Multicomponent reaction for the first synthesis of 2,2-dialkyl- and 2-alkyl-2-aralkyl-5,6-diaryl-2H-1,3-thiazines as scaffolds for various 3,4-dihydro-2H-1,3-thiazine derivatives

Article abstract of DOI:10.1039/c4ob00866a

A two-step sequence for the synthesis of various 3,4-dihydro-2H-1,3- thiazines is presented. In the first step, 2H-1,3-thiazines were prepared by a new multicomponent reaction (MCR). Starting from β-chlorovinyl aldehydes, this MCR offers an efficient and facile access to 2,2-dialkyl- and 2-alkyl-2-aralkyl-5,6-diaryl-2H-1,3-thiazines. The potential of these products in subsequent reactions was verified by the conversion to 3,4-dihydro-2H-1,3- thiazine-containing bisamides, β-lactams, and methoxy amides.

Full text of DOI:10.1039/c4ob00866a

Organic &
Biomolecular Chemistry
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PAPER
Multicomponent reaction for the first synthesis of
2,2-dialkyl- and 2-alkyl-2-aralkyl-5,6-diaryl-2H-
1,3-thiazines as scaffolds for various 3,4-dihydro-
2H-1,3-thiazine derivatives†
Cite this: Org. Biomol. Chem., 2014,
12, 5168
Fabian Brockmeyer, Robin Schoemaker, Marc Schmidtmann and Jürgen Martens*
A two-step sequence for the synthesis of various 3,4-dihydro-2H-1,3-thiazines is presented. In the first
step, 2H-1,3-thiazines were prepared by a new multicomponent reaction (MCR). Starting from β-chloro-
vinyl aldehydes, this MCR offers an efficient and facile access to 2,2-dialkyl- and 2-alkyl-2-aralkyl-5,6-
diaryl-2H-1,3-thiazines. The potential of these products in subsequent reactions was verified by the con-
version to 3,4-dihydro-2H-1,3-thiazine-containing bisamides, β-lactams, and methoxy amides.
Received 28th April 2014,
Accepted 20th May 2014
DOI: 10.1039/c4ob00866a
www.rsc.org/obc
advantageous method for the synthesis of heterocyclic com-
pounds. This synthesis strategy is characterized by a high
Introduction
Heterocyclic compounds containing sulfur and nitrogen are diversity.9
omnipresent in natural products and play a vital role in
1,4-Thiazine, an unsaturated six-membered ring containing
pharmaceutical applications and materials science.1 Conse- sulfur and nitrogen, and its hydrogenated structures dihydro-
quently, there is ongoing interest in drug discovery and other 1,4-thiazine and tetrahydro-1,4-thiazine (thiomorpholine) are
fields of application of organic chemistry in the development other well explored heterocycles. They can be found as sub-
of efficient synthesis routes to new and relevant heterocyclic structures in natural products extracted from plants like sea-
scaffolds containing sulfur and nitrogen.2
weeds10 and in pharmaceuticals used as antipsychotic,11
Well-known through the famous and widely applied penicil- soporific,12 analgesic,13 anticonvulsant,14 and antimycobacter-
lin, the substructure of 1,3-thiazolidine is one of the most ial15 drugs or as TACE inhibitors.16 In contrast, 1,3-thiazines
important heterocyclic skeletons.3,4 2,5-Dihydro-1,3-thiazole, and compounds containing the dihydro-1,3-thiazine and tetra-
one of the iminic unsaturated forms of the 1,3-thiazolidine, hydro-1,3-thiazine substructure have not been sufficiently
can also be found in several natural products and applicable investigated. Most notably the iminic 2,2,5,6-tetrasubstituted
compounds.5 Additionally, their use as scaffolds in the syn- 2H-1,3-thiazines and their derived forms, i.e. 2,2,5,6-tetra-
thesis of derivatives of 1,3-thiazolidines is prevalent.6 The substituted 3,4-dihydro-2H-1,3-thiazines, are interesting sub-
preparation of 2,5-dihydro-1,3-thiazoles can be realized by a structures and building blocks in the synthesis of novel
four-component reaction (4-CR) known as the Asinger reaction, potentially beneficial compounds.
using an α-chloro aldehyde, a second carbonyl compound,
Ceftazidime,17 one of the dihydro-1,3-thiazine based struc-
ammonia and sodium hydrosulfide.6b–d,7 In addition the tural analogues of penicillin utilized as an antibacterial agent,
Asinger reaction provided the basis for the synthesis of several and xylazine,18 a widely used drug in veterinary medicine, are
further heterocyclic structures.8 Combination of a multi- two of the few examples of known compounds containing a
component reaction (MCR) employed to synthesize relatively dihydro-1,3-thiazine substructure.
complex heterocyclic scaffolds with
a
subsequent post-
The main reason for the lack of known beneficial dihydro-
transformation has been abundantly highlighted as an 1,3-thiazine-containing compounds lies in the fact that only a
few synthesis routes to 1,3-thiazines and different types of
dihydro-1,3-thiazine, first of all 3,4-dihydro-2H-1,3-thiazine,
containing structures are developed.19 As a consequence, we
Institut für Chemie, Carl von Ossietzky Universität Oldenburg, P. O. Box 2503,
Carl-von-Ossietzky-Str. 9-11, 26111 Oldenburg, Germany.
developed a MCR for the synthesis of 2,2-dialkyl- and 2-alkyl-2-
aralkyl-5,6-diaryl-2H-1,3-thiazines (2), which have not been
accessible yet. According to the method mentioned above,
these cyclic imines serve as scaffolds for the preparation of
several 3,4-dihydro-2H-1,3-thiazines (5–7) (Fig. 1).
E-mail: juergen.martens@uni-oldenburg.de; http://www.martens.chemie.uni-olden-
burg.de
†Electronic supplementary information (ESI) available: 1H and 13C NMR spectra
of all new compounds. CCDC 976016. For ESI and crystallographic data in CIF
or other electronic format see DOI: 10.1039/c4ob00866a
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Screening of reaction conditions
In an initial attempt to synthesize the 2H-1,3-thiazines 2, we
selected (Z)-1a and acetone as model substrates to probe the
reaction conditions (Table 1). In the first experiment, we
adopted our standard reaction conditions6b–d used in the
Asinger reactions, but no 2H-1,3-thiazine 2a was formed. A
change of the solvent to the polar protic methanol resulted in
the formation of the intended product 2H-1,3-thiazine 2a
(Table 1, entry 1). But the known isothiazole 3a was formed
simultaneously. Starting from β-chlorovinyl aldehydes, the
preparation of isothiazoles is usually realized by treatment of
the aldehydes with ammonium cyanide.25 The observed for-
mation of isothiazole 3a is likely to proceed via a hitherto
unknown oxidation of the respective β-mercaptovinyl imine.
To improve the efficiency of the reaction, we examined clas-
sical conditions of the Asinger reaction based on α-chloro alde-
hydes.26 Stirring of the β-chlorovinyl aldehyde and NaSH in
methanol before addition of all the other reactants and the
usage of gaseous ammonia led to a better ratio 2a : 3a (Table 1,
Fig. 1 Retrosynthetic consideration of the target structures.
In consideration of our experience6b–d,7 in the synthesis of
2,5-dihydro-1,3-thiazoles, we envisioned that the formation of
2H-1,3-thiazines 2 could be realized on the lines of the Asinger
reaction by modifying the structure of the chloro aldehyde.
Results and discussion
Synthesis of the substrates
1
entry 2). However, according to H NMR of the crude product
To obtain 2H-1,3-thiazines 2 via a procedure analogous to the
Asinger reaction β-chlorovinyl aldehydes instead of α-chloro
aldehydes have to be converted with a second carbonyl com-
pound, ammonia and sodium hydrosulfide. β-Chlorovinyl
aldehydes are easily accessible by treatment of α-methylene
ketones with DMF and POCl3.20 We were able to synthesize
(E)-, (Z)-, (EZ)-2-chloro-2,3-diphenylacrylaldehyde21 (1a), (EZ)-3-
chloro-3-(4-chlorophenyl)-2-phenylacrylaldehyde22 (1b), (E)-3-
chloro-2,3-bis(4-methoxyphenyl)acrylaldehyde23 (1d), 2-chloro-
1-cyclopentene-1-carboxaldehyde24 (1e), and the previously
the quantity of other byproducts was likewise increased. Due
to the expectable low yield the isolation of the products was
consciously abandoned. The use of DMF as the solvent did not
lead to the formation of the desired products 2a or 3a. Upon
combining the pre-reaction time (aldehyde and NaSH) in
methanol and the use of an aqueous ammonia solution
(Table 1, entry 3) the yield of 2a was slightly increased, but the
ratio 2a : 3a was as unsatisfying as in the first successful experi-
ment (Table 1, entry 1). According to the observation that the
slower addition of ammonia using the gaseous one compared
to the all-at-once addition of an aqueous ammonia solution
had led to an increased formation of the thiazine 2a in com-
unknown
(EZ)-3-chloro-3-(4-hydroxyphenyl)-2-phenylacryl-
aldehyde (1c) and (E)-, (EZ)-3-chloro-2,3-bis(4-nitrophenyl)acryl-
aldehyde (1f).
Table 1 Optimization of the multicomponent reaction to prepare 2H-1,3-thiazine 2a
Yieldc [%]
Entry
Solvent
1a
1a : NaSH : acetone : NH3
Methoda
Addition of ammonia
Ratiob 2a : 3a
2a
3a
1
2
3
4
5
6
7
8
9
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
(Z)
(Z)
(Z)
(Z)
1 : 1.5 : 2 : 2
1 : 1.5 : 1.5
A
aq
g, 4 h
aq
aq
aq, in MeOH, 1 h
aq, in MeOH, 1 h
aq, in MeOH, 1 h
aq, in MeOH, 1 h
aq, in MeOH, 1 h
63 : 37
75 : 25
66 : 34
—
77 : 23
81 : 19
82 : 18
81 : 19
80 : 20
30
—
36
29
f
e
B, 2 h, r.t.
B, 3 h, r.t.
B, 3 h, 60 °C
B, 3 h, r.t.
B, 3 h, r.t.
B, 4 h, r.t.
B, 3 h, r.t.
B, 3 h, r.t.
—
—
—
—
—
—
—
e
d
e
e
e
e
1 : 1.5 : 1.5 : 2
1 : 1.5 : 1.5 : 2
1 : 1.5 : 1.5 : 2
1 : 1.5 : 1.5 : 2
1 : 1.5 : 1.5 : 2
1 : 1.5 : 2 : 2
1 : 1.5 : 3 : 2
d
—
(Z)
49
48
46
57
63
(EZ)
(EZ)
(EZ)
(EZ)
14
a (i) Method A: NaSH, NH3 in solvent, then acetone and 1a at 0 °C, for 18 h at r.t. (ii) Method B: 1a and NaSH under given conditions, then
acetone, and ammonia at once unless specified otherwise, for 18 h r.t. b The ratio according to 1H NMR of the crude product. c All yields are
isolated yields. d No product was formed. e The isolation of the byproduct was consciously abandoned. f Due to the excess undefined byproducts
according to the 1H NMR of the crude product the isolation of the thiazine was consciously abandoned.
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parison with the isothiazole 3a, we next added a more diluted
The results are summarized in Table 2. Thus, we expanded
solution of aqueous ammonia to the reaction mixture within the scope of the second carbonyl compound. Cyclic ketones
one hour. Under these conditions the product was obtained in such as cyclohexanone (Table 2, entries 2, 9, 12, and 18) as
a comparatively higher yield and a good ratio 2a : 3a (49%, well as aldehydes like isopentanal (Table 2, entries 6 and 17)
Table 1, entry 5).
or 3-phenylpropanal (Table 2, entries 7 and 10) were all feas-
It is noteworthy that the reaction could be performed using ible substrates in the reaction. Although the yields of the 2H-
a (EZ)-mixture of 1a without a significant decrease of yield 1,3-thiazines 2b and 2d were slightly lower, we were pleased to
(Table 1, entry 6). Due to the formation of a small amount of find that in both cases the ratio 2 : 3 was enhanced. Aromatic
(Z)-1, if at all, compared to (E)-1, by converting the respective ketones such as acetophenone cannot be converted to the
ketone and the complex isolation of (Z)-1, the feasibility of desired product 2 (Table 2, entry 4). Carbonyl compounds con-
using both isomers simplifies the synthesis of the thiazines 2 taining aromatic groups in the α- or β-position, however, are
tremendously. In addition, the efficiency of the synthesis route usable substrates for the synthesis of thiazines 2 (Table 2,
to the 2H-1,3-thiazines 2 starting from the ketone is increased.
entries 6, 7, 8, 10, 14, and 15). Moreover, the reaction tolerates
Finally, by raising the molar equivalents of acetone to 3.0 several functional groups on the carbonyl compound, such as
relative to the aldehyde, the yield of isolated 2a was improved sulfide (Table 2, entry 3), ether (Table 2, entry 14), ester
to 63% (Table 1, entry 9).
