Spirocyclohexadienones. 6. Three-component synthesis of 1-R-3,3-dimethyl-2-azaspiro[4.5]deca-1,6,9-trien-8-ones

Article abstract of DOI:10.1023/A:1016061607049

1-R-3,3-Dimethyl-2-azaspiro[4.5]deca-1,6,9-trien-8-ones were synthesized through three-component condensation of anisole, isobutyraldehyde, and a corresponding nitrile in dichloromethane in the presence of concentrated sulfuric acid.

Full text of DOI:10.1023/A:1016061607049

894
Russian Chemical Bulletin, International Edition, Vol. 51, No. 5, pp. 894—896, May, 2002
Brief Communications
Spirocyclohexadienones.
6*. Threeꢀcomponent synthesis of
1ꢀRꢀ3,3ꢀdimethylꢀ2ꢀazaspiro[4.5]decaꢀ1,6,9ꢀtrienꢀ8ꢀones
a
b
a
V. A. Glushkov,a O. G. Ausheva, S. N. Shurov, and Yu. V. Shklyaev
ꢀ
aInstitute of Technical Chemistry, Ural Branch of the Russian Academy of Sciences,
13 ul. Lenina, 614600 Perm, Russian Federation.
Fax: +7 (342 2) 12 6237. Eꢀmail: cheminst@mpm.ru
bA. M. Gorky Perm State University,
15 ul. Bukireva, 614600 Perm, Russian Federation.
Fax: +7 (342 2) 39 6367. Eꢀmail: info@psu.ru
1ꢀRꢀ3,3ꢀDimethylꢀ2ꢀazaspiro[4.5]decaꢀ1,6,9ꢀtrienꢀ8ꢀones were synthesized through threeꢀ
component condensation of anisole, isobutyraldehyde, and a corresponding nitrile in
dichloromethane in the presence of concentrated sulfuric acid.
Key words: spiro compounds, pyrroles, cyclohexaꢀ2,5ꢀdienꢀ1ꢀone, anisole, isobutyrꢀ
aldehyde, nitriles, the Ritter reaction, cascade heterocyclization.
Earlier,2 we have synthesized 1ꢀsubstituted 3,3ꢀdiꢀ
pot" synthesis of 1ꢀsubstituted 3,3ꢀdimethylꢀ2ꢀazaꢀ
spiro[4.5]decaꢀ1,6,9ꢀtrienꢀ8ꢀones from anisole, isobutyrꢀ
aldehyde, and a corresponding nitrile RCN in methylene
chloride in the presence of sulfuric acid at –15 to 15 °C.
The process can be regarded as a combination of the
known Baeyer4 and Ritter5 reactions finalized by inꢀ
tramolecular ipsoꢀattack in an intermediate nitrilium ion
C to form the azaspiro[4.5]decaꢀ1,6,9ꢀtrienꢀ8ꢀone sysꢀ
tem (Scheme 1). As can be seen in the scheme, this
reaction mechanism becomes possible because of equiꢀ
librium between carbenium ions A and B. The Baeyer
reaction product, namely, 1,1ꢀbis(pꢀanisyl)ꢀ2ꢀmethylꢀ
propane, was not isolated; apparently, the reaction of
nitrile with the intermediate carbocation B is faster than
methylꢀ2ꢀazaspiro[4.5]decaꢀ1,6,9ꢀtrienꢀ8ꢀones by the
Ritter reaction. Later, a threeꢀcomponent synthesis of
such compounds from anisole (or 1,3ꢀdimethoxyꢀ or
1,3,5ꢀtrimethoxybenzene), isobutylene oxide, and methyl
thiocyanate in the presence of sulfuric acid has been
described;3 isobutylene oxide was used to construct the
C(3)—C(4) fragment of the isoquinoline ring.
We found that isobutylene oxide can be successfully
replaced by an aliphatic aldehyde branched at the
αꢀcarbon atom, in particular, isobutyraldehyde. In the
present work, we propose a convenient preparative "oneꢀ
* For Part 5, see Ref. 1.
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 5, pp. 822—824, May, 2002.
1066ꢀ5285/02/5105ꢀ894 $27.00 © 2002 Plenum Publishing Corporation

