A new general route to thiophenophanes: Synthesis and properties of [n](2,5)thiophenophane-1,n-diones

Article abstract of DOI:10.1021/jo060889n

A series of [n](2,5)thiophenophane-1,n-diones (5) (n = 9, 10, 12, 14, 16, and 20) were synthesized in a simple four-step route starting from the appropriate 1,ω-oligomethylenedicarboxylic acids. The bis(halomethylketones) (6), which were obtained by successive treatment of the diacids with SOCl₂, diazomethane, and HBr or HCl, were cyclized by Na₂S under high dilution conditions. The obtained monomeric cyclic diketosulfides (4) were condensed with glyoxal in MeOH by slowly adding dilute NaOMe affording 5. The thiophene-2,5-dicarbonyl moiety of 5 (n = 9) is significantly deformed as shown by X-ray crystallography, and the effect of the strain is reflected in the C=O stretching frequencies and the π-π* and the n-π* absorptions.

Full text of DOI:10.1021/jo060889n

A New General Route to Thiophenophanes: Synthesis and
Properties of [n](2,5)Thiophenophane-1,n-diones
Yuji Miyahara
Department of Chemistry, Faculty of Sciences, Kyushu UniVersity,
Hakozaki, Higashi-ku, Fukuoka 812-8581, Japan
miyahscc@mbox.nc.kyushu-u.ac.jp
ReceiVed April 28, 2006
A series of [n](2,5)thiophenophane-1,n-diones (5) (n ) 9, 10, 12, 14, 16, and 20) were synthesized in a
simple four-step route starting from the appropriate 1,ω-oligomethylenedicarboxylic acids. The bis-
(halomethylketones) (6), which were obtained by successive treatment of the diacids with SOCl2, diazo-
methane, and HBr or HCl, were cyclized by Na2S under high dilution conditions. The obtained monomeric
cyclic diketosulfides (4) were condensed with glyoxal in MeOH by slowly adding dilute NaOMe affording
5. The thiophene-2,5-dicarbonyl moiety of 5 (n ) 9) is significantly deformed as shown by X-ray
crystallography, and the effect of the strain is reflected in the CdO stretching frequencies and the π-π*
and the n-π* absorptions.
Introduction
in the presence of excess (CF3CO)2O and a catalytic amount of
H3PO4 giving 2 (n ) 9, 10, 12, 14, and 18) in 9-66% yield.3
Since a thiophene ring is readily manipulated synthetically,
it has been used as a latent functionality in organic synthesis.1
However, thiophene-containing macrocycles, thiophenophanes,
have received only limited attention mainly because of the lack
of a general and mild synthetic method.
The most common [n](2,5)thiophenophanes (1) and their
derivatives have been synthesized by methods that can be
classified into two types: (I) cyclization of suitably substituted
thiophene derivatives and (II) construction of a thiophene ring
in a macrocycle. The first type includes intramolecular acylation
of ω-(2-thienyl)alkanoic acid chloride in chloroform in the
presence of partially hydrolyzed AlCl3 affording [n](2,5)-
thiophenophan-1-one (2) (n ) 9-12) in 8-64% yield2 or intra-
molecular acylation of ω-(2-thienyl)alkanoic acid in acetonitrile
Cyclization of thiophene derivatives also has been accom-
plished by intramolecular alkylation of ω-iodo-â-ketoesters (3)
in methyl ethyl ketone (MEK) in the presence of K2CO3
followed by hydrolysis with decarboxylation that provided 2
(n ) 11 and 13).4 This method was simplified later to use a
thienylacetate moiety instead of a â-ketoester group as the
(3) (a) Galli, C.; Illiminati, G.; Mandolini, L. J. Org. Chem. 1980, 45,
311-316. (b) Catoni, G.; Galli, C.; Mandolini, L. J. Org. Chem. 1980, 45,
1906-1908.
(4) Gol’dfarb, Ya. L.; Taits, S. Z.; Bulgakova, V. N. IzV. Akad. Nauk
SSSR, Ser. Khim. 1963, 1299-307.
(1) Meyers, A. I. Heterocycles in Organic Synthesis, John Wiley &
Sons: New York, 1974.
(2) Gol’dfarb, Ya. L.; Taits, S. Z.; Belen’kii, L. I. Tetrahedron 1963,
19, 1851-1866.
