Preparation of Tetrahydrothienoazocinone Derivatives

Article abstract of DOI:10.1055/s-0034-1379976

Three regioisomeric thieno[c]azocine derivatives were prepared in six steps from bromothiophene carboxylic acids. The reaction sequence started with an esterification with isopropyl alcohol. The resulting esters were submitted to a Heck reaction with tert-butyl acrylate followed by catalytic hydrogenation. Subsequent Dieckmann condensation gave cyclopentathiophenes with a cyclic β-oxo ester motif, which were α-alkylated with phenacyl bromide to furnish 1,4-diketones. The latter were converted in the key step, a bismuth-catalyzed ring transformation with methylamine, yielding the racemic eight-membered ring lactams, that is, tetrahydrothieno[2,3-c]-, [3,2-c]-, and -[3,4-c]azocine derivatives in overall yields of 25%, 16% and 12%, respectively.

Full text of DOI:10.1055/s-0034-1379976

SYNTHESIS
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
© Georg Thieme Verlag Stuttgart · New York
2015, 47, 1007–1015
paper
1007
M. Penning et al.
Paper
Synthesis
Preparation of Tetrahydrothienoazocinone Derivatives
Miriam Penning1
O
O
Me
O
Enno Aeissen
Br
N
Ph
MeNH2
S
Ph
COPh
CO2R
S
S
Jens Christoffers*
CO2H
Institut für Chemie, Carl von Ossietzky Universität Oldenburg,
26111 Oldenburg, Germany
jens.christoffers@uni-oldenburg.de
CO2R
Br
CO2R
Received: 19.11.2014
Accepted after revision: 15.12.2014
Published online: 26.01.2015
folds 1 as the basis of library synthesis.4 Two points of di-
versity in structures 1 are the residues R1 at N-1 and R2 at C-
8 originating from diketones 4 and primary amines, respec-
tively. As an additional site for further diversifying func-
tionalization (R3) the carboxylate moiety at C-6 was select-
ed, which could be converted with another amine R3NH2 to
carboxamides after saponification. As an extension of mo-
lecular diversity of the scaffold heterocyclic oxo esters were
considered as starting materials, which resulted in thiazo-
cane (X = S)5 and diazocane (X = NR4)6 scaffolds 2 and 3. We
have furthermore accessed benzo[c]- and pyrido[c]-annu-
lated azocanes when starting with indane7 and azaindane
derivatives.8 Compound 5 represents one of three regioiso-
meric pyrido[c]azocane motifs prepared by us.
DOI: 10.1055/s-0034-1379976; Art ID: ss-2014-t0707-op
Abstract Three regioisomeric thieno[c]azocine derivatives were pre-
pared in six steps from bromothiophene carboxylic acids. The reaction
sequence started with an esterification with isopropyl alcohol. The re-
sulting esters were submitted to a Heck reaction with tert-butyl acry-
late followed by catalytic hydrogenation. Subsequent Dieckmann con-
densation gave cyclopentathiophenes with a cyclic β-oxo ester motif,
which were α-alkylated with phenacyl bromide to furnish 1,4-dike-
tones. The latter were converted in the key step, a bismuth-catalyzed
ring transformation with methylamine, yielding the racemic eight-
membered ring lactams, that is, tetrahydrothieno[2,3-c]-, [3,2-c]-, and
-[3,4-c]azocine derivatives in overall yields of 25%, 16% and 12%, re-
spectively.
Key words ring expansion, heterocycles, medium-ring compounds,
lactams, thiophene derivatives, azocine derivatives
O
R1
O
R2
O
N
R2
X
CO2R1
Some years ago, a new, elegant, and relatively simple
route to prepare unsaturated 2-azocanone derivatives 1
(1,2,3,4,5,6-hexahydroazocin-2-ones, Figure 1) was discov-
ered.2 The reaction proceeded by a bismuth-catalyzed ring-
transformation of five-membered ring oxo esters 4 contain-
ing a 1,4-diketone moiety3 and primary amines R1NH2.
Since these products 1 exist in a folded conformation, they
represent an attractive molecular scaffold for combinatorial
chemistry. In our continuing efforts to identify sophisticat-
ed structural motifs as a basis for combinatorial library syn-
thesis in drug discovery, we are interested in such nonpla-
nar and easily accessible scaffolds that provide several
points of diversification. Such three-dimensional scaffolds
open additional opportunities for adapting the shape of
drug molecules to the requirements of binding sites on bio-
logical targets. Therefore, we have already explored scaf-
CONHR3
1 X = CH2
2 X = S
3 X = NR4
4
Me
N
O
N
R1
N
N
R2
N
Me
S
N
H
CONHR3
5
6
Figure 1 Some azocanones 1–3 and 5, precursor compound 4, and
the antipsychotic drug olanzapine (6)
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 1007–1015

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Inspired by the thienodiazepine constitution of the drug
olanzapine (6),9 which is an atypical antipsychotic drug ap-
proved for the treatment of schizophrenia, mania, and relat-
ed agitation, we projected the synthesis of tetrahydro-
thienoazocines 7–9 following the above mentioned route.
The target structures tetrahydrothieno[3,2-c]azocine 7,10
-thieno[3,4-c]azocine 8,11 -thieno[2,3-c]azocine 9,12 were
so far rarely reported in the literature (Scheme 1). However,
Voskressensky recently introduced a very elegant access to
the tetrahydrothieno[2,3-d]azocine ring system13 by using a
domino ring expansion sequence of annulated piperidines
with acceptor activated alkynes, which was developed in
his laboratory.14 The prospective retrosynthesis of com-
pounds 7–9 is exemplified for product 9. The last and key
step is the ring transformation of 1,4-diketone 11 with
MeNH2. Compound 11 could be obtained by α-alkylation of
β-oxo ester 10. The latter could be obtained by Dieckmann
condensation of the hydrogenated (compound 12) Heck-
product 13. Thus, the six-step sequence would start with
the bromothiophene carboxylic acids 14–16, respectively,
which are commercially available.
In a first series, methyl ester 11a was prepared from
carboxylic acid 16. The five steps followed the retrosynthet-
ic plan given Scheme 1: Esterification, Heck reaction with
methyl acrylate, hydrogenation, Dieckmann condensation
and alkylation with phenacyl bromide. Conversion with
MeNH2 gave a unique material, which turned out not to be
the expected eight-membered ring lactam 9a (Scheme 2).
The structure of the product 17 was established by mass
spectrometry (furnishing the molecular formula) and NMR
spectroscopy. Key features taken from the 2D-NMR spectra
were the following: The methyl amide group [δH = 3.01 (d,
J = 4.6 Hz, 3 H)] is associated with the carboxyl group at the
thiophene ring [δC = 164] (the latter is assigned by its HMBC
correlations to the thiophene hydrogen atoms), whereas
the other methyl group [δH = 2.77 (s, 3 H)] is coupling with
the carboxyl group in the pyrrolidine ring [δC = 172]. A
mechanistic rationale for the formation of compound 17 as-
sumes the formation of the enamine 18 followed by nucleo-
philic attack of the nitrogen to the sterically less hindered,
though less electrophilic ester group. A nucleophilic attack
at the more electrophilic ketone would be the expected
pathway leading to the eight-membered ring. Anyhow, the
spirocyclic intermediate 19 is cleaved by a second equiva-
lent of methylamine in retro-Claisen like fashion to afford
compound 17.
