Cyclization of dialkylpropyn-1-yl(allyl)(3-isopropenylpropyn-2-yl)ammonium bromides and water-base cleavage of 2,2-dialkyl-5-methyl-2,6,7,7a-tetrahydro-1H- isoindolium and 2,2-dialkyl-5-methylisoindolinium bromides

Article abstract of DOI:10.1002/jhet.5570450309

(Chemical Equation Presented) Dialkylpropyn-1-yl(or allyl)(3- isopropenylpropyn-2-yl)ammonium bromides under base-catalyzed condition instantly undergo intramolecular cyclization. The cyclization of dialkylpropyn-1-yl(3-isopropenylpropyn-2-yl)ammonium bro

Full text of DOI:10.1002/jhet.5570450309

May-Jun 2008
687
Cyclization of Dialkylpropyn-1-yl(allyl)(3-isopropenylpropyn-2-
yl)ammonium Bromides and Water-Base Cleavage of 2,2-Dialkyl-5-
methyl-2,6,7,7a-tetrahydro-1H-isoindolium and 2,2-Dialkyl-5-
methylisoindolinium Bromides
Emma H. Chukhajiana*, Martiros K. Nalbandyana, Hasmik R. Gevorkyana, Eliza H.
Chukhajiana, Henrik A. Panosyanb, Armen G. Ayvazyanb and Rafael A.Tamazyanb
a
Institute of Organic Chemistry of National Academy of Sciences of the Republic of Armenia, Yerevan
375091, hasulik4@mail.ru
Molecule Structure Research Center of National Academy of Sciences of the Republic of Armenia, Yerevan
375014, henry@msrc.am
b
Received March 15, 2007
R'=propyn-1-yl
OH
R2=morpholine
N
R2N
O
R'
R2N
Br
1,2-elim.
R2N
OH
R2N
R2N
R'=allyl
R2N
1,6-elim.
Dialkylpropyn-1-yl(or allyl)(3-isopropenylpropyn-2-yl)ammonium bromides under base-catalyzed
condition instantly undergo intramolecular cyclization. The cyclization of dialkylpropyn-1-yl(3-
isopropenylpropyn-2-yl)ammonium bromides leads to the formation of 2,2-dialkyl-5-methylisoindolinium
salts. In case of allyl analogs, instead of the expected 2,2-dialkyl-6-methyl-3a,4-dihydroisoindolinium salts
their isomeric forms – 2,2-dialkyl-5-methyl-2,6,7,7a-tetrahydro-1H-isoindolium bromides are obtained. In
alkaline medium they are transform into the dihydroisoindolinium salts, the cleavage of which in two
directions - 1,2 and 1,6 leads to the mixture of isomeric dialkyl-1,4-dimethyl- and 2,4-dimethylbenzyl-
amines.
Study of the behavior of 2,2-dialkyl-5-methylisoindolinium salts under conditions of water-base
cleavage showed, that only spiro[5-methylisoindolyn]morpholinium bromide undergoes 1,2-elimination,
forming 5-methylisoindoline 2-vinyl ethyl ester.
J. Heterocyclic Chem., 45, 687 (2008).
INTRODUCTION
RESULTS AND DISCUSSION
Among practically important nitrogen-containing
heterocycles, there is little data about isoindolinium and
dihydroisoindolinium salts and their condensed analogs.
This lack of data can be explained by the absence of
available methods of synthesis of these salts.
Continuing the investigations, of the cyclization
involved dialkylpropyn-1-yl(3-isopropenylpropyn-2-yl)
(1a-c) and dialkylallyl(3-isopropenylpropyn-2-yl)ammon-
ium (3a-c) bromides. Salts 1a-c and 3a-c were
synthesized by alkylation of dialkyl(3-isopropenylpropyn-
2-yl)amines, which have been prepared by the Mannich
reaction [10,11]. Synthesis of (3-isopropenylpropyn-2-
yl)pyrrolidine is described for the first time (see
experimental section).
The base-catalyzed intramolecular cyclization of
ammonium salts, containing β,γ-unsaturated groups with
enyne fragments of various types, first was discovered by
A.T. Babayan, E.O. Chukhajian and other authors [1]. It
includes enormous possibilities for obtaining bioactive
isoindolinium, dihydroisoindolinium salts as well as their
condensed analogs [2,3].
There are few works in literature dedicated to base-
catalyzed intramolecular cyclization of compounds
containing enyne fragments [4-9].
In case of success an accessible method for obtaining
new derivatives of potentially bioactive isoindolinium and
dihydroisoindolinium salts could be worked out. Apart
from the preparative value these investigations include
possibilities of revealing the influence of the methyl
group in the enyne fragment in 4-th position on the
cyclization process.
It was shown that salts 1a-c and 3a-c under base-
catalyzed condition instantly undergo intramolecular
cyclization even in molar ratio salt/alkali 13/1 by self-
heating. In case of salts 1a-c 2,2-tetramethylene- (2a),
Since the base-catalyzed intramolecular cyclization of
unsaturated ammonium salts leads to the new bioactive
derivatives of isoindolinium salts, the expansion and
development of investigations in this field are of great
interest.

