Base catalyzed intramolecular cyclization of dialkycrotyl(3-alkenylpropyn- 2-yl)ammonium salts and aqueous base fission of 2,2-dialkyl-4-methyl-and 2,2-dialkyl-4,6-dimethyl-2,6,7,7a-tetrahydro-1H-isoindolium bromides

Article abstract of DOI:10.1007/s10593-008-0090-9

Cyclization of dimethylcrotyl(3-vinyl-or-3-isopropenylpropyn-2-yl)ammonium bromides in the presence of base gave a mixture of the isomeric 2,2-dialkyl-4-methyl-and 2,2-dialkyl-4,6-dimethyl-2,6,7,7a-tetrahydro-1H- isoindolium bromides. Basic fission of the salts obtained at increased temperature gave a mixture of the isomeric N,N-disubstituted di-and trimethylbenzylamines whose structures were confirmed by their IR, ¹H NMR, and ¹³C NMR spectra.

Full text of DOI:10.1007/s10593-008-0090-9

Chemistry of Heterocyclic Compounds, Vol. 44, No. 6, 2008
BASE CATALYZED INTRAMOLECULAR
CYCLIZATION OF DIALKYCROTYL(3-ALKENYL-
PROPYN-2-YL)AMMONIUM SALTS AND AQUEOUS
BASE FISSION OF 2,2-DIALKYL-4-METHYL- AND
2,2-DIALKYL-4,6-DIMETHYL-2,6,7,7a-TETRAHYDRO-
1H-ISOINDOLIUM BROMIDES
E. O. Chukhajian1, M. K. Nalbandyan1, A. R. Gevorkyan1,
K. G. Shakhatuni1, and G. A. Panosyan2
Cyclization of dimethylcrotyl(3-vinyl- or -3-isopropenylpropyn-2-yl)ammonium bromides in the
presence of base gave a mixture of the isomeric 2,2-dialkyl-4-methyl- and 2,2-dialkyl-4,6-dimethyl-
2,6,7,7a-tetrahydro-1H-isoindolium bromides. Basic fission of the salts obtained at increased
temperature gave a mixture of the isomeric N,N- disubstituted di- and trimethylbenzylamines whose
structures were confirmed by their IR, 1H NMR, and 13C NMR spectra.
Keywords: 2,2-dialkyl-4-methyl- and -4,6-dimethyl-2,6,7,7a-tetrahydro-1H-isoindolium bromides,
isomeric N,N-dialkylmethyl- and -trimethylbenzylamines, intramolecular cyclization, aqueous base
fission, basic catalysis.
It is known that 2,2-dialkyl-3a,4-dihydroisoindolinium and 2,2-dialkyl-6-methyl-3a,4-dihydroiso-
indolinium bromides, obtained by the cyclization of dialkylallyl(3-vinyl- or 3-isopropenylpropyn-2-yl)ammo-
nium salts in aqueous base, isomerize to 2,2-dialkyl-2,6,7,7a-tetrahydro-1H-isoindolium and 2,2-dialkyl-
5-methyl-2,6,7,7a-tetrahydro-1H-isoindolium bromides [1].
In order to study the general nature of the isomerization observed by us for a series of dialkyl-
3a,4-dihydroisoindolinium salts and the preparation of novel bioactive tetrahydroisoindolinium derivatives we
have carried out the intramolecular cyclization of the bromides 1a-f in the presence of alkali.
It was found that the cyclization of these salts, in contrast to the allyl analogs [1], occurs even in a molar
ratio of salt to base of 5:1as a moderately exothermic reaction to give a mixture of the bromides 2a-f and 3a-f in
1
72-76% yields. According to their H NMR spectra the mixture contains 82-88% of the salt 3a-f. When a
solution of KOH (molar ratio of salt to base 12:1) is added to an aqueous solution of this mixture at room
temperature the salts 2a-f fully isomerize to the stable forms 3a-f [1].
__________________________________________________________________________________________
1
Institute of Organic Chemistry, National Academy of Sciences of the Republic of Armenia, Yerevan
375091; e-mail: hasulik4@mail.ru. 2 Molecular Structure Research Center, National Academy of Sciences of the
Republic of Armenia, Yerevan 375014; e-mail: henry@msrc.am. Translated from Khimiya Geterotsiklicheskikh
Soedinenii, No. 6, pp. 841-846, June, 2008. Original article submitted November 17, 2006; revision submitted
January 26, 2008.
0009-3122/08/4406-0671©2008 Springer Science+Business Media, Inc.
671

