limitations. Considerable academic efforts are aimed
at enhancing their properties (e.g., by chemical post-modification), including the development of
new platforms for drug delivery [46]. The insertion of vinyl groups modulates the functionality

Molecules 2018, 23, 648
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of a biologically active benzodiazepine core and creates novel opportunities for molecular binding.
An olanzapine-containing polymer, slowly releasing the active units by gradual depolymerization
and/or devinylation upon delivery, could be of great therapeutic relevance. The vinylation of
olanzapine (1n) under the developed conditions proceeded smoothly (Scheme 5), and the vinyl
derivative (2n) was isolated in a pure form as a solid substance. The molecular structure of product 2n
was determined by X-ray analysis (Scheme 6).
Scheme 6. Vinylation of olanzapine and X-ray structure of the vinylated olanzapine derivative.
3
. Materials and Methods
Granulated calcium carbide was purchased from Sigma Aldrich (St. Louis, MO, USA)
( 75% volumetric). NMR spectra of the compounds were recorded using a Bruker Avance DRX 400
≥
1
13
spectrometer at 298 K. The H and C-NMR chemical shifts are reported in ppm and were determined
by referencing the peaks to the residual solvent signals. The data were processed using MestReNova
(
version 6.0.2) desktop NMR data processing software. High-resolution mass spectra were registered
on a Bruker Micro-TOF mass spectrometer (ESI-MS). All melting points (m.p.) were measured in open
capillaries on an electrothermal apparatus and are uncorrected. Liquid monomers were distilled over
calcium hydride in vacuum before polymerization. Size exclusion chromatography (SEC) was carried
out using a Shimadzu LC-20AD modular system equipped with a TSKgel G5000HHR column (7.8 mm
×
300 mm) and an RID-10A differential refractive index detector. The average molar mass (MnSEC) and
molar mass distribution (Mw Mn) values were determined using SEC in tetrahydrofurane (THF) at
/
◦
−1
40 C (flow rate = 1.0 mL min ) vs. polystyrene standards. The unit calibration was conducted using
·
commercially available narrow molecular-weight-distribution polystyrene standards (0.5–1000 kDa,
Polymer Laboratories). The chromatograms were processed using Shimadzu LCsolution software.
The polymer samples were initially filtered through a pulytetrafluoroethylene (PTFE) filter (0.45
µ
m,
−
1
1
3 mm, Macherey-Nagel) and dissolved in THF (6 mg
·
mL ). Purification via column chromatography
on silica should be avoided due to the sensitivity of most of the N-vinyl amines towards undergoing
rapid polymerization or degradation. If purification via column chromatography is required for some
reason, the silica should be neutralized with triethylamine. The products may be sensitive to light and
should be stored in a dark place. Contact with acid or traces of metals may initiate polymerization and
should be avoided.

