Synthesis of bis-tetrahydroisoquinolines based on homoveratrylamine and a series of dibasic acids. 3.

Article abstract of DOI:10.1007/s10600-014-0997-6

Pyrido- and [1, 4]-oxazinoisoquinolines, bis-tetrahydroisoquinolines, the alkaloid corydaldine, cleavage products, and a series of intermediates were prepared from homoveratrylamine and dibasic acids (glutaric and diglycolic) using a Bischler-Napieralski reaction. Their structures were confirmed using IR and NMR spectra and an x-ray crystal structure analysis.

Full text of DOI:10.1007/s10600-014-0997-6

Chemistry of Natural Compounds, Vol. 50, No. 3, July, 2014 [Russian original No. 3, May–June, 2014]
SYNTHESIS OF bis-TETRAHYDROISOQUINOLINES BASED ON
HOMOVERATRYLAMINE AND A SERIES OF DIBASIC ACIDS. 3.
1*
2
2
2
A. Sh.Saidov, E. Yu. Mazur, K. K. Turgunov, B. Tashkhodzhaev,
2
2
M. G. Levkovich, and V. I. Vinogradova
Pyrido- and [1,4]-oxazinoisoquinolines, bis-tetrahydroisoquinolines, the alkaloid corydaldine, cleavage
products, and a series of intermediates were prepared from homoveratrylamine and dibasic acids (glutaric
and diglycolic) using a Bischler–Napieralski reaction. Their structures were confirmed using IR and NMR
spectra and an x-ray crystal structure analysis.
Keywords: glutaric and diglycolic acids, homoveratrylamine, amides, Bischler–Napieralski reaction, isoquinolines.
Organic chemists are faced with the problem of creating effective synthetic pathways to previously unknown compounds
with useful properties. Such compounds include heterocyclic compounds such as isoquinoline derivatives. Despite the variety
of known structures, research on the development of methods for preparing isoquinoline alkaloids and their synthetic analogs
is critical according to the number of publications [1–3].
We showed earlier [4] that the cyclization of diamides obtained from homoveratrylamine (1) and a series of dibasic
fatty acids (from C to C ) did not depend on the acid chain length whereas the cyclization of phthalic acid diamides depended
6
10
on their structure [5]. In continuation of systematic research on the synthesis of bis-tetrahydroisoquinolines via the
Bischler–Napieralski reaction, we used diamides of glutaric (2) and diglycolic acids (3) in the reaction.
Methods for preparing diglycolic acid from chloroacetic acid gave poor results [6, 7]. Diglycolic acid (3) was
synthesized via oxidation of diethyleneglycol by HNO according to the literature [8]. Use of 86% HNO increased the yield
3
3
of 3 to 90%.
Diamides 4 and 5 were synthesized by heating previously formed salts of 2 and 3 with 1 whereas others [9] prepared
diglycolic acid diamide in several steps. In the first step, the cyclic anhydride of diglycolic acid was prepared and used to
acylate an amine to form the monoamide. Then, the diamide was obtained through the acid chloride of the second carboxylic
acid. This decreased significantly the yield. The synthetic method proposed by us was performed in one flask in two steps
with 86% (5) and 79% (4) yields.
The structures of 4 and 5 were proved using IR and PMR spectra (see Experimental). IR spectra of 4 and 5 had strong
–1
absorption bands for amide carbonyl at 1638 and 1680 cm , respectively.
2
ꢁ
OCH
OCH
H CO
3
3
3
O
H CO
O
ꢂ
NH
3
tꢃ
C
C
+
NH
O
6
NH
2
H CO
3
OH
X
HO
H CO
3
C
C
O
X
1
2, 3
4, 5
2, 4: X = CH ; 3, 5: X = O
2
An x-ray crystal structure analysis (XSA) confirmed the structure of 5 as 2,2ꢀ-oxo-bis[N-(3,4-
dimethoxyphenylethyl)acetamide]. However, the molecular structure lacked symmetry [center, plane, and (or) axis of symmetry
passing through O3] according to the XSA (Fig. 1). The molecule was situated in a general position without symmetry at the
O3 position although the molecule was packed in the centrosymmetric triclinic system. The N–H groups in the crystal structure
formed intermolecular H-bonds with the methoxy O atoms of centrosymmetrically situated molecules. The H-bond distances
°
°
°
and angles were N1–H…O6, N1…O6, 3.118(4) A, H…O6, 2.28 A, and N–H…O, 164.0° and N2–H…O7, 3.238(4), 2.50 A,
and 145.0°, respectively.
1) A. Navoi Samarkand State University, e-mail: a-saidv85@mail.ru; 2) S. Yu. Yunusov Institute of the Chemistry of
Plant Substances, Academy of Sciences of the Republic of Uzbekistan, Tashkent. Translated from Khimiya Prirodnykh
Soedinenii, No. 3, May–June, 2014, pp. 435–441. Original article submitted February 17, 2014.
