The preparation of novel thiophene-based macrocyclic Mannich bases

Article abstract of DOI:10.1039/b007661i

A range of macrocyclic thiophene-based Mannich bases containing 10-22-membered rings has been prepared. The starting materials for the synthesis were substances of the type ArO-Z-OAr (where Ar = 2-methoxycarbonyl-3-thienyl and Z = alkyl or heteroalkyl), which were made by the reaction of α,ω -dihalides or -bis(toluene-p-sulfonate)s with two moles of methyl 3-hydroxythiophene-2-carboxylate. Saponification and subsequent decarboxylation of these compounds afforded the corresponding α,ω-bis(3-thienyloxy)alkanes. Macrocyclic Mannich bases were prepared from these ethers by aminomethylation. High dilution conditions were not required in many cases and, in the case of the heteroalkyl-bridged ethers, this is believed to be due to an internal template effect enhancing the yield.

Full text of DOI:10.1039/b007661i

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The preparation of novel thiophene-based macrocyclic Mannich
bases
Julie D. E. Chaffin,* John M. Barker and Patrick R. Huddleston
1
Department of Chemistry and Physics, Nottingham Trent University, Clifton Lane,
Nottingham, UK NG11 8NS
Received (in Cambridge, UK) 21st September 2000, Accepted 6th April 2001
First published as an Advance Article on the web 29th May 2001
A range of macrocyclic thiophene-based Mannich bases containing 10–22-membered rings has been prepared. The
starting materials for the synthesis were substances of the type ArO–Z–OAr (where Ar = 2-methoxycarbonyl-3-
thienyl and Z = alkyl or heteroalkyl), which were made by the reaction of α,ω-dihalides or -bis(toluene-p-sulfonate)s
with two moles of methyl 3-hydroxythiophene-2-carboxylate. Saponification and subsequent decarboxylation of
these compounds afforded the corresponding α,ω-bis(3-thienyloxy)alkanes. Macrocyclic Mannich bases were
prepared from these ethers by aminomethylation. High dilution conditions were not required in many cases and,
in the case of the heteroalkyl-bridged ethers, this is believed to be due to an internal template effect enhancing the
yield.
Thiophene-based macrocycles of the crown ether type have not
been widely reported, probably due to the poor donor prop-
erties of the thiophene sulfur atom and the inaccessibility of
dihydroxythiophenes of the type that would be necessary for
the crown ether syntheses. However, thiophene does have some
advantages over its oxygen and nitrogen counterparts. Thio-
phene derivatives are generally more stable and their reactivity
is comparable to that of their benzene analogues; the possibility
of desulfurisation adds further interest. A useful summary
of this area of work was written by Russell and Press in
1996;1 prior to this there had been no major reviews since
Meth-Cohn2 and Newkome et al.3 published their reports in the
1970’s. More recently there has been interest in the synthesis
and complexation properties of tetraimines, as precursors to
cyclic amines.4–6 A number of papers have described the prepar-
ation of thiophene-based crown esters and amides;7–9 generally,
there is a significant decrease in complexation ability when ester
groups replace ether oxygens in the crown. Thiacrown transi-
tion metal complexes are of interest due to their similarity to
systems of biological importance. A range of examples has
been prepared by the action of a dithiol on a bis(halomethyl)-
thiophene derivative under conditions of high dilution.10
Several groups have described the synthesis of thiophene-based
macrocycles incorporating polyethereal linkages.11–15 Use of the
(modified) Mannich reaction to prepare macrocycles (but not in
the macrocyclisation step) has been widely documented16 but as
far as we are aware, its use in thiophene-based systems is novel
and there have been no reports of thiophene-based lariat ether
systems. A preliminary account of the present work has been
published.17
Results and discussion
Initial work was concentrated on the preparation of thiophene
derivatives which were only substituted in the 2- and
3-positions. The preparation of the necessary intermediates and
of the open chain bis Mannich bases derived from them is
shown in Scheme 1.
A range of compounds with the formula ArO–Z–OAr
(where Ar = 2-methoxycarbonyl-3-thienyl) was prepared by the
coupling of α,ω-dihalides (Z = alkyl) or selected bis(toluene-p-
Scheme
1
Preparation and modification of α,ω-bis(2-methoxy-
carbonyl-3-thienyloxy)alkanes. For the nature of Z, see Table 1.
Reagents and conditions: (i) Br–Z–Br or TsO–Z–OTs (Ts = p-
tolylsulfonyl), K2CO3, DMF, 95–100 ЊC or Me2CO–∆; (ii) KOH, EtOH
(aq.), ∆ then Hϩ; (iii) Cu2O, C5H5N (py), ∆; (iv) R1R2NH, HCHO,
glacial AcOH, ∆ or RT.
1398
J. Chem. Soc., Perkin Trans. 1, 2001, 1398–1405
This journal is © The Royal Society of Chemistry 2001
DOI: 10.1039/b007661i

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Table 1 Classification of and abbreviations for Z
Class
Z
Abbreviation
a
b
c
d
e
f
g
h
i
CH2
(CH2)2
(CH2)3
(CH2)4
(CH2)6
(CH2)8
(CH2)10
(CH2)2O(CH2)2
(CH2)2O(CH2)2O(CH2)2
(CH2)2S(CH2)2
(CH2)2NTs(CH2)2
C1
C2
C3
C4
C6
C8
C10
C2OC2
C2OC2OC2
C2SC2
C2NTsC2
j
k
Fig. 1 Macrocyclic Mannich bases derived from N,NЈ-dimethyl-
ethylenediamine, piperazine, or ethylamine (see Table 1 for Z).
sulfonate)s (Z = heteroalkyl) with two equivalents of methyl 3-
hydroxythiophene-2-carboxylate18 1. The ester groups were
saponified and the resulting acids were decarboxylated, in high
yield, to give the corresponding α,ω-bis(3-thienyloxy)alkanes
4a–k (Ar = 3-thienyl). Decarboxylation of the C1-linked com-
pound 3a was atypical (a consequence of its acetal-like nature)
and, in this case, the product was contaminated with the lactone
5 resulting from intramolecular displacement of a hydroxy-
thiophene moiety. This by-product could be removed by an
alkaline wash. The lactone was the major product when the bis
acid 3a was treated with copper(0). Approaches to macrocyclic
compounds were hampered by the fact that the bis ethers 4a–k
(Ar = 3-thienyl) degrade under all but the mildest of reaction
conditions.
