Regioselective synthesis of 1-substituted 6-methoxy-3,3,4,4-tetramethyl-3,4-dihydroisoquinolines via Ritter reaction

Article abstract of DOI:10.1007/s11172-014-0706-4

2-(4-Methoxyphenyl)-3,3-dimethylbutan-2-ol and nitriles undergo the Ritter reaction in concentrated sulfuric acid to give 1-R-6-methoxy-3,3,4,4-tetramethyl-3,4-dihydroisoquinolines.

Full text of DOI:10.1007/s11172-014-0706-4

Russian Chemical Bulletin, International Edition, Vol. 63, No. 9, pp. 2087—2091, September, 2014
2087
Regioselective synthesis of 1ꢀsubstituted 6ꢀmethoxyꢀ3,3,4,4ꢀtetramethylꢀ
3
,4ꢀdihydroisoquinolines via Ritter reaction*
Yu. V. Shklyaev, Yu. S. Rozhkova, A. N. Perevoshchikova, and A. A. Gorbunov
Institute of Technical Chemistry, Ural Branch of the Russian Academy of Sciences,
3
ul. Akad. Koroleva, 614990 Perm, Russian Federation.
Fax: +7 (342) 237 8262. Eꢀmail: yushka@newmail.ru
2
ꢀ(4ꢀMethoxyphenyl)ꢀ3,3ꢀdimethylbutanꢀ2ꢀol and nitriles undergo the Ritter reaction
in concentrated sulfuric acid to give 1ꢀRꢀ6ꢀmethoxyꢀ3,3,4,4ꢀtetramethylꢀ3,4ꢀdihydroisoꢀ
quinolines.
Key words: 2ꢀ(4ꢀmethoxyphenyl)ꢀ3,3ꢀdimethylbutanꢀ2ꢀol, nitriles, sulfuric acid, 1ꢀRꢀ6ꢀ
methoxyꢀ3,3,4,4ꢀtetramethylꢀ3,4ꢀdihydroisoquinoline, Ritter reaction.
Earlier, we have shown that the acidꢀcatalyzed Ritter
reaction of 3,3ꢀdimethylꢀ2ꢀphenylbutanꢀ2ꢀol with nitriles
leads to the formation of 1ꢀRꢀ3,3,4,4ꢀtetramethylꢀ3,4ꢀ
phenyl)ꢀ3,3ꢀdimethylbutanꢀ2ꢀol (1) with nitriles catalyzed
by concentrated sulfuric acid.
We found that the reactions of carbinol 1 with nitrꢀ
iles 2a—g take an alternative pathway than those of 1ꢀ(4ꢀ
methoxyphenyl)ꢀ2ꢀmethylpropanꢀ1ꢀol, and in this case
instead of expected spirane system, the earlier unknown
1ꢀRꢀ6ꢀmethoxyꢀ3,3,4,4ꢀtetramethylꢀ3,4ꢀdihydroisoquinꢀ
olines 3a—g are formed, which were isolated in 56—82%
yields (Scheme 1).
1
dihydroisoquinolines and is an efficient approach to the
introduction of alkyl substituents simultaneously at posiꢀ
tions 3 and 4 of the 3,4ꢀdihydroisoquinoline ring. It is
known that in the case when the Ritter reaction involves
alcohols containing an alkoxy group at paraꢀposition of
the aromatic moiety, for example, 1ꢀ(4ꢀmethoxyphenyl)ꢀ
2
ꢀmethylpropanꢀ1ꢀol or (4ꢀmethoxyphenyl)cycleohexylꢀ
The structures of compounds 3a—g were confirmed by
1
13
methanol, the products are 1ꢀRꢀ3,3ꢀdimethylꢀ2ꢀazaꢀ
elemental analysis, mass, IR, and H and C NMR specꢀ
2,3
1
spiro[4,5]decaꢀ6,9ꢀdienꢀ and ꢀ1,6,9ꢀtrienꢀ8ꢀones, rathꢀ
er than 1ꢀRꢀ3,4ꢀdihydroisoquinolines. This work is diꢀ
rected on the studies of the reaction of 2ꢀ(4ꢀmethoxyꢀ
tra. The H NMR spectra of isoquinolines 3a—g exhibit
the signals for the methyl groups C(3)Me and C(4)Me
2
2
as two singlets at H 1.13—1.32. The singlet with the inteꢀ
Scheme 1
2
a—g, 3b—g: R = CH COOEt (a), Me (b), SMe (c), Ph (d), 4ꢀO NC H (e), 2ꢀPy (f), 3,4ꢀ(MeO) C H (g)
2 2 6 4 2 6 3
*
Based on the Materials of International Scientific Conference "New Directions in Chemistry of Heterocyclic Compounds" (Septemꢀ
ber 17—21, 2013, Pyatigorsk).
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 9, pp. 2087—2091, September, 2014.
1
066ꢀ5285/14/6309ꢀ2087 © 2014 Springer Science+Business Media, Inc.

