Efficient synthesis of fused isothiazolo C-nucleosides. III. Synthesis of 7-substituted isothiazolo [4,5-d] pyrimidine C-nucleosides*

Article abstract of DOI:10.1081/NCN-100002083

The Divakar-Reese procedure has been successfully applied for transforming 7-oxo-isothiazolo[4,5-d]pyrimidine C-nucleosides (4a,b, 5a,b, 6a) via 1,2,4-triazol-1-yl intermediates (7a,b, 8a,b) into various 7-substituted C-nucleosides 15a,b, 16a,b, 17a, 18a, 19a,b, 20a,b; their subsequent deprotection provides novel types of unusual C-glycosides 22b, 23a, 24a,b, 25b, 26b. C-Nucleosides, possessing on its heterocyclic base other than naturally occuring oxo- or amino substituents, are important model compounds for biological or medicinal studies (2,3). We want to report on the synthesis of novel 7-substituted isothiazolo = [4,5-d]pyrimidine C-nucleosides. As we could show in previous papers (1,4), there exists a simple approach to the protected C-glycosides 4-6.

Full text of DOI:10.1081/NCN-100002083

This article was downloaded by: [Northeastern University]
On: 27 October 2014, At: 15:32
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered office: Mortimer
House, 37-41 Mortimer Street, London W1T 3JH, UK
Nucleosides, Nucleotides and Nucleic Acids
Publication details, including instructions for authors and subscription information:
http://www.tandfonline.com/loi/lncn20
EFFICIENT SYNTHESIS OF FUSED ISOTHIAZOLO C-
NUCLEOSIDES. III. SYNTHESIS OF 7-SUBSTITUTED
ISOTHIAZOLO[4,5-d]PYRIMIDINE C-NUCLEOSIDES*
Heinrich Wamhoff a , Andrea Bamberg b & Pál Sohár b
a Kekulé-Institut für Organische Chemie und Biochemie der Universität Bonn , Gerhard-
Domagk-Str. 1, Bonn, D 53121, Germany
b Institute of Inorganic and General Chemistry, Eötvös Loránd University , Sétány u. 2,
Budapest, H-1117, Hungary
Published online: 17 Aug 2006.
To cite this article: Heinrich Wamhoff , Andrea Bamberg & Pál Sohár (2001) EFFICIENT SYNTHESIS OF FUSED ISOTHIAZOLO
C-NUCLEOSIDES. III. SYNTHESIS OF 7-SUBSTITUTED ISOTHIAZOLO[4,5-d]PYRIMIDINE C-NUCLEOSIDES* , Nucleosides,
Nucleotides and Nucleic Acids, 20:3, 229-241, DOI: 10.1081/NCN-100002083
To link to this article: http://dx.doi.org/10.1081/NCN-100002083
PLEASE SCROLL DOWN FOR ARTICLE
Taylor & Francis makes every effort to ensure the accuracy of all the information (the “Content”) contained
in the publications on our platform. However, Taylor & Francis, our agents, and our licensors make no
representations or warranties whatsoever as to the accuracy, completeness, or suitability for any purpose of
the Content. Any opinions and views expressed in this publication are the opinions and views of the authors,
and are not the views of or endorsed by Taylor & Francis. The accuracy of the Content should not be relied
upon and should be independently verified with primary sources of information. Taylor and Francis shall
not be liable for any losses, actions, claims, proceedings, demands, costs, expenses, damages, and other
liabilities whatsoever or howsoever caused arising directly or indirectly in connection with, in relation to or
arising out of the use of the Content.
This article may be used for research, teaching, and private study purposes. Any substantial or systematic
reproduction, redistribution, reselling, loan, sub-licensing, systematic supply, or distribution in any
form to anyone is expressly forbidden. Terms & Conditions of access and use can be found at http://
www.tandfonline.com/page/terms-and-conditions

NUCLEOSIDES, NUCLEOTIDES & NUCLEIC ACIDS, 20(3), 229–241 (2001)
EFFICIENT SYNTHESIS OF FUSED ISOTHIAZOLO
C-NUCLEOSIDES. III. SYNTHESIS OF
7-SUBSTITUTED
ISOTHIAZOLO[4,5-d]PYRIMIDINE
C-NUCLEOSIDES∗
Heinrich Wamhoff,1 Andrea Bamberg, and Pa´l Soha´r2
1Kekule´-Institut fu¨r Organische Chemie und Biochemie der Universita¨t
Bonn, Gerhard-Domagk-Str. 1, D 53121 Bonn, Germany
2Institute of Inorganic and General Chemistry, Eo¨tvo¨s Lora´nd
University, Se´ta´ny u. 2, H-1117 Budapest, Hungary
ABSTRACT
The Divakar-Reese procedure has been successfully applied for transforming
7-oxo-isothiazolo[4,5-d]pyrimidine C-nucleosides (4a,b, 5a,b, 6a) via 1,2,4-
triazol-1-yl intermediates (7a,b, 8a,b) into various 7-substituted C-nucle-
osides 15a,b, 16a,b, 17a, 18a, 19a,b, 20a,b; their subsequent deprotection
provides novel types of unusual C-glycosides 22b, 23a, 24a,b, 25b, 26b.
C-Nucleosides, possessing on its heterocyclic base other than naturally
occuring oxo- or amino substituents, are important model compounds for bio-
logical or medicinal studies (2,3). We want to report on the synthesis of novel 7-
substituted isothiazolo = [4,5-d]pyrimidine C-nucleosides. As we could show
in previous papers (1,4), there exists a simple approach to the protected C-
glycosides 4–6.
RESULTS AND DISCUSSIONS
The activation of the 4-CO-function with subsequent nucleophilic substitution
by a broad choice of N- and S-nucleophiles opens a efficient access to manifold
potentially active and novel C-glycosides. This activation method was introduced
∗See reference 1.
229
ꢀ
C
Copyright 2001 by Marcel Dekker, Inc.
www.dekker.com

ORDER
REPRINTS
´
230
WAMHOFF, BAMBERG, AND SOHAR
N
N
N
N
N
N
pyridine
POCl3
2
N
N
N
P
O
3
N
N
H
N
1
N
N
N
N
O
S
S
NH
N
N
N
N
TrO
TrO
N
H
N
N
O
O
R
R
POCl3
pyridine
O
O
O
O
or α
or α
4a,b R = H
5a,b R = SCH3
6a R = NH2
7a,b R = H
8a,b R = SCH3
9a R = NH2
Scheme 1.
by Divakar and Reese (5) on uracils and consists in the activation of an uracil
nucleoside (6) with a 1,2,4-triazole moiety 1 via a putative (5) tris-(1H-1,2,4-triazol-
1-yl)phosphinoxide 3 which has been isolated in pure state by reaction of 1,2,4-
triazole 1 and phosphorooxytrichloride 2 (7).
An alterated application of this Reese-Divakar procedure has been already re-
ported by Wamhoff and Berressem to afford the adenosine isostere (7-aminoisothia-
zolo[4,5-d]pyrimidine C-nucleoside) in high yield (1,4). Pedersen applied this
reaction to 2ꢁ,3ꢁ-Dideoxyuridine derivatives (8), and Robins et al. (9), however,
applied the 1,2,4-triazol-4-yl substituent for converting the amino group of adeno-
sine by treatment with bis-[(dimethylamino)methylene]hydrazine dihydrochloride
into a versatile leaving group. Recently, this method has been applied to the syn-
thesis of bicyclic N (4)-amino-2ꢁ-deoxycytidine derivatives (10).
==
We have treated the 4-C O group in 4a,b, 5a,b and 6a (11) with this system
1H-1,2,4-triazole, POCl3 (2:1) in pyridine as a base and obtained the appropriate 7-
(1,2,4-triazol-1-yl)-derivatives 7a,b, 8a,b and 9a after chromatographic purification
in 30–60% yield.
The isolated (12) 1,2,4-triazolyl-1-yl derivatives 7a,b, 8a,b enabled us to ex-
changethisheterocyclicsubstituentsmoothlyandundermildreactionconditionsfor

