Regioisomerism in the Ritter reaction. 1. Synthesis of 3,3,5,6,7-, 3,3,6,7,8-, 3,3,5,7,8-, and 3,3,5,6,8-pentamethyl-3,4-dihydroisoquinolines from 1,2,3- and 1,2,4-trimethylbenzenes

Article abstract of DOI:10.1023/B:RUCB.0000037862.92972.b4

Reactions of 1,2,3- or 1,2,4-trimethylbenzene with isobutyraldehyde and ethyl cyanoacetate (ECA) or reactions of the corresponding 1-aryl-2- methylpropan-1-ols with ECA afforded isomeric 3,3,5,6,7-, 3,3,6,7,8-, 3,3,5,7,8-, and 3,3,5,6,8-pentamethyl-3,4-di

Full text of DOI:10.1023/B:RUCB.0000037862.92972.b4

906
Russian Chemical Bulletin, International Edition, Vol. 53, No. 4, pp. 906—910, April, 2004
Regioisomerism in the Ritter reaction
1. Synthesis of 3,3,5,6,7ꢀ, 3,3,6,7,8ꢀ, 3,3,5,7,8ꢀ, and 3,3,5,6,8ꢀpentamethylꢀ
3,4ꢀdihydroisoquinolines from 1,2,3ꢀ and 1,2,4ꢀtrimethylbenzenes
Yu. V. Shklyaev,aꢀ R. R. Ismagilov,b Yu. S. Rozhkova,a A. A. Fatykhov,b I. B. Abdrakhmanov,b and A. G. Tolstikova
aInstitute of Technical Chemistry, Ural Division of the Russian Academy of Sciences,
13 ul. Lenina, 614990 Perm, Russian Federation.
Fax: +7 (342 2) 12 6237. Eꢀmail: cheminst@mpm.ru
bInstitute of Organic Chemistry, Ufa Research Center of the Russian Academy of Sciences,
71 prosp. Oktyabrya, 450054 Ufa, Russian Federation.
Fax: +7 (347 2) 35 6066
Reactions of 1,2,3ꢀ or 1,2,4ꢀtrimethylbenzene with isobutyraldehyde and ethyl cyanoacetate
(ECA) or reactions of the corresponding 1ꢀarylꢀ2ꢀmethylpropanꢀ1ꢀols with ECA afforded
isomeric 3,3,5,6,7ꢀ, 3,3,6,7,8ꢀ, 3,3,5,7,8ꢀ, and 3,3,5,6,8ꢀpentamethylꢀ3,4ꢀdihydroisoquinolines.
Isomerization is explained as the ring opening of a spiran intermediate in two possible ways
followed by the Jacobsen rearrangement.
Key words: Ritter reaction, pseudocumene, 1,2,3ꢀtrimethylbenzene, isobutyraldehyde, niꢀ
triles, spirocyclization, isomerization.
Reactions of activated arenes with nitriles and isoꢀ
butyraldehyde in conc. H2SO4 are known to yield deꢀ
rivatives of 3,3ꢀdimethylꢀ3,4ꢀdihydroisoquinoline.1,2
We found that the reaction of 1,2,4ꢀtrimethylbenꢀ
zene (pseudocumene, 1), isobutyraldehyde, and ethyl
cyanoacetate (ECA) gives a mixture of three prodꢀ
ucts (Scheme 1) in the ≈1 : 5 : 1 ratio determined
from the integral signal intensities in the 1H NMR
spectrum. According to NOE data, the products obꢀ
tained are ethyl 3,3,5,6,8ꢀpentamethylꢀ1,2,3,4ꢀtetraꢀ
hydroisoquinolylidenꢀ1ꢀacetate (3) and its isomeric
ethyl 3,3,5,6,7ꢀpentamethylꢀ (4) and 3,3,6,7,8ꢀpentaꢀ
methylꢀ1,2,3,4ꢀtetrahydroisoquinolylidenꢀ1ꢀacꢀ
etates (5).a
Scheme 1
3 : 4 : 5 = 1 : 5 : 1
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 4, pp. 869—873, April, 2004.
