The Staudinger reaction with 2-imino-1,3-thiaselenanes toward the synthesis of C4 spiro-β-lactams

Article abstract of DOI:10.1039/c3ob00073g

The Staudinger ketene-imine [2 + 2] cycloaddition reaction for conversion of α-heteroatom-substituted exocyclic imines to C4 heterocyclic spiro-β-lactams has rarely been investigated due to their instability. Herein, we describe the Staudinger reaction be

Full text of DOI:10.1039/c3ob00073g

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The Staudinger reaction with 2-imino-1,3-
thiaselenanes toward the synthesis of C4
Cite this: DOI: 10.1039/c3ob00073g
spiro-β-lactams†
Yosuke Toyoda,‡a Masayuki Ninomiya,b Masahiro Ebiharaa and Mamoru Koketsu*b
Received 14th January 2013,
Accepted 5th February 2013
The Staudinger ketene–imine [2 + 2] cycloaddition reaction for conversion of α-heteroatom-substituted
exocyclic imines to C4 heterocyclic spiro-β-lactams has rarely been investigated due to their instability.
Herein, we describe the Staudinger reaction between ketenes and α-selenium-substituted exocyclic
imines to synthesize C4 spiro-β-lactams.
DOI: 10.1039/c3ob00073g
www.rsc.org/obc
Introduction
The Staudinger ketene–imine [2 + 2] cycloaddition reaction
(the Staudinger reaction) was first reported in 1907.1 This
process took on interest after the discovery of penicillin in
1928 and still remains a general and effective method for the
synthesis of β-lactam (2-azetidinone) derivatives.2 Recently,
spiro-β-lactams have received much attention because they are
relatively unexplored compared with mono- and bicyclic
β-lactams,2,3 are found in biologically active natural com-
pounds such as chartelline,4 and behave as β-turn mimetics
which is one of the major molecular recognition events for
receptor–ligand interactions.5 There are two types of spiro-
β-lactams, C3 and C4 spiro-β-lactams. Several methods have
been described for the synthesis of C3 spiro-β-lactams using
the Staudinger reaction; in contrast, there are few reports on
the synthesis of C4 spiro-β-lactams.3 Especially the Staudinger
reactions with α-heteroatom-substituted imines, which form
C4 heterocyclic spiro-β-lactams, were limited because of their
instability caused by the bridgehead C4 heteroatom.6,7
Scheme 1 A strategy to synthesize C4 spiro-β-lactams in this study.
anti-microbial, etc.8 Recently, our group and other groups
reported the synthesis of selenium-containing heterocycles
bearing an exocyclic imine from isoselenocyanates.9–12 Also,
we have established the synthesis of the bicyclic seleno-
β-lactams starting from a selenium-modified 2-azetidinone
skeleton.13 However, the syntheses of seleno-β-lactams via the
Staudinger reaction were limited.14 To the best of our knowl-
edge, the Staudinger reaction for the conversion of α-sele-
nium-substituted exocyclic imines to C4 spiro-β-lactams has
never been reported. Herein, we investigated the synthesis of
C4 spiro-β-lactams via the Staudinger reaction using α-sele-
nium-substituted exocyclic imines (Scheme 1).
On the other hand, the synthesis and the biological evalu-
ation of selenium-containing heterocycles have been developed
because of their unique reactivities and potential biological
activities such as anti-oxidant, anti-inflammatory, anti-viral,
Results and discussion
First, we examined the Staudinger reaction of α-nitrogen- and
α-oxygen-substituted exocyclic imines such as 2-imino-1,3-sele-
nazine 19a and 2-imino-1,3-oxaselenane 3,15 with methoxyketene
generated in situ from the reaction of methoxyacetyl chloride
with Et3N. In the case of 2-imino-1,3-selenazine 1, the lone pair
on nitrogen in selenazine attacked the carbonyl group of the
acyl chloride to form N-methoxyacetyl-substituted 2-imino-1,3-
selenazine 2. When 2-imino-1,3-oxaselenane 3 was reacted with
methoxyketene, carbamoselenoate 4 was obtained (Scheme 2).
Next, we investigated the Staudinger reaction with the
α-thiaseleno-exocyclic imine. To this end, we examined the
aDepartment of Chemistry, Faculty of Engineering, Gifu University, Yanagido 1-1,
Gifu, 501-1193, Japan
bDepartment of Materials Science and Technology, Faculty of Engineering, Gifu
University, Yanagido 1-1, Gifu, 501-1193, Japan. E-mail: koketsu@gifu-u.ac.jp;
Fax: (+81) 58-293-2794
†Electronic supplementary information (ESI) available: Copies of 1H and 13C
NMR spectra for all new compounds. CCDC 911411 (6c), 911412 (8b) and
911413 (9a). For ESI and crystallographic data in CIF or other electronic format
see DOI: 10.1039/c3ob00073g
‡Present address: Department of Pharmacology, Kyoto University Graduate
School of Medicine.
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Fig. 1 ORTEP drawing of 2-(2-methylphenylimino)-1,3-thiaselenane (6c). In the
structure of 6c, S and Se atoms were disordered and refined as Se1A/S1B (Se
0.830(2), S 0.170(2)) and S1A/Se1B (Se 0.170(2), S 0.830(2)). Carbon atoms in
the ring (C2, C3, and C4) were also disordered as Se1A–C2A–C3A–C4A–S1B and
S1B–C2B–C3B–C4B–Se1B.
Scheme 2 The Staudinger reaction with 2-imino-1,3-selenazine 1 and 2-imino-
1,3-oxaselenane 3.
Table 1 Synthesis of 2-imino-1,3-thiaselenanes 6 and 2-selenoxoperhydro-1,3-
thiazines 7
aliphatic group. In the 77Se NMR spectra of 6, two 77Se signals
were observed at 339.0–386.7 ppm for the Z isomer and at
371.1–397.2 ppm for the E isomer, respectively. Most of the
77Se signals of the Z isomers of 6 were observed at higher
fields than those of the E isomers.10,11 On the other hand, the
5
6
7
77Se signals of compounds
7
were observed at
525.9–639.2 ppm. In the 13C NMR spectrum of benzyl-thiasele-
nane 6g, we found an interesting spectral feature at the
benzylic carbon. The selenium coupling 3J(77Se–13C) with the
(Z)-benzylic carbon was observed exclusively (3J(77Se–13C) =
26.9 Hz), while this coupling with the (E)-benzylic carbon was
not observed. Furthermore, 6c was examined by single-crystal
X-ray diffraction (Fig. 1). The structure of 6c showed disorder
of S and Se atoms in the heterocyclic moiety. This means that
the crystal included two isomers with an isomeric ratio of
Z/E = 83 : 17.
Entry
R1
Yielda (%)
Z/Eb
Yield (%)
1
2
3
4
5
6
7
8
C6H5 (5a)
88 (6a)
68 (6b)
64 (6c)
71 (6d)
76 (6e)
75 (6f)
44 (6g)
37 (6h)
77 : 23
77 : 23
85 : 15
77 : 23
75 : 25
80 : 20
67 : 33
68 : 32
6 (7a)
5 (7b)
5 (7c)
20 (7d)
14 (7e)
2 (7f)
17 (7g)
Trace (7h)
p-MeC6H4 (5b)
o-MeC6H4 (5c)
p-ClC6H4 (5d)
p-MeOC6H4 (5e)
2-Naphthyl (5f)
Benzyl (5g)
cyclo-Hexyl (5h)
a Isolated yield. b The ratio was calculated by 13C NMR.