10.1021/jo060889n CCC: $33.50 © 2006 American Chemical Society
Published on Web 07/26/2006
6516
J. Org. Chem. 2006, 71, 6516-6521

Synthesis and Properties of Thiophenophanes
SCHEME 1. Cyclization of Thiophene-Containing
Precursors
SCHEME 3. Condensation of Cyclic Diketosulfides 4 with
Glyoxal to Form Thiophenophanediones 5
SCHEME 4. Preparation of Bis(halomethylketones) 6
SCHEME 5. Cyclization of Bis(halomethylketones) 6
SCHEME 2. Construction of a Thiophene Ring
on a Macrocycle
of cyclic oligomethylene diketosulofides (4) with glyoxal to give
[n](2,5)thiophenophane-1,n-diones (5) as the key step (Scheme 3).
Results and Discussion
Commercially available 1,ω-oligomethylenedicarboxylic acids
were converted to the corresponding 1,ω-dihalooligomethylene-
2,(ω-1)-dione (6) (Scheme 4 ) by successive treatments with
thionyl chloride, diazomethane, and hydrochloric or hydro-
bromic acid in excellent yields.12-15 As reported already,11 the
more reactive bromides are preferred over the chlorides for the
subsequent cyclization reaction with Na2S, but because the
preparation of the bis(bromoacetyl) compounds requires a large
excess of diazomethane to make pure bis(diazoketones)12 we
utilized bromides only for short chain compounds.
Cyclization of 6 with Na2S. Cyclization of the bis(haloacetyl)
compounds 6 (Scheme 5) was conducted under our standard
high dilution conditions in which a solution of a bis(haloacetyl)
compound in benzene or other suitable solvents and a solution
of sodium sulfide in aqueous EtOH were added simultaneously
to refluxing EtOH over a period of 8-12 h. Chromatographic
separation (silica gel) of the crude products gave the monomeric
cyclic diketosulfide 4 and the corresponding dimer 7 as listed
in Table 1.
precursor of an anion for cyclization to thiophenophanes 3
(n ) 10 and 12).5 These methods have wide applicability but
suffer from the accessibility of the appropriate thiophene-
containing precursors (Scheme 1).6
The only reported method of the second type is the application
of the Paal-Knorr reaction on macrocyclic 1,4-dicarbonyl
compounds to produce 1 (Scheme 2). The drawbacks of this
method are limited availability of the diketones, and the con-
version to the thiophenophane is not always successful even
though several sulfurization reagents and conditions may be
applied: 80% yield for n ) 8,7-8 but 37% yield for n ) 11,9
and only a trace in the case of n ) 10.10
Here, we describe a new general synthetic method for 1,
which belongs to the second type. The method is an extension
of our thiophenophane synthesis11 and includes condensation
Most of the cyclic diketosulfides 4 (n ) 9, 10, 12-16, and
19) already have been prepared by Baccetti and co-workers
using 6 (X ) Cl).16 However, they obtained 4 (n ) 9) only as
an impure solid in yield of 5% as estimated from its bis(2,4-
dinitrophenylhydrazone). By using bromide 6 (n ) 9, X ) Br),
we could obtain pure 4 (n ) 9) in 20% yield.
(5) Taits, S. Z.; Bulgakova, V. N. IzV. Akad. Nauk SSSR, Ser. Khim.
1984, 218-225 (Bull. Acad. Sci. USSR, DiV. Chem. Sci. 1984, 105-201).
(6) For the synthesis of 3,4-dibromo derivatives of 1, a general method
applicable for n ) 8, 10-12, and 14 has been developed utilizing pyrolysis
of the appropriate disulfones of dithiathiophenophanes. See: Li, Y.-Q.;
Thiemann, T.; Mimura, K.; Sawada, T.; Mataka, S.; Tashiro, M. Eur. J.
Org. Chem. 1998, 1841-1850. Unfortunately, the method does not appear
to be examined for its applicability to unsubstituted 1, which requires a
method for selective oxidation of sulfide groups in the presence of electron-
rich thiophene.
(7) (a) Nozaki, H.; Koyama, T.; Mori, T.; Noyori, R. Tetrahedron Lett.
1968, 2181-2182. (b) Nozaki, H.; Koyama, T.; Mori, T. Tetrahedron 1969,
25, 5357-5364.
(8) Helder, R.; Wynberg, H. Tetrahedron 1975, 31, 2551-2557.
(9) Gronowitz, S.; Frejd, T. Acta Chem. Scand. 1976, B30, 341-344.
(10) Hadj-Abo, F.; Bienz, S.; Hesse, M. Tetrahedron 1994, 50, 8665-
8672
(12) Fahr, E. Liebigs Ann. Chem. 1960, 638, 1-32. If the bis(diazo-
ketones) were not isolated, even when an excess of diazomethane was used,
the bromides were contaminated with a small amount (ca. 5%) of the
chloride.
(13) Work, T. S. J. Chem. Soc. 1940, 1315-1320.
