Synthesis of 8-arylsulfoxyl/sulfonyl adenines

Article abstract of DOI:10.1016/j.tetlet.2004.11.009

We report a method for the synthesis of 9-N-alkyl-8-arylsulfoxyl adenines and 9-N-alkyl-8-arylsulfonyl adenines. The approach starts with a tandem one-pot reaction that by using Mitsunobu conditions converts 8-arylsulfanyl adenines to the corresponding im

Full text of DOI:10.1016/j.tetlet.2004.11.009

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 9549–9552
Synthesis of 8-arylsulfoxyl/sulfonyl adenines
Laura Llauger, Huazhong He and Gabriela Chiosis*
Department of Medicine and Program in Molecular Pharmacology and Chemistry,
Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA
Received 24 September 2004; revised 1November 2004; accepted 2 November 2004
Abstract—We report a method for the synthesis of 9-N-alkyl-8-arylsulfoxyl adenines and 9-N-alkyl-8-arylsulfonyl adenines. The
approach starts with a tandem one-pot reaction that by using Mitsunobu conditions converts 8-arylsulfanyl adenines to the corre-
sponding iminophosphorane protected 9-N-alkyl-8-arylsulfanyl adenines. These compounds were further subjected to selective
OXONEÒ/alumina mediated oxidation followed by deprotection of the amine leading to the desired sulfoxides and sulfones.
Ó 2004 Elsevier Ltd. All rights reserved.
Purine derivatives have been shown to exhibit potent
biological activities. Respectively, libraries of 2,6,9-pur-
ines have resulted in the identification of inhibitors of
many biological processes including those regulated by
cyclin-dependent kinases, sulfotransferases, and tubu-
lin.1 We have created libraries of 2,8,9-adenines in which
the adenine is linked to an aryl ring through a methylene
bridge at C8, and isolated selective inhibitors of the
molecular chaperone Hsp90.2 Our interest in exploring
the C8 position of the purine ring is furthered by the
strategic positioning of this carbon. Establishing a linker
between C8 and another aromatic/heteroaromatic ring
creates a biaromatic system in which the orientation of
the two rings is regulated by the nature and length of
the linker. Formation of a C–C, C–O, C–N, or C–S
bond at this position is already documented in several
publications.3 To our knowledge however, no method
on the formation of sulfoxides and sulfones has been
previously reported.
butylhydroperoxide,4g alone or in the presence of silica
gel or alumina have been reported for alkyl- and arylsul-
fides. A convenient method described by Kropp and co-
workers uses the magnesium salt of monoperoxyphtalic
acid (MMPP) as oxidant.5 This reagent is safer to han-
dle compared to m-CPBA and does not require assaying
for its stoichiometric addition. In our hands, its use to-
wards the oxidation of 8-arylsulfanyl adenine deriva-
tives led solely to recovery of starting material. Use of
m-CPBA or OXONEÒ at different temperatures (rt,
6
À10°C, À78°C) and reagent ratios (2.2, 2, 1, and 0.5
oxidant/starting material) resulted in mixtures of sul-
fides, sulfoxides, sulfones, and hydroxylamino-deriva-
tives (resulted by the oxidation of adenineÕs C6–NH2).
To avoid the later, we were compelled to protect the
C6 amino functionality with a group that could with-
stand transformation under strong oxidizing conditions.
