Optimisation of substitution at the 2- and 5- positions of 3,4-dialkoxythiophenes via the Mannich reaction: The influences of steric crowding, electrophile reactivity and temperature

Article abstract of DOI:10.1039/b105476g

A number of 3,4-dialkoxythiophene compounds have been synthesised and their reactivities assessed via the Mannich reaction with secondary amines. These reactions surprisingly gave the bis-Mannich bases substituted at the 2- and 5-positions as well as the expected mono-Mannich bases substituted at the 2-position. Conditions were optimised to give symmetrical bis-2,5-Mannich bases in one step and asymmetrical bis-2,5-Mannich bases in two steps. Several bis(thien-2-ylmethyl)amines derived from 3,4-dialkoxythiophenes are reported, their synthesis being performed under both normal and high dilution conditions. Some syntheses also afforded the (thien-2-ylmethyl)amine oligomers. Further substitution of the bis(thien-2-ylmethyl)amines at the 5-position via the Mannich reaction also proved successful. The factors affecting the yields and substitution patterns are discussed, together with molecular modelling of the spatial requirements.

Full text of DOI:10.1039/b105476g

View Article Online / Journal Homepage / Table of Contents for this issue
Optimisation of substitution at the 2- and 5- positions of
,4-dialkoxythiophenes via the Mannich reaction: the influences
3
of steric crowding, electrophile reactivity and temperature
1
-positions as well as the expected mono-Mannich bases substituted at the 2-position. Conditions were optimised
Joan Halfpenny,* Phillip B. Rooney and Zachary S. Sloman
Department of Chemistry and Physics, The Nottingham Trent University, Clifton Lane,
Nottingham, UK NG11 8NS
Received (in Cambridge, UK) 21st June 2001, Accepted 3rd August 2001
First published as an Advance Article on the web 27th September 2001
A number of 3,4-dialkoxythiophene compounds have been synthesised and their reactivities assessed via the Mannich
reaction with secondary amines. These reactions surprisingly gave the bis-Mannich bases substituted at the 2- and
5
to give symmetrical bis-2,5-Mannich bases in one step and asymmetrical bis-2,5-Mannich bases in two steps. Several
bis(thien-2-ylmethyl)amines derived from 3,4-dialkoxythiophenes are reported, their synthesis being performed under
both normal and high dilution conditions. Some syntheses also afforded the (thien-2-ylmethyl)amine oligomers.
Further substitution of the bis(thien-2-ylmethyl)amines at the 5-position via the Mannich reaction also proved
successful. The factors affecting the yields and substitution patterns are discussed, together with molecular modelling
of the spatial requirements.
Introduction
The first genuine Mannich reaction of a thiophene ring was
1
reported by Barker et al. who reacted electron rich alkoxythio-
phenes with secondary amines and formaldehyde to afford a
numberofMannichbasessubstitutedatthe2-position.Thework
presented here extends the use of this reaction to link the alkoxy-
thiophene units and investigate substitution at the 5-position
using various alkoxythiophenes. The reactivities of the alkoxy-
thiophenes were assessed via the yields of the Mannich bases
produced in each case under identical conditions.
ϩ
Scheme 1 (i) Me SO , ∆, 0.5 h; (ii) 6 M NaOH (aq), ∆, 1 h, then H O
2
4
3
(
yield, 74%); (iii) Cu O, quinoline, ∆, 0.5 h, N (yield, 74%).
2
2
3
and Lal, but with limited success. Their route relied upon the
thermal decarboxylation of the diacid derivative in the presence
of copper metal under reduced pressure, giving 3,4-dimethoxy-
thiophene as a distillate. Attempts to reproduce this work only
gave low yields (ca. 5–10%), and replacing the copper metal
with copper() oxide gave only a moderate improvement (21%).
The synthesis of 2 was achieved by the alkylation procedure
4
used by Dallacker and Mues which employed DMF and
potassium carbonate as the solvent and base, and by substi-
tuting 1,2-dibromoethane for bromochloromethane. This gave
the diester in 78% yield. Subsequent saponification and decarb-
oxylation gave 2,3-dihydrothieno[3,4-b][1,4]dioxin in sufficient
quantities to allow purification by distillation.
Results and discussion
Synthesis of the 3,4-dialkoxythiophenes
3
,4-Dimethoxythiophene 1 was prepared from disodium
Compounds 3 and 4 were synthesised similarly employing
-tosyl-2-ethoxyethane and bis(2-tosylethyl) ether as the alkyl-
2
,5-bis(ethoxycarbonyl)thiophene-3,4-diolate essentially by the
1
2
literature method, Scheme 1.
ating agents respectively.
In order to obtain a reference sample of diethyl 3,4-dimeth-
oxythiophene-2,5-dicarboxylate, in one instance the inter-
mediate diethyl ester was isolated. Further preparations of
Application of the Mannich reaction to 3,4-dimethoxythiophene,
1
3
,4-dimethoxythiophene-2,5-dicarboxylic acid were carried out
without isolation of the diester. Decarboxylation of the dicarb-
oxylic acid was attempted using the procedure of Overberger
Barker et al. observed an apparent lack of reactivity of 3,4-
dimethoxythiophene in their study of the Mannich reaction
DOI: 10.1039/b105476g
J. Chem. Soc., Perkin Trans. 1, 2001, 2595–2603
This journal is © The Royal Society of Chemistry 2001
2595

View Article Online
1
of electron rich thiophene systems. However only the reaction
methoxy groups. Molecular modelling calculations† show that
the two groups are forced away from each other and towards
the 2- and 5-positions of the thiophene ring, thus inhibiting
any attack by the iminium electrophile. There is no bulky sub-
stituent on the 4-position of 3-methoxythiophene so that the
2-position is more open to attack by the incoming electrophile.
of 3,4-dimethoxythiophene with formaldehyde and dimethyl-
amine in glacial acetic acid was reported, the bulk of their
paper dealing with the Mannich reactions of 2- and 3-methoxy-
thiophene. The aim of the present study was to broaden our
understanding of the reactive nature of dialkoxythiophenes.
An extension of the work of Barker et al., employing one
equivalent of aqueous formaldehyde and one equivalent of
dimethylamine, piperidine or morpholine, was undertaken.
In order to standardise the reaction conditions so that com-
parisons could be made, all reactions were carried out at room
temperature for a period of 24 hours, Scheme 2.
Application of the Mannich reaction to other 3,4-dialkoxythio-
phene systems
The performances of compounds 2, 3 and 4 (4 limited to
dimethylamine) in the Mannich reaction were assessed using
the standard reaction conditions developed earlier. The yields
of the Mannich bases derived from 2,3-dihydrothieno[3,4-b]-
[1,4]dioxin, 2, were generally higher than those derived from 1;
dimethylamine and piperidine gave 72 and 82% yields of the
expected tertiary amines 7a and 7b respectively. These greatly
improved yields over the dimethoxy counterpart reinforce the
proposal that steric effects hinder the substitution of 3,4-
dimethoxythiophene, 1, as clearly there can be no crowding of
the 2- and 5-positions for 2.
Scheme 2
The Mannich bases 5a and 5b were isolated in very low yields
as oils, although that derived from morpholine (5c) was formed
in much higher yield (53%). Purification of these amines was
achieved by extracting the basic components into an aqueous
solution of hydrochloric acid, followed by basification. The
residue obtained from this was purified further by column
chromatography since none of the Mannich bases derived
from 3,4-dimethoxythiophene withstood distillation. The NMR
spectra of material obtained by distillation showed the presence
of approximately 50% of 1, indicating that some of the crude
material had undergone a thermal retro-Mannich reaction.
Methiodides of the above Mannich bases were formed very
readily by their treatment, in diethyl ether, with methyl iodide;
the salts were used in conjunction with the free amine to obtain
microanalytical data, particularly for those Mannich bases
isolated as oils.
For a direct comparison of the reactivity of 3,4-dimethoxy-
thiophene with that of 3-methoxythiophene, the latter was
reacted under the conditions shown in Scheme 2. This gave the
Mannich bases 6a, 6b and 6c in yields of 62, 75 and 87%
respectively.
The Mannich base 7a was tolerant of distillation, the distil-
late showing no trace of 2. Interestingly the reaction employing
morpholine gave a mixture of two products, the expected
mono-Mannich base 7c (52%), and the bis-Mannich base 11c
(
13%). This particular reaction was exceedingly exothermic,
requiring prolonged cooling to attain a steady ambient tem-
perature. The fact that some 7c underwent further substitution
also indicates that the remaining 5-position must be relatively
unhindered.