688
E. H. Chukhajian, M. K. Nalbandyan, H. R. Gevorkyan, E. H. Chukhajian,
H. A. Panosyan, A. G. Ayvazyan and R. A.Tamazyan
Vol 45
2,2-pentamethylene-5-methylisoindolinium (2b) and
spiro[5-methylisoindoline]morpholinium (2c) bromides
are obtained in 83-85% yields. First discovered by us that
in case of cyclization of allylic analogs 3a-c, instead of
the expected 2,2-dialkyl-6-methyl-3a,4-dihydroisoindol-
inium bromides (4a-c) their isomeric forms – 2,2-tetra-
methylene- (5a), 2,2-pentamethylene-5-methyl-2,6,7,7a-
tetrahydro-1H-isoindolium (5b) and spiro[5-methyl-2,6,
7,7a-tetrahydro-1H-isoindol]morpholinium (5c) bromides,
are obtained in 85-87% yields (Scheme 1).
was established that in these cases also instead of the
expected 2,2-dialkyl-3a,4-dihydroisoindol-inium salts
their isomeric forms - 2,2-dimethyl-2,6,7,7a-tetrahydro-
1H-isoindolium (8) and 2,2-spiro[2,6,7,7a-tetrahydro-1H-
isoindol]morpholinium bromides (9) are obtained as final
products (Scheme 3).
Scheme 3
OH
R2N
Br
R2N
Br
Scheme 1
6, 7
8, 9
6, 8 R=CH3, 7, 9 R2=(CH2)2O (CH2)2
OH
R2N
Br
R2N
Br
2a-c
1a-c
The nmr spectral data of salts 8 and 9 are adduced in
the experimental section. The structure of salt 9 also was
determined by an X-ray diffraction method.
OH
R2N
Br
R2N
Br
R2N
Br
Based on the results of 5a-c salts water-base cleavage it
is assumed that in alkaline medium they are transform
into the salts 4a-c and the cleavage of salts 4a-c in two
directions - 1,2 and 1,6 leads to the mixture of isomeric
dialkyl-1,4-dimethyl- (10a-c) and 2,4-dimethylbenzyl-
amines (11a-c) in 66-69 % total yields (Scheme 4).
According to 1H nmr and GLC data the amount of
isomeric amines in the mixture is almost equal.
3a-c
4a-c
5a-c
1a-5a; R2=(-CH2-)4; 1b-5b; R2=(-CH2-)5; 1c-5c; R2=(CH2)2O(CH2)2
It is supposed, that the formation of bromides 5a-c
includes the steps of salts 3a-c prototropic isomerization
into the salts with α-allenic grouping (C) and their
cyclization (Scheme 2).
Scheme 4
Scheme 2
1,2-elimin.
R2N
R2N
R2N
OH
R2N
Br
R2N
Br
3a-c
10a-c
11a-c
OH
OH
5a-c
4a-c
•
5a-c
C
R2N
1,6-elimin.
However, the above-mentioned assumption is
incredible, because previously we showed, that during
cyclization of ammonium salts, which contain β,γ-
unsaturated groups along with enyne fragment of various
types, the latter immediately takes part in the
cycloaddition as a π4-fragment [12,13]. Salts 4a-c (in its
formation 3-alkenylpropyn-2-yl group is immediately
involved in cyclization as a diene fragment) are more
unstable compounds and in basic medium they are
isomerized into salts 5a-c.
10a,11a; R2=(-CH2-)4; 10b,11b; R2=(-CH2-)5; 10c,11c; R2=(CH2)2O(CH2)2
It is necessary to note that similar results are also
obtained by cyclization of salts 3a-c and direct water-base
cleavage of their cyclic salts 5a-c.
It was shown earlier that water-base cleavage of cyclic
products, obtained by base catalyzed cyclization of
dimethylallyl(3-isopropenylpropyn-2-yl)ammonium
bromide, leads to the isomeric amines mixtures, in which
the 1,2-elimination product comprises 89 % [16].
Comparing our data with those of literature it is
possible to state that the voluminous substitutes, at the
nitrogen atom, favorably affect the elimination process,
proceeding in two directions - 1,2 and 1,6.
Hybrid DFT (Density Functional Theory) calculations
by B3LYP/6-31G(2d, p) method show that energy of the
salts 4a-c is 5 kcal/mol higher than that of salts 5a-c.
Evidently salts 4a-c are really unstable compounds.
It was shown earlier, that by cyclization of dimethyl-
allyl(3-vinylpropyn-2-yl)ammonium (6) and allyl(3-vinyl-
propyn-2-yl)morpholinium (7) bromides 2,2-dialkyl-3a,4-
dihydroisoindolinium salts were obtained [14,15]. It is
Study of the behavior of salts 2a-c under conditions of
water-base cleavage showed, that only salt 2c undergoes
1,2-elimination, forming 5-methylisoindoline 2-vinyl
ethyl ester (12) in 62% yield (Scheme 5).
necessary to note that on the H- and 13C nmr spectral
investigations basis, made on two cyclic salts examples, it
1

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Cyclization of Dialkylpropyn-1-yl(allyl)(3-isopropenylpropyn-2-yl)ammonium Bromides
689
Scheme 5
Inerton AW-HMDS, imbrued with 10% Carbovax-20M, gas-
bearer helium 40 mL/min. at the temperature 220°.
Composition of the obtained compounds was consistent with the
results of elemental analysis.
-
OH
OH
N
1c
2c
O
To determine the structure of the salt 9 X-ray diffraction
structural investigation was carried out. The crystal of the size
0.2x0.24x0.28 mm was selected for diffraction measurements
carried out on CAD4 ‘Enraf-Nonius” diffractometer. The
compound has been crystallized in unusual for organic
compounds high symmetric hexagonal space group P61 (N169).
The set of 25 reflections with -angles in the range [14-15°]
degrees was used to refine the lattice constants. The integral
intensities of 14452 reflections were measured in full reciprocal
sphere up to max=30 degree. The number of unique reflections
was 3215 (Rint=0.08) from which the number of observed
reflections was 1834 with criteria I>2σ(I).
The initial structure model was defined by direct method
using the package of crystallographic programs SHELXTL [17].