(Table 2, entry 16) and hydroxy (Table 2, entry 15) groups.
Although the yield was a little lower compared to other carbo-
nyl compounds, it is noteworthy that even the use of a sub-
strate bearing a carbamate moiety led to the formation of the
perspective product 2 (Table 2, entry 8). Conversion of an
amine to thiazine 2k (Table 2, entry 13) revealed the best ratio
2 : 3 (99 : 01) and the highest yield (90%).
Reaction scope
Under these optimized conditions (Table 1, entry 9), we next
studied the influence of the substituents on the aldehydes 1
and the second carbonyl compound on the formation of the
products 2.
Table 2 Preparation of 2H-1,3-thiazines 2 and isothiazoles 3
Entry
Aldehyde
R1
R2
R3
R4
Ratioa 2 : 3
Yieldb [%]
1
2
3
4
5
6
7
8
(EZ)-1a
(EZ)-1a
(EZ)-1a
(EZ)-1a
(EZ)-1a
(EZ)-1a
(EZ)-1a
(EZ)-1a
(EZ)-1b
(EZ)-1c
(E)-1d
(E)-1d
(E)-1d
(E)-1d
(E)-1d
(E)-1d
(E)-1d
(E)-1f
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Me
–(CH2)5–
–(CH2)2S(CH2)2–
Me
Me
H
H
H
–(CH2)5–
H
Me
–(CH2)5–
–(CH2)2N(CH3)(CH2)2–
Me
Me
Me
Me
79 : 21
95 : 05
96 : 04
2a: 63
2b: 58
2c: 66
—
3a: 14
3a: 3
3a: —c
—
d
Ph
CF3
iBu
—
—
d
—
—
98 : 02
95 : 05
86 : 14
97 : 03
94 : 04
86 : 14
97 : 03
99 : 01
98 : 02
94 : 06
83 : 17
97 : 03
82 : 18
2d: 56
2e: 59
2f: 47
2g: 72
2h: 77
2i: 79
2j: 79
2k: 90
2l: 83
2m: 88
2n: 72
2o: 70
2p: 17
3a: —c
3a: —c
3a: —c
3b: 3
CH2CH2Ph
CH2CH2N(H)Cbz
9
H
H
Cl
10
11
12
13
14
15
16
17
18
OH
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
NO2
CH2CH2Ph
Me
3c: 4
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
NO2
3d: 11
3d: 3
3d: —c
3d: —c
3d: —c
3d: —c
3d: —c
3e: 3
CH2(4-OMe-Ph)
CH2CH2(4-OH-Ph)
CH2CH2COOEt
iBu
H
–(CH2)5–
a The ratio according to 1H NMR of the crude product. b All yields are isolated yields. c The isolation of the byproduct was consciously abandoned.
d No products (2 or 3) were formed.
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Besides the model substrate 1a, other β-chlorovinyl alde-
To investigate the reactivity of the synthesized 2H-1,3-thia-
hydes were examined likewise. Both substrates with electron- zines 2, we examined several subsequent reactions, which are
donating (Table 2, entries 9–17) and electron-withdrawing typical for imines, i.e. Ugi-3CR,28 the Staudinger reaction,29
(Table 2, entry 18) groups in the para-position afforded the target and addition of acyl chloride6b,c (Scheme 1). By treatment of
2H-1,3-thiazines 2. Comparison of the reactions forming pro- the imine with an isocyanide and an acid, the Ugi-3CR enables
ducts 2b, 2g, 2j, and 2p (Table 2, entries 2, 9, 12 and 18) as well the preparation of bisamides.28 Starting from 2H-1,3-thiazines
as products 2e and 2h (Table 2, entries 7 and 10) shows that the 2, the bisamides 5 were obtained in all cases in moderate
more electron-rich the β-chlorovinyl aldehydes 1, the better the yields.
ratio 2 : 3 and as a consequence the yield of the desired product
2. By the use of the electron-rich aldehyde 1d the desired 2H-1,3- verted to β-lactams.29 The 2H-1,3-thiazines 2 were therefore
thiazines (2i–o) are obtained in good to very good yields. treated with triethylamine and an acyl chloride. The desired
By means of the Staudinger reaction, imines could be con-
The formation of 2H-1,3-thiazines 2 is limited to 2,3-diaryl- β-lactams 6 were obtained in moderate to good yields. As
β-chlorovinyl aldehydes 1. Under identical reaction conditions expected, the 1H NMR of the crude product revealed the for-
β-chlorovinyl aldehyde 1e is converted to 1-chloro-2-(dimethoxy- mation of only one racemic diastereomer. We were able to
methyl)cyclopent-1-ene (4).27 Even a change of the solvent obtain single crystals of 6b to verify the proposed structure of
(acetonitrile, DMF, 1,4-dioxane) did not lead to the desired 2H- the β-lactams 6 and as a consequence thereof the constitution
1,3-thiazine 2.
of the 2H-1,3-thiazines 2 by X-ray crystal structure analysis
Nevertheless, the depicted results documented that the novel (Fig. 2) in addition to NMR, IR, and mass analysis. Further-
MCR (Table 2) allows the preparation of various 2H-1,3-thiazines more, the relative configuration between the two stereocenters
2 in moderate to excellent yields starting from readily accessible was determined. Analogously, the relative configuration of the
substrates. The synthesis of 2,2-dialkyl- and 2-alkyl-2-aralkyl-5,6- β-lactams 6a and 6c was appointed congruent to the configur-
diaryl-2H-1,3-thiazines is reported for the first time.
ation documented for the X-ray crystal structure of 6b. The
basis for this conclusion by analogy was the comparison of the
coupling constants between the protons at the stereocenters of
Derivatization
As mentioned in the Introduction, the 2H-1,3-thiazines 2 can 6a–c. Coupling constants of all three β-lactams 6, situated
serve as precursors in subsequent reactions to gain sundry 3,4- between 1.5 and 1.8 Hz, are in the same range and are charac-
dihydro-2H-1,3-thiazines.
teristic30 of trans β-lactams.
Scheme 1 Subsequent reactions to various 3,4-dihydro-2H-1,3-thiazine derivatives: bisamides 5, β-lactams 6, methoxy amides 7.
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ible to prepare a great number of products with high diversity,
which could be useful in pharmaceutical research.
Experimental
General methods
Synthetic procedures, performed under an argon atmosphere,
were performed on a vacuum line using standard Schlenk tech-
niques. Preparative column chromatography was carried out
using Grace SiO2 (0.035–0.070 mm, type KG 60). TLC was per-
formed on Machery–Nagel SiO2 F254 plates on aluminum
sheets. Melting points were obtained on melting point appar-
atus of Laboratory Devices and are uncorrected. 1H and 13C
NMR spectra were recorded with a Bruker AM 300 (measuring
frequency: 1H NMR = 300.1 MHz), a Bruker AMX R 500
(measuring frequency: 1H NMR = 500.1 MHz, 13C NMR =
125.8 MHz) or a Bruker Avance III 500 (measuring frequency:
1H NMR = 499.9 MHz, 13C NMR = 125.7 MHz) spectrometer in
CDCl3 or DMSO-d6 solution. Chemical shifts are referenced to
the residual peaks of the solvent [CDCl3: 7.26 ppm (1H NMR),
77.16 ppm (13C NMR); DMSO-d6: 2.50 ppm (1H NMR),
39.53 ppm (13C NMR)].32 Assignments of the signals were sup-
ported by measurements applying DEPT and COSY techniques.
Mass spectra were obtained on a Waters Q-TOF Premier (ESI)
and a Finnigan MAT 95 (EI) spectrometer. The IR spectra were
recorded with a Bruker Tensor 27 spectrometer equipped with
a “Golden Gate” diamond-ATR (attenuated total reflection)
unit. Elemental analyses were performed with a Eurovector
EA3000.
Fig. 2 X-ray crystal structure of the racemic β-lactam 6b (only one
enantiomer is shown).31 The atom numbering does not follow the IUPAC
nomenclature.
Treatment of imines with acyl chlorides led to the for-
mation of chloro amides. Substitution of the chloride with
methanol affords methoxy amides.6b,c
When using alkyl acyl chlorides like pivaloyl chloride to
convert the 2H-1,3-thiazines 2 no reaction was observed.
However, treatment of 2H-1,3-thiazines 2 with more reactive
4-nitrobenzoyl chloride led to the attainment of the desired
methoxy amides 7. Starting from 2a, the methoxy amide 7a
was obtained in 59% yield. The use of 2H-1,3-thiazine (2i)
bearing electron-donating groups results expectably in an
appreciable higher yield (82%).
Thus, several compounds containing the 3,4-dihydro-2H-
1,3-thiazine substructures in addition to another biologically
active structure (i.e. β-lactam) could be formed based on the
synthesized 2H-1,3-thiazines 2.
(E)-, (Z)-, (EZ)-2-Chloro-2,3-diphenylacrylaldehyde21 (1a),
(EZ)-3-chloro-3-(4-chlorophenyl)-2-phenylacrylaldehyde22 (1b),
(E)-3-chloro-2,3-bis(4-methoxyphenyl)acrylaldehyde21
(1d),
2-chloro-1-cyclopentene-1-carboxaldehyde23 (1e), and 1,2-bis-
(4-nitrophenyl)ethan-1-one33 were prepared according to pub-
lished procedures. CH2Cl2 was refluxed with CaH and freshly
distilled prior to use. MeOH was refluxed with Mg and freshly
distilled prior to use. Et3N was dried over molecular sieves
(3 Å) and freshly distilled prior to use.
These examples underline the feasibility to create plenty of
3,4-dihydro-2H-1,3-thiazine-containing compounds starting
from 2H-1,3-thiazines 2 using diverse subsequent reactions.