O
Me
O
Me
O
Me
N
N
N
Ph
Ph
Ph
S
S
S
As a consequence from this explanation, a sterically
more hindered tert-butyl ester 12b instead of methyl ester
might favor the formation of the eight-membered ring 9b.
Thus, Heck reaction needed to be performed with tert-butyl
acrylate. After hydrogenation, ester 10b (R1 = t-Bu, R2 = Me)
was submitted to Dieckmann condensation and a mixture
of t-Bu 11b and Me ester 11a was obtained (Scheme 3,Table
1, entry 2). Obviously, transesterification took place under
reaction conditions. In order to avoid this side-process, the
di-tert-butyl ester 10c was prepared, but this material
hardly underwent cyclization (entry 3). We therefore tried
the cyclization of ester 10d (R1 = t-Bu, R2 = Et), but the yield
of t-Bu ester 11b could not be increased; equal amounts of
t-Bu 11b and Et ester 11c were obtained (entry 4). Ester 10e
(R1 = t-Bu, R2 = i-Pr) gave satisfying results (entry 5): t-Bu
ester 11b was formed in 68% yield together with i-Pr ester
11d (11%), which could be separated by chromatography.
Finally, the bis-isopropyl ester 10f was investigated, which
gave isopropyl ester 11d also in 68% yield (entry 6). Howev-
er, isopropyl acrylate was required for the Heck reaction,
which was not commercially available, and needed to be
prepared according to a literature procedure (44% yield).15
Moreover, this Heck reaction gave only 42% yield. We there-
fore decided to accomplish the six-step sequence via esters
10e and 11b (entry 5) as shown in Table 1.
CO2R1
CO2R1
CO2R1
7
8
9
MeNH2
O
O
COPh
CO2R1
S
S
CO2R1
10
11
S
S
CO2R2
CO2R1
CO2R2
CO2R1
12
13
S
CO2H
CO2H
CO2H
S
S
Br
16
Br
Br
14
15
Scheme 1 Retrosynthesis of thieno[c]azocines 7–9 from carboxylic
acids 14–16
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Synthesis
CONHMe
S
O
Me
N
Ph
S
O
O
S
MeNH2
COPh
N
+
CO2Me
THF
140 °C, 16 h
Me
CO2Me
Ph
11a
17, 75%
9a, 0%
O
O
Ph
Ph
S
S
NHMe
N
CO2Me
18
Scheme 2 Attempted synthesis of lactam 9a from diketone 11a with an excess of MeNH2 gave pyrrolidone derivative 17
Me
O
19
O
O
S
CO2R2
CO2R1
S
S
KOt-Bu
CO2R1
CO2R2
+
THF, 0 °C, 45 min
12
10
10'
Scheme 3 Dieckmann condensation with by-product 10′ resulting from a transesterification; for yields and residues R1 and R2, see Table 1
Table 1 Results of the Dieckmann Condensation
Entry Starting material 12 Products 10 and 10′; yield
tion proceeded as already mentioned in Table 1. Alkylation
with phenacyl bromide and K2CO3 in acetone was straight-
forward (product 11b in 93% yield). The ring-expansion re-
action was another crucial reaction step, which required
again tedious optimization of reaction stoichiometry, tem-
perature, and time. For example, without additive and for
five days at 120 °C, only 31% of product 9b was isolated.
With bismuth nitrate as substoichiometric additive, the
yield rose to 47%, but could not further be improved so far.
The yield of racemic lactam 9b over six steps from acid 16
was 25% and therefore satisfactory.
1
2
3
4
5
6
12a R1 = R2 = Me
10a R1 = Me, 61%
12b R1 = t-Bu, R2 = Me
12c R1 = R2 = t-Bu
10b R1 = t-Bu, 48% + 10a R1 = Me, 26%
10b R1 = t-Bu, trace
12d R1 = t-Bu, R2 = Et
12e R1 = t-Bu, R2 = i-Pr
12f R1 = R2 = i-Pr
10b R1 = t-Bu, 39% + 10c R1 = Et, 39%
10b R1 = t-Bu, 68% + 10d R1 = i-Pr, 11%
10d R1 = i-Pr, 68%
The synthesis of the racemic regioisomeric thieno[3,2-
c]azocine and thieno[3,4-c]azocine derivatives 7 and 8 fol-
lowed the same route and used more or less identical reac-
tion conditions (Scheme 5 and Scheme 6), with the follow-
ing exception: When adopting conditions of a phosphane-
free Heck reaction (by using N,N-dimethylglycine as ligand
instead),16 the yield of compound 22 was improved to 85%
(61% by using conditions given in Scheme 4). Unfortunately,
this protocol did not improve yields of compounds 13 (15%
vs 88%) and 27 (37% vs 91%). The overall yields for the
preparation of compounds 7 and 8 were significantly lower
as for compound 9 (16% for compound 7 and 12% for 8 and
25% for 9).
The complete reaction sequence leading to thieno[2,3-
c]azocine 9b is given in Scheme 4. Commercially available
carboxylic acid 14 was esterified with i-PrOH via the acid
chloride (formed with SOCl2) to quantitatively yield the es-
ter 20. The latter was converted in a Heck reaction with an
excess of tert-butyl acrylate (product 13 with 88% yield).
The reaction conditions, in particular the stoichiometry, the
solvent (dimethylacetamide, DMA) and the temperature
(100 °C) were the result of a tedious optimization process.
Hydrogenation took place under ambient conditions fur-
nishing product 12e in almost quantitative yield. The sol-
vent isopropyl alcohol was superior to other alcohols in or-
der to avoid transesterifications. The Dieckmann condensa-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 1007–1015

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S
S
S
CO2H
CO2i-Pr
CO2i-Pr
CO2t-Bu
(a)
(b)
Br
Br
16
20 (99%)
13 (88%)
(c)
O
O
S
COPh
S
S
CO2i-Pr
(d)
(e)
CO2t-Bu
CO2t-Bu
CO2t-Bu
12e (96%)
11b (93%)
10b (68%)
(f)
O
Me
N
Ph
S
CO2t-Bu
9b (47%)
Scheme 4 Preparation of racemic thieno[2,3-c]azocine derivative 9b. Reagents and conditions: (a) 1. SOCl2 (excess), reflux, 3 h, 2. DMAP (cat.), i-PrOH
(excess), 90 °C, 19 h; (b) CH2=CHCO2t-Bu (10 equiv), Pd(OAc)2 (0.1 equiv), Ph3P (0.2 equiv), Et3N (5 equiv), DMA, 100 °C, 1 d; (c) Pd/C (cat.), 1 atm H2,
i-PrOH, 23 °C, 1 d; (d) KOt-Bu (2.5 equiv), THF, 0 °C, 45 min; (e) PhCOCH2Br (1.2 equiv), K2CO3 (1.2 equiv), acetone, 40 °C, 15 h; (f) MeNH2 (excess),
Bi(NO3)3·5 H2O (0.1 equiv), THF, 120 °C, 4 d.
