Synthesis of Thieno[3,2-e][1,4]diazepin-2-ones: Application of an Uncatalysed Pictet-Spengler Reaction

Article abstract of DOI:10.1002/ejoc.201500943

A series of 5-substituted thieno[3,2-e][1,4]diazepin-2-ones was synthesized in four steps from methyl 3-aminothiophene-2-carboxylate. After the coupling of 3-aminothiophene with α-amino acids, the key final step that involves an uncatalysed Pictet-Spengler reaction allowed the cyclization of the seven-membered diazepinone ring. The reaction was first optimized and then exemplified in three different series (phenylalanine, alanine and proline) that led to 24 target diazepinones, which includes 19 optically pure diastereomers. A new synthetic approach that uses an uncatalysed Pictet-Spengler cyclization reaction has been developed to access [3,2-e]-type fused thienodiazepinones.

Full text of DOI:10.1002/ejoc.201500943

FULL PAPER
DOI: 10.1002/ejoc.201500943
Synthesis of Thieno[3,2-e][1,4]diazepin-2-ones: Application of an Uncatalysed
Pictet–Spengler Reaction
Séverine Denoyelle,*[a] Guillaume Tambutet,[a] Nicolas Masurier,[a] Ludovic T. Maillard,[a]
Jean Martinez,[a] and Vincent Lisowski[a]
Keywords: Synthesis design / Cyclization / Fused-ring systems / Nitrogen heterocycles / Sulfur heterocycles
A series of 5-substituted thieno[3,2-e][1,4]diazepin-2-ones
was synthesized in four steps from methyl 3-aminothio-
phene-2-carboxylate. After the coupling of 3-aminothio-
phene with α-amino acids, the key final step that involves an
uncatalysed Pictet–Spengler reaction allowed the cyclization
of the seven-membered diazepinone ring. The reaction was
first optimized and then exemplified in three different series
(phenylalanine, alanine and proline) that led to 24 target
diazepinones, which includes 19 optically pure dia-
stereomers.
interesting properties over the past years. As an example,
Clotiazepam (Figure 1) is a thienodiazepine marketed drug
with anxiolytic, anticonvulsant, sedative and muscle relax-
ant properties.[21,22] Tricyclic structures derived from the lat-
ter have been further described and include Etizolam (Fig-
ure 1).[23] Their notable activities, and the opportunity to
introduce new diversity, led us to develop new methodolo-
Introduction
The concept of privileged structure, which is defined as
“a single molecular framework able to provide ligands for
diverse receptors”,[1] has emerged as a powerful approach
to increase the chances of discovering lead compounds. The
diazepine scaffold is one of the classical examples of privi-
leged structures, which has proved its effectiveness in a
number of pharmaceutical drugs and still continues to at-
tract much interest today in medicinal chemistry.[2] Aryl-
diazepine ring systems achieved popularity first in the 1960s
with diazepam as the first orally active anxiolytic by inter-
action with GABA receptors. This template was further
shown to interact with high affinity with multiple receptor
types and has also been used in the design of some enzyme
inhibitors.[3–6]
Since the discovery of benzodiazepines as central nervous
system depressants, many synthetic derivatives that display
a wide range of therapeutic applications in antithrom-
botic,[7] antibiotic,[8] and antitumor[9,10] areas, have been ex-
tensively developed. Much attention has been paid to the
replacement of the fused benzene ring by a heterocyclic
structure such as pyrazole,[11,12] imidazole,[13] pyrrole,[14–16]
and indole.[17,18] Recently, we focused our efforts on the de-
velopment of a new azaheterocycle-fused [1,3]diazepine
scaffold and successfully reported on the synthesis of the
first series of imidazopyridine-fused [1,3]diazepinones.[19,20]
We also investigated the thiophene isoster (namely thieno-
[1,4]diazepine) scaffold. Indeed, this scaffold has shown
[a] Institut des Biomolécules Max-Mousseron (IBMM),
UMR 5247-CNRS-ENSCM, Faculté de Pharmacie,
Université de Montpellier,
15 Avenue Charles Flahault, 34093 Montpellier, France
E-mail: severine.denoyelle@univ-montp1.fr
http://www.ibmm.univ-montp1.fr/
Supporting Information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201500943.
Figure 1. Representative thienodiazepines and target compounds.
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Synthesis of Thieno[3,2-e][1,4]diazepin-2-ones
gies to afford functionalized thienodiazepines as promising
structures for medicinal chemistry research.
Because most synthetic routes described in the literature
refer to a [2,3]-type fusion between thiophene and seven-
membered heterocycles,[24,25] access to isomeric [3,2]-type
fusion appears more intricate. In this context, we have re-
cently described a general synthetic protocol to generate
new thieno[3,2-e][1,4]diazepin-2,5-diones B by regioselec-
tive ring opening of 2-thiaisatoic anhydride A by α-amino
acids, followed by intramolecular cyclocondensation reac-
tion.[26] This methodology was further extended to the solid
phase by using N-alkylated α-amino acids that led to
C3,N4-substituted thieno[3,2-e][1,4]diazepin-2,5-diones B
(Figure 1).[27] More recently, diversity was introduced by N-
substituted thienodiazepinedione ring opening with a series
of organomagnesium bromides and subsequent cyclization
to afford 5-arylthienodiazepin-2-one C analogues (Fig-
ure 1).[28]
Scheme 1. Synthesis of N1-3-thienylaminoamides 5a–5c.
amine (DIEA) in CH2Cl2. Removal of the Boc protecting
In our on-going interest in the development of focused group with trifluoroacetic acid (TFA; 30%) in CH2Cl2 fol-
heterocyclic libraries and to enlarge the chemical diversity lowed by basic treatment with NH4OH yielded N1-3-thien-
of thienodiazepine scaffold, we present herein a new ef- ylaminoamides 5a–5c that were used in the Pictet–Spengler
ficient synthesis of 5-substituted thieno[3,2-e][1,4]diazepin- reaction without further purification.