2088
Russ.Chem.Bull., Int.Ed., Vol. 63, No. 9, September, 2014
Shklyaev et al.
gral intensity of 3 H in the region H 3.82—3.86 corꢀ
responds to the signal of the MeO group. The signal
C(15)
C(14)
for proton H(5) is found as a doublet at  6.88—7.04
H
4
(
J = 2.3—2.6 Hz). The doublet of doublets in the region
H 6.66—6.74 ( J = 8.4—8.6 Hz and J = 2.3—2.6 Hz)
C(13)
3
4
corresponds to proton H(7). The signal for proton H(8) is
C(3)
C(5)
3
O(1)
found as a doublet in the region H 7.42—7.46 ( J =
C(2)
3
C(4)
=
=
8.4—8.6 Hz) for 3a—c and H 7.00—7.20 ( J =
8.4—8.6 Hz) for isoquinolines 3d—g with an aromatic
N(1)
C(12)
C(6)
substituent at position 1. Isoquinoline 3a exists in the
C(9)
enamine form, which is confirmed by the presence in the
H NMR spectrum of a singlet for the vinyl proton at
C(1)
C(7)
C(10)
1
H 5.00, as well as a broad singlet at H 8.91 corresponding
to the NH proton. The IR spectrum of 3a exhibits an
C(8)
C(11)
–1
absorption band at 3441 cm corresponding to the stretchꢀ
ing vibrations of the NH group. It should be noted that
chromatoꢀmass spectrometric analysis of 3a is accompaꢀ
nied by thermolysis of ester 3a, with the detection of the
peak of only 1ꢀmethyl derivative 3b as it is described in the
S(1)
Fig. 1. Structure of 6ꢀmethoxyꢀ3,3,4,4ꢀtetramethylꢀ1ꢀmethylꢀ
thioꢀ3,4ꢀdihydroisoquinoline (3c) according to the Xꢀray difꢀ
fraction data.
4
work. The structure of 3,4ꢀdihydroisoquinoline 3c was
unambiguously confirmed by the data of Xꢀray diffraction
studies (Fig. 1).
C(3) and C(4) of spiroꢀsigmaꢀcomplex D hinders the formaꢀ
We believe that carbinol 1 upon treatment with an acid
initially undergoes the Wagner—Meerwein rearrangement.
The forming carbocation B is stabilized through the addiꢀ
tion of a nitrile, that leads to the nitrilium ion C, which
intramolecularly cyclizes at ipsoꢀposition because of the
orientation effect of methoxy group with the formation of
spiroꢀsigmaꢀcomplex D. By all accounts, the steric strain
developed by the vicinal gemꢀdimethyl groups at atoms
tion of stable spirane system, unlike it was observed earliꢀ
2,3,5
er,
and rather causes the 1,2ꢀshift of the C(4)—C(5)
bond in complex D, that leads to the final products 3
(Scheme 2).
The formation of 3,4ꢀdihydroisoquinoline derivaꢀ
tives through the spiro intermediates, including the Bisꢀ
chler—Napieralski and Ritter reactions, is described in
the works,6 however, they led to the isolation of mixꢀ
—8
Scheme 2

