Ni-Pd Catalyzed Cyclization of Sulfanyl 1,6-Diynes: Synthesis of 1′-Homonucleoside Analogues

Article abstract of DOI:10.1021/acs.joc.6b02841

The Ni-Pd catalyzed addition-cyclization of sulfanyl 1,6-diynes 2-9 with nucleobases is described. The reactions of N-tethered 1,6-diynes with N³-benzoylthymine, N⁴,N⁴-bis(Boc)cytosine, N³-benzoyluracil and N

Full text of DOI:10.1021/acs.joc.6b02841

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Article
Nucleobase-promoted cyclization of sulfanyl 1,6-diynes:
an efficient synthesis of 1’-homonucleotide analogs
Yuka Kobayashi, Mitsuhiro Yoshimatsu, Rena Tanahashi, Yui
Yamaguchi, Noriyuki Hatae, Masanori Kobayashi, and Yoshihito Ueno
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b02841 • Publication Date (Web): 02 Feb 2017
Downloaded from http://pubs.acs.org on February 3, 2017
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Ni–Pd catalyzed cyclization of sulfanyl 1,6-diynes: synthesis of 1’-homonucleoside analogs
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Yuka Kobayashi,a Rena Tanahashi,a Yui Yamaguchi,c Noriyuki Hatae,b Masanori Kobayashi,d
Yoshihito Uenoe and Mitsuhiro Yoshimatsu*a,c
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aDepartment of Chemistry, Faculty of Education, Gifu University, Yanagido 1-1, Gifu 501-1193,
Japan. Tel: 81-58-293-2251, Email: yoshimae@gifu-u.ac.jp; bSchool of Pharmaceutical Sciences,
Health Science University of Hokkaido, Ishikari-Tobetsu, Hokkaido 061-0293, Japan;
cLaboratory of Veterinary Microbiology, Faculty of Applied Biological Sciences, Gifu University,
1–1 Yanagido, Gifu 501–1193, Japan; dOrganization for Research and Community Development,
Department of Research Promotion, Gifu University; eDepartment of Smart Material Science, The
United Graduate School of Agricultural Science, Gifu University, Yanagido 1-1, Gifu 501-1193
Table of contents
Abstract
The Ni–Pd catalyzed addition-cyclization of sulfanyl 1,6-diynes 2-9 with nucleobases is described.
The reactions of N-tethered 1,6-diynes with N3-benzoylthymine, N4,N4-bis(Boc)cytosine, N3-
benzoyluracil and N6,N6-bis(Boc)adenine exclusively afforded the pyrrolylmethyl and
furylmethyl nucleotides in good yields. Deprotection of nucleobases was completed by
treatment with acids or bases. Furthermore, the reactions of pyrroles and furans with
nucleophiles such as alkoxides and amines underwent detosylation and conversion to the
alkoxymethyl- and arylaminomethyl-pyrroles and furans in good yields.
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Introduction
Modification of individual nucleosides is of major importance in the development of drugs.1
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wide variety of clinically used nucleosides have been afforded by modification of sugar residues
of nucleosides, including useful antiviral and anticancer agents such as azidothymidine (AZT),2
dideoxycytidine (ddC),3 dideoxyinosine (ddI),4 and acyclovir as well as their analogs, in addition
to lamivudine (3TC),5 in which the carbohydrate is replaced by carbocyclic, acyclic and
heterocyclic residues. To further increase the biological activity and selectivity of nucleoside
analogs, much attention has been focused on enzymatically stable derivatives such as 1’-homo-
N-nucleosides, which are tethered by a methylene group between the sugar moiety and the
nucleobases.6-7
Scheme 1. Synthesis of homonucleoside analogs
1’-Homo-N-nucleosides and their analogs are usually prepared from the nucleophilic
displacement reactions of nucleobases with pentofuranose rings bearing a leaving group at the C-
6’ position.8 Another common method is the nucleobase being constructed by condensation
from pentofuranosyl methylamines.8c,9 These methods have a complex multistep procedure
based on two fundamental processes: i) preparation of carbohydrates, heterocyclic rings, and
acyclic residues; ii) introduction of nucleobases by nucleophilic displacement of carbohydrates
or other residues bearing good leaving groups. These multistep syntheses of homonucleosides
gave rise to low yields and/or the formation of side-products. Recently, we developed a
secondary amine-promoted cyclization of sulfanyl 1,6-diynes leading to polysubstituted
heterocycles tethered by methylene groups between heterocycles and secondary amines.10 Our
strategy for the sulfanyl 1,6-diyne cyclization is highly regioselective due to the metal–
coordinated effects between the sulfur atom on the terminal alkyne and the intramolecular alkynyl
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group. If the nucleobases were applicable to our amination–cyclization process, the 1’-homo-
N-nucleosides bearing pyrroles and furans could be conveniently constructed from the readily
available 1,6-diynes and nucleobases. 1’-Homonucleosides with pyrrolidine, isoxazolidine, and
thiolane rings have been synthesized because of the interest in inhibiting glycosidases by
modification of the spatial and electronic environment around the heterocycles in the five–
membered rings.11-12 However, nucleobases having a pyrrole ring have not yet been reported to
the best of our knowledge. Here, we report a nucleobase-promoted cyclization reaction of
sulfanyl and selanyl 1,6-diynes leading to new homonucleoside analogs and their antiviral and
antiproliferative activities.
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Results and Discussions
First, we prepared nitrogen-tethered 1,6-diynes as shown in Scheme 1. Mitsunobu reactions of
propargyl alcohols 1 with phenylsulfanyl and phenylselanyl propargyl alcohols provided the
desired sulfanyl 2, 3-9 and selanyl 1,6-diynes 3. The other diynes 4-6 bearing substituents at the
-position of the nitrogen atom were also obtained from N-Boc tosylamide by a sequential process
containing the Mitsunobu reaction.
Scheme 2. Preparations of Sulfanyl and Selanyl 1,6-Diynes
Next, we examined a reaction of N-tethered 1,6-diyne 2 with N3-benzoylthymine in the
presence
of
bis(hexafluoroacetylacetonato)nickel(II)
hydrate
(0.1
equiv),
bis(triphenylphosphine)palladium(II) dichloride (0.1 equiv) and DBU (3 equiv) at 50 oC (Table 1,
entry 1) accordingly to our previous report.9a The cyclization-amination of 2 with N3-
benzoylthymine regioselectively proceeded to give 4-[(3-benzoyl-3,4-dihydro-5-methyl-2,4-
dioxo-1(2H)-pyrimidyl)methyl]-3-(phenylsulfanylmethyl)-1-(p-tosyl)pyrrole (10a) in 74% yield.
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The structure of product 10a was determined by its H NMR spectrum, which shows the
characteristic two doublet protons at  6.89 and 7.07 (J = 2.1 Hz) ppm due to the pyrrole ring and
the other two singlet protons at  3.85 and 4.76 ppm due to the 3- and 5-methylene groups of the
pyrrole. Since our process was found to be tolerated for the nucleobase-promoted cyclization
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reaction leading to the 1’-homonucleoside analogs, we next screened for optimized reaction
conditions as shown in Table 1. Nickel or palladium metals were suitable for the nucleobase-
promoted cyclizations. Tetrakis(triphenylphosphine)palladium is the most convenient and
suitable catalyst from the examination (entries 2-5). Water did not inhibit the formation of 10a
(entry 6). N3-Benzoylthymine derivative 10a easily underwent debenzoylation under the
alkaline conditions to give 4-[(3,4-dihydro-5-methyl-2,4-dioxo-1(2H)-pyrimidyl)methyl]-3-
(phenylsulfanylmethyl)-1-(p-tosyl)pyrrole (11a).
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Table 1. Screening for Catalysts of Thymine-promoted Cyclization of 1,6-Diyne 2
entry
Catalyst (equiv)[a]
NiCl2(PPh3)2, 2 h
Pd(PPh3)4, 1 h
Yield of 10ab
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87
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83
89
PdCl2(PPh3)2, 1.5 h
Nickelocene, 2 h
NiCl2(dppe), 2.5 h
Ni(hfa)2 H2O, 2.5 h
aThe commercially available catalysts were used without further purifications. bThe isolated
yields were listed in the table.
With the optimized reaction conditions in hand, we next screened the scope of 1,6-diynes and
nucleobases. The results are shown in Table 2. A similar reaction of selenium analog 3 afforded
the selenomethylpyrrole 12a in high yield (entry 1). The cyclization of N-3-butyn-2-ynyl diyne
4 successfully gave the 5-methylpyrrolyl derivative 13a (entry 2), while the 5-pentylpyrrolyl
homothymine 14a was obtained (entry 3). 2-Naphthalen-1-ylpyrrole 16a was obtained from
naphthalen-1-yldiyne 7 in a similar manner. Next, we examined the effect of the substituent on
nitrogen. N-p-Nitrophenyl- and methanesulfonyl 1,6-diynes 8 and 9 tolerated the thymine-
promoted cyclizations (entries 6-7).
We next examined the cyclization of the similar 1,6-diynes with N6,N6-bis(Boc)adenine.
Reaction of sulfanyl 1,6-diyne 2 with adenine afforded the pyrrolylmethyladenine 10b in 65%
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yield. The reactions of the other 1,6-diynes 4-6 and 8 gave the products 5-methylpyrrolyl-13b,
5-pentylpyrrolyl-14b, and 5-phenylpyrrolylmethyladenine 15b; however, most of these products
yields were relatively low. Surprisingly, the use of N-nitrophenylsulfonyl-1,6-diyne 8 improved
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the yields of products (entry 12).
On the other hand, it is difficult to yield the
pyrrolylmethyluracil; however, the product 10c was obtained in 27% yield as a sole uracil
derivative (entry 13), while the reaction of 2-5 with N4,N4-bis(Boc)cytosine afforded 1-
pyrrolylmethyl-N4,N4-bis(Boc)cytosines 10d, 13d, and 14d in high yield (entry 14-16). Since
we succeeded with the addition–cyclization of 1,6-diynes with four nucleobases, we next
examined the deprotection of pyrrolylmethylnucleosides according to standard methods.
Debenzoylation of thymine derivatives 14a and 15a easily proceeded under alkaline conditions
to give 1-(p-tosyl)pyrroles 19a-20a. Deprotection of the Boc groups of adenine and cytosine
derivatives 10b, 14b, 10d, and 14d under the usual acid-mediated conditions was accomplished
to give both adenines 11b and 19b and cytosines 11d and 19d in good yields.
Table 2. Substrate Scope for Nucleobase-Promoted Cyclization of N-Tethered 1,6-Diynes
entry
1
NB
PG
Bz
Diyne
3 (Y=Se)
4 (Y=S)
5 (Y=S)
6 (Y=S)
7 (Y=S)
8 (Y=S)
9 (Y=S)
2 (Y=S)
4 (Y=S)
5 (Y=S)
6 (Y=S)
R1
H
R2
R3
H
Time (h)
2
Yields (%)a
12a (81)
Thy
Ts
2
Me
pent
Ph
H
Ts
H
0.5
13a (62)
3
Ts
H
0.33
3.5
14a (65/78)
15a (17)
4
Ts
H
5
Ts
1naph
H
0.42
1 h
16a (57)
6
H
pNO2C6H4
17a (52)
7
H
Ms
Ts
Ts
Ts
Ts
H
2 h
18a (52)
8
Ade
Boc
H
H
2 h
10b (65/66)
13b (45)
9
Me
pent
Ph
H
5 h
10
11
H
6.7
14b (48/96)
15b (6)
H
9.5
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8 (Y=S)
2 (Y=S)
2 (Y=S)
4 (Y=S)
5 (Y=S)
H
H
pNO2C6H4
H
H
H
H
H
1
3
17b (63)
10c (73/49)
10d (89/90)
13d (39)
Ura
Cyt
Bz
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Ts
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Boc
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Me
pent
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6.25
14d (36/23)
aAll products were isolated.
We next examined the addition–cyclization of O-tethered 1,6-diynes, which were easily
prepared from the Lewis acid-catalyzed etherification of 1-arylpropargylic alcohol under similar
conditions to that of the N-tethered derivatives (Table 3). The reaction of p-methoxyphenyl-
substituted 4-oxahepta-1,6-diyne 20 with N3-benzoylthymine gave the nucleobase-substituted
furan 23a in 61% yield (entry 1). Accordingly, the substrates bearing electron-withdrawing
groups such as chlorine and fluorine atoms on aromatic rings accelerated the nucleobase-
promoted cyclization to afford the unique furans 24a and 25a (entries 2 and 3). To screen the
substrate scope using other bases, we selected the p-fluoro-, p-chloro-, and p-methoxyphenyl-
substituted 1,6-diynes 20-22 as more reactive substrates and performed the reaction with N6,N6-
bis(Boc)adenine and N4,N4-bis(Boc)cytosine. The reactions were completed in 45 min-1 h, and
the desired products 23b and 25b were obtained in moderate yield. Cytosine-promoted
cyclization of sulfanyl 1,6-diynes 20 and 22 proceeded; however, the yield of products was
relatively low (entries 6 and 7).
Table 3. Scope for Nucleobase-Promoted Cyclization of O-Tethered 1,6-Diynes
entry
NB
PG
Bz
Diyne
20
R
Time
20 min
4.25 h
1.6
Yields (%)a
23a (95/65)
24a (67/78)
25a (43)
1
2
3
4
Thy
pMeOC6H4
pClC6H4
pFC6H4
21
22
Ade
Boc
pClC6H4
2.8
24b (46)
21
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pFC6H4
pFC6H4
20 min
1 h
25b (53/48)
25c (65/39)
23d (38)
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22
20
22
Ura
Cyt
Bz
9
Boc
pMeOC6H4
pFC6H4
50 min
45 min
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25d (48)
To clarify the synthetic utilization of nucleobase-substituted pyrrole derivatives, we
performed transformations of thymine-substituted pyrroles as shown in Scheme 2. mCPBA
oxidation and the following treatment with trifluoroacetic anhydride (the Pummerer reaction
condition) gave the pyrrolemethanol 29. CAN oxidation of 10a in methanol afforded N-tosyl-
methoxymethylpyrrole 30, while the reaction with sodium hydroxide in alcohol gave the
deprotected methoxymethyl-31a and 31d and the ethoxymethylpyrroles 31b; however, the bulky
isopropyloxymethyl derivative 31c was obtained in low yield. The reductive deselenenylation
of 12a (Y=Se) proceeded by treatment with Et3SiH/Et3B to give 32 in 40% yield. The reaction
with p-anisidine in alkaline solution also underwent substitution to give 33. The 3-sulfanyl
group of products were found to be replaced by other versatile nucleophiles. We were also
interested in the biological activities and tested antiviral activity using Equine herpesvirus type 1
(EHV-1: family Herpesviridae, subfamily Alphaherpesvirinae, genus Varicellovirus; however,
we could not find any noticeable activities at this stage.