The hydrogen positions were determined from difference
Fourier electron density maps. In final refinement the positional
parameters of all atoms and anisotropic thermal parameters for
nonhydrogen atoms were refined together giving final R value
0.053 for 1834 unique observed reflections. The crystal
structure is constructed from C12H18ON+Br– molecule and H2O
solvent water molecule, which is connected to Br– ion by
hydrogen bonding. The positional parameters of nonhydrogen
atoms are given in the table 1. The interatomic distances are in
agreement with their statistical values and are given in the table
2. The perspective view of the molecule with our numbering of
atoms is depicted on the Figure 1. All necessary information on
structural data may be obtained from authors.
12
Proceeding from the fact that it was impossible to
obtain the salt 2c in a crystalline form, we realized its
immediate water-base cleavage after cyclization of
propyn-1-yl(3-isopropenylpropyn-2-yl)morpholinium
bromide without isolation of the cyclic product (2c).
According to several examples we confirmed that
during base catalyzed intramolecular cyclization the base
isn’t consumed and in case of its absence no cyclization
takes place. It means that the base is a momentum for the
replacement of electrons with six-membered cyclic
mechanism, clockwise or counterclockwise. The fact of
salts 1a-c, 3a-c cyclization in milder conditions (molar
ratio: salt/base=13/1) compared with the 3-vinylpropyn-2-
yl analogs [14,15] (molar ratio: salt/base=10/1), allows to
say that the methyl group available in the 4-th position of
the enyne fragment increases the nucleophilty of the
enyne by its inductive and hyperconjugative effects. And
so facilitates the nucleophile addition of 3-isopropenyl-
propyn-2-yl group to the propyn-2-yl or allylic group,
including the six-membered cyclic mechanism electron
replacement counter-clockwise (Scheme 6).
Scheme 6
OH
R2N
Br
R2N
Br
H
H
H
These data are in accord with our investigations,
dedicated to the mechanism of base-catalyzed intramol-
ecular cyclization of unsaturated ammonium salts [12,13].
EXPERIMENTAL
Figure 1. The molecular structure of the salt 9.
The ir spectra were recorded on an IR-20 spectrometer.
Samples were prepared as potassium bromide pellets or in
Vaseline oil. The uv spectra were recorded on a Specord UV-vis
spectrometer in ethanol. The nmr spectra were carried out on a
“Varian Mercury-300” spectrometer at 300.08 MHz 1H and
75.46 MHz for 13C at temperature of 303 K using TMS as an
internal standard. For confirming the structures of salts 5a-c, 8
Spectra of the above-mentioned compounds accord well with
suggested structures.
The initial dialkyl(3-isopropenylpropyn-2-yl)amines have
been synthesized by the Mannich reaction [10,11].
(3-Isopropenylpropyn-2-yl)pyrrolidine (13). Isopropenyl-
acetilene (33.5 g, 500 mmole), paraform (15.62 g, 520 mmole),
pyrrolidine (28.4 g, 400 mmole), and 0.2 g of iron chloride and
150 mL of dioxane were placed in a metallic vessel. The
reaction mixture was heated at 90-92 ˚C during 70 h and then
the reaction mixture was acidified by hydrochloric acid. The
solvent was removed by distillation under low pressure. By
alkalization of the hydrochloride and further extraction by ether
(3x70 mL) amine 13 was isolated. The ethereal extract was
washed with water and dried over magnesium sulfate. After
1
and 9 as well as for assignment the signals in H and 13C nmr
spectra, methods of double resonance, DEPT and two-
dimensional correlation COSY, NOESY, HMQC were used.
Purity of salts was established by the TLC method on Silufol
UV-254 in the system of 1-butanol/ethanol/water/acetic
acid=10/2/1/5. Development was realized by iodine vapors. The
purity of amines was established by the GLC method on the
chromatograph LXM-8MD, column 1,5mx4mm, filled with

690
E. H. Chukhajian, M. K. Nalbandyan, H. R. Gevorkyan, E. H. Chukhajian,
H. A. Panosyan, A. G. Ayvazyan and R. A.Tamazyan
Vol 45
Table 1
Final Coordinates and Equivalent Isotropic Displacement,
Parameters of the non-Hydrogen atoms for the salt 9.
Atom
x
y
z
U(eq) [Å2]
O10
N2
0.9389(3)
0.9180(2)
0.7200(2)
0.4616(2)
0.07500(11)
0.13885(10)
0.0687(8)
0.0430(7)
C1
C3
1.0400(3)
0.8344(3)
0.9098(3)
0.8694(3)
0.9550(3)
1.0887(4)
1.0941(4)
0.5143(3)
0.2893(3)
0.2419(3)
0.0860(3)
0.0665(3)
0.1948(4)
0.3487(4)
0.18601(13)
0.14502(15)
0.17686(12)
0.19378(14)
0.23295(15)
0.26280(16)
0.25772(15)
0.0454(9)
0.0527(9)
0.0427(9)
0.0488(9)
0.0530(10)
0.0614(13)
0.0564(10)
C3A
C4
C5
C6
C7
C7A
C8
C9
1.0623(3)
0.8085(3)
0.8841(4)
1.0538(4)
0.9915(4)
0.4800(3)
0.3756(3)
0.5230(4)
0.6924(4)
0.6764(4)
0.5069(4)
0.4752(4)
0.19699(13)
0.14664(17)
0.13225(17)
0.06833(17)
0.08017(13)
0.26221(16)
0.0419(8)
0.0545(10)
0.0686(13)
0.0646(11)
0.0551(10)
0.1064(11)
C11
C12
O1W
Br
0.47692(4)
0.68352(4)
0.14811(2)
0.0684(1)
U(eq) = 1/3 of the trace of the orthogonalized U Tensor
Table 2
Bond Distances for the salt 9.
