Amino-thiocyanation of electron rich olefins as an efficient purine and pyrimidine N-alkylation process

Article abstract of DOI:10.1081/SCC-120002117

This work describes a relatively simple process to form thiocyanate substituted nucleoside mimics. CISCN is slowly added to a solution of silylated heterocycle and suitable electron rich alkene. N-alkylated heterocycles are isolated in good yields after hydrolytic workup and flash chromatography.

Full text of DOI:10.1081/SCC-120002117

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AMINO-THIOCYANATION OF ELECTRON RICH OLEFINS
AS AN EFFICIENT PURINE AND PYRIMIDINE N-
ALKYLATION PROCESS
Jeremy Chmielewski a , Michelle Haun a , Krista Topmiller a , Jacob Ward a & Kevin M.
Church a
a Department of Chemistry , University of Dayton , 300 College Park, Dayton, OH, 45469,
U.S.A.
Published online: 16 Aug 2006.
To cite this article: Jeremy Chmielewski , Michelle Haun , Krista Topmiller , Jacob Ward & Kevin M. Church (2002) AMINO-
THIOCYANATION OF ELECTRON RICH OLEFINS AS AN EFFICIENT PURINE AND PYRIMIDINE N-ALKYLATION PROCESS, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry, 32:3, 343-353
To link to this article: http://dx.doi.org/10.1081/SCC-120002117
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SYNTHETIC COMMUNICATIONS, 32(3), 343–353 (2002)
AMINO-THIOCYANATION OF
ELECTRON RICH OLEFINS AS
AN EFFICIENT PURINE AND
PYRIMIDINE N-ALKYLATION PROCESS
Jeremy Chmielewski, Michelle Haun, Krista Topmiller,
Jacob Ward, and Kevin M. Church*
Department of Chemistry, University of Dayton,
300 College Park, Dayton, OH 45469
ABSTRACT
This work describes a relatively simple process to form thio-
cyanate substituted nucleoside mimics. ClSCN is slowly added
to a solution of silylated heterocycle and suitable electron rich
alkene. N-alkylated heterocycles are isolated in good yields
after hydrolytic workup and flash chromatography.
For many years nucleoside mimics have had important uses in the
treatment of viral and cancerous disease states.1 With the development of
anti-sense oligonucleotide technology the need for suitably functionalized
nucleosides is even greater.2 Acyclic nucleoside mimics which contain a non
cyclic sugar moiety have also shown promise in the treatment of several
disease states.3 Although many synthetic processes have been delineated
*Corresponding author.
343
Copyright & 2002 by Marcel Dekker, Inc.
www.dekker.com

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CHMIELEWSKI ET AL.
to form nucleosides the reaction of most general synthetic use is the
N-glycosylation process.4 Here suitably protected reactive sugars are con-
densed with silylated heterocycles generally giving yields in excess of 80%.
Relatively recently several researches have described strategies that utilize
protected furals and glycals.5 In these reactions electrophiles such as RSeCl
and RSCl are added across the fural double bond to give b-chloro selenide
or sulfide intermediates. These intermediates then undergo N-glycosylation
with heterocycles in the presence of strong Lewis acid catalysts giving
20-substituted nucleosides. In many cases good stereo- and regiochemical
control can be achieved. In this paper we outline the utility of trapping
alkene derived cyclic ion intermediates with silylated heterocycles to give
alkylated purines and pyrimidines containing abundant functionality.
We chose chlorothiocyanate (ClSCN) as a reactive electrophile based
on its known chemistry of addition across carbon–carbon double bonds to
give b-chlorothiocyanates.6 We envisioned (Scheme 1) reaction of ClSCN
with a fural to give a cyclic sulfonium ion that could be trapped with
silylated heterocycle to give thiocyanate substituted nucleoside mimics.
The trapping of this ion would be expected to give rise to trans addition
stereochemistry in the final product.7 The use of a Lewis acid such as SnCl4
could drive product formation via the open carbocation giving a mixture of
cis and trans addition products. We sought to eliminate this possibility by
not including a Lewis acid and relying on the reactivity of the electrophile
for product formation.
Scheme 1.

