Synthesis of methaprogerol analogs

Article abstract of DOI:10.1007/s11172-012-0036-3

Novel synthetic approaches towards analogs of methaprogerol, the efficient wound healing drug, were developed. Several hitherto unknown compounds obtained exhibited in vivo activity similar to methaprogerol. 2-(3-Dimethylaminopropyl)- 5-methylhex-4-enoic acid enhanced the efficacy of the treatment of diseases of various etiologies and different organ injuries by transplantation of mesenchymal stem cells (MSC) and MSC-derived cardiomyoblasts.

Full text of DOI:10.1007/s11172-012-0036-3

Russian Chemical Bulletin, International Edition, Vol. 61, No. 2, pp. 253—258, February, 2012
253
Synthesis of methaprogerol analogs
G. V. Kryshtal,a G. M. Zhdankina,a A. G. Konoplyannikov,b V. A. Tartakovsky,a
E. P. Serebryakov,a B. B. Smirnov,a O. A. Konoplyannikova,b E. V. Agaeva,b and S. G. Zlotina
aN. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences,
47 Leninsky prosp., 119991 Moscow, Russian Federation.
Fax: +7 (499) 135 5328. Eꢀmail: zlotin@ioc.ac.ru
bMedical Radiological Scientific Centrе, Ministry of Health and Social Development of the Russian Federation,
4 ul. Koroleva, 249036 Obninsk, Kaluga Region, Russian Federation.
Eꢀmail: konopl@mrrc.obninsk.ru
Novel synthetic approaches towards analogs of methaprogerol, the efficient wound healing
drug, were developed. Several hitherto unknown compounds obtained exhibited in vivo activity
similar to methaprogerol. 2ꢀ(3ꢀDimethylaminopropyl)ꢀ5ꢀmethylhexꢀ4ꢀenoic acid enhanced
the efficacy of the treatment of diseases of various etiologies and different organ injuries by
transplantation of mesenchymal stem cells (MSC) and MSCꢀderived cardiomyoblasts.
Key words: malonic ester, alkylation, the Michael addition, the Leuckart—Wallach reacꢀ
tion, methaprogerol, wound healing activity, cardiomyoblasts.
Methaprogerol,1—3 an efficient drug used for the treatꢀ
ment of myocardial infarction, belongs to (dialkylaminoꢀ
alkyl)(terpenyl)acetic acids of general formulae 1.
metal in refluxing toluene resulted in the corresponding
N,Nꢀdimethylaminoalkyl derivatives 6—8. The synthesis
was completed by hydrolysis (KOH, EtOH) and subseꢀ
quent decarboxylation of dicarboxylic acids 9—11 to give the
target amino acids 12—14. The total yields of compounds
12—14 based on diethyl malonates were 31, 15, and 20%,
respectively. It should be noted that the total yield of
methaprogerol obtained by similar procedure was ~5%.
1: n = 1, 2; m = 2—6; R = Me, Et, Prn
Methaprogerol: n = 1, m = 3, R = Me
Scheme 1
The patented procedure1,2 towards compounds of the
type 1 is based on the reaction sequence which involves
alkylation terpenyl malonate or dialkylaminoalkyl malꢀ
onate with the corresponding alkyl halides on treatment
with sodium metal in refluxing toluene followed by saponꢀ
ification of the resulting disubstituted malonic esters and
decarboxylation.
The aim of the present work was the synthesis of
hitherto unknown methaprogerol analogs with potent anꢀ
tibacterial and wound healing activities. For the synthesis
of compounds of the type 1 bearing shorter hydrocarbon
(isopentyl and prenyl groups) and dialkylaminoethyl (e.g.,
dimethylaminoethyl group) moieties, strategy similar to
one described earlier1,2 involving two subsequent alkylaꢀ
tion reactions as the key steps was employed (Scheme 1).
Alkylation of malonic ester with isoamyl bromide (2) or
prenyl bromide (3) in the presence of EtONa on heating
in EtOH for 3—4 h afforded diesters 4 and 5. Further
alkylation of the latter with dimethylaminopropyl chloride
or dimethylaminoethyl chloride on treatment with sodium
n = 3, R = Me2CHCH2CH2 (2, 4, 6, 9, 12), R = Me2C=CHCH2
(3, 5, 7, 10, 13); n = 2, R = Me2C=CHCH2 (8, 11, 14)
Reagents and conditions: i. CH2(COOEt)2, EtONa, EtOH, reꢀ
flux, 3—4 h; ii. Cl(CH2)nNMe2, Na, toluene, reflux, 3—4 h;
iii. KOH, EtOH, reflux, 0.5—2 h; iv. 140—150 C, 2—3 h.
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 2, pp. 253—258, February, 2012.
1066ꢀ5285/12/6102ꢀ253 © 2012 Springer Science+Business Media, Inc.

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Kryshtal et al.