Atom pair
distance[Å] Atom pair
distance[Å]
O10-C9
O10-C11
1.418(5)
1.416(5)
C1-H1A
C1-H1B
0.89(3)
1.00(2)
O1W-H1WA
O1W-H1WB
N2-C1
0.94(3)
1.03(8)
C3-H3
C4-H4
0.98(3)
0.89(3)
0.95(3)
0.98(4)
0.98(3)
1.06(3)
0.87(3)
1.08(3)
0.94(4)
0.93(3)
0.92(3)
0.90(4)
1.02(3)
0.93(4)
1.10(4)
0.86(3)
1.523(4)
1.512(4)
1.499(4)
1.488(3)
1.521(4)
1.299(5)
1.446(4)
1.505(4)
1.327(5)
1.476(5)
1.506(5)
1.506(5)
1.497(5)
1.500(5)
C5-H5
N2-C12
N2-C8
C6-H6B
C6-H6A
C7-H7A
C7-H7B
C7A-H7AA
C8-H8A
C8-H8B
C9-H9B
C9-H9A
C11-H11A
C11-H11B
C12-H12B
C12-H12A
N2-C3
C1-C7A
C3-C3A
C3A-C4
C3A-C7A
C4-C5
C5-C6
C6-C7
C7-C7A
C8-C9
C11-C12
removing of the ether amine 13 (45.89 g, 308 mmole, 77%) was
obtained by vacuum distillation, bp 63° (2 mm Hg), nD20 1.4910,
days the salts 1a-c and 3a-c were isolated by filtration and
washed with absolute ether (2 x 25 mL).
1
mp of picrate 77° (EtOH). ir, ν, cm-1: 890, 1610, 2240. H nmr
Propyn-1-yl(3-isopropenylpropyn-2-yl)pyrrolidinium
bromide (1a). Salt 1a (4.06 g, 15.52 mmole, 97%), mp 114°.
(DMSO -d6/CCl4 1/3), δ, ppm: 1.75 (m, 4H, CH2 pyrrolidine),
1.86 (dd, 3H, J1=1.6 Hz; J2=1.2 Hz, CH3), 2.53 (m, 4H, NCH2
pyrrolidine), 3.43 (s, 2H, NCH2), 5.15 (kvn, 1H, J=1.6, =CH2)
and 5.17 (br, 1H, =CH2). Anal. Calcld for C10H15N: C, 80.48; H,
10.13; N, 9.39. Found: C, 79.95; H, 10.38; N, 9.68
General procedure for the synthesis of salts 1a-c and 3a-c.
To a solution of (3-isopropenylpropyn-2-yl)pyrrolidine (13),
-piperidine and -morpholine [11] (16 mmole) in 15 mL of
absolute ether and 15 mL of acetonitrile a two-fold molar
quantity of propyn-2-yl or allyl bromides were added. After two
1
uv, λmax., nm: 225. ir, ν, cm -1: 880, 1600, 2110, 2240. H nmr
(DMSO-d6/CCl4 1/3), δ, ppm: 1.96 (m, 3H, CH3); 2.26 (m, 4H,
NCH2CH2); 3.86 (t, 4H, J=6.0 Hz, NCH2CH2); 3.75 (t, 1H,
J=2.5 Hz, CH); 4.69 (d, 2H, J=2.6 Hz, NCH2); 4.77 (s, 2H,
NCH2); 5.40 and 5.50 (m, 1H, =CH2). 13C nmr (DMSO-d6/CCl4
1/3), δ, ppm: 19.10 (NCH2CH2); 22.33 (CH3); 49.39 (NCH2);
50.24 (NCH2); 57.26 (NCH2CH2); 70.85 (≡C propin-1-yl);
75.16 (≡C); 82.77 (≡CH); 91.82 (≡CC(CH3)CH2); 124.37
(=CH2); 124.48 (=C). Anal. Calcld for C13H18BrN: C, 58.21; H,

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Cyclization of Dialkylpropyn-1-yl(allyl)(3-isopropenylpropyn-2-yl)ammonium Bromides
691
6.72; Br, 29.79; N, 5.22. Found: C, 58.59; H, 6.65; Br, 29.44;
N, 5.44.
3.82 m (4H, NCH2CH2); 4.96 (s, 2H, NCH2); 4.98 (s, 2H, NCH2);
7.18 (d, 1H, J=7.7 Hz, HAr); 7.23 (br, 1H, HAr); 7.30 (d 1H, J=7.7
Hz, HAr). 13C nmr (DMSO-d6/CCl4 1/3), δ, ppm: 20.87 (CH3);
29.17 (NCH2CH2); 62.91 (NCH2CH2); 65.73 (NCH2); 123.06
(=CH); 123.45 (=CH); 128.97 (=CH); 129.56 (=C); 133.62 (=C);
136.9 (=C). Anal. Calcld for C13H18BrN: C, 58.21; H, 6.72; Br,
29.79; N, 5.22. Found: C, 58.56; H, 6.52; Br, 29.49; N 5.47.
2,2-Pentamethylene-5-methylisoindolinium bromide (2b).
Salt 2b (2.1 g, 7.39 mmole, 85%), mp 192°. uv, λmax., nm: 248.
Propyn-1-yl(3-isopropenylpropyn-2-yl)piperidinium
bromide (1b). Salt 1b (4.33 g, 15.36 mmole, 96%) mp 102°. uv,
1
λmax., nm: 220. ir, ν, cm -1: 890, 1605, 2120, 2240. H nmr
(DMSO-d6/CCl4 1/3), δ, ppm: 1.72 (m, 2H, CH2 piperidine); 1.96
(m, 4H, NCH2CH2); 1.96 (m, 3H, CH3); 3.75 (t, 4H, J=6.0 Hz,
NCH2CH2); 3.77 (t, 1H, J=2.5 Hz, CH); 4.69 (d, 2H, J=2.6 Hz,
NCH2); 4.77 (s, 2H, NCH2); 5.42 and 5.51 (m, 1H, =CH2). 13C
nmr (DMSO-d6/CCl4 1/3), δ, ppm: 19.10 (NCH2CH2); 20.11
(CH2 piperidine); 22.33 (CH3); 49.39 (NCH2); 50.24 (NCH2);
57.26 (NCH2CH2); 70.85 (≡C propin-1-yl); 75.16 (≡C); 82.77
(≡CH); 91.82 (≡CC(CH3)CH2); 124.37 (=CH2); 124.48 (=C).
