Phenyl chloro(thionoformate): A new dealkylating agent of tertiary amines

Article abstract of DOI:10.1071/ch98147

Phenyl chloro(thionoformate) reacts rapidly with unhindered tertiary aliphatic amines at 20° to give a thiocarbamate and an alkyl chloride. Dialkylcyclohexylamines react surprisingly rapidly to form predominantly cyclohexene. The thiocarbamates are converted into the secondary amine salt by treatment with dimethyl sulfate, followed by hydrolysis with water. Rates of reaction and alkyl group cleavage selectivity in amines were found to be superior or comparable to those previously reported with chloroformates.

Full text of DOI:10.1071/ch98147

C S I R O P U B L I S H I N G
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Volume 52, 1999
© CSIRO Australia 1999
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Aust. J. Chem., 1999, 52, 841–849
Phenyl Chloro(thionoformate): a New
Dealkylating Agent of Tertiary Amines
David S. Millan and Rolf H. Prager
Department of Chemistry, The Flinders University of South Australia,
G.P.O. Box 2100, Adelaide, S.A. 5001.
Phenyl chloro(thionoformate) reacts rapidly with unhindered tertiary aliphatic amines at 20° to give a thiocarba-
mate and an alkyl chloride. Dialkylcyclohexylamines react surprisingly rapidly to form predominantly cyclohex-
ene. The thiocarbamates are converted into the secondary amine salt by treatment with dimethyl sulfate, followed
by hydrolysis with water. Rates of reaction and alkyl group cleavage selectivity in amines were found to be supe-
rior or comparable to those previously reported with chloroformates.
Introduction
sition of the salt (2) by chloride, forming the carbamate (3)
and an alkyl chloride (Scheme 1). In a general way this
appears also to be the case with chloro(thionoformates). The
reaction of unhindered tertiary amines with phenyl
chloro(thionoformate) was very rapid at 20° in chlorinated
solvents. When the reaction of triethylamine with 1 equiv. of
We have previously1 reported a preliminary account of
our study of the dealkylation of tertiary aliphatic amines with
phenyl chloro(thionoformate) (1). The reactivity and selec-
tivity of this reagent was found to be superior to that of a
number of previously used methods, such as the von Braun2
reaction or the use of ethyl chloroformate3 and phenyl chlo-
roformate.4 The latter reagents produce products (Scheme 1)
which are difficult to hydrolyse, and accordingly were
replaced by 1-chloroethyl chloroformate,5 2,2,2-trichloro-
ethyl chloroformate6 and vinyl chloroformate.7 We have
found that chloro(thionoformates) are even more reactive
toward amines than are chloroformates, but the ease and
selectivity of the analogous second dealkylation step in
Scheme 1 required elaboration.
1
(1) was followed by H n.m.r. analysis, the ammonium salt
appeared to form instantly ( CH2 4.35), and the
chloroethane formation could be followed to completion
over the next 30 min. As shown in Table 1,10–14 the reaction
of most unhindered tertiary amines also went to completion
within 1 h.
Olofson7 has used N-ethylpiperidine as the benchmark for
the determination of rate and selectivity of the dealkylation of
tertiary amines by vinyl chloroformate, cyanogen bromide,
phenyl chloroformate, ethyl chloroformate, 2,2,2-tri-
chloroethyl chloroformate and benzyl chloroformate. The
use of vinyl chloroformate gave the deethylated product in
90% yield but a period at 80° was required to effect decom-
position of the intermediate salt. The use of phenyl chloro-
formate resulted in dealkylation at 20°, while the other
chloroformates effected the conversion in, at best, 10% yield,
under similar conditions. Cyanogen bromide showed low
selectivity, giving cyanamide (18) (54%), accompanied by
the ring-opened cyanamide (19) (28%). Olofson5 reported
that the reaction of 1-chloroethyl chloroformate with N-
ethylpiperidine afforded the carbamate (20) in quantitative
yield at 80°. By contrast, phenyl chloro(thionoformate)
cleanly converted N-ethylpiperidine into the corresponding
thiocarbamate (4) at room temperature in dichloromethane
within 1 h. Together with the direct competition experiment
of phenyl chloroformate and phenyl chloro(thionoformate)
towards triethylamine, cited previously,1 this demonstrates
that the reactivity of phenyl chloro(thionoformate) with ter-
tiary amines is superior to that of vinyl chloroformate and 1-
chloroethyl chloroformate.
Charles8 has shown that the ease of cleavage of alkyl
groups from tertiary amines with chloroformates is benzyl >
allyl > methyl > alkyl, and in our preliminary communica-
tion we determined a similar pattern of reactivity for the
chloro(thionoformate) reagents.
In this paper we aim to ascertain more definitively the rel-
ative rates of cleavage of alkyl groups with phenyl
chloro(thionoformate), and to determine the scope of its
effectiveness as a dealkylating agent of tertiary aliphatic
amines.
Results and Discussion
The accepted pathway9 for dealkylation of tertiary amines
with chloroformates involves the rate determining decompo-
Manuscript received 18 September 1998
© CSIRO 1999
0004-9425/99/090841
10.1071/CH98147

842
D. S. Millan and R. H. Prager
Table 1. Dealkylation of tertiary amines with (1)
Amine
Conditions
Product(s)
Yield (%)
N-Ethylpiperidine
CH2Cl2, 1 h, 20°
CH2Cl2, 1 h, 20°
CH2Cl2, 1 h, 20°
CH2Cl2, 1 h, 20°
CH2Cl2, 1 h, 20°
CH2Cl2, 2 h, 40°
CH2Cl2, 1 h, 20°
neat, 16 h, 120°
neat, 16 h, 120°
CH2Cl2, 1 h, 20°
CH2Cl2, 1 h, 20°
CH2Cl2, 1h, 20°
Cl(CH2)2Cl, 16 h, 83°
neat, 24 h, 130°
CH2Cl2, 1 h, 40°
CH2Cl2, 1 h, 20°
CH2Cl2, 1 h, 20°
CH2Cl2, 1 h, 20°
CH2Cl2, 1 h, 20°
(4)10
(5)11
(5)
98A
Triethylamine
93A
N,N-Diethylbenzylamine
N-Methylmorpholine
97A
(6)10
(7)12
(7)
73A
N-(3-Phenylprop-2-enyl)dimethylamine
N,N-Dimethyl-t-butylamine
N,N-Diethylmethylamine
N-Allyl-N-t-butylbenzylamine
N-t-Butyl-N-methylbenzylamine
N-Allyl-N-methylbenzylamine
N-Allyl-N-methylbenzylamineD
NЈ-Benzyl-N-t-butyl-N,NЈ-dimethylpropane-1,3-diamine
N-t-Butyl-N-methylallylamine
N,N-Dimethylaniline
71A
36A,B
(44+12)A
(8)+(5)
C
C
(9)
97A
98E
77A
39A
60A
9A
(10)13
(11)
(9)
(12)14
(12)
N,N-Dimethylaniline/TiCl4
Quinuclidine
(13)
95A
>95G
96A
87A
Tropine
(14)+(15)F
(16)
Tropine acetate
Bicuculline
(17)H
A Isolated yield, chromatographically pure. B Yield of crude material was 76%. C No reaction. D Reaction of amine with cyanogen bromide (CH2Cl2, 1 h, 20°). E Yield based on unre-
F
covered starting material.