3
,3,4,4ꢀTetramethylꢀ3,4ꢀdihydroisoquinolines
Russ.Chem.Bull., Int.Ed., Vol. 63, No. 9, September, 2014
2089
1
0
tures of regioisomers in different ratios, whereas in our
case the formation of regioisomeric 7ꢀmethoxy derivatives
was not observed.
60 mmol) and CH3I (8.23 g, 58 mmol) in Et2O (18 mL) ) with
stirring at such a rate that the mixture was slightly boiling. After
ketone was added, the reaction mixture was refluxed for addiꢀ
tional 2 h. Then, the mixture was cooled with ice and hydrolyzed
The reaction of carbinol 1 with methylthiocyanate 2c,
besides compound 3c, gives 3,3,4,4ꢀtetramethylꢀ1ꢀmethylꢀ
thioꢀ3,4ꢀdihydroisoquinolinꢀ6ꢀol 4 as well, which was isoꢀ
lated in 14% yield (see Scheme 2). The structure of prodꢀ
by a slow dropwise addition of a saturated solution of NH Cl
35 mL). The phases formed were separated, the aqueous phase
was extracted with Et O (3×15 mL). The combined organic exꢀ
tracts were washed with water and dried with MgSO , the solꢀ
vent was evaporated. The residue was crystallized from hexane.
The yield was 6.53 g (68%), colorless crystals, m.p. 54—56 C.
Found (%): C, 74.84; H, 9.38. C13H20O2. Calculated (%): C, 74.96;
H, 9.68. IR, /cm– : 3525; 2946; 1610. H NMR (DMSOꢀd ),
: 0.85 (s, 9 H, CMe ); 1.48 (s, 3 H, Me); 3.77 (s, 3 H, MeO);
3
.63 (s, 1 H, OH); 6.86 (d, 2 H, H (3), H (5), J = 8.4 Hz); 7.36
Ar Ar
4
(
2
4
1
uct 4 was confirmed by the presence in its H NMR spectrum
of a singlet for the OH group at H 8.91 and the absence of
the signal for the methoxy group. The IR spectrum of 4
1
1
–
1
exhibits a broad band in the region 3200—3400 cm corꢀ
responding to the stretching vibrations of the Hꢀbound
OH group. We suggest that the formation of 4 occurs
through the addition of water to the spiro intermediate D
with subsequent elimination of a methanol molecule,
that leads to spiroꢀsigmaꢀcomplex F, the 1,2ꢀshift of the
C(4)—C(5) bond in which gives isoquinoline 4.
6