CO2H
CO2i-Pr
CO2i-Pr
CO2t-Bu
(a)
(b)
S
S
S
Br
Br
14
21 (94%)
22 (85%)
(c)
O
O
COPh
CO2t-Bu
CO2i-Pr
(d)
(e)
CO2t-Bu
S
S
S
CO2t-Bu
25 (99%)
23 (94%)
24 (54%)
(f)
O
Me
N
Ph
S
CO2t-Bu
7 (39%)
Scheme 5 Preparation of racemic thieno[3,2-c]azocine derivative 7. Reagents and conditions: (a) 1. SOCl2 (excess), reflux, 3.5 h, 2. DMAP (cat.), i-PrOH
(excess), 90 °C, 20 h; (b) CH2=CHCO2t-Bu (10 equiv), Pd(PhCN)2Cl2 (0.05 equiv), Me2NCH2CO2H (0.75 equiv), NaOAc (2 equiv), NMP, 130 °C, 20 h; (c)
Pd/C (cat.), 1 atm H2, i-PrOH, 23 °C, 1 d; (d) t-BuOK (2.5 equiv), THF, 0 °C, 45 min; (e) PhCOCH2Br (1.2 equiv), K2CO3 (1.2 equiv), acetone, 40 °C, 23 h; (f)
MeNH2 (excess), Bi(NO3)3·5 H2O (0.1 equiv), THF, 120 °C, 4 d.
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CO2H
CO2i-Pr
CO2i-Pr
CO2t-Bu
(a)
(b)
S
S
S
Br
Br
15
26 (96%)
27 (91%)
(c)
O
O
COPh
CO2i-Pr
(d)
(e)
S
S
S
CO2t-Bu
CO2t-Bu
CO2t-Bu
30 (86%)
28 (82%)
29 (51%)
(f)
O
Me
N
Ph
S
CO2t-Bu
8 (37%)
Scheme 6 Preparation of racemic thieno[3,4-c]azocine derivative 8. Reagents and conditions: (a) 1. SOCl2 (excess), reflux, 3 h, 2. DMAP (cat.), i-PrOH
(excess), 90 °C, 15 h; (b) CH2=CHCO2t-Bu (10 equiv), Pd(OAc)2 (0.1 equiv), Ph3P (0.2 equiv), Et3N (5 equiv), DMA, 130 °C, 21 h; (c) Pd/C (cat.), 1 atm H2,
i-PrOH, 23 °C, 4 d; (d) t-BuOK (2.5 equiv), THF, 0 °C, 45 min; (e) PhCOCH2Br (1.2 equiv), K2CO3 (1.2 equiv), acetone, 40 °C, 19 h; (f) MeNH2 (excess),
Bi(NO3)3·5 H2O (0.1 equiv), THF, 120 °C, 4 d.
Finally, we conclude that the bismuth-catalyzed ring
enlarging transformation of cyclopentathiophene deriva-
tives containing a 1,4-diketone moiety 11, 23, and 28 with
methylamine is the key step for the preparation of three re-
gioisomeric thieno[c]azocine derivatives 7, 8, and 9. The
six-step sequences started with three isomeric bromothio-
phene carboxylates 14, 15, and 16, which were submitted
to Heck reaction followed by catalytic hydrogenation.
The resulting diesters 12, 25, and 30 were cyclized in a
Dieckmann condensation giving the cyclic β-oxo esters 11,
24, and 29. Alkylation with phenacyl bromide gave the
above mentioned 1,4-diketones 11, 23, and 28. Overall
yields for the final, racemic products, that is, tetrahydro-
thieno[2,3-c]-, -[3,2-c]-, and -[3,4-c]azocine derivatives 7, 8,
9, were 25%, 16% and 12%, respectively.
Finnigan MAT95 (EI) and a Waters Q-TOF Premier (ESI, all in positive
mode) spectrometer. IR spectra were recorded on a Bruker Tensor 27
spectrometer equipped with a ‘GoldenGate’ diamond ATR unit; inten-
sities were not adjusted.
Methyl 6-Oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydrocyclopen-
ta[b]thiophene-5-carboxylate (11a)
Phenacyl bromide (55 mg, 0.28 mmol) and K2CO3 (38 mg, 0.28 mmol)
were added to a solution of β-oxo ester 10a (45 mg, 0.23 mmol) in
acetone (1 mL) and the mixture was stirred for 2 h at 40 °C. H2O (5
mL) and brine (5 mL) were added and the aqueous layer was extracted
with MTBE (3 × 10 mL). The combined organic extracts were dried
(MgSO4), filtered, and the solvent was evaporated. Diketone 11a was
isolated after column chromatography (SiO2; hexane–MTBE, 2:1; Rf =
0.32) as a colorless solid; yield: 64 mg, (0.20 mmol, 89%); mp 117 °C.
IR (ATR): 2952 (w), 1683 (s) cm–1
.
1H NMR (500 MHz, CDCl3): δ = 2.96 (d, J = 17.7 Hz, 1 H), 3.33 (d, J =
18.3 Hz, 1 H), 3.68 (s, 3 H), 4.01 (d, J = 17.7 Hz, 1 H), 4.22 (d, J = 18.3
Hz, 1 H), 7.07 (d, J = 4.8 Hz, 1 H), 7.45 (t, J = 7.8 Hz, 2 H), 7.55–7.58 (m,
1 H), 7.94–7.97 (m, 3 H).
13C{1H} NMR (125 MHz, CDCl3): δ = 36.28 (CH2), 44.36 (CH2), 53.31
(CH3), 64.05 (C), 124.22 (CH), 128.31 (2 CH), 128.90 (2 CH), 133.80
(CH), 136.33 (C), 138.42 (C), 142.44 (CH), 168.44 (C), 170.31 (C),
192.22 (C), 197.16 (C).
Reactions at temperatures above the boiling point of one of the reac-
tants or solvent were performed in tightly closed, Teflon screw-
capped, thick-walled glass vials. Preparative column chromatography
was carried out using Merck SiO2 (35–70 μm, type 60 A) with hexane,
tert-butyl methyl ether (MTBE), and CH2Cl2 as eluents. TLC was per-
formed on Merck aluminum plates coated with SiO2 F254.
1H and 13C
NMR spectra were recorded on Bruker Avance DRX 500 instruments
at 23 °C in CDCl3. Multiplicities of carbon signals were determined
with DEPT experiments. MS and HRMS spectra were obtained with a
HRMS (ESI): m/z calcd for C17H14NaO4S+ [M + Na+]: 337.0505; found:
337.0506.
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N-Methyl-3-[(1-methyl-2-oxo-5-phenyl-2,3-dihydro-3-pyr-
rolyl)methyl]thiophene-2-carboxamide (17)
1H NMR (500 MHz, CDCl3): δ = 1.37 (d, J = 6.3 Hz, 6 H), 1.52 (s, 9 H),
5.22 (sept, J = 6.3 Hz, 1 H), 6.26 (d, J = 16.1 Hz, 1 H), 7.30 (d, J = 5.2 Hz,
1 H), 7.42 (d, J = 5.2 Hz, 1 H), 8.39 (d, J = 16.1 Hz, 1 H).
13C{1H} NMR (125 MHz, CDCl3): δ = 22.17 (2 CH3), 28.40 (3 CH3), 69.49
(CH), 80.87 (C), 124.04 (CH), 126.89 (CH), 130.98 (CH), 132.41 (C),
135.98 (CH), 141.68 (C), 161.67 (C), 166.23 (C).
A solution of MeNH2 (2 mol/L in THF, 0.80 mL, 1.9 mmol) was added
to a solution of 1,4-diketone 12a (50 mg, 0.16 mmol) in THF (0.21 mL)
and the mixture was stirred for 16 h at 140 °C in a closed reaction vi-
al. Subsequently, the solvent was evaporated and thiophene 17 was
isolated after column chromatography [SiO2; hexane–MTBE, 1:2, then
hexane–EtOAc, 1:2; Rf (hexane–EtOAc) = 0.45] as a colorless oil; yield:
39 mg (0.12 mmol, 75%).