Relative ratio of products in mixture 66 : 34. G Yield of crude material. H Ratio of erythro to threo 3: 1.
cleaved totally to give the cinnamyl chloride. N,N-
Dimethyl-t-butylamine was cleaved exclusively at the ter-
tiary carbon centre when reacted with (1), as it did with vinyl
chloroformate,7 a result suggesting an SN1 mechanism in this
case.
The reaction of phenyl chloro(thionoformate) with N,N-
diethylmethylamine resulted in the formation of the thiocar-
bamates (8) and (5), in a 7: 1 ratio respectively; this
corresponds to cleavage of ethyl to methyl of 7 : 2. The pre-
ference for ethyl group cleavage over methyl was totally
unexpected, and clearly does not reflect the relative SN2
reactivity of ethyl and methyl groups. The product ratios
may be partially rationalized by consideration of the confor-
mations of the initial conjugate formed on attack of the
amine upon the chloroformate.
The selectivity of the cleavage of alkyl groups by phenyl
chloro(thionoformate) was now investigated in greater
detail. Reaction of N,N-diethylbenzylamine with (1)
resulted only in debenzylation, as was expected.6 While 1-
methylmorpholine undergoes considerable ring opening on
reaction with cyanogen bromide,15 with phenyl
chloro(thionoformate), as with 1-chloroethyl chlorofor-
mate,5 only demethylation was observed. N-(3-Phenylprop-
2-enyl)dimethylamine, prepared by the reaction of
dimethylamine and cinnamyl chloride in ethanol, was

Phenyl Chloro(thionoformate)
843
It is suggested that reestablishment of the thiocarbonyl
group from the intermediates (21a) and (21b) releases chlo-
ride, which undergoes essentially a concerted SNi reaction in
an ion pair with the most accessible alkyl group on nitrogen.
Assuming that the lowest energy conformation involves the
large sulfur anion flanked by a methyl and an ethyl group
(conformer (21a)), rather than two ethyl groups (conformer
(21b)), the observed ratio requires only a difference in free
energy between (21a) and (21b) of 2.9 kJ mol–1 K–1, which
appears quite reasonable.16 Support for the intermediacy of
the salt (21) comes from monitoring the reaction of N,N-
diethylmethylamine with (1) by 1H n.m.r. spectroscopy. The
amine disappeared totally in less than 1 min, and was being
replaced by a salt in which the two ethyl groups were non-
equivalent (CH2 groups were apparent sextets at 4.28 and
4.88), as might be expected with the presence of a chiral
carbon as in (21), and the hydrogens within each CH2 group
were also non-equivalent. The alternative ammonium salt,
equivalent to (2), would be unlikely to show such striking
non-equivalence in the ethyl groups, as rotation around
carbon–nitrogen bonds is not significantly restricted.
promote SN2 reactions on a possible thioacylammonium
intermediate, gave essentially the same ratio of products,
again favouring our SNi mechanism proposal.
The work of Charles8 on the reaction of various chloro-
formates with dialkylcyclohexylamines suggested that,
unless the alkyl groups were benzyl or allyl, such compounds
underwent exclusive elimination (Scheme 2) to give cyclo-
hexene. We have similarly found that N,N-dimethylcyclo-
hexylamine reacts with (1) to give cyclohexene (61%) and
1
the thiocarbamate (7) (82%). However, H n.m.r. analysis
showed the presence of chloromethane (18%) and O-phenyl
N-cyclohexyl-N-methylthiocarbamate (18%), and the pres-
ence of the latter was confirmed by g.c.–m.s. The disparity
between the yield of cyclohexene (61%) and the thiocarba-
mate (82%) suggested that the presence of chlorocyclohex-
ane should be expected, but no spectroscopic or g.c.–m.s.
evidence for its formation could be found. While Charles8
has suggested that the elimination to cyclohexene is likely to
be an E2 elimination from conformer (24) (Scheme 2), with
chloride as the base, we believe a syn elimination from (25)
appears more plausible.
In an attempt to ascertain the relative ease of cleavage of
allyl, benzyl and tertiary alkyl groups, N-allyl-N-t-butylben-
zylamine was synthesized from N-t-butylbenzylamine by
reaction with allyl bromide and solid potassium carbonate.
Unfortunately, the amine was too hindered for any reaction
to occur, even after heating the amine with the chloro(thiono-
formate) for 16 h at 120° in the absence of a solvent.
Likewise, N-t-butyl-N-methylbenzylamine17 was also totally
unreactive, even after prolonged heating in the absence of a
solvent. It was concluded that only small alkyl groups would
be tolerated on the nitrogen in the presence of a tertiary
centre. N-Allyl-N-methylbenzylamine was synthesized in
84% yield from N-allylbenzylamine by reaction with
formaldehyde and formic acid. The amine reacted readily
with (1) at 20°, giving the debenzylated product (9) in 97%
yield. Exclusive debenzylation was also observed when N-
allyl-N-methylbenzylamine was treated with ethyl chlorofor-
mate.8 By contrast, we have found that cyanogen bromide
effects deallylation of N-allyl-N-methylbenzylamine in
essentially quantitative yield, affording cyanamide (10).
Since N-t-butyl-N-methylbenzylamine was too hindered
to react with phenyl chloro(thionoformate), the relative ease
of cleavage of t-butyl and benzyl groups was determined by
an intermolecular competition reaction between N,N-
dimethylbenzylamine and N,N-dimethyl-t-butylamine with
0.5 equiv. of the chloroformate. Although both amines could
give the same product (7) after reaction with the
chloro(thionoformate), the proportion of benzyl or t-butyl
Since this rationalization departs from what has long been
accepted for chloroformates (Scheme 1), a number of addi-
tional experiments were performed. When phenyl chloro-
formate was reacted with N,N-diethylmethylamine, a similar
result to that above was observed in that again deethylation
was more prevalent than demethylation, giving a ratio of (22)
to (23) of 3 : 1, although the reaction was slower than that
with (1).
When N,N-diethylmethylamine was treated with (1) in
acetone the reaction proceeded to completion more rapidly
than in dichloromethane, but deethylation, leading to (8),
still predominated over demethylation, giving (5). Reaction
in acetone containing lithium bromide, in an attempt to

844
D. S. Millan and R. H. Prager
cleavage was ascertained by comparing the ratio of benzyl
chloride and the thiocarbamate (7) in the reaction mixture.
This ratio was determined spectroscopically and was found
to be 1 : 2, respectively, a result which suggests that benzyl
and t-butyl groups cleave with similar rates in boiling
dichloromethane. However, it was found (Table 1) that
cleavage of N,N-dimethyl-t-butylamine to the thiocarbamate
required heating at 40° for 2 h, while benzyl cleavage of
N,N-dimethylbenzylamine occurs at 20°. This reflects the
differing ease of formation of the initial thioacylammonium
salt. This implies that for synthetic purposes it is probable
that a benzyl group will undergo cleavage in preference to a
t-butyl group when the two are located on different tertiary
nitrogens in the same molecule.
We investigated this hypothesis by synthesizing diamine
(26) from ethyl 3-bromopropanoate, as shown in Scheme 3.
G.c.–m.s. analysis of the intermediate (28), prepared as
above, suggested that this product was contaminated by N-
benzyl-3-(benzylamino)propanamide (29) which presum-
ably arose by elimination of t-butylamine from (27) or (28),
followed by conjugate addition of benzylamine. To improve
the yield of the desired product (28), the mixture of (28) and
(29) was heated in a sealed tube with t-butylamine which
converted (29) into (28) (92%). The amide was then reduced
with diborane affording the diamine (30), which was then
methylated to give the diamine (26).
hyde/formic acid. To effect reaction of this amine with the
reagent (1), reaction at 80° for 16 h was required, affording
(9). Hence it can be concluded that a t-butyl group cleaves
faster than an allyl group with this reagent. From the results
above, it was concluded that the relative rate of cleavage of
common alkyl groups from tertiary nitrogen centres was the
following: benzyl у t-butyl > allyl > cyclohexyl > ethyl
> methyl > carbocyclic ring.