Chern and co-workers have reported that in nucleosides
this amine can be easily reacted under Mitsunobu condi-
tions to form an iminophosphorane, group that can be
ultimately removed under weak acidic conditions.7 Sub-
jecting 9-N-alkyl-8-arylsulfanyl adenine derivatives to
triphenylphosphine (PPh3)/di-tert-butylazodicarboxy-
late (DBAD) in CH2Cl2 or toluene/CH2Cl2 resulted
indeed in the corresponding N-triphenylphosphoranyl-
idene adenines.8 Alternatively in a more direct method,
the synthesis of C6–NH2 protected 9-N-alkyl-8-aryl-
sulfanyl adenine derivatives 1a–c and 2a–c could be
achieved in a two-step one-pot reaction from the corre-
sponding 8-arylsulfanyl adenines 1 and 23g using the
Mitsunobu conditions previously described by Lucas
et al.9 however allowing for longer reaction times
(Table 1).10 The desired products were isolated in yields
A survey of the existing literature offers several synthetic
procedures that exist on the oxidation of sulfides4 how-
ever, none addresses the particular case of adenine con-
taining derivatives. Oxidations that document the use of
peroxides such as hydrogen peroxide,4a urea–hydrogen
peroxide,4b hydrogen peroxide–LiNbMoO6,4c m-chloro-
perbenzoic acid (m-CPBA),4d OXONEÒ,4e–g or tert-
Keywords: Oxidation; Alumina supported OXONEÒ; 8-Arylsufoxyl
adenines; 8-Arylsufonyl adenines.
*
Corresponding author. Tel.: +1 212 639 8929; fax: +1 212 717
3627; e-mail: chiosisg@mskcc.org
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.11.009

9550
L. Llauger et al. / Tetrahedron Letters 45 (2004) 9549–9552
Table 1. Synthesis of the C6–NH2 protected 9-N-alkyl-8-arylsulfanyl
adenine derivatives 1a–c and 2a–c
providing contact between KOSO2OOH, the active
ingredient of OXONEÒ, and the sulfide. Formation of
sulfoxide or sulfone relied on the stoichiometry of the
reaction, and use of excess OXONEÒ over sulfide
favored sulfone formation (Table 2).11 In some cases,
a mixture of sulfoxide and sulfone was obtained regard-
less of the excess OXONEÒ present in the reaction
medium. Such instances were observed when aluminaÕs
water content was not carefully monitored. Prior to
use, the alumina had to be activated (48h/120°C) and
wetted for the reaction to occur; excessive wetting
seemed to favor sulfoxide formation. Nevertheless, in
the eventuality of sulfoxide and sulfone mixture forma-
tion, the two products are separable by silica gel column
chromatography.
NH
NPPh
2
3
7
N
6
DBAD/PPh
ROH
3
N
N
2
N
8
S
S
N 9
H
X
N
R
X
N
N
3
1; X = 3-OMe
1a-c
2a-c
2; X = 3,4,5-OMe
3
Entry Reactanta
R
Productsb Yieldc (%)
1
2
3
1
2
Butyl 1a
2-Isopropoxy-ethyl 1b
30 (79)d
32
36
Pent-4-ynyl
1c
4
5
6
Butyl
2a
51
45
50
2-Isopropoxy-ethyl 2b
Pent-4-ynyl 2c
Synthesis of 9-N-alkyl-8-arylsulfoxyl adenines (7a–c and
9a–c) and 9-N-alkyl-8-arylsulfonyl adenines (8a–c and
10a–c) was completed with the deprotection of C6–
NH2 triphenylphosphine group. The reaction was con-
veniently conducted in refluxing AcOH/EtOH to result
in complete deprotection (Table 2).12,13 The use of stron-
ger acidic conditions, such as HCl, resulted in com-
pound decomposition via cleavage of the C–S bond.
Due to the more labile nature of the C–S bond in 9-N-
alkyl-8-arylsulfoxyl adenines compared to the corre-
sponding sulfones, the reaction necessitated milder con-
ditions and was carried out with 1M12 instead of 2M
AcOH.13
a Syntheses of 1 and 2 were described in Ref. 3g.
b Reaction conditions: DBAD (5equiv), PPh3 (2.2equiv), ROH
(1.3equiv), CH2Cl2–toluene (1:5), overnight at room temperature.
c Yields isolated after chromatography.
d Yields by HPLC.
