Chemical modification of plant alkaloids. 4. Reaction of cotarnine with bifunctional NH- and CH-acids

Article abstract of DOI:10.1007/s10600-005-0174-z

1-Substituted 1,2,3,4-tetrahydroisoquinoline systems were prepared by reaction of cotarnine with the NH-and CH-acids methyl- and acyl derivatives of pyrazole and 1,3-dicarbonyl reagents. Depending on the structure and reaction conditions, bifunctional pyrazole nucleophiles can give substitution products at the N atom, methyl, or acyl group; 1,3-diketones, at the terminal methyl. Rearrangements occurring during the reaction of cotarnine with bifunctional substrates were studied. 2005 Springer Science+Business Media, Inc.

Full text of DOI:10.1007/s10600-005-0174-z

Chemistry of Natural Compounds, Vol. 41, No. 4, 2005
CHEMICAL MODIFICATION OF PLANT ALKALOIDS.
4. REACTION OF COTARNINE WITH BIFUNCTIONAL
NH- AND CH-ACIDS
K. A. Krasnov,1 V. G. Kartsev,2 and S. F. Vasilevskii3
UDC 547.854+547.689.6+547.833.3
1-Substituted 1,2,3,4-tetrahydroisoquinoline systems were prepared by reaction of cotarnine with the NH-
and CH-acids methyl- and acyl derivatives of pyrazole and 1,3-dicarbonyl reagents. Depending on the
structure and reaction conditions, bifunctional pyrazole nucleophiles can give substitution products at the
N atom, methyl, or acyl group; 1,3-diketones, at the terminal methyl. Rearrangements occurring during the
reaction of cotarnine with bifunctional substrates were studied.
Key words: cotarnine, pyrazoles, 1,3-dicarbonyls, rearrangement.
6-Methyl-5-hydroxy-4-methoxy-5,6,7,8-tetrahydro-2 -1,3-methylenedioxy-[4,5- ]isoquinoline, or cotarnine (1), is a
H
g
natural tautomeric pseudobase that is known to react with NH- and CH-acids to form the corresponding "anhydrocotarnyl
derivatives" [1], which are of interest as structural analogs ofisoquinoline plant alkaloids. The preparation ofcotarnine adducts
with NH-acids such as aniline, phenylhydrazine, urea [2-4], and indoles [5] has been reported. Among the CH-acids, HCN [6],
ketones (acetone and acetphenone), nitroalkanes (CH NO et al.), nitrotoluenes, phenylacetonitrile [7], cyclic β-dicarbonyls [8,
3
2
9], and compounds from certain other classes have been examined.
The mechanism of the reaction is an aminoalkylation. The reaction products are cyclic Mannich bases [10]. The
limited set ofexamined nucleophilic substrates must be noted because it leaves the synthetic possibilities ofcotarnine and related
pseudobases mostly unexplored. Reactions of cotarnine with bifunctional nucleophilic reagents are very little studied.
In consideration of this and in continuation of studies of the synthesis of new analogs of isoquinoline alkaloids, we
examined the reaction of 1 with a series of polyfunctional substrates including pyrazole, its methyl and acyl derivatives, and
certain -dicarbonyls.
The reaction of 1 with unsubstituted pyrazole (2a) in CH OH at 30°C proceeded rapidly to form the aminoalkylation
3
product ofpyrazole at the N atom 3a. Considering the labilityofcotarnine N-adducts, it can be assumed that electrophilic attack
under more forcing conditions would lead to substitution at the C atom of the heteroaromatic ring, as occurred for indole [5].
However, 3a turned out to be stable and isomerization was not observed on boiling in aqueous alcohol for 1 d.
R
3
O
O
O
+
N
N
N
O
N
R = Me
2
O
R = H
1
O
CH
CH
CH
3
3
3
R
2
N
R
OCH
N
3
OH
H CO
3
H CO
3
R
2
1
N
N
R
3
R
3
1
2a - d
a: R = R = R = H
3a - d
a: R = R = H
4a, b
N
a: R = Me
1
2
3
2
3
3
b: R = H, R = R = Me
b: R = R = Me
b: R = H
3
1
2
3
2
3
c: R = R = R = Me
c: R = H, R = Me
2 3
1
2
3
d: R = R = H, R = Me
d: R = Me, R = H
2 3
1
3
2
1) I. I. Mechnikov St. Petersburg State Medical Academy, 195067, St. Petersburg, Piskarevskii pr., 47, e-mail:
veselkoff@mail.ru; 2) ZAO "Interbioskrin," 142432, Chernogolovka, Moscow District, Institutskii prospekt, 7a, e-mail:
vkartsev@ibscreen.chg.ru; 3) Institute ofChemical Kinetics and Combustion, Siberian Division, Russian AcademyofSciences,
630090, Novosibirsk, ul. Institutskaya, 3, fax (3832)-30-73-50, e-mail: vasilev@nc.kinetics.nsc.ru. Translated from Khimiya
Prirodnykh Soedinenii, No. 4, pp. 360-364, July-August, 2005. Original article submitted May 6, 2005.