The bis acids 3a–k had some potential for macrocyclis-
ation via the carboxy functions but generally this class of
compounds exhibited limited solubility in solvents which
would have been appropriate for cyclisation procedures. More
active intermediates, viz. acid chlorides and anhydrides,
could be isolated via treatment of the bis acid with thionyl
chloride or acetic anhydride respectively, but these com-
pounds proved to be overly sensitive to hydrolysis and/or
decomposition.
The reagents commonly used to halogenate (e.g. iodine–nitric
acid or N-bromosuccinimide) or nitrate (e.g. nitric acid–acetic
acid–acetic anhydride or copper() nitrate–acetic anhydride)
thiophene derivatives proved to be too acidic for use on the
α,ω-bis(thienyloxy)alkanes 4a–k. Various reagents were
also employed to induce acylation, viz. acetic anhydride–
phosphoric acid, acetyl chloride–titanium tetrachloride, acetic
anhydride–boron trifluoride–diethyl ether or acetic acid–
trifluoroacetic anhydride–phosphoric acid,19 but yields were, at
best, poor.
and TLC data indicated that the products were monomeric;
dimers and higher polymers were formed to some extent, but
they could be removed by chromatography. Macrocyclisation
of the C2NTsC2-linked compounds was not undertaken since
trial attempts to effect detosylation of intermediates were
unsuccessful.
The C1-linked compound 4a failed to give a cyclic product
on reaction with N,NЈ-dimethylethylenediamine (presumably
due to the steric constraints involved in the ring formation),
but compounds in which the linking alkyl chain was longer
did undergo macrocyclisation. It is significant that use of high
dilution techniques resulted in only a modest increase in the
return of [1 ϩ 1] cyclic product, e.g. 46 to 62% yield in a typical
case. Interestingly, the yield of cyclic product decreased as the
linking chain length increased [69% for C2 (9b); 45% for C4 (9d);
23% for C10 9g], i.e. as the number of degrees of freedom in
the intermediate increased. The yields of the macrocyclic bases
were noticeably higher when the linking group between the aryl
rings was heteroalkyl rather than alkyl [53% for C2OC2 (9h);
77% for C2OC2OC2 (9i); 42% for C2SC2 (9j)]. This is thought to
be due to a template effect, i.e. the electrophile is coordinated to
a heteroatom and thus delivered to the reactive site. We suggest
that there is a dipole–dipole interaction between the negative
end of the carbon–heteroatom bond in the bridge and the posi-
tive end of the dipole in the CH ᎐Nϩ of the attacking cation.
᎐
2
This effect was increasingly marked in the sterically congested
macrocycles derived from piperazine: alkyl-bridged compounds
could not be isolated as extensive polymerisation was evident. It
is interesting to note that the yield of the C2-bridged macrocycle
9b is high in relation to that of the remaining compounds in this
class (69%; as opposed to the next highest recovery for C3 which
is 46%). Chain length is such that it is likely that the oxygen
atom at position 3Ј could act as an internal template in this
case.
Our data indicated that the C2OC2- and C2SC2-linked macro-
cyclic Mannich bases derived from piperazine and ethylamine
consisted in each case of a mixture of closely related sub-
stances. When Z = C2OC2 the major (slower eluting) compon-
ent could be isolated chromatographically; in the case of 10h
this was analysed separately, the remaining three compounds
were analysed as mixtures. In all cases the correct microanalyti-
cal data were obtained and the 13C NMR data showed a doub-
ling of the peaks, neither fewer nor more, so the compounds
must be very closely related (see Table 2). A likely explanation
would be that they must be either two forms of the same com-
pound with different spatial arrangements or a mixture of the
monomer and dimer. The following observations suggest that
the former explanation is likely. 1. The major component exhib-
ited an Rf value comparable to that of an acyclic analogue,
which suggested that it is monomeric. However, the minor
component eluted further on TLC, which would not be
expected of a higher oligomer. 2. Mass spectroscopic analysis
It was through the formation of the Mannich bases20 (6a–k,
7a–k and 8a–k) that entry into macrocyclic systems was
achieved. These bases were readily accessible from the bis
ethers via reaction with mild, imine-like electrophilic species;
they could also be obtained by decarboxylative substitution
of the related bis acids, but in poorer overall yields. Amino
alcohols, such as N-methyl-2-aminoethanol, could also be
used to prepare the pre-formed iminium species utilised in
the Mannich reaction, but in this case aminomethylation
was slow and its products were difficult to purify. Compounds
4a–k were particularly reactive towards mildly electro-
philic species; in the absence of a base they would condense
with formaldehyde alone under the Mannich reaction
conditions, to give the appropriate 2,2Ј-methylene-bridged
compounds.
Extension of these facile Mannich base preparations gave
macrocyclic compounds in what may be considered to be very
good yields for such processes. The bis ethers 4a–k, on treat-
ment with one equivalent of an α,ω-bis-secondary alkylamine of
the type RNH—NHR, under conditions of normal dilution,
gave the cyclic structures shown in Fig. 1. Mass spectroscopic
J. Chem. Soc., Perkin Trans. 1, 2001, 1398–1405
1399

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Table 2 13C chemical data for 10h and 10j, 11h and 11j
Elmer 1600 FT-IR spectrometer as potassium bromide discs or
thin films between sodium chloride plates. NMR spectra were
recorded on a Hitachi Perkin-Elmer R-24B 60 MHz (1H NMR
only), a JEOL FX60Q 60 MHz (13C NMR only) or a JEOL
EX-270 MHz NMR spectrometer, with tetramethylsilane
as an internal standard. Chemical shifts are given in ppm on the
δ scale; J values are given in Hz.
