Direct conversion of N-ethylamines into functionalised amides by S2Cl2

Article abstract of DOI:10.1070/MC2001v011n05ABEH001504

Hünig's base 1 is known to react extensively with S₂Cl₂ to give monocyclic, bicyclic and fused tricyclic 1,2-dithioles with the N-ethyl group intact, but with S₂Cl₂ and DABCO in chloroform at 0 °C 1 is converted

Full text of DOI:10.1070/MC2001v011n05ABEH001504

, 2001, 11(5), 168–167
Direct conversion of N-ethylamines into functionalised amides by S2Cl2
Lidia S. Konstantinova,a Oleg A. Rakitin*a and Charles W. Rees*b
a N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 119991 Moscow, Russian Federation.
Fax: +7 095 135 5328; e-mail: orakitin@ioc.ac.ru
b Department of Chemistry, Imperial College of Science, Technology and Medicine, London SW7 2AY, UK. E-mail: c.rees@ic.ac.uk
10.1070/MC2001v011n05ABEH001504
Hünig’s base 1 is known to react extensively with S2Cl2 to give monocyclic, bicyclic and fused tricyclic 1,2-dithioles with the
N-ethyl group intact, but with S2Cl2 and DABCO in chloroform at 0 °C 1 is converted into dichloroacetamide 2 by selective
reaction of the N-ethyl group in a new one-pot transformation; ethyl-substituted derivatives of 1, diethylisopropylamine 17 and
triethylamine react similarly though the last, less bulky, amine also gives trichloroacetamide 20.
We have recently shown that the complex reaction between
Hünig’s base 1 and disulfur dichloride, S2Cl2, which gives bi-
cyclic bis(1,2-dithiol-4-yl)amines1 and tricyclic bis[1,2]dithiolo-
[1,4]thiazines2 can, with a deficiency of S2Cl2, also give inter-
mediate monocyclic 1,2-dithioles in low to moderate yield.3
Since this reaction is an unusually mild route to 1,2-dithioles,4
we attempted to increase its synthetic utility by replacing that
part of the Hünig’s base which neutralises the hydrogen chlo-
ride liberated, by another amine DABCO; also the reaction tem-
perature was lowered to 0 °C to minimise conversion of the
second isopropyl group.
Unexpectedly, these conditions led to an entirely different
reaction in which the isopropyl groups are unchanged and the
ethyl group is transformed into a dichloroacetyl group, which,
as far as we are aware, is a new transformation. Thus, Hünig’s
base with S2Cl2 (7 equiv.) and DABCO (7 equiv.) in chloroform
at 0 °C for 3 days followed by addition of formic acid1–3 and
heating for 1.5 h gave (N-dichloroacetyl)diisopropylamine 2†
(41%) (Scheme 1).
This conversion of Hünig’s base into amide 2 is the first
example that we have encountered, in many such S2Cl2 reac-
tions, of attack at its ethyl rather than isopropyl group, in the
presence or absence of other bases.1,2 The key reaction is pre-
sumably oxidation of the tertiary amine to an iminium ion by
S2Cl2–DABCO complex 3,3 which is a potential source of Cl+
and Cl–, and the outcome depends upon which iminium ion is
formed. We assume that the present mild (0 °C) conditions result
in oxidative removal of the less hindered α -hydrogen, i.e., from
O
CHCl2
i, S2Cl2, DABCO, 0 °C
ii, HCO2H
N
N
1
2
N
N
S
S
Cl
Cl–
3
Scheme 1
ethyl rather than isopropyl, to give kinetically controlled iminium
ion 4 (Scheme 2) rather than the, presumably more stable, alter-
native. Ion 4 can isomerise to enamine 5, which can be oxidised
further, as shown in Scheme 2, to give ultimately tetrachloro