Scheme 2
Reagents and conditions: i. CH2(COOEt)2, Na2CO3, BTEAꢀCl, MePh, 40—45 C, 12 h; ii. HNMe2, HCOOH, 50—90 C, 5 h;
iii. 3, Na, toluene, reflux, 4 h; iv. KOH, EtOH, reflux, 3 h; v. 140—150 C, 2—3 h.
No increase in the yields of compounds 4 and 5 was
observed when the alkylation of malonic ester with isoamyl
bromide (2) or prenyl bromide (3) was carried out in the
K2CO3—ionic liquid mixture.4
Scheme 3
R = H (21, 22, 23); R = Me (15, 16, 24); R = H, n = 0 (25); R = Me, n = 0 (26); R = Me, n = 1 (27); R = H, Alk = Et, n = 0 (28, 31, 34);
R = H, Alk = Pri, n = 0 (29, 32, 35); R = Alk = Me, n = 1 (30, 33, 36)
Reagents and conditions: i. CH2(COOEt)2, Na2CO3, BTEAꢀCl, MePh, 40—45 C, 12 h; ii. HC(OMe)3, MeOH, HClO4 (cat.),
35—45 C, 0.5 h; iii. Me2C=CH(CH2CH2C(Me)=CH)nCH2Hal, Na, toluene, reflux, 4 h; iv. HNMe2, HCOOH, 50—90 C,
5 h; v. KOH, EtOH, reflux, 3 h; vi. 140—150 C, 2—3 h.

Methaprogerol analogs
Russ.Chem.Bull., Int.Ed., Vol. 61, No. 2, February, 2012
255
This approach cannot be used for the synthesis of methaꢀ
progerol analogs bearing branched alkylamino groups due
to low reactivity of the corresponding aminoalkyl halides.
In order to overcome this problem, we developed novel
scheme involving the sequence of the Michael addition
and the Leuckart—Wallach reaction (Scheme 2). The first
step of the synthesis was addition of malonic ester to
crotonaldehyde (15) in the presence of base (Na2CO3)
and phaseꢀtransfer catalyst (BTEAꢀCl).5 The resulting
diethyl 2ꢀ(4ꢀoxobutꢀ2ꢀyl)malonate (16) was subjected
to the Leuckart—Wallach reaction in the presence of
HNMe2—HCOOH. The resulting diethyl 2ꢀ(4ꢀdimethylꢀ
aminobutꢀ2ꢀyl)malonate (17) was then alkylated with preꢀ
nyl bromide (3). Hydrolysis of disubstituted malonic ester
18 afforded diacid 19, whose decaboxylation gave the tarꢀ
get 5ꢀmethylꢀ2ꢀ(4ꢀdimethylaminobutꢀ2ꢀyl)hexꢀ4ꢀenoic
acid (20). Yield of compound 20 based on diethyl malꢀ
onate and crotonaldehyde (15) was 13%.
Under described conditions, no reaction between gerꢀ
anyl chloride and compound 17 with the CHꢀacidic cenꢀ
ter bonded to the tertiary C atom occurred. This problem
was circumvented by changing the order of the key steps,
viz., the reductive amination and alkylation (Scheme 3).
Aldehydes 15 and 21 were used as the starting compounds.
To avoid side reactions, the aldehyde groups of oxo esters
16 and 22 sensitive to bases were transformed into acetal
moieties. Reaction of the resulting compounds 23 and 24
with prenyl bromide or geranyl bromide (Na—toluene)
resulted in the corresponding substituted malonates 25—27.
Under Leuckart—Wallach conditions, both the removal
of the acetal protection and reductive amination of the
aldehyde group took place; as a result, compounds 28—30
were accessed. Hydrolysis and subsequent decarboxylaꢀ
tion of diacids 31—33 completed the synthesis of methaꢀ
progerol analogs 34—36. The total yields on compounds
34—36 based on aldehydes 15 and 21 were 17, 23, and
11%, respectively.
2ꢀ(3ꢀdimethylaminopropyl)ꢀ5ꢀmethylhexꢀ4ꢀenoic acid (13)
turned to be promising as tracking drug for cell therapy
of various human diseases and injuries and the artificialꢀ
ly induced injuries of vital organs and tissues of the laboꢀ
ratory animals with mesenchymal stem cell (MSC) and
MSCꢀderived cardiomyoblasts.6 Thus, systemic transꢀ
plantation of MSCꢀderived cardiomyoblasts together
with additional administration of compound 13 in rats
with adriamycinꢀinduced serious cardiomyopathy resultꢀ
ed in significant increase in the content of proliferating
cells in the animal myocardium. This fact strongly sugꢀ
gested6 the enhanced regeneration of the injured myoꢀ
cardium (Table 1).
Experimental
1
H and 13C NMR spectra were run on a Bruker AMꢀ300
instrument (300.13 MHz (1H), 75.47 MHz (13C)) in CDCl3.
The chemical shifts are given in the  scale relative to Me4Si.