Subsequently, the Staudinger reactions of the resulting exo-
synthesis of the α-thiaseleno exocyclic imine by the reaction of cyclic imine 6a with methoxyketene were performed. Table 2
isoselenocyanates.12 Phenylisoselenocyanate 5a was reacted lists several reaction conditions. In entry 1, the reaction of 6a
with 3-chloro-1-propanethiol in the presence of NaH in THF at with methoxyacetyl chloride (1.2 equiv.) in the presence of
0 °C, yielding 2-imino-1,3-thiaselenane 6a in 88% yield and Et3N (1.2 equiv.) in toluene at 80 °C gave C4 spiro-β-lactam 8a
the by-product 1,3-thiazinane-2-selenone 7a in 6% yield in 69% yield. The diastereomer ratio (dr) of 8a was calculated
1
(Table 1, entry 1). Since 6a has not enough purity as a yellow by H NMR spectra. When we used 2 equiv. of both methoxy-
oil by silica gel column chromatography, 6a was further puri- acetyl chloride and Et3N, the reaction proceeded immediately
fied by alumina column chromatography and obtained as a to form spiro-β-lactam 8a in excellent yield (98%, entry 2).
colorless solid. In the NMR spectra, 6a was confirmed to be an However, the reaction at room temperature gave 8a in a lower
inseparable mixture of Z and E isomers at the exocyclic imine yield (49%, entry 3). When CH2Cl2 was used under reflux con-
position. Recently, we reported a similar Z/E isomerization for ditions for 2 h, 8a was obtained in 90% yield (entry 4). In con-
2-imino-1,3-oxaselenepanes by the reaction of isoselenocya- trast, when THF was used as a solvent for 30 h, enamide 9a, a
nates with 4-bromobutanol,10 and for 2-imino-1,3-thiaseleno- ring opening product from 8a, was obtained as stereoisomers;
lanes via the iodocyclization reaction of S-allyl- the major and minor isomers of 9a were isolated in 51% and
thioselenocarbamates.11
23% yields, respectively (entry 6).7 The structure of 9a was
Then we examined the reactions using various isoselenocya- determined by single crystal X-ray diffraction analysis
nates 5, and the corresponding exocyclic imines 6 and by-pro- (Fig. 2).16 In this structure, there were two isomers that showed
1
ducts 7 were obtained (Table 1). The higher nucleophilicity of disorder of S and Se with an isomer ratio of 84/16. In the H
selenium compared with nitrogen gave 6 as the predominant NMR of crystal 9a, the ratio of the isomers was determined as
product in higher yield than 7. All 2-imino-1,3-thiaselenanes 6 84/16. As a result, the conditions of entry 2 were optimal to
were confirmed to be inseparable Z/E isomer mixtures. The give the desired product 8a in a short time (10 min) in excel-
yields by the reactions with aliphatic isoselenocyanates lent yield (98%).
(entries 7 and 8) were lower compared to those of the aromatic
We next examined the Staudinger reactions using various
isoselenocyanates (entries 1–6) owing to instability of the imines 6 with methoxyacetyl chloride under the optimized
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Table 2 Effect of solvent and temperature on the Staudinger reaction of 6a
Table 3 Synthesis of spiro-β-lactams 8 with various imines 6
with methoxyketene
6
8
Entry
R1
Yielda (%)
drb
8a
9a
Yieldb
(%)
Yieldb
(%)
1
2
3
4
5
6
7
8
C6H5 (6a)
98 (8a)
95 (8b)
97 (8c)
88 (8d)
99 (8e)
93 (8f)
88 (8g)
99 (8h)
73 : 27
71 : 29
73 : 27
73 : 27
69 : 31
72 : 28
80 : 20
78 : 22
Entry Conditions
drc,d
drc,d
p-MeC6H4 (6b)
o-MeC6H4 (6c)
p-ClC6H4 (6d)
p-MeOC6H4 (6e)
2-Naphthyl (6f)
Benzyl (6g)
1a
2
3
Toluene, 80 °C, 5 h
69e
73 : 27
73 : 27
73 : 27
74 : 26
—
—
—
—
—
—
—
—
—
69 : 31
Toluene, 80 °C, 10 min 98
Toluene, rt, 48 h
49e
90
4
CH2Cl2, reflux, 2 h
cyclo-Hexyl (6h)
5
6
CH2Cl2, 0 °C to rt, 45 h 52
75 : 25 29
74
e
THF, reflux, 3 h
—
—
a Isolated yield. b The ratio was calculated by 1H NMR.
a 6a : acylchloride : Et3N = 1 : 1.2 : 1.2. b Isolated yield. c The ratio was
1
calculated by H NMR. d The ratio was calculated by isolated yield. e 6a
was recovered in 23%, 47%, and 21% yields, respectively.
Fig. 2 ORTEP drawing of 2-methoxy-N-phenyl-2-(1,3-thiaselenan-2-ylidene)-
acetamide (9a). In the structure of 9a, S and Se atoms were disordered and
refined as Se1A/S1B (Se 0.839(4), S 0.161(4)) and S1A/Se1B (Se 0.161(4), S
0.839(2)).
Fig. 3 ORTEP drawing of two independent structures of 3-methoxy-5-selena-
9-thia-1-(4-tolyl)-1-azaspiro[3.5]nonan-2-one (8b). The crystal of 8b had two
independent molecules in a unit cell. In one molecule (a), S and Se atoms are
disordered and refined as Se1A/S1B (Se 0.627(2), S 0.373(2)) and S1A/Se1B (Se
0.373(2), S 0.627(2)). In the other molecule (b), S and Se atoms are also
disordered and refined as Se2A/S2B (Se 0.542(3), S 0.458(3)) and S2A/Se2B
(Se 0.458(3), S 0.542(3)), and the methoxy group is disordered over two sites
(O4A and C28A 0.678(11), O4B and C28B 0.322(11)).
conditions. All imines 6 readily gave the corresponding spiro-
β-lactams 8 in excellent yields (Table 3). Spiro-β-lactams 8 were
obtained as a stereoisomer mixture. Among them, p-tolyl-
spiro-β-lactam 8b was determined by X-ray structure analysis
(Fig. 3).17 There are two independent structures of 8b in a unit
cell. Both of them showed disorder of chalcogen atoms in the
spirocycle and one of them also had a disordered methoxy
domain. The occupancy factor of each site and the ratio of
isomers (68/32) in the crystal suggest that a cis conformation
such as A shown in Table 3 is predominant.
9b was obtained in 61% yield after 24 h. However, when
p-chlorophenoxyacetyl chloride was used, the desired spiro-
β-lactam 8i was obtained in 89% yield after 30 min (Scheme 3).
These results would be explained by the previous report that
the reactivity of the Staudinger reaction is highly dependent
on the electronic effect of substituents of ketenes.18
We next investigated the Staudinger reactions of 8a with
various types of acyl chlorides, such as chloro-, propionyl-,
phenyl-, cyclohexyl-, phenoxy-, and p-chlorophenoxyacetyl
chloride. When chloroacetyl chloride was used, the reaction
Conclusions
yielded decomposed materials; on the other hand, when pro- In conclusion, we have reported the syntheses of 2-imino-1,3-
pionyl chloride, phenylacetyl chloride, and cyclohexylacetyl thiaselenanes 6, and confirmed the formation of Z/E isomers
chloride were used, the starting materials were recovered even at the exocyclic imine position via the reaction of isoselenocya-
after long reaction times and under reflux conditions. When nates 5 with 3-chloro-1-propanethiol. In addition, we obtained
phenoxyacetyl chloride was used, the corresponding enamide C4 spiro-β-lactams 8 via the Staudinger reaction of 6 with
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7.37 (2H, t, J = 7.8 Hz, Ar); 13C NMR (100 MHz, CDCl3): δ 22.0,
23.1, 43.4, 59.3, 72.6, 120.0, 125.0, 129.2, 147.8, 151.2, 169.5;
77Se NMR (75 MHz, CDCl3): δ 327.8; MS (FAB): m/z = 313
[M + H]+; Anal. Calcd for C13H16N2O2Se: C, 50.17; H, 5.18;
N, 9.00. Found: C, 50.10; H, 5.44; N, 8.92.
2-Phenylimino-1,3-oxaselenane (3). 3 was prepared by a
modified procedure of the previous report.15 To a stirred sus-
pension of NaH (60%, 71.6 mg, 1.79 mmol) in dry THF
(2.0 mL) was added phenylisoselenocyanate 5a (181.2 mg,
1.00 mmol) in dry THF (2.0 mL) at 0 °C. After 3-bromo-1-pro-
panol (97%, 140 μl, 1.50 mmol) was added dropwise, stirring
was continued for 1 h at 0 °C. The reaction mixture was
quenched with saturated aqueous NH4Cl solution, extracted
with ethyl acetate, and washed with water and brine. The com-
bined organic layer was dried over sodium sulfate and evapor-
ated to dryness. The residue was purified by flash
chromatography (SiO2: hexane–ethyl acetate = 3 : 1) to give 3
Scheme 3 The Staudinger reactions between 6a and O-aryl ketenes.
methoxyketene in excellent yields and the structure of 8c was
determined by X-ray crystal diffraction analysis. Furthermore,
the Staudinger reactions of several acetyl chlorides or various
types of exocyclic imines were investigated.
