Synthesis of perhydro-N-(2,2-disubstituted- 3-aminopropyl) heterocycles as potentially bioactive compounds and fragments for combinatorial chemistry

Article abstract of DOI:10.1515/hc-2012-0093

A new method for the preparation of perhydro- N - (2,2-disubstituted-3- aminopropyl) heterocycles that allows to obtain a large variety of corresponding derivatives with high to moderate yields using simple procedures is described.

Full text of DOI:10.1515/hc-2012-0093

DOI 10.1515/hc-2012-0093ꢀ
ꢀHeterocycl. Commun. 2012; 18(4): 189–192
Sargis S. Hayotsyan*, Gevorg G. Mkryan, Asya A. Aghekyan and Gagik S. Melikyan
Synthesis of perhydro-N-(2,2-disubstituted-
3-aminopropyl) heterocycles as potentially
bioactive compounds and fragments for
combinatorial chemistry
Abstract: A new method for the preparation of perhydro-N- with hydrogen over a Raney nickel at 20°C and elevated
pressures (Lamm et al., 1970).
(2,2-disubstituted-3-aminopropyl) heterocycles that allows
to obtain a large variety of corresponding derivatives
with high to moderate yields using simple procedures is
described.
Results and discussion
Keywords: 2,2-disubstituted-1,3-diaminopropane; ethyl
cyanoacetate; perhydroheterocycles.
In the current report, a new way for the synthesis of
N-(3-amino-2,2-disubstituted) perhydroheterocycles 3a–x
starting from a cyanoacetic ester is described. In the
first step, the reaction between ethyl cyanoacetate and
the corresponding perhydro-NH heterocycles furnished
the amides of cyanoacetic acid 1. These products 1 were
converted into the corresponding α,α-disubstituted
amides 2 by alkylation with appropriate alkyl halides.
Then the amides 2 were reduced with lithium aluminum
hydride (LAH) (Mndzhoyan et al., 1971) to give the desired
N-(3-amino-2,2-dialkyl)-perhydroheterocycles 3a–x in
yields of about 70% (Scheme 1). Some of the obtained
compounds (3b,c,h,i,k) are highly reactive toward carbon
dioxide from the air. Accordingly, after distillation, they
were converted into stable oxalates and further character-
ized in that form.
*Corresponding author: Sargis S. Hayotsyan, Scientific
Technological Centre of Organic and Pharmaceutical Chemistry,
National Academy of Sciences, 26 Azatutyan Avenue, 0014 Yerevan,
Armenia, e-mail: sargis@hayotsyan.com
Gevorg G. Mkryan and Asya A. Aghekyan: Scientific Technological
Centre of Organic and Pharmaceutical Chemistry, National Academy
of Sciences, 26 Azatutyan Avenue, 0014 Yerevan, Armenia
Gagik S. Melikyan: Yerevan State University, 1 Alex Manoogian,
0025 Yerevan, Armenia
Introduction
The 2,2-disubstituted-1,3-diaminopropane fragment is
a fairly common moiety in several biologically active
compounds. N-Cyclohexyl-1,3-diaminopropane acts as
a spermine synthase inhibitor, thus suppressing cancer
(particularly human breast cancer) cell growth (Huber
et al., 1995). Other types of 1,3-diamino fragments are
contained in several pharmaceutical substances, such as
apridine, desipiramine, ethylmemazine, and many other
analogous compounds.
Conclusions
A new, inexpensive, and highly convenient method for
the synthesis of N-substituted perhydroheterocycles is
described. These compounds are interesting as individual
substances as well as the fragments for the combinatorial
chemistry.