Microanalyses for C, H and N were determined by the
analytical department of Shell Research Centre, Sittingbourne
and the microanalysis unit of the University of Nottingham.
Mass spectroscopic determinations (chemical ionisation) were
carried out by Shell Research Centre, Sittingbourne. Prepar-
ative column chromatography employed 60–120 mesh silica gel
(particle size 0.13–0.25 µm) or Brockmann Grade 1 aluminium
oxide (activated, neutral) purchased from BDH Ltd. Pyridine
was distilled over potassium hydroxide and stored over sodium
hydroxide pellets. The bis(toluene-p-sulfonate)s were obtained
by methods adapted from the literature.
Piperazinea
N-Ethylaminea
C2OC2 11h C2SC2 11j
Carbon
atom
C2OC2 10h
C2SC2 10j
Ar 3-C
154.77
(154.16)
123.34
(122.66)
115.61
(118.18)
114.95
(117.36)
69.95
(71.43)
69.86
(70.22)
48.27
154.09
(153.71)
123.34
(122.78)
118.43
(118.33)
116.28
(117.09)
70.76
(71.79)
32.38
(32.08)
52.40
152.74
(153.55)
122.21
(122.53)
121.67
(121.36)
117.77
(117.36)
70.96
153.17
(153.22)
122.28
(122.84)
117.81
(117.07)
117.81
(116.96)
72.52
Ar 5-C
Ar 2-C
Ar 4-C
ArOCH2
ArOCH2CH2
ArCH2N
ArCH2NCH2
CH2CH3
(70.22)
69.24
(71.75)
31.28
(70.22)
48.18
(47.91)
46.59
(32.09)
47.62
(47.94)
47.69
(52.13)
47.49
(52.29)
—
(52.24)
47.89
(48.70)
—
(46.77)
13.37
(12.15)
(46.76)
12.74
(12.00)
Preparation of the ꢀ,ꢁ-bis(2-methoxycarbonyl-3-thienyloxy)-
alkanes 2a–k
a Figures in parentheses indicate the shifts of the minor component.
A stirred solution of the methyl 3-hydroxythiophene-2-carb-
oxylate 1, anhydrous potassium carbonate (0.55 eq.) and
the coupling agent (the corresponding α,ω-dibromoalkane for
2a–g or the corresponding α,ω-bis(toluene-p-sulfonate) for
2h–k; 0.55 eq.) in anhydrous N,N-dimethylformamide (DMF)
(for 2a–i and 2k; 5 ml gϪ1 of thiophene ester) was heated on
an oil bath maintained at 95–100 ЊC or boiled under reflux in
acetone (for 2j; 5 ml gϪ1 of thiophene ester) for 5h, and then
poured into ice. The alkyl-bridged 2a–g and the C2OC2- and
C2SC2-linked bis esters (2h and 2j, respectively) precipitated out
and were filtered off. The C2OC2OC2- and C2NTsC2-linked
esters (2i and 2k, respectively) were isolated by extraction with
dichloromethane (DCM). The crude products were either
digested in hot solvent (ethyl acetate, ethanol, methanol or
acetone) or recrystallised. The results of the individual
preparations are presented in Table 3.
of the mixtures gave the correct molecular weight for a [1 ϩ 1]
macrocycle.
Molecular modelling has shown that the molecule is
not planar and the smaller ring size of these macrocycles, in
contrast to the C2OC2OC2-linked compounds may restrict
rotation of, for example, the N-ethyl group; hence a form of
atropisomerism could exist. This phenomenon was increasingly
marked in the corresponding C2SC2-linked compounds 10j and
11j, which suggested that the presence of a larger heteroatom in
the bridge is significant. Dynamic 13C NMR studies on the
C2SC2-linked compounds indicated that the barrier to inter-
conversion of these compounds could not be overcome
below 150 ЊC and that individually they are very stable. It is
suggested that the reaction products are mixtures of stereo-
isomers but this cannot be proved from the data available at
present.
Preparation of the ꢀ,ꢁ-bis(2-carboxy-3-thienyloxy)alkanes 3a–k
In order to extend the scope of this work we decided to
undertake the preparation of lariat ethers via substitution at the
4- or 5-positions of the thiophene ring. Two general approaches
were examined, namely electrophilic substitution of the thio-
phene ring itself, and ring closure of intermediates carrying the
desired substituents. The first approach failed because condi-
tions vigorous enough to bring about electrophilic substitution
were generally harsh enough to bring about decomposition
(e.g. bromination, lithiation). It was possible to introduce the
nitro group but reductive methods leading to synthetically use-
ful intermediates (e.g. amines or acetamides) failed for the most
part. Moderate success was achieved via the ring closure
approach,21 but sterically bulky groups (e.g. 5-p-methoxy-
benzyl) interfered with the Mannich reaction and a 2,2Ј-
methylene-bridged compound was isolated. The 5-methyl
group could be incorporated using this methodology and would
undergo benzylic bromination, but the alkoxymethyl side chain
was not accessible via nucleophilic substitution. The 5-methoxy
group was introduced22 but it was found to destabilise the sys-
tem and the Mannich reaction failed.
A stirred solution of the α,ω-bis(2-methoxycarbonyl-3-thienyl-
oxy)alkane 2a–k and potassium hydroxide (4.0 eq.) in 50%
(when Z = alkyl) or 80% (when Z = heteroalkyl) aqueous
ethanol (16 or 20 ml gϪ1 respectively) was boiled under reflux
for 1–2 h. The solution was filtered through glass wool into a
stirred mixture of ice and a slight excess of hydrochloric acid.
Compounds 3a–h,j,k precipitated out and were filtered off,
washed with water and dried under vacuum at 60 ЊC. 1,8-Bis(2-
carboxy-3-thienyloxy)-3,6-dioxaoctane 3i was deposited as a
gum, which solidified on trituration. The solid was filtered off,
washed with water and dissolved in acetone. The solution
was dried (MgSO4) and evaporated at room temperature to
give a solid which was triturated in ether. Compound 3i was
filtered off, washed with ether and dried under vacuum at
ambient temperature. A summary of the results is presented in
Table 4.