(14) Canonica, L.; Bacchetti, T. Atti. Accad. Naz. Lincei, Rend., Cl. Sci.
Fis., Mat. Nat. 1951, 10, 479-484.
(15) Canonica, L.; Bacchetti, T. Atti. Accad. Naz. Lincei, Rend., Cl. Sci.
Fis., Mat. Nat. 1953, 15, 278-285.
(11) (a) Miyahara, Y.; Inazu, T.; Yoshino, T. Chem. Lett. 1978, 563-
566. (b) Miyahara, Y.; Inazu, T.; Yoshino, T. J. Org. Chem. 1984, 49, 1177-
1182.
(16) (a) Baccetti, T.; Canonica, L. Gazz. Chim. Ital. 1952, 82, 243-251
(Chem. Abstr. 1953, 47, 8718c). (b) Baccetti, T.; Canonica, L. Gazz. Chim.
Ital. 1953, 83, 832 (Chem. Abstr. 1954, 49, 4679h).
J. Org. Chem, Vol. 71, No. 17, 2006 6517

Miyahara
TABLE 1. Cyclization of 6 with Na2S
halide 6 monomer 4
mp (lit mp) °C
dimer 7
mp °C
N
X
yield, %
yield, %
8
9
Br12
Br12
12.3
19.5
30.2
46.1
47.0
53.5
33.3
52-53
27.4
11.6
2.9
3.1
6.6
119-120
114.5-115
132-133
73-74 (solid)16a
75.5-76.5 (75)16a
73-74 (74)16a
64-65 (67)16a
46-47 (44)16b
42-42.5
10 Cl12
12 Cl13
14 Cl14
16 Cl15
20 Cl
139-140
Conversion of 4 to [n](2,5)Thiophenophane-1,n-diones 5.
As reported, the cyclic aromatic diketosulfides could be con-
verted to the corresponding thiophenediones by condensation
with glyoxal in high yields for larger cyclic compounds.11
Although we have succeeded in extending the reaction to include
[3.3](2,5)furanothiophenophane and [3.3]metathiophenophane
and its derivatives from the corresponding alkyl chain-
substituted diketosulfides,17 the yields tend to be lower because
the acidity of the methylene attached to an alkyloyl group is
lower than the acidity of the methylene next to an aroyl group
in the thiophene-forming condensation, and the aldol-type side
reactions of the product diones are possible. Our original inten-
tion of the present study was to examine the scope of this
thiophenophane synthesis to [n](2,5)thiophenophanediones whose
ring sizes can be changed at will.
As compared with the corresponding open chain compounds,
the reactions of the conformationally restricted cyclic diketo-
sulfides are disfavored, since the thiophene-forming condensa-
tion of a diketosulfide with glyoxal involves two addition-
elimination sequences. Therefore, slow addition of a dilute
NaOMe solution to the mixture of 4 and glyoxal by a syringe
pump over 10-12 h was essential.11 Otherwise, the reaction
conditions are very simple and mild. After a workup including
filtration chromatography, the desired thiophenophanediones 5
were obtained in yields as shown in Table 2, except for 4 (n )
8), which has a high tendency for self-addition under the basic
conditions as noted above.
136.5-137.5
Even smaller 4 (n ) 8) also could be prepared in 12% yield
by using the bromide along with the dimer 7 (n ) 8) in 27%
yield. This reaction was extremely sensitive to the presence of
an excess of Na2S. Although we were aware that the addition
of excess Na2S should be avoided throughout the cyclization
reaction to prevent aldol-type condensation of the products,11
this reaction was far more sensitive to the excess of Na2S than
in the previous cases where intermolecular condensation oc-
curred between the carbonyl group and the methylene group,
which was doubly activated by a carbonyl group and a thioether
group. Without rigorous control of the addition of the solutions
keeping the bromide solution in slight excess, the yield of 4
(n ) 8) dropped seriously and provided an oily mixture of
products instead. On the other hand, the yield of the dimer was
barely affected by the presence of excess Na2S.
Separation of the oil by preparative TLC furnished colorless
plates with low Rf and an oil with high Rf. The former compound
1
showed a very complex H NMR spectrum, but its molecular
mass (M+ m/z 200) in the mass spectra and molecular composi-
tion by elemental analysis are the same as 4 (n ) 8). Since this
compound contains a hydroxyl group as suggested by the
presence of a sharp absorption at 3478 cm-1 in the IR spectrum
together with a carbonyl group (νCdO 1697 cm-1), it is assigned
as 8, which is formed by an intramolecular addition reaction.18
The participation of the less acidic methylene group activated
by one carbonyl group rather than the methylene activated by
a carbonyl group and a sulfide group was unexpected, but the
close proximity of the reacting groups and the thermodynamic
stability of the bicyclic structure 8 appears to make this trans-
formation feasible.