(EZ)-3-Chloro-3-(4-hydroxyphenyl)-2-phenylacrylaldehyde
(1c). Under an argon atmosphere, POCl3 (8.670 g,
56.55 mmol) and DMF (4.133 g, 56.55 mmol), dissolved in
15 mL anhydrous CH2Cl2, were cooled down to 0–5 °C. 1-(4-
Conclusions
Starting from readily accessible β-chlorovinyl aldehydes, we Hydroxyphenyl)-2-phenylethan-1-one (4.000 g, 18.85 mmol)
developed a two-step sequence to synthesize various 3,4- was added dropwise. After stirring for 40 h at r.t., the reaction
dihydro-2H-1,3-thiazines. First, 2H-1,3-thiazines were gener- mixture was brought to pH 7 by addition of saturated aqueous
ated by a new four-component reaction. Characterized by Na2CO3 solution and extracted with EtOAc (3 × 150 mL). The
easily accessible substrates, mild conditions, high yields and combined organic phases were washed with a saturated
the toleration of many functional groups this MCR allows the aqueous NaCl solution (2 × 150 mL), dried (MgSO4) and the
preparation of various previously unknown 2,2-dialkyl- and solvent was removed on a rotary evaporator. Analysis of the
2-alkyl-2-aralkyl-5,6-diaryl-2H-1,3-thiazines. The shown poten- crude product by 1H NMR spectroscopy revealed the formation
tial of these 2H-1,3-thiazines in subsequent reactions gives of both isomers in a ratio of 76 : 24 ((E)-1c : (Z)-1c). Column
access to 3,4-dihydro-2H-1,3-thiazines. In line with this fact chromatography (n-hexane–EtOAc, 5 : 1; Rf = 0.06) afforded the
several bisamides, β-lactams and methoxy amides with a S,N- desired (EZ)-β-chlorovinyl aldehyde (EZ)-1c as a mixture of
heterocyclic ring were synthesized. Exploiting the developed both isomers (3.507 mg, 72%; (E)-/(Z)-isomer 75 : 25) as a
MCR and following the new two-step synthesis route, it is poss- yellow solid, mp 160–161 °C (from CH2Cl2–n-hexane); IR (ATR)
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˜ν 3392, 3063, 2892, 1648, 1602, 1576, 1507, 1489, 1433, 1373, General procedure (GP A)
1
1271, 1232, 1212, 1173, 1083, 902, 828, 766, 707, 635 cm−1; H
NMR (500.1 MHz, CDCl3): δ 5.26 (1 H, br s, OHZ), 5.71 (1 H, br The respective β-chlorovinyl aldehyde (1.0 equiv.) was dissolved
s, OHE), 6.61–6.64 [2 H, m, 2 m-CHAr(CCl)Z], 6.90–6.93 [2 H, m, in MeOH (5 mL per mmol β-chlorovinyl aldehyde). NaSH·H2O
2 m-CHAr(CCl)E], 7.00–7.01 [2 H, m, 2 m-CHAr(CCHO)Z], (1.5 equiv.) was added and the solution was stirred for 3 h at
7.17–7.20 [2 H, m, 2 o-CHAr(CCl)Z], 7.25–7.30 [5 H, m, r.t. After addition of the respective carbonyl compound
2
m-CHAr(CCHO)E,
2
o-CHAr(CCHO)Z, p-CHAr(CCHO)Z], (3.0 equiv.), a mixture of aqueous ammonia solution (2.0
7.38–7.41 [1 H, m, p-CHAr(CCHO)E], 7.44–7.49 [4 H, m, equiv., 25%) and MeOH (5 mL per mmol β-chlorovinyl alde-
2 o-CHAr(CCHO)E, 2 o-CHAr(CCl)E], 9.67 (1 H, s, CHOE), 10.57 hyde) was added dropwise within 1 h. After stirring overnight
(1 H, s, CHOZ) ppm; 13C NMR (125.8 MHz, CDCl3): δ 115.10 at r.t., the reaction mixture was poured into water (10 mL
[2 m-CHAr(CCl)Z], 115.68 [2 m-CHAr(CCl)E], 128.09 [p-CHAr- per mmol β-chlorovinyl aldehyde) and extracted with CH2Cl2
(CCHO)Z], 128.16 (CArCClE), 128.43 [2 o-CHAr(CCHO)E], 128.51, (3 × 10 mL per mmol β-chlorovinyl aldehyde). The combined
128.53 [2 o-CHAr(CCHO)Z, p-CHAr(CCHO)E], 129.67 (CArCClZ), organic phases were dried (MgSO4), the solvent was removed
129.98 [2 m-CHAr(CCHO)E], 130.76 [2 m-CHAr(CCHO)Z], 132.00 on a rotary evaporator and the crude product was purified by
[2 o-CHAr(CCl)Z], 132.56 [2 o-CHAr(CCl)E], 134.32 (CArCCHOZ), column chromatography on silica gel or by recrystallization.
134.35 (CArCCHOE), 136.60 (CCHOZ), 140.13 (CCHOE), 155.99
2,2-Dimethyl-5,6-diphenyl-2H-1,3-thiazine (2a) and 4,5-
(CClE), 156.02 (CClZ), 157.30 (CArOHZ), 158.54 (CArOHE), 190.53 diphenylisothiazole.34 (3a). Following GP A, aldehyde (EZ)-1a
(CHOE), 191.84 (CHOZ) ppm; MS (ESI): m/z 281.1 (M + Na+, (485 mg, 2.00 mmol), NaSH·H2O (222 mg, 3.00 mmol),
100%); HRMS (ESI): Found 281.0342; Calc. for C15H11NaO2Cl acetone (348 mg, 6.00 mmol) and 25% aqueous ammonia
[M + Na]+ 281.0345.
solution (272 mg, 4.00 mmol) were used. Analysis of the crude
(E)-3-Chloro-2,3-bis(4-nitrophenyl)acrylaldehyde and (EZ)-3- product by 1H NMR spectroscopy revealed the formation of
chloro-2,3-bis(4-nitrophenyl)acrylaldehyde (1f). Under an both title compounds in a ratio of 79 : 21 (2a : 3a). Column
argon atmosphere, 1,2-bis(4-nitrophenyl)ethan-1-one (4.500 g, chromatography (n-hexane–EtOAc, 7 : 3; thiazine 2a, Rf = 0.43;
15.72 mmol) and DMF (2.298 g, 31.44 mmol), dissolved in isothiazole 3a Rf = 0.34) afforded the desired thiazine 2a
9 mL anhydrous CH2Cl2, were cooled down to 0–5 °C. POCl3 (352 mg, 63%) as a greenish-yellow solid, mp 70 °C (from
(4.821 g, 31.44 mmol) was added dropwise. After stirring for CH2Cl2–n-hexane); IR (ATR) ˜ν 3076, 3057, 3019, 2970, 2928,
20 h at 45 °C, the reaction mixture was brought to pH 7 by 1622, 1599, 1531, 1484, 1459, 1442, 1361, 1196, 1175, 875, 767,
1
addition of saturated aqueous Na2CO3 solution and 756, 695, 665 cm−1; H NMR (500.1 MHz, CDCl3): δ 1.72 [6 H,
extracted with EtOAc (3 × 90 mL). The combined organic s, C(CH3)2], 7.11–7.13 (2 H, m, 2 CHAr), 7.16–7.26 (8 H, m, 8
phases were washed with a saturated aqueous NaCl solution CHAr), 8.01 (1 H, s, NCH) ppm; 13C NMR (125.8 MHz, CDCl3):
(2 × 90 mL), dried (MgSO4) and the solvent was removed on a δ 28.99 [C(CH3)2], 63.59 [C(CH3)2], 126.46 (CHCvC), 126.94
rotary evaporator. Analysis of the crude product by 1H NMR (p-CHAr), 128.19, 128.66, 128.84 (4 m-CHAr, 2 o-CHAr), 129.10
spectroscopy revealed the formation of both isomers in a (p-CHAr), 130.67 (2 o-CHAr), 136.67 (CArCS), 137.39 (CArCCH),
ratio of 59 : 41 ((E)-1f : (Z)-1f). Column chromatography 143.98 (CHCvC), 158.22 (CvN) ppm; MS (ESI): m/z 280.2
(n-hexane–EtOAc, 7 : 3; (E)-1f, Rf = 0.44; (Z)-1f, Rf = 0.43) (M + H+, 100%); HRMS (ESI): Found 280.1152; Calc. for
afforded the desired (E)-β-chlorovinyl aldehyde (E)-1f (406 mg, C18H18NS [M + H]+ 280.1160. The isothiazole34 3a (66 mg, 14%)
8%) as a yellow solid, mp 232 °C (from CH2Cl2–n-hexane); was obtained as a brown oil; 1H NMR (500.1 MHz, CDCl3):
IR (ATR) ˜ν 3107, 3071, 1685, 1601, 1510, 1408, 1343, 1295, δ 7.31–7.33 (10 H, m, 10 CHAr), 8.52 (1 H, s, NCH) ppm;
1220, 857, 849, 812, 727, 695 cm−1 1H NMR (500.1 MHz, 13C NMR (125.8 MHz, CDCl3): δ 128.75, 128.79, 128.95, 128.97
;
DMSO-d6): δ 7.65–7.68 [2 H, m, 2 o-CHAr(C)], 8.04–8.07 [2 H, (4 o-CHAr, 4 m-CHAr), 129.06 (2 p-CHAr), 130.55 (CHCvC),
m, 2 o-CHAr(C)], 8.34–8.36 [2 H, m, 2 m-CHAr(C)], 8.40–8.43 132.87, 135.65 (CAr), 159.18 (CvN), 161.57 (CHCvC) ppm.
[2 H, m, 2 m-CHAr(C)], 9.50 (1 H, s, CHO) ppm; 13C NMR
2,3-Diphenyl-1-thia-5-azaspiro[5.5]undeca-2,4-diene (2b) and
(125.8 MHz, DMSO-d6): δ 123.31, 123.90 [4 m-CHAr(C)], 131.38, 4,5-diphenylisothiazole.34 (3a). Following GP A, aldehyde (EZ)-
131.59 [4 o-CHAr(C)], 139.86 (CCHO), 140.55, 140.82 (2 CCAr), 1a (485 mg, 2.00 mmol), NaSH·H2O (222 mg, 3.00 mmol),
147.36, 148.67 (2 NCAr), 150.85 (CCl), 188.04 (CHO) ppm; cyclohexanone (589 mg, 6.00 mmol) and 25% aqueous
MS (EI, 70 eV): m/z 231.7 (M+, 20%); HRMS (EI): ammonia solution (272 mg, 4.00 mmol) were used. Analysis of
Found 332.0196; Calc. for C15H9ClN2O5 [M + H]+ 332.0195. the crude product by 1H NMR spectroscopy revealed the for-
The (Z)-β-chlorovinyl aldehyde (Z)-1e was obtained as
a
mation of both title compounds in a ratio of 95 : 05 (2b : 3a).
mixture of both isomers (576 mg, 11%; (E)-/(Z)-isomer 74 : 26) Column chromatography (n-hexane–EtOAc, 9 : 1; thiazine 2b,
as a yellow solid; 1H NMR (500.1 MHz, CDCl3): δ 7.16–7.18 Rf = 0.29; isothiazole 3a, Rf = 0.16) afforded the desired thia-
[m, 2 H, 2 o-CHAr(C)], 7.43–7.44 [m, 2 H, 2 o-CHAr(C)], zine 2b (368 mg, 58%) as a yellow solid, mp 116 °C (from
8.11–8.13 [m, 4 H, 4 m-CHAr(C)], 10.58 (s, 1 H, CHO) ppm; CH2Cl2–n-hexane); IR (ATR) ˜ν 3078, 3060, 3025, 2926, 2855,
13C NMR (125.8 MHz, CDCl3): δ 123.82, 123.93 [4 m-CHAr(C)], 1623, 1600, 1539, 1485, 1459, 1445, 757, 716, 694, 662 cm−1
;
130.57, 131.75 [4 o-CHAr(C)], 137.56 (CCHO), 139.49, 142.60 1H NMR (500.1 MHz, CDCl3): δ 1.43–1.51 (1 H, m, CH2,Cy),
(2 CCAr), 147.83, 148.57 (2 NCAr), 148.95 (CCl), 188.79 1.67–1.72 (1 H, m, CH2,Cy), 1.76–1.80 (4 H, m, 3 CH2,Cy),
(CHO) ppm.
1.97–2.03 (2 H, m, 2 CH2,Cy), 2.12–2.16 (2 H, m, 2 CH2,Cy),
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7.11–7.12 (2 H, m, 2 CHAr), 7.16–7.26 (8 H, m, 8 CHAr), 8.06 (485 mg, 2.00 mmol), NaSH·H2O (222 mg, 3.00 mmol), 3-phenyl-
(1 H, s, NCH) ppm; 13C NMR (125.8 MHz, CDCl3): δ 22.24, propanal (805 mg, 6.00 mmol) and 25% aqueous ammonia
25.85, 37.28 (5 CH2,Cy), 67.99 [C(CH2)2], 126.87 (p-CHAr), solution (272 mg, 4.00 mmol) were used. Analysis of the crude
126.91 (CHCvC), 128.14, 128.63, 128.79 (4 m-CHAr, 2 o-CHAr), product by 1H NMR spectroscopy revealed the formation of
129.03 (p-CHAr), 130.84 (2 o-CHAr), 136.84 (CArCS), 137.42 both title compounds in a ratio of 95 : 05 (2e : 3a). Recrystalliza-
(CArCCH), 143.11 (CHCvC), 158.10 (CvN) ppm; MS (ESI): m/z tion from MeOH–n-hexane afforded the desired thiazine 2e
320.3 (M + H+, 100%); HRMS (ESI): Found 320.1468; Calc. for (421 mg, 59%) as a yellow solid, mp 91–92 °C; IR (ATR) ˜ν 3050,
C21H22NS [M + H]+ 320.1473. The isothiazole34 3a (14 mg, 3%) 3029, 2994, 2917, 2859, 1607, 1511, 1480, 1450, 1441, 1281,
was obtained as a brown oil.
