Direct C-H sulfenylation of purines and deazapurines

Article abstract of DOI:10.1039/c3ob40881g

A general method for Cu-catalyzed C-H sulfenylation of purines, 7-deaza- and 9-deazapurines with aryl- or alkyldisulfides has been developed. In purines, the reaction occurs at position 8, in 7-deazapurines at position 7 and in 9-deazapurines at position 9, leading to new interesting arylsulfanyl derivatives of purine or deazapurine bases. The resulting 8-arylsulfanylpurines undergo Liebesking-Srogl coupling with arylstannanes or boronic acids, whereas the (arylsulfanyl)deazapurines are not reactive under these conditions.

Full text of DOI:10.1039/c3ob40881g

Organic &
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Direct C–H sulfenylation of purines and deazapurines†
Martin Klečka,a,b Radek Pohl,b Jan Čejkab and Michal Hocek*a,b
Cite this: Org. Biomol. Chem., 2013, 11,
5189
A general method for Cu-catalyzed C–H sulfenylation of purines, 7-deaza- and 9-deazapurines with aryl-
or alkyldisulfides has been developed. In purines, the reaction occurs at position 8, in 7-deazapurines at
position 7 and in 9-deazapurines at position 9, leading to new interesting arylsulfanyl derivatives of
purine or deazapurine bases. The resulting 8-arylsulfanylpurines undergo Liebesking–Srogl coupling with
arylstannanes or boronic acids, whereas the (arylsulfanyl)deazapurines are not reactive under these
conditions.
Received 29th April 2013,
Accepted 11th June 2013
DOI: 10.1039/c3ob40881g
www.rsc.org/obc
Tri- and tetrasubstituted purines1 and their analogues show a starting compound of choice was 6-phenyl-7-deazapurine (1).
great variety of biological activities. However, compared to We started by testing several literature catalytic systems and
purines, 7-deazapurines (pyrrolo[2,3-d]pyrimidines) and 9-de- conditions for direct C–H sulfenylation (Scheme 1).8 The most
azapurines (pyrrolo[3,2-d]pyrimidines) have been studied less efficient was the reaction of 1 with disulphides in the presence
systematically due to underdeveloped synthesis and substi- of copper(I) catalyst (by analogy to the literature8a but replacing
tution chemistry. Among the most important biological effects DMSO with DMF) giving the desired 7-substituted product 5a
of deazapurines one should mention compound TWS1192 in excellent yield (96%, Table 1, entry 1). On a larger scale, a
which directs differentiation of neuronal cells in mice. Several 7,8-bis(phenylsulfanyl) derivative 6a was also isolated as a
types of 7-deazapurine nucleosides display antibiotic,3 anti- minor by-product (3%, entry 1). The reaction work-up by EDTA
viral4 or cytostatic5 effects. In order to synthesize libraries of was very important to break up stable complexes of the
tri- and tetrasubstituted purines, a combination of inherently product with copper (without such a work-up, the isolated
orthogonal cross-coupling reactions with C–H activations has yield of 5a was only moderate, ∼50%). These optimised con-
been developed in our group.6 6,8,9-Trisubstituted 7-deaza- ditions were then used for the synthesis of three other
purines were prepared by a “one pot” sequence of C–H boryla-
tion followed by Suzuki coupling.7 In order to extend the
portfolio of reactions and substituents available for modifi-
cation of purines and deazapurines, we report here on direct
C–H sulfenylations leading to hitherto unknown arylsulfanyl-
derivatives and some follow-up reactions.
Direct C–H sulfenylations8 have become quite popular in
recent years since they lead to hetarylthioethers suitable for
Scheme 1 Reagents and conditions: (i) R2S–SR2 (0.75 equiv.), CuI (10%), air,
further functional group transformations by Liebeskind–Srogl
cross-coupling9 or oxidation and aminations.10 Also some DMF, 110 °C, 18–60 h.
examples of biologically active hetarylthioesters were pre-
viously described.11
Our project started with the study of C–H sulfenylations of
Table 1 Direct C–H sulfenylation of 7-deazapurines
7-deazapurines which are closely related to indoles. The model
Start.
Entry
compd.