Note that 5 (n ) 12) has been isolated in 14% yield from the
cyclization of 10, and the formation of 10 was assumed to occur
via oxidative decarboxylation of the intermediate 115 (Scheme 6).
The dimer 7 (n ) 8), which was obtained as a major product,
can be converted to the corresponding thiophenophane 12 in
55% yield even though two thiophene rings have to be
constructed (Scheme 7).
Conversion of 5 (n ) 10) to 1 (n ) 10). As an example for
the reduction of thiophenophanedione 5 to the corresponding
1, the Wolff-Kishner reaction was carried out for n ) 10. By
TABLE 2. Conversion to Thiophenophanes
5 (from 4)
mp (lit. mp) °C
12 (from 7)
n
yield, %
yield, %
54.7
mp °C
The latter compound, an olefin 9,14 resulted from the
dehydration of 8, which was suggested from the presence of
olefinic carbon signals in its 13C NMR spectrum. The detri-
mental effect of a base was demonstrated by immediate changes
8
225-226
9
10
12
14
16
20
29.9
22.1
50.7
54.1
47.8
40.4
138-139
76.5-77.5
80.5-81 (77.5-78.5)
98-98.5
121.5-122
115.5-116
1
in the H NMR spectrum of pure 4 (n ) 8) in CDCl3 when a
catalytic amount of NaOMe in CD3OD was added: the singlet
peak for the COCH2S moiety of 4 (n ) 8) was completely
replaced by the peaks for 8 and 9.
SCHEME 6
(17) (a) Miyahara, Y.; Inazu, T.; Yoshino, T. Chem. Lett. 1980, 397-
400. (b) Miyahara, Y.; Inazu, T.; Yoshino, T. Tetrahedron Lett. 1984, 25,
415-418.
(18) The presumed structure depicted is the most stable structure obtained
by Monte Carlo conformational searches using MMFF94 force field as
implemented in Spartan and confirmed as the lowest energy structure by
DFT calculations at the B3LYP/6-31G(d) level (Gaussian03).
6518 J. Org. Chem., Vol. 71, No. 17, 2006

Synthesis and Properties of Thiophenophanes
FIGURE 1. The electronic spectra of 5 (n ) 9, 10, 12, and 20) and 14 (R ) n-Bu) in cyclohexane.
SCHEME 7. Conversion of the Dimer 7 (n ) 8) to
Thiophenophane 12
SCHEME 8. The Wolff-Kishner Reduction of the
Tetraketone 12 to Thiophenophane 13
use of the usual Kindler modification, 1 (n ) 10) was readily
obtained in 87% yield.
predicted by DFT calculations (Gaussian03) (trans,trans and
trans,cis forms are less stable than cis,cis by 1.34 and 0.20 kcal/
mol, respectively, for 14 (R ) Me) and 1.12 and 0.09 kcal/
mol, respectively, for 14 (R ) n-Bu) at the B3LYP/6-31(G)
level).
Reduction of the Tetraone 12 to [8.8](2,5)Thiophenophane
13. The Wolff-Kishner reduction of the tetraone 12 (n ) 6),
which is sparingly soluble in most solvents, was not as
straightforward as for 5 (n ) 10); the usual procedure led to
immediate precipitation of insoluble, possibly polymeric, orange
azines, and the yield of the reduction product was negligible.
This problem could be solved by reversing the order of addition.
Thus, when a hot solution of 12 (n ) 6) in diethylene glycol
was added to refluxing hydrazine hydrate in diethylene glycol
containing hydrazine dihydrochloride as a catalyst, a clear
yellow solution resulted without any sign of formation of azines.
After the addition of KOH, the solution was heated at 200 °C
for 15 h, and pure thiophenophane 13 was obtained in 70%
yield (Scheme 8).
However, when the thiophene-2,5-dicarbonyl moiety is
incorporated in macrocyclic systems, it no longer can be planar,
but it may be deformed depending on the ring size. In our pre-
vious paper,11b we disclosed that the effect of the ring size is
clearly reflected in the chemical shift of the thiophene proton
and the carbonyl stretching frequency of macrocyclic [n.1.1]-
paracyclo(2,5)thiophenoparacyclophane-(n + 7),(n + 13)-diones
(n ) 3-8, 10) 15.