Anal. Calcld for C14H20BrN: C, 59.57; H, 7.09; Br, 28.31; N,
4.96. Found: C, 59.86; H, 6.82; Br, 28.62; N, 4.66.
1
ir, ν, cm-1: 825, 1560, 1600, 3030, 3070. H nmr (DMSO-
d6/CCl4 1/3), δ, ppm: 1.77 (br.k, 2H, J=5.8 Hz CH2 piperidine);
1.96 (brk, 4H, J=5.8 Hz, NCH2CH2); 2.40 (s, 3H, CH3), 3.75 (t,
4H, J=5.8 Hz, NCH2 piperidine), 4.98 (br, 2H, NCH2), 4.99 (br,
2H, NCH2), 7.17 (d, 1H, J=7.7 Hz, HAr), 7.24 (br, 1H, HAr), 7.31
(d, 1H, J=7.7 Hz, HAr). 13C nmr (DMCO-d6/CCl4 1/3), δ, ppm:
20.53 (CH2 piperidine), 20.82 (NCH2CH2), 59.29 (NCH2
piperidine), 66.27 (NCH2), 122.88 (=CH), 123.53 (=CH), 128.80
(=CH), 129.89 (=C), 133.01 (=C), 137.78 (=C). Anal. Calcld for
C14H20BrN: C, 59.57; H, 7.09; Br, 28.31; N, 4.96. Found: C,
59.88; H, 6.92; Br, 28.65; N, 5.21.
Propyn-1-yl(3-isopropenylpropyn-2-yl)morpholinium
bromide (1C). Salt 1C (4.40 g, 15.52 mmole 97%), mp 122°.
-1
1
uv, λmax., nm: 230. ir, ν, cm : 870, 1610, 2130, 2230. H nmr
(DMSO-d6/CCl4 1/3), δ, ppm: 1.99 (m, 3H, CH3); 3.78 (m, 4H,
NCH2 morpholine); 3.86 (t, 1H, J=2.5, CH); 4.07 (m, 4H,
OCH2); 4.89 (d, 2H, J=2.5 Hz, NCH2); 4.96 (s, 2H, NCH2); 5.43
and 5.53 (m 1H, =CH2). 13C nmr (DMSO-d6/CCl4 1/3), δ, ppm:
21.79 (CH3); 49.34 (NCH2); 50.37 (NCH2); 55.38 (NCH2
morpholine); 59.00 (OCH2); 70.18 (≡C propin-1-yl); 74.40 (≡C);
82.64 (≡CH); 91.84 (≡CC(CH3)CH2); 114.71 (=C); 123.95
(=CH2);. Anal. Calcld for C13H18BrNO: C, 54.93; H, 6.34; Br,
28.12; N, 4.93. Found: C, 54.75; H, 6.22; Br, 28.34; N, 4.69.
Allyl(3-isopropenylpropyn-2-yl)pyrrolidine bromide (3a).
Salt 3a (4.19 g, 15.52 mmole, 97%), mp 104°. uv, λmax., nm: 225.
ir, ν, cm-1: 890, 910, 940, 1610, 1635, 2240. 1H nmr (DMSO-
d6/CCl4 1/3), δ, ppm: 1.95 (m, 4H, NCH2CH2); 1.96 (m, 3H,
CH3); 3.66 (t, 4H, J=5.8 Hz, NCH2CH2); 4.26 (d, 2H, J=7.3 Hz,
NCH2); 4.77 (s, 2H, NCH2); 5.42 and 5.49 (m, 1H, =CH2); 5.67
and 5.79 (dd, 1H, J1=10.0 Hz, J2=1.7 Hz and J1=16.8 Hz, J2=1.7
Hz CH2); 6.11 (ddt, 1H, J1=16.8 Hz, J2=10.0 Hz, J3=7.3 Hz
CH);. 13C nmr (DMSO-d6/CCl4 1/3), δ, ppm: 21.60 (NCH2CH2);
22.39 (CH3); 49.32 (NCH2); 59.74 (NCH2CH2); 60.93 (NCH2);
75.94 and 91.47 (≡C); 124.09 (=CH2); 124.54 (=C); 124.65 (=C
allyl); 127.43 (=CH2 allyl). Anal. Calcld for C13H20BrN: C,
57.78; H, 7.41; Br, 29.57; N, 5.18. Found: C, 57.50; H, 7.55; Br,
29.25; N, 5.36.
2,2-Tetramethylene-5-methyl-2,6,7,7a-tetrahydro-1H-iso-
indolium bromide (5a). Salt 5a (2.78 g, 10.32 mmole, 86%),
1
mp 192°. ir, ν, cm -1: 1600, 1640, 3080. H nmr (DMSO-d6/CCl4
1/3), δ, ppm: 1.52 (qd, 1H, J1=12.3 Hz, J2=5.3 Hz, CHCH2),
1.79 (s, 3H, CH3), 2.13 (m, 1H, CHCH2), 2.22 (m, 4H), 2.25 (m,
2H, =CCH2), 3.31 (m, 1H, CH), 3.43 (t, 1H, J=10.3 Hz, NCH2),
3.55 (dt, 1H, J1=11.0 Hz, J2=8.2 Hz), 3.76 (m, 1H), 3.89-4.00
(m, 2H), 4.36 (dd, 1H, J1=11.0 Hz, J2=6.8 Hz), 6.12 (br, 1H,
=CH), 6.46 (br, 1H, NCH=). 13C nmr (DMCO-d6/CCl4 1/3), δ,
ppm: 21.33 (CH2), 21.61 (CH2), 23.43 (CH3), 25.49 (CH2), 29.85
(CH2), 38.40 (CH), 63.32 (NCH2), 64.67 (NCH2), 66.92 (NCH2),
113.63 (=CH), 124.11 (=CHN), 137.85 (=C), 147.19 (=C). Anal.