We now turned our attention to the reactivity of (1) with
amines that have been dealkylated by previous literature
methods to compare their relative reactivites and selectivi-
ties. Demethylation of N,N-dimethylaniline with (1) was
very slow, but the demethylated product (12) was isolated in
60% yield after reaction at 130° for 24 h; a similar reaction,
with phenyl chloroformate,4 gave an 80% yield at 100° after
60 h. It was hoped that addition of titanium tetrachloride to
the reaction mixture would increase the reactivity of (1), but
no synthetically useful improvement to the isolated yield
was obtained after refluxing in dichloromethane for 16 h
(Table 1).
The ring opening of quinuclidine to form (13) was
achieved in 88% yield with phenyl chloroformate,4 but in
near quantitative yield with phenyl chloro(thionoformate).
The amino alcohol tropine has been successfully demethy-
lated only with vinyl chloroformate.7 We found that with 1
equiv. of (1), tropine was converted into a 2: 1 mixture of
tropine thiocarbonate (14) and the demethylated thiocarba-
mate (15). Efficient demethylation of tropine with (1)
required prior acetylation of the hydroxy group. Bicuculline
1
gave a mixture of epimers (17) in high yield and H n.m.r.
experiments established that epimerization had occurred
prior to nucleophilic attack by chloride anion, a result sug-
gesting an SN1 mechanism. The epimeric products were
found to be configurationally stable under the reaction con-
ditions. Treatment of bicuculline with phenyl chlorofor-
mate18 under basic conditions gave a mixture of the enol
lactone and the chlorinated species, while reaction7 of
hydrastine with vinyl chloroformate gave 88% of the enol
lactone.
We conclude that phenyl chloro(thionoformate) is a
useful dealkylating agent of tertiary amines, and appears to
complement existing literature procedures. The intra- and
inter-molecular competition reactions reported in this paper
provide a basis for predicting the outcome of dealkylation
from a tertiary amine with this reagent. While the dialkyl
thiocarbamate resulting from the reaction of phenyl
chloro(thionoformate) with a tertiary amine is readily
hydrolysed by refluxing with aqueous acid or alkali, it is
considerably more easily hydrolysed if the thiocarbamate is
first methylated with dimethyl sulfate (Scheme 4), and the
secondary amines are thus readily accessible.
Reaction of amine (26) with phenyl chloro(thionofor-
mate) at 20° for 1 h gave only the debenzylated thiocarba-
mate (11), which could be isolated in 77% yield; the same
result was obtained in refluxing dichloromethane. We con-
clude that preferential cleavage of the benzyl group over the
t-butyl group is probably due to the greater accessibility of
the benzyl-substituted nitrogen to the chloroformate reagent.
The question of relative reactivity of t-butyl and allyl
groups was easier to answer, by examining the reactivity of
N-t-butyl-N-methylallylamine with phenyl chloro(thiono-
formate). The amine was synthesized in 79% yield by react-
ing t-butylamine with allyl bromide to form N-t-butyl-
allylamine (63%), followed by methylation with formalde-

Phenyl Chloro(thionoformate)
845
yielded a pale yellow oil which was recrystallized from ether–light
petroleum to give white cubes of O-phenyl morpholine-4-carbo-
thioate10 (6) (0.16 g, 73%), m.p. 120–122° (Found: C, 59.4; H, 5.9; N,
6.2%; M+•, 223.0667. Calc. for C11H13NO2S: C, 59.2; H, 5.8; N, 6.3%;
M+•, 223.0667). 1H n.m.r. 3.74, t, J 4.6 Hz, 2H; 3.80, t, J 4.6 Hz, 2H;
3.95, t, J 5.1 Hz, 2H; 4.14, t, J 5.1 Hz, 2H; 7.01–7.10, m, 2H; 7.21–7.29,
m, 1H; 7.32–7.44, m, 2H. 13C n.m.r. 46.53, 49.92, 65.92, 66.14,
122.63, 125.98, 129.14, 153.75, 187.27. max 1507, 1488, 1437, 1282,
1249, 1189, 1128 cm–1. Mass spectrum m/z 223 (M+, 26%), 130 (55),
114 (100), 94 (11), 86 (67), 77 (13).
Experimental
General
1H and 13C n.m.r. spectra were recorded with a Varian Gemini spec-
trometer in CDCl3 at 300 and 75.5 MHz respectively. Spectra were
measured in (D)chloroform unless otherwise indicated and coupling
constants were recorded in Hertz. Infrared spectra were recorded on a
Perkin Elmer 1600 Fourier-transform i.r. spectrometer, with samples
measured as a Nujol mull (solid) or as a neat film (oil). Mass spectra
and high-resolution mass spectra were recorded on a Kratos MS25RF
spectrometer operating at an electron ionizing energy of 70 eV. Melting
points were determined on a Reichert hot-stage apparatus and remain
uncorrected.
N-(3-Phenylprop-2-enyl)dimethylamine
Cinnamyl chloride (5.00 g, 4.56 ml, 33 mmol) was added over 15
min at 20° to a stirred solution of 10 M dimethylamine (16.40 ml, 0.16
mol) in ethanol (50 ml). The reaction mixture was stirred for 7 h and
then the solvent was evaporated. The residue was diluted with water
(40 ml) and extracted twice with ether (50 ml) and the solvent dried and
evaporated. The residue was distilled to give the title compound as a
colourless oil (1.50 g, 28%), b.p. 200°C/25 mmHg (lit.20 137°C/18
Analytical thin-layer chromatography (t.l.c.) was carried out with
Merck silica gel 60 F254 aluminium-backed sheets. Radial chromato-
graphy was performed with silica gel PF254 coated glass rotors by
using a Chromatotron 7924T. G.c.–m.s. analyses were performed on a
Varian Saturn 4D instrument, with a J & W DB5 5% phenyl-
methylpolysiloxane column (30 m by 0.25 mm i.d.). The identity of
previously prepared compounds was confirmed by direct comparison
with an authentic compound or by comparison of spectroscopic data
with those published. Where the isolation of only a single thiocarba-
mate is reported, n.m.r. analysis of the crude reaction mixture con-
firmed that no other thiocarbamate was produced.
1
mmHg) (Found: M+•, 161.1207. Calc. for C11H15N: M+•, 161.1204). H
n.m.r. 2.26, s, 6H; 3.05, d, J 6.6 Hz, 2H; 6.25, dt, J 15.9, 6.6 Hz, 1H;
6.50, d, J 15.9 Hz, 1H; 7.16–7.23, m, 1H; 7.24–7.33, m, 2H; 7.34–7.40,
m, 2H. 13C n.m.r. 45.08, 61.91, 126.25, 127.35, 127.39, 128.49,
132.47, 137.02. Mass spectrum m/z 161 (M+, 99%), 146 (23), 117 (83),
115 (54), 91 (47), 84 (38), 70 (94), 58 (100).
The routine purification of reagents and solvents was carried out by
standard laboratory procedures.19 All organic extracts were dried with
anhydrous sodium sulfate.
