Tetrahedron Letters 54 (2013) 6469–6473

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Tetrahedron Letters

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Masked mercapto acid-driven MCR in task-specific ionic liquid:a new sterocontrolled entry into bicyclic 1,3-thiazines

0040-4039/$ - see front matter � 2013 Elsevier Ltd. All rights reserved.http://dx.doi.org/10.1016/j.tetlet.2013.09.068

⇑ Corresponding author. Tel.: +91 757 717 8627.E-mail address: vijaikrai@hotmail.com (V.K. Rai).

N

S

NH2/NHRO

S

OH

OHOH

N

S

NH2/NHRO

HS

OH

OHOH

CHOH

HO

CH2OH3

S

OPh O

[Bmim]SCN

AcONH4/RNH2

FourComponent

coupling

Me

Scheme 1. Retrosynthetic strategy for target 1,3-thiazines.

S

OPh

O

OHOH

3S

OPh

O

OHOH

4

A B

Me Me

Figure 1. Designed enone.

Vijai K. Rai a,⇑, Prashant Kumar Rai b, Yogita Thakur a

a Department of Chemistry, Guru Ghasidas Vishwavidyalaya, Bilaspur, Chhattisgarh 495 009, Indiab Department of NMR, All India Institute of Medical Sciences, New Delhi 110 029, India

a r t i c l e i n f o a b s t r a c t

Article history:Received 16 June 2013Revised 14 September 2013Accepted 16 September 2013Available online 21 September 2013

Keywords:Multi-component reactionThiosugar1,3-ThiazineIonic liquidCarbohydrate

An unprecedented multi-component reaction for the synthesis of thiosugar-annulated 1,3-thiazines isreported. The envisaged synthetic strategy involves the reaction of D-glucose/D-xylose and 2-methyl-2-phenyl-1,3-oxathiolan-5-one with AcONH4/RNH2 in task specific ionic liquid (TSIL), [bmim]SCN whichafforded thiosugar annulated 1,3-thiazines in excellent yields (83–93%). The reaction is effected via ionicliquid promoted Michael addition followed by mercaptoacetylative ring transformation in a one-pot pro-cedure and the ionic liquid, [bmim]OH could be easily recycled for further use without any loss of effi-ciency and be used for the synthesis of [bmim]SCN, thus allowing recycling of the TSIL for further use.

� 2013 Elsevier Ltd. All rights reserved.

Sugars incorporating intracyclic sulfur atom (thiosugars) arehighly interesting. For example, 5-thio-D-glucose is a a-glycosidaseinhibitor,1 and some 5-thioglycosidases have antithromboticeffect2 and other useful medicinal properties.3 Many naturallyoccurring thiosugars are potential targets for the carbohydrate-based therapeutics, such as thiolactomycin, salacinol, kotalonol,tagetioxin, and mycothiol.3 The biological interest in thiosugarshas expanded the studies on diabetes enzyme inhibitor, antiviral,and antitumour activities.4–9 Moreover, the 1,3-thiazine skeletonis the active core of cephalosporins, which are the most widelyused b-lactam antibiotics and its derivatives possess remarkablebiological activities such as antibacterial, antitumour, insecticide,and fungicide.10–12 These are also known as anti-radiation agentsand used as radiation-sickness drugs.13 From chemical viewpoint,1,3-thiazines also serve as intermediate as well as substrates forsynthetic transformations.10b,14,15 Owing to their chemical andbiological interest, the literature records a number of syntheticprotocols for the synthesis of various 1,3-thiazine derivatives.10,16

Our initial strategy involved the preparation of the 2-amino-5-mercapto-1,3-thiazine ring containing a sugar chain, whichunderwent intramolecular thia-heterocyclization to annulate thethiosugar moiety on the 1,3-thiazine ring (Scheme 1). Limitedefforts have been made for the synthesis of 1,3-thiazinesusing a,b-unsaturated carbonyl systems,10b,11,17,18 particularly,2-amino-1,3-thiazines from a,b-unsaturated carbonyl system.18