1154, 1095, 1026, 883, 768, 745, 699 cm−1 1H NMR
;
2,3-Diphenyl-1,9-dithia-5-azaspiro[5.5]undeca-2,4-diene (2c) (500.1 MHz, CDCl3): δ 2.34–2.49 (2 H, m, CHCH2), 2.96–3.05
3
3
4
and 4,5-diphenylisothiazole.34 (3a). Following GP A, aldehyde (2 H, m, CArCH2), 4.71 (1 H, ddd, J = 6.5 Hz, J = 6.5 Hz, J =
4
(EZ)-1a (485 mg, 2.00 mmol), NaSH·H2O (222 mg, 3.00 mmol), 1.8 Hz, SCH), 7.14–7.35 (15 H, m, 15 CHAr), 8.16 (1 H, d, J =
tetrahydro-4H-thiopyran-4-one (697 mg, 6.00 mmol) and 25% 1.8 Hz, NCH) ppm; 13C NMR (125.8 MHz, CDCl3): δ 32.23
aqueous ammonia solution (272 mg, 4.00 mmol) were used. (CHCH2), 36.30 (CArCH2), 61.41 (SCH), 126.19, 127.03
Analysis of the crude product by 1H NMR spectroscopy (2 p-CHAr), 128.20 (2 CHAr), 128.62 (CHCvC), 128.64, 128.67,
revealed the formation of both title compounds in a ratio of 128.74, 128.78 (8 CHAr), 129.28 (p-CHAr), 131.03 (2 CHAr),
96 : 04 (2c : 3a). Recrystallization from MeOH–n-hexane 136.32 (CArCS), 137.01 (CArCCH), 141.34 (CArCH2), 145.49
afforded the desired thiazine 2c (445 mg, 66%) as a yellow (CHCvC), 160.45 (CvN) ppm; MS (ESI): m/z 356.1 (M + H+,
solid, mp 123–124 °C; IR (ATR) ˜ν 3059, 3014, 2938, 2906, 1621, 100%); HRMS (ESI): Found 356.1462; Calc. for C24H22NOS
1574, 1533, 1482, 1442, 1425, 1414, 1271, 1237, 1195, 1094, [M + H]+ 356.1473. The isolation of the isothiazole34 3a was
1
1037, 920, 876, 816, 760, 691, 662 cm−1; H NMR (500.1 MHz, consciously abandoned.
CDCl3): δ 2.39–2.41 [4 H, m, C(CH2)2], 2.87–2.97 [4 H, m,
(RS)-2-{2-[(Benzyloxycarbonyl)amino]ethyl}-5,6-diphenyl-2H-
S(CH2)2], 7.10–7.13 (2 H, m, 2 CHAr), 7.18–7.25 (8 H, m, 1,3-thiazine (2f) and 4,5-diphenylisothiazole.34 (3a). Follow-
8 CHAr), 8.09 (1 H, s, NCH) ppm; 13C NMR (125.8 MHz, ing GP A, aldehyde (EZ)-1a (243 mg, 1.00 mmol), NaSH·H2O
CDCl3): δ 24.35 [S(CH2)2], 38.28 [C(CH2)2], 66.75 [C(CH2)2], (111 mg, 1.50 mmol), 3-[(benzyloxycarbonyl)amino]propanal
126.86 (CHCvC), 127.09 (p-CHAr), 128.26, 128.74 (6 CHAr), (622 mg, 3.00 mmol) and 25% aqueous ammonia solution
129.30 (p-CHAr), 130.80 (2 CHAr), 136.36 (CArCS), 137.01 (136 mg, 2.00 mmol) were used. Analysis of the crude product
1
(CArCCH), 142.29 (CHCvC), 158.45 (CvN) ppm; MS (ESI): m/z by H NMR spectroscopy revealed the formation of both title
338.0 (M + H+, 100%); HRMS (ESI): Found 338.1037; Calc. for compounds in a ratio of 86 : 14 (2f : 3a). Column chromato-
C20H20NS2 [M + H]+ 338.1037. The isolation of the isothiazole34 graphy (n-hexane–acetone–toluene, 4 : 3 : 3; thiazine 2f, Rf
=
3a was consciously abandoned.
(RS)-2-Isobutyl-5,6-diphenyl-2H-1,3-thiazine (2d) and 4,5- yellow oil; IR (ATR) ˜ν 3326, 3265, 3059, 3032, 2941, 1700, 1599,
diphenylisothiazole.34 (3a). Following GP A, aldehyde (EZ)-1a 1512, 1443, 1244, 1136, 1027, 759, 694 cm−1 1H NMR
(485 mg, 2.00 mmol), NaSH·H2O (222 mg, 3.00 mmol), iso- (500.1 MHz, CDCl3): δ 2.26–2.36 (2 H, m, CHCH2), 3.52–3.59,
0.43) afforded the desired thiazine 2f (201 mg, 47%) as a
;
3
3
pentanal (517 mg, 6.00 mmol) and 25% aqueous ammonia 3.60–3.67 (2 H, 2 m, NCH2), 4.76 (1 H, ddd, J = 6.7 Hz, J =
4
solution (272 mg, 4.00 mmol) were used. Analysis of the crude 6.7 Hz, J = 1.4 Hz, SCH), 5.14 (2 H, s, CArCH2), 5.66 (1 H, dd,
product by 1H NMR spectroscopy revealed the formation of 3J = 5.3 Hz, 3J = 5.3 Hz, NH), 7.13–7.40 (15 H, m, 15 CHAr), 8.13
4
both title compounds in a ratio of 98 : 02 (2d : 3a). Column (1 H, d, J = 1.4 Hz, NCH) ppm; 13C NMR (125.8 MHz, CDCl3):
chromatography (n-hexane–EtOAc, 9 : 1; thiazine 2d, Rf = 0.29) δ 34.24 (CHCH2), 38.51 (NCH2), 60.40 (SCH), 66.71 (CArCH2),
afforded the desired thiazine 2c (345 mg, 56%) as an orange 127.06, 128.14, 128.18, 128.22 (5 CHAr, CHCvC), 128.57,
oil; IR (ATR) ˜ν 3057, 3025, 2955, 2930, 1683, 1598, 1525, 1484, 128.66, 128.69, 129.37, 131.01 (10 CHAr), 135.94 (CArCS),
1466, 1444, 1367, 1197, 1172, 759, 694, 664 cm−1 1H NMR 136.71 (CArCCH, CArCH2), 146.03 (CHCvC), 156.51 (CvO),
;
(500.1 MHz, CDCl3): δ 1.04 [6 H, d, 3J = 6.5 Hz, CH(CH3)2], 160.75 (CvN) ppm; MS (ESI): m/z 429.2 (M + H+, 100%);
1.86–1.92, 2.01–2.07 (2 H, 2 m, CH2), 2.09–2.14 [1 H, m, HRMS (ESI): Found 429.1626; Calc. for C26H24N2O2S [M + H]+
3
3
4
CH(CH3)2], 4.73 (1 H, ddd, J = 7.1 Hz, J = 7.1 Hz, J = 1.9 Hz, 429.1637. The isolation of the isothiazole34 3a was consciously
4
SCH), 7.13–7.28 (10 H, m, 10 CHAr), 8.12 (1 H, d, J = 1.9 Hz, abandoned.
NCH) ppm; 13C NMR (125.8 MHz, CDCl3): δ 22.26, 22.81
2-(4-Chlorophenyl)-3-phenyl-1-thia-5-azaspiro[5.5]undeca-2,4-
[CH(CH3)2], 25.12 [CH(CH3)2], 43.87 (CH2), 60.47 (SCH), 126.99 diene (2g) and 5-(4-chlorophenyl)-4-diphenylisothiazole (3b).
(p-CHAr), 128.17 (2 CHAr), 128.64 (CHCvC), 128.65, 128.77 Following GP A, aldehyde (EZ)-1b (275 mg, 0.99 mmol),
(4 CHAr), 129.23 (p-CHAr), 131.04 (2 o-CHAr), 136.36 (CArCS), NaSH·H2O (110 mg, 1.49 mmol), acetone (172 mg, 2.97 mmol)
137.06 (CArCCH), 145.75 (CHCvC), 160.28 (CvN) ppm; MS and 25% aqueous ammonia solution (135 mg, 1.98 mmol)
1
(ESI): m/z 308.2 (M + H+, 100%); HRMS (ESI): Found 308.1465; were used. Analysis of the crude product by H NMR spectro-
Calc. for C20H22NS [M + H]+ 308.1473. The isolation of the iso- scopy revealed the formation of both title compounds in a
thiazole34 3a was consciously abandoned.
ratio of 97 : 03 (2g : 3b). Column chromatography (n-hexane–
(RS)-2-Phenethyl-5,6-diphenyl-2H-1,3-thiazine (2e) and 4,5- MTBE, 9 : 1; thiazine 2g, Rf = 0.13) afforded the desired thia-
diphenylisothiazole.34 (3a). Following GP A, aldehyde (EZ)-1a zine 2g (223 mg, 72%) as a yellow solid, mp 101 °C (from
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CH2Cl2–n-hexane); IR (ATR) ˜ν 2932, 2894, 2855, 1672, 1619, 8.63 (1 H, s, NCH), 9.90 (1 H, br s, OH) ppm; 13C NMR
1595, 1586, 1532, 1480, 1443, 1369, 1266, 1244, 1087, 1055, (125.7 MHz, DMSO-d6): δ 115.97 [2 o-CHAr(OH)], 120.28 (CArCS),
1014, 884, 830, 821, 765, 737 cm−1 1H NMR (500.1 MHz, 127.67 [p-CHAr(CCH)], 128.69, 128.78 [2 o-CHAr(CCH),
; 2
CDCl3): δ 1.42–1.50 (1 H, m, CH2,Cy), 1.66–1.72 (1 H, m, CH2, m-CHAr(CCH)], 129.78 [2 m-CHAr(OH)], 132.61 (CHCvC), 134.42
Cy), 1.74–1.79 (4 H, m, 2 CH2,Cy), 1.96–2.01 (2 H, m, 2 CH2,Cy), (CArCCH), 158.50 (CArOH), 159.72 (CvN), 161.33 (CHCvC)
2.09–2.13 (2 H, m, 2 CH2,Cy), 7.09–7.11 (2 H, m, CHAr), ppm; MS (ESI): m/z 276.0 (M + Na+, 100%); HRMS (ESI): Found
7.15–7.25 (7 H, m, CHAr), 8.04 (1H, s, NCH) ppm; 13C NMR 276.0455, Calc. for C15H11NNaOS [M + Na]+ 276.0459.
(125.8 MHz, CDCl3): δ 22.23, 25.81, 37.28 (5 CH2,Cy), 68.17
5,6-Bis(4-methoxyphenyl)-2,2-dimethyl-2H-1,3-thiazine (2i)
[C(CH2)2], 127.12 (p-CHAr), 127.19 (CHCvC), 128.46, 128.73, and 4,5-bis(4-methoxyphenyl)isothiazole.25a (3d). Following
128.83, 132.14 (4 o-CHAr, 4 m-CHAr), 135.07, 135.36 (CArCS, GP A, aldehyde (E)-1d (303 mg, 1.00 mmol), NaSH·H2O
CArCl), 137.06 (CArCCH), 141.66 (CHCvC), 157.99 (CvN) ppm; (111 mg, 1.50 mmol), acetone (174 mg, 3.00 mmol) and 25%
MS (ESI): m/z 354.1 (M + H+, 100%); HRMS (ESI): Found aqueous ammonia solution (136 mg, 2.00 mmol) were used.
354.1075, Calc. for C21H21ClNS [M + H]+ 354.1083. The isothia- Analysis of the crude product by 1H NMR spectroscopy
zole 3b was further purified by a second column chromato- revealed the formation of both title compounds in a ratio of
graphy (n-hexane–CH2Cl2–toluene–EtOH, 6 : 2 : 1 : 1; Rf = 0.62). 86 : 14 (2i : 3d). Column chromatography (n-hexane–EtOAc,
The isothiazole was obtained (8 mg, 3%) as a colorless solid, 9 : 1; thiazine 2i, Rf = 0.11, isothiazole 3d, Rf = 0.22) afforded
mp 115 °C; IR (ATR) ˜ν 3082, 3060, 3036, 3029, 2959, 1594, the desired thiazine 2i (267 mg, 79%) as an orange oil;
1576, 1495, 1481, 1397, 1261, 1208, 1089, 1015, 894, 825, 793, IR (ATR) ˜ν 3031, 2999, 2966, 2929, 2835, 1666, 1621, 1573,
758, 736, 700, 629, 542 cm−1
;
1H NMR (499.9 MHz, CDCl3): 1508, 1495, 1460, 1440, 1291, 1243, 1197, 1172, 828, 805,
1H NMR (500.1 MHz, CDCl3): δ 1.67 [6 H, s, C
δ 7.25–7.38 (9 H, m, 9 CHAr), 8.51 (1 H, s, NCH) ppm; 13C NMR 787 cm−1
;
(125.7 MHz, CDCl3): δ 128.02 [p-CHAr(C)], 129.00, 129.04 (CH3)2], 3.76, 3.76 (6 H, 2 s, 2 OCH3), 6.70–6.73 [2 H, m, 2 m-
(4 CHAr), 129.18 (CHCvC), 129.33, 130.09 (4 CHAr), 132.67 CHAr(CS)], 6.76–6.79 [2 H, m, 2 m-CHAr(CCH)], 7.03–7.06 [2 H,
(CArCS), 135.31 (CArCl), 136.12 (CArCCH), 159.33 (CvN), 160.24 m, 2 o-CHAr(CCH)], 7.18–7.21 [2 H, m, 2 o-CHAr(CS)], 7.96 (1 H,
(CHCvC) ppm; MS (ESI): m/z 272.1 (M + H+, 100%); HRMS s, NCH) ppm; 13C NMR (125.8 MHz, CDCl3): δ 28.96 [C(CH3)2],
(ESI): Found 272.0302, Calc. for C15H11ClNS [M + H]+ 272.0301.