©
0009-3130/14/5003-0503 2014 Springer Science+Business Media New York
503

C22
O5
C4
O4
C3
C21
C5
C2
C1
C7
C6
C8
C24
C14
O7
O6
C23
N1
O1
C13
C9
C15
C16
C12
O3
C10
N2
C11
C17
C19
O2
C20
C18
Fig. 1. Molecular structure of 5.
Fig. 2. Molecular structure of corydaldine (6).
Subsequent cyclization of 4 and 5 by the Bischler–Napieralski method depended on the dehydrating agent and solvent.
Cyclization in anhydrous benzene with POCl produced a mixture of products, e.g., three compounds (R 0.3, 0.6, 0.9) for 5.
3
f
Only compound 6 could be isolated pure. The others could not be separated because of rapid oxidation.
OCH
H CO
H CO
3
3
3
3
POCl
3
NH
O
NH
NH
C
O
OCH
H CO
3
H CO
3
C
O
O
6
5
The structure of 6 was proved using PMR spectra as 3,4-dihydro-6,7-dimethoxy-1(2H)-isoquinolinone and was
identified as the known alkaloid corydaldine, which was previously isolated from Berberis baluchistanica [10]. An XSA of 6
(Fig. 2) showed that it was identical to the reported crystal structure of corydaldine isolated from Corydalis solida subs.
brachyloba [11].
Cyclization of 4 and 5 in benzene with POCl and subsequent reduction of the dihydroisoquinolines by NaBH did
3
4
not give the expected bis-tetrahydroisoquinolines, despite the fact that POCl is a mild reagent. Instead, it gave various
3
destruction products [7 and 8 (14H CO ) for 5 and 9 for 4] and tricyclic products 10 and 11.
2
3
c, b
8
7
H CO
3
2
7
H CO
3
H CO
3
8
a, b
N
O
4
3
5
+
+
H CO
3
NH
6
NH
2
11b
1
11
H CO
3
H CO
3
5
CH CH
3
9
8
7
11
Cl
7'
8'
2
ꢁ
8
7
H CO
3
OCH
OCH
H CO
3
6'
NH
5'CH
3
3
6
ꢂ
a, b
A
B
4
+
6
NH
12'
N
4
H CO
3
2'
H CO
3
11b
11'
5
11
C
(CH ) CH
C
2
2 2
2
3
1
O
10
9
a. POCl , C H ; b. NaBH ; CH OH; c. POCl
3
6
6
4
3
3
–1
Amine 7 gave a Beilstein test for halide. The IR spectrum of 7 had a band for active H at 3434 cm . The PMR
spectrum of 7 showed resonances at 1.51 ppm (3H, d, J = 6.5, CH ) and 3.23 ppm (1H, m, CH) that were consistent with a
3
CH–CH group. Two multiplets at 3.07 ppm (2H, m) and 3.17 ppm (2H, m) corresponded to protons H-7 and H-8. The nature
3
of the resonances at 3.79 and 3.80 ppm (3H each, s, OCH ) and 6.71 and 6.72 ppm confirmed that two methoxyls were present
3
in the trisubstituted benzene ring. Amine 7 was N-(1-chloroethyl)homoveratrylamine according to these results.
504

Cl 1
C15
O2
C5
C6
C2
C14
C7
C1
C8
C4
C3
N1
C13
C12
C9
C10
O1
O11
C11
.
10 HCl
11
Fig. 3. Molecular structures of 104HCl and 11.
Compound 9 was N-(3,4-dimethoxyphenylethyl)-5-(3,4-dimethoxy-ꢂ-phenylethylamino)pentanamide according to
PMR spectra.
Compounds 10 and 11 probably formed through a single mechanism. Their formation was determined by the number
of atoms between the two amides and not their nature (CH –CH –CH or CH –O–CH ). The structures of 10 and 11 were
2
2
2
2
2
established using PMR spectra. The spectrum of 11 showed two 1H singlets at 6.53 ppm (1H, s, H-8) and 6.61 ppm (1H, s,
H-11) and one 1H doublet of doublets at 4.30 ppm with SSCC J = 10.5 and 2.8 Hz and indicated unambiguously that the ring
had closed and formed the tetrahydroisoquinoline. Methylene protons H-1, -3, and -4 resonated in the PMR spectrum at 2.57
(1H, td, J = 11.5, 11.5, 4.2, H-4a), 2.80 (1H, dd, J = 11.9, 1.2, H-4b), 3.35 (1H, br.d, J = 10.5, H-1a), 3.43 (1H, t, J = 10.3,
H-1b), 3.77 (1H, td, J = 11.3, 11.3, 2.6, H-3a), and 3.89 (1H, dd, J = 10.2, 3.1, H-3b). The pattern was analogous in the PMR
spectrum of 10 with 1H singlets at 6.80 and 6.83 ppm (H-8, 11) and a broad resonance at 4.38 ppm (H-11b). The methylene
protons appeared as multiplets at 1.78, 1.95, 3.04, 3.42, and 3.60 ppm. The results suggested that 10 and 11 were
9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinoline and 9,10-dimethoxy-1,3,4,6,7,11b-
hexahydro[1,4]oxazino[3,4-a]isoquinoline, respectively. We did not find in the literature natural products with structures
similar to 11. However, a series of hexahydro[1,4]oxazino[3,4-a]isoquinolines were reported [12–14]. The structures of 10
and 11 were confirmed by XSA studies.
