Synthesis of aza-1,2-thiophenophanes by double ring enlargement

Article abstract of DOI:10.1016/S0040-4020(00)00651-7

Two ring enlargement reactions are used to transform the alicyclic 8-membered allyl 2-oxocyclooctane-1-carboxylate (11) to the 13-membered 10-aza-[11]-(2,3)-thiophenophane-1,9-dione (17). The first step yielded the macrocyclic imide allyl N-(3-thienylmeth

Full text of DOI:10.1016/S0040-4020(00)00651-7

TETRAHEDRON
Pergamon
Tetrahedron 56 (2000) 7205–7210
Synthesis of Aza-1,2-thiophenophanes
by Double Ring Enlargement
*
J o¨ rg Heerklotz, Anthony Linden and Manfred Hesse
Organisch-chemisches Institut der Universit a¨ t Z u¨ rich, Winterthurerstrasse 190, CH-8057 Z u¨ rich, Switzerland
Received 26 June 2000; accepted 26 July 2000
Abstract—Two ring enlargement reactions are used to transform the alicyclic 8-membered allyl 2-oxocyclooctane-1-carboxylate (11) to the
3-membered 10-aza-[11]-(2,3)-thiophenophane-1,9-dione (17). The first step yielded the macrocyclic imide allyl N-(3-thienylmethyl)-2,10-
1
dioxo-1-azacyclodecane-3-carboxylate (15) and, after deprotection, N-(3-thienylmethyl)-1-azacyclodecane-2,10-dione (16). In the second
step the N-thienyl substituent is incorporated in the large ring by the use of LDA. The overall yield was 45%. This method was also used to
convert the 12-membered allyl 2-oxocyclododecane-1-carboxylate (20) to the 17-membered 14-aza-[15]-(2,3)-thiophenophane-1,13-dione
(
23). ᭧ 2000 Elsevier Science Ltd. All rights reserved.
Introduction
corresponding aza, oxa and thia compounds succeed with
high yields.
A well-established method for the synthesis of substituted
medium and large ring compounds is the ring enlargement
reaction. In quite a number of cases, the syntheses of the
Some years ago, a very powerful reaction was reported
where the CH-acidic ketone 1 was treated with base to
1
Scheme 1.
Keywords: 1,2-thiophenophanes; ring enlargement; isocyanates.
*
Corresponding author. Tel.: ϩ41-1-635-4281; fax: ϩ41-1-635-6812; e-mail: mtbohley@oci.unizh.ch
0
040–4020/00/$ - see front matter ᭧ 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)00651-7

7
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J. Heerklotz et al. / Tetrahedron 56 (2000) 7205–7210
enlargement reaction is possible and R becomes a member
of the new ring. During this process, the imide is changed to
amide 4 (see Scheme 1).
It was of interest to study the possibility of incorporating a
thiophene ring into the enlarged ring by this method. There-
fore, three thiophene isocyanates were prepared, 2-thienyl-
methyl isocyanate (5), 3-thienylmethyl isocyanate (6), and
2
-bromo-3-(thienylmethyl) isocyanate (7). Compound 5
was synthesized from 2-thienylacetic acid chloride (8) by
4
treatment with trimethylsilylazide.
Results and Discussion
Starting from 3-thienylacetic acid (9) in the presence of
Scheme 2.
triethylamine and diphenylphosphorylazide (DPPA), 3-thi-
5
enylmethyl isocyanate (6) was formed in 73% yield (see
Scheme 2). The corresponding 2-bromo-3-(thienylmethyl)
isocyanate (7) was prepared in an analogous way to 6 from
the 2-bromoacid 10 but in lower yield (63%).
The ring enlargement reaction of the anion of allyl 2-oxo-
cyclooctane-1-carboxylate (11) with 2-thienylmethyl iso-
cyanate (5) gave in good yield the enlarged product 12
which was decarboxyallylated to give the imide 13. It was
not possible to obtain the 14-membered oxolactam 14 by
treatment of the 10-membered imide 13 with n-BuLi, t-BuLi
or lithiumdiisopropylamide (LDA). Decomposition was
observed when LDA was used in excess or at higher
temperature (see Scheme 3). It is very likely that steric
properties are responsible for the negative result in this case.
Therefore, in order to avoid steric hindrance, we tried using
the isocyanate 6 in which a hydrogen atom was incorporated
at the 2-position and the methyl isocyanate substituent was
at the 3-position of the thiophene. The resulting reaction is
depicted in Scheme 4. The formation of the 10-membered
imide 15 from the 8-membered 11 and the isocyanate 6
proceeded under normal conditions with 72% yield. Decar-
boxyallylation of 15 formed the imide 16. Strong IR absorp-
Scheme 3. (a) NaH, THF, 2-thienylmethyl isocyanate (5), 72%;
n
t
3 4 3
(b) Pd(PPh ) (kat.), HCOOH, Et N, THF, 88%; (c) BuLi/ BuLi/LDA.
give the corresponding anion which reacts smoothly with
isocyanate to form the large-ring imide 2. For this step,
yields between 50 and 95% have been reported, depending
on both the ring size of the activated ketone and the nature
Ϫ1
tions at approx. 1690 cm are typical of an imide ring. The
structure of 16 was confirmed by an X-ray crystallographic
analysis (Fig. 1).