2-ones 6–23 (Figure 1) by means of an uncatalysed Pictet–
With these intermediates in hand, we were able to investi-
Spengler reaction as the key step. This reaction, commonly gate their reactivity towards the intramolecular Pictet–
used in the synthesis of many isoquinoline and β-carboline Spengler cyclization reaction. To explore the formation of
alkaloids,[29,30] has already been applied to thiophene.[31–34] the thieno[3,2-e][1,4]diazepin-2-one scaffold and the pos-
Moreover, few examples of the seven-membered diazepine sibility of introducing diversity at position 5 of the ring, N1-
ring closure have been described with electron-rich (hetero)- 3-thienylaminoamide 5a (from the phenylalanine series) was
cycles such as pyrrole[15,35] and imidazole.[36]
treated with p-nitrobenzaldehyde (1 equiv.) under various
experimental conditions (Table 1). Initially, a screen for sol-
vent performance was undertaken with chloroform, THF,
1,4-dioxane, n-butanol and toluene, at different tempera-
tures (25 °C and reflux). The reaction time was limited to
Results and Discussion
To access the target thieno[3,2-e][1,4]diazepin-2-ones, we 12 h when no conversion was observed. Reactions were
envisioned a strategy by which the Pictet–Spengler cycliza- monitored by TLC with silica gel (CH2Cl2/EtOAc, 9:1, v/v)
tion key reaction step consists of a condensation reaction of and diazepinones were isolated as pure diastereomers 6α
N1-3-thienylaminoamides 5a–5c with various aromatic and (with a syn configuration) and 6β (with an anti configura-
aliphatic aldehydes. These amides were achieved by cou- tion) by flash chromatography with silica gel (CH2Cl2 to
pling 3-aminothiophene 3 with tert-butoxycarbonyl (Boc)- CH2Cl2/EtOAc, 95:5, v/v). Absolute configurations were as-
amino acids, followed by a subsequent removal of the Boc certained by NOESY experiments (see Supporting infor-
protecting group under acidic conditions. According to the mation). The (3S,5R) and (3S,5S) relative stereochemistry
literature, compound 2 was generated by reacting methyl- was assigned based on the observed nuclear Overhauser ef-
thioglycolate 1 with 2-chloroacrylonitrile in the presence of fect between the resonances of the H3 and H5 protons of
sodium methoxide in MeOH (Scheme 1).[37] The ester func- the diazepine ring. These experiments showed no reaction
tion of 2 was then hydrolysed in a solution of sodium when performed at room temperature, whereas at reflux
hydroxide (2 m) in methanol at reflux temperatures as de- temperatures, the results indicated toluene at 110 °C as the
scribed by Florence et al.[38] Treatment with neat HCl al- best solvent, a yield of 49% was obtained after 6 h (Table 1,
lowed the precipitation and isolation of the resulting un- Entry 10). The same results were obtained with n-butanol
stable amino acid derivative that was immediately de- but only after 12 h (Table 1, Entry 8). With this model, the
carboxylated by using oxalic acid in 2-propanol at reflux ratio of diastereomers 6α/6β did not seem to be dependent
temperatures to yield the oxalate salt. This intermediate salt on the nature of the solvent or on the temperature and re-
was treated with an aqueous solution of ammonia (28%) to mained close to 1:1 after isolation of the compounds. Opti-
afford 3-aminothiophene (3) in 69% overall yield from 2.
mum conditions were obtained with freshly distilled toluene
Protected N1-3-thienylaminoamides 4a–4c were isolated in the presence of 4 Å molecular sieves under N2 atmo-
in 74–85% yields after acylation of 3-aminothiophene 3 sphere (Table 1, Entry 11), which suggests that the imine
with N-Boc-amino acids (Phe, Ala and Pro) in the presence intermediate formed during the reaction might be sensitive
of (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium to hydrolysis. Under these conditions, the yield was in-
hexafluorophosphate (BOP) and N,N-diisopropylethyl- creased to 72% and the reaction time was optimized to 3 h.
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To further improve the yield, classical acidic catalysis was ately electron-withdrawing substituents, such as p-bromo-
evaluated. Indeed, Lubell et al. reported that TFA was able benzaldehyde and benzaldehyde, gave slightly lower overall
to catalyse the Pictet–Spengler cyclization reaction on the yields 58–69% (Table 2, compounds 7 and 8, respectively);
pyrrole.[15,16] In the case of thiophene, degradation was ob- no influence on the diastereoselectivity was observed, and
served with a Brønsted acid, such as TFA (Table 1, En- the ratio of diastereomers α/β remained 1:1. However, a de-
try 12), or with a Lewis acid, such as TiCl4 (Table 1, En- crease in the overall yield was observed with aromatic elec-
try 13). Therefore, uncatalysed conditions in anhydrous tol- tron-donor p-anisaldehyde (49% overall yield; Table 2,
uene at 110 °C were selected to perform all the Pictet– compound 9). These results suggest that the aldehyde’s elec-
Spengler reactions described in this report. With these opti- tron properties influence imine stabilization. Indeed, the im-
mized conditions in hand, we investigated the reactivity of ine intermediate was less reactive to nucleophilic attack by
three different series (phenylalanine, alanine and proline) thiophene when electron-donor aldehydes were used.[39] The
towards several aromatic and aliphatic aldehydes that of- Pictet–Spengler condensation reaction with aliphatic alde-
fered a wide diversity of substituents.
hyde 3-methylbutyraldehyde gave 10 in 75% overall yield,
whereas with cyclohexylaldehyde, only diastereomer 11β
was isolated in 34% yield (Table 2). In this case, purification
by flash chromatography did not allow the isolation of dia-
stereomer 11α. With 3-methylbutyraldehyde syn stereoselec-
tivity was observed with a α/β ratio close to 2:1.
Table 1. Optimization of the Pictet–Spengler reaction.[a]
Table 2. Pictet–Spengler cyclization reaction with the phenylalanine
series.[a]
Entry
Solvent
T [°C] Time [h] Yield [%][e] α/β ratio[f]
1
2
3
4
5
6
7
8
9
10
11
12
13
chloroform
chloroform
THF
25
62
25
66
25
101
25
118
25
110
110
110
110
12
12
12
12
12
12
12
12
12
6
0
0
0
0
0
–
–
–
–
–
–
–
THF
R2
α [%][b] β [%][b]
Overall
α/β ratio[c]
1,4-dioxane
1,4-dioxane
n-butanol
n-butanol
toluene
yield [%]
0
0
6
7
8
9
p-O2NC6H4
p-BrC6H4
C6H5
34
29
34
25
50
0
38
29
35
24
25
34
72
58
69
49
75
34
47:53
50:50
49:51
51:49
67:33
0:100
50
0
49
72
0
45:55
–
45:55
47:53
–
toluene
p-MeOC6H4
anhydr. toluene[b]
anhydr. toluene[b,c]
anhydr. toluene[b,d]
3
12
12
10 CH2CH(CH3)2
11 C6H11
0
–
[a] Reaction was performed with 5a (100 mg) and aldehyde
(1 equiv.) in freshly distilled toluene (5 mL) in the presence of 4 Å
molecular sieves and was stirred at reflux temperatures for 3 h un-
der N2. [b] Isolated yields after flash chromatography in normal
phase. [c] Determined from isolated yields.
[a] Reaction was performed with: 5a (100 mg) and p-nitrobenzalde-
hyde (1 equiv.) in solvent (5 mL). [b] Molecular sieves (4 Å) under
N2. [c] TFA (0.5 equiv.). [d] TiCl4 (0.1 equiv.). [e] Overall yields af-
ter flash chromatography in normal phase. [f] Determined from iso-
lated yields.
