Synthesis of chiral thiazolo[3,4-a]pyrazine-5,8-diones

Article abstract of DOI:10.3987/COM-05-10662

A synthetic approach to chiral (3R,8aR)-3-phenyltetrahydro-thiazolo[3,4-a]pyrazine-5,8-diones starting from a (2S,4R)- and (2R,4R)-diastereoisomeric mixture of 2-phenylthiazolidine is described. The diastereoselective N-acylation of the thiazolidine follo

Full text of DOI:10.3987/COM-05-10662

HETEROCYCLES, Vol. 68, No. 4, 2006
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HETEROCYCLES, Vol. 68, No. 4, 2006, pp. 679 - 686. © The Japan Institute of Heterocyclic Chemistry
Received, 29th December, 2005, Accepted, 28th February, 2006, Published online, 3rd March, 2006. COM-05-10662
SYNTHESIS OF CHIRAL THIAZOLO[3,4-a]PYRAZINE-5,8-DIONES
Teresa M. V. D. Pinho e Melo,a* Susana M. M. Lopes,a António M. d’A.
Rocha Gonsalves,a José A. Paixão,b Ana Matos Beja,b and Manuela Ramos
Silvab
aDepartment of Chemistry, University of Coimbra, 3004-535 Coimbra, Portugal
bDepartment of Physics, University of Coimbra, 3004-516 Coimbra, Portugal
Abstract – A synthetic approach to chiral (3R,8aR)-3-phenyltetrahydro-
thiazolo[3,4-a]pyrazine-5,8-diones starting from a (2S,4R)- and (2R,4R)-
diastereoisomeric mixture of 2-phenylthiazolidine is described. The
diastereoselective N-acylation of the thiazolidine followed by condensation with
amines affords the chiral 1,3-thiazolidine-annulated system. The structure of
(3R,8aR)-7-(methoxycarbonylmethyl)-3-phenyltetrahydrothiazolo[3,4-a]pyrazine-
5,8-dione was determined by X-Ray crystallography.
INTRODUCTION
1,3-Thiazolidine-4-carboxylates are compounds of considerable importance, as some representatives
show interesting biological activities.1 They are well known as building blocks of natural penicillins and
analogues, as well as precursors of other pharmaceuticals.1 The most interesting aspect of thiazolidines
reactivity is the possibility of carrying out diastereoselective reactions thus allowing the development of
synthetic routes to chiral heterocycles.2
2-Substituted-1,3-thiazolidine-4-carboxylates are obtained from the reaction of aldehydes and L-cysteine
esters in a process where a new chiral center at the C-2 position of the thiazolidine is created leading to a
mixture of the (2S,4R)- and (2R,4R)-diastereoisomers. The acylation of the diastereomeric mixture can
lead to the selective synthesis of N-acyl-2-substituted-1,3-thiazolidine-4-carboxylates as pure
stereoisomers with (2R,4R) or (2S,4R) stereochemistry depending on the reaction conditions.3 In fact,
2-substituted-1,3-thiazolidine-4-carboxylates can undergo selective inversion at C-2 through a mechanism
involving the opening of the ring but the protection with the acyl group prevents this epimerization and
allows the isolation of pure diastereoisomers.