ORDER
REPRINTS
FUSED ISOTHIAZOLO C-NUCLEOSIDES. III
231
N
N
N
R′
10 HN(CH3)2
11 HN(CH2)17CH3
12 pyrrolidine
13 HSEt
S
S
N
N
N
N
TrO
TrO
N
14 H N
N
-
NH2/H2O
2
O
R
O
R
O
O
O
O
or α
or α
7a,b R = H
8a,b R = SCH3
15a,b R = H, R′ = N(CH3)2
16a,b R = SCH3 , R′ = N(CH3)2
17a R = H, R′ = N(CH2)17 CH3
18a R = H, R′ = pyrrolidin-1-yl
19a,b R = H, R′ = SEt
20a,b R = H, R′ = NHNH2
C(CH3)2
NHN
N
S
N
TrO
N
acetone
O
20a,b
O
O
or α
21a,b
Scheme 2.
several S- and N-nucleophiles and to generate a broad number of novel isothiazolo
[4,5-d]pyrimidine C-glycosides.
Thus, employing dimethylamine 10, octadecylamine 11, pyrrolidine 12, ethy-
lmercaptan 13, and hydrazine hydrate we converted 7a,b and 8a,b into the 4-
substituted C-glycosides 15a,b, 16a,b, 17a, 18a, 19a,b, 20a,b. The nucleophilic
displacement reaction was carried out at room temp. in absol. MeCN with DBU as
catalyst. After 6–12 h reaction time the products were purified by chromatography.
The reaction of hydrazine hydrate 14 with 7a,b in methylenechloride at room
temp. was accomplished already after 1.5 h duration to afford 20a,b. During the
chromatography with ethyl acetate/acetone these primary products 20a,b were con-
verted into the acetone hydrazones 21a,b.
Deprotection of 15b, 16a,b, 18a, 19a,b, 20a,b, and 21b to afford the free
C-glycosides 22b, 23a, 24a,b, 25b, 26b and 27a,b was effected by MeOH/HCl;
25b, 26b and 27a,b were obtained as monohydrochlorides.
EXPERIMENTAL
General Materials and Methods
1-β-D-Cyanomethylribofuranose was kindly supplied by Dr. Hagemann,
BAYER AG, Leverkusen; 5-Methylthio- and 5-Amino-3-(2,3-O-isopropylidene-5-
O-trityl-α(β)-D-ribofuranosyl)-isothiazolo[4,5-d]pyrimidine-7(6H)-ones 5a,b and

ORDER
REPRINTS
´
232
WAMHOFF, BAMBERG, AND SOHAR
R
R
N
S
S
N
N
N
N
14%ige HCl
MeOH
TrO
HO
N
O
O
O
O
OH OH
or α
or α
15a,b R = N(CH3)2
18a R = pyrrolidine
19a,b R = SEt
22a,b R = N(CH3)2
23a R = pyrrolidine
24a,b R = SEt
R
R
S
S
N
N
N
N
14%ige HCl
MeOH
TrO
HO
N
N
O
O
OH OH
or α
O
O
or α
20a,b R = NHNH2
21a,b R = NHNC(CH3)2
25a,b R = NHNH2
26a,b R = NHNC(CH3)2
N(CH3)
N(CH3)
S
S
N
N
N
N
14%ige HCl
MeOH
TrO
HO
N
N
SCH3
SCH3
O
O
or α
O
O
OH OH
or α
27a,b
16a,b
Scheme 3.
6a were prepared according to Lit (1,4,13). - 1H, 13C NMR spectra: Bruker AC-200
(200/50.29 MHz), WM-250 (250.13/62.19 MHz), AM-400 (400/100.62 MHz).
In some cases additionally DEPT 135 spectra were run, and CH-GEKO-,
NOE- and/or H, H-COSY measurements were undertaken. UV spectra: Beckman,
DU-640. IR spectra: Perkin-Elmer 1576 (in KBr). MS 50: FAB 70eV, 300 µA, DE

ORDER
REPRINTS
FUSED ISOTHIAZOLO C-NUCLEOSIDES. III
233
180◦ with 3-nitrobenzylalcohol as matrix. Melting points: SMP-20 of Bu¨chi and
apparatus of Leitz, Wetzlar. Microanalyses were performed in the Microanalytical
Laboratory of the Institute. TLC: on precoated plates Silica gel 60F254. Column
chromatography∗ was carried out on Silica gel 63–200 µm.
7-(1,2,4-Triazol-1-yl)isothiazolo[4,5-d]pyrimidines (7a,b, 8a,b, 9a)
General Procedure. To a solution of 1,2,4-1H-triazole 1 (1.8 g,
12.89 mmol) in absol. pyridine (45 mL) phosphoroxidtrichloride 2 (0.65 mL, 6.44
mmol) was added under ice-cooling and inert gas; then the reaction mixture was
stirred for 30 min. at 25◦C, and then 4a,b, 5a,b or 6a (1.97 mmol) were added and
stirred for additional 24 h at ambient temperature. The reaction mixture showed a
color change from yellow to lilac blue. Then ethyl acetate (50 mL) was added and
the solution was stirred for 2 h at room temp.. After evaporation to dryness, the
oily residue was purified firstly by flash-chromatography (PE/EE, 1:3) the obtained
product was dissolved in MeOH and further purified by chromatography.
7-(1,2,4-Triazol-1-yl)-3-(2,3-O-isopropylidene-5-O-trityl-α-D-ribofura-
nosyl)-isothiazolo[4,5-d]pyrimidine (7a) From 1.2 g (8.05 mmol of 1, 0.45 ml
(4.45 mmol) of 2, and 0.67 g (1.23 mmol) 4a in pyridine (30 mL); after chro-
matography (PE/EE 1:1) and recrystallization from MeOH yield 378 mg (54%),
white needles of mp 122–125◦C. IR ν 2990, 2915, 1570, 1500. UV (CHCl3) λmax
(log ε) 253 (3.97), 328 (3.85). 1H NMR (200 MHz, CDCl3) δ 1.18/1.24 (ss, 6H),
3.25 (dd, 1H, J = 10.4, 3.2), 3.58 (dd, 1H, J = 10.0, 3.2), 4.59 (m, 1H), 4.83 (d,
1H, J = 6.0), 5.57 (t, 1H, J = 4.8), 6.22 (d, 1H, J = 4.4), 7.48–7.21 (m, trityl),
8.31 (s, 1H), 9.42 (s, 1H), 9.15 (s, 1H). 13C NMR (50.3 MHz, CDCl3) δ 25.34,
26.09, 65.25, 82.60, 82.93, 83.80, 83.90, 87.75, 113.01, 127.34, 128.13, 128.79,
131.50, 142.30, 143.63, 149.20, 154.15, 154.30, 156.55, 162.23. MS (FAB) m/z
(rel. intens.) 619.2 (M + 1; 5.5), 618.2 (1.24), 243.1 (trityl; 5). HR-MS Calcd for
·
C34H30N6O4S: 618.2049; Found: 618.2042. Anal. Calcd for C34H30N6O4S H2O:
C, 64.13; H, 5.06; N, 13.18. Found: C, 63.98; H, 4.60; N, 13.26.
β-D-ribofuranosyl-isomer (7b). After chromatography (PE/EE 1:1) and
recrystallization from isopropanol yield 430 mg (35.0%), mp 93–95◦C. IR ν 3060,
2980, 2940, 1575, 1525, 1445. UV (CHCl3) λmax (log ε) 252 (3.83), 356 (3.84). 1H
NMR (200 MHz, CDCl3) δ 1.43, 1.66 (ss, 6H), 3.08–3.25 (m, 2H), 4.48 – 4.56 (m,
1H), 4.87(dd, 1H, J=6.25, 2.76), 5.59(d, 1H, J=6.25, 3.86), 5.69(d, 1H, J=3.86),
7.12–7.36 (m, 15H), 8.32 (s, 1H), 9.13 (s, 1H), 9.40 (s, 1H). 13C NMR (50.3 MHz,
CDCl3) δ 25.70, 27.48, 63.87, 81.62, 83,15, 83.34, 85.11, 86.60, 114.04, 126.90,
127.70, 128.61, 132.01, 142.36, 143.70, 149.13, 154.07, 154.47, 156.81, 163.17.
MS (FAB) m/z (rel. intens.) 619.2, (M + 1; 11.2) 243.1 (trityl; 100). Anal. Calcd
for C34H30N6O4S: C, 66.00; H, 4.89; N, 13.58. Found: C, 65.49; H, 4.82; N, 13.29.
∗Abbreviations for solvents: EE: ethyl acetate; PE: petroleum ether.