In the alanine series, amine 5b was treated with the same
We exemplified the reaction in the phenylalanine series aromatic and aliphatic aldehydes, as in the phenylalanine
by reacting amine 5a with several aromatic and aliphatic series. Results are reported in Table 3. Although the overall
aldehydes (Table 2). In all cases, both diastereomers α and yields were slightly better in most cases, diastereomers with
β were isolated by flash chromatography with silica gel aromatic substituents were not isolated as optically pure
(CH2Cl2/EtOAc) and their absolute configuration was as- compounds because efficient separation conditions could
certained by NOESY experiments (see Supporting infor- not be found either with reverse phase HPLC or normal
mation). As shown, ring closure, accomplished by the phase flash chromatography. Only compounds 16 and 17
Pictet–Spengler condensation reaction with aromatic alde- with aliphatic substituents, were isolated as optically pure
hydes with electron-withdrawing substituents, such as p- 3S,5S diastereomers (diastereomers 3S,5R could not be iso-
nitrobenzaldehyde, yielded thieno[3,2-e][1,4]diazepin-2-one lated in pure form). In both cases, the difference between
in good overall yield, although no diastereoselectivity was the retention factors of the two diastereomers allowed their
observed (Table 2, compound 6). Aldehydes with moder- separation by flash chromatography on silica gel (CH2Cl2/
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Synthesis of Thieno[3,2-e][1,4]diazepin-2-ones
EtOAc). It is noticeable that with electron-donor p-anis- matic (73–82%) or aliphatic aldehydes (70–92%). This fact
aldehyde (Table 3, compound 15), no yield was determined is in agreement with the idea that the tetraalkylated imin-
because a pure mixture of the two diastereomers could not ium intermediate must be more reactive to the thiophene’s
be isolated. Problems not only occurred during the purifica- nucleophilic attack as a result of exacerbated electrophilic-
tion process but the compound was also unstable if the mix- ity. All diastereomers were isolated as optically pure com-
ture was left at room temperature in CDCl3.
pounds and their configuration was ascertained by NOESY
experiments (see Supporting information). Interestingly, it
appears that when the C3- and C5-positions of the diazep-
ine ring are conformationally constrained by the proline
residue, anti stereoselectivity is observed because all the
major diastereomers are of 3S,5S configuration. Indeed,
when benzaldehyde (20), p-anisaldehyde (21), 3-methyl-
butyraldehyde (22) and cyclohexylaldehyde (23) are used in
the Pictet–Spengler cyclization reaction, the 3S,5R configu-
ration is not observed.
Table 3. Pictet–Spengler cyclization reaction with the alanine
series.[a]
Conclusions
R2
Yield [%][b]
We have developed a practical sequence for the synthesis
of original thieno[3,2-e][1,4]diazepin-2-ones that enables the
introduction of a wide diversity of substituents. The key
step was an uncatalysed Pictet–Spengler reaction that al-
lows the intramolecular cyclization of the seven-membered
diazepine ring. The reaction was exemplified in three dif-
ferent series (phenylalanine, alanine and proline series) by
using several aromatic and aliphatic aldehydes. The re-
12
13
14
15
16
17
p-O2NC6H4
p-BrC6H4
C6H5
p-MeOC6H4
CH2CH(CH3)2
C6H11
88
61
36
n.d.[c]
58[d]
58[d]
[a] Reaction was performed with 5b (100 mg) and aldehyde
(1 equiv.) in freshly distilled toluene (5 mL) in the presence of mo-
lecular sieves (4 Å) and was stirred at reflux temperatures for 3 h
under N2. [b] Isolated yields after flash chromatography in normal sulting diastereomers were usually easily isolated as op-
phase; n.d.: not determined. [c] Not determined owing to low prod-
uct stability. [d] Diastereomer 3S,5S optically pure.
tically pure in the phenylalanine and proline series and
more importantly, anti stereoselectivity was observed when
the C3- and C5-positions of the diazepine ring were confor-
In the proline series, amine 5c was reacted with the same
mationally constrained by the proline residue. In light of
aldehydes used in the previous series. Results are reported
the hopeful biological activities of diazepinone derivatives,
in Table 4 and show the best overall yields either with aro-
this new thiophene-fused [3,2]diazepinone scaffold is prom-
ising for the development of biologically active compounds.
Table 4. Pictet–Spengler cyclization reaction with the proline
series.[a]
Experimental Section
General Methods: All reactions were performed in flame-dried
glassware with magnetic stirring under an inert atmosphere (nitro-
gen). Toluene for reactions was distilled in the presence of sodium
as a drying agent and transferred under nitrogen. Reagents were
used as received. TLC was performed with Merck silica Gel 60
F254 plates. Visualization was accomplished by irradiation with a
UV lamp, and then by staining with a ninhydrin solution in MeOH.
Purification by flash column chromatography was performed with
Biotage SP1 pre-packed columns filled with silica gel and moni-
tored by UV detection at 254 and 280 nm. The H and 13C NMR
1
R2
α [%][b]
β [%][b]
Overall
yield [%]
α/β ratio[c]
spectroscopic data were recorded with a Bruker spectrometer at
300 and 75 MHz, respectively. Chemical shifts are reported [s (sing-
let), d (doublet), dd (doublet of doublets), t (triplet), td (triplet of
doublets), q (quartet), m (multiplet)] relative to the solvent peak
[δH = 7.26 ppm and δC = 77.16 ppm for CHCl3, δH = 2.50 ppm
and δC = 39.52 ppm for dimethyl sulfoxide (DMSO)]. Mass spec-
trum analyses were recorded with a Quatromicro (Micromass,
Manchester, U.K.) triple-quadrupole mass spectrometer fitted with
an electrospray interface. HRMS analyses were performed by the
Laboratoire de Mesures Physiques, University of Montpellier.
18
19
20
21
p-O2NC6H4
p-BrC6H4
C6H5
20
16
–
–
–
62
62
78
73
70
92
82
78
78
73
70
92
24:76
30:70
0:100
0:100
0:100
0:100
p-MeOC6H4
22 CH2CH(CH3)2
23 C6H11
–
[a] Reaction was performed with 5c (100 mg) and aldehyde
(1 equiv.) in freshly distilled toluene (5 mL) in the presence of 4 Å
molecular sieves and was stirred at reflux temperatures for 3 h un-
der N2. [b] Isolated yields after flash chromatography in normal
phase. [c] Determined from isolated yields.
General Procedure for the Synthesis of Aminoamides 4a–4c: To an
ice-cold solution of compound 3 (1 g, 10.10 mmol) in CH2Cl2
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S. Denoyelle et al.
FULL PAPER
(50 mL) were added Boc-AA-OH (11.11 mmol, 1.1 equiv.) and (3S,5R)-3-Benzyl-5-(4-nitrophenyl)-1,3,4,5-tetrahydro-2H-thieno-
BOP (4.9 g, 11.11 mmol, 1.1 equiv.). The pH was adjusted to 8–9
by adding DIEA (5 mL, 30.30 mmol, 3 equiv.). The solution was
[3,2-e][1,4]diazepin-2-one (6α): Orange wax, 34% (52.4 mg). [α]2D9
=
–104.4 (c = 1.0, MeOH). 1H NMR (CDCl3, 300 MHz): δ = 1.98 (s,
stirred for 4 h at room temp. The solvent was then removed in 1 H), 3.07 (dd, J = 5.1, J = 13.8 Hz, 1 H), 3.31 (dd, J = 5.1, J =
vacuo and the residue was dissolved in EtOAc (100 mL). The solu-
tion was washed with a saturated sodium hydrogen carbonate solu-
13.8 Hz, 1 H), 4.00–4.03 (m, 1 H), 5.81 (s, 1 H), 6.94–7.02 (m, 4
H), 7.10–7.28 (m, 6 H), 7.99 (d, J = 8.4 Hz, 2 H) ppm. 13C NMR
tion (2ϫ 100 mL) and brine (1ϫ 100 mL). The organic layer was (CDCl3, 75 MHz): δ = 36.79, 60.55, 76.06, 112.32, 120.83, 124.18,
dried with Na2SO4, filtered, and the solvent was evaporated in
vacuo. The residue was purified by flash chromatography with sil-
ica gel (CH2Cl2/EtOAc).