Elemental analysis were performed on a Perkin—Elmer 2400
analyzer. The course of the reaction was monitored by TLC on
Silufol plates (elution with 5% ethyl acetate in toluene, visualꢀ
ization by UV irradiation and iodine vapors). The compounds
synthesized were purified by column chromatography on silica gel
(Acros, 0.060—0.200 mm). Acrolein, crotonaldehyde, malonic
ester, isoamyl bromide, prenyl bromide, geranyl bromide,
Cl(CH2)2NMe2•HCl, Cl(CH2)3NMe2•HCl, HNMe2•HCl,
HNEt2, HNPri2, HC(OMe)3, catalysts BTEAꢀCl and HClO4
(all from Acros) were used as purchased.
Compounds 4 and 5 were synthesized by the known proceꢀ
dure modified as follows.7 To a solution of EtONa in EtOH
(prepared from Na (0.58 g, 0.025 mol) and anhydrous EtOH
(25 mL)), diethyl malonate (0.025 mol) was added dropwise
following by dropwise addition of alkylating halide 2 or 3
(0.025 mol) with the rate maintaining gentle boiling. The reacꢀ
tion mixture was refluxed for 3—4 h. The excess EtOH was
removed under reduced pressure (40 Torr, 40 C), the residue
was diluted with water (~30 mL), the organic phase was separatꢀ
ed, and the aqueous layer was extracted with diethyl ether
(2×10 mL). The combined organic layers were washed with waꢀ
ter (3×20 mL), dried with MgSO4, concentrated under reduced
pressure (40 Torr, 40 C), distillation of the residue afforded
pure product.
It should be noted that amino acids 12—14, 20, 34—36
and intermediates 6, 7, 24, 28—30 used for their syntheses
were not previously documented.
In the experiments on animals, amino acids 12—14,
20, and 34—36 exhibited wound healing activity similar to
methaprogerol (1, n = 1, m = 3, R = Me).6 Moreover,
Diethyl (3ꢀmethylbutyl)malonate (4). Yield 82%, colorless oil,
20
b.p. 125—127 C (10 Torr); nD 1.4215 (cf. Ref. 8: b.p. 133 C
20
(15 Torr); nD 1.4240). 1H NMR (CDCl3), : 0.82 (d, 6 H,
Table 1. Treatment of rat cardiomyopathy with MSCꢀderived cardiomyoblasts, 2ꢀ(3ꢀdimethylaminopropyl)ꢀ5ꢀmethylhexꢀ4ꢀenoic
acid (13), and stem cells together with acid 13
Parameters, 4 weeks after
Control
AD
AD + K
AD + 13
AD + K + 13
Heart weight/mg
870 45
3.42 0.13
795 20
740 41
8.84 0.24
664 18
862 59
9.75 0.20
757 30
808 34
8.96 0.12
686 28
894 45
9.58 0.18
767 21
PCNA of stroma cells (%)
Average area of cardiomyocyte cut/m2
PCNA of cardiomyocytes (%)
0.97 0.04
2.11 0.09
3.68 0.14
3.01 0.09
3.77 0.09
Note. AD is adriamycin used for cardiomyopathy modeling; PCNA (proliferating cell nuclear antigen) index correlates with the
fraction of proliferating cells; K is transplantation of MSCꢀderived cardiomyoblasts.

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Kryshtal et al.
CH3, J = 6.0 Hz); 1.10—1.25 (m, 2 H, CH2); 1.20 (t, 6 H, CH3,
J = 7.0 Hz); 1.50 (m, 1 H, CH); 1.76 (m, 2 H, CH2); 3.35 (t, 1 H,
CH, J = 7.5 Hz); 4.16 (q, 4 H, CH2, J = 7.0 Hz).
water (20 mL), and neutral impurities were removed by extracꢀ
tion with diethyl ether (2×5 mL). The water layer was cooled
and acidified with diluted HCl (1 : 1) until pH was ~5. Products
9—11, 19, and 31—33 were filtered, successfully washed with
water (3×5 mL), and dried on air until constant weight.
These compounds were used on the next step without further
purification.
Compounds 12—14, 20, and 34—36 (general procedure). Dry
diacid 9—11, 19, or 31—33 was heated in the Claisen flask at
140—150 C (oil bath) until evaluation of CO2 ceased (2—3 h).
The products thus obtained were purified by vacuum distillation
or column chromatography (SiO2, elution with CHCl3, 5%
MeOH in CHCl3, and 20% MeOH in CHCl3).
Diethyl (3ꢀmethylbutꢀ2ꢀenyl)malonate (5). Yield 52%, colorꢀ
less oil, b.p. 120—122 C (10 Torr); nD20 1.4412 (cf. Ref. 9: b.p.
125—126 C (11 Torr); nD20 1.4417). 1H NMR (CDCl3), : 1.22
(t, 6 H, CH3, J = 7.0 Hz); 1.58 (s, 3 H, CH3); 1.64 (s, 3 H, CH3);
2.55 (d, 2 H, CH2, J = 7.5 Hz); 3.26 (t, 1 H, CH, J = 7.5 Hz);
4.14 (q, 4 H, CH2, J = 7.0 Hz); 5.02 (t, 1 H, CH=, J = 7.5 Hz).