Prompted by this valid fact, we aimed to design and utilize suchtype of a,b-unsaturated carbonyl system (Fig. 1A and B), whichcould not only introduce a –SH group but also install a sugar tailinto the 2-amino-1,3-thiazine ring to construct the thiosugar ringinto target molecules 5 and 6. For this purpose, we tried mercapto-acetic acid in the present synthetic protocol for construction of thedesigned a,b-unsaturated carbonyl building block (Fig. 1A and B),

Table 1Optimization of reaction conditions for tandem Knoevenagel-hydrothiocyanationstepa

S

OPh OCHOH

HO

CH2OH3

1 2

KSCN/IL

orTSIL

S

OPh O

CHOHCH2OH

SN

3

Me Me

7a

Entry IL KSCN Timeb (h) Yieldc,d (%)

1 OHNN KSCN 8 48

2 BrNN KSCN 8 45

3 ClNN KSCN 10 42

4 BF4

NN KSCN 8 46

5 PF6

NN KSCN 10 49

6 SCNNN — 5 89

a For the experimental procedure, see Ref. 26.b Time required for completion of the reaction as monitored by TLC.c Isolated yield.d Compound was characterized by spectral (IR, 1H NMR, 13C NMR, and EIMS) data.

Table 2Microwave (MW) assisted synthesis of 5a

Entry Catalyst Timea (min) Yieldb,c (%)

1 Silica gel 21 202 Neutral alumina 25 153 Acidic alumina 25 124 Basic alumina 25 —5 CeCl3�7H2O 18 396 CeCl3�7H2O/NaI 18 487 K-10 clay 18 44

a Stirring time at room temperature.b Isolated yield.c Compound was characterized by spectral (IR, 1H NMR, 13C NMR, and EIMS) data.

6470 V. K. Rai et al. / Tetrahedron Letters 54 (2013) 6469–6473

but were unsuccessful, probably due to the presence of free –SHand –COOH groups of mercaptoacetic acid. Then we masked themercaptoacetic acid and thus activating its methylene group byconverting it into 2-methyl-2-phenyl-1,3-oxathiolan-5-one(Scheme 2),19 which not only acted as mercaptoacetyl transferagent for the construction of the thiosugar ring but also provideda completely new route to the target thiosugar annulated 2-ami-no-1,3-thiazines 5 and 6.

Herein, we report an original and practical route to thiosugarannulated 2-amino-1,3-thiazines 5 and 6 starting from D-xylose/D-glucose 1 as biorenewable resource in a task specific ionic liquid,[bmim]SCN 3 (Scheme 3), which is hitherto unreported and are notaccessible through any one of the known synthetic routes for 1,3-thiazines.10,16–18 The present synthesis of functionalized 1,3-thia-zines results from our quest for methodology developmentemploying green protocols,20–24 especially using ionic liquids.20,21

Furthermore, the present synthetic protocol is in accord with‘renewable resources’, a new and rapidly developing concept inenvironmental and chemical sciences that concerns the wide useof biorenewable materials for industry.25

In our preliminary experimentation, a model experiment for theinitial hydrothiocyanation step was carried out by taking D-xylose1, 2-methyl-2-phenyl-1,3-oxathiolan-5-one 2, and KSCN as sub-strates in a variety of room temperature ionic liquids (RTIL)(Table 1, entries 1–4) and b-thiocyanato derivative 7a wasobtained but yield was only moderate (42–49%) even after longreaction time (8–10 h). This is perhaps due to low nucleophilicityof the SCN anion at room temperature which requires rather harshreaction conditions. Then, we turned our attention to utilize[bmim]SCN 3 and it evidenced its catalytic efficacy affording thetarget compound 7 in excellent yield (Table 1, entry 6). No columnchromatography and crystallization were required thus avoidingthe possibility of rearrangement of thiocyanates 7 to thermody-namically favored isothiocyanates.

Then, we investigated the optimization of the reaction condi-tions for one-pot synthesis of the target compounds 5 and 6. Here,a controlled one-pot reaction was carried out using D-xylose 1, 2-methyl-2-phenyl-1,3-oxathiolan-5-one 2, AcONH4OAc 4, and[bmim]SCN 3 as model substrates and the result validated our pre-mise that [bmim]SCN would not only expedite the required hyd-rothiocyanation step, but also catalyze the mercaptoacetylativering transformation step in the present one-pot reaction to affordthe target compounds 5 and 6 in higher yields to our satisfaction.