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345
Figure 1.
Our first attempt at this strategy involved N-6-benzoyladenine as the
heterocyclic partner (See Figure 1). N-6-Benzoyladenine was silylated by
refluxing in hexamethyldisilizane as before.8 2,3-Dihydrofuran was added
and ClSCN slowly added to the reagents in 1,2-dichloroethane. Upon
hydrolytic workup the alkylated heterocycle was isolated as a mixture of
regioisomers 2a and 2b in 74% yield. Significantly no cis isomer could be
isolated in either case.9 Compounds 2a and 2b exhibited identical UV
absorption spectra with a ꢀ max of 280 nm. This result allowed us to deter-
mine the N-9 alkylation pattern rather than reaction at N-7 of N-6 benzoyl-
adenine.10 Presumably 2a and 2b are formed by attack of the nucleophilic
silylated heterocycle at either C-2 or C-3 of the alkene derived cyclic inter-
1
mediate. The H and 13C NMR spectra of 2a and 2b are very similar but it
was possible to assign the regioisomers by noting the chemical shift of the
carbon bearing the heterocycle in each case. In 2a this carbon is adjacent to
two electronegative atoms (N and O) whereas in 2b the same carbon is
adjacent to an O and an S. The 13C NMR shifts of 2a and 2b are respectively
91.4 and 86.6 ppm.11
Several other electron rich alkenes gave acceptable yields (Table 1)
outlining the general synthetic utility of the process. Vinyl ethers and
vinyl amines work well in this process presumably due to their high rate
of reaction with ClSCN to form reactive intermediates. Less reactive alkenes
such as 1-hexene and styrene failed in this reaction. Phenylvinylsulfide and
vinyldiphenylphosphine, although electron rich, also failed. We attribute
this result to possible side reactions of sulfur and phosphorus with ClSCN
rather than addition to the double bond of the alkene. This process was also
extended to the formation of pyrimidine analogs. When ClSCN was added
to a solution of N-vinylcarbazole and silylated thymine in 1,2-dichloro-
ethane the adduct 8 was isolated in 82% yield after hydrolytic workup
(Figure 2). No other alkylated products were formed.

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CHMIELEWSKI ET AL.
Table 1. Formation of Adenosine Analogs via Amino-Thiocyanation of Electron
Rich Alkenes
Alkylation at the N-1 position of Thymine rather than N-3 was made
1
apparent by the presence of a broad singlet in the H NMR spectrum at
11.52 ppm indicating a free succinimide proton. Again the synthetic utility is
evident from the outcome of reactions with other olefins (Table 2). In the
pyrimidine case again only the trans addition products 6 and 7 are formed.
This result would tend to argue against the intermediacy of a carbocationic

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347
Figure 2.
intermediate as in Scheme 1. Compounds 3, 5, 8 and 10 all being formed
from stable vinyl amines indicate the possibility of generating pyrrolidino
based nucleoside analogs via this chemistry.
Although the two different heterocycle alkylations were performed
under the same conditions the lack of isomer formation in the Thymine
case indicates a somewhat different mechanism. In the N-6-Benoyladenine
case it appears that product formation arises from attack on a cyclic inter-
mediate as in Scheme 1 to give two regioisomers whereas in the Thymine
case product formation may be completely via the open resonance stabilized
cation. Differences in mechanism could also be due to differences in the
nucleophilicity of the silylated heterocycle.
EXPERIMENTAL
All chemicals and solvents were of reagent grade purity and used
without further purification. N-6-Benzoyladenine was purchased from
Aldrich and used directly in the silylation reaction. All flash chromato-
graphic purifications were performed utilizing Merck 60 silica gel.
Whatman glass backed UV indicator impregnated 0.25 m analytical tlc
plates were used exclusively. Analytical HPLC determinations were carried
out on a Waters Baseline 810 chromatography workstation utilizing a
100 angstrom Deltapak C-18 column. Elution was carried out at a
2 mL/min flow rate with isocratic water/methanol solvent mixtures and
UV detection at 254 nm. NMR determinations were carried out on a
1
JEOL-FX270 instrument operating at 269.65 MHz for H and 67.8 MHz
for 13C. Frequencies are reported in parts per million (ppm) downfield
from the internal reference tetramethylsilane. NMR solvent utilized unless
otherwise noted was deuterochloroform. Coupling constants are in hertz.
High resolution mass spectra were determined in either the Electron