ORDER
REPRINTS
´
WAMHOFF, BAMBERG, AND SOHAR
234
5-Methylthio-7-(1,2,4-triazol-1-yl)-3-(2,3-O-isopropylidene-5-O-trityl-α-
D-ribofuranosyl)-isothiazolo[4,5-d]pyrimidine (8a). From 400 mg (0.65 mmol)
of 5a; after chromatography (EE/cyclohexane 2:1) and recrystallization from iso-
propanol/ MeOH yield 163 mg (37.8 %), mp 160–162◦C. IR ν 3050, 2980, 2920,
1560, 1490, 1445. UV (CHCl3) λmax (log ε) 244 (4.11), 269 (4.23), 373 (3.53).
1H NMR (200 MHz, CDCl3) δ 1.15/1.21 (ss, 6H), 2.59 (s, 3H), 3.15 (dd, 1H, J
= 10.33, 2.96), 3.55 (dd, 1H, J = 10.34, 3.20), 4.48–4.52 (m, 1H), 4.82 (d, 1H,
J = 5.90), 5.51 (t, 1H, J = 5.42), 6.07 (d, 1H, J = 4.68), 7.10–7.36 (m, 15H),
8.17 (s, 1H), 9.22 (s, 1H). 13C NMR (CDCl3) δ 14.69, 25.37, 26.09, 65.69, 82.69,
82.92, 83.72, 83.89, 87.67, 113.05, 127.22, 127.91, 128.70, 129.69, 142.36, 143.55,
148.49, 154.00, 156.87, 161.02, 169.11. MS (FAB) m/z (rel. intens.) 665.2 (M + 1;
·
15.7) 243.1 (trityl; 100). Anal. Calcd for C35H32N6O4S 0.5 MeOH: C, 62.62; H,
4.99; N, 12.34; S, 9.40. Found: C, 62.33; H, 4.76; N, 12.14; S, 9.40.
β-D-ribofuranosyl isomer (8b). From 410 mg (0.67 mmol) of 5b; after
chromatography (PE/EE 1:1) and recrystallization from isopropanol/MeOH yield
◦
268 mg (60.4 %), mp 102–103 C. IR ν 3060, 2970, 2920, 1560, 1520, 1445.
UV (CHCl3) λmax (log ε) 244 (4.40), 270 (4.55), 370 (3.86). 1H NMR (200 MHz,
CDCl3) δ 1.22/1.40 (s, 6H), 2.65 (s, 3H), 3.75–4.06 (m, 2H), 4.46–4.52 (m, 1H),
5.02 (d, 1H, J = 5.88), 5.13 (t, 1H, J = 5.40), 5.63 (d, 1H, J = 4.70), 7.12–7.41 (m,
15H), 8.28 (s, 1H), 9.31 (s, 1H). 13C NMR (CDCl3) δ 14.65, 25.63, 27.50, 64.30,
82.70, 83.79, 83.89, 84.71, 86.70, 114.11, 127.26, 128.05, 128.35, 129.70, 142.43,
143.78, 148.48, 154.00, 157.44, 162.22, 169.59. MS (FAB) m/z (rel. intens.) 665.2
(M+1; 8.92), 243.1 (trityl; 100). Anal. Calcd for C35H32N6O4S2 · 0.5 MeOH: C,
62.62; H, 4.99; N, 12.34; S, 9.40. Found: C, 62.64; H, 5.08; N, 12.15; S, 9.45.
5-Amino-7-(1,2,4-triazol-1-yl)-3-(2,3-O-isopropylidene-5-O-trityl-α-D-
ribo-furanosyl)-isothiazolo[4,5-d]pyrimidine (9a). From 180 mg (0.31 mmol)
of 6a; after chromatography (EE) and recrystallization from isopropanol yield
60 mg (30.6%), mp 120–125◦C (dec.). IR ν 3470, 3330, 3200, 3050, 2970, 2920,
1
1590, 1490, 1445. UV (CHCl3) λmax (log ε) 244 (4.18), 372 (3.66). H NMR
(CDCl3) δ 1.14/1.27 (s, 6H), 3.19 (dd, 1H, J = 10.34, 3.69), 3.50 (dd, 1H, J =
10.09, 3.69), 4.52 (d, 1H, J = 3.45), 4.75 (d, 1H, J = 5.91), 5.28 (s, 2H), 5.41 (t,
1H, J = 5.42), 5.92 (d, 1H, J = 4.92), 7.03–7.43 (m, 15H), 8.16 (s, 1H), 9.15 (s, 1H).
13C NMR (CDCl3) δ 25.41, 26.11, 65.13, 82.19, 82.65, 83.59, 83.68, 87.57, 113.06,
127.23, 127.99, 128.73, 129.98, 142.05, 143.61, 149.68, 153.70, 158.46, 160.03,
160.80. MS (FAB) m/z (rel. intens.): 634.2 (M + 1: 8.5), 243.1 (trityl; 100). Anal.
Calcd for C34H31N7O4S: C, 64.44; H, 4.93; N, 15.47; S, 5.06. Found: C, 64.24; H,
5.08; N, 15.78; S, 5.28.
7-Substituted Isothiazolo[4,5-d]pyrimidine C-glycosides 15a,b, 16a,b,
17a, 18a, 19a,b, 20a,b
General Procedure. A suspension of the 7-(1,2,4-triazol-1-yl) derivatives
7a,b, 8a,b (1.13 mmol) and the nucleophiles 10-14 (140 mmol) was stirred for