CHOH

HO

CH2OH1

S

OPh O

2

NNS3

r. t.n

n = 3,4

AcONH4

RNH2

or

4

Me

-PhCOM

Scheme 3. Synthesis of thiosugar-annulated 1,3-thiazines 5 and 6. Reactants; D-xylos[bmim]SCN 3 (6.0 mmol), AcONa or amine 4 (5.0 mmol), reaction time; 7–85 h, yield; 8

S

OPh OMe

HS CO2HMe

O

LiBr-H2O

Scheme 2. Formation of the masked mercapto acid, 2-methyl-2-phenyl-1,3-oxathiolan-5-one.

Thus, the envisaged synthetic strategy for the target thiosugarannulated 1,3-thiazines 5 and 6 was successful by stirring amixture of D-xylose/D-glucose 1, 2-methyl-2-phenyl-1,3-oxathio-lan-5-one 2, AcONH4, or an amine 4 in [bmim]SCN 3 at roomtemperature for 7–8.5 h (Scheme 3, Table 3).27 The pure products5 and 6 were extracted with ether from the ionic liquid. Isolationand purification by recrystallization from ethanol afforded 5 and6 in 83–93% yields with >94% diastereoselectivity (Table 3) infavor of isomer with cis ring junction as determined by 1H NMR

CN

SN

S

SN

S

NHR

NHR

O

O

H

H

H

H

HO

HOHO

HO

HO

HO

5

HO

6

n = 3

n = 4e

e/D-glucose 1 (5.0 mmol), 2-methyl-2-phenyl-1,3-oxathiolan-5-one 2 (5.0 mmol),3–93%, diastereoselectivity, 95–99% (cis).

Table 3[Bmim]SCN-promoted synthesis of thiosugar annulated 1,3-thiazine 5 and 6 containing thiosugar skeletons

Entry Product Timea (h) Yieldb,c (%) cis/trans ratiod

1

5a

SN

S NH2

O

H

H

HO

HO

HO

7.5 93 97/03

2

5b

SN

SHN

O

H

H

HO

HO

HO8 86 95/05

3

5c

SN

SHN

O

H

H

HO

HO

HO F

7 89 98/02

4

5d

SN

SHN

O

H

H

HO

HO

HO Cl8 85 97/03

5

5e

SN

SHN

O

H

H

HO

HO

HO OMe8.5 83 96/04

6

5f

SN

SHN

O

H

H

HO

HO

HO Me7.5 88 99/01

7

6a

SN

S NH2

O

H

H

HOHO

HO

HO 7.5 90 98/02

8

6b

SN

SHN

O

H

H

HOHO

HO

HO 7.5 87 96/04

9

6c

SN

SHN

O

H

H

HOHO

HO

HO

F

8.5 84 99/01

10

6d

SN

SHN

O

H

H

HOHO

HO

HO

Cl

8.5 92 97/03

11

6e

SN

SHN

O

H

H

HOHO

HO

HO

OMe

8 88 96/04

12

6f

SN

SHN

O

H

H

HOHO

HO

HO

Me

8 90 95/05

a Stirring time at room temperature.b Isolated yield.c Compound was characterized by spectral (IR, 1H NMR, 13C NMR, and EIMS) data.d As determined by 1H NMR spectroscopy.