The common way for the construction of N,N-disub-
stituted-2,2-disubstituted-1,3-diaminopropanes is through
the hydrogenation of corresponding α,α-disubstituted-β-
aminonitriles or oximes with lithium aluminum hydride
(Zaugg et al., 1953; Hine et al., 1975). Sodium in ethanol
(Faust et al., 1959) can also be used for the hydrogenation
of the oximes. 1,3-Dinitropropanes have also been reduced
Experimental section
All initial compounds were of commercial grade and used without
further purification. Yields refer to the isolated compounds. Melting
points were determined on SMP-10 melting point apparatus. Infra-
red spectra were recorded in KBr pellets on a Nicolet Avatar 330
1
spectrometer. H NMR spectra were obtained in a DMSO-d6 solution
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190ꢀ
ꢀS.S. Hayotsyan et al.: Synthesis of perhydro-N-(2,2-disubstituted-3-aminopropyl) heterocycles
MeI
X
LAH, Et2O
Reflux
X
N
N
NH2
NaOH; DMSO
15-20°C
CN
O
3a-e
X
2
X
NH
EtO
O
N
CN
CN
Y
r.t., 48 h
O
1
Y
Y
X
LAH, Et2O
Reflux
X
Cl
Cl
N
N
NH2
CN
NaOH; DMSO;
80-85°C
O
3f-x
2
3a: X = -(CH2)2-; 3b: X = -(CH2)3-; 3c: X = -(CH2)4-; 3d: X = -CH2N(CH3)CH2-; 3e: X = 1,2-
-CH2C6H4-; 3f: X = Y = -(CH2)2-; 3g: X = -(CH2)2-, Y = -(CH2)3-; 3h: X = -(CH2)2-, Y = -CH2OCH2-;
3i: X = -(CH2)3-, Y = -(CH2)2-; 3j: X = Y = -(CH2)3-; 3k: X = -(CH2)3-, Y = -CH2OCH2-; 3l: X =
-(CH2)4-, Y = -(CH2)2-; 3m: X = -(CH2)4-, Y = -(CH2)3-; 3n: X = -(CH2)4-, Y = -CH2OCH2-; 3o: X =
-CH2N(CH3)CH2-, Y = -(CH2)2-; 3p: X = -CH2N(CH3)CH2-, Y = -(CH2)3-; 3q: X =
-CH2N(CH2)CH2-, Y = -CH2OCH2-; 3r: X = 1,2- -CH2C6H4-, Y = -(CH2)2-; 3s: X = 1,2-
-CH2C6H4-, Y = -(CH2)3-; 3t: X = 1,2- -CH2C6H4-, Y = -CH2OCH2-; 3u: X = -CH2OCH2-, Y =
-(CH2)2-; 3v: X = -CH2OCH2-, Y = -(CH2)3-; 3w: X = -CH2OCH2-, Y = -CH2OCH2-; 3x: X =
-CH2NBnCH2-, Y = -(CH2)2-.
Scheme 1
at 30°C, at 300 MHz, on a Varian Mercury 300 VX spectrometer, with
TMS as internal standard.
treated with oxalic acid, and the resultant oxalate was crystallized
from water and dried at 50–60°C/20 mm Hg.
2,2-Dimethyl-3-pyrrolidinopropan-1-amine (3a)ꢁYield 77%; bp
59–60°C/2 mm Hg; IR: 3417, 3387, 3329 cm-1; H NMR: δ 0.81 (s, 6H,
1
General procedure for the synthesis of
N-(3-amino-2,2-disubstituted)-
perhydroheterocycles 3a–x
2CH3), 1.05–1.21 (br, 2H, NH2), 1.67–1.72 (m, 4H, (CH2)2), 2.27 (s, 2H,
NCH2), 2.40 (s, 2H, CH2NH2), 2.52–2.57 (m, 4H, (CH2)2N). Anal. Calcd
for C9H20N2: C, 69.17; H, 12.90; N, 17.93. Found: C, 69.06; H, 12.83; N,
18.04.