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In this context, we report a route to chiral thiazolo[3,4-a]pyrazine-5,8-diones starting from thiazolidines.
RESULTS AND DISCUSSION
The synthetic approach studied is outlined in Scheme 1. Thus, the diastereoselective acylation of
2-phenyl-1,3-thiazolidine-4-carboxylate (1) is required in order to obtain chiral thiazolo[3,4-a]pyrazine-
5,8-diones. Although two reports of the use of a similar route to thiazolo[3,4-a]pyrazine-5,8-diones were
known, the stereochemistry of the products was not determined.4 We found that carrying out the
N-acylation of thiazolidine (1) with chloroacetyl chloride at room temperature, in the presence of
potassium carbonate, the methyl (2R,4R)-N-chloroacetyl-2-phenyl-1,3-thiazolidine-4-carboxylate (2) is
obtained in diastereomeric pure form in 99% yield. Compound (2) can be converted quantitatively into
(2R,4R)-N-iodoacetyl derivative (3).
The one-pot synthesis of the thiazolo[3,4-a]pyrazine-5,8-diones from thiazolidine (3) involves the
reaction with amines which leads to nucleophilic halide displacement followed by cyclization. The
synthesis of the N-unsubstituted (3R,8aR)-3-phenyl-tetrahydro-thiazolo[3,4-a]pyrazine-5,8-dione (4a) as
single stereoisomer was achieved by reacting 3 with ammonium acetate in refluxing methanol. A more
efficient synthesis of 4a (60%) was obtained when a solution of 3 in methanol saturated with NH3 was
heated at reflux. The reaction of thiazolidine (3) and propargyl amine was carried out in refluxing
acetonitrile giving N-prop-2-ynyl derivative (4b) in 72% yield (Table 1).
CO2Me
NH
CO2Me
CO2Me
RNH2
S
S
N
S
N
ClCH2COCl
K2CO3, rt, 2 h
Base, !
Cl
NaI
rt, 12 h
I
O
O
Ph
Ph
Ph
1
2 99%
3 99%
O
CO2Me
R
H
N
4c R =
4e R =
4a R = H
4b R =
CO2Me
S
N
N
CO2Me
NH
O
Ph
4d R =
CO2Me
4
N
H
4f R =
Ph
Scheme 1

HETEROCYCLES, Vol. 68, No. 4, 2006
681
The work was extended to the reaction of thiazolidine (3) with α-amino esters. The condensation reaction
with methyl glycinate hydrochloride and triethylamine allowed the synthesis of the corresponding
bicyclic system (4c) in 37% yield.
The structure of this compound was determined by X-Ray crystallography (Figure 1 and Table 2). The
conformation of the five-membered ring is close to half-chair twisted on S2-C1, with Cremer&Pople5
puckering parameters: q2= 0.438(2) Å and ϕ2=203.9(3)º. The six-membered ring has an average torsion
angle of 27.95(9)º and boat conformation as shown by the puckering parameters q = 0.487(2) Å, θ =
94.9(2)º, ϕ = 126.3(2)º. The molecule has two chiral centers C3 and C8a corresponding to R
configuration.
Table 1 - Synthesis of the thiazolo[3,4-a]pyrazine-5,8-diones 4 from (2R,4R)-N-iodoacetylthiazolidine
(3).
Amine
Reaction conditions
Product
4a
Yield
47%
60%
72%
37%
51%
65%
64%
Ammonium acetate
NH3
Na2CO3, Refluxing MeOH, 48 h
MeOH sat. with NH3, Refluxing, 48 h
Na2CO3, Refluxing CH3CN, 3 h
NEt3, Refluxing DMF, 3 h
4a
Propargyl amine
4b
Methyl glycinate hydrochloride
L-Tryptophan methyl ester
L-Histidine methyl ester
L-Phenylalanine methyl ester
4c
NaHCO3, Refluxing Toluene, 40 h
NEt3, Refluxing MeOH, 24 h
NaHCO3, Refluxing toluene, 40 h
4d
4e
4f
Figure 1 - X-Ray Structure of thiazolo[3,4-a]pyrazine-5,8-dione (4c).

