Alkylation of 1-(prop-2-ynyl)piperidine with СН-acids in ihe presence of mercury(II) acetate

Article abstract of DOI:10.1134/S1070363217010066

General regilarities of the reaction of C-nucleophiles with 1-(prop-2-ynyl)piperidine in the presence of mercuty(II) acetate to form mono-and dicarbonyl derivatives of piperidine and bis[3-(piperidin-1-yl)prop-1-ynyl]mercury. Conditions of these reactions

Full text of DOI:10.1134/S1070363217010066

ISSN 1070-3632, Russian Journal of General Chemistry, 2017, Vol. 87, No. 1, pp. 29–32. © Pleiades Publishing, Ltd., 2017.
Original Russian Text © N.G. Hobosyan, K.V. Balyan, A.L. Petrosyan, S.A. Hovakimyan, Zh.A. Chobanyan, R.S. Nersisyan, 2017, published in Zhurnal
Obshchei Khimii, 2017, Vol. 87, No. 1, pp. 33–36.
Alkylation of 1-(Prop-2-ynyl)piperidine with СН-Acids
in ihe Presence of Mercury(II) Acetate
N. G. Hobosyana,b*, K. V. Balyana, A. L. Petrosyana,
S. A. Hovakimyanb, Zh. A. Chobanyana, and R. S. Nersisyana
a Institute of Organic Chemistry, Research and Technology Center of Organic and Pharmaceutical Chemistry,
National Academy of Sciences of Armenia, pr. Azatutyan 26, Yerevan, 0014 Armenia
*е-mail: ninahobosyan@mail.ru
b Аbobyan Armenian State Pedagogical University, Yerevan, Armenia
Received August 25, 2016
Abstract—General regilarities of the reaction of C-nucleophiles with 1-(prop-2-ynyl)piperidine in the presence
of mercuty(II) acetate to form mono-and dicarbonyl derivatives of piperidine and bis[3-(piperidin-1-yl)prop-1-
ynyl]mercury. Conditions of these reactions were optimized.
Keywords: alkylationе, acetylacetone, acetoacetic ester, prototropic isomers
DOI: 10.1134/S1070363217010066
We earlier studied the functionalization of terminal
acetylenic derivatives with various C-, N-, and O-
nucleophiles in the presence of mercury(II) acetate and
provided evidence for the formation of hydration
adducts, alkylation by the substituted carbon atom of
the triple bond, and subsequent prototropic isomeriza-
tions and intramolecular cyclization [1–3]. It was
shown that acetylacetone and acetoacetic ester are
readily alkylated with diethynylamine and propynyl-
morpholine in the presence of mercury(II) acetate to
form 1,3- and 1,5-diketoenol derivatives via direct
vinylation followed by protropic isomerization.
saturated aminoketones: (E)- and (Z)-4-methyl-5-
(piperidin-1-yl)pent-3-en-2-ones 5 and 6. It should be
noted that the alkaline cleavage of the mixture of linear
regioisomers 3 and 4 with 3 M NaOH, too, provides a
1 : 1 mixture of (E)- and (Z)-pentenones 5 and 6
(Scheme 1).
The structure of compounds 5 and 6 was proved by
1Н NMR spectroscopy and mass spectrometry. The
characteristic vinyl proton signals of isomers 5 and 6
1
appear in their Н NMR spectra at 6.22 and 6.40 ppm,
respectively. The mass spectra of these compounds
contain a molecular ion peak at m/z 181 and peaks of
the most stable fragment ions (Scheme 2).
Proceeding with the research in this field we have
studied the behavior of 1-(prop-2-ynyl)piperidine 1 as
the propargyl substrate in the alkylation with various
СН-acids in the presence of mercury(II) acetate. It was
found that the reaction of compound 1 with sodium
acetylacetonate in the presence of mercury(II) acetate
in THF forms a mixture of linear regioisomers 3-[3-
(piperidin-1-yl)prop-1-en-2-yl]pentane-2,4-dione 3 and
3-[1-(piperidin-1-yl)propan-2-ylidene]pentane-2,4-dione
4 after the demercurization of intermediate 2 with
aqueous sodium borohydride. The reduction of the inter-
mediate mercury derivative with the NaBH4–3 M NaOH
system alters the reaction route, and demercurization is
accompanied by alkaline cleavage of intermediate 2.
Elimination if acetic acid forms a mixture of un-
Further on we reacted 1-(prop-2-ynyl)piperidine 1
with sodium acetoacetate in the presence of mercury(II)
acetate in THF (Scheme 3). It was found that the
reduction of intermediate 7b with aqueous NaBH4 or
the NaBH4–3 M NaOH system forms a dialkynyl-
mercury derivative―bis[3-(piperidin-1-yl)prop-1-ynyl]-
mercury 8, which can be explained by the prevalence
of О-alkylation over С-alkylation, when acetoacetic
ester is used as the СН-acid. Thus, the intermediate
obtained by О-alkylation of 7b splits under the action
of hydride ion to form acetoacetic ester and alkynyl-
mercury acetate, and the latter undergoes a radical
reaction to form bis[3-(piperidin-1-yl)prop-1-ynyl]-
mercury 8 (Scheme 4).
29