Calcld for C13H20BrN: C, 57.78; H, 7.41; Br, 29.57; N, 5.18.
Found: C, 57.43; H, 7.52; Br, 29.85; N, 5.39.
2,2-Pentamethylene-5-methyl-2,6,7,7a-tetrahydro-1H-iso-
indolium bromide (5b). Salt 5b (2.98 g, 10.20 mmole, 85%),
1
mp 237°. ir, ν, cm -1: 1605, 1650 3070. H nmr (DMSO-d6/CCl4
1/3), δ, ppm: 1.53 (qd, 1H, J1=12.2 Hz, J2=5.3 Hz, CHCH2),
1.62-1.80 (m, 2H), 1.85-2.05 (m, 4H), 1.90 (s, 3H, CH3), 2.14
(m, 1H, CHCH2), 2.20 (m, 1H, =CCH2), 2.33 (m, 1H, =CCH2),
3.27 (m, 1H, CH), 3.34 (t, 1H, J=10.5 Hz, NCH2), 3.58 (m, 2H),
3.64 (ddd, 1H, J1=12.3 Hz, J2=6.4 Hz, J3=3.8 Hz), 3.77 (ddd,
1H, J1=12.3 Hz, J2=9.0 Hz, J3=3.8 Hz), 4.46 (dd, 1H, J1=11.0
Hz, J2=6.8 Hz), 6.12 (br, 1H, =CH), 6.57 (br, 1H, NCH=). 13C
nmr (DMCO-d6/CCl4 1/3), δ, ppm: 20.10 (CH2), 21.33 (CH2),
20.60 (CH2), 21.11 (CH2), 23.44 (CH3), 25.62 (CH2), 29.84
(CH2), 37.66 (CH), 60.09 (NCH2), 62.42 (NCH2), 65.36 (NCH2),
113.67 (=CH), 124.70 (=CHN), 137.74 (=C), 147.41 (=C). Anal.
Calcld for C14H22BrN: C, 59.15; H, 7.75; Br, 28.11; N, 4.93.
Found: C, 58.80; H, 8.00; Br, 28.39; N, 4.54.
Physico-chemical characteristics of the salts 3b and 3c are in
accordance with literature data [11].
General procedure for the cyclization of salts 1a-c and 3a-
c. To a solution of salts 1a-c (8.7 mmole) in 3 mL of water or
salts 3a-c (12 mmole) in 5 mL of water was added 0.35 or 0.46
mL of 2 N solution of potassium or sodium hydroxide (mole-
ratio:salt/base=13/1). During 5-6 min the reaction mixture
temperature rose from 25° to 80-85° by self-heating. After
cooling, the reaction mixture was extracted by ether (2x30 mL)
for removing the products of the side reaction. The reaction
mixture was acidified by hydrobromic acid then the solvent was
removed by distillation under low pressure. The cyclic salts
were extracted by absolute ethanol. Then salts 2a, 2b, 5a were
isolated by absolute ethereal settlement from ethanol solution.
Salts 5b and 5C were isolated from the reaction mixtures by
filtration at room temperature. It was impossible to obtain the
salt 2c in a crystalline form.
Spiro[5-methyl-2,6,7,7a-tetrahydro-1H-isoindol]morphol-
inium bromides (5C). Salt 5c (2. 98 g, (10.44 mmole 87%), mp
1
247°. ir, ν, cm -1: 1600, 1640, 3080. H nmr (DMSO-d6/CCl4
1/3), δ, ppm: 1.56 (qd, 1H, J1=12.4 Hz, J2=5.4 Hz, CHCH2),
1.89 (s, 3H, CH3), 2.14 (m, 1H, CHCH2), 2.20 (m, 1H, =CCH2),
2.34 (m, 1H, =CCH2), 3.35 (m, 1H, CH), 3.54 (t, 1H, J=10.5 Hz,
NCH2), 3.57-3.77 (m 3H), 3.83-4.12 (m, 5H), 4.68 (dd, 1H,
J1=11.2 Hz, J2=7.1 Hz), 6.13 (br, 1H, =CH), 6.72 (br, 1H,
NCH=). 13C nmr (DMCO-d6/CCl4 1/3), δ, ppm: 23.48 (CH3),
25.47 (CH2), 29.85 (CH2), 37.66 (CH), 58.90 (NCH2), 60.98
(NCH2), 61.17 (OCH2), 61.69 (OCH2), 65.36 (NCH2), 113.56
2,2-Tetramethylene-5-methylisoindolinium bromide (2a).