The Structural Features of [n](2,5)Thiophenophane-1,n-
diones 5. As summarized in several review articles, the
thiophene-2-carbonyl compounds have a tendency to take the
S,O-cis conformation.19
In the case of open chain 2,5-diacylthiophenes 14, the planar
O,S,O-cis,cis conformation is the most stable conformation,
which is revealed by their NMR and IR spectra.11b,20 The pref-
erence for cis,cis over trans,cis or trans,trans could be reasonably
(19) (a) Sheinker, V. N.; Garnovskii, A. D.; Osipov, O. A. Usp. Khim.
1981, 50, 632-664 (Russ. Chem. ReV. 1981, 50, 336-352). (b) Kucsman,
A.; Kapovits, I.. In Organic Sulfur Chemistry; Bernadi, F., Czimadia, I.
G., Mangini, A., Eds.; Elsevier: New York, 1985; pp 191-245. (c) Benassi,
R.; Folli, U.; Schenetti, L.; Taddei, F. AdV. Heterocycl. Chem. 1987, 41,
75-186.
1
Although the H NMR signals for the thiophene protons in
(20) Miyahara, Y. J. Heterocycl. Chem. 1979, 16, 1147-1151.
the present [n](2,5)thiophenophane-1,n-dione 5 system (δ 7.72,
J. Org. Chem, Vol. 71, No. 17, 2006 6519

Miyahara
or partially protected as ketals for later use. Although in this
investigation only simple thiophenophanes were synthesized,
the mild reaction conditions throughout the synthetic route
would be beneficial for synthesis of functionalized compounds.
Experimental Section
Cyclization of 1,ω-Bis(haloacetyl)alkane 6. Cyclization of
1,10-Dibromodecane-2,8-dione 6 (n ) 8, X ) Br). TSolutions
of the dibromide (13.1 g) in 500 mL of benzene, sodium sulfide
(9.6 g of decahydrate) in 150 mL of water, and 350 mL of ethanol
were added separately under high dilution conditions to refluxing
ethanol (1.0 L) over 9 h. After an additional hour of refluxing, the
colorless solution was evaporated and dissolved in 150 mL of
chloroform. Column chromatography (silica gel 37 × 250, 1:1
chloroform-benzene) gave 987 mg (12.3%) of the monomer 4
(n ) 8) and 2.19 g (27.4%) of the dimer 7 (n ) 8).
FIGURE 2. The ORTEP drawing of 5 (n ) 9) at the 50% probability
level.
7.75, 7.78, 7.82, 7.69, and 7.55 for n ) 20, 16, 14, 12, 10, and
9, respectively, compared to δ 7.70 and 7.68 for 14 (R ) Me)
and 14 (R ) n-Bu), respectively) appear to reflect the changes
around the thiophene-diacarbonyl moiety, the chemical shift
changes observed are very small compared to the NMR spectral
changes observed for 15. Because of the absence of the large
and far-reaching anisotropic shielding effect of the benzene rings
in 15, meaningful discussion of the whole series is not possible
at this stage. However, the gradual upfield shifts as the ring
size n decreases from 12 to 9 suggest the strain is in the
smallest 5.
Thiacycloundecane-3,10-dione 4 (n ) 8). Colorless plates
(hexane), mp 54-54.5 °C. Anal. Calcd for C10H16O2S: C, 59.97;
H, 8.05. Found: C, 59.83; H, 8.13. MS m/z 200 (M+). IR (KBr) ν:
1705, 1692 (equal intensity, CdO), 2922, 2860, 1459, 1402, 1208,
1
1103, 943 cm-1. H NMR (400 MHz, CDCl3): δ 3.33 (s, 4H),
2.60 (t, J ) 6.4 Hz, 4H), 1.70 (quint, J ) 6.4 Hz, 4H), 1.38 (quint,
J ) 6.4 Hz, 4H). 13C NMR (100 MHz, CDCl3): δ 207.1, 41.6,
39.0, 25.2, 22.4.
The uniqueness of 5 (n ) 9) also is apparent from its carbonyl
frequencies (νCdO) in the IR spectra in solution (CDCl3):
1,12-Dithiadocosane-3,10,14,21-tetraone 7 (n ) 8). Colorless
plates (PhH), mp 119-120 °C. Anal. Calcd for C20H32O4S2: C,
59.97; H, 8.05. Found: C, 59.92; H, 8.06. IR (KBr) ν: 1708 (CdO),
ν
CdO1667, 1667, 1668, 1669, 1665, and 1674 cm-1 for n ) 20,
2928, 2856, 1462, 1405, 1372, 1223, 1184, 1104, 713, 579 cm-1
.
16, 14, 12, 10, and 9, respectively.
1H NMR (400 MHz, CDCl3): δ 3.30 (s, 8H), 2.55 (t, J ) 7.3 Hz,
8H), 1.58 (quint, J ) 7.3 Hz, 8H), 1.30 (m, 8H). 13C NMR (100
MHz, CDCl3): δ 205.3, 41.4, 40.7, 28.6, 23.4.
