Dill and parsley seed extracts in scale up synthesis of aminopolyalkoxybenzenes - Beneficial synthons for fused nitrogen polyalkoxyheterocycles

Article abstract of DOI:10.1016/j.mencom.2016.01.026

Ecologically friendly transformation of readily accessible plant allylpolyalkoxybenzenes to hardly available aminotetraalkoxybenzenes has been developed. The efficacy of hydrogenation stage is substantially increased by the application of highly porous ceramic block Pd-catalysts featuring a large surface area, low hydraulic resistance, significant thermal and mechanical stabililty, multiple cycling and easy regeneration.

Full text of DOI:10.1016/j.mencom.2016.01.026

Mendeleev
Communications
Mendeleev Commun., 2016, 26, 66–68
Dill and parsley seed extracts in scale up synthesis
of aminopolyalkoxybenzenes – beneficial synthons
for fused nitrogen polyalkoxyheterocycles
Irina B. Karmanova,a Sergei I. Firgang,a Leonid D. Konyushkin,a Victor N. Khrustalev,b,c
Alexander V. Ignatov,d Leonid A. Kuznetsov,d Yuriy A. Pinchuk,a Ivan A. Kozlovd and Victor V. Semenov*a
a N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 119991 Moscow, Russian
Federation. Fax: +7 499 135 5328; e-mail: vs@zelinsky.ru
b Peoples’Friendship University of Russia, 117198 Moscow, Russian Federation
c A. N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences, 119991 Moscow,
Russian Federation
d ‘Russkii Katalizator’CJSC, 603004 Nizhnii Novgorod, Russian Federation
DOI: 10.1016/j.mencom.2016.01.026
Ecologically friendly transformation of readily accessible plant allylpolyalkoxybenzenes to hardly available aminotetraalkoxybenzenes
has been developed. The efficacy of hydrogenation stage is substantially increased by the application of highly porous ceramic block
Pd-catalysts featuring a large surface area, low hydraulic resistance, significant thermal and mechanical stabililty, multiple cycling and
easy regeneration.
OMe
OMe
Polyalkoxy-substituted heterocycles with multiple biological
activities are abundant in nature. Numerous natural cytostatics
(colchicine, combretastatins, steganacine, podophyllotoxin,
noscapine, shizandrins, some polyalkoxyflavanoids) and their
semisynthetic analogues that contain polymethoxybenzene frag-
ment are widely known as potent antimitotic and anticancer
agents.1–4 The pronounced antiproliferative effects of these mole-
cules is associated with inhibition of tubulin polymerization and
microtubule damage.
Nitrogen-containing polyalkoxy-substituted fused hetero-
cycles, both natural and synthetic, such as indoles,2 quinolones,3
acridones,4–6 furoquinolines,7 Cactaceae tetrahydroisoquinolines,8
etc., often exhibit significant cytotoxicity against human cancer
cells, providing a promising starting point in synthesis of bio-
logically active molecules. However, such N-heterocycles have
been poorly studied mostly due to the limited availability of the
souce material, namely, polyalkoxy-substituted aminobenzenes.
Such compounds with four and more alkoxy groups are quite
expensive and easily undergo oxidation during their synthesis
and/or storage.
R1
R2
R1
R2
Me
CH2
i
R3
R3
1a,b
2a,b (85–90%)
mixture of trans- (80–85%)
and cis-isomers (15–20%)
a R1 + R2 = OCH2O,
R3 = OMe; Apiol
b R1 = OMe, R2 + R3 = OCH2O;
ii
Dillapiol
OMe
OMe
R1
R2
CN
R1
R2
CHO
iii
R3
R3
4a,b (89–91%)
3a,b (60–80%)
iv
OMe
OMe
In the present study we have developed effective preparative
methods for the synthesis of diverse aminotetraalkoxybenzenes
from readily available plant allylpolyalkoxybenzenes apiol 1a
and dillapiol 1b. They can be easily isolated from Umbelliferae
plants essential oils by high-vacuum distillation. Liquid CO2
extraction technology developed by Karawan Ltd. (Krasnodar,
Russia, http://kuban-karawan.ru/) allows one to produce ~100 dm3
of the essential oils that contain 15–70% of alkoxybenzenes from
2500 kg of parsley and dill seeds.9 Natural allylbenzenes can be
considered as starting material in environmentally friendly and
selective syntheses in drug development. However, side reactions
in oxidizing medium, for instance, dimerization, Baeyer–Villiger
rearrangement, intra- and intermolecular condensations, present
a significant challenge to the selective polyalkoxybenzene trans-
formations.1(d) To overcome these difficulties, we have proposed
a combination of the specialized equipment and optimized
protocols.10 This technology allowed us to perform transforma-
tion of propenylbenzenes 2a,b to the aldehydes 3a,b in 60–85%
yields on a scale of 100 g (Scheme 1).