Figure 3 shows the molecular structures of 104HCl and 11 from the XSA studies. Rings B and C were trans-fused in
both molecules. Ring B had a half-chair conformation in both molecules [N(1) and C(8) deviating from the C(9)–C(1)–C(6)–
°
°
°
°
C(7) plane by –0.32(2) A and 0.45(2) A in 10 and by –0.425(5) A and 0.356(5) A in 11]. Ring C had a chair conformation. The
°
N–C bonds in 10 [N(1)–C(8) 1.493(2), N(1)–C(9) 1.508(2), and N(1)–C(13) 1.500(3) A] were slightly elongated relative to
the corresponding bonds in 11 [N(1)–C(8) 1.465(3), N(1)–C(9) 1.470(3), and N(1)–C(13) 1.463(4) A ] because the N atom
°
was protonated. The N–C bond was also elongated in the N-oxide of 10 [15].
°
Protonated N1 in the crystal of 104HCl formed an intermolecular H-bond with the Cl anion [N1…Cl 3.041(2) A ,
°
H1…Cl 2.13(3) A, N1–H…Cl 161(2)°].
The reaction of 4 in POCl as the solvent and reagent occurred more selectively. In this instance, only one reaction
3
product (12) was observed by chromatography. It was reduced to the target isoquinoline 13 whereas amide 5 cyclized under
analogous conditions without undergoing substantial changes compared with those above and gave 11 in ~70% yield.
H CO
3
H CO
3
N
NH
NaBH
4
H CO
3
H CO
3
POCl
CH OH
3
3
(CH )
(CH )
2 3
4
2 3
OCH
OCH
OCH
OCH
3
3
3
3
N
HN
12
13
The absence of the bis-tetrahydroisoquinoline in the reactions of 5 with POCl prompted us to study this reaction
3
using PCl , P O , and polyphosphoric acid (PPA) instead of POCl .
5
2
5
3
It is well known that PCl is a more forcing reagent than POCl . Therefore, syntheses involving it are carried out
5
3
under milder conditions. Diamide 5 was cyclized by PCl in anhydrous CHCl at room temperature over 4 d. The reaction
5
3
mixture was separated using the solubilities of the hydrochlorides. The hydrochloride of 14 precipitated from CHCl –Me CO
3
2
(1:1, 20% yield). Subsequent work up of the dried mother liquor by Me CO separated 15 (35% yield).
2
505

TABLE 1. Principal Crystallographic Parameters and Characteristics of an X-ray Crystal StructureAnalysis for 5, 104HCl, and 11
Parameter
5
11
104HCl
Molecular formula
MW
Space group
C24H32N2O7
460.52
C15H22NO2Cl
283.79
C14 H19 NO3
249.30
P-1
P21/n
P21/c
2
4
4
Z
°
, A
9.0171 (6)
11.7331 (9)
12.2617 (9)
97.836 (6)
90.062 (6)
110.753 (6)
1200.06 (15)
1.274
9.495 (1)
16.208 (2)
9.867(1)
90.00
105.67 (1)
90.00
18.135 (5)
7.191 (3)
10.170 (2)
90.00
95.25 (2)
90.00
a
b
c
°
, A
, A
°
ꢁ ꢃ
ꢂ, ꢃ
ꢄ, ꢃ
V
,
° 3
1462.0 (3)
1.289
1320.7 (7)
1.254
, A
ꢅ, g/cm3
Crystal size, mm
exp, cm–1
0.55 ꢇ 0.35 ꢇ 0.20
0.78
0.60 ꢇ 0.40 ꢇ 0.10
2.414
0.45 ꢇ 0.25 ꢇ 0.15
0.714
Number of reflections
4786
2585
2650
2844
0.074
0.235
1.05
2090
1333
Number of reflections with > 2ꢆ (I)
R1 (I > 2 ꢆ (I) and total)
wR2
I
0.040 (0.053)
0.108 (0.115)
1.036
0.22 and –0.19
998859
0.064 (0.120)
0.165 (0.199)
0.919
0.21 and –0.20
998860
GOOF
° –3
0.72 and –0.32
998858
Electron density difference peaks, eA
CCDC
5
4
5'
ꢁ
2'
H CO
3
OCH
3
5
OCH
3
3'
ꢂ
H CO
PCl
5
3
3
5
+
NH HN
HN
H CO
3
OCH
3
NH
OCH
3
8
5'
8'
H CO
3
O
8
1''
O
1''
1''
O
2''
14
15
NaBH
4
7'
OCH
OCH
CH OH
3
3
3
8'
H CO
3
HN
1
NH
H CO
3
O
1''
O
2''
16
Reduction of 14 by NaBH gave a mixture of greater than five products. This was possibly due to the instability of 14
4
in basic solution. Reduction of 15 by NaBH produced the free base 16. The structures of 14–16 were proved using PMR
4
spectra.