HRMS (ESI): m/z calcd for C15H20NaO4S+ [M + Na+]: 319.0975; found:
319.0979.
IR (ATR): 3247 (w), 3064 (w), 2921 (w), 1673 (vs), 1632 (s) cm–1
.
Isopropyl 3-[(2-(tert-Butoxycarbonyl)ethyl]thiophene-2-carboxyl-
1H NMR (500 MHz, CDCl3): δ = 2.77 (s, 3 H), 3.01 (d, J = 4.6 Hz, 3 H),
3.81 (s, 2 H), 4.89 (s, 1 H), 6.76 (d, J = 5.1 Hz, 1 H), 6.86 (s, 1 H), 7.06 (d,
J = 6.3 Hz, 2 H), 7.26 (d, J = 5.1 Hz, 1 H), 7.31–7.38 (m, 3 H), 8.91 (br s,
1 H).
13C{1H} NMR (125 MHz, CDCl3): δ = 26.61 (CH2), 26.95 (CH3), 27.56
(CH3), 67.44 (CH), 127.38 (2 CH), 127.65 (CH), 129.09 (CH), 129.42
(CH), 129.48 (2 CH), 134.67 (C), 136.54 (C), 136.70 (C), 136.86 (C),
142.06 (CH), 164.07 (C), 172.20 (C).
ate (12e)
A suspension of 10% Pd/C (113 mg), thiophene derivative 13 (629 mg,
2.14 mmol), and i-PrOH (7 mL) was degassed (three cycles of freeze,
pump, thaw) and then stirred under an atmosphere of H2 (1 bar) at
23 °C for 24 h. The solvent was evaporated and the residue was chro-
matographed (SiO2; hexane–MTBE, 10:1; Rf = 0.38) to afford com-
pound 12e as a colorless liquid; yield: 612 mg (2.05 mmol, 96%).
IR (ATR): 3107 (w), 2979 (w), 1727 (s), 1702 (vs), 1250 (vs), 1144 (vs),
1097 (s), 1072 (vs) cm–1
.
HRMS (ESI): m/z calcd for C18H18N2NaO2S+ [M + Na+]: 349.0981;
1H NMR (500 MHz, CDCl3): δ = 1.34 (d, J = 6.3 Hz, 6 H), 1.40 (s, 9 H),
2.54 (t, J = 7.7 Hz, 2 H), 3.24 (t, J = 7.7 Hz, 2 H), 5.17 (sept, J = 6.3 Hz, 1
H), 6.95 (d, J = 5.1 Hz, 1 H), 7.36 (d, J = 5.1 Hz, 1 H).
found: 349.0980.
Isopropyl 3-Bromothiophene-2-carboxylate (20)
13C{1H} NMR (125 MHz, CDCl3): δ = 22.17 (2 CH3), 25.41 (CH2), 28.29
(3 CH3), 36.10 (CH2), 68.68 (CH), 80.53 (C), 128.40 (C), 130.28 (CH),
148.61 (C), 162.30 (C), 171.37 (C).
HRMS (ESI): m/z calcd for C15H22NaO4S+ [M + Na+]: 321.1131; found:
321.1127.
SOCl2 (10.3 g, 86.6 mmol) was added to cold (ice-water bath) 3-bro-
mothiophene-2-carboxylic acid (16; 1.00 g, 4.83 mmol) and the mix-
ture was stirred for 3 h under reflux. The mixture was cooled (ice-wa-
ter bath), DMAP (30 mg, 0.24 mmol) and i-PrOH (100 mL) were added
to the solution and stirred at 80 °C for 19 h. H2O (50 mL) was added
and the aqueous layer was extracted with CH2Cl2 (4 × 40 mL). The
combined organic extracts were dried (MgSO4), filtered, and the sol-
vent was evaporated. Ester 20 was isolated after column chromatog-
raphy (SiO2; hexane–MTBE, 10:1; Rf = 0.51) as a pale yellow liquid;
yield: 1.19 g (4.78 mmol, 99%).
tert-Butyl 6-Oxo-4,5-dihydrocyclopenta[b]thiophene-5-carboxyl-
ate (10b)
KOt-Bu (575 mg, 5.13 mmol) was added to a solution of compound
12e (612 mg, 2.05 mmol) in anhydrous THF (10 mL) at 0 °C under an
exclusion of moisture and air (N2 atmosphere). The mixture was
stirred for 45 min at 0 °C and then H2O (15 mL) and concd hydrochlo-
ric acid (3 mL) were added. The aqueous layer was extracted with
CH2Cl2 (3 × 15 mL) and the combined organic extracts were dried
(MgSO4), filtered, and the solvent was evaporated. After column chro-
matography (SiO2; hexane–MTBE, 10:1; Rf = 0.15), the title compound
10b was isolated as a colorless oil; yield: 332 mg (1.39 mmol, 68%).
IR (ATR): 3017 (w), 2980 (w), 1712 (vs), 1416 (s), 1239 (vs), 1089 (s),
1067 (vs), 883 (s), 766 (s) cm–1
.
1H NMR (500 MHz, CDCl3): δ = 1.35 (d, J = 6.3 Hz, 6 H), 5.20 (sept, J =
6.3 Hz, 1 H), 7.07 (d, J = 5.2 Hz, 1 H), 7.43 (d, J = 5.2 Hz, 1 H).
13C{1H} NMR (125 MHz, CDCl3): δ = 22.09 (2 CH3), 69.55 (CH), 116.83
(C), 128.45 (C), 131.15 (CH), 133.15 (CH), 160.60 (C).
MS (EI, 70 eV): m/z (%) = 248 (17, [M+]), 206 (45), 109 (20), 95 (27).
IR (ATR): 2979 (w), 1696 (s), 1143 (s) cm–1
.
HRMS (EI): m/z calcd for C8H9BrO2S+ [M+]: 247.9501; found:
247.9501.
1H NMR (500 MHz, CDCl3): δ = 1.47 (s, 9 H), 3.19 (dd, J = 7.3, 17.2 Hz, 1
H), 3.33 (dd, J = 3.0, 17.2 Hz, 1 H), 3.87 (dd, J = 3.0, 7.3 Hz, 1 H), 7.04 (d,
J = 4.8 Hz, 1 H), 7.90 (d, J = 4.8 Hz, 1 H).
13C{1H} NMR (125 MHz, CDCl3): δ = 28.22 (3 CH3), 28.53 (CH2), 59.33
(CH), 82.40 (C), 124.03 (CH), 139.76 (C), 141.70 (CH), 167.96 (C),
168.35 (C), 190.57 (C).
Isopropyl (E)-3-[(2-(tert-Butoxycarbonyl)ethenyl]thiophene-2-
carboxylate (13)
tert-Butyl acrylate (3.10 g, 24.2 mmol), Pd(OAc)2 (54 mg, 0.24 mmol),
Ph3P (127 mg, 0.480 mmol), and Et3N (1.22 g, 12.1 mmol) were added
to a solution of thiophene derivative 20 (601 mg, 2.42 mmol) in anhy-
drous DMA (6 mL) under exclusion of air and moisture (N2 atmo-
sphere) and the mixture was stirred at 100 °C for 24 h. H2O (10 mL)
was then added and the aqueous layer was extracted with MTBE (3 ×
15 mL). The combined organic extracts were dried (MgSO4), filtered,
and the solvent was evaporated. The title compound 13 was isolated
after column chromatography (SiO2; hexane–MTBE, 10:1; Rf = 0.38) as
a colorless oil; yield: 629 mg (2.12 mmol, 88%).