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HETEROCYCLES, Vol. 68, No. 4, 2006
Table 2 - Bond Lengths (Å) for compound (4c).
S2-C1
S2-C3
1.814(3)
1.825(2)
1.342(3)
1.464(2)
1.474(2)
1.326(3)
C3A-C3
O5-C5
1.508(2)
1.228(2)
1.454(3)
1.457(2)
1.504(3)
1.396(3)
N4-C5
N7-C7A
N7-C6
N4-C3
N4-C8A
O7A-C7B
C5- C6
C3B-C3C
This X-Ray analysis confirmed the stereochemistry assignment of the methyl (2R,4R)-N-iodoacetyl-
2-phenyl-1,3-thiazolidine-4-carboxylate (3) and of the thiazolo[3,4-a]pyrazine-5,8-diones (4).
The same type of approach can be used to react (2R,4R)-N-iodoacetyl-2-phenyl-1,3-thiazolidine-
4-carboxylate (3) with other α-amino esters namely L-tryptophan methyl ester, L-histidine methyl ester
and L-phenylalanine methyl ester. This way (3R,8aR)-3-phenyltetrahydrothiazolo[3,4-a]pyrazine-
5,8-diones (4d-4f) having an extra chiral center were obtained in good yield (51−65%).
CONCLUSION
A simple and efficient route to chiral thiazolo[3,4-a]pyrazine-5,8-diones is reported. A range of new
(3R,8aR)-3-phenyltetrahydrothiazolo[3,4-a]pyrazine-5,8-diones, including derivatives bearing α-amino
ester residues as side chain was obtained in good yield. The diastereoselective synthesis of methyl
(2R,4R)-N-chloroacetyl-2-phenyl-1,3-thiazolidine-4-carboxylate and the subsequent condensation with
amines leads to the chiral thiazolo[3,4-a]pyrazine-5,8-diones. The configuration assignment was
confirmed by determining the structure of (3R,8aR)-7-(methoxycarbonylmethyl)-3-phenyltetrahydro-
thiazolo[3,4-a]pyrazine-5,8-dione (4c) by X-Ray crystallography.
EXPERIMENTAL
1H NMR spectra were recorded on a nmr spectrometer operating at 300 MHz and 500 MHz. 13C spectra
were recorded on a nmr spectrometer operating at 75.5 MHz and 125 MHz. The solvent is
deuteriochloroform. IR spectra were recorded on a Perkin Elmer 1720X FTIR spectrometer. Mass
spectra were recorded on a HP GC 6890/MSD5973 instrument under electron impact (EI) except where
indicated otherwise. Optical rotations were measured on an Optical Activity AA-5 electrical polarimeter.
Microanalyses were performed using an EA 1108-CHNS-O Fisons instrument. Mp were recorded on a

HETEROCYCLES, Vol. 68, No. 4, 2006
683
Reichert hot stage and are uncorrected. Flash column chromatography was performed with Merck 9385
silica as the stationary phase. Methyl 2-phenylthiazolidine-4-carboxylate was prepared using the general
procedure described in the literature and were isolated as mixture of the (2R,4R) and (2S,4R)
diastereomers.6
Methyl (2R,4R)-N-chloroacetyl-2-phenylthiazolidine-4-carboxylate (2). Methyl 2-phenylthiazolidine-