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3
.1. Synthetic Procedures
3
.1.1. General Procedure of Vinylation
An amine (1.0 mmol), crushed KOH (1.1 mmol, 62 mg), anhydrous KF (1.0 mmol, 58 mg),
and granulated calcium carbide (2.0 mmol, 130 mg) were added to a reaction tube (7 mL) with 1 mL
of DMSO. After stirring at room temperature for 5 min, water (4.0 mmol, 72
the tube was sealed, and the mixture was heated at 130 C for 4 h with vigorous stirring.
µL) was added,
◦
◦
After cooling to 25 C, the mixture was extracted with hexane (4
×
4 mL). Combined extracts
were treated with 5% aqueous NaOH, then with brine, with water, and finally dried over
Na SO . Concentration under reduced pressure gave the target compound. All vinylated amines were
obtained as oils except 9-vinyl-9H-carbazole (2a) (m.p. 64–65 C, lit. 64 C [42]), N,N-diphenylvinylamine
2
4
◦
◦
◦
◦
◦
(
2b) (m.p. 53–54 C, lit. 52–54 C [47]), N-(
β-naphthyl)-N-phenylvinylamine (2c) (m.p. 80–81 C,
◦
0
0
0
◦
lit. 70–82 C [47]), 9,9 -divinyl-9H,9 H-3,3 -bicarbazole (2m) (decomposes at 162 C), and 2-methyl-4-
◦
(4-methylpiperazin-1-yl)-10-vinyl-10H-benzo[b]thieno[2,3-e][1,4]diazepine (2n) (m.p. 188–190 C).
In case of compounds 2m and 2n, methyl tert-butyl ether (MTBE) was used for extraction
instead of hexane. N-vinyl derivatives were isolated by flash column chromatography with system
hexane/MTBE (5/1) as an eluent with gradient elution. Compounds characterization is reported in
the Supplementary Materials.
Caution: The experimental procedures described in the present study involve the
evolution of gaseous acetylene upon the reaction of water with calcium carbide—the necessary
safety requirements for experiments with gases, acetylene, and CaC should be implemented
2
(see corresponding regulations).
3
.1.2. Experimental Procedure for the Radical Polymerization of N-vinyl-1,2,3,4-tetrahydrocarbazole (1l
)
To start, 276 mg (1.4 mmol) of 1l and 5 mg (0.03 mmol) of AIBN were added to a Schlenk tube
containing 1 mL of dry and degassed toluene. The tube was sealed, and the reaction was performed
◦
with stirring under an inert atmosphere at 70 C for 48 h. Then, the reaction mixture was precipitated
in methanol (20 mL). The crude product was dissolved in chloroform (1 mL) and again precipitated in
methanol (20 mL). After the residue was washed with hexane (3
repeated. The residue was dried under a reduced pressure for two days at 40 C to obtain a yellow
×
3 mL), the work-up procedure was
◦
solid (97 mg, 35% yield, Mn,SEC = 6600 (g/mol), Đ = 1.50).
3
.1.3. Experimental Procedure for the Cationic Polymerization of N-vinyl-1,2,3,4-tetrahydrocarbazole (1l
)
To start, 276 mg (1.4 mmol) of 1l was placed into a Schlenk tube under an inert atmosphere.
Then, 1 mL of degassed dry toluene was injected into the tube. After three degassing cycles, a toluene
solution of boron trifluoride diethyl etherate (2 mol %) was injected into the tube under stirring at
◦
−
40 C. After 24 h in a cryostat, the toluene solution was poured into methanol. The yellow solid was
collected through a filter, washed with hexane, dissolved in chloroform, and precipitated in methanol
◦
again. The powder was dried under a reduced pressure for two days at 40 C (226 mg, 82% yield,
Mn,SEC = 50000 (g/mol), Đ = 1.61).
4
. Conclusions
In conclusion, a new strategy of vinylation was developed, and a variety of secondary amines
were effectively converted into N-vinyl derivatives. Calcium carbide was utilized as a vinylation
agent to avoid high pressure equipment when producing required amounts of acetylene and thereby
simplify the synthetic procedure. The application of KF/KOH as a base was important for efficient
transformation. The reaction turned out to have a good substrate scope, and various pyrrole, pyrazole,
indoles, aryl amines, and carbazoles were successfully involved in the transformation. Regular and
cross-linked polymers were obtained by radical and cationic polymerization of the studied carbazole-

Molecules 2018, 23, 648
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and bicarbazole-containing substrates. N-vinyl olanzapine was synthesized, and its molecular structure
was established for the first time.
Supplementary Materials: Supplementary data are available online.
Acknowledgments: We acknowledge the generous support of Russian Science Foundation (RSF), No. 16-13-10301.
This research used resources of the ‘Magnetic Resonance Research Centre’, ‘Chemical Analysis and Materials
Research Centre’, and ‘Centre for X-ray Diffraction Studies’ of Research Park of Saint Petersburg State University.
Author Contributions: K.S.R. and A.S.B. performed the experiments, elaborated and interpreted the spectroscopy
data; V.P.A. designed and supervised the project. All authors took part in the manuscript preparation.
Conflicts of Interest: The authors declare no conflict of interest.
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1
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Sample Availability: Samples of the compounds are not available from the authors.
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