2
,3
of the isocyanate substituent R. If, after deprotection,
the residue R can stabilize the negative charge, a second
n
Scheme 4. (a) NaH, THF, 72%; (b) Pd(PPh
Ϫ80ЊC, 3 h, 72%.
3
)
4
(kat.), HCOOH, Et
3
N, THF, 91%; (c) 4 eq. LDA, THF, Ϫ80ЊC, 4 h, 68%; (d) 1.1 eq. BuLi, Et
2
O, hexane,

J. Heerklotz et al. / Tetrahedron 56 (2000) 7205–7210
7207
Figure 1. The molecular structure of 16 showing the major conformation of the 5-membered ring (50% probability ellipsoids).
If the anion of compound 16 was formed by treatment of
LDA at Ϫ80ЊC in THF, the ring enlargement to the expected
It should be mentioned that when the isocyanate 6 is treated
with base, it is converted in variable yield to 3,3 -ureylene-
di-(3-methylene-thiophene) (24). This is a side reaction
observed quite frequently when compound 6 is used as a
reactant.
0
1
3-membered 10-aza-[11]-(2,3)-thiophenophane-1,9-dione
(
17) took place with a good yield of 68%. The same product
was observed when N-(2-bromo-3-(thienylmethyl)-1-aza-
cyclodecane-2,10-dione (19), prepared in an analogous
manner via 18 from compound 11 and the bromothienyl
isocyanate 7, was treated at Ϫ80ЊC in diethyl ether with
n-BuLi (see Scheme 4). Even the yield was similar to that
of the non-brominated material.
Conclusion
If the substituent R in compound 3 (see Scheme 1) is able to
carry a negative charge and if there is no steric hindrance,
the ring in these types of imide compounds can easily be
enlarged by several atoms depending on the nature of the
substituent.
In a further ring enlargement reaction, 3-thienylmethyl iso-
cyanate (6) was used to synthesize the 17-membered 23 in
an overall yield of 37% starting from the 12-membered allyl
2-oxocyclododecane-1-carboxylate (20, see Scheme 5).
3 4 3
Scheme 5. (a) NaH, THF, 3-thienylmethyl isocyanate (6), 68%; (b) Pd(PPh ) (kat.), HCOOH, Et N, THF, 87%; (c) 4 eq. LDA, THF, Ϫ80ЊC, 4 h, 62%.

7
208
J. Heerklotz et al. / Tetrahedron 56 (2000) 7205–7210
0
0
Experimental
6.92 (m, H-C(3 )); 6.89–6.86 (m, H-C(4 )); 4.94 (s,
NCH ); 2.76–2.72 (m, (4H); 1.79–1.71 (m, 4H); 1.46–
2
1
3
General
1.35 (m, 6H). C NMR: 178.31 (s, 2CO); 139.21 (s,
C(2 )); 126.48, 126.38 (2d, C(3 ),C(4 )); 125.64 (d, C(5 ));
0
0
0
0
All solvents were distilled prior to their use. Purification of
the solvents was performed according to standard methods.
Melting points were determined on a Mettler FP-5 instru-
42.21 (t, NCH ); 34.32, 24.87, 23.74, 22.20 (4t, 7CH ).
2
2
ϩ
ϩ⅐
EI-MS: 266 (23, [MϩH] ), 265 (50, [M] ), 238 (16), 237
(100), 208 (12), 194 (28), 180 (19), 166 (31), 152 (26), 112
(38), 111 (17), 110 (12), 97 (78), 55 (17).
ment. IR spectra (CHCl ) were obtained using a Perkin–
3
Elmer 297 or Perkin–Elmer 781 spectrophotometer; bands
are given in cm . H NMR spectra were recorded on a
Bruker ARX 300 (300 MHz) or Bruker AMX 600
Ϫ1
1
3-Thienylmethyl isocyanate (6). To a mixture of 2.0 g
(14.1 mmol) of 3-thienylacetic acid (9, Fluka) and 15 ml
of dry MeCN were added slowly, first 2.1 ml (15.0 mml)
(600 MHz) spectrometer; chemical shifts in d (ppm)
relative to TMS using the appropriate solvent as an internal
of Et
deep green colored reaction mixture was heated for 2 h at
55ЊC and evaporated. The residue was solved in CH Cl and
3
N and afterwards 3.24 ml (15.0 mml) of DPPA. The
1
3
standard. C NMR spectra at 75.47 MHz using a Bruker
ARX 300 spectrometer. Chemical shifts are reported as
2
2
1
for H and the multiplicities of the signals determined by
two times washed with hexane, dried in vacuo at 35ЊC:
1.43 g (10.3 mmol, 73%) 6. It was further purified by distil-
lation (0.04 Torr, 67–88.5ЊC). IR (measurement in situ):
DEPT experiments with sˆsinglet, dˆdoublet, tˆtriplet,
qˆquadruplet. EI- and CI-MS: Finnigan SSQ 700 or
Finnigan-MAT 90; m/z (rel. intensity in %); Electrospray-
Ionization (ESI): Finnigan TSQ 700.