V. K. Rai et al. / Tetrahedron Letters 54 (2013) 6469–6473 6471

Table 4Recyclability of TSIL

Table 3 Entry 1 Run 1 Run 2 Run 3 Run 4 Run 5

Yield (%) 93 93 92 92 91

6472 V. K. Rai et al. / Tetrahedron Letters 54 (2013) 6469–6473

spectroscopy.29–33 The crude isolates were checked by 1H NMR fortheir diastereomeric ratios to note any inadvertent alteration ofthese ratios during subsequent purification. In products 5 and 6,the rings are cis fused as indicated by the coupling constants of ringjunction protons 3a-H and 7a-H (J3a,7a = 4.6–4.8 Hz). The cis stereo-chemistry was also supported by NOE interaction experiments. Forexample, 10.9% and 11.9% NOEs were observed between 3a-H and7a-H in products 5a and 6a, respectively, indicating that the 4a-Hand 8a-H are located on the same face of the molecule, hence con-firming the cis fusion of the rings. The chiral carbons of the precur-sor carbohydrates retain their configuration in the product, as theyare not involved in any bond breaking/formation. It is noteworthythat the selection of aromatic amines and ammonium acetaterather aliphatic amines in the present synthesis was based onthe literature report that aliphatic amines, contrary to their aro-matic counterparts,34 are reported to be usually unstable and sus-ceptible to self condensation or polymerization under differentreaction conditions.35 However, in order to know how an aliphaticamine affects the synthesis, a controlled experiment was per-formed using D-xylose 1, 2-methyl-2-phenyl-1,3-oxathiolan-5-one 2, n-butylamine 4, and [bmim]SCN 3 employing the presentreaction conditions and the reaction was not only relatively slower(9.5 h) but also gave poor yield (31%) of the target compound.

With the aim to develop its solvent-free version and to compareits synthetic efficiency, we tried the same reaction in microwave(MW) irradiation condition. An intimate mixture of D-xylose 1(5.0 mmol), 2-phenyl-1,3-oxazolan-5-one 2 (5.0 mmol), KSCN(5.0 mmol), and AcONH4 4 (5.0 mmol) was taken in a 20 mL vialand subjected to microwave irradiation in a CEM Discover FocusedMicrowave Synthesis System for 18–25 min (Table 2) at 90 �C.After completion of the reaction as indicated by TLC, the productwas extracted with ether (3 � 20 mL). The combined ether extractswere dried over anhydrous sodium sulfate and evaporated underreduced pressure to leave the crude product, which was recrystal-lized from ethanol to afford the crude product, which on secondrecrystallization afforded the analytically pure compound 5a. Thereaction did not occur in the absence of a catalyst and various cat-alysts were screened for the formation of 5a at 90 �C in the presentreaction condition. Among the catalysts tested, CeCl3�7H2O/NaI-system gave the best result (Table 2, entry 6). K-10 clay andCeCl3�7H2O afforded product 5a in moderate yields (Table 2, en-tries 7 and 5), while poor yields of product 5a were obtained inthe case of silica gel and neutral and acidic alumina (Table 2,

SN

S

SN

S

NHR

NHR

O

O

H

H

H

H

HO

HOHO

HO

HO

HO

5

HO

6

CHOH

HO

CH2OH1

S

OPh O

2

NNSCN

3

r. t.S

OPh

CC

n

n = 3,4

NNOH

10

10

(i) HCl(ii) KSCN

MeMe

Scheme 4. Tentative mechanism for the formation of

entries 1–3). Moreover, the reaction did not take place using basicalumina (Table 2, entry 4). Thus, it was observed that a signifi-cantly lower yield of 5a was obtained in the solvent-free versionrather than its TSIL-promoted version. Therefore, we relied upon[bmim]SCN, which not only acts as the solvent but also catalyzesthe reaction, in the present investigation (Table 3).

The formation of thiosugar annulated 1,3-thiazines 5 and 6 canbe rationalized by N-nucleophilic attacks on b-thiocyanato deriva-tive 7 resulting in the 1,3-thiazine intermediate 9, which under-went mercaptoacetylative intramolecular ring transformationleading to the target compounds 5 and 6 (Scheme 4). This conclu-sion is based on the observation that the representative intermedi-ate 8a (n = 3, R = H) and 8g (n = 4, R = H) could be isolated in 50%and 53% yields, respectively. This could be converted into the cor-responding iminosugar 5a (R = H) and 6a (R = H) in quantitativeyield.28 After isolation of product 5, the ionic liquid [bmim]OH10, could be recycled to [bmim]SCN 3 for further use in subsequentruns without loss of efficiency (Table 4).