A mixture of ethyl cyanoacetate (10.7 mL, 0.1 mol) and corresponding
perhydroheterocycle (0.1 mol) was stirred for 2 h at room tempera- 2,2-Dimethyl-3-piperidinopropan-1-amine (3b)ꢁYield 75%; bp
ture and afterward kept at room temperature for 2 days. The resultant 61–62°C/3 mm Hg; (mp of oxalate 143–145°C); IR: 3431, 3392, 3342
1
crystals of 1 (yield 70–80%) were filtered and washed with diethyl cm-1; H NMR of oxalate: δ 0.98 (s, 6H, 2CH3), 1.42 (dd, J ꢀ=ꢀ 11 Hz and
ether.
Further, a solution of corresponding amide 1 (0.05 mol) in DMSO
6 Hz, 2H, CH2CH2CH2), 1.60 (td, J ꢀ=ꢀ 11 Hz and 6 Hz, 4H, CH2CH2CH2),
2.39 (s, 2H, NCH2), 2.53–2.63 (m, 4H, (CH2)2N), 2.83 (s, 2H, CH2NH2),
(100 mL) was treated with NaOH (8 g, 0.2 mol), and the mixture was 5.04–6.99 (br, 4H, NH2 + H2C2O4). Anal. Calcd for C10H22N2: C, 70.53; H,
treated dropwise with methyl iodide (7 mL, 0.11 mol) at 15–20°C or 13.02; N, 16.45. Found: 70.30; H, 12.93; N, 16.30.
with α,ω-dichloro derivative ClCH2YCH2Cl (0.055 mol) at 50–55°C
and then heated at 80–85°C for 2 h. After cooling, the mixture was 3-Azepano-2,2-dimethylpropan-1-amine (3c)ꢁYield 73%; bp
extracted with benzene (3ꢀ×ꢀ50 mL), and the extract was washed with 65–67°C/2 mm Hg; (mp of oxalate 140–142°C); IR: 3419, 3389, 3332
water, dried with MgSO4 and concentrated on a rotary evaporator. cm-1; 1H NMR of oxalate: δ 1.16 (s, 6H, 2CH3), 1.68 (br, 4H), and 1.86 br
The residue was distilled under reduced pressure (2–3 mm Hg).
(4H, (CH2)4), 2.94 (br, 2H, CH2N), 3.23 (br, 4H, (CH2)2N), 3.48 (br, 2H,
To obtain compounds 3a–x, the solution of amide 2 (0.02 mol) in CH2NH2), 12.43 (br, 4H, NH2 + H2C2O4). Anal. Calcd for C13H26N2O4: C,
dry diethyl ether (10 mL) was added dropwise to the stirred solution 56.91; H, 9.55; N, 10.21. Found: C, 57.15; H, 9.42; N, 10.49.
of LAH (6.08 g, 0.16 mol) in dry diethyl ether (30 mL) over 20 min.
Then the mixture was heated under reflux for 12 h and quenched 2,2-Dimethyl-3-(4-methylpiperazino)propan-1-amine (3d)ꢁYield
with water (20 mL) on the ice/water bath. The precipitate was filtered 85%; bp 85–90°C/2 mm Hg; IR: 3425, 3393, 3341 cm-1; 1H NMR: δ 0.78
off and washed with ether. The filtrate and the ether were combined (s, 6H, 2CH3), 0.90–1.30 (br, 2H, NH2), 2.11 (s, 2H, CH2N), 2.15 (s, 3H,
and dried with anhydrous sodium sulfate. After the removal of the
solvent, the residue was distilled under reduced pressure. In the (m, 4H, (CH2)2N). Anal. Calcd for C10H23N3: C, 64.81; H, 12.51; N, 22.68.
case when the amine was unstable in a free form, the distillate was Found: C, 64.98; H, 12.39; N, 22.57.
CH3N), 2.25–2.30 (m, 4H, (CH2)2N), 2.39 (s, 2H, CH2NH2), 2.44–2.50
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S.S. Hayotsyan et al.: Synthesis of perhydro-N-(2,2-disubstituted-3-aminopropyl) heterocyclesꢀ
ꢀ191
3-(3,4-dihydroisoquinolin-2(1H)-yl)-2,2-dimethylpropan- (s, 2H, CH2NH2), 2.65–2.70 (m, 4H, (CH2)2N), 2.40–3.00 (br, 2H, NH2).