55.34 (2 OCH3), 63.54 [C(CH3)2], 113.62 [2 m-CHAr(CS)], 114.24
(RS)-6-(4-Hydroxyphenyl)-2-phenethyl-5-phenyl-2H-1,3-thia- [2 m-CHAr(CCH)], 125.12 (CHCvC), 128.99 (CArCS), 129.82
zine (2h) and 5-(4-hydroxyphenyl)-4-phenylisothiazole (3c). [2 o-CHAr(CCH)], 129.87 (CArCCH), 132.12 [2 o-CHAr(CS)],
Following GP A, aldehyde (EZ)-1c (388 mg, 1.50 mmol), 142.46 (CHCvC), 158.51 [p-CAr(CCH)], 158.62 (CvN), 160.15
NaSH·H2O (167 mg, 2.25 mmol), 3-phenylpropanal (604 mg, [p-CAr(CS)] ppm; MS (ESI): m/z 340.2 (M + H+, 100%); HRMS
4.50 mmol) and 25% aqueous ammonia solution (204 mg, (ESI): Found 340.1368, Calc. for C20H21NO2S [M
+
H]+
3.00 mmol) were used. Analysis of the crude product by 1H 340.1371. The isothiazole25a 3d (33 mg, 11%) was obtained as
NMR spectroscopy revealed the formation of both title com- a yellow oil; 1H NMR (500.1 MHz, CDCl3): δ 3.81, 3.82 (6 H, 2s,
pounds in a ratio of 94 : 4 (2h : 3c). Column chromatography 2 OCH3), 6.85–6.89 [4 H, m, 4 m-CHAr(C)], 7.22–7.26 [4 H, m,
(n-hexane–EtOAc–CH2Cl2, 6 : 2 : 2; thiazine 2h, Rf = 0.29; iso- 4 o-CHAr(C)], 8.45 (1 H, s, NCH) ppm; 13C NMR (125.8 MHz,
thiazole 3c, Rf = 0.47) afforded the desired thiazine 2h CDCl3): δ 55.34, 55.38 (2 CH3), 114.29, 114.43 [4 m-CHAr(C)],
(429 mg, 77%) as a yellow solid, mp 198–200 °C (decomp.; 123.08, 125.46 (2 CArC), 130.03, 130.16 [4 o-CHAr(C)], 134.75
from CH2Cl2–n-hexane); IR (ATR) ˜ν 3029, 3990, 2917, 2854, (CHCvC), 159.18 [p-CAr(C)], 159.33 (CvN), 160.21 (CHCvC),
2661, 1598, 1574, 1495, 1475, 1438, 1289, 1217, 1171, 1090, 160.67 [p-CAr(C)] ppm.
1
958, 840, 767, 744, 700 cm−1; H NMR (500.1 MHz, DMSO-d6):
2,3-Bis(4-methoxyphenyl)-1-thia-5-azaspiro[5.5]undeca-2,4-
δ 2.19–2.31 (2 H, m, CHCH2), 2.89–2.92 (2 H, m, CArCH2), 4.62 diene (2j) and 4,5-bis(4-methoxyphenyl)isothiazole.25a (3d).
(1 H, ddd, J = 6.4 Hz, J = 6.4 Hz, J = 1.7 Hz, SCH), 6.60–6.62 Following GP A, aldehyde (EZ)-1d (303 mg, 1.00 mmol),
[2 H, m, 2 m-CHAr(CS)], 7.06–7.08 [2 H, m, 2 o-CHAr(CS)], NaSH·H2O (111 mg, 1.50 mmol), cyclohexanone (294 mg,
3
3
4
4
7.17–7.32 (10 H, m, 10 CHAr), 8.13 (1 H, d, J = 1.7 Hz, NCH), 3.00 mmol) and 25% aqueous ammonia solution (136 mg,
9.86 (1 H, s, OH) ppm; 13C NMR (125.8 MHz, DMSO-d6): 2.00 mmol) were used. Analysis of the crude product by
δ
31.53 (CHCH2), 35.77 (CArCH2), 60.97 (SCH), 115.10 1H NMR spectroscopy revealed the formation of both title com-
[2 m-CHAr(CS)], 125.94 (p-CHAr), 126.15 (CArCS), 126.61 pounds in a ratio of 97 : 03 (2j : 3d). Column chromatography
(p-CHAr), 127.12 (CHCvC), 128.40, 128.43, 128.47, 128.55 (8 (n-hexane–EtOAc, 7 : 3; thiazine 2j, Rf = 0.29, isothiazole 3c,
CHAr), 132.31 [2 o-CHAr(CS)], 136.99 (CArCCH), 141.22 Rf = 0.65) afforded the desired thiazine 2j (301 mg, 79%) as a
(CArCH2), 144.06 (CHCvC), 158.61 (CArOH), 159.91 (CvN) yellowish-orange solid, mp 162 °C (from CH2Cl2–n-hexane); IR
ppm; MS (ESI): m/z 372.1 (M + H+, 100%); HRMS (ESI): Found (ATR) ˜ν 3070, 3040, 3024, 2931, 2855, 2835, 1623, 1603, 1571,
372.1417, Calc. for C24H22NOS [M + H]+ 372.1422. The isothia- 1538, 1497, 1459, 1441, 1295, 1256, 1243, 1172, 846, 828, 802,
1
zole34 3c (15 mg, 4%) was obtained as a colorless solid, mp 786 cm−1; H NMR (500.1 MHz, CDCl3): δ 1.41–1.49 (1 H, m,
220–221 °C; IR (ATR) ˜ν 3114, 2801, 2730, 2667, 1612, 1586, 1542, CH2,Cy), 1.65–1.70 (1 H, m, CH2,Cy), 1.74–1.79 (4 H, m, 3 CH2,Cy),
1
1510, 1402, 1280, 1209, 1173, 827, 762, 695, 657 cm−1; H NMR 1.93–1.99 (2 H, m, 2 CH2,Cy), 2.08–2.12 (2 H, m, 2 CH2,Cy), 3.75
(499.9 MHz, DMSO-d6): δ 6.77–6.80 [2 H, m, 2 o-CHAr(OH)], (3 H, s, SCPhOCH3), 3.76 (3 H, s, CHCPhOCH3), 6.70–6.73
7.12–7.15 [2 H, m, 2 m-CHAr(OH)], 7.32–7.39 (5 H, m, 5 CHAr), [2 H, m, 2 m-CHAr(CS)], 6.75–6.78 [2 H, m, 2 m-CHAr(CCH)],
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7.02–7.05 [2 H, m, 2 o-CHAr(CCH)], 7.19–7.22 [2 H, m, 2 CHAr), 7.23–7.26 (2 H, m, CHAr) ppm; 13C NMR (125.8 MHz,
o-CHAr(CS)], 8.02 (1H, s, NCH) ppm; 13C NMR (125.8 MHz, CDCl3): δ 28.02 (CCH3), 46.44 (CH2), 55.27 (3 OCH3), 67.89
CDCl3): δ 22.27, 25.86, 37.23 (5 CH2,Cy), 55.31 (2 OCH3), 67.93 (CCH3), 113.35, 113.56, 114.07 [6 o-CHAr(O)], 124.83 (CHCvC),
[C(CH2)2], 113.55 [2 m-CHAr(CS)], 114.19 [2 m-CHAr(CCH)], 128.58, 128.91, 129.87 (3 CArC), 129.87, 131.92, 132.12
125.51 (CHCvC), 129.14 (CArCS), 129.75 [2 o-CHAr(CCH)], [6 m-CHAr(O)], 142.02 (CHCvC), 158.43, 158.60 [2 CArO],
129.90 (CArCCH), 132.24 [2 o-CHAr(CS)], 141.25 (CHCvC), 158.78 (CvN), 160.08 [CArO] ppm; MS (ESI): m/z 446.0 (M + H+,
158.43 [p-CAr(CCH)], 158.46 (CvN), 160.07 [p-CAr(CS)] ppm; 100%); HRMS (ESI): Found 446.1779, Calc. for C27H28NO3S
MS (ESI): m/z 380.3 (M + H+, 100%); HRMS (ESI): Found [M + H]+ 446.1790. The isolation of the isothiazole25a 3d was
380.1671, Calc. for C23H25NO2S [M + H]+ 380.1684. The isothia- consciously abandoned.
zole25a 3d (9 mg, 3%) was obtained as a yellow oil.
(RS)-2-(4-Hydroxyphenethyl)-5,6-bis(4-methoxyphenyl)-2-
2,3-Bis(4-methoxyphenyl)-9-methyl-1-thia-5,9-diazaspiro[5.5]- methyl-2H-1,3-thiazine (2m) and 4,5-bis(4-methoxyphenyl)iso-
undeca-2,4-diene (2k) and 4,5-bis(4-methoxyphenyl)isothiazo- thiazole.25a (3d). Following GP A, aldehyde (E)-1d (606 mg,
le.25a (3d). Following GP A, aldehyde (E)-1d (606 mg, 2.00 mmol), NaSH·H2O (222 mg, 3.00 mmol), 4-(4-hydroxy-
2.00 mmol), NaSH·H2O (222 mg, 3.00 mmol), N-methylpiperi- phenyl)butan-2-one (985 mg, 6.00 mmol) and 25% aqueous
din-4-one (678 mg, 6.00 mmol) and 25% aqueous ammonia ammonia solution (272 mg, 4.00 mmol) were used. Analysis of
solution (272 mg, 4.00 mmol) were used. Analysis of the crude the crude product by 1H NMR spectroscopy revealed the for-
product by 1H NMR spectroscopy revealed the formation of mation of both title compounds in a ratio of 94 : 6 (2m : 3d).
both title compounds in a ratio of 99 : 1 (2k : 3d). Column Column chromatography (n-hexane–EtOAc–CH2Cl2, 6 : 2 : 2;
chromatography (acetone–EtOH, 9 : 1; thiazine 2k, Rf = 0.06) thiazine 2m, Rf = 0.26) afforded the desired thiazine 2m
afforded the desired thiazine 2k (705 mg, 90%) as a yellow (780 mg, 88%) as a yellow solid, mp 161–162 °C (from CH2Cl2–
solid, mp 125–127 °C (from CH2Cl2–n-hexane); IR (ATR) n-hexane); IR (ATR) ˜ν 3101, 3004, 2931, 2836, 2679, 2607, 1601,
˜ν 3001, 2938, 2836, 2792, 2739, 1602, 1509, 1495, 1463, 1440, 1510, 1494, 1441, 1372, 1293, 1244, 1173, 1077, 1029,
1377, 1292, 1244, 1174, 1144, 1030, 881, 826, 729, 540 cm−1
;
825 cm−1 1H NMR (500.1 MHz, CDCl3): δ 1.71 (CCH3),
;
1H NMR (500.1 MHz, CDCl3): δ 2.06–2.18 [4 H, m, C(CH2)2], 2.15–2.22, 2.27–2.33 [2 H, 2 m, C(CH3)CH2], 2.72–2.87 (2 H, m,
2.28 (3 H, s, NCH3), 2.49–2.54 [2 H, m, N(CH2)2], 2.62–2.66 CArCH2), 3.77 (6 H, 2 s, OCH3), 6.73–6.76 [2 H, m, 2
[2 H, m, N(CH2)2], 3.63 (3 H, s, SCPhOCH3), 3.64 (3 H, s, m-CHAr(CS)], 6.77–6.80 [4 H, m, 2 m-CHAr(CCH), 2 o-CHAr(OH)],
CHCPhOCH3), 6.61–6.64 [2 H, m, 2 m-CHAr(CS)], 6.66–6.69 7.02–7.07 [4 H, m, 2 o-CHAr(CCH), 2 m-CHAr(OH)], 7.21–7.24
[2 H, m, 2 m-CHAr(CCH)], 6.94–6.97 [2 H, m, 2 o-CHAr(CCH)], [2 H, m, 2 o-CHAr(CS)], 7.61 (1H, br s, OH), 8.07 (1H, s, NCH)
7.11–7.14 [2 H, m, 2 o-CHAr(CS)], 7.98 (1H, s, NCH) ppm; ppm; 13C NMR (125.8 MHz, CDCl3): δ 27.11 (CCH3), 30.74
13C NMR (125.8 MHz, CDCl3): δ 36.71 [C(CH2)2], 46.04 (NCH3), (CArCH2), 43.89 [C(CH3)CH2], 55.35 (2 OCH3), 67.05 (CCH3),
51.37 [S(CH2)2], 54.99 (2 OCH3), 64.95 [C(CH2)2], 113.34 113.69 [2 m-CHAr(CS)], 114.13 [2 m-CHAr(CCH)], 115.67
[2 m-CHAr(CS)], 113.98 [2 m-CHAr(CCH)], 125.46 (CHCvC), [o-CHAr(OH)], 124.87 (CHCvC), 128.82 (CArCS), 129.56 [CArCCH,
128.53 (CArCS), 129.43 [2 o-CHAr(CCH)], 129.30 (CArCCH), 2 m-CHAr(OH)], 129.85 [2 o-CHAr(CCH)], 132.12 [2 o-CHAr(CS)],
131.99 [2 o-CHAr(CS)], 140.83 (CHCvC), 158.24 [p-CAr(CCH)], 133.31 (CArCH2), 143.20 (CHCvC), 154.74 (CArOH), 158.56
158.69 (CvN), 159.91 [p-CAr(CS)] ppm; MS (ESI): m/z 395.2 [p-CAr(CCH)], 159.26 (CvN), 160.30 [p-CAr(CS)] ppm; MS (ESI):
(M + H+, 100%); HRMS (ESI): Found 395.1782, Calc. for m/z 446.2 (M + H+, 100%); HRMS (ESI): Found 446.1786, Calc.