ORDER
REPRINTS
FUSED ISOTHIAZOLO C-NUCLEOSIDES. III
235
12 h at ambient temperature; then ethyl acetate (10 mL) was added and the reaction
mixture evaporated, purified by column chromatography, and recrystallization.
7-Dimethylamino-3-(2,3-O-isopropylidene-5-O-trityl-α-D-ribofuranosyl)-
isothiazolo[4,5-d]pyrimidine (15a). Obtained from 7a (400 mg, 0.65 mmol) and
aq. (40%) dimethylamine 10 (3 mL, 60 mmol); after chromatography (PE/EE 1:1)
andrecrystallizationfromisopropanol/methanolyield45mg(11.7%), mp78–80◦C.
IR ν 3050, 3010, 2960, 2920, 1560, 1445. UV (CHCl3) λmax (log ε) 242 (3.88), 271
(4.03), 332 (3.96). 1H NMR (CDCl3) δ 1.12/1.22 (s, 6H), 3.35 (s, 6H), 3.18–3.41
(m, 2H), 4.52–4.58 (m, 1H), 4.76 (d, 1H, J = 6.16), 5.38–5.44 (m, 1H), 5.86 (d,
1H, J = 4.68), 7.11–7.49 (m, 15H), 8.51 (s, 1H). 13C NMR (CDCl3) δ 25.36, 26.12,
38.50, 64.26, 82.10, 82.45, 83.57, 83.60, 87.41, 112.95, 127.15, 127.90, 128.69,
130.22, 143.62, 154.95, 154.99, 157.71, 161,78. MS (FAB) m/z (rel. intens.): 595.2
•
(M + 1; 24.1), 243.1 (trityl; 100). Anal. Calcd for C34H34N4O4S 0.5 MeOH: C,
67.84; H, 5.89; N, 9.17; S, 5.24. Found: C, 67.90; H, 5.59; N, 9.41; S, 5.50.
β-D-Ribofuranosyl isomer (15b). After chromatography (PE/EE 1:1) and
recrystallization from methanol yield 422 mg (62.9%), mp 188◦C. IR ν 3050, 3020,
2980, 2930, 1570, 1500, 1445. UV (CHCl3) λmax (log ε) 244 (3.88), 272 (4.12),
332 (3.88). 1H NMR (CDCl3) δ 1.31/1.55 (s, 6H), 3.07–3.13 (m, 2H), 3.28 (s, 2H),
4.38–4.44 (m, 1H), 4.73–4.80 (m, 1H), 5.47–5.58 (m, 1H), 7.03–7.38 (m, 15H),
8.52 (s, 1H). 13C NMR (CDCl3) δ 25.58, 25.81, 38.45, 64.14, 81.65, 83.26, 84.96,
86.59, 113,87, 127.72, 127.92, 128.72, 130.79, 143.91, 153.63, 155.51, 157.56,
163.28. MS (FAB) m/z (rel. intens.): 595.2 (M + 1; 89.3), 243.1 (trityl; 100). Anal.
Calcd for C34H34N4O4S: C, 68.67; H, 5.76; N, 9.42; S, 5.39. Found: C, 68.44; H,
5.79; N, 9.26; S, 5.23.
7-Dimethylamino-5-methylthio-3-(2,3-O-isopropylidene-5-O-trityl-α-D
-ribofuranosyl)-isothiazolo[4,5-d]pyrimidine (16a). Preparation from 8a
(130 mg, 0.2 mmol) and aq. (40%) dimethylamine 10 (3 mL, 60 mmol); after
chromatography (PE/EE 1:1) and recrystallization from isopropanol yield 50 mg
(39%), mp 108–110◦C. IR ν 3050, 2920, 1560, 1500. UV (CHCl3) λmax (log ε) 244
(4.54), 270 (4.36), 307 (3.63), 338 (4.01). 1H NMR (CDCl3) δ 1.18/1.25 (ss, 6H),
2.49 (s, 3H), 3.13–3.48 (m, 2H), 3.30 (s, 6H), 4.46–4.52 (m, 1H), 5.02 (d, 1H, J =
5.88), 5.13 (t, 1H, J = 5.40), 5.63 (d, 1H, J = 4.70), 7.12–7.41 (m, 15H).13C NMR
(CDCl3): δ 14.39, 25.35, 26.18, 38.32, 65.18, 82.90, 83.57, 83.72, 83.89, 87.66,
112.78, 127.25, 127.80, 128.03, 129.69, 143.64, 156.87, 161.07, 168.59, 169.13.
MS (FAB) m/z (rel. intens.) 641.1 (M + ; 100), 243.1 (trityl; 100). Anal. Calcd for
C35H36N6O4S2: C, 65.60; H, 5.66; N, 8.74; S, 10.01. Found: C, 65.20; H, 5.96; N,
8.35; S, 10.06.
β-D-ribofuranosyl isomer (16b). Obtained as 16a from 8b (140 mg,
0.21 mmol), aq. (44%) dimethylamine 10 (3 mL, 60 mmol); after chromatog-
raphy (PE/EE 1:1) and recrystallization from isopropanol yield 76 mg (56.7%),
mp 82–85◦C. IR ν 3050, 3020, 2980, 2920, 1560, 1500, 1445. UV (CHCl3) λmax
1
(log ε) 242 (3.87), 271 (4.08), 329 (4.00). H NMR (CDCl3) δ 1.28/1.54 (ss,
6H), 2.41 (s, 3H), 3.07–3.22 (m, 2H), 3.22 (s, 6H), 4.32–4.38 (m, 1H), 4.72–4.78
(m, 1H), 5.26–5.33 (m, 1H), 5.63 (d, 1H, J = 3.45), 7.05–7.37 (m, 15H). 13C NMR