1066ꢀ5285/04/5304ꢀ0906 © 2004 Plenum Publishing Corporation

Regioisomerism in the Ritter reaction
Russ.Chem.Bull., Int.Ed., Vol. 53, No. 4, April, 2004
907
Scheme 2
The reaction of ECA with a separately prepared alcoꢀ
hol 2 yielded the same products.
(H(1´), s, δ 5.12) exhibits cross peaks with singlets for the
C atoms at the double bond at δ 77.0 and 156.5. The
protons of the 4ꢀCH2 group (s, δ 2.76) show cross peaks
with the C atom of the 4ꢀCH2 group (t, δ 39.1), C(4a)
(s, δ 131.2), and C(5) (s, δ 134.2).
The reaction of compound 6 or 7 with methyl thioꢀ
cyanate proceeds analogously (Scheme 4); in this case,
crystallization of the resulting mixture of sulfides 9 and 10
gave pure compound 9, from which isocarbostyril 11 was
obtained. The minor isomers 10 and 12 were identified
only spectroscopically (1H NMR data).
Similar processes were observed earlier in the
Bischler—Napieralski cyclization3 of Nꢀphenethylꢀ and
Nꢀ[2ꢀ(6´ꢀmethoxynaphthꢀ2´ꢀyl)]ethylbenzamides, which
is genetically linked with the Ritter reaction since both
involve the formation of the same intermediate.4
Compounds 4 and 5 were also formed by the threeꢀ
component synthesis from 1,2,3ꢀtrimethylbenzene (6),
isobutyraldehyde, and ECA or from alcohol 7 (sepaꢀ
rately prepared from 1ꢀbromoꢀ2,3,4ꢀtrimethylbenꢀ
zene and isobutyraldehyde) and ECA (4 : 5 = 5 : 1)
(Scheme 2).
The formation of products 4 and 5 from arene 6
and alcohol 7 can be explained by the skeleton isoꢀ
merization of spiro intermediate A in two pathways
(Scheme 3).
Scheme 3
In the case of pseudocumene 1, the reaction intermeꢀ
diate seems to be a spiro compound B (Scheme 5), which
should first lead to isoquinolines 3 and 8, the latter being
dominant. Then, product 8 probably undergoes the
Jacobsen rearrangement5 observed upon heating of tetraꢀ
alkylbenzenes in H2SO4. Insofar as the Jacobsen reacꢀ
tion is characterized by the migration of alkyl from the
orthoꢀ to paraꢀposition relative to the electronꢀwithꢀ
drawing group, the Me group in the in situ protonated
isoquinoline 8 apparently migrates predominantly from
C(8) to C(6) to give product 4 (minor migration of the
Me group from C(5) to C(6) affords product 5). It is
beyond question that isoquinoline 3 containing the Me
group in position 6 of the ring, undergoes no rearꢀ
rangement.
The structure of the carbon framework of compound 4
was refined from the 2D spectrum (COLOC, Table 1)
containing cross peaks between the singlet at δ 7.40 for
the aromatic proton and 13C NMR singlet signals at δ 124.2
(Cipso), 138.3 (Co), and 156.5 (C(1)). The vinylic proton
When the reaction time was reduced from 15 to 2 min,
product 8 was also isolated; however, the Jacobsen rearꢀ
rangement of these compounds seems to proceed very
rapidly since the yield of isoquinoline 8 at the lowest
possible reaction time was no higher than 10%.

908
Russ.Chem.Bull., Int.Ed., Vol. 53, No. 4, April, 2004
Shklyaev et al.