R1
R2
CO2Me
R1
R2
CO2H
v
R3
6a,b (90%)
R3
5a,b (85–90%)
Scheme 1 Reagents and conditions:10 i, KOH, 100°C, 40 min; ii, O3, CHCl3–
MeOH–pyridine (80:20:3 v/v), 15°C, 1–2 h; iii, I2–NH4OH (28%)–H2O,
room temperature, 16 h; iv, CO(NH2)2·H2O2, MeOH, reflux, 1.5 h; v, SOCl2,
MeOH, reflux, 3 h.
Propenylbenzenes 2a,b were prepared by heating 1a,b for
40 min in the presence of KOH on a water bath in 90–95% yield.
Ozonolysis of 2a,b was conducted using a custom-designed
apparatus with a maximal capacity of 10 g of O3 per hour from
O2. Polyalkoxybenzonitriles 4a,b were obtained in >90% yields
via oxidation of aldehydes with iodine I2 (molar ratio 1:1.1) in
aqueous NH4OH at room temperature as described recently.10,11
Polyalkoxybenzoic acids 5a,b were synthesized in high yields
© 2016 Mendeleev Communications. Published by ELSEVIER B.V.
on behalf of the N. D. Zelinsky Institute of Organic Chemistry of the
Russian Academy of Sciences.
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Mendeleev Commun., 2016, 26, 66–68
(80–90%) from aldehydes 3a,b using the urea–hydrogen peroxide
of carboxy arenes 5 resulted in decarboxylation affording a mix-
ture of nitroapiol2,17 12a and dinitroapiol 13a (Scheme 3). The
structure of compound 13a was unambigously established by
X-ray diffraction (see Online Supplementary Materials).
We further examined hydrogenation of nitroalkenes 7, 8, 13
to access the target aminopolyalkoxybenzenes. In case of com-
pounds 13, the process was complicated by side reactions.
Generally, aminobenzenes with several electron-donating sub-
stituents (NH2, OMe) were obtained by hydrogenation over
Raney nickel18 and tin dichloride reduction.19–21 However, these
products were readily oxidized in air and largely lost during
isolation. In addition, the formation of polyaminobenzene com-
plexes with tin and nickel salts also hindered their purification,
especially when tin salts were removed by hydrogen sulfide.21
Formation of diaminoapiol 14a upon reduction of 13a with
SnCl2 was accompanied by the loss of product due to its oxida-
tion and by appearance of impurities.22 Further studies showed
that polyamine synthesis proceeded efficiently by hydrogenation
of dinitroanilines in a custom-designed reactor using granulated
graphite Sibunit with 2–5% Pd as a catalyst placed into stainless
steel mesh boxes.23
complex in water.10 Synthesis of polyalkoxybenzoic acids methyl
esters 6a,b (85–95% yield) was reported earlier.10 The above
conditions made it possible both to avoid side reactions9,10,12 and
to access the key building blocks 4–6 for the synthesis of amino-
polyalkoxybenzenes in high yields on a 100 g scale.
In our hands, the nitration of the starting tetraalkoxyallyl-
benzenes 1a,b in different reaction media, including pure HNO3
as well as HNO3 mixture with H2SO4, AcOH, Ac2O, CHCl3,
yielded mixtures of different nitrobenzenes which were difficult to
separate.Thereplacementofallylfragmentintetraalkoxybenzenes
1a,b with electron-withdrawing group raised the tolerance to
oxidation.Thus, compounds3, 4, 6werenitratedtocorresponding
nitroaromatic nitriles 7, esters 8, and aldehydes 9 in solution of
98% HNO3 in CHCl3 (Scheme 2).†
OMe
OMe
OMe
R1
R2
X
R1
R2
X
O
O
OH
NO2
i
ii
NO2
R3
R3
OMe
Highly porous ceramic blocks (Figure 1) as catalytic systems
are currently under active development. Due to a wide choice
of construction, large surface area, low hydraulic resistance,
and significant thermal and mechanical stabililty highly porous
catalytic systems become more and more abundant.24 Block
catalysts with cellular structure are promising candidates for
application in different liquid-phase catalytic syntheses of a wide
range of organic compounds.25
3a,b, 4a,b, 6a,b
7a,b, 8a,b, 9a,b
10a
93%
75–97%
3, 9 X = CHO
4, 7 X = CN
6, 8 X = CO2Me
a R1 + R2 = OCH2O, R3 = OMe
b R1 = OMe, R2 + R3 = OCH2O
Scheme 2 Reagents and conditions: i, CHCl3–HNO3 (98%), 0°C, 30–60 min;
ii, NaBH4, PriOH–MeOH, 40°C, 2 h.