C23H27N2O2S [M + H]+ 395.1793. The isolation of the isothiazo- for C27H28NO3S [M + H]+ 446.1790. The isolation of the isothia-
le25a 3d was consciously abandoned.
zole25a 3d was consciously abandoned.
(RS)-2-(4-Methoxybenzyl)-5,6-bis(4-methoxyphenyl)-2-methyl-
(RS)-2-(3-Ethoxy-3-oxopropyl)-5,6-bis(4-methoxyphenyl)-2-
2H-1,3-thiazine
(2l)
and
4,5-bis(4-methoxyphenyl)iso- methyl-2H-1,3-thiazine (2n) and 4,5-bis(4-methoxyphenyl)-
thiazole.25a (3d). Following GP A, aldehyde (E)-1d (606 mg, isothiazole.25a (3d). Following GP A, aldehyde (E)-1d (606 mg,
2.00 mmol), NaSH·H2O (222 mg, 3.00 mmol), 1-(4-methoxy- 2.00 mmol), NaSH·H2O (222 mg, 3.00 mmol), ethyl oxo-
phenyl)propan-2-one (985 mg, 6.00 mmol) and 25% aqueous pentanoate (865 mg, 6.00 mmol) and 25% aqueous ammonia
ammonia solution (272 mg, 4.00 mmol) were used. Analysis of solution (272 mg, 4.00 mmol) were used. Analysis of the crude
the crude product by 1H NMR spectroscopy revealed the for- product by 1H NMR spectroscopy revealed the formation of
mation of both title compounds in a ratio of 98 : 02 (2l : 3d). both title compounds in a ratio of 83 : 17 (2n : 3d). Column
Column chromatography (n-hexane–CH2Cl2–EtOAc, 10 : 4 : 1; chromatography (n-hexane–EtOAc–CH2Cl2, 6 : 2 : 2; thiazine 2n,
thiazine 2l, Rf = 0.06) afforded the desired thiazine 2l (738 mg, Rf = 0.27) afforded the desired thiazine 2n (525 mg, 72%) as an
83%) as an orange solid, mp 136–137 °C (from CH2Cl2–n- orange oil; IR (ATR) ˜ν 3032, 2972, 2930, 2836, 1730, 1602, 1509,
hexane); IR (ATR) ˜ν 3036, 3015, 2973, 2955, 2923, 2838, 1604, 1496, 1441, 1374, 1291, 1244, 1173, 1077, 1030, 828, 615 cm−1
1574, 1509, 1498, 1455, 1300, 1293, 1246, 1171, 1113, 1078, 1H NMR (500.1 MHz, CDCl3): δ 1.24 (3 H, t, 3J = 7.1 Hz,
;
1027, 830, 821, 806, 755 cm−1 1H NMR (500.1 MHz, CDCl3): CH2CH3), 1.63 (3 H, s, CCH3), 2.22–2.28 [1 H, m, C(CH3)CH2],
;
δ 1.67 (3 H, s, CCH3), 3.08 (1 H, d, 2J = 13.9 Hz, CH2), 3.20 2.31–2.37 [1 H, m, C(CH3)CH2], 2.54–2.65 (2 H, m, CH2CvO],
2
(1 H, d, J = 13.8 Hz, CH2), 3.75, 3.76, 3.78 (9 H, 3 s, 3 OCH3), 3.75 (3 H, s, SCPhOCH3), 3.76 (3 H, s, CHCPhOCH3), 4.13 (2 H,
6.69–6.72 (2 H, m, CHAr), 6.74–6.77 (2 H, m, CHAr), 6.83–6.86 q, 3J = 7.1 Hz, CH2CH3), 6.69–6.72 [2 H, m, 2 m-CHAr(CS)],
(2 H, m, CHAr), 6.93–6.96 (2 H, m, CHAr), 7.16–7.19 (2 H, m, 6.76–6.79 [2 H, m, 2 m-CHAr(CCH)], 7.02–7.05 [2 H, m, 2
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o-CHAr(CCH)], 7.17–7.20 [2 H, m, 2 o-CHAr(CS)], 7.98 (1H, s, m-CHAr(CCH)] ppm; 13C NMR (125.8 MHz, CDCl3): δ 22.07,
NCH) ppm; 13C NMR (125.8 MHz, CDCl3): δ 14.34 (CH2CH3), 25.59, 37.45 (5 CH2,Cy), 68.99 [Cq(CH2)2], 123.78 [2 o-CHAr(CS)],
27.06 (CCH3), 30.40 (CH2CvO), 36.42 (CH2CH2CvO), 55.32 124.26 [2 o-CHAr(CCH)], 126.67 (CHCvC), 129.38
(2 OCH3), 60.57 (CH2CH3), 66.53 (CCH3), 113.62 [2 m- [2 m-CHAr(CCH)], 131.70 [2 m-CHAr(CS)], 142.69, 143.36
CHAr(CS)], 114.24 [2 m-CHAr(CCH)], 124.76 (CHCvC), 128.91 [2 CArC], 144.21 (CHCvC), 146.92 [p-CAr(CCH)], 148.22
(CArCS), 129.75 (CArCCH), 129.84 [2 o-CHAr(CCH)], 132.05 [p-CAr(CS)], 155.82 (CvN) ppm; MS (ESI): m/z 410.1 (M + H+,
[2 o-CHAr(CS)], 141.95 (CHCvC), 158.53 [p-CAr(CCH)], 158.94 100%); HRMS (ESI): Found 410.1164, Calc. for C21H20N3O4S
(CvN), 160.18 [p-CAr(CS)] ppm; MS (ESI): m/z 426.2 (M + H+, [M + H]+ 410.1160. The isothiazole 3e was further purified by a
100%); HRMS (ESI): Found 426.1729, Calc. for C24H28NO4S second column chromatography (CH2Cl2–n-hexane–EtOAc,
[M + H]+ 426.1739. The isolation of the isothiazole25a 3d was 15 : 4 : 1; Rf = 0.71). The isothiazole was obtained (9 mg, 3%) as
consciously abandoned.
(RS)-2-Isobutyl-5,6-bis(4-methoxyphenyl)-2H-1,3-thiazine (2o) 1537, 1506, 1479, 1408, 1346, 1314, 1287, 898, 848, 795, 750,
and 4,5-bis(4-methoxyphenyl)isothiazole.25a (3d). Following GP 734, 693, 673, 523 cm−1 1H NMR (500.1 MHz, CDCl3):
a yellow solid, mp 226 °C; IR (ATR) ˜ν 3113, 3062, 3040, 1595,
;
A, aldehyde (EZ)-1d (303 mg, 1.00 mmol), NaSH·H2O (111 mg, δ 7.44–7.48 [4 H, m, 4 o-CHAr(C)], 8.23–8.26 [4 H, m, 4 m-
1.50 mmol), isopentanal (258 mg, 3.00 mmol) and 25% CHAr(C)], 8.61 (1 H, s, NCH) ppm; 13C NMR (125.8 MHz,
aqueous ammonia solution (136 mg, 2.00 mmol) were used. CDCl3): δ 124.55, 124.68 [4 m-CHAr(C)], 129.83, 129.88 [4 o-
Analysis of the crude product by 1H NMR spectroscopy CHAr(C)], 135.03 (CHCvC), 136.30, 138.68 (2 CArC), 147.69
revealed the formation of both title compounds in a ratio of 148.44 (CArN), 158.70 (CvN), 160.86 (CHCvC) ppm; MS (EI,
97 : 03 (2o : 3d). Column chromatography (n-hexane–EtOAc, 70 eV): m/z 326.8 (M+, 20%); HRMS (EI): Found 327.0300, Calc.
9 : 1; thiazine 2o, Rf = 0.17) afforded the desired thiazine 2o for C15H9N3O4S [M + H]+ 327.0308.
(257 mg, 70%) as an orange oil; IR (ATR) ˜ν 3036, 3002, 2956,
2935, 2910, 2870, 2838, 1656, 1603, 1575, 1529, 1511, 1496, GP A, 2-chloro-1-cyclopentene-1-carboxaldehyde (652 mg,
1465, 1443, 1294, 1246, 1176, 829, 799 cm−1 1H NMR 4.99 mmol), NaSH·H2O (555 mg, 7.49 mmol), acetone
1-Chloro-2-(dimethoxymethyl)cyclopent-1-ene (4). Following
;
(500.1 MHz, CDCl3): δ 1.02, 1.02 [6 H, 2 d, 3J = 6.5 Hz, (869 mg, 14.97 mmol) and 25% aqueous ammonia solution
CH(CH3)2,], 1.84–1.89, 2.00–2.06 (2 H, 2 m, CH2), 2.07–2.13 [1 (680 mg, 9.98 mmol) were used. Column chromatography
H, m, CH(CH3)2], 3.75 (3 H, s, SCPhOCH3), 3.76 (3 H, s, (n-hexane–MTBE–CH2Cl2, 6 : 3 : 1; Rf = 0.56) afforded the
CHCPhOCH3), 4.65 (1 H, ddd, 3J = 7.2 Hz, 3J = 7.2 Hz, 4J = dimethyl acetal 4 instead of the desired thiazine (352 mg,
1.9 Hz, SCH), 6.70–6.73 [2 H, m, 2 m-CHAr(CS)], 6.76–6.79 [2 H, 40%) as a dark brown oil; IR (ATR) ˜ν 2956, 2932, 2910, 2857,
m, 2 m-CHAr(CCH)], 7.06–7.09 [2 H, m, 2 o-CHAr(CCH)], 2828, 1663, 1443, 1363, 1184, 1111, 1090, 1069, 961, 917,
1
7.21–7.24 [2 H, m, 2 o-CHAr(CS)] 8.09 (1 H, d, 4J = 1.9 Hz, NCH) 905 cm−1; H NMR (500.1 MHz, CDCl3): δ 1.92–1.98 (2 H, m,
ppm; 13C NMR (125.8 MHz, CDCl3): δ 22.63, 22.80 [CH(CH3)2], CH2CH2CH2), 2.45–2.49 (2 H, m, CHCCH2), 2.59–2.63 (2 H, m,
25.17 [CH(CH3)2], 43.95 (CH2), 55.33 (2 OCH3), 60.52 (SCH), ClCCH2), 3.38 (6 H, s, 2 OCH3), 5.05 (1 H, s, CH) ppm; 13C
113.59 [2 m-CHAr(CS)], 114.24 [2 m-CHAr(CCH)], 127.27 NMR (125.8 MHz, CDCl3):
δ 20.96 (CH2CH2CH2), 29.67
[CHCvC], 128.70 (CArCS), 129.57 (CArCCH), 129.74 (CHCCH2), 38.39 (ClCCH2), 54.80 (2 OCH3), 100.83 (CH),
[2 o-CHAr(CCH)], 132.54 [2 o-CHAr(CS)], 144.31 [CHCvC], 131.05 (CHCvC), 134.50 (CHCvC) ppm; MS (ESI): m/z 199.1
158.54 [p-CAr(CCH)], 160.27 [p-CAr(CS)], 160.71 (CvN) ppm; (M + Na+, 100%); HRMS (ESI): Found 199.0496, Calc. for
MS (ESI): m/z 368.3 (M + H+, 100%); HRMS (ESI): Found C8H13NNaO2Cl [M + Na]+ 199.0502.
