Synthesis of Thiazinoimidazoles by Lewis Acid–Catalyzed [3+3] Cycloaddition Reactions of Propargyl Alcohols with 2-Mercaptoimidazoles

Article abstract of DOI:10.1002/ejoc.201900367

The unique ytterbium-catalyzed generation of sulfur- and selenium-substituted propargylic and allenic cations and their reactions with 2-mercaptoimidazole derivatives were described. The regioselective [3+3] annulation reactions proceeded to give a wide variety of S,N-acetal-containing bicyclic and tricyclic thiazinoimidazoles in good to high yields. Treatment of thiazinoimidazoles with LDA readily underwent ring contraction to afford thiazolobenzimidazoles. Deselenenylation and successive functionalization broaden the scope of accessible thiazinoimidazoles.

Full text of DOI:10.1002/ejoc.201900367

DOI: 10.1002/ejoc.201900367
Communication
[3+3] Cycloaddition
Synthesis of Thiazinoimidazoles by Lewis Acid–Catalyzed [3+3]
Cycloaddition Reactions of Propargyl Alcohols with 2-
Mercaptoimidazoles
Naoya Mishima,[a] Takahiro Ogawa,[a] Genzoh Tanabe,[b] Osamu Muraoka,[b]
Hiroaki Wasada,[c] Noriyuki Hatae,[d] and Mitsuhiro Yoshimatsu*[a]
Abstract: The unique ytterbium-catalyzed generation of sulfur- and tricyclic thiazinoimidazoles in good to high yields. Treat-
and selenium-substituted propargylic and allenic cations and ment of thiazinoimidazoles with LDA readily underwent ring
their reactions with 2-mercaptoimidazole derivatives were de- contraction to afford thiazolobenzimidazoles. Deselenenylation
scribed. The regioselective [3+3] annulation reactions pro- and successive functionalization broaden the scope of accessi-
ceeded to give a wide variety of S,N-acetal-containing bicyclic ble thiazinoimidazoles.
Introduction
Propargyl alcohol is a good tool for the generation of both
propargyl and allenic cations, which were extensively investi-
gated to achieve the regioselective carbon–carbon, carbon–
oxygen, carbon–nitrogen, and carbon–sulfur bond formation
reactions (Scheme 1). Nicholas reactions using alkyne–cobalt
complexes are one of the most well-known processes and dra-
matically enhance their stabilities by dicobalt–hexacarbonyl
complex.[1] Two decades' progress in this field has explored the
catalytic processes for propargyl and allenic substitutions and
their further transformations from useful alcohols or their syn-
thetic equivalents.[2] In particular, Watts and Müller independ-
ently provided Nicholas-type intermediates stabilized by ferro-
cene[3] and chromium complexes.[4] Dramatic progress in the
catalytic propargylations has been achieved by Uemura and
Nishibayashi's protocols using ruthenium–allenilidene com-
plexes.[5]
Scheme 1. Propargyl alcohols as a good tool for a wide variety of hetero-
cycles.
pyrroles,[8] isoxazoles,[9] indoles,[10] pyrrazoles,[11] oxazoles,[12]
and thiazoles.[13] In general, the six-membered ring formations
are only relevant cyclization models, except the rarer example,
the [3+3] annulation for pyrimidine synthesis by copper triflate-
catalyzed process.[14] We previously reported the Lewis acid-
catalyzed cyclization of sulfur- and selenium-substituted prop-
argyl alcohols with thioamides and selenamides.[13] The excel-
lent sulfur- and selenium-functional groups on the alkyne ter-
mini can effectively stabilize the corresponding cations and re-
act with thioamides and selenamides, respectively, to provide
thiazoles and selenazoles through their intermolecular [3+2]
cycloaddition reactions. In this process, sulfur-substituted prop-
argyl alcohols could act as a carbon electrophile (C=C+ synthon)
in Lewis acid-catalyzed cycloaddition reactions with thioamides
as a S–C–N synthon. However, our continuing study in this field
leads to a new finding that the propargyl alcohols could also
play an important role as a carbon electrophile (C=C–C+ syn-
Results and Discussion
Recent advances enable catalytic propargylation and allenyl-
ation, which are excellent tools for heterocycle synthesis.[6] Usu-
ally, most alcohols act as two carbon electrophiles in the [3+2]
annulations for five-membered heterocycles, such as furans,[7]
[a] Department of Chemistry, Faculty of Education Gifu University
Yanagido 1-1, Gifu 501-1193, Japan
E-mail: yoshimae@gifu-u.ac.jp
[b] Faculty of Pharmaceuticy, The Kindai University,
Kowakae 3-4-1, Higashi-osaka, Osaka 577-8502, Japan
[c] Department of Chemistry, Faculty of Regional Study, Gifu University
Gifu, Japan
[d] School of Pharmaceutical Sciences, Health Science University of Hokkaido,
Ishikari-Tobetsu, Hokkaido 061-0293, Japan
Supporting information and ORCID(s) from the author(s) for this article are
available on the WWW under https://doi.org/10.1002/ejoc.201900367.