HRMS (ESI): m/z calcd for C12H14NaO3S+ [M + Na+]: 261.0556; found:
261.0567.
tert-Butyl 6-Oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydrocyclopen-
ta[b]thiophene-5-carboxylate (11b)
Phenacyl bromide (555 mg, 2.79 mmol) and K2CO3 (386 mg, 2.79
mmol) were added to a solution of β-oxo ester 10b (554 mg, 2.32
mmol) in acetone (12 mL) and the mixture was stirred for 15 h at
40 °C. H2O (20 mL) and brine (5 mL) were added and the aqueous lay-
er was extracted with MTBE (3 × 15 mL). The combined organic ex-
tracts were dried (MgSO4), filtered, and the solvent was evaporated.
IR (ATR): 3107 (w), 3083 (w), 2979 (w), 1712 (vs), 1232 (vs), 1145
(vs), 1101 (s), 1073 (s) cm–1
.
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Diketone 11b was isolated after column chromatography (SiO2; hex-
ane–MTBE, 5:1; Rf = 0.24) as a colorless oil: yield: 770 mg (2.16 mmol,
93%).
Isopropyl (E)-2-[(2-(tert-Butoxycarbonyl)ethenyl]thiophene-3-
carboxylate (22)
A solution of thiophene derivative 21 (328 mg, 1.32 mmol) in anhy-
drous NMP (3.3 mL) and tert-butyl acrylate (1.69 g, 13.2 mmol) were
added to a mixture of Pd(PhCN)2Cl2 (25 mg, 0.066 mmol), N,N-di-
methylglycine (102 mg, 0.987 mmol), and NaOAc (216 mg, 2.63
mmol) under exclusion of air and moisture (N2 atmosphere) and the
resulting mixture was stirred at 130 °C for 20 h. Then, H2O (15 mL)
was added and the aqueous layer was extracted with MTBE (3 × 15
mL). The combined organic extracts were dried (MgSO4), filtered, and
the solvent was evaporated. Title compound 22 was isolated after col-
umn chromatography (SiO2; hexane–MTBE, 10:1; Rf = 0.38) as a yel-
lowish oil; yield: 333 mg (1.12 mmol, 85%).
IR (ATR): 2978 (w), 1696 (vs), 1152 (s) cm–1
.
1H NMR (500 MHz, CDCl3): δ = 1.34 (s, 9 H), 2.96 (d, J = 17.6 Hz, 1 H),
3.23 (d, J = 18.2 Hz, 1 H), 3.93 (d, J = 17.6 Hz, 1 H), 4.18 (d, J = 18.2 Hz,
1 H), 7.06 (d, J = 4.8 Hz, 1 H), 7.45 (t, J = 7.7 Hz, 2 H), 7.56 (t, J = 7.4 Hz,
1 H), 7.94 (d, J = 4.8 Hz, 1 H), 7.95–7.96 (m, 2 H).
13C{1H} NMR (125 MHz, CDCl3): δ = 27.88 (3 CH3), 36.44 (CH2), 44.11
(CH2), 64.99 (C), 82.38 (C), 124.14 (CH), 128.26 (2 CH), 128.89 (2 CH),
133.63 (CH), 136.68 (C), 138.64 (C), 141.96 (CH), 168.53 (C), 168.74
(C), 192.91 (C), 197.43 (C).
HRMS (ESI): m/z calcd for C20H20NaO4S+ [M + Na+]: 379.0975; found:
379.0973.
IR (ATR): 2978 (w), 1703 (s), 1247 (s), 1212 (m), 1144 (vs), 1105 (s)
cm–1
.
1H NMR (500 MHz, CDCl3): δ = 1.36 (d, J = 6.3 Hz, 6 H), 1.51 (s, 9 H),
5.20 (sept, J = 6.3 Hz, 1 H), 6.25 (d, J = 15.9 Hz, 1 H), 7.19 (d, J = 5.3 Hz,
1 H), 7.45 (d, J = 5.3 Hz, 1 H), 8.48 (d, J = 15.9 Hz, 1 H).
13C{1H} NMR (125 MHz, CDCl3): δ = 22.21 (2 CH3), 28.42 (3 CH3), 68.92
(CH), 80.99 (C), 123.15 (CH), 125.48 (CH), 130.91 (CH), 132.81 (C),
135.18 (CH), 145.09 (C), 162.57 (C), 165.67 (C).
tert-Butyl (Z)-2-Methyl-1-oxo-3-phenyl-1,2,5,6-tetrahydro-
thieno[2,3-c]azocine-5-carboxylate (9b)
A solution of MeNH2 (2 mol/L in THF, 2.1 mL, 4.2 mmol) and
Bi(NO3)3·5 H2O (10 mg, 0.021 mmol) were added to a solution of 1,4-
diketone 11b (75 mg, 0.21 mmol) in THF (0.21 mL) and the mixture
was stirred for 4 d at 120 °C in a closed reaction vial. Subsequently,
the solvent was evaporated and lactam 9b was isolated after column
chromatography (SiO2; hexane–MTBE, 2:1; Rf = 0.45) as a yellow res-
in; yield: 35 mg (0.098 mmol, 47%).
HRMS (ESI): m/z calcd for C15H20NaO4S+ [M + Na+]: 319.0975; found:
319.0971.
Isopropyl 2-[(2-(tert-Butoxycarbonyl)ethyl]thiophene-3-carboxyl-
ate (25)
IR (ATR): 2977 (w), 1725 (m), 1624 (m), 1151 (s), 731 (s) cm–1
.
1H NMR (500 MHz, CDCl3): δ = 1.51 (s, 9 H), 2.99 (dd, J = 13.2, 16.7 Hz,
1 H), 3.08 (s, 3 H), 3.35 (dd, J = 5.0, 16.8 Hz, 1 H), 3.85 (ddd, J = 5.0, 9.9,
13.8 Hz, 1 H), 6.00 (d, J = 9.9 Hz, 1 H), 6.65 (d, J = 5.1 Hz, 1 H), 7.25 (d,
J = 5.3 Hz, 1 H), 7.28–7.33 (m, 5 H).
13C{1H} NMR (125 MHz, CDCl3): δ = 28.33 (3 CH3), 34.41 (CH2), 34.87
(CH3), 42.73 (CH), 81.94 (C), 123.56 (CH), 126.51 (2 CH), 127.06 (CH),
128.80 (CH), 129.03 (2 CH), 129.11 (CH), 132.59 (C), 135.46 (C),
136.86 (C), 143.35 (C), 165.65 (C), 172.27 (C).
A suspension of 10% Pd/C (22 mg), thiophene derivative 22 (60 mg,
0.20 mmol), and i-PrOH (0.6 mL) was degassed (three cycles of freeze,
pump, thaw) and then stirred under an atmosphere of H2 (1 bar) at
23 °C for 24 h. The suspension was filtered and the solvent was evap-
orated to yield compound 25 as a pale yellow liquid; yield: 60 mg
(0.20 mmol, quant).
IR (ATR): 2979 (w), 1705 (s), 1255 (s), 1148 (s), 1106 (s) cm–1
.