R1
X
R2
Product (yield)
aDepartment of Organic Chemistry, Faculty of Science, Charles University in Prague,
Hlavova 8, CZ-12843 Prague 2, Czech Republic
1
1
1
1
1
2
3
4
H
H
H
H
Bn
H
H
Ph–
Ph–
Ph–
Ph–
Ph–
Cl–
Ph–
Me–
4-MeO–Ph–
4-NO2–Ph–
Ph–
Ph–
Ph–
5a (96%) + 6a (3%)
5b (71%) + 6b (15%)
5c (91%)
2a
3
bInstitute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech
4
5d (47%)
Republic, Gilead & IOCB Research Center, Flemingovo nam. 2, CZ-16610 Prague 6,
Czech Republic. E-mail: hocek@uochb.cas.cz
†Electronic supplementary information (ESI) available: Experimental procedures
5b
6a
7
5e (20%)b
5f (90%)
5g (79%)
NH2–
and characterization data, copies of NMR spectra. CCDC 926543 and 926544.
For ESI and crystallographic data in CIF or other electronic format see DOI:
10.1039/c3ob40881g
a 5 equiv. of R2S–SR2. b 2.5 equiv. of R2S–SR2 and recovery of the
starting compound (71%).
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Scheme 2 Reagents and conditions: (i) R2S–SR2 (1.5 equiv.), CuI (10%), air, bpy
or dtbpy (0.2 equiv.), DMF, 110 °C, 48–90 h; (ii) CuI or CuBr2 (1.1 equiv.), air,
DMF, 110 °C, 18 h.
Table 2 Direct C–H sulfenylation of 9-deazapurines
Start.
Entry compd. Ligand R1
X
R2 (or Y)
Product (yield)
1a
2
3
4
5
7
7
7
7
7
8
9
9
7
7
7
7
7
7
9
—
H
H
H
H
H
Ph Ph
Ph Ph
Ph Me
Ph 4-MeO–Ph 10c (85%)
Ph 4-NO2–Ph 10d (50%)
10a (14%) + 11a (9%)
10a (98%)
bpy
bpy
bpy
bpy
bpy
bpy
dtbpy
dtbpy
dtbpy
dtbpy
dtbpy
—
10b (30%)c
Fig. 1 ORTEP drawings of crystal structures of compounds 5e (CCDC 926544)
and 10a (CCDC 926543).
6
Bn Ph Ph
No reaction
Complex mixture
10e (90%)
10a (98%)
10b (25%)
7
H
H
H
H
H
H
H
H
H
Cl Ph
Cl Ph
Ph Ph
Ph Me
Ph 4-MeO–Ph 10c (41%)
Ph 4-NO2–Ph No reaction
Ph Y = I
Ph Y = Br
Cl Y = I
8b
9
10
11
12
13d
14d
15d
examples, 7-alkyl- or -arylsulfanyl derivatives 5b–d. While the
reactions with methyl and methoxyphenyl disulfide gave pro-
ducts 5b, c in good yields (entries 2, 3), the yield of nitro-
phenylsulfanyl derivative 5d was moderate. The reaction with
9-benzylated 6-phenyl-7-deazapurine 2 gives the 7-substituted
product 5e in poor yield (20%, entry 5) due to low conversion.
The structure of 5e was confirmed by X-ray (Fig. 1). Apparently,
the free NH at position 7 is crucial for the efficiency of this
11a (81%)
11b (75%)
11c (65%)
—
—
a No bpy added. b 7 equiv. of R2S–SR2. c Recovery of the starting
compound (40%). d Condition (ii) applied.
reaction. Another interesting substrate was 6-chloro-7-deaza- more details of the optimization, see ESI†) to give the desired
product 10e in good 90% yield (entry 8). The dtbpy ligand was
purine 3 that is suitable for further functional group trans-
formations at position 6. In this case, the C–H sulfenylation then also tested in the reactions of 7 with diverse disulfides.
also proceeded well to give the desired product 5f in high The phenylsulfenylation proceeded with quantitative conver-
sion (as with bpy) but in the case of other disulfides, the yields
(90%) yield (entry 6) without any trace of nucleophilic substi-
tution at position 6. Also the reaction of 7-deazaadenine (4) of products were lower than with bpy (entries 10–12). There-
proceeded under the same conditions to give 7-(phenylsulfa- fore, the dtbpy ligand was only practical for the reaction of
6-chloro derivative 9. On the other hand, using a stoichio-
nyl)-7-deazaadenine (5g) in good yield (entry 7) (Scheme 1).