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Communication
thon). Here we report the Lewis acid-catalyzed [3+3] annulation would undergo [3+3] annulation rather than usual [3+2] annu-
reaction of sulfur- and selenium-substituted propargyl alcohols lation reactions to give 4-(4-methoxyphenyl)-2-(phenylthio)-4H-
with three types of 2-mercaptoimidazoles as novel fused 1,3- [1,3]thiazino[3,2-a]benz-imidazole (2a). As the unique structure
thiazines as pharmacore[15] (Scheme 2).
of thiazinoimidazole was found to be rarer, we screened the
suitable reaction conditions: solvents and Lewis acids (Table 1).
From the results of entries 2–5, both DCE and nitromethane
were found to be suitable for the cycloaddition reactions.
Lanthanoide metals like ytterbium and lanthanum triflate effec-
tively played an important role in the thiazine synthesis. How-
ever, common Lewis acids such as boron trifluoride diethyl
ether and tin(II) triflate were not suitable for the cycloadditions.
Furthermore, tetrabutylammonium hydrogensulfate is neces-
sary for the completion of the reactions.
With the optimized reaction conditions in hand, we next
examined the substrate scope of sulfur-substituted propargyl
alcohols 1, as shown in Table 2. The study on the substituent
Table 2. Substrate scope.
Scheme 2. Cycloadditions of propargyl cations stabilized by sulfur- and selen-
ium-functional groups with 2-mercaptoimidazoles.
We first prepared the sulfur-substituted propargyl alcohols
1a–j and 1r–t from the nucleophilic addition reactions of aro-
matic and heteroaromatic aldehydes and ketones according to
our previous methods.[11a,11b,13a,13b,16] The selenium analogs
1k–p were also prepared by almost the same method. In ac-
cordance with our previous thiazole synthesis,[13a,13b] we se-
lected a suitable partner 1a for the Lewis acid- catalyzed reac-
tion with 2-mercaptobenzimidazole: scandium triflate as the
Lewis acid and nitromethane as the solvent, at 100 °C (entry 1,
Table 1). The reaction was completed in 2.5 h, and the product
2a was obtained in relatively good yield. The 1H NMR spectrum
of 2a showed two doublets at δ = 6.16 and 6.52 (J = 4.8 Hz)
ppm due to the vicinal protons of thiazine ring. The fact shows
that the Lewis acid-catalyzed cycloaddition reaction of sulfur-
substituted propargyl alcohols with 2-mercaptoimidazole
entry
Alcohol R1
R2
R3
2MID
Products[a]
(% yield)
1
2
3
4
5
6
7
8
1b
1c
1d
1e
1f
1g
1h
1i
1j
1k
1l
1m
1n
1o
1p
1q
1r
Ph
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
PhS
PhS
PhS
PhS
PhS
PhS
PhS
PhS
PhS
PhS
PhSe
PhSe
PhSe
PhSe
PhSe
PhSe
PhS
PhS
PhS
PhSe
Ph
PhS
PhS
PhS
PhS
PhS
PhS
PhSe
PhSe
PhS
PhS
PhS
PhSe
PhS
PhS
PhSe
MBI
MBI
MBI
MBI
MBI
MBI
MBI
MBI
MBI
MBI
MBI
MBI
MBI
MBI
MBI
MBI
MBI
MBI
MBI
MBI
MBI
MI
MI
MI
MI
MI
MI
MI
MI
MI
MI
MI
MI
TID
TID
TID
2b (81)
2c (70)
2d (66)[b]
2e (73)[b]
2f (87)
2g (89)
2h (91)
2i (96)
2j (93)
2k (77)
2l (70)
2m (54)
2n (96)
2o (56)[b]
2p (84)
2q (81)
2r (48)
2s (85)
2t (87)
2u (10)
2v (–)
3a (92)
3c (70)
3d (61)
3e (85)
3f (79)
3i (87)
3l (92)
3n (67)
3r (49)
3s (83)
3t (73)
3w (72)
4a (66)
4h (31)
4l (75)
pFC6H4
pClC6H4
pBrC6H4
3,4-(MeOC6H3)
2-furyl
2-thienyl
oMeOC6H4
m
9
MeOC6H4
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
3,4(OCH2O)C6H3
pMeOC6H4
pClC6H4
oMeOC6H4
pBrC6H4
2-furyl
2-thieyl
–(CH2)4-
Table 1. Screening of reaction condition.