1
2265s. H NMR: 7.36–7.34 (m, H-C(2)); 7.23–7.22 (m,
1
3
H-C(5)); 7.06–7.05 (m, H-C(4)); 4.49 (s, CH
39.76, 137.84 (2s, C(3), NCO); 126.93, 126.23, 122.01 (3d,
C(2), C(4), C(5)).
). C NMR:
2
1
2
(
4
-Thienylmethyl isocyanate (5). A solution of 4.0 g
25.0 mmol) of 2-thienylacetic acid chloride (8, Fluka) in
0 ml water free toluene and 3.95 ml (30.0 mmol) of
N SiMe were refluxed for 2 h. It was evaporated under
Allyl N-(3-thienylmethyl)-2,10-dioxo-1-azacyclodecane-
3-carboxylate (15). In accordance with experiment 3,
0.735 g (3.5 mmol) of 7, 172 mg NaH (3.6 mmol, 55% in
oil) and 0.5 g (3.6 mmol) of 6 dissolved in 20 ml of dry THF
were treated in a similar way. Purification was done by flash
chromatography (hexane/EtOAc 4:1): 1.01 g (2.9 mmol,
72%) 15 as a yellowish oil. IR: 3000w, 2940s, 2860m,
1730s, 1670s, 1510m, 1450m, 1415w, 1370w, 1330w,
3
3
vacuum and the residue distilled at 80–110ЊC/15 Torr.
The product was not purified further. IR of the raw material:
2260s.
Allyl N-(2-thienylmethyl)-2,10-dioxo-1-azacyclodecane-
-carboxylate (12). A solution of 1.0 g (4.8 mmol) of
3
3
1
allyl 2-oxocyclooctane-1-carboxylate (11), 70 ml water
free THF and 250 mg NaH (5.7 mmol, 55% NaH in oil)
was stirred for 30 min at room temperature until an
orange-yellow color appeared. A solution of 0.79 g
1270m, 1165w, 1045w, 990w, 940m, 860w, 830w. H
0
0
NMR: 7.29–7.26 (m, H-C(3 )); 7.13–7.12 (s, H-C(2 );
0
7.00–6.98 (m, H-C(4 )); 5.96–5.82 (m, CHvCH
); 5.34–
, H-C(3);
5H); 2.96–2.84 (m, 1H); 2.48–2.39 (m, 1H); 2.15–2.05 (m,
2
5.19 (m, CHvCH ); 4.65–4.47 (m, OCH , NCH
2 2 2
(
5.7 mmol) 5 in 2 ml THF was slowly added under vigorous
1
3
stirring. After 1 h it was neutralized with 1N aq. HCl at 0ЊC,
1H); 1.94–1.73 (m, 2H); 1.72–1.16 (m, 7H). C NMR:
extracted with CHCl , the extract was dried (MgSO ) and
178.66 (s, C(2)); 171.79 (s, C(10)); 169.33 (s, COOR);
3
4
0
evaporated. The residue gave after chromatography
hexane/EtOAc 4:1) 1.19 g (3.4 mmol, 72%) 12 as a yellow-
137.76 (s, C(3 )); 131.53 (d, CHvCH
2
); 127.32, 126.37,
);
); 36.47,
). EI-MS: 350
0
0
(
122.37 (3d, C(2 ), C(5), C(5 )); 118.60 (t, CHvCH
65.95 (t, OCH ); 52.78 (d, C(3)); 42.63 (t, NCH
28.71, 26.94, 25.46, 24.23, 22.35 (6t, 6CH
2
1
0
ish oil. H NMR: 7.15–7.13 (m, H-C(5 )); 6.91–6.81 (m, H-
C(3 ), H-C(4 ), 2H); 5.87–5.76 (m, CHvCH ); 5.27–4.36
2
2
0
0
2
2
ϩ
ϩ⅐
(
1
2
m, CHvCH , OCH , NCH , H-C(3), 5H); 2.95–2.86 (m,
(26, [MϩH] ), 349(9, M ), 321 (11), 250 (12), 152 (11),
2
2
2
H); 2.45–2.35 (m, 1H); 2.04–1.94 (m, 1H); 1.83–1.74 (m,
138 (13), 113 (14), 112 (100), 97 (76), 55 (32).