125.01, 127.21 (2 C), 127.65 (2 C), 128.95, 129.88 (3 C), 134.37,
136.11, 146.15, 148.22, 172.73 ppm. LC–MS (ESI+): m/z = 380.1
[M + H]+. HRMS: calcd. for C20H18N3O3S 380.1069 [M + H]+;
found 380.1070.
N-(tert-Butoxycarbonyl)-N-3-thienylphenylalaninamide (4a): White
solid, 74% (2.59 g), m.p. 154.1–154.9 °C. [α]2D9 = –12.7 (c = 1.0,
MeOH). 1H NMR ([D6]DMSO, 300 MHz): δ = 1.31 (s, 9 H), 2.78–
2.86 (m, 1 H), 2.94–3.00 (m, 1 H), 4.23–4.31 (m, 1 H), 7.09–7.32
(m, 7 H), 7.45 (dd, J = 3.3, J = 5.1 Hz, 1 H), 7.54 (d, J = 3.3 Hz,
1 H), 10.45 (s, 1 H) ppm. 13C NMR ([D6]DMSO, 75 MHz): δ =
28.18 (3 C), 37.46, 56.27, 78.10, 108.76, 121.43, 124.76, 126.30,
128.09 (2 C), 128.21, 129.22, 136.60, 138.06, 155.42, 169.91 ppm.
LC–MS (ESI+) m/z = 347.2 [M + H]+.
(3S,5S)-3-Benzyl-5-(4-nitrophenyl)-1,3,4,5-tetrahydro-2H-thieno-
[3,2-e][1,4]diazepin-2-one (6β): Orange wax, 38% (58.5 mg). [α]2D9
=
1
–24.7 (c = 1.0, MeOH). H NMR (CDCl3, 300 MHz): δ = 2.52 (s,
1 H), 3.11 (dd, J = 6.6, J = 14.1 Hz, 1 H), 3.16 (dd, J = 4.5, J =
14.1 Hz, 1 H), 3.99 (dd, J = 4.5, J = 6.6 Hz, 1 H), 5.68 (s, 1 H),
7.07–7.27 (m, 8 H), 7.40 (d, J = 8.7 Hz, 2 H), 8.13 (d, J = 8.7 Hz,
2 H) ppm. 13C NMR (CDCl3, 75 MHz): δ = 37.32, 59.26, 75.77,
111.51, 120.44, 124.31, 125.32, 127.05, 127.32 (3 C), 128.71 (3 C),
129.59, 134.63, 136.48, 146.23, 148.09, 172.55 ppm. LC–MS
(ESI+): m/z = 380.1 [M + H]+. HRMS: calcd. for C20H18N3O3S
380.1069 [M + H]+; found 380.1071.
N-(tert-Butoxycarbonyl)-N-3-thienylalaninamide (4b): White solid,
78% (2.13 g), m.p. 187.3–187.8 °C. [α]2D9 = –56.9 (c = 1.0, MeOH).
1H NMR ([D6]DMSO, 300 MHz): δ = 1.23 (d, J = 6.9 Hz, 3 H),
1.38 (s, 9 H), 4.05–4.09 (m, 1 H), 7.01 (d, J = 6.9 Hz, 1 H), 7.10
(dd, J = 1.2, J = 5.1 Hz, 1 H), 7.43 (dd, J = 3.3, J = 5.1 Hz, 1 H),
7.51 (dd, J = 1.2, J = 3.3 Hz, 1 H), 10.27 (s, 1 H) ppm. 13C NMR
([D6]DMSO, 75 MHz): δ = 18.00, 28.15 (3 C), 50.03, 77.99, 108.44,
121.37, 124.56, 136.67, 155.10, 170.83 ppm. LC–MS (ESI+): m/z =
293.2 [M + Na]+.
(3S,5R)-3-Benzyl-5-(4-bromophenyl)-1,3,4,5-tetrahydro-2H-thieno-
[3,2-e][1,4]diazepin-2-one (7α): Pale yellow solid, 29% (48.6 mg),
m.p. 112.0–114.1 °C. [α]2D9 = –122.3 (c = 1.0, MeOH). 1H NMR
(CDCl3, 300 MHz): δ = 1.94 (s, 1 H), 3.10 (dd, J = 4.5, J = 14.1 Hz,
1 H), 3.32 (dd, J = 5.4, J = 14.1 Hz, 1 H), 3.94–3.97 (m, 1 H), 5.64
(s, 1 H), 6.65–6.70 (m, 2 H), 6.99–7.11 (m, 3 H), 7.19–7.30 (m, 7
H) ppm. 13C NMR (CDCl3, 75 MHz): δ = 36.68, 60.72, 76.84,
112.21, 121.13, 123.41, 124.69, 127.25, 128.38, 129.08 (3 C), 129.94
(3 C), 132.31, 134.86, 136.27, 138.28, 173.17 ppm. LC–MS (ESI+):
m/z = 413.0 and 415.0 [M + H]+. HRMS: calcd. for C20H18BrN2OS
413.0323 [M + H]+; found 413.0322.
N-(tert-Butoxycarbonyl)-N-3-thienylprolinamide (4c): White solid,
85% (2.54 g), m.p. 210.8–212.9 °C. [α]2D9 = –77.4 (c = 1.0, MeOH);
two conformers detected by NMR spectroscopy in [D6]DMSO. 1H
NMR ([D6]DMSO, 300 MHz): δ = 1.26 (s, 6 H), 1.40 (s, 3 H); 1.76–
1.91 (m, 3 H), 2.14–2.22 (m, 1 H), 3.30–3.46 (m, 2 H), 4.12–4.22
(m, 1 H), 7.11 (m, 1 H), 7.42 (m, 1 H), 7.51 (m, 1 H), 10.29 (s, 0.6
H), 10.31 (s, 0.4 H) ppm. 13C NMR ([D6]DMSO, 75 MHz): δ =
23.30/23.90 (1 C), 27.87–28.11 (3 C), 30.14/30.96 (1 C), 46.47/46.68
(1 C), 59.64/60.07 (1 C), 78.45/78.60 (1 C), 108.44, 121.26, 124.52,
136.71, 153.12/153.56 (1 C), 170.14/170.53 (1 C) ppm. LC–MS
(ESI+): m/z = 319.2 [M + Na]+.