Compound 3 gave low yields of the Mannich base 8a (12%),
the yields of 8b were moderate (42%), and the results obtained
Given the yields of 5a–c and 6a–c, 3,4-dimethoxythiophene
must exhibit lower reactivity than 3-methoxythiophene. Clearly
electronic influences cannot explain this phenomenon. We
attribute this effect to the spatial requirements of the adjacent
2
596
J. Chem. Soc., Perkin Trans. 1, 2001, 2595–2603

View Article Online
with morpholine again indicated the presence of both the
mono- and bis-Mannich bases 8c (22%) and 12c (24%). The
latter two compounds showed similar chromatographic
properties to those of their 2,3-dihydrothieno[3,4-b][1,4]dioxin
counterparts. Compound 4 gave the Mannich base 9a (89%)
when reacted with dimethylamine. From these results it may be
seen that generally where dimethylamine and piperidine are
used, 3 is intermediate in reactivity between 1 (the least reactive)
and 2 (the most reactive).†
The yields of those Mannich bases derived from morpholine
were generally higher than those yields obtained with the other
secondary amines. From these data, conclusions about the
reactivity of the iminium electrophiles may be drawn. Under
the conditions employed here, the N,N-dimethyl-N-methylene-
ammonium ion is similar in reactivity to the 1-methylene-
piperidinium ion. The most reactive species is the 4-methylene-
morpholinium ion. Some corroboration of the reactivity of5
the 4-methylenemorpholinium ion is afforded by Jasor et al.
They observed that in the reaction of unsymmetrical ketones
with ammonium salts, the salt 4-methylenemorpholinium
trifluoroacetate exhibited enhanced reaction rates.
Substitution at the 5-position
Given that the 3,4-dimethoxythiophene, 1, was somewhat
unreactive under the conditions hitherto employed, we
embarked upon a study to investigate the conditions for
optimum reaction.
By reaction of the compound with the reagents used thus far,
but employing elevated temperatures, e.g. 100 ЊC, some reason-
able yields of Mannich bases were obtained. For example in
this manner 3,4-dimethoxythiophene gave a 53% yield of the
Mannich base 5b, which in turn was further reacted under
identical conditions to give the bis-Mannich base, 10b (27%)
(
4
Scheme 3). Because of the innate high reactivity of the
-methylenemorpholinium electrophile it was felt unnecessary
Scheme 3 (i) 1 eq. 37% HCHO(aq), 1 eq. piperidine, AcOH, 100 ЊC,
to use high reaction temperatures in a synthesis of the mono-
Mannich base, 5c. At higher temperatures an excellent yield
4
h (yields 5b, 53%, 10b, 27%); (ii) 2.2 eq. 37% HCHO(aq), 2.2 eq.
morpholine, AcOH, 100 ЊC, 4 h (yields, 5c, 21%, 10c, 78%).
(
78%) of the bis-Mannich base, 10c, was obtained, some mono-
substituted product also being isolated.
The dialkoxythiophene, 3, was also found to give a number
of Mannich bases in improved yields when the reactions were
carried out at 100 ЊC (Scheme 4).
The yields of the compounds 8a, 8c, 12b and 12c agree with
the predictions made about the reactivities of the thiophene
moieties and the iminium electrophiles.
Thus far 3,4-ethylenedioxythiophene, 2, had proved to be the
most susceptible to the Mannich reaction relative to 1 and 3.
This was illustrated further when only the bis-Mannich bases
were formed on reaction at elevated temperature. The
bis-Mannich bases 11b (86%) and 11c (91%) were synthesised
directly by the treatment of 2,3-dihydrothieno[3,4-b][1,4]dioxin
with 2.2 equivalents of both formaldehyde and secondary
amine at 100 ЊC, giving excellent yields of the desired products.
A successful synthesis of the bis-Mannich base 11a could not
be achieved, whether starting from the thiophene moiety 2 or
from the mono-Mannich base, 7a. This was not surprising
as the iminium electrophile formed from dimethylamine had
consistently proven to be the least reactive.
†
The lowest energy conformer of 3,4-dimethoxythiophene, 1, was
obtained via systematic modification of the two methyl–thiophene
torsions (defined by atoms C2-C3-O1-C6 and C5-C4-O2-C7) from
Syntheses of “mixed” bis-Mannich bases 13, 14 and 15 were
also attempted. The general strategy used here was to substitute
the vacant 5-position of a mono-Mannich base with the more
reactive iminium moiety. Thus, 7a was reacted at elevated
temperatures with formaldehyde and either piperidine or
morpholine in acetic acid to give the bis-Mannich bases 13 and
0
–180 degrees in 20 degree increments (one being fixed at 0, then Ϫ20
degrees etc.) and subsequent single point energy calculation. The
energy calculation was carried out via MOPAC using the PM3 semi-
1
0
empirical method. The coordinates of the lowest energy conformer
(
C2-C3-O1-C6 and C5-C4-O2-C7 = 0 degrees) were then used as the
11
starting point for a full geometry optimisation via GAUSSIAN98W
at the HF/6-31ϩG(d) level of theory. Harmonic frequencies were
computed in order to characterise the stationary point. No imaginary
frequencies were present.
1
4 in yields of 54 and 74%, respectively. However, both were
unstable and although satisfactory NMR spectra were
J. Chem. Soc., Perkin Trans. 1, 2001, 2595–2603
2597

View Article Online
solutions of 3,4-ethylenedioxythiophene and the diamine,
together with two equivalents of aqueous formaldehyde, were
Ϫ1
fed at a rate of 2.2 mmol h into a further small volume of
glacial acetic acid. The same two secondary diamines were
employed in this study, and a third, N,NЈ-dimethylpropane-1,3-
diamine, was also used. Under these conditions polymerisation
was still the dominating reaction, although this tendency was
at its lowest with N,NЈ-dimethylethylenediamine, which gave
the highest yield (45%) of the desired bis(thien-2-ylmethyl)
derivative, 18a. The homologous N,NЈ-dimethylpropane-1,3-
diamine showed the greatest tendency to polymerise, with the
result that only a 12% yield of compound 18b was obtained.
1
,4-Bis(2,3-dihydrothieno[3,4-b][1,4]dioxin-5-ylmethyl)piper-
azine, 18c, was given in a yield intermediate between the
previous two (22%). The nature of compounds 18a–c was clear
from their NMR and mass spectra. In all cases, the bis(thien-2-
ylmethyl) derivatives were accompanied by small quantities of
the oligomer 19a (7%), (19b) 6% or 19c (9%).
Scheme 4 (i) 2.2 eq. HCHO(aq), 2.2 eq. morpholine, AcOH, 100 ЊC,
h (yields, 8c, 52%, 12c, 16%); (ii) 1 eq. HCHO(aq), 1 eq. Me NH(aq),
4
2
AcOH, 100 ЊC, 4 h (yield, 8a, 37%); (iii) 1 eq. HCHO(aq), 1 eq.
piperidine, AcOH, 100 ЊC, 4 h (yield, 12b, 35%).
obtained, no microanalytically pure samples of 13 and 14 or
their methiodide salts could be isolated. Compound 15 was
synthesised by the reaction of 7b with formaldehyde and mor-
pholine to give a 91% yield of the desired bis-Mannich base.
Linking the thiophene moieties: synthesis of bis(thien-2-ylmethyl)
Mannich bases
Having studied the aminomethylation of a variety of 3,4-
dioxythiophenes and optimised substitution conditions for
both the 2- and 5-positions the work was extended to link the
thiophene moieties through primary amines or secondary
diamines. Thus, the reaction of methylamine and two equiv-
alents of 2,3-dihydrothieno[3,4-b][1,4]dioxin was initially
performed under non-high dilution conditions, which, with two
equivalents of formaldehyde gave the desired Mannich base, 16
(
37%), accompanied by the oligomeric compound, 17 (21%).
The latter was easily identifiable from the carbon-13 NMR
spectrum, which showed six signals in the aromatic region, two
signals arising from a symmetrically substituted 2,3-dihydro-
thieno[3,4-b][1,4]dioxin moiety, and four signals ascribed to a
Neither of the oligomers 19a or 19b were sufficiently stable
when isolated to obtain microanalytical data or mass spectra.
The mass spectrum of 18c is worthy of further discussion. In
common with all the thien-2-ylmethyl Mannich bases, com-
pound 18c gave an intense signal with an m/e value of 155
(89%). This was attributed to a 5-methylene-2,3-dihydrothieno-
[3,4-b][1,4]dioxin fragment, 20, which by comparison with the
cycloheptatriene cation (the tropylium ion), obtained when
toluene is subjected to mass spectroscopic analysis, may be
assumed to undergo a rearrangement to a thiopyrylium ion, 21.
Apart from the molecular ion the only other signal of any note
was that with an m/e value of 249 (100%) corresponding to the
loss of fragment 20 from the molecule 18c.
2
,3-dihydrothieno[3,4-b][1,4]dioxin ring substituted in the
2
-position. However, the compound decomposed too rapidly
for satisfactory microanalyses and mass spectra to be obtained.