1H NMR spectrum is in agreement with the published data.10
Compounds 6—8, 18, and 25—27 (general procedure). To
a boiling suspension of Na (0.5 g, 0.022 mol) in toluene (6 mL),
substituted malonic ester 4, 5, 17, 23, or 24 (0.022 mol) was
added dropwise with stirring followed by dropwise addition of
a solution of the corresponding alkylating halide (0.022 mol) in
toluene (3 mL) with the rate maintaining moderate boiling. The
reaction mixture was refluxed for 3—4 h. After completion of the
reaction, the reaction mixture was cooled down, diluted with
water (~30 mL), the organic phase was separated, and the aqueꢀ
ous layer was extracted with diethyl ether (2×10 mL). The comꢀ
bined organic layers were washed with water (3×20 mL), dried
with MgSO4, and the solvent was removed under reduced presꢀ
sure (40 Torr, 40 C). In the case of compounds 6—8, the residue
was distilled to give pure products; compounds 18 and 25—27
were used on the next step without further purification.
2ꢀ(3ꢀDimethylaminopropyl)ꢀ5ꢀmethylhexanoic acid (12).
Yield 57% (in two steps); colorless oil, b.p. 150 C (0.8 Torr),
1
crystallized on standing, m.p. 55—56 C. H NMR (CDCl3), :
0.85 (d, 6 H, CH3, J = 6.0 Hz); 1.15—1.70 (m, 10 H, CH2); 2.15
(m, 1 H, CH); 2.50 (s, 6 H, CH3); 2.75 (m, 1 H, CH); 11.80
(br.s, 1 H, COOH). 13C NMR, : 22.6 (Me2CH); 24.1 (CH2);
28.1 (CH2); 30.5 (CH2); 31.0 (CH); 37.0 (CH2); 43.1 (Me2N);
47.7 (CH—COOH); 58.2 (CH2N); 180.8 (C=O). Found (%):
C, 66.88; H, 11.73; N, 6.57. C12H25NO2. Calculated (%):
C, 66.93; H, 11.70; N, 6.50.
2ꢀ(3ꢀDimethylaminopropyl)ꢀ5ꢀmethylhexꢀ4ꢀenoic acid (13).
Yield 65% (in two steps); colorless oil, b.p. 160 C (0.8 Torr),
20
1
Diethyl 2ꢀ(3ꢀdimethylaminopropyl)ꢀ2ꢀ(3ꢀmethylbutyl)malonꢀ
ate (6). Yield 74%. Colorless oil, b.p. 115—120 C (0.5 Torr);
nD20 1.4420. 1H NMR (CDCl3), : 0.83 (d, 6 H, CH3, J = 6.0 Hz);
0.95—1.05 (m, 2 H, CH2); 1.20 (t, 6 H, CH3, J = 7.0 Hz); 1.30
(m, 2 H, CH2); 1.50 (m, 1 H, CH); 1.80—1.90 (m, 4 H, CH2);
2.17 (s, 6 H, CH3); 2.20 (m, 2 H, CH2); 4.15 (q, 4 H, CH2,
J = 7.0 Hz). 13C NMR, : 13.9 (MeCH2); 22.3 (Me2CH); 23.8
(CH2); 26.1 (CH2); 26.6 (CH2); 30.5 (CH2); 34.8 (CH); 42.5
(Me2N); 57.3 (>C<); 58.9 (CH2N); 59.8 (OCH2); 171.7 (C=O).
Found (%): C, 64.68; H, 10.50; N, 4.39. C17H33NO4. Calcuꢀ
lated (%): C, 64.73; H, 10.54; N, 4.44.
nD 1.4840. H NMR (CDCl3), : 1.21—1.50 (m, 4 H, CH2);
1.50 (s, 3 H, CH3); 1.61 (s, 3 H, CH3); 1.91—2.20 (m, 4 H,
CH2); 2.35 (s, 6 H, CH3); 2.65 (m, 1 H, CH); 5.02 (m, 1 H,
CH=); 14.20 (br.s, 1 H, COOH). 13C NMR, : 17.8 and 25.7
(Me2C=); 26.0 (CH2); 29.7 (CH2); 31.4 (CH2); 42.7 (Me2N);
45.4 (CH); 58.3 (CH2N); 121.8 (CH=); 133.4 (Me2C=); 179.8
(C=O). Found (%): C, 67.60; H, 10.83; N, 6.51. C12H23NO2.
Calculated (%): C, 67.57; H, 10.87; N, 6.57.
2ꢀ(2ꢀDimethylaminoethyl)ꢀ5ꢀmethylhexꢀ4ꢀenoic acid (14).