Table 1. COLOC 2D NMR spectrum of compound 4 ("+" indicates the presence of a cross peak)*
δ13 δ1
C
H
1.28
2.20
2.23
2.34
2.76
5.12
7.40
9.00
(3´,3´ꢀMe2)
(5´ꢀMe)
(6´ꢀMe)
(7´ꢀMe)
(C(4)H2)
(C(1´)H)
(C(8)H)
(NH)
15.4
(5´ꢀMe)
16.3
(6´ꢀMe)
20.9
(7´ꢀMe)
28.9
(3´,3´ꢀMe2)
39.1
(C(4)H2)
49.0
(C(3))
77.0
(C(1´)H)
124.2
(C(8)H)
125.7
(C(8a))
131.2
(C(4a))
134.2
(C(5))
134.3
(C(6))
138.3
(C(7))
156.5
—
—
—
+
+
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+
(C(1))
* The data for the ethoxycarbonyl group are not included.
Scheme 4

Regioisomerism in the Ritter reaction
Russ.Chem.Bull., Int.Ed., Vol. 53, No. 4, April, 2004
909
Scheme 5
Ethyl 3,3,5,6,8ꢀpentamethylꢀ1,2,3,4ꢀtetrahydroisoquinolylꢀ
idenꢀ1ꢀacetate (3). 1H NMR, δ: 1.22 (s, 6 H, Megem); 1.30 (t,
3 H, OCH2CH3, J = 7.2 Hz); 2.19 (s, 3 H, 5´ꢀMe); 2.32 (s, 3 H,
6´ꢀMe); 2.51 (s, 3 H, 8´ꢀMe); 2.78 (s, 2 H, C(4)H2); 4.20 (q,
2 H, OCH2Me, J = 7.2 Hz); 4.81 (s, 1 H, Hvinyl); 6.97 (s, H,
H(7) arom.); 9.11 (br.s, 1 H, NH).
Ethyl 3,3,5,7,8ꢀpentamethylꢀ1,2,3,4ꢀtetrahydroisoquinolylꢀ
idenꢀ1ꢀacetate (8), m.p. 71—72 °C (hexane). Found (%):
C, 75.19; H, 8.72; N, 4.93. C18H25NO2. Calculated (%):
C, 75.26; H, 8.71; N, 4.88. IR, ν/cm–1: 3250, 2960, 2850, 1640,
1600, 1370. 1H NMR, δ: 1.22 (s, 6 H, Megem); 1.29 (t, 3 H,
OCH2CH3, J = 7.2 Hz); 2.22 (s, 3 H, 5´ꢀMe); 2.26 (s, 3 H,
7´ꢀMe); 2.44 (s, 3 H, 8´ꢀMe); 2.67 (s, 2 H, 4ꢀCH2); 4.15 (q,
2 H, OCH2Me, J = 7.2 Hz); 4.76 (s, 1 H, Hvinyl); 7.01 (s, 1 H,
H arom.); 9.12 (br.s, 1 H, NH).
Ethyl 3,3,5,6,7ꢀpentamethylꢀ1,2,3,4ꢀtetrahydroisoquinolylꢀ
idenꢀ1ꢀacetate (4) (threeꢀcomponent synthesis). A mixture of
1,2,3ꢀtrimethylbenzene (1.2 g, 10 mmol), isobutyraldehyde
(0.72 g, 10 mmol), and ethyl cyanoacetate (1.13 g, 10 mmol)
was added dropwise at 5 to 10 °C for 3 min to stirred 95% H2SO4
(15 mL). Stirring was continued for 15 min and the mixture was
poured into crushed ice (100 g) and treated as described above
for the synthesis from pseudocumene. Column chromatography
(silica gel 30/50 deactivated with triethylamine, benzene—ether
(35 : 1)) gave pure compound 4 (1.5 g, 52%; m.p. 83—84 °C
(hexane)) and an inseparable mixture of esters 4 and 5
(5 : 4 = 4 : 1, 1H NMR data).
Ester 4. Found (%); C, 75.13; H, 8.62; N, 4.95. C18H25NO2.