(3S,5S)-3-Benzyl-5-(4-bromophenyl)-1,3,4,5-tetrahydro-2H-thieno-
[3,2-e][1,4]diazepin-2-one (7β): Pale yellow solid, 29 % (48.7 mg),
m.p. 127.8–129.0 °C. [α]2D9 = –28.1 (c = 1.0, MeOH). 1H NMR
(CDCl3, 300 MHz): δ = 2.30 (s, 1 H), 3.06 (dd, J = 6.6, J = 13.8 Hz,
1 H), 3.18 (dd, J = 4.5, J = 13.8 Hz, 1 H), 4.03 (dd, J = 4.5, J =
6.6 Hz, 1 H), 5.53 (s, 1 H), 7.09–7.17 (m, 5 H), 7.19–7.28 (m, 5 H),
7.44 (m, 2 H) ppm. 13C NMR (CDCl3, 75 MHz): δ = 37.65, 59.37,
76.30, 111.41, 120.67, 122.99, 124.87, 126.90, 127.85 (2 C), 128.60
(2 C), 129.60, 132.29 (3 C), 134.86, 136.90, 138.34, 172.64 ppm.
LC–MS (ESI+): m/z = 413.0 and 415.0 [M + H]+. HRMS: calcd.
for C20H18BrN2OS 413.0323 [M + H]+; found 413.0325.
General Procedure for the Isolation of Deprotected Amino Amides
5a–5c: Trifluoroacetic acid (3 mL) was carefully added to a solution
of 4a–4c (500 mg) in CH2Cl2 (7 mL). The reaction mixture was
stirred for 1.5 h at room temp. Trifluoroacetic acid and CH2Cl2
were then removed in vacuo and the crude mixture was dissolved
in water (10 mL). The pH of the solution was adjusted to 8–9 by
adding 28% aqueous ammonia and the solution was extracted with
CH2Cl2 (2ϫ 20 mL). The combined organic layers were washed
with brine, dried with anhydrous Na2SO4 and evaporated in vacuo
to afford 5a–5c (95–98%) as yellow waxes, which were used in the
next reaction step without further purification.
(3S,5R)-3-Benzyl-5-phenyl-1,3,4,5-tetrahydro-2H-thieno[3,2-e][1,4]-
diazepin-2-one (8α): Pale yellow solid, 34% (46.2 mg), m.p. 123.1–
126.1 °C. [α]2D9 = –118.4 (c = 1.0, MeOH). 1H NMR (CDCl3,
300 MHz): δ = 1.92 (s, 1 H), 3.16 (dd, J = 4.8, J = 14.1 Hz, 1 H),
3.32 (dd, J = 5.4, J = 14.1 Hz, 1 H), 3.97 (dd, J = 4.8, J = 5.4 Hz,
1 H), 5.39 (s, 1 H), 6.87–6.90 (m, 2 H), 7.02–7.12 (m, 3 H), 7.16–
7.17 (m, 8 H) ppm. 13C NMR (CDCl3, 75 MHz): δ = 36.82, 60.86,
77.61, 112.02, 121.26, 124.37, 126.68 (2 C), 127.14, 129.00 (2 C),
129.16, 129.22, 129.35, 129.87 (2 C), 135.23, 136.46, 139.24,
173.38 ppm. LC–MS (ESI+): m/z = 335.2 [M + H]+. HRMS: calcd.
for C20H19N2OS 335.1218 [M + H]+; found 335.1219.
General Procedure for the Synthesis of Thieno[3,2-e][1,4]diazepin-2-
ones 6–23: To a solution of 5a–5c (100 mg) in freshly distilled tolu-
ene (5 mL) kept under nitrogen were added molecular sieves 4 Å
and the appropriate aldehyde (1 equiv.). The reaction mixture was
stirred at 110 °C for 3 h under nitrogen. After the starting material
was totally consumed (the reaction was monitored by TLC with
CH2Cl2/EtOAc, 9:1 v/v), the reaction mixture was cooled to room
temperature and the molecular sieves were filtered off. The solvent
was removed in vacuo and the resulting mixture of two dia-
stereomers was purified by flash chromatography (CH2Cl2/EtOAc)
that, in some cases, allowed separation of diastereomers α and β.
(3S,5S)-3-Benzyl-5-phenyl-1,3,4,5-tetrahydro-2H-thieno[3,2-e][1,4]-
diazepin-2-one (8β): Yellow solid, 35 % (47.5 mg), m.p. 110.2–
1
118.8 °C (degradation). [α]2D9 = –44.2 (c = 1.0, MeOH). H NMR
(CDCl3, 300 MHz): δ = 2.27 (s, 1 H), 3.06 (dd, J = 7.2, J = 14.1 Hz,
1 H), 3.20 (dd, J = 4.5, J = 14.1 Hz, 1 H), 4.08 (dd, J = 4.5, J =
7.2 Hz, 1 H), 5.58 (s, 1 H), 7.12–7.17 (m, 3 H), 7.20–7.33 (m, 10
H) ppm. 13C NMR (CDCl3, 75 MHz): δ = 38.15, 59.68, 77.19,
7150
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© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2015, 7146–7153

Synthesis of Thieno[3,2-e][1,4]diazepin-2-ones
111.50, 121.02, 124.71, 126.22, 126.94, 128.69 (2 C), 129.18, 129.32
(3 C), 129.80 (2 C), 135.33, 137.43, 139.61, 172.89 ppm. LC–MS
(ESI+): m/z = 335.2 [M + H]+. HRMS: calcd. for C20H19N2OS
335.1218 [M + H]+; found 335.1217.
3-Methyl-5-(4-nitrophenyl)-1,3,4,5-tetrahydro-2H-thieno[3,2-e][1,4]-
diazepin-2-one (12): Yellow wax, 88 % (156.8 mg); two dia-
stereomers detected by NMR in CDCl3. 1H NMR (CDCl3,
300 MHz): δ = 1.36–1.41 (m, 3 H), 2.24 (s, 1 H), 3.63–3.73 (m, 1
H), 5.89 (s, 0.4 H), 5.93 (s, 0.6 H), 6.99–7.02 (m, 1 H), 7.09–7.20
(m, 2 H), 7.40–7.50 (m, 2 H), 8.14 (d, J = 9.0 Hz, 2 H) ppm. 13C
NMR (CDCl3, 75 MHz): δ = 17.04–18.13 (1 C), 54.06–55.74 (1 C),
75.52–76.06 (1 C), 110.94 (1 C), 112.20 (1 C), 120.28–120.93 (1
C), 124.38–124.47 (2 C), 125.18–125.49 (1 C), 127.44–127.93 (2 C),
135.11 (1 C), 146.25–146.47 (1 C), 174.06 (1 C) ppm. LC–MS
(ESI+): m/z = 304.1 [M + H]+. HRMS: calcd. for C14H14N3O3S
304.0756 [M + H]+; found 304.0755.