The same C–H sulfenylation protocol was then tested on metric amount of CuI or CuBr2 in the absence of bpy led to
9-deazapurines (pyrrolo[3,2-d]pyrimidines, Scheme 2). However, the formation of 9-halogenated products 11a–c in high yields
(entries 8–10). The same reaction with CuCl or CuCl2 pro-
in this case a competitive iodination of the heterocycle by CuI
occurred (Table 2, entry 1). The halogenation was suppressed ceeded as well but only in poor yield. Using the same catalytic
by complexation of the copper catalyst by a 2,2′-dipyridine system (CuI + bpy) for 7-deazapurine 1 gave the 7-substituted
product 5a in poor yield due to low conversion.
(bpy) ligand. The reaction of 6-phenyl-9-deazapurine (7) with
diphenyl disulfide in the presence of CuI + bpy (entry 2) gave
Our further efforts focused on the direct C–H sulfenylation
quantitatively the desired 9-phenylsulfanyl derivative 10a (for of purines. Unfortunately, employing the same catalytic
systems as above, no sulfenylation was observed. Using an
confirmation of its structure by X-ray, see Fig. 1). The reaction
with other disulfides allowed us to synthesize the target alternative protocol based on a Lewis acid activation,8e the
9-alkyl- or -arylsulfanyl derivatives in moderate (10b and 10d, reaction proceeded to give 8-(phenylsulfanyl)purine 13a in
moderate ∼40% yield. Finally, the sulfenylation in the pres-
30% and 55%, respectively, entries 3, 5) or high yields (10c,
85%, entry 4). The reaction with 9-benzyl-6-phenyl-9-deaza- ence of tBuOLi8c in dioxane at 130 °C for 120 h gave the
purine 8 did not proceed at all (entry 6). The C–H sulfenylation desired product 13a in acceptable 60% yield (Scheme 3,
Table 3, entry 1). An analogous reaction with electron-rich bis-
of 6-chloro-9-deazapurine 9 under standard conditions gave a
complex mixture of products (TLC, entry 7). Therefore, we (methoxyphenyl)disulphide proceeded well to give 13b in 56%
tried the reaction in the presence of a more bulky and elec- (entry 2), whereas the reaction with electron-poor bis(nitro-
phenyl)disulfide did not work.
tron-rich ligand dtbpy (4,4′-di-tert-butyl-2,2′-dipyridine, for
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Since no literature example of the Liebeskind–Srogl reaction of
the related 3-(arylsulfanyl)indole was known, we have tried this
reaction under the standard conditions and have confirmed
that it does not proceed either. Apparently, this reaction is not
applicable for electron-rich indole-type heterocycles.
In conclusion, the Cu-catalyzed C–H sulfenylation of 7- and
9-deazapurines proceeded very well and selectively at position
7 or 9, respectively, to give novel and interesting (arylsulfanyl)-
deazapurine derivatives. On the other hand, the C–H sulfeny-
lation of purines was less efficient, and the conditions had to
be changed. However, the 8-(arylsulfanyl)purines smoothly
undergo the Liebeskind–Srogl cross-coupling reactions leading
to 8-arylpurines, whereas the 7- and 9-arylsulfanylpurines were
not reactive in these reactions. Since all these C–H sulfeny-
lations can be performed with 6-chloro(deaza)purines, there is
a potential in combination with classical cross-couplings in
the synthesis of libraries of new di- and trisubstituted purines
and deazapurine derivatives combining aryl(alkyl)sulfanyl and
aryl or amino substituents for biological activity screening.
Scheme 3 Reagents and conditions: RS–SR (2.5 equiv.), tBuOLi (3 equiv.), 1,4-
dioxane, 130 °C, 120 h.
Table 3 Direct C–H sulfenylations of purine 12
Entry
X
R
Product (yield)
1
2
3
Ph–
Ph–
Ph–
Ph–
4-MeO–Ph–
4-NO2–Ph–
13a (60%)
13b (56%)
No reaction
Having access to the arylsulfanyl derivatives of purines and
deazapurines, we further explored their synthetic applications.