4
(
13
d, 2 H, HAr(2), H (6), J = 8.4 Hz). C NMR (CDCl ),
A
r
3

: 25.23(Me), 25.67 (CMe ), 37.99(C(3)), 54.08 (MeO), 78.18
3
(
C(2)), 112.30 (C (3), C (5)), 128.11 (C (2), C (6)), 138.39
Ar Ar Ar Ar
+
(
C (1)), 157.97 (CAr(4)). MS, m/z (Irel (%)): 208 [M] (0.1),
Ar
+
151 [M – C H ] (100), 43 (30).
4
9
In conclusion, we established that the Ritter reaction
of 2ꢀ(4ꢀmethoxyphenyl)ꢀ3,3ꢀdimethylbutanꢀ2ꢀol with
nitriles leads to 1ꢀRꢀ6ꢀmethoxyꢀ3,3,4,4ꢀtetramethylꢀ3,4ꢀ
dihydroisoquinolines. In contrast to the reactions studied
earlier,2 no formation of the spirane system is observed
in this case, most likely, because of steric factors.
Synthesis of compounds 3 and 4 (general procedure). A mixꢀ
ture of compound 1 (1 mmol) and nitrile 2a—f (1 mmol) (1 mmol)
was added dropwise to 92% H SO (1 mL) with vigorous stirring
2
4
and cooling with icy water. Then, the reaction mixture was stirred
for 30 min at room temperature, poured into a mixture of crushed
ice and aqueous ammonia (4 mL). The reaction product was
extracted with CH Cl (3×5 mL). The combined extracts were
,3
2
2
washed with water and dried with MgSO , the solvent was evapꢀ
4
Experimental
orated. The residue was subjected to chromatography (3a,c,d,f,g)
or recrystallized (3b,e). Isolation of compound 3c also gave comꢀ
pound 4 as a byꢀproduct.
Commercially available reactants and solvents purchased
from Alfa Aesar, Sigma—Aldrich, and Reakhim were used in
Ethyl 2ꢀ(6ꢀmethoxyꢀ3,3,4,4ꢀtetramethylꢀ1,2,3,4ꢀtetrahyꢀ
droisoquinolinꢀ1ꢀylidene)acetate (3a). The yield was 0.20 g (62%),
a yellowish orange oil (eluent hexane—ethyl acetate, 8 : 1).
Found (%): C, 71.03; H, 8.15; N, 4.33. C H NO Calculated (%):
this work.
1
H and 13C NMR (DEPT) NMR spectra were recorded on
a Varian Mercury Plus 300 spectrometer ( H: 300.06 MHz, C:
5.46 MHz, internal standard HMDS). Mass spectra were obꢀ
tained on an Agilent Technologies 6890N/5975B chromatoꢀmass
spectrometer, an HPꢀ5ms column, 30 m×0.25 mm, 0.25 m,
carrier gas helium (1 mL min–1), ionization by electron impact
1
13
1
8
25
3.
–
1
7
C, 71.26; H, 8.31; N, 4.62. IR, /cm : 3441; 2974; 1735; 1599.
H NMR (CDCl ), : 1.17—1.32 (m, 15 H, C(3)Me , C(4)Me ,
1
3
2
2
OCH Me); 3.84 (s, 3 H, OMe); 4.14 (q, 2 H, OCH Me,
2
2
3
3
J = 7.1 Hz); 5.00 (s, 1 H, —CH=); 6.75 (dd, 1 H, H(7), J = 8.5 Hz,
4
4
(
70 eV). IR spectra were recorded on a Bruker IFSꢀ66/S Fouriꢀ
J = 2.6 Hz); 6.88 (d, 1 H, H(5), J = 2.6 Hz); 7.60 (d, 1 H,
3
13
erꢀtransform IR spectrometer for neat samples. Elemental analꢀ
ysis was performed on a Leco CHNSꢀ932 analyzer. Reaction
progress and purity of compounds obtained were carried out by
TLC on Silufol plates, visualizing with 0.5% solution of chloraꢀ
nyl in toluene and UV light. Column chromatography was perꢀ
formed on silica gel (0.06—0.20 mm, 70—230 mesh., Lancastꢀ
er). Melting points were measured on a PTP heating stage and
were not corrected.
H(8), J = 8.5 Hz); 8.91 (br.s, 1 H, NH). C NMR (CDCl ),
3
: 14.67 (OCH Me), 22.14, 24.31 (C(4)Me , C(3)Me ), 40.56
2
2
2
(C(4)), 55.18 (OMe), 58.23 (OCH Me), 61.54 (C(3)), 75.54
2
(—CH=), 110.60, 110.85 (C(5), C(7)), 126.94 (C(8a)), 128.38
(C(8)), 149.19 (C(4a)), 161.91, 162.65 (C(1), C(6)), 171.24 (C=O).
6ꢀMethoxyꢀ1,3,3,4,4ꢀpentamethylꢀ3,4ꢀdihydroisoquinoline
(3b). The yield was 0.13 g (56%), orange crystals, m.p. 100—102 C
(from hexane). Found (%): C, 77.53; H, 9.35; N, 5.93. C H NO.
1
5
21
–
1
1
ꢀ(4ꢀMethoxyphenyl)ꢀ2,2ꢀdimethylpropanꢀ1ꢀone was obꢀ
tained from anisole (64.88 g, 600 mmol) and trimethylacetyl
Calculated (%): C, 77.88; H, 9.15; N, 6.05. IR, /cm : 2970;
1
1612; 1599. H NMR (CDCl ), : 1.15, 1.19 (both s, 6 H each,
3
chloride (24.12 g, 200 mmol) with catalysis by AlCl (26.67 g,
C(3)Me , C(4)Me ); 2.38 (s, 3 H, C(1)Me); 3.85 (s, 3 H,
3
2
2
9
3
4
2
00 mmol) according to the procedure described earlier. The
OMe); 6.74 (dd, 1 H, H(7), J = 8.6 Hz, J = 2.6 Hz); 6.90 (d, 1 H,
4
3
13
yield was 32.01 g (83%), colorless liquid, b.p. 131—133 C (6 Torr).
Found (%): C, 75.13; H, 8.25. C H O . Calculated (%):
H(5), J = 2.6 Hz); 7.42 (d, 1 H, H(8), J = 8.6 Hz). C NMR
(CDCl ), : 23.13, 23.23 (C(1)Me, C(3)Me , C(4)Me ), 38.57
1
2
16
2
3
2
2
C, 74.97; H, 8.39. IR, /cm–1: 2978, 1665, 1602. H NMR (CDCl ),
1
(C(4)), 55.10 (OMe), 58.78 (C(3)), 109.56, 110.56 (C(5), C(7)),
121.23 (C(8a)), 126.85 (C(8)), 148.82 (C(4a)), 160.04, 161.64
3