ranging from 35% to 70%. Formation of 3-N (5–30%)
and 7-N (traces) alkylation products (separable by silica
gel chromatography) was mostly responsible for the
moderate yields whilst protection of the C6–NH2
occurred quantitatively. The use of OXONEÒ in pres-
ence of alumina as reported by Kropp et al.4g allowed
for monitoring the reaction to either sulfoxides (3a–c
and 5a–c) or sulfones (4a–c and 6a–c). Mediation of oxi-
dation by OXONEÒ involves activation by its being
dispersed on the surface of the alumina adsorbent,
In summary, we present the first report on the synthesis
of 9-N-alkyl-8-arylsulfoxyl/sulfonyl adenine derivatives.
Table 2. Oxidation of sulfides 1a–c and 2a–c to the corresponding sulfoxides 3a–c; 5a–c, and sulfones 4a–c; 6a–c, followed by deprotection of the
triphenylphosphine group to result in sulfoxides 7a–c; 9a–c, and sulfones 8a–c; 10a–c, respectively
NPPh
Y
Y
3
O
S
O
S
O
1. OXONE®/Al O
2
N
N
N
3
N
N
N
+
S
X
N
R
X
N
R
X
N
R
2. AcOH/EtOH
N
N
N
1a-c
2a-c
Y = NPPh 3a-c and 5a-c
Y = NPPh 4a-c and 6a-c
3
3
Y = NH 7a-c and 9a-c
Y = NH 8a-c and 10a-c
2
2
For:
1, 3, 4, 7 and 8 X = 3-OMe
2, 5, 6, 9 and 10 X = 3,4,5-OMe
3
Entry Substrate OXONEÒ (equiv) Oxidation productsa Yieldc (%) oxidation Deprotection productsd Yieldc (%) deprotection
1
1a
1a
1b
1b
1c
1c
2a
2a
2b
1
3a
4a
3b
4b
3c
4c
5a
6a
5b
6b
5c
6c
61
69
19
54
17
21
40
42
34
60
5
7a
8a
48
59
42
70
61
61
71
65
78
69
––
60
2
4
3
4
7b
8b
4
4
5
4
7c
8c
6
4
7
0.6
4
9a
8
10a
9b
9
1.2
4
6b
6b
102b
11
12
10b
9c
2c
2c
63
10c
a Reaction conditions: Al2O3 (2.5g/mmol), H2O (0.3mL/mmol OXONEÒ), OXONEÒ (indicated), CH2Cl2 (5mL/mmol), room temperature, 4h
(sulfoxide) and overnight (sulfone).
b Unreacted starting material was observed with only 4equiv OXONEÒ.
c Yields isolated after chromatography.
d For sulfoxide: 1M AcOH used, reaction refluxed for 1h; for sulfones: 2M AcOH used, reaction refluxed for 3h.

L. Llauger et al. / Tetrahedron Letters 45 (2004) 9549–9552
9551
Tung, J. C.; Loomis, B. R. J. Am. Chem. Soc. 2000, 122,
4280–4285.
The methodology can conveniently be applied to pro-
duce an array of such compounds containing the desired
oxidation state on sulfur.
5. Foti, C. J.; Fields, J. D.; Kropp, P. J. Org. Lett. 1999, 6,
903–904.
6. OXONEÒ is a product of the Du Pont Company
consisting of a 2:1:1 mixture of the active ingredient
KOSO2OOH, along with KHSO4, and K2SO4,
respectively.
Acknowledgements
The work was funded in part by AACR-Cancer Re-
search and Prevention Foundation, Mr. William H.
Goodwin and Mrs. Alice Goodwin and the Common-
wealth Cancer Foundation for Research and MSKCC
Experimental Therapeutics Program and a generous
donation from the Taub Foundation.
7. Chien, T.-C.; Chen, C.-S.; Yeh, J.-Y.; Wang, K.-C.;
Chern, J.-W. Tetrahedron Lett. 1995, 36, 7881–7884.