1-amine (3e)ꢁYield 69%; bp 148–150°C/2 mm Hg; IR: 3427, 3381, Anal. Calcd for C14H28N2: C, 74.94; H, 12.58; N, 12.48. Found: C, 74.81;
3341 cm-1; 1H NMR: δ 0.85 (s, 6H, 2CH3), 1.95 (brs, 2H, NH2), 2.31 (s, 2H, H, 12.49; N, 12.61.
CH2N), 2.47 (s, 2H, CH2NH2), 2.71–2.85 (m, 4H, NCH2CH2), 3.66 (s, 2H,
NCH2Ar), 6.86–6.92 (m, 1H), and 6.94–7.04 (m, 3H, Ar). Anal. Calcd for 4-Aminomethyl-4-(azepanomethyl)tetrahydro-4H-pyran
C14H22N2: C, 77.01; H, 10.16; N, 12.83. Found: C, 76.97; H, 10.03; N, 12.95. (3n)ꢁYield 58%; bp 142–145°C/2 mm Hg; IR: 3423, 3378, 3328 cm-1;
1H NMR: δ 1.33–1.38 (m, 4H, 2 CH2), 1.57 (br, 8H, (CH2)4), 1.50–1.70
1-Aminomethyl-1-(pyrrolidinomethyl)cyclopentaneꢀ(3f)ꢁYield (br, 2H, NH2), 2.44 (s, 2H, CH2N), 2.63 (s, 2H, CH2NH2), 2.67–2.73 (m,
68%; bp 135–136°C/2 mm Hg; IR: 3422, 3379, 3335 cm-1; 1H NMR: δ
4H, (CH2)2N), 3.46–3.56 (m, 4H, (CH2)2O). Anal. Calcd for C13H26N2O: C,
1.22–1.32 (m, 2H) and 1.44–1.58 (m, 6H, (CH2)4), 1.37–1.61 (br, 2H, NH2), 68.98; H, 11.58; N, 12.38. Found: C, 68.82; H, 11.71; N, 12.47.
1.66–1.73 (m, 4H, (CH2)2), 2.41 (s, 2H, NCH2), 2.48–2.53 (m, 6H, (CH2)2N
and CH2NH2). Anal. Calcd for C11H22N2: C, 72.47; H, 12.16; N, 15.37. 1-Aminomethyl-1-(4-methylpiperazinomethyl)cyclopentane
Found: C, 72.55; H, 12.01; N, 15.26.
(3o)ꢁYield 72%; bp 128–130°C/3 mm Hg; IR: 3418, 3393, 3341 cm-1;
1H NMR: δ 1.20–1.32 (m, 2H) and 1.39–1.58 (m, 6H, (CH2)4), 2.10–2.50
1-Aminomethyl-1-(pyrrolidinomethyl)cyclohexaneꢀ(3g)ꢁYield (br, 2H, NH2), 2.15 (s, 3H, CH3N), 2.25 (s, 2H, CH2N), 2.25–2.33 (m, 4H,
67%; bp 140–141°C/2 mm Hg; IR: 3420, 3380, 3330 cm-1; H NMR: δ
(CH2)2N), 2.39–2.47 (m, 4H, (CH2)2N), 2.45 (s, 2H, CH2NH2). Anal. Calcd
for C12H25N3: C, 68.20; H, 11.92; N, 19.88. Found: C, 68.05; H, 11.83; N,
1
1.18–1.47 (m, 10H, (CH2)5), 1.67–1.74 (m, 4H, (CH2)2), 2.43 (s, 2H, NCH2),
2.55–2.62 (m, 4H, (CH2)2N), 2.66 (s, 2H, CH2NH2), 4.10 (brs, 2H, NH2). 19.78.
Anal. Calcd for C12H24N2: C, 73.41; H, 12.32; N, 14.27. Found: C, 73.54;
H, 12.15; N, 14.12.