ORDER
REPRINTS
´
WAMHOFF, BAMBERG, AND SOHAR
236
(CDCl3) δ 14.23, 25.69, 27.53, 38.35, 65.36, 81.30, 83.49, 83.75, 85.04, 86.64,
113.80, 126.98, 127.81, 128.77, 129.70, 143.95, 154.47, 156.59, 162.50, 160.09.
MS (FAB) m/z (rel. intens.) 641.1 (M + ; 80.3), 243.1 (trityl; 100). Anal. Calcd for
C35H36N4O4 S2: C, 65.60; H, 5.66; N, 8.74; S, 10.01. Found: C, 65.16; H, 5.83; N,
8.27; S, 10.06.
7-Octadecylamino-3-(2,3-O-isopropylidene-5-O-trityl-α-D-ribofuranosyl)
-isothiazolo[4,5-d]pyrimidine (17a). Obtained from 7a (190 mg, 0.3 mmol) in
absol. MeCN (15 mL) and octadecylamine 11 (1.0 g, 3.7 mmol) and DBU (0.2 mL,
1.3 mmol) and 12 h stirring at ambient temperature and in an argon atmosphere.
After evaporation, chromatography (PE/EE 7:3) and recrystallization from EtOH
yield 98 mg (40%), mp 68–70◦C. IR ν 3310, 3050, 3010, 2910, 2840, 1560, 1530,
1480, 1445. UV (CHCl3) λmax (log ε) 244 (3.91), 302 (3.91). 1H NMR (CDCl3) δ
0.82–1.44 (m, 43H, alkyl, 2 CH3), 3.13–3.55 (m, 2H), 4.50–4.60 (m, 1H), 4.75 (d,
1H, J = 6.16), 5.44 (t, 1H, J = 5.08), 6.02 (d, 1H, J = 4.68), 7.10–7.45 (m, 15H),
8.71 (s, 1H). 13C NMR (CDCl3) δ 14.33, 22.72, 25.35, 26.08, 26.13, 26.94, 29.31,
29.39, 29.56, 29.61, 29.68, 29.73, 31.95, 54.62, 63.74, 82.50, 82.69, 83.64, 83.69,
87.55, 113.05, 127.20, 128.01, 128.79, 132.58, 143.58, 154.50, 155.23, 162.21,
163.06. MS (FAB) m/z (rel. intens.) 819.5 (M + 1; 57.1), 243.1 (trityl; 100), Anal.
·
Calcd for C50H66N4O4S EtOH: C, 72.18; H, 8.02; N, 6.47. Found: C, 71.81; H,
7.44; N, 6.51.
7-Pyrrolidino-3-(2,3-O-isopropylidene-5-O-trityl-α-D-ribofuranosyl)-iso-
thiazolo[4,5-d]pyrimidine (18a). Obtained from 7a (470 mg, 0.75 mmol) in ab-
sol. MeCN (40 mL), pyrrolidine (12) (1.03 mL, 12.22 mmol), and DBU (0.47 mL,
3.1 mmol) with 6 h stirring at 25◦C in an argon atmosphere; after evaporation the
residue was recrystallized from isopropanol; yield 440 mg (94.4%), mp 176–178◦C.
IR ν 3050, 3020, 2970, 2930, 2860, 1560, 1500, 1445. UV (CHCl3) λ (qualit.) 248,
1
274, 330. H NMR (CDCl3) δ 1.14/1.20 (ss, 6H), 1.91–2.06 (m, 4H), 3.15–3.38
(m, 2H), 3.61–3.90 (m, 4H), 4.50–4.55 (m, 1H), 4.76 (d, 1H, J = 6.16), 5.36–
5.41 (m, 1H), 5.81 (d, 1H, J = 4.68), 7.11–7.41 (m, 15H), 8.49 (s, 1H). 13C NMR
(CDCl3) δ 24.55, 25.35, 26.00, 26.14, 47.37, 47.78, 64.21, 82.10, 82.42, 83.57,
87.39, 112.93, 127.17, 127.98, 128.69, 131.10, 143.63, 155.32, 154.99, 161.78.
MS (FAB) m/z (rel. intens.): 621.3 (M + 1; 29.0), 243.1 (trityl; 100). Anal. Calcd
for C36H36N4O4S: C, 69.66; H, 5.85; N, 9.03; S, 5.16. Found: C, 69.38; H, 5.85;
N, 8.85; S, 5.31.
7-Ethylthio-3-(2,3-O-isopropylidene-5-O-trityl-α-D-ribofuranosyl)-iso-
thiazolo[4,5-d]pyrimidine (19a). Obtained from 7a (500 mg, 0.81 mmol), ethyl-
mercaptan (1.0 mL, 13 mmol), DBU (0.43 mL, 2.8 mmol) in absol. MeCN (50 mL).
The solvent was removed in vacuo and the residue chromatographed (PE/EE 7:2);
recrystallization from isopropanol; yield 346 mg (70%) colorless needles of mp
135◦C. IR ν 2990, 2915, 1585, 1510. UV (CHCl3) λmax (log ε) 239 (3.91), 270
(3.92), 324 (4.15). 1H NMR (250 MHz, CDCl3) δ 1.18/1.25 (ss, 6H), 1.46 (t, 3H, J
= 7.3), 3.22 (dd, 1H, J = 10.1, 3.6), 3.52 (dd, 1H, J = 10.2, 4.0), 3.69 (q, 2H, J =
6.9), 4.55 (m, 4ꢁ-H), 4.81 (d, 1H, J = 6.1), 5.50 (t, 1H, J = 4.7), 6.06 (d, 1H, J = 4.6),

ORDER
REPRINTS
FUSED ISOTHIAZOLO C-NUCLEOSIDES. III
237
7.12–7.45 (m, trityl), 8.97 (s, 1H). 13C NMR (62.9 MHz, CDCl3) δ 14.58, 24.33,
25.44, 26.18, 64.96, 82.65, 82.82, 83.74, 83.82, 87.66, 113.17, 127.30, 128.10,
128.78, 141.62, 143.65, 150.94, 154.25, 162.80, 164.17. MS m/z (rel. intens.):
611 (M+; 0.13), 368 (0.98), 243 (2). HR-MS Calcd. for C34H33N3O4S2: 611.1913;
Found: 611.1913. Anal. Calcd for C34H33N3O4S2: C, 66.75; H, 5.44; N, 6.87. Found
C, 66.62; H, 5.53; N, 6.92.
β-D-ribofuranosyl-isomer (19b). Obtained from 7a (320 mg, 0.52 mmol)
in absol. MeCN (50 mL); ethylmercaptan (0.7 mL, 9.1 mmol) and DBU (0.3 mL, 2
mmol) with 6 h stirring at 25◦C in an argon atmosphere. Evaporating of the solvent
and chromatography (PE/EE 7:2) of the yellow sirupous residue and recrystalliza-
tion from isopropanol gave 240 mg (76%) of colorless crystals of mp 75◦C. IR ν
3060, 2990, 2930, 1590, 1530, 1445. UV (CHCl3) λmax (log ε) 244 (3.91), 271
(3.90), 325 (4.07). 1H NMR (250 MHz, CDCl3) δ 1.48 (t, 3H, J = 7.38), 1.48/1.63
(ss, 6H), 3.13 (d, 2H, J = 5.26), 3.43 (q, 2H, J = 7.35), 4.45–4.51 (m, 1H), 4.85 (dd,
1H, J = 6.18, 2.74), 5.59 (dd, 1H, J = 6.18, 3.65), 5.61 (d, 1H, J = 3.58), 7.15–7.34
(m, 15H), 8.99 (s, 1H). 13C NMR (62.9 MHz, CDCl3) δ 15.06, 24.92, 26.36, 28.90,
64.66, 82.55, 83.88, 83.98, 85.79, 87.24, 114.52, 127.54, 128.32, 129.27, 142.72,
144.40, 152.15, 155.02, 164.68, 164.87. MS (FAB) m/z (rel. intens.): 612.2 (M+1;
1.55), 596.2 (M-15; 0.52), 243.1 (trityl; 32.8). Anal. Calcd for C34H33N3O4S2: C,
66.75; H, 5.44; N, 6.87. Found: C, 66.25; H, 5.26; N, 6.67.
7-Hydrazino-3-(2,3-O-isopropylidene-5-O-trityl-α-D-ribofuranosyl)-iso-
thiazolo[4,5-d]pyrimidine (20a). Obtained by treatment of 7a (250 mg, 0.4
mmol) in CH2Cl2 (30 mL) with hydrazine hydrate (98%, 2 mL), and stirring for
4 h at 25◦C. Evaporation of the solvent; after chromatography (EE) and recrys-
tallization from isopropanol; yield 21.4 mg (7.4%), mp 205–210◦C. IR ν 3340,
3230, 2930, 1650, 1560, 1540. UV (CHCl3) λmax (log ε) 239 (3.75), 260 (3.80),
1
317 (3.87). H NMR (250 MHz, CDCl3) δ 1.24/1.32 (ss, 6H), 3.24 (dd, 1H, J =
10.0, 4.4), 3.44 (dd, 1H, J = 10.1, 4.6), 4.12 (s, br, NH2), 4.59 (m, 4ꢁ-H), 4.80
(d, 1H, J = 5.8), 5.43 (t, 1H, J = 4.9), 5.91 (d, 1H, J = 4.2), 7.46–7.18 (m,
trityl), 8.44 (s, 1H), 8.58 (s, br, NH). 13C NMR (62.9 MHz, CDCl3) δ 25.48, 26.28,
64.39, 81.81, 82.59, 83.63, 83.70, 87.63, 113.10, 127.34, 128.14, 128.44, 128.84,
143.73, 153.00, 153.93, 160.60, 160.96. MS m/z (rel. intens.): 581 (M+; 0.40),
243 (trityl; 5). HR-MS Calcd for C32H31N5O4S2: 581.2097; Found 581.2104. Anal.
Calcd for C32H31N5O4S: C, 66.08; H, 5.37; N, 12.04. Found: C, 67.70; H, 5.30; N,
11.52.
β-D-ribofuranosyl isomer (20b). Obtained by treatment of a solution of 7b
(650 mg, 1.05 mmol) in CH2Cl2 (100 mL) with hydrazine hydrate 14 (98%, 4 mL)
and stirring for 1.5 h at room temp. Evaporation of the solvent is followed by chro-
matography (EE/EtOH 8:1) of the residue and recrystallization from isopropanol/
MeOH; yield 210 mg (34.4%), mp 200–203◦C. IR ν 3330, 3210, 3050, 2970,
2930, 1660, 1560, 1445. UV (CHCl3) λ (qualit.): 259, 319. 1H NMR (250 MHz,
CDCl3) δ 1.36/1.62 (ss, 6H), 3.17 (dd, 1H, J = 5.15, 9.93), 3.28 (dd, 1H, J = 4.96,
9.93), 4.06 (s, br, 2H), 4.41–4.49 (m, 1H), 4.78–4.84 (m, 1H), 5.53–5.57 (m, 2H),