The electronic spectra of 5 (n ) 9) in cyclohexane also are
different from the larger thiophenophanes as shown in Fig-
ure 1. Although the λmax of thiophene π-π* absorption at ca.
290 nm does not change appreciably, the intensity reduces
with decreasing ring size, while the n-π* band appears as a
shoulder at ca 350 nm and increases its intensity with ca. 10 nm
red shift for 5 (n ) 9): λmax(ꢀ) 290 (16800), 291 (16500), 292
(17200), 292 (18400), 293 (15200), 292 (13500) for n ) 20,
16, 14, 12, 10, and 9, respectively, as compared with 14 (R )
n-Bu) [289 (16200)].
Since all the data indicate the strained nature of 5 (n ) 9),
the X-ray crystal structure was determined. As shown in
Figure 2, the thiophene-2,5-dicarbonyl moiety is in an O,S,O-
trans,trans conformation and is deformed significantly out of
planarity. While the thiophene ring itself is almost planar, the
Cthiophene-Ccarbonyl bonds are significantly bent from the thiophene
plane (18.6° and 14.6°).
When Na2S was added in excess in the reaction even if tem-
porarily, the monomer fractions in chromatographic separation
contained unstable side products, ketoalcohol 10 and ketoolefin 11
in varying amounts and ratios. Preparative TLC (silica gel,
chloroform-hexane 1:1) gave two products along with 4 (n ) 8)
(TLC (silica gel, chloroform): 9 Rf 0.70, 4 Rf 0.54, 8 Rf 0.30).
Ketoalcohol 8. Colorless needles (hexane), mp 53-54 °C. Anal.
Calcd. for C10H16O2S: C, 59.97; H, 8.05. Found: C, 59.89; H,
8.00. MS m/z 200 (M+). IR (KBr) ν: 3478 (sp, OH), 1697 (CdO),
1
2926, 2856, 1457, 1327, 1223, 1066 cm-1. H NMR (400 MHz,
C6D6): δ 2.65 (s, 1H, OH), 2.64 (d, J ) 12.2 Hz, 1H), 2.55 (dd,
J ) 12.2, 2.0 Hz, 1H), 2.48 (d, J ) 13.7 Hz, 1H), 2.06 (ddd, J )
14.7, 5.9, 2.4 Hz, 1H), 1.92 (dd, J ) 13.7, 2.4 Hz, 1H), 1.78 (td,
J ) 12.2, 2.4 Hz, 1H), 1.67 (m, 1H), 1.61 (ddd, J ) 14.7, 9.3, 1.5
Hz, 1H), 1.35 (ddd, J ) 14.7, 10.3, 1.5 Hz, 1H), 1.43 (m, 1H),
1.29 (m, 1H), 1.09 (m, 1H), 0.94 (m, 1H). 13C NMR (100 MHz,
C6D6): δ 203.2, 81.0, 61.8, 42.5, 42.1, 37.7, 28.6, 27.2, 21.7, 21.5.
Ketoolefin 9. Light yellow oil, bp 109-110 °C/0.2 mmHg,
decomposed on standing. Anal. Calcd for C10H14OS: C, 65.89; H,
7.74. Found: C, 65.23; H, 7.68 (attempts at further purification
resulted in loss of the material and in decomposition). IR (neat) ν:
1655 (CdO), 1624 (CdC), 2923, 2851, 1451, 1270, 1215, 1070,
963, 754 cm-1. 1H NMR (400 MHz, CDCl3): δ 3.36 (s, 2H), 3.21
(s, 2H), 2.55 (t, J ) 5.0 Hz, 2H), 2.37 (t, J ) 5.0 Hz, 2H), 1.77
(quint, J ) 6.0 Hz, 2H), 1.58 (quint, J ) 5.5 Hz, 2H), 1.44 (quint,
J ) 5.5 Hz, 2H). 13C NMR (100 NHz, CDCl3): δ 191.7, 157.8,
138.2, 36.9, 33.5, 32.0, 31.8, 25.9, 25.2, 25.0.
The larger cyclic diketosulfides 4 and the corresponding dimers
7 were prepared in a similar fashon except that the solvent for the
halides was changed according to its solubility: PhH, PhH, THF,
PhH-dioxane (7:1), THF, and PhH-dioxane (1:1) for n ) 9, 10,
12, 14, 16, and 20, respectively (see Supporting Information).
Conversion of 4 to [n](2,5)Thiophenophane-1,n-dione 5.