The PMR spectrum of 14 had two 2H singlets at 7.09 ppm (2H, s, H-8, 8ꢀ) and 7.26 (2H, s, H-5, 5ꢀ) and a single 1H
singlet at 5.47 ppm that indicated unambiguously that two rings had closed and formed the bis-dihydrohydroisoquinoline. The
double bonds on C-1 and C-1ꢀ caused the resonances of aromatic protons H-5 and H-8 to shift to weak field compared with
those in 10, 11, and 13.
The PMR spectrum of 15 exhibited 1H singlets at 7.06 ppm (1H, s, H-8) and 7.17 (1H, s, H-5) in addition to resonances
at 6.71 ppm (2H, d, J = 8, H-6ꢀ), 6.76 (2H, s, H-2ꢀ), and 6.79 (2H, d, J = 8, H-5ꢀ). This indicated that only one cyclization
occurred and formed not the bis-isoquinoline but amidodihydroisoquinoline 15. The incomplete cyclization was also confirmed
by PMR spectra of free base 16. Distinguishing features of the latter were a resonance at 4.12 ppm (H-1) and the lack of a
resonance at 5.10 ppm (H-1ꢀꢀ) that was characteristic of free base 15.
P O is a more energetic condensing agent and is used for amides if they are poor cyclized. We used xylene as the
2
5
solvent because 5 did not dissolve in toluene. The reaction was carried out for 4 h with constant stirring. Product 15 was
insoluble in xylene and precipitated and mixed with the P O . This may have reduced the activity of the P O . The yield of
2
5
2 5
pure 15 was 20% whereas the mixture of other compounds could not be separated.
We started with a temperature of 60–70°C for the cyclization with PPA. However, 5 did not dissolve at this temperature.
The mixture became homogeneous if the temperature was increased gradually to 110°C (5 had mp 112°C). The comparatively
506

low (0.2 g, 13%) yield of 14 was explained by the fact that PPA is a very active reagent. This led to side reactions and the
formation of organophosphorus compounds.
Our research showed that the Bischler–Napieralski reaction of dibasic acids with a chain of five atoms depended on
both the type of atoms in the chain and the used solvents and reagents. Simple methods for preparing both hexahydropyrido-
(10) and hexahydro[1,4]oxazino (11) -isoquinolines in addition to bis-isoquinoline derivatives (13, 14) could be proposed by
varying the reaction conditions.
EXPERIMENTAL
IR spectra were recorded from KBr pellets on an FTIR system 2000 instrument (PerkinElmer). PMR spectra were
recorded on a Unity-400+ Varian spectrometer (400 MHz, CDCl solvent, HMDS internal standard). R values were determined
3
f
on LS 5/40 silica gel plates (Czechoslovakia) using solvent systems CHCl –MeOH (12:1, system 1; 10:1, 2; 8:1, 3; 6:1, 4; and
3
4:1, 5). Melting points of all synthesized compounds were determined on a Boetius apparatus.
N,Nꢀ-(3,4-Dimethoxy-ꢂ-phenylethyl)glutardiamide (4), C H N O . A mixture of 1 (5 g, 0.027 mol) and 2 (2 g,
25 34
2 6
0.011 mol) was dissolved in MeOH (5 mL). Then, the salt was heated on an oil bath at 178°C for 2 h. The reaction mixture
was dissolved in CHCl (100 mL) and washed with HCl solution (3%), NaOH solution (2%), and H O until neutral. The
3
2
CHCl was distilled off. The residue was crystallized from Me CO. The resulting crystals were filtered off. Yield 79% (5 g),
3
2
–1
mp 132–135ꢃC (Me CO), R 0.76 (system 3). IR spectrum (KBr, ꢈ, cm ): 3290 (NH), 2931 (Ar-CH), 1638 (N-C=O), 1591,
1551, 1519 (Ar-H). Í NMR spectrum (400 MHz, ÑDCl , ꢉ, ppm, J/Hz): 1.82 (2H, t, J = 6.9, H-2ꢀ), 2.10 (4H, t, J = 7, H-1ꢀ, 3ꢀ),
2
f
1
3
2.70 (4H, t, J = 7, H-ꢁ), 3.41 (4H, q, J = 6.2, H-ꢂ), 3.79 (6Í, s, ÎÑÍ ), 3.80 (6Í, s, ÎÑÍ ), 5.69 (2H, t, NH), 6.64 (2H, d,
3
3
J = 2, H-2), 6.66 (2H, dd, J = 2, 8.6, H-6), 6.74 (2H, d, J = 8.6, H-5).