Calculated (%): C, 75.26; H, 8.71; N, 4.88. IR, ν/cm–1: 3260,
2960, 2850, 1630, 1600, 1380. 1H NMR, δ: 1.28 (s, 6 H,
2 Megem); 1.30 (t, 3 H, OCH2CH3, J = 7.1 Hz); 2.20 (s, 3 H,
5´ꢀMe); 2.23 (s, 3 H, 6´ꢀMe); 2.34 (s, 3 H, 7´ꢀMe); 2.76
(s, 2 H, C(4)H2); 4.16 (q, 2 H, OCH2CH3, J = 7.1 Hz); 5.12
(s, 1 H, Hvinyl); 7.40 (s, 1 H, H(8)); 9.00 (br.s, 1 H, NH).
13C NMR, δ: 14.8 (CH2CH3); 15.4 (5´ꢀMe); 16.3 (6´ꢀMe);
20.9 (7´ꢀMe); 28.9 (Megem); 39.1 (C(4)H2); 49.0 (C(3)); 58.4
(CH2Me); 77.0 (Cvinyl); 124.2 (C(8)); 125.7 (C(8a)); 131.2
Experimental
Melting points were determined on a PTP instrument and
are given noncorrected. IR spectra were recorded on a URꢀ20
1
spectrophotometer (Nujol). H and 13C NMR spectra were reꢀ
corded in DMSOꢀd6 at 303 K on Bruker DRXꢀ500 (500.13 MHz)
and Bruker AMꢀ300 instruments (75.470 MHz), respectively.
The residual signal for protons in DMSOꢀd6 (δ 2.50) was used as
1
a reference signal in H NMR spectra; the chemical shift of the
signal for DMSOꢀd6 in 13C NMR spectra was δ 39.5. 2D spectra
were recorded according to Bruker standard procedures. The
mixing time in NOESY spectra was 500 ms. The HMBC experiꢀ
ment was optimized for a spinꢀspin coupling constant of 8 Hz.
Mass spectra were recorded on a Finnigan MAT instrument
under standard conditions (EI, 70 eV). The course of the reacꢀ
tion was monitored and the purity of the compounds obꢀ
tained was checked by TLC on Silufol UVꢀ254 plates in
CHCl3—Me2CO (9 : 1); spots were visualized with 0.5%
chloranil in toluene.
Threeꢀcomponent synthesis from 1,2,4ꢀtrimethylbenzene.
A mixture of pseudocumene (1.2 g, 10 mmol), isobutyraldehyde
(0.72 g, 10 mmol), and ECA (1.13 g, 10 mmol) was added
dropwise at 5 to 10 °C for 1 min to stirred 95% H2SO4 (15 mL).
Stirring was continued for 3 to 5 min and the mixture was
poured into crushed ice (100 g). The organic material was exꢀ
tracted with benzene (25 mL), the benzene was separated, and
the aqueous layer was neutralized with ammonium carbonate to
pH 8—9. The product that formed was extracted with CHCl3
(2×50 mL) and dried over MgSO4. The solvent was removed in a
rotary evaporator to give a mixture of products (2.3 g). Column
chromatography of the mixture (silica gel 30/50 deactivated
with triethylamine, benzene—ether (35 : 1)) gave pure comꢀ
pound 4 (1.5 g, 52%), m.p. 83—84 °C (hexane) and isoꢀ
quinoline 5 (170 mg), m.p. 71—72 °C (hexane). The purity of
compound 3 was 85% (content of isoquinoline 4 was 15%), and
the purity of compound 5 was 80% (isoquinoline 4, 20%)
(1H NMR data).

910
Russ.Chem.Bull., Int.Ed., Vol. 53, No. 4, April, 2004
Shklyaev et al.
(C(4a)); 134.2 (C(5)); 134.3 (C(6)); 138.3 (C(7)); 156.5 (C(1));
171.3 (C=O).