Spirocyclohexadienones
Russ.Chem.Bull., Int.Ed., Vol. 51, No. 5, May, 2002
895
Scheme 1
1,2: R = SMe (1a, 2a); Ph (1b, 2b); CH2COOEt (1c)
that of anisole with cation A. In addition, an equimolar
ratio of anisole to a nitrile and an aldehyde should be
taken into account.
The 13C NMR spectra of compounds 2a—c contain a
characteristic signal at δ 72.4—76.4 for the spiro carꢀ
bon atom.
This method was used to obtain spiran 2a in 34%
yield and previously6 inaccessible compounds 2b,c in 10
and 30% yields, respectively. The H NMR spectrum of
The structures of compounds 2b,c were also conꢀ
firmed by their mass spectra. No molecular ion peak
appears in the mass spectrum of 2b; compounds 2b,c
decompose through loss of benzonitrile or ethyl cyanoꢀ
acetate (for 2b and 2c, respectively) and the methyl groups
(see Experimental).
Compounds 2a—c are rather stable and do not deꢀ
compose under normal conditions for two to three
months; however, in the presence of atmospheric moisꢀ
ture and acid traces, compound 2a virtually quantitaꢀ
tively transforms (through dienoneꢀphenol rearrangeꢀ
ment) into the corresponding pꢀhydroxyphenylethyl
amide.2
1
2c suggests that this compound in DMSOꢀd6 exists enꢀ
tirely in the enamine form, as has been observed earꢀ
lier for ethyl (3,4ꢀdihydroisoquinolinꢀ1ꢀyl)acetates.7,8
ZꢀConfiguration of such compounds is due to an inꢀ
tramolecular hydrogen bond (IHB).8,9 Indeed, the abꢀ
sorption band of the ester group in the IR spectrum of 2c
is shifted to the lowꢀfrequency region (1615 cm–1), which
indicates the formation of an IHB between the carbonyl
and NH groups.
We performed quantumꢀchemical calculations for the
enamine and imine forms of spiran 2c using the semiꢀ
empirical SCF MO LCAO method in the AM1 approxiꢀ
mation.10 The results obtained show that the Zꢀenamine
form is more stable (the calculated enthalpy of its formaꢀ
tion ∆Hf is 339.91 kJ mol–1) than the Eꢀenamine and
imine forms (∆Hf = 303.29 and 319.48 kJ mol–1, respecꢀ
tively).
Experimental
IR spectra were recorded on a URꢀ20 instrument (Vaseline
1
oil, paste). H NMR spectra were recorded on Bruker AMꢀ300
(300 MHz) and TeslaꢀBS 487C (80 MHz) instruments with
HMDS as the internal standard. 13C NMR spectra were taken