Unfortunately, under these reaction conditions, polymeris-
ation was extensive with the secondary diamines N,NЈ-
dimethylethylenediamine and piperazine. N,NЈ-Dimethylethyl-
enediamine gave a polymeric oil which was highly unstable,
darkening rapidly in the air. Piperazine afforded high yields
(
>80%) of an amorphous white solid possessing high thermal
stability, not decomposing until ca. 300 ЊC. In view of these
disappointing results, a series of high dilution Mannich
reactions were performed in which separate glacial acetic acid
The reactive thiophene macrocycle, 4, was also used in the
synthesis of a bis(thien-2-ylmethyl) compound, by the reaction
2
598
J. Chem. Soc., Perkin Trans. 1, 2001, 2595–2603

View Article Online
Fig. 1 Bond lengths: S(1)–C(2) 1.733 Å, S(1)–C(5) 1.733 Å, O(1)–C(3)
.337 Å, O(1)–C(6) 1.400 Å, C(2)–C(3) 1.346 Å, O(2)–C(4) 1.337 Å,
1
O(2)–C(7) 1.400 Å, C(3)–C(4) 1.449 Å, C(4)–C(5) 1.346 Å. Bond
angles: C(2)–S(1)–C(5) 91.30Њ, C(3)–O(1)–C(6) 117.74Њ, S(1)–C(2)–C(3)
1
11.86Њ, C(4)–O(2)–C(7) 117.74Њ, O(1)–C(3)–C(2) 129.09Њ, O(1)–C(3)–
C(4) 118.42Њ, C(2)–C(3)–C(4) 112.49Њ, O(2)–C(4)–C(3) 118.42Њ, O(2)–
C(4)–C(5) 129.09Њ, C(3)–C(4)–C(5) 112.49Њ, S(1)–C(5)–C(4) 111.86Њ.
1
9a,b, was not sufficiently stable to permit mass spectroscopic
or microanalysis, but NMR spectroscopy supported the
structural assignment given.
Substitution at the 5-position of the thien-2-ylmethyl Mannich
bases
In a study of the behaviour towards a further Mannich reaction
of the 2-thienylmethyl Mannich bases, 16 and 18a–c, the bases
were treated with morpholine and two equivalents of formalde-
hyde. In this way, a series of morpholine derivatives, 24 (97%),
2
5a (97%), 25b (92%) and 25c (83%) were prepared in excellent
yields.
with N,NЈ-dimethylethylenediamine and two equivalents of
formaldehyde under the high dilution conditions described.
This gave compound 22 (46%), accompanied by the tetraamine,
Conclusions
2
3 (5%), Scheme 5. Compound 23, like the related compounds
The reactivities of 3,4-dialkoxythiophenes towards electrophilic
substitution via the Mannich reaction were found to be depend-
ent on the nature of the oxygen substituents, the electrophile
employed and the temperature of the reaction. The nature of
the groups attached to the oxygens at the 3- and 4-positions
influences the reactivity of the thiophene moiety via the steric
crowding imposed at the 2- and 5-positions. Hence 3,4-
dimethoxythiophene, 1, is less likely to undergo the Mannich
reaction under the standard conditions used than is 2,3-
dihydrothieno[3,4-b][1,4]dioxin, 2. This is easily visualised from
the molecular modelling† where for compound 1 the lowest
energy conformer (Fig. 1) has both the 2- and 5-positions
crowded by the methoxy groups, whereas for compound 2
clearly the 2- and 5-positions must be unhindered and open to
attack by the electrophile.
The nature of the electrophile employed influences the yields
of the Mannich bases. For the amines used in this work the
order of reactivity of the iminium electrophiles proved to
be morpholine > piperidine > dimethylamine. The greater reac-
tivity of the morpholine ion was also demonstrated by the fact
that in the mono-substitution reactions, often some bis-
Mannich base substituted at both the 2- and 5-positions was
obtained.
To optimise reaction at the 5-position elevated temperature
was employed. Substitution at both the 2- and 5-positions in
one reaction was achieved, giving symmetrical Mannich bases
in high yields. Asymmetrical Mannich bases were prepared via
isolation of the mono-Mannich base, which was then subjected
to the Mannich reaction at elevated temperature with the
appropriate amine.
In order to link the thiophene moieties the best results were
achieved under high dilution conditions. Even under these
conditions some oligomeric compounds containing three thio-
phene moieties (one thiophene moiety undergoing substitution
Scheme 5
J. Chem. Soc., Perkin Trans. 1, 2001, 2595–2603
2599

View Article Online
at the 2- and 5-positions) were isolated in low yields although
these were generally unstable. Substitution at the 5-position
of the bis(thien-2-ylmethyl) Mannich bases was achieved at
elevated temperature using the more reactive morpholine
electrophile.
solvent and base, and by substituting 1,2-bromoethane for
bromochloromethane. Distillation afforded the title compound
(71%), bp 110–112 ЊC/20 mmHg. The spectroscopic data were
9
in accordance with the literature values (Found: C, 50.98; H,
ϩ
4.34. C H O S requires C, 50.69; H, 4.25%); m/e 142 (M ).
6
6
2
In conclusion, a series of 2- and 2,5-substituted 3,4-dialk-
oxythiophenes were prepared and the optimum conditions
for mono- and disubstitution investigated. The important
factors affecting reaction conditions were found to be the
crowding imposed upon the 2- and 5-positions by the 3- and 4-
substituents, the nature of the electrophile and the temperature
of reaction. This investigation is part of our ongoing work on
3,4-Bis(2-ethoxyethoxy)thiophene, 3. Prepared by the liter-
ature method, employing DMF and potassium carbonate as
solvent and base, and by substituting 1-tosyl-2-ethoxyethane
for bromochloromethane. Distillation gave the title aromatic
4
ether (70%), bp 162–164 ЊC/2 mmHg; νmax(film) 3110, 2980,
Ϫ1
2930, 2870 and 1565 cm ; δ
(CDCl
CH
EtOCH ), 4.11–4.17 (4H, m, ArOCH ), 6.23 (2H, s, ArH);
) 1.22 (6H, t, J 6.93,
H
3
6–8
novel thiophene based ligands and macrocycles.
OCH
2
CH
3
), 3.58 (4H, q, J 6.93, OCH
2
), 3.76–3.80 (4H, m,
3
2
2
δ (CDCl ) 15.1 and 15.2 (CH ), 66.8, 68.7 and 69.9 (OCH ),
C
3
3
2
Experimental
97.7–98.5 (C2/C5), 147.2 (C3/C4) (Found: C, 55.53; H, 7.97.
C H O S requires C, 55.36; H, 7.74%).
12 20 4
General
All reagents and solvents were used as supplied unless other-
wise stated. In general, organic solutions of products were dried
2
,3,5,6-Tetrahydrothieno[3,4-b][1,4,7]trioxonin, 4. Prepared
4
by the literature method, employing DMF and potassium
carbonate as solvent and base, and by substituting bis(2-
tosylethyl) ether for bromochloromethane. Purification by
column chromatography (silica; light petroleum–EtOAc, 3 : 1)
gave the title aromatic ether as a colourless oil (74%); νmax(film)
100, 2940, 2860 and 1550 cm ; δ (CDCl ) 3.87–3.90 (4H, m,
(
MgSO ), filtered, and the solvent was removed by rotary
4
evaporation. Solvents for chromatographic analysis were dis-
tilled prior to use. Unless otherwise stated, light petroleum
refers to the fraction bp 40–60 ЊC.
Ϫl
3
H 3
Chromatographic analysis
CH OCH ), 4.27–4.30 (4H, m, ArOCH ), 6.56 (2H, s, ArH);
2
2
2
For thin layer chromatography (TLC), 250 pm silica gel 60A
MK 6F plates were used. Alumina plates were aluminium oxide
δ (CDCl ) 72.4 and 74.2 (OCH ), 107.8 (C2/C5), 150.0 (C3/C4)
C
3
2
(Found: C, 51.50; H, 5.58. C H O S requires C, 51.60; H,
8
10
3
1
50F254, neutral (type T), layer thickness 0.2 mm. For column
5.41%).
chromatography, silica gel 0.06–0.2 mm, pore diameter ca. 4 nm
was employed. Alumina was neutral Brockmann Grade 1 for
chromatographic analysis. For centrifugal chromatography, a
Chromatotron Model 7924 T was used. The adsorbents used to
coat the rotors were silica gel 60PF254, containing gypsum and
aluminium oxide, 60PF254, Type E. The coatings with alumina
Application of the Mannich reaction to 3,4-dialkyloxythiophene
systems: synthesis of mono-Mannich bases from secondary
amines. General method
1
The amine (40% aqueous solution, for dimethylamine) (1.1 eq.)
and aqueous formaldehyde (37%, 1.1 eq.) were added to glacial
3
were glue bound to the rotors, added at a rate of 1–5 cm per 60
g of adsorbent, to the initial slurry.