1-Aminomethyl-1-(4-methylpiperazinomethyl)cyclohexane
(3p)ꢁYield 81%; bp 136–138°C/3 mm Hg; IR: 3420, 3384, 3337 cm-1;
4-Aminomethyl-4-(pyrrolidinomethyl)tetrahydro-4H-pyran 1H NMR: δ 1.14–1.45 (m, 10H, (CH2)5), 2.14 (s, 3H, CH3N), 2.18 (s, 2H,
(3h)ꢁYield 65%; bp 145–146°C/2 mm Hg; (mp of oxalate 150–151°C);
CH2N), 2.23–2.33 (m, 4H, (CH2)2N), 2.44–2.49 (m, 4H, (CH2)2N), 2.51
(s, 2H, CH2NH2), 2.55–3.05 (br, 2H, NH2). Anal. Calcd for C13H27N3: C,
IR: 3429, 3381, 3329 cm-1; 1H NMR of oxalate: δ 1.42–1.50 (m, 4H, 2CH2),
1.71–1.74 (m, 4H, (CH2)2), 2.73–2.80 (m, 4H, (CH2)2N), 2.81 (s, 2H, NCH2), 69.28; H, 12.08; N, 18.64. Found: C, 69.08; H, 12.17; N, 18.70.
3.07 (s, 2H, CH2NH2), 3.48–3.64 (m, 4H, (CH2)2O), 5.70–6.70 (br, 4H,
NH2 + H2C2O4). Anal. Calcd for C11H22N2O: C, 66.62; H, 11.18; N, 14.13. 4-Aminomethyl-4-(4-methylpiperazinomethyl)tetrahydro-
Found: 66.45; H, 11.29; N, 14.23.
4H-pyran (3q)ꢁYield 77%; bp 154–155°C/2 mm Hg; IR: 3429, 3378,
1
3335 cm-1; H NMR: δ 1.37 (dd, J ꢀ=ꢀ 6.6, 4.7 Hz, 4H, 2 CH2), 1.05–2.09
1-Aminomethyl-1-(piperidinomethyl)cyclopentane
(3i)ꢁYield (br, 2H, NH2), 2.16 (s, 3H, CH3N), 2.27 (s, 2H, CH2N), 2.28–2.33 (m, 4H,
68%; bp 138–140°C/2 mm Hg; (mp of oxalate 149–150°C); IR: 3430, (CH2)2N), 2.47–2.52 (m, 4H, (CH2)2N), 2.62 (s, 2H, CH2NH2). Anal. Calcd
1
3389, 3345 cm-1; H NMR of oxalate: δ 1.34–1.49 (m, 5H) and 1.58–1.72 for C12H25N3O: C, 63.40; H, 11.08; N, 18.48. Found: C, 63.51; H, 11.02;
(m, 9H, 7CH2), 2.59–2.68 (m, 6H, 3NCH2), 2.93 (s, 2H, CH2NH2), 6.06–
6.09 (br, 4H, NH2 + H2C2O4). Anal. Calcd for C14H26N2O4: C, 58.72; H,
9.15; N, 9.78. Found: C, 58.55; H, 9.26; N, 9.89.
N, 18.51.