(3S,5R)-3-Benzyl-5-(4-methoxyphenyl)-1,3,4,5-tetrahydro-2H-
thieno[3,2-e][1,4]diazepin-2-one (9α): Pale yellow wax, 25 %
(37.0 mg). [α]2D9 = –121.3 (c = 1.0, MeOH). 1H NMR (CDCl3,
300 MHz): δ = 1.89 (s, 1 H), 3.14 (dd, J = 4.5, J = 13.8 Hz, 1 H),
3.32 (dd, J = 5.4, J = 14.1 Hz, 1 H), 3.72 (s, 3 H), 3.95 (m, 1 H),
5.64 (s, 1 H), 6.68–6.79 (m, 4 H), 7.09–7.12 (m, 3 H), 7.22–7.29 (m,
5 H) ppm. 13C NMR (CDCl3, 75 MHz): δ = 36.59, 55.18, 60.64,
77.14, 111.98, 114.38 (2 C), 121.24, 124.14, 127.00, 127.86 (2 C),
128.88, 129.77 (2 C), 131.08, 135.14, 136.36, 160.17, 162.41,
173.22 ppm. LC–MS (ESI+): m/z = 365.2 [M + H]+. HRMS: calcd.
for C21H21N2O2S 365.1324 [M + H]+; found 365.1323.
3-Methyl-5-(4-bromophenyl)-1,3,4,5-tetrahydro-2H-thieno[3,2-e]-
[1,4]diazepin-2-one (13): Uncoloured wax, 61% (120.8 mg); two dia-
stereomers detected by NMR in CDCl3. 1H NMR (CDCl3,
300 MHz): δ = 1.45 (d, J = 6.6 Hz, 2 H), 1.51 (d, J = 6.6 Hz, 1 H),
2.20 (s, 1 H), 3.72–3.85 (m, 1 H), 5.82 (s, 0.4 H), 5.89 (s, 0.6 H),
7.12–7.14 (m, 1 H), 7.17–7.30 (m, 4 H), 7.51–7.55 (m, 2 H) ppm.
13C NMR (CDCl3, 75 MHz): δ = 17.39–17.89 (1 C), 54.08–55.89
(1 C), 76.08–76.74 (1 C), 110.95–110.97 (1 C), 120.59–121.09 (1 C),
121.35 (1 C), 124.77–125.10 (1 C), 128.02–128.47 (2 C), 132.48–
132.62 (2 C) 135.36 (1 C), 138.35–138.42 (1 C), 161.26 (1 C) ppm.
LC–MS (ESI+): m/z = 337.0 and 339.0 [M + H]+. HRMS: calcd.
for C14H14N2OSBr 337.0010 [M + H]+; found 337.0009.
(3S,5S)-3-Benzyl-5-(4-methoxyphenyl)-1,3,4,5-tetrahydro-2H-
thieno[3,2-e][1,4]diazepin-2-one (9β): Pale yellow wax, 24 %
(35.5 mg). [α]2D9 = –70.7 (c = 1.0, MeOH). 1H NMR (CDCl3,
300 MHz): δ = 2.19 (s, 1 H), 3.04 (dd, J = 7.2, J = 13.8 Hz, 1 H),
3.18 (dd, J = 4.2, J = 13.8 Hz, 1 H), 3.74 (s, 3 H), 4.08 (dd, J =
4.2, J = 7.2 Hz, 1 H), 5.53 (s, 1 H), 6.81–6.84 (d, J = 8.7 Hz, 2 H),
7.10–7.28 (m, 10 H) ppm. 13C NMR (CDCl3, 75 MHz): δ = 38.04,
55.24, 59.61, 76.74, 111.44, 114.48 (2 C), 120.95, 124.43, 126.72,
127.39 (2 C), 128.48 (2 C), 129.62, 131.50, 135.16, 137.34, 160.04,
162.42, 172.76 ppm. LC–MS (ESI+): m/z = 365.2 [M + H]+.
HRMS: calcd. for C21H21N2O2S 365.1324 [M + H]+; found
365.1324.
3-Methyl-5-phenyl-1,3,4,5-tetrahydro-2H-thieno[3,2-e][1,4]diazepin-
2-one (14): Pale yellow wax, 36% (54.6 mg); two diastereomers de-
1
tected by NMR in CDCl3. H NMR (CDCl3, 400 MHz): δ = 1.42
(d, J = 6.8 Hz, 1.8 H), 1.48 (d, J = 6.8 Hz, 1.2 H), 2.12 (s, 1 H),
3.71 (q, J = 6.8 Hz, 0.4 H), 3.83 (q, J = 6.8 Hz, 0.6 H), 5.80 (s, 0.4
H), 5.89 (s, 0.6 H), 7.09–7.26 (m, 4 H), 7.30–7.37 (m, 4 H) ppm.
13C NMR (CDCl3, 100 MHz): δ = 17.54–17.75 (1 C), 54.10–55.98
(1 C), 76.71 (1 C), 110.82–111.70 (1 C), 120.72–121.13 (1 C),
124.45–124.79 (1 C), 126.19–126.67 (2 C), 129.16–129.36 (1 C),
129.44–129.56 (2 C), 135.39–135.52 (1 C), 139.26 (1 C), 174.36–
175.01 (1 C) ppm. LC–MS (ESI+): m/z = 259.1 [M + H]+. HRMS:
calcd. for C14H15N2OS 259.0905 [M + H]+; found 259.0905.
(3S,5R)-3-Benzyl-5-isobutyl-1,3,4,5-tetrahydro-2H-thieno[3,2-e]-
[1,4]diazepin-2-one (10α): Pale yellow solid, 50% (64.0 mg), m.p.
66.7–67.4 °C. [α]2D9 = –122.2 (c = 1.0, MeOH). H NMR (CDCl3,
1
300 MHz): δ = 0.90 (d, J = 6.3 Hz, 3 H), 0.92 (d, J = 6.6 Hz, 3 H),
1.36–1.54 (m, 2 H), 1.81 (m, 1 H), 2.08 (s, 1 H), 3.13 (d, J = 5.1 Hz,
2 H), 3.93 (t, J = 5.1 Hz, 1 H), 4.67 (dd, J = 3.0, J = 9.9 Hz, 1 H),
7.15–7.30 (m, 8 H) ppm. 13C NMR (CDCl3, 75 MHz): δ = 21.48,
23.79, 24.71, 36.81, 42.09, 59.63, 73.76, 111.68, 120.97, 125.09,
126.92, 126.97, 128.70, 129.83 (2 C), 135.11, 136.90, 172.65 ppm.
LC–MS (ESI+): m/z = 315.2 [M + H]+. HRMS: calcd. for
C18H23N2OS 315.1531 [M + H]+; found 315.1531.
(3S,5S)-3-Methyl-5-isobutyl-1,3,4,5-tetrahydro-2H-thieno[3,2-e]-
[1,4]diazepin-2-one (16): Pale yellow wax, 58% (81.2 mg). [α]2D9
=
1
–47.6 (c = 1.0, MeOH). H NMR (CDCl3, 300 MHz): δ = 0.89 (d,
J = 6.6 Hz, 3 H), 0.94 (d, J = 6.6 Hz, 3 H), 1.33 (d, J = 6.9 Hz, 3
H), 1.44–1.49 (m, 2 H), 1.80–1.89 (m, 1 H), 1.99 (m, 1 H), 3.63 (q,
J = 6.9 Hz, 1 H), 4.89–4.93 (m, 1 H), 7.23–7.24 (m, 2 H), 7.30 (m,
1 H) ppm. 13C NMR (CDCl3, 75 MHz): δ = 16.80, 21.45, 23.73,
24.90, 41.58, 54.32, 73.46, 110.58, 120.40, 125.10, 135.26,
173.77 ppm. LC–MS (ESI+): m/z = 239.2 [M + H]+. HRMS: calcd.
for C12H19N2OS 239.1218 [M + H]+; found 239.1219.
