Synthesis from Undecylenic Acid of Macroheterocycles with Diacylhydrazine and Ester Fragments

Article abstract of DOI:10.1007/s10600-019-02840-2

A three-step synthesis of potentially biologically active 30- and 32-membered macroheterocycles with esters and acylhydrazines starting from methyl undecylenate was developed based on [1+1]-condensation of intermediate tetraesters, i.e., bis(10′ -methoxy-10′-oxodecyl)- or bis(11′-methoxy-11′ -oxoundecyl)hexanedioate, with hydrazine hydrate. The structures of the synthesized compounds were confirmed using IR and NMR spectroscopy and mass spectrometry.

Full text of DOI:10.1007/s10600-019-02840-2

DOI 10.1007/s10600-019-02840-2
Chemistry of Natural Compounds, Vol. 55, No. 5, September, 2019
SYNTHESIS FROM UNDECYLENIC ACID OF
MACROHETEROCYCLES WITH DIACYLHYDRAZINE
AND ESTER FRAGMENTS
G. R. Mingaleeva, M. P. Yakovleva,* and G. Yu. Ishmuratov
A three-step synthesis of potentially biologically active 30- and 32-membered macroheterocycles with esters
and acylhydrazines starting from methyl undecylenate was developed based on [1+1]-condensation of
intermediate tetraesters, i.e., bis(10′-methoxy-10′-oxodecyl)- or bis(11′-methoxy-11′-
oxoundecyl)hexanedioate, with hydrazine hydrate. The structures of the synthesized compounds were
confirmed using IR and NMR spectroscopy and mass spectrometry.
Keywords: undecylenic acid, ozonolysis, hydroboration-oxidation, [2+1]-condensation, [1+1]-condensation,
macroheterocycles, synthesis.
1,2-Diacylhydrazines are interesting and important as reagents for concentrating base metal ions [Co(II), Cu(II),
Zn(II), Ni(II), Fe(III)] by precipitation and ionic flotation [1]. They exhibit anticancer [2] and antituberculosis activity [3] and
act as substrates for synthesizing 1,3,4-oxadiazoles with broad spectra of biological activity including analgesic,
anti-inflammatory, antituberculosis, antimicrobial, etc. [2].
Previously, the optically pure 21-membered macrocycle (8S,11R,18R,21S)-8,21-diisopropyl-11,18-dimethyl-1,7-dioxa-
14,15-diazacycloheneicosane-2,6,13,16-tetrone was synthesized by us from l-menthone [4] and 34-membered macroheterocycle
(9R,11Z,31Z,34R)-9,34-dihexyl-1,8-dioxa-21,22-diazacyclotetratriaconta-11,31-diene-2,7,20,23-tetrone, from
12R-hydroxyoctadec-9Z-enoic (ricinoleic) acid [5] with a diacylhydrazine fragment.
OH
O
Me(H C)
2
(CH ) C
2 7
O
O
O
5
5
5
OH
OH
O
O
a
d
c
b
Me(H C)
2
(CH ) C
(CH ) COOH
2 8
(CH ) COOMe
2 8
HO(CH )n
OMe
2 7
2
O
3
1
4, 5
Me(H C)
2
(CH ) C
2 7
2
H
N
H
O
N
O
O
OMe
MeO
O
O
e
(CH )n
2
O
(CH )n
(CH )n
2
2
(CH )n
2
O
O
4
4
O
O
O
O
6, 7
n = 10 (4, 6, 8); 9 (5, 7, 9)
a. 500°C [6]; b. MeOH, TsOH [9]; c. 9-BBN, THF, then H O , AcONa (89% for 4) or O , MeOH, then NaBH [10] (91% for 5);
8, 9
2
2
3
4
Cl
Cl
, DMAP, Py, CH Cl ; e. N H ⋅H O, dioxane
4
O
d.
2
2
2
4
2
O
Ufa Institute of Chemistry, Ufa Federal Research Center, Russian Academy of Sciences, 71 Prosp. Oktyabrya, Ufa,
450054, e-mail: insect@anrb.ru. Translated from Khimiya Prirodnykh Soedinenii, No. 5, September–October, 2019,
pp. 770–772. Original article submitted January 16, 2019.
©
0009-3130/19/5505-0895 2019 Springer Science+Business Media, LLC
895

In continuation of these studies, potentially pharmacologically active 30- and 32-membered macroheterocycles
containing carboxylic and diacylhydrazine groups were synthesized. The starting compound was 10-undecenoic (undecylenic)
acid (1), which was prepared via destructive distillation of commercially available castor oil (2) from seeds of Ricinus communis
[6] and is widely used in targeted organic synthesis [7], medicine as a fungicidal preparation, and cosmetology as a fragrance
and softener [8].