672

Under aqueous alkali conditions the salts 3a-c, probably again isomerizing to the corresponding
3a,4-dihydroisoindolinium salts 2a-c, undergo fission upon heating in two directions, i.e. with breaking of the
C(1)–N(2) or the N(2)–C(3) bond to give a mixture of the isomeric benzylamines 4a-c and 5a-c in 60-65%
overall yield.
Me
Me
OH
OH
+
R2N
+
R2N
+
R2N
X
X
Br
Br
Br
X
1a–f
3a–f
2a–f
OH
Me
Me
Me
R2N
R2N
Me
X
X
4a,b,d
5a,b,d
1−5 a, b, d R2 = (CH2)4, X = H; b R2 = (CH2)5, X = H; d R2 = (CH2)2O(CH2)2, X = Me;
1−3 c R2 = (CH2)5, X = Me; e R2 = (CH2)2O(CH2)2, X = H; f R = Pr, X = Me
1
According to H NMR spectroscopic data and gas liquid chromatography the content of amines 4a-c in
the mixture is 75-85%. The mixtures of isomeric amines 4a-c and 5a-c were separated by vacuum distillation in
60-65% yields.
The structures of the salts 1a-f, 3a-f and amines 4a,b,d and 5a,b,d were in agreement with their IR
spectra. The structures of salts 3a-f and amines 4a,b,d, and 5a,b,d were also shown on the basis of their
1H NMR spectra and of the salts 3a-f from their 13C NMR spectra (Table 1). For confirmation of the structure of
1
13
salts 3a-f and assignment of the signals in the H and C NMR spectra we have used COSY, NOESY, DEPT,
and HMQC double resonance and 2D correlation spectroscopic methods.
EXPERIMENTAL
1
IR Spectra were taken on a UR-20 spectrometer for KBr tablets or in vaseline oil. H and 13C NMR
spectra were obtained on a Varian Mercury-300 (300 and 75 MHz respectively) at 303ºK using a mixture of
DMSO-d6 and CCl4 (1:3) and with TMS as internal standard. The purity of the salts was established by TLC on
Silufol UV-254 plates in the system n-butanol-ethanol-water-acetic acid (10:2:1:5) and revealed using iodine
vapor. The ratio of amines 4a,b,d and 5a,b,d was shown by GLC on an LXM-8MD chromatograph, column
1.5 m×4 mm filled with Inerton AW-HMDS coated with 10% Carbowax-20M, gas carrier helium (40 ml/min),
and temperature 230ºC. The composition of the compounds obtained was proved by elemental analysis.
The starting dialkyl(3-isopropenylpropyn-2-yl)amines were synthesized via a Mannich reaction [1-3].
Synthesis of salts 1a-f (General Method). Crotyl bromide (25 mmol) was added to a solution of the
corresponding amine (17 mmol) in a mixture of ether (15 ml) and acetonitrile (5 ml). The reaction occurs with a
moderate exotherm. The precipitated salts 1a-f were washed with absolute ether (2×25 ml).
673