3
Ϫ1
acetic acid (0.3 cm mmol ) with ice cooling. The thiophene
moiety (1.0 eq.) was added and the reaction was stirred for 24
hours. Basification with aqueous sodium hydroxide (4 M) and
Instrumentation
3
extraction with diethyl ether (3 × 30 cm ) gave the free organic
Where a syringe pump was used, the type was a model A pump
fitted with motors colour coded yellow, manufactured by Razel
Scientific Instruments Inc., Stamford, Connecticut, USA.
components. The ethereal solution was extracted with aqueous
3
hydrochloric acid (2 M, 3 × 50 cm ). The aqueous acidic layer
was basified with sodium hydroxide solution (4 M) and
3
Ϫ1
3
These motors gave flow rates of 0.661, 1.179 and 2.412 cm h
extracted with dichloromethane (3 × 30 cm ). The organic
3
with 10, 20, and 50 cm syringes, respectively. Melting points
were taken on a Gallenkamp apparatus model 3A 5120, and are
reported uncorrected.
phase was treated in the usual way, to give the crude Mannich
base. Purification was by centrifugal chromatography (alumina;
light petroleum–EtOAc, 6 : 1), unless stated otherwise.
Infrared spectra were obtained using a Perkin–Elmer 1600
series FTIR Spectrophotometer. Nuclear magnetic resonance
spectroscopy (NMR) was performed with a JEOL EX 270
MHz machine; solvents used were deuterated chloroform or
deuterated dimethyl sulfoxide. The solvent is specified in the
experimental section in parenthesis before the NMR data. Mass
spectra were obtained using a Finnigan Mat LCQ(TM) mass
spectrometer. Microanalyses were carried out by the University
of Nottingham analytical services department.
N-[(3,4-Dimethoxythien-2-yl)methyl]-N,N-dimethylamine,
5a. Purification by column chromatography (alumina; light
petroleum–EtOAc, 2 : 1) gave the title compound (5%) as an oil,
mp (methiodide) 152–154 ЊC; δ (CDCl ) 2.27 (6H, s, N(CH ) ),
H
3
3 2
3.53 (2H, s, ArCH N), 3.81 (6H, s, ArOCH ), 6.10 (1H, s,
2
3
Ar-H); δ (CDCl ) 45.1 (NCH ), 54.5 (ArCH N), 57.1 (OCH
C
3
2
2
3
on C4), 60.8 (OCH on C3), 94.4 (C5), 123.9 (C2), 144.7 (C3),
3
150.3 (C4) (Found: C, 53.63; H, 7.75; N, 6.75. C H NO S
9
15
2
ϩ
requires C, 53.70; H, 7.51; N, 6.96%); m/e 201 (M ).
3
,4-Dialkoxythiophenes
1
-[(3,4-Dimethoxythien-2-yl)methyl]piperidine,
5b.
5%
These were prepared (with appropriate adaptation) via the
(
reaction at 100 ЊC gives 53%), oil, mp (methiodide) 148–150
ЊC; δ (CDCl ) 1.43 (2H, quintet, J 5.61, CH CH CH ), 1.57
4H, quintet, J 5.61, CH CH CH ), 2.41–2.44 (4H, m, NCH ),
2 2 2 2
.59 (2H, s, ArCH N), 3.81 (6H, s, ArOCH ), 6.08 (1H, s,
reactions outlined in Scheme 1, employing methods previously
2–4,9
reported in the literature.
Details of treatment after the final
H
3
2
2
2
(
3
(
decarboxylation) reaction are given.
2
3
3
,4-Dimethoxythiophene, 1. Prepared from disodium 2,5-bis-2
Ar-H); δ
54.0 (ArCH
C
(CDCl
3
) 24.3 (CH
2
CH
2
CH
2
), 26.0 (CH CH CH ),
2 2 2
(
ethoxycarbonyl)thiophen-3,4-diolate by the literature method.
The crude material was distilled to give the title compound
74%), bp 115–118 ЊC/20 mmHg (Literature 110 ЊC/17
mmHg).
2
N), 54.1 (NCH ), 57.0 (OCH on C4), 60.8 (OCH
2
3
3
on C3), 94.1 (C5), 124.0 (C2), 144.6 (C3), 150.3 (C4) (Found: C,
60.18; H, 8.22; N, 5.81. C12
N, 5.80%); m/e 241 (M ).
3
(
H
19NO
2
S requires C, 59.82; H, 7.94;
ϩ
2
,3-Dihydrothieno[3,4-b][1,4]dioxin, 2. Prepared by the liter-
4-[(3,4-Dimethoxythien-2-yl)methyl]morpholine, 5c. 53%, oil,
mp (methiodide) 143–145 ЊC; δ (CDCl ) 2.48–2.51 (4H, m,
4
ature method, employing DMF and potassium carbonate as
H
3
2
600 J. Chem. Soc., Perkin Trans. 1, 2001, 2595–2603

View Article Online
NCH ), 3.60 (2H, s, ArCH N), 3.68–3.72 (4H, m, CH OCH ),
OCH CH ), 1.24 (3H, t, J 6.93, OCH CH ), 2.48–2.52 (4H, m,
2 3 2 3
2
2
2
2
3
.81 (3H, s, ArOCH ), 3.82 (3H, s, ArOCH ), 6.10 (1H, s,
NCH ), 3.57 (2H, q, J 6.93, OCH CH ), 3.58 (2H, q, J 6.93,
3
3
2
2
3
Ar-H); δ (CDCl ) 53.2 (NCH ), 53.7 (ArCH N), 57.1 (OCH
OCH CH ), 3.64 (2H, s, ArCH N), 3.65–3.79 (4H, m, CH OEt
2 3 2 2
C
3
2
2
3
on C4), 60.8 (OCH on C3), 67.0 (morpholino OCH ), 94.5
and 4H, m, morpholino OCH ), 4.07–4.11 (2H, m, ArOCH ),
3
2
2
2
(
C5), 122.8 (C2), 144.9 (C3), 150.3 (C4) (Found: C, 54.29; H,
4.15–4.19 (2H, m, ArOCH ), 6.12 (1H, s, Ar-H); δ (CDCl )
2 C 3
7
5
.20; N, 5.74. C H NO S requires C, 54.30; H, 7.04; N,
.76%); m/e 243 (M ).
15.2 and 15.3 (OCH CH ), 53.2 (NCH ), 53.5 (ArCH N), 66.5,
11
17
3
2 3 2 2
ϩ
66.8, 68.8, 69.4, 69.5 and 72.0 (OCH ), 67.0 (morpholino
2
OCH ) 95.6 (C5), 123.2 (C2), 143.9 (C3), 149.2 (C4) (Found: C,
2
Compounds 6a–c. The analytical data for these compounds
agreed with the literature values.
56.59; H, 8.22; N, 3.82. C H NO S requires C, 56.8; H, 8.13;
17
29
5
1
N, 3.90%); m/e 314 (M Ϫ OEt).
N-[(2,3-Dihydrothieno[3,4-b][1,4]dioxin-5-yl)methyl]-N,N-
dimethylamine, 7a. 72%, oil, bp 115 ЊC/18 mmHg; δ (CDCl )
N,N-Dimethyl[(2,3,5,6-tetrahydrothieno[3,4-b][1,4,7]-
H
3
trioxonin-8-yl)methyl]amine, 9a. Purification by column
chromatography (alumina; light petroleum–EtOAc, 4 : 1) gave
the title compound (89%) as an oil, mp (methiodide) 178–180
ЊC; δ (CDCl ) 2.27 (6H, s, NCH ), 3.51 (2H, s, ArCH N), 3.87–
2
.27 (6H, s, N(CH ) ), 3.48 (2H, s, ArCH N), 4.18 (4H, s,
3
2
2
ArOCH ), 6.24 (1H, s, Ar-H); δ (CDCl ) 44.9 (NCH ), 53.8
2
C
3
3
(
ArCH N), 64.6 (ArOCH ), 97.6 (C5), 114.1 (C2), 139.2 (C3),
2
2
H
3
3
2
1
41.2 (C4) (Found: C, 53.96; H, 6.77; N, 6.88. C H NO S
9 13 2
ϩ
3
(
.92 (4H, m, CH OCH ), 4.24–4.29 (4H, m, ArOCH ), 6.49
2
2
2
requires C, 54.25; H, 6.58; N, 7.03%); m/e 199 (M ).
1H, s, Ar-H); δ (CDCl ) 45.2 (NCH ), 54.7 (ArCH N), 71.9,
C 3 3 2
7
2.3, 73.6, 74.3 (OCH ) (Found: C, 54.18; H, 7.25; N, 5.52.
2
1
-[(2,3-Dihydrothieno[3,4-b][1,4]dioxin-5-yl)methyl]piper-
C H NO S requires C, 54.30; H, 7.04; N, 5.76%); highest
fragment m/e 182.
11
17
3
idine, 7b. 82%, oil, mp (methiodide) 161–163 ЊC; δ (CDCl )
.47 (2H, quintet, J 5.61, CH CH CH ), 1.57 (4H, quintet,
2 2 2
H
3
1
J 5.61, CH CH CH ), 2.42–2.45 (4H, m, NCH ), 3.56 (2H, s,
2
2
2
2
Substitution at the 5-position: synthesis of the bis-Mannich
bases. General method
ArCH N), 4.17 (4H, s, ArOCH ), 6.22 (1H, s, Ar-H); δ (CDCl )
2
2
C
3
2
4.2 (CH CH CH ), 25.9 (CH CH CH ), 53.3 (ArCH N), 53.8
2 2 2 2 2 2 2
(
1
NCH ), 64.6 (ArOCH ), 97.5 (C5), 114.2 (C2), 139.2 (C3),
41.2 (C4) (Found: C, 60.11; H, 7.55; N, 5.67. C H NO S
12 17 2
ϩ
The bis-Mannich bases were obtained as by-products from the
mono-substitution reactions or were prepared by the reaction
of either: the mono-Mannich base (1.0 eq.) with the amine
2
2
requires C, 60.22; H, 7.16; N, 5.85%); m/e 239 (M ).