Microanalyses were performed by
Reaction of N-(3-Phenylprop-2-enyl)dimethylamine with (1)
Chemical and Micro Analytical Services, Melbourne.
Phenyl chloro(thionoformate) (0.11 g, 0.09 ml, 0.62 mmol) was
reacted with N-(3-phenylprop-2-enyl)dimethylamine (0.10 g, 0.62
mmol) as above. Radial chromatography (dichloromethane–light
petroleum, 1: 19) on silica gave a pale yellow oil, identified as O-
phenyl N,N-dimethylthiocarbamate12 (7) (0.08 g, 71%). 1H n.m.r.
3.32, s, 3H; 3.44, s, 3H; 7.04–7.12, m, 2H; 7.21–7.28, m, 1H;
7.34–7.44, m, 2H. 13C n.m.r. 38.48, 43.01, 122.70, 125.81, 129.08,
154.04, 187.84. max 2939, 1592, 1533, 1490, 1394, 1287 cm–1. Mass
spectrum m/z 181 (M+, 28%), 94 (18), 88 (91), 72 (100).
Typical Reaction of a Tertiary Amine with (1): Reaction of
N-Ethylpiperidine
Phenyl chloro(thionoformate) (1) (0.15 g, 0.12 ml, 0.88 mmol) was
added to a solution of N-ethylpiperidine (0.1 g, 0.88 mmol) in
dichloromethane (10 ml) and the solution stirred at 20° for 1 h. The
solvent was evaporated affording a pale yellow oil which was purified
by radial chromatography (dichloromethane–light petroleum, 1 : 4) on
silica. The major fraction yielded a pale yellow oil, identified as O-
phenyl piperidine-1-carbothioate10 (4) (0.19 g, 98%) (Found: M+•,
221.0874. Calc. for C12H15NOS: M+•, 221.0874). 1H n.m.r. 1.60–1.84,
m, 6H; 3.84–3.98, m, 2H; 4.04–4.38, m, 2H; 7.03–7.10, m, 2H;
7.16–7.26, m, 1H; 7.36–7.44, m, 2H. 13C n.m.r. 23.85, 24.92, 25.74,
47.15, 51.41, 122.63, 125.60, 128.94, 153.95, 186.15. max 1593, 1504,
1489, 1444, 1289, 1268, 1243, 1203, 1168, 1147 cm–1. Mass spectrum
m/z 221 (M+, 15%), 128 (52), 112 (100), 77 (14).
Reaction of N,N-Dimethyl-t-butylamine with (1)
Phenyl chloro(thionoformate) (0.17 g, 0.14 ml, 0.99 mmol) was
added to a solution of N,N-dimethyl-t-butylamine21 (0.10 g, 0.99
mmol), prepared by the reaction of t-butylamine with formaldehyde and
formic acid in dichloromethane (10 ml), and the solution refluxed for 2
h. The solvent was evaporated to give a yellow oil which was diluted
with ether (20 ml) and washed twice with water (20 ml); solvent was
dried and evaporated affording a pale yellow oil (0.14 g, crude yield
76%). The oil was purified by radial chromatography (ether–di-
chloromethane–light petroleum, 1: 1: 8) on silica to give a colourless
oil which was identified as O-phenyl N,N-dimethylthiocarbamate (7)
(0.065 g, 36%), with spectroscopic and analytical data identical to those
obtained above.
Reaction of Triethylamine with (1)
Phenyl chloro(thionoformate) (0.20 g, 0.16 ml, 1.19 mmol) was
reacted with triethylamine (0.12 g, 0.17 ml, 1.19 mmol) at 20° for 1 h
as above. Radial chromatography (dichloromethane–light petroleum,
1: 4) on silica gave a pale yellow oil identified as O-phenyl N,N-
diethylthiocarbamate11 (5) (0.23 g, 93%) (Found: M+•, 209.0873. Calc.
for C11H15NOS: M+•, 209.0874). H n.m.r. 1.33, t, J 7.2 Hz, 6H; 3.70,
1
Reaction of N,N-Dimethylcyclohexylamine with (1)
q, J 7.2 Hz, 2H; 3.91, q, J 7.2 Hz, 2H; 7.05–7.09, m, 2H; 7.21–7.30, m,
The reaction was performed in an n.m.r. tube with the amine
(0.05 g, 0.06 ml, 0.39 mmol) dissolved in (D)chloroform (0.5 ml) to
which was added phenyl chloro(thionoformate) (0.07 g, 0.06 ml, 0.39
mmol). The reaction was monitored by 1H n.m.r. spectroscopy and after
30 min no further reaction occurred. The pale yellow solution was anal-
1H; 7.36–7.43, m, 2H. 13C n.m.r. 11.75, 13.44, 44.21, 48.35, 122.89,
125.93, 129.27, 154.13, 186.87.
1512, 1490, 1429, 1317, 1286,
max
1243, 1203, 1126 cm–1. Mass spectrum m/z 209 (M+, 17%), 116 (38),
100 (100), 94 (15), 88 (42), 77 (19).
1
ysed by H n.m.r. spectroscopy and g.c.–m.s. and was identified as a
Reaction of N,N-Diethylbenzylamine with (1)
mixture of cyclohexene (61%), O-phenyl N,N-dimethylthiocarbamate
(7) (82%) [mass spectrum m/z 180 (M+ –H), 88, 72], O-phenyl N-
cyclohexyl-N-methylthiocarbamate (25) (18%) [mass spectrum m/z
250 (M++H), 156, 140, 83, 74, 55], and chloromethane (18%). The
above yields were based on reacted N,N-dimethylcyclohexylamine.
Spectroscopic data for (7) were identical to those above.
Phenyl chloro(thionoformate) (0.11 g, 0.09 ml, 0.61 mmol) was
reacted with N,N-diethylbenzylamine (0.10 g, 0.11 ml, 0.61 mmol) at
20° for 1 h as above. Radial chromatography on silica (dichloro-
methane–light petroleum, 1 : 4) gave a colourless oil (0.13 g, 97%)
identical with the sample of (5) obtained above.
Reaction of N-Methylmorpholine with (1)
Reaction of N,N-Dimethylethylamine with (1)
Phenyl chloro(thionoformate) (0.17 g, 0.14 ml, 0.99 mmol) and
N-methylmorpholine (0.10 g, 0.99 mmol) were reacted as above. Radial
chromatography on silica (dichloromethane–light petroleum, 1: 4)
(i) Phenyl chloro(thionoformate) (0.40 g, 0.32 ml, 2.30 mmol) was
added to a solution of N,N-diethylmethylamine (0.2 g, 2.30 mmol) in
dichloromethane (10 ml) and the solution stirred at 20° for 3 h. The

846
D. S. Millan and R. H. Prager
solvent was evaporated affording a pale yellow oil that contained, by
1H n.m.r. spectroscopy, thiocarbamate material and N,N-diethylmethyl-
amine hydrochloride (30%). Water (10 ml) was added, the mixture was
extracted twice with ether (20 ml) and the extract dried and evaporated
affording a pale yellow oil (0.45 g). Radial chromatography on silica
(dichloromethane–light petroleum, 1: 9) afforded a pale yellow oil
identified as a mixture of O-phenyl N,N-diethylthiocarbamate (5)
(12%) and O-phenyl N-ethyl-N-methylthiocarbamate (8) (44%)
(0.25 g). The spectroscopic data for (5) were identical to those above.
O-Phenyl N-ethyl-N-methylthiocarbamate (8) (Found: M+•, 195.0712.