(3S,5S)-3-Benzyl-5-isobutyl-1,3,4,5-tetrahydro-2H-thieno[3,2-e]-
[1,4]diazepin-2-one (10β): Pale yellow wax, 25% (32.0 mg). [α]2D9
=
–74.8 (c = 1.0, MeOH). 1H NMR (CDCl3, 300 MHz): δ = 0.80–
0.90 (m, 7 H), 1.55–1.64 (m, 1 H), 1.66–1.74 (m, 1 H), 1.89 (m, 1
H), 3.09 (dd, J = 6.9, J = 14.1 Hz, 1 H), 3.18 (dd, J = 4.5, J =
14.1 Hz, 1 H), 3.86 (dd, J = 4.5, J = 6.9 Hz, 1 H), 4.91 (dd, J =
2.1, J = 9.6 Hz, 1 H), 7.11 (d, J = 5.4 Hz, 1 H), 7.20–7.32 (m, 6
H) ppm. 13C NMR (CDCl3, 75 MHz): δ = 21.74, 23.92, 24.09,
38.14, 43.99, 60.89, 73.35, 113.74, 122.02, 125.02, 126.94, 128.68 (3
C), 129.75, 134.97, 137.40, 172.89 ppm. LC–MS (ESI+): m/z =
315.2 [M + H]+. HRMS: calcd. for C18H23N2OS 315.1531 [M +
H]+; found 315.1532.
(3S,5S)-3-Methyl-5-cyclohexyl-1,3,4,5-tetrahydro-2H-thieno[3,2-e]-
[1,4]diazepin-2-one (17): Pale yellow wax, 58% (90.0 mg). [α]2D9
=
–42.4 (c = 1.0, MeOH). 1H NMR (CDCl3, 300 MHz): δ = 0.95–
1.26 (m, 5 H), 1.31 (d, J = 6.9 Hz, 3 H), 1.47–1.73 (m, 6 H), 1.97
(s, 1 H), 3.63 (q, J = 6.9 Hz, 1 H), 4.81 (d, J = 2.7 Hz, 1 H), 7.17–
7.25 (m, 2 H), 7.35 (m, 1 H) ppm. 13C NMR (CDCl3, 75 MHz): δ =
18.21, 25.12, 25.80, 26.30, 26.36, 29.38, 41.32, 56.06, 78.63, 112.31,
121.34, 125.00, 135.16, 174.17 ppm. LC–MS (ESI+): m/z = 265.1
[M + H]+. HRMS: calcd. for C14H21N2OS 265.1375 [M + H]+;
found 265.1375.
(3S,5S)-3-Benzyl-5-cyclohexyl-1,3,4,5-tetrahydro-2H-thieno[3,2-e]-
[1,4]diazepin-2-one (11β): White solid, 34% (47.0 mg), m.p. 109.9–
112.5 °C. [α]2D9 = –93.2 (c = 1.0, MeOH). 1H NMR (CDCl3,
300 MHz): δ = 1.01–1.27 (m, 5 H), 1.47 (m, 2 H), 1.59–1.74 (m, 4
H), 2.05 (s, 1 H), 3.03 (dd, J = 6.3, J = 14.1 Hz, 1 H), 3.62 (dd, J
= 4.5, J = 14.1 Hz, 1 H), 3.92–3.96 (m, 1 H), 4.63 (d, J = 1.8 Hz,
1 H), 7.13 (d, J = 5.1 Hz, 1 H), 7.21–7.30 (m, 6 H), 7.33 (m, 1 (3S,5R)-10-(4-Nitrophenyl)-4,5a,6,7,8,10-hexahydro-5H-pyrrolo-
H) ppm. 13C NMR (CDCl3, 75 MHz): δ = 24.86, 25.71, 26.25, [1,2-a]thieno[3,2-e][1,4]diazepin-2-one (18α): Pale orange wax, 20%
26.28, 29.07, 38.05, 41.23, 61, 78.79, 113.10, 121.58, 124.93 (2 C), (33.6 mg). [α]2D9 = +30.9 (c = 1.0, MeOH). 1H NMR (CDCl3,
126.87 (2 C), 128.72, 129.65, 134.92, 136.97, 172.79 ppm. LC–MS 300 MHz): δ = 1.62–1.70 (m, 2 H), 2.05–2.22 (m, 3 H), 2.26–2.37
(ESI+): m/z = 341.2 [M + H]+. HRMS: calcd. for C20H25N2OS
(m, 1 H), 3.94 (dd, J = 5.1, J = 8.7 Hz, 1 H), 6.22 (s, 1 H), 6.92–
6.96 (m, 2 H), 7.07–7.10 (m, 1 H), 7.42 (d, J = 8.4 Hz, 2 H), 8.11
341.1688 [M + H]+; found 341.1689.
Eur. J. Org. Chem. 2015, 7146–7153
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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S. Denoyelle et al.
FULL PAPER
(t, J = 8.4 Hz, 2 H) ppm. 13C NMR (CDCl3, 75 MHz): δ = 24.94,
26.95, 49.25, 65.33, 78.73, 111.98, 121.01, 123.74 (3 C), 124.79,
129.08, 135.03, 141.74, 148.11, 175.43 ppm. LC–MS (ESI+): m/z =
1
(179.0 mg). 59.0–59.7 °C. [α]2D9 = –55.7 (c = 1.0, MeOH). H NMR
(CDCl3, 300 MHz): δ = 0.89 (d, J = 6.6 Hz, 3 H), 0.96 (d, J =
6.6 Hz, 3 H), 1.38–1.54 (m, 2 H), 1.69–1.81 (m, 2 H), 1.86–2.52 (m,
330.1 [M + H]+. HRMS: calcd. for C16H16N3O3S 330.0912 [M + 3 H), 2.56 (td, J = 7.2, J = 9.0 Hz, 1 H), 3.15–3.22 (m, 1 H), 3.86
H]+; found 330.0915.
(dd, J = 4.2, J = 9.0 Hz, 1 H), 4.62 (dd, J = 3, J = 9.3 Hz, 1 H),
7.20–7.27 (m, 2 H), 7.34 (m, 1 H) ppm. 13C NMR (CDCl3,
75 MHz): δ = 21.45, 23.56, 24.73, 24.90, 27.19, 42.87, 55.87, 63.98,
80.89, 110.38, 120.34, 124.88, 135.64, 173.34 ppm. LC–MS (ESI+):
m/z = 265.1 [M + H]+. HRMS: calcd. for C14H21N2OS 265.1375
[M + H]+; found 265.1375.