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CHMIELEWSKI ET AL.
Table 2. Formation of Thymidine Analogs via Amino-Thiocyanation of Electron
Rich Alkenes
Impact or Fast Atom Bombardment mode. Representative synthetic
procedures for the amino thiocyanation process follow. Full spectral data
for major isomers shown.
6-N-Benzoyl-9-[(3-thiocyanato)-2-pyranyl ]adenine: 1a N-6-Benzoyl-
adenine (0.6 g, 2.51 mmol) was silylated by refluxing in 30 mL of HMDS

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349
containing 30 mg of (NH4)2SO4 for 5 h. Excess HMDS was removed in vacuo
and co-evaporated once with toluene to give a yellow syrup. In a separate
reaction vessel chlorothiocyanate was generated by the addition of 5.2 mL of
1 M SO2Cl2 (5 mmol) in dichloromethane to a suspension of 0.84 g
(2.5 mmol) of Pb(SCN)2 in 10 mL of dichloromethane at 25ꢀC. This solution
was stirred for one hour under nitrogen gas atmosphere. The resulting
thiocyanate solution was filtered into an addition funnel and slowly added
to a solution of the silylated base and 0.69 mL (7.5 mmol) of 2,3-dihydro-
pyran in 5 mL of dichloromethane. The subsequent mixture was allowed
to react at 25ꢀC for 18 h under a nitrogen gas atmosphere. The reaction
was poured into 150 mL of cold aqueous bicarbonate and stirred for 15 min.
This solution was extracted 3X with EtOAc and the combined extracts
dried with MgSO4. Subsequent reduction of solvent and flash chromato-
graphy on silica gel with 5% acetone in dichloromethane gave the product
1
as a mixture of regioisomers (0.54 g) in 57% yield. HPLC and H-NMR
analysis showed the isomers were present in a 2.2 to 1 ratio. MP; 83–84ꢀC.
HPLC retention times (50% MeOH/50% water); major isomer ¼ 5.88 min,
minor isomer ¼ 7.87 min. UV (EtOH); 234 and 281 nm. IR (KBr); 3247,
3090, 2949, 2861, 2155, 1699, 1612, 1582, 1453, 1334, 1249, 1073, 945,
1
797, 710 cmꢁ1. H-NMR; 9.25 (s, 1H), 8.82 (s, 1H), 8.17 (s, 1H), 8.03 (d,
2H, J ¼ 7.7), 7.61 (t, 1H, J ¼ 6.9), 7.52 (t, 2H, J ¼ 7.6), 5.65 (d, 1H, J ¼ 9.9),
4.29 (m, 2H), 3.82 (t, 1H, J ¼ 10.6), 2.63 (m, 1H), 2.22–1.83 (m, 3H).
13C-NMR; 164.7, 153.0, 151.7, 150.0, 142.1, 133.6, 132.9, 128.9,
127.9, 123.3, 108.6, 85.9, 68.7, 45.8, 31.2, 26.1. EI-HRMS; C18H16N6O2S
calcd. for 380.1055 (obs. 380.1056). Anal. Calcd. for C18H16N6O2S:
C, 56.83; H, 4.24; N, 22.09. Found: C, 56.97; H, 4.17; N, 22.13.
6-N-Benzoyl-9-{[1-(N-carbazoyl )-2-thiocyanato]ethyl }adenine: 3a MP;
117–118ꢀC. HPLC retention time; major 6.3 min and minor 4.46 min (75%
MeOH/25% water). UV (EtOH); 231, 248, 283, 289, and 328 nm. IR (KBr);
3251, 3060, 2157, 1702, 1608, 1581, 1484, 1448, 1324, 1246, 1209, 1158, 797,
1
751, 722 cmꢁ1. H-NMR; 9.30 (s, 1H), 8.83 (s, 1H), 8.08 (d, 2H, J ¼ 7.7),
7.95 (s, 1H), 7.91 (d, 2H, J ¼ 7.3), 7.59 (d, 2H, J ¼ 8.0), 7.55–7.20 (m, 8H),
5.07 (dd, 1H), 4.31 (dd, 1H). 13C-NMR; 164.9, 153.0, 152.0, 150.0, 142.0,
135.5, 133.4, 132.9, 128.8, 127.9, 126.9, 124.3, 122.9, 121.5, 121.0, 110.6,
109.7, 66.1, 34.2. FAB-HRMS; C27H20N7OS calcd. for 490.1450 (obs.
490.1467). Anal. Calcd. for C27H19N7OS: C, 66.24; H, 3.91; N, 20.03.
Found: C, 66.35; H, 4.06; N, 20.14.
6-N-Benzoyl-9-{[1-(N-pyrrolidinonyl )-2-thiocyanato]ethyl }adenine: 5a
HPLC retention time major 5.01 min and minor 3.60 min (50% MeOH/
50% water). MP; 126–127ꢀC. UV (EtOH); 231 nm and 280 nm. IR (KBr);
3170, 3087, 2976, 2160, 1680, 1665, 1578, 1513, 1456, 1411, 1250, 896,
736, 707 cmꢁ1 1H-NMR (DMSOd ); 11.26 (s, 1H), 8.79 (s, 1H), 8.69
.
6