C10H13NOS requires M+•, 195.0718). 1H n.m.r. (rotamer 1) 1.28, t, J
7.2 Hz, 3H; 3.25, s, 3H; 3.92, q, J 7.2 Hz, 2H; 7.03–7.09, m, 2H;
7.20–7.27, m, 1H; 7.34–7.42, m, 2H. 1H n.m.r. (rotamer 2) 1.28, t, J
7.2 Hz, 3H; 3.39, s, 3H; 3.73, q, J 7.2 Hz, 2H; 7.03–7.09, m, 2H;
7.20–7.27, m, 1H; 7.34–7.42, m, 2H. 13C n.m.r. (rotamer 1) 10.85,
35.73, 49.94, 122.69, 125.67, 128.95, 153.98, 187.10. 13C n.m.r.
(rotamer 2) 12.60, 40.77, 46.29, 122.58, 125.67, 129.01, 153.89,
187.28.
0.20 mol) and 97% formic acid (15.66 g, 12.83 ml, 0.34 mol) with
cooling in an ice bath. The solution was then refluxed for 16 h. The
mixture was poured into ice-cold water (50 ml), basified (solid NaOH),
and the solution extracted twice with ether (60 ml). The extracts were
dried and evaporated affording a colourless oil (10.57 g). The yield of
title compound (83%) was calculated from the 1H n.m.r. spectrum. The
product was fractionally distilled, a process giving several fractions
boiling in the range 60–72°/1 mmHg, all of which contained some N,N-
diallylbenzylamine (c. 17%) and the title compound.25 1H n.m.r. 2.18,
s, 3H; 3.02, dt, J 6.6, 1.2 Hz, 2H; 5.10–5.24, m, 2H; 5.80–5.98, m, 1H;
7.18–7.35, m, 5H. 13C n.m.r. 41.94, 60.46, 61.59, 117.42, 126.95,
128.23, 129.07, 136.01, 139.10. Mass spectrum m/z 161 (M+), 143, 91.
1
N,N-diallylbenzylamine: H n.m.r. 3.06, dt, J 6.3, 1.2 Hz, 4H;
3.56, s, 2H; 5.10–5.24, m, 4H; 5.80–5.98, m, 2H; 7.18–7.35, m, 5H. 13C
n.m.r. 56.23, 57.37, 117.26, 127.00, 128.13, 128.83, 135.89, 139.43.
Mass spectrum m/z 187 (M+), 172, 160, 146, 110, 91.
Reaction of N-Allyl-N-methylbenzylamine (and
N,N-Diallylbenzylamine) with (1)
(ii) The above reaction was repeated except that acetone replaced
dichloromethane. After 1 h at 20° a 6 : 1 mixture of thiocarbamates (8)
The above mixture of N-allyl-N-methylbenzylamine (83%) and
N,N-diallylbenzylamine (17%) (0.1 g) was reacted with a solution of
phenyl chloro(thionoformate) (0.11 g, 0.09 ml, 0.62 mmol) in
dichloromethane (5 ml) at 20° for 1 h. The resultant pale yellow oil
(0.19 g) was analysed by g.c.–m.s. The oil was found to contain O-
phenyl N-allyl-N-methylthiocarbamate (9) (89.2%) [mass spectrum m/z
207 (M+), 179, 148, 114, 98], O-phenyl N,N-diallylthiocarbamate
(9.5%) [mass spectrum m/z 233 (M+), 124, 98, 91, 77], O-phenyl N-
benzyl-N-methylthiocarbamate (1.2%) [mass spectrum m/z 257 (M+),
163, 147, 109, 91, 77], and O-phenyl N-allyl-N-benzylthiocarbamate
(0.1%) [mass spectrum m/z 283 (M+), 193, 131, 109, 91, 77]. The oil
was purified by radial chromatography on silica (dichloromethane–
light petroleum, 1: 4) to give O-phenyl N-allyl-N-methylthiocarbamate
(9) (0.1 g, 97% based on the N-allyl-N-methylbenzylamine present in
the starting material) as the major fraction (Found: M+•, 207.0715.
C11H13NOS requires M+•, 207.0718). 1H n.m.r. (rotamer 1) 3.24, s,
3H; 4.24–4.32, m, 2H; 5.14–5.34, m, 2H; 5.80–6.00, m, 1H; 7.00–7.12,
1
and (5), respectively, was obtained, as determined by H n.m.r. anal-
ysis.
(iii) Reaction (ii) was repeated except that lithium bromide (1.0 g,
0.015 mol) was present before addition of (1). After 1 h at 20° the
mixture was added to water (10 ml) and extracted twice with ether
(20 ml), affording a pale yellow oil (0.344 g) which was identified as a
1
6 : 1 mixture of thiocarbamates (8) and (5), respectively, by H n.m.r.
analysis.
Reaction of Phenyl Chloroformate with N,N-Diethylmethylamine
A solution of N,N-diethylmethylamine (0.1 g, 1.15 mmol) in
dichloromethane (10 ml) was added to phenyl chloroformate (0.18 g,
0.14 ml, 1.15 mmol) and the solution stirred at 20° for 3 h. The solvent
was evaporated affording a colourless oil containing carbamate mater-
ial (41%) and ammonium salts (59%). Water (10 ml) was added to the
residue, the mixture extracted twice with ether (20 ml) and the extracts
dried and evaporated affording a pale yellow oil (0.17 g). Radial chro-
matography on silica (ether–dichloromethane, 1: 4) gave a pale yellow
oil identified as a mixture of O-phenyl N,N-diethylcarbamate22 (23)
(10%) and O-phenyl N-ethyl-N-methylcarbamate (22) (32%) (0.09 g).
O-Phenyl N,N-diethylcarbamate (23) (Found: M+•, 193.1105. Calc.
for C11H15NO2: M+•, 193.1103). 1H n.m.r. 1.23, m, 6H; 3.40, m, 4H;
7.09–7.22, m, 3H; 7.30–7.39, m, 2H. 13C n.m.r. 13.24, 14.09, 41.81,
42.14, 121.85, 125.13, 129.28, 151.68, 154.41.
1
m, 2H; 7.20–7.30, m, 1H; 7.32–7.44, m, 2H. H n.m.r. (rotamer 2)
3.40, s, 3H; 4.48–4.56, m, 2H; 5.14–5.34, m, 2H; 5.80–6.00, m, 1H;
7.00–7.12, m, 2H; 7.20–7.30, m, 1H; 7.32–7.44, m, 2H. 13C n.m.r.
(rotamer 1) 35.87, 57.55, 118.50, 122.70, 125.85, 129.08, 131.02,
153.99, 188.21. 13C n.m.r. (rotamer 2) 41.02, 53.60, 117.67, 122.66,
125.85, 129.10, 131.42, 154.03, 187.84. max 1592, 1513, 1490, 1400,
1299, 1247, 1201, 1135 cm–1. Mass spectrum m/z 207 (M+, 11%), 114
(20), 98 (65), 41 (100).
O-Phenyl N-ethyl-N-methylcarbamate (22) (Found: M+•, 179.0950.
C10H13NO2 requires M+•, 179.0946). 1H n.m.r. (rotamer 1) 1.20, m,
3H; 2.97, s, 3H; 3.41, m, 2H; 7.07–7.22, m, 3H; 7.30–7.39, m, 2H. 1H
n.m.r. (rotamer 2) 1.20, m, 3H; 3.04, s, 3H; 3.41, m, 2H; 7.07–7.22,
m, 3H; 7.30–7.39, m, 2H. 13C n.m.r. (rotamer 1) 12.30, 33.65, 41.78,
121.62, 125.00, 129.05, 151.37, 156.50. 13C n.m.r. (rotamer 2) 13.04,
34.08, 42.11, 121.62, 125.00, 129.05, 151.37, 156.50.