Compound 1 was converted to methyl ester 3 via esterification by MeOH as before [9]. Compound 3 was transformed
into the methyl ester of 11-hydroxyundecanoic acid (4) via hydroboration-oxidation using 9-borobicyclo[3.3.1]nonane
(9-BBN) (89%). Compound 2 was converted in 91% yield to the methyl ester of 10-hydroxydecanoic acid (5) by the
well-known method of ozonolysis of methyl ester 3 followed by NaBH reduction [10].
4
[2+1]-Condensation of hydroxymethyl esters 4 and 5 with adipic acid chloride produced high yields of their
bis-derivatives 6 and 7, [1+1]-condensation of which with hydrazine hydrate at room temperature and high dilution (1:100) in
1,4-dioxane gave corresponding macrocycles 8 and 9 with diacylhydrazine and two ester fragments.
The structures of synthesized intermediates 4–7 and macroheterocycles 8 and 9 were elucidated using IR, PMR, and
13
C NMR spectroscopy and were confirmed using GC-MS.
–1
IR spectra of 6 and 7 lacked absorption bands at 3413 and 3446 cm that were characteristic of hydroxyester OH
–1
–1
groups (4 and 5) and showed paired bands (1733, 1735 cm for 6 and 1733, 1738 cm for 7) indicating two types of esters
–1
–1
were present. IR spectra of 8 and 9 had ester (1735 and 1734 cm ), CONH (1646 and 1648 cm ), and NH absorption bands
–1
(3336 and 3307 cm ) that proved the diacylhydrazine fragment formed.
13
C NMR spectra of 8 and 9 contained resonances for ester C atoms (172.58 ppm for 8 and 173.28 ppm for 9) and
singlets for NHC=O (174.10 ppm for 8 and 174.12 ppm for 9). PMR spectra of 8 and 9 had weak-field resonances (7.88 ppm
for 8 and 7.82 ppm for 9), the chemical shifts and integrated intensities of which were consistent with two NHC=O amide
protons of the macrocycles. This indicated that the diacylhydrazine fragment [-–C(O)NHNHC(O)–] had formed. Spectral
data indicated that macrocycles 8 and 9 with esters and hydrazines had formed. This was also confirmed by mass spectral data.
+
–
Strong peaks for protonated MH and deprotonated ions [M – H] were recorded. Also, their ion pairs with water molecules
provided proof that the target macroheterocycles formed.
Thus, a synthetic method for symmetric 30- and 32-membered macroheterocycles containing carboxyl and
diacylhydrazine fragments was developed based on undecylenic acid.
EXPERIMENTAL
Equipment at the Khimiya Common Use Center, UfIC, UFRC, RAS was used in the work. IR spectra were recorded
from thin layers on a Shimadzu Prestige-21 IR instrument. NMR spectra were recorded in CDCl solutions with TMS internal
3
1
13
standard on a Bruker AM-500 spectrometer (operating frequency 500.13 MHz for H and 126.75 MHz for C).
Chromatographic analysis used a Chrom-5 instrument [column length 1.2 m, stationary phase silicone SE-30 (5%) on Chromaton
N-AW-DMCS (0.16–0.20 mm), operating temperature 50–300°C] with He carrier gas. Column chromatography used SiO
2
(70–230, Lancaster, England). TLC monitoring used Sorbfil SiO (Russia). Elemental analyses of all compounds agreed with
2
those calculated. Mass spectra of 6–9 were taken on a Shimadzu LCMS 2010 EV instrument using APCI conditions with
electron energy 20 eV in positive- and negative-ion modes. The liquid mobile phase (H O) flow rate was 0.03 mL/min.
2
Products were synthesized, isolated, and purified using THF, Et O, petroleum ether (PE, 40–70°C), tert-butylmethyl ether
2
(MTBE), Py, and 1,4-dioxane that were purified and dried as usual [11]. 9-BBN and N,N-dimethyl-4-aminopyridine (DMAP)
were purchased (Sigma-Aldrich).
Methyl 11-Hydroxyundecanoate (4). A suspension of 9-BBN (0.50 g, 4.1 mmol) in anhydrous THF (5 mL) at 10°C
was treated over 10 min with a solution of alkene 3 (0.60 g, 3.0 mmol) in anhydrous THF (2 mL). After 2 h, the mixture was
treated at 0°C with NaOAc solution (3 N, 3 mL) and then over 15 min with H O (30%, 3 mL); stirred at 25°C for 2 h; diluted
2
2
with Et O (30 mL); washed sequentially with saturated NaCl (2 × 5 mL), Na S O (2 × 5 mL), and saturated NaCl solutions
2
2 2 3
(2 × 5 mL); dried over Na SO ; evaporated; and chromatographed (PE–MTBE, 2:1). Yield of 4, 0.56 g (89%), R 0.25
2
4
f
–1
13
(PE–MTBE, 2:1). IR spectrum (KBr, ν, cm ): 3413 (OH), 1733 (COO) [12]. PMR and C NMR spectra were identical to
those published earlier [12].