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CHMIELEWSKI ET AL.
(s, 1H), 8.05 (d, 2H, J ¼ 6.8), 7.58 (mult, 3H), 6.66 (t, 1H, J ¼ 7.7), 4.65 (dd,
1H), 4.55 (dd, 1H), 3.68 (q, 1H, J ¼ 6.0), 3.53 (q, 1H, J ¼ 6.8), 2.30 (m, 2H),
1.95 (m, 2H). 13C-NMR (DMSOd ); 175.1, 165.6, 152.0, 151.7, 150.4, 143.4,
6
133.2, 132.4, 128.4, 125.1, 62.1, 43.5, 40.9, 29.9, 17.6. FAB-HRMS;
C19H18N7O2S calcd. for 408.1243 (obs. 408.1219). Anal. Calcd.
for C19H18N7O2S: C, 56.01; H, 4.21; N, 24.06. Found: C, 55.87; H, 4.37;
N, 23.94.
6-N-Benzoyl-9-[(1-isobutyloxy-2-thiocyanato)ethyl ]adenine: 4a HPLC
retention time; major 4.33 min and minor 5.02 min (65% MeOH/35%
water). MP; 49–50ꢀC. UV (EtOH); 233 nm and 280 nm. IR (KBr); 3246,
3067, 2959, 2158, 1700, 1610, 1580, 1510, 1458, 1251, 1208, 1111, 895,
1
798, 709 cmꢁ1. H-NMR; 9.09 (s, 1H), 8.81 (s, 1H), 8.22 (s, 1H), 8.04 (d,
2H, J ¼ 7.0), 7.55 (m, 3H), 6.00 (t, 1H, J ¼ 5.7), 4.00 (m, 2H), 3.37 (dd, 1H),
3.21 (dd, 1H), 1.91 (m, 1H), 0.90 (dd, 6H). 13C-NMR; 164.8, 152.9, 152.1,
149.7, 140.8, 133.6, 132.8, 128.9, 127.9, 123.1, 84.3, 44.7, 28.3, 19.0.
EI-HRMS; C19H20N6O2S calcd. for 396.1368 (obs. 396.1346). Anal.
Calcd. for C19H20N6O2S: C, 57.56; H, 5.08; N, 21.20. Found: C, 57.52; H,
5.05; N, 21.26.
6-N-Benzoyl-9-[(3-thiocyanato)-2-furanyl ]adenine: 2a HPLC retention
time; major 4.15 min and minor 4.88 min (50% MeOH/50% water). MP;
70–72ꢀC. UV (EtOH); 233 and 281 nm. IR (KBr); 3100, 2967, 2899, 2156,
1
1699, 1612, 1579, 1453, 1250, 1068, 797, 710 cmꢁ1. H-NMR; 9.27 (s, 1H),
8.79 (s, 1H), 8.18 (s, 1H), 8.06–8.02 (m, 2H), 7.61–7.50 (m, 3H), 6.48 (d, 1H,
J ¼ 5.6), 4.59 (m, 1H), 4.36 (m, 1H), 4.20 (m, 1H), 2.79 (m, 2H). 13C-NMR;
164.8, 152.9, 151.3, 149.9, 141.2, 133.6, 132.8, 128.9, 127.9, 123.2, 109.3,
86.6, 68.3, 49.2, 31.5. EI-HRMS; C17H14N6O2S calcd. for 366.0898 (obs.
366.0895). Anal. Calcd. for C17H14N6O2S: C, 55.73; H, 3.85; N, 22.92.
Found: C, 55.57; H, 4.00; N, 22.87.
1-[(3-Thiocyanato)-2-pyranyl ]thymine:
6
HPLC retention time;
3.71 min (35% MeOH/65% water). MP; 169–170ꢀC. IR (KBr); 3020,
2842, 2157, 1704, 1665, 1479, 1431, 1300, 1258, 1211, 1134, 1076, 1042, 952,
1
758 cmꢁ1. H-NMR (DMSOd ); 11.48 (s, 1H), 7.56 (s, 1H), 5.62 (d, 1H,
6
J ¼ 10.1), 3.99 (t, 2H), 3.67 (t, 1H), 2.29 (d, 1H), 1.92 (m, 1H), 1.79 (s,
3H), 1.73 (m, 2H). 13C-NMR (DMSOd ); 163.4, 150.5, 135.9, 110.1, 108.7,
6
83.0, 67.6, 45.6, 29.9, 25.6, 11.9. EI-HRMS; C11H13N3O3S calcd. for
267.0677 (obs. 267.0674). Anal. Calcd. for C11H13N3O3S: C, 49.43; H,
4.90; N, 15.72. Found: C, 49.36; H, 4.94; N, 15.85.
1-{[1-(N-Carbazoyl )-2-thiocyanato]ethyl }thymine: 8 HPLC retention
time; 4.43 min (60% MeOH/35% water). MP; 211–212ꢀC. IR(KBr); 3160,
3039,2831,2150,1690,1448,1426,1274,1213,1196,1126,751 cmꢁ1.1H-NMR
(DMSOd , CDCl3); 11.52 (s, 1H), 8.09 (d, 2H, J ¼ 7.4), 7.88 (d, 2H, J ¼ 8.3),
6
7.81 (s, 1H), 7.47 (t, 2H, J ¼ 7.4), 7.36 (t, 1H, J ¼ 7.4), 7.28 (t, 2H, J ¼ 7.4),