Attempts at obtaining 12 (n ) 8) gave brown oils, which decom-
posed upon standing.
The detailed conformational analysis of 5 in solution, which
must take the large flexibility of the oligomethylene chain and
possibilities of the cis,cis, cis,trans, and trans,trans forms for
the thiophenedicarbonyl moiety into account, is in progress and
will be reported elsewhere.
Conclusions
We disclosed that a suitable diacid can be converted through
diacid chloride, bis(diazoketone), and cyclic ketosulfide to the
corresponding thiophenophanediones under mild reaction condi-
tions. This method fails for n ) 8 because the intramolecular
self-addition of the monomeric diketosulfide readily occurs, but
both of the diketosulfide moieties of the dimer 9 (n ) 8)
obtained as the major product can be transformed to thiophene
rings, which opens a new route to thiophenophanes with two
thiophene rings.
In the present investigation, the carbonyl groups simply were
reduced to give [n](2,5)thiophenophanes so they may be fully
6520 J. Org. Chem., Vol. 71, No. 17, 2006

Synthesis and Properties of Thiophenophanes
[9](2,5)Thiophenophane-1,9-dione 5 (n ) 9). To a mixture of
4 (n ) 9) (860 mg, 4.0 mmol) in 160 mL of MeOH and 40 mL of
a solution of glyoxal (8.40 g of glyoxal trimer dihydrate dissolved
in 500 mL of MeOH), 20 mL of a solution of NaOMe (0.55 g of
Na dissolved in 100 mL of MeOH) was injected over 10 h via a
syringe pump, and the solution was stirred overnight at room
temperature. The resulting solution was evaporated, and the residue
was treated with 100 mL of water, acidified with dil HCl, and
extracted with chloroform. The extract was dried (MgSO4) and
filtered through a column of silica gel and evaporated. The residue
was sublimed (140 °C/0.1 mmHg) to give pale yellow crystals,
284 mg (29.9%). Recrystallization from acetone gave colorless
prisms, mp 138-139 °C. Anal. Calcd for C13H16O2S: C, 66.07;
H, 6.82. Found: C, 65.84; H, 6.87. IR (KBr) ν: 1689 (m), 1671
(s) (CdO, 1674 in CDCl3), 2935, 1503, 1253, 1230, 1112, 841,
804 cm-1. 1H NMR (400 MHz, CDCl3): δ 7.55 (s, 2H), 2.81 (t, J )
6.8 Hz), 1.68 (quint, J ) 7.3 Hz, 4H), 1.60 (br quint, J ) 5.9 Hz,
4H), 1.03 (br quint, 4H). 13C NMR (100 MHz, CDCl3): δ 194.2,
147.2, 130.9, 25.7, 24.7, 24.4.
out by distillation in a sublimator at ca 100 °C/20 mmHg. Anal.
Calcd for C14H22S: C, 75.61; H, 9.97. Found: C, 75.45; H, 9.85.
1H NMR (400 MHz, CDCl3): δ 6.62 (s, 2H), 2.75 (t, J ) 6.0 Hz,
4H), 1.60 (m, 4H), 1.34 (m, 4H), 1.07 (m, 4H), 0.81 (quint, J )
7.5 Hz, 4H). 13C NMR (400 MHz, CDCl3): δ 143.4, 124.9, 30.7,
30.5, 28.4, 27.2, 27.1.
[8.8](2,5)Thiophenophane 13. The tetraketone 12 (200 mg, 0.45
mmol) was dissolved in 20 mL of diethylene glycol by heating at
140 °C, and the solution was added gradually to a refluxing solution
of hydrazine hydrate (100%, 10 mL) in 10 mL of diethylene glycol-
containing 60 mg of hydrazine dihydrochloride with a Pasteur pipet
over 5 min. The clear yellow solution was refluxed for 1 h then
2.0 g of KOH was added and refluxing was continued for 1 h. The
excess of hydrazine was distilled out using a Dean-Stark trap and
the bath temperature was raised to 200 °C. After the mixture was
heated at 200 °C for 15 h, the resultant colorless solution was cooled
and diluted with water. The mixture was extracted (2 × 30 mL
hexane) and the combined extract was washed with dil HCl and
then with water. After drying (MgSO4), the solution was filtered
through a short column of silica gel. Evaporation of the solvent
left a colorless oil (122 mg, 69.9%), which crystallized immediately
(mp 52-53 °C). Anal. Calcd. for C24H36S2: C, 74.16; H, 9.34.
The larger thiophenophanediones 5 were prepared similarly and
described in the Supporting Information.