: 1.35 (s, 9 H, C(2)(Me) ); 3.81 (s, 3 H, OMe); 6.87 (d, 2 H,
3
+
+
HAr(3), H (5), J = 8.7 Hz); 7.84 (d, 2 H, H (2), H (6),
(C(1), C(6)). MS, m/z (Irel (%)): 231 [M] (100), 216 [M – Me]
Ar
Ar
Ar
+
t +
J = 8.7 Hz). MS, m/z (Irel (%)): 192 [M] (2), 135 [M – Bu ] (100).
ꢀ(4ꢀMethoxyphenyl)ꢀ3,3ꢀdimethylꢀbutanꢀ2ꢀol (1). A solution
of 1ꢀ(4ꢀmethoxyphenyl)ꢀ2,2ꢀdimethylpropanꢀ1ꢀone (8.83 g,
6 mmol) in Et O (10 mL) was added dropwise to a freshly
(59), 188 (62), 174 (93), 159 (88), 115 (34).
2
6ꢀMethoxyꢀ3,3,4,4ꢀtetramethylꢀ1ꢀmethylthioꢀ3,4ꢀdihydroꢀ
isoquinoline (3c). The yield was 0.17 g (65%), colorless crystals,
m.p. 82—83.5 C (eluent hexane—ethyl acetate, 8 : 1). Found (%):
4
2
prepared solution of CH MgI in Et O (obtained from Mg (1.46 g,
C, 68.19; H, 8.05; N, 5.40; S, 12.29. C H NOS. Calculatꢀ
3
2
15 21