Preparation of the ꢀ,ꢁ-bis(3-thienyloxy)alkanes 4a–k
A mixture of the α,ω-bis(2-carboxy-3-thienyloxy)alkane 3a–k
and copper() oxide (1.2 wt eq.) in pyridine (10 ml gϪ1 of bis
acid) was boiled under reflux for 1 h. The solvent was removed
under reduced pressure and the residue was extracted repeat-
edly with DCM. The combined organic extracts were washed
with dilute hydrochloric acid, then with dilute sodium
hydroxide or saturated sodium hydrogen carbonate solution,
dried (MgSO4 or K2CO3) and evaporated to give the crude
bis ether. Compounds 4b–k were recrystallised. An ethereal
solution of the liquid containing bis(3-thienyloxy)methane 4a
was treated with several portions of concentrated sodium
In summary, [1 ϩ 1] macrocyclic Mannich bases are readily
accessible from α,ω-bis(3-thienyloxy)alkanes, but efforts to pre-
pare lariat ethers via the corresponding 4- or 5-substituted
derivatives were not successful.
Experimental
Melting points were determined using open capillary tubes in
an electrically heated Gallenkamp melting point apparatus and
are uncorrected. Infrared spectra were determined on a Perkin-
1400
J. Chem. Soc., Perkin Trans. 1, 2001, 1398–1405

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Table 3 Analytical data for the bis esters
Found (required)
%C
Compound
Yield (%)
Mp/ЊC (solvent)
Mϩ (M)
%H
3.7 (3.7)
2a
71
89
80
83
90
93
90
86
98
70
96
174–176 (DMF)
189–190 (MeCN)
138–140 (Me2CO)
190–192 (MeCN)
166–167 (MeCN)
150–152 (Me2CO)
141–143 (Me2CO)
76 (aq MeOH)
n/a (328.4)
343 (342.4)
357 (356.4)
371 (370.5)
n/a (398.5)
427 (426.6)
455 (454.6)
387 (386.5)
431 (430.5)
n/a (402.5)
No Mϩ (539.7)
47.6 (47.6)
49.1 (49.1)
50.9 (50.6)
51.7 (51.7)
54.2 (54.3)
56.5 (56.3)
58.1 (58.1)
49.9 (49.7)
49.6 (50.2)
47.7 (47.7)
n/ab
C13H12O6S2
2b
4.3 (4.1)
4.6 (4.5)
4.9 (4.9)
5.6 (5.6)
6.1 (6.1)
6.7 (6.7)
4.7 (4.7)
5.1 (5.1)
47.7 (47.7)
n/ab
C14H14O6S2
2c
C15H16O6S2
2d
C16H18O6S2
2e
C18H22O6S2
2f
C20H26O6S2
2g
C22H30O6S2
2h
C16H22O7S2
2i
C18H22O8S2
2j
C16H18O6S3
2k
C23H25NO8S
67–69 (1 : 1 EA–PE)a
118 (EtOH)
99–100 (1 : 1 EA–PE)a
a 1 : 1 ethyl acetate–petroleum ether. b Unsatisfactory microanalytical data were obtained for the C2NTsC2-linked compound 2k on three occasions,
although the spectroscopic properties were as expected and the subsequent bis acid 3k could be analysed correctly (see Table 4).
Table 4 Analytical data for the bis acids
Found (required)
Compound
Yield (%)
Mp/ЊC
M
ϩ Ϫ 43(M)
%C
%H
3a
99
93
211–212
219–220
207–208
228–229
184–186
170–171
172–174
189
n/a (300.3)
271 (314.3)
285 (328.4)
No Mϩ (342.4)
n/a (370.4)
355 (398.5)
383 (426.6)
315 (358.4)
359 (402.5)
331 (374.5)
No Mϩ (511.6)
44.0 (44.0)
45.8 (45.9)
47.6 (47.6)
48.9 (49.1)
52.1 (51.9)
53.9 (54.3)
55.9 (56.3)
46.6 (46.9)
n/aa
2.7 (2.7)
3.3 (3.2)
3.7 (3.7)
4.3 (4.1)
5.1 (4.9)
5.8 (5.6)
6.5 (6.1)
3.9 (3.9)
n/aa
C11H8O6S2
3b
C12H10O6S2
3c
C13H12O6S2
3d
C14H14O6S2
3e
C16H18O6S2
3f
C18H22O6S2
3g
C20H26O6S2
3h
C14H14O7S2
3i
100
100
85
100
98
100
88
91–99
C16H28O8S2
3j
91
178–179
168
45.2 (44.9)
49.1 (49.3)
4.0 (3.8)
4.3 (4.1)
C14H14O6S3
3kb
99
C21H21NO8S3
a Unsatisfactory microanalytical data were obtained for the C2OC2OC2-linked compound 3i on two occasions, although the spectroscopic properties
were as expected and the subsequent decarboxylated material 4i could be analysed correctly (see Table 5). b %N Found 2.7%, required 2.7%.
hydroxide solution. The organic solution was dried (MgSO4)
and evaporated and the liquid was distilled under vacuum. See
Table 5 for results of individual preparations.
darken. The product solidified on cooling; it was subjected to
chromatography on silica (gravity column) using chloroform
as the eluent. After a fore-run the title compound (1.24 g)
was eluted from the column, this material was recrystallised
from 50% aq. MeOH (0.81 g, 31%); mp 74–75 ЊC (Found:
C, 45.7; H, 2.4. C6H4O3S requires C, 46.2; H, 2.6%); δH (CDCl3)
7.72 (1H, d, J = 5.5 Hz, Ar(5)H), 6.83 (1H, d, J 6, Ar
4-H) and 5.69 (2H, s, ArOCH2) ppm; δC (CDCl3) 163.11
Preparation of the lactone 5
α,ω-Bis(2-carboxy-3-thienyloxy)methane 3a (5.0 g, 0.017 mol,
1.0 eq.) and copper bronze (5.0 g, 1.0 wt eq.) were thoroughly
mixed in a Claisen distillation flask. The solid was sealed
with a glass wool plug and the mixture was distilled (free
flame) at ca. 15 mmHg. An orange liquid (bp ca. 200 ЊC) was
collected; distillation was halted when the distillate began to
(C᎐O), 157.58 (Ar 3-H), 135.97 (Ar 5-H), 116.93 (Ar
᎐
4-H), 108.87 (Ar 2-H) and 92.33 (ArOCH2); νmax (film) 1737.0s
(C᎐O) and 1545.2m (C᎐C) cmϪ1; m/z (CI, CH4) 157 (100%,
᎐
᎐
M ϩ 1).