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351
4.67 (dd, 1H), 4.35 (dd, 1H), 1.79 (s, 3H), 13C-NMR (DMSOd , CDCl3);
6
163.5, 151.1, 139.2, 136.2, 126.3, 123.5, 120.5, 120.2, 111.1, 110.8, 110.7,
65.4, 34.1, 12.4. EI-HRMS; C20H16N4O2S calcd. for 376.0993 (obs.
376.0986). Anal. Calcd. for C20H16N4O2S: C, 63.81; H, 4.28; N, 14.88.
Found: C, 63.82; H, 4.40; N, 14.77.
1-{[1-(N-Pyrrolidinonyl )-2-thiocyanato]ethyl }thymine: 10 HPLC reten-
tion time; 5.78 min (20% MeOH/80% water). MP; 204–205ꢀC. IR (KBr);
3173, 3027, 2836, 2154, 1724, 1700, 1427, 1364, 1291, 1270, 1221, 1115,
1
762 cmꢁ1. H-NMR (DMSOd ); 11.41 (s, 1H), 7.58 (s, 1H), 6.15 (t, 1H,
6
J ¼ 7.4), 3.89 (m, 2H), 3.49 (hex., 2H, J ¼ 8.8), 2.29 (t, 2H, J ¼ 9.9), 1.95
(t, 2H, J ¼ 6.9), 1.78 (s, 3H). 13C-NMR (DMSOd ); 175.4, 163.6, 150.6,
6
138.4, 112.2, 109.1, 64.3, 44.7, 32.4, 30.2, 17.9, 12.0. FAB-HRMS;
C12H15N4O3S calcd. for 295.0864 (obs. 295.0876). Anal. Calcd. for
C12H14N4O3S: C, 48.97; H, 4.79; N, 19.04. Found: C, 48.90; H, 4.75;
N, 19.11.
1-[(3-Thiocyanato)-2-furanyl ]thymine:
7.58 min (25% MeOH/75% water). MP; 209–210ꢀC. IR (KBr); 3084,
3016, 2830, 2158, 1708, 1666, 1477, 1272, 1102, 899 cmꢁ1 1H-NMR
7
HPLC retention time;
.
(DMSOd ); 11.42 (s, 1H), 7.52 (s, 1H), 5.94 (d, 1H, J ¼ 5.2), 4.28 (m, 2H),
6
4.05 (quart, 1H, J ¼ 5.2), 2.58 (hex, 1H, J ¼ 6.1), 2.21 (hex, 1H, J ¼ 7.5), 1.80
(s, 3H). 13C-NMR (DMSOd ); 163.8, 150.5, 136.1, 111.1, 109.8, 89.8, 68.0,
6
47.8, 31.4, 12.1. EI-HRMS; C10H11N3O3S calcd. for 253.0521 (obs.
253.0521). Anal. Calcd. for C10H11N3O3S: C, 47.42; H, 4.38; N, 16.59.
Found: C, 47.51; H, 4.42; N, 16.66.
1-[(1-Isobutyloxy-2-thiocyanato)ethyl ]thymine: 9 HPLC retention time;
7.49 min (50% MeOH/50% water). MP; 175–176ꢀC. IR (KBr); 3170, 3042,
2958, 2158, 1711, 1678, 1474, 1279, 1216, 1127, 1091 cmꢁ1 1H-NMR
.
(DMSOd ); 11.33 (brd. s, 1H), 7.55 (s, 1H), 5.79 (t, 1H, J ¼ 6.2), 3.55
6
(dd, 2H, J ¼ 2.2, 6.1), 3.23 (dd, 2H, J ¼ 1.8, 6.2), 1.83 (hept., 1H, J ¼ 6.6),
1.79 (s, 3H), 0.87 (dd, 6H, J ¼ 1.8, 6.6). 13C-NMR (DMSOd ); 163.6, 150.9,
6
135.0, 112.4, 110.1, 82.7, 75.07, 35.2, 27.6, 18.9, 12.1. EI-HRMS;
C12H17N3O3S calcd. for 283.0990 (obs. 283.0992). Anal. Calcd. for
C12H17N3O3S: C, 50.87; H, 6.05; N, 14.83. Found: C, 50.77; H, 6.07;
N, 14.64.
ACKNOWLEDGMENTS
We would like to thank the Department of Chemistry and the Honors
Program at the University of Dayton for funding this project. Mass spectral
determinations were carried out at the Chemical Instrumentation Center of