Scheme 3. Transformation of Thymine-substituted Pyrroles.
Certain nucleoside analogs, fluorouracil and cytarabine, are commercially available as anticancer
drugs. Fluorouracil, which includes the structure of pyrimidine, irreversibly inhibits the
thymidylate synthase.13 The cytosine arabinoside triphosphate, which is a metabolite of cytarabine,
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attenuated DNA synthase in malignant cells by convertion into cytosine arabinoside
triphosphate.14 In the present work, the antiproliferative activity of our synthesized nucleotide
analogs against HCT-116 cells was assessed, and the data are shown in Figure 1. In 100 M
treatment of the derivatives, the 3-phenylsulfanylmethyl derivatives 27a and 28b, with 2-(p-
chlorophenyl) and (p-fluorophenyl) moieties respectively, almost completely inhibited the tumor
cell viability, while the derivatives without the 3-phenylsulfanylmethyl moiety scarcely
attenuated the HCT-116 cell viability. Furthermore, the 4-pyrimidylmethyl derivatives with a 3-
phenylsulfanylmethyl moiety, 11d, 19a, 27a, and 28b, demonstrated relatively good
antiproliferative activity.
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Figure 1. Antiproliferative activities of synthesized nucleotide derivatives against HCT-
116 cells.
HCT-116 cells were treated with 10 (filled column) and 100 M (gray column) of the compounds,
and then their viability was assessed using MTT method. Data are means ± SEM values (n = 3).
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Experimental Section
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General Experimental Methods. All nucleic base-promoted cyclization reactions were
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conducted using standard Erlenmeyer flask in 30 C water bath. Analytical thin layer
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chromatography (TLC) was performed using silica gel precorted glass plates and visualized by
ultraviolet radiation (254 nm). Flash column chromatography on silica gel was performed using
silica gel (particle size 0.063-0.200 mm) under air pressure. Melting points were determined
and uncorrected. 1H and 13C NMR spectra were determined with 600 MHz spectrometer.
Chemical shifts are expressed in parts per million (ppm) with respect to tetramethylsilane as an
internal standard. Splitting patterns are designated as follows: s, singlet; d, doublet; t, triplet; q,
quartet. IR spectra were determined on a FT-IR infrared spectrometer and are expressed in
reciprocal centimeters. EI mass spectra (MS) were obtained with direct-insertion probe at 70 eV.
ESI measurements and their high reolution mass were performed using DART system. 4-
Methyl-N-[3-(phenylthio)-2-proryn-1-yl]-N-2-propyn-1-ylbenzenesulfonamide (1) and the
selenium analog (2) were prepared according to the method for the previous report10a. N3-
Benzoylthymine was prepared from thymine, benzoyl chloride, pyridine in acetonitrile15. N3-
Benzoyluracil was prepared from uracil, benzoyl chloride, and trimethylamine in acetonitrile16.
Both N4,N4-bis(Boc)cytosine and N6,N6-bis(Boc)adenine were prepared by the protection-
monodeprotection procedure of the corresponding nucleic bases such as cytosine and adenine
from the corresponding nucleic bases, di-t-butyl dicarbonate, and in THF and the following de
protection process using NaHCO3 in methanol or K2CO3 in dioxane.17
4-Methyl-N-prop-2-ynyl-N-(3-phenylselanylprop-2-ynyl)benzenesulfonamide (3).
To a THF (3.0 mL) solution of N-propargyl-N-4-methylphenylsulfonamide (0.50 g, 2.39 mmol),
3-phenylselanylprop-2-yn-1-ol (0.51 g, 2.39 mmol) and triphenylphosphine (0.63 g, 2.39 mmol)
was added diethyl azodicarboxylate (2.20 M THF solution, 1.10 mL, 2.39 mmol) under an Ar
atmosphere. The reaction mixture was stirred for 15 min and evaporated under reduced pressure.
The residue was purified by column chromatography on silica gel eluting with AcOEt-n-hexane
(1:10) to provide the titled compound 3 (0.44 g, 46%) as a yellow oil.
IR (KBr, cm-1) 3287, 3058, 2922, 2177, 1597, 1577, 1477, 1440, 1351, 1250, 1164, 1093, 1020,
893, 815; 1H NMR (600 MHz, CDCl3)  2.18 (1H, t, J = 2.7 Hz), 2.36 (3H, s), 4.15 (2H, d, J =
2.1 Hz), 4.41 (2H, s), 7.21-7.23 (2H, d, J = 8.3 Hz), 7.26-7.30 (3H, m), 7.38-7.39 (2H, d, J = 7.6
Hz), 7.69-7.71 (2H, d, J = 8.3 Hz); 13C NMR (150 MHz, CDCl3)  21.5(q), 36.5 (t), 37.9 (t),
66.3(s), 74.1 (d), 76.3 (s), 95.8 (s), 127.2 (d), 127.8 (d×2), 127.9 (s), 129.0 (d×2), 129.5 (d×2),
129.5 (d×2), 135.0 (s), 144.0 (s); EIMS m/z 403 (M+), 247 (M+-Tos). Anal. Calcd for
C19H17NO2SSe: C, 56.72; H, 4.26; N, 3.48. Found: C, 56.58; H, 4.25; N, 3.33.
N-(But-3-yn-2-yl)-4-methyl-N-(3-phenylsulfanylprop-2-yn-1-yl)benzenesulfonamide (4).
To a THF (0.9 mL) solution of N-(but-3-yn-2-yl)-4-methylbenzenesulfonamide21 (200 mg, 0.900
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mmol), 3-phenylsulfanyl-2-propyn-1-ol (148 mg, 0.900 mmol) and triphenylphosphine (236 mg,
0.900 mmol) was added diethyl azodicarboxylate (0.40 mL of 2.2 M THF solution, 0.900 mmol)
under an Ar atmosphere. The reaction mixture was stirred for 15 min and evaporated under
reduced pressure. The residue was purified by column chromatography on silica gel eluting with
AcOEt-n-hexane (1:10) to provide the titled compound 4 (213 mg, 64%) as white powders (mp
80-81 oC).
IR (KBr, cm-1) 3299, 2970, 1713, 1582, 1478, 1442, 1354, 1328, 1287, 1222, 1108, 1084, 1062,
1035, 989, 894, 834, 821, 741, 663, 589, 545, 526; 1H NMR (600 MHz, CDCl3)  1.53 (3H, d, J
= 7.6 Hz), 2.23 (1H, d, J = 2.0 Hz), 2.34 (3H, s), 4.33 (1H, d, J = 18.6 Hz), 4.44 (1H, d, J = 18.6
Hz), 4.93 (1H, dd, J =2.7 and 6.9 Hz), 7.22 (3H, d, J = 7.6 Hz), 7.29-7.33 (4H, m), 7.77 (2H, d, J
= 8.9 Hz); 13C NMR (150 MHz, CDCl3)  21.5 (q), 21.9 (q), 34.8 (t), 45.8 (d), 71.3 (s), 73.7 (s),
81.0 (d), 94.6 (s), 126.3 (d × 2), 126.6 (d), 127.6 (d × 2), 129.1 (d × 2), 129.5 (d × 2), 132.3 (s),
136.5 (s), 143.6 (s); EIMS m/z 369 (M+), 354 (M+-Me), 214 (M+-Ts), 199 (M+-Me-Ts); MS (ESI)
m/z 392 [M+Na]+; HRMS (ESI-DART) m/z: [M+Na]+ calcd for C20H19NNaO2S2 392.07549;
Found 392.07621.
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4-Methyl-N-(oct-1-yn-3-yl)-N-(3-phenylsulfanylprop-2-yn-1-yl)benzenesulfonamide (5).
To a THF (7.4 mL) solution of 4-methyl-N-(oct-1-yn-3-yl)benzenesulfonamide22 (2.0 g, 7.16
mmol), 3-phenylsulfanyl-2-propyn-1-ol (1.18 g, 7.16 mmol) and triphenylphosphine (1.88 g, 7.16
mmol) was added diethyl azodicarboxylate (2.20 M THF solution, 3.25 mL, 7.16 mmol) under an
Ar atmosphere. The residue was purified by column chromatography on silica gel eluting with
AcOEt-n-hexane (1:10) to provide the titled compound 5 (2.35 g, 77 %) as white powders (mp
83-84 oC).
IR (KBr, cm-1) 3246, 2952, 2863, 1713, 1481, 1363, 1335, 1289, 1222, 1167, 1152, 1092, 1056,
878, 811, 736, 689, 666, 583, 532; 1H NMR (600 MHz, CDCl3)  0.85 (3H, t, J = 7.5 Hz), 1.23-
1.28 (4H, m), 1.39-1.48 (2H, m), 1.78-1.87 (2H, m), 2.19 (1H, d, J = 2.0 Hz), 2.35 (3H, s), 4.25
(1H, d, J = 18.6 Hz), 4.38 (1H, d, J = 18.6 Hz), 4.72 (1H, dd, J = 2.8 and 8.3 Hz), 7.20-7.24 (3H,
m), 7.29-7.34 (4H, m), 7.76 (2H, d, J = 8.3 Hz); 13C NMR (150 MHz, CDCl3)  13.9(q), 21.5 (q),
22.4 (t), 25.7 (t), 31.1 (t), 34.9 (t), 35.2 (t), 50.5 (d), 71.0 (s), 74.1 (s), 80.4 (d), 94.5 (s), 126.3 (d
× 2), 126.5 (d), 127.7 (d × 2), 129.1 (d × 2), 129.4 (d × 2), 132.3 (s), 136.5 (s), 143.6 (s); MS m/z
426 (M++1); MS (ESI) m/z 448 [M+Na]+; HRMS (ESI-DART) m/z: [M+Na]+ calcd for
C24H27NNaO2S2 448.13809; Found 448.13879.
4-Methyl-N-(1-phenylprop-2-yn-1-yl)-N-(3-phenylsulfanylprop-2-yn-1-
yl)benzenesulfonamide (6).
To a THF (0.30 mL) solution of 4-methyl-N-(1-phenylprop-2-yn-1-yl)benzenesulfonamide23 (90
mg, 0.32 mmol), 3-phenylsulfanyl-2-propyn-1-ol (52.6 mg, 0.32 mmol) and triphenylphosphine
(83.9 mg, 0.32 mmol) was added diethyl azodicarboxylate (0.15 mL of 2.20 M THF solution, 0.32
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mmol) under an Ar atmosphere. The residue was purified by preparative TLC on silica gel eluting
with AcOEt-n-hexane (1:15) to provide the titled compound 6 (63 mg, 46%) as pale yellow
powders (mp 77-79 oC).
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IR (KBr, cm-1) 3290, 1712, 1598, 1583, 1494, 1479, 1452, 1442, 1353, 1163, 1092, 1062, 899,
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814, 740, 696, 667, 584, 547; H NMR (600 MHz, CDCl3)  2.34 (3H, s), 2.40 (1H, d, J = 2.1
Hz), 3.99 (1H, d, J = 18.5 Hz), 4.29 (1H, d, J = 18.5 Hz), 6.14 (1H, d, J = 2.7 Hz), 7.16 (2H, d, J
= 4.8 Hz), 7.19 (1H, t, J = 7.5 Hz), 7.23-7.27 (4H, m), 7.30 (1H, t, J = 7.5 Hz), 7.36 (2H, t, J =
7.5 Hz), 7.64 (2H, d, J = 7.5 Hz), 7.86 (2H, d, J = 8.2 Hz); 13C NMR (150 MHz, CDCl3)  21.5
(q), 35.2 (t), 52.7 (d), 71.4 (s), 76.9 (s), 77.9 (d), 93.5 (s), 126.2 (d × 2), 126.4 (d), 127.9 (d × 2),
128.0 (d × 2), 128.5 (d × 2), 128.6 (d), 129.0 (d × 2), 129.4 (d × 2), 132.3 (s), 135.1 (s), 136.3 (s),
143.8 (s); MS m/z 431 (M+), 354 (M+-Ph); MS (ESI) m/z 454 [M+Na]+; HRMS (ESI-DART) m/z:
[M+Na]+ calcd for C25H21NNaO2S2 454.09114; Found 454.08898.
4-Methyl-N-(1-naphthalen-1-yl-3-phenylsulfanylprop-2-yn-1-yl)benzenesulfonamide.24
To a toluene (4.5 mL) solution of ethynyl phenyl sulfide (134.2 mg, 1.0 mmol), diethyl zinc (0.90
mL of 1.06 M, 1.0 mmol), (Z)-4-methyl-N-(naphthalen-1-ylmethylene)benzenesulfonamide25
(133 mg, 0.500 mmol) under an Ar atmosphere. The workup procedure gave the titled compound
(166 mg, 75%) as pale yellow needles (mp 177-179 oC).
IR (KBr, cm-1) 3233, 1479, 1440, 1324, 1157, 1089, 1038, 1024, 932, 806, 779, 738, 723, 671,
581, 552, 486; 1H NMR (600 MHz, CDCl3)  2.27 (3H, s), 4.98 (1H, d, J = 8.2 Hz), 6.24 (1H, d,
J = 8.3 Hz), 7.13 (2H, d, J = 8.3 Hz), 7.19-7.22 (3H, m), 7.27 (3H, t, J = 7.6 Hz), 7.39 (1H, t, J
= 7.6 Hz), 7.52 (1H, t, J = 6.8 Hz), 7.58 (1H, t, J = 6.8 Hz), 7.72 (1H, d, J = 6.9 Hz), 7.75 (2H, d,
J = 8.2 Hz), 7.82 (1H, d, J = 8.2 Hz), 7.86 (1H, d, J = 8.2 Hz), 8.29 (1H, d, J = 8.2 Hz); 13C NMR
(150 MHz, CDCl3)  21.4 (q), 48.5 (d), 74.3 (s), 94.8 (s), 123.4 (d), 125.0 (d), 126.1 (d), 126.2
(d), 126.3 (d × 2), 126.7 (d), 127.1 (d), 127.5 (d × 2), 128.8 (d), 129.2 (d × 2), 129.4 (d × 2), 129.9
(d), 130.1 (s), 131.9 (s), 132.0 (s), 134.0 (s), 137.0 (s), 143.7 (s); MS m/z 443 (M+), 334 (M+-
SPh); MS (ESI) m/z 466 [M+Na]+; HRMS (ESI-DART) m/z: [M+Na]+ calcd for C26H21NNaO2S2
466.09114; Found 466.09339.
4-Methyl-N-(1-naphthalen-1-yl)-3-phenylsulfanylprop-2-yn-1-yl)-N-(prop-2-yn-1-
yl)benzenesulfonamide (7).