Yield 49% (in two steps); colorless oil. b.p. 145—150 C (0.8 Torr),
1
crystallized on standing, m.p. 61—62 C. H NMR (CDCl3), :
Diethyl 2ꢀ(3ꢀdimethylaminopropyl)ꢀ2ꢀ(3ꢀmethylbutꢀ2ꢀenyl)ꢀ
malonate (7). Yield 63%. Yellowish oil, b.p. 130—132 C
(0.8 Torr); nD20 1.4555. 1H NMR (CDCl3), : 1.20 (t, 6 H, CH3,
J = 7.0 Hz); 1.30 (m, 2 H, CH2); 1.55 (s, 3 H, CH3); 1.62 (s, 3 H,
CH3); 1.8 (m, 2 H, CH2); 2.15 (s, 6 H, CH3); 2.20 (m, 2 H,
CH2); 2.55 (d, 2 H, CH2, J = 7.5 Hz); 4.12 (q, 4 H, CH2, J = 7.0 Hz);
4.95 (t, 1 H, CH=, J = 7.5 Hz). 13C NMR, : 14.1 (MeCH2);
17.9 and 22.4 (Me2C=); 26.0 (CH2); 30.0 (CH2): 31.2 (CH2);
45.4 (Me2N); 57.5 (>C<); 59.9 (CH2N); 61.0 (OCH2), 117.9
(CH=); 135.1 (Me2C=); 171.6 (C=O). Found (%): C, 65.08;
H, 9.93; N, 4.51. C17H31NO4. Calculated (%): C, 65.14; H, 9.97;
N, 4.47.
Diethyl 2ꢀ(2ꢀdimethylaminoethyl)ꢀ2ꢀ(3ꢀmethylbutꢀ2ꢀenyl)ꢀ
malonate (8). Yield 65%. Yellowish oil, b.p. 120—122 C (0.7 Torr)
(cf. Ref. 11: b.p. 115—117 C (0.2 Torr)); nD20 1.4540. 1H NMR
(CDCl3), : 1.17 (t, 6 H, CH3, J = 7.0 Hz); 1.10—1.20 (m, 2 H,
CH2); 1.55 (s, 3 H, CH3); 1.60 (s, 3 H, CH3); 2.00 (m, 2 H,
CH2); 2.10 (s, 6 H, CH3); 2.55 (d, 2 H, CH2, J = 7.5 Hz); 4.10
(q, 4 H, CH2, J = 7.0 Hz); 4.90 (t, 1, CH=, J = 7.5 Hz).
Compounds 9—11, 19, and 31—33 (general procedure). To
a solution of KOH (6 g, 0.11 mol) in EtOH (9 mL), substituted
malonate 6—8, 18, or 28—30 (0.02 mol) was added in one porꢀ
tion (strong foaming) and the mixture was refluxed for 0.5—2 h
with stirring. The reaction mixture was concentrated under reꢀ
duced pressure (40 Torr, 40 C), the residue was diluted with
1.50 (s, 3 H, CH3); 1.55 (s, 3 H, CH3); 1.65—1.75 (m, 2 H,
CH2); 2.00—2.20 (m, 3 H, CH2, CH); 2.42 (s, 6 H, CH3); 2.65
(m, 2 H, CH2); 5.02 (m, 1 H, CH=); 13.70 (br.s, 1 H, COOH).
13C NMR, : 17.8 and 25.7 (Me2C=); 26.0 (CH2); 31.1 (CH2);
42.6 (Me2N); 45.3 (CH); 56.3 (CH2N); 121.8 (CH=); 133.1
(Me2C=); 179.2 (C=O). Found (%): C, 66.34; H, 10.57;
N, 6.98. C11H21NO2. Calculated (%): C, 66.29; H, 10.62; N, 7.03.
2ꢀ(4ꢀDimethylaminobutꢀ2ꢀyl)ꢀ5ꢀmethylhexꢀ4ꢀenoic acid (20),
a mixture of diastereomers in the ratio 1 : 1. Yield 56% (in two
steps); colorless oil; nD 1.4810. 1H NMR (CDCl3), : 0.95
20
(d, 3 H, CH3, J = 6.0 Hz); 1.50 (s, 3 H, CH3); 1.60 (s, 3 H, CH3);
1.91—2.22 (m, 6 H, CH2); 2.35 (s, 6 H, CH3); 2.51 (m, 2 H,
CH); 5.02 (m, 1 H, CH=); 14.95 (br.s, 1 H, COOH). 13C NMR,
: 17.1 (MeCH); 17.9 и 25.3 (Me2C=); 23.5 (CH2); 27.0 (CH2);
33.6 (CH); 42.7 (Me2N); 51.0 (CH—COOH); 56.1 (CH2N);
125.9 (CH=); 133.2 (Me2C=); 179.5 (C=O). Found (%): C, 68.41;
H, 11.03; N, 6.21. C13H25NO2. Calculated (%): C, 68.68;
H, 11.08; N, 6.16.
2ꢀ(3ꢀDiethylaminopropyl)ꢀ5ꢀmethylhexꢀ4ꢀenoic acid (34).