368.1678, Calc. for C22H26NO2S [M + H]+ 368.1684. The iso-
General procedure (GP B)
lation of the isothiazole25a 3d was consciously abandoned.
2,3-Bis(4-nitrophenyl)-1-thia-5-azaspiro[5.5]undeca-2,4-diene The respective imine (1.0 equiv.), dissolved in anhydrous
(2p) and 4,5-bis(4-nitrophenyl)isothiazole (3e). Following GP MeOH (2 mL per mmol imine), was treated with the respective
A, aldehyde (E)-1f (318 mg, 0.96 mmol), NaSH·H2O (107 mg, isocyanide (1.0 equiv.), dissolved in anhydrous MeOH (2 mL
1.44 mmol), cyclohexanone (283 mg, 2.88 mmol) and 25% per mmol imine), and the respective acid (1.0 equiv.), dis-
aqueous ammonia solution (107 mg, 1.44 mmol) were used. solved in anhydrous MeOH (2 mL per mmol imine). After stir-
Analysis of the crude product by 1H NMR spectroscopy ring for 72 h at r.t., the solvent was removed on a rotary
revealed the formation of both title compounds in a ratio of evaporator. The crude product was purified by column
82 : 18 (2p : 3e). Column chromatography (n-hexane–EtOAc, chromatography on silica gel.
8 : 2; thiazine 2p, Rf = 0.16) afforded the desired thiazine 2p
(RS)-3-(2-Bromoacetyl)-4-(N-cyclohexylcarbamoyl)-2,2-dimethyl-
(65 mg, 17%) as an orange solid, mp 138 °C; IR (ATR) ˜ν 3107, 5,6-diphenyl-3,4-dihydro-2H-1,3-thiazine (5a). Following GP B,
3032, 2921, 2856, 1624, 1594, 1516, 1481, 1451, 1340, 1294, 2H-1,3-thiazine 2a (279 mg, 1.00 mmol), bromoacetic acid
1252, 1209, 905, 890, 856, 843, 751, 728, 707, 694, 633 cm−1
;
(139 mg, 1.00 mmol) and isocyanocyclohexane (109 mg,
1H NMR (500.1 MHz, CDCl3): δ 1.46–1.52 (1 H, m, CH2,Cy), 1.00 mmol) were used. Column chromatography (n-hexane–
1.66–1.88 (5 H, m, 3 CH2,Cy), 2.01–2.06 (2 H, m, 2 CH2,Cy), EtOAc, 7 : 3; Rf = 0.57) afforded the desired bisamide 5a
2.09–2.13 (2 H, m,
2
CH2,Cy), 7.25–7.26 [2 H, m,
2
(105 mg, 20%) as a colourless solid, mp 75 °C (from CH2Cl2–
o-CHAr(CCH)], 7.38–7.41 [2 H, m, 2 o-CHAr(CS)], 8.04 (1 H, s, n-hexane); IR (ATR) ˜ν 3058, 3037, 3021, 2974, 2941, 2931, 2854,
NCH), 8.07–8.09 [2 H, m, 2 m-CHAr(CS)], 8.08–8.11 [2 H, m, 2 1678, 1651, 1599, 1497, 1462, 1444, 1393, 1377, 1359, 1337,
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1
1205, 1162, 787, 763, 695 cm−1; H NMR (500.1 MHz, CDCl3): (p-CHAr), 130.10 (2 CHAr), 136.33 (CHCvC), 137.06 (CArCS),
δ 1.09–1.28 (3 H, m, 3 CH2,Cy), 1.31–1.46 (2 H, m, 2 CH2,Cy), 137.62 (CvOCAr), 137.93 (CH2CAr), 138.97 (CArCCH), 140.37
1.55–1.63 (2 H, m, 2 CH2,Cy), 1.68–1.70 (1 H, m, CH2,Cy), (CHCvC), 169.55 (CvOCH), 172.08 (CvOCAr) ppm; MS (ESI):
1.90–1.93 (1 H, m, CH2,Cy), 1.97–2.01 (1 H, m, CH2,Cy), 1.98, m/z 541.1 (M + Na+, 100%); HRMS (ESI): Found 541.1918, Calc.
2.05 [6 H, s, C(CH3)2], 3.77 (1 H, d, 2J = 10.9 Hz, CvOCH2), for C33H30N2NaO2S [M + Na]+ 541.1926.
2
3.82–3.91 (1 H, m, CHCy), 3.95 (1 H, d, J = 10.9 Hz, CvOCH2),
General procedure (GP C)
5.24 (1 H, s, NCHCvO), 6.12 (1 H, d, 3J = 8.3 Hz, NH),
7.16–7.24 (8 H, m, 8 CHAr), 7.29–7.31 (2 H, m, 2 CHAr) ppm; Under an argon atmosphere, the respective 2H-1,3-thiazine
13C NMR (125.8 MHz, CDCl3): δ 24.48, 24.66, 25.49 (3 CH2,Cy), (1.0 equiv.), dissolved in anhydrous CH2Cl2 (5 mL per mmol
26.26, 28.62 [C(CH3)2], 29.44 (CvOCH2), 32.47, 33.02 (2 CH2, thiazine), was cooled down to 0–5 °C. After addition of anhy-
Cy), 48.83 (NHCHCy), 67.38 (NCHCvO), 69.37 [C(CH3)2], 127.77 drous Et3N (2.0 equiv.), the respective acyl chloride
(p-CHAr), 128.53, 128.60, 128.82 (6 CHAr), 128.86 (p-CHAr), (1.0 equiv.), dissolved in anhydrous CH2Cl2 (5 mL per mmol
129.96 (2 CHAr), 135.10 (CHCvC), 136.83 (CArCS), 139.26 thiazine), was added dropwise. After stirring overnight at r.t.,
(CArCCH), 141.04 (CHCvC), 166.65 (CvOCH2), 168.03 the reaction mixture was poured into saturated aqueous NH4Cl
(CvOCH) ppm; MS (ESI): m/z 549.3 (M + Na+, 100%); HRMS solution (20 mL per mmol thiazine). The layers were separated
(ESI): Found 549.1176, Calc. for C27H31BrN2NaO2S [M + Na]+ and the organic phase was washed with water (20 mL per
549.1187.
mmol thiazine). The combined aqueous phases were extracted
(RS)-4-(N-(4-Chlorophenyl)carbamoyl)-2,2-dimethyl-5,6-di- with CH2Cl2 (2 × 20 mL per mmol thiazine). The combined
phenyl-3-(2-phenylacetyl)-3,4-dihydro-2H-1,3-thiazine (5b). Fol- organic phases were dried (MgSO4) and the solvent was
lowing GP B, 2H-1,3-thiazine 2a (10 mg, 0.07 mmol), removed on a rotary evaporator. The crude product was puri-
phenylacetic acid (10 mg, 0.07 mmol) and p-chloroisocyano- fied by column chromatography on silica gel.
benzene (10 mg, 0.07 mmol) were used. Column chromato-
(6R*,7R*)-2,2-Dimethyl-4,5,7-triphenyl-3-thia-1-azabicyclo-
graphy (n-hexane–EtOAc, 7 : 3; Rf = 0.44) afforded the desired [4.2.0]oct-4-en-8-one (6a). Following GP C, 2H-1,3-thiazine 2a
bisamide 5b (18 mg, 43%) as a yellow solid, mp 96 °C; IR (138 mg, 0.49 mmol), Et3N (99 mg, 0.98 mmol) and phenyl-
(ATR) ˜ν 3407, 3059, 3027, 2977, 2930, 1693, 1650, 1492, 1444, acetyl chloride (77 mg, 0.49 mmol) were used. Column chrom-
1375, 1304, 1163, 1090, 1030, 1013, 826, 757, 721, 693, 627, atography (CHCl3–n-hexane–toluene–MTBE, 4 : 3 : 2 : 1; Rf
=
579 cm−1; H NMR (500.1 MHz, CDCl3): δ 2.09, 2.16 [6 H, 2 s, 0.41) afforded the desired β-lactam 6a (95 mg, 49%) as a yellow
C(CH3)2], 3.78 (2 H, s, CH2), 5.44 (1 H, s, NCH), 6.98–7.01 (3 H, solid, mp 142 °C (from CH2Cl2–n-hexane); IR (ATR) ˜ν 3057,
m, 3 CHAr), 7.02–7.07 (4 H, m, 4 CHAr), 7.09–7.15 (3 H, m, 3 3027, 3007, 2972, 2934, 1751, 1599, 1494, 1454, 1442, 1155,
CHAr), 7.18–7.22 (3 H, m, 3 CHAr), 7.27–7.31 (4 H, m, 4 CHAr), 1136, 1117, 766, 754, 729, 702, 682 cm−1; 1H NMR (499.9 MHz,
7.40–7.42 (2 H, m, 2 NCArCHAr), 7.84 (1 H, s, NH) ppm; 13C CDCl3): δ 1.83, 2.14 [6 H, 2 s, C(CH3)2], 4.21–4.22 (1 H, m,
1
3
NMR (125.8 MHz, CDCl3): δ 26.96, 28.88 [C(CH3)2], 44.36 CHCAr), 4.44 (1 H, d, J = 1.8 Hz, NCH), 7.00–7.02 (2 H, m, 2 ×
(CH2), 67.44 (NCH), 69.47 [C(CH3)2], 121.35 (2 NCArCHAr), CHAr), 7.04–7.06 [2 H, m, 2 o-CHAr(CH)], 7.11–7.18 (8 H, m, 8
127.25, 127.65, 128.17, 128.49, 128.84, 128.92, 128.98, 129.27, CHAr), 7.21–7.27 (3 H, m, 3 CHAr) ppm; 13C NMR (125.7 MHz,
130.08 (17 CHAr), 134.04 (CH2CAr), 135.80 (CHCvC), 136.10 CDCl3): δ 26.28, 29.73 [C(CH3)2], 58.80 (NCH), 60.66 (CHCAr),
(NCAr), 136.94 (CArCS), 139.24 (CArCCH), 140.57 (CHCvC), 61.68 [C(CH3)2], 127.24 (p-CHAr), 127.46 (o-CHArCH), 127.68
168.05 (CHCvO), 171.47 (CH2CvO) ppm; MS (ESI): m/z 575.0 (p-CHAr), 127.76 (CHCvC), 127.94 (p-CHAr), 128.24, 128.46,
(M + Na+, 100%); HRMS (ESI): Found 575.1522; Calc. for 128.90, 129.56, 129.76 (10 CHAr), 133.66 (CHCvC), 134.99
C33H29ClN2NaO2S [M + Na]+ 575.1536.
(CArCH), 138.22, 138.76 (2 CAr), 166.50 (CvO) ppm; MS (ESI):
(RS)-3-Benzoyl-4-(N-benzylcarbamoyl)-2,2-dimethyl-5,6-di- m/z 398.2 (M + H+, 100%); HRMS (ESI): Found 398.2388; Calc.
phenyl-3,4-dihydro-2H-1,3-thiazine (5c). Following GP B, 2H- for C26H24NOS [M + H]+ 398.2394.