(184 mg, 77%, Z/E = 86 : 14). Colorless oil; IR (KBr): 1675 cm−1
;
Experimental section
General information
Z-isomer: 1H NMR (600 MHz, CDCl3): δ 2.11–2.16 (2H, m,
2
CH2), 2.96 (2H, t, J = 6.9 Hz, J(77Se–1H) = 31.0 Hz, CH2), 4.30
All solvents and commercially available reagents were pur- (2H, t, J = 5.2 Hz, CH2), 6.83 (2H, d, J = 7.5 Hz, Ar), 7.03 (1H, t,
chased from the suppliers and used without further purifi- J = 7.4 Hz, Ar), 7.23 (2H, t, J = 7.6 Hz, Ar); 13C NMR (150 MHz,
cation. All reactions were performed under argon or nitrogen. CDCl3): δ 20.3, 23.3, 70.1, 121.4, 124.1, 129.0, 146.8, 152.7; 77Se
Evaporation and condensation were carried out in vacuo. TLC NMR (114 MHz, CDCl3): δ 249.8; E-isomer: 1H NMR (600 MHz,
analysis was performed on Merck silica gel 60F254 on glass CDCl3): δ 2.11–2.16 (2H, m, CH2), 2.96 (2H, t, J = 6.9 Hz, 2J
plates. Silica gel (Kanto Chemical Co. Inc., 60N, spherical, (77Se–1H) = 31.0 Hz, CH2), 4.30 (2H, t, J = 5.2 Hz, CH2), 6.83
neutral) and alumina (Merck, aluminium oxide 90 active (2H, d, J = 7.5 Hz, Ar), 7.03 (1H, t, J = 7.4 Hz, Ar), 7.23 (2H, t, J
basic) were used for flash column chromatography. Melting = 7.6 Hz, Ar); 13C NMR (150 MHz, CDCl3): δ 20.5, 23.1, 70.8,
points were measured by a Yanagimoto micromelting point 122.6, 123.5, 128.4, 146.2, 151.0; 77Se NMR (114 MHz, CDCl3):
apparatus (uncorrected). IR spectra were measured on a JASCO δ 266.9; MS (EI): m/z = 241 [M]+; HRMS (EI): Calcd for
FT/IR-410 Fourier Transform Infrared Spectrometer. The 1H C10H11NOSe: 241.0006, Found: 240.9995.
NMR spectra, 13C NMR spectra and 77Se NMR spectra were
Se-(3-Chloropropyl)
(2-methoxyacetyl)(phenyl)carbamo-
measured on JEOL:JNM ECX-400P, JEOL:JNM ECA-600 spec- selenoate (4). 4 was prepared by the same method of synthesis
trometers in CDCl3. The chemical shifts of protons are of spiro-β-lactams 8 as described below. Colorless oil; IR (KBr):
reported in δ values referred to TMS as an internal standard. 1105, 1186, 1686, 1722 cm−1 1H NMR (600 MHz, CDCl3): δ
;
The 77Se chemical shifts were expressed in δ values deshielded 2.14 (2H, tt, J = 6.9 Hz, CH2), 2.92 (2H, t, J = 7.2 Hz, 2J(77Se–1H)
with respect to neat Me2Se. The mass spectra (MS) and high = 30.3 Hz, CH2), 3.46 (3H, s, Me), 3.57 (2H, t, J = 6.9 Hz, CH2),
resolution mass spectra (HRMS) were measured on a JEOL 4.38 (2H, s, CH2), 7.23–7.26 (2H, m, Ar), 7.47–7.53 (3H, m, Ar);
JMS-700.
13C NMR (150 MHz, CDCl3): δ 24.8, 32.5, 44.4, 59.4, 73.5,
Isoselenocyanates (5) were prepared according to the 129.6, 130.0, 130.1, 135.6, 169.6, 171.2; 77Se NMR (114 MHz,
literature.19
CDCl3): δ 487.4; MS (EI): m/z = 349 [M]+; Anal. Calcd for
(Z)-Perhydro(2-phenylimino)-1,3-selenazine (1). 1 was pre- C13H16ClNO3Se: C, 44.78; H, 4.63; N, 4.02. Found: C, 45.03; H,
pared according to the literature.9a 1H NMR (400 MHz, CDCl3): 4.85; N, 3.70.
2
δ 2.02 (2H, quint, J = 5.9 Hz, CH2), 2.92 (2H, t, J = 6.5 Hz, J
Typical procedure for the preparation of 2-imino-1,3-thia-
(77Se–1H) = 29.5 Hz, CH2), 3.28 (2H, t, J = 5.2 Hz, CH2), selenanes (6) and 1,3-thiazinane-2-selenone (7). To a stirred sus-
6.97–7.03 (3H, m, Ar), 7.24 (2H, t, J = 7.9 Hz, Ar). 13C NMR pension of NaH (60%, 96 mg, 2.40 mmol) in dry THF (2.0 mL)
(100 MHz, CDCl3): δ 20.7 (1J (77Se–13C) = 54.9 Hz), 24.1, 44.1, was added phenylisoselenocyanate 5a (365.0 mg, 2.00 mmol)
122.3, 122.9, 128.6, 148.0, 149.8. 77Se NMR (75 MHz, CDCl3): δ in dry THF (2.0 mL) at 0 °C. After 3-chloro-1-propanethiol
250.1. MS (EI): m/z = 239 [M]+.
(98%, 218.6 μl, 2.20 mmol) was added dropwise, stirring was
2-Methoxy-1-(2-(phenylimino)-1,3-selenazan-3-yl)ethanone continued for 10 min at 0 °C. The reaction mixture was
(2). 2 was prepared by the same method of synthesis of spiro- quenched with saturated aqueous NH4Cl solution, extracted
β-lactams 6 as described below. Colorless oil; IR (KBr): 1118, with diethyl ether, and washed with water and brine. The com-
1621, 1690 cm−1; 1H NMR (400 MHz, CDCl3): δ 2.18 (2H, tt, J = bined organic layer was dried over sodium sulfate and evapor-
6.2 Hz, CH2), 2.97 (2H, t, J = 6.8 Hz, 2J(77Se–1H) = 30.6 Hz, ated to dryness. The residue was purified by flash
CH2), 3.49 (3H, s, Me), 4.02 (2H, t, J = 6.2 Hz, CH2), 4.56 (2H, s, chromatography
(SiO2:
hexane–diethyl
ether
=
CH2), 6.89 (2H, d, J = 7.4 Hz, Ar), 7.17 (1H, t, J = 7.5 Hz, Ar), 10 : 1→2 : 1→hexane–ethyl acetate = 2 : 1) (alumina: hexane–
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diethyl ether = 10 : 1) to give 6a (449.5 mg, 88%) and 7a
(28.6 mg, 6%).
3-(2-Methylphenyl)-1,3-thiazinane-2-selenone
(7c). Yellow
solid; mp: 182–183 °C; IR (KBr): 1323, 1483 cm−1 1H NMR
;
2-Phenylimino-1,3-thiaselenane (6a). Colorless solid; mp: (400 MHz, CDCl3): δ 2.28 (3H, s, Me), 2.40–2.58 (2H, m, CH2),
101–103 °C; IR (KBr): 1551 cm−1; 1H NMR (600 MHz, CDCl3): δ 2.91–2.99 (1H, m, CH2) 3.03–3.11 (1H, m, CH2), 3.58–3.72 (2H,
2.10–2.20 (2H, m, CH2), 2.98 (minor 2H, t, J = 6.2 Hz, CH2), m, CH2) 7.15 (1H, d, J = 8.2 Hz, Ar), 7.26–7.32 (3H, m, Ar); 13C
3.02 (2H, t, J = 6.9 Hz, CH2), 3.11 (2H, t, J = 6.6 Hz, CH2), 3.17 NMR (100 MHz, CDCl3): δ 17.6, 22.7, 32.9, 53.5, 126.2, 127.6,
(minor 2H, t, J = 6.8 Hz, CH2), 6.86 (2H, d, J = 8.3 Hz, Ar), 7.11 128.7, 131.4, 133.9, 146.9, 192.3; 77Se NMR (75 MHz, CDCl3): δ
(1H, t, J = 7.2 Hz, Ar), 7.30 (2H, t, J = 7.5 Hz, Ar); 13C NMR 613.9; MS (FAB): m/z = 272 [M + H]+; Anal. Calcd for
(150 MHz, CDCl3): major: δ 22.2, 24.2, 32.1, 119.6, 124.4, C11H13NSSe: C, 48.89; H, 4.85; N, 5.18. Found: C, 49.26; H,
128.7, 150.1, 162.0; minor: δ 22.0, 24.5, 32.8, 119.8, 124.1, 5.07; N, 4.78.