0009-3130/05/4104-0446 ©2005 Springer Science+Business Media, Inc.
446

Reaction of 1 with 3,5-dimethylpyrazole (2b) in aqueous methanol at 30°C produced the N-substituted pyrazole
derivative 3b, which was stable in the crystalline state and in solutions in slightly polar solvents (CHCl , ether). However, it
3
isomerized in aqueous alcohol to the thermodynamically more stable 4a. At 70°C, this conversion was complete after 1 h. It
is interesting that electrophilic attack of cotarnine at the analogous methyl ofpyrazole derivatives that have no active NH proton
was impossible due to its low reactivity, for example, 1,3,5-trimethylpyrazole (2c), which does not undergo the corresponding
reaction even under more forcing conditions. Taking this into consideration, it can be assumed that the pyrazolyl methyl was
activated during rearrangement of the N-adduct 3b into the C-isomer 4a by an intramolecular migration of the
tetrahydroisoquinoline substituent.
3-Methylpyrazole (2d) reacted readily with 1 in CH OH to form a mixture of two isomeric N-adducts (3c and 3d) in
3
a 5:1 ratio according to 1H NMR spectra. In contrast with the 3,5-dimethylpyrazole N-adduct 3b, N-adducts 3c and 3d were
much less prone to the analogous rearrangement. Thus, heating at 70 C for 1 h produced no evidence of formation of the
corresponding derivative 4b. Furthermore, prolonged heating (24 h) of a reaction mixture containing 3c and 3b led mainly to
decomposition.
The 4-acetyl derivatives of 1,3-dimethyl- (5a) and 1,3,5-trimethylpyrazole (5b) reacted with 1 in CH OH to form
3
substitution products at the acetyl 6a and 6b. These adducts were stable, did not decompose upon prolonged boiling in aqueous
alcohol, and produced no evidence of transformation into the theoretically possible pyrazolylmethyl-substituted isomers.
O
O
N
O
O
O
CH
O
-H O
2
3
+
N
N
H CO
3
R
CH
3
N
OH
H CO
3
CH
3
N
R
1
5a, b
N
CH
6a, b
3
a: R = H;b: R = Me
We isolated 8a from the reaction of 1 with 4-acetoacetyl-1,3,5-trimethylpyrazole (7), the product of substitution at the
terminal methyl of the 1,3-diketone, and identified it using PMR spectra. This result was considered unexpected because
1,3-diketones reacting as nucleophiles usuallygive productsofsubstitution attheacidicCHoftheα-methylene. In this instance,
O
this should have formed 9.
O
O
O
O
−H O
2
+
N
N
O
N
O
CH
N
3
N
N
OH
H CO
3
H CO
3
O
1
7
8a
O
O
N
O
N
N
O
H CO
3
N
OH
O
N
8b
H CO
3
N
O
O
O
O
N
N
N
9
H CO
3
OH
O
8c
Compound 8a existed as a tautomer. The PMR spectra indicated that the enol form predominated in CHCl solution
3
(probably a mixture of spectrally indistinguishable forms 8b and 8c totaling 68-69%). The fraction of the corresponding
447

dicarbonyl form 8a was 31-32%. For a quantitative estimate of the content of 8b and 8c, the most informative signals in the
PMR spectrum were the singlet at 5.76 ppm (vinyl CH) and the broad singlet at 16.44 ppm (chelated OH proton). An AB
quartet of methylene (COCH CO) at 3.94 ppm was characteristic of the dicarbonyl form 8a. Signals in the spectra were
2
1
1
identified based on standard methods of 2D H— H NMR and by comparison with known related structures.