–1
Methyl 10-hydroxydecanoate (5) was prepared in 91% yield as before [10]. IR spectrum (KBr, ν, cm ):
3446 (OH), 1738 (COO). PMR and C NMR spectra were identical to those published earlier [13].
13
896

General Method for Preparing bis-Derivatives 6 and 7. A solution of 4 or 5 (9.3 mmol) in anhydrous Py (3 mL)
with one DMAP crystallite was stirred, treated with adipic acid chloride (0.84 g, 4.6 mmol, prepared as before [14]) in
anhydrous Et O (1 mL), diluted after 24 h (TLC monitoring for disappearance of 4 or 5) with Et O (50 mL), washed sequentially
2
2
with HCl (5%, 3 × 5 mL) and saturated NaCl solutions (3 × 5 mL), dried over MgSO , and evaporated at reduced pressure.
4
The residue was chromatographed (SiO , PE–MTBE, 2:1) to afford tetraester 6 or 7.
2
–1
bis(11′-Methoxy-11′-oxoundecyl)hexanedioate (6). C H O . Yield 2.00 g (80%). IR spectrum (KBr, ν , cm ):
30 54
8
max
1
1733, 1735 (COO). Í NMR spectrum (300 MHz, ÑDCl , δ, ppm, J/Hz): 1.09–1.22 (24Í, m, Í-3′÷8′), 1.30–1.40 (8Í, m,
3
Í-2′, 9′), 1.41–1.46 (4Í, m, Í-3, 4), 2.01 (4Í, t, J = 7.5, Í-10′), 2.10 (4Í, t, J = 7.2, Í-2, 5), 3.44 (6Í, s, ÑÍ ), 3.80 (4Í, t,
3
13
J = 6.7, Í-1′). C NMR spectrum (75 MHz, ÑDCl , δ, ppm): 24.14 (ÑÍ , Ñ-3, 4), 24.63 (ÑÍ , Ñ-3′), 25.64 (ÑÍ , Ñ-9′),
3
2
2
2
28.36 (ÑÍ , Ñ-2′), 28.82, 28.89, 28.91, 28.99, 29.04 (ÑÍ , Ñ-4’÷8′), 33.50 (ÑÍ , Ñ-10′), 33.60 (ÑÍ , Ñ-2, 5), 50.93 (ÑH ,
2
2
2
2
3
ÎÑÍ ), 64.01 (ÑÍ , Ñ-1′), 172.73 (Ñ, Ñ-1), 173.55 (Ñ, Ñ-11′). Mass spectrum (ÀÐÑI, 20 eV), m/z (I , %): 543 (100)
3
2
rel
+
+
[M + H] , 561 (76) [M + H + H O] . Calcd for C H O , 542.7450.
2
30 54 8
–1
bis(10′-Methoxy-10′-oxodecyl)hexanedioate (7). C H O . Yield 1.73 g (73%). IR spectrum (KBr, ν , cm ):
28 50
8
max
1
1733, 1738 (COO). Í NMR spectrum (300 MHz, ÑDCl , δ, ppm, J/Hz): 1.10–1.23 (20Í, m, Í-3′÷7′), 1.33–1.40 (8Í, m,
3
Í-2′, 8′), 1.40–1.46 (4Í, m, Í-3, 4), 2.03 (4Í, t, J = 7.5, Í-9′), 2.09 (4Í, t, J = 7.2, Í-2, 5), 3.43 (6Í, s, ÑÍ ), 3.82 (4Í, t,
3
13
J = 6.7, Í-1′). C NMR spectrum (75 MHz, ÑDCl , δ, ppm): 24.13 (ÑÍ , Ñ-3, 4), 24.61 (ÑÍ , Ñ-3′), 25.63 (ÑÍ , Ñ-8′),
3
2
2
2
28.37 (ÑÍ , Ñ-2′), 28.82, 28.91, 28.89, 29.04 (ÑÍ , Ñ-4′÷7′), 33.52 (ÑÍ , Ñ-9′), 33.62 (ÑÍ , Ñ-2, 5), 50.91 (ÑH , ÎÑÍ ),
2
2
2
2
3
3
+
63.98 (ÑÍ , Ñ-1′), 172.75 (Ñ, Ñ-1), 173.52 (Ñ, Ñ-10′). Mass spectrum (ÀÐÑI, 20 eV), m/z (I , %): 515 (100) [M + H] , 533
2
rel
+
(50) [M + H + H O] . Calcd for C H O , 514.6918.