The most obvious option was the Liebeskind–Srogl cross-coup- Also there is a further potential in testing other reactivities of
ling reaction.9 The reactions of the 8-(phenylsulfanyl)purine
the (arylsulfanyl)deazapurines (oxidations, other couplings,
13a with phenylboronic acid and diverse stannanes performed
under standard conditions proceeded generally well to give the
desired 8-aryl products 14a–14c in high yields (57–83%,
Scheme 4, Table 4).
Surprisingly, analogous Liebeskind–Srogl reactions of
7-phenylsulfanyl-7-deazapurine 5a or 9-phenylsulfanyl-9-deaza-
purine 10a did not proceed at all. Neither stannanes nor
boronic acids gave any reaction under a number of different
catalytic systems (Cu, Pd, In) and conditions tried (including
MW irradiation). This lack of reactivity of arylsulfanyl-deaza-
etc.). Studies along these lines are under way in our laboratory.
Experimental
For a complete set of experimental procedures and characteriz-
ation data, see ESI.†
Sulfenylation of 7-deazapurines. General procedure
A mixture of 7-deazapurines 1–4 (2 mmol), disulphides
purines is probably due to the electron-rich nature of the de- (1.5 mmol), and CuI (0.2 mmol, 10 mol%) in DMF (20 mL) was
azapurine moiety which prevents efficient oxidative addition.
stirred at 110 °C under an air atmosphere for 18 hours until
complete consumption of the starting material as monitored
by TLC. The solution was then cooled to room temperature,
diluted with EtOAc (30 mL), and washed with a 1 M solution
of sodium salt of EDTA (20 mL). The aqueous solution was
then extracted three times with EtOAc and the combined
organic layers were dried over Na2SO4, filtered, and evaporated
under vacuum. The crude product was purified by column
chromatography on silica gel.
4-Phenyl-5-(phenylsulfanyl)-7H-pyrrolo[2,3-d]pyrimidine
(5a). 6-Phenyl-7-deazapurine 1 (390 mg, 2 mmol) and diphenyl-
disulfide (328 mg, 1.5 mmol) were used as starting com-
pounds to give products 5a (582 mg, 96%) and 6a (25 mg, 3%)
as white solids after chromatography eluting with hexane–
EtOAc 5 : 1 to 1 : 1. Crystallization in hexane–EtOAc gave white
needles. M.p. 184–186 °C. 1H NMR (499.8 MHz, DMSO-d6):
6.70 (m, 2H, H-o-SPh); 6.99 (m, 1H, H-p-SPh); 7.06 (m, 2H,
H-m-SPh); 7.27 (m, 2H, H-m-Ph); 7.38 (m, 1H, H-p-Ph); 7.53 (m,
2H, H-o-Ph); 8.05 (d, 1H, J6,NH = 2.5, H-6); 8.88 (s, 1H, H-2);
12.86 (bs, 1H, NH). 13C NMR (125.7 MHz, DMSO-d6): 99.90
(C-5); 115.26 (C-4a); 125.25 (CH-p-SPh); 126.04 (CH-o-SPh);
127.29 (CH-m-Ph); 128.80 (CH-m-SPh); 129.23 (CH-p-Ph);
129.86 (CH-o-Ph); 135.69 (CH-6); 137.04 (C-i-Ph); 138.47 (C-i-
SPh); 151.53 (CH-2); 153.55 (C-7a); 159.40 (C-4). IR(KBr): 3104,
Scheme 4 Reagents and conditions: (i) ArSnBu3 (1.2 equiv.), Pd(PPh3)4 (5 mol%),
CuMeSal (2.2 equiv.), 50 °C, THF, 17 h; (ii) ArB(OH)2, Pd2(dba)3 (4 mol%),
(2-furyl)3P (16 mol%), CuTc (1.3 equiv.), 50 °C, THF, 18 h.
Table 4 The Liebeskind–Srogl reactions of 8-(phenylsulfanyl)purine 13a
Entry
1
Ar–M
Product (yield)
14a (70%)
2
3
14b (83%)
14c (54%)a
a Recovery of the starting compound (15%).