128.6, 149.4, 160.9; 77Se NMR (114 MHz, CDCl3): major: δ
2-(4-Chlorophenylimino)-1,3-thiaselenane
(6d). Colorless
1
379.2; minor: δ 391.6; MS (EI): m/z = 257 [M]+; Anal. Calcd for solid; mp: 70–71 °C; IR (KBr): 1560 cm−1; H NMR (400 MHz,
C10H11NSSe: C, 46.88; H, 4.33; N, 5.47. Found: C, 46.58; H, CDCl3): δ 2.21 (2H, tt, J = 6.6 Hz, CH2), 3.03 (minor 2H, t, J =
4.30; N, 5.44.
6.2 Hz, CH2), 3.08 (2H, t, J = 6.7 Hz, CH2), 3.14 (2H, t, J =
3-Phenyl-1,3-thiazinane-2-selenone (7a). Yellow solid; mp: 6.4 Hz, CH2), 3.21 (minor 2H, t, J = 6.9 Hz, CH2), 6.80 (2H, d,
110–111 °C; IR (KBr): 1483 cm−1; 1H NMR (400 MHz, CDCl3): δ J = 8.7 Hz, Ar), 7.27 (2H, d, J = 8.7 Hz, Ar); 13C NMR (100 MHz,
2.48 (2H, tt, J = 5.8 Hz CH2), 3.01 (2H, t, J = 6.0 Hz, CH2), 3.77 CDCl3): major: δ 22.4, 24.5, 32.3, 121.2, 128.9, 129.7, 148.7,
(2H, t, J = 5.4 Hz, CH2), 7.29 (2H, d, J = 7.5 Hz, Ar), 7.38 (1H, t, 163.2; minor: δ 22.1, 24.6, 33.0, 121.5, 128.8, 129.4, 147.9,
J = 7.5 Hz, Ar), 7.46 (2H, t, J = 7.5 Hz, Ar); 13C NMR (100 MHz, 162.1; 77Se NMR (75 MHz, CDCl3): major: δ 382.5; minor: δ
CDCl3): δ 22.6, 33.0, 54.6, 126.3, 128.2, 129.6, 148.2, 193.2; 77Se 397.2; MS (EI): m/z = 291 [M]+; Anal. Calcd for C10H10ClNSSe:
NMR (75 MHz, CDCl3): δ 624.1; MS (EI): m/z = 257 [M]+; Anal. C, 41.32; H, 3.47; N, 4.82. Found: C, 41.22; H, 3.50; N, 4.78.
Calcd for C10H11NSSe: C, 46.88; H, 4.33; N, 5.47. Found: C,
46.87; H, 4.38; N, 5.36.
3-(4-Chlorophenyl)-1,3-thiazinane-2-selenone
(7d). Yellow
1H
solid; mp: 109–110 °C, IR (KBr): 1024, 1321, 1480 cm−1
;
2-(4-Methylphenylimino)-1,3-thiaselenane
(6b). Colorless NMR (400 MHz, CDCl3): δ 2.49 (2H, tt, J = 5.9 Hz, CH2), 3.02
solid; mp: 72–73 °C; IR (KBr): 1564 cm−1; H NMR (400 MHz, (2H, t, J = 5.8 Hz, CH2), 3.75 (2H, t, J = 5.5 Hz, CH2), 7.23 (2H,
CDCl3): δ 2.18 (2H, tt, J = 6.6 Hz, CH2), 2.31 (3H, s, Me), 3.03 d, J = 8.7 Hz, Ar), 7.42 (2H, d, J = 8.7 Hz, Ar); 13C NMR
(2H, t, J = 6.8 Hz, CH2), 3.11 (2H, t, J = 6.4 Hz, CH2), 3.18 (100 MHz, CDCl3): δ 22.6, 33.1, 54.6, 127.9, 134.0, 146.6, 194.0;
(minor 2H, t, J = 7.1 Hz, CH2), 6.76 (2H, d, J = 7.7 Hz, Ar), 7.11 77Se NMR (75 MHz, CDCl3): δ 639.2; MS (EI): m/z = 291 [M]+;
(2H, d, J = 7.8 Hz, Ar); 13C NMR (100 MHz, CDCl3): major: δ Anal. Calcd for C10H10ClNSSe: C, 41.32; H, 3.47; N, 4.82.
20.8, 22.4, 24.2, 32.2, 119.5, 129.3, 134.0, 147.7, 161.3; minor: δ Found: C, 41.39; H, 3.69; N, 4.48.
1
20.8, 22.1, 24.4, 32.9, 119.8, 129.2, 133.6, 146.9, 160.2; 77Se
2-(4-Methoxyphenylimino)-1,3-thiaselenane (6e). Yellow oil,
NMR (75 MHz, CDCl3): major: δ 378.1; minor: δ 390.8; MS (EI): IR (KBr): 1563 cm−1; 1H NMR (400 MHz, CDCl3): δ 2.15 (2H, tt,
m/z = 271 [M]+; Anal. Calcd for C11H13NSSe: C, 48.89; H, 4.85; J = 6.6 Hz, CH2), 3.01 (2H, t, J = 6. 8 Hz, CH2), 3.09 (2H, t, J =
N, 5.18. Found: C, 49.11; H, 5.01; N, 5.08.
3-(4-Methylphenyl)-1,3-thiazinane-2-selenone (7b). Yellow MeO), 6.77–6.88 (4H, m, Ar); 13C NMR (100 MHz, CDCl3):
solid; mp: 144–145 °C; IR (KBr): 1028, 1319, 1479 cm−1
major: δ 22.2, 24.0, 31.9, 54.9, 113.6, 120.6, 143.2, 156.3, 160.8;
6.4 Hz, CH2), 3.15 (minor 2H, t, J = 6.8 Hz, CH2), 3.73 (3H, s,
;
1H NMR (400 MHz, CDCl3): δ 2.38 (3H, s, Me), 2.48 (2H, tt, minor: δ 21.9, 24.3, 32.7, 54.9, 113.5, 121.1, 142.2, 156.1, 159.6,
J = 5.8 Hz, CH2), 3.00 (2H, t, J = 6.1 Hz, CH2), 3.75 (2H, t, J = 77Se NMR (75 MHz, CDCl3): major: δ 379.5; minor: δ 390.9; MS
5.5 Hz, CH2), 7.16 (2H, d, J = 8.2 Hz, Ar), 7.26 (2H, d, J = (FAB): m/z = 288 [M + H]+; Anal. Calcd for C11H13NOSSe: C,
8.2 Hz, Ar); 13C NMR (100 MHz, CDCl3): δ 21.2, 22.7, 33.0, 46.15; H, 4.58; N, 4.89. Found: C, 46.24; H, 4.64; N, 4.84.
54.7, 126.0, 130.3, 138.3, 145.8, 193.2; 77Se NMR (75 MHz,
3-(4-Methoxyphenyl)-1,3-thiazinane-2-selenone (7e). Yellow
1
CDCl3): δ 618.1; MS (FAB): m/z = 272 [M + H]+; Anal. Calcd for solid; mp: 180 °C; IR (KBr): 1247, 1321, 1480, 1506 cm−1; H
C11H13NSSe: C, 48.89; H, 4.85; N, 5.18. Found: C, 48.79; H, NMR (400 MHz, CDCl3): δ 2.45 (2H, tt, J = 5.8 Hz, CH2), 3.00
5.16; N, 4.80.