In conclusion, we have documented an original stereoselectivesynthesis of thiosugar annulated 2-amino-1,3-thiazines viahydrothiocyanation mercaptoacetylative intramolecular thiahet-erocyclization cascades using D-xylose/D-glucose as biorenewableresources. In the developed methodology, the ionic liquid[bmim]SCN works as reaction media as well as reagent and the[bmim]OH could easily be recycled and converted into [bmim]SCNfor further use in the subsequent reactions. Thus, this simple andgreen methodology would be a practical alternative to the existingprocedures for the production of this kind of fine chemical to caterfor the needs of academia as well as industry.

Acknowledgments

We sincerely thank the CSIR, New Delhi (01(2441)/10/EMR-II)for financial support. We are also thankful to Professor J.S. Dangi,Institute of Pharmacy, Guru Ghasidas Vishwavidyalaya, for provid-ing necessary facilities in the work.

O

HOH

S

N

H2OHn

7

AcONH4

RNH2

or

4

S

OPh O

CHOH

S

CH2OH

NRn

8

HSN

SH

H O

NHRHO

OH

HO

OH

9, n = 3

HSN

SH

H O

NHRHO

HO

OH

9, n = 4HO

HO

or

cyclodehydration

cyclodehydration

-H2O

-H2O

Me

-PhCOMe

NH2

target thiosugar annulated 1,3-thiazines 5 and 6.

V. K. Rai et al. / Tetrahedron Letters 54 (2013) 6469–6473 6473

References and notes

1. Korytnyk, W.; Angelio, N.; Dodson-Simmons, O.; Hanchak, M.; Madson, M.;Valenteckovic-Horvath, S. J. Carbohydr. Res. 1983, 113, 166–171.

2. Bozo, E.; Boros, S.; Kuszmann, J. Carbohydr. Res. 1998, 311, 191–202.3. Witczak, Z. J.; Culhane, J. M. Appl. Microbiol. Biotechnol. 2005, 69, 237–244.4. Hellman, B.; Lernmark, A.; Sehlin, J. B.; Taljedal, J. B.; Whistler, R. L. Biochem.

Pharmacol. 1973, 22, 29–35.5. Zysk, J.; Bushway, A. A.; Whistler, R. L.; Carlton, W. W. J. Reprod. Fertil. 1975, 45,

69–72.6. Kim, J. H.; Kim, S. H. E.; Hahn, W.; Song, C. W. Science 1978, 200, 206–207.7. Hashimoto, H.; Fujimori, T.; Yuasa, H. J. Carbohydr. Chem. 1990, 9, 683–694.8. Wong, C.-H.; Ichikawa, Y.; Krach, T.; Narvor, C. G.-L.; Dumas, D. P.; Look, G. C. J.

Am. Chem. Soc. 1991, 113, 8137–8145.9. Johnston, B. D.; Pinto, B. P. J. Org. Chem. 1998, 63, 5797–5800.

10. (a) Patel, H. S.; Patel, N. P. Orient. J. Chem. 1997, 13, 69–72; (b) Madkour, H. M.F.; Salem, M. A. I.; Soliman, E. A.; Mahmoud, N. F. H. Phosphorus, Sulfur SiliconRelat. Elem. 2001, 170, 15–27.

11. Ingarsal, N.; Amutha, P.; Nagarajan, S. J. Sulfur Chem. 2006, 27, 455–459.12. (a) Bózsing, D.; Sohár, P.; Gigler, G.; Kovács, G. Eur. J. Med. Chem. 1996, 31, 663–

671; (b) Tozkoparan, B.; Aktay, G.; Yeilada, E. Il Farmaco 2002, 57, 145–152.13. Campaigne, E.; Nargund, P. K. J. Org. Chem. 1964, 29, 224–226.14. Schmidt, R. R. Synthesis 1972, 333–350.15. Yuskovets, V. N.; Ivin, B. A. Tetrahedron Lett. 2003, 44, 5279–5280.16. (a) Jansen, J. E.; Mathes, R. A. J. Am. Chem. Soc. 1955, 77, 2866–2868; (b)