(3S,5S)-10-(4-Nitrophenyl)-4,5a,6,7,8,10-hexahydro-5H-pyrrolo-
[1,2-a]thieno[3,2-e][1,4]diazepin-2-one (18β): Pale orange wax, 62%
(104.0 mg). [α]2D9 = +8.8 (c = 1.0, MeOH). 1H NMR (CDCl3,
300 MHz): δ = 1.83–1.92 (m, 2 H), 2.14–2.21 (m, 2 H), 2.90 (td, J
= 8.7 Hz, 1 H), 3.41–3.47 (m, 1 H), 3.91 (t, J = 6.6 Hz, 1 H), 5.66
(s, 1 H), 7.17–7.24 (m, 3 H), 7.44 (d, J = 8.7 Hz, 2 H), 8.18 (t, J =
8.7 Hz, 2 H) ppm. 13C NMR (CDCl3, 75 MHz): δ = 24.88, 27.44,
56.40, 63.70, 82.66, 111.10, 120.28, 124.26 (2 C), 125.37, 127.05 (2
C), 135.23, 146.30, 147.97, 173.56 ppm. LC–MS (ESI+): m/z =
330.1 [M + H]+. HRMS: calcd. for C16H16N3O3S 330.0912 [M +
H]+; found 330.0914.
(3S,5S)-10-Cyclohexyl-4,5a,6,7,8,10-hexahydro-5H-pyrrolo[1,2-a]-
thieno[3,2-e][1,4]diazepin-2-one (23β): White powder, 92%
(258.0 mg). 168.5–169.8 °C. [α]2D9 = –63.2 (c = 1.0, MeOH). 1H
NMR (CDCl3, 300 MHz): δ = 0.99–1.24 (m, 4 H), 1.39–1.79 (m, 9
H), 1.91–2.02 (m, 1 H), 2.10–2.22 (m, 1 H), 2.67 (td, J = 6.6, J =
8.7 Hz, 1 H), 3.22–3.29 (m, 1 H), 3.88 (dd, J = 4.8, J = 8.7 Hz, 1
H), 4.50 (dd, J = 2.4 Hz, 1 H), 7.24–7.30 (m, 2 H), 7.43 (m, 1
H) ppm. 13C NMR (CDCl3, 75 MHz): δ = 25.07, 25.27, 25.63,
26.06, 26.18, 28.66, 28.92, 41.43, 58.12, 65.77, 87.24, 112.12,
121.67, 124.67, 135.29, 173.63 ppm. LC–MS (ESI+): m/z = 291.1
[M + H]+. HRMS: calcd. for C16H23N2OS 291.1531 [M + H]+;
found 291.1532.
(3S,5R)-10-(4-Bromophenyl)-4,5a,6,7,8,10-hexahydro-5H-pyrrolo-
[1,2-a]thieno[3,2-e][1,4]diazepin-2-one (19α): Pale yellow wax, 16%
(29.6 mg). [α]2D9 = –4.2 (c = 1.0, MeOH). 1H NMR (CDCl3,
300 MHz): δ = 1.60–1.68 (m, 2 H), 2.08–2.24 (m, 3 H), 2.31–2.40
(m, 1 H), 3.92 (dd, J = 5.1, J = 9.0 Hz, 1 H), 6.08 (s, 1 H), 6.92–
6.98 (m, 2 H), 7.05–7.10 (m, 3 H), 7.40 (d, J = 8.7 Hz, 2 H) ppm.
13C NMR (CDCl3, 75 MHz): δ = 25.01, 27.20, 49.22, 65.38, 79.28,
111.88, 121.22, 123.13, 124.47, 129.74 (2 C), 131.91 (2 C), 133.71,
135.33, 175.63 ppm. LC–MS (ESI+): m/z = 363.1 and 365.1 [M +
H]+. HRMS: calcd. for C16H16N2OSBr 363.0167 [M + H]+; found
363.0166.
Supporting Information (see footnote on the first page of this arti-
cle): 1H and 13C NMR spectra of intermediates and final com-
pounds, and NOESY experiment of diastereomers 10α, 10β, 18α
and 18β.
(3S,5S)-10-(4-Bromophenyl)-4,5a,6,7,8,10-hexahydro-5H-pyrrolo-
[1,2-a]thieno[3,2-e][1,4]diazepin-2-one (19β): Pale yellow wax, 62%
(114.7 mg). [α]2D9 = +16.0 (c = 1.0, MeOH). 1H NMR (CDCl3,
300 MHz): δ = 1.78–1.88 (m, 2 H), 2.11–2.18 (m, 2 H), 2.81 (td, J
= 8.1, J = 9.0 Hz, 1 H), 3.36–3.43 (m, 1 H), 3.92 (t, J = 6.6 Hz, 1
H), 6.23 (s, 1 H), 7.13 (d, J = 8.4 Hz, 2 H), 7.17–7.21 (m, 3 H),
7.45 (d, J = 8.7 Hz, 2 H) ppm. 13C NMR (CDCl3, 75 MHz): δ =
24.73, 27.33, 56.18, 63.64, 83.05, 109.56, 110.92, 120.50, 122.57,
124.98, 127.66 (2 C), 132.18, 135.51, 138.34, 173.78 ppm. LC–MS
(ESI+): m/z = 363.1 and 365.1 [M + H]+. HRMS: calcd. for
C16H16N2OSBr 363.0167 [M + H]+; found 363.0168.
Acknowledgments
The authors thank the Institut des Biomolécules Max Mousseron,
the University of Montpellier, the Centre National de la Recherche
Scientifique (CNRS) and the ENSCM for financial support. We
are grateful to Aurélien Lebrun (Laboratoire de Mesures Physiques,
University of Montpellier) for his assistance in performing the
NOESY experiments.
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(3S,5S)-10-Phenyl-4,5a,6,7,8,10-hexahydro-5H-pyrrolo[1,2-a]thieno-
[3,2-e][1,4]diazepin-2-one (20β): White powder, 78 % (113.0 mg),
m.p. 147.9–150.1 °C. [α]2D9 = +27.9 (c = 1.0, MeOH). 1H NMR
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2.82 (td, J = 8.1 Hz, 1 H), 3.42 (m, 1 H), 3.98 (t, J = 6.6 Hz, 1 H),
5.57 (s, 1 H), 7.13–7.36 (m, 8 H) ppm. 13C NMR (CDCl3, 75 MHz):
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(3S,5S)-10-(4-Methoxyphenyl)-4,5a,6,7,8,10-hexahydro-5H-pyrrolo-
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= 6.6 Hz, 1 H), 5.51 (s, 1 H), 6.83 (d, J = 8.7 Hz, 2 H), 7.10–7.23
(m, 5 H) ppm. 13C NMR (CDCl3, 75 MHz): δ = 24.79, 27.29,
55.24, 56.00, 63.67, 83.33, 110.76 (2 C), 114.45, 120.71, 124.62,
127.12 (2 C), 131.39, 135.84, 159.73, 173.81 ppm. LC–MS (ESI+):
m/z = 315.1 [M + H]+. HRMS: calcd. for C17H19N2O2S 315.1167
[M + H]+; found 315.1168.
(3S,5S)-10-Isobutyl-4,5a,6,7,8,10-hexahydro-5H-pyrrolo[1,2-a]-
thieno[3,2-e][1,4]diazepin-2-one (22β): White powder, 70 %
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Eur. J. Org. Chem. 2015, 7146–7153

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Received: July 17, 2015
Published Online: October 1, 2015
Eur. J. Org. Chem. 2015, 7146–7153
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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