1s
1t
–(CH2)5-
–(CH2)6-
1u
1v
1a
1c
1d
1e
1f
1i
1l
1n
1r
1s
1t
O2NC6H4
Ph
H
H
H
H
H
H
H
H
H
H
pMeOC6H4
pFC6H4
pClC6H4
entry
solvent
Lewis acids
(equiv.)
T [°C], time
Product
pBrC6H4
(% yield)[b]
3,4-(MeO)2C6H3
oMeOC6H4
pMeOC6H4
oMeOC6H4
–(CH2)4-
[a]
1
2
3
4
5
6
7
8
9
MeNO2
MeNO2
DCE
Sc(OTf)3 (0.1)
Sc(OTf)3 (0.1)
Sc(OTf)3 (0.1)
Sc(OTf)3 (0.1)
Sc(OTf)3 (0.1)
Yb(OTf)3 (0.1)
BF3Et2O (0.2)
La(OTf)3 (0.1)
Sn(OTf)2 (0.1)
Mg(OTf)2 (0.1)
100, 2.5 h
100, 15 min
85, 10 min
100, 10 min
100, 10 min
85, 10 min
85, 10 min
85, 2 h
81
67
84
67
54
95
24
74
dioxane
toluene
DCE
–(CH2)5-
–(CH2)6-
DCE
DCE
DCE
DCE
1w
1a
1h
1i
–(CH2)5-
pMeOC6H4
2-thienyl
pMeOC6H4
H
H
H
85, 10 min
85, 3 h
50
mixture
10
[a] H2O was added. [b] Yields of isolated product.
[a] Yields of isolated product. [b] The reaction was performed at 50 °C.
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on propargyl alcohols revealed that phenyl- and p-fluoro-
phenylpropargyl alcohols afforded thiazines 2b–c in high yields
(entries 1 and 2). However, the similar reactions of p-chloro-
phenyl alcohol 1d gave a complex mixture. The reaction of p-
bromophenyl derivatives 2e has given almost the same result.
Therefore, we performed the same reactions of both 1d–e at
50 °C succeeded to give the thiazine 2d–e; however, the yields
of products were moderate (entries 3 and 4).
When 3,4-dimethoxyphenyled alcohol 1f underwent regio-
selective cycloaddition to lead the exclusive formation of thiaz-
inoimidazole 2f (entry 5). Heteroaromatic analogs, such as furan
and thiophene, could give 2g–h in high yields (entries 6 and
7). o-and m-substituted arylthiazines 2i–j were also obtained in
excellent yields (entries 8 and 9). Moreover, the bicyclic hetero-
aromatic 3,4-methylenedioxyphenyl derivative 2k was also ob-
tained in 77 % yield (entry 10). Next, we examined the reactions
of 3-phenylselenopropargyl alcohols 1l–q with 2-mercapto-
benzoimidazole under similar reaction conditions (entries 11–
15). Most of 2-(phenylseleno)thiazines 2l–q were also obtained
in good yields. The similar tendency is that the halo-substituted
phenyl propargyl alcohols 1m and 1o would provide thiazine
2m and 2o formation in moderate yields (entries 23 and 24).
Unfortunately, the nitrophenyled propargyl alcohol 1u gave
product 2u in low yield (entru 20). To elucidate the sulfur- and
selenium-stabilizing effects in the thiazine formation, we per-
formed the reaction of 1,3-diphenyl propargyl alcohol 1v with
2-mercaptobenzoimidazole; however, any cycloadduct was not
observed (entry 21). The quaternary alcohols, such as 1-phenyl-
sulfanylcycloalkanols 1r–w, succeeded in giving spirothiazine
derivatives 2r–w in moderate to high yields (entries 30–33).