ORDER
REPRINTS
´
WAMHOFF, BAMBERG, AND SOHAR
238
7.13–7.42 (m, 15H), 8.44 (s, 1H). 13C NMR (62.9 MHz, CDCl3) δ 25.66, 27.48,
64.22, 80.97, 82.78, 83.19, 84.80, 86.82, 114.25, 127.05, 127.83, 128.67, 128.90,
143.68, 153.36, 155.00, 160.71, 161.17. MS (FAB) m/z (rel. intens.): 582.2 (M + 1;
98), 243.1 (trityl; 100). Anal. Calcd for C34H33N3O4S2 · 0.5 MeOH: C, 65.25; H,
5.52; N, 11.71. Found: C, 65.18; H, 5.68; N, 11.70.
7-Isopropylidenehydrazino-3-(2,3-O-isopropylidene-5-O-trityl-α-D-ribo
-furanosyl)-isothiazolo[4,5-d]pyrimidine (21a). 7a (250 mg, 0.4 mmol) was
treated with hydrazine hydrate (98%, 2 mL) in CH2Cl2 (100 mL) for 1.5 h at
room temp. After evaporation the residue was treated with acetone for 1 h at am-
bient temp., and the mixture concentrated in vacuo; chromatography (EE/acetone
2:1) and recrystallization from Petroleum ether 60/90/ethyl acetate; yield 62.3 mg
(25%), mp 215◦C. IR ν 3340, 3240, 2940, 1630, 1560. UV (CHCl3) λmax (log ε)
239 (3.7), 277 (3.85), 330 (3.95).1H NMR (250 MHz, CDCl3) δ 1.21/1.28 (ss, 6H),
2.01/2.18 (s, 6H), 3.23 (dd, 1H, J = 10.0, 4.1), 3.45 (dd, 1H, J = 10.0, 4.7), 4.57
(t, 1H, J = 4.2), 4.82 (d, 1H, J = 6.2), 5.47 (t, 1H, J = 4.9), 5.97 (d, 1H, J =
4.6), 7.47–7.16 (m, trityl), 8.58 (s, 1H), 8.64 (s, NH).13C NMR (62.9 MHz, CDCl3)
δ 16.77, 25.47, 25.56, 26.26, 64.60, 82.14, 82.76, 83.66, 83.78, 87.58, 113.09,
127.29, 128.10, 128.84, 129.95, 143.76, 151.43, 154.27, 156.63, 160.97, 162.97.
MS (FAB) m/z (rel. intens.): 622.2 (M + 1; 70), 243.1 (trityl; 55). Anal. Calcd for
C35H35N3O4S2: C, 67.61; H, 5.67; N, 11.26. Found: C, 65.63; H, 5.00; N, 12.11.
β-D-ribofuranosyl isomer (21b). A solution of 7b (250 mg, 0.40 mmol) in
CH2Cl2 (100 mL) was stirred with hydrazine hydrate 14 (98%, 2 mL) for 1.5 h at
room temp. After evaporation the residue was treated with acetone for 1 h at ambient
temp., and the mixture concentrated in vacuo; after chromatography (EE/acetone
2:1) and recrystallization from ethyl acetate; yield 210 mg (89.4%), mp 245–256◦C
(dec). IR ν 3250, 3060, 2990, 2930, 1660, 1560, 1490, 1445. UV (CHCl3) λmax (log
ε) 244 (4.11), 276 (4.47), 331 (4.61). 1H NMR (250 MHz, CDCl3) δ 1.39/1.63 (ss,
6H), 1.99 (s, 3H), 2.19 (s, 3H), 3.11–3.18 (m, 2H), 4.44–4.52 (m, 1H), 4.82–4.86 (m,
1H), 5.58–5.62 (m, 2H), 7.16–7.38 (m, 15H), 8.50 (s, 1H), 8.59 (s, 1H). 13C NMR
(62.9 MHz, CDCl3): δ 16.94, 24.20, 24.45, 26.43, 63.06, 79.83, 81.89, 82.20, 83.75,
85.16, 112.19, 125.85, 126.65, 127.37, 129.30, 142.71, 147.60. 151.50, 155.80,
160.75. MS (FAB) m/z (rel. intens.): 622.2 (M + 1; 4.23), 243.1 (trityl; 41.5).
Anal. Calcd for C34H33N3O4S2: C, 67.61; H, 5.67; N, 11.26. Found: C, 67.14; H,
5.64; N, 11.48.
Synthesis of the Free C-Glycosides 22b, 23a, 24a,b, 25b,
26b, 27a,b by Deprotection.
General Procedure. A solution of the protected nucleoside was stirred in
methanolicHCl (14%HCl) for1–2hatroomtemp. Thenthesolventwas removedin
vacuo and the residue was treated with ether. The solid obtained was recrystallized.
7-Dimethylamino-3-β-D-ribofuranosylisothiazolo[4,5-d]pyrimidine(22b).
Prepared from 15b (500 mg, 0.84 mmol) in HCl/MeOH (15 mL) by 1 h stirring;