1
3
H); 1.63–1.13 (m, 7H). C NMR: 180.31 (s, C(2)); 171.91
0
(
s, C(10)); 169.43 (s, COOR); 138.47 (s, C(2 )); 131.64 (d,
N-(3-Thienylmethyl)-1-azacyclodecane-2,10-dione (16).
The hydrolysis and decarboxylation of 400 mg (1.2 mmol)
of 15 was realized in a similar way as given in experiment 4:
0
0
0
CHvCH ); 126.67, 126.48, 124.88 (3d, C(3 ), C(4 ), C(5 ));
2
1
17.90 (t, CHvCH ); 65.57 (t, OCH ); 51.52 (d, C(3));
2 2
4
2.41 (t, NCH ); 36.99, 28.63, 26.90, 22.82, 22.32, 22.03
87 ml HCOOH, 400 ml Et N and 54 mg Pd (PPh ) in 2.5 ml
3 3 4
2
ϩ
(6t, 6CH ). CI-MS (NH ): 367 (10, [MϩNH ] ), 351 (20),
dry THF: 277 mg (1.1 mmol, 91%) 16 as colorless crystals.
Mp 84.3–84.5ЊC. IR: 2920s, 2835m, 1710s, 1675s, 1440m,
2
3
4
ϩ
3
50 (100, [MϩH] ).
1
360w, 1345w, 1330m, 1265w, 1200br, 1170w, 1145m,
1
N-(2-Thienylmethyl)-1-azacyclodecane-2,10-dione (13).
To a solution of 600 mg (1.7 mmol) of 12 in 20 ml dry
THF was added a mixture of 129 ml of HCOOH, 600 ml
of Et N and 80 mg Pd (PPh ) in 2.5 ml dry THF. After
1070w, 1015w, 995w, 965w, 920w, 830w. H NMR:
7.27–7.23 (m, H-C(5 )); 7.12–7.11 (s, H-C(2 )); 6.99–
6.97 (m, H-C(4 )); 4.89 (s, NCH
0
0
0
); 2.75–2.71 (t,
2
Jˆ6.3 Hz, 4H); 1.82–1.74 (m, 4H); 1.47–1.30 (m, 6H).
3
3 4
1
3
0
C NMR: 178.65 (s, C(2), C(10)); 137.77 (s, C(3 ));
the formation of carbon dioxide had ceased, the solution
was stirred for 1 h and the solvent evaporated. Purification
of the residue was done by flash chromatography (hexane/
EtOAc 4:1): 400 mg (1.5 mmol, 88%) 13 as a yellow
lacquer. IR: 2930s, 2850m, 1710s, 1675s, 1440m, 1360w,
0
0
0
126.88, 126.34, 122.23, (3d, C(2 ), C(4 ), C(5 )); 42.60 (t,
NCH ); 34.38, 24.48, 23.76, 22.26 (4t, 7CH ). CI-MS
(NH
2
2
ϩ
): 531 (11), 267 (16), 266 (100, [MϩH] ), 265 (27),
3
237 (38), 166 (11), 112 (25), 97 (27). EI-MS: 265 (15,
ϩ⅐
1
1
345m, 1330m, 1265w, 1200br, 1160w, 1140m, 1065w,
040w, 915m. H NMR: 7.18–7.16 (m, H-C(5 )); 6.94–
[M] ), 237 (15), 194 (13), 180 (15), 166 (18), 152 (20),
1
0
127 (25), 125 (12), 113 (25), 112 (99), 111 (31), 110 (19),

J. Heerklotz et al. / Tetrahedron 56 (2000) 7205–7210
7209
9
8 (23), 97 (100), 55 (40). ESI-MS (MeOH): 288
55% NaH in oil); IR: 2970s, 2930m, 1740s, 1700s, 1520w,
ϩ
ϩ
([MϩNa] ), 266 ([MϩH] ). ESI-MS/MS (DAU 288,
1460m, 1440m, 1415w, 1370m, 1235w, 1160m, 1140m,
ϩ
1
Ϫ30 eV, MeOH): 288 (50, [MϩNa] ), 97 (100). ESI-MS/
MS (DAU 266, Ϫ30 eV, MeOH): 266 (17, [MϩH] ), 248
1105w, 1080w, 990m, 940m, 860w, 840w, 690w.
H
ϩ
0
0
NMR: 7.23–7.20 (m, H-C(5 )); 7.07–7.05 (s, H-C(2 ));
0
(20), 135 (40), 97 (100). Anal. Calcd for C H NO S
6.93–6.91 (m, H-C(4 )); 5.90–5.77 (m, CHvCH ); 5.28–
1
4
19
2
2
(
7
265.37): C 63.37, H 7.22, N 5.28; found: C 63.10, H
.10, N 5.26.