J. Chem. Soc., Perkin Trans. 1, 2001, 1398–1405
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Table 5 Analytical data for the bis ethers
Found (required)
%C
Compound
(Formula)
Yield (%)
Mp/ЊC
Mϩ (M)
%H
a
4a
52
73
85
88
90
98
73
98
96
81
94
213 (212.3)
227 (226.3)
241 (240.4)
255 (254.4)
n/a (282.4)
51.6 (51.3)
52.9 (53.1)
54.7 (55.0)
56.9 (56.7)
59.7 (59.5)
62.2 (61.9)
64.1 (63.9)
53.5 (53.3)
53.7 (53.5)
50.1 (50.3)
53.9 (53.9)
4.0 (3.8)
4.6 (4.5)
5.1 (5.0)
5.5 (5.6)
6.7 (6.4)
7.0 (7.1)
7.7 (7.7)
5.2 (5.2)
5.7 (5.8)
4.9 (4.9)
5.0 (5.0)
C11H8O6S2
4b
156–159
C12H10O6S2
4c
C13H12O6S2
4d
C14H14O6S2
4e
C16H18O6S2
4f
C18H22O6S2
4g
C20H26O6S2
4h
C14H14O7S2
4i
65–66
104–106
117–119 (EtOH)
73–74 (EtOH)
98
311 (310.5)
339 (338.5)
271 (270.4)
315 (314.4)
287 (286.4)
[Mϩ Ϫ Ts 270] (423.6)
58–60 (MeOH)
54–57 (EtOH)
94–97 (EtOH)
81–83 (MeOH)
C16H28O8S2
4j
C14H14O6S3
4kb
C21H21NO8S3
a Bp = 134–138 ЊC/0.4 mmHg. b %N Found 3.3%, required 3.1%.
Table 6 Analytical data for the bis(dimethylaminomethyl) Mannich bases
Found (required)
Compound
Yield (%, crude)
Mp/ЊC
Mϩ (M)
%C
%H
%N
6a
88
96
Oil
327 (326.5)
341 (340.5)
355 (354.5)
369 (368.6)
n/a (396.6)
n/a (424.7)
453 (452.7)
385 (384.6)
429 (428.6)
n/a (400.6)
538 (537.8)
54.9 (55.2)
56.2 (56.4)
57.9 (57.6)
58.4 (58.7)
60.2 (60.6)
62.4 (62.2)
63.2 (63.7)
56.2 (56.2)
56.1 (56.1)
53.7 (54.0)
55.7 (55.8)
6.5 (6.8)
6.9 (7.1)
7.5 (7.4)
7.8 (7.7)
8.0 (8.1)
8.9 (8.6)
8.8 (8.9)
7.3 (7.3)
7.8 (7.5)
7.3 (7.0)
6.7 (6.6)
8.4 (8.6)
7.7 (8.2)
7.7 (7.9)
7.8 (7.6)
7.4 (7.1)
6.6 (6.6)
6.0 (6.2)
7.0 (7.3)
6.7 (6.5)
6.8 (7.0)
7.9 (7.8)
C15H22N2O2S2
6b
45–48a
Oil
C16H24N2O2S2
6c
100
90
C17H26N2O2S2
6d
63–64b
42–44
Oil
C18H28N2O2S2
6e
85
C20H32N2O2S2
6f
94
C22H36N2O2S2
6g
93
Oil
C24H40N2O2S2
6h
98
Oil
C18H28N2O3S2
6i
100
87
Oil
C20H32N2O4S2
6j
Oil
C18H28N2O2S3
6k
C25H35N3O4S3
97
Oil
a Trituration. b MeOH.
with 4 M sodium hydroxide solution and extracted with DCM
(×2). The combined organic extracts were dried (K2CO3 or
MgSO4) and evaporated to give the Mannich base. The products
were essentially analytically pure as obtained. The solids were
purified either by recrystallisation or by trituration with light
petroleum, bp 40–60 ЊC. The oils could be purified by extrac-
tion into dilute acid, where necessary. See Tables 6, 7 and 8 for
results of individual preparations.