1H NMR (500 MHz, CDCl3): δ = 1.33 (d, J = 6.3 Hz, 6 H), 1.42 (s, 9 H),
2.61 (t, J = 7.5 Hz, 2 H), 3.42 (t, J = 7.7 Hz, 2 H), 5.18 (sept, J = 6.3 Hz, 1
H), 7.00 (d, J = 5.4 Hz, 1 H), 7.38 (d, J = 5.4 Hz, 1 H).
HRMS (ESI): m/z calcd for C21H23NNaO3S+ [M + Na+]: 392.1291; found:
392.1295.
13C{1H} NMR (125 MHz, CDCl3): δ = 22.22 (2 CH3), 25.20 (CH2), 28.33
(3 CH3), 37.00 (CH2), 68.07 (CH), 80.80 (C), 121.75 (CH), 129.19 (C),
129.81 (CH), 152.15 (C), 163.10 (C), 171.79 (C).
HRMS (ESI): m/z calcd for C15H22NaO4S+ [M + Na+]: 321.1131; found:
321.1142.
Isopropyl 2-Bromothiophene-3-carboxylate (21)
SOCl2 (3.10 g, 26.1 mmol) was added to cold (ice-water bath) 2-bro-
mothiophene-3-carboxylic acid (14; 300 mg, 1.45 mmol) and the
mixture was stirred for 3.5 h under reflux. After cooling (ice-water
bath), DMAP (13 mg, 0.11 mmol) and i-PrOH (22 mL) were added and
the resulting mixture was stirred under reflux for 20 h. H2O (15 mL)
was added and the aqueous layer was extracted with CH2Cl2 (3 × 15
mL). The combined organic extracts were dried (MgSO4), filtered, and
the solvent was evaporated. Ester 21 was isolated after column chro-
matography (SiO2, hexane–MTBE, 20:1, Rf = 0.49) as a pale yellow liq-
uid; yield: 338 mg (1.36 mmol, 94%).
tert-Butyl 4-Oxo-5,6-dihydrocyclopenta[b]thiophene-5-carboxyl-
ate (24)
KOt-Bu (452 mg, 4.03 mmol) was added to a solution of compound 25
(479 mg, 1.61 mmol) in anhydrous THF (8 mL) at 0 °C under an exclu-
sion of moisture and air (N2 atmosphere). The mixture was stirred for
45 min at 0 °C and then H2O (15 mL) and concd hydrochloric acid
(3 mL) were added. The aqueous layer was extracted with CH2Cl2 (3 ×
15 mL) and the combined organic extracts were dried (MgSO4), fil-
tered, and the solvent was evaporated. After column chromatography
(SiO2; hexane–MTBE, 10:1; Rf = 0.13), the title compound 24 was iso-
lated as a colorless solid; yield: 208 mg (0.873 mmol, 54%); mp 65–
66 °C.
IR (ATR): 3112 (w), 3093 (w), 1704 (s), 1269 (s), 1246 (vs), 1105 (s),
700 (s) cm–1
.
1H NMR (500 MHz, CDCl3): δ = 1.34 (d, J = 6.3 Hz, 6 H), 5.20 (hept, J =
6.3 Hz, 1 H), 7.18 (d, J = 5.8 Hz, 1 H), 7.33 (d, J = 5.8 Hz, 1 H).
13C{1H} NMR (125 MHz, CDCl3): δ = 22.15 (2 CH3), 68.92 (CH), 119.60
(C), 125.85 (CH), 129.68 (CH), 131.97 (C), 161.76 (C).
HRMS (ESI): m/z calcd for C8H9BrNaO2S+ [M + Na+]: 270.9399; found:
IR (ATR): 3005 (w), 2978 (w), 1696 (s), 1144 (s) cm–1
.
270.9413.
1H NMR (500 MHz, CDCl3): δ = 1.49 (s, 9 H), 3.33 (dd, J = 7.3, 17.3 Hz, 1
H), 3.50 (dd, J = 2.8, 17.3 Hz, 1 H), 3.88 (dd, J = 2.8, 7.2 Hz, 1 H), 7.11 (d,
J = 5.1 Hz, 1 H), 7.30 (d, J = 5.1 Hz, 1 H).
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13C{1H} NMR (125 MHz, CDCl3): δ = 28.25 (3 CH3), 28.73 (CH2), 59.88
(CH), 82.47 (C), 120.10 (CH), 131.51 (CH), 144.48 (C), 168.03 (C),
169.97 (C), 191.32 (C).
the solvent was evaporated. Ester 26 was isolated after column chro-
matography (SiO2; hexane–MTBE, 20:1; Rf = 0.38) as a pale yellow liq-
uid; yield: 1.15 g (4.62 mmol, 96%).
MS (EI, 70 eV): m/z (%) = 238 (9, [M+]), 182 (100), 165 (69), 154 (55).
HRMS (EI): m/z calcd for C12H14O3S+ [M+]: 238.0658; found: 238.0654.
IR (ATR): 3111 (w), 2980 (w), 1717 (s), 1233 (vs), 1102 (vs), 981 (s),
770 (s) cm–1
.
1H NMR (500 MHz, CDCl3): δ = 1.35 (d, J = 6.3 Hz, 6 H), 5.20 (hept, J =
6.3 Hz, 1 H), 7.28 (d, J = 3.6 Hz, 1 H), 8.07 (d, J = 3.7 Hz, 1 H).
13C{1H} NMR (125 MHz, CDCl3): δ = 22.12 (2 CH3), 68.93 (CH), 111.09
tert-Butyl 4-Oxo-5-(2-oxo-2-phenylethyl)-5,6-dihydrocyclopen-
ta[b]thiophene-5-carboxylate (23)
(C), 125.39 (CH), 132.17 (C), 134.09 (CH), 161.15 (C).
HRMS (ESI): m/z calcd for C8H9BrNaO2S+ [M + Na+]: 270.9399; found:
270.9402.
Phenacyl bromide (280 mg, 1.41 mmol) and K2CO3 (194 mg, 1.41
mmol) were added to a solution of β-oxo ester 24 (279 mg, 1.17
mmol) in acetone (7 mL) and the mixture was stirred for 23 h at 40 °C.
H2O (10 mL) and brine (5 mL) were added and the aqueous layer was
extracted with MTBE (3 × 10 mL). The combined organic extracts
were dried (MgSO4), filtered, and the solvent was evaporated. Dike-
tone 23 was isolated after column chromatography (SiO2; hexane–
MTBE, 5:1; Rf = 0.21) as a colorless oil; yield: 392 mg (1.10 mmol,
94%).
Isopropyl (E)-4-[(2-(tert-Butoxycarbonyl)ethenyl]thiophene-3-
carboxylate (27)
tert-Butyl acrylate (1.06 g, 8.22 mmol), Pd(OAc)2 (18 mg, 0.082
mmol), Ph3P (43 mg, 0.17 mmol), and Et3N (416 mg, 4.11 mmol) were
added to a solution of thiophene derivative 26 (205 mg, 823 mmol) in
anhydrous DMA (2.1 mL) under an exclusion of air and moisture (N2
atmosphere) and the mixture was stirred at 130 °C for 21 h. H2O (15
mL) was then added and the aqueous layer was extracted with MTBE
(3 × 10 mL). The combined organic extracts were dried (MgSO4), fil-
tered, and the solvent was evaporated. The title compound 27 was
isolated after column chromatography (SiO2; hexane–MTBE, 20:1;
Rf = 0.16) as a colorless liquid; yield: 222 mg (0.750 mmol, 91%).