5.17 (m, CHvCH ); 4.59–4.56 (m, OCH ); 4.54–4.42 (m,
2
2
NCH ); 4.32–4.27 (m, H-C(3); 2.86–2.76 (m, 1H); 2.43–
2
2
.35 (m, 1H); 2.05–1.93 (m, 1H); 1.86–1.74 (m, 2H); 1.55–
13
For the X-ray crystallographic analysis, the sample was
crystallized from hexane/diethyl ether.
1.10 (m, 17H). C NMR: 176.82 (s, C(2)); 172.71 (s,
C(14)); 169.63 (s, COOR); 137.76 (s, C(3 )); 131.86 (d,
CHvCH ); 126.89, 126.51, 122.31 (3d, C(2 ), C(4 ), C5 );
0
0
0
0
2
1
1
0-Aza-[11]-(2,3)-thiophenophane-1,9-dione (17). From
6: To a solution of 130 mg (0.5 mmol) of 16 in 20 ml of
118.38 (t, CHvCH ); 65.81 (t, OCH ); 52.61 (d, C(3));
2
2
43.15 (t, NCH ); 35.94, 28.92, 26.27, 26.06, 25.97, 25.85,
2
dry THF at Ϫ80ЊC, 4.0 equiv. of LDA (350 ml of a 1.4 M
solution in hexane) was dropwise with stirring. After 5 h,
the yellowish colored solution was quenched by dropwise
addition of 1N aq. HCl. It was warmed to room temperature
and the mixture extracted with CH Cl . The solvent was
25.73, 25.17, 24.99, 24.08 (10t, 10CH ). CI-MS (NH ): 423
2
3
ϩ
ϩ
(38, [MϩNH ] ), 407 (21), 406 (100, [MϩH] ), 337 (13).
4
N-(3-Thienylmethyl)-1-azacyclotetradecane-2,14-dione
(22). Analogously to experiment 4, 359 mg (0.9 mmol) of
21, 67 ml HCOOH, 186 ml Et N and 41 mg of Pd (PPh ) ) in
2
2
evaporated and the residue purified by flash chromatography
3
3 4
(
CH Cl /MeOH 19:1): 88 mg (0.3 mmol, 68%) of 17 as a
2 ml dry THF were converted to 248 mg (0.8 mmol, 87%)
of 22 as colorless crystals. For flash chromatography
hexane/EtOAc 4:1 was used. Mp. 70.5–72.0ЊC. IR: 2930s,
2860m, 1690s, 1455m, 1370m, 1320w, 1160m, 1135m,
2
2
colorless lacquer.
From 19: All additions were performed through the rubber
septum using nitrogen-flushed syringes which were rinsed
with abs. THF before use. The assembly was flame dried (at
1
0
980w, 830w. H NMR: 7.29–7.26 (m, H-C(5 )); 7.10–
0
0
7.08 (m, H-C(2 )); 6.99–6.97 (m, H-C(4 )); 4.90 (s, 2H);
0
.02 mbar) and flushed with dry N while cooling. The flask
2.78–2.73 (t, Jˆ6.6 Hz, 4H); 1.68–1.61 (m, 4H); 1.37–
2
1
3
was charged with a solution of 19 (112 mg, 0.325 mmol) in
5 ml THF using a syringe and the solution was cooled to
Ϫ80ЊC. A ca. 1.6 M solution of n-BuLi in hexane (0.25 ml,
.4 mmol) was added dropwise through the septum and
1.27 (m, 14H). C NMR: 177.32 (s, C(2), C(10)); 138.34
0
0
0
0
2
(s, C(3 )); 126.94, 125.43, 122.04 (3d, C(2 ), C(4 ), C(5 ));
43.16 (t, NCH ); 36.37, 29.14, 26.13, 25.90, 25.65, 24.64
2
ϩ
0
(6t, 11CH ). CI-MS (NH ): 322 ([MϩH] ). EI-MS: 322 (16,
2
3
ϩ
ϩ⅐
stirred for 2 h at Ϫ80ЊC. The mixture slowly reached
[MϩH] ), 321 (83, M ), 294 (16), 293 (90), 196 (30), 183
(11), 166 (18), 138 (13), 137 (13), 113 (29), 112 (83), 111
(28), 110 (14), 98 (13), 97 (100), 81 (11), 69 (13), 57 (21),
55 (29), 54 (11), 43 (14), 41 (30). ESI-MS (MeOHϩNaI):
room temperature overnight. The flask was cooled in an
ice bath while satd. aq. NH Cl solution was added dropwise
and the mixture was stirred for 30 min at 0–4ЊC (still under
N ). Small amounts of H O were added to dissolve any
4
ϩ
344 ([MϩNa] ). ESI-MS/MS (DAU 344, Ϫ26 eV,
2
2
ϩ
precipitates and the mixture was extracted with CH Cl .