A studyof the reaction of1 with other 1,3-dicarbonyls showed that formation ofthe substitution product at the terminal
methyl of the ketone is a common feature of these reactions. The ethyl ester of acetoacetic acid (10a) reacted with 1 in CH OH
3
to form 11a. Acetylacetone (10b) formed analogously11b. The reaction proceeded efficiently in not only polar but also slightly
polar media, for example, in CHCl .
3
O
N
O
O
O
O
O
O
+
R
2
R
H CO
3
N
2
1
O
O
N
O
CN
O
H CO
-H O
2
3
R = Me
1
H CO
3
R
1
R
2
O
R
1
R
1
CH
_
R
2
O
N
O
O
O
R
2
H CO
3
10a - c
12a - c
EN
OH
O
a: R = Me, R = COOEt;b: R = R = Me; c: R = R = COOEt
1
2
1
2
1
2
11a, b
a: R = COOEt; b: R = Me
2
2
We used PMR spectroscopy to establish the structures of tautomeric 11a and 11b.
The acetoacetic-acid derivative11a existed in CDCl solution at 20°C and 0.2 M primarilyas the dicarbonyl form (CN,
3
98%). The fraction of the corresponding enol form (EN) that was calculated from the strength of the vinyl-proton signal in the
PMR spectra was ~2%. This was rather low compared with similar systems. For example, unsubstituted acetoacetic ester (10a)
in slightly polar solvents is enolized by ~30% (29.4% in ether and 36.2% in CCl ) according to the literature [7]. On the other
4
hand, acetylacetone derivative 11b existed in solutions primarily as the EN form. In CHCl , the content of the enol tautomer
3
was 76%; in DMSO, 64%. In this sense, 11b differed little from unsubstituted diketone 10b, which, according to the literature,
enolized by 81% in CHCl ; 60% in DMSO [7].
3
Reacting 1 with diethylmalonate (10c) in CHCl led to the isolation of 12c, which is substituted at the α-C of the
3
1,3-dicarbonyl. The α-adduct 12c was a relatively unstable compound that was reversibly hydrolyzed in the presence of water
into the starting materials 1 and 10c.
The lability of 12c and its high formation rate indicate that the reaction of 1 with 1,3-dicarbonyls such as 7, 10a, and
10b involves an intermediate of the corresponding α
-adducts such as
8a, 11a, and 11b, which are substituted at the terminal methyl.
12a
, which then rearrange into the more stable derivatives
The following arguments can be given in favor of this two-step reaction mechanism. It is known that the α-methylene
in 10a and 10b has distinct CH-acidity (pKa for aqueous solutions of 10.75 and 9.00, respectively [7]). Therefore, addition of
a base such as 1 (pK 12.6 [1]) should deprotonate these acids to form the corresponding monoanions in pairs with the cation
B
(1a). Recombination of this ion pair can lead to the corresponding α-adduct of type 12a whereas attack at the unactivated
methylketone under similar conditions seems improbable. After theα-adduct forms, it can isomerizeintothemorestablesystem
through migration of a 1,2,3,4-tetrahydroisoquinoline fragment onto the terminal methyl. A rearrangment of this type, which
requirespreliminarydeprotonation oftheCOCH , isapparentlymoreeasilyaccomplishedthrough an intramolecular mechanism
3
involving a six-membed cyclic transition state.
Thus, the results indicate that substrates 2b, 7, 10a, and 10b, which have several centers for electrophilic attack, react
during aminoalkylation of 1 with substitution of the more active protons. However, the adducts formed by this are less stable
and can rearrange into stabler isomers. The studied features have fundamental significance for carrying out regiospecific
synthesis of substituted 1,2,3,4-tetrahydroisoquinolines from 1 and polyfunctional nucleophilic reagents.
448

EXPERIMENTAL
PMR spectra were recorded in CDCl on a Bruker AM-500 (500 MHz) spectrometer. The purity of the products was
3
monitored using PMR spectra, elemental analyses, and TLC (on Silufol UV-254 plates using CHCl :EtOAc, 1:1; propan-2-
3
ol:water, 4:1; and DMF:NH OH (25%), 10:1).
4
Compounds 2a-d and 10a-c were used as received. Compounds 5a [8] and 5b and 7 [9] were prepared as before. Their
physicochemical properties agreed with those in the literature.
4-Methoxy-6-methyl-5,6,7,8-tetrahydro-2H-1,3-methylenedioxy-[4,5-g]isoquinolin-5-ol(cotarnine) 1 wasisolated
from an aqueous solution of cotarnine chloride (pharm.) using NaOH solution (10%) by the literature method [5], mp 130-
132°C.