ORDER
REPRINTS
FUSED ISOTHIAZOLO C-NUCLEOSIDES. III
239
recrystallization from MeOH; yield 200 mg (75.7%), white crystals of mp
213−215◦C. IR ν 3260, 2920, 1600, 1570. UV (CHCl3) λ (qualit.) 271, 332.
1H NMR (DMSO-d6) δ 3.45 (s, br, 6H), 3.35–5.41 (m, br 9H), 8.61 (s, 1H).
13C NMR (DMSO-d6) δ 38.98, 61.88, 71.86, 74.35, 80.46, 85.92, 131.57, 146.69,
152.37, 157.17, 161.84. MS (FAB) m/z (rel. intens.) 313.1 (M + 1; 31.2). Anal.
Calcd for C12H10N4O4S: C, 46.13; H, 5.12; N, 17.94. Found: C, 45.85; H, 4.99; N,
17.78.
7-Pyrrolidino-3-α-D-ribofuranosylisothiazolo[4,5-d]pyrimidine (23a).
Obtained from 18a (434 mg, 0.7 mmol) in MeOH/HCl (20 mL) by stirring ◦for
2 h, and recrystallization from ethanol; yield 200 mg (84.7%), mp 112–115 C.
IR ν 3030–3400, 2900, 1580, 1540, 1445. UV (CHCl3) λ (qualit.) 276, 322,
1
336. H NMR (DMSO-d6) δ 1.98–2.20 (m, 4H), 3.51 (d, 1H, J = 11.57), 3.69
(d, 1H, J = 11.32), 3.82–4.11 (m, 4H), 4.23 (m, 2H), 4.43 (m, 1H), 5.23 (s,
br. 3H), 5.53 (d, 1H, J = 3.94), 8.71 (s, 1H). 13C NMR (DMSO-d6) δ 23.79,
25.38, 48.88, 49.65, 61.20, 71.87, 73.48, 80.57, 83.18, 132.80, 144.00, 150.15,
154.20, 159.17. MS (FAB) m/z (rel. intens.) 339.1 (M + 1; 100). Anal. Calcd for
C14H18N4O4S•MeOH: C, 48.63; H, 5.94; N, 15.13. Found: C, 48.43; H, 5.72; N,
14.69.
7-Ethylthio-3-α-D-ribofuranosylisothiazolo[4,5-d]pyrimidine(24a) From
19a (320 mg, 0.52 mmol) in MeOH/HCl (5 mL); recrystallization from ethanol;
yield 142 mg (83%) of colorless crystals of mp 145◦C. IR ν 3390, 3250, 2910,
1570, 1545. UV (EtOH) λmax (log ε) 271 (3.71), 324 (3.94). 1H NMR (250 MHz,
DMSO-d6) δ ), 1.39 (t, 3H, J = 5.2), 3.4 (s, br. OH), 3.45 (q, 2H, J = 5.0), 3.97 (m,
1H), 4.14 (m, 1H), 4.54 (q, 1H, J = 3.2), 4.74 (m, 1H), 4.99 (d, 1H, J = 5.2), 5.63 (d,
1H, J = 3.0) 9.08 (s, 1H).13C NMR (62.9 MHz, DMSO-d6) δ 14.45, 23.80, 61.32,
71.87, 72.68, 80.41, 82.48, 140.20, 151.07, 154.21, 163.21, 165.25. MS (FAB) m/z
(rel. intens.): 330.0 (M + 1; 13). Anal. Calcd for C12H15N3O4S2: C, 43.76; H, 4.59;
N, 12.76. Found: C, 44.10; H, 4.42; N, 12.58.
β-D-ribofuranosylisothiazolo isomer (24b). Obtained from 19b (150 mg,
16 mmol) in MeOH/HCl (5 mL); recrystallization from ethanol; yield 69.95 mg
(86.4%) of white pearly crystals of mp 156–158◦C. IR ν 3380, 3250, 2940, 2900,
2880, 1530. UV (EtOH) λmax (log ε) 203 (4.26), 225 (4.34), 270 (3.87), 324 (4.20).
1H NMR (250 MHz, DMSO-d6) δ 1.39 (t, 3H, J = 7.32), 3.45 (q, 2H, J = 7.32),
3.51–3.66 (m, 2H), 3.94 (q, 1H, J = 4.26), 4.12 (q, 1H, J = 5.0), 4.55 (q, 1H, J
= 6.09), 4.87–4.92 (m, 1H), 5.05 (d, 1H, J = 5.19), 5.18 (d, 1H, J = 6.29), 5.24
(d, 1H, J = 6.28), 9.11 (s, 1H). 13C NMR (62.9 MHz, DMSO-d6) δ 14.36, 23.91,
62.26, 71.81, 74.16, 79.85, 85.78, 141.24, 150.97, 154.25, 163.85, 165.51. MS
(FAB) m/z (rel. intens.): 330.0 (M + 1; 100). Anal. Calcd for C12H15N3O4S2: C,
43.76; H, 4.59; N, 12.76. Found: C, 44.02; H, 4.47; N, 12.50.
7-Hydrazino-3-β-D-ribofuranosylisothiazolo[4,5-d]pyrimidine (25b).
Obtained from 20b (150 mg, 0.25 mmol) in HCl/MeOH (5 mL) after stirring 1
h; recrystallization from MeOH; yield 51.0 mg (68.9%), mp 205–208◦C. IR ν
3380, 3250, 2930, 1590. UV (EtOH) λ (qualit.) 203, 269, 322. 1H NMR (250 MHz,
DMSO-d6) δ 3.61–3.70 (m, 2H), 4.00–4.06 (m, 1H), 4.09 (dd, 1H, J = 3.49, 4.78),

ORDER
REPRINTS
´
WAMHOFF, BAMBERG, AND SOHAR
240
4.18 (s, br, 3H), 4.32 (dd, 1H, J = 5.33, 6.22), 5.08 (d, 1H, J = 6.80), 5.33 (s, br, 2H),
8.58 (s, 1H), 11.41 (s, br, 1H). 13C NMR measurements turned out to be impossible
due to the poor solubility. MS (FAB) m/z (rel. intens.): 300.0 (M+1; 57.9). Anal.
Calcd for C10H13N5O4S · HCl · 0.5 MeOH: C, 34.28; H, 4.35; N, 19.05. Found: C
34.37; H, 4.40; N, 19.59.
7-Isopropylidenehydrazino-3-β-D-ribofuranosylisothiazolo[4,5-d]pyri-
midine (26b). By treatment of 21b (140 mg, 0.23 mmol) in MeOH/HCl (5 mL);
recrystallization from MeOH; yield 53.0 mg (67.9%), mp 195–198◦C. IR ν 3330,
3120, 2930, 1590, 1560. UV (EtOH) λmax (log ε) 204 (4.20), 281 (3.70), 333 (3.87).
1H NMR (200 MHz, DMSO-d6) δ 2.11, 2.15 (ss, 2H), 3.57 (dd, 1H, J = 11.95,
3.31), 3.67 (dd, 1H, J = 11.95, 3.12), 3.97 (d, 1H, J = 3.31), 4.08 (dd, 1H, J = 4.78,
3.86), 4.41 (dd, 1H, J = 6.62, 5.15), 4.48 (s, br, 3H), 5.14 (d, 1H, J = 6.80), 8.67
(s, 1H), 11.68 (s, br, 1H).13C NMR (62.9 MHz, DMSO-d6) δ 18.68, 25.23, 61.78,
71.85, 74.73, 81.29, 85.81, 130.78, 150.16, 151.97, 157.49, 159.45, 160.49. MS
(FAB) m/z (rel. intens.): 340 (M + 1; 100). Anal. Calcd for C13H17N5O4S · HCl:
C, 41.58; H, 4.79; N, 18.66. Found: 41.10; H, 4.29; N, 18.43.
7-Dimethylamino-5-methylthio-3-α-D-ribofuranosylisothiazolo[4,5-d]
pyrimidine (27a). By treatment of 16a (150 mg, 0.23 mmol) in MeOH/HCl
(10 mL) for 1 h. The solid obtained was recrystallized from EtOH; yield 48 mg
(65.7%), mp 173–175◦C. IR ν 3400–3100, 2900, 1590, 1560, 1445. UV (EtOH)
δ (qualit.) 252, 266, 322, 342.1H NMR (DMSO-d6) δ 2.52 (s, 3H), 3.22 (s, 6H),
3.48–3.71 (m, 2H), 3.94–4.00 (m, 1H), 4.12–4.18 (m, 1H), 4.56 (t, 1H, J-4.18),
4.94 (s, br, 3H), 5.49 (d, 1H, J-4.18). 13C NMR (DMSO-d6) δ 13.60, 51.48, 61.31,
80.47, 82.09, 82.47, 86.32, 143.55, 147.68, 155.93, 161.96, 167.06. MS (FAB) m/z
(rel. intens.) 359.0 (M+1; 52.7). Anal. Calcd for C13H18N4O4S2 · HCl: C, 39.48,
H, 4.80; N, 14.17. Found: C, 39.10; H, 4.57; N, 14.10.
β-D-ribofuranosylisothiazolo isomer (27b). Obtained like 27a from 16b
(200 mg, 0.31 mmol) in MeOH/HCl (20 mL); recrystallization from ethanol; yield
80 mg (72.7%), mp 168–170◦C. IR ν 3050–3400, 2930, 1570, 1445. UV (CHCl3)
λ (qualit.) 250, 276, 332. 1H NMR (DMSO-d6) δ 2.52 (s, 3H), 3.35 (s, 6H), 3.48–
3.98 (m, 3H), 4.11 (t, 1H, J = 4.68), 4.50 (t, 1H, J = 5.67), 5.15 (d, 1H, J = 5.91),
5.59 (s, br, 3H). 13C NMR (DMSO-d6) δ 13.70, 51.49, 62.16, 79.67, 80.47, 85.32,
86.31, 143.55, 147.68, 155.88, 162.22, 167.43. MS (FAB) m/z (rel. intens.) 359.1
(M + 1; 22.4). Anal. Calcd for C13H18N4O4S2 · HCl: C, 39.48; H, 4.80; N, 14.17.
Found: C, 39.15; H, 4.72; N, 14.05.
ACKNOWLEDGMENT
This work was supported by the Deutsche Forschungsgemeinschaft, the Fonds
der Chemischen Industrie, and the BAYER AG. We thank the International Bu¨ro of
the DLR for supporting the German-Hungarian Research Project (BMBF/OMFB
Agreement UNGX-234).