(2H, t, J = 6.1 Hz, CH2), 3.75 (2H, t, J = 5.5 Hz, CH2), 3.82 (3H,
2-(2-Methylphenylimino)-1,3-thiaselenane
(6c). Colorless s, MeO), 6.95 (2H, d, J = 8.8 Hz, Ar), 7.20 (2H, d J = 8.8 Hz, Ar);
solid; mp: 62–63 °C; IR (KBr): 1420 cm−1; H NMR (400 MHz, 13C NMR (100 MHz, CDCl3): δ 22.7, 33.0, 54.9, 55.3, 114.6,
CDCl3): δ 2.11–2.21 (2H, m, CH2), 2.13 (3H, s, Me), 3.03 (2H, t, 127.3, 141.2, 158.9, 193.5; 77Se NMR (75 MHz, CDCl3): δ 616.1;
J = 6. 6 Hz, CH2), 3.11 (2H, t, J = 6.2 Hz, CH2), 6.72 (1H, d, J = MS (EI): m/z = 287 [M]+; HRMS (FAB): Calcd for C11H13NOSSe:
7.8 Hz, Ar), 7.02 (1H, t, J = 7.1 Hz, Ar), 7.11 (1H, t, J = 6.3 Hz, 286.9883, Found: 286.9880 [M]+.
1
Ar) 7.16 (1H, d, J = 7.3 Hz, Ar); 13C NMR (100 MHz, CDCl3):
major: δ 17.5, 22.3, 24.1, 32.2, 118.7, 124.4, 126.0, 127.9, 130.4, mp: 99–101 °C; IR (KBr): 1564 cm−1
2-(2-Naphthylimino)-1,3-thiaselenane (6f). Colorless solid;
1H NMR (400 MHz,
;
149.3, 160.8; minor: δ 17.5, 22.3, 24.4, 32.7, 118.9, 124.1, 126.0, CDCl3): δ 2.09–2.22 (2H, m, CH2), 3.02 (2H, t, J = 6. 8 Hz, CH2),
127.6, 130.4, 148.8, 159.5; 77Se NMR (75 MHz, CDCl3): major: δ 3.13 (2H, t, J = 6.6 Hz, CH2), 3.19 (2H, t, J = 6.6 Hz, CH2), 7.08
386.7; minor: δ 385.9; MS (EI): m/z = 271 [M]+; Anal. Calcd for (1H, dd, J = 2.1, 8.5 Hz, Ar), 7.25 (1H, s, Ar), 7.28 (minor 1H, s,
C11H13NSSe: C, 48.89; H, 4.85; N, 5.18. Found: C, 48.67; H, Ar), 7.34–7.46 (2H, m, Ar), 7.72–7.82 (3H, m, Ar); 13C NMR
5.01; N, 5.02.
(100 MHz, CDCl3): major: δ 22.5, 24.4, 32.3, 116.0, 120.6,
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124.9, 126.2, 127.5, 127.6, 128.9, 131.0, 133.7, 148.0, 162.5; evaporated to dryness. The residue was purified by flash
minor: δ 22.2, 24.6, 33.0, 116.4, 120.8, 124.8, 126.2, 127.5, chromatography (SiO2: hexane–ethyl acetate = 10 : 1) to give 8a
127.6, 128.7, 130.8, 133.7, 147.2, 161.4; 77Se NMR (75 MHz, (64.0 mg, 98%, major : minor = 73 : 27).
CDCl3): δ major: 384.2; minor: 393.6; MS (EI): m/z = 307 [M]+;
3-Methoxy-1-phenyl-5-selena-9-thia-1-azaspiro[3.5]nonan-2-
Anal. Calcd for C14H13NSSe: C, 54.90; H, 4.28; N, 4.57. Found: one (8a). Colorless oil; IR (KBr): 1363, 1495, 1763 cm−1 1H
C, 55.21; H, 4.43; N, 4.52. NMR (400 MHz, CDCl3): δ 1.95–2.20 (2H, m, CH2), 2.85–3.23
3-(2-Naphthyl)-1,3-thiazinane-2-selenone (7f). Yellow solid; (4H, m, CH2), 3.75 (3H, s, Me), 3.77 (minor 3H, s, Me), 4.67
mp: 149–150 °C; IR (KBr): 1311, 1480 cm−1 1H NMR (1H, s, CH), 4.99 (minor 1H, s, CH), 7.18–7.22 (1H, m, Ar), 7.37
;
;
(400 MHz, CDCl3): δ 2.42 (2H, tt, J = 5.8 Hz, CH2), 2.96 (2H, t, J (2H, t, J = 7.9 Hz, Ar), 7.77 (2H, d, J = 7.5 Hz, Ar); 13C NMR
= 5.9 Hz, CH2), 3.76 (2H, t, J = 5.5 Hz, CH2), 7.39 (1H, dd, J = (100 MHz, CDCl3): major: δ 22.1 (1J(77Se–13C) = 60.7 Hz), 22.8,
2.1, 8.3 Hz, Ar), 7.44–7.52 (2H, m, Ar), 7.71 (1H, s, Ar), 31.1, 59.9, 69.2, 95.9, 120.1, 125.6, 129.0, 135.4, 161.8; minor: δ
7.75–7.90 (3H, m, Ar); 13C NMR (100 MHz, CDCl3): δ 22.5, 33.0, 23.0, 23.3, 30.5, 59.7, 65.9, 96.8, 119.6, 125.6, 129.0, 135.6,
54.8, 124.4, 124.5, 126.4, 126.6, 127.7, 127.9, 129.3, 132.4, 162.2; 77Se NMR (75 MHz, CDCl3): major: δ 310.0; minor: δ
133.4, 145.6, 193.1; 77Se NMR (75 MHz, CDCl3): δ 628.3; MS 394.1; MS (EI): m/z = 329 [M]+; Anal. Calcd for C13H15NO2SSe:
(EI): m/z = 307 [M]+; HRMS (FAB): Calcd for C14H14NSSe: C, 47.56; H, 4.61; N, 4.27. Found: C, 47.71; H, 4.72; N, 4.21.
308.0007, Found: 308.0046 [M + H]+.
2-Benzylimino-1,3-thiaselenane (6g). Yellow oil; IR (KBr): one (8b). Colorless oil; IR (KBr): 1364, 1513, 1751 cm−1
3-Methoxy-5-selena-9-thia-1-(4-tolyl)-1-azaspiro[3.5]nonan-2-
,
1574 cm−1; H NMR (400 MHz, CDCl3): δ 2.13 (2H, tt, J = 6.7 major-isomer: H NMR (400 MHz, CDCl3): δ 2.00–2.13 (2H, m,
Hz, CH2), 3.02 (2H, t, J = 6.6 Hz, CH2), 3.09 (2H, t, J = 6.6 Hz, CH2), 2.33 (3H, s, Me), 2.85–3.14 (4H, m, CH2), 3.74 (3H, s,
CH2), 4.59 (2H, s, CH2), 4.60 (minor 2H, s, CH2), 7.21 (1H, t, J Me), 4.65 (1H, s, CH), 7.17 (1H, d, J = 8.2 Hz, Ar), 7.63 (1H, d, J
= 6.9 Hz, Ar), 7.26–7.36 (4H, m, Ar); 13C NMR (100 MHz, = 8.7 Hz, Ar); 13C NMR (100 MHz, CDCl3): δ 21.0, 21.9, 22.7,
CDCl3): major: δ 22.4, 24.3, 31.7, 59.8 (3J(77Se–13C) = 26.9 Hz), 31.1, 59.9, 69.4, 95.8, 120.6, 129.6, 132.8, 135.8, 161.8; 77Se
126.6, 127.6, 128.1, 138.5, 158.9; minor: δ 22.2, 24.0, 32.7, 57.8, NMR (75 MHz, CDCl3): δ 311.7; minor-isomer: 1H NMR
126.5, 127.6, 128.0, 138.9, 157.2; 77Se NMR (75 MHz, CDCl3): (400 MHz, CDCl3): δ 1.96–2.20 (2H, m, CH2), 2.33 (3H, s, Me),
major: δ 350.4; minor: δ 378.4; MS (EI): m/z = 271 [M]+; Anal. 2.85–3.22 (4H, m, CH2), 3.77 (3H, s, Me), 4.97 (1H, s, CH), 7.17
Calcd for C11H13NSSe: C, 48.89; H, 4.85; N, 5.18. Found: C, (1H, d, J = 8.3 Hz, Ar), 7.66 (1H, d, J = 8.7 Hz, Ar); 13C NMR
1
1
49.12; H, 5.00; N, 5.02.
