Reactions offl-substituted a m i n e s - III
1771
Microanalyses were performed through the courtesy of
Dr. W. C. Alford of the National Institutes of Health's
Microanalytical Laboratory.
the a t t a c k of the a n i o n o f 4a or 5a at position 2 or 3
of the intermediate, 3. If the r e a c t i o n of 2 with 25%
a q u e o u s s o d i u m hydroxide is s t o p p e d before it is
half c o m p l e t e d , only starting material, 2, and a l c o -
hols, 4a and 5a, are f o u n d as products. The r a t i o of
the three bis-[3- amino-ethers, 6, 7 and 8 to alcohols,
4a and 5a, f o u n d in t h e product, is g o v e r n e d by the
concentration of the base in the r e a c t i o n mixture.
Iris f o u n d to vary from less than 10% bis-[3-andno-
ethers for r e a c t i o n in dilute a q u e o u s s o d i u m hy-
d r o x i d e to a b o u t 60% for r e a c t i o n in 25% a q u e o u s
s o d i u m hydroxide.
3-Chloro-l-ethylpiperidine, (1). An aqueous soln of
1-HCI (10.0 g in 200 ml) was covered with ether (200 ml)
and NaHCO3 (5 g) was slowly added to the magnetically
stirred soln. The ether was separated and the water layer
was extracted several times with ether. The combined
ether extracts were dried over MgSO4 and evaporated.
The chloroamine (1) was distilled, b.p. 43-44° (3.7 nun),
5-9g (74%) n[5 1.4663 [fitJ° b.p. 74-76° (20 mm), n~
1-4678].
2-Chloromethyl-l-ethylpyrrolidinium chloride, 2-HCI
was synthesized by reacting 4a with thionyl chloride in
chloroform by a previously reported procedure.TM Pure
2-HCI was obtained after decolorizing four times with
charcoal (Norit A), recrystallization from MeOH and
drying under vacuum (6ram at room temp), m.p. 210-
210-5° [lit.1° m.p. 193.5-194°]. When the sample was air
The e v i d e n c e c i t e d a b o v e demonstrates the struc-
t u r e s of the t h r e e previously unreported bis-[3-
aminoethers, 6, 7, and 8, isolated from the r e a c t i o n
of
1 or 2 with a q u e o u s s o d i u m hydroxide. T h e s e
products are not only consistent with the m e c h a n -
ism previously p r o p o s e dL4 for the reactions of 1
and 2 with nucleophiles, but lend s u p p o r t to it.
dried,
a crystalline solvate of uncertain composition,
approximately 1 : 1 (2-HCi) :MeOH, was obtained.
3-Ethoxy- 1-ethylpiperidine, (5c). To a N~ purged slurry
of sodamide (2.15 g, 0.055 mole) in toluene (30 ml, puri-
fied over Na wire), 5a (7.0 g, 0.05 moles) was added over a
20 rain period. The soln was gradually heated until the
evolution of ammonia ceased. EtI (4"9 ml, 0.06 mole) was
added and the soln was refluxed for 3 hr, cooled and allow-
ed to stand overnight. The soln was filtered and the filtrate
was extracted with 6 N HCI (5 × 10 ml). An excess of
KOH was added to the combined acid extract and the
soln was extracted with ether. The ether was dried over
MgSO4, filtered and evaporated. The residual oil was dis-
tilled, b.p. 88-89° (26-27mm), 1.Sg (17%) [lit." b.p.
80-82° (20 mm), 64% yield].
The reaction of 1 with 10% aqueous sodium hydroxide.
N a O H a q (50ml of 10% N a O H , 0.12 mole) was slowly
added to freshly distilled 1 (7.2 g, 0-05 mole), the mixture
was brought to a boil and refiuxed for 5 hr. The mixture
was cooled and extracted in a continuous extractor for 3
days with refiuxing ether. The ether was dried over MgSO4
and evaporated giving a yellow oil (4.0 g, 82%) that was
separated by GLC on the 12% Carbowax 20 M column.