4-carboxylate (1) (2 g, 9 mmol) was dissolved in dry dichloromethane (40 mL). Anhydrous potassium
carbonate (2 g, 14.5 mmol) was added followed by a solution of the chloroacetyl chloride (1.2 g, 10.8
mmol) in dichloromethane (10 mL). The reaction mixture was stirred under nitrogen at rt for 2 h. The
organic solvent was evaporated giving a pale yellow solid (99%). mp 86.1-88.2 °C (from ethyl
1
acetate-hexane). IR (KBr) 1666, 1745 and 2900 cm-1; H NMR δ: 3.35-3.43 (2H, m), 3.71 (1H, d, J =
13.0 Hz), 3.84 (1H, d, J = 13.0 Hz), 3.85 (3H, s), 5.08 (1H, approx. t, J = 6.5 Hz), 6.20 (1H, s), 7.35-7.43
13
(3H, m, Ar-H), 7.67-7.69 (2H, m, Ar-H); C NMR δ: 31.9, 41.7, 52.9, 65.1, 65.8, 126.4, 128.9, 129.2,
139,9, 165.2, 169.9; MS (EI) m/z 299 (M+, 2%), 264 (54), 222 (100), 164 (67) and 77 (61). Anal. Calcd
25
for C13H14NO3ClS: C, 52.09; H, 4.71; N, 4.67. Found: C, 52.14; H, 4.71; N, 4.24%.
CH2Cl2).
= + 110 (c = 1,
[!]
D
Methyl (2R,4R)-N-iodoacetyl-2-phenylthiazolidine-4-carboxylate (3). A solution of sodium iodide (1 g,
7 mmol) in acetone (20 mL) was added to a solution of methyl (2R,4R)-N-chloroacetyl-2-
phenylthiazolidine-4-carboxylate (2) (2 g, 7 mmol) in acetone (60 mL). The reaction mixture was
stirred overnight. The organic solvent was evaporated giving quantitatively methyl (2R,4R)-N-
iodoacetyl-2-phenylthiazolidine-4-carboxylate (3) as a yellow solid. mp 114.1-115.3 °C (from ethyl
acetate-hexane). IR (KBr) 1665, 1734 and 3100 cm-1; 1H NMR δ: 3.26 (1H, dd, J = 6.9 and 12.1 Hz), 3.32
(1H, dd, J 0 6.5 and 12.1 Hz), 3.40 (1H, d, J = 10.1 Hz), 3.54 (1H, d, J = 10.1 Hz), 3.85 (3H, s), 5.01 (1H,
approx. t, J = 6.7 Hz), 6.15 (1H, s), 7.25-7.43 (3H, m, Ar-H), 7.68-7.71 (2H, m, Ar-H); 13C NMR δ: 31.9,
52.8, 65.3, 66.8, 126.2, 128.8, 129.1, 139,7, 166.8, 170.0; MS (EI) m/z 392 (MH+, 0.1%), 332 (4), 264
(100), 222 (83) and 77 (20). Anal. Calcd for C13H14NO3IS: C, 39.91; H, 3.61; N, 3.58. Found: C, 40.0; H,
25
3.35; N, 3.31%.
= + 130 (c = 1, CH2Cl2).
[!]
D
General procedure for the synthesis of the chiral thiazolo[3,4-a]pyrazine-5,8-diones (4). A solution
of the amine (4.0 mmol in 10 mL of the appropriated solvent) was added to a solution of methyl
(2R,4R)-N-iodoacetyl-2-phenylthiazolidine-4-carboxylate (1.5 g, 3.8 mmol) and a base (3.8 mmol) in
20 mL of the appropriated solvent. The reaction mixture was heated at reflux. The organic solvent was
evaporated off and the crude product was purified by flash chromatography [hexane-ethyl acetate (1:3)]
(see Table 1 for additional details).