3-Benzyl-1,3-thiazinane-2-selenone (7g). Yellow solid; mp: 120.1, 129.6, 133.1, 135.7, 162.1; 77Se NMR (75 MHz, CDCl3): δ
148–149 °C; IR (KBr): 1343, 1504 cm−1 1H NMR (400 MHz, 391.5; MS (EI): m/z = 343 [M]+; Anal. Calcd for C14H17NO2SSe:
CDCl3): δ 2.25 (2H, tt, J = 5.8 Hz, CH2), 2.88 (2H, t, J = 5.9 Hz, C, 49.12; H, 5.01; N, 4.09. Found: C, 49.33; H, 5.22; N, 3.87.
CH2), 3.40 (2H, t, J = 5.5 Hz, CH2), 5.51 (2H, s, CH2), 7.30–7.43 3-Methoxy-5-selena-9-thia-1-(2-tolyl)-1-azaspiro[3.5]nonan-2-
1H NMR
(100 MHz, CDCl3): δ 21.1, 23.1, 23.3, 30.5, 59.8, 66.3, 96.8,
;
(5H, m, Ar); 13C NMR (100 MHz, CDCl3): δ 22.8, 33.1, 49.2, one (8c). Colorless oil; IR (KBr): 1363, 1774 cm−1
;
61.4, 127.9, 128.1, 128.8, 134.4, 191.9; 77Se NMR (75 MHz, (400 MHz, CDCl3): δ 1.93–2.00 (2H, m, CH2), 2.41 (3H, s, Me),
CDCl3): δ 525.9; MS (EI): m/z = 271 [M]+; Anal. Calcd for 2.70–2.96 (4H, m, CH2), 3.72 (3H, s, Me), 3.74 (minor 3H, s,
C11H13NSSe: C, 48.89; H, 4.85; N, 5.18. Found: C, 48.97; H, Me), 4.56 (1H, s, CH), 4.81 (minor 1H, s, CH), 7.14–7.33 (3H,
5.10; N, 4.81.
2-Cyclohexylimino-1,3-thiaselenane (6h). Colorless solid; Hz, Ar), 13C NMR (100 MHz, CDCl3): major: δ 18.9, 20.4, 22.9,
mp: 55–57 °C; IR (KBr): 1572 cm−1 1H NMR (400 MHz, 30.0, 60.2, 69.7, 93.5, 126.4, 126.9, 129.1, 131.0, 132.9, 137.1,
m, Ar), 7.62 (minor 1H, d, J = 7.8 Hz, Ar), 7.66 (1H, d, J = 7.3
;
CDCl3): δ 1.15–1.38 (3H, m, ringCH2), 1.38–1.53 (2H, m, 162.4; minor: δ 18.9, 22.5, 22.7, 28.7, 60.2, 69.7, 94.5, 126.4,
ringCH2) 1.63 (2H, d, J = 12.4 Hz, Ar)1.69–1.82 (4H, m, 126.7, 129.1, 131.0, 132.9, 137.0, 162.7; 77Se NMR (75 MHz,
ringCH2), 2.20 (2H, tt, J = 6.6 Hz, CH2), 3.05–3.18 (4H, m, CDCl3): major: δ 346.4; minor: δ 368.5; MS (EI): m/z = 343 [M]+;
CH2), 3.23–3.42 (1H, m, CH), 3.51–3.60 (minor 1H, m, CH); 13
NMR (100 MHz, CDCl3): major: δ 22.7, 23.9, 24.5, 25.4, 31.8, 343.0190 [M]+.
C
HRMS (FAB): Calcd for C14H17NO2SSe: 343.0145, Found:
32.9, 65.5, 154.4; minor: δ 22.5, 24.1, 24.6, 25.5, 32.7, 32.8,
1-(4-Chlorophenyl)-3-methoxy-5-selena-9-thia-1-azaspiro[3.5]-
1
63.2, 153.4; 77Se NMR (75 MHz, CDCl3): major: δ 339.0; minor: nonan-2-one (8d). Colorless oil; IR (KBr): 1492, 1764 cm−1; H
δ 371.1; MS (EI): m/z = 263 [M]+; Anal. Calcd for C10H17NSSe: C, NMR (400 MHz, CDCl3): δ 1.95–2.20 (2H, m, CH2), 2.86–3.23
45.79; H, 6.53; N, 5.34. Found: C, 45.64; H, 6.50; N, 5.21.
(4H, m, CH2), 3.74 (3H, s, Me), 3.77 (minor 3H, s, Me), 4.67
Typical procedure for the preparation of 2, 4, 8, 9, 11 and (1H, s, CH), 4.99 (minor 1H, s, CH), 7.33 (2H, d, J = 8.7 Hz, Ar),
12. To a stirred solution of 6a (54.0 mg, 0.200 mmol) in 1 ml 7.74 (2H, d, J = 8.7 Hz, Ar), 13C NMR (100 MHz, CDCl3): major:
of dry toluene was added methoxyacetyl chloride (97%, 37.6 μl, δ 22.2, 22.5, 31.2, 60.0, 69.4, 96.2, 121.2, 129.1, 130.9, 134.0,
0.400 mmol) at 80 °C. Then triethylamine (55.5 μl, 161.7; minor: δ 22.9, 23.4, 30.6, 59.8, 66.0, 97.1, 120.8, 129.1,
0.400 mmol) in 0.5 ml of toluene was added dropwise, and 130.8, 134.2, 162.1; 77Se NMR (75 MHz, CDCl3): major: δ 305.4;
stirring was continued for 10 min at 80 °C. The reaction minor: δ 392.3; MS (EI): m/z = 364 [M]+; HRMS (EI): Calcd for
mixture was quenched by saturated aqueous NaHCO3 solution, C13H14ClNO2SSe: 362.9599, Found: 362.9581.
extracted with ethyl acetate, and washed with water and brine.
3-Methoxy-1-(4-methoxyphenyl)-5-selena-9-thia-1-azaspiro-
The combined organic layer was dried over sodium sulfate and [3.5]nonan-2-one (8e). Colorless oil; IR (KBr): 1510, 1759 cm−1
,
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1H NMR (400 MHz, CDCl3): δ 1.95–2.20 (2H, m, CH2), (75 MHz, CDCl3): major: δ 319.6; minor: δ 380.1; MS (EI): m/z =
2.80–3.15 (4H, m, CH2), 3.73 (3H, s, Me), 3.75 (minor 3H, s, 425 [M]+; HRMS (EI): Calcd for C18H16ClNO2SSe: 424.9755,
Me), 3.80 (3H, s, Me), 4.62 (1H, s, CH), 4.94 (minor 1H, s, CH), Found: 424.9772.
6.91 (2H, d, J = 9.1 Hz, Ar), 7.64 (2H, d, J = 8.7 Hz, Ar), 13C
2-Methoxy-N-phenyl-2-(1,3-thiaselenan-2-ylidene)acetamide
NMR (100 MHz, CDCl3): major; δ 21.6, 22.6, 30.8, 55.4, 60.0, (9a). Major isomer: colorless solid; mp: 115–116 °C; IR (KBr):
69.6, 95.4, 114.2, 123.1, 128.0, 157.9, 161.8, minor: δ 22.9, 23.1, 1003, 1235, 1438, 1509, 1537, 1592, 1649 cm−1 1H NMR
;
30.2, 55.4, 59.8, 66.6, 96.4, 114.2, 122.4, 128.3, 157.6, 162.0, (400 MHz, CDCl3): δ 2.22 (2H, tt, J = 6.8 Hz, CH2), 2.88 (2H, t, J
2
77Se NMR (75 MHz, CDCl3): major: δ 313.7; minor: δ 384.9; MS = 6.8 Hz, J(77Se–1H) = 32.5 Hz, CH2), 2.99 (2H, t, J = 6.8 Hz,
(EI): m/z = 359 [M]+; Anal. Calcd for C14H17NO3SSe: C, 46.93; CH2), 3.73 (3H, s, Me), 7.10 (1H, t, J = 7.4 Hz, Ar), 7.32 (2H, t, J
H, 4.78; N, 3.91. Found: C, 46.58; H, 4.97; N, 3.55.