species 6, which is converted into product 2 by formic acid.
Once the ethyl group has been oxidised (Scheme 2), the N-iso-
propyl groups will be deactivated to electrophilic attack. N-Di-
chloroacetyl diisopropylamine 2 is inert to the reaction mixture
even at room temperature, and we have previously shown that
N-acetyl- and N-cyanodiisopropylamine are inert to S2Cl2 under
similar conditions.2
Cl–
R2N
R2N
1
R2N
Cl
4
5
Cl
Cl
Cl
†
General procedure for the reaction of tertiary amines with S2Cl2.
R2N
R2N
R2N
R2N
Disulfur dichloride (0.8 ml, 10 mmol) was added dropwise at –15–20 °C
to a stirred solution of a corresponding amine (2 mmol) and DABCO
(10 mmol) (in the case of N-ethyldiisopropylamine without DABCO) in
chloroform (25 ml). The mixture was stirred at 0 °C for 72 h. Formic
acid (3.75 ml, 100 mmol) was added, the mixture was refluxed for 1.5 h
and filtered; and the solvents were evaporated. The residue was separated
by column chromatography (Silica gel Merck 60, light petroleum and
then light petroleum–CH2Cl2 mixtures).
Cl
Cl
Cl
Cl
Cl
O
Cl
Cl
HCO2H
R2N
Cl–
R2N
Cl
CHCl2
Cl
Cl
6
2
All new compounds were fully characterised by elemental analysis, 1H
R = Pri
and 13C NMR, IR and mass spectra, and HMRS.
Scheme 2
Dichloroacetamides 2, 18, 19, trichloroacetamide 20 and compound
11 are identical with the known compounds.5–9
9: an oil prepared from 7 and sodium azide in DMSO at room tempe-
rature in 88% yield.
10: yellow oil. 1H NMR (CDCl3) d: 1.10 (d, 6H, 2Me, J 6.5 Hz), 3.10–
3.45 (m, 5H, CH, 2CH2). 13C NMR (CDCl3) d: 187.42 (C=O), 154.87
and 137.02 (2sp2 tertiary C), 54.33 and 50.80 (2CH2), 44.98 (CH), 21.50
(Me). IR, n/cm–1: 2980 (CH), 2120 (N3), 1660 (C=O). MS, m/z (%): 278
(M+, 11%), 222 (69), 180 (100).
The formation of iminium ion 4 to the exclusion of its isomer
has previously been demonstrated by Schreiber10 in the oxida-
tion of Hünig’s base with trifluoroacetic anhydride in dichloro-
methane at 0 °C; no attack at isopropyl was detected.
In the Hünig’s base–S2Cl2 reactions, there is a relatively fine
balance between conversion of the ethyl group into dichloro-
acetyl (Schemes 1 and 2) and the isopropyl group into dithioles,3
bisdithioles1 and bisdithiolothiazines.2 It could be instructive to
see how substituents on the ethyl group influence this balance.
We therefore treated N-(2-chloroethyl)diisopropylamine 7 with
S2Cl2, DABCO and formic acid under the same conditions as
for 1. Two products were isolated: the same dichloroacetyl com-
pound 2 (21%) as from 1 and 1,2-dithiole-3-one 83 (34%)
(Scheme 3). The chloroethyl group has been oxidised like the
ethyl group but presumably more slowly, thus allowing com-
peting oxidation of isopropyl to give dithiolone 8. On the above
13: yellow oil. 1H NMR (CDCl3) d: 1.12 (d, 6H, 2Me, J 6.6 Hz), 3.51
(q, 1H, CH, J 6.5 Hz), 4.01 (s, 2H, CH2). 13C NMR (CDCl3) d: 187.17
(C=O), 155.97 and 136.12 (2sp2 tertiary C), 117.15 (CN), 53.59 (CH),
35.93 (CH2), 21.17 (Me). IR, n/cm–1: 2980 (CH), 2140 (CN), 1660
(C=O). MS, m/z (%): 248 (M+, 74%), 233 (47), 206 (61), 179 (33).
1
14: yellow crystals, mp 75–78 °C. H NMR (CDCl3) d: 1.35 (d, 6H,
2Me, J 6.2 Hz), 1.57 (d, 6H, 2Me, J 6.2 Hz), 4.26 (br. s, 2H, 2CH). 13
C
NMR (CDCl3) d: 163.74 (C=S), 113.02 (CN), 51.86 (CH), 21.42 and
18.53 (2Me). IR, n/cm–1: 2980 (CH), 2150 (CN). MS, m/z (%): 170 (M+,
87%), 127 (86), 113 (14), 101 (43).
– 167 –