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(3R,8aR)-3-Phenyltetrahydrothiazolo[3,4-a]pyrazine-5,8-dione (4a) was obtained as a white solid
(47%). mp 225-227 °C (from dichloromethane-ethyl ether).. IR (KBr) 1295, 1639, 1678 and 3257 cm-1;
1H NMR δ: 3.34-3.36 (2H, m), 3.55 (3H, s), 3.62-3.81 (1H, m), 4.13-4.21 (1H, m), 4.78 (1H, approx. t, J
13
= 6.6 Hz), 6.43 (1H, s), 7.27-7.38 (5H, Ar-H); C NMR δ: 34.7, 46.2, 60.3, 64.7, 126.8, 128.6, 128.7,
139.1, 161.1, 166.3; MS (EI) m/z 248 (M+, 100%), 177 (25), 121 (36) and 77 (16). Anal. Calcd for
25
C12H12N2O2S: C, 58.05; H, 4.87; N, 11.28. Found: C, 57.77; H, 5.23; N, 11.30%.
CH2Cl2).
= + 310 (c = 0.5,
[!]
D
(3R,8aR)-3-Phenyl-7-prop-2-ynyltetrahydrothiazolo[3,4-a]pyrazine-5,8-dione (4b) was obtained as a
white solid (72%). mp 122.2-123.8 °C (from ethyl acetate-hexane). IR (KBr) 1676, 2123, 3228 and 3288
cm-1; 1H NMR δ: 2.34 (1H, t, J = 2.5 Hz) 3.38 (1H, dd, J = 6.0 and J = 12.9 Hz) 3.46-3.53 (1H, m), 4.08
(1H, d, J = 17 Hz), 4.21 (1H, dd, J = 2.5 and J = 17.5 Hz), 4.26 (1H, d, J = 17 Hz), 4.47 (1H, dd, J = 2.5
and J = 17.5 Hz), 4.63 (1H, ddd, J = 0.9, J = 6.0 and J = 12.9 Hz) 6.25 (1H, s), 7.17-7.20 (2H, m, Ar-H),
7.26-7.35 (3H, m, Ar-H); 13C NMR δ: 31.1, 34.9, 51.0, 63.6, 64.8, 73.3, 76.5, 125.1, 128.2, 128.8, 141.2,
163.5, 165.9; MS (EI) m/z 286 (M+, 100%), 162 (23), 121 (34) and 77 (10). Anal.: Calcd. for
25
C15H14N2O2S: C, 62.92; H, 4.93; N, 9.78. Found: C, 62.58; H, 5.07; N, 9.87%.
2Cl2).
= + 115 (c = 1, CH-
[!]
D
(3R,8aR)-7-Methoxycarbonylmethyl-3-phenyltetrahydrothiazolo[3,4-a]pyrazine-5,8-dione (4c) was
obtained as a white solid (37%). mp 118.5-120.7 °C (from ethyl acetate-hexane). IR (KBr) 1677, 1745
1
and 2961 cm-1; H NMR δ: 3.37 (1H, dd, J = 5.8 and J = 12.3 Hz), 3.51 (1H, dd, J = 10.1 and J = 12.3
Hz), 3.79 (3H, s), 3.83 (1H, d, J = 17.6 Hz), 4.02 (1H, d, J = 17.6 Hz), 4.70 (1H, dd, J = 5.8 and J = 10.1
Hz), 6.23 (1H, s), 7.21-7.23 (2H, m, Ar-H), 7.25-7.28 (1H, m, Ar-H), 7.32-7.34 (2H, m, Ar-H); 13C NMR
δ: 30.8, 47.3, 52.7, 53.2, 63.4, 64.7, 125.0, 128.2, 128.8, 141.1, 163.4, 167.1, 168.33; MS (EI) m/z 320
(M+, 100%), 302 (18), 177 (28), 121 (35), 102 (42) and 77 (89). Anal.: Calcd. for C15H16N2O4S: C, 56.24;
25
H, 5.03; N, 8.74. Found: C, 56.11; H, 5.10; N, 8.50%.
= + 80 (c = 0.5, CH2Cl2).
[!]
D
(3R,8aR)-7-[(1R)-2-(1H-Indol-3-yl)-1-methoxycarbonylethyl]-3-phenyltetrahydrothiazolo[3,4-a]-
pyrazine-5,8-dione (4d) was obtained as a solid (51%). mp 179.9-180.8 °C (from ethyl acetate-hexane).
IR (KBr) 1680, 1735 and 3386 cm-1; 1H NMR δ: 3.08 (1H, dd, J = 12.0 and J = 14.8 Hz), 3.21-3.28 (2H,
m), 3.48 (1H, dd, J = 4.8 and J = 14.8 Hz), 3.81 (3H, s), 3.88 (1H, d, J = 16.9 Hz), 4.10 (1H, d, J = 16.9
Hz), 4.57 (1H, ddd, J = 0.8, J = 6.7 and J = 10.0 Hz), 5.43 (1H, dd, J = 4.8 and J = 12.0 Hz), 6.11 (1H, s),
13
6.81-6.83 (2H, m, Ar-H), 7.18-7.29 (8H, m, Ar-H); C NMR δ: 29.6, 30.3, 49.2, 52.7, 56.4, 63.6, 64.2,
109.3, 111.4, 118.3, 119.8, 122.3, 122.9, 124.8, 126.7, 127.8, 128.6, 136.2, 141.1, 163.8, 167.3, 170.5;
MS (ES) m/z 450 (MH+, 100%), 390 (29), 217 (17), 202 (12). Anal. Calcd for C24H23N3O4S: C, 64.13; H,
25
5.16; N, 9.35. Found: C, 64.27; H, 4.92; N, 9.13%.
= − 15 (c = 1, CH2Cl2).
[!]
D