Yield 62% (in two steps); colorless oil, b.p. 160 C (0.8 Torr),
1
crystallized on standing, m.p. 72—73 C. H NMR (CDCl3), :
1.02 (t, 6 H, CH3, J = 7.0 Hz); 1.45 (s, 3 H, CH3); 1.52 (s, 3 H,
CH3); 1.91—2.20 (m, 4 H, CH2); 2.50—2.72 (m, 5 H, CH2,
CH); 2.81 (q, 4 H, CH2, J = 7.0 Hz); 5.01 (m, 1 H, CH=); 15.2
(br.s, 1 H, COOH). 13C NMR, : 8.1 (MeCH2); 17.8 and 25.8

Methaprogerol analogs
Russ.Chem.Bull., Int.Ed., Vol. 61, No. 2, February, 2012
257
(Me2C=); 22.7 (CH2); 29.5 (CH2); 31.8 (CH2); 44.8 (CH); 47.7
(CH2N); 52.0 (CH2N); 122.6 (CH=); 132.5 (Me2C=); 180.7
(C=O). Found (%): C, 69.60; H, 11.31; N, 5.85. C14H27NO2.
Calculated (%): C, 69.66; H, 11.27; N, 5.80.
4.45 (t, 1 H, CH, J = 6.0 Hz). Found (%): C, 56.45; H, 8.83.
C
13H24O6. Calculated (%): C, 56.51; H, 8.75.
Compounds 17 and 28—30 (general procedure). To HNAlk2
(0.03 mol) cooled approximately to –50 C, HCOOH (4.5 mL,
0.12 mol) was slowly added by drops with stirring, the temperaꢀ
ture of the reaction mixture was maintained at about –50 C.
Then the mixture was slowly heated to 50—60 C, and comꢀ
pound 16, 23 or 24 (0.015 mol) was added dropwise with stirring.
The stirring was continued until evaluation of CO2 ceased (~4—5 h)
gradually raising the reaction temperature to 100 C. The reacꢀ
tion mixture was acidified at cooling with diluted HCl (1 : 1), the
neutral impurities were removed by extraction with diethyl ether
(3×20 mL). To the aqueous layer, anhydrous K2CO3 was added
until saturated solution formed, the products were extracted with
diethyl ether (3×50 mL), the combined organic layers were dried
with MgSO4, the solvent was removed under reduced pressure
(40 Torr, 40 C), distillation of the residue afforded pure prodꢀ
uct.
2ꢀ(3ꢀDiisopropylaminopropyl)ꢀ5ꢀmethylhexꢀ4ꢀenoic acid (35).
Yield 72% (in two steps), colorless oil, b.p. 160—162 C
(0.5 Torr); nD 1.4870. 1H NMR (CDCl3), : 1.10 (d, 12 H,
20
CH3, J = 7.0 Hz); 1.32 (m, 2 H, CH2); 1.45 (s, 3 H, CH3); 1.51
(s, 3 H, CH3); 1.60 (m, 2 H, CH2); 2.02 (m, 1 H, CH); 2.10
(m, 2 H, CH2); 2.60 (m, 2 H, CH2); 3.30 (m, 2 H, CH); 5.02
(m, 1 H, CH=); 12.70 (br.s, 1 H, COOH). 13C NMR, : 17.8
and 25.8 (Me2C=); 18.4 (Me2CH); 18.5 (Me2CH); 25.6, (CH2);
30.1 (CH2); 32.0 (CH2); 47.1 (CH); 47.7 (CHN); 51.8 (CH2N);
123.3 (CH=); 131.7 (Me2C=); 180.2 (C=O). Found (%): C, 71.40;
H, 11.64; N, 5.27. C16H31NO2. Calculated (%): C, 71.33;
H, 11.60; N, 5.20.
2ꢀ(4ꢀDimethylaminobutꢀ2ꢀyl)ꢀ5,9ꢀdimethyldecaꢀ4,8ꢀdienoic
acid (36), a 1 : 1 mixture of diastereomers. Yield 14% (in four
20
steps), yellowish oil, b.p. 175—177 C (0.4 Torr), nD 1.4910.
Diethyl 2ꢀ(4ꢀdimethylaminobutꢀ2ꢀyl)malonate (17). Yield
20
1H NMR (CDCl3), : 0.95 (d, 3 H, CH3, J = 6.0 Hz); 1.52 (s, 3 H,
CH3); 1.60 (s, 6 H, CH3); 1.90—2.20 (m, 10 H, CH2); 2.39
(s, 6 H, CH3); 2.62 (m, 2 H, CH); 5.05 (m, 2 H, CH=); 13.6 (br.s,
1 H, COOH). 13C NMR, : 15.2 (CH3); 15.7 (CH3); 17.3 and
25.3 (Me2C=); 26.3 (CH2); 27.3 (CH); 30.6 (CH2); 32.9 (CH2);
39.5 (CH2); 42.8 (Me2N); 51.0 (CH—COOH); 56.6 (CH2N);
122.8 (CH=); 124.0 (CH=); 130.7 (Me2C=); 135.4 (MeCH=);
178.0 (C=O). Found (%): C, 73.14; H, 11.30; N, 4.80. C18H33NO2.