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3059, 2988, 2862, 2818, 1598, 1581, 1551, 1478, 1435, 1322. H-m,p-PhS); 7.45–7.50 (m, 3H, H-m,p-Ph); 7.59 (m, 2H, H-o-PhS);
HRMS (ESI) calculated for C18H14N3S: 304.0902; found: 8.74 (m, 2H, H-o-Ph); 8.96 (s, 1H, H-2). 13C NMR (125.7 MHz,
304.0901. Anal. calculated for C18H13N3S (303.08): C 71.26%, CDCl3): 46.59 (CH2Ph); 127.75 (CH-o-Bn); 128.18 (CH-p-Bn);
H 4.32%, N 13.85%, S 10.57%; found: C 71.07%, H 4.15%, 128.50 (CH-m-Ph); 128.68 (C-i-PhS); 128.82 (CH-m-Bn); 129.03
N 13.57%, S 10.47%.
(CH-p-PhS); 129.37 (CH-m-PhS); 129.68 (CH-o-Ph); 130.78 (CH-
p-Ph); 131.16 (C-5); 132.91 (CH-o-PhS); 135.24 (C-i-Bn); 135.54
(C-i-Ph); 151.95 (CH-2); 152.37 (C-6); 152.92 (C-8); 154.46 (C-4).
Sulfenylation of 9-deazapurines. General procedure
A mixture of CuI (0.2 mmol, 10 mol%) and 2,2′-bipyridine IR(KBr): 2921, 2851, 1580, 1561, 1495, 1459, 1429, 1258, 764.
(0.4 mmol, 20 mol%) in DMF (10 mL) was stirred at rt for HRMS (ESI) calculated for C24H19N4S: 395.1325; found:
15 minutes and then it was added to a mixture of 9-deazapur- 395.1323.
ines 7–9 (2 mmol) and disulphides (3 mmol) in DMF (20 mL)
Liebeskind–Srogl cross-coupling of 9-benzyl-6-phenyl-8-
(phenylsulfanyl)-9H-purine with stannanes. General procedure
and then was stirred at 110 °C under an air atmosphere for
48 hours until complete consumption of the starting material
as monitored by TLC. The solution was then cooled to room
temperature, diluted with EtOAc (30 mL), and washed with a
1 M solution of sodium salt of EDTA (20 mL). The aqueous
solution was then extracted three times with EtOAc and the
combined organic layers were dried over Na2SO4, filtered, and
evaporated under vacuum. The crude product was purified by
column chromatography on silica gel.
4-Phenyl-7-(phenylsulfanyl)-5H-pyrrolo[3,2-d]pyrimidine (10a).
6-Phenyl-9-deazapurine 7 (390 mg, 2 mmol) and diphenyl-
disulfide (656 mg, 3 mmol) were used as starting compounds
to give product 10a (595 mg, 96%) as white solids after chro-
matography eluting with hexane–EtOAc 5 : 1 to 1 : 2. Crystalliza-
tion in hexane–EtOAc gave white needles. M.p. 210–216 °C.
1H NMR (499.8 MHz, DMSO-d6): 7.10 (m, 3H, H-o,p-SPh); 7.22
(m, 2H, H-m-SPh); 7.61 (m, 1H, H-p-Ph); 7.63 (m, 2H, H-m-Ph);
8.11 (m, 2H, H-o-Ph); 8.29 (s, 1H, H-6); 8.95 (s, 1H, H-2); 12.56
(bs, 1H, NH). 13C NMR (125.7 MHz, DMSO-d6): 101.28 (C-7);
124.83 (C-4a); 125.30 (CH-p-SPh); 126.02 (CH-o-SPh); 128.99
(CH-o-Ph); 129.10, 129.15 (CH-m-Ph, CH-m-SPh); 130.61 (CH-
p-Ph); 135.77 (C-i-Ph); 138.63 (C-i-SPh); 140.37 (CH-6); 148.88
(C-4); 151.29 (CH-2); 151.43 (C-7a). IR(KBr): 3066, 2835, 1594,
1542, 1505, 1490, 1480, 1429. HRMS (ESI) calculated for
C18H14N3S: 304.0902; found: 304.0902.