30
HOBOSYAN et al.
Scheme 1.
O
O
O
O
AcOHg
N
_
Na+
N
Hg(OAc)2, THF
1
2
NaBH4_3 M NaOH
NaBH4_H2O
NaOH
N
N
N
N
O
O
O
O
O
O
3
4
5
6
Scheme 2.
N
O
84 98
138
CH
N
N
NCH2
m/z 84
m/z 98 (100%)
Scheme 3.
m/z 138
C-alkylation
N
HgOAc
OC2H5
O
O
_
O
7a
O
OC2H5
Na+
1
Hg(OAc)2
THF
N
HgOAc
O
O
O-alkylation
OC2H5
7b
NaBH4_H2O
NaBH4_3 M NaOH
N
N
Hg
8
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 87 No. 1 2017

ALKYLATION OF 1-(PROP-2-YNYL)PIPERIDINE WITH СН-ACIDS
31
Scheme 4.
N
HgOAc
O
N
O
8
_Hg
O
O
_
_CH3COOH
OC2H5
OC2H5
HgOAc
H
7b
It should be noted that the demercurization products
of intermediate 7а were not detected. The structure of
compound 8 was confirmed by 1Н and 13С NMR spec-
EXPERIMENTAL
The Н and 13С NMR spectra were registered on a
Varian Mercury-300 VX spectrometer (300.1 and
75.5 MHz, respectively). The chemical shifts were
measure against internal TMS at 303 K for solutions in
DMSO-d6–CCl4, 1 : 3. Reaction progress was
monitored by TLC on Silufol UV-254 plates,
development with KMnO4 and iodine vapor. Gas
chromatography was performed on an LKhM-80М
(model 3) chromatograph on a 1.5-m column packed
with 10% of Carbowax-20M on Inerton AW-NMDC,
helium (40 mL/min), detector and injector
temperatures 200°С and 250°С, respectively. The IR
spectra were obtained on a Nicolet AVATAR 330FT-
IR spectrometer. The UV spectra were run on a Helios
γ UV-VIS instrument. The mass spectra were
measured on a MX-1321A mass spectrometer.
1
1
troscopy [4, 5]. The Н NMR spectrum of this com-
pound contains three types of characteristic signals at
1.4–1.6 (СН2), 2.4 (СН2N), and 3.2 ppm (≡С–CH2–N).
The 13С NMR spectrum displays a characteristic
doublet from the sp-carbon atoms linked to mercury at
116.0 ppm (1JCHg = 2540 Hz). Evidence for the
presence of the ≡C–Hg group in compound 8 comes
from the observation of characteric IR absorption
bands at 440 and 520 cm–1. The formation of bis[3-
(piperidin-1-yl)prop-1-ynyl]mercury and lack of
complex formation between the acetylene fragment
and mercury are also confirmed by the absence of
characteristic maxima from the UV-vis spectra.
We also studied the effect of the solvent on the
regiochemistryof the reaction of propargylpiperidine
with СН-acids in the presence of mercuty(II) acetate.
The С-alkylations of acetylacetone with 1-(prop-2-
ynyl)piperidine were performed in THF, 1,4-dioxane,
and DMSO. The yield of the target products in the
reaction in THF was 52%, whereas the reactions of
1,4-dioxane and DMSO gave a lot of unidentified
compounds. With acetoacetic ester, bismercury deri-
vative 8 formed in all the solvents, but the highest
yield was, too, obtained in THF.
Commercial 1-(prop-2-ynyl)piperidine (Аurum
Pharmatech) was used.
Synthesis of compounds 3–6. а. 1-(Prop-2-ynyl)-
piperidine, 6.2 g (0.05 mol), and 50 mL THF were
added to 16 g (0.05 mol) of mercury(II) acetate at –5 to
–7°С. The resulting complex of 1-(prop-2-ynyl)piperi-
dine and mercury(II) acetate was added to sodium
acetylacetonate prepared by the reaction of 1.2 g
(0.05 mol) of Na with 10 mL of acetylacetone in THF.
Sodium borohydride 0.95 g (0.025 mol), 50 mL of
water, and 50 mL of diethyl ether were then added, and
the reaction mixture was stirred for 2 h. The amor-
phous mercury precipitate was filtered off, the filtrate
was extracted with ether, the extract was dried over
magnesium sulfate, and the solvent was removed to
obtain 5.8 g (52%) of a mixture of 3-[3-(piperidin-1-
yl)prop-1-en-2-yl]pentane-2,4-dione 3 and 3-[1-(pipe-
ridin-1-yl)propan-2-ylidene]pentane-2,4-dione 4, bp
89°C (2 mmHg).
The effect of the reducer on the regiochemistry of
this reaction was also studied. Thus, with sodium
borohydride, the mercury intermediates derived from
acetylacetone underwent acid cleavage to form amines,
which was accompanied by tarring of the reaction
mixture. It should be noted that bis[3-(piperidin-1-yl)-
prop-1-ynyl]mercury was cleaved with HCl to form
the starting propargylamine but proved to be insen-
sitive to sodium borohydride.
Thus, we have studied the regularities of the С- and
О-alkylation of acetyacetone and acetoacetic ester with
1-(prop-2-ynyl)piperidine in the presence of Hg(OAc)2.
3-[3-(Piperidin-1-yl)prop-1-en-2-yl]pentane-2,4-
dione (3). H NMR spectrum, δ, ppm: 1.35–1.45 m
1
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 87 No. 1 2017