, 2001, 11(5), 168–167
When one of the isopropyl groups of Hünig’s base was re-
placed by ethyl, the same conversion of ethyl into dichloro-
acetyl by S2Cl2 was observed. Thus, diethylisopropylamine 17
with S2Cl2 and DABCO in chloroform at 0 °C for 3 days, fol-
lowed by the formic acid treatment, gave dichloroacetamide 18
(34%); when run at 20 °C for 3 days, the yield was 54%
(Scheme 6). When both isopropyl groups of Hünig’s base were
replaced by ethyl, the same reaction was observed, to give
dichloroacetamide 19 in 51% yield; however, at lower tempe-
ratures (0 °C and –20 °C), the yield of 19 is much reduced (to
8% and to traces, respectively) and the major product is now
trichloroacetyl derivative 20 (22%). The direct transformation
of N-Et to N-COCCl3 also appears to be new. Formation of 20
in addition to 19 could result from reduced steric hindrance by
the ethyl groups in the chlorination sequence of Scheme 2,
before the formic acid reaction.
The established formation of monocyclic, bicyclic and fused
tricyclic 1,2-dithioles from ethylisopropylamines and S2Cl2 re-
quires attack at the isopropyl groups. We have now shown that
the presence of DABCO in the cold reaction mixture favours
selective attack at the ethyl group to give N-dichloroacetyl deri-
vatives such as 2, 18 and 19, probably by the mechanism of
Scheme 2. Ethyl-substituted diisopropylamines behave similarly,
by minor variations of this mechanism, to give 2, 11 and 14,
and the less bulky triethylamine also gives some of trichloro-
acetyl derivatives 20.
Cl
Cl
i, S2Cl2,
DABCO, 0 °C
ii, HCO2H
O
CHCl2
O
N
N
N
S
S
Cl
7
8
2
Scheme 3
mechanism (Scheme 2) formation of isopropyl-functionalised
product 8 should be favoured by a higher reaction temperature
and formation of ethyl-functionalised product 2 by a lower
reaction temperature. Some evidence for this was obtained by
running the reaction exactly as before but in boiling chloroform
(61 °C) when several products, all of which were cyclic 1,2-di-
thiole derivatives,1–3 were formed in low yields, and only traces
of compound 2 were seen (TLC). When the same reaction was
run at –20 °C, all transformations were much slower and only a
low yield (12%) of compound 8 could be isolated.
N-(2-Azidoethyl)diisopropylamine 9 treated similarly also
reacted by both pathways to give corresponding dithiolone 103
(12%) and an acyldiisopropylamine; the latter was not the analo-
gous 2-azidoacetyl derivative but cyanoformyl derivative 11 (19%)
(Scheme 4) obtained as a yellow oil. This product could arise
readily by the general mechanism of Scheme 2 with a late
diversion, caused by elimination of nitrogen and formation of
the cyano group, as shown in Scheme 4.
O
CHCl2
i, S2Cl2, DABCO
ii, HCO2H
N3
N3
N
N
i, S2Cl2,
DABCO, 0 °C
ii, HCO2H
O
CN
O
17
18
N
N
N
S
i, S2Cl2, DABCO
ii, HCO2H
S
Cl
9
11
Et3N
Et2N COCHCl2
19
Scheme 6
Et2N COCCl3
10
20
HCO2H
Cl
H
Cl
Cl
[Cl+]
R2N
– N2
– H+
Cl
Cl
R2N
R2N
This work was supported by the Russian Foundation for Basic
Research (grant no. 99-03-32984a), the Royal Society, MDL
Information Systems (UK) Ltd and an RSC Journals Grant to
O.A.R., and we thank the Wolfson Foundation for establishing
the Wolfson Centre for Organic Chemistry in Medical Science
at Imperial College.
N3
N
N2
CN
H
R = Pri
Scheme 4
Formation of cyanoformamide 11 from azidoethyl compound
9 prompted similar treatment of N-(cyanomethyl)diisopropyl-
amine 12,11 which was expected to give the same product 11
but possibly in higher yield. However, cyanothioformyl deriva-
tive 14 (24%), mp 75–77 °C, was formed instead, together with
dithiolone 133 (20%) (Scheme 5). Formation of thioamide 14
instead of carboxamide 11, after formic acid treatment, suggests
that a different mechanism is operating. It seems reasonable that
S2Cl2 could be reacting, through sulfur, with the activated meth-
ylene group of 12. This could be through its ketenimine tautomer
15 as shown in Scheme 5 or by a radical mechanism induced by
the enhanced stabilisation of captodative radical 16.12
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i, S2Cl2,
DABCO, 0 °C
ii, HCO2H
CN
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O
3
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N
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5
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Scheme 5
15
Received: 18th July 2001; Com. 01/1830
– 168 –