Crotyl(3-vinylpropyn-2-yl)pyrrolidinium Bromide (1a). Yield 4.4 g (96%) as a hygroscopic salt.
IR spectrum, ν, cm-1: 870, 920, 980, 1600, 1660, 2230, 3100. Found, %: Br 29.31; N 5.44. C13H20BrN.
Calculated, %: Br 29.63; N 5.19.
Crotyl(3-vinylpropyn-2-yl)piperidinium Bromide (1b). Yield 4.5 g (97%); mp 120ºC. IR spectrum, ν,
cm-1: 870, 930, 970, 1600, 1660, 2230, 3100. Found, %: Br 28.49; N 5.21. C14H22BrN. Calculated, %: Br 28.17;
N 4.93.
Crotyl(3-isopropenylpropyn-2-yl)piperidinium Bromide (1c). Yield 4.8 g (96%) as a hygroscopic
salt. IR spectrum, ν, cm-1: 870, 1600, 1660, 2230, 3100. Found, %: Br 26.56; N 4.92. C15H24BrN. Calculated, %:
Br 26.85; N 4.70.
Crotyl(3-isopropenylpropyn-2-yl)morpholinium Bromide (1d). Yield 4.98 g (98%); mp 152ºC. IR
spectrum, ν, cm-1: 870, 890, 1600, 1660, 2240, 3100. Found, %: Br 26.96; N 4.46. C14H22BrNO. Calculated, %:
Br 26.67; N 4.67.
Crotyl(3-isopropenyl-2-yl)morpholinium Bromide (1e). Yield 4.75 g (98%); mp 155ºC. IR spectrum,
ν, cm-1: 870, 890, 1580, 1670, 2240, 3100. Found, %: Br 28.30; N 4.63. C13H20BrNO. Calculated, %: Br 27.97;
N 4.90.
Dipropylcrotyl(3-isopropenylpropyn-2-yl)ammonium Bromide (1f). Yield 5.25 g (98%) as a
hygroscopic salt. IR spectrum, ν, cm-1: 870, 1600, 1670, 2230, 3100. Found, %: Br 25.79; N 4.67. C16H30BrN.
Calculated, %: Br 25.48; N 4.46.
Cyclization of salts 1a-f (General Method). KOH solution (2N, 1 ml) (molar ratio of salt to base 5:1)
was added to a solution of salt 1 (10 mmol) in water (3.5-4 ml). After 5-10 min an exotherm was observed and
the temperature of the reaction mixture increased from 25ºC to 60-65ºC. The reaction mixture was cooled
externally using cold water. After 10-15 min the mixture was extracted with ether (2×30 ml) to remove possible
neutral side products. When the alkaline medium stood at room temperature or in the fridge crystals of the salts
2a-f and 3a-f precipitated from the solution in 72-76% overall yield and these were removed from the aqueous
solution by filtration. Addition of 2N KOH solution (0.3 ml) to a solution of this mixture (7.4 mmol) in water
(2 ml) caused a total conversion of salts 2a-f to 3a-f which were separated from the reaction mixture by
filtration.
2,2-Tetramethylene-4-methyl-2,6,7,7a-tetrahydro-1H-isoindolium Bromide (3a). Yield 2.05 g (76%);
1
mp 261-262ºC. IR spectrum, ν, cm-1: 1600, 1650, 3070. H NMR spectrum, δ, ppm (J, Hz): 1.02 (3H, d, J = 6.5,
CH3); 1.73 (1H, tqd, J = 11.3, 6.5, 4.7, CHCH3); 1.98 (1H, dd, J = 18.6, 4.7, =CHCH2); 2.12-2.28 (4H, m,
NCH2CH2 pyrrolidine); 2.35 (1H, dt, J = 18.6, 5.1, =CHCH2); 3.02 (1H, m, NCH2CH); 3.45 (1H, m, NCH2
pyrrolidine); 3.47 (1H, t, J = 10.8, CH2 pyrrolidine); 3.69 (1H, m, NCH2 pyrrolidine); 3.79-3.88 (2H, m, NCH2
pyrrolidine); 4.28 (1H, dd, J = 11.2, 7.1, NCH2); 6.25 (1H, ddd, J = 9.8, 5.6, 2.1 =CHCH2); 6.35 (1H, dd, J = 9.8,
2.7, =CH); 6.45 (1H, br, NCH=). Found, %: Br 29.34; N 5.42. C13H20BrN. Calculated, %: Br 29.63; N 5.19.
2,2-Pentamethylene-4-methyl-2,6,7,7a-tetrahydro-1H-isoindolium Bromide (3b). Yield 2.05 g
(72%); mp 283-284ºC. IR spectrum, ν, cm-1: 1605, 1650, 3080. 1H NMR spectrum, δ, ppm (J, Hz): 1.04 (3H, d,
J = 6.5, CH3); 1.54-1.96 (7H, m, CH2 piperidine, NCH2CH2 piperidine and CHCH3); 1.98 (1H, m, =CHCH2);
2.34 (1H, dt, J = 18.7, 5.1, =CHCH2); 3.00 (1H, m, NCH2CH2); 3.38 (1H, dd, J = 11.5, 10.6, NCH2); 4.40 (1H,
dd, J = 11.5, 7.2, NCH2); 3.46-3.66 (4H, m, NCH2 piperidine); 6.26 (1H, ddd, J = 9.8, 5.5, 2.0, =CHCH2); 6.34
(1H, dd, J = 9.8, 2.6, =CH); 6.58 (1H, br, NCH=). Found, %: Br 28.46; N 4.62. C14H22BrN. Calculated, %:
Br 28.17; N 4.93.
2,2-Pentamethylene-4,6-dimethyl-2,6,7,7a-tetrahydro-1H-isoindolium Bromide (3c). Yield 2.18 g
(73%); mp 267-268ºC. IR spectrum, ν, cm-1: 1600, 1650, 3070. 1H NMR spectrum, δ, ppm (J, Hz): 1.07 (3H, d,
J = 6.5, CH3CH); 1.61-1.86 (6H, m, CH2 piperidine and NCH2CH2 piperidine); 1.7 (1H, m, CHCH3); 1.89 (3H,
s, =CCH3); 2.00 (1H, m, =CCH2); 2.19 (1H, dd, J = 18.1, 4.9, =CCH2); 2.96 (1H, m, CHCHCH3); 3.39 (1H, dd,
674