8. Synthesis of 1a is representative: To a solution of 9-butyl-
8-(3-methoxy-phenylsulfanyl)adenine3h (260mg, 0.8mmol)
in toluene–CH2Cl2 (26:5), were added PPh3 (674mg,
2.5mmol) and DBAD (240mg, 1.0mmol). The reaction
mixture was stirred overnight at room temperature. The
organic layer was washed with brine, dried over anhy-
drous Na2SO4, and evaporated under vacuum. Subse-
quent to solvent removal, the crude was chromatographed
on silica gel eluting with CHCl3–hexanes–EtOAc at 2:2:1
to provide 1a (360mg, 70% isolated yield).
Supplementary data
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tet-
let.2004.11.009. Supplementary data for the analytical
characterization (1H NMR, 13C NMR, IR, and MS)
of all presented compounds is available on line with
the paper in ScienceDirect.
9. Lucas, B.; Rosen, N.; Chiosis, G. J. Comb. Chem. 2001, 3,
518–520.
10. Synthesis of 1a is representative: To a solution of sulfide 1
(200mg, 0.73mmol) in toluene–CH2Cl2 (22:4.4mL) (5:1),
were added butanol (87lL, 0.95mmol), PPh3 (425mg,
1.6mmol) and DBAD (860mg, 3.7mmol). The reaction
was stirred at room temperature overnight. The product
was purified by flash silica gel column chromatography,
eluting with CHCl3–hexanes–EtOAc at 2:2:1to provide
References and notes
1
130mg of 1a. H NMR (400MHz, CDCl3): d 8.01(s, 1H,
1. (a) Arris, C. E.; Boyle, F. T.; Calvert, A. H.; Curtin, N. J.;
Endicott, J. A.; Garman, E. F.; Gibson, A. E.; Golding, B.
T.; Grant, S.; Griffin, R. J.; Jewsbury, P.; Johnson, L. N.;
Lawrie, A. M.; Newell, D. R.; Noble, M. E.; Sausville, E.
A.; Schultz, R.; Yu, W. J. Med. Chem. 2000, 43, 2797–
2804; (b) Chapman, E.; Ding, S.; Schultz, P. G.; Wong, C.
H. J. Am. Chem. Soc. 2002, 124, 14524–14525; (c) Perez,
O. D.; Chang, Y. T.; Rosania, G.; Sutherlin, D.; Schultz,
P. G. Chem. Biol. 2002, 4, 475–483.
H-2), 7.84 (m, 6H, o-PPh3), 7.45 (m, 3H, p-PPh3), 7.37
(m, 6H, m-PPh3), 7.09 (t, J = 8.0Hz, 1H), 6.83 (t, J =
1.8Hz, 1H), 6.80 (m, 1H), 6.67 (dd, J = 2.0, 8.3Hz, 1H),
4.00 (t, J = 7.7Hz, 2H, NCH2), 3.67 (s, 3H, OCH3), 1.54
(m, 2H), 1.17 (m, 2H), 0.75 (t, J = 7.4Hz, 3H, CH3). 13C
NMR (100MHz, CDCl3): d 160.5, 159.9, 152.1, 151.5,
142.3, 134.6, 133.2, 131.7, 129.9, 129.2, 128.3, 121.4, 114.6,
112.8, 55.2, 43.4, 31.5, 19.8, 13.5. MS (EIS) m/z 590.2
(M+1).
2. Chiosis, G.; Lucas, B.; Huezo, H.; Solit, D.; Basso, A.;
Rosen, N. Curr. Cancer Drug Targets 2003, 5, 371–
376.