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the Ohio State University. Elemental analysis determinations were carried
out by Onieda Research Services.
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Vorbruggen, H.; Krolikiewicz, K.; Bennua, B. Chem. Ber. 1981, 114,
1234–1255.
9. Proton coupling constants of the protons on C2 and C3 of compounds
1a, 2a, 6 and 7 were used to assign their relative stereochemistry. 1a
(J2,3 ¼ 9.9 Hz), 2a (J2,3 ¼ 5.6 Hz), 6 (J2,3 ¼ 10.1), 7 (J2,3 ¼ 5.2 Hz). For
examples of coupling constants in these types of systems see Fuertes,
M.; Garcia-Munoz, G.; Madronero, R.; Stud, M. Tetrahedron 1972,
28, 623–635. Leutzinger, E.; Bowles, W.; Robins, R.; Townsend, L. J.
Amer. Chem. Soc. 1968, 90(1), 150.
10. Augustyns, K.; Rozenski, J.; Van Aerschot, A.; Janssen, G.;
Herdewijn, P. J. Org. Chem. 1993, 58, 2977–2982. Baud, M.; Chavis, C.;
Lucas, M.; Imbach, J. Tetrahedron 1991, 47(48), 9993–10002.

ORDER
REPRINTS
AMINO-THIOCYANATION OF ELECTRON RICH OLEFINS
353
Bessodes, M.; Lakaf, R.; Antonakis, K. Carbohydrate Res. 1986, 148,
148–152.
11. UV and 13C-NMR (carbon bearing the heterocycle) chemical shift data
of the major and minor isomers; 1a and 1b through 5a and 5b.
Compounds
UV (EtOH, nm)
13C NMR (ppm, DMSOd )
6
1a
1b
2a
2b
3a
3b
4a
4b
5a
5b
234, 281
234, 281
233, 281
85.9
84.3
91.4
86.6
66.8
66.1
84.3
81.7
73.6
62.1
233, 281
231, 282, 329
231, 282, 329
233, 280
232, 279
231, 280
231, 280
Received in the USA March 19, 2001

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