Preparation of the open chain Mannich bases 6a–k, 7a–k and
8a–k
The α,ω-bis(3-thienyloxy)alkane 4a–k was added to a stirred
solution of 2.2 equivalents of the secondary amine (40% aque-
ous solution of dimethylamine for 8a–k, piperidine for 9a–k or
morpholine for 10a–k) and formaldehyde (37% aqueous solu-
tion; 2.2 eq.) in glacial acetic acid (25 ml gϪ1 of bis ether). When
Z was C1 alkyl, the mixture was boiled under reflux for 1 h, and
then cooled. When Z was C2–C10 alkyl, the mixture was heated
to reflux until the bis ether had just dissolved and was then
cooled. When Z was heteroalkyl, the mixture was stirred at
ambient temperature for 48 h. The solution was then basified
Preparation of the macrocyclic Mannich bases 9b–j, 10h–j and
11h–j
The α,ω-bis(3-thienyloxy)alkane 4b–j was added to a solution
1402
J. Chem. Soc., Perkin Trans. 1, 2001, 1398–1405

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Table 7 Analytical data for the bis(piperidinomethyl) Mannich bases
Found (required)
%C
Compound
Yield (%, crude)
Mp/ЊC
Mϩ (M)
%H
%N
7a
99
100
98
Oil
407 (406.6)
421 (420.6)
435 (434.7)
n/a (448.7)
61.7 (62.0)
62.8 (62.8)
63.9 (63.6)
64.3 (64.3)
65.5 (65.5)
66.2 (66.6)
67.8 (67.6)
62.3 (62.0)
61.1 (61.4)
59.7 (60.0)
60.2 (60.3)
7.2 (7.4)
8.0 (7.7)
7.7 (7.9)
8.4 (8.1)
8.5 (8.5)
8.9 (8.8)
9.4 (9.4)
7.7 (7.8)
8.0 (7.9)
7.9 (7.6)
7.2 (7.0)
6.6 (6.9)
6.5 (6.7)
6.6 (6.4)
6.2 (6.2)
5.9 (5.9)
5.5 (5.6)
5.4 (5.3)
6.2 (6.0)
5.5 (5.5)
5.9 (5.8)
6.7 (6.8)
C21H30N2O2S2
7b
48–51a
Oil
C22H32N2O2S2
7c
C23H34N2O2S2
7d
100
92
78–79b
67–69
Oil
C24H36N2O2S2
7e
n/a (476.8)
C26H40N2O2S2
7f
92
505 (504.8)
533 (532.9)
465 (464.7)
509 (508.8)
n/a (480.8)
C28H44N2O2S2
7g
91
Oil
C30H48N2O2S2
7h
97
Oil
C24H36N2O3S2
7i
100
96
Oil
C26H40N2O4S2
7j
Oil
C24H36N2O2S3
7k
C31H43N3O4S3
97
Oil
[Mϩ Ϫ Ts 464] (617.9)
a Trituration. b MeOH.
Table 8 Analytical data for the bis(morpholinomethyl) Mannich bases
Found (required)
Compound
(Formula)
Yield
(%, crude)
Mp/ЊC
Mϩ (M)
%C
%H
%N
8a
99
100
98
70–72
113–115a
85–87a
146–147a
58–61
49–50b
56–60b
Oil
411 (410.6)
425 (424.6)
439 (438.6)
453 (452.6)
n/a (480.7)
509 (508.8)
537 (536.8)
469 (468.6)
513 (512.7)
n/a (484.7)
No Mϩ (621.8)
55.8 (55.6)
56.3 (56.6)
57.6 (57.5)
58.2 (58.4)
59.8 (60.0)
61.4 (61.4)
43.6 (43.9)
56.0 (56.4)
56.0 (56.2)
54.4 (54.5)
56.3 (56.0)
6.7 (6.4)
6.7 (6.7)
7.1 (6.9)
6.9 (7.1)
7.6 (7.6)
7.9 (7.9)
6.1 (6.1)
6.5 (6.9)
7.3 (7.1)
6.8 (6.7)
6.4 (6.3)
6.5 (6.8)
6.5 (6.6)
6.4 (6.4)
6.2 (6.2)
5.5 (5.8)
5.3 (5.5)
3.2 (3.4)
6.1 (6.0)
5.4 (5.5)
5.9 (5.8)
6.7 (6.8)
C15H22N2O2S2
8b
C16H24N2O2S2
8c
C17H26N2O2S2
8d
95
C18H28N2O2S2
8e
93
C20H32N2O2S2
8f
100
100
99
C22H36N2O2S2
8g
C24H40N2O2S2
8h
C15H22N2O2S2
8i
98
Oil
C15H22N2O2S2
8j
97
71–73a
Oil
C15H22N2O2S2
8k
C15H22N2O2S2
100
a MeOH. b Trituration.
of 1.1 equivalents of the amine (N,NЈ-dimethylethylenediamine
for 9b–j, piperazine for 10h–j, ethylamine for 11h–j) and
formaldehyde (37% aqueous solution, 2.2 eq.) in glacial acetic
acid (25 ml gϪ1 of bis ether). The mixture was stirred at room
temperature for 24 h, then basified with 4 M sodium hydroxide
solution and extracted into ether (for 9b–j) or DCM (for 10h–j,
and 11h–j) (×2). The combined organic extracts were dried
(MgSO4) and evaporated. The crude material was preabsorbed
onto alumina and subjected to column chromatography
(gravity column). The macrocyclic Mannich bases 9b–j, 10h–j
and 11h–j were eluted with 1 : 1 chloroform–toluene. Details
of the individual preparations are described in Tables 9, 10
and 11.
Infrared data
All of the bridged thiophene compounds exhibited a strong
thiophene C᎐C stretch at 1566–1535 cmϪ1. Additional charac-
᎐
teristic absorptions include those of the bis esters 1718–1678
cmϪ1, s (C᎐O); the bis acids 2928–2604 cmϪ1, s (COOH) and
᎐
1698–1629 cmϪ1, s (C᎐O); and the tosyl compounds 1600–1595
᎐
cmϪ1, m–w (C᎐C).
᎐
J. Chem. Soc., Perkin Trans. 1, 2001, 1398–1405
1403

View Article Online
Table 9 Analytical data for the macrocyclic Mannich bases derived from N,NЈ-dimethylethylenediamine
Found (required)
Compound
Yield (%)
Mp/ЊCa
Mϩ (M)
%C
%H
%N
9b
69
46
45
37
30
23
47
54
51
Oil
339 (338.5)
353 (352.5)
367 (366.6)
395 (394.6)
423 (422.6)
451 (450.7)
383 (382.6)
n/a (426.6)
399 (398.6)
56.6 (56.8)
57.6 (57.9)
58.8 (59.0)
61.2 (60.9)
62.5 (62.5)
63.8 (64.0)
56.2 (56.6)
56.4 (56.3)
53.9 (54.2)
6.4 (6.6)
6.8 (6.9)
7.1 (7.2)
7.6 (7.7)
7.9 (8.1)
8.2 (8.5)
6.9 (6.9)
7.3 (7.1)
6.5 (6.6)
8.4 (8.3)
7.6 (8.0)
7.6 (7.6)
7.1 (7.1)
6.9 (6.6)
6.6 (6.2)
7.0 (7.3)
6.5 (6.6)
6.7 (7.0)
C16H22N2O2S2
9c
Oil
C17H24N2O2S2
9d
Oil
C18H26N2O2S2
9e
Oil
C20H30N2O2S2
9f
Oil
C22H34N2O2S2
9g
Oil
C24H38N2O2S2
9h
Oil
C18H26N2O3S2
9i
90–92
87–89
C20H30N2O4S2
9j
C18H26N2O2S3
a Chromatography.