J = 11.5, 10.5) and 4.48 (1H, dd, J = 11.5, 7.2, NCH2); 3.50-3.66 (3H, m) and 3.78 (1H, ddd, J = 12.4, 8.9, 4.2,
NCH2 piperidine); 6.11 (1H, br, =CH); 6.58 (1H, br, NCH=). Found, %: Br 27.17; N 4.43. C15H24BrN.
Calculated, %: Br 26.85; N 4.70.
[4,6-Dimethyl-2,6,7,7a-tetrahydrospiro-1H-isoindole-2,4'-morpholinium] Bromide (3d). Yield 2.25
g (75%); mp 275-276ºC. IR spectrum, ν, cm-1: 1600, 1650, 3080. 1H NMR spectrum, δ, ppm (J, Hz): 1.08 (3H,
d, J = 6.5, CHCH3); 1.81 (1H, m, CHCH3); 1.89 (3H, s, =CCH3); 2.01 (1H, dd, J = 18.0, 10.1) and 2.20 (1H, dd,
J = 18.0, 4.8, =CCH2); 3.03 (1H, m, CHCHCH3); 3.58 (1H, dd, J = 11.5, 10.5) and 4.70 (1H, dd, J = 11.5, 7.3,
NCH2); 3.56-3.71 (3H, m) and 3.82-4.14 (5H, m, CH2 morpholine); 6.12 (1H, br, =CH); 6.55 (1H, br, NCH=).
Found, %: Br 26.98; N 4.44. C14H22BrNO. Calculated, %: Br 26.67; N 4.67.
[4-Methyl-2,6,7,7a-tetrahydrospiro-1H-isoindole-2,4'-morpholinium] Bromide (3e). Yield 2.06 g
(72%); mp 291-292ºC. IR spectrum, ν, cm-1: 1595, 1650, 3070. 1H NMR spectrum, δ, ppm (J, Hz): 1.06 (3H, d,
J = 6.5, CH3); 1.78 (1H, tqd, J = 11.2, 6.5, 4.7, CHCH3); 2.00 (1H, dd, J = 18.7, 5.3) and 2.36 (1H, dt, J = 18.7,
5.3, =CHCH2); 3.06 (1H, m, NCH2CH); 3.50-3.67 (4H, m, NCH2 morpholine); 3.80 (1H, ddd, J = 12.5, 8.4, 3.6)
and 4.63 (1H, dd, J = 11.5, 7.3, NCH2); 3.91-4.11 (4H, m, OCH2); 6.28 (1H, ddd, J = 9.9, 5.3, 2.0, =CHCH2);
6.35 (1H, dd, J = 9.9, 2.7, =CH); 6.69 (1H, br, NCH=). Found, %: Br 28.26; N 4.63. C13H20BrNO. Calculated,
%: Br 27.97; H 4.90.
2,2-Dipropyl-4,6-dimethyl-2,6,7,7a-tetrahydro-1H-isoindolium Bromide (3f). Yield 2.3 g (72%); mp
1
260-262ºC. IR spectrum, ν, cm-1: 1610, 1650, 3070. H NMR spectrum, δ, ppm (J, Hz): 0.98 (3H, t, J = 7.2,
CH3CH2); 1.01 (3H, t, J = 7.2, CH3CH2); 1.04 (3H, d, J = 6.5, CHCH3); 1.67 (1H, m, CHCH3); 1.65-1.79 (4H,
m, CH2CH3); 1.86 (3H, s, =CCH3); 1.97 (1H, dd, J = 18.1, 10.2, =CCH2); 2.17 (1H, dd, J = 18.1, 4.9, =CCH2);
2.83 (1H, m, CHCHCH3); 3.45 (1H, m) and 4.28 (1H, dd, J = 12.2, 7.7, NCH2); 3.41-3.65 (4H, m, NCH2); 6.10
(1H, t, J = 1.6, =CH); 6.31 (1H, d, J = 2,2, NCH=). Found, %: Br 25.77; N 4.67. C16H28BrN. Calculated, %: Br
25.48; N 4.46.
Aqueous Alkali Fission of Salts 3a-c (General Method). 25% KOH solution (6.8 g) was added to the
salt 3 (13 mmol) in water (5 ml), water was distilled off, and from time to time, water was added to the reaction
mixture via a dropping funnel. During the fission the reaction mixture temperature was held at 110-120ºC. At