2090
Russ.Chem.Bull., Int.Ed., Vol. 63, No. 9, September, 2014
Shklyaev et al.
ed (%): C, 68.40; H, 8.04; N, 5.32; S, 12.17. IR, /cm–1: 2973;
2869; 1604. H NMR (CDCl ), : 1.25 (m, 12 H, C(3)(Me) ,
1
3
2
1
1
604; 1557. H NMR (CDCl ), : 1.13, 1.18 (both s, 6 H each,
(C(4)Me ); 3.85 (s, 3 H, OMe); 3.90 (s, 3 H, OMe); 3.91 (s, 3 H,
OMe); 6.66 (dd, 1 H, H(7), J = 8.6 Hz, 4J = 2.6 Hz);
6.88 (d, 1 H, H (5), J = 8.1 Hz); 6.95 (d, 1 H, H(5), J = 2.6 Hz);
7.08 (dd, 1 H, H (6), J = 8.1 Hz, J = 1.8 Hz); 7.11 (d, 1 H,
Ar
3
2
3
C(3)Me , C(4)Me ); 2.40 (s, 3 H, SMe); 3.83 (s, 3 H, OMe);
2
2
3
4
3
4
6
.71 (dd, 1 H, H(7), J = 8.4 Hz, J = 2.6 Hz); 6.87 (d, 1 H,
H(5), J = 2.6 Hz); 7.56 (d, 1 H, H(8), J = 8.4 Hz). C NMR
Ar
4
3
13
3
4
4
3
13
(
CDCl ), : 11.99 (SMe), 23.38, 23.66 (C(3)Me , C(4)Me ),
H (2), J = 1.8 Hz); 7.17 (d, 1 H, H(8), J = 8.6 Hz). C NMR
3
2
2
Ar
3
9.06 (C(4)), 55.15 (OMe), 61.03 (C(3)), 109.60, 110.62 (C(5),
(CDCl ), : 23.76 (C(3)Me , C(4)Me ), 38.53 (C(4)), 55.14
3
2
2
C(7)), 121.14 (C(8a)), 126.12 (C(8)), 148.13 (C(4a)), 158.53,
(OMe), 55.85 (OMe), 55.91 (OMe), 59.53 (C(3)), 109.21,
110.53, 110.65, 111.81 (C(5), C(7), CAr(2), CAr(5)), 120.73
(C(8a)), 121.54, 129.78 (C(8), C (6)), 132.51 (C (1)), 148.68,
1
61.82 (C(1), C(6)). MS, m/z (I (%)): 263 [M]+ (10.7), 248
rel
+
[
M – Me] (100).
Ar
Ar
6
ꢀMethoxyꢀ3,3,4,4ꢀtetramethylꢀ1ꢀphenylꢀ3,4ꢀdihydroisoꢀ
149.68, 149.98 (C(4a), C (3), C (4)), 161.69, 163.07 (C(1),
Ar Ar
+
+
quinoline (3d). The yield was 0.24 g (82%), a yellow oil (eluent
hexane—ethyl acetate, 4 : 1). Found (%): C, 81.63; H, 7.74;
N, 4.49. C H NO. Calculated (%): C, 81.87; H, 7.90; N, 4.77.
C(6)). MS, m/z (I (%)): 353 [M] (79), 352 [M – H] (100),
rel
+
338 [M – Me] (40), 297 (37), 282 (22).
3,3,4,4ꢀTetramethylꢀ1ꢀmethylthioꢀ3,4ꢀdihydroisoquinolinꢀ6ꢀ
ol (4). The yield was 0.03 g (14%), a yellow powder, m.p. 60—68 C.
2
1
0
23
–
1
IR, /cm : 2969; 1605. H NMR (CDCl ), : 1.21, 1.28 (both s,
3
6
H each, C(3)Me ), C(4)Me ); 3.84 (s, 3 H, OMe); 6.64 (dd, 1
Found (%): C, 67.54; H, 7.79; N, 5.51; S, 12.84. C H NOS.
2
2
14 19
3
4
–1
H, H(7), J = 8.6 Hz, J = 2.6 Hz); 6.95 (d, 1 H, H(5),
Calculated (%): C, 67.43; H, 7.68; N, 5.62; S, 12.86. IR, /cm :
4
3
1
J = 2.6 Hz); 7.09 (d, 1 H, H(8), J = 8.6 Hz); 7.39—7.40 (m, 3 H,
3150 (br); 2975; 1602; 1570. H NMR (DMSOꢀd ), : 1.11, 1.14
6
Ar); 7.50—7.53 (m, 2 H, Ar). 13C NMR (CDCl ), : 23.04
(both s, 6 H each, C(3)Me , C(4)Me ); 2.36 (s, 3 H, SMe); 6.69
3
2
2
3
4
(
(
1
C(3)Me , C(4)Me ), 38.56 (C(4)), 55.18 (OMe), 59.69
C(3)), 109.25, 110.70 (C(5), C(7)), 120.76(C(8a)), 128.06,
28.61, 128.69, 129.77 (C(8), C (2), CAr(3), C (4), CAr(5),
(dd, 1 H, H(7), J = 8.2 Hz, J = 2.5 Hz); 6.84 (d, 1 H,
H(5), J = 2.5 Hz); 7.42 (d, 1 H, H(8), J = 8.2 Hz); 10.02 (s, 1 H,
OH). C NMR (DMSOꢀd ), : 11.41 (SMe), 23.25, 23.73
2
2
4
3
1
3
Ar
Ar
6
C (6)), 139.78 (C (1)), 149.85 (C(4a)), 161.75, 163.62 (C(1),
(C(3)(Me) , C(4)(Me) ), 40.13 (C(4)), 60.71 (C(3)), 111.18,
112.55 ((C(5), C(7)), 119.05 (C(8a)), 125.91 (C(8)), 147.85
Ar
Ar
2
2
+
+
C(6)). MS, m/z (I (%)): 293 [M] (72.8), 292 [M – H] (100),
rel
+
2
88 [M – Me] (22), 237 (45), 221 (21).
(C(4a)), 158.08, 160.50 (C(1), C(6)). MS, m/z (I (%)): 249
rel
+
+
6
ꢀMethoxyꢀ3,3,4,4ꢀtetramethylꢀ1ꢀ(4ꢀnitrophenyl)ꢀ3,4ꢀdiꢀ
[M] (11), 234 [M – CH ] (100).
3
hydroisoquinoline (3e). The yield was 0.23 g (68%), light yellow
crystals, m.p. 108—110 C (from acetone). IR, /cm–1: 2973;
1
604; 1520. Found (%): C, 70.69; H, 6.83; N, 8.32. C H N O
20 22 2 3
Table 1. Crystallographic data and parameters of Xꢀray diffracꢀ
tion experiment for compound 3c
1
Calculated (%): C, 70.99; H, 6.55; N, 8.28. H NMR (CDCl ),
3