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685
(3R,8aR)-7-[(1R)-2-(1H-Imidazol-4-yl)-1-methoxycarbonylethyl]-3-phenyltetrahydrothiazolo[3,4-a]-
pyrazine-5,8-dione (4e) was obtained as a solid (65%). mp 93.6-95.0 °C (from dichloromethane- diethyl
ether). IR (KBr) 1669, 1738 and 3398 cm-1; 1H NMR δ: 3.79 (3H, s), 3.79 (3H, s), 3.90 (1H, d, J = 16.9
Hz), 4.14 (1H, d, J = 16.9 Hz), 4.59 (1H, dd, J = 6.1 and J = 10.3 Hz), 5.36 (1H, dd, J = 4.8 and J = 10.6
Hz), 6.17 (1H, s), 6.71 (1H, s), 7.03-7.06 (2H, m, Ar-H), 7.26-7.33 (3H, m, Ar-H), 7.46 (1H, s); 13C NMR
δ: 26.5, 30.6, 49.7, 52.7, 56.5, 63.6, 64.3, 65.8, 125.1, 126.3, 128.0, 128.7, 129.4, 135.2, 141.3, 164.0,
25
167.1, 170.3; MS (ES) m/z 401 (MH+, 100%), 217 (6).
= + 40 (c = 0.25, CH2Cl2).
[!]
D
(3R,8aR)-7-[(1R)-2-Phenyl-1-methoxycarbonylethyl]-3-phenyltetrahydrothiazolo[3,4-a]pyrazine-
5,8-dione (4f) was obtained as a solid (64%). mp 44.8-45.7 °C (from ethyl acetate-hexane). IR (KBr)
1678, 1742, 3025 and 3063 cm-1; 1H NMR δ: 3.07 (1H, dd, J = 12.0 and J = 14.8 Hz), 3.21-3.28 (2H, m),
3.44-3.51 (1H, m), 3.81 (3H, s), 3.88 (1H, d, J = 16.9 Hz), 4.10 (1H, d, J = 16.9 Hz), 4.56 (1H, ddd, J =
0.9, J = 6.2 and J = 9.6 Hz), 5.43 (1H, dd, J = 4.8 and J = 12.0 Hz), 6.11 (1H, s), 6.81-6.83 (2H, m, Ar-H),
6.91-7.30 (8H, m, Ar-H); 13C NMR δ: 30.5, 33.9, 49.0, 52.8, 56.8, 63.7, 64.4, 124.7, 127.2, 127.8, 128.5,
128.8, 129.0, 135.5, 141.0, 163.5, 167.2, 170.0; MS (ES) m/z 411 (MH+, 100%), 351 (16), 205 (7), 183
25
(15).
= + 60 (c = 0.25, CH2Cl2).
[!]
D
X-Ray structure determination of (3R,8aR)-7-methoxycarbonylmethyl-3-phenyl-tetrahydro-
thiazolo[3,4-a]pyrazine-5,8-dione (4c)
Crystal data: C15H16N2O4S, M = 320.36, crystal dimensions 0.19x0.25x0.40 mm3, monoclinic, P21, a =
11.1409(8) Å, b = 5.6755(5) Å, c = 12.7460(10) Å, α = 90º, β = 108.338(9)º, γ= 90º, V = 765.00(11) Å3,
Z = 2, ρcalc = 1.391 gcm-3, µ = 2.063 mm-1, 5875 reflections measured, 3027 independent, R = 0.0369
(2862 reflections with I > 2σ(I)), Rw = 0.1101 for all reflections, GOF = 1.048, 200 parameters, non-H
atoms refined anisotropically, H atoms refined as riding, residual density 0.196/-0.218 e Å-3.
Data collection: The X-Ray data were collected on an Enraf-nonius Mach-3 single crystal diffractometer,
at 298(3) K, using graphite-monochromated Cu Ka radiation (λ= 1.5418 Å). Intensities were recorded as
full profiles of ω−θ scans.
Structure solution and refinement: The structures were solved by direct methods as implemented in
SHELXS97 and refined by full-matrix least-squares using SHELXL97. Examination of the structure with
PLATON confirmed the absence of voids in the crystal structures, which might be occupied by solvent
molecules.
ACKNOWLEDGEMENTS

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HETEROCYCLES, Vol. 68, No. 4, 2006
The research was supported by Chymiotechnon and Fundação para a Ciência e Tecnologia
(POCI/QUI/55584/2004) and FEDER.
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