Calculated (%): C, 73.17; H, 11.26; N, 4.74.
74%, yellowish oil, b.p. 105—107 C (0.5 Torr); nD 1.4390
1
(cf. Ref. 14: b.p 120—122 C (14 Torr)). H NMR (CDCl3), :
0.98 (d, 3 H, CH3, J = 6.0 Hz); 1.22 (t, 6 H, CH3, J = 7.0 Hz);
1.33 and 1.62 (both m, 1 H each, CH2); 2.18 (s, 6 H, CH3); 2.25
(m, 3 H, CH2, CH); 3.22 (d, 1 H, CH, J = 6.0 Hz); 4.16 (q, 4 H,
CH2, J = 7.0 Hz).
Diethyl 2ꢀ(3ꢀdiethylaminopropyl)ꢀ2ꢀ(3ꢀmethylbutꢀ2ꢀenyl)ꢀ
malonate (28). Yield 73%, yellowish oil, b.p. 118—120 C
(0.5 Torr); nD20 1.4620. 1H NMR (CDCl3), : 0.95 (t, 6 H, CH3,
J = 6.0 Hz); 1.22 (t, 6 H, CH3, J = 7.0 Hz); 1.30 (m, 2 H, CH2);
1.57 (s, 3 H, CH3); 1.65 (s, 3 H, CH3); 1.80 (m, 2 H, CH2);
2.32—2.50 (m, 6 H, CH2); 2.57 (m, 2 H, CH2); 4.12 (q, 4 H,
CH2, J = 7.0 Hz); 4.92 (m, 1 H, CH=). 13C NMR, : 8.7
(MeCH2N); 13.7 (MeCH2); 17.7 and 24.8 (Me2C=); 26.1 (CH2);
30.2 (CH2); 31.6 (CH2); 46.7 (CH2N); 52.9 (CH2N); 57.7 (>C<);
61.0 (OCH2); 125.7 (CH=); 133.2 (Me2C=); 180.1 (C=O).
Found (%): C, 66.87; H, 10.38; N, 4.17. C19H35NO4. Calculatꢀ
ed (%): C, 66.83; H, 10.33; N, 4.10.
Diethyl 2ꢀ(3ꢀoxopropyl)malonate (16) was synthesized by the
known procedure.5 Yield 47%, colorless oil, b.p. 105—107 C
20
(0.7 Torr); nD 1.4370 (cf. Ref. 5: b.p. 103—104 C (0.5 Torr);
nD20 1.4382). 1H NMR (CDCl3), : 0.96 (d, 3 H, CH3, J = 6.0 Hz);
1.28 (t, 6 H, CH3, J = 7.0 Hz); 2.16—2.80 (m, 3 H, CH2, CH);
3.20 (d, 1 H, CH, J = 6.0 Hz); 4.06 (q, 4 H, CH2, J = 7.0 Hz);
9.52 (s, 1 H, CHO).
Diethyl 2ꢀ(4ꢀoxobutꢀ2ꢀyl)malonate (22) was synthesized by
the known procedure.5 Yield 62%, colorless oil, b.p. 95—97 C
20
(0.4 Torr); nD 1.4375 (cf. Ref. 12: b.p. 125—130 C (5 Torr);
Diethyl 2ꢀ(3ꢀdiisopropylaminopropyl)ꢀ2ꢀ(3ꢀmethylbutꢀ2ꢀ
enyl)malonate (29). Yield 85%, yellowish oil, b.p. 120—125 C
nD20 1.4391). 1H NMR (CDCl3), : 1.20 (t, 6 H, CH3, J = 7.0 Hz);
2.12 (m, 2 H, CH2); 2.54 (m, 2 H, CH2); 3.30 (t, 1 H, CH,
J = 6.0 Hz); 4.16 (q, 4 H, CH2, J = 7.0 Hz); 9.5 (s, 1 H, CHO).
Compounds 23 and 24 (general procedure). To a stirred mixꢀ
ture of aldehyde 16 or 22 (0.02 mol) and CH(OMe)3 (0.022 mol)
in MeOH (5 mL), catalytic amount of 70% HClO4 (1 drop) was
added and the stirring was continued for 0.5 h maintaining the
reaction temperature below 35—40 C (cooling with cold water
if necessary). Then the reaction mixture was cooled to ambient
temperature, kept for 0.5 h, neutralized with 5% NaOH in
MeOH, and distilled under reduced pressure.