Reaction of N-Allyl-N-methylbenzylamine (and
N,N-Diallylbenzylamine) with Cyanogen Bromide
The above mixture (0.2 g) was treated with a solution of cyanogen
bromide (0.13 g, 1.24 mmol) in dichloromethane (5 ml). After 1 h at
20° the reaction mixture was analysed by g.c.–m.s. The oil was found
to contain a mixture of (1: 12) N,N-diallylcyanamide [mass spectrum
m/z 122 (M+), 107, 94, 81, 68, 55] and N-allyl-N-benzylcyanamide
[mass spectrum m/z 172 (M+), 91, 77, 65] from reaction of the N,N-di-
allylbenzylamine, and only N-benzyl-N-methylcyanamide13 (10) [mass
spectrum m/z 146 (M+), 131, 91, 65] from reaction of the N-allyl-N-
methylbenzylamine.
N-Allyl-N-t-butylbenzylamine
To a solution of potassium carbonate (4.66 g, 0.034 mol) in ethanol
(50 ml) were added N-t-butylbenzylamine21 and allyl bromide (3.71 g,
2.65 ml, 0.03 mol) and the solution was refluxed for 16 h. The solvent
was evaporated, the mixture diluted with water (50 ml) and extracted
with ether (50 ml). The extract was evaporated and distilled to give a
colourless oil (4.84 g, 78%), b.p. 67°/0.5 mmHg (lit.23 63–65°/0.5
Competition Between N,N-Dimethylbenzylamine and
N,N-Dimethyl-t-butylamine for (1)
1
mmHg) (Found: M+•, 203.1675. Calc. for C14H21N: M+•, 203.1674). H
n.m.r. 1.13, s, 9H; 3.20, d, J 6.3 Hz, 2H; 3.68, s, 2H; 4.86–5.02, m,
2H; 5.74–5.90, m, 1H; 7.12–7.39, m, 5H. 13C n.m.r. 27.61, 52.43,
52.50, 54.95, 115.10, 126.20, 127.98, 128.14, 138.80, 143.03. Mass
spectrum m/z 203 (M+, 9%), 188 (79), 148 (15), 91 (100).
To a refluxing solution of N,N-dimethylbenzylamine (0.13 g; 0.99
mmol) and N,N-dimethyl-t-butylamine (0.1 g, 0.99 mmol) in
dichloromethane (5 ml) was added phenyl chloro(thionoformate)
(0.09 g, 0.07 ml, 0.50 mmol) dropwise. The solution was refluxed for
2 h and the solvent evaporated at 20°/20 mmHg affording a pale yellow
N-Allyl-N-methylbenzylamine
1
oil which was analysed by H n.m.r. spectroscopy; this suggested the
A mixture (10 g) of N-allylbenzylamine24 (79%) and N,N-diallyl-
benzylamine (21%), prepared by the reaction of benzylamine and allyl
bromide, was added to a solution of 40% formalin (15.32 g, 14.15 ml,
presence of O-phenyl N,N-dimethylthiocarbamate (7) (67%) and
benzyl chloride (33%), which were identified by direct comparison
with authentic samples.

Phenyl Chloro(thionoformate)
847
1
Ethyl 3-(t-Butylamino)propanoate (27)
Hz, 2H; 7.01–7.08, m, 2H; 7.21–7.29, m, 1H; 7.35–7.43, m, 2H. H
n.m.r. (rotamer 2) 1.28, s, 9H; 2.20, m, J 7.3 Hz, 2H; 2.48, s, 3H; 2.79,
t, J 7.3 Hz, 2H; 3.34, s, 3H; 3.96, t, J 7.3 Hz, 2H; 7.01–7.08, m, 2H;
7.21–7.29, m, 1H; 7.35–7.43, m, 2H. 13C n.m.r. (rotamer 1) 25.52,
26.44, 34.60, 41.45, 47.88, 49.71, 55.97, 122.52, 125.70, 128.94,
153.70, 187.31. 13C n.m.r. (rotamer 2) 24.07, 25.05, 34.36, 36.74,
47.96, 52.90, 58.96, 122.52, 125.70, 128.94, 153.70, 187.81. max 3429,
2974, 1519, 1490, 1404, 1204, 1135 cm–1.
Ethyl 3-bromopropanoate (20 g, 0.11 mol) and t-butylamine (16.16
g, 23.22 ml, 0.22 mol) in ethanol (50 ml) were refluxed for 16 h under
nitrogen. The solvent was evaporated, water (50 ml) and 10 M NaOH
(5 ml) were added, and the mixture was extracted twice with ethyl
acetate (60 ml). The extracts were dried and evaporated affording a pale
brown oil identified spectroscopically as the title compound26 (27)
(9.53 g, 50%). The oil was used without further purification (Found:
M+•, 173.1415. Calc. for C9H19NO2: M+•, 173.1416). 1H n.m.r. 1.11, s,
9H; 1.27, t, J 7.0 Hz, 3H; 2.16, br s, 1H; 2.50, t, J 6.7 Hz, 2H; 2.83, t, J
6.7 Hz, 2H; 4.14, q, J 7.0 Hz, 2H. 13C n.m.r. 13.98, 28.60, 35.16,
37.78, 50.43, 60.11, 172.58. Mass spectrum m/z 173 (M+, 1%), 158
(100), 112 (17), 86 (42), 70 (90).
When the reaction was repeated at 50° for 1 h the same result was
obtained, as determined by 1H n.m.r. spectroscopy.
N-t-Butyl-N-methylallylamine
N-t-Butylallylamine28 (5 g, 0.04 mol), made from the reaction of
allyl bromide with t-butylamine in ethanol, was added to 40% formalin
(9.96 g, 9.2 ml, 0.133 mol) and 90% formic acid (11.31 g, 9.27 ml, 0.22
mol) and the solution heated at 90° for 16 h. The mixture was poured
onto water (20 ml), basified (10 M NaOH), extracted twice with ether
(60 ml) and the extracts were dried and evaporated. The oil was dis-
tilled to give the title compound as a colourless oil (4.46 g, 79%), b.p.
42°/25 mmHg (Found: M+•, 127.1370. C8H7N requires M+•, 127.1361).
1H n.m.r. 1.09, s, 9H; 2.17, s, 3H; 3.02, d, J 6.3 Hz, 2H; 5.05–5.20, m,
2H; 5.80–5.95, m, 1H. 13C n.m.r. 25.77, 34.32, 54.04, 54.13, 116.49,
137.53.
N-Benzyl-3-(t-butylamino)propanamide (28)
The ester (27) obtained above (8.0 g, 0.05 mol) was dissolved in
benzylamine (20 ml) and heated at 130° for 16 h. Excess benzylamine
was removed under vacuum and the residue transferred to a sealed tube
containing t-butylamine (5 ml) and the mixture heated at 130° for 4 h.