Our studies revealed that these catalysts markedly facilitated
hydrogenation of polyalkoxynitrobenzenes (Scheme 4).‡
As an example, aminopolyalkoxybenzens 14–16 were obtained
under mild conditions at room temperature and hydrogen pres-
sure of 30 atm during 3 h. The process required lesser amount
of the catalyst, namely, 1% Pd/6% g-Al2O3, as compared to the
typical 5% Pd/C. Moreover, the conventional hydrogenation of
Aldehyde moiety in 9a was selectively reduced with NaBH4
to afford nitrobenzyl alcohol 10a.
Apiol nitrobenzoic acid methyl ester 8a was prepared pre-
viously by nitration of the corresponding ester 6a in Ac2O solu-
tion using Cu(NO3)2·6H2O.13
Apiol nitrobenzaldehyde 9a was obtained in high yield by
nitration of the corresponding arene 3a with 62% HNO3 in
AcOH, although minor by-products nitroapiolacylal 11a and
nitroapiol 12a (~10%) were also formed. Benzaldehydes 3a,b
were transformed efficiently to corresponding nitrobenzalde-
hydes 9a,b in solution of 98% HNO3 in CHCl3 at 0°C within
30–40 min. On the other hand, the use of excess 70% HNO3 and
prolongation of the reaction time to 4 h gave directly dinitro deriva-
tives 13a,b. The synthesis of dinitroapiol 13a by nitration of
isoapiol 2a and apiolic acid 5a was described previously without
specifying the yield.14–16 Following these procedures, we failed
to prepare 13a in more than 15% yield. In our hands the nitration
1 mm
Figure 1 Typical highly porous cellular block catalyst manufactured by
company ‘Russkii Katalizator CJSC’, www.rus-cat.com, www.chemblock.com.
†
OMe
General procedure for the nitration of tetraalkoxybenzenes 3, 4, 6 to
OMe
R1
R2
CHO
NO2
R1
R2
NO2
NO2
mononitro derivatives 7–9. Nitric acid (98%, 4 ml, 96 mmol) was added
dropwise on stirring to the solution of aldehyde 3 (nitrile 4 or methyl
ester 6a,10 20 mmol) in dry CHCl3 (50 ml) at 0–5°C (ice bath). The
reaction mixture was stirred at 0–5°C for 30–60 min and diluted with
ice-water (100 g). The organic phase was separated and the water phase
was extracted with CHCl3 (2×40 ml). The combined extracts were
washed with water (40 ml), aqueous solution of NaHCO3 (10%, 40 ml),
again with water (40 ml), and evaporated in vacuo. The residue was
crystallized from MeOH to afford products 7–9. Yields 75–97%.
General procedure for the nitration of tetraalkoxybenzaldehydes 9a,b
to tetraalkoxydinitrobenzenes 13a,b. Nitric acid (72%, 190 ml, 3.1 mol)
was added dropwise on stirring within 2 h to the solution of aldehyde 3a
or 3b (40 g, 0.19 mol) in dry CHCl3 (180 ml) at 0–5°C. The mixture was
stirred for additional 3 h at 0–5°C, 5 h at room temperature, and diluted
with ice-water (400 g). The water phase wasextractedwithCHCl3 (2×100 ml),
the combined extracts were washed with water (100 ml), aqueous solution
of NaHCO3 (100 ml), and again with water (100 ml), dried (MgSO4) and
evaporated in vacuo. The residue was crystallized from EtOH to afford
13a or 13b. Yields 72–79%.
i
ii
3a,b
75–79%
75–80%
R3
R3
9a,b
13a,b
iii
< 15%
ref. 14
2a
5a
OMe
OMe
CH(OAc)2
O
O
O
O
+
a R1 + R2 = OCH2O,
R3 = OMe
NO2
NO2
b R1 = OMe,
OMe
OMe
11a
12a
R2 + R3 = OCH2O
Scheme 3 Reagents and conditions: i, CHCl3–HNO3 (98%), 0°C, 40 min,
ii, CHCl3–HNO3 (71–79%), room temperature, 5 h; iii, AcOH–Ac2O–HNO3
(62%), 30–40°C.