To the mixture of CuMeSal (47 mg, 0.22 mmol, 2.2 equiv.), Pd-
(PPh3)4 (5.8 mg, 0.005 mmol, 0.05 equiv.) and 9-benzyl-
6-phenyl-8-(phenylthio)-9H-purine 13a (39 mg, 0.1 mmol,
1.0 equiv.) and stannane (0.12 mmol, 1.2 equiv.) in THF
(2 mL) were added. The reaction mixture was stirred under
nitrogen at 50 °C for 18 h, and then 10% aqueous NH4OH
(10 mL) was added and the mixture was stirred for an
additional 10 min. The reaction mixture was filtered through a
plug of Celite, and the filtrate was extracted with ethylacetate
(3 × 15 mL). The organic layer was washed with brine (5 mL),
dried over NaSO4, and evaporated. The crude product was puri-
fied by column chromatography on silica gel.
9-Benzyl-8-(furan-2-yl)-6-phenyl-9H-purine
(14a). 2-(Tri-n-
butylstannyl)furan (38 μL, 0.12 mmol, 1.2 equiv.) was used as
the starting compound to give product 14a (25 mg, 70%) as
white crystals after chromatography eluting with hexane–
EtOAc 5 : 1 to 2 : 1. M.p. 135–141 °C. 1H NMR (500.0 MHz,
CDCl3): 5.86 (s, 2H, CH2Ph); 6.59 (dd, 1H, J4,3 = 3.6, J4,5 = 1.8,
H-4-furyl); 7.22 (m, 2H, H-o-Bn); 7.26 (m, 1H, H-p-Bn); 7.28 (m,
2H, H-m-Bn); 7.29 (dd, 1H, J3,4 = 3.6, J3,5 = 0.8, H-3-furyl); 7.52
(m, 1H, H-p-Ph); 7.58 (m, 2H, H-m-Ph); 7.64 (dd, 1H, J5,4 = 1.8,
J5,3 = 0.8, H-5-furyl); 8.88 (m, 2H, H-o-Ph); 9.02 (s, 1H, H-2).
13C NMR (125.7 MHz, CDCl3): 46.96 (CH2Ph); 112.34 (CH-
4-furyl); 114.88 (CH-3-furyl);126.85 (CH-o-Bn); 127.84 (CH-p-Bn);
128.62 (CH-m-Ph); 128.76 (CH-m-Bn); 129.79 (CH-o-Ph); 130.82
(CH-p-Ph); 131.05 (C-5); 135.75 (C-i-Ph); 136.16 (C-i-Bn); 144.70
(C-2-furyl); 144.93 (CH-5-furyl); 145.47 (C-8); 152.27 (CH-2);
153.64 (C-6); 154.18 (C-4). IR(KBr): 3068, 1605, 1603, 1562,
1497, 1454, 1334, 1321, 1016. HRMS (ESI) calculated for
C22H17ON4: 353.1397; found: 353.1397.
Sulfenylation of 9-benzyl-6-phenyl-9H-purine. General
procedure
A 20 mL sealable tube equipped with a magnetic stirring bar
was charged with all solid reaction components, 9-benzyl-
6-phenyl-9H-purine 12 (286 mg, 1 mmol), disulfide (2.5 mmol),
tBuOLi (240 mg, 3 mmol) and 1,4-dioxane (2 mL) via a syringe.
The vessel was closed by a Teflon-coated screw cap under Ar
and was placed in a pre-heated oil bath at 130 °C and stirred
until complete consumption of the starting material as moni-
tored by TLC, approx. 130 hours. It was cooled to room temp-
erature and diluted with ethyl acetate (15 mL). The resulting
solution was directly filtered through a filter paper and con-
centrated under reduced pressure.
This work was supported by the institutional support of the
Charles University and Academy of Sciences of the Czech
Republic (RVO: 61388963), by the Czech Science Foundation
(P207/12/0205) and by Gilead Sciences, Inc.
Notes and references
9-Benzyl-6-phenyl-8-(phenylsulfanyl)-9H-purine
(13a). Di-
phenyldisulfide (546 mg, 2.5 mmol) was used as the starting
compound to give product 13a (237 mg, 60%) as white crystals
after chromatography eluting with hexane–EtOAc 5 : 1 to 1 : 2.
M.p. 101–104 °C. 1H NMR (499.8 MHz, CDCl3): 5.50 (s, 2H,
CH2Ph); 7.27–7.35 (m, 5H, H-o,m,p-Bn); 7.37–7.41 (m, 5H,
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