11. Syntheses of sulfoxide 3a and sulfone 4a are representa-
tive: Alumina (Fisher A540; 480mg) was equilibrated with
air at 120°C for at least 48h previous to use. The flask was
stoppered and the contents allowed to cool to 25°C. Water
(0.06mL) was added and the adsorbent was tumbled on a
rotatory evaporator at atmospheric pressure until uni-
formly free flowing. A solution of sulfide 1a (115mg,
0.186mmol) in CH2Cl2 (1mL) was added with stirring,
followed by OXONEÒ (120mg, 0.194mmol) or (480mg,
0.776mmol) if sulfoxide 3a or sulfone 4a were desired,
respectively. The slurry was stirred for 4h or overnight at
25°C if sulfoxide 3a or sulfone 4a were desired, respec-
tively. The adsorbent was then removed by vacuum
filtration and washed first with EtOAc and then with a
solution of CHCl3–hexanes–EtOAc–MeOH–NH4OH at
2:2:1:0.5:0.1. The combined organic fractions were washed
with a saturated aqueous solution of FeSO4 and dried over
anhydrous Na2SO4. Following concentration under
reduced pressure, the residue was chromatographed
through silica gel by elution with CH2Cl2–EtOAc at 2:1
to afford 70mg of sulfoxide 3a or 76mg of sulfone 4a,
3. (a) Young, R. C.; Jones, M.; Milliner, K. J.; Rana, K. K.;
Ward, J. G. J. Med. Chem. 1990, 33, 2073–2080; (b)
Gonnella, N. C.; Nakanishi, H.; Holtwick, J. B.; Horo-
witz, D. S.; Kanamori, K. J. Am. Chem. Soc. 1983, 105,
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4. (a) Sato, K.; Hyodo, M.; Aoki, M.; Zheng, X.-Q.; Noyori,
R. Tetrahedron 2001, 57, 2469–2476; (b) Varma, R. S.;
Naicker, K. P. Org. Lett. 1999, 2, 189–191; (c) Choi, S.;
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8192–8198; (d) Nicolaou, K. C.; Magolda, R. L.; Sipio, W.
J.; Barnette, W. E.; Lysenko, Z.; Joullie, M. M. J. Am.
Chem. Soc. 1980, 102, 3784–3793; (e) Greenhalgh, R. P.
Synlett 1992, 235–236; (f) Ceccherelli, P.; Curini, M.;
Marcotullio, M. C.; Epifano, F.; Rosati, O. Synlett 1996,
767–768; (g) Kropp, P. J.; Breton, G. W.; Fields, J. D.;
1
respectively. Spectra of sulfoxide 3a: H NMR (400MHz,
CDCl3): d 8.02 (s, 1H, H-2), 7.82 (m, 6H, o-PPh3), 7.46 (m,
3H, p-PPh3), 7.36 (m, 6H, m-PPh3), 7.29 (t, J = 8.0Hz,
1H), 7.26 (m, 1H), 7.13 (br d, J = 7.8Hz, 1H), 6.89 (dd,
J = 2.3, 8.0Hz, 1H), 4.18 and 3.97 (2m, 2H, NCH2), 3.74
(s, 3H, OCH3), 1.62 and 0.85 (2m, 2H), 1.12 (t, J = 7.0Hz,
2H), 0.68 (t, J = 7.0Hz, 3H, CH3). 13C NMR (100MHz,
CDCl3): d 160.4, 153.4, 151.9, 148.0, 143.2, 133.3, 132.0,
130.3, 128.9, 128.4, 127.9, 116.9, 116.7, 109.1, 55.6, 43.5,

9552
L. Llauger et al. / Tetrahedron Letters 45 (2004) 9549–9552
31.4, 19.9, 13.5. MS (EIS) m/z 606.4 (M+1). Spectra of
1H), 1.18 (m, 3H), 0.77 (t, J = 7.0Hz, 3H, CH3). 13C
NMR (100MHz, CDCl3): d 160.6, 156.0, 154.2, 151.6,
150.1, 142.3, 130.6, 119.3, 117.7, 116.8, 109.5, 55.6, 43.8,
31.6, 19.9, 13.5. MS (EIS) m/z 346.2 (M+1).