Salt 2a (1.93 g, 7.22 mmole, 83%), mp 194°. uv, λmax., nm: 245. ir,
1
ν, cm-1: 820, 850, 1580, 1600, 3020, 3070. H nmr (DMSO-
d6/CCl4 1/3), δ, ppm: 2.27 (m, 4H, NCH2CH2); 2.38 s (3H, CH3);

692
E. H. Chukhajian, M. K. Nalbandyan, H. R. Gevorkyan, E. H. Chukhajian,
H. A. Panosyan, A. G. Ayvazyan and R. A.Tamazyan
Vol 45
(=CH), 124.49 (=CHN), 138.34 (=C), 147.84 (=C). Anal. Calcld
for C13H20BrNO: C, 54.55; H, 7.04; Br, 27.92; N, 4.89. Found:
C, 54.25; H, 7.26; Br, 28.23; N, 4.65.
morpholine), 3.36 (s, 2H, NCH2), 3.57 (m, 4H, OCH2), 6.84-
7.02 (m, 3H, HAr). Anal. Calcld for C13H19NO: C, 76.10; H, 9.27;
N, 6.83. Found: C, 75.71; H, 9.51; N, 6.58.
The step cyclization of the salt 1c and immediate
cleavage of cyclic product. 5-Methylisoindoline 2-vinyl
ethyl ester (12). To a solution of salt 1c (9 mmole) in 3.5 mL
of water was added 0.35 mL of 2 N solution of potassium or
sodium hydroxide (mole-ratio:salt/base=13/1). The reaction
mixture temperature rose up to 80-85° by self-heating during
5-6 min. After cooling, the reaction mixture was extracted by
ether (2×30 mL) in order to remove the side reaction
products. Then a two-fold molar quantity of potassium
hydroxide was added to the reaction mixture. The cleavage
carried out with distillation. From time to time water was
added to the reaction mixture through a dropping funnel.
During water-base cleavage the reaction mixture temperature
is maintained at 110-120°. For the process completion the
reaction mixture temperature was raised up to 140-145° for
several minutes in the end. Then the reaction mixture and
distillate were extracted by ether (3×40 mL). The ethereal
extracts were combined and washed by water and dried over
magnesium sulfate. After removing ether, amine 12 was
distilled. Compound 12 (0.85 g, 4.2 mmole 60%), bp 125° (2
mm Hg.), oil. ir, ν, cm-1: 810, 870, 1600, 1660, 3020, 3070,
3130. 1H nmr (DMSO-d6/CCl4 1/3), δ, ppm: 2.32 (s, 3H, CH3),
2.96 (t, 2H, J=5.9 Hz, NCH2), 3.82 (t, 2H, J=5.9 Hz, OCH2),
3.95 (dd, 1H, J1=6.8 Hz, J2=2.0 Hz, =CH2), 4.15 (dd, 1H,
J1=14.3 Hz, J2=2.0 Hz, =CH2), 6.44 (dd, 1H, J1=14.3 Hz,
J2=6.8 Hz, =CH), 6.90-6.95 (m, 2H) and 7.00 (d, 1H, J=7.4
Hz, HAr). Anal. Calcld for C13H17NO: C, 76.85; H, 8.43; N,
6.90. Found: C, 76.47; H, 8.28; N, 7.14.
2,2-Dimethyl-2,6,7,7a-tetrahydro-1H-isoindolium bromide
(8). Salt 8 was obtained in 87% yield, mp 162°. ir, ν, cm -1: 1650,
3010. 1H nmr (DMSO-d6/CCl4 1/3), δ, ppm: 1.54 (m, 1H,
CHCH2), 2.12 (m, 1H, CHCH2), 2.43 (m, 2H, CH2), 3.38 (s, 3H,
CH3) and 3.49 (s, 3H, CH3), 3.38-3.54 (m, 2H, CH and NCH2),
4.39 (m, 1H, NCH2), 6.25 (ddd, 1H, J1=9.8 Hz; J2=4.8 Hz; J3 =3.0
Hz, =CHCH2), 6.35 (dt, 1H, J1=9.8 Hz; J2=2.0 Hz, =CH), 6.61 (br,
1H, =CHN). 13C nmr (DMSO-d6/CCl4 1/3), δ, ppm: 24.63 (CH2),
25.12 (CH2), 38.61 (CH), 52.44 (CH3), 53.54 (CH3), 69.88
(NCH2), 117.80 (=CH), 128.53 (=CHN), 135.73 (=C), 137.70
(=CHCH2). Anal. Calcld for C10H16BrN: C, 52.19; H, 7.01; Br,
34.72; N, 6.09. Found: C, 52.45; H, 7.16; Br, 34.60; N, 6.40.
2,2-Spiro[2,6,7,7a-tetrahydro-1H-isoindol]morpholinium
bromide (9). Salt 9 was obtained in 82% yield, mp 240°. uv,
λmax., nm: 235. 1H nmr (DMSO-d6/CCl4 1/3), δ, ppm: 1.56 and 2.10
(m, 1H, CHCH2), 2.24-2.43 (m, 2H, CH2), 3.35 (m, 1H, CH), 3.48
(t, 1H, J=11.0 Hz, NCH2), 3.57 (m, 1H, NCH2 morpholine), 3.63
(ddd, 1H, J1=12.5 Hz; J2=5.0 Hz; J3 =2.8 Hz, NCH2), 3.76 (ddd,
1H, J1=12.5 Hz; J2=8.2 Hz; J3 =3.3 Hz, NCH2), 3.86-4.08 (m, 4H,
OCH2), 4.55 (dd, 1H, J1=11.0 Hz; J2=6.9 Hz, NCH2 morpholine),
6.31 (ddd, 1H, J1=9.9 Hz; J2=4.5 Hz; J3 =2.4 Hz, =CHCH2), 6.36
(dd, 1H, J1=9.9 Hz; J2=1.8 Hz, =CH), 6.69 (br, 1H, =CHN). 13C
nmr (DMSO-d6/CCl4 1/3), δ, ppm: 24.68 (CH2), 25.27 (CH2),
37.81 (CH2CH), 58.93 and 60.90 (NCH2 morpholine), 61.07 and
61.54 (OCH2), 65.38 (NCH2), 117.82 (=CH), 126.20 (=CHN),
137.61 (=C), 138.61 (=CHCH2). Anal. Calcld for C12H18BrNO: C,
52.95; H, 6.67; Br, 29.36; N, 5.15; O, 5.88. Found: C, 52.65; H,
6.83; Br, 29.70; N, 5.14.