IR (ATR): 3085 (w), 2977 (w), 1703 (s), 1687 (s), 1151 (s) cm–1
.
1H NMR (500 MHz, CDCl3): δ = 1.34 (s, 9 H), 3.10 (d, J = 17.9 Hz, 1 H),
3.20 (d, J = 18.3 Hz, 1 H), 4.11 (d, J = 17.9 Hz, 1 H), 4.19 (d, J = 18.3 Hz,
1 H), 7.15 (d, J = 5.1 Hz, 1 H), 7.33 (d, J = 5.1 Hz, 1 H), 7.45 (t, J = 7.8 Hz,
2 H), 7.56 (t, J = 7.4 Hz, 1 H), 7.95 (d, J = 8.5 Hz, 2 H).
13C{1H} NMR (125 MHz, CDCl3): δ = 27.87 (3 CH3), 36.40 (CH2), 44.03
(CH2), 65.57 (C), 82.45 (C), 120.16 (CH), 128.26 (2 CH), 128.89 (2 CH),
131.45 (CH), 133.66 (CH), 136.61 (C), 143.29 (C), 168.46 (C), 170.88
(C), 193.68 (C), 197.43 (C). .
IR (ATR): 2978 (w), 1704 (s), 1144 (vs) cm–1
.
1H NMR (500 MHz, CDCl3): δ = 1.35 (d, J = 6.3 Hz, 6 H), 1.51 (s, 9 H),
5.20 (sept, J = 6.3 Hz, 1 H), 6.20 (d, J = 16.0 Hz, 1 H), 7.49 (dd, J = 3.3,
0.6 Hz, 1 H), 8.10 (d, J = 3.4 Hz, 1 H), 8.15 (dd, J = 16.1, 0.6 Hz, 1 H).
HRMS (ESI): m/z calcd for C20H20NaO4S+ [M + Na+]: 379.0975; found:
379.0976.
13C{1H} NMR (125 MHz, CDCl3): δ = 22.19 (2 CH3), 28.45 (3 CH3), 68.73
(CH), 80.64 (C), 122.59 (CH), 124.75 (CH), 132.55 (C), 134.72 (CH),
137.17 (CH), 137.82 (C), 162.39 (C), 166.13 (C).
tert-Butyl (Z)-2-Methyl-1-oxo-3-phenyl-1,2,5,6-tetrahydro-
thieno[3,2-c]azocine-5-carboxylate (7)
HRMS (ESI): m/z calcd for C15H20NaO4S+ [M + Na+]: 319.0975; found:
319.0969.
A solution of MeNH2 (2 mol/L in THF, 6.20 mL, 12.4 mmol) and
Bi(NO3)3·5 H2O (30 mg, 0.062 mmol) were added to a solution of 1,4-
diketone 23 (220 mg, 0.617 mmol) in THF (0.6 mL) and the mixture
was stirred for 4 d at 120 °C in a closed reaction vial. Subsequently,
the solvent was evaporated and lactam 7 was isolated after column
chromatography (SiO2; hexane–MTBE, 3:1; Rf = 0.39) as a yellow
resin; yield: 88 mg (0.24 mmol, 39%).
Isopropyl 4-[(2-(tert-Butoxycarbonyl)ethyl]thiophene-3-carboxyl-
ate (30)
A suspension of 10% Pd/C (13 mg), thiophene derivative 27 (71 mg,
0.24 mmol), and i-PrOH (1.5 mL) was degassed (three cycles of freeze,
pump, thaw) and then stirred under an atmosphere of H2 (1 bar) at
23 °C for 4 d. The suspension was filtered and the solvent was evapo-
rated. The residue was chromatographed (SiO2; hexane–MTBE, 10:1;
Rf = 0.43) to afford compound 30 as a pale yellow oil; yield: 61 mg
(0.20 mmol, 86%).
IR (ATR): 2976 (w), 1727 (s), 1636 (s), 1153 (vs) cm–1
.
1H NMR (500 MHz, CDCl3): δ = 1.51 (s, 9 H), 3.06 (s, 3 H), 3.08 (dd, J =
12.8, 16.7 Hz, 1 H), 3.49 (dd, J = 5.6, 16.7 Hz, 1 H), 3.88 (ddd, J = 5.6,
9.9, 13.0 Hz, 1 H), 5.99 (d, J = 9.8 Hz, 1 H), 7.03 (d, J = 5.2 Hz, 1 H), 7.10
(d, J = 5.3 Hz, 1 H), 7.26–7.31 (m, 5 H).
13C{1H} NMR (125 MHz, CDCl3): δ = 28.32 (3 CH3), 32.66 (CH2), 34.28
(CH3), 43.07 (CH), 82.14 (C), 122.79 (CH), 123.20 (CH), 126.49 (2 CH),
129.03 (2 CH), 129.15 (CH), 129.90 (CH), 132.95 (C), 135.42 (C),
138.57 (C), 143.95 (C), 168.01 (C), 171.86 (C).
IR (ATR): 2978 (w), 1708 (vs), 1249 (s), 1145 (s), 1060 (s) cm–1
.
1H NMR (500 MHz, CDCl3): δ = 1.33 (d, J = 6.3 Hz, 6 H), 1.40 (s, 9 H),
2.54 (t, J = 7.5 Hz, 2 H), 3.15 (t, J = 7.5 Hz, 2 H), 5.18 (sept, J = 6.3 Hz, 1
H), 6.97 (d, J = 3.4 Hz, 1 H), 8.06 (d, J = 3.4 Hz, 1 H).
13C{1H} NMR (125 MHz, CDCl3): δ = 22.17 (2 CH3), 25.81 (CH2), 28.32
(3 CH3), 36.18 (CH2), 68.10 (CH), 80.42 (C), 123.06 (CH), 132.42 (C),
134.63 (CH), 142.07 (C), 162.76 (C), 172.58 (C).
MS (EI, 70 eV): m/z (%) = 369 (2, [M+]), 241 (27), 118 (100).
HRMS (EI): m/z calcd for
C
21H23NO3S+ [M+]: 369.1393; found:
369.1397.
HRMS (ESI): m/z calcd for C15H22NaO4S+ [M + Na+]: 321.1131; found:
321.1135.
Isopropyl 4-Bromothiophene-3-carboxylate (26)
SOCl2 (10.3 g, 86.6 mmol) was added to cooled (ice-water bath) 4-bro-
mothiophene-3-carboxylic acid (15; 1.00 g, 4.83 mmol) and the mix-
ture was stirred for 3 h under reflux. After cooling (ice-water bath)
DMAP (30 mg, 0.24 mmol) and i-PrOH (100 mL) were added to the
solution and the mixture was stirred at 90 °C for 15 h. H2O (50 mL)
was added and the aqueous layer was extracted with CH2Cl2 (3 × 30
mL). The combined organic extracts were dried (MgSO4), filtered, and
tert-Butyl 3-Oxo-4,5-dihydrocyclopenta[c]thiophene-4-carboxyl-
ate (29)
KOt-Bu (497 mg, 4.42 mmol) was added to a solution of compound 30
(528 mg, 1.77 mmol) in anhydrous THF (9 mL) at 0 °C under an exclu-
sion of moisture and air (N2 atmosphere). The mixture was stirred for
45 min at 0 °C and then H2O (15 mL) and concd hydrochloric acid (3
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 1007–1015

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M. Penning et al.