Preparation of 2,2ꢀ-oxy-bis[N-(3,4-dimethoxyphenyl)acetamide] (5), C H N O . A solution of 1 (2 g,
24 32
2 7
0.011 mol) in MeOH (5 mL) was treated with 3 (0.8 g, 0.006 mol) to form the salt. The reaction mixture was heated at 180°C
for 1.5 h after complete crystallization. When the reaction was finished, the mixture was dissolved in CHCl (100 mL) and
3
washed with aqueous NaOH (5%) and HCl (10%). The CHCl was removed in vacuo. The oily product was dissolved in
3
Me CO (25 mL) with added H O (3 mL) and left to crystallize slowly. The crystalline amide was filtered off and washed with
2
2
–1
H O. Yield 86% (2 g), mp 110–112ꢃÑ (Me CO), R 0.8 (system 5). IR spectrum (KBr, ꢈ, cm ): 3365 (Í-N), 1680 (N-C=O),
1464 (-CH -C=O), 1261 (C-N), 1141 (C-O-C). Í NMR spectrum (400 MHz, CDCl , ꢉ, ppm, J/Hz): 2.75 (4Í, t, J = 7.2,
2
2
f
1
2
3
H-ꢁ), 3.44 (4Í, t, J = 7.2, H-ꢂ), 3.77 (6H, s, OCH ), 3.80 (6H, s, OCH ), 3.96 (4H, s, H-1ꢀ), 6.74 (2H, d, J = 8.2, H-6), 6.83
3
3
(2H, s, H-2), 6.84 (2H, d, J = 8.2, H-5). Crystals for the XSA were grown from Me CO–C H .
2
6 6
Reaction of 4 with POCl in C H . A mixture of 4 (1.5 g, 0.006 mol), anhydrous C H (30 mL), and POCl (2 mL)
3
6
6
6
6
3
was refluxed for 2 h. The course of the reaction was monitored by TLC. The C H and POCl were distilled off. The residue
6
6
3
was dissolved in MeOH (30 mL), cooled to 0–5°C, and treated in portions with NaBH (0.015 mol). The MeOH was distilled
4
off. The residue was treated with H O and extracted with CHCl . The CHCl was removed. The residue was separated over
2
3
3
a column of silica gel (25 g) with elution by CHCl and CHCl –MeOH (100:0.5–0:100) to afford two crystalline compounds
3
3
9 and 10.
N-(3,4-Dimethoxyphenylethyl)-5-(3,4-dimethoxy-ꢂ-phenylethylamino)pentanamide (9), C H N O . Mass
25 36
2 5
+
spectrum m/z 445.2678 (M + 1) . Yield 22% (0.2 g), mp 147–149ꢃC (Me CO), R 0.41 (system 3). IR spectrum (KBr, ꢈ,
2
f
–1
1
cm ): 3325 (NH), 2942, 2777, 2461, 1642 (NC=O), 1591, 1519, 1470. Í NMR spectrum (400 MHz, ÑDCl , ꢉ, ppm, J/Hz):
3
1.77, 1.91 (each 2Í, t, J = 7, Í -3ꢀ, 4ꢀ), 2.24 (2Í, t, J = 7, Í -2ꢀ), 2.77 (2Í, t, J = 7, Í -5ꢀ), 2.98 (2Í, m, Í-ꢂ), 3.18 (4Í, m,
2
2
2
Í-ꢁ, 7ꢀ), 3.44 (2Í, q, J = 7, Í-6ꢀ), 3.83 (3Í, s, ÎÑÍ ), 3.84 (6Í, s, ÎÑÍ ), 3.85 (3Í, s, ÎÑÍ ), 6.58 (1Í, broad, NH), 6.72
3
3
3
(2Í, d, J = 8, Í-6, 12ꢀ), 6.77 (2Í, s, Í-2, 8ꢀ), 6.78 (2Í, d, J = 8, Í-5, 11ꢀ), 9.70 (2Í, br.s, NH).
9,10-Dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinoline (10), C H NO , Yield 55% (0.5 g),
15 21
2
–1
hydrochloride mp 201–203ꢃC (Me CO), R 0.55 (system 3). IR spectrum (KBr, ꢈ, cm ): 2962, 2450, 1611, 1709, 1525.
Í NMR spectrum (400 MHz, ÑDCl , ꢉ, ppm): 1.78 (2Í, m, ÑÍ ), 1.95 (4Í, m, 2ÑÍ ), 3.04 (2Í, m, ÑÍ ), 3.42 (2Í, m,
2
f
1
3
2
2
2
ÑÍ ), 3.60 (2Í, m, ÑÍ ), 3.81 (6Í, s, ÎÑÍ ), 4.38 (1Í, broad, Í-11b), 6.80 (1Í, s, Í-8), 6.83 (1Í, s, Í-11). Crystals of
2
2
3
104HCl for the XSA were grown from MeOH.
Reaction of 4 with POCl . A mixture of 4 (0.5 g, 0.6 mmol) and POCl (1.5 mL) was refluxed on a water bath for
3
3
6 h. The course of the reaction was monitored by TLC. The reaction mixture was poured onto ice, made basic with NH OH
4
solution (25%) to pH 9, and extracted with CHCl . The CHCl was removed. The residue was crystallized from Me CO to
3
3
2
afford 12 (0.4 g, 87%).