General Procedure for the salts 5a-c water-base cleavage
reaction. To a solution of salts 5a-c (8.2 mmole) in 4 mL of
water was added a two-fold molar quantity of potassium or
sodium hydroxide dissolved in 3-4 mL of water. The cleavage
reaction process and further treatment are analogs to the above-
mentioned. The mixtures of isomeric amines 10a-c, 11a-c were
distilled.
REFERENCES AND NOTES
[1] Chukhajian, E. H.; Khim. Geterotsikl. Soedin. 1993, 4, 433.
[2] Chukhajian, E. H.; Chukhajian, El. H.; Gevorkyan, H. R.;
Shahkhatuni, K. G.; Kinoyan, F. S.; Panosyan, H. A. Khim. Geterotsikl.
Soedin. 2004, 34.
1-(2,5-Dimethylbenzyl)pyrrolidine (10a) and 1-(2,4-di-
methylbenzyl)pyrrolidine (11a) (1 g, 5.33 mmole, with general
yield 65%), bp 88-89° (1-2 mm Hg), nD20 1.5275. ir, ν, cm-1: 805,
[3] Gevorkyan, H. R.; Chukhajian, E. H.; Chukhajian, El. H.;
Panosyan, H. A. Khim. Geterotsikl. Soedin. 2004, 212.
[4] Iwai, I.; Hiraoca, T. Chem.Pharm.Bull. 1963, 11, 1556.
[5] Iwai, I.; Ide, J. Chem. Pharm. Bull. 1964, 12, 1094.
[6] Bartlett, A. J.; Laird, T.; Ollis, W. D. J. Chem. Soc., Chem.
Commun., 1974, 496.
[7] Bartlett, A. J.; Laird, T.; Ollis, W. D. J. Chem. Soc., Perkin
Trans. I 1975, 1315.
[8] Laird, T.; Ollis, W.D.; J. Chem. Soc., Chem. Commun. 1972,
557.
1
825, 1580, 1600, 3030. H nmr (DMSO-d6/CCl4 1/3), δ, ppm:
1.73 (m, 4H, CH2 pyrrolidine), 2.27 (s, 1.5H, CH3), 2.28 (s, 3H,
CH3), 2.29 (s, 1.5H, CH3), 2.43 (m, 4H, NCH2 pyrrolidine), 3.47
(s, 2H, NCH2), 6.85-7.04 (m, 3H, HAr). Anal. Calcld for
C13H19N: C, 82.54; H, 10.05; N, 7.41. Found: C, 82.91; H, 9.82;
N, 7.62.
1-(2,5-Dimethylbenzyl)piperidine (10b) and 1-(2,4-di-
methylbenzyl)piperidine (11b) (1.11 g, 5.49 mmole, with
general yield 67%), bp 110° (1-2 mm Hg), nD 1.5220. ir, ν,
[9] Garratt, P. J.; Neoh, S. B. J. Am. Chem. Soc. 1975, 97, 3255.
[10] Mannich, C. Ber. 1933, 66, 418.
[11] Chukhajian, E. H.; Gevorkyan, H. R.; Nalbandyan, M. K.
Russ. J. Org. Chem. 2006, 42, 1784.
20
1
cm-1: 825, 870, 1500, 1600, 3070. H nmr (DMSO-d6/CCl4 1/3),
[12] Chukhajian, E. H.; Gevorkyan, H. R.; Chukhajian, El. H.;
Kinoyan, F. S. Russ. J. Org. Chem., 2005, 41, 369.
[13] Chukhajian, E. H.; Nalbandyan, M. K.; Gevorkyan, H. R.;
Kinoyan, F. S. Chem. J. Arm., 2007, 60, 83.
[14] Babayan, A. T.; Chukhajian, E. H.; Babayan, G.; Chukhajian,
El. H.; Kinoyan, F. S. Chem. J. Arm. 1970, 23, 149; Chem. Abstr. 1970,
73, 25225x.
[15] Chukhajian, E. H.; Gabrielyan, G.; Babayan, A. T. Chem. J.
Arm. 1976, 29, 649.
[16] Babayan, A. T.; Taqmazyan, K., Babayan, G. Chem. J.
Arm.1966, 19, 685; Chem. Abstr. 1967, 66, 104532d.
[17] Bruker AXS, Copyright 2000, SHELXTL version 6.10.
δ, ppm: 1.43 (m, 2H, CH2 piperidine), 1.52 (m, 4H, NCH2CH2),
2.27 (s, 1.5H, CH3), 2.28 (s, 3H, CH3), 2.29 (s, 1.5H, CH3), 2.32
(m, 4H, NCH2 piperidine), 3.30 (s, 2H, NCH2), 6.80-7.01 (m,
3H, HAr). Anal. Calcld for C14H21N: C, 82.76; H, 10.34; N, 6.90.
Found: C, 82.38; H, 10.61; N, 7.11.
4-(2,5-Dimethylbenzyl)morpholine (10C) and 4-(2,4-di-
methylbenzyl)morpholine (11C) (1.16 g, 5.66 mmole, with
20
general yield 69%), bp 105° (1-2 mm Hg), nD 1.5240. ir, ν,
1
cm-1: 805, 825, 870, 1500, 1560, 1600, 3020. H nmr (DMSO -
d6/CCl4 1/3), δ, ppm: 2.27 (s, 1.5H, CH3), 2.28 (s, 1.5H, CH3),
2.30 (s, 1.5H, CH3), 2.31 (s, 1.5H, CH3), 2.36 (m, 4H, NCH2