sulfone 4a. 1H NMR (400MHz, CDCl3): d 8.07 (s, 1H, H-
2), 7.80 (m, 6H, o-PPh3), 7.54 (m, 2H), 7.45 (m, 3H, p-
PPh3), 7.36 (m, 7H), 7.07 (dd, J = 2.4, 8.2Hz, 1H), 4.36 (t,
J = 7.9Hz, 2H, NCH2), 3.80 (s, 3H, OCH3), 1.65 (m, 2H),
1.30 (m, 2H), 0.82 (t, J = 7.3Hz, 3H, CH3). 13C NMR
(100MHz, CDCl3): d 159.9, 154.2, 151, 144.6, 140.8, 133.3,
132.1, 130.2, 128.9, 128.4, 127.9, 120.9, 120.7, 112.9, 55.8,
44.5, 32.4, 20.0, 13.6. MS (EIS) m/z 622.3 (M+1).
13. Synthesis of sulfone 8a is representative: To a solution of
4a (120mg, 0.19mmol) in EtOH (1.9mL) was added 2M
AcOH aqueous solution (1.9mL). The reaction mixture
was refluxed for 3h. Following cooling to room temper-
ature, the solvent was removed under high vacuum and
the crude taken up in CH2Cl2. The organic phase was
washed with NaHCO3 and brine, and dried over anhy-
drous Na2SO4. Subsequent to solvent removal, the residue
was chromatographed on silica gel eluting with a gradient
of CHCl3–hexanes–EtOAc–MeOH at 2:2:1:0.1, followed
by CHCl3–MeOH at 98:2 to afford 46mg of 8a. IR (film)
12. Synthesis of sulfoxide 7a is representative: To a solution of
3a (70mg, 0.11mmol) in EtOH (1.2mL) was added 1M
aqueous AcOH solution (1.2mL). The reaction mixture
was refluxed for 1h. Following cooling to room temper-
ature, the solvent was removed under high vacuum and
the crude taken up in CH2Cl2. The organic phase was
washed with NaHCO3 and brine, and dried over anhy-
drous Na2SO4. Subsequent to solvent removal, the residue
was chromatographed on silica gel eluting with CHCl3–
hexanes–EtOAc–MeOH at 2:2:1:0.1 to afford 23mg of 7a.
IR (film) mmax 3321–2872, 1650, 1593, 1573, 1479, 1298,
1247, 1076 (SO), 1038 (SO). 1H NMR (400MHz, CDCl3):
d 8.29 (s, 1H, H-2), 7.35 (t, J = 8.0Hz, 1H), 7.25 (m, 1H),
6.96 (dd, J = 2.0, 8.0Hz, 1H), 6.26 (br s, 2H, NH2), 4.25
and 4.14 (2m, 2H, NCH2), 3.76 (s, 3H, OCH3), 1.65 (m,
mmax 3314–2873, 1650, 1595, 1574, 1480, 1321 (SO2), 1246,
1154 (SO2). 1H NMR (400MHz, CDCl3): d 8.30 (s, 1H, H-
2), 7.55 (d, J = 7.9Hz, 1H), 7.47 (m, 1H), 7.40 (t,
J = 8.0Hz, 1H), 7.10 (dd, J = 2.0, 8.0Hz, 1H), 6.70 (br s,
2H, NH2), 4.41(t, J = 7.9Hz, 2H, NCH2), 3.76 (s, 3H,
OCH3), 1.68 (m, 2H), 1.31 (m, 2H), 0.86 (t, J = 7.4Hz, 3H,
CH3). 13C NMR (100MHz, CDCl3): d 160.1, 156.9, 155.2,
151.0, 146.1, 139.9, 130.5, 121.0, 120.5, 118.9, 112.9, 55.7,
44.8, 32.3, 19.9, 13.5. MS (EIS) m/z 362.2 (M+1).