Garraway, J. L. J. Chem. Soc. 1964, 4004–4007; (c) Hanefeld, W. Arch. Pharm.1984, 317, 297–303; (d) Okazaki, R.; Unno, M.; Inamoto, N. Heterocycles 1987,25, 183–188; (e) Perjesi, P.; Foldesi, A.; Batta, G.; Tamas, J. Chem. Ber. 1989, 122,651–656; (f) Yadav, L. D. S.; Sharma, S. Synthesis 1992, 919–920; (g) Yadav, L. D.S.; Yadav, D. S. Liebigs Ann. 1995, 2231–2233; (h) Yadav, L. D. S.; Shukla, S.;Saigal, S. J. Indian Chem. 1996, 35B, 102–105; (i) Noshio, T.; Konno, Y.; Ori, M.;Sakamoto, M. Eur. J. Org. Chem. 2001, 3533–3537; (j) Koketsu, M.; Tanaka, K.;Takenaka, Y.; Kwong, C. D.; Ishihara, H. Eur. J. Pharm. Sci. 2002, 15, 307–310; (k)Yadav, L. D. S.; Singh, S. J. Indian Chem. 2003, 42B, 1115–1118; (l) Murai, T.;Niwa, H.; Kimura, T.; Shibahara, F. Chem. Lett. 2004, 33, 508–509; (m) Yadav, L.D. S.; Singh, A. Tetrahedron Lett. 2003, 44, 5637–5640; (n) Huang, S.; Pan, Y.;Zhu, Y.; Wu, A. Org. Lett. 2005, 7, 3797–3799; (o) Rasovic, A.; Steel, P. J.;Kleinpeter, E.; Markovic, R. Tetrahedron 2007, 63, 1937–1945.

17. Yadav, L. D. S.; Patel, R.; Rai, V. K.; Srivastava, V. P. Tetrahedron Lett. 2007, 48,7793–7795.

18. Yadav, L. D. S.; Rai, V. K.; Yadav, B. S. Tetrahedron 2009, 65, 1306–1315.19. Yadav, L. D. S.; Yadav, S.; Rai, V. K. Tetrahedron 2005, 61, 10013–10017.20. Rai, V. K.; Sharma, R.; Kumar, A. Tetrahedron Lett. 2013, 54, 1071–1075.21. Rai, V. K.; Sharma, N.; Kumar, A. Synlett 2013, 97–101.22. Rai, V. K.; Singh, N. Nucleos. Nucleot. Nucl. Acids 2013, 32, 247–255.23. Rai, V. K.; Tiku, P.; Kumar, A. Synth. Commun. 2012, 42, 1489–1499.24. Rai, V. K.; Rai, P. K.; Bajaj, S.; Kumar, A. Green Chem. 2011, 13, 1217–1223.25. Renewable Bioresources: Scope and Modification for Non-Food Applications In

Stevens, C. V., Verhé, R. G., Eds.; John Wiley and Sons: Chichester, England,2004.

26. Procedure for the preparation of hydrothiocyanate 7a: A mixture of D-xylose/D-glucose 1 (5.0 mmol), 2-methyl-2-phenyl-1,3-oxathiolan-5-one 2 (5.0 mmol),[bmim]SCN 3 (6.0 mmol), and a few drops of distilled water was taken in around bottom flask and stirred at room temperature for 3.5 h. After completionof the reaction as indicated by TLC, the product was extracted with ether(3 � 20 mL). The combined ether extracts were dried over anhydrous sodiumsulfate and evaporated under reduced pressure to give a purehydrothiocyanate 7a as yellowish solid. The remaining ionic liquid,[bmim]OH 10 was dissolved in acetone (10 mL) and treated with conc. HCl(1.2 equiv) followed by reaction with KSCN (2 equiv) at rt for 48 h to affordTSIL, [bmim]SCN 3, which was used in subsequent runs. Physical data ofrepresentative compound. Compound 7a: yellowish solid, mp 127–129 �C. IR(KBr) mmax 3340, 3135, 3010, 2063, 1775, 1605, 1585, 1455 cm�1. 1H NMR(400 MHz; DMSO-d6 + D2O): d = 2.25 (s, 3H), 3.81 (d, 1H, J = 4.3 Hz), 4.01 (dd,1H, J = 6.8, 4.1 Hz), 4.14 (ddd, 1H, J = 4.1, 5.2, 5.2 Hz), 4.20 (dd, 1H, J = 4.3,5.5 Hz), 4.24 (dd, 1H, J = 5.2, 11.0 Hz,), 4.31 (dd, 1H, J = 6.8, 5.5 Hz), 4.85 (dd,1H, J = 5.2, 11.0 Hz), 7.21–7.79 (m, 5H). 13C NMR (100 MHz; DMSO-d6):d = 23.2, 38.5, 50.7, 67.3, 70.1, 71.9, 74.7, 92.7, 112.8, 126.2, 127.9, 130.5,138.3, 172.2. MS (FAB) m/z: 386 (MH+). Anal. Calcd for C16H19NO6S2: C, 49.86;H, 4.97; N, 3.63. Found: C, 50.15; H, 4.78; N, 3.49.