MeOHϩNaI): 344 (50, [MϩNa] ), 97 (100).
2
2
The extracts were dried over Na SO , evaporated and the
residue was purified by chromatography on silica gel
2
4
14-Aza-[15]-(2,3)-thiophenophane-1,13-dione (23).
A
(
3
1
CH Cl /MeOH 19:1) resulting in 62 mg (72%) of 17. IR:
solution of 200 mg (0.6 mmol) of 22 and 10 ml dry THF
was treated at Ϫ80ЊC with 4.0 equiv. of LDA (443 ml of a
1.4 M solution in hexane) as described for experiment 8.
Yield after flash chromatography (CH Cl /MeOH 19:1)
2
2
450m, 2995w, 2915s, 2860m, 1660s, 1505s, 1410m,
1
380m, 1275m, 1135w, 1020w, 840w. H NMR: 7.44 (d,
0
0
Jˆ4.9 Hz, H-C(5 )); 7.20 (d, Jˆ4.9 Hz, H-C(4 )); 6.95 (s,
2
2
NH); 4.53 (d, Jˆ6.6 Hz, NCH ); 2.81–2.77 (m, CH CO);
123 mg (0.4 mmol, 62%) of 23 as a colorless lacquer. IR:
2
2
2
(
.16–2.12 (m, CH NHCO); 1.91–1.83 (m, 2H); 1.60–1.46
3440m, 2930s, 2860m, 1655s, 1505m, 1455w, 1410m,
2
1
3
1
m, 4H); 1.24–1.15 (m, 2H); 1.03–0.96 (m, 2H). C NMR:
97.19 (s, CO); 173.13 (s, NHCO); 146.78 (s, C(2 )); 134.93
1380w, 1350w, 1270w, 1110w, 905w, 840w. H NMR:
0
0
0
1
7.45 (d, Jˆ4.9 Hz, H-C(5 )); 7.23 (d, Jˆ4.9 Hz, H-C(4 ));
0
0
0
(s, C(3 )), 132.70 (d, C(5 )); 129.92 (d, C(4 )); 43.59 (t,
6.93 (s, NH); 4.52 (d, Jˆ6.5 Hz, 2H); 2.93–2.90 (m, 2H);
1
3
CH CO); 38.84 (t, NHCH ); 35.53 (t, CH NHCO); 28.34,
2.15 (t, Jˆ7.3 Hz, 2H); 1.53–1.09 (m, 18H); C NMR:
2
2
2
0
2
6.62, 26.41, 25.39, 24.78 (5t, 5CH ). EI-MS: 266 (15), 265
194.73 (s, CO); 173.02 (s, CONHR); 146.24 (s, C(2 )).
2
ϩ⅐
0
0
0
(100, M ), 237 (35), 209 (29), 192 (14), 166 (18), 154 (12),
136.71 (s, C(3 )); 132.80, 130.00 (2d, C(5 ), C(4 )); 40.76,
37.97, 36.82, 29.32, 27.81, 27.46, 27.10, 26.85, 26.43,
26.05, 25.07, 24.21 (12t, 12CH ). CI-MS (NH ): 323 (19),
1
1
(
53 (11), 152 (39), 140 (14), 139 (12), 138 (16), 125 (19),
12 (16), 111 (13), 55 (13), 41 (11). ESI-MS (MeOH): 288
2
3
ϩ
ϩ
ϩ
ϩ
[MϩNa] ), 266 ([MϩH] ). ESI-MS/MS (DAU 288,
322 (100, [MϩH] ), 643 (10 [2MϩH] ). EI-MS: 322(19,
ϩ
ϩ ϩ⅐
Ϫ30 eV, MeOH): 288 (100, [MϩNa] ). ESI-MS/MS
[MϩH] ), 321 (100, [M] ), 294 (16), 293 (92), 265 (28),
ϩ
(DAU 266, Ϫ30 eV, MeOH): 266 (40, [MϩH] ), 249
153 (16), 152 (19), 140 (13), 138 (12), 125 (12), 112 (17), 57
(20), 151 (22), 135 (50), 97 (100).
(63), 56 (14), 45 (36), 41 (28). ESI-MS (MeOH/CHCl
3
ϩ
ϩ
3
:1ϩNaI): 344 ([MϩNa] ), 322 ([MϩH] ). ESI-MS/MS
Allyl
N-(3-thienylmethyl)-2,14-dioxo-1-azacyclotetra-
(DAU 344, Ϫ30 eV, MeOH/CHCl 3:1ϩNaI): 344 (100,
[MϩNa] ).