To a DMF (1.0 mL) solution of 4-methyl-N-(1-(naphthalen-1-yl)-3-(phenylthio)prop-2-yn-1-
yl)benzenesulfonamide (90 mg, 0.2 mmol), propargyl bromide (119.0 mg, 0.8 mmol), sodium
o
hydride (16.0 mg, 0.4 mmol). The reaction mixture was stirred for 10 min at 0 C. The residue
was purified by preparative TLC on silica gel eluting with AcOEt-n-hexane (1:10) to provide the
o
titled compound 7 (46 mg, 47 %) as pale yellow powders (mp 93-95 C, 74% purity). The
compound 7 was contaminated with the unknown compounds.
IR (KBr, cm-1) 3294, 1712, 1598, 1479, 1350, 1162, 1091, 1048, 892, 854, 792, 742, 704, 689,
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665, 576, 545; 1H NMR (600 MHz, CDCl3)  1.25 (1H, t, J = 7.3 Hz), 2.27 (3H, s), 3.51 (1H, dd,
J = 18.5 and 2.7 Hz), 4.09 (1H, dd, J = 18.5 and 2.7 Hz), 4.12 (1H, s), 7.03 (1H, s), 7.17 (2H, d,
J = 8.2 Hz), 7.22-7.26 (1H, m), 7.27-7.31 (3H, m), 7.45-7.47 (1H, m), 7.53-7.55 (1H, m), 7.63-
7.65 (1H, m), 7.85-7.89 (2H, m), 7.92 (2H, d, J = 8.3 Hz), 8.01 (1H, d, J = 7.5 Hz), 8.51 (1H, d,
J = 9.0 Hz); 13C NMR (150 MHz, CDCl3)  21.5 (q), 33.6 (t), 52.0 (d), 72.9 (d), 75.5 (s), 77.8 (s),
93.3 (s), 123.5 (d), 124.8 (d), 126.2 (d), 126.6 (d × 2), 126.7 (d), 127.3 (d), 128.2 (d), 128.5 (d ×
2), 128.6 (d), 129.1 (d × 2), 129.2 (d × 2), 129.9 (s), 130.3 (d), 131.0 (s), 132.0 (s), 133.8 (s),
135.7 (s), 143.9 (s); EIMS m/z 481 (M+); MS (ESI) m/z 504 [M+Na]+; HRMS (ESI-DART) m/z:
[M+Na]+ calcd for C29H23NNaO2S2 504.10679; Found 504.10828.
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N-(3-Phenylsulfanylprop-2-yn-1-yl)-N-(prop-2-yn-1-yl)methanesulfonamide (9).
To a THF (2.9 mL) solution of N-(prop-2-yn-1-yl)methanesulfonamide21 (300 mg, 2.3 mmol), 3-
phenylsulfanyl-2-propyn-1-ol (377.7 mg, 2.3 mmol) and triphenylphosphine (603.3 mg, 2.3
mmol) was added diethyl azodicarboxylate (1.0 mL of 2.20 M THF solution, 2.3 mmol) under an
Ar atmosphere. The residue was purified by preparative TLC on silica gel eluting with AcOEt-
n-hexane (1:6) to provide the titled compound 9 (119 mg, 21 %) as yellow powders (mp 35-36
oC).
IR (KBr, cm-1) 3285, 2929, 1712, 1582, 1479, 1441, 1347, 1257, 1222, 1156, 1024, 966, 895, 784,
742, 689, 512; 1H NMR (600 MHz, CDCl3)  2.41 (1H, t, J = 2.8 Hz), 2.98 (3H, s), 4.21 (2H, d,
J = 2.7 Hz), 4.43 (2H, s), 7.25 (1H, t, J = 7.6 Hz), 7.35 (2H, t, J = 7.6 Hz), 7.41 (2H, d, J = 8.2
Hz); 13C NMR (150 MHz, CDCl3)  36.7 (t), 38.1 (t), 38.6 (q), 73.7 (s), 74.7 (d), 76.7 (s), 91.6
(s), 126.4 (d × 2), 126.9 (d), 129.0 (d × 2), 131.6 (s); MS m/z 279 (M+); MS (ESI) m/z 302
[M+Na]+; HRMS (ESI-DART) m/z: [M+Na]+ calcd for C13H13NNaO2S2 302.02854; Found
302.02825.
Synthesis of 4-[(3-benzoyl-3,4-dihydro-5-methyl-2,4-dioxo-1(2H)-pyrimidyl)- methyl]-3-
(phenylsulfanylmethyl)-1-(p-tosyl)pyrrole (10a), typical procedure (Table 1, entry 1).
To a DMSO (0.50 mL) solution of 4-methyl-N-[3-(phenylthio)-2-propyn-1-yl]-N-2-propyn-1-
ylbenzenesulfonamide (2) (50 mg, 0.14 mmol) were added N3-benzoylthimine (55.3 mg, 0.24
mmol), bis(triphenylphosphine)palladium (II) dichloride (5.6 mg, 0.008 mmol), and DBU(36.5
mg, 0.24 mmol). The reaction mixture was stirred for 1.5 h at 50 oC. The cooled mixture was
poured into water (50 mL). The organic layer was separated and the aqueous layer was extracted
with AcOEt. The combined organic layer was dried over MgSO4. The solvent was removed
under reduced pressure. The residue was purified by preparative TLC on silica gel eluting with
AcOEt-n-hexane (1:1) to give the title compound 10a (49.0 mg, 99%) as yellow powders.
yellow crystals, mp 45-46 oC, IR (KBr, cm-1)  3133, 3064, 2927, 1747, 1698, 1656, 1598, 1519,
1
1481, 1439, 1372, 1230, 1255, 1173, 1092, 1066, 993, 950, 814, 744, 673, 588, 539; H NMR
(600 MHz, CDCl3) 1.86 (3H, s), 2.41 (3H, s), 3.85 (2H, s), 4.76 (2H, s), 6.89 (1H, brs), 7.07
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(1H, brs), 7.18 (6H, s), 7.27 (2H, d, J = 9.0 Hz), 7.40 (2H, t, J = 7.6 Hz), 7.59 (1H, t, J = 6.8 Hz),
7.63 (2H, d, J = 7.6 Hz), 7.91 (2H, d, J = 7.6 Hz); 13C NMR (125 MHz, CDCl3)  12.3 (q), 21.6
(q), 29.4 (t), 42.0 (t), 111.0 (s), 120.6 (d), 121.2 (d), 121.6 (s), 123.0 (s), 126.8 (d × 2), 126.9 (d),
128.9 (d × 2), 129.0 (d × 2), 130.1 (d × 2), 130.4 (d × 2), 130.7 (d × 2), 131.4 (s), 134.8 (s), 134.9
(d), 135.3 (s), 138.9 (d), 145.4 (s), 149.9 (s), 163.0 (s), 169.0 (s); EIMS m/z 585 (M+), 476 (M+-
SPh); MS (ESI) m/z 608 [M+Na]+; HRMS (ESI-DART) m/z: [M+Na]+ calcd for C31H27N3NaO5S2
608.12898, found 608.13068.
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Synthesis
of
4-[(3,4-dihydro-5-methyl-2,4-dioxo-1(2H)-pyrimidyl)methyl]-3-
(phenylsulfanylmethyl)-1-(p-tosyl)pyrrole (entry 1, debenzoylation of 10a).
To a NaOH (0.85 mL, 1.7 mmol) in MeOH (3.4 mL) was added 4-[(3-benzoyl-3,4-dihydro-5-
methyl-2,4-dioxo-1(2H)-pyrimidyl)methyl]-3-(phenylsulfanylmethyl)-1-(p-tosyl)pyrrole (10a)
(100 mg, 0.17 mmol). The reaction mixture was stirred for 2 h and poured into water (50 mL).
The organic layer was separated and the aqueous layer was extracted with AcOEt. The
combined organic layer was dried over MgSO4. The solvent was removed under reduced
pressure. The residue was purified by preparative TLC on silica gel eluting with AcOEt-n-
hexane (1:1) to give the title compound 11a (44.0 mg, 90%) as yellow powders (mp 54-56 oC).
IR (KBr, cm-1)  2927, 1678, 1470, 1372, 1305, 1250, 1173, 1092, 1067, 813, 747, 674, 588, 539;
1H NMR (600 MHz, CDCl3) 1.85 (3H, s), 2.43 (3H, s), 3.87 (2H, s), 4.74 (2H, s), 6.91 (1H, d,
J = 2.3 Hz), 6.95 (1H, d, J = 1.4 Hz), 7.11 (1H, d, J = 2.3 Hz), 7.19 (5H, brs), 7.29 (2H, d, J = 7.8
Hz), 7.65 (2H, d, J = 8.7 Hz), 8.77 (1H, brs); 13C NMR (125 MHz, CDCl3) 12.4 (q), 21.7 (q),
29.4 (t), 41.8 (t), 111.1 (s), 120.6 (d), 120.7 (d), 122.2 (s), 122.9 (s), 126.9 (d × 2), 128.5 (s), 128.9
(d × 2), 130.1 (d × 2), 130.6 (d × 2), 135.0 (s), 135.4 (s), 139.1 (d), 145.4 (s), 150.7 (s), 163.8 (s);
MS m/z 481 (M+), 438 (M+-CONH); high resolution mass (EI) calcd for C24H23N3O4S2: 481.1130,
found m/z 481.1135. MS (ESI) m/z 504 [M+Na]+; HRMS (ESI-DART) m/z: [M+Na]+ calcd for
C24H23N3NaO4S2 504.10277; Found 504.10074.
Synthesis of 4-[(3-benzoyl-3,4-dihydro-5-methyl-2,4-dioxo-1(2H)-pyrimidyl)methyl]-3-
(phenylselanylmethyl)-1-(p-tosyl)pyrrole (12a) (Table 2, entry 1).
To a DMSO (0.50 mL) solution of 4-methyl-N-[3-(phenylthio)-2-propyn-1-yl]-N-2-propyn-1-
ylbenzeneselenoamide (3) (30 mg, 0.07 mmol) were added N3-benzoylthimine (48.3 mg, 0.21
mmol), bis(triphenylphosphine)palladium (II) dichloride (4.9 mg, 0.007 mmol), and DBU(32.0
mg, 0.21 mmol). The reaction mixture was stirred for 2 h at 50 oC. The cooled mixture was
poured into water (50 mL). The organic layer was separated and the aqueous layer was extracted
with AcOEt. The combined organic layer was dried over MgSO4. The solvent was removed
under reduced pressure. The residue was purified by preparative TLC on silica gel eluting with
AcOEt-n-hexane (1:1) to give the title compound 12a (38 mg, 81%) as pale yellow powders (mp
67-70 oC).
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IR (KBr, cm-1)  3133, 3069, 2928, 1747, 1697, 1655, 1598, 1518, 1439, 1372, 1299, 1254, 1173,
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1092, 1066, 1021, 993, 950, 904, 814, 740, 672, 587, 539, 478; H NMR (600 MHz, CDCl3)
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1.89 (3H, s), 2.42 (3H, s), 3.82 (2H, s), 4.75 (2H, s), 6.77 (1H, d, J = 2.1 Hz), 7.06 (1H, s), 7.15
(2H, t, J = 7.6 Hz), 7.23 (1H, t, J = 7.6 Hz), 7.28-7.30 (4H, m), 7.41-7.43 (2H, m), 7.60 (1H, t, J
= 7.5 Hz), 7.64 (2H, d, J = 8.3 Hz), 7.92 (2H, d, J = 7.5Hz); 13C NMR (125 MHz, CDCl3) 12.4
(q), 21.2 (t), 41.9 (t), 111.1 (s), 120.2 (d), 121.1 (d), 121.4 (s), 124.0 (s), 126.9 (d × 2), 127.7 (d),
128.9 (d × 2), 129.0 (d × 2), 129.2 (s), 130.1 (d × 2), 130.4 (d × 2), 131.4 (s), 133.9 (d × 2), 135.0
(d), 135.3 (s), 138.9 (d), 145.4 (s), 150.0 (s), 163.1 (s), 169.0 (s); EIMS m/z 633 (M+) 476 (M+-
SePh); HRMS (EI) m/z: [M]+ calcd for C31H27N3O5SSe: 633.0836; Found 633.0858. Anal.
Calcd for C31H27N3O5SSe (+ 2 H2O): C, 55.69; H, 4.67; N, 6.28. Found: C, 55.39; H, 4.31; N,
5.84.
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4-[(3-Benzoyl-3,4-dihydro-5-methyl-2,4-dioxo-1(2H)-pyrimidyl)methyl]-5-methyl-3-
(phenylsulfanylmethyl)-1-(p-tosyl)pyrrole (13a), entry 2.
To a DMSO (1.0 mL) solution of 4-methyl-N-[3-(phenylsulfanyl)-2-propyn-1-yl]-N-(1-methyl-2-
propyn-1-yl)benzenesulfonamide (4)18 (100 mg, 0.27 mmol) were added N3-benzoylthimine
(186.5 mg, 0.81 mmol), bis(triphenylphosphine)palladium (II) dichloride (19.0 mg, 0.027 mmol),
o
and DBU(123.3 mg, 0.81 mmol). The reaction mixture was stirred for 0.5 h at 50 C. The
cooled mixture was poured into water (50 mL). The workup procedure gave the titled compound
13a (100 mg, 62%) as yellow powders (mp 68-70 oC).
IR (KBr, cm-1) 3431, 2928, 1748, 1698, 1656, 1599, 1440, 1368, 1239, 1171, 1093, 1024, 817,
762, 671, 590, 542, 478; 1H NMR (600 MHz, CDCl3) 1.92 (3H, s), 1.94 (3H, s), 2.44 (3H, s),
3.77 (2H, s), 4.78 (2H, s), 7.10-7.13 (3H, m), 7.16-7.19 (3H, m), 7.31 (2H, d, J = 8.2 Hz), 7.35-
7.38 (3H, m), 7.57 (1H, t, J = 7.6 Hz), 7.63 (2H, d, J = 8.2 Hz), 7.93 (2H, d, J = 6.8 Hz); 13C NMR
(125 MHz, CDCl3)  10.6 (q), 12.4 (q), 21.7 (q), 29.5 (t), 42.2 (t), 111.1 (s), 119.6 (s), 119.7 (s),
121.1 (d), 127.0 (d × 2), 127.3 (d), 128.8 (d × 2), 129.0 (d × 2), 130.1 (d × 2), 130.2 (s), 130.5 (d
× 2), 131.6 (s), 132.1 (d × 2), 134.8 (s), 134.9 (d, 135.6 (s), 138.9 (s), 145.3 (s), 150.0 (s), 163.0
(s), 169.1 (s); MS m/z 599 (M+), 490 (M+-SPh), 230 (M+-SPh-COPh-Ts). MS (ESI) m/z 622
[M+Na]+, 638 [M+K]+; HRMS (ESI-DART) m/z: [M+Na]+ calcd for C32H29N3NaO5S2
622.14463; Found 622.14452.