(0.5 Torr); nD 1.4580. 1H NMR (CDCl3), : 0.95 (d, 12 H,
20
CH3, J = 6.0 Hz); 1.20 (m, 8 H, CH3, CH2); 1.60 (s, 3 H, CH3);
1.65 (s, 3 H, CH3); 1.80 (m, 2 H, CH2); 2.35 (m, 2 H, CH2);
2.57 (m, 2 H, CH2); 2.95 (m, 2 H, CH); 4.12 (q, 4 H, CH2,
J = 7.0 Hz); 4.91 (m, 1 H, CH=). 13C NMR, : 17.8 and 22.3
(Me2C=); 18.6 (Me2CH); 18.7 (Me2CH); 25.6 (CH2); 30.4
(CH2); 31.2 (CH2); 47.7 (CHN) 52.1 (CH2N); 57.5 (>C<); 61.2
(OCH2); 121.8 (CH=); 133.7 (Me2C=); 179.8 (C=O). Found (%):
C, 68.27; H, 10.68; N, 3.75. C21H39NO4. Calculated (%):
C, 68.25; H, 10.64; N, 3.79.
Diethyl 2ꢀ(3,3ꢀdimethoxypropyl)malonate (23). Yield 87%,
colorless oil, b.p. 98—100 C (0.4 Torr); nD20 1.4325. 1H NMR
(CDCl3), : 1.20 (t, 6 H, CH3, J = 7.0 Hz); 1.60 (m, 2 H, CH2);
1.91 (m, 2 H, CH2); 3.25 (s, 6 H, CH3); 3.30 (t, 1 H, CH,
J = 6.0 Hz); 4.15 (q, 4 H, CH2, J = 7.0 Hz); 4.35 (t, 1 H, CH,
J = 6.0 Hz). 1H NMR spectrum is in agreement with the pubꢀ
lished data.13
Diethyl 2ꢀ(4,4ꢀdimethoxybutꢀ2ꢀyl)malonate (24). Yield 85%,
colorless oil, b.p. 95—100 C (0.3 Torr); nD20 1.4370. 1H NMR
(CDCl3), : 1.05 (d, 6 H, CH3, J = 7.0 Hz); 1.22 (t, 6 H, CH3,
J = 7.0 Hz); 1.50—1.80 (m, 2 H, CH2); 2.45 (m, 1 H, CH); 3.30
(s, 6 H, CH3); 3.30 (m, 1 H, CH); 4.15 (q, 4 H, CH2, J = 7.0 Hz);
Diethyl 2ꢀ(4ꢀdimethylaminobutꢀ2ꢀyl)ꢀ2ꢀ(3,7ꢀdimethyloctaꢀ
2,6ꢀdienyl)malonate (30). Yield 77%, yellowish oil, b.p. 151—154 C
(0.2 Torr); nD 1.4652. 1H NMR (CDCl3), : 0.97 (d, 3 H,
20
CH3, J = 6.0 Hz); 1.29 (t, 6 H, CH3, J = 7.0 Hz); 1.23—1.33
(m, 2 H, CH2); 1.54 (s, 3 H, CH3); 1.57 (s, 3 H, CH3); 1.63 (c, 3 H,
CH3); 1.75—1.83 (m, 2 H, CH2); 1.90—2.04 (m, 2 H, CH2);
2.10—2.23 (m, 3 H, CH2, CH); 2.12 (s, 6 H, CH3); 2.58 (d, 2 H,
CH2, J = 7.5 Hz); 4.12 (q, 4 H, CH2, J = 7.0 Hz); 4.90—5.08
(m, 2 H, CH=). 13C NMR, : 14.0 (MeCH2); 15.2 (MeC=);
15.9 (MeCH); 17.5 and 25.4 (Me2C=); 26.4 (CH2); 27.4 (CH2);
29.4 (CH2); 31.5 (CH); 39.6 (CH2); 45.5 (Me2N); 57.7 (>C<);
59.8 (CH2N); 61.2 (OCH2); 117.6 (CH=); 124.2 (CH=); 130.9

258
Russ.Chem.Bull., Int.Ed., Vol. 61, No. 2, February, 2012
Kryshtal et al.
(Me2C=); 135.9 (MeCH=); 171.7 (C=O). Found (%): C, 69.77;
H, 10.38; N, 3.57. C23H41NO4. Calculated (%): C, 69.83;
H, 10.45; N, 3.54.
6. RF Pat. 2301667; Chem. Abstr., 2007, 147, 110262.
7. A. C. Cope, H. L. Holmes, H. O. House, Organic Reactions,
New York, 1957, 9, 107.
8. N. N. Sukhanov, L. N. Trappel´, V. P. Chetverikov, L. A.
Yanovskaya, Zh. Org. Khim., 1985, 21, 2503 [J. Org. Chem.
USSR (Engl. Transl.), 1985, 21, 2341].
9. H. L. Simon, A. Kaufmann, H. Schinz, Helv. Chim. Acta,
1946, 29, 1133.
This work was financially supported by the Presidium
of the Russian Academy of Sciences (Program "The Bacis
Sciences for Medicine").
10. D. Necas, M. Tursky, M. Kotora, J. Am. Chem. Soc., 2004,
126, 10222.
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Received July 7, 2011;
in revised form November 9, 2011