507

1
1,3-Bis(6,7-dimethoxy-3,4-dihydroisoquinolin-1-yl)propane (12), C H N O . Í NMR spectrum (400 MHz,
25 32
2 4
ÑDCl , ꢉ, ppm, J/Hz): 2.02 (2Í, m, ÑÍ ), 2.57 (4Í, t, J = 7.3, 2ÑÍ ), 2.81 (4Í, t, J = 7.5, H-4, 4ꢀ), 3.57 (4Í, t, J = 7.5, Í-3,
3
2
2
3ꢀ), 3.84 (6Í, s, ÎÑÍ ), 3.85 (6Í, s, ÎÑÍ ), 6.62 (2Í, s, Í-8, 8ꢀ), 7.00 (2Í, s, Í-5, 5ꢀ).
3
3
1,3-Bis(6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolin-1-yl)propane (13), C H N O . Compound 12 (0.39 g)
25 34
2 4
was dissolved in MeOH (40 mL), cooled to 0–5°C, and treated in portions with NaBH (0.04 mol). The MeOH was distilled
4
off. The residue was dissolved in H O and extracted with CHCl . The CHCl was removed. The residue was crystallized
2
3
3
–1
from Me CO to afford 13. Yield 13 84% (0.33 g), mp 99–101ꢃC (Me CO), R 0.35 (system 5). IR spectrum (ꢈ, cm ): 3378,
2
2
f
1
2917, 1612, 1520, 1468, 1257, 1223. Í NMR spectrum (400 MHz, ÑDCl , ꢉ, ppm, J/Hz): 1.57 (4Í, q, J = 7.4, H-1ꢀ, 2ꢀ), 1.83
3
(2Í, m, ÑÍ ), 2.63 (4Í, dt, J = 6, Í-4, 4ꢀ), 2.89 (2Í, dt, J = 5, 2, Í-3), 3.14 (2Í, dt, J = 5.4, 2.4, Í-3ꢀ), 3.77 (6Í, s, ÎÑÍ ), 3.78
(6Í, s, ÎÑÍ ), 3.87 (2Í, dd, J = 3.5, 8.5, Í-1, 1ꢀ), 6.50 (2Í, s, Í-8, 8ꢀ), 6.55 (2Í, s, Í-5, 5ꢀ).
2
3
3
Reaction of 5 with POCl in C H . A solution of 5 (1.5 g, 0.003 mol) in C H (20 mL) was treated with POCl
3
6
6
6
6
3
(2.72 g, 0.017 mol) and refluxed for 2 h. The course of the reaction was monitored by TLC. The resulting mixture was made
basic with NH OH solution (10%) to pH 8–9 and extracted with CHCl . The CHCl was distilled off. The resulting product
4
3
3
mixture consisted mainly of three compounds with R 0.3, 0.6, and 0.9 (system 4). The resulting mixture was divided into two
f
portions (A and B).
Sample A. The crude oily product (0.8 g) was placed onto a column of silica gel (15 g) and eluted by CHCl with a
3
gradient of MeOH from 0 to 100%. A total of 25 fractions were collected. Fractions 8–10 afforded pure 6 (0.25 g), R 0.6.
f
1
6,7-Dimethoxy-3,4-dihydroisoquinoline-1(2H)-oxo (6), C H NO . Yield 36% (0.25 g). Í NMR spectrum
11 13
3
(400 MHz, CDCl , ꢉ, ppm, J/Hz): 2.86 (2H, t, J = 7, H-4), 3.49 (2H, m, H-3), 3.82 (3H, s, OCH ), 3.85 (3H, s, OCH ), 6.42
3
3
3
(1Í, s, N-H), 6.61 (1Í, s, Í-8), 7.50 (1Í, s, Í-5).
Sample B. The crude oily product (0.8 g) was dissolved in MeOH (20 mL), cooled with ice, and treated in small
portions with NaBH (2 g). The MeOH was distilled off. The mixture was dissolved in H O and extracted with CHCl . The
4
2
3
total CHCl compounds (1 g) were separated over a column of silica gel (40 g). A total of 29 fractions were collected to afford
3
11 (0.3 g), R 0.8; 7 (0.04 g), R 0.66; and 8 (0.075 g), R 0.2 (system 4).