: 1.25, 1.29 (both br.s, 6 H each, C(3)Me , C(4)Me ); 3.86
2 2
3
4
(
s, 3 H, OMe); 6.68 (dd, 1 H, H(7), J = 8.5 Hz, J = 2.3 Hz);
4
3
Parameter
Value
6
7
.99 (d, 1 H, H(5), J = 2.3 Hz); 7.00 (d, 1 H, H(8), J = 8.5 Hz);
3
.73 (d, 2 H, H (2), H (6), J = 9.0 Hz); 8.23 (d, 2 H, H (3),
Ar
Ar
13
Ar
Molecular formula
Molecular weight
Crystal system
Space structure
Unit cell parameters
a/Å
C H NOS
3
15 21
HAr(5), J = 9.0 Hz). C NMR (CDCl ), : 22.79, 23.22
3
263.39
Monoclinic
P21
(
C(3)Me , C(4)Me ), 38.58 (C(4)), 55.23 (OMe), 60.32 (C(3)),
2 2
1
1
1
09.57, 111.10 (C(5), C(7)), 119.75 (C(8a)), 123.35, 129.10,
29.61 (C(8), CAr(2), C (3), C (5), C (6)), 145.97, 148.03,
Ar
Ar
Ar
49.83 (C(4a), C (1), C (4)), 162.03, 162.24 (C(1), C(6)). MS,
Ar
Ar
+
8.5094 (8)
7.3761 (8)
11.6703(10)
90.00
97.446
90.00
726.323
2
1.204
m/z (Irel (%)): 338 [M] (87.9), 323 [M – Me]+ (20), 291 (24),
b/Å
c/Å
2
82 (100), 266 (28).
ꢀMethoxyꢀ3,3,4,4ꢀtetramethylꢀ1ꢀ(pyridinꢀ2ꢀyl)ꢀ3,4ꢀdihydroꢀ
isoquinoline (3f). The yield was 0.21 g (72%), a light yellow oil
eluent hexane—ethyl acetate, 2 : 1). Found (%): C, 77.48 ; H, 7.69;
N, 9.37. C19H22N O. Calculated (%): C, 77.52; H, 7.53;
6

/deg
/deg
/deg


(
2
3
V/Å
–1
1
N, 9.52. IR, /cm : 2972; 1606; 1569. H NMR (CDCl ), : 1.25,
1
OMe); 6.67 (dd, 1 H, H(7), J = 8.5 Hz, J = 2.7 Hz); 7.04 (d, 1 H,
H(5), J = 2.4 Hz); 7.23—7.38 (m, 2 H, H (5), H(8)); 7.72—7.82
3
Z
d

.28 (both br.s, 6 H each, C(3)Me ), C(4)Me ); 3.82 (s, 3 H,
2 2
/g cm–3
3
4
calc
/mm–1
0.212
4
Ру
Range of data collection/deg
Reflection collected
2.80—28.28
3381
3
(
4
m, 2 H, HРу(3), HРу(4)); 8.65 (dt, 1 H, HРу(6), J = 4.8 Hz,
J = 1.2 Hz). C NMR (CDCl ), : 22.88, 23.22 (C(3)Me ,
13
3
2
Number of independent reflections
Number of refined parameters N
Rint
2645
163
0.0159
3.26
C(4)Me ), 38.59 (C(4)), 55.17 (OMe), 60.05 (C(3)), 109.52,
1
CРу(4)), 129.97 (C(8)), 136.70 (CРу(5)), 148.40 (CРу(3)), 149.68
2
10.6 (C(5), C(7)), 119.85 (C(8a)), 123.43, 123.84 (CРу(6),
R ꢀfactor (%)
1
(
(
C(4a)), 157.72, 161.96, 162.22 (C(1), C(6), CРу(2)). MS, m/z
Rꢀfactors on I > 2(I)
+
+
Irel (%)): 294 [M] (10), 279 [M – Me] (100).
ꢀ(3,4ꢀDimethoxyphenyl)ꢀ6ꢀmethoxyꢀ3,3,4,4ꢀtetramethylꢀ
,4ꢀdihydroisoquinoline (3g). The yield was 0.24 g (68%), colorꢀ
R1
wR2
0.0326
0.0751
1
3
Rꢀfactors on all reflections
less crystals, m.p. 102 C (eluent hexane—ethyl acetate, 4 : 1).
Found (%): C, 74.87; H, 7.95; N, 3.68. C22H NO . Calꢀ
culated (%): C, 74.76; H, 7.70; N, 3.96. IR, /cm : 2972;
R1
wR2
0.0537
0.0778
27
3
1
–