The fractions were collected as described above and com-
penents identified as described in the text.
Reactions in 25% aqueous sodium hydroxide. I-HCI,
2-HCI, and (2-HCI): MeOH were reacted with 25% N a O H -
aq by adding the sample (usually about 0-1 mole) to 25%
N a O H a q (50 ml) and refluxing overnight (about 14 hr).
The mixture was then cooled and extracted with ether, the
ether was dried and evaporat~l and the resulted oil mix-
ture separated by preparative GLC. The separated com-
ponents were further purified by molecular distillation
before IR, NMR, refractive indices and elemental analy-
ses were determined.
EXPERIMENTAL
NMR spectra were recorded at 60 MHz on a Varian
Associates A-60 spectrometer and/or at 90 MHz on a
Brocker HX-90 spectrometer and/or at 100 MHz on a
Varian Associates HA-100 spectrometer. All chemical
shifts are reported in 8 ppm and couplings in Hz. Medium
resolution mass spectra were obtained on an AEI-MS
1201 mass spectrometer. IR spectra were taken on the
neat liquid films with a Perkin-EImer model 337 spectro-
meter. IR spectra of the vapor phase were determined on
a Perkin-Elmer model 337 in a Carle Instruments "light
pipe" cell attached to a stopped-flow gas chromatograph.*
Analytical GLC separations were done with a Barber-
Coleman Model 5000 analytical gas chromatograph fitted
with
Carbowax 20 M on Anachrom ABS. The carrier gas was
N~ and the detector was flame ionization detector
a 12ft×¼inch copper column packed with 12%
a
operating off a 1 : 10 splitter. Collections were done by
a hand-held "U" tube cooled with liquid N2 and attached
to the outlet of the splitter. Samples to be separated by
preparative GLC were first examined on a Varian Aero-
graph Series 1200 gas chromatograph fitted with a 6 fl by
1/8 inch glass column packed with 10% OV-17 on 160 to
180 mesh Chromsorb-W, with N2 as a carrier gas on a
flame ionization detector. In all cases, temp programming
was necessary because 4a, 5a, 4b, 5b, 4c, and 5¢ were not
resolved at a temp high enough to elute 6, 7 and 8 from the
column. Preparative GLC separations were done on a
Hewlett-Packard model 776 Prepmaster Jr. fitted with an
80 in by 3/8 in stainless steel column packed with 25%
Triton X-305 on 60 to 80 mesh Chromsorb-W. A flame
ionization detector was operated off a 1:9 splitter and
N2 was used as the carrier gas. The collectors, which were
manually operated, were cooled in an ice bath. The separa-
tion of the mixture required several passes since the entire
mixture of products could not be separated at one temp
and it was not possible to temp program the preparative
chromatograph. This was done by first crudely separating
the low retention-time alcohols and alkyl ethers from the
bis-~-aminoethers and then rechromatography of the two
crude fractions.
The GLC retention times, IR, NMR spectra and refrac-
tive indices of 4a and 5a were compared with authentic
samples for identification:
The IR, NMR, mass spectra and refractive indices and
elemental analyses were obtained for the bis-~-andno-
ethers), 6 and 7. The spectra and elemental analysis were~
obtained for 8, but there wast~'t sufficient sample for refrac-
tive index determination, NMR, IR and MS spectral data
are given in the text above.
6 n~ 1.4730. (Calc: C, 69-95; H, 11.74. Found: C, 69.84;
*The stopped flow gas chromatograph was a system
devised and built in this laboratory by C. F. Hammer, D.
Korte and P. Rankin.
H, 11.75%,)
7 n~ 1-4766. (Calc: C, 69.95; H, 11.74; N, 11-66. Found:
C, 69.73; H, 11-41; N, 11-53%)
Hammer et al.