(
1.1 eq.) and aqueous formaldehyde (37%, 1.1 eq.) in glacial
4
-[(2,3-Dihydrothieno[3,4-b][1,4]dioxin-5-yl)methyl]morpho-
line, 7c. 52% (and 11c, 13%), oil, mp (methiodide) 116–118 ЊC;
δ (CDCl ) 2.45–2.49 (4H, m, NCH ), 3.55 (2H, s, ArCH N),
3 Ϫ1
acetic acid (1 cm mmol ); or the 3,4-dialkoxythiophene (1.0
eq.) with the amine (2.2 eq.) and aqueous formaldehyde (37%,
2.2 eq.) in glacial acetic acid (1 cm mmol ). Heat was applied
for 4 hours by means of an oil bath (100 ЊC). The cooled
reaction mixture was basified with aqueous sodium hydroxide
3
Ϫ1
H
3
2
2
3
.66–3.69 (4H, m, CH OCH ), 4.14 (4H, s, ArOCH ), 6.23
1H, s, Ar-H); δ (CDCl ) 52.9 (ArCH N), 53.0 (NCH ), 64.4
ArOCH ), 64.5 (ArOCH ), 66.8 (morpholino OCH ), 97.8
C5), 113.2 (C2), 139.4 (C3), 141.1 (C4) (Found: C, 54.66; H,
.54; N, 5.67. C H NO S requires C, 54.75; H, 6.27; N,
11 15 3
ϩ
.80%); m/e 241 (M ).
2
2
2
(
(
(
C 3 2 2
3
2
2
2
(4 M) and extracted with diethyl ether (3 × 30 cm ). The
ethereal portions were treated in the usual fashion. The bis-
Mannich bases were purified by centrifugal chromato-
graphy (alumina; light petroleum–EtOAc, 6 : 1) unless stated
otherwise.
6
5
N-{[3,4-Bis(2-ethoxyethoxy)thien-2-yl]methyl}-N,N-dimethyl-
amine, 8a. Purification by column chromatography (alumina;
light petroleum–EtOAc, 10 : 1) gave the title compound (12%)
as an oil; δ (CDCl ) 1.22 (3H, t, J 6.93, OCH CH ), 1.24 (3H, t,
2
,5-Bis(piperidin-1-ylmethyl)-3,4-dimethoxythiophene, 10b.
Purification by centrifugal chromatography (alumina; light
petroleum–EtOAc, 30 : 1) gave the title compound (27%) as
an oil; δ (CDCl ) 1.41 (4H, quintet, J 5.61, CH CH CH ),
.57 (8H, quintet, J 5.61, CH CH CH ), 2.41–2.45 (8H, m,
CH NCH ), 3.55 (4H, s, ArCH N), 3.81 (6H, s ArOCH );
δ (CDCl ) 24.3 (CH CH CH ), 26.0 (CH CH CH ), 54.1
NCH ), 54.1 (ArCH N), 60.7 (ArOCH ), 121.4 (C2/C5), 146.8
C3/C4) (Found: C, 63.89; H, 9.17; N, 8.19. C H N O S
requires C, 63.87; H, 8.93; N, 8.28%); m/e 241 (M Ϫ
H
3
2
3
J 5.61, OCH CH ), 2.27 (6H, s, NCH ), 3.57 (2H, s, ArCH N),
2
3
3
2
H
3
2
2
2
3
3
4
.57 (2H, q, J 6.93, OCH CH ), 3.58 (2H, q, J 5.61, OCH CH ),
2
3
2
3
1
2 2 2
.65–3.69 (2H, m, CH OEt), 3.76–3.79 (2H, m, CH OEt), 4.08–
2
2
2
2
2
3
.11 (2H, m, ArOCH ), 4.14–4.18 (2H, m, ArOCH ), 6.12 (1H,
2
2
C
3
2
2
2
2
2
2
s, Ar-H); δ (CDCl ) 15.2 and 15.3 (OCH CH ), 45.1 (NCH ),
C
3
2
3
3
(
(
2
2
3
5
4.4 (ArCH N), 66.5, 66.8, 68.8, 69.4, 69.5 and 72.0 (OCH ),
2
2
1
8
30
2
2
9
5.4 (C5), 124.4 (C2), 143.5 (C3), 149.1 (C4) (Found: C, 56.71;
H, 8.92; N, 4.59. C H NO S requires C, 56.75; H, 8.57; N,
15
27
4
CH N(CH ) ).
2
2 5
4
.41%); m/e 273 (M Ϫ N(Me) ).
2
2
,5-Bis(morpholin-4-ylmethyl)-3,4-dimethoxythiophene, 10c.
1
-{[3,4-Bis(2-ethoxyethoxy)thien-2-yl]methyl}piperidine, 8b.
7
8%, mp 85.5–87.5 ЊC; δ (CDCl ) 2.48–2.51 (8H, m, CH -
NCH ), 3.57 (4H, s, ArCH N), 3.69–3.72 (8H, m, CH OCH ),
.82 (6H, s ArOCH ); δ (CDCl ) 53.2 (NCH ), 53.7 (ArCH N),
0.8 (ArOCH ), 67.0 (CH OCH ), 120.8 (C2/C5), 147.2 (C3/
C4) (Found: C, 56.29; H, 7.93; N, 8.35. C H N O S requires
C, 56.12; H, 7.65; N, 8.18%); m/e 240 (M Ϫ CH N(CH CH ) O
Ϫ 2H).
Purification by column chromatography (alumina; light
petroleum–EtOAc, 10 : 1) gave the title compound (42%) as an
oil; δ (CDCl ) 1.22 (3H, t, J 6.93, OCH CH ), 1.24 (3H, t,
J 6.93, OCH CH ), 1.42 (2H, quintet, J 5.61, CH CH CH ),
.56 (4H, quintet, J 5.61, CH CH CH ), 2.41 (4H, m, NCH ),
H
3
2
2
2
2
2
3
6
3 C 3 2 2
H
3
2
3
3
2
2
2
3
2
2
2
1
3
3
16 26
2
4
2
2
2
2
.56 (2H, q, J 6.93, OCH CH ), 3.58 (2H, q, J 6.93, OCH CH ),
.62 (2H, s, ArCH N), 3.64–3.69 (2H, m, CH OEt), 3.76–3.79
2
2
2 2
2
3
2
3
2
2
(
2H, m, CH OEt), 4.07–4.11 (2H, m, ArOCH ), 4.14–4.17 (2H,
2
2
m, ArOCH ), 6.09 (1H, s, Ar-H); δ (CDCl ) 15.2 and 15.3
2,5-Bis(piperidin-1-ylmethyl)-2,3-dihydrothieno[3,4-b][1,4]-
CDCl ) 1.39 (4H, quintet,
2
C
3
OCH CH ), 24.3 (CH CH CH ), 26.0 (CH CH CH ), 54.1
NCH ), 53.9 (ArCH N), 66.5, 66.8, 68.9, 69.4, 69.5 and 72.0
OCH ), 95.2 (C5), 124.3 (C2), 143.5 (C3), 149.2 (C4) (Found:
dioxin, 11b. 86%, mp 98–100 ЊC; δH(
CH CH ), 1.58 (8H, quintet, J 5.61, CH CH CH ),
3
(
(
(
2
3
2
2
2
2
2
2
J 5.61, CH
2.43–2.46 (8H, m, CH
; δ (CDCl ) 24.2 (CH CH CH ), 26.0 (CH CH -
2
2
2
2
2
2
2
2
NCH ), 3.56 (4H, s, ArCH N), 4.16 (4H,
2
2
2
2
C, 60.46; H, 9.17; N, 3.90. C H NO S requires C, 60.47; H,
8
s ArOCH2)
, 53.2 (NCH ), 53.9 (ArCH N), 64.6 (ArOCH ), 111.8
C
3
2
2
2
2
2
18
31
4
.74; N, 3.92%); m/e 155 (M Ϫ N(CH ) Ϫ 2(CH OEt)).
CH2)
C2/C5), 138.6 (C3/C4) (Found: C, 64.26; H, 8.61; N, 8.30.
C H N O S requires C, 64.25; H, 8.39; N, 8.33%); m/e 336
2
2
2
2
5
2
(
4
-{[3,4-Bis(2-ethoxyethoxy)thien-2-yl]methyl}morpholine, 8c.
1
8
28
2
2
ϩ
4
6% (and 12c, 24%), oil; δ (CDCl ) 1.22 (3H, t, J 6.93,
(M ).