1,3-thiazine 2a (100 mg, 0.36 mmol), benzoic acid (44 mg,
(6R*,7R*)-7-Methoxy-2,2-dimethyl-4,5-diphenyl-3-thia-1-azabi-
0.36 mmol) and (isocyanomethyl)benzene (42 mg, 0.36 mmol) cyclo[4.2.0]oct-4-en-8-one (6b). Following GP C, 2H-1,3-thiazine
were used. Column chromatography (n-hexane–EtOAc, 7 : 3; 2a (200 mg, 0.72 mmol), Et3N (146 mg, 1.44 mmol) and
Rf = 0.35) afforded the desired bisamide 5c (55 mg, 31%) as an 2-methoxyacetyl chloride (78 mg, 0.72 mmol) were used.
orange oil; IR (ATR) ˜ν 3353, 3059, 3028, 2974, 2929, 1718, 1676, Column chromatography (CHCl3–toluene–n-hexane–MTBE,
1638, 1600, 1492, 1444, 1377, 1360, 1298, 1169, 754, 729, 6 : 2 : 1 : 1; Rf = 0.41) afforded the desired β-lactam 6b (187 mg,
694 cm−1 1H NMR (500.1 MHz, CDCl3): δ 2.16, 2.22 [6 H, s, 74%) as a yellow solid, mp 81 °C (from CH2Cl2–n-hexane);
;
C(CH3)2], 4.47 (1 H, dd, 2J = 14.8 Hz, 3J = 5.2 Hz, CH2), 4.57 IR (ATR) ˜ν 3086, 3058, 3033, 3006, 2970, 2943, 2924, 2841,
2
3
(1 H, dd, J = 14.8 Hz, J = 5.9 Hz, CH2), 5.29 (1 H, s, NCH), 1741, 1595, 1586, 1493, 1457, 1440, 1392, 1372, 1324, 1220,
6.26–6.29 (1 H, m, NH), 6.97–6.98 (2 H, m, 2 CHAr), 7.05–7.07 1206, 1131, 1122, 936, 913, 893, 851, 732, 705, 692, 666 cm−1
;
(2 H, m, 2 CHAr), 7.11–7.32 (16 H, m, 16 CHAr) ppm; 13C NMR 1H NMR (500.1 MHz, CDCl3): δ 1.80, 2.06 [6 H, 2 s, C(CH3)2],
3
(125.8 MHz, CDCl3): δ 26.76, 29.55 [C(CH3)2], 44.64 (CH2), 3.21 (3 H, s, OCH3), 4.42 (1 H, d, J = 1.5 Hz, NCH), 4.44 (1 H,
3
68.87 (CH), 69.39 [C(CH3)2], 125.89 (2 CHAr), 127.62 (p-CHAr), d, J = 1.5 Hz, CHOCH3), 7.04–7.06 (2 H, m, 2 CHAr), 7.11–7.19
127.82, 128.48, 128.49 (6 CHAr), 128.52 (p-CHAr), 128.56 (8 H, m, 8 CHAr) ppm; 13C NMR (125.8 MHz, CDCl3): δ 25.84,
(2 CHAr), 128.75 (p-CHAr), 128.79, 128.86 (4 CHAr), 129.32 29.14 [C(CH3)2], 57.67 (OCH3), 58.63 (NCH), 61.39 [C(CH3)2],
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87.65 (CHOCH3), 125.73 (CHCvC), 127.15, 127.91 (2 p-CHAr),
(RS)-2,2-Dimethyl-5,6-diphenyl-4-methoxy-3-(4-nitrobenzoyl)-
128.15, 128.35, 129.23, 129.54 (8 CHAr), 134.03 (CHCvC), 2H-1,3-thiazine (7a). Following GP D, 2H-1,3-thiazine 2a
137.72, 138.49 (2 CAr), 164.02 (CvO) ppm; MS (ESI): m/z 374.1 (1.321 g, 4.73 mmol), 4-nitrobenzoyl chloride (798 mg,
(M + Na+, 100%); HRMS (ESI): Found 374.1183, Calc. for 5.20 mmol), Et3N (689 mg, 8.28 mmol) and MeOH (661 mg,
C21H21NNaO2S [M + Na]+ 374.1191.
17.50 mmol) were used. Column chromatography (n-hexane–
diethyl ether–CH2Cl2, 7 : 2 : 1; Rf = 0.43) afforded the desired
methoxy amide 7a (1.294 g, 59%) as a yellow solid, mp 107 °C
Crystal structure determination of β-lactam 6b
Crystal data. C21H21NO2S, M = 351.45, monoclinic, a = (from CH2Cl2–n-hexane); Anal. Found: C, 68.12; H, 5.62; N,
15.9577(7), b = 6.3713(3), c = 17.8868(8) Å, U = 1804.89(14) Å3, 6.10; O, 13.62; S, 6.53. Calc. for C26H24N2O4S: C, 67.81; H, 5.25;
T = 120 K, space group P21/c, Z = 4, 75519 reflection measured, N, 6.08; O, 13.90; S, 6.96%; IR (ATR) ˜ν 3189, 3103, 3078, 3056,
7935 unique (Rint = 0.0291) which were used in all calculations. 3026, 2975, 2928, 2858, 1661, 1599, 1524, 1498, 1462, 1443,
The final wR(F2) was 0.1351 (all data).
1389, 1344, 1332, 1197, 1174, 1121, 908, 862, 756, 730, 713,
(6R*,7R*)-7-Methoxy-4,5-bis(4-methoxyphenyl)-3-thia-1-aza- 694 cm−1; H NMR (500.1 MHz, CDCl3): δ 2.17, 2.17 [6 H, 2 s,
spiro[bicyclo[4.2.0]octane-2,1′-cyclohexan]-4-en-8-one (6c). Fol- C(CH3)2], 3.33 (3 H, s, OCH3), 5.36 (1 H, s, NCH), 6.93–6.95
lowing GP C, 2H-1,3-thiazine 2j (85 mg, 0.22 mmol), Et3N (2 H, m, 2 CHAr), 7.11–7.23 (6 H, m, 6 CHAr), 7.32–7.34 (2 H,
(45 mg, 0.44 mmol) and 2-methoxyacetyl chloride (24 mg, m, 2 CHAr), 7.42–7.44 [2 H, m, 2 m-CHAr(NO2)], 8.07–8.09 [2 H,
0.22 mmol) were used. Column chromatography (CH2Cl2–n- m, 2 o-CHAr(NO2)] ppm; 13C NMR (125.8 MHz, CDCl3): δ 27.81,
hexane–toluene–MTBE, 4 : 3 : 2 : 1; Rf = 0.39) afforded the 29.48 [C(CH3)2], 54.97 (OCH3), 66.43 [C(CH3)2], 90.27 (NCH),
1
desired β-lactam 6c (64 mg, 64%) as a yellow oil; IR (ATR) 123.67
[2
o-CHAr(NO2)],
127.50
(p-CHAr),
128.18
˜ν 2998, 2934, 2855, 2836, 1753, 1604, 1507, 1462, 1442, 1291, [2 m-CHAr(NO2)], 128.35 (2 CHAr), 128.71 (2 CHAr), 128.73
1245, 1219, 1174, 1123, 1031, 1014, 909, 827, 800, 793, (p-CHAr), 128.78 (2 CHAr), 130.19 (2 CHAr), 132.73 (CHCvC),
1
728 cm−1; H NMR (500.1 MHz, CDCl3): δ 1.42–1.48 (1 H, m, 137.26 (CArCS), 138.69 (CHCvC), 138.92 (CArCCH), 143.01
CH2,Cy), 1.56–1.63 (2 H, m, 2 CH2,Cy), 1.68–1.73 (2 H, m, 2 (CArCvO), 148.54 (CArNO2), 170.03 (CvO) ppm.
CH2,Cy), 1.85–1.94 (2 H, m, 2 CH2,Cy), 2.04–2.09 (1 H, m, CH2,
(RS)-2,2-Dimethyl-4-methoxy-5,6-bis(4-methoxyphenyl)-3-(4-
Cy), 2.25–2.29 (1 H, m, CH2,Cy), 2.73–2.77 (1 H, m, CH2,Cy), 3.30 nitrobenzoyl)-2H-1,3-thiazine (7b). Following GP D, 2H-1,3-
(3 H, s, CHOCH3), 3.73 [3 H, s, CHCPhOCH3], 3.74 [3 H, s, thiazine 2i (1.500 g, 4.42 mmol), 4-nitrobenzoyl chloride
3
3
SCPhOCH3], 4.30 (1 H, d, J = 1.5 Hz, NCH), 4.44 (1 H, d, J = (798 mg, 4.86 mmol), Et3N (689 mg, 7.74 mmol) and MeOH
1.5 Hz, CHOCH3), 6.68–6.72 [4 H, m, m-CHAr(CS), (661 mg, 16.35 mmol) were used. Column chromatography
2
2 m-CHAr(CCH)], 6.93–6.96 [2 H, m, 2 o-CHAr(CCH)], 7.06–7.08 (n-hexane–diethyl ether–CH2Cl2, 5 : 3 : 2; Rf = 0.37) afforded the
[2 H, m, 2 o-CHAr(CS)] ppm; 13C NMR (125.8 MHz, CDCl3): desired methoxy amide 7b (1.885 g, 82%) as a yellow solid, mp
δ 22.64, 22.70, 25.23, 34.44, 36.67 (5 CH2,Cy), 55.24, 55.28 112 °C (from CH2Cl2–n-hexane); Anal. Found: C, 64.56; H,
(2 CArOCH3) 57.59 (CHOCH3), 58.04 (NCH), 65.69 [C(CH2)2], 5.68; N, 5.36; O, 18.51; S, 5.89. Calc. for C28H28N2O6S: C, 64.60;
87.63 (CHOCH3), 113.69 [2 m-CHAr(CCH)], 113.83 [2 H, 5.42; N, 5.38; O, 18.44; S, 6.16%; IR (ATR) ˜ν 3034, 2933,
m-CHAr(CS)], 124.71 (CHCvC), 130.39 [CArCS, 2 o-CHAr(CCH)], 2837, 1660, 1602, 1524, 1508, 1462, 1442, 1393, 1345, 1292,
131.03 [2 o-CHAr(CS)], 131.18 (CArCCH), 132.43 (CHCvC), 1246, 1174, 1030, 910, 860, 834, 731, 633 cm−1 1H NMR
;
158.39 [p-CAr(CCH)], 159.16 [p-CAr(CS)], 164.81 (CvO) ppm; (500.1 MHz, CDCl3): δ 2.13, 2.15 [6 H, 2 s, C(CH3)2], 3.32 (3 H,
MS (ESI): m/z 474.1 (M + Na+, 100%); HRMS (ESI): Found s, CHOCH3), 3.75, 3.77 (6 H, 2 s, 2 CArOCH3), 5.29 (1 H, s,
474.1717, Calc. for C26H29NNaO4S [M + Na]+ 474.1715.
NCH), 6.65–6.68 [2 H, m, 2 m-CHAr(CS)], 6.72–6.75 [2 H, m,
2 m-CHAr(CCH)], 6.86–6.89 [2 H, m, 2 o-CHAr(CCH)], 7.26–7.29
[2 H, m, 2 o-CHAr(CS)], 7.45–7.47 [2 H, m, 2 m-CHAr(NO2)],
General procedure (GP D)
Under an argon atmosphere, the respective 2H-1,3-thiazine 8.10–8.12 [2 H, m, 2 o-CHAr(NO2)] ppm; 13C NMR (125.8 MHz,
(1.0 equiv.), dissolved in anhydrous CH2Cl2 (5 mL per mmol CDCl3): δ 27.59, 29.28 [C(CH3)2], 54.83 (CHOCH3), 55.33, 55.34
thiazine), was cooled down to 0–5 °C. A solution of the respect- (2 CArOCH3), 66.44 [C(CH3)2], 90.38 (NCH), 113.81
ive acyl chloride (1.1 equiv.) in anhydrous CH2Cl2 (5 mL per [2
m-CHAr(CCH)],
114.16
[2
m-CHAr(CS)],
123.65
mmol thiazine) was added dropwise. After stirring overnight at [2 o-CHAr(NO2)], 128.18 [2 m-CHAr(NO2)], 129.66 (CArCCH),
r.t., a solution of anhydrous MeOH (3.7 equiv.) and anhydrous 130.03 [2 o-CHAr(CCH)], 130.94 (CHCvC), 131.26 (CArCS),
Et3N (1.75 equiv.) in anhydrous CH2Cl2 (5 mL per mmol thia- 131.48 [2 o-CHAr(CS)], 137.36 (CHCvC), 143.17, 148.51
zine) was added dropwise at 0–5 °C. After stirring overnight at (CArNO2, CArCvO) 158.73 [p-CAr(CS)], 159.84 [p-CAr(CCH)],
r.t., the reaction mixture was poured into ice-water (20 mL per 169.94 (CvO) ppm.
mmol thiazine). The layers were separated and the aqueous
phase was extracted with CH2Cl2 (3 × 10 mL per mmol thia-
zine). The combined organic phases were washed with satu-
rated aqueous NaHCO3 solution (20 mL per mmol thiazine)
Notes and references
and water (20 mL per mmol thiazine) and dried (MgSO4). The
solvent was removed on a rotary evaporator and the crude
product was purified by column chromatography on silica gel.
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Organic & Biomolecular Chemistry
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