= 7.8 Hz, Ar), 7.60 (2H, d, J = 8.2 Hz, Ar), 8.14 (1H, brs, NH);
3-Methoxy-1-(naphthalen-2-yl)-5-selena-9-thia-1-azaspiro[3.5]- 13C NMR (100 MHz, CDCl3): δ 22.4, 22.8, 31.4, 119.6, 124.1,
nonan-2-one (8f). Colorless oil; IR (KBr): 1761 cm−1; H NMR 128.9, 137.1, 137.6, 141.1, 160.7; 77Se NMR (75 MHz, CDCl3): δ
1
(400 MHz, CDCl3): δ 2.00–2.20 (2H, m, CH2), 2.87–3.25 (4H, m, 315.0; MS (EI): m/z = 329 [M]+; HRMS (EI): Calcd for
CH2), 3.77 (3H, s, Me), 3.79 (minor 3H, s, Me), 4.71 (1H, s, C13H15NO2SSe: 328.9989, Found: 328.9977; minor isomer: col-
CH), 5.04 (minor 1H, s, CH), 7.42–7.50 (2H, m, Ar) 7.77–7.85 orless solid; mp: 119–120 °C; IR (KBr): 1024, 1256, 1316, 1440,
(3H, m, Ar), 7.95–8.05 (1H, m, Ar), 8.15–8.20 (1H, m, Ar); 13C 1536, 1593, 1635 cm−1; 1H NMR (400 MHz, CDCl3): δ 2.18 (2H,
2
NMR (100 MHz, CDCl3): major: δ 22.1, 22.6, 31.2, 60.0, 69.4, tt, J = 6.9 Hz, CH2), 2.92 (2H, t, J = 6.7 Hz, J(77Se–1H) = 27.5
96.0, 117.7, 119.1, 125.7, 126.6, 127.6, 127.8, 128.9, 131.1, Hz, CH2), 3.04 (2H, t, J = 7.1 Hz, CH2), 3.71 (3H, s, Me), 7.10
133.0, 133.2, 162.0; minor: δ 23.0, 23.4, 30.6, 59.8, 60.0, 96.9, (1H, t, J = 7.6 Hz, Ar), 7.32 (2H, t, J = 7.8 Hz, Ar), 7.60 (2H, d, J
117.2, 118.8, 125.7, 126.6, 127.8, 128.9, 131.0, 133.0, 133.2, = 7.8 Hz, Ar), 8.04 (1H, brs, NH), 13C NMR (100 MHz, CDCl3): δ
162.4; 77Se NMR (75 MHz, CDCl3): major: δ 311.6; minor: δ 22.6, 22.7, 32.1, 59.2, 119.5, 124.1, 128.9, 137.7, 141.2, 159.5,
396.7; MS (EI): m/z = 380 [M]+; HRMS (EI): Calcd for 77Se NMR (75 MHz, CDCl3): δ 259.2, MS (EI): m/z = 329 [M]+,
C17H17NO2SSe: 379.0145, Found: 379.0130.
1-Benzyl-3-methoxy-5-selena-9-thia-1-azaspiro[3.5]nonan-2- 328.9977 [M]+.
one (8g). Colorless solid; mp: 76–77 °C; IR (KBr): 1385, 2-Phenoxy-N-phenyl-2-(1,3-thiaselenan-2-ylidene)acetamide
1755 cm−1 1H NMR (400 MHz, CDCl3): δ 1.87–2.00 (2H, m, (9b). Major isomer: colorless solid; mp: 142–143 °C; IR (KBr):
HRMS (FAB): Calcd for C13H15NO2SSe: 328.9989, Found:
;
CH2), 2.70 (2H, t, J = 6.0 Hz, CH2), 2.80 (2H, t, J = 6.4 Hz, CH2), 1213, 1435, 1503, 1595, 1632 cm−1; 1H NMR (400 MHz, CDCl3):
2.89 (minor 2H, t, J = 6.2 Hz, CH2), 3.66 (3H, s, Me), 3.67 δ 2.17 (2H, tt, J = 6.9Hz, CH2), 2.94–3.00 (4H, m, CH2), 7.06
(minor 3H, s, Me), 4.49 (minor 1H, s, CH), 4.50 (1H, s, CH), (4H, d, J = 8.2 Hz, Ar), 7.26 (4H, t, J = 8.0 Hz, Ar), 7.33 (2H, t, J
7.25–7.42 (5H, m, Ar); 13C NMR (100 MHz, CDCl3): major: δ = 7.8 Hz, Ar), 7.47 (2H, d, J = 7.8 Hz, Ar), 7.72 (1H, brs, NH);
20.8, 22.4, 30.4, 44.1, 60.0, 69.7, 95.4, 127.8, 128.3, 128.4, 13C NMR (100 MHz, CDCl3): δ 22.5, 23.2, 32.3, 114.9, 119.8,
135.4, 163.9; minor: δ 20.8, 22.6, 29.3, 44.2, 59.9, 67.7, 96.2, 123.1, 124.2, 128.8, 130.3, 135.2, 137.4, 142.1, 155.9, 159.3;
127.8, 128.3, 128.4, 135.4, 164.2; 77Se NMR (75 MHz, CDCl3): 77Se NMR (75 MHz, CDCl3): δ 276.6; MS (EI): m/z = 391 [M]+;
major: δ 305.7; minor: δ 341.6; MS (EI): m/z = 343 [M]+; HRMS HRMS (FAB): Calcd for C18H17NO2SSe: 391.0145, Found:
(EI): Calcd for C14H17NO2SSe: 343.0145, Found: 343.0126.
1-Cyclohexyl-3-methoxy-5-selena-9-thia-1-azaspiro[3.5]- IR (KBr): 1436, 1489, 1594, 1642 cm−1
nonan-2-one (8h). Colorless solid; mp: 73.5–75 °C; IR (KBr): CDCl3): δ 2.18 (2H, tt, J = 6.9 Hz, CH2), 2–86–2.96 (4H, m,
1760 cm−1 1H NMR (400 MHz, CDCl3): δ 1.14–1.32 (m), CH2), 6.97–7.10 (4H, m, Ar), 7.26 (2H, t, J = 7.7 Hz, Ar), 7.33
391.0100 [M]+; minor isomer: colorless solid; mp: 134–136 °C;
1H NMR (400 MHz,
;
;
1.58–1.66 (m), 1.76–2.10 (m), 2.80–3.12 (m), 3.18–3.28 (m), (2H, t, J = 8.0 Hz, Ar), 7.47 (2H, d, J = 8.3 Hz, Ar), 7.81 (1H, brs,
3.64 (3H, s, Me), 3.67 (minor 3H, s, Me), 4.40 (1H, s, CH), 4.71 NH); 13C NMR (100 MHz, CDCl3): δ 22.6, 31.5, 114.8, 119.8,
(minor 1H, s, CH); 13C NMR (100 MHz, CDCl3): major: δ 21.4, 122.9, 124.2, 128.8, 130.0, 134.8, 137.3, 140.8, 156.1, 160.4;
22.2, 24.9, 25.35, 25.49, 30.9, 31.1, 31.3, 54.2, 59.7, 70.7, 95.5, 77Se NMR (75 MHz, CDCl3): δ 328.4; MS (EI): m/z = 391 [M]+;
162.8; minor: δ 22.6, 23.1, 24.9, 25.35, 25.49, 30.1, 31.3, 31.6, HRMS (FAB): Calcd for C18H17NO2SSe: 391.0145, Found:
54.3, 59.6, 67.8, 96.3, 163.4; 77Se NMR (75 MHz, CDCl3): major: 391.0165 [M]+.
δ 291.8; minor: δ 356.0; MS (EI): m/z = 336 [M]+; HRMS (EI):
Calcd for C13H21NO2SSe: 335.0458, Found: 335.0433.