H
3
J. Chem. Soc., Perkin Trans. 1, 2001, 2595–2603
2601

View Article Online
2
,5-Bis(morpholin-4-ylmethyl)-2,3-dihydrothieno[3,4-b][1,4]-
formaldehyde (37%, 2.0 eq.) with ice cooling. The solutions
were fed separately and simultaneously into glacial acetic acid
dioxin, 11c. 91%, mp 83–85 ЊC; δ (CDCl ) 2.49–2.52 (8H,
m, CH NCH ), 3.56 (4H, s, ArCH N), 3.69–3.73 (8H, m,
CH OCH ), 4.17 (4H, s, ArOCH ); δ (CDCl ) 52.9 (ArCH N),
3.0 (NCH ), 64.7 (ArOCH ), 66.9 (CH OCH ), 111.4 (C2/C5),
38.9 (C3/C4) (Found: C, 56.43; H, 7.18; N, 8.42. C H N O S
requires C, 56.45; H, 7.11; N, 8.23%); m/e 254 (M Ϫ
N(CH CH ) O).
H
3
3
Ϫ1
(0.3 cm mmol ) by means of a syringe pump with stirring.
After addition was complete, the solution was stirred for a
further 12 hours. The solvent was removed in vacuo to give
a dark oily residue. The work-up was similar to that applied
to the mono-Mannich bases. Purification by column chrom-
atography (alumina; light petroleum–EtOAc, 5 : 1) gave
the required Mannich base. Also isolated in these experiments
were a series of oligomeric Mannich bases containing three
thiophene moieties, 17, 19a–c and 23.
2
2
2
2
2
2
C
3
2
5
1
2 2 2 2
16
24
2
4
2
2 2
2
,5-Bis(piperidin-1-ylmethyl)-3,4-bis(2-ethoxyethoxy)thio-
phene, 12b. 35%, oil; δ (CDCl ) 1.23 (6H, t, J 6.93, OCH CH ),
.39 (4H, quintet, J 5.61, CH CH CH ), 1.57 (8H, quintet,
2 2 2
H
3
2
3
1
J 5.61, CH CH CH ), 2.43–2.46 (8H, m, CH NCH ), 3.56 (4H,
N,N-Bis[(2,3-dihydrothieno[3,4-b][1,4]dioxin-5-yl)methyl]-N-
methylamine, 16. 37%, mp 78–80 ЊC; δ (CDCl ) 2.29 (3H, s,
2
2
2
2
2
q, J 6.93, OCH CH ), 3.62 (4H, s, ArCH N), 3.64–3.69 (4H,
2
3
2
H
3
m, CH OEt), 4.11–4.15 (4H, m, ArOCH ); δ (CDCl ) 15.3
NCH ), 3.65 (4H, s, ArCH N), 4.18 (8H, s, ArOCH ), 6.25 (2H,
2
2
C
3
3
2
2
(
(
(
OCH CH ), 24.3 (CH CH CH ), 26.0 (CH CH CH ), 53.5
s, Ar-H); δ (CDCl ) 41.7 (NCH ), 51.0 (ArCH N), 64.7
C 3 3 2
2
3
2
2
2
2
2
2
ArCH N), 54.1 (NCH ), 66.6, 69.4 and 72.4 (OCH ), 121.8
(ArOCH ), 97.8 (C5), 114.6 (C2), 139.2 (C3), 141.2 (C4)
2
2
2
2
C2/C5), 145.7 (C3/C4) (Found: C, 63.51; H, 9.50; N, 6.05.
(Found: C, 53.20; H, 5.05; N, 4.06. C H NO S requires C,
15
17
4 2
ϩ
C H N O S requires C, 63.40; H, 9.31; N, 6.16%); m/e 454
53.08; H, 5.05; N, 4.13%); m/e 339 (M ).
2
4
42
2
4
ϩ
(
M ).
5
,7-Bis{[2,3-dihydrothieno[3,4-b][1,4]dioxin-5-ylmethyl-
methyl)amino]methyl}-2,3-dihydrothieno[3,4-b][1,4]dioxin, 17.
21%, oil; δ (CDCl ) 2.28 (6H, s, NCH ), 3.63, 3.64 (4H, s,
2
,5-Bis(morpholin-4-ylmethyl)-3,4-bis(2-ethoxyethoxy)thio-
(
phene, 12c. 24%, oil; δ (CDCl ) 1.23 (6H, t, J 6.93, OCH CH ),
.49–2.52 (8H, m, CH NCH ), 3.56 (4H, q, J 6.93, OCH CH ),
2 2 2 3
.61 (4H, s, ArCH N), 3.64–3.68 (4H, m, CH OEt), 3.69–3.73
8H, m, morpholino OCH ), 4.12–4.16 (4H, m, ArOCH );
δ (CDCl ) 15.3 (OCH CH ), 53.2 (NCH ), 53.6 (ArCH N),
6.6, 69.4 and 72.4 (OCH ), 67.0 (morpholino OCH ), 121.5
C2/C5), 146.1 (C3/C4) (Found: C, 57.80; H, 8.35; N, 5.99.
H
3
2
3
H
3
3
2
3
(
ArCH N), 4.16 (4H, s, ArOCH ), 4.17 (8H, s, ArOCH ), 6.23
(2H, s, Ar-H); δ (CDCl ) 41.5 (NCH ), 50.8, 50.9 (ArCH N),
C 3 3 2
64.6 (ArOCH ), 97.9 (C5Ј), 112.1 (C2/C5), 114.2 (C2Ј), 138.7
(C3/C4), 139.3 (C3Ј), 141.2 (C4Ј).
2
2
2
2
2
2
2
2
C
3
2
3
2
2
6
(
2
2
1
2
N ,N -Bis(2,3-dihydrothieno[3,4-b][1,4]dioxin-5-ylmethyl)-
1
2
C H N O S requires C, 57.62; H, 8.35; N, 6.11%); m/e 458
2
2
38
2
6
N ,N -dimethylethane-1,2-diamine, 18a. 45%, mp 75.5–77.5 ЊC,
ϩ
(
M ).
δ (CDCl ) 2.29 (6H, s, N(CH )), 2.58 (4H, s, R NCH ), 3.63
H
3
3
2
2
(
4H, s, ArCH N), 4.17 (8H, s, ArOCH ), 6.25 (2H, s, Ar-H);
2
n
N,N-Dimethyl-N-{[7-(piperidin-1-ylmethyl)-2,3-dihydrothieno-
3,4-b][1,4]dioxin-5-yl]methyl}amine, 13. 54%, oil; δ (CDCl )
δ (CDCl ) 42.4 (NCH ), 52.0 (NCH ), 54.2 (ArCH N), 64.6
and 64.7 (ArOCH ), 97.7 (C5), 114.0 (C2), 139.3 (C3), 141.2
(C4) (Found: C, 54.62; H, 6.18; N, 6.77; C H N O S requires
C, 54.52; H, 6.10; N, 7.07%); m/e 396 (M ).
C
3
3
2
2
[
H
3
2
1
.39 (2H, quintet, J 5.61, CH CH CH ), 1.56 (4H, quintet,
2 2 2
18
24
2
4 2
J 5.61, CH CH CH ), 2.21 (6H, s, N(CH ) ), 2.41–2.44 (4H, m,
ϩ
2
2
2
3
2
CH NCH ), 3.51 (2H, s, ArCH N), 3.53 (2H, s, ArCH N),
2
2
2
2
4
.17 (4H, s, ArOCH ); δ (CDCl ) 24.1 (CH CH CH ), 25.9
1
3
2
C
3
2
2
2
N ,N -Bis(2,3-dihydrothieno[3,4-b][1,4]dioxin-5-ylmethyl)-
(
CH CH CH ), 45.0 (NCH ), 53.0 (ArCH N), 53.2 (NCH ),
1
3
2
2
2
3
2
2
N ,N -dimethylpropane-1,3-diamine, 18b. 12%, oil, δ (CDCl )
1.73 (2H, quintet, J 7.59 Hz, CH CH CH ), 2.26 (6H, s,
N(CH )), 2.39–2.44 (4H, s, R NCH ), 3.58 (4H, s, ArCH N),
H
3
5
1
4.2 (ArCH N), 64.6, 64.7 (ArOCH ), 110.8, 112.5 (C2/C5),
38.5, 138.9 (C3/C4).
2
2
2 2 2
3
2
2
2
4
.16 (8H, s, ArOCH ), 6.22 (2H, s, Ar-H); δ (CDCl ) 25.2
n
C
3
N,N-Dimethyl-N-{[7-(morpholin-4-ylmethyl)-2,3-dihydro-
thieno[3,4-b][1,4]dioxin-5-yl]methyl}amine, 14. 74%, oil;
(
CH CH CH ), 42.2 (NCH ), 52.0 (NCH ), 54.2 (ArCH N),
2 2 2 3 2 2
6
1
4.3 and 64.6 (ArOCH ), 97.5 (C5), 114.5 (C2), 139.1 (C3),
2
δ (CDCl ) 2.21 (6H, s, N(CH ) ), 2.50–2.52 (4H, m,
H
3
3 2
41.2 (C4) (Found: C, 55.52; H, 6.58; N, 6.99. C H N O S
19
20
2
4 2
CH NCH ), 3.52 (2H, s, ArCH N), 3.53 (2H, s, ArCH N),
ϩ
2
2
2
2
requires C, 55.59; H, 6.38; N, 6.82%); m/e 410 (M ).