3
,3,4,4ꢀTetramethylꢀ3,4ꢀdihydroisoquinolines
Russ.Chem.Bull., Int.Ed., Vol. 63, No. 9, September, 2014
2091
Xꢀray diffraction analysis. Single crystals of compound 3c
3. V. A. Glushkov, O. G. Ausheva, Yu.V. Shklyaev. Chem.
Heterocycl. Compd. (Engl. Transl.), 2000, 5, 607 [Khim.
Geterotsikl. Soedin., 2000, 5, 693].
4. Yu. V. Shklyaev, A. A. Smolyak, A. A. Gorbunov, Russ. J.
Org. Chem. (Engl. Transl.), 2011, 47, 239 [Zh. Org. Khim.,
2011, 47, 247].
5. V. A. Glushkov, Yu. V. Shklyaev, V. I. Sokol, V. S. Sergienꢀ
ko, V. V. Davidov, Mendeleev Commun., 1998, 6, 227.
6. Yu. V. Shklyaev, V. A. Glushkov, M. A. El´tzov, Y. V. Gatilov,
I. Y. Bagryanskaya, A. G. Tolstikov, Mendeleev Commun.,
were obtained by crystallization from ethyl acetate. Xꢀray difꢀ
fraction experiments were performed on a Xcaliburꢀ3 diffractoꢀ
meter with a CCD detector at 295(2) K (ꢀMoꢀK, graphite
monochromator, ꢀ and ꢀscan technique). The structure of
compound 3c was solved by direct method using the SHELXSꢀ97
program and refined using the SHELXLꢀ97 program in anisoꢀ
tropic (isotropic for hydrogen atoms) approximation. Principal
crystallographic data for compound 3c and some experimental
characteristics are given in Table 1.
2
005, 15, 125.
The author are deeply grateful to P. A. Slepukhin (I. Ya.
Postovsky Institute of Organic Synthesis of the Ural
Branch of the Russian Academy of Sciences).
This work was financially supported by the Russian
Academy of Sciences (Program of the Presidium of RAS,
Project No. 2ꢀPꢀ3ꢀ1007).
7. S. Doi, N. Shirai, Y. Sato, J. Chem. Soc., Perkin Trans. 1,
1997, 2217.
8. Yu. V. Shklyaev, M. A. El´tsov, Butlerovskiye Soobshcheniya
[
Butlerov Commun.] 2007, 11, 25 (in Russian).
9
. A. G. Ismailov, M. A. Rustamov, F. A. Rustamov, Zh. Org.
Khim., 1971, 7, 2115 [J. Org. Chem. USSR (Engl. Transl.),
1
971, 7].
1
0. H. Becker, W. Berger, G. Domschke, E. Fanghanel, J. Faust,
M. Fischer, F. Gentz, K. Gewald, R. Gluch, R. Mayer,
K. Muller, D. Pavel, H. Schmidt, K. Schollberg, K. Schwetꢀ
lick, E. Seiler, G. Zeppenfeld, Ed. K. Schwetlick, Organikum
II, Veb Deutscher Verlag der Wissenschaften, Berlin, 1976.
References
1
2
. Pat. RF 2326114; Byul. isobret. [Invention Bull.] 2008, 16
in Russian).
. V. A. Glushkov, O. G. Ausheva, L. V. Anikina, Yu. B.
(
Vikharev, V. A. Safin, Yu. V. Shklyaev, Pharm. Chem. J.
Received November 14, 2013;
in revised form March 19, 2014
(Engl. Transl.), 2001, 35, 358 [Khim. Farm. Zh., 2001, 35, 12].