Table 10 Analytical data for the macrocyclic Mannich bases derived from piperazine
Found (required)
%C
Compound
Yield (%)
Mp/ЊCa
Mϩ (M)
%H
%N
10h
C15H22N2O2S2
10i
C15H22N2O2S2
10j
C15H22N2O2S2
53
77
42
131–168
101
381 (380.5)
425 (424.6)
397 (396.6)
56.8 (56.8)
56.7 (56.6)
54.9 (54.5)
6.3 (6.4)
6.6 (6.7)
6.2 (6.1)
7.3 (7.4)
6.6 (6.6)
6.9 (7.1)
116–122
a Chromatography.
Table 11 Analytical data for the macrocyclic Mannich bases derived from ethylamine
Found (required)
%C
Compound
Yield (%)
Mp/ЊCa
Mϩ (M)
%H
%N
11h
C15H22N2O2S2
11i
C15H22N2O2S2
11j
C15H22N2O2S2
84
80
64
87–94
102–104
Oil
340 (339.5)
384 (383.5)
356 (355.5)
56.3 (56.6)
56.3 (56.4)
53.7 (54.1)
6.2 (6.2)
6.5 (6.6)
5.9 (6.0)
4.2 (4.1)
3.6 (3.7)
3.9 (3.9)
a Chromatography.
NMR data
References
Listed in Tables 12 and 13 are the NMR data for the α,ω-bis-
(3-thienyloxy)alkanes.
1 R. K. Russell and J. B. Press, Comprehensive Heterocyclic Chemistry
II, eds. K. R. Scriven and A. R. Katritzky, Elsevier Science, Oxford,
1996, vol. 2, p. 721.
2 O. Meth-Cohn, Q. Rep. Sulfur Chem., 1970, 5, 129.
3 G. R. Newkome, J. D. Sauer, J. M. Roper and D. C. Hager,
Chem. Rev., 1977, 77, 513.
Acknowledgements
4 (a) N. A. Bailey, M. M. Eddy, D. E. Fenton, G. Jones, S. Moss and
A. Mukhopadhyay, J. Chem. Soc., Chem. Commun., 1981, 628;
(b) N. A. Bailey, M. M. Eddy, D. E. Fenton, S. Moss, A.
Mukhopadhyay and G. Jones, J. Chem. Soc., Dalton Trans., 1984,
2281; (c) H. Adams, N. A. Bailey, D. E. Fenton, R. J. Good,
We are grateful to Shell Research Ltd, Sittingbourne, Kent for
financial support and to Synthetic Chemicals Ltd, Four Ashes,
Wolverhampton for a ready supply of methyl 3-hydroxy-
thiophene-2-carboxylate and their interest in the project.
1404
J. Chem. Soc., Perkin Trans. 1, 2001, 1398–1405

View Article Online
Table 12 1H NMR data ranges for the α,ω-bis(3-thienyloxy)alkanes
Compound
Ar 5-H
Ar 4-H
ArCH2N
ArCH2NCHx
Other signalsa
2a–k
3a–k
4a–k
6a–k
7a–k
8a–k
7.35–7.81 (d, J 5–6)
7.52–7.79 (d, J 5–6)
7.07–7.26 (m)
7.02–7.16 (d, J 5–6)
6.99–7.10 (d, J 5–6)
7.02–7.22 (d, J 4–6)
6.84–7.18 (d, J 6)
6.90–7.18 (d, J 5–6)
6.64–6.80 (m)
6.76–6.97 (d, J 5–6)
6.70–6.92 (d, J 5–6)
6.66–6.99 (d, J 5–6)
—
—
—
—
—
—
3.70–3.88 (s, CO2Me)
br, variable, CO2H
6.15–6.62 (m, Ar 2-H)
—
1.39–1.57 (m, NCH2(CH2)3)
3.62–3.71 (m or t, J 5,
NCH2CH2O)
3.48–3.67 (s)
3.53–3.65 (s)
3.54–3.69 (s)
2.20–2.32 (s, NMe)
2.37–2.44 (m or t, J 5, NCH2)
2.38–2.50 (m or t, J 5, NCH2)
9b–j
7.02–7.17 (d, J 5–6)
6.76–6.87 (d, J 5–6)
3.56–3.80 (s)
2.41–2.69 (s, NCH2)
2.28–2.44 (s, NMe)
—
10h–j
11h–j
7.05–7.14 (d, J 5)
7.05–7.08 (d, J 4–6)
6.73–6.77 (d, J 5–8)
6.73–6.78 (d, J 5–7)
3.49–3.85 (s)
3.76–3.96 (s)
2.44–2.85 (s, NCH2)
2.57–2.67 (t or q, J 5–7, NCH2Me)
—
1.08–1.14 (t, J 7–8, Me)
a Additional characteristic NMR signals for bridging group Z (cf. Table 1): C1 (a) 5.50–5.81 (2H, s, ArOCH2); C2 (b) 4.20–4.48 (4H, s, 2 × ArOCH2);
C3 (c) 4.08–4.36 (4H, t, J 6–7, 2 × ArOCH2), 2.10–2.20 (2H, m, ArOCH2CH2); C4 (d) 3.97–4.16 (4H, m or t, J 4–7, ArOCH2), 1.87–1.94 (4H, m,
2 × ArOCH2CH2); C6 (e) 3.95–4.15 (4H, m or t, J 6–7, 2 × ArOCH2), 1.87–1.94 (8H, m and m or br s, 2 × ArOCH2(CH2)2); C8 (f) 3.94–4.12 (4H, t,
J 6–7, 2 × ArOCH2), 1.36–1.72 (12H, m and m or br s, 2 × ArOCH2(CH2)3); C10 (g) 3.88–4.14 (4H, t, J 5–7, 2 × ArOCH2), 1.29–1.73 (16H, m and m
or br s, 2 × ArOCH2(CH2)4); C2OC2 (h) 4.07–4.37 (4H, m or t, J 5, 2 × ArOCH2), 3.67–3.99 (4H, m or t, J 5, 2 × ArOCH2CH2O); C2OC2OC2 (i) 4.05–
4.33 (4H, m or t, J 4–6, 2 × ArOCH2), 3.60–3.84 (8H, m or m and s, 2 × ArOCH2CH2OCH2); C2SC2 (j) 4.12–4.34 (4H, t, J 6–7, 2 × ArOCH2), 2.85–
3.10 (4H, t, J 6–7, 2 × ArOCH2CH2S); C2N(Ts)C2 (k) 7.70–7.74 (2H, d, J 7–9, Ph 2-H and Ph 6-H; i.e. ortho to SO2), 7.19–7.29 (2H, d, J 6–9, Ph 3-H
and Ph 5-H; i.e. meta to SO2), 4.16–4.33 (4H, m or t, J 6, 2 × ArOCH2), 3.59–3.76 (4H, m or t, J 6, 2 × ArOCH2CH2N), 2.23–2.42 (3H, s, PhMe).