Scheme 3. Mechanistic investigation.
sulfur and selenium atoms and reacts with 2-mercaptoimidaz-
ole in a regioselective manner to give S-allenylimidazo-2-yl in-
termediate 9 or N-propargyl-2-mercapto-imidazole 10. The
intramolecular cyclization of either 9 or 10 would proceed via
the 6-endo-dig mode and the successive protonation to give
To confirm both the structure of thiazines and the mecha-
nism for [3+3] cycloaddition reaction of sulfur- and selenium-
substituted propargyl alcohols with 2-mercaptoimidazoles, we
performed some experiments, and the results were shown in
Scheme 3. Base-promoted isomerization of 2H-[1,3]thiazino-
[3,2-a]benzimidazole to 4H-derivatives 5a–h was observed. For-
tunately, the single X-ray analysis of 5c, which was obtained as
pure crystals, disclosed the unique fused ring system as shown
in the ORTEP drawing. Furthermore, we conducted the ytter-
bium-catalyzed reactions of both 2a and 2d in order to confirm
the possibility of either isomerization or ring contraction; how-
ever, most of thiazines were recovered. When we performed
the [3+3] annulation reaction of 1a in [D3]nitromethane/D2O,
thiazine 2a deuterated at 3-position was obtained in 44 % DD.
Based on these results and our previous mechanistic investiga-
tions for the thiazole synthesis, we could not determine
whether the first addition of 2-mercaptoimidazole toward the
cationic intermediates would occur either between the allenic
cation and the sulfur atom of 2-mercaptoimidazoles or between
the propargylic cation and the nitrogen atom of 2-mercaptoim-
idazoles.[13b] However, the intramolecular cyclization and the
successive protonation would proceed the thiazine derivatives
from these experimental results.
The plausible mechanism for the formation of products is
shown in Scheme 4. Dehydration of sulfur- and selenium-substi-
tuted propargyl alcohol 1 proceeds via 7 to give the propargyl
cation 8p, and its tautomer allenyl cation 8a is stabilized by α-
Scheme 4. Proposed mechanism.
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Communication
the thiazinoimidazole 11. However, we previously confirmed
The antiproliferative activity of these new compounds
that the thiazole synthesis using sulfur- and selenium-substi- against HCT-116 colon tumor cells was assessed, and the data
tuted propargylic cations with thioamides or selenamides are shown in Table 3. At the treatment of 100 μ analogs, the
M
would proceed via the sulfur attack of thioamides toward the 3a, 3s, 3t, and 16a almost inhibited cell viability completely.
allenyl carbon of 8a confirmed by the deuterium experiments, The analog 2h decreased tumor cell viability to the half level
except the 1,1-diarylpropargyl alcohols. On the other hand, the and indicated the antiproliferative activity with lower concen-
5-exo-mode cyclization of 9 and protonation of 13 give the tration.
thiazole 14. We have not isolated the thiazoles in this annula-
tion system, and the reactions would proceed via the 6-endo-
dig mode to give the thiazine derivatives because of the angles
Table 3. Antiproliferative activities of synthesized thiazine and thiazole deriva-
tives against HCT-116 cells.
of the second attack of fixed 2-mercaptoimidazoles. Whether
this thiazine formation could not be accompanied by the thiaz-
ole formation in the reactions of both p-chloro- and p-bromo-
propargyl alcohols with 2-mercaptobenzimidazole remains un-
clear. Tetrabutylammonium hydrogensulfate would play an im-
portant role in the ytterbium-catalyzed generation of propadi-
enyl cations.
The synthetic utilization of thiazines was examined using
benzimidazole derivative 2 as shown in Scheme 5. We have
already described above the base-promoted isomerization of
thiazines and further investigated the reactions with other
bases, such as LDA or nBuLi. The reaction of 2k with LDA sur-
prisingly afforded the ring-contracted thiazole 15k. The unique
ring contraction proceeded in the treatment of 6,7,8,9-tetra-
hydro-4H-[1,3]thiazino[3,2-a]benzimidazole (4a) with LDA. The
transmetalation of 2-seleno-1,3-thiazine with nBuLi proceeded,
and the successive hydration gave 17a. The successive methyl-
ation with iodomethane afforded 17b in good yield. The useful
selenium-substituted spirothiazines were also converted into
the no-selenium-thiazines 18a–b by the sequential transmeta-
lation-alkylation process. Our unique [3+3] annulation reactions
produced a new type of two and three ring-fused thiazines.