5-(1H-Pyrazol-1-yl)-4-methoxy-6-methyl-5,6,7,8-tetrahydro-[1,3]dioxolo[4,5-g]isoquinoline (3a). A solution of
1 (1.18 g, 5 mmol) in CH OH (10 mL) at 30°C was treated with a solution of pyrazole (2a, 0.34 g, 5 mmol) in CH OH (5 mL)
3
3
and H O (2 mL). The solution was held for 1 h at room temperature. The resulting crystals were separated, washed with
2
CH OH, and dried in air to afford 3a (1.29 g, 89%) as colorless crystals, mp 112-113°C (alcohol).
3
1
PMR spectrum (δ, ppm, J/Hz): 2.36 (3H, s, NCH ), 2.66 + 2.75 (2H, dd + dd, AB-system, J = 14.0, ArCH ), 2.98 (2H,
3
2
m, NCH ), 3.52 (3H, s, OCH ), 5.86 + 5.87 (2H, s + s, OCH O), 6.16 [1H, t, J = 2.4, C(4)H
], 6.17 (1H, s, NCHN), 6.37
2
3
2
pyraz
(1H, s, CH
), 7.17 [1H, d, J = 2.4, C(3)H
], 7.47 [1H, d, J = 2.4, C(5)H
].
arom
pyraz
pyraz
5-(3,5-Dimethyl-1H-pyrazol-1-yl)-4-methoxy-6-methyl-5,6,7,8-tetrahydro-[1,3]dioxolo[4,5-g]isoquinoline (3b)was
prepared analogously from 1 and 3,5-trimethylpyrazole (2b), yield 80%, colorless crystals, mp 121-123°C (not recrystallized).
PMR spectrum (δ, ppm, J/Hz): 2.12 [3H, s, C(3)
CH ], 2.23 [3H, s, C(5)
CH ], 2.34 (3H, s, NCH ), 2.59 + 2.84
pyraz 3 3
pyraz
3
1
(2H, m + m, AB-system, J = 16.1, ArCH ), 2.92 + 3.58 (2H, m + m, AB-system, NCH ), 3.48 (3H, s, OCH ), 5.71 (1H, s,
2
2
3
NCH), 5.84 (2H, s, OCH O), 5.87 (1H, s, CH
), 6.38 (1H, s, CH
).
2
pyraz
arom
4-Methoxy-6-methyl-5-(3-methyl-1H-5-pyrazolylmethyl)-5,6,7,8-tetrahydro-[1,3]dioxolo[4,5-g]isoquinoline (4a).
Compound 3b (1.66 g, 5 mmol) was treated with ethanol (70%, 20 mL), boiled and stirred for 1 h, and cooled. The resulting
crystals were separated, washed with alcohol, and dried in air to afford 4a (1.12 g, 71%) as colorless crystals, mp 166-168°C
(alcohol).
PMR spectrum (δ, ppm, J/Hz): 2.33 (3H, s, C
2CH ), 3.28 (1H, m, J = 11.4, NCHH), 3.84 (1H, dd, J = 9.6, J = 3.0, NCH), 3.98 (3H, s, OCH ), 5.23 (1H, s, CH
CH ), 2.42 (1H, m, NCHH), 2.45 (3H, s, N
CH ), 2.82 (4H, m,
pyraz
1
3
piperid 3
1
2
), 5.81
2
3
pyraz
(1H, br.s, NH), 5.85 (2H, s, OCH O), 6.23 (1H, s, CH
).
2
arom
1-(1,5-Dimethyl-1H-pyrazol-4-yl)-2-(4-methoxy-6-methyl-5,6,7,8-tetrahydro-[1,3]dioxolo[4,5-g]isoquinolin-5-
yl)ethan-1-one (6a). A solution of 1 (5 mmol) in CH OH (5 mL) was added to a methanolic solution of 5a (0.69 g, 5 mmol).
3
The resulting solution was held for 1 h at 50°C and left at room temperature for 1 d. The resulting crystals were separated,
washed with cold CH OH, and dried in air to afford 6a (1.10 g, 61%) as colorless crystals, mp 158-159°C (alcohol).
3
1
PMR spectrum (δ, ppm, J/Hz): 2.39 (3H, s, C
CH ), 2.40 + 2.76 (2H, m + m, AB-system, J = 13.2, ArCH ), 2.49
pyraz
3
2
1
1
(3H, s, N
CH ), 2.84 + 2.96 (2H, dd + dd, AB-system, J = 15.6, COCH ), 2.86 + 3.09 (2H, m + m, AB-system, J = 12.6,
3 2
piperid
1
2
NCH ), 3.82 (3H, s, N
CH ), 3.93 (3H, s, OCH ), 4.40 (1H, dd, J = 8.6, J = 3.5, NCH), 5.84 (2H, s, OCH O), 6.28 (1H,
2
pyraz
3
3
2
s, CH
), 7.75 (1H, s, CH
).
arom
pyraz
1-(1,3,5-Trimethyl-1H-pyrazol-4-yl)-2-(4-methoxy-6-methyl-5,6,7,8-tetrahydro-[1,3]dioxolo[4,5-g]isoquinolin-5-
yl)-ethan-1-one (6b) was prepared analogously from 1 and 5b, yield 66%, colorless crystals, mp 75-76°C (alcohol).
PMR spectrum (δ, ppm, J/Hz): 2.39 [3H, s, C(3)
CH ], 2.41 [3H, s, C(5)
CH ], 2.42 + 2.74 (2H, m + m,
pyraz
3
pyraz
3
1
1
AB-system, J = 13.4, ArCH ), 2.51 (3H, s, N
CH ), 2.82 + 3.01 (2H, dd + dd, AB-system, J = 16.1, COCH ), 2.87 + 3.03
2
piperid
3
2
1
1
2
(2H, m + m, AB-system, J = 11.1, NCH ), 3.71 (3H, s, N
CH ), 3.91 (3H, s, OCH ), 4.49 (1H, dd, J = 8.5, J = 2.6, NCH),
3 3
2
pyraz
5.84 (2H, s, OCH O), 6.28 (1H, s, CH
).
2
arom
4-(4-Methoxy-6-methyl-5,6,7,8-tetrahydro-[1,3]dioxolo[4,5-g]isoquinolin-5-yl)-1-(1,3,5-trimethyl-1H-pyrazol-4-
yl)-butan-1,3-dione (8a). A solution of 1 (1.02 g, 4.0 mmol) in CH OH (5 mL) was added to a methanolic solution of 7
3
(0.87 g, 4.5 mmol), held for 1 h at 40°C, left at room temperature for 1 d, treated dropwise with water (15 mL), and cooled to
10°C. The resulting amorphous precipitate was separated and washed with aqueous alcohol. The isolated solid was worked up
at 20°C with HCl (1%, 30 mL) with stirring for 2 h. The insoluble solid was separated. The acidic aqueous solution was washed
with CCl (15 mL) and made basic with ammonia. The resulting solid was separated, washed with water, recrystallized from
4
the minimal amount of ethanol (60%), and dried in air to afford8a (0.92 g, 51%), as light cream-colored crystals, mp 91-92°C.
449

*
*
PMR spectrum (δ, ppm, J/Hz): 8a (CN): 2.36 [3H, s, C(3)
CH ], 2.39 + 2.61 (2H, m + m, AB-system, ArCH ),
3 2
pyraz
*
2.44 [3H, s, C(5)
CH ], 2.50 (3H, s, N
CH ), 2.66 + 2.88 (2H, m + m, AB-system, COCH CH), 2.70 + 3.05 (2H, m
pyraz
*
3
piperid 3 2
*
1
*
+ m, AB-system, NCH ), 3.71 (3H, s, N
CH ), 3.94 (2H, q, AB-system, J = 8.7, COCH CO), 3.99 (3H, s, OCH ), 4.22
2
pyraz
3
2
3
1
*
(1H, dd, J = 8.0, NCH), 5.84 (2H, s, OCH O), 6.24 (1H, s, CH
); 8b + 8c (EN): 2.36 [3H, s, C(3)
CH ], 2.39 + 2.62
CH ), 2.64 + 2.85 (2H, m + m, AB-system,
CH ), 3.99 (3H, s, OCH ), 4.24 (1H, dd,
3 3
2
arom
pyraz
3
*
*
(2H, m + m, AB-system, , ArCH ), 2.43 [3H, s, C(5)
CH ), 2.47 (3H, s, N
2
pyraz
*
3
piperid 3
*
*
COCH CH), 2.76 + 3.14 (2H, m + m, AB-system, NCH ), 3.72 (3H, s, N
2
2
pyraz
1
J = 8.1, NCH), 5.76 (1H, s, =CH), 5.83 (2H, s, OCH O), 6.26 (1H, s, CH
), 16.44 (1H, br.s, OH).