27. General procedure for the synthesis of iminosugar-annulated 2-amino-1,3-thiazines 5 and 6: A mixture of D-xylose/D-glucose 1 (5.0 mmol), 2-methyl-2-phenyl-1,3-oxathiolan-5-one 2 (5.0 mmol), [bmim]SCN 3 (6.0 mmol), and afew drops of distilled water was taken in a round bottom flask and stirred atroom temperature for 4–5 h. Then, AcONa or an amine 4 (5.0 mmol) was addedand the reaction mixture was stirred at rt for further 3–4 h. After completion ofthe reaction as indicated by TLC, the product was extracted with ether(3 � 20 mL). The combined ether extracts were dried over anhydrous sodiumsulfate and evaporated under reduced pressure to leave the crude product,which was recrystallized from ethanol to afford a diastereomeric mixture(>94:<6) of 5 and 6 in favor of cis isomer; in the crude products, the ratio was>92:<8, as determined by the 1H NMR spectroscopy. The product on secondrecrystallization from ethanol furnished an analytically pure sample of a singlediastereomer 5 or 6 as yellowish solid. On the basis of comparison of J valueswith literature values,29–33 the cis stereochemistry was assigned to 5 and 6, asthe coupling constant (J3a,7a = 4.6–4.8 Hz) of the major cis diastereomer waslower than that for minor trans diastereomer (J3a,7a = 10.8 Hz). The remainingionic liquid, [bmim]OH 10 was converted into [bmim]SCN 3 for further use insubsequent runs as described above.26 Physical data of representativecompound. Compound 5a: yellowish solid, mp 143–145 �C. IR (KBr) mmax

3341, 3325, 3140, 3012, 1772, 1668, 1608, 1589, 1451 cm�1. 1H NMR(400 MHz; DMSO-d6 + D2O): d = 3.03 (ddd, 1H, J = 9.9, 6.4, 3.2 Hz), 3.98 (dd,1H, J = 9.9, 9.1 Hz), 4.07 (dd, 1H, J = 6.4, 11.5 Hz), 4.16 (dd, 1H, J = 7.6, 9.1 Hz),4.51 (dd, 1H, J = 3.2, 11.5 Hz), 4.81 (dd, 1H, J = 4.8, 7.6 Hz,), 5.23 (d, 1H, J = 4.8Hz). 13C NMR (100 MHz; DMSO-d6): d = 25.5, 49.2, 51.8, 70.6, 72.1, 83.0, 162.5,173.0. MS (FAB) m/z: 265 (MH+). Anal. Calcd for C8H12N2O4S2: C, 36.35; H, 4.58;N, 10.60. Found: C, 36.56; H, 4.95; N, 10.37. Compound 6a: Yellowish solid, mp151–153 �C. IR (KBr) mmax 3345, 3321, 3139, 3015, 1775, 1669, 1559, 1581,1458 cm�1. 1H NMR (400 MHz; DMSO-d6 + D2O): d = 3.21 (dd, 1H, J = 9.8,6.0 Hz), 3.97 (dd, 1H, J = 9.8, 9.1 Hz), 4.08 (ddd, 1H, J = 6.0, 6.3, 3.1 Hz), 4.13 (dd,1H, J = 6.3, 11.7 Hz), 4.23 (dd, 1H, J = 7.6, 9.1 Hz), 4.63 (dd, 1H, J = 3.1, 11.7 Hz),4.79 (dd, 1H, J = 4.6, 7.6 Hz,), 5.27 (d, 1H, J = 4.6 Hz). 13C NMR (100 MHz;DMSO-d6): d = 26.1, 41.7, 51.2, 70.2, 72.9, 77.5, 85.3, 162.8, 173.4. MS (FAB) m/z: 295 (MH+). Anal. Calcd for C9H14N2O5S2: C, 50.39; H, 5.02; N, 11.02. Found: C,50.21; H, 5.37; N, 11.19.