896
Russ.Chem.Bull., Int.Ed., Vol. 51, No. 5, May, 2002
Glushkov et al.
using a Bruker DRX 500 instrument (125.76 MHz). The mass
spectra of compound 2b,c were recorded on a Finnigan MAT
instrument (EI, 70 eV). The course of the reaction was moniꢀ
tored and the purity of the products was checked by TLC on
Silufol plates in chloroform—acetone (9 : 1); spots were visualꢀ
ized with a 3% solution of chloranil in toluene. Methylene
chloride (Lancaster Co., Great Britain) was used. Quantumꢀ
chemical calculations were performed on a Pentiumꢀ133 PC
with the MOPAC 7.0 program package.11
3,3ꢀDimethylꢀ1ꢀmethylthioꢀ2ꢀazaspiro[4.5]decaꢀ1,6,9ꢀtrienꢀ
8ꢀone (2a). A solution of anisole (5.4 mL, 0.05 mol), freshly
distilled isobutyraldehyde (4.5 mL, 0.05 mol), and thiocyanate
1a (3.5 mL, 0.05 mol) in 40 mL of CH2Cl2 was added dropwise
at –15 °C to vigorously stirred 96% H2SO4 (12 mL, 0.22 mol).
After 40 min, the reaction mixture was poured onto a mixture
of ice (300 mL) and 20% NH4OH (45 mL). The aqueous layer
was separated, and the organic material was extracted with
CH2Cl2 (3×20 mL). The combined organic phases were washed
with water and dried over MgSO4. The solvent was removed,
and the residue was recrystallized from methanol with addition
of water. The yield of compound 2a was 3.7 g (34%), Rf 0.48.
The melting point and spectroscopic characteristics of spiran
2a are identical with those reported in Ref. 6.
3,3ꢀDimethylꢀ1ꢀphenylꢀ2ꢀazaspiro[4.5]decaꢀ1,6,9ꢀtrienꢀ8ꢀ
one (2b) was obtained analogously from anisole (10.9 mL,
0.1 mol), isobutyraldehyde (9.1 mL, 0.1 mol), benzonitrile
(10.0 mL, 0.1 mol), and 96% H2SO4 (24 mL, 0.44 mol) in
100 mL of CH2Cl2 at 10 to 15 °C. Removal of the solvent gave
a partially crystallized residue; the crystals were filtered off and
recrystallized from hexane (100 mL) to give compound 2b
(2.51 g, 10%), m.p. 130—132 °C, Rf 0.53. MS, m/z (Irel (%)):
148 [M+ – PhCN] (100); 133 (49); 104 (35); 77 (21).
IR (Vaseline oil), ν/cm–1: 1660 (C=O); 1625 (C=C); 1605
(C=N and C=Carom); 1575 (C=N). 1H NMR (300 MHz,
DMSOꢀd6), δ: 1.45 (s, 6 H, C(3)Me2); 2.23 (s, 2 H, C(4)H2);
6.28 (d, 2 H, C(7)H and C(9)H, J = 10.2 Hz); 7.15 (d, 2 H,
C(6)H and C(10)H, J = 10.2 Hz); 7.32 (m, 2 H, Harom); 7.40
(m, 1 H, Harom); 7.64 (m, 2 H, Harom). 13C NMR (DMSOꢀd6),
δ: 30.22 (C(3)Me2); 48.96 (C(4)); 60.71 (C(3)); 72.36 (C(5));
127.26*, 127.83* (C(7), C(9)); 128.04, 130.27, 133.49 (Ph);
152.01 (C(6), C(10)); 164.02 (C(1)); 183.83 (C(8)). Found (%):
C, 81.35; H, 6.90; N, 5.42. C17H17NO. Calculated (%):
C, 81.24; H, 6.82; N, 5.57.
(16); 216 [M – OEt]+ (22); 200 [M – Me – OEt – H]+ (70);
188 [M – COOEt]+ (21); 172 [M – Me – COOEt – H]+ (28);
160 [M – C4H8 – OEt]+ (43); 148 [M – NCCH2COOEt]+
(93); 133 [M – Me – NCCH2COOEt]+ (100); 120 (12); 107
(48). IR (Vaseline oil), ν/cm–1: 3325 (NH), 1660 (C=O), 1615
(sh, O—C=O), 1600 (C=C). 1H NMR (300 MHz, DMSOꢀd6),
δ: 1.15 (t, 3 H, Me, J = 7.0 Hz); 1.44 (s, 6 H, C(3)Me2); 2.15
(s, 2 H, C(4)H2); 3.97 (m, 3 H, OCH2 + —CH=); 6.15 (d,
2 H, C(7)H and C(9)H, J = 10.1 Hz); 6.99 (d, 2 H, C(6)H and
1
C(10)H, J = 10.1 Hz); 8.23 (s, 1 H, NH). H NMR (80 MHz,
CDCl3), δ: 1.16 (t, 3 H, Me, J = 7.0 Hz); 1.40 (s, 6 H, C(3)Me2);
2.11 (s, 2 H, C(4)H2); 3.98 (q, 3 H, OCH2, J = 7.0 Hz); 4.23
(s, 1 H, —CH=); 6.13 (d, 2 H, C(7)H and C(9)H, J = 10.1 Hz);
6.77 (d, 2 H, C(6)H and C(10)H, J = 10.1 Hz); 7.85 (br.s, 1 H,
NH). 13C NMR (DMSOꢀd6), δ: 14.38 (Me); 30.18 (C(3)Me2);
45.39 (C(4)); 52.76* (OCH2); 57.62* (C(3)); 61.49* (—CH=);
76.39 (C(5)); 126.83 (C(7), C(9)); 150.77 (C(6), C(10)); 160.74
(C(1)); 168.56 (OC(=O); 184.09 (C(8)). Found (%): C, 69.02;
H, 7.27, N, 5.49. C15H19NO3. Calculated (%): C, 68.94;
H, 7.33; N, 5.36.
This work was financially supported by the Russian
Foundation for Basic Research (Project No. 01ꢀ03ꢀ
96479).
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Zꢀ1ꢀEthoxycarbonylmethylideneꢀ3,3ꢀdimethylꢀ2ꢀazaꢀ
spiro[4.5]decaꢀ6,9ꢀdienꢀ8ꢀone (2c). A solution of anisole
(5.4 mL, 0.05 mol), freshly distilled isobutyraldehyde (4.5 mL,
0.05 mol), and ethyl cyanoacetate (5.3 mL, 0.05 mol) in 30 mL
of CH2Cl2 was added dropwise to vigorously stirred 96% H2SO4
(12 mL, 0.22 mol) while cooling it with water. After 40 min,
the reaction mixture was poured onto a mixture of ice (150 mL)
and aqueous 20% NH4OH (45 mL). The aqueous layer was
separated, and the organic material was extracted with CH2Cl2
(3×20 mL). The combined organic phases were washed with
water and dried over MgSO4. The solvent was removed, and
the residue was recrystallized from ethanol. The yield of comꢀ
pound 1c was 3.92 g (30%), colorless plates, m.p. 195.5—197 °C,
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Received April 24, 2001;
* These signals may be interchanged.
in revised form December 14, 2001