[8.8](2,5)Thiophenophane-1,8,14,21-tetraone 12. To a solution
of 7 (n ) 6) (801.2 mg, 4.0 mmol) in 100 mL of CH2Cl2, 40 mL
of the glyoxal solution mentioned above was added and 20 mL of
the NaOMe solution was injected over 12 h at room temperature.
The mixture was diluted with water and was acidified with HCl.
After the organic layer was separated, the aqueous phase was
extracted twice with CH2Cl2 (50 mL × 2). The solution was washed
with water and brine, dried over MgSO4, and passed through a short
column of silica gel eluted with CH2Cl2. Evaporation of the eluate
gave 486.3 mg (54.7%) of a pale tan granular powder. Recrystalli-
zation from N,N-dimethylformamide gave pale yellow crystalline
powder, mp 225-226 °C. Anal. Calcd for C24H28O4S2: C, 64.83;
H, 6.35. Found: C, 64.58; H, 6.32. IR (KBr) ν: 1668, 1649 (CdO,
equal intensity), 2945, 2924, 2902, 1457, 1325, 1259, 1214, 1185
1
Found: C, 74.07; H, 9.32. H NMR (400 MHz, CDCl3): δ 6.53
(s, 4H), 2.74 (t, J ) 7.0 Hz, 8H), 1.62 (quint, J ) 7.0 Hz, 8H),
1.29 (s, 16H). 13C NMR (100 MHz, CDCl3): δ 143.3, 123.5, 31.0,
29.6, 28.2, 27.4.
The X-ray Crystal Structure Determination of 5 (n ) 9). A
colorless prismatic crystal grown from acetone was cut into 0.4 ×
0.4 × 0.4 mm, suspended in liquid paraffin, and taken up with a
sampling loop. The X-ray reflection data were collected at -180 °C
and treated with teXan. Crystal data belongs to monoclinic space
group P21/n (No. 14) with a ) 7.0433(3) Å, b ) 11.6066(4) Å,
c ) 14.5664(8) Å, â ) 101.330(2)°, V ) 1167.57(9) Å3, Dcalc
)
1.344 g cm-3, and Z ) 4. The structure was solved by the direct
methods (SIR92) and refined to R1 ) 0.0339, Rw ) 0.1169, GOF
) 1.056 for 2423 reflections with F2 > 2.0σ (F2). The details are
in the Supporting Information.
1
cm-1. H NMR (400 MHz, CDCl3): δ 7.61 (s, 2H), 2.83 (t, J )
7.0 Hz), 1.79 (quint, J ) 6.5 Hz, 2H), 1.37 (quint, J ) 3.3 Hz,
4H). 13C NMR (100 MHz, CDCl3): δ 194.1, 148.9, 131.7, 38.4,
27.0, 24.1.
Acknowledgment. We thank Okamura Oil Mill Ltd. for
the generous gift of 1,14-tetradecanedicarboxylic and 1,18-
octadecanedicarboxylic acids. We also thank Professor Teruo
Shinmyozu for the X-ray data collection.
The Wolff-Kishner Reduction to Thiophenophanes. [10](2,5)-
Thiophenophane 1 (n ) 10). The diketone 5 (n ) 10) (98.0 mg,
0.40 mmol) was dissolved in 10 mL of diethylene glycol by heating
briefly at 100 °C and by adding 5 mL of 100% hydrazine hydrate.
After the addition of 20 mg of hydrazine dihydrochloride, the
mixture was refluxed for 30 min then 1.0 g of KOH was added
and the mixture was refluxed for an additional 30 min. The mixture
was heated to 200 °C while distilling off the hydrazine for 1 h.
After the reaction, the reaction mixture and the distillate were
combined, diluted with water, and extracted with hexane (2 × 10
mL). The combined extract was washed with dil HCl and then with
water, dried over MgSO4, passed through a short column of silica
gel, and evaporated to give 75.8 mg (86.5%) of a colorless liquid,
which was almost pure by1H NMR. Further purification was carried
Supporting Information Available: The experimental proce-
dures for the preparation of 1,ω-(bishaloacetyl)alkanes 6, the
1
properties of 4, 5, and 7, the H and 13C spectra of 1 (n )10), 4
(n ) 8, 9, 10, 12, 14, 16, and 20), 5 (n ) 9, 10, 12, 14, 16, and
20), 7 (n ) 8, 9, 10, 12, and 14), 8, 9, 12, and 14 (R ) n-Bu) and
the CH correlation spectra for 8 and 9, the molecular calculation
results for 8, 9, and 14 (R ) Me, n-Bu), and the details of the
X-ray structural analysis of 5 (n ) 9). These materials are available
free of charge via the Internet at http://pubs.acs.org.
JO060889N
J. Org. Chem, Vol. 71, No. 17, 2006 6521