Table 13 13C NMR data ranges for the α,ω-bis(3-thienyloxy)alkanes
Compound
Ar 3-C
Ar 5-C
Ar 4-C
Ar 2-C
ArCH2N
ArCH2N(CH2)x
Othersa
2a–k
156.0–161.4
130.3–131.5
116.9–119.5
108.0–112.7
—
—
161.0–162.2 (C᎐O)
51.1–51.6 (CO2Me)
᎐
3a–k
4a–k
6a–k
7a–k
8a–k
9b–j
157.3–160.6
154.8–158.1
151.4–154.6
151.4–154.4
151.5–154.6
150.6–154.5
128.9–130.8
124.5–124.9
122.3–123.3
122.3–123.5
122.7–123.9
122.5–123.8
116.1–119.8
119.2–119.8
115.9–118.4
116.7–118.5
116.7–118.3
116.2–117.3
109.2–113.8
97.0–102.5
117.3–121.6
118.2–121.4
120.4–117.1
116.6–123.3
—
—
—
—
161.0–162.9 (C᎐O)
—
—
26.0, 24.3 (NCH2(CH2)3)
67.0–67.1 (NCH2CH2O)
—
᎐
53.2–53.6
53.1–53.2
52.1–53.2
52.1–54.3
44.1–45.0 (NMe)
53.8–54.0 (NCH2)
52.8–53.2 (NCH2)
49.9–51.9 (NCH2)
42.3–44.7 (NMe)
47.5–52.3 (NCH2)
46.6–47.7 (NCH2Me)
10h–j
11h–j
154.1–154.8
152.7–153.6
122.4–123.3
122.2–122.8
115.0–117.4
117.0–117.8
115.6–118.4
117.1–121.7
48.3–52.2
47.6–48.2
—
12.0–13.4 (Me)
a Additional characteristic NMR signals for bridging group Z (cf. Table 1): C1 (a) 93.9–94.7 (ArOCH2); C2 (b) 68.6–70.8 (2 × ArOCH2); C3 (c) 66.7–
68.4 (2 × ArOCH2), 29.1–30.2 (ArOCH2CH2); C4 (d) 69.7–71.4 (2 × ArOCH2), 25.6–26.4 (2 × ArOCH2CH2); C6 (e) 70.0–71.5 (2 × ArOCH2), 25.1–
29.6 (2 × ArOCH2(CH2)2); C8 (f) 70.3–72.0 (2 × ArOCH2), 23.4–29.7 (2 × ArOCH2(CH2)3); C10 (g) 70.3–71.8 (2 × ArOCH2), 25.3–29.7 (2 × ArO-
CH2(CH2)4) C2OC2 (h) 69.7–71.7 (2 × ArOCH2), 67.8–70.3 (2 × ArOCH2CH2O); C2OC2OC2 (i) 70.8–71.8 (2 × ArOCH2), 69.67–71.16 (2 × ArOCH2-
CH2OCH2); C2SC2 (j) 70.0–72.5 (2 × ArOCH2), 29.4–32.4 (2 × ArOCH2CH2S); C2N(Ts)C2 (k) 143.4–143.7 (Ph 4-C; i.e. para to SO2), 136.4–136.8
(Ph 1-C; i.e. adjacent to SO2), 129.6–129.9 (Ph 3-C and Ph 5-C; i.e. meta to SO2), 126.3–127.2 (Ph 2-C and Ph 6-C; i.e. ortho to SO2), 69.2–71.0
(2 × ArOCH2), 48.7–49.3 (2 × ArOCH2CH2N), 21.3–21.5 (PhMe).
R. Moody and C. O. Rodriguez de Barbarin, J. Chem. Soc., Dalton
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G. Jones, Synth. Commun., 1986, 16, 795; (e) D. E. Fenton and
R. Moody, J. Chem. Soc., Dalton Trans., 1987, 219.
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12 T. Sone, K. Sato and Y. Ohba, Bull. Chem. Soc. Jpn., 1989, 62, 838.
13 H. Zimmer, A. Amer, R. Shabana, D. Ho, H. B. Mark Jr.,
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14 M. J. Marsella and T. M. Swager, J. Am. Chem. Soc., 1993, 115,
12214.
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Trans. 1, 1994, 2323.
6 D. MacDowell and J. Nelson, Tetrahedron Lett., 1988, 29, 385.
7 B. Oussaid and B. Garrigues, Phosphorus, Sulfur Silicon Relat.
Elem., 1992, 73, 41.
8 J. S. Bradshaw, S. L. Baxter, J. D. Lamb, R. M. Izatt and J. J.
Christensen, J. Am. Chem. Soc., 1981, 103, 1821.
9 K. T. Potts and M. J. Cipullo, J. Org. Chem., 1982, 47, 3038.
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