9,10-Dimethoxy-1,3,4,6,7,11b-hexahydro[1,4]oxazino[3,4-a]isoquinoline (11), C H NO , mp 113°C. IR spectrum
(KBr, ꢈ, cm ): 2879 (Í C-Î), 1226 (C-N), 1132 (C-Î-Ñ). Í NMR spectrum (400 MHz, CDCl , ꢉ, ppm, J/Hz): 2.57 (1H, td,
f
f
f
14 19
3
–1
1
3
3
J = 11.5, 11.5, 4.2, H-4a), 2.61 (1H, td, J = 11.5, 11.5, 3.5, H-7b), 2.66 (1H, dd, J = 16.5, 5.0, H-7à), 2.80 (1H, dd, J = 11.9, 1.2,
H-4b), 2.95 (1H, ddd, J = 10.5, 5.0, 1.1, H-6b), 3.11 (1H, td, J = 16.5, 11.8, 5.6, H-6à), 3.35 (1Í, br.d, J = 10.5, H-1a), 3.43 (1Í,
t, J = 10.3, H-1b), 3.77 (1H, td, J = 11.3, 11.3, 2.6, H-3a), 3.89 (1H, dd, J = 10.2, 3.1, H-3b), 3.84 (3Í, s, ÎÑÍ ), 3.85 (3Í, s,
3
ÎÑÍ ), 4.30 (1H, dd, J = 10.5, 2.8, H-11b), 6.53 (1H, s, H-8), 6.61 (1H, s, H-11). Crystals of 11 for the XSA were grown from
3
Me CO.
2
–1
1
N-(1-Chloroethyl)homoveratrylamine (7), mp 200°C. IR spectrum (KBr, ꢈ, cm ): 3434 (N-H). Í NMR spectrum
(400 MHz, CDCl , ꢉ, ppm, J/Hz): 1.51 (3H, d, J = 6.5, ÑÍ ), 3.07 (2H, m, H-7), 3.17 (2H, m, H-8), 3.23 (1Í, m, Í-9), 3.79
3
3
(3H, s, ÎCÍ ), 3.80 (3H, s, ÎCÍ ), 6.71 (2H, d, J = 8.2, H-6), 6.72 (1H, s, H-2), 6.73 (1H, d, J = 8.2, H-5).
3
3
–1
1
Homoveratrylamine (8) was isolated as the salt 14H CO . IR spectrum (KBr, ꢈ, cm ): 3174 (N-H). Í NMR
2
3
spectrum (400 MHz, CDCl , ꢉ, ppm, J/Hz): 2.89 (2H, t, J = 8, H-ꢁ), 3.08 (2H, t, J = 8, H-ꢂ), 3.79 (3H, s, ÎCÍ ), 3.81 (3H, s,
3
3
ÎCÍ ), 6.74 (2H, d, J = 8.2, H-6), 6.75 (2H, s, H-2), 6.78 (2H, d, J = 8.2, H-5).
3
(1Z,1ꢀZ)-1,1ꢀ-Oxa-bis(methane-1-ylidene-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline) (14), C H N O .
24 28
2 5
A suspension of PCl (1.6 g, 0.008 mol) in anhydrous CHCl (10 mL) was cooled with ice and treated over 10 min with small
5
3
portions of 5 (1.5 g, 0.003 mol). The solution was red after 5 was totally added. Then, the reaction mixture was stored for
3 d at room temperature. The course of the reaction was monitored by TLC. The mixture was made basic with NH OH
4
solution (10%) to pH 9 and extracted with CHCl . The CHCl was removed. The resulting oily product was converted to the
3
3
hydrochloride by adding HCl-saturated MeOH. The resulting mixture of hydrochlorides was dried in vacuo. Addition to the
dry residue of CHCl –Me CO (1:1) isolated 14 (0.3 g) with R 0.25 (system 3), mp 185–186°C. The crystals were separated.
3
2
f
The mother liquor was dried. The residue was dissolved in Me CO to afford 15 (0.5 g) with R 0.83 (system 3), mp 183–
2
f
184°C.
–1
1
Compound 14, mp 185–186°C. IR spectrum (KBr, ꢈ, cm ): 3429 (Í-N), 1276 (C-N), 1141 (C-O-C). Í NMR
spectrum (400 MHz, CD OD, ꢉ, ppm, J/Hz): 3.14 (4H, s, H-4, 4ꢀ), 3.86 (6H, s, ÎCÍ ), 3.93 (2H, m, H-3, 3ꢀ), 3.94 (6H, s,
3
3
ÎCÍ ), 5.47 (2H, s, H-1ꢀꢀ), 7.09 (2H, s, H-8, 8ꢀ), 7.26 (2H, s, H-5, 5ꢀ).
3
–1
Compound 15, mp 183–184°C. IR spectrum (KBr, ꢈ, cm ): 3205 (Í-N), 1651 (C=O), 1469 (-CH -C=O), 1274
2
1
(C-N), 1130 (C-O-C). Í NMR spectrum (400 MHz, CD OD, ꢉ, ppm, J/Hz): 2.74 (2H, t, J = 7.5, H-ꢁ), 3.10 (2H, t, J = 7.5,
3
H-4), 3.44 (2H, t, J = 7.5, H-ꢂ), 3.68 (3H, s, 6-OCH ), 3.74 (3H, s, 7-OCH ), 3.83 (2H, t, J = 7.5, H-3), 3.83 (3H, s, 3ꢀ-OCH ),
3
3
3
508

3.92 (3H, s, 4ꢀ-OCH ), 4.22 (2H, s, H-2ꢀꢀ), 5.10 (1H, s, H-1ꢀꢀ), 6.71 (2H, d, J = 8, H-6ꢀ), 6.76 (2H, s, H-2ꢀ), 6.79 (2H, d, J = 8,
3
H-5ꢀ), 7.06 (1H, s, H-8), 7.17 (1H, s, H-5).