28. Isolation of intermediates 8a (R = H, n = 3) and 8g (R = H, n = 4) and theirconversion into corresponding iminosugar-annulated 2-amino-1,3-thiazines 5aand 6a: A mixture of D-xylose/D-glucose 1 (5.0 mmol), 2-phenyl-1,3-oxazolan-5-one 2 (5.0 mmol), [bmim]SCN 3 (6.0 mmol), and a few drops of distilledwater was taken in a round bottom flask and stirred at room temperature for4 h. Then, AcONa 4 (5.0 mmol) was added and the reaction mixture was stirredat rt for further 2.0 h. After completion of the reaction as indicated by TLC, theproduct was extracted with ether (3 � 20 mL). The combined ether extractswere dried over anhydrous sodium sulfate and evaporated under reducedpressure to leave the crude product, which was recrystallized from ethanol togive an analytically pure sample of intermediates 8a and 8g. Finally, theseintermediates were stirred at the rt for next 1.5 h to give the correspondingcyclized products 5a and 6a, respectively. The remaining ionic liquid,[bmim]OH 10 was converted into [bmim]SCN 3 for further use insubsequent runs as described above.26 Physical data of representativecompound. Compound 8a: yellowish solid, mp 113–115 �C. IR (KBr) mmax

3341, 3132, 3013, 1772, 1665, 1598, 1581, 1449 cm�1. 1H NMR (400 MHz;DMSO-d6 + D2O): d = 2.23 (s, 3H), 3.80 (d, 1H, J = 4.3 Hz), 4.02 (dd, 1H, J = 6.7,4.2 Hz), 4.11 (ddd, 1H, J = 4.2, 5.5, 5.5 Hz), 4.17 (dd, 1H, J = 4.3, 5.2 Hz), 4.28 (dd,1H, J = 5.5, 10.9 Hz,), 4.34 (dd, 1H, J = 6.7, 5.2 Hz), 4.83 (dd, 1H, J = 5.5, 10.9 Hz),7.13–7.73 (m, 5H). 1H NMR (100 MHz; DMSO-d6): d = 23.5, 38.8, 51.2, 67.1,70.5, 71.8, 75.3, 92.1, 125.9, 128.1, 131.3, 136.3, 167.1, 173.1. MS (FAB) m/z:403 (MH+). Anal. Calcd for C16H22N2O6S2: C, 47.75; H, 5.51; N, 6.96. Found: C,47.38; H, 5.69; N, 7.21.

29. Evans, D. A.; Nelson, J. V.; Vogel, E.; Taber, T. R. J. Am. Chem. Soc. 1981, 103,3099–3111.

30. Mukaiyama, T.; Iwasawa, N. Chem. Lett. 1984, 753–756.31. Evans, D. A.; Taber, T. R. Tetrahedron Lett. 1980, 21, 4675–4678.32. Hirayama, M.; Gamoh, K.; Ikekawa, N. Chem. Lett. 1982, 491–494.33. Tanikaga, R.; Hamamura, K.; Kaji, A. Chem. Lett. 1988, 977–980.34. (a) Kimpe, N.; Verhe, R.; Schamp, N. Synth. Commun. 1975, 5, 269–274; (b)

Musick, B. J. Org. Chem. 1990, 55, 910–918; (c) Zhao, D.; Moore, J. S. J. Org. Chem.2002, 67, 3548–3554.

35. (a) Tiollais, R. Bull. Soc. Chim. Fr. 1947, 14, 716; (b) Schenkel, L. B.; Ellman, J. A.Org. Lett. 2004, 6, 3621–3624; (c) Trincado, M.; Ellman, J. A. Angew. Chem., Int.Ed. 2008, 120, 5705–5708.