IR, ν/cm–1: 1610, 1580, 1500. 1H NMR, δ: 1.15 (s, 6 H,
2 Megem); 2.18 (s, 3 H, 5ꢀMe); 2.22 (s, 3 H, 6ꢀMe); 2.28 (s, 3 H,
7ꢀMe); 2.35 (s, 3 H, SMe); 2.61 (s, 2 H, C(4)H2); 7.90 (s, 1 H,
H(8) arom.).
1H NMR difference spectrum of 3,3,6,7,8ꢀpentamethylꢀ1ꢀ
methylthioꢀ3,4ꢀdihydroisoquinoline (10), δ: 1.11 (s, 6 H,
2 Megem); 2.15 (s, 3 H, 6ꢀMe); 2.26 (s, 3 H, 7ꢀMe); 2.32 (s, 3 H,
8ꢀMe); 2.47 (s, 3 H, SMe); 2.54 (s, 2 H, 4ꢀCH2); 6.33 (s, 1 H,
H(5) arom.).
3,3,5,6,7ꢀPentamethylꢀ3,4ꢀdihydroisocarbostyril (11). One
to two scales of dry NaOH were added to a solution of comꢀ
pound 9 (2.47 g, 0.01 mol) in 50% AcOH (10 mL). The reaction
mixture was heated for 1 h and worked up as described earlier8
to give compound 11 (2.1 g). Crystallization from benzene
gave pure isocarbostyril 11 (1.9 g, 88%), m.p. 219—220 °C.
Found (%): C, 77.54; H, 8.84; N, 6.55. C14H19NO. Calcuꢀ
lated (%): C, 77.42; H, 8.76; N, 6.45. IR, ν/cm–1: 3195, 1660,
1595, 1510. 1H NMR, δ: 1.25 (s, 6 H, Megem); 2.20 (s, 3 H,
5ꢀMe); 2.24 (s, 3 H, 6ꢀMe); 2.33 (s, 3 H, 7ꢀMe); 2.77 (s, 2 H,
C(4)H2); 7.31 (br.s, 1 H, NH); 7.72 (s, 1 H, H(8) arom.).
1H NMR difference spectrum of 3,3,6,7,8ꢀpentamethylꢀ3,4ꢀ
dihydroisocarbostyril (12), δ: 1.20 (s, 6 H, Megem); 2.18 (s, 3 H,
6ꢀMe); 2.24 (s, 3 H, 7ꢀMe); 2.29 (s, 3 H, 8ꢀMe); 2.73 (s, 2 H,
C(4)H2); 6.77 (s, 1 H, H(5) arom.); 7.20 (br.s, 1 H, NH).
1H NMR difference spectrum of ethyl 3,3,6,7,8ꢀpentaꢀ
methylꢀ1,2,3,4ꢀtetrahydroisoquinolylidenꢀ1ꢀacetate (5), δ: 1.22
(s, 6 H, 2 Megem); 1.29 (t, 3 H, OCH2CH3, J = 7.2 Hz); 2.21 (s,
3 H, 6´ꢀMe); 2.30 (s, 3 H, 7´ꢀMe); 2.48 (s, 3 H, 8´ꢀMe); 4.15 (q,
2 H, OCH2Me, J = 7.2 Hz); 4.77 (s, 1 H, C(4)H2); 6.81 (s, 1 H,
H(5)); 9.12 (br.s, 1 H, NH).
1ꢀBromoꢀ2,3,4ꢀtrimethylbenzene. Water (100 mL) was added
to 1,2,3ꢀtrimethylbenzene (60 g, 0.5 mol) in 400 mL of CCl4.