ORDER
REPRINTS
FUSED ISOTHIAZOLO C-NUCLEOSIDES. III
241
REFERENCES
1. Part 2: Wamhoff, H.; Berressem, R.; Nieger, M. J. Org. Chem. 1994, 59, 1912–1917.
2. cf. Hanessian, S.; Pernet, A.G. Adv. Carbohydr. Chem. Biochem. 1976, 32, 111– 188;
Mizuno, Y. The Organic Chemistry of Nucleic Acids, Elsevier, Amsterdam 1986;
Huryn, D.M.; Okabe, M. Chem. Rev. 1992, 92, 1745–1768; Ha¨bich, D. Chem. in
uns. Zeit 1991, 25, 295–307; Uhlmann, E.; Peyman, A. Chem. Rev. 1990, 90, 543–
584; Thuong, N.T.; Helene, C. Angew. Chem. 1993, 105, 697–723; Angew. Chem.
Int. Ed. Engl. 1993, 33, 666–690; Yarchoan, R.; Mitsuya, H.; Zhomas, R.V.; Pluda,
J.M.; Hartman, N.R.; Perno, C.F.; Marczyk, K.S.; Allain, J.P.; Johns, D.G.; Broder,
S. Science 1989, 245, 412– 414; Tanaka, H.; Baba, M.; Hayakawa, H.; Sakamaki, T.;
Miyasaka, T. Ubasawa, M.; Takashima, H.; Sekiya, E.; Nitta, I.; Shigeta, S.;Walker,
R.T.; Balzarini, J.; De Clerq, E. J. Med. Chem. 1991, 34, 349–357.
3. Some C-glycosides with antibiotic, antiviral (HIV), and anticancer activities: Koyama,
G.; Maeda, K.; Umezawa, H.; Iitaka, Y. Tetrahedron Lett. 1966, 597–602; Hori, M.;
Wakashiro, T.; Ito, E.; Sawa, T.; Takeuchi, T.; Umezawa, H.J. J. Antibiot. 1968, 21A,
ˇ
264–270 [Chem. Abstr. 1968, 69, 11356j]; Farkas, J.; Sorm, F. Collect. Czech. Chem.
Commun. 1972, 37, 2798–2803; Acton, E.M.; Ryan, K.J.; Henry, D.W.; Goodman, L.
J. Chem. Soc., Chem. Commun. 1971, 986–988; Nakagawa, Y.; Kano, H.; Tsukuda,
Y. Koyama, H. Tetrahedron Lett. 1967, 4105–4109; Inoue, I.; Kuwaijama, I. J. Chem.
Soc., Chem. Commun. 1980, 251–253; Buchanan, J.G.; Stobie, A.; Wightman, R.H.
ibid. 1980, 916–917; Hildebrand, S.; Leumann, C. Angew. Chem. 1996, 108, 2100–
2102; Angew. Chem. Int. Ed. Engl. 1996, 35, 1968–1970.
4. Wamhoff, H.; Berressem, R.; Nieger, M. J. Org. Chem. 1993, 58, 5181– 5185.
5. Divakar, K.J.; Reese, C.B. J.C.S., Perkin Trans. 1, 1982, 1171–1176.
6. Wigerinck, P.; Pannecouque; Snoeck, R.; Claes, P.; De Clerq, E.; Herdewijn, P. J. Med.
Chem. 1991, 34, 2380–2389.
7. Kraszewski, A.; Stawinsky, J. Teterahedron Lett. 1980, 21, 2935–2936. Here the iso-
lated phosphoryl tris-triazole was used as phosphorylating agent.
8. Abdel-Megied, A.E.-S.; Pedersen, H.; Pedersen, E.B.; Nielsen, C. Heterocycles 1993,
36, 681– 692.
9. Miles, R.W.; Samano, V.; Robins, M.J. J. Am. Chem. Soc. 1995, 117, 5951–5957;
J. Org. Chem. 1995, 60, 7066–7069.
10. Loakes, D.; Bazzanini, R.; Brown, D.M. Helv. Chim. Acta 1999, 82, 2028–2036.
11. The different configurations have been assigned with a and b for the α-and β-isomers,
respectively.
12. Other isolated C4-triazole derivatives of zidovudine and other pyrimidine nucleosides
cf. Wallis, M.P.; Mahmood, N.; Fraser, W. Il Farmaco 1999, 54, 83-89; Lin, T.-S.;
Gao, Y.-S.; Mancini, W.R. J. Med. Chem. 1983, 26, 1691–1696.
13. Berressem, R. Dissertation, University of Bonn 1992.
Received May 5, 2000
Accepted October 27, 2000

Request Permission or Order Reprints Instantly!
Interested in copying and sharing this article? In most cases, U.S. Copyright
Law requires that you get permission from the article’s rightsholder before
using copyrighted content.
All information and materials found in this article, including but not limited
to text, trademarks, patents, logos, graphics and images (the "Materials"), are
the copyrighted works and other forms of intellectual property of Marcel
Dekker, Inc., or its licensors. All rights not expressly granted are reserved.
Get permission to lawfully reproduce and distribute the Materials or order
reprints quickly and painlessly. Simply click on the "Request
Permission/Reprints Here" link below and follow the instructions. Visit the
U.S. Copyright Office for information on Fair Use limitations of U.S.
copyright law. Please refer to The Association of American Publishers’
(AAP) website for guidelines on Fair Use in the Classroom.
The Materials are for your personal use only and cannot be reformatted,
reposted, resold or distributed by electronic means or otherwise without
permission from Marcel Dekker, Inc. Marcel Dekker, Inc. grants you the
limited right to display the Materials only on your personal computer or
personal wireless device, and to copy and download single copies of such
Materials provided that any copyright, trademark or other notice appearing
on such Materials is also retained by, displayed, copied or downloaded as
part of the Materials and is not removed or obscured, and provided you do
not edit, modify, alter or enhance the Materials. Please refer to our Website
User Agreement for more details.
Order now!
Reprints of this article can also be ordered at
http://www.dekker.com/servlet/product/DOI/101081NCN100002083