Excess t-butylamine was evaporated affording a thick brown oil which
was triturated with ether–light petroleum. The brown solid obtained
was recrystallized from ethanol–ether affording a white powder identi-
fied as the title compound (28) (10 g, 92%), m.p. 172–174° (Found:
1
M+•, 234.1727. C14H22N2O requires M+•, 234.1732). H n.m.r. 1.38, s,
9H; 2.99, t, J 6.6 Hz, 2H; 3.11, t, J 6.6 Hz, 2H; 4.04, br s, 1H; 4.33, d,
J 6.0 Hz, 2H; 7.14–7.40, m, 5H; 8.26, br s, 1H. 13C n.m.r. 25.76,
31.01, 38.02, 43.15, 57.08, 127.17, 127.82, 128.47, 138.23, 170.23.
max 3265, 2463, 1642, 1559 cm–1.
Reaction of N-t-Butyl-N-methylallylamine with (1)
To a solution of N-t-butyl-N-methylallylamine (0.1 g, 0.79 mmol) in
1,2-dichloroethane (10 ml) was added phenyl chloro(thionoformate)
(0.14 g, 0.11 ml, 0.79 mmol) and the solution refluxed for 16 h. The
solvent was evaporated affording a pale brown solid identified as a
mixture of thiocarbamate material (40%) and N-t-butyl-N-methylallyl-
amine hydrochloride (60%). The solid was chromatographed on silica
by radial chromatography (dichloromethane–light petroleum, 1 : 1)
affording a pale brown oil identified as O-phenyl N-allyl-N-methyl-
thiocarbamate (9) (0.06 g, 39%), with spectroscopic data identical to
those obtained above.
N-Benzyl-NЈ-t-butylpropane-1,3-diamine (30)
Diborane (10 M in dimethyl sulfide) (3.21 ml, 0.03 mol) was added
to a solution of the amide (28) (1.5 g, 6.41 mmol) in tetrahydrofuran (30
ml) and the solution was refluxed for 16 h. HCl (6 M, 5 ml) was added
dropwise and the mixture stirred for 20 min. The solvent was evapo-
rated and the residue made alkaline (10 M NaOH) and extracted twice
with ether (60 ml). The solvent was dried and evaporated affording a
colourless oil which was distilled (Kugelrohr) to give the title com-
pound27 (30) as a colourless oil (0.68 g, 48%), b.p. 100°/2 mmHg
(Found: M+•, 220.1940. C14H24N2 requires M+•, 220.1939). 1H n.m.r.
1.08, s, 9H; 1.66, m, J 6.7 Hz, 2H; 1.84, br s, 1H; 2.61, t, J 6.7 Hz, 2H;
2.69, t, J 6.7 Hz, 2H; 3.54, br s, 1H; 3.77, s, 2H; 7.20–7.40, m, 5H. 13C
n.m.r. 28.82, 30.91, 40.95, 47.93, 50.05, 53.88, 126.67, 127.91,
128.17, 140.29.
Reaction of N,N-Dimethylaniline with (1)
(i) Phenyl chloro(thionoformate) (1) (0.29 g, 0.23 ml, 1.65 mmol)
was added to N,N-dimethylaniline (0.2 g, 1.65 mmol) and the solution
heated at 130° under a nitrogen atmosphere for 24 h. A blue oil was
obtained which was purified by radial chromatography (dichloro-
methane–light petroleum, 1: 4) on silica. The major fraction yielded a
pale yellow solid which was recrystallized from ether–light petroleum
affording pale yellow needles, identified as O-phenyl N-methyl-N-
phenylthiocarbamate (12) (0.24 g, 60%), m.p. 102° (lit.14 103°)
(Found: M+•, 243.0710. Calc. for C14H13NOS: M+•, 243.0718).
1H n.m.r. 3.72, s, 3H; 6.95–7.50, m, 10H. 13C n.m.r. 44.53, 122.5,
N-Benzyl-NЈ-t-Butyl-N,NЈ-dimethylpropane-1,3-diamine (26)
Formic acid (90%, 0.58 g, 0.48 ml, 0.01 mol) was added to a mixture
of the amine (28) (0.5 g, 2.27 mmol) and 40% formalin (0.51 g, 0.47 ml,
6.82 mmol) and the solution heated at 90° for 16 h. The mixture was
poured onto water (20 ml), basified (10 M NaOH) and extracted twice
with ether (60 ml). The extracts were dried and evaporated affording the
title compound (26) as a colourless oil (0.45 g, 79%) which was used
without further purification (Found: M+•, 248.2259. C16H28N2 requires
M+•, 248.2252). 1H n.m.r. 1.05, s, 9H; 1.67, m, J 7.8 Hz, 2H; 2.17, s,
3H; 2.20, s, 3H; 2.34–2.42, m, 4H; 3.47, s, 2H; 7.17–7.33, m, 5H. 13C
n.m.r. 25.89, 27.25, 35.03, 42.04, 48.89, 53.93, 55.54, 62.10, 126.64,
127.96, 128.83, 139.13.
125.60, 125.88, 127.67, 129.12, 129.40, 143.53, 154.05, 188.08.
max
1591, 1491, 1455, 1381, 1210 cm–1. Mass spectrum m/z 243 (M+, 17%),
214 (12), 150 (59), 134 (100), 109 (19), 94 (19), 77 (61).
(ii) To a solution of N,N-dimethylaniline (0.2 g, 1.65 mmol) in
dichloromethane (5 ml) was added phenyl chloro(thionoformate)
(0.29 g, 0.23 ml, 1.65 mmol) followed by titanium tetrachloride
(0.31 g, 0.18 ml, 1.65 mmol) and the solution refluxed for 16 h. The
reaction mixture was washed twice with water (60 ml) and the solvent
dried and evaporated affording a dark blue oil (0.362 g). The oil was
purified by radial chromatography on silica (dichloromethane–light
petroleum, 1: 4) to give O-phenyl N-methyl-N-phenylthiocarbamate
(12) as a pale yellow oil (0.04 g, 9%) with spectroscopic properties
identical to those obtained above.
Reaction of N-Benzyl-NЈ-t-butyl-N,NЈ-dimethylpropane-1,3-diamine
(26) with (1)
Phenyl chloro(thionoformate) (0.07 g, 0.06 ml, 0.40 mmol) was
reacted with the amine (26) (0.1 g, 0.40 mmol) as above. Radial chro-
matography on silica (methanol–ethyl acetate, 1: 1) of the product
When the reaction was carried out with excess phenyl
chloro(thionoformate) and excess titanium tetrachloride an intractable
black tar was obtained.
afforded
a pale yellow oil identified as O-phenyl N-(3-[t-
butyl(methyl)amino]propyl)-N-methylthiocarbamate (11) (0.09 g,
77%) as the major fraction (Found: M+•, 294.1760. C16H26N2OS
requires M+•, 294.1766). 1H n.m.r. (rotamer 1) 1.14, s, 9H; 1.98, m, J
7.3 Hz, 2H; 2.31, s, 3H; 2.56, t, J 7.3 Hz, 2H; 3.43, s, 3H; 3.77, t, J 7.3
Reaction of Quinuclidine with (1)
Phenyl chloro(thionoformate) (0.16 g, 0.12 ml, 0.90 mmol) was
reacted with quinuclidine (0.10 g, 0.90 mmol) as above. The product

848
D. S. Millan and R. H. Prager
N, 2.5. C27H2235ClNO7S requires C, 60.0; H, 4.1; N, 2.6%). The tenta-
tive assignment of stereochemistry is based on the coupling constants.
was purified by radial chromatography (dichloromethane–light
petroleum, 1 : 1) on silica. The major fraction yielded O-phenyl 4-(2-
chloroethyl)piperidine-1-carbothioate (13) (0.24 g, 95%) as an orange
oil (Found: M+•, 283.0803. C14H1835ClNOS requires M+•, 283.0798).