2[(6,7-Dimethoxy-1,2,3,4-tetrahydroisoquinolin-1-yl)methoxy]-N-(3,4-dimethoxyphenylethyl)acetamide (16).
Compound 15 (0.3 g) was dissolved in MeOH (5 mL), cooled with ice, and reduced by NaBH . The MeOH was removed. The
4
product was extracted with CHCl to afford 16 (0.25 g) with R 0.55, mp 173°C, C H N O . The yield of the reduced
3
f
24 32 2 6
–1
product was 0.25 g (90%). IR spectrum (KBr, ꢈ, cm ): 3272 (ÍN), 1672 (C=O), 1455 (-CH -C=O), 1261 (CN), 1133
(C-O-C). Í NMR spectrum (400 MHz, CDCl , ꢉ, ppm, J/Hz): 2.74 (2H, t, J = 7.5, H-7ꢀ), 3.10 (2H, s, H-4), 3.40 (2H, m,
2
1
3
H-8ꢀ), 3.43 (2H, m, H-3), 3.73 (3H, s, 6-OCH ), 3.74 (3H, s, 7-OCH ), 3.75 (3H, s, 3ꢀ-OCH ), 3.76 (3H, s, 4ꢀ-OCH ), 3.83
3
3
3
3
(2H, d, J = 8, H-4), 3.91, 4.02 (each 1H, d, J = 15.5, H-2ꢀꢀ), 4.12 (1H, dd, J = 3, 8, H-1ꢀꢀ), 6.46 (1H, s, H-5), 6.54 (1H, s, H-8),
6.60 (2H, d, J = 8, H-6ꢀ), 6.64 (2H, s, H-2ꢀ), 6.70 (2H, d, J = 8, H-5ꢀ).
(Z)-2-[(6,7-Dimethoxy-3,4-dihydroisoquinolin-1(2H)-ylidene)methoxy]-N-(3,4-dimethoxyphenylethyl)acetamide
(15), C H N O . A suspension of P O (1 g, 0.007 mol) in xylene (25 mL) was stirred, treated with 5 (1.5 g, 0.003 mol),
24 30
2
6
2 5
stirred on a magnetic stirrer, and refluxed for 3 h. The course of the reaction was monitored by TLC. When the reaction was
finished, the mixture was made basic with NH OH solution (10%) to pH 9 and extracted with CHCl . The resulting total
4
3
compounds were dried in vacuo, dissolved in MeOH, and reduced by NaBH . The resulting mixture (0.7 g) was separated
4
th
over a column of silica gel (15 g). A total of 20 fractions were collected. The 8 fraction afforded pure 15 (0.2 g, 20%), R 0.8
f
(system 3).
Reaction of 5 with P O . P O (1.3 g) was treated with stirring with H PO (0.9 mL) and heated at 100–110°C on
2
5
2
5
3
4
a glycerin bath in a flask with a stopper for 2 h. The freshly prepared PPA (2.6) was treated with 5 (1.5 g) and heated at 110°C
on a glycerin bath for 2 h. When the reaction was finished, the mixture was neutralized with NH OH solution (10%) to pH 9
4
and extracted with CHCl to afford a mixture (0.2 g) consisting of five compounds. The extracted aqueous part was acidified
3
with HCl to pH 2 and again extracted with CHCl to afford pure 14 (0.2 g), R 0.25.
3
f
X-ray Crystal Structure Analysis. Transparent crystals of 5, 104HCl, and 11 were prepared as elongated prisms by
slow evaporation of the corresponding solvents at room temperature. Unit-cell constants were determined and refined on a
CCD Xcalibur Ruby diffractometer (Oxford Diffraction) using Cu Kꢁ-radiation (300 K, graphite monochromator). A three-
dimensional data set of reflections was obtained on the same diffractometer. Absorption corrections were applied using a
semi-empirical method in the SADABS program [16]. Table 1 presents the principal crystallographic parameters and the
characteristics of the XSA experiments and crystal structure refinement calculations.
The structures were solved by direct methods using the SHELXS-97 program set. The structures were refined using
the SHELXL-97 program [17]. All non-hydrogen atoms were refined by anisotropic full-matrix least-squares methods (over
2
F ). Positions of H atoms were found geometrically and refined with fixed isotropic thermal parameters U = nU , where
iso
eq
n = 1.5 for methyls and 1.2 for others and U is the equivalent isotropic thermal parameter of the corresponding C atoms.
eq
Results from the XSA experiments were deposited in the Cambridge Crystallographic Data Centre (CCDC).
ACKNOWLEDGMENT
The work was financed by the Basic Research Program of KKRNT, RUz, Grant FA-F7-T185.
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