3
ϩ
decane-3-carboxylate (21). The conversion of 0.68 g
(
(
2.6 mmol) of allyl 2-oxocyclododecane-1-carboxylate
20) and 0.375 g (2.7 mmol) of 6 to 716 mg (2.9 mmol,
3
0
3,3 -Ureylene-di-(3-methylenethiophene) (24). This com-
6
8%) of the yellowish oil of 21 was done in a similar manner
pound was always observed when the isocyanate 6 was
treated with base under the conditions given in experiments
to experiment 3 in the presence of 125 mg NaH (2.6 mmol,

7
210
J. Heerklotz et al. / Tetrahedron 56 (2000) 7205–7210
1
Ϫ1
6
and 9. The yields are irreproducible. H NMR (300 MHz,
Tˆ173(1) K, (MoKa)ˆ0.231 mm , colorless crystals,
3
DMSO-d ): 7.47–7.44 (m, H-C(5)); 7.22 (s, H-C(2)); 7.02
dimensions: 0.20×0.32×0.40 mm , Rigaku AFC5R diffract-
6
(
d, Jˆ4.9 Hz, H-C(4)); 6.31 (t, Jˆ5.8 Hz, NH); 4,21 (d,
ometer, graphite-monochromated Mo
K
a
radiation,
1
3
˚
Jˆ5.8 Hz, CH ). C NMR (300 MHz, DMSO-d ): 158,03
lˆ0.71073 A, cell constants from 25 centered reflections,
v –2u scans, intensities of three standards checked after
every 150 reflections, no decay, 2u range 5–60Њ, 4749
measured reflections of which 3984 were unique
2
6
(
s, CO); 142.00 (s, C(3)); 127.58, 126.32, 121.20 (3d, 3
arom. C-H), 38.80 (t, CH ). CI-MS (NH ): 254 (13), 253
2
3
ϩ
(100, [MϩH] ).
(
R ˆ0.048). The intensities were corrected for Lorentz
int
2
-Bromo-(3-thienyl)-acetic acid (10). A solution of 3.0 g
and polarization effects, but not for absorption. Structure
solution by direct methods using shelxs-86. The five-
7
(21.1 mmol) of 3-thienyl acetic acid (9) in 40 ml acetic acid
and 1.1 ml (21.4 mmol) of Br in 10 ml acetic acid was
refluxed for 2 h. After addition of a small amount of
membered ring is disordered in that it is mirrored about
2
0
0
0
the line from C(3 ) to the mid-point of the S(1 )–C(5 )
0
0
NaHSO , the reaction mixture was poured into 100 ml ice-
bond. Two positions were defined for S(1 ) and C(5 ), so
3
0
water at 0ЊC. It was filtered and the filtrate extracted with
that the site of S(1 ) is partially occupied by the alternate
position of C(5 ) and vice versa. The two orientations are
0
CHCl . After evaporation, the residue was dried in HV:
3
1
3
.01 g (13.6 mmol, 64.5%) of 10 as a yellowish oil. H
occupied unequally with the major orientation, shown in
Fig. 1, contributing to approximately 70% of the total
structure. The structure was refined on F by full-matrix
NMR: 11.66 (s, COOH); 7.20 (d, Jˆ5.6 Hz, H–C(5));
6
2
.89 (d, Jˆ6.1 Hz, H–C(4)); 3.64 (s, CH ). EI-MS: 222,
2
ϩ⅐
ϩ⅐
8
20 (34, 32, M ), 177, 175 (82, 76, [MϪHCO ] ).
least-squares methods using texsan. The non-H atoms
2
were refined anisotropically. The position of the H-atom
attached to C(5a ) was calculated, all other H-atoms were
0
2-Bromo-(3-thienylmethyl) isocyanate (7). According to
experiment 5, 2.25 g (10.2 mmol) of 10 in 20 ml MeCN
refined isotropically. The refinement of 258 parameters
were treated first with 1.6 ml (11.2 mmol) Et N, afterwards
using 2563 observed reflections with lϾ2s(l) gave
3
2
with 2.3 ml (11.2 mmol) of DPPA and worked up: 1.39 g
Rˆ0.0427, wRˆ0.0357, Sˆ1.437, weights: [s (F )ϩ
o
2
Ϫ1
Ϫ3
˚
(6.4 mmol, 63%) of 7. IR: 2270s.
(0.005F ) ] , max. and min. Drˆ0.23; Ϫ0.26 e A .
o
Allyl
decane-3-carboxylate (18). The reaction between 0.5 g
2.4 mmol) of 11, 131 mg NaH (2.8 mmol, 55% NaH in
N-(2-bromo-3-thienyl)-2,10-dioxo-1-azacyclo-
Acknowledgements
(
oil) and 0.52 g (2.4 mmol) of 7 in 15 ml dry THF was
Support of this work by the Swiss National Science Foun-
dation is kindly acknowledged.
carried out as described for experiment 6 and gave 0.64 g
1
(
1.5 mmol, 63%) of 18 as a yellowish oil. H NMR: 7.22 (d,
0
0
Jˆ5.7 Hz, H-C(5 )); 6.88 (d, Jˆ5.5 Hz, H-C(4 )); 5.97–
5
.85 (m, CHvCH ); 5.35–5.19 (m, CHvCH ); 4.67–4.47
References
2
2
(
m, OCH , NCH H-C(3), 5H); 3.04–2.93 (m, 1H); 2.47–
2 2,
2
.37 (m, 1H); 2.15–1.21 (m, 10H). CI-MS (NH ): 447, 445
1. Hesse, M. Ring Enlargement in Organic Chemistry, Verlag
Chemie: Weinheim, 1991.