4-[(3-Benzoyl-3,4-dihydro-5-methyl-2,4-dioxo-1(2H)-pyrimidyl)methyl]-5-pentyl-3-
(phenylsulfanylmethyl)-1-(p-tosyl)pyrrole (14a), entry 3.
To a DMSO (0.50 mL) solution of 4-methyl-N-[3-(phenylsulfanyl)-2-propyn-1-yl]-N-(1-pentyl-
2-propyn-1-yl)benzenesulfonamide (5)19 (30 mg, 0.07 mmol) were added N3-benzoylthimine
(48.3 mg, 0.21 mmol), bis(triphenylphosphine)palladium (II) dichloride (4.9 mg, 0.007 mmol),
o
and DBU (32.0 mg, 0.21 mmol). The reaction mixture was stirred for 20 min at 40 C. The
cooled mixture was poured into water (50 mL). The workup procedure gave the titled compound
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14a (30 mg, 65%) as yellow powders (mp 51-54 oC).
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IR (KBr, cm-1) 3431, 2957, 2930, 1748, 1698, 1656, 1599, 1440, 1371, 1261, 1238, 1170, 1094,
1066, 995, 817, 762, 671, 589, 544; 1H NMR (600 MHz, CDCl3) t, J = 6.9 Hz), 1.21-
1.36 (8H, m), 1.90 (3H, s), 2.44 (3H, m), 2.41-2.45 (2H, t, J = 6.9 Hz), 3.82 (2H, s), 4.78 (2H, s),
7.10 (1H, s), 7.14-7.18 (3H, m), 7.20-7.22 (2H, m), 7.28 (2H, d, J = 8.3 Hz), 7.32 (1H, s), 7.36
(2H, t, J = 8.3 Hz), 7.56 (1H, t, J = 7.6 Hz), 7.61 (2H, d, J = 8.3 Hz), 7.91 (2H, d, J = 6.9 Hz); 13C
NMR (125 MHz, CDCl3) 12.4 (q), 14.0 (q), 21.6 (q), 22.2 (t), 25.1 (t), 29.5 (t), 30.3 (t), 31.8 (t),
42.5 (t), 111.0 (s), 120.0 (s), 120.1 (s), 121.7 (d), 126.8 (d × 2), 127.1 (d), 128.9 (d × 2), 129.0 (d
× 2), 130.1 (d × 2), 130.5 (d × 2), 131.2 (d × 2), 131.6 (s), 134.8 (d), 135.4 (s), 135.5 (s), 136.1
(s), 139.0 (d), 145.2 (s), 150.0 (s), 163.0 (s), 169.0 (s); EIMS m/z 655 (M+), 546 (M+-SPh), 286
(M+-SPh-Ts-COPh). MS (ESI) m/z 678 [M+Na]+, 694 [M+K]+; HRMS (ESI-DART) m/z:
[M+Na]+ calcd for C36H37N3NaO5S2 678.20723; Found 678.21118.
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Deprotection of 14a.
To a NaOH (2N aq 0.40 mL, 0.8mmol) in MeOH (1.6 mL) was added 4-[(3-Benzoyl-3,4-dihydro-
5-methyl-2,4-dioxo-1(2H)-pyrimidyl)methyl]-5-pentyl-3-(phenylsulfanylmethyl)-1-(p-
tosyl)pyrrole (14a) (50 mg, 0.08 mmol). The reaction mixture was stirred at 70 oC for 20 min
and poured into water (50 mL). The organic layer was separated and the aqueous layer was
extracted with AcOEt. The combined organic layer was dried over MgSO4. The solvent was
removed under reduced pressure. The residue was purified by preparative TLC on silica gel
eluting with AcOEt-n-hexane (1:1) to give the title compound 19a (33 mg, 78%) as pale yellow
powders(mp 57-60 oC).
IR (KBr, cm-1) 3036, 2954, 2930, 2854, 1671, 1596, 1466, 1438, 1369, 1242, 1221, 1190, 1170,
1093, 1066, 815, 761, 739, 700, 673, 609, 587; 1H NMR (600 MHz, CDCl3) 0.86 (3H, t, J = 6.9
Hz), 1.20-1.27 (4H, m), 1.31-1.36 (2H, m), 2.43-2.47 (5H, m), 3.84 (2H, s), 4.74 (2H, s), 6.97
(1H, s), 7.17 (2H, d, J = 6.2 Hz), 7.18-7.19 (1H, m), 7.22 (2H, dd, J = 2.1 and 7.6 Hz), 7.27 (1H,
s), 7.31 (2H, d, J = 8.2 Hz), 7.62 (2H, d, J = 8.2 Hz), 9.01 (1H, brs); 13C NMR (125 MHz, CDCl3)
12.3 (q), 13.9 (q), 21.6 (t), 25.1 (t), 29.1 (t), 30.4 (t), 31.8 (t), 42.0 (t), 111.0 (s), 119.4 (s), 120.7
(s), 121.2 (d), 126.7 (d × 2), 126.8 (d), 128.8 (d × 2), 130.0 (d × 2), 130.6 (d × 2), 135.4 (s), 135.7
(s), 136.2 (s), 139.2 (d), 145.2 (s), 150.9 (s), 164.0 (s); EIMS m/z 551 (M+), 442 (M+-SPh). Anal.
Calcd for C29H33N3O4S2 (+ 1/2 H2O): C, 62.12; H, 6.11; N, 7.49. Found: C, 62.23; H, 6.07; N,
7.29.
4-[(3-Benzoyl-3,4-dihydro-5-methyl-2,4-dioxo-1(2H)-pyrimidyl)methyl]-5-phenyl-3-
(phenylsulfanylmethyl)-1-(p-tosyl)pyrrole (15a), entry 4.
To a DMSO (0.50 mL) solution of 4-methyl-N-[3-(phenylsulfanyl)-2-propyn-1-yl]-N-(1-phethyl-
2-propyn-1-yl)benzenesulfonamide (6) (50 mg, 0.1 mmol) were added N3-benzoylthimine (69.1
mg, 0.3 mmol), bis(triphenylphosphine)palladium (II) dichloride (14.0 mg, 0.02 mmol), and DBU
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(45.7 mg, 0.3 mmol). The reaction mixture was stirred for 1.5 h at 50 oC. The cooled mixture
was poured into water (50 mL). The workup procedure gave the titled compound 15a (13 mg,
17%) as brown powders (mp 55-58 oC).
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IR (KBr, cm-1) 3444, 2925, 1748, 1698, 1658, 1598, 1440, 1374, 1239, 1175, 1092, 816, 761,
701, 670, 583, 542; 1H NMR (600 MHz, CDCl3) 1.94 (3H, s), 2.38 (3H, s), 3.65 (2H, s), 4.91
(2H, s), 6.85 (2H, d, J = 6.9 Hz), 7.05 (2H, d, J = 6.8 Hz), 7.09-7.16 (6H, m), 7.22 (4H, t, J = 7.6
Hz), 7.35 (1H, t, J = 7.6 Hz), 7.43 (2H, t, J = 7.6 Hz), 7.47 (1H, s), 7.60 (1H, t, J = 7.5 Hz), 7.95
(2H, d, J = 7.5 Hz); 13C NMR (125 MHz, CDCl3) 12.5 (q), 21.6 (q), 29.4 (t), 43.0 (t), 111.0 (s),
120.0 (s), 121.5 (s), 122.3 (d), 127.0 (d), 127.3 (d × 2), 127.4 (d × 2), 128.6 (s), 128.9 (d × 3),
129.1 (d × 2), 129.5 (d × 2), 130.5 (d × 2), 131.2 (d × 2), 131.6 (s), 131.8 (d × 2), 134.1 (s), 134.8
(s), 134.9 (d), 135.1 (s), 139.3 (d), 145.1 (s), 150.0 (s), 163.1 (s), 169.1 (s); MS (ESI) m/z 684
[M+Na]+, 700 [M+K]+; HRMS (ESI-DART) m/z: [M+Na]+ calcd for C37H31N3NaO5S2
684.16028; Found 684.16301.
4-[(3,4-dihydro-5-methyl-2,4-dioxo-1(2H)-pyrimidyl)methyl]-3-(phenylsulfanylmethyl)-2-
(1-naphthyl)-1-(p-tosyl)pyrrole (16a).
To a DMSO (0.50 mL) solution of 4-methyl-N-[2-(naphthalene-1-yl)-3-(phenylthio)-2-proryn-1-
yl]-N-2-propyn-1-ylbenzenesulfonamide (7) (46 mg, 0.10 mmol) were added N3-benzoylthimine
(69.1 mg, 0.30 mmol) bis(triphenylphosphine)palladium (II) dichloride (7.0 mg, 0.01 mmol), and
DBU (45.7 mg, 0.30 mmol). The reaction mixture was stirred at rt for 0.5 h. The mixture was
poured into water (50 mL). The organic layer was separated and the aqueous layer was extracted
with AcOEt. The combined organic layer was dried over MgSO4. The solvent was removed
under reduced pressure. The residue was purified by preparative TLC on silica gel eluting with
Et2O-Hexane (1:3) to give the title compound 16a (39 mg, 57%) as yellow powders (mp 81-83
oC).
IR (KBr, cm-1) 3442, 3060, 2925, 1748, 1699, 1656, 1598, 1439, 1372, 1237, 1174, 1112, 1092,
1
994, 953, 808, 776, 670, 584, 543, 445, 424, 403; H NMR (600 MHz, CDCl3) 1.97 (3H, s),
2.17 (3H, d, J = 13.1 Hz), 3.41 (1H, d, J = 13.1 Hz), 3.62 (1H, d, J = 13.1 Hz), 4.95 (1H, d, J =
15.8 Hz), 5.03 (1H, d, J = 15.1 Hz), 6.74 (2H, d, J = 7.6 Hz), 6.81 (1H, d, J = 8.2 Hz), 6.91-6.98
(6H, m), 7.04-7.13 (4H, m), 7.32-7.38 (3H, m), 7.43 (2H, t, J = 7.6 Hz), 7.58-7.63 (1H, m), 7.76
13
(1H, d, J = 8.2 Hz), 7.87 (1H, d, J = 8.3 Hz), 7.96 (2H, d, J = 7.5 Hz); C NMR (125 MHz,
CDCl3) 12.5 (q), 21.4 (q), 29.4 (t), 43.1 (t), 111.0 (s), 119.4 (s), 122.1 (d), 122.6 (s), 124.5 (d),
125.1 (d), 125.4 (d), 125.7 (s), 126.2 (d), 126.8 (d), 127.4 (d × 2), 127.8 (d), 128.8 (d × 2), 129.1
(d × 2), 129.2 (d × 2), 129.8 (d), 130.5 (d × 2), 130.9 (d × 2), 131.6 (d), 131.6 (s), 132.8 (s), 133.3
(s), 134.2 (s), 134.8 (d), 134.9 (s), 139.6 (d), 144.9 (s), 150.0 (s), 163.2 (s), 169.1 (s); EIMS m/z
711 (M+), 602 (M+-SPh). MS (ESI) m/z 734 [M+Na]+, 750 [M+K]+; HRMS (ESI-DART) m/z:
[M+Na]+ calcd for C41H33N3NaO5S2 734.17593; Found 734.17635.
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(phenylsulfanylmethyl)-1-(p-nitrophenylsulfonyl)pyrrole (17a).
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To a DMSO (0.50 mL) solution of 4-nitro-N-[3-(phenylthio)-2-propyn-1-yl]-N-2-propyn-1-
ylbenzenesulfonamide (8) (30 mg, 0.08 mmol) were added N3-benzoylthimine (55.3 mg, 0.24
mmol), bis(triphenylphosphine)palladium (II) dichloride (5.6 mg, 0.008 mmol), and DBU (36.5
mg, 0.24 mmol). The reaction mixture was stirred for 1.0 h at 50 oC. The workup procedure
gave the title compound 17a (22 mg, 52%) as yellow powders.
IR (KBr, cm-1) 3481, 2926, 1747, 1698, 1656, 1532, 1440, 1380, 1350, 1241, 1182, 1091, 1068,
856, 741, 684, 629, 583; 1H NMR (600 MHz, CDCl3) 1.91 (3H, s), 3.88 (2H, s), 4.78 (2H, s),
6.89 (1H, s), 7.12 (1H, s), 7.17 (1H, s), 7.21 (4H, brs), 7.45 (2H, t, J = 7.6 Hz), 7.62 (1H, t, J =
7.6 Hz), 7.88 (2H, d, J = 8.3 Hz), 7.91 (2H, d, J = 7.6 Hz), , 8.28 (2H, d, J = 8.9 Hz); 13C NMR
(125 MHz, CDCl3) 12.4 (q), 29.4 (t), 42.7 (t), 111.3 (s), 120.5 (d), 121.4 (d), 123.2 (s), 124.4
(s), 124.8 (d × 2), 127.1 (d), 128.1 (d × 2), 129.0 (d × 2), 129.1 (d × 2), 130.5 (d × 2), 130.7 (d ×
2), 131.5 (s), 134.5 (s), 135.1 (d), 139.0 (d), 143.6 (s), 149.9 (s), 150.7 (s), 162.9 (s), 168.9 (s);
EIMS m/z 189 (M+-Thy-p-NO2C6H4SO2). MS (ESI) m/z 639 [M+Na]+; HRMS (ESI-DART)
m/z: [M+Na]+ calcd for C30H24N4NaO7S2 639.09841; Found 639.09979.
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Synthesis of 4-[(3-benzoyl-3,4-dihydro-5-methyl-2,4-dioxo-1(2H)-pyrimidyl)- methyl]-3-
(phenylsulfanylmethyl)-1-(methanesulfonyl)pyrrole (18a), entry 7.
To a DMSO (0.50 mL) solution of N-[3-(phenylsulfanyl)prop-2yn-1-yl]-N-2-propyn-1-
ylmethanesulfonamide (9) (30 mg, 0.08 mmol) were added N3-benzoylthimine (103 mg, 0.45
mmol), bis(triphenylphosphine)palladium (II) dichloride (10.5mg, 0.015 mmol), and DBU (685
mg, 0.45 mmol). The reaction mixture was stirred for 2.0 h at 50 oC. The workup procedure
gave the title compound 18a (33 mg, 52%) as yellow powders (mp 54-56 oC).
IR (KBr, cm-1) 2927, 1746, 1697, 1655, 1598, 1439, 1365, 1300, 1242, 1173, 1070, 987, 948,
819, 772, 692, 553, 474; 1H NMR (600 MHz, CDCl3) 1.94 (3H, s), 3.05 (3H, s), 3.94 (2H, s),
4.85 (2H, s), 6.83 (1H, d, J = 2.0 Hz), 7.12 (1H, d, J = 2.8 Hz), 7.17 (1H, d, J = 1.4 Hz), 7.22-
7.28 (5H, m), 7.44 (2H, t, J = 7.5 Hz), 7.61 (1H, t, J = 7.6 Hz), 7.93 (2H, d, J = 6.9 Hz); 13C NMR
(125 MHz, CDCl3) 12.4 (q), 29.7 (t), 42.4 (t), 42.8 (q), 111.3 (s), 120.3 (d), 120.8 (d), 121.8 (s),
123.0 (s), 127.1 (d), 129.0 (d × 2), 129.1 (d × 2), 130.4 (d × 2), 131.1 (d × 2), 131.5 (s), 134.8 (s),
135.0 (d), 139.1 (d), 150.0 (s), 163.0 (s), 169.0 (s); EIMS m/z 509 (M+). MS (ESI) m/z 532
[M+Na]+; HRMS (ESI-DART) m/z: [M+Na]+ calcd for C25H23N3NaO5S2 532.09768; Found
532.09634.
Synthesis of 4-[N6,N6-bis(Boc)adenin-9-ylmethyl]-3-[(phenylsulfanyl)methyl]-2- pyrrole
(10b), entry 8.
To a DMSO (0.50 mL) solution of 4-methyl-N-[3-(phenylthio)-2-propyn-1-yl]-N-2-propyn-1-
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ylbenzenesulfonamide (2) (30 mg, 0.08 mmol) were added 4-[N6,N6-bis(Boc)amino]-9H-purine
(80.5 mg, 0.24 mmol), 1,2-bis(diphenylphosphino)ethane nickel (II) chloride (4.2 mg, 0.008
mmol), and DBU (36.5 mg, 0.24 mmol). The reaction mixture was stirred for 2 h at 50 oC. The
cooled mixture was poured into water (50 mL). The organic layer was separated and the aqueous
layer was extracted with AcOEt. The combined organic layer was dried over MgSO4. The
solvent was removed under reduced pressure. The residue was purified by preparative TLC on
silica gel eluting with AcOEt-n-hexane (1:2) to give the title compound 10b (38.0 mg, 65%) as
pale yellow powders (mp 58-60 oC).
IR (KBr, cm-1) 3435, 2980, 2928, 1788, 1758, 1602, 1456, 1370, 1335, 1280, 1254, 1173, 1144,
1109, 1067, 852, 814, 759, 673, 588, 539; 1H NMR (600 MHz, CDCl3) 1.43 (18H, s), 2.43
(3H, s), 3.82 (2H, s), 5.31 (2H, s), 6.88 (1H, d, J = 2.0 Hz), 7.15-7.20 (6H, m), 7.28 (2H, d, J =
8.3 Hz), 7.61 (2H, d, J = 8.3 Hz), 7.99 (1H, s), 8.84 (1H, s); 13C NMR (125 MHz, CDCl3)  21.6
(q), 27.7 (qx6), 29.6 (t), 38.5 (t), 83.8 (s), 120.5 (d), 120.8 (d), 121.5 (s), 122.7 (s), 126.8 (d ×
2), 127.0 (d), 128.7 (s), 128.9 (d × 2), 130.1 (d × 2), 130.9 (d × 2), 134.6 (s), 135.3 (s), 144.4 (d
× 2), 145.4 (s), 150.2 (s), 150.4 (s), 152.1 (d × 2), 153.1 (s); EIMS (m/z) 690 (small M+), 535
(M+-155). MS (ESI) m/z 713 [M+Na]+, 729 [M+K]+; HRMS (ESI-DART) m/z: [M+Na]+
calcd for C34H38N6NaO6S2 713.21919; Found 713.21728.
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Deprotection of 10b.
1N HCl (0.6 mL, 0.6 mmol) solution was added to a MeOH (1.2 mL) solution of 10b (30 mg,
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0.04 mmol) at room temperature. The reaction mixture was stirred for 7.5 h at 50 C. The
cooled mixture was dried over MgSO4. The solvent was removed under reduced pressure. The
residue was purified by preparative TLC on silica gel eluting with CHCl3-MeOH (45:1) to give
the title compound 11b (14 mg, 66%) as white powders (mp 59-61 oC).
IR (KBr, cm-1)  3626, 3408, 3272, 3115, 2924, 2853, 1676, 1604, 1521, 1480, 1420, 1370, 1335,
1305, 1247, 1188, 1171, 1089, 1067, 1016, 970, 906, 833, 809, 767, 674, 586, 542; 1H NMR (600
MHz, CDCl3) 2.42 (3H, s), 3.81 (2H, s), 5.23 (2H, s), 5.78 (2H, brs), 6.89 (1H, d, J = 2.0 Hz),
7.09 (1H, d, J = 2.0 Hz), 7.14-7.19 (5H, m), 7.28 (2H, s), 7.62 (2H, d, J = 8.2 Hz), 7.71 (1H, s),
8.34 (1H, s); 13C NMR (125 MHz, CDCl3)  21.6 (q), 29.5 (t), 38.3 (t), 119.5 (s), 120.4 (d), 120.5
(d), 122.3 (s), 122.8 (s), 126.9 (d × 2), 128.8 (d × 2), 130.1 (d × 2), 130.7 (d × 2), 134.9 (s), 135.5
(s), 140.2 (d), 145.3 (s), 150.0 (s), 153.1 (d), 155.4 (s); EIMS m/z 490 (M+), 381 (M+-SPh), 335
(M+-Tos), 226 (M+-SPh-Tos); HRMS (EI) [M]+ m/z: calcd for C24H22N6O2S2 490.1245; Found
490.1263.
4-[7-(N6,N6-Bis(Boc)amino)-9H-purin-9-yl]methyl-5-methyl-3-(phenylsulfanylmethyl)-1-
tosylpyrrole (13b), entry 9.
To a DMSO (0.50 mL) solution of 4-methyl-N-[3-(phenylsulfanyl)-2-propyn-1-yl]-N-(1-methyl-
2-propyn-1-yl)benzenesulfonamide (4) (30 mg, 0.08 mmol) were added 4-[N6,N6-
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bis(Boc)amino]-9H-purine (81 mg, 0.24 mmol), bis(hexafluoroacetylacetonato)nickel (II)
hydrate (3.8 mg, 0.008 mmol) and DBU (36.5 mg, 0.24 mmol). The reaction mixture was stirred
for 5 h at 50 oC. The cooled mixture was poured into water (50 mL). The workup procedure
gave the titled compound 13b (26 mg, 45%) as pale yellow powders (mp 60-62 oC).
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IR (KBr, cm-1) 2979, 2932, 1789, 1725, 1577, 1452, 1370, 1335, 1280, 1250, 1170, 1145, 1105,
1
1094, 1049, 1000, 852, 816, 749, 669, 607, 584; H NMR (600 MHz, CDCl3) 1.43 (18H, s),
1.91 (3H, s), 2.45 (3H, s), 3.71 (2H, s), 5.30 (2H, s), 7.09-7.18 (5H, m), 7.31 (2H, d, J = 8.2 Hz),
13
7.34 (1H, s), 7.61 (2H, d, J = 8.2 Hz), 8.04 (1H, s), 8.85 (1H, s); C NMR (125 MHz, CDCl3)
10.5 (q), 21.6 (q), 27.8 (q × 6), 29.5 (t), 38.7 (t), 83.8 (s × 2), 119.4 (s), 119.6 (s), 120.9 (d),
127.0 (d × 2), 127.4 (d), 128.8 (d × 2), 128.9 (s), 129.9 (s), 130.1 (d × 2), 132.3 (d × 2), 134.5 (s),
135.6 (s), 144.5 (s), 145.3 (s), 150.2 (s), 150.5 (s × 2), 152.1 (d), 153.3 (s); EIMS m/z 370 (M+-
Ade). MS (ESI) m/z 705 [M+H]+, 727 [M+Na]+, 743 [M+K]+; HRMS (ESI-DART) m/z:
[M+Na]+ calcd for C35H40N6NaO6S2 727.23484; Found 727.23226.
4-[7-(N6,N6-Bis(Boc)amino)-9H-purin-9-yl]methyl-5-pentyl-3-(phenylsulfanylmethyl)-1-
tosylpyrrole (14b), entry 10.
To a DMSO (0.50 mL) solution of 4-methyl-N-[3-(phenylsulfanyl)-2-proryn-1-yl]-N-(1-pentyl-
2-propyn-1-yl)benzenesulfonamide (5) (30 mg, 0.07 mmol) were added 4-[N6,N6-
bis(Boc)amino]-9H-purine (70 mg, 0.21 mmol), bis(hexafluoroacetylacetonato)nickel (II)
hydrate (3.3 mg, 0.007 mmol) and DBU (32 mg, 0.21 mmol). The reaction mixture was stirred
for 7 h at 50 oC. The cooled mixture was poured into water (50 mL). The workup procedure
gave the titled compound 14b (26 mg, 48%) as pale yellow powders (mp 49-50 oC).
IR (KBr, cm-1) 3434, 2926, 2856, 1790, 1749, 1601, 1577, 1456, 1370, 1283, 1250, 1171, 1107,
874, 745, 669, 606, 587; 1H NMR (600 MHz, CDCl3) 0.83 (3H, t, J = 6.9 Hz), 1.17-1.32 (6H,
m), 1.43 (18H, s), 2.39-2.43 (5H, m), 3.76 (2H, s), 5.30 (2H, s), 7.16-7.19 (5H, m), 7.29-7.31 (3H,
m), 7.58 (2H, d, J = 8.2 Hz), 8.02 (1H, s), 8.83 (1H, s); 13C NMR (125 MHz, CDCl3) 13.9 (q),
21.6 (q), 22.2 (t), 25.1 (t), 27.8 (q × 6), 29.4 (t), 30.4 (t), 31.7 (t), 38.8 (t), 83.9 (s × 2), 119.3 (s),
120.0 (s), 121.5 (d), 126.7 (d × 2), 127.2 (d), 128.9 (d × 2), 129.8 (s), 130.1 (d × 2), 131.4 (d × 2),
135.2 (s), 135.3 (s), 136.1 (s), 144.5 (d), 145.2 (s), 150.2 (s), 150.5 (s × 2), 152.0 (d), 153.3 (s);
EIMS m/z 761 (M++1). Anal. Calcd for C39H48N6O6S2 (+ 1.5 H2O): C, 59.45; H, 6.52; N, 10.67.
Found: C, 59.18; H, 6.11; N, 10.25.
Deprotection of 14b.
1N HCl (2.3 mL, 2.3 mmol) solution was added to a MeOH (4.6 mL) solution of 14b (108 mg,
0.15 mmol) at room temperature. The reaction mixture was stirred for 8 h at 50 oC. The solvent
was removed under reduced pressure. The residue was purified by preparative TLC on silica gel
eluting with CHCl3-MeOH (10:1) to give the title compound 19b (78 mg, 96%) as white powders
(mp 136-138 oC).
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IR (KBr, cm-1)  3300, 3136, 2956, 2925, 2858, 1677, 1645, 1604, 1573, 1539, 1480, 1419, 1362,
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1330, 1302, 1282, 1234, 1170, 1092, 1068, 1026, 962, 905, 816, 748, 716, 676, 585, 536; H
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NMR (600 MHz, DMSO) 0.78 (3H, t, J = 6.2 Hz), 1.13-1.16 (3H, m), 1.17-1.24 (3H, m), 2.36
(2H, t, J = 7.6 Hz), 2.51 (3H, s), 3.96 (2H, s), 5.22 (2H, s), 7.19-7.24 (7H, m), 7.39 (1H, s), 7.44
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(2H, d, J = 8.2 Hz), 7.65 (2H, d, J = 9.0 Hz), 8.13 (2H, d, J = 13.8 Hz); C NMR (125 MHz,
DMSO)  13.8 (q), 21.1 (q), 21.7 (t), 24.4 (t), 27.9 (t), 30.0 (t), 31.1 (t), 37.3 (t), 119.7 (s), 121.5
(d), 122.3 (s), 126.5 (d × 2), 126.6 (d × 2), 128.8 (d × 2), 130.3 (d × 2), 130.4 (d × 2), 133.9 (s),
135.2 (s), 135.4 (s), 145.4 (s), 149.3 (s), 152.4 (d), 155.9 (s); EIMS m/z 560 (small M+), 451 (M+-
SPh), 405 (M+-Ts). MS (ESI) m/z 561 [M+H]+; HRMS (ESI-DART) m/z: [M+Na]+ calcd for
C29H33N6O2S2 561.21064; Found 561.20937. Anal. Calcd for C29H32N6O2S2 (+ 2 H2O): C,
58.37; H, 6.08; N, 14.08. Found: C, 58.45; H, 5.76; N, 13.64.
4-[7-(N6,N6-Bis(Boc)amino)-9H-purin-9-yl]methyl-5-phenyl-3-(phenylsulfanylmethyl)-1-
tosylpyrrole (14b), entry 11.
To a DMSO (0.50 mL) solution of 4-methyl-N-[3-(phenylsulfanyl)-2-propyn-1-yl]-N-(1-phethyl-
2-propyn-1-yl)benzenesulfonamide (6) (50 mg, 0.1 mmol) were added 4-[N6,N6-bis(Boc)amino]-
9H-purine (100.6 mg, 0.3 mmol), bis(hexafluoroacetylacetonato)nickel (II) hydrate (9.5 mg, 0.02
mmol), and DBU(45.7 mg, 0.3 mmol). The reaction mixture was stirred for 9.5 h at 50 oC. The
cooled mixture was poured into water (50 mL). The workup procedure gave the titled compound
15b (5 mg, 6%) as pale yellow powders (mp 80-83 oC).
IR (KBr, cm-1) 2925, 2853, 1751, 1609, 1466, 1369, 1323, 1232, 1175, 1146, 1093, 972, 814,
791, 751, 701, 668, 583, 543; 1H NMR (600 MHz, CDCl3) 1.57 (18H, s), 2.38 (3H, s), 3.58 (2H,
s), 5.43 (2H, s), 6.81 (2H, d, J = 6.9 Hz), 7.02 (2H, d, J = 6.9 Hz), 7.10 (2H, d, J = 8.2 Hz), 7.12-
7.17 (4H, m), 7.22 (2H, t, J = 7.6 Hz), 7.35 (1H, t, J = 7.6 Hz), 7.44 (1H, s), 7.97 (1H, brs), 7.99
(1H, s), 8.74 (1H, s); MS (ESI) m/z 789 [M+Na]+, 805 [M+K]+; HRMS (ESI-DART) m/z:
[M+Na]+ calcd for C40H42N6NaO6S2 789.25049; Found 789.24628.
4-[7-(N6,N6-Bis(Boc)amino)-9H-purin-9-yl]methyl-3-(phenylsulfanylmethyl)-1-(p-
nitrophenylsulfonyl)pyrrole (17b), entry 12.
To a DMSO (0.50 mL) solution of 4-nitro-N-[3-(phenylthio)-2-propyn-1-yl]-N-2-propyn-1-
ylbenzenesulfonamide (8) (30 mg, 0.08 mmol) were added 9-[N6,N6-bis(Boc)amino]-9H-purine
(80.5 mg, 0.24 mmol), bis(hexafluoroacetylacetonato)nickel (II) hydrate (4.2 mg, 0.008 mmol),
o
and DBU (36.5 mg, 0.24 mmol). The reaction mixture was stirred for 1.0 h at 50 C. The
workup procedure gave the title compound 17b (32 mg, 63%) as pale yellow powders (mp 69-71
oC).
IR (KBr, cm-1) 3106, 2981, 2928, 2853, 1789, 1720, 1604, 1577, 1535, 1453, 1370, 1349, 1280,
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1250, 1211, 1183, 1141, 1108, 1067, 1108, 1067, 953, 854, 741, 683, 629, 586; H NMR (600
MHz, CDCl3) 1.46 (18H, s), 3.86 (2H, s), 5.33 (2H, s), 6.89 (1H, d, J = 2.0 Hz), 7.15 (1H, d, J
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= 2.0 Hz), 7.17-7.21 (5H, m), 7.86 (2H, d, J = 9.0 Hz), 8.04 (1H, s), 8.28 (2H, d, J = 9.0 Hz), 8.84
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(1H, s); C NMR (125 MHz, CDCl3) 27.8 (q × 6), 29.3 (t), 38.4 (t), 83.9 (s × 2), 120.4 (d),
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120.9 (d), 123.1 (s), 124.1 (s), 124.8 (d × 2), 127.1 (d), 128.1 (d × 2), 128.6 (s), 128.9 (d × 2),
130.8 (d × 2), 134.3 (s), 143.5 (s), 144.3 (d), 150.4 (s), 150.5 (s × 2), 150.7 (s), 152.1 (d), 153.1
(s); EIMS m/z 657 (M+). MS (ESI) m/z 744 [M+Na]+; HRMS (ESI-DART) m/z: [M+Na]+ calcd
for C33H35N7NaO8S2 744.18862; Found 744.19164.
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4-(N3-Benzoyluracil-1-yl)methyl-3-(phenylsulfanylmethyl)-1-tosylpyrrole (10c), entry 13.
To a DMSO (0.50 mL) solution of 4-methyl-N-[3-(phenylthio)-2-propyn-1-yl]-N-2-propyn-1-
ylbenzenesulfonamide (2) (50 mg, 0.14 mmol) were added N3-benzoyluracil (90.8 mg, 0.42
mmol), bis(triphenylphosphine)palladium (II) dichloride (19.7 mg, 0.028 mmol),
bis(hexafluoroacetylacetonato)nickel (II) hydrate (13.2 mg, 0.028 mmol), and DBU (63.9 mg,
0.42 mmol). The reaction mixture was stirred for 3 h at 40 oC. The cooled mixture was poured
into water (50 mL). The organic layer was separated and the aqueous layer was extracted with
AcOEt. The combined organic layer was dried over MgSO4. The solvent was removed under
reduced pressure. The residue was purified by preparative TLC on silica gel eluting with
AcOEt-n-hexane (1:1) to give the title compound 10c (59.0 mg, 73%) as pale yellow powders
(mp 58-60 oC).
IR (KBr, cm-1)  2924, 2853, 2360, 1748, 1704, 1665, 1597, 1519, 1439, 1374, 1300, 1254, 1173,
1092, 1067, 984, 942, 813, 745, 673, 587, 540; 1H NMR (600 MHz, CDCl3) 2.41 (3H, s), 3.85
(2H, s), 4.78 (2H, s), 5.75 (1H, d, J = 7.6 Hz), 6.87 (1H, d, J = 1.4 Hz), 7.18 (6H, brs), 7.25-7.28
(3H, m), 7.41 (2H, t, J = 7.6 Hz), 7.60 (1H, t, J = 7.6 Hz), 7.64 (2H, d, J = 8.2 Hz), 7.93 (2H, d,
J = 7.6 Hz); 13C NMR (125 MHz, CDCl3) 21.6 (q), 29.5 (t), 42.2 (t), 102.4 (d), 120.6 (d), 121.2
(s), 121.3 (d), 123.0 (s), 126.9 (d × 2), 127.0 (d), 128.9 (d × 2), 129.1 (d × 2), 130.1 (d × 2), 130.4
(d × 2), 131.0 (d × 2), 131.3 (s), 134.6 (s), 135.0 (d), 135.2 (s), 143.0 (d), 145.5 (s), 149.9 (s),
162.3 (s), 168.8 (s); EIMS m/z 571 (small M+), 466 (M+-COPh); MS (ESI) m/z 594 [M+Na]+;
HRMS (ESI-DART) m/z: [M+Na]+ calcd for C30H25N3NaO5S2 594.11333; Found 594.11482.
Debenzoylation of 10c.
To a NaOH (0.9 mL, 1.7 mmol) in MeOH (3.4 mL) was added 4-(N3-Benzoyluracil-1-yl)methyl-
3-(phenylsulfanylmethyl)-1-tosylpyrrole (10c) (100 mg, 0.17 mmol). The reaction mixture was
stirred for 2 h and poured into water (50 mL). The organic layer was separated and the aqueous
layer was extracted with AcOEt. The combined organic layer was dried over MgSO4. The
solvent was removed under reduced pressure. The residue was purified by preparative TLC on
silica gel eluting with AcOEt-n-hexane (1:1) to give the title compound 11c (40 mg, 49%) as pale
yellow powders (mp 55-57 oC).
IR (KBr, cm-1)  3054, 1683, 1460, 1370, 1302, 1248, 1172, 1092, 1067, 812, 745, 673, 587, 540;
1H NMR (600 MHz, CDCl3) 2.43 (3H, s), 3.86 (2H, s), 4.77 (2H, s), 5.67 (1H, d, J = 8.2 Hz),
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6.89 (1H, d, J = 2.1 Hz), 7.12 (1H, d, J = 2.1 Hz), 7.14 (1H, d, J = 8.3 Hz), 7.19 (5H, s), 7.29 (2H,
d, J = 8.2 Hz), 7.65 (2H, d, J = 8.9 Hz), 9.12 (1H, brs); 13C NMR (125 MHz, CDCl3) 1.7 (q),
29.5 (t), 42.0 (t), 102.6 (d), 120.6 (d), 120.8 (d), 121.8 (s), 122.9 (s), 126.9 (d × 3), 128.9 (d × 2),
130.1 (d × 2), 130.7 (d × 2), 134.9 (s), 135.4 (s), 143.2 (d), 145.4 (s), 150.9 (s), 163.4 (s); MS
(ESI) m/z 490 [M+Na]+; HRMS (ESI-DART) m/z: [M+Na]+ calcd for C23H21N3NaO4S2
490.08712; Found 490.08588.
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Synthesis
of
4-[N4,N4-bis(Boc)cytosin-1-ylmethyl]-3-[(phenylsulfanyl)methyl]-1-(p-
tosyl)pyrrole (10d) (entry 14).
To a DMSO (1.8 mL) solution of 4-methyl-N-[3-(phenylthio)-2-propyn-1-yl]-N-2-propyn-1-
ylbenzenesulfonamide (2) (100 mg, 0.28 mmol) were added 4-[N6,N6-bis(Boc)amino]-1H-
cytosine (261.5 mg, 0.84 mmol), bis(hexafluoroacetylacetonato)nickel (II) hydrate (26.5 mg,
0.056 mmol), bis(triphenylphosphine)palladium (II) dichloride (39.3 mg, 0.056 mmol), and
o
DBU(127.9 mg, 0.84 mmol). The reaction mixture was stirred for 2 h at 30 C. The cooled
mixture was poured into water (50 mL). The organic layer was separated and the aqueous layer
was extracted with AcOEt. The combined organic layer was dried over MgSO4. The solvent
was removed under reduced pressure. The residue was purified by preparative TLC on silica
gel eluting with AcOEt-n-hexane (1:2) to give the title compound 10d (166.0 mg, 89%) as yellow
powders (mp 54-56 oC).
IR (KBr, cm-1)  2981, 2932, 1778, 1744, 1671, 1626, 1527, 1462, 1371, 1321, 1257, 1159, 1066,
969, 858, 790, 746, 673, 587, 540; 1H NMR (600 MHz, CDCl3) 1.55 (18H, s), 2.43 (3H, s), 3.86
(2H, s), 4.88 (2H, s), 6.89 (1H, s), 6.97 (1H, d, J = 7.6 Hz), 7.12 (1H, s), 7.20 (5H, s), 7.27-7.31
(2H, m), 7.50 (1H, d, J = 6.8 Hz), 7.64 (2H, d, J = 8.2 Hz); 13C NMR (125 MHz, CDCl3)  21.6
(q), 27.7 (q × 6), 29.6 (t), 43.9 (t), 84.9 (s), 96.5 (d), 120.3 (d), 121.0 (d), 121.8 (s), 123.1 (s),
126.9 (d × 2), 128.9 (d × 2), 129.7 (s), 130.1 (d × 2), 130.9 (d × 2), 134.8 (s), 135.4 (s), 145.3 (d),
146.8 (s), 149.5 (s × 2), 155.0 (s), 162.1 (s); EIMS m/z 666 (M+); MS (ESI) m/z 667 [M+H]+, 689
[M+Na]+; HRMS (ESI-DART) m/z: [M+Na]+ calcd for C33H38N4NaO7S2 689.20796; Found
689.20968.
Synthesis of 4-(Cytosin-1-yl)methyl-3-[(phenylsulfanyl)methyl]-1-(p-
toluenesulfonyl)pyrrole (11d).
1N HCl (2.2 mL, 2.2 mmol) solution was added to a MeOH (2.2 mL) solution of 10d (100 mg,
0.15 mmol) at room temperature. The reaction mixture was stirred for 20 min at reflux. The
solvent was removed under reduced pressure. The residue was purified by column
chromatography eluting with CHCl3-MeOH (40:1 to 20:1) to give the title compound 11d (63 mg,
90%) as white powders (mp 78-80 oC).
IR (KBr, cm-1)  3187, 2925, 2854, 2360, 2342, 1733, 1652, 1491, 1375, 1302, 1172, 1093, 1066,
809, 743, 670, 584, 409; 1H NMR (600 MHz, CDCl3) 2.38 (3H, s), 3.84 (2H, s), 4.77 (2H, s),
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5.78 (1H, d, J = 6.9 Hz), 6.45 (1H, brs), 6.85 (1H, d, J = 2.0 Hz), 7.05 (1H, d, J = 1.4 Hz), 7.13-
7.18 (6H, m), 7.24 (2H, d, J = 8.3 Hz), 7.60 (2H, d, J = 8.2 Hz), 7.92 (1H, brs); 13C NMR (125
MHz, CDCl3)  21.6 (q), 29.3 (t), 43.2 (t), 95.2 (d), 120.0 (d), 120.4 (d), 123.1 (s), 123.2 (s), 126.6
(d), 126.8 (d × 2), 130.0 (d × 2), 130.5 (d × 2), 135.1 (s), 135.3 (s), 144.3 (d), 145.2 (s), 156.5 (s),
165.9 (s); EIMS m/z 384 (M+-cytosine); HRMS (EI) [M]+ m/z: calcd for C24H22N6O2S2: 490.1245;
Found 490.1263. Anal. Calcd for C23H22N4O3S2 (+ H2O): C, 57.01; H, 4.99; N, 11.56. Found:
C, 56.72; H, 4.66; N, 11.44.
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Synthesis of 4-[N4,N4-bis(Boc)cytosin-1-ylmethyl]-5-methyl-3-[(phenylsulfanyl)methyl]-1-
(p-tosyl)pyrrole (13d), entry 15.
To a DMSO (0.50 mL) solution of 4-methyl-N-[3-(phenylsulfanyl)-2-propyn-1-yl]-N-(1-methyl-
2-propyn-1-yl)benzenesulfonamide (4) (50 mg, 0.10 mmol) were added 4-[N6,N6-
bis(Boc)amino]-1H-cytosine (93 mg, 0.30 mmol), bis(triphenylphosphine)palladium (II)
dichloride (7.0 mg, 0.01 mmol), and DBU (45.7 mg, 0.30 mmol). The reaction mixture was
o
stirred for 6 h at 50 C. The cooled mixture was poured into water (50 mL). The workup
procedure gave the titled compound 13d (36 mg, 39%) as yellow powders (mp 57-60 oC)
IR (KBr, cm-1) 3446, 2924, 2852, 1776, 1743, 1669, 1526, 1463, 1371, 1320, 1257, 1161, 1092,
908, 793, 738, 671, 587; 1H NMR (600 MHz, CDCl3) 1.55 (18H, s), 1.93 (3H, s), 2.45 (3H, s),
3.77 (2H, s), 4.88 (2H, s), 6.98 (1H, d, J = 7.5 Hz), 7.11-7.15 (2H, m), 7.20 (2H, d, J = 8.2 Hz),
7.28 (1H, s), 7.32 (2H, d, J = 8.2 Hz), 7.53 (1H, d, J = 7.6 Hz), 7.63 (2H, d, J = 8.3 Hz); 13C NMR
(125 MHz, CDCl3) 10.6 (q), 21.6 (q), 27.7 (q × 6), 29.6 (t), 44.0 (t), 84.8 (s × 2), 96.5 (d), 119.9
(s), 120.0 (s), 120.9 (d), 127.0 (d × 2), 127.4 (d), 128.8 (d × 2), 129.7 (s), 130.1 (d × 2), 132.5 (d
× 2), 134.6 (s), 135.7 (s), 145.2 (s), 146.8 (d), 149.5 (s × 2), 155.0 (s), 162.1 (s); MS (ESI) m/z
703 [M+Na]+, 719 [M+K]+; HRMS (ESI-DART) m/z: [M+Na]+ calcd for C34H40N4NaO7S2
703.22361; Found 703.22401.
Synthesis of 4-[N4,N4-bis(Boc)cytosin-1-ylmethyl]-5-pentyl-3-[(phenylsulfanyl)methyl]-1-
(p-tosyl)pyrrole (14d), entry 16.
To a DMSO (2.0 mL) solution of 4-methyl-N-[3-(phenylsulfanyl)-2-propyn-1-yl]-N-(1-pentyl-2-
propyn-1-yl)benzenesulfonamide (5) (200 mg, 0.47 mmol) were added 4-[N6,N6-bis(Boc)amino]-
1H-cytosine (409.7 mg, 1.32 mmol), bis(triphenylphosphine)palladium (II) dichloride (33.0 mg,
0.047 mmol), and DBU (214.7 mg, 1.41 mmol). The reaction mixture was stirred for 6 h at 50
oC. The cooled mixture was poured into water (50 mL). The workup procedure gave the titled
compound 14d (126 mg, 36%) as yellow powders (mp 55-57 oC).
IR (KBr, cm-1) 3441, 2930, 2871, 1778, 1743, 1672, 1625, 1526, 1462, 1370, 1320, 1257, 1165,
1
1137, 1114, 1093, 1066, 1024, 969, 859, 813, 789, 744, 670, 588, 545; H NMR (600 MHz,
CDCl3)  t, J = 7.3 Hz), 1.20-1.35 (6H, m), 1.55 (18H, s), 2.42-2.45 (5H, m), 3.81 (2H,
s), 4.87 (2H, s), 6.97 (1H, d, J = 7.4 Hz), 7.16-7.19 (3H, m), 7.24-7.26 (3H, m), 7.30-7.35 (2H,
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m), 7.50 (2H, d, J = 8.6 Hz); 13C NMR (125 MHz, CDCl3) 13.9 (q), 21.6 (q), 22.2 (t), 25.1 (t),
27.7 (q × 6), 29.6 (t), 30.3 (t), 31.8 (t), 44.2 (t), 84.8 (s × 2), 96.5 (d), 119.8 (s), 120.4 (s), 121.5
(d), 126.8 (d × 2), 127.1 (d), 128.8 (d × 2), 130.0 (d × 2), 131.6 (d × 2), 135.0 (s), 135.3 (s), 136.1
(s), 145.1 (s), 146.9 (d), 149.5 (s × 2), 155.0 (s), 162.1 (s); EIMS m/z 736 (M+). MS (ESI) m/z
759 [M+Na]+, 775 [M+K]+; HRMS (ESI-DART) m/z: [M+Na]+ calcd for C38H48N4NaO7S2
759.2862; Found 759.2876.
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4-(Cytosin-1-ylmethyl)-5-pentyl-3-[(phenylsulfanyl)methyl]-1-(p-tosyl)pyrrole (19d).
1N HCl (2.0 mL, 2.0 mmol) solution was added to a MeOH (2.0 mL) solution of 14d (100 mg,
0.14 mmol) at room temperature. The reaction mixture was stirred for 20 min at reflux. The
solvent was removed under reduced pressure. The residue was purified by column
chromatography eluting with CHCl3-MeOH (40:1 to 30:1) to give the title compound 19d (17 mg,
23%) as white powders (mp 71-73 oC).
IR (KBr, cm-1) 3352, 3182, 2956, 2927, 2854, 1719, 1648, 1526, 1492, 1438, 1369, 1278, 1190,
1169, 1093, 1065, 975, 813, 741, 671, 587, 542; 1H NMR (600 MHz, CDCl3)  t, J =
6.9 Hz), 1.19-1.26 (5H, m), 1.29-1.33 (3H, m), 1.68 (2H, brs), 2.43 (3H, s), 3.83 (2H, s), 4.84
(2H, s), 5.68 (1H, d, J = 6.9 Hz), 7.17-7.19 (3H, m), 7.25-7.27 (4H, m), 7.30 (2H, d, J = 8.2 Hz),
7.61 (2H, d, J = 8.3 Hz); 13C NMR (125 MHz, CDCl3) 13.9 (q), 21.6 (q), 22.2 (t), 25.1 (t), 29.4
(t), 30.4 (t), 31.8 (t), 43.5 (t), 94.8 (d), 119.6 (s), 120.9 (d), 121.6 (s), 126.7 (d × 2), 126.9 (d),
128.8 (d × 2), 130.0 (d × 2), 131.3 (d × 2), 134.9 (s), 135.6 (s), 136.2 (s), 144.6 (d), 145.0 (s),
156.6 (s), 165.8 (s); EIMS m/z 536 (small M+). MS (ESI) m/z 559 [M+Na]+, 575 [M+K]+; HRMS
(ESI-DART) m/z: [M+Na]+ calcd for C28H32N4NaO3S2 559.18135; Found 559.17943.
Synthesis of 4-[(N3-benzoylthymin-1-yl)methyl]-2-(p-methoxyphenyl)-3-[(phenyl-
sulfanyl)methyl]furan (23a), Table 2, entry 1.
To a DMSO (0.50 mL) solution of 1-methoxy-4-[4-(2-propynyloxy)-3-(phenylsulfanyl)-2-
propyn-1-yl]benzene (20) (30 mg, 0.10 mmol) were added N3-benzoylthymine (69.1 mg, 0.30
mmol), bis(triphenylphosphine)palladium(II) dichloride (14.0 mg, 0.02 mmol),
bis(hexafluoroacetylacetonato)nickel(II) hydrate (9.5 mg, 0.02 mmol), and DBU (45.7 mg, 0.30
mmol). The whole was stirred for 23 h at 30 oC and the workup procedure and purification by
the preparative TLC on silica gel eluting with (AcOEt-n-hexane=1:2) gave 23a (31.8 mg, 61 %)
as pale yellow powders (mp 63-65 oC).
IR (KBr, cm-1)  3065, 2928, 2854, 1747, 1697, 1657, 1600, 1507, 1440, 1349, 1307, 1254, 1179,
1029, 993, 950, 836, 762, 690, 628; 1H NMR (600 MHz, CDCl3) 1.91 (3H, s), 3.84 (3H, s), 4.12
(2H, s), 4.85 (2H, s), 6.94 (2H, d, J = 8.2 Hz), 7.21-7.26 (4H, m), 7.30-7.33 (4H, m), 7.52 (1H,
13
s), 7.54 (1H, t, J = 7.6 Hz), 7.57 (2H, d, J = 8.3 Hz), 7.92 (2H, d, J = 7.6 Hz); C NMR (125
MHz, CDCl3)  12.4 (q), 29.0 (t), 40.8 (t), 55.3 (q), 111.0 (s), 113.1 (s), 114.2 (d × 2), 121.1 (s),
122.7 (s), 126.8 (d), 127.8 (d × 2), 128.96 (d × 2), 129.0 (d × 2), 130.2 (d × 2), 130.5 (d × 2),
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(s); EIMS m/z 538 (M+), 429 (M+-SPh); MS (ESI) m/z 561 [M+Na]+; HRMS (ESI-DART) m/z:
[M+Na]+ calcd for C31H26N2NaO5S 561.14601; Found 561.14457.
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Debenzoylation of 23a.
To a NaOH (0.47 mL, 0.93 mmol) in MeOH (1.9 mL) was added 4-[(N3-benzoylthymin-1-
yl)methyl]-2-(p-methoxyphenyl)-3-[(phenyl- sulfanyl)methyl]furan (23a) (50 mg, 0.093 mmol).
The reaction mixture was stirred for 5.5 h at 40 oC and poured into water (50 mL). The organic
layer was separated and the aqueous layer was extracted with AcOEt. The combined organic
layer was dried over MgSO4. The solvent was removed under reduced pressure. The residue
was purified by preparative TLC on silica gel eluting with AcOEt-n-hexane (1:1) to give the title
compound 26a (26.0 mg, 65%) as (mp 148-150 oC).
IR (KBr, cm-1)  3167, 3052, 2926, 2836, 1680, 1506, 1467, 1438, 1385, 1307, 1252, 1222, 1181,
1065, 1030, 953, 834, 761, 689, 623; 1H NMR (600 MHz, CDCl3) 1.88 (3H, s), 3.83 (3H, s),
4.13 (2H, s), 4.81 (2H, s), 6.94 (2H, d, J = 8.9 Hz), 7.06 (1H, d, J = 1.4 Hz), 7.20 (1H, t, J = 7.6
Hz), 7.28 (2H, d, J = 7.6 Hz), 7.32 (2H, d, J = 7.6 Hz), 7.47 (1H, s), 7.58 (2H, d, J = 9.0 Hz), 8.41
(1H, brs); 13C NMR (125 MHz, CDCl3)  12.4 (q), 28.7 (t), 40.6 (t), 55.3 (q), 111.2 (s), 113.1 (s),
114.3 (d × 2), 121.8 (s), 122.9 (s), 126.6 (d), 127.8 (d × 2), 129.0 (d × 2), 129.6 (d × 2), 135.9 (s),
139.2 (d), 140.3 (d), 150.9 (s), 153.0 (s), 159.6 (s), 163.8 (s); EIMS m/z 434 (M+), 325 (M+-SPh).
MS (ESI) m/z 457 [M+Na]+; HRMS (ESI-DART) m/z: [M+Na]+ calcd for C24H22N2NaO4S
457.11980; Found 457.11876. Anal. Calcd for C24H22N2O4S (+ 1/2 H2O): C, 64.99; H, 5.00; N,
6.32. Found: C, 65.09; H, 5.49; N, 5.83.
Synthesis
of
4-[(N3-benzoylthimin-1-yl)methyl]-2-(p-chlorophenyl)-3-[(phenyl-
sulfanyl)methyl]furan (24a), entry 2.
To a DMSO (0.50 mL) solution of 1-chloro-4-[4-(2-propynyloxy)-3-(phenylsulfanyl)-2-propyn-
1-yl]benzene (21) (30 mg, 0.10 mmol) were added N3-benzoylthymine (69.1 mg, 0.30 mmol),
bis(triphenylphosphine)palladium(II)
dichloride
(14.0
mg,
0.02
mmol),
bis(hexafluoroacetylacetonato)nickel(II) hydrate (9.5 mg, 0.02 mmol), and DBU (45.7 mg, 0.30
o
mmol). The whole was stirred for 4 h at 30 C and the workup procedure and purification by
the preparative TLC on silica gel eluting with (AcOEt-n-hexane=1:1) gave 24a (35 mg, 67 %) as
pale yellow powders.
o
mp 71-73 C, IR (KBr, cm-1)  3061, 2928, 2364, 1746, 1697, 1656, 1599, 1488, 1439, 1350,
1315, 1259, 1236, 1152, 1093, 994, 949, 833, 762, 689, 620; 1H NMR (600 MHz, CDCl3) 1.91
(3H, s), 4.11 (2H, s), 4.85 (2H, s, 7.21 (2H, d, J = 7.8 Hz), 7.25 (2H, d, J = 6.6 Hz), 7.30-7.34
13
(6H, m), 7.37 (2H, d, J = 8.7 Hz), 7.54-7.57 (4H, m), 7.91 (2H, d, J = 7.4 Hz); C NMR (125
MHz, CDCl3)  12.4 (q), 28.9 (t), 40.7 (t), 111.2 (s), 115.2 (s), 121.5 (s), 127.2 (d), 127.5 (d × 2),
128.4 (s), 129.0 (d × 2), 129.1 (d × 2), 130.5 (d × 2), 130.6 (d × 2), 131.4 (s), 134.2 (s), 134.9 (d
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× 2), 138.9 (d), 141.6 (d), 151.7 (s), 169.1 (s); EIMS m/z 543 (M++1). MS (ESI) m/z 543
[M+H]+, 565 [M+Na]+; HRMS (ESI-DART) m/z: [M+Na]+ calcd for C30H23ClN2NaO4S
565.09647; Found 565.10123.
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Debenzoylation of 24a.
To a NaOH (0.3 mL, 0.6 mmol) in MeOH (1.2 mL) was added 4-[(N3-benzoylthimin-1-
yl)methyl]-2-(p-chlorophenyl)-3-[(phenyl- sulfanyl)methyl]furan (24a) (30 mg, 0.06 mmol).
The reaction mixture was stirred for 19 h at 40 oC and poured into water (50 mL). The organic
layer was separated and the aqueous layer was extracted with CHCl3. The combined organic
layer was dried over MgSO4. The solvent was removed under reduced pressure. The residue
was purified by preparative TLC on silica gel eluting with AcOEt-n-hexane (1:1) to give the title
compound 27a (19.0 mg, 78%) as pale yellow powders (mp 127-128 oC).
IR (KBr, cm-1)  3433, 3053, 1679, 1481, 1354, 1219, 1120, 1094, 1012, 950, 833, 745, 692, 614,
542, 470; 1H NMR (600 MHz, CDCl3) 1.89 (3H, s), 4.12 (2H, s), 4.81 (2H, s), 7.06 (1H, s), 7.21
(1H, t, J = 7.3 Hz), 7.26-7.28 (4H, m), 7.31-7.33 (2H, m), 7.37 (2H, d, J = 8.3 Hz), 7.46 (1H, m),
7.52 (1H, s), 7.55-7.57 (2H, m), 7.65-7.69 (1H, m), 8.86 (1H, brs); 13C NMR (125 MHz, CDCl3)
 12.4 (q), 28.6 (t), 40.5 (t), 111.3 (s), 115.0 (s), 122.1 (s), 126.9 (d), 127.5 (d × 2), 128.5 (d),
129.0 (d × 2), 129.1 (d × 2), 129.9 (d × 2), 134.1 (s), 135.4 (s), 139.1 (d), 141.1 (d), 151.0 (s),
151.6 (s), 163.9 (s); EIMS m/z 438 (M+), 329 (M+-SPh); MS (ESI) m/z 437 [M-H]-; HRMS (ESI-
DART) m/z: [M+Na]+ calcd for C23H18ClN2O3S 437.07267; Found 437.07303.
Synthesis
of
4-[(N3-benzoylthimin-1-yl)methyl]-2-(p-fluorophenyl)-3-[(phenyl-
sulfanyl)methyl]furan (25a), entry 3.
To a DMSO (0.50 mL) solution of 1-fluoro-4-[4-(2-propynyloxy)-3-(phenylsulfanyl)-2-propyn-
1-yl]benzene (22) (30 mg, 0.10 mmol) were added N3-benzoylthymine (69.1 mg, 0.30 mmol),
bis(triphenylphosphine)palladium(II)
dichloride
(14.0
mg,
0.02
mmol),
bis(hexafluoroacetylacetonato)nickel(II) hydrate (9.5 mg, 0.02 mmol), and DBU (45.7 mg, 0.30
mmol). The whole was stirred for 1.5 h at 30 oC and the workup procedure and purification by
the preparative TLC on silica gel eluting with (AcOEt-n-hexane=1:2) gave 25a (22.6 mg, 43 %)
as yellow powders (mp 108-110 oC).
IR (KBr, cm-1)  3427, 3063, 2929, 1747, 1698, 1657, 1599, 1504, 1440, 1350, 1314, 1235, 1158,
994, 950, 841, 763, 674, 628, 544; 1H NMR (600 MHz, CDCl3) 1.96 (3H, s), 4.11 (2H, s), 4.85
(2H, s, 7.10 (2H, t, J = 8.7 Hz), 7.19-7.25 (5H, m), 7.30-7.34 (3H, m), 7.52-7.61 (4H, m), 7.91
(2H, d, J = 7.8 Hz); 13C NMR (125 MHz, CDCl3)  12.4 (q), 28.9 (t), 40.7 (t), 111.1 (s), 115.7 (d),
115.9 (d), 121.3 (s), 126.2 (s), 127.0 (d), 128.2 (d), 128.3 (d), 129.0 (d × 2), 129.1 (d × 2), 130.4
(d), 131.4 (s), 134.9 (d), 135.0 (s), 139.0 (d), 141.4 (d), 151.9 (s), 162.5 (d, J = 248.5 Hz), 169.1
(s); EIMS m/z 526 (M+), 417 (M+-SPh); MS (ESI) m/z 549 [M+Na]+; HRMS (ESI-DART) m/z:
[M+Na]+ calcd for C30H23FN2NaO4S 549.12603; Found 549.12851.
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Synthesis of 4-[N6,N6-bis(Boc)adenin-9-ylmethyl]-3-[(phenylsulfanyl)methyl]-2- (p-
chlorophenyl)furan (24b), entry 4.
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To a DMSO (0.50 mL) solution of 1-chloro-4-[4-(2-propynyloxy)-3-(phenylsulfanyl)-2-propyn-
1-yl]benzene (21) (50 mg, 0.16 mmol) were added N6,N6-bis(Boc)adenine (161 mg, 0.48 mmol),
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bis(triphenylphosphine)palladium(II)
dichloride
(22
mg,
0.032
mmol),
bis(hexafluoroacetylacetonato)nickel (II) hydrate (15 mg, 0.032 mmol), and DBU (73 mg, 0.48
o
mmol). The whole was stirred for 3 h at 30 C and the workup procedure and purification by
the preparative TLC on silica gel eluting with (AcOEt-n-hexane=1:1) gave 24b (48 mg, 46 %) as
white powders (mp 44-45 oC).
IR (KBr, cm-1)  2980, 2934, 1787, 1758, 1602, 1578, 1531, 1489, 1455, 1409, 1394, 1370, 1335,
1279, 1254, 1211, 1144, 1108, 950, 851, 833, 753, 691, 640; 1H NMR (600 MHz, CDCl3) 1.43
(18H, s), 4.06 (2H, s), 5.35 (2H, s), 7.23-7.26 (5H, m), 7.35 (2H, d, J = 8.2 Hz), 7.48 (2H, d, J =
8.3 Hz), 7.54 (1H, s), 8.14 (1H, s), 8.82 (1H, s); 13C NMR (125 MHz, CDCl3)  27.7 (q × 6), 28.8
(t), 37.0 (t), 83.8 (s × 2), 115.1 (s), 121.5 (s), 127.2 (d), 127.5 (d × 2), 128.3 (s), 128.6 (s), 128.9
(d × 2), 129.0 (d × 2), 130.7 (d × 2), 134.1 (s), 134.7 (s), 141.1 (d), 144.4 (d), 150.2 (s), 150.4 (s
× 2), 151.5 (s), 152.0 (d), 153.2 (s); EIMS m/z 647 (M+). MS (ESI) m/z 670 [M+Na]+; HRMS
(ESI-DART) m/z: [M+Na]+ calcd for C33H34ClN5NaO5S 670.18669; Found 670.18729.
Synthesis of 4-[N6,N6-bis(Boc)adenin-9-ylmethyl]-3-[(phenylsulfanyl)methyl]-2- (p-
fluorophenyl)furan (25b), entry 5.
To a DMSO (0.80 mL) solution of 1-fluoro-4-[4-(2-propynyloxy)-3-(phenylsulfanyl)-2-propyn-
1-yl]benzene (22) (80 mg, 0.27 mmol) were added N6,N6-bis(Boc)adenine (181.1 mg, 0.54 mmol),
Pd(PPh3)4 (57.8 mg, 0.05 mmol), bis(hexafluoroacetylacetonato)nickel(II) hydrate (23.6 mg, 0.05
mmol), and DBU (82.2 mg, 0.54 mmol). The whole was stirred for 3.5 h at 30 oC and the workup
procedure and purification by the preparative TLC on silica gel eluting with (AcOEt-n-
hexane=1:1) gave 25b (86 mg, 50 %) as a pale yellow oil.
IR (KBr, cm-1) 3060, 2981, 2933, 1787, 1760, 1602, 1578, 1532, 1504, 1481, 1454, 1409, 1394,
1
1370, 1336, 1310, 1279, 1252, 1211, 1143, 1108, 951, 847, 753, 692, 639, 590; H NMR (600
MHz, CDCl3) 1.43 (18H, s), 4.05 (2H, s), 5.36 (2H, s), 7.08 (2H, t, J = 8.6 Hz), 7.24-7.27 (5H,
m), 7.52 (3H, t, J = 6.9 Hz), 8.14 (1H, s), 8.82 (1H, s); 13C NMR (125 MHz, CDCl3)  27.7 (q ×
6), 28.8 (t), 37.1 (t), 83.9 (s × 2), 144.4 (s), 115.7 (d), 115.9 (d), 121.4 (s), 126.1 (s), 127.1 (d),
128.2 (d), 128.3 (d), 128.7 (s), 129.0 (d × 2), 130.7 (d × 2), 134.9 (s), 140.9 (d), 144.5 (d), 150.1
(s), 150.5 (s × 2), 151.9 (s), 152.1 (d), 153.3 (s), 162.0 (d, J = 250.0 Hz); EIMS m/z 631 (M+);
HRMS[M]+ calcd for C33H34N5O5SF 631.2264; Found 631.2227. MS (ESI) m/z 670 [M+Na]+,
686 [M+K]+; HRMS (ESI-DART) m/z: [M+Na]+ calcd for C33H34ClN5NaO5S 670.18669; Found
670.18188.
Synthesis of 4-(9H-adenin-9-ylmethyl)-3-(phenylsulfanylmethyl)-2-(p-fluorophenyl)furan
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(28b).
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1N HCl (2.0 mL, 2.0 mmol) solution was added to a MeOH (4.0 mL) solution of 25b (80 mg,
0.13 mmol) at room temperature. The reaction mixture was stirred at 50 oC for 24 h. The workup
procedure gave the titled compound 28b (26 mg, 48%) as pale yellow powders (mp 66-68 oC).
IR (KBr, cm-1) 3314, 3118, 2926, 1760, 1672, 1601, 1505, 1480, 1418, 1331, 1306, 1238, 1158,
1062, 1013, 953, 839, 756, 718, 691; 1H NMR (600 MHz, CDCl3) 4.04 (2H, s), 5.29 (2H, s),
5.97 (2H, brs), 7.08 (2H, t, J = 8.3 Hz), 7.19-7.25 (5H, m), 7.49 (1H, s), 7.53-7.56 (2H, m), 7.85
(1H, s), 8.29 (1H, s); 13C NMR (125 MHz, CDCl3) 28.6 (t), 36.9 (t), 114.4 (s), 115.7 (d), 115.9
(d), 119.5 (s), 122.0 (s), 126.2 (s), 126.9 (d), 128.2 (d), 128.3 (d), 128.9 (d × 2), 130.2 (d × 2),
135.2 (s), 140.2 (d), 140.6 (d), 150.0 (s), 151.8 (s), 153.0 (d), 155.4 (s), 162.01 (d, J = 250.0 Hz);
EIMS m/z 431 (M+), 322 (M+-SPh). Anal. Calcd for C23H18N5OSF (+ 2/5 H2O): C, 62.97; H,
4.32; N, 15.96. Found: C, 63.17; H, 4.52; N, 15.66.
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Synthesis
of
3-(N3-Benzoyluracil-1-yl)-2-(p-fluorophenyl)-3-[(phenyl-
sulfanyl)methyl]furan (25c), entry 6.
To a DMSO (0.50 mL) solution of 1-fluoro-4-[4-(2-propynyloxy)-3-(phenylsulfanyl)-2-propyn-
1-yl]benzene (22) (50 mg, 0.17 mmol) were added N3-benzoyluracil (110.3 mg, 0.51 mmol),
bis(triphenylphosphine)palladium(II)
dichloride
(23.9
mg,
0.034
mmol),
bis(hexafluoroacetylacetonato)nickel(II) hydrate (16.1 mg, 0.034 mmol), and DBU (77.6 mg,
0.51 mmol). The whole was stirred for 1 h at 40 oC and the workup procedure and purification
by the preparative TLC on silica gel eluting with (AcOEt-n-hexane=1:1) gave 25c (56 mg, 65 %)
as pale yellow powders (mp 70-72 oC).
IR (KBr, cm-1) 2925, 2360, 1748, 1704, 1665, 1598, 1504, 1439, 1383, 1255, 1237, 1179, 1146,
944, 842, 692, 544, 418; 1H NMR (600 MHz, CDCl3) 4.10 (2H, s). 4.87 (2H, s), 5.83 (1H, d, J
= 5.5 Hz), 7.10 (2H, t, J = 8.2 Hz), 7.20-7.26 (3H, m), 7.31-7.35 (4H, m), 7.38 (1H, d, J = 6.2
Hz), 7.55-7.59 (4H, m), 7.93 (2H, d, J = 7.6 Hz); 13C NMR (125 MHz, CDCl3)  28.9 (t), 40.9 (t),
102.5 (s), 114.4 (s), 115.8 (d), 115.9 (d), 120.9 (s × 2), 126.1 (s), 126.2 (s), 127.2 (d), 128.2 (d),
128.3 (d), 129.0 (d × 2), 129.1 (d × 2), 130.5 (d × 2), 130.7 (d × 2), 131.3 (s), 134.9 (s), 135.0 (d),
141.5 (d), 143.0 (d), 152.0 (s), 162.5 (d, J = 249.9 Hz), 168.8 (s); MS (ESI) m/z 535 [M+Na]+;
HRMS (ESI-DART) m/z: [M+Na]+ calcd for C29H21FN2NaO4S 535.11038; Found 535.11398.
Debenzoylation of 25c.
To a NaOH (0.35 mL, 0.7 mmol) in MeOH (1.4 mL) was added Synthesis of 3-(N3-Benzoyluracil-
1-yl)-2-(p-fluorophenyl)-3-[(phenyl- sulfanyl)methyl]furan (25c) (42 mg, 0.08 mmol). The
reaction mixture was stirred for 3.5 h at 40 oC and poured into water (50 mL). The organic layer
was separated and the aqueous layer was extracted with CHCl3. The combined organic layer
was dried over MgSO4. The solvent was removed under reduced pressure. The residue was
purified by preparative TLC on silica gel eluting with AcOEt-n-hexane (2:1) to give the title
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The Journal of Organic Chemistry
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compound 28c (13 mg, 39%) as pale yellow powders (mp 170-173 oC).
7
8
9
IR (KBr, cm-1)  3182, 3058, 2924, 2852, 1681, 1500, 1457, 1391, 1322, 1236, 1158, 1120, 1092,
849, 783, 736, 691, 624, 543; 1H NMR (600 MHz, CDCl3) 4.11 (2H, s), 4.84 (2H, s), 7.10 (2H,
t, J = 8.9 Hz), 7.21 (1H, t, J = 7.5 Hz), 7.24-7.28 (3H, m), 7.31 (2H, d, J = 8.2 Hz), 7.52 (1H, s),
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
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35
36
37
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39
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41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
13
7.58-7.60 (2H, m), 8.72 (1H, brs); C NMR (125 MHz, CDCl3)  28.6 (t), 40.7 (t), 102.8 (d),
114.3 (s), 115.8 (d), 116.0 (d), 121.6 (s), 126.2 (s), 126.9 (d), 128.2 (d), 128.3 (d), 129.1 (d × 2),
129.9 (d × 2), 135.3 (s), 141.0 (d), 143.2 (d), 150.9 (s), 152.1 (s), 163.2 (s), 163.4 (s); MS (ESI)
m/z 431 [M+Na]+; HRMS (ESI-DART) m/z: [M+Na]+ calcd for C22H17FN2NaO3S 431.08416;
Found 431.08558.
Synthesis
of
4-[N4,N4-bis(Boc)cytosin-1-ylmethyl]-3-[(phenylsulfanyl)methyl]-2-(p-
methoxyphenyl)furan (23d), entry 7.
To a DMSO (0.50 mL) solution of 1-methoxy-4-[4-(2-propynyloxy)-3-(phenylsulfanyl)-2-
propyn-1-yl]benzene (20) (30 mg, 0.10 mmol) were added N4,N4-bis(Boc)cytosine (93.4 mg, 0.30
mmol), bis(triphenylphosphine)palladium(II) dichloride (14.0 mg, 0.02 mmol),
bis(hexafluoroacetylacetonato)nickel(II) hydrate (9.5 mg, 0.02 mmol), and DBU (45.7 mg, 0.30
mmol). The whole was stirred for 23 h at 30 oC and the workup procedure and purification by
the preparative TLC on silica gel eluting with (AcOEt-n-hexane=1:3) gave 23d (23 mg, 38 %) as
pale yellow powders (mp 112-114 oC).
IR (KBr, cm-1) 3441, 2981, 2934, 1777, 1744, 1670, 1625, 1529, 1507, 1463, 1371, 1321, 1255,
1157, 1028, 969, 837, 789, 749, 692; 1H NMR (600 MHz, CDCl3) 1.54 (18H, s), 3.84 (3H, s),
4.10 (2H, s), 4.93 (2H, s), 6.93 (2H, d, J = 8.7 Hz), 7.00 (1H, d, J = 7.4 Hz), 7.22-7.29 (3H, m),
7.35 (2H, d, J = 7.3 Hz), 7.50 (1H, s), 7.53 (2H, d, J = 8.2 Hz), 7.66 (1H, d, J = 7.5 Hz); 13C NMR
(125 MHz, CDCl3)  27.6 (q × 6), 29.1 (t), 43.0 (t), 55.3 (q), 84.9 (s × 2), 96.7 (d), 113.4 (s), 114.1
(d × 2), 121.1 (s), 122.9 (s), 127.0 (d), 127.9 (d × 2), 129.0 (d × 2), 130.6 (d × 2), 135.3 (s), 141.1
(d), 147.1 (d), 149.5 (s × 2), 152.5 (s), 155.2 (s), 159.5 (s), 162.2 (s); MS (ESI) m/z 642 [M+Na]+,
658 [M+K]+; HRMS (ESI-DART) m/z: [M+Na]+ calcd for C33H37N3NaO7S 642.22499; Found
642.22116.
Synthesis of 4-[N4,N4-bis(Boc)cytosin-1-ylmethyl]-3-[(phenylsulfanyl)methyl]-2- (p-
fluorophenyl)furan (25d), entry 8.
To a DMSO (0.50 mL) solution of 1-fluoro-4-[4-(2-propynyloxy)-3-(phenylsulfanyl)-2-propyn-
1-yl]benzene (22) (30 mg, 0.10 mmol) were added N4,N4-bis(Boc)cytosine (93.4 mg, 0.30 mmol),
bis(triphenylphosphine)palladium(II)
dichloride
(14.0
mg,
0.02
mmol),
bis(hexafluoroacetylacetonato)nickel(II) hydrate (9.5 mg, 0.02 mmol), and DBU (45.7 mg, 0.30
mmol). The whole was stirred for 23 h at 30 oC and the workup procedure and purification by
the preparative TLC on silica gel eluting with (AcOEt-n-hexane=1:3) gave 25d (35 mg, 57 %) as
pale yellow powders (mp 71-72 oC).
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