– 67 –

Mendeleev Commun., 2016, 26, 66–68
OMe
OMe
OMe
OMe NH2
(53% on 2 steps in one pot starting from 13a) than synthesized
CN
CN
O
O
O
O
O
O
by two stages (45% on 2 steps with separation). Diamine
dihydrochloride 14a·2HCl was transformed to 1,4-dihydro-
quinoxaline-2,3-dione 19a on reflux with oxalic acid in 2 n HCl.
In conclusion, dill and parsley seed extracts represent suitable
starting material for the large-scale synthesis of fused nitrogen
polyalkoxyheterocycles with strong antimitotic activity. The inter-
mediate polyalkoxyarenediamines can be considered as promising
synthons for the preparation of polymethoxy-substituted fused
heterocycles.
O
i or ii
+
NO2
NH2
NH2
OMe
OMe
7a
16a
81%
17a
impurity 10%
OMe
OMe
CO2Me
NO2
CO2Me
O
O
O
O
i
NH2
Online Supplementary Materials
Supplementary data associated with this article can be found
in the online version at doi:10.1016/j.mencom.2016.01.026.
OMe
OMe
8a
15a
85%
13a,b
i
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OMe
OMe
OMe
OMe
H
N
R1
R2
R1
R2
NH2
O
O
N
O
O
iii
iv
NH
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N
H
R3
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18a,b
53–72%
14a,b
63–75%
19a
76%
a R1 + R2 = OCH2O, R3 = OMe
b R1 = OMe, R2 + R3 = OCH2O
Scheme 4 Reagents and conditions: i, H2 (30 bar), block highly porous
ceramic catalyst (1% Pd/6% g-Al2O3), MeOH, room temperature, 3 h; ii, H2
(30 bar), granulated 5% Pd/C, MeOH, 40–45°C, 4.5 h; iii, HCOOH, reflux,
3 h; iv, (HO2C)2, 2 n HCl, reflux, 3 h.
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7a with 5% Pd/C brought about 10% of aminobenzamide 17a
as a by-product. This type of block catalysts can be repeatedly
regenerated by hydrogen directly in the reactor at 400°C up to
30–40 times without activity loss.
The reaction mixture could be quickly extracted from the
reactor without filtration devices. Diamines 14a,b were separated
as stable diaminobenzene hydrochlorides. Diamines 14a,b can
be condensed with HOOCH–CH(OEt)3 to afford benzimidazoles
18a,b directly in the course of hydrogenation in a stainless steel
reactor. Diamine 14b cannot be isolated and purified due to its
instability in air, but can be converted in situ to benzimidazole
18b in high yield (72% starting from 13b in one pot). Similarly,
18a was also obtained without separation of 14a in higher yield
15 G. Ciamician and P. Silber, Chem. Ber., 1890, 20, 35.
‡
Hydrogenation of polyalkoxynitrobenzenes 7a, 8a and 13a with block
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highly porous ceramic catalyst. The process employed block highly porous
cellular catalyst.25(b) Highly porous ceramic material (a-Al2O3) covered
by sol g-Al2O3 with pores no less than 70–95% was used as catalyst carrier,
readily permeable to air and water. This catalyst carrier was impregnated
with Pd(NO3)2 and heated at 450°C to provide PdO-coating, which was
hydrogenated to metallic Pd with hydrogen at 50–55°C, yielding the
target block highly porous ceramic catalyst with 1% Pd/6% g-Al2O3.
Block highly porous ceramic catalyst cylinder (1% Pd/6% g-Al2O3,
50 mm diameter, 50 mm height, 10 ppi cell, 33.9 g, 70–95% pores) was
fixed in the middle of stainless steel cylinder autoclave (50 mm inner
diameter) equipped with thermocouple, hydrogen inlet tube, and electric
heating system. The stirring of the reaction mixture was provided by
shaking device (capacity 120–160 min–1).
The solution of nitroarene 7a, 8a or 13a (20 mmol) in MeOH (200 ml)
was hydrogenated at room temperature for 3 h at hydrogen pressure of
30 bar. The reaction mixture was removed from autoclave, the solvent was
evaporated, and the residue was recrystallized from a proper solvent to
afford 15a (or 16a). In case of separation of 14a, HCl (36.5%, 7 ml) was
added immediately to autoclave, the reaction mixture was removed,
diluted with additional portion of HCl to pH 2, evaporated to dryness.
The residue was mixed with CH2Cl2 (120 ml) within 5–10 min, filtered,
washed with CH2Cl2 (100 ml), and dried in air to afford 14a·2HCl as
brown crystals.
24 (a)
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Received: 29th May 2015; Com. 15/4638
– 68 –