3
.68–3.72 (4H, m, CH OCH ), 4.17 (4H, s, ArOCH );
2
2
2
δ (CDCl ) 44.9 (NCH ), 53.0 (ArCH N), 53.8 (NCH ), 54.6
C
3
3
2
2
1
,4-Bis(2,3-dihydrothieno[3,4-b][1,4]dioxin-5-ylmethyl)piper-
(
ArCH N), 64.6, 64.7 (ArOCH ), 67.2 (CH OCH ), 110.7,
2
2
2
2
azine, 18c. 22%, mp 158 ЊC (decomp.), δ (CDCl ) 2.55 (6H, s,
N(CH )), 2.55 (4H, s, R NCH ), 3.59 (4H, s, ArCH N), 4.17
8H, s, ArOCH ), 6.22 (2H, s, Ar-H); δ (CDCl ) 52.4 (NCH ),
2.5 (ArCH N), 64.6 (ArOCH ), 97.7 (C5), 113.6 (C2), 139.3
2 2
H
3
1
12.4 (C2/C5), 138.5, 138.9 (C3/C4).
-{[7-(Piperidin-1-ylmethyl)-2,3-dihydrothieno[3,4-b][1,4]-
3
2
2
2
(
5
(
n C 3 2
4
dioxin-5-yl]methyl}morpholine, 15. 91%, mp 64–66 ЊC;
C3), 141.2 (C4) (Found: C, 55.52; H, 6.58; N, 6.99.
δ (CDCl ) 1.40 (2H, quintet, J 5.61, CH CH CH ), 1.58 (4H,
H
3
2
2
2
C H N O S requires C, 55.59; H, 6.38; N, 6.82%); m/e 394
1
8
22
2
4 2
quintet, J 5.61, CH CH CH ), 2.42–2.45 (4H, m, piperidino
ϩ
2
2
2
(
M ).
CH NCH ), 2.49–2.52 (4H, m, morpholino CH NCH ),
2
2
2
2
3
.55 (2H, s, ArCH N), 3.56 (2H, s, ArCH N), 3.69–3.73 (4H,
2
2
5
,7-Bis{[{2-[(2,3-dihydrothieno[3,4-b][1,4]dioxin-5-ylmethyl)-
m, CH OCH ), 4.17 (4H, s, ArOCH ); δ (CDCl ) 24.2
2
2
2
C
3
(
[
methyl)amino]ethyl}(methyl)amino]methyl}-2,3-dihydrothieno-
3,4-b][1,4]dioxin, 19a. 7%, oil; δ (CDCl ) 2.30 (6H, s,
N(CH )), 2.31 (6H, s, N(CH )), 2.62 (8H, m, NCH ), 3.61 (4H,
s, ArCH N), 3.62 (4H, s, ArCH N), 4.16 (8H, s, ArOCH ), 4.18
8H, s, ArOCH ), 6.24 (2H, s, Ar-H); δ (CDCl ) 42.3, 42.4
(
CH CH CH ), 26.0 (CH CH CH ), 52.9 (ArCH N), 53.0
2 2 2 2 2 2 2
H
3
(
NCH ), 53.2 (ArCH N), 53.9 (NCH ), 64.6, 64.7 (ArOCH ),
2 2 2 2
3
3
2
6
7.0 (CH OCH ), 110.8, 112.3 (C2/C5), 138.6, 138.9 (C3/C4)
2 2
2
2
2
(
Found: C, 60.12; H, 7.91; N, 8.04. C H N O S requires C,
17 26 2 3
(
(
2
C
3
6
0.33; H, 7.74; N, 8.28%); m/e 252 (M Ϫ N(CH CH ) O).
2 2 2
NCH ), 51.8, 52.0 (NCH ), 54.1, 54.2 (ArCH N), 64.6
3
2
2
(
1
ArOCH ), 97.7 (C Ј), 111.7 (C /C ), 114.0 (C Ј), 138.8 (C /C ),
2 5 2 5 2 3 4
Linking the thiophene moieties: synthesis of bis(thien-2-ylmethyl)
Mannich bases. General method
39.3 (C Ј), 141.2 (C Ј).
3 4
The thiophene moiety (2.0 eq.) was dissolved in glacial acetic
5,7-Bis{[{3-[(2,3-dihydrothieno[3,4-b][1,4]dioxin-5-ylmethyl)-
3
Ϫ1
acid (1.25 cm mmol ). To an equal volume of glacial acetic
acid was added the secondary diamine or primary amine (40%
aqueous solution for methylamine) (1.0 eq.) and aqueous
(methyl)amino]propyl}(methyl)amino]methyl}-2,3-dihydrothieno-
[3,4-b][1,4]dioxin, 19b. 6%, oil; δ (CDCl ) 1.70–1.78 (4H, m,
H
3
CH CH CH ), 2.27 (12H, s, N(CH )), 2.41 (8H, m, NCH ), 3.61
2
2
2
3
2
2
602
J. Chem. Soc., Perkin Trans. 1, 2001, 2595–2603

View Article Online
(
8H, s, ArCH N), 4.17 (12H, s, ArOCH ), 6.23 (2H, s, Ar-H);
2.48–2.51 (8H, m, NCH ), 2.56 (4H, s, bridging NCH ), 3.55
2 2
2
2
δ (CDCl ) 24.7 (CH CH CH ), 41.9, 42.0 (NCH ), 52.9,
(4H, s, morpholino ArCH N), 3.60 (4H, s, bridging ArCH N),
C
3
2
2
2
3
2
2
5
3.0 (NCH ), 54.4 (ArCH N), 64.6 (ArOCH ), 97.8 (C Ј), 112.3
3.68–3.72 (8H, m, morpholino OCH ), 4.17 (8H, s, ArOCH );
2 2
2
2
2
5
(
C /C ), 113.7 (C Ј), 138.1 (C /C ), 139.3 (C Ј), 141.2 (C Ј).
δ (CDCl ) 42.4 (NCH ), 52.0 (bridging CH N), 52.9 (mor-
C 3 3 2
2
5
2
3
4
3
4
pholino ArCH N), 53.0 (morpholino CH N), 64.6 (ArOCH ),
2
2
2
5
,7-Bis{[4-(2,3-dihydrothieno[3,4-b][1,4]dioxin-5-ylmethyl)-
64.7 (ArOCH ), 67.0 (morpholino CH O), 111.0 (C ), 112.3
(C ), 138.7 (C ), 138.9 (C ) (Found: C, 56.39; H, 7.23; N, 9.28.
2 3 4
2
2
5
piperazin-1-yl]methyl}-2,3-dihydrothieno[3,4-b][1,4]dioxin, 19c.
%, mp 285 ЊC (decomp.); δ (CDCl ) 2.55 (16H, s, NCH ), 3.56
4H, s, ArCH N), 3.60 (4H, s, ArCH N), 4.16 (8H, s, ArOCH ),
9
(
C H N O S requires C, 56.54; H, 7.12; N, 9.42%); m/e 594
H
3
2
28 42
4
6 2
ϩ
(M ).
2
2
2
4
.17 (8H, s, ArOCH ), 6.22 (2H, s, Ar-H); δ (CDCl ) 52.4
2
C
3
1
3
1
3
(
NCH ), 52.5 (ArCH N), 64.6 (ArOCH ), 97.7 (C Ј), 111.5 (C /
N ,N -Dimethyl-N ,N -bis{[7-(morpholin-4-ylmethyl)-2,3-
dihydrothieno[3,4-b][1,4]dioxin-5-yl]methyl}propane-1,3-
diamine, 25b. 92%, oil; δ (CDCl ) 1.73 (2H, quintet, J 7.59 Hz,
2
2
2
5
2
C ), 113.6 (C Ј), 138.8 (C /C ), 139.3 (C Ј), 141.3 (C Ј) (Found:
C, 55.71; H, 5.85; N, 8.46. C H N O S requires C, 55.71; H,
5
2
3
4
3
4
30
38
4
6
3
H
3
ϩ
5
.92; N, 8.66%); m/e 646 (M ).
CH CH CH ), 2.25 (6H, s, N(CH )), 2.39–2.45 (4H, m, bridg-
2 2 2 3
ing NCH ), 2.48–2.51 (8H, m, morpholino NCH ), 3.55 (8H, s,
2
2
1
2
1
2
N ,N -Dimethyl-N ,N -bis(2,3,5,6-tetrahydrothieno[3,4-b]-
1,4,7]trioxonin-8-ylmethyl)ethane-1,2-diamine, 22. 46%, oil;
δ (CDCl ) 2.28 (6H, s, N(CH )), 2.57 (4H, s, R NCH ), 3.62
ArCH
ArOCH
ArCH N), 52.9 (morpholino ArCH
CH N), 64.6 (ArOCH ), 67.0 (morpholino CH
111.6 (C ), 138.8 (C ), 138.9 (C ) (Found: C, 56.93; H, 7.46; N,
9.60. C ϩ2 9 requires C, 57.21; H, 7.29; N, 9.20%); m/e
608 (M ).