the end the temperature of the reaction mixture was raised to 140-150ºC to ensure completion of the process.
The reaction mixture and the distilled fraction were extracted with ether (3×40 ml). The combined ether extracts
were washed with 15% HCl solution. The hydrochloric acid layer was separated from the ether solution,
basified, and extracted with ether to remove the amine products. The ether extract was washed with water and
dried over MgSO4. Distillation of the ether and vacuum distillation gave a mixture of the isomeric amines 4a-c
and 5a-c respectively.
1-(2,3-Dimethylbenzyl)pyrrolidine (4a) and 1-(2,6-Dimethylbenzyl)pyrrolidine (5a). Overall yield
1.47 g (60%); bp 94-95ºC (2-3 mm Hg), nD20 1.5286. IR spectrum, ν, cm-1: 720, 760 (1,2,3-substituted benzene
ring), 1580, 3030, 3070 (arom. ring). 1H NMR spectrum of a mixture of 4a (75%) and 5a (25%), δ, ppm (J, Hz):
1.68-1.76 (4H, m, NCH2CH2); 2.24 (2.25H, s, CH3); 2.27 (2.25H, s, CH3); 2.37 (1.5H, s, CH3); 2.41-2.49 (4H,
m, NCH2CH2); 3.52 (1.5H, s, CH2); 3.56 (0.5H, s, CH2); 6.87-7.02 (3H, m, HAr). Found, %: C 82.05; H 10.36;
N 7.80. C13H19N. Calculated, %: C 82.54; H 10.11; N 7.41.
1-(2,3-Dimethylbenzyl)piperidine (4b) and 1-(2,6-Dimethylbenzyl)piperidine (5b). Overall yield
20
1.66 g (63%); bp 92-94ºC (1-2 mm Hg), nD 1.5260. IR spectrum, ν, cm-1: 710, 770 (1,2,3-sub benzene ring),
1
1570, 3030, 3080 (arom. ring). H NMR spectrum of a mixture of 4b (75%) and 5b (25%) δ, ppm: 1.39-1.56
(6H, m, β,γ-CH2 piperidine); 2.22 (2.25H, s, CH3); 2.26 (3H, s, CH3); 2.35 (1.5H, s, CH3); 2.29-2.35 (4H, α-CH2
piperidine); 3.33 (1.5H, s, CH2); 3.37 (0.5H, s. CH2); 6.86-6.98 (3H, m, HAr). Found, %: C 82.27; H 10.67; N
6.55. C14H21N. Calculated, %: C 82.76; H 10.34; N 6.90.
4-(2,3,5-Trimethylbenzyl)morpholine (4d) and 4-(2,4,6-trimethylbenzyl)morpholine (5d). Overall
20
yield 1.85 g (65%); bp 96-97ºC (2-3 mm Hg), nD 1.5320. IR spectrum, ν, cm-1: 870 (1,2,3,5- substituted
1
benzene ring), 1570, 3030, 3080 (arom. ring). H NMR spectrum of a mixture of 4d (85%) and 5d (15%), δ,
675

ppm: 2.19 (2.55H, s, CH3); 2.22 (0.45H, s, CH3); 2.22 (2.55H, s, CH3); 2.23 (2.55H, s, CH3); 2.31 (0.9H, s,
CH3); 2.33-2.38 (4H, m, N(CH2)2); 3.35 (1.7H, s, CH2); 3.40 (0.3H, s, CH2); 3.51-3.60 (4H, m, (OCH2)2); 6.71
(0.3H, s, HAr); 6.77 (0.85H, d, J = 1.8, HAr); 6.79 (1H, d, J = 1.8, HAr). Found, %: C 76.30; H 9.88; N 6.67.
C14H21NO. Calculated, %: C 76.71; H 9.95; N 6.39.
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