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Synthesis
mL) were added. The aqueous layer was extracted with CH2Cl2 (3 × 15
mL) and the combined organic extracts were dried (MgSO4), filtered,
and the solvent was evaporated. After column chromatography (SiO2,
hexane–MTBE, 20:1, Rf = 0.25), the title compound 29 was isolated as
a colorless oil; yield: 215 mg (0.902 mmol, 51%).
HRMS (EI): m/z calcd for
369.1397.
C
21H23NO3S+ [M+]: 369.1393; found:
Supporting Information
IR (ATR): 3104 (w), 2978 (w), 1705 (s), 1143 (s) cm–1
.
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0034-1379976.
1H NMR (500 MHz, CDCl3): δ = 1.47 (s, 9 H), 3.17 (dd, J = 8.6, 16.7 Hz, 1
H), 3.31 (dd, J = 4.6, 16.7 Hz, 1 H), 3.89 (dd, J = 4.6, 8.6 Hz, 1 H), 7.02 (d,
J = 1.0 Hz, 1 H), 7.84 (d, J = 2.1 Hz, 1 H).
S
u
p
p
ortiInfogrmoaitn
S
u
p
p
o
nrtogI
f
rmoaitn
13C{1H} NMR (125 MHz, CDCl3): δ = 26.51 (CH2), 28.24 (3 CH3), 61.42
(CH), 82.29 (C), 117.54 (CH), 125.80 (CH), 143.26 (C), 152.38 (C),
168.39 (C), 190.95 (C).
MS (EI, 70 eV): m/z (%) = 238 (5, [M+]), 182 (100), 165 (75), 154 (72).
HRMS (EI): m/z calcd for C12H14O3S+ [M+]: 238.0658; found: 238.0654.
References
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Wiehl-Bomig, Germany.
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tert-Butyl 3-Oxo-4-(2-oxo-2-phenylethyl)-4,5-dihydrocyclopen-
ta[c]thiophene-4-carboxylate (28)
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J. Eur. J. Org. Chem. 2007, 3227. (b) Christoffers, J. Catal. Today
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Phenacyl bromide (271 mg, 1.36 mmol) and K2CO3 (188 mg, 1.96
mmol) were added to a solution of β-oxo ester 29 (270 mg, 1.13
mmol) in acetone (7.0 mL) and the mixture was stirred for 19 h at
40 °C. H2O (10 mL) and brine (5 mL) were added and the aqueous lay-
er was extracted with MTBE (3 × 10 mL). The combined organic ex-
tracts were dried (MgSO4), filtered, and the solvent was evaporated.
Diketone 28 was isolated after column chromatography (SiO2; hex-
ane–MTBE, 5:1; Rf = 0.24) as a colorless oil; yield: (332 mg (0.931
mmol, 82%).
IR (ATR): 3102 (w), 2977 (w), 1733 (s), 1706 (vs), 1685 (s), 1150 (vs)
cm–1
.
1H NMR (500 MHz, CDCl3): δ = 1.32 (s, 9 H), 2.93 (d, J = 16.9 Hz, 1 H),
3.45 (d, J = 18.4 Hz, 1 H), 3.77 (d, J = 16.9 Hz, 1 H), 4.06 (d, J = 18.4 Hz,
1 H), 7.02 (d, J = 1.1 Hz, 1 H), 7.43 (t, J = 7.6 Hz, 2 H), 7.55 (t, J = 7.4 Hz,
1 H), 7.89 (d, J = 1.9 Hz, 1 H), 7.95 (d, J = 8.1 Hz, 2 H).
13C{1H} NMR (125 MHz, CDCl3): δ = 27.84 (3 CH3), 34.29 (CH2), 44.19
(CH2), 66.56 (C), 82.36 (C), 117.15 (CH), 125.86 (CH), 128.87 (2 CH),
128.85 (2 CH), 133.62 (CH), 136.57 (C), 143.02 (C), 152.30 (C), 169.19
(C), 193.42 (C), 197.20 (C).
(11) Neidlein, R.; Kolb, N. Arch. Pharm. (Weinheim, Germany) 1979,
312, 397.
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Mehta, V. P.; Van Meervelt, L.; Kappe, C. O.; Van der Eycken, E. V.
Org. Lett. 2010, 12, 2774. (b) Herrero, M. T.; Tellitu, I.;
Dominguez, E.; Hernandez, S.; Moreno, I.; SanMartin, R. Tetra-
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Matveeva, M. D.; Galaktionova, D. V.; Tolkunov, S. V.; Tolkunova,
V. S.; Eresko, A. B.; Varlamov, A. V. Chem. Heterocycl. Compd.
2014, 50, 1338.
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A. V.; Borisov, R. S.; Kulikova, L. N.; Varlamov, A. V. Tetrahedron
2010, 66, 5140. (b) Voskressensky, L. G.; Kovaleva, S. A.;
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Varlamov, A. V. Chem. Heterocycl. Compd. 2013, 49, 1180.
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A. V. Chem. Heterocycl. Compd. 2014, 50, 658.
HRMS (ESI): m/z calcd for C20H20NaO4S+ [M + Na+]: 379.0975; found:
379.0979.
tert-Butyl (Z)-2-Methyl-1-oxo-3-phenyl-1,2,5,6-tetrahydro-
thieno[3,4-c]azocine-5-carboxylate (8)
A solution of MeNH2 (2 mol/L in THF, 8.7 mL, 17.4 mmol) and
Bi(NO3)3·5 H2O (42 mg, 0.087 mmol) were added to a solution of 1,4-
diketone 28 (310 mg, 0.870 mmol) in THF (0.7 mL) and the mixture
was stirred for 4 d at 120 °C in a closed reaction vial. Subsequently,
the solvent was evaporated and lactam 8 was isolated after column
chromatography (SiO2; hexane–MTBE, 3:1; Rf = 0.26) as a yellow
resin; yield: 120 mg (0.32 mmol, 37%).
IR (ATR): 2977 (w), 1726 (s), 1688 (m), 1154 (vs), 633 (s) cm–1
.
1H NMR (500 MHz, CDCl3): δ = 1.51 (s, 9 H), 3.04 (s, 4 H), 3.05 (dd, J =
12.4, 15.7 Hz, 1 H), 3.36 (ddd, J = 1.5, 7.2, 15.8 Hz, 1 H), 3.84 (ddd, J =
7.2, 9.8, 12.3 Hz, 1 H), 5.97 (d, J = 9.8 Hz, 1 H), 6.79 (d, J = 3.3 Hz, 1 H),
7.25–7.32 (m, 5 H), 7.54 (d, J = 3.4 Hz, 1 H).
13C{1H} NMR (125 MHz, CDCl3): δ = 28.30 (3 CH3), 32.53 (CH2), 34.12
(CH3), 42.68 (CH), 81.89 (C), 121.71 (CH), 123.66 (CH), 126.39 (2 CH),
128.05 (CH), 128.97 (2 CH), 129.08 (CH), 135.12 (C), 136.30 (C),
137.66 (C), 142.98 (C), 168.48 (C), 172.46 (C).
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dron Lett. 1998, 39, 8449.
MS (EI, 70 eV): m/z (%) = 369 (2, [M+]), 313 (22), 196 (26), 151 (67),
118 (56).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 1007–1015