32
HOBOSYAN et al.
(2H, γ-CH2), 1.51–1.60 m (4H, β-CH2), 2.15 s (6H,
СОСН3), 2.39–2.44 m (4H, α-CH2), 3.03 s (2Н, CH2 ),
3.91 s (1Н, СН), 5.15 d.d (1H, =CH2 J = 2.3, 1.5 Hz),
5.48 d.d (1H, =CH2, J = 2.1, 1.9 Hz). Mass spectrum,
m/z: 181 [M]+.
of 1,4-dioxane were added to 5.1 g (0.016 mol) of
mercury(II) acetate at –5 to 0°С. The resulting mixture
was stirred for 30 min at 25°C. Sodium acetoacetate
prepared from 0.016 mol of sodium ethylate and
0.016 mol of acetoacetic ester was added dropwise to
the reaction mixture, which was stirred for 10 h at 25°C
and, after addition of 0.3 g (0.008 mol) of NaBH4,
50 mL of 3 М of aqueous NaOH (or 50 mL of water),
and 50 mL of diethyl ether, stirring was continued for
an additional 3 h. The mercury metal precipitate was
filtered off, the filtrate was extracted with ether, the
extracts were dried over sodium sulfate, the solvent
was removed by distillation, and the residue was
washed with CCl4 and dried. Yield 2.6 g (73%), mp
105°C, Rf 0.56 (hexane–ether, 2 : 1). IR spectrum, ν,
3-[1-(Piperidin-1-yl)propan-2-ylidene]pentane-2,4-
1
dione (4). H NMR spectrum, δ, ppm: 1.35–1.45 m
(2H, γ-CH2), 1.51–1.60 m (4H, β-CH2), 1.8 s (3H,
C=C–CH3), 2.23 s (6H, СОСН3), 2.39–2.44 m (4H, α-
CH2), 3.03 s (2Н, CH2).
b. 1-(Prop-2-ynyl)piperidine, 6.2 g (0.05 mol), and
50 mL THF were added to 16 g (0.05 mol) of mercury(II)
acetate at –5 to –7°С. The resulting complex of 1-(prop-
2-ynyl)piperidine and mercury(II) acetate was added to
sodium acetylacetonate prepared by the reaction of
1.2 g (0.05 mol) of Na with 10 mL of acetylacetone in
THF. Sodium borohydride, 0.95 g (0.025 mol), 50 mL
of 3 М NaOH, and 50 mL of diethyl ether were then
added, and the reaction mixture was stirred for 3 h.
The amorphous mercury precipitate was filtered off,
the filtrate was extracted with ether, the extract was
dried over magnesium sulfate, and the solvent was
removed to obtain 4.35 g (48.6%) of a mixture of (E)-
and (Z)-4-methyl-5-(piperidin-1-yl)pent-3-en-2-ones 5
and 6, bp 79–81°C (3 mmHg).
1
cm–1: 2150, 440, 520. H NMR spectrum, δ, ppm:
1.35–1.60 m (12H, γ-CH2, β-CH2), 2.39–2.5 m (8H,
α-CH2), 3.17 s (4Н, CH2 C≡). 13C NMR spectrum, δС,
ppm: 23.5 (γ-CH2), 25.3 (β-CH2), 47.8 (NCH2), 52.3
(α-CH2), 99.9 (C≡), 116.0 (≡C).
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RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 87 No. 1 2017