1H n.m.r. 1.18–1.45, m, 2H; 1.69–1.94, m, 5H; 2.96–3.21, m, 2H;
3.57, t, J 6.6 Hz, 2H; 4.77, d, J 13.3 Hz, 1H; 5.09, d, J 13.3 Hz, 1H;
7.02–7.10, m, 2H; 7.20–7.27, m, 1H; 7.34–7.42, m, 2H. 13C n.m.r.
30.48, 31.31, 32.48, 38.10, 41.95, 46.05, 50.37, 122.57, 125.62, 128.92,
153.83, 186.17. max 2932, 1592, 1504, 1489, 1284, 1193 cm–1. Mass
spectrum m/z 283 (M+, 7%), 192 (14), 190 (34), 174 (100), 94 (46), 77
(32).
1
Erythro: H n.m.r. 2.89–3.02, m, 1H; 3.18–3.32, m, 1H; 3.24, s,
3H; 3.78–3.92, m, 2H; 5.70, d, J 3.7 Hz, 1H; 5.84, d, J 3.7 Hz, 1H, CH;
5.98, s, 2H; 6.18, s, 2H; 6.72, s, 1H; 6.95, d, J 7.8 Hz, 1H; 7.00–7.12,
m, 3H; 7.20, s, 1H; 7.24–7.35, m, 1H; 7.36–7.50, m, 2H. 13C n.m.r.
29.32, 38.17, 57.26, 59.10, 83.02, 101.62, 103.55, 109.03, 109.49,
109.80, 113.97, 116.05, 122.89, 126.21, 129.15, 129.31, 129.97,
139.03, 145.07, 147.28, 148.52, 149.83, 153.94, 166.71, 188.00.
Threo: 1H n.m.r. 2.89–3.02, m, 2H; 3.41, s, 3H; 3.92–4.06, m, 2H;
5.36, d, J 5.7 Hz, 1H; 5.67, d, J 5.7 Hz, 1H; 5.98, s, 2H; 6.19, s, 2H;
6.46, d, J 7.9 Hz, 1H; 6.65, s, 1H; 6.85, d, J 7.9 Hz, 1H; 7.00-7.12, m,
2H; 7.24-7.35, m, 2H; 7.36-7.50, m, 2H. max 1749, 1488, 1468, 1037
cm–1. Mass spectrum m/z 503 (M+ –HCl, 11%), 161 (72), 117 (87), 91
(100), 70 (99).
Reaction of Tropine with (1)
Reaction of tropine (0.1 g, 0.71 mmol) with (1) (0.12 g, 0.098 ml,
0.71 mmol) as above gave a creamy white solid which was diluted with
water (10 ml) and the mixture basified with 20% sodium carbonate
solution. The mixture was extracted twice with ether (40 ml) and the
solvent dried and evaporated affording a light brown solid which was
separated on silica by radial chromatography (dichloromethane). This
afforded a colourless oil which later solidified and was identified as the
carbothioate* (15) (0.014 g, 8%), m.p. 128–130° (Found: M+•,
263.0984. C14H17NO2S requires M+•, 263.0980). 1H n.m.r. 1.88, t, J
16.5 Hz, 2H; 2.07–2.20, m, 2H; 2.22, t, J 4.5 Hz, 1H; 2.27, t, J 4.5 Hz,
2.30–2.46, m, 2H; 2.49, t, J 4.5 Hz, 1H; 2.54, t, J 4.5 Hz, 1H; 4.23, t, J
4.8 Hz, 1H; 4.90, m, 2H; 7.05–7.12, m, 2H; 7.24–7.29, m, 1H;
7.35–7.44, m, 2H. 13C n.m.r. 26.71, 28.11, 37.72, 39.61, 55.34, 58.66,
64.91, 122.88, 125.96, 129.33, 153.73, 182.17. max 3278, 1482, 1456,
1191, 1165, 1084 cm–1. Mass spectrum m/z 263 (M+, 12%), 170 (30),
154 (79), 110 (15), 93 (100).
Hydrolysis of (5)
(i) The thiocarbamate (5) (0.07 g, 0.33 mmol) was added to a solu-
tion of 10 M HCl (5 ml) in ethanol (5 ml) and refluxed for 16 h. The
solvent was evaporated affording a white solid which was identified by
its spectroscopic properties as diethylamine hydrochloride (0.04 g,
95%).
(ii) The thiocarbamate (5) (0.08 g, 0.38 mmol) was added to a solu-
tion of 10 M NaOH (5 ml) in ethanol (5 ml) and refluxed for 16 h. The
solution was acidified with 10 M HCl and the solvent evaporated afford-
ing a white solid which was extracted twice with chloroform (40 ml).
The solvent was dried and evaporated affording a white solid identified
as diethylamine hydrochloride (0.04 g, 84%).
(iii) The thiocarbamate (5) (0.2 g, 0.96 mmol) and dimethyl sulfate
(0.24 g, 0.18 ml, 1.91 mmol) were refluxed under nitrogen for 2 h in
dichloromethane (10 ml). The solvent was evaporated affording a
green oil which was washed twice with ether (20 ml) to give the
iminium salt as a pale green oil (0.32 g). The salt (0.1 g, 0.28 mmol)
was dissolved in water (5 ml) and refluxed for 2 h. Excess water was
evaporated under reduced pressure to afford diethylamine hydrogen
sulfate as a spectroscopically pure orange oil (0.04g, >95%).
The aqueous solution was evaporated, the residue extracted with
ethyl acetate (50 ml) and the solvent dried and evaporated affording a
white solid (0.144 g) identified as tropine.
The above reaction was repeated in an n.m.r. tube with tropine
(0.02 g, 0.14 mmol) dissolved in (D)chloroform followed by addition
of phenyl chloro(thionoformate) (0.024 g, 0.02 ml, 0.14 mmol). After
30 min a mixture (34: 66) of compound (15) (spectroscopically identi-
cal with that above) and the carbothioate† (14) was obtained. For (14):
1H n.m.r. 2.00–3.00, m, 8H; 3.85, s, 3H; 5.05, br s, 2H; 5.66, br s, 1H;
7.20–7.60, m, 5H.
Acknowledgments
The authors are grateful to the Australian Research
Council for support of this work. D.S.M. acknowledges an
Australian Postgraduate Award.
Reaction of O-Acetyltropine with (1)
Reaction of O-acetyltropine (0.1 g, 0.55 mmol) with (1) (0.09 g,
0.08 ml, 0.55 mmol) as above gave a pale yellow solid which was
recrystallized from ether–dichloromethane–light petroleum affording
colourless needles of the carbothioate‡ (16) (0.16 g, 96%), m.p.
159–161° (Found: C, 62.9; H, 6.3; N, 4.6%; M+•, 305.1083.
C16H19NO3S requires C, 63.0; H, 6.3; N, 4.6%; M+•, 305.1086).
1H n.m.r. 1.90, t, J 14.7 Hz, 2H; 2.02–2.32, m, 8H; 2.08, s, 3H; 2.50,
t, J 4.2 Hz, 2.55, t, J 4.2 Hz, 1H; 4.90, d, J 13.2 Hz, 2H; 5.15, t, J 4.8
Hz, 1H; 7.05–7.16, m, 2H; 7.20–7.30, m, 1H; 7.31–7.49, m, 2H.
13C n.m.r. 21.20, 26.24, 27.73, 34.42, 36.51, 54.62, 58.01, 67.06,
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