Furthermore, some transformations afforded another function-
alized thiazines 21a. Surprisingly, the reactions with DMAD
afforded the thiopyrans 19a and 20 accompanied by debenzo-
imidazolylation.
Conclusions
In summary, we have disclosed a new Lewis acid-catalyzed
[3+3] annulation reaction of sulfur- and selenium-substituted
propargyl alcohols with 2-mercaptoimizaoles. The protocol is an
exclusive formation of thiazines and shows a wide variety of
substrate scope. Three types of 2-mercatoimidazoles of the
sulfur- and selenium-substituted propargyl alcohols succeeded
to afford 35 kinds of thiazines in good to high yields. We are
currently investigating the syntheses of other heterocycles us-
ing the Lewis acid-catalyzed sulfur- and selenium-substituted
Scheme 5. Transformation of 2.
propargyl alcohols.
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Experimental Section
2a: To a 1,2-dichloroethane (0.600 mL) solution of 1a (20.0 mg,
0.074 mmol), 2-mecaptobenzimidazole (22.0 mg, 0.148 mmol) and
tetrabutylammonium hydrogensulfate (5.00 mg, 0.015 mmol) was
added ytterbium triflate (4.00 mg, 0.007 mmol) at room tempera-
ture. The reaction mixture was heated at 85 °C for 10 min. The
almost same procedure as that of entry 1 and purification by pre-
parative TLC gave 2a (28 mg, 95 %) as white powders. Mp. 166–
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1
168 °C (CH2Cl2/n-hexane), H NMR (600 MHz, CDCl3): δ = 3.76 (3H,
s, MeO), 6.16 (1H, d, J = 4.8 Hz, CH), 6.52 (1H, d, J = 4.8 Hz, CH),
6.85 (2H, d, J = 8.9 Hz, ArH), 7.03 (1H, d, J = 8.3 Hz, ArH), 7.06–7.09
(1H, m, ArH), 7.17–7.22 (3H, m, ArH), 7.29–7.32 (3H, m, ArH), 7.42
(1H, d, J = 6.9 Hz, ArH), 7.63 (1H, d, J = 7.5 Hz). 13C NMR (150 MHz,
CDCl3): δ = 55.2 (q), 59.2 (d), 109.8 (d), 114.7 (d × 2), 118.6 (d), 122.2
(d), 122.7 (d), 123.0 (s), 126.2 (d), 127.6 (d × 2), 128.1 (d), 129.3 (d
× 2), 130.7 (d × 2), 132.1 (s), 133.7 (s), 143.5 (s), 145.1 (s), 159.8 (s).
IR (ATP): ν = 3053, 3003, 2955, 2928, 2835, 1710, 1609, 1583, 1510,
˜
1476, 1440, 1392, 1351, 1335, 1305, 1253, 1218, 1175, 1153, 1113,
1032, 958, 906, 856, 831, 740, 689, 568, 528 cm–1; EIMS m/z 402
(M+), 293 (M+ – SPh). Anal. Calcd for C23H16N2OS2 + 1/4H2O: C,
67.94; H, 4.59; N, 6.89; found C, 67.89; H, 4.49; N, 6.86.
CCDC 1898519 (for 5c) contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge from
The Cambridge Crystallographic Data Centre.
Keywords: Thiazines · [3+3] Annulation · Cycloaddition ·
Mercaptoimidazoles · Ring contraction
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Received: March 6, 2019
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© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Communication
[3+3] Cycloaddition
N. Mishima, T. Ogawa, G. Tanabe,
O. Muraoka, H. Wasada, N. Hatae,
M. Yoshimatsu* ................................... 1–6
Synthesis of Thiazinoimidazoles by
Lewis Acid–Catalyzed [3+3] Cyclo-
addition Reactions of Propargyl Al-
cohols with 2-Mercaptoimidazoles
Fused thiazinoimidazole synthesis 2-mercaptoimidazoles. The reactions
from the sulfur- and selenium-substi- were regioselective, atom economical,
tuted propargyl alcohols with 2-mer- and versatile. Further transmetalation
captoimidazoles were reported. The and the successive hydration and alk-
protocol is utilized for [3+3] annulation ylation could provide the more useful
reactions of a wide variety of prop- thiazines.
argyl alcohols with three types of
DOI: 10.1002/ejoc.201900367
Eur. J. Org. Chem. 0000, 0–0
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© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim