Copper-Catalyzed Regioselective Direct C–H Thiolation and Thiocyanation of Uracils

Article abstract of DOI:10.1002/ejoc.201900343

A novel copper-catalyzed direct C–H thiolation and thiocyanation of uracils using disulfides and thiocyanate salts respectively as coupling partners are described. These reactions enable the C–H bond cleavage and C–S bond formation to proceed efficiently under relatively mild conditions, providing useful methods for a preparation of a series of thio-substituted at the C5 position of uracil derivatives. These protocols exhibit several merits including simple experimental procedures, readily accessible substrates and reagents, broad scopes, high yields, and excellent regioselectivity. Preliminary mechanistic studies revealed that a radical pathway is likely to be involved.

Full text of DOI:10.1002/ejoc.201900343

DOI: 10.1002/ejoc.201900343
Full Paper
C–H Thiolation
Copper-Catalyzed Regioselective Direct C–H Thiolation and
Thiocyanation of Uracils
Medena Noikham[a] and Sirilata Yotphan*[a]
Abstract: A novel copper-catalyzed direct C–H thiolation and the C5 position of uracil derivatives. These protocols exhibit sev-
thiocyanation of uracils using disulfides and thiocyanate salts eral merits including simple experimental procedures, readily
respectively as coupling partners are described. These reactions accessible substrates and reagents, broad scopes, high yields,
enable the C–H bond cleavage and C–S bond formation to pro- and excellent regioselectivity. Preliminary mechanistic studies
ceed efficiently under relatively mild conditions, providing use- revealed that a radical pathway is likely to be involved.
ful methods for a preparation of a series of thio-substituted at
Introduction
Uracils represent ubiquitous structural motifs found in a num-
ber of natural products, agrochemicals and pharmaceuticals.[1]
A number of uracil analogues possess antiviral, antitumor, anti-
bacterial as well as herbicidal and insecticidal properties.[2] Due
to their wide array of biological and pharmacological activities
as well as their synthetic accessibility, they have attracted con-
siderable attention as important lead pharmacophores in drug
discovery and other related applications.[3] Over the past two
decades, many researchers have devoted their efforts to de-
velop efficient methods for preparations and manipulations of
functionalized uracil ring.[4]
Sulfur atom containing compounds are significant oriented
targets in synthesis, medicinal chemistry, and material sci-
ence.[5] The incorporation of sulfur moiety into organic mole-
cules can partially modify the physical and biological properties
of the parent compounds.[6] Despite the high impact to many
research areas, a few strategies for introducing sulfur moiety
into uracil cores were found in literature, including the transi-
tion metal-catalyzed C–S cross coupling reactions of arylthiols
Scheme 1. Approaches for installation of sulfur moiety into uracil cores.
or other nucleophilic sulfur sources with halides or iodonium
salts (Scheme 1a),[7] as well as the metal-free (I2 or NCS)-pro-
moted C–S bond formation (Scheme 1b),[8] which requires for
ile and efficient methods for the direct construction of C–S
bond of uracil derivatives is still highly desirable.
pre-functionalization of substrates or the presence of an adja-
cent nucleophilic assisting group (such as NH2 group).
Our group have been focused on the oxidative C–H function-
alization strategies to manipulate various N-heterocycles.[9] In
continuation of our recent research interest, we aim to ac-
complish the direct C–S coupling of uracils with commercially
available and easy-to-handle sulfur precursors. Herein, we dis-
close a highly efficient, convenient and regioselective copper-
catalyzed direct C–H thiolation and thiocyanation of uracil de-
rivatives with disulfides and thiocyanate salts to access a good
range of products in moderate to excellent yields. In addition,
these oxidative coupling reactions proceed very well under rela-
tively mild and air-tolerant conditions, which makes these pro-
tocols useful for the preparation of a series of 5-thio-substituted
Besides, these existing approaches also suffer from other lim-
itations, such as the need for odorous, expensive and/or toxic
reagents, harsh conditions under inert atmosphere and tedious
reaction procedures, which could greatly reduce their scope,
structural diversity and further utilization. Thus, developing fac-
[a] Center of Excellence for Innovation in Chemistry (PERCH-CIC), Department
of Chemistry, Faculty of Science, Mahidol University,
Rama VI Road, Bangkok 10400, Thailand
E-mail: sirilata.yot@mahidol.ac.th
http://chemistry.sc.mahidol.ac.th/en/people/faculty/sirilata-yotphan/
Supporting information and ORCID(s) from the author(s) for this article are
available on the WWW under
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uracils which can be further exploited in a number of applica- strates. In general, this reaction is quite versatile and can ac-
tions.
commodate a good range of substrates, and both electronic
and steric variations exert certain effect on this transformation.
As shown in Table 2, thiolation reactions of uracil 1a with elec-
tron rich diaryl disulfides proceeded smoothly, providing 5-thio-
substituted uracil products (3a–3d and 3h) in good to excellent
yields. It is noteworthy that the hydroxyl and amide functionali-
ties were well tolerated. Meanwhile, low yield of product was
obtained with chloro substituted diaryl disulfides (3e). In the
case of electron deficient diaryl disulfides (such as 4-nitro or 4-
cyano phenyl disulfides), only trace amount of products was
detected (3f–g). These outcomes indicate that the electronic
effect from disulfides is crucial for the efficiency of the transfor-
mation. In addition, we tested the reactions with diheteroaryl
and dialkyl disulfides, unfortunately, low to fair extents of the
desired products were obtained (3i and 3j). It is likely that the
sulfur species generated from heteroaryl or alkyl disulfides are
less stable than those sulfur species generated from the diaryl
disulfide sources.
Results and Discussion
Optimization of Reaction Conditions
Our initial studies on direct C–H functionalization/C–S bond
coupling were performed with an extensive screening of reac-
tion conditions,[10] and we found that a reaction of uracil (1a)
and p-tolyl disulfide (2a) in the presence of CuBr (10 mol-%)
and K2S2O8 (2 equiv.) in DMSO at 60 °C under atmospheric air
produced a 14 % yield of the 5-thio-substituted product 3a
(Table 1, entry 1). We next proceeded to conduct a solvent
screening,[10] and pleasingly a reaction in CH3CN solvent gave
the desired product in 74 % (entry 4). Subsequent optimization
of a catalytic source (entries 4–10) revealed that Cu(OTf)2 could
successfully delivered a complete conversion, affording a maxi-
mum 89 % yield of 3a (entry 10). Additional investigation on
the effect of an oxidant led to a further improvement of yield
to 96 % as 1.5 equiv. of K2S2O8 was employed (entry 13). Unfor-
tunately, only trace amount of product was detected when con-
ducting a reaction at room temperature. Finally, we carried out
reactions in the absence of copper or persulfate and the out-
comes indicated a necessity of both Cu(OTf)2 and K2S2O8 in this
transformation (entries 15–16).
Table 2. Copper-catalyzed direct thiolation of uracils with disulfides.[a,b]
Table 1. Optimization of reaction conditions.[a]
Entry
Catalyst
Oxidant (equiv.)
Solvent
Yield [%][b]
1
2
3
4
5
6
7
8
CuBr
CuBr
CuBr
CuBr
CuCl
CuI
CuCl2
CuBr2
Cu(OAc)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
–
K2S2O8 (2)
K2S2O8 (2)
K2S2O8 (2)
K2S2O8 (2)
K2S2O8 (2)
K2S2O8 (2)
K2S2O8 (2)
K2S2O8 (2)
K2S2O8 (2)
K2S2O8 (2)
Na2S2O8 (2)
(NH4)2S2O8 (2)
K2S2O8 (1.5)
K2S2O8 (1)
–
DMSO
THF
14
Trace
Trace
74
78
32
74
65
15
89
51
21
96 (4 h)
36
Trace
Trace
MeOH
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
9
10
11
12
13
14
15
16
K2S2O8 (1.5)
[a] Conditions: 1a (0.25 mmol, 1 equiv.), 2a (1.5 equiv.), catalyst (10 mol-%)
in 1 mL of solvent at 60 °C under an air atmosphere for 4–16 h, as monitored
by TLC. [b] GC yield.
Substrate Scope and Limitation
[a] Conditions: uracil (1 mmol, 1 equiv.), disulfide (1.5 equiv.), Cu(OTf)2
(10 mol-%), K2S2O8 (1.5 equiv.) in CH3CN (4 mL) at 60 °C under an air atmos-
phere for 4–16 h, as monitored by TLC. [b] Isolated yields. [c] Reaction was
conducted using Cu(OTf)2 (20 mol-%) for 48 h.
Under the optimal reaction conditions, we assessed the scope
of the direct thiolation with various disulfide and uracil sub-
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Next, the effect of substituents on the nitrogen atoms of eral, the thiocyanation reaction tolerated a diverse range of N-
uracil substrates was examined, and the results revealed that alkylated uracil substrates (4a–4e), providing the expected
no substantial impact was observed upon increasing a steric products in good to excellent yields, with the exception of the
hindrance of alkyl substituents on nitrogen atoms (3k–3n). uracil substrate with an alkyl ester on nitrogen (4f). The NH
Nonetheless, the presence of N-allyl or N-alkyl ester groups (3o uracils were also feasible substrates, affording the products in
and 3p) showed a deleterious effect on this C–H thiolation reac- moderate to decent quantities (4g and 4h). Similarly to the di-
tion and they delivered the corresponding products in some- rect thiolation, thiocyanation reactions of N-phenyl protected
what lower yields, suggesting a possible interruption of these uracils resulted in lower yields (4i–4j) due to their poor nucleo-
functional groups in the catalytic oxidative coupling process. philicity. In the case of the uracil bearing a methyl group at
The copper-catalyzed thiolation was also readily amenable to C6, no significant reduction of product yield was found (4k).
the synthesis of 5-thiolated products from non-protected NH- Strikingly, uracils possessing functional group such as amino
uracil substrates (3q–3r and 3x). Thus, these outcomes implied (NH2) and chloro at 6-position were also compatible to the di-
that the presence of imide or amide hydrogen (R1 or R2 = H) rect C–H thiocynation, furnishing the corresponding products
would not impede the direct C–S bond coupling in this transfor- (4l–4m) in moderate to good yields. Other possible side reac-
mation. However, due to a poor nucleophilicity, low yield was tions such as dechlorination or competitive coupling at 6 posi-
obtained for the N-phenyl uracil (3s). On the other hand, uracil tion were not observed.
substrates bearing a substitution on the C6 position (R3 group)
exhibited a decreased reactivity towards the reaction, and only
Table 3. Substrate Scope of the Direct Thiocyanation.[a,b]
fair yield of product (3t) was obtained, indicative of a possible
steric interference from R3 group in thiolation process. However,
we were delighted to observe that uracils with a chloro or a
chloromethyl substituent proved to be a viable substrate, pro-
viding an opportunity for further functionalization (3u–3x).
Other side reactions such as coupling reaction or dehalogen-
ation were not detected under the optimal conditions. Lastly,
the optimized system also proved applicable to the C–H selen-
ylation of uracils with diphenyl diselenide, affording the corre-
sponding product 3y1–3y4 in satisfied quantities.
After having the encouraging results for the copper-cata-
lyzed direct C–S bond coupling of uracil with disulfide, we then
turned our interest toward the direct thiocyanation, which
could lead to a useful building block and a pivotal synthetic
intermediate to a variety of sulfur containing compounds.[11]
Under the previously established conditions, however, no reac-
tion between uracil and NH4SCN occurred (Scheme 2). As we
screened a set of additives,[10] we found that the direct C–H
[a] Conditions: uracil (1 mmol, 1 equiv.), NH4SCN (1.5 equiv.), Cu(OTf)2 (2 mol-
%), I2 (1 equiv.), K2S2O8 (2 equiv.) in CH3CN (4 mL) at 60 °C under an air
atmosphere, 4 h. [b] Isolated yield.
thiocyanation could be fruitfully accomplished upon adding a
molecular iodine (I2, 1equiv.) into the reaction, and the uracil
1a was completely converted into the corresponding product
4a (99 %) with thiocyanate group installed exclusively at the 5-
position. Gratifyingly, other thiocyanate salts such as NaSCN
and KSCN were also very well effective, giving excellent yields
of product under the newly optimized conditions.
Reaction Mechanism
To investigate the reaction mechanism, several control experi-
ments were performed. In the case of the direct thiolation, no
reaction was observed when adding a radical scavenger (such
as TEMPO or BHT) to the standard conditions (Scheme 3a),
which is indicative of a radical process. Besides, the sulfur spe-
cies such as thiol or oxidized disulfide should not be an inter-
mediate involved in this transformation (Scheme 3b and 3c).
Moreover, no reaction was observed when employing 5-methyl-
substituted uracil, suggesting that the copper-catalyzed thiol-
ation takes place solely at the 5-position of uracil substrate
(Scheme 3d). The regiocontrol of this transformation was also
explained by the deuterium incorporation experiment, in which
the C–H bond metallation occurred at the most electron-rich
Scheme 2. Copper-catalyzed direct thiocyanation of uracil with thiocyanate
salt.
Having affirmed the optimal conditions for the copper-cata- C5 position of uracil substrate (Scheme 3e). Additionally, upon
lyzed regioselective direct thiocyanation, the scope was then evaluating two parallel reactions (Scheme 3f), no kinetic iso-
explored using NH4SCN with various uracils (Table 3). In gen- tope effect (KIE) was observed (KIE ≈ 1). Thus, the C–H bond
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cleavage under this copper catalysis might not be a rate-deter- effect (KIE ≈ 1), and I2 is likely to play a vital role in a radical
mining step. Lastly, competition experiments showed that this generation.[10]
thiolation reaction favored to form the product with more elec-
tron rich aryl sulfide (Scheme 3g and 3h). These results could
be a consequence of a stability of the radical intermediate that
was generated during the course of reaction. For the direct
thiocyanation, the control experiments also suggested a possi-
ble involvement of a radical process with no kinetic isotope
To account for the transformation, a plausible reaction mech-
anism for the direct thiolation and thiocyanation is proposed
as shown in Scheme 4. We believed that a radical pathway is
likely to be involved. First, the CuII species initially interacts with
uracil substrate leading to a facile C–H bond metallation to pro-
duce the CuII uracil complex (intermediate I).[9b,12] Then, this
copper intermediate I is subsequently attacked by sulfide radi-
cal (·SR) or thiocyanate radical (·SCN), which is generated from
a reaction of disulfide with K2S2O8[13] or a reaction of thiocyan-
ate salt with I2/K2S2O8, respectively,[14] to form the CuIII interme-
diate (II), which simultaneously undergoes reductive elimina-
tion to furnish the corresponding 5-thio-substituted uracil
product and release CuI species.[15] Finally, oxidation of CuI
would regenerate the CuII species to resume the cycle.
Scheme 4. Plausible reaction mechanism.
Conclusions
In summary, we have successfully established a novel and
highly efficient Cu-catalyzed regioselective direct C–S bond for-
mation of uracils with disulfides and thiocyanate salts through
C–H functionalization. Both thiolation and thiocyanation ap-
proaches were applicable to a broad range of substrates, pro-
viding a series of 5-thio-substituted uracil compounds in mod-
erate to excellent yields. The notable features included using
readily available starting materials, bypassing the requirement
for pre-functionalization or the presence of the nearby assisting
group, employing catalytic amounts of low-cost transition metal
catalyst, working very well with simple experimental proce-
Scheme 3. Control experiments for the direct thiolation.
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1,3-Dimethyl-5-(phenylthio)pyrimidine-2,4(1H,3H)-dione
dures under relatively mild conditions, good functional group
tolerance, and robustness of reactions under air atmosphere,
which render these protocols attractive and applicational po-
tential for further utilization in organic synthesis, discovery re-
search and other related fields.
1
(3b):[7e] Yellow solid (134 mg, 54 % yield); m.p. 123.8– 124.7 °C; H
NMR (400 MHz, CDCl3): δ = 7.60 (s, 1H), 7.33–7.28 (m, 4H), 7.21 (t,
J = 6.9 Hz, 1H), 3.44 (s, 3H), 3.38 (s, 3H); 13C NMR (100 MHz, CDCl3):
δ = 161.9, 151.7, 147.7, 135.3, 129.2, 128.9, 126.9, 106.2, 37.4, 28.8;
IR (neat, cm–1): ν = 3067, 2921, 1706, 1537, 1510, 1433, 1338, 1230,
˜
1150, 1023, 769, 735, 548; HRMS (ESI): calcd. for C12H12N2O2SNa [M
+ Na]+ 271.0512, found 271.0515.
Experimental Section
5-[(4-Methoxyphenyl)thio]-1,3-dimethylpyrimidine-2,4(1H,3H)-
dione (3c): Yellow solid (247 mg, 89 % yield); m.p. 101.7– 102.6 °C;
1H NMR (400 MHz, CDCl3): δ = 7.40 (d, J = 8.8 Hz, 2H), 7.38 (s, 1H),
6.84 (d, J = 8.4 Hz, 2H), 3.78 (s, 3H), 3.38 (s, 3H), 3.35 (s, 3H); 13C
NMR (100 MHz, CDCl3): δ = 161.9, 159.9, 151.7, 144.9, 133.6, 124.6,
General Information: Unless otherwise noted, all reagents were
obtained from commercial suppliers and used without further puri-
fication. All experiments were carried out under air atmosphere,
and oven-dried glassware were used in all cases. Column chroma-
tography was performed over silica gel (SiO2; 60 Å silica gel, Merck
Grade, 70–230 Mesh). 1H and 13C NMR spectra were recorded on
Bruker-AV400 spectrometers in CDCl3 or [D6]DMSO solution, at 400
and 100 MHz, respectively. NMR chemical shifts are reported in
ppm, and were measured relative to CHCl3 (7.26 ppm for 1H and
77.16 ppm for 13C) or DMSO (2.50 ppm for 1H and 39.52 ppm for
13C). IR spectra were recorded on Bruker FT-IR Spectrometer Model
ALPHA by neat method, and only partial data are listed. Melting
points were determined on Buchi Melting Point M-565 apparatus.
High resolution mass spectroscopy (HRMS) data were analyzed by
a high-resolution micrOTOF instrument with electrospray ionization
(ESI). The structures of known compounds were corroborated by
comparing their 1H NMR, 13C NMR data with those of litera-
ture.[7e,7f,8a]
115.1, 109.3, 55.5, 37.3, 28.7; IR (neat, cm–1): ν = 3061, 2923, 1708,
˜
1659, 1589, 1433, 1288, 1242, 1172, 1025, 838, 766, 528; HRMS (ESI):
calcd. for C13H14N2O3SNa [M + Na]+ 301.0617, found 301.0614.
5-[(4-Hydroxyphenyl)thio]-1,3-dimethylpyrimidine-2,4(1H,3H)-
dione (3d): Brown solid (187 mg, 71 % yield); m.p. 180.0 °C (decom-
1
posed); H NMR (400 MHz, [D6]DMSO): δ = 8.28 (s, 1H), 7.36 (d, J =
7.2 Hz, 2H), 7.28–7.21 (m, 3H), 3.34 (s, 3H), 3.20 (s, 3H); 13C NMR
(100 MHz, [D6]DMSO): δ = 161.5, 151.5, 151.1, 131.5, 129.5, 129.3,
126.5, 98.2, 36.6, 28.4; IR (neat, cm–1): ν = 3266, 2923, 1706, 1632,
˜
1581, 1492, 1434, 1222, 1022, 998, 820, 768, 633, 516; HRMS (ESI):
calcd. for C12H12N2O3SNa [M + Na]+ 287.0461, found 287.0458.
5-[(4-Chlorophenyl)thio]-1,3-dimethylpyrimidine-2,4(1H,3H)-di-
one (3e): Orange solid (48 mg, 17 % yield); m.p. 121.7– 122.1 °C;
1H NMR (400 MHz, CDCl3): δ = 7.66 (s, 1H), 7.28–7.24 (m, 4H), 3.46
(s, 3H), 3.39 (s, 3H); 13C NMR (100 MHz, CDCl3): δ = 161.8, 151.6,
147.9, 133.9, 133.1, 130.2, 129.4, 105.7, 37.5, 28.9; IR (neat, cm–1):
General Procedure for the Copper-Catalyzed Direct Thiolation
of Uracils with Disulfides: To a 20 mL scintillation vial equipped
with a magnetic stir bar, uracil 1 (1 mmol, 1.0 equiv.), disulfide 2
(1.5 mmol, 1.5 equiv.), copper(II)trifate [Cu(OTf)2] (0.10 mmol,
10 mol-%), potassium persulfate (K2S2O8) (1.5 mmol, 1.5 equiv.) and
acetonitrile (CH3CN) (4 mL) were added, respectively. The reaction
mixture was stirred at 60 °C for 4–16 h. Upon completion (moni-
tored by TLC), distilled deionized H2O (20 mL) was added, and the
mixture was extracted with ethyl acetate (EtOAc) (2 × 40 mL). The
combined organic layer was washed with saturated NaCl, dried with
anhydrous Na2SO4, and concentrated in vacuo. The crude product
was purified by SiO2 column chromatography to afford the 5-thi-
olated uracil product 3.
ν = 2922, 2852, 1712, 1659, 1511, 1471, 1337, 1142, 1089, 1005,
˜
811, 765, 542; HRMS (ESI): calcd. for C12H11ClN2O2SNa [M + Na]+
305.0122, found 305.0125.
N-{2-[(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-
thio]phenyl}benzamide (3h): White solid (220 mg, 60 % yield);
m.p. 222.6– 223.2 °C; 1H NMR (400 MHz, CDCl3): δ = 10.54 (s, 1H),
8.29 (d, J = 8.4 Hz, 1H), 8.22 (d, J = 7.6 Hz, 2H), 7.72 (s, 1H), 7.58–
7.50 (m, 4H), 7.44–7.40 (m, 1H), 7.09 (t, J = 7.6 Hz, 1H), 3.42 (s, 3H),
3.31 (s, 3H); 13C NMR (100 MHz, CDCl3): δ = 165.8, 163.3, 151.3,
147.0, 140.8 (2C), 136.5, 134.9, 131.9, 130.9, 128.7, 127.9, 125.1,
123.7, 108.7, 37.5, 29.0; IR (neat, cm–1): ν = 3306, 2923, 1701, 1637,
˜
General Procedure for the Copper-Catalyzed Direct Thiocyan-
ation of Uracils with Ammoniumthiocyanate: To a 20 mL scintilla-
tion vial equipped with a magnetic stir bar, uracil 1 (1 mmol,
1 equiv.), ammonium thiocyanate (NH4SCN) (1.5 mmol, 1.5 equiv.),
copper(II)trifate [Cu(OTf)2] (0.02 mmol, 2 mol-%), Iodine (I2) (1 mmol,
1 equiv.), potassium persulfate (K2S2O8) (2 mmol, 2 equiv.) and
acetonitrile (CH3CN) (4 mL) were added, respectively. The reaction
mixture was stirred at 60 °C for 4 h. Upon completion, distilled
deionized H2O (20 mL) and sat. Na2S2O3 (10 mL) was added, and
the mixture was extracted with ethyl acetate (EtOAc) (2 × 40 mL).
The combined organic layer was washed with saturated NaCl, dried
with anhydrous Na2SO4, and concentrated in vacuo. The crude
product was purified by SiO2 column chromatography to afford the
5-thiocyanated uracil product 4.
1578, 1492, 1433, 1305, 1073, 1019, 755, 704, 607; HRMS (ESI): calcd.
for C19H17N3O3SNa [M + Na]+ 390.0883, found 390.0885.
5-(Benzo[d]thiazol-2-ylthio)-1,3-dimethylpyrimidine-2,4-
(1H,3H)-dione (3i): Brown solid (70 mg, 23 % yield); m.p. 185.4–
186.0 °C; 1H NMR (400 MHz, CDCl3): δ = 7.89 (s, 1H), 7.84 (d, J =
8.0 Hz, 1H), 7.70 (d, J = 7.8 Hz, 1H), 7.39 (t, J = 7.5 Hz, 1H), 7.28 (t,
J = 7.2 Hz, 1H), 3.47 (s, 3H), 3.39 (s, 3H); 13C NMR (100 MHz, CDCl3):
δ = 166.8, 161.2, 153.7, 151.4, 150.4, 135.7, 126.3, 124.7, 122.1, 121.1,
102.2, 37.7, 29.0; IR (neat, cm–1): ν = 3057, 2923, 1714, 1651, 1608,
˜
1456, 1332, 1274, 1123, 1009, 941, 760, 666, 535; HRMS (ESI): calcd.
for C13H11N3O2S2Na [M + Na]+ 328.0185, found 328.0183.
1,3-Dimethyl-5-(propylthio)pyrimidine-2,4(1H,3H)-dione (3j):
Yellow solid (96 mg, 45 % yield); m.p. 63.6– 64.5 °C; 1H NMR
(400 MHz, CDCl3): δ = 7.48 (s, 1H), 3.40 (s, 3H), 3.37 (s, 3H), 2.73 (t,
J = 7.2 Hz, 2H), 1.60–1.51 (m, 2H ), 0.97 (t, J = 7.4 Hz, 3H); 13C NMR
(100 MHz, CDCl3): δ = 162.4, 151.8, 145.7, 106.9, 37.2, 35.6, 28.6,
1,3-Dimethyl-5-(p-tolylthio)pyrimidine-2,4(1H,3H)-dione (3a):
White solid (257 mg, 98 % yield); m.p. 124.1– 125.0 °C; 1H NMR
(400 MHz, CDCl3): δ = 7.51 (s, 1H), 7.25 (d, J = 8.0 Hz, 2H), 7.09 (d,
J = 8.0 Hz, 2H), 3.40 (s, 3H), 3.35 (s, 3H), 2.30 (s, 3H); 13C NMR
(100 MHz, CDCl3): δ = 161.9, 151.6, 146.5, 137.4, 131.2, 130.1, 130.0,
22.7, 13.3; IR (neat, cm–1): ν = 3063, 2929, 1695, 1637, 1615, 1430,
˜
1388, 1340, 1228, 1149, 1019, 964, 768, 755, 537; HRMS (ESI): calcd.
for C9H14N2O2SNa [M + Na]+ 237.0668, found 237.0670.
107.4, 37.3, 28.7, 21.1; IR (neat, cm–1): ν = 3045, 2945, 1707, 1652,
˜
1510, 1435, 1340, 1113, 1011, 947, 837, 766, 539; HRMS (ESI): calcd.
1,3-Diethyl-5-(p-tolylthio)pyrimidine-2,4(1H,3H)-dione (3k): Yel-
1
for C13H14N2O2SNa [M + Na]+ 285.0668, found 285.0673.
low oil (244 mg, 84 % yield); H NMR (400 MHz, CDCl3): δ = 7.54 (s,
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1H), 7.25 (d, J = 8.0 Hz, 2H), 7.09 (d, J = 8.0 Hz, 2H), 4.02 (q, J = (100 MHz, [D6]DMSO): δ = 161.9, 151.8, 150.8, 135.2, 133.0, 129.6,
7.0 Hz, 2H), 3.81 (q, J = 7.2 Hz, 2H), 2.30 (s, 3H), 1.32 (t, J = 7.2 Hz,
127.0, 103.2, 48.0, 28.1, 28.0, 21.8, 20.5, 13.8; IR (neat, cm–1): ν =
˜
3H), 1.21 (t, J = 7.0 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ = 161.3, 3400, 3016, 2850, 1698, 1650, 1607, 1456, 1425, 1359, 1024, 949,
150.6, 145.6, 137.0, 131.2, 129.9, 129.6, 107.3, 45.1, 37.3, 21.0, 14.4,
795, 564; HRMS (ESI): calcd. for C16H20N2O2SNa [M + Na]+ 327.1138,
found 327.1137.
12.7; IR (neat, cm–1): ν = 3055, 2977, 1702, 1611, 1491, 1437, 1326,
˜
1260, 1206, 1086, 1015, 802, 770, 562, 511; HRMS (ESI): calcd. for
1-Benzyl-5-(p-tolylthio)pyrimidine-2,4(1H,3H)-dione (3r): Yellow
C15H18N2O2SNa [M + Na]+ 313.0981, found 313.0979.
1
solid (227 mg, 70 % yield); m.p. 215.3– 216.2 °C; H NMR (400 MHz,
[D6]DMSO): δ = 11.72 (s, 1H), 8.38 (s, 1H), 7.39–7.28 (m, 5H), 7.13 (d,
J = 8.4 Hz, 2H), 7.09 (d, J = 8.8 Hz, 2H), 4.96 (s, 2H), 2.24 (s, 3H); 13C
NMR (100 MHz, [D6]DMSO): δ = 161.8, 151.4, 150.9, 136.5, 135.3,
132.7, 129.7, 128.7, 127.8, 127.6, 127.1, 103.9, 50.8, 20.5; IR (neat,
1,3-Dipentyl-5-(p-tolylthio)pyrimidine-2,4(1H,3H)-dione (3l): Or-
ange oil (344 mg, 92 % yield); H NMR (400 MHz, CDCl3): δ = 7.52
1
(s, 1H), 7.27 (d, J = 8.0 Hz, 2H), 7.11 (d, J = 8.0 Hz, 2H), 3.97 (t, J =
7.4 Hz, 2H), 3.77 (t, J = 7.4 Hz, 2H), 2.33 (s, 3H), 1.75–1.61 (m, 4H),
1.41–1.30 (m, 8H), 0.95–0.89 (m, 6H); 13C NMR (100 MHz, CDCl3): δ =
161.4, 151.0, 146.0, 137.1, 131.4, 129.9, 129.7, 107.2, 50.1, 42.2, 29.0,
cm–1): ν = 3400, 2955, 2848, 1648, 1602, 1488, 1427, 1333, 1239,
˜
1137, 1027, 796, 754, 694, 601, 534; HRMS (ESI): calcd. for
18H16N2O2SNa [M + Na]+ 347.0825, found 347.0830.
28.7, 28.6, 27.1, 22.3, 22.2, 21.0, 14.0, 13.9; IR (neat, cm–1): ν = 2955,
C
˜
2925, 1706, 1655, 1614, 1492, 1438, 1331, 1216, 1144, 803, 770, 654,
584, 509; HRMS (ESI): calcd. for C21H31N2O2S [M + H]+ 375.2101,
found 375.2108.
1-Phenyl-5-(p-tolylthio)pyrimidine-2,4(1H,3H)-dione (3s): Yellow
1
solid (84 mg, 27 % yield); m.p. 186.2– 187.0 °C. H NMR (400 MHz,
CDCl3): δ = 8.56 (s, 1H), 7.68 (s, 1H), 7.52– 7.43 (m, 3H), 7.37– 7.31
(m, 4H), 7.12 (d, J = 8.0 Hz, 2H), 2.32 (s, 3H); 13C NMR (100 MHz,
CDCl3): δ = 161.4, 149.8, 147.8, 138.1, 137.9, 130.6, 130.2, 129.9,
1,3-Diisopropyl-5-(p-tolylthio)pyrimidine-2,4(1H,3H)-dithione
(3m): Yellow solid (299 mg, 94 % yield); m.p. 110.5– 111.3 °C; 1H
NMR (400 MHz, CDCl3): δ = 7.48 (s, 1H), 7.23 (d, J = 8.0 Hz, 2H), 7.09
(d, J = 8.0 Hz, 2H), 5.20 (sep, J = 6.8 Hz, 1H), 4.86 (sep, J = 6.8 Hz,
129.4, 126.4, 125.2, 109.7, 29.8; IR (neat, cm–1): ν = 2921, 2851, 1712,
˜
1654, 1590, 1490, 1412, 1305, 1277, 795, 758, 694, 576, 515; HRMS
(ESI): calcd. for C17H14N2O2SNa [M + Na]+ 333.0668, found 333.0665.
1H), 2.30 (s, 3H), 1.44 (d, J = 6.8 Hz, 6H), 1.30 (d, J = 6.8 Hz, 6H); 13
C
NMR (100 MHz, CDCl3): δ = 161.5, 150.9, 141.7, 137.1, 131.5, 130.0,
1,3-Diethyl-6-methyl-5-(p-tolylthio)pyrimidine-2,4(1H,3H)-di-
one (3t): Yellow solid (116 mg, 38 % yield); m.p. 87.7– 88.3 °C; 1H
NMR (400 MHz, CDCl3): δ = 7.11 (d, J = 8.0 Hz, 2H), 7.04 (d, J =
7.6 Hz, 2H), 4.04–3.97 (m, 4H), 2.65 (s, 3H), 2.26 (s, 3H), 1.30 (t, J =
7.0 Hz, 3H), 1.20 (t, J = 7.0 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ =
161.1, 157.1, 150.9, 136.0, 132.9, 129.8, 127.8, 105.7, 41.9, 37.6, 21.0,
129.6, 107.6, 48.3, 47.0, 21.6, 21.1, 19.2; IR (neat, cm–1): ν = 2974,
˜
2922, 1698, 1650, 1613, 1492, 1432, 1331, 1270, 1083, 1051, 802,
772, 554; HRMS (ESI): calcd. for C17H22N2O2SNa [M + Na]+ 341.1294,
found 341.1299.
1,3-Dibenzyl-5-(p-tolylthio)pyrimidine-2,4(1H,3H)-dithione
(3n): Brown solid (389 mg, 94 % yield); m.p. 133.6– 134.3 °C. 1H
NMR (400 MHz, CDCl3): δ = 7.46 (d, J = 7.2 Hz, 2H), 7.42 (s, 1H),
7.33–7.21 (m, 8H), 7.16 (d, J = 8.0 Hz, 2H), 7.04 (d, J = 7.6 Hz, 2H),
5.12 (s, 2H), 4.85 (s, 2H), 2.27 (s, 3H); 13C NMR (100 MHz, CDCl3): δ =
161.3, 151.3, 145.1, 137.2, 136.5, 134.9, 130.7, 130.0, 129.8, 129.3,
129.2, 128.6, 128.4, 128.2, 127.8, 108.2, 52.6, 45.4, 21.1; IR (neat, cm–1):
18.4, 14.1, 12.8; IR (neat, cm–1): ν = 2983, 2853, 1699, 1642, 1572,
˜
1491, 1440, 1332, 1181, 1016, 801, 771, 642, 547; HRMS (ESI): calcd.
for C16H21N2O2S [M + H]+ 305.1318, found 305.1315.
6-Chloro-1,3-dimethyl-5-(p-tolylthio)pyrimidine-2,4(1H,3H)-di-
one (3u): Yellow solid (184 mg, 62 % yield); m.p. 123.0– 123.6 °C;
1H NMR (400 MHz, CDCl3): δ = 7.23 (d, J = 8.4 Hz, 2H), 7.04 (d, J =
7.6 Hz, 2H), 3.61 (s, 3H), 3.32 (s, 3H), 2.26 (s, 3H); 13C NMR (100 MHz,
CDCl3): δ = 160.1, 151.9, 150.4, 137.1, 131.1, 129.8, 129.6, 107.2, 35.4,
ν = 3063, 2921, 1713, 1652, 1606, 1492, 1434, 1320, 1076, 805, 744,
˜
687, 598, 525; HRMS (ESI): calcd. for C25H23N2O2S [M + H]+ 415.1475,
found 415.1483.
29.3, 21.0; IR (neat, cm–1): ν = 2921, 2852, 1706, 1650, 1562, 1413,
˜
1376, 1340, 1182, 1029, 995, 801, 759, 594; HRMS (ESI): calcd. for
1,3-Diallyl-5-(p-tolylthio)pyrimidine-2,4(1H,3H)-dithione (3o):
C13H13ClN2O2SNa [M + Na]+ 319.0278, found 319.0275.
1
Yellow oil (60 mg, 19 % yield); H NMR (400 MHz, CDCl3): δ = 7.48
(s, 1H), 7.25 (d, J = 8.0 Hz, 2H), 7.09 (d, J = 8.0 Hz, 2H), 5.93– 5.82
(m, 2H), 5.34– 5.17 (m, 4H), 4.56 (d, J = 5.6 Hz, 2H), 4.38 (d, J =
5.6 Hz, 2H), 2.31 (s, 3H); 13C NMR (100 MHz, CDCl3): δ = 161.1, 150.9,
145.3, 137.4, 131.4, 131.3, 131.0, 130.1, 130.0, 120.1, 118.6, 108.1,
6-Chloro-1-ethyl-3-methyl-5-(p-tolylthio)pyrimidine-2,4(1H,3H)-
dione (3v): Brown solid (171 mg, 55 % yield); m.p. 88.6– 89.5 °C; 1H
NMR (400 MHz, CDCl3): δ = 7.25 (d, J = 8.4 Hz, 2H), 7.06 (d, J =
7.6 Hz, 2H), 4.22 (q, J = 7.0 Hz, 2H), 3.34 (s, 3H), 2.28 (s, 3H), 1.32 (t,
J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ = 160.2, 151.4, 150.1,
137.1, 131.2, 129.9, 129.6, 107.3, 44.5, 29.3, 21.1, 13.9; IR (neat, cm–1):
51.4, 44.3, 21.2; IR (neat, cm–1): ν = 3070, 2923, 1708, 1656, 1613,
˜
1492, 1433, 1327, 1231, 990, 927, 803, 772, 511; HRMS (ESI): calcd.
for C17H18N2O2SNa [M + Na]+ 337.0981, found 337.0985.
ν = 2982, 2918, 1708, 1652, 1556, 1424, 1206, 1084, 1000, 859, 795,
˜
760, 595; HRMS (ESI): calcd. for C14H15ClN2O2SNa [M + Na]+
333.0435, found 333.0439.
Diethyl 2,4-dithioxo-5-(p-tolylthio)pyrimidine-1,3(2H,4H)-di-
carboxylate (3p): Brown oil (158 mg, 39 % yield); 1H NMR
(400 MHz, CDCl3): δ = 7.46 (s, 1H), 7.25 (d, J = 7.2 Hz, 2H), 7.09 (d,
J = 7.6 Hz, 2H), 4.68 (s, 2H), 4.47 (s, 2H), 4.25 (q, J = 7.1 Hz, 2H), 4.18
(q, J = 7.1 Hz, 2H), 2.30 (s, 3H), 1.29 (t, J = 7.0 Hz, 3H), 1.24 (t, J =
7.0 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ = 167.4, 167.1, 160.9,
151.0, 146.1, 145.4, 137.5, 130.6, 130.2, 129.9, 108.5, 62.5, 61.8, 50.1,
1-Benzyl-6-chloro-3-methyl-5-(p-tolylthio)pyrimidine-2,4-
(1H,3H)-dione (3w): Yellow solid (156 mg, 42 % yield); m.p. 103.3–
1
104.1 °C; H NMR (400 MHz, CDCl3): δ = 7.38–7.31 (m, 5H), 7.26 (d,
J = 8.0 Hz, 2H), 7.08 (d, J = 8.0 Hz, 2H), 5.38 (s, 2H), 3.39 (s, 3H), 2.30
(s, 3H); 13C NMR (100 MHz, CDCl3): δ = 160.1, 151.5, 150.7, 137.3,
135.2, 131.0, 129.9, 129.7, 128.9, 128.3, 127.5, 108.0, 51.7, 29.6, 21.1;
42.9, 21.2, 14.2; IR (neat, cm–1): ν = 2920, 2851, 1745, 1716, 1663,
˜
IR (neat, cm–1): ν = 2921, 2855, 1704, 1656, 1555, 1423, 1384, 1203,
1617, 1492, 1348, 1275, 1199, 1016, 805, 774, 542; HRMS (ESI): calcd.
˜
for C19H22N2O6SNa [M + Na]+ 429.1091, found 429.1088.
996, 963, 804, 760, 732, 545; HRMS (ESI): calcd. for C19H17ClN2O2SNa
[M + Na]+ 395.0591, found 395.0592.
1-Pentyl-5-(p-tolylthio)pyrimidine-2,4(1H,3H)-dione (3q): Yellow
1
solid (262 mg, 86 % yield); m.p. 188.5– 189.4 °C; H NMR (400 MHz,
6-(Chloromethyl)-5-(p-tolylthio)pyrimidine-2,4(1H,3H)-dione
1
[D6]DMSO): δ = 11.59 (s, 1H), 8.23 (s, 1H), 7.11 (d, J = 8.8 Hz, 2H),
7.08 (d, J = 8.4 Hz, 2H), 3.71 (t, J = 7.2 Hz, 2H), 2.23 (s, 3H), 1.63–
(3x): Brown solid (166 mg, 59 % yield); m.p. 79.5– 80.4 °C; H NMR
(400 MHz, [D6]DMSO): δ = 11.71 (s, 1H), 11.49 (s, 1H), 7.11 (d, J =
1.56 (m, 2H), 1.31–1.22 (m, 4H), 0.85 (t, J = 7.0 Hz, 3H); 13C NMR 8.0 Hz, 2H), 7.07 (d, J = 8.0 Hz, 2H), 4.63 (s, 2H), 2.23 (s, 3H);
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13C NMR (100 MHz, [D6]DMSO): δ = 162.1, 155.9, 150.5, 135.3, 132.2,
614, 549; HRMS (ESI): calcd. for C15H23N3O2SNa [M + Na]+ 332.1403,
129.6, 127.1, 103.4, 40.1, 20.5; IR (neat, cm–1): ν = 3053, 2920, 2260, found 332.1400.
˜
1706, 1670, 1604, 1492, 1410, 1321, 1165, 1044, 823, 736, 579; HRMS
1,3-Diisopropyl-5-thiocyanatopyrimidine-2,4(1H,3H)-dione
(ESI): calcd. for C12H11ClN2O2SNa [M + Na]+ 305.0122, found
305.0122.
(4d): Orange solid (220 mg, 87 % yield); m.p. 97.0– 97.8 °C; 1H NMR
(400 MHz, CDCl3): δ = 7.71 (s, 1H), 5.13 (sep, J = 6.9 Hz, 1H), 4.81
(sep, J = 6.8 Hz, 1H), 1.40 (d, J = 7.0 Hz, 6H), 1.32 (d, J = 6.8 Hz, 6H);
13C NMR (100 MHz, CDCl3): δ = 159.6, 150.0, 143.3, 109.8, 97.0, 49.5,
1,3-Dimethyl-5-(phenylselanyl)pyrimidine-2,4(1H,3H)-dione
1
(3y1):[7f] Yellow solid (189 mg, 64 % yield); m.p. 100.9– 101.3 °C; H
47.5, 21.4, 18.9; IR (neat, cm–1): ν = 3047, 2968, 2156, 1701, 1643,
NMR (400 MHz, [D6]DMSO): δ = 9.55 (s, 1H), 8.14 (s, 1H), 7.16 (d, J =
8.5 Hz, 2H), 6.70 (d, J = 8.4 Hz, 2H), 3.32 (s, 3H), 3.16 (s, 3H); 13C
NMR (100 MHz, [D6]DMSO): δ = 161.5, 156.8, 151.3, 149.2, 131.1,
˜
1615, 1435, 1334, 1279, 1052, 965, 770, 669, 553; HRMS (ESI): calcd.
for C11H15N3O2SNa [M + Na]+ 276.0777, found 276.0776.
123.7, 116.1, 104.3, 36.6, 28.2; IR (neat, cm–1): ν = 3040, 2919, 1703,
˜
1,3-Dibenzyl-5-thiocyanatopyrimidine-2,4(1H,3H)-dione (4e):
Orange oil (227 mg, 65 % yield); 1H NMR (400 MHz, CDCl3): δ =
7.71(s, 1H), 7.44 (d, J = 6.8 Hz, 2H), 7.38–7.32 (m, 3H), 7.28–7.21 (m,
5H), 5.10 (s, 2H), 4.92 (s, 2H); 13C NMR (100 MHz, CDCl3): δ = 159.6,
150.7, 146.8, 135.7, 134.2, 129.3, 129.1, 128.9, 128.5, 128.3, 128.0,
1638, 1608, 1433, 1340, 1278, 1146, 1021, 767, 533; HRMS (ESI):
calcd. for C12H12N2O2SeNa [M + Na]+ 318.9956, found 318.9957.
1,3-Dibenzyl-5-(phenylselanyl)pyrimidine-2,4(1H,3H)-dione
(3y2): Yellow oil (296 mg, 66 % yield); 1H NMR (400 MHz, CDCl3):
δ = 7.47 (d, J = 6.8 Hz, 2H), 7.41– 7.39 (m, 2H), 7.32– 7.16 (m, 12H),
5.13 (s, 2H), 4.81 (s, 2H); 13C NMR (100 MHz, CDCl6): δ = 161.4, 151.4,
144.6, 136.6, 135.0, 132.7, 129.5, 129.2, 129.1, 129.0, 128.5, 128.4,
109.5, 97.4, 53.1, 45.7; IR (neat, cm–1): ν = 3033, 2853, 2158, 1711,
˜
1650, 1495, 1438, 1324, 1220, 937, 748, 696, 601, 523; HRMS (ESI):
calcd. for C19H15N3O2SNa [M + Na]+ 372.0777, found 372.0775.
128.1, 127.9, 127.7, 104.3, 52.4, 45.4; IR (neat, cm–1): ν = 3060, 2927,
˜
Diethyl 2,2′-[2,4-dioxo-5-thiocyanatopyrimidine-1,3(2H,4H)-
diyl]diacetate (4f): Orange oil (61 mg, 18 % yield); 1H NMR
(400 MHz, CDCl3): δ = 7.73 (s, 1H), 4.70 (s, 2H), 4.55 (s, 2H), 4.29–
4.19 (m, 4H), 1.32–1.26 (m, 6H); 13C NMR (100 MHz, CDCl3): δ =
166.9, 166.7, 159.2, 150.2, 147.0, 109.1, 98.6, 62.8, 62.1, 50.4, 43.1,
1702, 1641, 1612, 1431, 1323, 1218, 1067, 1029, 823, 733, 629, 521;
HRMS (ESI): calcd. for C24H20N2O2SeNa [M + Na]+ 471.0582, found
471.0583.
6-Chloro-1,3-dimethyl-5-(phenylselanyl)pyrimidine-2,4(1H,3H)-
dione (3y3): Brown solid (145 mg, 44 % yield); m.p. 87.3– 88.1 °C;
1H NMR (400 MHz, CDCl3): δ = 7.52– 7.49 (m, 2H), 7.28– 7.24 (m,
3H), 3.67 (s, 3H), 3.38 (s, 3H); 13C NMR (100 MHz, CDCl3): δ = 160.5,
151.8, 150.9, 132.1, 130.3, 129.4, 127.7, 104.4, 35.8, 29.7; IR (neat,
14.2(2C); IR (neat, cm–1): ν = 3077, 2923, 2161, 1743, 1718, 1662,
˜
1442, 1374, 1200, 1020, 770, 618, 542; HRMS (ESI): calcd. for
C
13H15N3O6SNa [M + Na]+ 364.0574, found 364.0577.
1-Pentyl-5-thiocyanatopyrimidine-2,4(1H,3H)-dione (4g): White
cm–1): ν = 2952, 2852, 1699, 1643, 1559, 1415, 1370, 1230, 1175,
1
˜
solid (201 mg, 84 % yield); m.p. 159.8– 160.7 °C; H NMR (400 MHz,
1 0 2 2 , 9 8 6 , 8 6 3 , 7 5 6 , 7 3 5 , 6 8 6 ; H R M S ( E S I ) : c a l cd. fo r
[D6]DMSO): δ = 11.90 (s, 1H), 8.50 (s, 1H), 3.70 (t, J = 7.2 Hz, 2H),
1.62–1.55 (m, 2H), 1.31–1.18 (m, 4H), 0.85 (t, J = 7.0 Hz, 3H); 13C
NMR (100 MHz, [D6]DMSO): δ = 160.7, 152.6, 150.4, 111.2, 94.7, 48.5,
C12H11ClN2O2SeNa [M + Na]+ 352.9566, found 352.9561.
6-(Chloromethyl)-5-(phenylselanyl)pyrimidine-2,4(1H,3H)-dione
(3y4): Yellow solid (180 mg, 57 % yield); m.p. 214.7 °C (decom-
posed); 1H NMR (400 MHz, [D6]DMSO): δ = 11.69 (s, 1H), 11.48 (s,
1H), 7.35–7.19 (m, 5H), 4.68 (s, 2H); 13C NMR (100 MHz, [D6]DMSO):
δ = 162.5, 155.9, 150.8, 131.4, 129.5, 129.2, 126.5, 101.6, 42.4; IR
28.1, 27.9, 21.8, 13.8; IR (neat, cm–1): ν = 3031, 2927, 2161, 1653,
˜
1613, 1460, 1430, 1362, 1268, 1025, 871, 757, 556; HRMS (ESI): calcd.
for C10H13N3O2SNa [M + Na]+ 262.0621, found 262.0625.
1-Benzyl-5-thiocyanatopyrimidine-2,4(1H,3H)-dione (4h): Yellow
(neat, cm–1): ν = 3138, 2963, 2845, 1722, 1651, 1601, 1417, 1311,
1
˜
solid (155 mg, 60 % yield); m.p. 185.8– 186.2 °C; H NMR (400 MHz,
1089, 771, 727, 685, 576. HRMS (ESI): calcd. for C11H9ClN2O2SeNa [M
[D6]DMSO): δ = 12.04 (s, 1H), 8.68 (s, 1H), 7.36–7.30 (m, 5H), 4.95 (s,
+ Na]+ 338.9410, found 338.9407.
2H); 13C NMR (100 MHz, [D6]DMSO): δ = 160.6, 152.4, 150.4, 136.1,
128.6, 127.9, 127.7, 111.2, 95.7, 51.4; IR (neat, cm–1): ν = 3410, 3162,
˜
1,3-Dimethyl-5-thiocyanatopyrimidine-2,4(1H,3H)-dione (4a):
Yellow solid (195 mg, 99 % yield); m.p. 256.8– 257.3 °C; 1H NMR
(400 MHz, CDCl3): δ = 7.77 (s, 1H), 3.49 (s, 3H), 3.39 (s, 3H); 13C NMR
(100 MHz, CDCl3): δ = 160.1, 150.9, 147.3, 109.6, 97.2, 38.0, 29.0; IR
2846, 2156, 1714, 1667, 1425, 1359, 1244, 1026, 867, 739, 598; HRMS
(ESI): calcd. for C12H9N3O2SNa [M + Na]+ 282.0308, found 282.0308.
1-Phenyl-5-thiocyanatopyrimidine-2,4(1H,3H)-dione (4i): Or-
ange solid (61 mg, 25 % yield); m.p. 213.8 °C (decomposed); 1H NMR
(400 MHz, [D6]DMSO): δ = 12.11 (s, 1H), 8.54 (s, 1H), 7.54–7.45 (m,
5H); 13C NMR (100 MHz, [D6]DMSO): δ = 160.7, 152.0, 149.9, 138.1,
(neat, cm–1): ν = 3042, 2950, 2157, 1935, 1699, 1641, 1616, 1487,
˜
1342, 1151, 1019, 765, 540; HRMS (ESI): calcd. for C7H7N3O2SNa [M
+ Na]+ 220.0151, found 220.0156.
129.1, 128.8, 127.0, 111.0, 95.9; IR (neat, cm–1): ν = 3159, 3032, 2848,
˜
1,3-Diethyl-5-thiocyanatopyrimidine-2,4(1H,3H)-dione (4b): Yel-
low solid (205 mg, 91 % yield); m.p. 130.0– 130.8 °C; 1H NMR
(400 MHz, CDCl3): δ = 7.80 (s, 1H), 3.97 (q, J = 7.1 Hz, 2H), 3.86 (d,
J = 7.2 Hz, 2H), 1.31 (t, J = 7.2 Hz, 3H), 1.17 (t, J = 7.2 Hz, 3H); 13C
NMR (100 MHz, CDCl3): δ = 159.6, 150.0, 147.0, 109.7, 96.8, 45.9,
2157, 1681, 1590, 1488, 1413, 1349, 1282, 861, 770, 696, 575; HRMS
(ESI): calcd. for C11H7N3O2SNa [M + Na]+ 268.0151, found 268.0150.
1-(4-Fluorophenyl)-5-thiocyanatopyrimidine-2,4(1H,3H)-dione
1
(4j): Orange solid (121 mg, 46 % yield); m.p. 96.2– 97.1 °C. H NMR
37.7, 14.4, 12.6; IR (neat, cm–1): ν = 3049, 2982, 2155, 1703, 1642,
(400 MHz, [D6]DMSO): δ = 12.17 (s, 1H), 8.37 (s, 1H), 7.38–7.29 (m,
4H); 13C NMR (100 MHz, [D6]DMSO): δ = 162.9, 160.6 (d, J = 18.8 Hz),
150.8, 148.8, 131.3 (d, J = 2.8 Hz), 130.9 (d, J = 8.7 Hz), 115.9 (d, J =
22.7 Hz), 111.2, 94.7; 19F NMR (376 MHz, [D6]DMSO): δ = –113.6; IR
˜
1441, 1268, 1155, 1087, 972, 771, 669, 562, 530; HRMS (ESI): calcd.
for C9H11N3O2SNa [M + Na]+ 248.0464, found 248.0460.
1,3-Dipentyl-5-thiocyanatopyrimidine-2,4(1H,3H)-dione (4c):
Orange oil (306 mg, 99 % yield); 1H NMR (400 MHz, CDCl3): δ = 7.69
(s, 1H), 3.94 (t, J = 7.6 Hz, 2H), 3.79 (t, J = 7.6 Hz, 2H), 1.74–1.67 (m,
2H), 1.64–1.57 (m, 2H) 1.40– 1.26 (m, 8H), 0.92–0.86 (m, 6H); 13C
(neat, cm–1): ν = 3391, 3077, 2159, 1724, 1667, 1506, 1407, 1331,
˜
1218, 1023, 995, 824, 761, 611; HRMS (ESI): calcd. for C11H7FN3O2S
[M + H]+ 264.0238, found 264.0230.
NMR (100 MHz, CDCl3): δ = 159.8, 150.4, 146.4, 109.7, 97.3, 50.9, 1,3-Diethyl-6-methyl-5-thiocyanatopyrimidine-2,4(1H,3H)-di-
1
42.7, 29.0, 28.9, 28.5, 27.1, 22.3, 22.2, 14.0, 13.9; IR (neat, cm–1): ν =
3051, 2956, 2159, 1712, 1653, 1617, 1444, 1333, 1216, 1066, 766,
one (4k): Orange solid (222 mg, 93 % yield); m.p. 76.7– 77.5 °C; H
NMR (400 MHz, CDCl3): δ = 4.00–3.93 (m, 4H), 2.66 (s, 3H), 1.26 (t,
˜
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J = 7.2 Hz, 3H), 1.16 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3):
δ = 159.3, 158.6, 150.1, 110.0, 96.4, 42.3, 37.9, 18.9, 13.9, 12.5; IR
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(neat, cm–1): ν = 3337, 2973, 2932, 2160, 1702, 1644, 1582, 1422,
˜
1333, 1207, 1092, 1054, 770, 590, 545; HRMS (ESI): calcd. for
C10H13N3O2SNa [M + Na]+ 262.0621, found 262.0625.
6-Amino-1,3-dimethyl-5-thiocyanatopyrimidine-2,4(1H,3H)-di-
one (4l):[8a] Brown solid (159 mg, 75 % yield); m.p. 262.5– 263.0 °C;
1H NMR (400 MHz, [D6]DMSO): δ = 7.86 (s, 2H), 3.36 (s, 3H), 3.14 (s,
3H); 13C NMR (100 MHz, [D6]DMSO): δ = 160.2, 157.3, 150.3, 112.4,
66.3, 31.0, 28.3; IR (neat, cm–1): ν = 3416, 3374, 2926, 2158, 1706,
˜
1611, 1497, 1370, 1222, 1084, 1021, 757, 747, 582, 530; HRMS (ESI):
calcd. for C7H8N4O2SNa [M + Na]+ 235.0260, found 235.0259.
6-Chloro-1-ethyl-3-methyl-5-thiocyanatopyrimidine-
2,4(1H,3H)-dione (4m): Yellow solid (98 mg, 40 % yield); m.p.
1
141.5– 142.0 °C; H NMR (400 MHz, CDCl3): δ = 4.25 (q, J = 7.1 Hz,
2H), 3.38 (s, 3H), 1.34 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3):
δ = 158.5, 153.1, 149.4, 108.7, 97.5, 45.2, 29.6, 13.8; IR (neat, cm–1):
ν = 3346, 2927, 2159, 1704, 1649, 1565, 1425, 1347, 1204, 1086,
˜
1003, 863, 757, 599, 533; HRMS (ESI): calcd. for C8H8ClN3O2SNa [M
+ Na]+ 267.9918, found 267.9917.
Acknowledgments
This work was supported by Thailand Research Fund
(RSA5980008 and DBG6080007), Center of Excellence for Inno-
vation in Chemistry (PERCH-CIC), Office of the Higher Education
Commission (OHEC), Ministry of Education, Central Instrument
Facility, Faculty of Science, Mahidol University and the Science
Achievement Scholarship of Thailand (to M. N.).
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Keywords: Copper · Uracil · Disulfides · Thiolation ·
Thiocyanation
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Received: March 4, 2019
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C–H Thiolation
M. Noikham, S. Yotphan* ................ 1–9
Copper-Catalyzed Regioselective Di-
rect C–H Thiolation and Thiocyan-
ation of Uracils
The copper-catalyzed direct C–H thiol- age and C–S bond formation to pro-
ation and thiocyanation of uracils us- ceed efficiently, providing useful meth-
ing disulfides and thiocyanate salts re- ods to access of a diverse array of thio-
spectively as coupling partners have substituted at the 5 position of uracil
been successfully developed. These derivatives in good to excellent yields.
protocols enable the C–H bond cleav-
DOI: 10.1002/ejoc.201900343
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