2. (a) Ognyanov, V. I.; Hesse, M. Helv. Chim. Acta 1989, 72,
1522–1526. (b) Ognyanov, V. I.; Hesse, M. Helv. Chim. Acta
3
ϩ
(
[
[
45, 51, [MϩNH ] ), 446 (12), 431 (17), 430, 428 (87, 100,
4
ϩ
MϩH] ), 429 (25), 387 (10), 350 (20), 349 (21), 348 (77,
ϩ
MϪBr] ), 313 (13), 309 (14), 236 (11), 228 (14).
1
990, 73, 272–276. (c) Koch, T.; Ognyanov, V. I.; Hesse, M.
N-(2-Bromo-3-thienylmethyl)-1-azacyclodecane-2,10-
dione (19). The decarboxyallylation of 0.4 g (1.0 mmol) of
Helv. Chim. Acta 1992, 75, 62–68.
3. Koch, T.; Hesse, M. Helv. Chim. Acta 1994, 77, 819–828.
4. Kricheldorf, H. R. Synthesis 1972, 551–553.
18 was performed according to experiment 4 with 75 ml
HCOOH, 350 ml Et N and 47 mg Pd (PPh ) in 2 ml dry
THF. Chromatography was done with hexane/EtOAc 20:1,
colorless crystals. Mp 73.2–75.4ЊC. IR: 2940s, 2870m,
5. (a) Shioiri, T.; Ninomiya, K.; Yamada, S. J. Am. Chem. Soc.
1972, 94, 6203–6205. (b) Gilman, J. W.; Otonari, Y. A. Synth.
Commun. 1993, 23, 335–341. (c) Danieli, B.; Lesma, G.;
Palmisano, G.; Tollari, S. Synthesis 1984, 353–356. (d) Choshi,
T.; Tonari, A.; Yoshioka, H.; Harada, K.; Sugino, E.; Hibino, S.
J. Org. Chem. 1993, 58, 7952–7954. (e) Lyga, J. W. Synth.
Commun. 1986, 16, 163–167. (f) Mironov, V. F. J. Organomet.
Chem. 1984, 271, 207–224.
6. Crystallographic data (excluding structure factors) for the
structure of 16 have been deposited with the Cambridge Crystallo-
graphic Data Center as supplementary publication no. CCDC-
145511. Copies of the data can be obtained free of charge on
application to the CCDC, 12 Union Road, Cambridge CB2 1EZ,
UK (fax: ϩ44-1223-336033; e-mail: deposit@ccdc.cam.ac.uk).
7. Sheldrick, G. M. Acta Crystallogr. Sect. A 1990, 46, 467–473.
8. texsan; Single Crystal Structure Analysis Software, Version
5.0. Molecular Structure Corporation, The Woodlands, TX, USA,
1989.
3
3 4
1
1
9
6
4
1
1
3
3
710s, 1675s, 1440m, 1410m, 1360m, 1345m, 1330m,
270w, 1220w, 1165m, 1150m, 1070w, 1020w, 995w,
1
0
65w, 915, 820w. H NMR: 7.13 (d, Jˆ5.7 Hz, H–C(5 ));
0
.76 (d, Jˆ5.7 Hz, H–C(4 )); 4.70 (s, NCH ); 2.65–2.61 (m,
2
1
3
H); 1.71–1.54 (m, 4H); 1.35–1.29 (m, 8H). C NMR:
0
0
78.72 (s, 2CO); 138.86 (s, C(2 )); 127.96 (d, C(5 ));
26.46 (d, C(4 )); 110.01 (s, C(3 )); 41.86 (t, NCH );
0
0
2
4.37, 24.82, 23.75, 22.24 (4t, 7CH ). CI-MS (NH ): 363,
2
3
ϩ
ϩ
61 (52, 60, [MϩNH ] ), 346, 344 (98, 89, [MϩH] ), 264
4
ϩ
(100, [MϪBr] ).
6
X-Ray crystallographic details for compound 16.
C H NO S, M ˆ265.37, orthorhombic, space group
1
4
19
2
r
˚
Pbca, aˆ22.111(1), bˆ11.175(1), cˆ11.050(1) A, Vˆ
3
Ϫ3
˚
2
730.2(4) A , Zˆ8, D ˆ1.291 Mg m , F(000)ˆ1136,
c