Then Br2 (80 g, 0.5 mol) was added dropwise to the stirred
solution so that it remained slightly colored. After the addition
was completed, the reaction mixture was stirred for 30 min. The
aqueous layer was separated and the organic layer was washed
with water (2×200 mL), saturated NaHCO3 (200 mL), and again
water to pH 7. The solvent was removed in a rotary evaporator
and ethanol (200 mL) and solid KOH (20 g) were added to the
residue. The solution was stirred for 20 min, heated in the boilꢀ
ing solvent for 30 min, and poured into water (700 mL). The
product was extracted with tertꢀbutyl methyl ether (2×300 mL)
and dried with MgSO4. The solvent was removed in a water bath
and the residue was distilled in vacuo. A fraction with b.p.
110—115 °C (15 Torr) was collected. The yield of 1ꢀbromoꢀ
2,3,4ꢀtrimethylbenzene was 65 g (65%). The 1H NMR spectrum
was identical with that described earlier.6
This work was financially supported by the President
of the Russian Federation (Grant for Support of Leading
Scientific Schools NShꢀ2020.2003.3), the Program of the
Presidium of the Russian Academy of Sciences "New Prinꢀ
ciples and Methods of Directed Synthesis of Compounds
with Desired Properties", and the Russian Foundation for
Basic Research (r 2004 Ural Project No. 04ꢀ03ꢀ96045).
2ꢀMethylꢀ1ꢀ(2´,3´,4´ꢀtrimethylphenyl)propanꢀ1ꢀol (7).
Freshly distilled isobutyraldehyde (15 g, 0.21 mol) in 50 mL of
dry THF was added dropwise to a cooled (water + ice) solution
of 2,3,4ꢀtrimethylphenylmagnesium bromide (0.2 mol) prepared
from 1ꢀbromoꢀ2,3,4ꢀtrimethylbenzene (40 g, 0.2 mol) and magꢀ
nesium (5 g, 0.21 mol) in 150 mL of dry THF. The stirred
reaction mixture was heated for 30 min, cooled, and treated
with saturated NH4Cl. The organic layer was separated and the
product was extracted from the aqueous layer with tertꢀbutyl
methyl ether (2×150 mL). The combined organic layers were
washed with water and dried over MgSO4. The solvent was reꢀ
moved in a water bath and the residue was distilled in vacuo.
A fraction with b.p. 140—145 °C (5 Torr) was collected. The
yield of compound 7 was ≈30 g (77%). Found (%): C, 81.33;
H, 10.61. C13H20O. Calculated (%): C, 81.20; H, 10.48.
Reaction of compound 7 with ethyl cyanoacetate. A mixture
of compound 7 (1.92 g, 0.01 mol) and ethyl cyanoacetate (1.13 g,
0.01 mol) was added dropwise to conc. H2SO4 (15 mL). The
reaction mixture was treated as described above for the threeꢀ
component synthesis. The total yield and the ratio between prodꢀ
ucts 4 and 5 were identical with those obtained in the threeꢀ
component synthesis.
Threeꢀcomponent synthesis involving methyl thiocyanate
(compounds 9 and 10). The synthesis was carried out as deꢀ
scribed for compound 4. An oil obtained from 1,2,3ꢀtrimethylꢀ
benzene (1.2 g, 10 mmol), isobutyraldehyde (0.72 g, 10 mmol),
and methyl thiocyanate (0.73 g, 10 mmol) was distilled in vacuo.
A fraction with b.p. 150—160 °C (5 Torr) was collected. The
yield was 1.9 g (77%). Found (%): C, 73.0; H, 8.59; N, 5.58;
S, 13.01. C15H21NS. Calculated (%): C, 72.87; H, 8.50; N, 5.67;
S, 12.95. On prolonged storage, the mass solidified and double
crystallization from MeOH gave pure 3,3,5,6,7ꢀpentamethylꢀ1ꢀ
methylthioꢀ3,4ꢀdihydroisoquinoline (9) 7 in 52% yield, m.p.
55—56 °C. Found (%): C, 72.99; H, 8.60; N, 5.50; S, 12.90.
C15H21NS. Calculated (%): C, 72.87; H, 8.50; N, 5.67; S, 12.96.
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Received December 16, 2003;
in revised form March 15, 2004