3-(4-Chlorophenoxy)-1-phenyl-5-selena-9-thia-1-azaspiro[3.5]-
Single crystal X-ray structure analysis
nonan-2-one (8i). Colorless oil; IR (KBr): 1235, 1365, 1489, Crsytals of 6c, 8b, and 9a were obtained by slow evaporation of
1769 cm−1 1H NMR (400 MHz, CDCl3): δ 1.94–2.13 (2H, m, hexane–EtOAc solution. X-ray diffraction measurements were
;
CH2), 2.80–3.10 (4H, m, CH2), 5.38 (1H, s, CH), 5.62 (minor carried out on a Rigaku AFC-7R Mercury CCD diffractometer
1H, s, CH), 7.15 (2H, d, J = 9.2 Hz, Ar), 7.20–7.27 (1H, m, Ar), with graphite-monochromated Mo-Kα radiation (λ
=
7.32 (2H, d, J = 9.2 Hz, Ar), 7.36–7.45 (2H, m, Ar), 7.80 (2H, d, J 0.71069 Å). The structures were solved by direct methods
= 8.7 Hz, Ar); 13C NMR (100 MHz, CDCl3): major: δ 22.4, 22.1, SIR97 and refined with Shelxl97 using interface program Yado-
31.4, 68.7, 91.7, 117.6, 120.8, 126.3, 127.8, 129.1, 129.6, 135.2, kari2009. The final least-squares cycle included non-hydrogen
155.8, 160.6; minor: δ 22.3, 23.6, 30.4, 66.3, 92.7, 117.4, 120.3, atoms with anisotropic thermal parameters. H atoms on C and
126.1, 127.8, 129.1, 129.6, 135.3, 155.9, 160.9; 77Se NMR N atoms were placed in idealized positions and treated as
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riding atoms with C–H distances in the range 0.93–0.99 Å and
N–H distances of 0.86 Å.
M. Koketsu, Heterocycles, 2010, 81, 2027; (c) M. Ninomiya,
D. R. Garud and M. Koketsu, Coord. Chem. Rev., 2011, 255,
2968.
9 (a) G. L. Sommen, A. Linden and H. Heimgartner,
Eur. J. Org. Chem., 2005, 3128; (b) G. L. Sommen, A. Linden
and H. Heimgartner, Tetrahedron Lett., 2005, 46, 6723;
(c) Y. Toyoda, D. R. Garud and M. Koketsu, Heterocycles,
2009, 78, 449.
10 D. R. Garud, Y. Toyoda and M. Koketsu, Tetrahedron Lett.,
2009, 50, 3035.
11 For the Z/E isomerism of selenium-containing exocyclic
imines, see: Y. Toyoda and M. Koketsu, Tetrahedron, 2012,
68, 10496.
Acknowledgements
The authors thank Dr Dinesh R. Garud for helpful discussions;
Masaki Makimura for providing the initial finding of selenium
coupling at the benzylic carbon in related compounds; Yosuke
Hattori for X-ray analysis. This work was supported by a Grant-
in-Aid for Science Research from the Ministry of Education,
Culture, Sports, Science and Technology of Japan (No.
20590005) for which we are grateful.
12 For reviews of isoselenocyanate, see: (a) D. R. Garud,
M. Koketsu and H. Ishihara, Molecules, 2007, 12, 504;
(b) H. Heimgartner, Y. Zhou, P. K. Atanassov and
G. L. Sommen, Phosphorus, Sulfur Silicon Relat. Elem., 2008,
183, 840.
Notes and references
1 H. Staudinger, Justus Liebigs Ann. Chem., 1907, 356, 51.
2 For recent reviews of the Staudinger reaction, see:
(a) F. P. Cossio, A. Arrieta and M. A. Sierra, Acc. Chem. Res., 13 (a) D. R. Garud, H. Ando, Y. Kawai, H. Ishihara and
2008, 41, 925; (b) A. Brandi, S. Cicchi and F. M. Cordero,
Chem. Rev., 2008, 108, 3988; (c) N. Y. Fu and T. T. Tidwell,
Tetrahedron, 2008, 64, 10465.
3 For reviews of spiro-β-lactams, see: (a) S. S. Bari and
A. Bhalla, Top. Heterocycl. Chem., 2010, 22, 49;
(b) G. S. Singh, M. D’hooghe and M. De Kimpe, Tetra-
hedron, 2011, 67, 1989 and references there in.
4 (a) L. Chevolot, A. M. Chevolot, M. Gajhede, C. Larsen,
U. Anthoni and C. Christophersen, J. Am. Chem. Soc., 1985,
107, 4542; (b) U. Anthoni, L. Chevolot, C. Larsen,
P. H. Nielsen and C. Christophersen, J. Org. Chem., 1987,
52, 4709; (c) P. S. Baran and R. A. Shenvi, J. Am. Chem. Soc.,
2006, 128, 14028.
M. Koketsu, Org. Lett., 2007, 9, 4455; (b) D. R. Garud and
M. Koketsu, Org. Lett., 2008, 10, 3319; (c) D. R. Garud,
D. D. Garud and M. Koketsu, Org. Biomol. Chem., 2009, 7,
2591; (d) D. B. Banker and M. Koketsu, Eur. J. Org. Chem.,
2010, 2742; (e) D. R. Garud, M. Makimura and M. Koketsu,
New J. Chem., 2011, 35, 581.
14 (a) Y. Nagao, T. Kumagai, S. Takao, T. Abe, M. Ochiai,
Y. Inoue, T. Taga and E. Fujita, J. Org. Chem., 1986, 51,
4737; (b) T. Inayama, K. Izawa, K. Soda, H. Tanaka and
H. Nagao, 1988, JP 63,83,091; Chem. Abstr., 1999, 109,
149216; (c) G. A. Brown, K. M. Anderson, M. Murray,
T. Gallagher and N. J. Hales, Tetrahedron, 2000, 56, 5579;
(d) K. Tsuchii, Y. Tsuboi, S. Kawaguchi, J. Takahashi,
N. Sonoda, A. Nomoto and A. Ogawa, J. Org. Chem., 2007,
72, 415.
5 (a) E. Alonso, F. Lopez-Ortiz, C. del-Pozo, E. Peralta,
A. Macia and J. Gonzalez, J. Org. Chem., 2001, 66, 6333;
(b) J. D. Tyndall, B. Pfeiffer, G. Abbenante and D. P. Fairlie, 15 2-Imino-1,3-oxaselenane 12 was obtained as a Z/E mixture
Chem. Rev., 2005, 105, 793; (c) H. Bittermann and
P. Gmeiner, J. Org. Chem., 2006, 71, 97; (d) G. Ruiz-Gomez,
J. D. A. Tyndall, B. Pfeiffer, G. Abbenante and D. P. Fairlie,
Chem. Rev., 2010, 110, 1.
(86 : 14) by the reaction of phenylisoselenocyanate 1a with
3-bromo-1-propanol. This compound was reported in:
G. L. Sommen and H. Heimgartner, Pol. J. Chem., 2007, 81,
1413.
6 (a) M. Perelman and S. A. Mizsak, J. Am. Chem. Soc., 1962, 16 A single crystal for the X-ray analysis was obtained by
84, 4988; (b) A. K. Bose, J. C. Kapur, S. G. Amin and
M. S. Manhas, Tetrahedron Lett., 1974, 15, 1917;
(c) M. Cardellini, F. Claudi and F. M. Moracci, Synthesis,
1984, 1070; (d) I. Antonini, M. Cardellini, F. Claudi and
recrystallization of the major isomer of the target com-
pounds, which was stored at 4 °C after isomer separation
with column chromatography. During this storage period,
the isomeric equilibrium reaction proceeded.
F. M. Moracci, Synthesis, 1986, 379; (e) K. Thiagarajan, 17 A single crystal for the X-ray analysis was obtained from the
V. G. Puranik, A. R. A. S. Deshmukh and B. M. Bhawal,
separated major isomer. As well as 9a, isomerization would
Tetrahedron, 2000, 56, 7811.
occur over long storage periods.
7 S. D. Sharma, U. Mehra, J. P. S. Khurana and S. B. Pandhi, 18 L. Jiao, Y. Liang and J. Xu, J. Am. Chem. Soc., 2006, 128,
Synthesis, 1987, 990. 6060.
8 (a) C. W. Nogueira, G. Zeni and J. B. T. Rocha, Chem. Rev., 19 J. G. Fernández-Bolaños, Ó. López, V. Ulgar, I. Maya and
2004, 104, 6255; (b) M. Ninomiya, D. R. Garud and
J. Fuentes, Tetrahedron Lett., 2004, 45, 4081.
Org. Biomol. Chem.
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