2
28 50 8
General Method for Preparing Macrocycles 8 and 9. Compound 6 or 7 (3.5 mmol) was dissolved in dioxane
(30 mL), stirred vigorously, treated slowly dropwise with hydrazine hydrate (64%, 0.22 g, 3.5 mmol), stirred for 24 h
(TLC monitoring for disappearance of 6 or 7), and evaporated at reduced pressure.
1,8-Dioxa-20,21-diazacyclotriaconta-2,7,19,22-tetrone (8). C H N O . Yield 1.51 g (85%). IR spectrum (KBr,
28 50
2 6
–1
1
ν
, cm ): 1646 (CÎNÍ), 1735 (COO), 3336 (NH). Í NMR spectrum (300 MHz, ÑDCl , δ, ppm, J/Hz): 0.67–0.70 (24Í,
max
3
m, Í-11÷ 16, Í-25÷30), 1.52–1.61 (12Í, m, Í-4, 5, 10, 17, 24, 31), 2.25 (4Í, t, J = 7.5, Í-18, 23), 2.23 (4Í, t, J = 7.0, Í-3,
13
6), 3.99 (4Í, t, J = 6.6, H-9, 32), 7.88 (2H, br.s, NH). C NMR spectrum (75 MHz, ÑDCl , δ, ppm): 24.36 (ÑÍ , C-4, 5),
3
2
24.59, 25.66, 26.40 (ÑÍ , Ñ-15÷17, Ñ-24÷26), 27.98, 28.48, 28.79, 29.18, 29.49 (ÑÍ , Ñ-10÷14, C-27÷31), 34.82 (ÑÍ ,
2
2
2
Ñ-3, 6), 34.93 (ÑÍ , Ñ-18, 23), 64.24 (ÑÍ , Ñ-9, 32), 172.58 (Ñ, Ñ-2, 7), 174.10 (Ñ, Ñ-19, 22). Mass spectrum (ÀÐÑI, 20 eV),
2
2
+
+
m/z (I , %): 511 (100) [M + H] , 529 (65) [M + H + H O] . Calcd for C H N O , 510.7065.
rel
2
28 50 2 6
1,8-Dioxa-19,20-diazacyclotriaconta-2,7,18,21-tetrone (9). C H N O . Yield 1.41 g (84%). IR spectrum (KBr,
26 46
2 6
–1
1
ν
, cm ): 1648 (CÎNÍ), 1734 (COO), 3307 (NH). Í NMR spectrum (300 MHz, ÑDCl , δ, ppm, J/Hz): 0.67–0.70 (20Í,
max
3
m, Í-11÷15, Í-24÷28), 1.49–1.60 (12Í, m, Í-4, 5, 10, 16, 23, 29), 2.27 (4Í, t, J = 7.5, Í-17, 22), 2.21 (4Í, t, J = 7.1, Í-3, 6),
13
3.97 (4Í, t, J = 6.4, H-9, 30), 7.82 (2H, br.s, NH). C NMR spectrum (75 MHz, ÑDCl , δ, ppm): 24.31 (ÑÍ , C-4, 5), 24.79
3
2
(ÑÍ , Ñ-14, 25), 25.76 (ÑÍ , Ñ-16, 23), 28.49 (ÑÍ , Ñ-15, 24), 28.91, 28.97, 29.04, 29.17 (ÑÍ , Ñ-10÷13, C-26÷29), 33.82
2
2
2
2
(ÑÍ , Ñ-3, 6), 33.93 (ÑÍ , Ñ-17, 22), 64.35 (ÑÍ , Ñ-9, 30), 173.28 (Ñ, Ñ-2, 7), 174.12 (Ñ, Ñ-18, 21). Mass spectrum (ÀÐÑI,
2
2
2
+
+
20 eV), m/z (I , %): 483 (80) [M + H] , 501 (100) [M + H + H O] . Calcd for C H N O , 482.6533.
rel
2
26 46 2 6
ACKNOWLEDGMENT
The work was financially supported by RAS program “Basic Principles of Chemistry” on topic No. 8 “Chemo-,
regio-, and stereoselective transformations of terpenoids, steroids, and lipids for targeted synthesis of low-molecular-mass
bioregulators” (State Reg. No. AAAA-A17-117011910023-2, 2017).
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