1-Aminomethyl-1-{[3,4-dihydroisoquinolin-2(1H)-yl]methyl}
cyclopentane (3r)ꢁYield 68%; bp 175–176°C/2 mm Hg; IR: 3418,
1
1-Aminomethyl-1-(piperidinomethyl)cyclohexaneꢀ(3j)ꢁYield
3389, 3327 cm-1; H NMR: δ 1.30–1.42 (m, 2H) and 1.45–1.63 (m, 6H,
70%; bp 150–155°C/2 mm Hg; IR: 3425, 3375, 3327 cm-1; H NMR: δ
(CH2)4), 2.19–2.90 (br, 2H, NH2), 2.45 (s, 2H, CH2N), 2.53 (s, 2H, CH2NH2),
1
1.13–1.44 (m, 10H, (CH2)5), 1.15–1.65 (br, 2H, NH2), 1.46–1.56 (m, 6H,
2.73–2.78 (m, 2H), and 2.80–2.86 (m, 2H, NCH2CH2), 3.64 (s, 2H,
(CH2)3), 2.12 (s, 2H, NCH2), 2.37–2.45 (m, 4H, (CH2)2N), 2.52 (s, 2H, NCH2Ar), 6.89–6.95 (m, 1H), and 6.99–7.04 (m, 3H, Ar). Anal. Calcd for
CH2NH2). Anal. Calcd for C13H26N2: C, 74.23; H, 12.46; N, 13.32. Found: C16H24N2: C, 78.64; H, 9.90; N, 11.46. Found: C, 78.51; H, 9.95; N, 11.59.
C, 74.35; H, 12.34; N, 13.19.
1-Aminomethyl-1-{[3,4-dihydroisoquinolin-2(1H)-yl]methyl}
4-Aminomethyl-4-(piperidinomethyl)tetrahydro-4H-pyran cyclohexane (3s)ꢁYield 65%; bp 182–185°C/2 mm Hg; IR: 3431,
(3k)ꢁYield 65%; bp 160–162°C/2 mm Hg; (mp of oxalate 148–150°C); 3386, 3325 cm-1; 1H NMR: δ 1.22–1.49 (m, 10H, (CH2)5), 2.37 (s, 2H,
IR: 3427, 3384, 3321 cm-1; 1H NMR of oxalate: δ 1.38–1.52 (m, 6H, (CH2)3), CH2N), 2.54–2.90 (br, 2H, NH2), 2.59 (s, 2H, CH2NH2), 2.73–2.83 (m, 4H,
1.57 (dt, J ꢀ=ꢀ 11 Hz and 6 Hz, 2CH2), 2.49 (s, 2H, NCH2), 2.52–2.62 (br, 4H,
(CH2)2N), 3.09 (s, 2H, CH2NH2), 3.53–3.61 (m, 4H, (CH2)2O), 5.28–6.70
NCH2CH2), 3.65 (s, 2H, NCH2Ar), 6.85–6.91 (m, 1H), and 6.96–7.02 (m,
3H, Ar). Anal. Calcd for C17H26N2: C, 79.02; H, 10.14; N, 10.84. Found: C,
(br, 4H, NH2 + H2C2O4). Anal. Calcd for C14H26N2O5: C, 55.61; H, 8.67; N, 79.15; H, 10.06; N, 10.79.
9.26. Found: C, 55.48; H, 8.49; N, 9.32.
4-Aminomethyl-4-{[3,4-dihydroisoquinolin-2(1H)-yl]methyl}
1-Aminomethyl-1-(azepanomethyl)cyclopentane (3l)ꢁYield 75%; tetrahydro-4H-pyran (3t)ꢁYield 62%; bp 195–198°C/2 mm Hg; IR:
1
bp 127–130°C/3 mm Hg; IR: 3432, 3395, 3335 cm-1; H NMR: δ 1.21–1.44 3426, 3379, 3329 cm-1; 1H NMR: δ 1.39–1.46 (m, 4H, 2 CH2), 2.46 (s, 2H,
(m, 4H) and 1.50–1.63 (m, 12H, 8 CH2), 1.84 (br, 2H, NH2), 2.41 (s, 2H, CH2N), 2.68 (s, 2H, CH2NH2), 2.76–2.85 (m, 4H, NCH2CH2), 2.75–3.03 (br,
CH2N), 2.49 (s, 2H, CH2NH2), 2.63–2.70 (m, 4H, (CH2)2N). Anal. Calcd for 2H, NH2), 3.52–3.57 (m, 4H, (CH2)2O), 3.68 (s, 2H, NCH2Ar), 6.89–6.94
C13H26N2: C, 74.23; H, 12.46; N, 13.32. Found: C, 74.52; H, 12.39; N, 13.46. (m, 1H), and 6.99–7.04 (m, 3H, Ar). Anal. Calcd for C16H24N2O: C, 73.81;
H, 9.29; N, 10.76. Found: C, 73.70; H, 9.45; N, 10.55.