2
arom
Ethyl-4-(4-methoxy-6-methyl-5,6,7,8-tetrahydro-[1,3]dioxolo[4,5-g]isoquinolin-5-yl)-3-oxobutanoate (11a) was
prepared analogously to 8a from 1 and acetoacetic ester (10a) as light yellow-colored crystals, 66% yield, mp 61-62°C
(CHCl :CCl ).
3
4
PMR spectrum (δ, ppm, J/Hz): 11a (CN): 1.28 (3H, t, J = 7.2, CH CH ), 2.39 + 2.70 (2H, m + m, AB-system,
2
3
1
1
2
J = 13.3, ArCH ), 2.41 (3H, s, NCH ), 2.76 (2H, dd, AB-system, J = 6.4, J = 2.2, COCH CH), 2.82 + 3.02 (2H, m + m,
2
3
2
1
1
AB-system, J = 11.6, NCH ), 3.48 (2H, AB-q, J = 15.2, COCH CO), 3.97 (3H, s, OCH ), 4.04 (1H, dd, J = 8.0, NCH), 4.18
2
2
3
(2H, q, J = 7.2, OCH ), 5.83 (2H, s, OCH O), 6.24 (1H, s, CH
).
2
2
arom
4-(4-Methoxy-6-methyl-5,6,7,8-tetrahydro-[1,3]dioxolo[4,5-g]isoquinolin-5-yl)-pentan-2,4-dione (11b)wasprepared
analogouslyto 8a from 1 and actylacetone (10b) to give light cream-colored crystals, 76% yield, mp 111-112°C (CHCl :CCl ).
3
4
PMR spectrum (δ, ppm, J/Hz): 11b (EN): 2.03 (3H, s, COCH ), 2.35 (3H, s, NCH ), 2.38 + 3.06 (2H, m + m,
3
3
1
1
AB-system, J = 12.2, NCH ), 2.44 + 2.52 (2H, m + m, AB-system, J = 13.4, COCH C=), 2.66 + 2.80 (2H, m + m, AB-system,
J = 16.0, ArCH ), 3.99 (3H, s, OCH ), 4.09 (1H, dd, J = 9.5, J = 3.6, NCH), 5.51 (1H, s, HC=), 5.86 (2H, s, OCH O), 6.22
2
2
1
1
2
2
3
2
(1H, s, CH
), 15.55 (1H, br.s, OH); 11b (CN): 2.16 (3H, s, COCH ), 2.31 (3H, s, NCH ), 3.57 (2H, AB-q, J = 15.1,
3 3
arom
1
COCH CO), 4.03 (1H, dd, J = 8.6, NCH), remaining signals overlap those of the EN form.
2
Diethyl-2-(4-methoxy-6-methyl-5,6,7,8-tetrahydro-[1,3]dioxolo[4,5-g]isoquinolin-5-yl)malonate (12c). Asolution
of 1 (1.02 g, 4.0 mmol) in CHCl (8 mL) was added to a solution of diethylmalonate (10c, 0.70 g, 4.4 mmol) in CHCl (3 mL),
3
3
treated with ground anhydrous Na SO (1 g), stirred for 1 h at 20°C, and filtered through a paper filter. The desiccant was
2
4
washed with CHCl . The combined filtrate was evaporated in vacuo to a volume of 3 mL. The resulting solution was diluted
3
with hexane (15 mL) and cooled to -10°C. The resulting amorphous solid was separated, washed with a small amount of ether,
and recrystallized from hexane. Drying in a vacuum desiccator produced 12c (0.63 g, 40%) as colorless crystals, mp 72-73°C.
PMR spectrum (δ, ppm, J/Hz): 1.15 (3H, t, J = 6.7, CH ), 1.24 (3H, t, J = 6.7, CH ), 2.41 (3H, s, NCH ), 2.58 (2H,
3
3
3
1
m, ArCH ), 2.72 + 3.33 (2H, m + m, AB-system, J = 15.8, NCH ), 3.66 (1H, d, J = 7.3, OCCHCO), 3.93 (3H, s, OCH ), 4.48
2
2
3
(1H, d, J = 7.3, NCH), 4.17 (4H, m, J = 6.7, 2×COOCH ), 5.83 (2H, s, OCH O), 6.26 (1H, s, CH ).
arom
2
2
ACKNOWLEDGMENT
The work was supported by grant CRDF-008-XI.
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