2
N), 3.68–3.72 (8H, m, morpholino OCH ), 4.16 (8H, s,
2
[
); δ
2
C
(CDCl
3
) 52.4 (bridging CH
N), 53.1 (morpholino
O), 111.2 (C ),
2
N), 52.4 (bridging
H
3
3
2
2
2
2
(
4H, s, ArCH N), 3.84–3.89 (8H, m, CH OCH ), 4.21–4.27
8H, m, ArOCH ), 6.46 (2H, s, Ar-H); δ (CDCl ) 42.5 (NCH ),
3.0 (NCH ), 54.5 (ArCH N), 71.8, 72.2, 73.5, 74.2 (ArOCH
and OCH ), 105.6 (C ), 112.7 (C ), 146.6 (C ), 149.4 (C )
2
2
2
5
2
2
2
(
2
3
4
n
C
3
3
5
H N O S
44 4 6 2
2
2
2
2
5
2
3
4
(
5
Found: C, 54.68; H, 6.81; N, 5.98. C H N O S requires C,
6.40; H, 6.66; N, 5.78%); m/e 484 (M ).
22
ϩ
32
2
6 2
1,4-Bis{[7-(morpholin-4-ylmethyl)-2,3-dihydrothieno[3,4-b]-
1,4]dioxin-5-yl]methyl}piperazine, 25c. 83%, mp 220 ЊC
[
8
,10-Bis{[{2-[(2,3,5,6-tetrahydrothieno[3,4-b][1,4,7]trioxonin-
(decomp.); δ
2.55 (8H, m, bridging NCH
ArCH N), 3.59 (4H, s, bridging ArCH
morpholino OCH ), 4.16 (8H, s, ArOCH
(bridging CH N), 52.4 (bridging ArCH N), 52.9 (morpholino
ArCH N), 53.1 (morpholino CH N), 64.6 (ArOCH ), 67.0
(morpholino CH O), 111.2 (C ), 111.6 (C ), 138.8 (C ), 138.9
(C ) (Found: C, 56.59; H, 6.79; N, 9.65. C28 requires
H
(CDCl
3
) 2.48–2.51 (8H, m, morpholino NCH
), 3.54 (4H, s, morpholino
N), 3.68–3.73 (8H, m,
); δ (CDCl ) 52.4
),
2
8
-ylmethyl)(methyl)amino]ethyl}(methyl)amino]methyl}-2,3,5,6-
tetrahydrothieno[3,4-b][1,4,7]trioxonin, 23. 5%, oil; δ (CDCl )
.32 (6H, s, N(CH )), 2.33 (6H, s, N(CH )), 2.69 (8H, s, NCH ),
.71 (4H, s, ArCH N), 3.72 (4H, s, ArCH N), 3.87–3.88 (12H,
m, CH OCH ), 4.23–4.31 (12H, m, ArOCH ), 6.52 (2H, s,
Ar-H); δ (CDCl ) 41.7 (NCH ), 52.1, 52.3 (NCH ), 53.1
ArCH N), 71.6, 71.7, 72.4, 72.9, 73.3 (OCH ), 106.8 (C Ј),
18.9 (C /C ), 119.9 (C Ј), 146.7 (C Ј), 147.0 (C /C ), 149.5
2
H
3
2
2
2
3
2
2
C
3
3
3
2
2
2
2
2
2
2
2
2
2
2
C
3
3
2
2
5
2
3
(
1
4
H N O S
40 4 6 2
ϩ
2
2
5
C, 56.73; H, 6.80; N, 9.45%); m/e 592 (M ).
2
5
2
3
3
4
(
C Ј).
4
References
Substitution at the 5-position of the thien-2-ylmethyl Mannich
bases: bis-morpholino derivatives of the bis(thien-2-ylmethyl)
Mannich bases. General method
1 J. M. Barker, P. R. Huddleston and M. L. Wood, Synth. Commun.,
975, 5, 59.
E. W. Fager, J. Am. Chem. Soc., 1945, 67, 2217.
3 C. G. Overberger and J. Lal, J. Am. Chem. Soc., 1951, 73,
956.
1
2
To the bis(thien-2-ylmethyl) Mannich base (0.50 g) in glacial
3
2
acetic acid (3 cm ), cooled in ice, was added aqueous formalde-
4
5
F. Dallacker and V. Mues, Chem. Ber., 1975, 108, 576.
Y. Jasor, M.-J. Luche, M. Gaudry and A. Marquet, J. Chem. Soc.,
Chem. Commun., 1974, 253.
J. M. Barker, J. D. E. Chaffin, J. Halfpenny, P. R. Huddleston and
P. F. Tseki, J. Chem. Soc., Chem. Commun., 1993, 1733.
hyde (37%, 2.2 eq.) and morpholine (2.2 eq.). The mixture
was stirred for 12 hours. Basification with aqueous sodium
hydroxide (4 M) was followed by extraction with dichlorometh-
6
3
ane (3 × 10 cm ). The organic phase was worked up in the usual
manner, and the crude product was then purified by column
chromatography (alumina; light petroleum–EtOAc, 4 : 1).
7 J. Halfpenny and Z. S. Sloman, J. Chem. Soc., Perkin Trans. 1, 2000,
877.
J. Halfpenny, P. B. Rooney and Z. S. Sloman, Tetrahedron Lett.,
000, 41, 6223.
Q. Pei, G. Zuccarello, M. Ahlskog and O. Inganas, Polymer, 1994,
5, 1347.
10 MOPAC, J. J. P. Stewart, J. Comput. Aid. Mol. Des., 1990, 4(1), 1.
11 Gaussian 98, Revision A.7, M. J. Frisch, G. W. Trucks, H. B.
Schlegel, G. E. Scuseria, M. A. Robb, J. R. Cheeseman, V. G.
Zakrzewski, J. A. Montgomery Jr., R. E. Stratmann, J. C. Burant,
S. Dapprich, J. M. Millam, A. D. Daniels, K. N. Kudin, M. C.
Strain, O. Farkas, J. Tomasi, V. Barone, M. Cossi, R. Cammi,
B. Mennucci, C. Pomelli, C. Adamo, S. Clifford, J. Ochterski, G. A.
Petersson, P. Y. Ayala, Q. Cui, K. Morokuma, D. K. Malick, A. D.
Rabuck, K. Raghavachari, J. B. Foresman, J. Cioslowski, J. V. Ortiz,
A. G. Baboul, B. B. Stefanov, G. Liu, A. Liashenko, P. Piskorz,
I. Komaromi, R. Gomperts, R. L. Martin, D. J. Fox, T. Keith, M. A.
Al-Laham, C. Y. Peng, A. Nanayakkara, C. Gonzalez,
M. Challacombe, P. M. W. Gill, B. Johnson, W. Chen, M. W. Wong,
J. L. Andres, M. Head-Gordon, E. S. Replogle and J. A. Pople,
Gaussian, Inc., Pittsburgh, PA, USA, 1998.
1
8
9
2
N-Methyl-N,N-bis{[7-(morpholin-4-ylmethyl)-2,3-dihydro-
thieno[3,4-b][1,4]dioxin-5-yl]methyl}amine, 24. 97%, mp
3
9
0–92 ЊC; δ (CDCl ) 2.28 (3H, s, N(CH )), 2.49–2.53 (8H, m,
H
3
3
NCH ), 3.57 (4H, s, morpholino ArCH N), 3.61 (4H, s, bridging
2
2
ArCH N), 3.70–3.73 (8H, m, morpholino OCH ), 4.17 (8H, s,
2
2
ArOCH ); δ (CDCl ) 41.7 (NCH ), 51.0 (bridging ArCH N),
2
C
3
3
2
5
2.9 (morpholino ArCH N), 53.0 (morpholino CH N), 64.6
2
2
(
ArOCH ), 64.7 (ArOCH ), 67.0 (morpholino CH O), 111.1
2
2
2
(
C ), 112.8 (C ), 138.7 (C ), 138.9 (C ) (Found: C, 55.91; H,
5 2 3 4
6
7
.43; N, 7.66. C H N O S requires C, 55.85; H, 6.56; N,
25 35 3 6 2
ϩ
.62%); m/e 537 (M ).
1
2
1
2
N ,N -Dimethyl-N ,N -bis{[7-(morpholin-4-ylmethyl)-2,3-
dihydrothieno[3,4-b][1,4]dioxin-5-yl]methyl}ethane-1,2-diamine,
5a. 97%, mp 111–113 ЊC; δ (CDCl ) 2.27 (6H, s, N(CH )),
2
H
3
3
J. Chem. Soc., Perkin Trans. 1, 2001, 2595–2603
2603