1-Aminomethyl-1-(azepanomethyl)cyclohexaneꢀ(3m)ꢁYield
1
78%; bp 128–134°C/2 mm Hg; IR: 3430, 3390, 3341 cm-1; H NMR: δ
1-Aminomethyl-(1-morpholinomethyl)cyclopentane (3u)ꢁYield
1
1.12–1.48 (m, 10H, (CH2)5), 1.56 (br, 8H, (CH2)4), 2.35 (s, 2H, CH2N), 2.53
61%; bp 148–149°C/3 mm Hg; IR: 3422, 3382, 3335 cm-1; H NMR: δ
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192ꢀ
ꢀS.S. Hayotsyan et al.: Synthesis of perhydro-N-(2,2-disubstituted-3-aminopropyl) heterocycles
1.21–1.34 (m, 2H) and 1.42–1.59 (m, 6H, (CH2)4), 2.27 (s, 2H, CH2N), CH2N), 2.44–2.48 (m, 4H, (CH2)2N), 2.63 (s, 2H, CH2NH2), 3.47–3.57 (m,
2.30–2.78 (br, 2H, NH2), 2.41–2.45 (m, 4H, (CH2)2N), 2.50 (s, 2H, 8H, 2 (CH2)2O). Anal. Calcd for C11H22N2O2: C, 61.65; H, 10.35; N, 13.07.
CH2NH2), 3.54–3.58 (m, 4H, (CH2)2O). Anal. Calcd for C11H22N2O: C, Found: C, 61.52; H, 10.46; N, 13.25.
66.62; H, 11.18; N, 14.13. Found: C, 66.44; H, 11.38; N, 14.36.
1-Aminomethyl-1-(4-benzylpiperazinomethyl)cyclopentane
1-Aminomethyl-1-(morpholinomethyl)cyclohexane (3v)ꢁYield (3x)ꢁYield 52%; bp 155–156°C/3 mm Hg; IR: 3420, 3380, 3341 cm-1;
60%; bp 120–122°C/3 mm Hg; IR: 3425, 3376, 3328 cm-1; 1H NMR: δ 1H NMR: δ 1.20–1.32 (m, 2H) and 1.40–1.60 (m, 6H, (CH2)4), 1.86–2.12
1.10–1.50 (br, 2H, NH2), 1.15–1.46 (m, 10H, (CH2)5), 2.18 (s, 2H, CH2N), (br, 2H, NH2), 2.27 (s, 2H, NCH2C), 2.33–2.43 (m, 4H, (CH2)2N), 2.43–2.50
2.43–2.48 (m, 4H, (CH2)2N), 2.54 (s, 2H, CH2NH2), 3.50–3.57 (m, 4H, (m, 4H, (CH2)2N), 2.47 (br, 2H, NH2), 3.42 (s, 2H, PhCH2), 7.13–7.28 (m,
(CH2)2O). Anal. Calcd for C12H24N2O: C, 67.88; H, 11.39; N, 13.19. Found: 5H, Ph). Anal. Calcd for C18H29N3: C, 75.21; H, 10.17; N, 14.62. Found: C,
C, 68.01; H, 11.16; N, 12.98.
75.35; H, 10.02; N, 14.48.
1-Aminomethyl-4-morpholinomethyl-tetrahydro-4H-pyran
(3w)ꢁYield 70%; bp 152–153°C/2 mm Hg; IR: 3421, 3385, 3330 cm-1;
1H NMR: δ 1.32–1.40 (m, 4H, 2 CH2), 2.16–2.40 (br, 2H, NH2), 2.26 (s, 2H,
Received June 7, 2012; accepted July 19, 2012; previously published
online September 1, 2012
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